1	32507359	These molecular changes were initially discovered through the study of rare familial tumor syndromes such as McCune-Albright Syndrome, Carney complex, Li-Fraumeni syndrome, and Beckwith-Wiedemann syndrome with identification of alterations in genes and molecular pathways that subsequently lead to the discovery of aberrations in these or related genes and pathways in sporadic tumors.	('molecular pathways', 'Pathway', (253, 271))	('Beckwith-Wiedemann syndrome', 'Disease', (177, 204))	('Li-Fraumeni syndrome', 'Disease', (151, 171))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (151, 171))	('tumors', 'Phenotype', 'HP:0002664', (378, 384))	('familial tumor syndromes', 'Disease', (76, 100))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (177, 204))	('McCune-Albright Syndrome', 'Disease', (109, 133))	('aberrations', 'Var', (315, 326))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (378, 383))	('familial tumor syndromes', 'Disease', 'MESH:D009386', (76, 100))	('tumors', 'Disease', (378, 384))	('McCune-Albright Syndrome', 'Disease', 'MESH:D005357', (109, 133))	('rat', 'Species', '10116', (232, 235))	('Carney complex', 'Disease', (135, 149))	('tumors', 'Disease', 'MESH:D009369', (378, 384))	('alterations', 'Var', (228, 239))	('rat', 'Species', '10116', (319, 322))
2	32507359	Genetic alterations in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B, leading to aberrant cyclic adenosine monophosphate-protein kinase A signaling were identified as playing a major role in the development of benign cortisol-producing adrenocortical tumors and/or hyperplasias, whereas genetic defects in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2 were implicated in the development of benign aldosterone-producing tumors and/or hyperplasias through modification of intracellular calcium signaling.	('PDE11A', 'Gene', '50940', (54, 60))	('KCNJ5', 'Gene', (309, 314))	('tumors', 'Disease', (254, 260))	('phosphate', 'Chemical', 'MESH:D010710', (114, 123))	('PDE11A', 'Gene', (54, 60))	('PRKACA', 'Gene', (38, 44))	('adenosine', 'Chemical', 'MESH:D000241', (100, 109))	('aldosterone', 'Chemical', 'MESH:D000450', (405, 416))	('adrenocortical tumors', 'Disease', (239, 260))	('PRKAR1A', 'Gene', '5573', (29, 36))	('tumors', 'Phenotype', 'HP:0002664', (427, 433))	('PRKACB', 'Gene', (46, 52))	('GNAS', 'Gene', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('KCNJ5', 'Gene', '3762', (309, 314))	('CACNA1H', 'Gene', (341, 348))	('ATP2B3', 'Gene', '492', (324, 330))	('tumor', 'Phenotype', 'HP:0002664', (427, 432))	('GNAS', 'Gene', '2778', (23, 27))	('ATP2B3', 'Gene', (324, 330))	('PDE8B', 'Gene', '8622', (66, 71))	('CACNA1H', 'Gene', '8912', (341, 348))	('CACNA1D', 'Gene', '776', (332, 339))	('CACNA1D', 'Gene', (332, 339))	('tumors', 'Disease', (427, 433))	('implicated', 'Reg', (365, 375))	('rat', 'Species', '10116', (12, 15))	('genetic defects', 'Disease', 'MESH:D030342', (290, 305))	('genetic defects', 'Disease', (290, 305))	('alterations', 'Var', (8, 19))	('cyclic adenosine monophosphate-protein', 'MPA', (93, 131))	('cortisol', 'Chemical', 'MESH:D006854', (220, 228))	('PRKACA', 'Gene', '5566', (38, 44))	('PRKACB', 'Gene', '5567', (46, 52))	('ATP1A1', 'Gene', (316, 322))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (239, 260))	('aberrant', 'Var', (84, 92))	('tumors', 'Disease', 'MESH:D009369', (427, 433))	('calcium', 'Chemical', 'MESH:D002118', (492, 499))	('modification', 'Reg', (462, 474))	('PRKAR1A', 'Gene', (29, 36))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('hyperplasias', 'Disease', (268, 280))	('intracellular calcium signaling', 'MPA', (478, 509))	('hyperplasias', 'Disease', (441, 453))	('hyperplasias', 'Disease', 'MESH:D006965', (268, 280))	('CLCN2', 'Gene', '1181', (354, 359))	('ATP1A1', 'Gene', '476', (316, 322))	('PDE8B', 'Gene', (66, 71))	('hyperplasias', 'Disease', 'MESH:D006965', (441, 453))	('CLCN2', 'Gene', (354, 359))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
3	32507359	Germline ARMC5 defects were found to cause the development of primary bilateral macronodular adrenal hyperplasia with cortisol and/or aldosterone oversecretion.	('ARMC5', 'Gene', (9, 14))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (80, 112))	('aldosterone', 'Chemical', 'MESH:D000450', (134, 145))	('bilateral macronodular adrenal hyperplasia', 'Disease', (70, 112))	('aldosterone oversecretion', 'MPA', (134, 159))	('bilateral macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (70, 112))	('cortisol', 'MPA', (118, 126))	('defects', 'Var', (15, 22))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (93, 112))	('cortisol', 'Chemical', 'MESH:D006854', (118, 126))	('cause', 'Reg', (37, 42))
4	32507359	Adrenocortical carcinoma was linked primarily to aberrant Wnt-beta-catenin signaling, p53 signaling, and/or IGF2 overexpression, with frequent genetic alterations in TP53, ZNRF3, CTNNB1, and 11p15.	('CTNNB1', 'Gene', '1499', (179, 185))	('IGF2', 'Gene', (108, 112))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (0, 24))	('aberrant', 'Var', (49, 57))	('p53', 'Gene', '7157', (86, 89))	('TP53', 'Gene', '7157', (166, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (0, 24))	('CTNNB1', 'Gene', (179, 185))	('IGF2', 'Gene', '3481', (108, 112))	('rat', 'Species', '10116', (155, 158))	('p53', 'Gene', (86, 89))	('Wnt-beta-catenin signaling', 'MPA', (58, 84))	('overexpression', 'PosReg', (113, 127))	('linked', 'Reg', (29, 35))	('Adrenocortical carcinoma', 'Disease', (0, 24))	('ZNRF3', 'Gene', '84133', (172, 177))	('ZNRF3', 'Gene', (172, 177))	('11p15', 'Gene', (191, 196))	('TP53', 'Gene', (166, 170))
8	32507359	Aberrant cAMP-protein kinase A signaling was initially implicated in the development of Cushing syndrome in McCune-Albright syndrome through early embryonic postzygotic somatic activating defects in the GNAS gene, with subsequent discovery of inactivating germline PRKAR1A defects as the causative genetic alteration in Carney complex and primary pigmented nodular adrenocortical disease.	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (108, 132))	('defects', 'Var', (273, 280))	('PRKAR1A', 'Gene', '5573', (265, 272))	('cAMP', 'Chemical', 'MESH:D000242', (9, 13))	('inactivating germline PRKAR1A defects', 'Phenotype', 'HP:0011791', (243, 280))	('McCune-Albright syndrome', 'Disease', (108, 132))	('rat', 'Species', '10116', (310, 313))	('Cushing syndrome', 'Disease', 'MESH:D003480', (88, 104))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (347, 387))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (88, 104))	('Carney complex', 'Disease', (320, 334))	('Cushing syndrome', 'Disease', (88, 104))	('GNAS', 'Gene', (203, 207))	('pigmented nodular adrenocortical disease', 'Disease', (347, 387))	('defects', 'Var', (188, 195))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (347, 387))	('implicated', 'Reg', (55, 65))	('GNAS', 'Gene', '2778', (203, 207))	('inactivating', 'Var', (243, 255))	('PRKAR1A', 'Gene', (265, 272))
9	32507359	Activating somatic PRKACA defects were later found to be a major cause of cortisol-producing adrenocortical adenomas.	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (93, 116))	('PRKACA', 'Gene', '5566', (19, 25))	('cortisol', 'Chemical', 'MESH:D006854', (74, 82))	('cause', 'Reg', (65, 70))	('defects', 'Var', (26, 33))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (93, 116))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (93, 115))	('PRKACA', 'Gene', (19, 25))	('adrenocortical adenomas', 'Disease', (93, 116))
10	32507359	Additionally, germline defects in ARMC5, a tumor suppressor gene, were identified as the primary underlying genetic alteration in primary bilateral macronodular adrenal hyperplasia (PBMAH).	('bilateral macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (138, 180))	('bilateral macronodular adrenal hyperplasia', 'Disease', (138, 180))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (161, 180))	('PBMAH', 'Chemical', '-', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ARMC5', 'Gene', (34, 39))	('rat', 'Species', '10116', (120, 123))	('tumor', 'Disease', (43, 48))	('germline defects', 'Var', (14, 30))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (148, 180))
13	32507359	Further studies have identified somatic molecular alterations affecting p53 and Wnt-beta-catenin signaling, and IGF2 expression as major drivers of adrenocortical carcinoma development.	('IGF2', 'Gene', '3481', (112, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('expression', 'MPA', (117, 127))	('p53', 'Gene', (72, 75))	('alterations', 'Var', (50, 61))	('rat', 'Species', '10116', (54, 57))	('p53', 'Gene', '7157', (72, 75))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (148, 172))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (148, 172))	('IGF2', 'Gene', (112, 116))	('adrenocortical carcinoma', 'Disease', (148, 172))
22	32507359	Aberrant cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling has been shown to play a key role in the development of most benign cortisol-producing adrenocortical tumors.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (167, 188))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('Aberrant', 'Var', (0, 8))	('adrenocortical tumors', 'Disease', (167, 188))	('cAMP', 'Chemical', 'MESH:D000242', (41, 45))	('phosphate', 'Chemical', 'MESH:D010710', (30, 39))	('adenosine', 'Chemical', 'MESH:D000241', (16, 25))	('cortisol', 'Chemical', 'MESH:D006854', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
32	32507359	This gene encodes the alpha-subunit of the stimulatory G protein (Gsalpha), with mosaic gain-of-function mutations leading to constitutive activation of the cAMP-PKA pathway.	('constitutive', 'MPA', (126, 138))	('gain-of-function', 'PosReg', (88, 104))	('activation', 'PosReg', (139, 149))	('Gsalpha', 'Gene', (66, 73))	('cAMP', 'Chemical', 'MESH:D000242', (157, 161))	('mutations', 'Var', (105, 114))	('Gsalpha', 'Gene', '2778', (66, 73))	('cAMP-PKA pathway', 'Pathway', (157, 173))
40	32507359	Germline inactivating defects in PRKAR1A gene are found in 37% of patients with sporadic CNC and more than 70% of patients with familial CNC, with almost 100% penetrance.	('PRKAR1A', 'Gene', (33, 40))	('PRKAR1A', 'Gene', '5573', (33, 40))	('found', 'Reg', (50, 55))	('Germline', 'Var', (0, 8))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (66, 74))
42	32507359	Inactivating defects of PRKAR1A lead to constitutive activation of the cAMP-PKA pathway through loss of regulation of the catalytic subunits of PKA.	('PRKAR1A', 'Gene', '5573', (24, 31))	('regulation', 'MPA', (104, 114))	('activation', 'PosReg', (53, 63))	('cAMP', 'Chemical', 'MESH:D000242', (71, 75))	('PRKAR1A', 'Gene', (24, 31))	('Inactivating defects', 'Var', (0, 20))	('cAMP-PKA pathway', 'Pathway', (71, 87))	('loss', 'NegReg', (96, 100))
43	32507359	Most pathogenic PRKAR1A variants are subject to mRNA nonsense-mediated decay of the mutant sequence, leading to predicted absence of mutant protein products in affected cells and PRKAR1A haploinsufficiency.	('variants', 'Var', (24, 32))	('PRKAR1A', 'Gene', '5573', (16, 23))	('haploinsufficiency', 'Disease', (187, 205))	('mRNA nonsense-mediated decay', 'MPA', (48, 76))	('PRKAR1A', 'Gene', (179, 186))	('mutant', 'Var', (84, 90))	('absence', 'NegReg', (122, 129))	('pathogenic', 'Reg', (5, 15))	('subject', 'Reg', (37, 44))	('haploinsufficiency', 'Disease', 'MESH:D058495', (187, 205))	('mutant protein products', 'MPA', (133, 156))	('PRKAR1A', 'Gene', '5573', (179, 186))	('PRKAR1A', 'Gene', (16, 23))
47	32507359	Copy number gains on chromosome 1 of the PRKACB gene locus, encoding the catalytic subunit beta (Cbeta) of PKA, were also found in a single patient with CNC that presented with abnormal skin pigmentation, myxomas, and acromegaly, though defects in PRKACB have not been linked to c-PPNAD.	('abnormal skin pigmentation', 'Disease', (177, 203))	('abnormal skin', 'Phenotype', 'HP:0000951', (177, 190))	('myxomas', 'Disease', (205, 212))	('PRKACB', 'Gene', '5567', (41, 47))	('PRKACB', 'Gene', '5567', (248, 254))	('gains', 'PosReg', (12, 17))	('PRKACB', 'Gene', (41, 47))	('patient', 'Species', '9606', (140, 147))	('abnormal skin pigmentation', 'Disease', 'MESH:D010859', (177, 203))	('skin pigmentation', 'Phenotype', 'HP:0000953', (186, 203))	('acromegaly', 'Phenotype', 'HP:0000845', (218, 228))	('found', 'Reg', (122, 127))	('abnormal skin pigmentation', 'Phenotype', 'HP:0001000', (177, 203))	('PRKACB', 'Gene', (248, 254))	('acromegaly', 'Disease', (218, 228))	('Copy number', 'Var', (0, 11))	('myxomas', 'Disease', 'MESH:D009232', (205, 212))	('acromegaly', 'Disease', 'MESH:D000172', (218, 228))
49	32507359	PRKAR1A mutations also cause i-PPNAD, where there is a genotype-phenotype correlation, as demonstrated in a study that included 353 patients with germline PRKAR1A defects or a diagnosis of CNC and/or PPNAD, where among patients with i-PPNAD and PRKAR1A mutations, most had a germline c.709-7del6 mutation whereas the remainder of these patients carried the p.Met1Val mutation.	('PRKAR1A', 'Gene', (245, 252))	('PRKAR1A', 'Gene', '5573', (155, 162))	('c.709-7del6 mutation', 'Var', (284, 304))	('patients', 'Species', '9606', (132, 140))	('rat', 'Species', '10116', (97, 100))	('i-PPNAD', 'Disease', (29, 36))	('PRKAR1A', 'Gene', '5573', (0, 7))	('PRKAR1A', 'Gene', (0, 7))	('mutations', 'Var', (253, 262))	('mutations', 'Var', (8, 17))	('PRKAR1A', 'Gene', '5573', (245, 252))	('PRKAR1A', 'Gene', (155, 162))	('patients', 'Species', '9606', (336, 344))	('patients', 'Species', '9606', (219, 227))	('cause', 'Reg', (23, 28))	('c.709-7del6', 'Mutation', 'c.709-7del6', (284, 295))	('p.Met1Val', 'Mutation', 'rs281864779', (357, 366))
52	32507359	ACC has also been reported in two patients with CNC and c-PPNAD due to PRKAR1A defects.	('defects', 'Var', (79, 86))	('PRKAR1A', 'Gene', '5573', (71, 78))	('CNC', 'Disease', (48, 51))	('patients', 'Species', '9606', (34, 42))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('PRKAR1A', 'Gene', (71, 78))	('ACC', 'Disease', (0, 3))
54	32507359	Defects in genes encoding cyclic nucleotide PDEs have also been implicated in the pathogenesis of micronodular BAH and other cortisol producing ACTs.	('PDEs', 'Gene', (44, 48))	('cyclic nucleotide', 'Chemical', 'MESH:D009712', (26, 43))	('micronodular BAH', 'Disease', (98, 114))	('Defects', 'Var', (0, 7))	('BAH', 'Chemical', '-', (111, 114))	('implicated', 'Reg', (64, 74))	('cortisol', 'Chemical', 'MESH:D006854', (125, 133))	('PDEs', 'Gene', '50940', (44, 48))
55	32507359	This was demonstrated in patients with i-MAD or i-PPNAD not caused by known genetic defects (mutations in GNAS or PRKAR1A) through a single-nucleotide polymorphism-based genome-wide association study that included both leukocyte and tumor DNA.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('mutations', 'Var', (93, 102))	('i-MAD', 'Disease', (39, 44))	('GNAS', 'Gene', (106, 110))	('tumor', 'Disease', (233, 238))	('rat', 'Species', '10116', (16, 19))	('PRKAR1A', 'Gene', '5573', (114, 121))	('GNAS', 'Gene', '2778', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('patients', 'Species', '9606', (25, 33))	('genetic defects', 'Disease', 'MESH:D030342', (76, 91))	('genetic defects', 'Disease', (76, 91))	('PRKAR1A', 'Gene', (114, 121))
56	32507359	In this study mutations in genetic loci harboring PDE genes were most likely to be associated with the disease, with inactivating mutations of the PDE11A gene, encoding phosphodiesterase type 11A, being the most frequently linked, followed by the PDE8B gene, which encodes phosphodiesterase type 8B.	('inactivating mutations', 'Var', (117, 139))	('PDE', 'Gene', (247, 250))	('disease', 'Disease', (103, 110))	('PDE', 'Gene', (147, 150))	('linked', 'Reg', (223, 229))	('PDE', 'Gene', '50940', (247, 250))	('PDE11A', 'Gene', '50940', (147, 153))	('PDE8B', 'Gene', (247, 252))	('PDE8B', 'Gene', '8622', (247, 252))	('PDE11A', 'Gene', (147, 153))	('associated', 'Reg', (83, 93))	('PDE', 'Gene', (50, 53))	('PDE', 'Gene', '50940', (50, 53))	('mutations', 'Var', (14, 23))	('PDE', 'Gene', '50940', (147, 150))
57	32507359	Tumor specimens most often demonstrated loss of heterozygosity in the 2q31-2q35 region (the location of PDE11A) with decreased protein expression as well as evidence of increased cAMP-PKA signaling with high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation.. A higher frequency of PDE11A variants has also been noted in patients with CNC.	('CREB', 'Gene', '1385', (278, 282))	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cyclic nucleotide', 'Chemical', 'MESH:D009712', (208, 225))	('patients', 'Species', '9606', (363, 371))	('cAMP-responsive element binding protein', 'Gene', (237, 276))	('Tumor', 'Disease', (0, 5))	('CNC', 'Disease', (377, 380))	('CREB', 'Gene', (278, 282))	('cAMP-responsive element binding protein', 'Gene', '1385', (237, 276))	('PDE11A', 'Gene', (104, 110))	('PDE11A', 'Gene', '50940', (104, 110))	('PDE11A', 'Gene', '50940', (324, 330))	('variants', 'Var', (331, 339))	('rat', 'Species', '10116', (34, 37))	('cAMP', 'Chemical', 'MESH:D000242', (179, 183))	('cAMP', 'Chemical', 'MESH:D000242', (237, 241))	('PDE11A', 'Gene', (324, 330))
58	32507359	Among patients with CNC and PRKAR1A defects, those with PPNAD and/or testicular large-cell calcifying Sertoli cell tumors (LCCSCT) were more commonly carriers of PDE11A germline variants compared to those without PPNAD and/or LCCSCT, suggesting that PDE11A may be a genetic modifying factor for the development of adrenal and testicular tumors in this population.	('variants', 'Var', (178, 186))	('testicular tumors', 'Phenotype', 'HP:0010788', (326, 343))	('testicular tumors', 'Disease', 'MESH:D013736', (326, 343))	('CS', 'Phenotype', 'HP:0003118', (125, 127))	('patients', 'Species', '9606', (6, 14))	('PDE11A', 'Gene', '50940', (250, 256))	('CS', 'Phenotype', 'HP:0003118', (228, 230))	('PDE11A', 'Gene', (250, 256))	('CNC', 'Gene', (20, 23))	('PRKAR1A', 'Gene', '5573', (28, 35))	('tumors', 'Phenotype', 'HP:0002664', (337, 343))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('PDE11A', 'Gene', '50940', (162, 168))	('PDE11A', 'Gene', (162, 168))	('testicular large', 'Phenotype', 'HP:0000053', (69, 85))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (337, 343))	('tumors', 'Disease', (115, 121))	('carriers', 'Reg', (150, 158))	('CS', 'Gene', '1431', (125, 127))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (102, 121))	('testicular tumors', 'Disease', (326, 343))	('CS', 'Gene', '1431', (228, 230))	('defects', 'Var', (36, 43))	('tumors', 'Disease', 'MESH:D009369', (337, 343))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('adrenal and testicular tumors', 'Phenotype', 'HP:0100631', (314, 343))	('PRKAR1A', 'Gene', (28, 35))
61	32507359	A single germline PDE8B missense substitution was initially reported in a pediatric patient with i-MAD and CS who inherited the mutation from her father.	('PDE8B', 'Gene', (18, 23))	('PDE8B', 'Gene', '8622', (18, 23))	('CS', 'Phenotype', 'HP:0003118', (107, 109))	('CS', 'Gene', '1431', (107, 109))	('missense substitution', 'Var', (24, 45))	('patient', 'Species', '9606', (84, 91))
63	32507359	In a subsequent case-control study of 216 unrelated patients with adrenocortical tumors (including PPNAD, PBMAH, CPAs, non-secreting adrenocortical tumors, and ACC) and 192 controls, nine different PDE8B sequence changes were identified in the patients and controls, with two variations that were seen only in the patient group, demonstrating significant potential to impair protein function in vitro and in silico.	('adrenocortical tumors', 'Disease', (66, 87))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (133, 154))	('PA', 'Phenotype', 'HP:0011736', (114, 116))	('non-secreting adrenocortical tumors', 'Phenotype', 'HP:0011745', (119, 154))	('patients', 'Species', '9606', (244, 252))	('PDE8B', 'Gene', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('ACC', 'Phenotype', 'HP:0006744', (160, 163))	('adrenocortical tumors', 'Disease', (133, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('patients', 'Species', '9606', (52, 60))	('PBMAH', 'Chemical', '-', (106, 111))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (66, 87))	('patient', 'Species', '9606', (244, 251))	('impair', 'NegReg', (368, 374))	('CPA', 'Chemical', '-', (113, 116))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('PDE8B', 'Gene', '8622', (198, 203))	('protein', 'Protein', (375, 382))	('changes', 'Var', (213, 220))	('rat', 'Species', '10116', (336, 339))	('patient', 'Species', '9606', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('patient', 'Species', '9606', (314, 321))
64	32507359	Genetic alterations involving genes encoding the catalytic subunits of PKA have also been linked to micronodular BAH.	('Genetic alterations', 'Var', (0, 19))	('rat', 'Species', '10116', (12, 15))	('linked', 'Reg', (90, 96))	('micronodular BAH', 'Disease', (100, 116))	('BAH', 'Chemical', '-', (113, 116))
65	32507359	In addition to the aforementioned patient with CNC due to germline PRKACB copy number gains, germline copy number gains resulting in amplification of PRKACA, which encodes the catalytic subunit (Calpha) of PKA, have been implicated in the development of i-MAD.	('copy number gains', 'Var', (102, 119))	('PRKACA', 'Gene', (150, 156))	('PRKACA', 'Gene', '5566', (150, 156))	('implicated', 'Reg', (221, 231))	('PRKACB', 'Gene', '5567', (67, 73))	('patient', 'Species', '9606', (34, 41))	('i-MAD', 'Disease', (254, 259))	('copy number gains', 'Var', (74, 91))	('PRKACB', 'Gene', (67, 73))	('amplification', 'MPA', (133, 146))
66	32507359	Germline copy number gains of the genomic region on chromosome 19p that includes the entire PRKACA gene were initially described in three patients with sporadic i-MAD, as well as 2 patients with familial PBMAH.	('PRKACA', 'Gene', (92, 98))	('copy number gains', 'Var', (9, 26))	('patients', 'Species', '9606', (181, 189))	('PRKACA', 'Gene', '5566', (92, 98))	('patients', 'Species', '9606', (138, 146))	('PBMAH', 'Chemical', '-', (204, 209))
67	32507359	Tumor tissues from patients with PRKACA copy number gains had higher PKA Calpha mRNA and protein levels with associated higher basal and cAMP stimulated PKA activity.	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (19, 27))	('Tumor', 'Disease', (0, 5))	('higher', 'PosReg', (120, 126))	('cAMP', 'Chemical', 'MESH:D000242', (137, 141))	('higher', 'PosReg', (62, 68))	('PRKACA', 'Gene', (33, 39))	('PKA activity', 'MPA', (153, 165))	('PRKACA', 'Gene', '5566', (33, 39))	('copy number gains', 'Var', (40, 57))
76	32507359	Somatic beta-catenin gene (CTNNB1) defects were identified in 2 of 18 (11%) of patients with PPNAD in one study (a germline PRKAR1A mutation was identified in 1 of the 2 patients with somatic CTNNB1 mutations).	('patients', 'Species', '9606', (170, 178))	('CTNNB1', 'Gene', (192, 198))	('PRKAR1A', 'Gene', '5573', (124, 131))	('CTNNB1', 'Gene', (27, 33))	('patients', 'Species', '9606', (79, 87))	('PRKAR1A', 'Gene', (124, 131))	('CTNNB1', 'Gene', '1499', (192, 198))	('CTNNB1', 'Gene', '1499', (27, 33))	('defects', 'Var', (35, 42))
78	32507359	In another study, involving tissue from 9 subjects with PPNAD (with 8 of the 9 harboring PRKAR1A defects), including 5 with macronodules, beta-catenin accumulation was found in all PPNAD tissues including within the macronodules, micronodules, and internodular tissue, whereas activating somatic CTNNB1 mutations were found in 2 of the 5 macronodules but not in the micronodules or in the contralateral adrenal gland.	('activating', 'PosReg', (277, 287))	('mutations', 'Var', (303, 312))	('CTNNB1', 'Gene', '1499', (296, 302))	('PRKAR1A', 'Gene', (89, 96))	('beta-catenin accumulation', 'MPA', (138, 163))	('CTNNB1', 'Gene', (296, 302))	('PRKAR1A', 'Gene', '5573', (89, 96))
84	32507359	Aberrant receptors have been identified less frequently in adrenocortical adenomas and ACC.	('ACC', 'Phenotype', 'HP:0006744', (87, 90))	('Aberrant', 'Var', (0, 8))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (59, 82))	('adrenocortical adenomas', 'Disease', (59, 82))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (59, 82))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (59, 81))
87	32507359	The duplicated 19q13.32 region was rearranged with other chromosome regions in two of the samples that were consistent with CPAs.	('CPAs', 'Disease', (124, 128))	('rearranged', 'Var', (35, 45))	('PA', 'Phenotype', 'HP:0011736', (125, 127))	('CPA', 'Chemical', '-', (124, 127))
92	32507359	As aforementioned, germline PDE11A variants have also been implicated in PBMAH with a prevalence of 24-28%, as have germline PDE8B mutations, somatic GNAS mutations without MAS, and PRKACA copy number gains.	('PBMAH', 'Disease', (73, 78))	('PRKACA', 'Gene', (182, 188))	('variants', 'Var', (35, 43))	('PDE11A', 'Gene', (28, 34))	('PDE11A', 'Gene', '50940', (28, 34))	('GNAS', 'Gene', (150, 154))	('PRKACA', 'Gene', '5566', (182, 188))	('PDE8B', 'Gene', (125, 130))	('PDE8B', 'Gene', '8622', (125, 130))	('implicated', 'Reg', (59, 69))	('PBMAH', 'Chemical', '-', (73, 78))	('GNAS', 'Gene', '2778', (150, 154))
95	32507359	A single case of PBMAH has been described due to 2 mutations in the same allele of the MC2R gene encoding the ACTH or melanocortin 2 receptor, which resulted in clinical hypersensitivity to ACTH through constitutive activation of the cAMP-PKA pathway.	('cAMP-PKA pathway', 'Pathway', (234, 250))	('mutations', 'Var', (51, 60))	('ACTH', 'Gene', (190, 194))	('MC2R', 'Gene', (87, 91))	('ACTH', 'Gene', '5443', (190, 194))	('hypersensitivity', 'Disease', 'MESH:D004342', (170, 186))	('PBMAH', 'Chemical', '-', (17, 22))	('MC2R', 'Gene', '4158', (87, 91))	('hypersensitivity', 'Disease', (170, 186))	('cAMP', 'Chemical', 'MESH:D000242', (234, 238))	('due', 'Reg', (42, 45))	('melanocortin 2 receptor', 'Gene', '4158', (118, 141))	('activation', 'PosReg', (216, 226))	('ACTH', 'Gene', (110, 114))	('PBMAH', 'Disease', (17, 22))	('resulted in', 'Reg', (149, 160))	('ACTH', 'Gene', '5443', (110, 114))	('melanocortin 2 receptor', 'Gene', (118, 141))
96	32507359	Either mutation alone (p.C21R and p.S247G mutation) would have produced an inactive receptor with loss of ligand binding and responsiveness; however, it appears that the presence of both mutations in the same molecule resulted in a receptor with constitutive activity, and the co-expression of the normal MC2R allele lead to retention of a normal response to ACTH.	('ACTH', 'Gene', (359, 363))	('MC2R', 'Gene', '4158', (305, 309))	('ACTH', 'Gene', '5443', (359, 363))	('presence', 'Var', (170, 178))	('p.C21R', 'Mutation', 'p.C21R', (23, 29))	('p.S247G', 'Mutation', 'p.S247G', (34, 41))	('mutations', 'Var', (187, 196))	('resulted', 'Reg', (218, 226))	('p.S247G mutation', 'Var', (34, 50))	('constitutive activity', 'MPA', (246, 267))	('MC2R', 'Gene', (305, 309))	('p.C21R', 'Var', (23, 29))
99	32507359	FAP is caused by germline inactivating defects in the adenomatous polyposis coli (APC) tumor suppressor gene, which encodes the APC protein that comprises the beta-catenin degradation complex and acts as a negative regulator of the Wnt-beta-catenin signaling pathway.	('APC', 'Gene', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('FAP', 'Disease', 'MESH:C567782', (0, 3))	('APC', 'Gene', '324', (82, 85))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (54, 75))	('APC', 'Phenotype', 'HP:0005227', (128, 131))	('APC', 'Gene', (128, 131))	('adenomatous polyposis coli (APC) tumor', 'Disease', 'MESH:D011125', (54, 92))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (54, 80))	('APC', 'Gene', '324', (128, 131))	('caused by', 'Reg', (7, 16))	('FAP', 'Disease', (0, 3))	('APC', 'Phenotype', 'HP:0005227', (82, 85))	('germline inactivating defects', 'Var', (17, 46))
100	32507359	Mutations of both APC alleles in a single cell result in the absence of functional APC protein, aberrant accumulation of beta-catenin, and transcriptional activation of the Wnt-signaling pathway.	('beta-catenin', 'Protein', (121, 133))	('absence', 'NegReg', (61, 68))	('APC', 'Phenotype', 'HP:0005227', (83, 86))	('transcriptional', 'MPA', (139, 154))	('APC', 'Gene', (18, 21))	('Mutations', 'Var', (0, 9))	('APC', 'Gene', (83, 86))	('APC', 'Phenotype', 'HP:0005227', (18, 21))	('APC', 'Gene', '324', (18, 21))	('accumulation', 'PosReg', (105, 117))	('APC', 'Gene', '324', (83, 86))	('Wnt-signaling pathway', 'Pathway', (173, 194))
107	32507359	This syndrome is caused by inactivating defects of the tumor suppressor gene MEN1 located at the 11q13 locus, that encodes the protein menin.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('menin', 'Gene', '4221', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('inactivating defects', 'Var', (27, 47))	('menin', 'Gene', (135, 140))	('tumor', 'Disease', (55, 60))	('MEN1', 'Gene', (77, 81))	('caused by', 'Reg', (17, 26))	('MEN1', 'Gene', '4221', (77, 81))
119	32507359	Genotyping (both blood and tumor) of 33 patients with PBMAH, led to detection of inactivating mutations in the ARMC5 gene in 55% (18/33) of tumors.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('PBMAH', 'Chemical', '-', (54, 59))	('tumor', 'Disease', (140, 145))	('tumor', 'Disease', (27, 32))	('patients', 'Species', '9606', (40, 48))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('inactivating mutations', 'Var', (81, 103))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('ARMC5', 'Gene', (111, 116))
120	32507359	Patients with PBMAH due to ARMC5 defects are more likely to have overt CS, larger adrenal glands, and more adrenal nodules, when compared to those with PBMAH that do not have ARMC5 mutations.	('larger adrenal glands', 'Phenotype', 'HP:0008221', (75, 96))	('CS', 'Phenotype', 'HP:0003118', (71, 73))	('CS', 'Gene', '1431', (71, 73))	('PBMAH', 'Chemical', '-', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('defects', 'Var', (33, 40))	('ARMC5', 'Gene', (27, 32))	('PBMAH', 'Chemical', '-', (152, 157))	('PBMAH', 'Disease', (14, 19))
121	32507359	Of the 18 cases of PBMAH with ARMC5 defects that were initially described, biallelic defects of ARMC5 were identified at the tumor level with four cases harboring nodule-specific secondary ARMC5 mutations, whereas leukocyte DNA only carried one of the two genetic alterations, suggesting that ARMC5 is a tumor suppressor gene.	('PBMAH', 'Chemical', '-', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('rat', 'Species', '10116', (268, 271))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('ARMC5', 'Gene', (30, 35))	('defects', 'Var', (36, 43))	('tumor', 'Disease', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('ARMC5', 'Gene', (189, 194))	('mutations', 'Var', (195, 204))	('tumor', 'Disease', (304, 309))	('ARMC5', 'Gene', (96, 101))
123	32507359	Initial functional investigations demonstrated that inactivation of ARMC5 was associated with reduced expression of steroidogenic enzymes and MC2R with abnormal cortisol production and that the large size of the adrenal glands may be related to loss of the ability to induce apoptosis in adrenocortical cells with ARMC5 mutations.	('cortisol production', 'MPA', (161, 180))	('MC2R', 'Gene', (142, 146))	('steroidogenic enzymes', 'Enzyme', (116, 137))	('expression', 'MPA', (102, 112))	('reduced', 'NegReg', (94, 101))	('mutations', 'Var', (320, 329))	('loss', 'NegReg', (245, 249))	('cortisol', 'Chemical', 'MESH:D006854', (161, 169))	('MC2R', 'Gene', '4158', (142, 146))	('ARMC5', 'Gene', (68, 73))	('inactivation', 'Var', (52, 64))	('large size of the adrenal glands', 'Phenotype', 'HP:0008221', (194, 226))	('rat', 'Species', '10116', (41, 44))	('apoptosis', 'CPA', (275, 284))	('abnormal cortisol', 'Phenotype', 'HP:0011731', (152, 169))	('ARMC5', 'Gene', (314, 319))
125	32507359	ARMC5 defects may also play a role in the development of meningiomas, which was described in one family with adrenal hyperplasia and meningioma, with ARMC5 loss of heterozygosity in the meningioma DNA.	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (109, 128))	('meningioma', 'Phenotype', 'HP:0002858', (186, 196))	('meningioma', 'Disease', (57, 67))	('meningioma', 'Disease', (133, 143))	('meningioma', 'Phenotype', 'HP:0002858', (57, 67))	('meningiomas', 'Disease', (57, 68))	('ARMC5', 'Gene', (150, 155))	('meningioma', 'Disease', 'MESH:D008577', (186, 196))	('meningiomas', 'Disease', 'MESH:D008577', (57, 68))	('meningioma', 'Phenotype', 'HP:0002858', (133, 143))	('meningioma', 'Disease', (186, 196))	('meningioma', 'Disease', 'MESH:D008577', (57, 67))	('loss of', 'NegReg', (156, 163))	('ARMC5', 'Gene', (0, 5))	('meningioma', 'Disease', 'MESH:D008577', (133, 143))	('meningiomas', 'Phenotype', 'HP:0002858', (57, 68))	('defects', 'Var', (6, 13))	('adrenal hyperplasia and meningioma', 'Disease', 'MESH:D000312', (109, 143))
126	32507359	Other possible genetic alterations associated with PBMAH have been reported in a small number of patients including somatic mutations the genes DOTIL, which encodes a histone H3 lysine methyl-transferase, and HDAC9, which encodes a histone deacetylase, both of which are involved in histone modification, chromatin organization and modification of gene transcription.	('mutations', 'Var', (124, 133))	('PBMAH', 'Chemical', '-', (51, 56))	('HDAC9', 'Gene', '9734', (209, 214))	('HDAC9', 'Gene', (209, 214))	('rat', 'Species', '10116', (27, 30))	('DOTIL', 'Gene', (144, 149))	('PBMAH', 'Disease', (51, 56))	('patients', 'Species', '9606', (97, 105))
127	32507359	A single study demonstrated a mutation in the Endothelin receptor type A EDNRA gene, which encodes a G-coupled protein, in adrenal tissue from two siblings from a family with familial PBMAH.	('rat', 'Species', '10116', (22, 25))	('mutation', 'Var', (30, 38))	('PBMAH', 'Chemical', '-', (184, 189))	('EDNRA', 'Gene', (73, 78))
130	32507359	Additional sequencing of another 129 adenomas revealed a p.Leu206Arg variant in 14 of these 129 adrenocortical adenomas.	('adenomas', 'Disease', 'MESH:D000236', (111, 119))	('adenomas', 'Disease', (111, 119))	('p.Leu206Arg', 'Var', (57, 68))	('adenomas', 'Disease', 'MESH:D000236', (37, 45))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (96, 119))	('adenomas', 'Disease', (37, 45))	('p.Leu206Arg', 'Mutation', 'rs386352352', (57, 68))	('adrenocortical adenomas', 'Disease', (96, 119))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (96, 119))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (96, 118))
131	32507359	PRKACA gene mutations were found only in patients with overt CS and were associated with a more severe phenotype.	('CS', 'Gene', '1431', (61, 63))	('PRKACA', 'Gene', (0, 6))	('mutations', 'Var', (12, 21))	('patients', 'Species', '9606', (41, 49))	('PRKACA', 'Gene', '5566', (0, 6))	('associated with', 'Reg', (73, 88))	('CS', 'Phenotype', 'HP:0003118', (61, 63))
132	32507359	Following the publication of these data in 2013, another 3 studies from China, Japan, and the United States demonstrated similar findings, with PRKACA mutations identified in 86 of 206 (42%) CPAs with overt CS.	('CS', 'Phenotype', 'HP:0003118', (207, 209))	('PRKACA', 'Gene', (144, 150))	('CS', 'Gene', '1431', (207, 209))	('rat', 'Species', '10116', (115, 118))	('PRKACA', 'Gene', '5566', (144, 150))	('identified in', 'Reg', (161, 174))	('CPA', 'Chemical', '-', (191, 194))	('PA', 'Phenotype', 'HP:0011736', (192, 194))	('CPAs', 'Disease', (191, 195))	('mutations', 'Var', (151, 160))
133	32507359	Activating mutations of PRCACA abolish the interaction between the regulatory and catalytic subunits of PKA, leading to constitutive activation of PKA, and may also alter substrate specificity with hyperphosphorylation of certain PKA substrates.	('constitutive activation', 'MPA', (120, 143))	('mutations', 'Var', (11, 20))	('abolish', 'NegReg', (31, 38))	('rat', 'Species', '10116', (176, 179))	('substrate specificity', 'MPA', (171, 192))	('alter', 'Reg', (165, 170))	('rat', 'Species', '10116', (239, 242))	('PKA', 'MPA', (147, 150))	('hyperphosphorylation', 'MPA', (198, 218))	('PRCACA', 'Gene', (24, 30))	('interaction', 'Interaction', (43, 54))
136	32507359	Though both PRKAR1A and GNAS genetic alterations may lead to increased cAMP-PKA signaling, a whole genome expression profile study revealed that not all cAMP activation is the same, with adrenal lesions harboring PRKAR1A or GNAS defects both showing overexpression of the MAPK and p53 signaling pathways but GNAS-mutant tissues showing increased expression of genes involved in extracellular matrix receptor interaction and focal adhesion pathways (NFKB, NFKBIA, and TNFRSF1A) whereas PRKARlA-mutant tissues overexpressed genes related to the Wnt-signaling pathway (CCND1, CTNNB1, LEF1, LRP5, WISP1, and WNT3).	('CCND1', 'Gene', '595', (566, 571))	('GNAS', 'Gene', '2778', (224, 228))	('PRKAR1A', 'Gene', '5573', (12, 19))	('CCND1', 'Gene', (566, 571))	('GNAS', 'Gene', (24, 28))	('alterations', 'Var', (37, 48))	('p53', 'Gene', (281, 284))	('CTNNB1', 'Gene', '1499', (573, 579))	('GNAS', 'Gene', '2778', (24, 28))	('GNAS', 'Gene', (308, 312))	('cAMP', 'Chemical', 'MESH:D000242', (153, 157))	('PRKAR1A', 'Gene', (213, 220))	('adrenal lesions', 'Disease', 'MESH:D000312', (187, 202))	('NFKBIA', 'Gene', (455, 461))	('NFKB', 'Gene', '4792', (449, 453))	('LRP5', 'Gene', '4041', (587, 591))	('GNAS', 'Gene', '2778', (308, 312))	('TNFRSF1A', 'Gene', '7132', (467, 475))	('increased', 'PosReg', (336, 345))	('NFKBIA', 'Gene', '4792', (455, 461))	('LEF1', 'Gene', (581, 585))	('WISP1', 'Gene', '8840', (593, 598))	('NFKB', 'Gene', (449, 453))	('cAMP', 'Chemical', 'MESH:D000242', (71, 75))	('CTNNB1', 'Gene', (573, 579))	('TNFRSF1A', 'Gene', (467, 475))	('NFKB', 'Gene', '4792', (455, 459))	('WNT3', 'Gene', (604, 608))	('WNT3', 'Gene', '7473', (604, 608))	('PRKAR1A', 'Gene', '5573', (213, 220))	('adrenal lesions', 'Disease', (187, 202))	('PRKAR1A', 'Gene', (12, 19))	('expression', 'MPA', (346, 356))	('NFKB', 'Gene', (455, 459))	('WISP1', 'Gene', (593, 598))	('GNAS', 'Gene', (224, 228))	('rat', 'Species', '10116', (41, 44))	('LRP5', 'Gene', (587, 591))	('LEF1', 'Gene', '51176', (581, 585))	('p53', 'Gene', '7157', (281, 284))	('focal adhesion pathways', 'Pathway', (424, 447))
137	32507359	Furthermore, in a study of samples from 27 patients with CPAs without mutations in GNAS, PRKAR1A, PDE11A, or PDE8B, abnormalities of the cAMP-signaling pathway were found, with mutation-negative CPAs having significantly decreased PDE activity.	('CPA', 'Chemical', '-', (57, 60))	('PDE', 'Gene', (109, 112))	('PDE8B', 'Gene', '8622', (109, 114))	('PRKAR1A', 'Gene', (89, 96))	('cAMP-signaling pathway', 'Pathway', (137, 159))	('cAMP', 'Chemical', 'MESH:D000242', (137, 141))	('PDE', 'Gene', '50940', (98, 101))	('decreased', 'NegReg', (221, 230))	('PDE', 'Gene', '50940', (231, 234))	('PRKAR1A', 'Gene', '5573', (89, 96))	('mutation-negative', 'Var', (177, 194))	('PDE8B', 'Gene', (109, 114))	('PDE', 'Gene', (98, 101))	('CPA', 'Chemical', '-', (195, 198))	('PDE11A', 'Gene', '50940', (98, 104))	('patients', 'Species', '9606', (43, 51))	('PDE11A', 'Gene', (98, 104))	('GNAS', 'Gene', (83, 87))	('PDE', 'Gene', (231, 234))	('PA', 'Phenotype', 'HP:0011736', (196, 198))	('PDE', 'Gene', '50940', (109, 112))	('CPAs', 'Gene', (195, 199))	('GNAS', 'Gene', '2778', (83, 87))	('PA', 'Phenotype', 'HP:0011736', (58, 60))
149	32507359	GRA occurs as the result of unequal crossing over between 2 highly homologous genes on chromosome 8 that encode isozymes of 11-beta-hydroxylase, to form a chimeric gene: CYP11B1, encoding 11beta-hydroxylase that catalyzes conversion of 11-deoxycortisol to cortisol, and CYP11B2, encoding aldosterone synthase which converts deoxycorticosterone to corticosterone and 18-hydroxycorticosterone to aldosterone.	('corticosterone', 'Chemical', 'MESH:D003345', (376, 390))	('CYP11B2', 'Gene', '1585', (270, 277))	('CYP11B1', 'Gene', (170, 177))	('aldosterone', 'Chemical', 'MESH:D000450', (288, 299))	('11-deoxycortisol', 'Chemical', 'MESH:D003350', (236, 252))	('aldosterone synthase', 'Gene', (288, 308))	('aldosterone synthase', 'Gene', '1585', (288, 308))	('18-hydroxycorticosterone', 'Chemical', 'MESH:D015069', (366, 390))	('cortisol', 'Chemical', 'MESH:D006854', (256, 264))	('crossing', 'Var', (36, 44))	('deoxycorticosterone', 'Chemical', 'MESH:D003900', (324, 343))	('aldosterone', 'Chemical', 'MESH:D000450', (394, 405))	('cortisol', 'Chemical', 'MESH:D006854', (244, 252))	('CYP11B1', 'Gene', '1584', (170, 177))	('corticosterone', 'Chemical', 'MESH:D003345', (329, 343))	('corticosterone', 'Chemical', 'MESH:D003345', (347, 361))	('CYP11B2', 'Gene', (270, 277))
150	32507359	The fusion of the promoter region of CYP11B1 with CYP11B2, results in ectopic expression of CYP11B2 in the zona fasciculata and ACTH-dependent activation of the aldosterone synthase with aldosterone overproduction.	('ACTH', 'Gene', '5443', (128, 132))	('CYP11B2', 'Gene', (92, 99))	('CYP11B2', 'Gene', '1585', (50, 57))	('zona fasciculata', 'Disease', (107, 123))	('zona fasciculata', 'Disease', 'MESH:D006562', (107, 123))	('CYP11B2', 'Gene', '1585', (92, 99))	('CYP11B1', 'Gene', (37, 44))	('fusion', 'Var', (4, 10))	('aldosterone', 'Chemical', 'MESH:D000450', (161, 172))	('aldosterone', 'MPA', (187, 198))	('ectopic expression', 'MPA', (70, 88))	('aldosterone synthase', 'Gene', (161, 181))	('aldosterone synthase', 'Gene', '1585', (161, 181))	('activation', 'PosReg', (143, 153))	('CYP11B1', 'Gene', '1584', (37, 44))	('CYP11B2', 'Gene', (50, 57))	('ACTH', 'Gene', (128, 132))	('aldosterone', 'Chemical', 'MESH:D000450', (187, 198))
153	32507359	Though FH-II was initially described in 1992, it did not have a known genetic cause until the recent discovery of mutations in the CLCN2 gene in a study of a family with FH-II and 80 additional probands with unsolved early-onset PA.	('FH-II', 'Gene', '79179', (170, 175))	('early-onset PA', 'Disease', (217, 231))	('mutations', 'Var', (114, 123))	('FH-II', 'Gene', (7, 12))	('PA', 'Phenotype', 'HP:0011736', (229, 231))	('CLCN2', 'Gene', '1181', (131, 136))	('FH-II', 'Gene', '79179', (7, 12))	('FH-II', 'Gene', (170, 175))	('CLCN2', 'Gene', (131, 136))
154	32507359	This study identified eight probands with heterozygous variants in CLCN2, including two de novo mutations, with all relatives with early-onset PA carrying the CLCN2 variant found in the probands.	('CLCN2', 'Gene', (67, 72))	('variants', 'Var', (55, 63))	('CLCN2', 'Gene', '1181', (159, 164))	('CLCN2', 'Gene', '1181', (67, 72))	('PA', 'Phenotype', 'HP:0011736', (143, 145))	('CLCN2', 'Gene', (159, 164))
155	32507359	CLCN2 encodes the chloride channel ClC-2, with gain of function mutations causing increased chloride permeability and depolarization that results in voltage-gated calcium influx.	('age', 'Gene', (153, 156))	('calcium', 'Chemical', 'MESH:D002118', (163, 170))	('gain of function', 'PosReg', (47, 63))	('age', 'Gene', '5973', (153, 156))	('CLCN2', 'Gene', (0, 5))	('chloride', 'Chemical', 'MESH:D002712', (92, 100))	('mutations', 'Var', (64, 73))	('increased', 'PosReg', (82, 91))	('depolarization', 'MPA', (118, 132))	('CLCN2', 'Gene', '1181', (0, 5))	('chloride permeability', 'MPA', (92, 113))	('chloride', 'Chemical', 'MESH:D002712', (18, 26))
156	32507359	FH-III was first described in 2008 in a father and his two daughters who presented with a new form of glucocorticoid-refractory PA due to a germline mutation in KCNJ5.	('FH-II', 'Gene', (0, 5))	('PA', 'Phenotype', 'HP:0011736', (128, 130))	('KCNJ5', 'Gene', '3762', (161, 166))	('FH-II', 'Gene', '79179', (0, 5))	('germline mutation', 'Var', (140, 157))	('due to', 'Reg', (131, 137))	('KCNJ5', 'Gene', (161, 166))
157	32507359	The KCNJ5 gene encodes the GIRK4 (G-protein-activated inward rectifier potassium channel 4), an inwardly rectifying potassium channel, with mutations causing altered channel selectivity that leads to increased sodium conductance and cell depolarization, ultimately resulting in increased intracellular calcium and calcium signaling.	('increased sodium', 'Phenotype', 'HP:0003228', (200, 216))	('sodium conductance', 'MPA', (210, 228))	('increased', 'PosReg', (278, 287))	('potassium', 'Chemical', 'MESH:D011188', (71, 80))	('calcium', 'Chemical', 'MESH:D002118', (314, 321))	('KCNJ5', 'Gene', '3762', (4, 9))	('increased', 'PosReg', (200, 209))	('potassium', 'Chemical', 'MESH:D011188', (116, 125))	('G-protein-activated inward rectifier potassium channel 4', 'Gene', '3762', (34, 90))	('calcium', 'Chemical', 'MESH:D002118', (302, 309))	('increased intracellular calcium', 'Phenotype', 'HP:0003575', (278, 309))	('sodium', 'Chemical', 'MESH:D012964', (210, 216))	('mutations', 'Var', (140, 149))	('cell depolarization', 'CPA', (233, 252))	('GIRK4', 'Gene', (27, 32))	('GIRK4', 'Gene', '3762', (27, 32))	('KCNJ5', 'Gene', (4, 9))
158	32507359	Recently a case of early-onset PA due to BAH was described that was caused by mosaicism for KCNJ5.	('PA', 'Phenotype', 'HP:0011736', (31, 33))	('BAH', 'Chemical', '-', (41, 44))	('caused by', 'Reg', (68, 77))	('KCNJ5', 'Gene', (92, 97))	('early-onset PA', 'Disease', (19, 33))	('mosaicism', 'Var', (78, 87))	('KCNJ5', 'Gene', '3762', (92, 97))
159	32507359	FH-IV was first described in 2015, when germline mutations in CACNA1H, which encodes a T-type calcium channel, were found to be the cause of early-onset PA in five unrelated individuals with family analysis suggesting incomplete penetrance and demonstrating de novo occurrence in two kindreds.	('PA', 'Phenotype', 'HP:0011736', (153, 155))	('germline mutations', 'Var', (40, 58))	('CACNA1H', 'Gene', (62, 69))	('FH-I', 'Gene', (0, 4))	('CACNA1H', 'Gene', '8912', (62, 69))	('early-onset PA', 'Disease', (141, 155))	('rat', 'Species', '10116', (251, 254))	('FH-I', 'Gene', '1584', (0, 4))	('cause', 'Reg', (132, 137))	('calcium', 'Chemical', 'MESH:D002118', (94, 101))
161	32507359	Germline mutations in CACNA1D, encoding an L-type calcium channel, can also cause PA, however these mutations exclusively occur de novo due to the severity of the associated phenotype.	('Germline mutations', 'Var', (0, 18))	('CACNA1D', 'Gene', '776', (22, 29))	('calcium', 'Chemical', 'MESH:D002118', (50, 57))	('CACNA1D', 'Gene', (22, 29))	('PA', 'Phenotype', 'HP:0011736', (82, 84))	('cause', 'Reg', (76, 81))
163	32507359	Mutant channels show activation at less depolarized membrane potentials and impaired inactivation, leading to increased calcium influx.	('calcium influx', 'MPA', (120, 134))	('increased', 'PosReg', (110, 119))	('calcium', 'Chemical', 'MESH:D002118', (120, 127))	('activation', 'PosReg', (21, 31))	('Mutant', 'Var', (0, 6))	('inactivation', 'MPA', (85, 97))
165	32507359	Somatic mutations in KCNJ5 are associated with 40% of APAs.	('PA', 'Phenotype', 'HP:0011736', (55, 57))	('KCNJ5', 'Gene', (21, 26))	('KCNJ5', 'Gene', '3762', (21, 26))	('associated', 'Reg', (31, 41))	('APAs', 'Disease', (54, 58))	('Somatic mutations', 'Var', (0, 17))
166	32507359	In a study of 22 patients with APAs, two recurrent somatic mutations (p.G151R and p.L168R), in and near the selectivity filter of KCNJ5, were present in 36% of APA samples.	('KCNJ5', 'Gene', '3762', (130, 135))	('PA', 'Phenotype', 'HP:0011736', (32, 34))	('p.G151R', 'Var', (70, 77))	('patients', 'Species', '9606', (17, 25))	('KCNJ5', 'Gene', (130, 135))	('p.L168R', 'Mutation', 'rs386352318', (82, 89))	('PA', 'Phenotype', 'HP:0011736', (161, 163))	('p.L168R', 'Var', (82, 89))	('p.G151R', 'Mutation', 'rs386352319', (70, 77))
167	32507359	These two hotspot mutations were later shown to be accountable for the majority of KCNJ5 mutations in APAs.	('PA', 'Phenotype', 'HP:0011736', (103, 105))	('KCNJ5', 'Gene', '3762', (83, 88))	('mutations', 'Var', (89, 98))	('KCNJ5', 'Gene', (83, 88))
168	32507359	With some exceptions, APA-causing somatic KCNJ5 mutations lead to a more severe phenotype when found in the germline, whereas KCNJ5 mutations found solely in the germline are typically associated with a milder phenotype.	('KCNJ5', 'Gene', (42, 47))	('APA-causing', 'Disease', (22, 33))	('KCNJ5', 'Gene', '3762', (126, 131))	('KCNJ5', 'Gene', '3762', (42, 47))	('KCNJ5', 'Gene', (126, 131))	('PA', 'Phenotype', 'HP:0011736', (23, 25))	('mutations', 'Var', (48, 57))
169	32507359	KCNJ5 mutations appear to be more common in females than in males (53-63% vs. 22-31%), with higher frequency in some Asian cohorts (60-70% APAs) compared to European cohorts.	('KCNJ5', 'Gene', '3762', (0, 5))	('PA', 'Phenotype', 'HP:0011736', (140, 142))	('KCNJ5', 'Gene', (0, 5))	('common', 'Reg', (34, 40))	('mutations', 'Var', (6, 15))
170	32507359	Additionally, APAs due to KCNJ5 mutations are larger and are associated with more pronounced PA at a younger age.	('associated with', 'Reg', (61, 76))	('KCNJ5', 'Gene', '3762', (26, 31))	('age', 'Gene', (109, 112))	('PA', 'Phenotype', 'HP:0011736', (93, 95))	('PA', 'Phenotype', 'HP:0011736', (15, 17))	('age', 'Gene', '5973', (109, 112))	('mutations', 'Var', (32, 41))	('KCNJ5', 'Gene', (26, 31))
171	32507359	CACNA1D mutations are the second most common somatic driver mutations in APAs with a prevalence of 21-42% when using panel sequencing of the entire coding sequence to detect these genetic alterations.	('mutations', 'Var', (8, 17))	('rat', 'Species', '10116', (192, 195))	('PA', 'Phenotype', 'HP:0011736', (74, 76))	('CACNA1D', 'Gene', '776', (0, 7))	('CACNA1D', 'Gene', (0, 7))
172	32507359	Somatic CACNA1D mutations were the most common genetic defects in APAs from blacks, accounting for 42%, followed by KCNJ5 defects which accounted for 34%, then ATP1A1 defects which comprised 8%, and ATP2B3 mutations which were found in 4%.	('ATP2B3', 'Gene', '492', (199, 205))	('ATP2B3', 'Gene', (199, 205))	('KCNJ5', 'Gene', '3762', (116, 121))	('ATP1A1', 'Gene', (160, 166))	('CACNA1D', 'Gene', '776', (8, 15))	('CACNA1D', 'Gene', (8, 15))	('PA', 'Phenotype', 'HP:0011736', (67, 69))	('genetic defects', 'Disease', 'MESH:D030342', (47, 62))	('mutations', 'Var', (16, 25))	('genetic defects', 'Disease', (47, 62))	('KCNJ5', 'Gene', (116, 121))	('ATP1A1', 'Gene', '476', (160, 166))
173	32507359	These CACNA1D variants were more common in APAs from black males than those from black females, whereas KCNJ5 genetic alterations were more frequent in APAs from black females compared with those from black males.	('PA', 'Phenotype', 'HP:0011736', (153, 155))	('KCNJ5', 'Gene', (104, 109))	('variants', 'Var', (14, 22))	('common', 'Reg', (33, 39))	('PA', 'Phenotype', 'HP:0011736', (44, 46))	('KCNJ5', 'Gene', '3762', (104, 109))	('rat', 'Species', '10116', (122, 125))	('CACNA1D', 'Gene', '776', (6, 13))	('CACNA1D', 'Gene', (6, 13))
174	32507359	Gain of function somatic mutations in the ATPases ATP1A1 and ATP2B3 are responsible for 3-17% of APAs.	('ATP2B3', 'Gene', (61, 67))	('ATP1A1', 'Gene', (50, 56))	('mutations', 'Var', (25, 34))	('ATP', 'Chemical', 'MESH:D000255', (61, 64))	('ATPases', 'Protein', (42, 49))	('APAs', 'Disease', (97, 101))	('PA', 'Phenotype', 'HP:0011736', (98, 100))	('ATP', 'Chemical', 'MESH:D000255', (42, 45))	('ATP2B3', 'Gene', '492', (61, 67))	('ATP1A1', 'Gene', '476', (50, 56))	('Gain of function', 'PosReg', (0, 16))	('ATP', 'Chemical', 'MESH:D000255', (50, 53))
175	32507359	These mutations cause abnormal Na+ or H+ permeability and enhanced aldosterone production.	('Na+ or H+ permeability', 'MPA', (31, 53))	('abnormal', 'Reg', (22, 30))	('enhanced aldosterone', 'Phenotype', 'HP:0000859', (58, 78))	('enhanced', 'PosReg', (58, 66))	('aldosterone production', 'MPA', (67, 89))	('aldosterone production', 'Phenotype', 'HP:0000859', (67, 89))	('abnormal Na+', 'Phenotype', 'HP:0010931', (22, 34))	('mutations', 'Var', (6, 15))	('aldosterone', 'Chemical', 'MESH:D000450', (67, 78))
176	32507359	In addition to genetic alterations that affect ion channels and ATPases, activating somatic mutations in CTNNB1 have been described in 2-5% of APAs, with a high proportion of APAs found to have constitutive activation of the Wnt-beta-catenin pathway.	('ATP', 'Chemical', 'MESH:D000255', (64, 67))	('activation', 'PosReg', (207, 217))	('mutations', 'Var', (92, 101))	('CTNNB1', 'Gene', '1499', (105, 111))	('activating', 'PosReg', (73, 83))	('rat', 'Species', '10116', (27, 30))	('PA', 'Phenotype', 'HP:0011736', (144, 146))	('Wnt-beta-catenin pathway', 'Pathway', (225, 249))	('PA', 'Phenotype', 'HP:0011736', (176, 178))	('CTNNB1', 'Gene', (105, 111))
177	32507359	Somatic CTNNB1 mutations have also been described in two women with APAs that presented in pregnancy that had highly upregulated adrenocortical expression of the LH/hCG receptor and gonadotropin releasing hormone (GnRH) receptor.	('PA', 'Phenotype', 'HP:0011736', (69, 71))	('mutations', 'Var', (15, 24))	('women', 'Species', '9606', (57, 62))	('CTNNB1', 'Gene', '1499', (8, 14))	('adrenocortical expression', 'MPA', (129, 154))	('upregulated', 'PosReg', (117, 128))	('CTNNB1', 'Gene', (8, 14))
186	32507359	The frequency of TP53 germline mutations in ACC decreases with age with approximately 50% of children diagnosed with ACC harboring germline TP53 mutations, as opposed to less than 10% of adults diagnosed with ACC.	('ACC', 'Phenotype', 'HP:0006744', (117, 120))	('children', 'Species', '9606', (93, 101))	('TP53', 'Gene', (140, 144))	('mutations', 'Var', (145, 154))	('ACC', 'Phenotype', 'HP:0006744', (44, 47))	('ACC', 'Phenotype', 'HP:0006744', (209, 212))	('age', 'Gene', (63, 66))	('age', 'Gene', '5973', (63, 66))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', '7157', (140, 144))	('TP53', 'Gene', (17, 21))
187	32507359	A TP53 p.R337H mutation is highly prevalent among children with ACC from Southern Brazil, with this founder mutation accounting for 90% of cases in this region.	('p.R337H', 'Var', (7, 14))	('p.R337H', 'Mutation', 'rs121912664', (7, 14))	('children', 'Species', '9606', (50, 58))	('ACC', 'Phenotype', 'HP:0006744', (64, 67))	('TP53', 'Gene', '7157', (2, 6))	('TP53', 'Gene', (2, 6))
188	32507359	Lynch syndrome (LS) or hereditary nonpolyposis colorectal cancer (HNPCC) is another autosomal dominant cancer predisposition syndrome, that is attributed to germline mutations in one of several DNA-mismatch repair (MMR) genes including MLH1, MSH2, MSH6, and PMS2 or loss of expression of MSH2 due to deletion in the EPCAM gene.	('expression', 'MPA', (274, 284))	('MSH2', 'Gene', '4436', (288, 292))	('MSH2', 'Gene', '4436', (242, 246))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('EPCAM', 'Gene', (316, 321))	('hereditary nonpolyposis colorectal cancer', 'Disease', (23, 64))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (166, 175))	('PMS2', 'Gene', (258, 262))	('HNPCC', 'Disease', (66, 71))	('MLH1', 'Gene', (236, 240))	('HNPCC', 'Disease', 'None', (66, 71))	('deletion', 'Var', (300, 308))	('MLH1', 'Gene', '4292', (236, 240))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (23, 64))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (23, 64))	('Lynch syndrome', 'Disease', (0, 14))	('loss of', 'NegReg', (266, 273))	('MSH2', 'Gene', (242, 246))	('MSH2', 'Gene', (288, 292))	('HNPCC', 'Phenotype', 'HP:0006716', (66, 71))	('MSH6', 'Gene', (248, 252))	('EPCAM', 'Gene', '4072', (316, 321))	('MSH6', 'Gene', '2956', (248, 252))	('PMS2', 'Gene', '5395', (258, 262))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (84, 109))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('autosomal dominant cancer', 'Disease', (84, 109))
189	32507359	Biallelic inactivation of MMR genes in a cell lead to failure to repair DNA mismatches that occur during normal DNA synthesis and resulting genomic instability, with tumors demonstrating microsatellite instability.	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('rat', 'Species', '10116', (180, 183))	('MMR genes', 'Gene', (26, 35))	('failure', 'NegReg', (54, 61))	('Biallelic inactivation', 'Var', (0, 22))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
192	32507359	Immunohistochemistry to evaluate for MMR deficiency in these three cases and another 5 previously reported showed lack of expression of the mutated MMR gene in 6 of the 8 cases though all tumors were microsatellite stable.	('expression', 'MPA', (122, 132))	('MMR deficiency', 'Disease', 'MESH:C536928', (37, 51))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('MMR', 'Gene', (148, 151))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('MMR deficiency', 'Disease', (37, 51))	('lack', 'NegReg', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('mutated', 'Var', (140, 147))
196	32507359	In greater than 80% of patients, molecular/cytogenetic testing detects one of the following alterations on chromosome 11p15.5 affecting imprinted genes in this region: loss of methylation of maternal imprinting center (IC) 2 (50%), gain of methylation of maternal IC1 (5%) , paternal uniparental disomy (20%), mutation of the CDKN1C (5% in sporadic cases), or rarely duplication, inversion or translocation of 11p15.5.	('loss', 'NegReg', (168, 172))	('mutation', 'Var', (310, 318))	('CDKN1C', 'Gene', '1028', (326, 332))	('patients', 'Species', '9606', (23, 31))	('methylation', 'MPA', (240, 251))	('uniparental disomy', 'Disease', 'MESH:D024182', (284, 302))	('translocation', 'Var', (393, 406))	('IC1', 'Gene', '105259599', (264, 267))	('methylation', 'MPA', (176, 187))	('rat', 'Species', '10116', (96, 99))	('CDKN1C', 'Gene', (326, 332))	('gain', 'PosReg', (232, 236))	('IC1', 'Gene', (264, 267))	('uniparental disomy', 'Disease', (284, 302))
199	32507359	Physiologically, IC1 is unmethylated on the maternal allele and methylated on the paternal allele.	('methylated', 'Var', (64, 74))	('IC1', 'Gene', (17, 20))	('IC1', 'Gene', '105259599', (17, 20))
200	32507359	Molecular defects in 11p15.5 can lead to overexpression of IGF2, decreased expression of H19, and/or decreased expression of CDKN1C, with gain of methylation at IC1 or paternal uniparental disomy being associated with a higher risk of tumor development in BWS.	('IC1', 'Gene', '105259599', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('gain', 'PosReg', (138, 142))	('decreased', 'NegReg', (65, 74))	('H19', 'Gene', '283120', (89, 92))	('IGF2', 'Gene', (59, 63))	('defects', 'Var', (10, 17))	('CDKN1C', 'Gene', '1028', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('expression', 'MPA', (111, 121))	('uniparental disomy', 'Disease', (177, 195))	('uniparental disomy', 'Disease', 'MESH:D024182', (177, 195))	('decreased', 'NegReg', (101, 110))	('IGF2', 'Gene', '3481', (59, 63))	('IC1', 'Gene', (161, 164))	('overexpression', 'PosReg', (41, 55))	('methylation', 'Var', (146, 157))	('CDKN1C', 'Gene', (125, 131))	('tumor', 'Disease', (235, 240))	('H19', 'Gene', (89, 92))	('expression', 'MPA', (75, 85))
204	32507359	NF1 is an autosomal dominant genetic disorder that is familial in half of the cases, and is due to inactivating defects in the tumor suppressor gene NF1, located at chromosome 17q11.2, that encodes the protein neurofibromin.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('inactivating defects', 'Var', (99, 119))	('neurofibromin', 'Gene', '4763', (210, 223))	('autosomal dominant genetic disorder', 'Disease', 'MESH:D030342', (10, 45))	('tumor', 'Disease', (127, 132))	('autosomal dominant genetic disorder', 'Disease', (10, 45))	('NF1', 'Disease', (0, 3))	('neurofibromin', 'Gene', (210, 223))	('NF1', 'Gene', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
206	32507359	These GAPs stimulate intrinsic GTPase activity in the ras p21 family (21 kD rat sarcoma viral oncogene homologs), with ras being an activator of several signaling pathways including the mechanistic target of rapamycin (mTOR), stem cell factor (SCF)/c-kit signaling, and mitogen-activated protein kinase (MAPK) pathways.	('mTOR', 'Gene', (219, 223))	('GTPase', 'Enzyme', (31, 37))	('sarcoma', 'Disease', 'MESH:D012509', (80, 87))	('sarcoma', 'Disease', (80, 87))	('mTOR', 'Gene', '56718', (219, 223))	('p21', 'Gene', '24525', (58, 61))	('GAPs', 'Var', (6, 10))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('stem cell factor', 'Gene', (226, 242))	('mechanistic target of rapamycin', 'Gene', (186, 217))	('SCF', 'Gene', (244, 247))	('activity', 'MPA', (38, 46))	('SCF', 'Gene', '60427', (244, 247))	('mechanistic target of rapamycin', 'Gene', '56718', (186, 217))	('GTP', 'Chemical', 'MESH:D006160', (31, 34))	('stem cell factor', 'Gene', '60427', (226, 242))	('intrinsic', 'MPA', (21, 30))	('p21', 'Gene', (58, 61))	('rat', 'Species', '10116', (76, 79))	('stimulate', 'PosReg', (11, 20))
210	32507359	Recently, nine germline inactivating variants in PDEs and related genes (PDE3B, PDE5A, PDE6B, PDE8A, and PDE11A, and the phosphodiesterase interacting protein PDE4DIP) were identified in a cohort of 37 pediatric patients with ACT (24%), with tumor DNA loss of heterozygosity, suggesting that these germline variants may play a role in the development of ACC in children.	('play', 'Reg', (320, 324))	('PDE6B', 'Gene', '5158', (87, 92))	('PDE3B', 'Gene', (73, 78))	('children', 'Species', '9606', (361, 369))	('patients', 'Species', '9606', (212, 220))	('PDEs', 'Gene', (49, 53))	('loss', 'NegReg', (252, 256))	('tumor', 'Disease', (242, 247))	('PDE5A', 'Gene', '8654', (80, 85))	('PDE4DIP', 'Gene', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('PDE8A', 'Gene', '5151', (94, 99))	('PDE6B', 'Gene', (87, 92))	('PDE8A', 'Gene', (94, 99))	('PDE5A', 'Gene', (80, 85))	('PDE11A', 'Gene', (105, 111))	('PDE11A', 'Gene', '50940', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('PDE3B', 'Gene', '5140', (73, 78))	('PDE4DIP', 'Gene', '9659', (159, 166))	('ACC', 'Phenotype', 'HP:0006744', (354, 357))	('ACC', 'Disease', (354, 357))	('PDEs', 'Gene', '50940', (49, 53))	('variants', 'Var', (37, 45))
211	32507359	As in familial ACC, somatic genetic alterations leading to changes in p53 signaling, Wnt-beta-catenin signaling, IGF2 overexpression, and less so cAMP-PKA signaling, amongst others, have been implicated in the development of sporadic ACC.	('sporadic ACC', 'Disease', (225, 237))	('IGF2', 'Gene', '3481', (113, 117))	('Wnt-beta-catenin signaling', 'MPA', (85, 111))	('familial ACC', 'Disease', (6, 18))	('overexpression', 'MPA', (118, 132))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('ACC', 'Phenotype', 'HP:0006744', (15, 18))	('alterations', 'Var', (36, 47))	('rat', 'Species', '10116', (40, 43))	('changes', 'Reg', (59, 66))	('IGF2', 'Gene', (113, 117))	('implicated', 'Reg', (192, 202))	('cAMP', 'Chemical', 'MESH:D000242', (146, 150))	('ACC', 'Phenotype', 'HP:0006744', (234, 237))
215	32507359	CTNNB1 mutations were present in 16% of ACCs and were mutually exclusive with ZNRF3 alterations, whereas APC mutations were identified in 2%.	('CTNNB1', 'Gene', '1499', (0, 6))	('ZNRF3', 'Gene', '84133', (78, 83))	('APC', 'Gene', '324', (105, 108))	('ZNRF3', 'Gene', (78, 83))	('ACC', 'Phenotype', 'HP:0006744', (40, 43))	('APC', 'Phenotype', 'HP:0005227', (105, 108))	('rat', 'Species', '10116', (88, 91))	('CTNNB1', 'Gene', (0, 6))	('ACCs', 'Gene', '84680', (40, 44))	('alterations', 'Var', (84, 95))	('ACCs', 'Gene', (40, 44))	('APC', 'Gene', (105, 108))	('mutations', 'Var', (7, 16))
216	32507359	The MED12 gene was found to be mutated in 5% of tumors with mutations affecting the C-terminal region of the protein that was found to physically interact with beta-catenin, leading to the recruitment of mediator to Wnt-responsive genes.	('recruitment', 'MPA', (189, 200))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('mediator', 'MPA', (204, 212))	('MED12', 'Gene', (4, 9))	('Wnt-responsive genes', 'Gene', (216, 236))	('MED12', 'Gene', '9968', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations affecting', 'Var', (60, 79))
218	32507359	Genetic changes affecting this pathway included defects in the tumor suppressor genes TP53 (16%), CDKN2A (11%) and RB1 (7%) and amplifications in the oncogenes CDK4 (2%) and MDM2 (2%).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CDK4', 'Gene', (160, 164))	('TP53', 'Gene', '7157', (86, 90))	('RB1', 'Gene', (115, 118))	('CDK4', 'Gene', '1019', (160, 164))	('MDM2', 'Gene', '4193', (174, 178))	('TP53', 'Gene', (86, 90))	('MDM2', 'Gene', (174, 178))	('CDKN2A', 'Gene', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('RB1', 'Gene', '5925', (115, 118))	('amplifications', 'Var', (128, 142))	('CDKN2A', 'Gene', '1029', (98, 104))	('defects', 'NegReg', (48, 55))
219	32507359	Mutations in genes associated with chromatin remodeling or telomere maintenance were also identified including MEN1 (7%), DAXX (6%), ATRX (2 tumors), and TERT (6%).	('DAXX', 'Gene', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('TERT', 'Gene', (154, 158))	('MEN1', 'Gene', (111, 115))	('tumors', 'Disease', (141, 147))	('ATRX', 'Gene', '546', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('MEN1', 'Gene', '4221', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', '7015', (154, 158))	('DAXX', 'Gene', '1616', (122, 126))	('ATRX', 'Gene', (133, 137))
224	32507359	Collectively, 22% of cases demonstrated genetic changes in histone modification genes (MLL, MLL2, and MLL4) and chromatin remodeling genes (ATRX and DAXX).	('MLL', 'Gene', '4297', (102, 105))	('MLL', 'Gene', (92, 95))	('MLL4', 'Gene', (102, 106))	('MLL', 'Gene', '4297', (92, 95))	('MLL', 'Gene', (102, 105))	('DAXX', 'Gene', (149, 153))	('ATRX', 'Gene', (140, 144))	('DAXX', 'Gene', '1616', (149, 153))	('MLL2', 'Gene', (92, 96))	('histone modification', 'MPA', (59, 79))	('MLL', 'Gene', '4297', (87, 90))	('genetic changes', 'Var', (40, 55))	('ATRX', 'Gene', '546', (140, 144))	('MLL', 'Gene', (87, 90))	('MLL2', 'Gene', '8085', (92, 96))	('rat', 'Species', '10116', (34, 37))	('MLL4', 'Gene', '8085', (102, 106))
228	32507359	Additionally, genome-wide DNA copy number analysis demonstrated increased frequency of DNA loss, followed by whole genome doubling, which was associated with more aggressive tumors.	('aggressive tumors', 'Disease', 'MESH:D001523', (163, 180))	('DNA', 'Var', (87, 90))	('aggressive tumors', 'Disease', (163, 180))	('rat', 'Species', '10116', (58, 61))	('loss', 'NegReg', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
232	32507359	Molecular analysis of the tumor demonstrated 17p13 loss of heterozygosity, 11p15 uniparental disomy, and IGF2 gene overexpression, as well as chromosomal gains and losses in the malignant tissue, which were not present in the benign tissue.	('uniparental disomy', 'Disease', (81, 99))	('chromosomal', 'Var', (142, 153))	('IGF2', 'Gene', '3481', (105, 109))	('loss of', 'NegReg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('uniparental disomy', 'Disease', 'MESH:D024182', (81, 99))	('11p15', 'Gene', (75, 80))	('rat', 'Species', '10116', (39, 42))	('IGF2', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('losses', 'NegReg', (164, 170))	('overexpression', 'PosReg', (115, 129))
233	32507359	In recent years, with the study of adrenocortical tumors using genomic tools and next generation sequencing, significant strides have been made in understanding the genomic underpinnings of adrenocortical tumorigenesis highlighting the roles of the cAMP-PKA pathway and ARMC5 in the development of benign cortisol-producing tumors, aberrant intracellular calcium signaling in PA, and molecular alterations in the Wnt-beta-catenin and p53 pathways and IGF2 expression in ACC.	('adrenocortical tumors', 'Disease', (35, 56))	('calcium', 'Chemical', 'MESH:D002118', (355, 362))	('PA', 'Phenotype', 'HP:0011736', (376, 378))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cAMP', 'Chemical', 'MESH:D000242', (249, 253))	('cortisol', 'Chemical', 'MESH:D006854', (305, 313))	('expression', 'MPA', (456, 466))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('alterations', 'Reg', (394, 405))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('IGF2', 'Gene', '3481', (451, 455))	('ACC', 'Phenotype', 'HP:0006744', (470, 473))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumors', 'Disease', (324, 330))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (50, 55))	('aberrant', 'Var', (332, 340))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('p53', 'Gene', '7157', (434, 437))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (35, 56))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('rat', 'Species', '10116', (90, 93))	('IGF2', 'Gene', (451, 455))	('intracellular calcium signaling', 'MPA', (341, 372))	('ARMC5', 'Gene', (270, 275))	('tumor', 'Disease', (324, 329))	('p53', 'Gene', (434, 437))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('rat', 'Species', '10116', (398, 401))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
236	32507359	This was achieved initially through the study of rare familial tumor syndromes such as McCune-Albright syndrome (MAS), Carney complex (CNC), Li-Fraumeni syndrome (LFS), and Beckwith-Wiedemann syndrome (BWS), with identification of disease-causing alterations in genes and molecular pathways that subsequently led to the discovery of aberrations in these or related genes and pathways in sporadic ACTs.	('Beckwith-Wiedemann syndrome', 'Disease', (173, 200))	('LFS', 'Disease', 'MESH:D016864', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('rat', 'Species', '10116', (337, 340))	('familial tumor syndromes', 'Disease', 'MESH:D009386', (54, 78))	('McCune-Albright syndrome', 'Disease', (87, 111))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (141, 161))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (87, 111))	('LFS', 'Disease', (163, 166))	('familial tumor syndromes', 'Disease', (54, 78))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (173, 200))	('sporadic ACTs', 'Disease', (387, 400))	('Carney complex', 'Disease', (119, 133))	('Li-Fraumeni syndrome', 'Disease', (141, 161))	('alterations', 'Var', (247, 258))	('aberrations', 'Var', (333, 344))	('rat', 'Species', '10116', (251, 254))
241	32507359	The pathogenesis of most benign cortisol-producing ACTs can be linked to aberrant cAMP-protein kinase A (PKA) signaling.	('aberrant', 'Var', (73, 81))	('benign cortisol-producing ACTs', 'Disease', (25, 55))	('cortisol', 'Chemical', 'MESH:D006854', (32, 40))	('cAMP', 'Chemical', 'MESH:D000242', (82, 86))
243	32507359	i-PPNAD and i-MAD have been linked to germline defects in PDE11A and PDE8B, encoding phosphodiesterases that play a regulatory role in the cAMP-PKA pathway and i-MAD has been associated with germline copy number gains in PRKACA, encoding the catalytic subunit (Calpha) of PKA, that lead to increased cAMP-PKA signaling.	('phosphodiesterases', 'Gene', (85, 103))	('cAMP', 'Chemical', 'MESH:D000242', (139, 143))	('PRKACA', 'Gene', '5566', (221, 227))	('PDE11A', 'Gene', '50940', (58, 64))	('PDE8B', 'Gene', (69, 74))	('phosphodiesterases', 'Gene', '50940', (85, 103))	('PDE11A', 'Gene', (58, 64))	('PDE8B', 'Gene', '8622', (69, 74))	('defects', 'Var', (47, 54))	('cAMP-PKA signaling', 'MPA', (300, 318))	('copy number', 'Var', (200, 211))	('gains', 'PosReg', (212, 217))	('PRKACA', 'Gene', (221, 227))	('increased', 'PosReg', (290, 299))	('cAMP', 'Chemical', 'MESH:D000242', (300, 304))
244	32507359	Activating mutations in PRKACA account for up to 42% of cortisol-producing adrenocortical adenomas presenting with Cushing syndrome.	('PRKACA', 'Gene', (24, 30))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (75, 98))	('Cushing syndrome', 'Disease', (115, 131))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (75, 98))	('Activating mutations', 'Var', (0, 20))	('adrenocortical adenomas', 'Disease', (75, 98))	('PRKACA', 'Gene', '5566', (24, 30))	('Cushing syndrome', 'Disease', 'MESH:D003480', (115, 131))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (75, 97))	('cortisol', 'Chemical', 'MESH:D006854', (56, 64))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (115, 131))
247	32507359	Germline defects in the tumor suppressor gene ARMC5 account for 21-26% of cases of PBMAH, whereas PBMAH is rarely associated with familial tumor syndromes such as familial adenomatous polyposis (FAP), multiple endocrine neoplasia type 1 (MEN1), or hereditary leiomyomatosis and renal cell carcinoma.	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (172, 193))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('tumor', 'Disease', (139, 144))	('hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C538614', (248, 298))	('MEN1', 'Gene', '4221', (238, 242))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (210, 229))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('multiple endocrine neoplasia type 1', 'Gene', (201, 236))	('multiple endocrine neoplasia type 1', 'Gene', '4221', (201, 236))	('defects', 'Var', (9, 16))	('PBMAH', 'Chemical', '-', (83, 88))	('MEN1', 'Gene', (238, 242))	('familial tumor syndromes', 'Disease', (130, 154))	('PBMAH', 'Disease', (83, 88))	('PBMAH', 'Chemical', '-', (98, 103))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('familial tumor syndromes', 'Disease', 'MESH:D009386', (130, 154))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('neoplasia', 'Phenotype', 'HP:0002664', (220, 229))	('FAP', 'Disease', (195, 198))	('ARMC5', 'Gene', (46, 51))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (278, 298))	('FAP', 'Disease', 'MESH:C567782', (195, 198))	('associated', 'Reg', (114, 124))	('familial adenomatous polyposis', 'Disease', (163, 193))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (163, 193))
251	32507359	FH-I is caused by fusion of the promoter region of the gene for CYP11B1 and the coding sequences of CYP11B2, resulting in ACTH-dependent activation of aldosterone synthase.	('FH-I', 'Gene', (0, 4))	('caused by', 'Reg', (8, 17))	('ACTH', 'Gene', (122, 126))	('CYP11B2', 'Gene', (100, 107))	('CYP11B1', 'Gene', (64, 71))	('ACTH', 'Gene', '5443', (122, 126))	('fusion', 'Var', (18, 24))	('activation', 'PosReg', (137, 147))	('aldosterone synthase', 'Gene', (151, 171))	('aldosterone synthase', 'Gene', '1585', (151, 171))	('CYP11B1', 'Gene', '1584', (64, 71))	('CYP11B2', 'Gene', '1585', (100, 107))	('FH-I', 'Gene', '1584', (0, 4))
252	32507359	FH-II is caused by defects in CLCN2, whereas FH-III is caused by KCNJ5 defects, and FH-IV is caused by defects in CACNA1H.	('KCNJ5', 'Gene', '3762', (65, 70))	('FH-I', 'Gene', (45, 49))	('FH-II', 'Gene', (45, 50))	('defects', 'Var', (19, 26))	('FH-I', 'Gene', '1584', (0, 4))	('FH-I', 'Gene', (84, 88))	('caused by', 'Reg', (9, 18))	('defects', 'Var', (71, 78))	('FH-II', 'Gene', '79179', (0, 5))	('FH-I', 'Gene', '1584', (45, 49))	('FH-II', 'Gene', (0, 5))	('defects', 'Var', (103, 110))	('FH-I', 'Gene', '1584', (84, 88))	('CLCN2', 'Gene', '1181', (30, 35))	('caused by', 'Reg', (93, 102))	('caused by', 'Reg', (55, 64))	('KCNJ5', 'Gene', (65, 70))	('CLCN2', 'Gene', (30, 35))	('FH-I', 'Gene', (0, 4))	('CACNA1H', 'Gene', (114, 121))	('CACNA1H', 'Gene', '8912', (114, 121))	('FH-II', 'Gene', '79179', (45, 50))
256	32507359	39-41% of sporadic ACC cases harbor genetic alterations affecting Wnt-beta-catenin signaling, whereas 33-44.9% harbor molecular changes that affect p53-Rb signaling.	('affect', 'Reg', (141, 147))	('p53', 'Gene', (148, 151))	('Wnt-beta-catenin signaling', 'MPA', (66, 92))	('p53', 'Gene', '7157', (148, 151))	('ACC', 'Phenotype', 'HP:0006744', (19, 22))	('ACC', 'Disease', (19, 22))	('affecting', 'Reg', (56, 65))	('genetic alterations', 'Var', (36, 55))	('rat', 'Species', '10116', (48, 51))
258	32507359	Mutations in genes associated with chromatin remodeling or telomere maintenance have also been identified in ACC including MEN1, DAXX, ATRX, and TERT.	('identified', 'Reg', (95, 105))	('ATRX', 'Gene', '546', (135, 139))	('TERT', 'Gene', (145, 149))	('DAXX', 'Gene', '1616', (129, 133))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('Mutations', 'Var', (0, 9))	('ACC', 'Disease', (109, 112))	('ATRX', 'Gene', (135, 139))	('MEN1', 'Gene', (123, 127))	('DAXX', 'Gene', (129, 133))	('MEN1', 'Gene', '4221', (123, 127))	('TERT', 'Gene', '7015', (145, 149))
260	32561853	Wnt/beta-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('aggressive malignancy', 'Disease', 'MESH:D009369', (143, 164))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (65, 89))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (98, 122))	('aggressive malignancy', 'Disease', (143, 164))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (65, 89))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (98, 122))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '22059', (52, 55))	('Adrenocortical carcinoma', 'Disease', (98, 122))	('cause', 'Reg', (59, 64))	('beta-catenin', 'Gene', '12387', (4, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('loss', 'Var', (44, 48))	('adrenocortical carcinoma', 'Disease', (65, 89))	('ACC', 'Phenotype', 'HP:0006744', (124, 127))	('beta-catenin', 'Gene', (4, 16))
262	32561853	We analyzed The Cancer Genome Atlas (TCGA) dataset for ACC and found that patients harboring alterations in both p53/Rb and Wnt/beta-catenin signaling pathways show a worse prognosis compared with patients that harbored alterations in only one.	('ACC', 'Phenotype', 'HP:0006744', (55, 58))	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer', 'Disease', (16, 22))	('patients', 'Species', '9606', (197, 205))	('Cancer', 'Disease', 'MESH:D009369', (16, 22))	('alterations', 'Var', (93, 104))	('patients', 'Species', '9606', (74, 82))	('Wnt/beta-catenin signaling pathways', 'Pathway', (124, 159))	('p53/Rb', 'Protein', (113, 119))
263	32561853	To model this, we utilized the Cyp11b2(AS)Cre mouse line to generate mice with adrenocortical-specific Wnt/beta-catenin activation, Trp53 deletion, or the combination of both.	('Cyp11b2', 'Gene', '13072', (31, 38))	('mouse', 'Species', '10090', (46, 51))	('mice', 'Species', '10090', (69, 73))	('Trp53', 'Gene', (132, 137))	('deletion', 'Var', (138, 146))	('Cyp11b2', 'Gene', (31, 38))
264	32561853	Mice with targeted Wnt/beta-catenin activation or Trp53 deletion showed no changes associated with tumor formation.	('deletion', 'Var', (56, 64))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Mice', 'Species', '10090', (0, 4))	('Trp53', 'Gene', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
265	32561853	In contrast, alterations in both pathways led to ACC with pulmonary metastases.	('ACC', 'Disease', (49, 52))	('pulmonary metastases', 'Disease', 'MESH:D009362', (58, 78))	('pulmonary metastases', 'Disease', (58, 78))	('alterations', 'Var', (13, 24))	('led to', 'Reg', (42, 48))	('ACC', 'Phenotype', 'HP:0006744', (49, 52))
268	32561853	Altogether, these data show that altering both Wnt/beta-catenin and p53/Rb signaling is sufficient to drive ACC in mouse.	('ACC', 'Phenotype', 'HP:0006744', (108, 111))	('altering', 'Var', (33, 41))	('ACC', 'Disease', (108, 111))	('mouse', 'Species', '10090', (115, 120))
280	32561853	Gain-of-function (GOF) mutations in CTNNB1 (the gene encoding beta-catenin) and biallelic deletion or loss of function mutation in ZNRF3 (a negative regulator of the Wnt/beta-catenin pathway), which lead to constitutive activation of Wnt/beta-catenin signaling, are among the most common somatic alterations in ACC.	('CTNNB1', 'Gene', (36, 42))	('loss of function', 'NegReg', (102, 118))	('Wnt/beta-catenin signaling', 'Pathway', (234, 260))	('ZNRF3', 'Gene', '407821', (131, 136))	('ACC', 'Phenotype', 'HP:0006744', (311, 314))	('mutations', 'Var', (23, 32))	('Gain-of-function', 'PosReg', (0, 16))	('activation', 'PosReg', (220, 230))	('biallelic', 'Var', (80, 89))	('ZNRF3', 'Gene', (131, 136))
281	32561853	Despite the high frequency of mutations in Wnt/beta-catenin pathway genes in human ACC, such mutations alone are insufficient to induce malignant transformation in mouse models, although they have been linked to the development of benign adrenocortical tumors.	('linked to', 'Reg', (202, 211))	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('ACC', 'Disease', (83, 86))	('mouse', 'Species', '10090', (164, 169))	('mutations', 'Var', (93, 102))	('benign adrenocortical tumors', 'Disease', (231, 259))	('benign adrenocortical tumors', 'Disease', 'MESH:D018268', (231, 259))	('Wnt/beta-catenin pathway genes', 'Gene', (43, 73))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('mutations', 'Var', (30, 39))	('human', 'Species', '9606', (77, 82))
284	32561853	Mutations in TP53, the gene that encodes human p53, have also been associated with ACC in both familial and sporadic forms.	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('TP53', 'Gene', (13, 17))	('ACC', 'Disease', (83, 86))	('human', 'Species', '9606', (41, 46))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (67, 77))
286	32561853	Consistent with this, a 10-fold increase in the incidence of adrenocortical tumors has been observed in Southeastern Brazil, where a common germline mutation exists within the p53 oligomerization domain [p.R337H].	('[p.R337H]', 'Var', (203, 212))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('adrenocortical tumors', 'Disease', (61, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (61, 82))	('p.R337H', 'Mutation', 'rs121912664', (204, 211))
287	32561853	Despite this, neither mice carrying a homolog of the human TP53 R337H mutation nor a global deletion of Trp53, the gene encoding murine p53, develop ACC, arguing that p53 disruption alone is insufficient to induce malignant transformation in the adrenal cortex.	('R337H', 'Var', (64, 69))	('TP53', 'Gene', (59, 63))	('R337H', 'SUBSTITUTION', 'None', (64, 69))	('deletion', 'Var', (92, 100))	('Trp53', 'Gene', (104, 109))	('murine', 'Species', '10090', (129, 135))	('human', 'Species', '9606', (53, 58))	('mice', 'Species', '10090', (22, 26))	('ACC', 'Phenotype', 'HP:0006744', (149, 152))
289	32561853	Here, we demonstrate that the combination of adrenal-specific beta-catenin GOF and p53 deletion in mice resulted in metastatic ACC that produce corticosteroids in excess, a key feature of human ACC.	('mice', 'Species', '10090', (99, 103))	('human', 'Species', '9606', (188, 193))	('p53', 'Gene', (83, 86))	('adrenal-specific beta-catenin', 'Protein', (45, 74))	('metastatic ACC', 'CPA', (116, 130))	('steroid', 'Chemical', 'MESH:D013256', (151, 158))	('ACC', 'Phenotype', 'HP:0006744', (194, 197))	('GOF', 'PosReg', (75, 78))	('ACC', 'Phenotype', 'HP:0006744', (127, 130))	('resulted in', 'Reg', (104, 115))	('deletion', 'Var', (87, 95))	('excess', 'PosReg', (163, 169))
292	32561853	Previously, unsupervised clustering analysis identified two unique transcriptional subtypes of ACC, C1A (CoCII-III) and C1B (CoCI).	('C1A', 'Gene', '100862690', (100, 103))	('ACC', 'Phenotype', 'HP:0006744', (95, 98))	('C1A', 'Gene', (100, 103))	('ACC', 'Disease', (95, 98))	('C1B', 'Var', (120, 123))
293	32561853	The C1A subtype is comprised of more aggressive tumors and shows enrichment for tumors with somatic mutations in genes linked to the Wnt/beta-catenin and p53/Rb pathways.	('p53/Rb pathways', 'Pathway', (154, 169))	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('aggressive tumors', 'Disease', 'MESH:D001523', (37, 54))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('aggressive tumors', 'Disease', (37, 54))	('C1A', 'Gene', (4, 7))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('C1A', 'Gene', '100862690', (4, 7))
298	32561853	Of interest, patients with ACCs harboring alterations in genes from both pathways showed an overall lower survival rate compared with patients harboring alterations in only one pathway (Fig.	('ACCs', 'Phenotype', 'HP:0006744', (27, 31))	('alterations', 'Var', (42, 53))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (134, 142))	('lower', 'NegReg', (100, 105))	('ACC', 'Phenotype', 'HP:0006744', (27, 30))	('survival rate', 'CPA', (106, 119))
299	32561853	To investigate the effect of Wnt/beta-catenin activation and p53/Rb dysfunction in the adrenal cortex, we crossed the adrenal-specific Aldosterone Synthase (AS) ASCre/+ mouse strain, in which Cre expression is first noted within the zona Glomerulosa (zG) around the time of birth, with mice harboring the conditional p53 Loss-of-function (p53-LOF) allele Trp53flox/flox and/or the conditional beta-catenin GOF (betacat-GOF) allele Ctnnbflox(ex3)/+.	('p53', 'Gene', (317, 320))	('Rb dysfunction', 'Disease', (65, 79))	('Aldosterone Synthase', 'Gene', '13072', (135, 155))	('Trp53flox/flox', 'Var', (355, 369))	('Aldosterone Synthase', 'Gene', (135, 155))	('zona Glomerulosa', 'Disease', (233, 249))	('Rb dysfunction', 'Disease', 'MESH:D009461', (65, 79))	('mice', 'Species', '10090', (286, 290))	('Loss-of-function', 'NegReg', (321, 337))	('mouse', 'Species', '10090', (169, 174))	('zona Glomerulosa', 'Disease', 'MESH:D006562', (233, 249))
313	32561853	Non-linear regression analysis of average adrenal weights (per animal) over time revealed an exponential rate of adrenal growth for BPCreAS/+ mice (~200-fold increase at 12 months) compared with control mice (Fig.	('mice', 'Species', '10090', (203, 207))	('BPCreAS/+', 'Var', (132, 141))	('mice', 'Species', '10090', (142, 146))	('adrenal growth', 'CPA', (113, 127))	('increase', 'PosReg', (158, 166))
336	32561853	Human ACC harboring alterations in the Wnt/beta-Catenin pathway have previously shown increased expression of AXIN2 and LEF1 and beta-catenin status in ACC correlates with a gene signature rich in TCF/LEF target genes.	('alterations', 'Var', (20, 31))	('Human', 'Species', '9606', (0, 5))	('increased', 'PosReg', (86, 95))	('ACC', 'Phenotype', 'HP:0006744', (152, 155))	('LEF1', 'Gene', '51176', (120, 124))	('beta-Catenin', 'Gene', (43, 55))	('expression', 'MPA', (96, 106))	('beta-Catenin', 'Gene', '1499', (43, 55))	('LEF1', 'Gene', (120, 124))	('TCF', 'Gene', (197, 200))	('AXIN2', 'Gene', (110, 115))	('TCF', 'Gene', '51176;16842', (197, 200))	('ACC', 'Phenotype', 'HP:0006744', (6, 9))	('AXIN2', 'Gene', '8313', (110, 115))
339	32561853	Next, we assessed the expression of EZH2, a histone methyltransferase which is overexpressed in human ACC and associated with disease progression, poor prognosis and inactivating mutations in the p53/Rb pathway.	('inactivating mutations', 'Var', (166, 188))	('human', 'Species', '9606', (96, 101))	('associated with', 'Reg', (110, 125))	('p53/Rb pathway', 'Pathway', (196, 210))	('ACC', 'Phenotype', 'HP:0006744', (102, 105))	('EZH2', 'Gene', '2146', (36, 40))	('EZH2', 'Gene', (36, 40))
354	32561853	Interestingly, the combination of mutations affecting both TP53 and CTNNB1 have been described in a small group of both pediatric and adult patients presenting with malignant adrenocortical tumors and correlates with poor prognosis, though, in general, the majority of high-risk patients do not simultaneously harbor mutations in both genes.	('TP53', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('CTNNB1', 'Gene', (68, 74))	('patients', 'Species', '9606', (279, 287))	('patients', 'Species', '9606', (140, 148))	('malignant adrenocortical tumors', 'Disease', 'MESH:D009369', (165, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('malignant adrenocortical tumors', 'Disease', (165, 196))	('mutations', 'Var', (34, 43))
356	32561853	A recent study showed that adrenocortical specific expression of SV40 large T-antigen (AdTAg mice) (driven by a 0.5 kb region of the Akr1b7 promoter) leads to ACC in mice.	('leads to', 'Reg', (150, 158))	('ACC', 'Phenotype', 'HP:0006744', (159, 162))	('ACC', 'Disease', (159, 162))	('mice', 'Species', '10090', (93, 97))	('mice', 'Species', '10090', (166, 170))	('Akr1b7', 'Gene', '11997', (133, 139))	('Akr1b7', 'Gene', (133, 139))	('SV40', 'Var', (65, 69))
359	32561853	In summary, we have demonstrated that Wnt/beta-catenin activation cooperates with loss of p53 to promote murine ACC tumorigenesis, which mimics the cardinal features of human ACC.	('p53', 'Gene', (90, 93))	('murine', 'Species', '10090', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('ACC', 'Phenotype', 'HP:0006744', (112, 115))	('human', 'Species', '9606', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('ACC', 'Phenotype', 'HP:0006744', (175, 178))	('loss', 'Var', (82, 86))	('tumor', 'Disease', (116, 121))	('promote', 'PosReg', (97, 104))
383	32127935	Pediatric patients with ACC seem to present more endocrine dysfunction features and TP53 mutations than adult patients.	('ACC', 'Disease', 'MESH:D000306', (24, 27))	('ACC', 'Disease', (24, 27))	('endocrine dysfunction', 'Disease', (49, 70))	('endocrine dysfunction', 'Phenotype', 'HP:0000818', (49, 70))	('TP53', 'Gene', '7157', (84, 88))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (10, 18))	('TP53', 'Gene', (84, 88))	('endocrine dysfunction', 'Disease', 'MESH:D004700', (49, 70))	('patients', 'Species', '9606', (110, 118))
624	30978697	Initiator caspases are produced as inactive monomeric procaspases and are activated by dimerization via the designated 'induced proximity model'.	('dimerization', 'Var', (87, 99))	('caspases', 'Gene', (57, 65))	('caspases', 'Gene', '834;835;837;838;839;841;842;843', (10, 18))	('activated', 'PosReg', (74, 83))	('caspases', 'Gene', (10, 18))	('caspases', 'Gene', '834;835;837;838;839;841;842;843', (57, 65))
652	30978697	Moreover, high TNFAIP3 expression was significantly associated with poor overall survival of ACC patients.	('ACC', 'Phenotype', 'HP:0006744', (93, 96))	('overall', 'MPA', (73, 80))	('poor', 'NegReg', (68, 72))	('TNFAIP3', 'Gene', '7128', (15, 22))	('associated', 'Reg', (52, 62))	('patients', 'Species', '9606', (97, 105))	('high', 'Var', (10, 14))	('TNFAIP3', 'Gene', (15, 22))	('expression', 'MPA', (23, 33))
693	30978697	It has also been described that P53 overexpression increases Fas levels at the cell surface, by promoting its trafficking from Golgi complex.	('Fas levels at the cell surface', 'MPA', (61, 91))	('P53', 'Gene', '7157', (32, 35))	('Fas', 'Chemical', '-', (61, 64))	('promoting', 'PosReg', (96, 105))	('increases', 'PosReg', (51, 60))	('trafficking from Golgi complex', 'MPA', (110, 140))	('P53', 'Gene', (32, 35))	('overexpression', 'Var', (36, 50))
695	30978697	TP53 mutations usually result in the loss of p53 tumor suppressive activity, mainly due to repression of p53 target genes transactivation.	('transactivation', 'MPA', (122, 137))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('repression', 'NegReg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (5, 14))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('loss', 'NegReg', (37, 41))
696	30978697	TP53 mutations in ACT was demonstrated to be absent in the majority of ACA.	('ACA', 'Disease', (71, 74))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
697	30978697	In contrast, the prevalence of somatic TP53 mutations in sporadic ACC can varies from 20 to 30% of the cases.	('ACC', 'Phenotype', 'HP:0006744', (66, 69))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
698	30978697	Besides that, the majority of ACC patients with mutated TP53 were observed to have poor outcomes.	('mutated', 'Var', (48, 55))	('TP53', 'Gene', '7157', (56, 60))	('ACC', 'Phenotype', 'HP:0006744', (30, 33))	('ACC', 'Disease', (30, 33))	('TP53', 'Gene', (56, 60))	('patients', 'Species', '9606', (34, 42))
699	30978697	Aberrant p53 protein expression was also found to be associated with decreased disease-free survival.	('Aberrant', 'Var', (0, 8))	('decreased', 'NegReg', (69, 78))	('disease-free survival', 'CPA', (79, 100))	('expression', 'MPA', (21, 31))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('protein', 'Protein', (13, 20))
703	30978697	Nevertheless, LOH at 17q13 is not always associated with TP53 mutations suggesting that other genes in the same chromosomal region contribute to ACC biology.	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('ACC', 'Phenotype', 'HP:0006744', (145, 148))	('mutations', 'Var', (62, 71))
704	30978697	TP53 gene germline pathogenic variants are typically associated with Li-Fraumeni or Li-Fraumeni-like syndrome, which is associated with an hereditary predisposition to neoplasms, in particular to pediatric ACC.	('variants', 'Var', (30, 38))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('pediatric ACC', 'Disease', (196, 209))	('neoplasms', 'Disease', 'MESH:D009369', (168, 177))	('neoplasms', 'Disease', (168, 177))	('Li-Fraumeni or Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (69, 109))	('associated', 'Reg', (53, 63))	('Li-Fraumeni or Li-Fraumeni-like syndrome', 'Disease', (69, 109))	('neoplasms', 'Phenotype', 'HP:0002664', (168, 177))	('ACC', 'Phenotype', 'HP:0006744', (206, 209))
705	30978697	Contrarily to the majority of mutations associated with LFS that are in p53 DNA-binding domain, 80% of pediatric ACC have mutations in p53 oligomerization domain, in particular in the exon 10 of the short arm of chromosome 17 (p.R337H).	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('p53', 'Gene', (135, 138))	('p.R337H', 'Mutation', 'rs121912664', (227, 234))	('p53', 'Gene', '7157', (135, 138))	('mutations in', 'Var', (122, 134))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('short arm', 'Phenotype', 'HP:0009824', (199, 208))
707	30978697	These tumor-suppressive activity alterations have been proposed to be sufficient to induce tumorigenesis and to confer tumor growth advantages.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('alterations', 'Var', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('induce', 'PosReg', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
708	30978697	Otherwise, genomic profiles of ACC with p.R337H mutation were found to be similar to ACC with a different TP53 mutation.	('p.R337H', 'Mutation', 'rs121912664', (40, 47))	('ACC', 'Phenotype', 'HP:0006744', (31, 34))	('ACC', 'Phenotype', 'HP:0006744', (85, 88))	('p.R337H', 'Var', (40, 47))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
709	30978697	Pediatric ACT with p.R337H mutation were found to have a significantly lower expression of apoptosis-related genes when compared to non-neoplastic adrenals.	('p.R337H', 'Mutation', 'rs121912664', (19, 26))	('neoplastic adrenals', 'Phenotype', 'HP:0100631', (136, 155))	('expression', 'MPA', (77, 87))	('apoptosis-related genes', 'Gene', (91, 114))	('p.R337H', 'Var', (19, 26))	('lower', 'NegReg', (71, 76))
716	30978697	Loss of pRB induces apoptosis and the mechanisms behind this phenomena are mainly related to the action of the E2F transcription factors, the well-known targets of pRB.	('pRB', 'Gene', '5925', (8, 11))	('pRB', 'Gene', (164, 167))	('pRB', 'Gene', '5925', (164, 167))	('apoptosis', 'CPA', (20, 29))	('pRB', 'Gene', (8, 11))	('induces', 'Reg', (12, 19))	('Loss', 'Var', (0, 4))
720	30978697	The loss of pRB was suggested to be a marker of poor prognosis as it appears to be a characteristic of the more aggressive ACC.	('pRB', 'Gene', (12, 15))	('ACC', 'Phenotype', 'HP:0006744', (123, 126))	('pRB', 'Gene', '5925', (12, 15))	('loss', 'Var', (4, 8))
722	30978697	Functional studies showed that abnormal miRNA expression is a key to cancer development by abnormally regulating several cellular processes, including apoptosis.	('abnormal', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cellular processes', 'CPA', (121, 139))	('abnormally regulating', 'Reg', (91, 112))	('miRNA', 'Protein', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('apoptosis', 'CPA', (151, 160))	('cancer', 'Disease', (69, 75))
728	30978697	miRNA-205 was able to activate Bcl-2, in ACC tumor cells, leading to the activation of the intrinsic apoptosis pathway by activating caspase-9 and caspase-3.	('activation', 'PosReg', (73, 83))	('activating', 'PosReg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('caspase-3', 'Gene', '836', (147, 156))	('Bcl-2', 'Gene', (31, 36))	('Bcl-2', 'Gene', '596', (31, 36))	('miRNA-205', 'Var', (0, 9))	('tumor', 'Disease', (45, 50))	('miRNA-205', 'Chemical', '-', (0, 9))	('caspase-9', 'Gene', '842', (133, 142))	('caspase-9', 'Gene', (133, 142))	('ACC', 'Phenotype', 'HP:0006744', (41, 44))	('caspase-3', 'Gene', (147, 156))	('activate', 'PosReg', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('intrinsic apoptosis pathway', 'Pathway', (91, 118))
756	30978697	LOH in the chromosome were TP53 is harbored and TP53 mutations are the most frequent alterations observed in ACC, leading to abnormal cell cycle progression and apoptosis inhibition.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('abnormal cell cycle', 'Phenotype', 'HP:0011018', (125, 144))	('apoptosis inhibition', 'CPA', (161, 181))
757	30978697	Targeted therapies with the goal of recovering or reactivating p53 function in TP53 mutants were already developed and are currently being tested for the treatment of several tumors, other than ACC (e.g.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('p53', 'Gene', (63, 66))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('p53', 'Gene', '7157', (63, 66))	('ACC', 'Phenotype', 'HP:0006744', (194, 197))	('mutants', 'Var', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('reactivating', 'Var', (50, 62))
759	30978697	The high prevalence of alterations related to TP53 in ACC makes these tumors good candidates for TP53 modulators therapies.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TP53', 'Gene', '7157', (97, 101))	('ACC', 'Phenotype', 'HP:0006744', (54, 57))	('TP53', 'Gene', '7157', (46, 50))	('tumors', 'Disease', (70, 76))	('TP53', 'Gene', (97, 101))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('TP53', 'Gene', (46, 50))	('alterations', 'Var', (23, 34))
766	30978697	Tumor cells are not only characterized by genetic alterations leading to increased proliferation but also by a compromised apoptosis signaling, a fact that adds to the imbalance between cell death and survival, leading to tumor development, invasion and resistance to treatment.	('increased', 'PosReg', (73, 82))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('imbalance', 'Phenotype', 'HP:0002172', (168, 177))	('resistance', 'CPA', (254, 264))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('leading to', 'Reg', (211, 221))	('alterations', 'Var', (50, 61))	('apoptosis', 'MPA', (123, 132))	('tumor', 'Disease', (222, 227))	('compromised', 'NegReg', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('invasion', 'CPA', (241, 249))
786	30348224	Genomic studies indicate that mutations in defined driver genes, including zinc and ring finger 3 (ZNRF3), telomerase reverse transcriptase (TERT), protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A), ribosomal protein L22 (RPL22), telomeric repeat binding factor 2 (TERF2), cyclin E1 (CCNE1), and neurofibromin 1 (NF1), may have a major role in the etiology of ACC, and that ACC has a moderate overall mutation burden compared with other tumor types.	('cyclin E1', 'Gene', '898', (295, 304))	('telomerase reverse transcriptase', 'Gene', (107, 139))	('PRKAR1A', 'Gene', '5573', (211, 218))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('ACC', 'Gene', '104371', (396, 399))	('TERT', 'Gene', (141, 145))	('TERT', 'Gene', '7015', (141, 145))	('RPL22', 'Gene', '6146', (244, 249))	('TERF2', 'Gene', (287, 292))	('zinc and ring finger 3', 'Gene', '84133', (75, 97))	('ribosomal protein L22', 'Gene', (221, 242))	('TERF2', 'Gene', '7014', (287, 292))	('telomerase reverse transcriptase', 'Gene', '7015', (107, 139))	('RPL22', 'Gene', (244, 249))	('cyclin E1', 'Gene', (295, 304))	('CCNE1', 'Gene', (306, 311))	('telomeric repeat binding factor 2', 'Gene', '7014', (252, 285))	('telomeric repeat binding factor 2', 'Gene', (252, 285))	('NF1', 'Gene', '4763', (335, 338))	('ACC', 'Gene', (382, 385))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (459, 464))	('CCNE1', 'Gene', '898', (306, 311))	('PRKAR1A', 'Gene', (211, 218))	('neurofibromin 1', 'Gene', '4763', (318, 333))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('NF1', 'Gene', (335, 338))	('ZNRF3', 'Gene', '84133', (99, 104))	('ZNRF3', 'Gene', (99, 104))	('ACC', 'Gene', (396, 399))	('ACC', 'Gene', '104371', (382, 385))	('ribosomal protein L22', 'Gene', '6146', (221, 242))	('neurofibromin 1', 'Gene', (318, 333))
806	30348224	Treatment was discontinued following: 1) any grade 4 adverse event (AE) except for single laboratory values out of the normal range that were unrelated to study treatment, without clinical correlate, and resolved within 7 days with medical management; 2) any grade 3 AE except for: (i) transient (<=6 h) influenza-like symptoms or pyrexia controlled with medical management; (ii) fatigue, local infusion-related reaction, headache, nausea, or emesis that resolved to grade <= 1 within 24 h; (iii) single laboratory values out of the normal range that were unrelated to study treatment and without clinical correlate (excluding grade >= 3 increase in liver enzyme concentrations) that resolved to grade <= 1 within 7 days; (iv) tumor flare phenomena (local pain, irritation, or localized rash at a tumor site); (v) grade >= 3 amylase or lipase abnormality not associated with symptoms or clinical manifestations of pancreatitis; or 3) increase in Eastern Cooperative Oncology Group performance status to >=3 not resolved to <=2 by Day 14 of the following cycle.	('pyrexia', 'Phenotype', 'HP:0001945', (331, 338))	('pyrexia', 'Disease', (331, 338))	('headache', 'Phenotype', 'HP:0002315', (422, 430))	('tumor', 'Disease', 'MESH:D009369', (727, 732))	('pancreatitis', 'Disease', (914, 926))	('tumor', 'Disease', (797, 802))	('emesis', 'Phenotype', 'HP:0002013', (443, 449))	('nausea', 'Disease', (432, 438))	('pain', 'Disease', (756, 760))	('emesis', 'Disease', 'MESH:D014839', (443, 449))	('emesis', 'Disease', (443, 449))	('man', 'Species', '9606', (240, 243))	('fatigue', 'Phenotype', 'HP:0012378', (380, 387))	('increase in liver enzyme', 'Phenotype', 'HP:0002910', (638, 662))	('tumor', 'Disease', 'MESH:D009369', (797, 802))	('rash', 'Phenotype', 'HP:0000988', (787, 791))	('increase', 'PosReg', (934, 942))	('headache', 'Disease', (422, 430))	('pain', 'Phenotype', 'HP:0012531', (756, 760))	('nausea', 'Disease', 'MESH:D009325', (432, 438))	('man', 'Species', '9606', (896, 899))	('fatigue', 'Disease', 'MESH:D005221', (380, 387))	('tumor', 'Phenotype', 'HP:0002664', (727, 732))	('rash', 'Disease', (787, 791))	('Oncology', 'Phenotype', 'HP:0002664', (966, 974))	('pyrexia', 'Disease', 'MESH:D005334', (331, 338))	('tumor', 'Phenotype', 'HP:0002664', (797, 802))	('pain', 'Disease', 'MESH:D010146', (756, 760))	('man', 'Species', '9606', (363, 366))	('irritation', 'Disease', (762, 772))	('headache', 'Disease', 'MESH:D006261', (422, 430))	('pancreatitis', 'Disease', 'MESH:D010195', (914, 926))	('rash', 'Disease', 'MESH:D005076', (787, 791))	('pancreatitis', 'Phenotype', 'HP:0001733', (914, 926))	('grade >', 'Var', (814, 821))	('nausea', 'Phenotype', 'HP:0002018', (432, 438))	('tumor', 'Disease', (727, 732))	('fatigue', 'Disease', (380, 387))	('man', 'Species', '9606', (987, 990))	('irritation', 'Disease', 'MESH:D001523', (762, 772))
853	30348224	Three patients (6.0%) had an objective response, including patients with PD-L1+ and PD-L1- tumors, and all of whom had received only 1 (n = 2) or 2 (n = 1) prior lines of treatment.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('PD-L1- tumors', 'Disease', 'MESH:D010300', (84, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (59, 67))	('PD-L1- tumors', 'Disease', (84, 97))	('PD-L1+', 'Var', (73, 79))
863	30348224	Patients receiving concomitant mitotane had a higher rate of grade 3 TRAEs than those not receiving mitotane (24.0% vs 8.0%), particularly liver enzyme elevations.	('mitotane', 'Var', (31, 39))	('AEs', 'Chemical', 'MESH:C045560', (71, 74))	('mitotane', 'Chemical', 'MESH:D008939', (31, 39))	('mitotane', 'Chemical', 'MESH:D008939', (100, 108))	('Patients', 'Species', '9606', (0, 8))	('liver enzyme elevations', 'MPA', (139, 162))	('liver enzyme elevations', 'Phenotype', 'HP:0002910', (139, 162))	('grade', 'Disease', (61, 66))
893	29754632	Somatic mutations leading to overactivation of the 3',5'-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and wingless-type MMTV integration site family (WNT)/beta-catenin (CTNNB1) pathways are the main molecular mechanisms underlying adrenocortical tumorigenesis causing CS.	("3',5'-cyclic adenosine monophosphate", 'Chemical', '-', (51, 87))	('adrenocortical', 'Disease', (247, 261))	('MMTV', 'Species', '11757', (136, 140))	('CTNNB1', 'Gene', '1499', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('adrenocortical', 'Disease', 'MESH:D018268', (247, 261))	('tumor', 'Disease', (262, 267))	('mutations', 'Var', (8, 17))	('cAMP', 'Chemical', '-', (89, 93))	('CTNNB1', 'Gene', (185, 191))	('overactivation', 'PosReg', (29, 43))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('CS', 'Phenotype', 'HP:0003118', (284, 286))
894	29754632	In the pituitary gland, corticotropinomas are characterized by resistance to glucocorticoid negative feedback, dysregulation of pathways controlling cell cycle progression and overexpression of pathways that sustain overactive ACTH production and secretion.	('corticotropinomas', 'Disease', (24, 41))	('secretion', 'MPA', (247, 256))	('glucocorticoid negative', 'Phenotype', 'HP:0008163', (77, 100))	('overactive ACTH production', 'MPA', (216, 242))	('dysregulation', 'Var', (111, 124))	('pathways', 'Pathway', (194, 202))	('overexpression', 'PosReg', (176, 190))	('corticotropinomas', 'Disease', 'None', (24, 41))
901	29754632	Nuclear and cytoplasmic accumulation of the CTNN1B protein are common findings in human benign and malignant adrenocortical tumors of various types, and these lesions often display somatic mutations in the CTNNB1 gene (located on chromosome 3p22.1).	('CTNNB1', 'Gene', '1499', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('malignant adrenocortical tumors', 'Disease', 'MESH:D018268', (99, 130))	('benign', 'Disease', (88, 94))	('CTNNB1', 'Gene', (206, 212))	('malignant adrenocortical tumors', 'Disease', (99, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('CTNN1B', 'Gene', (44, 50))	('mutations', 'Var', (189, 198))	('human', 'Species', '9606', (82, 87))
902	29754632	Within cortisol-producing adenomas (CPAs), the frequency of CTNN1B mutations is around 15%, while two-thirds of nonfunctioning adenomas and one-third of adrenocortical carcinomas carry these genetic defects, which are apparently associated with a more aggressive phenotype.	('genetic defects', 'Disease', (191, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('genetic defects', 'Disease', 'MESH:D030342', (191, 206))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (153, 178))	('mutations', 'Var', (67, 76))	('adenomas', 'Disease', 'MESH:D000236', (26, 34))	('CPAs', 'Chemical', '-', (36, 40))	('adrenocortical carcinomas', 'Disease', (153, 178))	('adenomas', 'Disease', 'MESH:D000236', (127, 135))	('CTNN1B', 'Gene', (60, 66))	('adenomas', 'Disease', (26, 34))	('adenomas', 'Disease', (127, 135))	('cortisol', 'Chemical', 'MESH:D006854', (7, 15))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (153, 178))
903	29754632	Most of the patients carry a missense mutation affecting the residue S45, which prevents phosphorylation of the protein by the "destruction complex" (see below), resulting in protein accumulation and activation of its target genes, and therefore resulting in constitutive activation of the wingless-type MMTV integration site family (WNT)/CTNNB1 pathway.	('patients', 'Species', '9606', (12, 20))	('prevents', 'NegReg', (80, 88))	('CTNNB1', 'Gene', (339, 345))	('protein accumulation', 'MPA', (175, 195))	('activation', 'PosReg', (200, 210))	('MMTV', 'Species', '11757', (304, 308))	('missense mutation', 'Var', (29, 46))	('activation', 'PosReg', (272, 282))	('CTNNB1', 'Gene', '1499', (339, 345))	('phosphorylation of the protein', 'MPA', (89, 119))
904	29754632	Beyond CTNNB1 sequence mutations, CTNN1B accumulation may also be due to overactivation of the 3',5'-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, as it occurs in most adrenocortical lesions.	('adrenocortical lesions', 'Disease', (192, 214))	('cAMP', 'Chemical', '-', (133, 137))	('accumulation', 'PosReg', (41, 53))	('mutations', 'Var', (23, 32))	('overactivation', 'PosReg', (73, 87))	('CTNNB1', 'Gene', (7, 13))	("3',5'-cyclic adenosine monophosphate", 'Chemical', '-', (95, 131))	('adrenocortical lesions', 'Disease', 'MESH:C565972', (192, 214))	('CTNN1B', 'Gene', (34, 40))	('CTNNB1', 'Gene', '1499', (7, 13))
905	29754632	Germline loss-of-function mutations in the APC gene (on chromosome 5q22.2) are associated with adrenocortical adenomas or primary macronodular adrenal hyperplasia (PMAH) in patients with familial adenomatous polyposis; however, this gene does not seem to play a significant role in sporadic CS.	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (187, 217))	('CS', 'Phenotype', 'HP:0003118', (291, 293))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (143, 162))	('PMAH', 'Chemical', '-', (164, 168))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (95, 118))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (95, 118))	('macronodular adrenal hyperplasia', 'Disease', (130, 162))	('APC', 'Gene', '324', (43, 46))	('adrenocortical adenomas', 'Disease', (95, 118))	('patients', 'Species', '9606', (173, 181))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (130, 162))	('familial adenomatous polyposis', 'Disease', (187, 217))	('mutations', 'Var', (26, 35))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (196, 217))	('loss-of-function', 'NegReg', (9, 25))	('APC', 'Gene', (43, 46))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (130, 162))
908	29754632	Therefore, APC loss-of-function results in constitutive activation of the WNT/CTNNB1 pathway, in a way that is similar to that of CTNNB1 mutations.	('APC', 'Gene', (11, 14))	('CTNNB1', 'Gene', (78, 84))	('mutations', 'Var', (137, 146))	('CTNNB1', 'Gene', '1499', (130, 136))	('APC', 'Gene', '324', (11, 14))	('CTNNB1', 'Gene', '1499', (78, 84))	('loss-of-function', 'NegReg', (15, 31))	('activation', 'PosReg', (56, 66))	('CTNNB1', 'Gene', (130, 136))
909	29754632	Adrenal CS is most often caused by CPAs and one to two-thirds of these tumors bear the somatic recurrent mutation p.L206R in the PRKACA gene (on chromosome 19p13.12), encoding the catalytic subunit alpha of PKA.	('p13', 'Gene', (158, 161))	('caused', 'Reg', (25, 31))	('PRKACA', 'Gene', '5566', (129, 135))	('p13', 'Gene', '440926', (158, 161))	('p.L206R', 'Mutation', 'rs386352352', (114, 121))	('CS', 'Phenotype', 'HP:0003118', (8, 10))	('CPAs', 'Disease', (35, 39))	('p.L206R', 'Var', (114, 121))	('Adrenal CS', 'Disease', (0, 10))	('CPAs', 'Chemical', '-', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('PRKACA', 'Gene', (129, 135))
910	29754632	The functional effect of the L206R mutation is constitutive activation of the cAMP/PKA molecular pathway and therefore increased steroidogenesis, given that these mutations affect a site of the protein that is essential for its interaction with the regulatory subunits of PKA.	('cAMP', 'Chemical', '-', (78, 82))	('affect', 'Reg', (173, 179))	('cAMP/PKA molecular pathway', 'Pathway', (78, 104))	('activation', 'PosReg', (60, 70))	('steroidogenesis', 'MPA', (129, 144))	('interaction', 'Interaction', (228, 239))	('L206R', 'Mutation', 'rs386352352', (29, 34))	('L206R', 'Var', (29, 34))	('increased', 'PosReg', (119, 128))
912	29754632	In addition, germline amplification of the 19p13.2-p13.12 chromosomal region was identified in five cases of CS from four different families.	('germline', 'Var', (13, 21))	('CS', 'Phenotype', 'HP:0003118', (109, 111))	('p13', 'Gene', (45, 48))	('p13', 'Gene', (51, 54))	('p13', 'Gene', '440926', (45, 48))	('p13', 'Gene', '440926', (51, 54))
916	29754632	A genome-wide association study identified germline inactivating mutations in the phosphodiesterase 11A gene (PDE11A, 2q31.2) in four patients with CS due to iMAD, including two affected individuals from the same kindred.	('germline inactivating mutations', 'Var', (43, 74))	('phosphodiesterase 11A', 'Gene', (82, 103))	('patients', 'Species', '9606', (134, 142))	('PDE11A', 'Gene', '50940', (110, 116))	('CS', 'Phenotype', 'HP:0003118', (148, 150))	('PDE11A', 'Gene', (110, 116))	('phosphodiesterase 11A', 'Gene', '50940', (82, 103))
919	29754632	Both phosphodiesterases are highly expressed (although not exclusively) in the adrenal tissue, and the mutations found in iMAD lead to increased cAMP signaling, in a similar way than PRKACA gain-of-function and other cAMP defects identified in adrenal tumors.	('adrenal tumors', 'Disease', (244, 258))	('phosphodiesterases', 'Gene', (5, 23))	('mutations', 'Var', (103, 112))	('gain-of-function', 'PosReg', (190, 206))	('cAMP', 'Chemical', '-', (145, 149))	('iMAD', 'Gene', (122, 126))	('phosphodiesterases', 'Gene', '50940', (5, 23))	('increased', 'PosReg', (135, 144))	('adrenal tumors', 'Disease', 'MESH:D000310', (244, 258))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('PRKACA', 'Gene', (183, 189))	('cAMP', 'Chemical', '-', (217, 221))	('cAMP signaling', 'MPA', (145, 159))	('PRKACA', 'Gene', '5566', (183, 189))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))
920	29754632	Loss-of-function mutations in the armadillo repeat containing 5 gene (ARMC5) are the most common genetic cause of CS due to PMAH.	('Loss-of-function', 'NegReg', (0, 16))	('PMAH', 'Disease', (124, 128))	('armadillo repeat containing 5', 'Gene', '79798', (34, 63))	('PMAH', 'Chemical', '-', (124, 128))	('CS', 'Phenotype', 'HP:0003118', (114, 116))	('ARMC5', 'Gene', (70, 75))	('armadillo repeat containing 5', 'Gene', (34, 63))	('mutations', 'Var', (17, 26))	('ARMC5', 'Gene', '79798', (70, 75))
921	29754632	Around 26-55% patients bear ARMC5 mutations (on chromosome 16p11.2) at both the somatic and the germline levels; within the PMAH tissue, different ARMC5 mutations can be found in each nodule ARMC5 encodes a ubiquitously expressed pro-apoptotic protein, with an additional role as a regulator of steroidogenesis, as demonstrated in vitro.	('ARMC5', 'Gene', '79798', (28, 33))	('mutations', 'Var', (153, 162))	('ARMC5', 'Gene', '79798', (191, 196))	('ARMC5', 'Gene', (191, 196))	('PMAH', 'Chemical', '-', (124, 128))	('ARMC5', 'Gene', (28, 33))	('ARMC5', 'Gene', '79798', (147, 152))	('ARMC5', 'Gene', (147, 152))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (34, 43))
922	29754632	In mice, Armc5 is required for gastrulation and its knockout is lethal, while haploinsufficiency leads to late-onset CS.	('knockout', 'Var', (52, 60))	('haploinsufficiency', 'Disease', 'MESH:D058495', (78, 96))	('mice', 'Species', '10090', (3, 7))	('CS', 'Phenotype', 'HP:0003118', (117, 119))	('haploinsufficiency', 'Disease', (78, 96))	('leads to', 'Reg', (97, 105))	('Armc5', 'Gene', (9, 14))	('Armc5', 'Gene', '233912', (9, 14))
924	29754632	Patients with ARMC5 mutations have higher midnight serum cortisol, as well as higher urinary 17-hydroxycorticosteroids and free cortisol levels during the 6-day test Liddle, and their nodules are larger and more numerous, compared with other PMAH patients.	('cortisol', 'Chemical', 'MESH:D006854', (57, 65))	('midnight serum cortisol', 'MPA', (42, 65))	('higher', 'PosReg', (78, 84))	('patients', 'Species', '9606', (247, 255))	('Patients', 'Species', '9606', (0, 8))	('ARMC5', 'Gene', '79798', (14, 19))	('cortisol', 'Chemical', 'MESH:D006854', (128, 136))	('ARMC5', 'Gene', (14, 19))	('higher', 'PosReg', (35, 41))	('mutations', 'Var', (20, 29))	('PMAH', 'Chemical', '-', (242, 246))
926	29754632	Loss-of function mutations in the FH gene (1q43) cause an autosomal dominant syndrome characterized by the association of cutaneous leiomyomatosis and renal cell carcinoma.	('cutaneous leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C535516', (122, 171))	('1q43', 'Gene', (43, 47))	('cutaneous leiomyomatosis', 'Phenotype', 'HP:0007620', (122, 146))	('Loss-of function', 'NegReg', (0, 16))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (151, 171))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (58, 85))	('FH', 'Gene', '2271', (34, 36))	('mutations', 'Var', (17, 26))	('autosomal dominant syndrome', 'Disease', (58, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
928	29754632	Loss of the normal allele has been demonstrated in the PMAH tissue, supporting the causative role of FH in these lesions; however, FH mutations have not been associated to sporadic PMAH.	('associated', 'Reg', (158, 168))	('FH', 'Gene', '2271', (131, 133))	('PMAH', 'Chemical', '-', (181, 185))	('PMAH', 'Chemical', '-', (55, 59))	('FH', 'Gene', '2271', (101, 103))	('mutations', 'Var', (134, 143))	('PMAH', 'Disease', (181, 185))
929	29754632	The finding of local ACTH production and aberrant GPCR expression as stimuli driving steroidogenesis in PMAH brings attention to the role of ectopic hormone signaling in adrenal tumorigenesis.	('tumor', 'Disease', (178, 183))	('GPCR', 'Gene', (50, 54))	('aberrant', 'Var', (41, 49))	('PMAH', 'Chemical', '-', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('GPCR', 'Gene', '117196', (50, 54))	('PMAH', 'Disease', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
930	29754632	Glucose-dependent insulinotropic polypeptide (GIP)-dependent CS is a rare condition in which ectopic GIP receptor (GIPR) expression in PMAH or CPA tissue leads to hypercortisolemia in response to the physiological posprandial release of GIP by the small bowel.	('leads to', 'Reg', (154, 162))	('GIP receptor', 'Gene', '2696', (101, 113))	('hypercortisolemia', 'Disease', (163, 180))	('hypercortisolemia', 'Disease', 'None', (163, 180))	('Glucose-dependent insulinotropic polypeptide', 'Gene', '2695', (0, 44))	('GIP', 'Gene', '2695', (237, 240))	('CS', 'Phenotype', 'HP:0003118', (61, 63))	('GIP', 'Gene', '2695', (46, 49))	('GIP', 'Gene', (237, 240))	('expression', 'Var', (121, 131))	('GIP', 'Gene', (46, 49))	('GIPR', 'Gene', (115, 119))	('GIPR', 'Gene', '2696', (115, 119))	('GIP', 'Gene', '2695', (101, 104))	('Glucose-dependent insulinotropic polypeptide', 'Gene', (0, 44))	('PMAH', 'Chemical', '-', (135, 139))	('GIP', 'Gene', (101, 104))	('GIP receptor', 'Gene', (101, 113))	('ectopic', 'Var', (93, 100))	('GIP', 'Gene', '2695', (115, 118))	('GIP', 'Gene', (115, 118))	('CPA', 'Chemical', '-', (143, 146))
931	29754632	A recent study identified somatic duplications of the 19q13.32 chromosomal region, including the GIPR gene, in 3/14 patients with GIP-dependent CS.	('GIP', 'Gene', '2695', (97, 100))	('GIP', 'Gene', (130, 133))	('patients', 'Species', '9606', (116, 124))	('CS', 'Phenotype', 'HP:0003118', (144, 146))	('GIP', 'Gene', '2695', (130, 133))	('GIP', 'Gene', (97, 100))	('duplications', 'Var', (34, 46))	('GIPR', 'Gene', '2696', (97, 101))	('GIPR', 'Gene', (97, 101))
934	29754632	A germline mutation (p.F278C), in the MC2R gene (on chromosome 18p11.21), encoding the ACTH receptor MC2R, was identified in a single patient with PMAH and resulted in constitutive receptor activation in vitro.	('MC2R', 'Gene', (38, 42))	('p.F278C', 'Var', (21, 28))	('activation', 'PosReg', (190, 200))	('patient', 'Species', '9606', (134, 141))	('PMAH', 'Chemical', '-', (147, 151))	('MC2R', 'Gene', '4158', (38, 42))	('ACTH receptor', 'Gene', '4158', (87, 100))	('MC2R', 'Gene', (101, 105))	('MC2R', 'Gene', '4158', (101, 105))	('p.F278C', 'Mutation', 'rs28926182', (21, 28))	('ACTH receptor', 'Gene', (87, 100))	('constitutive receptor', 'MPA', (168, 189))
935	29754632	Two additional MC2R mutations (p.C21R and p.S247G) found in a patient with hypersensitivity to ACTH, had the same effect.	('p.S247G', 'Var', (42, 49))	('hypersensitivity', 'Disease', 'MESH:D004342', (75, 91))	('p.C21R', 'Var', (31, 37))	('patient', 'Species', '9606', (62, 69))	('p.S247G', 'Mutation', 'p.S247G', (42, 49))	('MC2R', 'Gene', (15, 19))	('MC2R', 'Gene', '4158', (15, 19))	('p.C21R', 'Mutation', 'p.C21R', (31, 37))	('hypersensitivity', 'Disease', (75, 91))
936	29754632	MC2R mutations appear to be a very rare cause of CS, if at all contributory.	('cause', 'Reg', (40, 45))	('MC2R', 'Gene', '4158', (0, 4))	('mutations', 'Var', (5, 14))	('CS', 'Phenotype', 'HP:0003118', (49, 51))	('MC2R', 'Gene', (0, 4))
937	29754632	Early postzygotic mutations in GNAS (on chromosome 20q13.32) affecting the amino acid 201 of the best-known product of GNAS, the G stimulatory protein subunit alpha, cause the McCune-Albright syndrome (MAS).	('MAS', 'Disease', (202, 205))	('affecting', 'Reg', (61, 70))	('GNAS', 'Gene', '2778', (31, 35))	('GNAS', 'Gene', (119, 123))	('MAS', 'Disease', 'MESH:D005357', (202, 205))	('amino', 'MPA', (75, 80))	('McCune-Albright syndrome', 'Disease', (176, 200))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (176, 200))	('GNAS', 'Gene', (31, 35))	('GNAS', 'Gene', '2778', (119, 123))	('cause', 'Reg', (166, 171))	('mutations', 'Var', (18, 27))
939	29754632	Such mutations cause loss of the GTPase function of the protein, resulting in constitutively active GNAS (gsp oncogene).	('GNAS', 'Gene', '2778', (100, 104))	('GNAS', 'Gene', (100, 104))	('mutations', 'Var', (5, 14))	('gsp', 'Gene', '2778', (106, 109))	('GTPase function of the protein', 'Protein', (33, 63))	('gsp', 'Gene', (106, 109))	('loss', 'NegReg', (21, 25))
942	29754632	Besides MAS, somatic mutations in GNAS codons 201 or 227 (which have the same functional effects) can also be found as somatic changes in 4-15% of CPAs.	('CPAs', 'Disease', (147, 151))	('changes', 'Reg', (127, 134))	('GNAS', 'Gene', (34, 38))	('MAS', 'Disease', (8, 11))	('MAS', 'Disease', 'MESH:D005357', (8, 11))	('GNAS', 'Gene', '2778', (34, 38))	('CPAs', 'Chemical', '-', (147, 151))	('mutations', 'Var', (21, 30))
943	29754632	The same mutations are a common finding in sporadic pituitary adenomas, (mainly somatotropinomas), although they are rarely found in corticotrotropinomas, with only three cases reported so far.	('somatotropinomas', 'Disease', (80, 96))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (52, 70))	('mutations', 'Var', (9, 18))	('somatotropinomas', 'Disease', 'MESH:D049912', (80, 96))	('pituitary adenomas', 'Disease', (52, 70))	('corticotrotropinomas', 'Disease', (133, 153))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (52, 69))	('sporadic pituitary adenomas', 'Phenotype', 'HP:0011761', (43, 70))	('pituitary adenomas', 'Disease', 'MESH:D010911', (52, 70))	('corticotrotropinomas', 'Disease', 'None', (133, 153))
947	29754632	Ninety percent of the MEN1 cases bear loss-of-function germline mutations or deletions in the MEN1 gene (on chromosome 11q13.1), encoding the tumor suppressor menin, a scaffolding protein that regulates the expression and function of proteins involved in transcriptional regulation, genome stability and cell proliferation.	('deletions', 'Var', (77, 86))	('function', 'MPA', (222, 230))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('loss-of-function', 'NegReg', (38, 54))	('tumor', 'Disease', (142, 147))	('MEN1', 'Gene', (94, 98))	('menin', 'Gene', (159, 164))	('MEN1', 'Gene', '4221', (22, 26))	('MEN1', 'Gene', '4221', (94, 98))	('MEN1', 'Gene', (22, 26))	('germline mutations', 'Var', (55, 73))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('menin', 'Gene', '4221', (159, 164))
956	29754632	Three-quarters of CNC cases are caused by loss-of-function mutations in the PRKAR1A gene (on chromosome 17q24.2), 6% are due to deletions in 17q24.2-q24.3, and a triplication of the PRKACB gene was identified as the cause of disease in a single patient, while other cases are linked to an uncharacterized defect in 2p16.	('PRKACB', 'Gene', '5567', (182, 188))	('PRKACB', 'Gene', (182, 188))	('PRKAR1A', 'Gene', '5573', (76, 83))	('CNC', 'Disease', (18, 21))	('loss-of-function', 'NegReg', (42, 58))	('mutations', 'Var', (59, 68))	('PRKAR1A', 'Gene', (76, 83))	('patient', 'Species', '9606', (245, 252))	('deletions', 'Var', (128, 137))
957	29754632	No germline or somatic PRKAR1A mutations have been identified in sporadic pituitary adenomas.	('pituitary adenoma', 'Phenotype', 'HP:0002893', (74, 91))	('PRKAR1A', 'Gene', (23, 30))	('mutations', 'Var', (31, 40))	('pituitary adenomas', 'Disease', (74, 92))	('sporadic pituitary adenomas', 'Phenotype', 'HP:0011761', (65, 92))	('PRKAR1A', 'Gene', '5573', (23, 30))	('pituitary adenomas', 'Disease', 'MESH:D010911', (74, 92))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (74, 92))
962	29754632	So far, only three cases of CD have been reported among CNC patients, all of them with frameshift PRKAR1A mutations, although the corticotropinoma was highly suspected but not fully proven in one of the patients.	('frameshift', 'Var', (87, 97))	('PRKAR1A', 'Gene', (98, 105))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (203, 211))	('CD', 'Chemical', 'MESH:D002104', (28, 30))	('mutations', 'Var', (106, 115))	('corticotropinoma', 'Disease', (130, 146))	('PRKAR1A', 'Gene', '5573', (98, 105))	('corticotropinoma', 'Disease', 'None', (130, 146))
965	29754632	Mutations in the exon 14 of the USP8 gene (15q21.2), encoding the ubiquitin-specific protease 8, have been reported in 31-60% of corticotropinomas occurring in children and adults in tumor-extracted DNA, accounting for the most common somatic gene alteration in CD.	('CD', 'Chemical', 'MESH:D002104', (262, 264))	('USP8', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('USP8', 'Gene', '9101', (32, 36))	('reported', 'Reg', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('children', 'Species', '9606', (160, 168))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (183, 188))	('corticotropinomas', 'Disease', (129, 146))	('corticotropinomas', 'Disease', 'None', (129, 146))
966	29754632	Under physiological conditions, USP8 binds and deubiquitinates target ubiquitinated proteins to prevent their proteasomal degradation.	('USP8', 'Gene', (32, 36))	('USP8', 'Gene', '9101', (32, 36))	('proteasomal degradation', 'MPA', (110, 133))	('prevent', 'NegReg', (96, 103))	('binds', 'Interaction', (37, 42))	('deubiquitinates', 'Var', (47, 62))
967	29754632	Cleavage of USP8 at a site immediately upstream to the 14-3-3 binding motif by still unknown proteases results in enhanced deubiquitinase activity from a C-terminal 40-kDa protein fragment.	('Cleavage', 'Var', (0, 8))	('USP8', 'Gene', '9101', (12, 16))	('USP8', 'Gene', (12, 16))	('enhanced', 'PosReg', (114, 122))	('deubiquitinase activity', 'MPA', (123, 146))
969	29754632	A key target protein for USP8 in corticotroph cells is the epidermal growth factor receptor (EGFR), and USP8 gain-of-function mutations are translated into continuous EGFR recycling, and therefore increased EGFR signaling, resulting in increased POMC transcription.	('gain-of-function', 'PosReg', (109, 125))	('POMC', 'Gene', (246, 250))	('cyclin', 'Gene', '5111', (174, 180))	('increased', 'PosReg', (197, 206))	('increased', 'PosReg', (236, 245))	('EGFR', 'Gene', '1956', (93, 97))	('cyclin', 'Gene', (174, 180))	('EGFR', 'Gene', (207, 211))	('mutations', 'Var', (126, 135))	('EGFR', 'Gene', (167, 171))	('epidermal growth factor receptor', 'Gene', (59, 91))	('epidermal growth factor receptor', 'Gene', '1956', (59, 91))	('USP8', 'Gene', (25, 29))	('USP8', 'Gene', (104, 108))	('USP8', 'Gene', '9101', (25, 29))	('USP8', 'Gene', '9101', (104, 108))	('EGFR', 'Gene', '1956', (207, 211))	('EGFR', 'Gene', (93, 97))	('EGFR', 'Gene', '1956', (167, 171))	('POMC', 'Gene', '5443', (246, 250))
970	29754632	Along these lines, corticotropinomas carrying USP8 mutations are usually microadenomas that strongly express POMC.	('mutations', 'Var', (51, 60))	('USP8', 'Gene', (46, 50))	('USP8', 'Gene', '9101', (46, 50))	('POMC', 'Gene', (109, 113))	('adenomas', 'Disease', 'MESH:D000236', (78, 86))	('corticotropinomas', 'Disease', (19, 36))	('adenomas', 'Disease', (78, 86))	('POMC', 'Gene', '5443', (109, 113))	('corticotropinomas', 'Disease', 'None', (19, 36))
971	29754632	Although EGFR overexpression is not a consistent finding in USP8 mutation positive tumors, in vitro studies have proven that USP8 mutants inhibit the degradation of the ligand-bound EGFR in EGF-stimulated cells.	('USP8', 'Gene', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('USP8', 'Gene', '9101', (60, 64))	('USP8', 'Gene', (60, 64))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('EGFR', 'Gene', '1956', (9, 13))	('degradation', 'MPA', (150, 161))	('EGFR', 'Gene', (9, 13))	('mutants', 'Var', (130, 137))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('inhibit', 'NegReg', (138, 145))	('USP8', 'Gene', '9101', (125, 129))
973	29754632	The frequency of USP8 mutations is higher in females in all the cohorts reported so far, but there are discrepancies among studies regarding other clinical and biochemical features.	('USP8', 'Gene', '9101', (17, 21))	('mutations', 'Var', (22, 31))	('USP8', 'Gene', (17, 21))
974	29754632	Interestingly, the frequency of USP8 mutations in a recently reported cohort of patients with Nelson's syndrome (45%), was not higher than what has been reported for CD, although such mutations were associated with lower frequency of ACTH normalization after surgery.	('ACTH normalization', 'MPA', (234, 252))	('patients', 'Species', '9606', (80, 88))	('USP8', 'Gene', (32, 36))	('CD', 'Chemical', 'MESH:D002104', (166, 168))	('USP8', 'Gene', '9101', (32, 36))	("Nelson's syndrome", 'Disease', (94, 111))	('mutations', 'Var', (37, 46))	("Nelson's syndrome", 'Phenotype', 'HP:0010891', (94, 111))	("Nelson's syndrome", 'Disease', 'MESH:D009347', (94, 111))
978	29754632	A novel missense mutation in the RASD1 gene was detected in a small allelic fraction by whole exome sequencing in corticotropinoma tissue from a young adult CD female; a coexistent hotspot USP8 mutation was identified in the same tumor.	('tumor', 'Disease', (230, 235))	('corticotropinoma tissue', 'Phenotype', 'HP:0008291', (114, 137))	('corticotropinoma', 'Disease', 'None', (114, 130))	('corticotropinoma', 'Disease', (114, 130))	('RASD1', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('USP8', 'Gene', (189, 193))	('USP8', 'Gene', '9101', (189, 193))	('CD', 'Chemical', 'MESH:D002104', (157, 159))	('missense mutation', 'Var', (8, 25))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
979	29754632	It was hypothesized that, in this genetically heterogeneous tumor, the RASD1 mutation could contribute to cell proliferation and ACTH secretion in a small subpopulation of cells.	('cell proliferation', 'CPA', (106, 124))	('ACTH secretion', 'MPA', (129, 143))	('contribute', 'Reg', (92, 102))	('mutation', 'Var', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('RASD1', 'Gene', (71, 76))	('tumor', 'Disease', (60, 65))
980	29754632	Only three CD cases have so far been associated with somatic inactivating missense TP53 mutations, including two patients with ACTH-secreting pituitary carcinomas (one heterozygous and one not specified) and one patient with an invasive corticotropinoma with high Ki-67 index and a homozygous mutation.	('invasive corticotropinoma', 'Disease', (228, 253))	('TP53', 'Gene', '7157', (83, 87))	('patient', 'Species', '9606', (113, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('ACTH-secreting pituitary carcinomas', 'Phenotype', 'HP:0008291', (127, 162))	('TP53', 'Gene', (83, 87))	('patients', 'Species', '9606', (113, 121))	('patient', 'Species', '9606', (212, 219))	('mutations', 'Var', (88, 97))	('pituitary carcinomas', 'Disease', (142, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('pituitary carcinomas', 'Phenotype', 'HP:0011763', (142, 162))	('not specified', 'Species', '32644', (189, 202))	('missense', 'Var', (74, 82))	('CD', 'Chemical', 'MESH:D002104', (11, 13))	('pituitary carcinomas', 'Disease', 'MESH:D010911', (142, 162))	('inactivating missense', 'Var', (61, 82))	('invasive corticotropinoma', 'Disease', 'MESH:D009362', (228, 253))
983	29754632	Mutations in the N3CR1 gene, encoding the glucocorticoid receptor, have been identified by direct sequencing in two cases of CD: a patient with a frameshift somatic mutation and Nelson's syndrome and a case of CD with generalized glucocorticoid resistance and a dominant-negative de novo germline mutation.	("Nelson's syndrome", 'Disease', (178, 195))	('glucocorticoid resistance', 'Phenotype', 'HP:0008163', (230, 255))	('frameshift somatic', 'Var', (146, 164))	("Nelson's syndrome", 'Phenotype', 'HP:0010891', (178, 195))	("Nelson's syndrome", 'Disease', 'MESH:D009347', (178, 195))	('mutation', 'Var', (165, 173))	('N3CR1', 'Gene', (17, 22))	('CD', 'Chemical', 'MESH:D002104', (210, 212))	('Mutations', 'Var', (0, 9))	('glucocorticoid receptor', 'Gene', '2908', (42, 65))	('patient', 'Species', '9606', (131, 138))	('CD', 'Chemical', 'MESH:D002104', (125, 127))	('glucocorticoid receptor', 'Gene', (42, 65))
984	29754632	Whole-exome sequencing of 12 corticotropinomas demonstrated an additional case with a somatic nonsense mutation.	('nonsense mutation', 'Var', (94, 111))	('corticotropinomas', 'Disease', 'None', (29, 46))	('corticotropinomas', 'Disease', (29, 46))
986	29754632	Activating mutations in the rearranged during transfection protooncogene (RET, 10q.11.2) are associated with the syndrome of multiple endocrine neoplasia type 2, an autosomal dominant entity that includes three distinctive clinical presentations: familial medullary thyroid carcinoma (MTC), MEN2A (association of MTC, pheochromocytomas, hyperparathyroidism), and MEN2B (MTC, pheochromocytomas, characteristic facies, marfanoid habitus, ocular abnormalities, musculoskeletal manifestations and generalized ganglioneuromatosis).	('mutations', 'Var', (11, 20))	('MTC', 'Phenotype', 'HP:0002865', (285, 288))	('hyperparathyroidism', 'Disease', (337, 356))	('marfanoid habitus', 'Disease', (417, 434))	('marfanoid habitus', 'Disease', 'MESH:C537724', (417, 434))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (337, 356))	('MEN2A', 'Gene', (291, 296))	('MEN2A', 'Gene', '5979', (291, 296))	('ganglioneuromatosis', 'Phenotype', 'HP:0025151', (505, 524))	('RET', 'Gene', (74, 77))	('characteristic facies', 'Phenotype', 'HP:0001999', (394, 415))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (375, 392))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (266, 283))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (256, 283))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (318, 335))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (125, 160))	('thyroid carcinoma', 'Disease', (266, 283))	('ocular abnormalities', 'Disease', (436, 456))	('neoplasia', 'Phenotype', 'HP:0002664', (144, 153))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (337, 356))	('MTC', 'Phenotype', 'HP:0002865', (370, 373))	('rearranged during transfection protooncogene', 'Gene', (28, 72))	('ocular abnormalities', 'Disease', 'MESH:D005124', (436, 456))	('MTC', 'Phenotype', 'HP:0002865', (313, 316))	('associated', 'Reg', (93, 103))	('characteristic', 'Disease', (394, 408))	('musculoskeletal manifestations', 'Disease', 'MESH:D009140', (458, 488))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (266, 283))	('ocular abnormalities', 'Phenotype', 'HP:0000478', (436, 456))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (134, 153))	('pheochromocytomas', 'Disease', 'MESH:D010673', (318, 335))	('musculoskeletal manifestations', 'Disease', (458, 488))	('ganglioneuromatosis', 'Disease', (505, 524))	('MEN2B', 'Gene', (363, 368))	('MEN2B', 'Gene', '5979', (363, 368))	('marfanoid habitus', 'Phenotype', 'HP:0001519', (417, 434))	('ganglioneuromatosis', 'Disease', 'MESH:C563519', (505, 524))	('rearranged during transfection protooncogene', 'Gene', '5979', (28, 72))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (375, 391))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (318, 334))	('pheochromocytomas', 'Disease', (375, 392))	('RET', 'Gene', '5979', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('pheochromocytomas', 'Disease', 'MESH:D010673', (375, 392))	('pheochromocytomas', 'Disease', (318, 335))	('multiple endocrine neoplasia type 2', 'Disease', (125, 160))
988	29754632	Activating mutations result in constitutive RET function and activation of pro-proliferative molecular pathways, including the RAS/RAF proto-oncogene serine/threonine-protein kinase (RAF)/mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (AKT) pathway.	('MAPK', 'Gene', (222, 226))	('mutations', 'Var', (11, 20))	('RET', 'Gene', (44, 47))	('MAPK', 'Gene', '5595;5594;5595', (222, 226))	('constitutive', 'MPA', (31, 43))	('AKT', 'Gene', '207', (304, 307))	('RAF proto-oncogene serine/threonine-protein kinase', 'Gene', (131, 181))	('RAF', 'Gene', '22882', (183, 186))	('activation', 'PosReg', (61, 71))	('RAF', 'Gene', '22882', (131, 134))	('RAF', 'Gene', (183, 186))	('RAF', 'Gene', (131, 134))	('RET', 'Gene', '5979', (44, 47))	('AKT', 'Gene', (304, 307))	('RAF proto-oncogene serine/threonine-protein kinase', 'Gene', '5894', (131, 181))	('pro-proliferative molecular pathways', 'Pathway', (75, 111))
998	29754632	This female patient carrried a frameshift CDKN1B mutation (p.K25fs) and was diagnosed with CD at the age of 46 years; loss of the normal allele was demonstrated in the tumor tissue.	('frameshift', 'Var', (31, 41))	('p.K25fs', 'Var', (59, 66))	('tumor', 'Disease', (168, 173))	('CDKN1B', 'Gene', (42, 48))	('CD', 'Chemical', 'MESH:D002104', (91, 93))	('CD', 'Chemical', 'MESH:D002104', (42, 44))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('patient', 'Species', '9606', (12, 19))	('p.K25fs', 'Mutation', 'p.K25fsX', (59, 66))	('CDKN1B', 'Gene', '1027', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
1000	29754632	Although the association of CDKN1B mutations with human corticotropinomas is rare, CDKN1B plays a crucial role in the control of corticotroph proliferation.	('CDKN1B', 'Gene', '1027', (83, 89))	('CDKN1B', 'Gene', (28, 34))	('corticotropinomas', 'Disease', (56, 73))	('corticotropinomas', 'Disease', 'None', (56, 73))	('CDKN1B', 'Gene', (83, 89))	('human', 'Species', '9606', (50, 55))	('CDKN1B', 'Gene', '1027', (28, 34))	('mutations', 'Var', (35, 44))
1004	29754632	Out of the cases with a known genetic cause, twenty one are due to germline loss-of-function mutations in genes that are known to be causative of pheo/PGL: SDHB, SDHD, SDHC and SDHA genes (SDHx genes), in nine, six, two, two and one cases, respectively, while an SDHAF2 and a MAX mutation were reported in one case each.	('SDHD', 'Gene', (162, 166))	('SDHB', 'Gene', '6390', (156, 160))	('mutations', 'Var', (93, 102))	('SDHB', 'Gene', (156, 160))	('SDHC', 'Gene', (168, 172))	('SDHA', 'Gene', '6389', (177, 181))	('SDHA', 'Gene', '6389', (263, 267))	('SDHAF2', 'Gene', (263, 269))	('SDHC', 'Gene', '6391', (168, 172))	('loss-of-function', 'NegReg', (76, 92))	('SDHAF2', 'Gene', '54949', (263, 269))	('SDHA', 'Gene', (177, 181))	('SDHD', 'Gene', '6392', (162, 166))	('SDHA', 'Gene', (263, 267))
1005	29754632	A few other cases presenting with this phenotype represent variants of classic syndromes of multiple endocrine neoplasia: three cases with RET mutations (MEN2A), two cases with MEN1 mutations (MEN1) and one with a VHL mutation (Von Hippel-Lindau disease).	('MEN2A', 'Gene', (154, 159))	('RET', 'Gene', (139, 142))	('multiple endocrine neoplasia', 'Disease', (92, 120))	('Von Hippel-Lindau disease', 'Disease', (228, 253))	('Von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (228, 253))	('MEN2A', 'Gene', '5979', (154, 159))	('neoplasia', 'Phenotype', 'HP:0002664', (111, 120))	('VHL', 'Gene', (214, 217))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (101, 120))	('MEN1', 'Gene', (193, 197))	('VHL', 'Gene', '7428', (214, 217))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (92, 120))	('MEN1', 'Gene', '4221', (193, 197))	('RET', 'Gene', '5979', (139, 142))	('MEN1', 'Gene', (177, 181))	('MEN1', 'Gene', '4221', (177, 181))	('mutations', 'Var', (143, 152))
1009	29754632	Although it is feasible that mutations in other pheo/PGL-related genes could lead to CD, this has not been demonstrated so far.	('lead to', 'Reg', (77, 84))	('CD', 'Chemical', 'MESH:D002104', (85, 87))	('mutations', 'Var', (29, 38))
1011	29754632	One-fifth of the FIPA cases are due to germline loss-of-function mutations in the AIP gene (11q13.2).	('FIPA', 'Disease', (17, 21))	('AIP', 'Gene', '9049', (82, 85))	('loss-of-function', 'NegReg', (48, 64))	('AIP', 'Gene', (82, 85))	('mutations', 'Var', (65, 74))
1012	29754632	AIP mutations are also detected in a subset of sporadic pituitary adenomas affecting young patients, and in one-third of cases of gigantism.	('patients', 'Species', '9606', (91, 99))	('pituitary adenomas', 'Disease', 'MESH:D010911', (56, 74))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (56, 74))	('pituitary adenomas', 'Disease', (56, 74))	('detected', 'Reg', (23, 31))	('AIP', 'Gene', '9049', (0, 3))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (56, 73))	('mutations', 'Var', (4, 13))	('AIP', 'Gene', (0, 3))	('sporadic pituitary adenomas', 'Phenotype', 'HP:0011761', (47, 74))
1014	29754632	Ninety-three percent of the AIP mutation positive patients have macroadenomas and the clinical phenotype is growth hormone excess in 80% of the cases.	('AIP', 'Gene', (28, 31))	('patients', 'Species', '9606', (50, 58))	('growth hormone excess', 'Phenotype', 'HP:0000845', (108, 129))	('macroadenomas', 'Disease', 'None', (64, 77))	('macroadenomas', 'Disease', (64, 77))	('mutation', 'Var', (32, 40))	('growth hormone excess', 'MPA', (108, 129))	('AIP', 'Gene', '9049', (28, 31))
1015	29754632	Only three cases of CD associated with AIP mutations have been described so far in one pediatric and two young adult patients with missense mutations (p.K103R in the pediatric case and p.R304Q in the adults), all of them with apparently sporadic presentation.	('p.R304Q', 'Mutation', 'rs104894190', (185, 192))	('p.K103R', 'Mutation', 'rs267606548', (151, 158))	('AIP', 'Gene', '9049', (39, 42))	('p.R304Q', 'Var', (185, 192))	('mutations', 'Var', (43, 52))	('AIP', 'Gene', (39, 42))	('CD', 'Chemical', 'MESH:D002104', (20, 22))	('patients', 'Species', '9606', (117, 125))	('p.K103R', 'Var', (151, 158))
1020	29754632	Nevertheless, GPR101 gene defects have not been implicated in CD as yet.	('GPR101', 'Gene', (14, 20))	('defects', 'Var', (26, 33))	('CD', 'Chemical', 'MESH:D002104', (62, 64))	('GPR101', 'Gene', '83550', (14, 20))
1022	29754632	CABLES1 stabilizes and prevents the degradation of cell cycle regulators and interacts with TP53 and TP73 to trigger apoptosis; such tumor suppressor activity is inhibited by 14-3-3 or AKT-mediated phosphorylation  CABLES1 expression is lost in a variety of human cancers, and CABLES1 gene inactivation promotes cell proliferation and survival, as well as tumor formation in vitro, and replicates the human neoplasms in mouse models.	('survival', 'CPA', (335, 343))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mouse', 'Species', '10090', (420, 425))	('CABLES1', 'Gene', '91768', (215, 222))	('neoplasms', 'Disease', (407, 416))	('TP53', 'Gene', (92, 96))	('AKT', 'Gene', '207', (185, 188))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('inactivation', 'Var', (290, 302))	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('CABLES1', 'Gene', '91768', (0, 7))	('cancers', 'Disease', (264, 271))	('cell proliferation', 'CPA', (312, 330))	('TP73', 'Gene', '7161', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('CABLES1', 'Gene', (215, 222))	('CABLES1', 'Gene', (0, 7))	('CABLES1', 'Gene', '91768', (277, 284))	('neoplasms', 'Phenotype', 'HP:0002664', (407, 416))	('TP73', 'Gene', (101, 105))	('CABLES1', 'Gene', (277, 284))	('tumor', 'Disease', (133, 138))	('promotes', 'PosReg', (303, 311))	('TP53', 'Gene', '7157', (92, 96))	('neoplasm', 'Phenotype', 'HP:0002664', (407, 415))	('human', 'Species', '9606', (401, 406))	('tumor', 'Disease', (356, 361))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('AKT', 'Gene', (185, 188))	('human', 'Species', '9606', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('neoplasms', 'Disease', 'MESH:D009369', (407, 416))
1023	29754632	We have recently identified four CD patients with loss-of-function CABLES1 missense mutations, accounting for 2% of the patients tested.	('CABLES1', 'Gene', (67, 74))	('missense mutations', 'Var', (75, 93))	('patients', 'Species', '9606', (36, 44))	('CD', 'Chemical', 'MESH:D002104', (33, 35))	('CABLES1', 'Gene', '91768', (67, 74))	('patients', 'Species', '9606', (120, 128))	('loss-of-function', 'NegReg', (50, 66))
1025	29754632	The mutations were demonstrated at the germline level in two of the patients, while only tumor-derived DNA was available in the other two cases; one of the germline mutations was demonstrated in an apparently unaffected parent.	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('patients', 'Species', '9606', (68, 76))	('mutations', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
1026	29754632	These mutations displayed reduced ability to block corticotroph cell proliferation in response to dexamethasone stimulation in vitro.	('response to dexamethasone stimulation', 'MPA', (86, 123))	('dexamethasone', 'Chemical', 'MESH:D003907', (98, 111))	('block', 'NegReg', (45, 50))	('mutations', 'Var', (6, 15))	('corticotroph cell proliferation', 'CPA', (51, 82))
1028	29754632	Given its function, CABLES1 could provide a link between two of the main molecular mechanisms disrupted in corticotropinomas: dysfunction of the CDK/cyclin-dependent cell cycle regulation and EGFR activation of the epidermal growth factor receptor (EGFR) pathway, which uses AKT1 as one of its main effectors.	('AKT1', 'Gene', '207', (275, 279))	('epidermal growth factor receptor', 'Gene', '1956', (215, 247))	('CD', 'Chemical', 'MESH:D002104', (145, 147))	('cyclin', 'Gene', (149, 155))	('corticotropinomas', 'Disease', 'None', (107, 124))	('corticotropinomas', 'Disease', (107, 124))	('dysfunction', 'Var', (126, 137))	('activation', 'PosReg', (197, 207))	('AKT1', 'Gene', (275, 279))	('EGFR', 'Gene', '1956', (249, 253))	('EGFR', 'Gene', (249, 253))	('CABLES1', 'Gene', '91768', (20, 27))	('CABLES1', 'Gene', (20, 27))	('cyclin', 'Gene', '5111', (149, 155))	('epidermal growth factor receptor', 'Gene', (215, 247))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (192, 196))
1030	29754632	This syndrome is caused by loss-of-function mutations in the DICER1 gene (14q32.13), and has autosomal dominant presentation, with very low penetrance.	('loss-of-function', 'NegReg', (27, 43))	('mutations', 'Var', (44, 53))	('DICER1', 'Gene', (61, 67))	('DICER1', 'Gene', '23405', (61, 67))
1031	29754632	Eighty percent of the mutations are inherited and 20% present de novo and only one-third of the mutation carriers have a known familial history of DICER1-related tumours.	('tumours', 'Disease', 'MESH:D009369', (162, 169))	('DICER1', 'Gene', (147, 153))	('DICER1', 'Gene', '23405', (147, 153))	('tumours', 'Disease', (162, 169))	('mutations', 'Var', (22, 31))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))
1033	29754632	Somatic DICER1 loss-of-function variants have been reported in DICER1-related tumors, most of them affecting the RNase IIIb catalytic domain, in the presence or absence of germline mutations.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('affecting', 'Reg', (99, 108))	('DICER1', 'Gene', (63, 69))	('DICER1', 'Gene', '23405', (63, 69))	('RNase IIIb catalytic domain', 'MPA', (113, 140))	('DICER1', 'Gene', (8, 14))	('DICER1', 'Gene', '23405', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('variants', 'Var', (32, 40))	('loss-of-function', 'NegReg', (15, 31))
1036	29754632	Somatic DICER1 mutations were detected in seven cases, and two cases displayed LOH in the tumor, accounting for a total of nine patients with somatic alterations; seven of these cases were also positive for germline mutations.	('mutations', 'Var', (15, 24))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('DICER1', 'Gene', (8, 14))	('DICER1', 'Gene', '23405', (8, 14))	('detected', 'Reg', (30, 38))	('patients', 'Species', '9606', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
1042	29754632	This syndrome is due to loss-of-function mutations in either the TSC1 (9q34.13) or the TSC2 (16p13.3) gene, whose protein products (hamartin and tuberin) act as negative regulators of the mammalian target of rapamycin complex1 (mTORC1), therefore inhibiting cell growth.	('mutations', 'Var', (41, 50))	('tuberin', 'Gene', (145, 152))	('mTORC1', 'Gene', (228, 234))	('TSC2', 'Gene', '7249', (87, 91))	('loss-of-function', 'NegReg', (24, 40))	('TSC2', 'Gene', (87, 91))	('inhibiting', 'NegReg', (247, 257))	('TSC1', 'Gene', '7248', (65, 69))	('hamartin', 'Gene', '7248', (132, 140))	('tuberin', 'Gene', '7249', (145, 152))	('p13', 'Gene', (95, 98))	('hamartin', 'Gene', (132, 140))	('mTORC1', 'Gene', '382056', (228, 234))	('TSC1', 'Gene', (65, 69))	('mammalian', 'Species', '9606', (188, 197))	('p13', 'Gene', '440926', (95, 98))	('cell growth', 'CPA', (258, 269))
1043	29754632	Pituitary adenomas are not a common feature of the tuberous sclerosis complex, but CD has been described in two of such patients so far: a pediatric patient with a TSC2 mutation and a young adult who was not genetically tested; both patients presented with other coexistent manifestations of TSC.	('CD', 'Chemical', 'MESH:D002104', (83, 85))	('mutation', 'Var', (169, 177))	('tuberous sclerosis', 'Disease', (51, 69))	('TSC2', 'Gene', (164, 168))	('patient', 'Species', '9606', (233, 240))	('TSC', 'Gene', (164, 167))	('TSC', 'Gene', '7248', (164, 167))	('patient', 'Species', '9606', (120, 127))	('Pituitary adenomas', 'Disease', (0, 18))	('TSC', 'Gene', (292, 295))	('TSC', 'Gene', '7248', (292, 295))	('Pituitary adenomas', 'Phenotype', 'HP:0002893', (0, 18))	('patients', 'Species', '9606', (120, 128))	('patient', 'Species', '9606', (149, 156))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (51, 69))	('patients', 'Species', '9606', (233, 241))	('Pituitary adenomas', 'Disease', 'MESH:D010911', (0, 18))	('TSC2', 'Gene', '7249', (164, 168))
1044	29754632	The clinical association of adrenal hypoplasia with glucocorticoid and mineralocorticoid deficiency and hypogonadotropic hypogonadism is due to loss of function mutations in the DAX1 gene (Xp21.2), encoding an orphan nuclear receptor.	('glucocorticoid and mineralocorticoid deficiency', 'Phenotype', 'HP:0008163', (52, 99))	('mineralocorticoid deficiency', 'Phenotype', 'HP:0004319', (71, 99))	('mineralocorticoid deficiency', 'Disease', (71, 99))	('mineralocorticoid deficiency', 'Disease', 'MESH:C567596', (71, 99))	('DAX1', 'Gene', '190', (178, 182))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (28, 46))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (28, 46))	('adrenal hypoplasia', 'Disease', (28, 46))	('DAX1', 'Gene', (178, 182))	('hypogonadotropic hypogonadism', 'Disease', (104, 133))	('hypogonadotropic hypogonadism', 'Disease', 'MESH:D007006', (104, 133))	('mutations', 'Var', (161, 170))	('hypogonadotropic hypogonadism', 'Phenotype', 'HP:0000044', (104, 133))	('hypogonadism', 'Phenotype', 'HP:0000135', (121, 133))
1045	29754632	A single case of a corticotropinoma associated with a germline frameshift DAX1 mutation has been described.	('frameshift', 'Var', (63, 73))	('DAX1', 'Gene', (74, 78))	('corticotropinoma', 'Disease', (19, 35))	('corticotropinoma', 'Disease', 'None', (19, 35))	('DAX1', 'Gene', '190', (74, 78))	('associated', 'Reg', (36, 46))
1054	29754632	Somatic gain-of-function mutations in the USP8 gene constitute the most common genetic defect in corticotropinomas.	('mutations', 'Var', (25, 34))	('genetic defect in corticotropinomas', 'Disease', 'MESH:D030342', (79, 114))	('gain-of-function', 'PosReg', (8, 24))	('genetic defect in corticotropinomas', 'Disease', (79, 114))	('USP8', 'Gene', (42, 46))	('USP8', 'Gene', '9101', (42, 46))
1082	29225829	Furthermore, Ki67, the proliferation marker, has raised attention for its use in the differential diagnosis of adrenal tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('adrenal tumors', 'Disease', (111, 125))	('Ki67', 'Var', (13, 17))	('Ki67', 'Chemical', '-', (13, 17))	('adrenal tumors', 'Disease', 'MESH:D000310', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
1084	29225829	In addition, Ki67 is the most useful prognostic marker in both localized and advanced ACC 7.	('Ki67', 'Var', (13, 17))	('Ki67', 'Chemical', '-', (13, 17))	('localized', 'Disease', (63, 72))	('ACC', 'Phenotype', 'HP:0006744', (86, 89))	('ACC 7', 'Disease', (86, 91))
1116	26452132	Despite these challenges two delivery systems have reached the clinic and are currently under assessment in cancer clinical trials using liposome formulated miR-34a for liver cancer and miR-16 packaged in genetically modified bacterial minicell particles called EnGeneIc Delivery Vehicles (EDVs) for mesothelioma.	('miR-34a', 'Var', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('clinical', 'Species', '191496', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('mesothelioma', 'Disease', (300, 312))	('miR-16', 'Gene', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('liver cancer', 'Phenotype', 'HP:0002896', (169, 181))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('miR-16', 'Gene', '51573', (186, 192))	('liver cancer', 'Disease', 'MESH:D006528', (169, 181))	('mesothelioma', 'Disease', 'MESH:D008654', (300, 312))	('EDVs', 'Chemical', '-', (290, 294))	('cancer', 'Disease', (108, 114))	('liver cancer', 'Disease', (169, 181))
1118	26452132	We demonstrate that miR-7 therapy leads to repression of multiple genes involved in the pathogenesis of ACC, including Raf-1 proto-oncogene serine/threonine kinase (RAF1), mechanistic target of rapamycin (MTOR) and cyclin dependent kinase 1 (CDK1).	('ACC', 'Disease', (104, 107))	('CDK1', 'Gene', (242, 246))	('repression', 'NegReg', (43, 53))	('miR-7', 'Var', (20, 25))	('cyclin dependent kinase 1', 'Gene', (215, 240))	('mechanistic target of rapamycin', 'Gene', (172, 203))	('RAF1', 'Gene', (165, 169))	('cyclin dependent kinase 1', 'Gene', '983', (215, 240))	('Raf-1 proto-oncogene serine/threonine kinase', 'Gene', (119, 163))	('mechanistic target of rapamycin', 'Gene', '2475', (172, 203))	('Raf-1 proto-oncogene serine/threonine kinase', 'Gene', '5894', (119, 163))	('ACC', 'Phenotype', 'HP:0006744', (104, 107))
1125	26452132	H295R cells are hormone producing (functional) and the best characterized in study of the ACC, while SW-13 are non-hormone producing and while derived from an adrenal surgical sample it is not clear whether they arose from a primary ACC or metastasis.	('hormone producing', 'MPA', (16, 33))	('H295R', 'Var', (0, 5))	('SW-13', 'CellLine', 'CVCL:0542', (101, 106))	('ACC', 'Phenotype', 'HP:0006744', (233, 236))	('ACC', 'Phenotype', 'HP:0006744', (90, 93))
1134	26452132	Reduced expression of RAF1, EGFR and MTOR protein by miR-7 was detected by Western blotting in H295R cells (Figure 3C).	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('Reduced', 'NegReg', (0, 7))	('RAF1', 'Protein', (22, 26))	('MTOR', 'Protein', (37, 41))	('expression', 'MPA', (8, 18))	('miR-7', 'Var', (53, 58))
1138	26452132	Taken together, these results indicate miR-7 acts as a tumor suppressor in ACC by affecting multiple molecular targets, involved in the mTOR and MAPK signalling pathways.	('affecting', 'Reg', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('ACC', 'Disease', (75, 78))	('mTOR', 'Gene', (136, 140))	('mTOR', 'Gene', '2475', (136, 140))	('miR-7', 'Var', (39, 44))
1142	26452132	After 17 days, ACC tumor volume had increased by over two fold in the miR-NC treated group and remained unchanged in the miR-7 treated group (Figure 4B).	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('ACC', 'Phenotype', 'HP:0006744', (15, 18))	('miR-NC', 'Var', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('increased', 'PosReg', (36, 45))	('tumor', 'Disease', (19, 24))
1146	26452132	Systemic delivery of ten doses of miR-7 in this xenograft model showed significant tumor reduction in the miR-7 group vs. miR-NC group at the end of the treatment period (Figure 4E).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR-7', 'Var', (106, 111))	('tumor', 'Disease', (83, 88))	('reduction', 'NegReg', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
1147	26452132	Taken together, we have demonstrated that systemic targeted miR-7 replacement using a nanoparticle delivery system inhibits ACC growth in both cell line and patient-derived xenografts.	('patient', 'Species', '9606', (157, 164))	('replacement', 'Var', (66, 77))	('inhibits', 'NegReg', (115, 123))	('ACC growth', 'CPA', (124, 134))	('miR-7', 'Gene', (60, 65))	('ACC', 'Phenotype', 'HP:0006744', (124, 127))
1148	26452132	To assess how miR-7 replacement reduces ACC xenograft growth, we first confirmed that the EDVs delivered miR-7 to the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('replacement', 'Var', (20, 31))	('ACC', 'Phenotype', 'HP:0006744', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('reduces', 'NegReg', (32, 39))	('tumor', 'Disease', (118, 123))	('ACC xenograft growth', 'CPA', (40, 60))	('EDVs', 'Chemical', '-', (90, 94))
1152	26452132	Histopathology showed similar tumor morphology between the miR-7 (Figure 5J) and miR-NC treated groups (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('miR-7', 'Var', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (30, 35))
1161	26452132	For the molecular endpoints reduced in the xenografts (RAF1, MTOR and CDK1), no significant difference could be seen in the liver, lung or kidney of mice treated with miR-7 compared to miR-NC (Figure 5F, 5G, 5H).	('mice', 'Species', '10090', (149, 153))	('miR-7', 'Var', (167, 172))	('CDK1', 'Gene', (70, 74))
1167	26452132	This study highlights the advantage of miRNA replacement over other RNA therapies such as short interfering RNAs in that miRNAs can target multiple cellular pathways as demonstrated by the observation that miR-7 therapy down-regulates both the mTOR and MAPK pathways.	('mTOR', 'Gene', (244, 248))	('down-regulates', 'NegReg', (220, 234))	('miR-7', 'Var', (206, 211))	('mTOR', 'Gene', '2475', (244, 248))	('MAPK pathways', 'Pathway', (253, 266))
1170	26452132	The MAPK and mTOR pathways are documented targets in ACC and with the added benefit of CDK1 knockdown we have seen with miR-7 in vivo therapy, this treatment offers the potential to improve ACC outcomes.	('ACC', 'Phenotype', 'HP:0006744', (190, 193))	('knockdown', 'Var', (92, 101))	('improve', 'PosReg', (182, 189))	('ACC', 'Disease', (190, 193))	('ACC', 'Phenotype', 'HP:0006744', (53, 56))	('mTOR', 'Gene', (13, 17))	('mTOR', 'Gene', '2475', (13, 17))	('CDK1', 'Gene', (87, 91))	('MAPK', 'Pathway', (4, 8))
1171	26452132	Our finding that miR-7 reduces xenograft tumor growth in both cell lines and patient derived cells is also of great interest.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('miR-7', 'Var', (17, 22))	('reduces', 'NegReg', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('patient', 'Species', '9606', (77, 84))
1181	26452132	The finding that miR-7 can induce G1 cell cycle arrest has also been seen in hepatocellular carcinoma and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colorectal cancer', 'Disease', (106, 123))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (37, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('miR-7', 'Var', (17, 22))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (77, 101))	('G1 cell cycle arrest', 'CPA', (34, 54))	('hepatocellular carcinoma', 'Disease', (77, 101))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (77, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))
1188	26452132	The cause for these different results are not clear, however it may be possible that EGFR repression is achieved at higher levels of miR-7 delivery in vitro with Lipofectamine transfections compared to the nanoparticle delivery in vivo.	('Lipofectamine', 'Chemical', 'MESH:C086724', (162, 175))	('EGFR', 'Gene', (85, 89))	('transfections', 'Var', (176, 189))	('EGFR', 'Gene', '1956', (85, 89))
1189	26452132	A further explanation could be due to miR-7 reducing but not abolishing the expression of its targets, that a considerable reduction in EGFR expression was not achieved in vivo in the context of an established adrenal cancer xenograft with strong expression of EGFR.	('reducing', 'NegReg', (44, 52))	('adrenal cancer', 'Disease', (210, 224))	('EGFR', 'Gene', '1956', (261, 265))	('adrenal cancer', 'Disease', 'MESH:D000310', (210, 224))	('miR-7', 'Var', (38, 43))	('EGFR', 'Gene', (261, 265))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
1195	26452132	The effect of miRNA replacement to improve response rates has been shown using miR-34a in lung cancer, with increased survival times seen in mouse xenograft models of lung cancer treated with combined miRNA, siRNA and Cisplatin therapy.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('miR-34a', 'Var', (79, 86))	('lung cancer', 'Disease', (167, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('response', 'MPA', (43, 51))	('Cisplatin', 'Chemical', 'MESH:D002945', (218, 227))	('increased', 'PosReg', (108, 117))	('lung cancer', 'Disease', (90, 101))	('mouse', 'Species', '10090', (141, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('improve', 'PosReg', (35, 42))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
1230	26452132	H295R cells (1 x 107 cells in 100 mul serum free DMEM/F12K medium) with 100 mul BD Matrigel basement membrane matrix-growth factor reduced, phenol red free (BD Biosciences), which contains less than 0.5 ng/ml of epidermal growth factor, were inoculated subcutaneously into the left flank of each nude mouse.	('epidermal growth factor', 'Gene', (212, 235))	('epidermal growth factor', 'Gene', '1950', (212, 235))	('DMEM', 'Chemical', '-', (49, 53))	('phenol red', 'Chemical', 'MESH:D010637', (140, 150))	('mouse', 'Species', '10090', (301, 306))	('F12K', 'SUBSTITUTION', 'None', (54, 58))	('F12K', 'Var', (54, 58))
1232	26452132	Mice were randomized to six mice per group to receive a control: scrambled miRNA sequences (EGFREDVTMmiR-NC) or treatment: miR-7 (EGFREDVTMmiR-7) when tumors reached ~100 mm3.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('mice', 'Species', '10090', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('miR-7', 'Var', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('EGFR', 'Gene', '1956', (92, 96))	('Mice', 'Species', '10090', (0, 4))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))
1248	19849700	Aberrant expression of G protein-coupled receptors (GPCRs) has been identified as the main molecular mechanism that underlies the cause of MMAD in the majority of the cases.	('cause', 'Reg', (130, 135))	('Aberrant', 'Var', (0, 8))	('MMAD', 'Disease', (139, 143))	('GPCR', 'Gene', '441931', (52, 56))	('GPCR', 'Gene', (52, 56))	('G protein-coupled receptors', 'Protein', (23, 50))
1249	19849700	Somatic mutations of the GNAS gene are present in patients with McCune-Albright syndrome (MAS) and CS due to BAH; in addition, a number of patients with MMAD were found to harbor GNAS mutations in their adrenocortical tissue.	('GNAS', 'Gene', '2778', (179, 183))	('CS', 'Phenotype', 'HP:0003118', (99, 101))	('adrenocortical', 'Disease', (203, 217))	('MMAD', 'Disease', (153, 157))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (139, 147))	('mutations', 'Var', (184, 193))	('GNAS', 'Gene', (179, 183))	('MAS', 'Disease', 'MESH:D005357', (90, 93))	('MAS', 'Disease', (90, 93))	('adrenocortical', 'Disease', 'MESH:D018268', (203, 217))	('GNAS', 'Gene', (25, 29))	('BAH', 'Chemical', '-', (109, 112))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (64, 88))	('McCune-Albright syndrome', 'Disease', (64, 88))	('GNAS', 'Gene', '2778', (25, 29))
1250	19849700	In these cases, aberrant GPCR expression may be due to activation of the protein kinase A (PKA) signaling pathway by increased cAMP levels; in most patients with MMAD the underlying cause of this phenomenon remains a mystery, as sated above.	('aberrant', 'Var', (16, 24))	('patients', 'Species', '9606', (148, 156))	('increased', 'PosReg', (117, 126))	('cAMP', 'Chemical', 'MESH:D000242', (127, 131))	('GPCR', 'Gene', (25, 29))	('GPCR', 'Gene', '441931', (25, 29))	('cAMP levels', 'MPA', (127, 138))	('activation', 'PosReg', (55, 65))
1256	19849700	Consequently, microRNAs have been implicated in the pathogenesis or progression of several diseases, including many types of cancer, where they can act as tumor suppressors or oncogenes.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Disease', (155, 160))	('implicated', 'Reg', (34, 44))	('cancer', 'Disease', (125, 131))	('microRNAs', 'Var', (14, 23))
1274	19849700	HEK293 cells in 6-well plates were transfected using Fugene6 (Roche, Penzberg, Germany).	('Fugene6', 'Var', (53, 60))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('transfected', 'Var', (35, 46))
1299	19849700	In our previous study HIF1A was found over-expressed (3.68-fold); our new finding, that miR-210 is also over-expressed in MMAD tissues, is consistent with the cDNA expression and other data such as fumarate hydratase (FH) mutations and adrenocortical tumors and the hypothesis that activation of the hypoxia pathway may be involved in MMAD pathogenesis.	('HIF1A', 'Gene', '3091', (22, 27))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (236, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('over-expressed', 'PosReg', (104, 118))	('miR-210', 'Gene', (88, 95))	('adrenocortical tumors', 'Disease', (236, 257))	('FH', 'Gene', '2271', (218, 220))	('hypoxia', 'Disease', 'MESH:D000860', (300, 307))	('mutations', 'Var', (222, 231))	('MMAD', 'Disease', (335, 339))	('miR-210', 'Gene', '406992', (88, 95))	('hypoxia', 'Disease', (300, 307))	('fumarate hydratase', 'Gene', '2271', (198, 216))	('HIF1A', 'Gene', (22, 27))	('fumarate hydratase', 'Gene', (198, 216))
1300	19849700	Studies in a renal carcinoma cell line showed that inactivating mutations in the VHL gene had as a result the suppression of HIF degradation and the induction of hypoxia and miR-210 upregulation.	('HIF degradation', 'Disease', (125, 140))	('suppression', 'NegReg', (110, 121))	('VHL', 'Gene', (81, 84))	('renal carcinoma', 'Disease', 'MESH:C538614', (13, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('inactivating mutations', 'Var', (51, 73))	('VHL', 'Gene', '7428', (81, 84))	('renal carcinoma', 'Disease', (13, 28))	('hypoxia', 'Disease', 'MESH:D000860', (162, 169))	('miR-210', 'Gene', (174, 181))	('miR-210', 'Gene', '406992', (174, 181))	('renal carcinoma', 'Phenotype', 'HP:0005584', (13, 28))	('HIF degradation', 'Disease', 'MESH:D055959', (125, 140))	('upregulation', 'PosReg', (182, 194))	('hypoxia', 'Disease', (162, 169))
1310	19849700	It has been shown that MATR3 is the main substrate of PKA after activation of NMDA (N-methyl-D-aspartate) receptors and that PKA mediated phosphorylation leads to the degradation of MATR3 in cerebellar neurons in culture inducing neuronal death.	('NMDA', 'Protein', (78, 82))	('phosphorylation', 'Var', (138, 153))	('neuronal death', 'Disease', (230, 244))	('MATR3', 'Gene', (182, 187))	('rat', 'Species', '10116', (46, 49))	('MATR3', 'Gene', '9782', (182, 187))	('neuronal death', 'Disease', 'MESH:D009410', (230, 244))	('MATR3', 'Gene', (23, 28))	('inducing', 'Reg', (221, 229))	('MATR3', 'Gene', '9782', (23, 28))	('degradation', 'MPA', (167, 178))
1316	18786438	High frequency of loss of heterozygosity at 11p15 and IGF2 overexpression is not associated with clinical outcome in childhood adrenocortical tumors positive for the R337H TP53 mutation A germline TP53 R337H mutation is present in childhood adrenocortical tumors (ACT) from southern Brazil.	('child', 'Species', '9606', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (127, 148))	('R337H', 'Var', (166, 171))	('R337H', 'Mutation', 'rs121912664', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('childhood adrenocortical tumors', 'Disease', 'MESH:D018268', (231, 262))	('TP53', 'Gene', (197, 201))	('IGF2', 'Gene', '3481', (54, 58))	('childhood adrenocortical tumors', 'Disease', 'MESH:D018268', (117, 148))	('TP53', 'Gene', (172, 176))	('p15', 'Gene', (46, 49))	('child', 'Species', '9606', (117, 122))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (241, 262))	('childhood adrenocortical tumors', 'Disease', (231, 262))	('TP53', 'Gene', '7157', (197, 201))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('p15', 'Gene', '1030', (46, 49))	('childhood adrenocortical tumors', 'Disease', (117, 148))	('TP53', 'Gene', '7157', (172, 176))	('R337H', 'Mutation', 'rs121912664', (202, 207))	('IGF2', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))
1318	18786438	This study was designed to assess whether alterations of the 11p15 region exist in childhood ACT, accounting for IGF2 overexpression in these tumours, and how they are related to clinical outcome.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('tumours', 'Disease', (142, 149))	('overexpression', 'PosReg', (118, 132))	('alterations', 'Var', (42, 53))	('p15', 'Gene', (63, 66))	('p15', 'Gene', '1030', (63, 66))	('IGF2', 'Gene', (113, 117))	('related', 'Reg', (168, 175))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('child', 'Species', '9606', (83, 88))
1321	18786438	In contrast to the single case of paternal LOH, IGF2 was overexpressed in tumors with maternal allele loss.	('IGF2', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('maternal allele loss', 'Var', (86, 106))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('overexpressed', 'PosReg', (57, 70))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
1331	18786438	The possibility of abnormal fetal zone cell survival followed by proliferation is likely to occur whenever TP53 is non-functional, which is the case in more than 50% of the cases of sporadic ACT or linked to the Li-Fraumeni syndrome.	('proliferation', 'CPA', (65, 78))	('Li-Fraumeni syndrome', 'Disease', (212, 232))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('linked', 'Reg', (198, 204))	('non-functional', 'Var', (115, 129))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (212, 232))
1332	18786438	In southern Brazil, where the incidence of childhood ACT is about ten to fifteen times higher than in the rest of the world, almost all tumors present the germline TP53 R337H mutation, with loss of the wild type allele in most of the cases.	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Disease', (136, 142))	('TP53', 'Gene', (164, 168))	('TP53', 'Gene', '7157', (164, 168))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('child', 'Species', '9606', (43, 48))	('R337H', 'Var', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('R337H', 'Mutation', 'rs121912664', (169, 174))
1334	18786438	In addition, other factors may play an important role in the pathogenesis of ACT, including an increased copy number and expression of transcription factor Steroidogenic Factor 1 (SF-1), loss of the putative protective role of the alpha inhibin gene (INHA) and increased levels of the IGF2 growth factor.	('levels', 'MPA', (271, 277))	('copy', 'Var', (105, 109))	('increased', 'PosReg', (261, 270))	('loss', 'NegReg', (187, 191))	('expression', 'MPA', (121, 131))	('Steroidogenic Factor 1 (SF-1', 'Gene', '7536', (156, 184))	('INHA', 'Gene', '3623', (251, 255))	('ACT', 'Disease', (77, 80))	('INHA', 'Gene', (251, 255))	('increased', 'PosReg', (95, 104))
1341	18786438	Importantly, a defect of imprinting of the 11p15 region causes the Beckwith-Wiedemann syndrome, which manifests as a syndrome of somatic overgrowth, congenital malformations and tumor (including adrenocortical cancer) predisposition.	('adrenocortical cancer', 'Disease', 'MESH:D000306', (195, 216))	('Beckwith-Wiedemann syndrome', 'Disease', (67, 94))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('overgrowth', 'Phenotype', 'HP:0001548', (137, 147))	('defect', 'Var', (15, 21))	('p15', 'Gene', (45, 48))	('adrenocortical cancer', 'Disease', (195, 216))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (67, 94))	('causes', 'Reg', (56, 62))	('p15', 'Gene', '1030', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('congenital malformations and tumor', 'Disease', 'MESH:D000013', (149, 183))
1344	18786438	These data suggest that alterations in the 11p15 imprinted region exist in childhood ACT positive for the R337H TP53 mutation and prompted us to analyze this genomic region and to correlate our findings to clinical and pathological data.	('R337H', 'Mutation', 'rs121912664', (106, 111))	('R337H', 'Var', (106, 111))	('positive', 'Reg', (89, 97))	('child', 'Species', '9606', (75, 80))	('p15', 'Gene', (45, 48))	('p15', 'Gene', '1030', (45, 48))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (112, 116))
1352	18786438	The presence of the TP53 R337H mutation was evaluated by PCR-RFLP analysis, as previously described.	('R337H', 'Mutation', 'rs121912664', (25, 30))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (20, 24))	('R337H', 'Var', (25, 30))
1353	18786438	The minisatellite markers D11S922, D11S4046, Tyrosine Hydroxylase (TH) and D11S1318 (Fig.	('D11S1318', 'Var', (75, 83))	('D11S922', 'Var', (26, 33))	('D11S4046', 'Var', (35, 43))	('Tyrosine Hydroxylase', 'Gene', '7054', (45, 65))	('Tyrosine Hydroxylase', 'Gene', (45, 65))
1365	18786438	Methylation analysis in this tumor sample (Fig.	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))
1367	18786438	In one single case (patient 12), the LOH analysis was inconclusive due to the lack of peripheral blood and maternal samples (results indicated either a complete loss of the paternal allele, or homozygosity at all loci; Table 3).	('patient', 'Species', '9606', (20, 27))	('homozygosity', 'Var', (193, 205))	('loss', 'NegReg', (161, 165))
1368	18786438	Methylation analysis (Figure 1B, C) showed very strong hypomethylation at the sixth CTCF binding site (2.8% methylation) and hypermethylation at IC2 (60.8% methylation) in tumor DNA of patient 12, indicative of the potential loss or aberrant methylation of the paternal allele.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('CTCF', 'Gene', '10664', (84, 88))	('hypermethylation', 'Var', (125, 141))	('tumor', 'Disease', (172, 177))	('patient', 'Species', '9606', (185, 192))	('IC2', 'Gene', (145, 148))	('hypomethylation', 'MPA', (55, 70))	('CTCF', 'Gene', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
1370	18786438	In the present analysis of 12 childhood ACT (4 adenomas and 8 carcinomas) patients presenting with the R337H TP53 germline mutation and TP53 LOH in the tumor, all of them showed LOH for microsatellite markers located in 11p15 at both sides of the IGF2 gene.	('R337H', 'Var', (103, 108))	('carcinomas', 'Disease', (62, 72))	('R337H', 'Mutation', 'rs121912664', (103, 108))	('adenomas', 'Disease', 'MESH:D000236', (47, 55))	('adenomas', 'Disease', (47, 55))	('TP53', 'Gene', '7157', (136, 140))	('tumor', 'Disease', (152, 157))	('TP53', 'Gene', '7157', (109, 113))	('IGF2', 'Gene', (247, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('p15', 'Gene', (222, 225))	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('carcinomas', 'Disease', 'MESH:D002277', (62, 72))	('patients', 'Species', '9606', (74, 82))	('child', 'Species', '9606', (30, 35))	('TP53', 'Gene', (136, 140))	('p15', 'Gene', '1030', (222, 225))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('TP53', 'Gene', (109, 113))
1375	18786438	on a series of only 4 cases, only one of which presented a germline TP53 mutation.	('mutation', 'Var', (73, 81))	('TP53', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (68, 72))
1376	18786438	The very high incidence of 11p15 LOH in our series could be linked to genomic instability in these ACT determined by the TP53 mutation, and possibly influenced by exposure to yet unknown environmental factors.	('p15', 'Gene', '1030', (29, 32))	('TP53', 'Gene', '7157', (121, 125))	('mutation', 'Var', (126, 134))	('TP53', 'Gene', (121, 125))	('p15', 'Gene', (29, 32))
1378	18786438	It is then possible that altered expression of other genes in 11p15 may synergize with elevated IGF2 levels to confer growth advantage to adrenocortical cell clones presenting 11p15 LOH.	('elevated IGF2', 'Phenotype', 'HP:0030269', (87, 100))	('p15', 'Gene', (64, 67))	('LOH', 'Var', (182, 185))	('altered', 'Var', (25, 32))	('p15', 'Gene', '1030', (64, 67))	('growth advantage', 'CPA', (118, 134))	('p15', 'Gene', (178, 181))	('p15', 'Gene', '1030', (178, 181))	('adrenocortical', 'Disease', (138, 152))	('adrenocortical', 'Disease', 'MESH:D018268', (138, 152))
1379	18786438	In particular, the role of a diminished expression of the Cdk inhibitor p57Kip2 encoded by the CDKN1C gene appears important, since mutations in this gene are associated with the Beckwith-Wiedemann syndrome and mice lacking p57Kip2 have adrenocortical hyperplasia together with other signs present in humans with Beckwith-Wiedemann syndrome.	('expression', 'MPA', (40, 50))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (179, 206))	('mutations', 'Var', (132, 141))	('p57Kip2', 'Gene', (72, 79))	('p57Kip2', 'Gene', '12577', (72, 79))	('associated', 'Reg', (159, 169))	('humans', 'Species', '9606', (301, 307))	('p57Kip2', 'Gene', (224, 231))	('p57Kip2', 'Gene', '12577', (224, 231))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (313, 340))	('CDKN1C', 'Gene', (95, 101))	('Beckwith-Wiedemann syndrome', 'Disease', (179, 206))	('mice', 'Species', '10090', (211, 215))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (237, 263))	('Beckwith-Wiedemann syndrome', 'Disease', (313, 340))	('adrenocortical hyperplasia', 'Disease', (237, 263))
1380	18786438	We suggest that tumorigenesis in childhood ACT positive for the R337H TP53 mutation is a result of multiple events triggered by defective apoptosis and genomic instability produced by the mutation.	('R337H', 'Var', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('child', 'Species', '9606', (33, 38))	('TP53', 'Gene', '7157', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('TP53', 'Gene', (70, 74))	('apoptosis', 'CPA', (138, 147))	('tumor', 'Disease', (16, 21))	('defective', 'NegReg', (128, 137))	('R337H', 'Mutation', 'rs121912664', (64, 69))
1381	18786438	A cascade of genetic alterations may then ensue with varying incidence [11p15 LOH, amplification and overexpression of transcription factor SF-1, growth factor and growth factor receptor overexpression, inhibin alpha gene mutations and possibly other factors] that are involved in adenoma formation, but not in malignancy.	('p15', 'Gene', (74, 77))	('malignancy', 'Disease', (311, 321))	('overexpression', 'PosReg', (187, 201))	('overexpression', 'PosReg', (101, 115))	('p15', 'Gene', '1030', (74, 77))	('adenoma', 'Disease', 'MESH:D000236', (281, 288))	('SF-1, growth factor and growth factor receptor', 'Gene', '7536', (140, 186))	('adenoma', 'Disease', (281, 288))	('mutations', 'Var', (222, 231))	('malignancy', 'Disease', 'MESH:D009369', (311, 321))	('amplification', 'Var', (83, 96))	('inhibin alpha', 'Gene', (203, 216))
1382	18786438	This latter may result from the intervention of further, yet unknown genetic lesions which modify the tumor pattern of gene expression producing a characteristic signature.	('lesions', 'Var', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))
1383	18786438	Each one of these genetic alterations represents then a possible target for new drugs that will hopefully complement cytotoxic treatments in use today in patients with extended disease.	('genetic alterations', 'Var', (18, 37))	('patients', 'Species', '9606', (154, 162))	('alterations', 'Var', (26, 37))
1390	33680972	Especially, high CD96 expression was associated with poorer overall survival (OS) and disease-specific survival (DSS) in the TCGA lower grade glioma (LGG) cohort (OS, HR = 2.18, 95% CI = 1.79-2.66, P < 0.001).	('CD96', 'Gene', (17, 21))	('high', 'Var', (12, 16))	('glioma', 'Disease', (142, 148))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('disease-specific survival', 'CPA', (86, 111))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('poorer', 'NegReg', (53, 59))	('overall', 'MPA', (60, 67))	('DSS', 'Chemical', '-', (113, 116))	('expression', 'MPA', (22, 32))
1392	33680972	Notably, SKCM samples demonstrated the highest CD96 mutation frequency among all cancer types.	('CD96', 'Gene', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('SKCM', 'Chemical', '-', (9, 13))	('mutation', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
1394	33680972	CD96 was identified as a risk factor, protective factor, and irrelevant variable in LGG, SKCM and adrenocortical carcinoma (ACC), respectively.	('SKCM', 'Chemical', '-', (89, 93))	('adrenocortical carcinoma', 'Disease', (98, 122))	('ACC', 'Phenotype', 'HP:0006744', (124, 127))	('CD96', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('LGG', 'Disease', (84, 87))	('SKCM', 'Disease', (89, 93))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (98, 122))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (98, 122))
1409	33680972	Anti-CD96 monoclonal antibody (mAb) also demonstrates higher efficacy in combination with either anti-CTLA-4 or anti-PD-1 mAbs, depending on the activation of CD226 signaling in NK cells.	('CD226', 'Gene', (159, 164))	('higher', 'PosReg', (54, 60))	('Anti-CD96', 'Var', (0, 9))	('CD226', 'Gene', '10666', (159, 164))	('efficacy', 'MPA', (61, 69))	('combination', 'Interaction', (73, 84))
1425	33680972	Results based on eight cohorts [GSE5287, GSE13507, GSE19615, GSE2034, GSE17537, GSE8894, GSE17260, GSE19234 ] suggested that high expression of CD96 was significantly associated with better prognosis (COX P < 0.05;  Figures 3A-H ).	('GSE2034', 'Chemical', '-', (61, 68))	('CD96', 'Gene', (144, 148))	('GSE5287', 'Chemical', '-', (32, 39))	('high expression', 'Var', (125, 140))	('better', 'PosReg', (183, 189))	('GSE8894', 'Chemical', '-', (80, 87))
1433	33680972	We then employed cBioPortal to inspect the mutation frequency of CD96 in the TCGA database (10967 samples in 32 studies), and we found that LUSC and SKCM shared relatively high mutation level with the CD96 alteration frequency exceeding 8% ( Figures 4A, B ).	('mutation', 'MPA', (177, 185))	('SKCM', 'Chemical', '-', (149, 153))	('alteration', 'Var', (206, 216))	('CD96', 'Gene', (201, 205))	('LUSC', 'Phenotype', 'HP:0030359', (140, 144))
1434	33680972	Among them, E24K and E574K were the two most frequent mutation sites.	('E574K', 'Var', (21, 26))	('E574K', 'Mutation', 'p.E574K', (21, 26))	('E24K', 'Var', (12, 16))	('E24K', 'Mutation', 'rs758011865', (12, 16))
1435	33680972	COSMIC provided detailed information on the CD96 mutation types, including substitution missense, non-sense, and synonymous mutations in different cancers.	('CD96', 'Gene', (44, 48))	('synonymous mutations', 'Var', (113, 133))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('substitution missense', 'Var', (75, 96))	('cancers', 'Disease', (147, 154))	('non-sense', 'Var', (98, 107))
1436	33680972	Non-sense substitutions were found in cervix cancer (25%), large intestine cancer (2.47%), lung cancer (4.90%), and skin cancer (0.58%), while missense substitutions were observed in biliary tract cancer (5.56%), breast cancer (8.94%), cervix cancer (25%), central nervous system (CNS) cancer (33.33%), endometrial cancer (41.67%), hematopoietic and lymphoid cancer (7.41%), kidney cancer (25%), large intestine cancer (35.80%), liver cancer (8.70%), lung cancer (34.31%), esophageal cancer (25.53%), ovary cancer (12.50%), pancreas cancer (6.25%), prostate cancer (3.28%), skin cancer (44.77%), stomach cancer (16.22%), thyroid cancer (100%), upper aerodigestive tract cancer (46.15%), and urinary tract cancer (53.33%).	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('endometrial cancer', 'Disease', (303, 321))	('cancer', 'Disease', (629, 635))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (533, 539))	('cancer', 'Disease', (382, 388))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('kidney cancer', 'Disease', (375, 388))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (456, 462))	('cancer', 'Disease', 'MESH:D009369', (558, 564))	('thyroid cancer', 'Disease', (621, 635))	('ovary cancer', 'Disease', (501, 513))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', (315, 321))	('cancer', 'Disease', (220, 226))	('large intestine cancer', 'Phenotype', 'HP:0100834', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('thyroid cancer', 'Disease', 'MESH:D013964', (621, 635))	('cancer', 'Disease', (75, 81))	('liver cancer', 'Disease', (429, 441))	('ovary cancer', 'Disease', 'MESH:D010051', (501, 513))	('cancer', 'Disease', (359, 365))	('large intestine cancer', 'Phenotype', 'HP:0100834', (396, 418))	('cancer', 'Disease', 'MESH:D009369', (435, 441))	('skin cancer', 'Disease', (116, 127))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (183, 203))	('stomach cancer', 'Phenotype', 'HP:0012126', (596, 610))	('ovary cancer', 'Phenotype', 'HP:0100615', (501, 513))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cervix cancer', 'Phenotype', 'HP:0030079', (236, 249))	('cancer', 'Disease', (507, 513))	('cancer', 'Disease', (579, 585))	('cancer', 'Disease', 'MESH:D009369', (604, 610))	('cancer', 'Disease', 'MESH:D009369', (484, 490))	('skin cancer', 'Disease', 'MESH:D012878', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('skin cancer', 'Disease', 'MESH:D012878', (574, 585))	('lymphoid cancer', 'Disease', (350, 365))	('endometrial cancer', 'Phenotype', 'HP:0012114', (303, 321))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (691, 711))	('cancer', 'Disease', 'MESH:D009369', (705, 711))	('cancer', 'Disease', (121, 127))	('thyroid cancer', 'Phenotype', 'HP:0002890', (621, 635))	('cancer', 'Disease', (456, 462))	('cancer', 'Disease', (558, 564))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('prostate cancer', 'Disease', 'MESH:D011471', (549, 564))	('skin cancer', 'Disease', (574, 585))	('prostate cancer', 'Phenotype', 'HP:0012125', (549, 564))	('skin cancer', 'Phenotype', 'HP:0008069', (116, 127))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (670, 676))	('cancer', 'Disease', (705, 711))	('missense', 'Var', (143, 151))	('lung cancer', 'Disease', 'MESH:D008175', (451, 462))	('pancreas cancer', 'Disease', (524, 539))	('cancer', 'Disease', (435, 441))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (533, 539))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('cancer', 'Disease', (243, 249))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('cancer', 'Disease', 'MESH:D009369', (412, 418))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('kidney cancer', 'Disease', 'MESH:D007680', (375, 388))	('cancer', 'Disease', (604, 610))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cervix cancer', 'Phenotype', 'HP:0030079', (38, 51))	('endometrial cancer', 'Disease', 'MESH:D016889', (303, 321))	('cancer', 'Disease', (484, 490))	('lung cancer', 'Disease', (451, 462))	('lymphoid cancer', 'Disease', 'MESH:D009369', (350, 365))	('cancer', 'Disease', (286, 292))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('prostate cancer', 'Disease', (549, 564))	('kidney cancer', 'Phenotype', 'HP:0009726', (375, 388))	('breast cancer', 'Disease', (213, 226))	('pancreas cancer', 'Disease', 'MESH:D010190', (524, 539))	('cancer', 'Disease', (412, 418))	('skin cancer', 'Phenotype', 'HP:0008069', (574, 585))	('cancer', 'Disease', 'MESH:D009369', (359, 365))	('central nervous system', 'Disease', (257, 279))	('lung cancer', 'Disease', (91, 102))	('pancreas cancer', 'Phenotype', 'HP:0002894', (524, 539))	('liver cancer', 'Disease', 'MESH:D006528', (429, 441))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (350, 365))	('cancer', 'Disease', 'MESH:D009369', (629, 635))	('cancer', 'Disease', (45, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (451, 462))	('liver cancer', 'Phenotype', 'HP:0002896', (429, 441))	('cancer', 'Disease', 'MESH:D009369', (507, 513))	('cancer', 'Disease', 'MESH:D009369', (579, 585))	('cancer', 'Disease', (670, 676))
1443	33680972	DNA mismatch repair deficiency and subsequent microsatellite instability (MSI), a hypermutator phenotype secondary to frequent polymorphism in short repetitive DNA sequences and single nucleotide substitution, lead to the accumulation of mutation loads in cancer-related genes and the aggravation of tumor mutation burden (TMB).	('polymorphism', 'Var', (127, 139))	('deficiency', 'Disease', 'MESH:D007153', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('tumor', 'Disease', (300, 305))	('cancer', 'Disease', (256, 262))	('TMB', 'Chemical', '-', (323, 326))	('mutation loads', 'MPA', (238, 252))	('microsatellite instability', 'MPA', (46, 72))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('aggravation', 'PosReg', (285, 296))	('deficiency', 'Disease', (20, 30))	('accumulation', 'PosReg', (222, 234))	('single nucleotide substitution', 'Var', (178, 208))
1449	33680972	Despite the significances of these correlations, the correlation coefficients between CD96 and TMB, as well as MSI, were below 0.6 in almost all cancers, suggesting that CD96 was rather unlikely to affect tumorigenesis by participating in the process of genetic alterations, and was not sufficient to independently predict the patient's response to ICBs either.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('affect', 'Reg', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('patient', 'Species', '9606', (327, 334))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('TMB', 'Chemical', '-', (95, 98))	('CD96', 'Var', (170, 174))
1465	33680972	This intriguing difference suggested that CD96 mediated immunosuppressive effects in glioma patients, but participated in completely opposite immune processes in melanoma patients, highly indicating that CD96 impacted patient prognosis via an immune-related manner.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('impacted', 'Reg', (209, 217))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('patient', 'Species', '9606', (92, 99))	('patient', 'Species', '9606', (218, 225))	('melanoma', 'Disease', (162, 170))	('patient', 'Species', '9606', (171, 178))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('patients', 'Species', '9606', (92, 100))	('immunosuppressive effects', 'MPA', (56, 81))	('CD96', 'Gene', (42, 46))	('patients', 'Species', '9606', (171, 179))	('glioma', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('CD96', 'Var', (204, 208))
1476	33680972	On the one hand, it has an immunoreceptor tyrosine-based inhibition motif (ITIM) motif, which is conserved in inhibit receptors such as KIR2DL; On the other hand, similar to the activating receptor NKG2D, CD96 harbors a YXXM motif.	('YXXM', 'MPA', (220, 224))	('NKG2D', 'Gene', '22914', (198, 203))	('NKG2D', 'Gene', (198, 203))	('CD96', 'Var', (205, 209))	('tyrosine', 'Chemical', 'MESH:D014443', (42, 50))
1477	33680972	Therefore, whether CD96 activates NK cells to exert tumor cell killing effect or inhibits its activity is still inconclusive.	('inhibits', 'NegReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('activity', 'MPA', (94, 102))	('activates', 'PosReg', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('CD96', 'Var', (19, 23))
1487	33680972	This suggests that CD96 can affect patient prognosis by influencing cancer malignant characteristics.	('affect', 'Reg', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patient', 'Species', '9606', (35, 42))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('influencing', 'Reg', (56, 67))	('cancer', 'Disease', (68, 74))	('CD96', 'Var', (19, 23))
1491	33680972	Notably, further analysis showed that CD96 in SKCM, but not in LGG, was positively associated with Th1 markers, again corroborating that CD96 participates in Th1 activation, thereby enhancing tumor inhibiting effects and prolonging patient survival time in SKCM, again suggesting CD96 impacted patient survival in an immunity-depended manner.	('patient', 'Species', '9606', (294, 301))	('patient survival time', 'CPA', (232, 253))	('tumor', 'Disease', (192, 197))	('CD96', 'Var', (137, 141))	('prolonging', 'PosReg', (221, 231))	('enhancing', 'PosReg', (182, 191))	('SKCM', 'Chemical', '-', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patient', 'Species', '9606', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('SKCM', 'Chemical', '-', (257, 261))
1492	33680972	Although the unique infiltration of immune cells in different tumors may affect our analysis results, we have reason to speculate that CD96 can influence the fate of immune infiltrates in TME, and may alter their distribution and subsequent interactions with malignancy cells, leading to distinct survival outcomes for different cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('alter', 'Reg', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('leading to', 'Reg', (277, 287))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', (329, 335))	('influence', 'Reg', (144, 153))	('interactions', 'Interaction', (241, 253))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('malignancy', 'Disease', 'MESH:D009369', (259, 269))	('patients', 'Species', '9606', (336, 344))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('malignancy', 'Disease', (259, 269))	('CD96', 'Var', (135, 139))	('fate', 'MPA', (158, 162))	('distribution', 'MPA', (213, 225))
1494	33680972	Moreover, we mainly employed TCGA database to perform these analyses, the included studies did not cover all previous published literatures involved CD96 and certain cancers, for instance, CD96 did not significantly related to LGG patient survival in GEO datasets by Prognoscan site.	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('LGG', 'Disease', (227, 230))	('CD96', 'Var', (189, 193))	('related', 'Reg', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('patient', 'Species', '9606', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
1495	33680972	In summary, we applied integrated bioinformatics approaches to suggest that CD96 expression may mediate immune infiltration and impact patient prognosis in pan-cancer, sharing the potential as a prognostic biomarker and providing a novel direction to explore the pathogenesis malignance of these prevailing cancers.	('impact', 'Reg', (128, 134))	('cancer', 'Disease', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('immune infiltration', 'CPA', (104, 123))	('cancers', 'Disease', 'MESH:D009369', (307, 314))	('patient', 'Species', '9606', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancers', 'Disease', (307, 314))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('expression', 'Var', (81, 91))	('mediate', 'Reg', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (307, 314))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('CD96', 'Gene', (76, 80))	('patient prognosis', 'CPA', (135, 152))
1519	33680972	We also employed TISIDB  to assess whether CD96 had a significant expression difference between responders and non-responders to immunotherapy (e.g., anti-PD-L1 and anti-PD-1).	('PD-L1', 'Gene', '29126', (155, 160))	('PD-L1', 'Gene', (155, 160))	('anti-PD-1', 'Var', (165, 174))	('CD96', 'Gene', (43, 47))
1538	32957442	The protein products of individual CGB genes show amino acid differences at position 117.	('amino acid differences', 'Var', (50, 72))	('CGB', 'Gene', (35, 38))	('CGB', 'Gene', '93659', (35, 38))
1545	32957442	The insertion led to the deletion of a 52-base long segment of the proximal promoter, as well as the entire 5' untranslated region (5'UTR) region of the CGB gene.	(', as', 'Gene', '112935892', (84, 88))	('CGB', 'Gene', (153, 156))	('to', 'Gene', '6999', (18, 20))	('deletion', 'Var', (25, 33))	('CGB', 'Gene', '93659', (153, 156))
1546	32957442	The consequence of this mutation was the creation of a new promoter sequence for CGB1 and CGB2, a new 5'UTR region with an alternative start codon, and a new first exon.	('CGB2', 'Gene', (90, 94))	('CGB1', 'Gene', (81, 85))	('CGB1', 'Gene', '114335', (81, 85))	('mutation', 'Var', (24, 32))	('CGB2', 'Gene', '114336', (90, 94))
1580	32957442	It was also demonstrated that specific targeting of CGB1 and CGB2 with siRNA was much more effective in reducing cancer cell numbers than silencing other CGB genes.	('CGB', 'Gene', '93659', (154, 157))	('CGB', 'Gene', (52, 55))	('targeting', 'Var', (39, 48))	('CGB2', 'Gene', '114336', (61, 65))	('CGB', 'Gene', '93659', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('CGB', 'Gene', (154, 157))	('reducing', 'NegReg', (104, 112))	('CGB', 'Gene', (61, 64))	('cancer', 'Disease', (113, 119))	('CGB', 'Gene', '93659', (52, 55))	('CGB2', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CGB1', 'Gene', (52, 56))	('CGB1', 'Gene', '114335', (52, 56))
1601	30886049	Mutant Lef1 controls Gata6 in sebaceous gland development and cancer Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear.	('sebaceous gland', 'Phenotype', 'HP:0032227', (30, 45))	('Lef1', 'Gene', '16842', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Lef1', 'Gene', (7, 11))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('sebaceous gland', 'Disease', (112, 127))	('human', 'Species', '9606', (96, 101))	('Gata6', 'Gene', '14465', (21, 26))	('cancer', 'Disease', (62, 68))	('tumors', 'Disease', (133, 139))	('Lef1', 'Gene', '16842', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Lef1', 'Gene', (82, 86))	('carcinogenesis', 'Disease', (167, 181))	('Mutations', 'Var', (69, 78))	('Mutant', 'Var', (0, 6))	('mouse', 'Species', '10090', (106, 111))	('carcinogenesis', 'Disease', 'MESH:D063646', (167, 181))	('sebaceous gland', 'Phenotype', 'HP:0032227', (112, 127))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('SG', 'Phenotype', 'HP:0032227', (129, 131))	('Gata6', 'Gene', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
1603	30886049	In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mice', 'Species', '10090', (3, 7))	('increases', 'PosReg', (51, 60))	('tumors', 'Disease', (86, 92))	('decreases', 'NegReg', (97, 106))	('Lef1', 'Gene', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('skin tumors', 'Disease', (81, 92))	('skin tumors', 'Phenotype', 'HP:0008069', (81, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('ablation', 'Var', (42, 50))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('SG', 'Phenotype', 'HP:0032227', (125, 127))	('skin tumors', 'Disease', 'MESH:D012878', (81, 92))	('mutant', 'Var', (23, 29))
1611	30886049	In humans, stabilizing mutations in beta-catenin are found in a majority of pilomatricomas (Chan et al, 1999) and pilomatrix carcinomas (Lazar et al, 2005).	('pilomatrix carcinomas', 'Disease', (114, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('pilomatrix carcinomas', 'Phenotype', 'HP:0030434', (114, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('beta-catenin', 'Protein', (36, 48))	('pilomatricomas', 'Disease', (76, 90))	('mutations', 'Var', (23, 32))	('humans', 'Species', '9606', (3, 9))	('pilomatrix carcinomas', 'Disease', 'MESH:D002277', (114, 135))	('pilomatricomas', 'Disease', 'MESH:D018296', (76, 90))
1612	30886049	While genetic deletion of beta-catenin from the epidermis is not associated with tumor development (Huelsken et al, 2001; Malanchi et al, 2008), transgenic mice expressing DeltaNLef1 under the control of the keratin 14 promoter (K14DeltaNLef1) spontaneously develop skin tumors, most of which are sebaceous adenomas and sebaceomas (Niemann et al, 2002).	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('develop', 'PosReg', (258, 265))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('skin tumors', 'Phenotype', 'HP:0008069', (266, 277))	('DeltaNLef1', 'Var', (172, 182))	('tumor', 'Disease', (271, 276))	('skin tumors', 'Disease', (266, 277))	('transgenic mice', 'Species', '10090', (145, 160))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('skin tumors', 'Disease', 'MESH:D012878', (266, 277))	('sebaceous adenomas and sebaceomas', 'Disease', 'MESH:D000236', (297, 330))	('sebaceous adenomas', 'Phenotype', 'HP:0009720', (297, 315))	('tumor', 'Disease', (81, 86))
1613	30886049	In K14DeltaNLef1 mice, DeltaNLef1 decreases endogenous Lef1 expression and acts as a dominant negative inhibitor of beta-catenin (Niemann et al, 2002).	('expression', 'MPA', (60, 70))	('decreases', 'NegReg', (34, 43))	('mice', 'Species', '10090', (17, 21))	('DeltaNLef1', 'Var', (23, 33))	('Lef1', 'Gene', (55, 59))	('negative', 'NegReg', (94, 102))	('endogenous', 'MPA', (44, 54))
1615	30886049	Tumors that develop upon DeltaNLef1 expression exhibit sebaceous differentiation rather than the papillomas and squamous cell carcinomas characteristic of wild-type (WT) mice (Niemann et al, 2007).	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (112, 136))	('squamous cell carcinomas', 'Disease', (112, 136))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('papillomas', 'Disease', 'MESH:D010212', (97, 107))	('expression', 'Var', (36, 46))	('papillomas', 'Disease', (97, 107))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (112, 136))	('Tumors', 'Disease', (0, 6))	('DeltaNLef1 expression', 'Var', (25, 46))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('mice', 'Species', '10090', (170, 174))	('sebaceous differentiation', 'CPA', (55, 80))	('papilloma', 'Phenotype', 'HP:0012740', (97, 106))	('papillomas', 'Phenotype', 'HP:0012740', (97, 107))
1616	30886049	Consistent with these findings, mutations in the N-terminus of Lef1 that prevent beta-catenin binding are found in approximately 30% of human benign sebaceous tumors (Takeda et al, 2006) and 20% of eyelid sebaceous carcinomas (Jayaraj et al, 2015).	('human', 'Species', '9606', (136, 141))	('sebaceous carcinoma', 'Phenotype', 'HP:0030410', (205, 224))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('binding', 'Interaction', (94, 101))	('eyelid sebaceous carcinomas', 'Disease', (198, 225))	('eyelid sebaceous carcinomas', 'Disease', 'MESH:D005142', (198, 225))	('found', 'Reg', (106, 111))	('beta-catenin', 'Protein', (81, 93))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('mutations', 'Var', (32, 41))	('Lef1', 'Gene', (63, 67))	('sebaceous carcinomas', 'Phenotype', 'HP:0030410', (205, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('carcinomas', 'Phenotype', 'HP:0030731', (215, 225))	('benign sebaceous tumors', 'Disease', 'MESH:C563610', (142, 165))	('benign sebaceous tumors', 'Disease', (142, 165))
1617	30886049	We recently reported that the transcription factor Gata6 plays a role in sebaceous lineage determination and is highly upregulated in the junctional zone (JZ) of K14DeltaNLef1 mice (Donati et al, 2017).	('sebaceous lineage determination', 'CPA', (73, 104))	('upregulated', 'PosReg', (119, 130))	('mice', 'Species', '10090', (176, 180))	('K14DeltaNLef1', 'Var', (162, 175))	('Gata6', 'Gene', (51, 56))
1624	30886049	RNAi-mediated knockdown of Lef1 led to a striking Gata6 downregulation (Fig 1F), while DeltaNLef1 overexpression in the SebE6E7 sebocyte cell line increased Gata6 expression (Fig 1G).	('increased', 'PosReg', (147, 156))	('Gata6', 'Gene', (50, 55))	('downregulation', 'NegReg', (56, 70))	('Lef1', 'Gene', (27, 31))	('expression', 'MPA', (163, 173))	('E7', 'CellLine', 'CVCL:J153', (125, 127))	('knockdown', 'Var', (14, 23))	('DeltaNLef1', 'Gene', (87, 97))
1628	30886049	The correlation between bulge and SG signatures in K14DeltaNLef1 mice significantly increased when we selected genes that were direct targets of DeltaNLef1 (white box in Fig 1J), suggesting a direct role of DeltaNLef1 in the formation of ectopic SG in the HF.	('correlation', 'MPA', (4, 15))	('SG', 'Phenotype', 'HP:0032227', (246, 248))	('mice', 'Species', '10090', (65, 69))	('increased', 'PosReg', (84, 93))	('SG', 'Phenotype', 'HP:0032227', (34, 36))	('K14DeltaNLef1', 'Var', (51, 64))
1631	30886049	Loss-of-function mutations in Slco2a1 are associated with sebaceous hyperplasia (Guo et al, 2017).	('Loss-of-function', 'NegReg', (0, 16))	('sebaceous hyperplasia', 'Disease', 'MESH:D006965', (58, 79))	('sebaceous hyperplasia', 'Phenotype', 'HP:0032227', (58, 79))	('Slco2a1', 'Gene', (30, 37))	('sebaceous hyperplasia', 'Disease', (58, 79))	('Slco2a1', 'Gene', '24059', (30, 37))	('mutations', 'Var', (17, 26))
1632	30886049	We conclude that DeltaNLef1 has activating and repressive functions that converge in promoting a SD/SG phenotype in K14DeltaNLef1 mice.	('mice', 'Species', '10090', (130, 134))	('DeltaNLef1', 'Gene', (17, 27))	('SD/SG', 'Disease', (97, 102))	('activating', 'MPA', (32, 42))	('promoting', 'PosReg', (85, 94))	('K14DeltaNLef1', 'Var', (116, 129))	('SG', 'Phenotype', 'HP:0032227', (100, 102))
1639	30886049	Cells expressing low levels of Gata6 co-expressed Lgr6 and Lrig1 in neonatal P1 mice, as in adult animals (Donati et al, 2017).	('Lrig1', 'Gene', '16206', (59, 64))	('Gata6', 'Var', (31, 36))	('Lgr6', 'Gene', '329252', (50, 54))	('Lrig1', 'Gene', (59, 64))	('Lgr6', 'Gene', (50, 54))	('mice', 'Species', '10090', (80, 84))
1648	30886049	We observed induced ectopic Sox9 expression in K14Cre/betaCat Flox(ex3)/+ epidermis.	('Sox9', 'Gene', '20682', (28, 32))	('Sox9', 'Gene', (28, 32))	('ectopic', 'MPA', (20, 27))	('K14Cre/betaCat', 'Var', (47, 61))
1650	30886049	However, an in-depth analysis of tail epidermis did indicate that in the absence of Gata6 the proportion of hypotrophic SG was significantly higher than in WT and heterozygous mice, albeit constituting a minority of the total SG (Fig 3A).	('SG', 'Phenotype', 'HP:0032227', (120, 122))	('mice', 'Species', '10090', (176, 180))	('SG', 'Phenotype', 'HP:0032227', (226, 228))	('higher', 'PosReg', (141, 147))	('absence', 'Var', (73, 80))
1655	30886049	Gata6 overexpression also resulted in the ectopic expression of the differentiating sebocyte marker Fasn in the SG and in the HF but not in the IFE, suggesting that Gata6 is able to promote SG identity in a cell compartment-dependent manner (Fig 3B).	('SG', 'Phenotype', 'HP:0032227', (190, 192))	('resulted in', 'Reg', (26, 37))	('Gata6', 'Var', (165, 170))	('Fasn', 'Gene', (100, 104))	('ectopic expression', 'MPA', (42, 60))	('promote', 'PosReg', (182, 189))	('SG', 'Phenotype', 'HP:0032227', (112, 114))	('Fasn', 'Gene', '14104', (100, 104))	('SG identity', 'CPA', (190, 201))
1667	30886049	Ablation of Gata6 in K14DeltaNLef1 mice (K14DeltaNLef1:cKO) resulted in an increased rate of tumor formation following DMBA treatment, and in an increased number of tumors per mouse (Fig 4B), indicating that Gata6 acted as a tumor suppressor.	('Gata6', 'Gene', (12, 17))	('tumor', 'Disease', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('DMBA', 'Chemical', 'MESH:D015127', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('increased', 'PosReg', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('Ablation', 'Var', (0, 8))	('tumors', 'Disease', (165, 171))	('increased', 'PosReg', (145, 154))	('mice', 'Species', '10090', (35, 39))	('tumor', 'Disease', (165, 170))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('mouse', 'Species', '10090', (176, 181))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
1668	30886049	In addition to increasing the overall number of tumors per mouse, loss of Gata6 led to an increase in papilloma-like tumors and a decrease in tumors with SG elements (Fig 4C).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('Gata6', 'Gene', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (48, 54))	('papilloma', 'Phenotype', 'HP:0012740', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', (142, 148))	('papilloma-like tumors', 'Disease', (102, 123))	('mouse', 'Species', '10090', (59, 64))	('decrease', 'NegReg', (130, 138))	('SG', 'Phenotype', 'HP:0032227', (154, 156))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('increase', 'PosReg', (90, 98))	('loss', 'Var', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('papilloma-like tumors', 'Disease', 'MESH:D010212', (102, 123))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
1671	30886049	This autosomal dominant variant of Lynch syndrome is caused by mutations in DNA mismatch repair (MMR) genes, resulting in microsatellite instability (Eisen & Michael, 2009a,b; John & Schwartz, 2016).	('mutations', 'Var', (63, 72))	('Lynch syndrome', 'Disease', (35, 49))	('MMR', 'Gene', (97, 100))	('caused by', 'Reg', (53, 62))	('Lynch syndrome', 'Disease', 'MESH:D003123', (35, 49))	('DNA', 'Gene', (76, 79))	('microsatellite instability', 'MPA', (122, 148))
1672	30886049	Since loss of Gata6 in cultured mouse keratinocytes leads to DNA damage, triggering apoptosis (Wang et al, 2017), we investigated whether the tumor suppressive function of Gata6 might be due to an effect on MMR gene transcription.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('loss', 'Var', (6, 10))	('apoptosis', 'MPA', (84, 93))	('MMR', 'Gene', (207, 210))	('tumor', 'Disease', (142, 147))	('leads', 'Reg', (52, 57))	('DNA damage', 'MPA', (61, 71))	('effect', 'Reg', (197, 203))	('mouse', 'Species', '10090', (32, 37))	('Gata6', 'Gene', (14, 19))	('triggering', 'Reg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
1678	30886049	We first evaluated MSI in skin tumors from K14DeltaNLef1 mice and K14DeltaNLef1:cKO mice.	('mice', 'Species', '10090', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('skin tumors', 'Phenotype', 'HP:0008069', (26, 37))	('skin tumors', 'Disease', (26, 37))	('K14DeltaNLef1', 'Var', (66, 79))	('K14DeltaNLef1', 'Var', (43, 56))	('mice', 'Species', '10090', (84, 88))	('skin tumors', 'Disease', 'MESH:D012878', (26, 37))
1679	30886049	This indicated a more unstable microsatellite phenotype in K14DeltaNLef1:cKO mice.	('unstable microsatellite phenotype', 'MPA', (22, 55))	('mice', 'Species', '10090', (77, 81))	('K14DeltaNLef1', 'Var', (59, 72))
1681	30886049	Mlh1 (Fig 5D and Appendix Fig S2A) and Msh2 (Fig 5E and Appendix Fig S2B) expression were significantly reduced in K14DeltaNLef1:cKO as compared to K14DeltaNLef1 tumors.	('Msh2', 'Gene', (39, 43))	('expression', 'MPA', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('reduced', 'NegReg', (104, 111))	('cKO', 'Disease', (129, 132))	('Mlh1', 'Gene', (0, 4))	('K14DeltaNLef1', 'Var', (115, 128))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('K14DeltaNLef1 tumors', 'Disease', 'MESH:D009369', (148, 168))	('K14DeltaNLef1 tumors', 'Disease', (148, 168))
1683	30886049	Altogether, these results indicate that the increased incidence of tumors in K14DeltaNLef1:cKO mice could be due to a decrease in expression of Gata6-dependent MMR proteins.	('Gata6-dependent MMR proteins', 'Protein', (144, 172))	('expression', 'MPA', (130, 140))	('mice', 'Species', '10090', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('decrease', 'NegReg', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('K14DeltaNLef1', 'Var', (77, 90))
1695	30886049	Within this dataset, we found GATA6 mutations in approximately 30% of SebC harboring a MSI or UV damage signature (Fig 7A).	('SebC', 'Phenotype', 'HP:0030410', (70, 74))	('MSI', 'MPA', (87, 90))	('GATA6', 'Gene', (30, 35))	('GATA6', 'Gene', '14465', (30, 35))	('mutations', 'Var', (36, 45))	('SebC', 'Gene', (70, 74))
1696	30886049	GATA6 missense mutations were mostly deleterious (Fig 7B).	('GATA6', 'Gene', (0, 5))	('missense mutations', 'Var', (6, 24))	('GATA6', 'Gene', '14465', (0, 5))
1698	30886049	Despite the different mutational mechanisms associated with MSI-related and UV-induced SebC, Gata6-mutated tumors (Gata6mut) displayed a higher number of mutations/Mb (Fig 7D), of somatic single-nucleotide variants (SSNV) (Fig 7E) and Indel (Fig 7F) than Gata6 wild-type tumors (Gata6wt).	('SebC', 'Phenotype', 'HP:0030410', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (271, 277))	('tumors', 'Disease', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('single-nucleotide variants', 'Var', (188, 214))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('mutations/Mb', 'Var', (154, 166))	('Indel', 'Var', (235, 240))	('Gata6wt', 'Chemical', '-', (279, 286))
1699	30886049	In addition, Gata6mut tumors displayed a trend of downregulation in MMR genes when compared to Gata6wt tumors (Fig 7G).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('downregulation', 'NegReg', (50, 64))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('MMR genes', 'Gene', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('Gata6wt', 'Chemical', '-', (95, 102))	('Gata6mut', 'Var', (13, 21))	('tumors', 'Disease', (22, 28))
1700	30886049	However, these results suggest that Gata6 affects DNA damage pathways in human sebaceous tumors as in mice.	('Gata6', 'Var', (36, 41))	('mice', 'Species', '10090', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('sebaceous tumors', 'Disease', 'MESH:C563610', (79, 95))	('sebaceous tumors', 'Disease', (79, 95))	('human', 'Species', '9606', (73, 78))	('affects', 'Reg', (42, 49))	('DNA damage pathways', 'Pathway', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
1703	30886049	Although Gata6 is strongly upregulated in the epidermis of K14DeltaNLef1 mice (Fig 1H) and is a direct DeltaNLef1 target gene (Fig 1C), we saw no evidence for co-expression of Gata6 and Lef1 in developing or adult epidermis and Gata6 was not induced upon beta-catenin activation (Fig 2), even though Gata6 synergizes with or activates Wnt signaling in a number of contexts (Afouda et al, 2008; Zhang et al, 2008b; Whissell et al, 2014).	('K14DeltaNLef1', 'Var', (59, 72))	('mice', 'Species', '10090', (73, 77))	('activates', 'PosReg', (325, 334))	('upregulated', 'PosReg', (27, 38))	('Gata6', 'Gene', (9, 14))
1713	30886049	Gata6 was expressed in sebaceous tumors of K14DeltaNLef1 mice (Fig 4A) and deletion of Gata6 reduced the proportion of tumors with sebaceous differentiation (Fig 4C).	('mice', 'Species', '10090', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('sebaceous tumors', 'Disease', (23, 39))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('deletion', 'Var', (75, 83))	('reduced', 'NegReg', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('Gata6', 'Gene', (87, 92))	('sebaceous tumors', 'Disease', 'MESH:C563610', (23, 39))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (33, 39))
1719	30886049	In addition, Ki67-positive cells are twice as frequent in the basal layer of K14DeltaNLef1 as WT IFE (Niemann et al, 2002).	('Ki67', 'Gene', (13, 17))	('Ki67', 'Gene', '17345', (13, 17))	('K14DeltaNLef1', 'Var', (77, 90))
1720	30886049	Thus, Ki67 is mostly expressed in the Gata6-negative regions of K14DeltaNLef1 epidermis.	('K14DeltaNLef1', 'Var', (64, 77))	('Ki67', 'Gene', (6, 10))	('Ki67', 'Gene', '17345', (6, 10))
1721	30886049	K14DeltaNLef1 mice develop sebaceous tumors at high frequency.	('K14DeltaNLef1', 'Var', (0, 13))	('sebaceous tumors', 'Disease', 'MESH:C563610', (27, 43))	('mice', 'Species', '10090', (14, 18))	('sebaceous tumors', 'Disease', (27, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))
1724	30886049	In addition, we and others have confirmed the existence of proliferative cells in K14DeltaNLef1 sebaceous tumors by showing Ki67 expression (Niemann et al, 2002), BrdU incorporation (Niemann et al, 2007), and isolating tumor-propagating cells that form secondary tumors in serial transplantation assays (Petersson et al, 2015).	('tumor', 'Disease', (219, 224))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', (106, 111))	('sebaceous tumors', 'Disease', 'MESH:C563610', (96, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (263, 268))	('Ki67', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('sebaceous tumors', 'Disease', (96, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('K14DeltaNLef1', 'Var', (82, 95))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('Ki67', 'Gene', '17345', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumors', 'Disease', (263, 269))
1727	30886049	In this syndrome, mutations in the MMR genes Msh2 or, less frequently, Mlh1 and Msh6, predispose cells to DNA base errors (shown by the acquisition of MSI status; John & Schwartz, 2016).	('Mlh1', 'Gene', (71, 75))	('predispose', 'Reg', (86, 96))	('Msh6', 'Gene', (80, 84))	('Msh2', 'Gene', (45, 49))	('Msh6', 'Gene', '17688', (80, 84))	('DNA base errors', 'MPA', (106, 121))	('MMR', 'Gene', (35, 38))	('mutations', 'Var', (18, 27))
1730	30886049	Microsatellite stability and expression of Msh2 and Mlh1 were reduced upon Gata6 knockout in K14DeltaNLef1 mice (Figs 5C, D and E, and Appendix Fig S2).	('Gata6', 'Gene', (75, 80))	('Microsatellite stability', 'MPA', (0, 24))	('knockout', 'Var', (81, 89))	('K14DeltaNLef1', 'Var', (93, 106))	('mice', 'Species', '10090', (107, 111))	('Mlh1', 'Gene', (52, 56))	('expression', 'MPA', (29, 39))	('Msh2', 'Gene', (43, 47))	('reduced', 'NegReg', (62, 69))
1731	30886049	This would explain why tumor incidence was increased in K14DeltaNLef1:cKO mice (Fig 4B).	('K14DeltaNLef1:cKO', 'Var', (56, 73))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('increased', 'PosReg', (43, 52))	('tumor', 'Disease', (23, 28))	('mice', 'Species', '10090', (74, 78))
1733	30886049	The increased mutation load resulting from MMR inactivation generates multiple neo-antigens and stimulates immune surveillance and cancer clearance (Germano et al, 2017).	('inactivation', 'Var', (47, 59))	('cancer', 'Disease', (131, 137))	('immune surveillance', 'CPA', (107, 126))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('MMR', 'Gene', (43, 46))	('stimulates', 'PosReg', (96, 106))	('neo-antigens', 'MPA', (79, 91))	('mutation', 'Var', (14, 22))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('increased', 'PosReg', (4, 13))
1739	30886049	However, sebaceous carcinoma can also acquire Gata6 mutations correlating with the total mutational burden (Fig 7).	('mutations', 'Var', (52, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('sebaceous carcinoma', 'Disease', 'MESH:D018266', (9, 28))	('sebaceous carcinoma', 'Disease', (9, 28))	('sebaceous carcinoma', 'Phenotype', 'HP:0030410', (9, 28))	('Gata6', 'Gene', (46, 51))
1740	30886049	Gata6mut tumors display reduced expression of several MMR genes (Fig 7G).	('reduced', 'NegReg', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('Gata6mut', 'Var', (0, 8))	('expression', 'MPA', (32, 42))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('MMR genes', 'Gene', (54, 63))
1744	30886049	K14DeltaNLef1 (Niemann et al, 2002), Lef1-/- (Van Genderen et al, 1994), K14DeltaNbeta-CateninER (D2 and D4 lines; Lo Celso et al, 2004), K14Cre/betaCat Flox(ex3)/+ (Zhang et al, 2008a), epidermal Gata6 conditional knockout (cKO) (Donati et al, 2017), Gata6EGFPCreERT2 (Donati et al, 2017), Lgr6EGFPCreERT2 (Snippert et al, 2010), and Rosa26-fl/STOP/fl-tdTomato (Madisen et al, 2010) mice were previously described.	('Rosa26-fl/STOP/fl-tdTomato', 'Var', (335, 361))	('mice', 'Species', '10090', (384, 388))	('K14Cre/betaCat', 'Var', (138, 152))	('Lgr6', 'Gene', '329252', (291, 295))	('Lgr6', 'Gene', (291, 295))
1745	30886049	The K14DeltaNbeta-CateninER transgene was activated by one or six topical applications of 1.5 mg 4-hydroxytamoxifen (4OHT) (Sigma) (Donati et al, 2017).	('4-hydroxytamoxifen', 'Chemical', '-', (97, 115))	('activated', 'PosReg', (42, 51))	('4OHT', 'Chemical', 'MESH:C032278', (117, 121))	('K14DeltaNbeta-CateninER', 'Var', (4, 27))
1746	30886049	For lineage tracing experiments, pregnant females were injected intraperitoneally with a dose of 50 mug/g of tamoxifen (Sigma) at E16.5 and E18.5.	('E18.5', 'Var', (140, 145))	('E16.5', 'Var', (130, 135))	('tamoxifen', 'Chemical', 'MESH:D013629', (109, 118))
1749	30886049	For skin carcinogenesis experiments, K14DeltaNLef1 and K14DeltaNLef1:cKO mice received a single 100 nmol dose of DMBA (7,12-dimethylbenz(a)anthracene; Niemann et al, 2007).	('7,12-dimethylbenz', 'Chemical', '-', (119, 136))	('DMBA', 'Chemical', 'MESH:D015127', (113, 117))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (4, 23))	('skin carcinogenesis', 'Disease', (4, 23))	('mice', 'Species', '10090', (73, 77))	('K14DeltaNLef1', 'Var', (55, 68))	('anthracene', 'Chemical', 'MESH:C034020', (139, 149))
1756	30886049	Primary antibodies were used at the indicated dilutions: Fabp5 (1:100, R&D Systems AF1476); Krt15 (1:1,000, LHK-15 clone, Abcam ab80522); Lef1 (1:100-500, C12A5 clone, Cell Signaling 2230 and 8490); Gata6 (1:100-1,000, D61E4 clone, Cell Signaling 5851 and 26452); Krt14 (1:1,000, LL002 clone, Abcam ab7800 and 1:1,000, Covance SIG-3476); Sox9 (1:100, R&D Systems AF3075 and 1:400, D8G8H clone, Cell Signaling 71273); Ki67 (1:50, Tec3 clone, Dako); Lrig1 (1:200, R&D Systems AF3688); Cd34 (1:100, RAM34 clone, BD Biosciences 553731); Tcf3/4 (1:100, Abcam ab12065); pankeratin (1:1,000, clone LP34, LSBio LS-C95318); Fasn (1:100, G-11, Santa Cruz sc-48357); GFP (1:200, Abcam 6673 and 1:800, Thermo Fisher Scientific A-11122); Plet1 (1:200, LSBio LS-C149191); Atp6v1c2 (1:200, Sigma HPA034735); Mlh1 (1:100, Abcam ab92312); and Msh2 (1:100, Clone D24B5, Cell Signaling 2017).	('Atp6v1c2', 'Gene', '68775', (758, 766))	('Krt15', 'Gene', '16665', (92, 97))	('Cd34', 'Gene', '12490', (483, 487))	('Lrig1', 'Gene', (448, 453))	('Plet1', 'Gene', (725, 730))	('Krt15', 'Gene', (92, 97))	('Lrig1', 'Gene', '16206', (448, 453))	('Fasn', 'Gene', '14104', (615, 619))	('Fabp5', 'Gene', (57, 62))	('Ki67', 'Gene', (417, 421))	('Krt14', 'Gene', '16664', (264, 269))	('Krt14', 'Gene', (264, 269))	('Sox9', 'Gene', '20682', (338, 342))	('; and', 'Var', (820, 825))	('Atp6v1c2', 'Gene', (758, 766))	('Tcf3/4 (1:100', 'Gene', '21423;21413', (533, 546))	('Fasn', 'Gene', (615, 619))	('Ki67', 'Gene', '17345', (417, 421))	('Cd34', 'Gene', (483, 487))	('Sox9', 'Gene', (338, 342))	('Plet1', 'Gene', '76509', (725, 730))	('Fabp5', 'Gene', '16592', (57, 62))
1776	30886049	Microsatellite instability in sebaceous tumors was determined as previously published (Woerner et al, 2015; Germano et al, 2017).	('Microsatellite', 'Var', (0, 14))	('sebaceous tumors', 'Disease', 'MESH:C563610', (30, 46))	('sebaceous tumors', 'Disease', (30, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
1805	31040822	Recently, PSMA has been identified as a potential diagnostic and therapeutic target in ACCs because it is highly expressed in carcinomas, and Zr89-J591 WB-PET-CT was reported to be useful for detecting metastases.	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('metastases', 'Disease', 'MESH:D009362', (202, 212))	('PSMA', 'Gene', (10, 14))	('Zr89-J591', 'Var', (142, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('PSMA', 'Gene', '2346', (10, 14))	('carcinomas', 'Disease', (126, 136))	('carcinomas', 'Disease', 'MESH:D002277', (126, 136))	('metastases', 'Disease', (202, 212))
1950	29628290	Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers.	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('TP53', 'Gene', '7157', (89, 93))	('IDH1', 'Gene', '3417', (66, 70))	('CTNNB1', 'Gene', '1499', (49, 55))	('lower', 'NegReg', (42, 47))	('NRAS', 'Gene', (57, 61))	('mutations', 'Var', (16, 25))	('leukocyte levels', 'MPA', (105, 121))	('higher', 'PosReg', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('CTNNB1', 'Gene', (49, 55))	('BRAF', 'Gene', '673', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('BRAF', 'Gene', (83, 87))	('CASP8', 'Gene', '841', (98, 103))	('TP53', 'Gene', (89, 93))	('NRAS', 'Gene', '4893', (57, 61))	('IDH1', 'Gene', (66, 70))	('CASP8', 'Gene', (98, 103))
1951	29628290	Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('involved', 'Reg', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('copy number', 'Var', (103, 114))
1959	29628290	Antibodies against CTLA-4, PD-1, and PD-L1 are effective in treating a variety of malignancies.	('Antibodies', 'Var', (0, 10))	('PD-L1', 'Gene', (37, 42))	('CTLA-4', 'Gene', '1493', (19, 25))	('malignancies', 'Disease', (82, 94))	('PD-1', 'Gene', (27, 31))	('PD-1', 'Gene', '5133', (27, 31))	('PD-L1', 'Gene', '29126', (37, 42))	('CTLA-4', 'Gene', (19, 25))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
1974	29628290	The six resulting clusters "Immune Subtypes", C1-C6 (with 2416, 2591, 2397, 1157, 385 and 180 cases, respectively) were characterized by a distinct distribution of scores over the five representative signatures (Figure 1A, bottom panel), and showed distinct immune signatures based on the dominant sample characteristics of their tumor samples (Figure 1B-C).	('C1-C6', 'Var', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Disease', (330, 335))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
1984	29628290	IDH mutations were enriched in C5 over C4 (80% of IDH mutations, p<2x10-16, Fisher's exact test), suggesting an association of IDH-mutations with favorable immune composition.	('association', 'Interaction', (112, 123))	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (54, 63))	('IDH', 'Gene', (50, 53))	('mutations', 'Var', (4, 13))	('IDH', 'Gene', '3417', (50, 53))
1997	29628290	The spatial fraction of tumor regions with tumor infiltrating lymphocytes (TILs), estimated by analysis of digitized TCGA H&E stained slides, varied by immune subtype, with C2 the highest (p<10-16, Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('with', 'Var', (168, 172))	('H&E', 'Chemical', '-', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
2010	29628290	The immune infiltrate was related to measures of DNA damage, including copy number variation (CNV) burden (both in terms of number of segments and fraction of genome alterations), aneuploidy, loss of heterozygosity (LOH), homologous recombination deficiency (HRD), and intratumor heterogeneity (ITH) (Figure 4A).	('aneuploidy', 'Disease', (180, 190))	('loss of heterozygosity', 'Var', (192, 214))	('homologous recombination deficiency', 'Disease', (222, 257))	('copy number variation', 'MPA', (71, 92))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('HRD', 'Disease', (259, 262))	('aneuploidy', 'Disease', 'MESH:D000782', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('HRD', 'Disease', 'None', (259, 262))	('men', 'Species', '9606', (137, 140))
2011	29628290	LF correlated negatively with CNV segment burden, with strongest correlation in C6 and C2, and positively with aneuploidy, LOH, HRD, and mutation load, particularly in C3.	('HRD', 'Disease', (128, 131))	('LOH', 'Var', (123, 126))	('aneuploidy', 'Disease', (111, 121))	('negatively', 'NegReg', (14, 24))	('HRD', 'Disease', 'None', (128, 131))	('men', 'Species', '9606', (37, 40))	('aneuploidy', 'Disease', 'MESH:D000782', (111, 121))	('CNV segment burden', 'MPA', (30, 48))	('mutation load', 'Var', (137, 150))
2012	29628290	Chromosome 1p (including TNFRS9 and VTCN1) amplification associated with higher LF, while its deletion did the opposite.	('VTCN1', 'Gene', '79679', (36, 41))	('amplification', 'Var', (43, 56))	('TNFRS9', 'Gene', (25, 31))	('VTCN1', 'Gene', (36, 41))	('higher', 'PosReg', (73, 79))
2014	29628290	Amplification of chr2, 20q, and 22q (including CTLA4, CD40, and ADORA2 respectively), and deletions of 5q, 9p, and chr19 (including IL13 and IL4, IFNA1 and IFNA2, and ICAM1 respectively) associated with changes in macrophage polarity (Figure S4A).	('macrophage polarity', 'CPA', (214, 233))	('IFNA1', 'Gene', '3439', (146, 151))	('ADORA2', 'Gene', (64, 70))	('chr19', 'Gene', (115, 120))	('CTLA4', 'Gene', (47, 52))	('chr2', 'Gene', (17, 21))	('IL13', 'Gene', (132, 136))	('ICAM1', 'Gene', (167, 172))	('deletions', 'Var', (90, 99))	('ICAM1', 'Gene', '3383', (167, 172))	('IFNA2', 'Gene', (156, 161))	('CD40', 'Gene', (54, 58))	('IFNA2', 'Gene', '3440', (156, 161))	('associated', 'Reg', (187, 197))	('changes', 'Reg', (203, 210))	('ADORA2', 'Gene', '135', (64, 70))	('IFNA1', 'Gene', (146, 151))	('CD40', 'Gene', '958', (54, 58))	('IL4', 'Gene', '3565', (141, 144))	('IL4', 'Gene', (141, 144))	('IL13', 'Gene', '3596', (132, 136))	('CTLA4', 'Gene', '1493', (47, 52))
2015	29628290	IL-13 influences macrophage polarization, implying a possible basis for our observation that IL13 deletions associated with altered M0 macrophage fractions.	('IL-13', 'Gene', '3596', (0, 5))	('influences', 'Reg', (6, 16))	('IL13', 'Gene', (93, 97))	('IL13', 'Gene', '3596', (93, 97))	('macrophage polarization', 'CPA', (17, 40))	('IL-13', 'Gene', (0, 5))	('deletions', 'Var', (98, 107))
2018	29628290	We correlated mutations in 299 cancer driver genes with immune subtypes, and found 33 significant associations (q<0.1) (Figure 4C, Table S2).	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('associations', 'Interaction', (98, 110))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (14, 23))
2019	29628290	C1 was enriched in mutations in driver genes, such as TP53, PIK3CA, PTEN or KRAS.	('PIK3CA', 'Gene', (60, 66))	('KRAS', 'Gene', (76, 80))	('PIK3CA', 'Gene', '5290', (60, 66))	('mutations', 'Var', (19, 28))	('KRAS', 'Gene', '3845', (76, 80))	('PTEN', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (54, 58))	('PTEN', 'Gene', '5728', (68, 72))	('TP53', 'Gene', (54, 58))
2021	29628290	C3 was enriched in BRAF, CDH1 and PBRM1 mutations, a finding of note since patients with PBRM1 mutations respond particularly well to IM therapy.	('BRAF', 'Gene', '673', (19, 23))	('CDH1', 'Gene', '999', (25, 29))	('BRAF', 'Gene', (19, 23))	('PBRM1', 'Gene', (89, 94))	('PBRM1', 'Gene', (34, 39))	('patients', 'Species', '9606', (75, 83))	('PBRM1', 'Gene', '55193', (34, 39))	('PBRM1', 'Gene', '55193', (89, 94))	('mutations', 'Var', (40, 49))	('mutations', 'Var', (95, 104))	('CDH1', 'Gene', (25, 29))
2022	29628290	C4 was enriched in CTNNB1, EGFR, and IDH1 mutations.	('CTNNB1', 'Gene', (19, 25))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('IDH1', 'Gene', (37, 41))	('CTNNB1', 'Gene', '1499', (19, 25))	('IDH1', 'Gene', '3417', (37, 41))	('mutations', 'Var', (42, 51))
2024	29628290	C6 only showed an enrichment in KRAS G12 mutations.	('mutations', 'Var', (41, 50))	('men', 'Species', '9606', (24, 27))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (32, 36))
2025	29628290	Mutations in 23 driver genes associated with increased LF either in specific tumor types or across them, including TP53, HLA-B, BRAF, PTEN, NF1, APC and CASP8.	('BRAF', 'Gene', '673', (128, 132))	('HLA-B', 'Gene', '3106', (121, 126))	('HLA-B', 'Gene', (121, 126))	('TP53', 'Gene', '7157', (115, 119))	('PTEN', 'Gene', '5728', (134, 138))	('tumor type', 'Disease', (77, 87))	('NF1', 'Gene', (140, 143))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (115, 119))	('tumor type', 'Disease', 'MESH:D009369', (77, 87))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('NF1', 'Gene', '4763', (140, 143))	('CASP8', 'Gene', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CASP8', 'Gene', '841', (153, 158))	('APC', 'Disease', (145, 148))	('PTEN', 'Gene', (134, 138))	('BRAF', 'Gene', (128, 132))
2026	29628290	Twelve other events were associated with lower LF, including the IDH1 R132H mutation, GATA3, KRAS, NRAS, CTNNB1 and NOTCH1 (Figure 4D).	('IDH1', 'Gene', '3417', (65, 69))	('GATA3', 'Gene', (86, 91))	('R132H', 'Var', (70, 75))	('KRAS', 'Gene', (93, 97))	('NOTCH1', 'Gene', '4851', (116, 122))	('NOTCH1', 'Gene', (116, 122))	('R132H', 'Mutation', 'rs121913500', (70, 75))	('GATA3', 'Gene', '2625', (86, 91))	('lower', 'NegReg', (41, 46))	('KRAS', 'Gene', '3845', (93, 97))	('CTNNB1', 'Gene', '1499', (105, 111))	('NRAS', 'Gene', (99, 103))	('NRAS', 'Gene', '4893', (99, 103))	('IDH1', 'Gene', (65, 69))	('CTNNB1', 'Gene', (105, 111))
2028	29628290	PI3K, NOTCH and RTK/RAS pathway disruptions showed variable, tumor type specific effects on immune factors, while TGF-beta pathway disruptions more consistently associated with lower LF (most prominently in C2 and C6; Figure S4C), higher eosinophils (C2), and increased macrophages.	('lower', 'NegReg', (177, 182))	('TGF-beta', 'Gene', '7040', (114, 122))	('disruptions', 'Var', (131, 142))	('disruptions', 'Var', (32, 43))	('RTK/RAS pathway', 'Gene', (16, 31))	('increased', 'PosReg', (260, 269))	('eosinophils', 'MPA', (238, 249))	('higher', 'PosReg', (231, 237))	('TGF-beta', 'Gene', (114, 122))	('tumor type', 'Disease', (61, 71))	('eosin', 'Chemical', 'MESH:D004801', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor type', 'Disease', 'MESH:D009369', (61, 71))	('macrophages', 'CPA', (270, 281))
2030	29628290	Thus, TGF-beta pathway disruption has context-dependent effects on LF, but may promote increased macrophages, particularly M1.	('TGF-beta', 'Gene', (6, 14))	('disruption', 'Var', (23, 33))	('promote increased', 'PosReg', (79, 96))	('macrophages', 'CPA', (97, 108))	('TGF-beta', 'Gene', '7040', (6, 14))
2036	29628290	No single cis-eQTL significantly correlated with PD-L1 expression, although the SNP rs822337, approximately 1KB upstream of CD274 transcription start, correlated weakly (p=0.074;1.3x10-4 unadjusted; Figure S4G).	('CD274', 'Gene', (124, 129))	('PD-L1', 'Gene', '29126', (49, 54))	('CD274', 'Gene', '29126', (124, 129))	('rs822337', 'Var', (84, 92))	('PD-L1', 'Gene', (49, 54))	('rs822337', 'Mutation', 'rs822337', (84, 92))
2037	29628290	Lymphocyte fractions tended to be lower in people of Asian ancestry, particularly in UCEC and BLCA (Figure S4H).	('BLCA', 'Disease', (94, 98))	('lower', 'NegReg', (34, 39))	('Asian ancestry', 'Var', (53, 67))	('Lymphocyte fractions', 'CPA', (0, 20))	('UCEC', 'Disease', (85, 89))	('people', 'Species', '9606', (43, 49))	('BLCA', 'Chemical', '-', (94, 98))
2038	29628290	Peptides predicted to bind with MHC proteins (pMHCs) and induce antitumor adaptive immunity were identified from SNV and indel mutations.	('tumor', 'Disease', (68, 73))	('MHC proteins', 'Protein', (32, 44))	('indel mutations', 'Var', (121, 136))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('bind', 'Interaction', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('induce', 'PosReg', (57, 63))
2040	29628290	Neoantigen load also associated with higher content of CD8 T cells, M1 macrophages, and CD4 memory T cells, and lower Tregs, mast, dendritic, and memory B cells in multiple tumor types (Figure S4K).	('content', 'MPA', (44, 51))	('CD8', 'Gene', '925', (55, 58))	('higher', 'PosReg', (37, 43))	('CD4 memory T cells', 'CPA', (88, 106))	('tumor type', 'Disease', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor type', 'Disease', 'MESH:D009369', (173, 183))	('CD8', 'Gene', (55, 58))	('Neoantigen', 'Var', (0, 10))	('multiple tumor', 'Disease', 'MESH:D009369', (164, 178))	('multiple tumor', 'Disease', (164, 178))	('Tregs', 'CPA', (118, 123))	('lower', 'NegReg', (112, 117))
2048	29628290	In a regression model of all tumors, high load of each virus type associated with immune features (Figure S5C, cancer-type adjusted).	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('immune', 'Disease', (82, 88))	('associated', 'Reg', (66, 76))	('cancer', 'Disease', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('high load', 'Var', (37, 46))
2067	29628290	CD40 (Figure 6C), IL10 and IDO1, inversely correlated with gene expression, suggesting epigenetic silencing.	('IDO1', 'Gene', (27, 31))	('CD40', 'Gene', (0, 4))	('IL10', 'Gene', (18, 22))	('IL10', 'Gene', '3586', (18, 22))	('correlated', 'Reg', (43, 53))	('gene expression', 'MPA', (59, 74))	('epigenetic silencing', 'Var', (87, 107))	('IDO1', 'Gene', '3620', (27, 31))	('CD40', 'Gene', '958', (0, 4))
2070	29628290	In particular, IMs SLAMF7, SELP, TNFSF4 (OX40L), IL10, and CD40 were amplified less frequently in C5 relative to all samples, while TGFB1, KIR2DL1, and KIR2DL3 deletions were enriched in C5 (Figure 6D), consistent with our observation of lower immune infiltration with TGFB1 deletion (Figure S4A).	('CD40', 'Gene', (59, 63))	('IL10', 'Gene', '3586', (49, 53))	('TGFB1', 'Gene', '7040', (269, 274))	('TGFB1', 'Gene', (269, 274))	('SELP', 'Gene', '6403', (27, 31))	('CD40', 'Gene', '958', (59, 63))	('TNFSF4', 'Gene', '7292', (33, 39))	('SELP', 'Gene', (27, 31))	('TGFB1', 'Gene', '7040', (132, 137))	('deletion', 'Var', (275, 283))	('KIR2DL1', 'Gene', '3802', (139, 146))	('TGFB1', 'Gene', (132, 137))	('OX40L', 'Gene', (41, 46))	('KIR2DL3', 'Gene', (152, 159))	('TNFSF4', 'Gene', (33, 39))	('KIR2DL3', 'Gene', '3804', (152, 159))	('lower', 'NegReg', (238, 243))	('IL10', 'Gene', (49, 53))	('SLAMF7', 'Gene', '57823', (19, 25))	('KIR2DL1', 'Gene', (139, 146))	('OX40L', 'Gene', '7292', (41, 46))	('SLAMF7', 'Gene', (19, 25))
2084	29628290	Some T cell associated ligands were subtype specific, such as CD276 (C2, C6), IL1B (C6), and VEGFB (C4).	('VEGFB', 'Gene', '7423', (93, 98))	('IL1B', 'Gene', (78, 82))	('VEGFB', 'Gene', (93, 98))	('IL1B', 'Gene', '3553', (78, 82))	('CD276', 'Var', (62, 67))
2089	29628290	Somatic alterations in AKAP9, HRAS, KRAS and PREX2 were inferred to modulate the activity of IMs according to both the MR- and SYGNAL-PanImmune, a significant overlap (p=1.6x10-7, Fisher's exact test).	('HRAS', 'Gene', (30, 34))	('PREX2', 'Gene', (45, 50))	('alterations', 'Var', (8, 19))	('KRAS', 'Gene', (36, 40))	('modulate', 'Reg', (68, 76))	('KRAS', 'Gene', '3845', (36, 40))	('AKAP9', 'Gene', '10142', (23, 28))	('activity', 'MPA', (81, 89))	('HRAS', 'Gene', '3265', (30, 34))	('AKAP9', 'Gene', (23, 28))	('PREX2', 'Gene', '80243', (45, 50))
2094	29628290	Conversely, causal mutations shared across tumor types may associate with different tumor-specific downstream regulators.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mutations', 'Var', (19, 28))	('tumor type', 'Disease', (43, 53))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor type', 'Disease', 'MESH:D009369', (43, 53))	('tumor', 'Disease', (43, 48))	('associate', 'Reg', (59, 68))
2099	29628290	C3 was regulated by KLF15 and miR-141-3p.	('KLF15', 'Gene', (20, 25))	('miR-141-3p', 'Var', (30, 40))	('KLF15', 'Gene', '28999', (20, 25))
2119	29628290	For example, KRAS mutations were enriched in C1 and but infrequent in C5, suggesting that mutations in driver oncogenes alter pathways that affect immune cells.	('mutations', 'Var', (90, 99))	('alter', 'Reg', (120, 125))	('pathways', 'Pathway', (126, 134))	('affect', 'Reg', (140, 146))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
2120	29628290	Driver mutations such as TP53, by inducing genomic instability, may alter the immune landscape via the generation of neoantigens.	('TP53', 'Gene', (25, 29))	('inducing', 'Reg', (34, 42))	('alter', 'Reg', (68, 73))	('genomic instability', 'MPA', (43, 62))	('immune landscape', 'MPA', (78, 94))	('TP53', 'Gene', '7157', (25, 29))	('neoantigens', 'MPA', (117, 128))	('mutations', 'Var', (7, 16))
2121	29628290	Our findings confirmed previous work showing that mutations in BRAF enhance the immune infiltrate while those in IDH1 diminish it.	('diminish', 'NegReg', (118, 126))	('immune infiltrate', 'CPA', (80, 97))	('IDH1', 'Gene', (113, 117))	('mutations', 'Var', (50, 59))	('IDH1', 'Gene', '3417', (113, 117))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))	('enhance', 'PosReg', (68, 75))
2129	29628290	Predicted intracellular networks implied that seven immune related TFs(including interferon and STAT-family transcription factors) may play an active role in transcriptional events related to leukocyte infiltration, and that mutations in six genes (including Ras-family proteins) may influence immune infiltration.	('influence', 'Reg', (284, 293))	('mutations', 'Var', (225, 234))	('STAT', 'Disease', (96, 100))	('immune infiltration', 'CPA', (294, 313))	('STAT', 'Disease', 'None', (96, 100))
2197	29628290	Comparing functional annotations of these clusters, we found that overlap to be reflected in the concordant distribution of mean scores of IFN-gamma, TGF-beta, mutation load and overall leukocyte infiltrate among the overlapping clusters.	('IFN-gamma', 'Gene', '3458', (139, 148))	('IFN-gamma', 'Gene', (139, 148))	('TGF-beta', 'Gene', '7040', (150, 158))	('mutation load', 'Var', (160, 173))	('TGF-beta', 'Gene', (150, 158))
2227	29628290	All clonality calls for quantifying intratumoral heterogeneity (ITH) were also determined by ABSOLUTE, which models tumor copy number alterations and mutations as mixtures of subclonal and clonal components of varying ploidy.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (116, 121))
2229	29628290	Scores for copy number burden, aneuploidy, loss of heterozygosity, and homologous recombination deficiency (HRD) were derived.	('aneuploidy', 'Disease', (31, 41))	('aneuploidy', 'Disease', 'MESH:D000782', (31, 41))	('HRD', 'Disease', 'None', (108, 111))	('copy number burden', 'Var', (11, 29))	('loss of heterozygosity', 'Var', (43, 65))	('HRD', 'Disease', (108, 111))
2230	29628290	Copy number burden scores frac_altered and n_segs ("fraction altered", and "number of segments", respectively) represent the fraction of bases deviating from baseline ploidy (defined as above 0.1 or below - 0.1 in log2 relative copy number (CN) space), and the total number of segments in each sample's copy number profile, respectively.	('men', 'Species', '9606', (89, 92))	('deviating', 'NegReg', (143, 152))	('frac_altered', 'Var', (26, 38))	('men', 'Species', '9606', (280, 283))
2231	29628290	LOH_n_seg and LOH_frac_altered are the number of segments with LOH events and fraction of bases with LOH events, respectively.	('LOH_n_seg', 'Var', (0, 9))	('men', 'Species', '9606', (52, 55))	('LOH_frac_altered', 'Var', (14, 30))
2232	29628290	HRD score is a measure quantifying defects in homologous recombination that sums 3 separate metrics of genomic scarring: large (>15 Mb) non-arm-level regions with LOH, large-scale state transitions (breaks between adjacent segments of >10 Mb), and subtelomeric regions with allelic imbalance.	('imbalance', 'Phenotype', 'HP:0002172', (282, 291))	('HRD', 'Disease', 'None', (0, 3))	('scarring', 'Phenotype', 'HP:0100699', (111, 119))	('defects', 'Var', (35, 42))	('HRD', 'Disease', (0, 3))	('LOH', 'NegReg', (163, 166))	('men', 'Species', '9606', (226, 229))
2233	29628290	Aneuploidy scores were calculated as the sum total of amplified or deleted (collectively "altered") arms.	('deleted', 'Var', (67, 74))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('Aneuploidy', 'Disease', (0, 10))
2234	29628290	To call arm alterations, sample chromosome arms were first stratified by sample tumor type, type of alteration being tested (amplification or deletion), and chromosome arm (1p, 1q, etc.).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('alterations', 'Var', (12, 23))	('tumor type', 'Disease', 'MESH:D009369', (80, 90))	('tumor type', 'Disease', (80, 90))	('deletion', 'Var', (142, 150))
2240	29628290	Furthermore, for each gene, we similarly computed significances of differences of CIBERSORT-estimated relative immune cell subtype levels from their expected levels first in "amplified" and then in "deleted" samples in order to identify the effects of copy number amplification and deletion respectively on immune infiltrate composition while controlling for cancer disease type.	('cancer disease', 'Disease', 'MESH:D009369', (359, 373))	('deletion', 'Var', (282, 290))	('effects', 'Reg', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('cancer disease', 'Disease', (359, 373))	('copy number amplification', 'Var', (252, 277))
2241	29628290	Contributors: Galen Gao, Andrew Cherniack We focused our analysis on genes identified as drivers by the TCGA PanCancer Atlas Driver Mutation Working Group (the CGAT list; TCGA Research Network, "Comprehensive Discovery and Characterization of Driver Genes and Mutations in Human Cancers", unpublished data) that were identified as 1) having 10 or more mutations overall and 2) mutated in two or more tissues.	('CGAT', 'Gene', (160, 164))	('Human', 'Species', '9606', (273, 278))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Disease', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (352, 361))	('Cancer', 'Phenotype', 'HP:0002664', (279, 285))	('Cancers', 'Disease', (279, 286))	('Cancer', 'Disease', (279, 285))	('Cancers', 'Disease', 'MESH:D009369', (279, 286))	('Cancers', 'Phenotype', 'HP:0002664', (279, 286))	('Cancer', 'Disease', 'MESH:D009369', (279, 285))	('CGAT', 'Gene', '6570', (160, 164))
2244	29628290	Contributor: Eduard Porta Pardo We used domainXplorer to identify driver genes and mutations that correlate with the leukocyte fraction of the tumor sample.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
2245	29628290	The algorithm uses a linear model that takes into account potential biases caused by differences in the immune responses between the tissues of origin of the tumors, the gender of the patient, the total number of missense mutations in the sample or the patient's age as covariates.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('patient', 'Species', '9606', (253, 260))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('missense mutations', 'Var', (213, 231))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patient', 'Species', '9606', (184, 191))
2249	29628290	For each pathway, samples from each of 30 tumor types were divided into two groups of altered and intact cases based on acquisition of non-silent or frameshift mutations, heterozygous or homozygous deletions, or amplifications, in at least one member of the pathway.	('tumor type', 'Disease', (42, 52))	('amplifications', 'Var', (212, 226))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor type', 'Disease', 'MESH:D009369', (42, 52))
2259	29628290	To perform association analyses with single nucleotide polymorphisms (SNPs) at the PDL1 locus, we imputed the genotype data using the Haplotype Reference Consortium as a reference.	('PDL1', 'Gene', '29126', (83, 87))	('single nucleotide polymorphisms', 'Var', (37, 68))	('PDL1', 'Gene', (83, 87))
2268	29628290	Variation in sequencing coverage and tumor purity require careful consideration in order to mitigate the risk of impacting mutation calls and on pMHC, and prior to pMHC calling, sequencing data was subjected to rigorous harmonization efforts, performed by the PanCancer MC3 Consortium.	('Cancer', 'Disease', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('impacting', 'Reg', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutation calls', 'Var', (123, 137))	('Cancer', 'Disease', 'MESH:D009369', (263, 269))
2295	29628290	Using output from a PanCan GISTIC2.0 run on ISAR-corrected Affymetrix genome-wide human SNP6.0 array data, deep amplifications, shallow amplifications, non-alterations, shallow deletions, and deep deletions of each immunomodulator gene were called as described in "Genomic Correlations with Immune Phenotype" above for 8461 tumors that both were immune subtyped and had ABSOLUTE purity and ploidy calls.	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('non-alterations', 'Var', (152, 167))	('human', 'Species', '9606', (82, 87))	('tumors', 'Disease', (324, 330))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('shallow deletions', 'Var', (169, 186))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('deep deletions', 'Var', (192, 206))	('shallow amplifications', 'Var', (128, 150))
2311	29628290	Mutation or copy-number events identified by the domainXplorer algorithm were tested for statistical association with the 32 cMRs identified, using the DIGGIT algorithm (above), and retained if associated with one or more of the 32 cMRs in at least one tumor-specific context.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))	('copy-number', 'Var', (12, 23))
2344	29625051	Transcriptional and epigenetic dysregulation of cancer cells frequently leads to oncogenic de-differentiation and acquisition of stemness features by altering core signaling pathways that regulate the phenotypes of normal stem cells.	('altering', 'Reg', (150, 158))	('core signaling pathways', 'Pathway', (159, 182))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('epigenetic dysregulation', 'Var', (20, 44))	('acquisition', 'CPA', (114, 125))	('stemness features', 'CPA', (129, 146))	('oncogenic de-differentiation', 'CPA', (81, 109))	('leads to', 'Reg', (72, 80))	('dysregulation', 'Var', (31, 44))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
2384	29625051	This result could arise from a high frequency of IDH1/2 mutations and resulting DNA hypermethylation.	('IDH1/2', 'Gene', '3417;3418', (49, 55))	('DNA hypermethylation', 'MPA', (80, 100))	('mutations', 'Var', (56, 65))	('IDH1/2', 'Gene', (49, 55))
2387	29625051	BRCA samples with high mRNAsi were more likely to be ER-negative, and enriched for FAT3 and TP53 mutations.	('mutations', 'Var', (97, 106))	('BRCA', 'Gene', (0, 4))	('FAT3', 'Gene', (83, 87))	('TP53', 'Gene', (92, 96))	('TP53', 'Gene', '7157', (92, 96))	('FAT3', 'Gene', '120114', (83, 87))	('BRCA', 'Gene', '672', (0, 4))
2396	29625051	High mRNAsi was associated with higher expression of miR-181c-3p, miR-22-3p, and miR-30b-3p (Figure 3B, right bottom).	('miR-22-3p', 'Gene', '407008', (66, 75))	('higher', 'PosReg', (32, 38))	('miR-30b-3p', 'Var', (81, 91))	('miR-181c-3p', 'Var', (53, 64))	('expression', 'MPA', (39, 49))	('miR-22-3p', 'Gene', (66, 75))
2397	29625051	We found a strong association between high mDNAsi, high pathologic grade and recently published molecular subtypes of glioma (Figure 3C).	('glioma', 'Disease', (118, 124))	('high', 'Var', (38, 42))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('mole', 'Phenotype', 'HP:0003764', (96, 100))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
2398	29625051	mDNAsi was low in less aggressive gliomas that are characterized by codel and G-CIMP-high features and was highest in highly aggressive GBMs characterized by IDH mutations (G-CIMP-low) and poor clinical outcome.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('aggressive gliomas', 'Disease', 'MESH:D005910', (23, 41))	('mutations', 'Var', (162, 171))	('IDH', 'Gene', '3417', (158, 161))	('less', 'Disease', (18, 22))	('G-CIMP', 'Chemical', '-', (173, 179))	('low', 'NegReg', (11, 14))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('aggressive gliomas', 'Disease', (23, 41))	('G-CIMP', 'Chemical', '-', (78, 84))	('IDH', 'Gene', (158, 161))	('highest', 'Reg', (107, 114))
2399	29625051	Also, high mDNAsi is strongly associated with more aggressive classical and mesenchymal subtypes of GBM, suggesting that it can stratify tumors with distinct clinical outcomes.	('associated', 'Reg', (30, 40))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('GBM', 'Disease', (100, 103))	('high', 'Var', (6, 10))	('mDNAsi', 'Gene', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
2400	29625051	We also found that high mDNAsi was associated with mutations in NF1 and EGFR and infrequent mutations in IDH1, TP53, CIC, and ATRX (Figure 3C, left), with higher expression of ANNEXIN-A1 protein and lower expression of ANNEXIN-A7, and with expression of the miR-200 family (Figure 3C, right bottom).	('mutations', 'Var', (51, 60))	('EGFR', 'Gene', '1956', (72, 76))	('ATRX', 'Gene', (126, 130))	('mDNAsi', 'Disease', (24, 30))	('NF1', 'Gene', (64, 67))	('IDH1', 'Gene', '3417', (105, 109))	('ATRX', 'Gene', '546', (126, 130))	('ANNEXIN-A7', 'Gene', '310', (219, 229))	('TP53', 'Gene', '7157', (111, 115))	('CIC', 'Gene', (117, 120))	('ANNEXIN-A7', 'Gene', (219, 229))	('higher', 'PosReg', (155, 161))	('ANNEXIN-A1', 'Gene', (176, 186))	('lower', 'NegReg', (199, 204))	('EGFR', 'Gene', (72, 76))	('expression', 'MPA', (205, 215))	('ANNEXIN-A1', 'Gene', '301', (176, 186))	('IDH1', 'Gene', (105, 109))	('TP53', 'Gene', (111, 115))	('expression', 'MPA', (162, 172))	('NF1', 'Gene', '4763', (64, 67))
2403	29625051	IDH1 mutations are known to reduce cell differentiation, and high values of the mRNAsi in a subset of IDH mutant gliomas might capture this phenomenon.	('IDH', 'Gene', '3417', (102, 105))	('IDH', 'Gene', (0, 3))	('mutant', 'Var', (106, 112))	('mRNAsi', 'MPA', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('cell differentiation', 'CPA', (35, 55))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Disease', (113, 120))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('reduce', 'NegReg', (28, 34))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('IDH1', 'Gene', (0, 4))	('IDH', 'Gene', (102, 105))	('IDH1', 'Gene', '3417', (0, 4))
2406	29625051	The most salient associations of mRNAsi and mDNAsi are presented in Figure 4, while the following results of the comprehensive analyses are shown in the supplementary material: associations with mutations (Figure S3), associations with miRNA expression and protein abundance (Figure S4), associations with the tumor grading and clinical outcome (Figure S5).	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('miRNA expression', 'MPA', (236, 252))	('tumor', 'Disease', (310, 315))	('mutations', 'Var', (195, 204))	('protein abundance', 'MPA', (257, 274))	('associations', 'Interaction', (218, 230))	('associations', 'Interaction', (288, 300))	('associations', 'Interaction', (177, 189))
2407	29625051	We found a strong association between mDNAsi and known molecular subtypes, somatic mutations in SETD2 and TP53 genes, and with tobacco smoking status in LUAD (Figures 4A and S3).	('mutations', 'Var', (83, 92))	('tobacco', 'Species', '4097', (127, 134))	('mDNAsi', 'Disease', (38, 44))	('SETD2', 'Gene', '29072', (96, 101))	('mole', 'Phenotype', 'HP:0003764', (55, 59))	('SETD2', 'Gene', (96, 101))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
2414	29625051	Analyses of HNSC samples revealed that high indices are correlated with NSD1 mutation, E-cadherin protein expression, miR-200-3p, and previously identified classical molecular subtypes (Figure 4B).	('NSD1', 'Gene', '64324', (72, 76))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('mole', 'Phenotype', 'HP:0003764', (166, 170))	('mutation', 'Var', (77, 85))	('miR-200-3p', 'Var', (118, 128))	('expression', 'MPA', (106, 116))	('NSD1', 'Gene', (72, 76))
2415	29625051	NSD1 mutation was recently linked in HNSC tumors to blockade of cellular differentiation and promotion of oncogenesis.	('cellular differentiation', 'CPA', (64, 88))	('NSD1', 'Gene', (0, 4))	('linked', 'Reg', (27, 33))	('promotion', 'PosReg', (93, 102))	('oncogenesis', 'CPA', (106, 117))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('HNSC tumors', 'Disease', 'MESH:D009369', (37, 48))	('blockade', 'NegReg', (52, 60))	('mutation', 'Var', (5, 13))	('NSD1', 'Gene', '64324', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('HNSC tumors', 'Disease', (37, 48))
2424	29625051	Detailed analyses of ACC samples revealed an association between high mRNAsi and defined molecular subtypes, clinical stage, and mutations in PRKAR1A and TP53 genes (Figure 4D).	('TP53', 'Gene', (154, 158))	('ACC', 'Gene', (21, 24))	('PRKAR1A', 'Gene', '5573', (142, 149))	('mutations', 'Var', (129, 138))	('ACC', 'Gene', '31', (21, 24))	('mole', 'Phenotype', 'HP:0003764', (89, 93))	('PRKAR1A', 'Gene', (142, 149))	('TP53', 'Gene', '7157', (154, 158))
2431	29625051	Roughly 80% of LGG tumors carry an IDH1/2 mutation and, as demonstrated by our group and others, tconfers a genome-wide hypermethylator phenotype (G-CIMP).	('IDH1/2', 'Gene', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('LGG tumors', 'Disease', (15, 25))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('mutation', 'Var', (42, 50))	('hypermethylator', 'MPA', (120, 135))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('LGG tumors', 'Disease', 'MESH:D009369', (15, 25))	('G-CIMP', 'Chemical', '-', (147, 153))
2434	29625051	Compared to G-CIMP-high tumors, G-CIMP-low tumors are known to be more proliferative, express cell-cycle-related genes, and have various stem cell-like genomic features.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('G-CIMP-low', 'Var', (32, 42))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('G-CIMP', 'Chemical', '-', (12, 18))	('proliferative', 'CPA', (71, 84))	('G-CIMP', 'Chemical', '-', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('more', 'PosReg', (66, 70))	('cell-cycle-related', 'Gene', (94, 112))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
2489	29625051	High mRNAsi was associated with basal breast carcinomas but also Her2 and lumB subtypes that are more aggressive than the hormone-dependent lumA group.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('associated', 'Reg', (16, 26))	('Her2', 'Gene', '2064', (65, 69))	('lumA', 'Gene', (140, 144))	('breast carcinomas', 'Disease', 'MESH:D001943', (38, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('breast carcinomas', 'Disease', (38, 55))	('High mRNAsi', 'Var', (0, 11))	('breast carcinomas', 'Phenotype', 'HP:0003002', (38, 55))	('lumB', 'Disease', (74, 78))	('Her2', 'Gene', (65, 69))	('lumA', 'Gene', '79188', (140, 144))
2490	29625051	In contrast, high mDNAsi was strongly associated with high-grade glioblastomas, poor overall and progression-free survival.	('mDNAsi', 'Gene', (18, 24))	('associated', 'Reg', (38, 48))	('poor', 'NegReg', (80, 84))	('high', 'Var', (13, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (65, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (65, 78))	('glioblastomas', 'Disease', (65, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))
2492	29625051	Dedifferentiated cells can arise from different sources: from long-lived stem or progenitor cells that accumulate mutations in oncogenic pathways, or via dedifferentiation from non-stem cancer cells that convert to CSCs through deregulation of developmental and/or non-developmental pathways.	('deregulation', 'Reg', (228, 240))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('oncogenic pathways', 'Pathway', (127, 145))	('developmental and/or', 'Pathway', (244, 264))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
2498	29625051	Cancer cells in many primary solid tumors are basically epithelial regardless of their degrees of dedifferentiation, but some cells in such contexts could acquire mesenchymal characteristics, either by accumulating additional mutations or by undergoing epigenetic changes shaped by the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('solid tumors', 'Disease', 'MESH:D009369', (29, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('epigenetic changes', 'Var', (253, 271))	('undergoing', 'Reg', (242, 252))	('mutations', 'Var', (226, 235))	('mesenchymal characteristics', 'CPA', (163, 190))	('acquire', 'PosReg', (155, 162))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('solid tumors', 'Disease', (29, 41))	('accumulating', 'PosReg', (202, 214))
2538	29625051	Additionally, we downloaded independent, non-TCGA datasets of gliomas [ (GSE36245, GSE36278) and (GSE30339)] and BRCA samples (GSE59000) and applied our metrics to measure the stemness in the validation data.	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('GSE59000', 'Var', (127, 135))	('BRCA', 'Gene', '672', (113, 117))	('GSE30339)]', 'Var', (98, 108))	('gliomas', 'Disease', (62, 69))	('BRCA', 'Gene', (113, 117))	('GSE36278', 'Var', (83, 91))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
2542	29625051	To eliminate somatic tissue-specific probes, we removed probes that were consistently methylated (standard deviation beta value > 0.05) in non-tumor adult tissues available through TCGA.	('non-tumor', 'Disease', 'MESH:D009369', (139, 148))	('methylated', 'Var', (86, 96))	('non-tumor', 'Disease', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
2578	28989884	Adrenocortical tumors (ACTs) diagnosed on resected specimens including the variants during January 2010-June 2016 were retrieved from the pathology records.	('ACTs', 'Phenotype', 'HP:0100641', (23, 27))	('Adrenocortical tumors', 'Disease', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Adrenocortical tumors', 'Disease', 'MESH:D018268', (0, 21))	('variants', 'Var', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
2763	27590329	However, on a subset analysis of T4M0 tumors, a survival benefit was noted if any lymphadenectomy was performed.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('T4M0', 'Var', (33, 37))
2764	27590329	Another finding in our study that deserves attention was that the effort to perform a LAD was not associated with increased morbidity or mortality, despite the fact that LAD patients had larger tumors, often requiring multivisceral resections.	('tumors', 'Disease', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('patients', 'Species', '9606', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('LAD', 'Var', (170, 173))
2833	19059462	Analysis of constructs containing sequential deletions of the HSD3B2 promoter suggested a putative regulatory element between -166 and -101.	('deletions', 'Var', (45, 54))	('HSD3B2', 'Gene', '3284', (62, 68))	('HSD3B2', 'Gene', (62, 68))
2834	19059462	Mutation of an inverted repeat between -137 and -124 completely blocked CDCA/FXR induced reporter activity.	('CDCA/FXR induced reporter activity', 'MPA', (72, 106))	('blocked', 'NegReg', (64, 71))	('Mutation', 'Var', (0, 8))	('CDCA', 'Chemical', 'MESH:D002635', (72, 76))
2838	19059462	Alterations in this enzyme would influence the capacity of the adrenal gland to produce corticosteroids.	('Alterations', 'Var', (0, 11))	('steroids', 'Chemical', 'MESH:D013256', (95, 103))	('influence', 'Reg', (33, 42))
2873	19059462	The 5' flanking DNA from the human HSD3B2 gene (-963), CYP11A1 (-1680), CYP17 (-1124) and StAR (-1300) was inserted upstream of the firefly luciferase gene in the reporter vector pGL3 Basic (Promega, Madison, WI).	('HSD3B2', 'Gene', (35, 41))	('HSD3B2', 'Gene', '3284', (35, 41))	('pGL3', 'Gene', '6391', (179, 183))	('-963', 'Var', (48, 52))	('CYP17', 'Gene', (72, 77))	('CYP11A1', 'Gene', '1583', (55, 62))	('human', 'Species', '9606', (29, 34))	('CYP17', 'Gene', '1586', (72, 77))	('pGL3', 'Gene', (179, 183))	('CYP11A1', 'Gene', (55, 62))
2875	19059462	Mutations to putative FXR and NGFI-B binding sites in the HSD3B2 promoter were created using the QuikChange XL site-directed mutagenesis kit (Stratagene, La Jolla, CA) following the manufacturer's recommendations.	('HSD3B2', 'Gene', '3284', (58, 64))	('Mutations', 'Var', (0, 9))	('NGFI-B', 'Gene', '3164', (30, 36))	('NGFI-B', 'Gene', (30, 36))	('HSD3B2', 'Gene', (58, 64))
2876	19059462	In the NGFI-B response element mutant construct, the sequence 5'-AAAGGTCA-3' (-131/-124) was changed to 5'-AgAatTCA-3', and in the FXR response element mutant construct, the sequence 5'-TAACCTAA-3' (-137/-130) was changed to 5'-TAgaCTAA-3'.	('mutant', 'Var', (31, 37))	('NGFI-B', 'Gene', (7, 13))	('NGFI-B', 'Gene', '3164', (7, 13))
2904	19059462	FXR expression was relatively high in both the adult (0.12 attomoles/mug 18S RNA) and fetal (0.097 attomoles/mug 18S RNA) adrenal, although it was still less than half the value seen in liver (0.29 attomoles/mug 18S RNA).	('0.097 attomoles/mug', 'Var', (93, 112))	('FXR expression', 'MPA', (0, 14))	('high', 'PosReg', (30, 34))	('expression', 'Species', '29278', (4, 14))
2911	19059462	3A, OSTalpha was the top gene stimulated by treatment of FXR ligand GW4064.	('GW4064', 'Chemical', 'MESH:C412815', (68, 74))	('OSTalpha', 'Gene', '200931', (4, 12))	('OSTalpha', 'Gene', (4, 12))	('stimulated', 'PosReg', (30, 40))	('GW4064', 'Var', (68, 74))
2915	19059462	Data from three experiments demonstrated that GW4064 caused a 12-fold increase in HSD3B2 mRNA levels.	('increase', 'PosReg', (70, 78))	('HSD3B2', 'Gene', (82, 88))	('HSD3B2', 'Gene', '3284', (82, 88))	('GW4064', 'Var', (46, 52))	('GW4064', 'Chemical', 'MESH:C412815', (46, 52))	('mRNA levels', 'MPA', (89, 100))
2917	19059462	GW4064 had a greater stimulatory effect for both FXR-mediated HSD3B2 and OSTalpha mRNA expression (Fig.	('stimulatory effect', 'MPA', (21, 39))	('GW4064', 'Var', (0, 6))	('GW4064', 'Chemical', 'MESH:C412815', (0, 6))	('expression', 'Species', '29278', (87, 97))	('OSTalpha', 'Gene', '200931', (73, 81))	('OSTalpha', 'Gene', (73, 81))	('HSD3B2', 'Gene', (62, 68))	('HSD3B2', 'Gene', '3284', (62, 68))
2926	19059462	A previous study indicated that this region also contains a consensus NGFI-B response element (NBRE) at -131 to -124.	('NGFI-B', 'Gene', '3164', (70, 76))	('at -131 to -124', 'Var', (101, 116))	('NGFI-B', 'Gene', (70, 76))
2932	19059462	3), FXR binding to HSD3B2 promoter was also increased with the synthetic ligand GW4064.	('GW4064', 'Var', (80, 86))	('GW4064', 'Chemical', 'MESH:C412815', (80, 86))	('HSD3B2', 'Gene', (19, 25))	('FXR binding', 'MPA', (4, 15))	('HSD3B2', 'Gene', '3284', (19, 25))	('increased', 'PosReg', (44, 53))
2943	19059462	The recent study by Auwerx and colleagues showed that FXR expression in mouse adrenal glands can be stimulated by oral feeding of the agonist GW4064.	('expression', 'Species', '29278', (58, 68))	('mouse', 'Species', '10090', (72, 77))	('GW4064', 'Var', (142, 148))	('GW4064', 'Chemical', 'MESH:C412815', (142, 148))	('FXR expression', 'Gene', (54, 68))	('stimulated', 'PosReg', (100, 110))
2989	33513905	Somatic pathogenic variants and structural variations, which cause the deletion of multiple exons of ATRX were associated with germline TP53 pathogenic variants in a pediatric cohort.	('associated', 'Reg', (111, 121))	('deletion', 'Var', (71, 79))	('ATRX', 'Gene', (101, 105))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))	('variants', 'Var', (19, 27))
2990	33513905	reported alterations in TP53 and ATRX in 32% of their cohort, and these alterations were associated with advanced disease and poor event-free survival in pediatric patients with adrenocortical tumor.	('associated', 'Reg', (89, 99))	('TP53', 'Gene', (24, 28))	('alterations', 'Var', (9, 20))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (178, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('patients', 'Species', '9606', (164, 172))	('adrenocortical tumor', 'Disease', (178, 198))	('ATRX', 'Gene', (33, 37))	('advanced disease', 'Disease', (105, 121))	('TP53', 'Gene', '7157', (24, 28))
2992	33513905	studied an adult ACC cohort and reported a frequency of 19.3% for ACCs with deletions or non-silent somatic pathogenic variants in the ZNRF3 gene.	('ACCs', 'Gene', '84680', (66, 70))	('deletions', 'Var', (76, 85))	('ZNRF3', 'Gene', (135, 140))	('ACCs', 'Gene', (66, 70))
2998	33513905	showed the most frequent mutated genes as ZNRF3 (21%), CTNNB1 (16%), TP53 (16%), and CDKN2A (11%).	('CTNNB1', 'Gene', '1499', (55, 61))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('21%', 'Gene', (49, 52))	('CDKN2A', 'Gene', (85, 91))	('21%', 'Gene', '6700', (49, 52))	('CDKN2A', 'Gene', '1029', (85, 91))	('ZNRF3', 'Gene', (42, 47))	('CTNNB1', 'Gene', (55, 61))	('mutated', 'Var', (25, 32))
3006	33513905	In addition, the Cox regression of OS showed a hazard ratio (HR) of 0.521 (95%CI, 0.273-0.997) for ATRX expression of >1.5 when compared with expression of <=1.5 (Wald = 3.881; df1; p = 0.049; Cox's proportional hazards model).	('Cox', 'Gene', '1351', (17, 20))	('ATRX', 'Gene', (99, 103))	('Cox', 'Gene', (17, 20))	('Cox', 'Gene', '1351', (193, 196))	('Cox', 'Gene', (193, 196))	('expression', 'Var', (104, 114))
3008	33513905	Tumors with high ZNRF3 expression presented with lower Weiss score (average 4.7) than the group with low ZNRF3 expression (average 6.1) (Z = -2.942; p = 0.003; Mann-Whitney U test).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('high', 'Var', (12, 16))	('expression', 'Var', (23, 33))	('Tumors', 'Disease', (0, 6))	('ZNRF3', 'Gene', (17, 22))	('lower', 'NegReg', (49, 54))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Weiss score', 'CPA', (55, 66))
3023	33513905	The Cox regression of RFS showed an HR of 0.332 (95% CI, 0.111-0.932) for ATRX expression >2.7 compared with the value for an expression level of <=2.7 (Wald = 4.365; df1; p = 0.037; Cox's proportional hazards model).	('Cox', 'Gene', '1351', (4, 7))	('Cox', 'Gene', (4, 7))	('Cox', 'Gene', '1351', (183, 186))	('Cox', 'Gene', (183, 186))	('>2.7', 'Var', (90, 94))	('ATRX', 'Gene', (74, 78))
3026	33513905	Categorization of the Ki-67 proliferation marker into groups (<10%, >=10% and <20%, >=20%) impacted the RFS curve (X2(2) = 16.357; p < 0.001; Kaplan-Meier method and log rank test), as seen in Figure 9.	('Ki-67', 'Gene', '17345', (22, 27))	('RFS curve', 'MPA', (104, 113))	('impacted', 'Reg', (91, 99))	('Ki-67', 'Gene', (22, 27))	('<10%', 'Var', (62, 66))
3036	33513905	analyzed 9127 patients and 31 cancer types and showed that inactivation of ATRX is associated with telomere length elongation, reinforcing the idea of an association between ATRX and ALT.	('ATRX', 'Gene', (75, 79))	('telomere length', 'MPA', (99, 114))	('inactivation', 'Var', (59, 71))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('associated', 'Reg', (83, 93))	('patients', 'Species', '9606', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
3037	33513905	Cohorts of different malignancies have shown that ATRX alterations have prognostic value.	('malignancies', 'Disease', (21, 33))	('ATRX', 'Gene', (50, 54))	('malignancies', 'Disease', 'MESH:D009369', (21, 33))	('alterations', 'Var', (55, 66))
3053	33513905	The high expression of ZNRF3 was associated with smaller tumors in our cohort.	('ZNRF3', 'Gene', (23, 28))	('smaller', 'NegReg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('high', 'Var', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
3057	33513905	They also revealed that ZNRF3 overexpression causes significantly more apoptosis and lowered proliferation of cancer cells by reducing the level of Lgr5, a component of Wnt/beta-catenin signaling, while also reducing Gli1, a component of Hedgehog signaling (SHH).	('Lgr5', 'Gene', (148, 152))	('cancer', 'Disease', (110, 116))	('lowered', 'NegReg', (85, 92))	('apoptosis', 'CPA', (71, 80))	('SHH', 'Gene', (258, 261))	('proliferation', 'CPA', (93, 106))	('reducing', 'NegReg', (126, 134))	('Gli1', 'Gene', '2735', (217, 221))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Lgr5', 'Gene', '8549', (148, 152))	('ZNRF3', 'Gene', (24, 29))	('level', 'MPA', (139, 144))	('reducing', 'NegReg', (208, 216))	('more', 'PosReg', (66, 70))	('overexpression', 'Var', (30, 44))	('SHH', 'Gene', '6469', (258, 261))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('Gli1', 'Gene', (217, 221))
3063	33513905	The Cox regression showed an HR of 0.441 (95% CI, 0.229-0.852) for tumors with high ZNRF3 expression; furthermore, this factor was positively associated with a better RFS than the loss of its expression.	('Cox', 'Gene', '1351', (4, 7))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('Cox', 'Gene', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('expression', 'MPA', (90, 100))	('high', 'Var', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('RFS', 'MPA', (167, 170))	('tumors', 'Disease', (67, 73))	('ZNRF3', 'Gene', (84, 89))
3068	33513905	Tumors with active Wnt/beta-catenin signaling due to CTNNB1, ZNRF3, or APC mutations present a dismal prognosis, according to TCGA Research Network.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('APC', 'Disease', (71, 74))	('ZNRF3', 'Gene', (61, 66))	('CTNNB1', 'Gene', '1499', (53, 59))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('active Wnt/beta-catenin signaling', 'MPA', (12, 45))	('mutations', 'Var', (75, 84))	('APC', 'Disease', 'MESH:D011125', (71, 74))	('CTNNB1', 'Gene', (53, 59))
3071	33513905	Regarding germline TP53 pathogenic variants, two patients presented TP53 p.R337H variant (cases 51 and 58), and one patient presented TP53 p.R273H (case 68) (Table S2).	('TP53', 'Gene', (134, 138))	('patient', 'Species', '9606', (116, 123))	('p.R273H', 'Mutation', 'rs28934576', (139, 146))	('patient', 'Species', '9606', (49, 56))	('p.R337H', 'Var', (73, 80))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('patients', 'Species', '9606', (49, 57))	('TP53', 'Gene', '7157', (68, 72))	('p.R337H', 'Mutation', 'rs121912664', (73, 80))	('TP53', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (134, 138))
3073	33513905	It remains unclear as to whether an association between the loss of ATRX expression and germline TP53 pathogenic variants exists and could impact OS in the adult ACC population.	('impact', 'Reg', (139, 145))	('ATRX', 'Protein', (68, 72))	('TP53', 'Gene', '7157', (97, 101))	('loss', 'NegReg', (60, 64))	('TP53', 'Gene', (97, 101))	('variants', 'Var', (113, 121))
3108	30664326	S1PR2 inhibition significantly abolished TCDCA-induced cortisol secretion, lowered phosphorylation of ERK and abrogated enhanced transcription of steroidogenesis-related genes in H295R cells.	('transcription', 'MPA', (129, 142))	('lowered', 'NegReg', (75, 82))	('ERK', 'Protein', (102, 105))	('abrogated', 'NegReg', (110, 119))	('enhanced', 'PosReg', (120, 128))	('TCDCA', 'Chemical', 'MESH:D013655', (41, 46))	('abolished', 'NegReg', (31, 40))	('steroidogenesis-related genes', 'Gene', (146, 175))	('phosphorylation', 'MPA', (83, 98))	('cortisol', 'Chemical', 'MESH:D006854', (55, 63))	('inhibition', 'Var', (6, 16))	('steroid', 'Chemical', 'MESH:D013256', (146, 153))	('cortisol secretion', 'MPA', (55, 73))	('S1PR2', 'Gene', (0, 5))
3111	30664326	Treatment with SF-1 inverse agonist AC45594 also reduced TCDCA-induced steroidogenesis.	('reduced', 'NegReg', (49, 56))	('SF-1', 'Gene', (15, 19))	('TCDCA-induced', 'Disease', (57, 70))	('TCDCA', 'Chemical', 'MESH:D013655', (57, 62))	('SF-1', 'Gene', '2516', (15, 19))	('AC45594', 'Chemical', 'MESH:C527833', (36, 43))	('AC45594', 'Var', (36, 43))	('steroid', 'Chemical', 'MESH:D013256', (71, 78))
3112	30664326	Our findings indicate that supraphysiological bile acid levels as observed in cholestasis stimulate steroidogenesis via an S1PR2-ERK-SF-1 signalling pathway.	('cholestasis', 'Disease', 'MESH:D002779', (78, 89))	('cholestasis', 'Disease', (78, 89))	('supraphysiological', 'Var', (27, 45))	('SF-1', 'Gene', (133, 137))	('steroid', 'Chemical', 'MESH:D013256', (100, 107))	('bile acid', 'Gene', '230101', (46, 55))	('bile acid', 'Gene', (46, 55))	('cholestasis', 'Phenotype', 'HP:0001396', (78, 89))	('stimulate', 'PosReg', (90, 99))	('steroidogenesis', 'MPA', (100, 115))	('SF-1', 'Gene', '2516', (133, 137))
3115	30664326	Our findings indicate that supraphysiological bile acid levels modulate adrenal gland function with potential important clinical implications.	('adrenal gland function', 'CPA', (72, 94))	('supraphysiological', 'Var', (27, 45))	('bile acid', 'Gene', '230101', (46, 55))	('bile acid', 'Gene', (46, 55))	('modulate', 'Reg', (63, 71))
3155	30664326	Serum corticosterone levels significantly increased more than twofolds in CBDL mice compared to sham-operated controls (Figure 1A).	('increased', 'PosReg', (42, 51))	('CBDL', 'Var', (74, 78))	('mice', 'Species', '10090', (79, 83))	('Serum corticosterone levels', 'MPA', (0, 27))	('corticosterone', 'Chemical', 'MESH:D003345', (6, 20))	('rat', 'Species', '10116', (104, 107))
3169	30664326	Comparable to our findings in the animal models, TCDCA significantly stimulated STAR, CYP21A2 (homologue of mouse Cyp21a1) and HSD3B2 (homologue of mouse Hsd3b1) mRNA expression in H295R cells in a dose-dependent manner (Figure 3B).	('STAR', 'Gene', (80, 84))	('stimulated', 'PosReg', (69, 79))	('TCDCA', 'Var', (49, 54))	('CYP21A2', 'Gene', '1589', (86, 93))	('Cyp21a1', 'Gene', '13079', (114, 121))	('CYP21A2', 'Gene', (86, 93))	('TCDCA', 'Chemical', 'MESH:D013655', (49, 54))	('mouse', 'Species', '10090', (148, 153))	('mouse', 'Species', '10090', (108, 113))	('Hsd3b1', 'Gene', '15492', (154, 160))	('Hsd3b1', 'Gene', (154, 160))	('HSD3B2', 'Gene', (127, 133))	('Cyp21a1', 'Gene', (114, 121))	('mRNA expression', 'MPA', (162, 177))
3175	30664326	When H295R cells were incubated with 10 mumol/L U0126, induction of cortisol secretion and mRNA levels of STAR, HSD3B2 and CYP21A2 by TCDCA was completely abolished (Figure 3E,F).	('U0126', 'Chemical', 'MESH:C113580', (48, 53))	('cortisol secretion', 'MPA', (68, 86))	('cortisol', 'Chemical', 'MESH:D006854', (68, 76))	('abolished', 'NegReg', (155, 164))	('mRNA levels', 'MPA', (91, 102))	('STAR', 'MPA', (106, 110))	('U0126', 'Var', (48, 53))	('TCDCA', 'Chemical', 'MESH:D013655', (134, 139))	('CYP21A2', 'Gene', (123, 130))	('CYP21A2', 'Gene', '1589', (123, 130))
3176	30664326	STAR protein levels were not increased upon U0126 co-treatment in contrast to TCDCA treatment alone (Figure S1B).	('U0126', 'Var', (44, 49))	('U0126', 'Chemical', 'MESH:C113580', (44, 49))	('STAR protein levels', 'MPA', (0, 19))	('TCDCA', 'Chemical', 'MESH:D013655', (78, 83))
3181	30664326	In line with our chemical inhibitor experiments, TCDCA-induced cortisol secretion, phosphorylation of ERK and mRNA levels of steroidogenesis-related genes in siRNA-transfected cells were also reduced significantly (Figure 5B-E).	('TCDCA-induced', 'Var', (49, 62))	('TCDCA', 'Chemical', 'MESH:D013655', (49, 54))	('mRNA levels of steroidogenesis-related', 'MPA', (110, 148))	('phosphorylation', 'MPA', (83, 98))	('cortisol', 'Chemical', 'MESH:D006854', (63, 71))	('cortisol secretion', 'MPA', (63, 81))	('ERK', 'Gene', (102, 105))	('steroid', 'Chemical', 'MESH:D013256', (125, 132))	('reduced', 'NegReg', (192, 199))
3184	30664326	However, when H295R cells were incubated with 400 mumol/L TCDCA plus AC45594, a SF-1 inverse agonist, TCDCA-induced cortisol secretion was reduced by 65% (Figure 6B).	('TCDCA', 'Chemical', 'MESH:D013655', (58, 63))	('cortisol secretion', 'MPA', (116, 134))	('SF-1', 'Gene', (80, 84))	('cortisol', 'Chemical', 'MESH:D006854', (116, 124))	('AC45594', 'Var', (69, 76))	('AC45594', 'Chemical', 'MESH:C527833', (69, 76))	('SF-1', 'Gene', '2516', (80, 84))	('reduced', 'NegReg', (139, 146))	('TCDCA', 'Chemical', 'MESH:D013655', (102, 107))
3185	30664326	The treatment with AC45594 also successfully abolished the enhanced mRNA levels of STAR, HSD3B2 and CYP21A2 (Figure 6C).	('CYP21A2', 'Gene', (100, 107))	('HSD3B2', 'MPA', (89, 95))	('CYP21A2', 'Gene', '1589', (100, 107))	('abolished', 'NegReg', (45, 54))	('enhanced', 'PosReg', (59, 67))	('AC45594', 'Var', (19, 26))	('AC45594', 'Chemical', 'MESH:C527833', (19, 26))	('mRNA levels of STAR', 'MPA', (68, 87))
3191	30664326	Application of the agonists for FXR (INT-747) and TGR5 (INT-777) failed to increase cortisol secretion in vitro.	('cortisol', 'Chemical', 'MESH:D006854', (84, 92))	('cortisol secretion', 'MPA', (84, 102))	('INT-777', 'Var', (56, 63))	('TGR5', 'Gene', (50, 54))	('increase cortisol', 'Phenotype', 'HP:0003118', (75, 92))	('INT-747', 'Var', (37, 44))	('increase', 'PosReg', (75, 83))
3196	30664326	These effects appear to depend on S1PR2, since S1RP2 inhibition attenuated TCDCA-induced downstream signalling via the ERK pathway, which is in line with a previous report from rat hepatocytes using conjugated bile acids.25 S1PR2 activation does probably not directly lead to ERK phosphorylation but is mediated indirectly via the epidermal growth factor receptor (EGFR) as suggested in a previous study.29, 30 The overall importance of the ERK signalling pathways for our findings is highlighted by separate experiments, which show that direct inhibition of ERK abrogated TCDCA-induced cortisol production and transcriptional effects.	('transcriptional', 'MPA', (611, 626))	('TCDCA', 'Chemical', 'MESH:D013655', (573, 578))	('EGFR', 'Gene', '24329', (365, 369))	('rat', 'Species', '10116', (177, 180))	('rat', 'Species', '10116', (504, 507))	('TCDCA-induced cortisol production', 'MPA', (573, 606))	('inhibition', 'Var', (545, 555))	('cortisol', 'Chemical', 'MESH:D006854', (587, 595))	('bile acids', 'Chemical', 'MESH:D001647', (210, 220))	('ERK', 'Gene', (559, 562))	('EGFR', 'Gene', (365, 369))	('epidermal growth factor receptor', 'Gene', '24329', (331, 363))	('TCDCA', 'Chemical', 'MESH:D013655', (75, 80))	('epidermal growth factor receptor', 'Gene', (331, 363))	('abrogated', 'NegReg', (563, 572))
3198	30664326	The potential downstream transcription factor for ERK signalling is SF-1, a nuclear transcription factor, which is well established to regulate the transcription of a wide range of steroidogenesis-related enzymes including STAR, HSD3B2 and CYP21.31, 32 ERK directs the transactivation activity of SF-1 in steroidogenic tissues.33 In our study, TCDCA increased SF-1 transactivation activity, which at least to our knowledge, has not been noted before.	('TCDCA', 'Var', (344, 349))	('SF-1', 'Gene', '2516', (360, 364))	('SF-1', 'Gene', (68, 72))	('SF-1', 'Gene', (297, 301))	('increased', 'PosReg', (350, 359))	('steroid', 'Chemical', 'MESH:D013256', (181, 188))	('TCDCA', 'Chemical', 'MESH:D013655', (344, 349))	('SF-1', 'Gene', '2516', (297, 301))	('CYP21', 'Gene', (240, 245))	('transactivation activity', 'MPA', (365, 389))	('SF-1', 'Gene', (360, 364))	('SF-1', 'Gene', '2516', (68, 72))	('CYP21', 'Gene', '1589', (240, 245))	('steroid', 'Chemical', 'MESH:D013256', (305, 312))
3201	30664326	This could be related to reduced SF-1 protein stability because of reduced ERK phosphorylation, a mechanism which has been described for PKA-mediated phosphorylation of SF-1 before.34 Together, our data clearly demonstrate that inhibition of the S1PR2-MEK-ERK-SF-1 pathway at several signalling levels abrogates the effects of TCDCA on adrenocortical cells, highlighting the importance of this distinct pathway in bile acid-induced steroidogenesis.	('inhibition', 'Var', (228, 238))	('SF-1', 'Gene', '2516', (260, 264))	('abrogates', 'NegReg', (302, 311))	('SF-1', 'Gene', (169, 173))	('SF-1', 'Gene', (33, 37))	('TCDCA', 'Chemical', 'MESH:D013655', (327, 332))	('steroid', 'Chemical', 'MESH:D013256', (432, 439))	('reduced ERK', 'Phenotype', 'HP:0000654', (67, 78))	('bile acid', 'Gene', (414, 423))	('SF-1', 'Gene', (260, 264))	('bile acid', 'Gene', '230101', (414, 423))	('rat', 'Species', '10116', (218, 221))	('SF-1', 'Gene', '2516', (33, 37))	('SF-1', 'Gene', '2516', (169, 173))	('MEK', 'Gene', (252, 255))	('MEK', 'Gene', '5609', (252, 255))	('adrenocortical cells', 'MPA', (336, 356))
3217	27764813	In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts.	('tumor', 'Disease', (63, 68))	('ACC', 'Gene', '31', (80, 83))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('status', 'Var', (116, 122))	('SF-1 and EGF-receptor', 'Gene', '7536;1956', (94, 115))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('ACC', 'Gene', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('human', 'Species', '9606', (57, 62))
3246	27764813	Moreover, we detected significantly reduced tumor sizes in LEDP-M-treated tumors in comparison with EDP-M-treated tumors following the second therapeutic cycle as depicted by stars (Figure 1K,).	('tumor', 'Disease', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('LEDP-M-treated', 'Var', (59, 73))	('tumor', 'Disease', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('EDP-M', 'Chemical', '-', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (114, 119))	('EDP-M', 'Chemical', '-', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (114, 120))	('reduced', 'NegReg', (36, 43))	('tumors', 'Disease', (74, 80))
3296	27764813	In addition to its value as prognostic marker, the Ki67 Index has been recently integrated in treatment flow charts for ACC patients and represents thereby an important determinant for ACC tumors.	('ACC', 'Gene', (120, 123))	('ACC', 'Gene', (185, 188))	('Ki67 Index', 'Var', (51, 61))	('ACC', 'Gene', '31', (120, 123))	('rat', 'Species', '10116', (85, 88))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('ACC', 'Gene', '31', (185, 188))	('ACC', 'Phenotype', 'HP:0006744', (120, 123))	('ACC', 'Phenotype', 'HP:0006744', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('patients', 'Species', '9606', (124, 132))
3302	27764813	Genetic analyses of known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and of genes recently reported to be of importance in ACC (ZNRF3, DAXX, TERT and MED12) revealed in the original patient tumor (also representing passage 1) a somatic mutation in TP53 (a frameshift deletion: Hg19 positions: 7574003 on Chr 17: G is deleted) while the tumor was devoid of mutations in any of the other investigated genes (T91/L91 in).	('DAXX', 'Gene', '1616', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('ACC', 'Phenotype', 'HP:0006744', (130, 133))	('CDKN2A', 'Gene', '1029', (54, 60))	('TERT', 'Gene', (148, 152))	('ZNRF3', 'Gene', '84133', (135, 140))	('TERT', 'Gene', '7015', (148, 152))	('ZNRF3', 'Gene', (135, 140))	('TP53', 'Gene', '7157', (48, 52))	('Hg19', 'Var', (284, 288))	('RB1', 'Gene', '5925', (62, 65))	('ACC', 'Gene', '31', (130, 133))	('RB1', 'Gene', (62, 65))	('MEN1', 'Gene', '4221', (70, 74))	('MED12', 'Gene', '9968', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('CTNNB1', 'Gene', '1499', (40, 46))	('tumor', 'Disease', (343, 348))	('TP53', 'Gene', (255, 259))	('ACC', 'Gene', (130, 133))	('MEN1', 'Gene', (70, 74))	('patient', 'Species', '9606', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('CTNNB1', 'Gene', (40, 46))	('MED12', 'Gene', (157, 162))	('TP53', 'Gene', (48, 52))	('CDKN2A', 'Gene', (54, 60))	('DAXX', 'Gene', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('tumor', 'Disease', (197, 202))	('TP53', 'Gene', '7157', (255, 259))
3303	27764813	SW-13 cells carry a homozygous TP53 point mutation, NCI-H295R cells harbor a large deletion in the TP53 locus and SJ-ACC3 cells display a TP53 haplotype with G245C mutation as previously described for Li-Fraumeni syndrome.	('TP53', 'Gene', (99, 103))	('ACC', 'Phenotype', 'HP:0006744', (117, 120))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (201, 221))	('TP53', 'Gene', '7157', (138, 142))	('SW-13', 'CellLine', 'CVCL:0542', (0, 5))	('SJ-ACC3', 'Gene', '31', (114, 121))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('TP53', 'Gene', (138, 142))	('SJ-ACC3', 'Gene', (114, 121))	('Li-Fraumeni syndrome', 'Disease', (201, 221))	('NCI-H295R', 'CellLine', 'CVCL:0458', (52, 61))	('deletion', 'Var', (83, 91))	('TP53', 'Gene', '7157', (99, 103))	('G245C mutation', 'Var', (158, 172))	('G245C', 'Mutation', 'rs28934573', (158, 163))
3304	27764813	NCI-H295R cells are furthermore known to have acquired an activating CTNNB1 mutation, which has not been described for SW-13 and SJ-ACC3 yet.	('SW-13', 'CellLine', 'CVCL:0542', (119, 124))	('CTNNB1', 'Gene', '1499', (69, 75))	('ACC', 'Phenotype', 'HP:0006744', (132, 135))	('activating', 'PosReg', (58, 68))	('NCI-H295R', 'CellLine', 'CVCL:0458', (0, 9))	('CTNNB1', 'Gene', (69, 75))	('SJ-ACC3', 'Gene', '31', (129, 136))	('mutation', 'Var', (76, 84))	('SJ-ACC3', 'Gene', (129, 136))
3317	27764813	Moreover, we provide evidence that the implementation of a panel of NCI-H295R, SJ-ACC3 and MUC-1 might be helpful for a more successful clinical translation of novel therapeutic regimens for ACC in the future.	('ACC', 'Gene', (82, 85))	('ACC', 'Gene', '31', (191, 194))	('SJ-ACC3', 'Gene', '31', (79, 86))	('ACC', 'Phenotype', 'HP:0006744', (191, 194))	('ACC', 'Gene', '31', (82, 85))	('MUC-1', 'Gene', (91, 96))	('SJ-ACC3', 'Gene', (79, 86))	('NCI-H295R', 'CellLine', 'CVCL:0458', (68, 77))	('ACC', 'Phenotype', 'HP:0006744', (82, 85))	('ACC', 'Gene', (191, 194))	('NCI-H295R', 'Var', (68, 77))	('clinical', 'Species', '191496', (136, 144))
3356	27764813	21 independent PCR loci (Amelogenin, D3S1358, D1S1656, D6S1043, D13S317, Penta E, D16S539, D18S51, D2S1338, CSF1PO, Penta D, TH01, vWA, D21S11, D7S820, D5S818, TPOX, D8S1179, D12S391, D19S433 and FGA) were investigated (Promega, PowerPlex 21 PCR Kit).	('D13S317', 'Var', (64, 71))	('FGA', 'Gene', '2243', (196, 199))	('D12S391', 'Var', (175, 182))	('D2S1338', 'Var', (99, 106))	('D16S539', 'Var', (82, 89))	('FGA', 'Gene', (196, 199))	('D6S1043', 'Var', (55, 62))	('D18S51', 'Var', (91, 97))
3416	28099114	Previously we described mtDNA copy number depletion across many solid tumor types (Reznik et al., 2016).	('copy number depletion', 'Var', (30, 51))	('solid tumor', 'Disease', (64, 75))	('solid tumor', 'Disease', 'MESH:D009369', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
3424	28099114	A drop in mtDNA copy number can decrease the expression of critical (and necessary) proteins of the electron transport chain (ETC)/ATP synthase.	('copy number', 'Var', (16, 27))	('drop', 'NegReg', (2, 6))	('expression of', 'MPA', (45, 58))	('ATP', 'Chemical', 'MESH:D000255', (131, 134))	('decrease', 'NegReg', (32, 40))	('mtDNA', 'Gene', (10, 15))
3436	28099114	In, we observed widespread mtDNA copy number depletion in tumors compared to matched adjacent normal tissue in a number of solid tumor types.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('copy number depletion', 'Var', (33, 54))	('solid tumor', 'Disease', (123, 134))	('solid tumor', 'Disease', 'MESH:D009369', (123, 134))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mtDNA', 'Gene', (27, 32))
3441	28099114	We also observed that LUAD (lung adenocarcinoma), which we found to be the only cancer type with increased mtDNA copy number in, had lower expression of 6/13 mtRNAs, suggesting that any increase in mtDNA copy number in LUAD was compensated for at the transcriptional level.	('mtDNA', 'Gene', (107, 112))	('lung adenocarcinoma', 'Disease', (28, 47))	('mtRNAs', 'Protein', (158, 164))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (28, 47))	('copy number', 'Var', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('expression', 'MPA', (139, 149))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('lower', 'NegReg', (133, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('LUAD', 'Disease', (22, 26))	('cancer', 'Disease', (80, 86))
3446	28099114	Two recent publications have highlighted the role that mtDNA mutations have in the development of one substype of chromophobes, eosinophilic chromophobe renal cell carcinomas.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (153, 174))	('mtDNA', 'Gene', (55, 60))	('eosinophilic chromophobe renal cell carcinomas', 'Disease', (128, 174))	('mutations', 'Var', (61, 70))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (153, 173))	('eosinophilic chromophobe renal cell carcinomas', 'Disease', 'MESH:C538614', (128, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
3448	28099114	This phenotype arises from two critical dysfunctions: somatic mtDNA mutations that render mitochondrial OXPHOS non-functional, and defective mitophagy that prevents clearance of dysfunctional mitochondria.	('mtDNA', 'Gene', (62, 67))	('mitophagy', 'CPA', (141, 150))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (178, 204))	('mitochondrial OXPHOS non-functional', 'MPA', (90, 125))	('mutations', 'Var', (68, 77))	('dysfunctional mitochondria', 'Disease', (178, 204))	('prevents', 'NegReg', (156, 164))
3455	28099114	Among these, papillary renal cell carcinoma (KIRP), esophageal carcinoma (ESCA), and thyroid cancer (THCA) showed an association between high mtRNA expression and increased age.	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (13, 43))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (13, 43))	('esophageal carcinoma', 'Disease', (52, 72))	('high', 'Var', (137, 141))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (52, 72))	('papillary renal cell carcinoma', 'Disease', (13, 43))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (23, 43))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (52, 72))	('thyroid cancer', 'Disease', (85, 99))	('thyroid cancer', 'Phenotype', 'HP:0002890', (85, 99))	('expression', 'MPA', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('thyroid cancer', 'Disease', 'MESH:D013964', (85, 99))
3464	28099114	Of the seven cancer types with mtDNA depletion in tumors relative to normal tissue, five (all but esophageal and head and neck) showed positive correlation between mtDNA copy number and expression.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mtDNA', 'Gene', (31, 36))	('positive correlation', 'Reg', (135, 155))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('expression', 'MPA', (186, 196))	('mtDNA', 'Gene', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('copy number', 'Var', (170, 181))
3469	28099114	Upon closer examination of samples from KICH (Figure 4:figure supplement 3), we found that tumor and normal samples had strong but distinct patterns of correlation between mtDNA copy number and mtRNA levels.	('mtRNA levels', 'MPA', (194, 206))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('copy number', 'Var', (178, 189))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('correlation', 'Interaction', (152, 163))	('tumor', 'Disease', (91, 96))	('mtDNA', 'Gene', (172, 177))
3472	28099114	Given that many KICH tumors harbor mtDNA mutations, these observations suggest that compensation for such mitochondrial dysfunction in KICH may be via transcriptional mechanisms, rather than changes to mtDNA ploidy.	('mutations', 'Var', (41, 50))	('mitochondrial dysfunction', 'Disease', (106, 131))	('mtDNA', 'Gene', (35, 40))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (106, 131))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (106, 131))	('KICH tumors', 'Disease', (16, 27))	('KICH tumors', 'Disease', 'MESH:D009369', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
3486	28099114	While changes in mtDNA copy number and mtRNA expression cannot be used as surrogates for changes in respiratory flux, several of the cancer types examined here are driven by genetic changes affecting mitochondrial respiration, suggesting that changes in mtRNA levels may reflect bona fide changes in respiration.	('driven by', 'Reg', (164, 173))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('changes', 'Var', (182, 189))	('mitochondrial respiration', 'MPA', (200, 225))	('affecting', 'Reg', (190, 199))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
3487	28099114	For example, clear-cell renal cell carcinomas are driven by homozygous loss of VHL, which leads to activation of hypoxia inducible factor (HIF), and subsequently increased transcription of glycolytic enzymes.	('VHL', 'Gene', '7428', (79, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (24, 44))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('increased', 'PosReg', (162, 171))	('transcription', 'MPA', (172, 185))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('hypoxia', 'Disease', (113, 120))	('activation', 'PosReg', (99, 109))	('clear-cell renal cell carcinomas', 'Disease', 'MESH:C538614', (13, 45))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (24, 45))	('clear-cell renal cell carcinomas', 'Disease', (13, 45))	('loss', 'Var', (71, 75))	('VHL', 'Gene', (79, 82))	('glycolytic enzymes', 'Enzyme', (189, 207))
3503	28099114	Prior studies of mitochondrial-nuclear (mitonuclear) protein imbalance in C. elegans claimed that it promotes longevity via activation of the mitochondrial unfolded protein response (UPRMT), a transcriptional response preserving mitochondrial function in the face of stress.	('activation', 'PosReg', (124, 134))	('mitochondrial unfolded protein response', 'MPA', (142, 181))	('imbalance', 'Var', (61, 70))	('longevity', 'CPA', (110, 119))	('imbalance', 'Phenotype', 'HP:0002172', (61, 70))	('promotes', 'PosReg', (101, 109))	('C. elegans', 'Species', '6239', (74, 84))
3504	28099114	If cancer cells indeed have substantial changes in mtDNA copy number and transcription (and mtDNA mutations), then activation of the mammalian UPR may be critical in supporting their proliferation in the face of increased mitochondrial stress.	('mtDNA', 'Gene', (51, 56))	('changes', 'Reg', (40, 47))	('transcription', 'MPA', (73, 86))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (98, 107))	('mammalian', 'Species', '9606', (133, 142))	('cancer', 'Disease', (3, 9))	('mtDNA', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
3530	28099114	Several recent studies based on the TCGA specimens have revealed that mitochondria DNAs are altered in cancers, including mtDNA mutations as well as copy number changes.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('copy number changes', 'Var', (149, 168))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (128, 137))	('mitochondria DNAs', 'MPA', (70, 87))	('mtDNA', 'Disease', (122, 127))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('altered', 'Reg', (92, 99))	('cancers', 'Disease', (103, 110))
3531	28099114	The authors previously reported that mtDNA copy number depletion in human cancers.	('human', 'Species', '9606', (68, 73))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('mtDNA', 'Gene', (37, 42))	('copy number depletion', 'Var', (43, 64))	('cancers', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
3555	28099114	We are unable to perform in vivo or in vitro experiments to measure how suppression of mtRNAs affects respiratory flux and proliferation/malignancy.	('malignancy', 'Disease', (137, 147))	('mtRNAs', 'Gene', (87, 93))	('suppression', 'Var', (72, 83))	('affects', 'Reg', (94, 101))	('respiratory flux', 'MPA', (102, 118))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
3558	28099114	In both of these cancer types, we propose that changes in mtRNA are an adaptive response to "driver" genetic mutations and upstream changes in cell signaling.	('mtRNA', 'Gene', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('changes', 'Var', (47, 54))	('cancer', 'Disease', (17, 23))	('mutations', 'Var', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
3559	28099114	For example, VHL inactivation in KIRC leads to activation of HIF which upregulates glycolytic genes and suppresses OXPHOS gene expression.	('suppresses', 'NegReg', (104, 114))	('inactivation', 'Var', (17, 29))	('glycolytic genes', 'MPA', (83, 99))	('upregulates', 'PosReg', (71, 82))	('activation', 'PosReg', (47, 57))	('VHL', 'Gene', (13, 16))	('OXPHOS gene expression', 'MPA', (115, 137))	('VHL', 'Gene', '7428', (13, 16))
3584	27742784	The discovery of the genetic mutations causing the MEN1 and MEN2 syndromes has clarified much about the molecular biology of the syndromes and their component tumors, and in many cases has led to improved methods of diagnosis and treatment.	('MEN1', 'Gene', (51, 55))	('MEN1', 'Gene', '4221', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mutations', 'Var', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('component tumors', 'Disease', (149, 165))	('MEN', 'Species', '9606', (51, 54))	('MEN2 syndromes', 'Disease', (60, 74))	('component tumors', 'Disease', 'MESH:D009369', (149, 165))	('MEN', 'Species', '9606', (60, 63))
3611	27742784	The Cancer Genome Atlas study of ACC confirmed and expanded the Weiss classification by integrating tumor subsets identified across the DNA copy-number and mutations, DNA-methylation, mRNA-expression, and miRNA-expression platforms.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (156, 165))	('tumor', 'Disease', (100, 105))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
3626	27742784	Interestingly, the partial responses only occurred in patients with SDHB mutations.	('SDHB', 'Gene', '6390', (68, 72))	('patients', 'Species', '9606', (54, 62))	('SDHB', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
3628	27742784	Most patients who had a clinical benefit carried the SDHB mutation.	('mutation', 'Var', (58, 66))	('patients', 'Species', '9606', (5, 13))	('SDHB', 'Gene', '6390', (53, 57))	('SDHB', 'Gene', (53, 57))
3631	27742784	In 65% of pheochromocyctomas, mutations have been discovered in 19 mutually exclusive susceptibility genes.	('pheochromocyctomas', 'Disease', 'None', (10, 28))	('pheochromocyctomas', 'Disease', (10, 28))	('mutations', 'Var', (30, 39))
3634	27742784	Pheochromocytomas can be divided into 3 clusters, depending on whether they have mutations in genes that alter proteins constituting the Krebs cycle (SDHA, SDHB, SDHC, SDHD, SDHAF2, MDH2, and FH), in genes associated with the hypoxic response (VHL and EPAS1), or in genes linked to signaling in the RAS/RAF, MAPK or mTOR pathways.	('EPAS1', 'Gene', (252, 257))	('RAF', 'Gene', '22882', (303, 306))	('FH', 'Gene', (192, 194))	('mTOR', 'Gene', '2475', (316, 320))	('MDH2', 'Gene', (182, 186))	('mutations', 'Var', (81, 90))	('SDHD', 'Gene', '6392', (168, 172))	('SDHB', 'Gene', '6390', (156, 160))	('Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 17))	('alter', 'Reg', (105, 110))	('RAF', 'Gene', (303, 306))	('VHL', 'Disease', 'MESH:D006623', (244, 247))	('SDHC', 'Gene', (162, 166))	('SDHAF2', 'Gene', '54949', (174, 180))	('SDHD', 'Gene', (168, 172))	('SDHAF2', 'Gene', (174, 180))	('EPAS1', 'Gene', '2034', (252, 257))	('SDHA', 'Gene', (174, 178))	('SDHA', 'Gene', (150, 154))	('SDHB', 'Gene', (156, 160))	('MDH2', 'Gene', '4191', (182, 186))	('Krebs', 'Chemical', '-', (137, 142))	('Pheochromocytomas', 'Disease', (0, 17))	('SDHA', 'Gene', '6389', (150, 154))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('SDHA', 'Gene', '6389', (174, 178))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('mTOR', 'Gene', (316, 320))	('proteins', 'Protein', (111, 119))	('VHL', 'Disease', (244, 247))	('SDHC', 'Gene', '6391', (162, 166))
3636	27742784	Pheochromocytoma was the first human tumor shown to be caused by a germline mutation of SDHD, a gene that encodes a metabolic enzyme, and also the first human tumor shown to have activating mutations in HIF2A.	('Pheochromocytoma', 'Disease', (0, 16))	('caused by', 'Reg', (55, 64))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('HIF2A', 'Gene', '2034', (203, 208))	('SDHD', 'Gene', (88, 92))	('SDHD', 'Gene', '6392', (88, 92))	('mutation', 'Var', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('human', 'Species', '9606', (31, 36))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('human', 'Species', '9606', (153, 158))	('HIF2A', 'Gene', (203, 208))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
3649	27742784	Prior work demonstrated mutually exclusive clonal mutations in papillary thyroid carcinoma (BRAF; 60%, RAS; 15%, and chromosomal rearrangements involving RET, and NTRK1; 5 to 40%), follicular thyroid carcinoma (RAS; 40 to 55%, and rearranged PPARG1; 25 to 60%), poorly differentiated thyroid carcinoma (BRAF; 0 to 13%, RAS; 20 to 30%, CTNNB1; 0 to 5%, and TP53; 17 to 40%), and anaplastic thyroid carcinoma (BRAF; 10 to 35%, RAS; 20 to 60%, CTNNB1; 66%, and TP53; 67 to 90%).	('TP53', 'Gene', (356, 360))	('RET', 'Gene', (154, 157))	('NTRK1', 'Gene', '4914', (163, 168))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (389, 406))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (284, 301))	('NTRK1', 'Gene', (163, 168))	('PPARG1', 'Gene', (242, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('CTNNB1', 'Gene', '1499', (335, 341))	('TP53', 'Gene', (458, 462))	('anaplastic thyroid carcinoma', 'Disease', (378, 406))	('CTNNB1', 'Gene', (441, 447))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (192, 209))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (63, 90))	('rearranged', 'Var', (231, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (397, 406))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (73, 90))	('papillary thyroid carcinoma', 'Disease', (63, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('TP53', 'Gene', '7157', (356, 360))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (63, 90))	('BRAF', 'Gene', '673', (92, 96))	('PPARG1', 'Gene', '5468', (242, 248))	('CTNNB1', 'Gene', (335, 341))	('BRAF', 'Gene', (92, 96))	('TP53', 'Gene', '7157', (458, 462))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (192, 209))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (181, 209))	('RET', 'Gene', '5979', (154, 157))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (378, 406))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (378, 406))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (389, 406))	('follicular thyroid carcinoma', 'Disease', 'MESH:D018263', (181, 209))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (284, 301))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (73, 90))	('mutations', 'Var', (50, 59))	('thyroid carcinoma', 'Disease', (284, 301))	('CTNNB1', 'Gene', '1499', (441, 447))	('follicular thyroid carcinoma', 'Disease', (181, 209))	('BRAF', 'Gene', '673', (408, 412))	('BRAF', 'Gene', '673', (303, 307))	('BRAF', 'Gene', (408, 412))	('BRAF', 'Gene', (303, 307))
3650	27742784	A recent Cancer Genome Atlas study of 496 papillary thyroid carcinomas identified new mutations in EIFIAX, PPM1D, CHEK2 genes, and novel chromosomal rearrangements of BRAF, RET, NTRK, and ALK, thereby reducing the number of unknown driver mutations from 25% to 3.5%.	('EIFIAX', 'Gene', (99, 105))	('ALK', 'Gene', (188, 191))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('NTRK', 'Gene', (178, 182))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('RET', 'Gene', '5979', (173, 176))	('CHEK2', 'Gene', (114, 119))	('papillary thyroid carcinomas', 'Disease', (42, 70))	('mutations', 'Var', (86, 95))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (42, 70))	('PPM1D', 'Gene', '8493', (107, 112))	('NTRK', 'Gene', '4914;4916', (178, 182))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (52, 69))	('CHEK2', 'Gene', '11200', (114, 119))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (52, 70))	('RET', 'Gene', (173, 176))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (42, 69))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (42, 70))	('PPM1D', 'Gene', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('ALK', 'Gene', '238', (188, 191))
3651	27742784	The Cancer Genome Atlas study investigators were able to divide papillary thyroid carcinomas into 3 molecular subtypes with mutually exclusive mutations and variable degrees of differentiation: (1) recurrent mutations in genes; the most prominent being BRAF (59.7%), NRAS and HRAS, (14.0, (2) gene fusions of BRAF, RET, PPARG, NTRK1, NTRK3, ALK, LTK, MET, FGFR2, and THDA (15.3%), and (3) somatic copy number alterations.	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (64, 92))	('NTRK3', 'Gene', '4916', (334, 339))	('gene fusions', 'Var', (293, 305))	('THDA', 'Chemical', '-', (367, 371))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (74, 92))	('NTRK3', 'Gene', (334, 339))	('mutations', 'Var', (208, 217))	('MET', 'Gene', (351, 354))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('BRAF', 'Gene', '673', (309, 313))	('BRAF', 'Gene', (309, 313))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('NTRK1', 'Gene', '4914', (327, 332))	('PPARG', 'Gene', '5468', (320, 325))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (64, 91))	('BRAF', 'Gene', '673', (253, 257))	('PPARG', 'Gene', (320, 325))	('NTRK1', 'Gene', (327, 332))	('BRAF', 'Gene', (253, 257))	('LTK', 'Gene', '4058', (346, 349))	('NRAS', 'Gene', '4893', (267, 271))	('RET', 'Gene', '5979', (315, 318))	('LTK', 'Gene', (346, 349))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (74, 91))	('papillary thyroid carcinomas', 'Disease', (64, 92))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (64, 92))	('FGFR2', 'Gene', (356, 361))	('HRAS', 'Gene', '3265', (276, 280))	('RET', 'Gene', (315, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('NRAS', 'Gene', (267, 271))	('ALK', 'Gene', '238', (341, 344))	('HRAS', 'Gene', (276, 280))	('FGFR2', 'Gene', '2263', (356, 361))	('ALK', 'Gene', (341, 344))
3652	27742784	The investigators also found that BRAFV600E mutated PTCs signal preferentially through the MAPK pathway, while RAS mutated PTCs signal through either the MAPK pathway or the PI3K pathway.	('BRAFV600E', 'Mutation', 'rs113488022', (34, 43))	('PTCs', 'Gene', (52, 56))	('MAPK pathway', 'Pathway', (91, 103))	('PI3K pathway', 'Pathway', (174, 186))	('BRAFV600E mutated', 'Var', (34, 51))	('preferentially', 'PosReg', (64, 78))	('MAPK pathway', 'Pathway', (154, 166))
3660	27742784	Approximately 50% of sporadic medullary thyroid carcinomas have somatic RET mutations, and a lesser number have RAS mutations.	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('medullary thyroid carcinomas', 'Phenotype', 'HP:0002865', (30, 58))	('mutations', 'Var', (76, 85))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (40, 58))	('thyroid carcinomas', 'Disease', (40, 58))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (30, 57))	('RET', 'Gene', '5979', (72, 75))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (40, 57))	('RET', 'Gene', (72, 75))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (40, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
3661	27742784	Virtually all hereditary medullary thyroid carcinomas have germline RET mutations, and there is a strong genotype-phenotype relationship in patients with MEN2A and MEN2B, not only regarding the range of disease expression, but also the severity of disease.	('MEN2A', 'Gene', (154, 159))	('mutations', 'Var', (72, 81))	('MEN2A', 'Gene', '5979', (154, 159))	('MEN2B', 'Gene', (164, 169))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (35, 52))	('MEN2B', 'Gene', '5979', (164, 169))	('RET', 'Gene', (68, 71))	('germline', 'Var', (59, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('medullary thyroid carcinomas', 'Phenotype', 'HP:0002865', (25, 53))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (35, 53))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (25, 52))	('patients', 'Species', '9606', (140, 148))	('RET', 'Gene', '5979', (68, 71))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (35, 53))	('thyroid carcinomas', 'Disease', (35, 53))
3678	27742784	No MEN1 mutation is found in 10 to 30% of typical MEN1 kindreds (probably the result of current DNA sequencing strategies) and 10% of the mutations are de novo, there being no family history.	('MEN1', 'Gene', '4221', (3, 7))	('MEN1', 'Gene', (3, 7))	('MEN1', 'Gene', (50, 54))	('MEN1', 'Gene', '4221', (50, 54))	('mutation', 'Var', (8, 16))	('mutations', 'Var', (138, 147))
3679	27742784	MEN1 is also the most common mutation in sporadic pancreatic neuroendocrine tumors, followed by mutations in DAXX/ATRX (Death-Domain Associated Protein/Mental Retardation Syndrome X-Linked Genes) and the mTOR (Molecular Target of Rapamycin) pathway.	('MEN1', 'Gene', '4221', (0, 4))	('DAXX', 'Gene', '1616', (109, 113))	('Mental Retardation Syndrome', 'Disease', (152, 179))	('mTOR', 'Gene', '2475', (204, 208))	('common', 'Reg', (22, 28))	('pancreatic neuroendocrine tumors', 'Disease', (50, 82))	('mutations', 'Var', (96, 105))	('MEN1', 'Gene', (0, 4))	('Mental Retardation Syndrome', 'Disease', 'MESH:D008607', (152, 179))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (61, 82))	('endocrine tumor', 'Phenotype', 'HP:0100568', (66, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('Molecular Target of Rapamycin', 'Gene', '2475', (210, 239))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ATRX', 'Gene', (114, 118))	('Molecular Target of Rapamycin', 'Gene', (210, 239))	('ATRX', 'Gene', '546', (114, 118))	('Mental Retardation', 'Phenotype', 'HP:0001249', (152, 170))	('mTOR', 'Gene', (204, 208))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (50, 82))	('DAXX', 'Gene', (109, 113))
3707	27742784	The term, MEN4, applies to rare patients with the MEN1 phenotype, who have germline mutations in CDKN1B, not MEN1.	('patients', 'Species', '9606', (32, 40))	('CDKN1B', 'Gene', '1027', (97, 103))	('MEN4', 'Gene', '1027', (10, 14))	('mutations', 'Var', (84, 93))	('MEN1', 'Gene', (50, 54))	('MEN1', 'Gene', (109, 113))	('CDKN1B', 'Gene', (97, 103))	('MEN4', 'Gene', (10, 14))	('MEN1', 'Gene', '4221', (109, 113))	('MEN1', 'Gene', '4221', (50, 54))
3708	27742784	The Carney complex, characterized by multiple skin lesions cardiac myxoma, acromegaly, schwannoma, thyroid tumors, and pigmented nodular adrenocortical disease, is caused by germline mutations in CNC1 which encodes the regulatory subunit of the protein kinase A (PRKAR1A).	('acromegaly', 'Disease', 'MESH:D000172', (75, 85))	('thyroid tumors', 'Disease', 'MESH:D013959', (99, 113))	('germline mutations', 'Var', (174, 192))	('schwannoma', 'Disease', 'MESH:D009442', (87, 97))	('acromegaly', 'Disease', (75, 85))	('acromegaly', 'Phenotype', 'HP:0000845', (75, 85))	('skin lesions cardiac myxoma', 'Disease', (46, 73))	('PRKAR1A', 'Gene', (263, 270))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (119, 159))	('Carney complex', 'Disease', (4, 18))	('thyroid tumors', 'Disease', (99, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('pigmented nodular adrenocortical disease', 'Disease', (119, 159))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (119, 159))	('PRKAR1A', 'Gene', '5573', (263, 270))	('schwannoma', 'Phenotype', 'HP:0100008', (87, 97))	('CNC1', 'Gene', (196, 200))	('CNC1', 'Gene', '5573', (196, 200))	('cardiac myxoma', 'Phenotype', 'HP:0011672', (59, 73))	('schwannoma', 'Disease', (87, 97))	('caused by', 'Reg', (164, 173))	('skin lesions cardiac myxoma', 'Disease', 'MESH:D006331', (46, 73))
3709	27742784	Approximately 65% of patients have mutations in PRKARIA and 20% have mutations in the putative CNC2 gene located on chromosome 2; however, the specific gene has not been identified.	('mutations', 'Var', (69, 78))	('PRKARIA', 'Gene', (48, 55))	('patients', 'Species', '9606', (21, 29))	('CNC2', 'Gene', '1257', (95, 99))	('CNC2', 'Gene', (95, 99))	('mutations', 'Var', (35, 44))
3711	27742784	The large majority of pituitary tumors are sporadic, and not associated with any known syndrome; however, germline AIP mutations are found in 4% of them; the incidence being higher in children and in young adults with macroadenomas or gigantism.	('pituitary tumors', 'Disease', (22, 38))	('AIP', 'Gene', '9049', (115, 118))	('AIP', 'Gene', (115, 118))	('macroadenomas', 'Disease', 'None', (218, 231))	('children', 'Species', '9606', (184, 192))	('macroadenomas', 'Disease', (218, 231))	('pituitary tumors', 'Disease', 'MESH:D010911', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('gigantism', 'Disease', (235, 244))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (119, 128))
3712	27742784	Sporadic tumors with AIP mutations, compared to those without AIP mutations, are more common in males, are larger and invasive, and secrete growth hormone, or prolactin.	('mutations', 'Var', (25, 34))	('common', 'Reg', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('growth hormone', 'Gene', (140, 154))	('Sporadic tumors', 'Disease', 'MESH:D009369', (0, 15))	('AIP', 'Gene', '9049', (62, 65))	('Sporadic tumors', 'Disease', (0, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('growth hormone', 'Gene', '2688', (140, 154))	('AIP', 'Gene', (21, 24))	('prolactin', 'MPA', (159, 168))	('AIP', 'Gene', '9049', (21, 24))	('AIP', 'Gene', (62, 65))
3713	27742784	Germline mutations in MEN1 are found in 0.6 to 2.6% of very young patients with isolated pituitary tumors.	('Germline mutations', 'Var', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('MEN1', 'Gene', (22, 26))	('isolated pituitary tumors', 'Disease', 'MESH:D010911', (80, 105))	('MEN1', 'Gene', '4221', (22, 26))	('patients', 'Species', '9606', (66, 74))	('isolated pituitary tumors', 'Disease', (80, 105))
3714	27742784	There are few reports of CDKN1B mutations, and no reports of PRKAR1A mutations in sporadic pituitary tumors.	('pituitary tumors', 'Disease', (91, 107))	('PRKAR1A', 'Gene', (61, 68))	('CDKN1B', 'Gene', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('pituitary tumors', 'Disease', 'MESH:D010911', (91, 107))	('mutations', 'Var', (32, 41))	('PRKAR1A', 'Gene', '5573', (61, 68))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('CDKN1B', 'Gene', '1027', (25, 31))
3715	27742784	Although the subject of intense investigation, the role of epigenetic regulation on the pathogenesis of pituitary adenomas, is unclear and merits further investigation.	('pituitary adenomas', 'Phenotype', 'HP:0002893', (104, 122))	('pituitary adenomas', 'Disease', (104, 122))	('epigenetic regulation', 'Var', (59, 80))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (104, 121))	('pituitary adenomas', 'Disease', 'MESH:D010911', (104, 122))
3717	27742784	They also describe a number of somatic mutations associated with sporadic pituitary tumors, but note that the role of these mutations in tumor pathogenesis and progression is unclear.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (137, 142))	('pituitary tumors', 'Disease', (74, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('associated', 'Reg', (49, 59))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', (84, 89))	('pituitary tumors', 'Disease', 'MESH:D010911', (74, 90))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
3725	26587828	Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('associated', 'Reg', (64, 74))	('MCT1', 'Gene', '6566', (12, 16))	('shorter', 'NegReg', (216, 223))	('CAIX', 'Gene', '768', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('expressions', 'Var', (33, 44))	('GLUT1', 'Gene', (18, 23))	('metastasis', 'CPA', (193, 203))	('tumor', 'Disease', (166, 171))	('high mitotic index', 'MPA', (137, 155))	('GLUT1', 'Gene', '6513', (18, 23))	('disease free survival', 'CPA', (236, 257))	('MCT1', 'Gene', (12, 16))	('CAIX', 'Gene', (28, 32))
3757	26587828	The glycolytic phenotype was significantly associated with the mitotic index of the cases [8.3% (2/24) of cases with low mitotic index show a glycolytic phenotype versus 35.3% (6/17) of cases with high mitotic index; p = 0.049] and tumor p53 status [10.5% (2/19) of cases with normal p53 show a glycolytic phenotype versus 80.0% (4/5) of cases with mutated p53; p = 0.006].	('low', 'Var', (117, 120))	('mitotic index', 'MPA', (63, 76))	('p53', 'Gene', (238, 241))	('p53', 'Gene', '7157', (238, 241))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('glycolytic phenotype', 'MPA', (142, 162))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('p53', 'Gene', (284, 287))	('p53', 'Gene', '7157', (284, 287))	('associated', 'Reg', (43, 53))	('p53', 'Gene', '7157', (357, 360))	('tumor', 'Disease', (232, 237))	('p53', 'Gene', (357, 360))
3865	26322079	Inactivating mutations in the regulatory subunit of type 1 alpha of the protein kinase A (PRKAR1A) gene have been identified in most of the patients with PPNAD.	('PRKAR1A', 'Gene', '5573', (90, 97))	('identified', 'Reg', (114, 124))	('Inactivating mutations', 'Var', (0, 22))	('patients', 'Species', '9606', (140, 148))	('PRKAR1A', 'Gene', (90, 97))	('PPNAD', 'Disease', (154, 159))
3901	25334044	Marked Cortisol Production by Intracrine ACTH in GIP-Treated Cultured Adrenal Cells in Which the GIP Receptor Was Exogenously Introduced The ectopic expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR) in the human adrenal gland causes significant hypercortisolemia after ingestion of each meal and leads to Cushing's syndrome, implying that human GIPR activation is capable of robustly activating adrenal glucocorticoid secretion.	('GIP', 'Gene', '2695', (97, 100))	('GIP', 'Gene', (49, 52))	('causes', 'Reg', (255, 261))	('ACTH', 'Gene', (41, 45))	('GIP', 'Gene', (97, 100))	('GIP', 'Gene', '2695', (374, 377))	('leads to', 'Reg', (325, 333))	('hypercortisolemia', 'Disease', (274, 291))	('hypercortisolemia', 'Disease', 'None', (274, 291))	('GIP', 'Gene', (374, 377))	('GIP', 'Gene', '2695', (222, 225))	('GIP', 'Gene', (222, 225))	('Cortisol', 'Chemical', 'MESH:D006854', (7, 15))	('human', 'Species', '9606', (235, 240))	('ACTH', 'Gene', '5443', (41, 45))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (334, 352))	('hypercortisolemia after ingestion', 'Phenotype', 'HP:0011744', (274, 307))	('human', 'Species', '9606', (368, 373))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (334, 352))	("Cushing's syndrome", 'Disease', (334, 352))	('GIP', 'Gene', '2695', (49, 52))	('glucose-dependent insulinotropic polypeptide receptor', 'Gene', '2696', (167, 220))	('ectopic expression', 'Var', (141, 159))
3918	25334044	The ectopic expression of these receptors functionally coupled to steroidogenesis confers inappropriate sensitivity on adrenocortical cells to either GIP, catecholamines or other hormones (angiotensin II, glucagon, serotonin 5HT7, thyrotropin, luteinizing hormone, V2-vasopressin etc).	('adrenocortical', 'Disease', 'MESH:D018268', (119, 133))	('coupled', 'Reg', (55, 62))	('steroid', 'Chemical', 'MESH:D013256', (66, 73))	('glucagon', 'MPA', (205, 213))	('sensitivity', 'MPA', (104, 115))	('angiotensin II', 'Gene', '183', (189, 203))	('serotonin 5HT7', 'MPA', (215, 229))	('serotonin', 'Chemical', 'MESH:D012701', (215, 224))	('ectopic expression', 'Var', (4, 22))	('angiotensin II', 'Gene', (189, 203))	('catecholamines', 'Chemical', 'MESH:D002395', (155, 169))	('adrenocortical', 'Disease', (119, 133))	('vasopressin', 'Gene', '551', (268, 279))	('vasopressin', 'Gene', (268, 279))
3921	25334044	Tissues containing aberrant GPCRs release ACTH and cortisol during perifusion with GIP, serotonin, or human chorionic gonadotropin.	('ACTH', 'Gene', '5443', (42, 46))	('release', 'PosReg', (34, 41))	('serotonin', 'Chemical', 'MESH:D012701', (88, 97))	('cortisol', 'Chemical', 'MESH:D006854', (51, 59))	('ACTH', 'Gene', (42, 46))	('aberrant', 'Var', (19, 27))	('human', 'Species', '9606', (102, 107))
3923	25334044	Thus, they showed that cortisol production is apparently controlled dually by aberrant GPCRs and by ACTH produced within the adrenocortical tissue, amplifying the effect of the aberrant receptors.	('cortisol', 'Chemical', 'MESH:D006854', (23, 31))	('aberrant', 'Var', (78, 86))	('adrenocortical', 'Disease', (125, 139))	('adrenocortical', 'Disease', 'MESH:D018268', (125, 139))	('ACTH', 'Gene', (100, 104))	('cortisol production', 'MPA', (23, 42))	('ACTH', 'Gene', '5443', (100, 104))
3924	25334044	The ectopic expression of GIPR in the human adrenal gland causes significant hypercortisolemia after ingestion of a meal and leads to food-dependent Cushing's syndrome (FD-CS), demonstrating that activation of human GIPR is capable of robustly activating adrenal glucocorticoid secretion.	('hypercortisolemia', 'Disease', 'None', (77, 94))	('adrenal glucocorticoid secretion', 'MPA', (255, 287))	('human', 'Species', '9606', (38, 43))	('hypercortisolemia after ingestion', 'Phenotype', 'HP:0011744', (77, 110))	('rat', 'Species', '10116', (184, 187))	('causes', 'Reg', (58, 64))	('GIPR', 'Gene', (26, 30))	('activating', 'PosReg', (244, 254))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (149, 167))	('human', 'Species', '9606', (210, 215))	('leads to', 'Reg', (125, 133))	('activation', 'PosReg', (196, 206))	('ectopic expression', 'Var', (4, 22))	('hypercortisolemia', 'Disease', (77, 94))	("Cushing's syndrome", 'Disease', (149, 167))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (149, 167))
3928	25334044	Thus, several indirect sources of evidence demonstrate that GIP promotes cAMP activation via GIPR, followed by steroidogenesis in adrenocortical cells.	('rat', 'Species', '10116', (50, 53))	('steroidogenesis', 'MPA', (111, 126))	('cAMP activation', 'MPA', (73, 88))	('GIP', 'Var', (60, 63))	('cAMP', 'Chemical', 'MESH:D000242', (73, 77))	('steroid', 'Chemical', 'MESH:D013256', (111, 118))	('GIPR', 'Protein', (93, 97))	('adrenocortical', 'Disease', (130, 144))	('adrenocortical', 'Disease', 'MESH:D018268', (130, 144))
3938	25334044	The following antibodies were used in this study: primary antibodies: anti-mouse FLAG M2 monoclonal (F1804; Sigma-Aldrich), anti-rabbit GIPR monoclonal (ab124939; Abcam plc, Cambridge, UK), anti-goat CYP21A2 polyclonal (C-17) (sc-48466, Santa Cruz, Santa Cruz, CA), anti-rabbit CYP17A1 polyclonal (ab80206; Abcam) antibodies, and secondary antibodies: Alexa Fluor 647 goat a anti-mouse/rabbit IgG (H+L) (A-21236/A-21245; Molecular Probes, Eugene, OR, USA), Alexa Fluor 647 donkey anti-goat IgG (H+L) (A-21447, Molecular Probes), Alexa Fluor 546 goat anti-mouse IgG (H+L) (A-11030, Molecular Probes), Alexa Fluor 546 donkey anti-mouse/rabbit IgG (A-10036/A-10040; Molecular Probes).	('mouse', 'Species', '10090', (628, 633))	('rabbit', 'Species', '9986', (386, 392))	('C-17', 'Gene', (220, 224))	('goat', 'Species', '9925', (485, 489))	('CYP21A2', 'Gene', (200, 207))	('mouse', 'Species', '10090', (380, 385))	('mouse', 'Species', '10090', (555, 560))	('CYP17A1', 'Gene', (278, 285))	('CYP17A1', 'Gene', '1586', (278, 285))	('CYP21A2', 'Gene', '1589', (200, 207))	('rabbit', 'Species', '9986', (129, 135))	('rabbit', 'Species', '9986', (271, 277))	('C-17', 'Gene', '54360', (220, 224))	('mouse', 'Species', '10090', (75, 80))	('A-10036/A-10040', 'Var', (646, 661))	('goat', 'Species', '9925', (545, 549))	('donkey', 'Species', '9793', (616, 622))	('goat', 'Species', '9925', (195, 199))	('rabbit', 'Species', '9986', (634, 640))	('goat', 'Species', '9925', (368, 372))	('donkey', 'Species', '9793', (473, 479))
3951	25334044	The primary antibodies, anti-flag, anti-GIPR, anti-CYP17A1, anti-CYP21A2, and anti-ACTH were used at concentrations of 1:1000, 1:50, 1:250, 1:50, 1:100 respectively, and 2nd antibodies were used at a concentration of 1:500.	('ACTH', 'Gene', '5443', (83, 87))	('CYP17A1', 'Gene', '1586', (51, 58))	('rat', 'Species', '10116', (108, 111))	('CYP21A2', 'Gene', '1589', (65, 72))	('CYP17A1', 'Gene', (51, 58))	('rat', 'Species', '10116', (207, 210))	('CYP21A2', 'Gene', (65, 72))	('anti-GIPR', 'Var', (35, 44))	('ACTH', 'Gene', (83, 87))
3967	25334044	In the cells transfected with GIPR, but not with GIP, there were some FLAG-positive [FLAG (+)] cells, but they expressed neither CYP17A1 (Fig.	('CYP17A1', 'Gene', (129, 136))	('CYP17A1', 'Gene', '1586', (129, 136))	('GIPR', 'Var', (30, 34))
3972	25334044	Furthermore, the concentration of cortisol in the medium increased 1.5-fold in hGIPR cells treated with GIP compared to those with vehicle alone (Fig.	('GIP', 'Var', (104, 107))	('concentration of cortisol', 'MPA', (17, 42))	('cortisol', 'Chemical', 'MESH:D006854', (34, 42))	('increased', 'PosReg', (57, 66))	('rat', 'Species', '10116', (24, 27))
3998	25334044	The ectopic expression of other GPCRs in the adrenal glands, such as GIPR, is also known to induce steroidogenesis through cAMP activation.	('cAMP', 'Chemical', 'MESH:D000242', (123, 127))	('induce', 'PosReg', (92, 98))	('steroidogenesis', 'MPA', (99, 114))	('ectopic expression', 'Var', (4, 22))	('steroid', 'Chemical', 'MESH:D013256', (99, 106))
4031	25334044	It is noted that H89, an inhibitor of PKA, completely inhibited the mRNA expression of steroidogenic factors, whereas its inhibition by ACTH (7-38) was partial.	('inhibited', 'NegReg', (54, 63))	('H89', 'Chemical', 'MESH:C063509', (17, 20))	('ACTH', 'Gene', (136, 140))	('steroid', 'Chemical', 'MESH:D013256', (87, 94))	('ACTH', 'Gene', '5443', (136, 140))	('H89', 'Var', (17, 20))	('mRNA expression of steroidogenic factors', 'MPA', (68, 108))
4033	25334044	These indicate that while steroidogenesis is promoted mainly by ACTH-MC2R axis in FLAG (-) cells, GIP-GIPR partially activates steroid production independently of ACTH-MC2R axis in FLAG (+) cells.	('activates', 'PosReg', (117, 126))	('MC2R', 'Gene', (69, 73))	('steroid', 'Chemical', 'MESH:D013256', (127, 134))	('ACTH', 'Gene', (163, 167))	('MC2R', 'Gene', (168, 172))	('GIP-GIPR', 'Var', (98, 106))	('ACTH', 'Gene', (64, 68))	('MC2R', 'Gene', '4158', (168, 172))	('ACTH', 'Gene', '5443', (163, 167))	('MC2R', 'Gene', '4158', (69, 73))	('ACTH', 'Gene', '5443', (64, 68))	('promoted', 'PosReg', (45, 53))	('steroidogenesis', 'MPA', (26, 41))	('steroid production', 'MPA', (127, 145))	('steroid', 'Chemical', 'MESH:D013256', (26, 33))
4043	25334044	In growth condition, secretion of cortisol was clearly stimulated by GIP-GIPR, forskolin or 8-bromo cAMP, but not in the control medium.	('stimulated', 'PosReg', (55, 65))	('8-bromo cAMP', 'Chemical', 'MESH:D015124', (92, 104))	('forskolin', 'Chemical', 'MESH:D005576', (79, 88))	('cortisol', 'Chemical', 'MESH:D006854', (34, 42))	('secretion of cortisol', 'MPA', (21, 42))	('GIP-GIPR', 'Var', (69, 77))
4047	25334044	It is reported that ectopic expression of GIPR in adrenal gland induces steroidogenesis, resulting in FD-CS.	('FD-CS', 'Disease', (102, 107))	('induces', 'Reg', (64, 71))	('resulting in', 'Reg', (89, 101))	('steroid', 'Chemical', 'MESH:D013256', (72, 79))	('ectopic expression', 'Var', (20, 38))	('GIPR', 'Gene', (42, 46))	('steroidogenesis', 'MPA', (72, 87))
4057	25334044	In summary, we showed that GIP activates steroidogenesis in GIPR-expressing H295R adrenocortical cells through the expression of genes for steroidogenic factors and enzymes and the accumulation of their respective proteins.	('adrenocortical', 'Disease', (82, 96))	('GIP', 'Var', (27, 30))	('activates', 'PosReg', (31, 40))	('adrenocortical', 'Disease', 'MESH:D018268', (82, 96))	('accumulation', 'PosReg', (181, 193))	('steroid', 'Chemical', 'MESH:D013256', (41, 48))	('proteins', 'Protein', (214, 222))	('steroid', 'Chemical', 'MESH:D013256', (139, 146))	('H295R', 'CellLine', 'CVCL:0458', (76, 81))	('steroidogenesis', 'MPA', (41, 56))
4150	23915220	Epigenetic silencing of RASSF1A deregulates cytoskeleton and promotes malignant behavior of adrenocortical carcinoma Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with high mutational heterogeneity and a generally poor clinical outcome.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('endocrine malignancy', 'Phenotype', 'HP:0100568', (158, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('adrenocortical carcinoma', 'Disease', (92, 116))	('promotes', 'PosReg', (61, 69))	('endocrine malignancy', 'Disease', (158, 178))	('RASSF1A', 'Gene', (24, 31))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (92, 116))	('deregulates', 'Reg', (32, 43))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (117, 141))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (117, 141))	('endocrine malignancy', 'Disease', 'MESH:D009369', (158, 178))	('Epigenetic silencing', 'Var', (0, 20))	('RASSF1A', 'Gene', '11186', (24, 31))	('Adrenocortical carcinoma', 'Disease', (117, 141))	('malignant behavior', 'CPA', (70, 88))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (92, 116))	('cytoskeleton', 'MPA', (44, 56))
4151	23915220	This study specifically evaluates the potential role of epigenetic silencing of RASSF1A, the most commonly silenced tumor suppressor gene, in adrenocortical malignancy.	('adrenocortical malignancy', 'Disease', 'MESH:D018268', (142, 167))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('epigenetic silencing', 'Var', (56, 76))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('RASSF1A', 'Gene', (80, 87))	('tumor', 'Disease', (116, 121))	('adrenocortical malignancy', 'Disease', (142, 167))
4154	23915220	Enforced expression of ectopic RASSF1A in the SW-13 ACC cell line reduced the overall malignant behavior of the cells, which included impairment of invasion through the basement membrane, cell motility, and solitary cell survival and growth.	('reduced', 'NegReg', (66, 73))	('cell motility', 'CPA', (188, 201))	('invasion through the basement membrane', 'CPA', (148, 186))	('growth', 'CPA', (234, 240))	('ectopic', 'Var', (23, 30))	('RASSF1A', 'Gene', (31, 38))	('expression', 'Species', '29278', (9, 19))	('malignant behavior of the cells', 'CPA', (86, 117))	('solitary cell survival', 'CPA', (207, 229))	('impairment', 'NegReg', (134, 144))	('SW-13', 'CellLine', 'CVCL:0542', (46, 51))
4155	23915220	On the other hand, expression of RASSF1A/A133S, a loss-of-function mutant form of RASSF1A, failed to elicit similar malignancy-suppressing responses in ACC cells.	('malignancy', 'Disease', (116, 126))	('A133S', 'Var', (41, 46))	('A133S', 'SUBSTITUTION', 'None', (41, 46))	('malignancy', 'Disease', 'MESH:D009369', (116, 126))	('loss-of-function', 'NegReg', (50, 66))	('expression', 'Species', '29278', (19, 29))	('RASSF1A', 'Gene', (82, 89))
4156	23915220	Downregulation of RASSF1A via promoter hypermethylation may play a role in the malignant progression of adrenocortical carcinoma possibly by abrogating differentiation-promoting RASSF1A- microtubule interactions.	('differentiation-promoting', 'CPA', (152, 177))	('Downregulation', 'NegReg', (0, 14))	('play', 'Reg', (60, 64))	('RASSF1A', 'Gene', (18, 25))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (104, 128))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (104, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('adrenocortical carcinoma', 'Disease', (104, 128))	('promoter hypermethylation', 'Var', (30, 55))	('abrogating', 'NegReg', (141, 151))
4168	23915220	Epigenetic aberrations, including DNA methylation and histone modifications, are increasingly being recognized for their role in altering patterns of gene expression, potentially contributing to tumorigenesis .	('contributing', 'Reg', (179, 191))	('tumor', 'Disease', (195, 200))	('expression', 'Species', '29278', (155, 165))	('patterns of gene expression', 'MPA', (138, 165))	('DNA methylation', 'Var', (34, 49))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('histone modifications', 'Var', (54, 75))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('altering', 'Reg', (129, 137))
4170	23915220	Hypermethylation of the RASSF1 promoter responsible for RASSF1A expression has a well-established role in tumor progression in several organ systems and tissue types , including several endocrine tumors.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('endocrine tumors', 'Disease', 'MESH:D004701', (186, 202))	('tumor', 'Disease', (196, 201))	('Hypermethylation', 'Var', (0, 16))	('RASSF1', 'Gene', '11186', (24, 30))	('endocrine tumors', 'Disease', (186, 202))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('role', 'Reg', (98, 102))	('expression', 'Species', '29278', (64, 74))	('RASSF1', 'Gene', (24, 30))	('RASSF1', 'Gene', '11186', (56, 62))	('RASSF1', 'Gene', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (106, 111))
4171	23915220	Specifically, epigenetic suppression of RASSF1A expression in papillary thyroid carcinoma has been strongly implicated in early tumor formation .	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('expression', 'Species', '29278', (48, 58))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (72, 89))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (62, 89))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('papillary thyroid carcinoma', 'Disease', (62, 89))	('tumor', 'Disease', (128, 133))	('RASSF1A', 'Gene', (40, 47))	('epigenetic suppression', 'Var', (14, 36))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (62, 89))	('implicated', 'Reg', (108, 118))
4172	23915220	Similarly, epigenetic silencing of RASSF1A has been demonstrated in neural crest tumors such as neuroblastoma and pheochromocytoma .	('neuroblastoma', 'Disease', (96, 109))	('epigenetic silencing', 'Var', (11, 31))	('demonstrated', 'Reg', (52, 64))	('RASSF1A', 'Gene', (35, 42))	('pheochromocytoma', 'Disease', 'MESH:D010673', (114, 130))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (114, 130))	('neuroblastoma', 'Phenotype', 'HP:0003006', (96, 109))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('neural crest tumors', 'Disease', (68, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('neural crest tumors', 'Disease', 'MESH:C536408', (68, 87))	('neuroblastoma', 'Disease', 'MESH:D009447', (96, 109))	('pheochromocytoma', 'Disease', (114, 130))
4173	23915220	Alternatively, genetic silencing of RASSF1A gene by mutations and other aberrations are possible, but rarely seen in human cancers .	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('human', 'Species', '9606', (117, 122))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('RASSF1A', 'Gene', (36, 43))	('genetic', 'Var', (15, 22))
4174	23915220	In this study, we hypothesized that RASSF1A functions as a tumor suppressor in adrenal cortex and that its epigenetic suppression by promoter methylation may be a key step in tumor progression.	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('RASSF1A', 'Gene', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('epigenetic suppression', 'Var', (107, 129))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
4176	23915220	RASSF1 CpG island A hypermethylation is the most common epigenetic mechanism observed in tumors with silenced RASSF1A function .	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('hypermethylation', 'Var', (20, 36))	('RASSF1', 'Gene', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('RASSF1', 'Gene', '11186', (0, 6))	('silenced', 'Var', (101, 109))	('function', 'MPA', (118, 126))	('RASSF1', 'Gene', '11186', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('RASSF1', 'Gene', (0, 6))
4180	23915220	A direct correlation between RASSF1 promoter hypermethylation and reduced RASSF1A expression is observed in a variety of cancers (15).	('reduced', 'NegReg', (66, 73))	('cancers', 'Disease', (121, 128))	('expression', 'Species', '29278', (82, 92))	('hypermethylation', 'Var', (45, 61))	('RASSF1', 'Gene', '11186', (74, 80))	('RASSF1', 'Gene', (29, 35))	('expression', 'MPA', (82, 92))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('RASSF1', 'Gene', (74, 80))	('RASSF1', 'Gene', '11186', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
4181	23915220	To test whether the observed CpG Island A hypermethylation in ACC (Figure  1B) is associated with a corresponding reduction in RASSF1A expression, we compared the mRNA and protein expression in ACC samples to that of normal adrenal cortex tissue samples.	('RASSF1A', 'Gene', (127, 134))	('hypermethylation', 'Var', (42, 58))	('reduction', 'NegReg', (114, 123))	('expression', 'Species', '29278', (180, 190))	('expression', 'Species', '29278', (135, 145))	('expression', 'MPA', (135, 145))
4195	23915220	In addition to the empty vector transfection controls (Figure  3A; a, e), we also expressed a variant of RASSF1A (RASSF1A/A133S) with demonstrated inability to elicit tumor suppressor function , as a control.	('elicit', 'Reg', (160, 166))	('variant', 'Var', (94, 101))	('A133S', 'SUBSTITUTION', 'None', (122, 127))	('inability', 'Disease', 'MESH:D016388', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('A133S', 'Var', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('inability', 'Disease', (147, 156))	('RASSF1A', 'Gene', (105, 112))	('tumor', 'Disease', (167, 172))
4196	23915220	Expression of ectopic RASSF1A (Figure  3A; b-d) and RASSF1A/A133S (Figure  3A; f-h) were confirmed using anti-RASSF1A antibody (Figure  3A; b & f) or anti-DDK antibody (Figure  3A; c & g), both of which co-localized to the same epitope (Figure  3A; d & h).	('A133S', 'SUBSTITUTION', 'None', (60, 65))	('Expression', 'Species', '29278', (0, 10))	('A133S', 'Var', (60, 65))	('anti-RASSF1A', 'Var', (105, 117))
4197	23915220	Constitutive expression of RASSF1A (SW-13/A) or RASSF1A/A133S mutant (SW-13/AM) showed no significant impact on the proliferation (Figure  3B) or viability (Figure  3C) of SW-13 cells in comparison with SW-13 transiently transfected with the empty vector (SW-13/V) alone (Figures  3B &3C).	('expression', 'Species', '29278', (13, 23))	('A133S', 'Var', (56, 61))	('SW-13', 'CellLine', 'CVCL:0542', (256, 261))	('SW-13', 'CellLine', 'CVCL:0542', (203, 208))	('viability', 'CPA', (146, 155))	('A133S', 'SUBSTITUTION', 'None', (56, 61))	('SW-13', 'CellLine', 'CVCL:0542', (172, 177))	('SW-13', 'CellLine', 'CVCL:0542', (70, 75))	('proliferation', 'CPA', (116, 129))	('SW-13', 'CellLine', 'CVCL:0542', (36, 41))
4199	23915220	After confirming the lack of apoptosis-inducing and cell cycle arrest functions in SW-13 cells via transient transfection experiments (Figures  3B &3C), we generated stable SW-13 cell derivatives that expressed RASSF1A and RASSF1A/A133S mutant proteins, to study potential tumor suppressor functions of RASSF1A in adrenal carcinomas.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('adrenal carcinomas', 'Disease', (314, 332))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('A133S', 'Var', (231, 236))	('SW-13', 'CellLine', 'CVCL:0542', (83, 88))	('adrenal carcinomas', 'Phenotype', 'HP:0006744', (314, 332))	('adrenal carcinomas', 'Disease', 'MESH:D000310', (314, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('carcinomas', 'Phenotype', 'HP:0030731', (322, 332))	('and', 'Var', (219, 222))	('A133S', 'SUBSTITUTION', 'None', (231, 236))	('tumor', 'Disease', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('mutant', 'Protein', (237, 243))	('SW-13', 'CellLine', 'CVCL:0542', (173, 178))	('expressed', 'Gene', (201, 210))
4201	23915220	Wild-type RASSF1A were found distributed both in the cytoplasm and nucleus of cells (Figure  4B; b) while RASSF1A/A133S mutant proteins were found predominantly localized in the cytoplasm (Figure  4B; c).	('A133S', 'Var', (114, 119))	('proteins', 'Protein', (127, 135))	('A133S', 'SUBSTITUTION', 'None', (114, 119))
4206	23915220	Cell invasiveness was evaluated using an overnight Matrigel invasion assay, which showed a significant reduction in the invasive potential of SW-13 cells constitutively expressing RASSF1A (SW-13/A) compared to empty vector (SW-13/V) or RASSF1A mutant (SW-13/AM) (Figure  5A).	('invasive potential', 'CPA', (120, 138))	('SW-13', 'CellLine', 'CVCL:0542', (252, 257))	('SW-13', 'CellLine', 'CVCL:0542', (189, 194))	('RASSF1A', 'Var', (180, 187))	('SW-13', 'CellLine', 'CVCL:0542', (142, 147))	('SW-13', 'CellLine', 'CVCL:0542', (224, 229))	('reduction', 'NegReg', (103, 112))
4207	23915220	After 4 hours, SW-13 cells expressing RASSF1A showed a 5-fold reduction in the number of cells migrated across the membrane (Figure  5B), suggesting a strong motility-inhibitory response from re-expressed RASSF1A.	('RASSF1A', 'Var', (38, 45))	('SW-13', 'CellLine', 'CVCL:0542', (15, 20))	('motility-inhibitory', 'MPA', (158, 177))	('reduction', 'NegReg', (62, 71))
4208	23915220	Similarly, cells constitutively expressing high levels of RASSF1A also showed a significantly impaired clonogenic survival/growth response when compared to cells not expressing RASSF1A or cells expressing high levels of RASSF1A/A133S mutant proteins (Figure  5C).	('impaired', 'NegReg', (94, 102))	('clonogenic survival/growth response', 'CPA', (103, 138))	('A133S', 'Var', (228, 233))	('RASSF1A', 'Var', (58, 65))	('A133S', 'SUBSTITUTION', 'None', (228, 233))
4209	23915220	In summary, RASSF1A expression resulted in an overall reduced malignant behavior of SW-13 ACC cells which was not observed in cells expressing the RASSF1A/A133S mutant protein.	('malignant behavior of SW-13 ACC cells', 'CPA', (62, 99))	('A133S', 'Var', (155, 160))	('expression', 'Var', (20, 30))	('RASSF1A', 'Gene', (12, 19))	('reduced', 'NegReg', (54, 61))	('A133S', 'SUBSTITUTION', 'None', (155, 160))	('SW-13', 'CellLine', 'CVCL:0542', (84, 89))	('expression', 'Species', '29278', (20, 30))
4210	23915220	To test whether the observed malignant-dampening effect of RASSF1A in SW-13 cells is through modulating cytoskeletal function, we examined the localization pattern of RASSF1A (Figure  6A; b & c)) and RASSF1A/A133S mutant (Figure  6A; e & f) proteins in the context of localization of microtubule-binding phalloidins (Figure  6A; a, c, d & f).	('RASSF1A', 'Gene', (167, 174))	('and', 'Gene', (196, 199))	('A133S', 'Var', (208, 213))	('SW-13', 'CellLine', 'CVCL:0542', (70, 75))	('A133S', 'SUBSTITUTION', 'None', (208, 213))	('phalloidins', 'Chemical', 'MESH:D010590', (304, 315))
4211	23915220	Co-localization of microtubules with RASSF1A was observed predominantly in cells expressing the wild-type RASSF1A protein (Note the arrows in Figure  6A; c), which was found significantly reduced (6B) in cells expressing RASSF1A/A133S mutant proteins (Figure  6A; f), suggesting a potential microtubule modulatory role for RASSF1A, not the mutant A133S mutant, in eliciting the observed reduced malignant behavior in SW-13 cells constitutively expressing RASSF1A.	('A133S', 'Var', (347, 352))	('RASSF1A', 'Gene', (106, 113))	('A133S', 'Var', (229, 234))	('A133S', 'SUBSTITUTION', 'None', (347, 352))	('A133S', 'SUBSTITUTION', 'None', (229, 234))	('mutant', 'Var', (235, 241))	('malignant behavior', 'CPA', (395, 413))	('reduced', 'NegReg', (387, 394))	('SW-13', 'CellLine', 'CVCL:0542', (417, 422))
4212	23915220	Despite the absence of RASSF1A/A133S co-localization with microtubules, the overall microtubule distribution appeared to be similar between RASSF1A-expressing and A133S mutant-expressing cells (6A; a & b).	('RASSF1A-expressing', 'Var', (140, 158))	('microtubule', 'MPA', (84, 95))	('A133S', 'Var', (31, 36))	('A133S', 'Var', (163, 168))	('A133S', 'SUBSTITUTION', 'None', (31, 36))	('co-localization', 'Interaction', (37, 52))	('A133S', 'SUBSTITUTION', 'None', (163, 168))
4217	23915220	Recent studies in gene expression profiling have suggested a potential role for aberrant DNA methylation events (both hypo- and hypermethylation) in the origin and/or progression of ACC, as in many other malignancies, including endocrine tumors such as neuroblastoma and pheochromocytoma .	('DNA', 'Gene', (89, 92))	('malignancies', 'Disease', (204, 216))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (271, 287))	('neuroblastoma', 'Disease', 'MESH:D009447', (253, 266))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('endocrine tumors', 'Disease', 'MESH:D004701', (228, 244))	('neuroblastoma', 'Disease', (253, 266))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('neuroblastoma', 'Phenotype', 'HP:0003006', (253, 266))	('endocrine tumors', 'Disease', (228, 244))	('aberrant', 'Var', (80, 88))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('pheochromocytoma', 'Disease', (271, 287))	('expression', 'Species', '29278', (23, 33))	('ACC', 'Disease', (182, 185))	('methylation', 'Var', (93, 104))	('pheochromocytoma', 'Disease', 'MESH:D010673', (271, 287))
4221	23915220	Expression analysis of RASSF1A in ACC demonstrated the functional consequence of hypermethylation as a significant decrease in both gene transcription and translation of RASSF1A in ACC cells as determined by qPCR, and immunohistochemistry respectively.	('Expression', 'Species', '29278', (0, 10))	('gene transcription', 'MPA', (132, 150))	('RASSF1A', 'Gene', (170, 177))	('translation', 'MPA', (155, 166))	('decrease', 'NegReg', (115, 123))	('hypermethylation', 'Var', (81, 97))
4222	23915220	To test the hypothesized role for RASSF1A silencing in promoting adrenocortical malignancy, we sought to use a well-established cell culture model.	('silencing', 'Var', (42, 51))	('adrenocortical malignancy', 'Disease', 'MESH:D018268', (65, 90))	('RASSF1A', 'Gene', (34, 41))	('promoting', 'PosReg', (55, 64))	('adrenocortical malignancy', 'Disease', (65, 90))
4226	23915220	After confirming no growth disadvantage consequent to enforced over expression of RASSF1A, SW-13 cell variants constitutively expressing RASSF1A and RASSF1A/A133S were then assayed for other advanced malignancy or metastasis associated tumor behaviors such as invasion and solitary cell growth.	('expression', 'Species', '29278', (68, 78))	('RASSF1A', 'Gene', (137, 144))	('malignancy', 'Disease', 'MESH:D009369', (200, 210))	('invasion', 'CPA', (260, 268))	('metastasis', 'CPA', (214, 224))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('assayed', 'Reg', (173, 180))	('A133S', 'Var', (157, 162))	('malignancy', 'Disease', (200, 210))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('solitary cell growth', 'CPA', (273, 293))	('tumor', 'Disease', (236, 241))	('SW-13', 'CellLine', 'CVCL:0542', (91, 96))	('A133S', 'SUBSTITUTION', 'None', (157, 162))
4228	23915220	To test whether the reduced invasive potential we observed in SW-13 cells with forced RASSF1A expression was due to decreased migratory ability, transwell migration assays were performed.	('reduced', 'NegReg', (20, 27))	('RASSF1A', 'Gene', (86, 93))	('invasive potential', 'CPA', (28, 46))	('migratory ability', 'CPA', (126, 143))	('SW-13', 'CellLine', 'CVCL:0542', (62, 67))	('expression', 'Species', '29278', (94, 104))	('decreased', 'NegReg', (116, 125))	('expression', 'Var', (94, 104))
4230	23915220	Finally, under low seeding conditions that mimic solitary cell growth, constitutive expression of RASSF1A reduced the clonogenicity of solitary SW-13 cells with decreased ability to establish, survive and grow into individual clones.	('expression', 'Var', (84, 94))	('RASSF1A', 'Gene', (98, 105))	('SW-13', 'CellLine', 'CVCL:0542', (144, 149))	('expression', 'Species', '29278', (84, 94))	('clonogenicity', 'CPA', (118, 131))	('reduced', 'NegReg', (106, 113))
4233	23915220	In cells expressing RASSF1A, but not in cells expressing the A133S mutant, we observed sporadic co-localization of RASSF1A with microtubules, which may have a stabilizing effect on microtubule dynamics.	('co-localization', 'Interaction', (96, 111))	('A133S', 'Var', (61, 66))	('RASSF1A', 'Gene', (115, 122))	('microtubules', 'Protein', (128, 140))	('A133S', 'SUBSTITUTION', 'None', (61, 66))	('RASSF1A', 'Var', (20, 27))
4234	23915220	Interestingly, it has been recently suggested that the A133S point mutation in RASSF1A abrogates its ability to modulate cytoskeletal interactions, contributing to loss of its tumor suppressor function .	('A133S', 'Var', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('RASSF1A', 'Gene', (79, 86))	('tumor', 'Disease', (176, 181))	('A133S', 'SUBSTITUTION', 'None', (55, 60))	('modulate cytoskeletal interactions', 'MPA', (112, 146))	('abrogates', 'NegReg', (87, 96))	('ability', 'MPA', (101, 108))	('loss', 'NegReg', (164, 168))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
4235	23915220	Stabilization of microtubules by RASSF1A has been shown to disrupt malignant behavior in many cancer cell types .	('disrupt', 'NegReg', (59, 66))	('microtubules', 'Protein', (17, 29))	('malignant behavior in', 'CPA', (67, 88))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Stabilization', 'Var', (0, 13))	('RASSF1A', 'Gene', (33, 40))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
4246	23915220	Anti-DDK (DYKDDDDK epitope) monoclonal antibody (1:200; Origene, Rockville, MD) was used for detecting DDK-tagged RASSF1A and RASSF1A/A133S in transfected cells.	('A133S', 'Var', (134, 139))	('DDK-tagged', 'Var', (103, 113))	('A133S', 'SUBSTITUTION', 'None', (134, 139))	('RASSF1A', 'Gene', (114, 121))
4255	23915220	Stable clones expressing RASSF1A and RASSF1A/A133S were selected in 800 mug/ml G-418 (Life technologies Inc., Rockville, MD) containing growth medium.	('A133S', 'SUBSTITUTION', 'None', (45, 50))	('RASSF1A', 'Gene', (25, 32))	('G-418', 'Chemical', 'MESH:C010680', (79, 84))	('A133S', 'Var', (45, 50))
4257	23915220	Established populations (designated SW-13/V, SW-13/A, and SW-13/AM representing pCMV vector alone, pCMV-RASSF1A, and pCMV-RASSF1A/A133S mutant, respectively) were used to determine the effects of constitutive expression of RASSF1A or RASSF1A/A133S on SW-13 cell's malignant behavior.	('A133S', 'SUBSTITUTION', 'None', (130, 135))	('RASSF1A', 'Gene', (223, 230))	('SW-13', 'CellLine', 'CVCL:0542', (58, 63))	('SW-13', 'CellLine', 'CVCL:0542', (251, 256))	('A133S', 'Var', (242, 247))	('SW-13', 'CellLine', 'CVCL:0542', (45, 50))	('A133S', 'Var', (130, 135))	('malignant behavior', 'CPA', (264, 282))	('A133S', 'SUBSTITUTION', 'None', (242, 247))	('expression', 'Species', '29278', (209, 219))	('SW-13', 'CellLine', 'CVCL:0542', (36, 41))
4269	31695023	Studies conducted in the last eight years have identified somatic driver mutations in a substantial portion of aldosterone-producing adenomas, including the genes KCNJ5 (encoding inwardly rectifying potassium channel GIRK4), CACNA1D (encoding a subunit of L-type voltage-gated calcium channel CaV1.3), ATP1A1 (encoding a subunit of Na+/K+-ATPase), ATP2B3 (encoding a Ca2+-ATPase), and CTNNB1 (encoding ss-catenin).	('adenomas', 'Disease', 'MESH:D000236', (133, 141))	('adenomas', 'Disease', (133, 141))	('aldosterone', 'Chemical', 'MESH:D000450', (111, 122))	('Ca2+', 'Chemical', 'MESH:D002118', (367, 371))	('CTNNB1', 'Gene', (385, 391))	('ATP2B3', 'Gene', '492', (348, 354))	('ATP2B3', 'Gene', (348, 354))	('ATP1A1', 'Gene', (302, 308))	('GIRK4', 'Gene', (217, 222))	('KCNJ5', 'Gene', (163, 168))	('ATP1A1', 'Gene', '476', (302, 308))	('ATPase', 'Gene', (372, 378))	('GIRK4', 'Gene', '3762', (217, 222))	('CaV1.3', 'Gene', (293, 299))	('ATPase', 'Gene', (339, 345))	('ATPase', 'Gene', '1769', (372, 378))	('CaV1.3', 'Gene', '12289', (293, 299))	('CACNA1D', 'Gene', '776', (225, 232))	('CACNA1D', 'Gene', (225, 232))	('calcium', 'Chemical', 'MESH:D002118', (277, 284))	('potassium', 'Chemical', 'MESH:D011188', (199, 208))	('KCNJ5', 'Gene', '3762', (163, 168))	('ATPase', 'Gene', '1769', (339, 345))	('mutations', 'Var', (73, 82))
4272	31695023	The fact that they are associated with somatic mutations implicated in aldosterone-producing adenomas also suggests a precursor function for adenomas.	('aldosterone', 'Chemical', 'MESH:D000450', (71, 82))	('adenomas', 'Disease', (93, 101))	('adenomas', 'Disease', (141, 149))	('mutations', 'Var', (47, 56))	('adenomas', 'Disease', 'MESH:D000236', (93, 101))	('adenomas', 'Disease', 'MESH:D000236', (141, 149))
4273	31695023	Rare germline variants of CYP11B2 (encoding aldosterone synthase), CLCN2 (encoding voltage-gated chloride channel ClC-2), KCNJ5, CACNA1H (encoding a subunit of T-type voltage-gated calcium channel CaV3.2), and CACNA1D have been reported in different subtypes of familial hyperaldosteronism.	('CACNA1H', 'Gene', '8912', (129, 136))	('familial hyperaldosteronism', 'Disease', (262, 289))	('KCNJ5', 'Gene', '3762', (122, 127))	('CLCN2', 'Gene', (67, 72))	('chloride channel ClC-2', 'Gene', (97, 119))	('CaV3.2', 'Gene', (197, 203))	('aldosterone synthase', 'Gene', '1585', (44, 64))	('CaV3.2', 'Gene', '8912', (197, 203))	('chloride channel ClC-2', 'Gene', '1181', (97, 119))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (271, 289))	('aldosterone synthase', 'Gene', (44, 64))	('KCNJ5', 'Gene', (122, 127))	('CACNA1D', 'Gene', (210, 217))	('familial hyperaldosteronism', 'Disease', 'MESH:C580087', (262, 289))	('CACNA1D', 'Gene', '776', (210, 217))	('variants', 'Var', (14, 22))	('CLCN2', 'Gene', '1181', (67, 72))	('CACNA1H', 'Gene', (129, 136))	('calcium', 'Chemical', 'MESH:D002118', (181, 188))	('reported', 'Reg', (228, 236))	('CYP11B2', 'Gene', (26, 33))
4296	31695023	In recent years, next-generation sequencing approaches have allowed for the identification of somatic (tumor-specific) mutations in APAs as well as germline mutations in FH (Table 1), offering a completely new perspective on the pathophysiology underlying PA and improving our understanding of the regulation of aldosterone production in the adrenal gland.	('aldosterone production', 'Phenotype', 'HP:0000859', (312, 334))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('PA', 'Disease', 'MESH:D006929', (133, 135))	('tumor', 'Disease', (103, 108))	('aldosterone', 'Chemical', 'MESH:D000450', (312, 323))	('PA', 'Phenotype', 'HP:0011736', (256, 258))	('FH', 'Disease', 'MESH:C580087', (170, 172))	('PA', 'Phenotype', 'HP:0011736', (133, 135))	('mutations', 'Var', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('PA', 'Disease', 'MESH:D006929', (256, 258))
4298	31695023	The overall number of somatic (tumor-specific) mutations in APAs was low (2.3 protein-altering and 0.8 silent mutations per tumor) in comparison to malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('PA', 'Phenotype', 'HP:0011736', (61, 63))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (124, 129))	('mutations', 'Var', (47, 56))	('protein-altering', 'MPA', (78, 94))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('malignant tumors', 'Disease', (148, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('PA', 'Disease', 'MESH:D006929', (61, 63))	('malignant tumors', 'Disease', 'MESH:D009369', (148, 164))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
4300	31695023	discovered heterozygous somatic mutations in the gene KCNJ5 (G151R and L168R) encoding the inwardly rectifying potassium channel Kir3.4.	('G151R', 'Var', (61, 66))	('KCNJ5', 'Gene', '3762', (54, 59))	('L168R', 'Mutation', 'p.L168R', (71, 76))	('Kir3.4', 'Gene', '3762', (129, 135))	('L168R', 'Var', (71, 76))	('G151R', 'Mutation', 'p.G151R', (61, 66))	('Kir3.4', 'Gene', (129, 135))	('KCNJ5', 'Gene', (54, 59))	('potassium', 'Chemical', 'MESH:D011188', (111, 120))
4301	31695023	Subsequent targeted Sanger sequencing in 18 APAs revealed six additional somatic KCNJ5 mutations (one G151R and five L168R).	('G151R', 'Var', (102, 107))	('G151R', 'Mutation', 'p.G151R', (102, 107))	('PA', 'Disease', 'MESH:D006929', (45, 47))	('L168R', 'Mutation', 'p.L168R', (117, 122))	('KCNJ5', 'Gene', (81, 86))	('L168R', 'Var', (117, 122))	('PA', 'Phenotype', 'HP:0011736', (45, 47))	('KCNJ5', 'Gene', '3762', (81, 86))
4302	31695023	These two hotspot mutations were later shown to account for the vast majority of KCNJ5 mutations in APAs; other mutations are very rare (L168R: 23-44%, G151R: 54-79%, others: 0-4.5%).	('G151R', 'Mutation', 'p.G151R', (152, 157))	('PA', 'Phenotype', 'HP:0011736', (101, 103))	('KCNJ5', 'Gene', '3762', (81, 86))	('L168R', 'Mutation', 'p.L168R', (137, 142))	('G151R', 'Var', (152, 157))	('KCNJ5', 'Gene', (81, 86))	('PA', 'Disease', 'MESH:D006929', (101, 103))	('mutations', 'Var', (87, 96))	('L168R:', 'Var', (137, 143))
4303	31695023	Ensuing studies in large cohorts have revealed that KCNJ5 mutations may account for approximately 40% of mutations in APAs, with considerable variation among different ethnicities and among women versus men (see below).	('mutations', 'Var', (58, 67))	('men', 'Species', '9606', (203, 206))	('women', 'Species', '9606', (190, 195))	('KCNJ5', 'Gene', (52, 57))	('PA', 'Disease', 'MESH:D006929', (119, 121))	('KCNJ5', 'Gene', '3762', (52, 57))	('mutations', 'Var', (105, 114))	('PA', 'Phenotype', 'HP:0011736', (119, 121))	('men', 'Species', '9606', (192, 195))
4307	31695023	The most common KCNJ5 mutations in APAs are located either within (G151R) or close to (L168R) the selectivity filter.	('G151R', 'Mutation', 'p.G151R', (67, 72))	('PA', 'Phenotype', 'HP:0011736', (36, 38))	('KCNJ5', 'Gene', (16, 21))	('L168R', 'Mutation', 'p.L168R', (87, 92))	('mutations', 'Var', (22, 31))	('PA', 'Disease', 'MESH:D006929', (36, 38))	('G151R', 'Var', (67, 72))	('KCNJ5', 'Gene', '3762', (16, 21))
4309	31695023	proposed that in APAs with KCNJ5 mutations, tumor formation and autonomous aldosterone production are driven by membrane depolarization of glomerulosa cells, leading to increased calcium influx via voltage-gated calcium channels and subsequent changes in the expression of genes implicated in proliferation and aldosterone synthesis.	('depolarization', 'NegReg', (121, 135))	('aldosterone', 'Chemical', 'MESH:D000450', (75, 86))	('KCNJ5', 'Gene', (27, 32))	('PA', 'Phenotype', 'HP:0011736', (18, 20))	('aldosterone', 'Chemical', 'MESH:D000450', (311, 322))	('increased', 'PosReg', (169, 178))	('calcium influx', 'MPA', (179, 193))	('KCNJ5', 'Gene', '3762', (27, 32))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('expression of genes', 'MPA', (259, 278))	('changes', 'Reg', (244, 251))	('calcium', 'Chemical', 'MESH:D002118', (212, 219))	('calcium', 'Chemical', 'MESH:D002118', (179, 186))	('PA', 'Disease', 'MESH:D006929', (18, 20))	('aldosterone production', 'Phenotype', 'HP:0000859', (75, 97))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
4310	31695023	Evidence that KCNJ5 mutations are likely sufficient to cause both aldosterone production and tumor formation is provided by the overall rarity of additional somatic variants in APAs with pathogenic KCNJ5 mutations, specifically the absence of additional mutations that explain proliferation and the fact that patients with germline KCNJ5 mutations found in APAs typically develop massive adrenal hyperplasia as well as early-onset, therapy-resistant PA (see below).	('aldosterone production', 'Phenotype', 'HP:0000859', (66, 88))	('PA', 'Disease', 'MESH:D006929', (178, 180))	('adrenal hyperplasia', 'Disease', (388, 407))	('KCNJ5', 'Gene', (198, 203))	('develop', 'Reg', (372, 379))	('KCNJ5', 'Gene', (332, 337))	('KCNJ5', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('early-onset', 'Disease', (419, 430))	('PA', 'Phenotype', 'HP:0011736', (358, 360))	('PA', 'Disease', 'MESH:D006929', (358, 360))	('cause', 'Reg', (55, 60))	('KCNJ5', 'Gene', '3762', (198, 203))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (388, 407))	('KCNJ5', 'Gene', '3762', (332, 337))	('mutations', 'Var', (204, 213))	('KCNJ5', 'Gene', '3762', (14, 19))	('aldosterone', 'Chemical', 'MESH:D000450', (66, 77))	('mutations', 'Var', (20, 29))	('PA', 'Phenotype', 'HP:0011736', (450, 452))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (388, 407))	('mutations', 'Var', (338, 347))	('tumor', 'Disease', (93, 98))	('PA', 'Disease', 'MESH:D006929', (450, 452))	('PA', 'Phenotype', 'HP:0011736', (178, 180))	('patients', 'Species', '9606', (309, 317))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
4311	31695023	A proliferative effect of KCNJ5 mutations is also suggested by the peculiar case of a patient with germline mosaicism in whom adrenal hyperplasia was restricted to those areas of the adrenal gland that carried KCNJ5 mutations.	('KCNJ5', 'Gene', '3762', (26, 31))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (126, 145))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (126, 145))	('KCNJ5', 'Gene', (210, 215))	('patient', 'Species', '9606', (86, 93))	('mutations', 'Var', (32, 41))	('KCNJ5', 'Gene', '3762', (210, 215))	('KCNJ5', 'Gene', (26, 31))	('mutations', 'Var', (216, 225))	('adrenal hyperplasia', 'Disease', (126, 145))
4312	31695023	Despite these considerations, a two-hit model of APA formation has been proposed involving the activation of signaling pathways such as shh (sonic hedgehog signaling molecule) or Wnt/beta-catenin leading to abnormal proliferation (first hit) and subsequent acquisition of somatic mutations in driver genes such as KCNJ5 leading to increased and autonomous aldosterone production (second hit).	('increased', 'PosReg', (331, 340))	('beta-catenin', 'Gene', (183, 195))	('and autonomous aldosterone production', 'MPA', (341, 378))	('mutations', 'Var', (280, 289))	('KCNJ5', 'Gene', (314, 319))	('abnormal proliferation', 'CPA', (207, 229))	('aldosterone', 'Chemical', 'MESH:D000450', (356, 367))	('PA', 'Phenotype', 'HP:0011736', (50, 52))	('beta-catenin', 'Gene', '1499', (183, 195))	('KCNJ5', 'Gene', '3762', (314, 319))	('aldosterone production', 'Phenotype', 'HP:0000859', (356, 378))	('PA', 'Disease', 'MESH:D006929', (50, 52))
4313	31695023	In very rare cases, this may be due to germline mutations in tumor suppressor genes (published case with APC mutation).	('APC', 'Gene', '324', (105, 108))	('germline mutations', 'Var', (39, 57))	('due', 'Reg', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('APC', 'Gene', (105, 108))	('tumor', 'Disease', (61, 66))
4314	31695023	Two groups independently discovered APAs with somatic mutations in CACNA1D, encoding for the alpha1-subunit of an l-type calcium channel (CaV1.3) via exome sequencing.	('PA', 'Disease', 'MESH:D006929', (37, 39))	('CaV1.3', 'Gene', '12289', (138, 144))	('calcium', 'Chemical', 'MESH:D002118', (121, 128))	('mutations', 'Var', (54, 63))	('CACNA1D', 'Gene', '776', (67, 74))	('PA', 'Phenotype', 'HP:0011736', (37, 39))	('CACNA1D', 'Gene', (67, 74))	('CaV1.3', 'Gene', (138, 144))
4316	31695023	Mutations in CACNA1D are more scattered throughout the protein compared with KCNJ5 mutations.	('KCNJ5', 'Gene', '3762', (77, 82))	('Mutations', 'Var', (0, 9))	('CACNA1D', 'Gene', '776', (13, 20))	('KCNJ5', 'Gene', (77, 82))	('CACNA1D', 'Gene', (13, 20))
4317	31695023	By electrophysiology, both groups demonstrated that the somatic mutations discovered caused an increase in calcium permeability, which was inferred to directly lead to increased aldosterone production and proliferation (Fig.	('calcium permeability', 'MPA', (107, 127))	('increased', 'PosReg', (168, 177))	('calcium', 'Chemical', 'MESH:D002118', (107, 114))	('increase', 'PosReg', (95, 103))	('increased aldosterone', 'Phenotype', 'HP:0000859', (168, 189))	('proliferation', 'CPA', (205, 218))	('aldosterone', 'Chemical', 'MESH:D000450', (178, 189))	('mutations', 'Var', (64, 73))	('aldosterone production', 'MPA', (178, 200))	('aldosterone production', 'Phenotype', 'HP:0000859', (178, 200))
4319	31695023	Studies that relied on Sanger sequencing of only a few exons for somatic mutation detection may have systematically underestimated the prevalence of CACNA1D mutations (21-42% prevalence in studies using panel sequencing of the entire coding sequence vs. 1.5-10.3% in studies using Sanger sequencing of select regions).	('mutations', 'Var', (157, 166))	('underestimated', 'NegReg', (116, 130))	('CACNA1D', 'Gene', '776', (149, 156))	('CACNA1D', 'Gene', (149, 156))
4321	31695023	They described heterozygous mutations in ATP1A1 (encoding for a Na+-K+-ATPase subunit) and ATP2B3 (encoding for a plasma membrane Ca2+ ATPase).	('Na+-K', 'Chemical', 'MESH:D011188', (64, 69))	('ATPase', 'Gene', '1769', (135, 141))	('plasma membrane Ca2+ ATPase', 'Gene', '491', (114, 141))	('ATP1A1', 'Gene', '476', (41, 47))	('ATPase', 'Gene', '1769', (71, 77))	('ATPase', 'Gene', (71, 77))	('ATPase', 'Gene', (135, 141))	('ATP1A1', 'Gene', (41, 47))	('ATP2B3', 'Gene', '492', (91, 97))	('plasma membrane Ca2+ ATPase', 'Gene', (114, 141))	('ATP2B3', 'Gene', (91, 97))	('mutations', 'Var', (28, 37))
4322	31695023	Mutations were clustered within the M4 helix involved in ion binding, suggesting a gain-of-function mechanism; however, the authors originally described the loss of pump function in mutant ATPases (which may contribute to depolarization).	('ATPase', 'Gene', '1769', (189, 195))	('ATPase', 'Gene', (189, 195))	('pump function', 'MPA', (165, 178))	('loss', 'NegReg', (157, 161))	('mutant', 'Var', (182, 188))
4323	31695023	Subsequent studies demonstrated that mutations in ATP1A1 and ATP2B3 cause abnormal Na+ or H+ permeability (Fig.	('ATP2B3', 'Gene', (61, 67))	('ATP1A1', 'Gene', (50, 56))	('cause', 'Reg', (68, 73))	('mutations', 'Var', (37, 46))	('ATP2B3', 'Gene', '492', (61, 67))	('ATP1A1', 'Gene', '476', (50, 56))	('abnormal Na+', 'Phenotype', 'HP:0010931', (74, 86))	('Na+ or H+ permeability', 'MPA', (83, 105))
4324	31695023	1) and enhance aldosterone production in the human adrenocortical H295R cell line, suggesting an underlying pathomechanism similar to that of KCNJ5 mutations.	('mutations', 'Var', (148, 157))	('enhance', 'PosReg', (7, 14))	('aldosterone', 'Chemical', 'MESH:D000450', (15, 26))	('KCNJ5', 'Gene', (142, 147))	('enhance aldosterone', 'Phenotype', 'HP:0000859', (7, 26))	('aldosterone production', 'MPA', (15, 37))	('human', 'Species', '9606', (45, 50))	('aldosterone production', 'Phenotype', 'HP:0000859', (15, 37))	('KCNJ5', 'Gene', '3762', (142, 147))	('H295R', 'CellLine', 'CVCL:0458', (66, 71))
4326	31695023	In addition to ion channels and ATPases, APAs, in rare cases, also carry gain-of-function mutations in CTNNB1, encoding for beta-catenin, the effector of the canonical Wnt signaling pathway.	('mutations', 'Var', (90, 99))	('beta-catenin', 'Gene', (124, 136))	('beta-catenin', 'Gene', '1499', (124, 136))	('PA', 'Disease', 'MESH:D006929', (42, 44))	('CTNNB1', 'Gene', (103, 109))	('ATPase', 'Gene', '1769', (32, 38))	('gain-of-function', 'PosReg', (73, 89))	('PA', 'Phenotype', 'HP:0011736', (42, 44))	('ATPase', 'Gene', (32, 38))
4328	31695023	A universal role of CTNNB1 mutations in adrenal tumor formation is supported by the fact that mutations in CTNNB1 are also found in ACC, cortisol-producing adenomas and nonproducing adenomas.	('mutations', 'Var', (27, 36))	('adrenal tumor', 'Disease', (40, 53))	('adenomas', 'Disease', 'MESH:D000236', (156, 164))	('ACC', 'Phenotype', 'HP:0006744', (132, 135))	('cortisol-producing', 'MPA', (137, 155))	('mutations', 'Var', (94, 103))	('ACC', 'Disease', (132, 135))	('CTNNB1', 'Gene', (20, 26))	('adenomas', 'Disease', (156, 164))	('cortisol', 'Chemical', 'MESH:D006854', (137, 145))	('adrenal tumor', 'Phenotype', 'HP:0100631', (40, 53))	('CTNNB1', 'Gene', (107, 113))	('found', 'Reg', (123, 128))	('ACC', 'Disease', 'MESH:D018268', (132, 135))	('adenomas', 'Disease', 'MESH:D000236', (182, 190))	('adenomas', 'Disease', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('adrenal tumor', 'Disease', 'MESH:D000310', (40, 53))
4330	31695023	In one study, somatic CTNNB1 mutations were reported in two pregnant women.	('CTNNB1', 'Gene', (22, 28))	('women', 'Species', '9606', (69, 74))	('mutations', 'Var', (29, 38))
4332	31695023	However, this has been disputed because CTNNB1 mutations are found in APAs of both male and female (typically nonpregnant) patients.	('PA', 'Disease', 'MESH:D006929', (71, 73))	('CTNNB1', 'Gene', (40, 46))	('PA', 'Phenotype', 'HP:0011736', (71, 73))	('patients', 'Species', '9606', (123, 131))	('found', 'Reg', (61, 66))	('mutations', 'Var', (47, 56))
4337	31695023	Mutations in KCNJ5 appear to be more frequent in females (56-63%; compared to 22-31% in males).	('KCNJ5', 'Gene', '3762', (13, 18))	('Mutations', 'Var', (0, 9))	('frequent', 'Reg', (37, 45))	('KCNJ5', 'Gene', (13, 18))
4338	31695023	Higher frequencies in some Asian cohorts (approximately 60-70% of APAs) were in part attributed to different diagnostic criteria; however, a recent study reporting CACNA1D as the gene with the highest mutational burden and lower KCNJ5 mutation frequencies in a cohort of black subjects with APAs suggests that mutation frequencies may indeed be influenced by ethnicity.	('mutation', 'Var', (235, 243))	('lower', 'NegReg', (223, 228))	('PA', 'Phenotype', 'HP:0011736', (67, 69))	('PA', 'Phenotype', 'HP:0011736', (292, 294))	('KCNJ5', 'Gene', (229, 234))	('PA', 'Disease', 'MESH:D006929', (292, 294))	('CACNA1D', 'Gene', '776', (164, 171))	('KCNJ5', 'Gene', '3762', (229, 234))	('CACNA1D', 'Gene', (164, 171))	('PA', 'Disease', 'MESH:D006929', (67, 69))
4340	31695023	It has been suggested that selective inhibitors of mutant KCNJ5 channels have the potential to improve this situation: a drop in blood pressure and/or aldosterone upon administration of such inhibitors could allow for the noninvasive identification of patients with adenomas carrying KCNJ5 mutations.	('KCNJ5', 'Gene', (58, 63))	('adenomas', 'Disease', 'MESH:D000236', (266, 274))	('aldosterone', 'MPA', (151, 162))	('blood pressure', 'MPA', (129, 143))	('patients', 'Species', '9606', (252, 260))	('adenomas', 'Disease', (266, 274))	('mutant', 'Var', (51, 57))	('KCNJ5', 'Gene', '3762', (58, 63))	('drop', 'NegReg', (121, 125))	('aldosterone', 'Chemical', 'MESH:D000450', (151, 162))	('mutations', 'Var', (290, 299))	('allow', 'Reg', (208, 213))	('KCNJ5', 'Gene', (284, 289))	('KCNJ5', 'Gene', '3762', (284, 289))
4342	31695023	Interestingly, in a high-throughput screen, macrolide antibiotics such as roxithromycin and clarithromycin were identified as specific inhibitors of both KCNJ5G151R and KCNJ5L168R, with no significant inhibition of the wild-type channel.	('clarithromycin', 'Chemical', 'MESH:D017291', (92, 106))	('macrolide', 'Chemical', 'MESH:D018942', (44, 53))	('roxithromycin', 'Chemical', 'MESH:D015575', (74, 87))	('KCNJ5G151R', 'Var', (154, 164))	('KCNJ5L168R', 'Var', (169, 179))
4346	31695023	Specifically, tumors carrying KCNJ5 mutations are characterized by higher production of the so-called hybrid steroid 18-oxocortisol, which could serve to identify APAs for surgery.	('steroid', 'Chemical', 'MESH:D013256', (109, 116))	('higher', 'PosReg', (67, 73))	('KCNJ5', 'Gene', '3762', (30, 35))	('production of the', 'MPA', (74, 91))	('PA', 'Disease', 'MESH:D006929', (164, 166))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (36, 45))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('PA', 'Phenotype', 'HP:0011736', (164, 166))	('KCNJ5', 'Gene', (30, 35))	('18-oxocortisol', 'Chemical', 'MESH:C038135', (117, 131))
4350	31695023	Rather, with increasing age, so-called aldosterone-producing cell clusters (APCCs) develop, which express CYP11B2 and protrude into the zona fasciculata.	('protrude', 'CPA', (118, 126))	('aldosterone', 'Chemical', 'MESH:D000450', (39, 50))	('zona fasciculata', 'Disease', (136, 152))	('APC', 'Gene', (76, 79))	('zona fasciculata', 'Disease', 'MESH:D006562', (136, 152))	('APC', 'Gene', '324', (76, 79))	('CYP11B2', 'Var', (106, 113))
4357	31695023	Interestingly, no KCNJ5 variants were detected.	('KCNJ5', 'Gene', '3762', (18, 23))	('KCNJ5', 'Gene', (18, 23))	('variants', 'Var', (24, 32))
4358	31695023	Lesions with KCNJ5 mutations may quickly progress to APAs and hence may be underrepresented in this study.	('PA', 'Disease', 'MESH:D006929', (54, 56))	('KCNJ5', 'Gene', '3762', (13, 18))	('progress', 'PosReg', (41, 49))	('PA', 'Phenotype', 'HP:0011736', (54, 56))	('mutations', 'Var', (19, 28))	('KCNJ5', 'Gene', (13, 18))
4362	31695023	Sequencing of 99 APCCs in this cohort revealed CACNA1D mutations in 58% and KCNJ5 mutations in 1% of the lesions.	('mutations', 'Var', (55, 64))	('APC', 'Gene', (17, 20))	('KCNJ5', 'Gene', (76, 81))	('APC', 'Gene', '324', (17, 20))	('mutations', 'Var', (82, 91))	('KCNJ5', 'Gene', '3762', (76, 81))	('CACNA1D', 'Gene', (47, 54))	('CACNA1D', 'Gene', '776', (47, 54))
4363	31695023	All adrenals had at least one APCC with such a mutation, but the causes of the remaining lesions are currently unknown.	('APC', 'Gene', (30, 33))	('mutation', 'Var', (47, 55))	('APC', 'Gene', '324', (30, 33))
4372	31695023	One study reported CACNA1D mutations in two patients with PA and UAH, suggesting a common underlying pathomechanism in UAH and APAs.	('mutations', 'Var', (27, 36))	('PA', 'Phenotype', 'HP:0011736', (128, 130))	('patients', 'Species', '9606', (44, 52))	('UAH', 'Disease', (119, 122))	('PA', 'Disease', 'MESH:D006929', (58, 60))	('CACNA1D', 'Gene', '776', (19, 26))	('CACNA1D', 'Gene', (19, 26))	('PA', 'Disease', 'MESH:D006929', (128, 130))	('PA', 'Phenotype', 'HP:0011736', (58, 60))
4373	31695023	In many cases, one nodule expresses aldosterone synthase and carries a known APA driver mutation, whereas other nodules represent nonproducing adenomas or nodules without such mutations, but two APAs in a single gland with independent driver mutations have also been reported.	('mutation', 'Var', (88, 96))	('PA', 'Disease', 'MESH:D006929', (78, 80))	('aldosterone synthase', 'Gene', (36, 56))	('aldosterone synthase', 'Gene', '1585', (36, 56))	('PA', 'Disease', 'MESH:D006929', (196, 198))	('adenomas', 'Disease', 'MESH:D000236', (143, 151))	('PA', 'Phenotype', 'HP:0011736', (78, 80))	('adenomas', 'Disease', (143, 151))	('PA', 'Phenotype', 'HP:0011736', (196, 198))
4386	31695023	The chimeric gene was detected in 29 patients from 12 unrelated pedigrees, including the two patients described by Sutherland et al.. Not all subjects with the chimeric gene are hypertensive, but even in those who are normotensive, excessive aldosterone levels lead to increased left ventricular wall thickness and reduced diastolic function compared to normotensive controls.	('left ventricular wall', 'MPA', (279, 300))	('hypertensive', 'Disease', (178, 190))	('patients', 'Species', '9606', (37, 45))	('excessive aldosterone', 'Phenotype', 'HP:0000859', (232, 253))	('increased', 'PosReg', (269, 278))	('chimeric gene', 'Var', (160, 173))	('diastolic function', 'MPA', (323, 341))	('aldosterone levels', 'MPA', (242, 260))	('excessive aldosterone levels', 'Phenotype', 'HP:0000859', (232, 260))	('excessive', 'PosReg', (232, 241))	('reduced', 'NegReg', (315, 322))	('hypertensive', 'Disease', 'MESH:D006973', (178, 190))	('patients', 'Species', '9606', (93, 101))	('aldosterone', 'Chemical', 'MESH:D000450', (242, 253))
4391	31695023	Exome sequencing of selected individuals from this kindred demonstrated a mutation in the CLCN2 gene, encoding the chloride channel ClC-2.	('mutation', 'Var', (74, 82))	('CLCN2', 'Gene', '1181', (90, 95))	('chloride channel ClC-2', 'Gene', (115, 137))	('CLCN2', 'Gene', (90, 95))	('chloride channel ClC-2', 'Gene', '1181', (115, 137))
4392	31695023	An investigation of 80 individuals with early-onset unexplained PA revealed seven additional subjects with CLCN2 mutations, and it was suggested to refer to individuals with CLCN2 mutations as FH-II.	('PA', 'Disease', 'MESH:D006929', (64, 66))	('FH-II', 'Gene', '79179', (193, 198))	('CLCN2', 'Gene', '1181', (107, 112))	('PA', 'Phenotype', 'HP:0011736', (64, 66))	('CLCN2', 'Gene', (174, 179))	('mutations', 'Var', (113, 122))	('CLCN2', 'Gene', (107, 112))	('CLCN2', 'Gene', '1181', (174, 179))	('FH-II', 'Gene', (193, 198))
4394	31695023	CLCN2 mutations cause a gain of function.	('gain of function', 'PosReg', (24, 40))	('CLCN2', 'Gene', '1181', (0, 5))	('mutations', 'Var', (6, 15))	('CLCN2', 'Gene', (0, 5))
4399	31695023	In conjunction with the identification of somatic KCNJ5 mutations in APAs, a germline KCNJ5 mutation (T158A) was found in this family; this mutation is also rarely found in APAs.	('mutations', 'Var', (56, 65))	('mutation', 'Var', (92, 100))	('KCNJ5', 'Gene', (86, 91))	('PA', 'Disease', 'MESH:D006929', (174, 176))	('KCNJ5', 'Gene', '3762', (86, 91))	('PA', 'Disease', 'MESH:D006929', (70, 72))	('PA', 'Phenotype', 'HP:0011736', (174, 176))	('KCNJ5', 'Gene', (50, 55))	('T158A', 'Mutation', 'c.158T>A', (102, 107))	('PA', 'Phenotype', 'HP:0011736', (70, 72))	('KCNJ5', 'Gene', '3762', (50, 55))
4400	31695023	Since then, other families with mutations in or close to the KCNJ5 selectivity filter have been reported.	('mutations', 'Var', (32, 41))	('KCNJ5', 'Gene', (61, 66))	('KCNJ5', 'Gene', '3762', (61, 66))
4401	31695023	With some exceptions, KCNJ5 mutations that are also found in APAs, when present in the germline, appear to be associated with the development of macroscopic adrenal hyperplasia and a severe phenotype.	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (157, 176))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (157, 176))	('PA', 'Disease', 'MESH:D006929', (62, 64))	('associated with', 'Reg', (110, 125))	('KCNJ5', 'Gene', (22, 27))	('adrenal hyperplasia', 'Disease', (157, 176))	('PA', 'Phenotype', 'HP:0011736', (62, 64))	('men', 'Species', '9606', (137, 140))	('mutations', 'Var', (28, 37))	('KCNJ5', 'Gene', '3762', (22, 27))
4403	31695023	Similarly, E145Q (found in an APA) was reported as a de novo mutation in a female patient diagnosed with PA at 2 years of age due to massively elevated aldosterone levels and blood pressure, treatable only by bilateral adrenalectomy.	('aldosterone', 'Chemical', 'MESH:D000450', (152, 163))	('PA', 'Disease', 'MESH:D006929', (105, 107))	('patient', 'Species', '9606', (82, 89))	('E145Q', 'Mutation', 'p.E145Q', (11, 16))	('blood pressure', 'MPA', (175, 189))	('elevated aldosterone', 'Phenotype', 'HP:0000859', (143, 163))	('PA', 'Phenotype', 'HP:0011736', (105, 107))	('aldosterone levels', 'MPA', (152, 170))	('elevated', 'PosReg', (143, 151))	('E145Q', 'Var', (11, 16))	('PA', 'Disease', 'MESH:D006929', (31, 33))	('PA', 'Phenotype', 'HP:0011736', (31, 33))
4404	31695023	In contrast, mutations that are only found in the germline are typically associated with a milder clinical phenotype without macroscopic adrenal hyperplasia and without requirement for bilateral adrenalectomy.	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (137, 156))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (137, 156))	('men', 'Species', '9606', (176, 179))	('adrenal hyperplasia', 'Disease', (137, 156))	('associated with', 'Reg', (73, 88))	('mutations', 'Var', (13, 22))
4406	31695023	Similarly, a Y152C mutation was found in a patient diagnosed at the age of 48 years with hypertension and a milder phenotype.	('hypertension', 'Phenotype', 'HP:0000822', (89, 101))	('hypertension', 'Disease', 'MESH:D006973', (89, 101))	('patient', 'Species', '9606', (43, 50))	('Y152C', 'Var', (13, 18))	('hypertension', 'Disease', (89, 101))	('Y152C', 'Mutation', 'p.Y152C', (13, 18))
4407	31695023	Functional studies suggest that while all variants affect the ion selectivity of the channel, G151E causes more profound sodium permeability, which may impair cell survival and prevent the development of hyperplasia.	('men', 'Species', '9606', (196, 199))	('G151E', 'Mutation', 'p.G151E', (94, 99))	('affect', 'Reg', (51, 57))	('ion selectivity of the channel', 'MPA', (62, 92))	('G151E', 'Var', (94, 99))	('hyperplasia', 'Disease', (204, 215))	('cell survival', 'CPA', (159, 172))	('sodium permeability', 'MPA', (121, 140))	('hyperplasia', 'Disease', 'MESH:D006965', (204, 215))	('causes', 'Reg', (100, 106))	('sodium', 'Chemical', 'MESH:D012964', (121, 127))	('prevent', 'NegReg', (177, 184))	('more', 'PosReg', (107, 111))	('impair', 'NegReg', (152, 158))
4408	31695023	These findings again support a role for APA-associated KCNJ5 mutations not only in aldosterone production but also in cellular proliferation (see above).	('aldosterone production', 'MPA', (83, 105))	('cellular proliferation', 'CPA', (118, 140))	('role', 'Reg', (31, 35))	('aldosterone production', 'Phenotype', 'HP:0000859', (83, 105))	('KCNJ5', 'Gene', (55, 60))	('mutations', 'Var', (61, 70))	('PA', 'Disease', 'MESH:D006929', (41, 43))	('KCNJ5', 'Gene', '3762', (55, 60))	('aldosterone', 'Chemical', 'MESH:D000450', (83, 94))	('PA', 'Phenotype', 'HP:0011736', (41, 43))
4410	31695023	However, following the description of patients with KCNJ5 mutations with variable phenotypes, FH-III has been used to refer to PA patients with germline KCNJ5 mutations.	('FH-II', 'Gene', '79179', (94, 99))	('KCNJ5', 'Gene', (52, 57))	('PA', 'Disease', 'MESH:D006929', (127, 129))	('mutations', 'Var', (159, 168))	('KCNJ5', 'Gene', (153, 158))	('KCNJ5', 'Gene', '3762', (52, 57))	('patients', 'Species', '9606', (130, 138))	('FH-II', 'Gene', (94, 99))	('PA', 'Phenotype', 'HP:0011736', (127, 129))	('patients', 'Species', '9606', (38, 46))	('KCNJ5', 'Gene', '3762', (153, 158))
4414	31695023	The mutant calcium channel showed dramatically impaired channel inactivation and activation at more hyperpolarized membrane potentials, resulting in increased intracellular Ca2+, the signal for aldosterone production.	('Ca2+', 'Chemical', 'MESH:D002118', (173, 177))	('aldosterone', 'Chemical', 'MESH:D000450', (194, 205))	('channel inactivation', 'MPA', (56, 76))	('mutant', 'Var', (4, 10))	('increased', 'PosReg', (149, 158))	('activation', 'PosReg', (81, 91))	('intracellular Ca2+', 'MPA', (159, 177))	('impaired', 'NegReg', (47, 55))	('aldosterone production', 'Phenotype', 'HP:0000859', (194, 216))	('increased intracellular Ca2+', 'Phenotype', 'HP:0003575', (149, 177))	('calcium', 'Chemical', 'MESH:D002118', (11, 18))
4415	31695023	The expression of the mutant channel in H295R cells and its subclone HAC15 resulted in increased aldosterone production compared to the wild-type channel, which was abolished by the inhibition of CACNA1H channels with the T-type calcium channel blocker mibefradil.	('CACNA1H', 'Gene', (196, 203))	('increased', 'PosReg', (87, 96))	('aldosterone production', 'MPA', (97, 119))	('aldosterone production', 'Phenotype', 'HP:0000859', (97, 119))	('H295R', 'CellLine', 'CVCL:0458', (40, 45))	('CACNA1H', 'Gene', '8912', (196, 203))	('calcium', 'Chemical', 'MESH:D002118', (229, 236))	('increased aldosterone', 'Phenotype', 'HP:0000859', (87, 108))	('mibefradil', 'Chemical', 'MESH:D020748', (253, 263))	('mutant', 'Var', (22, 28))	('HAC15', 'CellLine', 'CVCL:S898', (69, 74))	('aldosterone', 'Chemical', 'MESH:D000450', (97, 108))
4416	31695023	Further CACNA1H germline variants were identified by whole-exome sequencing in patients with different types of PA: another de novo case carrying M1549I in a patient with early-onset PA; S196L in a brother and a sister; P2083L in brothers diagnosed with FH; and V1951E in a patient with APA.	('V1951E', 'Var', (262, 268))	('S196L', 'Mutation', 'p.S196L', (187, 192))	('M1549I', 'Mutation', 'p.M1549I', (146, 152))	('PA', 'Phenotype', 'HP:0011736', (112, 114))	('CACNA1H', 'Gene', (8, 15))	('V1951E', 'Mutation', 'p.V1951E', (262, 268))	('PA', 'Phenotype', 'HP:0011736', (288, 290))	('CACNA1H', 'Gene', '8912', (8, 15))	('PA', 'Disease', 'MESH:D006929', (112, 114))	('PA', 'Disease', 'MESH:D006929', (288, 290))	('PA', 'Phenotype', 'HP:0011736', (183, 185))	('FH', 'Disease', 'MESH:C580087', (254, 256))	('M1549I', 'Var', (146, 152))	('patient', 'Species', '9606', (158, 165))	('patient', 'Species', '9606', (79, 86))	('PA', 'Disease', 'MESH:D006929', (183, 185))	('P2083L', 'Mutation', 'p.P2083L', (220, 226))	('patient', 'Species', '9606', (274, 281))	('P2083L', 'Var', (220, 226))	('patients', 'Species', '9606', (79, 87))
4417	31695023	Whether variants at residues other than M1549 are causative for FH-IV, however, remains to be established.	('M1549', 'CellLine', 'CVCL:X081', (40, 45))	('variants', 'Var', (8, 16))	('causative', 'Reg', (50, 59))	('FH-IV', 'Disease', (64, 69))	('M1549', 'Var', (40, 45))
4418	31695023	In addition to somatic mutations in APAs, the CACNA1D gene also shows germline variants in PA. Due to the associated very severe phenotype, such variants exclusively occur de novo.	('PA', 'Disease', 'MESH:D006929', (37, 39))	('CACNA1D', 'Gene', (46, 53))	('PA', 'Phenotype', 'HP:0011736', (37, 39))	('PA', 'Phenotype', 'HP:0011736', (91, 93))	('CACNA1D', 'Gene', '776', (46, 53))	('variants', 'Var', (145, 153))	('PA', 'Disease', 'MESH:D006929', (91, 93))
4419	31695023	investigated 100 unrelated individuals with unexplained early-onset PA and identified de novo CACNA1D germline mutations in two subjects: G403D in a patient with hypertension at birth along with cardiac pathophysiology (e.g., ventricular septal defect) and neurological disorders (e.g., seizures and apparent cerebral palsy), and I770M in a subject with cerebral palsy and seizures since birth and elevated blood pressure at 5 years of age.	('PA', 'Disease', 'MESH:D006929', (68, 70))	('cerebral palsy', 'Disease', (309, 323))	('hypertension', 'Disease', 'MESH:D006973', (162, 174))	('ventricular septal defect', 'Disease', (226, 251))	('hypertension', 'Disease', (162, 174))	('neurological disorders', 'Disease', (257, 279))	('I770M', 'Var', (330, 335))	('ventricular septal defect', 'Disease', 'MESH:D006345', (226, 251))	('CACNA1D', 'Gene', '776', (94, 101))	('cerebral palsy', 'Disease', 'MESH:D002547', (309, 323))	('CACNA1D', 'Gene', (94, 101))	('seizures', 'Disease', (287, 295))	('septal defect', 'Phenotype', 'HP:0001671', (238, 251))	('I770M', 'Mutation', 'p.I770M', (330, 335))	('seizures', 'Disease', (373, 381))	('patient', 'Species', '9606', (149, 156))	('cerebral palsy', 'Phenotype', 'HP:0100021', (354, 368))	('hypertension', 'Phenotype', 'HP:0000822', (162, 174))	('seizures', 'Disease', 'MESH:D012640', (373, 381))	('seizures', 'Disease', 'MESH:D012640', (287, 295))	('seizures', 'Phenotype', 'HP:0001250', (287, 295))	('seizures', 'Phenotype', 'HP:0001250', (373, 381))	('cerebral palsy', 'Disease', (354, 368))	('neurological disorders', 'Disease', 'MESH:D009422', (257, 279))	('G403D', 'Mutation', 'p.G403D', (138, 143))	('ventricular septal defect', 'Phenotype', 'HP:0001629', (226, 251))	('G403D', 'Var', (138, 143))	('elevated blood pressure', 'Phenotype', 'HP:0032263', (398, 421))	('cerebral palsy', 'Disease', 'MESH:D002547', (354, 368))	('PA', 'Phenotype', 'HP:0011736', (68, 70))	('cerebral palsy', 'Phenotype', 'HP:0100021', (309, 323))
4420	31695023	By electrophysiology, mutant channels showed activation at less depolarized membrane potentials and impaired inactivation in G403D mutants, which were inferred to cause increased Ca2+ influx and CYP11B2 upregulation.	('G403D', 'Mutation', 'p.G403D', (125, 130))	('Ca2+', 'Chemical', 'MESH:D002118', (179, 183))	('increased', 'PosReg', (169, 178))	('Ca2+ influx', 'MPA', (179, 190))	('G403D', 'Var', (125, 130))	('inactivation', 'MPA', (109, 121))	('activation', 'PosReg', (45, 55))	('upregulation', 'PosReg', (203, 215))
4421	31695023	A de novo G403D mutation was also identified in a subject with persistent congenital hyperinsulinaemic hypoglycemia (HH), mild aortic insufficiency, and seizures.	('congenital hyperinsulinaemic hypoglycemia', 'Disease', 'MESH:D007003', (74, 115))	('hyperinsulinaemic hypoglycemia', 'Phenotype', 'HP:0000825', (85, 115))	('aortic insufficiency', 'Disease', (127, 147))	('seizures', 'Disease', (153, 161))	('G403D', 'Var', (10, 15))	('seizures', 'Phenotype', 'HP:0001250', (153, 161))	('HH', 'Phenotype', 'HP:0000825', (117, 119))	('hypoglycemia', 'Phenotype', 'HP:0001943', (103, 115))	('aortic insufficiency', 'Disease', 'MESH:D001022', (127, 147))	('aortic insufficiency', 'Phenotype', 'HP:0001659', (127, 147))	('congenital hyperinsulinaemic hypoglycemia', 'Disease', (74, 115))	('G403D', 'Mutation', 'p.G403D', (10, 15))	('seizures', 'Disease', 'MESH:D012640', (153, 161))
4423	31695023	Finally, de novo CACNA1D variants with similar functional consequences as in PA have been implicated in autism and epilepsy.	('implicated', 'Reg', (90, 100))	('variants', 'Var', (25, 33))	('PA', 'Disease', 'MESH:D006929', (77, 79))	('autism', 'Phenotype', 'HP:0000717', (104, 110))	('PA', 'Phenotype', 'HP:0011736', (77, 79))	('epilepsy', 'Phenotype', 'HP:0001250', (115, 123))	('CACNA1D', 'Gene', '776', (17, 24))	('CACNA1D', 'Gene', (17, 24))	('autism and epilepsy', 'Disease', 'MESH:D001321', (104, 123))
4424	31695023	While genetic mouse models replicating human FH mutations are sparse, PA mouse models with mutations in genes hitherto not implicated in FH have been generated, in part due to species differences in the adrenal expression of ion channels.	('FH', 'Disease', 'MESH:C580087', (137, 139))	('adrenal expression of ion channels', 'MPA', (203, 237))	('FH', 'Disease', 'MESH:C580087', (45, 47))	('mouse', 'Species', '10090', (14, 19))	('PA', 'Disease', 'MESH:D006929', (70, 72))	('mouse', 'Species', '10090', (73, 78))	('mutations', 'Var', (91, 100))	('human', 'Species', '9606', (39, 44))	('PA', 'Phenotype', 'HP:0011736', (70, 72))
4426	31695023	A model with adrenal expression of wild-type and mutant human KCNJ5 under the control of the Akr1b7 promoter has been reported only in abstract form but did not show adrenal hyperplasia or severe aldosteronism.	('adrenal hyperplasia', 'Disease', (166, 185))	('KCNJ5', 'Gene', (62, 67))	('mutant', 'Var', (49, 55))	('KCNJ5', 'Gene', '3762', (62, 67))	('human', 'Species', '9606', (56, 61))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (166, 185))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (166, 185))
4427	31695023	Another transgenic mouse model expresses human CYP11B2 under the control of a human CYP11B1 promoter mimicking the condition of FH-I.	('human', 'Species', '9606', (78, 83))	('transgenic', 'Species', '10090', (8, 18))	('human', 'Species', '9606', (41, 46))	('CYP11B1', 'Gene', (84, 91))	('CYP11B1', 'Gene', '1584', (84, 91))	('mouse', 'Species', '10090', (19, 24))	('CYP11B2', 'Var', (47, 54))
4431	31695023	The disruption of both Kcnk3 and Kcnk9 (TASK-3) in mice leads to a depolarization of adrenal glomerulosa cells and an overproduction of aldosterone resistant to both salt suppression and treatment with candesartan along with unchanged or lower renin concentrations.	('Kcnk3', 'Gene', (23, 28))	('adrenal glomerulosa', 'Disease', 'MESH:D000312', (85, 104))	('renin', 'Gene', (244, 249))	('aldosterone', 'Chemical', 'MESH:D000450', (136, 147))	('mice', 'Species', '10090', (51, 55))	('salt suppression', 'Phenotype', 'HP:0000127', (166, 182))	('adrenal glomerulosa', 'Disease', (85, 104))	('men', 'Species', '9606', (192, 195))	('candesartan', 'Chemical', 'MESH:C081643', (202, 213))	('Kcnk9', 'Gene', (33, 38))	('renin', 'Gene', '5972', (244, 249))	('overproduction', 'PosReg', (118, 132))	('lower renin concentrations', 'Phenotype', 'HP:0003351', (238, 264))	('aldosterone', 'MPA', (136, 147))	('disruption', 'Var', (4, 14))	('depolarization', 'MPA', (67, 81))	('overproduction of aldosterone', 'Phenotype', 'HP:0000859', (118, 147))
4432	31695023	Deletion of only Kcnk9 leads to salt-sensitive hypertension, slightly elevated aldosterone levels and low plasma renin levels.	('aldosterone levels', 'MPA', (79, 97))	('elevated', 'PosReg', (70, 78))	('Kcnk9', 'Gene', (17, 22))	('low plasma renin', 'Phenotype', 'HP:0003351', (102, 118))	('renin', 'Gene', '5972', (113, 118))	('hypertension', 'Disease', 'MESH:D006973', (47, 59))	('hypertension', 'Disease', (47, 59))	('low', 'NegReg', (102, 105))	('hypertension', 'Phenotype', 'HP:0000822', (47, 59))	('aldosterone', 'Chemical', 'MESH:D000450', (79, 90))	('elevated aldosterone', 'Phenotype', 'HP:0000859', (70, 90))	('renin', 'Gene', (113, 118))	('leads to', 'Reg', (23, 31))	('Deletion', 'Var', (0, 8))
4433	31695023	Zona-glomerulosa-specific disruption of Kcnk3 and Kcnk9 causes mild autonomous aldosterone production despite low renin and thereby chronic blood pressure elevation.	('aldosterone production', 'Phenotype', 'HP:0000859', (79, 101))	('Kcnk3', 'Gene', (40, 45))	('disruption', 'Var', (26, 36))	('autonomous aldosterone production', 'MPA', (68, 101))	('blood pressure elevation', 'Phenotype', 'HP:0032263', (140, 164))	('blood pressure', 'MPA', (140, 154))	('chronic blood pressure', 'Phenotype', 'HP:0000822', (132, 154))	('renin', 'Gene', (114, 119))	('aldosterone', 'Chemical', 'MESH:D000450', (79, 90))	('causes', 'Reg', (56, 62))	('Kcnk9', 'Gene', (50, 55))	('low', 'NegReg', (110, 113))	('elevation', 'PosReg', (155, 164))	('low renin', 'Phenotype', 'HP:0003351', (110, 119))	('renin', 'Gene', '5972', (114, 119))
4434	31695023	In humans, KCNK3 (TASK-1) single-nucleotide polymorphisms have been associated with blood pressure traits and aldosterone levels.	('associated', 'Reg', (68, 78))	('aldosterone levels', 'MPA', (110, 128))	('single-nucleotide polymorphisms', 'Var', (26, 57))	('humans', 'Species', '9606', (3, 9))	('aldosterone', 'Chemical', 'MESH:D000450', (110, 121))	('blood pressure traits', 'MPA', (84, 105))	('KCNK3', 'Gene', (11, 16))	('KCNK3', 'Gene', '3777', (11, 16))
4439	31695023	These mice were carriers of point mutations in seven candidate genes, of which a variant in SCO-spondin (SSpo) was suggested as the most promising based on a phenotype of increased aldosterone values, associated Cyp11b2 upregulation as well as elevated ARR.	('SSpo', 'Gene', (105, 109))	('SCO-spondin', 'Gene', (92, 103))	('increased aldosterone', 'Phenotype', 'HP:0000859', (171, 192))	('ARR', 'MPA', (253, 256))	('elevated', 'PosReg', (244, 252))	('mice', 'Species', '10090', (6, 10))	('SCO-spondin', 'Gene', '243369', (92, 103))	('variant', 'Var', (81, 88))	('aldosterone', 'Chemical', 'MESH:D000450', (181, 192))	('SSpo', 'Gene', '243369', (105, 109))	('upregulation', 'PosReg', (220, 232))	('aldosterone values', 'MPA', (181, 199))	('Cyp11b2', 'Gene', (212, 219))	('increased', 'PosReg', (171, 180))	('Cyp11b2', 'Gene', '13072', (212, 219))
4441	31695023	Sporadic PA is likely a disease continuum that starts with a somatic driver mutation in a single adrenal cell and subsequently progresses to APCC and/or APA.	('progresses', 'Reg', (127, 137))	('PA', 'Disease', 'MESH:D006929', (154, 156))	('APC', 'Gene', (141, 144))	('PA', 'Phenotype', 'HP:0011736', (9, 11))	('PA', 'Phenotype', 'HP:0011736', (154, 156))	('APC', 'Gene', '324', (141, 144))	('mutation', 'Var', (76, 84))	('PA', 'Disease', 'MESH:D006929', (9, 11))
4446	31695023	KCNJ5 variants explain a substantial portion (approximately 40%) of the somatic mutations in APAs but are also the basis of FH-III.	('FH-II', 'Gene', '79179', (124, 129))	('PA', 'Phenotype', 'HP:0011736', (94, 96))	('variants', 'Var', (6, 14))	('KCNJ5', 'Gene', '3762', (0, 5))	('mutations', 'Var', (80, 89))	('FH-II', 'Gene', (124, 129))	('PA', 'Disease', 'MESH:D006929', (94, 96))	('KCNJ5', 'Gene', (0, 5))
4447	31695023	CACNA1D variants are involved as somatic mutations in APAs as well as in an inherited form of PA, PASNA syndrome.	('mutations', 'Var', (41, 50))	('PA', 'Phenotype', 'HP:0011736', (55, 57))	('PA', 'Phenotype', 'HP:0011736', (94, 96))	('PA', 'Disease', 'MESH:D006929', (98, 100))	('involved', 'Reg', (21, 29))	('variants', 'Var', (8, 16))	('PASNA', 'Gene', (98, 103))	('PA', 'Phenotype', 'HP:0011736', (98, 100))	('PA', 'Disease', 'MESH:D006929', (94, 96))	('PASNA', 'Gene', '776', (98, 103))	('CACNA1D', 'Gene', '776', (0, 7))	('PA', 'Disease', 'MESH:D006929', (55, 57))	('CACNA1D', 'Gene', (0, 7))
4448	31695023	So far, CACNA1H mutations have been reported only as germline mutations in FH-IV, similar to CLCN2 mutations in FH-II and CYP11B2 mutations in FH-I; whether they account for rare instances of APAs remains to be determined.	('FH-IV', 'Gene', (75, 80))	('CLCN2', 'Gene', '1181', (93, 98))	('PA', 'Disease', 'MESH:D006929', (193, 195))	('FH-II', 'Gene', '79179', (112, 117))	('mutations', 'Var', (16, 25))	('PA', 'Phenotype', 'HP:0011736', (193, 195))	('CACNA1H', 'Gene', (8, 15))	('CLCN2', 'Gene', (93, 98))	('CACNA1H', 'Gene', '8912', (8, 15))	('FH-II', 'Gene', (112, 117))
4453	31695023	The underlying pathophysiology of the vast majority of mutations appears to involve increased calcium influx, followed by upregulated CYP11B2 expression and aldosterone production.	('mutations', 'Var', (55, 64))	('aldosterone', 'Chemical', 'MESH:D000450', (157, 168))	('upregulated', 'PosReg', (122, 133))	('CYP11B2 expression', 'MPA', (134, 152))	('increased', 'PosReg', (84, 93))	('aldosterone production', 'MPA', (157, 179))	('calcium influx', 'MPA', (94, 108))	('aldosterone production', 'Phenotype', 'HP:0000859', (157, 179))	('calcium', 'Chemical', 'MESH:D002118', (94, 101))
4454	31695023	This increased calcium influx can occur directly, via mutations in voltage-gated calcium channels, or indirectly, via changes in ion permeability or selectivity that cause the depolarization of glomerulosa cells and the subsequent opening of voltage-gated calcium channels.	('changes', 'Reg', (118, 125))	('calcium', 'Chemical', 'MESH:D002118', (15, 22))	('mutations', 'Var', (54, 63))	('calcium', 'Chemical', 'MESH:D002118', (256, 263))	('depolarization', 'MPA', (176, 190))	('opening', 'Reg', (231, 238))	('calcium', 'Chemical', 'MESH:D002118', (81, 88))	('increased', 'PosReg', (5, 14))	('voltage-gated calcium', 'MPA', (242, 263))	('calcium influx', 'MPA', (15, 29))
4455	31695023	The latter mechanism applies to KCNJ5, CLCN2, and ATPase mutations.	('CLCN2', 'Gene', (39, 44))	('ATPase', 'Gene', '1769', (50, 56))	('KCNJ5', 'Gene', (32, 37))	('mutations', 'Var', (57, 66))	('CLCN2', 'Gene', '1181', (39, 44))	('ATPase', 'Gene', (50, 56))	('KCNJ5', 'Gene', '3762', (32, 37))
4458	31695023	Distinct from all other mutations is the formation of a hybrid gene by unequal crossing over between CYP11B2 and CYP11B1 along with an aberrant expression pattern of CYP11B2 in the adrenal cortex, leading to ACTH-dependent aldosterone overproduction in FH-I.	('ACTH', 'Gene', (208, 212))	('aldosterone', 'Chemical', 'MESH:D000450', (223, 234))	('CYP11B2', 'Var', (166, 173))	('ACTH', 'Gene', '5443', (208, 212))	('CYP11B1', 'Gene', (113, 120))	('CYP11B1', 'Gene', '1584', (113, 120))	('overproduction', 'PosReg', (235, 249))
4463	29183089	Successful Treatment of Estrogen Excess in Primary Bilateral Macronodular Adrenocortical Hyperplasia with Leuprolide Acetate Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is an uncommon cause of adrenal Cushing syndrome (CS) in which cortisol and occasionally other steroid hormones can be secreted under the influence of aberrantly expressed G-protein coupled receptors (GPCRs) in the adrenal cortex.	('macronodular adrenocortical hyperplasia', 'Phenotype', 'HP:0008231', (143, 182))	('GPCR', 'Gene', '441931', (392, 396))	('Macronodular Adrenocortical Hyperplasia', 'Phenotype', 'HP:0008231', (61, 100))	('tic', 'Phenotype', 'HP:0100033', (165, 168))	('aberrantly', 'Var', (342, 352))	('Primary Bilateral Macronodular Adrenocortical Hyperplasia', 'Disease', 'MESH:C565662', (43, 100))	('G-protein coupled receptors', 'Protein', (363, 390))	('CS', 'Phenotype', 'HP:0003118', (241, 243))	('adrenal Cushing syndrome', 'Disease', 'MESH:D003480', (215, 239))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (223, 239))	('tic', 'Phenotype', 'HP:0100033', (83, 86))	('cortisol', 'Chemical', 'MESH:D006854', (254, 262))	('steroid hormone', 'Chemical', 'MESH:D013256', (286, 301))	('Estrogen Excess', 'Phenotype', 'HP:0025134', (24, 39))	('adrenal Cushing syndrome', 'Disease', (215, 239))	('Primary bilateral macronodular adrenocortical hyperplasia', 'Disease', 'MESH:C565662', (125, 182))	('PBMAH', 'Chemical', '-', (184, 189))	('GPCR', 'Gene', (392, 396))
4468	29183089	Targeted sequencing revealed a pathogenic PDE11A mutation, as well as variants in the ARMC5 and INHA genes.	('pathogenic', 'Reg', (31, 41))	('PDE11A', 'Gene', (42, 48))	('mutation', 'Var', (49, 57))	('variants', 'Var', (70, 78))	('INHA', 'Gene', '3623', (96, 100))	('INHA', 'Gene', (96, 100))	('ARMC5', 'Gene', '79798', (86, 91))	('ARMC5', 'Gene', (86, 91))
4474	29183089	Inactivating mutations in Armadillo repeat containing 5 (ARMC5), a putative tumor suppressor gene, is the primary genetic cause of PBMAH, being mutated in approximately half of the known cases Other genetic defects implicated in the pathogenesis of PBMAH include loss of protein kinase A (PKA) type I regulatory subunit alpha (PRKAR1A) expression or activating mutations of the guanine nucleotide binding protein alpha stimulating subunit (GNAS) gene both at the somatic (tumor) level only, and germline mutations in the phosphodiesterase 11 A (PDE11A) or 8B (PDE8B), menin (MEN1), adenomatous polyposis coli (APC), and fumarate hydrat (FH) genes.	('activating', 'PosReg', (350, 360))	('menin', 'Gene', (568, 573))	('PDE11A', 'Gene', (545, 551))	('tumor', 'Disease', (76, 81))	('ARMC5', 'Gene', '79798', (57, 62))	('phosphodiesterase 11 A', 'Gene', (521, 543))	('genetic defects', 'Disease', (199, 214))	('tumor', 'Disease', (472, 477))	('APC', 'Phenotype', 'HP:0005227', (610, 613))	('PKA', 'Gene', (289, 292))	('genetic defects', 'Disease', 'MESH:D030342', (199, 214))	('PDE8B', 'Gene', '8622', (560, 565))	('APC', 'Disease', 'MESH:D011125', (610, 613))	('PRKAR1A', 'Gene', (327, 334))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('APC', 'Disease', (610, 613))	('tumor', 'Disease', 'MESH:D009369', (472, 477))	('tic', 'Phenotype', 'HP:0100033', (203, 206))	('PBMAH', 'Chemical', '-', (131, 136))	('PBMAH', 'Chemical', '-', (249, 254))	('ARMC5', 'Gene', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('PRKAR1A', 'Gene', '5573', (327, 334))	('tumor', 'Phenotype', 'HP:0002664', (472, 477))	('GNAS', 'Gene', (440, 444))	('loss', 'NegReg', (263, 267))	('MEN1', 'Gene', '4221', (575, 579))	('PDE8B', 'Gene', (560, 565))	('Armadillo repeat containing 5', 'Gene', '79798', (26, 55))	('GNAS', 'Gene', '2778', (440, 444))	('Armadillo repeat containing 5', 'Gene', (26, 55))	('tic', 'Phenotype', 'HP:0100033', (467, 470))	('guanine nucleotide binding protein alpha stimulating subunit', 'Gene', '2778', (378, 438))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (582, 608))	('MEN1', 'Gene', (575, 579))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (582, 608))	('mutations', 'Var', (504, 513))	('phosphodiesterase 11 A', 'Gene', '50940', (521, 543))	('tic', 'Phenotype', 'HP:0100033', (118, 121))	('adenomatous polyposis coli', 'Disease', (582, 608))	('menin', 'Gene', '4221', (568, 573))
4475	29183089	In PBMAH, the synthesis of cortisol, and/or other steroid hormones, such as aldosterone, testosterone, and estrogen, can be stimulated by aberrant G-protein coupled receptors (GPCRs).	('GPCR', 'Gene', (176, 180))	('synthesis', 'MPA', (14, 23))	('GPCR', 'Gene', '441931', (176, 180))	('steroid hormone', 'Chemical', 'MESH:D013256', (50, 65))	('testosterone', 'Chemical', 'MESH:D013739', (89, 101))	('aberrant', 'Var', (138, 146))	('PBMAH', 'Chemical', '-', (3, 8))	('cortisol', 'Chemical', 'MESH:D006854', (27, 35))	('G-protein coupled receptors', 'Protein', (147, 174))	('aldosterone', 'Chemical', 'MESH:D000450', (76, 87))	('stimulated', 'PosReg', (124, 134))
4506	29183089	After 1 h blocking, sections were incubated over-night at 4  C with the following primary antibodies: rabbit anti-luteinizing hormone receptor (1:2000, Sigma, Saint Louis, MO, USA), rabbit anti-Aromatase (1:1500, Sigma, Saint Louis, MO, USA), and rabbit anti-17-alpha-hydroxylase (1:1000, Abcam, Cambridge, MA, USA), and rabbit PDE11A (1:200, Abcam, Cambridge, MA, USA).	('Aromatase', 'Gene', '1588', (194, 203))	('rabbit', 'Species', '9986', (321, 327))	('rabbit', 'Species', '9986', (102, 108))	('Aromatase', 'Gene', (194, 203))	('rabbit', 'Species', '9986', (247, 253))	('1:1500', 'Var', (205, 211))	('luteinizing hormone receptor', 'Gene', (114, 142))	('luteinizing hormone receptor', 'Gene', '3973', (114, 142))	('rabbit', 'Species', '9986', (182, 188))
4514	29183089	Our patient's oldest daughter was found to have the same PDE11A mutation; she has PBMAH on imaging but retains normal bone mineral density, HbA1c, androgen, estrogen, and cortisol levels.	('HbA1c', 'Gene', (140, 145))	('PDE11A', 'Gene', (57, 63))	('androgen', 'MPA', (147, 155))	('mutation', 'Var', (64, 72))	('PBMAH', 'Chemical', '-', (82, 87))	('cortisol', 'Chemical', 'MESH:D006854', (171, 179))	('estrogen', 'MPA', (157, 165))	('patient', 'Species', '9606', (4, 11))	('retains', 'NegReg', (103, 110))	('bone', 'MPA', (118, 122))
4515	29183089	WES from blood leukocytes revealed a non-novel p.Arg52Thr (c.155 G > C; rs77972073; NM_016953) pathogenic mutation in PDE11A which was also present in adrenocortical tissue from the right adrenalectomy ( Fig.	('adrenocortical', 'Disease', (151, 165))	('p.Arg52Thr (c.155 G > C; rs77972073', 'Var', (47, 82))	('p.Arg52Thr', 'Mutation', 'rs77972073', (47, 57))	('pathogenic', 'Reg', (95, 105))	('adrenocortical', 'Disease', 'MESH:D018268', (151, 165))	('rs77972073', 'Mutation', 'rs77972073', (72, 82))	('PDE11A', 'Gene', (118, 124))	('c.155 G > C', 'Mutation', 'rs77972073', (59, 70))	('c.155 G > C; rs77972073;', 'Var', (59, 83))	('tic', 'Phenotype', 'HP:0100033', (160, 163))
4516	29183089	There were two single nucleotide INHA polymorphisms: the first was located early in the 5' non-cod-ing region of exon 1 (g.3081 G > T; NM_002191), and the second was a rare synonymous variant in exon 1 (c.207 C > T; rs371366906; NM_002191), corresponding to amino acid 69.	('INHA', 'Gene', '3623', (33, 37))	('c.207 C > T', 'Mutation', 'rs371366906', (203, 214))	('INHA', 'Gene', (33, 37))	('rs371366906', 'Mutation', 'rs371366906', (216, 227))	('NM_002191', 'Var', (229, 238))	('g.3081 G > T', 'Mutation', 'g.3081G>T', (121, 133))	('g.3081 G > T;', 'Var', (121, 134))	('c.207 C > T; rs371366906; NM_002191', 'Var', (203, 238))
4517	29183089	No effect on the splice site was identified using the splice site calculator by Desmet et al.. Genetic analysis for germline ARMC5 defects revealed only the common benign polymorphism (p.Ala705Val; c.2114C > T; rs11150624; NM_024742).	('tic', 'Phenotype', 'HP:0100033', (99, 102))	('NM_024742', 'Var', (223, 232))	('p.Ala705Val; c.2114C > T; rs11150624; NM_024742', 'Var', (185, 232))	('rs11150624', 'Mutation', 'rs11150624', (211, 221))	('c.2114C > T', 'Mutation', 'rs11150624', (198, 209))	('ARMC5', 'Gene', '79798', (125, 130))	('p.Ala705Val', 'Mutation', 'rs11150624', (185, 196))	('ARMC5', 'Gene', (125, 130))
4529	29183089	Genetic testing revealed several variants in modifier genes, including what may be a pathogenic mutation in PDE11A, which could have potentiated adrenal steroid hormone production by increased PKA signaling through the LHr.	('tic', 'Phenotype', 'HP:0100033', (4, 7))	('increased', 'PosReg', (183, 192))	('mutation', 'Var', (96, 104))	('potentiated', 'PosReg', (133, 144))	('PDE11A', 'Gene', (108, 114))	('steroid hormone', 'Chemical', 'MESH:D013256', (153, 168))	('PKA signaling', 'MPA', (193, 206))	('variants', 'Var', (33, 41))	('adrenal steroid hormone production', 'MPA', (145, 179))
4535	29183089	After the initial discovery of LH/hCG receptors in cells that contain cytochrome P450 side chain cleavage enzyme in zona reticularis, several reports have confirmed the presence of aberrant LHr expression in adrenocortical tumors.	('LH', 'Chemical', 'MESH:D007986', (190, 192))	('tic', 'Phenotype', 'HP:0100033', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('aberrant', 'Var', (181, 189))	('P450', 'Gene', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tic', 'Phenotype', 'HP:0100033', (217, 220))	('LHr', 'Protein', (190, 193))	('adrenocortical tumors', 'Disease', (208, 229))	('hCG', 'Gene', '93659', (34, 37))	('LH', 'Chemical', 'MESH:D007986', (31, 33))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (208, 229))	('P450', 'Gene', '1555', (81, 85))	('hCG', 'Gene', (34, 37))
4539	29183089	The fact that leuprolide decreases adrenal androgen production has also been confirmed in other settings, such as men being treated for prostate cancer.	('decreases', 'NegReg', (25, 34))	('prostate cancer', 'Disease', (136, 151))	('men', 'Species', '9606', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('leuprolide', 'Var', (14, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (136, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))	('decreases adrenal', 'Phenotype', 'HP:0000835', (25, 42))	('adrenal androgen production', 'MPA', (35, 62))
4545	29183089	It has been suggested that aberrant receptors may be a frequent cause of increased steroid hormone production by ADTs.	('steroid hormone', 'Chemical', 'MESH:D013256', (83, 98))	('increased', 'PosReg', (73, 82))	('steroid hormone production', 'MPA', (83, 109))	('aberrant', 'Var', (27, 35))
4552	29183089	Despite the presence of what may be a pathogenic variant in the PDE11A gene, our patient did not have LOH of PDE11A in the previously excised affected adrenal gland ( Fig.	('variant', 'Var', (49, 56))	('PDE11A', 'Gene', (64, 70))	('patient', 'Species', '9606', (81, 88))	('pathogenic', 'Reg', (38, 48))
4555	29183089	The report speaks volumes for the clinical heterogeneity of PBMAH over time even in the same patient; in addition, this case represents one of the longest successfully medically treated patients with a hormonal syndrome due to an aberrantly expressed GPCR.	('hormonal syndrome', 'Disease', (202, 219))	('PBMAH', 'Chemical', '-', (60, 65))	('hormonal syndrome', 'Disease', 'MESH:D009384', (202, 219))	('patient', 'Species', '9606', (93, 100))	('aberrantly expressed', 'Var', (230, 250))	('GPCR', 'Gene', (251, 255))	('GPCR', 'Gene', '441931', (251, 255))	('patient', 'Species', '9606', (186, 193))	('patients', 'Species', '9606', (186, 194))
4559	29884238	The potential mechanistic effect(s) of SLC12A7 amplifications in portending an aggressive behavior in ACC has not been previously studied and is investigated here using two established ACC cell lines, SW-13 and NCI-H295R.	('NCI-H295R', 'CellLine', 'CVCL:0458', (211, 220))	('SLC12A7', 'Gene', (39, 46))	('ACC', 'Phenotype', 'HP:0006744', (102, 105))	('aggressive behavior', 'CPA', (79, 98))	('aggressive behavior', 'Phenotype', 'HP:0000718', (79, 98))	('ACC', 'Phenotype', 'HP:0006744', (185, 188))	('SW-13', 'CellLine', 'CVCL:0542', (201, 206))	('amplifications', 'Var', (47, 61))
4561	29884238	In vitro studies tested the outcomes of experimental alterations in SLC12A7 expression on malignant characteristics, including cell viability, growth, colony formation potential, motility, invasive capacity, adhesion and detachment kinetics, and cell membrane organization.	('cell viability', 'CPA', (127, 141))	('motility', 'CPA', (179, 187))	('colony formation potential', 'CPA', (151, 177))	('growth', 'CPA', (143, 149))	('SLC12A7', 'Gene', (68, 75))	('cell membrane organization', 'CPA', (246, 272))	('alterations', 'Var', (53, 64))	('tested', 'Reg', (17, 23))	('expression', 'Species', '29278', (76, 86))	('malignant characteristics', 'CPA', (90, 115))	('invasive capacity', 'CPA', (189, 206))
4564	29884238	SLC12A7 overexpression also significantly increased rates of cellular attachment and detachment turnover (p < 0.05), potentially propelled by increased filopodia formation and/or Ezrin interaction.	('increased', 'PosReg', (42, 51))	('increased', 'PosReg', (142, 151))	('SLC12A7', 'Gene', (0, 7))	('cellular attachment', 'CPA', (61, 80))	('interaction', 'Interaction', (185, 196))	('detachment turnover', 'Disease', (85, 104))	('Ezrin', 'Gene', (179, 184))	('filopodia formation', 'CPA', (152, 171))	('expression', 'Species', '29278', (12, 22))	('overexpression', 'Var', (8, 22))	('detachment turnover', 'Disease', 'MESH:D012163', (85, 104))	('Ezrin', 'Gene', '7430', (179, 184))
4567	29884238	Amplification of SLC12A7 observed in ACCs is shown here, in vitro, to exacerbate the malignant behavior of ACC cells by promoting invasive capacities, possibly mediated by alterations in multiple signaling pathways, including the osmotic stress pathway.	('Amplification', 'Var', (0, 13))	('promoting', 'PosReg', (120, 129))	('ACC', 'Phenotype', 'HP:0006744', (107, 110))	('exacerbate', 'PosReg', (70, 80))	('SLC12A7', 'Gene', (17, 24))	('ACCs', 'Gene', '84680', (37, 41))	('malignant behavior of', 'CPA', (85, 106))	('ACC', 'Phenotype', 'HP:0006744', (37, 40))	('invasive capacities', 'CPA', (130, 149))	('alterations', 'Reg', (172, 183))	('ACCs', 'Gene', (37, 41))
4573	29884238	Moreover, experiments showed that SLC12A7 promotes the malignant behavior of adrenal cancer cells by changing their cell membrane attachment kinetics and consequently, accelerates their invasive behavior.	('cell', 'CPA', (116, 120))	('SLC12A7', 'Var', (34, 41))	('changing', 'Reg', (101, 109))	('invasive behavior', 'CPA', (186, 203))	('adrenal cancer', 'Disease', (77, 91))	('accelerates', 'PosReg', (168, 179))	('promotes', 'PosReg', (42, 50))	('adrenal cancer', 'Disease', 'MESH:D000310', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('malignant behavior', 'CPA', (55, 73))
4581	29884238	Activation of canonical Wnt/beta-catenin signaling occurs frequently in ACC via mutations of the proto-oncogene CTNNB1 (beta-Catenin), which in turn stimulates target gene transcription and promotes tumor formation.	('tumor', 'Disease', (199, 204))	('target gene transcription', 'MPA', (160, 185))	('ACC', 'Phenotype', 'HP:0006744', (72, 75))	('CTNNB1', 'Gene', (112, 118))	('beta-catenin', 'Gene', (28, 40))	('mutations', 'Var', (80, 89))	('beta-catenin', 'Gene', '1499', (28, 40))	('CTNNB1', 'Gene', '1499', (112, 118))	('beta-Catenin', 'Gene', (120, 132))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('Activation', 'PosReg', (0, 10))	('beta-Catenin', 'Gene', '1499', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('stimulates', 'PosReg', (149, 159))	('promotes', 'PosReg', (190, 198))
4583	29884238	Furthermore, Li Fraumeni Syndrome, which is caused by germline TP53 mutations, is often associated with childhood ACCs.	('Li Fraumeni Syndrome', 'Disease', 'MESH:D016864', (13, 33))	('ACC', 'Phenotype', 'HP:0006744', (114, 117))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('associated', 'Reg', (88, 98))	('ACCs', 'Gene', (114, 118))	('ACCs', 'Gene', '84680', (114, 118))	('mutations', 'Var', (68, 77))	('caused', 'Reg', (44, 50))	('Li Fraumeni Syndrome', 'Disease', (13, 33))
4589	29884238	However, it has also been demonstrated that amplified expression of SLC12A7 promotes the malignant behavior of several different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('SLC12A7', 'Gene', (68, 75))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('promotes', 'PosReg', (76, 84))	('expression', 'Species', '29278', (54, 64))	('amplified', 'Var', (44, 53))
4591	29884238	Furthermore, SCL12A7 has been shown to promote in vitro tumor cell invasion, potentially mediated through interactions with Ezrin (EZR), a membrane cytoskeleton/extra-cellular matrix linker.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('promote', 'PosReg', (39, 46))	('interactions', 'Interaction', (106, 118))	('SCL12A7', 'Var', (13, 20))	('EZR', 'Gene', (131, 134))	('tumor', 'Disease', (56, 61))	('Ezrin', 'Gene', '7430', (124, 129))	('EZR', 'Gene', '7430', (131, 134))	('Ezrin', 'Gene', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
4609	29884238	Enforced overexpression of SLC12A7 protein in SW-13 cells was confirmed via Western blot technique using anti-SLC12A7 rabbit polyclonal antibody (Novus), anti-rabbit-HRP goat antibody (Santa Cruz Biotech), mini-PROTEAN TGX gel (BioRad), PVDF blotting membrane (BioRad), and enhanced chemiluminescence detection reagents (ThermoFisher Scientific) according to the manufacturer's protocols.	('rabbit', 'Species', '9986', (159, 165))	('goat', 'Species', '9925', (170, 174))	('expression', 'Species', '29278', (13, 23))	('Rad', 'Gene', (264, 267))	('chemiluminescence detection reagents', 'MPA', (283, 319))	('rabbit', 'Species', '9986', (118, 124))	('PVDF', 'Chemical', 'MESH:C024865', (237, 241))	('Rad', 'Gene', '6236', (231, 234))	('Rad', 'Gene', (231, 234))	('SW-13', 'CellLine', 'CVCL:0542', (46, 51))	('enhanced', 'PosReg', (274, 282))	('Rad', 'Gene', '6236', (264, 267))	('anti-SLC12A7', 'Var', (105, 117))
4635	29884238	Expression analysis demonstrated a robust increase in mRNA SLC12A7 transcript levels in SW-13/S cells compared to controls (SW-13/V and SW-13 cells; p < 0.05, Fig.	('SW-13/S', 'CellLine', 'CVCL:0542', (88, 95))	('SW-13', 'CellLine', 'CVCL:0542', (136, 141))	('SW-13/S', 'Var', (88, 95))	('transcript levels', 'MPA', (67, 84))	('mRNA', 'MPA', (54, 58))	('Expression', 'Species', '29278', (0, 10))	('SW-13', 'CellLine', 'CVCL:0542', (124, 129))	('SW-13', 'CellLine', 'CVCL:0542', (88, 93))	('increase', 'PosReg', (42, 50))
4638	29884238	RNAi gene silencing in NCI-H295R cells known to a have gene amplification of SLC12A7 resulted in the suppression of SLC12A7 mRNA levels up to 60% (siB), compared to the control siRNA treatments, including the scrambled siRNA (p < 0.05, Fig.	('SLC12A7', 'Gene', (77, 84))	('NCI-H295R', 'CellLine', 'CVCL:0458', (23, 32))	('RNAi', 'Gene', (0, 4))	('suppression', 'NegReg', (101, 112))	('gene', 'Var', (5, 9))	('silencing', 'NegReg', (10, 19))	('SLC12A7 mRNA levels', 'MPA', (116, 135))
4643	29884238	Growth and clonogenic survival were not tested in NCI-H295R cells due to the slow growth rate and the transient effect of RNAi gene silencing.	('RNAi', 'Gene', (122, 126))	('slow growth', 'Phenotype', 'HP:0001510', (77, 88))	('gene silencing', 'Var', (127, 141))	('NCI-H295R', 'CellLine', 'CVCL:0458', (50, 59))
4647	29884238	SLC12A7 overexpression also promoted cell invasion through Matrigel with a similar 50% increase in invasive capacity observed in SW-13/S cells during a 24 h period (p < 0.05; Fig.	('increase', 'PosReg', (87, 95))	('SLC12A7', 'Gene', (0, 7))	('cell invasion through Matrigel', 'CPA', (37, 67))	('overexpression', 'Var', (8, 22))	('expression', 'Species', '29278', (12, 22))	('promoted', 'PosReg', (28, 36))	('SW-13/S', 'CellLine', 'CVCL:0542', (129, 136))	('invasive capacity', 'CPA', (99, 116))
4648	29884238	As can be predicted, opposite to the outcome of enforced SLC12A7 overexpression in SW-13 cells, inhibition of SLC12A7 expression by RNAi gene silencing resulted in a significant reduction of migration and Matrigel-invasion behavior of NCI-H295R cells (Fig.	('NCI-H295R', 'CellLine', 'CVCL:0458', (235, 244))	('expression', 'Species', '29278', (69, 79))	('SW-13', 'CellLine', 'CVCL:0542', (83, 88))	('gene silencing', 'Var', (137, 151))	('RNAi', 'Gene', (132, 136))	('reduction', 'NegReg', (178, 187))	('SLC12A7', 'Gene', (110, 117))	('expression', 'Species', '29278', (118, 128))	('expression', 'MPA', (118, 128))	('inhibition', 'NegReg', (96, 106))
4652	29884238	5a, SW-13/S cells adhered to the substratum at a significantly faster rate compared to SW-13 and SW-13/V cells (p < 0.05), indicating that SLC12A7 may promote faster ACC cell adhesion.	('ACC', 'Phenotype', 'HP:0006744', (166, 169))	('faster', 'PosReg', (63, 69))	('SW-13', 'CellLine', 'CVCL:0542', (4, 9))	('SW-13/S', 'CellLine', 'CVCL:0542', (4, 11))	('SW-13', 'CellLine', 'CVCL:0542', (87, 92))	('SW-13', 'CellLine', 'CVCL:0542', (97, 102))	('promote', 'PosReg', (151, 158))	('SLC12A7', 'Var', (139, 146))	('adhered', 'CPA', (18, 25))
4653	29884238	SLC12A7 also promoted faster detachment of SW-13/S cells as well (p < 0.05, Fig.	('promoted', 'PosReg', (13, 21))	('SLC12A7', 'Var', (0, 7))	('SW-13/S cells', 'CPA', (43, 56))	('SW-13/S', 'CellLine', 'CVCL:0542', (43, 50))
4655	29884238	Notably, SLC12A7 gene silencing resulted in a dose-dependent decrease in cell attachment strength, with the NCI-H295R cells affected by the highest knock down of SLC12A7 (siRNA B) also demonstrating the greatest perturbation of attachment strength (p < 0.05, Fig.	('decrease', 'NegReg', (61, 69))	('gene', 'Var', (17, 21))	('knock down', 'Var', (148, 158))	('silencing', 'NegReg', (22, 31))	('attachment strength', 'CPA', (228, 247))	('SLC12A7', 'Gene', (162, 169))	('NCI-H295R', 'CellLine', 'CVCL:0458', (108, 117))	('cell attachment strength', 'CPA', (73, 97))	('SLC12A7', 'Gene', (9, 16))
4657	29884238	Assessment of the cell membrane projections associated with cell motility, specifically lamellipodia, lobopodia, and filopodia, showed a distinct difference in their organization in SW-13/S cells compared to SW-13/V cells (left panel, Fig.	('SW-13/S', 'CellLine', 'CVCL:0542', (182, 189))	('SW-13', 'CellLine', 'CVCL:0542', (182, 187))	('organization', 'MPA', (166, 178))	('SW-13/S', 'Var', (182, 189))	('difference', 'Reg', (146, 156))	('SW-13', 'CellLine', 'CVCL:0542', (208, 213))
4659	29884238	Microscopic quantification revealed increased filopodia formation, partly at the expense of reduced lamellipodia extensions, in SW-13/S cells compared to parental SW-13 and SW-13/V cells (p < 0.05, right panel, Fig.	('filopodia formation', 'CPA', (46, 65))	('increased', 'PosReg', (36, 45))	('lamellipodia extensions', 'Disease', (100, 123))	('SW-13/S', 'CellLine', 'CVCL:0542', (128, 135))	('SW-13', 'CellLine', 'CVCL:0542', (128, 133))	('reduced', 'NegReg', (92, 99))	('SW-13', 'CellLine', 'CVCL:0542', (163, 168))	('SW-13/S', 'Var', (128, 135))	('SW-13', 'CellLine', 'CVCL:0542', (173, 178))	('lamellipodia extensions', 'Disease', 'MESH:D000079822', (100, 123))
4665	29884238	Perturbations in these pathways downstream to SLC12A7 overexpression can potentially alter the adhesion kinetics and invasive properties of ACC cells, as observed in this study.	('SLC12A7', 'Gene', (46, 53))	('expression', 'Species', '29278', (58, 68))	('adhesion kinetics', 'CPA', (95, 112))	('alter', 'Reg', (85, 90))	('invasive properties', 'CPA', (117, 136))	('ACC', 'Phenotype', 'HP:0006744', (140, 143))	('overexpression', 'Var', (54, 68))	('Perturbations', 'Var', (0, 13))
4682	29884238	Moreover, co-localization of SLC12A7 with EZR, a structural and functional linker for cell motility at the leading edges of fast moving SW-13/S cells, further suggests an active role for SLC12A7 in accentuating ACC cell motility and invasive behavior.	('SW-13/S', 'CellLine', 'CVCL:0542', (136, 143))	('ACC', 'Phenotype', 'HP:0006744', (211, 214))	('SLC12A7', 'Gene', (187, 194))	('EZR', 'Gene', '7430', (42, 45))	('accentuating', 'PosReg', (198, 210))	('co-localization', 'Var', (10, 25))	('ACC cell motility', 'CPA', (211, 228))	('invasive behavior', 'CPA', (233, 250))	('EZR', 'Gene', (42, 45))	('SLC12A7', 'Gene', (29, 36))
4685	29884238	Clarification of the probable aggressiveness of SLC12A7 amplification in a larger clinical study cohort would help further clarify the potential translational aspect of these findings.	('aggressiveness', 'Disease', (30, 44))	('aggressiveness', 'Phenotype', 'HP:0000718', (30, 44))	('SLC12A7', 'Gene', (48, 55))	('aggressiveness', 'Disease', 'MESH:D001523', (30, 44))	('amplification', 'Var', (56, 69))
4686	29884238	We previously demonstrated that SLC12A7 amplification was associated with hormonally inactive (potentially more de-differentiated) tumors in a smaller discovery cohort of ACC tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('ACC', 'Phenotype', 'HP:0006744', (171, 174))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('associated', 'Reg', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('amplification', 'Var', (40, 53))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('SLC12A7', 'Gene', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
4687	29884238	However, determination of a likely association of SLC12A7 amplifications with tumor stage, invasiveness, and survival needs to be explored in a larger cohort.	('SLC12A7', 'Gene', (50, 57))	('amplifications', 'Var', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('invasiveness', 'CPA', (91, 103))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('association', 'Interaction', (35, 46))	('tumor', 'Disease', (78, 83))
4688	29884238	In conclusion, this study demonstrates that SLC12A7 amplification may promote tumor cell migration and invasion in ACC, at least in part by modulating cell membrane organization and perturbed osmotic signaling.	('cell membrane organization', 'CPA', (151, 177))	('modulating', 'Reg', (140, 150))	('perturbed', 'NegReg', (182, 191))	('SLC12A7', 'Gene', (44, 51))	('ACC', 'Phenotype', 'HP:0006744', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('ACC', 'Disease', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('promote', 'PosReg', (70, 77))	('tumor', 'Disease', (78, 83))	('amplification', 'Var', (52, 65))	('invasion', 'CPA', (103, 111))	('osmotic signaling', 'MPA', (192, 209))
4734	28378549	These tumors ranged in size from 3.8 to 22.0 cm in their greatest dimension and weighed between 38.5 and 2,292.0 g. These showed immunopositivity for inhibin, synaptophysin, melan-A, and immunonegativity for chromogranin at the time of initial diagnosis, which is supportive of the diagnosis of ACC.	('melan-A', 'Gene', (174, 181))	('immunonegativity', 'Var', (187, 203))	('synaptophysin', 'Gene', '6855', (159, 172))	('melan-A', 'Gene', '2315', (174, 181))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('ACC', 'Phenotype', 'HP:0006744', (295, 298))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('synaptophysin', 'Gene', (159, 172))
4746	28378549	After adjusting for age and sex, rare variants of ACC (HR, 3.59; 95% CI, 1.13-11.38; P = 0.030), and the Ki-67 labeling index (HR, 3.97; 95% CI, 1.18-13.41; P = 0.030) were found to be independent predictors of overall survival in ACC patients on multivariate analysis (Table 4).	('variants', 'Var', (38, 46))	('overall survival', 'MPA', (211, 227))	('patients', 'Species', '9606', (235, 243))	('ACC', 'Phenotype', 'HP:0006744', (231, 234))	('ACC', 'Phenotype', 'HP:0006744', (50, 53))	('ACC', 'Disease', (231, 234))	('predictors', 'Reg', (197, 207))	('ACC', 'Gene', (50, 53))
4796	27413559	However, the patient meets all the four minor criteria used to define oncocytic neoplasms of uncertain malignant potential (borderline), including large size (>10 cm) and/or huge weight (>200 g), extended necrosis, capsular invasion, and sinusoidal invasion.	('capsular invasion', 'CPA', (215, 232))	('patient', 'Species', '9606', (13, 20))	('oncocytic neoplasms', 'Disease', 'MESH:C535584', (70, 89))	('necrosis', 'Disease', (205, 213))	('sinusoidal invasion', 'CPA', (238, 257))	('>200 g', 'Var', (187, 193))	('neoplasm', 'Phenotype', 'HP:0002664', (80, 88))	('necrosis', 'Disease', 'MESH:D009336', (205, 213))	('neoplasms', 'Phenotype', 'HP:0002664', (80, 89))	('oncocytic neoplasms', 'Disease', (70, 89))
4817	25268545	Inactivating mutations of PRKAR1A are associated with Carney complex and a subset of sporadic tumors and the abundance of R2B protein is low in a subset of secreting adrenocortical adenomas.	('adrenocortical adenomas', 'Disease', (166, 189))	('sporadic tumors', 'Disease', 'MESH:D009369', (85, 100))	('PRKAR1A', 'Gene', (26, 33))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (166, 189))	('associated', 'Reg', (38, 48))	('secreting adrenocortical adenoma', 'Phenotype', 'HP:0011746', (156, 188))	('low', 'NegReg', (137, 140))	('Inactivating mutations', 'Var', (0, 22))	('sporadic tumors', 'Disease', (85, 100))	('PRKAR1A', 'Gene', '5573', (26, 33))	('Carney complex', 'Disease', (54, 68))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('secreting adrenocortical adenomas', 'Phenotype', 'HP:0011746', (156, 189))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (166, 189))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (166, 188))
4818	25268545	We previously showed that PRKAR1A and PRKAR2B inactivation have anti-apoptotic effects on the adrenocortical carcinoma cell line H295R.	('H295R', 'CellLine', 'CVCL:0458', (129, 134))	('PRKAR1A', 'Gene', (26, 33))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (94, 118))	('anti-apoptotic effects', 'CPA', (64, 86))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (94, 118))	('PRKAR2B', 'Gene', (38, 45))	('PRKAR2B', 'Gene', '5577', (38, 45))	('PRKAR1A', 'Gene', '5573', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('inactivation', 'Var', (46, 58))	('adrenocortical carcinoma', 'Disease', (94, 118))
4823	25268545	The depletion of PRKAR1A leads to the accumulation of cyclin D1 and p27kip, whereas the depletion of PRKAR2B promotes the accumulation of cyclin A, B, cdk1, cdc2, and p21Cip.	('cyclin D1', 'Gene', '595', (54, 63))	('p21Cip', 'Var', (167, 173))	('PRKAR2B', 'Gene', '5577', (101, 108))	('accumulation', 'PosReg', (122, 134))	('cyclin A', 'Gene', '890', (138, 146))	('cdc2', 'Gene', (157, 161))	('cyclin D1', 'Gene', (54, 63))	('accumulation', 'PosReg', (38, 50))	('cdk1', 'Gene', '983', (151, 155))	('p27kip', 'Var', (68, 74))	('PRKAR1A', 'Gene', (17, 24))	('cdk1', 'Gene', (151, 155))	('cyclin A', 'Gene', (138, 146))	('PRKAR1A', 'Gene', '5573', (17, 24))	('cdc2', 'Gene', '983', (157, 161))	('PRKAR2B', 'Gene', (101, 108))
4824	25268545	In conclusion, although the depletion of PRKAR1A and PRKAR2B in adrenocortical cells has similar effects on cell proliferation and apoptosis; loss of these PKA subunits differentially affects cyclin expression.	('PRKAR2B', 'Gene', (53, 60))	('PRKAR2B', 'Gene', '5577', (53, 60))	('PRKAR1A', 'Gene', '5573', (41, 48))	('affects', 'Reg', (184, 191))	('adrenocortical', 'Disease', 'MESH:D018268', (64, 78))	('loss', 'Var', (142, 146))	('cyclin', 'Gene', '5111', (192, 198))	('cyclin', 'Gene', (192, 198))	('PRKAR1A', 'Gene', (41, 48))	('depletion', 'MPA', (28, 37))	('adrenocortical', 'Disease', (64, 78))
4828	25268545	Alterations in cAMP-mediated signal transduction are associated with neoplastic transformation.	('Alterations', 'Var', (0, 11))	('cAMP', 'Gene', '820', (15, 19))	('neoplastic transformation', 'Disease', 'MESH:D002471', (69, 94))	('neoplastic transformation', 'Disease', (69, 94))	('associated', 'Reg', (53, 63))	('cAMP', 'Gene', (15, 19))
4829	25268545	PRKAR1A inactivating mutations are found in Carney complex (CNC) patients and are responsible for bilateral cortisol-secreting adrenocortical tumors, named primary pigmented nodular adrenocortical disease (PPNAD).	('responsible for', 'Reg', (82, 97))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (164, 204))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (127, 148))	('PRKAR1A', 'Gene', (0, 7))	('inactivating mutations', 'Var', (8, 30))	('pigmented nodular adrenocortical disease', 'Disease', (164, 204))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (164, 204))	('Carney complex', 'Disease', (44, 58))	('patients', 'Species', '9606', (65, 73))	('cortisol', 'Chemical', 'MESH:D006854', (108, 116))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('adrenocortical tumors', 'Disease', (127, 148))	('PRKAR1A', 'Gene', '5573', (0, 7))
4830	25268545	Somatic PRKAR1A mutations are also found in sporadic endocrine tumors.	('sporadic endocrine tumors', 'Disease', (44, 69))	('PRKAR1A', 'Gene', '5573', (8, 15))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (16, 25))	('sporadic endocrine tumors', 'Disease', 'MESH:D004701', (44, 69))	('PRKAR1A', 'Gene', (8, 15))	('found', 'Reg', (35, 40))
4832	25268545	Indeed, 2 studies described a new mechanism of cAMP pathway dysregulation in adrenocortical tumorigenesis involving the loss of PKA R2B protein in cortisol secreting adenoma due to a post-transcriptional mechanism.	('cAMP', 'Gene', (47, 51))	('cAMP', 'Gene', '820', (47, 51))	('cortisol secreting', 'MPA', (147, 165))	('cortisol', 'Chemical', 'MESH:D006854', (147, 155))	('adenoma', 'Disease', 'MESH:D000236', (166, 173))	('loss', 'NegReg', (120, 124))	('protein', 'Protein', (136, 143))	('adrenocortical', 'Disease', (77, 91))	('adrenocortical', 'Disease', 'MESH:D018268', (77, 91))	('adenoma', 'Disease', (166, 173))	('dysregulation', 'Var', (60, 73))	('PKA R2B', 'Gene', (128, 135))
4834	25268545	Prkar2b inactivation by siRNA in mice adrenocortical Y1 cells promotes cell proliferation.	('adrenocortical', 'Disease', (38, 52))	('Y1', 'CellLine', 'CVCL:0585', (53, 55))	('Prkar2b', 'Gene', (0, 7))	('adrenocortical', 'Disease', 'MESH:D018268', (38, 52))	('Prkar2b', 'Gene', '19088', (0, 7))	('promotes', 'PosReg', (62, 70))	('inactivation', 'Var', (8, 20))	('mice', 'Species', '10090', (33, 37))	('cell proliferation', 'CPA', (71, 89))
4836	25268545	The effect of alterations to PKA signaling during endocrine tumorigenesis is likely to be complex, because the defective expression of PKA Type I and Type II enhances PKA activity but causes different types of tumors.	('alterations', 'Var', (14, 25))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('defective', 'Var', (111, 120))	('causes', 'Reg', (184, 190))	('enhances', 'PosReg', (158, 166))	('PKA', 'Gene', (135, 138))	('activity', 'MPA', (171, 179))	('PKA', 'Enzyme', (167, 170))
4837	25268545	Here, we used siRNA to inactivate either PRKAR1A or PRKAR2B in human adrenocortical carcinoma H295R cells and studied the resulting effects on cell proliferation/apoptosis, signaling pathways, and cell cycle control.	('PRKAR1A', 'Gene', '5573', (41, 48))	('inactivate', 'Var', (23, 33))	('human', 'Species', '9606', (63, 68))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (69, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (69, 93))	('PRKAR1A', 'Gene', (41, 48))	('PRKAR2B', 'Gene', '5577', (52, 59))	('adrenocortical carcinoma', 'Disease', (69, 93))	('H295R', 'CellLine', 'CVCL:0458', (94, 99))	('PRKAR2B', 'Gene', (52, 59))
4838	25268545	We show that the inactivation of PRKAR1A or PRKAR2B had a common effect on the resistance of cells to apoptosis; however, this effect was mediated through distinct targets and at different components of cell cycle control.	('inactivation', 'Var', (17, 29))	('PRKAR2B', 'Gene', (44, 51))	('PRKAR1A', 'Gene', (33, 40))	('PRKAR1A', 'Gene', '5573', (33, 40))	('resistance of cells to apoptosis', 'CPA', (79, 111))	('PRKAR2B', 'Gene', '5577', (44, 51))
4845	25268545	We assayed PKA activity, and found no difference in basal activity in the absence of forskolin (FSK) between siR1A or siR2B and siCtl cell lysates (Fig.	('forskolin', 'Chemical', 'MESH:D005576', (85, 94))	('siR1A', 'Var', (109, 114))	('assayed', 'Reg', (3, 10))	('PKA', 'Enzyme', (11, 14))	('siR2', 'Gene', '23411', (118, 122))	('siR2', 'Gene', (118, 122))	('FSK', 'Chemical', 'MESH:D005576', (96, 99))
4848	25268545	Knockdown of R1A impaired the activity of the type I fraction in the absence of cAMP; however, the addition of cAMP enhanced the activity of both PKA type I and type II (although the activity of PKA type 1 was lower than in the control).	('enhanced', 'PosReg', (116, 124))	('type I fraction', 'MPA', (46, 61))	('cAMP', 'Gene', '820', (80, 84))	('PKA type I', 'Enzyme', (146, 156))	('impaired', 'NegReg', (17, 25))	('activity', 'MPA', (129, 137))	('cAMP', 'Gene', (80, 84))	('cAMP', 'Gene', (111, 115))	('addition', 'Var', (99, 107))	('activity', 'MPA', (30, 38))	('cAMP', 'Gene', '820', (111, 115))
4853	25268545	1SA), the percentage of apoptotic cells was significantly lower in both siR1A and siR2B cells than in control cells.	('siR2', 'Gene', (82, 86))	('lower', 'NegReg', (58, 63))	('apoptotic cells', 'CPA', (24, 39))	('siR1A', 'Var', (72, 77))	('siR2', 'Gene', '23411', (82, 86))
4854	25268545	The abundance of the pro-apoptotic Bax protein showed no significant variation between siR1A, siR2B, and siCtl cells, whereas the abundance of anti-apoptotic Bcl-xL protein was higher in both siR1A and siR2B cells than in control cells (Fig.	('siR2', 'Gene', (202, 206))	('higher', 'PosReg', (177, 183))	('Bcl-xL', 'Gene', '598', (158, 164))	('siR2', 'Gene', '23411', (94, 98))	('Bax', 'Gene', '581', (35, 38))	('siR1A', 'Var', (192, 197))	('Bcl-xL', 'Gene', (158, 164))	('siR2', 'Gene', '23411', (202, 206))	('siR2', 'Gene', (94, 98))	('Bax', 'Gene', (35, 38))	('abundance', 'MPA', (130, 139))
4855	25268545	The percentage of BrdU-positive cells corresponding to cells in S phase of the cell cycle was also higher in both siR1A and siR2B cells than in siCtl cells (Fig.	('siR2', 'Gene', '23411', (124, 128))	('higher', 'PosReg', (99, 105))	('siR2', 'Gene', (124, 128))	('BrdU', 'Chemical', 'MESH:D001973', (18, 22))	('S phase of the cell cycle', 'CPA', (64, 89))	('siR1A', 'Var', (114, 119))
4856	25268545	The propidium iodide staining showed that the percentage of cells in the G1 phase was lower in siR1A and siR2B cells than in control cells, whereas the percentage of cells in the G2 phase was higher (Fig.	('siR1A', 'Var', (95, 100))	('cells in the G1 phase', 'CPA', (60, 81))	('siR2', 'Gene', '23411', (105, 109))	('lower', 'NegReg', (86, 91))	('siR2', 'Gene', (105, 109))	('propidium iodide', 'Chemical', 'MESH:D011419', (4, 20))
4857	25268545	This suggests that siR1A and siR2B cells progress more quickly through the cell cycle than control cells.	('siR2', 'Gene', (29, 33))	('progress', 'CPA', (41, 49))	('siR1A', 'Var', (19, 24))	('siR2', 'Gene', '23411', (29, 33))
4862	25268545	Immunoblotting with IKBalpha-specific antibodies showed that the amount of IkBalpha protein was significantly lower in both siR1A and siR2B cells than in control cells (Fig.	('siR2', 'Gene', (134, 138))	('IKBalpha', 'Gene', (20, 28))	('amount', 'MPA', (65, 71))	('IkBalpha', 'Gene', '4792', (75, 83))	('lower', 'NegReg', (110, 115))	('IKBalpha', 'Gene', '4792', (20, 28))	('siR1A', 'Var', (124, 129))	('protein', 'Protein', (84, 91))	('IkBalpha', 'Gene', (75, 83))	('siR2', 'Gene', '23411', (134, 138))
4864	25268545	In contrast, only the knockdown of R2B promoted the translocation of NF-kappaB p65(RelA) to the nucleus (Fig.	('p65', 'Gene', '5970', (79, 82))	('promoted', 'PosReg', (39, 47))	('NF-kappaB', 'Gene', (69, 78))	('RelA', 'Gene', '5970', (83, 87))	('NF-kappaB', 'Gene', '4790', (69, 78))	('knockdown', 'Var', (22, 31))	('RelA', 'Gene', (83, 87))	('translocation', 'MPA', (52, 65))	('p65', 'Gene', (79, 82))
4872	25268545	We studied the expression of cyclins and their distribution between the cytosol and the nucleus because knockdown of PRKAR1A or PRKAR2B was associated with a high percentage of cells in G2 phase (Fig.	('cyclin', 'Gene', (29, 35))	('associated', 'Reg', (140, 150))	('PRKAR1A', 'Gene', '5573', (117, 124))	('G2 phase', 'CPA', (186, 194))	('PRKAR2B', 'Gene', '5577', (128, 135))	('cyclin', 'Gene', '5111', (29, 35))	('PRKAR2B', 'Gene', (128, 135))	('PRKAR1A', 'Gene', (117, 124))	('knockdown', 'Var', (104, 113))
4884	25268545	Although siR1A cells expressed a high amount of cyclin D, the abundance of cdk4 and cdk6 protein was similar to control cells (Fig.	('cdk4', 'Gene', (75, 79))	('cdk6', 'Gene', (84, 88))	('cyclin', 'Gene', '5111', (48, 54))	('cdk4', 'Gene', '1019', (75, 79))	('siR1A', 'Var', (9, 14))	('cyclin', 'Gene', (48, 54))	('cdk6', 'Gene', '1021', (84, 88))
4888	25268545	The abundance of p21Cip was significantly higher in siR2B cells than in control cells, and p27Kip accumulated in siR1A cells (Fig.	('p27Kip', 'Var', (91, 97))	('siR2', 'Gene', '23411', (52, 56))	('siR2', 'Gene', (52, 56))	('p21Cip', 'Var', (17, 23))	('higher', 'PosReg', (42, 48))	('abundance', 'MPA', (4, 13))
4892	25268545	Inactivation of the regulatory subunit R1A, either by genetic mutation in humans or by targeted deletion in the mouse, promotes PKA activity, which has been attributed to the development of neoplasms.	('promotes', 'PosReg', (119, 127))	('PKA', 'Enzyme', (128, 131))	('neoplasms', 'Disease', 'MESH:D009369', (190, 199))	('neoplasms', 'Disease', (190, 199))	('humans', 'Species', '9606', (74, 80))	('deletion', 'Var', (96, 104))	('mouse', 'Species', '10090', (112, 117))	('Inactivation', 'Var', (0, 12))	('neoplasms', 'Phenotype', 'HP:0002664', (190, 199))
4896	25268545	By contrast, the abundance of R1A protein, but not R1A mRNA, was higher in siR2B H295R cells than in control cells (Fig.	('abundance', 'MPA', (17, 26))	('H295R', 'CellLine', 'CVCL:0458', (81, 86))	('H295R', 'Var', (81, 86))	('siR2', 'Gene', '23411', (75, 79))	('R1A protein', 'Protein', (30, 41))	('higher', 'PosReg', (65, 71))	('siR2', 'Gene', (75, 79))
4898	25268545	A similar accumulation of R1A protein was also reported in mouse adrenocortical Y1 cells after the inactivation of Prkar2b.	('mouse', 'Species', '10090', (59, 64))	('accumulation', 'PosReg', (10, 22))	('adrenocortical', 'Disease', (65, 79))	('adrenocortical', 'Disease', 'MESH:D018268', (65, 79))	('R1A protein', 'Protein', (26, 37))	('Prkar2b', 'Gene', (115, 122))	('Prkar2b', 'Gene', '19088', (115, 122))	('Y1', 'CellLine', 'CVCL:0585', (80, 82))	('inactivation', 'Var', (99, 111))
4912	25268545	We found that the depletion of either PKA R1A or R2B in H295R cells impaired the expression of IkBalpha, as evidenced by its low abundance and the nuclear translocation of NF-kappaB transcription factors.	('IkBalpha', 'Gene', '4792', (95, 103))	('NF-kappaB', 'Gene', '4790', (172, 181))	('impaired', 'NegReg', (68, 76))	('IkBalpha', 'Gene', (95, 103))	('abundance', 'MPA', (129, 138))	('PKA R1A', 'Var', (38, 45))	('R2B', 'Var', (49, 52))	('NF-kappaB', 'Gene', (172, 181))	('nuclear translocation', 'MPA', (147, 168))	('H295R', 'CellLine', 'CVCL:0458', (56, 61))	('depletion', 'MPA', (18, 27))	('expression', 'MPA', (81, 91))
4913	25268545	We found higher NF-kappaB DNA-binding activity in both siR1A and siR2B cells than in control cells.	('siR2', 'Gene', '23411', (65, 69))	('siR2', 'Gene', (65, 69))	('NF-kappaB', 'Gene', (16, 25))	('siR1A', 'Var', (55, 60))	('NF-kappaB', 'Gene', '4790', (16, 25))	('higher', 'PosReg', (9, 15))
4929	25268545	Silencing of PRKAR1A may lead to the immortalization of the cells as shown by Nadella et al., whereas the depletion of PRKAR2B enhances cell cycle progression.	('PRKAR2B', 'Gene', (119, 126))	('PRKAR2B', 'Gene', '5577', (119, 126))	('PRKAR1A', 'Gene', (13, 20))	('enhances', 'PosReg', (127, 135))	('PRKAR1A', 'Gene', '5573', (13, 20))	('lead to', 'Reg', (25, 32))	('immortalization of the cells', 'CPA', (37, 65))	('depletion', 'MPA', (106, 115))	('Silencing', 'Var', (0, 9))	('cell cycle progression', 'CPA', (136, 158))
4931	25268545	Altogether these findings underline the complexity of the cellular effects of alterations to PKA subunits that occur in adrenocortical tumors.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (120, 141))	('adrenocortical tumors', 'Disease', (120, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('alterations', 'Var', (78, 89))	('PKA subunits', 'Protein', (93, 105))
5010	26312764	Results from in vitro and in vivo experiments showed that XCT790 reduced H295R cell growth.	('reduced', 'NegReg', (65, 72))	('H295R cell growth', 'CPA', (73, 90))	('XCT790', 'Var', (58, 64))	('XCT790', 'Chemical', 'MESH:C488234', (58, 64))	('H295R', 'CellLine', 'CVCL:0458', (73, 78))
5020	26312764	ESR1 knock down was more effective than an IGF1R antibody in reducing H295R cell proliferation in vitro and the selective estrogen receptor modulator (SERM) tamoxifen prevented the growth of H295R both in vitro and as xenografts in vivo.	('reducing', 'NegReg', (61, 69))	('estrogen receptor', 'Gene', '2099', (122, 139))	('ESR1', 'Gene', (0, 4))	('H295R', 'CellLine', 'CVCL:0458', (191, 196))	('IGF1R', 'Gene', (43, 48))	('tamoxifen', 'Chemical', 'MESH:D013629', (157, 166))	('H295R cell proliferation', 'CPA', (70, 94))	('IGF1R', 'Gene', '3480', (43, 48))	('knock down', 'Var', (5, 15))	('H295R', 'CellLine', 'CVCL:0458', (70, 75))	('ESR1', 'Gene', '2099', (0, 4))	('estrogen receptor', 'Gene', (122, 139))	('prevented', 'NegReg', (167, 176))
5038	26312764	The latter results confirmed the ability of XCT790 to reduce the expression of ERRalpha most probably by proteasome degradation.	('XCT790', 'Chemical', 'MESH:C488234', (44, 50))	('reduce', 'NegReg', (54, 60))	('XCT790', 'Var', (44, 50))	('ERRalpha', 'Gene', (79, 87))	('expression', 'MPA', (65, 75))	('ERRalpha', 'Gene', '2101', (79, 87))
5041	26312764	The maximum inhibitory effect on ACC cell proliferation was seen at 10 muM XCT790 that was then used for all the following experiments.	('ACC cell proliferation', 'CPA', (33, 55))	('XCT790', 'Var', (75, 81))	('XCT790', 'Chemical', 'MESH:C488234', (75, 81))	('ACC', 'Phenotype', 'HP:0006744', (33, 36))	('inhibitory', 'NegReg', (12, 22))
5045	26312764	As shown in Figure 2A, mice treated with XCT790 displayed a significant tumor growth reduction compared to the vehicle treated control group.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor growth reduction', 'Disease', (72, 94))	('tumor growth reduction', 'Disease', 'MESH:D006130', (72, 94))	('XCT790', 'Chemical', 'MESH:C488234', (41, 47))	('XCT790', 'Var', (41, 47))	('mice', 'Species', '10090', (23, 27))
5046	26312764	Accordingly, tumor reduction upon XCT790 treatment is evidenced both in terms of tumor mass (Figure 2B) and proliferation as seen in Figure 2C, showing a strong decrease in Ki67staining (value score control: 7.2 +- 0,46 (SD); value score XCT790 treated cells: 4.7 +- 0.53* (SD), *p < 0.05).	('tumor', 'Disease', (13, 18))	('reduction', 'NegReg', (19, 28))	('decrease', 'NegReg', (161, 169))	('XCT790', 'Var', (34, 40))	('XCT790', 'Chemical', 'MESH:C488234', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('proliferation', 'CPA', (108, 121))	('Ki67staining', 'MPA', (173, 185))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('XCT790', 'Chemical', 'MESH:C488234', (238, 244))	('tumor', 'Disease', (81, 86))
5050	26312764	48 hours later, FACS analysis revealed that XCT790 treated cells accumulated in the G0/G1-phase of the cell cycle while the fraction of cells in S phase decreased compared with vehicle treated cells (Figure 3A).	('XCT790', 'Chemical', 'MESH:C488234', (44, 50))	('accumulated', 'PosReg', (65, 76))	('XCT790', 'Var', (44, 50))	('decreased', 'NegReg', (153, 162))	('G0/G1-phase of the cell cycle', 'CPA', (84, 113))	('CS', 'Chemical', '-', (18, 20))
5052	26312764	After 48 h treatment, XCT790 reduced Cyclin D1 and Cyclin E protein content while expression levels of CDK2 and CDK4 proteins were unaffected.	('XCT790', 'Var', (22, 28))	('XCT790', 'Chemical', 'MESH:C488234', (22, 28))	('CDK2', 'Gene', (103, 107))	('Cyclin D1', 'Gene', '595', (37, 46))	('Cyclin D1', 'Gene', (37, 46))	('CDK4', 'Gene', (112, 116))	('reduced', 'NegReg', (29, 36))	('CDK4', 'Gene', '1019', (112, 116))	('CDK2', 'Gene', '1017', (103, 107))
5054	26312764	Surprisingly, results from Western blotting analysis for PARP-1 (Figure 3D) and caspase 3/7 activity assay (Figure 3E) clearly showed that XCT790 did not activate an apoptotic pathway.	('caspase 3', 'Gene', (80, 89))	('PARP-1', 'Gene', (57, 63))	('caspase 3', 'Gene', '836', (80, 89))	('PARP-1', 'Gene', '142', (57, 63))	('apoptotic', 'CPA', (166, 175))	('XCT790', 'Chemical', 'MESH:C488234', (139, 145))	('XCT790', 'Var', (139, 145))
5056	26312764	Moreover, it has been observed that XCT790 treatment, causing ERRalpha proteasome degradation, also down-regulates PGC1-alpha.	('XCT790', 'Var', (36, 42))	('XCT790', 'Chemical', 'MESH:C488234', (36, 42))	('PGC1-alpha', 'Gene', (115, 125))	('ERRalpha', 'Gene', (62, 70))	('down-regulates', 'NegReg', (100, 114))	('PGC1-alpha', 'Gene', '10891', (115, 125))	('ERRalpha', 'Gene', '2101', (62, 70))
5058	26312764	To this aim, ACC cells were left untreated or treated with 10 muM XCT790 for 48 h. Results from Western blotting showed (Figure 4A-4B) that XCT790 treated cells display a reduced expression of PGC1-alpha, with no effect on PGC-1beta levels.	('PGC1-alpha', 'Gene', '10891', (193, 203))	('expression', 'MPA', (179, 189))	('XCT790', 'Chemical', 'MESH:C488234', (140, 146))	('XCT790', 'Var', (140, 146))	('PGC1-alpha', 'Gene', (193, 203))	('PGC-1beta', 'Gene', '133522', (223, 232))	('ACC', 'Phenotype', 'HP:0006744', (13, 16))	('XCT790', 'Chemical', 'MESH:C488234', (66, 72))	('PGC-1beta', 'Gene', (223, 232))	('reduced', 'NegReg', (171, 178))
5060	26312764	Using flow cytometric analysis (Figure 4C), fluorescent imaging (Figure 4D) and fluorescent plate reader (Figure 4E), we found that XCT790 significantly decreased mitochondrial mass.	('mitochondrial mass', 'MPA', (163, 181))	('decreased', 'NegReg', (153, 162))	('decreased mitochondrial mass', 'Phenotype', 'HP:0040013', (153, 181))	('XCT790', 'Var', (132, 138))	('XCT790', 'Chemical', 'MESH:C488234', (132, 138))
5062	26312764	We used CIC protein expression as a marker of both mitochondrial mass and function and found that XCT790 decreased mitochondrial CIC expression (Figure 4F-4G) as well as its transport activity (Figure 4H) in H295R-treated cells compared to vehicle-treated control cells.	('H295R', 'CellLine', 'CVCL:0458', (208, 213))	('CIC', 'Gene', (8, 11))	('XCT790', 'Var', (98, 104))	('transport activity', 'MPA', (174, 192))	('CIC', 'Gene', '23152', (129, 132))	('XCT790', 'Chemical', 'MESH:C488234', (98, 104))	('CIC', 'Gene', (129, 132))	('decreased', 'NegReg', (105, 114))	('CIC', 'Gene', '23152', (8, 11))
5067	26312764	Based on this observation and accordingly to our above reported results showing the ability of XCT790 to down-regulate CIC expression in H295R cells, we wanted to verify if autophagic features were detected in our experimental conditions.	('XCT790', 'Var', (95, 101))	('XCT790', 'Chemical', 'MESH:C488234', (95, 101))	('CIC', 'Gene', '23152', (119, 122))	('H295R', 'CellLine', 'CVCL:0458', (137, 142))	('CIC', 'Gene', (119, 122))	('down-regulate', 'NegReg', (105, 118))
5073	26312764	These results corroborate the observation that XCT790, increases the formation of AVOs which suggests autophagy/mitophagy as possible mechanisms to explain the reduced mitochondrial mass.	('XCT790', 'Var', (47, 53))	('XCT790', 'Chemical', 'MESH:C488234', (47, 53))	('reduced mitochondrial mass', 'Phenotype', 'HP:0040013', (160, 186))	('increases', 'PosReg', (55, 64))	('mitochondrial', 'MPA', (168, 181))	('formation of AVOs', 'MPA', (69, 86))
5075	26312764	A careful evaluation of the autophagic/mitophagic process by investigating changes in autophagic markers such as Beclin 1, LC3B, BNIP3 and Cathepsin B (Figure 6B), suggested that XCT790 treatment promotes the initial stages of the autophagic process.	('Cathepsin B', 'Gene', '1508', (139, 150))	('Cathepsin B', 'Gene', (139, 150))	('promotes', 'PosReg', (196, 204))	('Beclin 1', 'Gene', '8678', (113, 121))	('BNIP3', 'Gene', '664', (129, 134))	('LC3B', 'Gene', '81631', (123, 127))	('Beclin 1', 'Gene', (113, 121))	('XCT790', 'Var', (179, 185))	('XCT790', 'Chemical', 'MESH:C488234', (179, 185))	('LC3B', 'Gene', (123, 127))	('autophagic process', 'CPA', (231, 249))	('BNIP3', 'Gene', (129, 134))
5080	26312764	As shown in Figure 6C, H295R displayed a significant increase in the number of positive stained cells compared to control cells indicating that membrane integrity and permeability were lost accounting for a necrotic event following a bionergetic failure triggered by ERRalpha depletion.	('ERRalpha', 'Gene', (267, 275))	('H295R', 'CellLine', 'CVCL:0458', (23, 28))	('H295R', 'Var', (23, 28))	('membrane integrity', 'MPA', (144, 162))	('permeability', 'MPA', (167, 179))	('necrotic', 'Disease', (207, 215))	('lost', 'NegReg', (185, 189))	('ERRalpha', 'Gene', '2101', (267, 275))	('increase', 'PosReg', (53, 61))	('necrotic', 'Disease', 'MESH:D009336', (207, 215))
5082	26312764	Results from these studies have highlighted the presence of different and important modifications such as somatic TP53 mutations, alterations at 11p15, a chromosomal locus of IGFII, H19 and cyclin-dependent kinase inhibitor 1C, beta-catenin accumulation and activation of the Wnt signaling pathway and overexpression of SF-1 protein.	('SF-1', 'Gene', (320, 324))	('cyclin-dependent kinase inhibitor 1C', 'Gene', '1028', (190, 226))	('SF-1', 'Gene', '7536', (320, 324))	('H19', 'Gene', '283120', (182, 185))	('beta-catenin', 'Gene', '1499', (228, 240))	('TP53', 'Gene', (114, 118))	('IGFII', 'Gene', (175, 180))	('TP53', 'Gene', '7157', (114, 118))	('alterations', 'Var', (130, 141))	('cyclin-dependent kinase inhibitor 1C', 'Gene', (190, 226))	('beta-catenin', 'Gene', (228, 240))	('overexpression', 'PosReg', (302, 316))	('activation', 'PosReg', (258, 268))	('Wnt signaling pathway', 'Pathway', (276, 297))	('mutations', 'Var', (119, 128))	('H19', 'Gene', (182, 185))	('IGFII', 'Gene', '3481', (175, 180))
5086	26312764	Indeed, it has already been observed that high ERRalpha gene expression correlates with unfavorable clinical outcomes in breast and ovarian cancer and that breast cancer cells exhibiting high ERRalpha activity are more sensitive to growth inhibition by an ERRalpha inverse agonist such as XCT790.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ERRalpha', 'Gene', (192, 200))	('ERRalpha', 'Gene', (47, 55))	('ERRalpha', 'Gene', (256, 264))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (121, 146))	('ERRalpha', 'Gene', '2101', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('sensitive', 'MPA', (219, 228))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('growth', 'CPA', (232, 238))	('ERRalpha', 'Gene', '2101', (256, 264))	('breast cancer', 'Disease', (156, 169))	('XCT790', 'Chemical', 'MESH:C488234', (289, 295))	('ERRalpha', 'Gene', '2101', (47, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('high', 'Var', (187, 191))
5093	26312764	Our results indicated that XCT790 caused a significant increase in autophagic vesicles.	('autophagic vesicles', 'CPA', (67, 86))	('increase', 'PosReg', (55, 63))	('XCT790', 'Var', (27, 33))	('XCT790', 'Chemical', 'MESH:C488234', (27, 33))
5104	26312764	Moreover, our current data obtained performing in vivo experiments by using H295R cells as xenograft model and according to previous in vivo studies performed in breast and leukemia tumor cells also suggest that chemical depletion of ERRalpha may be specific for high energy demanding cells such as tumor cells without exerting any toxic effect on other tissues.	('breast and leukemia tumor', 'Disease', 'MESH:D001943', (162, 187))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('tumor', 'Disease', (299, 304))	('tumor', 'Disease', (182, 187))	('ERRalpha', 'Gene', (234, 242))	('ERRalpha', 'Gene', '2101', (234, 242))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('leukemia', 'Phenotype', 'HP:0001909', (173, 181))	('H295R', 'CellLine', 'CVCL:0458', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('chemical depletion', 'Var', (212, 230))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
5154	26124749	PA occurs as a result of a dysregulation of the normal mechanisms controlling adrenal aldosterone production.	('aldosterone production', 'Phenotype', 'HP:0000859', (86, 108))	('dysregulation', 'Var', (27, 40))	('adrenal aldosterone', 'Phenotype', 'HP:0000859', (78, 97))	('PA', 'Phenotype', 'HP:0011736', (0, 2))	('aldosterone', 'Chemical', 'MESH:D000450', (86, 97))	('adrenal aldosterone production', 'MPA', (78, 108))
5161	26124749	The identification of recurrent and somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) allowed highlighting the central role of calcium signaling in autonomous aldosterone production by the adrenal.	('aldosterone production', 'Phenotype', 'HP:0000859', (212, 234))	('ATP1A1', 'Gene', '476', (120, 126))	('calcium', 'Chemical', 'MESH:D002118', (180, 187))	('ATP1A1', 'Gene', (120, 126))	('aldosterone', 'Chemical', 'MESH:D000450', (212, 223))	('ATP2B3', 'Gene', '492', (131, 137))	('KCNJ5', 'Gene', (88, 93))	('CACNA1D', 'Gene', '776', (98, 105))	('mutations', 'Var', (44, 53))	('ATP2B3', 'Gene', (131, 137))	('CACNA1D', 'Gene', (98, 105))	('KCNJ5', 'Gene', '3762', (88, 93))
5168	26124749	Deregulation of the mechanisms regulating aldosterone biosynthesis results in primary aldosteronism (PA), the most common form of secondary hypertension with an estimated prevalence of about 10% in referred patients and 4% in primary care and as high as 20% in patients with resistant hypertension.	('patients', 'Species', '9606', (207, 215))	('PA', 'Phenotype', 'HP:0011736', (101, 103))	('hypertension', 'Disease', 'MESH:D006973', (140, 152))	('Deregulation', 'Var', (0, 12))	('results in', 'Reg', (67, 77))	('hypertension', 'Disease', 'MESH:D006973', (285, 297))	('hypertension', 'Disease', (140, 152))	('aldosterone', 'Chemical', 'MESH:D000450', (42, 53))	('hypertension', 'Phenotype', 'HP:0000822', (140, 152))	('primary aldosteronism', 'Disease', (78, 99))	('hypertension', 'Disease', (285, 297))	('patients', 'Species', '9606', (261, 269))	('hypertension', 'Phenotype', 'HP:0000822', (285, 297))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (78, 99))
5173	26124749	During the last few years, major advances have been made in understanding the genetic basis of APA, with the identification of mutations in genes coding for ion channels [KCNJ5, coding for the G protein-activated inward rectifier potassium channel 4 (GIRK4) and CACNA1D, encoding the Cav1.3 channel (calcium channel, voltage-dependent, L type, alpha 1d subunit) ] and ATPases [ATP1A1, coding for the alpha1 subunit of the Na+/K+-ATPase and ATP2B3 encoding the plasma membrane Ca2+-ATPase, type 3 ] in more than 50% of APA.	('KCNJ5', 'Gene', '3762', (171, 176))	('Cav1.3', 'Gene', '776', (284, 290))	('ATP2B3', 'Gene', '492', (440, 446))	('CACNA1D', 'Gene', '776', (262, 269))	('PA', 'Phenotype', 'HP:0011736', (519, 521))	('ATP1A1', 'Gene', '476', (377, 383))	('CACNA1D', 'Gene', (262, 269))	('GIRK4', 'Gene', '3762', (251, 256))	('ATP2B3', 'Gene', (440, 446))	('Cav1.3', 'Gene', (284, 290))	('Ca2+', 'Chemical', 'MESH:D000069285', (476, 480))	('ATP1A1', 'Gene', (377, 383))	('G protein-activated inward rectifier potassium channel 4', 'Gene', '3762', (193, 249))	('KCNJ5', 'Gene', (171, 176))	('mutations', 'Var', (127, 136))	('GIRK4', 'Gene', (251, 256))	('PA', 'Phenotype', 'HP:0011736', (96, 98))	('calcium', 'Chemical', 'MESH:D002118', (300, 307))
5174	26124749	Interestingly, all these mutations lead to the activation of calcium signaling, the major trigger for aldosterone production (Figure 1).	('mutations', 'Var', (25, 34))	('calcium signaling', 'MPA', (61, 78))	('activation', 'PosReg', (47, 57))	('aldosterone', 'Chemical', 'MESH:D000450', (102, 113))	('calcium', 'Chemical', 'MESH:D002118', (61, 68))	('aldosterone production', 'Phenotype', 'HP:0000859', (102, 124))
5175	26124749	However, if the role of these mutations in regulating aldosterone production has been clearly established, their implication in proliferation and APA formation are still matter of debate.	('aldosterone', 'Chemical', 'MESH:D000450', (54, 65))	('aldosterone production', 'MPA', (54, 76))	('mutations', 'Var', (30, 39))	('aldosterone production', 'Phenotype', 'HP:0000859', (54, 76))	('PA', 'Phenotype', 'HP:0011736', (147, 149))
5181	26124749	These mutations (p.Gly151Arg and p.Leu168Arg) are located near or within the selectivity filter of the channel GIRK4.	('p.Leu168Arg', 'Var', (33, 44))	('GIRK4', 'Gene', '3762', (111, 116))	('p.Gly151Arg', 'Mutation', 'rs386352319', (17, 28))	('p.Leu168Arg', 'Mutation', 'rs386352318', (33, 44))	('p.Gly151Arg', 'Var', (17, 28))	('GIRK4', 'Gene', (111, 116))
5182	26124749	Additional mutations in or surrounding the selectivity filter have been identified, including p.Gly151Glu, p.Thr158Ala, p.Glu141Gln, p.Ile157Ser, delIle157, InsThr149.	('p.Glu141Gln', 'Var', (120, 131))	('p.Thr158Ala', 'Var', (107, 118))	('p.Thr158Ala', 'Mutation', 'rs387906778', (107, 118))	('InsThr149', 'Var', (157, 166))	('p.Gly151Glu', 'Var', (94, 105))	('p.Ile157Ser', 'Var', (133, 144))	('p.Glu141Gln', 'Mutation', 'p.E141Q', (120, 131))	('delIle157', 'Var', (146, 155))	('p.Ile157Ser', 'Mutation', 'rs587777438', (133, 144))	('p.Gly151Glu', 'Mutation', 'rs587777437', (94, 105))
5183	26124749	All these mutations result in a significant decrease in K+ selectivity and greater influx of Na+ into the cell, resulting in chronic cell depolarization followed by opening of voltage-dependent calcium channels and activation of calcium signaling and aldosterone production.	('aldosterone production', 'Phenotype', 'HP:0000859', (251, 273))	('depolarization', 'NegReg', (138, 152))	('cell', 'CPA', (133, 137))	('decrease', 'NegReg', (44, 52))	('activation', 'PosReg', (215, 225))	('voltage-dependent calcium channels', 'MPA', (176, 210))	('calcium', 'Chemical', 'MESH:D002118', (194, 201))	('opening', 'PosReg', (165, 172))	('calcium', 'Chemical', 'MESH:D002118', (229, 236))	('aldosterone', 'Chemical', 'MESH:D000450', (251, 262))	('greater', 'PosReg', (75, 82))	('K+ selectivity', 'MPA', (56, 70))	('mutations', 'Var', (10, 19))	('aldosterone production', 'MPA', (251, 273))	('calcium signaling', 'MPA', (229, 246))	('influx of Na+ into the cell', 'MPA', (83, 110))
5184	26124749	Germline KCNJ5 mutations were also identified as the causative event of Familial hyperaldosteronism type III (FH-III).	('Familial hyperaldosteronism type III', 'Disease', (72, 108))	('KCNJ5', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))	('Familial hyperaldosteronism type', 'Phenotype', 'HP:0011739', (72, 104))	('KCNJ5', 'Gene', '3762', (9, 14))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (81, 99))	('Familial hyperaldosteronism type III', 'Disease', 'MESH:D003480', (72, 108))
5187	26124749	Further exome sequencing performed on APA allowed the identification of other somatic mutations in genes coding for ATPases, namely ATP1A1 and ATP2B3 and the Cav1.3 calcium channel, CACNA1D.	('ATP2B3', 'Gene', '492', (143, 149))	('mutations', 'Var', (86, 95))	('ATPases', 'Gene', (116, 123))	('Cav1.3', 'Gene', '776', (158, 164))	('ATP2B3', 'Gene', (143, 149))	('PA', 'Phenotype', 'HP:0011736', (39, 41))	('Cav1.3', 'Gene', (158, 164))	('ATP1A1', 'Gene', '476', (132, 138))	('CACNA1D', 'Gene', '776', (182, 189))	('calcium', 'Chemical', 'MESH:D002118', (165, 172))	('ATP1A1', 'Gene', (132, 138))	('CACNA1D', 'Gene', (182, 189))
5188	26124749	Whereas mutations in KCNJ5 and ATP1A1 affect adrenal zona glomerulosa cell membrane potential and intracellular ionic homeostasis, with chronic depolarization leading to opening of voltage-dependent calcium channels and activation of calcium signaling and aldosterone production, mutations in ATP2B3 and CACNA1D modify directly intracellular calcium equilibrium, also leading to an activation of calcium signaling and aldosterone production (Figure 1).	('intracellular ionic homeostasis', 'MPA', (98, 129))	('aldosterone production', 'Phenotype', 'HP:0000859', (256, 278))	('calcium', 'Chemical', 'MESH:D002118', (234, 241))	('aldosterone production', 'MPA', (418, 440))	('aldosterone', 'Chemical', 'MESH:D000450', (418, 429))	('ATP2B3', 'Gene', '492', (293, 299))	('mutations', 'Var', (8, 17))	('calcium signaling', 'MPA', (234, 251))	('ATP2B3', 'Gene', (293, 299))	('voltage-dependent calcium channels', 'MPA', (181, 215))	('opening', 'MPA', (170, 177))	('KCNJ5', 'Gene', (21, 26))	('activation', 'PosReg', (382, 392))	('calcium', 'Chemical', 'MESH:D002118', (342, 349))	('ATP1A1', 'Gene', (31, 37))	('aldosterone', 'MPA', (256, 267))	('adrenal zona glomerulosa cell membrane potential', 'MPA', (45, 93))	('calcium', 'Chemical', 'MESH:D002118', (199, 206))	('aldosterone production', 'Phenotype', 'HP:0000859', (418, 440))	('aldosterone', 'Chemical', 'MESH:D000450', (256, 267))	('KCNJ5', 'Gene', '3762', (21, 26))	('calcium', 'Chemical', 'MESH:D002118', (396, 403))	('mutations', 'Var', (280, 289))	('ATP1A1', 'Gene', '476', (31, 37))	('modify', 'Reg', (312, 318))	('CACNA1D', 'Gene', '776', (304, 311))	('calcium signaling', 'MPA', (396, 413))	('CACNA1D', 'Gene', (304, 311))	('activation', 'PosReg', (220, 230))	('affect', 'Reg', (38, 44))
5189	26124749	KCNJ5 mutations are the most frequent genetic abnormalities reported in APA with a prevalence of ~40% in Caucasian population, and as high as 70% in series from Japan.	('KCNJ5', 'Gene', '3762', (0, 5))	('PA', 'Phenotype', 'HP:0011736', (73, 75))	('genetic abnormalities', 'Disease', 'MESH:D030342', (38, 59))	('genetic abnormalities', 'Disease', (38, 59))	('KCNJ5', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
5190	26124749	The mutations affecting ATP1A1 and ATP2B3 genes are less frequent with a reported prevalence of 5.3 and 1.7, respectively.	('ATP1A1', 'Gene', '476', (24, 30))	('ATP2B3', 'Gene', '492', (35, 41))	('ATP1A1', 'Gene', (24, 30))	('ATP2B3', 'Gene', (35, 41))	('mutations', 'Var', (4, 13))
5191	26124749	Mutations in the CACNA1D gene are the second most frequent genetic alterations observed in APA with a prevalence comprised between 5 and 9.3%.	('PA', 'Phenotype', 'HP:0011736', (92, 94))	('CACNA1D', 'Gene', '776', (17, 24))	('Mutations', 'Var', (0, 9))	('CACNA1D', 'Gene', (17, 24))
5192	26124749	Interestingly, whereas mutations in KCNJ5, ATP1A1, and ATP2B3 are located in specific "hot spots," a large number of mutations were reported in different exons of the CACNA1D gene, affecting more frequently segment M4 and M6 of the protein, implying the necessity of a large genotyping of CACNA1D in APA.	('mutations', 'Var', (117, 126))	('CACNA1D', 'Gene', '776', (289, 296))	('ATP1A1', 'Gene', (43, 49))	('CACNA1D', 'Gene', (289, 296))	('ATP2B3', 'Gene', '492', (55, 61))	('affecting', 'Reg', (181, 190))	('M6 of the protein', 'Protein', (222, 239))	('KCNJ5', 'Gene', '3762', (36, 41))	('PA', 'Phenotype', 'HP:0011736', (301, 303))	('protein', 'Protein', (232, 239))	('mutations', 'Var', (23, 32))	('ATP2B3', 'Gene', (55, 61))	('CACNA1D', 'Gene', '776', (167, 174))	('KCNJ5', 'Gene', (36, 41))	('CACNA1D', 'Gene', (167, 174))	('ATP1A1', 'Gene', '476', (43, 49))	('segment M4', 'Protein', (207, 217))
5194	26124749	Hence, patients with KCNJ5 mutations were more frequently female and diagnosed younger than patients harboring CACNA1D mutations and non-carriers; and CACNA1D mutations associated with smaller adenoma size.	('mutations', 'Var', (27, 36))	('adenoma', 'Disease', (193, 200))	('CACNA1D', 'Gene', '776', (111, 118))	('KCNJ5', 'Gene', (21, 26))	('CACNA1D', 'Gene', (111, 118))	('KCNJ5', 'Gene', '3762', (21, 26))	('patients', 'Species', '9606', (92, 100))	('adenoma', 'Disease', 'MESH:D000236', (193, 200))	('CACNA1D', 'Gene', '776', (151, 158))	('patients', 'Species', '9606', (7, 15))	('CACNA1D', 'Gene', (151, 158))
5196	26124749	APA harboring KCNJ5 mutations would be composed essentially of zona fasciculata-like cells whereas those carrying CACNA1D mutations of a majority of zona glomerulosa-like cells, although this association was not replicated in all series.	('zona fasciculata', 'Disease', (63, 79))	('KCNJ5', 'Gene', (14, 19))	('zona fasciculata', 'Disease', 'MESH:D006562', (63, 79))	('CACNA1D', 'Gene', '776', (114, 121))	('CACNA1D', 'Gene', (114, 121))	('KCNJ5', 'Gene', '3762', (14, 19))	('PA', 'Phenotype', 'HP:0011736', (1, 3))	('mutations', 'Var', (20, 29))	('fasciculata-', 'Phenotype', 'HP:0002380', (68, 80))
5197	26124749	The exploration of the relationship between adrenal cortex remodeling and KCNJ5 mutations revealed the absence of association between the KCNJ5 mutational status and the nodulation score in the peritumoral tissue, the vascularization and the presence of zona glomerulosa hyperplasia in the peritumoral cortex, suggesting that KCNJ5 mutations are not likely to be responsible for a specific microenvironment propitious to promote adrenal cortex remodeling and APA formation.	('tumor', 'Disease', (294, 299))	('KCNJ5', 'Gene', (138, 143))	('zona glomerulosa hyperplasia', 'Disease', (254, 282))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('KCNJ5', 'Gene', '3762', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('APA formation', 'CPA', (459, 472))	('KCNJ5', 'Gene', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('KCNJ5', 'Gene', (326, 331))	('mutational', 'Var', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Disease', (198, 203))	('KCNJ5', 'Gene', '3762', (74, 79))	('zona glomerulosa hyperplasia', 'Disease', 'MESH:D006562', (254, 282))	('PA', 'Phenotype', 'HP:0011736', (460, 462))	('KCNJ5', 'Gene', '3762', (326, 331))
5198	26124749	Though the role of all these mutations in abnormal aldosterone secretion has been clearly established, their impact in adenoma formation still remains unclear.	('abnormal aldosterone secretion', 'MPA', (42, 72))	('abnormal aldosterone', 'Phenotype', 'HP:0040085', (42, 62))	('adenoma', 'Disease', (119, 126))	('mutations', 'Var', (29, 38))	('aldosterone', 'Chemical', 'MESH:D000450', (51, 62))	('adenoma', 'Disease', 'MESH:D000236', (119, 126))
5199	26124749	Indeed, whereas in HAC15 cells, the overexpression of GIRK4 carrying the p.Thr158Ala mutation was responsible for a significant increase in aldosterone production, it induced, in parallel, a decrease in cell proliferation, independently of intracellular Ca2+ concentration.	('increase in aldosterone', 'Phenotype', 'HP:0000859', (128, 151))	('increase', 'PosReg', (128, 136))	('cell proliferation', 'CPA', (203, 221))	('p.Thr158Ala', 'Mutation', 'rs387906778', (73, 84))	('overexpression', 'PosReg', (36, 50))	('Ca2+', 'Chemical', 'MESH:D000069285', (254, 258))	('HAC15', 'CellLine', 'CVCL:S898', (19, 24))	('aldosterone', 'Chemical', 'MESH:D000450', (140, 151))	('GIRK4', 'Gene', (54, 59))	('GIRK4', 'Gene', '3762', (54, 59))	('aldosterone production', 'MPA', (140, 162))	('p.Thr158Ala', 'Var', (73, 84))	('aldosterone production', 'Phenotype', 'HP:0000859', (140, 162))	('decrease', 'NegReg', (191, 199))
5200	26124749	Likewise, the overexpression of p.Glu151Arg or p.Glu151Gln in HEK293T cells resulted in rapid Na+-dependent lethality.	('p.Glu151Gln', 'Var', (47, 58))	('p.Glu151Arg', 'Var', (32, 43))	('p.Glu151Gln', 'Mutation', 'p.E151Q', (47, 58))	('p.Glu151Arg', 'Mutation', 'p.E151R', (32, 43))	('HEK293T', 'CellLine', 'CVCL:0063', (62, 69))	('overexpression', 'PosReg', (14, 28))	('Na+-dependent', 'MPA', (94, 107))
5201	26124749	More extensively, a still open question is to know whether a modification in the ionic equilibrium and the regulation of the cell membrane potential are also able to promote adenoma formation.	('adenoma', 'Disease', 'MESH:D000236', (174, 181))	('modification', 'Var', (61, 73))	('ionic equilibrium', 'MPA', (81, 98))	('adenoma', 'Disease', (174, 181))	('promote', 'PosReg', (166, 173))
5206	26124749	Deletions of task1 and task3, respectively, lead to the development of hyperaldosteronism or low-renin hypertension In task1-/- mice, hyperaldosteronism was due to aberrant functional zonation of the adrenal cortex, with intense cyp11b2 expression being localized in zona fasciculata instead of the zona glomerulosa.	('task3', 'Gene', (23, 28))	('renin', 'Gene', (97, 102))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (71, 89))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (134, 152))	('renin', 'Gene', '5972', (97, 102))	('lead to', 'Reg', (44, 51))	('zona fasciculata', 'Disease', (267, 283))	('cyp11b2', 'Gene', '13072', (229, 236))	('hyperaldosteronism', 'Disease', (71, 89))	('hyperaldosteronism', 'Disease', (134, 152))	('mice', 'Species', '10090', (128, 132))	('hypertension', 'Disease', 'MESH:D006973', (103, 115))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (71, 89))	('hypertension', 'Disease', (103, 115))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (134, 152))	('task1', 'Gene', (13, 18))	('cyp11b2', 'Gene', (229, 236))	('zona fasciculata', 'Disease', 'MESH:D006562', (267, 283))	('hypertension', 'Phenotype', 'HP:0000822', (103, 115))	('Deletions', 'Var', (0, 9))
5209	26124749	Deletion of task3 in mice leads to low-renin salt-sensitive hypertension, with suppressed plasma renin and aldosterone secretion that is not suppressible by increasing salt intake.	('task3', 'Gene', (12, 17))	('renin', 'Gene', '5972', (97, 102))	('hypertension', 'Disease', (60, 72))	('leads to', 'Reg', (26, 34))	('renin', 'Gene', '5972', (39, 44))	('mice', 'Species', '10090', (21, 25))	('salt', 'Chemical', 'MESH:D012492', (45, 49))	('salt', 'Chemical', 'MESH:D012492', (168, 172))	('suppressed plasma renin and aldosterone', 'Phenotype', 'HP:0004319', (79, 118))	('renin', 'Gene', (97, 102))	('suppressed', 'NegReg', (79, 89))	('low-renin salt-', 'Phenotype', 'HP:0000127', (35, 50))	('hypertension', 'Phenotype', 'HP:0000822', (60, 72))	('renin', 'Gene', (39, 44))	('suppressed plasma renin', 'Phenotype', 'HP:0003351', (79, 102))	('aldosterone', 'Chemical', 'MESH:D000450', (107, 118))	('hypertension', 'Disease', 'MESH:D006973', (60, 72))	('Deletion', 'Var', (0, 8))
5211	26124749	Finally, deletion of both task1 and task3 results in a marked depolarization of the zona glomerulosa cell membrane potential and a mild hyperaldosteronism with plasma aldosterone levels stimulated by a low-sodium diet but not suppressed by a high-sodium diet and partially responsive to AngII blockade.	('stimulated', 'PosReg', (186, 196))	('low-sodium diet', 'Phenotype', 'HP:0002902', (202, 217))	('task3', 'Gene', (36, 41))	('deletion', 'Var', (9, 17))	('aldosterone', 'Chemical', 'MESH:D000450', (167, 178))	('hyperaldosteronism', 'Disease', (136, 154))	('high-sodium diet', 'Phenotype', 'HP:0003228', (242, 258))	('plasma aldosterone levels', 'MPA', (160, 185))	('sodium', 'Chemical', 'MESH:D012964', (247, 253))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (136, 154))	('task1', 'Gene', (26, 31))	('plasma aldosterone levels', 'Phenotype', 'HP:0000859', (160, 185))	('sodium', 'Chemical', 'MESH:D012964', (206, 212))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (136, 154))	('depolarization', 'NegReg', (62, 76))
5212	26124749	Interestingly, invalidation of these different potassium channels leads to hyperaldosteronism due to abnormal depolarization of the zona glomerulosa cell membrane resulting in increased intracellular Ca2+ concentration and stimulation of aldosterone biosynthesis; however formation of adrenal tumors has never been observed in these models indicating that other mechanisms are required to promote increased cell proliferation in APA.	('invalidation', 'Var', (15, 27))	('adrenal tumors', 'Disease', (285, 299))	('increased', 'PosReg', (176, 185))	('potassium', 'Chemical', 'MESH:D011188', (47, 56))	('stimulation', 'PosReg', (223, 234))	('intracellular Ca2+ concentration', 'MPA', (186, 218))	('hyperaldosteronism', 'Disease', (75, 93))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('increased intracellular Ca2+ concentration', 'Phenotype', 'HP:0003575', (176, 218))	('aldosterone biosynthesis', 'MPA', (238, 262))	('depolarization', 'MPA', (110, 124))	('adrenal tumors', 'Disease', 'MESH:D000310', (285, 299))	('Ca2+', 'Chemical', 'MESH:D000069285', (200, 204))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (75, 93))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('PA', 'Phenotype', 'HP:0011736', (430, 432))	('aldosterone', 'Chemical', 'MESH:D000450', (238, 249))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (75, 93))
5214	26124749	However a reduced expression of TASK2, encoded by KCNK5, has been recently described in APA compared with normal adrenal, and the expression in H295R cells of a TASK2 dominant-negative mutant resulted in increased aldosterone production and CYP11B2 and StAR expression.	('KCNK5', 'Gene', '8645', (50, 55))	('aldosterone', 'Chemical', 'MESH:D000450', (214, 225))	('mutant', 'Var', (185, 191))	('reduced', 'NegReg', (10, 17))	('StAR', 'Gene', '6770', (253, 257))	('CYP11B2', 'Gene', (241, 248))	('increased', 'PosReg', (204, 213))	('aldosterone production', 'MPA', (214, 236))	('PA', 'Phenotype', 'HP:0011736', (89, 91))	('H295R', 'CellLine', 'CVCL:0458', (144, 149))	('KCNK5', 'Gene', (50, 55))	('aldosterone production', 'Phenotype', 'HP:0000859', (214, 236))	('expression', 'MPA', (18, 28))	('CYP11B2', 'Gene', '1585', (241, 248))	('TASK2', 'Gene', (161, 166))	('increased aldosterone', 'Phenotype', 'HP:0000859', (204, 225))	('StAR', 'Gene', (253, 257))
5216	26124749	Inactivation of dkk3 in task1-/- mice resulted in the extension of the phenotype of hyperaldosteronism to male animals, without inducing abnormal zonation of the adrenal cortex.	('hyperaldosteronism', 'Disease', (84, 102))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (84, 102))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (84, 102))	('mice', 'Species', '10090', (33, 37))	('dkk3', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
5218	26124749	The role of specific mutations of channels and ATPases in affecting aldosterone biosynthesis is now clearly established, whereas the question of the mechanism responsible for abnormal proliferation leading to adenoma formation is still open.	('adenoma', 'Disease', 'MESH:D000236', (209, 216))	('adenoma', 'Disease', (209, 216))	('aldosterone', 'Chemical', 'MESH:D000450', (68, 79))	('affecting', 'Reg', (58, 67))	('ATPases', 'Protein', (47, 54))	('aldosterone biosynthesis', 'MPA', (68, 92))	('mutations', 'Var', (21, 30))
5219	26124749	In 2011, Lifton suggested that KCNJ5 mutations could be responsible for both autonomous aldosterone production and abnormal cell proliferation; however it has been rapidly shown that cells expressing mutated KCNJ5 channels were less proliferative, raising the questions as to the events leading to abnormal cell proliferation and adenoma formation?	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (115, 142))	('aldosterone', 'Chemical', 'MESH:D000450', (88, 99))	('KCNJ5', 'Gene', (31, 36))	('adenoma', 'Disease', 'MESH:D000236', (330, 337))	('less', 'NegReg', (228, 232))	('mutated', 'Var', (200, 207))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (298, 325))	('aldosterone production', 'Phenotype', 'HP:0000859', (88, 110))	('KCNJ5', 'Gene', '3762', (208, 213))	('KCNJ5', 'Gene', (208, 213))	('KCNJ5', 'Gene', '3762', (31, 36))	('adenoma', 'Disease', (330, 337))	('proliferative', 'CPA', (233, 246))
5232	26124749	The loss of Wnt4 was associated with abnormal differentiation of the definitive zone of the adrenal cortex and aberrant migration of adrenocortical cells into the developing gonad and with a decrease of the number of zona glomerulosa cells which results in a decrease of aldosterone production.	('aldosterone production', 'Phenotype', 'HP:0000859', (271, 293))	('adrenocortical', 'Disease', (133, 147))	('loss', 'Var', (4, 8))	('aldosterone production', 'MPA', (271, 293))	('adrenocortical', 'Disease', 'MESH:D018268', (133, 147))	('decrease of aldosterone', 'Phenotype', 'HP:0004319', (259, 282))	('Wnt4', 'Gene', (12, 16))	('aldosterone', 'Chemical', 'MESH:D000450', (271, 282))	('aberrant migration of adrenocortical cells', 'Phenotype', 'HP:0002269', (111, 153))	('Wnt4', 'Gene', '54361', (12, 16))	('decrease', 'NegReg', (191, 199))	('decrease', 'NegReg', (259, 267))
5235	26124749	The disruption of beta-catenin specifically in adrenocortical cells, through the use of a sf-1 (steroidogenic factor-1)-Cre mouse, resulted in complete adrenal aplasia or defects in maintenance of the adult cortex resulting in depletion of adrenocortical cells.	('beta-catenin', 'Protein', (18, 30))	('complete adrenal aplasia or defects', 'Disease', 'MESH:D000310', (143, 178))	('adrenal aplasia', 'Phenotype', 'HP:0011743', (152, 167))	('adrenocortical', 'Disease', (240, 254))	('adrenocortical', 'Disease', 'MESH:D018268', (240, 254))	('mouse', 'Species', '10090', (124, 129))	('sf-1 (steroidogenic factor-1)-Cre', 'Gene', '22668', (90, 123))	('adrenocortical', 'Disease', (47, 61))	('complete adrenal aplasia or defects', 'Disease', (143, 178))	('maintenance of the adult cortex', 'CPA', (182, 213))	('disruption', 'Var', (4, 14))	('depletion', 'MPA', (227, 236))	('adrenocortical', 'Disease', 'MESH:D018268', (47, 61))
5240	26124749	Whereas activating mutations of the beta-catenin are found in a wide variety of human cancers including adrenocortical tumors and adrenocortical adenoma, only few mutations were reported in APA strongly suggesting that the activation of beta-catenin was not associated with the presence of mutation.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('adrenocortical adenoma', 'Disease', (130, 152))	('adrenocortical tumors', 'Disease', (104, 125))	('PA', 'Phenotype', 'HP:0011736', (191, 193))	('beta-catenin', 'Protein', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (19, 28))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (130, 152))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (104, 125))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (130, 152))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('activating', 'PosReg', (8, 18))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
5244	26124749	Interestingly, sfrp2 knockout mice exhibit an increase in plasma aldosterone concentration, associated with ectopic expression of cyp11b2 in adrenal cortex, similarly to what observed in mice expressing the constitutive active form of beta-catenin in adrenal cortex.	('sfrp2', 'Gene', (15, 20))	('mice', 'Species', '10090', (30, 34))	('increase', 'PosReg', (46, 54))	('plasma aldosterone concentration', 'Phenotype', 'HP:0000859', (58, 90))	('plasma aldosterone concentration', 'MPA', (58, 90))	('knockout', 'Var', (21, 29))	('mice', 'Species', '10090', (187, 191))	('cyp11b2', 'Gene', '13072', (130, 137))	('increase in plasma aldosterone', 'Phenotype', 'HP:0000859', (46, 76))	('aldosterone', 'Chemical', 'MESH:D000450', (65, 76))	('sfrp2', 'Gene', '20319', (15, 20))	('cyp11b2', 'Gene', (130, 137))
5254	26124749	Remarkably, the antagonism of hedgehog signaling has been shown to inhibit the proliferation of H295R cells and to decrease cell viability.	('proliferation', 'CPA', (79, 92))	('inhibit', 'NegReg', (67, 74))	('hedgehog', 'Protein', (30, 38))	('cell viability', 'CPA', (124, 138))	('H295R', 'CellLine', 'CVCL:0458', (96, 101))	('decrease', 'NegReg', (115, 123))	('antagonism', 'Var', (16, 26))
5259	26124749	Different circadian mutant mice models show abnormalities in BP regulation and/or plasma aldosterone concentration.	('mice', 'Species', '10090', (27, 31))	('aldosterone', 'Chemical', 'MESH:D000450', (89, 100))	('plasma aldosterone concentration', 'Phenotype', 'HP:0000859', (82, 114))	('plasma aldosterone concentration', 'MPA', (82, 114))	('BP regulation', 'MPA', (61, 74))	('mutant', 'Var', (20, 26))
5267	26124749	The inactivation of Cry genes leads to chronically enhanced mineralocorticoid production, which, in turn, renders BP salt sensitive.	('inactivation', 'Var', (4, 16))	('mineralocorticoid production', 'MPA', (60, 88))	('renders', 'Reg', (106, 113))	('BP salt', 'Chemical', '-', (114, 121))	('enhanced', 'PosReg', (51, 59))	('Cry genes', 'Gene', (20, 29))	('enhanced mineralocorticoid production', 'Phenotype', 'HP:0000859', (51, 88))	('BP salt sensitive', 'MPA', (114, 131))
5268	26124749	Remarkably, Per1 knockout mice exhibit lower BP when compared to wild-type mice.	('mice', 'Species', '10090', (75, 79))	('knockout', 'Var', (17, 25))	('Per1', 'Gene', (12, 16))	('lower', 'NegReg', (39, 44))	('mice', 'Species', '10090', (26, 30))
5271	26124749	In addition, they have demonstrated that Per1 heterozygous mice exhibited lower plasma aldosterone levels and reduced Hsd3b6 mRNA expression in vivo, with a significant blunted circadian expression of this gene.	('aldosterone', 'Chemical', 'MESH:D000450', (87, 98))	('mice', 'Species', '10090', (59, 63))	('Hsd3b6', 'Gene', '15497', (118, 124))	('reduced', 'NegReg', (110, 117))	('Per1', 'Var', (41, 45))	('plasma aldosterone levels', 'MPA', (80, 105))	('lower plasma aldosterone', 'Phenotype', 'HP:0004319', (74, 98))	('circadian expression', 'MPA', (177, 197))	('lower', 'NegReg', (74, 79))	('plasma aldosterone levels', 'Phenotype', 'HP:0000859', (80, 105))	('blunted', 'NegReg', (169, 176))	('Hsd3b6', 'Gene', (118, 124))
5277	26124749	It is possible that APA formation is the result of the combination of two events: (1) the activation of signaling pathways such as wnt/beta-catenin or shh pathways driving abnormal cell proliferation and creating a favorable environment for (2) the occurrence of recurrent somatic mutations responsible for autonomous aldosterone production.	('aldosterone', 'Chemical', 'MESH:D000450', (318, 329))	('wnt/beta-catenin', 'Pathway', (131, 147))	('shh', 'Gene', '6469', (151, 154))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (172, 199))	('aldosterone production', 'Phenotype', 'HP:0000859', (318, 340))	('mutations', 'Var', (281, 290))	('PA', 'Phenotype', 'HP:0011736', (21, 23))	('shh', 'Gene', (151, 154))	('APA formation', 'Disease', (20, 33))
5278	26124749	Although it was suggested that genetic alterations leading to abnormal calcium signaling are sufficient for both abnormal proliferation and inappropriate aldosterone production in APA, there are some evidences suggesting that mutations in potassium and calcium channel and ATPases may not be sufficient for promoting cell proliferation and tumor formation.	('potassium', 'Chemical', 'MESH:D011188', (239, 248))	('aldosterone', 'Chemical', 'MESH:D000450', (154, 165))	('promoting', 'PosReg', (307, 316))	('calcium', 'Chemical', 'MESH:D002118', (71, 78))	('cell proliferation', 'CPA', (317, 335))	('calcium', 'Chemical', 'MESH:D002118', (253, 260))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('alterations', 'Var', (39, 50))	('mutations', 'Var', (226, 235))	('aldosterone production', 'MPA', (154, 176))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('ATPases', 'Protein', (273, 280))	('aldosterone production', 'Phenotype', 'HP:0000859', (154, 176))	('PA', 'Phenotype', 'HP:0011736', (181, 183))	('tumor', 'Disease', (340, 345))
5279	26124749	It could be speculated that some groups of cells start to abnormally proliferate creating a propitious environment for the emergence of specific mutations affecting ionic channels and ATPases leading to increased aldosterone production.	('mutations', 'Var', (145, 154))	('increased aldosterone', 'Phenotype', 'HP:0000859', (203, 224))	('aldosterone', 'Chemical', 'MESH:D000450', (213, 224))	('ionic channels', 'Gene', (165, 179))	('aldosterone production', 'MPA', (213, 235))	('ATPases', 'Gene', (184, 191))	('aldosterone production', 'Phenotype', 'HP:0000859', (213, 235))	('increased', 'PosReg', (203, 212))
5290	28332880	Medical teams took important strides towards personalized medicine when previously identified patients with a genetic mutation were screened for associated tumors and underwent expedited treatment, ultimately saving lives.	('patients', 'Species', '9606', (94, 102))	('tumors', 'Disease', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('genetic mutation', 'Var', (110, 126))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
5295	28332880	Decades later, the same lead investigator for the GRA discovery, Dr. Richard Lifton, was involved in the identification of the KCNJ5 mutation in the zona glomerulosa, which was initially described in adults.	('mutation', 'Var', (133, 141))	('KCNJ5', 'Gene', '3762', (127, 132))	('zona glomerulosa', 'Disease', (149, 165))	('zona glomerulosa', 'Disease', 'MESH:D006562', (149, 165))	('KCNJ5', 'Gene', (127, 132))
5296	28332880	For over 50 years, we knew little about the somatic mutations driving aldosterone production in aldosterone-producing adenomas (APAs) until the observation of a mutation in the inwardly rectifying potassium channel called KCNJ5, which comprises over 35% of APAs.	('adenomas', 'Disease', (118, 126))	('APA', 'Gene', '2028', (257, 260))	('aldosterone production', 'Phenotype', 'HP:0000859', (70, 92))	('mutation', 'Var', (161, 169))	('APA', 'Gene', (257, 260))	('adenomas', 'Disease', 'MESH:D000236', (118, 126))	('APA', 'Gene', '2028', (128, 131))	('KCNJ5', 'Gene', (222, 227))	('aldosterone', 'Chemical', 'MESH:D000450', (96, 107))	('APA', 'Gene', (128, 131))	('aldosterone', 'Chemical', 'MESH:D000450', (70, 81))	('KCNJ5', 'Gene', '3762', (222, 227))
5298	28332880	Specifically, a report describing APA with KCNJ5 mutation and familial adenomatous polyposis was described.	('KCNJ5', 'Gene', '3762', (43, 48))	('APA', 'Gene', '2028', (34, 37))	('APA', 'Gene', (34, 37))	('familial adenomatous polyposis', 'Disease', (62, 92))	('mutation', 'Var', (49, 57))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (71, 92))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (62, 92))	('KCNJ5', 'Gene', (43, 48))
5299	28332880	Besides the KCNJ5 mutation, other somatic mutations affecting the Na+/K+ ATPase 1 (ATP1A1), Ca2+-ATPase 3 (ATP2B3), and L-type voltage-gated calcium channel (CACNA1D) were discovered, which comprise the other 15% of somatic APA mutations.	('CACNA1D', 'Gene', '776', (158, 165))	('Na+/K+ ATPase 1', 'Gene', '476', (66, 81))	('ATP2B3', 'Gene', '492', (107, 113))	('mutations', 'Var', (228, 237))	('APA', 'Gene', '2028', (224, 227))	('ATP2B3', 'Gene', (107, 113))	('Na+/K+ ATPase 1', 'Gene', (66, 81))	('KCNJ5', 'Gene', (12, 17))	('APA', 'Gene', (224, 227))	('KCNJ5', 'Gene', '3762', (12, 17))	('affecting', 'Reg', (52, 61))	('mutation', 'Var', (18, 26))	('calcium', 'Chemical', 'MESH:D002118', (141, 148))	('ATP1A1', 'Gene', '476', (83, 89))	('ATP1A1', 'Gene', (83, 89))	('CACNA1D', 'Gene', (158, 165))	('mutations', 'Var', (42, 51))	('Ca2+', 'Chemical', 'MESH:D000069285', (92, 96))
5301	28332880	The cellular origins of APA were questioned following the discovery of these new channel mutations.	('APA', 'Gene', '2028', (24, 27))	('mutations', 'Var', (89, 98))	('APA', 'Gene', (24, 27))
5302	28332880	Rainey and colleagues uncovered clues when they found that normal adrenal cortical tissue contained somatic mutations in ATP1A1, ATP2B3, and CACNA1D in aldosterone-producing cell clusters (APCCs).	('CACNA1D', 'Gene', (141, 148))	('ATP2B3', 'Gene', (129, 135))	('PCC', 'Gene', (190, 193))	('aldosterone', 'Chemical', 'MESH:D000450', (152, 163))	('mutations', 'Var', (108, 117))	('PCC', 'Gene', '1421', (190, 193))	('ATP1A1', 'Gene', '476', (121, 127))	('ATP1A1', 'Gene', (121, 127))	('ATP2B3', 'Gene', '492', (129, 135))	('CACNA1D', 'Gene', '776', (141, 148))
5303	28332880	Up to 35% of these clusters revealed somatic mutations in ATP1A1 and CACNA1D, which raises the question of whether APCCs could be the precursor to hyperaldosteronism (Fig.	('mutations', 'Var', (45, 54))	('CACNA1D', 'Gene', '776', (69, 76))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (147, 165))	('CACNA1D', 'Gene', (69, 76))	('PCC', 'Gene', (116, 119))	('ATP1A1', 'Gene', '476', (58, 64))	('ATP1A1', 'Gene', (58, 64))	('hyperaldosteronism', 'Disease', (147, 165))	('PCC', 'Gene', '1421', (116, 119))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (147, 165))
5307	28332880	In the coming years, investigators will gain understanding of how to better utilize these genetic advances in hyperaldosteronism in order to treat a patient effectively with accurate genotype-phenotype correlations.	('hyperaldosteronism', 'Disease', (110, 128))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (110, 128))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (110, 128))	('genetic', 'Var', (90, 97))	('patient', 'Species', '9606', (149, 156))
5313	28332880	In vitro studies showed that cortisol production is controlled by corticotropin produced within the adrenocortical tissue and by aberrant G-protein-coupled receptors.	('cortisol production', 'MPA', (29, 48))	('controlled', 'Reg', (52, 62))	('G-protein-coupled receptors', 'Protein', (138, 165))	('cortisol', 'Chemical', 'MESH:D006854', (29, 37))	('aberrant', 'Var', (129, 137))
5315	28332880	A list of other important genetic mutations associated with bilateral adrenal disease causing excess in cortisol production is provided in Table 1.	('associated', 'Reg', (44, 54))	('bilateral adrenal disease', 'Disease', (60, 85))	('excess in cortisol', 'Phenotype', 'HP:0003118', (94, 112))	('cortisol production', 'MPA', (104, 123))	('genetic mutations', 'Var', (26, 43))	('bilateral adrenal disease', 'Disease', 'MESH:D000310', (60, 85))	('excess', 'PosReg', (94, 100))	('cortisol', 'Chemical', 'MESH:D006854', (104, 112))	('adrenal disease', 'Phenotype', 'HP:0000834', (70, 85))	('mutations', 'Var', (34, 43))
5317	28332880	Study results identified new driver mutations associated with the Wnt signaling and retinoblastoma pathways.	('retinoblastoma', 'Disease', 'MESH:D012175', (84, 98))	('retinoblastoma', 'Disease', (84, 98))	('mutations', 'Var', (36, 45))	('retinoblastoma', 'Phenotype', 'HP:0009919', (84, 98))	('associated', 'Reg', (46, 56))	('Wnt signaling', 'Pathway', (66, 79))
5318	28332880	A subset of tumors were found to have specific methylation signatures that could help identify patients that would be better candidates for a certain types of combination chemotherapy.	('patients', 'Species', '9606', (95, 103))	('methylation', 'Var', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
5322	28332880	Such PCC/PGL tumors have a succinate dehydrogenase subunit B (SDHB) mutation, thereby affecting types of treatment options inpatients presenting with metastases.	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('PGL tumors', 'Disease', (9, 19))	('PCC', 'Gene', (5, 8))	('succinate dehydrogenase subunit B', 'Gene', '6390', (27, 60))	('mutation', 'Var', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('succinate dehydrogenase subunit B', 'Gene', (27, 60))	('PGL tumors', 'Disease', 'MESH:D010235', (9, 19))	('PCC', 'Gene', '1421', (5, 8))	('metastases', 'Disease', (150, 160))	('affecting', 'Reg', (86, 95))	('metastases', 'Disease', 'MESH:D009362', (150, 160))	('SDHB', 'Gene', '6390', (62, 66))	('SDHB', 'Gene', (62, 66))	('patients', 'Species', '9606', (125, 133))
5325	28332880	SDHx, FH, MDH2, and von Hippel-Lindau mutations share a common pathway: the pseudohypoxia pathway with a noradrenergic phenotype (Fig.	('MDH2', 'Gene', '4191', (10, 14))	('FH', 'Gene', '2271', (6, 8))	('MDH2', 'Gene', (10, 14))	('hypoxia', 'Disease', (82, 89))	('hypoxia', 'Disease', 'MESH:D000860', (82, 89))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (20, 37))	('SDHx', 'Gene', (0, 4))	('mutations', 'Var', (38, 47))	('von Hippel-Lindau', 'Disease', (20, 37))
5327	28332880	Patients harboring these mutations tend to have PCCs and mainly produce epinephrine.	('mutations', 'Var', (25, 34))	('PCC', 'Gene', '1421', (48, 51))	('Patients', 'Species', '9606', (0, 8))	('produce epinephrine', 'MPA', (64, 83))	('PCC', 'Gene', (48, 51))	('epinephrine', 'Chemical', 'MESH:D004837', (72, 83))
5328	28332880	MYC-associated factor X (MAX) gene mutation tumors can have a mixed adrenergic and noradrenergic phenotype.	('tumors', 'Disease', (44, 50))	('MAX', 'Gene', '4149', (25, 28))	('MAX', 'Gene', (25, 28))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('MYC-associated factor X', 'Gene', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutation', 'Var', (35, 43))	('MYC-associated factor X', 'Gene', '4149', (0, 23))
5330	28332880	In addition, the TCGA dataset revealed that a Wnt-altered pathway mutation driven by the master-mind-like transcriptional coactivator 3 (MAML3) fusion gene and transcriptional regulator ATRX (ATRX) somatic mutations is linked with poor clinical outcomes.	('ATRX', 'Gene', (192, 196))	('MAML3', 'Gene', '55534', (137, 142))	('MAML3', 'Gene', (137, 142))	('master-mind-like transcriptional coactivator 3', 'Gene', (89, 135))	('ATRX', 'Gene', '546', (192, 196))	('mutation', 'Var', (66, 74))	('ATRX', 'Gene', (186, 190))	('master-mind-like transcriptional coactivator 3', 'Gene', '55534', (89, 135))	('ATRX', 'Gene', '546', (186, 190))
5331	28332880	Like ACC, aggressive PCC has been linked to telomerase activity, as demonstrated by the discovery of the somatic ATRX gene mutation.	('ATRX', 'Gene', '546', (113, 117))	('mutation', 'Var', (123, 131))	('aggressive PCC', 'Disease', (10, 24))	('ACC', 'Phenotype', 'HP:0006744', (5, 8))	('aggressive PCC', 'Disease', 'OMIM:115700', (10, 24))	('ATRX', 'Gene', (113, 117))	('linked', 'Reg', (34, 40))
5334	28332880	The genetics of CAH are well known, with 21-hydroxylase (CYP21A2) deficiency comprising up to 95% of cases, and other enzyme deficiencies, including HSD3B2, CYP11B1, and CYP17A1 contributing to the remaining 5%.	('CAH', 'Disease', (16, 19))	('HSD3B2', 'Gene', '3284', (149, 155))	('enzyme deficiencies', 'Disease', 'MESH:D008661', (118, 137))	('CYP17A1', 'Gene', (170, 177))	('deficiency', 'Var', (66, 76))	('CYP17A1', 'Gene', '1586', (170, 177))	('CYP11B1', 'Gene', (157, 164))	('CYP11B1', 'Gene', '1584', (157, 164))	('CAH', 'Phenotype', 'HP:0008258', (16, 19))	('CYP21A2', 'Gene', '1589', (57, 64))	('CYP21A2', 'Gene', (57, 64))	('enzyme deficiencies', 'Disease', (118, 137))	('HSD3B2', 'Gene', (149, 155))
5339	28332880	For that reason, a detailed analysis of 21-carbon steroids from the serum of CAH patients (19 to 59 years of age) with 21-hydroyxlase deficiency was undertaken by liquid chromatography/tandem mass spectroscopy (LC-MS/MS).	('LC-MS', 'Disease', 'MESH:D009103', (211, 216))	('deficiency', 'Var', (134, 144))	('carbon steroids', 'Chemical', '-', (43, 58))	('patients', 'Species', '9606', (81, 89))	('LC-MS', 'Disease', (211, 216))	('CAH', 'Phenotype', 'HP:0008258', (77, 80))
5364	28332880	Recent studies examined the metabolic perturbations characteristic of tissues harboring SDHB mutations.	('SDHB', 'Gene', '6390', (88, 92))	('metabolic perturbations', 'MPA', (28, 51))	('mutations', 'Var', (93, 102))	('SDHB', 'Gene', (88, 92))
5367	28332880	In the last 3 decades, imaging has enhanced our ability to characterize adrenal tumors by measuring Hounsheld units, contrast medium wash out, and derilling imaging qualities that differentiate benign versus malignant lesions on computed tomography (CT).	('adrenal tumor', 'Phenotype', 'HP:0100631', (72, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Hounsheld units', 'MPA', (100, 115))	('derilling', 'Var', (147, 156))	('adrenal tumors', 'Disease', 'MESH:D000310', (72, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('enhanced', 'PosReg', (35, 43))	('adrenal tumors', 'Disease', (72, 86))
5371	28332880	PCC/PGL tumors with metastatic potential, such as those with the SDHB mutation, utilize aerobic glycolysis and are therefore likely to express more glucose transporters, hence the success of 18F-FDG uptake in aggressive PCC/PGL tumors.	('PCC', 'Gene', '1421', (220, 223))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('PGL tumors', 'Disease', (4, 14))	('glucose', 'Chemical', 'MESH:D005947', (148, 155))	('more', 'PosReg', (143, 147))	('aggressive PCC/PGL tumors', 'Disease', 'MESH:D010235', (209, 234))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('PGL tumors', 'Disease', 'MESH:D010235', (4, 14))	('18F-FDG', 'Chemical', '-', (191, 198))	('PCC', 'Gene', (0, 3))	('aggressive PCC/PGL tumors', 'Disease', (209, 234))	('PGL tumors', 'Disease', 'MESH:D010235', (224, 234))	('SDHB', 'Gene', '6390', (65, 69))	('PCC', 'Gene', '1421', (0, 3))	('aerobic glycolysis', 'MPA', (88, 106))	('PCC', 'Gene', (220, 223))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('mutation', 'Var', (70, 78))	('glucose transporters', 'MPA', (148, 168))	('SDHB', 'Gene', (65, 69))
5374	28332880	As a proof-of-concept study, 20 patients with head and neck PGLs underwent [68Ga] DOTATATE PET/CT, [18F]-FDOPA PET/CT, [18F]-FDG PET/CT, and CT/magnetic resonance imaging (MRI).	('patients', 'Species', '9606', (32, 40))	('[18F]-FDG', 'Var', (119, 128))	('[18F]-FDOPA', 'Var', (99, 110))	('[68Ga]', 'Var', (75, 81))	('FDG', 'Chemical', 'MESH:D019788', (125, 128))	('[18F]-FDOPA', 'Chemical', 'MESH:C043437', (99, 110))	('DOTATATE', 'Chemical', '-', (82, 90))
5389	28332880	Patients with HIF2A or SDHx mutations will be encouraged from an earlier age to forego tobacco use, which can worsen hypoxia, or relocate to lower altitudes to reduce hypoxia and therefore the chance of PCC/PGL development.	('HIF2A', 'Gene', '2034', (14, 19))	('SDHx', 'Gene', (23, 27))	('hypoxia', 'Disease', (167, 174))	('hypoxia', 'Disease', 'MESH:D000860', (167, 174))	('Patients', 'Species', '9606', (0, 8))	('PCC', 'Gene', (203, 206))	('HIF2A', 'Gene', (14, 19))	('hypoxia', 'Disease', 'MESH:D000860', (117, 124))	('PCC', 'Gene', '1421', (203, 206))	('tobacco', 'Species', '4097', (87, 94))	('hypoxia', 'Disease', (117, 124))	('worsen', 'PosReg', (110, 116))	('mutations', 'Var', (28, 37))
5392	28332880	Patients with hyperaldosteronism with a certain "chamielopathy" mutation can be treated with specific inhibitors that can target specific channels that cause constant zona glomemlosa cell depolarization.	('mutation', 'Var', (64, 72))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (14, 32))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (14, 32))	('Patients', 'Species', '9606', (0, 8))	('hyperaldosteronism', 'Disease', (14, 32))
5395	28332880	In PCC/PGL, metabolites produced as a result of an aberrant Krebs cycle will create new waves of drugs that can be given to patients earlier to possibly correct an "error in metabolism and energy production" to prevent tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('PCC', 'Gene', '1421', (3, 6))	('Krebs', 'Chemical', '-', (60, 65))	('tumor', 'Disease', (219, 224))	('aberrant', 'Var', (51, 59))	('PCC', 'Gene', (3, 6))	('aberrant Krebs cycle', 'Phenotype', 'HP:0000816', (51, 71))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('patients', 'Species', '9606', (124, 132))
5451	32325994	Treatment with SB525334 (TGF-beta type I receptor inhibitor) or chemerin rescued the expression of E-cadherin detected along the plasma membranes and inhibited the translocation of beta-catenin and SMAD2/3 into the nucleus in TGF-beta-treated breast cancer cells.	('TGF-beta', 'Gene', '7039', (226, 234))	('translocation', 'MPA', (164, 177))	('TGF-beta', 'Gene', (226, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('TGF-beta', 'Gene', '7039', (25, 33))	('TGF-beta type I receptor', 'Gene', (25, 49))	('SB525334', 'Var', (15, 23))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('beta-catenin', 'Gene', (181, 193))	('TGF-beta', 'Gene', (25, 33))	('breast cancer', 'Disease', (243, 256))	('beta-catenin', 'Gene', '1499', (181, 193))	('SMAD2/3', 'Gene', (198, 205))	('rescued', 'PosReg', (73, 80))	('TGF-beta type I receptor', 'Gene', '7046', (25, 49))	('expression', 'MPA', (85, 95))	('inhibited', 'NegReg', (150, 159))	('SMAD2/3', 'Gene', '4087;4088', (198, 205))	('E-cadherin', 'Protein', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('SB525334', 'Chemical', 'MESH:C521813', (15, 23))
5458	32325994	Treatment with ZSTK474 (PI3K inhibitor), PD98059 (MEK1/2 inhibitor), or chemerin reversed these effects of IGF-1 by elevating the levels of E-cadherin and beta-catenin detected along the membrane.	('beta-catenin', 'Gene', (155, 167))	('ZSTK474', 'Chemical', 'MESH:C510150', (15, 22))	('PD98059', 'Var', (41, 48))	('beta-catenin', 'Gene', '1499', (155, 167))	('MEK1/2', 'Gene', '5604;5605', (50, 56))	('ZSTK474', 'Var', (15, 22))	('PD98059', 'Chemical', 'MESH:C093973', (41, 48))	('levels of E-cadherin', 'MPA', (130, 150))	('MEK1/2', 'Gene', (50, 56))	('elevating', 'PosReg', (116, 125))	('IGF-1', 'Gene', '3479', (107, 112))	('IGF-1', 'Gene', (107, 112))
5474	32325994	The serum levels of the bone turnover markers calcium, C-terminal cross-linking telopeptide of type I collagen (CTX), and TRAP were increased by MDA-MB-231 inoculation but reduced to control levels by chemerin administration (Figure 6C).	('reduced', 'NegReg', (172, 179))	('calcium', 'Chemical', 'MESH:D002118', (46, 53))	('TRAP', 'Gene', '11433', (122, 126))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (145, 155))	('increased', 'PosReg', (132, 141))	('serum levels of', 'MPA', (4, 19))	('MDA-MB-231', 'Gene', (145, 155))	('bone turnover markers calcium', 'MPA', (24, 53))	('TRAP', 'Gene', (122, 126))	('inoculation', 'Var', (156, 167))
5509	32325994	Recombinant human chemerin (Glu21-Ser157, with an N-terminal Met), mouse soluble receptor activator of nuclear factor kappa beta (RANK) ligand (RANKL), and macrophage colony-stimulating factor (M-CSF) were purchased from R&D Systems (Minneapolis, MN, USA).	('MN', 'CellLine', 'CVCL:U508', (247, 249))	('Glu21-Ser157', 'Var', (28, 40))	('macrophage colony-stimulating factor', 'Gene', (156, 192))	('Glu21-Ser157', 'Mutation', 'p.E21,157S', (28, 40))	('macrophage colony-stimulating factor', 'Gene', '12977', (156, 192))	('human', 'Species', '9606', (12, 17))	('mouse', 'Species', '10090', (67, 72))
5586	32295632	In this review, we will focus on specific cancer core mechanisms to illustrate how sexual dimorphisms in basic biological functions influence cancer biology, and might impact response to treatment.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('sexual dimorphisms', 'Var', (83, 101))	('rat', 'Species', '10116', (74, 77))	('impact', 'Reg', (168, 174))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('men', 'Species', '9606', (192, 195))	('influence', 'Reg', (132, 141))	('cancer', 'Disease', (142, 148))
5591	32295632	Over the past two decades, epigenetic dysregulation has emerged as a critical mechanism of cancer initiation and adaptation.	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('epigenetic dysregulation', 'Var', (27, 51))
5592	32295632	We now recognize that essentially all cancer hallmarks that can be acquired through genetic mutation can similarly be achieved through epigenetic mechanisms.	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('genetic mutation', 'Var', (84, 100))	('cancer', 'Disease', (38, 44))
5593	32295632	Genes encoding epigenetic readers, writers, and erasers, as well as histone proteins themselves, are frequently mutated in human tumors, drawing a direct link between epigenetic dysregulation and tumorigenesis.	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', (196, 201))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('human', 'Species', '9606', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('epigenetic', 'Var', (167, 177))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
5595	32295632	Epigenetic mechanisms also contribute to intra-tumor heterogeneity and therapeutic resistance.	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('intra-tumor', 'Disease', 'MESH:D009369', (41, 52))	('contribute', 'Reg', (27, 37))	('therapeutic resistance', 'CPA', (71, 93))	('Epigenetic mechanisms', 'Var', (0, 21))	('intra-tumor', 'Disease', (41, 52))
5596	32295632	Thus, targeting tumor epigenetics may be a strategy for improving treatment response.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('men', 'Species', '9606', (71, 74))	('tumor', 'Disease', (16, 21))	('epigenetics', 'Var', (22, 33))	('rat', 'Species', '10116', (45, 48))
5606	32295632	Knocking out Dnmt3A or pharmacologically inhibiting Dnmts masculinized sexual behavior in females, even when treatment was given outside the critical window.	('sexual behavior', 'Disease', 'MESH:D020018', (71, 86))	('sexual behavior', 'Phenotype', 'HP:0030214', (71, 86))	('men', 'Species', '9606', (114, 117))	('masculinized', 'Reg', (58, 70))	('Dnmts', 'Gene', (52, 57))	('Dnmt3A', 'Gene', '13435', (13, 19))	('Knocking out', 'Var', (0, 12))	('sexual behavior', 'Disease', (71, 86))	('Dnmt3A', 'Gene', (13, 19))
5608	32295632	Together, these studies suggest that DNA methylation actively suppresses masculinizing genes in order to maintain brain feminization, and that this depends on levels of gonadal hormones during development.	('masculinizing genes', 'Gene', (73, 92))	('methylation', 'Var', (41, 52))	('brain feminization', 'MPA', (114, 132))	('men', 'Species', '9606', (200, 203))	('suppresses', 'NegReg', (62, 72))	('maintain', 'PosReg', (105, 113))
5611	32295632	Differences in male and female methylation patterns may have important implications for cancer development.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('methylation', 'Var', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('implications', 'Reg', (71, 83))	('men', 'Species', '9606', (102, 105))
5612	32295632	One epigenetic change recognized in many cancers, though with some exceptions (notably isocitrate dehydrogenase (IDH)-mutant gliomas), is a propensity for global hypomethylation.	('IDH', 'Gene', '3417', (113, 116))	('global hypomethylation', 'MPA', (155, 177))	('gliomas', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('isocitrate dehydrogenase', 'Gene', '3417', (87, 111))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('-mutant', 'Var', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('IDH', 'Gene', (113, 116))	('cancers', 'Disease', (41, 48))	('isocitrate dehydrogenase', 'Gene', (87, 111))
5613	32295632	DNA hypomethylation is associated with increased cancer malignancy, and mutations in Dnmts are cancer promoting in multiple mouse models.	('mutations', 'Var', (72, 81))	('hypomethylation', 'Var', (4, 19))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Dnmts', 'Gene', (85, 90))	('cancer', 'Disease', (95, 101))	('cancer malignancy', 'Disease', 'MESH:D009369', (49, 66))	('mouse', 'Species', '10090', (124, 129))	('increased', 'PosReg', (39, 48))	('cancer malignancy', 'Disease', (49, 66))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (49, 55))
5614	32295632	Broad regions of hypomethylation (both DNA and histone) are believed to contribute to dedifferentiation and the cancer stemcell-like state, and to increase epigenetic plasticity.	('hypomethylation', 'Var', (17, 32))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('epigenetic plasticity', 'MPA', (156, 177))	('increase', 'PosReg', (147, 155))	('contribute', 'Reg', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('dedifferentiation', 'CPA', (86, 103))
5617	32295632	Thus, male- and female-specific methylation patterns could influence the ability of cancer cells to adopt a stem cell-like phenotype.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('methylation patterns', 'Var', (32, 52))	('influence', 'Reg', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
5622	32295632	Together, these studies provide strong evidence that gonadal steroid exposure during the critical period mediates sexual differentiation of the brain via epigenetic mechanisms.	('mediates', 'Reg', (105, 113))	('epigenetic', 'Var', (154, 164))	('steroid', 'Chemical', 'MESH:D013256', (61, 68))	('sexual differentiation of the brain', 'CPA', (114, 149))
5624	32295632	This inactivation is orchestrated by the long non-coding RNA (lncRNA) XIST, which mediates chromosome-wide silencing through histone deacetylation and subsequent enrichment of repressive chromatin marks.	('deacetylation', 'Var', (133, 146))	('XIST', 'Gene', '7503', (70, 74))	('histone', 'MPA', (125, 132))	('men', 'Species', '9606', (168, 171))	('XIST', 'Gene', (70, 74))	('rat', 'Species', '10116', (28, 31))	('silencing', 'NegReg', (107, 116))
5628	32295632	Furthermore, there is evidence that X inactivation is lost in some female cancers, through either mitotic errors or epigenetic dysregulation and reactivation.	('reactivation', 'Var', (145, 157))	('epigenetic dysregulation', 'Var', (116, 140))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('male cancers', 'Disease', 'MESH:D018567', (69, 81))	('mitotic errors', 'Disease', 'MESH:D004314', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mitotic errors', 'Disease', (98, 112))	('male cancers', 'Disease', (69, 81))	('lost', 'NegReg', (54, 58))
5632	32295632	Surprisingly, two meta-analyses of XIST in cancer identified no association between XIST and sex/gender, but did find that high levels were associated with poor overall survival.	('poor', 'NegReg', (156, 160))	('XIST', 'Gene', '7503', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('XIST', 'Gene', (84, 88))	('high', 'Var', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('XIST', 'Gene', '7503', (35, 39))	('overall survival', 'MPA', (161, 177))	('XIST', 'Gene', (35, 39))
5647	32295632	These genes, along with ATRX, DDX3X, CNKSR2, and MAGEC3 are more frequently mutated in male tumors, presumably because females have a second copy to compensate for any loss of function mutations via XCI escape.	('CNKSR2', 'Gene', (37, 43))	('ATRX', 'Gene', (24, 28))	('mutated', 'Var', (76, 83))	('MAGEC3', 'Gene', '139081', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('male tumors', 'Disease', (87, 98))	('CNKSR2', 'Gene', '22866', (37, 43))	('DDX3X', 'Gene', (30, 35))	('ATRX', 'Gene', '546', (24, 28))	('male tumors', 'Disease', 'MESH:D018567', (87, 98))	('mutations', 'Var', (185, 194))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('DDX3X', 'Gene', '1654', (30, 35))	('MAGEC3', 'Gene', (49, 55))
5692	32295632	In the second, high visceral fat quantity correlated with decreased survival in women with renal cell carcinoma but not men.	('high', 'Var', (15, 19))	('women', 'Species', '9606', (80, 85))	('renal cell carcinoma', 'Disease', (91, 111))	('decreased', 'NegReg', (58, 67))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (91, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('survival', 'MPA', (68, 76))	('men', 'Species', '9606', (82, 85))	('men', 'Species', '9606', (120, 123))
5716	32295632	ROS can be both pro-tumorigenic and anti-tumorigenic.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (20, 25))
5717	32295632	Certain oncogenic mutations, such as mutations in the Ras pathway, lead to increased ROS levels.	('Ras pathway', 'Pathway', (54, 65))	('increased ROS levels', 'Phenotype', 'HP:0025464', (75, 95))	('mutations', 'Var', (37, 46))	('increased', 'PosReg', (75, 84))	('ROS levels', 'MPA', (85, 95))	('ROS', 'Chemical', 'MESH:D017382', (85, 88))
5737	32295632	Among the notable recent discoveries in cancer genome-wide sequencing was the discovery of the isocitrate dehydrogenase 1 and 2 (IDH1/2) R132H mutation.	('IDH1/2', 'Gene', '3417;3418', (129, 135))	('R132H', 'Mutation', 'rs121913500', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('isocitrate dehydrogenase', 'Gene', (95, 119))	('cancer', 'Disease', (40, 46))	('IDH1/2', 'Gene', (129, 135))	('isocitrate dehydrogenase', 'Gene', '3417', (95, 119))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('R132H', 'Var', (137, 142))
5739	32295632	Mutant IDH1/2 exhibits loss of normal function and gain of aberrant function, in which isocitrate is converted into D-2-hydroxyglutarate (2-HG), an onco-metabolite that has far-reaching pro-tumorigenic effects on epigenetic regulation, DNA repair, and redox state.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('IDH1/2', 'Gene', '3417;3418', (7, 13))	('2-HG', 'Chemical', 'MESH:C019417', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (116, 136))	('isocitrate', 'Chemical', 'MESH:C034219', (87, 97))	('tumor', 'Disease', (190, 195))	('IDH1/2', 'Gene', (7, 13))	('Mutant', 'Var', (0, 6))
5740	32295632	Due to its importance for mitochondrial biomass production, oxidative phosphorylation, and fatty acid synthesis, disruption of the TCA cycle through mutant IDH1/2 will most likely result in sex-specific effects during tumor development, progression, and treatment response.	('result in', 'Reg', (180, 189))	('IDH1/2', 'Gene', (156, 162))	('effects', 'Reg', (203, 210))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('mutant', 'Var', (149, 155))	('men', 'Species', '9606', (259, 262))	('men', 'Species', '9606', (231, 234))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('fatty acid', 'Chemical', 'MESH:D005227', (91, 101))	('tumor', 'Disease', (218, 223))	('IDH1/2', 'Gene', '3417;3418', (156, 162))	('TCA', 'Chemical', 'MESH:D014238', (131, 134))
5741	32295632	In concordance, mutant IDH1/2 inhibitors, which are currently in clinical trials for multiple cancers might exhibit sex-specific effects.	('multiple cancers', 'Disease', 'MESH:D009369', (85, 101))	('IDH1/2', 'Gene', '3417;3418', (23, 29))	('IDH1/2', 'Gene', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutant', 'Var', (16, 22))	('effects', 'Reg', (129, 136))	('multiple cancers', 'Disease', (85, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))
5742	32295632	In glioblastoma, a sex-specific effect of IDH mutations on overall survival has been evaluated in multiple publications; however, the findings are inconsistent and further study will be required to define how interaction between IDH1 mutation and patient sex impacts on survival.	('IDH', 'Gene', (42, 45))	('impacts', 'Reg', (259, 266))	('IDH1', 'Gene', (229, 233))	('patient', 'Species', '9606', (247, 254))	('IDH', 'Gene', '3417', (42, 45))	('mutation', 'Var', (234, 242))	('IDH1', 'Gene', '3417', (229, 233))	('glioblastoma', 'Disease', (3, 15))	('IDH', 'Gene', (229, 232))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('IDH', 'Gene', '3417', (229, 232))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))
5743	32295632	The tumor suppressor TP53 (p53) is the most frequently mutated gene in cancer, with mutations occurring across almost all cancer types and in approximately half of all tumors.	('tumor', 'Disease', (4, 9))	('TP53', 'Gene', (21, 25))	('tumors', 'Disease', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cancer', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TP53', 'Gene', '7157', (21, 25))	('tumor', 'Disease', (168, 173))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('occurring', 'Reg', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('p53', 'Gene', (27, 30))
5745	32295632	In this simplified model, p53 inhibits tumorigenesis by arresting or eliminating preneoplastic cells.	('eliminating', 'NegReg', (69, 80))	('preneoplastic cells', 'CPA', (81, 100))	('p53', 'Var', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('arrest', 'Disease', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('inhibits', 'NegReg', (30, 38))	('arrest', 'Disease', 'MESH:D006323', (56, 62))
5746	32295632	Loss of p53 function through mutation or alterations in upstream regulators eliminates this barrier, leading to increased proliferation, genomic instability, and the accumulation of new mutations that drive tumorigenesis.	('mutation', 'Var', (29, 37))	('p53', 'Gene', (8, 11))	('mutations', 'Var', (186, 195))	('rat', 'Species', '10116', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('Loss', 'NegReg', (0, 4))	('rat', 'Species', '10116', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('increased', 'PosReg', (112, 121))	('proliferation', 'CPA', (122, 135))	('tumor', 'Disease', (207, 212))	('genomic instability', 'CPA', (137, 156))	('alterations', 'Var', (41, 52))
5748	32295632	Currently, tumors are most typically bifurcated into p53-WT and p53-mutant groups, but this is an oversimplification.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('p53-mutant', 'Var', (64, 74))	('WT', 'Disease', 'MESH:C536751', (57, 59))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))
5757	32295632	p53 directly regulates the long non-coding RNA X-inactivation specific transcript (Xist), which is a primary effector of X-inactivation, and the loss of p53 decreases Xist expression.	('Xist', 'Gene', (83, 87))	('Xist', 'Gene', '7503', (167, 171))	('long', 'MPA', (27, 31))	('loss', 'Var', (145, 149))	('expression', 'MPA', (172, 182))	('regulates', 'Reg', (13, 22))	('p53', 'Gene', (153, 156))	('Xist', 'Gene', '7503', (83, 87))	('Xist', 'Gene', (167, 171))	('decreases', 'NegReg', (157, 166))
5758	32295632	Sex differences in birth defects in p53 mutant mice may also be related to a sexually dimorphic role for p53 in epigenetic imprinting.	('birth defects', 'Disease', (19, 32))	('p53', 'Gene', (36, 39))	('birth defects', 'Disease', 'MESH:D000014', (19, 32))	('mutant', 'Var', (40, 46))	('mice', 'Species', '10090', (47, 51))
5762	32295632	Kim and Casaccia-Bonnefil found that as mice mature, the number of neural progenitor cells in the SVZ decreases faster in males than in females; deletion of p53 eliminated this sex difference.	('mice', 'Species', '10090', (40, 44))	('decreases', 'NegReg', (102, 111))	('p53', 'Gene', (157, 160))	('deletion', 'Var', (145, 153))
5766	32295632	LFS is a familial cancer predisposition syndrome associated with germline mutations in p53.	('familial cancer', 'Disease', 'MESH:D009369', (9, 24))	('LFS', 'Disease', (0, 3))	('germline mutations', 'Var', (65, 83))	('p53', 'Gene', (87, 90))	('associated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('LFS', 'Disease', 'MESH:D016864', (0, 3))	('familial cancer', 'Disease', (9, 24))
5769	32295632	Even when controlling for the high rate of female breast cancer, multiple LFS family cohort studies have concluded that female mutant p53 carriers have an increased risk of developing cancer compared to male carriers.	('mutant', 'Var', (127, 133))	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('rat', 'Species', '10116', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('LFS', 'Disease', 'MESH:D016864', (74, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('p53', 'Gene', (134, 137))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('LFS', 'Disease', (74, 77))
5770	32295632	Importantly, the numbers of mutant p53 carriers were equivalent between males and females, suggesting that males and females have differential responses to the same mutations in p53, leading to greater risk of cancer development in females.	('men', 'Species', '9606', (224, 227))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('mutations', 'Var', (165, 174))	('p53', 'Gene', (178, 181))	('greater', 'PosReg', (194, 201))	('cancer', 'Disease', (210, 216))
5771	32295632	They observed that mutant p53 carriers exhibited a male bias in cancer incidence that matched the male bias in incidence observed in individuals with sporadic p53 mutations.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('p53', 'Gene', (26, 29))	('mutant', 'Var', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
5773	32295632	Pediatric ACC is a rare cancer (0.72/million/year in the USA) and is strongly associated with mutations in p53.	('associated', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (94, 103))	('p53', 'Gene', (107, 110))	('Pediatric ACC', 'Disease', (0, 13))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('ACC', 'Phenotype', 'HP:0006744', (10, 13))
5774	32295632	Because many of these patients are prepubescent, these data provide further support that males and females respond differently to p53 mutations in a tissue-specific manner, and that these differential responses cannot be explained by the effects of circulating sex hormones.	('patients', 'Species', '9606', (22, 30))	('mutations', 'Var', (134, 143))	('p53', 'Gene', (130, 133))
5775	32295632	The p53 pathway, encompassing p53 and its upstream regulators, is mutated in approximately 84% of primary GBM tumors.	('p53 pathway', 'Pathway', (4, 15))	('mutated', 'Var', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))
5784	32295632	In many tumors with WTp53, the p53 pathway is suppressed through amplification and overexpression of Mdm2.	('p53 pathway', 'Pathway', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('suppressed', 'NegReg', (46, 56))	('overexpression', 'PosReg', (83, 97))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('amplification', 'Var', (65, 78))	('Mdm2', 'Gene', (101, 105))
5786	32295632	The T/G allele drives an estrogen-dependent increase in cancer risk in females.	('T/G', 'Var', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('increase', 'PosReg', (44, 52))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
5787	32295632	This increased rate of non-expressed mutations occurred more frequently in p53 pathway linked-genes than unaffiliated genes, suggesting that females may be able to protect the p53 pathway through selective inactivation of mutant genes on the X-chromosome.	('mutant genes', 'Var', (222, 234))	('rat', 'Species', '10116', (15, 18))	('inactivation', 'NegReg', (206, 218))	('p53 pathway', 'Pathway', (176, 187))
5789	32295632	Each of these methods is based on the observation that WTp53 is induced in response to oncogenic stress, so that reactivation of the p53 pathway may slow or eliminate cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('reactivation', 'Var', (113, 125))	('eliminate', 'NegReg', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('slow', 'NegReg', (149, 153))	('p53 pathway', 'Pathway', (133, 144))
5817	32295632	When the damage is determined as irreparable, DDR kinases upregulate the p53-p21 and p16INK4a-Rb pathways, resulting in either senescence or apoptosis.	('p16INK4a-Rb pathways', 'Pathway', (85, 105))	('upregulate', 'PosReg', (58, 68))	('DDR', 'Chemical', '-', (46, 49))	('senescence', 'CPA', (127, 137))	('apoptosis', 'CPA', (141, 150))	('DDR kinases', 'Var', (46, 57))
5850	32295632	Additionally, there exists a large sex disparity in lung cancer oncogenesis following epithelial Stat3 deletion in mice with induced mutant K-ras.	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('oncogenesis', 'CPA', (64, 75))	('Stat3', 'Gene', (97, 102))	('Stat3', 'Gene', '20848', (97, 102))	('lung cancer', 'Disease', (52, 63))	('K-ras', 'Gene', (140, 145))	('K-ras', 'Gene', '16653', (140, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mice', 'Species', '10090', (115, 119))	('mutant', 'Var', (133, 139))	('deletion', 'Var', (103, 111))
5851	32295632	In males, the absence of epithelial STAT3 promotes lung tumorigenesis via enhanced IL-6 signaling and neutrophilic inflammation, which is inhibited in females by estrogen signaling.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('neutrophilic inflammation', 'Disease', 'MESH:D007249', (102, 127))	('tumor', 'Disease', (56, 61))	('STAT3', 'Gene', '20848', (36, 41))	('neutrophilic inflammation', 'Disease', (102, 127))	('promotes', 'PosReg', (42, 50))	('STAT3', 'Gene', (36, 41))	('enhanced', 'PosReg', (74, 82))	('IL-6', 'Gene', (83, 87))	('IL-6', 'Gene', '16193', (83, 87))	('epithelial', 'Gene', (25, 35))	('absence', 'Var', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
5857	32295632	These include IFN-gamma, IFI6, CX3CL1, CX3CL2, IL-1, IL-5, and IL-16.	('IL-5', 'Gene', (53, 57))	('IL-1', 'Gene', (63, 67))	('IFN-gamma', 'Gene', (14, 23))	('IL-16', 'Gene', (63, 68))	('CX3CL1', 'Gene', (31, 37))	('IL-1', 'Gene', '3552', (63, 67))	('IFN-gamma', 'Gene', '3458', (14, 23))	('CX3CL1', 'Gene', '6376', (31, 37))	('IFI6', 'Gene', '2537', (25, 29))	('IL-16', 'Gene', '3603', (63, 68))	('IFI6', 'Gene', (25, 29))	('IL-1', 'Gene', '3552', (47, 51))	('IL-1', 'Gene', (47, 51))	('CX3CL2', 'Var', (39, 45))	('IL-5', 'Gene', '3567', (53, 57))
5880	32295632	Furthermore, PD-L1 expression has been shown to be modulated by several X-linked micro-RNAs (miRNAs), such as miR-221, miR-222, miR106b, miR-20b, and miR-513.	('miR-221', 'Gene', (110, 117))	('expression', 'MPA', (19, 29))	('miR-513', 'Var', (150, 157))	('miR106b', 'Gene', (128, 135))	('miR-222', 'Gene', '407007', (119, 126))	('miR106b', 'Gene', '406900', (128, 135))	('miR-20b', 'Gene', '574032', (137, 144))	('miR-222', 'Gene', (119, 126))	('PD-L1', 'Gene', (13, 18))	('miR-221', 'Gene', '407006', (110, 117))	('miR-20b', 'Gene', (137, 144))	('modulated', 'Reg', (51, 60))	('PD-L1', 'Gene', '29126', (13, 18))
5929	32295632	While completely randomized treatment assignments among a cohort of mice of both sexes is a valid approach to study an interaction effect, deviation from balanced treatment assignments to the two sexes will critically reduce the efficiency of detecting interactions.	('men', 'Species', '9606', (179, 182))	('mice', 'Species', '10090', (68, 72))	('reduce', 'NegReg', (218, 224))	('deviation', 'Var', (139, 148))	('men', 'Species', '9606', (44, 47))	('men', 'Species', '9606', (168, 171))	('men', 'Species', '9606', (33, 36))	('interactions', 'Interaction', (253, 265))
5961	32295632	Work in the Klein lab is supported by NIH grants U19 AI083019 (RSK), R01 NS052632 (RSK), and R01 AI101400 (RSK) and National Society of Multiple Sclerosis (RSK).	('RSK', 'Gene', '6196', (156, 159))	('Multiple Sclerosis', 'Disease', 'MESH:D009103', (136, 154))	('RSK', 'Gene', (63, 66))	('RSK', 'Gene', '6196', (107, 110))	('R01 NS052632', 'Var', (69, 81))	('RSK', 'Gene', (107, 110))	('Multiple Sclerosis', 'Disease', (136, 154))	('RSK', 'Gene', (83, 86))	('RSK', 'Gene', (156, 159))	('U19 AI083019', 'Var', (49, 61))	('RSK', 'Gene', '6196', (63, 66))	('RSK', 'Gene', '6196', (83, 86))	('R01 AI101400', 'Var', (93, 105))
5979	31533818	Single-agent pembrolizumab has modest efficacy as a salvage therapy in ACC regardless of the tumor's hormonal function, microsatellite instability status, or programmed cell death ligand-1 status.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ACC', 'Phenotype', 'HP:0006744', (71, 74))	('tumor', 'Disease', (93, 98))	('ACC', 'Disease', (71, 74))	('microsatellite instability', 'Var', (120, 146))	('ACC', 'Disease', 'MESH:D018268', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
5991	31533818	In the past decade, cancer therapy has undergone a major change since the introduction of immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 monoclonal antibodies.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('anti-PD-1', 'Var', (127, 136))	('PD-L1', 'Gene', '29126', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('PD-L1', 'Gene', (146, 151))
5995	31533818	However, published data on pembrolizumab use in ACC are limited to two case reports including three patients; one complete response (CR) was seen in a patient who carried the MSH2 mutation.	('ACC', 'Disease', (48, 51))	('MSH2', 'Gene', (175, 179))	('MSH2', 'Gene', '4436', (175, 179))	('patient', 'Species', '9606', (151, 158))	('ACC', 'Disease', 'MESH:D018268', (48, 51))	('patient', 'Species', '9606', (100, 107))	('patients', 'Species', '9606', (100, 108))	('ACC', 'Phenotype', 'HP:0006744', (48, 51))	('mutation', 'Var', (180, 188))
6062	31533818	Only 3-5% of patients with ACC carry germline MSI-H/dMMR mutations.	('MSI', 'Gene', (46, 49))	('patients', 'Species', '9606', (13, 21))	('ACC', 'Disease', 'MESH:D018268', (27, 30))	('MSI', 'Gene', '5928', (46, 49))	('mutations', 'Var', (57, 66))	('ACC', 'Phenotype', 'HP:0006744', (27, 30))	('ACC', 'Disease', (27, 30))
6063	31533818	Data on pembrolizumab use in ACC with MSH2 mutation are limited to two reported cases, and only one patient had a CR.	('mutation', 'Var', (43, 51))	('ACC', 'Phenotype', 'HP:0006744', (29, 32))	('MSH2', 'Gene', (38, 42))	('MSH2', 'Gene', '4436', (38, 42))	('patient', 'Species', '9606', (100, 107))	('ACC', 'Disease', (29, 32))	('ACC', 'Disease', 'MESH:D018268', (29, 32))
6097	29935265	LFS is associated with germline mutations of the tumor suppressor gene p53 (TP53), which is implicated in cell proliferation, apoptosis, and genomic stability.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('germline mutations', 'Var', (23, 41))	('LFS', 'Disease', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TP53', 'Gene', '7157', (76, 80))	('associated', 'Reg', (7, 17))	('tumor', 'Disease', (49, 54))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('TP53', 'Gene', (76, 80))
6100	29935265	As many as 1:5000 individuals have TP53 germline mutations, which are familial; these are currently being identified more commonly due to increasing use of genetic screens.	('man', 'Species', '9606', (3, 6))	('TP53', 'Gene', '7157', (35, 39))	('germline mutations', 'Var', (40, 58))	('TP53', 'Gene', (35, 39))
6101	29935265	Carriers of TP53 gene mutation have the following probabilities of developing cancer: approximately 40% by age 20, more than 90% by age 70, and an 83-fold increased risk of developing multiple malignancies.	('malignancies', 'Disease', (193, 205))	('mutation', 'Var', (22, 30))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('TP53', 'Gene', '7157', (12, 16))	('malignancies', 'Disease', 'MESH:D009369', (193, 205))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('TP53', 'Gene', (12, 16))
6124	29935265	Further genetic testing showed heterozygous change from thymine to adenine at nucleotide 712 and missense mutation from cysteine to serine at codon 238 in the p53 gene.	('change', 'Reg', (44, 50))	('cysteine to serine at codon 238', 'Mutation', 'rs730882005', (120, 151))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('adenine', 'Chemical', 'MESH:D000225', (67, 74))	('thymine', 'Chemical', 'MESH:D013941', (56, 63))	('missense mutation from', 'Var', (97, 119))
6148	29935265	Sequencing revealed the presence of a germline mutation (codon 1009C>T, protein Arg337Cys, exon 10 of TP53 gene) in both this patient and his nephew who died at the age of 20 from bone sarcoma.	('bone sarcoma', 'Phenotype', 'HP:0002669', (180, 192))	('TP53', 'Gene', (102, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('Arg337Cys', 'Var', (80, 89))	('1009C>T', 'SUBSTITUTION', 'None', (63, 70))	('patient', 'Species', '9606', (126, 133))	('1009C>T', 'Var', (63, 70))	('bone sarcoma', 'Disease', (180, 192))	('Arg337Cys', 'SUBSTITUTION', 'None', (80, 89))	('TP53', 'Gene', '7157', (102, 106))	('bone sarcoma', 'Disease', 'MESH:D001847', (180, 192))
6151	29935265	TP53 mutation was found in 80% of patients with ACC younger than 18-years-old.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (34, 42))	('found', 'Reg', (18, 23))	('ACC', 'Phenotype', 'HP:0006744', (48, 51))	('mutation', 'Var', (5, 13))
6154	29935265	Although common GU malignancies were not associated with the TP53 syndrome (with the exception of ACC), the authors could not exclude the possibility of increased risk of these cancers in TP53 mutation carriers exposed to environmental carcinogens such as tobacco or other genetic factors.	('tobacco', 'Species', '4097', (256, 263))	('malignancies', 'Disease', (19, 31))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('GU malignancies', 'Phenotype', 'HP:0007379', (16, 31))	('mutation', 'Var', (193, 201))	('ACC', 'Phenotype', 'HP:0006744', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('TP53', 'Gene', '7157', (188, 192))	('malignancies', 'Disease', 'MESH:D009369', (19, 31))	('TP53', 'Gene', (188, 192))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
6157	29935265	The rationale for surgical management of cancers in LFS patients with good performance status and adequate life expectancy resided in the relative radio- and chemo-resistance conferred to cancers by TP53 mutations, which render p53 dysfunctional.	('patients', 'Species', '9606', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('TP53', 'Gene', (199, 203))	('mutations', 'Var', (204, 213))	('dysfunctional', 'MPA', (232, 245))	('p53', 'Gene', (228, 231))	('p53', 'Gene', '7157', (228, 231))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('man', 'Species', '9606', (27, 30))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('TP53', 'Gene', '7157', (199, 203))	('cancers', 'Disease', (41, 48))	('man', 'Species', '9606', (81, 84))
6159	29935265	Additionally, defective DNA repair due to mutant p53 increases the risk of radiation- and chemotherapy-induced malignancies in these patients.	('mutant', 'Var', (42, 48))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('radiation-', 'CPA', (75, 85))	('patients', 'Species', '9606', (133, 141))	('DNA repair', 'MPA', (24, 34))	('defective', 'NegReg', (14, 23))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('increases', 'PosReg', (53, 62))	('malignancies', 'Disease', (111, 123))
6161	29935265	It is currently not clear whether increased screening for TP53 mutation carriers would have an overall beneficial effect.	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (58, 62))	('mutation', 'Var', (63, 71))
6167	29935265	At these institutions, consenting adult patients undergoing TP53 mutation screening should be provided with high-quality information and counseling, and made aware of their right to decide whether or not to have the genetic data disclosed to them.	('patients', 'Species', '9606', (40, 48))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('mutation', 'Var', (65, 73))
6169	29935265	However, in recent studies, genetic counseling and mutation testing, including TP53 mutation testing, have shown benefits in young patients with osteosarcoma and history of cancer in close relatives, and also in children and adolescents with cancer and a negative family history of malignancy.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('osteosarcoma', 'Phenotype', 'HP:0002669', (145, 157))	('mutation', 'Var', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('TP53', 'Gene', '7157', (79, 83))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('malignancy', 'Disease', 'MESH:D009369', (282, 292))	('patients', 'Species', '9606', (131, 139))	('cancer', 'Disease', (173, 179))	('mutation testing', 'Var', (84, 100))	('malignancy', 'Disease', (282, 292))	('benefits', 'PosReg', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('children', 'Species', '9606', (212, 220))	('osteosarcoma', 'Disease', (145, 157))	('osteosarcoma', 'Disease', 'MESH:D012516', (145, 157))	('cancer', 'Disease', (242, 248))	('TP53', 'Gene', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
6171	29935265	Although reliable screening tests for other LFS-related malignancies have yet to be established , the utilization of one such protocol resulted in a durable 3-year survival advantage of 100% vs. 21% (95% confidence interval 4-48%, p= .0155), for 7 TP53 mutation carriers with asymptomatic tumors who underwent surveillance compared to 10 individuals in the non-surveillance group who developed high-stage cancers.	('TP53', 'Gene', '7157', (248, 252))	('mutation', 'Var', (253, 261))	('advantage', 'PosReg', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('TP53', 'Gene', (248, 252))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('cancers', 'Phenotype', 'HP:0002664', (405, 412))	('tumors', 'Disease', (289, 295))	('cancers', 'Disease', (405, 412))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('cancers', 'Disease', 'MESH:D009369', (405, 412))	('malignancies', 'Disease', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (405, 411))
6180	29935265	Other strategies aiming at the degradation or inhibition of aggregation of mutant TP53, or the reactivation of wild-type functions in mutant TP53, are pending clinical investigation in LFS patients with solid tumors.	('TP53', 'Gene', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('aggregation', 'MPA', (60, 71))	('solid tumors', 'Disease', (203, 215))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('mutant', 'Var', (75, 81))	('TP53', 'Gene', '7157', (82, 86))	('patients', 'Species', '9606', (189, 197))	('solid tumors', 'Disease', 'MESH:D009369', (203, 215))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
6184	29935265	Although definitive associations between common GU malignancies and LFS have not been elucidated to date, the concomitant presence of TP53 mutations, environmental carcinogens, and other genetic factors might increase the risk of developing GU malignancies in carriers.	('GU malignancies', 'Phenotype', 'HP:0007379', (241, 256))	('TP53', 'Gene', (134, 138))	('presence', 'Reg', (122, 130))	('mutations', 'Var', (139, 148))	('malignancies', 'Disease', 'MESH:D009369', (51, 63))	('malignancies', 'Disease', 'MESH:D009369', (244, 256))	('GU malignancies', 'Phenotype', 'HP:0007379', (48, 63))	('malignancies', 'Disease', (51, 63))	('malignancies', 'Disease', (244, 256))	('TP53', 'Gene', '7157', (134, 138))	('increase', 'PosReg', (209, 217))
6187	31508193	In southern Brazil, one form of Li-Fraumeni syndrome, associated with childhood adrenocortical carcinoma, is caused by a mutation in the R337H TP53 tetramerisation domain and is attributed to a familial founder effect.	('adrenocortical carcinoma', 'Disease', (80, 104))	('TP53', 'Gene', (143, 147))	('R337H', 'Var', (137, 142))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (32, 52))	('R337H', 'Mutation', 'rs121912664', (137, 142))	('caused by', 'Reg', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('Li-Fraumeni syndrome', 'Disease', (32, 52))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (80, 104))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (80, 104))	('TP53', 'Gene', '7157', (143, 147))	('associated', 'Reg', (54, 64))
6191	31508193	The presence of the R337H TP53 mutation suggests a mechanism for the observed response to metformin.	('TP53', 'Gene', (26, 30))	('R337H', 'Mutation', 'rs121912664', (20, 25))	('R337H', 'Var', (20, 25))	('response', 'MPA', (78, 86))	('TP53', 'Gene', '7157', (26, 30))	('metformin', 'Chemical', 'MESH:D008687', (90, 99))
6195	31508193	Recognizing a 10-fold higher incidence of ACC in southern Brazil, Ribeiro and co-investigators identified a unique germ-line mutation in TP53 that encodes for an arginine to histidine amino acid substitution at position 337.	('arginine to histidine amino acid substitution at position 337', 'Mutation', 'rs121912664', (162, 223))	('arginine', 'Var', (162, 170))	('TP53', 'Gene', '7157', (137, 141))	('ACC', 'Phenotype', 'HP:0006744', (42, 45))	('encodes for', 'Reg', (147, 158))	('mutation', 'Var', (125, 133))	('TP53', 'Gene', (137, 141))
6196	31508193	Unlike the more common TP53 mutations that cluster in the DNA binding and transactivational domains, the R337H mutation occurs in the tetramerisation domain resulting in a conditional mutant protein whose function is pH dependent.	('TP53', 'Gene', (23, 27))	('protein', 'Protein', (191, 198))	('TP53', 'Gene', '7157', (23, 27))	('R337H', 'Var', (105, 110))	('R337H', 'Mutation', 'rs121912664', (105, 110))
6231	31508193	The reference sequences of the detected genes were NM_000546.5 (TP53) and NM_007194.3 (CHEK2).	('NM_000546.5', 'Var', (51, 62))	('CHEK2', 'Gene', (87, 92))	('NM_007194.3', 'Var', (74, 85))	('CHEK2', 'Gene', '11200', (87, 92))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))
6241	31508193	Patients in the EDP-mitotane group achieved a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs 9.2%, p < 0.001) and longer median progression-free survival (5.0 months vs 2.1 months, p < 0.001), although there was no significant difference in overall survival between the groups (14.8 months vs 12.0 months, p = 0.07).	('EDP-mitotane', 'Var', (16, 28))	('higher', 'PosReg', (60, 66))	('longer', 'PosReg', (158, 164))	('streptozocin-mitotane', 'Chemical', '-', (99, 120))	('response', 'CPA', (67, 75))	('progression-free survival', 'CPA', (172, 197))	('EDP-mitotane', 'Chemical', '-', (16, 28))	('Patients', 'Species', '9606', (0, 8))
6245	31508193	Other pathways such as those involving fibroblast growth factor receptor (FGFR) and Wnt-beta-catenin signaling cascades and loss of p53 function have been implicated in ACC tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('loss', 'Var', (124, 128))	('ACC', 'Phenotype', 'HP:0006744', (169, 172))	('p53', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('beta-catenin', 'Gene', (88, 100))	('implicated', 'Reg', (155, 165))	('beta-catenin', 'Gene', '1499', (88, 100))
6259	31508193	Although the mechanisms of action of metformin are not fully understood, it has been suggested that inhibition of mitochondrial complex I may downregulate mTOR via the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK).	('adenosine monophosphate', 'Chemical', 'MESH:D000249', (182, 205))	('metformin', 'Chemical', 'MESH:D008687', (37, 46))	('AMP', 'Chemical', 'MESH:D000249', (238, 241))	('AMP', 'Chemical', 'MESH:D000249', (207, 210))	('mTOR', 'MPA', (155, 159))	('inhibition', 'Var', (100, 110))	('adenosine monophosphate', 'MPA', (182, 205))	('activation', 'PosReg', (168, 178))	('mitochondrial complex I', 'Enzyme', (114, 137))	('downregulate', 'NegReg', (142, 154))
6262	31508193	In cell culture, metformin inhibits the proliferation of a range of cancer cells including breast, endometrial, ovarian, prostate, colon, pancreatic, gastric, and glioma.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('glioma', 'Disease', (163, 169))	('colon', 'Disease', 'MESH:D015179', (131, 136))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('colon', 'Disease', (131, 136))	('proliferation', 'CPA', (40, 53))	('pancreatic', 'Disease', 'MESH:D010195', (138, 148))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('breast', 'Disease', (91, 97))	('gastric', 'Disease', (150, 157))	('inhibits', 'NegReg', (27, 35))	('pancreatic', 'Disease', (138, 148))	('metformin', 'Var', (17, 26))	('metformin', 'Chemical', 'MESH:D008687', (17, 26))	('ovarian', 'Disease', (112, 119))	('ovarian', 'Disease', 'MESH:D010051', (112, 119))	('endometrial', 'Disease', (99, 110))	('cancer', 'Disease', (68, 74))	('prostate', 'Disease', (121, 129))
6263	31508193	The effects of metformin on cancer cell proliferation are associated with AMPK activation, reduced mammalian target of rapamycin (mTOR) signaling, and protein synthesis, as well as a variety of other responses including decreased EGFR, Src, and mitogen-activated protein kinase (MAPK) activation, decreased expression of cyclins, and increased expression of p27.	('EGFR', 'Gene', '1956', (230, 234))	('MAPK', 'Gene', '26413;26417', (279, 283))	('AMPK', 'MPA', (74, 78))	('expression', 'MPA', (344, 354))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('Src', 'Gene', (236, 239))	('cyclins', 'Protein', (321, 328))	('MAPK', 'Gene', (279, 283))	('activation', 'PosReg', (79, 89))	('Src', 'Gene', '6714', (236, 239))	('EGFR', 'Gene', (230, 234))	('decreased', 'NegReg', (220, 229))	('p27', 'Gene', '10534', (358, 361))	('mammalian target of rapamycin', 'Gene', '2475', (99, 128))	('AMP', 'Chemical', 'MESH:D000249', (74, 77))	('metformin', 'Var', (15, 24))	('cancer', 'Disease', (28, 34))	('activation', 'PosReg', (285, 295))	('metformin', 'Chemical', 'MESH:D008687', (15, 24))	('increased', 'PosReg', (334, 343))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mammalian target of rapamycin', 'Gene', (99, 128))	('p27', 'Gene', (358, 361))	('reduced', 'NegReg', (91, 98))	('decreased', 'NegReg', (297, 306))	('protein synthesis', 'MPA', (151, 168))	('expression', 'MPA', (307, 317))
6267	31508193	In a mouse model of LFS that expresses mutant p53, metformin inhibited OXPHOS mitochondrial respiration, providing an intriguing evidence of how this drug may operate in inhibiting cancer progression in p53-inactivated tumors related to LFS.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('inhibited', 'NegReg', (61, 70))	('OXPHOS mitochondrial respiration', 'MPA', (71, 103))	('tumors', 'Disease', (219, 225))	('LFS', 'Disease', (20, 23))	('LFS', 'Disease', (237, 240))	('p53', 'Gene', (46, 49))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('LFS', 'Disease', 'MESH:D016864', (20, 23))	('mouse', 'Species', '10090', (5, 10))	('metformin', 'Chemical', 'MESH:D008687', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('mutant', 'Var', (39, 45))	('LFS', 'Disease', 'MESH:D016864', (237, 240))	('cancer', 'Disease', (181, 187))	('inhibiting', 'NegReg', (170, 180))
6268	31508193	Mechanistically, inhibition of mitochondrial function in this mouse model increased autophagy and decreased the aberrant proliferation signaling caused by mutant p53.	('aberrant', 'MPA', (112, 120))	('mouse', 'Species', '10090', (62, 67))	('p53', 'Gene', (162, 165))	('mitochondrial function', 'CPA', (31, 53))	('mutant', 'Var', (155, 161))	('increased', 'PosReg', (74, 83))	('autophagy', 'CPA', (84, 93))	('decreased', 'NegReg', (98, 107))
6270	31508193	They used nutlin-3a and CP/31398 to reactivate p53 and enhance the anti-tumor effect of metformin.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('metformin', 'Chemical', 'MESH:D008687', (88, 97))	('tumor', 'Disease', (72, 77))	('enhance', 'PosReg', (55, 62))	('p53', 'Protein', (47, 50))	('reactivate', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
6275	31508193	In H295R, metformin was shown to induce inhibition of extracellular-signal-regulated kinase (ERK) 1/2 and mTOR, associated with the stimulation of AMPK that led to apoptosis as measured by Annexin V and caspase-3, a reduction in Ki-67 and growth inhibition in a xenograft mouse model.	('mouse', 'Species', '10090', (272, 277))	('Ki-67', 'Gene', '17345', (229, 234))	('Annexin V', 'Gene', (189, 198))	('growth inhibition', 'CPA', (239, 256))	('caspase-3', 'Gene', '12367', (203, 212))	('H295R', 'Var', (3, 8))	('inhibition', 'NegReg', (40, 50))	('apoptosis', 'CPA', (164, 173))	('reduction', 'NegReg', (216, 225))	('Annexin V', 'Gene', '11747', (189, 198))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))	('extracellular-signal-regulated kinase (ERK) 1/2', 'Gene', '26417;26413', (54, 101))	('H295R', 'CellLine', 'CVCL:0458', (3, 8))	('Ki-67', 'Gene', (229, 234))	('AMP', 'Chemical', 'MESH:D000249', (147, 150))	('mTOR', 'Gene', (106, 110))	('AMPK', 'MPA', (147, 151))	('caspase-3', 'Gene', (203, 212))
6276	31508193	Of interest, the H295R cell line carries p53 deletions in codons 8 and 9 that determine a frame shift at codon 261 resulting in a stop codon at position 271.	('deletions', 'Var', (45, 54))	('H295R', 'CellLine', 'CVCL:0458', (17, 22))	('p53', 'Gene', (41, 44))
6381	26676603	Indeed, we also noted that these 2 factors were strongly linked to outcomes because the risk of death was 3-fold higher among patients with an R1 margin, and the risk of recurrence was 2-fold higher among patients with stage III/IV disease.	('patients', 'Species', '9606', (205, 213))	('higher', 'PosReg', (113, 119))	('death', 'Disease', 'MESH:D003643', (96, 101))	('IV disease', 'Disease', (229, 239))	('patients', 'Species', '9606', (126, 134))	('IV disease', 'Disease', 'MESH:D020432', (229, 239))	('death', 'Disease', (96, 101))	('R1 margin', 'Var', (143, 152))
6464	27486349	In contrast to steroidogenesis inhibitors, which inhibit steroidogenesis in both abnormal and normal adrenocortical tissue, mifepristone does not affect adrenal steroidogenesis because it acts at the glucocorticoid receptor level.	('glucocorticoid receptor', 'Gene', (200, 223))	('steroid', 'Chemical', 'MESH:D013256', (57, 64))	('adrenal', 'MPA', (153, 160))	('mifepristone', 'Chemical', 'MESH:D015735', (124, 136))	('steroid', 'Chemical', 'MESH:D013256', (161, 168))	('glucocorticoid receptor', 'Gene', '2908', (200, 223))	('mifepristone', 'Var', (124, 136))	('steroid', 'Chemical', 'MESH:D013256', (15, 22))
6465	27486349	In addition, by antagonizing the glucocorticoid receptor at the pituitary and the hypothalamus level, mifepristone may significantly expedite the recovery of the HPA axis.	('glucocorticoid receptor', 'Gene', '2908', (33, 56))	('expedite', 'PosReg', (133, 141))	('glucocorticoid receptor', 'Gene', (33, 56))	('hypothalamus', 'Disease', (82, 94))	('mifepristone', 'Var', (102, 114))	('recovery', 'CPA', (146, 154))	('hypothalamus', 'Disease', 'MESH:D007029', (82, 94))	('antagonizing', 'NegReg', (16, 28))	('HPA axis', 'CPA', (162, 170))	('mifepristone', 'Chemical', 'MESH:D015735', (102, 114))
6466	27486349	Fleseriu et al showed that the use of mifepristone in patients with Cushing's disease was associated with a mean 2.76-fold rise in ACTH from baseline that returned back to baseline within a month upon discontinuation of mifepristone therapy.	('mifepristone', 'Chemical', 'MESH:D015735', (38, 50))	('ACTH', 'Gene', (131, 135))	("Cushing's disease", 'Disease', (68, 85))	('ACTH', 'Gene', '5443', (131, 135))	('patients', 'Species', '9606', (54, 62))	('mifepristone', 'Var', (38, 50))	('rise', 'PosReg', (123, 127))	('mifepristone', 'Chemical', 'MESH:D015735', (220, 232))	("Cushing's disease", 'Disease', 'MESH:D003480', (68, 85))
6485	27486349	It is important to note that patients receiving mifepristone may experience cortisol withdrawal symptoms or symptoms of excessive glucocorticoid receptor antagonism, such as nausea, fatigue, and decreased appetite.	('nausea', 'Phenotype', 'HP:0002018', (174, 180))	('patients', 'Species', '9606', (29, 37))	('nausea', 'Disease', (174, 180))	('nausea', 'Disease', 'MESH:D009325', (174, 180))	('withdrawal symptoms', 'Disease', (85, 104))	('glucocorticoid receptor', 'Gene', '2908', (130, 153))	('decreased appetite', 'Phenotype', 'HP:0004396', (195, 213))	('fatigue', 'Phenotype', 'HP:0012378', (182, 189))	('decreased', 'NegReg', (195, 204))	('fatigue', 'Disease', (182, 189))	('mifepristone', 'Chemical', 'MESH:D015735', (48, 60))	('glucocorticoid receptor', 'Gene', (130, 153))	('glucocorticoid receptor antagonism', 'Phenotype', 'HP:0008163', (130, 164))	('appetite', 'Disease', (205, 213))	('cortisol', 'Chemical', 'MESH:D006854', (76, 84))	('withdrawal symptoms', 'Disease', 'MESH:D013375', (85, 104))	('mifepristone', 'Var', (48, 60))
6496	31263451	MEN1 is caused by inactivating mutations of the tumor suppressor gene MEN1 which encodes the protein menin.	('menin', 'Gene', '4221', (101, 106))	('MEN1', 'Gene', '4221', (0, 4))	('tumor', 'Disease', (48, 53))	('inactivating mutations', 'Var', (18, 40))	('caused by', 'Reg', (8, 17))	('menin', 'Gene', (101, 106))	('MEN1', 'Gene', (70, 74))	('MEN1', 'Gene', '4221', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('MEN1', 'Gene', (0, 4))
6500	31263451	Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary tumor syndrome with a high degree of penetrance, that is caused by inactivating mutations of the tumor suppressor gene MEN1, and is characterized by a predisposition to a multitude of endocrine and nonendocrine tumors.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Disease', (83, 88))	('Multiple endocrine neoplasia type 1', 'Gene', '4221', (0, 35))	('neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('nonendocrine tumors', 'Disease', (281, 300))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('autosomal dominant hereditary tumor syndrome', 'Disease', 'MESH:D030342', (53, 97))	('nonendocrine tumors', 'Disease', 'MESH:D009369', (281, 300))	('MEN1', 'Gene', '4221', (37, 41))	('MEN1', 'Gene', '4221', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Multiple endocrine neoplasia type 1', 'Gene', (0, 35))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (9, 28))	('MEN1', 'Gene', (37, 41))	('MEN1', 'Gene', (202, 206))	('inactivating mutations', 'Var', (150, 172))	('tumor', 'Disease', (294, 299))	('tumor', 'Disease', (180, 185))	('caused by', 'Reg', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('autosomal dominant hereditary tumor syndrome', 'Disease', (53, 97))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))
6520	31263451	More than 1,200 germline mutations in the MEN1 gene have been identified, which are scattered over the entire coding region of the gene without any significant hot spots or genotype-phenotype correlations.	('germline mutations', 'Var', (16, 34))	('MEN1', 'Gene', '4221', (42, 46))	('MEN1', 'Gene', (42, 46))
6521	31263451	The majority of MEN1 germline mutations (69%) are predicted to be pathogenic due to either premature truncation of menin due to frame-shift mutations (42%) and nonsense mutations (14%), or exon region deletions which are attributed to splicing defects (10.5%) and large deletions (2.5%).	('menin', 'Gene', '4221', (115, 120))	('exon region deletions', 'Var', (189, 210))	('frame-shift mutations', 'Var', (128, 149))	('menin', 'Gene', (115, 120))	('nonsense mutations', 'Var', (160, 178))	('germline mutations', 'Var', (21, 39))	('premature truncation', 'MPA', (91, 111))	('MEN1', 'Gene', (16, 20))	('MEN1', 'Gene', '4221', (16, 20))	('pathogenic', 'Reg', (66, 76))
6522	31263451	Other MEN1 germline mutations include missense mutations (25.5%) and single or few amino acid in-frame deletions or insertions (5.5%), which require further investigation to determine their pathogenicity.	('MEN1', 'Gene', (6, 10))	('missense mutations', 'Var', (38, 56))	('MEN1', 'Gene', '4221', (6, 10))
6523	31263451	Approximately 5-25% of patients with MEN1 may not have mutations in the MEN1 coding region.	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (23, 31))	('MEN1', 'Gene', (72, 76))	('MEN1', 'Gene', '4221', (72, 76))	('MEN1', 'Gene', (37, 41))	('MEN1', 'Gene', '4221', (37, 41))
6524	31263451	In addition, the occurrence of phenocopies, or patients that develop disease manifestations typically associated with mutations in the MEN1 gene but instead are due to another etiology, has been described in 5-10% of MEN1 kindreds.	('MEN1', 'Gene', (217, 221))	('MEN1', 'Gene', '4221', (217, 221))	('mutations', 'Var', (118, 127))	('patients', 'Species', '9606', (47, 55))	('MEN1', 'Gene', (135, 139))	('MEN1', 'Gene', '4221', (135, 139))
6527	31263451	This syndrome results from inactivating mutations of the tumor suppressor gene CDKNIB, that encodes the p27kip1 inhibitor of cyclin dependent kinase 2, with manifestations such as parathyroid and pituitary adenomas, neuroendocrine tumors and various benign, and malignant tumors.	('p27kip1', 'Gene', '1027', (104, 111))	('pituitary adenomas', 'Disease', 'MESH:D010911', (196, 214))	('p27kip1', 'Gene', (104, 111))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (216, 237))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (196, 214))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (196, 213))	('tumor', 'Disease', (272, 277))	('pituitary adenomas', 'Disease', (196, 214))	('inactivating mutations', 'Var', (27, 49))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (216, 236))	('cyclin dependent kinase 2', 'Gene', (125, 150))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (216, 237))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('results from', 'Reg', (14, 26))	('cyclin dependent kinase 2', 'Gene', '1017', (125, 150))	('malignant tumors', 'Disease', 'MESH:D018198', (262, 278))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('neuroendocrine tumors', 'Disease', (216, 237))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('CDKN', 'Gene', (79, 83))	('malignant tumors', 'Disease', (262, 278))	('CDKN', 'Gene', '1033', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))
6528	31263451	Less common germline mutations that may be identified in another 1-2% of phenocopies include those attributed to mutations in genes encoding additional members of the cyclin-dependent kinase inhibitor (CDKN) family, such as CDKN1A (P21cip1), CDKN2B (p15Ink4b), or CDKN2C (p18Ink4c).	('p18Ink4c', 'Gene', '1031', (272, 280))	('cyclin-dependent kinase inhibitor', 'Gene', (167, 200))	('mutations', 'Var', (113, 122))	('CDKN2C', 'Gene', (264, 270))	('p15Ink4b', 'Gene', (250, 258))	('p15Ink4b', 'Gene', '1030', (250, 258))	('CDKN', 'Gene', (202, 206))	('CDKN', 'Gene', '1033', (202, 206))	('CDKN1A', 'Gene', (224, 230))	('CDKN1A', 'Gene', '1026', (224, 230))	('cyclin-dependent kinase inhibitor', 'Gene', '1033', (167, 200))	('p18Ink4c', 'Gene', (272, 280))	('CDKN', 'Gene', (242, 246))	('CDKN2B', 'Gene', (242, 248))	('CDKN', 'Gene', '1033', (242, 246))	('CDKN2C', 'Gene', '1031', (264, 270))	('CDKN', 'Gene', (224, 228))	('CDKN', 'Gene', (264, 268))	('CDKN', 'Gene', '1033', (224, 228))	('CDKN', 'Gene', '1033', (264, 268))	('P21cip1', 'Gene', '1026', (232, 239))	('P21cip1', 'Gene', (232, 239))	('CDKN2B', 'Gene', '1030', (242, 248))
6531	31263451	Defects in AIP, which encodes the aryl hydrocarbon receptor interacting protein and is associated with familial isolated pituitary adenomas, should also be evaluated in children and adolescents with prolactinoma or somatotropinoma.	('prolactinoma', 'Phenotype', 'HP:0040278', (199, 211))	('isolated pituitary adenomas', 'Phenotype', 'HP:0011761', (112, 139))	('prolactinoma or somatotropinoma', 'Disease', 'MESH:D015175', (199, 230))	('Defects', 'Var', (0, 7))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (121, 139))	('aryl hydrocarbon receptor interacting protein', 'Gene', '9049', (34, 79))	('associated', 'Reg', (87, 97))	('children', 'Species', '9606', (169, 177))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (121, 138))	('AIP', 'Gene', (11, 14))	('aryl hydrocarbon receptor interacting protein', 'Gene', (34, 79))	('prolactinoma or somatotropinoma', 'Disease', (199, 230))	('familial isolated pituitary adenomas', 'Disease', (103, 139))	('familial isolated pituitary adenomas', 'Disease', 'MESH:C566321', (103, 139))
6532	31263451	Germline MEN1 mutations have also been noted in families with a parathyroid only disorder, familial isolated primary hyperparathyroidism, where there is a higher frequency of missense mutations compared to patients with the MEN1 syndrome.	('MEN1', 'Gene', (224, 228))	('parathyroid only disorder', 'Disease', (64, 89))	('familial isolated primary hyperparathyroidism', 'Disease', (91, 136))	('MEN1', 'Gene', '4221', (224, 228))	('parathyroid only disorder', 'Disease', 'MESH:D010279', (64, 89))	('primary hyperparathyroidism', 'Phenotype', 'HP:0008200', (109, 136))	('missense mutations', 'Var', (175, 193))	('MEN1 syndrome', 'Disease', (224, 237))	('MEN1', 'Gene', '4221', (9, 13))	('familial isolated primary hyperparathyroidism', 'Disease', 'MESH:C564166', (91, 136))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (117, 136))	('patients', 'Species', '9606', (206, 214))	('MEN1', 'Gene', (9, 13))	('MEN1 syndrome', 'Disease', 'MESH:D018761', (224, 237))	('parathyroid only disorder', 'Phenotype', 'HP:0011767', (64, 89))	('mutations', 'Var', (14, 23))
6533	31263451	Similarly, germline MEN1 mutations have been reported in 5 cases of "sporadic" pNETs.	('MEN1', 'Gene', (20, 24))	('mutations', 'Var', (25, 34))	('MEN1', 'Gene', '4221', (20, 24))	('reported', 'Reg', (45, 53))
6535	31263451	Patients with germline inactivating mutations in MEN1 demonstrate loss of heterozygosity (LOH) in more than 90% of their tumors, though LOH involving chromosome 11q13 has also been observed in 5-50% of sporadic endocrine tumors.	('loss', 'NegReg', (66, 70))	('MEN1', 'Gene', (49, 53))	('endocrine tumors', 'Disease', 'MESH:D004701', (211, 227))	('MEN1', 'Gene', '4221', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('endocrine tumors', 'Disease', (211, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('germline inactivating mutations', 'Var', (14, 45))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumors', 'Disease', (221, 227))
6536	31263451	Neoplasms develop (as described in Knudson's two-hit hypothesis), when a second somatic inactivating mutation occurs in one MEN1 allele in the setting of the preexisting germline inactivating mutation in the alternate allele.	('Neoplasms', 'Phenotype', 'HP:0002664', (0, 9))	('MEN1', 'Gene', (124, 128))	('MEN1', 'Gene', '4221', (124, 128))	('Neoplasms', 'Disease', 'MESH:D009369', (0, 9))	('mutation', 'Var', (101, 109))	('Neoplasms', 'Disease', (0, 9))
6540	31263451	Mutations in MEN1 that lead to premature protein truncation may lead to functional inactivation of menin through loss of one or both main NLSs.	('inactivation', 'NegReg', (83, 95))	('lead', 'Reg', (64, 68))	('one or both main NLSs', 'MPA', (121, 142))	('premature protein truncation', 'MPA', (31, 59))	('loss', 'NegReg', (113, 117))	('menin', 'Gene', '4221', (99, 104))	('functional', 'MPA', (72, 82))	('Mutations', 'Var', (0, 9))	('MEN1', 'Gene', '4221', (13, 17))	('menin', 'Gene', (99, 104))	('MEN1', 'Gene', (13, 17))
6545	31263451	In genetically engineered mouse models, germline targeted deletion of both copies of the Men1 gene leads to death in utero, whereas germline targeted deletion of one copy of the Men1 gene results in live mice that develop endocrine tumors similar to those in humans.	('death', 'Disease', 'MESH:D003643', (108, 113))	('endocrine tumors', 'Disease', (222, 238))	('Men1', 'Gene', '4221', (89, 93))	('Men1', 'Gene', '4221', (178, 182))	('Men1', 'Gene', (178, 182))	('Men1', 'Gene', (89, 93))	('deletion', 'Var', (150, 158))	('endocrine tumors', 'Disease', 'MESH:D004701', (222, 238))	('humans', 'Species', '9606', (259, 265))	('mouse', 'Species', '10090', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('mice', 'Species', '10090', (204, 208))	('death', 'Disease', (108, 113))	('develop', 'Reg', (214, 221))
6546	31263451	Screening for MEN1 mutations in the appropriate setting has several benefits including confirmation of the clinical diagnosis of MEN1, identification of family members that are carriers of MEN1 mutations, so that appropriate screening and/or treatment can be implemented, and identification of the 50% of family members that do not harbor a pathogenic mutation in MEN1 and thus do not require screening.	('MEN1', 'Gene', '4221', (364, 368))	('MEN1', 'Gene', '4221', (14, 18))	('men', 'Species', '9606', (264, 267))	('MEN1', 'Gene', (364, 368))	('MEN1', 'Gene', (189, 193))	('MEN1', 'Gene', (14, 18))	('MEN1', 'Gene', '4221', (189, 193))	('mutations', 'Var', (194, 203))	('mutations', 'Var', (19, 28))	('MEN1', 'Gene', (129, 133))	('MEN1', 'Gene', '4221', (129, 133))	('men', 'Species', '9606', (247, 250))
6547	31263451	Genetic testing for defects in the MEN1 gene currently includes PCR-based screening for mutations in the coding region and splice junctions.	('defects', 'Var', (20, 27))	('MEN1', 'Gene', (35, 39))	('mutations in', 'Var', (88, 100))	('MEN1', 'Gene', '4221', (35, 39))
6548	31263451	If a mutation is not identified by the aforementioned method, then multiplex ligation probe amplification (MLPA)-based screening is performed in order to detect large deletions of the MEN1 gene.	('men', 'Species', '9606', (44, 47))	('MEN1', 'Gene', (184, 188))	('MEN1', 'Gene', '4221', (184, 188))	('deletions', 'Var', (167, 176))
6551	31263451	MEN1 mutational analysis should be performed in index cases with two or more MEN1-associated endocrine tumors (parathyroid, pancreatic, or pituitary tumors), asymptomatic first-degree relatives of a known MEN1 mutation carrier, first-degree relatives of a MEN1 mutation carrier expressing familial MEN1 (in order to exclude phenocopies), and in patients with suspicious or atypical MEN1 (individuals with parathyroid adenomas occurring prior to 30 years of age or multi-gland parathyroid disease, gastrinoma, or multiple pNET at any age, or those who have at least two MEN1-associated tumors not part of the classical triad of parathyroid, entero-pancreatic, and anterior pituitary tumors) (Table 1).	('pancreatic', 'Disease', 'MESH:D010195', (647, 657))	('MEN1', 'Gene', '4221', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('MEN1', 'Gene', '4221', (205, 209))	('MEN1', 'Gene', (382, 386))	('mutation', 'Var', (210, 218))	('tumors', 'Disease', (103, 109))	('entero-pancreatic', 'Disease', 'MESH:D010195', (640, 657))	('tumors', 'Phenotype', 'HP:0002664', (585, 591))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (682, 687))	('MEN1', 'Gene', (256, 260))	('tumors', 'Disease', (682, 688))	('MEN1', 'Gene', (0, 4))	('gastrinoma', 'Disease', 'MESH:D015408', (497, 507))	('pancreatic', 'Disease', (124, 134))	('tumors', 'Phenotype', 'HP:0002664', (682, 688))	('tumor', 'Phenotype', 'HP:0002664', (585, 590))	('pancreatic', 'Disease', (647, 657))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('parathyroid adenomas', 'Phenotype', 'HP:0002897', (405, 425))	('tumors', 'Disease', (585, 591))	('MEN1', 'Gene', (205, 209))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (149, 155))	('pituitary tumors', 'Disease', 'MESH:D010911', (672, 688))	('multi-gland parathyroid disease', 'Disease', 'MESH:C564969', (464, 495))	('MEN1', 'Gene', '4221', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (682, 688))	('MEN1', 'Gene', '4221', (298, 302))	('patients', 'Species', '9606', (345, 353))	('MEN1', 'Gene', '4221', (569, 573))	('entero-pancreatic', 'Disease', (640, 657))	('parathyroid disease', 'Phenotype', 'HP:0000828', (476, 495))	('parathyroid adenomas', 'Disease', (405, 425))	('tumors', 'Disease', 'MESH:D009369', (585, 591))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('MEN1', 'Gene', '4221', (256, 260))	('parathyroid adenomas', 'Disease', 'MESH:D010282', (405, 425))	('pituitary tumors', 'Disease', 'MESH:D010911', (139, 155))	('MEN1', 'Gene', (77, 81))	('gastrinoma', 'Disease', (497, 507))	('MEN1', 'Gene', (298, 302))	('anterior pituitary tumors', 'Disease', (663, 688))	('MEN1', 'Gene', (569, 573))	('endocrine tumors', 'Disease', 'MESH:D004701', (93, 109))	('parathyroid adenoma', 'Phenotype', 'HP:0002897', (405, 424))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('anterior pituitary tumors', 'Disease', 'MESH:D010900', (663, 688))	('endocrine tumors', 'Disease', (93, 109))	('MEN1', 'Gene', '4221', (382, 386))	('multi-gland parathyroid disease', 'Disease', (464, 495))	('pituitary tumors', 'Disease', (139, 155))	('pancreatic', 'Disease', 'MESH:D010195', (124, 134))
6553	31263451	Per the most recent clinical practice guidelines, a patient can be diagnosed with MEN1 by meeting any one of the following three conditions: the occurrence of at least two primary MEN1-associated endocrine tumors (i.e., parathyroid adenoma, enteropancreatic tumor, and pituitary adenoma); the development of one MEN1-associated tumor in a first degree relative of a patient with a clinical diagnosis of MEN1; and the identification of a germline MEN1 mutation in an individual, who may be asymptomatic without biochemical or radiological evidence of MEN1.	('MEN1', 'Gene', (446, 450))	('patient', 'Species', '9606', (366, 373))	('parathyroid adenoma', 'Phenotype', 'HP:0002897', (220, 239))	('tumor', 'Disease', (258, 263))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('MEN1', 'Gene', (550, 554))	('germline', 'Var', (437, 445))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', (328, 333))	('parathyroid adenoma', 'Disease', (220, 239))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('pituitary adenoma', 'Disease', 'MESH:D010911', (269, 286))	('MEN1', 'Gene', '4221', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('parathyroid adenoma', 'Disease', 'MESH:D010282', (220, 239))	('MEN1', 'Gene', '4221', (403, 407))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (269, 286))	('enteropancreatic tumor', 'Disease', 'MESH:C535650', (241, 263))	('enteropancreatic tumor', 'Disease', (241, 263))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('pituitary adenoma', 'Disease', (269, 286))	('MEN1', 'Gene', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('endocrine tumors', 'Disease', 'MESH:D004701', (196, 212))	('MEN1', 'Gene', (403, 407))	('MEN1', 'Gene', '4221', (312, 316))	('endocrine tumors', 'Disease', (196, 212))	('mutation', 'Var', (451, 459))	('MEN1', 'Gene', '4221', (82, 86))	('MEN1', 'Gene', '4221', (446, 450))	('men', 'Species', '9606', (300, 303))	('tumor', 'Disease', (206, 211))	('MEN1', 'Gene', '4221', (550, 554))	('patient', 'Species', '9606', (52, 59))	('MEN1', 'Gene', (312, 316))	('MEN1', 'Gene', (82, 86))
6554	31263451	Genetic evaluation in family members of patients with MEN1 was recently shown to result in the diagnosis of MEN 1, 10 years earlier than clinical or biochemical diagnosis.	('MEN 1', 'Gene', '4221', (108, 113))	('MEN 1', 'Gene', (108, 113))	('patients', 'Species', '9606', (40, 48))	('Genetic', 'Var', (0, 7))	('result in', 'Reg', (81, 90))	('MEN1', 'Gene', (54, 58))	('MEN1', 'Gene', '4221', (54, 58))
6566	31263451	This "negative feedback loop" mimics the second hit in Knudson's hypothesis by silencing the expression of the second MEN1 wild type allele through a post-transcriptional, reversible, epigenetic effect, which may precede the permanent genetic deletion or inactivation of the second wild type allele.	('epigenetic', 'Var', (184, 194))	('MEN1', 'Gene', '4221', (118, 122))	('expression', 'MPA', (93, 103))	('MEN1', 'Gene', (118, 122))	('silencing', 'NegReg', (79, 88))
6587	31263451	In addition, somatic MEN1 mutations can be observed in >40% of sporadic pNETs.	('mutations', 'Var', (26, 35))	('MEN1', 'Gene', (21, 25))	('pNETs', 'Disease', (72, 77))	('MEN1', 'Gene', '4221', (21, 25))
6594	31263451	Several MEN1 genotype-phenotype correlations regarding pNET growth and/or malignant potential have been identified (mutations in JunD, CHES1, truncating mutations in the N- or C- terminal regions of the MEN1 gene [exons 2,8,9] and the CDKN1B V109G polymorphism), and particular pathological characteristics such as high mitotic count in large NF-pNETs, may characterize more aggressive tumors, however these have not been studied prospectively and are not broadly used.	('CHES1', 'Gene', (135, 140))	('high', 'MPA', (315, 319))	('MEN1', 'Gene', '4221', (8, 12))	('CDKN1B', 'Gene', (235, 241))	('JunD', 'Gene', (129, 133))	('V109G', 'Mutation', 'rs2066827', (242, 247))	('V109G', 'Var', (242, 247))	('MEN1', 'Gene', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (386, 392))	('aggressive tumors', 'Disease', (375, 392))	('MEN1', 'Gene', '4221', (203, 207))	('CHES1', 'Gene', '1112', (135, 140))	('CDKN1B', 'Gene', '1027', (235, 241))	('mutations', 'Var', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('aggressive tumors', 'Disease', 'MESH:D001523', (375, 392))	('MEN1', 'Gene', (203, 207))	('JunD', 'Gene', '3727', (129, 133))	('truncating mutations in', 'Var', (142, 165))
6615	31263451	As aforementioned, hypercalcemia from concomitant PHPT may worsen the symptoms of ZES, with parathyroidectomy leading to decreased fasting and secretin simulated gastrin levels and basal acid secretion.	('PHPT', 'Phenotype', 'HP:0008200', (50, 54))	('ZES', 'Phenotype', 'HP:0002044', (82, 85))	('basal acid secretion', 'MPA', (181, 201))	('ZES', 'Disease', (82, 85))	('parathyroidectomy', 'Disease', (92, 109))	('men', 'Species', '9606', (8, 11))	('PHPT', 'Var', (50, 54))	('decreased', 'NegReg', (121, 130))	('hypercalcemia', 'Phenotype', 'HP:0003072', (19, 32))	('gastrin', 'Gene', '2520', (162, 169))	('hypercalcemia', 'Disease', (19, 32))	('symptoms', 'Disease', (70, 78))	('worsen', 'PosReg', (59, 65))	('gastrin', 'Gene', (162, 169))	('hypercalcemia', 'Disease', 'MESH:D006934', (19, 32))
6666	31263451	This profile is similar to that of sporadic PITs but differs from that of other hereditary pituitary tumors (due to GNAS, AIP, or PRKAR1A defects) that secrete primarily GH.	('PRKAR1A', 'Gene', (130, 137))	('defects', 'Var', (138, 145))	('GNAS', 'Gene', (116, 120))	('hereditary pituitary tumors', 'Disease', (80, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('PRKAR1A', 'Gene', '5573', (130, 137))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('GNAS', 'Gene', '2778', (116, 120))	('hereditary pituitary tumors', 'Disease', 'MESH:D010911', (80, 107))
6751	30838516	Particularly, the BWS is a genetic syndrome associated with childhood ACC, other childhood tumors and a somatic overgrowth syndrome in which deregulation of imprinted genes on chromosomal locus 11p15 leads to biallelic expression of IGF2.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('BWS', 'Disease', 'MESH:D001506', (18, 21))	('ACC', 'Phenotype', 'HP:0006744', (70, 73))	('genetic syndrome', 'Disease', 'MESH:D030342', (27, 43))	('childhood ACC', 'Disease', (60, 73))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('overgrowth syndrome', 'Disease', 'MESH:C537340', (112, 131))	('deregulation', 'Var', (141, 153))	('genetic syndrome', 'Disease', (27, 43))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('biallelic expression', 'MPA', (209, 229))	('IGF2', 'Gene', '3481', (233, 237))	('leads to', 'Reg', (200, 208))	('overgrowth syndrome', 'Disease', (112, 131))	('BWS', 'Disease', (18, 21))	('overgrowth', 'Phenotype', 'HP:0001548', (112, 122))	('IGF2', 'Gene', (233, 237))
6820	30838516	At the condition tested, only the highest concentrations used of sirolimus (10-6 M) showed significant additive effect with linsitinib in increasing annexin V, used as measure of apoptosis, in H295R (Fig.	('sirolimus', 'Chemical', 'MESH:D020123', (65, 74))	('linsitinib', 'Chemical', 'MESH:C551528', (124, 134))	('H295R', 'Var', (193, 198))	('annexin V', 'Gene', '308', (149, 158))	('annexin V', 'Gene', (149, 158))	('increasing', 'PosReg', (138, 148))
6821	30838516	Everolimus did not show a statistically significant additive effect in increasing annexin V in H295R (Fig.	('increasing', 'PosReg', (71, 81))	('H295R', 'Var', (95, 100))	('annexin V', 'Gene', (82, 91))	('annexin V', 'Gene', '308', (82, 91))	('Everolimus', 'Chemical', 'MESH:D000068338', (0, 10))
6845	30838516	Loss of heterozygosis at the locus of IGF2R gene has been reported to be a frequent event in ACC, supporting a potential role of IGF2R as a tumor suppressor gene also in ACC development.	('IGF2R', 'Gene', '3482', (129, 134))	('ACC', 'Phenotype', 'HP:0006744', (93, 96))	('Loss of heterozygosis', 'Var', (0, 21))	('ACC', 'Disease', (93, 96))	('tumor', 'Disease', (140, 145))	('ACC', 'Phenotype', 'HP:0006744', (170, 173))	('IGF2R', 'Gene', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('IGF2R', 'Gene', '3482', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('IGF2R', 'Gene', (38, 43))
6851	30838516	Therefore, whether high IGFBP2 and/or low IGFBP6 could play a role in the regulation of IGF pathway in adrenocortical tumorigenesis deserves further investigation.	('high', 'Var', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('adrenocortical', 'Disease', (103, 117))	('adrenocortical', 'Disease', 'MESH:D018268', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('IGFBP6', 'Gene', (42, 48))	('tumor', 'Disease', (118, 123))	('low', 'NegReg', (38, 41))	('IGFBP2', 'Gene', '3485', (24, 30))	('IGFBP6', 'Gene', '3489', (42, 48))	('IGFBP2', 'Gene', (24, 30))	('IGF pathway', 'Pathway', (88, 99))
6865	30838516	Mitotane is a strong inducer of CYP3A4 and was shown to decrease bioavailability of sunitinib in patients with ACC.	('Mitotane', 'Var', (0, 8))	('CYP3A4', 'Gene', '1576', (32, 38))	('ACC', 'Phenotype', 'HP:0006744', (111, 114))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('decrease', 'NegReg', (56, 64))	('sunitinib', 'Chemical', 'MESH:D000077210', (84, 93))	('CYP3A4', 'Gene', (32, 38))	('bioavailability of sunitinib', 'MPA', (65, 93))	('patients', 'Species', '9606', (97, 105))
6885	29976214	Multivariate analysis indicated that the operative duration (OR, 3.78; P < 0.001), estimated blood loss (OR, 1.08; P = 0.02), and transfusion (OR, 2.13; P = 0.038) during/after surgery were positively associated with higher mortality and morbidity.	('transfusion', 'Var', (130, 141))	('blood loss', 'Disease', (93, 103))	('blood loss', 'Disease', 'MESH:D006473', (93, 103))
6946	29976214	Multivariate analysis indicated that operative duration (OR, 3.78; P < 0.001), estimated blood loss (OR, 1.08; P = 0.02), and transfusion (OR, 2.13; P = 0.038) during/after surgery were each positively associated with increased mortality and morbidity.	('transfusion', 'Var', (126, 137))	('blood loss', 'Disease', 'MESH:D006473', (89, 99))	('blood loss', 'Disease', (89, 99))	('associated', 'Reg', (202, 212))
7031	29342266	Samples were separated chromatographically using an isocratic elution profile, ionized using positive atmospheric pressure chemical ionization, and detected using the following transitions: T, 289 > 109 and 289 > 97; T-d3, 292 > 97; A4, 287 > 109 and 287 > 97; and A4-d7, 294 > 100.	('ionization', 'Disease', 'MESH:D004194', (132, 142))	('A4', 'Chemical', '-', (233, 235))	('A4', 'Chemical', '-', (265, 267))	('ionized', 'Disease', (79, 86))	('ionization', 'Disease', (132, 142))	('ionized', 'Disease', 'MESH:D004194', (79, 86))	('A4-d7', 'Var', (265, 270))	('T-d3', 'Var', (217, 221))	('289 > 97', 'Var', (207, 215))
7193	28420713	The impact of diet on PKA signaling has not been defined, although perturbations in individual PKA subunits are associated with changes in adiposity, physical activity, and energy intake in mice and humans.	('perturbations', 'Var', (67, 80))	('physical activity', 'MPA', (150, 167))	('humans', 'Species', '9606', (199, 205))	('mice', 'Species', '10090', (190, 194))	('adiposity', 'MPA', (139, 148))	('changes', 'Reg', (128, 135))
7194	28420713	We hypothesized that a high fat diet (HFD) would elicit peripheral and central alterations in the PKA system that would differ depending on length of exposure to HFD; these differences could protect against or promote diet-induced obesity (DIO).	('obesity', 'Disease', 'MESH:D009765', (231, 238))	('protect', 'Reg', (191, 198))	('obesity', 'Disease', (231, 238))	('DIO', 'Chemical', '-', (240, 243))	('differences', 'Var', (173, 184))	('promote', 'PosReg', (210, 217))	('diet-induced obesity', 'Phenotype', 'HP:0012743', (218, 238))	('obesity', 'Phenotype', 'HP:0001513', (231, 238))
7207	28420713	Individuals that harbor mutations and other defects in PKA signaling molecules develop corticotropin-independent Cushing Syndrome (CS).	('develop', 'Reg', (79, 86))	('Cushing Syndrome', 'Disease', 'MESH:D003480', (113, 129))	('Cushing Syndrome', 'Disease', (113, 129))	('mutations', 'Var', (24, 33))	('Cushing Syndrome', 'Phenotype', 'HP:0003118', (113, 129))
7208	28420713	For example, mutations of the PRKAR1A gene (that codes for RIalpha subunit) cause primary pigmented nodular adrenocortical disease (PPNAD) and mutations of GNAS1 (that codes for the stimulatory subunit alpha or GSalpha) cause primary bimorphic adrenocortical disease in the context of McCune Albright syndrome.	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (90, 130))	('McCune Albright syndrome', 'Disease', (285, 309))	('pigmented nodular adrenocortical disease', 'Disease', (90, 130))	('adrenocortical disease', 'Disease', (244, 266))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (90, 130))	('adrenocortical disease', 'Disease', 'MESH:D018268', (108, 130))	('GNAS1', 'Gene', (156, 161))	('RIalpha', 'Gene', (59, 66))	('mutations', 'Var', (143, 152))	('PRKAR1A', 'Gene', (30, 37))	('cause', 'Reg', (220, 225))	('PRKAR1A', 'Gene', '19084', (30, 37))	('cause', 'Reg', (76, 81))	('mutations', 'Var', (13, 22))	('McCune Albright syndrome', 'Disease', 'MESH:D005357', (285, 309))	('RIalpha', 'Gene', '19084', (59, 66))	('GNAS1', 'Gene', '14683', (156, 161))	('primary bimorphic adrenocortical disease', 'Phenotype', 'HP:0008207', (226, 266))	('adrenocortical disease', 'Disease', 'MESH:D018268', (244, 266))
7209	28420713	GNAS1 mutations are also infrequently found in primary macronodular adrenocortical hyperplasia.	('GNAS1', 'Gene', (0, 5))	('macronodular adrenocortical hyperplasia', 'Phenotype', 'HP:0008231', (55, 94))	('GNAS1', 'Gene', '14683', (0, 5))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (68, 94))	('adrenocortical hyperplasia', 'Disease', (68, 94))	('found', 'Reg', (38, 43))	('mutations', 'Var', (6, 15))
7212	28420713	Dysregulated PKA activity in mouse models of PKA deficiency is associated with changes in adiposity, energy balance, and response to obesogenic diet.	('changes', 'Reg', (79, 86))	('energy balance', 'MPA', (101, 115))	('PKA deficiency', 'Disease', 'MESH:D007153', (45, 59))	('PKA deficiency', 'Disease', (45, 59))	('Dysregulated', 'Var', (0, 12))	('mouse', 'Species', '10090', (29, 34))	('adiposity', 'MPA', (90, 99))	('activity', 'MPA', (17, 25))	('PKA', 'Enzyme', (13, 16))
7222	28420713	As expected, long-term HFD caused increased body weight, fat mass and glucose intolerance compared to weight-matched littermates fed a CD.	('body weight', 'CPA', (44, 55))	('CD', 'Chemical', '-', (135, 137))	('glucose intolerance', 'Phenotype', 'HP:0001952', (70, 89))	('glucose intolerance', 'MPA', (70, 89))	('HFD', 'Var', (23, 26))	('fat mass', 'MPA', (57, 65))	('increased body weight', 'Phenotype', 'HP:0004324', (34, 55))	('increased', 'PosReg', (34, 43))	('glucose', 'Chemical', 'MESH:D005947', (70, 77))
7223	28420713	Conversely, chronic HFD access and subsequent DIO caused increased PKA activity in liver and hypothalamus that likely potentiate the deleterious physiologic effects of excess adiposity, contribute to glucose intolerance, and act as a committed step to promote development of obesity, an observation not previously made.	('obesity', 'Disease', (275, 282))	('obesity', 'Disease', 'MESH:D009765', (275, 282))	('DIO', 'Chemical', '-', (46, 49))	('glucose intolerance', 'MPA', (200, 219))	('contribute', 'Reg', (186, 196))	('glucose intolerance', 'Phenotype', 'HP:0001952', (200, 219))	('excess', 'PosReg', (168, 174))	('activity', 'MPA', (71, 79))	('hypothalamus', 'Disease', (93, 105))	('promote', 'PosReg', (252, 259))	('hypothalamus', 'Disease', 'MESH:D007029', (93, 105))	('adiposity', 'MPA', (175, 184))	('obesity', 'Phenotype', 'HP:0001513', (275, 282))	('DIO', 'Var', (46, 49))	('PKA', 'Enzyme', (67, 70))	('increased', 'PosReg', (57, 66))	('potentiate', 'PosReg', (118, 128))	('glucose', 'Chemical', 'MESH:D005947', (200, 207))	('men', 'Species', '9606', (267, 270))	('excess adiposity', 'Phenotype', 'HP:0009126', (168, 184))
7287	28420713	Mounting evidence shows that inhibition of hepatic PKA activity or its downstream targets is therapeutically beneficial in the treatment of type II diabetes-related hyperglycemia and complications related to hyperglycemia.	('type II diabetes', 'Phenotype', 'HP:0005978', (140, 156))	('type II diabetes', 'Disease', 'MESH:D003924', (140, 156))	('hyperglycemia', 'Disease', (208, 221))	('hyperglycemia', 'Disease', 'MESH:D006943', (165, 178))	('men', 'Species', '9606', (132, 135))	('hyperglycemia', 'Phenotype', 'HP:0003074', (165, 178))	('hyperglycemia', 'Disease', (165, 178))	('hyperglycemia', 'Phenotype', 'HP:0003074', (208, 221))	('hepatic PKA activity', 'Enzyme', (43, 63))	('type II diabetes', 'Disease', (140, 156))	('inhibition', 'Var', (29, 39))	('hyperglycemia', 'Disease', 'MESH:D006943', (208, 221))
7339	27705928	Unraveling the expression of the oncogene YAP1, a Wnt/beta-catenin target, in adrenocortical tumors and its association with poor outcome in pediatric patients Overexpression of the oncogene yes-associated-protein-1 (YAP1) is associated with increased cell proliferation in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('YAP1', 'Gene', (217, 221))	('YAP1', 'Gene', (42, 46))	('cancers', 'Disease', (280, 287))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Overexpression', 'Var', (160, 174))	('adrenocortical tumors', 'Disease', (78, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('increased', 'PosReg', (242, 251))	('beta-catenin', 'Gene', (54, 66))	('beta-catenin', 'Gene', '1499', (54, 66))	('cancers', 'Disease', 'MESH:D009369', (280, 287))	('cell proliferation', 'CPA', (252, 270))	('yes-associated-protein-1', 'Gene', '10413', (191, 215))	('YAP1', 'Gene', '10413', (217, 221))	('yes-associated-protein-1', 'Gene', (191, 215))	('YAP1', 'Gene', '10413', (42, 46))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (78, 99))	('human', 'Species', '9606', (274, 279))
7346	27705928	The inhibition of the Wnt/beta-catenin pathway increased YAP1 mRNA expression.	('beta-catenin', 'Gene', '1499', (26, 38))	('YAP1', 'Gene', '10413', (57, 61))	('inhibition', 'Var', (4, 14))	('increased', 'PosReg', (47, 56))	('beta-catenin', 'Gene', (26, 38))	('YAP1', 'Gene', (57, 61))
7349	27705928	The interaction between YAP1 and the Wnt/beta-catenin pathway was assessed in NCI-H295 adrenocortical cells by inhibiting the TCF/beta-catenin complex and by knocking down YAP1.	('beta-catenin', 'Gene', (41, 53))	('YAP1', 'Gene', (24, 28))	('TCF', 'Gene', (126, 129))	('adrenocortical', 'Disease', (87, 101))	('NCI-H295', 'CellLine', 'CVCL:0456', (78, 86))	('TCF', 'Gene', '3172', (126, 129))	('beta-catenin', 'Gene', '1499', (41, 53))	('YAP1', 'Gene', '10413', (24, 28))	('YAP1', 'Gene', (172, 176))	('YAP1', 'Gene', '10413', (172, 176))	('adrenocortical', 'Disease', 'MESH:D018268', (87, 101))	('inhibiting', 'NegReg', (111, 121))	('beta-catenin', 'Gene', (130, 142))	('knocking down', 'Var', (158, 171))	('beta-catenin', 'Gene', '1499', (130, 142))
7353	27705928	Several genetic abnormalities have been found in adrenocortical tumors (ACT), the most prominent being IGF2 overexpression, TP53 mutations and Wnt/beta-catenin abnormal signaling in both adult and pediatric ACT.	('beta-catenin', 'Gene', '1499', (147, 159))	('IGF2', 'Gene', (103, 107))	('genetic abnormalities', 'Disease', (8, 29))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('TP53', 'Gene', '7157', (124, 128))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (49, 70))	('mutations', 'Var', (129, 138))	('IGF2', 'Gene', '3481', (103, 107))	('TP53', 'Gene', (124, 128))	('overexpression', 'PosReg', (108, 122))	('adrenocortical tumors', 'Disease', (49, 70))	('beta-catenin', 'Gene', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('genetic abnormalities', 'Disease', 'MESH:D030342', (8, 29))
7362	27705928	In vitro, YAP1 nuclear accumulation resulted in worsening of the malignant phenotype and induced chemotherapy resistance in ovarian cancer cell lines.	('YAP1', 'Gene', (10, 14))	('induced', 'Reg', (89, 96))	('YAP1', 'Gene', '10413', (10, 14))	('worsening', 'NegReg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (124, 138))	('malignant phenotype', 'CPA', (65, 84))	('chemotherapy resistance', 'CPA', (97, 120))	('nuclear accumulation', 'Var', (15, 35))	('ovarian cancer', 'Disease', (124, 138))	('ovarian cancer', 'Disease', 'MESH:D010051', (124, 138))
7380	27705928	Regarding TP53 status, ACT harboring the P53 p.R337H mutation showed no differential expression of YAP1 when compared with tumors that do not harbor this mutation (Mann-Whitney test: p=0.35; Figure 2F).	('expression', 'MPA', (85, 95))	('tumors', 'Disease', (123, 129))	('YAP1', 'Gene', (99, 103))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('YAP1', 'Gene', '10413', (99, 103))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('p.R337H', 'Var', (45, 52))	('TP53', 'Gene', (10, 14))	('p.R337H', 'Mutation', 'rs121912664', (45, 52))	('P53', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('TP53', 'Gene', '7157', (10, 14))
7385	27705928	ACT harboring CTNNB1 mutations were not included in Bayesian analysis and YAP1 was analyzed as an independent factor.	('CTNNB1', 'Gene', '1499', (14, 20))	('CTNNB1', 'Gene', (14, 20))	('YAP1', 'Gene', (74, 78))	('YAP1', 'Gene', '10413', (74, 78))	('mutations', 'Var', (21, 30))
7386	27705928	We recently reported that PNU-74654 inhibited the Wnt/beta-catenin signaling by impairment of the beta-catenin expression at mRNA and protein levels, including dose-dependent decrease of the nuclear beta-catenin in NCI-H295 ACC cells.	('NCI-H295 ACC', 'CellLine', 'CVCL:0456', (215, 227))	('PNU-74654', 'Var', (26, 35))	('inhibited', 'NegReg', (36, 45))	('beta-catenin', 'Gene', '1499', (199, 211))	('decrease', 'NegReg', (175, 183))	('impairment', 'NegReg', (80, 90))	('PNU-74654', 'Chemical', '-', (26, 35))	('beta-catenin', 'Gene', (54, 66))	('beta-catenin', 'Gene', (98, 110))	('beta-catenin', 'Gene', '1499', (98, 110))	('beta-catenin', 'Gene', '1499', (54, 66))	('beta-catenin', 'Gene', (199, 211))
7388	27705928	We observed decreased YAP1 protein expression 48 hours after treatment with 100 muM PNU-74654 (one-way ANOVA: p=0.01; Figure 3A).	('YAP1', 'Gene', (22, 26))	('PNU-74654', 'Chemical', '-', (84, 93))	('decreased', 'NegReg', (12, 21))	('PNU-74654', 'Var', (84, 93))	('YAP1', 'Gene', '10413', (22, 26))
7389	27705928	Additionally, we observed increased YAP1 mRNA expression 48 hours after treatment with 50 muM and 100 muM PNU-74654 (One-way ANOVA: p=0.0035 and p=0.0019, respectively; Figure 3B).	('PNU-74654', 'Var', (106, 115))	('YAP1', 'Gene', (36, 40))	('PNU-74654', 'Chemical', '-', (106, 115))	('YAP1', 'Gene', '10413', (36, 40))	('increased', 'PosReg', (26, 35))
7390	27705928	The half-maximal inhibitory concentration (IC50) of PNU-74654 for NCI-H295 cells 48 hours after treatment as well as the effect of PNU-74654 on cell viability, apoptosis and steroidogenesis had been previously described by our group.	('apoptosis', 'CPA', (160, 169))	('cell viability', 'CPA', (144, 158))	('PNU-74654', 'Chemical', '-', (131, 140))	('PNU-74654', 'Var', (52, 61))	('steroidogenesis', 'CPA', (174, 189))	('NCI-H295', 'CellLine', 'CVCL:0456', (66, 74))	('PNU-74654', 'Chemical', '-', (52, 61))
7395	27705928	After 72 hours of YAP1 knockdown, the cells were prone to impaired migration (-20%; Students t test: p=0.08; Figure 4E).	('YAP1', 'Gene', (18, 22))	('knockdown', 'Var', (23, 32))	('impaired', 'NegReg', (58, 66))	('YAP1', 'Gene', '10413', (18, 22))
7396	27705928	In addition, after 96 hours of YAP1 knockdown, cell viability was significantly decreased (-18%; Students t test: p<0.0001; Figure 4D).	('YAP1', 'Gene', '10413', (31, 35))	('YAP1', 'Gene', (31, 35))	('knockdown', 'Var', (36, 45))	('decreased', 'NegReg', (80, 89))	('cell viability', 'CPA', (47, 61))
7406	27705928	Similar to our findings, a meta-analysis study confirmed that YAP1 overexpression was associated with lower overall survival and lower disease-free survival in other cancers.	('lower', 'NegReg', (102, 107))	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('YAP1', 'Gene', (62, 66))	('overall survival', 'CPA', (108, 124))	('YAP1', 'Gene', '10413', (62, 66))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('overexpression', 'Var', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('disease-free survival', 'CPA', (135, 156))	('lower', 'NegReg', (129, 134))
7415	27705928	In the present study, YAP1 knockdown resulted in a decrease in cell migration and cell viability, demonstrating the potential involvement of YAP1 in adrenocortical cell growth and metastasis.	('cell viability', 'CPA', (82, 96))	('knockdown', 'Var', (27, 36))	('adrenocortical', 'Disease', (149, 163))	('cell migration', 'CPA', (63, 77))	('YAP1', 'Gene', (141, 145))	('YAP1', 'Gene', '10413', (141, 145))	('decrease', 'NegReg', (51, 59))	('YAP1', 'Gene', '10413', (22, 26))	('adrenocortical', 'Disease', 'MESH:D018268', (149, 163))	('YAP1', 'Gene', (22, 26))
7423	27705928	In order to evaluate the interaction between YAP1 and the Wnt/beta-catenin pathway, we treated the NCI-H295 ACC cell line with a TCF/beta-catenin complex inhibitor (PNU-74654), which effectively inhibits the Wnt/beta-catenin pathway.	('beta-catenin', 'Gene', '1499', (133, 145))	('beta-catenin', 'Gene', '1499', (212, 224))	('beta-catenin', 'Gene', (62, 74))	('inhibits', 'NegReg', (195, 203))	('YAP1', 'Gene', (45, 49))	('YAP1', 'Gene', '10413', (45, 49))	('PNU-74654', 'Var', (165, 174))	('beta-catenin', 'Gene', '1499', (62, 74))	('beta-catenin', 'Gene', (133, 145))	('PNU-74654', 'Chemical', '-', (165, 174))	('TCF', 'Gene', (129, 132))	('TCF', 'Gene', '3172', (129, 132))	('beta-catenin', 'Gene', (212, 224))	('NCI-H295 ACC', 'CellLine', 'CVCL:0456', (99, 111))
7424	27705928	The NCI-H295 cell line harbors the p.S45P beta-catenin mutation, which triggers the Wnt/beta-catenin pathway activation.	('beta-catenin', 'Gene', (42, 54))	('beta-catenin', 'Gene', '1499', (42, 54))	('activation', 'PosReg', (109, 119))	('NCI-H295', 'CellLine', 'CVCL:0456', (4, 12))	('triggers', 'Reg', (71, 79))	('beta-catenin', 'Gene', (88, 100))	('p.S45P', 'Mutation', 'rs121913407', (35, 41))	('p.S45P', 'Var', (35, 41))	('beta-catenin', 'Gene', '1499', (88, 100))
7426	27705928	Interestingly, we found that inhibition of the Wnt/beta-catenin pathway decreased YAP1 protein expression in parallel to the reduction of beta-catenin expression.	('reduction', 'NegReg', (125, 134))	('beta-catenin', 'Gene', (138, 150))	('YAP1', 'Gene', '10413', (82, 86))	('beta-catenin', 'Gene', '1499', (51, 63))	('decreased', 'NegReg', (72, 81))	('beta-catenin', 'Gene', '1499', (138, 150))	('YAP1', 'Gene', (82, 86))	('inhibition', 'Var', (29, 39))	('beta-catenin', 'Gene', (51, 63))
7434	27705928	Our group had previously described the activation of the Wnt/beta-catenin pathway in pediatric ACT mostly due to underexpression of the Wnt/beta-catenin pathway inhibitors besides CTNNB1 mutations.	('beta-catenin', 'Gene', '1499', (61, 73))	('beta-catenin', 'Gene', '1499', (140, 152))	('CTNNB1', 'Gene', '1499', (180, 186))	('activation', 'PosReg', (39, 49))	('underexpression', 'MPA', (113, 128))	('mutations', 'Var', (187, 196))	('CTNNB1', 'Gene', (180, 186))	('beta-catenin', 'Gene', (61, 73))	('beta-catenin', 'Gene', (140, 152))
7435	27705928	Mutations in the beta-catenin gene (CTNNB1) are rare in pediatric ACT, but they are associated to a poor prognosis in this group.	('CTNNB1', 'Gene', (36, 42))	('beta-catenin', 'Gene', '1499', (17, 29))	('CTNNB1', 'Gene', '1499', (36, 42))	('Mutations', 'Var', (0, 9))	('beta-catenin', 'Gene', (17, 29))
7459	27705928	The PNU-74654 compound (Sigma Aldrich), a Wnt/beta-catenin antagonist, was resuspended in dimethyl sulfoxide (DMSO; Sigma Aldrich) at a stock concentration of 31.2 mM, and diluted in complete growth medium to the required concentrations.	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (90, 108))	('PNU-74654', 'Var', (4, 13))	('beta-catenin', 'Gene', (46, 58))	('beta-catenin', 'Gene', '1499', (46, 58))	('DMSO', 'Chemical', 'MESH:D004121', (110, 114))	('PNU-74654', 'Chemical', '-', (4, 13))
7463	27705928	After 24 hours, the medium was replaced by antibiotic-free complete medium and the cells were transfected with 25nM of either small-interfering RNA (siYAP1) or a silencer negative control (siNonTargeting) (ON-TARGETplus siRNA, Dharmacon GE) using DharmaFECT 1 transfection reagent (Dharmacon GE).	('YAP1', 'Gene', (151, 155))	('YAP1', 'Gene', '10413', (151, 155))	('small-interfering', 'Var', (126, 143))
7480	27705928	For in vitro analysis, data are described as median and standard error (SEM) and one-way ANOVA followed by Dunnett's multiple comparison tests or Student t-test were used to determine differences between PNU-74654 treatment, YAP1 silencing, and controls.	('PNU-74654', 'Chemical', '-', (204, 213))	('YAP1', 'Gene', '10413', (225, 229))	('silencing', 'NegReg', (230, 239))	('YAP1', 'Gene', (225, 229))	('PNU-74654', 'Var', (204, 213))
7481	27705928	We used the presence of mutations in the CTNNB1 gene as an exclusion criterion and therefore pediatric ACT harboring CTNNB1 mutations were not included in these analyses.	('CTNNB1', 'Gene', '1499', (117, 123))	('CTNNB1', 'Gene', (41, 47))	('CTNNB1', 'Gene', (117, 123))	('mutations', 'Var', (24, 33))	('CTNNB1', 'Gene', '1499', (41, 47))
7551	27200272	Surgical manipulation of the adrenal gland can lead to a catecholamine surge and subsequent cardiovascular manifestations, regardless of the adrenal tumour type present (Lang et al., 2011).	('cardiovascular manifestations', 'Phenotype', 'HP:0001626', (92, 121))	('lead to', 'Reg', (47, 54))	('regardless of the adrenal tumour', 'Disease', 'MESH:D000310', (123, 155))	('catecholamine surge', 'Phenotype', 'HP:0003334', (57, 76))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('Surgical manipulation', 'Var', (0, 21))	('catecholamine', 'Chemical', 'MESH:D002395', (57, 70))	('catecholamine surge', 'MPA', (57, 76))	('cardiovascular manifestations', 'CPA', (92, 121))	('regardless of the adrenal tumour', 'Disease', (123, 155))
7599	22691887	Molecular genetics of adrenocortical tumor formation and potential pharmacologic targets Abnormalities in the cAMP/PKA signaling pathway have been linked to the formation of benign adrenal tumors, as well as a possible predisposition to adrenocortical cancer.	('adrenocortical tumor', 'Disease', 'MESH:D018268', (22, 42))	('linked', 'Reg', (147, 153))	('Abnormalities', 'Var', (89, 102))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (237, 258))	('adrenocortical tumor', 'Disease', (22, 42))	('benign adrenal tumors', 'Disease', (174, 195))	('adrenal tumor', 'Phenotype', 'HP:0100631', (181, 194))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('cAMP', 'Gene', (110, 114))	('cAMP', 'Gene', '820', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('benign adrenal tumors', 'Disease', 'MESH:D000310', (174, 195))	('adrenocortical cancer', 'Disease', (237, 258))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
7600	22691887	Mutations in the G-protein coupled receptor are associated with McCune-Albright syndrome and ACTH-independent macronodular adrenal hyperplasia, while defects in cAMP-dependent protein kinase A can lead to the development of Carney's complex, as well as primary pigmented nodular adrenocortical disease (PPNAD), and micronodular adrenocortical hyperplasia (MAH).	('macronodular adrenal hyperplasia', 'Disease', (110, 142))	('lead to', 'Reg', (197, 204))	('G-protein coupled receptor', 'Gene', (17, 43))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (328, 354))	('associated', 'Reg', (48, 58))	('cAMP', 'Gene', '820', (161, 165))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (110, 142))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (110, 142))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (123, 142))	('Mutations', 'Var', (0, 9))	('defects', 'Var', (150, 157))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (261, 301))	('G-protein coupled receptor', 'Gene', '151', (17, 43))	('cAMP', 'Gene', (161, 165))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (64, 88))	('pigmented nodular adrenocortical disease', 'Disease', (261, 301))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (261, 301))	("Carney's complex", 'Disease', (224, 240))	('adrenocortical hyperplasia', 'Disease', (328, 354))	('McCune-Albright syndrome', 'Disease', (64, 88))
7611	22691887	Abnormalities in any of the steps on this pathway can lead to alterations in cell activation and proliferation.	('lead', 'Reg', (54, 58))	('Abnormalities', 'Var', (0, 13))	('cell activation', 'CPA', (77, 92))	('rat', 'Species', '10116', (66, 69))	('alterations', 'Reg', (62, 73))	('rat', 'Species', '10116', (104, 107))
7617	22691887	The first association of adrenal tumors with abnormalities in PKA signaling was observed in McCune-Albright syndrome, a disease caused by an activating mutation in the Gsalpha subunit (the GNAS gene) of the GPCR.	('GPCR', 'Gene', (207, 211))	('GNAS', 'Gene', '2778', (189, 193))	('adrenal tumors with abnormalities', 'Disease', (25, 58))	('GPCR', 'Gene', '151', (207, 211))	('Gsalpha', 'Gene', (168, 175))	('a disease', 'Disease', 'MESH:D004194', (118, 127))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (92, 116))	('activating', 'PosReg', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('GNAS', 'Gene', (189, 193))	('a disease', 'Disease', (118, 127))	('Gsalpha', 'Gene', '2778', (168, 175))	('McCune-Albright syndrome', 'Disease', (92, 116))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('adrenal tumor', 'Phenotype', 'HP:0100631', (25, 38))	('adrenal tumors with abnormalities', 'Disease', 'MESH:D000310', (25, 58))	('mutation', 'Var', (152, 160))
7618	22691887	The presence of this somatic mutation leads to unregulated cAMP production, thereby resulting in autonomous hyperfunction of affected tissues, as well as unregulated cell growth.	('autonomous hyperfunction', 'CPA', (97, 121))	('leads to', 'Reg', (38, 46))	('cAMP', 'Gene', (59, 63))	('cAMP', 'Gene', '820', (59, 63))	('presence', 'Var', (4, 12))	('resulting in', 'Reg', (84, 96))
7626	22691887	In contrast to over-expression of the GPCRs or activating GNAS mutations, Carney complex (CNC) is the result of inactivating mutations of the PRKAR1A gene, which codes for the type 1alpha regulatory subunit of PKA.	('GNAS', 'Gene', '2778', (58, 62))	('PRKAR1A', 'Gene', '5573', (142, 149))	('result', 'Reg', (102, 108))	('GNAS', 'Gene', (58, 62))	('Carney complex', 'Disease', (74, 88))	('GPCR', 'Gene', (38, 42))	('inactivating mutations', 'Var', (112, 134))	('PRKAR1A', 'Gene', (142, 149))	('GPCR', 'Gene', '151', (38, 42))
7628	22691887	Germline mutations in the PRKAR1A gene are inherited in an autosomal dominant fashion and result most of the time (but not alays) in the complete lack of normal PRKAR1A protein in affected tissues.	('Germline mutations', 'Var', (0, 18))	('PRKAR1A', 'Gene', (26, 33))	('lack', 'NegReg', (146, 150))	('protein', 'Protein', (169, 176))	('PRKAR1A', 'Gene', (161, 168))	('PRKAR1A', 'Gene', '5573', (26, 33))	('PRKAR1A', 'Gene', '5573', (161, 168))
7630	22691887	While the majority of patients with PRKAR1A mutations have functionally null mutations, variants with mutations leading to abnormal PRKAR1A proteins have also been described.	('PRKAR1A', 'Gene', (36, 43))	('proteins', 'Protein', (140, 148))	('PRKAR1A', 'Gene', '5573', (132, 139))	('patients', 'Species', '9606', (22, 30))	('PRKAR1A', 'Gene', '5573', (36, 43))	('mutations', 'Var', (44, 53))	('PRKAR1A', 'Gene', (132, 139))
7632	22691887	Those patients with null mutations typically had less severe disease compared with those patients with mutant PRKAR1A protein.	('PRKAR1A', 'Gene', '5573', (110, 117))	('mutant', 'Var', (103, 109))	('null mutations', 'Var', (20, 34))	('protein', 'Protein', (118, 125))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (6, 14))	('PRKAR1A', 'Gene', (110, 117))
7634	22691887	Somatic mutations in the PRKAR1A gene or loss of the 17q22-24 region (that harbors the gene) were also found in 5 out of 22 patients with sporadic adrenal adenomas, and in 8 of 15 patient with adrenocortical carcinomas in another study by Bertherat, et al..	('sporadic adrenal adenomas', 'Disease', (138, 163))	('patients', 'Species', '9606', (124, 132))	('sporadic adrenal adenomas', 'Disease', 'MESH:D018246', (138, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('rat', 'Species', '10116', (245, 248))	('carcinomas', 'Phenotype', 'HP:0030731', (208, 218))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (193, 218))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (193, 218))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (147, 163))	('mutations', 'Var', (8, 17))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (193, 217))	('adrenocortical carcinomas', 'Disease', (193, 218))	('PRKAR1A', 'Gene', (25, 32))	('patient', 'Species', '9606', (124, 131))	('found', 'Reg', (103, 108))	('PRKAR1A', 'Gene', '5573', (25, 32))	('loss', 'NegReg', (41, 45))	('patient', 'Species', '9606', (180, 187))
7636	22691887	In addition, adenomas with loss of 17q region had increased PKA activity in response to cAMP as compared with those adenomas without mutations.	('loss', 'Var', (27, 31))	('cAMP', 'Gene', (88, 92))	('cAMP', 'Gene', '820', (88, 92))	('17q', 'Gene', (35, 38))	('adenomas', 'Disease', 'MESH:D000236', (13, 21))	('increased', 'PosReg', (50, 59))	('adenomas', 'Disease', 'MESH:D000236', (116, 124))	('adenomas', 'Disease', (116, 124))	('adenomas', 'Disease', (13, 21))	('PKA', 'Enzyme', (60, 63))
7638	22691887	Mutations in phosphodiesterases, the enzymes that break down cAMP, have also been associated with adrenal tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('associated', 'Reg', (82, 92))	('phosphodiesterases', 'Gene', (13, 31))	('cAMP', 'Gene', (61, 65))	('cAMP', 'Gene', '820', (61, 65))	('adrenal tumor', 'Phenotype', 'HP:0100631', (98, 111))	('adrenal tumors', 'Disease', (98, 112))	('phosphodiesterases', 'Gene', '50940', (13, 31))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('break down', 'Phenotype', 'HP:0001061', (50, 60))	('adrenal tumors', 'Disease', 'MESH:D000310', (98, 112))
7641	22691887	performed a genome-wide genotyping, and discovered a mutation in the 2q31-35 region, which codes for phosphodiesterase 11A (PDE11A).	('mutation', 'Var', (53, 61))	('phosphodiesterase 11A', 'Gene', '50940', (101, 122))	('PDE11A', 'Gene', '50940', (124, 130))	('PDE11A', 'Gene', (124, 130))	('phosphodiesterase 11A', 'Gene', (101, 122))
7642	22691887	This inactivating mutation results in elevated cAMP levels, and therefore increased PKA activity.	('cAMP', 'Gene', (47, 51))	('cAMP', 'Gene', '820', (47, 51))	('PKA activity', 'CPA', (84, 96))	('inactivating', 'Var', (5, 17))	('increased', 'PosReg', (74, 83))	('elevated', 'PosReg', (38, 46))
7643	22691887	Mutations in the gene encoding PDE11A were also found to be present in a small percentage of the normal population, suggesting that the gene may also contribute to predisposition to adrenal hyperplasia and adenomas.	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (182, 201))	('predisposition', 'Reg', (164, 178))	('contribute', 'Reg', (150, 160))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (182, 201))	('PDE11A', 'Gene', (31, 37))	('Mutations', 'Var', (0, 9))	('PDE11A', 'Gene', '50940', (31, 37))	('adenomas', 'Disease', 'MESH:D000236', (206, 214))	('adenomas', 'Disease', (206, 214))	('adrenal hyperplasia', 'Disease', (182, 201))
7646	22691887	Mutations in genes along this pathway have been associated with colon cancer, gastric cancer, and hepatocellular carcinoma, and also occur in adrenocortical tumors.	('associated', 'Reg', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('adrenocortical tumors', 'Disease', (142, 163))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('gastric cancer', 'Disease', (78, 92))	('Mutations', 'Var', (0, 9))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('occur', 'Reg', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('colon cancer', 'Disease', 'MESH:D015179', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (98, 122))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (142, 163))	('colon cancer', 'Disease', (64, 76))	('hepatocellular carcinoma', 'Disease', (98, 122))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
7647	22691887	Mutations in the Wnt pathway leading to excessive accumulation of beta-catenin were found in 38% of adrenocortical adenomas, and 85% of adrenocortical carcinomas.	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (136, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (151, 161))	('beta-catenin', 'Gene', (66, 78))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (136, 161))	('found', 'Reg', (84, 89))	('Wnt pathway', 'Pathway', (17, 28))	('beta-catenin', 'Gene', '1499', (66, 78))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (100, 123))	('Mutations', 'Var', (0, 9))	('adrenocortical adenomas', 'Disease', (100, 123))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (136, 161))	('accumulation', 'PosReg', (50, 62))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (100, 123))	('adrenocortical carcinomas', 'Disease', (136, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
7648	22691887	The majority of mutations were activating somatic mutations of the beta-catenin gene, and were more common in non-functional adrenocortical adenomas.	('common', 'Reg', (100, 106))	('mutations', 'Var', (16, 25))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (125, 148))	('activating', 'PosReg', (31, 41))	('adrenocortical adenomas', 'Disease', (125, 148))	('beta-catenin', 'Gene', (67, 79))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (125, 148))	('beta-catenin', 'Gene', '1499', (67, 79))
7652	22691887	One of the first studies to link miRNAs to tumorigenesis was by Calin, et al.. Chromosomal analysis was performed in patients with B-cell chronic lymphocytic leukemia to evaluate for gene deletions on chromosome 13q14, a region known to be deleted in the majority of CLL patients.	('-cell chronic lymphocytic leukemia', 'Phenotype', 'HP:0005539', (132, 166))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (138, 166))	('gene deletions', 'Var', (183, 197))	('lymphocytic leukemia', 'Disease', (146, 166))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('CLL', 'Disease', 'MESH:D015451', (267, 270))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (146, 166))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('patients', 'Species', '9606', (271, 279))	('CLL', 'Disease', (267, 270))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Disease', (43, 48))
7654	22691887	This data suggested that miR15 and miR16 act as tumor suppressors, and their deletion results in unregulated cell proliferation.	('cell proliferation', 'CPA', (109, 127))	('tumor', 'Disease', (48, 53))	('deletion', 'Var', (77, 85))	('miR16', 'Gene', '51573', (35, 40))	('unregulated', 'MPA', (97, 108))	('miR16', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('results in', 'Reg', (86, 96))	('miR15', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('rat', 'Species', '10116', (121, 124))
7658	22691887	The expression of the glucocorticoid receptor was significantly increased after 10 minutes, followed by up-regulation of miR96, miR101a, miR142-3p, and miR433, and subsequent down-regulation of the glucocorticoid nuclear receptor by 60 minutes following ACTH stimulation.	('up-regulation', 'PosReg', (104, 117))	('glucocorticoid receptor', 'Gene', '2908', (22, 45))	('miR101a', 'Var', (128, 135))	('miR96', 'Gene', (121, 126))	('miR433', 'Gene', '574034', (152, 158))	('expression', 'MPA', (4, 14))	('miR142-3p', 'Var', (137, 146))	('glucocorticoid receptor', 'Gene', (22, 45))	('miR96', 'Gene', '407053', (121, 126))	('down-regulation', 'NegReg', (175, 190))	('increased', 'PosReg', (64, 73))	('miR433', 'Gene', (152, 158))
7660	22691887	MiRNAs were recently linked to adrenal tumors via the Wnt signaling pathway in both PPNAD and MMAD.	('linked', 'Reg', (21, 27))	('MiRNAs', 'Var', (0, 6))	('adrenal tumors', 'Disease', 'MESH:D000310', (31, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('adrenal tumor', 'Phenotype', 'HP:0100631', (31, 44))	('Wnt signaling pathway', 'Pathway', (54, 75))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('adrenal tumors', 'Disease', (31, 45))	('MMAD', 'Disease', (94, 98))
7677	22691887	In a study evaluating steroid production in the human placenta, the inhibition of PKA by H89 resulted in decreased progesterone synthesis in the mitochondria.	('PKA', 'Gene', (82, 85))	('progesterone synthesis in the mitochondria', 'MPA', (115, 157))	('human', 'Species', '9606', (48, 53))	('progesterone', 'Chemical', 'MESH:D011374', (115, 127))	('H89', 'Var', (89, 92))	('inhibition', 'NegReg', (68, 78))	('decreased progesterone', 'Phenotype', 'HP:0008233', (105, 127))	('steroid', 'Chemical', 'MESH:D013256', (22, 29))	('decreased', 'NegReg', (105, 114))
7679	22691887	H89 has been demonstrated to reduce postischemic contractile recovery as well as reducing the size of infarct in rat heart isolates.	('reducing', 'NegReg', (81, 89))	('reduce postischemic contractile recovery', 'Phenotype', 'HP:0002486', (29, 69))	('size', 'MPA', (94, 98))	('infarct', 'Disease', 'MESH:D007238', (102, 109))	('rat', 'Species', '10116', (113, 116))	('infarct', 'Disease', (102, 109))	('rat', 'Species', '10116', (20, 23))	('postischemic contractile recovery', 'CPA', (36, 69))	('reduce', 'NegReg', (29, 35))	('H89', 'Var', (0, 3))
7683	22691887	Replacement of let-7 miRNA resulted in decreased tumor size when injected intratumorally in two mouse lung cancer models, as well as reduced tumor burden in established lung tumors when given intranasally.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mouse', 'Species', '10090', (96, 101))	('decreased tumor', 'Disease', (39, 54))	('Replacement', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('lung tumors', 'Disease', (169, 180))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('rat', 'Species', '10116', (77, 80))	('let-7', 'Chemical', '-', (15, 20))	('lung cancer', 'Disease', (102, 113))	('let-7', 'Gene', (15, 20))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (49, 54))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('reduced', 'NegReg', (133, 140))	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('decreased tumor', 'Disease', 'MESH:D009369', (39, 54))	('tumor', 'Disease', (141, 146))	('lung tumors', 'Disease', 'MESH:D008175', (169, 180))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('lung tumors', 'Phenotype', 'HP:0100526', (169, 180))
7690	22691887	In a study by Park, et al., the effects of Quercetin on colon cancer cells with genetic mutations resulting in constitutively activated beta-catenin was evaluated.	('beta-catenin', 'Gene', (136, 148))	('beta-catenin', 'Gene', '1499', (136, 148))	('Quercetin', 'Chemical', 'MESH:D011794', (43, 52))	('colon cancer', 'Disease', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (88, 97))	('colon cancer', 'Phenotype', 'HP:0003003', (56, 68))	('colon cancer', 'Disease', 'MESH:D015179', (56, 68))
7696	22691887	Mutations in the cAMP/PKA signaling pathway are present in the majority of benign cortisol-producing tumors of the adrenal cortex.	('cAMP', 'Gene', (17, 21))	('cAMP', 'Gene', '820', (17, 21))	('cortisol', 'Chemical', 'MESH:D006854', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('present', 'Reg', (48, 55))	('tumors of the adrenal cortex', 'Disease', 'MESH:D000303', (101, 129))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors of the adrenal cortex', 'Phenotype', 'HP:0100641', (101, 129))	('tumors of the adrenal cortex', 'Disease', (101, 129))
7910	20123619	To account for the volumes of the cells, Vcell, and medium, Vmed, the molecular balance equation VcellCMET,cell(t)+VmedCMET,med(t) :  =VcellCMET,cell(0)+VmedCMET,med(0), [3] is solved for CMET,med(t) and substituted into Equation 2 with CMET,cell(0) = 0 to yield For the two CYP11B1 enzymatic reactions competitively inhibited by MET, the kinetic parameters k16 and k17 are respectively divided by (CORTICO = 1 + (CMET,cell/k41) and (CORT = 1 + (CMET,cell/k42) with MET inhibition constants k41 and k42 (Figure 1B).	('CMET', 'Gene', (237, 241))	('k16', 'Gene', (358, 361))	('CMET', 'Gene', '4233', (140, 144))	('CMET', 'Gene', (140, 144))	('CYP11B1', 'Gene', '1584', (275, 282))	('CORT', 'Gene', (399, 403))	('CORT', 'Gene', '1325', (399, 403))	('CMET', 'Gene', '4233', (446, 450))	('CYP11B1', 'Gene', (275, 282))	('CMET', 'Gene', (446, 450))	('CORTICO', 'Chemical', 'MESH:D003345', (399, 406))	('CMET', 'Gene', '4233', (414, 418))	('k17', 'Gene', (366, 369))	('CMET', 'Gene', (414, 418))	('CMET', 'Gene', '4233', (119, 123))	('CMET', 'Gene', (119, 123))	('k17', 'Gene', '3872', (366, 369))	('k41', 'Var', (491, 494))	('CMET', 'Gene', '4233', (188, 192))	('CMET', 'Gene', '4233', (102, 106))	('CORT', 'Gene', (434, 438))	('CMET', 'Gene', (188, 192))	('CMET', 'Gene', '4233', (157, 161))	('CORT', 'Gene', '1325', (434, 438))	('k16', 'Gene', '3868', (358, 361))	('CMET', 'Gene', (157, 161))	('CMET', 'Gene', (102, 106))	('CMET', 'Gene', '4233', (237, 241))
7928	20123619	., k18), a CHOL import rate (k1), two enzyme inhibition constants for MET (k41, k42), and the partition coefficient for MET (q40).	('k18', 'Gene', '3875', (3, 6))	('rat', 'Species', '10116', (23, 26))	('CHOL', 'Chemical', 'MESH:D002784', (11, 15))	('k42', 'Var', (80, 83))	('CHOL import rate', 'MPA', (11, 27))	('k18', 'Gene', (3, 6))
7933	20123619	., k18, k41, k42) were estimated with the time-course data from the control and MET studies using the weighted least squares method.	('k42', 'Var', (13, 16))	('k41', 'Var', (8, 11))	('k18', 'Gene', (3, 6))	('k18', 'Gene', '3875', (3, 6))
7935	20123619	., k18, k41, k42).	('k42', 'Var', (13, 16))	('k41', 'Var', (8, 11))	('k18', 'Gene', (3, 6))	('k18', 'Gene', '3875', (3, 6))
7937	20123619	., k18*, k41*, k42*), is the parameter values k, which minimizes the cost function Parameters for the metabolic pathway were estimated with an iterative optimization algorithm using MATLAB R2009a (Mathworks, Natick, MA, USA) software.	('k18', 'Gene', '3875', (3, 6))	('rat', 'Species', '10116', (146, 149))	('k42*', 'Var', (15, 19))	('k41*', 'Var', (9, 13))	('k18', 'Gene', (3, 6))
7954	20123619	For the steroids (CORTICO, ALDO, and CORT) downstream from the enzyme inhibited by MET (CYP11B1), the model-predicted concentrations closely correspond to the mean time-course measurements in cells [see Supplemental Material, Figure 5 (doi:10.1289/ehp-118-265.S1)] and in medium (Figure 3AC), which decrease as MET increases.	('rat', 'Species', '10116', (125, 128))	('CORT', 'Gene', (18, 22))	('ALDO', 'Chemical', 'MESH:D000450', (27, 31))	('CORT', 'Gene', '1325', (18, 22))	('steroids', 'Chemical', 'MESH:D013256', (8, 16))	('CYP11B1', 'Gene', (88, 95))	('MET', 'Var', (311, 314))	('CYP11B1', 'Gene', '1584', (88, 95))	('CORT', 'Gene', (37, 41))	('inhibited', 'NegReg', (70, 79))	('CORT', 'Gene', '1325', (37, 41))	('CORTICO', 'Chemical', 'MESH:D003345', (18, 25))
7958	20123619	For ALDO, two parameters (k18, q22) were highly sensitive at each MET dose, and six parameters were moderately sensitive, with their sensitivity decreased (k2, k5, k16, q21) or increased (k41, q40) as MET increased.	('k16', 'Gene', (164, 167))	('rat', 'Species', '10116', (104, 107))	('k16', 'Gene', '3868', (164, 167))	('ALDO', 'Chemical', 'MESH:D000450', (4, 8))	('increased', 'PosReg', (177, 186))	('decreased', 'NegReg', (145, 154))	('k2', 'Var', (156, 158))	('k18', 'Gene', (26, 29))	('k18', 'Gene', '3875', (26, 29))	('k41', 'Var', (188, 191))	('q21', 'Var', (169, 172))	('sensitivity', 'MPA', (133, 144))
7959	20123619	For CORT, two parameters (k17, q27) were highly sensitive at each MET dose, and five parameters (k2, k3, k26, q40, q42) were moderately sensitive with their sensitivity decreased as MET increased.	('CORT', 'Gene', '1325', (4, 8))	('sensitivity', 'MPA', (157, 168))	('k26', 'Gene', '353288', (105, 108))	('k26', 'Gene', (105, 108))	('rat', 'Species', '10116', (129, 132))	('sensitive', 'Reg', (48, 57))	('k2', 'Var', (97, 99))	('decreased', 'NegReg', (169, 178))	('q40', 'Var', (110, 113))	('k17', 'Gene', (26, 29))	('k17', 'Gene', '3872', (26, 29))	('CORT', 'Gene', (4, 8))
7960	20123619	The HPREG pathway appears to be the preferred pathway for CORT synthesis because CORT was more sensitive to the HPREG pathway (k3, k6) and less sensitive to the PROG pathway (k5, k8).	('CORT', 'Gene', '1325', (81, 85))	('CORT', 'Gene', (58, 62))	('CORT', 'Gene', '1325', (58, 62))	('sensitive', 'MPA', (95, 104))	('HPREG pathway', 'Pathway', (112, 125))	('k3', 'Var', (127, 129))	('CORT', 'Gene', (81, 85))
7971	20123619	In addition, the mechanism of action for MET, the EAC used in this study, was previously characterized as a potential CYP11B1 enzyme inhibitor.	('CYP11B1', 'Gene', (118, 125))	('CYP11B1', 'Gene', '1584', (118, 125))	('EAC', 'Gene', '1540', (50, 53))	('EAC', 'Gene', (50, 53))	('MET', 'Var', (41, 44))
7978	20123619	Furthermore, cell assays allow for the use of RNA interferencemediated gene knockdowns, gene knockouts, or steroid precursors to selectively block or bypass certain reactions and isolate regions of the steroidogenic pathway for refinement of parameter estimates.	('steroidogenic pathway', 'Pathway', (202, 223))	('reactions', 'MPA', (165, 174))	('bypass', 'NegReg', (150, 156))	('steroid', 'Chemical', 'MESH:D013256', (202, 209))	('RNA interferencemediated', 'MPA', (46, 70))	('block', 'NegReg', (141, 146))	('knockdowns', 'Var', (76, 86))	('steroid', 'Chemical', 'MESH:D013256', (107, 114))
8001	32915435	Autonomous cortisol secretion (ACS) was diagnosed in the presence of cortisol after 1 mg DST > 5 mug/dl (138 nmol/l) or >1.8 and <=5 mug/dl (50-138 nmol/l) and at least one of the following: (i) low ACTH; (ii) increased 24-h urinary-free cortisol; (iii) absence of cortisol rhythm; and (iv) post-LDDST cortisol level > 1.8 mug/dl (50 nmol/l).	('<=5', 'Var', (129, 132))	('increased', 'PosReg', (210, 219))	('Autonomous cortisol secretion', 'Disease', (0, 29))	('cortisol', 'Chemical', 'MESH:D006854', (69, 77))	('absence', 'NegReg', (254, 261))	('cortisol', 'Chemical', 'MESH:D006854', (11, 19))	('cortisol', 'Chemical', 'MESH:D006854', (265, 273))	('cortisol', 'Chemical', 'MESH:D006854', (238, 246))	('increased 24-h urinary-free cortisol', 'Phenotype', 'HP:0012030', (210, 246))	('ACTH', 'Gene', (199, 203))	('cortisol', 'Chemical', 'MESH:D006854', (302, 310))	('cortisol rhythm', 'MPA', (265, 280))	('ACTH', 'Gene', '5443', (199, 203))
8029	32915435	Dyslipidemia was defined in the presence of total cholesterol levels >=200 mg/dl (5.17 mmol/l), LDL-C > 150 mg/dl (3.88 mmol/l), or HDL-C <= 50 mg/dl (1.3 mmol/l) for females and <=40 mg/dl (1 mmol/l) for males, triglycerides >= 150 mg/dl (1.69 mmol/l), or use of lipid-lowering medications.	('cholesterol', 'Chemical', 'MESH:D002784', (50, 61))	('triglycerides', 'MPA', (212, 225))	('lipid', 'Chemical', 'MESH:D008055', (264, 269))	('lipid', 'Chemical', 'MESH:D008055', (3, 8))	('Dyslipidemia', 'Phenotype', 'HP:0003119', (0, 12))	('triglycerides', 'Chemical', 'MESH:D014280', (212, 225))	('Dyslipidemia', 'Disease', (0, 12))	('LDL-C > 150 mg/dl', 'Var', (96, 113))
8050	32915435	In a multiple regression model, including also age, sex, BMI, size, and bilaterality of adenomas, the presence of hypertension was significantly associated with ACS (OR 1.95, P = 0.045), with an independent role for age (OR 1.05, P < 0.0001), and BMI (OR 1.11, P < 0.0001), and independently from sex and adenoma size.	('adenoma', 'Disease', (305, 312))	('adenomas', 'Disease', 'MESH:D000236', (88, 96))	('age', 'Gene', (47, 50))	('adenoma', 'Disease', 'MESH:D000236', (88, 95))	('ACS', 'Disease', (161, 164))	('adenoma', 'Disease', (88, 95))	('age', 'Gene', (216, 219))	('adenomas', 'Disease', (88, 96))	('associated', 'Reg', (145, 155))	('hypertension', 'Disease', 'MESH:D006973', (114, 126))	('presence', 'Var', (102, 110))	('age', 'Gene', '5973', (47, 50))	('adenoma', 'Disease', 'MESH:D000236', (305, 312))	('hypertension', 'Disease', (114, 126))	('BMI', 'Disease', (247, 250))	('hypertension', 'Phenotype', 'HP:0000822', (114, 126))	('age', 'Gene', '5973', (216, 219))
8061	32915435	Cortisol concentrations after 1 mg DST tended to be higher in ACSfu+ patients compared to those in ACSfu- group (1.6 (1.0-3.1) vs 1.1 (0.8-1.4) mug/dl, P = 0.079); however, no association between the degree of cortisol hypersecretion (cortisol levels post 1 mg DST) and metabolic and cardiovascular complications was found (data not shown).	('Cortisol', 'Chemical', 'MESH:D006854', (0, 8))	('cortisol', 'Chemical', 'MESH:D006854', (235, 243))	('rat', 'Species', '10116', (16, 19))	('ACSfu', 'Chemical', '-', (99, 104))	('cardiovascular complications', 'Disease', 'MESH:D002318', (284, 312))	('ACSfu+', 'Var', (62, 68))	('cortisol', 'Chemical', 'MESH:D006854', (210, 218))	('ACSfu', 'Chemical', '-', (62, 67))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (284, 312))	('higher', 'PosReg', (52, 58))	('Cortisol concentrations', 'MPA', (0, 23))	('patients', 'Species', '9606', (69, 77))	('cardiovascular complications', 'Disease', (284, 312))
8062	32915435	Finally, ACSfu+ patients had a higher prevalence of IFG, stroke, and atherosclerosis compared to those in ACSfu-group (Table 4).	('IFG', 'Disease', (52, 55))	('atherosclerosis', 'Disease', (69, 84))	('ACSfu', 'Chemical', '-', (106, 111))	('patients', 'Species', '9606', (16, 24))	('stroke', 'Disease', 'MESH:D020521', (57, 63))	('ACSfu+', 'Var', (9, 15))	('atherosclerosis', 'Phenotype', 'HP:0002621', (69, 84))	('stroke', 'Phenotype', 'HP:0001297', (57, 63))	('ACSfu', 'Chemical', '-', (9, 14))	('atherosclerosis', 'Disease', 'MESH:D050197', (69, 84))	('stroke', 'Disease', (57, 63))
8064	32915435	Using this threshold, we divided the entire cohort in two groups: those with adenoma size <28 mm (Group A) or >=28 mm (Group B).	('adenoma', 'Disease', 'MESH:D000236', (77, 84))	('>=28', 'Var', (110, 114))	('adenoma', 'Disease', (77, 84))	('A) or >=28', 'Species', '878555', (104, 114))
8067	32915435	Furthermore, when considering ACTH levels as a categorical variable [< or >=10 ng/l (2.2 pmol/l)], patients in ACSfu+ group showed a significantly higher frequency of ACTH suppression compared to those in ACSfu- group (57.1 vs 12.1%, P = 0.007).	('ACTH', 'Gene', (30, 34))	('ACTH', 'Gene', (167, 171))	('patients', 'Species', '9606', (99, 107))	('ACSfu+', 'Var', (111, 117))	('ACTH', 'Gene', '5443', (167, 171))	('higher', 'PosReg', (147, 153))	('ACSfu', 'Chemical', '-', (111, 116))	('ACTH', 'Gene', '5443', (30, 34))	('ACSfu', 'Chemical', '-', (205, 210))
8068	32915435	The survival analysis showed a higher incidence of ACS in patients with ACTH < 10 ng/l compared to those with higher levels of ACTH (3.61 per 1000 PYs vs 0.38 per 1000 PYs; K-M log rank: chi-square 11.625; df: 1; P = 0.001) (Fig.	('ACTH', 'Gene', (72, 76))	('ACTH', 'Gene', '5443', (72, 76))	('ACTH', 'Gene', (127, 131))	('ACS', 'Disease', (51, 54))	('ACTH', 'Gene', '5443', (127, 131))	('< 10 ng/l', 'Var', (77, 86))	('patients', 'Species', '9606', (58, 66))
8069	32915435	After adjusting for multiple confounders, the presence of low ACTH levels at entry was found to be an independent risk factor for ACS development during follow-up (HR: 11.2, 95% CI 2.06-60.77; P = 0.005) (Supplementary Material S4).	('ACTH', 'Gene', '5443', (62, 66))	('low ACTH levels', 'Phenotype', 'HP:0002920', (58, 73))	('low', 'Var', (58, 61))	('ACS development', 'Disease', (130, 145))	('ACTH', 'Gene', (62, 66))
8093	32915435	Several studies report AI size as an important predictor of endocrine function development over time, and it has been suggested that AIs >=3 cm are more likely to develop subtle hypercortisolism than smaller tumors.	('hypercortisolism', 'Disease', 'MESH:D003480', (178, 194))	('develop', 'PosReg', (163, 170))	('hypercortisolism', 'Disease', (178, 194))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('hypercortisolism', 'Phenotype', 'HP:0003118', (178, 194))	('AIs >=3 cm', 'Var', (133, 143))
8103	32915435	reported that adiponectin receptors were present in all layers of the rat adrenal cortex and medulla, and treatment with adiponectin enhanced adrenocortical cell proliferation.	('rat', 'Species', '10116', (169, 172))	('rat', 'Species', '10116', (70, 73))	('adiponectin', 'Var', (121, 132))	('adrenocortical cell proliferation', 'CPA', (142, 175))	('enhanced', 'PosReg', (133, 141))
8175	32426170	High Ki-67 and a poorly differentiated morphology classify the tumor as a grade 3 neuroendocrine carcinoma, which predicts a poor prognosis right from the beginning.	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (82, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (82, 106))	('neuroendocrine carcinoma', 'Disease', (82, 106))	('Ki-67', 'Var', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('grade', 'Disease', (74, 79))
8235	26324161	Subclinical hypercortisolism was diagnosed in patients without clinical signs and symptoms of hypercortisolism with at least two out of three positive biochemical tests: DST > 3.0 mcg/dl, elevated UFC, and/or morning suppressed basal ACTH < 2.2 pmol/l with elevated cortisol.	('patients', 'Species', '9606', (46, 54))	('elevated cortisol', 'Phenotype', 'HP:0003118', (257, 274))	('DST >', 'Var', (170, 175))	('ACTH', 'Gene', '5443', (234, 238))	('hypercortisolism', 'Phenotype', 'HP:0003118', (12, 28))	('cortisol', 'Chemical', 'MESH:D006854', (17, 25))	('UFC', 'MPA', (197, 200))	('hypercortisolism', 'Phenotype', 'HP:0003118', (94, 110))	('cortisol', 'Chemical', 'MESH:D006854', (99, 107))	('elevated', 'PosReg', (188, 196))	('hypercortisolism', 'Disease', 'MESH:D003480', (94, 110))	('ACTH', 'Gene', (234, 238))	('hypercortisolism', 'Disease', 'MESH:D003480', (12, 28))	('hypercortisolism', 'Disease', (12, 28))	('cortisol', 'Chemical', 'MESH:D006854', (266, 274))	('hypercortisolism', 'Disease', (94, 110))
8333	29088715	Depending on the tumor type, expression of CXCR4 has been reported in 20%-80% of cases, where it has been implicated in multiple processes, including tumor growth, invasion of adjacent tissue, metastasis, and resistance to therapy.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('resistance', 'CPA', (209, 219))	('tumor', 'Disease', (17, 22))	('reported', 'Reg', (58, 66))	('metastasis', 'CPA', (193, 203))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('invasion of adjacent tissue', 'CPA', (164, 191))	('implicated', 'Reg', (106, 116))	('tumor', 'Disease', (150, 155))	('CXCR4', 'Var', (43, 48))
8334	29088715	Meta-analysis of studies of CXCR4 expression in multiple cancers including prostate cancer, non-small cell lung cancer, pancreatic ductal adenocarcinoma and others concluded that CXCR4 expression is associated with a poor prognosis and lower overall survival.	('lower', 'NegReg', (236, 241))	('prostate cancer', 'Disease', (75, 90))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (92, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (120, 152))	('CXCR4 expression', 'Var', (179, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (92, 118))	('overall survival', 'MPA', (242, 258))	('pancreatic ductal adenocarcinoma', 'Disease', (120, 152))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('non-small cell lung cancer', 'Disease', (92, 118))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (120, 152))	('prostate cancer', 'Disease', 'MESH:D011471', (75, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (75, 90))
8392	29088715	The organs that contributed the most for exposure were the liver and kidneys (0.0638 and 0.00243 rem/mCi, respectively).	('0.00243', 'Var', (89, 96))	('mCi', 'Gene', (101, 104))	('mCi', 'Gene', '622408', (101, 104))
8415	29088715	It is of interest, therefore, that we found higher frequencies of CXCR4+ samples from metastatic as compared with primary tumors for squamous cell cancer of the lung and clear cell renal cell cancer.	('clear cell renal cell cancer', 'Disease', 'MESH:C538614', (170, 198))	('CXCR4+', 'Var', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer of the lung', 'Phenotype', 'HP:0100526', (147, 165))	('renal cell cancer', 'Phenotype', 'HP:0005584', (181, 198))	('squamous cell cancer of the lung', 'Phenotype', 'HP:0030359', (133, 165))	('clear cell renal cell cancer', 'Phenotype', 'HP:0006770', (170, 198))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('metastatic', 'Disease', (86, 96))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (133, 153))	('primary tumors for squamous cell cancer of the lung', 'Disease', 'MESH:D002294', (114, 165))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('clear cell renal cell cancer', 'Disease', (170, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
8419	29088715	The comparatively high frequencies for some cancers did not bear a simple relationship to the site of metastasis, since most metastases were to lymph nodes for both the metastases that were CXCR4+ and those that were CXCR4-.	('metastases', 'Disease', (125, 135))	('rat', 'Species', '10116', (9, 12))	('metastases', 'Disease', (169, 179))	('CXCR4+', 'Var', (190, 196))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('metastases', 'Disease', 'MESH:D009362', (125, 135))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('metastases', 'Disease', 'MESH:D009362', (169, 179))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
8436	29088715	It has been suggested that ACKR3 and CXCR4 cooperate in enhancing tumor growth, sometimes through separate effects on cancer cells and angiogenesis, and blocking ACKR3 has been shown to diminish growth of tumors in mouse models.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('enhancing', 'PosReg', (56, 65))	('mouse', 'Species', '10090', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('rat', 'Species', '10116', (48, 51))	('diminish', 'NegReg', (186, 194))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('rat', 'Species', '10116', (102, 105))	('tumors', 'Disease', (205, 211))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('ACKR3', 'Gene', (162, 167))	('cancer', 'Disease', (118, 124))	('diminish growth', 'Phenotype', 'HP:0001510', (186, 201))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (205, 210))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('blocking', 'Var', (153, 161))
8441	29088715	In addition, CX3CR1 has been implicated in metastasis of prostate cancer cells and breast cancer cells to bone, and CXCR4 may have a particular role in bone metastasis.	('CX3CR1', 'Gene', (13, 19))	('CXCR4', 'Var', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('implicated', 'Reg', (29, 39))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('metastasis of prostate cancer', 'Disease', 'MESH:D009362', (43, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('CX3CR1', 'Gene', '1524', (13, 19))	('metastasis of prostate cancer', 'Disease', (43, 72))	('bone metastasis', 'CPA', (152, 167))
8447	29088715	We detected significant uptake of 64Cu-plerixafor in organs of the hematopoietic and immune systems, which contain high numbers of CXCR4-expressing cells, including bone marrow, lymph nodes, and spleen.	('64Cu-plerixafor', 'Chemical', '-', (34, 49))	('64Cu-plerixafor', 'Var', (34, 49))	('uptake', 'MPA', (24, 30))
8448	29088715	As in our mouse studies, we also detected accumulation of 64Cu-plerixafor in the liver.	('mouse', 'Species', '10090', (10, 15))	('accumulation', 'PosReg', (42, 54))	('64Cu-plerixafor', 'Var', (58, 73))	('64Cu-plerixafor', 'Chemical', '-', (58, 73))
8456	29088715	The most extensive published data have been with a newly developed synthetic pentapeptide labeled with 68Ga, 68Ga-pentixafor, which has been evaluated recently in patients with lymphoma, multiple myeloma, small cell lung cancer, glioblastoma, neuroendocrine tumors, and other cancers.	('glioblastoma', 'Phenotype', 'HP:0012174', (229, 241))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('multiple myeloma', 'Phenotype', 'HP:0006775', (187, 203))	('68Ga-pentixafor', 'Chemical', 'MESH:C000597686', (109, 124))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (243, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('lymphoma', 'Phenotype', 'HP:0002665', (177, 185))	('multiple myeloma', 'Disease', 'MESH:D009101', (187, 203))	('small cell lung cancer', 'Disease', 'MESH:D055752', (205, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('small cell lung cancer', 'Disease', (205, 227))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('patients', 'Species', '9606', (163, 171))	('cancers', 'Disease', (276, 283))	('neuroendocrine tumors', 'Disease', (243, 264))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('multiple myeloma', 'Disease', (187, 203))	('lymphoma', 'Disease', (177, 185))	('68Ga', 'Var', (103, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (229, 241))	('lymphoma', 'Disease', 'MESH:D008223', (177, 185))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (205, 227))	('glioblastoma', 'Disease', (229, 241))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (243, 264))
8463	29088715	A number of studies are underway assessing the safety and efficacy of CXCR4 antagonists in patients with solid tumors, such as glioblastoma multiforme, and cancers of the pancreas, ovaries, and colon (ClinicalTrials.gov identifiers NCT02179970, NCT02737072, NCT02765165).	('cancers of the pancreas', 'Disease', (156, 179))	('cancers of the pancreas', 'Phenotype', 'HP:0002894', (156, 179))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('glioblastoma multiforme', 'Disease', (127, 150))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (127, 150))	('C', 'Chemical', 'MESH:D003545', (70, 71))	('C', 'Chemical', 'MESH:D003545', (259, 260))	('patients', 'Species', '9606', (91, 99))	('solid tumors', 'Disease', (105, 117))	('C', 'Chemical', 'MESH:D003545', (233, 234))	('C', 'Chemical', 'MESH:D003545', (201, 202))	('ovaries', 'Disease', 'MESH:D010051', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('solid tumors', 'Disease', 'MESH:D009369', (105, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('ovaries', 'Disease', (181, 188))	('NCT02765165', 'Var', (258, 269))	('glioblastoma', 'Phenotype', 'HP:0012174', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('C', 'Chemical', 'MESH:D003545', (72, 73))	('cancers of the pancreas', 'Disease', 'MESH:D010190', (156, 179))	('C', 'Chemical', 'MESH:D003545', (246, 247))
8465	29088715	Human ACC samples were acquired and analyzed from study subjects after obtaining informed consent under National Cancer Institute Center for Cancer Research (NCICCR) protocol "Natural History and Tissue Acquisition Study of Adrenocortical Carcinoma", number 14-C-0029, ClinicalTrials.gov Identifier NCT02015026, and/or under NCICCR protocols 04-C-0011, 08-C-0176, 10-C-0203, 06-C-0014, and 01-C-0129.	('Human', 'Species', '9606', (0, 5))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (224, 248))	('C', 'Chemical', 'MESH:D003545', (239, 240))	('C', 'Chemical', 'MESH:D003545', (356, 357))	('C', 'Chemical', 'MESH:D003545', (7, 8))	('C', 'Chemical', 'MESH:D003545', (261, 262))	('C', 'Chemical', 'MESH:D003545', (300, 301))	('Cancer', 'Disease', 'MESH:D009369', (141, 147))	('C', 'Chemical', 'MESH:D003545', (141, 142))	('C', 'Chemical', 'MESH:D003545', (269, 270))	('06-C-0014', 'Var', (375, 384))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('C', 'Chemical', 'MESH:D003545', (378, 379))	('01-C-0129', 'Var', (390, 399))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (224, 248))	('C', 'Chemical', 'MESH:D003545', (162, 163))	('C', 'Chemical', 'MESH:D003545', (345, 346))	('C', 'Chemical', 'MESH:D003545', (393, 394))	('C', 'Chemical', 'MESH:D003545', (328, 329))	('Cancer', 'Disease', (113, 119))	('C', 'Chemical', 'MESH:D003545', (130, 131))	('C', 'Chemical', 'MESH:D003545', (161, 162))	('C', 'Chemical', 'MESH:D003545', (329, 330))	('Adrenocortical Carcinoma', 'Disease', (224, 248))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ACC', 'Phenotype', 'HP:0006744', (6, 9))	('Carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('C', 'Chemical', 'MESH:D003545', (326, 327))	('10-C-0203', 'Var', (364, 373))	('Cancer', 'Disease', 'MESH:D009369', (113, 119))	('C', 'Chemical', 'MESH:D003545', (113, 114))	('C', 'Chemical', 'MESH:D003545', (367, 368))	('Cancer', 'Disease', (141, 147))	('C', 'Chemical', 'MESH:D003545', (159, 160))	('04-C-0011', 'Var', (342, 351))	('C', 'Chemical', 'MESH:D003545', (8, 9))
8511	28956362	CTNNB1 Mutation in Aldosterone Producing Adenoma Discoveries of somatic mutations permit the recognition of subtypes of aldosterone-producing adenomas (APAs) with distinct clinical presentations and pathological features.	('adenomas', 'Disease', (142, 150))	('mutations', 'Var', (72, 81))	('CTNNB1', 'Gene', '1499', (0, 6))	('Adenoma', 'Disease', (41, 48))	('aldosterone', 'Chemical', 'MESH:D000450', (120, 131))	('CTNNB1', 'Gene', (0, 6))	('Mutation', 'Var', (7, 15))	('Adenoma', 'Disease', 'MESH:D000236', (41, 48))	('adenomas', 'Disease', 'MESH:D000236', (142, 150))
8512	28956362	Catenin beta1 (CTNNB1) mutation in APAs has been recently described and discussed in the literature.	('Catenin beta1', 'Gene', (0, 13))	('Catenin beta1', 'Gene', '1499', (0, 13))	('CTNNB1', 'Gene', (15, 21))	('mutation', 'Var', (23, 31))
8513	28956362	However, significant knowledge gaps still remain regarding the prevalence, clinical characteristics, pathophysiology, and outcomes in APA patients harboring CTNNB1 mutations.	('CTNNB1', 'Gene', (157, 163))	('mutations', 'Var', (164, 173))	('patients', 'Species', '9606', (138, 146))
8514	28956362	Aberrant activation of the Wnt/beta-catenin signaling pathway will further modulate tumorigenesis.	('activation', 'PosReg', (9, 19))	('Wnt/beta-catenin signaling pathway', 'Pathway', (27, 61))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('modulate', 'Reg', (75, 83))
8515	28956362	We also discuss the recent knowledge of CTNNB1 mutation in adrenal adenomas.	('CTNNB1', 'Gene', (40, 46))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (59, 75))	('mutation', 'Var', (47, 55))	('adrenal adenomas', 'Disease', 'MESH:D018246', (59, 75))	('adrenal adenomas', 'Disease', (59, 75))
8517	28956362	In aldosterone-producing adenoma (APA), the majority of somatic mutations were potassium voltage-gated channel subfamily J member 5 (KCNJ5) mutations (ranging from 52.9% to 76.8% in Asia).	('adenoma', 'Disease', 'MESH:D000236', (25, 32))	('aldosterone', 'Chemical', 'MESH:D000450', (3, 14))	('potassium', 'Chemical', 'MESH:D011188', (79, 88))	('adenoma', 'Disease', (25, 32))	('KCNJ5', 'Gene', (133, 138))	('mutations', 'Var', (64, 73))	('mutations', 'Var', (140, 149))	('KCNJ5', 'Gene', '3762', (133, 138))
8518	28956362	Recently, the prevalence of a novel catenin beta1 (CTNNB1) mutation in APAs was 3.7% to 5.1%.	('mutation', 'Var', (59, 67))	('catenin beta1', 'Gene', '1499', (36, 49))	('catenin beta1', 'Gene', (36, 49))	('CTNNB1', 'Gene', (51, 57))
8519	28956362	CTNNB1 mutations were associated with stabilized beta-catenin and increased AXIN2 (axis inhibition protein 2) expression, suggesting the activation of Wnt signaling.	('axis inhibition protein 2', 'Gene', (83, 108))	('increased', 'PosReg', (66, 75))	('axis inhibition protein 2', 'Gene', '8313', (83, 108))	('stabilized', 'MPA', (38, 48))	('CTNNB1', 'Gene', (0, 6))	('Wnt signaling', 'Pathway', (151, 164))	('expression', 'MPA', (110, 120))	('activation', 'PosReg', (137, 147))	('AXIN2', 'Gene', (76, 81))	('AXIN2', 'Gene', '8313', (76, 81))	('beta-catenin', 'Protein', (49, 61))	('mutations', 'Var', (7, 16))
8520	28956362	In APA, CTNNB1 mutations occurred mutually exclusively from KCNJ5, ATPase Na+/K+ transporting subunit alpha1 (ATP1A1), ATPase plasma membrane Ca2+ transporting 3 (ATP2B3), and calcium voltage-gated channel subunit alpha1 D (CACNA1D) mutated tumors, implying that aberrant Wnt activation plays a pivotal role in APA formation.	('KCNJ5', 'Gene', '3762', (60, 65))	('CACNA1D', 'Gene', '776', (224, 231))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('calcium voltage-gated channel subunit alpha1 D', 'Gene', (176, 222))	('mutations', 'Var', (15, 24))	('calcium voltage-gated channel subunit alpha1 D', 'Gene', '776', (176, 222))	('mutated', 'Var', (233, 240))	('ATPase Na+/K+ transporting subunit alpha1', 'Gene', (67, 108))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('ATP2B3', 'Gene', '492', (163, 169))	('ATP2B3', 'Gene', (163, 169))	('KCNJ5', 'Gene', (60, 65))	('CTNNB1', 'Gene', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('ATP1A1', 'Gene', (110, 116))	('ATPase Na+/K+ transporting subunit alpha1', 'Gene', '476', (67, 108))	('tumors', 'Disease', (241, 247))	('ATP1A1', 'Gene', '476', (110, 116))	('CACNA1D', 'Gene', (224, 231))
8521	28956362	Accordingly, tumors with CTNNB1 mutations were associated with relatively large adenomas and predominantly expressed in females.	('tumors', 'Disease', (13, 19))	('adenomas', 'Disease', 'MESH:D000236', (80, 88))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('large adenomas', 'Phenotype', 'HP:0040261', (74, 88))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('adenomas', 'Disease', (80, 88))	('CTNNB1', 'Gene', (25, 31))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('associated', 'Reg', (47, 57))
8524	28956362	Due to alterations in exon 3 of the CTNNB1 gene, mice with activating Wnt signaling develop hyperaldosteronism and adrenocortical tumors.	('CTNNB1', 'Gene', (36, 42))	('adrenocortical tumors', 'Disease', (115, 136))	('hyperaldosteronism', 'Disease', (92, 110))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (92, 110))	('mice', 'Species', '10090', (49, 53))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (115, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (92, 110))	('develop', 'PosReg', (84, 91))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('alterations', 'Var', (7, 18))
8525	28956362	Mutations in CTNNB1 also cause increased and abnormal Wnt activation in human adrenocortical tumors, and augment the Wnt signaling pathway, leading to tumor formation.	('Wnt', 'CPA', (54, 57))	('augment', 'NegReg', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('CTNNB1', 'Gene', (13, 19))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (151, 156))	('leading to', 'Reg', (140, 150))	('adrenocortical tumors', 'Disease', (78, 99))	('human', 'Species', '9606', (72, 77))	('Mutations', 'Var', (0, 9))	('Wnt signaling pathway', 'Pathway', (117, 138))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (78, 99))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
8526	28956362	In one recent series, cases of APAs harboring activating mutations of beta-catenin were described in three women (two during pregnancy and one postmenopausal), who had a heterozygous somatic mutation (C G, p.Ser33Cys in case 1, C T, p.Ser45Phe in case 2, and G A, p.Gly34Arg in case 3) in exon 3 of CTNNB1.	('p.Gly34Arg', 'Var', (264, 274))	('p.Ser33Cys', 'Mutation', 'rs121913400', (206, 216))	('C G', 'Var', (201, 204))	('p.Gly34Arg', 'Mutation', 'rs121913399', (264, 274))	('p.Ser33Cys', 'Var', (206, 216))	('mutations', 'Var', (57, 66))	('CTNNB1', 'Gene', (299, 305))	('women', 'Species', '9606', (107, 112))	('activating', 'PosReg', (46, 56))	('p.Ser45Phe', 'Var', (233, 243))	('p.Ser45Phe', 'Mutation', 'rs121913409', (233, 243))
8527	28956362	All three mutations are predicted to affect a GSK-3beta (glycogen synthase kinase 3beta) phosphorylation consensus motif and could thus impair beta-catenin degradation and up-regulate Wnt activity, resulting in elevated levels of active beta-catenin.	('glycogen synthase kinase 3beta', 'Gene', '2932', (57, 87))	('impair', 'NegReg', (136, 142))	('up-regulate', 'PosReg', (172, 183))	('elevated', 'PosReg', (211, 219))	('glycogen synthase kinase 3beta', 'Gene', (57, 87))	('GSK-3beta', 'Gene', (46, 55))	('affect', 'Reg', (37, 43))	('GSK-3beta', 'Gene', '2932', (46, 55))	('Wnt activity', 'CPA', (184, 196))	('mutations', 'Var', (10, 19))	('phosphorylation consensus motif', 'MPA', (89, 120))	('levels of active beta-catenin', 'MPA', (220, 249))	('beta-catenin degradation', 'MPA', (143, 167))
8529	28956362	A recent study showed that somatic mutations in the KCNJ5, ATP1A1, or CACNA1D genes are not limited to APAs, but are also found in the more frequent multinodular adrenals.	('KCNJ5', 'Gene', (52, 57))	('APAs', 'Disease', (103, 107))	('ATP1A1', 'Gene', '476', (59, 65))	('KCNJ5', 'Gene', '3762', (52, 57))	('found', 'Reg', (122, 127))	('ATP1A1', 'Gene', (59, 65))	('CACNA1D', 'Gene', '776', (70, 77))	('CACNA1D', 'Gene', (70, 77))	('mutations', 'Var', (35, 44))
8531	28956362	The primary hit, consisting of somatic mutation of one of the known genes in about 60% of cases and of other unknown genetic mutation in the remaining patients, can cause aldosterone hypersecretion.	('cause', 'Reg', (165, 170))	('aldosterone hypersecretion', 'Phenotype', 'HP:0000859', (171, 197))	('aldosterone', 'Chemical', 'MESH:D000450', (171, 182))	('patients', 'Species', '9606', (151, 159))	('aldosterone hypersecretion', 'MPA', (171, 197))	('mutation', 'Var', (125, 133))
8534	28956362	APAs harboring CTNNB1 mutation could display CYP11B1 or CYP11B2 heterogeneous expression, or in both CYP11B2-positive and CYP11B2-negative regions.	('CYP11B1', 'Gene', '1584', (45, 52))	('mutation', 'Var', (22, 30))	('CTNNB1', 'Gene', (15, 21))	('CYP11B2', 'Gene', (122, 129))	('CYP11B2', 'Gene', '1585', (122, 129))	('CYP11B2', 'Gene', (56, 63))	('CYP11B2', 'Gene', (101, 108))	('CYP11B1', 'Gene', (45, 52))	('CYP11B2', 'Gene', '1585', (56, 63))	('CYP11B2', 'Gene', '1585', (101, 108))
8535	28956362	It is also consistent with our result that the Wnt/beta-catenin pathway activates downstream cyclin D1 transcription, which is a gene involved in cell growth in adenomas with CTNNB1 mutations compared with wild-type APA adenomas.	('activates', 'PosReg', (72, 81))	('cyclin D1', 'Gene', (93, 102))	('APA adenomas', 'Phenotype', 'HP:0012028', (216, 228))	('CTNNB1', 'Gene', (175, 181))	('adenomas', 'Disease', 'MESH:D000236', (161, 169))	('adenomas', 'Disease', 'MESH:D000236', (220, 228))	('adenomas', 'Disease', (161, 169))	('adenomas', 'Disease', (220, 228))	('cyclin D1', 'Gene', '595', (93, 102))	('mutations', 'Var', (182, 191))
8536	28956362	All of these findings, together with the reported higher prevalence of CTNNB1 mutations among other adrenal adenomas and adrenal cancers, suggest that CTNNB1 mutations may be more related to tumor cell growth (tumorigenesis), rather than to actual aldosterone production.	('aldosterone production', 'Phenotype', 'HP:0000859', (248, 270))	('related', 'Reg', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (100, 116))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('tumor', 'Disease', (210, 215))	('mutations', 'Var', (78, 87))	('CTNNB1', 'Gene', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('adrenal adenomas and adrenal cancers', 'Disease', 'MESH:D000310', (100, 136))	('aldosterone', 'Chemical', 'MESH:D000450', (248, 259))	('mutations', 'Var', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
8538	28956362	APAs harboring CTNNB1 mutations have shown variable expression of CYP11B1 and CYP11B2.	('CYP11B2', 'Gene', (78, 85))	('CTNNB1', 'Gene', (15, 21))	('CYP11B2', 'Gene', '1585', (78, 85))	('mutations', 'Var', (22, 31))	('CYP11B1', 'Gene', (66, 73))	('CYP11B1', 'Gene', '1584', (66, 73))
8539	28956362	Of note, APAs harboring CTNNB1 mutations could express luteinizing hormone/choriogonadotropin receptor (LHCGR) and gonadotropin releasing hormone receptor (GNRHR), encoding gonadal receptors, at levels that were more than 100 times higher than the levels in other APAs in one report.	('LHCGR', 'Gene', '3973', (104, 109))	('mutations', 'Var', (31, 40))	('GNRHR', 'Gene', '2798', (156, 161))	('gonadotropin releasing hormone receptor', 'Gene', '2798', (115, 154))	('luteinizing hormone/choriogonadotropin receptor', 'Gene', '3973', (55, 102))	('CTNNB1', 'Gene', (24, 30))	('gonadotropin releasing hormone receptor', 'Gene', (115, 154))	('LHCGR', 'Gene', (104, 109))	('luteinizing hormone/choriogonadotropin receptor', 'Gene', (55, 102))	('GNRHR', 'Gene', (156, 161))
8540	28956362	Constitutive activation of the Wnt signaling pathway in ZG-like adenomatous cells could lead to de-differentiation toward the common adrenal-gonadal precursor cell type, and to the aberrant expression of gonadal receptors LHCGR and/or GNRHR.	('LHCGR', 'Gene', (222, 227))	('lead to', 'Reg', (88, 95))	('aberrant', 'Var', (181, 189))	('expression', 'MPA', (190, 200))	('activation', 'PosReg', (13, 23))	('LHCGR', 'Gene', '3973', (222, 227))	('Wnt signaling pathway', 'Pathway', (31, 52))	('adenomatous', 'Disease', (64, 75))	('GNRHR', 'Gene', (235, 240))	('adenomatous', 'Disease', 'MESH:D011125', (64, 75))	('de-differentiation toward the common', 'CPA', (96, 132))	('GNRHR', 'Gene', '2798', (235, 240))
8541	28956362	However, GNRHR could present diffuse cytoplasmic, membranous, and nuclear expression in adenomas, and was especially enhanced in adenomas harboring CTNNB1 mutations from female patients.	('adenomas', 'Disease', 'MESH:D000236', (88, 96))	('mutations', 'Var', (155, 164))	('adenomas', 'Disease', 'MESH:D000236', (129, 137))	('adenomas', 'Disease', (88, 96))	('patients', 'Species', '9606', (177, 185))	('adenomas', 'Disease', (129, 137))	('GNRHR', 'Gene', (9, 14))	('enhanced', 'PosReg', (117, 125))	('GNRHR', 'Gene', '2798', (9, 14))	('CTNNB1', 'Gene', (148, 154))	('diffuse cytoplasmic', 'MPA', (29, 48))
8542	28956362	GNRHR was attenuated in KCNJ5 mutated adenomas.	('GNRHR', 'Gene', (0, 5))	('attenuated', 'NegReg', (10, 20))	('GNRHR', 'Gene', '2798', (0, 5))	('KCNJ5', 'Gene', '3762', (24, 29))	('mutated', 'Var', (30, 37))	('adenomas', 'Disease', 'MESH:D000236', (38, 46))	('adenomas', 'Disease', (38, 46))	('KCNJ5', 'Gene', (24, 29))
8543	28956362	LHCGR was diffusely expressed in adrenal tissues and was prominent in adenomas harboring CTNNB1 mutations.	('adenomas', 'Disease', (70, 78))	('CTNNB1', 'Gene', (89, 95))	('LHCGR', 'Gene', (0, 5))	('LHCGR', 'Gene', '3973', (0, 5))	('adenomas', 'Disease', 'MESH:D000236', (70, 78))	('mutations', 'Var', (96, 105))
8544	28956362	Compared with KCNJ5 mutated APAs, no difference in CYP11B1 expression levels were observed, but significantly higher CYP11B2 expression was observed in CTNNB1 mutated tumors in a single report.	('KCNJ5', 'Gene', (14, 19))	('CYP11B1', 'Gene', '1584', (51, 58))	('mutated', 'Var', (159, 166))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('CYP11B1', 'Gene', (51, 58))	('KCNJ5', 'Gene', '3762', (14, 19))	('expression', 'MPA', (125, 135))	('expression', 'MPA', (59, 69))	('CYP11B2', 'Gene', (117, 124))	('CYP11B2', 'Gene', '1585', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('higher', 'PosReg', (110, 116))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('CTNNB1', 'Gene', (152, 158))
8545	28956362	CTNNB1 mutated APAs were more often observed in female patients (60% to 75%) and older patients, with a shorter duration of hypertension.	('observed', 'Reg', (36, 44))	('CTNNB1', 'Gene', (0, 6))	('hypertension', 'Disease', 'MESH:D006973', (124, 136))	('hypertension', 'Phenotype', 'HP:0000822', (124, 136))	('APAs', 'Protein', (15, 19))	('hypertension', 'Disease', (124, 136))	('patients', 'Species', '9606', (55, 63))	('mutated', 'Var', (7, 14))	('patients', 'Species', '9606', (87, 95))
8546	28956362	There were no significant differences in preoperative aldosterone levels, tumor size at surgery, and the ratio of parental hypertension in patients with tumors harboring CTNNB1 mutations compared to those with tumors harboring KCNJ5 mutations.	('mutations', 'Var', (177, 186))	('hypertension', 'Disease', (123, 135))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Disease', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('aldosterone', 'Chemical', 'MESH:D000450', (54, 65))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (153, 158))	('hypertension', 'Phenotype', 'HP:0000822', (123, 135))	('CTNNB1', 'Gene', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('KCNJ5', 'Gene', (227, 232))	('patients', 'Species', '9606', (139, 147))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('aldosterone levels', 'MPA', (54, 72))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('KCNJ5', 'Gene', '3762', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('hypertension', 'Disease', 'MESH:D006973', (123, 135))
8547	28956362	However, CTNNB1 mutations led to higher serum potassium and creatinine levels compared to KCNJ5 mutations in one study.	('higher', 'PosReg', (33, 39))	('KCNJ5', 'Gene', (90, 95))	('mutations', 'Var', (16, 25))	('higher serum potassium', 'Phenotype', 'HP:0002153', (33, 55))	('KCNJ5', 'Gene', '3762', (90, 95))	('CTNNB1', 'Gene', (9, 15))	('creatinine', 'Chemical', 'MESH:D003404', (60, 70))	('potassium', 'Chemical', 'MESH:D011188', (46, 55))
8548	28956362	Patients with tumors harboring CTNNB1 mutation have a small but increased risk of malignant transformation.	('CTNNB1', 'Gene', (31, 37))	('tumors', 'Disease', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('malignant transformation', 'CPA', (82, 106))	('mutation', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
8552	28956362	Adrenal carcinomas harboring CTNNB1 mutation are also extremely rare.	('Adrenal carcinomas', 'Disease', 'MESH:D000310', (0, 18))	('Adrenal carcinomas', 'Disease', (0, 18))	('Adrenal carcinomas', 'Phenotype', 'HP:0006744', (0, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (8, 18))	('CTNNB1', 'Gene', (29, 35))	('mutation', 'Var', (36, 44))
8553	28956362	According to our study, CTNNB1 mutation carriers had a higher possibility (87.5%) of residual hypertension than other APA patients after adrenalectomy.	('hypertension', 'Phenotype', 'HP:0000822', (94, 106))	('CTNNB1', 'Gene', (24, 30))	('mutation', 'Var', (31, 39))	('patients', 'Species', '9606', (122, 130))	('hypertension', 'Disease', 'MESH:D006973', (94, 106))	('hypertension', 'Disease', (94, 106))
8554	28956362	Compared with KCNJ5 mutation carriers (12.5% vs. 79.3%, P<0.001), CTNNB1 mutation carriers had a much lower chance of recovery from hypertension, even after 1-year follow-up.	('lower', 'NegReg', (102, 107))	('hypertension', 'Phenotype', 'HP:0000822', (132, 144))	('KCNJ5', 'Gene', (14, 19))	('recovery', 'MPA', (118, 126))	('KCNJ5', 'Gene', '3762', (14, 19))	('CTNNB1', 'Gene', (66, 72))	('hypertension', 'Disease', 'MESH:D006973', (132, 144))	('mutation', 'Var', (73, 81))	('hypertension', 'Disease', (132, 144))
8555	28956362	One of the possible explanations of the higher postadrenalectomy residual hypertension among patients harboring CTNNB1 mutations could be that age-related essential hypertension plays an important role in the hypertension observed in these patients.	('CTNNB1', 'Gene', (112, 118))	('hypertension', 'Disease', 'MESH:D006973', (209, 221))	('higher', 'PosReg', (40, 46))	('hypertension', 'Disease', 'MESH:D006973', (165, 177))	('hypertension', 'Disease', (74, 86))	('hypertension', 'Phenotype', 'HP:0000822', (74, 86))	('hypertension', 'Disease', (165, 177))	('hypertension', 'Phenotype', 'HP:0000822', (165, 177))	('hypertension', 'Disease', (209, 221))	('patients', 'Species', '9606', (240, 248))	('hypertension', 'Phenotype', 'HP:0000822', (209, 221))	('mutations', 'Var', (119, 128))	('hypertension', 'Disease', 'MESH:D006973', (74, 86))	('patients', 'Species', '9606', (93, 101))
8556	28956362	CTNNB1 mutations and activation of the Wnt/beta-catenin pathway are also found in other benign and malignant adrenocortical neoplasms that do not produce aldosterone, including cortisol producing adenomas (CPA).	('neoplasms', 'Phenotype', 'HP:0002664', (124, 133))	('CPA', 'Chemical', '-', (206, 209))	('cortisol', 'Chemical', 'MESH:D006854', (177, 185))	('aldosterone', 'Chemical', 'MESH:D000450', (154, 165))	('Wnt/beta-catenin pathway', 'Pathway', (39, 63))	('CTNNB1', 'Gene', (0, 6))	('malignant adrenocortical neoplasms', 'Disease', 'MESH:D009369', (99, 133))	('adenomas', 'Disease', 'MESH:D000236', (196, 204))	('adenomas', 'Disease', (196, 204))	('activation', 'PosReg', (21, 31))	('malignant adrenocortical neoplasms', 'Disease', (99, 133))	('mutations', 'Var', (7, 16))
8558	28956362	CTNNB1 mutation has been described in a 4-month-old Thai infant with Cushing's syndrome secondary to bilateral adrenal tumors with hepatic metastasis.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('hepatic metastasis', 'Disease', 'MESH:D009362', (131, 149))	('bilateral adrenal tumors', 'Disease', (101, 125))	('CTNNB1', 'Gene', (0, 6))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (69, 87))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (69, 87))	('bilateral adrenal tumors', 'Disease', 'MESH:D000310', (101, 125))	('mutation', 'Var', (7, 15))	("Cushing's syndrome", 'Disease', (69, 87))	('infant', 'Species', '9606', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('adrenal tumor', 'Phenotype', 'HP:0100631', (111, 124))	('hepatic metastasis', 'Disease', (131, 149))
8559	28956362	Following molecular investigations, a deletion mutation of beta-catenin involving codons 44 to 45 was detected in the right adrenal tumor and peripheral blood of this patient, which indicates systemic mutation.	('deletion mutation', 'Var', (38, 55))	('right adrenal tumor', 'Disease', (118, 137))	('patient', 'Species', '9606', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('right adrenal tumor', 'Disease', 'MESH:D000310', (118, 137))	('adrenal tumor', 'Phenotype', 'HP:0100631', (124, 137))	('beta-catenin', 'Protein', (59, 71))
8561	28956362	For CPAs, mutations in the catalytic subunit of protein kinase A (PKA) were identified and shown to occur mutually exclusively to CTNNB1 mutations.	('CPAs', 'Gene', (4, 8))	('CPA', 'Chemical', '-', (4, 7))	('PKA', 'Gene', (66, 69))	('mutations', 'Var', (137, 146))	('mutations', 'Var', (10, 19))	('CTNNB1', 'Gene', (130, 136))
8563	28956362	Activating mutations in PKA led to constitutively activated cyclic adenosine monophosphate (cAMP) signaling, causing increased cortisol production and tumor formation.	('cortisol production', 'MPA', (127, 146))	('mutations', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cAMP', 'Chemical', 'MESH:D000242', (92, 96))	('activated', 'PosReg', (50, 59))	('increased', 'PosReg', (117, 126))	('cortisol', 'Chemical', 'MESH:D006854', (127, 135))	('tumor', 'Disease', (151, 156))	('cyclic adenosine monophosphate', 'Chemical', 'MESH:D000242', (60, 90))	('PKA', 'Gene', (24, 27))	('increased cortisol', 'Phenotype', 'HP:0003118', (117, 135))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
8564	28956362	Expression analysis revealed the increased expression of genes involved in the biosynthesis and metabolism of steroids in tumors with protein kinase cAMP-activated catalytic subunit alpha (PRKACA) mutation.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('cAMP', 'Chemical', 'MESH:D000242', (149, 153))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('steroids', 'Chemical', 'MESH:D013256', (110, 118))	('PRKACA', 'Gene', (189, 195))	('increased', 'PosReg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PRKACA', 'Gene', '5566', (189, 195))	('expression', 'MPA', (43, 53))	('mutation', 'Var', (197, 205))
8565	28956362	Somatic gain-of-function mutations in the PRKACA have been found in cortisol-producing adrenocortical adenomas, but the presence of genetic alterations in genes involved in the PKA pathway in APA is currently unknown.	('mutations', 'Var', (25, 34))	('cortisol', 'Chemical', 'MESH:D006854', (68, 76))	('PRKACA', 'Gene', (42, 48))	('PRKACA', 'Gene', '5566', (42, 48))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (87, 110))	('adrenocortical adenomas', 'Disease', (87, 110))	('gain-of-function', 'PosReg', (8, 24))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (87, 110))
8567	28956362	Tumors harboring these mutations have a variable histological and CYP11B2/B1 expression pattern, and show different clinical characteristics, such as female gender dominance and a higher risk of postadrenalectomy residual hypertension.	('hypertension', 'Phenotype', 'HP:0000822', (222, 234))	('hypertension', 'Disease', (222, 234))	('CYP11B2', 'Gene', (66, 73))	('mutations', 'Var', (23, 32))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CYP11B2', 'Gene', '1585', (66, 73))	('hypertension', 'Disease', 'MESH:D006973', (222, 234))
8568	28956362	CTNNB1 mutations in APAs could relate to tumorigenesis rather than aldosterone production by activating Wnt/beta-catenin signaling.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('Wnt/beta-catenin signaling', 'MPA', (104, 130))	('CTNNB1', 'Gene', (0, 6))	('APAs', 'Gene', (20, 24))	('relate', 'Reg', (31, 37))	('activating', 'PosReg', (93, 103))	('aldosterone production', 'Phenotype', 'HP:0000859', (67, 89))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('aldosterone', 'Chemical', 'MESH:D000450', (67, 78))	('mutations', 'Var', (7, 16))
8677	27430645	CYP11B2, CYP11B1, and 3betaHSD were expressed sporadically, and their expression patterns varied significantly among the different tumor portions examined.	('3betaHSD', 'Gene', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('CYP11B2', 'Gene', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('CYP11B2', 'Gene', '1585', (0, 7))	('tumor', 'Disease', (131, 136))	('varied', 'Reg', (90, 96))	('CYP11B1', 'Var', (9, 16))	('3betaHSD', 'Gene', '3283', (22, 30))
8679	27430645	Small tumor cell populations were aldosterone- or cortisol-producing cells, as judged by 3betaHSD coinciding with either CYP11B2 or CYP11B1, respectively.	('CYP11B2', 'Gene', '1585', (121, 128))	('3betaHSD', 'Gene', '3283', (89, 97))	('3betaHSD', 'Gene', (89, 97))	('aldosterone', 'Chemical', 'MESH:D000450', (34, 45))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('CYP11B2', 'Gene', (121, 128))	('CYP11B1', 'Var', (132, 139))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('cortisol', 'Chemical', 'MESH:D006854', (50, 58))
8688	27430645	recently developed monoclonal antibodies for human CYP11B2 and CYP11B1.	('CYP11B2', 'Gene', (51, 58))	('CYP11B2', 'Gene', '1585', (51, 58))	('CYP11B1', 'Var', (63, 70))	('human', 'Species', '9606', (45, 50))
8690	27430645	We herein performed immunohistochemical analyses for CYP11B1, CYP11B2, 3betaHSD, and CYP17 in a case of ACC that presented with subclinical Cushing's syndrome (SCS) and mild primary aldosteronism (PA).	('primary aldosteronism', 'Phenotype', 'HP:0011736', (174, 195))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (140, 158))	('3betaHSD', 'Gene', '3283', (71, 79))	('3betaHSD', 'Gene', (71, 79))	("Cushing's syndrome", 'Disease', (140, 158))	('PA', 'Phenotype', 'HP:0011736', (197, 199))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (140, 158))	('CYP11B2', 'Gene', (62, 69))	('SCS', 'Disease', (160, 163))	('CYP17', 'Gene', '1586', (85, 90))	('CYP17', 'Gene', (85, 90))	('CYP11B2', 'Gene', '1585', (62, 69))	('SCS', 'Disease', 'MESH:D000168', (160, 163))	('mild primary aldosteronism', 'Disease', (169, 195))	('ACC', 'Phenotype', 'HP:0006744', (104, 107))	('CYP11B1', 'Var', (53, 60))
8692	27430645	Single staining for CYP11B2, CYP11B1, 3betaHSD, and CYP17 was performed as previously reported, in which the nucleus was counterstained by hematoxylin.	('hematoxylin', 'Chemical', 'MESH:D006416', (139, 150))	('CYP11B1', 'Var', (29, 36))	('3betaHSD', 'Gene', '3283', (38, 46))	('3betaHSD', 'Gene', (38, 46))	('CYP17', 'Gene', (52, 57))	('CYP11B2', 'Gene', (20, 27))	('CYP11B2', 'Gene', '1585', (20, 27))	('CYP17', 'Gene', '1586', (52, 57))
8701	27430645	PCA/TA was measured as follows: (1) High resolution images (2400 dpi) of immunostained sections for CYP11B2, CYP11B1, and 3betaHSD were captured using a scanner machine.	('3betaHSD', 'Gene', '3283', (122, 130))	('3betaHSD', 'Gene', (122, 130))	('CYP11B2', 'Gene', (100, 107))	('CYP11B2', 'Gene', '1585', (100, 107))	('CYP11B1', 'Var', (109, 116))
8702	27430645	Five sites of CYP11B2-positive area, CYP11B1-positive area, 3betaHSD-positive area, and area negative for these enzymes (black circles in Figs.	('3betaHSD', 'Gene', (60, 68))	('CYP11B2', 'Gene', (14, 21))	('CYP11B2', 'Gene', '1585', (14, 21))	('3betaHSD', 'Gene', '3283', (60, 68))	('CYP11B1-positive', 'Var', (37, 53))
8726	27430645	In order to examine the expression patterns of the steroidogenic enzymes responsible for hormone production, 10 tumor blocks were subjected to immunohistochemical analyses for CYP11B2, CYP11B1, and 3betaHSD (1st and 3rd column panels in Figs.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('CYP11B1', 'Var', (185, 192))	('steroid', 'Chemical', 'MESH:D013256', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CYP11B2', 'Gene', (176, 183))	('tumor', 'Disease', (112, 117))	('3betaHSD', 'Gene', '3283', (198, 206))	('3betaHSD', 'Gene', (198, 206))	('CYP11B2', 'Gene', '1585', (176, 183))
8727	27430645	CYP11B2, CYP11B1, and 3betaHSD were expressed sporadically throughout the tumor with their specific patterns not being associated with each other.	('3betaHSD', 'Gene', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('CYP11B2', 'Gene', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CYP11B2', 'Gene', '1585', (0, 7))	('tumor', 'Disease', (74, 79))	('CYP11B1', 'Var', (9, 16))	('3betaHSD', 'Gene', '3283', (22, 30))
8732	27430645	Mitotic cells (median value [25th percentile value-75th percentile value]) in five CYP11B2-positive area, CYP11B1-positive area, 3betaHSD-positive area, and area negative for these enzymes (black circles in Figs.	('3betaHSD', 'Gene', '3283', (129, 137))	('CYP11B1-positive', 'Var', (106, 122))	('3betaHSD', 'Gene', (129, 137))	('CYP11B2', 'Gene', (83, 90))	('Mitotic cells', 'CPA', (0, 13))	('CYP11B2', 'Gene', '1585', (83, 90))
8745	27430645	However, only a few potential cortisol-producing cells, i.e., cells co-expressing 3betaHSD and CYP11B1, were observed.	('cortisol', 'Chemical', 'MESH:D006854', (30, 38))	('3betaHSD', 'Gene', '3283', (82, 90))	('3betaHSD', 'Gene', (82, 90))	('CYP11B1', 'Var', (95, 102))
8748	27430645	We delineate for the first time the expression patterns of steroidogenic enzymes including CYP11B2 and CYP11B1 in ACC.	('CYP11B2', 'Gene', '1585', (91, 98))	('ACC', 'Phenotype', 'HP:0006744', (114, 117))	('steroidogenic', 'Enzyme', (59, 72))	('steroid', 'Chemical', 'MESH:D013256', (59, 66))	('CYP11B1', 'Var', (103, 110))	('CYP11B2', 'Gene', (91, 98))
8750	27430645	We have found only an old report describing ACC immunohistochemistry using steroidogenic enzyme antibodies including cholesterol side chain cleavage, 3betaHSD, steroid 21-hydroxylase (CYP21), CYP17, and CYP11B1.	('CYP17', 'Gene', (192, 197))	('CYP21', 'Gene', (184, 189))	('3betaHSD', 'Gene', '3283', (150, 158))	('3betaHSD', 'Gene', (150, 158))	('CYP21', 'Gene', '1589', (184, 189))	('steroid', 'Chemical', 'MESH:D013256', (75, 82))	('cholesterol', 'MPA', (117, 128))	('ACC', 'Phenotype', 'HP:0006744', (44, 47))	('CYP11B1', 'Var', (203, 210))	('CYP17', 'Gene', '1586', (192, 197))	('steroid 21-hydroxylase', 'Gene', '1589', (160, 182))	('cholesterol', 'Chemical', 'MESH:D002784', (117, 128))	('steroid 21-hydroxylase', 'Gene', (160, 182))	('steroid', 'Chemical', 'MESH:D013256', (160, 167))
8752	27430645	The antibody for CYP11B1 used in that study was targeted for bovine CYP11B1, which presumably detect both human CYP11B1 and CYP11B2.	('human', 'Species', '9606', (106, 111))	('CYP11B1', 'Var', (112, 119))	('CYP11B2', 'Gene', (124, 131))	('CYP11B2', 'Gene', '1585', (124, 131))	('bovine', 'Species', '9913', (61, 67))
8824	24348556	In conclusion, in ACC patients, mitotane caused significant increases in HDL-c that may counteract the deleterious atherosclerotic effects of LDL-c and Tg rise.	('Tg', 'Chemical', '-', (152, 154))	('LDL-c', 'Gene', '22796', (142, 147))	('LDL-c', 'Gene', (142, 147))	('patients', 'Species', '9606', (22, 30))	('atherosclerotic', 'Disease', (115, 130))	('ACC', 'Phenotype', 'HP:0006744', (18, 21))	('atherosclerotic', 'Disease', 'MESH:D050197', (115, 130))	('mitotane', 'Var', (32, 40))	('mitotane', 'Chemical', 'MESH:D008939', (32, 40))	('increases', 'PosReg', (60, 69))	('HDL-c', 'Protein', (73, 78))
8869	24348556	In our cohort, mitotane therapy was associated with a significant increase in HDL-c, LDL-c, and triglyceride levels.	('increase', 'PosReg', (66, 74))	('LDL-c', 'Gene', (85, 90))	('HDL-c', 'Disease', (78, 83))	('mitotane', 'Chemical', 'MESH:D008939', (15, 23))	('LDL-c', 'Gene', '22796', (85, 90))	('mitotane', 'Var', (15, 23))	('triglyceride', 'Chemical', 'MESH:D014280', (96, 108))	('triglyceride levels', 'MPA', (96, 115))
8872	24348556	Mitotane as adjuvant therapy has been associated with improved ACC outcomes in a large series of patients analyzed retrospectively, but it also has multiple adverse effects, which were prospectively assessed and summarized in 17 ACC patients by Daffara et al.. Our work validated the previous observation that mitotane treatment is associated with an increase in HDL-c of about 60-65%, which was directly correlated with serum mitotane concentrations.	('increase', 'PosReg', (351, 359))	('men', 'Species', '9606', (324, 327))	('HDL-c', 'Disease', (363, 368))	('ACC', 'Phenotype', 'HP:0006744', (229, 232))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('mitotane', 'Chemical', 'MESH:D008939', (427, 435))	('ACC', 'Phenotype', 'HP:0006744', (63, 66))	('mitotane', 'Var', (310, 318))	('patients', 'Species', '9606', (233, 241))	('mitotane', 'Chemical', 'MESH:D008939', (310, 318))	('patients', 'Species', '9606', (97, 105))
8875	24348556	We also validated the previous reports of a marked increase in LDL-c with mitotane therapy.	('increase', 'PosReg', (51, 59))	('LDL-c', 'Gene', (63, 68))	('LDL-c', 'Gene', '22796', (63, 68))	('mitotane', 'Var', (74, 82))	('mitotane', 'Chemical', 'MESH:D008939', (74, 82))
8890	24348556	The carriers of a mutation in SR-BI had increased HDL-c levels without increases in atherosclerosis and had reduced adrenal steroidogenesis.	('atherosclerosis', 'Disease', 'MESH:D050197', (84, 99))	('atherosclerosis', 'Phenotype', 'HP:0002621', (84, 99))	('SR-BI', 'Gene', (30, 35))	('reduced', 'NegReg', (108, 115))	('HDL-c levels', 'MPA', (50, 62))	('atherosclerosis', 'Disease', (84, 99))	('increased', 'PosReg', (40, 49))	('mutation', 'Var', (18, 26))	('SR-BI', 'Gene', '949', (30, 35))	('adrenal steroidogenesis', 'MPA', (116, 139))	('increased HDL', 'Phenotype', 'HP:0012184', (40, 53))
8892	24348556	Studies are needed to investigate whether mitotane causes SR-BI dysfunction and whether the corresponding increase in HDL-c is atherogenic.	('BI dysfunction', 'Disease', (61, 75))	('SR-BI', 'Gene', '949', (58, 63))	('mitotane', 'Var', (42, 50))	('SR-BI', 'Gene', (58, 63))	('mitotane', 'Chemical', 'MESH:D008939', (42, 50))	('causes', 'Reg', (51, 57))	('BI dysfunction', 'Disease', 'MESH:D006331', (61, 75))	('increase', 'PosReg', (106, 114))	('HDL-c', 'Gene', (118, 123))
8894	24348556	Glucocorticosteroids replacement during mitotane therapy is unlikely to explain HDL-c rise as glucocorticosteroids are often associated with increased plasma levels of total cholesterol, LDL-c, and triglycerides with decreased plasma levels of HDL-c.	('increased plasma levels of total cholesterol', 'Phenotype', 'HP:0003124', (141, 185))	('LDL-c', 'Gene', (187, 192))	('triglycerides', 'MPA', (198, 211))	('men', 'Species', '9606', (28, 31))	('total cholesterol', 'MPA', (168, 185))	('increased', 'PosReg', (141, 150))	('cholesterol', 'Chemical', 'MESH:D002784', (174, 185))	('LDL-c', 'Gene', '22796', (187, 192))	('triglycerides', 'Chemical', 'MESH:D014280', (198, 211))	('glucocorticosteroids', 'Chemical', '-', (94, 114))	('glucocorticosteroids', 'Var', (94, 114))	('decreased plasma levels of HDL', 'Phenotype', 'HP:0003233', (217, 247))	('plasma levels', 'MPA', (151, 164))	('mitotane', 'Chemical', 'MESH:D008939', (40, 48))
8923	23367496	It seems that high rate of mutations in the tumor suppressor gene P53 (TP53) can be a contributory factor in this unexpectedly high prevalence.	('mutations', 'Var', (27, 36))	('P53', 'Gene', '7157', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('P53', 'Gene', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('P53', 'Gene', (72, 75))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('P53', 'Gene', '7157', (66, 69))	('tumor', 'Disease', (44, 49))
8994	23028800	p53 Stabilization Induces Cell Growth Inhibition and Affects IGF2 Pathway in Response to Radiotherapy in Adrenocortical Cancer Cells Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis.	('endocrine tumour', 'Phenotype', 'HP:0100568', (179, 195))	('Cell Growth Inhibition', 'CPA', (26, 48))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('Adrenocortical Cancer', 'Disease', (105, 126))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('Affects', 'Reg', (53, 60))	('tumour', 'Disease', (189, 195))	('IGF2', 'Gene', (61, 65))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('ACC', 'Phenotype', 'HP:0006744', (159, 162))	('p53', 'Gene', '7157', (0, 3))	('endocrine tumour', 'Disease', 'MESH:D004701', (179, 195))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (133, 157))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('tumour', 'Disease', (235, 241))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Stabilization', 'Var', (4, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('p53', 'Gene', (0, 3))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (133, 157))	('endocrine tumour', 'Disease', (179, 195))	('IGF2', 'Gene', '3481', (61, 65))	('Adrenocortical carcinoma', 'Disease', (133, 157))	('Adrenocortical Cancer', 'Disease', 'MESH:D000306', (105, 126))
8997	23028800	We studied the status of p53 in two adrenocortical cell lines, H295R and SW-13, harbouring non-functioning forms of this protein, owing to the lack of exons 8 and 9 and a point mutation in exon 6, respectively.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('lack', 'NegReg', (143, 147))	('SW-13', 'CellLine', 'CVCL:0542', (73, 78))	('adrenocortical', 'Disease', (36, 50))	('adrenocortical', 'Disease', 'MESH:D018268', (36, 50))	('point mutation', 'Var', (171, 185))
8998	23028800	Moreover, these cell lines show high levels of p-Akt and IGF2, especially H295R.	('IGF2', 'Gene', (57, 61))	('Akt', 'Gene', '207', (49, 52))	('H295R', 'Var', (74, 79))	('Akt', 'Gene', (49, 52))
9015	23028800	Patients affected by Li-Fraumeni syndrome, who inherit germline mutations of TP53, are more likely to develop malignant adrenocortical tumours.	('develop', 'PosReg', (102, 109))	('Li-Fraumeni syndrome', 'Disease', (21, 41))	('malignant adrenocortical tumours', 'Disease', 'MESH:D000306', (110, 142))	('malignant adrenocortical tumours', 'Disease', (110, 142))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('Patients', 'Species', '9606', (0, 8))	('germline mutations', 'Var', (55, 73))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (21, 41))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', '7157', (77, 81))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
9016	23028800	Moreover, a specific mutation in codon 337 (R337H) seems to be responsible for the majority of cases of ACC in the child population of Southern Brazil.	('ACC', 'Disease', (104, 107))	('R337H', 'Var', (44, 49))	('child', 'Species', '9606', (115, 120))	('responsible', 'Reg', (63, 74))	('ACC', 'Phenotype', 'HP:0006744', (104, 107))	('R337H', 'Mutation', 'rs121912664', (44, 49))
9020	23028800	Here, we showed that the restoration of p53 activity, by transfection of wild type p53 (wtp53), led to inhibition of growth and induced cell death by apoptosis following IR administration in both cell lines.	('p53', 'Gene', (90, 93))	('cell death', 'CPA', (136, 146))	('p53', 'Gene', (83, 86))	('transfection', 'Var', (57, 69))	('growth', 'CPA', (117, 123))	('p53', 'Gene', '7157', (83, 86))	('p53', 'Gene', '7157', (90, 93))	('p53', 'Gene', (40, 43))	('activity', 'MPA', (44, 52))	('p53', 'Gene', '7157', (40, 43))	('inhibition', 'NegReg', (103, 113))
9026	23028800	Sequencing analysis of TP53 coding sequence in SW-13 cells confirmed the presence of a homozygous point mutation in exon 6 (r.577c>u), which was described for the first time by Reincke et al.	('r.577c>u', 'Var', (124, 132))	('r.577c>u', 'SUBSTITUTION', 'None', (124, 132))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('SW-13', 'CellLine', 'CVCL:0542', (47, 52))
9028	23028800	Moreover, we identified a polymorphism in codon 72 (CCC to CGC) (Figure 1, panel A, bottom) in this cell line, resulting in an amino acid substitution at this position (arginine instead of proline) (Figure 1, panel C, bottom).	('arginine', 'Chemical', 'MESH:D001120', (169, 177))	('72 (CCC to CGC', 'Mutation', 'c.72CCC>CGC', (48, 62))	('CCC to CGC', 'Gene', (52, 62))	('arginine', 'Var', (169, 177))	('proline', 'Chemical', 'MESH:D011392', (189, 196))	('in an', 'Reg', (121, 126))	('amino', 'Var', (127, 132))	('polymorphism', 'Var', (26, 38))
9030	23028800	To assess the significance of TP53 mutations on cell proliferation, we transiently transfected H295R and SW-13 cells with empty vector (mock) or a vector expressing the wild type form of TP53 (WT) and evaluated the effect on cell growth 24, 48 and 72 hours after transfection.	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', '7157', (187, 191))	('TP53', 'Gene', (187, 191))	('TP53', 'Gene', '7157', (30, 34))	('SW-13', 'CellLine', 'CVCL:0542', (105, 110))	('mutations', 'Var', (35, 44))
9040	23028800	In SK-OV-3 cells (Figure 2, panel A, bottom), the restoration of wtp53 induced a slight inhibition of cell growth, which however did not exceed 17% after 72 h. We also observed that IR treatment at a dose of 6 Gy induced a growth inhibition of -27% (p<0.05) after 24 h in cells transfected with empty vector, which reached -35% (p<0.01) after 48 h. However, the presence of wtp53 strengthened the effect of IR treatment.	('SK-OV-3', 'CellLine', 'CVCL:0532', (3, 10))	('strengthened', 'PosReg', (380, 392))	('presence', 'Var', (362, 370))	('p53', 'Gene', '7157', (67, 70))	('p53', 'Gene', (376, 379))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (376, 379))
9084	23028800	Even in this case, no effect on IGF2 expression was observed after IR administration in cells expressing endogenous mutant p53, while a strong decrease in IGF2 mRNA levels was observed in cells transfected with wtp53 vector.	('endogenous mutant', 'Var', (105, 122))	('decrease', 'NegReg', (143, 151))	('IGF2 mRNA levels', 'MPA', (155, 171))	('p53', 'Gene', (123, 126))	('p53', 'Gene', (213, 216))	('p53', 'Gene', '7157', (213, 216))	('p53', 'Gene', '7157', (123, 126))
9089	23028800	In accordance with our data concerning cell proliferation and apoptosis, the effect on Akt phosphorylation was evident at 48 h after transfection (-16% in H295R and -17% in SW-13 cells, respectively) and was maximum at 72 h after transfection (-53% in H295R and -51% in SW-13 cells; p<0.01).	('Akt', 'Gene', (87, 90))	('-16', 'Var', (147, 150))	('H295R', 'Var', (155, 160))	('Akt', 'Gene', '207', (87, 90))	('SW-13', 'CellLine', 'CVCL:0542', (173, 178))	('SW-13', 'CellLine', 'CVCL:0542', (270, 275))
9094	23028800	Extensive evidence over the last two decades reporting that p53 is required for efficacy of radiation therapy has generated considerable interest in developing strategies in tumours with defective p53.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('p53', 'Gene', (60, 63))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('tumours', 'Disease', (174, 181))	('p53', 'Gene', (197, 200))	('p53', 'Gene', '7157', (197, 200))	('p53', 'Gene', '7157', (60, 63))	('defective', 'Var', (187, 196))
9095	23028800	In fact, many reports have found a correlation between TP53 mutations and radio-resistance in many cancer cell lines.	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('correlation', 'Interaction', (35, 46))	('radio-resistance', 'CPA', (74, 90))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
9097	23028800	An association between TP53 mutations and Li-Fraumeni syndrome has been found in more than 70% of families affected by this pathology, which means a higher risk of developing ACC, especially during childhood.	('association', 'Interaction', (3, 14))	('child', 'Species', '9606', (198, 203))	('Li-Fraumeni syndrome', 'Disease', (42, 62))	('ACC', 'Phenotype', 'HP:0006744', (175, 178))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (42, 62))	('mutations', 'Var', (28, 37))
9099	23028800	Moreover, LOH in 17p13 locus occurs in about 85% of cases of ACC, but not in benign adrenocortical adenomas.	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (84, 107))	('LOH', 'Var', (10, 13))	('benign adrenocortical adenomas', 'Disease', 'MESH:D018246', (77, 107))	('ACC', 'Phenotype', 'HP:0006744', (61, 64))	('ACC', 'Disease', (61, 64))	('benign adrenocortical adenomas', 'Disease', (77, 107))
9100	23028800	Although, these statistics strongly suggest an extensive role for TP53 mutations in ACC onset, currently no data exist for the association between TP53 status and radiotherapy efficacy in ACC.	('TP53', 'Gene', (147, 151))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('ACC', 'Phenotype', 'HP:0006744', (188, 191))	('mutations', 'Var', (71, 80))	('ACC', 'Disease', (84, 87))	('TP53', 'Gene', '7157', (147, 151))
9109	23028800	These cell lines, especially H295R, are typical of ACC and represent two useful models since they carry different mutations in the TP53 gene.	('mutations', 'Var', (114, 123))	('TP53', 'Gene', (131, 135))	('ACC', 'Phenotype', 'HP:0006744', (51, 54))	('TP53', 'Gene', '7157', (131, 135))
9114	23028800	A major susceptibility to cancer has been observed in homozygous carriers of the arginine allele and a reduction in disease-free and overall survival has been found in proline/arginine heterozygous patients with breast cancer.	('arginine allele', 'Var', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('breast cancer', 'Disease', (212, 225))	('patients', 'Species', '9606', (198, 206))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('proline/arginine', 'Var', (168, 184))	('arginine', 'Chemical', 'MESH:D001120', (81, 89))	('proline', 'Chemical', 'MESH:D011392', (168, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', (219, 225))	('arginine', 'Chemical', 'MESH:D001120', (176, 184))	('reduction', 'NegReg', (103, 112))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))
9115	23028800	p53 mutant in H295R cells lacks part of the DNA binding domain and the entire C-terminal domain and SW-13 cells bare a homozygous point mutation in DBD, suggesting that p53 activity in these cell lines is completely lost.	('lacks', 'NegReg', (26, 31))	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('mutant', 'Var', (4, 10))	('lost', 'NegReg', (216, 220))	('mutation', 'Var', (136, 144))	('p53', 'Gene', (169, 172))	('p53', 'Gene', '7157', (169, 172))	('SW-13', 'CellLine', 'CVCL:0542', (100, 105))	('activity', 'MPA', (173, 181))	('DNA binding', 'Interaction', (44, 55))
9117	23028800	It was previously demonstrated that lack of p53 is responsible for SK-OV-3 cells insensitivity to radiation treatment at low doses, while reintroduction of wild type p53 determines an effect on cell growth and viability in response to irradiation.	('effect', 'Reg', (184, 190))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('SK-OV-3', 'CellLine', 'CVCL:0532', (67, 74))	('lack', 'Var', (36, 40))	('insensitivity', 'NegReg', (81, 94))
9127	23028800	Many post-translational modifications affecting both p53 and Mdm2 prevent p53 degradation, thus allowing this protein to promote cell cycle arrest, senescence and apoptosis.	('apoptosis', 'CPA', (163, 172))	('senescence', 'CPA', (148, 158))	('Mdm2', 'Gene', (61, 65))	('prevent', 'NegReg', (66, 73))	('p53', 'Gene', (74, 77))	('degradation', 'MPA', (78, 89))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('Mdm2', 'Gene', '4193', (61, 65))	('p53', 'Gene', '7157', (74, 77))	('cell cycle arrest', 'CPA', (129, 146))	('promote', 'PosReg', (121, 128))	('modifications', 'Var', (24, 37))
9131	23028800	BCL2 levels were not influenced by irradiation in the absence of wtp53, whereas restoration of p53 led to a strong decrease in its expression.	('restoration', 'Var', (80, 91))	('BCL2', 'Gene', (0, 4))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('expression', 'MPA', (131, 141))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('decrease', 'NegReg', (115, 123))	('BCL2', 'Gene', '596', (0, 4))
9133	23028800	Moreover, our results shed new light on the functional characterization of H295R and SW-13 p53 mutants.	('p53', 'Gene', '7157', (91, 94))	('p53', 'Gene', (91, 94))	('SW-13', 'CellLine', 'CVCL:0542', (85, 90))	('H295R', 'Var', (75, 80))
9134	23028800	In fact, when cells expressing the endogenous mutant forms of p53 were subjected to IR treatment, we observed no effect on apoptosis or BCL2 expression, thus indicating that the mutations we identified cause a loss of the ability of p53 to induce apoptosis.	('BCL2', 'Gene', (136, 140))	('loss', 'NegReg', (210, 214))	('ability', 'MPA', (222, 229))	('apoptosis', 'CPA', (247, 256))	('mutant', 'Var', (46, 52))	('mutations', 'Var', (178, 187))	('p53', 'Gene', '7157', (233, 236))	('BCL2', 'Gene', '596', (136, 140))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('p53', 'Gene', (233, 236))
9136	23028800	Moreover, new therapeutic approaches, based on mutant or inactive p53 re-activation by small molecules, like nutlins, PRIMA-1 and RITA, associated with radiotherapy, may be considered.	('PRIMA-1', 'Gene', (118, 125))	('p53', 'Gene', '7157', (66, 69))	('PRIMA-1', 'Gene', '145270', (118, 125))	('RITA', 'Gene', '84934', (130, 134))	('re-activation', 'PosReg', (70, 83))	('mutant', 'Var', (47, 53))	('p53', 'Gene', (66, 69))	('RITA', 'Gene', (130, 134))
9149	23028800	The absence of these effects in irradiated H295R and SW-13 cells expressing only endogenous mutants of p53 clearly indicates that the wild type form of this protein is required to inhibit the aberrantly activated IGF-II/Akt signal transduction pathway in ACC.	('IGF-II', 'Gene', (213, 219))	('p53', 'Gene', (103, 106))	('IGF-II', 'Gene', '3481', (213, 219))	('inhibit', 'NegReg', (180, 187))	('p53', 'Gene', '7157', (103, 106))	('Akt', 'Gene', '207', (220, 223))	('mutants', 'Var', (92, 99))	('ACC', 'Phenotype', 'HP:0006744', (255, 258))	('SW-13', 'CellLine', 'CVCL:0542', (53, 58))	('Akt', 'Gene', (220, 223))
9154	23028800	The inhibitory effect of wtp53 on IGF-II and Akt may thus promote tumour radio-responsiveness and prevent the onset of aberrant phenotypes due to non-specific recombination, which is one of the major limits to radiation-based therapies.	('IGF-II', 'Gene', (34, 40))	('non-specific', 'Var', (146, 158))	('prevent', 'NegReg', (98, 105))	('Akt', 'Gene', (45, 48))	('p53', 'Gene', '7157', (27, 30))	('IGF-II', 'Gene', '3481', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('promote', 'PosReg', (58, 65))	('inhibitory', 'NegReg', (4, 14))	('Akt', 'Gene', '207', (45, 48))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))	('p53', 'Gene', (27, 30))
9156	23028800	In conclusion, our study demonstrates that functional p53 is able to induce cell growth inhibition and apoptosis in response to radiotherapy in ACC cell lines, independently from their differentiation status and endocrine characteristics.	('apoptosis', 'CPA', (103, 112))	('p53', 'Gene', (54, 57))	('functional', 'Var', (43, 53))	('induce', 'PosReg', (69, 75))	('cell growth inhibition', 'CPA', (76, 98))	('p53', 'Gene', '7157', (54, 57))	('ACC', 'Phenotype', 'HP:0006744', (144, 147))
9158	23028800	Therefore, we postulate that p53 status should be taken into consideration during therapeutic planning, since the presence of wild type p53 may represent a favorable predictive factor for radiotherapy in ACC cases.	('presence', 'Var', (114, 122))	('p53', 'Gene', '7157', (136, 139))	('ACC', 'Phenotype', 'HP:0006744', (204, 207))	('ACC', 'Disease', (204, 207))	('p53', 'Gene', (29, 32))	('p53', 'Gene', '7157', (29, 32))	('p53', 'Gene', (136, 139))
9203	21788046	Cases were limited to patients aged 18 and older with International Disease for Oncology (ICD-O-3) histology code 8370, and primary site codes C740 and C749.	('C749', 'Var', (152, 156))	('Oncology', 'Phenotype', 'HP:0002664', (80, 88))	('patients', 'Species', '9606', (22, 30))	('C740', 'Var', (143, 147))
9251	22848660	Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear.	('Adrenal Aldosterone', 'Phenotype', 'HP:0000859', (31, 50))	('Mutations', 'Var', (90, 99))	('hypertension', 'Disease', (204, 216))	('hypertension', 'Phenotype', 'HP:0000822', (204, 216))	('KCNJ5', 'Gene', '3762', (109, 114))	('cause', 'Reg', (195, 200))	('hypertension', 'Disease', 'MESH:D006973', (204, 216))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (246, 251))	('KCNJ5', 'Gene', (109, 114))
9252	22848660	Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas.	('L168R', 'Mutation', 'rs386352318', (71, 76))	('KCNJ5', 'Gene', '3762', (113, 118))	('adenomas', 'Disease', 'MESH:D000236', (149, 157))	('potassium', 'Chemical', 'MESH:D011188', (95, 104))	('adenomas', 'Disease', (149, 157))	('L168R', 'Var', (71, 76))	('aldosterone', 'Chemical', 'MESH:D000450', (127, 138))	('G151R', 'Var', (62, 67))	('KCNJ5', 'Gene', (113, 118))	('G151R', 'Mutation', 'rs386352319', (62, 67))
9253	22848660	These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation.	('alter', 'Reg', (16, 21))	('cell proliferation', 'CPA', (147, 165))	('result in', 'Reg', (57, 66))	('depolarization', 'NegReg', (92, 106))	('aldosterone', 'Chemical', 'MESH:D000450', (120, 131))	('channel selectivity filter', 'MPA', (26, 52))	('Na+ conductance', 'MPA', (67, 82))	('cell', 'CPA', (87, 91))	('aldosterone production', 'MPA', (120, 142))	('stimulating', 'PosReg', (108, 119))	('aldosterone production', 'Phenotype', 'HP:0000859', (120, 142))	('stimulating aldosterone production', 'Phenotype', 'HP:0000859', (108, 142))	('mutations', 'Var', (6, 15))
9254	22848660	Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production.	('Mendelian form of primary aldosteronism', 'Phenotype', 'HP:0011739', (39, 78))	('aldosterone', 'MPA', (147, 158))	('aldosterone production', 'Phenotype', 'HP:0000859', (147, 169))	('form of primary aldosteronism', 'Phenotype', 'HP:0011739', (49, 78))	('aldosterone', 'Chemical', 'MESH:D000450', (147, 158))	('mutation', 'Var', (18, 26))	('primary aldosteronism', 'Disease', (57, 78))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (57, 78))
9255	22848660	The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.	('adrenocortical lesions', 'Disease', 'MESH:C565972', (72, 94))	('adrenocortical lesions', 'Disease', (72, 94))	('KCNJ5', 'Gene', (31, 36))	('mutations', 'Var', (37, 46))	('KCNJ5', 'Gene', '3762', (31, 36))
9258	22848660	G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency.	('L168R', 'Var', (9, 14))	('G151R', 'Var', (0, 5))	('G151R', 'Mutation', 'rs386352319', (0, 5))	('adenomas', 'Disease', 'MESH:D000236', (81, 89))	('aldosterone', 'Chemical', 'MESH:D000450', (59, 70))	('adenomas', 'Disease', (81, 89))	('L168R', 'Mutation', 'rs386352318', (9, 14))
9260	22848660	Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia.	('hyperplasia', 'Disease', 'MESH:D006965', (113, 124))	('G151R', 'Mutation', 'rs386352319', (8, 13))	('men', 'Species', '9606', (142, 145))	('unilateral hyperplasia', 'Phenotype', 'HP:0001528', (159, 181))	('hyperplasia', 'Disease', (170, 181))	('L168R', 'Mutation', 'rs386352318', (17, 22))	('adenomas', 'Disease', 'MESH:D000236', (81, 89))	('hyperplasia', 'Disease', (113, 124))	('unilateral hyperplasia', 'Disease', 'MESH:D006965', (159, 181))	('aldosterone', 'Chemical', 'MESH:D000450', (59, 70))	('adenomas', 'Disease', (81, 89))	('hyperplasia', 'Disease', 'MESH:D006965', (170, 181))	('unilateral hyperplasia', 'Disease', (159, 181))	('G151R', 'Var', (8, 13))	('L168R', 'Var', (17, 22))
9262	22848660	KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%).	('aldosterone', 'Chemical', 'MESH:D000450', (40, 51))	('adenomas', 'Disease', (62, 70))	('KCNJ5', 'Gene', '3762', (0, 5))	('overrepresented', 'PosReg', (21, 36))	('patients', 'Species', '9606', (100, 108))	('adenomas', 'Disease', 'MESH:D000236', (62, 70))	('KCNJ5', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
9263	22848660	Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005).	('KCNJ5', 'Gene', (11, 16))	('larger', 'PosReg', (149, 155))	('KCNJ5', 'Gene', '3762', (11, 16))	('KCNJ5', 'Gene', (128, 133))	('APA', 'Gene', '2028', (118, 121))	('mutations', 'Var', (134, 143))	('KCNJ5', 'Gene', '3762', (128, 133))	('APA', 'Gene', (118, 121))	('mutations', 'Var', (17, 26))
9264	22848660	Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions.	('aldosterone producing lesions', 'Disease', (76, 105))	('KCNJ5', 'Gene', (22, 27))	('aldosterone', 'Chemical', 'MESH:D000450', (76, 87))	('mutations', 'Var', (28, 37))	('KCNJ5', 'Gene', '3762', (22, 27))
9269	22848660	Hypersecretion of aldosterone causes increased renal sodium retention and potassium excretion, and the diagnosis was in the past only recognized in hypertensive patients with hypokalemia.	('potassium excretion', 'MPA', (74, 93))	('hypokalemia', 'Phenotype', 'HP:0002900', (175, 186))	('sodium', 'Chemical', 'MESH:D012964', (53, 59))	('potassium', 'Chemical', 'MESH:D011188', (74, 83))	('hypertensive', 'Disease', 'MESH:D006973', (148, 160))	('renal sodium retention', 'MPA', (47, 69))	('hypertensive', 'Disease', (148, 160))	('hypokalemia', 'Disease', (175, 186))	('patients', 'Species', '9606', (161, 169))	('increased', 'PosReg', (37, 46))	('hypokalemia', 'Disease', 'MESH:D007008', (175, 186))	('renal sodium retention', 'Phenotype', 'HP:0012606', (47, 69))	('Hypersecretion of aldosterone', 'Phenotype', 'HP:0000859', (0, 29))	('aldosterone', 'Chemical', 'MESH:D000450', (18, 29))	('Hypersecretion', 'Var', (0, 14))
9277	22848660	Recently, exome sequencing has identified either of two recurrent somatic mutations (G151R and L168R) in the inwardly rectifying potassium channel KCNJ5 (Kir3.4, GIRK4) in APAs, these results were verified in other studies.	('KCNJ5', 'Gene', (147, 152))	('GIRK4', 'Gene', (162, 167))	('GIRK4', 'Gene', '3762', (162, 167))	('potassium', 'Chemical', 'MESH:D011188', (129, 138))	('G151R', 'Var', (85, 90))	('Kir3.4', 'Gene', '3762', (154, 160))	('L168R', 'Mutation', 'rs386352318', (95, 100))	('KCNJ5', 'Gene', '3762', (147, 152))	('APA', 'Gene', '2028', (172, 175))	('APA', 'Gene', (172, 175))	('L168R', 'Var', (95, 100))	('G151R', 'Mutation', 'rs386352319', (85, 90))	('Kir3.4', 'Gene', (154, 160))
9278	22848660	Germline KCNJ5 mutations (G151R, G151E and T158A) were also reported to cause a rare dominant form of primary aldosteronism, Familial hyperaldosteronism type III.	('primary aldosteronism', 'Disease', (102, 123))	('G151R', 'Var', (26, 31))	('Familial hyperaldosteronism type III', 'Disease', (125, 161))	('KCNJ5', 'Gene', (9, 14))	('G151E', 'Var', (33, 38))	('T158A', 'Var', (43, 48))	('T158A', 'Mutation', 'rs387906778', (43, 48))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (134, 152))	('G151R', 'Mutation', 'rs386352319', (26, 31))	('form of primary aldosteronism', 'Phenotype', 'HP:0011739', (94, 123))	('cause', 'Reg', (72, 77))	('G151E', 'Mutation', 'rs587777437', (33, 38))	('KCNJ5', 'Gene', '3762', (9, 14))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (102, 123))	('Familial hyperaldosteronism type', 'Phenotype', 'HP:0011739', (125, 157))	('Familial hyperaldosteronism type III', 'Disease', 'MESH:D003480', (125, 161))
9279	22848660	All these mutations were shown to alter the selectivity filter of KCNJ5, resulting in a channel that can conduct Na+ as well as K+.	('KCNJ5', 'Gene', (66, 71))	('KCNJ5', 'Gene', '3762', (66, 71))	('alter', 'Reg', (34, 39))	('mutations', 'Var', (10, 19))	('selectivity', 'MPA', (44, 55))
9281	22848660	We now report analysis of KCNJ5 gene mutations in a large multi-center cohort of adrenocortical tumors.	('KCNJ5', 'Gene', '3762', (26, 31))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (81, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (37, 46))	('adrenocortical tumors', 'Disease', (81, 102))	('KCNJ5', 'Gene', (26, 31))
9294	22848660	GenBank accession numbers were: NP_000881.3 (human), NP_034735.3 (mouse), XP_417864.2 (chicken), NP_001016901.1 (frog), XP_700619.4 (zebrafish), and XP_002122831.1 (tunicate).	('XP_417864.2', 'Var', (74, 85))	('mouse', 'Species', '10090', (66, 71))	('NP_034735.3', 'Var', (53, 64))	('NP_001016901.1', 'Var', (97, 111))	('XP_002122831.1', 'Var', (149, 163))	('human', 'Species', '9606', (45, 50))	('XP_700619.4', 'Var', (120, 131))	('chicken', 'Species', '9031', (87, 94))	('zebrafish', 'Species', '7955', (133, 142))
9295	22848660	ANOVA, mixed model, was used for comparison between two groups based on absence or presence of KCNJ5 mutations, followed by Chi square test.	('KCNJ5', 'Gene', (95, 100))	('mutations', 'Var', (101, 110))	('KCNJ5', 'Gene', '3762', (95, 100))
9296	22848660	In total KCNJ5 mutations were identified in 157 of 348 (45%) of aldosterone producing lesions (Table 1).	('KCNJ5', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))	('aldosterone producing lesions', 'Disease', (64, 93))	('aldosterone', 'Chemical', 'MESH:D000450', (64, 75))	('KCNJ5', 'Gene', '3762', (9, 14))	('identified', 'Reg', (30, 40))
9297	22848660	Of these, 155 resulted in the previously reported G151R and L168R substitutions (found in 24% and 20% of all samples, respectively) (Figure 1).	('G151R', 'Var', (50, 55))	('L168R', 'Var', (60, 65))	('G151R', 'Mutation', 'rs386352319', (50, 55))	('L168R', 'Mutation', 'rs386352318', (60, 65))
9298	22848660	In addition, two APAs had a single base substitution resulting in a novel E145Q mutation located near the selectivity filter at a highly conserved position (Figure 1 and 2).	('APA', 'Gene', (17, 20))	('E145Q', 'Var', (74, 79))	('E145Q', 'Mutation', 'p.E145Q', (74, 79))	('APA', 'Gene', '2028', (17, 20))
9299	22848660	G151R, L168R, T158A as well as I157S and G151E substitutions have been shown to affect protein structure and disturb selectivity filter specificity, thus it is likely that E145Q would also affect the selectivity filter specificity.	('selectivity filter specificity', 'MPA', (117, 147))	('affect', 'Reg', (80, 86))	('affect', 'Reg', (189, 195))	('G151E', 'Var', (41, 46))	('G151E', 'Mutation', 'rs587777437', (41, 46))	('G151R', 'Var', (0, 5))	('disturb', 'NegReg', (109, 116))	('selectivity filter specificity', 'MPA', (200, 230))	('G151R', 'Mutation', 'rs386352319', (0, 5))	('L168R', 'Mutation', 'rs386352318', (7, 12))	('E145Q', 'Mutation', 'p.E145Q', (172, 177))	('I157S', 'Var', (31, 36))	('T158A', 'Var', (14, 19))	('I157S', 'Mutation', 'rs587777438', (31, 36))	('T158A', 'Mutation', 'rs387906778', (14, 19))	('L168R', 'Var', (7, 12))	('E145Q', 'Var', (172, 177))	('protein structure', 'MPA', (87, 104))
9300	22848660	The L168R mutation was observed in one of three adrenocortical carcinomas with excess aldosterone production.	('aldosterone production', 'MPA', (86, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('aldosterone production', 'Phenotype', 'HP:0000859', (86, 108))	('adrenocortical carcinomas', 'Disease', (48, 73))	('L168R', 'Mutation', 'rs386352318', (4, 9))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (48, 72))	('observed', 'Reg', (23, 31))	('excess aldosterone', 'Phenotype', 'HP:0000859', (79, 97))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (48, 73))	('L168R', 'Var', (4, 9))	('aldosterone', 'Chemical', 'MESH:D000450', (86, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (48, 73))
9301	22848660	In all 137 cases in which matched DNA from blood or surrounding normal tissue was available, KCNJ5 mutations were specific to adenomas, consistent with these representing somatic mutations.	('KCNJ5', 'Gene', (93, 98))	('KCNJ5', 'Gene', '3762', (93, 98))	('adenomas', 'Disease', 'MESH:D000236', (126, 134))	('mutations', 'Var', (99, 108))	('adenomas', 'Disease', (126, 134))
9302	22848660	Stratifying by lesion type, 136 mutations were found in 287 APAs in which surrounding hyperplasia was not found (47%).	('hyperplasia', 'Disease', (86, 97))	('APA', 'Gene', (60, 63))	('hyperplasia', 'Disease', 'MESH:D006965', (86, 97))	('mutations', 'Var', (32, 41))	('APA', 'Gene', '2028', (60, 63))
9304	22848660	No KCNJ5 mutations were found in 9 specimens with hyperplasia without APA, including sampling selected macronodules of variable size from the same lesion (Table 1).	('KCNJ5', 'Gene', (3, 8))	('mutations', 'Var', (9, 18))	('KCNJ5', 'Gene', '3762', (3, 8))	('hyperplasia', 'Disease', (50, 61))	('APA', 'Gene', '2028', (70, 73))	('men', 'Species', '9606', (40, 43))	('APA', 'Gene', (70, 73))	('hyperplasia', 'Disease', 'MESH:D006965', (50, 61))
9305	22848660	KCNJ5 mutation (L168R) was also found in one of three aldosterone-secreting adrenocortical carcinomas (33%).	('secreting adrenocortical carcinoma', 'Phenotype', 'HP:0011746', (66, 100))	('KCNJ5', 'Gene', '3762', (0, 5))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (76, 101))	('aldosterone', 'Chemical', 'MESH:D000450', (54, 65))	('found', 'Reg', (32, 37))	('L168R', 'Var', (16, 21))	('adrenocortical carcinomas', 'Disease', (76, 101))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (76, 101))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (76, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('mutation (L168R', 'Var', (6, 21))	('KCNJ5', 'Gene', (0, 5))	('L168R', 'Mutation', 'rs386352318', (16, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))
9306	22848660	In contrast, no KCNJ5 mutations were detected in 130 non-aldosterone secreting adrenocortical specimens (Table S2).	('aldosterone', 'Chemical', 'MESH:D000450', (57, 68))	('adrenocortical', 'Disease', (79, 93))	('adrenocortical', 'Disease', 'MESH:D018268', (79, 93))	('KCNJ5', 'Gene', (16, 21))	('men', 'Species', '9606', (99, 102))	('mutations', 'Var', (22, 31))	('KCNJ5', 'Gene', '3762', (16, 21))
9307	22848660	Genotype-phenotype correlation demonstrated a dramatic difference in the prevalence of KCNJ5 mutations in women and men (Figure 3).	('KCNJ5', 'Gene', (87, 92))	('mutations', 'Var', (93, 102))	('men', 'Species', '9606', (108, 111))	('KCNJ5', 'Gene', '3762', (87, 92))	('women', 'Species', '9606', (106, 111))	('men', 'Species', '9606', (116, 119))
9308	22848660	While KCNJ5 mutations were found in 63% of APA's without surrounding hyperplasia in women (112/178), they were present in only 22% of APA's in males (24/109) (Table 1).	('APA', 'Gene', '2028', (43, 46))	('women', 'Species', '9606', (84, 89))	('APA', 'Gene', '2028', (134, 137))	('KCNJ5', 'Gene', '3762', (6, 11))	('APA', 'Gene', (134, 137))	('mutations', 'Var', (12, 21))	('hyperplasia', 'Disease', 'MESH:D006965', (69, 80))	('hyperplasia', 'Disease', (69, 80))	('found', 'Reg', (27, 32))	('KCNJ5', 'Gene', (6, 11))	('APA', 'Gene', (43, 46))
9310	22848660	A similar female bias for KCNJ5 mutations was seen among APAs with surrounding hyperplasia (ratio 2.0:1).	('KCNJ5', 'Gene', '3762', (26, 31))	('APA', 'Gene', '2028', (57, 60))	('hyperplasia', 'Disease', (79, 90))	('APA', 'Gene', (57, 60))	('hyperplasia', 'Disease', 'MESH:D006965', (79, 90))	('mutations', 'Var', (32, 41))	('KCNJ5', 'Gene', (26, 31))
9311	22848660	Females with and without KCNJ5 mutations had surgery at similar ages and their adenomas were of similar size at surgery (Table 1).	('mutations', 'Var', (31, 40))	('KCNJ5', 'Gene', (25, 30))	('KCNJ5', 'Gene', '3762', (25, 30))	('adenomas', 'Disease', 'MESH:D000236', (79, 87))	('adenomas', 'Disease', (79, 87))
9312	22848660	Males with KCNJ5 mutations were in average 9 years younger at the time of surgery than those without (45 vs. 54, respectively; p<0.005).	('KCNJ5', 'Gene', (11, 16))	('KCNJ5', 'Gene', '3762', (11, 16))	('mutations', 'Var', (17, 26))
9313	22848660	APAs with KCNJ5 mutations in male patients were on average 1 cm larger than those without (27.1 mm vs. 17.1 mm; p<0.005); this was attributable to males with G151R mutations having the largest APAs.	('G151R', 'Var', (158, 163))	('APA', 'Gene', (0, 3))	('KCNJ5', 'Gene', '3762', (10, 15))	('APA', 'Gene', '2028', (0, 3))	('mutations', 'Var', (16, 25))	('G151R', 'Mutation', 'rs386352319', (158, 163))	('patients', 'Species', '9606', (34, 42))	('APA', 'Gene', '2028', (193, 196))	('APA', 'Gene', (193, 196))	('KCNJ5', 'Gene', (10, 15))
9316	22848660	The present findings confirm and extend the recent discovery of recurrent mutations in KCNJ5 as a prevalent cause of APA (Table 2).	('KCNJ5', 'Gene', (87, 92))	('mutations', 'Var', (74, 83))	('KCNJ5', 'Gene', '3762', (87, 92))	('APA', 'Gene', '2028', (117, 120))	('APA', 'Gene', (117, 120))	('cause', 'Reg', (108, 113))
9317	22848660	The previously identified mutations resulting in G151R and L168R were found in similar frequencies that together comprise 46% of APAs, which is comparable to other published studies.	('APA', 'Gene', '2028', (129, 132))	('APA', 'Gene', (129, 132))	('L168R', 'Mutation', 'rs386352318', (59, 64))	('G151R', 'Var', (49, 54))	('L168R', 'Var', (59, 64))	('G151R', 'Mutation', 'rs386352319', (49, 54))
9320	22848660	In addition, one KCNJ5 mutation was found in an aldosterone-secreting adrenocortical carcinoma.	('KCNJ5', 'Gene', (17, 22))	('mutation', 'Var', (23, 31))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (70, 94))	('KCNJ5', 'Gene', '3762', (17, 22))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (70, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('secreting adrenocortical carcinoma', 'Phenotype', 'HP:0011746', (60, 94))	('aldosterone', 'Chemical', 'MESH:D000450', (48, 59))	('adrenocortical carcinoma', 'Disease', (70, 94))
9321	22848660	These findings demonstrate that the G151R and L168R mutations account for nearly 99% of KCNJ5 mutations in APAs and suggest that few additional mutations in this gene are unlikely to account for significant fractions of APA.	('G151R', 'Var', (36, 41))	('L168R', 'Var', (46, 51))	('mutations', 'Var', (94, 103))	('APA', 'Gene', (220, 223))	('G151R', 'Mutation', 'rs386352319', (36, 41))	('APA', 'Gene', '2028', (220, 223))	('KCNJ5', 'Gene', (88, 93))	('APA', 'Gene', (107, 110))	('L168R', 'Mutation', 'rs386352318', (46, 51))	('APA', 'Gene', '2028', (107, 110))	('KCNJ5', 'Gene', '3762', (88, 93))
9322	22848660	KCNJ5 mutations were prevalent in tumors in which there was a solitary or dominant nodule; the tumors with mutation were of variable size (6-47 mm) at the time of surgery and patients with and without mutations generally had surgery at similar ages.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('KCNJ5', 'Gene', '3762', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('patients', 'Species', '9606', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('KCNJ5', 'Gene', (0, 5))	('tumors', 'Disease', (95, 101))	('prevalent', 'Reg', (21, 30))	('mutations', 'Var', (6, 15))
9325	22848660	In contrast, no KCNJ5 mutations were found among 9 cases prospectively classified as unilateral hyperplasia with or without multiple nodules despite analyzing DNA from most of the available nodules in each sample (p<0.005 for difference in frequency compared with all APAs).	('unilateral hyperplasia', 'Disease', 'MESH:D006965', (85, 107))	('unilateral hyperplasia', 'Disease', (85, 107))	('unilateral hyperplasia', 'Phenotype', 'HP:0001528', (85, 107))	('KCNJ5', 'Gene', (16, 21))	('APA', 'Gene', '2028', (268, 271))	('mutations', 'Var', (22, 31))	('APA', 'Gene', (268, 271))	('KCNJ5', 'Gene', '3762', (16, 21))
9326	22848660	Similarly, no KCNJ5 mutations were found in other non-aldosterone secreting adrenal lesions, demonstrating their specificity for aldosteronism.	('KCNJ5', 'Gene', (14, 19))	('non-aldosterone secreting adrenal lesions', 'Phenotype', 'HP:0011745', (50, 91))	('aldosterone', 'Chemical', 'MESH:D000450', (54, 65))	('KCNJ5', 'Gene', '3762', (14, 19))	('non-aldosterone secreting', 'Disease', (50, 75))	('mutations', 'Var', (20, 29))
9328	22848660	A striking gender dimorphism in the prevalence of KCNJ5 mutations were observed in this study and by others.	('mutations', 'Var', (56, 65))	('KCNJ5', 'Gene', (50, 55))	('KCNJ5', 'Gene', '3762', (50, 55))
9330	22848660	It appears that this entire excess can be accounted for by the increased prevalence of KCNJ5 mutations among APAs in women compared to men since we observed a 2.6 - fold increase in the prevalence of KCNJ5 mutations in female compared to male APAs.	('APA', 'Gene', '2028', (109, 112))	('APA', 'Gene', '2028', (243, 246))	('mutations', 'Var', (206, 215))	('KCNJ5', 'Gene', (87, 92))	('APA', 'Gene', (109, 112))	('mutations', 'Var', (93, 102))	('APA', 'Gene', (243, 246))	('KCNJ5', 'Gene', (200, 205))	('men', 'Species', '9606', (135, 138))	('KCNJ5', 'Gene', '3762', (87, 92))	('men', 'Species', '9606', (119, 122))	('KCNJ5', 'Gene', '3762', (200, 205))	('women', 'Species', '9606', (117, 122))
9331	22848660	APAs without KCNJ5 mutations actually had a higher prevalence in males than females in our cohort.	('APA', 'Gene', (0, 3))	('KCNJ5', 'Gene', '3762', (13, 18))	('APA', 'Gene', '2028', (0, 3))	('mutations', 'Var', (19, 28))	('prevalence', 'MPA', (51, 61))	('KCNJ5', 'Gene', (13, 18))
9332	22848660	Whether this gender bias for KCNJ5 mutation is attributable to a difference in the rate at which these mutations occur in females vs. males or to differences in the likelihood of tumor development following mutation will be of interest to determine.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('KCNJ5', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('mutation', 'Var', (35, 43))	('men', 'Species', '9606', (192, 195))	('KCNJ5', 'Gene', '3762', (29, 34))	('tumor', 'Disease', (179, 184))
9333	22848660	The identification of a very small number of mutations that account for a large fraction of APAs indicates that these mutations account for a large number of patients with severe hypertension worldwide.	('mutations', 'Var', (45, 54))	('APA', 'Gene', (92, 95))	('hypertension', 'Disease', 'MESH:D006973', (179, 191))	('hypertension', 'Disease', (179, 191))	('hypertension', 'Phenotype', 'HP:0000822', (179, 191))	('patients', 'Species', '9606', (158, 166))	('APA', 'Gene', '2028', (92, 95))
9334	22848660	The potential to detect specific somatic mutations in DNA shed into plasma with high sensitivity suggests a potential screening test that could detect a large fraction of APAs noninvasively.	('mutations', 'Var', (41, 50))	('APA', 'Gene', '2028', (171, 174))	('APA', 'Gene', (171, 174))
9335	22848660	Similarly, the specific KCNJ5 mutations likely result in specific alterations in channel structure that might allow selective inhibition of mutant channels, which would be expected to inhibit aldosterone secretion and arrest progression of tumor growth in affected patients.	('KCNJ5', 'Gene', (24, 29))	('tumor growth', 'Disease', (240, 252))	('inhibit', 'NegReg', (184, 191))	('result', 'Reg', (47, 53))	('channel structure', 'MPA', (81, 98))	('tumor growth', 'Disease', 'MESH:D006130', (240, 252))	('KCNJ5', 'Gene', '3762', (24, 29))	('aldosterone secretion', 'MPA', (192, 213))	('arrest', 'Disease', 'MESH:D006323', (218, 224))	('aldosterone', 'Chemical', 'MESH:D000450', (192, 203))	('inhibition', 'NegReg', (126, 136))	('mutations', 'Var', (30, 39))	('patients', 'Species', '9606', (265, 273))	('arrest', 'Disease', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('mutant', 'Var', (140, 146))	('alterations', 'Reg', (66, 77))
9470	32915499	HNRNPM, HNRNPUL1, and HNRNPL showed high mutation frequencies, and most hnRNP genes were frequently mutated in uterine corpus endometrial carcinoma (UCEC).	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('mutated', 'Var', (100, 107))	('hnRNP', 'Gene', (72, 77))	('endometrial carcinoma', 'Disease', (126, 147))	('HNRNPM', 'Gene', (0, 6))	('HNRNPM', 'Gene', '4670', (0, 6))	('HNRNPL', 'Gene', '3191', (22, 28))	('HNRNPUL1', 'Gene', '11100', (8, 16))	('hnRNP', 'Gene', '3183', (72, 77))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (126, 147))	('HNRNPL', 'Gene', (22, 28))	('HNRNPUL1', 'Gene', (8, 16))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (126, 147))
9471	32915499	HNRNPA2B1 showed widespread copy number amplification across various cancer types.	('copy number amplification', 'Var', (28, 53))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('HNRNPA2B1', 'Gene', '3181', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('HNRNPA2B1', 'Gene', (0, 9))	('cancer', 'Disease', (69, 75))
9478	32915499	1 ,  2  Almost each transcript derived from human genes undergoes diverse patterns of alternative splicing (AS) including exclusion or inclusion of ''cassette'' exons, changes of AS sites, intron retentions, alternative promoter or terminator, and mutually exclusive exons.	('human', 'Species', '9606', (44, 49))	('as', 'Gene', '112935892', (151, 153))	('AS', 'Gene', '112935892', (179, 181))	('AS', 'Gene', '112935892', (108, 110))	('changes', 'Var', (168, 175))	('intron', 'MPA', (189, 195))	('alternative splicing', 'MPA', (86, 106))
9479	32915499	3 ,  4  Alternative splicing of pre-mRNA is responsible various aspects of biological processes and aberrant AS contribute to a series of disorders even cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('contribute', 'Reg', (112, 122))	('responsible', 'Reg', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('as', 'Gene', '112935892', (64, 66))	('disorders', 'Disease', (138, 147))	('Alternative splicing', 'Var', (8, 28))	('AS', 'Gene', '112935892', (109, 111))
9487	32915499	16  In pancreas cancer, hnRNP E1 cancer cell metastasis via controlling the alternative splicing of integrin beta1, a membrane receptor involved in cell adhesion, immune response and metastatic diffusion of cancer cells.	('cancer', 'Disease', (33, 39))	('as', 'Gene', '112935892', (186, 188))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('alternative splicing', 'Var', (76, 96))	('as', 'Gene', '112935892', (51, 53))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('pancreas cancer', 'Disease', 'MESH:D010190', (7, 22))	('pancreas cancer', 'Phenotype', 'HP:0002894', (7, 22))	('integrin beta1', 'Gene', '3688', (100, 114))	('as', 'Gene', '112935892', (48, 50))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('pancreas cancer', 'Disease', (7, 22))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('hnRNP E1', 'Gene', '5093', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('as', 'Gene', '112935892', (13, 15))	('hnRNP E1', 'Gene', (24, 32))	('integrin beta1', 'Gene', (100, 114))
9493	32915499	It is anticipated that the comprehensive pan-cancer analysis could shed light on the way alternative splicing lead to cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('lead to', 'Reg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('alternative', 'Var', (89, 100))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
9497	32915499	All of the TCGA data including TPM (Transcripts Per Kilobase Million) expression, copy number variation, mutation and clinical information (survival status, stages, grades, survival time) were download from UCSC XENA (https://xenabrowser.net/).	('copy number variation', 'Var', (82, 103))	('as', 'Gene', '112935892', (57, 59))	('TCGA', 'Gene', (11, 15))	('TPM', 'Gene', (31, 34))
9516	32915499	The mutation frequency of hnRNP genes were analysed, and the results indicated that most hnRNP genes were frequently mutated in UCEC (Figure 2A).	('UCEC', 'Disease', (128, 132))	('mutated', 'Var', (117, 124))	('hnRNP', 'Gene', (26, 31))	('hnRNP', 'Gene', (89, 94))	('hnRNP', 'Gene', '3183', (26, 31))	('hnRNP', 'Gene', '3183', (89, 94))
9518	32915499	Several cancers such as THCA, PCPG and UVM demonstrated rare hnRNP gene mutations.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('mutations', 'Var', (72, 81))	('PCPG', 'Disease', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('THCA', 'Disease', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('hnRNP', 'Gene', '3183', (61, 66))	('hnRNP', 'Gene', (61, 66))	('UVM', 'Disease', (39, 42))	('as', 'Gene', '112935892', (21, 23))
9521	32915499	The results indicated that colorectal cancer and lung cancer cell lines suggested frequent mutations of most hnRNP genes.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('colorectal cancer', 'Disease', (27, 44))	('lung cancer', 'Disease', (49, 60))	('mutations', 'Var', (91, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('hnRNP', 'Gene', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('hnRNP', 'Gene', '3183', (109, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
9522	32915499	In addition, the copy number variations of hnRNP genes were also investigated across different cancer types (Figure 2D): HNRNPA2B1 gene showed widespread copy number amplification across various cancer types whereas almost no CNV was detected in LAML.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('HNRNPA2B1', 'Gene', '3181', (121, 130))	('HNRNPA2B1', 'Gene', (121, 130))	('cancer', 'Disease', (195, 201))	('copy number', 'Var', (154, 165))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('hnRNP', 'Gene', (43, 48))	('as', 'Gene', '112935892', (231, 233))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('hnRNP', 'Gene', '3183', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('as', 'Gene', '112935892', (213, 215))
9546	32915499	20  In lung cancer, knockdown of HNRNPA1 suppressed the viability and growth as well as induced cell cycle arrest of lung cancer cells.	('lung cancer', 'Disease', (7, 18))	('viability', 'CPA', (56, 65))	('suppressed', 'NegReg', (41, 51))	('knockdown', 'Var', (20, 29))	('induced', 'Reg', (88, 95))	('arrest of lung cancer', 'Disease', (107, 128))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('growth', 'CPA', (70, 76))	('HNRNPA1', 'Gene', '3178', (33, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('arrest of lung cancer', 'Disease', 'MESH:D012131', (107, 128))	('HNRNPA1', 'Gene', (33, 40))	('as', 'Gene', '112935892', (77, 79))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('as', 'Gene', '112935892', (85, 87))
9554	32915499	27  It is worth noting that most hnRNP genes were frequently mutated in UCEC, a certain type of cancer with high global mutation burden.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('hnRNP', 'Gene', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutated', 'Var', (61, 68))	('hnRNP', 'Gene', '3183', (33, 38))	('cancer', 'Disease', (96, 102))	('UCEC', 'Disease', (72, 76))
9555	32915499	28  Several cancers such as THCA, PCPG and UVM demonstrated rare hnRNP gene mutations.	('hnRNP', 'Gene', (65, 70))	('as', 'Gene', '112935892', (25, 27))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('PCPG', 'Disease', (34, 38))	('mutations', 'Var', (76, 85))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('THCA', 'Disease', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('UVM', 'Disease', (43, 46))	('hnRNP', 'Gene', '3183', (65, 70))
9556	32915499	Besides, human cancer cell lines analysis based on CCLE demonstrated that colorectal cancer and lung cancer cell lines possess frequent mutations of most hnRNP genes.	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('human', 'Species', '9606', (9, 14))	('as', 'Gene', '112935892', (43, 45))	('mutations', 'Var', (136, 145))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('hnRNP', 'Gene', '3183', (154, 159))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', (85, 91))	('hnRNP', 'Gene', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (101, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('lung cancer', 'Disease', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('colorectal cancer', 'Disease', (74, 91))
9557	32915499	Future investigations concerning the mutations of hnRNP genes in lung cancer and colorectal cancer might reveal critical evidence of contribution of hnRNPs in the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('hnRNP', 'Gene', '3183', (149, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('colorectal cancer', 'Disease', (81, 98))	('hnRNP', 'Gene', (149, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (37, 46))	('hnRNP', 'Gene', '3183', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('lung cancer', 'Disease', (65, 76))	('cancer', 'Disease', (178, 184))	('hnRNP', 'Gene', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
9558	32915499	In addition, the copy number variations investigation revealed that HNRNPA2B1 gene showed widespread copy number amplification across various cancer types whereas almost no CNV was detected in LAML.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('copy number amplification', 'Var', (101, 126))	('as', 'Gene', '112935892', (160, 162))	('as', 'Gene', '112935892', (178, 180))	('HNRNPA2B1', 'Gene', '3181', (68, 77))	('HNRNPA2B1', 'Gene', (68, 77))	('cancer', 'Disease', (142, 148))
9574	32915499	Previously, high HNRNPUL2 expression has been reported to predict poor survival of multiple cancers.	('expression', 'MPA', (26, 36))	('high', 'Var', (12, 16))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('HNRNPUL2', 'Gene', '221092', (17, 25))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('HNRNPUL2', 'Gene', (17, 25))	('poor survival', 'CPA', (66, 79))	('as', 'Gene', '112935892', (38, 40))
9580	32915499	In summary, our study systematically demonstrated the expression, mutation, copy number variation, functional pathways and prognostic value of alternative splicing regulator hnRNPs across a series of cancers.	('hnRNP', 'Gene', '3183', (174, 179))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('hnRNP', 'Gene', (174, 179))	('mutation', 'Var', (66, 74))	('copy number variation', 'Var', (76, 97))
9693	30217968	In our case, the neoplastic cells had a KI-67 and MIB1 rate of 20%.	('MIB1', 'Gene', '57534', (50, 54))	('KI-67', 'Var', (40, 45))	('rat', 'Species', '10116', (55, 58))	('MIB1', 'Gene', (50, 54))
9733	28778197	The number of patients with a primary tumour size of >10 cm was significantly higher in the non-resection group (82.4%) compared to the surgical group (55.8%).	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('non-resection', 'Var', (92, 105))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('tumour', 'Disease', (38, 44))	('patients', 'Species', '9606', (14, 22))
9776	28778197	In the group of liver resection, the site of primary ACC was more often on the right side (60%), whereas an equal distribution of the primary ACC to both sides was observed in all 77 patients with isolated liver metastases.	('isolated liver metastases', 'Disease', (197, 222))	('ACC', 'Phenotype', 'HP:0006744', (142, 145))	('ACC', 'Phenotype', 'HP:0006744', (53, 56))	('isolated liver metastases', 'Disease', 'MESH:D009362', (197, 222))	('liver resection', 'Var', (16, 31))	('patients', 'Species', '9606', (183, 191))
9792	27222021	When used in a clinical setting, 18F-FDG PET/CT leads to a significant improvement in diagnostic accuracy and has had a considerable impact on patient management, including diagnosis, initial staging, optimization of treatment, restaging, monitoring of the response to therapy, and prognostication of many malignant tumors.	('malignant tumors', 'Disease', 'MESH:D018198', (306, 322))	('diagnostic', 'MPA', (86, 96))	('18F-FDG PET/CT', 'Var', (33, 47))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('patient', 'Species', '9606', (143, 150))	('impact', 'Reg', (133, 139))	('improvement', 'PosReg', (71, 82))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('men', 'Species', '9606', (222, 225))	('men', 'Species', '9606', (78, 81))	('men', 'Species', '9606', (157, 160))	('malignant tumors', 'Disease', (306, 322))	('18F-FDG', 'Chemical', 'MESH:D019788', (33, 40))
9800	27222021	showed that the pooled sensitivity of 18F-FDG PET or PET/CT was 79 % for intrarenal tumors and 84 % for extrarenal metastases, and that 18F-FDG PET/ CT increased the pooled sensitivity to 91 %.	('metastases', 'Disease', (115, 125))	('18F-FDG', 'Chemical', 'MESH:D019788', (136, 143))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('18F-FDG PET', 'Var', (38, 49))	('18F-FDG', 'Chemical', 'MESH:D019788', (38, 45))	('18F-FDG', 'Var', (136, 143))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
9801	27222021	evaluated the clinical impact of 18F-FDG PET/CT for restaging 104 patients after surgery and demonstrated that (1) the sensitivity and specificity were 74 % and 80 %, respectively, (2) 18F-FDG PET/CT findings influenced therapeutic management in 45/104 cases (43 %), and (3) in analysis of overall survival (OS), positive versus negative 18F-FDG-PET/CT findings were associated with poorer cumulative survival rates over a 5-year period (19 vs 69 %, respectively; p < 0.05).	('men', 'Species', '9606', (238, 241))	('18F-FDG', 'Chemical', 'MESH:D019788', (33, 40))	('18F-FDG', 'Chemical', 'MESH:D019788', (185, 192))	('influenced', 'Reg', (209, 219))	('poorer', 'NegReg', (383, 389))	('positive', 'Var', (313, 321))	('18F-FDG', 'Chemical', 'MESH:D019788', (338, 345))	('patients', 'Species', '9606', (66, 74))
9805	27222021	demonstrated that a higher maximum standardized uptake value (SUVmax) on 18F-FDG PET was associated with elevated tumor levels of phosphorylated-Akt, phosphorylated-S6 protein, aggressive behavior and metastatic potential, early relapse, and shorter OS after radical nephrectomy.	('Akt', 'Gene', (145, 148))	('aggressive behavior', 'CPA', (177, 196))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('elevated', 'PosReg', (105, 113))	('metastatic potential', 'CPA', (201, 221))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('early relapse', 'CPA', (223, 236))	('18F-FDG', 'Var', (73, 80))	('higher', 'PosReg', (20, 26))	('aggressive behavior', 'Phenotype', 'HP:0000718', (177, 196))	('phosphorylated-S6 protein', 'MPA', (150, 175))	('tumor', 'Disease', (114, 119))	('maximum standardized uptake value', 'MPA', (27, 60))	('18F-FDG', 'Chemical', 'MESH:D019788', (73, 80))	('Akt', 'Gene', '207', (145, 148))
9806	27222021	Their Kaplan-Meier survival analysis indicated that patients with a high SUVmax (>=4.35) had a significantly lower OS rate than those with a low SUV-max (<4.35) irrespective of the presence of distant metastasis before surgery, and among 52 patients without distant metastasis before surgery, those with a high SUVmax (>=3.50) had a significantly lower recurrence-free survival rate than those with a low SUVmax (<3.50).	('lower', 'NegReg', (109, 114))	('high', 'Var', (68, 72))	('lower', 'NegReg', (347, 352))	('recurrence-free survival rate', 'CPA', (353, 382))	('patients', 'Species', '9606', (241, 249))	('patients', 'Species', '9606', (52, 60))
9819	27222021	compared 18F-FLT and 18F-FDG for early measurement of response to sunitinib treatment in 20 patients with metastatic RCC and demonstrated that while FLT-PET could be used to identify response as early as 1 week after the start of treatment, 18F-FDG PET was more effective at a later time point of 3-4 weeks, suggesting that inhibition of VEGF signaling with sunitinib exerts an early effect on tumor proliferation, which is then followed by a reduction in tumor metabolism.	('tumor', 'Disease', (394, 399))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('VEGF', 'Gene', (338, 342))	('18F', 'Chemical', 'MESH:C000615276', (9, 12))	('sunitinib', 'Chemical', 'MESH:D000077210', (358, 367))	('18F-FDG', 'Chemical', 'MESH:D019788', (241, 248))	('men', 'Species', '9606', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (394, 399))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('FLT', 'Gene', (149, 152))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Disease', (456, 461))	('18F', 'Chemical', 'MESH:C000615276', (21, 24))	('FLT', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('tumor', 'Disease', 'MESH:D009369', (456, 461))	('FLT', 'Gene', '2321', (149, 152))	('men', 'Species', '9606', (46, 49))	('FLT', 'Gene', '2321', (13, 16))	('18F', 'Chemical', 'MESH:C000615276', (241, 244))	('inhibition', 'Var', (324, 334))	('tumor', 'Phenotype', 'HP:0002664', (456, 461))	('18F-FDG', 'Chemical', 'MESH:D019788', (21, 28))	('sunitinib', 'Chemical', 'MESH:D000077210', (66, 75))	('VEGF', 'Gene', '7422', (338, 342))	('men', 'Species', '9606', (235, 238))	('reduction', 'NegReg', (443, 452))
9821	27222021	Furthermore, one preliminary report has demonstrated that anti-3-18F-FACBC PET showed better conspicuity for papillary RCC than for clear cell RCC.	('anti-3-18F-FACBC', 'Var', (58, 74))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Disease', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('conspicuity', 'MPA', (93, 104))	('18F', 'Chemical', 'MESH:C000615276', (65, 68))
9826	27222021	A meta-analysis showed that the sensitivity and specificity of 18F-FDG PET/CT for detecting bladder cancer was 80 % (95 % CI 71-87 %) and 84 % (95 % CI 69-93 %), respectively.	('18F-FDG', 'Var', (63, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (92, 106))	('bladder cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('18F-FDG', 'Chemical', 'MESH:D019788', (63, 70))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))
9858	27222021	Although 18F-FDG PET is less sensitive than conventional bone scintigraphy for identification of osteoblastic bony metastases, 18F-FDG PET may be able to distinguish between metabolically active lesions from non-viable bony lesions.	('metabolically active', 'MPA', (174, 194))	('18F-FDG', 'Chemical', 'MESH:D019788', (127, 134))	('18F-FDG PET', 'Var', (127, 138))	('osteoblastic bony metastases', 'Disease', 'MESH:D009362', (97, 125))	('18F-FDG', 'Chemical', 'MESH:D019788', (9, 16))	('osteoblastic bony metastases', 'Disease', (97, 125))
9890	27222021	Anti-3-18F-FACBC uptake is related to the functional activity of two different amino acid transporters (ASC and LAT1), which appear to be upregulated when prostate cancer progresses to metastatic disease.	('functional', 'MPA', (42, 52))	('Anti-3-18F-FACBC', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('prostate cancer', 'Disease', 'MESH:D011471', (155, 170))	('prostate cancer', 'Phenotype', 'HP:0012125', (155, 170))	('metastatic disease', 'Disease', (185, 203))	('LAT1', 'Gene', '8140', (112, 116))	('LAT1', 'Gene', (112, 116))	('18F', 'Chemical', 'MESH:C000615276', (7, 10))	('upregulated', 'PosReg', (138, 149))	('prostate cancer', 'Disease', (155, 170))
9903	27222021	As PSMA-617 can be labeled with 68Ga, 177Lu, 111In, or 90Y, it can be used for PET imaging as well as for radioligand-based therapy.	('177Lu', 'Var', (38, 43))	('68Ga', 'Var', (32, 36))	('PSMA', 'Gene', (3, 7))	('90Y', 'Var', (55, 58))	('111In', 'Var', (45, 50))	('PSMA', 'Gene', '2346', (3, 7))
9926	28249601	This study investigates whether silencing of the WNT negative regulator DKK3 (Dickkopf-related protein 3), an implicated adrenocortical differentiation marker and an established tumor suppressor in multiple cancers, allows dedifferentiation of the adrenal cortex.	('tumor', 'Disease', (178, 183))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('adrenocortical', 'Disease', (121, 135))	('multiple cancers', 'Disease', (198, 214))	('adrenocortical', 'Disease', 'MESH:D018268', (121, 135))	('silencing', 'Var', (32, 41))	('DKK3', 'Gene', (72, 76))	('DKK3', 'Gene', '27122', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('allows', 'Reg', (216, 222))	('multiple cancers', 'Disease', 'MESH:D009369', (198, 214))	('dedifferentiation', 'CPA', (223, 240))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
9930	28249601	Both genetic (gene copy loss) and epigenetic (promoter methylation) events were found to play significant roles in DKK3 down-regulation in ACCs.	('ACC', 'Phenotype', 'HP:0006744', (139, 142))	('DKK3', 'Gene', '27122', (115, 119))	('ACCs', 'Gene', (139, 143))	('DKK3', 'Gene', (115, 119))	('gene copy loss', 'Var', (14, 28))	('down-regulation', 'NegReg', (120, 135))	('ACCs', 'Gene', '84680', (139, 143))
9931	28249601	While NCI-H295R cells harboring beta-catenin activating mutations failed to respond to DKK3 silencing, SW-13 cells showed increased motility and reduced clonal growth.	('reduced', 'NegReg', (145, 152))	('clonal growth', 'CPA', (153, 166))	('DKK3', 'Gene', '27122', (87, 91))	('beta-catenin', 'Gene', (32, 44))	('silencing', 'Var', (92, 101))	('DKK3', 'Gene', (87, 91))	('SW-13', 'CellLine', 'CVCL:0542', (103, 108))	('motility', 'CPA', (132, 140))	('beta-catenin', 'Gene', '1499', (32, 44))	('NCI-H295R', 'CellLine', 'CVCL:0458', (6, 15))	('increased', 'PosReg', (122, 131))
9934	28249601	DKK3-over-expressing cells also showed increased expression of Forkhead Box Protein O1 (FOXO1) transcription factor, RNAi silencing of which partially restored the migratory proficiency of cells without interfering with their viability.	('DKK3', 'Gene', '27122', (0, 4))	('restored', 'PosReg', (151, 159))	('DKK3', 'Gene', (0, 4))	('FOXO1', 'Gene', (88, 93))	('expression', 'Species', '29278', (49, 59))	('expression', 'MPA', (49, 59))	('migratory proficiency of cells', 'CPA', (164, 194))	('increased', 'PosReg', (39, 48))	('silencing', 'Var', (122, 131))
9935	28249601	DKK3 suppression observed in ACCs and the effects of manipulation of DKK3 expression in ACC cell lines suggest a FOXO1-mediated differentiation-promoting role for DKK3 in the adrenal cortex, silencing of which may allow adrenocortical dedifferentiation and malignancy.	('DKK3', 'Gene', '27122', (0, 4))	('DKK3', 'Gene', (69, 73))	('adrenocortical', 'Disease', (220, 234))	('FOXO1-mediated', 'Gene', (113, 127))	('silencing', 'Var', (191, 200))	('differentiation-promoting', 'CPA', (128, 153))	('adrenocortical dedifferentiation', 'Phenotype', 'HP:0008207', (220, 252))	('DKK3', 'Gene', '27122', (69, 73))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('DKK3', 'Gene', (163, 167))	('malignancy', 'Disease', 'MESH:D009369', (257, 267))	('manipulation', 'Var', (53, 65))	('suppression', 'NegReg', (5, 16))	('ACCs', 'Gene', '84680', (29, 33))	('DKK3', 'Gene', '27122', (163, 167))	('ACCs', 'Gene', (29, 33))	('expression', 'Species', '29278', (74, 84))	('allow', 'Reg', (214, 219))	('DKK3', 'Gene', (0, 4))	('ACC', 'Phenotype', 'HP:0006744', (29, 32))	('malignancy', 'Disease', (257, 267))	('adrenocortical', 'Disease', 'MESH:D018268', (220, 234))
9938	28249601	Genetic and epigenetic dysregulations of the WNT, p53, and IGF2 pathways appear to dominate various cancer-driving anomalies in the majority of ACCs.	('ACCs', 'Gene', '84680', (144, 148))	('ACC', 'Phenotype', 'HP:0006744', (144, 147))	('ACCs', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Genetic', 'Var', (0, 7))	('WNT', 'Pathway', (45, 48))	('epigenetic dysregulations', 'Var', (12, 37))	('p53', 'Pathway', (50, 53))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('IGF2', 'Gene', (59, 63))
9942	28249601	Aberrant WNT signaling has been well-established in the origin of many tumor types and is strongly associated with stabilization of beta-catenin in the cytoplasm and/or in the nucleus and constitutive activation of WNT target genes.	('stabilization', 'MPA', (115, 128))	('activation', 'PosReg', (201, 211))	('Aberrant', 'Var', (0, 8))	('beta-catenin', 'Gene', (132, 144))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('WNT signaling', 'Pathway', (9, 22))	('beta-catenin', 'Gene', '1499', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
9944	28249601	However, only 10% of ACCs with constitutively active beta-catenin carry mutations in the beta-catenin gene (CTNNB1), suggesting alternate mechanisms of aberrant WNT activation, including dysregulation of WNT inhibitors such as Wif-1.	('mutations', 'Var', (72, 81))	('ACCs', 'Gene', '84680', (21, 25))	('ACCs', 'Gene', (21, 25))	('CTNNB1', 'Gene', '1499', (108, 114))	('beta-catenin', 'Gene', '1499', (89, 101))	('WNT', 'MPA', (161, 164))	('beta-catenin', 'Gene', (53, 65))	('beta-catenin', 'Gene', (89, 101))	('ACC', 'Phenotype', 'HP:0006744', (21, 24))	('CTNNB1', 'Gene', (108, 114))	('beta-catenin', 'Gene', '1499', (53, 65))	('activation', 'PosReg', (165, 175))
9945	28249601	Other WNT regulatory mutations found in ACCs include PRKAR1A and recently identified KREMEN1 and ZNRF3 gene deletions.	('ACC', 'Phenotype', 'HP:0006744', (40, 43))	('ACCs', 'Gene', '84680', (40, 44))	('KREMEN1', 'Gene', (85, 92))	('deletions', 'Var', (108, 117))	('ACCs', 'Gene', (40, 44))	('ZNRF3', 'Gene', (97, 102))
9950	28249601	Furthermore, ectopic expression of DKK3 in a variety of cancer cell types stifled aggressive malignant behavior, reversed epithelial-mesenchymal transition (EMT), and impaired cell motility, pointing towards a comprehensive dedifferentiation-blocking role for DKK3.	('DKK3', 'Gene', (260, 264))	('epithelial-mesenchymal transition', 'CPA', (122, 155))	('reversed', 'NegReg', (113, 121))	('impaired cell motility', 'Disease', (167, 189))	('expression', 'Species', '29278', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('impaired cell motility', 'Disease', 'MESH:D015835', (167, 189))	('DKK3', 'Gene', '27122', (35, 39))	('DKK3', 'Gene', (35, 39))	('aggressive malignant behavior', 'CPA', (82, 111))	('ectopic expression', 'Var', (13, 31))	('stifled', 'PosReg', (74, 81))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('DKK3', 'Gene', '27122', (260, 264))
9958	28249601	Quantitative real-time PCR (qRT-PCR) was performed in triplicate using TaqMan PCR master mix with FAM fluorophore and probe/primer pairs specific to human DKK3 (Hs00951307_m1), FOXO1 (Hs01054576_m1), and RPLP0 (Hs99999902_m1) (ThermoFisher Scientific) according to manufacturer's cycling conditions using CFX96 thermal cyclers (Bio-Rad).	('RPLP0', 'Gene', '6175', (204, 209))	('Hs99999902_m1', 'Var', (211, 224))	('DKK3', 'Gene', '27122', (155, 159))	('Hs00951307_m1', 'Var', (161, 174))	('DKK3', 'Gene', (155, 159))	('human', 'Species', '9606', (149, 154))	('RPLP0', 'Gene', (204, 209))	('Rad', 'Gene', '6236', (332, 335))	('Hs01054576_m1', 'Var', (184, 197))	('Rad', 'Gene', (332, 335))
9985	28249601	FlowJo software was used to analyze the best Gaussian distribution curve to each peak for the cell populations of G0-G1 and G2-M. To assess invasive proficiencies, 100,000 SW-13, SW-Neo, or SW-DKK3 cells were allowed to invade through Matrigel from upper chambers containing serum-free medium to lower chambers containing 10% FBS medium in BD BioCoat Matrigel invasion chambers (BD Biosciences).	('SW-Neo', 'CellLine', 'CVCL:J816', (179, 185))	('FBS', 'Gene', (326, 329))	('SW-DKK3', 'Var', (190, 197))	('FBS', 'Gene', '26269', (326, 329))	('SW-13', 'CellLine', 'CVCL:0542', (172, 177))	('SW-DKK3', 'CellLine', 'CVCL:R777', (190, 197))
9991	28249601	Recent comprehensive genetic analyses identified WNT signaling as the most common target of genetic aberrations in ACCs.	('ACCs', 'Gene', (115, 119))	('ACC', 'Phenotype', 'HP:0006744', (115, 118))	('ACCs', 'Gene', '84680', (115, 119))	('genetic aberrations', 'Var', (92, 111))
10010	28249601	Twelve of 18 ACC samples with hyper- or intermediate promoter methylation (67%) also showed significant reduction in DKK3 expression, concurring with the established role of promoter methylation in DKK3 silencing in other tumors.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('expression', 'MPA', (122, 132))	('reduction', 'NegReg', (104, 113))	('hyper-', 'Var', (30, 36))	('intermediate promoter methylation', 'Var', (40, 73))	('DKK3', 'Gene', '27122', (117, 121))	('DKK3', 'Gene', (117, 121))	('ACC', 'Phenotype', 'HP:0006744', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('DKK3', 'Gene', '27122', (198, 202))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('DKK3', 'Gene', (198, 202))	('tumors', 'Disease', (222, 228))	('expression', 'Species', '29278', (122, 132))
10012	28249601	Recent genetic analyses of ACCs by us and others have shown significant copy number alterations in genes potentially involved in various signaling pathways.	('copy number alterations', 'Var', (72, 95))	('ACCs', 'Gene', '84680', (27, 31))	('ACCs', 'Gene', (27, 31))	('ACC', 'Phenotype', 'HP:0006744', (27, 30))
10014	28249601	Seven of the 9 samples with copy loss (78%) showed marked reduction in DKK3 expression; 4 showed concurrent DKK3 promoter methylation.	('copy loss', 'Var', (28, 37))	('expression', 'Species', '29278', (76, 86))	('DKK3', 'Gene', '27122', (108, 112))	('DKK3', 'Gene', (108, 112))	('expression', 'MPA', (76, 86))	('DKK3', 'Gene', '27122', (71, 75))	('reduction', 'NegReg', (58, 67))	('DKK3', 'Gene', (71, 75))
10018	28249601	Despite carrying TP53 gene mutations, non-hormone-secreting SW-13 cells maintain an unperturbed and modifiable WNT signaling pathway, whereas the adrenal hormone-producing NCI-H295R cells harbor CTNNB1 and axin1 mutations, resulting in constitutive WNT activation.	('mutations', 'Var', (27, 36))	('SW-13', 'CellLine', 'CVCL:0542', (60, 65))	('CTNNB1', 'Gene', (195, 201))	('axin1', 'Gene', '8312', (206, 211))	('CTNNB1', 'Gene', '1499', (195, 201))	('constitutive WNT activation', 'MPA', (236, 263))	('mutations', 'Var', (212, 221))	('axin1', 'Gene', (206, 211))	('NCI-H295R', 'CellLine', 'CVCL:0458', (172, 181))	('TP53', 'Gene', '7157', (17, 21))	('unperturbed', 'MPA', (84, 95))	('TP53', 'Gene', (17, 21))
10020	28249601	Silencing of DKK3 expression in SW-13 (Fig.	('DKK3', 'Gene', '27122', (13, 17))	('DKK3', 'Gene', (13, 17))	('expression', 'Species', '29278', (18, 28))	('Silencing', 'Var', (0, 9))	('SW-13', 'CellLine', 'CVCL:0542', (32, 37))
10022	28249601	DKK3 silencing did not result in significant loss of viability in either cell type for the duration of study (48 h).	('DKK3', 'Gene', '27122', (0, 4))	('silencing', 'Var', (5, 14))	('DKK3', 'Gene', (0, 4))
10023	28249601	Due to low baseline levels of DKK3 in H295R (Fig.	('DKK3', 'Gene', '27122', (30, 34))	('H295R', 'Var', (38, 43))	('DKK3', 'Gene', (30, 34))
10024	28249601	Next, we examined whether silencing of DKK3 modulates clonal growth or migratory potential of ACC cells.	('ACC', 'Phenotype', 'HP:0006744', (94, 97))	('migratory potential', 'CPA', (71, 90))	('modulates', 'Reg', (44, 53))	('clonal growth', 'CPA', (54, 67))	('silencing', 'Var', (26, 35))	('DKK3', 'Gene', '27122', (39, 43))	('DKK3', 'Gene', (39, 43))
10032	28249601	However, migratory potential of SW-13 cells was found to be accentuated with exogenous DKK3 (Fig.	('migratory potential', 'CPA', (9, 28))	('DKK3', 'Gene', '27122', (87, 91))	('DKK3', 'Gene', (87, 91))	('accentuated', 'PosReg', (60, 71))	('exogenous', 'Var', (77, 86))	('SW-13', 'CellLine', 'CVCL:0542', (32, 37))
10033	28249601	The exogenous DKK3 in this instance appears to have a dominant effect over the motility-impeding effect of endogenous DKK3 (Fig.	('exogenous', 'Var', (4, 13))	('DKK3', 'Gene', '27122', (14, 18))	('DKK3', 'Gene', (14, 18))	('DKK3', 'Gene', '27122', (118, 122))	('DKK3', 'Gene', (118, 122))
10040	28249601	Expression of ectopic DKK3 was confirmed (Fig.	('Expression', 'Species', '29278', (0, 10))	('ectopic', 'Var', (14, 21))	('DKK3', 'Gene', '27122', (22, 26))	('DKK3', 'Gene', (22, 26))
10043	28249601	The slow rate of growth of SW-DKK3 cells was found to be caused by an increase in the percentage of cells accumulated in G1 phase (47.5% SW-Neo compared to 56.3% SW-DKK3 cells) of the cell cycle (Additional file 1: Figure S6).	('SW-DKK3', 'Var', (27, 34))	('increase', 'PosReg', (70, 78))	('SW-DKK3', 'CellLine', 'CVCL:R777', (27, 34))	('growth', 'MPA', (17, 23))	('SW-DKK3', 'CellLine', 'CVCL:R777', (162, 169))	('SW-Neo', 'Var', (137, 143))	('slow', 'NegReg', (4, 8))	('SW-Neo', 'CellLine', 'CVCL:J816', (137, 143))
10048	28249601	SW-DKK3 cells exhibited significantly decreased migratory potential compared to parental SW13 and SW-Neo cells (p < 0.001) (Fig.	('SW-DKK3', 'CellLine', 'CVCL:R777', (0, 7))	('decreased', 'NegReg', (38, 47))	('SW13', 'CellLine', 'CVCL:0542', (89, 93))	('migratory potential', 'CPA', (48, 67))	('SW-DKK3', 'Var', (0, 7))	('SW-Neo', 'CellLine', 'CVCL:J816', (98, 104))
10050	28249601	As reported previously in other cancer types, over-expression of DKK3 significantly impaired SW-13 cells' ability to invade through reconstituted matrix (p < 0.001) (Fig.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('ability to invade through reconstituted matrix', 'CPA', (106, 152))	('over-expression', 'Var', (46, 61))	('cancer', 'Disease', (32, 38))	('DKK3', 'Gene', '27122', (65, 69))	('impaired', 'NegReg', (84, 92))	('expression', 'Species', '29278', (51, 61))	('DKK3', 'Gene', (65, 69))	('SW-13', 'CellLine', 'CVCL:0542', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
10053	28249601	While the parental SW-13 and SW-Neo cells displayed a significantly higher number of filopodia in a planar orientation, SW-DKK3 cells displayed a significantly higher proportion of lobopodial extensions (p < 0.01) (Fig.	('SW-DKK3', 'CellLine', 'CVCL:R777', (120, 127))	('lobopodial extensions', 'CPA', (181, 202))	('higher', 'PosReg', (160, 166))	('SW-Neo', 'CellLine', 'CVCL:J816', (29, 35))	('SW-DKK3', 'Var', (120, 127))	('filopodia in a planar orientation', 'CPA', (85, 118))	('SW-13', 'CellLine', 'CVCL:0542', (19, 24))
10057	28249601	Towards understanding the potential transcriptional modulation of cell adhesion and motility by DKK3 over-expression, we compared global difference in the expression pattern of 84 transcription factors using an expanded transcription array.	('over-expression', 'Var', (101, 116))	('DKK3', 'Gene', '27122', (96, 100))	('expression', 'Species', '29278', (106, 116))	('DKK3', 'Gene', (96, 100))	('expression', 'Species', '29278', (155, 165))
10058	28249601	Relative expression of 3 transcription factors, ID1, JUN, and FOXO1, consistently demonstrated >4-fold difference in expression between SW-DKK3 and SW-Neo/SW-13 cells (Additional file 1: Figure S8 A&B).	('expression', 'Species', '29278', (117, 127))	('ID1', 'Gene', (48, 51))	('expression', 'MPA', (117, 127))	('JUN', 'Gene', (53, 56))	('expression', 'Species', '29278', (9, 19))	('SW-Neo', 'CellLine', 'CVCL:J816', (148, 154))	('SW-13', 'CellLine', 'CVCL:0542', (155, 160))	('SW-DKK3', 'Var', (136, 143))	('FOXO1', 'Gene', (62, 67))	('SW-DKK3', 'CellLine', 'CVCL:R777', (136, 143))
10064	28249601	The magnitude of relief in migratory inhibition was found to be more pronounced in SW-DKK3 cells (45% increase in motility with 43% FOXO1 suppression) than in SW-Neo cells (30% increase in motility with 66% FOXO1 suppression; Additional file 1: Figure S10).	('migratory inhibition', 'CPA', (27, 47))	('SW-DKK3', 'Var', (83, 90))	('motility', 'CPA', (114, 122))	('SW-Neo', 'CellLine', 'CVCL:J816', (159, 165))	('suppression', 'NegReg', (138, 149))	('SW-DKK3', 'CellLine', 'CVCL:R777', (83, 90))	('increase', 'PosReg', (102, 110))	('FOXO1', 'Gene', (132, 137))
10070	28249601	Despite the relatively small cohort size, this study did not find an association between DKK3 silencing and prognosis, unlike in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('DKK3', 'Gene', '27122', (89, 93))	('DKK3', 'Gene', (89, 93))	('silencing', 'Var', (94, 103))	('gastric cancer', 'Disease', (129, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (129, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))
10071	28249601	Of note, the majority of this cohort of ACCs was previously shown not to harbor mutations in DKK3 or FOXO1 genes while <10% carried beta-catenin mutations.	('mutations', 'Var', (80, 89))	('FOXO1', 'Gene', (101, 106))	('ACC', 'Phenotype', 'HP:0006744', (40, 43))	('DKK3', 'Gene', '27122', (93, 97))	('beta-catenin', 'Gene', (132, 144))	('DKK3', 'Gene', (93, 97))	('beta-catenin', 'Gene', '1499', (132, 144))	('ACCs', 'Gene', '84680', (40, 44))	('ACCs', 'Gene', (40, 44))
10072	28249601	Epigenetic modifications, including promoter methylation and chromatin condensation, have been proposed as major DKK3 silencing mechanisms in a variety of tumors.	('silencing', 'NegReg', (118, 127))	('chromatin', 'CPA', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('promoter', 'MPA', (36, 44))	('Epigenetic', 'Var', (0, 10))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('DKK3', 'Gene', '27122', (113, 117))	('DKK3', 'Gene', (113, 117))
10073	28249601	This study also supports a role for promoter hypermethylation in DKK3 silencing in ACCs.	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('promoter hypermethylation', 'Var', (36, 61))	('silencing', 'NegReg', (70, 79))	('ACCs', 'Gene', (83, 87))	('ACCs', 'Gene', '84680', (83, 87))	('DKK3', 'Gene', '27122', (65, 69))	('DKK3', 'Gene', (65, 69))
10077	28249601	In light of recent findings that gene copy number variations may contribute to adrenocortical carcinogenesis, we analyzed a portion of our samples for DKK3 gene copy number variations.	('DKK3', 'Gene', '27122', (151, 155))	('DKK3', 'Gene', (151, 155))	('adrenocortical carcinogenesis', 'Disease', 'MESH:D063646', (79, 108))	('adrenocortical carcinogenesis', 'Disease', (79, 108))	('gene copy number variations', 'Var', (33, 60))	('contribute', 'Reg', (65, 75))
10078	28249601	The majority of samples identified with DKK3 copy loss also had significantly reduced DKK3 expression.	('expression', 'MPA', (91, 101))	('DKK3', 'Gene', '27122', (86, 90))	('copy loss', 'Var', (45, 54))	('DKK3', 'Gene', (86, 90))	('DKK3', 'Gene', '27122', (40, 44))	('DKK3', 'Gene', (40, 44))	('reduced', 'NegReg', (78, 85))	('expression', 'Species', '29278', (91, 101))
10085	28249601	Silencing of DKK3 in SW13, a human ACC cell line with intact and inductile WNT signaling and endogenously expresses DKK3, did not affect growth or viability of cells but resulted in reduced clonogenic growth and increased motility, consistent with a tumor suppressor role for DKK3.	('DKK3', 'Gene', '27122', (13, 17))	('DKK3', 'Gene', '27122', (116, 120))	('clonogenic growth', 'CPA', (190, 207))	('DKK3', 'Gene', (116, 120))	('DKK3', 'Gene', (13, 17))	('SW13', 'CellLine', 'CVCL:0542', (21, 25))	('increased', 'PosReg', (212, 221))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('DKK3', 'Gene', '27122', (276, 280))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('SW13', 'Gene', (21, 25))	('human', 'Species', '9606', (29, 34))	('motility', 'CPA', (222, 230))	('DKK3', 'Gene', (276, 280))	('Silencing', 'Var', (0, 9))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))	('tumor', 'Disease', (250, 255))	('reduced', 'NegReg', (182, 189))
10088	28249601	Overall, intracellular DKK3 appears to confer a more differentiated phenotype to SW-13 cells.	('SW-13', 'CellLine', 'CVCL:0542', (81, 86))	('intracellular', 'Var', (9, 22))	('confer', 'Reg', (39, 45))	('more', 'PosReg', (48, 52))	('DKK3', 'Gene', '27122', (23, 27))	('DKK3', 'Gene', (23, 27))	('differentiated phenotype', 'CPA', (53, 77))
10091	28249601	While parental SW-13 and SW-Neo cells produced an overwhelming number of dynamic filopodia that confer polarity and promote directional movement (41-43), SW-DKK3 cells showed predominantly lobopodia, indicative of multipolar spreading and hence arrested motility.	('SW-Neo', 'CellLine', 'CVCL:J816', (25, 31))	('lobopodia', 'CPA', (189, 198))	('promote', 'PosReg', (116, 123))	('directional movement', 'CPA', (124, 144))	('polarity', 'MPA', (103, 111))	('SW-13', 'CellLine', 'CVCL:0542', (15, 20))	('SW-DKK3', 'Var', (154, 161))	('SW-DKK3', 'CellLine', 'CVCL:R777', (154, 161))
10095	28249601	Of the 3 transcription factors found to be over-expressed in SW-DKK3 cells (ID1, JUN and FOXO1), FOXO1 secured our immediate attention for 3 primary reasons: (1) FOXO1 is known to promote functional differentiation of myofibroblasts, (2) FOXO1 inhibits osteosarcoma malignancy via WNT inhibition, and (3) FOXO1 transcription has been suggested in response to steroid hormones.	('steroid hormones', 'Chemical', 'MESH:D013256', (359, 375))	('osteosarcoma malignancy', 'Disease', 'MESH:D012516', (253, 276))	('osteosarcoma malignancy', 'Disease', (253, 276))	('inhibits', 'NegReg', (244, 252))	('FOXO1', 'Var', (162, 167))	('functional differentiation', 'CPA', (188, 214))	('osteosarcoma', 'Phenotype', 'HP:0002669', (253, 265))	('SW-DKK3', 'CellLine', 'CVCL:R777', (61, 68))	('promote', 'PosReg', (180, 187))	('FOXO1', 'Gene', (238, 243))
10096	28249601	We hypothesized that intracellular DKK3 promotes cellular differentiation signaling encompassing cellular spreading and stifled motility, at least in part, via FOXO1 up-regulation.	('FOXO1', 'Gene', (160, 165))	('stifled motility', 'CPA', (120, 136))	('up-regulation', 'PosReg', (166, 179))	('cellular spreading', 'CPA', (97, 115))	('DKK3', 'Gene', '27122', (35, 39))	('DKK3', 'Gene', (35, 39))	('intracellular', 'Var', (21, 34))	('cellular differentiation signaling', 'MPA', (49, 83))	('promotes', 'PosReg', (40, 48))
10124	23533247	Given the overexpression of TOP2A, we tested 14 TOP2A inhibitors for their antiproliferative effect and found 11 of the 14 had good efficacy.	('TOP2A', 'Gene', (48, 53))	('inhibitors', 'Var', (54, 64))	('antiproliferative effect', 'CPA', (75, 99))	('TOP2A', 'Gene', (28, 33))	('tested', 'Reg', (38, 44))	('TOP2A', 'Gene', '7153', (28, 33))	('TOP2A', 'Gene', '7153', (48, 53))
10131	23533247	The PCR primers and probes for TOP2A (Hs_010180383_m1) and GAPDH (Hs_99999905_m1) were obtained from Applied Biosystems.	('TOP2A', 'Gene', '7153', (31, 36))	('Hs_010180383_m1', 'Var', (38, 53))	('GAPDH', 'Gene', (59, 64))	('TOP2A', 'Gene', (31, 36))	('Hs_99999905_m1', 'Var', (66, 80))	('GAPDH', 'Gene', '2597', (59, 64))
10142	23533247	A nonspecific negative control siRNA (AM4613) and TOP2A-specific siRNAs at a final concentration of 90 nM were used (si#1; s14308 and si#3; s14309, Applied Biosystems).	('si#3; s14309', 'Var', (134, 146))	('TOP2A', 'Gene', (50, 55))	('TOP2A', 'Gene', '7153', (50, 55))
10167	23533247	Given the high expression of TOP2A in ACC, we next determined whether TOP2A regulates cell proliferation in ACC cells by using siRNA to knockdown TOP2A expression in NCI-H295R and SW13 cells (Fig.	('ACC', 'Phenotype', 'HP:0006744', (108, 111))	('TOP2A', 'Gene', '7153', (70, 75))	('TOP2A', 'Gene', '7153', (146, 151))	('TOP2A', 'Gene', (70, 75))	('TOP2A', 'Gene', (146, 151))	('TOP2A', 'Gene', '7153', (29, 34))	('knockdown', 'Var', (136, 145))	('SW13', 'CellLine', 'CVCL:0542', (180, 184))	('TOP2A', 'Gene', (29, 34))	('NCI-H295R', 'CellLine', 'CVCL:0458', (166, 175))	('ACC', 'Phenotype', 'HP:0006744', (38, 41))
10168	23533247	In NCI-H295R, cell proliferation decreased by as much as 30% as compared to the negative control (p < 0.05) (Fig.	('decreased', 'NegReg', (33, 42))	('NCI-H295R', 'CellLine', 'CVCL:0458', (3, 12))	('cell proliferation', 'CPA', (14, 32))	('NCI-H295R', 'Var', (3, 12))
10169	23533247	In SW13 cells, cellular proliferation was decreased modestly with siRNA knockdown of TOP2A as compared to the negative control (p < 0.05) (Fig.	('TOP2A', 'Gene', (85, 90))	('cellular proliferation', 'CPA', (15, 37))	('decreased', 'NegReg', (42, 51))	('SW13', 'CellLine', 'CVCL:0542', (3, 7))	('TOP2A', 'Gene', '7153', (85, 90))	('knockdown', 'Var', (72, 81))
10170	23533247	TOP2A knockdown did not have a significant effect on the cell cycle (data not shown).	('knockdown', 'Var', (6, 15))	('TOP2A', 'Gene', (0, 5))	('TOP2A', 'Gene', '7153', (0, 5))
10172	23533247	Cell invasion decreased by 57-71% with TOP2A knockdown as compared to the negative control in both ACC cell lines (p < 0.05) (Fig.	('decreased', 'NegReg', (14, 23))	('TOP2A', 'Gene', '7153', (39, 44))	('ACC', 'Phenotype', 'HP:0006744', (99, 102))	('Cell invasion', 'CPA', (0, 13))	('TOP2A', 'Gene', (39, 44))	('knockdown', 'Var', (45, 54))
10175	23533247	Eleven of 14 TOP2A inhibitors had an antiproliferative effect in the NCI-H295R ACC cell line.	('TOP2A', 'Gene', (13, 18))	('inhibitors', 'Var', (19, 29))	('antiproliferative effect', 'CPA', (37, 61))	('NCI-H295R', 'CellLine', 'CVCL:0458', (69, 78))	('TOP2A', 'Gene', '7153', (13, 18))	('ACC', 'Phenotype', 'HP:0006744', (79, 82))
10189	23533247	Several investigators have demonstrated that TOP2A is overexpressed in a variety of human malignancies and that high levels may be associated with more aggressive disease and a worse prognosis.	('aggressive disease', 'Disease', 'MESH:D001523', (152, 170))	('malignancies', 'Disease', (90, 102))	('TOP2A', 'Gene', '7153', (45, 50))	('TOP2A', 'Gene', (45, 50))	('aggressive disease', 'Disease', (152, 170))	('associated with', 'Reg', (131, 146))	('overexpressed', 'PosReg', (54, 67))	('human', 'Species', '9606', (84, 89))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('high levels', 'Var', (112, 123))
10190	23533247	Methylation in the DNA promoter regions (CpG islands) is a mechanism that leads to aberrant gene expression in cancer.	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('aberrant gene expression', 'MPA', (83, 107))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('leads', 'Reg', (74, 79))
10191	23533247	Recently, a study has described the epigenetic regulation of the TOP2A gene in a panel of 45 breast cancer cell lines.	('TOP2A', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('epigenetic', 'Var', (36, 46))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('TOP2A', 'Gene', '7153', (65, 70))
10193	23533247	Thus, epigenetically increasing TOP2A expression with the use of demethylating agents may be an effective strategy for increasing TOP2A expression when using agents which target TOP2A.	('TOP2A', 'Gene', (130, 135))	('TOP2A', 'Gene', (178, 183))	('expression', 'MPA', (136, 146))	('expression', 'MPA', (38, 48))	('increasing', 'PosReg', (119, 129))	('TOP2A', 'Gene', '7153', (32, 37))	('epigenetically', 'Var', (6, 20))	('increasing', 'PosReg', (21, 31))	('TOP2A', 'Gene', '7153', (130, 135))	('TOP2A', 'Gene', (32, 37))	('TOP2A', 'Gene', '7153', (178, 183))
10213	23533247	In summary, the data from our study demonstrates that TOP2A is overexpressed and epigenetically regulated in ACC and may influence tumor progression, as it regulates anchorage-independent growth and invasion of ACC cells.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('ACC', 'Phenotype', 'HP:0006744', (211, 214))	('anchorage-independent growth', 'CPA', (166, 194))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('epigenetically regulated', 'Var', (81, 105))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('tumor', 'Disease', (131, 136))	('ACC', 'Disease', (109, 112))	('invasion', 'CPA', (199, 207))	('TOP2A', 'Gene', '7153', (54, 59))	('influence', 'Reg', (121, 130))	('regulates', 'Reg', (156, 165))	('TOP2A', 'Gene', (54, 59))
10248	25945066	Most pituitary tumors are sporadic, resulting from monoclonal expansion of a single mutated cell.	('pituitary tumors', 'Disease', (5, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('pituitary tumors', 'Disease', 'MESH:D010911', (5, 21))	('monoclonal expansion', 'Var', (51, 71))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('resulting from', 'Reg', (36, 50))
10259	25945066	In childhood and adolescence, as in adults, exogenous glucocorticoids are the most common cause of Cushing's syndrome.	("Cushing's syndrome", 'Disease', (99, 117))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (99, 117))	('cause', 'Reg', (90, 95))	('exogenous', 'Var', (44, 53))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (99, 117))
10273	25945066	Classically, patients with ectopic Cushing's have severe hypercortisolemia associated with a rapid onset of symptoms and a florid presentation, hypokalemia, and severe or opportunistic infections.	('hypercortisolemia', 'Disease', 'None', (57, 74))	('opportunistic infections', 'Disease', 'MESH:D009894', (171, 195))	('ectopic Cushing', 'Var', (27, 42))	('hypokalemia', 'Disease', (144, 155))	('patients', 'Species', '9606', (13, 21))	('hypokalemia', 'Disease', 'MESH:D007008', (144, 155))	('opportunistic infections', 'Disease', (171, 195))	('hypercortisolemia', 'Disease', (57, 74))	('opportunistic infections', 'Phenotype', 'HP:0031690', (171, 195))	('hypokalemia', 'Phenotype', 'HP:0002900', (144, 155))
10333	25945066	Patients with proven ACTH-independent hypercortisolism but normal adrenal imaging studies should undergo screening for exogenous glucocorticoids, assessment for other features of Carney's complex, and possibly genetic testing for PRKAR1A mutations.	('hypercortisolism', 'Phenotype', 'HP:0003118', (38, 54))	('mutations', 'Var', (238, 247))	('Carney', 'Disease', (179, 185))	('hypercortisolism', 'Disease', 'MESH:D003480', (38, 54))	('men', 'Species', '9606', (152, 155))	('PRKAR1A', 'Gene', (230, 237))	('exogenous glucocorticoids', 'MPA', (119, 144))	('ACTH', 'Gene', (21, 25))	('Patients', 'Species', '9606', (0, 8))	('ACTH-independent hypercortisolism', 'Phenotype', 'HP:0001579', (21, 54))	('hypercortisolism', 'Disease', (38, 54))	('ACTH', 'Gene', '5443', (21, 25))	('PRKAR1A', 'Gene', '5573', (230, 237))
10335	25945066	Recently, an inactivating germ-line mutation of ARMC5, a putative tumor-suppressor gene, has been implicated in the development of primary bilateral macronodular hyperplasia.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('hyperplasia', 'Disease', (162, 173))	('men', 'Species', '9606', (123, 126))	('implicated', 'Reg', (98, 108))	('hyperplasia', 'Disease', 'MESH:D006965', (162, 173))	('inactivating', 'Var', (13, 25))	('ARMC5', 'Gene', (48, 53))	('ARMC5', 'Gene', '79798', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('mutation', 'Var', (36, 44))
10426	25945066	Mitotane increases CBG levels, leading to falsely high total cortisol levels, complicating titration of therapy.	('Mitotane', 'Var', (0, 8))	('cortisol', 'Chemical', 'MESH:D006854', (61, 69))	('total cortisol levels', 'MPA', (55, 76))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('CBG', 'Gene', (19, 22))	('increases', 'PosReg', (9, 18))	('high total cortisol levels', 'Phenotype', 'HP:0003118', (50, 76))	('CBG', 'Gene', '866', (19, 22))
10435	25945066	Seventy-three percent of patients treated with pasireotide develop glucose intolerance due to inhibition of incretin secretion, with a concomitant decrease in insulin secretion.	('pasireotide', 'Var', (47, 58))	('glucose intolerance', 'Disease', (67, 86))	('inhibition', 'NegReg', (94, 104))	('glucose', 'Chemical', 'MESH:D005947', (67, 74))	('decrease', 'NegReg', (147, 155))	('incretin secretion', 'MPA', (108, 126))	('patients', 'Species', '9606', (25, 33))	('insulin secretion', 'Disease', 'MESH:D007333', (159, 176))	('glucose intolerance', 'Phenotype', 'HP:0001952', (67, 86))	('insulin secretion', 'Disease', (159, 176))
10451	25089899	We also carried out a similar analysis in an ACC cell line (H295R) in which IGF2 expression was knocked down with si- or shRNA.	('H295R', 'CellLine', 'CVCL:0458', (60, 65))	('IGF2', 'Gene', (76, 80))	('si-', 'Var', (114, 117))	('knocked down', 'NegReg', (96, 108))	('H295', 'CellLine', 'CVCL:0456', (60, 64))	('ACC', 'Phenotype', 'HP:0006744', (45, 48))	('expression', 'MPA', (81, 91))
10454	25089899	Finally, analysis of the 11p15 locus showed a paternal uniparental disomy in both IGF2-high and IGF2-low tumors, but low IGF2 expression could be explained in most IGF2-low ACC by an additional epigenetic modification at the 11p15 locus.	('epigenetic modification', 'Var', (194, 217))	('ACC', 'Phenotype', 'HP:0006744', (173, 176))	('expression', 'MPA', (126, 136))	('p15', 'Gene', (27, 30))	('paternal uniparental disomy', 'Disease', (46, 73))	('IGF2-high', 'Gene', (82, 91))	('p15', 'Gene', '1030', (27, 30))	('p15', 'Gene', (227, 230))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('paternal uniparental disomy', 'Disease', 'MESH:C536471', (46, 73))	('p15', 'Gene', '1030', (227, 230))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
10466	25089899	The ACC cell line H295R recapitulates the IGF2 abnormalities of most ACC, with a high abundance of IGF2 mRNA and protein, a low abundance of H19 and CDKN1C suggesting 11p15 pUPD, and TP53 mutation.	('ACC', 'Phenotype', 'HP:0006744', (69, 72))	('IGF2', 'Gene', (42, 46))	('CDKN1C', 'Gene', (149, 155))	('TP53', 'Gene', '7157', (183, 187))	('H19', 'Gene', '283120', (141, 144))	('mutation', 'Var', (188, 196))	('CDKN1C', 'Gene', '1028', (149, 155))	('H19', 'Gene', (141, 144))	('TP53', 'Gene', (183, 187))	('ACC', 'Phenotype', 'HP:0006744', (4, 7))	('IGF2', 'Gene', (99, 103))
10473	25089899	For the transient knock-down of IGF2, siRNA duplexes against IGF2 (forward sequence 5'UCGUUGAGGAGUGCUGUUUdTdT3') and a control siRNA with no target in the human genome (forward sequence 5'GGCAUAGAUGUAGCUGUAAdTdT3') were designed and obtained from Eurogentec.	('IGF2', 'Gene', (32, 36))	('IGF2', 'Gene', (61, 65))	('human', 'Species', '9606', (155, 160))	('knock-down', 'Var', (18, 28))
10479	25089899	TNF-alpha-induced apoptosis was analyzed in H295R cells after transient IGF2 knock-down by siRNA for 48 h, followed by a 48 h treatment with 20 ng/mL TNF-alpha (eBioscience).	('TNF-alpha', 'Gene', (150, 159))	('TNF-alpha', 'Gene', (0, 9))	('IGF2', 'Gene', (72, 76))	('TNF-alpha', 'Gene', '7124', (150, 159))	('TNF-alpha', 'Gene', '7124', (0, 9))	('knock-down', 'Var', (77, 87))
10486	25089899	Transcriptomic analyses of three different H295R clones, with or without IGF2 knock-down for 2 or 10 days, was carried with Human gene 1.0 ST array (Affymetrix).	('Human', 'Species', '9606', (124, 129))	('IGF2', 'Gene', (73, 77))	('knock-down', 'Var', (78, 88))
10493	25089899	IGF2 status is clearly correlated with malignancy, but it is not a prognostic marker in carcinoma.	('status', 'Var', (5, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('malignancy', 'Disease', 'MESH:D009369', (39, 49))	('correlated', 'Reg', (23, 33))	('malignancy', 'Disease', (39, 49))	('IGF2', 'Gene', (0, 4))
10497	25089899	The phosphorylation of IGF1 and insulin receptors was higher in IGF2-high carcinoma than in IGF2-low carcinoma, but there was no difference in the phosphorylation status of Akt and Erk1/2 when normalizing to total Akt or Erk1/2 respectively (Figure 3) or actin (data not shown).	('insulin receptors', 'Protein', (32, 49))	('Erk1/2', 'Gene', '5595;5594', (181, 187))	('higher', 'PosReg', (54, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('IGF1', 'Protein', (23, 27))	('IGF2-high', 'Var', (64, 73))	('Erk1/2', 'Gene', (181, 187))	('phosphorylation', 'MPA', (4, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('Erk1/2', 'Gene', '5595;5594', (221, 227))	('carcinoma', 'Disease', (74, 83))	('Erk1/2', 'Gene', (221, 227))
10498	25089899	Indeed, our comparison of the transcriptome between IGF2-high and IGF2-low ACC identified some growth factors (FGF9, PDGFA, TNFSF10, and TNFSF4) that were 2-fold more expressed in IGF2-low ACC than in IGF2-high ACC (underlined in yellow in Table S3_ACC_genes).	('TNFSF10', 'Gene', (124, 131))	('ACC', 'Phenotype', 'HP:0006744', (211, 214))	('TNFSF4', 'Gene', '7292', (137, 143))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('ACC', 'Phenotype', 'HP:0006744', (249, 252))	('FGF9', 'Gene', (111, 115))	('TNFSF10', 'Gene', '8743', (124, 131))	('expressed', 'MPA', (167, 176))	('PDGFA', 'Gene', (117, 122))	('more', 'PosReg', (162, 166))	('ACC', 'Phenotype', 'HP:0006744', (189, 192))	('TNFSF4', 'Gene', (137, 143))	('IGF2-low', 'Var', (180, 188))
10499	25089899	The stable knock-down of IGF2 dramatically impaired cell proliferation in an MTT assay (Figure 4A), whereas cell proliferation was not affected in a doxycycline-treated control clone (Figure 4B).	('cell proliferation in an MTT assay', 'CPA', (52, 86))	('knock-down', 'Var', (11, 21))	('impaired', 'NegReg', (43, 51))	('IGF2', 'Gene', (25, 29))	('MTT', 'Chemical', 'MESH:C070243', (77, 80))
10501	25089899	Transcriptome analysis shows an increase in PMAIP1 and BCL2L11 expression following IGF2 knock-down suggesting the involvement of the intrinsic apoptotic pathway.	('BCL2L11', 'Gene', '10018', (55, 62))	('knock-down', 'Var', (89, 99))	('increase', 'PosReg', (32, 40))	('intrinsic apoptotic pathway', 'Pathway', (134, 161))	('BCL2L11', 'Gene', (55, 62))	('PMAIP1', 'Gene', (44, 50))	('expression', 'MPA', (63, 73))	('IGF2', 'Gene', (84, 88))	('PMAIP1', 'Gene', '5366', (44, 50))
10503	25089899	Methylation of ICR1 controls the expression of the IGF2/H19 genes and its methylation prevents the binding of the CTCF protein to DNA, which acts as an insulator between the two genes (Figure 5A).	('CTCF', 'Gene', '10664', (114, 118))	('methylation', 'Var', (74, 85))	('prevents', 'NegReg', (86, 94))	('controls', 'Reg', (20, 28))	('ICR1', 'Gene', (15, 19))	('CTCF', 'Gene', (114, 118))	('expression', 'MPA', (33, 43))	('IGF2/H19', 'Gene', (51, 59))	('binding', 'Interaction', (99, 106))
10534	33679865	Previous studies have presented the association of certain miRNAs with lung metastasis, including miR-629-3p, miR-106b-5p, and so on.	('miR-629-3p', 'Var', (98, 108))	('miR-106b', 'Gene', (110, 118))	('miR-106b', 'Gene', '406900', (110, 118))	('association', 'Interaction', (36, 47))	('lung', 'Disease', (71, 75))
10581	33679865	Compared the TNM stage alone, the NRI values for miRNA-based prediction nomogram were 0.216 (95% CI, 0.048-0.384, value of p = 0.012), 0.307 (95% CI, 0.020-0.594, value of p = 0.036) and 0.308 (95% CI, 0.081-0.535, value of p = 0.008) in the training cohort and two validation cohorts, respectively (Table 5).	('age', 'Gene', (19, 22))	('0.308', 'Var', (187, 192))	('0.307', 'Var', (135, 140))	('age', 'Gene', '5973', (19, 22))
10653	30753137	Genetics of aldosterone-producing adenomas with pathogenic KCNJ5 variants Somatic variants in genes that regulate intracellular ion homeostasis have been identified in aldosterone-producing adenomas (APA).	('variants', 'Var', (82, 90))	('aldosterone', 'Chemical', 'MESH:D000450', (12, 23))	('adenomas', 'Disease', 'MESH:D000236', (190, 198))	('KCNJ5', 'Gene', '3762', (59, 64))	('adenomas', 'Disease', (190, 198))	('PA', 'Phenotype', 'HP:0011736', (201, 203))	('variants', 'Var', (65, 73))	('aldosterone', 'Chemical', 'MESH:D000450', (168, 179))	('identified', 'Reg', (154, 164))	('adenomas', 'Disease', 'MESH:D000236', (34, 42))	('adenomas', 'Disease', (34, 42))	('KCNJ5', 'Gene', (59, 64))
10655	30753137	In the present study, we have performed whole exome sequencing (WES) to characterize the landscape of somatic alterations in a homogeneous series of APA with pathogenic KCNJ5 variants.	('variants', 'Var', (175, 183))	('PA', 'Phenotype', 'HP:0011736', (150, 152))	('KCNJ5', 'Gene', (169, 174))	('KCNJ5', 'Gene', '3762', (169, 174))	('pathogenic', 'Reg', (158, 168))
10656	30753137	Besides the KCNJ5 gene, only two genes (MED13 and ZNF669) harbored somatic variants in more than one APA.	('ZNF669', 'Gene', (50, 56))	('MED13', 'Gene', (40, 45))	('KCNJ5', 'Gene', (12, 17))	('ZNF669', 'Gene', '79862', (50, 56))	('PA', 'Phenotype', 'HP:0011736', (102, 104))	('MED13', 'Gene', '9969', (40, 45))	('KCNJ5', 'Gene', '3762', (12, 17))	('variants', 'Var', (75, 83))
10657	30753137	Unlike adrenocortical carcinomas, no chromosomal instability was observed by the somatic copy-number alteration and loss of heterozygosity analyses.	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (7, 32))	('adrenocortical carcinomas', 'Disease', (7, 32))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (7, 32))	('loss of heterozygosity analyses', 'Var', (116, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('copy-number alteration', 'Var', (89, 111))	('chromosomal instability', 'Phenotype', 'HP:0040012', (37, 60))
10659	30753137	Based on the results of PureCN analysis, the KCNJ5 variants appear to be clonal.	('KCNJ5', 'Gene', (45, 50))	('KCNJ5', 'Gene', '3762', (45, 50))	('variants', 'Var', (51, 59))
10660	30753137	In conclusion, in addition to KCNJ5 somatic pathogenic variants, no significant somatic event that would obviously explain proliferation or tumor growth was observed in our homogeneous cohort of KCNJ5-mutated APA.	('PA', 'Phenotype', 'HP:0011736', (210, 212))	('KCNJ5', 'Gene', '3762', (30, 35))	('KCNJ5', 'Gene', '3762', (195, 200))	('variants', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('KCNJ5', 'Gene', (30, 35))	('KCNJ5', 'Gene', (195, 200))	('tumor', 'Disease', (140, 145))
10663	30753137	Aldosterone-producing adenoma (APA) is one of the major subtypes of PA. Over the past decade, there has been a considerable focus on defining the genetic bases of excess aldosterone production in PA. After the initial identification of somatic and germline KCNJ5 variants in PA patients, different germline and somatic variants have been identified in familial and sporadic forms of PA.	('KCNJ5', 'Gene', (257, 262))	('Aldosterone', 'Chemical', 'MESH:D000450', (0, 11))	('adenoma', 'Disease', (22, 29))	('PA', 'Phenotype', 'HP:0011736', (383, 385))	('identified', 'Reg', (338, 348))	('KCNJ5', 'Gene', '3762', (257, 262))	('PA', 'Phenotype', 'HP:0011736', (32, 34))	('excess aldosterone', 'Phenotype', 'HP:0000859', (163, 181))	('aldosterone production', 'Phenotype', 'HP:0000859', (170, 192))	('PA', 'Phenotype', 'HP:0011736', (68, 70))	('PA', 'Phenotype', 'HP:0011736', (196, 198))	('patients', 'Species', '9606', (278, 286))	('variants', 'Var', (263, 271))	('familial', 'Disease', (352, 360))	('PA', 'Phenotype', 'HP:0011736', (275, 277))	('adenoma', 'Disease', 'MESH:D000236', (22, 29))	('aldosterone', 'Chemical', 'MESH:D000450', (170, 181))
10664	30753137	The immediate functional consequences of these alterations are disruption of intracellular ion homeostasis, which ultimately lead to increased aldosterone synthase (CYP11B2) transcription, and inappropriate aldosterone production.	('aldosterone', 'Chemical', 'MESH:D000450', (207, 218))	('disruption', 'Reg', (63, 73))	('disruption of intracellular ion homeostasis', 'Phenotype', 'HP:0003575', (63, 106))	('increased aldosterone', 'Phenotype', 'HP:0000859', (133, 154))	('transcription', 'MPA', (174, 187))	('CYP11B2', 'Gene', (165, 172))	('aldosterone', 'Chemical', 'MESH:D000450', (143, 154))	('aldosterone synthase', 'Gene', (143, 163))	('aldosterone production', 'MPA', (207, 229))	('CYP11B2', 'Gene', '1585', (165, 172))	('aldosterone production', 'Phenotype', 'HP:0000859', (207, 229))	('aldosterone synthase', 'Gene', '1585', (143, 163))	('increased', 'PosReg', (133, 142))	('alterations', 'Var', (47, 58))	('intracellular ion homeostasis', 'MPA', (77, 106))
10665	30753137	KCNJ5 mutations are the most common somatic variants in APA with greater frequency in East Asian populations.	('KCNJ5', 'Gene', (0, 5))	('KCNJ5', 'Gene', '3762', (0, 5))	('mutations', 'Var', (6, 15))	('PA', 'Phenotype', 'HP:0011736', (57, 59))
10666	30753137	Recent studies have demonstrated that in patients with PA and multiple adrenal nodules, somatic variants in different aldosterone-driver genes can be present in distinct CYP11B2-expressing, but not in CYP11B2-negative nodules within the same adrenal.	('PA', 'Phenotype', 'HP:0011736', (55, 57))	('CYP11B2', 'Gene', '1585', (170, 177))	('variants', 'Var', (96, 104))	('aldosterone-driver genes', 'Gene', (118, 142))	('patients', 'Species', '9606', (41, 49))	('CYP11B2', 'Gene', (201, 208))	('aldosterone', 'Chemical', 'MESH:D000450', (118, 129))	('CYP11B2', 'Gene', (170, 177))	('CYP11B2', 'Gene', '1585', (201, 208))
10667	30753137	Additionally, in-vitro studies indicate that mutated KCNJ5 channels do not confer growth advantage when expressed in the human adrenocortical HAC15 cell line.	('human', 'Species', '9606', (121, 126))	('growth advantage', 'CPA', (82, 98))	('KCNJ5', 'Gene', (53, 58))	('KCNJ5', 'Gene', '3762', (53, 58))	('HAC15', 'CellLine', 'CVCL:S898', (142, 147))	('mutated', 'Var', (45, 52))
10671	30753137	In this study, we used whole-exome sequencing (WES) to characterize the landscape of somatic alterations in a homogeneous series of APA with KCNJ5 variants.	('variants', 'Var', (147, 155))	('KCNJ5', 'Gene', (141, 146))	('PA', 'Phenotype', 'HP:0011736', (133, 135))	('KCNJ5', 'Gene', '3762', (141, 146))
10672	30753137	We were particularly interested in identifying novel recurrent mutations and somatic alterations that may contribute to APA tumorigenesis, and to further characterize KCNJ5-mutated tumors in terms of tumor purity, ploidy, and clonal composition.	('PA', 'Phenotype', 'HP:0011736', (121, 123))	('tumor', 'Disease', (124, 129))	('ploidy', 'Disease', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('KCNJ5', 'Gene', '3762', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('mutations', 'Var', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', (200, 205))	('ploidy', 'Disease', 'None', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumors', 'Disease', (181, 187))	('contribute', 'Reg', (106, 116))	('APA', 'Disease', (120, 123))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('alterations', 'Var', (85, 96))	('KCNJ5', 'Gene', (167, 172))
10681	30753137	For samples which paired germline DNA were not available, we calculated the allele frequencies of pathogenic KCNJ5 variants from the VCF files generated with samtools mpileup/bcftools.	('variants', 'Var', (115, 123))	('KCNJ5', 'Gene', (109, 114))	('KCNJ5', 'Gene', '3762', (109, 114))
10683	30753137	PureCN infers tumor purity and ploidy by simultaneously analyzing depth-of-coverage and variant allele frequencies from germline and tumor DNA.	('tumor', 'Disease', (14, 19))	('PureCN infers tumor', 'Disease', 'MESH:D009369', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('ploidy', 'Disease', (31, 37))	('PureCN infers tumor', 'Disease', (0, 19))	('variant', 'Var', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('ploidy', 'Disease', 'None', (31, 37))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
10699	30753137	Apart from KCNJ5 variants, which were detected by the three callers in all samples, only two other genes had variants in more than one APA: MED13 (NM_005121:exon26:c.T5866G:p.Ser1956Ala, [APA-78 and APA-86]) and ZNF669 (NM_001142572:exon4:c.A1052C:p.Glu351Ala, [APA-78 and APA-86]) (Supplementary Figure 4-7).	('c.T5866G:p.Ser1956Ala', 'Var', (164, 185))	('KCNJ5', 'Gene', (11, 16))	('ZNF669', 'Gene', '79862', (212, 218))	('PA', 'Phenotype', 'HP:0011736', (189, 191))	('PA', 'Phenotype', 'HP:0011736', (200, 202))	('PA', 'Phenotype', 'HP:0011736', (263, 265))	('KCNJ5', 'Gene', '3762', (11, 16))	('c.T5866G:p.Ser1956Ala', 'SUBSTITUTION', 'None', (164, 185))	('MED13', 'Gene', (140, 145))	('ZNF669', 'Gene', (212, 218))	('NM_001142572:', 'Var', (220, 233))	('c.A1052C:p.Glu351Ala', 'SUBSTITUTION', 'None', (239, 259))	('PA', 'Phenotype', 'HP:0011736', (136, 138))	('PA', 'Phenotype', 'HP:0011736', (274, 276))	('c.A1052C:p.Glu351Ala', 'Var', (239, 259))	('MED13', 'Gene', '9969', (140, 145))	('NM_005121:', 'Var', (147, 157))
10700	30753137	Of note, the MED13 and ZNF669 variants were not confirmed by direct Sanger sequencing likely due to the low variant frequencies.	('variants', 'Var', (30, 38))	('ZNF669', 'Gene', (23, 29))	('MED13', 'Gene', (13, 18))	('ZNF669', 'Gene', '79862', (23, 29))	('MED13', 'Gene', '9969', (13, 18))
10701	30753137	Among the identified mutated genes, 6 of them have been reported as cancer-associated (COSMIC v85): JAK1, NAB2, FOXP1, ATM, MEN1, and USP6.	('USP6', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('MEN1', 'Gene', (124, 128))	('FOXP1', 'Gene', (112, 117))	('ATM', 'Gene', (119, 122))	('NAB2', 'Gene', '4665', (106, 110))	('MEN1', 'Gene', '4221', (124, 128))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('FOXP1', 'Gene', '27086', (112, 117))	('JAK1', 'Gene', (100, 104))	('cancer', 'Disease', (68, 74))	('NAB2', 'Gene', (106, 110))	('ATM', 'Gene', '472', (119, 122))	('mutated', 'Var', (21, 28))	('JAK1', 'Gene', '3716', (100, 104))	('USP6', 'Gene', '9098', (134, 138))
10702	30753137	Mutations in these genes have been shown to affect cellular processes that are frequently dysregulated in cancer and are thought to be tumor promoting.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cellular processes', 'CPA', (51, 69))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (106, 112))	('affect', 'Reg', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
10703	30753137	Additionally, we identified variants in PDE11A and CYP17A1, genes that are essential components of the adrenal steroidogenesis machinery and have been implicated in other adrenal diseases, such as forms of adrenal micronodular hyperplasia, cortisol-producing adenomas (CPA), and congenital adrenal hyperplasia.	('CYP17A1', 'Gene', '1586', (51, 58))	('PDE11A', 'Gene', '50940', (40, 46))	('adenomas', 'Disease', 'MESH:D000236', (259, 267))	('CYP17A1', 'Gene', (51, 58))	('PDE11A', 'Gene', (40, 46))	('adrenal diseases', 'Disease', 'MESH:C537027', (171, 187))	('variants', 'Var', (28, 36))	('adenomas', 'Disease', (259, 267))	('cortisol', 'Chemical', 'MESH:D006854', (240, 248))	('adrenal diseases', 'Disease', (171, 187))	('PA', 'Phenotype', 'HP:0011736', (270, 272))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (279, 309))	('adrenal micronodular hyperplasia', 'Disease', 'MESH:D000312', (206, 238))	('adrenal micronodular hyperplasia', 'Disease', (206, 238))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (279, 309))	('implicated', 'Reg', (151, 161))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (290, 309))	('congenital adrenal hyperplasia', 'Disease', (279, 309))
10704	30753137	Finally, we identified variants in other ionic channels such as CACNA1E and KCNA1 (Supplementary Table 3-6).	('KCNA1', 'Gene', '3736', (76, 81))	('KCNA1', 'Gene', (76, 81))	('CACNA1E', 'Gene', (64, 71))	('variants', 'Var', (23, 31))	('CACNA1E', 'Gene', '777', (64, 71))
10705	30753137	Noteworthy, exome sequencing confirmed the presence of four previously identified KCNJ5 variants in out cohort: c.T503G (p.L168R), c.G451A (p.G151R), c.G451C (p.G151R), and c.477_478insATT (p.T149delinsTI) with allele frequencies ranging from 14-48% (Table 1).	('c.T503G', 'Mutation', 'rs386352318', (112, 119))	('p.G151R', 'Var', (159, 166))	('p.G151R', 'Mutation', 'rs386352319', (159, 166))	('p.G151R', 'Var', (140, 147))	('c.G451C (p.G151R', 'Var', (150, 166))	('c.477_478insATT', 'Var', (173, 188))	('c.G451A (p.G151R', 'Var', (131, 147))	('p.L168R', 'Mutation', 'rs386352318', (121, 128))	('p.T149delinsTI', 'Mutation', 'p.149delinsT,TI', (190, 204))	('p.G151R', 'Mutation', 'rs386352319', (140, 147))	('c.G451C', 'Mutation', 'rs386352319', (150, 157))	('KCNJ5', 'Gene', (82, 87))	('KCNJ5', 'Gene', '3762', (82, 87))	('c.G451A', 'Mutation', 'rs386352319', (131, 138))	('c.477_478insATT', 'Mutation', 'c.477_478insATT', (173, 188))
10708	30753137	Furthermore, PureCN analysis also demonstrated that KCNJ5 variants are heterozygous and likely clonal in all tumors, suggesting that these variants are early events in adenoma formation (Table 1, Supplementary Figure 8).	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('adenoma', 'Disease', 'MESH:D000236', (168, 175))	('KCNJ5', 'Gene', (52, 57))	('variants', 'Var', (58, 66))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('adenoma', 'Disease', (168, 175))	('KCNJ5', 'Gene', '3762', (52, 57))	('variants', 'Var', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
10709	30753137	In recent years, high-throughput molecular profiling studies have identified recurrent variants targeting different regulators of intracellular calcium homeostasis, including KCNJ5, ATP1A1, ATP2B3, and CACNA1D in over half of APA.	('CACNA1D', 'Gene', (202, 209))	('KCNJ5', 'Gene', '3762', (175, 180))	('ATP1A1', 'Gene', '476', (182, 188))	('PA', 'Phenotype', 'HP:0011736', (227, 229))	('variants', 'Var', (87, 95))	('ATP2B3', 'Gene', '492', (190, 196))	('ATP1A1', 'Gene', (182, 188))	('ATP2B3', 'Gene', (190, 196))	('calcium', 'Chemical', 'MESH:D002118', (144, 151))	('KCNJ5', 'Gene', (175, 180))	('CACNA1D', 'Gene', '776', (202, 209))
10710	30753137	Despite the well-characterized effects of these variants in abnormal CYP11B2 expression and aldosterone production, the contribution to cell growth remain poorly understood.	('effects', 'Reg', (31, 38))	('expression', 'MPA', (77, 87))	('aldosterone', 'Chemical', 'MESH:D000450', (92, 103))	('variants', 'Var', (48, 56))	('aldosterone production', 'MPA', (92, 114))	('aldosterone production', 'Phenotype', 'HP:0000859', (92, 114))	('CYP11B2', 'Gene', (69, 76))	('CYP11B2', 'Gene', '1585', (69, 76))
10711	30753137	So far, a growth-promoting effect of KCNJ5 variants has not been demonstrated in-vitro studies using HAC15 cells.	('KCNJ5', 'Gene', (37, 42))	('growth-promoting', 'MPA', (10, 26))	('variants', 'Var', (43, 51))	('KCNJ5', 'Gene', '3762', (37, 42))	('HAC15', 'CellLine', 'CVCL:S898', (101, 106))
10712	30753137	Although it is difficult to assess a cell proliferation effect of these variants using highly proliferative H295R/HAC15 cells which have a beta-catenin mutation, these in vitro studies suggest that alternative mechanisms might play a role in tumor formation.	('HAC15', 'CellLine', 'CVCL:S898', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('variants', 'Var', (72, 80))	('beta-catenin', 'Gene', (139, 151))	('tumor', 'Disease', (242, 247))	('beta-catenin', 'Gene', '1499', (139, 151))	('mutation', 'Var', (152, 160))
10717	30753137	In fact, we observed at least two variants of uncertain significance in genes that have been previously associated with adrenocortical tumorigenesis: the MEN1 NM_130804:exon3:c.T364C (p.Ser122Pro) and the PDE11A NM_001077197:exon5:c.C514T (p.Arg172Cys) variants, both predicted to be pathogenic by SIFT, polyphen2, and CADD.	('MEN1', 'Gene', (154, 158))	('PDE11A', 'Gene', (205, 211))	('c.T364C', 'Mutation', 'c.364T>C', (175, 182))	('MEN1', 'Gene', '4221', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('p.Ser122Pro', 'Mutation', 'p.S122P', (184, 195))	('associated', 'Reg', (104, 114))	('p.Arg172Cys', 'Mutation', 'rs762697508', (240, 251))	('PDE11A', 'Gene', '50940', (205, 211))	('c.T364C', 'Var', (175, 182))	('c.C514T', 'Mutation', 'rs762697508', (231, 238))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
10718	30753137	Although somatic variants in MED13 and ZNF669 were identified in more than one APA, the pathological role of these variants is unclear.	('MED13', 'Gene', (29, 34))	('ZNF669', 'Gene', (39, 45))	('PA', 'Phenotype', 'HP:0011736', (80, 82))	('variants', 'Var', (17, 25))	('ZNF669', 'Gene', '79862', (39, 45))	('MED13', 'Gene', '9969', (29, 34))
10720	30753137	Mutations and altered expression of different Mediator components have been described in rare neurodevelopmental disorders and in a broad spectrum of benign and malignant tumors.	('altered', 'Reg', (14, 21))	('neurodevelopmental disorders', 'Phenotype', 'HP:0012759', (94, 122))	('described', 'Reg', (76, 85))	('neurodevelopmental disorders', 'Disease', 'MESH:D002658', (94, 122))	('malignant tumors', 'Disease', (161, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (161, 177))	('Mutations', 'Var', (0, 9))	('neurodevelopmental disorders', 'Disease', (94, 122))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('expression', 'MPA', (22, 32))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
10722	30753137	Noteworthily, we did not identify variants in other genes previously described in APA, such as CTNNB1 (encoding beta-catenin), suggesting a dominant role for KCNJ5 variants.	('KCNJ5', 'Gene', (158, 163))	('CTNNB1', 'Gene', (95, 101))	('PA', 'Phenotype', 'HP:0011736', (83, 85))	('variants', 'Var', (164, 172))	('KCNJ5', 'Gene', '3762', (158, 163))	('CTNNB1', 'Gene', '1499', (95, 101))	('beta-catenin', 'Gene', (112, 124))	('beta-catenin', 'Gene', '1499', (112, 124))
10723	30753137	These results are consistent with previous studies on APA genetics, in which KCNJ5 and CTNNB1 variants were mutually exclusive.	('PA', 'Phenotype', 'HP:0011736', (55, 57))	('KCNJ5', 'Gene', '3762', (77, 82))	('CTNNB1', 'Gene', '1499', (87, 93))	('variants', 'Var', (94, 102))	('CTNNB1', 'Gene', (87, 93))	('KCNJ5', 'Gene', (77, 82))
10724	30753137	Previous reports have demonstrated that the activation of Wnt/beta-catenin pathway is frequent in APA regardless of the mutation status of CTNNB1.	('beta-catenin', 'Gene', (62, 74))	('CTNNB1', 'Gene', '1499', (139, 145))	('activation', 'PosReg', (44, 54))	('mutation', 'Var', (120, 128))	('beta-catenin', 'Gene', '1499', (62, 74))	('PA', 'Phenotype', 'HP:0011736', (99, 101))	('APA', 'Disease', (98, 101))	('CTNNB1', 'Gene', (139, 145))
10726	30753137	For better understanding of the role of Wnt/beta-catenin signaling pathway activation in APA development, further analysis including APA with variants in other aldosterone-driver genes, such as CACNA1D, ATP1A1, and ATP2B3 will be needed.	('aldosterone', 'Chemical', 'MESH:D000450', (160, 171))	('ATP1A1', 'Gene', '476', (203, 209))	('variants', 'Var', (142, 150))	('ATP1A1', 'Gene', (203, 209))	('beta-catenin', 'Gene', (44, 56))	('CACNA1D', 'Gene', '776', (194, 201))	('PA', 'Phenotype', 'HP:0011736', (134, 136))	('CACNA1D', 'Gene', (194, 201))	('ATP2B3', 'Gene', '492', (215, 221))	('beta-catenin', 'Gene', '1499', (44, 56))	('ATP2B3', 'Gene', (215, 221))	('PA', 'Phenotype', 'HP:0011736', (90, 92))
10728	30753137	Certain KCNJ5 variants, including p.G151R and p.T158A appear to have potential impact on cell proliferation considering the fact that these variants have been identified both in sporadic APA (as somatic variants) and in patients with massive hyperplasia (as germline variants), whereas a KCNJ5 variant p.G151E has only been documented in individuals without massive adrenal hyperplasia as a germline variant.	('p.T158A', 'Mutation', 'rs387906778', (46, 53))	('patients', 'Species', '9606', (220, 228))	('KCNJ5', 'Gene', (8, 13))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (366, 385))	('KCNJ5', 'Gene', '3762', (288, 293))	('p.G151E', 'Mutation', 'rs587777437', (302, 309))	('KCNJ5', 'Gene', (288, 293))	('identified', 'Reg', (159, 169))	('p.G151R', 'Var', (34, 41))	('KCNJ5', 'Gene', '3762', (8, 13))	('p.G151R', 'Mutation', 'rs386352319', (34, 41))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (366, 385))	('p.T158A', 'Var', (46, 53))	('hyperplasia', 'Disease', (242, 253))	('PA', 'Phenotype', 'HP:0011736', (188, 190))	('hyperplasia', 'Disease', 'MESH:D006965', (242, 253))	('impact', 'Reg', (79, 85))	('variants', 'Var', (14, 22))	('cell', 'CPA', (89, 93))	('adrenal hyperplasia', 'Disease', (366, 385))	('hyperplasia', 'Disease', (374, 385))	('hyperplasia', 'Disease', 'MESH:D006965', (374, 385))
10729	30753137	Furthermore, in an early-onset PA patient, the identical somatic KCNJ5 p.G151R variant has been identified in multiple CYP11B2-expressing hyperplastic lesions and APA in bilateral adrenals and the variant has not been observed in non-hyperplastic lesions, supporting the potential role of the KCNJ5 variant on cell proliferation.	('CYP11B2', 'Gene', (119, 126))	('p.G151R', 'Var', (71, 78))	('KCNJ5', 'Gene', (65, 70))	('KCNJ5', 'Gene', '3762', (65, 70))	('CYP11B2', 'Gene', '1585', (119, 126))	('identified', 'Reg', (96, 106))	('p.G151R', 'Mutation', 'rs386352319', (71, 78))	('hyperplastic lesions', 'Disease', (234, 254))	('KCNJ5', 'Gene', (293, 298))	('patient', 'Species', '9606', (34, 41))	('hyperplastic lesions', 'Disease', 'MESH:D000796', (234, 254))	('hyperplastic lesions', 'Disease', (138, 158))	('hyperplastic lesions', 'Disease', 'MESH:D000796', (138, 158))	('PA', 'Phenotype', 'HP:0011736', (164, 166))	('KCNJ5', 'Gene', '3762', (293, 298))	('PA', 'Phenotype', 'HP:0011736', (31, 33))
10730	30753137	However, since our study included only a homogeneous population of APA with KCNJ5 variants, the findings cannot be generalized.	('variants', 'Var', (82, 90))	('KCNJ5', 'Gene', (76, 81))	('PA', 'Phenotype', 'HP:0011736', (68, 70))	('KCNJ5', 'Gene', '3762', (76, 81))
10732	30753137	A recent case report describes the co-occurrence of a germline APC variant and a somatic KCNJ5 variant in a young PA patient with multinodular adrenal hyperplasia.	('PA', 'Phenotype', 'HP:0011736', (114, 116))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (143, 162))	('KCNJ5', 'Gene', '3762', (89, 94))	('variant', 'Var', (95, 102))	('variant', 'Var', (67, 74))	('multinodular adrenal hyperplasia', 'Disease', 'MESH:D000312', (130, 162))	('patient', 'Species', '9606', (117, 124))	('APC', 'Disease', 'MESH:D011125', (63, 66))	('multinodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (130, 162))	('APC', 'Disease', (63, 66))	('multinodular adrenal hyperplasia', 'Disease', (130, 162))	('KCNJ5', 'Gene', (89, 94))
10733	30753137	In the resected adrenal from the patient, the KCNJ5 variant was identified only in a CYP11B2-expressing nodule, whereas biallelic APC inactivation due to LOH was observed in both CYP11B2-positive and negative nodules, indicating "two-hit" model as a possible mechanism of APA development at least for some cases.	('variant', 'Var', (52, 59))	('patient', 'Species', '9606', (33, 40))	('CYP11B2', 'Gene', '1585', (85, 92))	('APC', 'Disease', 'MESH:D011125', (130, 133))	('CYP11B2', 'Gene', (179, 186))	('KCNJ5', 'Gene', (46, 51))	('PA', 'Phenotype', 'HP:0011736', (273, 275))	('APC', 'Disease', (130, 133))	('CYP11B2', 'Gene', '1585', (179, 186))	('KCNJ5', 'Gene', '3762', (46, 51))	('CYP11B2', 'Gene', (85, 92))
10734	30753137	A recent study of integrated transcriptome and methylome analysis has demonstrated global hypomethylation in APA and up-regulated genes with CpG hypomethylation in APA, including five potentially tumorigenesis-related genes.	('PA', 'Phenotype', 'HP:0011736', (110, 112))	('APA', 'Gene', (109, 112))	('tumor', 'Disease', (196, 201))	('up-regulated', 'PosReg', (117, 129))	('hypomethylation', 'Var', (90, 105))	('hypomethylation', 'Var', (145, 160))	('PA', 'Phenotype', 'HP:0011736', (165, 167))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
10738	30753137	In conclusion, our study did not identify recurrent somatic events that could explain proliferation or tumor formation in APA with KCNJ5 variants.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('KCNJ5', 'Gene', (131, 136))	('tumor', 'Disease', (103, 108))	('KCNJ5', 'Gene', '3762', (131, 136))	('PA', 'Phenotype', 'HP:0011736', (123, 125))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('variants', 'Var', (137, 145))
10877	32640719	Furthermore, NRP2, PLXNC1 and PLXNB3 were also positively associated with cell sensitivity to Dabrafenib, which is the treatment for late-stage melanoma and metastatic non-small cell lung cancer with BRAF V600E or V600K mutations (Figure 5C and Table S5).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('BRAF', 'Gene', (200, 204))	('Dabrafenib', 'Chemical', 'MESH:C561627', (94, 104))	('V600E', 'Mutation', 'rs113488022', (205, 210))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('NRP2', 'Gene', (13, 17))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('V600K', 'Var', (214, 219))	('cell sensitivity', 'MPA', (74, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('PLXNB3', 'Gene', '5365', (30, 36))	('PLXNC1', 'Gene', '10154', (19, 25))	('PLXNB3', 'Gene', (30, 36))	('PLXNC1', 'Gene', (19, 25))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('associated', 'Reg', (58, 68))	('NRP2', 'Gene', '8828', (13, 17))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('lung cancer', 'Disease', (183, 194))	('V600K', 'Mutation', 'rs121913227', (214, 219))	('BRAF', 'Gene', '673', (200, 204))	('metastatic', 'CPA', (157, 167))
10889	32640719	Various cell types in the TME of breast cancer tumors might contribute to the dysregulated expression of SEMA3 and their receptors.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('expression', 'MPA', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer tumors', 'Disease', 'MESH:D001943', (33, 53))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (33, 52))	('SEMA', 'Gene', '7869', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('breast cancer tumors', 'Disease', (33, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('dysregulated', 'Var', (78, 90))	('SEMA', 'Gene', (105, 109))
10904	32640719	The semaphorin/neuropilin/plexin complexes control a wide range of biological processes and deregulation of these complexes is associated with multiple pathological statuses.	('sema', 'Gene', '7869', (4, 8))	('associated', 'Reg', (127, 137))	('control', 'Reg', (43, 50))	('sema', 'Gene', (4, 8))	('neuropilin', 'Gene', '8829', (15, 25))	('deregulation', 'Var', (92, 104))	('neuropilin', 'Gene', (15, 25))
10921	32640719	The dysregulated expression of NRPs and PLXNs in cancer tumors was generally associated with patient overall survival and progression free interval in 33 cancer types, while the direction of association is dependent on the cancer type tested and the genes queried.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer tumors', 'Disease', (49, 62))	('PLXNs', 'Gene', (40, 45))	('cancer', 'Disease', (223, 229))	('dysregulated', 'Var', (4, 16))	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('expression', 'MPA', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('associated', 'Reg', (77, 87))	('patient', 'Species', '9606', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer tumors', 'Disease', 'MESH:D009369', (49, 62))	('NRP', 'Gene', '8829', (31, 34))	('NRP', 'Gene', (31, 34))	('cancer', 'Disease', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
11079	25797237	The chromosomal passenger complex (CPC) supermodule comprises six experimental modules that were derived from various purification methods, including anti bait coimmunoprecipitation (MI:0006), anti tag coimmunoprecipitation (MI:0007), coimmunoprecipitation (MI:0019), pull down (MI:0096), and fluorescence microscopy (MI:0416) (Fig.	('MI:0007', 'Var', (225, 232))	('MI:0019', 'Var', (258, 265))	('MI:0416', 'Var', (318, 325))	('CPC', 'Chemical', '-', (35, 38))	('MI:0096', 'Var', (279, 286))
11113	25797237	The dysregulation of the CPC in proliferation has proposed to be associated with aggressive solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('CPC', 'Chemical', '-', (25, 28))	('aggressive solid tumors', 'Disease', (81, 104))	('dysregulation', 'Var', (4, 17))	('associated', 'Reg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('aggressive solid tumors', 'Disease', 'MESH:D009369', (81, 104))
11118	25797237	S10A), including the cell cycle checkpoint proteins RAD1/RAD9A/RAD17 (RAD1/RAD9A/RAD17), the replication factor C subunits 2/3/4/5 (RFC2/RFC3/RFC4/RFC5), and checkpoint protein HUS1 (HUS1).	('RAD9A', 'Gene', (57, 62))	('replication factor C', 'Gene', '5981', (93, 113))	('RAD17', 'Gene', '5884', (81, 86))	('checkpoint protein HUS1', 'Gene', (158, 181))	('replication factor C', 'Gene', (93, 113))	('RFC4', 'Gene', (142, 146))	('RAD17', 'Gene', (81, 86))	('checkpoint protein HUS1', 'Gene', '3364', (158, 181))	('RAD17', 'Gene', '5884', (63, 68))	('S10A', 'SUBSTITUTION', 'None', (0, 4))	('HUS1', 'Gene', (183, 187))	('RAD1', 'Gene', (52, 56))	('RAD17', 'Gene', (63, 68))	('RFC5', 'Gene', (147, 151))	('RAD1', 'Gene', '5810', (81, 85))	('HUS1', 'Gene', (177, 181))	('S10A', 'Var', (0, 4))	('RAD1', 'Gene', '5810', (63, 67))	('RFC3', 'Gene', '5983', (137, 141))	('RAD1', 'Gene', (81, 85))	('RFC4', 'Gene', '5984', (142, 146))	('RAD1', 'Gene', '5810', (70, 74))	('RAD1', 'Gene', (63, 67))	('HUS1', 'Gene', '3364', (183, 187))	('RFC2', 'Gene', '5982', (132, 136))	('RFC3', 'Gene', (137, 141))	('RAD9A', 'Gene', '5883', (75, 80))	('RFC2', 'Gene', (132, 136))	('RFC5', 'Gene', '5985', (147, 151))	('RAD9A', 'Gene', (75, 80))	('HUS1', 'Gene', '3364', (177, 181))	('RAD1', 'Gene', '5810', (52, 56))	('RAD1', 'Gene', (70, 74))	('RAD9A', 'Gene', '5883', (57, 62))
11177	23662106	Sigmoidectomy and locoregional lymph node dissection revealed a stage IIIB (T3N1M0) adenocarcinoma of the colon (Figure 1), while resection of the adrenal mass disclosed a stage III (T3N0M0) adrenal carcinoma with Weiss score of 4, a mitotic rate of 10 per 50 high power fields (HPF), atypical mitoses, and capsular invasion (Figures 2(a), 2(b) and 2(c)).	('adenocarcinoma of the colon', 'Disease', (84, 111))	('adrenal carcinoma', 'Disease', 'MESH:D000310', (191, 208))	('adrenal carcinoma', 'Phenotype', 'HP:0006744', (191, 208))	('T3N1M0', 'Var', (76, 82))	('adenocarcinoma of the colon', 'Disease', 'MESH:D003110', (84, 111))	('adenocarcinoma of the colon', 'Phenotype', 'HP:0040276', (84, 111))	('adrenal carcinoma', 'Disease', (191, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('capsular invasion', 'CPA', (307, 324))
11224	32526884	Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib.	('Patched Drug Efflux', 'MPA', (14, 33))	('vemurafenib', 'Chemical', 'MESH:D000077484', (175, 186))	('Melanoma', 'Disease', (98, 106))	('BrafV600E', 'Mutation', 'rs113488022', (88, 97))	('BrafV600E', 'Var', (88, 97))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (44, 55))	('patients', 'Species', '9606', (116, 124))	('Melanoma', 'Disease', 'MESH:D008545', (107, 115))	('Melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('Effectiveness', 'MPA', (56, 69))	('BRAFV600E', 'Var', (139, 148))	('BRAFV600E', 'Mutation', 'rs113488022', (139, 148))	('Increases', 'PosReg', (34, 43))	('Melanoma', 'Disease', (107, 115))	('Melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('Melanoma', 'Disease', 'MESH:D008545', (98, 106))
11248	32526884	These discoveries suggest that the use of inhibitors of Ptch1 drug efflux activity in combination with classical chemotherapy, such as doxorubicin, could be a novel way to circumvent drug resistance, recurrence and metastasis of tumors expressing Ptch1.	('drug resistance', 'MPA', (183, 198))	('circumvent', 'NegReg', (172, 182))	('metastasis of tumors', 'Disease', 'MESH:D009362', (215, 235))	('metastasis of tumors', 'Disease', (215, 235))	('doxorubicin', 'Chemical', 'MESH:D004317', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('drug resistance', 'Phenotype', 'HP:0020174', (183, 198))	('Ptch1', 'Gene', '5727', (247, 252))	('inhibitors', 'Var', (42, 52))	('Ptch1', 'Gene', (247, 252))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('Ptch1', 'Gene', '5727', (56, 61))	('drug efflux activity', 'MPA', (62, 82))	('recurrence', 'CPA', (200, 210))	('Ptch1', 'Gene', (56, 61))
11249	32526884	Around 45-50% of cutaneous melanomas have mutations in the BRAF serine/threonine kinase.	('serine', 'Chemical', 'MESH:D012694', (64, 70))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (17, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (17, 35))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (17, 36))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('cutaneous melanomas', 'Disease', (17, 36))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('mutations', 'Var', (42, 51))
11257	32526884	We did not observe a significant difference in the distribution of PTCH1 gene expression between tumors carrying or not BRAFV600 mutation for primary or metastatic samples (Figure 1A middle).	('PTCH1', 'Gene', (67, 72))	('mutation', 'Var', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BRAF', 'Gene', '673', (120, 124))	('PTCH1', 'Gene', '5727', (67, 72))	('BRAF', 'Gene', (120, 124))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
11258	32526884	In this cohort, the Kaplan-Meier analysis for a subset of patients with metastatic disease who did not receive immunotherapy indicated that a high level of Ptch1 in patient samples significantly correlated with a lower overall survival time (Figure 1A right).	('lower', 'NegReg', (213, 218))	('metastatic disease', 'Disease', 'MESH:C538445', (72, 90))	('Ptch1', 'Gene', '5727', (156, 161))	('patient', 'Species', '9606', (58, 65))	('Ptch1', 'Gene', (156, 161))	('patient', 'Species', '9606', (165, 172))	('metastatic disease', 'Disease', (72, 90))	('high', 'Var', (142, 146))	('patients', 'Species', '9606', (58, 66))	('overall', 'MPA', (219, 226))
11262	32526884	Interestingly, the depletion of Ptch1 using specific silencing RNA in the MeWo melanoma cell line induced cell retention of doxorubicin (dxr), a fluorescent chemotherapeutic drug commonly used to treat many types of cancers, while control cells showed a strong decrease of intracellular dxr fluorescence 30 min after the removal of this drug from the medium (Figure 1C).	('Ptch1', 'Gene', '5727', (32, 37))	('silencing', 'NegReg', (53, 62))	('induced', 'Reg', (98, 105))	('cell retention', 'CPA', (106, 120))	('MeWo melanoma', 'Disease', 'MESH:D008545', (74, 87))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('intracellular dxr fluorescence', 'MPA', (273, 303))	('dxr', 'Chemical', 'MESH:D004317', (137, 140))	('depletion', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('doxorubicin', 'MPA', (124, 135))	('C', 'Chemical', 'MESH:D002244', (367, 368))	('dxr', 'Chemical', 'MESH:D004317', (287, 290))	('MeWo melanoma', 'Disease', (74, 87))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('doxorubicin', 'Chemical', 'MESH:D004317', (124, 135))	('Ptch1', 'Gene', (32, 37))	('decrease', 'NegReg', (261, 269))
11271	32526884	Melanoma cells from the MeWo cell line and the BRAFV600E mutant cell line A375 were treated with increasing concentrations of dxr, with or without natural or synthetic PAH for either 48 or 24 h, before assessment of cell viability.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('dxr', 'Chemical', 'MESH:D004317', (126, 129))	('Melanoma', 'Disease', (0, 8))	('PAH', 'Chemical', '-', (168, 171))	('BRAFV600E', 'Var', (47, 56))	('BRAFV600E', 'Mutation', 'rs113488022', (47, 56))	('A375', 'CellLine', 'CVCL:0132', (74, 78))
11273	32526884	Interestingly, our results showed that sPAH also strongly increased drx cytotoxicity in MeWo cells rendered resistant to dxr (MeWo-DxrR) (Figure 2C, Table 1).	('increased', 'PosReg', (58, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (72, 84))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('dxr', 'Chemical', 'MESH:D004317', (121, 124))	('cytotoxicity', 'Disease', (72, 84))	('sPAH', 'Chemical', '-', (39, 43))	('sPAH', 'Var', (39, 43))
11292	32526884	These results show that the hydroquinone moiety is essential for sPAH activity as a Ptch1 drug efflux inhibitor, and that the loss of the double bond slightly reduces its activity.	('double', 'Protein', (138, 144))	('Ptch1', 'Gene', '5727', (84, 89))	('hydroquinone', 'Chemical', 'MESH:C031927', (28, 40))	('Ptch1', 'Gene', (84, 89))	('sPAH', 'Chemical', '-', (65, 69))	('reduces', 'NegReg', (159, 166))	('activity', 'MPA', (171, 179))	('loss', 'Var', (126, 130))
11305	32526884	Vemurafenib is a targeted chemotherapy agent which interrupts the BRAF/MEK step in the BRAF/MEK/ERK pathway when BRAF has the V600E mutation.	('V600E', 'Var', (126, 131))	('BRAF', 'Gene', '673', (113, 117))	('MEK', 'Gene', (92, 95))	('BRAF', 'Gene', (66, 70))	('interrupts', 'NegReg', (51, 61))	('MEK', 'Gene', '5609', (92, 95))	('BRAF', 'Gene', (113, 117))	('V600E', 'Mutation', 'rs113488022', (126, 131))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('ERK', 'Gene', '5594', (96, 99))	('BRAF', 'Gene', '673', (66, 70))	('MEK', 'Gene', (71, 74))	('BRAF', 'Gene', (87, 91))	('MEK', 'Gene', '5609', (71, 74))	('ERK', 'Gene', (96, 99))	('BRAF', 'Gene', '673', (87, 91))
11309	32526884	Remarkably, sPAH also increased the effectiveness of vemurafenib against WM9 cells rendered resistant to vemurafenib (WM9R) with a decrease by a factor of ten of the IC50 of vemurafenib in the presence of sPAH 20 microM (Figure 5A).	('vemurafenib', 'Chemical', 'MESH:D000077484', (174, 185))	('effectiveness', 'MPA', (36, 49))	('decrease', 'NegReg', (131, 139))	('C', 'Chemical', 'MESH:D002244', (167, 168))	('IC50', 'MPA', (166, 170))	('sPAH', 'Chemical', '-', (205, 209))	('increased', 'PosReg', (22, 31))	('sPAH', 'Chemical', '-', (12, 16))	('vemurafenib', 'Chemical', 'MESH:D000077484', (53, 64))	('sPAH', 'Var', (12, 16))	('vemurafenib', 'Chemical', 'MESH:D000077484', (105, 116))
11317	32526884	Using microscale thermophoresis (MST), we showed that sPAH binds to membranes prepared from yeast expressing human Ptch1 with a Kd around 7 microM, while sPAH does not bind to membranes prepared from yeast expressing another human membrane protein, Smoothened (Figure 6A).	('Ptch1', 'Gene', (115, 120))	('yeast', 'Species', '4932', (200, 205))	('human', 'Species', '9606', (109, 114))	('binds', 'Interaction', (59, 64))	('yeast', 'Species', '4932', (92, 97))	('sPAH', 'Chemical', '-', (154, 158))	('human', 'Species', '9606', (225, 230))	('sPAH', 'Chemical', '-', (54, 58))	('human', 'Var', (109, 114))	('Ptch1', 'Gene', '5727', (115, 120))
11322	32526884	Figure 6C reports the mean percentage of dxr accumulated in cells in the presence of vemurafenib relative to dxr accumulated in the absence of vemurafenib.	('vemurafenib', 'Chemical', 'MESH:D000077484', (143, 154))	('dxr', 'Chemical', 'MESH:D004317', (41, 44))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('vemurafenib', 'Chemical', 'MESH:D000077484', (85, 96))	('vemurafenib', 'Var', (85, 96))	('dxr accumulated', 'MPA', (41, 56))	('dxr', 'Chemical', 'MESH:D004317', (109, 112))
11327	32526884	Among the amino acids surrounding the cholesterol in the central cavity, five are conserved in proteins from Patched family, of which two have side chains directed toward the cholesterol (Leu427 and Ala497; Figure S3).	('cholesterol', 'Chemical', 'MESH:D002784', (38, 49))	('cholesterol', 'Chemical', 'MESH:D002784', (175, 186))	('Ala497', 'Chemical', '-', (199, 205))	('Ala497', 'Var', (199, 205))	('Leu427', 'Var', (188, 194))	('Leu427', 'Chemical', '-', (188, 194))
11328	32526884	We also observed that single nucleotide variations in seven of the residues surrounding the cholesterol are responsible for diseases according to the BioMuta database (Table 3).	('cholesterol', 'Chemical', 'MESH:D002784', (92, 103))	('diseases', 'Disease', (124, 132))	('responsible', 'Reg', (108, 119))	('single nucleotide variations', 'Var', (22, 50))
11329	32526884	Being built between loops, this cavity is flexible and should be able to accommodate many types of ligands thanks to a large number of aromatic amino acids with polar groups (tyrosines and tryptophans) and some polar residues among the hydrophobic ones.	('aromatic', 'Var', (135, 143))	('tyrosines', 'Chemical', 'MESH:D014443', (175, 184))	('polar residues', 'Var', (211, 225))	('aromatic amino acids', 'Chemical', 'MESH:D024322', (135, 155))	('tryptophans', 'Chemical', 'MESH:D014364', (189, 200))
11331	32526884	We observed at least one hydrogen bond with nearby amino acids for dxr, vemurafenib, and PAH (Leu775 or Asp776), both with the oxygen of the peptide bond.	('Asp776', 'Var', (104, 110))	('Leu775', 'Chemical', '-', (94, 100))	('hydrogen', 'Interaction', (25, 33))	('PAH', 'Chemical', '-', (89, 92))	('oxygen', 'Chemical', 'MESH:D010100', (127, 133))	('vemurafenib', 'Chemical', 'MESH:D000077484', (72, 83))	('hydrogen', 'Chemical', 'MESH:D006859', (25, 33))	('dxr', 'Chemical', 'MESH:D004317', (67, 70))	('Leu775', 'Var', (94, 100))	('Asp776', 'Chemical', '-', (104, 110))
11332	32526884	Interestingly, when Asp776 is mutated to glycine, the probability of a damaging phenotype is high (with a score of 0.87 according to the BioMuta database) supporting the importance of this amino acid for Ptch1 function.	('Asp776 is mutated to glycine', 'Mutation', 'p.D776G', (20, 48))	('Ptch1', 'Gene', '5727', (204, 209))	('Asp776', 'Var', (20, 26))	('Ptch1', 'Gene', (204, 209))
11333	32526884	Another amino acid predicted to interact with dxr, vemurafenib and PAH is Trp129, either by pi-stacking or hydrophobic interaction.	('pi-stacking', 'Var', (92, 103))	('Trp129', 'Chemical', '-', (74, 80))	('interact', 'Interaction', (32, 40))	('vemurafenib', 'Chemical', 'MESH:D000077484', (51, 62))	('Trp129', 'Gene', (74, 80))	('dxr', 'Chemical', 'MESH:D004317', (46, 49))	('PAH', 'Chemical', '-', (67, 70))
11344	32526884	A formulation of 2.44 mg of encapsulated sPAH/mL (7 mM) was tested on melanoma cells and results show that sPAH encapsulated in i-Particles (iP-sPAH) was able to increase the cytotoxicity of vemurafenib against A375 cells in a manner that was comparable to the free sPAH (Figure 8A).	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('increase', 'PosReg', (162, 170))	('sPAH', 'Chemical', '-', (41, 45))	('sPAH', 'Chemical', '-', (144, 148))	('sPAH', 'Chemical', '-', (107, 111))	('cytotoxicity', 'Disease', (175, 187))	('sPAH', 'Chemical', '-', (266, 270))	('sPAH', 'Var', (107, 111))	('vemurafenib', 'Chemical', 'MESH:D000077484', (191, 202))	('A375', 'CellLine', 'CVCL:0132', (211, 215))	('cytotoxicity', 'Disease', 'MESH:D064420', (175, 187))	('iP-sPAH', 'Chemical', '-', (141, 148))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
11356	32526884	Moreover, quantification of the vemurafenib contained within the tumors showed that extracts from all the tumors treated with the combination iP-sPAH + vemurafenib exhibited a vemurafenib peak area that was greater than 106 units, corresponding to approximately 100 nM, while extracts from two of seven tumors treated with vemurafenib alone showed a vemurafenib peak area of 2.105 to 4.105 units corresponding to the background signal (Figure 8E).	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', (303, 309))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('vemurafenib', 'Chemical', 'MESH:D000077484', (176, 187))	('iP-sPAH', 'Var', (142, 149))	('vemurafenib', 'Chemical', 'MESH:D000077484', (32, 43))	('vemurafenib', 'Chemical', 'MESH:D000077484', (152, 163))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('iP-sPAH', 'Chemical', '-', (142, 149))	('vemurafenib', 'Chemical', 'MESH:D000077484', (350, 361))	('vemurafenib', 'MPA', (176, 187))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('vemurafenib', 'Chemical', 'MESH:D000077484', (323, 334))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))
11358	32526884	Interestingly, this analysis revealed that tumors treated with iP-sPAH contained significantly more cholesterol than the other tumors (Figure 8F).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('cholesterol', 'MPA', (100, 111))	('more', 'PosReg', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('iP-sPAH', 'Var', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cholesterol', 'Chemical', 'MESH:D002784', (100, 111))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('iP-sPAH', 'Chemical', '-', (63, 70))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
11360	32526884	Vemurafenib is known to selectively block the RAF/MEK/ERK pathway in BRAF mutant cells.	('MEK', 'Gene', '5609', (50, 53))	('ERK', 'Gene', '5594', (54, 57))	('BRAF', 'Gene', (69, 73))	('RAF', 'Gene', (70, 73))	('RAF', 'Gene', (46, 49))	('ERK', 'Gene', (54, 57))	('RAF', 'Gene', '673', (70, 73))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('RAF', 'Gene', '673', (46, 49))	('BRAF', 'Gene', '673', (69, 73))	('mutant', 'Var', (74, 80))	('MEK', 'Gene', (50, 53))	('block', 'NegReg', (36, 41))
11370	32526884	Nearly half of patients with metastatic melanomas harbor a valine-glutamine substitution in codon 600 of the serine/threonine kinase BRAF.	('serine', 'Chemical', 'MESH:D012694', (109, 115))	('melanomas', 'Disease', (40, 49))	('patients', 'Species', '9606', (15, 23))	('BRAF', 'Gene', '673', (133, 137))	('valine-glutamine', 'Var', (59, 75))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('BRAF', 'Gene', (133, 137))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('valine', 'Chemical', 'MESH:D014633', (59, 65))	('glutamine', 'Chemical', 'MESH:D005973', (66, 75))
11375	32526884	Both intrinsic and acquired resistances can be driven by genetic and epigenetic alterations that drive gene expression changes and intratumor heterogeneity which, in turn, enable tumor regrowth and disease relapse.	('epigenetic alterations', 'Var', (69, 91))	('disease relapse', 'CPA', (198, 213))	('changes', 'Var', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('gene expression', 'MPA', (103, 118))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (136, 141))	('enable', 'PosReg', (172, 178))	('tumor', 'Disease', (179, 184))
11395	32526884	We also observed that sPAH was able to increase the cytotoxicity of cisplatin, another chemotherapeutic agent that we previously identified as a substrate of Ptch1, against melanoma cells in vitro (Figure S2).	('sPAH', 'Var', (22, 26))	('cytotoxicity', 'Disease', 'MESH:D064420', (52, 64))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('increase', 'PosReg', (39, 47))	('Ptch1', 'Gene', '5727', (158, 163))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('Ptch1', 'Gene', (158, 163))	('cytotoxicity', 'Disease', (52, 64))	('sPAH', 'Chemical', '-', (22, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
11396	32526884	We then wanted to know if sPAH could also enhance the efficiency of targeted chemotherapy such as vemurafenib against BRAFV600E melanoma cells, and found that sPAH strongly increased the cytotoxicity of vemurafenib, even in resistant BRAFV600E melanoma cells (Figure 5).	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('cytotoxicity', 'Disease', 'MESH:D064420', (187, 199))	('vemurafenib', 'Chemical', 'MESH:D000077484', (203, 214))	('sPAH', 'Chemical', '-', (159, 163))	('BRAFV600E', 'Mutation', 'rs113488022', (118, 127))	('BRAFV600E', 'Mutation', 'rs113488022', (234, 243))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('increased', 'PosReg', (173, 182))	('sPAH', 'Chemical', '-', (26, 30))	('sPAH', 'Var', (159, 163))	('cytotoxicity', 'Disease', (187, 199))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('vemurafenib', 'Chemical', 'MESH:D000077484', (98, 109))	('melanoma', 'Disease', (244, 252))	('melanoma', 'Disease', (128, 136))
11400	32526884	Altogether, our in vitro results suggest that sPAH increases doxorubicin and vemurafenib efficacy by binding to the same pocket as these chemotherapeutic agents on Ptch1 and inhibiting their efflux by Ptch1.	('Ptch1', 'Gene', (201, 206))	('inhibiting', 'NegReg', (174, 184))	('Ptch1', 'Gene', '5727', (201, 206))	('doxorubicin', 'Chemical', 'MESH:D004317', (61, 72))	('increases', 'PosReg', (51, 60))	('sPAH', 'Chemical', '-', (46, 50))	('vemurafenib', 'Gene', (77, 88))	('efficacy', 'MPA', (89, 97))	('sPAH', 'Var', (46, 50))	('doxorubicin', 'MPA', (61, 72))	('binding', 'Interaction', (101, 108))	('Ptch1', 'Gene', (164, 169))	('Ptch1', 'Gene', '5727', (164, 169))	('vemurafenib', 'Chemical', 'MESH:D000077484', (77, 88))	('efflux', 'MPA', (191, 197))
11401	32526884	The fact that sPAH also inhibited cholesterol efflux strengthens this interpretation.	('sPAH', 'Chemical', '-', (14, 18))	('cholesterol', 'Chemical', 'MESH:D002784', (34, 45))	('cholesterol efflux', 'MPA', (34, 52))	('sPAH', 'Var', (14, 18))	('inhibited', 'NegReg', (24, 33))
11408	32526884	We injected immune-compromised mice with BRAFV600E A375 melanoma, which is a cell line typically used as a model of xenograft melanoma for testing novel anti-melanoma compounds.	('BRAFV600E', 'Mutation', 'rs113488022', (41, 50))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('A375', 'CellLine', 'CVCL:0132', (51, 55))	('melanoma', 'Disease', (56, 64))	('BRAFV600E', 'Var', (41, 50))	('mice', 'Species', '10090', (31, 35))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))
11409	32526884	Experiments performed on these mice showed that the addition of iP-sPAH to the vemurafenib treatment inhibited tumor growth more significantly than vemurafenib alone (Figure 8B).	('iP-sPAH', 'Var', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('vemurafenib', 'Gene', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('iP-sPAH', 'Chemical', '-', (64, 71))	('vemurafenib', 'Chemical', 'MESH:D000077484', (79, 90))	('tumor', 'Disease', (111, 116))	('mice', 'Species', '10090', (31, 35))	('vemurafenib', 'Chemical', 'MESH:D000077484', (148, 159))	('inhibited', 'NegReg', (101, 110))
11413	32526884	Analyses of tumor extracts revealed that the addition of iP-sPAH to vemurafenib treatment more significantly inhibited the phosphorylation of ERK1/2 than vemurafenib alone, indicating an increase in the effectiveness of vemurafenib.	('vemurafenib', 'Chemical', 'MESH:D000077484', (154, 165))	('iP-sPAH', 'Var', (57, 64))	('phosphorylation', 'MPA', (123, 138))	('increase', 'PosReg', (187, 195))	('vemurafenib', 'Chemical', 'MESH:D000077484', (220, 231))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('inhibited', 'NegReg', (109, 118))	('ERK1/2', 'Gene', (142, 148))	('iP-sPAH', 'Chemical', '-', (57, 64))	('ERK1/2', 'Gene', '5595;5594', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('vemurafenib', 'Gene', (68, 79))	('tumor', 'Disease', (12, 17))	('vemurafenib', 'Chemical', 'MESH:D000077484', (68, 79))
11421	32526884	We therefore quantified the amount of cholesterol in tumor extracts and, indeed, found that tumors treated with iP-sPAH contained significantly more cholesterol than other tumors (Figure 8F), indicating that sPAH inhibited cholesterol efflux mediated by Ptch1 in this system.	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (92, 97))	('sPAH', 'Chemical', '-', (115, 119))	('cholesterol', 'Chemical', 'MESH:D002784', (223, 234))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('iP-sPAH', 'Var', (112, 119))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('iP-sPAH', 'Chemical', '-', (112, 119))	('cholesterol', 'Chemical', 'MESH:D002784', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cholesterol efflux', 'MPA', (223, 241))	('more', 'PosReg', (144, 148))	('sPAH', 'Chemical', '-', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cholesterol', 'Chemical', 'MESH:D002784', (149, 160))	('tumors', 'Disease', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('cholesterol', 'MPA', (149, 160))	('Ptch1', 'Gene', (254, 259))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('inhibited', 'NegReg', (213, 222))	('Ptch1', 'Gene', '5727', (254, 259))	('tumor', 'Disease', (53, 58))
11424	32526884	Indeed, in healthy cells, accumulation of free cholesterol has been shown to induce many mechanisms of cellular toxicity, including disrupted function of the integral membrane proteins and signaling proteins that reside in membrane domains, intracellular cholesterol crystallization, oxysterol formation, and the triggering of apoptotic signaling pathways.	('toxicity', 'Disease', (112, 120))	('cholesterol', 'Chemical', 'MESH:D002784', (47, 58))	('integral membrane proteins', 'Protein', (158, 184))	('oxysterol', 'Chemical', 'MESH:D000072376', (284, 293))	('free cholesterol', 'Var', (42, 58))	('function', 'MPA', (142, 150))	('cholesterol', 'Chemical', 'MESH:D002784', (255, 266))	('apoptotic signaling pathways', 'Pathway', (327, 355))	('accumulation', 'Var', (26, 38))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))
11474	32526884	MeWo cells were transfected with 400 pmol of human Ptch1 Silencer  Select pre-designed siRNA (Ambion, #4392420, s11441 (sense: 5'GCACUUACUUUACGACCUAtt3'; as: 5'UAGGUCGUAAAGUAAGUGCtg3') or control (medium GC) siRNA oligos (Invitrogen) using Lipofectamine RNAiMAX reagent (Invitrogen) following the manufacturer's protocol, then seeded in 24-well plates and incubated at 37  C and 5% CO2 for 16 h before Western blotting and dxr efflux measurements.	('Ptch1', 'Gene', (51, 56))	('s11441', 'Var', (112, 118))	('C', 'Chemical', 'MESH:D002244', (145, 146))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('C', 'Chemical', 'MESH:D002244', (382, 383))	('dxr', 'Chemical', 'MESH:D004317', (423, 426))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('C', 'Chemical', 'MESH:D002244', (205, 206))	('human', 'Species', '9606', (45, 50))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('C', 'Chemical', 'MESH:D002244', (178, 179))	('C', 'Chemical', 'MESH:D002244', (144, 145))	('C', 'Chemical', 'MESH:D002244', (136, 137))	('CO2', 'Chemical', 'MESH:D002245', (382, 385))	('C', 'Chemical', 'MESH:D002244', (165, 166))	('Ptch1', 'Gene', '5727', (51, 56))	('C', 'Chemical', 'MESH:D002244', (373, 374))
11496	32526884	Titration of sPAH results in a gradual change in MST signal, which is plotted as Fnorm against the sPAH concentration to yield a dose-response curve, which has been fitted to derive binding constants (Kd).	('sPAH', 'Gene', (13, 17))	('MST signal', 'MPA', (49, 59))	('Titration', 'Var', (0, 9))	('change', 'Reg', (39, 45))	('sPAH', 'Chemical', '-', (99, 103))	('sPAH', 'Chemical', '-', (13, 17))
11561	32526884	We conclude that sPAH is a very promising lead for vemurafenib resistant BRAFV600E melanoma where Ptch1 is overexpressed.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('BRAFV600E', 'Var', (73, 82))	('BRAFV600E', 'Mutation', 'rs113488022', (73, 82))	('Ptch1', 'Gene', '5727', (98, 103))	('Ptch1', 'Gene', (98, 103))	('vemurafenib', 'Chemical', 'MESH:D000077484', (51, 62))	('sPAH', 'Chemical', '-', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
11566	32526884	Dxr-IC50 values calculated in the presence of sPAH or sPAH analogue 13 are presented, Figure S2: sPAH increases cisplatin cytotoxicity against MeWo and A375 melanoma cell lines.	('cytotoxicity', 'Disease', (122, 134))	('sPAH', 'Chemical', '-', (97, 101))	('sPAH', 'Var', (97, 101))	('sPAH', 'Chemical', '-', (46, 50))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('melanoma', 'Disease', (157, 165))	('A375', 'CellLine', 'CVCL:0132', (152, 156))	('sPAH', 'Chemical', '-', (54, 58))	('cytotoxicity', 'Disease', 'MESH:D064420', (122, 134))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('increases', 'PosReg', (102, 111))
11599	31842516	These results emphasize that, in spite of the heterogeneous mutational burden among different cancers and even within the same tumor, some common hubs do exist.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutational', 'Var', (60, 70))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('cancers', 'Disease', (94, 101))
11628	31842516	As expected, point mutations in RAS are not common in breast and prostate cancer.	('breast and prostate cancer', 'Disease', 'MESH:D001943', (54, 80))	('point mutations', 'Var', (13, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('RAS', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
11629	31842516	Interestingly, genetic alterations in HDAC4 are more frequent in uterine and stomach cancers, with a conspicuous incidence of truncations and point mutations of still unknown impact on the activities of this deacetylase (Figure 1).	('activities', 'MPA', (189, 199))	('frequent', 'Reg', (53, 61))	('stomach cancers', 'Disease', 'MESH:D013274', (77, 92))	('stomach cancers', 'Disease', (77, 92))	('truncations', 'MPA', (126, 137))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('genetic alterations', 'Var', (15, 34))	('point mutations', 'Var', (142, 157))	('HDAC4', 'Gene', '9759', (38, 43))	('uterine', 'Disease', (65, 72))	('HDAC4', 'Gene', (38, 43))	('stomach cancers', 'Phenotype', 'HP:0012126', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
11633	31842516	To prove the above enounced concept, we interrogated the gene expression profiles of BJ-hTERT/ST/LT/MYC, BJ-hTERT/ST/LT/HRASG12V, and BJ-hTERT/ST/LT/HDAC4-S246A, S467A, S632A, relatively to the isogenic pre-transformed control cells, expressing the SV40 LT and ST or the entire early region.	('S246A', 'Mutation', 'p.S246A', (155, 160))	('HDAC4', 'Gene', (149, 154))	('MYC', 'Gene', (100, 103))	('HDAC4', 'Gene', '9759', (149, 154))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (134, 142))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (85, 93))	('S632A', 'Var', (169, 174))	('S632A', 'SUBSTITUTION', 'None', (169, 174))	('MYC', 'Gene', '4609', (100, 103))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (105, 113))	('S467A', 'Var', (162, 167))	('S467A', 'SUBSTITUTION', 'None', (162, 167))
11665	31842516	Finally, SRPX (sushi repeat containing protein X-linked), known also as ETX1 or DRS, was initially isolated as deleted in patients with X-linked retinitis pigmentosa, as well as downregulated by v-src.	('X-linked retinitis pigmentosa', 'Disease', (136, 165))	('retinitis', 'Phenotype', 'HP:0032118', (145, 154))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (145, 165))	('ETX1', 'Gene', '8406', (72, 76))	('sushi repeat containing protein X-linked', 'Gene', '8406', (15, 55))	('downregulated', 'NegReg', (178, 191))	('SRPX', 'Gene', (9, 13))	('DRS', 'Gene', '8406', (80, 83))	('deleted', 'Var', (111, 118))	('patients', 'Species', '9606', (122, 130))	('SRPX', 'Gene', '8406', (9, 13))	('sushi repeat containing protein X-linked', 'Gene', (15, 55))	('DRS', 'Gene', (80, 83))	('ETX1', 'Gene', (72, 76))	('X-linked retinitis pigmentosa', 'Disease', 'MESH:D012174', (136, 165))
11674	31842516	In fact in ACC, which is a rare, aggressive malignancy, G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal disease, amenable to targeted assessment using routine molecular diagnostics.	('aggressive malignancy', 'Disease', 'MESH:D001523', (33, 54))	('ACC', 'Disease', 'MESH:D018268', (11, 14))	('hypermethylation', 'Var', (61, 77))	('G0S2', 'Gene', (56, 60))	('aggressive malignancy', 'Disease', (33, 54))	('ACC', 'Disease', (11, 14))
11675	31842516	Very low levels of G0S2 mRNA expression characterize tumors with G0S2 hypermethylation.	('hypermethylation', 'Var', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('G0S2', 'Gene', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))	('G0S2', 'Protein', (19, 23))
11710	31842516	G0S2 is abundantly expressed in adipose tissue and G0S2 transgenic mice experience difficulties in shifting from carbohydrate to FA oxidation during fasting.	('transgenic mice', 'Species', '10090', (56, 71))	('shifting from carbohydrate to FA oxidation', 'MPA', (99, 141))	('G0S2', 'Gene', (51, 55))	('carbohydrate', 'Chemical', 'MESH:D002241', (113, 125))	('transgenic', 'Var', (56, 66))
11718	31842516	The recent discovery that the targeting of MYC through an epigenetic therapy provides an important advantage for an efficient immunotherapy could represent an important clinical perspective of all these studies.	('advantage', 'PosReg', (99, 108))	('MYC', 'Gene', '4609', (43, 46))	('epigenetic therapy', 'Var', (58, 76))	('MYC', 'Gene', (43, 46))
11729	31842516	In each dataset, the transformation model represented by pre-transformed BJ cells expressing RAS G12V (GSE17941) or MYC (GSE72530) or HDAC4 (GSE120040) was compared to the pre-transformation model which is represented by BJ fibroblasts expressing hTERT, LT, and ST SV40 genes.	('G12V', 'Mutation', 'rs104894230', (97, 101))	('BJ', 'CellLine', 'CVCL:6573', (73, 75))	('BJ', 'CellLine', 'CVCL:6573', (221, 223))	('hTERT', 'Gene', (247, 252))	('MYC', 'Gene', '4609', (116, 119))	('HDAC4', 'Gene', '9759', (134, 139))	('GSE120040', 'Var', (141, 150))	('HDAC4', 'Gene', (134, 139))	('hTERT', 'Gene', '7015', (247, 252))	('GSE17941', 'Var', (103, 111))	('GSE72530', 'Var', (121, 129))	('MYC', 'Gene', (116, 119))
11740	31842516	To evaluate the contribution/disturbance of the inflammatory infiltrate to the prediction of survival based on the transformation signatures, patients were divided into four groups accordingly to the expression levels of genes belonging to the MCPcounter signatures and to the transformation signatures: High-high (high levels of both), high-low (high MCP/low transformation), low-low (low levels of both), or low-high (low MCP-high transformation).	('MCP', 'Gene', (352, 355))	('MCP', 'Gene', (424, 427))	('MCP', 'Gene', '822', (244, 247))	('low-high', 'Var', (410, 418))	('MCP', 'Gene', '822', (352, 355))	('MCP', 'Gene', '822', (424, 427))	('patients', 'Species', '9606', (142, 150))	('MCP', 'Gene', (244, 247))	('low MCP', 'Phenotype', 'HP:0025066', (420, 427))
11809	31890370	Glucocorticoid excess in PBMAH is also reported to be due to aberrant expression of certain receptors in adrenocortical cells which result in unregulated steroidogenesis and hormone excess.	('aberrant', 'Var', (61, 69))	('result in', 'Reg', (132, 141))	('Glucocorticoid excess', 'Phenotype', 'HP:0003118', (0, 21))	('unregulated steroidogenesis', 'MPA', (142, 169))	('PBMAH', 'Chemical', '-', (25, 30))	('Glucocorticoid', 'MPA', (0, 14))	('hormone excess', 'Phenotype', 'HP:0000845', (174, 188))	('PBMAH', 'Disease', (25, 30))	('hormone excess', 'MPA', (174, 188))
11848	31383012	Rats that received etomidate or isopropoxy-etomidate had significant reductions (90 and 57%, respectively) in plasma testosterone concentrations whereas those that received naphthalene-etomidate had significant increases (1400%) in plasma dehydroepiandrosterone concentrations.	('Rats', 'Species', '10116', (0, 4))	('plasma testosterone concentrations', 'MPA', (110, 144))	('plasma dehydroepiandrosterone concentrations', 'MPA', (232, 276))	('isopropoxy-etomidate', 'Var', (32, 52))	('etomidate', 'Chemical', 'MESH:D005045', (19, 28))	('etomidate', 'Chemical', 'MESH:D005045', (43, 52))	('naphthalene-etomidate', 'Chemical', '-', (173, 194))	('etomidate', 'Chemical', 'MESH:D005045', (185, 194))	('rat', 'Species', '10116', (137, 140))	('testosterone', 'Chemical', 'MESH:D013739', (117, 129))	('dehydroepiandrosterone', 'Chemical', 'MESH:D003687', (239, 261))	('increases', 'PosReg', (211, 220))	('isopropoxy-etomidate', 'Chemical', '-', (32, 52))	('rat', 'Species', '10116', (269, 272))	('reductions', 'NegReg', (69, 79))
11913	31383012	Consistent with our previous studies, both etomidate and dimethoxy-etomidate significantly reduced ACTH-stimulated plasma corticosterone concentrations in rats by 92 and 84%, respectively, as compared to those concentrations measured in vehicle control group rats.	('dimethoxy-etomidate', 'Var', (57, 76))	('dimethoxy-etomidate', 'Chemical', '-', (57, 76))	('etomidate', 'Chemical', 'MESH:D005045', (67, 76))	('rat', 'Species', '10116', (259, 262))	('etomidate', 'Chemical', 'MESH:D005045', (43, 52))	('corticosterone', 'Chemical', 'MESH:D003345', (122, 136))	('rats', 'Species', '10116', (155, 159))	('stimulated plasma corticosterone', 'Phenotype', 'HP:0032362', (104, 136))	('ACTH', 'Gene', (99, 103))	('reduced', 'NegReg', (91, 98))	('ACTH', 'Gene', '5443', (99, 103))	('rats', 'Species', '10116', (259, 263))	('rat', 'Species', '10116', (155, 158))	('rat', 'Species', '10116', (144, 147))	('rat', 'Species', '10116', (217, 220))
11926	31383012	The hCG-stimulated plasma concentrations of androstenedione and dihydrotestosterone in control rats that had received vehicle alone were 14,500 +- 3100 pg/mL and 1700 +- 260 pg/mL, respectively.	('1700 +- 260 pg/mL', 'Var', (162, 179))	('rats', 'Species', '10116', (95, 99))	('rat', 'Species', '10116', (95, 98))	('rat', 'Species', '10116', (33, 36))	('hCG', 'Gene', '93659', (4, 7))	('androstenedione', 'Chemical', 'MESH:D000735', (44, 59))	('hCG', 'Gene', (4, 7))	('dihydrotestosterone', 'Chemical', 'MESH:D013196', (64, 83))
11936	31383012	Because ketoconazole inhibits enzymatic steps that are relatively proximal in the steroidogenesis pathway and thus required for the biosynthesis of both adrenocortical and androgenic steroids, it reduces the plasma concentrations of steroids from both classes (e.g.	('inhibits', 'NegReg', (21, 29))	('steroids', 'Chemical', 'MESH:D013256', (233, 241))	('reduces', 'NegReg', (196, 203))	('steroidogenesis', 'Enzyme', (82, 97))	('steroid', 'Chemical', 'MESH:D013256', (82, 89))	('steroid', 'Chemical', 'MESH:D013256', (233, 240))	('rat', 'Species', '10116', (222, 225))	('ketoconazole', 'Chemical', 'MESH:D007654', (8, 20))	('adrenocortical', 'Disease', (153, 167))	('steroid', 'Chemical', 'MESH:D013256', (183, 190))	('steroids', 'Chemical', 'MESH:D013256', (183, 191))	('ketoconazole', 'Var', (8, 20))	('adrenocortical', 'Disease', 'MESH:D018268', (153, 167))	('enzymatic', 'Enzyme', (30, 39))	('plasma concentrations of steroids', 'MPA', (208, 241))
11940	31383012	Inhibition of these two enzymes selectively reduces adrenocortical steroid production and causes adrenocortical steroid precursors to accumulate.	('adrenocortical steroid', 'Disease', 'MESH:D018268', (52, 74))	('adrenocortical steroid', 'Disease', 'MESH:D018268', (97, 119))	('Inhibition', 'Var', (0, 10))	('causes', 'Reg', (90, 96))	('accumulate', 'PosReg', (134, 144))	('adrenocortical steroid', 'Disease', (52, 74))	('adrenocortical steroid', 'Disease', (97, 119))	('reduces', 'NegReg', (44, 51))
11963	31383012	This work was supported by the National Institutes of Health, Bethesda, MD [GM087316 and GM122806] and the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.	('Pain', 'Disease', 'MESH:D010146', (152, 156))	('Pain', 'Disease', (152, 156))	('Pain', 'Phenotype', 'HP:0012531', (152, 156))	('GM122806]', 'Var', (89, 98))
12072	29739388	However, for benign tumors, partial RLA should be considered to reduce the need for hormone supplementation.	('benign tumors', 'Disease', (13, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('benign tumors', 'Disease', 'MESH:D009369', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('partial RLA', 'Var', (28, 39))
12091	29184417	The most responsive combination therapy, etoposide, doxorubicin, cisplatin with mitotane (EDP-M), was superior to the streptozotocin with mitotane (Sz-M) regimen and had a similar incidence of adverse events in the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) trial.	('EDP', 'Chemical', '-', (90, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('etoposide', 'Chemical', 'MESH:D005047', (41, 50))	('Metastatic Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (276, 311))	('Sz-M', 'Chemical', '-', (148, 152))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (287, 311))	('Metastatic Adrenocortical Carcinoma', 'Disease', (276, 311))	('mitotane', 'Chemical', 'MESH:D008939', (138, 146))	('cisplatin', 'Var', (65, 74))	('Carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('streptozotocin', 'Chemical', 'MESH:D013311', (118, 132))	('mitotane', 'Chemical', 'MESH:D008939', (80, 88))	('doxorubicin', 'Chemical', 'MESH:D004317', (52, 63))
12125	29184417	Erdogan et al from the German Adrenocortical Carcinoma Study Group reached to a similar conclusion that surgery of R0 (microscopically complete resection) could decrease the disease progression and overall mortality risk, though they did not perform a deep analysis for the recurrence subgroup, which was regarded as not amenable to radical resection due to advanced disease.	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (30, 54))	('surgery', 'Var', (104, 111))	('decrease', 'NegReg', (161, 169))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (30, 54))	('Carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('disease progression', 'CPA', (174, 193))	('Adrenocortical Carcinoma', 'Disease', (30, 54))
12141	26687711	Although the number of kinases varies across species, it is worthy to note that gene duplication events have enlarged several plant, Dinoflagellata and Arabidopsis kinomes.	('Dinoflagellata', 'Disease', (133, 147))	('Arabidopsis', 'Species', '3702', (152, 163))	('enlarged', 'PosReg', (109, 117))	('Dinoflagellata', 'Disease', 'None', (133, 147))	('gene duplication events', 'Var', (80, 103))
12176	26687711	Although the physiological significance of this putative C subunit isozyme is unclear, a number of decisive biochemical studies have conclusively demonstrated that Cchi can interact with the R subunits to form a modified PKA holoenzyme.	('PKA', 'Gene', '282323', (221, 224))	('Cchi', 'Chemical', '-', (164, 168))	('interact', 'Interaction', (173, 181))	('PKA', 'Gene', (221, 224))	('Cchi', 'Var', (164, 168))
12179	26687711	In mice, targeted deletion of this gene results in growth retardation in the small number of animals that survive, while a Calpha deficiency has also been linked to spinal neural tube defects.	('spinal neural tube defects', 'Disease', 'MESH:D009436', (165, 191))	('spinal neural tube defects', 'Disease', (165, 191))	('growth retardation', 'Phenotype', 'HP:0001510', (51, 69))	('linked', 'Reg', (155, 161))	('Calpha deficiency', 'Disease', (123, 140))	('mice', 'Species', '10090', (3, 7))	('neural tube defects', 'Phenotype', 'HP:0045005', (172, 191))	('growth retardation', 'Disease', 'MESH:D006130', (51, 69))	('Calpha deficiency', 'Disease', 'MESH:D007153', (123, 140))	('deletion', 'Var', (18, 26))	('growth retardation', 'Disease', (51, 69))
12180	26687711	On the other hand, a double knockout of Calpha and Cbeta or haploinsufficiency of Cbeta in the context of a Calpha total knockout is embryonic lethal.	('double knockout', 'Var', (21, 36))	('Cbeta or haploinsufficiency of Cbeta', 'Disease', (51, 87))	('Cbeta or haploinsufficiency of Cbeta', 'Disease', 'MESH:D058495', (51, 87))
12181	26687711	In contrast, deletion of Cbeta results in phenotypically normal mice.	('deletion', 'Var', (13, 21))	('Cbeta', 'Gene', (25, 30))	('mice', 'Species', '10090', (64, 68))
12209	26687711	Probably the most common pathological effects of defective cAMP signaling underlie the onset of coronary heart disease and cardiomyopathies.	('cardiomyopathies', 'Phenotype', 'HP:0001638', (123, 139))	('cardiomyopathies', 'Disease', (123, 139))	('cAMP', 'Gene', (59, 63))	('cAMP', 'Gene', '820', (59, 63))	('cardiomyopathies', 'Disease', 'MESH:D009202', (123, 139))	('defective', 'Var', (49, 58))	('coronary heart disease', 'Disease', (96, 118))	('coronary heart disease', 'Phenotype', 'HP:0001677', (96, 118))	('coronary heart disease', 'Disease', 'MESH:D003324', (96, 118))
12210	26687711	It has been known since the early 1960's that blocking beta adrenergic stimulation of cAMP synthesis is protective against heart disease.	('cAMP', 'Gene', (86, 90))	('heart disease', 'Disease', (123, 136))	('heart disease', 'Disease', 'MESH:D006331', (123, 136))	('cAMP', 'Gene', '820', (86, 90))	('blocking', 'Var', (46, 54))
12217	26687711	Nonetheless, it is evident that modulation of PKA activation is a therapeutic strategy that manages some stages of progressive and congestive heart failure.	('heart failure', 'Phenotype', 'HP:0001635', (142, 155))	('congestive heart failure', 'Disease', (131, 155))	('PKA', 'Gene', '282323', (46, 49))	('modulation', 'Var', (32, 42))	('congestive heart failure', 'Phenotype', 'HP:0001635', (131, 155))	('PKA', 'Gene', (46, 49))	('congestive heart failure', 'Disease', 'MESH:D006333', (131, 155))
12218	26687711	An elegant series of studies suggest that mutations in a gene encoding the A-kinase anchoring protein Yotiao/AKAP6 underlie the onset of arrhythmias.	('AKAP6', 'Gene', (109, 114))	('Yotiao', 'Gene', (102, 108))	('AKAP6', 'Gene', '9472', (109, 114))	('Yotiao', 'Gene', '10142', (102, 108))	('arrhythmias', 'Disease', 'MESH:D001145', (137, 148))	('arrhythmias', 'Disease', (137, 148))	('arrhythmias', 'Phenotype', 'HP:0011675', (137, 148))	('mutations', 'Var', (42, 51))
12221	26687711	Nonetheless, it is possible that the mis-localization or mis-regulation of PKA in the sinoatrial node may be a contributing factor to the onset of certain arrhythmias.	('mis-localization', 'Var', (37, 53))	('PKA', 'Gene', '282323', (75, 78))	('arrhythmias', 'Disease', 'MESH:D001145', (155, 166))	('arrhythmias', 'Disease', (155, 166))	('arrhythmias', 'Phenotype', 'HP:0011675', (155, 166))	('mis-regulation', 'Var', (57, 71))	('PKA', 'Gene', (75, 78))
12226	26687711	Recently several groups have independently reported that whole-exome sequencing of cortisol-producing ACTs resulted in the identification of c.T617G heterozygous mutation that results in an amino acid substitution, Leu206Arg.	('Leu206Arg', 'Var', (215, 224))	('c.T617G', 'Var', (141, 148))	('c.T617G', 'Mutation', 'rs386352352', (141, 148))	('Leu206Arg', 'Chemical', '-', (215, 224))
12227	26687711	This mutation L206R is found in the p+1 loop of PKA, and interferes with binding between the catalytic subunit and the R subunits of PKA in the presence of cAMP.	('PKA', 'Gene', (133, 136))	('L206R', 'Mutation', 'rs386352352', (14, 19))	('binding', 'Interaction', (73, 80))	('L206R', 'Var', (14, 19))	('PKA', 'Gene', '282323', (133, 136))	('cAMP', 'Gene', '820', (156, 160))	('PKA', 'Gene', (48, 51))	('interferes', 'NegReg', (57, 67))	('cAMP', 'Gene', (156, 160))	('PKA', 'Gene', '282323', (48, 51))
12228	26687711	Further studies have confirmed this mutation in PRKACA, and concluded that the Leu206Arg mutation of PKA results in higher basal PKA activity.	('PKA', 'Gene', '282323', (101, 104))	('PKA', 'Gene', (129, 132))	('higher', 'PosReg', (116, 122))	('PRKACA', 'Gene', (48, 54))	('PRKACA', 'Gene', '5566', (48, 54))	('PKA', 'Gene', '282323', (129, 132))	('Leu206Arg', 'Var', (79, 88))	('Leu206Arg', 'Chemical', '-', (79, 88))	('ACA', 'Phenotype', 'HP:0008256', (51, 54))	('PKA', 'Gene', (101, 104))
12229	26687711	Three insertions have been found in patients with adrenocortical adenomas; c.595_596insCAC that results in an insertion of a tryptophan (Leu199_Cys200insTrp), c.600_601insGTG that results in a insertion of valine (p.Cys200_Gly201insVal), and a missense mutation, c.639C>G that changes Ser213 to Arg while inserting four amino acids.	('c.600_601insGTG', 'Mutation', 'c.600_601insGTG', (159, 174))	('Leu199_Cys200insTrp', 'Var', (137, 156))	('c.639C>G', 'Mutation', 'rs1187481745', (263, 271))	('c.639C>G', 'Var', (263, 271))	('p.Cys200_Gly201insVal', 'Var', (214, 235))	('p.Cys200_Gly201insVal', 'Mutation', 'p.C200_,201G,V', (214, 235))	('insertion', 'Reg', (193, 202))	('patients', 'Species', '9606', (36, 44))	('Leu199_Cys200insTrp', 'Mutation', 'p.L,C199,200W', (137, 156))	('changes', 'Reg', (277, 284))	('c.595_596insCAC', 'Var', (75, 90))	('valine', 'MPA', (206, 212))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (50, 73))	('Ser213 to Arg', 'Mutation', 'rs1187481745', (285, 298))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (50, 73))	('adrenocortical adenomas', 'Disease', (50, 73))	('Ser213 to Arg', 'MPA', (285, 298))	('c.600_601insGTG', 'Var', (159, 174))	('c.595_596insCAC', 'Mutation', 'c.595_596insCAC', (75, 90))
12230	26687711	This mutation is found in a highly conserved region of the catalytic subunit of PKA, and is thought to elevate basal activity of PKA.	('PKA', 'Gene', (129, 132))	('PKA', 'Gene', '282323', (80, 83))	('basal activity', 'CPA', (111, 125))	('elevate', 'PosReg', (103, 110))	('PKA', 'Gene', '282323', (129, 132))	('PKA', 'Gene', (80, 83))	('mutation', 'Var', (5, 13))
12231	26687711	In contrast, the Leu206Arg, Leu199_Cys200insTrp, and the Cys200_Gly201insVal mutations are all found near the autoinhibitory sequence of the regulatory subunit.	('Leu199_Cys200insTrp', 'Var', (28, 47))	('Leu206Arg', 'Var', (17, 26))	('Leu206Arg', 'Chemical', '-', (17, 26))	('Leu199_Cys200insTrp', 'Mutation', 'p.L,C199,200W', (28, 47))	('Cys200_Gly201insVal', 'Var', (57, 76))
12233	26687711	Collectively these findings provide further evidence that disruption of this conserved structure of the catalytic subunit of PKA can lead to aberrant and unregulated kinase activity.	('lead to', 'Reg', (133, 140))	('PKA', 'Gene', '282323', (125, 128))	('disruption', 'Var', (58, 68))	('PKA', 'Gene', (125, 128))
12235	26687711	Interestingly, exome sequencing revealed that none of these harbored mutations in the PRKACA gene, but rather exhibited increased copy numbers of PRKACA transcript.	('mutations', 'Var', (69, 78))	('PRKACA', 'Gene', '5566', (146, 152))	('ACA', 'Phenotype', 'HP:0008256', (89, 92))	('ACA', 'Phenotype', 'HP:0008256', (149, 152))	('PRKACA', 'Gene', (86, 92))	('copy numbers', 'MPA', (130, 142))	('PRKACA', 'Gene', (146, 152))	('PRKACA', 'Gene', '5566', (86, 92))	('increased', 'PosReg', (120, 129))
12237	26687711	Inactivating mutations in the gene that encodes RIalpha (PRKAR1A) have been identified in over 60% of patients with CNC.	('CNC', 'Disease', (116, 119))	('identified', 'Reg', (76, 86))	('PRKAR1A', 'Gene', (57, 64))	('patients', 'Species', '9606', (102, 110))	('Inactivating mutations', 'Var', (0, 22))	('PRKAR1A', 'Gene', '5573', (57, 64))
12239	26687711	Thus it would appear that each of these endocrine disorders are perpetuated by defective cAMP signaling and misregulated PKA activity.	('endocrine disorders', 'Disease', (40, 59))	('cAMP', 'Gene', (89, 93))	('cAMP', 'Gene', '820', (89, 93))	('misregulated', 'Var', (108, 120))	('defective', 'NegReg', (79, 88))	('PKA', 'Gene', (121, 124))	('endocrine disorders', 'Disease', 'MESH:D004700', (40, 59))	('endocrine disorders', 'Phenotype', 'HP:0000818', (40, 59))	('PKA', 'Gene', '282323', (121, 124))
12245	26687711	described a 400kb deletion on chromosome 19 in 100% of FL-HCC patients.	('400kb', 'Var', (12, 17))	('FL-HCC', 'Disease', (55, 61))	('patients', 'Species', '9606', (62, 70))
12247	26687711	Other groups have also validated this deletion, and confirmed the fusion of the first exon of DNAJB1 to exons two through ten of PRKACA, shown in Figure 2.	('PRKACA', 'Gene', '5566', (129, 135))	('DNAJB1', 'Gene', (94, 100))	('PRKACA', 'Gene', (129, 135))	('fusion', 'Var', (66, 72))	('ACA', 'Phenotype', 'HP:0008256', (132, 135))	('DNAJB1', 'Gene', '3337', (94, 100))
12258	26687711	For example, developing strategies that target some of the PKA C subunit mutant forms that underlie Cushing's syndrome may hold some therapeutic promise, as will small molecules to help reform the type I PKA holoenzymes in patients with Carney complex.	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (100, 118))	('PKA', 'Gene', '282323', (204, 207))	('mutant', 'Var', (73, 79))	('PKA', 'Gene', (59, 62))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (100, 118))	("Cushing's syndrome", 'Disease', (100, 118))	('patients', 'Species', '9606', (223, 231))	('PKA', 'Gene', '282323', (59, 62))	('PKA', 'Gene', (204, 207))
12262	24472523	Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA) Aberrant expression of gonadotropin-releasing hormone receptor (GnRHR) has been reported in human adrenal tissues including aldosterone-producing adenoma (APA).	('GnRHR', 'Gene', (50, 55))	('adrenal aldosterone', 'Phenotype', 'HP:0000859', (139, 158))	('GnRHR', 'Gene', (247, 252))	('Aberrant', 'Var', (183, 191))	('adenoma', 'Disease', 'MESH:D000236', (169, 176))	('gonadotropin-releasing hormone receptor', 'Gene', '2798', (206, 245))	('gonadotropin-releasing hormone receptor', 'Gene', (9, 48))	('aldosterone production', 'Phenotype', 'HP:0000859', (113, 135))	('aldosterone', 'Chemical', 'MESH:D000450', (307, 318))	('CYP11B2', 'Gene', '1585', (90, 97))	('GnRHR', 'Gene', '2798', (50, 55))	('aldosterone', 'Chemical', 'MESH:D000450', (147, 158))	('gonadotropin-releasing hormone receptor', 'Gene', (206, 245))	('GnRHR', 'Gene', '2798', (247, 252))	('PA', 'Phenotype', 'HP:0011736', (339, 341))	('gonadotropin-releasing hormone receptor', 'Gene', '2798', (9, 48))	('adenoma', 'Disease', (329, 336))	('aldosterone', 'Chemical', 'MESH:D000450', (113, 124))	('human', 'Species', '9606', (275, 280))	('CYP11B2', 'Gene', (90, 97))	('PA', 'Phenotype', 'HP:0011736', (179, 181))	('adenoma', 'Disease', 'MESH:D000236', (329, 336))	('adenoma', 'Disease', (169, 176))
12333	24472523	Similarly the stimulation in aldosterone production was inhibited by KN93 and calmidazolium by 95% and 40%, respectively.	('aldosterone', 'Chemical', 'MESH:D000450', (29, 40))	('calmidazolium', 'Chemical', 'MESH:C031938', (78, 91))	('aldosterone production', 'MPA', (29, 51))	('aldosterone production', 'Phenotype', 'HP:0000859', (29, 51))	('inhibited', 'NegReg', (56, 65))	('KN93', 'Var', (69, 73))
12343	24472523	Taken together, it is postulated that the aberrant GNRHR in human adrenal tissue may be controlled by the paracrine/autocrine action of GNRH1 expressed in the adrenal gland.	('GNRHR', 'Gene', (51, 56))	('GNRH1', 'Gene', (136, 141))	('aberrant', 'Var', (42, 50))	('paracrine/autocrine', 'MPA', (106, 125))	('GNRHR', 'Gene', '2798', (51, 56))	('human', 'Species', '9606', (60, 65))	('GNRH1', 'Gene', '2796', (136, 141))
12345	24472523	Albiger and colleagues were the first to report a case of primary aldosteronism (PA) during pregnancy with response to GnRH and human chorionic gonadotropin (hCG) administration, which also suggested the roles of aberrant expression of non-adrenal GPCRs as one of the sporadic causes of PA.	('primary aldosteronism', 'Phenotype', 'HP:0011736', (58, 79))	('GnRH', 'Gene', (119, 123))	('primary aldosteronism', 'Disease', (58, 79))	('GnRH', 'Gene', '2796', (119, 123))	('PA', 'Phenotype', 'HP:0011736', (287, 289))	('aberrant', 'Var', (213, 221))	('GPCR', 'Gene', '10663', (248, 252))	('PA', 'Phenotype', 'HP:0011736', (81, 83))	('human', 'Species', '9606', (128, 133))	('GPCR', 'Gene', (248, 252))	('case of primary aldosteronism', 'Phenotype', 'HP:0011739', (50, 79))
12346	24472523	They further demonstrated, in a series of non-pregnant PA patients, that aberrant GnRHR was expressed and several of these patients increased aldosterone secretion in response to GnRH administration.	('GnRHR', 'Gene', (82, 87))	('PA', 'Phenotype', 'HP:0011736', (55, 57))	('GnRH', 'Gene', (82, 86))	('patients', 'Species', '9606', (58, 66))	('GnRHR', 'Gene', '2798', (82, 87))	('GnRH', 'Gene', '2796', (82, 86))	('GnRH', 'Gene', (179, 183))	('GnRH', 'Gene', '2796', (179, 183))	('patients', 'Species', '9606', (123, 131))	('increased', 'PosReg', (132, 141))	('aberrant', 'Var', (73, 81))	('aldosterone', 'Chemical', 'MESH:D000450', (142, 153))	('aldosterone secretion', 'MPA', (142, 163))	('increased aldosterone', 'Phenotype', 'HP:0000859', (132, 153))
12357	24472523	Somatic mutations of the KCNJ5 potassium channel have been reported to cause a loss of channel ion selectivity leading to sodium influx and increased adrenal cell Ca2+ via activation of voltage gated Ca2+ channels.	('voltage gated Ca2+', 'MPA', (186, 204))	('loss', 'NegReg', (79, 83))	('channel ion selectivity', 'MPA', (87, 110))	('sodium influx', 'MPA', (122, 135))	('KCNJ5', 'Gene', (25, 30))	('sodium', 'Chemical', 'MESH:D012964', (122, 128))	('increased adrenal', 'Phenotype', 'HP:0008221', (140, 157))	('mutations', 'Var', (8, 17))	('Ca2+', 'Chemical', 'MESH:D000069285', (163, 167))	('KCNJ5', 'Gene', '3762', (25, 30))	('Ca2+', 'Chemical', 'MESH:D000069285', (200, 204))	('activation', 'PosReg', (172, 182))	('adrenal cell Ca2+', 'MPA', (150, 167))	('increased', 'PosReg', (140, 149))
12374	25279464	Pro-gamma-MSH potentiates the steroidogenic actions of ACTH, triggering an increase of cholesterol and cholesterol ester hydroxylase activity.	('Pro-gamma-MSH', 'Var', (0, 13))	('potentiates', 'PosReg', (14, 25))	('ACTH', 'Gene', '18976', (55, 59))	('cholesterol', 'Chemical', 'MESH:D002784', (87, 98))	('increase', 'PosReg', (75, 83))	('steroidogenic actions', 'MPA', (30, 51))	('increase of cholesterol', 'Phenotype', 'HP:0003124', (75, 98))	('ACTH', 'Gene', (55, 59))	('cholesterol', 'Chemical', 'MESH:D002784', (103, 114))
12377	25279464	Recent work from our group has shown that synthetic N-POMC1-28 induced in vivo S-phase entry in the entire rat adrenal cortex by up-regulating cyclins D and E  .	('S-phase entry', 'MPA', (79, 92))	('POMC1', 'Gene', (54, 59))	('cyclins', 'Protein', (143, 150))	('synthetic', 'Var', (42, 51))	('up-regulating', 'PosReg', (129, 142))	('rat', 'Species', '10116', (107, 110))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('induced', 'Reg', (63, 70))	('POMC1', 'Gene', '24664', (54, 59))
12379	25279464	It is well-known that inhibition of the HPA axis by dexamethasone (DEX) or hypophysectomy can cause atrophy only in the innermost portion of the adrenal cortex.	('inhibition', 'Var', (22, 32))	('atrophy', 'Disease', (100, 107))	('DEX', 'Chemical', 'MESH:D003907', (67, 70))	('dexamethasone', 'Chemical', 'MESH:D003907', (52, 65))	('atrophy', 'Disease', 'MESH:D001284', (100, 107))
12388	25279464	In order to avoid undefined disulfide bonds, the N-POMCMet peptide was synthesized and characterized in the Department of Biochemistry and Biophysics at the Federal University of Sao Paulo (UNIFESP) by replacing cysteine with methionine.	('N', 'Chemical', 'MESH:D009584', (191, 192))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('cysteine', 'MPA', (212, 220))	('methionine', 'Chemical', 'MESH:D008715', (226, 236))	('N-POMCMet', 'Chemical', '-', (49, 58))	('cysteine', 'Chemical', 'MESH:D003545', (212, 220))	('replacing', 'Var', (202, 211))	('disulfide', 'Chemical', 'MESH:D004220', (28, 37))
12402	25279464	The membranes were subsequently incubated with anti-Nek2 (1:1000; Santa Cruz) or beta-actin (1:2000, Santa Cruz) for two hours at room temperature.	('anti-Nek2', 'Protein', (47, 56))	('rat', 'Species', '10116', (140, 143))	('1:2000', 'Var', (93, 99))
12406	25279464	These sections were washed and incubated in PBS with anti-Nek2 1:200 (Santa Cruz), or anti-Notch 1 1:100 (Cell Signaling Technology, Inc. Danvers, MA, USA) or anti-Notch 2 1:100 (Cell Signaling) or even Notch 3 1:500 (Cell Signaling).	('Notch', 'Gene', (91, 96))	('PBS', 'Chemical', '-', (44, 47))	('Notch', 'Gene', (164, 169))	('Notch', 'Gene', (203, 208))	('1:200', 'Var', (63, 68))	('anti-Nek2 1:200', 'Var', (53, 68))	('Notch', 'Gene', '25496', (91, 96))	('Notch', 'Gene', '25496', (164, 169))	('Notch', 'Gene', '25496', (203, 208))
12421	25279464	These distinct responses could be partially due to the larger number of repressed genes in common between treatments with the two N-POMC peptides (14) compared to those repressed in common between treatment with ACTH and either N-POMC peptide (4).	('ACTH', 'Gene', '18976', (212, 216))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('N-POMC', 'Var', (130, 136))	('N', 'Chemical', 'MESH:D009584', (228, 229))	('ACTH', 'Gene', (212, 216))
12437	25279464	After treatments with either ACTH or N-POMCMet, there was an increase in Nek2b expression in the ZG fraction (2.35-fold and 2.31-fold, respectively) and also in the ZF fraction (1.93-fold and 1.85-fold, respectively) (Figure 5A).	('N-POMCMet', 'Chemical', '-', (37, 46))	('ACTH', 'Gene', (29, 33))	('expression', 'MPA', (79, 89))	('Nek2b', 'Gene', (73, 78))	('N-POMCMet', 'Var', (37, 46))	('ACTH', 'Gene', '18976', (29, 33))	('increase', 'PosReg', (61, 69))
12467	25279464	In the current study, we showed that Nek2b gene and protein are induced in both adrenal fractions after treatments with ACTH or N-POMCMet, suggesting that Nek2b could be associated with the control of adrenocortical cell proliferation, since these treatments promoted an increase in the number of cells in the S-phase.	('ACTH', 'Gene', '18976', (120, 124))	('Nek2b', 'Var', (155, 160))	('rat', 'Species', '10116', (228, 231))	('ACTH', 'Gene', (120, 124))	('adrenocortical', 'Disease', (201, 215))	('Nek2b', 'Gene', (37, 42))	('N-POMCMet', 'Chemical', '-', (128, 137))	('increase', 'PosReg', (271, 279))	('adrenocortical', 'Disease', 'MESH:D018268', (201, 215))
12468	25279464	Following HPA-axis inhibition, there was an increase in the expression of Tumor protein p53 (Tp53) and Cyclin-dependent kinase 1A (Cdkn1a) in the ZG fraction.	('expression', 'MPA', (60, 70))	('p53', 'Gene', (94, 97))	('inhibition', 'Var', (19, 29))	('p53', 'Gene', '24842', (94, 97))	('Cdkn1a', 'Gene', '114851', (131, 137))	('Cdkn1a', 'Gene', (131, 137))	('Tp53', 'Gene', (93, 97))	('p53', 'Gene', (88, 91))	('increase', 'PosReg', (44, 52))	('p53', 'Gene', '24842', (88, 91))	('Tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Tp53', 'Gene', '24842', (93, 97))
12472	25279464	Regarding the effects of POMC-derived peptides in the adrenal cortex, we previously demonstrated that N-POMCMet peptide and ACTH promoted an increase in the number of cells in S-phase in all adrenal zones, whereas N-POMCCys was effective only in ZG and ZR.	('N-POMCMet', 'Chemical', '-', (102, 111))	('rat', 'Species', '10116', (91, 94))	('increase', 'PosReg', (141, 149))	('ACTH', 'Gene', '18976', (124, 128))	('N-POMCMet', 'Var', (102, 111))	('ACTH', 'Gene', (124, 128))	('N-POMCCys', 'Chemical', '-', (214, 223))
12504	19660215	Several series have documented that laparoscopic adrenalectomy is followed by lower complication rates, less operative blood loss, and less need for transfusion, less postoperative pain, earlier return to activity and diet, better cosmetic results, shorter hospital stay, and lower overall costs.	('postoperative pain', 'Disease', (167, 185))	('postoperative pain', 'Disease', 'MESH:D010149', (167, 185))	('laparoscopic', 'Var', (36, 48))	('blood loss', 'Disease', 'MESH:D006473', (119, 129))	('complication', 'CPA', (84, 96))	('pain', 'Phenotype', 'HP:0012531', (181, 185))	('blood loss', 'Disease', (119, 129))	('lower', 'NegReg', (78, 83))
12528	19660215	About 10% of pheochromocytomas were thought to be hereditary, but recently it has been shown that approximately 25% of patients with sporadic pheochromocytoma and no family history have germ-line mutations in 1 of 4 susceptible genes for pheochromocytoma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (142, 158))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (13, 29))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (238, 254))	('pheochromocytomas', 'Disease', (13, 30))	('pheochromocytoma', 'Disease', 'MESH:D010673', (142, 158))	('sporadic pheochromocytoma', 'Disease', (133, 158))	('pheochromocytomas', 'Disease', 'MESH:D010673', (13, 30))	('pheochromocytoma', 'Disease', 'MESH:D010673', (238, 254))	('patients', 'Species', '9606', (119, 127))	('pheochromocytoma', 'Disease', (13, 29))	('sporadic pheochromocytoma', 'Disease', 'MESH:D010673', (133, 158))	('pheochromocytoma', 'Disease', 'MESH:D010673', (13, 29))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (13, 30))	('pheochromocytoma', 'Disease', (142, 158))	('mutations', 'Var', (196, 205))	('pheochromocytoma', 'Disease', (238, 254))
12529	19660215	These mutations may be seen in isolation or as part of a syndrome, such as multiple endocrine neoplasia (MEN) IIA and IIB, and various neuroectodermal disorders including neurofibromatosis, von Hippel-Lindau syndrome, Sturge-Weber syndrome, and Carney triad, the latter being associated with multifocal extraadrenal pheochromocytomas.	('von Hippel-Lindau syndrome', 'Disease', (190, 216))	('Weber syndrome', 'Phenotype', 'HP:0002277', (225, 239))	('neuroectodermal disorders', 'Disease', 'MESH:D017599', (135, 160))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (190, 216))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (84, 103))	('multifocal extraadrenal pheochromocytomas', 'Disease', 'MESH:C565335', (292, 333))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (171, 188))	('neuroectodermal disorders', 'Disease', (135, 160))	('mutations', 'Var', (6, 15))	('Carney triad', 'Disease', (245, 257))	('neurofibromatosis', 'Disease', 'MESH:C537392', (171, 188))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (316, 333))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (218, 239))	('neurofibromatosis', 'Disease', (171, 188))	('neoplasia', 'Phenotype', 'HP:0002664', (94, 103))	('Sturge-Weber syndrome', 'Disease', (218, 239))	('multifocal extraadrenal pheochromocytomas', 'Disease', (292, 333))	('extraadrenal pheochromocytomas', 'Phenotype', 'HP:0006737', (303, 333))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (75, 103))	('IIA', 'Disease', (110, 113))	('multiple endocrine neoplasia', 'Disease', (75, 103))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (316, 332))	('MEN', 'Species', '9606', (105, 108))
12567	19660215	Additionally, laparoscopic adrenalectomy for clinically unsuspected adrenocortical cancer was associated with a high recurrence rate.	('adrenocortical cancer', 'Disease', (68, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('laparoscopic', 'Var', (14, 26))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (68, 89))
12600	33237039	N6-methyladenosine (m6A), also known as RNA methylation modification, occurs on the sixth nitrogen atom (N) of adenine (A) and is enriched in mRNA.	('m6A', 'Gene', '56339', (20, 23))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (0, 18))	('adenine', 'Chemical', 'MESH:D000225', (111, 118))	('nitrogen', 'Chemical', 'MESH:D009584', (90, 98))	('m6A', 'Gene', (20, 23))
12603	33237039	Regulatory gene interactions affect m6A regulation.	('m6A', 'Gene', (36, 39))	('interactions', 'Var', (16, 28))	('m6A', 'Gene', '56339', (36, 39))	('affect', 'Reg', (29, 35))
12608	33237039	's study found that inhibition of the FTO-FOXO1 pathway resulted in weight loss and decreased blood sugar, which could be considered for the treatment of the metabolic syndrome.	('metabolic syndrome', 'Disease', 'MESH:D024821', (158, 176))	('weight loss', 'Phenotype', 'HP:0001824', (68, 79))	('inhibition', 'Var', (20, 30))	('FTO', 'Gene', '79068', (38, 41))	('weight loss and decreased blood sugar', 'Disease', 'MESH:D016063', (68, 105))	('FOXO1', 'Gene', (42, 47))	('FOXO1', 'Gene', '2308', (42, 47))	('decreased blood sugar', 'Phenotype', 'HP:0001943', (84, 105))	('FTO', 'Gene', (38, 41))	('metabolic syndrome', 'Disease', (158, 176))
12613	33237039	Previous studies have reported that changing the expression of the METTL3 gene to increase the m6A regulatory genes level in U251 cells affects the occurrence and development of glioma.	('occurrence', 'CPA', (148, 158))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('changing', 'Var', (36, 44))	('affects', 'Reg', (136, 143))	('U251', 'CellLine', 'CVCL:0021', (125, 129))	('m6A', 'Gene', (95, 98))	('increase', 'PosReg', (82, 90))	('METTL3', 'Gene', '56339', (67, 73))	('m6A', 'Gene', '56339', (95, 98))	('development', 'CPA', (163, 174))	('glioma', 'Disease', (178, 184))	('METTL3', 'Gene', (67, 73))
12615	33237039	found that mutations in m6A regulatory gene are closely related to the presence of TP53 mutations in acute myeloid leukemia patients.	('m6A', 'Gene', (24, 27))	('TP53', 'Gene', '7157', (83, 87))	('mutations', 'Var', (11, 20))	('patients', 'Species', '9606', (124, 132))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (101, 123))	('m6A', 'Gene', '56339', (24, 27))	('TP53', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (101, 123))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (107, 123))	('acute myeloid leukemia', 'Disease', (101, 123))	('related', 'Reg', (56, 63))
12733	33381672	The possibility of sodium-glucose cotransporter protein 2 (SGLT2) inhibitor causing bilateral hyperplasia of the zona glomerulosa of the adrenal gland will also be discussed.	('sodium-glucose cotransporter protein 2', 'Gene', '6524', (19, 57))	('hyperplasia of the zona glomerulosa', 'Disease', 'MESH:D006562', (94, 129))	('SGLT2', 'Gene', (59, 64))	('inhibitor', 'Var', (66, 75))	('causing', 'Reg', (76, 83))	('sodium-glucose cotransporter protein 2', 'Gene', (19, 57))	('SGLT2', 'Gene', '6524', (59, 64))	('hyperplasia of the zona glomerulosa', 'Disease', (94, 129))
12802	33381672	Serum renin and aldosterone levels have been reported to increase significantly with SGLT2 inhibitor use within 1 month, which is associated with a decrease in extracellular fluid.	('renin', 'Gene', (6, 11))	('SGLT2', 'Gene', (85, 90))	('aldosterone', 'Chemical', 'MESH:D000450', (16, 27))	('extracellular fluid', 'MPA', (160, 179))	('renin', 'Gene', '5972', (6, 11))	('increase', 'PosReg', (57, 65))	('SGLT2', 'Gene', '6524', (85, 90))	('decrease', 'NegReg', (148, 156))	('inhibitor', 'Var', (91, 100))
12809	33381672	These results suggest the possibility of SGLT2 inhibitors having some effect on the zona glomerulosa of the adrenal gland; for instance, the latent loss of plasma volume caused by the SGLT2 inhibitor stimulating the zona glomerulosa chronically, leading to hyperplasia.	('hyperplasia', 'Disease', (257, 268))	('SGLT2', 'Gene', '6524', (41, 46))	('loss', 'NegReg', (148, 152))	('SGLT2', 'Gene', '6524', (184, 189))	('plasma volume', 'MPA', (156, 169))	('leading to', 'Reg', (246, 256))	('hyperplasia', 'Disease', 'MESH:D006965', (257, 268))	('zona glomerulosa', 'Disease', 'MESH:D006562', (216, 232))	('SGLT2', 'Gene', (41, 46))	('zona glomerulosa', 'Disease', (84, 100))	('SGLT2', 'Gene', (184, 189))	('zona glomerulosa', 'Disease', 'MESH:D006562', (84, 100))	('inhibitor', 'Var', (190, 199))	('zona glomerulosa', 'Disease', (216, 232))	('stimulating', 'Reg', (200, 211))
12879	32260362	Mitotane, the standard treatment for ACC, impairs adrenocortical steroid biosynthesis and cholesterol metabolism.	('Mitotane', 'Var', (0, 8))	('cholesterol metabolism', 'Disease', (90, 112))	('adrenocortical steroid biosynthesis', 'MPA', (50, 85))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('cholesterol metabolism', 'Disease', 'MESH:D008659', (90, 112))	('steroid', 'Chemical', 'MESH:D013256', (65, 72))	('ACC', 'Phenotype', 'HP:0006744', (37, 40))	('impairs', 'NegReg', (42, 49))
12880	32260362	In the H295R cell line, a standard ACC in vitro model, mitotane was previously reported to enhance the production of some oxysterols.	('mitotane', 'Var', (55, 63))	('H295R', 'CellLine', 'CVCL:0458', (7, 12))	('production of some oxysterols', 'MPA', (103, 132))	('oxysterols', 'Chemical', 'MESH:D000072376', (122, 132))	('mitotane', 'Chemical', 'MESH:D008939', (55, 63))	('enhance', 'PosReg', (91, 98))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))
12883	32260362	In this cell model, mitotane was confirmed to affect mitochondrial transmembrane potential and induce apoptosis.	('mitochondrial transmembrane potential', 'MPA', (53, 90))	('apoptosis', 'CPA', (102, 111))	('mitotane', 'Var', (20, 28))	('mitotane', 'Chemical', 'MESH:D008939', (20, 28))	('affect', 'Reg', (46, 52))	('induce', 'Reg', (95, 101))
12898	32260362	Only a single:while seminal:report is available showing that mitotane is able to induce specific changes in lipid metabolism in ACC cells.	('mitotane', 'Var', (61, 69))	('ACC', 'Phenotype', 'HP:0006744', (128, 131))	('mitotane', 'Chemical', 'MESH:D008939', (61, 69))	('lipid', 'Chemical', 'MESH:D008055', (108, 113))	('lipid metabolism', 'MPA', (108, 124))	('changes', 'Reg', (97, 104))
12900	32260362	Mitotane was demonstrated to markedly increase the steady-state level of cholesterol precursors lanosterol and lathosterol in H295 ACC cells, but also a couple of oxysterols of non-enzymatic origin, namely 7-ketocholesterol and 7beta-hydroxycholesterol, the latter two compounds being well known as potentially toxic lipid oxidation products.	('Mitotane', 'Var', (0, 8))	('increase', 'PosReg', (38, 46))	('lathosterol', 'Chemical', 'MESH:C001521', (111, 122))	('7beta-hydroxycholesterol', 'Chemical', 'MESH:C011724', (228, 252))	('ACC', 'Phenotype', 'HP:0006744', (131, 134))	('lipid', 'Chemical', 'MESH:D008055', (317, 322))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('lanosterol', 'MPA', (96, 106))	('oxysterols', 'Chemical', 'MESH:D000072376', (163, 173))	('cholesterol', 'Chemical', 'MESH:D002784', (212, 223))	('lanosterol', 'Chemical', 'MESH:D007810', (96, 106))	('cholesterol', 'Chemical', 'MESH:D002784', (241, 252))	('cholesterol', 'Chemical', 'MESH:D002784', (73, 84))	('7-ketocholesterol', 'Chemical', 'MESH:C003001', (206, 223))	('increase the steady-state level of cholesterol', 'Phenotype', 'HP:0003124', (38, 84))	('H295', 'CellLine', 'CVCL:0456', (126, 130))
12948	32260362	Here, preliminary unreported analyses showed that the 48-h challenge with 27OHC actually affected H295R cell viability exhibiting an IC50 of 28.72 microM +- 1.87.	('27OHC', 'Chemical', 'MESH:C076996', (74, 79))	('H295R', 'CellLine', 'CVCL:0458', (98, 103))	('affected', 'Reg', (89, 97))	('H295R cell viability', 'CPA', (98, 118))	('27OHC', 'Var', (74, 79))
12950	32260362	In the latter amount, 27OHC caused about a 20% fall in cell viability, after 48 h of treatment, while 5-microM 27OHC only slightly affected this parameter (Figure 2, Panel A).	('fall', 'Phenotype', 'HP:0002527', (47, 51))	('27OHC', 'Chemical', 'MESH:C076996', (22, 27))	('cell viability', 'CPA', (55, 69))	('fall', 'NegReg', (47, 51))	('27OHC', 'Chemical', 'MESH:C076996', (111, 116))	('27OHC', 'Var', (22, 27))
12951	32260362	With regard to mitotane, after the 48-h cell challenge, a 5 microM final concentration reduced of about 10% cell viability as for 5-microM 27OHC, while a 10 microM concentration affected cell viability slightly more than 10-microM 27OHC (Figure 2, panel A).	('5-microM 27OHC', 'Var', (130, 144))	('27OHC', 'Chemical', 'MESH:C076996', (231, 236))	('27OHC', 'Chemical', 'MESH:C076996', (139, 144))	('reduced', 'NegReg', (87, 94))	('cell viability', 'CPA', (108, 122))	('mitotane', 'Chemical', 'MESH:D008939', (15, 23))
12956	32260362	The mitotane treatment carried out on the employed cancer cell line showed to be markedly effective in activating caspase-3 after 48 h, moderately increasing in 10-microM-treated cells in comparison to 5-microM-treated ones (Figure 2, Panel C).	('caspase-3', 'Gene', (114, 123))	('activating', 'MPA', (103, 113))	('mitotane', 'Chemical', 'MESH:D008939', (4, 12))	('10-microM-treated', 'Var', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('increasing', 'PosReg', (147, 157))	('caspase-3', 'Gene', '836', (114, 123))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
12957	32260362	Notably, identical micromolar concentrations of 27OHC perfectly matched the mitotane induced caspase-3 activation, with no apparent difference in efficacy between the two concentrations used (Figure 2, Panel C).	('caspase-3', 'Gene', (93, 102))	('27OHC', 'Var', (48, 53))	('caspase-3', 'Gene', '836', (93, 102))	('mitotane', 'MPA', (76, 84))	('mitotane', 'Chemical', 'MESH:D008939', (76, 84))	('27OHC', 'Chemical', 'MESH:C076996', (48, 53))	('activation', 'PosReg', (103, 113))
12964	32260362	Notably, even though no correlation between 27OHC and cholesterol plasma levels was found in the single ACC patient, 24OHC doubled the control mean value, while the 27OHC plasma level reached an increase of 3.6 times.	('doubled', 'PosReg', (123, 130))	('cholesterol', 'Chemical', 'MESH:D002784', (54, 65))	('24OHC', 'Var', (117, 122))	('27OHC', 'Chemical', 'MESH:C076996', (44, 49))	('control mean value', 'MPA', (135, 153))	('27OHC', 'Chemical', 'MESH:C076996', (165, 170))	('patient', 'Species', '9606', (108, 115))	('ACC', 'Phenotype', 'HP:0006744', (104, 107))
12974	32260362	As far as human adrenal cancer cells are concerned, this paper provides solid evidence of specific cytotoxic and pro-apoptotic actions of 27OHC, which matches the in vitro effect exerted by an identical micromolar amount of mitotane (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('human', 'Species', '9606', (10, 15))	('adrenal cancer', 'Disease', (16, 30))	('mitotane', 'Chemical', 'MESH:D008939', (224, 232))	('27OHC', 'Var', (138, 143))	('27OHC', 'Chemical', 'MESH:C076996', (138, 143))	('adrenal cancer', 'Disease', 'MESH:D000310', (16, 30))	('pro-apoptotic actions', 'CPA', (113, 134))	('cytotoxic', 'CPA', (99, 108))
12977	32260362	The content of two other side-chain oxysterols:24OHC and 25OHC:increased, even if it was to a lesser extent, in ACC patients (Table 3).	('increased', 'PosReg', (63, 72))	('25OHC', 'Var', (57, 62))	('patients', 'Species', '9606', (116, 124))	('ACC', 'Phenotype', 'HP:0006744', (112, 115))	('25OHC', 'Chemical', '-', (57, 62))	('content', 'MPA', (4, 11))	('oxysterols', 'Chemical', 'MESH:D000072376', (36, 46))
12995	32260362	To summarize, the main findings of this study are: (1) mitotane treatment induces a net increase in 27OHC in ACC cells and in ACC patients; (2) 27OHC is responsible for at least part of the cytotoxic and pro-apoptotic effects exerted by mitotane on ACC cells.	('27OHC', 'MPA', (100, 105))	('27OHC', 'Var', (144, 149))	('ACC', 'Phenotype', 'HP:0006744', (249, 252))	('increase', 'PosReg', (88, 96))	('mitotane', 'Chemical', 'MESH:D008939', (237, 245))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('patients', 'Species', '9606', (130, 138))	('mitotane', 'Chemical', 'MESH:D008939', (55, 63))	('27OHC', 'Chemical', 'MESH:C076996', (144, 149))	('ACC', 'Phenotype', 'HP:0006744', (126, 129))	('27OHC', 'Chemical', 'MESH:C076996', (100, 105))
13022	32184394	Upon GPX4 inhibition lipid peroxidation is triggered which lead to the specific oxidation of an ill-characterized phosphatidylethanolamine (PE) pool.	('phosphatidylethanolamine', 'Chemical', 'MESH:C483858', (114, 138))	('PE', 'Chemical', 'MESH:C483858', (140, 142))	('lipid', 'Chemical', 'MESH:D008055', (21, 26))	('lead to', 'Reg', (59, 66))	('specific oxidation of an', 'MPA', (71, 95))	('inhibition', 'Var', (10, 20))	('GPX4', 'Gene', (5, 9))
13072	32184394	We hence investigated whether mitotane leads to the accumulation of oxidized lipids and induces ferroptosis in ACC cells.	('induces', 'Reg', (88, 95))	('ferroptosis', 'CPA', (96, 107))	('mitotane', 'Var', (30, 38))	('mitotane', 'Chemical', 'MESH:D008939', (30, 38))	('ACC', 'Phenotype', 'HP:0006744', (111, 114))	('ACC', 'Disease', (111, 114))	('lipids', 'Chemical', 'MESH:D008055', (77, 83))	('ACC', 'Disease', 'MESH:D018268', (111, 114))	('accumulation of oxidized lipids', 'MPA', (52, 83))
13082	32184394	However, in the extremely RSL3-sensitive CU-ACC2 cells, RSL3 led to a concentration dependent reduction of cell viability in combination with 75 microM mitotane (58 +- 2.5 to 46 +- 7.1% with 10 nM RSL3 and to 24% with 15 nM RSL3; p < 0.01; Fig.	('reduction', 'NegReg', (94, 103))	('rat', 'Species', '10116', (77, 80))	('RSL3', 'Chemical', '-', (56, 60))	('CU', 'Chemical', 'MESH:D003300', (41, 43))	('RSL3', 'Var', (56, 60))	('ACC', 'Phenotype', 'HP:0006744', (44, 47))	('cell viability', 'CPA', (107, 121))	('ACC', 'Disease', (44, 47))	('RSL3', 'Chemical', '-', (197, 201))	('RSL3', 'Chemical', '-', (26, 30))	('mitotane', 'Chemical', 'MESH:D008939', (152, 160))	('RSL3', 'Chemical', '-', (224, 228))	('ACC', 'Disease', 'MESH:D018268', (44, 47))
13097	32184394	RSL3 is a potent inhibitor of GPX4 and since GPX4 is the only enzyme that reduces esterified peroxidized fatty acids and cholesterol hydroperoxides, inhibition of this enzyme results in the accumulation of peroxidized lipids and subsequently ferroptosis.	('cholesterol hydroperoxides', 'Chemical', 'MESH:C002843', (121, 147))	('fatty acids', 'Chemical', 'MESH:D005227', (105, 116))	('RSL3', 'Chemical', '-', (0, 4))	('peroxidized lipids', 'MPA', (206, 224))	('ferroptosis', 'CPA', (242, 253))	('lipids', 'Chemical', 'MESH:D008055', (218, 224))	('inhibition', 'Var', (149, 159))	('reduces', 'NegReg', (74, 81))	('accumulation', 'PosReg', (190, 202))	('cholesterol hydroperoxides', 'MPA', (121, 147))
13107	32184394	Since GPX4 is dependent on GSH, inhibition of cystine uptake theoretically leads to reduced intracellular GSH levels, reduced GPX4 activity and hence, increased ferroptosis.	('increased', 'PosReg', (151, 160))	('GSH', 'Chemical', '-', (27, 30))	('inhibition', 'Var', (32, 42))	('GPX4', 'Enzyme', (126, 130))	('reduced', 'NegReg', (118, 125))	('activity', 'MPA', (131, 139))	('reduced', 'NegReg', (84, 91))	('cystine', 'Chemical', 'MESH:D003553', (46, 53))	('intracellular GSH levels', 'MPA', (92, 116))	('GSH', 'Chemical', '-', (106, 109))	('ferroptosis', 'CPA', (161, 172))
13165	32184394	log2 normalized expression data (Human Genome U133 Plus 2.0 Kit, Affymetrix) of ACSL4 (probe 1557418_at), GPX4 (probe 201106_at) and SLC7A11 (probe 217678_at) in 10 normal adrenal glands (nAG), 22 adrenocortical adenomas, and 33 ACC were retrieved together with limited clinical data on the samples from the National Center for Biotechnology Information's Gene Expression Omnibus (GSE10927).	('adrenocortical adenomas', 'Disease', (197, 220))	('nAG', 'Chemical', '-', (188, 191))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (197, 220))	('SLC7A11', 'Gene', (133, 140))	('probe 1557418_at', 'Var', (87, 103))	('ACC', 'Phenotype', 'HP:0006744', (229, 232))	('ACC', 'Disease', (229, 232))	('SLC7A11', 'Gene', '23657', (133, 140))	('probe 201106_at', 'Var', (112, 127))	('probe 217678_at', 'Var', (142, 157))	('Human', 'Species', '9606', (33, 38))	('ACC', 'Disease', 'MESH:D018268', (229, 232))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (197, 220))
13172	26793526	Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by CYP 21(21-hydroxylase) deficiency.	('CAH', 'Disease', (32, 35))	('CYP 21', 'Gene', (82, 88))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (43, 71))	('CAH', 'Disease', 'None', (32, 35))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (11, 30))	('autosomal recessive disorder', 'Disease', (43, 71))	('Congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (0, 30))	('Congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (0, 30))	('CAH', 'Phenotype', 'HP:0008258', (32, 35))	('Congenital adrenal hyperplasia', 'Disease', (0, 30))	('caused by', 'Reg', (72, 81))	('deficiency', 'Var', (105, 115))
13214	26317117	Genomic and immunohistochemical analysis in human adrenal cortical neoplasia reveal beta-catenin mutations as potential prognostic biomarker Evaluation for malignancy of the adrenal cortex, adrenal cortical carcinoma (ACC), is a challenge in surgical pathology due to its relative rarity and histologic overlap with its benign counterpart, adrenocortical adenoma (ACA).	('human', 'Species', '9606', (44, 49))	('mutations', 'Var', (97, 106))	('adrenal cortical carcinoma', 'Phenotype', 'HP:0006744', (190, 216))	('ACC', 'Phenotype', 'HP:0006744', (218, 221))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (340, 362))	('neoplasia', 'Phenotype', 'HP:0002664', (67, 76))	('adrenal cortical carcinoma', 'Disease', (190, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (340, 362))	('ACA', 'Phenotype', 'HP:0008256', (364, 367))	('adrenal cortical carcinoma', 'Disease', 'MESH:D018268', (190, 216))	('malignancy of the adrenal cortex', 'Disease', 'MESH:D000303', (156, 188))	('adrenal cortical neoplasia', 'Disease', (50, 76))	('adrenocortical adenoma', 'Disease', (340, 362))	('adrenal cortical neoplasia', 'Disease', 'MESH:D009369', (50, 76))	('beta-catenin', 'Gene', (84, 96))	('adrenal cortical neoplasia', 'Phenotype', 'HP:0100641', (50, 76))	('malignancy of the adrenal cortex', 'Phenotype', 'HP:0100641', (156, 188))	('beta-catenin', 'Gene', '1499', (84, 96))	('malignancy of the adrenal cortex', 'Disease', (156, 188))
13218	26317117	By mutational screen, 12/31 (38.7%) carcinomas harbored CTNNB1 mutations, 1 with an additional TP53 mutation; 1 case each had isolated APC and TP53 mutations; 16 were wild-type for all tested loci; and 1 case demonstrated repeated assay failures.	('mutations', 'Var', (63, 72))	('TP53', 'Gene', (143, 147))	('CTNNB1', 'Gene', '1499', (56, 62))	('APC', 'Disease', (135, 138))	('harbored', 'Reg', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('carcinomas', 'Disease', 'MESH:D002277', (36, 46))	('CTNNB1', 'Gene', (56, 62))	('TP53', 'Gene', '7157', (143, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('APC', 'Disease', 'MESH:D011125', (135, 138))	('carcinomas', 'Disease', (36, 46))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
13219	26317117	Two of the 10 ACA (20%) demonstrated CTNNB1 mutations by mutational screen, with no additional mutations.	('ACA', 'Phenotype', 'HP:0008256', (14, 17))	('mutations', 'Var', (44, 53))	('CTNNB1', 'Gene', (37, 43))	('CTNNB1', 'Gene', '1499', (37, 43))
13221	26317117	Strong nuclear beta-catenin immunopositivity corresponded to the presence of CTNNB1 mutation by genotyping in 10 of 12 cases (83% sensitivity); the mismatched case(s) demonstrated strong membranous staining by immunohistochemistry.	('CTNNB1', 'Gene', (77, 83))	('CTNNB1', 'Gene', '1499', (77, 83))	('beta-catenin', 'Gene', (15, 27))	('beta-catenin', 'Gene', '1499', (15, 27))	('mutation', 'Var', (84, 92))
13222	26317117	Seventeen of the 18 cases without CTNNB1 mutation showed membranous staining or did not stain (94% specificity); the mismatched case demonstrated scattered (<10%) positive nuclei.	('mutation', 'Var', (41, 49))	('CTNNB1', 'Gene', (34, 40))	('CTNNB1', 'Gene', '1499', (34, 40))	('membranous staining', 'MPA', (57, 76))
13224	26317117	Based on these results, mutational status of CTNNB1 in adrenal cortical neoplasms can be predicted with reasonable accuracy by immunohistochemical cellular localization.	('CTNNB1', 'Gene', '1499', (45, 51))	('adrenal cortical neoplasms', 'Disease', (55, 81))	('adrenal cortical neoplasms', 'Disease', 'MESH:D000310', (55, 81))	('CTNNB1', 'Gene', (45, 51))	('neoplasm', 'Phenotype', 'HP:0002664', (72, 80))	('adrenal cortical neoplasms', 'Phenotype', 'HP:0100641', (55, 81))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))	('mutational', 'Var', (24, 34))
13235	26317117	The insulin-like growth factor 2 (IGF2) family of developmental signaling molecules have emerged as key participants in adrenal carcinogenesis, including increased expression and abnormal methylation.	('adrenal carcinogenesis', 'Disease', (120, 142))	('abnormal', 'Var', (179, 187))	('insulin-like growth factor 2', 'Gene', '3481', (4, 32))	('insulin-like growth factor 2', 'Gene', (4, 32))	('expression', 'MPA', (164, 174))	('adrenal carcinogenesis', 'Disease', 'MESH:D063646', (120, 142))	('IGF2', 'Gene', '3481', (34, 38))	('men', 'Species', '9606', (57, 60))	('participants', 'Species', '9606', (104, 116))	('increased', 'PosReg', (154, 163))	('IGF2', 'Gene', (34, 38))	('methylation', 'MPA', (188, 199))
13237	26317117	Mutations in beta-catenin, or CTNNB1, the major intracellular mediator of the Wnt signaling pathway, have been implicated across proliferative adrenal lesions, including ACC, ACA, and models of adrenal hyperplasia, with proliferation rate appearing to parallel the frequency of beta-catenin nuclear translocation.	('beta-catenin', 'Gene', '1499', (13, 25))	('CTNNB1', 'Gene', (30, 36))	('beta-catenin', 'Gene', (278, 290))	('adrenal hyperplasia', 'Disease', (194, 213))	('ACC', 'Phenotype', 'HP:0006744', (170, 173))	('ACC', 'Disease', (170, 173))	('ACA', 'Phenotype', 'HP:0008256', (175, 178))	('adrenal lesions', 'Disease', 'MESH:D000307', (143, 158))	('beta-catenin', 'Gene', '1499', (278, 290))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (194, 213))	('adrenal lesions', 'Disease', (143, 158))	('Mutations', 'Var', (0, 9))	('CTNNB1', 'Gene', '1499', (30, 36))	('ACA', 'Disease', (175, 178))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (194, 213))	('beta-catenin', 'Gene', (13, 25))	('implicated', 'Reg', (111, 121))
13238	26317117	Indeed, mutations in the Wnt developmental and differentiation signal transduction pathway are seen in a variety of endocrine and other tumors, as the adrenal and other endocrine glands depend on appropriate Wnt signaling for development.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mutations', 'Var', (8, 17))	('Wnt', 'Gene', (25, 28))	('men', 'Species', '9606', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('endocrine', 'Disease', (116, 125))	('seen', 'Reg', (95, 99))	('men', 'Species', '9606', (233, 236))
13240	26317117	We predict that knowledge of the mutational status of beta-catenin and other genes implicated in adrenal cortical neoplasia may be useful as diagnostic adjuvants in characterizing adrenal cortical lesions in routine clinical practice.	('adrenal cortical lesions', 'Disease', (180, 204))	('adrenal cortical neoplasia', 'Phenotype', 'HP:0100641', (97, 123))	('mutational', 'Var', (33, 43))	('adrenal cortical neoplasia', 'Disease', 'MESH:D009369', (97, 123))	('neoplasia', 'Phenotype', 'HP:0002664', (114, 123))	('beta-catenin', 'Gene', (54, 66))	('beta-catenin', 'Gene', '1499', (54, 66))	('adrenal cortical neoplasia', 'Disease', (97, 123))	('adrenal cortical lesions', 'Disease', 'MESH:D000309', (180, 204))
13250	26317117	The assay performs tumor genotyping of recognized driver point mutations and small insertions and deletions in 15 cancer genes (Supplementary Table 1).	('15 cancer', 'Disease', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('men', 'Species', '9606', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('15 cancer', 'Disease', 'MESH:C567447', (111, 120))	('point mutations', 'Var', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Disease', (19, 24))	('deletions', 'Var', (98, 107))
13282	26317117	Beta-catenin (CTNNB1) mutations were detected in 12 of the 31 (39%) ACC cases and in 2 of the 10 (20%) ACA cases.	('CTNNB1', 'Gene', '1499', (14, 20))	('ACA', 'Phenotype', 'HP:0008256', (103, 106))	('Beta-catenin', 'Gene', (0, 12))	('ACC', 'Phenotype', 'HP:0006744', (68, 71))	('detected', 'Reg', (37, 45))	('ACC', 'Disease', (68, 71))	('mutations', 'Var', (22, 31))	('CTNNB1', 'Gene', (14, 20))	('Beta-catenin', 'Gene', '1499', (0, 12))
13283	26317117	In one of the ACC cases with a beta-catenin mutation (ACC9), a concomitant mutation in TP53 was identified.	('TP53', 'Gene', '7157', (87, 91))	('mutation', 'Var', (44, 52))	('beta-catenin', 'Gene', (31, 43))	('beta-catenin', 'Gene', '1499', (31, 43))	('ACC', 'Phenotype', 'HP:0006744', (54, 57))	('TP53', 'Gene', (87, 91))	('ACC', 'Phenotype', 'HP:0006744', (14, 17))
13286	26317117	Among the 12 cases with beta-catenin mutations, 8 distinct point mutations were detected at 4 loci on the CTNNB1 gene: S45P (133T>C); S45A (133T>G); S45C (134C>G); S45F (134C>T); G34V (101G>T); G34E (101G>A); S37P (109T>C); and T41I (122C>T) (see Table legend).	('G34E (101G>A', 'Var', (194, 206))	('133T>C', 'Mutation', 'rs121913407', (125, 131))	('CTNNB1', 'Gene', '1499', (106, 112))	('T41I (122C>T', 'Var', (228, 240))	('G34V (101G>T', 'Var', (179, 191))	('134C>T', 'Mutation', 'rs121913409', (170, 176))	('beta-catenin', 'Gene', (24, 36))	('S45P', 'Mutation', 'rs121913407', (119, 123))	('S37P', 'Mutation', 'rs121913228', (209, 213))	('beta-catenin', 'Gene', '1499', (24, 36))	('S45C (134C>G', 'Var', (149, 161))	('G34E', 'Mutation', 'rs28931589', (194, 198))	('S45C', 'Mutation', 'rs121913409', (149, 153))	('CTNNB1', 'Gene', (106, 112))	('122C>T', 'Mutation', 'rs121913413', (234, 240))	('101G>T', 'Mutation', 'rs28931589', (185, 191))	('mutations', 'Var', (37, 46))	('S45A', 'Mutation', 'rs121913407', (134, 138))	('S45F', 'Mutation', 'rs121913409', (164, 168))	('G34V', 'Mutation', 'rs28931589', (179, 183))	('S45A (133T>G', 'Var', (134, 146))	('T41I', 'Mutation', 'rs121913413', (228, 232))	('109T>C', 'Mutation', 'rs121913228', (215, 221))	('134C>G', 'Mutation', 'rs121913409', (155, 161))	('S37P (109T>C', 'Var', (209, 221))	('133T>G', 'Mutation', 'rs121913407', (140, 146))	('101G>A', 'Mutation', 'rs28931589', (200, 206))	('S45P (133T>C', 'Var', (119, 131))	('S45F (134C>T', 'Var', (164, 176))
13289	26317117	Strong nuclear localization of beta-catenin immunostain corresponded with the presence of CTNNB1 mutation by genotyping in 10 of 12 cases (83% sensitivity); the mismatched cases demonstrated strong membranous staining by IHC.	('nuclear localization', 'MPA', (7, 27))	('CTNNB1', 'Gene', '1499', (90, 96))	('beta-catenin', 'Gene', (31, 43))	('mutation', 'Var', (97, 105))	('beta-catenin', 'Gene', '1499', (31, 43))	('membranous staining', 'MPA', (198, 217))	('CTNNB1', 'Gene', (90, 96))
13292	26317117	CTNNB1 mutational status was corroborated by immunohistochemistry in all 10 ACA cases.	('CTNNB1', 'Gene', '1499', (0, 6))	('ACA', 'Disease', (76, 79))	('CTNNB1', 'Gene', (0, 6))	('ACA', 'Phenotype', 'HP:0008256', (76, 79))	('mutational', 'Var', (7, 17))
13293	26317117	Similarly, the quality of membranous beta-catenin immunohistochemical localization patterns were not discernibly different in the ACC with the APC and/or TP53 mutations from the other cases WT for CTNNB1.	('CTNNB1', 'Gene', (197, 203))	('TP53', 'Gene', (154, 158))	('APC', 'Disease', 'MESH:D011125', (143, 146))	('mutations', 'Var', (159, 168))	('TP53', 'Gene', '7157', (154, 158))	('APC', 'Disease', (143, 146))	('beta-catenin', 'Gene', (37, 49))	('CTNNB1', 'Gene', '1499', (197, 203))	('ACC', 'Phenotype', 'HP:0006744', (130, 133))	('beta-catenin', 'Gene', '1499', (37, 49))
13297	26317117	The majority (9/12, 75%) of ACCs with beta-catenin mutations either DBD or were alive but with a clinically apparent disease burden (alive with disease, or AWD; Table 1); in one subject, the clinical outcome was unknown.	('beta-catenin', 'Gene', (38, 50))	('mutations', 'Var', (51, 60))	('DBD', 'Chemical', 'MESH:C036010', (68, 71))	('ACCs', 'Gene', (28, 32))	('ACCs', 'Gene', '84680', (28, 32))	('beta-catenin', 'Gene', '1499', (38, 50))	('AWD', 'Gene', (156, 159))	('DBD', 'Disease', (68, 71))	('ACC', 'Phenotype', 'HP:0006744', (28, 31))	('AWD', 'Gene', '4830', (156, 159))
13298	26317117	Interestingly, the subject with concomitant beta-catenin and TP53 mutations (ACC9) was alive without disease (AOD) after nearly 9 years of follow-up; this subject also met few Weiss criteria for malignancy and had negative surgical resection margins.	('mutations', 'Var', (66, 75))	('malignancy', 'Disease', (195, 205))	('ACC', 'Phenotype', 'HP:0006744', (77, 80))	('beta-catenin', 'Gene', (44, 56))	('beta-catenin', 'Gene', '1499', (44, 56))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('malignancy', 'Disease', 'MESH:D009369', (195, 205))
13299	26317117	By contrast, in ACC cases without beta-catenin mutations, only 7 of 18 subjects (39%) DBD or AWD, with the clinical outcome in one subject unknown.	('DBD', 'Disease', (86, 89))	('ACC', 'Phenotype', 'HP:0006744', (16, 19))	('beta-catenin', 'Gene', '1499', (34, 46))	('AWD', 'Gene', (93, 96))	('mutations', 'Var', (47, 56))	('DBD', 'Chemical', 'MESH:C036010', (86, 89))	('AWD', 'Gene', '4830', (93, 96))	('beta-catenin', 'Gene', (34, 46))
13300	26317117	The case with the isolated APC mutation was alive with metastatic disease at the time of last follow-up (ACC10, 8 months); no follow-up clinical information was available for the subject with the isolated TP53 mutation (ACC25).	('ACC2', 'Gene', '597', (220, 224))	('ACC2', 'Gene', (220, 224))	('APC', 'Disease', 'MESH:D011125', (27, 30))	('mutation', 'Var', (31, 39))	('TP53', 'Gene', '7157', (205, 209))	('TP53', 'Gene', (205, 209))	('ACC', 'Phenotype', 'HP:0006744', (105, 108))	('APC', 'Disease', (27, 30))	('ACC', 'Phenotype', 'HP:0006744', (220, 223))
13302	26317117	The two cases of ACA with beta-catenin mutations, 5.0 cm and 7.5 cm lesions, had variable clinical findings of cortisol production in the former and cystic degenerative changes in the latter without clinical symptoms.	('cortisol', 'Chemical', 'MESH:D006854', (111, 119))	('beta-catenin', 'Gene', '1499', (26, 38))	('ACA', 'Phenotype', 'HP:0008256', (17, 20))	('mutations', 'Var', (39, 48))	('cortisol production', 'MPA', (111, 130))	('degenerative changes', 'Phenotype', 'HP:0002180', (156, 176))	('beta-catenin', 'Gene', (26, 38))	('ACA', 'Disease', (17, 20))
13308	26317117	CTNNB1 mutations were a common finding on the molecular screen and consistent with previously reported findings.	('CTNNB1', 'Gene', '1499', (0, 6))	('CTNNB1', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
13309	26317117	Beta-catenin mutations appeared modestly but not statistically enriched in ACC (39%) compared with ACA (20%) and control adrenal tissue (0%).	('ACA', 'Phenotype', 'HP:0008256', (99, 102))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('Beta-catenin', 'Gene', (0, 12))	('ACC', 'Disease', (75, 78))	('mutations', 'Var', (13, 22))	('Beta-catenin', 'Gene', '1499', (0, 12))
13310	26317117	Moreover, there was a trend toward higher prevalance of CTNNB1 mutations in ACCs with poor prognosis (75% DBD or AWD) compared with ACCs with relatively favorable prognosis (39% AOD).	('mutations', 'Var', (63, 72))	('CTNNB1', 'Gene', '1499', (56, 62))	('ACC', 'Phenotype', 'HP:0006744', (76, 79))	('ACC', 'Phenotype', 'HP:0006744', (132, 135))	('AWD', 'Gene', '4830', (113, 116))	('ACCs', 'Gene', (132, 136))	('DBD', 'Chemical', 'MESH:C036010', (106, 109))	('ACCs', 'Gene', '84680', (132, 136))	('ACCs', 'Gene', (76, 80))	('ACCs', 'Gene', '84680', (76, 80))	('CTNNB1', 'Gene', (56, 62))	('higher', 'PosReg', (35, 41))	('AWD', 'Gene', (113, 116))
13312	26317117	The few discrepancies seen between our molecular and immunohistochemical studies could be accounted for by a number of mechanisms, including alternative aberrant protein interactions with the product of an intact beta-catenin allele.	('beta-catenin', 'Gene', '1499', (213, 225))	('protein', 'Protein', (162, 169))	('interactions', 'Interaction', (170, 182))	('aberrant', 'Var', (153, 161))	('beta-catenin', 'Gene', (213, 225))
13313	26317117	One carcinoma (ACC2) showed a CTNNB1 G34A (101G>C) mutation on screen but a predominantly membranous staining pattern on section.	('G34A', 'Mutation', 'rs28931589', (37, 41))	('carcinoma', 'Disease', (4, 13))	('CTNNB1', 'Gene', (30, 36))	('G34A (101G>C', 'Var', (37, 49))	('ACC', 'Phenotype', 'HP:0006744', (15, 18))	('101G>C', 'Mutation', 'rs28931589', (43, 49))	('CTNNB1', 'Gene', '1499', (30, 36))	('ACC2', 'Gene', '597', (15, 19))	('ACC2', 'Gene', (15, 19))	('carcinoma', 'Disease', 'MESH:D002277', (4, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (4, 13))
13314	26317117	This particular CTNNB1 mutation has never been reported in an ACC to our knowledge, and its function is unknown.	('CTNNB1', 'Gene', (16, 22))	('CTNNB1', 'Gene', '1499', (16, 22))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('mutation', 'Var', (23, 31))
13315	26317117	The Tissier study showed a greater number of cases with aberrant nuclear stain over documented CTNNB1 mutation, including 77% of carcinomas (31% mutation) and 38% of adenomas, with staining in adenomas stated to be very focal.	('CTNNB1', 'Gene', (95, 101))	('adenomas', 'Disease', 'MESH:D000236', (193, 201))	('adenomas', 'Disease', (166, 174))	('adenomas', 'Disease', (193, 201))	('mutation', 'Var', (102, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('aberrant', 'Var', (56, 64))	('CTNNB1', 'Gene', '1499', (95, 101))	('men', 'Species', '9606', (88, 91))	('carcinomas', 'Disease', 'MESH:D002277', (129, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('carcinomas', 'Disease', (129, 139))	('adenomas', 'Disease', 'MESH:D000236', (166, 174))
13316	26317117	The increased staining in malignancy over actually determined mutation rate in CTNNB1 was speculated to occur due to mutations in other members of the Wnt signalling pathway or via cross talk.	('mutations', 'Var', (117, 126))	('CTNNB1', 'Gene', '1499', (79, 85))	('mutation', 'Var', (62, 70))	('staining', 'MPA', (14, 22))	('CTNNB1', 'Gene', (79, 85))	('malignancy', 'Disease', 'MESH:D009369', (26, 36))	('increased', 'PosReg', (4, 13))	('malignancy', 'Disease', (26, 36))
13317	26317117	Here, we have only one determined APC mutation with membranous (intact) beta-catenin staining, and two P53 mutations, also with intact, membranous beta-catenin staining.	('beta-catenin', 'Gene', '1499', (147, 159))	('mutations', 'Var', (107, 116))	('beta-catenin', 'Gene', (72, 84))	('APC', 'Disease', 'MESH:D011125', (34, 37))	('beta-catenin', 'Gene', '1499', (72, 84))	('APC', 'Disease', (34, 37))	('P53', 'Gene', (103, 106))	('beta-catenin', 'Gene', (147, 159))	('P53', 'Gene', '7157', (103, 106))
13318	26317117	The possible function of the CTNNB1 mutation in benign and malignant adrenal cortical neoplasia is poorly understood, even as the Wnt signaling pathway is better elucidated.	('malignant adrenal cortical neoplasia', 'Disease', 'MESH:D009369', (59, 95))	('CTNNB1', 'Gene', '1499', (29, 35))	('neoplasia', 'Phenotype', 'HP:0002664', (86, 95))	('adrenal cortical neoplasia', 'Phenotype', 'HP:0100641', (69, 95))	('malignant adrenal cortical neoplasia', 'Disease', (59, 95))	('CTNNB1', 'Gene', (29, 35))	('benign', 'Disease', (48, 54))	('mutation', 'Var', (36, 44))
13319	26317117	Dysfunction of beta-catenin in malignant lesions, if physiologically relevant, is modulated by epigenetic changes within the lesion, subsequent mutations (less likely, as concomitant mutations are rarely presented in this scenario); or modification, locally or distally, of peri-Wnt signals.	('epigenetic changes', 'Var', (95, 113))	('modification', 'Reg', (236, 248))	('modulated', 'Reg', (82, 91))	('beta-catenin', 'Gene', (15, 27))	('beta-catenin', 'Gene', '1499', (15, 27))	('mutations', 'Var', (144, 153))
13320	26317117	In addition, mutations in adenomas could represent precursors for more aggressive biological behavior that has been curtailed by early intervention or without adequate follow-up.	('aggressive biological behavior', 'CPA', (71, 101))	('aggressive biological behavior', 'Phenotype', 'HP:0000718', (71, 101))	('adenomas', 'Disease', 'MESH:D000236', (26, 34))	('adenomas', 'Disease', (26, 34))	('mutations', 'Var', (13, 22))
13321	26317117	For patients in our cohort with CTNNB1 mutations and a diagnosis of an adenoma, follow up is limited (months), and now six years post-excision, there is no indication of recurrent disease.	('adenoma', 'Disease', (71, 78))	('mutations', 'Var', (39, 48))	('CTNNB1', 'Gene', '1499', (32, 38))	('patients', 'Species', '9606', (4, 12))	('adenoma', 'Disease', 'MESH:D000236', (71, 78))	('CTNNB1', 'Gene', (32, 38))
13322	26317117	However, these are the patients that would be critical to follow up long term to assess for the role of mutated beta-catenin in biological tumor behavior.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutated', 'Var', (104, 111))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('beta-catenin', 'Gene', (112, 124))	('beta-catenin', 'Gene', '1499', (112, 124))
13325	26317117	In conclusion, the findings from our study suggest that CTNNB1 mutational status may be a beneficial adjuvant to traditional morphologic evaluation of tumors of adrenal cortical origin in select cases because of their modestly greater prevalence in ACCs compared with ACAs.	('mutational status', 'Var', (63, 80))	('CTNNB1', 'Gene', '1499', (56, 62))	('tumors of adrenal cortical origin', 'Phenotype', 'HP:0100641', (151, 184))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('ACC', 'Phenotype', 'HP:0006744', (249, 252))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors of adrenal cortical', 'Disease', 'MESH:D000310', (151, 177))	('ACCs', 'Gene', '84680', (249, 253))	('CTNNB1', 'Gene', (56, 62))	('ACCs', 'Gene', (249, 253))	('tumors of adrenal cortical', 'Disease', (151, 177))	('ACA', 'Phenotype', 'HP:0008256', (268, 271))
13326	26317117	For patients harboring tumoral beta-catenin mutations and no overt features of morphologic malignancy, this cohort may benefit from closer clinical follow up.	('beta-catenin', 'Gene', (31, 43))	('beta-catenin', 'Gene', '1499', (31, 43))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutations', 'Var', (44, 53))	('malignancy', 'Disease', 'MESH:D009369', (91, 101))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (23, 28))	('malignancy', 'Disease', (91, 101))	('morphologic malignancy', 'Phenotype', 'HP:0002664', (79, 101))
13440	26013141	reported that the recurrence-free interval is nearly the same for patients with ACC who underwent surgery and received mitotane and patients who did not receive mitotane.	('mitotane', 'Chemical', 'MESH:D008939', (161, 169))	('mitotane', 'Chemical', 'MESH:D008939', (119, 127))	('ACC', 'Disease', (80, 83))	('patients', 'Species', '9606', (132, 140))	('patients', 'Species', '9606', (66, 74))	('mitotane', 'Var', (119, 127))
13452	25743702	TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in 28 ACTs (76%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (70, 74))	('mutations', 'Var', (5, 14))	('TP53', 'Gene', (70, 74))
13453	25743702	Chromosomes 11p and 17 undergo copy-neutral LOH early during tumorigenesis, suggesting tumor-driver events.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('copy-neutral LOH', 'Var', (31, 47))	('tumor', 'Disease', (61, 66))
13454	25743702	Additional genetic alterations include recurrent somatic mutations in ATRX and CTNNB1 and integration of human herpesvirus-6 in chromosome 11p.	('human herpesvirus-6', 'Species', '10368', (105, 124))	('CTNNB1', 'Gene', '1499', (79, 85))	('ATRX', 'Gene', '546', (70, 74))	('mutations', 'Var', (57, 66))	('ATRX', 'Gene', (70, 74))	('CTNNB1', 'Gene', (79, 85))
13455	25743702	A dismal outcome is predicted by concomitant TP53 and ATRX mutations and associated genomic abnormalities, including massive structural variations and frequent background mutations.	('TP53', 'Gene', (45, 49))	('background', 'MPA', (160, 170))	('ATRX', 'Gene', '546', (54, 58))	('genomic abnormalities', 'Disease', (84, 105))	('mutations', 'Var', (59, 68))	('genomic abnormalities', 'Disease', 'MESH:D042822', (84, 105))	('TP53', 'Gene', '7157', (45, 49))	('ATRX', 'Gene', (54, 58))
13456	25743702	Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in pediatric ACT and outline a hypothetical model of pediatric adrenocortical tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('pediatric adrenocortical', 'Disease', 'MESH:C565973', (178, 202))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (188, 208))	('adrenocortical tumor', 'Disease', (188, 208))	('pediatric adrenocortical', 'Disease', (178, 202))	('alterations', 'Var', (113, 124))
13460	25743702	Childhood ACT is often associated with germline TP53 mutations (Li-Fraumeni syndrome, LFS) or constitutional genetic and/or epigenetic alterations affecting chromosome 11p15 (Beckwith-Wiedemann syndrome, BWS).	('p15', 'Gene', '1030', (170, 173))	('TP53', 'Gene', '7157', (48, 52))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (175, 202))	('epigenetic alterations', 'Var', (124, 146))	('BWS', 'Disease', (204, 207))	('TP53', 'Gene', (48, 52))	('LFS', 'Disease', (86, 89))	('LFS', 'Disease', 'MESH:D016864', (86, 89))	('mutations', 'Var', (53, 62))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (64, 84))	('Beckwith-Wiedemann syndrome', 'Disease', (175, 202))	('BWS', 'Disease', 'MESH:D001506', (204, 207))	('Childhood ACT', 'Disease', (0, 13))	('associated', 'Reg', (23, 33))	('p15', 'Gene', (170, 173))	('Li-Fraumeni syndrome', 'Disease', (64, 84))
13466	25743702	Finally, a cluster of ACTs arising from a founder TP53 mutation (R337H) in southern Brazil allows biologic, prognostic and therapeutic studies in a relatively large group of cases with a common predisposing factor.	('R337H', 'Mutation', 'rs121912664', (65, 70))	('R337H', 'Var', (65, 70))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))
13471	25743702	Tumors were sporadic (n=10) or associated with constitutional cancer predisposition conditions [Brazilian founder TP53-R337H (n=12); other types of germline TP53 mutations (n=13) and BWS (n=2)] and included 29 carcinomas, 3 adenomas, and 5 tumors of undetermined malignant potential.	('TP53', 'Gene', (157, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (210, 220))	('carcinomas', 'Disease', 'MESH:D002277', (210, 220))	('TP53', 'Gene', '7157', (114, 118))	('tumors', 'Disease', (240, 246))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BWS', 'Disease', 'MESH:D001506', (183, 186))	('BWS', 'Disease', (183, 186))	('R337H', 'Mutation', 'rs121912664', (119, 124))	('associated', 'Reg', (31, 41))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('Tumors', 'Disease', (0, 6))	('cancer', 'Disease', (62, 68))	('TP53', 'Gene', '7157', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('carcinomas', 'Disease', (210, 220))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('adenomas', 'Disease', 'MESH:D000236', (224, 232))	('TP53', 'Gene', (114, 118))	('adenomas', 'Disease', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('mutations', 'Var', (162, 171))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
13477	25743702	All genetic lesions, including single nucleotide variations (SNV), small insertions/deletions (indels) and structural variations (SVs) were experimentally validated (Supplementary Fig.	('genetic lesions', 'Disease', (4, 19))	('structural variations', 'Var', (107, 128))	('genetic lesions', 'Disease', 'MESH:D020022', (4, 19))	('single nucleotide variations', 'Var', (31, 59))
13479	25743702	Germline TP53 mutations were present in 25 of the 37 patients (68%) in the combined WGS and WES cohorts, 12 of which were the Brazilian founder R337H mutation (Fig.	('R337H', 'Mutation', 'rs121912664', (144, 149))	('patients', 'Species', '9606', (53, 61))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
13480	25743702	Somatic mutations (R175H, R273C, and a homozygous deletion of ~200 Kb of chromosome 17 encompassing TP53) were also identified in 3 of the 12 ACTs associated with wild-type germline TP53 (Supplementary Figs.	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', '7157', (182, 186))	('R273C', 'Mutation', 'rs121913343', (26, 31))	('TP53', 'Gene', (182, 186))	('TP53', 'Gene', (100, 104))	('R175H', 'Mutation', 'rs28934578', (19, 24))	('R273C', 'Var', (26, 31))	('R175H', 'Var', (19, 24))
13481	25743702	Sanger sequencing identified germline TP53 mutations in 11 of 34 cases (32%) in the independent comparison cohort (Supplementary Table 1c).	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', '7157', (38, 42))
13482	25743702	Of the 23 ACTs in this group associated with germline wild-type TP53, three tumors acquired a TP53 mutation (c.134_135 insT, E180K and R273H) (Supplementary Fig.	('c.134_135 insT', 'Mutation', 'c.134_135insT', (109, 123))	('R273H', 'Var', (135, 140))	('R273H', 'Mutation', 'rs28934576', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('TP53', 'Gene', '7157', (94, 98))	('E180K', 'Var', (125, 130))	('TP53', 'Gene', (94, 98))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('c.134_135 insT', 'Var', (109, 123))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('E180K', 'Mutation', 'rs879253911', (125, 130))
13484	25743702	ATRX somatic nonsense mutations and SVs deleting multiple exons were identified by WGS in 6 of 19 ACTs (32%), all of which were associated with germline TP53 mutations (Figs.	('nonsense mutations', 'Var', (13, 31))	('ATRX', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (153, 157))	('associated', 'Reg', (128, 138))	('ATRX', 'Gene', '546', (0, 4))	('TP53', 'Gene', (153, 157))	('mutations', 'Var', (158, 167))
13485	25743702	An ATRX somatic missense mutation (R2164S) was also identified by WES in the case with somatic homozygous deletion of TP53 (Fig.	('R2164S', 'Var', (35, 41))	('ATRX', 'Gene', (3, 7))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('ATRX', 'Gene', '546', (3, 7))	('R2164S', 'Mutation', 'p.R2164S', (35, 41))
13489	25743702	WGS-based telomere length analysis showed an increase of telomeric DNA in all 6 tumors with ATRX mutations, but not in tumors with wild-type ATRX (P = 3.7 x 10-5, Fisher's exact test) (Fig.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('ATRX', 'Gene', (92, 96))	('mutations', 'Var', (97, 106))	('tumors', 'Disease', (119, 125))	('telomeric DNA', 'MPA', (57, 70))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('ATRX', 'Gene', '546', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('ATRX', 'Gene', (141, 145))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ATRX', 'Gene', '546', (141, 145))	('increase', 'PosReg', (45, 53))
13491	25743702	2d) in cases harboring ATRX mutations (n=5), suggesting the activation of an alternative lengthening of telomeres (ALT) mechanism.	('ATRX', 'Gene', '546', (23, 27))	('ATRX', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
13492	25743702	Telomere foci were also observed in the SJACT023 tumor, although WES did not detect an ATRX mutation.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('observed', 'Reg', (24, 32))	('tumor', 'Disease', (49, 54))	('ATRX', 'Gene', (87, 91))	('Telomere foci', 'MPA', (0, 13))	('SJACT023', 'Var', (40, 48))	('ATRX', 'Gene', '546', (87, 91))
13493	25743702	Somatic beta-catenin (CTNNB1) mutations were identified in 3 of the 37 (8%) tumors analyzed in the combined WGS and WES cohorts (Fig.	('CTNNB1', 'Gene', (22, 28))	('identified', 'Reg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CTNNB1', 'Gene', '1499', (22, 28))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (30, 39))
13494	25743702	Targeted Sanger sequencing of CTNNB1 exon 3 revealed 10 additional somatic mutations in 34 pediatric ACTs in the independent comparison cohort (Supplementary Fig.	('CTNNB1', 'Gene', '1499', (30, 36))	('mutations', 'Var', (75, 84))	('CTNNB1', 'Gene', (30, 36))
13495	25743702	Overall, CTNNB1 mutations (n=13) were detected only in tumors with wild-type germline TP53 (n=35) and not in those with constitutional TP53 mutations (n=36) (P = 2.5 x 10-5, Fisher's exact test).	('TP53', 'Gene', '7157', (86, 90))	('CTNNB1', 'Gene', '1499', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('TP53', 'Gene', '7157', (135, 139))	('mutations', 'Var', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('TP53', 'Gene', (86, 90))	('tumors', 'Disease', (55, 61))	('TP53', 'Gene', (135, 139))	('CTNNB1', 'Gene', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (55, 61))
13496	25743702	However, three tumors with somatic CTNNB1 mutations had also acquired a TP53 mutation (IPACTR001, IPACTR013 and IPACTR019) (Supplementary Fig.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('CTNNB1', 'Gene', '1499', (35, 41))	('TP53', 'Gene', '7157', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('TP53', 'Gene', (72, 76))	('CTNNB1', 'Gene', (35, 41))	('mutations', 'Var', (42, 51))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
13497	25743702	WGS defined three groups of pediatric ACT based on the mutational status of TP53 and ATRX: Group 1) germline TP53 and somatic ATRX mutations (n=6); Group 2) germline TP53 mutations and no ATRX mutation (n=9); and Group 3) both wild-type TP53 and ATRX (n=4) (Fig.	('mutations', 'Var', (131, 140))	('ATRX', 'Gene', (246, 250))	('ATRX', 'Gene', (85, 89))	('TP53', 'Gene', '7157', (237, 241))	('ATRX', 'Gene', (126, 130))	('ATRX', 'Gene', '546', (246, 250))	('TP53', 'Gene', (237, 241))	('ATRX', 'Gene', '546', (188, 192))	('TP53', 'Gene', '7157', (166, 170))	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', '7157', (109, 113))	('ATRX', 'Gene', '546', (85, 89))	('TP53', 'Gene', (76, 80))	('TP53', 'Gene', (109, 113))	('TP53', 'Gene', (166, 170))	('ATRX', 'Gene', '546', (126, 130))	('mutations', 'Var', (171, 180))	('ATRX', 'Gene', (188, 192))
13500	25743702	Although all cases in Group 2 carried germline TP53 mutations (8 of 9 cases had the founder R337H mutation and were diagnosed in southern Brazil), they displayed variable clinical findings.	('mutations', 'Var', (52, 61))	('TP53', 'Gene', '7157', (47, 51))	('R337H', 'Mutation', 'rs121912664', (92, 97))	('R337H', 'Var', (92, 97))	('TP53', 'Gene', (47, 51))
13501	25743702	Group 2 patients with the R337H mutation were young (median age, 30 months), exhibited signs of virilization and had relatively small tumors [median tumor weight 68 g vs 585 g in Group 1 (P < 0.006, Wilcoxon rank sum test)].	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('exhibited', 'Reg', (77, 86))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('R337H', 'Mutation', 'rs121912664', (26, 31))	('R337H', 'Var', (26, 31))	('patients', 'Species', '9606', (8, 16))
13503	25743702	A distinguishing feature of this group is the lack of ATRX mutations and the shortening of telomeres as compared to Group 1.	('ATRX', 'Gene', '546', (54, 58))	('lack', 'NegReg', (46, 50))	('mutations', 'Var', (59, 68))	('shortening of telomeres', 'Phenotype', 'HP:0031413', (77, 100))	('shortening', 'NegReg', (77, 87))	('ATRX', 'Gene', (54, 58))
13506	25743702	However, R337H tumors that had acquired an ATRX mutation (cases SJACT062 and SJACT069) clustered in Group 1 and exhibited an aggressive phenotype (Figs.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('ATRX', 'Gene', '546', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('R337H', 'Var', (9, 14))	('R337H', 'Mutation', 'rs121912664', (9, 14))	('exhibited', 'Reg', (112, 121))	('ATRX', 'Gene', (43, 47))	('tumors', 'Disease', (15, 21))
13509	25743702	All tumors with germline (n=25) and somatic (n=3) TP53 mutations underwent LOH with selection against the wild-type allele (Supplementary Fig.	('mutations', 'Var', (55, 64))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
13510	25743702	More specifically, WGS demonstrated copy-neutral LOH (cn-LOH) of the entire chromosome 17 in all tumors associated with germline TP53 mutations (n=15), as well as in two (SJACT003, SJATC004) of the four cases with wild-type TP53 (Supplementary Fig.	('TP53', 'Gene', (224, 228))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TP53', 'Gene', '7157', (129, 133))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (134, 143))	('TP53', 'Gene', (129, 133))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('TP53', 'Gene', '7157', (224, 228))
13511	25743702	Two BWS patients (SJACT009 and SJACT065) with germline 11p homozygosity, indicative of uniparental disomy (UPD), were excluded from the analysis as LOH could not be assessed (Supplementary Fig.	('UPD', 'Disease', (107, 110))	('SJACT065', 'Var', (31, 39))	('uniparental disomy', 'Disease', (87, 105))	('UPD', 'Disease', 'MESH:D024182', (107, 110))	('BWS', 'Disease', (4, 7))	('uniparental disomy', 'Disease', 'MESH:D024182', (87, 105))	('BWS', 'Disease', 'MESH:D001506', (4, 7))	('patients', 'Species', '9606', (8, 16))
13521	25743702	These findings indicate that cn-LOH of chromosomes 11p and 17p occurs early in adrenocortical tumorigenesis and precedes the accumulation of SNVs in these regions.	('cn-LOH', 'Var', (29, 35))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (79, 99))	('adrenocortical tumor', 'Disease', (79, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))
13524	25743702	PCR analysis demonstrated paternal transmission of chromosomally integrated HHV6 in SJACT017 (Fig.	('HHV6', 'Gene', (76, 80))	('HHV6', 'Species', '10368', (76, 80))	('chromosomally integrated', 'Var', (51, 75))
13525	25743702	Microsatellite marker analysis and WGS confirmed chromosome 11 LOH with retention of integrated HHV6 in both cases (Supplementary Fig.	('HHV6', 'Gene', (96, 100))	('LOH', 'Var', (63, 66))	('HHV6', 'Species', '10368', (96, 100))
13528	25743702	Deletion of chromosome 4q34 was observed in 11 of 19 tumors (58%) (Supplementary Fig.	('observed', 'Reg', (32, 40))	('19 tumors', 'Disease', (50, 59))	('19 tumors', 'Disease', 'MESH:D009369', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('Deletion', 'Var', (0, 8))
13532	25743702	Although pediatric ACT is strongly associated with germline TP53 mutations (60-70% of children with ACT), only 4-6% of carriers develop adrenocortical tumors, suggesting the involvement of cooperating genetic alterations.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (136, 157))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('children', 'Species', '9606', (86, 94))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('associated', 'Reg', (35, 45))	('germline', 'Var', (51, 59))	('TP53', 'Gene', '7157', (60, 64))	('develop', 'Reg', (128, 135))	('adrenocortical tumors', 'Disease', (136, 157))	('ACT', 'Disease', (19, 22))	('TP53', 'Gene', (60, 64))
13533	25743702	We propose that germline TP53 mutations may contribute to adrenocortical tumorigenesis by promoting chromosomal instability.	('adrenocortical tumor', 'Disease', (58, 78))	('TP53', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('contribute', 'Reg', (44, 54))	('chromosomal instability', 'Phenotype', 'HP:0040012', (100, 123))	('promoting', 'PosReg', (90, 99))	('mutations', 'Var', (30, 39))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (58, 78))	('chromosomal instability', 'MPA', (100, 123))	('TP53', 'Gene', '7157', (25, 29))
13534	25743702	In this setting, aneuploid adrenocortical cells that experience chromosome 11p LOH and deregulation of imprinted genes on 11p15 may be selected and expanded via constitutive overexpression of IGF2, which encodes a potent mitogen and fetal growth-promoting protein.	('deregulation', 'Var', (87, 99))	('overexpression', 'PosReg', (174, 188))	('p15', 'Gene', (124, 127))	('aneuploid adrenocortical', 'Disease', 'MESH:D000782', (17, 41))	('aneuploid adrenocortical', 'Disease', (17, 41))	('p15', 'Gene', '1030', (124, 127))	('IGF2', 'Gene', (192, 196))
13535	25743702	This mechanism is consistent with chromosome 11p abnormalities and IGF2 overexpression in all cases of ACT with germline TP53 mutations.	('chromosome 11p abnormalities', 'Disease', 'MESH:C541598', (34, 62))	('TP53', 'Gene', '7157', (121, 125))	('chromosome 11p abnormalities', 'Disease', (34, 62))	('TP53', 'Gene', (121, 125))	('mutations', 'Var', (126, 135))
13537	25743702	In support of this hypothesis, our temporal studies place cn-LOH of chromosomes 11p and 17 during early tumorigenesis, before the acquisition of widespread genomic alterations.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('cn-LOH', 'Var', (58, 64))
13540	25743702	Our genomic studies showed that some cases with the R337H mutation had secondary genetic events that were similar to those seen with other types of TP53 mutations, such as concomitant cn-LOH of chromosomes 11 and 17p early during tumorigenesis, as well as the deregulation of IGF2 expression and acquired ATRX mutations.	('tumor', 'Disease', (230, 235))	('deregulation', 'Var', (260, 272))	('ATRX', 'Gene', (305, 309))	('TP53', 'Gene', '7157', (148, 152))	('R337H', 'Mutation', 'rs121912664', (52, 57))	('TP53', 'Gene', (148, 152))	('R337H', 'Var', (52, 57))	('IGF2', 'Gene', (276, 280))	('ATRX', 'Gene', '546', (305, 309))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('expression', 'MPA', (281, 291))
13541	25743702	These findings are consistent with those from high-density SNP analysis that demonstrated the pattern of gains and losses is similar in pediatric ACTs with R337H and other TP53 mutations.	('losses', 'NegReg', (115, 121))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('gains', 'PosReg', (105, 110))	('R337H', 'Mutation', 'rs121912664', (156, 161))	('R337H', 'Var', (156, 161))
13542	25743702	However other cases with R337H mutations had much simpler genomes similar to those with wild type TP53.	('R337H', 'Var', (25, 30))	('R337H', 'Mutation', 'rs121912664', (25, 30))	('TP53', 'Gene', '7157', (98, 102))	('TP53', 'Gene', (98, 102))
13548	25743702	Consistent with these findings, CTNNB1-activating mutations were relatively frequent in our cohort, particularly in cases with germline wild- type TP53.	('TP53', 'Gene', (147, 151))	('mutations', 'Var', (50, 59))	('CTNNB1', 'Gene', '1499', (32, 38))	('TP53', 'Gene', '7157', (147, 151))	('CTNNB1', 'Gene', (32, 38))
13550	25743702	Remarkably, 11p15 LOH involving the IGF2 locus was observed in both pediatric ACT (91%) and adult ACC (82%), underscoring the critical role of deregulated IGF2 expression in adrenal cortex tumorigenesis.	('tumor', 'Disease', (189, 194))	('IGF2', 'Gene', (155, 159))	('deregulated', 'Var', (143, 154))	('IGF2', 'Gene', (36, 40))	('p15', 'Gene', (14, 17))	('p15', 'Gene', '1030', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
13551	25743702	Aneuploidy with widespread chromosomal gains (e.g., chromosome 19) and deletions (e.g., 4q34.3) was also observed in both pediatric and adult cases.	('deletions', 'Var', (71, 80))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('Aneuploidy', 'Disease', (0, 10))
13552	25743702	However, amplification of chromosome 9q, a region that includes NOTCH1 and NR5A1 (Steroidogenic Factor-1), occurred in 90% of pediatric ACTs (Supplementary Fig.	('occurred', 'Reg', (107, 115))	('amplification', 'Var', (9, 22))	('NOTCH1', 'Gene', '4851', (64, 70))	('NOTCH1', 'Gene', (64, 70))	('NR5A1', 'Gene', (75, 80))	('Steroidogenic Factor-1', 'Gene', '2516', (82, 104))	('pediatric ACTs', 'Disease', (126, 140))	('NR5A1', 'Gene', '2516', (75, 80))	('Steroidogenic Factor-1', 'Gene', (82, 104))
13553	25743702	Activating mutations in CTNNB1 were common to both pediatric and adult ACT, but additional mutations within the Wnt/beta-catenin signaling pathway, in particular ZNRF3, were only observed in adult tumors.	('mutations', 'Var', (11, 20))	('Activating', 'PosReg', (0, 10))	('adult tumors', 'Disease', (191, 203))	('CTNNB1', 'Gene', (24, 30))	('adult tumors', 'Disease', 'MESH:C538052', (191, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('ZNRF3', 'Gene', '84133', (162, 167))	('CTNNB1', 'Gene', '1499', (24, 30))	('ZNRF3', 'Gene', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))
13554	25743702	Germline TP53 mutations were predominantly associated with pediatric ACT, whereas somatic TP53 mutations were relatively infrequent in both groups.	('pediatric ACT', 'Disease', (59, 72))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('TP53', 'Gene', (90, 94))	('associated', 'Reg', (43, 53))	('mutations', 'Var', (14, 23))
13555	25743702	The alternative lengthening of telomeres (ALT phenotype) was associated with DAXX or ATRX mutations in adult tumors, but exclusively with ATRX mutations in pediatric cases.	('ATRX', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('adult tumors', 'Disease', 'MESH:C538052', (103, 115))	('DAXX', 'Gene', '1616', (77, 81))	('ATRX', 'Gene', (138, 142))	('ATRX', 'Gene', '546', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('adult tumors', 'Disease', (103, 115))	('ATRX', 'Gene', '546', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('DAXX', 'Gene', (77, 81))
13556	25743702	Amplification of TERT was common in both groups, but no TERT mutations were detected in the pediatric cases, consistent with the absence of TERT expression.	('Amplification', 'Var', (0, 13))	('TERT', 'Gene', (17, 21))	('TERT', 'Gene', (140, 144))	('TERT', 'Gene', '7015', (17, 21))	('TERT', 'Gene', '7015', (140, 144))	('TERT', 'Gene', (56, 60))	('TERT', 'Gene', '7015', (56, 60))
13563	25743702	Notably, tumors with both germline TP53 and somatic ATRX mutations (Group 1) were significantly associated with high tumor weight, advanced disease (COG stage III/IV), and poor event-free survival.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('advanced disease', 'Disease', (131, 147))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('associated', 'Reg', (96, 106))	('tumor', 'Disease', (117, 122))	('TP53', 'Gene', '7157', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('TP53', 'Gene', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (9, 14))	('mutations', 'Var', (57, 66))	('ATRX', 'Gene', (52, 56))	('tumors', 'Disease', (9, 15))	('poor', 'NegReg', (172, 176))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('ATRX', 'Gene', '546', (52, 56))
13566	25743702	Cases with germline TP53 mutations and wild-type ATRX (Group 2) are clinically and molecularly heterogeneous.	('mutations', 'Var', (25, 34))	('TP53', 'Gene', (20, 24))	('ATRX', 'Gene', (49, 53))	('ATRX', 'Gene', '546', (49, 53))	('TP53', 'Gene', '7157', (20, 24))
13567	25743702	Although all cases in this group carried TP53 mutations (8 of 9 cases harbor the founder R337H), they had fewer genomic abnormalities, smaller tumors and generally much better clinical outcome than cases in Group 1.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('R337H', 'Var', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (46, 55))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('genomic abnormalities', 'Disease', (112, 133))	('fewer', 'NegReg', (106, 111))	('genomic abnormalities', 'Disease', 'MESH:D042822', (112, 133))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('R337H', 'Mutation', 'rs121912664', (89, 94))
13570	25743702	The two cases with R337H required chemotherapy because of advanced stage disease in one and tumor rupture in the other.	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('R337H', 'Var', (19, 24))	('R337H', 'Mutation', 'rs121912664', (19, 24))	('tumor rupture', 'Disease', 'MESH:D012421', (92, 105))	('tumor rupture', 'Disease', (92, 105))
13571	25743702	The patient with the G245C, a child more than 10 years of age at diagnosis of ACT, had delayed diagnosis of a very large tumor in the absence of endocrine signs (a "non-functional" tumor).	('G245C', 'Mutation', 'rs28934573', (21, 26))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('G245C', 'Var', (21, 26))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', (121, 126))	('child', 'Species', '9606', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
13581	25743702	In summary, our study identified key genetic alterations and their temporal relationships in pediatric adrenocortical tumorigenesis.	('pediatric adrenocortical', 'Disease', (93, 117))	('adrenocortical tumor', 'Disease', (103, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('genetic alterations', 'Var', (37, 56))	('pediatric adrenocortical', 'Disease', 'MESH:C565973', (93, 117))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (103, 123))
13582	25743702	The genomic complexity of childhood ACTs, particularly those with both germline TP53 and acquired ATRX mutations, may explain the failure of standard chemotherapy, underscoring the importance of early diagnosis and improved prognostic classification.	('germline', 'Var', (71, 79))	('mutations', 'Var', (103, 112))	('ATRX', 'Gene', (98, 102))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('ATRX', 'Gene', '546', (98, 102))	('child', 'Species', '9606', (26, 31))	('childhood ACTs', 'Disease', (26, 40))
13590	25743702	An additional group of 34 IPACTR patients with matched primary tumor and blood samples, and blood-derived DNA from 23 sets of parents, were included for analysis of chromosome 11p LOH, TP53 and CTNNB1 mutation.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('patients', 'Species', '9606', (33, 41))	('TP53', 'Gene', (185, 189))	('CTNNB1', 'Gene', '1499', (194, 200))	('mutation', 'Var', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('CTNNB1', 'Gene', (194, 200))	('TP53', 'Gene', '7157', (185, 189))
13593	25743702	For germline heterogeneous SNPs, loss of heterozygosity (LOH) measures the absolute difference between the mutant allele fraction in tumor and that in germline sample (0.5).	('mutant', 'Var', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('loss of heterozygosity', 'NegReg', (33, 55))	('tumor', 'Disease', (133, 138))
13594	25743702	LOH is the result of copy number alterations and/or cn-LOH in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('copy number alterations', 'Var', (21, 44))	('tumor', 'Disease', (62, 67))	('LOH', 'Disease', (0, 3))	('result', 'Reg', (11, 17))	('cn-LOH', 'CPA', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
13595	25743702	Compared to copy number gains (a single copy gain in 100% tumor results in a LOH value of 0.167), regions with copy number loss showed stronger LOH (a single copy loss in 100% tumor result in a LOH value of 0.5).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('copy number loss', 'Var', (111, 127))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('LOH', 'NegReg', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
13596	25743702	Consequently, we used LOH signals in copy neutral or heterozygous copy number loss regions (CNA value between [-1, 0]) to estimate tumor purity for all WGS samples.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('loss', 'NegReg', (78, 82))	('copy number', 'Var', (66, 77))
13597	25743702	Briefly, a single copy loss in x% tumor cells resulted in an estimated CNA value of   and a LOH value of  .	('tumor', 'Disease', (34, 39))	('CNA value', 'CPA', (71, 80))	('LOH', 'NegReg', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('single copy loss', 'Var', (11, 27))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
13598	25743702	Assuming the remaining LOH signal came from cn-LOH (cn-LOH in x% tumor cell resulted in a LOH value of  ), the tumor content in a region could be estimated as the sum of the fraction with copy number loss and the fraction with cn-LOH by:  .	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('copy number loss', 'Var', (188, 204))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
13605	25743702	Tier 1: Coding synonymous, nonsynonymous, and splice-site variants and non-coding RNA variants Tier 2: Conserved variants (cutoff conservation score >= 500, based on either the phastConsElements28way table or the phastConsElements17way table from the UCSC genome browser [http://genome.ucsc.edu/] and variants in regulatory regions annotated by UCSC annotation [regulatory annotations included targetScanS, ORegAnno, tfbsConsSites, vistaEnhancers,eponine, firstEF, L1 TAF1 Valid, Poly(A), switchDbTss, encodeUViennaRnaz, laminB1, and cpgIslandExt]) Tier 3: Variants in non-repeat masked regions.	('Variants', 'Var', (557, 565))	('laminB1', 'Gene', '4001', (521, 528))	('laminB1', 'Gene', (521, 528))
13606	25743702	DNA from diagnostic tumor samples and matched germline samples was used for each primer set to confirm the presence of the SNV/indel in the diagnostic sample.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('SNV/indel', 'Var', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
13611	25743702	We identified significantly amplified genes as those with segments of gain or loss (SGOL) scores 3 standard deviations above the mean SGOL scores of all "gains".	('gain or loss', 'Disease', 'MESH:D015430', (70, 82))	('gain or loss', 'Disease', (70, 82))	('scores', 'Var', (90, 96))
13619	25743702	Fluorescence PCR semi- automated genotyping was used to detect and analyze allelic losses by using a panel of 5 microsatellite markers (D11S1363, D11S922, D11S4046, HUMTH01 and D11S988).	('D11S1363', 'Var', (136, 144))	('D11S4046', 'Var', (155, 163))	('D11S988', 'Var', (177, 184))	('HUMTH01', 'CellLine', 'CVCL:9726', (165, 172))	('S988', 'CellLine', 'CVCL:V789', (180, 184))	('HUMTH01', 'Var', (165, 172))	('D11S922', 'Var', (146, 153))
13620	25743702	To detect and validate TP53 and CTNNB1 mutations, genomic DNA from ACT samples was tested by PCR-based bi-directional DNA sequencing of exons 2-11 and intron-exon boundaries for TP53 and exon 3 (codons 5-70) for CTNNB1.	('TP53', 'Gene', '7157', (178, 182))	('TP53', 'Gene', (178, 182))	('CTNNB1', 'Gene', (212, 218))	('mutations', 'Var', (39, 48))	('CTNNB1', 'Gene', '1499', (32, 38))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('CTNNB1', 'Gene', '1499', (212, 218))	('CTNNB1', 'Gene', (32, 38))
13664	24765408	CO2 insufflation of the abdomen during laparoscopy may cause spread of the tumor cells with subsequent peritoneal carcinomatosis.	('carcinomatosis', 'Disease', 'MESH:D002277', (114, 128))	('men', 'Species', '9606', (28, 31))	('carcinomatosis', 'Disease', (114, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('CO2', 'Var', (0, 3))	('spread', 'CPA', (61, 67))	('CO2', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('insufflation', 'Disease', (4, 16))	('cause', 'Reg', (55, 60))	('tumor', 'Disease', (75, 80))	('insufflation', 'Disease', 'None', (4, 16))
13825	21067996	The presence of macroscopic fat in an adrenal mass has classically been associated with a myelolipoma.	('myelolipoma', 'Disease', (90, 101))	('presence', 'Var', (4, 12))	('associated', 'Reg', (72, 82))	('myelolipoma', 'Disease', 'MESH:D018209', (90, 101))
13840	21067996	Although other rare macroscopic fat-containing lesions have been shown to occur in the adrenal gland (including primary adrenal lipomas, liposarcomas, collision tumors, teratomas, and potentially pheochromocytomas), the presence of macroscopic fat in an adrenal lesion has classically been described as virtually diagnostic of an adrenal myelolipoma.	('collision tumors', 'Disease', 'MESH:D009369', (151, 167))	('teratomas', 'Disease', (169, 178))	('adrenal myelolipoma', 'Disease', 'MESH:D018209', (330, 349))	('adrenal lesion', 'Disease', 'MESH:D000307', (254, 268))	('pheochromocytomas', 'Disease', (196, 213))	('pheochromocytomas', 'Disease', 'MESH:D010673', (196, 213))	('macroscopic fat', 'Var', (232, 247))	('liposarcomas', 'Disease', 'MESH:D008080', (137, 149))	('lipomas', 'Phenotype', 'HP:0012032', (128, 135))	('presence', 'Var', (220, 228))	('adrenal lipomas', 'Disease', (120, 135))	('liposarcomas', 'Phenotype', 'HP:0012034', (137, 149))	('collision tumors', 'Disease', (151, 167))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (196, 213))	('teratomas', 'Phenotype', 'HP:0009792', (169, 178))	('adrenal lesion', 'Disease', (254, 268))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('adrenal myelolipoma', 'Disease', (330, 349))	('liposarcomas', 'Disease', (137, 149))	('teratomas', 'Disease', 'MESH:D013724', (169, 178))	('adrenal lipomas', 'Disease', 'MESH:D008067', (120, 135))
13849	21067996	Although the presence of macroscopic fat within an adrenal lesion is much more likely to represent a benign adrenal lesion such as a myelolipoma, adrenocortical carcinoma should be included in the differential diagnosis when additional features suggesting malignancy are noted, particularly in the presence of a large heterogeneous mass with a heterogeneous predominantly peripheral enhancement.	('adrenal lesion', 'Disease', (51, 65))	('adrenal lesion', 'Disease', 'MESH:D000307', (51, 65))	('adrenal lesion', 'Disease', 'MESH:D000307', (108, 122))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (146, 170))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (146, 170))	('benign adrenal lesion', 'Disease', 'MESH:D000307', (101, 122))	('presence', 'Var', (13, 21))	('myelolipoma', 'Disease', 'MESH:D018209', (133, 144))	('myelolipoma', 'Disease', (133, 144))	('malignancy', 'Disease', 'MESH:D009369', (256, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('benign adrenal lesion', 'Disease', (101, 122))	('malignancy', 'Disease', (256, 266))	('adrenocortical carcinoma', 'Disease', (146, 170))
13853	20157589	In the nematode C. elegans, disruption of either conjugation or oxidation of 4-HNE leads to fat accumulation, whereas augmentation of 4-HNE conjugation results in a lean phenotype.	('disruption', 'Var', (28, 38))	('conjugation', 'MPA', (49, 60))	('lean phenotype', 'MPA', (165, 179))	('C. elegans', 'Species', '6239', (16, 26))	('fat accumulation', 'MPA', (92, 108))
13859	20157589	In this paper, we present evidence for a biochemical mechanism by which 4-HNE could trigger increased lipid storage, and discuss possible adaptive and maladaptive roles of the self-reinforcing loop that involves triglycerides and 4-HNE, in particular, in the context of aging.	('lipid storage', 'MPA', (102, 115))	('increased lipid', 'Phenotype', 'HP:0003077', (92, 107))	('increased', 'PosReg', (92, 101))	('4-HNE', 'Var', (72, 77))	('triglycerides', 'Chemical', 'MESH:D014280', (212, 225))
13860	20157589	Expression of the gst-10 gene product, which is capable of conjugating 4-HNE, is inversely related to the level of whole-body 4-HNE-protein adducts  As we have previously shown, the capacity of C. elegans to conjugate 4-HNE with glutathione was reduced by RNAi-mediated knockdown of CeGSTP2-2, the product of the gst-10 gene.	('gst-10', 'Gene', '178725', (313, 319))	('gst-10', 'Gene', '178725', (18, 24))	('gst-10', 'Gene', (313, 319))	('gst-10', 'Gene', (18, 24))	('knockdown', 'Var', (270, 279))	('conjugate', 'MPA', (208, 217))	('CeGSTP2-2', 'Gene', (283, 292))	('reduced', 'NegReg', (245, 252))	('glutathione', 'Chemical', 'MESH:D005978', (229, 240))
13891	20157589	Following staining, worms were washed for 4 x 10 min with M9 buffer [6 g Na2HPO4, 3 g KH2PO4, 5 g NaCl and 0.25 g MgSO4 7H2O per liter; ref.	('Na2HPO4', 'Var', (73, 80))	('MgSO4 7H2O', 'Chemical', 'MESH:D008278', (114, 124))	('KH2PO4', 'Chemical', '-', (86, 92))	('M9 buffer', 'Chemical', '-', (58, 67))	('KH2PO4', 'Var', (86, 92))	('Na2HPO4', 'Chemical', 'MESH:C018279', (73, 80))
13926	19773375	Despite of the inhibition of the VEGF receptor, sunitinib leads to a compensatory plasma VEGF increase and may leave tumors exposed to VEGF effects during the 2 week off period of each cycle.	('inhibition', 'NegReg', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('VEGF receptor', 'Gene', (33, 46))	('sunitinib', 'Var', (48, 57))	('sunitinib', 'Chemical', 'MESH:D000077210', (48, 57))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('increase', 'PosReg', (94, 102))	('tumors', 'Disease', (117, 123))	('leave', 'Reg', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('plasma VEGF', 'MPA', (82, 93))	('VEGF receptor', 'Gene', '3791', (33, 46))
13929	19773375	Patients were required to have a Karnofsky performance status of >= 60% and adequate bone marrow, hepatic and renal function (as defined by granulocytes >= 1,500/microL, hemoglobin >=10.0 g/dL, platelet count >= 100,000/L, AST/ALT <= 2.5 x upper limit of normal (ULN), serum bilirubin <= 1.5 x ULN, urine protein creatinine (UPC) ratio as determined by urinalysis < 0.5 (for UPC ratio > 0.5, 24-hour urine protein must have been <1 gram) and serum creatinine <= 1.5 x ULN).	('serum bilirubin', 'MPA', (269, 284))	('urine protein', 'Phenotype', 'HP:0000093', (400, 413))	('bilirubin', 'Chemical', 'MESH:D001663', (275, 284))	('AST', 'Gene', (223, 226))	('urine protein creatinine', 'MPA', (299, 323))	('Patients', 'Species', '9606', (0, 8))	('AST', 'Gene', '26503', (223, 226))	('>=10.0', 'Var', (181, 187))	('urine protein', 'Phenotype', 'HP:0000093', (299, 312))
14001	19773375	VEGF gene deletion in a murine model lead to glomerular fibrin deposits and intracapillary thrombi.	('glomerular fibrin deposits', 'Phenotype', 'HP:0030949', (45, 71))	('intracapillary thrombi', 'Disease', (76, 98))	('VEGF gene', 'Gene', (0, 9))	('lead to', 'Reg', (37, 44))	('murine', 'Species', '10090', (24, 30))	('glomerular fibrin deposits', 'CPA', (45, 71))	('deletion', 'Var', (10, 18))	('intracapillary thrombi', 'Disease', 'MESH:D003928', (76, 98))
14005	19773375	It can be hypothesized that more complete VEGF blockade with combination therapy may lead to more severe renal TMA, and further to more widespread endothelial damage creating a thrombogenic endothelium.	('VEGF', 'Protein', (42, 46))	('TMA', 'Disease', 'MESH:D000783', (111, 114))	('blockade', 'Var', (47, 55))	('lead', 'Reg', (85, 89))	('TMA', 'Disease', (111, 114))
14015	19338683	One particular CHEK2 germline mutation, c.1100delC, has been shown to be associated with elevated breast cancer risk.	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('elevated breast cancer', 'Disease', 'MESH:D001943', (89, 111))	('elevated breast cancer', 'Disease', (89, 111))	('CHEK2', 'Gene', '11200', (15, 20))	('c.1100delC', 'Mutation', 'rs555607708', (40, 50))	('CHEK2', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('c.1100delC', 'Var', (40, 50))
14017	19338683	The question remains nevertheless whether CHEK2 germline mutations contribute to the Li-Fraumeni phenotype.	('CHEK2', 'Gene', '11200', (42, 47))	('Li-Fraumeni', 'Disease', (85, 96))	('CHEK2', 'Gene', (42, 47))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (85, 96))	('germline', 'Var', (48, 56))	('contribute', 'Reg', (67, 77))
14019	19338683	We identified six index patients with a CHEK2 sequence variant, four with the c.1100delC variant and two sequence variants of unknown significance, p.Phe328Ser and c.1096-?_1629+?del.	('c.1100delC', 'Var', (78, 88))	('p.Phe328Ser', 'Var', (148, 159))	('c.1096-?_1629+?del', 'Mutation', 'c.1096-?_1629+?del', (164, 182))	('c.1100delC', 'Mutation', 'rs555607708', (78, 88))	('CHEK2', 'Gene', '11200', (40, 45))	('patients', 'Species', '9606', (24, 32))	('p.Phe328Ser', 'Mutation', 'rs748839289', (148, 159))	('CHEK2', 'Gene', (40, 45))	('c.1096-?_1629+?del', 'Var', (164, 182))
14029	19338683	At present, in approximately 75% of LFS and 40% of LFL families, a germline TP53 mutation can be detected; i.e.	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))	('mutation', 'Var', (81, 89))
14033	19338683	Subsequent studies have addressed the possible contribution of CHEK2 germline mutations to LFS and LFL syndrome, but could not confirm CHEK2 as a major gene involved in LFS.	('CHEK2', 'Gene', (63, 68))	('LFL syndrome', 'Disease', (99, 111))	('LFL syndrome', 'Disease', 'MESH:D016864', (99, 111))	('CHEK2', 'Gene', '11200', (135, 140))	('CHEK2', 'Gene', (135, 140))	('germline mutations', 'Var', (69, 87))	('CHEK2', 'Gene', '11200', (63, 68))	('LFS', 'Disease', (91, 94))
14034	19338683	In other studies, the specific CHEK2 c.1100delC frameshift mutation was shown to be associated with an elevated breast cancer risk and it has been suggested that it contributes to a hereditary breast and colorectal cancer phenotype.	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('hereditary breast and colorectal cancer', 'Disease', 'MESH:D015179', (182, 221))	('CHEK2', 'Gene', '11200', (31, 36))	('contributes', 'Reg', (165, 176))	('c.1100delC', 'Mutation', 'rs555607708', (37, 47))	('elevated breast cancer', 'Disease', (103, 125))	('CHEK2', 'Gene', (31, 36))	('colorectal cancer', 'Phenotype', 'HP:0003003', (204, 221))	('elevated breast cancer', 'Disease', 'MESH:D001943', (103, 125))	('associated', 'Reg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('c.1100delC frameshift', 'Var', (37, 58))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
14039	19338683	In families with multiple breast cancer cases and individuals with breast and ovarian cancer, BRCA1 or BRCA2 mutations were excluded, according to standard procedures.	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('BRCA2', 'Gene', '675', (103, 108))	('BRCA1', 'Gene', '672', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (67, 92))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('BRCA1', 'Gene', (94, 99))	('mutations', 'Var', (109, 118))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('BRCA2', 'Gene', (103, 108))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))
14043	19338683	All 65 TP53-negative individuals were screened for the c.1100delC CHEK2 mutation and CHEK2 DNA rearrangements by multiplex ligation-dependent probe amplification (MLPA, see Table 1).	('c.1100delC', 'Mutation', 'rs555607708', (55, 65))	('CHEK2', 'Gene', (85, 90))	('CHEK2', 'Gene', '11200', (66, 71))	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('CHEK2', 'Gene', (66, 71))	('c.1100delC', 'Var', (55, 65))	('CHEK2', 'Gene', '11200', (85, 90))
14046	19338683	Three silent sequence variants were seen and not further analysed: c.252A>G, p.Glu84Glu in exon 1, a previously reported silent polymorphism, found once, c.1566C>T, p.Pro522Pro and c.1608A>G, p.Pro536Pro, both in exon 14, found in five and seven families, respectively.	('p.Pro522Pro', 'Var', (165, 176))	('c.1608A>G', 'Mutation', 'rs17886242', (181, 190))	('p.Pro522Pro', 'Mutation', 'rs202104749', (165, 176))	('c.1608A>G', 'Var', (181, 190))	('c.252A>G', 'Var', (67, 75))	('p.Glu84Glu', 'Mutation', 'rs587780191', (77, 87))	('c.252A>G', 'Mutation', 'rs587780191', (67, 75))	('p.Pro536Pro', 'Var', (192, 203))	('c.1566C>T', 'Mutation', 'rs202104749', (154, 163))	('p.Pro536Pro', 'Mutation', 'rs17886242', (192, 203))	('c.1566C>T', 'Var', (154, 163))	('p.Glu84Glu', 'Var', (77, 87))
14048	19338683	A chi-square test was used to determine the statistical significance of the proportion of CHEK2 mutation carriers in our study group compared to healthy controls.	('CHEK2', 'Gene', '11200', (90, 95))	('mutation', 'Var', (96, 104))	('CHEK2', 'Gene', (90, 95))
14049	19338683	Sixty-five TP53-negative individuals from 65 families were screened for the CHEK2 1100delC germline mutation and DNA rearrangements.	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('1100delC', 'Mutation', 'rs555607708', (82, 90))	('CHEK2', 'Gene', (76, 81))	('CHEK2', 'Gene', '11200', (76, 81))	('1100delC', 'Var', (82, 90))
14050	19338683	Thirty-four of these individuals were screened comprehensively by DGGE for CHEK2 mutations.	('CHEK2', 'Gene', (75, 80))	('CHEK2', 'Gene', '11200', (75, 80))	('mutations', 'Var', (81, 90))
14051	19338683	Six index patients were found to carry a possibly pathogenic germline CHEK2 sequence variant.	('CHEK2', 'Gene', '11200', (70, 75))	('pathogenic', 'Reg', (50, 60))	('variant', 'Var', (85, 92))	('CHEK2', 'Gene', (70, 75))	('patients', 'Species', '9606', (10, 18))
14052	19338683	The c.1100delC in exon 10 of the CHEK2 gene, a mutation located in the kinase domain of the gene and abolishing the kinase activity of the protein, was detected in four index patients.	('c.1100delC in', 'Var', (4, 17))	('kinase activity of the protein', 'MPA', (116, 146))	('CHEK2', 'Gene', '11200', (33, 38))	('patients', 'Species', '9606', (175, 183))	('CHEK2', 'Gene', (33, 38))	('c.1100delC', 'Mutation', 'rs555607708', (4, 14))	('abolishing', 'NegReg', (101, 111))
14053	19338683	In one family, a classical LFS family, the c.1100delC was detected in a patient who developed breast cancer at the age of 48 years (Figure 1A), which is in line with the c.1100delC acting as a low penetrance breast cancer susceptibility allele.	('c.1100delC', 'Mutation', 'rs555607708', (43, 53))	('c.1100delC', 'Mutation', 'rs555607708', (170, 180))	('patient', 'Species', '9606', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('c.1100delC', 'Var', (43, 53))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('c.1100delC', 'Var', (170, 180))	('breast cancer', 'Disease', (208, 221))	('breast cancer', 'Disease', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))
14054	19338683	Relatives with a 50% chance of being a c.1100delC carrier in this family who had developed breast cancer were not available for testing.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('c.1100delC', 'Mutation', 'rs555607708', (39, 49))	('c.1100delC', 'Var', (39, 49))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
14055	19338683	However, it is not likely to be the LFS-causing mutation in this family, considering the absence of the c.1100delC in the patient's son who developed a sarcoma at 15 years of age.	('sarcoma', 'Disease', 'MESH:D012509', (152, 159))	('c.1100delC', 'Mutation', 'rs555607708', (104, 114))	('patient', 'Species', '9606', (122, 129))	('sarcoma', 'Disease', (152, 159))	('c.1100delC', 'Var', (104, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))
14056	19338683	In an LFL and LFS-suggestive family, the patients identified as carrying the c.1100delC had breast cancer (Figure 1B and 1D); in a fourth family, a LFS-suggestive family, the patient identified with the c.1100delC sequence variant had both breast and colorectal cancer (Figure 1C).	('Figure 1B', 'Disease', 'MESH:C565748', (107, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('breast and colorectal cancer', 'Disease', 'MESH:D015179', (240, 268))	('c.1100delC', 'Var', (203, 213))	('patient', 'Species', '9606', (175, 182))	('colorectal cancer', 'Phenotype', 'HP:0003003', (251, 268))	('c.1100delC', 'Mutation', 'rs555607708', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('patient', 'Species', '9606', (41, 48))	('patients', 'Species', '9606', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('c.1100delC', 'Var', (77, 87))	('c.1100delC', 'Mutation', 'rs555607708', (203, 213))	('Figure 1B', 'Disease', (107, 116))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
14057	19338683	In all four of the c.1100delC families, this sequence variant seemed to be associated with breast cancer or breast and colorectal cancer, rather than LFS.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('breast cancer', 'Disease', (91, 104))	('breast and colorectal cancer', 'Disease', 'MESH:D015179', (108, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('c.1100delC', 'Mutation', 'rs555607708', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('c.1100delC', 'Var', (19, 29))	('associated', 'Reg', (75, 85))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
14058	19338683	The reported frequency of the CHEK c.1100delC in Dutch controls is 1.4%, in Dutch breast cancer patients not selected for family history 2.5% and in Dutch BRCA1/2-negative families with breast cancer 4.9%.	('breast cancer', 'Disease', (82, 95))	('CHEK c.1100delC', 'Var', (30, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('BRCA1', 'Gene', '672', (155, 160))	('c.1100delC', 'Var', (35, 45))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('BRCA1', 'Gene', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (186, 199))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('c.1100delC', 'Mutation', 'rs555607708', (35, 45))
14059	19338683	Another sequence variant, c.983T>C, p.Phe328Ser in exon 8, localised in the kinase domain of the gene, was detected in a female patient who had developed a leiomyosarcoma at 2 years of age and a schwannoma at 27 years of age (Figure 1E).	('c.983T>C', 'Var', (26, 34))	('leiomyosarcoma', 'Disease', (156, 170))	('schwannoma', 'Disease', (195, 205))	('schwannoma', 'Disease', 'MESH:D009442', (195, 205))	('c.983T>C', 'Mutation', 'rs965316043', (26, 34))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (156, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('schwannoma', 'Phenotype', 'HP:0100008', (195, 205))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (156, 170))	('p.Phe328Ser', 'Var', (36, 47))	('patient', 'Species', '9606', (128, 135))	('p.Phe328Ser', 'Mutation', 'rs748839289', (36, 47))
14066	19338683	One CHEK2 DNA rearrangement was found, c.1096-?_1629+?del, a deletion of exons 10-14 of the gene.	('c.1096-?_1629+?del', 'Var', (39, 57))	('CHEK2', 'Gene', (4, 9))	('CHEK2', 'Gene', '11200', (4, 9))	('c.1096-?_1629+?del', 'Mutation', 'c.1096-?_1629+?del', (39, 57))
14072	19338683	Of the seven variants presented, only the c.1100delC, the p.Ile157Thr and the p.Arg145Trp mutation are of reported functional significance.	('c.1100delC', 'Var', (42, 52))	('p.Arg145Trp', 'Mutation', 'rs137853007', (78, 89))	('p.Ile157Thr', 'Mutation', 'rs17879961', (58, 69))	('p.Ile157Thr', 'Var', (58, 69))	('c.1100delC', 'Mutation', 'rs555607708', (42, 52))	('p.Arg145Trp', 'Var', (78, 89))
14073	19338683	Bell et al found the p.Ile157Thr in an index patient with three primary cancers; no other family members were tested.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('patient', 'Species', '9606', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('p.Ile157Thr', 'Mutation', 'rs17879961', (21, 32))	('primary cancers', 'Disease', (64, 79))	('p.Ile157Thr', 'Var', (21, 32))	('primary cancers', 'Disease', 'MESH:D009369', (64, 79))
14075	19338683	Some authors found an association between the p.Ile157Thr mutation and risk of female breast cancer, others found no association.	('p.Ile157Thr', 'Mutation', 'rs17879961', (46, 57))	('p.Ile157Thr', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))
14076	19338683	The p.Arg145Trp, leading to a destabilised protein, was described in a Li-Fraumeni-like kindred; it was only tested in one family-member with a sarcoma at 20 years and breast cancer at 42 years.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('p.Arg145Trp', 'Var', (4, 15))	('destabilised protein', 'MPA', (30, 50))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (71, 82))	('breast cancer', 'Disease', (168, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('p.Arg145Trp', 'Mutation', 'rs137853007', (4, 15))	('Li-Fraumeni', 'Disease', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
14077	19338683	In our study six index patients were found to carry a CHEK2 sequence variant by screening 65 TP53-negative index patients, with no evidence that the sequence variants found caused the complete LFS phenotype in their families.	('variant', 'Var', (69, 76))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (113, 121))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('CHEK2', 'Gene', '11200', (54, 59))	('CHEK2', 'Gene', (54, 59))
14078	19338683	Our data are in line with the hypothesis that the CHEK2 c.1100delC might be associated with an elevated breast cancer risk, and possibly with a breast and colorectal cancer phenotype or more generally a multi-organ cancer susceptibility.	('CHEK2', 'Gene', (50, 55))	('elevated breast cancer', 'Disease', (95, 117))	('breast and colorectal cancer', 'Disease', 'MESH:D015179', (144, 172))	('c.1100delC', 'Mutation', 'rs555607708', (56, 66))	('elevated breast cancer', 'Disease', 'MESH:D001943', (95, 117))	('c.1100delC', 'Var', (56, 66))	('multi-organ cancer', 'Disease', (203, 221))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('multi-organ cancer', 'Disease', 'MESH:D009369', (203, 221))	('associated', 'Reg', (76, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('CHEK2', 'Gene', '11200', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
14079	19338683	We propose that the germline CHEK2 sequence variants contribute to tumour development in the index patients.	('contribute', 'Reg', (53, 63))	('tumour', 'Disease', (67, 73))	('CHEK2', 'Gene', '11200', (29, 34))	('patients', 'Species', '9606', (99, 107))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('CHEK2', 'Gene', (29, 34))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('variants', 'Var', (44, 52))
14081	19338683	In this way, the individual CHEK2 sequence variants may contribute to the Li-Fraumeni phenotype seen in these families.	('CHEK2', 'Gene', '11200', (28, 33))	('Li-Fraumeni', 'Disease', (74, 85))	('CHEK2', 'Gene', (28, 33))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (74, 85))	('variants', 'Var', (43, 51))	('contribute', 'Reg', (56, 66))
14082	19338683	Because only 75% of classical LFS families and 40% of LFL families have germline TP53 mutations, research groups have looked at candidate genes like Bcl10 , CDKN2 , TP63 , PTEN , CHEK1  and BAX ; no possible alternative LFS genes were found.	('mutations', 'Var', (86, 95))	('PTEN', 'Gene', '5728', (172, 176))	('BAX', 'Gene', '581', (190, 193))	('CDKN2', 'Gene', '1029', (157, 162))	('CHEK1', 'Gene', '1111', (179, 184))	('CDKN2', 'Gene', (157, 162))	('CHEK1', 'Gene', (179, 184))	('Bcl10', 'Gene', '8915', (149, 154))	('TP63', 'Gene', (165, 169))	('TP63', 'Gene', '8626', (165, 169))	('Bcl10', 'Gene', (149, 154))	('TP53', 'Gene', '7157', (81, 85))	('BAX', 'Gene', (190, 193))	('TP53', 'Gene', (81, 85))	('PTEN', 'Gene', (172, 176))
14083	19338683	Two polymorphisms, p.Arg72Pro (TP53 gene) and SNP309 T>G (MDM2 gene), have been shown to have a modifying effect, resulting in an earlier age of onset of cancer in TP53 mutation carriers; there is even a synergistic effect when both polymorphisms are present.	('earlier', 'PosReg', (130, 137))	('TP53', 'Gene', '7157', (164, 168))	('mutation', 'Var', (169, 177))	('TP53', 'Gene', (164, 168))	('p.Arg72Pro', 'Mutation', 'rs1042522', (19, 29))	('SNP309 T>G', 'Var', (46, 56))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('p.Arg72Pro', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('MDM2', 'Gene', '4193', (58, 62))	('MDM2', 'Gene', (58, 62))
14086	19338683	We did find a larger proportion of homozygotes for the G-allele of MDM2 SNP309 in our TP53-negative group, suggesting a modifier effect on the TP53 negative Li-Fraumeni phenotype.	('TP53', 'Gene', (143, 147))	('MDM2', 'Gene', '4193', (67, 71))	('Li-Fraumeni', 'Disease', (157, 168))	('SNP309', 'Var', (72, 78))	('MDM2', 'Gene', (67, 71))	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', (86, 90))	('TP53', 'Gene', '7157', (143, 147))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (157, 168))
14096	33591997	High expression of IL-13Ralpha2 in ACC tumors was significantly associated with a lower patient survival rate and period of survival compared to low expression (p = 0.0084).	('patient', 'Species', '9606', (88, 95))	('High expression', 'Var', (0, 15))	('ACC tumors', 'Disease', 'MESH:D004476', (35, 45))	('period of survival', 'CPA', (114, 132))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('IL-13Ralpha2', 'Gene', (19, 31))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))	('IL-13Ralpha2', 'Gene', '3598', (19, 31))	('patient survival rate', 'CPA', (88, 109))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('ACC tumors', 'Disease', (35, 45))	('lower', 'NegReg', (82, 87))
14097	33591997	In addition, high IL-13Ralpha2 expression was significantly associated with a higher incidence of new tumor events and excess hormone production compared to low or medium IL-13Ralpha2 expression.	('excess', 'MPA', (119, 125))	('IL-13Ralpha2', 'Gene', '3598', (171, 183))	('IL-13Ralpha2', 'Gene', (18, 30))	('high', 'Var', (13, 17))	('IL-13Ralpha2', 'Gene', '3598', (18, 30))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('expression', 'MPA', (31, 41))	('IL-13Ralpha2', 'Gene', (171, 183))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
14139	33591997	The GDC database also provides the genetic mutations in individual tumor gene sequences that exhibited altered expression in global transcriptional analysis in ACC tumors.	('tumor', 'Disease', (164, 169))	('altered', 'Reg', (103, 110))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('ACC tumors', 'Disease', (160, 170))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('ACC', 'Phenotype', 'HP:0006744', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('expression', 'MPA', (111, 121))	('ACC tumors', 'Disease', 'MESH:D004476', (160, 170))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
14159	33591997	In contrast, subjects with medium and high IL-13Ralpha2 expression had a 62% and 48% survival rate, respectively (Fig 1C).	('IL-13Ralpha2', 'Gene', (43, 55))	('IL-13Ralpha2', 'Gene', '3598', (43, 55))	('high', 'Var', (38, 42))
14166	33591997	For IL-13Ralpha2, there was no significant difference in the incidence of tumor metastasis among ACC subjects with low, medium, and high expression.	('ACC', 'Phenotype', 'HP:0006744', (97, 100))	('IL-13Ralpha2', 'Gene', '3598', (4, 16))	('tumor metastasis', 'Disease', (74, 90))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('high expression', 'Var', (132, 147))	('tumor metastasis', 'Disease', 'MESH:D009362', (74, 90))	('IL-13Ralpha2', 'Gene', (4, 16))
14169	33591997	In contrast, medium (n = 5) IL-13Ralpha2 expression was associated with a 20% survival rate of ACC subjects with tumor metastasis while ACC subjects with medium (n = 20) IL-13Ralpha2 expression and no metastasis showed a 70% survival rate (p = .1206).	('IL-13Ralpha2', 'Gene', (28, 40))	('tumor metastasis', 'Disease', (113, 129))	('ACC', 'Phenotype', 'HP:0006744', (95, 98))	('medium', 'Var', (13, 19))	('IL-13Ralpha2', 'Gene', (170, 182))	('IL-13Ralpha2', 'Gene', '3598', (28, 40))	('ACC', 'Phenotype', 'HP:0006744', (136, 139))	('IL-13Ralpha2', 'Gene', '3598', (170, 182))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor metastasis', 'Disease', 'MESH:D009362', (113, 129))
14170	33591997	Similarly, high (n = 6) IL-13Ralpha2 expression was associated with 16.7% survival rate of ACC subjects with tumor metastasis along with a survival rate of 60% for subjects without metastatic tumors (n = 20) (p = .1602).	('tumor metastasis', 'Disease', (109, 125))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('IL-13Ralpha2', 'Gene', '3598', (24, 36))	('ACC', 'Phenotype', 'HP:0006744', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('high', 'Var', (11, 15))	('expression', 'MPA', (37, 47))	('tumor metastasis', 'Disease', 'MESH:D009362', (109, 125))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('IL-13Ralpha2', 'Gene', (24, 36))
14181	33591997	Using the Fisher's Exact Test, there was a statistically significant difference in the overall survival rate of subjects with low (n = 26) versus medium (n = 26) (p = 0.0227) and low (n = 26) versus high (n = 27) (p = 0.0267) expression of IL-13Ralpha1.	('IL-13Ralpha1', 'Gene', '3597', (240, 252))	('low', 'NegReg', (179, 182))	('IL-13Ralpha1', 'Gene', (240, 252))	('high', 'Var', (199, 203))
14184	33591997	There was also no significant difference in the incidence of excess adrenal hormones among ACC subjects with low, medium, and high IL-13Ra1 expression.	('adrenal hormones', 'MPA', (68, 84))	('ACC', 'Phenotype', 'HP:0006744', (91, 94))	('excess adrenal', 'Phenotype', 'HP:0008221', (61, 75))	('high', 'Var', (126, 130))	('medium', 'Var', (114, 120))	('IL-13Ra1', 'Gene', '3597', (131, 139))	('IL-13Ra1', 'Gene', (131, 139))
14186	33591997	Additionally, there was no significant difference in the incidence of tumor metastasis among ACC subjects with low, medium, and high IL-13Ra1 expression.	('IL-13Ra1', 'Gene', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ACC', 'Phenotype', 'HP:0006744', (93, 96))	('IL-13Ra1', 'Gene', '3597', (133, 141))	('expression', 'MPA', (142, 152))	('tumor metastasis', 'Disease', 'MESH:D009362', (70, 86))	('high', 'Var', (128, 132))	('tumor metastasis', 'Disease', (70, 86))
14193	33591997	By analyzing the National Cancer Institute's TCGA database, we demonstrated that IL13Ralpha2 gene expression is related with the survival of patients with ACC where analysis indicated that high IL-13Ralpha2 expression is associated with negative clinical outcomes as measured by four different metrics.	('IL13Ralpha2', 'Gene', (81, 92))	('Cancer', 'Disease', 'MESH:D009369', (26, 32))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('IL-13Ralpha2', 'Gene', '3598', (194, 206))	('ACC', 'Phenotype', 'HP:0006744', (155, 158))	('high', 'Var', (189, 193))	('negative', 'NegReg', (237, 245))	('IL13Ralpha2', 'Gene', '3598', (81, 92))	('IL-13Ralpha2', 'Gene', (194, 206))	('expression', 'MPA', (207, 217))	('patients', 'Species', '9606', (141, 149))	('Cancer', 'Disease', (26, 32))
14194	33591997	First, subjects with high IL-13Ralpha2 expression had a lower survival rate and reduced length of survival than subjects with low IL-13Ralpha2 expression.	('IL-13Ralpha2', 'Gene', '3598', (26, 38))	('length', 'MPA', (88, 94))	('IL-13Ralpha2', 'Gene', '3598', (130, 142))	('survival rate', 'CPA', (62, 75))	('high', 'Var', (21, 25))	('reduced', 'NegReg', (80, 87))	('lower', 'NegReg', (56, 61))	('IL-13Ralpha2', 'Gene', (26, 38))	('IL-13Ralpha2', 'Gene', (130, 142))
14195	33591997	Second, subjects with medium and high IL-13Ralpha2 expression had a higher incidence of a new tumor events than subjects with low IL-13Ralpha2 expression.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('high', 'Var', (33, 37))	('IL-13Ralpha2', 'Gene', '3598', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('IL-13Ralpha2', 'Gene', '3598', (38, 50))	('tumor', 'Disease', (94, 99))	('IL-13Ralpha2', 'Gene', (130, 142))	('IL-13Ralpha2', 'Gene', (38, 50))
14196	33591997	Third, subjects with medium and high IL-13Ralpha2 expression exhibited a higher incidence of excess hormone production than subjects with low IL-13Ralpha2 expression.	('high', 'Var', (32, 36))	('IL-13Ralpha2', 'Gene', (142, 154))	('expression', 'Var', (50, 60))	('excess hormone production', 'MPA', (93, 118))	('IL-13Ralpha2', 'Gene', (37, 49))	('IL-13Ralpha2', 'Gene', '3598', (142, 154))	('IL-13Ralpha2', 'Gene', '3598', (37, 49))
14197	33591997	Fourth, among subjects with excess hormone production, patients with high IL-13Ralpha2 expression had a significantly lower survival rate compared to patients with low IL-13Ralpha2 expression.	('IL-13Ralpha2', 'Gene', (168, 180))	('IL-13Ralpha2', 'Gene', '3598', (168, 180))	('survival rate', 'CPA', (124, 137))	('patients', 'Species', '9606', (55, 63))	('IL-13Ralpha2', 'Gene', (74, 86))	('patients', 'Species', '9606', (150, 158))	('high', 'Var', (69, 73))	('lower', 'NegReg', (118, 123))	('IL-13Ralpha2', 'Gene', '3598', (74, 86))
14200	33591997	In both reports, we observed that high IL-13Ralpha2 expression is associated with advanced stage disease.	('advanced stage disease', 'Disease', (82, 104))	('associated', 'Reg', (66, 76))	('expression', 'MPA', (52, 62))	('high', 'Var', (34, 38))	('IL-13Ralpha2', 'Gene', (39, 51))	('IL-13Ralpha2', 'Gene', '3598', (39, 51))
14203	33591997	Therefore, we searched the TCGA database for possible mutations in the sequence of the IL-13Ralpha2 gene from ACC tumor samples.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('IL-13Ralpha2', 'Gene', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', (114, 119))	('IL-13Ralpha2', 'Gene', '3598', (87, 99))	('ACC', 'Phenotype', 'HP:0006744', (110, 113))
14205	33591997	It is of interest to note that high expression of IL-13Ralpha1 in ACC was associated with higher % of survival.	('ACC', 'Phenotype', 'HP:0006744', (66, 69))	('IL-13Ralpha1', 'Gene', (50, 62))	('high expression', 'Var', (31, 46))	('higher', 'PosReg', (90, 96))	('IL-13Ralpha1', 'Gene', '3597', (50, 62))
14207	33591997	Consistent with this observation, the age at death was also significantly higher in patients with high versus low IL-13Ralpha1 expression.	('higher', 'PosReg', (74, 80))	('IL-13Ralpha1', 'Gene', (114, 126))	('expression', 'MPA', (127, 137))	('patients', 'Species', '9606', (84, 92))	('high', 'Var', (98, 102))	('IL-13Ralpha1', 'Gene', '3597', (114, 126))	('death', 'Disease', 'MESH:D003643', (45, 50))	('death', 'Disease', (45, 50))
14212	33591997	For example, Kwon et al showed that high expression of IL-13Ralpha1 was associated with a lower risk of recurrence and cancer-induced mortality in patients with oral cavity squamous cell carcinoma.	('IL-13Ralpha1', 'Gene', (55, 67))	('high expression', 'Var', (36, 51))	('mortality', 'Disease', 'MESH:D003643', (134, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (173, 196))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('IL-13Ralpha1', 'Gene', '3597', (55, 67))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (173, 196))	('lower', 'NegReg', (90, 95))	('cancer', 'Disease', (119, 125))	('squamous cell carcinoma', 'Disease', (173, 196))	('mortality', 'Disease', (134, 143))	('patients', 'Species', '9606', (147, 155))	('recurrence', 'CPA', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
14213	33591997	In contrast, high IL-13Ralpha1 expression was significantly associated with clinicopathological parameters of aggressive phenotypes and with reduced survival in patients with invasive breast cancer.	('IL-13Ralpha1', 'Gene', (18, 30))	('reduced', 'NegReg', (141, 148))	('high', 'Var', (13, 17))	('IL-13Ralpha1', 'Gene', '3597', (18, 30))	('invasive breast cancer', 'Disease', 'MESH:D001943', (175, 197))	('expression', 'MPA', (31, 41))	('patients', 'Species', '9606', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('invasive breast cancer', 'Disease', (175, 197))
14228	33591997	Studies have shown that IL-13-Pseudomonas exotoxin (IL-13-PE38QQR) is highly cytotoxic in vitro and in vivo to several types of IL-13Ralpha2-positive cancer cells including ACC cells.	('ACC', 'Phenotype', 'HP:0006744', (173, 176))	('IL-13Ralpha2', 'Gene', (128, 140))	('IL-13-Pseudomonas', 'Var', (24, 41))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('IL-13Ralpha2', 'Gene', '3598', (128, 140))	('cytotoxic', 'CPA', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
14230	33591997	Furthermore, in this same study, it was shown that treatment of animals with IL-13-PE resulted in significant tumor regression and prolonged survival in a murine xenograft model of ACC.	('IL-13-PE', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('prolonged', 'PosReg', (131, 140))	('survival', 'CPA', (141, 149))	('ACC', 'Phenotype', 'HP:0006744', (181, 184))	('murine', 'Species', '10090', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
14250	33195693	For example, circ_0001649 inhibits cholangiocarcinoma progression in vitro and in vivo.	('inhibits', 'NegReg', (26, 34))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('cholangiocarcinoma', 'Disease', (35, 53))	('circ_0001649', 'Var', (13, 25))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (35, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (35, 53))
14253	33195693	For example, hsa_circ_101141 acts as a competing endogenous RNA (ceRNA) to facilitate progression of hepatocellular carcinoma by regulating miR-1297/ROCK1 signaling.	('si', 'Chemical', 'MESH:D012825', (93, 95))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('miR-1297', 'Gene', '100302187', (140, 148))	('regulating', 'Reg', (129, 139))	('hsa_circ_101141', 'Var', (13, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (101, 125))	('hepatocellular carcinoma', 'Disease', (101, 125))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (101, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('facilitate', 'PosReg', (75, 85))	('miR-1297', 'Gene', (140, 148))	('ROCK1', 'Gene', '6093', (149, 154))	('ROCK1', 'Gene', (149, 154))
14257	33195693	Silencing of circ-CCAC1 inhibits ACC cell progression in vitro.	('inhibits', 'NegReg', (24, 32))	('ACC', 'Phenotype', 'HP:0006744', (33, 36))	('ACC cell', 'Disease', (33, 41))	('circ-CCAC1', 'Gene', (13, 23))	('Silencing', 'Var', (0, 9))	('si', 'Chemical', 'MESH:D012825', (49, 51))
14283	33195693	For the dual-luciferase reporter gene test, we seeded ACC cells into a 24-well plate and cultured the plate for 24 h. To confirm the interaction between miR-514a-5p and circ-CCAC1/3'-UTR of C22orf46, we transfected the following into ACC cells: circ-CCAC1/3'-UTR of C22orf46 wild reporter vector (pmirGLO), circ-CCAC1/3'-UTR of C22orf46 mutant reporter vector (Mut), and miR-514a-5p mimics or miR-NC.	('C22orf46', 'Gene', '79640', (328, 336))	('miR-514a-5p', 'Chemical', '-', (371, 382))	('mutant', 'Var', (337, 343))	('ACC', 'Phenotype', 'HP:0006744', (54, 57))	('C22orf46', 'Gene', (266, 274))	('miR-514a-5p', 'Chemical', '-', (153, 164))	('C22orf46', 'Gene', (190, 198))	('C22orf46', 'Gene', (328, 336))	('C22orf46', 'Gene', '79640', (190, 198))	('C22orf46', 'Gene', '79640', (266, 274))	('ACC', 'Phenotype', 'HP:0006744', (234, 237))
14301	33195693	We found that the half-life of circ-CCAC1 was longer than its linear isoform (ERBB2 mRNA) (Figure 1(b)).	('ERBB2', 'Gene', '2064', (78, 83))	('longer', 'PosReg', (46, 52))	('circ-CCAC1', 'Var', (31, 41))	('half-life', 'MPA', (18, 27))	('ERBB2', 'Gene', (78, 83))
14304	33195693	We found that high circ-CCAC1 expression was linked to worse overall survival (P = 0.006) for the ACC patients after surgery (Figure 1(d)).	('expression', 'MPA', (30, 40))	('high circ-CCAC1', 'Var', (14, 29))	('patients', 'Species', '9606', (102, 110))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('worse', 'NegReg', (55, 60))	('ACC', 'Phenotype', 'HP:0006744', (98, 101))	('overall survival', 'MPA', (61, 77))
14307	33195693	To facilitate explorations of the roles that circ-CCAC1 may have played in the progression of ACC, we designed two circ-CCAC1 siRNAs that would knock down circ-CCAC1.	('ACC', 'Phenotype', 'HP:0006744', (94, 97))	('ACC', 'Disease', (94, 97))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('knock', 'Var', (144, 149))	('circ-CCAC1', 'MPA', (155, 165))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('si', 'Chemical', 'MESH:D012825', (86, 88))
14308	33195693	We found that the levels of circ-CCAC1 were notably downregulated in H295R cells that had been transfected with si-circ-CCAC1-1/-2 (Figure 2(a)).	('downregulated', 'NegReg', (52, 65))	('levels', 'MPA', (18, 24))	('si-circ-CCAC1-1/-2', 'Var', (112, 130))	('si', 'Chemical', 'MESH:D012825', (112, 114))
14310	33195693	Furthermore, ERBB2 mRNA expression levels were unaffected after circ-CCAC1 knockdown/overexpression (Figure 2(b)).	('si', 'Chemical', 'MESH:D012825', (30, 32))	('knockdown/overexpression', 'Var', (75, 99))	('ERBB2', 'Gene', '2064', (13, 18))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('ERBB2', 'Gene', (13, 18))	('knockdown/overexpression', 'PosReg', (75, 99))
14311	33195693	We used CCK-8 and colony formation tests to detect ACC cell viability and clone-forming capacity affected by circ-CCAC1.	('clone-forming capacity', 'CPA', (74, 96))	('ACC', 'Phenotype', 'HP:0006744', (51, 54))	('CCK-8', 'Chemical', '-', (8, 13))	('circ-CCAC1', 'Var', (109, 119))
14312	33195693	The results confirmed that silencing of circ-CCAC1 significantly inhibited cell viability and clone-forming capacity (Figures 2(c) and 2(e)).	('silencing', 'Var', (27, 36))	('circ-CCAC1', 'Gene', (40, 50))	('clone-forming capacity', 'CPA', (94, 116))	('inhibited', 'NegReg', (65, 74))	('cell viability', 'CPA', (75, 89))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('si', 'Chemical', 'MESH:D012825', (27, 29))
14315	33195693	Results from Transwell assays indicated that silencing of circ-CCAC1 attenuated the migratory and invasive potential of H295R cells (Figure 2(i)).	('silencing', 'Var', (45, 54))	('attenuated', 'NegReg', (69, 79))	('si', 'Chemical', 'MESH:D012825', (102, 104))	('circ-CCAC1', 'Gene', (58, 68))	('si', 'Chemical', 'MESH:D012825', (45, 47))
14316	33195693	By contrast, elevated circ-CCAC1 strengthened the migratory and invasive capacities of SW-13 cells (Figure 2(j)).	('migratory', 'CPA', (50, 59))	('SW-13', 'CellLine', 'CVCL:0542', (87, 92))	('circ-CCAC1', 'Var', (22, 32))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('strengthened', 'PosReg', (33, 45))	('invasive capacities', 'CPA', (64, 83))
14319	33195693	As a result, five miRNAs (miR-182-5p, miR-1343-3p, miR-514a-5p, miR-3619-5p, and miR-6746-5p) were predicted by both circBank and starBase 2.0 databases (Figure 3(c)).	('miR-1343', 'Gene', '100616437', (38, 46))	('miR-182', 'Gene', (26, 33))	('miR-514a-5p', 'Var', (51, 62))	('miR-3619', 'Gene', '100500828', (64, 72))	('miR-3619', 'Gene', (64, 72))	('miR-514a-5p', 'Chemical', '-', (51, 62))	('miR-182', 'Gene', '406958', (26, 33))	('miR-6746', 'Gene', '102465446', (81, 89))	('miR-1343', 'Gene', (38, 46))	('miR-6746', 'Gene', (81, 89))
14320	33195693	Silencing of circ-CCAC1 increased miR-514a-5p expression in H295R and SW-13 cells.	('miR-514a-5p expression', 'MPA', (34, 56))	('SW-13', 'CellLine', 'CVCL:0542', (70, 75))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('circ-CCAC1', 'Gene', (13, 23))	('Silencing', 'Var', (0, 9))	('miR-514a-5p', 'Chemical', '-', (34, 45))	('increased', 'PosReg', (24, 33))
14323	33195693	TCGA datasets indicated that the patients with low expression of miR-514a-5p had a worse prognosis (Figure 3(g)).	('patients', 'Species', '9606', (33, 41))	('miR-514a-5p', 'Var', (65, 76))	('low', 'NegReg', (47, 50))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('miR-514a-5p', 'Chemical', '-', (65, 76))	('si', 'Chemical', 'MESH:D012825', (95, 97))
14325	33195693	A negative association between circ-CCAC1 and miR-514a-5p was identified in ACC tissues (Figure 3(i)).	('negative', 'NegReg', (2, 10))	('circ-CCAC1', 'Gene', (31, 41))	('ACC', 'Phenotype', 'HP:0006744', (76, 79))	('ACC tissues', 'Disease', (76, 87))	('miR-514a-5p', 'Var', (46, 57))	('miR-514a-5p', 'Chemical', '-', (46, 57))
14328	33195693	The TargetScan database was used to predict the downstream targets of miR-514a-5p, and C22orf46 was chosen for further study.	('miR-514a-5p', 'Chemical', '-', (70, 81))	('C22orf46', 'Gene', '79640', (87, 95))	('C22orf46', 'Gene', (87, 95))	('miR-514a-5p', 'Var', (70, 81))
14332	33195693	Additionally, we found that knocking down of miR-514a-5p significantly enhanced the levels of C22orf46 mRNA in H295R cells, whereas ectopic-expressed miR-514a-5p attenuated C22orf46 mRNA expression (Figure 3(p)).	('enhanced', 'PosReg', (71, 79))	('miR-514a-5p', 'Chemical', '-', (45, 56))	('knocking down', 'Var', (28, 41))	('si', 'Chemical', 'MESH:D012825', (193, 195))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('miR-514a-5p', 'Gene', (45, 56))	('attenuated', 'NegReg', (162, 172))	('levels', 'MPA', (84, 90))	('C22orf46', 'Gene', (94, 102))	('C22orf46', 'Gene', (173, 181))	('C22orf46', 'Gene', '79640', (94, 102))	('miR-514a-5p', 'Var', (150, 161))	('miR-514a-5p', 'Chemical', '-', (150, 161))	('C22orf46', 'Gene', '79640', (173, 181))
14334	33195693	We then cotransfected with si-circ-CCAC1-1 and C22orf46 vector in H295R cells, followed by Western blotting.	('C22orf46', 'Gene', (47, 55))	('si-circ-CCAC1-1', 'Var', (27, 42))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('C22orf46', 'Gene', '79640', (47, 55))
14335	33195693	circ-CCAC1 inhibition downregulated C22orf46 expression, whereas cotransfection with C22orf46 vector significantly increased C22orf46 expression levels (Figure 4(a)).	('C22orf46', 'Gene', (125, 133))	('increased', 'PosReg', (115, 124))	('C22orf46', 'Gene', '79640', (85, 93))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('C22orf46', 'Gene', (36, 44))	('expression', 'MPA', (45, 55))	('inhibition', 'Var', (11, 21))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('C22orf46', 'Gene', '79640', (36, 44))	('C22orf46', 'Gene', '79640', (125, 133))	('downregulated', 'NegReg', (22, 35))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('expression levels', 'MPA', (134, 151))	('C22orf46', 'Gene', (85, 93))
14338	33195693	CCK-8, colony formation, and Transwell experiments displayed that increasing C22orf46 reversed the inhibition of H295R cell growth and invasion caused by si-circ-CCAC1-1 (Figures 4(b), 4(d), and 4(f)).	('C22orf46', 'Gene', '79640', (77, 85))	('si-circ-CCAC1-1', 'Var', (154, 169))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('increasing', 'PosReg', (66, 76))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('C22orf46', 'Gene', (77, 85))	('CCK-8', 'Chemical', '-', (0, 5))	('H295R cell growth', 'CPA', (113, 130))	('invasion', 'CPA', (135, 143))
14342	33195693	Although numerous studies have revealed that alterations in the oncogene and tumor suppressor gene contribute to the progression and metastasis of ACC, the precise molecular mechanism remains vague.	('alterations', 'Var', (45, 56))	('contribute', 'Reg', (99, 109))	('tumor suppressor', 'Gene', (77, 93))	('oncogene', 'Gene', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('progression', 'CPA', (117, 128))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('ACC', 'Phenotype', 'HP:0006744', (147, 150))	('metastasis', 'CPA', (133, 143))	('tumor suppressor', 'Gene', '7248', (77, 93))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('ACC', 'Disease', (147, 150))
14345	33195693	A recent study indicated that circRNA_100782 promotes proliferation and metastasis of gastric cancer by downregulating tumor suppressor gene Rb by adsorbing miR-574-3p in a sponge form.	('miR-574-3p', 'Gene', (157, 167))	('miR-574-3p', 'Gene', '693159', (157, 167))	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('si', 'Chemical', 'MESH:D012825', (79, 81))	('metastasis', 'CPA', (72, 82))	('downregulating', 'NegReg', (104, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('tumor suppressor', 'Gene', (119, 135))	('circRNA_100782', 'Var', (30, 44))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('promotes', 'PosReg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('proliferation', 'CPA', (54, 67))	('tumor suppressor', 'Gene', '7248', (119, 135))	('gastric cancer', 'Disease', (86, 100))
14349	33195693	A recent study indicated that circ-CCAC1 was enhanced in cholangiocarcinoma and indicated that circ-CCAC1 was likely to affect tumorigenesis and metastasis in human cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('circ-CCAC1', 'Var', (95, 105))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('si', 'Chemical', 'MESH:D012825', (152, 154))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('human', 'Species', '9606', (159, 164))	('circ-CCAC1', 'Gene', (30, 40))	('cholangiocarcinoma', 'Disease', (57, 75))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (57, 75))	('enhanced', 'PosReg', (45, 53))	('affect', 'Reg', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('metastasis', 'CPA', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
14353	33195693	Gain- and loss-of-function assays illustrated that circ-CCAC1 significantly increased the viability, clone-forming, migration, and invasion of ACC cells.	('clone-forming', 'CPA', (101, 114))	('invasion', 'CPA', (131, 139))	('circ-CCAC1', 'Var', (51, 61))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('increased', 'PosReg', (76, 85))	('ACC', 'Phenotype', 'HP:0006744', (143, 146))	('viability', 'CPA', (90, 99))	('migration', 'CPA', (116, 125))	('si', 'Chemical', 'MESH:D012825', (62, 64))
14358	33195693	In this work, our results indicated that miR-514a-5p expression was significantly lower in ACC tissues and cell lines.	('miR-514a-5p', 'Chemical', '-', (41, 52))	('ACC', 'Phenotype', 'HP:0006744', (91, 94))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('ACC', 'Disease', (91, 94))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('miR-514a-5p', 'Var', (41, 52))	('lower', 'NegReg', (82, 87))
14359	33195693	Meanwhile, a negative correlation was observed between miR-514a-5p and circ-CCAC1 expression.	('negative', 'NegReg', (13, 21))	('miR-514a-5p', 'Var', (55, 66))	('miR-514a-5p', 'Chemical', '-', (55, 66))	('expression', 'MPA', (82, 92))	('circ-CCAC1', 'Gene', (71, 81))	('si', 'Chemical', 'MESH:D012825', (88, 90))
14361	33195693	In fact, miR-514a-5p has been confirmed as a tumor suppressor gene in some types of human cancers.	('cancers', 'Disease', (90, 97))	('tumor suppressor', 'Gene', '7248', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('miR-514a-5p', 'Var', (9, 20))	('human', 'Species', '9606', (84, 89))	('tumor suppressor', 'Gene', (45, 61))	('miR-514a-5p', 'Chemical', '-', (9, 20))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
14363	33195693	For example, miR-514a-5p could be sponged by long noncoding RNA TRIM52-AS1 and SNHG7, thus releasing its suppression on MRPS18A and ELAVL1, respectively.	('releasing', 'PosReg', (91, 100))	('ELAVL1', 'Gene', (132, 138))	('SNHG7', 'Gene', (79, 84))	('MRPS18A', 'Gene', '55168', (120, 127))	('AS1', 'Gene', '5729', (71, 74))	('AS1', 'Gene', (71, 74))	('TRIM52', 'Gene', (64, 70))	('MRPS18A', 'Gene', (120, 127))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('TRIM52', 'Gene', '84851', (64, 70))	('ELAVL1', 'Gene', '1994', (132, 138))	('SNHG7', 'Gene', '84973', (79, 84))	('miR-514a-5p', 'Var', (13, 24))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('suppression', 'MPA', (105, 116))	('miR-514a-5p', 'Chemical', '-', (13, 24))
14364	33195693	However, the functions and mechanisms of miR-514a-5p in ACC are still unclear.	('ACC', 'Phenotype', 'HP:0006744', (56, 59))	('miR-514a-5p', 'Var', (41, 52))	('ACC', 'Disease', (56, 59))	('miR-514a-5p', 'Chemical', '-', (41, 52))
14365	33195693	The above evidence suggested that miR-514a-5p functions as a tumor suppressor gene in tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumor suppressor', 'Gene', (61, 77))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR-514a-5p', 'Var', (34, 45))	('tumor suppressor', 'Gene', '7248', (61, 77))	('miR-514a-5p', 'Chemical', '-', (34, 45))
14366	33195693	Next, we verified that miR-514a-5p directly combined with the 3'-UTR of C22orf46.	('miR-514a-5p', 'Var', (23, 34))	('miR-514a-5p', 'Chemical', '-', (23, 34))	('C22orf46', 'Gene', '79640', (72, 80))	('C22orf46', 'Gene', (72, 80))
14367	33195693	Hence, we hypothesized that circ-CCAC1 induces the promotion of ACC malignancy by way of its interactions with miR-514a-5p to upregulate C22orf46 expression.	('si', 'Chemical', 'MESH:D012825', (152, 154))	('promotion', 'PosReg', (51, 60))	('malignancy', 'Disease', (68, 78))	('malignancy', 'Disease', 'MESH:D009369', (68, 78))	('miR-514a-5p', 'Chemical', '-', (111, 122))	('interactions', 'Interaction', (93, 105))	('ACC', 'Phenotype', 'HP:0006744', (64, 67))	('upregulate', 'PosReg', (126, 136))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('C22orf46', 'Gene', (137, 145))	('ACC', 'Disease', (64, 67))	('expression', 'MPA', (146, 156))	('circ-CCAC1', 'Var', (28, 38))	('C22orf46', 'Gene', '79640', (137, 145))
14392	32478073	Moreover, these changes are associated with an enhanced ability to sustain breast cancer cell proliferation and in vivo tumorigenicity.	('changes', 'Var', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('enhanced', 'PosReg', (47, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
14420	32478073	Moreover, the differentiation potential and multipotency toward different cell types, such as chondrogenic, osteoblastogenic, neurogenic, and muscle, are significantly higher in S-ASCs than in V-ASCs, suggesting a strong intrinsic difference in precursor fate potential according to the depot origin.	('neurogenic', 'CPA', (126, 136))	('osteoblastogenic', 'Disease', 'None', (108, 124))	('osteoblastogenic', 'Disease', (108, 124))	('multipotency toward different cell types', 'CPA', (44, 84))	('ASC', 'Chemical', '-', (195, 198))	('S-ASCs', 'Var', (178, 184))	('higher', 'PosReg', (168, 174))	('differentiation potential', 'CPA', (14, 39))	('ASC', 'Chemical', '-', (180, 183))
14452	32478073	Of note, aggressive adrenocortical cancers are often characterized by hyper-activating mutation or upregulation of Wnt/beta catenin pathways and hyper-methylation/repression of the G0/G1 switch gene 2 (G0S2) gene.	('hyper-methylation/repression', 'NegReg', (145, 173))	('beta catenin', 'Gene', '1499', (119, 131))	('G0S2', 'Gene', '50486', (202, 206))	('aggressive adrenocortical cancers', 'Disease', 'MESH:D000306', (9, 42))	('beta catenin', 'Gene', (119, 131))	('hyper-activating', 'PosReg', (70, 86))	('aggressive adrenocortical cancers', 'Disease', (9, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('upregulation', 'PosReg', (99, 111))	('G0S2', 'Gene', (202, 206))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('G0/G1 switch gene 2', 'Gene', '50486', (181, 200))	('G0/G1 switch gene 2', 'Gene', (181, 200))	('hyper-methylation/repression', 'Var', (145, 173))
14474	32478073	The causal effect is demonstrated by reversion of browning and muscle wasting cachectic effects through neutralization of PTHrP secretion or genetic deletion of the PTH receptor.	('PTHrP', 'Gene', (122, 127))	('browning', 'CPA', (50, 58))	('neutralization', 'MPA', (104, 118))	('genetic deletion', 'Var', (141, 157))	('PTHrP', 'Gene', '19227', (122, 127))	('muscle wasting cachectic effects', 'CPA', (63, 95))	('PTH receptor', 'Gene', (165, 177))	('muscle wasting', 'Phenotype', 'HP:0003202', (63, 77))
14479	32478073	p107, a co-transcriptional repressor, is involved in cell cycle progression, as its over-expression is known to block cell cycle of many cancer cell lines and its loss associated with proliferative effects.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('p107', 'Var', (0, 4))	('associated', 'Reg', (168, 178))	('loss', 'NegReg', (163, 167))	('proliferative effects', 'CPA', (184, 205))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('cell cycle', 'CPA', (118, 128))	('block', 'NegReg', (112, 117))	('over-expression', 'PosReg', (84, 99))
14482	32478073	According to these findings, a suggestive role of p107 in driving CA-ASC fate following ASC interaction with tumor cells can be theorized.	('ASC', 'Chemical', '-', (88, 91))	('p107', 'Var', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('ASC', 'Chemical', '-', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('CA-ASC fate', 'CPA', (66, 77))	('tumor', 'Disease', (109, 114))
14483	32478073	In this case, the cancer cell crosstalk with ASCs results in constraining white adipocyte differentiation potential and stimulating proliferation, similar to the process observed following p107 suppression in fat precursors.	('stimulating', 'PosReg', (120, 131))	('constraining', 'NegReg', (61, 73))	('proliferation', 'CPA', (132, 145))	('white adipocyte differentiation potential', 'CPA', (74, 115))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('ASC', 'Chemical', '-', (45, 48))	('crosstalk', 'Var', (30, 39))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
14490	32478073	p107 expression levels were significantly lower in B-ASCs compared with W-ASCs (Figure 2A), confirming that p107 might also interfere with the thermogenic program in human adipocyte precursors, and is not only restricted to mouse.	('p107', 'Gene', (0, 4))	('ASC', 'Chemical', '-', (74, 77))	('p107', 'Var', (108, 112))	('lower', 'NegReg', (42, 47))	('ASC', 'Chemical', '-', (53, 56))	('human', 'Species', '9606', (166, 171))	('mouse', 'Species', '10090', (224, 229))	('expression levels', 'MPA', (5, 22))	('interfere', 'NegReg', (124, 133))	('thermogenic program', 'MPA', (143, 162))
14492	32478073	This is supported by the significant increase in ASC glucose uptake (Figure 2B), which was significantly higher in B-ASCs compared to ASCs in monoculture, suggesting a higher basal metabolism in the latter type of cells.	('higher', 'PosReg', (105, 111))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('ASC', 'Chemical', '-', (134, 137))	('basal metabolism', 'MPA', (175, 191))	('B-ASCs', 'Var', (115, 121))	('increase', 'PosReg', (37, 45))	('ASC glucose uptake', 'MPA', (49, 67))	('higher', 'PosReg', (168, 174))	('ASC', 'Chemical', '-', (117, 120))	('ASC', 'Chemical', '-', (49, 52))
14502	32478073	Moreover, V-ASCs in obese males are shown to contribute to prostate cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('obese', 'Disease', 'MESH:D009765', (20, 25))	('V-ASCs', 'Var', (10, 16))	('obese', 'Disease', (20, 25))	('prostate cancer', 'Disease', (59, 74))	('contribute', 'Reg', (45, 55))	('ASC', 'Chemical', '-', (12, 15))
14505	32478073	V-ASCs rather than S-ASCs have been described to be more prone to sustain endometrial cancer survival and progression of endometrial cancer in a mouse xenograft model.	('ASC', 'Chemical', '-', (2, 5))	('endometrial cancer', 'Disease', 'MESH:D016889', (74, 92))	('endometrial cancer', 'Disease', (121, 139))	('mouse', 'Species', '10090', (145, 150))	('ASC', 'Chemical', '-', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('endometrial cancer', 'Disease', 'MESH:D016889', (121, 139))	('endometrial cancer', 'Phenotype', 'HP:0012114', (121, 139))	('V-ASCs', 'Var', (0, 6))	('endometrial cancer', 'Disease', (74, 92))	('endometrial cancer', 'Phenotype', 'HP:0012114', (74, 92))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('sustain', 'CPA', (66, 73))
14630	29283884	A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas High proliferation rate and high mutation density are both indicators of poor prognosis in adrenocortical carcinomas.	('adrenocortical carcinomas', 'Disease', (219, 244))	('CDK4', 'Gene', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (102, 127))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (219, 243))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('high mutation density', 'Var', (156, 177))	('CDK4', 'Gene', '1019', (40, 44))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (219, 244))	('CDK6', 'Gene', (49, 53))	('CDK6', 'Gene', '1021', (49, 53))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (102, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (102, 126))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (219, 244))	('adrenocortical carcinomas', 'Disease', (102, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (234, 244))
14632	29283884	In 79 samples downloaded from The Cancer Genome Atlas portal, high Cyclin Dependent Kinase 6 (CDK6) mRNA levels gave the most significant association with shorter time to relapse and poorer survival of patients.	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Cyclin Dependent Kinase 6', 'Gene', '1021', (67, 92))	('shorter', 'NegReg', (155, 162))	('Cancer Genome Atlas', 'Disease', (34, 53))	('Cyclin Dependent Kinase 6', 'Gene', (67, 92))	('patients', 'Species', '9606', (202, 210))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (34, 53))	('poorer', 'NegReg', (183, 189))	('CDK6', 'Gene', (94, 98))	('high', 'Var', (62, 66))	('mRNA levels', 'MPA', (100, 111))
14634	29283884	These tumors tend to cumulate mutations activating the Wnt/beta-catenin pathway and show reduced MIR506 expression.	('activating', 'PosReg', (40, 50))	('beta-catenin', 'Gene', '1499', (59, 71))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('expression', 'MPA', (104, 114))	('mutations', 'Var', (30, 39))	('MIR506', 'Gene', '574511', (97, 103))	('reduced', 'NegReg', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('MIR506', 'Gene', (97, 103))	('beta-catenin', 'Gene', (59, 71))
14640	29283884	Taken together, these data underline the impact of CDK4 and CDK6 inhibitors in treating adrenocortical carcinomas.	('CDK6', 'Gene', (60, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (88, 113))	('inhibitors', 'Var', (65, 75))	('adrenocortical carcinomas', 'Disease', (88, 113))	('CDK4', 'Gene', (51, 55))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (88, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (88, 113))
14645	29283884	In ACCs, mutation density has recently been associated with clinicopathological parameters such as overall survival time and time to recurrence.	('associated', 'Reg', (44, 54))	('mutation density', 'Var', (9, 25))	('ACCs', 'Phenotype', 'HP:0006744', (3, 7))	('ACC', 'Gene', (3, 6))	('ACC', 'Gene', '31', (3, 6))
14649	29283884	We found that CDK6 mRNA is overexpressed in a group of aggressive ACCs enriched in mutations in genes of the Wnt/beta-catenin pathway.	('mutations', 'Var', (83, 92))	('ACCs', 'Phenotype', 'HP:0006744', (66, 70))	('ACC', 'Gene', (66, 69))	('overexpressed', 'PosReg', (27, 40))	('ACC', 'Gene', '31', (66, 69))	('beta-catenin', 'Gene', (113, 125))	('CDK6', 'Gene', (14, 18))	('beta-catenin', 'Gene', '1499', (113, 125))
14651	29283884	Palbociclib (PD-0332991, IBRANCE , Pfizer), and ribociclib (LEE011, Kisqali , Novartis) are both CDK4 and CDK6 (CDK4/6) inhibitors.	('PD-0332991', 'Var', (13, 23))	('CDK4/6', 'Gene', '1021;1019', (112, 118))	('CDK4/6', 'Gene', (112, 118))	('Palbociclib', 'Chemical', 'MESH:C500026', (0, 11))	('PD-0332991', 'Chemical', 'MESH:C500026', (13, 23))	('Novartis', 'Disease', 'None', (78, 86))	('Novartis', 'Disease', (78, 86))
14654	29283884	We thus characterized the impacts of these two FDA-approved CDK4/6 inhibitors on the cell cycle and survival of SW-13 and NCI-H295R cell lines as a first step to test their potential therapeutic properties against ACCs.	('inhibitors', 'Var', (67, 77))	('SW-13', 'CellLine', 'CVCL:0542', (112, 117))	('cell cycle', 'CPA', (85, 95))	('CDK4/6', 'Gene', '1021;1019', (60, 66))	('NCI-H295R', 'CellLine', 'CVCL:0458', (122, 131))	('test', 'Reg', (162, 166))	('ACC', 'Gene', '31', (214, 217))	('survival', 'CPA', (100, 108))	('CDK4/6', 'Gene', (60, 66))	('ACCs', 'Phenotype', 'HP:0006744', (214, 218))	('ACC', 'Gene', (214, 217))
14670	29283884	Increased expression associated with poor prognosis was also observed for genes involved in E2F-dependent G1/S transition (CDK6, CCND1, E2F3-5 and TFDP2), in DNA replication initiation (ORC2L, ORC4L and ORC5L), in S phase checkpoint (TIPIN, TP53) and stalled fork restart and double-strand break repair (SMARCAL1 and MUS81).	('TP53', 'Gene', '7157', (241, 245))	('CCND1', 'Gene', (129, 134))	('E2F3-5', 'Gene', (136, 142))	('MUS81', 'Gene', (317, 322))	('TFDP2', 'Gene', '7029', (147, 152))	('TIPIN', 'Gene', (234, 239))	('expression', 'MPA', (10, 20))	('SMARCAL1', 'Gene', '50485', (304, 312))	('ORC2L', 'Gene', '4999', (186, 191))	('E2F3-5', 'Gene', '1871;1874;1875', (136, 142))	('TFDP2', 'Gene', (147, 152))	('ORC5L', 'Gene', (203, 208))	('SMARCAL1', 'Gene', (304, 312))	('G1/S transition', 'Disease', (106, 121))	('ORC2L', 'Gene', (186, 191))	('TP53', 'Gene', (241, 245))	('Increased', 'PosReg', (0, 9))	('MUS81', 'Gene', '80198', (317, 322))	('TIPIN', 'Gene', '54962', (234, 239))	('ORC5L', 'Gene', '5001', (203, 208))	('ORC4L', 'Gene', (193, 198))	('ORC4L', 'Gene', '5000', (193, 198))	('CCND1', 'Gene', '595', (129, 134))	('E2F-dependent', 'Var', (92, 105))
14675	29283884	The Kaplan-Meier analyses demonstrate a shorter time of OS and RFS of patients associated with high CDK6 expression (Figure 1).	('high', 'Var', (95, 99))	('CDK6', 'Gene', (100, 104))	('OS', 'Chemical', '-', (56, 58))	('patients', 'Species', '9606', (70, 78))
14677	29283884	Since our cell cycle / DNA metabolism approach highlighted the association of high CDK6 expression with short times to relapse and death, we looked for other clinical and molecular features shared by patients showing CDK6 overexpression.	('CDK6', 'Gene', (83, 87))	('expression', 'MPA', (88, 98))	('high', 'Var', (78, 82))	('patients', 'Species', '9606', (200, 208))
14678	29283884	Hierarchical clustering based on mRNA levels of the 500 most variant genes in ACCs led to the constitution of clusters designated 1, 2 and 3.	('ACC', 'Gene', '31', (78, 81))	('ACC', 'Gene', (78, 81))	('variant', 'Var', (61, 68))	('ACCs', 'Phenotype', 'HP:0006744', (78, 82))
14680	29283884	A clinical feature significantly associated with the CDK6 mRNA level is the synthesis of hormones, that are known to be an indication of poor prognosis in ACC patients (Table 2).	('CDK6', 'Var', (53, 57))	('synthesis of hormones', 'MPA', (76, 97))	('ACC', 'Gene', (155, 158))	('associated', 'Reg', (33, 43))	('ACC', 'Gene', '31', (155, 158))	('patients', 'Species', '9606', (159, 167))
14681	29283884	Cluster 2 also includes the majority of mutations and copy number variations that activate the Wnt/beta-catenin signaling pathway.	('activate', 'PosReg', (82, 90))	('mutations', 'Var', (40, 49))	('copy number variations', 'Var', (54, 76))	('beta-catenin', 'Gene', (99, 111))	('beta-catenin', 'Gene', '1499', (99, 111))
14686	29283884	Palbociclib and ribociclib inhibit CDK4/6 and are used for the treatment of breast cancer.	('Palbociclib', 'Chemical', 'MESH:C500026', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ribociclib', 'Var', (16, 26))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('CDK4/6', 'Gene', '1021;1019', (35, 41))	('inhibit', 'NegReg', (27, 34))	('CDK4/6', 'Gene', (35, 41))
14705	29283884	In SW-13 cells treated with palbociclib or ribociclib, we observed a significant increase in the percentage of cells harboring beta-galacto-sidase activity, an indicator of senescence (Figure 4b and Supplementary Figure 2b).	('SW-13', 'CellLine', 'CVCL:0542', (3, 8))	('palbociclib', 'Var', (28, 39))	('palbociclib', 'Chemical', 'MESH:C500026', (28, 39))	('ribociclib', 'Var', (43, 53))	('increase', 'PosReg', (81, 89))	('beta-galacto-sidase', 'Protein', (127, 146))	('activity', 'MPA', (147, 155))
14708	29283884	Taken together, these observations indicate induction of senescence in SW-13 cells after treatment with either palbociclib or ribociclib.	('senescence', 'MPA', (57, 67))	('SW-13', 'CellLine', 'CVCL:0542', (71, 76))	('ribociclib', 'Var', (126, 136))	('palbociclib', 'Chemical', 'MESH:C500026', (111, 122))
14713	29283884	Thus, NCI-H295R cells treated with palbociclib show some features of senescence, but less pronounced than SW-13 cells (Figure 4h).	('SW-13', 'CellLine', 'CVCL:0542', (106, 111))	('palbociclib', 'Chemical', 'MESH:C500026', (35, 46))	('NCI-H295R', 'CellLine', 'CVCL:0458', (6, 15))	('palbociclib', 'Var', (35, 46))	('senescence', 'CPA', (69, 79))
14717	29283884	Such treatments also significantly lowered the amounts of both Phospho-Rb and pRB (Figures 5a and b).	('pRB', 'Gene', (78, 81))	('treatments', 'Var', (5, 15))	('amounts', 'MPA', (47, 54))	('pRB', 'Gene', '5925', (78, 81))	('lowered', 'NegReg', (35, 42))	('Phospho-Rb', 'MPA', (63, 73))
14719	29283884	pRB was not detected in NCI-H295R protein extracts (Figure 5a), which is consistent with the fact that this cell line carries a homozygous deletion of the RB transcriptional corepressor 1 (RB1) gene (COSMIC mutation ID: 19554, c.862_2787del1926).	('c.862_2787del1926', 'Mutation', 'c.862_2787del1926', (227, 244))	('deletion', 'Var', (139, 147))	('pRB', 'Gene', (0, 3))	('NCI-H295R', 'CellLine', 'CVCL:0458', (24, 33))	('OS', 'Chemical', '-', (201, 203))	('pRB', 'Gene', '5925', (0, 3))	('RB transcriptional corepressor 1 (RB1', 'Gene', '5925', (155, 192))
14722	29283884	SW-13 cells treated with either palbociclib or ribociclib showed no detectable apoptotic activity (Figure 6a).	('ribociclib', 'Var', (47, 57))	('SW-13', 'CellLine', 'CVCL:0542', (0, 5))	('palbociclib', 'Chemical', 'MESH:C500026', (32, 43))	('apoptotic activity', 'CPA', (79, 97))
14736	29283884	A previous analysis showed that apoptosis induced by PNU-74654 (an inhibitor of the T cell factor (Tcf)/beta-catenin complex) was preceded by reduction of steroid secretion.	('PNU-74654', 'Var', (53, 62))	('reduction', 'NegReg', (142, 151))	('Tcf', 'Gene', (99, 102))	('beta-catenin', 'Gene', (104, 116))	('T cell factor', 'Gene', (84, 97))	('apoptosis', 'CPA', (32, 41))	('beta-catenin', 'Gene', '1499', (104, 116))	('PNU-74654', 'Chemical', '-', (53, 62))	('steroid secretion', 'MPA', (155, 172))	('T cell factor', 'Gene', '3172', (84, 97))	('steroid', 'Chemical', 'MESH:D013256', (155, 162))	('Tcf', 'Gene', '3172', (99, 102))
14740	29283884	Yet, 100 muM PNU-74654 decreased cortisol production by 80% after 24 h treatment (p value = 0.14) and by 72% after 48 h treatment (p value = 6.7 x 10-4).	('cortisol', 'Chemical', 'MESH:D006854', (33, 41))	('PNU-74654', 'Var', (13, 22))	('muM', 'Gene', '56925', (9, 12))	('cortisol production', 'MPA', (33, 52))	('PNU-74654', 'Chemical', '-', (13, 22))	('decreased cortisol', 'Phenotype', 'HP:0008163', (23, 41))	('decreased', 'NegReg', (23, 32))	('muM', 'Gene', (9, 12))
14743	29283884	Together, these results show that palbociclib-induced apoptosis is associated with a remarkable reduction of the amount of beta-catenin and alters beta-catenin-dependent transcription.	('apoptosis', 'CPA', (54, 63))	('beta-catenin', 'Gene', '1499', (147, 159))	('beta-catenin', 'Gene', '1499', (123, 135))	('beta-catenin', 'Gene', (123, 135))	('alters', 'Reg', (140, 146))	('palbociclib-induced', 'Var', (34, 53))	('palbociclib', 'Chemical', 'MESH:C500026', (34, 45))	('beta-catenin', 'Gene', (147, 159))	('reduction', 'NegReg', (96, 105))
14755	29283884	Altered gene expression and mutations affecting translesion polymerases have been observed in a variety of tumors and have been suggested to act as biomarkers in response to treatments.	('translesion polymerases', 'Enzyme', (48, 71))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('observed', 'Reg', (82, 90))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('gene expression', 'MPA', (8, 23))	('mutations', 'Var', (28, 37))
14756	29283884	The ability of translesion polymerases to perform synthesis despite DNA lesions contributes to resistance to DNA damaging treatments, and previous analyses have shown that their inhibition sensitizes tumors to chemotherapeutic agents.	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('lesions', 'Var', (72, 79))	('synthesis', 'MPA', (50, 59))	('resistance', 'MPA', (95, 105))	('contributes', 'Reg', (80, 91))	('translesion', 'Enzyme', (15, 26))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('inhibition', 'NegReg', (178, 188))	('DNA', 'Gene', (68, 71))	('sensitizes', 'Reg', (189, 199))
14757	29283884	Translesion polymerases are also error-prone, and thus can contribute to mutagenesis in tumors and progression of cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Disease', (114, 121))	('mutagenesis', 'Var', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Translesion', 'Protein', (0, 11))	('tumors', 'Disease', (88, 94))	('contribute', 'Reg', (59, 69))
14758	29283884	Our analyses show that abnormal gene expression of translesion DNA polymerases is indeed a marker of poor prognosis independent of proliferation in ACCs.	('translesion DNA polymerases', 'Protein', (51, 78))	('ACC', 'Gene', '31', (148, 151))	('ACCs', 'Phenotype', 'HP:0006744', (148, 152))	('ACC', 'Gene', (148, 151))	('abnormal gene', 'Var', (23, 36))
14770	29283884	However, the senescence phenotype was more pronounced in palbociclib-treated cells and we could not exclude the involvement of other targets.	('senescence', 'MPA', (13, 23))	('palbociclib-treated', 'Var', (57, 76))	('palbociclib', 'Chemical', 'MESH:C500026', (57, 68))
14772	29283884	A homozygous deletion in the RB1 gene was previously described, and we confirmed the absence of the pRB protein in NCI-H295R extracts (Figure 5).	('absence', 'NegReg', (85, 92))	('deletion', 'Var', (13, 21))	('pRB', 'Gene', (100, 103))	('RB1', 'Gene', (29, 32))	('NCI-H295R', 'CellLine', 'CVCL:0458', (115, 124))	('RB1', 'Gene', '5925', (29, 32))	('pRB', 'Gene', '5925', (100, 103))
14773	29283884	The absence of pRB is probably involved in the NCI-H295R resistance to ribociclib, and also the relative resistance to palbociclib, as was observed in different types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('NCI-H295R', 'CellLine', 'CVCL:0458', (47, 56))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('involved', 'Reg', (31, 39))	('pRB', 'Gene', '5925', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('absence', 'Var', (4, 11))	('pRB', 'Gene', (15, 18))	('palbociclib', 'Chemical', 'MESH:C500026', (119, 130))
14782	29283884	Our results are consistent with the higher AXIN2 mRNA level observed in NCI-H295R cells after treatment with PNU-74654, an inhibitor of Wnt/beta-catenin signaling.	('higher', 'PosReg', (36, 42))	('beta-catenin', 'Gene', '1499', (140, 152))	('PNU-74654', 'Var', (109, 118))	('AXIN2', 'Gene', '8313', (43, 48))	('PNU-74654', 'Chemical', '-', (109, 118))	('NCI-H295R', 'CellLine', 'CVCL:0458', (72, 81))	('AXIN2', 'Gene', (43, 48))	('beta-catenin', 'Gene', (140, 152))
14784	29283884	Taken together, our observations suggest that palbociclib induces a strong reduction of active beta-catenin, leading to aberrant transcription of beta-catenin targets and to apoptosis.	('palbociclib', 'Var', (46, 57))	('beta-catenin', 'Gene', (146, 158))	('apoptosis', 'CPA', (174, 183))	('active', 'MPA', (88, 94))	('beta-catenin', 'Gene', (95, 107))	('transcription of', 'MPA', (129, 145))	('beta-catenin', 'Gene', '1499', (146, 158))	('reduction', 'NegReg', (75, 84))	('palbociclib', 'Chemical', 'MESH:C500026', (46, 57))	('beta-catenin', 'Gene', '1499', (95, 107))
14785	29283884	Besides its impact on beta-catenin-dependent transcription, PNU-74654 also decreased steroid hormone secretion by NCI-H295R cells, as early as after 24 h of treatment, at con-centrations higher than 50 muM.	('beta-catenin', 'Gene', '1499', (22, 34))	('muM', 'Gene', '56925', (202, 205))	('steroid hormone secretion', 'MPA', (85, 110))	('steroid hormone', 'Chemical', 'MESH:D013256', (85, 100))	('PNU-74654', 'Var', (60, 69))	('muM', 'Gene', (202, 205))	('beta-catenin', 'Gene', (22, 34))	('PNU-74654', 'Chemical', '-', (60, 69))	('NCI-H295R', 'CellLine', 'CVCL:0458', (114, 123))	('decreased', 'NegReg', (75, 84))
14786	29283884	This reduction preceded the decreased of viability (only after 72 h treatment with 50 muM PNU-74654) and was supposed to result partially from the reduction in gene expression of SF1 and CYP21A2 genes.	('gene expression', 'MPA', (160, 175))	('PNU-74654', 'Chemical', '-', (90, 99))	('SF1', 'Gene', (179, 182))	('muM', 'Gene', '56925', (86, 89))	('reduction', 'NegReg', (5, 14))	('decreased', 'NegReg', (28, 37))	('CYP21A2', 'Gene', (187, 194))	('viability', 'CPA', (41, 50))	('muM', 'Gene', (86, 89))	('CYP21A2', 'Gene', '1589', (187, 194))	('SF1', 'Gene', '7536', (179, 182))	('PNU-74654', 'Var', (90, 99))	('reduction', 'NegReg', (147, 156))
14787	29283884	While we confirmed that 100 muM PNU-74654 decreased cortisol secretion, we observed no effect of palbociclib and ribociclib on the concentration of cortisol in the medium, after 24 h and 48 h of treatments (Figure 6f).	('PNU-74654', 'Var', (32, 41))	('decreased', 'NegReg', (42, 51))	('muM', 'Gene', '56925', (28, 31))	('decreased cortisol', 'Phenotype', 'HP:0008163', (42, 60))	('PNU-74654', 'Chemical', '-', (32, 41))	('cortisol secretion', 'MPA', (52, 70))	('muM', 'Gene', (28, 31))	('palbociclib', 'Chemical', 'MESH:C500026', (97, 108))	('cortisol', 'Chemical', 'MESH:D006854', (52, 60))	('cortisol', 'Chemical', 'MESH:D006854', (148, 156))
14788	29283884	Actually, PNU-74654 results in direct inhibition of beta-catenin-dependent transcription that might cause the reduction of cortisol secretion as soon as after 24 h, comparatively to palbociclib that induces beta-catenin degradation (Figures 6b and 6d).	('palbociclib', 'Chemical', 'MESH:C500026', (182, 193))	('reduction', 'NegReg', (110, 119))	('beta-catenin', 'Gene', (52, 64))	('cortisol', 'Chemical', 'MESH:D006854', (123, 131))	('beta-catenin', 'Gene', (207, 219))	('PNU-74654', 'Var', (10, 19))	('cortisol secretion', 'MPA', (123, 141))	('beta-catenin', 'Gene', '1499', (52, 64))	('inhibition', 'NegReg', (38, 48))	('beta-catenin', 'Gene', '1499', (207, 219))	('PNU-74654', 'Chemical', '-', (10, 19))
14797	29283884	In conclusion, we showed that patients with high CDK6 expression levels present a poor prognosis, and are found in a unique gene expression-based cluster.	('expression', 'MPA', (54, 64))	('CDK6', 'Gene', (49, 53))	('patients', 'Species', '9606', (30, 38))	('high', 'Var', (44, 48))
14798	29283884	They share common clinical and molecular features, such as secretion of hormones and the tendency to accumulate mutations in the Wnt/beta-catenin pathway.	('mutations', 'Var', (112, 121))	('secretion', 'MPA', (59, 68))	('beta-catenin', 'Gene', (133, 145))	('beta-catenin', 'Gene', '1499', (133, 145))
14806	29283884	Palbociclib (PD-0332991, IBRANCE ), Ribociclib (LEE-011, Kiskali ), Mitotane and PNU-74654 were purchased from CliniSciences (A8316, A8641, sc-205754 and sc-258020, respectively).	('Mitotane', 'Chemical', 'MESH:D008939', (68, 76))	('Palbociclib', 'Chemical', 'MESH:C500026', (0, 11))	('PD-0332991', 'Chemical', 'MESH:C500026', (13, 23))	('A8316', 'Var', (126, 131))	('A8641', 'Var', (133, 138))	('PNU-74654', 'Chemical', '-', (81, 90))
14843	27603373	First case report of an adrenocortical carcinoma caused by a BRCA2 mutation Adrenocortical carcinoma (ACC) may rarely be a component of inherited cancer syndromes such as Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome.	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (196, 223))	('adrenocortical carcinoma', 'Disease', (24, 48))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Adrenocortical carcinoma', 'Disease', (76, 100))	('mutation', 'Var', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('Li-Fraumeni syndrome', 'Disease', (171, 191))	('caused by', 'Reg', (49, 58))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (24, 48))	('BRCA2', 'Gene', (61, 66))	('Beckwith-Wiedemann syndrome', 'Disease', (196, 223))	('ACC', 'Phenotype', 'HP:0006744', (102, 105))	('component of inherited cancer', 'Disease', (123, 152))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (171, 191))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (76, 100))	('component of inherited cancer', 'Disease', 'MESH:D009386', (123, 152))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (24, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('BRCA2', 'Gene', '675', (61, 66))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (76, 100))
14844	27603373	ACC caused by a BRCA2 mutation has never been reported.	('mutation', 'Var', (22, 30))	('BRCA2', 'Gene', (16, 21))	('caused by', 'Reg', (4, 13))	('BRCA2', 'Gene', '675', (16, 21))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('ACC', 'Disease', (0, 3))
14846	27603373	A germline BRCA2 2 bp heterozygous deletion at nucleotide 8765 (8765delAG) leading to a frameshift mutation (p.Glu2846GlyfsX23) was detected.	('8765delAG', 'Mutation', 'c.8765delAG', (64, 73))	('BRCA2', 'Gene', '675', (11, 16))	('p.Glu2846GlyfsX23', 'Var', (109, 126))	('8765delAG', 'Var', (64, 73))	('BRCA2', 'Gene', (11, 16))	('p.Glu2846GlyfsX23', 'Mutation', 'rs80359714', (109, 126))
14849	27603373	Loss of heterozygosity in ACC DNA suggests a causal link with the BRCA2 8765delAG mutation.	('BRCA2', 'Gene', (66, 71))	('ACC', 'Phenotype', 'HP:0006744', (26, 29))	('BRCA2', 'Gene', '675', (66, 71))	('8765delAG', 'Mutation', 'c.8765delAG', (72, 81))	('8765delAG', 'Var', (72, 81))
14851	27603373	Germline mutations in BRCA1 (MIM 113705) and BRCA2 (MIM 600185) genes account for cancer predisposition in majority of families with breast only or breast-ovarian cancer families.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('BRCA2', 'Gene', (45, 50))	('BRCA2', 'Gene', '675', (45, 50))	('MIM 600185', 'Var', (52, 62))	('breast-ovarian cancer', 'Disease', 'MESH:D010051', (148, 169))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('BRCA1', 'Gene', '672', (22, 27))	('breast only', 'Disease', (133, 144))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('breast-ovarian cancer', 'Disease', (148, 169))	('MIM 113705', 'Var', (29, 39))	('account', 'Reg', (70, 77))	('BRCA1', 'Gene', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (163, 169))
14852	27603373	To date, BRCA2 mutation in ACC has never been reported.	('mutation', 'Var', (15, 23))	('BRCA2', 'Gene', (9, 14))	('BRCA2', 'Gene', '675', (9, 14))	('ACC', 'Phenotype', 'HP:0006744', (27, 30))
14853	27603373	We describe here a case of ACC associated with a germline BRCA2 mutation in a family whose cancer history was compatible with a Li-Fraumeni-like (LFL) syndrome.	('mutation', 'Var', (64, 72))	('BRCA2', 'Gene', '675', (58, 63))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('associated', 'Reg', (31, 41))	('germline', 'Var', (49, 57))	('Li-Fraumeni-like (LFL) syndrome', 'Disease', 'MESH:C567189', (128, 159))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ACC', 'Phenotype', 'HP:0006744', (27, 30))	('BRCA2', 'Gene', (58, 63))	('ACC', 'Disease', (27, 30))
14862	27603373	The 8765delAG BRCA2 mutation was identified in this family.	('8765delAG', 'Mutation', 'c.8765delAG', (4, 13))	('BRCA2', 'Gene', (14, 19))	('BRCA2', 'Gene', '675', (14, 19))	('8765delAG', 'Var', (4, 13))
14863	27603373	After giving his written informed consent, the patient had genetic analysis for the 8765delAG BRCA2 mutation and the TP53 gene.	('patient', 'Species', '9606', (47, 54))	('8765delAG', 'Var', (84, 93))	('BRCA2', 'Gene', (94, 99))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('BRCA2', 'Gene', '675', (94, 99))	('8765delAG', 'Mutation', 'c.8765delAG', (84, 93))
14867	27603373	The germline BRCA2 2 bp heterozygous deletion at nucleotide 8765 (8765delAG) (Breast Cancer Information Core nomenclature) or c.8537_8538delAG (human genome variation society nomenclature) was identified.	('Breast Cancer', 'Disease', (78, 91))	('c.8537_8538delAG', 'Var', (126, 142))	('c.8537_8538delAG', 'Mutation', 'rs80359714', (126, 142))	('human', 'Species', '9606', (144, 149))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('8765delAG', 'Mutation', 'c.8765delAG', (66, 75))	('Breast Cancer', 'Disease', 'MESH:D001943', (78, 91))	('Breast Cancer', 'Phenotype', 'HP:0003002', (78, 91))	('BRCA2', 'Gene', (13, 18))	('8765delAG', 'Var', (66, 75))	('BRCA2', 'Gene', '675', (13, 18))
14868	27603373	The deletion leads to a frameshift mutation (p.Glu2846Glyfs) and a stop codon (Fig.	('p.Glu2846Gly', 'SUBSTITUTION', 'None', (45, 57))	('p.Glu2846Gly', 'Var', (45, 57))	('leads to', 'Reg', (13, 21))
14870	27603373	In addition, TP53 gene analysis revealed a previously reported heterozygous polymorphism in exon 4 (c.215C>G, p.Pro72Arg) (rs1042522, NM_000546.5).	('rs1042522', 'Var', (123, 132))	('c.215C>G', 'Var', (100, 108))	('TP53', 'Gene', (13, 17))	('p.Pro72Arg', 'Mutation', 'rs1042522', (110, 120))	('TP53', 'Gene', '7157', (13, 17))	('NM_000546.5', 'Var', (134, 145))	('c.215C>G', 'Mutation', 'rs1042522', (100, 108))	('rs1042522', 'Mutation', 'rs1042522', (123, 132))
14875	27603373	Analyses of inherited syndromes related to ACC led to the progress in the pathogenesis of ACC including the LFS due to germline TP53 mutations, the BWS due to the deregulation of imprinted genes in the chromosome 11p15.5 region, which contains the insulin-like growth factor 2 and the closed linked H19 gene in the imprinting center 1, the Lynch syndrome due to a defect in the mismatch repair system (MSH2, MSH6, MLH1), and more rarely the MEN1 (menin) and FAP syndromes (APC).	('TP53', 'Gene', '7157', (128, 132))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('insulin-like growth factor 2', 'Gene', (248, 276))	('menin', 'Gene', '4221', (447, 452))	('mismatch repair system', 'Protein', (378, 400))	('menin', 'Gene', (447, 452))	('Lynch syndrome', 'Disease', (340, 354))	('deregulation', 'Var', (163, 175))	('MEN1', 'Gene', '4221', (441, 445))	('mutations', 'Var', (133, 142))	('FAP syndromes', 'Disease', (458, 471))	('APC', 'Disease', 'MESH:D011125', (473, 476))	('defect', 'NegReg', (364, 370))	('APC', 'Disease', (473, 476))	('Lynch syndrome', 'Disease', 'MESH:D003123', (340, 354))	('H19', 'Gene', (299, 302))	('TP53', 'Gene', (128, 132))	('MEN1', 'Gene', (441, 445))	('insulin-like growth factor 2', 'Gene', '3481', (248, 276))	('MSH2', 'Gene', (402, 406))	('LFS', 'Disease', (108, 111))	('MLH1', 'Gene', (414, 418))	('LFS', 'Disease', 'MESH:D016864', (108, 111))	('MSH6', 'Gene', (408, 412))	('H19', 'Gene', '283120', (299, 302))	('MSH6', 'Gene', '2956', (408, 412))	('FAP syndromes', 'Disease', 'MESH:C567782', (458, 471))	('MSH2', 'Gene', '4436', (402, 406))	('ACC', 'Phenotype', 'HP:0006744', (90, 93))	('MLH1', 'Gene', '4292', (414, 418))
14876	27603373	LFS results from a germline mutation in the TP53 gene predisposing individuals to cancers with early onset, including breast cancer, soft tissue and osteosarcomas, brain cancers, leukemia, and ACC.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('ACC', 'Phenotype', 'HP:0006744', (193, 196))	('brain cancers', 'Disease', 'MESH:D001932', (164, 177))	('ACC', 'Disease', (193, 196))	('cancers', 'Disease', (170, 177))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('osteosarcomas', 'Phenotype', 'HP:0002669', (149, 162))	('TP53', 'Gene', (44, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('LFS', 'Disease', (0, 3))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('LFS', 'Disease', 'MESH:D016864', (0, 3))	('breast cancer', 'Disease', (118, 131))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('leukemia', 'Phenotype', 'HP:0001909', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('soft tissue', 'Disease', (133, 144))	('TP53', 'Gene', '7157', (44, 48))	('osteosarcoma', 'Phenotype', 'HP:0002669', (149, 161))	('osteosarcomas', 'Disease', 'MESH:D012516', (149, 162))	('leukemia', 'Disease', (179, 187))	('brain cancers', 'Disease', (164, 177))	('germline mutation', 'Var', (19, 36))	('leukemia', 'Disease', 'MESH:D007938', (179, 187))	('results from', 'Reg', (4, 16))	('osteosarcomas', 'Disease', (149, 162))
14877	27603373	TP53 mutations account for up to 50% to 70% of the families with classic LFS.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('LFS', 'Disease', (73, 76))	('LFS', 'Disease', 'MESH:D016864', (73, 76))
14879	27603373	Up to 20% to 40% of LFL families carry TP53 mutations.	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
14880	27603373	Of all the cancers associated with mutations of TP53, ACC is the one whose frequency is the most increased compared with the general population.	('TP53', 'Gene', '7157', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ACC', 'Phenotype', 'HP:0006744', (54, 57))	('TP53', 'Gene', (48, 52))	('ACC', 'Disease', (54, 57))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('mutations', 'Var', (35, 44))
14882	27603373	Two genes were studied: BRCA2 because the French Canadian founder mutation 8765delAG was previously found to be associated with breast, ovarian, and pancreatic cancers in his maternal family, and TP53 because of his family history and his diagnosis of ACC; recently the prevalence of germline TP53 mutations in apparently sporadic adult ACC patients was found to be between 3% and 6% supporting to propose TP53 genetic analysis to all patients with ACC.	('TP53', 'Gene', (196, 200))	('ACC', 'Phenotype', 'HP:0006744', (337, 340))	('patients', 'Species', '9606', (341, 349))	('TP53', 'Gene', '7157', (406, 410))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (149, 167))	('BRCA2', 'Gene', (24, 29))	('pancreatic cancers', 'Disease', (149, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('TP53', 'Gene', '7157', (293, 297))	('patients', 'Species', '9606', (435, 443))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('TP53', 'Gene', '7157', (196, 200))	('ovarian', 'Disease', (136, 143))	('pancreatic cancers', 'Disease', 'MESH:D010190', (149, 167))	('BRCA2', 'Gene', '675', (24, 29))	('ACC', 'Phenotype', 'HP:0006744', (252, 255))	('TP53', 'Gene', (406, 410))	('8765delAG', 'Mutation', 'c.8765delAG', (75, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('TP53', 'Gene', (293, 297))	('breast', 'Disease', (128, 134))	('ACC', 'Phenotype', 'HP:0006744', (449, 452))	('8765delAG', 'Var', (75, 84))	('mutations', 'Var', (298, 307))	('associated', 'Reg', (112, 122))
14883	27603373	We found that our patient was a heterozygous carrier of the 8765delAG BRCA2 mutation.	('8765delAG', 'Mutation', 'c.8765delAG', (60, 69))	('BRCA2', 'Gene', '675', (70, 75))	('8765delAG', 'Var', (60, 69))	('patient', 'Species', '9606', (18, 25))	('BRCA2', 'Gene', (70, 75))
14884	27603373	The BRCA2 8765delAG or c.8537_8538delAG mutation was first described in breast cancer families from French-Canadian and Jewish-Yemenite populations and is one of the most frequent founder mutations reported in French Canadian breast-only or breast-ovarian cancer families; many of the families had members with cancers at other sites but no ACC was described in BRCA2-linked families to this date.	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast-ovarian cancer', 'Disease', (241, 262))	('BRCA2', 'Gene', '675', (362, 367))	('breast cancer', 'Disease', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('c.8537_8538delAG', 'Mutation', 'rs80359714', (23, 39))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('ACC', 'Phenotype', 'HP:0006744', (341, 344))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('BRCA2', 'Gene', (4, 9))	('8765delAG', 'Mutation', 'c.8765delAG', (10, 19))	('BRCA2', 'Gene', (362, 367))	('breast-ovarian cancer', 'Disease', 'MESH:D010051', (241, 262))	('ovarian cancer', 'Phenotype', 'HP:0100615', (248, 262))	('8765delAG', 'Var', (10, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('BRCA2', 'Gene', '675', (4, 9))	('c.8537_8538delAG', 'Var', (23, 39))
14885	27603373	Two cases of adrenal tumors in BRCA1/BRCA2 mutation carriers have been described previously: the first was a cystic lymphangioma in a 46 yo Ashkenazi woman diagnosed with breast and ovarian cancer and carrying the 185delAG mutation in the BRCA1 gene; the second was a pheochromocytoma in a 61 yo Ashkenazi woman diagnosed with breast cancer and harboring the BRCA2 6174delT mutation.	('BRCA2', 'Gene', (359, 364))	('pheochromocytoma', 'Disease', 'MESH:D010673', (268, 284))	('cystic lymphangioma', 'Disease', (109, 128))	('ovarian cancer', 'Phenotype', 'HP:0100615', (182, 196))	('woman', 'Species', '9606', (150, 155))	('lymphangioma', 'Phenotype', 'HP:0100764', (116, 128))	('adrenal tumor', 'Phenotype', 'HP:0100631', (13, 26))	('cystic lymphangioma', 'Phenotype', 'HP:0030785', (109, 128))	('pheochromocytoma', 'Disease', (268, 284))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (268, 284))	('adrenal tumors', 'Disease', 'MESH:D000310', (13, 27))	('185delAG', 'Mutation', 'c.185delAG', (214, 222))	('mutation', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('BRCA2', 'Gene', '675', (359, 364))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('BRCA1', 'Gene', '672', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('BRCA1', 'Gene', (239, 244))	('woman', 'Species', '9606', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('BRCA2', 'Gene', (37, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (327, 340))	('adrenal tumors', 'Disease', (13, 27))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (171, 196))	('BRCA1', 'Gene', '672', (31, 36))	('breast cancer', 'Disease', 'MESH:D001943', (327, 340))	('6174delT', 'Mutation', 'rs786204278', (365, 373))	('BRCA1', 'Gene', (31, 36))	('breast cancer', 'Disease', (327, 340))	('185delAG', 'Var', (214, 222))	('BRCA2', 'Gene', '675', (37, 42))	('6174delT mutation', 'Var', (365, 382))	('cystic lymphangioma', 'Disease', 'MESH:D018191', (109, 128))
14888	27603373	In the case of our patient, loss of heterozygosity in ACC tumoral DNA as described previously in most tumors related to BRCA2 gene mutations suggests a causal link between the BRCA2 8765delAG mutation and the ACC.	('BRCA2', 'Gene', (176, 181))	('patient', 'Species', '9606', (19, 26))	('BRCA2', 'Gene', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('8765delAG', 'Mutation', 'c.8765delAG', (182, 191))	('BRCA2', 'Gene', '675', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('BRCA2', 'Gene', '675', (120, 125))	('8765delAG', 'Var', (182, 191))	('tumors', 'Disease', (102, 108))	('ACC', 'Phenotype', 'HP:0006744', (54, 57))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (131, 140))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('ACC', 'Phenotype', 'HP:0006744', (209, 212))	('ACC', 'Disease', (209, 212))
14889	27603373	The simultaneous presence of TP53 gene p.Pro72Arg polymorphism and the BRCA2 8765delAG mutation may suggest a potential interaction between these 2 genetic defects.	('genetic defects', 'Disease', 'MESH:D030342', (148, 163))	('interaction', 'Interaction', (120, 131))	('8765delAG', 'Var', (77, 86))	('BRCA2', 'Gene', (71, 76))	('p.Pro72Arg', 'Mutation', 'rs1042522', (39, 49))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('BRCA2', 'Gene', '675', (71, 76))	('p.Pro72Arg', 'Var', (39, 49))	('genetic defects', 'Disease', (148, 163))	('8765delAG', 'Mutation', 'c.8765delAG', (77, 86))
14893	27603373	Furthermore, the efficacy of ACC surveillance strategy among children found to have a TP53 mutation was proven with better outcome and survival.	('mutation', 'Var', (91, 99))	('TP53', 'Gene', '7157', (86, 90))	('ACC', 'Phenotype', 'HP:0006744', (29, 32))	('TP53', 'Gene', (86, 90))	('children', 'Species', '9606', (61, 69))
14894	27603373	Thus, the identification of an unsuspected germline TP53 mutation may entail a clinical surveillance protocol for the detection of asymptomatic nonadrenal neoplasms in individuals with germline TP53 mutations.	('mutation', 'Var', (57, 65))	('TP53', 'Gene', '7157', (52, 56))	('neoplasms', 'Disease', 'MESH:D009369', (155, 164))	('neoplasms', 'Disease', (155, 164))	('TP53', 'Gene', (52, 56))	('TP53', 'Gene', '7157', (194, 198))	('TP53', 'Gene', (194, 198))	('mutations', 'Var', (199, 208))	('neoplasms', 'Phenotype', 'HP:0002664', (155, 164))
14896	27603373	Loss of heterozygosity in tumoral DNA confirms that the BRCA2 8765delAG mutation plays a role in adrenal oncogenesis supporting that ACC may be included in the spectrum of cancer-related BRCA2 gene.	('adrenal oncogenesis', 'CPA', (97, 116))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('BRCA2', 'Gene', '675', (56, 61))	('BRCA2', 'Gene', (187, 192))	('8765delAG', 'Mutation', 'c.8765delAG', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Disease', (26, 31))	('BRCA2', 'Gene', '675', (187, 192))	('ACC', 'Phenotype', 'HP:0006744', (133, 136))	('cancer', 'Disease', (172, 178))	('8765delAG', 'Var', (62, 71))	('BRCA2', 'Gene', (56, 61))
14932	27104180	The pathogenesis of Carney complex has been attributed predominantly to an inactivating germline mutation in protein kinase A regulatory-subunit type 1alpha (PRKAR1A) and in rare circumstance to alterations of the Carney complex type 2 (CNC2) gene loci.	('germline mutation', 'Var', (88, 105))	('CNC2', 'Gene', (237, 241))	('PRKAR1A', 'Gene', (158, 165))	('Carney complex type 2', 'Gene', (214, 235))	('inactivating', 'Reg', (75, 87))	('PRKAR1A', 'Gene', '5573', (158, 165))	('Carney complex', 'Disease', (20, 34))	('Carney complex type 2', 'Gene', '1257', (214, 235))	('CNC2', 'Gene', '1257', (237, 241))
14933	27104180	MAD cases have been associated with inactivating mutations in phosphodiesterase genes (PDE11A, PDE8B), and alterations of 2p12-p16 and 5q.	('phosphodiesterase', 'Gene', (62, 79))	('associated', 'Reg', (20, 30))	('2p12-p16', 'Gene', (122, 130))	('PDE8B', 'Gene', '8622', (95, 100))	('PDE8B', 'Gene', (95, 100))	('phosphodiesterase', 'Gene', '50940', (62, 79))	('alterations', 'Var', (107, 118))	('PDE11A', 'Gene', '50940', (87, 93))	('inactivating mutations', 'Var', (36, 58))	('PDE11A', 'Gene', (87, 93))
14946	27104180	Judging by the above-mentioned information, we can cautiously conclude that this patient might have a proliferation malfunction or a mutation in a tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('mutation', 'Var', (133, 141))	('patient', 'Species', '9606', (81, 88))	('proliferation malfunction', 'CPA', (102, 127))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
15016	24155044	The prolonged median interval between PP onset and diagnosis followed by favorable outcome in patients with low grade brain tumors can likely be explained by the less aggressive nature of the tumor, and the adolescent age of most of the patients which may have masked pathologic puberty.	('brain tumors', 'Disease', (118, 130))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('patients', 'Species', '9606', (94, 102))	('brain tumor', 'Phenotype', 'HP:0030692', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('low grade', 'Var', (108, 117))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('brain tumors', 'Phenotype', 'HP:0030692', (118, 130))	('patients', 'Species', '9606', (237, 245))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('PP', 'Phenotype', 'HP:0000826', (38, 40))	('brain tumors', 'Disease', 'MESH:D001932', (118, 130))
15051	24155044	However, as observed in our study, patients with low-grade brain tumors may have a long history of neuroendocrine dysregulation before other signs and symptoms prompt additional evaluation.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('neuroendocrine dysregulation', 'Disease', 'MESH:D018358', (99, 127))	('low-grade', 'Var', (49, 58))	('brain tumors', 'Disease', 'MESH:D001932', (59, 71))	('neuroendocrine dysregulation', 'Disease', (99, 127))	('brain tumors', 'Phenotype', 'HP:0030692', (59, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (35, 43))	('brain tumors', 'Disease', (59, 71))	('brain tumor', 'Phenotype', 'HP:0030692', (59, 70))
15358	22008415	The size of the tumor, presence of hemorrhage, and nuclear pleomorphism in the present case were suggestive of a malignant nature.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('hemorrhage', 'Disease', (35, 45))	('nuclear pleomorphism', 'Var', (51, 71))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('hemorrhage', 'Disease', 'MESH:D006470', (35, 45))	('tumor', 'Disease', (16, 21))
15373	31973134	The highest mutation was found in the R321*/Q amino acid of BMP5 corresponding to colorectal and breast cancer whereas the alteration frequency was higher in lung squamous carcinoma datasets (>4%).	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (158, 181))	('R321*', 'Var', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (163, 181))	('R321*', 'SUBSTITUTION', 'None', (38, 43))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (158, 181))	('BMP5', 'Gene', (60, 64))	('colorectal and breast cancer', 'Disease', 'MESH:D001943', (82, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('lung squamous carcinoma', 'Disease', (158, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))
15379	31973134	One of the most dominant causes of oncogenesis is the accumulation of gene alterations which has a positive correlation to the prognosis of cancer patients.	('gene alterations', 'Var', (70, 86))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patients', 'Species', '9606', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
15382	31973134	Mutation in BMP5 is associated with a wide range of skeletal defects such as reduction in the long bone width and the size of the vertebral processes as well as the reduction of lower body mass.	('associated', 'Reg', (20, 30))	('skeletal defects', 'Phenotype', 'HP:0000924', (52, 68))	('BMP5', 'Gene', (12, 16))	('reduction', 'NegReg', (77, 86))	('Mutation', 'Var', (0, 8))	('skeletal defects', 'Disease', 'MESH:D009358', (52, 68))	('long bone width', 'CPA', (94, 109))	('lower body mass', 'Phenotype', 'HP:0004325', (178, 193))	('reduction', 'NegReg', (165, 174))	('lower body mass', 'CPA', (178, 193))	('skeletal defects', 'Disease', (52, 68))	('long bone width', 'Phenotype', 'HP:0005622', (94, 109))
15384	31973134	Previous studies on colorectal cancer showed a significant correlation between BMP5 down-expression and mutation and the prognostic value of colorectal cancer (CRC), triggering the initiation and development of tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CRC', 'Phenotype', 'HP:0003003', (160, 163))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('colorectal cancer', 'Disease', (20, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('down-expression', 'NegReg', (84, 99))	('mutation', 'Var', (104, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (20, 37))	('colorectal cancer', 'Disease', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('triggering', 'Reg', (166, 176))	('BMP5', 'Gene', (79, 83))
15385	31973134	One study reported that 13 cases of BMP5 mutation across seven cancers where gastrointestinal cancers (GICs) were the most influenced by recurrent hotspot mutations.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (77, 101))	('BMP5', 'Gene', (36, 40))	('gastrointestinal cancers', 'Disease', (77, 101))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutation', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', (94, 101))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
15432	31973134	In Figure 3C,E-G the GSE17536 and GSE17333 datasets exhibited that the patient group with low level of BMP5 mRNA expression (n = 93, 101, 118 and 146, respectively) reported significantly poor overall survival compared to the high expression group (n = 84, 76, 108 and 31, respectively), whereas one alteration reported by dataset GSE17537 contradicted the association of BMP5 low expression with overall survival of colorectal cancer patients (Figure 3D).	('colorectal cancer', 'Disease', (417, 434))	('overall survival', 'MPA', (193, 209))	('poor', 'NegReg', (188, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (417, 434))	('patients', 'Species', '9606', (435, 443))	('cancer', 'Phenotype', 'HP:0002664', (428, 434))	('colorectal cancer', 'Phenotype', 'HP:0003003', (417, 434))	('patient', 'Species', '9606', (71, 78))	('low', 'Var', (90, 93))	('patient', 'Species', '9606', (435, 442))
15433	31973134	Analysis of GSE31210 and Jacob-00182-MSK datasets of PrognoScan showed significantly (p-value) lower survival of lung cancer patients in the low BMP5 mRNA expression group (n = 35, 42, 12, 39 and 24, respectively) compared to their higher expression counterparts (n = 169, 162, 92, 65 and 180, respectively; Figure 3H-L and Supplementary Table S3).	('lower', 'NegReg', (95, 100))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('survival', 'MPA', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('low BMP5', 'Var', (141, 149))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('patients', 'Species', '9606', (125, 133))
15434	31973134	High survival ratio was exhibited in low BMP5 expression group (n = 70 and 90, respectively) of ovarian cancer compared to the high expression group (n = 63 and 43, respectively), according to the DUKE-OC dataset (Figure 3M,N and Supplementary Table S3).	('low BMP5 expression', 'Var', (37, 56))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (96, 110))	('ovarian cancer', 'Disease', (96, 110))
15443	31973134	The database queried for the BMP5 gene mutations in 15,405 number of samples from 26 cancer studies of breast, colorectal, lung, bladder, and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colorectal', 'Disease', (111, 121))	('ovarian cancer', 'Disease', (142, 156))	('breast', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('BMP5', 'Gene', (29, 33))	('bladder', 'Disease', (129, 136))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', (85, 91))	('ovarian cancer', 'Phenotype', 'HP:0100615', (142, 156))	('cancer', 'Disease', (150, 156))	('ovarian cancer', 'Disease', 'MESH:D010051', (142, 156))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('lung', 'Disease', (123, 127))
15446	31973134	Highest mutations were reported in breast invasive ductal and colorectal carcinoma and occurred in a hotspot in R321*/Q.	('R321*', 'SUBSTITUTION', 'None', (112, 117))	('occurred', 'Reg', (87, 95))	('breast invasive ductal', 'Disease', (35, 57))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (62, 82))	('mutations', 'Var', (8, 17))	('R321*', 'Var', (112, 117))	('colorectal carcinoma', 'Disease', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
15447	31973134	Total fourmutations were reported in R321*/Q site, among which missense mutations were found in total 5397 breast invasive ductal carcinoma samples whereas, 837 samples of colorectal adenocarcinoma showed nonsense mutation (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('breast invasive ductal carcinoma', 'Disease', (107, 139))	('colorectal adenocarcinoma', 'Disease', (172, 197))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (123, 139))	('breast invasive ductal carcinoma', 'Disease', 'MESH:D001943', (107, 139))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (172, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('R321*', 'Var', (37, 42))	('R321*', 'SUBSTITUTION', 'None', (37, 42))
15448	31973134	Total 3 cases of mutation were reported in the hotspot V5A/L/S in lung squamous carcinoma datasets (Figure 5A).	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (71, 89))	('mutation', 'Var', (17, 25))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (66, 89))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (66, 89))	('lung squamous carcinoma', 'Disease', (66, 89))
15449	31973134	Alteration frequency was found highest in lung squamous carcinoma samples (>4%) among five cancer types (Figure 5B).	('squamous carcinoma', 'Phenotype', 'HP:0002860', (47, 65))	('Alteration', 'Var', (0, 10))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (42, 65))	('highest', 'Reg', (31, 38))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('lung squamous carcinoma', 'Disease', (42, 65))
15452	31973134	Mutated BMP5 proteins were profiled in 11 cases of breast and colorectal cancers, whereas only a single missense mutation was reported in ovarian cancer.	('BMP5', 'Gene', (8, 12))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('breast', 'Disease', (51, 57))	('colorectal cancers', 'Disease', 'MESH:D015179', (62, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('colorectal cancers', 'Disease', (62, 80))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian cancer', 'Disease', 'MESH:D010051', (138, 152))	('Mutated', 'Var', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('ovarian cancer', 'Disease', (138, 152))
15496	31973134	observed the down-regulation of BMP5 in colorectal cancer due to the miR-32 deregulation.	('BMP5', 'Gene', (32, 36))	('colorectal cancer', 'Disease', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('down-regulation', 'NegReg', (13, 28))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('deregulation', 'Var', (76, 88))	('miR-32', 'Gene', '407036', (69, 75))	('miR-32', 'Gene', (69, 75))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))
15504	31973134	Somatic loss-of-function or gain-of-function alterations ensue in particular genomic regions which engaged in potential inhibitory or carcinogenic effects, respectively.	('alterations', 'Var', (45, 56))	('carcinogenic', 'Disease', 'MESH:D063646', (134, 146))	('carcinogenic', 'Disease', (134, 146))	('gain-of-function', 'PosReg', (28, 44))	('loss-of-function', 'NegReg', (8, 24))
15505	31973134	The G-to-A mutation at nucleotide 932 cleaves the nucleotides encoding arginine (CGA) residue and thus destroys the Taq I polymerase restriction site resulting in the blockage of the post-translational processing of the BMP5 protein.	('arginine', 'Chemical', 'MESH:D001120', (71, 79))	('post-translational processing of the', 'MPA', (183, 219))	('cleaves', 'Reg', (38, 45))	('Taq', 'Protein', (116, 119))	('destroys', 'NegReg', (103, 111))	('blockage', 'NegReg', (167, 175))	('G-to-A mutation at nucleotide 932', 'Mutation', 'c.932G>A', (4, 37))	('BMP5', 'Protein', (220, 224))	('mutation', 'Var', (11, 19))
15506	31973134	In our analysis, we found diverse missense and truncating mutations in the BMP5 protein-coding sequence while exposed to cancer cells.	('missense', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('truncating mutations', 'Var', (47, 67))	('BMP5', 'Gene', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
15507	31973134	This study revealed mutations in breast invasive ductal and colorectal carcinoma in a hotspot at position R321*/Q and position V5A/L/S in lung squamous carcinoma between BMP5-propeptide and BMP5 domain.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('R321*', 'SUBSTITUTION', 'None', (106, 111))	('lung squamous carcinoma', 'Disease', (138, 161))	('colorectal carcinoma', 'Disease', (60, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (143, 161))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (138, 161))	('breast invasive ductal', 'Disease', (33, 55))	('propeptide', 'Chemical', '-', (175, 185))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (138, 161))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (60, 80))	('R321*', 'Var', (106, 111))	('mutations', 'Var', (20, 29))
15508	31973134	Similar results of mutation at R321*/Q stop-codon (4 cases) was also found in a previous study which may impact cleavage of the protein to the mature secreted form.	('R321*', 'SUBSTITUTION', 'None', (31, 36))	('cleavage of the protein', 'MPA', (112, 135))	('impact', 'Reg', (105, 111))	('R321*', 'Var', (31, 36))
15510	31973134	Another BMP5 mRNA expression (RNA Seq V2) analysis via cBioPortal web found a higher mutation rate in lung cancer and then in bladder cancers.	('bladder cancer', 'Phenotype', 'HP:0009725', (126, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('bladder cancers', 'Phenotype', 'HP:0009725', (126, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('bladder cancers', 'Disease', 'MESH:D001749', (126, 141))	('mutation', 'Var', (85, 93))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('bladder cancers', 'Disease', (126, 141))
15511	31973134	These mutations may have played an essential role in cancer progression and prognosis.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('played', 'Reg', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (6, 15))
15561	31423440	The results of laboratory tests were as follows: CA199, 112.0 U/mL (reference < 37.0 U/mL); alpha fetoprotein, 1.4 ng/mL (reference < 20.0 ng/mL); alanine transaminase, 89 U/L (reference < 35.0 U/L); aspartate transaminase, 49 U/L (reference < 40 U/L); and serum potassium, 4.40 mmol/L (reference 3.50-5.20 mmol/L).	('alpha fetoprotein', 'MPA', (92, 109))	('potassium', 'Chemical', 'MESH:D011188', (263, 272))	('serum potassium', 'MPA', (257, 272))	('aspartate transaminase', 'MPA', (200, 222))	('alanine transaminase', 'MPA', (147, 167))	('CA199', 'Var', (49, 54))
15573	31423440	Aberrant adrenal tissue can be found anywhere, but typically in the testes, ovaries, spermatic cord, and kidneys.	('Aberrant', 'Var', (0, 8))	('ovaries', 'Disease', (76, 83))	('ovaries', 'Disease', 'MESH:D010051', (76, 83))
15584	31423440	Rupture of the tumor capsule, metastasis, and a high Ki67 index are associated with reduced disease-free and overall survival.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('reduced disease-free', 'Disease', 'MESH:D015673', (84, 104))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Ki67', 'Gene', (53, 57))	('metastasis', 'CPA', (30, 40))	('tumor', 'Disease', (15, 20))	('reduced disease-free', 'Disease', (84, 104))	('high', 'Var', (48, 52))
15595	30357412	Experiments chosen for the analysis, E-GEOD-2034, E-GEOD-4183 and E-GEOD-10927, have been described as demonstrating a high proportion of variance due to batch effects in.	('E-GEOD', 'Chemical', '-', (50, 56))	('E-GEOD', 'Chemical', '-', (37, 43))	('E-GEOD-10927', 'Var', (66, 78))	('E-GEOD-2034', 'Var', (37, 48))	('E-GEOD', 'Chemical', '-', (66, 72))
15601	30357412	In all nine different groups of samples, in the three datasets E-GEOD-2034, E-GEOD-4183 and E-GEOD-10927, the use of batch effect correction based on combining dynamic programming algorithm with ComBat algorithm leads to the increase of the intragroup mean correlation.	('E-GEOD', 'Chemical', '-', (92, 98))	('intragroup mean correlation', 'MPA', (241, 268))	('increase', 'PosReg', (225, 233))	('E-GEOD', 'Chemical', '-', (76, 82))	('E-GEOD', 'Chemical', '-', (63, 69))	('E-GEOD-10927', 'Var', (92, 104))
15605	30357412	In the case of experiment E-GEOD-10927 which is a study on adrenocortical carcinoma and adenoma the terms were matched with literature knowledge on these processes.	('E-GEOD', 'Chemical', '-', (26, 32))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (59, 83))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (59, 83))	('adenoma', 'Disease', (88, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('adrenocortical carcinoma', 'Disease', (59, 83))	('E-GEOD-10927', 'Var', (26, 38))	('adenoma', 'Disease', 'MESH:D000236', (88, 95))
15612	30357412	The subsequent entry identifiers are E-GEOD-19419, E-GEOD-36398, E-GEOD-2034, E-GEOD-4183, E-GEOD-10927, E-GEOD-65683.	('E-GEOD', 'Chemical', '-', (37, 43))	('E-GEOD', 'Chemical', '-', (91, 97))	('E-GEOD', 'Chemical', '-', (105, 111))	('E-GEOD', 'Chemical', '-', (78, 84))	('E-GEOD-19419', 'Var', (37, 49))	('E-GEOD-10927', 'Var', (91, 103))	('E-GEOD-36398', 'Var', (51, 63))	('E-GEOD', 'Chemical', '-', (65, 71))	('E-GEOD', 'Chemical', '-', (51, 57))	('E-GEOD-2034', 'Var', (65, 76))	('E-GEOD-65683', 'Var', (105, 117))	('E-GEOD-4183', 'Var', (78, 89))
15652	30623061	The mean age of patients with a non-functional mass (55 +- 11.7) was found to be significantly higher than the mean age of patients who had a functional mass (46 +- 12.50) (P < .001).	('non-functional', 'Var', (32, 46))	('higher', 'PosReg', (95, 101))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (123, 131))
15706	29515971	Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Cancer Genome Atlas', 'Disease', (108, 127))	('tumor', 'Disease', (32, 37))	('screened', 'Reg', (181, 189))	('variation', 'Var', (194, 203))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (108, 127))	('CYT', 'Gene', (207, 210))
15735	29515971	Using the Genomic Data Commons (GDC) Data Portal (The Cancer Genome Atlas, TCGA program3) and the GTEx web portal (Genotype-Tissue Expression project4), we extracted data from a total of 10,355 tumor resection samples and 2,935 normal samples and screened the variation of CYT across these 32 different cancer types and 28 different normal solid tissue types.	('CYT', 'Gene', (273, 276))	('Cancer Genome Atlas', 'Disease', (54, 73))	('cancer', 'Disease', (303, 309))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('variation', 'Var', (260, 269))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (54, 73))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('screened', 'Reg', (247, 255))	('tumor', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
15752	29515971	GZMA was stained with an anti-GZMA antibody produced in rabbit (HPA054134, 1:200 dilution, Sigma-Aldrich) and PRF1 using two different antibodies produced in rabbit (either HPA037940, 1:29 dilution, or CAB002436, 1:10 dilution, Sigma-Aldrich).	('rabbit', 'Species', '9986', (56, 62))	('CAB002436', 'Var', (202, 211))	('rabbit', 'Species', '9986', (158, 164))	('GZMA', 'Gene', (30, 34))	('GZMA', 'Gene', (0, 4))	('GZMA', 'Gene', '3001', (30, 34))	('GZMA', 'Gene', '3001', (0, 4))
15769	29515971	Importantly, we show for the first time that DLBCL and testicular cancer also rank among the top cytolytic active tumors, with DLBCL exhibiting even higher cytolytic levels compared to KIRC (>100 TPM).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('testicular cancer', 'Phenotype', 'HP:0010788', (55, 72))	('testicular cancer', 'Disease', (55, 72))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('DLBCL', 'Disease', (45, 50))	('cytolytic levels', 'MPA', (156, 172))	('higher', 'PosReg', (149, 155))	('DLBCL', 'Var', (127, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (55, 72))
15794	29515971	We next performed Kaplan-Meier survival analysis on 37 TCGA-datasets deriving from 25 different cancer types in order to estimate the risk of individual and/or simultaneous high (or low) PRF1 and GZMA expression on patient overall survival.	('high', 'Var', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('low', 'NegReg', (182, 185))	('GZMA', 'Gene', (196, 200))	('PRF1', 'Gene', (187, 191))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('GZMA', 'Gene', '3001', (196, 200))	('cancer', 'Disease', (96, 102))	('patient', 'Species', '9606', (215, 222))
15795	29515971	In TCGA-ACC, non-metastatic cutaneous melanoma ("m0" TCGA-SKCM), and bladder urothelial carcinoma (TCGA-BLCA but not the GSE32894 dataset), both individual and simultaneous high levels of PRF1 and GZMA were significantly associated with better prognosis.	('ACC', 'Phenotype', 'HP:0006744', (8, 11))	('non-metastatic cutaneous melanoma', 'Phenotype', 'HP:0012057', (13, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('cutaneous melanoma', 'Disease', (28, 46))	('bladder urothelial carcinoma', 'Disease', (69, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('high levels', 'Var', (173, 184))	('GZMA', 'Gene', (197, 201))	('GZMA', 'Gene', '3001', (197, 201))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (69, 97))	('PRF1', 'Gene', (188, 192))
15799	29515971	In TCGA-LIHC, only the individual high levels of PRF1 and GZMA were significantly associated with a positive effect on patient survival.	('GZMA', 'Gene', '3001', (58, 62))	('patient', 'Species', '9606', (119, 126))	('LIHC', 'Disease', (8, 12))	('PRF1', 'Gene', (49, 53))	('LIHC', 'Disease', 'None', (8, 12))	('high levels', 'Var', (34, 45))	('GZMA', 'Gene', (58, 62))
15800	29515971	A similar non-significant association of (individual or simultaneous) high GZMA and PRF1 expression with better effect on patient survival could also be observed in TCGA-MESO, ovarian cancer (GSE13876 and GSE49997), TCGA-STAD, TCGA-THCA, and TCGA-UCEC (Figure S1 in Supplementary Material).	('GZMA', 'Gene', '3001', (75, 79))	('patient', 'Species', '9606', (122, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('GSE49997', 'Var', (205, 213))	('TCGA-MESO', 'Disease', (165, 174))	('GSE13876', 'Var', (192, 200))	('TCGA-UCEC', 'Disease', (242, 251))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('GZMA', 'Gene', (75, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('high', 'Var', (70, 74))	('TCGA-THCA', 'Disease', (227, 236))	('TCGA-STAD', 'Disease', (216, 225))	('ovarian cancer', 'Disease', (176, 190))	('PRF1', 'Gene', (84, 88))
15801	29515971	These data suggest that high CYT is widely associated with an improved prognosis among the above-mentioned cancer types.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('improved', 'PosReg', (62, 70))	('high CYT', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
15802	29515971	On the contrary, across TCGA-LGG, BRCAs (GSE25066), and TCGA-THYM, both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both genes led to a significant shift toward positive effect (Figure 6B).	('BRCA', 'Gene', '672', (34, 38))	('GSE25066', 'Var', (41, 49))	('BRCA', 'Gene', (34, 38))	('GZMA', 'Gene', (115, 119))	('GZMA', 'Gene', '3001', (115, 119))	('PRF1', 'Gene', (124, 128))	('associated with', 'Reg', (148, 163))
15805	29515971	Analogous non-significant associations of (individual or simultaneous) high cytolytic levels with worse effect on patient survival were also observed in lung cancer (GSE30219, TCGA-LUAD, and TCGA-LUSC), TCGA-PAAD, TCGA-PRAD and GSE16560, and TCGA-READ (Figure S2 in Supplementary Material).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('lung cancer', 'Disease', (153, 164))	('high cytolytic levels', 'MPA', (71, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('patient', 'Species', '9606', (114, 121))	('GSE30219', 'Var', (166, 174))	('PAAD', 'Phenotype', 'HP:0006725', (208, 212))
15807	29515971	Depending on the probe used, it seemed that a combination of high PRF1 and low GZMA levels yields a better patient outcome (GSE39582, TCGA-COAD, TCGA-COADREAD).	('COAD', 'Disease', (150, 154))	('low', 'NegReg', (75, 78))	('GZMA', 'Gene', '3001', (79, 83))	('PRF1', 'MPA', (66, 70))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('high', 'Var', (61, 65))	('COAD', 'Disease', 'MESH:D029424', (150, 154))	('COAD', 'Disease', (139, 143))	('patient', 'Species', '9606', (107, 114))	('GZMA', 'Gene', (79, 83))
15813	29515971	In DLBCL (GSE10846, and GSE32918), using various combinations of distinct molecular probes for the two cytolytic genes (PRF1, 214617_AT, 1553681_A_AT, or ILMN_1740633; GZMA, 205488_AT, or ILMN_1779324), we could not provide any significant association with patient survival.	('GSE32918', 'Var', (24, 32))	('GZMA', 'Gene', '3001', (168, 172))	('ILMN_1740633', 'Var', (154, 166))	('patient', 'Species', '9606', (257, 264))	('AT', 'Disease', 'None', (133, 135))	('AT', 'Disease', 'None', (147, 149))	('GSE10846', 'Var', (10, 18))	('PRF1', 'Var', (120, 124))	('AT', 'Disease', 'None', (181, 183))	('GZMA', 'Gene', (168, 172))
15814	29515971	A similar absence of significant associations was also detected in glioblastoma (GSE4271, GSE13041, and TCGA-GBM) and non-metastatic HNSCs.	('glioblastoma', 'Disease', (67, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('non-metastatic HNSCs', 'Disease', (118, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('GSE13041', 'Var', (90, 98))	('GSE4271', 'Chemical', '-', (81, 88))	('GSE4271', 'Var', (81, 88))
15852	29515971	Among them, recurrent mutations in immune-related genes have been proposed, such as B2M, HLA-A, -B, and -C, and CASP8, as well as copy number aberrations in loci containing immunosuppressive factors, including the receptors PD-L1/2 and CTLA-4.	('B2M', 'Gene', (84, 87))	('CASP8', 'Gene', '841', (112, 117))	('B2M', 'Gene', '567', (84, 87))	('CTLA-4', 'Gene', '1493', (236, 242))	('copy number aberrations', 'Var', (130, 153))	('CTLA-4', 'Gene', (236, 242))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (89, 106))	('mutations', 'Var', (22, 31))	('PD-L1/2', 'Gene', '29126;80380', (224, 231))	('PD-L1/2', 'Gene', (224, 231))	('CASP8', 'Gene', (112, 117))
15857	29515971	Actually, recent clinical trials have demonstrated that blockage of this signaling can benefit patients with advanced melanoma, kidney, or non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (139, 165))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('non-small cell lung cancer', 'Disease', (139, 165))	('blockage', 'Var', (56, 64))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (139, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (143, 165))	('kidney', 'Disease', (128, 134))
15865	29515971	Importantly, CTLA-4 blockade was reported to associate with bowel inflammation in melanoma patients, signifying that its signaling is crucial for the preservation of immune homeostasis in the gut.	('associate', 'Reg', (45, 54))	('patients', 'Species', '9606', (91, 99))	('bowel inflammation', 'Phenotype', 'HP:0002037', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('CTLA-4', 'Gene', '1493', (13, 19))	('blockade', 'Var', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('bowel inflammation', 'Disease', 'MESH:D007249', (60, 78))	('CTLA-4', 'Gene', (13, 19))	('bowel inflammation', 'Disease', (60, 78))
15871	29515971	Inhibition of both IDO and arginase can enhance intratumoral inflammation.	('IDO', 'Gene', '3620', (19, 22))	('IDO', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('arginase', 'Protein', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('tumor', 'Disease', (53, 58))	('Inhibition', 'Var', (0, 10))	('enhance', 'PosReg', (40, 47))
15885	29515971	A very interesting improvement in the field was further made by Riaz et al., who showed that the mutation burden in melanoma patients decreases with successful anti-PD-1 blockade therapy, suggesting that the selection against mutant neoepitopes is a critical mechanism of action of this immunotherapy.	('Riaz', 'Gene', (64, 68))	('mutant', 'Var', (226, 232))	('mutation burden', 'MPA', (97, 112))	('PD-1', 'Gene', (165, 169))	('PD-1', 'Gene', '5133', (165, 169))	('Riaz', 'Gene', '23598', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('decreases', 'NegReg', (134, 143))	('patients', 'Species', '9606', (125, 133))
15889	29515971	Overall, it seems that CYT is part of an inflammatory environment in a premalignant state of certain tumor types, whereas, in others, oncogenic mutations, copy number aberrations, or viral infection can induce a tumor-promoting inflammatory microenvironment, within which complex interactions between different cell types regulate cancer development and metastasis.	('copy number aberrations', 'Var', (155, 178))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('induce', 'PosReg', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('viral infection', 'Disease', 'MESH:D001102', (183, 198))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('viral infection', 'Disease', (183, 198))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('mutations', 'Var', (144, 153))	('tumor', 'Disease', (212, 217))
15896	29515971	In some tumor types (ACC, SKCM, BLCA, LIHC, MESO, OV, STAD, THCA, and UCEC), high CYT was associated with an improved outcome; whereas in others (LGG, BRCA, THYM, LUAD/LUSC, PAAD, PRAD, and READ) it is correlated with a worse outcome.	('BRCA', 'Gene', '672', (151, 155))	('LIHC', 'Disease', 'None', (38, 42))	('BRCA', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MESO', 'Disease', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ACC', 'Phenotype', 'HP:0006744', (21, 24))	('PAAD', 'Phenotype', 'HP:0006725', (174, 178))	('PAAD', 'Disease', (174, 178))	('improved', 'PosReg', (109, 117))	('LUAD/LUSC', 'Disease', (163, 172))	('tumor', 'Disease', (8, 13))	('THYM', 'Disease', (157, 161))	('PRAD', 'Disease', (180, 184))	('LIHC', 'Disease', (38, 42))	('high CYT', 'Var', (77, 85))
15897	29515971	Among LGG, THYM, and BRCA, we showed that both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both cytolytic genes led to a significant shift toward a positive effect.	('associated', 'Reg', (123, 133))	('GZMA', 'Gene', (90, 94))	('BRCA', 'Gene', (21, 25))	('PRF1', 'Gene', (99, 103))	('high', 'Var', (75, 79))	('GZMA', 'Gene', '3001', (90, 94))	('BRCA', 'Gene', '672', (21, 25))
15936	28994759	Familial hyperaldosteronism types 1 - 3 are rare types of PA, and type 3 is caused by a KCNJ5 germ-line mutation.	('Familial hyperaldosteronism', 'Disease', 'MESH:C580087', (0, 27))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (9, 27))	('KCNJ5', 'Gene', (88, 93))	('mutation', 'Var', (104, 112))	('PA', 'Phenotype', 'HP:0011736', (58, 60))	('Familial hyperaldosteronism types 1', 'Phenotype', 'HP:0011739', (0, 35))	('KCNJ5', 'Gene', '3762', (88, 93))	('Familial hyperaldosteronism', 'Disease', (0, 27))	('caused by', 'Reg', (76, 85))
15937	28994759	A case of a novel type of juvenile PA, which was presumably due to the genetic mosaicism of normal and KCNJ5 mutant adrenocortical cells, was recently identified.	('PA', 'Phenotype', 'HP:0011736', (35, 37))	('adrenocortical', 'Disease', 'MESH:D018268', (116, 130))	('KCNJ5', 'Gene', (103, 108))	('juvenile PA', 'Phenotype', 'HP:0005681', (26, 37))	('KCNJ5', 'Gene', '3762', (103, 108))	('mutant', 'Var', (109, 115))	('adrenocortical', 'Disease', (116, 130))
16015	28994759	In cAVS, PAC/PCC in the right and left central veins were ([57,600 pg/mL] / [901 microg/dL] = 63.9) and ([18,000 pg/mL] / [389 microg/dL] = 46.3), respectively, suggesting that she had bilateral PA (lateralized ratio = 1.4, cut-off: <2.6, Table 1).	('PAC', 'Phenotype', 'HP:0000859', (9, 12))	('PAC', 'Chemical', '-', (9, 12))	('[18,000 pg/mL', 'Var', (105, 118))	('PA', 'Phenotype', 'HP:0011736', (9, 11))	('PA', 'Phenotype', 'HP:0011736', (195, 197))	('PAC', 'Phenotype', 'HP:0006699', (9, 12))	('[57,600 pg/mL', 'Var', (59, 72))	('PCC', 'Chemical', '-', (13, 16))
16043	28994759	In order to prove this concept, current attempts are being made to detect APA-associated mutations including KCNJ5 using ssAVS samples and a high performance next generation sequencer, which may contribute to future APA treatments.	('KCNJ5', 'Gene', '3762', (109, 114))	('PA', 'Phenotype', 'HP:0011736', (75, 77))	('contribute', 'Reg', (195, 205))	('mutations', 'Var', (89, 98))	('PA', 'Phenotype', 'HP:0011736', (217, 219))	('KCNJ5', 'Gene', (109, 114))	('APA-associated', 'Gene', (74, 88))
16149	26191527	ACC were frequently associated to the Li-Fraumeni syndrome, due to germline TP53 mutations and the Beckwith-Wiedemann syndrome, due to alterations of the insulin-like growth factor IGF2.	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (99, 126))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (38, 58))	('associated', 'Reg', (20, 30))	('Li-Fraumeni syndrome', 'Disease', (38, 58))	('alterations', 'Reg', (135, 146))	('TP53', 'Gene', '7157', (76, 80))	('IGF2', 'Gene', '3481', (181, 185))	('Beckwith-Wiedemann syndrome', 'Disease', (99, 126))	('TP53', 'Gene', (76, 80))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('mutations', 'Var', (81, 90))	('IGF2', 'Gene', (181, 185))	('ACC', 'Disease', (0, 3))
16150	26191527	At somatic level, inactivating mutations of TP53 and activating mutations of the proto-oncogene beta-catenin (CTNNB1) were the most frequent mutations identified in ACC.	('ACC', 'Disease', (165, 168))	('beta-catenin', 'Gene', '1499', (96, 108))	('inactivating mutations', 'Var', (18, 40))	('CTNNB1', 'Gene', '1499', (110, 116))	('TP53', 'Gene', '7157', (44, 48))	('ACC', 'Phenotype', 'HP:0006744', (165, 168))	('activating', 'PosReg', (53, 63))	('CTNNB1', 'Gene', (110, 116))	('TP53', 'Gene', (44, 48))	('beta-catenin', 'Gene', (96, 108))
16179	26191527	Recent studies have been demonstrated that Ki67 is a powerful prognostic marker in both localized and metastatic ACC to guide treatment decision (Berruti et al.,; Libe et al.,; Beuschlein et al.,).	('Ki67', 'Var', (43, 47))	('localized', 'Disease', (88, 97))	('metastatic ACC', 'Disease', (102, 116))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('Ki67', 'Chemical', '-', (43, 47))
16186	26191527	Three major criteria are mandatory in order to define the disease free survival for the localized ACC (stage I, II, and some III) and the overall survival for stage IV ACC: (1) staging; (2) resection status "R"; (3) Grading (proliferation index, as Ki67% and mitotic count).	('Ki67%', 'Var', (249, 254))	('ACC', 'Phenotype', 'HP:0006744', (98, 101))	('mitotic count', 'CPA', (259, 272))	('ACC', 'Phenotype', 'HP:0006744', (168, 171))	('Ki67', 'Chemical', '-', (249, 253))
16191	26191527	Hypermethylation status, miRNA profile or driver genes mutations, as TP53, ZNRF3, beta-catenin constitute valuable candidates that could integrate a future clinico-molecular prognostic classification of ACC patients (Assie et al.,).	('ZNRF3', 'Gene', '84133', (75, 80))	('patients', 'Species', '9606', (207, 215))	('mutations', 'Var', (55, 64))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('ZNRF3', 'Gene', (75, 80))	('beta-catenin', 'Gene', (82, 94))	('ACC', 'Phenotype', 'HP:0006744', (203, 206))	('ACC', 'Disease', (203, 206))	('beta-catenin', 'Gene', '1499', (82, 94))
16209	26191527	In terms of adjuvant therapy in "localized ACC" after surgery, a large retrospective analysis comparing two independent cohorts (Terzolo et al.,) demonstrated that patients with adjuvant mitotane had a significantly improved recurrence-free survival.	('recurrence-free survival', 'CPA', (225, 249))	('improved', 'PosReg', (216, 224))	('ACC"', 'Gene', '31', (43, 47))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('ACC"', 'Gene', (43, 47))	('mitotane', 'Var', (187, 195))	('mitotane', 'Chemical', 'MESH:D008939', (187, 195))	('patients', 'Species', '9606', (164, 172))
16219	26191527	In fact mitotane induces the cytochrome P450 3A4 (CYP3A4) leading to lower the blood levels of many drugs (including the steroids, anti-hypertensives, antibiotics) (Kroiss et al.,).	('CYP3A4', 'Gene', '1576', (50, 56))	('cytochrome P450 3A4', 'Gene', (29, 48))	('lower', 'NegReg', (69, 74))	('steroids', 'Chemical', 'MESH:D013256', (121, 129))	('mitotane', 'Var', (8, 16))	('blood levels of many drugs', 'MPA', (79, 105))	('mitotane', 'Chemical', 'MESH:D008939', (8, 16))	('hypertensives', 'Disease', 'MESH:D006973', (136, 149))	('anti-hypertensives', 'Phenotype', 'HP:0000822', (131, 149))	('hypertensives', 'Disease', (136, 149))	('CYP3A4', 'Gene', (50, 56))	('cytochrome P450 3A4', 'Gene', '1576', (29, 48))
16226	26191527	It was shown that the M-EDP was associated with a better progression-free survival and objective response rate compared to M-Sz (5.0 vs. 2.1 months, 23.2 vs. 9.2%, respectively), although no significant difference was demonstrated on overall survival (Fassnacht et al.,).	('objective response', 'CPA', (87, 105))	('M-EDP', 'Chemical', '-', (22, 27))	('M-Sz', 'Chemical', '-', (123, 127))	('progression-free survival', 'CPA', (57, 82))	('better', 'PosReg', (50, 56))	('M-EDP', 'Var', (22, 27))
16244	26191527	Recently, as [123I]IMTO single-photon emission CT imaging showed high tracer uptake in issue of adrenocortical origin, [131I]IMTO might represent a suitable compound for targeted radionuclide therapy.	('adrenocortical', 'Disease', (96, 110))	('adrenocortical', 'Disease', 'MESH:D018268', (96, 110))	('[131I]', 'Var', (119, 125))	('123I', 'Chemical', 'MESH:C000614958', (14, 18))	('tracer uptake', 'MPA', (70, 83))	('131I', 'Chemical', 'MESH:C000614965', (120, 124))
16269	25038520	This discrepancy may relate in part to the fact that TZDs may have both direct and indirect effects on aldosterone production.	('aldosterone production', 'MPA', (103, 125))	('aldosterone production', 'Phenotype', 'HP:0000859', (103, 125))	('TZDs', 'Chemical', 'MESH:D045162', (53, 57))	('TZDs', 'Var', (53, 57))	('effects', 'Reg', (92, 99))	('aldosterone', 'Chemical', 'MESH:D000450', (103, 114))
16271	25038520	On the other hand, pioglitazone reduces serum lipids, including serum triglycerides, a marker of very low density lipoprotein (VLDL) levels, which are known to stimulate aldosterone production in vitro, suggesting that any beneficial effect of pioglitazone on aldosterone levels may occur through its improvement of elevated VLDL levels.	('aldosterone', 'Chemical', 'MESH:D000450', (260, 271))	('triglycerides', 'Chemical', 'MESH:D014280', (70, 83))	('serum lipids', 'MPA', (40, 52))	('pioglitazone', 'Chemical', 'MESH:D000077205', (19, 31))	('aldosterone production', 'Phenotype', 'HP:0000859', (170, 192))	('lipids', 'Chemical', 'MESH:D008055', (46, 52))	('reduces', 'NegReg', (32, 39))	('pioglitazone', 'Var', (19, 31))	('aldosterone', 'Chemical', 'MESH:D000450', (170, 181))	('aldosterone levels', 'MPA', (260, 278))	('serum triglycerides', 'MPA', (64, 83))	('pioglitazone', 'Chemical', 'MESH:D000077205', (244, 256))	('VLDL levels', 'MPA', (325, 336))	('stimulate aldosterone', 'Phenotype', 'HP:0000859', (160, 181))
16282	25038520	Trypsin-EDTA (0.05%) was obtained from Life Technologies, GW6471 from Tocris Biosciences (Minneapolis, MN) and tauroursodeoxycholic acid (TUDCA) from EMD Millipore (Billerica, MA).	('GW6471', 'Chemical', 'MESH:C449302', (58, 64))	('tauroursodeoxycholic acid', 'Chemical', 'MESH:C031655', (111, 136))	('MN', 'CellLine', 'CVCL:U508', (103, 105))	('TUDCA', 'Chemical', 'MESH:C031655', (138, 143))	('Tocris Biosciences', 'Disease', (70, 88))	('EMD', 'Disease', (150, 153))	('EMD', 'Disease', 'None', (150, 153))	('EDTA', 'Chemical', 'MESH:D004492', (8, 12))	('Tocris Biosciences', 'Disease', 'None', (70, 88))	('GW6471', 'Var', (58, 64))
16291	25038520	For the dose response experiments, the supernatants were collected and cells were harvested after treatment for 24hr with 300nM, 1muM, 3muM and 10muM pioglitazone.	('muM', 'Gene', (130, 133))	('muM', 'Gene', (136, 139))	('300nM', 'Var', (122, 127))	('muM', 'Gene', '56925', (146, 149))	('pioglitazone', 'Chemical', 'MESH:D000077205', (150, 162))	('muM', 'Gene', (146, 149))	('muM', 'Gene', '56925', (130, 133))	('muM', 'Gene', '56925', (136, 139))
16295	25038520	For some experiments, cells were treated with 10muM pioglitazone and 10muM GW9662 or GW6471 or 500muM TUDCA for 24hr.	('muM', 'Gene', (71, 74))	('GW9662', 'Chemical', 'MESH:C457499', (75, 81))	('muM', 'Gene', (98, 101))	('muM', 'Gene', '56925', (48, 51))	('TUDCA', 'Chemical', 'MESH:C031655', (102, 107))	('muM', 'Gene', (48, 51))	('muM', 'Gene', '56925', (71, 74))	('GW6471', 'Var', (85, 91))	('GW6471', 'Chemical', 'MESH:C449302', (85, 91))	('muM', 'Gene', '56925', (98, 101))	('pioglitazone', 'Chemical', 'MESH:D000077205', (52, 64))	('GW9662', 'Var', (75, 81))
16304	25038520	The probe sets for human CYP11B2 (Hs01597732_m1), CYP11B1 (Hs01596404_m1), CYP17A1 (Hs01124136_m1), CYP21A2 (Hs00416901_g1), DDIT3 (Hs00358796_g1), StAR (Hs00986559_g1) and PPIA (Hs04194521_s1) were purchased from Applied Biosystems (Supplemental Table 1).	('DDIT3', 'Gene', (125, 130))	('CYP11B2', 'Gene', (25, 32))	('Hs01124136_m1', 'Var', (84, 97))	('PPIA', 'Gene', '5478', (173, 177))	('CYP21A2', 'Gene', (100, 107))	('Hs01597732_m1', 'Var', (34, 47))	('Hs04194521_s1', 'Var', (179, 192))	('CYP11B1', 'Gene', '1584', (50, 57))	('CYP17A1', 'Gene', (75, 82))	('CYP11B2', 'Gene', '1585', (25, 32))	('CYP17A1', 'Gene', '1586', (75, 82))	('StAR', 'Gene', (148, 152))	('Hs01596404_m1', 'Var', (59, 72))	('CYP21A2', 'Gene', '1589', (100, 107))	('Hs00416901_g1', 'Var', (109, 122))	('CYP11B1', 'Gene', (50, 57))	('DDIT3', 'Gene', '1649', (125, 130))	('Hs00986559_g1', 'Var', (154, 167))	('Hs00358796_g1', 'Var', (132, 145))	('PPIA', 'Gene', (173, 177))	('human', 'Species', '9606', (19, 24))	('StAR', 'Gene', '6770', (148, 152))
16341	25038520	Phosphorylated eIF2alpha subsequently attenuates the rate of global translation to prevent further protein synthesis and reduce the ER protein load (reviewed in).	('Phosphorylated', 'Var', (0, 14))	('attenuates', 'NegReg', (38, 48))	('eIF2alpha', 'Gene', '83939', (15, 24))	('protein synthesis', 'MPA', (99, 116))	('eIF2alpha', 'Gene', (15, 24))	('prevent', 'NegReg', (83, 90))	('reduce', 'NegReg', (121, 127))	('ER protein load', 'MPA', (132, 147))	('rate', 'MPA', (53, 57))
16356	25038520	To determine the mechanism by which pioglitazone induced the expression of CYP11B2 and DDIT3, cells were stimulated with or without pioglitazone in the presence or absence of antagonists selective for PPARgamma or PPARalpha, GW9662 and GW6471, respectively.	('GW9662', 'Chemical', 'MESH:C457499', (225, 231))	('pioglitazone', 'Chemical', 'MESH:D000077205', (132, 144))	('CYP11B2', 'Gene', '1585', (75, 82))	('pioglitazone', 'Chemical', 'MESH:D000077205', (36, 48))	('PPARalpha', 'Gene', (214, 223))	('DDIT3', 'Gene', '1649', (87, 92))	('GW6471', 'Var', (236, 242))	('PPARgamma', 'Var', (201, 210))	('GW6471', 'Chemical', 'MESH:C449302', (236, 242))	('GW9662', 'Var', (225, 231))	('CYP11B2', 'Gene', (75, 82))	('DDIT3', 'Gene', (87, 92))	('PPARalpha', 'Gene', '5465', (214, 223))
16357	25038520	As shown in Figure 7A, pioglitazone-induced DDIT3 expression was inhibited by GW9662, suggesting that this effect was mediated through PPARgamma.	('GW9662', 'Chemical', 'MESH:C457499', (78, 84))	('pioglitazone', 'Chemical', 'MESH:D000077205', (23, 35))	('DDIT3', 'Gene', (44, 49))	('inhibited', 'NegReg', (65, 74))	('DDIT3', 'Gene', '1649', (44, 49))	('GW9662', 'Var', (78, 84))
16358	25038520	On the other hand, incubation with GW6471 alone stimulated DDIT3 expression, and had no effect on pioglitazone-induced DDIT3 mRNA levels (Supplemental Figure 5).	('DDIT3', 'Gene', '1649', (119, 124))	('GW6471', 'Var', (35, 41))	('GW6471', 'Chemical', 'MESH:C449302', (35, 41))	('DDIT3', 'Gene', '1649', (59, 64))	('pioglitazone', 'Chemical', 'MESH:D000077205', (98, 110))	('DDIT3', 'Gene', (119, 124))	('expression', 'MPA', (65, 75))	('stimulated', 'PosReg', (48, 58))	('DDIT3', 'Gene', (59, 64))
16359	25038520	In contrast, GW6471 inhibited pioglitazone-induced CYP11B2 expression, suggesting the involvement of PPARalpha in this process (Figure 7B).	('PPARalpha', 'Gene', (101, 110))	('CYP11B2', 'Gene', (51, 58))	('pioglitazone', 'Chemical', 'MESH:D000077205', (30, 42))	('inhibited', 'NegReg', (20, 29))	('CYP11B2', 'Gene', '1585', (51, 58))	('PPARalpha', 'Gene', '5465', (101, 110))	('GW6471', 'Chemical', 'MESH:C449302', (13, 19))	('GW6471', 'Var', (13, 19))
16360	25038520	On the other hand, the PPARgamma-selective antagonist GW9962 also inhibited pioglitazone-induced expression of CYP11B2, as well as CYP11B1 (Supplemental Figure 6).	('pioglitazone', 'Chemical', 'MESH:D000077205', (76, 88))	('pioglitazone-induced expression', 'MPA', (76, 107))	('CYP11B1', 'Gene', (131, 138))	('GW9962', 'Var', (54, 60))	('CYP11B1', 'Gene', '1584', (131, 138))	('GW9962', 'Chemical', '-', (54, 60))	('inhibited', 'NegReg', (66, 75))	('CYP11B2', 'Gene', (111, 118))	('CYP11B2', 'Gene', '1585', (111, 118))
16361	25038520	However, it should be noted that GW9962 is reported to inhibit ligand binding to PPARalpha, albeit at an approximately 10-fold lesser potency.	('PPARalpha', 'Gene', '5465', (81, 90))	('ligand binding', 'Interaction', (63, 77))	('inhibit', 'NegReg', (55, 62))	('GW9962', 'Chemical', '-', (33, 39))	('PPARalpha', 'Gene', (81, 90))	('GW9962', 'Var', (33, 39))
16371	25038520	As with CYP11B2, inhibition of PPARalpha with GW6471 completely blocked pioglitazone-induced CYP11B1 expression (Figure 8D).	('PPARalpha', 'Gene', (31, 40))	('CYP11B1', 'Gene', (93, 100))	('CYP11B1', 'Gene', '1584', (93, 100))	('GW6471', 'Var', (46, 52))	('blocked', 'NegReg', (64, 71))	('GW6471', 'Chemical', 'MESH:C449302', (46, 52))	('PPARalpha', 'Gene', '5465', (31, 40))	('CYP11B2', 'Gene', (8, 15))	('CYP11B2', 'Gene', '1585', (8, 15))	('pioglitazone', 'Chemical', 'MESH:D000077205', (72, 84))
16389	25038520	Our results showing that the PPARalpha antagonist GW6471 inhibited pioglitazone-enhanced CYP11B2 and CYP11B1 expression suggest the likely importance of pioglitazone's effect on PPARalpha.	('CYP11B2', 'Gene', (89, 96))	('expression', 'MPA', (109, 119))	('pioglitazone', 'Chemical', 'MESH:D000077205', (153, 165))	('CYP11B1', 'Gene', (101, 108))	('inhibited', 'NegReg', (57, 66))	('PPARalpha', 'Gene', (29, 38))	('CYP11B1', 'Gene', '1584', (101, 108))	('CYP11B2', 'Gene', '1585', (89, 96))	('pioglitazone', 'Chemical', 'MESH:D000077205', (67, 79))	('GW6471', 'Chemical', 'MESH:C449302', (50, 56))	('PPARalpha', 'Gene', '5465', (178, 187))	('pioglitazone-enhanced', 'PosReg', (67, 88))	('GW6471', 'Var', (50, 56))	('PPARalpha', 'Gene', (178, 187))	('PPARalpha', 'Gene', '5465', (29, 38))
16390	25038520	Conversely, the PPARgamma antagonist GW9662 inhibited pioglitazone-induced DDIT3 expression (Figure 6).	('pioglitazone', 'Chemical', 'MESH:D000077205', (54, 66))	('inhibited', 'NegReg', (44, 53))	('DDIT3', 'Gene', (75, 80))	('GW9662', 'Var', (37, 43))	('DDIT3', 'Gene', '1649', (75, 80))	('GW9662', 'Chemical', 'MESH:C457499', (37, 43))
16391	25038520	However, surprisingly, GW6471 significantly increased DDIT3 gene expression as well and this effect could be partially inhibited by GW9662 (data not shown), similarly to the effect of pioglitazone (Supplemental Figure 4), suggesting that these antagonists are not entirely selective.	('DDIT3', 'Gene', '1649', (54, 59))	('pioglitazone', 'Chemical', 'MESH:D000077205', (184, 196))	('GW9662', 'Chemical', 'MESH:C457499', (132, 138))	('DDIT3', 'Gene', (54, 59))	('GW9662', 'Var', (132, 138))	('GW6471', 'Var', (23, 29))	('GW6471', 'Chemical', 'MESH:C449302', (23, 29))	('increased', 'PosReg', (44, 53))
16418	25038520	On the other hand, phosphorylated eIF2alpha can selectively increase the translation of certain mRNAs, such as activating transcription factor 4 (ATF4), with the result that these genes can escape from the eIF2alpha-mediated translation attenuation (reviewed in).	('ATF4', 'Gene', '468', (146, 150))	('eIF2alpha', 'Gene', (206, 215))	('eIF2alpha', 'Gene', '83939', (34, 43))	('increase', 'PosReg', (60, 68))	('eIF2alpha', 'Gene', '83939', (206, 215))	('activating transcription factor 4', 'Gene', '468', (111, 144))	('ATF4', 'Gene', (146, 150))	('translation', 'MPA', (73, 84))	('phosphorylated', 'Var', (19, 33))	('activating transcription factor 4', 'Gene', (111, 144))	('eIF2alpha', 'Gene', (34, 43))
16433	12085205	Whether Bcl-2 positivity found in some carcinomas and non-functioning adenomas may constitute, in the latter, a negative prognostic marker is still unknown.	('adenomas', 'Disease', (70, 78))	('Bcl-2', 'Gene', '596', (8, 13))	('positivity', 'Var', (14, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('Bcl-2', 'Gene', (8, 13))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('carcinomas', 'Disease', (39, 49))	('carcinomas', 'Disease', 'MESH:D002277', (39, 49))	('adenomas', 'Disease', 'MESH:D000236', (70, 78))
16438	12085205	Mutations in the p53 tumour suppressor gene, which constitute the most common type of genetic alteration in several human cancers (Velculescu and El-Deiry, 1996), do not seem to be frequent in adrenocortical tumours (Ohgaki et al, 1993; Reincke et al, 1994; Reincke et al, 1996).	('tumours', 'Phenotype', 'HP:0002664', (208, 215))	('tumour', 'Disease', (208, 214))	('adrenocortical tumours', 'Disease', 'MESH:D000306', (193, 215))	('adrenocortical tumours', 'Disease', (193, 215))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancers', 'Disease', (122, 129))	('frequent', 'Reg', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumour', 'Disease', (21, 27))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('p53', 'Gene', (17, 20))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('p53', 'Gene', '7157', (17, 20))	('human', 'Species', '9606', (116, 121))
16439	12085205	Different results were found in studies on pathological adrenal cortex (Lin et al, 1994; Reincke et al, 1994, 1996; Barzon et al, 2001) for what concerns p53 overexpression, a well-established immunohistochemical marker of p53 mutations (Davidoff et al, 1991), Bcl-2, a cellular oncogene which encodes for proteins that inhibit apoptosis, thereby determining resistance to programmed cell death (Hockenbery et al, 1990, 1993), is overexpressed in different types of solid tumours (Pilotti et al, 1994; Vargas et al, 1997).	('Bcl-2', 'Gene', (261, 266))	('Bcl-2', 'Gene', '596', (261, 266))	('p53', 'Gene', (223, 226))	('p53', 'Gene', '7157', (223, 226))	('apoptosis', 'CPA', (328, 337))	('solid tumours', 'Disease', 'MESH:D009369', (466, 479))	('solid tumours', 'Disease', (466, 479))	('tumour', 'Phenotype', 'HP:0002664', (472, 478))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('tumours', 'Phenotype', 'HP:0002664', (472, 479))	('inhibit', 'NegReg', (320, 327))	('mutations', 'Var', (227, 236))
16481	12085205	Accordingly, mutations in the p53 gene constitute the most common type of genetic alteration in human cancers (Hollstein et al, 1991; Velculescu and El-Deiry, 1996).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('human', 'Species', '9606', (96, 101))	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('mutations', 'Var', (13, 22))
16482	12085205	However, few data refer to adrenocortical CA and those reported indicate that p53 mutations are uncommon in these tumours (Ohgaki et al, 1993; Reincke et al, 1994).	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumours', 'Disease', (114, 121))	('adrenocortical CA', 'Disease', (27, 44))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (82, 91))	('p53', 'Gene', (78, 81))	('adrenocortical CA', 'Disease', 'MESH:D018268', (27, 44))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('p53', 'Gene', '7157', (78, 81))
16487	12085205	Different results have been reported in APA where no or poor p53 immunoreactivity was found not only in adenomas without p53 mutations (Reincke et al, 1996) but also in those with ascertained genetic alterations (Lin et al, 1994; Adleff et al, 1998).	('mutations', 'Var', (125, 134))	('adenomas', 'Disease', (104, 112))	('p53', 'Gene', '7157', (121, 124))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('adenomas', 'Disease', 'MESH:D000236', (104, 112))
16489	12085205	All these findings imply that in APA p53 mutations are likewise uncommon but do not exclude the possibility that in these adenomas the immunohistochemical method may have low sensitivity.	('mutations', 'Var', (41, 50))	('adenomas', 'Disease', 'MESH:D000236', (122, 130))	('p53', 'Gene', '7157', (37, 40))	('p53', 'Gene', (37, 40))	('adenomas', 'Disease', (122, 130))
16490	12085205	Indeed a mutant p53 protein may be not recognisable by the antibody, deletion mutations do not necessarily induce abnormal p53 protein and in the case of missense mutations several events may be required for p53 overexpression (Casey et al, 1996).	('deletion mutations', 'Var', (69, 87))	('missense mutations', 'Var', (154, 172))	('protein', 'Protein', (20, 27))	('mutant', 'Var', (9, 15))	('p53', 'Gene', (16, 19))	('p53', 'Gene', (208, 211))	('p53', 'Gene', '7157', (208, 211))	('p53', 'Gene', '7157', (16, 19))	('p53', 'Gene', (123, 126))	('p53', 'Gene', '7157', (123, 126))
16492	12085205	No genetic p53 mutation and no p53 immunoreactivity was detected in isolated cases (Reincke et al, 1994) and in a group of NFA (Adleff et al, 1998).	('p53', 'Gene', (11, 14))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (11, 14))	('mutation', 'Var', (15, 23))	('p53', 'Gene', '7157', (31, 34))	('NFA', 'Chemical', '-', (123, 126))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('N', 'Chemical', 'MESH:D009584', (123, 124))
16503	12085205	Thus, in human tumours the expression of Bcl-2 and mutant p53 does not always coexist, even if both markers block programmed cell death.	('Bcl-2', 'Gene', (41, 46))	('Bcl-2', 'Gene', '596', (41, 46))	('programmed cell death', 'CPA', (114, 135))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('mutant', 'Var', (51, 57))	('tumours', 'Disease', (15, 22))	('block', 'NegReg', (108, 113))	('human', 'Species', '9606', (9, 14))	('p53', 'Gene', (58, 61))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))	('p53', 'Gene', '7157', (58, 61))
16528	33364199	FAs are the crucial building blocks of several lipid species, and dysregulated FA metabolism is a vital component of lipid metabolism reprograming in cancer.	('FAs', 'Chemical', 'MESH:D005227', (0, 3))	('dysregulated', 'Var', (66, 78))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('lipid', 'Chemical', 'MESH:D008055', (117, 122))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('lipid', 'Chemical', 'MESH:D008055', (47, 52))
16540	33364199	In pancreatic ductal adenocarcinoma, CD36 can also enhance the expression of several anti-apoptotic proteins, contributing to the resistance to gemcitabine and poor prognosis.	('gemcitabine', 'Chemical', 'MESH:C056507', (144, 155))	('resistance to gemcitabine', 'MPA', (130, 155))	('CD36', 'Var', (37, 41))	('enhance', 'PosReg', (51, 58))	('contributing', 'Reg', (110, 122))	('expression', 'MPA', (63, 73))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (3, 35))	('pancreatic ductal adenocarcinoma', 'Disease', (3, 35))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('anti-apoptotic', 'Protein', (85, 99))
16561	33364199	It has previously been reported that p53-mediated transactivation can also increase PTEN levels, as it has a functional p53 binding site within its promoter.	('p53', 'Gene', '7157', (120, 123))	('PTEN', 'Gene', (84, 88))	('binding', 'Interaction', (124, 131))	('PTEN', 'Gene', '5728', (84, 88))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('increase', 'PosReg', (75, 83))	('p53', 'Gene', (120, 123))	('transactivation', 'Var', (50, 65))
16592	33364199	LDs accumulation is associated with a more aggressive cancer phenotype and increased migration via elevated levels of pro-oncogenic signaling lipids, particularly lysophosphatidylcholines, and activation of pro-oncogenic SRC kinase signaling.	('accumulation', 'Var', (4, 16))	('lysophosphatidylcholines', 'MPA', (163, 187))	('pro-oncogenic SRC kinase signaling', 'Pathway', (207, 241))	('activation', 'PosReg', (193, 203))	('lipids', 'Chemical', 'MESH:D008055', (142, 148))	('aggressive cancer', 'Disease', 'MESH:D009369', (43, 60))	('elevated', 'PosReg', (99, 107))	('LDs', 'Protein', (0, 3))	('lysophosphatidylcholines', 'Chemical', 'MESH:D008244', (163, 187))	('migration', 'CPA', (85, 94))	('aggressive cancer', 'Disease', (43, 60))	('increased', 'PosReg', (75, 84))	('levels of pro-oncogenic signaling lipids', 'MPA', (108, 148))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
16613	33364199	confirmed that promoter methylation of large tumor suppressor kinase 1 (LATS1) resulted in the dysfunction of the Hippo signal pathway, which induced overexpression of MAGL in HCC.	('LATS1', 'Gene', '9113', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MAGL', 'Gene', '11343', (168, 172))	('HCC', 'Phenotype', 'HP:0001402', (176, 179))	('MAGL', 'Gene', (168, 172))	('promoter methylation', 'Var', (15, 35))	('overexpression', 'PosReg', (150, 164))	('large tumor suppressor kinase 1', 'Gene', '9113', (39, 70))	('resulted in', 'Reg', (79, 90))	('LATS1', 'Gene', (72, 77))	('large tumor suppressor kinase 1', 'Gene', (39, 70))	('dysfunction', 'MPA', (95, 106))	('Hippo signal pathway', 'Pathway', (114, 134))
16616	33364199	Perturbation of sphingolipid homeostasis has been reported in various solid tumors and hematological malignancies.	('sphingolipid homeostasis', 'Disease', 'MESH:D013106', (16, 40))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('hematological malignancies', 'Disease', (87, 113))	('hematological malignancies', 'Disease', 'MESH:D019337', (87, 113))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('reported', 'Reg', (50, 58))	('Perturbation', 'Var', (0, 12))	('sphingolipid homeostasis', 'Disease', (16, 40))	('hematological malignancies', 'Phenotype', 'HP:0004377', (87, 113))
16638	33364199	A meta-analysis encompassing 865 primary breast cancer patients reported that high HMGCR and additional mevalonate pathway genes mRNA levels correlated with poor patient prognosis and reduced survival.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('HMGCR', 'Gene', (83, 88))	('high', 'Var', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('survival', 'CPA', (192, 200))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('HMGCR', 'Gene', '3156', (83, 88))	('poor', 'NegReg', (157, 161))	('reduced', 'NegReg', (184, 191))	('patients', 'Species', '9606', (55, 63))	('mevalonate pathway genes', 'Gene', (104, 128))	('mRNA levels', 'MPA', (129, 140))	('patient', 'Species', '9606', (55, 62))	('patient', 'Species', '9606', (162, 169))	('mevalonate', 'Chemical', 'MESH:D008798', (104, 114))
16644	33364199	In contrast, HSF1 inhibition sensitizes HCC cells to the antiproliferative effects of simvastatin.	('HSF1', 'Gene', (13, 17))	('sensitizes', 'Reg', (29, 39))	('HSF1', 'Gene', '3297', (13, 17))	('antiproliferative effects', 'CPA', (57, 82))	('HCC', 'Phenotype', 'HP:0001402', (40, 43))	('simvastatin', 'Chemical', 'MESH:D019821', (86, 97))	('inhibition', 'Var', (18, 28))
16647	33364199	In breast cancer cells, mutant p53, which is the most frequent target for mutation in tumors, contributes to the upregulation of the mevalonate pathway, through recruitment of many sterol biosynthesis genes, or probably through one or more of the SREBP proteins.	('mutant', 'Var', (24, 30))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('recruitment', 'PosReg', (161, 172))	('mevalonate', 'Chemical', 'MESH:D008798', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('upregulation', 'PosReg', (113, 125))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('sterol', 'Chemical', 'MESH:D013261', (181, 187))	('sterol', 'Enzyme', (181, 187))	('mevalonate pathway', 'Pathway', (133, 151))
16655	33364199	As a selective endogenous estrogen receptor (ER) agonist and liver-X-receptor (LXR) agonist, 27-HC may contribute to ER-positive breast cancer growth and metastasis by inducing several EMT genes and disrupting constitutive p53 signaling in an MDM2-dependent manner.	('MDM2', 'Gene', (243, 247))	('disrupting', 'NegReg', (199, 209))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('estrogen receptor', 'Gene', '2099', (26, 43))	('ER', 'Gene', '2099', (117, 119))	('p53', 'Gene', '7157', (223, 226))	('MDM2', 'Gene', '4193', (243, 247))	('inducing', 'PosReg', (168, 176))	('growth', 'CPA', (143, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('p53', 'Gene', (223, 226))	('constitutive', 'MPA', (210, 222))	('ER', 'Gene', '2099', (45, 47))	('EMT genes', 'Gene', (185, 194))	('metastasis', 'CPA', (154, 164))	('contribute', 'Reg', (103, 113))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('estrogen receptor', 'Gene', (26, 43))	('breast cancer', 'Disease', (129, 142))	('27-HC', 'Var', (93, 98))
16664	33364199	At the same time, the use of anti-CD36 neutralizing antibodies causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('anti-CD36', 'Gene', (29, 38))	('anti-CD36', 'Var', (29, 38))	('human', 'Species', '9606', (176, 181))	('immunodeficient', 'Disease', 'MESH:D007153', (114, 129))	('metastasis', 'CPA', (100, 110))	('immunodeficient', 'Disease', (114, 129))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('mouse', 'Species', '10090', (160, 165))	('inhibition', 'NegReg', (86, 96))
16677	33364199	In multiple phases, 1/2 FASN inhibitor studies have been conducted (e.g., NCT00908791 for breast cancer, NCT02980029 for colon cancer, etc.	('NCT02980029', 'Var', (105, 116))	('NCT00908791', 'Var', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colon cancer', 'Disease', (121, 133))	('FASN', 'Gene', (24, 28))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('FASN', 'Gene', '2194', (24, 28))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('colon cancer', 'Phenotype', 'HP:0003003', (121, 133))	('colon cancer', 'Disease', 'MESH:D015179', (121, 133))
16678	33364199	TVB-3166 and TVB-3664 have shown anti-tumor activity in oral squamous cell carcinoma, breast, and colorectal cancer preclinical studies.	('colorectal cancer', 'Disease', (98, 115))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('TVB-3166', 'Var', (0, 8))	('TVB', 'Chemical', '-', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast', 'Disease', (86, 92))	('TVB-3664', 'Var', (13, 21))	('TVB', 'Chemical', '-', (0, 3))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 84))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('oral squamous cell carcinoma', 'Disease', (56, 84))	('TVB-3664', 'Chemical', 'MESH:C000615721', (13, 21))
16682	33364199	To date, several clinical trials aimed at evaluating different AKT inhibitors such as MK-2206 (NCT01245205, NCT01277757, NCT01251861), Capivasertib/AZD5363 (NCT03310541, NCT01226316, NCT02525068, NCT01992952), and GSK2141795 (NCT01935973) in multiple cancers; however, the results of these studies have not been reported to date.	('NCT01992952', 'Var', (196, 207))	('NCT01226316', 'Var', (170, 181))	('AKT', 'Gene', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('NCT01245205', 'Var', (95, 106))	('NCT03310541', 'Var', (157, 168))	('NCT01251861', 'Var', (121, 132))	('NCT02525068', 'Var', (183, 194))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('NCT01277757', 'Var', (108, 119))	('cancers', 'Disease', (251, 258))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('AKT', 'Gene', '207', (63, 66))	('NCT01935973', 'Var', (226, 237))
16685	33364199	Since knockdown and inhibition of SREBP-1 thwarts the glucose uptake, glycolytic activity, and lipid metabolism of HCC cells, betulin, a SREBP-1 inhibitor, has been shown to enhance the sensitivity of HCC cells to sorafenib (a first-line antitumor agent for advanced HCC treatment) and to facilitate its antitumor effect in vivo, suggesting that a SREBP-1 inhibitor and sorafenib combination can be a novel therapeutic option.	('SREBP-1', 'Gene', (348, 355))	('glucose', 'Chemical', 'MESH:D005947', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('SREBP-1', 'Gene', '6720', (137, 144))	('tumor', 'Disease', (242, 247))	('sensitivity', 'MPA', (186, 197))	('SREBP-1', 'Gene', '6720', (34, 41))	('sorafenib', 'Chemical', 'MESH:D000077157', (370, 379))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('facilitate', 'PosReg', (289, 299))	('SREBP-1', 'Gene', '6720', (348, 355))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('HCC', 'Phenotype', 'HP:0001402', (267, 270))	('SREBP-1', 'Gene', (137, 144))	('SREBP-1', 'Gene', (34, 41))	('tumor', 'Disease', (308, 313))	('lipid', 'Chemical', 'MESH:D008055', (95, 100))	('HCC', 'Phenotype', 'HP:0001402', (201, 204))	('HCC', 'Phenotype', 'HP:0001402', (115, 118))	('inhibition', 'Var', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('sorafenib', 'Chemical', 'MESH:D000077157', (214, 223))	('betulin', 'Chemical', 'MESH:C002503', (126, 133))	('glucose', 'CPA', (54, 61))	('knockdown', 'Var', (6, 15))	('enhance', 'PosReg', (174, 181))
16686	33364199	In therapy-resistant melanoma, the inhibition of SREBP-1 re-sensitizes resistant cells to BRAF-targeting therapy in vivo, partly through alterations of membrane polyunsaturation and subsequent lipid peroxidation.	('BRAF', 'Gene', (90, 94))	('lipid peroxidation', 'MPA', (193, 211))	('lipid', 'Chemical', 'MESH:D008055', (193, 198))	('membrane polyunsaturation', 'MPA', (152, 177))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('alterations', 'Reg', (137, 148))	('melanoma', 'Disease', (21, 29))	('inhibition', 'Var', (35, 45))	('BRAF', 'Gene', '673', (90, 94))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('SREBP-1', 'Gene', (49, 56))	('SREBP-1', 'Gene', '6720', (49, 56))
16691	33364199	A combined pharmacological approach involving SCD1 may counteract cancer cell chemoresistance and enhance the therapeutic efficacy of commonly used chemotherapeutic drugs, such as SCD1 inhibitor (CVT-11127 or CVT-12012) + gefitinib, SCD1 inhibitor (A939572) + temozolomide, SCD1 inhibitor (A939572) + temsirolimus.	('temozolomide', 'Chemical', 'MESH:D000077204', (260, 272))	('enhance', 'PosReg', (98, 105))	('A939572) + temsirolimus', 'Var', (290, 313))	('CVT-11127', 'Chemical', '-', (196, 205))	('therapeutic', 'MPA', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('CVT-12012', 'Var', (209, 218))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('A939572', 'Chemical', '-', (249, 256))	('temsirolimus', 'Chemical', 'MESH:C401859', (301, 313))	('A939572) +', 'Var', (249, 259))	('gefitinib', 'Chemical', 'MESH:D000077156', (222, 231))	('A939572', 'Chemical', '-', (290, 297))	('cancer', 'Disease', (66, 72))
16694	33364199	Moreover, since SCD1 plays a major role in the de novo synthesis of TGs, cholesterol esters, and wax esters required for normal skin and eyelid function, the targeted disruption of SCD1 in mice causes atrophy of sebaceous and meibomian glands and depletion of wax esters in the eyelid.	('atrophy', 'Disease', 'MESH:D001284', (201, 208))	('depletion of wax esters', 'MPA', (247, 270))	('disruption', 'Var', (167, 177))	('mice', 'Species', '10090', (189, 193))	('wax esters', 'Chemical', '-', (97, 107))	('atrophy', 'Disease', (201, 208))	('cholesterol esters', 'Chemical', 'MESH:D002788', (73, 91))	('SCD1', 'Gene', (181, 185))	('TGs', 'Chemical', 'MESH:D014280', (68, 71))	('wax esters', 'Chemical', '-', (260, 270))	('causes', 'Reg', (194, 200))
16699	33364199	This suggests that inhibiting FA catabolism can be a promising therapeutic strategy in combination with conventional chemotherapy for patients with gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (148, 172))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (148, 171))	('inhibiting', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('patients', 'Species', '9606', (134, 142))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('FA catabolism', 'MPA', (30, 43))	('gastrointestinal cancers', 'Disease', (148, 172))
16700	33364199	MAGL inhibition also decreases cyclin D1 and Bcl-2 expression, thereby inhibiting the proliferation and promoting tumor apoptosis or/and cell cycle arrest in endometrial cancer and CRC.	('CRC', 'Phenotype', 'HP:0003003', (181, 184))	('endometrial cancer', 'Phenotype', 'HP:0012114', (158, 176))	('inhibition', 'Var', (5, 15))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('expression', 'MPA', (51, 61))	('endometrial cancer', 'Disease', (158, 176))	('endometrial cancer', 'Disease', 'MESH:D016889', (158, 176))	('decreases', 'NegReg', (21, 30))	('Bcl-2', 'Gene', (45, 50))	('MAGL', 'Gene', (0, 4))	('CRC', 'Disease', 'MESH:D015179', (181, 184))	('proliferation', 'CPA', (86, 99))	('tumor', 'Disease', (114, 119))	('arrest', 'Disease', (148, 154))	('MAGL', 'Gene', '11343', (0, 4))	('cyclin D1', 'Gene', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Bcl-2', 'Gene', '596', (45, 50))	('cyclin D1', 'Gene', '595', (31, 40))	('inhibiting', 'NegReg', (71, 81))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('promoting', 'PosReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CRC', 'Disease', (181, 184))
16721	33364199	Several ACAT inhibitors, such as avasimibe, K604, and ATR-101, have been studied preclinically, and ATR-101 has entered clinical trials in patients with advanced adrenocortical carcinoma (NCT01898715).	('ATR-101', 'Chemical', 'MESH:C079534', (54, 61))	('K604', 'Chemical', 'MESH:C520671', (44, 48))	('patients', 'Species', '9606', (139, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('ATR-101', 'Var', (100, 107))	('ATR-101', 'Chemical', 'MESH:C079534', (100, 107))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (162, 186))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (162, 186))	('ACAT', 'Gene', (8, 12))	('ACAT', 'Gene', '38', (8, 12))	('adrenocortical carcinoma', 'Disease', (162, 186))	('avasimibe', 'Chemical', 'MESH:C423185', (33, 42))
16732	32164326	Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma Mitotane is a steroidogenesis inhibitor and adrenolytic drug used for treatment of adrenocortical cancer (ACC).	('Adrenocortical Carcinoma', 'Disease', (95, 119))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('Mitotane', 'Var', (120, 128))	('Mitotane', 'Chemical', 'MESH:D008939', (61, 69))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (95, 119))	('cancer', 'Disease', (218, 224))	('Adrenal Insufficiency', 'Disease', (12, 33))	('Mitotane', 'Chemical', 'MESH:D008939', (120, 128))	('Adrenal Insufficiency', 'Phenotype', 'HP:0000846', (12, 33))	('Patients', 'Species', '9606', (81, 89))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (95, 119))	('Adrenal Insufficiency', 'Disease', 'MESH:D000309', (12, 33))	('ACC', 'Phenotype', 'HP:0006744', (226, 229))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('Carcinoma', 'Phenotype', 'HP:0030731', (110, 119))
16733	32164326	Mitotane therapy causes adrenal insufficiency requiring glucocorticoid replacement in all patients.	('adrenal insufficiency', 'Disease', (24, 45))	('Mitotane', 'Var', (0, 8))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('causes', 'Reg', (17, 23))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (24, 45))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (24, 45))	('patients', 'Species', '9606', (90, 98))
16752	32164326	It was also found that mitotane could potentially interfere with pituitary function by comparing adrenocorticotropic hormone (ACTH) levels between patients treated with mitotane for ACC and patients with primary adrenal insufficiency (autoimmune or post-adrenalectomy).	('interfere', 'NegReg', (50, 59))	('mitotane', 'Chemical', 'MESH:D008939', (169, 177))	('adrenocorticotropic hormone', 'Gene', (97, 124))	('mitotane', 'Chemical', 'MESH:D008939', (23, 31))	('patients', 'Species', '9606', (190, 198))	('primary adrenal insufficiency', 'Disease', 'MESH:D000224', (204, 233))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (212, 233))	('primary adrenal insufficiency', 'Phenotype', 'HP:0008207', (204, 233))	('pituitary', 'MPA', (65, 74))	('ACTH', 'Gene', (126, 130))	('patients', 'Species', '9606', (147, 155))	('primary adrenal insufficiency', 'Disease', (204, 233))	('ACC', 'Phenotype', 'HP:0006744', (182, 185))	('adrenocorticotropic hormone', 'Gene', '5443', (97, 124))	('mitotane', 'Var', (23, 31))	('ACTH', 'Gene', '5443', (126, 130))	('comparing', 'Reg', (87, 96))
16797	32164326	found that mitotane-treated patients with adrenal insufficiency had lower ACTH levels than patients with primary adrenal insufficiency of other etiologies.	('mitotane-treated', 'Var', (11, 27))	('lower ACTH levels', 'Phenotype', 'HP:0002920', (68, 85))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (113, 134))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (113, 134))	('adrenal insufficiency', 'Disease', (42, 63))	('lower', 'NegReg', (68, 73))	('ACTH', 'Gene', (74, 78))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (42, 63))	('patients', 'Species', '9606', (91, 99))	('primary adrenal insufficiency', 'Disease', 'MESH:D000224', (105, 134))	('primary adrenal insufficiency', 'Phenotype', 'HP:0008207', (105, 134))	('ACTH', 'Gene', '5443', (74, 78))	('mitotane', 'Chemical', 'MESH:D008939', (11, 19))	('primary adrenal insufficiency', 'Disease', (105, 134))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (42, 63))	('patients', 'Species', '9606', (28, 36))
16813	32164326	After obtaining institutional ethical committee approval from each center, CE2010-304, 09.244 (CHUM), and CE 36/2012 (San Luigi Hospital), every case from 1992 (Italy) and 1995 (Montreal) to this day with pathologically confirmed ACC of stage I-II-III based on ENSAT classification was reviewed.	('ACC', 'Phenotype', 'HP:0006744', (230, 233))	('CE2010-304', 'Var', (75, 85))	('CHUM', 'Disease', 'None', (95, 99))	('CHUM', 'Disease', (95, 99))
16835	32154490	Subsequent analysis of the patient's tumor revealed mutations in TP53 and MEN1.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('patient', 'Species', '9606', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('MEN1', 'Gene', (74, 78))	('MEN1', 'Gene', '4221', (74, 78))
16837	32154490	The tumor also demonstrated a low BUB1B/PINK1 ratio and G0S2 hypermethylation, both predictive of very aggressive ACC.	('tumor', 'Disease', (4, 9))	('PINK1', 'Gene', (40, 45))	('ACC', 'Phenotype', 'HP:0006744', (114, 117))	('BUB1B', 'Gene', (34, 39))	('ACC', 'Disease', (114, 117))	('low', 'NegReg', (30, 33))	('G0S2', 'Gene', '50486', (56, 60))	('ACC', 'Disease', 'MESH:D018268', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('hypermethylation', 'Var', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('PINK1', 'Gene', '65018', (40, 45))	('G0S2', 'Gene', (56, 60))	('BUB1B', 'Gene', '701', (34, 39))
16862	32154490	Pathology confirmed ACC Stage 3, pT3pN1Mx with 1/1 lymph node positive with a high Ki67 score of 60% and no detection of abnormalities in mismatch repair proteins (Fig.	('Ki67', 'Chemical', '-', (83, 87))	('ACC', 'Disease', 'MESH:D018268', (20, 23))	('pT3pN1Mx', 'Var', (33, 41))	('ACC', 'Phenotype', 'HP:0006744', (20, 23))	('ACC', 'Disease', (20, 23))
16872	32154490	Whole-exome sequencing revealed only two somatic mutations predicted to be damaging: TP53 p.V14G and MEN1 p.E368X, both unfortunately, nonactionable.	('TP53', 'Gene', (85, 89))	('p.V14G', 'Var', (90, 96))	('p.E368X', 'Var', (106, 113))	('MEN1', 'Gene', (101, 105))	('MEN1', 'Gene', '4221', (101, 105))	('TP53', 'Gene', '7157', (85, 89))	('p.V14G', 'Mutation', 'rs1057519747', (90, 96))	('p.E368X', 'Mutation', 'p.E368X', (106, 113))
16884	32154490	Similar to the patients included in Tables 2 and 3, she also had liver and lung metastases at the time of the CNS spread, a mutation in TP53 and her post-treatment survival was poor.	('liver and lung metastases', 'Disease', 'MESH:D009362', (65, 90))	('patients', 'Species', '9606', (15, 23))	('mutation in', 'Var', (124, 135))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))
16887	32154490	More recently, hypermethylation of another cell cycle regulator G0S2 (G0/G1 switch 2) was shown to be an independent predictor of recurrence-free survival and overall survival in ACC patients.	('ACC', 'Disease', (179, 182))	('overall survival', 'CPA', (159, 175))	('G0S2', 'Gene', (64, 68))	('G0/G1 switch 2', 'Gene', (70, 84))	('recurrence-free survival', 'CPA', (130, 154))	('ACC', 'Disease', 'MESH:D018268', (179, 182))	('hypermethylation', 'Var', (15, 31))	('ACC', 'Phenotype', 'HP:0006744', (179, 182))	('G0/G1 switch 2', 'Gene', '50486', (70, 84))	('patients', 'Species', '9606', (183, 191))	('G0S2', 'Gene', '50486', (64, 68))
16888	32154490	Moreover, patients with hypermethylation of G0S2 (>4.69% detected by the Epitect Methylation kit) combined with a BUB1B-PINK1 score less than 5.2 resulted in intermediate or poor outcomes.	('hypermethylation', 'Var', (24, 40))	('PINK1', 'Gene', (120, 125))	('G0S2', 'Gene', (44, 48))	('BUB1B', 'Gene', '701', (114, 119))	('BUB1B', 'Gene', (114, 119))	('patients', 'Species', '9606', (10, 18))	('PINK1', 'Gene', '65018', (120, 125))	('G0S2', 'Gene', '50486', (44, 48))
16892	32154490	While this patient presented with a hormonally active tumor and high Ki67%, both prognosticators of aggressive disease, she did not have widely metastatic disease at presentation.	('high Ki67%', 'Var', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Ki67', 'Chemical', '-', (69, 73))	('patient', 'Species', '9606', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('aggressive disease', 'Disease', 'MESH:D001523', (100, 118))	('tumor', 'Disease', (54, 59))	('Ki67%', 'Var', (69, 74))	('aggressive disease', 'Disease', (100, 118))
16893	32154490	With substantial variability reported in Ki67 scoring even between expert laboratories, additional predictive biomarkers such as the BUB1B-PINK1 score and hypermethylation of G0S2 could be useful prognostic tools to estimate disease aggressiveness.	('hypermethylation', 'Var', (155, 171))	('G0S2', 'Gene', '50486', (175, 179))	('aggressiveness', 'Disease', 'MESH:D001523', (233, 247))	('Ki67', 'Chemical', '-', (41, 45))	('aggressiveness', 'Disease', (233, 247))	('PINK1', 'Gene', '65018', (139, 144))	('G0S2', 'Gene', (175, 179))	('BUB1B', 'Gene', '701', (133, 138))	('PINK1', 'Gene', (139, 144))	('aggressiveness', 'Phenotype', 'HP:0000718', (233, 247))	('BUB1B', 'Gene', (133, 138))
16910	32000700	Causes of TMA are separated between thrombotic thrombocytopenic purpura, typical Hemolytic uremic syndrome (HUS), primary atypical HUS in patients with an abnormality of the alternative complement pathway, and HUS secondary to a heterogeneous group of causes: infections, drugs, genetic disorders, systemic diseases and cancers.	('systemic diseases', 'Disease', (298, 315))	('HUS', 'Disease', (210, 213))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('systemic diseases', 'Disease', 'MESH:D034721', (298, 315))	('HUS', 'Disease', (131, 134))	('abnormality of the alternative complement pathway', 'Phenotype', 'HP:0005482', (155, 204))	('HUS', 'Disease', 'MESH:D006463', (210, 213))	('thrombotic thrombocytopenic purpura', 'Disease', (36, 71))	('thrombotic thrombocytopenic purpura', 'Disease', 'MESH:D011697', (36, 71))	('HUS', 'Disease', 'MESH:D006463', (131, 134))	('Hemolytic uremic syndrome', 'Disease', (81, 106))	('Hemolytic uremic syndrome', 'Phenotype', 'HP:0005575', (81, 106))	('abnormality', 'Var', (155, 166))	('TMA', 'Disease', 'MESH:D057049', (10, 13))	('thrombotic thrombocytopenic purpura', 'Phenotype', 'HP:0001973', (36, 71))	('cancers', 'Disease', 'MESH:D009369', (320, 327))	('patients', 'Species', '9606', (138, 146))	('Hemolytic uremic syndrome', 'Disease', 'MESH:D006463', (81, 106))	('genetic disorders', 'Disease', 'MESH:D030342', (279, 296))	('HUS', 'Phenotype', 'HP:0005575', (108, 111))	('purpura', 'Phenotype', 'HP:0000979', (64, 71))	('genetic disorders', 'Disease', (279, 296))	('HUS', 'Phenotype', 'HP:0005575', (210, 213))	('HUS', 'Disease', (108, 111))	('TMA', 'Disease', (10, 13))	('alternative', 'Pathway', (174, 185))	('cancers', 'Phenotype', 'HP:0002664', (320, 327))	('HUS', 'Disease', 'MESH:D006463', (108, 111))	('HUS', 'Phenotype', 'HP:0005575', (131, 134))	('cancers', 'Disease', (320, 327))
16917	32000700	Other lab results revealed plasma creatinine = 97 mumol/L, proteinuria = 0.7 g/g of urine creatinine, haemoglobin 9.9 g/dL, platelet 143 G/L.	('proteinuria', 'Phenotype', 'HP:0000093', (59, 70))	('proteinuria', 'Disease', 'MESH:D011507', (59, 70))	('143 G/L', 'Var', (133, 140))	('plasma creatinine', 'MPA', (27, 44))	('creatinine', 'Chemical', 'MESH:D003404', (90, 100))	('haemoglobin', 'MPA', (102, 113))	('143 G/L', 'SUBSTITUTION', 'None', (133, 140))	('proteinuria', 'Disease', (59, 70))	('creatinine', 'Chemical', 'MESH:D003404', (34, 44))
16919	32000700	She presented thrombocytopenia (67G/L) and mechanical hemolytic anemia: haemoglobin = 7.9 g/dL, reticulocyte = 175G/L, presence of schistocytes, Lactate Dehydrogenase (LDH) = 1058 UI/L and haptoglobin < 0.1 g/L.	('thrombocytopenia', 'Phenotype', 'HP:0001873', (14, 30))	('67G/L', 'SUBSTITUTION', 'None', (32, 37))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (54, 70))	('175G/L', 'Var', (111, 117))	('Lactate', 'Chemical', 'MESH:D019344', (145, 152))	('hemolytic anemia', 'Disease', 'MESH:D000743', (54, 70))	('thrombocytopenia', 'Disease', (14, 30))	('schistocytes', 'Phenotype', 'HP:0001981', (131, 143))	('67G/L', 'Var', (32, 37))	('hemolytic anemia', 'Disease', (54, 70))	('haptoglobin', 'Gene', '3240', (189, 200))	('haptoglobin', 'Gene', (189, 200))	('175G/L', 'SUBSTITUTION', 'None', (111, 117))	('anemia', 'Phenotype', 'HP:0001903', (64, 70))	('thrombocytopenia', 'Disease', 'MESH:D013921', (14, 30))
16924	32000700	ACC was confirmed by pathology, with a Weiss score at 6/9, Ki67 = 45% and 25 mitotic figures per 50 high-power field.	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('ACC', 'Disease', 'MESH:D018268', (0, 3))	('Ki67', 'Var', (59, 63))	('ACC', 'Disease', (0, 3))
16934	32000700	During all the follow-up, the patient remained anuric in hemodialysis and had persistent hemolysis with schistocytes, high LDH's value and decreased haptoglobin.	('high', 'Var', (118, 122))	('patient', 'Species', '9606', (30, 37))	('schistocytes', 'Phenotype', 'HP:0001981', (104, 116))	("LDH's value", 'MPA', (123, 134))	('decreased', 'NegReg', (139, 148))	('haptoglobin', 'Gene', '3240', (149, 160))	('hemolysis', 'Disease', (89, 98))	('hemolysis', 'Disease', 'MESH:D006461', (89, 98))	('decreased haptoglobin', 'Phenotype', 'HP:0020181', (139, 160))	('haptoglobin', 'Gene', (149, 160))
16941	32000700	Two weeks later, biological data found a KDIGO 3 AKI with plasma creatinine = 200 mumol/L.	('AKI', 'Disease', 'MESH:D058186', (49, 52))	('creatinine', 'Chemical', 'MESH:D003404', (65, 75))	('KDIGO', 'Var', (41, 46))	('AKI', 'Disease', (49, 52))
16943	32000700	Cytopenias were also investigated at this time and revealed TMA with haptoglobin < 0.1 g/L, schistocytes, LDH = 703 UI/L and plasma creatinine = 429 mumol/L.	('TMA', 'Disease', (60, 63))	('Cytopenias', 'Disease', 'MESH:D006402', (0, 10))	('TMA', 'Disease', 'MESH:D057049', (60, 63))	('schistocytes', 'Disease', (92, 104))	('haptoglobin', 'Gene', '3240', (69, 80))	('creatinine', 'Chemical', 'MESH:D003404', (132, 142))	('Cytopenias', 'Disease', (0, 10))	('schistocytes', 'Phenotype', 'HP:0001981', (92, 104))	('haptoglobin', 'Gene', (69, 80))	('< 0.1', 'Var', (81, 86))
16947	32000700	After 14 plasma-exchanges, platelet count improved (145 G/L), and LDH decreased (422 UI/L) but schistocytes and undetectable haptoglobin persisted.	('145 G/L', 'Var', (52, 59))	('haptoglobin', 'Gene', (125, 136))	('schistocytes', 'Phenotype', 'HP:0001981', (95, 107))	('improved', 'PosReg', (42, 50))	('decreased', 'NegReg', (70, 79))	('platelet count', 'MPA', (27, 41))	('haptoglobin', 'Gene', '3240', (125, 136))	('LDH', 'MPA', (66, 69))	('145 G/L', 'SUBSTITUTION', 'None', (52, 59))
16953	32000700	Laboratory results revealed hemolytic anemia (Hb = 9.8 g/dL, haptoglobin < 0.1 g/L and schistocytes) and thrombocytopenia (platelet count 99 G/L).	('anemia', 'Phenotype', 'HP:0001903', (38, 44))	('hemolytic anemia', 'Disease', (28, 44))	('haptoglobin', 'Gene', (61, 72))	('haptoglobin', 'Gene', '3240', (61, 72))	('schistocytes', 'Phenotype', 'HP:0001981', (87, 99))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (28, 44))	('99 G/L', 'Var', (138, 144))	('thrombocytopenia', 'Disease', 'MESH:D013921', (105, 121))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (105, 121))	('99 G/L', 'SUBSTITUTION', 'None', (138, 144))	('schistocytes', 'Disease', (87, 99))	('hemolytic anemia', 'Disease', 'MESH:D000743', (28, 44))	('thrombocytopenia', 'Disease', (105, 121))
17015	31917677	For example, Li-Fraumeni syndrome results from dominantly inherited germline mutations in the TP53 gene and has an increased risk of ACC.	('Li-Fraumeni syndrome', 'Disease', (13, 33))	('ACC', 'Disease', 'MESH:D018268', (133, 136))	('results from', 'Reg', (34, 46))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('germline mutations', 'Var', (68, 86))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (13, 33))	('ACC', 'Phenotype', 'HP:0006744', (133, 136))	('ACC', 'Disease', (133, 136))
17016	31917677	Mutations in the TP53 gene are more frequently identified in children with ACC (~50-80%) than adults with ACC.	('ACC', 'Disease', 'MESH:D018268', (75, 78))	('ACC', 'Disease', 'MESH:D018268', (106, 109))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('ACC', 'Disease', (75, 78))	('Mutations', 'Var', (0, 9))	('children', 'Species', '9606', (61, 69))	('ACC', 'Phenotype', 'HP:0006744', (106, 109))	('ACC', 'Disease', (106, 109))	('identified', 'Reg', (47, 57))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
17017	31917677	Lynch syndrome also predisposes patients to certain cancers due to mutations in the DNA mismatch repair genes MSH2, MSH6, MLH1, and PMS2.	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('patients', 'Species', '9606', (32, 40))	('cancers', 'Disease', (52, 59))	('MSH6', 'Gene', '2956', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('MLH1', 'Gene', (122, 126))	('PMS2', 'Gene', (132, 136))	('MLH1', 'Gene', '4292', (122, 126))	('mutations', 'Var', (67, 76))	('MSH2', 'Gene', (110, 114))	('Lynch syndrome', 'Disease', (0, 14))	('MSH2', 'Gene', '4436', (110, 114))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('PMS2', 'Gene', '5395', (132, 136))	('MSH6', 'Gene', (116, 120))	('predisposes', 'Reg', (20, 31))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
17031	31917677	A pathogenic mutation (p.Q46X) in the MSH2 gene was identified and she was subsequently referred for genetic counseling and diagnosed with Lynch syndrome.	('Lynch syndrome', 'Disease', (139, 153))	('p.Q46X', 'Var', (23, 29))	('MSH2', 'Gene', (38, 42))	('pathogenic', 'Reg', (2, 12))	('Lynch syndrome', 'Disease', 'MESH:D003123', (139, 153))	('MSH2', 'Gene', '4436', (38, 42))	('p.Q46X', 'Mutation', 'p.Q46X', (23, 29))
17065	31917677	Nuclear pleomorphism can be seen in both cancers but is generally higher in pheochromocytoma.	('higher', 'Reg', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('pheochromocytoma', 'Disease', (76, 92))	('pheochromocytoma', 'Disease', 'MESH:D010673', (76, 92))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (76, 92))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('Nuclear pleomorphism', 'Var', (0, 20))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
17074	31917677	The Weiss diagnostic criteria for the diagnosis of ACC includes three or more of the following features: high nuclear grade, mitotic rate >5 per 50 high-power fields, atypical mitotic figures, clear cells comprising 25% or less of the tumor, diffuse architecture, tissue necrosis, and venous, sinusoidal, and capsular invasion.	('venous', 'CPA', (285, 291))	('ACC', 'Disease', (51, 54))	('necrosis', 'Disease', (271, 279))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('diffuse architecture', 'CPA', (242, 262))	('necrosis', 'Disease', 'MESH:D009336', (271, 279))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('ACC', 'Disease', 'MESH:D018268', (51, 54))	('atypical', 'Var', (167, 175))	('tumor', 'Disease', (235, 240))	('mitotic rate', 'CPA', (125, 137))	('capsular invasion', 'CPA', (309, 326))	('ACC', 'Phenotype', 'HP:0006744', (51, 54))	('tissue necrosis', 'Phenotype', 'HP:0010885', (264, 279))
17084	31917677	Tumors with a PASS score of 4 or greater have a potential to be malignant while tumors with a PASS score of less than 4 are benign.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PASS score', 'Var', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('malignant', 'CPA', (64, 73))
17087	31917677	As a result, this patient was advised against radiation treatment because of the presence of a pathogenic mutation in MSH2.	('presence', 'Reg', (81, 89))	('MSH2', 'Gene', '4436', (118, 122))	('mutation', 'Var', (106, 114))	('pathogenic', 'Reg', (95, 105))	('patient', 'Species', '9606', (18, 25))	('MSH2', 'Gene', (118, 122))
17114	29959979	A survey of recent literature shows that HAC15 cells have been used to explore the contrasting effects of thiazolidinedione drugs on cortisol and aldosterone production, the contribution of inwardly rectifying K+ channel mutations in hyperaldosteronism, and to establish a role for Ca2+/calmodulin-dependent protein kinase kinase in regulating steroidogenesis.	('hyperaldosteronism', 'Disease', 'MESH:D006929', (234, 252))	('mutations', 'Var', (221, 230))	('cortisol', 'Chemical', 'MESH:D006854', (133, 141))	('calmodulin', 'Gene', (287, 297))	('steroidogenesis', 'MPA', (344, 359))	('calmodulin', 'Gene', '801', (287, 297))	('aldosterone production', 'MPA', (146, 168))	('rat', 'Species', '10116', (23, 26))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (234, 252))	('thiazolidinedione', 'Chemical', 'MESH:D045162', (106, 123))	('aldosterone production', 'Phenotype', 'HP:0000859', (146, 168))	('hyperaldosteronism', 'Disease', (234, 252))	('Ca2+', 'Chemical', 'MESH:D002118', (282, 286))	('steroid', 'Chemical', 'MESH:D013256', (344, 351))	('HAC15', 'CellLine', 'CVCL:S898', (41, 46))	('aldosterone', 'Chemical', 'MESH:D000450', (146, 157))	('cortisol', 'MPA', (133, 141))
17160	29959979	Previous work in primary glomerulosa cells showed that picomolar concentrations of angiotensin II could elicit Ca2+ oscillations, while nanomolar amounts caused larger transients that plateaued and did not oscillate.	('rat', 'Species', '10116', (72, 75))	('picomolar concentrations', 'Var', (55, 79))	('Ca2+', 'Chemical', 'MESH:D002118', (111, 115))	('elicit', 'Reg', (104, 110))	('angiotensin II', 'Gene', '183', (83, 97))	('Ca2+ oscillations', 'MPA', (111, 128))	('angiotensin II', 'Gene', (83, 97))
17217	29959979	In trials using muscarinic receptor antagonists, we found that tiotropium markedly inhibited aldosterone production induced by ACh or carbachol, while pirenzepine and methoctramine did not.	('ACh', 'Chemical', 'MESH:D000109', (127, 130))	('tiotropium', 'Var', (63, 73))	('aldosterone production', 'MPA', (93, 115))	('carbachol', 'Chemical', 'MESH:D002217', (134, 143))	('inhibited aldosterone production', 'Phenotype', 'HP:0004319', (83, 115))	('aldosterone production', 'Phenotype', 'HP:0000859', (93, 115))	('inhibited', 'NegReg', (83, 92))	('tiotropium', 'Chemical', 'MESH:C079890', (63, 73))	('methoctramine', 'Chemical', 'MESH:C054938', (167, 180))	('aldosterone', 'Chemical', 'MESH:D000450', (93, 104))	('pirenzepine', 'Chemical', 'MESH:D010890', (151, 162))
17234	29959979	This enhancement is lost in mice with targeted disruption of the M2 receptor.	('enhancement', 'PosReg', (5, 16))	('mice', 'Species', '10090', (28, 32))	('disruption', 'Var', (47, 57))	('M2 receptor', 'Protein', (65, 76))
17247	26438728	CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1alpha) of cAMP-dependent protein kinase (PKA).	('inactivating mutations', 'Var', (38, 60))	('cAMP', 'Chemical', 'MESH:D000242', (135, 139))	('PRKAR1A', 'Gene', (64, 71))	('CNC', 'Disease', (0, 3))	('PPNAD', 'Chemical', '-', (8, 13))	('caused', 'Reg', (18, 24))	('PPNAD', 'Disease', (8, 13))
17255	26438728	We conclude that, in vitro and in vivo, Celecoxib led to decreased steroidogenesis.	('Celecoxib', 'Chemical', 'MESH:D000068579', (40, 49))	('steroidogenesis', 'MPA', (67, 82))	('Celecoxib', 'Var', (40, 49))	('steroid', 'Chemical', 'MESH:D013256', (67, 74))	('decreased', 'NegReg', (57, 66))
17256	26438728	In a mouse model of PPNAD, Celecoxib caused histological changes that reversed, at least in part, BAH and this was associated with a reduction of corticosterone levels.	('corticosterone levels', 'MPA', (146, 167))	('corticosterone', 'Chemical', 'MESH:D003345', (146, 160))	('reduction', 'NegReg', (133, 142))	('PPNAD', 'Chemical', '-', (20, 25))	('mouse', 'Species', '10090', (5, 10))	('Celecoxib', 'Chemical', 'MESH:D000068579', (27, 36))	('Celecoxib', 'Var', (27, 36))	('reduction of corticosterone levels', 'Phenotype', 'HP:0032363', (133, 167))	('BAH', 'Chemical', '-', (98, 101))
17258	26438728	1989,) and is caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1alpha) of cAMP-dependent protein kinase (PKA).	('caused', 'Reg', (14, 20))	('PRKAR1A', 'Gene', (60, 67))	('inactivating mutations', 'Var', (34, 56))	('cAMP', 'Chemical', 'MESH:D000242', (131, 135))
17268	26438728	Our data support this hypothesis, both in vitro and in vivo, Celecoxib decreased steroidogenesis and reversed, at least in part, BAH in the treated animals.	('steroid', 'Chemical', 'MESH:D013256', (81, 88))	('Celecoxib', 'Var', (61, 70))	('Celecoxib', 'Chemical', 'MESH:D000068579', (61, 70))	('steroidogenesis', 'MPA', (81, 96))	('BAH', 'Chemical', '-', (129, 132))	('decreased', 'NegReg', (71, 80))
17319	26438728	mRNA expression levels were detected by caspase-1 (Casp1, Mm00438023_m1), interleukin 1beta (Il1b, Mm00434228_m1), PTGS2 (COX2) (Ptgs2, Mm00478374_m1), sf1 (Nr5a1, Mm00446826_m1), beta-catenin (Ctnnb1, Mm00483039_m1), cyclin D1 (Ccnd1, Mm00432359_m1), and cyp17a (Cyp17a1, Mm00484040_m1) Taqman Gene Expression Assays (Applied Biosystems, Foster City, CA).	('sf1', 'Gene', '22668', (152, 155))	('mRNA expression levels', 'MPA', (0, 22))	('Cyp17a1', 'Gene', '13074', (264, 271))	('interleukin 1beta', 'Gene', '16176', (74, 91))	('Mm00446826_m1', 'Var', (164, 177))	('interleukin 1beta', 'Gene', (74, 91))	('Casp1', 'Gene', '12362', (51, 56))	('Nr5a1', 'Gene', (157, 162))	('Ptgs2', 'Gene', '19225', (129, 134))	('Mm00438023_m1', 'Var', (58, 71))	('Ctnnb1', 'Gene', '12387', (194, 200))	('beta-catenin', 'Gene', '12387', (180, 192))	('Cyp17a1', 'Gene', (264, 271))	('beta-catenin', 'Gene', (180, 192))	('sf1', 'Gene', (152, 155))	('Nr5a1', 'Gene', '26423', (157, 162))	('Ctnnb1', 'Gene', (194, 200))	('Mm00478374_m1', 'Var', (136, 149))	('Il1b', 'Gene', (93, 97))	('Mm00483039_m1', 'Var', (202, 215))	('Casp1', 'Gene', (51, 56))	('cyclin D1', 'Gene', '12443', (218, 227))	('Mm00432359_m1', 'Var', (236, 249))	('Ccnd1', 'Gene', (229, 234))	('cyclin D1', 'Gene', (218, 227))	('Il1b', 'Gene', '16176', (93, 97))	('caspase-1', 'Gene', (40, 49))	('Ccnd1', 'Gene', '12443', (229, 234))	('Ptgs2', 'Gene', (129, 134))	('caspase-1', 'Gene', '12362', (40, 49))
17322	26438728	CAR47 is the first (and only) immortalized human cell line with an inactivating PRKAR1A mutation; it was derived from the adrenal gland of a patient diagnosed with PPNAD and CNC.	('mutation', 'Var', (88, 96))	('patient', 'Species', '9606', (141, 148))	('PPNAD', 'Chemical', '-', (164, 169))	('human', 'Species', '9606', (43, 48))	('PRKAR1A', 'Gene', (80, 87))
17323	26438728	H295R is an adrenocortical carcinoma cell line that retains the ability to produce adrenal steroids, including cortisol, whereas CAR47 does not.	('cortisol', 'Chemical', 'MESH:D006854', (111, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('adrenocortical carcinoma', 'Disease', (12, 36))	('produce adrenal steroids', 'MPA', (75, 99))	('H295R', 'Var', (0, 5))	('cortisol', 'MPA', (111, 119))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (12, 36))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (12, 36))	('steroids', 'Chemical', 'MESH:D013256', (91, 99))
17335	26438728	The number of Ki67-positive cells was reduced in the adrenal glands of Celecoxib-treated mice compared to vehicle (Figure 5B).	('Ki67', 'Gene', '17345', (14, 18))	('reduced', 'NegReg', (38, 45))	('mice', 'Species', '10090', (89, 93))	('Celecoxib', 'Chemical', 'MESH:D000068579', (71, 80))	('Celecoxib-treated', 'Var', (71, 88))	('Ki67', 'Gene', (14, 18))
17337	26438728	Apoptotic cells were detected only in the adrenal gland of Celecoxib-treated mice, but not in those of untreated animals by both IHC and fluorescence (Figures 6A and 6B).	('Celecoxib-treated', 'Var', (59, 76))	('mice', 'Species', '10090', (77, 81))	('Celecoxib', 'Chemical', 'MESH:D000068579', (59, 68))	('Apoptotic cells', 'CPA', (0, 15))
17352	26438728	In addition, in at least two other lesions caused by Prkar1a deficiency, mouse osteochondromyxomas and FDL tumors, PGE2 levels were elevated both at the tumor level and systemically, as well as linked to abnormal growth and proliferation of aBSCs, relatively undifferentiated cells of the osteoblastic lineage.	('elevated', 'PosReg', (132, 140))	('tumor', 'Disease', (107, 112))	('abnormal growth', 'Phenotype', 'HP:0001507', (204, 219))	('Prkar1a', 'Gene', '19084', (53, 60))	('mouse', 'Species', '10090', (73, 78))	('PGE2', 'Chemical', 'MESH:D015232', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('PGE2', 'Gene', (115, 119))	('osteochondromyxomas and FDL tumors', 'Disease', 'MESH:D009369', (79, 113))	('deficiency', 'Var', (61, 71))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('linked to', 'Reg', (194, 203))	('tumor', 'Disease', (153, 158))	('growth', 'CPA', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('proliferation', 'CPA', (224, 237))	('Prkar1a', 'Gene', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('levels', 'MPA', (120, 126))
17353	26438728	Indeed, our data support an effect of systemic Celecoxib therapy in mouse BAH caused by Prkar1a deficiency, in addition to an inhibitory effect on human adrenal cell viability in culture.	('mouse', 'Species', '10090', (68, 73))	('human', 'Species', '9606', (147, 152))	('caused by', 'Reg', (78, 87))	('Celecoxib', 'Chemical', 'MESH:D000068579', (47, 56))	('Prkar1a', 'Gene', '19084', (88, 95))	('deficiency', 'Var', (96, 106))	('Prkar1a', 'Gene', (88, 95))	('BAH', 'Chemical', '-', (74, 77))	('BAH', 'Disease', (74, 77))
17357	26438728	The present study suggested that Celecoxib inhibition of COX2 led to decreased PGE2 levels and glucocorticoid secretion, but more importantly an improvement in the histologic phenotype of the BAH associated with Prkar1a deficiency.	('improvement', 'PosReg', (145, 156))	('Celecoxib', 'Chemical', 'MESH:D000068579', (33, 42))	('inhibition', 'NegReg', (43, 53))	('COX2', 'Gene', (57, 61))	('decreased', 'NegReg', (69, 78))	('deficiency', 'Var', (220, 230))	('PGE2', 'Chemical', 'MESH:D015232', (79, 83))	('PGE2 levels', 'MPA', (79, 90))	('Prkar1a', 'Gene', (212, 219))	('Prkar1a', 'Gene', '19084', (212, 219))	('glucocorticoid secretion', 'MPA', (95, 119))	('BAH', 'Chemical', '-', (192, 195))	('BAH', 'Disease', (192, 195))
17365	26438728	Humans with PRKAR1A mutations and BAH (mostly PPNAD) demonstrate paradoxical increase in their glucocorticoid secretion in response to dexamethasone.	('Humans', 'Species', '9606', (0, 6))	('BAH', 'Chemical', '-', (34, 37))	('response to dexamethasone', 'MPA', (123, 148))	('increase', 'PosReg', (77, 85))	('dexamethasone', 'Chemical', 'MESH:D003907', (135, 148))	('glucocorticoid secretion', 'MPA', (95, 119))	('PRKAR1A', 'Gene', (12, 19))	('mutations', 'Var', (20, 29))	('PPNAD', 'Chemical', '-', (46, 51))
17366	26438728	However, this has not been seen in any of the animal models of PPNAD studied to date and it is not universally present among patients with BAH and PRKAR1A mutations.	('mutations', 'Var', (155, 164))	('PRKAR1A', 'Gene', (147, 154))	('PPNAD', 'Chemical', '-', (63, 68))	('BAH', 'Chemical', '-', (139, 142))	('patients', 'Species', '9606', (125, 133))
17368	26438728	In conclusion, our study of Celecoxib, a COX2 inhibitor, showed promising results in the treatment of mice with a form of BAH caused by Prkar1a deficiency.	('mice', 'Species', '10090', (102, 106))	('BAH', 'Chemical', '-', (122, 125))	('deficiency', 'Var', (144, 154))	('Prkar1a', 'Gene', (136, 143))	('Prkar1a', 'Gene', '19084', (136, 143))	('Celecoxib', 'Chemical', 'MESH:D000068579', (28, 37))	('BAH', 'Disease', (122, 125))
17387	25069860	Using the NCDB (1998-2011), patients with ACC were identified on the basis of International Classification of Diseases for Oncology, 2nd and 3rd editions (ICD-O-2/3) for site C74.0-C74.9 and histology 8370.3 (malignant adrenocortical carcinoma).	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (219, 243))	('C74.0-C74.9', 'Var', (175, 186))	('Oncology', 'Phenotype', 'HP:0002664', (123, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('malignant adrenocortical carcinoma', 'Disease', 'MESH:D018268', (209, 243))	('malignant adrenocortical carcinoma', 'Disease', (209, 243))	('ACC', 'Phenotype', 'HP:0006744', (42, 45))	('patients', 'Species', '9606', (28, 36))
17490	24849545	Preclinical studies have demonstrated that inhibition of IGF1R signaling significantly reduces cell proliferation and enhances apoptosis.	('cell proliferation', 'CPA', (95, 113))	('enhances', 'PosReg', (118, 126))	('inhibition', 'Var', (43, 53))	('IGF1R', 'Gene', (57, 62))	('reduces', 'NegReg', (87, 94))	('apoptosis', 'CPA', (127, 136))	('IGF1R', 'Gene', '3480', (57, 62))
17491	24849545	Moreover, preclinical data have shown that inhibition of IGF1R potentiates mitotane cytotoxic activity.	('inhibition', 'Var', (43, 53))	('IGF1R', 'Gene', (57, 62))	('mitotane', 'Chemical', 'MESH:D008939', (75, 83))	('IGF1R', 'Gene', '3480', (57, 62))	('mitotane cytotoxic activity', 'MPA', (75, 102))	('potentiates', 'PosReg', (63, 74))
17531	24849545	Thus, targeting the IGF1R would be a logical approach to treat advanced ACC.	('IGF1R', 'Gene', (20, 25))	('targeting', 'Var', (6, 15))	('IGF1R', 'Gene', '3480', (20, 25))	('ACC', 'Phenotype', 'HP:0006744', (72, 75))
17537	24849545	This trial was specifically designed to assess whether the synergistic effects between mitotane and IGF1R inhibitors, as demonstrated by preclinical studies, also occur in the clinical setting.	('inhibitors', 'Var', (106, 116))	('mitotane', 'Chemical', 'MESH:D008939', (87, 95))	('IGF1R', 'Gene', (100, 105))	('mitotane', 'Gene', (87, 95))	('IGF1R', 'Gene', '3480', (100, 105))
17540	24849545	In addition, PD was documented in the majority of patients at 6 weeks and median PFS in patients treated with mitotane+IMC-A12 was lower than that reported in patients treated with EDP+M (6 versus 20 weeks).	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (159, 167))	('patients', 'Species', '9606', (88, 96))	('IMC-A12', 'Chemical', 'MESH:C557414', (119, 126))	('PD', 'Chemical', 'MESH:D010165', (13, 15))	('mitotane', 'Chemical', 'MESH:D008939', (110, 118))	('lower', 'NegReg', (131, 136))	('EDP', 'Chemical', '-', (181, 184))	('mitotane+IMC-A12', 'Var', (110, 126))	('PFS', 'MPA', (81, 84))
17551	24849545	The challenge for future trials is to correctly identify subgroups of patients that may benefit from IGF1R inhibitors.	('IGF1R', 'Gene', '3480', (101, 106))	('inhibitors', 'Var', (107, 117))	('IGF1R', 'Gene', (101, 106))	('patients', 'Species', '9606', (70, 78))
17553	24849545	Abnormalities in IGF signaling pathway have been shown to mediate resistance to IGF1R inhibitors.	('IGF1R', 'Gene', (80, 85))	('IGF signaling pathway', 'Pathway', (17, 38))	('IGF1R', 'Gene', '3480', (80, 85))	('Abnormalities', 'Var', (0, 13))
17555	24849545	Other possible molecular mechanism that may contribute for resistance to IGF1R inhibitors is the crosstalk and functional redundancy between different oncogenic pathways.	('IGF1R', 'Gene', '3480', (73, 78))	('inhibitors', 'Var', (79, 89))	('crosstalk', 'Reg', (97, 106))	('oncogenic pathways', 'Pathway', (151, 169))	('IGF1R', 'Gene', (73, 78))
17558	24849545	Interestingly, mTOR inhibitors are known to cause feedback increase in AKT signaling by an IGF1R-independent mechanism, which overcomes its antiproliferative effects.	('IGF1R', 'Gene', (91, 96))	('mTOR', 'Gene', (15, 19))	('inhibitors', 'Var', (20, 30))	('mTOR', 'Gene', '2475', (15, 19))	('IGF1R', 'Gene', '3480', (91, 96))	('AKT signaling', 'MPA', (71, 84))	('increase', 'PosReg', (59, 67))
17559	24849545	More recently, it has been demonstrated that treatment with IGF1R inhibitors may paradoxically increase mTOR signaling.	('mTOR', 'Gene', (104, 108))	('mTOR', 'Gene', '2475', (104, 108))	('increase', 'PosReg', (95, 103))	('IGF1R', 'Gene', (60, 65))	('IGF1R', 'Gene', '3480', (60, 65))	('inhibitors', 'Var', (66, 76))
17560	24849545	Thus, pharmacological inhibition of both IGF1R and mTOR may have complementary effects on inhibiting proliferative cell signaling.	('mTOR', 'Gene', (51, 55))	('inhibition', 'Var', (22, 32))	('IGF1R', 'Gene', '3480', (41, 46))	('proliferative cell signaling', 'MPA', (101, 129))	('inhibiting', 'NegReg', (90, 100))	('IGF1R', 'Gene', (41, 46))	('mTOR', 'Gene', '2475', (51, 55))
17608	20531296	The activating mutation R201C in GNAS promotes intestinal tumourigenesis in ApcMin/+ mice via activation of Wnt and ERK1/2 MAPK pathways Somatically acquired, activating mutations of GNAS, the gene encoding the stimulatory G-protein Gsalpha subunit, have been identified in kidney, thyroid, pituitary, leydig cell, adrenocortical and more recently, in colorectal tumours, suggesting that mutations such as R201C may be oncogenic in these tissues.	('GNAS', 'Gene', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (363, 369))	('promotes', 'PosReg', (38, 46))	('colorectal tumours', 'Disease', 'MESH:D015179', (352, 370))	('activating', 'PosReg', (159, 169))	('mice', 'Species', '10090', (85, 89))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('R201C', 'Var', (406, 411))	('GNAS', 'Gene', '14683', (183, 187))	('R201C', 'Var', (24, 29))	('GNAS', 'Gene', '14683', (33, 37))	('colorectal tumours', 'Disease', (352, 370))	('intestinal tumourigenesis', 'CPA', (47, 72))	('ERK1/2', 'Gene', (116, 122))	('adrenocortical', 'Disease', 'MESH:D018268', (315, 329))	('activation', 'PosReg', (94, 104))	('tumours', 'Phenotype', 'HP:0002664', (363, 370))	('ERK1/2', 'Gene', '26417;26413', (116, 122))	('GNAS', 'Gene', (183, 187))	('adrenocortical', 'Disease', (315, 329))
17614	20531296	Furthermore, the effects of GNAS R201C on the Wnt pathway were additive to inactivation of Apc.	('Apc', 'Gene', (91, 94))	('Apc', 'Gene', '11789', (91, 94))	('GNAS R201C', 'Var', (28, 38))	('Wnt pathway', 'Pathway', (46, 57))
17620	20531296	Somatically acquired, activating mutations of GNAS have been identified in adrenal hyperplasia and ovarian cysts, as well as thyroid carcinomas (5%), adrenocortical, pituitary (22-40%), kidney (17%), and leydig cell tumours (67%).	('mutations', 'Var', (33, 42))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (125, 143))	('thyroid carcinomas', 'Disease', (125, 143))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (75, 94))	('GNAS', 'Gene', (46, 50))	('tumours', 'Phenotype', 'HP:0002664', (216, 223))	('ovarian cysts', 'Disease', (99, 112))	('ovarian cysts', 'Disease', 'MESH:D010048', (99, 112))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (125, 143))	('adrenocortical', 'Disease', 'MESH:D018268', (150, 164))	('activating', 'PosReg', (22, 32))	('leydig cell tumours', 'Disease', 'MESH:D007984', (204, 223))	('tumour', 'Phenotype', 'HP:0002664', (216, 222))	('adrenal hyperplasia', 'Disease', (75, 94))	('ovarian cysts', 'Phenotype', 'HP:0000138', (99, 112))	('kidney', 'Disease', (186, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('adrenocortical', 'Disease', (150, 164))	('leydig cell tumours', 'Disease', (204, 223))	('pituitary', 'Disease', (166, 175))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (75, 94))
17622	20531296	The common mutations of GNAS that have been identified in tumours, including R201C, R201H and Q227R, are thought to inhibit GTP hydrolysis and result in the constitutive activation of Gsalpha and its effector adenylate cyclase, leading to autonomous synthesis of cAMP.	('cAMP', 'Gene', (263, 267))	('leading to', 'Reg', (228, 238))	('activation', 'PosReg', (170, 180))	('R201H', 'Mutation', 'rs121913495', (84, 89))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('cAMP', 'Gene', '12796', (263, 267))	('GTP', 'Chemical', 'MESH:D006160', (124, 127))	('Q227R', 'Mutation', 'rs121913494', (94, 99))	('R201C', 'Var', (77, 82))	('GNAS', 'Gene', (24, 28))	('tumours', 'Disease', (58, 65))	('inhibit', 'NegReg', (116, 123))	('Gsalpha', 'Protein', (184, 191))	('R201H', 'Var', (84, 89))	('GTP hydrolysis', 'MPA', (124, 138))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('Q227R', 'Var', (94, 99))
17625	20531296	The most frequent early event in >80% of sporadic colorectal carcinomas is loss of function mutations of the adenomatous polyposis coli (APC) gene, which is also mutated in the germline of patients with familial adenomatous polyposis.	('colorectal carcinomas', 'Disease', (50, 71))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (50, 71))	('loss of function', 'NegReg', (75, 91))	('familial adenomatous polyposis', 'Disease', (203, 233))	('mutations', 'Var', (92, 101))	('sporadic', 'Disease', (41, 49))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (109, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (203, 233))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (109, 135))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (109, 135))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (212, 233))	('patients', 'Species', '9606', (189, 197))	('adenomatous polyposis coli', 'Disease', (109, 135))
17628	20531296	A number of groups have shown that loss of cyclooxygenase-1 or -2 (COX) dramatically reduces tumour formation in ApcMin/+ mice (reviewed in ref.).	('mice', 'Species', '10090', (122, 126))	('cyclooxygenase-1 or -2', 'Gene', '19224;19225', (43, 65))	('tumour', 'Disease', (93, 99))	('loss', 'Var', (35, 39))	('Apc', 'Gene', (113, 116))	('cyclooxygenase-1 or -2', 'Gene', (43, 65))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('Apc', 'Gene', '11789', (113, 116))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('reduces', 'NegReg', (85, 92))
17635	20531296	Activating mutations of either KRAS or BRAF are found in 40-50% of colorectal cancers and lead to activation of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK) pathway, which enhances proliferation, neoplastic transformation, differentiation and survival of many cell types.	('BRAF', 'Gene', '109880', (39, 43))	('colorectal cancers', 'Disease', (67, 85))	('differentiation', 'CPA', (271, 286))	('mutations', 'Var', (11, 20))	('KRAS', 'Gene', (31, 35))	('survival', 'CPA', (291, 299))	('neoplastic transformation', 'CPA', (244, 269))	('activation', 'PosReg', (98, 108))	('KRAS', 'Gene', '16653', (31, 35))	('BRAF', 'Gene', (39, 43))	('proliferation', 'CPA', (229, 242))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('colorectal cancers', 'Disease', 'MESH:D015179', (67, 85))	('enhances', 'PosReg', (220, 228))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
17638	20531296	Here, we have generated mice that specifically express GNAS R201C in the intestinal stem cells and all epithelial cell lineages from E14.5 into adulthood to assess whether the mutation participates in the formation and/or progression of colorectal cancer in vivo.	('GNAS R201C', 'Var', (55, 65))	('mice', 'Species', '10090', (24, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (237, 254))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('colorectal cancer', 'Disease', (237, 254))	('colorectal cancer', 'Disease', 'MESH:D015179', (237, 254))
17640	20531296	The mutation R201C was chosen over R201H and Q227R because is it found more frequently in cancers, however, all mutations have both been shown to have a similar affect on adenylyl cyclase stimulation.	('cancers', 'Disease', (90, 97))	('R201H', 'Mutation', 'rs121913495', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('adenylyl cyclase stimulation', 'MPA', (171, 199))	('Q227R', 'Mutation', 'rs121913494', (45, 50))	('R201H', 'Var', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('R201C', 'Var', (13, 18))	('Q227R', 'Var', (45, 50))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('affect', 'Reg', (161, 167))
17641	20531296	To express the mutant GNAS R201C cDNA specifically in the intestinal epithelium we obtained and modified a Lox-Stop-Lox targeting vector to place it under the control of the endogenous Gpa33-antigen gene promoter (Fig 1A; ref 30).	('mutant', 'Var', (15, 21))	('Gpa33', 'Gene', '59290', (185, 190))	('Gpa33', 'Gene', (185, 190))	('GNAS', 'Gene', (22, 26))
17643	20531296	Upon Cre-mediated recombination of the loxP sites, GNAS R201C cDNA is predicted to be expressed bicistronically from the Gpa33 gene locus (Fig.	('Gpa33', 'Gene', (121, 126))	('Gpa33', 'Gene', '59290', (121, 126))	('GNAS R201C', 'Var', (51, 61))
17644	20531296	In adult mice Gpa33 is exclusively expressed throughout the epithelium of intestinal tract, thus directing mutant GNAS R201C expression exclusively to proliferating and differentiating intestinal epithelial cells and crypt stem cells.	('mutant', 'Var', (107, 113))	('Gpa33', 'Gene', '59290', (14, 19))	('GNAS R201C', 'Gene', (114, 124))	('Gpa33', 'Gene', (14, 19))	('mice', 'Species', '10090', (9, 13))
17648	20531296	This is the expected 1:1 Mendelian ratio, therefore expression of mutant GNAS R201C from the Gpa33 locus does not cause embryonic lethality.	('embryonic lethality', 'Disease', 'MESH:D020964', (120, 139))	('mutant', 'Var', (66, 72))	('Gpa33', 'Gene', '59290', (93, 98))	('embryonic lethality', 'Disease', (120, 139))	('GNAS', 'Gene', (73, 77))	('Gpa33', 'Gene', (93, 98))
17649	20531296	RT-PCR expression analysis was performed on RNA extracted from a range of tissues from Gpa33tm1(GnasR201C)Wtsi/+ and wildtype (Gpa33+/+) littermates using primers specific for the Gpa33 locus (exon 5) and the mutant GNAS cDNA.	('Gpa33', 'Gene', '59290', (127, 132))	('Gpa33', 'Gene', '59290', (87, 92))	('Gpa33', 'Gene', '59290', (180, 185))	('Gpa33', 'Gene', (127, 132))	('Gpa33', 'Gene', (87, 92))	('Gpa33', 'Gene', (180, 185))	('mutant', 'Var', (209, 215))
17654	20531296	We used immunofluorescence and flow cytometry to show that expression of GNAS R201C leads to a 1.5-fold increase in cAMP levels in the intestinal epithelium of Gpa33tm1(GnasR201C)Wtsi/+ mice relative to wildtype littrmate controls (P<0.05; Fig.	('increase', 'PosReg', (104, 112))	('GNAS R201C', 'Var', (73, 83))	('Gpa33', 'Gene', (160, 165))	('cAMP', 'Gene', (116, 120))	('cAMP', 'Gene', '12796', (116, 120))	('mice', 'Species', '10090', (186, 190))	('littrmate', 'Chemical', '-', (212, 221))	('Gpa33', 'Gene', '59290', (160, 165))
17659	20531296	To establish the phenotypic effect of expression of mutant GNAS R201C in the intestine we aged a cohort of 21 Gpa33tm1(GnasR201C)Wtsi/+ and 20 wildtype littermate controls (Gpa33+/+) mice to 12 months.	('Gpa33', 'Gene', (110, 115))	('Gpa33', 'Gene', (173, 178))	('mutant', 'Var', (52, 58))	('GNAS R201C', 'Gene', (59, 69))	('mice', 'Species', '10090', (183, 187))	('Gpa33', 'Gene', '59290', (110, 115))	('Gpa33', 'Gene', '59290', (173, 178))
17664	20531296	The activating R201C mutation of GNAS resulted in a mean adenoma number of 62 +- 5.2 (n = 11), a 2-fold increase (P=0.0001; Fig.	('GNAS', 'Gene', (33, 37))	('increase', 'PosReg', (104, 112))	('adenoma', 'Disease', (57, 64))	('activating', 'PosReg', (4, 14))	('R201C', 'Var', (15, 20))	('adenoma', 'Disease', 'MESH:D000236', (57, 64))
17668	20531296	To identify a mechanism for the enhanced formation of adenomas in ApcMin/+ mice carrying the mutant GNAS R201C allele, we examined two of the most important signaling pathways in intestinal tumourigenesis, the ERK1/2 MAPK and Wnt pathways.	('ERK1/2 MAPK', 'Pathway', (210, 221))	('mice', 'Species', '10090', (75, 79))	('adenomas', 'Disease', 'MESH:D000236', (54, 62))	('Wnt pathways', 'Pathway', (226, 238))	('examined', 'Reg', (122, 130))	('GNAS', 'Gene', (100, 104))	('intestinal tumour', 'Disease', 'MESH:D007414', (179, 196))	('adenomas', 'Disease', (54, 62))	('mutant', 'Var', (93, 99))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('enhanced', 'PosReg', (32, 40))	('Apc', 'Gene', '11789', (66, 69))	('Apc', 'Gene', (66, 69))	('intestinal tumour', 'Disease', (179, 196))
17678	20531296	3C), indicating that the effects of GNAS R201C occur independently and downstream of COX-2.	('COX-2', 'Gene', '17709', (85, 90))	('COX-2', 'Gene', (85, 90))	('GNAS R201C', 'Var', (36, 46))
17681	20531296	Somatically acquired, activating mutations of GNAS have been identified in kidney, thyroid, leydig cell, pituitary and adrenocortical tumours.	('kidney', 'Disease', (75, 81))	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('leydig cell', 'Disease', (92, 103))	('thyroid', 'Disease', (83, 90))	('mutations', 'Var', (33, 42))	('pituitary and adrenocortical tumours', 'Disease', 'MESH:D000306', (105, 141))	('activating', 'PosReg', (22, 32))	('GNAS', 'Gene', (46, 50))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
17682	20531296	However, a recent mutational analysis of 35 colorectal cancers by Sjoblom et al., (1-2) was the first study to suggest that the R201 mutations of GNAS occurs frequently (9%) in colorectal cancers.	('colorectal cancers', 'Disease', 'MESH:D015179', (44, 62))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('colorectal cancers', 'Disease', (44, 62))	('R201 mutations', 'Var', (128, 142))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))	('GNAS', 'Gene', (146, 150))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('colorectal cancers', 'Disease', 'MESH:D015179', (177, 195))	('colorectal cancers', 'Disease', (177, 195))
17684	20531296	To examine the role of GNAS R201C in intestinal tumourigenesis we generated mice expressing GNAS R201C under the control of the Gpa33-antigen promoter, which is almost exclusively expressed by intestinal stem cells and all epithelial cell lineages from E14.5 into adulthood.	('intestinal tumour', 'Disease', 'MESH:D007414', (37, 54))	('Gpa33', 'Gene', (128, 133))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('GNAS R201C', 'Var', (92, 102))	('mice', 'Species', '10090', (76, 80))	('Gpa33', 'Gene', '59290', (128, 133))	('intestinal tumour', 'Disease', (37, 54))
17685	20531296	Gpa33tm1(GnasR201C)Wtsi/+ mice were shown to express mutant GNAS R201C in the intestine which led to a significant increase in cAMP levels in the intestinal mucosa, in agreement with a previous report indicating that the R201C mutation leads to constitutive activation of Gsalpha protein.	('Gpa33', 'Gene', '59290', (0, 5))	('cAMP', 'Gene', (127, 131))	('GNAS', 'Gene', (60, 64))	('R201C', 'Var', (221, 226))	('cAMP', 'Gene', '12796', (127, 131))	('increase', 'PosReg', (115, 123))	('Gpa33', 'Gene', (0, 5))	('mutant', 'Var', (53, 59))	('mice', 'Species', '10090', (26, 30))
17691	20531296	Since high levels of cAMP are subject to negative feedback control by upregulation of phosphodiesterases, our data suggest that Gsalpha R201C is localized to the same cellular compartment(s) as Pde4a and Pde8b.	('upregulation', 'PosReg', (70, 82))	('cAMP', 'Gene', (21, 25))	('Pde4a', 'Gene', '18577', (194, 199))	('Pde8b', 'Gene', '218461', (204, 209))	('Pde4a', 'Gene', (194, 199))	('cAMP', 'Gene', '12796', (21, 25))	('phosphodiesterases', 'Gene', (86, 104))	('Gsalpha', 'Gene', (128, 135))	('R201C', 'Var', (136, 141))	('phosphodiesterases', 'Gene', '241489', (86, 104))	('Pde8b', 'Gene', (204, 209))
17699	20531296	Although we have not established the exact mechanism of cAMP-mediated activation of ERK1/2 MAPK following constitutive activation of Gsalpha in intestinal cells, activation of ERK1/2 MAPK is a significant contributory factor in the genesis of colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('colorectal cancer', 'Disease', (243, 260))	('cAMP', 'Gene', '12796', (56, 60))	('activation', 'PosReg', (70, 80))	('ERK1/2 MAPK', 'Gene', (84, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (243, 260))	('colorectal cancer', 'Phenotype', 'HP:0003003', (243, 260))	('ERK1/2', 'Var', (176, 182))	('cAMP', 'Gene', (56, 60))
17702	20531296	In support, our data suggest that the intestinal expression of mutationally activated GNAS and subsequent increase in activated ERK1/2 within the intestine was insufficient (by 12 months) to induce tumourigenesis alone, but in combination with inactivation of Apc, tumour number doubled.	('tumour', 'Disease', (198, 204))	('activated', 'PosReg', (76, 85))	('ERK1/2', 'Gene', (128, 134))	('Apc', 'Gene', (260, 263))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('tumour', 'Phenotype', 'HP:0002664', (265, 271))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('GNAS', 'Protein', (86, 90))	('activated', 'MPA', (118, 127))	('Apc', 'Gene', '11789', (260, 263))	('tumour', 'Disease', 'MESH:D009369', (265, 271))	('increase', 'PosReg', (106, 114))	('insufficient', 'Disease', (160, 172))	('insufficient', 'Disease', 'MESH:D000309', (160, 172))	('tumour', 'Disease', (265, 271))	('mutationally', 'Var', (63, 75))
17703	20531296	Aberrant activation of the Wnt/beta-catenin pathway is an initiating event in the vast majority of colorectal adenomas and cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('activation', 'PosReg', (9, 19))	('beta-catenin', 'Gene', (31, 43))	('Aberrant', 'Var', (0, 8))	('colorectal adenomas and cancers', 'Disease', 'MESH:D015179', (99, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('beta-catenin', 'Gene', '12387', (31, 43))
17709	20531296	In agreement, we found that the effects of loss of Apc and activation of Gnas were additive since expression of the Wnt targets Myc and Birc5 were increased further in polyps from double mutant mice when compared those from ApcMin/+ mice (Supplemental Fig.	('Apc', 'Gene', (51, 54))	('Apc', 'Gene', '11789', (51, 54))	('Apc', 'Gene', '11789', (224, 227))	('increased', 'PosReg', (147, 156))	('mice', 'Species', '10090', (233, 237))	('Birc5', 'Gene', (136, 141))	('polyps', 'Disease', (168, 174))	('Birc5', 'Gene', '11799', (136, 141))	('Myc', 'Gene', (128, 131))	('Myc', 'Gene', '17869', (128, 131))	('polyps', 'Disease', 'MESH:D011127', (168, 174))	('Apc', 'Gene', (224, 227))	('mice', 'Species', '10090', (194, 198))	('double mutant', 'Var', (180, 193))	('expression', 'MPA', (98, 108))
17712	20531296	Examples are Cushing's syndrome due to mutations in GNAS, primary pigmented nodular adrenocortical disease (Carney Complex) due to mutations of the PKA regulatory subunit type 1A (PRKAR1A), macronodular adrenocortical disease associated with aberrant expression of G-protein-coupled receptors in the tumour tissue and more recently, micronodular adrenocortical hyperplasia with inactivating mutations of phosphodiesterases PDE11A and PDE8B.	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (66, 106))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (13, 31))	('macronodular adrenocortical disease', 'Phenotype', 'HP:0008231', (190, 225))	('adrenocortical disease', 'Disease', 'MESH:D018268', (84, 106))	('phosphodiesterases', 'Gene', (404, 422))	('pigmented nodular adrenocortical disease', 'Disease', (66, 106))	('PDE11A', 'Gene', '241489', (423, 429))	('adrenocortical disease', 'Disease', 'MESH:D018268', (203, 225))	('phosphodiesterases', 'Gene', '241489', (404, 422))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (13, 31))	('PDE8B', 'Gene', '218461', (434, 439))	("Cushing's syndrome", 'Disease', (13, 31))	('mutations', 'Var', (39, 48))	('adrenocortical disease', 'Disease', (203, 225))	('PDE8B', 'Gene', (434, 439))	('due', 'Reg', (124, 127))	('adrenocortical hyperplasia', 'Disease', (346, 372))	('GNAS', 'Gene', (52, 56))	('PDE11A', 'Gene', (423, 429))	('PRKAR1A', 'Gene', (180, 187))	('mutations', 'Var', (131, 140))	('tumour', 'Phenotype', 'HP:0002664', (300, 306))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (346, 372))	('PRKAR1A', 'Gene', '19084', (180, 187))	('tumour', 'Disease', 'MESH:D009369', (300, 306))	('tumour', 'Disease', (300, 306))
17713	20531296	Moreover, somatic activating mutations of the beta-catenin gene (CTNNB1), which cause activation of the Wnt pathway, are the most frequent genetic defects in adrenocortical tumours and activating mutations of either BRAF, KRAS, NRAS or EGFR, which all result in activation of ERK1/2 MAPK, are also frequently found in this type of tumour.	('tumour', 'Disease', (173, 179))	('CTNNB1', 'Gene', '12387', (65, 71))	('activating', 'PosReg', (18, 28))	('KRAS', 'Gene', '16653', (222, 226))	('tumour', 'Phenotype', 'HP:0002664', (331, 337))	('beta-catenin', 'Gene', '12387', (46, 58))	('tumour', 'Disease', 'MESH:D009369', (331, 337))	('tumour', 'Disease', (331, 337))	('beta-catenin', 'Gene', (46, 58))	('activation', 'PosReg', (262, 272))	('adrenocortical tumours', 'Disease', 'MESH:D000306', (158, 180))	('mutations', 'Var', (29, 38))	('BRAF', 'Gene', '109880', (216, 220))	('Wnt pathway', 'Pathway', (104, 115))	('ERK1/2 MAPK', 'Pathway', (276, 287))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('CTNNB1', 'Gene', (65, 71))	('activation', 'PosReg', (86, 96))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('genetic defects', 'Disease', 'MESH:D030342', (139, 154))	('NRAS', 'Gene', (228, 232))	('genetic defects', 'Disease', (139, 154))	('NRAS', 'Gene', '18176', (228, 232))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('KRAS', 'Gene', (222, 226))	('BRAF', 'Gene', (216, 220))	('adrenocortical tumours', 'Disease', (158, 180))	('EGFR', 'Gene', (236, 240))	('EGFR', 'Gene', '13649', (236, 240))
17714	20531296	Given the involvement of the phosphodiesterase Pde8b, Wnt and ERK1/2 MAPK pathways in intestinal tumourigenesis that is driven by activating mutations of Gsalpha in mice, it may be hypothesized that the above signalling molecules are localized to the same cAMP-signalling compartment in these two cell types and are involved in the development of both colorectal and adrenocortical cancers.	('ERK1/2', 'Gene', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (382, 389))	('mice', 'Species', '10090', (165, 169))	('mutations', 'Var', (141, 150))	('intestinal tumour', 'Disease', (86, 103))	('Gsalpha', 'Gene', (154, 161))	('cAMP', 'Gene', (256, 260))	('Pde8b', 'Gene', (47, 52))	('cAMP', 'Gene', '12796', (256, 260))	('colorectal and adrenocortical cancers', 'Disease', 'MESH:D015179', (352, 389))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('Pde8b', 'Gene', '218461', (47, 52))	('involved', 'Reg', (316, 324))	('intestinal tumour', 'Disease', 'MESH:D007414', (86, 103))	('involvement', 'Reg', (10, 21))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))
17717	20531296	Our data show that the R201C activating mutation of GNAS causes augmentation of the both the Wnt and ERK1/2 MAPK pathway in the intestinal epithelium of mice, and that the mutation co-operates with inactivation of APC in intestinal tumour formation in vivo.	('augmentation', 'PosReg', (64, 76))	('R201C', 'Var', (23, 28))	('intestinal tumour', 'Disease', (221, 238))	('GNAS', 'Gene', (52, 56))	('mice', 'Species', '10090', (153, 157))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('ERK1/2 MAPK pathway', 'Pathway', (101, 120))	('intestinal tumour', 'Disease', 'MESH:D007414', (221, 238))
17718	20531296	Presumably, the activating R201H mutation of GNAS that has been identified in other human cancers contributes to tumour formation via the same mechanism.	('cancers', 'Disease', (90, 97))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('R201H', 'Var', (27, 32))	('GNAS', 'Gene', (45, 49))	('tumour', 'Disease', (113, 119))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('activating', 'PosReg', (16, 26))	('R201H', 'Mutation', 'rs121913495', (27, 32))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
17719	20531296	Taken together with previous human colorectal cancer mutational analysis our data strongly suggests that activating mutations of GNAS are likely, together with inactivation of APC, to contribute to colorectal tumourigenesis.	('contribute', 'Reg', (184, 194))	('colorectal tumourigenesis', 'Disease', 'MESH:D015179', (198, 223))	('GNAS', 'Gene', (129, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (35, 52))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('colorectal cancer', 'Phenotype', 'HP:0003003', (35, 52))	('mutations', 'Var', (116, 125))	('colorectal tumourigenesis', 'Disease', (198, 223))	('colorectal cancer', 'Disease', (35, 52))	('human', 'Species', '9606', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('activating', 'PosReg', (105, 115))
17734	20531296	Primary antibodies: anti-Ki67 (DCS - Innovative Diagnostik-Systeme, Hamburg, Germany), anti-chromogranin A (Abcam: ab15160), and anti-phospho-Thr202/Tyr204 p44/42 ERK1/2 MAPK (Cell Signalling Technology, Danvers, MA, USA: 20G11).	('p44', 'Gene', (156, 159))	('Ki67', 'Gene', '17345', (25, 29))	('chromogranin A', 'Gene', '12652', (92, 106))	('p44', 'Gene', '26417', (156, 159))	('anti-phospho-Thr202/Tyr204', 'Var', (129, 155))	('chromogranin A', 'Gene', (92, 106))	('Ki67', 'Gene', (25, 29))	('Thr202', 'Chemical', '-', (142, 148))	('Tyr204', 'Chemical', '-', (149, 155))
17746	18366613	It follows from a comprehensive statistical analysis that a number of antigens such as hTERT, PCNA and Ki-67 can be considered as cancer markers, while another set of antigens such as P27KIP1 and FHIT are possible markers for normal tissue.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('PCNA', 'Gene', '5111', (94, 98))	('P27KIP1', 'Gene', '1027', (184, 191))	('Ki-67', 'Var', (103, 108))	('cancer', 'Disease', (130, 136))	('hTERT', 'Gene', (87, 92))	('FHIT', 'Gene', (196, 200))	('FHIT', 'Gene', '2272', (196, 200))	('P27KIP1', 'Gene', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('PCNA', 'Gene', (94, 98))	('hTERT', 'Gene', '7015', (87, 92))
17759	18366613	mutations of genes) but changes of gene expressions and regulatory networks that are ultimately responsible for cancer development.	('gene expressions', 'MPA', (35, 51))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('regulatory networks', 'MPA', (56, 75))	('changes', 'Reg', (24, 31))	('mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
17760	18366613	Under this parallel paradigm, mutations of genes and un-mutated genes with differential expressions and alternative splicing cause changes in gene regulatory networks (that also cause cancer) when cells are subjected to unusual environments.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cause', 'Reg', (178, 183))	('gene regulatory networks', 'MPA', (142, 166))	('mutations', 'Var', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('changes', 'Reg', (131, 138))
17767	18366613	Once tested, our intelligent medical decision system achieved 92.6% accuracy on three types of Cushing's syndrome, indicating that the joint use of differential gene expressions has enhanced our ability to diagnose diseases.	('differential gene expressions', 'Var', (148, 177))	("Cushing's syndrome", 'Disease', (95, 113))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (95, 113))	('enhanced', 'PosReg', (182, 190))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (95, 113))
17782	18366613	While the biological function of the FHIT in the human genome has not been fully characterized yet, it is known that deletion and the degree of deletion in the gene expression level of FHIT are closely associated to the malignancies and prognosis of variety of human tumors.	('malignancies', 'Disease', 'MESH:D009369', (220, 232))	('FHIT', 'Gene', (37, 41))	('FHIT', 'Gene', '2272', (37, 41))	('associated', 'Reg', (202, 212))	('human', 'Species', '9606', (49, 54))	('human', 'Species', '9606', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('deletion', 'Var', (144, 152))	('malignancies', 'Disease', (220, 232))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('gene expression level', 'MPA', (160, 181))	('FHIT', 'Gene', (185, 189))	('FHIT', 'Gene', '2272', (185, 189))	('tumors', 'Disease', (267, 273))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('deletion', 'Var', (117, 125))
17884	18366613	Abnormal expressions of the FHIT gene are connected to diverse forms of malignant tumor development.	('malignant tumor', 'Disease', (72, 87))	('malignant tumor', 'Disease', 'MESH:D018198', (72, 87))	('connected', 'Reg', (42, 51))	('FHIT', 'Gene', (28, 32))	('Abnormal', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('FHIT', 'Gene', '2272', (28, 32))	('expressions', 'MPA', (9, 20))
17885	18366613	The bioinformatics studies showed that in a great variety of human tumors or tumor cell lines, the FHIT gene presents frequent homozygous deletion, loss of heterozygosity (LOH) and abnormal transcription.	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('FHIT', 'Gene', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('FHIT', 'Gene', '2272', (99, 103))	('abnormal', 'Reg', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('loss of heterozygosity', 'Var', (148, 170))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (67, 72))	('transcription', 'MPA', (190, 203))	('human', 'Species', '9606', (61, 66))	('tumor', 'Disease', (77, 82))	('tumors', 'Disease', (67, 73))
17886	18366613	Furthermore, the bioinformatics studies showed diversiform human epithelial malignancies, FHIT gene absence, abnormal methylation and deplete of FHIT protein express level contribute 70% of human cancers relating the functionality of FHIT.	('FHIT', 'Gene', '2272', (145, 149))	('malignancies', 'Disease', (76, 88))	('FHIT', 'Gene', '2272', (90, 94))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('abnormal', 'Var', (109, 117))	('protein', 'Protein', (150, 157))	('FHIT', 'Gene', (234, 238))	('human', 'Species', '9606', (190, 195))	('absence', 'NegReg', (100, 107))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('FHIT', 'Gene', '2272', (234, 238))	('cancers', 'Disease', (196, 203))	('FHIT', 'Gene', (90, 94))	('deplete', 'MPA', (134, 141))	('FHIT', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('human', 'Species', '9606', (59, 64))	('methylation', 'MPA', (118, 129))	('malignancies', 'Disease', 'MESH:D009369', (76, 88))
17888	18366613	For many tumors, abnormal FHIT gene regulatory transcription and FHIT protein deletion or re-education have been identified in a great variety of human tumors and tumor cell lines, such as lung cancer, breast cancer, cervical carcinoma, ovarian cancer, and so on.	('ovarian cancer', 'Phenotype', 'HP:0100615', (237, 251))	('FHIT', 'Gene', '2272', (26, 30))	('tumor', 'Disease', (163, 168))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('tumors', 'Disease', (152, 158))	('identified', 'Reg', (113, 123))	('protein', 'Protein', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('deletion', 'Var', (78, 86))	('tumor', 'Disease', (152, 157))	('cervical carcinoma', 'Disease', (217, 235))	('tumor', 'Disease', (9, 14))	('lung cancer', 'Disease', (189, 200))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cervical carcinoma', 'Disease', 'MESH:D002575', (217, 235))	('ovarian cancer', 'Disease', 'MESH:D010051', (237, 251))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('FHIT', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('FHIT', 'Gene', (26, 30))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('breast cancer', 'Disease', (202, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('human', 'Species', '9606', (146, 151))	('ovarian cancer', 'Disease', (237, 251))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('FHIT', 'Gene', '2272', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
17893	18366613	Because FHIT is a protein-coding gene with its ultimate product of fragile histindine triad protein that belongs to the histindine triad protein family with carcinoma suppression activity, FHIT gene mutation leads to FHIT protein abnormal expression.	('abnormal expression', 'MPA', (230, 249))	('FHIT', 'Gene', (8, 12))	('FHIT', 'Gene', '2272', (8, 12))	('mutation', 'Var', (199, 207))	('FHIT', 'Gene', (217, 221))	('FHIT', 'Gene', (189, 193))	('carcinoma', 'Disease', 'MESH:D002277', (157, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('leads to', 'Reg', (208, 216))	('FHIT', 'Gene', '2272', (189, 193))	('carcinoma', 'Disease', (157, 166))	('FHIT', 'Gene', '2272', (217, 221))
17895	18366613	FHIT protein deletion and the degrees of deletions in tissues are closely linked to malignancies and prognoses of tumors have detected pathological analyses.	('malignancies', 'Disease', (84, 96))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('deletion', 'Var', (13, 21))	('FHIT', 'Gene', (0, 4))	('FHIT', 'Gene', '2272', (0, 4))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('linked', 'Reg', (74, 80))
17898	18366613	The findings of other types tumors also show that FHIT protein deletion or low expression suggests malignant transformation, while on the contrary, high levels of FHIT protein suggest benign status.	('low', 'NegReg', (75, 78))	('FHIT', 'Gene', '2272', (163, 167))	('expression', 'MPA', (79, 89))	('FHIT', 'Gene', '2272', (50, 54))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('deletion', 'Var', (63, 71))	('malignant transformation', 'CPA', (99, 123))	('FHIT', 'Gene', (163, 167))	('FHIT', 'Gene', (50, 54))
17903	18366613	It suggests that the degree of FHIT gene abnormal transcription and FHIT protein deletion or reduction in adrenocortical carcinoma is more serious than that in adenoma and hyperplasia.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (106, 130))	('reduction', 'NegReg', (93, 102))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (106, 130))	('protein', 'Protein', (73, 80))	('FHIT', 'Gene', (68, 72))	('FHIT', 'Gene', '2272', (68, 72))	('deletion', 'Var', (81, 89))	('adenoma and hyperplasia', 'Disease', 'MESH:D000236', (160, 183))	('adrenocortical carcinoma', 'Disease', (106, 130))	('abnormal transcription', 'Var', (41, 63))	('FHIT', 'Gene', (31, 35))	('FHIT', 'Gene', '2272', (31, 35))
17904	18366613	FHIT gene abnormal transcript and FHIT protein deletion or reduction are closely linked to the malignancies of tumors in hypercortisolism of adrenocortical diseases.	('malignancies of tumors in hypercortisolism of adrenocortical diseases', 'Disease', 'MESH:D003480', (95, 164))	('abnormal', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('hypercortisolism', 'Phenotype', 'HP:0003118', (121, 137))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('deletion', 'Var', (47, 55))	('FHIT', 'Gene', (0, 4))	('FHIT', 'Gene', (34, 38))	('reduction', 'NegReg', (59, 68))	('FHIT', 'Gene', '2272', (0, 4))	('FHIT', 'Gene', '2272', (34, 38))	('linked', 'Reg', (81, 87))	('protein', 'Protein', (39, 46))
17905	18366613	FHIT protein deletion or reduction might indicate malignant transformation.	('reduction', 'NegReg', (25, 34))	('deletion', 'Var', (13, 21))	('FHIT', 'Gene', (0, 4))	('malignant transformation', 'CPA', (50, 74))	('FHIT', 'Gene', '2272', (0, 4))
17918	18366613	Results of researches in this field showed that Ki-67 can reflect malignant tumor cell multiplication capacity credibly and speedily; Ki-67 is correlated with a great variety of malignant tumor development, excessive inversion and prognosis.	('malignant tumor', 'Disease', (66, 81))	('malignant tumor', 'Disease', 'MESH:D018198', (178, 193))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('malignant tumor', 'Disease', 'MESH:D018198', (66, 81))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('correlated', 'Reg', (143, 153))	('malignant tumor', 'Disease', (178, 193))	('Ki-67', 'Var', (134, 139))
18014	18366613	Among hypercortisolism, adrenocortical carcinoma, adenoma and hyperplasia secreting cortisol freely, high blood cortisol level inhibits pituitary secreting ACTH and making blood ACTH level decreased.	('cortisol', 'Chemical', 'MESH:D006854', (84, 92))	('ACTH', 'Gene', '5443', (178, 182))	('ACTH', 'Gene', (156, 160))	('inhibits', 'NegReg', (127, 135))	('decreased', 'NegReg', (189, 198))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (24, 48))	('cortisol', 'Chemical', 'MESH:D006854', (112, 120))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (24, 48))	('ACTH', 'Gene', '5443', (156, 160))	('hypercortisolism', 'Disease', 'MESH:D003480', (6, 22))	('adenoma and hyperplasia', 'Disease', 'MESH:D000236', (50, 73))	('hypercortisolism', 'Phenotype', 'HP:0003118', (6, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('cortisol', 'Chemical', 'MESH:D006854', (11, 19))	('hypercortisolism', 'Disease', (6, 22))	('ACTH', 'Gene', (178, 182))	('high', 'Var', (101, 105))	('adrenocortical carcinoma', 'Disease', (24, 48))
18059	33725886	Much research has been conducted on N6-methyladenosine (m6A), the most common RNA modification in eukaryotic mRNAs and lncRNAs.	('m6A', 'Gene', (56, 59))	('m6A', 'Gene', '56339', (56, 59))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (36, 54))	('N6-methyladenosine', 'Var', (36, 54))
18060	33725886	M6A methylation is associated with multiple RNA biofunctions and is dynamically regulated via a variety of genes known as "writers", "erasers," and "readers".	('associated', 'Reg', (19, 29))	('M6A', 'Gene', '56339', (0, 3))	('M6A', 'Gene', (0, 3))	('methylation', 'Var', (4, 15))
18094	33725886	Additionally, the Kaplan-Meier survival curves showed that the prognosis of patients with ACC in cluster 2 was worse than that of patients in cluster 1 (P = .004) (Fig.	('patients', 'Species', '9606', (76, 84))	('ACC', 'Var', (90, 93))	('worse', 'NegReg', (111, 116))	('patients', 'Species', '9606', (130, 138))	('ACC', 'Phenotype', 'HP:0006744', (90, 93))
18103	33725886	Univariable Cox regression showed that high M classification, high T classification, advanced clinical stage and high risk score were strongly correlated with poor prognosis (Fig.	('Cox', 'Gene', (12, 15))	('high M', 'Var', (39, 45))	('Cox', 'Gene', '1351', (12, 15))	('high', 'Var', (62, 66))
18106	33725886	With the development of epigenetics, m6A methylation has become a promising research direction and has been demonstrated to be closely associated with the occurrence and development of tumors.	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('methylation', 'Var', (41, 52))	('associated', 'Reg', (135, 145))	('m6A', 'Gene', (37, 40))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('m6A', 'Gene', '56339', (37, 40))
18108	33725886	In pancreatic cancer cells, the knockdown of METTL3 was found to decrease chemo- and radio-resistance, and increased expression of METTL3 was found to promote the invasion and migration of melanoma cells via the actions of matrix metallopeptidase 2.	('pancreatic cancer', 'Disease', (3, 20))	('matrix metallopeptidase 2', 'Gene', '4313', (223, 248))	('matrix metallopeptidase 2', 'Gene', (223, 248))	('increased', 'PosReg', (107, 116))	('melanoma', 'Disease', (189, 197))	('METTL3', 'Gene', (45, 51))	('expression', 'MPA', (117, 127))	('knockdown', 'Var', (32, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('METTL3', 'Gene', '56339', (131, 137))	('METTL3', 'Gene', '56339', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('promote', 'PosReg', (151, 158))	('decrease', 'NegReg', (65, 73))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('METTL3', 'Gene', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))
18110	33725886	In acute myeloid leukemia, the upregulation of YTHDF2 was found to decrease the half-life of diverse m6A transcripts, and YTHDF2 knockdown was shown to inhibit cancer stem cell development.	('inhibit', 'NegReg', (152, 159))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('YTHDF2', 'Gene', '51441', (47, 53))	('upregulation', 'PosReg', (31, 43))	('YTHDF2', 'Gene', (122, 128))	('cancer', 'Disease', (160, 166))	('knockdown', 'Var', (129, 138))	('half-life', 'MPA', (80, 89))	('m6A', 'Gene', '56339', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('decrease', 'NegReg', (67, 75))	('m6A', 'Gene', (101, 104))	('acute myeloid leukemia', 'Disease', (3, 25))	('YTHDF2', 'Gene', '51441', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('YTHDF2', 'Gene', (47, 53))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
18111	33725886	Furthermore, an "eraser" of m6A, FTO, was shown to be suppressed in clear cell renal cell carcinoma (ccRCC) tissues, and overexpression of FTO was found to activate oxidative stress and ROS production by increasing the expression of PGC-1alpha.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('activate', 'PosReg', (156, 164))	('FTO', 'Gene', '79068', (139, 142))	('increasing', 'PosReg', (204, 214))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (74, 99))	('cell renal cell carcinoma', 'Disease', (74, 99))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (68, 99))	('FTO', 'Gene', (139, 142))	('oxidative stress', 'Phenotype', 'HP:0025464', (165, 181))	('overexpression', 'Var', (121, 135))	('ROS production', 'MPA', (186, 200))	('FTO', 'Gene', '79068', (33, 36))	('FTO', 'Gene', (33, 36))	('m6A', 'Gene', '56339', (28, 31))	('PGC-1alpha', 'Gene', '10891', (233, 243))	('ROS', 'Chemical', '-', (186, 189))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (79, 99))	('m6A', 'Gene', (28, 31))	('expression', 'MPA', (219, 229))	('PGC-1alpha', 'Gene', (233, 243))	('oxidative stress', 'MPA', (165, 181))
18112	33725886	Although an increasing number of studies have confirmed that m6A modification is significantly associated with tumors, the relationships between m6A modification and ACC have to date been unknown.	('m6A', 'Gene', (145, 148))	('ACC', 'Phenotype', 'HP:0006744', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('m6A', 'Gene', '56339', (145, 148))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('modification', 'Var', (65, 77))	('m6A', 'Gene', (61, 64))	('associated', 'Reg', (95, 105))	('m6A', 'Gene', '56339', (61, 64))
18121	33725886	M6A methyltransferase complex ("writers") could mediate m6A methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing.	('m6A', 'Gene', (56, 59))	('M6A', 'Gene', '56339', (0, 3))	('methylation', 'Var', (60, 71))	('m6A', 'Gene', '56339', (56, 59))	('M6A', 'Gene', (0, 3))	('RNAs', 'Gene', (75, 79))
18144	32451468	Cancer incidence and spectrum among children with genetically confirmed Beckwith-Wiedemann spectrum in Germany: a retrospective cohort study Beckwith-Wiedemann syndrome (BWS) is a cancer predisposition syndrome caused by defects on chromosome 11p15.5.	('BWS', 'Gene', (170, 173))	('cancer', 'Disease', (180, 186))	('BWS', 'Gene', '283120', (170, 173))	('caused by', 'Reg', (211, 220))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (141, 168))	('defects', 'Var', (221, 228))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('children', 'Species', '9606', (36, 44))	('Beckwith-Wiedemann', 'Disease', (141, 159))	('Cancer', 'Disease', (0, 6))	('Beckwith-Wiedemann', 'Disease', (72, 90))	('Beckwith-Wiedemann', 'Disease', 'MESH:D001506', (141, 159))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Beckwith-Wiedemann', 'Disease', 'MESH:D001506', (72, 90))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('Beckwith-Wiedemann syndrome', 'Disease', (141, 168))
18152	32451468	Our findings suggest that the highest cancer risk is associated with UPDpat.	('UPDpat', 'Var', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (38, 44))
18159	32451468	The molecular BWSp subgroups are: (a) KCNQ1OT1:TSS DMR (IC2) loss of methylation (IC2-LOM); (b) chromosome 11p15.5 paternal uniparental disomy (UPDpat); (c) H19/IGF2:IG DMR (IC1) gain of methylation (IC1-GOM); (d) pathogenetic variants in CDKN1C and (e) deletions/duplications of 11p15.5.	('gain', 'PosReg', (179, 183))	('methylation', 'MPA', (69, 80))	('KCNQ1OT1', 'Gene', '10984', (38, 46))	('BWSp', 'Gene', '283120', (14, 18))	('variants', 'Var', (227, 235))	('deletions/duplications', 'Var', (254, 276))	('methylation', 'MPA', (187, 198))	('IC1', 'Gene', '105259599', (200, 203))	('uniparental disomy', 'Disease', (124, 142))	('CDKN1C', 'Gene', '1028', (239, 245))	('loss', 'NegReg', (61, 65))	('IC2', 'Gene', '1781', (56, 59))	('uniparental disomy', 'Disease', 'MESH:D024182', (124, 142))	('KCNQ1OT1', 'Gene', (38, 46))	('IC2', 'Gene', (56, 59))	('IC1', 'Gene', '105259599', (174, 177))	('IGF2', 'Gene', (161, 165))	('H19', 'Gene', (157, 160))	('CDKN1C', 'Gene', (239, 245))	('H19', 'Gene', '283120', (157, 160))	('IC2', 'Gene', '1781', (82, 85))	('IC1', 'Gene', (200, 203))	('IC2', 'Gene', (82, 85))	('IC1', 'Gene', (174, 177))	('IGF2', 'Gene', '3481', (161, 165))	('BWSp', 'Gene', (14, 18))
18164	32451468	The published overall childhood cancer risk in the various subgroups are the following: IC2-LOM 2.6%, IC1-GOM 28.1% (mainly Wilms tumour), UPDpat 16% (mainly Wilms tumour and hepatoblastoma), CDKN1C pathogenic variant 6.9% (mainly neuroblastoma) (reviewed in).	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('IC2', 'Gene', (88, 91))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (175, 189))	('neuroblastoma', 'Disease', (231, 244))	('IC1', 'Gene', (102, 105))	('neuroblastoma', 'Phenotype', 'HP:0003006', (231, 244))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('Wilms tumour', 'Disease', (158, 170))	('neuroblastoma', 'Disease', 'MESH:D009447', (231, 244))	('Wilms tumour', 'Disease', (124, 136))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CDKN1C', 'Gene', (192, 198))	('IC1', 'Gene', '105259599', (102, 105))	('hepatoblastoma', 'Disease', (175, 189))	('Wilms tumour', 'Phenotype', 'HP:0002667', (158, 170))	('Wilms tumour', 'Phenotype', 'HP:0002667', (124, 136))	('hepatoblastoma', 'Disease', 'MESH:D018197', (175, 189))	('pathogenic', 'Reg', (199, 209))	('Wilms tumour', 'Disease', 'MESH:D009396', (158, 170))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('Wilms tumour', 'Disease', 'MESH:D009396', (124, 136))	('variant', 'Var', (210, 217))	('CDKN1C', 'Gene', '1028', (192, 198))	('IC2', 'Gene', '1781', (88, 91))
18182	32451468	The following epigenetic and genetic defects were identified in peripheral blood: IC2-LOM (n = 208), UPDpat (n = 64), IC1-GOM (n = 31), duplication/deletion (n = 12), pathogenetic variant in CDKN1C (n = 6).	('IC1', 'Gene', (118, 121))	('duplication/deletion', 'Var', (136, 156))	('genetic defects', 'Disease', 'MESH:D030342', (29, 44))	('genetic defects', 'Disease', (29, 44))	('IC2', 'Gene', '1781', (82, 85))	('CDKN1C', 'Gene', (191, 197))	('IC2', 'Gene', (82, 85))	('CDKN1C', 'Gene', '1028', (191, 197))	('UPDpat', 'PosReg', (101, 107))	('IC1', 'Gene', '105259599', (118, 121))	('pathogenetic', 'Reg', (167, 179))
18185	32451468	Thirteen patients with cancer, presenting between 1989 and 2018 and diagnosed with a BWSp-causing molecular defect between the years 2006 and 2018 were identified in the BWSp cohort (Table 1).	('patients', 'Species', '9606', (9, 17))	('BWSp', 'Gene', (170, 174))	('BWSp', 'Gene', '283120', (85, 89))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('molecular defect', 'Var', (98, 114))	('BWSp', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('BWSp', 'Gene', '283120', (170, 174))
18187	32451468	The childhood cancer risk in BWSp patients due to UPDpat was 153-fold increased (SIR = 152.5, 95% CI = 73.1-280.5), whereas patients with IC2-LOM had an 11-fold (SIR = 11.4, 95% CI = 2.3-33.2) increased risk.	('cancer', 'Disease', (14, 20))	('increased', 'PosReg', (70, 79))	('BWSp', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('UPDpat', 'Var', (50, 56))	('IC2', 'Gene', '1781', (138, 141))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('IC2', 'Gene', (138, 141))	('BWSp', 'Gene', '283120', (29, 33))	('patients', 'Species', '9606', (124, 132))
18188	32451468	There were no cancers observed either among the 31 IC1-GOM patients (268.9 PY; 0.0449 cases expected), the 12 duplication/deletion patients or the six patients with a pathogenetic variant in CDKN1C.	('cancers', 'Disease', (14, 21))	('patients', 'Species', '9606', (131, 139))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('CDKN1C', 'Gene', (191, 197))	('IC1', 'Gene', '105259599', (51, 54))	('duplication/deletion', 'Var', (110, 130))	('patients', 'Species', '9606', (151, 159))	('CDKN1C', 'Gene', '1028', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('patients', 'Species', '9606', (59, 67))	('IC1', 'Gene', (51, 54))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
18194	32451468	This is, to our knowledge, the first population-based study to quantify the cancer risk in children with BWSp with IC1-LOM, IC2-GOM, UPDpat, deletions/duplications and pathogenetic variants in CDKN1C.	('IC1', 'Gene', (115, 118))	('CDKN1C', 'Gene', (193, 199))	('variants', 'Var', (181, 189))	('children', 'Species', '9606', (91, 99))	('BWSp', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('IC1', 'Gene', '105259599', (115, 118))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('CDKN1C', 'Gene', '1028', (193, 199))	('deletions/duplications', 'Var', (141, 163))	('IC2', 'Gene', (124, 127))	('IC2', 'Gene', '1781', (124, 127))	('cancer', 'Disease', (76, 82))	('BWSp', 'Gene', '283120', (105, 109))
18200	32451468	Therefore, the observed high cancer risk in individuals with BWSp who carry a constitutional or mosaic lesion in the 11p15.5 region is biologically plausible.	('cancer', 'Disease', (29, 35))	('BWSp', 'Gene', '283120', (61, 65))	('11p15.5', 'Gene', (117, 124))	('mosaic lesion', 'Var', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('constitutional', 'Var', (78, 92))	('BWSp', 'Gene', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
18202	32451468	studied 407 patients with BWSp including 257 patients with IC2-LOM, 81 with UPDpat, 35 with IC1-GOM and 34 individuals with a pathogenic variant in CDKN1C.	('patients', 'Species', '9606', (12, 20))	('CDKN1C', 'Gene', (148, 154))	('BWSp', 'Gene', '283120', (26, 30))	('CDKN1C', 'Gene', '1028', (148, 154))	('variant', 'Var', (137, 144))	('BWSp', 'Gene', (26, 30))	('IC1', 'Gene', (92, 95))	('IC2', 'Gene', '1781', (59, 62))	('patients', 'Species', '9606', (45, 53))	('IC2', 'Gene', (59, 62))	('IC1', 'Gene', '105259599', (92, 95))
18242	32320669	Beta-Catenin Causes Adrenal Hyperplasia by Blocking Zonal Transdifferentiation Activating mutations in the canonical Wnt/beta-catenin pathway are key drivers of hyperplasia, the gateway for tumor development.	('Adrenal Hyperplasia', 'Phenotype', 'HP:0008221', (20, 39))	('mutations', 'Var', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('Beta-Catenin', 'Gene', (0, 12))	('canonical Wnt/beta-catenin pathway', 'Pathway', (107, 141))	('hyperplasia', 'Disease', 'MESH:D006965', (161, 172))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('Beta-Catenin', 'Gene', '12387', (0, 12))	('Adrenal Hyperplasia', 'Disease', 'MESH:D000312', (20, 39))	('Blocking', 'NegReg', (43, 51))	('hyperplasia', 'Disease', (161, 172))	('Zonal Transdifferentiation', 'CPA', (52, 78))	('Adrenal Hyperplasia', 'Disease', (20, 39))
18244	32320669	The adrenal cortex is an ideal system in which to explore this question, as it undergoes hyperplasia following somatic beta-catenin gain-of-function (betacat-GOF) mutations.	('hyperplasia', 'Disease', 'MESH:D006965', (89, 100))	('mutations', 'Var', (163, 172))	('beta-catenin', 'Protein', (119, 131))	('hyperplasia', 'Disease', (89, 100))	('gain-of-function', 'PosReg', (132, 148))
18251	32320669	Consistent with this role, constitutive activation of this pathway, either following somatic gain-of-function (GOF) mutations in beta-catenin or loss-of-function (LOF) mutations in key negative regulators, such as APC (adenomatous polyposis coli) or in the transmembrane E3 ubiquitin ligase ZNRF3 (zinc and ring finger 3), leads to tissue hyperplasia and ultimately to neoplastic transformation.	('hyperplasia', 'Disease', 'MESH:D006965', (339, 350))	('APC (adenomatous polyposis coli', 'Gene', '11789', (214, 245))	('ZNRF3', 'Gene', (291, 296))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (219, 245))	('beta-catenin', 'Protein', (129, 141))	('leads to', 'Reg', (323, 331))	('neoplastic transformation', 'CPA', (369, 394))	('activation', 'PosReg', (40, 50))	('zinc and ring finger 3', 'Gene', '407821', (298, 320))	('hyperplasia', 'Disease', (339, 350))	('mutations', 'Var', (116, 125))	('ZNRF3', 'Gene', '407821', (291, 296))	('loss-of-function', 'NegReg', (145, 161))	('gain-of-function', 'PosReg', (93, 109))	('mutations', 'Var', (168, 177))
18255	32320669	In fact, beta-catenin GOF mutations and LOF mutations in APC and ZNRF3 are among the most common somatic changes in adrenocortical carcinoma.	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (116, 140))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (116, 140))	('ZNRF3', 'Gene', '407821', (65, 70))	('beta-catenin', 'Protein', (9, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('APC', 'Disease', 'MESH:D011125', (57, 60))	('LOF', 'NegReg', (40, 43))	('APC', 'Disease', (57, 60))	('GOF', 'PosReg', (22, 25))	('mutations', 'Var', (26, 35))	('adrenocortical carcinoma', 'Disease', (116, 140))	('mutations', 'Var', (44, 53))	('ZNRF3', 'Gene', (65, 70))
18257	32320669	To address this, we specifically targeted zG cells with a somatic beta-catenin GOF mutation in mice.	('mutation', 'Var', (83, 91))	('beta-catenin', 'Protein', (66, 78))	('mice', 'Species', '10090', (95, 99))	('GOF', 'PosReg', (79, 82))
18259	32320669	Together, our data identify a proliferation-independent mechanism, a block in zonal transdifferentiation, whereby betacat-GOF can cause tissue hyperplasia.	('betacat-GOF', 'Var', (114, 125))	('cause', 'Reg', (130, 135))	('hyperplasia', 'Disease', (143, 154))	('hyperplasia', 'Disease', 'MESH:D006965', (143, 154))
18261	32320669	Deletion of the third exon of beta-catenin results in an in-frame protein devoid of GSK3beta-specific phosphorylation sites that normally target beta-catenin for degradation.	('results in', 'Reg', (43, 53))	('degradation', 'MPA', (162, 173))	('GSK3beta', 'Gene', (84, 92))	('GSK3beta', 'Gene', '606496', (84, 92))	('devoid', 'NegReg', (74, 80))	('Deletion', 'Var', (0, 8))
18268	32320669	This result confirms that nearly all zG cells in the expanded region underwent recombination of the Ctnnb1 locus.	('underwent', 'Reg', (69, 78))	('recombination', 'Var', (79, 92))	('Ctnnb1', 'Gene', (100, 106))	('Ctnnb1', 'Gene', '12387', (100, 106))
18277	32320669	Analysis of the number of DAPI-positive nuclei per unit area (mm2) within each region revealed that the cellular density within the expanded zG region of betacat-GOF adrenals was indistinguishable from that within the zG region of betacat-WT adrenals (14,002 +- 796 versus 13,704 +- 780 nuclei/mm2, respectively) and markedly different from the zF (6,838 +- 502 versus 7,212 +- 990 nuclei/mm2, respectively) (Figure 1G), indicating that the expansion in the zG area in betacat-GOF mice is the result of hyperplasia and not hypertrophy.	('hyperplasia', 'Disease', 'MESH:D006965', (503, 514))	('expansion', 'Var', (441, 450))	('betacat-GOF', 'Gene', (469, 480))	('hyperplasia', 'Disease', (503, 514))	('hypertrophy', 'Disease', (523, 534))	('mice', 'Species', '10090', (481, 485))	('hypertrophy', 'Disease', 'MESH:D006984', (523, 534))	('DAPI', 'Chemical', 'MESH:C007293', (26, 30))
18278	32320669	Consistent with a progressive hyperplastic increase in total mass of the zG-layer, overall adrenal weight was increased in aged betacat-GOF mice, compared with betacat-WT controls (Figure S1H).	('betacat-GOF', 'Var', (128, 139))	('mice', 'Species', '10090', (140, 144))	('increased', 'PosReg', (110, 119))	('adrenal weight', 'CPA', (91, 105))	('increase', 'PosReg', (43, 51))
18281	32320669	Although a modest increase in Ki67-positive cells was observed in the zG of betacat-GOF compared with control adrenals in both adult and aged mice (Figure S2A), when normalized by the zG area the fraction of proliferating cells was significantly decreased (Figure 2A).	('increase', 'PosReg', (18, 26))	('mice', 'Species', '10090', (142, 146))	('Ki67', 'Gene', (30, 34))	('fraction of proliferating cells', 'CPA', (196, 227))	('Ki67', 'Gene', '17345', (30, 34))	('decreased', 'NegReg', (246, 255))	('betacat-GOF', 'Var', (76, 87))
18288	32320669	Together, these data indicate that stabilization of beta-catenin within zG cells leads to progressive zG hyperplasia, in part, through a block in zonal transdifferentiation, defining a new paradigm for hyperplastic expansion.	('beta-catenin', 'Protein', (52, 64))	('block', 'NegReg', (137, 142))	('zG hyperplasia', 'Disease', 'MESH:D006965', (102, 116))	('zG hyperplasia', 'Disease', (102, 116))	('zonal transdifferentiation', 'CPA', (146, 172))	('stabilization', 'Var', (35, 48))
18290	32320669	By hydrolyzing and inactivating cAMP, an essential signaling intermediate of the PKA signaling pathway, zF function is blocked (Figure 3A).	('cAMP', 'Chemical', 'MESH:D000242', (32, 36))	('cAMP', 'Gene', (32, 36))	('inactivating', 'Var', (19, 31))	('hydrolyzing', 'Var', (3, 14))
18291	32320669	Phosphodiesterase activity within the adrenal gland is almost exclusively the result of PDE2A in the zG.	('activity', 'MPA', (18, 26))	('PDE2A', 'Var', (88, 93))	('Phosphodiesterase', 'Gene', (0, 17))	('result', 'Reg', (78, 84))	('Phosphodiesterase', 'Gene', '5138;207728', (0, 17))
18292	32320669	To assess the impact of betacat-GOF on phosphodiesterase activity, we first performed quantitative real-time PCR for Pde2a, which revealed a significant upregulation in betacat-GOF adrenals compared with controls (Figure 3B).	('phosphodiesterase', 'Gene', '5138;207728', (39, 56))	('upregulation', 'PosReg', (153, 165))	('phosphodiesterase', 'Gene', (39, 56))	('Pde2a', 'Gene', '207728', (117, 122))	('Pde2a', 'Gene', (117, 122))	('betacat-GOF', 'Var', (169, 180))
18300	32320669	betacat-GOF mice show an ~3.5-fold increase in the levels of aldosterone compared to betacat-WT mice (445 +- 317 pg/mL versus 131 +- 83 pg/mL, respectively) (Figure S3A).	('increase in the levels of aldosterone', 'Phenotype', 'HP:0000859', (35, 72))	('increase', 'PosReg', (35, 43))	('aldosterone', 'Chemical', 'MESH:D000450', (61, 72))	('mice', 'Species', '10090', (96, 100))	('levels of aldosterone', 'MPA', (51, 72))	('mice', 'Species', '10090', (12, 16))	('betacat-GOF', 'Var', (0, 11))
18302	32320669	Thus, the increase in aldosterone production in betacat-GOF mice is insufficient to suppress the renin-AngII-aldosterone system (RAAS) and indicates that the relative decrease in zG-specific proliferation is not a consequence of altered RAAS activity.	('betacat-GOF', 'Var', (48, 59))	('aldosterone', 'Chemical', 'MESH:D000450', (22, 33))	('aldosterone', 'Chemical', 'MESH:D000450', (109, 120))	('mice', 'Species', '10090', (60, 64))	('decrease', 'NegReg', (167, 175))	('suppress', 'NegReg', (84, 92))	('aldosterone production', 'MPA', (22, 44))	('AngII', 'Gene', '11606', (103, 108))	('zG-specific proliferation', 'CPA', (179, 204))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (10, 33))	('AngII', 'Gene', (103, 108))	('increase', 'PosReg', (10, 18))
18303	32320669	To assess the impact of trophic factor induction on the betacat-GOF-induced block in transdifferentiation, we utilized ASCre/Cre mice (AS(KO)), a model of CYP11B2(AS) deficiency that results in a dramatic ~5-fold increase in RAAS activity from an early age.	('CYP11B2', 'Gene', (155, 162))	('RAAS', 'Enzyme', (225, 229))	('mice', 'Species', '10090', (129, 133))	('increase', 'PosReg', (213, 221))	('activity', 'MPA', (230, 238))	('deficiency', 'Var', (167, 177))
18309	32320669	Taken together, these results indicate that enhanced trophic drive via AngII induces zG expansion via cell proliferation, whereas betacat-GOF induces zG expansion via a block in transdifferentiation and that the combination of both leads to a dramatic increase in adrenal mass.	('AngII', 'Gene', '11606', (71, 76))	('transdifferentiation', 'CPA', (178, 198))	('increase in adrenal mass', 'Phenotype', 'HP:0008221', (252, 276))	('trophic', 'CPA', (53, 60))	('trophic drive', 'Phenotype', 'HP:0010834', (53, 66))	('AngII', 'Gene', (71, 76))	('betacat-GOF', 'Var', (130, 141))	('increase', 'PosReg', (252, 260))	('adrenal mass', 'CPA', (264, 276))	('cell proliferation', 'CPA', (102, 120))	('enhanced', 'PosReg', (44, 52))
18310	32320669	Aberrant activation of the Wnt/beta-catenin signaling pathway has also been implicated in the initiation and progression of numerous cancers, including adenocarcinoma of the colon and of the adrenal cortex.	('Wnt/beta-catenin signaling pathway', 'Pathway', (27, 61))	('numerous cancers', 'Disease', (124, 140))	('activation', 'PosReg', (9, 19))	('adenocarcinoma of the colon', 'Disease', (152, 179))	('Aberrant', 'Var', (0, 8))	('adenocarcinoma of the colon', 'Disease', 'MESH:D003110', (152, 179))	('adenocarcinoma of the colon', 'Phenotype', 'HP:0040276', (152, 179))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('numerous cancers', 'Disease', 'MESH:D009369', (124, 140))	('implicated', 'Reg', (76, 86))
18311	32320669	In the intestine, a rapidly cycling tissue, stabilization of oncogenic beta-catenin or deletion of key tumor-suppressor genes results in a prompt increase in proliferation leading to tissue hyperplasia.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('increase', 'PosReg', (146, 154))	('oncogenic beta-catenin', 'Protein', (61, 83))	('hyperplasia', 'Disease', (190, 201))	('tumor', 'Disease', (103, 108))	('stabilization', 'Var', (44, 57))	('hyperplasia', 'Disease', 'MESH:D006965', (190, 201))	('deletion', 'Var', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('proliferation', 'CPA', (158, 171))
18313	32320669	Our data show that betacat-GOF mice develop zG hyperplasia via a block in zonal transdifferentiation rather than an increase in cell proliferation (Figure 4H).	('block', 'NegReg', (65, 70))	('zonal transdifferentiation', 'CPA', (74, 100))	('betacat-GOF', 'Var', (19, 30))	('mice', 'Species', '10090', (31, 35))	('zG hyperplasia', 'Disease', (44, 58))	('zG hyperplasia', 'Disease', 'MESH:D006965', (44, 58))
18315	32320669	In contrast, activation of RAAS leads to exacerbation of the block in transdifferentiation and can lead to frank adrenomegaly, an observation with potential clinical consequence.	('frank adrenomegaly', 'Disease', 'MESH:D001946', (107, 125))	('activation', 'Var', (13, 23))	('block', 'CPA', (61, 66))	('lead to', 'Reg', (99, 106))	('frank adrenomegaly', 'Phenotype', 'HP:0008186', (107, 125))	('RAAS', 'Gene', (27, 31))	('frank adrenomegaly', 'Disease', (107, 125))	('exacerbation', 'PosReg', (41, 53))
18331	32320669	This hypothesis is consistent with a previous study indicating that PDE2A is over-expressed preferentially in adrenal tumors carrying activating mutations in the gene encoding beta-catenin.	('mutations', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('adrenal tumors', 'Disease', 'MESH:D000310', (110, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('PDE2A', 'Gene', (68, 73))	('over-expressed', 'PosReg', (77, 91))	('adrenal tumors', 'Disease', (110, 124))
18336	32320669	Consistent with this, we found that chronic activation of RAAS in the setting of aldosterone synthase deficiency leads to an increase in cellular proliferation in both betacat-GOF mice and betacat-WT mice.	('aldosterone synthase', 'Gene', '13072', (81, 101))	('increase', 'PosReg', (125, 133))	('deficiency', 'Var', (102, 112))	('activation', 'PosReg', (44, 54))	('aldosterone synthase', 'Gene', (81, 101))	('synthase deficiency', 'Phenotype', 'HP:0003524', (93, 112))	('RAAS', 'Gene', (58, 62))	('mice', 'Species', '10090', (180, 184))	('mice', 'Species', '10090', (200, 204))	('cellular proliferation', 'CPA', (137, 159))
18337	32320669	These findings suggest that RAAS activation, and specifically AngII, may contribute to GOF events with potentially important clinical implications in the context of somatic and/or germline mutations that lead to betacat-GOF within the zG.	('mutations', 'Var', (189, 198))	('AngII', 'Gene', '11606', (62, 67))	('betacat-GOF', 'Var', (212, 223))	('AngII', 'Gene', (62, 67))
18338	32320669	Delineation of the impact of chronic RAAS activation will require careful retrospective analysis in patients discovered to have underlying betacat-GOF mutations at the time of resection or prospective analysis in cohorts with germline mutations.	('patients', 'Species', '9606', (100, 108))	('mutations', 'Var', (151, 160))	('betacat-GOF', 'Gene', (139, 150))
18353	32320669	The TaqMan Universal PCR Master Mix and the following Taqman primers from Life Technologies were used: Axin2 (Mm00443610_m1), Lef1 (Mm00550265_m1), Cyp11b2 (Mm01204955_g1), Pde2a (Mm01136644_m1) and Actb (Mm026119580_g1).	('Pde2a', 'Gene', (173, 178))	('Mm00550265_m1', 'Var', (132, 145))	('Mm026119580_g1', 'Var', (205, 219))	('Cyp11b2', 'Gene', (148, 155))	('Mm01204955_g1', 'Var', (157, 170))	('Mm01136644_m1', 'Var', (180, 193))	('Actb', 'Gene', (199, 203))	('Cyp11b2', 'Gene', '13072', (148, 155))	('Actb', 'Gene', '11461', (199, 203))	('Lef1', 'Gene', '16842', (126, 130))	('Mm00443610_m1', 'Var', (110, 123))	('Lef1', 'Gene', (126, 130))	('Axin2', 'Gene', '12006', (103, 108))	('Axin2', 'Gene', (103, 108))	('Pde2a', 'Gene', '207728', (173, 178))
18410	31618839	Notably, within both the favorable prognosis group Cluster 2 and the unfavorable prognosis group Cluster 4, TMB/TGF- score positive cases showed significantly longer OS intervals than the TMB/TGF- score negative counterparts (Table 3).	('positive', 'Var', (123, 131))	('TMB/TGF- score', 'Gene', (108, 122))	('TMB', 'Chemical', 'MESH:D014289', (188, 191))	('TMB', 'Chemical', 'MESH:D014289', (108, 111))	('OS intervals', 'MPA', (166, 178))	('longer', 'PosReg', (159, 165))
18449	31555752	Whole exome sequencing analysis was performed followed by in silico protein function prediction, revealing a probably deleterious germline TP53 L265P mutation.	('L265P', 'Mutation', 'p.L265P', (144, 149))	('L265P', 'Var', (144, 149))	('TP53', 'Gene', '7157', (139, 143))	('TP53', 'Gene', (139, 143))
18470	31555752	However, the base-change spectrum of the syndromic case's mutations relative to the sporadic cases was distinct (P < 0.001 by chi2 analysis of syndromic vs pooled sporadic variants).	('mutations', 'Var', (58, 67))	('syndromic', 'Disease', (41, 50))	('syndromic', 'Disease', 'MESH:D061325', (143, 152))	('syndromic', 'Disease', 'MESH:D061325', (41, 50))	('syndromic', 'Disease', (143, 152))
18474	31555752	Nonsynonymous germline variants were identified in 8 genes, including a probably damaging heterozygous TP53 variant not identified in the previous pediatric ACC cohort (Table 2).	('TP53', 'Gene', '7157', (103, 107))	('variant', 'Var', (108, 115))	('ACC', 'Disease', 'MESH:D018268', (157, 160))	('TP53', 'Gene', (103, 107))	('ACC', 'Phenotype', 'HP:0006744', (157, 160))	('variants', 'Var', (23, 31))	('ACC', 'Disease', (157, 160))
18479	31555752	In particular, the tumor carried relatively few Signature 1 mutations (associated with aging) and an unusually high number of Signature 25 mutations (a signature of unknown etiology that has been previously identified in Hodgkin lymphoma cells).	('lymphoma', 'Phenotype', 'HP:0002665', (229, 237))	('Signature 25', 'Gene', (126, 138))	('mutations', 'Var', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('Signature 1', 'Gene', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Hodgkin lymphoma', 'Disease', (221, 237))	('tumor', 'Disease', (19, 24))	('mutations', 'Var', (60, 69))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (221, 237))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (221, 237))
18480	31555752	Admittedly, the lack of Signature 1 mutations is possibly a consequence of the patient's young age, rather than the tumor predisposition syndrome per se.	('Signature 1', 'Gene', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mutations', 'Var', (36, 45))	('patient', 'Species', '9606', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
18487	31555752	ACC adrenocortical carcinoma SNV single nucleotide variants WES whole exome sequencing	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('ACC', 'Disease', 'MESH:D018268', (0, 3))	('single nucleotide variants', 'Var', (33, 59))	('adrenocortical carcinoma', 'Disease', (4, 28))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('ACC', 'Disease', (0, 3))
18500	31119141	Evaluations of ACTH and cortisol showed a significant decrease after left adenomectomy but could still not be suppressed, and the circadian rhythm was absent.	('left adenomectomy', 'Var', (69, 86))	('decrease', 'NegReg', (54, 62))	('ACTH', 'Gene', (15, 19))	('ACTH', 'Gene', '5443', (15, 19))	('cortisol', 'Chemical', 'MESH:D006854', (24, 32))
18538	31119141	The immunohistochemistry results revealed MelanA(+), CgA(-), Syn(+), Ki-67(+2%), Inhibin-a(+), CK(-), and S-100(spotty+) (Figure 2A, 2B and Figure 3).	('Syn', 'Gene', '6855', (61, 64))	('S-100', 'Var', (106, 111))	('Ki-67', 'Var', (69, 74))	('CK(-', 'Var', (95, 99))	('mi', 'Chemical', 'MESH:C011506', (18, 20))	('CgA', 'Gene', (53, 56))	('spotty', 'Species', '1203425', (112, 118))	('Syn', 'Gene', (61, 64))	('CgA', 'Gene', '1113', (53, 56))
18539	31119141	The immuno-histochemistry results revealed MelanA(+), CgA(-), Syn(+), Ki-67(+2%), Inhibin-a(+), CK(-), S-100(spotty +) (Figure 2C, 2D and Figure 4).	('Syn', 'Gene', '6855', (62, 65))	('Ki-67', 'Var', (70, 75))	('CgA', 'Gene', (54, 57))	('Syn', 'Gene', (62, 65))	('S-100', 'Var', (103, 108))	('CK(-', 'Var', (96, 100))	('spotty', 'Species', '1203425', (109, 115))	('mi', 'Chemical', 'MESH:C011506', (19, 21))	('CgA', 'Gene', '1113', (54, 57))
18550	31119141	The possible mechanism may be a novel mutation in the type lalpha regulatory subunit of the protein kinase A (PRKAR1A) gene: p.E17X (c.49G>T), which confirms that the diagnosis of PPNAD could be one component of Carney complex.	('p.E17X (c.49G>T', 'Var', (125, 140))	('c.49G>T', 'Mutation', 'c.49G>T', (133, 140))	('PRKAR1A', 'Gene', '5573', (110, 117))	('p.E17X', 'Mutation', 'p.E17X', (125, 131))	('PRKAR1A', 'Gene', (110, 117))	('PPNAD', 'Chemical', '-', (180, 185))	('Carney complex', 'Disease', (212, 226))
18839	26936751	In 1 study, urinary cortisol to creatinine ratio (UCCR) was significantly increased in ferrets affected by AAE.	('AAE', 'Chemical', '-', (107, 110))	('cortisol', 'Chemical', 'MESH:D006854', (20, 28))	('increased', 'PosReg', (74, 83))	('creatinine', 'Chemical', 'MESH:D003404', (32, 42))	('AAE', 'Var', (107, 110))	('ferrets', 'Species', '9669', (87, 94))	('urinary cortisol to creatinine ratio', 'MPA', (12, 48))
18893	26936751	Epigenetic modification of promoter region by hypomethylation led to upregulation of Igfbp6 and Foxs1 genes in adrenocortical neoplasms of gonadectomized mice.	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (111, 135))	('Igfbp6', 'Gene', (85, 91))	('upregulation', 'PosReg', (69, 81))	('mice', 'Species', '10090', (154, 158))	('Foxs1', 'Gene', (96, 101))	('Foxs1', 'Gene', '14239', (96, 101))	('neoplasm', 'Phenotype', 'HP:0002664', (126, 134))	('adrenocortical neoplasms', 'Disease', (111, 135))	('hypomethylation', 'Var', (46, 61))	('Igfbp6', 'Gene', '16012', (85, 91))	('neoplasms', 'Phenotype', 'HP:0002664', (126, 135))	('Epigenetic modification', 'Var', (0, 23))
18908	26936751	In humans, the MEN syndromes are associated with genetic alterations in tumor suppressor genes and are inherited as autosomal dominant traits.	('genetic alterations', 'Var', (49, 68))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('MEN syndrome', 'Disease', 'MESH:D018813', (15, 27))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('associated', 'Reg', (33, 43))	('humans', 'Species', '9606', (3, 9))	('MEN syndrome', 'Disease', (15, 27))
18910	26936751	The MEN1 is derived from an alteration in tumor suppressor menin (MEN1).	('MEN1', 'Gene', (4, 8))	('tumor', 'Disease', (42, 47))	('MEN1', 'Gene', '4221', (4, 8))	('MEN1', 'Gene', '4221', (66, 70))	('MEN1', 'Gene', (66, 70))	('alteration', 'Var', (28, 38))	('menin', 'Gene', '4221', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('menin', 'Gene', (59, 64))
18911	26936751	The MEN2 are derived from germ-line mutations in the Rearranged during Transfection (RET) gene, a proto-oncogene that results in RET gene gain of function variant.	('Rearranged during Transfection', 'Gene', (53, 83))	('MEN', 'Species', '9606', (4, 7))	('mutations', 'Var', (36, 45))	('RET gene', 'Gene', (129, 137))	('Rearranged during Transfection', 'Gene', '5979', (53, 83))	('gain of function', 'PosReg', (138, 154))	('variant', 'Var', (155, 162))
19011	26936751	The thrombocytopenia ranges between 20 000-50 000/muL with a platelet count less than 20 000/muL resulting in hemorrhage.	('thrombocytopenia', 'Phenotype', 'HP:0001873', (4, 20))	('hemorrhage', 'Disease', (110, 120))	('thrombocytopenia', 'Disease', (4, 20))	('hemorrhage', 'Disease', 'MESH:D006470', (110, 120))	('less', 'Var', (76, 80))	('thrombocytopenia', 'Disease', 'MESH:D013921', (4, 20))
19013	26936751	Clinical signs of bone marrow depression are apparent with PCV less than 20% and platelets below 50 000/muL.	('below 50 000/muL', 'Var', (91, 107))	('bone marrow depression', 'Disease', 'MESH:D001855', (18, 40))	('bone marrow depression', 'Phenotype', 'HP:0005528', (18, 40))	('bone marrow depression', 'Disease', (18, 40))	('depression', 'Phenotype', 'HP:0000716', (30, 40))
19084	26936751	However, evaluation of epigenetic changes, post-transcriptional, and post-translational alterations in these genes and gene products may provide valuable insights into mechanisms operable in age-related endocrinopathies in ferrets.	('epigenetic changes', 'Var', (23, 41))	('insights', 'Reg', (154, 162))	('endocrinopathies', 'Disease', (203, 219))	('endocrinopathies', 'Disease', 'MESH:C567425', (203, 219))	('ferrets', 'Species', '9669', (223, 230))
19107	27057164	Increased reactive oxygen species (ROS) caused by any perturbation in this balance may lead to oxidative stress and cell dysfunction or death.	('oxidative stress', 'Phenotype', 'HP:0025464', (95, 111))	('death', 'Disease', 'MESH:D003643', (136, 141))	('death', 'Disease', (136, 141))	('perturbation', 'Var', (54, 66))	('cell dysfunction', 'Disease', 'MESH:C538614', (116, 132))	('ROS', 'Chemical', 'MESH:D017382', (35, 38))	('cell dysfunction', 'Disease', (116, 132))	('oxidative stress', 'MPA', (95, 111))	('reactive oxygen species', 'MPA', (10, 33))	('Increased', 'PosReg', (0, 9))	('lead to', 'Reg', (87, 94))	('Increased reactive oxygen species', 'Phenotype', 'HP:0025464', (0, 33))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (10, 33))
19109	27057164	They also render steroidogenic tissues acutely vulnerable to redox imbalance and dysfunction of macromolecules within the adrenocortical cells and other cells.	('adrenocortical', 'Disease', 'MESH:D018268', (122, 136))	('vulnerable', 'Reg', (47, 57))	('steroid', 'Chemical', 'MESH:D013256', (17, 24))	('redox imbalance', 'Phenotype', 'HP:0025463', (61, 76))	('imbalance', 'Phenotype', 'HP:0002172', (67, 76))	('redox imbalance', 'MPA', (61, 76))	('adrenocortical', 'Disease', (122, 136))	('dysfunction', 'Var', (81, 92))
19134	27057164	The membranes were incubated overnight at 4 C with primary antibodies, including rabbit anti-Nox2 (1 : 1000, ab31092, Abcam, Cambridge, MA, USA), rabbit anti-p22phox (1 : 1000, Ab75941, Abcam), and anti-GAPDH (1 : 1000, ab181602, Abcam).	('GAPDH', 'Gene', '2597', (203, 208))	('GAPDH', 'Gene', (203, 208))	('1 : 1000', 'Var', (167, 175))	('1 : 1000', 'Var', (210, 218))	('1 : 1000', 'Var', (99, 107))	('rabbit', 'Species', '9986', (146, 152))	('ab31092', 'Var', (109, 116))	('p22phox', 'Gene', (158, 165))	('p22phox', 'Gene', '1535', (158, 165))	('rabbit', 'Species', '9986', (81, 87))	('Nox2', 'Gene', (93, 97))	('Nox2', 'Gene', '1536', (93, 97))
19139	27057164	Blocking of endogenous peroxidase was performed by incubating tissue sections in 3.0% hydrogen peroxide for 15 min at 37 C. Sections were then incubated with the primary antibody for Nox2 (1 : 100, ab31092, Abcam) and p22phox (1 : 200, ab75941, Abcam) at 4 C for overnight.	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (86, 103))	('p22phox', 'Gene', '1535', (218, 225))	('p22phox', 'Gene', (218, 225))	('1 : 200', 'Var', (227, 234))	('Nox2', 'Gene', (183, 187))	('Nox2', 'Gene', '1536', (183, 187))
19163	27057164	In this study, we did not use CYP11B2 as a specific ZG marker due in part to the 95% homology between CY11B2 and CYP11B1, which is the key rate-limiting enzyme for production of glucocorticoid hormones.	('CYP11B2', 'Gene', (30, 37))	('CYP11B2', 'Gene', '1585', (30, 37))	('CY11B2', 'Var', (102, 108))	('CYP11B1', 'Gene', (113, 120))	('CYP11B1', 'Gene', '1584', (113, 120))
19174	27057164	The high IRS value for Nox2 in APA suggests that its expression may affect aldosterone biosynthesis.	('aldosterone', 'Chemical', 'MESH:D000450', (75, 86))	('Nox2', 'Gene', (23, 27))	('expression', 'Var', (53, 63))	('IRS', 'MPA', (9, 12))	('Nox2', 'Gene', '1536', (23, 27))	('PA', 'Phenotype', 'HP:0011736', (32, 34))	('aldosterone biosynthesis', 'MPA', (75, 99))	('affect', 'Reg', (68, 74))
19204	27057164	Many studies have shown that aldosterone can increase Nox activity, resulting in ROS production and leading to myocyte apoptosis and glomerular diseases.	('aldosterone', 'Chemical', 'MESH:D000450', (29, 40))	('ROS production', 'MPA', (81, 95))	('glomerular diseases', 'Disease', (133, 152))	('Nox activity', 'MPA', (54, 66))	('aldosterone', 'Var', (29, 40))	('myocyte', 'Disease', (111, 118))	('leading to', 'Reg', (100, 110))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))	('aldosterone can increase', 'Phenotype', 'HP:0000859', (29, 53))	('glomerular diseases', 'Disease', 'MESH:D007674', (133, 152))	('resulting in', 'Reg', (68, 80))	('increase', 'PosReg', (45, 53))
19247	22047791	Dysregulation of cAMP homeostasis can be linked to tumorigenesis, both directly and indirectly.	('linked', 'Reg', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', (51, 56))	('cAMP', 'Chemical', 'MESH:D000242', (17, 21))	('cAMP homeostasis', 'MPA', (17, 33))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
19250	22047791	Alterations in cAMP signaling pathways have been linked to tumorigenesis at different levels.	('cAMP', 'Chemical', 'MESH:D000242', (15, 19))	('tumor', 'Disease', (59, 64))	('linked', 'Reg', (49, 55))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('rat', 'Species', '10116', (4, 7))	('cAMP signaling pathways', 'Pathway', (15, 38))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
19254	22047791	Altered cAMP signaling, somatic PRKAR1A mutations, and somatic losses in the 17q22-24 locus have all been reported in adrenocortical adenomas and adrenocortical cancer.	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (118, 141))	('cAMP', 'Chemical', 'MESH:D000242', (8, 12))	('17q22-24', 'Gene', (77, 85))	('reported', 'Reg', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (146, 167))	('PRKAR1A', 'Gene', '5573', (32, 39))	('mutations', 'Var', (40, 49))	('Altered', 'Reg', (0, 7))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (118, 141))	('cAMP signaling', 'MPA', (8, 22))	('adrenocortical cancer', 'Disease', (146, 167))	('PRKAR1A', 'Gene', (32, 39))	('losses', 'NegReg', (63, 69))	('adrenocortical adenomas', 'Disease', (118, 141))
19255	22047791	Specifically, 17q22-24 losses were found in 23% and 53% of adrenocortical adenomas and adrenocortical cancer samples, respectively.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('17q22-24', 'Var', (14, 22))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (87, 108))	('losses', 'NegReg', (23, 29))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (59, 82))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (59, 82))	('adrenocortical adenomas', 'Disease', (59, 82))	('adrenocortical cancer', 'Disease', (87, 108))	('found', 'Reg', (35, 40))
19258	22047791	Inactivating molecular defects in PDEs lead to high cAMP or cGMP levels that in turn generate a continuous activation of the cAMP/PKA cascade.	('PDEs', 'Gene', (34, 38))	('cAMP', 'MPA', (52, 56))	('Inactivating molecular defects', 'Var', (0, 30))	('cAMP', 'Chemical', 'MESH:D000242', (52, 56))	('rat', 'Species', '10116', (89, 92))	('PDEs', 'Gene', '5138;5152;10846;50940', (34, 38))	('cAMP/PKA cascade', 'Pathway', (125, 141))	('cGMP levels', 'MPA', (60, 71))	('cGMP', 'Chemical', 'MESH:D006152', (60, 64))	('activation', 'PosReg', (107, 117))	('cAMP', 'Chemical', 'MESH:D000242', (125, 129))
19259	22047791	In 2006, our laboratory identified five PDE11A mutations in a group of 16 patients with adrenocortical hyperplasia.	('PDE11A', 'Gene', '50940', (40, 46))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (88, 114))	('PDE11A', 'Gene', (40, 46))	('patients', 'Species', '9606', (74, 82))	('adrenocortical hyperplasia', 'Disease', (88, 114))	('mutations', 'Var', (47, 56))	('rat', 'Species', '10116', (17, 20))
19260	22047791	Three of these mutations led to premature terminations with truncated proteins, and the other two were missense mutations (R804H and R867G), leading to defective proteins.	('R867G', 'Var', (133, 138))	('truncated', 'MPA', (60, 69))	('proteins', 'MPA', (162, 170))	('proteins', 'Protein', (70, 78))	('R804H', 'Var', (123, 128))	('R867G', 'Mutation', 'rs61306957', (133, 138))	('R804H', 'Mutation', 'rs75127279', (123, 128))	('defective', 'NegReg', (152, 161))
19261	22047791	Although germline PDE11A truncating-protein mutations are seen in the general population, they are significantly more common among patients with adrenal hyperplasia.	('patients', 'Species', '9606', (131, 139))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (145, 164))	('common', 'Reg', (118, 124))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (145, 164))	('truncating-protein', 'MPA', (25, 43))	('PDE11A', 'Gene', (18, 24))	('mutations', 'Var', (44, 53))	('PDE11A', 'Gene', '50940', (18, 24))	('adrenal hyperplasia', 'Disease', (145, 164))
19262	22047791	Somatic missense mutations are frequently found in adrenocortical tumors: adrenocortical cancer (ACA), adrenocortical adenomas, and corticotrophin (ACTH)-independent macronodular adrenal hyperplasia or AIMAH.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (166, 198))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('macronodular adrenal hyperplasia', 'Disease', (166, 198))	('adrenocortical cancer', 'Disease', (74, 95))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (179, 198))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (51, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('found', 'Reg', (42, 47))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (103, 126))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (74, 95))	('adrenocortical tumors', 'Disease', (51, 72))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (103, 126))	('adrenocortical adenomas', 'Disease', (103, 126))	('missense mutations', 'Var', (8, 26))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (166, 198))
19264	22047791	Interestingly, a higher frequency of PDE11A variants has been found in patients with PRKAR1A mutations, suggesting a contribution of PDE11A to adrenal and testicular tumor formation in CNC.	('PDE11A', 'Gene', (37, 43))	('PRKAR1A', 'Gene', (85, 92))	('mutations', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('PDE11A', 'Gene', (133, 139))	('patients', 'Species', '9606', (71, 79))	('PDE11A', 'Gene', '50940', (133, 139))	('PRKAR1A', 'Gene', '5573', (85, 92))	('testicular tumor', 'Phenotype', 'HP:0010788', (155, 171))	('contribution', 'Reg', (117, 129))	('testicular tumor', 'Disease', 'MESH:D013736', (155, 171))	('PDE11A', 'Gene', '50940', (37, 43))	('variants', 'Var', (44, 52))	('testicular tumor', 'Disease', (155, 171))
19265	22047791	More recently, PDE11A genetic defects were found to be significantly increased in prostatic cancer patients, compared with healthy controls, suggesting that PDE11A genetic variants may play a role in susceptibility to prostatic cancer, as well.	('PDE11A', 'Gene', (15, 21))	('PDE11A', 'Gene', '50940', (15, 21))	('genetic defects', 'Disease', (22, 37))	('prostatic cancer', 'Disease', (82, 98))	('increased', 'PosReg', (69, 78))	('genetic defects', 'Disease', 'MESH:D030342', (22, 37))	('prostatic cancer', 'Disease', 'MESH:D011471', (218, 234))	('prostatic cancer', 'Disease', 'MESH:D011471', (82, 98))	('prostatic cancer', 'Phenotype', 'HP:0012125', (218, 234))	('prostatic cancer', 'Phenotype', 'HP:0012125', (82, 98))	('PDE11A', 'Gene', (157, 163))	('PDE11A', 'Gene', '50940', (157, 163))	('patients', 'Species', '9606', (99, 107))	('genetic variants', 'Var', (164, 180))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('susceptibility', 'Reg', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('prostatic cancer', 'Disease', (218, 234))
19267	22047791	A PDE8B missense mutation (p.H305P) was then described in a young girl with isolated micronodular adrenocortical disease.	('adrenocortical disease', 'Disease', (98, 120))	('p.H305P', 'Mutation', 'rs121918360', (27, 34))	('p.H305P', 'Var', (27, 34))	('adrenocortical disease', 'Disease', 'MESH:D018268', (98, 120))	('girl', 'Species', '9606', (66, 70))
19268	22047791	Functional studies showed high levels of cAMP in HEK293 cells transfected with the mutant gene.	('cAMP', 'Chemical', 'MESH:D000242', (41, 45))	('cAMP', 'MPA', (41, 45))	('HEK293', 'CellLine', 'CVCL:0045', (49, 55))	('mutant', 'Var', (83, 89))
19269	22047791	Subsequently, additional three novel mutations in PDE8B were described in patients with adrenal tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('patients', 'Species', '9606', (74, 82))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('adrenal tumors', 'Disease', (88, 102))	('mutations', 'Var', (37, 46))	('described', 'Reg', (61, 70))	('adrenal tumors', 'Disease', 'MESH:D000310', (88, 102))	('PDE8B', 'Gene', (50, 55))
19273	22047791	A strong association between high TSH levels and polymorphisms in the PDE8B gene was described in a genome-wide association study.	('TSH', 'Chemical', '-', (34, 37))	('high TSH', 'Phenotype', 'HP:0002925', (29, 37))	('polymorphisms', 'Var', (49, 62))	('PDE8B', 'Gene', (70, 75))
19274	22047791	The segregation of those polymorphic variants in a family with micronodular adrenal disease, with a PDE8 defect leading to Cushing syndrome was also studied.	('adrenal disease', 'Disease', (76, 91))	('PDE8', 'Gene', '18584', (100, 104))	('leading to', 'Reg', (112, 122))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (123, 139))	('Cushing syndrome', 'Disease', (123, 139))	('PDE8', 'Gene', (100, 104))	('Cushing syndrome', 'Disease', 'MESH:D003480', (123, 139))	('adrenal disease', 'Phenotype', 'HP:0000834', (76, 91))	('variants', 'Var', (37, 45))	('adrenal disease', 'Disease', 'MESH:D000309', (76, 91))
19279	22047791	An association between upregulation of PDEs in a growth hormone (GH)-producing pituitary adenoma carrying a GNAS mutation has been investigated; increased PDE4C and PDE4D expression and activity were discussed as a possible protective mechanism against GNAS-dependent activation of the cAMP pathway.	('pituitary adenoma', 'Disease', 'MESH:D010911', (79, 96))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (79, 96))	('PDE4C', 'Gene', '5143', (155, 160))	('growth hormone', 'Gene', '2688', (49, 63))	('pituitary adenoma', 'Disease', (79, 96))	('PDE4D', 'Gene', '5144', (165, 170))	('GNAS', 'Gene', (253, 257))	('PDE4C', 'Gene', (155, 160))	('mutation', 'Var', (113, 121))	('upregulation', 'PosReg', (23, 35))	('GNAS', 'Gene', (108, 112))	('GNAS', 'Gene', '2778', (253, 257))	('GH', 'Gene', '2688', (65, 67))	('cAMP', 'Chemical', 'MESH:D000242', (286, 290))	('PDEs', 'Gene', (39, 43))	('GNAS', 'Gene', '2778', (108, 112))	('PDE4D', 'Gene', (165, 170))	('activity', 'MPA', (186, 194))	('PDEs', 'Gene', '5138;5152;10846;50940', (39, 43))	('growth hormone', 'Gene', (49, 63))
19282	22047791	For example, inhibition of PDE1B stimulates apoptosis in human leukemia cells.	('stimulates', 'PosReg', (33, 43))	('PDE1B', 'Gene', '5153', (27, 32))	('apoptosis', 'CPA', (44, 53))	('leukemia', 'Disease', (63, 71))	('inhibition', 'Var', (13, 23))	('leukemia', 'Disease', 'MESH:D007938', (63, 71))	('leukemia', 'Phenotype', 'HP:0001909', (63, 71))	('PDE1B', 'Gene', (27, 32))	('human', 'Species', '9606', (57, 62))
19285	22047791	PDE2 inhibitors have been mainly tested for effects on endothelial permeability, and to treat learning and memory disorders in animal studies.	('PDE', 'Gene', (0, 3))	('inhibitors', 'Var', (5, 15))	('memory disorders', 'Phenotype', 'HP:0002354', (107, 123))	('PDE', 'Gene', '5138;5152;10846;50940', (0, 3))	('memory disorders', 'Disease', 'MESH:D008569', (107, 123))	('endothelial permeability', 'MPA', (55, 79))	('memory disorders', 'Disease', (107, 123))
19295	22047791	In colon cancer cells and in rat bladder tumors; exisulind reduced multiplicity and incidence of the tumorigenic events.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('incidence', 'CPA', (84, 93))	('reduced', 'NegReg', (59, 66))	('bladder tumors', 'Phenotype', 'HP:0009725', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('multiplicity', 'CPA', (67, 79))	('bladder tumors', 'Disease', 'MESH:D001749', (33, 47))	('tumor', 'Disease', (41, 46))	('rat', 'Species', '10116', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('colon cancer', 'Disease', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('bladder tumors', 'Disease', (33, 47))	('tumor', 'Disease', (101, 106))	('exisulind', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
19314	22047791	However, another study showed that inhibition of PDE5 can induce cell proliferation, and enhance new vessel growth and cell migration through activation of MAPKs.	('enhance', 'PosReg', (89, 96))	('activation', 'PosReg', (142, 152))	('MAPKs', 'Protein', (156, 161))	('induce', 'PosReg', (58, 64))	('rat', 'Species', '10116', (77, 80))	('PDE5', 'Gene', '8654', (49, 53))	('PDE5', 'Gene', (49, 53))	('rat', 'Species', '10116', (127, 130))	('cell proliferation', 'CPA', (65, 83))	('inhibition', 'Var', (35, 45))	('new vessel growth', 'CPA', (97, 114))	('cell migration', 'CPA', (119, 133))
19317	22047791	A very selective PDE8 inhibitor, PF-04957325 (Pfizer Inc., Groton Laboratories, Groton, CT), has been used in the characterization of T-cell adhesion and proliferation.	('rat', 'Species', '10116', (70, 73))	('proliferation', 'CPA', (154, 167))	('PF-04957325', 'Chemical', '-', (33, 44))	('PF-04957325', 'Var', (33, 44))	('PDE8', 'Gene', (17, 21))	('rat', 'Species', '10116', (161, 164))	('Groton Laboratories', 'Disease', 'MESH:D007757', (59, 78))	('PDE8', 'Gene', '18584', (17, 21))	('Groton Laboratories', 'Disease', (59, 78))
19318	22047791	The association between PDE8B genetic defects and adrenal hyperplasia was described above, and although the use of PF-04957325 is known to potentiate steroidogenesis in Y-1 adrenal cell line and in mouse primary adrenocortical cells, no other reference of effects of PDE8 inhibitors on adrenal hyperplasia or tumorigenesis has been reported.	('adrenocortical', 'Disease', (212, 226))	('PDE8', 'Gene', (267, 271))	('steroidogenesis', 'MPA', (150, 165))	('PDE8', 'Gene', '18584', (267, 271))	('mouse', 'Species', '10090', (198, 203))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (50, 69))	('adrenal hyperplasia', 'Disease', (286, 305))	('genetic defects', 'Disease', (30, 45))	('genetic defects', 'Disease', 'MESH:D030342', (30, 45))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (50, 69))	('tumor', 'Disease', (309, 314))	('PDE8', 'Gene', (24, 28))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (286, 305))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('PDE8', 'Gene', '18584', (24, 28))	('PF-04957325', 'Chemical', '-', (115, 126))	('PF-04957325', 'Var', (115, 126))	('adrenal hyperplasia', 'Disease', (50, 69))	('adrenocortical', 'Disease', 'MESH:D018268', (212, 226))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (286, 305))	('potentiate', 'PosReg', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
19319	22047791	As mentioned, PDE11A defects have been described in different endocrine tumors, and high PDE11A immunoreactivity was detected by immunohistochemistry in renal, prostate, colon, lung, and breast carcinoma tissues.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('detected', 'Reg', (117, 125))	('prostate', 'Disease', (160, 168))	('colon', 'Disease', 'MESH:D015179', (170, 175))	('breast carcinoma', 'Phenotype', 'HP:0003002', (187, 203))	('renal', 'Disease', (153, 158))	('PDE11A', 'Gene', '50940', (14, 20))	('colon', 'Disease', (170, 175))	('immunoreactivity', 'MPA', (96, 112))	('PDE11A', 'Gene', (14, 20))	('lung', 'Disease', (177, 181))	('breast carcinoma tissues', 'Disease', 'MESH:D001943', (187, 211))	('PDE11A', 'Gene', '50940', (89, 95))	('PDE11A', 'Gene', (89, 95))	('breast carcinoma tissues', 'Disease', (187, 211))	('defects', 'Var', (21, 28))	('endocrine tumors', 'Disease', 'MESH:D004701', (62, 78))	('endocrine tumors', 'Disease', (62, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))
19324	24625776	Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs.	('patient', 'Species', '9606', (214, 221))	('mTOR', 'Gene', (11, 15))	('mTOR', 'Gene', '2475', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (16, 25))	('pazopanib', 'Chemical', 'MESH:C516667', (107, 116))	('improve', 'PosReg', (206, 213))	('everolimus', 'Chemical', 'MESH:D000068338', (92, 102))	('patient', 'Species', '9606', (31, 38))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('Activating', 'Reg', (0, 10))
19327	24625776	Whole exome sequencing of a patient with a 14-month complete response on this trial revealed two simultaneous mutations in mTOR, the target of everolimus.	('everolimus', 'Chemical', 'MESH:D000068338', (143, 153))	('mutations', 'Var', (110, 119))	('patient', 'Species', '9606', (28, 35))	('mTOR', 'Gene', '2475', (123, 127))	('mTOR', 'Gene', (123, 127))
19328	24625776	In vitro experiments demonstrate that both mutations are activating, suggesting a biological mechanism for exquisite sensitivity to everolimus in this patient.	('mutations', 'Var', (43, 52))	('patient', 'Species', '9606', (151, 158))	('everolimus', 'Chemical', 'MESH:D000068338', (132, 142))	('activating', 'PosReg', (57, 67))
19329	24625776	The use of precision (or "personalized") medicine approaches to screen cancer patients for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.	('mTOR', 'Gene', (110, 114))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('mTOR', 'Gene', '2475', (110, 114))	('mTOR', 'Gene', (221, 225))	('mTOR', 'Gene', '2475', (221, 225))	('cancer', 'Disease', (71, 77))	('patients', 'Species', '9606', (78, 86))	('alterations', 'Var', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('patients', 'Species', '9606', (155, 163))
19366	24625776	These findings suggest that the pharmacokinetics of pazopanib are unaffected by everolimus whereas the apparent oral clearance of everolimus is markedly diminished by pazopanib, resulting in increased concentrations of the drug in whole blood, when the two agents were given together on a continuous basis.	('everolimus', 'Chemical', 'MESH:D000068338', (80, 90))	('pazopanib', 'Var', (167, 176))	('concentrations', 'MPA', (201, 215))	('increased', 'PosReg', (191, 200))	('pazopanib', 'Chemical', 'MESH:C516667', (52, 61))	('everolimus', 'Chemical', 'MESH:D000068338', (130, 140))	('diminished', 'NegReg', (153, 163))	('apparent oral clearance', 'MPA', (103, 126))	('increased concentrations of the drug', 'Phenotype', 'HP:0020170', (191, 227))	('pazopanib', 'Chemical', 'MESH:C516667', (167, 176))
19372	24625776	Of these 340 alterations, 5 were in genes in the Cancer Gene Census (CGC), a curated catalogue of genes for which mutations have been causally implicated in cancer: PCM1, RANBP17, CTNNB1, FANCA, and TP53.	('PCM1', 'Gene', '5108', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CTNNB1', 'Gene', '1499', (180, 186))	('TP53', 'Gene', (199, 203))	('RANBP17', 'Gene', '64901', (171, 178))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('PCM1', 'Gene', (165, 169))	('FANCA', 'Gene', '2175', (188, 193))	('CTNNB1', 'Gene', (180, 186))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Cancer', 'Disease', (49, 55))	('cancer', 'Disease', (157, 163))	('FANCA', 'Gene', (188, 193))	('alterations', 'Var', (13, 24))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))	('RANBP17', 'Gene', (171, 178))	('TP53', 'Gene', '7157', (199, 203))
19375	24625776	Indels in PDGFRA, ATRX, NUP214, and CEBPA were all present at an AF of < 10%.	('NUP214', 'Gene', '8021', (24, 30))	('PDGFRA', 'Gene', '5156', (10, 16))	('CEBPA', 'Gene', (36, 41))	('PDGFRA', 'Gene', (10, 16))	('ATRX', 'Gene', '546', (18, 22))	('AF', 'Disease', 'MESH:D001281', (65, 67))	('ATRX', 'Gene', (18, 22))	('CEBPA', 'Gene', '1050', (36, 41))	('Indels', 'Var', (0, 6))	('NUP214', 'Gene', (24, 30))
19376	24625776	Examination of the sequencing data for biologically plausible mechanisms of sensitivity to everolimus or pazopanib revealed two mutations in mTOR, the target of everolimus (Figure 2).	('pazopanib', 'Chemical', 'MESH:C516667', (105, 114))	('mTOR', 'Gene', '2475', (141, 145))	('mTOR', 'Gene', (141, 145))	('mutations', 'Var', (128, 137))	('everolimus', 'Chemical', 'MESH:D000068338', (91, 101))	('everolimus', 'Chemical', 'MESH:D000068338', (161, 171))
19377	24625776	Although 96 somatic nonsynonymous mutations in mTOR have been reported in the COSMIC database to date, neither mutation identified in this patient has been previously reported in human cancer.	('human', 'Species', '9606', (179, 184))	('nonsynonymous mutations', 'Var', (20, 43))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mTOR', 'Gene', '2475', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('mTOR', 'Gene', (47, 51))	('cancer', 'Disease', (185, 191))	('patient', 'Species', '9606', (139, 146))
19380	24625776	There, a single mutation in Tor2, E2221K, was identified that conferred constitutive activation of TOR.	('E2221K', 'Var', (34, 40))	('Tor2', 'Gene', '853632', (28, 32))	('TOR', 'MPA', (99, 102))	('activation', 'PosReg', (85, 95))	('Tor2', 'Gene', (28, 32))	('E2221K', 'Mutation', 'p.E2221K', (34, 40))
19381	24625776	The homologous mutation in human mTOR, E2419K, was subsequently generated in human cell lines and shown to be constitutively activating through increased kinase activity and hyperactivation of the mTOR pathway.	('increased', 'PosReg', (144, 153))	('mTOR', 'Gene', '2475', (33, 37))	('human', 'Species', '9606', (27, 32))	('mTOR', 'Gene', (197, 201))	('mTOR', 'Gene', (33, 37))	('activating', 'PosReg', (125, 135))	('mTOR', 'Gene', '2475', (197, 201))	('kinase activity', 'MPA', (154, 169))	('E2419K', 'Mutation', 'rs587777900', (39, 45))	('E2419K', 'Var', (39, 45))	('hyperactivation', 'PosReg', (174, 189))	('human', 'Species', '9606', (77, 82))
19385	24625776	In another study of potential hyperactivating mutations in mTOR, 2 FRB mutations, I2017T and A2020V, were shown to enhance kinase activity and cause hyperactivation of the mTOR pathway.	('mTOR', 'Gene', (172, 176))	('hyperactivation', 'PosReg', (149, 164))	('A2020V', 'Mutation', 'p.A2020V', (93, 99))	('mTOR', 'Gene', '2475', (172, 176))	('kinase activity', 'MPA', (123, 138))	('I2017T', 'Var', (82, 88))	('enhance', 'PosReg', (115, 122))	('mTOR', 'Gene', '2475', (59, 63))	('I2017T', 'Mutation', 'p.I2017T', (82, 88))	('A2020V', 'Var', (93, 99))	('mTOR', 'Gene', (59, 63))
19386	24625776	Moreover, a mutant mTOR with both E2419K and I2017T exhibited higher activity of mTOR as compared to each individual mutation.	('I2017T', 'Mutation', 'p.I2017T', (45, 51))	('I2017T', 'Var', (45, 51))	('activity', 'MPA', (69, 77))	('E2419K', 'Var', (34, 40))	('mTOR', 'Gene', '2475', (19, 23))	('mTOR', 'Gene', (19, 23))	('higher', 'PosReg', (62, 68))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))	('E2419K', 'Mutation', 'rs587777900', (34, 40))
19387	24625776	To confirm that these mutations are activating, we assessed them using an established mTOR activity assay.	('mTOR', 'Gene', (86, 90))	('mutations', 'Var', (22, 31))	('mTOR', 'Gene', '2475', (86, 90))
19390	24625776	To determine if these mutations might exert additive activating effects, a variant of mTOR harboring both mutations was generated.	('mTOR', 'Gene', '2475', (86, 90))	('mTOR', 'Gene', (86, 90))	('mutations', 'Var', (22, 31))	('mutations', 'Var', (106, 115))
19392	24625776	The mTOR residues E2014 and E2419 are conserved throughout all eukaryotic TOR genes.	('E2419', 'Var', (28, 33))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('E2014', 'Var', (18, 23))
19394	24625776	Though functional experiments show E2014K and E2419K to be activating mutations, neither make contact with the mTOR activation loop (Figure 3, light yellow) and thus are not likely to directly change its conformation.	('E2014K', 'Mutation', 'rs1057519780', (35, 41))	('mTOR', 'Gene', '2475', (111, 115))	('mTOR', 'Gene', (111, 115))	('E2014K', 'Var', (35, 41))	('E2419K', 'Mutation', 'rs587777900', (46, 52))	('E2419K', 'Var', (46, 52))
19395	24625776	Similarly, neither mutation interfaces directly with bound rapamycin (Figure 3, cyan), and therefore would not be likely to directly alter binding to rapamycin or everolimus.	('mutation', 'Var', (19, 27))	('everolimus', 'Chemical', 'MESH:D000068338', (163, 173))	('interfaces', 'Reg', (28, 38))	('rapamycin', 'Chemical', 'MESH:D020123', (150, 159))	('rapamycin', 'Chemical', 'MESH:D020123', (59, 68))
19396	24625776	To test this, HEK-293T cells overexpressing wildtype or mutant mTOR were treated with rapamycin and the effect on S6K1 phosphorylation was assessed.	('mTOR', 'Gene', (63, 67))	('S6K1', 'Gene', '6198', (114, 118))	('mutant', 'Var', (56, 62))	('S6K1', 'Gene', (114, 118))	('HEK-293T', 'CellLine', 'CVCL:0063', (14, 22))	('mTOR', 'Gene', '2475', (63, 67))	('rapamycin', 'Chemical', 'MESH:D020123', (86, 95))
19397	24625776	As shown in Figure 2C, treatment with 0.1 muM rapamycin completely abrogated S6K1 phosphorylation by both wildtype and mutant mTOR, suggesting that these mutations remain highly sensitive to allosteric inhibition.	('S6K1', 'Gene', '6198', (77, 81))	('rapamycin', 'Chemical', 'MESH:D020123', (46, 55))	('muM', 'Gene', '56925', (42, 45))	('abrogated', 'NegReg', (67, 76))	('muM', 'Gene', (42, 45))	('mTOR', 'Gene', (126, 130))	('mutant', 'Var', (119, 125))	('mTOR', 'Gene', '2475', (126, 130))	('S6K1', 'Gene', (77, 81))
19399	24625776	Taken together, these results are consistent with the notion that the occurrence of two activating mTOR mutations within the same bladder tumor might contribute to an exquisite dependency on mTOR signaling and therefore an exceptional response to mTOR inhibition.	('mutations', 'Var', (104, 113))	('mTOR', 'Gene', (191, 195))	('mTOR', 'Gene', '2475', (191, 195))	('bladder tumor', 'Disease', 'MESH:D001749', (130, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('activating', 'PosReg', (88, 98))	('mTOR', 'Gene', (247, 251))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', '2475', (247, 251))	('bladder tumor', 'Phenotype', 'HP:0009725', (130, 143))	('mTOR', 'Gene', (99, 103))	('bladder tumor', 'Disease', (130, 143))
19401	24625776	While we cannot rule out a direct contribution from pazopanib to the exquisite sensitivity in this patient, the doses of pazopanib required to overcome the effects of these mTOR mutations were more than 100-fold higher than those for rapamycin.	('patient', 'Species', '9606', (99, 106))	('mTOR', 'Gene', '2475', (173, 177))	('pazopanib', 'Chemical', 'MESH:C516667', (121, 130))	('pazopanib', 'Chemical', 'MESH:C516667', (52, 61))	('mTOR', 'Gene', (173, 177))	('rapamycin', 'Chemical', 'MESH:D020123', (234, 243))	('mutations', 'Var', (178, 187))
19403	24625776	Although PDGFRA is a target of pazopanib, the indel identified in this gene (p.Y102fs) was detected at an AF of 2%, and is therefore unlikely to be functionally relevant in this tumor.	('tumor', 'Disease', (178, 183))	('AF', 'Disease', 'MESH:D001281', (106, 108))	('PDGFRA', 'Gene', (9, 15))	('PDGFRA', 'Gene', '5156', (9, 15))	('pazopanib', 'Chemical', 'MESH:C516667', (31, 40))	('p.Y102fs', 'Var', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('p.Y102fs', 'Mutation', 'p.Y102fsX', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
19410	24625776	Whole exome sequencing revealed the presence of 2 simultaneous activating mTOR mutations in the urothelial carcinoma tumor sample, suggesting a biological mechanism for exquisite sensitivity to everolimus in this patient.	('urothelial carcinoma tumor', 'Disease', (96, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('urothelial carcinoma tumor', 'Disease', 'MESH:D009369', (96, 122))	('everolimus', 'Chemical', 'MESH:D000068338', (194, 204))	('patient', 'Species', '9606', (213, 220))	('mTOR', 'Gene', (74, 78))	('activating', 'PosReg', (63, 73))	('mTOR', 'Gene', '2475', (74, 78))	('mutations', 'Var', (79, 88))
19413	24625776	In hamartoma syndromes such as tuberous sclerosis complex and Peutz-Jeghers Syndrome, inactivating mutations in the tumor suppressor genes TSC1, TSC2, and STK11 (LKB1) result in mTOR pathway activation and are targetable by TOR inhibitors.	('tuberous sclerosis', 'Disease', (31, 49))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('STK11', 'Gene', (155, 160))	('mTOR', 'Gene', (178, 182))	('TSC1', 'Gene', (139, 143))	('LKB1', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('hamartoma syndromes', 'Disease', 'MESH:D006222', (3, 22))	('mTOR', 'Gene', '2475', (178, 182))	('STK11', 'Gene', '6794', (155, 160))	('TSC1', 'Gene', '7248', (139, 143))	('hamartoma', 'Phenotype', 'HP:0010566', (3, 12))	('Peutz-Jeghers Syndrome', 'Disease', (62, 84))	('activation', 'PosReg', (191, 201))	('TSC2', 'Gene', '7249', (145, 149))	('hamartoma syndromes', 'Disease', (3, 22))	('inactivating mutations', 'Var', (86, 108))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (31, 49))	('TSC2', 'Gene', (145, 149))	('LKB1', 'Gene', '6794', (162, 166))	('tumor', 'Disease', (116, 121))
19415	24625776	In a recent phase II study of everolimus in chemotherapy refractory urothelial carcinoma, whole genome sequencing of a single patient who had a durable complete remission was found to have somatic TSC1 mutation (along with a somatic NF2 mutation).	('NF2', 'Gene', (233, 236))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (68, 88))	('TSC1', 'Gene', '7248', (197, 201))	('patient', 'Species', '9606', (126, 133))	('NF2', 'Gene', '4771', (233, 236))	('TSC1', 'Gene', (197, 201))	('mutation', 'Var', (202, 210))	('urothelial carcinoma', 'Disease', (68, 88))	('everolimus', 'Chemical', 'MESH:D000068338', (30, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))
19416	24625776	In addition, four of five additional patients with TSC1 mutations experienced tumor shrinkage with everolimus on that trial.	('mutations', 'Var', (56, 65))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('TSC1', 'Gene', '7248', (51, 55))	('everolimus', 'Chemical', 'MESH:D000068338', (99, 109))	('tumor', 'Disease', (78, 83))	('TSC1', 'Gene', (51, 55))
19418	24625776	Here, we describe the first activating mutations in mTOR found in a patient tumor that was exquisitely sensitive to mTOR inhibition.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('patient', 'Species', '9606', (68, 75))	('activating', 'PosReg', (28, 38))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutations', 'Var', (39, 48))	('mTOR', 'Gene', (116, 120))	('mTOR', 'Gene', '2475', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
19419	24625776	One of these constitutively activating mutations, mTORE2419K, had previously been evaluated in human tissue culture based on its homology to an activating mutation observed in yeast.	('human', 'Species', '9606', (95, 100))	('activating', 'PosReg', (28, 38))	('mTORE2419K', 'Var', (50, 60))	('yeast', 'Species', '4932', (176, 181))
19421	24625776	Indeed, very few activating mTOR mutations in human tumors have been described.	('mTOR', 'Gene', '2475', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mTOR', 'Gene', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('human', 'Species', '9606', (46, 51))
19423	24625776	Recurrent mutations include R2505P (N = 4), S2215Y (3), E1799K (2), T1977R (2), L1433S (2), C1483F (2), and L1460P (2).	('E1799K', 'Mutation', 'rs863225264', (56, 62))	('S2215Y', 'Mutation', 'rs587777894', (44, 50))	('L1460P', 'Var', (108, 114))	('L1460P', 'Mutation', 'rs1057519779', (108, 114))	('T1977R', 'Mutation', 'p.T1977R', (68, 74))	('R2505P', 'Mutation', 'rs1057519777', (28, 34))	('R2505P', 'Var', (28, 34))	('L1433S', 'Var', (80, 86))	('S2215Y', 'Var', (44, 50))	('E1799K', 'Var', (56, 62))	('T1977R', 'Var', (68, 74))	('C1483F', 'Mutation', 'rs786205165', (92, 98))	('C1483F', 'Var', (92, 98))	('L1433S', 'SUBSTITUTION', 'None', (80, 86))
19424	24625776	To date, 3 of these mTOR mutations found in human tumors have been shown to be activating in vitro.	('human', 'Species', '9606', (44, 49))	('mutations', 'Var', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('activating', 'MPA', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mTOR', 'Gene', '2475', (20, 24))	('tumors', 'Disease', (50, 56))	('mTOR', 'Gene', (20, 24))
19425	24625776	L1460P was identified as an activating mutation along with E2419K via the aforementioned fission yeast screen.	('fission yeast', 'Species', '4896', (89, 102))	('L1460P', 'Mutation', 'rs1057519779', (0, 6))	('L1460P', 'Var', (0, 6))	('E2419K', 'Mutation', 'rs587777900', (59, 65))	('E2419K', 'Var', (59, 65))
19426	24625776	More recently, additional mutations present in the COSMIC database were tested, and S2215Y and R2505P were shown to be activating in vitro.	('activating', 'MPA', (119, 129))	('S2215Y', 'Var', (84, 90))	('R2505P', 'Mutation', 'rs1057519777', (95, 101))	('R2505P', 'Var', (95, 101))	('S2215Y', 'Mutation', 'rs587777894', (84, 90))
19427	24625776	Notably, all 3 of these mutations remain sensitive to rapamycin exposure in vitro, though clinical information regarding the patients from whom these mutations were isolated is not available.	('sensitive', 'Reg', (41, 50))	('mutations', 'Var', (24, 33))	('rapamycin', 'Chemical', 'MESH:D020123', (54, 63))	('patients', 'Species', '9606', (125, 133))
19428	24625776	An additional mTOR mutation, L2431P, was recently identified in a patient with metastatic renal cell carcinoma and shown to be activating in vitro.	('mTOR', 'Gene', '2475', (14, 18))	('L2431P', 'Var', (29, 35))	('metastatic renal cell carcinoma', 'Disease', (79, 110))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (79, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('activating', 'PosReg', (127, 137))	('patient', 'Species', '9606', (66, 73))	('L2431P', 'Mutation', 'rs1057524044', (29, 35))	('mTOR', 'Gene', (14, 18))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (90, 110))
19432	24625776	Moreover, if the mTOR mutation detected in the renal cell carcinoma was present at a low allelic fraction, a clinical response may not have been apparent.	('mutation', 'Var', (22, 30))	('renal cell carcinoma', 'Disease', (47, 67))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (47, 67))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (47, 67))
19433	24625776	The case described here provides evidence that activating mTOR mutations can confer clinically significant sensitivity to mTOR inhibition.	('mutations', 'Var', (63, 72))	('mTOR', 'Gene', (58, 62))	('mTOR', 'Gene', (122, 126))	('mTOR', 'Gene', '2475', (122, 126))	('activating', 'PosReg', (47, 57))	('mTOR', 'Gene', '2475', (58, 62))
19436	24625776	Systematic functional analysis of mutations in mTOR, as well as other members of the mTOR pathway, may help to identify activating mutations a priori, generating a catalogue of activating mTOR-pathway alterations that may predict sensitivity to mTOR inhibition.	('mutations', 'Var', (131, 140))	('alterations', 'Var', (201, 212))	('mTOR', 'Gene', '2475', (245, 249))	('mTOR', 'Gene', (245, 249))	('mTOR', 'Gene', '2475', (47, 51))	('mTOR', 'Gene', (188, 192))	('activating', 'PosReg', (177, 187))	('mTOR', 'Gene', '2475', (188, 192))	('mTOR', 'Gene', (47, 51))	('mTOR', 'Gene', '2475', (85, 89))	('mTOR', 'Gene', (85, 89))	('mutations', 'Var', (34, 43))
19437	24625776	Furthermore, routine screening of cancer patients for these alterations may help to identify a subset of patients who may respond to targeted therapies against mTOR, including everolimus and other rapamycin analogues as well as direct mTOR kinase inhibitors now in clinical trials.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (105, 113))	('respond', 'Reg', (122, 129))	('mTOR', 'Gene', '2475', (160, 164))	('rapamycin', 'Chemical', 'MESH:D020123', (197, 206))	('mTOR', 'Gene', (235, 239))	('mTOR', 'Gene', (160, 164))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('mTOR', 'Gene', '2475', (235, 239))	('patients', 'Species', '9606', (41, 49))	('cancer', 'Disease', (34, 40))	('alterations', 'Var', (60, 71))	('everolimus', 'Chemical', 'MESH:D000068338', (176, 186))
19442	24625776	It has become increasingly clear that the spectrum of actionable cancer gene alterations exhibits a "long tail" pattern, in which the vast majority of cancer genes are mutated at frequencies of <5% within any given histologic tumor subtype.	('mutated', 'Var', (168, 175))	('long tail', 'Phenotype', 'HP:0002831', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('alterations', 'Var', (77, 88))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Disease', (226, 231))
19459	24625776	Here, we identify two activating mTOR mutations in a patient with exquisite sensitivity to everolimus and pazopanib, suggesting an approach to identifying patients who might benefit most from mTOR inhibitors.	('mTOR', 'Gene', '2475', (33, 37))	('mTOR', 'Gene', '2475', (192, 196))	('patient', 'Species', '9606', (155, 162))	('everolimus', 'Chemical', 'MESH:D000068338', (91, 101))	('mTOR', 'Gene', (33, 37))	('patients', 'Species', '9606', (155, 163))	('mTOR', 'Gene', (192, 196))	('mutations', 'Var', (38, 47))	('activating', 'PosReg', (22, 32))	('patient', 'Species', '9606', (53, 60))	('pazopanib', 'Chemical', 'MESH:C516667', (106, 115))
19540	21210147	Finally, we review the emerging recommendations in screening for patients with germline INI1/SMARCB1 mutations, who are predisposed to the development of rhabdoid tumors, as an example where data on surveillance is scarce, but screening may nonetheless prove important for patient management.	('SMARCB1', 'Gene', (93, 100))	('mutations', 'Var', (101, 110))	('patient', 'Species', '9606', (273, 280))	('INI1', 'Gene', (88, 92))	('INI1', 'Gene', '6598', (88, 92))	('rhabdoid tumors', 'Disease', (154, 169))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (154, 169))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('men', 'Species', '9606', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('patient', 'Species', '9606', (65, 72))	('men', 'Species', '9606', (37, 40))	('patients', 'Species', '9606', (65, 73))	('men', 'Species', '9606', (287, 290))	('SMARCB1', 'Gene', '6598', (93, 100))
19552	21210147	The epigenetic aberrations in BWS and IHH lead to aberrant hypomethylation, and thus overexpression, of IGF2, as well as aberrant hypermethylation and repression, of CDKN1C.	('repression', 'MPA', (151, 161))	('BWS', 'Gene', (30, 33))	('IGF2', 'Gene', (104, 108))	('CDKN1C', 'Gene', (166, 172))	('BWS', 'Gene', '1028', (30, 33))	('overexpression', 'PosReg', (85, 99))	('epigenetic aberrations', 'Var', (4, 26))	('CDKN1C', 'Gene', '1028', (166, 172))	('IGF2', 'Gene', '3481', (104, 108))	('lead to', 'Reg', (42, 49))	('aberrant', 'MPA', (121, 129))	('IHH', 'Phenotype', 'HP:0001528', (38, 41))	('IHH', 'Gene', (38, 41))
19556	21210147	About 5% of patients with sporadic BWS harbor germline mutations in CDKN1C, whereas approximately 40% of familial cases display this defect.	('patients', 'Species', '9606', (12, 20))	('germline mutations', 'Var', (46, 64))	('BWS', 'Gene', (35, 38))	('BWS', 'Gene', '1028', (35, 38))	('CDKN1C', 'Gene', (68, 74))	('CDKN1C', 'Gene', '1028', (68, 74))
19558	21210147	The remaining patients may harbor mutations in novel and as yet unidentified BWS-associated genes, or be genetic mosaics for alterations in known genes linked to this condition.	('BWS', 'Gene', '1028', (77, 80))	('BWS', 'Gene', (77, 80))	('patients', 'Species', '9606', (14, 22))	('harbor', 'Reg', (27, 33))	('mutations', 'Var', (34, 43))
19560	21210147	For example, studies indicate that paternal UPD and abnormalities at one of the imprinting control centers have the highest risk of tumor development, whereas mutations of CDKN1C may not increase a child's risk for malignancy.	('CDKN1C', 'Gene', '1028', (172, 178))	('men', 'Species', '9606', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('mutations', 'Var', (159, 168))	('child', 'Species', '9606', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('malignancy', 'Disease', 'MESH:D009369', (215, 225))	('tumor', 'Disease', (132, 137))	('UPD', 'Disease', (44, 47))	('CDKN1C', 'Gene', (172, 178))	('UPD', 'Disease', 'MESH:D024182', (44, 47))	('malignancy', 'Disease', (215, 225))	('abnormalities', 'Var', (52, 65))
19564	21210147	Apparently unaffected monozygotic twins of children with BWS or IHH should also be screened, as they may have mosaicism that makes the condition difficult to detect.	('BWS', 'Gene', (57, 60))	('BWS', 'Gene', '1028', (57, 60))	('mosaicism', 'Var', (110, 119))	('children', 'Species', '9606', (43, 51))	('IHH', 'Phenotype', 'HP:0001528', (64, 67))	('IHH', 'Gene', (64, 67))
19590	21210147	While VHL is most often familial, approximately 20% of cases are sporadic and caused by new mutations.	('VHL', 'Gene', '7428', (6, 9))	('caused by', 'Reg', (78, 87))	('VHL', 'Gene', (6, 9))	('mutations', 'Var', (92, 101))
19598	21210147	The genetic abnormality responsible for VHL is mutation or deletion of the VHL gene, which resides at chromosome band 3p25.3.	('VHL', 'Gene', (75, 78))	('VHL', 'Gene', (40, 43))	('mutation', 'Var', (47, 55))	('VHL', 'Gene', '7428', (75, 78))	('VHL', 'Gene', '7428', (40, 43))	('deletion', 'Var', (59, 67))
19623	21210147	To facilitate the identification of early stage pheochromocytomas, plasma metanephrines should also be evaluated annually starting at age 5 years, particularly for those whose VHL mutations confer a greater risk for developing this tumor.	('VHL', 'Gene', (176, 179))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (48, 64))	('mutations', 'Var', (180, 189))	('VHL', 'Gene', '7428', (176, 179))	('pheochromocytomas', 'Disease', (48, 65))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('pheochromocytomas', 'Disease', 'MESH:D010673', (48, 65))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (232, 237))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (48, 65))
19645	21210147	Abnormalities in the TP53 gene lead to the production of altered proteins with aberrant transcriptional regulatory capabilities.	('TP53', 'Gene', (21, 25))	('Abnormalities', 'Var', (0, 13))	('transcriptional regulatory', 'MPA', (88, 114))	('production', 'MPA', (43, 53))	('TP53', 'Gene', '7157', (21, 25))
19647	21210147	While TP53 was initially thought to be a typical tumor suppressor in which a second hit is needed to inactivate the remaining normal gene before the cell can progress to malignancy, in many cases this appears not to be true.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('malignancy', 'Disease', 'MESH:D009369', (170, 180))	('malignancy', 'Disease', (170, 180))	('inactivate', 'Var', (101, 111))
19648	21210147	Rather, mutated TP53 often acts in a dominant fashion, probably by directly interfering with the function of the normal protein product of the unmutated allele.	('function of', 'MPA', (97, 108))	('interfering', 'NegReg', (76, 87))	('mutated', 'Var', (8, 15))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))
19650	21210147	The decision of whether to test a pre-symptomatic child for a familial TP53 mutation is itself a difficult one.	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('mutation', 'Var', (76, 84))	('child', 'Species', '9606', (50, 55))
19651	21210147	As there is not yet a generally accepted screening protocol, and little data to show that screening would alter outcomes, there is concern that knowledge of a mutation would lead only to increased anxiety and psychological distress.	('psychological distress', 'CPA', (209, 231))	('mutation', 'Var', (159, 167))	('anxiety', 'Disease', (197, 204))	('increased', 'PosReg', (187, 196))	('anxiety', 'Phenotype', 'HP:0000739', (197, 204))	('anxiety', 'Disease', 'MESH:D001007', (197, 204))
19652	21210147	However, the few studies conducted have not shown increased psychological distress in individuals once they find that they have a mutation compared to how they felt prior to testing, or in patients with LFS compared to other hereditary cancer syndromes.	('hereditary cancer syndromes', 'Disease', (225, 252))	('mutation', 'Var', (130, 138))	('LFS', 'Disease', (203, 206))	('hereditary cancer syndromes', 'Disease', 'MESH:D061325', (225, 252))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('patients', 'Species', '9606', (189, 197))	('LFS', 'Disease', 'MESH:D016864', (203, 206))
19655	21210147	Of these two unrelated children, one was found to have a TP53 mutation, and the other was not.	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))	('children', 'Species', '9606', (23, 31))
19657	21210147	It appears that in some cases the knowledge of the presence of a mutation is less anxiety provoking than the state of not knowing.	('anxiety', 'Disease', 'MESH:D001007', (82, 89))	('mutation', 'Var', (65, 73))	('anxiety', 'Phenotype', 'HP:0000739', (82, 89))	('anxiety', 'Disease', (82, 89))
19668	21210147	15 patients with known TP53 mutations or obligate mutation carrier status underwent whole body and brain FDG-PET/CT evaluation.	('FDG', 'Chemical', 'MESH:D019788', (105, 108))	('patients', 'Species', '9606', (3, 11))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
19679	21210147	EFS appears to be better in patients with gross total resection compared to those who had subtotal resections or biopsies of their tumors.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('gross total resection', 'Var', (42, 63))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('patients', 'Species', '9606', (28, 36))
19681	21210147	The characteristic genetic abnormalities and the primary initiating event for rhabdoid tumors are a mutation and/or deletion of the INI1/SMARCB1 gene located in chromosome band 22q11.2.	('genetic abnormalities', 'Disease', (19, 40))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('rhabdoid tumors', 'Disease', (78, 93))	('deletion', 'Var', (116, 124))	('mutation', 'Var', (100, 108))	('SMARCB1', 'Gene', '6598', (137, 144))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (78, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('SMARCB1', 'Gene', (137, 144))	('INI1', 'Gene', (132, 136))	('INI1', 'Gene', '6598', (132, 136))	('genetic abnormalities', 'Disease', 'MESH:D030342', (19, 40))
19684	21210147	Approximately 35% of patients with rhabdoid tumors have germline INI1/SMARCB1 alterations.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('patients', 'Species', '9606', (21, 29))	('alterations', 'Var', (78, 89))	('rhabdoid tumors', 'Disease', (35, 50))	('INI1', 'Gene', '6598', (65, 69))	('SMARCB1', 'Gene', '6598', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('INI1', 'Gene', (65, 69))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (35, 50))	('SMARCB1', 'Gene', (70, 77))
19687	21210147	Most cases of familial schwannomatosis are associated with germline INI1/SMARCB1 mutations.	('SMARCB1', 'Gene', (73, 80))	('familial schwannomatosis', 'Disease', (14, 38))	('INI1', 'Gene', (68, 72))	('INI1', 'Gene', '6598', (68, 72))	('familial schwannomatosis', 'Disease', 'MESH:C536641', (14, 38))	('mutations', 'Var', (81, 90))	('associated', 'Reg', (43, 53))	('SMARCB1', 'Gene', '6598', (73, 80))
19688	21210147	The penetrance and expressivity of INI1/SMARCB1 abnormalities are under investigation, and may vary with the specific genetic mutation.	('INI1', 'Gene', (35, 39))	('abnormalities', 'Var', (48, 61))	('SMARCB1', 'Gene', '6598', (40, 47))	('SMARCB1', 'Gene', (40, 47))	('INI1', 'Gene', '6598', (35, 39))
19689	21210147	Recommendations for surveillance in patients with germline INI1/SMARCB1 mutations have been developed based on the epidemiology and clinical course of rhabdoid tumors.	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (36, 44))	('SMARCB1', 'Gene', '6598', (64, 71))	('rhabdoid tumors', 'Disease', (151, 166))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (151, 166))	('INI1', 'Gene', (59, 63))	('INI1', 'Gene', '6598', (59, 63))	('SMARCB1', 'Gene', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('men', 'Species', '9606', (5, 8))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
19694	21210147	Although there are as yet no studies to confirm the benefit of screening patients with germline INI1/SMARCB1 mutations, the aggressive natural history of the disease, apparently high penetrance and well-defined age of onset for CNS AT/RT suggest that screening could prove beneficial.	('SMARCB1', 'Gene', '6598', (101, 108))	('AT', 'Disease', 'None', (232, 234))	('SMARCB1', 'Gene', (101, 108))	('INI1', 'Gene', (96, 100))	('INI1', 'Gene', '6598', (96, 100))	('mutations', 'Var', (109, 118))	('patients', 'Species', '9606', (73, 81))
19730	31953726	Even though the rate of previous abdominal surgery was significantly higher for TP [TP: 61 (45.18%) vs. RP: 4 (14%); p = 0.038], the conversion rate was considerably (however, not significantly) higher for RP [TP: 6 (4.44%) vs. RP: 5 (18%); p = 0.257] (Table 2).	('RP [TP', 'Var', (206, 212))	('TP', 'Chemical', '-', (210, 212))	('TP', 'Chemical', '-', (80, 82))	('TP', 'Chemical', '-', (84, 86))	('higher', 'PosReg', (195, 201))	('TP [', 'Var', (80, 84))	('conversion', 'MPA', (133, 143))
19804	32414619	The etiology of endogenous CS involves either an ACTH-dependent source, most commonly pituitary adenomas (PAs), described as Cushing disease (CD), or less often ectopic CRH and/or ACTH secretion, or ACTH-independent (adrenal-related) hypercortisolemia (Table 1).	('hypercortisolemia', 'Disease', (234, 251))	('pituitary adenomas', 'Disease', 'MESH:D010911', (86, 104))	('hypercortisolemia', 'Disease', 'None', (234, 251))	('CD', 'Phenotype', 'HP:0003118', (142, 144))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (86, 104))	('ectopic', 'Var', (161, 168))	('pituitary adenomas', 'Disease', (86, 104))	('CS', 'Gene', '1431', (27, 29))	('ACTH', 'Gene', (49, 53))	('ACTH', 'Gene', '5443', (180, 184))	('Cushing disease', 'Disease', (125, 140))	('Cushing disease', 'Disease', 'MESH:D047748', (125, 140))	('CRH', 'Gene', '1392', (169, 172))	('ACTH', 'Gene', (199, 203))	('CS', 'Phenotype', 'HP:0003118', (27, 29))	('ACTH', 'Gene', '5443', (49, 53))	('ACTH', 'Gene', (180, 184))	('CRH', 'Gene', (169, 172))	('Cushing disease', 'Phenotype', 'HP:0003118', (125, 140))	('PAs', 'Phenotype', 'HP:0002893', (106, 109))	('ACTH', 'Gene', '5443', (199, 203))
19808	32414619	On the other hand, germline gene defects in patients with ACTH-independent CS may explain more than half of cases depending on the subtype of adrenal pathology identified.	('ACTH', 'Gene', '5443', (58, 62))	('patients', 'Species', '9606', (44, 52))	('CS', 'Gene', '1431', (75, 77))	('ACTH', 'Gene', (58, 62))	('CS', 'Phenotype', 'HP:0003118', (75, 77))	('germline', 'Var', (19, 27))
19809	32414619	In either case, several lessons can be taught by the gene defects found about the possible pathways that may be affected and lead to hypercortisolemia.	('hypercortisolemia', 'Disease', 'None', (133, 150))	('hypercortisolemia', 'Disease', (133, 150))	('lead to', 'Reg', (125, 132))	('gene defects', 'Var', (53, 65))
19811	32414619	Other genomic mechanisms potentially involved in pathogenesis of CS, such as variable expression of components of certain pathways, methylation changes or miRNA changes, also contribute to the genetic background of CS.	('CS', 'Phenotype', 'HP:0003118', (215, 217))	('CS', 'Gene', '1431', (215, 217))	('contribute', 'Reg', (175, 185))	('expression', 'MPA', (86, 96))	('miRNA changes', 'MPA', (155, 168))	('CS', 'Phenotype', 'HP:0003118', (65, 67))	('CS', 'Gene', '1431', (65, 67))	('methylation changes', 'Var', (132, 151))
19818	32414619	Only few case reports of ACTH-secreting PAs have been reporting in the context of the other MEN syndromes, types 2 and 4 (MEN2 and MEN4, respectively): RET [MEN2A (OMIM#171400) and MEN2B (OMIM#162300)] and CDKN1B gene mutations [MEN4 (OMIM#610755)] suggesting that these syndromes play a less important role in pituitary tumorigenesis.	('MEN2A', 'Gene', (157, 162))	('CD', 'Phenotype', 'HP:0003118', (206, 208))	('RET', 'Gene', '5979', (152, 155))	('PAs', 'Phenotype', 'HP:0002893', (40, 43))	('MEN', 'Species', '9606', (122, 125))	('ACTH', 'Gene', (25, 29))	('tumor', 'Disease', (321, 326))	('CDKN1B', 'Gene', '1027', (206, 212))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('RET', 'Gene', (152, 155))	('MEN', 'Species', '9606', (229, 232))	('MEN', 'Species', '9606', (157, 160))	('MEN', 'Species', '9606', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('ACTH', 'Gene', '5443', (25, 29))	('MEN', 'Species', '9606', (92, 95))	('MEN2B', 'Gene', (181, 186))	('CDKN1B', 'Gene', (206, 212))	('MEN2B', 'Gene', '5979', (181, 186))	('mutations', 'Var', (218, 227))	('MEN', 'Species', '9606', (131, 134))	('MEN2A', 'Gene', '5979', (157, 162))
19827	32414619	Fifteen percent of patients carry an aryl hydrocarbon receptor-interacting protein (AIP) gene mutation.	('patients', 'Species', '9606', (19, 27))	('aryl hydrocarbon receptor-interacting protein', 'Gene', '9049', (37, 82))	('aryl hydrocarbon receptor-interacting protein', 'Gene', (37, 82))	('AIP', 'Gene', '9049', (84, 87))	('AIP', 'Gene', (84, 87))	('mutation', 'Var', (94, 102))
19829	32414619	Thus, AIP gene defects cause increased cAMP production leading to aberrant cell proliferation.	('cAMP', 'Chemical', '-', (39, 43))	('increased', 'PosReg', (29, 38))	('defects', 'Var', (15, 22))	('AIP', 'Gene', '9049', (6, 9))	('AIP', 'Gene', (6, 9))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (66, 93))	('cAMP production', 'MPA', (39, 54))	('cell proliferation', 'CPA', (75, 93))
19831	32414619	Only few patients with CD and AIP mutations have been reported in either familial or sporadic cases, with the youngest patient presenting at 6 years of age.	('patients', 'Species', '9606', (9, 17))	('patient', 'Species', '9606', (119, 126))	('AIP', 'Gene', '9049', (30, 33))	('AIP', 'Gene', (30, 33))	('CD', 'Phenotype', 'HP:0003118', (23, 25))	('patient', 'Species', '9606', (9, 16))	('mutations', 'Var', (34, 43))
19834	32414619	CNC is caused by mutations of the PRKAR1A gene in 70% of cases, whereas a second locus on chromosome 2p16 has been identified for some of the remaining cases.	('CNC', 'Disease', (0, 3))	('PRKAR1A', 'Gene', (34, 41))	('caused by', 'Reg', (7, 16))	('mutations', 'Var', (17, 26))	('PRKAR1A', 'Gene', '5573', (34, 41))
19835	32414619	PRKAR1A encodes the type 1 alpha regulatory subunit of the protein kinase A (PKA), and gene defects lead to increased free catalytic subunits which lead to increased downstream activity of PKA.	('PKA', 'Enzyme', (189, 192))	('downstream activity', 'MPA', (166, 185))	('increased', 'PosReg', (108, 117))	('PRKAR1A', 'Gene', (0, 7))	('free catalytic subunits', 'MPA', (118, 141))	('increased', 'PosReg', (156, 165))	('defects', 'Var', (92, 99))	('PRKAR1A', 'Gene', '5573', (0, 7))
19839	32414619	More recently, two cases of corticotropinomas in patients with pathogenic variants in PRKAR1A have been reported, expanding the spectrum of the known pituitary involvement in CNC, previously limited to growth hormone and/or prolactin secreting PAs and somato(mamo)troph hyperplasia.	('corticotropinomas', 'Disease', (28, 45))	('corticotropinomas', 'Disease', 'None', (28, 45))	('prolactin', 'Gene', (224, 233))	('prolactin', 'Gene', '5617', (224, 233))	('somato(mamo)troph hyperplasia', 'Disease', 'MESH:D006965', (252, 281))	('PRKAR1A', 'Gene', (86, 93))	('growth hormone', 'Gene', (202, 216))	('patients', 'Species', '9606', (49, 57))	('variants', 'Var', (74, 82))	('PRKAR1A', 'Gene', '5573', (86, 93))	('PAs', 'Phenotype', 'HP:0002893', (244, 247))	('growth hormone', 'Gene', '2688', (202, 216))
19844	32414619	Of note, few cases of corticotropinomas with somatic mutations or amplifications of PIK3CA, another component of the mTOR/PI3K/Akt pathway, have been reported especially in more aggressive tumors.	('PIK3CA', 'Gene', '5290', (84, 90))	('reported', 'Reg', (150, 158))	('mTOR', 'Gene', (117, 121))	('mTOR', 'Gene', '2475', (117, 121))	('amplifications', 'Var', (66, 80))	('Akt', 'Gene', '207', (127, 130))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('aggressive tumors', 'Disease', 'MESH:D001523', (178, 195))	('corticotropinomas', 'Disease', (22, 39))	('corticotropinomas', 'Disease', 'None', (22, 39))	('PIK3CA', 'Gene', (84, 90))	('Akt', 'Gene', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('aggressive tumors', 'Disease', (178, 195))
19853	32414619	Somatic mutations of b-catenin gene (CTNNB1) explain up to half of the these cases where Wnt signaling is found increased.	('b-catenin', 'Gene', '1499', (21, 30))	('mutations', 'Var', (8, 17))	('CTNNB1', 'Gene', '1499', (37, 43))	('b-catenin', 'Gene', (21, 30))	('CTNNB1', 'Gene', (37, 43))
19855	32414619	Inactivation of APC has been reported in cases of adrenocortical adenomas and hyperplasia.	('APC', 'Disease', 'MESH:D011125', (16, 19))	('reported', 'Reg', (29, 37))	('hyperplasia', 'Disease', (78, 89))	('hyperplasia', 'Disease', 'MESH:D006965', (78, 89))	('adenomas', 'Disease', 'MESH:D000236', (65, 73))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (50, 73))	('adenomas', 'Disease', (65, 73))	('Inactivation', 'Var', (0, 12))	('APC', 'Disease', (16, 19))
19859	32414619	MAS is caused by postzygotic somatic mutations of the GNAS gene, which codes for the Gsa subunit of G-protein coupled receptor, leading to constitutive activation and increased intracellular cAMP.	('cAMP', 'Chemical', '-', (191, 195))	('MAS', 'Disease', (0, 3))	('GNAS', 'Gene', (54, 58))	('caused', 'Reg', (7, 13))	('Gsa', 'Gene', (85, 88))	('mutations', 'Var', (37, 46))	('increased', 'PosReg', (167, 176))	('constitutive activation', 'MPA', (139, 162))	('GNAS', 'Gene', '2778', (54, 58))	('intracellular cAMP', 'MPA', (177, 195))	('Gsa', 'Gene', '2778', (85, 88))
19865	32414619	They further identified DICER1 variants in the available samples, with or without loss of heterozygosity at the tumor level.	('DICER1', 'Gene', '23405', (24, 30))	('variants', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('DICER1', 'Gene', (24, 30))
19869	32414619	Most of the cases of ectopic CS with an identified genetic cause correspond to MEN1 or RET gene mutations.	('MEN1', 'Gene', '4221', (79, 83))	('MEN1', 'Gene', (79, 83))	('RET', 'Gene', '5979', (87, 90))	('correspond', 'Reg', (65, 75))	('RET', 'Gene', (87, 90))	('CS', 'Phenotype', 'HP:0003118', (29, 31))	('CS', 'Gene', '1431', (29, 31))	('mutations', 'Var', (96, 105))
19870	32414619	Some additional causes of ectopic CS that have been reported in the literature include BRAF and TP53 mutations, in neuroendocrine tumors of the colon, and a case report of ectopic CS in the context of a pancreatic neuroendocrine tumor in a patient with VHL mutation.	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('VHL', 'Gene', (253, 256))	('CS', 'Gene', '1431', (34, 36))	('patient', 'Species', '9606', (240, 247))	('CS', 'Phenotype', 'HP:0003118', (180, 182))	('BRAF', 'Gene', '673', (87, 91))	('BRAF', 'Gene', (87, 91))	('neuroendocrine tumors of the colon', 'Disease', (115, 149))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (115, 135))	('VHL', 'Gene', '7428', (253, 256))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (115, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumors of the colon', 'Phenotype', 'HP:0100273', (130, 149))	('pancreatic neuroendocrine tumor', 'Disease', 'MESH:D018358', (203, 234))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', (96, 100))	('CS', 'Phenotype', 'HP:0003118', (34, 36))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ectopic', 'Disease', (26, 33))	('pancreatic neuroendocrine tumor', 'Disease', (203, 234))	('CS', 'Gene', '1431', (180, 182))	('neuroendocrine tumors of the colon', 'Disease', 'MESH:D018358', (115, 149))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (203, 234))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (214, 234))	('TP53', 'Gene', '7157', (96, 100))
19872	32414619	In 2015, two independent groups reported somatic variants in the USP8 gene in corticotropinomas.	('variants', 'Var', (49, 57))	('corticotropinomas', 'Disease', (78, 95))	('corticotropinomas', 'Disease', 'None', (78, 95))	('USP8', 'Gene', (65, 69))	('USP8', 'Gene', '9101', (65, 69))
19874	32414619	Since then additional groups have reported a frequency of 20-60% of USP8 mutations in CD, and have studied potential implication in patient prognosis, with some reporting a more aggressive behavior of these tumors.	('USP8', 'Gene', (68, 72))	('aggressive behavior', 'CPA', (178, 197))	('USP8', 'Gene', '9101', (68, 72))	('CD', 'Phenotype', 'HP:0003118', (86, 88))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('aggressive behavior', 'Phenotype', 'HP:0000718', (178, 197))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('patient', 'Species', '9606', (132, 139))	('mutations', 'Var', (73, 82))
19875	32414619	Recently, Cohen et al reported the first patient with a germline USP8 gene defect.	('patient', 'Species', '9606', (41, 48))	('USP8', 'Gene', '9101', (65, 69))	('defect', 'Var', (75, 81))	('USP8', 'Gene', (65, 69))
19877	32414619	USP8-negative corticotropinomas have been recently linked to somatic variants in other genes of the MAPK pathway (USP48 and BRAF), which may explain up to 20% of all cases.	('corticotropinomas', 'Disease', (14, 31))	('corticotropinomas', 'Disease', 'None', (14, 31))	('USP48', 'Gene', (114, 119))	('linked', 'Reg', (51, 57))	('variants', 'Var', (69, 77))	('BRAF', 'Gene', '673', (124, 128))	('USP48', 'Gene', '84196', (114, 119))	('USP8', 'Gene', (0, 4))	('USP8', 'Gene', '9101', (0, 4))	('BRAF', 'Gene', (124, 128))
19879	32414619	ARMC5 gene defects were identified in 55% of all cases.	('ARMC5', 'Gene', '79798', (0, 5))	('defects', 'Var', (11, 18))	('ARMC5', 'Gene', (0, 5))
19880	32414619	Biallelic inactivation was present in all cases, with patients carrying a germline mutation and a second "hit" (another inactivating variant or deletion at the other allele) occurring at the tumor level.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('patients', 'Species', '9606', (54, 62))	('deletion', 'Var', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))
19882	32414619	The description of PRKAR1A gene defects in adrenal CS and the involvement of abnormal cAMP-PKA activity in several adrenal disorders leading to excess cortisol production, led to identification of additional genes of the cAMP-PKA pathway which are causative or contributory to adrenal-related hypercortisolemia.	('PRKAR1A', 'Gene', (19, 26))	('adrenal-related hypercortisolemia', 'Phenotype', 'HP:0011744', (277, 310))	('adrenal disorders', 'Disease', 'MESH:D000310', (115, 132))	('adrenal CS', 'Disease', (43, 53))	('defects', 'Var', (32, 39))	('cortisol', 'Chemical', 'MESH:D006854', (151, 159))	('PRKAR1A', 'Gene', '5573', (19, 26))	('excess', 'PosReg', (144, 150))	('adrenal disorders', 'Disease', (115, 132))	('excess cortisol', 'Phenotype', 'HP:0003118', (144, 159))	('hypercortisolemia', 'Disease', 'None', (293, 310))	('involvement', 'Reg', (62, 73))	('CS', 'Phenotype', 'HP:0003118', (51, 53))	('cAMP', 'Chemical', '-', (221, 225))	('cortisol production', 'MPA', (151, 170))	('cortisol', 'Chemical', 'MESH:D006854', (298, 306))	('adrenal CS', 'Disease', 'MESH:D006223', (43, 53))	('hypercortisolemia', 'Disease', (293, 310))	('adrenal disorders', 'Phenotype', 'HP:0000834', (115, 132))	('cAMP', 'Chemical', '-', (86, 90))
19883	32414619	PDE11A (and possibly PDE8B) mutations contribute to a variety of pathologic adrenal lesions.	('PDE8B', 'Gene', (21, 26))	('adrenal lesions', 'Disease', 'MESH:D000312', (76, 91))	('PDE8B', 'Gene', '8622', (21, 26))	('PDE11A', 'Gene', (0, 6))	('PDE11A', 'Gene', '50940', (0, 6))	('contribute to', 'Reg', (38, 51))	('adrenal lesions', 'Disease', (76, 91))	('mutations', 'Var', (28, 37))
19884	32414619	Phosphodiesterases (PDEs) are enzymes involved in the hydrolysis of cAMP and defects in these genes lead to increased levels of cAMP and aberrant PKA signaling (Figure 1).	('PDEs', 'Gene', '50940', (20, 24))	('cAMP', 'Chemical', '-', (68, 72))	('levels', 'MPA', (118, 124))	('increased', 'PosReg', (108, 117))	('defects', 'Var', (77, 84))	('PDEs', 'Gene', (20, 24))	('Phosphodiesterases', 'Gene', (0, 18))	('cAMP', 'Chemical', '-', (128, 132))	('Phosphodiesterases', 'Gene', '50940', (0, 18))
19885	32414619	Amplifications and activating mutations of the PRKACA gene, coding for the C alpha catalytic subunit of PKA, have also been involved in the pathogenesis of adrenal CS, caused by either isolated cortisol producing adenomas (CPAs) or adrenocortical hyperplasia.	('activating', 'PosReg', (19, 29))	('caused', 'Reg', (168, 174))	('PRKACA', 'Gene', '5566', (47, 53))	('adrenal CS', 'Disease', (156, 166))	('cortisol', 'Chemical', 'MESH:D006854', (194, 202))	('adrenocortical hyperplasia', 'Disease', (232, 258))	('adrenal CS', 'Disease', 'MESH:D006223', (156, 166))	('CS', 'Phenotype', 'HP:0003118', (164, 166))	('adenomas', 'Disease', (213, 221))	('Amplifications', 'Var', (0, 14))	('mutations', 'Var', (30, 39))	('involved', 'Reg', (124, 132))	('adrenocortical hyperplasia', 'Disease', 'MESH:D006965', (232, 258))	('adenomas', 'Disease', 'MESH:D000236', (213, 221))	('PAs', 'Phenotype', 'HP:0002893', (224, 227))	('PRKACA', 'Gene', (47, 53))
19886	32414619	After initial reports of rare TP53 mutations in PAs and their association mainly with aggressive tumors, a recent study and metanalysis of corticotropinomas changed this assumption and reported that up to 12% of tumors may have a somatic TP53 mutation.	('mutation', 'Var', (243, 251))	('association', 'Interaction', (62, 73))	('aggressive tumors', 'Disease', (86, 103))	('tumors', 'Disease', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('PAs', 'Phenotype', 'HP:0002893', (48, 51))	('aggressive tumors', 'Disease', 'MESH:D001523', (86, 103))	('TP53', 'Gene', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('TP53', 'Gene', '7157', (238, 242))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumors', 'Disease', (212, 218))	('corticotropinomas', 'Disease', 'None', (139, 156))	('corticotropinomas', 'Disease', (139, 156))	('TP53', 'Gene', '7157', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('TP53', 'Gene', (238, 242))	('mutations', 'Var', (35, 44))
19887	32414619	Authors reported TP53 mutations in 33% of USP8-negative tumors and hypothesized that p53 protein is important for regulation of apoptosis (one of the main pathways affected in corticotropinomas) or the BRCA1 mediated DNA-repair in corticotroph cells.	('BRCA1', 'Gene', '672', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('corticotropinomas', 'Disease', (176, 193))	('USP8', 'Gene', '9101', (42, 46))	('corticotropinomas', 'Disease', 'None', (176, 193))	('BRCA1', 'Gene', (202, 207))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (22, 31))	('p53', 'Gene', (85, 88))	('TP53', 'Gene', '7157', (17, 21))	('p53', 'Gene', '7157', (85, 88))	('USP8', 'Gene', (42, 46))	('TP53', 'Gene', (17, 21))
19894	32414619	Although ectopic GIP receptors (GIPRs) in adrenal tumor cells were described many years ago, it was in 2017 when researchers identified the genetic basis of this rare variant of adrenal CS, and reported somatic duplications in chromosome 19q13.3 containing GIPR gene in 3 patients with food-dependent CS.	('CS', 'Gene', '1431', (186, 188))	('GIP', 'Gene', '2695', (32, 35))	('GIP', 'Gene', (17, 20))	('adrenal tumor', 'Disease', (42, 55))	('GIP', 'Gene', (32, 35))	('duplications', 'Var', (211, 223))	('GIPR', 'Gene', (32, 36))	('GIPR', 'Gene', '2696', (257, 261))	('adrenal CS', 'Disease', (178, 188))	('adrenal tumor', 'Phenotype', 'HP:0100631', (42, 55))	('CS', 'Phenotype', 'HP:0003118', (186, 188))	('CS', 'Gene', '1431', (301, 303))	('adrenal tumor', 'Disease', 'MESH:D000310', (42, 55))	('GIP', 'Gene', '2695', (257, 260))	('patients', 'Species', '9606', (272, 280))	('GIPR', 'Gene', '2696', (32, 36))	('GIP', 'Gene', (257, 260))	('GIP', 'Gene', '2695', (17, 20))	('GIPR', 'Gene', (257, 261))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('adrenal CS', 'Disease', 'MESH:D006223', (178, 188))	('CS', 'Phenotype', 'HP:0003118', (301, 303))
19903	32414619	On the other hand, germline gene defects in patients with ACTH-independent CS may explain high percentage of cases depending on the subtype of adrenal pathology identified.	('ACTH', 'Gene', '5443', (58, 62))	('patients', 'Species', '9606', (44, 52))	('CS', 'Gene', '1431', (75, 77))	('ACTH', 'Gene', (58, 62))	('CS', 'Phenotype', 'HP:0003118', (75, 77))	('germline', 'Var', (19, 27))
19906	32414619	Additional genomic mechanisms, such as methylation and miRNA changes, potentially contribute to the pathogenesis or the variable phenotype of patients with CS.	('methylation', 'Var', (39, 50))	('CS', 'Gene', '1431', (156, 158))	('contribute', 'Reg', (82, 92))	('miRNA changes', 'MPA', (55, 68))	('patients', 'Species', '9606', (142, 150))	('CS', 'Phenotype', 'HP:0003118', (156, 158))
19924	31945643	Despite the success of third generation aromatase inhibitors for the treatment of breast cancer, in approximately one third of patients diagnosed with metastatic ER+ breast cancer, therapies involving these drugs lead to the mutation of the ER gene, resulting in a treatment-resistant cancer that is often incurable.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('ER', 'Gene', '2069', (162, 164))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('cancer', 'Disease', (89, 95))	('aromatase', 'Gene', '1588', (40, 49))	('breast cancer', 'Disease', (166, 179))	('mutation', 'Var', (225, 233))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('ER', 'Gene', '2069', (241, 243))	('cancer', 'Disease', (285, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('cancer', 'Disease', (173, 179))	('aromatase', 'Gene', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('breast cancer', 'Disease', (82, 95))	('lead to', 'Reg', (213, 220))	('patients', 'Species', '9606', (127, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
19949	31945643	For instance, the ruthenium (III) complex KP1339 did not only show cytotoxicity in different in vivo tumor models (more specifically in colon cancer) in preclinical studies, but was also found to stabilize the disease in clinical studies involving cancer patients while only inducing mild side effects.	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cytotoxicity', 'Disease', (67, 79))	('KP1339', 'Chemical', 'MESH:C551585', (42, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (136, 148))	('tumor', 'Disease', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('patients', 'Species', '9606', (255, 263))	('KP1339', 'Var', (42, 48))	('cytotoxicity', 'Disease', 'MESH:D064420', (67, 79))	('ruthenium (III)', 'Chemical', '-', (18, 33))	('stabilize', 'Reg', (196, 205))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('cancer', 'Disease', (142, 148))
20135	21990323	In thyroid cancer cells, functional knockdown of CDC23 resulted in an increase in the number of cells in both the S and G2M phases of the cell cycle, and an inhibition of cellular proliferation, tumor spheroid formation, and anchorage-independent growth.	('anchorage-independent growth', 'CPA', (225, 253))	('tumor', 'Disease', (195, 200))	('increase', 'PosReg', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CDC23', 'Gene', (49, 54))	('thyroid cancer', 'Disease', 'MESH:D013964', (3, 17))	('knockdown', 'Var', (36, 45))	('cellular proliferation', 'CPA', (171, 193))	('inhibition', 'NegReg', (157, 167))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('thyroid cancer', 'Disease', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('thyroid cancer', 'Phenotype', 'HP:0002890', (3, 17))
20136	21990323	Cellular arrest in both S and G2M phases was associated with significant cyclin B1 and securin protein accumulation after CDC23 knockdown.	('cyclin B1', 'Protein', (73, 82))	('securin protein', 'Protein', (87, 102))	('arrest', 'Disease', 'MESH:D006323', (9, 15))	('knockdown', 'Var', (128, 137))	('G2M phases', 'CPA', (30, 40))	('accumulation', 'PosReg', (103, 115))	('arrest', 'Disease', (9, 15))	('CDC23', 'Gene', (122, 127))
20161	21990323	Human PTC cell line (TPC-1) and follicular thyroid cancer cell line (FTC-133) were maintained in DMEM supplemented with 10% FCS, penicillin (100 U/ml), streptomycin (100 mug/ml), fungizone (250 ng/ml), TSH (10 IU/l), and insulin (10 mug/ml) in a 5% CO2 atmosphere at 37  C. The human breast cancer cell line, MCF-7, was maintained in DMEM supplemented with 10% FCS, penicillin (100 U/ml), streptomycin (100 mug/ml), and fungizone (250 ng/ml).	('Human', 'Species', '9606', (0, 5))	('insulin', 'Gene', (221, 228))	('CO2', 'Chemical', 'MESH:D002245', (249, 252))	('breast cancer', 'Phenotype', 'HP:0003002', (284, 297))	('MCF-7', 'CellLine', 'CVCL:0031', (309, 314))	('penicillin', 'Chemical', 'MESH:D010406', (366, 376))	('penicillin', 'Chemical', 'MESH:D010406', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('follicular thyroid cancer', 'Disease', 'MESH:C572845', (32, 57))	('men', 'Species', '9606', (345, 348))	('fungizone', 'Chemical', 'MESH:D000666', (420, 429))	('breast cancer', 'Disease', 'MESH:D001943', (284, 297))	('100 mug/ml', 'Var', (403, 413))	('TPC-1', 'Gene', '53373', (21, 26))	('breast cancer', 'Disease', (284, 297))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (32, 57))	('human', 'Species', '9606', (278, 283))	('fungizone', 'Chemical', 'MESH:D000666', (179, 188))	('streptomycin', 'Chemical', 'MESH:D013307', (389, 401))	('insulin', 'Gene', '3630', (221, 228))	('streptomycin', 'Chemical', 'MESH:D013307', (152, 164))	('PTC', 'Gene', (6, 9))	('100 U/ml', 'Var', (378, 386))	('thyroid cancer', 'Phenotype', 'HP:0002890', (43, 57))	('TPC-1', 'Gene', (21, 26))	('PTC', 'Gene', '5979', (6, 9))	('PTC', 'Phenotype', 'HP:0002895', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('follicular thyroid cancer', 'Disease', (32, 57))	('men', 'Species', '9606', (108, 111))
20168	21990323	The small interfering (si)RNA for human CDC23 (siRNA ID- s16570 and s16572) and scrambled negative controls (Part #: 4390843) were purchased from Applied Biosystems.	('CDC23', 'Gene', (40, 45))	('human', 'Species', '9606', (34, 39))	('s16572', 'Var', (68, 74))
20198	21990323	We also found no significant association between CDC23 mRNA expression and other clinicopathologic variables or by common somatic mutation status (14 wild type, 15 BRAF V600E, and 5 RET/PTC3).	('V600E', 'Mutation', 'rs113488022', (169, 174))	('CDC23', 'Gene', (49, 54))	('RET', 'Gene', (182, 185))	('PTC', 'Phenotype', 'HP:0002895', (186, 189))	('PTC3', 'Gene', '8031', (186, 190))	('V600E', 'Var', (169, 174))	('BRAF', 'Gene', '673', (164, 168))	('mRNA expression', 'MPA', (55, 70))	('RET', 'Gene', '5979', (182, 185))	('BRAF', 'Gene', (164, 168))	('PTC3', 'Gene', (186, 190))
20199	21990323	Even though, we did not see a difference in the tissue samples, we also tested the idea of whether activating mutation in the MAPK pathways that are common in PTC may modulate CDC23 mRNA expression.	('activating', 'PosReg', (99, 109))	('PTC', 'Phenotype', 'HP:0002895', (159, 162))	('MAPK', 'Gene', (126, 130))	('CDC23 mRNA expression', 'MPA', (176, 197))	('modulate', 'Reg', (167, 175))	('mutation', 'Var', (110, 118))	('PTC', 'Gene', (159, 162))	('tested', 'Reg', (72, 78))	('PTC', 'Gene', '5979', (159, 162))
20211	21990323	SiRNA directed CDC23 knockdown was performed in thyroid cancer cell lines (TPC-1 and FTC-133) and qRT-PCR and immunoblot were used to confirm good CDC23 knockdown (Fig.	('CDC23', 'Gene', (147, 152))	('knockdown', 'Var', (153, 162))	('TPC-1', 'Gene', (75, 80))	('thyroid cancer', 'Disease', 'MESH:D013964', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('TPC-1', 'Gene', '53373', (75, 80))	('thyroid cancer', 'Phenotype', 'HP:0002890', (48, 62))	('thyroid cancer', 'Disease', (48, 62))
20212	21990323	CDC23 knockdown dramatically inhibited thyroid cancer cell growth (Fig.	('inhibited', 'NegReg', (29, 38))	('thyroid cancer', 'Phenotype', 'HP:0002890', (39, 53))	('thyroid cancer', 'Disease', (39, 53))	('thyroid cancer', 'Disease', 'MESH:D013964', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('knockdown', 'Var', (6, 15))	('CDC23', 'Gene', (0, 5))
20215	21990323	In TPC-1 cells, CDC23 knockdown increased the percentage of Annexin V positive cells moderately (3-10%) after 5 days of transfection.	('Annexin V', 'Gene', (60, 69))	('knockdown', 'Var', (22, 31))	('TPC-1', 'Gene', (3, 8))	('CDC23', 'Gene', (16, 21))	('increased', 'PosReg', (32, 41))	('TPC-1', 'Gene', '53373', (3, 8))	('Annexin V', 'Gene', '308', (60, 69))
20216	21990323	Given the profound effect of CDC23 on thyroid cancer cell proliferation and cell cycle progression and the previous observation in yeast that mutations in APC genes lead to abnormal levels of cell cycle regulatory proteins, especially the B-type cyclins, we explored the idea that cyclin B1 may be a substrate of CDC23 protein.	('APC genes', 'Gene', (155, 164))	('abnormal levels of cell cycle regulatory proteins', 'MPA', (173, 222))	('mutations', 'Var', (142, 151))	('thyroid cancer', 'Disease', 'MESH:D013964', (38, 52))	('lead to', 'Reg', (165, 172))	('effect', 'Reg', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('B-type cyclins', 'MPA', (239, 253))	('thyroid cancer', 'Phenotype', 'HP:0002890', (38, 52))	('thyroid cancer', 'Disease', (38, 52))	('yeast', 'Species', '4932', (131, 136))
20217	21990323	In both FTC-133 and TPC-1 cells, CDC23 knockdown resulted in a dramatic buildup of cyclin B1 protein, starting 3 days after transfection (Fig.	('cyclin', 'Protein', (83, 89))	('buildup', 'PosReg', (72, 79))	('knockdown', 'Var', (39, 48))	('TPC-1', 'Gene', (20, 25))	('TPC-1', 'Gene', '53373', (20, 25))	('CDC23', 'Gene', (33, 38))
20244	21990323	We found dramatic inhibition of cell growth, anchorage-independent growth, and tumor spheroid formation with cell cycle arrest as a result of CDC23 knockdown in thyroid cancer cells.	('arrest', 'Disease', (120, 126))	('inhibition', 'NegReg', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('thyroid cancer', 'Disease', 'MESH:D013964', (161, 175))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (109, 126))	('cell growth', 'CPA', (32, 43))	('CDC23', 'Gene', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('anchorage-independent growth', 'CPA', (45, 73))	('arrest', 'Disease', 'MESH:D006323', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('thyroid cancer', 'Phenotype', 'HP:0002890', (161, 175))	('thyroid cancer', 'Disease', (161, 175))	('knockdown', 'Var', (148, 157))
20246	21990323	Given the profound effect of CDC23 on thyroid cancer cell proliferation and cell cycle progression, and the observation that alterations in APC genes lead to abnormal levels of cell cycle regulatory proteins, we explored the idea that cyclin B1 and securin may be a substrate of CDC23 protein and mediate its function.	('thyroid cancer', 'Disease', 'MESH:D013964', (38, 52))	('abnormal levels of cell cycle regulatory proteins', 'MPA', (158, 207))	('CDC23', 'Gene', (279, 284))	('alterations', 'Var', (125, 136))	('lead', 'Reg', (150, 154))	('effect', 'Reg', (19, 25))	('CDC23', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('APC genes', 'Gene', (140, 149))	('thyroid cancer', 'Phenotype', 'HP:0002890', (38, 52))	('thyroid cancer', 'Disease', (38, 52))
20268	31839882	Consistent with that study were previous publications showing that high expression of immune gene signatures was associated with favorable prognosis in breast and colorectal cancer.	('high', 'Var', (67, 71))	('breast and colorectal cancer', 'Disease', 'MESH:D001943', (152, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('immune gene signatures', 'Gene', (86, 108))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
20293	31839882	CTNNB1 gene mutation has been shown to be associated with low immune response.	('CTNNB1', 'Gene', '1499', (0, 6))	('low immune response', 'CPA', (58, 77))	('low immune response', 'Phenotype', 'HP:0002721', (58, 77))	('CTNNB1', 'Gene', (0, 6))	('mutation', 'Var', (12, 20))
20294	31839882	On the other hand, patients with POLE gene mutations had higher immune activity and were associated with favorable prognosis compared with patients without POLE mutations.	('patients', 'Species', '9606', (19, 27))	('immune activity', 'MPA', (64, 79))	('higher', 'PosReg', (57, 63))	('patients', 'Species', '9606', (139, 147))	('mutations', 'Var', (43, 52))	('POLE gene', 'Gene', (33, 42))
20331	31839882	MHC class I molecules, including HLA-A, -B, and -C, present peptides from inside the cell to T lymphocytes, while MHC class II molecules (HLA-DP, -DM, -DO, -DQ, and -DR) present antigens from outside the cell.	('peptides', 'MPA', (60, 68))	('HLA-DP', 'Var', (138, 144))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (33, 50))
20549	29734384	Complementary DNA was generated using M-MLVT RT (200U/mul) (Invitrogen, Carlsbad, United States) and oligodT primers (500mul/ml) (Invitrogen, Carlsbad, United States) from 1mug of total RNA.	('500mul/ml', 'Var', (118, 127))	('MLVT', 'Gene', '2202', (40, 44))	('MLVT', 'Gene', (40, 44))
20570	29734384	Silencing CYP11B1 gene in H295R cells did not determinate any change in the effects of mitotane on cell viability (Fig 6A) and did not influence mitotane uptake, bioavailability and metabolism into o,p'DDE and o,p'DDA (p = ns) (Fig 6B) (S5 Table).	('influence', 'Reg', (135, 144))	('H295R', 'CellLine', 'CVCL:0458', (26, 31))	('mitotane', 'Chemical', 'MESH:D008939', (145, 153))	('mitotane uptake', 'MPA', (145, 160))	('mitotane', 'Chemical', 'MESH:D008939', (87, 95))	('CYP11B1', 'Gene', (10, 17))	('Silencing', 'Var', (0, 9))	('metabolism', 'MPA', (182, 192))	('CYP11B1', 'Gene', '1584', (10, 17))	('bioavailability', 'MPA', (162, 177))
20578	29734384	The issue remains controversial since in vitro research by our group found that mitotane metabolites (o,p'-DDE and o,p'-DDA) had cytotoxic activity in H295R cells.	("o,p'-DDE", 'Chemical', '-', (102, 110))	("o,p'-DDA", 'Chemical', '-', (115, 123))	("o,p'-DDA", 'Var', (115, 123))	('cytotoxic activity', 'CPA', (129, 147))	('H295R', 'CellLine', 'CVCL:0458', (151, 156))	('mitotane', 'Chemical', 'MESH:D008939', (80, 88))
20583	29734384	In H295R cells, uptake and metabolism of mitotane into o,p'-DDE and o,p'-DDA was unchanged after metyrapone treatment or CYP11B1 silencing.	('CYP11B1', 'Gene', (121, 128))	("o,p'-DDE", 'Chemical', '-', (55, 63))	('uptake', 'MPA', (16, 22))	('CYP11B1', 'Gene', '1584', (121, 128))	('metyrapone', 'Chemical', 'MESH:D008797', (97, 107))	('mitotane', 'Chemical', 'MESH:D008939', (41, 49))	('silencing', 'Var', (129, 138))	('H295R', 'CellLine', 'CVCL:0458', (3, 8))	("o,p'-DDA", 'Chemical', '-', (68, 76))	('metabolism', 'MPA', (27, 37))
20592	29734384	It has been recently demonstrated how mitotane may inhibit the sterol-O-acyl-transferase 1 (SOAT1) that is predominantly expressed by the adrenals.	('SOAT1', 'Gene', '6646', (92, 97))	('mitotane', 'Var', (38, 46))	('sterol-O-acyl-transferase 1', 'Gene', (63, 90))	('sterol-O-acyl-transferase 1', 'Gene', '6646', (63, 90))	('mitotane', 'Chemical', 'MESH:D008939', (38, 46))	('SOAT1', 'Gene', (92, 97))	('inhibit', 'NegReg', (51, 58))
20594	29734384	Conversely, the inhibition of steroidogenesis is not limited to the adrenal glands, since mitotane is able to impair testicular production of testosterone in patients on chronic treatment.	('testicular production of testosterone', 'MPA', (117, 154))	('testosterone', 'Chemical', 'MESH:D013739', (142, 154))	('impair', 'NegReg', (110, 116))	('mitotane', 'Var', (90, 98))	('mitotane', 'Chemical', 'MESH:D008939', (90, 98))	('patients', 'Species', '9606', (158, 166))
20597	28476230	The most frequently mutated genes in adrenocortical tumors are also factors in normal adrenal development and homeostasis, including those that alter the p53 and Wnt/beta-catenin pathways.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('beta-catenin', 'Gene', (166, 178))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (37, 58))	('alter', 'Reg', (144, 149))	('adrenocortical tumors', 'Disease', (37, 58))	('beta-catenin', 'Gene', '1499', (166, 178))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('mutated', 'Var', (20, 27))
20598	28476230	In addition, dysregulated protein kinase A (PKA) signaling and ARMC5 mutations have been identified as key mediators of adrenocortical tumorigenesis.	('mutations', 'Var', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (120, 140))	('dysregulated protein kinase', 'MPA', (13, 40))	('ARMC5', 'Gene', '79798', (63, 68))	('adrenocortical tumor', 'Disease', (120, 140))	('ARMC5', 'Gene', (63, 68))
20601	28476230	Several genes have been implicated as tumor drivers in sporadic ACC, including mutations in insulin-like growth factor 2 (IGF2), beta-catenin (CTNNB1 or ZNRF3), and TP53.	('ZNRF3', 'Gene', (153, 158))	('TP53', 'Gene', (165, 169))	('insulin-like growth factor 2', 'Gene', '3481', (92, 120))	('mutations', 'Var', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('ACC', 'Phenotype', 'HP:0006744', (64, 67))	('ACC', 'Disease', (64, 67))	('IGF2', 'Gene', (122, 126))	('CTNNB1', 'Gene', '1499', (143, 149))	('TP53', 'Gene', '7157', (165, 169))	('insulin-like growth factor 2', 'Gene', (92, 120))	('tumor', 'Disease', (38, 43))	('ACC', 'Disease', 'MESH:D018268', (64, 67))	('CTNNB1', 'Gene', (143, 149))	('IGF2', 'Gene', '3481', (122, 126))	('beta-catenin', 'Gene', (129, 141))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('ZNRF3', 'Gene', '84133', (153, 158))	('beta-catenin', 'Gene', '1499', (129, 141))
20602	28476230	Importantly, germline variants of some of the same genes identified to be drivers of sporadic ACC are also associated with familial tumor syndromes characterized by ACC, including Beckwith-Wiedemann syndrome (BWS), familial adenomatous polyposis (FAP), and Li-Fraumeni syndrome.	('ACC', 'Phenotype', 'HP:0006744', (94, 97))	('familial adenomatous polyposis', 'Disease', (215, 245))	('Li-Fraumeni syndrome', 'Disease', (257, 277))	('FAP', 'Disease', 'MESH:C567782', (247, 250))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (180, 207))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (215, 245))	('associated', 'Reg', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('variants', 'Var', (22, 30))	('BWS', 'Disease', 'MESH:D001506', (209, 212))	('familial tumor syndromes', 'Disease', 'MESH:D009386', (123, 147))	('BWS', 'Disease', (209, 212))	('ACC', 'Phenotype', 'HP:0006744', (165, 168))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (257, 277))	('FAP', 'Disease', (247, 250))	('familial tumor syndromes', 'Disease', (123, 147))	('Beckwith-Wiedemann syndrome', 'Disease', (180, 207))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (224, 245))
20604	28476230	The first human disease that directly linked cAMP signaling to cortisol-producing lesions was with the discovery more than 25 years ago that activating mutations in GNAS1 caused adrenocortical tumors in infants with McCune-Albright syndrome (MAS).	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (216, 240))	('human', 'Species', '9606', (10, 15))	('mutations', 'Var', (152, 161))	('GNAS1', 'Gene', '2778', (165, 170))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (178, 199))	('activating', 'PosReg', (141, 151))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('cortisol', 'Chemical', 'MESH:D006854', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cAMP', 'Chemical', 'MESH:D000242', (45, 49))	('infants', 'Species', '9606', (203, 210))	('caused', 'Reg', (171, 177))	('McCune-Albright syndrome', 'Disease', (216, 240))	('GNAS1', 'Gene', (165, 170))	('adrenocortical tumors', 'Disease', (178, 199))
20605	28476230	Mutations in the regulatory subunit type 1 alpha (R1alpha) of the cAMPdependent protein kinase or PKA were then identified as the cause of another form of cortisol-producing hyperplasia, primary pigmented nodular adrenocortical disease (PPNAD).	('cause', 'Reg', (130, 135))	('PKA', 'Gene', (98, 101))	('pigmented nodular adrenocortical disease', 'Disease', (195, 235))	('hyperplasia', 'Disease', (174, 185))	('cortisol', 'Chemical', 'MESH:D006854', (155, 163))	('Mutations', 'Var', (0, 9))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (195, 235))	('R1alpha', 'Gene', (50, 57))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (195, 235))	('cAMP', 'Chemical', 'MESH:D000242', (66, 70))	('hyperplasia', 'Disease', 'MESH:D006965', (174, 185))
20606	28476230	Inactivating mutations in inhibitors of the cAMP-signaling pathway (phosphodiesterases [PDEs]) were later identified as another cause of adrenocortical hyperplasia.	('cAMP', 'Chemical', 'MESH:D000242', (44, 48))	('Inactivating mutations', 'Var', (0, 22))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (137, 163))	('adrenocortical hyperplasia', 'Disease', (137, 163))	('PDE', 'Gene', '501', (88, 91))	('cause', 'Reg', (128, 133))	('PDE', 'Gene', (88, 91))
20611	28476230	Germline mutations in the tumor suppressor gene ARMC-5 lead to the development of an autosomal dominantly inherited form of Cushing syndrome (CS).	('Germline mutations', 'Var', (0, 18))	('ARMC-5', 'Gene', '79798', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('Cushing syndrome', 'Disease', 'MESH:D003480', (124, 140))	('tumor', 'Disease', (26, 31))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (124, 140))	('CS', 'Phenotype', 'HP:0003118', (142, 144))	('ARMC-5', 'Gene', (48, 54))	('lead to', 'Reg', (55, 62))	('Cushing syndrome', 'Disease', (124, 140))
20620	28476230	Current understanding of normal adrenocortical development sheds light on the molecular pathways that, when altered, may stimulate abnormal proliferation and drive adrenocortical tumor formation.	('adrenocortical', 'Disease', (164, 178))	('adrenocortical', 'Disease', 'MESH:D018268', (164, 178))	('adrenocortical', 'Disease', 'MESH:D018268', (32, 46))	('abnormal proliferation', 'CPA', (131, 153))	('altered', 'Var', (108, 115))	('drive', 'PosReg', (158, 163))	('adrenocortical', 'Disease', (32, 46))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (164, 184))	('stimulate', 'PosReg', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('adrenocortical tumor', 'Disease', (164, 184))
20635	28476230	BWS is caused by mutation, deletion, or hypermethylation of imprinted genes within the chromosome 11p15.5 region, encompassing CDKN1C, H19, IGF2, and P57.	('CDKN1C', 'Gene', '1028', (127, 133))	('mutation', 'Var', (17, 25))	('H19', 'Gene', '283120', (135, 138))	('IGF2', 'Gene', '3481', (140, 144))	('deletion', 'Var', (27, 35))	('H19', 'Gene', (135, 138))	('hypermethylation', 'Var', (40, 56))	('P57', 'Gene', '1028', (150, 153))	('P57', 'Gene', (150, 153))	('BWS', 'Disease', 'MESH:D001506', (0, 3))	('CDKN1C', 'Gene', (127, 133))	('BWS', 'Disease', (0, 3))	('caused by', 'Reg', (7, 16))	('IGF2', 'Gene', (140, 144))
20644	28476230	Defects in Wnt pathway activation, including genetic loss of APC or gain-of-function mutations in CTNNB1, are known driver mutations of ACC.	('APC', 'Disease', 'MESH:D011125', (61, 64))	('Defects', 'NegReg', (0, 7))	('CTNNB1', 'Gene', (98, 104))	('gain-of-function', 'PosReg', (68, 84))	('APC', 'Disease', (61, 64))	('activation', 'PosReg', (23, 33))	('Wnt pathway', 'Pathway', (11, 22))	('mutations', 'Var', (85, 94))	('loss', 'NegReg', (53, 57))	('ACC', 'Phenotype', 'HP:0006744', (136, 139))	('CTNNB1', 'Gene', '1499', (98, 104))
20651	28476230	Germline inactivating mutations of the tumor suppressor gene APC characterize FAP, leading to multiple colonic polyps, colon cancer, and adrenocortical tumors caused by dysregulated Wnt/beta-catenin signaling.	('colonic polyps', 'Disease', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('colonic polyps', 'Disease', 'MESH:D003111', (103, 117))	('tumor', 'Disease', (152, 157))	('FAP', 'Disease', (78, 81))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (137, 158))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('FAP', 'Disease', 'MESH:C567782', (78, 81))	('APC', 'Disease', 'MESH:D011125', (61, 64))	('Germline inactivating mutations', 'Var', (0, 31))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('APC', 'Disease', (61, 64))	('colon cancer', 'Disease', 'MESH:D015179', (119, 131))	('multiple colonic polyps', 'Phenotype', 'HP:0005227', (94, 117))	('tumor', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('beta-catenin', 'Gene', (186, 198))	('colon cancer', 'Disease', (119, 131))	('adrenocortical tumors', 'Disease', (137, 158))	('beta-catenin', 'Gene', '1499', (186, 198))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('leading to', 'Reg', (83, 93))
20652	28476230	Gain-of-function mutations in beta-catenin have been found in roughly 25% of benign and malignant adrenocortical tumors, highlighting the importance of activation of the Wnt signaling pathway.	('malignant adrenocortical tumors', 'Disease', 'MESH:D018268', (88, 119))	('beta-catenin', 'Gene', '1499', (30, 42))	('malignant adrenocortical tumors', 'Disease', (88, 119))	('Gain-of-function', 'PosReg', (0, 16))	('mutations', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('beta-catenin', 'Gene', (30, 42))	('benign and', 'Disease', (77, 87))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
20655	28476230	Another large whole exome sequencing analysis of 41 tumors and matched normal samples found homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 in 9.8% and 7.3% of tumors, respectively.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('KREMEN1', 'Gene', (162, 169))	('tumors', 'Disease', (52, 58))	('22q12.1', 'Gene', (115, 122))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (190, 196))	('ZNRF3', 'Gene', '84133', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('ZNRF3', 'Gene', (152, 157))	('KREMEN1', 'Gene', '83999', (162, 169))	('deletion', 'Var', (103, 111))
20660	28476230	Whole-genome, whole-exome, and/or transcriptome sequencing of 37 ACCs found TP53 mutations and chromosome 17 loss of heterozygosity in 76% of pediatric ACCs.	('ACC', 'Phenotype', 'HP:0006744', (152, 155))	('ACCs', 'Gene', '84680', (65, 69))	('ACCs', 'Gene', (65, 69))	('TP53', 'Gene', '7157', (76, 80))	('ACCs', 'Gene', (152, 156))	('TP53', 'Gene', (76, 80))	('ACCs', 'Gene', '84680', (152, 156))	('mutations', 'Var', (81, 90))	('loss of heterozygosity', 'NegReg', (109, 131))	('ACC', 'Phenotype', 'HP:0006744', (65, 68))
20661	28476230	Li-Fraumeni syndrome is an autosomal-dominant cancer syndrome caused by heterozygous germline mutations in the p53 gene, and is associated with an increased risk of malignancies.	('autosomal-dominant cancer syndrome', 'Disease', 'MESH:D009386', (27, 61))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('autosomal-dominant cancer syndrome', 'Disease', (27, 61))	('malignancies', 'Disease', 'MESH:D009369', (165, 177))	('p53', 'Gene', (111, 114))	('germline mutations', 'Var', (85, 103))	('p53', 'Gene', '7157', (111, 114))	('malignancies', 'Disease', (165, 177))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('caused by', 'Reg', (62, 71))
20663	28476230	The median age of ACC diagnosis among TP53 mutation carriers is 4.8 years of age.	('ACC', 'Disease', (18, 21))	('carriers', 'Reg', (52, 60))	('TP53', 'Gene', (38, 42))	('mutation', 'Var', (43, 51))	('ACC', 'Phenotype', 'HP:0006744', (18, 21))	('TP53', 'Gene', '7157', (38, 42))
20666	28476230	Loss of function mutations in MENIN disrupt cell cycle regulation and lead to cell proliferation.	('MENIN', 'Gene', (30, 35))	('MENIN', 'Gene', '4221', (30, 35))	('cell cycle regulation', 'CPA', (44, 65))	('lead to', 'Reg', (70, 77))	('Loss of function', 'NegReg', (0, 16))	('disrupt', 'NegReg', (36, 43))	('mutations', 'Var', (17, 26))	('cell proliferation', 'CPA', (78, 96))
20668	28476230	In two recent studies reporting exome sequencing in ACC, between 4% and 7% of tumors had inactivating mutations in MENIN.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('ACC', 'Phenotype', 'HP:0006744', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MENIN', 'Gene', (115, 120))	('MENIN', 'Gene', '4221', (115, 120))	('inactivating mutations', 'Var', (89, 111))
20675	28476230	Modifications in specific subunits of PKA, including, PRKAR1alpha and PRKACalpha, play a major role in adrenal physiology and pathophysiology (Fig.	('adrenal physiology', 'MPA', (103, 121))	('PRKACalpha', 'Gene', (70, 80))	('PKA', 'Gene', (38, 41))	('play', 'Reg', (82, 86))	('PRKAR1alpha', 'Gene', '5573', (54, 65))	('Modifications', 'Var', (0, 13))	('PRKAR1alpha', 'Gene', (54, 65))
20676	28476230	MAS is the first disorder identified to connect cAMP/PKA pathway alterations to the growth of adrenal tumors.	('adrenal tumors', 'Disease', (94, 108))	('alterations', 'Var', (65, 76))	('MAS', 'Disease', (0, 3))	('adrenal tumor', 'Phenotype', 'HP:0100631', (94, 107))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('adrenal tumors', 'Disease', 'MESH:D000310', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('cAMP', 'Chemical', 'MESH:D000242', (48, 52))	('growth', 'MPA', (84, 90))
20677	28476230	MAS is caused by postzygotic gain-of-function mutations in the alpha subunit of the gene for the stimulatory guanine-nucleotide-binding protein (Gsa) leading to constitutive activation of adenylate cyclase.	('gain-of-function', 'PosReg', (29, 45))	('MAS', 'Disease', (0, 3))	('mutations', 'Var', (46, 55))	('adenylate cyclase', 'MPA', (188, 205))	('Gsa', 'Gene', '2778', (145, 148))	('constitutive activation', 'MPA', (161, 184))	('Gsa', 'Gene', (145, 148))
20679	28476230	CS is present in a subset of patients with MAS caused by activating mutations of Gsa.	('patients', 'Species', '9606', (29, 37))	('Gsa', 'Gene', (81, 84))	('CS', 'Phenotype', 'HP:0003118', (0, 2))	('activating mutations', 'Var', (57, 77))	('Gsa', 'Gene', '2778', (81, 84))	('MAS', 'Disease', (43, 46))	('caused', 'Reg', (47, 53))
20681	28476230	In a small number of sporadic cortisol-producing adenomas, somatic mutations of GNAS have been identified.	('GNAS', 'Gene', '2778', (80, 84))	('cortisol', 'Chemical', 'MESH:D006854', (30, 38))	('mutations', 'Var', (67, 76))	('adenomas', 'Disease', 'MESH:D000236', (49, 57))	('GNAS', 'Gene', (80, 84))	('identified', 'Reg', (95, 105))	('adenomas', 'Disease', (49, 57))
20684	28476230	Germline inactivating mutations of the PRKAR1A gene coding for the regulatory 1-alpha (R1alpha) subunit of PKA are the cause of for CNC in most patients.	('PRKAR1A', 'Gene', (39, 46))	('cause', 'Reg', (119, 124))	('PRKAR1A', 'Gene', '5573', (39, 46))	('Germline', 'Var', (0, 8))	('patients', 'Species', '9606', (144, 152))	('CNC', 'Disease', (132, 135))
20687	28476230	Somatic mutations in PRKAR1A and chromosomal loss of the region encompassing PRKAR1A have been identified in sporadic cortisol-secreting adenomas.	('adenomas', 'Disease', 'MESH:D000236', (137, 145))	('PRKAR1A', 'Gene', (21, 28))	('PRKAR1A', 'Gene', '5573', (77, 84))	('chromosomal loss of', 'Var', (33, 52))	('adenomas', 'Disease', (137, 145))	('cortisol', 'Chemical', 'MESH:D006854', (118, 126))	('PRKAR1A', 'Gene', '5573', (21, 28))	('identified', 'Reg', (95, 105))	('PRKAR1A', 'Gene', (77, 84))
20690	28476230	More recently, in whole exome sequencing from 84 ACCs, seven (8%) cases were found to have inactivating PRKAR1A mutations, and three additional cases had homozygous deletions of PRKAR1A, increasing the role of PKA signaling in ACC.	('ACCs', 'Gene', (49, 53))	('inactivating', 'NegReg', (91, 103))	('ACCs', 'Gene', '84680', (49, 53))	('PRKAR1A', 'Gene', (178, 185))	('deletions', 'Var', (165, 174))	('mutations', 'Var', (112, 121))	('PRKAR1A', 'Gene', '5573', (178, 185))	('PRKAR1A', 'Gene', (104, 111))	('ACC', 'Phenotype', 'HP:0006744', (227, 230))	('PRKAR1A', 'Gene', '5573', (104, 111))	('ACC', 'Phenotype', 'HP:0006744', (49, 52))
20693	28476230	The role of PDEs is to lower cAMP levels after stimulation of the cAMP/PKA pathway; inactivating mutations of PDE cause buildup of cAMP and stimulation of the PKA signaling cascade.	('cAMP', 'Chemical', 'MESH:D000242', (29, 33))	('stimulation', 'PosReg', (140, 151))	('buildup', 'MPA', (120, 127))	('PDE', 'Gene', '501', (110, 113))	('PDE', 'Gene', (110, 113))	('inactivating mutations', 'Var', (84, 106))	('cAMP', 'MPA', (131, 135))	('PDE', 'Gene', (12, 15))	('PDE', 'Gene', '501', (12, 15))	('PKA signaling cascade', 'Pathway', (159, 180))	('cAMP', 'Chemical', 'MESH:D000242', (66, 70))	('cAMP', 'Chemical', 'MESH:D000242', (131, 135))
20694	28476230	PDE11 A and PDE8B mutations have been found in patients with PPNAD and iMAD, and PDE8B have also been shown to be associated with predisposition to iMAD.	('PDE8B', 'Gene', (81, 86))	('PDE8B', 'Gene', '8622', (12, 17))	('iMAD', 'Disease', (148, 152))	('PDE8B', 'Gene', '8622', (81, 86))	('iMAD', 'Disease', (71, 75))	('patients', 'Species', '9606', (47, 55))	('PPNAD', 'Disease', (61, 66))	('associated', 'Reg', (114, 124))	('PDE11 A', 'Gene', (0, 7))	('found', 'Reg', (38, 43))	('PDE11 A', 'Gene', '50940', (0, 7))	('PDE8B', 'Gene', (12, 17))	('mutations', 'Var', (18, 27))
20696	28476230	PRKACA-activating mutations are responsible for 42% of sporadic CS.	('CS', 'Phenotype', 'HP:0003118', (64, 66))	('responsible', 'Reg', (32, 43))	('PRKACA', 'Gene', (0, 6))	('PRKACA', 'Gene', '5566', (0, 6))	('mutations', 'Var', (18, 27))
20697	28476230	Activating PRKACA mutations obstruct the interaction of the regulatory subunit with the catalytic subunit, leading to constitutive activation of PKA, increased cortisol production, and altered tumor growth.	('activation', 'PosReg', (131, 141))	('altered', 'Reg', (185, 192))	('cortisol', 'Chemical', 'MESH:D006854', (160, 168))	('interaction', 'Interaction', (41, 52))	('PRKACA', 'Gene', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('PKA', 'Gene', (145, 148))	('PRKACA', 'Gene', '5566', (11, 17))	('cortisol production', 'MPA', (160, 179))	('increased cortisol', 'Phenotype', 'HP:0003118', (150, 168))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('increased', 'PosReg', (150, 159))	('tumor', 'Disease', (193, 198))	('obstruct', 'NegReg', (28, 36))	('mutations', 'Var', (18, 27))
20698	28476230	Genetic copy number gains encompassing PRKACA on chromosome 19p13.2p13.12 locus are another described cause of CS related to activation of the PKA pathway.	('activation', 'PosReg', (125, 135))	('PKA pathway', 'Pathway', (143, 154))	('Genetic copy number gains', 'Var', (0, 25))	('CS', 'Phenotype', 'HP:0003118', (111, 113))	('PRKACA', 'Gene', (39, 45))	('PRKACA', 'Gene', '5566', (39, 45))
20701	28476230	PBMAD may be seen in multiple tumor syndromes MEN-1 and FAP and also include hereditary leiomyomatosis and renal cell carcinoma (HLRCC, caused by fumarate hydratase gene [FH] mutations).	('hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C535516', (77, 127))	('fumarate hydratase', 'Gene', (146, 164))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (107, 127))	('FAP', 'Disease', (56, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('caused by', 'Reg', (136, 145))	('multiple tumor', 'Disease', (21, 35))	('mutations', 'Var', (175, 184))	('MEN-1', 'Gene', (46, 51))	('PBMAD', 'Chemical', '-', (0, 5))	('FAP', 'Disease', 'MESH:C567782', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('multiple tumor', 'Disease', 'MESH:D009369', (21, 35))	('fumarate hydratase', 'Gene', '2271', (146, 164))	('MEN-1', 'Gene', '4221', (46, 51))
20702	28476230	In HLRCC, inactivating mutations of FH lead predominantly to hereditary leiomyomatosis and renal cancer; however, in approximately 8% of patients adrenal lesions are found.	('inactivating mutations', 'Var', (10, 32))	('hereditary leiomyomatosis and renal cancer', 'Disease', 'MESH:C535516', (61, 103))	('adrenal lesion', 'Disease', (146, 160))	('lead', 'Reg', (39, 43))	('patients', 'Species', '9606', (137, 145))	('adrenal lesion', 'Disease', 'MESH:D000307', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('renal cancer', 'Phenotype', 'HP:0009726', (91, 103))
20705	28476230	Inactivating ARMC5 mutations have been found in more than half of cases of primary bilateral macronodular adrenal hyperplasia.	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (93, 125))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (106, 125))	('found', 'Reg', (39, 44))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (106, 125))	('mutations', 'Var', (19, 28))	('Inactivating', 'Var', (0, 12))	('ARMC5', 'Gene', (13, 18))	('ARMC5', 'Gene', '79798', (13, 18))	('adrenal hyperplasia', 'Disease', (106, 125))
20706	28476230	Additional studies have confirmed the high frequency of ARMC5 mutations in this disorder.	('ARMC5', 'Gene', (56, 61))	('mutations', 'Var', (62, 71))	('ARMC5', 'Gene', '79798', (56, 61))
20714	28476230	KCNJ5 mutations, a gene that encodes a potassium channel, have also been found in 40% of aldosterone-producing adenomas.	('adenomas', 'Disease', 'MESH:D000236', (111, 119))	('found', 'Reg', (73, 78))	('KCNJ5', 'Gene', '3762', (0, 5))	('adenomas', 'Disease', (111, 119))	('potassium', 'Chemical', 'MESH:D011188', (39, 48))	('aldosterone', 'Chemical', 'MESH:D000450', (89, 100))	('KCNJ5', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
20715	28476230	Mutations in KCNJ5 alter the channel's permeability to potassium ultimately leading to activation of the calcium-calmodulin-dependent protein kinase II.	('potassium', 'Chemical', 'MESH:D011188', (55, 64))	('alter', 'Reg', (19, 24))	('activation', 'PosReg', (87, 97))	('permeability to potassium', 'MPA', (39, 64))	('KCNJ5', 'Gene', '3762', (13, 18))	('calcium', 'Chemical', 'MESH:D002118', (105, 112))	('calcium-calmodulin-dependent protein kinase', 'Pathway', (105, 148))	('Mutations', 'Var', (0, 9))	('KCNJ5', 'Gene', (13, 18))
20716	28476230	Germline ARMC5 variants may also be associated with primary aldosteronism.	('ARMC5', 'Gene', (9, 14))	('ARMC5', 'Gene', '79798', (9, 14))	('primary aldosteronism', 'Disease', (52, 73))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (52, 73))	('variants', 'Var', (15, 23))	('associated', 'Reg', (36, 46))
20717	28476230	The most frequently mutated genes in adrenocortical tumors are also factors involved in normal adrenal development and homeostasis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutated', 'Var', (20, 27))	('adrenocortical tumors', 'Disease', (37, 58))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (37, 58))
20719	28476230	The most common somatic alterations in ACC are mutations or deletions of TP53 and ZNRF3 or CTNNB1, altering either the p53 or the Wnt/beta-catenin pathway.	('beta-catenin', 'Gene', '1499', (134, 146))	('TP53', 'Gene', '7157', (73, 77))	('ZNRF3', 'Gene', '84133', (82, 87))	('CTNNB1', 'Gene', (91, 97))	('altering', 'Reg', (99, 107))	('ZNRF3', 'Gene', (82, 87))	('deletions', 'Var', (60, 69))	('TP53', 'Gene', (73, 77))	('p53', 'Gene', '7157', (119, 122))	('mutations', 'Var', (47, 56))	('ACC', 'Phenotype', 'HP:0006744', (39, 42))	('CTNNB1', 'Gene', '1499', (91, 97))	('p53', 'Gene', (119, 122))	('beta-catenin', 'Gene', (134, 146))
20720	28476230	The PKA/cAMP signaling pathway plays a crucial role in adrenocortical physiology and pathophysiology; activating mutations of pathway regulators and inactivating mutations of pathway inhibitors both lead to cortisol excess.	('cortisol excess', 'Phenotype', 'HP:0003118', (207, 222))	('cortisol excess', 'MPA', (207, 222))	('cAMP', 'Chemical', 'MESH:D000242', (8, 12))	('activating', 'PosReg', (102, 112))	('inactivating mutations', 'Var', (149, 171))	('adrenocortical', 'Disease', (55, 69))	('adrenocortical', 'Disease', 'MESH:D018268', (55, 69))	('mutations', 'Var', (113, 122))	('lead to', 'Reg', (199, 206))	('adrenocortical physiology', 'Phenotype', 'HP:0008207', (55, 80))	('cortisol', 'Chemical', 'MESH:D006854', (207, 215))
20722	28476230	Somatic PRKACA-activating, PRKAR1A-inactivating, or GNAS-activating mutations may cause cortisol-secreting adenomas.	('PRKAR1A', 'Gene', '5573', (27, 34))	('adenomas', 'Disease', (107, 115))	('cause', 'Reg', (82, 87))	('cortisol', 'Chemical', 'MESH:D006854', (88, 96))	('adenomas', 'Disease', 'MESH:D000236', (107, 115))	('GNAS', 'Gene', '2778', (52, 56))	('GNAS', 'Gene', (52, 56))	('PRKAR1A', 'Gene', (27, 34))	('PRKACA', 'Gene', (8, 14))	('mutations', 'Var', (68, 77))	('PRKACA', 'Gene', '5566', (8, 14))
20727	28476230	It therefore follows that mutations in genes that involve dysregulated cAMP/PKA pathway components are implicated in adrenocortical pathology.	('cAMP/PKA pathway', 'Pathway', (71, 87))	('cAMP', 'Chemical', 'MESH:D000242', (71, 75))	('adrenocortical pathology', 'Disease', 'MESH:D018268', (117, 141))	('adrenocortical pathology', 'Disease', (117, 141))	('mutations', 'Var', (26, 35))	('implicated', 'Reg', (103, 113))
20741	27433417	Studying the gene mutations in patients presenting with oncocytic malignancies and other tumors that demonstrate mitochondrial proliferation as PTC might help to understand the role of mitochondrial proliferation in cancer development.	('PTC', 'Phenotype', 'HP:0002895', (144, 147))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('oncocytic malignancies', 'Disease', 'MESH:C535584', (56, 78))	('oncocytic malignancies', 'Disease', (56, 78))	('patients', 'Species', '9606', (31, 39))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutations', 'Var', (18, 27))
20828	27433417	Studying the gene mutations in patients presenting with oncocytic malignancies and other tumors that demonstrate mitochondrial proliferation as papillary thyroid cancer in this report might help to better understand the role of mitochondrial proliferation in cancer development.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (259, 265))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('oncocytic malignancies', 'Disease', 'MESH:C535584', (56, 78))	('papillary thyroid cancer', 'Disease', (144, 168))	('oncocytic malignancies', 'Disease', (56, 78))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (144, 168))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('patients', 'Species', '9606', (31, 39))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (144, 168))	('thyroid cancer', 'Phenotype', 'HP:0002890', (154, 168))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutations', 'Var', (18, 27))
20889	27227935	The risk of death was significantly increased in patients with a score of 1 (HR = 4.29, 95% CI 1.43-12.91, P < 0.01) or a score of 2 (HR = 9.56, 95% CI 2.41-37.87, P < 0.01) compared with patients with a score of 0.	('death', 'Disease', (12, 17))	('score of 2', 'Var', (122, 132))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (49, 57))	('death', 'Disease', 'MESH:D003643', (12, 17))
20892	27227935	Patients with high Ki-67 index and elevated new prognostic score displayed a trend toward more recurrences in our study subjects, but these trends were not statistically significant (Figure 2C and D).	('recurrences', 'CPA', (95, 106))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('new prognostic score', 'MPA', (44, 64))	('Ki-67 index', 'Protein', (19, 30))
20973	26376405	In the present case, the focal keratin AE1/AE3 positivity increased the diagnostic difficulty, especially in the first endoscopically performed biopsy.	('diagnostic', 'MPA', (72, 82))	('increased', 'PosReg', (58, 67))	('focal', 'Var', (25, 30))	('AE3', 'Gene', '6508', (43, 46))	('AE3', 'Gene', (43, 46))	('AE1', 'Gene', (39, 42))	('positivity', 'Var', (47, 57))	('AE1', 'Gene', '6521', (39, 42))
20989	25605410	The goal is enhancing our understanding of the connection between dysregulated DUBs and cancer to permit the design of therapeutics and to establish biomarkers that could be used in diagnosis and prognosis.	('dysregulated', 'Var', (66, 78))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
20990	25605410	Malfunction, dysregulation, or molecular defects within the UPS lead to several different disease states including various cancers as well as neurodegenerative disorders.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lead to', 'Reg', (64, 71))	('dysregulation', 'Var', (13, 26))	('neurodegenerative disorders', 'Disease', (142, 169))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (142, 169))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (142, 169))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('Malfunction', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('molecular defects within the UPS', 'Disease', 'MESH:D001929', (31, 63))	('molecular defects within the UPS', 'Disease', (31, 63))
20995	25605410	The N-terminal methionine and the seven lysine residues in ubiquitin (K6, K11, K27, K29, K33 K48, and K63) can form polyubiquitin chains.	('K33 K48', 'Var', (89, 96))	('polyubiquitin chains', 'MPA', (116, 136))	('K11', 'Var', (74, 77))	('K63', 'Var', (102, 105))	('K6', 'Var', (70, 72))	('form', 'Reg', (111, 115))	('K27', 'Gene', '342574', (79, 82))	('K27', 'Gene', (79, 82))	('lysine', 'Chemical', 'MESH:D008239', (40, 46))	('methionine', 'Chemical', 'MESH:D008715', (15, 25))	('K29', 'Var', (84, 87))
20999	25605410	K63 and linear polyubiquitination function in the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) signaling pathway.	('NFkappaB', 'Gene', '4790', (132, 140))	('K63', 'Var', (0, 3))	('NFkappaB', 'Gene', (132, 140))	('linear polyubiquitination', 'MPA', (8, 33))
21031	25605410	Subsequently, USP7 was also shown to interact with the EBNA1 protein from Epstein-Barr virus, vIRF4 and LANA proteins from Kaposi's sarcoma herpesvirus, UL35 from cytomegalovirus, and E1B-55K from adenovirus.	('EBNA1', 'Gene', '17494214', (55, 60))	("Kaposi's sarcoma herpesvirus", 'Species', '37296', (123, 151))	("Kaposi's sarcoma herpesvirus", 'Disease', (123, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (132, 139))	('UL35', 'Gene', '3077429', (153, 157))	('interact', 'Interaction', (37, 45))	('E1B-55K', 'Var', (184, 191))	('UL35', 'Gene', (153, 157))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (123, 139))	('USP7', 'Gene', (14, 18))	('protein', 'Protein', (61, 68))	('USP7', 'Gene', '7874', (14, 18))	('EBNA1', 'Gene', (55, 60))	('Epstein-Barr virus', 'Species', '10376', (74, 92))
21038	25605410	The deletion of the USP7 gene resulted in early embryonic lethality partly due to increased p53 levels.	('resulted in', 'Reg', (30, 41))	('embryonic lethality', 'Disease', 'MESH:D020964', (48, 67))	('embryonic lethality', 'Disease', (48, 67))	('USP7', 'Gene', (20, 24))	('p53', 'Gene', (92, 95))	('deletion', 'Var', (4, 12))	('increased', 'PosReg', (82, 91))	('p53', 'Gene', '7157', (92, 95))	('USP7', 'Gene', '7874', (20, 24))
21048	25605410	In cancers that are caused by a dysregulated Hdm2 protein but retain WT p53, the ability to inhibit USP7 deubiquitination of Hdm2 is considered to be of therapeutic importance because Hdm2 degradation would lead to p53 stabilization and activation.	('USP7', 'Gene', '7874', (100, 104))	('Hdm2', 'Gene', '4193', (125, 129))	('p53', 'Gene', '7157', (215, 218))	('Hdm2', 'Gene', (184, 188))	('degradation', 'MPA', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('p53', 'Gene', '7157', (72, 75))	('p53', 'Gene', (215, 218))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('Hdm2', 'Gene', (45, 49))	('Hdm2', 'Gene', '4193', (184, 188))	('Hdm2', 'Gene', (125, 129))	('p53', 'Gene', (72, 75))	('dysregulated', 'Var', (32, 44))	('inhibit', 'NegReg', (92, 99))	('stabilization', 'MPA', (219, 232))	('USP7', 'Gene', (100, 104))	('activation', 'PosReg', (237, 247))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('caused by', 'Reg', (20, 29))	('Hdm2', 'Gene', '4193', (45, 49))
21049	25605410	Therefore, a drug that prevents the formation of the Hdm2/USP7 complex or inhibits its catalytic activity will benefit patients with cancer associated with a dysregulated Hdm2 protein.	('USP7', 'Gene', '7874', (58, 62))	('Hdm2', 'Gene', (171, 175))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('Hdm2', 'Gene', '4193', (171, 175))	('cancer', 'Disease', (133, 139))	('Hdm2', 'Gene', '4193', (53, 57))	('benefit', 'PosReg', (111, 118))	('USP7', 'Gene', (58, 62))	('catalytic activity', 'MPA', (87, 105))	('inhibits', 'NegReg', (74, 82))	('Hdm2', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('dysregulated', 'Var', (158, 170))
21054	25605410	Several USP7 inhibitors have been tested in a variety of in vitro and in vivo assays.	('inhibitors', 'Var', (13, 23))	('USP7', 'Gene', '7874', (8, 12))	('USP7', 'Gene', (8, 12))
21055	25605410	HBX 41,108 and P5091 are USP7 inhibitors with IC50 values of submicromolar concentrations.	('USP7', 'Gene', (25, 29))	('P5091', 'Var', (15, 20))	('USP7', 'Gene', '7874', (25, 29))
21057	25605410	The potency of P5091 was shown to induce apoptosis in multiple myeloma cells resistant to bortezomib.	('induce', 'PosReg', (34, 40))	('P5091', 'Var', (15, 20))	('multiple myeloma', 'Phenotype', 'HP:0006775', (54, 70))	('multiple myeloma', 'Disease', 'MESH:D009101', (54, 70))	('apoptosis', 'CPA', (41, 50))	('multiple myeloma', 'Disease', (54, 70))	('bortezomib', 'Chemical', 'MESH:D000069286', (90, 100))
21061	25605410	Dysregulation of the NFkappaB pathway is involved not only in cancer, but also in a number of other diseases such as viral infection and inflammatory diseases.	('viral infection', 'Disease', 'MESH:D001102', (117, 132))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Dysregulation', 'Var', (0, 13))	('NFkappaB', 'Gene', (21, 29))	('inflammatory diseases', 'Disease', (137, 158))	('involved', 'Reg', (41, 49))	('NFkappaB', 'Gene', '4790', (21, 29))	('viral infection', 'Disease', (117, 132))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
21082	25605410	This dual E3 ligase-DUB function allows A20 to elegantly inhibit NFkappaB-related signaling by removing K63-linked polyubiquitin chains from substrate molecules such as TRAF6 and receptor-interacting serine/threonine protein kinase 1 (RIP1) and label them for 26S proteasomal degradation by attaching a K48-linked polyubiquitin chain.	('K63-linked polyubiquitin chains', 'MPA', (104, 135))	('RIP1', 'Gene', (235, 239))	('removing', 'NegReg', (95, 103))	('inhibit', 'NegReg', (57, 64))	('A20', 'Gene', (40, 43))	('TRAF6', 'Gene', (169, 174))	('attaching', 'Reg', (291, 300))	('TRAF6', 'Gene', '7189', (169, 174))	('NFkappaB', 'Gene', '4790', (65, 73))	('RIP1', 'Gene', '8737', (235, 239))	('NFkappaB', 'Gene', (65, 73))	('receptor-interacting serine/threonine protein kinase 1', 'Gene', '8737', (179, 233))	('A20', 'Gene', '7128', (40, 43))	('K48-linked', 'Var', (303, 313))
21102	25605410	Mutations in UCHL1 have been linked to Parkinson's disease.	("Parkinson's disease", 'Disease', (39, 58))	('linked', 'Reg', (29, 35))	('Mutations', 'Var', (0, 9))	("Parkinson's disease", 'Disease', 'MESH:D010300', (39, 58))	('UCHL1', 'Gene', (13, 18))	('UCHL1', 'Gene', '7398', (13, 18))
21103	25605410	Both protein and mRNA levels of UCHL1 are down-regulated in prostate cancer due to hypo-methylation of the UCHL1 promoter.	('UCHL1', 'Gene', (107, 112))	('prostate cancer', 'Disease', (60, 75))	('hypo-methylation', 'Var', (83, 99))	('down-regulated', 'NegReg', (42, 56))	('protein', 'MPA', (5, 12))	('UCHL1', 'Gene', '7398', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('UCHL1', 'Gene', (32, 37))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('mRNA levels', 'MPA', (17, 28))	('UCHL1', 'Gene', '7398', (107, 112))	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))
21105	25605410	An extensive study found mutations and deletions to BAP1 to be particularly associated with the detrimental outcome of various common cancers, especially in renal clear cell carcinoma.	('mutations', 'Var', (25, 34))	('deletions', 'Var', (39, 48))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('men', 'Species', '9606', (101, 104))	('BAP1', 'Gene', (52, 56))	('associated', 'Reg', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (157, 183))	('renal clear cell carcinoma', 'Disease', (157, 183))
21121	25605410	ATXN3 mutations with extended polyQ stretches cause MJD.	('MJD', 'Disease', 'MESH:D017827', (52, 55))	('MJD', 'Disease', (52, 55))	('polyQ', 'Chemical', 'MESH:C097188', (30, 35))	('cause', 'Reg', (46, 51))	('ATXN3', 'Gene', (0, 5))	('ATXN3', 'Gene', '4287', (0, 5))	('mutations', 'Var', (6, 15))
21131	25605410	It had been observed earlier that Rpn11 can specifically cleave K63-linked poly-ubiquitin chains, which is contrary to its cleavage of K48-linked chains targeted for proteasomal digestion, but fits to the K63 specificity of other zinc metalloproteases such as AMSH (associated molecule with the SH3 domain of signal transducting adapter molecule 1) and AMSH-LP (AMSH-like protein).	('AMSH-like protein', 'Gene', (362, 379))	('Rpn11', 'Gene', (34, 39))	('AMSH-like protein', 'Gene', '57559', (362, 379))	('AMSH', 'Gene', (362, 366))	('fits', 'Disease', 'MESH:D012640', (193, 197))	('K63-linked', 'Var', (64, 74))	('AMSH', 'Gene', '10617', (260, 264))	('AMSH', 'Gene', '10617', (362, 366))	('AMSH-LP', 'Gene', '57559', (353, 360))	('AMSH', 'Gene', (353, 357))	('Rpn11', 'Gene', '10213', (34, 39))	('AMSH', 'Gene', '10617', (353, 357))	('AMSH', 'Gene', (260, 264))	('cleave', 'Reg', (57, 63))	('AMSH-LP', 'Gene', (353, 360))	('fits', 'Disease', (193, 197))
21140	25605410	The molecular basis of disease is quite complex and mutations in many different oncogenes and tumor suppressor genes have been implicated including TP53, RB1, EZH2, BMI, and PTEN.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('PTEN', 'Gene', '5728', (174, 178))	('implicated', 'Reg', (127, 137))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('tumor', 'Disease', (94, 99))	('EZH2', 'Gene', '2146', (159, 163))	('RB1', 'Gene', (154, 157))	('EZH2', 'Gene', (159, 163))	('RB1', 'Gene', '5925', (154, 157))	('PTEN', 'Gene', (174, 178))
21142	25605410	In light of all of the identified mutations, prostate cancer appears to be caused by dysregulation of many different cellular signaling pathways especially those involved in cell survival and apoptosis.	('prostate cancer', 'Disease', 'MESH:D011471', (45, 60))	('prostate cancer', 'Phenotype', 'HP:0012125', (45, 60))	('caused', 'Reg', (75, 81))	('prostate cancer', 'Disease', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (34, 43))
21144	25605410	The involvement of overexpressed USP7 has already been described in prostate cancer via dysregulation of PTEN.	('USP7', 'Gene', (33, 37))	('prostate cancer', 'Phenotype', 'HP:0012125', (68, 83))	('PTEN', 'Gene', (105, 109))	('USP7', 'Gene', '7874', (33, 37))	('prostate cancer', 'Disease', (68, 83))	('men', 'Species', '9606', (11, 14))	('PTEN', 'Gene', '5728', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('overexpressed', 'PosReg', (19, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (68, 83))	('dysregulation', 'Var', (88, 101))
21154	25605410	Single nucleotide polymorphisms in Hdm2, HdmX, and USP7 have also been associated with aggressive prostate cancer.	('aggressive prostate cancer', 'Disease', 'MESH:D011471', (87, 113))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('aggressive prostate cancer', 'Disease', (87, 113))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('HdmX', 'Gene', '4193', (41, 45))	('Hdm2', 'Gene', '4193', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Hdm2', 'Gene', (35, 39))	('USP7', 'Gene', (51, 55))	('HdmX', 'Gene', (41, 45))	('USP7', 'Gene', '7874', (51, 55))	('associated with', 'Reg', (71, 86))
21159	25605410	The inactivation of USP2a via knockdown, mutations, or low expression has a negative effect on fatty acid synthase levels and p53-regulated genes, which enhances apoptosis.	('fatty acid synthase', 'Gene', (95, 114))	('mutations', 'Var', (41, 50))	('p53', 'Gene', '7157', (126, 129))	('enhances', 'PosReg', (153, 161))	('inactivation', 'Var', (4, 16))	('USP2', 'Gene', '9099', (20, 24))	('fatty acid synthase', 'Gene', '2194', (95, 114))	('low', 'NegReg', (55, 58))	('negative', 'NegReg', (76, 84))	('USP2', 'Gene', (20, 24))	('p53', 'Gene', (126, 129))	('apoptosis', 'CPA', (162, 171))
21166	25605410	The derepression of microRNAs miR-34b/c, miR-98, and let-7c resulting in increased levels of MYC is attributed to increased levels of USP2a.	('increased', 'PosReg', (73, 82))	('USP2', 'Gene', '9099', (134, 138))	('levels', 'MPA', (83, 89))	('miR-34b', 'Gene', (30, 37))	('MYC', 'Gene', (93, 96))	('miR-34b', 'Gene', '407041', (30, 37))	('let-7c', 'Gene', (53, 59))	('let-7c', 'Gene', '406885', (53, 59))	('USP2', 'Gene', (134, 138))	('miR-98', 'Gene', '407054', (41, 47))	('miR-98', 'Gene', (41, 47))	('microRNAs', 'Var', (20, 29))	('MYC', 'Gene', '4609', (93, 96))
21167	25605410	Inhibitors targeting the catalytic activity of USP2a could attack prostate cancer cells via several different mechanisms, such as i) reducing MYC levels, thus reducing proliferation and ii) increasing p53 levels leading to increased apoptosis.	('increased', 'PosReg', (223, 232))	('proliferation', 'CPA', (168, 181))	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('MYC', 'Gene', (142, 145))	('p53', 'Gene', (201, 204))	('Inhibitors', 'Var', (0, 10))	('reducing', 'NegReg', (159, 167))	('USP2', 'Gene', '9099', (47, 51))	('p53', 'Gene', '7157', (201, 204))	('USP2', 'Gene', (47, 51))	('apoptosis', 'CPA', (233, 242))	('prostate cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('increasing', 'PosReg', (190, 200))	('MYC', 'Gene', '4609', (142, 145))	('reducing', 'NegReg', (133, 141))
21187	25605410	The greatest risk factor for ovarian cancer is genetic with several common mutations.	('ovarian cancer', 'Disease', (29, 43))	('genetic', 'Var', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (75, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (29, 43))	('ovarian cancer', 'Disease', 'MESH:D010051', (29, 43))
21189	25605410	Many tumor suppressor genes including TP53, PTEN, RB1, and BRCA1 are either mutated or dysregulated in ovarian cancer.	('BRCA1', 'Gene', '672', (59, 64))	('TP53', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('dysregulated in ovarian cancer', 'Disease', 'MESH:D010051', (87, 117))	('BRCA1', 'Gene', (59, 64))	('mutated', 'Var', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('PTEN', 'Gene', (44, 48))	('RB1', 'Gene', (50, 53))	('tumor', 'Disease', (5, 10))	('PTEN', 'Gene', '5728', (44, 48))	('RB1', 'Gene', '5925', (50, 53))	('dysregulated in ovarian cancer', 'Disease', (87, 117))	('TP53', 'Gene', '7157', (38, 42))
21194	25605410	UCHL1 knockdown in ovarian cancer cell lines where it was overexpressed caused increased proliferation.	('proliferation', 'CPA', (89, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (19, 33))	('increased', 'PosReg', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('ovarian cancer', 'Disease', (19, 33))	('UCHL1', 'Gene', '7398', (0, 5))	('ovarian cancer', 'Phenotype', 'HP:0100615', (19, 33))	('knockdown', 'Var', (6, 15))	('UCHL1', 'Gene', (0, 5))
21202	25605410	Furthermore, knockdown of USP15 in HeLa cells also lead to paclitaxel resistance corroborating its important role in this resistance.	('HeLa', 'CellLine', 'CVCL:0030', (35, 39))	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('lead to', 'Reg', (51, 58))	('USP15', 'Gene', '9958', (26, 31))	('knockdown', 'Var', (13, 22))	('USP15', 'Gene', (26, 31))	('paclitaxel resistance', 'MPA', (59, 80))
21205	25605410	USP44 plays a role in cancer through its dysregulation of the DNA damage response mediated by the E3 ligase RNF168 on histone H2A.	('USP44', 'Gene', '84101', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('dysregulation', 'Var', (41, 54))	('USP44', 'Gene', (0, 5))	('cancer', 'Disease', (22, 28))	('RNF168', 'Gene', (108, 114))	('DNA damage response', 'MPA', (62, 81))	('RNF168', 'Gene', '165918', (108, 114))
21210	25605410	Von Hippel-Lindau disease is caused by mutations in the gene encoding the VHL protein (pVHL).	('pVHL', 'Gene', '7428', (87, 91))	('pVHL', 'Gene', (87, 91))	('caused by', 'Reg', (29, 38))	('Von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (0, 25))	('VHL', 'Gene', (88, 91))	('VHL', 'Gene', (74, 77))	('mutations', 'Var', (39, 48))	('VHL', 'Gene', '7428', (74, 77))	('VHL', 'Gene', '7428', (88, 91))	('Von Hippel-Lindau disease', 'Disease', (0, 25))
21215	25605410	Mutations in pVHL disrupt the ubiquitination of HIF1alpha.	('disrupt', 'Reg', (18, 25))	('HIF1alpha', 'Gene', (48, 57))	('Mutations', 'Var', (0, 9))	('HIF1alpha', 'Gene', '3091', (48, 57))	('pVHL', 'Gene', '7428', (13, 17))	('pVHL', 'Gene', (13, 17))	('ubiquitination', 'MPA', (30, 44))
21226	25605410	The knockdown of USP20 caused the sensitization of two different cancer cell lines to cisplatin, strongly suggesting that an inhibitor against USP20 may function as a cancer therapeutic drug.	('USP20', 'Gene', '10868', (143, 148))	('USP20', 'Gene', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('USP20', 'Gene', (143, 148))	('USP20', 'Gene', '10868', (17, 22))	('cancer', 'Disease', (167, 173))	('inhibitor', 'Var', (125, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('knockdown', 'Var', (4, 13))	('cancer', 'Disease', (65, 71))	('sensitization', 'MPA', (34, 47))
21230	25605410	Kaplan-Meier analysis indicated that the survival of patients with papillary carcinoma was significantly lower with high USP22 expression levels.	('lower', 'NegReg', (105, 110))	('patients', 'Species', '9606', (53, 61))	('survival', 'CPA', (41, 49))	('high', 'Var', (116, 120))	('papillary carcinoma', 'Disease', (67, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('USP22', 'Gene', '23326', (121, 126))	('USP22', 'Gene', (121, 126))	('papillary carcinoma', 'Disease', 'MESH:D002291', (67, 86))
21232	25605410	There is one case of MALT lymphoma of the thyroid that has been associated with the deletion of A20.	('associated', 'Reg', (64, 74))	('deletion', 'Var', (84, 92))	('MALT lymphoma of the thyroid', 'Disease', 'MESH:D018442', (21, 49))	('A20', 'Gene', '7128', (96, 99))	('MALT lymphoma of the thyroid', 'Disease', (21, 49))	('lymphoma', 'Phenotype', 'HP:0002665', (26, 34))	('A20', 'Gene', (96, 99))
21262	25605410	Additional studies are needed to define the actual landscape of DUBs that are mutated, deleted, or differentially regulated in these cancers.	('deleted', 'Var', (87, 94))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
21290	22295121	This shift was mainly attributed to an increase in CYP17-17,20 lyase activity due to enhanced serine phosphorylation of CYP17 and a decrease of HSD3B2 expression and activity.	('activity', 'MPA', (69, 77))	('expression', 'Species', '29278', (151, 161))	('enhanced', 'PosReg', (85, 93))	('activity', 'MPA', (166, 174))	('expression', 'MPA', (151, 161))	('increase', 'PosReg', (39, 47))	('serine', 'Chemical', 'MESH:D012694', (94, 100))	('HSD3B2', 'Gene', (144, 150))	('HSD3B2', 'Gene', '3284', (144, 150))	('CYP17', 'Var', (120, 125))	('serine phosphorylation', 'MPA', (94, 116))	('decrease', 'NegReg', (132, 140))
21298	22295121	First, if AMP is increased intracellular after energy consumption, AMP binds allosterically to a regulatory gamma subunit of AMPK and induces a conformational change that allows the activation of AMPK by phosphorylation.	('AMP', 'Chemical', 'MESH:D000249', (125, 128))	('AMP', 'Chemical', 'MESH:D000249', (67, 70))	('conformational change', 'MPA', (144, 165))	('AMP', 'Var', (67, 70))	('phosphorylation', 'MPA', (204, 219))	('binds', 'Interaction', (71, 76))	('AMP', 'Chemical', 'MESH:D000249', (196, 199))	('AMP', 'Chemical', 'MESH:D000249', (10, 13))	('AMPK', 'MPA', (196, 200))	('induces', 'Reg', (134, 141))
21303	22295121	For instance, AICAR-mediated AMPK phosphorylation/activation was found to decrease progesterone secretion by way of ERK1/2 signaling pathway in rat granulosa cells.	('progesterone', 'Chemical', 'MESH:D011374', (83, 95))	('decrease', 'NegReg', (74, 82))	('AICAR-mediated', 'Var', (14, 28))	('AICAR', 'Chemical', '-', (14, 19))	('decrease progesterone', 'Phenotype', 'HP:0008233', (74, 95))	('progesterone secretion', 'MPA', (83, 105))	('ERK1/2', 'Gene', '50689;116590', (116, 122))	('ERK1/2', 'Gene', (116, 122))	('AMPK phosphorylation/activation', 'Var', (29, 60))	('rat', 'Species', '10116', (144, 147))
21313	22295121	Wild-type HA-AMPK or HA-AMPK-DN constructs of subunits alpha 1 and 2 were generously provided by Ken Inoki.	('HA-AMPK-DN', 'Var', (21, 31))	('Ken', 'Gene', (97, 100))	('alpha 1 and 2', 'Gene', '146', (55, 68))	('Ken', 'Gene', '5116', (97, 100))
21343	22295121	The reaction mixture consisted also of a hot/cold steroid mix (15 microM or 150 microM (14C)-progesterone (20'000 cpm/rct), 50 microM (3H) pregnenolone (40'000 cpm/rct) or 50 microM (3H) 17alpha-hydroxypregnenolone (50'000 cpm/rct), 1 mM NADPH or 1 mM NAD+ in a total volume of 200 microl 50 mM KIP buffer.	('steroid', 'Chemical', 'MESH:D013256', (50, 57))	('mix', 'Gene', '83881', (13, 16))	("40'000 cpm/rct", 'Var', (153, 167))	('progesterone', 'Chemical', 'MESH:D011374', (93, 105))	("20'000 cpm/rct", 'Var', (107, 121))	('mix', 'Gene', '83881', (58, 61))	('mix', 'Gene', (13, 16))	("50'000 cpm/rct", 'Var', (216, 230))	('(3H) 17alpha-hydroxypregnenolone', 'Chemical', '-', (182, 214))	('ADP', 'Chemical', 'MESH:D000244', (239, 242))	('mix', 'Gene', (58, 61))	('(3H) pregnenolone', 'Chemical', '-', (134, 151))
21347	22295121	We used Lipofectamine 2000 (Invitrogen) to either transfect an empty vector (pGL3, Deltaluc) or promoter-reporter constructs (-3.7CYP17, -1.05HSD3B2, -1.3b5, -325POR, -1.08SULT2A1) into NCI-H295R cells (1.5x105 cells/well in a 24-well format; Falcon 3047; BD Biosciences, Bedford, MA, USA).	('transfect', 'Reg', (50, 59))	('HSD3B2', 'Gene', (142, 148))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (8, 26))	('HSD3B2', 'Gene', '3284', (142, 148))	('POR', 'Gene', (162, 165))	('pGL3', 'Gene', (77, 81))	('POR', 'Gene', '5447', (162, 165))	('pGL3', 'Gene', '6391', (77, 81))	('NCI-H295R', 'CellLine', 'CVCL:0458', (186, 195))	('-3.7CYP17', 'Var', (126, 135))
21392	22295121	Time-course experiment revealed an increased phosphorylation of AMPK in response to 1 mM AICAR within 3 h which remained sustained for 48 h (Fig.	('AICAR', 'Chemical', '-', (89, 94))	('increased', 'PosReg', (35, 44))	('AMPK', 'Protein', (64, 68))	('1 mM', 'Var', (84, 88))	('phosphorylation', 'MPA', (45, 60))
21400	22295121	In contrast to the enzyme kinetic assays, AICAR slightly enhanced androgen production in the cell model (Fig.	('AICAR', 'Var', (42, 47))	('androgen production', 'MPA', (66, 85))	('AICAR', 'Chemical', '-', (42, 47))	('enhanced androgen production', 'Phenotype', 'HP:0030348', (57, 85))	('enhanced', 'PosReg', (57, 65))
21405	22295121	To test whether AICAR or compound C modulate the activities of promoters of steroidogenic genes, we transfected NCI-H295R cells with specific promoter constructs (-3.7 CYP17, -1.05 HSD3B2, -1.3 CYb5, -325 POR, -1.08 SULT2A1).	('NCI-H295R', 'CellLine', 'CVCL:0458', (112, 121))	('HSD3B2', 'Gene', '3284', (181, 187))	('CYb5', 'Gene', '1528', (194, 198))	('-3.7 CYP17', 'Var', (163, 173))	('POR', 'Gene', (205, 208))	('steroid', 'Chemical', 'MESH:D013256', (76, 83))	('AICAR', 'Chemical', '-', (16, 21))	('CYb5', 'Gene', (194, 198))	('POR', 'Gene', '5447', (205, 208))	('HSD3B2', 'Gene', (181, 187))
21433	22295121	Interestingly, the expression pattern of AMPK subunits of NCI-H295R cells resembles that of the human adrenal tissue when compared to NCI-H295A cells.	('expression', 'MPA', (19, 29))	('NCI-H295R', 'Var', (58, 67))	('NCI-H295A', 'CellLine', 'CVCL:0457', (134, 143))	('human', 'Species', '9606', (96, 101))	('NCI-H295R', 'CellLine', 'CVCL:0458', (58, 67))	('expression', 'Species', '29278', (19, 29))
21448	22295121	We observed a specific, dose-dependent, direct inhibition of the CYP17 enzyme activity through compound C. By contrast, enzyme activities of HSD3B2 and CYP21A2 were not affected by compound C directly.	('HSD3B2', 'Gene', (141, 147))	('HSD3B2', 'Gene', '3284', (141, 147))	('compound', 'Var', (95, 103))	('inhibition', 'NegReg', (47, 57))	('CYP21A2', 'Gene', '1589', (152, 159))	('CYP21A2', 'Gene', (152, 159))	('activity', 'MPA', (78, 86))	('CYP17 enzyme', 'Enzyme', (65, 77))
21450	22295121	In this study, compound C delayed the decrease of p21 levels in cycloheximide-treated (chemical inhibitor of protein synthesis) cells, indicating that compound C may cause protein stabilization.	('p21 levels', 'MPA', (50, 60))	('protein stabilization', 'MPA', (172, 193))	('compound C', 'Var', (151, 161))	('cycloheximide', 'Chemical', 'MESH:D003513', (64, 77))
21534	29850793	Inactivating human NNT mutations result in congenital adrenal insufficiency.	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (54, 75))	('congenital adrenal insufficiency', 'Disease', (43, 75))	('human', 'Species', '9606', (13, 18))	('congenital adrenal insufficiency', 'Phenotype', 'HP:0008244', (43, 75))	('result in', 'Reg', (33, 42))	('Inactivating', 'Var', (0, 12))	('mutations', 'Var', (23, 32))	('NNT', 'Gene', (19, 22))	('congenital adrenal insufficiency', 'Disease', 'MESH:C566130', (43, 75))
21535	29850793	To explore this, we transiently knocked down NNT in NCI-H295R ACC cells.	('NNT', 'Gene', (45, 48))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('NCI-H295R', 'CellLine', 'CVCL:0458', (52, 61))	('knocked', 'Var', (32, 39))
21536	29850793	As predicted, this manipulation increased intracellular levels of oxidative stress; this resulted in a pronounced suppression of cell proliferation and higher apoptotic rates, as well as sensitization of cells to chemically induced oxidative stress.	('cell proliferation', 'CPA', (129, 147))	('higher', 'PosReg', (152, 158))	('rat', 'Species', '10116', (169, 172))	('oxidative stress', 'Phenotype', 'HP:0025464', (232, 248))	('manipulation', 'Var', (19, 31))	('suppression', 'NegReg', (114, 125))	('apoptotic rates', 'CPA', (159, 174))	('oxidative stress', 'Phenotype', 'HP:0025464', (66, 82))	('increased', 'PosReg', (32, 41))	('intracellular levels of oxidative stress', 'MPA', (42, 82))	('sensitization', 'Reg', (187, 200))	('rat', 'Species', '10116', (141, 144))	('increased intracellular levels', 'Phenotype', 'HP:0003575', (32, 62))
21539	29850793	After long-term culture, cells adapted metabolically to chronic NNT knockdown, restoring their redox balance and resilience to oxidative stress, although their proliferation remained suppressed.	('resilience to oxidative stress', 'MPA', (113, 143))	('oxidative stress', 'Phenotype', 'HP:0025464', (127, 143))	('redox balance', 'MPA', (95, 108))	('NNT', 'Gene', (64, 67))	('knockdown', 'Var', (68, 77))	('rat', 'Species', '10116', (167, 170))	('restoring', 'PosReg', (79, 88))
21548	29850793	Recent genetic studies have provided new insights into adrenal pathophysiology, revealing that inactivating mutations in the gene encoding the antioxidant enzyme nicotinamide nucleotide transhydrogenase (NNT) underlie a rare, hereditary form of primary adrenal insufficiency.	('nicotinamide nucleotide transhydrogenase', 'Gene', (162, 202))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (253, 274))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (253, 274))	('NNT', 'Gene', (204, 207))	('primary adrenal insufficiency', 'Phenotype', 'HP:0008207', (245, 274))	('nicotinamide nucleotide transhydrogenase', 'Gene', '23530', (162, 202))	('adrenal insufficiency', 'Disease', (253, 274))	('inactivating mutations', 'Var', (95, 117))	('underlie', 'Reg', (209, 217))
21561	29850793	Three alternative siRNAs targeting different areas of the NNT gene were tried (HSS118900, HSS118901, and HSS118902; Life Technologies/Thermo Fisher, Waltham, MA), and the one exhibiting the most consistent efficiency in knocking down NNT (HSS118902) was selected for subsequent experiments.	('HSS118902', 'Var', (105, 114))	('HSS118901', 'Chemical', '-', (90, 99))	('NNT', 'Gene', (58, 61))
21563	29850793	Lentiviral vectors were obtained from Dharmacon (Lafayette, CO) in a p.GIPZ backbone and contained five short hairpin RNAs (shRNAs) specific for human NNT (RHS4430-98851990, RHS4430-98913600, RHS4430-98524425, RHS4430-101033169, and RHS4430-101025114) under the control of the cytomegalovirus promoter, as well as the puromycin resistance and green fluorescence protein genes.	('human', 'Species', '9606', (145, 150))	('RHS4430-98851990', 'Var', (156, 172))	('RHS4430-98913600', 'Var', (174, 190))	('RHS4430-101025114', 'Var', (233, 250))	('puromycin', 'Chemical', 'MESH:D011691', (318, 327))	('RHS4430-98524425', 'Var', (192, 208))	('RHS4430-101033169', 'Var', (210, 227))
21580	29850793	Changes in proton concentration (or pH) provide the extracellular acidification rate (ECAR), reflective of the rate of glycolysis.	('extracellular acidification rate', 'MPA', (52, 84))	('rat', 'Species', '10116', (111, 114))	('rat', 'Species', '10116', (80, 83))	('proton concentration', 'MPA', (11, 31))	('Changes', 'Var', (0, 7))	('rat', 'Species', '10116', (25, 28))
21596	29850793	Additionally, RNA sequencing data from recently published work on three different mouse strains [Nnt inactivating mutation, C57BL/6J (RRID: MGI:3702942); wild-type, C57BL/6NHsd (RRID: MGI:2161078); and transgenic Nnt overexpressor, C57BL/6JBAC] were reanalyzed employing the same pathway analysis as for the human cell-based model; detailed information on this dataset can be found in Supplemental Methods.	('Nnt', 'Gene', '18115', (97, 100))	('Nnt', 'Gene', '18115', (213, 216))	('Nnt', 'Gene', (97, 100))	('C57BL/6J', 'Var', (124, 132))	('Nnt', 'Gene', (213, 216))	('human', 'Species', '9606', (308, 313))	('mouse', 'Species', '10090', (82, 87))	('inactivating', 'NegReg', (101, 113))
21600	29850793	NNT siRNA transfection in NCI-H295R cells yielded efficient gene silencing for at least 166 hours posttransfection with two different siRNAs (Supplemental Fig.	('gene', 'MPA', (60, 64))	('transfection', 'Var', (10, 22))	('NCI-H295R', 'CellLine', 'CVCL:0458', (26, 35))
21607	29850793	NNT KD by KD siRNA transfection led to a marked decrease in cellular proliferation rates (Fig.	('transfection', 'Var', (19, 31))	('rat', 'Species', '10116', (83, 86))	('rat', 'Species', '10116', (76, 79))	('cellular proliferation rates', 'CPA', (60, 88))	('decrease', 'NegReg', (48, 56))
21609	29850793	To establish whether the increased oxidative stress observed with NNT KD leads to higher rates of apoptosis, as predicted by ROS physiology, we measured intracellular caspase-3 and caspase-7 activity 120 hours posttransfection.	('caspase-7', 'Gene', (181, 190))	('NNT KD', 'Var', (66, 72))	('oxidative stress', 'Phenotype', 'HP:0025464', (35, 51))	('higher', 'PosReg', (82, 88))	('caspase-7', 'Gene', '840', (181, 190))	('activity', 'MPA', (191, 199))	('caspase-3', 'Gene', (167, 176))	('rat', 'Species', '10116', (89, 92))	('ROS', 'Chemical', 'MESH:D017382', (125, 128))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (25, 51))	('caspase-3', 'Gene', '836', (167, 176))	('oxidative stress', 'MPA', (35, 51))
21616	29850793	Treatment with 10 muM paraquat for 96 hours led to a statistically significant decrease in cell proliferation in cells transfected with KD siRNA, but not in their counterparts that had been transfected with SCR siRNA (Fig.	('rat', 'Species', '10116', (103, 106))	('paraquat', 'Chemical', 'MESH:D010269', (22, 30))	('muM', 'Gene', '56925', (18, 21))	('decrease', 'NegReg', (79, 87))	('muM', 'Gene', (18, 21))	('KD siRNA', 'Var', (136, 144))	('cell proliferation', 'CPA', (91, 109))
21618	29850793	The distinct metabolic consequences of NNT silencing in the stable KD setting, in comparison with acute KD by NNT siRNA, translated into an attenuated response with respect to cellular proliferation and viability.	('viability', 'CPA', (203, 212))	('rat', 'Species', '10116', (192, 195))	('silencing', 'Var', (43, 52))	('NNT', 'Gene', (39, 42))	('response', 'MPA', (151, 159))	('attenuated', 'NegReg', (140, 150))	('cellular proliferation', 'CPA', (176, 198))
21622	29850793	Interestingly, NNT KD shRNA cells consumed more oxygen than did SCR shRNA cells at baseline (Fig.	('oxygen', 'Chemical', 'MESH:D010100', (48, 54))	('consumed', 'MPA', (34, 42))	('NNT KD', 'Var', (15, 21))	('oxygen', 'MPA', (48, 54))
21625	29850793	We postulated that NNT silencing will disrupt steroidogenesis, either depriving mitochondrial steroidogenic monooxygenases [cholesterol side-chain cleaving enzyme (CYP11A1), 11beta-hydroxylase (CYP11B1), aldosterone synthase (CYP11B2)] of their essential electron donor NADPH, or due to oxidative stress-induced downregulation of key steroidogenic enzymes.	('oxidative stress', 'Phenotype', 'HP:0025464', (287, 303))	('depriving', 'NegReg', (70, 79))	('disrupt', 'NegReg', (38, 45))	('steroid', 'Chemical', 'MESH:D013256', (334, 341))	('silencing', 'Var', (23, 32))	('donor', 'Species', '9606', (264, 269))	('mitochondrial', 'MPA', (80, 93))	('steroidogenesis', 'MPA', (46, 61))	('key steroidogenic enzymes', 'Enzyme', (330, 355))	('CYP11B2', 'Gene', '1585', (226, 233))	('steroid', 'Chemical', 'MESH:D013256', (94, 101))	('steroid', 'Chemical', 'MESH:D013256', (46, 53))	('NADPH', 'Chemical', 'MESH:D009249', (270, 275))	('CYP11A1', 'Gene', '1583', (164, 171))	('CYP11B1', 'Gene', '1584', (194, 201))	('cholesterol', 'Chemical', 'MESH:D002784', (124, 135))	('oxygen', 'Chemical', 'MESH:D010100', (112, 118))	('CYP11B1', 'Gene', (194, 201))	('CYP11B2', 'Gene', (226, 233))	('downregulation', 'NegReg', (312, 326))	('CYP11A1', 'Gene', (164, 171))	('NNT', 'Gene', (19, 22))
21626	29850793	Surprisingly, NNT KD siRNA-transfected cells actually produced significantly more glucocorticoids (cortisol) and androgens (androstenedione) than did controls (Fig.	('androstenedione', 'Chemical', 'MESH:D000735', (124, 139))	('more', 'PosReg', (77, 81))	('NNT KD', 'Var', (14, 20))	('cortisol', 'Chemical', 'MESH:D006854', (99, 107))	('androgens', 'MPA', (113, 122))	('glucocorticoids', 'MPA', (82, 97))
21628	29850793	In contrast, in the shRNA-transfected cells with chronic NNT silencing we observed no significant impact on steroidogenesis, with similar rates of cortisol or androstenedione synthesis between KD shRNA and SCR shRNA cells (Fig.	('rat', 'Species', '10116', (138, 141))	('cortisol', 'MPA', (147, 155))	('steroidogenesis', 'MPA', (108, 123))	('androstenedione', 'Chemical', 'MESH:D000735', (159, 174))	('cortisol', 'Chemical', 'MESH:D006854', (147, 155))	('androstenedione synthesis', 'MPA', (159, 184))	('steroid', 'Chemical', 'MESH:D013256', (108, 115))	('silencing', 'Var', (61, 70))	('NNT', 'Gene', (57, 60))
21637	29850793	NCI-H295R treatment with doses of >=1 muM was associated with major cytotoxicity (Fig.	('muM', 'Gene', '56925', (38, 41))	('cytotoxicity', 'Disease', (68, 80))	('NCI-H295R', 'CellLine', 'CVCL:0458', (0, 9))	('muM', 'Gene', (38, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (68, 80))	('NCI-H295R', 'Var', (0, 9))
21642	29850793	performed RNA sequencing on mouse adrenal glands derived from three different mouse strains: a strain that carries an inactivating mutation of Nnt (C57BL/6J), a strain with wild-type Nnt expression (C57BL/6N), and transgenic mice overexpressing Nnt on the background of the NNT-deficient mouse strain (rescue model; C57BL/6JBAC).	('mouse', 'Species', '10090', (288, 293))	('transgenic mice', 'Species', '10090', (214, 229))	('mouse', 'Species', '10090', (28, 33))	('Nnt', 'Gene', (183, 186))	('Nnt', 'Gene', '18115', (143, 146))	('Nnt', 'Gene', (245, 248))	('mouse', 'Species', '10090', (78, 83))	('Nnt', 'Gene', (143, 146))	('inactivating mutation', 'Var', (118, 139))	('Nnt', 'Gene', '18115', (183, 186))	('Nnt', 'Gene', '18115', (245, 248))
21643	29850793	Detailed information on significantly dysregulated pathways in C57BL/6J vs C57BL/6N mice and C57BL/6J vs C57BL/6JBAC mice are presented in Supplemental Table 5.	('C57BL/6J', 'Var', (63, 71))	('mice', 'Species', '10090', (117, 121))	('C57BL/6J', 'Var', (93, 101))	('dysregulated', 'Reg', (38, 50))	('mice', 'Species', '10090', (84, 88))
21644	29850793	Significant dysregulation of the major cell signaling pathway of mitogen-activated signaling kinases was one of the salient molecular changes in both comparisons; the same pathway was also dysregulated with transient NNT KD in NCI-H295R cells.	('dysregulated', 'Reg', (189, 201))	('NNT KD', 'Var', (217, 223))	('NCI-H295R', 'CellLine', 'CVCL:0458', (227, 236))
21645	29850793	Oxidative phosphorylation was upregulated in both comparisons, but changes were much more pronounced in the C57BL/6J vs C57BL/6N comparison and likely to reflect a strain, rather than gene, effect.	('upregulated', 'PosReg', (30, 41))	('C57BL/6N', 'Var', (120, 128))	('C57BL/6J', 'Var', (108, 116))	('rat', 'Species', '10116', (172, 175))	('Oxidative phosphorylation', 'MPA', (0, 25))
21656	29850793	We hypothesized that NNT inhibition would compromise the ability of adrenocortical mitochondria to deal with oxidative stress, leading to progressive accumulation of ROS.	('ROS', 'MPA', (166, 169))	('accumulation', 'PosReg', (150, 162))	('oxidative stress', 'Phenotype', 'HP:0025464', (109, 125))	('adrenocortical mitochondria', 'Disease', (68, 95))	('adrenocortical mitochondria', 'Disease', 'MESH:D018268', (68, 95))	('ability', 'MPA', (57, 64))	('compromise', 'NegReg', (42, 52))	('deal with oxidative stress', 'MPA', (99, 125))	('ROS', 'Chemical', 'MESH:D017382', (166, 169))	('inhibition', 'Var', (25, 35))	('NNT', 'Gene', (21, 24))
21657	29850793	ROS excess has multiple toxic sequelae and can directly impair cell viability, triggering apoptosis.	('ROS excess', 'Var', (0, 10))	('ROS excess', 'Phenotype', 'HP:0025464', (0, 10))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('impair', 'NegReg', (56, 62))	('triggering', 'Reg', (79, 89))	('cell viability', 'CPA', (63, 77))	('apoptosis', 'CPA', (90, 99))
21658	29850793	Importantly, the adrenal-specific clinical phenotype in humans and the reported increased rate of adrenocortical cell apoptosis in otherwise healthy NNT mutant mice suggest that this manipulation may selectively target ACC cells, sparing other organs.	('NNT', 'Gene', (149, 152))	('ACC', 'Phenotype', 'HP:0006744', (219, 222))	('mutant', 'Var', (153, 159))	('mice', 'Species', '10090', (160, 164))	('adrenocortical', 'Disease', (98, 112))	('adrenocortical', 'Disease', 'MESH:D018268', (98, 112))	('humans', 'Species', '9606', (56, 62))	('rat', 'Species', '10116', (90, 93))
21660	29850793	Redox balance perturbations in response to NNT loss have been previously demonstrated in a limited number of cell lines in vitro, as well as in lymphocytes derived from NNT mutant patients ex vivo.	('Redox balance perturbations', 'MPA', (0, 27))	('rat', 'Species', '10116', (80, 83))	('NNT', 'Gene', (169, 172))	('mutant', 'Var', (173, 179))	('loss', 'NegReg', (47, 51))	('NNT', 'Gene', (43, 46))	('patients', 'Species', '9606', (180, 188))
21662	29850793	Importantly, in our study we observed that NNT silencing led to an immediate and marked inhibition of cell proliferation accompanied by increased apoptotic rates.	('rat', 'Species', '10116', (114, 117))	('rat', 'Species', '10116', (156, 159))	('inhibition', 'NegReg', (88, 98))	('silencing', 'Var', (47, 56))	('NNT', 'Gene', (43, 46))	('apoptotic rates', 'CPA', (146, 161))	('increased', 'PosReg', (136, 145))	('cell proliferation', 'CPA', (102, 120))
21666	29850793	Transient NNT silencing was previously shown to increase rates of apoptosis in PC12 (rat pheochromocytoma) cells; stable NNT KD in human melanoma cells was associated with reduced viability and high apoptotic rates in vitro, as well as slower growth of melanoma xenografts in mice.	('rat', 'Species', '10116', (57, 60))	('silencing', 'Var', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('melanoma', 'Disease', (253, 261))	('rat', 'Species', '10116', (85, 88))	('melanoma xenografts', 'Disease', (253, 272))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('slower growth', 'CPA', (236, 249))	('rat', 'Species', '10116', (209, 212))	('PC12', 'CellLine', 'CVCL:0481', (79, 83))	('pheochromocytoma', 'Disease', 'MESH:D010673', (89, 105))	('reduced', 'NegReg', (172, 179))	('apoptotic rates', 'CPA', (199, 214))	('human', 'Species', '9606', (131, 136))	('pheochromocytoma', 'Disease', (89, 105))	('melanoma xenografts', 'Disease', 'MESH:D008545', (253, 272))	('melanoma', 'Disease', 'MESH:D008545', (253, 261))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('mice', 'Species', '10090', (276, 280))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (89, 105))
21667	29850793	reported high levels of apoptosis in the zona fasciculata of the adrenal cortex from NNT mutant mice, as well as NCI-H295R cells stably transfected with shRNA against NNT in vitro.	('mice', 'Species', '10090', (96, 100))	('NCI-H295R', 'CellLine', 'CVCL:0458', (113, 122))	('apoptosis', 'MPA', (24, 33))	('NNT', 'Gene', (85, 88))	('zona fasciculata', 'Disease', (41, 57))	('mutant', 'Var', (89, 95))	('zona fasciculata', 'Disease', 'MESH:D006562', (41, 57))
21668	29850793	Although ROS have typically been associated with a stimulation of cellular proliferation, a number of in vitro models have demonstrated the opposite effect (suppression of cell division), in a complex relationship that may depend on the magnitude of ROS excess and/or tissue type.	('cellular proliferation', 'CPA', (66, 88))	('ROS excess', 'Phenotype', 'HP:0025464', (250, 260))	('stimulation', 'PosReg', (51, 62))	('rat', 'Species', '10116', (82, 85))	('rat', 'Species', '10116', (130, 133))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('ROS', 'Var', (9, 12))	('ROS', 'Chemical', 'MESH:D017382', (250, 253))	('suppression', 'NegReg', (157, 168))
21669	29850793	NNT inhibition may also interfere with cellular proliferation in a ROS-independent way, curtailing the amount of NADPH available to fuel the pressing anabolic needs of malignant cells.	('NADPH', 'Chemical', 'MESH:D009249', (113, 118))	('cellular proliferation', 'CPA', (39, 61))	('inhibition', 'Var', (4, 14))	('interfere', 'NegReg', (24, 33))	('ROS', 'Chemical', 'MESH:D017382', (67, 70))	('NNT', 'Gene', (0, 3))	('rat', 'Species', '10116', (55, 58))	('curtailing', 'NegReg', (88, 98))
21678	29850793	Previous studies on the effect of NNT silencing on oxygen consumption have shown mixed results, which may be cell type-dependent.	('NNT', 'Gene', (34, 37))	('oxygen consumption', 'MPA', (51, 69))	('silencing', 'Var', (38, 47))	('oxygen', 'Chemical', 'MESH:D010100', (51, 57))
21694	29850793	Pertinently, human mutations in thioredoxin reductase 2 have also been shown to result in isolated glucocorticoid deficiency.	('result in', 'Reg', (80, 89))	('isolated glucocorticoid deficiency', 'Disease', 'MESH:C565974', (90, 124))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (99, 124))	('human', 'Species', '9606', (13, 18))	('mutations', 'Var', (19, 28))	('thioredoxin reductase 2', 'Gene', (32, 55))	('isolated glucocorticoid deficiency', 'Disease', (90, 124))	('thioredoxin reductase 2', 'Gene', '10587', (32, 55))
21700	29850793	The observed effects of NNT silencing on NCI-H295R steroidogenesis were surprising.	('NNT', 'Gene', (24, 27))	('steroid', 'Chemical', 'MESH:D013256', (51, 58))	('NCI-H295R', 'CellLine', 'CVCL:0458', (41, 50))	('silencing', 'Var', (28, 37))	('NCI-H295R', 'MPA', (41, 50))
21705	29850793	Human patients with inactivating NNT mutations and a murine Nnt deletion model have been shown to have disrupted steroidogenesis; the data from our in vitro NNT KD models suggest that NNT loss is not limiting for adrenal steroidogenesis.	('Human', 'Species', '9606', (0, 5))	('Nnt', 'Gene', '18115', (60, 63))	('murine', 'Species', '10090', (53, 59))	('mutations', 'Var', (37, 46))	('NNT', 'Gene', (33, 36))	('patients', 'Species', '9606', (6, 14))	('inactivating', 'Var', (20, 32))	('Nnt', 'Gene', (60, 63))	('steroid', 'Chemical', 'MESH:D013256', (221, 228))	('steroid', 'Chemical', 'MESH:D013256', (113, 120))	('disrupted steroidogenesis', 'MPA', (103, 128))
21707	29850793	Taken together, we show that NNT silencing can induce cytotoxicity and impede cell growth in ACC cells, as well as sensitize them to chemically induced oxidative stress.	('cytotoxicity', 'Disease', (54, 66))	('sensitize', 'Reg', (115, 124))	('ACC', 'Phenotype', 'HP:0006744', (93, 96))	('silencing', 'Var', (33, 42))	('cell growth', 'CPA', (78, 89))	('NNT', 'Gene', (29, 32))	('impede', 'NegReg', (71, 77))	('cytotoxicity', 'Disease', 'MESH:D064420', (54, 66))	('induce', 'Reg', (47, 53))	('oxidative stress', 'Phenotype', 'HP:0025464', (152, 168))
21708	29850793	Moreover, we have demonstrated how the plasticity of ACC cells can lead to the development of a compensatory molecular response with time and described how changes in polyamine metabolism and ER protein processing are involved in this process (Fig.	('ER protein processing', 'MPA', (192, 213))	('involved', 'Reg', (218, 226))	('lead to', 'Reg', (67, 74))	('changes', 'Reg', (156, 163))	('compensatory molecular response', 'MPA', (96, 127))	('polyamine', 'Chemical', 'MESH:D011073', (167, 176))	('ACC', 'Phenotype', 'HP:0006744', (53, 56))	('plasticity', 'Var', (39, 49))	('rat', 'Species', '10116', (25, 28))	('polyamine metabolism', 'MPA', (167, 187))
21717	29403439	Histopathology revealed benign AO that was BRAFV600E negative, with low Ki-67, and no somatic mutation found on NGS.	('AO', 'Phenotype', 'HP:0011798', (31, 33))	('BRAFV600E negative', 'Var', (43, 61))	('low', 'NegReg', (68, 71))	('BRAFV600E', 'Mutation', 'rs113488022', (43, 52))	('Ki-67', 'MPA', (72, 77))
21718	29403439	Thyroidectomy revealed invasive, BRAFV600E-positive PTC.	('BRAFV600E-positive', 'Var', (33, 51))	('PTC', 'Gene', '5979', (52, 55))	('PTC', 'Phenotype', 'HP:0002895', (52, 55))	('BRAFV600E', 'Mutation', 'rs113488022', (33, 42))	('TC', 'Phenotype', 'HP:0002890', (53, 55))	('PTC', 'Gene', (52, 55))
21728	29403439	Mutations with activation of MAPK and PI3K-AKT signaling pathways are crucial in the pathogenesis of PTC.	('activation', 'PosReg', (15, 25))	('PI3K-AKT signaling pathways', 'Pathway', (38, 65))	('PTC', 'Gene', '5979', (101, 104))	('TC', 'Phenotype', 'HP:0002890', (102, 104))	('PTC', 'Phenotype', 'HP:0002895', (101, 104))	('Mutations', 'Var', (0, 9))	('MAPK', 'Gene', (29, 33))	('PTC', 'Gene', (101, 104))
21729	29403439	Common alterations are point mutations of BRAF (most commonly V600E) and RAS genes as well as RET/PTC and PAX8/PPARgamma chromosomal rearrangements.	('BRAF', 'Gene', '673', (42, 46))	('TC', 'Phenotype', 'HP:0002890', (99, 101))	('alterations', 'Reg', (7, 18))	('PPARgamma', 'Gene', '5468', (111, 120))	('point mutations', 'Var', (23, 38))	('PAX8', 'Gene', '7849', (106, 110))	('V600E', 'Var', (62, 67))	('PAX8', 'Gene', (106, 110))	('RET', 'Gene', '5979', (94, 97))	('PTC', 'Gene', (98, 101))	('PTC', 'Gene', '5979', (98, 101))	('RET', 'Gene', (94, 97))	('PTC', 'Phenotype', 'HP:0002895', (98, 101))	('BRAF', 'Gene', (42, 46))	('RAS genes', 'Gene', (73, 82))	('V600E', 'Mutation', 'rs113488022', (62, 67))	('PPARgamma', 'Gene', (111, 120))
21735	29403439	ACC is known to appear in Li-Fraumeni syndrome with TP53 mutation.	('mutation', 'Var', (57, 65))	('TP53', 'Gene', '7157', (52, 56))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (26, 46))	('TP53', 'Gene', (52, 56))	('appear', 'Reg', (16, 22))	('Li-Fraumeni syndrome', 'Disease', (26, 46))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))
21753	29403439	In addition, next-generation sequencing (NGS) was performed on the adrenal tissue, including known mutations in ACC [p53, RB1, and CTNNB1 ]; 2,800 (hotspot) mutations in a classic panel of 50 genes associated with different cancers (Ion Ampliseq Cancer Hotspot v2) were assessed using the Ion Proton  system (see Table S1 in Supplementary Material for list of the 50 tested genes).	('RB1', 'Gene', '5925', (122, 125))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('CTNNB1', 'Gene', '1499', (131, 137))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('ACC', 'Phenotype', 'HP:0006744', (112, 115))	('mutations', 'Var', (157, 166))	('mutations', 'Var', (99, 108))	('CTNNB1', 'Gene', (131, 137))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('RB1', 'Gene', (122, 125))	('cancers', 'Disease', (224, 231))	('Cancer', 'Phenotype', 'HP:0002664', (246, 252))
21841	23123734	In other primary tumors, ERRalpha was reported to be associated with reduced survival in ovarian cancer, with a higher tumor grade in colon cancer, with high grade and invasion in endometrial cancer and with clinical advanced stage in prostate cancer.	('prostate cancer', 'Disease', (235, 250))	('tumors', 'Disease', (17, 23))	('endometrial cancer', 'Phenotype', 'HP:0012114', (180, 198))	('colon cancer', 'Disease', (134, 146))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('endometrial cancer', 'Disease', (180, 198))	('ovarian cancer', 'Disease', 'MESH:D010051', (89, 103))	('ERRalpha', 'Var', (25, 33))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('endometrial cancer', 'Disease', 'MESH:D016889', (180, 198))	('tumor', 'Disease', (17, 22))	('colon cancer', 'Phenotype', 'HP:0003003', (134, 146))	('ovarian cancer', 'Disease', (89, 103))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ovarian cancer', 'Phenotype', 'HP:0100615', (89, 103))	('tumor', 'Disease', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('higher', 'PosReg', (112, 118))	('reduced', 'NegReg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('colon cancer', 'Disease', 'MESH:D015179', (134, 146))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('survival', 'MPA', (77, 85))	('prostate cancer', 'Disease', 'MESH:D011471', (235, 250))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('prostate cancer', 'Phenotype', 'HP:0012125', (235, 250))
21901	24498411	Re-localization of GRIM-19 could lead to dysfunctional mitochondria and STAT3 hyperactivation, which in turn could drive the tumorigenesis in ACCs.	('Re-localization', 'Var', (0, 15))	('lead to', 'Reg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('STAT3', 'Gene', (72, 77))	('GRIM-19', 'Gene', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('ACCs', 'Phenotype', 'HP:0006744', (142, 146))	('tumor', 'Disease', (125, 130))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (41, 67))	('drive', 'PosReg', (115, 120))	('STAT3', 'Gene', '6774', (72, 77))	('dysfunctional mitochondria', 'Disease', (41, 67))
21909	24498411	Cases with high nuclear grade, increased mitotic figures and tumor necrosis were suspected to be malignant.	('tumor necrosis', 'Disease', (61, 75))	('increased', 'PosReg', (31, 40))	('tumor necrosis', 'Disease', 'MESH:D009336', (61, 75))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('high', 'Var', (11, 15))	('mitotic figures', 'CPA', (41, 56))
22022	23323831	While EGFR and RAS mutants are not commonly observed in ovarian cancer , activation of these well-studied oncogenes may still play an important role in progression and survival in ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('EGFR', 'Gene', (6, 10))	('ovarian cancer', 'Phenotype', 'HP:0100615', (56, 70))	('ovarian cancer', 'Phenotype', 'HP:0100615', (180, 194))	('mutants', 'Var', (19, 26))	('ovarian cancer', 'Disease', 'MESH:D010051', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('ovarian cancer', 'Disease', 'MESH:D010051', (180, 194))	('ovarian cancer', 'Disease', (56, 70))	('EGFR', 'Gene', '1956', (6, 10))	('ovarian cancer', 'Disease', (180, 194))
22050	23323831	In the Additional file 1, two other examples of GSVA applications can be found including differential pathway analysis in a multi-class adrenocortical carcinoma data set (Additional file 1: Figure S3 and Table S1), and correlation analysis of pathways and copy-number alterations in ovarian carcinoma (Additional file 1: Figure S5).	('copy-number alterations', 'Var', (256, 279))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (136, 160))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (136, 160))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (283, 300))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (283, 300))	('ovarian carcinoma', 'Disease', (283, 300))	('adrenocortical carcinoma', 'Disease', (136, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('GSVA', 'Chemical', '-', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
22051	23323831	For future directions, we believe GSVA may be used in genetical genomics strategies analogous to eQTL mapping to study, what we might call, pathway-QTL to identify DNA polymorphisms that impact pathway activity .	('impact', 'Reg', (187, 193))	('pathway', 'Pathway', (194, 201))	('polymorphisms', 'Var', (168, 181))	('GSVA', 'Chemical', '-', (34, 38))	('activity', 'MPA', (202, 210))
22082	21120066	In case of adrenal hyperplasia with ectopic adrenocorticotropic hormone (ACTH) secretion, one patient underwent pituitary magnetic resonance imaging (MRI), Chest computed tomography (CT) scan and a high-dose dexamethaone suppression test (2 mg every 6 hours for 2 days).	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (11, 30))	('ACTH', 'Gene', '5443', (73, 77))	('ectopic', 'Var', (36, 43))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (11, 30))	('adrenocorticotropic hormone', 'Gene', (44, 71))	('adrenocorticotropic hormone', 'Gene', '5443', (44, 71))	('dexamethaone', 'Chemical', '-', (208, 220))	('patient', 'Species', '9606', (94, 101))	('ACTH', 'Gene', (73, 77))	('adrenal hyperplasia', 'Disease', (11, 30))
22115	21120066	In our study, both patients of ectopic ACTH secretion have shown thickening and elongation of the adrenal rami.	('patients', 'Species', '9606', (19, 27))	('thickening', 'CPA', (65, 75))	('ACTH', 'Gene', (39, 43))	('ACTH', 'Gene', '5443', (39, 43))	('ectopic', 'Var', (31, 38))	('elongation of the adrenal rami', 'CPA', (80, 110))
22150	33808494	The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG).	('U87MG', 'CellLine', 'CVCL:0022', (186, 191))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('U87MG', 'Var', (186, 191))	('U251MG', 'Var', (175, 181))	('AT101', 'Chemical', 'MESH:C028178', (43, 48))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('TMZ', 'Chemical', 'MESH:D000077204', (93, 96))	('U251MG', 'CellLine', 'CVCL:0021', (175, 181))	('temozolomide', 'Chemical', 'MESH:D000077204', (79, 91))	('GBM', 'Phenotype', 'HP:0012174', (159, 162))	('glioma', 'Disease', (123, 129))	('AT101', 'Gene', (43, 48))
22151	33808494	AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells.	('U251MG', 'Var', (54, 60))	('U251MG', 'CellLine', 'CVCL:0021', (54, 60))	('AT101', 'Var', (0, 5))	('cytotoxic effects', 'CPA', (33, 50))	('AT101', 'Chemical', 'MESH:C028178', (0, 5))	('U87MG', 'CellLine', 'CVCL:0022', (65, 70))	('U87MG', 'Var', (65, 70))
22154	33808494	Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.	('tumor', 'Disease', (68, 73))	('GBM', 'Phenotype', 'HP:0012174', (220, 223))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('AT101', 'Var', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('AT101', 'Chemical', 'MESH:C028178', (131, 136))	('tumor', 'Disease', (6, 11))
22161	33808494	AT101 is characterized by versatile modes of action resulting in, e.g., anti-inflammatory, anti-oxidative, or especially anti-tumorigenic effects (alone or in combination with other drugs) on several tumor entities, including GBMs.	('anti-oxidative', 'MPA', (91, 105))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('AT101', 'Var', (0, 5))	('GBM', 'Phenotype', 'HP:0012174', (226, 229))	('tumor', 'Disease', (200, 205))	('AT101', 'Chemical', 'MESH:C028178', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('GBMs', 'Phenotype', 'HP:0012174', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('anti-inflammatory', 'MPA', (72, 89))	('tumor', 'Disease', (126, 131))
22162	33808494	AT101 was able to trigger autophagic, mitophagic, or apoptotic cell death by competitive inhibition of Bcl-2 proteins.	('Bcl-2', 'Gene', '596', (103, 108))	('mitophagic', 'CPA', (38, 48))	('apoptotic cell death', 'CPA', (53, 73))	('AT101', 'Var', (0, 5))	('trigger', 'PosReg', (18, 25))	('AT101', 'Chemical', 'MESH:C028178', (0, 5))	('autophagic', 'CPA', (26, 36))	('inhibition', 'NegReg', (89, 99))	('Bcl-2', 'Gene', (103, 108))
22167	33808494	Interestingly, AT101 was also able to suppress the growth of TMZ-resistant GBM tumorspheres and could target glioma stem-like cells via the inhibition of the hedgehog and notch signaling pathways resulting in the inhibition of tumor growth.	('tumor', 'Disease', (227, 232))	('growth', 'CPA', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('inhibition', 'NegReg', (213, 223))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('GBM', 'Phenotype', 'HP:0012174', (75, 78))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('AT101', 'Chemical', 'MESH:C028178', (15, 20))	('inhibition', 'NegReg', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Disease', (79, 84))	('TMZ-resistant GBM tumorspheres', 'Disease', 'MESH:D005910', (61, 91))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('suppress', 'NegReg', (38, 46))	('AT101', 'Var', (15, 20))	('glioma', 'Disease', (109, 115))	('TMZ-resistant GBM tumorspheres', 'Disease', (61, 91))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
22172	33808494	As a first step, we compared the influence of an AT101, TMZ, or a combinational treatment of both on the survival of native and stem-like U251MG and U87MG GBM cells by cytotoxicity assays (Figure 1A-D) and determination of proliferation (Figure 2A-D) for up to six days, respectively.	('cytotoxicity', 'Disease', 'MESH:D064420', (168, 180))	('AT101', 'Chemical', 'MESH:C028178', (49, 54))	('TMZ', 'Chemical', 'MESH:D000077204', (56, 59))	('U87MG', 'CellLine', 'CVCL:0022', (149, 154))	('U87MG', 'Var', (149, 154))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))	('cytotoxicity', 'Disease', (168, 180))	('U251MG', 'CellLine', 'CVCL:0021', (138, 144))
22174	33808494	This effect could be slightly enhanced by the combinational treatment with TMZ (50 microM) and AT101 (5 microM), especially after six days of treatment (25-35% dead cells).	('enhanced', 'PosReg', (30, 38))	('TMZ', 'Var', (75, 78))	('AT101', 'Chemical', 'MESH:C028178', (95, 100))	('AT101', 'Var', (95, 100))	('TMZ', 'Chemical', 'MESH:D000077204', (75, 78))
22177	33808494	In contrast, stem-like U251MG and U87MG GBM cells were strongly affected by solely applied AT101 (Figure 1C,D) in comparison to the respective controls.	('GBM', 'Phenotype', 'HP:0012174', (40, 43))	('affected', 'Reg', (64, 72))	('U251MG', 'CellLine', 'CVCL:0021', (23, 29))	('AT101', 'Chemical', 'MESH:C028178', (91, 96))	('U87MG', 'CellLine', 'CVCL:0022', (34, 39))	('U87MG', 'Var', (34, 39))
22181	33808494	Accordingly, AT101, and the combination of TMZ plus AT101 strongly inhibited the proliferation in stem-like cells, whereas solely applied TMZ showed only moderate anti-proliferative effects (Figure 2C,D).	('TMZ', 'Chemical', 'MESH:D000077204', (138, 141))	('inhibited', 'NegReg', (67, 76))	('AT101', 'Chemical', 'MESH:C028178', (13, 18))	('AT101', 'Var', (13, 18))	('TMZ', 'Chemical', 'MESH:D000077204', (43, 46))	('AT101', 'Var', (52, 57))	('proliferation in stem-like cells', 'CPA', (81, 113))	('AT101', 'Chemical', 'MESH:C028178', (52, 57))
22182	33808494	To analyze whether the high responsiveness of GBM stem-like cells on an AT101 treatment is determined by the environmental stem cell niche as marked by, e.g., stem cell-secreted and probably autocrine and/or paracrine active factors, we started to produce stem-like cell-conditioned media of stem-like U251MG and U87MG GBM cells and performed cytotoxicity and proliferation assays (Figure 3A-F).	('GBM', 'Phenotype', 'HP:0012174', (319, 322))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))	('U87MG', 'Var', (313, 318))	('cytotoxicity', 'Disease', (343, 355))	('U251MG', 'CellLine', 'CVCL:0021', (302, 308))	('cytotoxicity', 'Disease', 'MESH:D064420', (343, 355))	('U87MG', 'CellLine', 'CVCL:0022', (313, 318))	('AT101', 'Chemical', 'MESH:C028178', (72, 77))
22183	33808494	Therefore, the corresponding native U251MG and U87MG GBM cells were stimulated with stem-like cell-conditioned media containing AT101, TMZ, or the combination of both for up to six days.	('AT101', 'Chemical', 'MESH:C028178', (128, 133))	('U251MG', 'CellLine', 'CVCL:0021', (36, 42))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('TMZ', 'Chemical', 'MESH:D000077204', (135, 138))	('U87MG', 'CellLine', 'CVCL:0022', (47, 52))	('U87MG', 'Var', (47, 52))	('AT101', 'Var', (128, 133))
22185	33808494	On the contrary, stimulation with stem-like cell-conditioned media with AT101 yielded a strong enhancement of the cytotoxic effects of AT101 on the native U251MG and U87MG cells.	('AT101', 'Chemical', 'MESH:C028178', (135, 140))	('cytotoxic effects', 'CPA', (114, 131))	('enhancement', 'PosReg', (95, 106))	('U251MG', 'CellLine', 'CVCL:0021', (155, 161))	('AT101', 'Var', (72, 77))	('AT101', 'Var', (135, 140))	('AT101', 'Chemical', 'MESH:C028178', (72, 77))	('U87MG', 'CellLine', 'CVCL:0022', (166, 171))
22186	33808494	In detail, comparable to the effects of AT101 measured in the stem-like U251MG and U87MG cells (Figure 1C,D), up to 70-90% of native cells treated with stem-like cell-conditioned media containing AT101 died after six days of stimulation (Figure 3A,B).	('AT101', 'Chemical', 'MESH:C028178', (40, 45))	('AT101', 'Chemical', 'MESH:C028178', (196, 201))	('AT101', 'Var', (196, 201))	('U251MG', 'CellLine', 'CVCL:0021', (72, 78))	('died', 'Disease', (202, 206))	('died', 'Disease', 'MESH:D003643', (202, 206))	('U87MG', 'CellLine', 'CVCL:0022', (83, 88))
22187	33808494	Thus, the stem-like cell-conditioned media seemed to enhance the cytotoxic potential of the AT101 treatment.	('cytotoxic potential', 'CPA', (65, 84))	('AT101', 'Chemical', 'MESH:C028178', (92, 97))	('AT101', 'Var', (92, 97))	('enhance', 'PosReg', (53, 60))
22188	33808494	However, an enhancement of the cytotoxic activity of AT101 was also observed using media without any stem-like cell contact (control media) (Figure 3A,B).	('AT101', 'Chemical', 'MESH:C028178', (53, 58))	('AT101', 'Var', (53, 58))	('enhancement', 'PosReg', (12, 23))	('cytotoxic activity', 'CPA', (31, 49))
22191	33808494	Summarizing this point, although the control media itself seemed to be able to enhance the cytotoxic potential of AT101 (15-35% dead cells), the stem-like cell-conditioned media produced by the U251MG and U87MG stem-like cells was clearly more efficient (70-90% dead native cells).	('U87MG', 'CellLine', 'CVCL:0022', (205, 210))	('cytotoxic potential', 'CPA', (91, 110))	('U87MG', 'Var', (205, 210))	('enhance', 'PosReg', (79, 86))	('U251MG', 'CellLine', 'CVCL:0021', (194, 200))	('AT101', 'Chemical', 'MESH:C028178', (114, 119))	('U251MG', 'Var', (194, 200))
22193	33808494	Indeed, a further enhancement of the cytotoxic efficiency of the combinational treatment was detectable upon application of the stem-like cell conditioned media in the native U251MG and U87MG cells, respectively (80-95% dead cells).	('U87MG', 'CellLine', 'CVCL:0022', (186, 191))	('enhancement', 'PosReg', (18, 29))	('U87MG', 'Var', (186, 191))	('U251MG', 'Var', (175, 181))	('U251MG', 'CellLine', 'CVCL:0021', (175, 181))	('cytotoxic efficiency', 'CPA', (37, 57))
22195	33808494	Nevertheless, the amounts of dead cells distinctly increased further when AT101 and TMZ plus AT101 were added to the GBM cells together with stem-like cell-conditioned media (Figure 3A,B).	('AT101', 'Chemical', 'MESH:C028178', (74, 79))	('AT101', 'Var', (74, 79))	('increased', 'PosReg', (51, 60))	('TMZ', 'Chemical', 'MESH:D000077204', (84, 87))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('AT101', 'Var', (93, 98))	('AT101', 'Chemical', 'MESH:C028178', (93, 98))
22197	33808494	In contrast, both AT101 and the combination of TMZ plus AT101 were able to induce strong anti-proliferative effects on both native GBM cell lines, respectively.	('GBM', 'Phenotype', 'HP:0012174', (131, 134))	('AT101', 'Var', (18, 23))	('anti-proliferative effects', 'CPA', (89, 115))	('AT101', 'Chemical', 'MESH:C028178', (18, 23))	('TMZ', 'Chemical', 'MESH:D000077204', (47, 50))	('AT101', 'Chemical', 'MESH:C028178', (56, 61))	('AT101', 'Var', (56, 61))
22198	33808494	Control media were able to promote the anti-proliferative effects of AT101 and TMZ plus AT101, but stem-like cell-conditioned media were clearly more efficient (Figure 3C-F).	('AT101', 'Var', (88, 93))	('anti-proliferative effects', 'CPA', (39, 65))	('AT101', 'Chemical', 'MESH:C028178', (88, 93))	('AT101', 'Var', (69, 74))	('promote', 'PosReg', (27, 34))	('AT101', 'Chemical', 'MESH:C028178', (69, 74))	('TMZ', 'Chemical', 'MESH:D000077204', (79, 82))
22199	33808494	As a next step, we performed investigations regarding the influence of the different treatment conditions with stem-like cell-conditioned media on the activation of the ERK signaling pathway in native U251MG and U87MG GBM cells.	('ERK', 'Gene', '5594', (169, 172))	('ERK', 'Gene', (169, 172))	('GBM', 'Phenotype', 'HP:0012174', (218, 221))	('U87MG', 'CellLine', 'CVCL:0022', (212, 217))	('U87MG', 'Var', (212, 217))	('U251MG', 'Var', (201, 207))	('U251MG', 'CellLine', 'CVCL:0021', (201, 207))
22201	33808494	Whereas, in relation to controls, no clear influence on the phosphorylation/activation of p42/44 was detectable upon solely applied TMZ treatment, irrespective of whether administered with control or stem-like cell-conditioned media, a treatment with AT101 as well as with TMZ plus AT101 yielded strong inhibitory effects on the phospho-p42/44 signals.	('TMZ', 'Chemical', 'MESH:D000077204', (132, 135))	('TMZ', 'Chemical', 'MESH:D000077204', (273, 276))	('phospho-p42/44 signals', 'MPA', (329, 351))	('AT101', 'Var', (251, 256))	('inhibitory effects', 'NegReg', (303, 321))	('AT101', 'Chemical', 'MESH:C028178', (251, 256))	('AT101', 'Chemical', 'MESH:C028178', (282, 287))
22202	33808494	Especially in native U251MG GBM cells, the application of the chemotherapeutic agents combined with the stem-like cell-conditioned media showed very pronounced effects compared to the corresponding control media (Figure 4A).	('U251MG', 'Var', (21, 27))	('effects', 'Reg', (160, 167))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('U251MG', 'CellLine', 'CVCL:0021', (21, 27))
22204	33808494	As a next step, we considered whether the native U251MG and U87MG cells did undergo dedifferentiation and responded to the stimulation with stem-like cell-conditioned media with a change of the expression of stem cell markers.	('U87MG', 'Var', (60, 65))	('dedifferentiation', 'CPA', (84, 101))	('U87MG', 'CellLine', 'CVCL:0022', (60, 65))	('U251MG', 'CellLine', 'CVCL:0021', (49, 55))	('expression', 'MPA', (194, 204))	('U251MG', 'Var', (49, 55))
22205	33808494	Thus, we measured the messenger RNA (mRNA) expression of the stem cell markers kruppel-like factor 4 (KLF4), octamer binding transcription factor (OCT4), and Nestin in native U251MG and U87MG GBM cells treated with solely TMZ, AT101, or the combination of TMZ plus AT101 in stem-like cell-conditioned media including the different control samples (Figure 5).	('U87MG', 'CellLine', 'CVCL:0022', (186, 191))	('OCT4', 'Gene', '5460', (147, 151))	('KLF4', 'Gene', (102, 106))	('KLF4', 'Gene', '9314', (102, 106))	('Nestin', 'Gene', (158, 164))	('U251MG', 'CellLine', 'CVCL:0021', (175, 181))	('Nestin', 'Gene', '10763', (158, 164))	('GBM', 'Phenotype', 'HP:0012174', (192, 195))	('TMZ', 'Chemical', 'MESH:D000077204', (256, 259))	('kruppel-like factor 4', 'Gene', '9314', (79, 100))	('AT101', 'Chemical', 'MESH:C028178', (227, 232))	('TMZ', 'Chemical', 'MESH:D000077204', (222, 225))	('AT101', 'Var', (265, 270))	('kruppel-like factor 4', 'Gene', (79, 100))	('OCT4', 'Gene', (147, 151))	('AT101', 'Chemical', 'MESH:C028178', (265, 270))
22206	33808494	In relation to the corresponding controls, an upregulation of the expression of KLF4 was observed after treatment with solely AT101 or TMZ plus AT101 in both U251MG and U87MG native cells (Figure 5A,B).	('U87MG', 'CellLine', 'CVCL:0022', (169, 174))	('upregulation', 'PosReg', (46, 58))	('U251MG', 'CellLine', 'CVCL:0021', (158, 164))	('U87MG', 'Var', (169, 174))	('AT101', 'Var', (126, 131))	('U251MG', 'Var', (158, 164))	('AT101', 'Chemical', 'MESH:C028178', (126, 131))	('expression', 'MPA', (66, 76))	('AT101', 'Chemical', 'MESH:C028178', (144, 149))	('TMZ', 'Chemical', 'MESH:D000077204', (135, 138))	('KLF4', 'Gene', '9314', (80, 84))	('KLF4', 'Gene', (80, 84))
22207	33808494	The expression of OCT4 was upregulated upon treatment with solely AT101 or TMZ plus AT101 only in U251 native cells, which was again found for both culturing conditions, respectively, whereas in U87MG native cells, no effects of the treatment conditions on OCT4 expression were observed (Figure 5C,D).	('AT101', 'Chemical', 'MESH:C028178', (84, 89))	('OCT4', 'Gene', (18, 22))	('expression', 'MPA', (4, 14))	('TMZ', 'Chemical', 'MESH:D000077204', (75, 78))	('upregulated', 'PosReg', (27, 38))	('AT101', 'Var', (66, 71))	('U87MG', 'CellLine', 'CVCL:0022', (195, 200))	('AT101', 'Chemical', 'MESH:C028178', (66, 71))	('OCT4', 'Gene', '5460', (257, 261))	('OCT4', 'Gene', '5460', (18, 22))	('OCT4', 'Gene', (257, 261))
22209	33808494	Interestingly, Nestin expression was found to be significantly downregulated upon treatment with solely AT101 or AT101 plus TMZ in comparison to the respective controls in U87MG native cells after three days of treatment, whereas in U251MG, no regulation was observed (Figure 5E,F).	('TMZ', 'Chemical', 'MESH:D000077204', (124, 127))	('AT101', 'Var', (113, 118))	('Nestin', 'Gene', '10763', (15, 21))	('AT101', 'Chemical', 'MESH:C028178', (113, 118))	('U251MG', 'CellLine', 'CVCL:0021', (233, 239))	('downregulated', 'NegReg', (63, 76))	('Nestin', 'Gene', (15, 21))	('AT101', 'Var', (104, 109))	('U87MG', 'CellLine', 'CVCL:0022', (172, 177))	('expression', 'MPA', (22, 32))	('AT101', 'Chemical', 'MESH:C028178', (104, 109))
22210	33808494	However, after six days of treatment of U87MG native cells, the expression levels of Nestin were comparable to the respective controls.	('expression', 'MPA', (64, 74))	('Nestin', 'Gene', '10763', (85, 91))	('U87MG', 'CellLine', 'CVCL:0022', (40, 45))	('U87MG', 'Var', (40, 45))	('Nestin', 'Gene', (85, 91))
22212	33808494	Thus, firstly, the mRNA expression of different cytokine and chemokine ligands was analyzed in both U251MG and U87MG GBM stem-like cells (Figure 6A,B).	('U87MG', 'CellLine', 'CVCL:0022', (111, 116))	('U87MG', 'Var', (111, 116))	('U251MG', 'Var', (100, 106))	('U251MG', 'CellLine', 'CVCL:0021', (100, 106))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))
22215	33808494	In U251MG stem-like cells, the chemokine ligands CXCL11, CXCL12, CXCL16, and CX3CL1, as well as the cytokines transforming growth factor beta (TGF-beta) and interleukin 6 (IL-6) were all expressed in moderate but clearly detectable amounts (DeltaCT values 9-13) (Figure 6A).	('IL-6', 'Gene', '3569', (172, 176))	('interleukin 6', 'Gene', (157, 170))	('TGF-beta', 'Gene', '7039', (143, 151))	('U251MG', 'CellLine', 'CVCL:0021', (3, 9))	('U251MG', 'Var', (3, 9))	('TGF-beta', 'Gene', (143, 151))	('CXCL16', 'Gene', (65, 71))	('interleukin 6', 'Gene', '3569', (157, 170))	('CXCL12', 'Gene', (57, 63))	('CX3CL1', 'Gene', '6376', (77, 83))	('IL-6', 'Gene', (172, 176))	('CXCL16', 'Gene', '58191', (65, 71))	('CXCL11', 'Gene', (49, 55))	('CX3CL1', 'Gene', (77, 83))	('CXCL11', 'Gene', '6373', (49, 55))	('CXCL12', 'Gene', '6387', (57, 63))
22219	33808494	When comparing both native GBM cell types, CXCL16 and CX3CL1 were clearly lower expressed in U87MG native cells (DeltaCT values ~15-25), whereas CXCR7 was highly expressed (DeltaCT values ~6) (Figure 6C,D).	('U87MG', 'Var', (93, 98))	('CXCL16', 'Gene', '58191', (43, 49))	('U87MG', 'CellLine', 'CVCL:0022', (93, 98))	('CXCR7', 'Gene', '57007', (145, 150))	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('CX3CL1', 'Gene', '6376', (54, 60))	('CXCL16', 'Gene', (43, 49))	('lower', 'NegReg', (74, 79))	('CX3CL1', 'Gene', (54, 60))	('CXCR7', 'Gene', (145, 150))
22221	33808494	Additionally, an influence on the CXCR7 expression seemed to be more pronounced in the native U251MG cells compared to the U87MG GBM cells (Figure 7A,B).	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('influence', 'Reg', (17, 26))	('CXCR7', 'Gene', (34, 39))	('U87MG', 'CellLine', 'CVCL:0022', (123, 128))	('U251MG', 'Var', (94, 100))	('U251MG', 'CellLine', 'CVCL:0021', (94, 100))	('CXCR7', 'Gene', '57007', (34, 39))
22223	33808494	In particular, native U251MG cells responded to an AT101 or a combined TMZ plus AT101 treatment with an upregulation of CXCR7 upon stimulation with the control media, and this effect was clearly smaller upon stimulation with stem-like cell-conditioned media (Figure 7A).	('upregulation', 'PosReg', (104, 116))	('AT101', 'Chemical', 'MESH:C028178', (80, 85))	('U251MG', 'CellLine', 'CVCL:0021', (22, 28))	('CXCR7', 'Gene', (120, 125))	('TMZ', 'Chemical', 'MESH:D000077204', (71, 74))	('AT101', 'Chemical', 'MESH:C028178', (51, 56))	('AT101', 'Var', (51, 56))	('AT101', 'Var', (80, 85))	('CXCR7', 'Gene', '57007', (120, 125))
22224	33808494	In detail, the CXCR7 expression accounted only for the 0.13-fold amount that was detected upon AT101 treatment and for the 0.28-fold amount found upon TMZ plus AT101 application compared to the respective controls.	('CXCR7', 'Gene', (15, 20))	('AT101', 'Chemical', 'MESH:C028178', (160, 165))	('AT101', 'Chemical', 'MESH:C028178', (95, 100))	('AT101', 'Var', (95, 100))	('CXCR7', 'Gene', '57007', (15, 20))	('TMZ', 'Chemical', 'MESH:D000077204', (151, 154))
22227	33808494	In native U87MG cells, which were treated with stem-like cell-conditioned media plus AT101 or TMZ plus AT101, both CXCL16 and CX3CL1 seemed to be downregulated (Figure 7D,F).	('CX3CL1', 'Gene', (126, 132))	('TMZ', 'Chemical', 'MESH:D000077204', (94, 97))	('AT101', 'Var', (85, 90))	('AT101', 'Chemical', 'MESH:C028178', (85, 90))	('CXCL16', 'Gene', (115, 121))	('U87MG', 'CellLine', 'CVCL:0022', (10, 15))	('downregulated', 'NegReg', (146, 159))	('AT101', 'Chemical', 'MESH:C028178', (103, 108))	('CX3CL1', 'Gene', '6376', (126, 132))	('CXCL16', 'Gene', '58191', (115, 121))
22231	33808494	Further, IL-6R expression was induced up to 3.59-fold higher amounts upon AT101 treatment in comparison to control media in U87MG cells.	('AT101', 'Chemical', 'MESH:C028178', (74, 79))	('IL-6R', 'Gene', '3570', (9, 14))	('higher', 'PosReg', (54, 60))	('AT101 treatment', 'Var', (74, 89))	('IL-6R', 'Gene', (9, 14))	('expression', 'MPA', (15, 25))	('induced', 'PosReg', (30, 37))	('U87MG', 'CellLine', 'CVCL:0022', (124, 129))
22234	33808494	Further, stem-like cell-conditioned media was able to enhance the chemosensitivity of native U251MG and U87MG GBM cells upon AT101 and TMZ plus AT101 treatment.	('U87MG', 'Var', (104, 109))	('TMZ', 'Chemical', 'MESH:D000077204', (135, 138))	('AT101', 'Chemical', 'MESH:C028178', (144, 149))	('GBM', 'Phenotype', 'HP:0012174', (110, 113))	('enhance', 'PosReg', (54, 61))	('chemosensitivity', 'MPA', (66, 82))	('U251MG', 'CellLine', 'CVCL:0021', (93, 99))	('AT101', 'Chemical', 'MESH:C028178', (125, 130))	('U87MG', 'CellLine', 'CVCL:0022', (104, 109))
22235	33808494	These effects were mirrored by inhibition of the ERK signaling pathway and by a regulation of the expression of different stem cell markers, the chemokine receptor CXCR7 and the cytokine receptor IL-6R upon AT101 and TMZ plus AT101 treatment.	('inhibition', 'NegReg', (31, 41))	('IL-6R', 'Gene', '3570', (196, 201))	('TMZ', 'Chemical', 'MESH:D000077204', (217, 220))	('CXCR7', 'Gene', '57007', (164, 169))	('AT101', 'Chemical', 'MESH:C028178', (207, 212))	('expression', 'MPA', (98, 108))	('IL-6R', 'Gene', (196, 201))	('AT101', 'Chemical', 'MESH:C028178', (226, 231))	('regulation', 'Reg', (80, 90))	('CXCR7', 'Gene', (164, 169))	('ERK', 'Gene', '5594', (49, 52))	('ERK', 'Gene', (49, 52))	('AT101', 'Var', (207, 212))
22241	33808494	AT101 is able to trigger autophagic, mitophagic, or apoptotic cell death by versatile mechanisms of action as the inhibition of Bcl-2 proteins, the induction of mitochondrial dysfunction, or by modulating serval signaling pathways in a specific manner.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (161, 186))	('inhibition', 'NegReg', (114, 124))	('mitochondrial dysfunction', 'Disease', (161, 186))	('serval', 'Species', '61405', (205, 211))	('AT101', 'Var', (0, 5))	('Bcl-2', 'Gene', (128, 133))	('Bcl-2', 'Gene', '596', (128, 133))	('AT101', 'Chemical', 'MESH:C028178', (0, 5))	('trigger', 'Reg', (17, 24))	('mitophagic', 'CPA', (37, 47))	('apoptotic cell death', 'CPA', (52, 72))	('modulating', 'Reg', (194, 204))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (161, 186))	('autophagic', 'CPA', (25, 35))	('serval signaling pathways', 'Pathway', (205, 230))
22242	33808494	Moreover, since it is known that AT101 is able to suppress the growth of glioma stem cells, AT101 seems to be a promising chemotherapeutic agent to prevent GBM recurrences, which often arise from dysfunctional (tumor) stem cells.	('dysfunctional', 'Disease', (196, 209))	('glioma', 'Disease', (73, 79))	('AT101', 'Var', (92, 97))	('AT101', 'Chemical', 'MESH:C028178', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('AT101', 'Chemical', 'MESH:C028178', (92, 97))	('growth', 'CPA', (63, 69))	('suppress', 'NegReg', (50, 58))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('GBM recurrences', 'Disease', (156, 171))	('tumor', 'Disease', (211, 216))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('dysfunctional', 'Disease', 'MESH:D009461', (196, 209))	('GBM', 'Phenotype', 'HP:0012174', (156, 159))	('AT101', 'Var', (33, 38))
22243	33808494	In this study, we were able to show that stem-like cells generated from two different GBM cell lines (U251MG and U87MG) responded to treatment with AT101 or TMZ plus AT101 with a pronounced induction of cell death and inhibition of proliferation.	('inhibition', 'NegReg', (218, 228))	('U251MG', 'CellLine', 'CVCL:0021', (102, 108))	('cell death', 'CPA', (203, 213))	('U87MG', 'CellLine', 'CVCL:0022', (113, 118))	('AT101', 'Var', (166, 171))	('proliferation', 'CPA', (232, 245))	('GBM', 'Phenotype', 'HP:0012174', (86, 89))	('AT101', 'Var', (148, 153))	('TMZ', 'Chemical', 'MESH:D000077204', (157, 160))	('AT101', 'Chemical', 'MESH:C028178', (166, 171))	('AT101', 'Chemical', 'MESH:C028178', (148, 153))
22245	33808494	Further, the stem cell markers KLF4 and OCT4 were (slightly) upregulated upon these treatment conditions in the native U251MG and U87MG cells, and this effect was reflected by the inhibition of the ERK signaling pathway.	('upregulated', 'PosReg', (61, 72))	('U251MG', 'CellLine', 'CVCL:0021', (119, 125))	('OCT4', 'Gene', '5460', (40, 44))	('ERK', 'Gene', '5594', (198, 201))	('OCT4', 'Gene', (40, 44))	('U87MG', 'CellLine', 'CVCL:0022', (130, 135))	('KLF4', 'Gene', '9314', (31, 35))	('U87MG', 'Var', (130, 135))	('stem cell', 'CPA', (13, 22))	('ERK', 'Gene', (198, 201))	('KLF4', 'Gene', (31, 35))
22247	33808494	Thus, a more pronounced inhibition indeed could result in a more distinct induction of cell death and inhibition of proliferation upon AT101 and TMZ plus AT101 treatment in our stem-like cell niche model.	('AT101', 'Chemical', 'MESH:C028178', (135, 140))	('TMZ', 'Chemical', 'MESH:D000077204', (145, 148))	('AT101', 'Chemical', 'MESH:C028178', (154, 159))	('inhibition', 'NegReg', (102, 112))	('proliferation', 'CPA', (116, 129))	('AT101', 'Var', (135, 140))	('cell death', 'CPA', (87, 97))
22249	33808494	showed that AT101 in combination with desmethoxycurcumin yielded anti-proliferative effects via the reduction of the phosphorylation of the ERK signal in human primary GBM cells.	('reduction', 'NegReg', (100, 109))	('human', 'Species', '9606', (154, 159))	('AT101', 'Chemical', 'MESH:C028178', (12, 17))	('GBM', 'Phenotype', 'HP:0012174', (168, 171))	('phosphorylation', 'MPA', (117, 132))	('desmethoxycurcumin', 'Chemical', 'MESH:C542280', (38, 56))	('ERK', 'Gene', '5594', (140, 143))	('anti-proliferative effects', 'CPA', (65, 91))	('ERK', 'Gene', (140, 143))	('AT101', 'Var', (12, 17))
22250	33808494	Further, AT101 could target glioma stem-like cells via the inhibition of the hedgehog and notch signaling pathways resulting in the inhibition of tumor growth.	('inhibition', 'NegReg', (59, 69))	('notch signaling pathways', 'Pathway', (90, 114))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('inhibition', 'NegReg', (132, 142))	('tumor', 'Disease', (146, 151))	('AT101', 'Var', (9, 14))	('hedgehog', 'Pathway', (77, 85))	('glioma', 'Disease', (28, 34))	('AT101', 'Chemical', 'MESH:C028178', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
22254	33808494	In adrenocortical carcinoma cells, the membranes exposed to gossypol became more rigid, and gossypol also increased the microviscosity of isolated mitochondrial and microsomal enriched membrane preparations.	('microviscosity', 'MPA', (120, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (3, 27))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (3, 27))	('gossypol', 'Var', (92, 100))	('more', 'PosReg', (76, 80))	('adrenocortical carcinoma', 'Disease', (3, 27))	('rigid', 'MPA', (81, 86))	('gossypol', 'Chemical', 'MESH:D006072', (60, 68))	('increased', 'PosReg', (106, 115))	('gossypol', 'Chemical', 'MESH:D006072', (92, 100))
22261	33808494	Thus, exemplified for a select panel of different chemokines and cytokines, we proved whether the expression of these factors differed upon AT101 or TMZ plus AT101 treatment in native GBM cells when stimulated with stem-like cell-conditioned media.	('TMZ', 'Chemical', 'MESH:D000077204', (149, 152))	('GBM', 'Phenotype', 'HP:0012174', (184, 187))	('AT101', 'Var', (140, 145))	('AT101', 'Chemical', 'MESH:C028178', (140, 145))	('differed', 'Reg', (126, 134))	('AT101', 'Chemical', 'MESH:C028178', (158, 163))	('expression', 'MPA', (98, 108))
22266	33808494	Contrary, the IL-6R was significantly upregulated in native U251MG and U87MG GBM cells when stimulated with AT101 or TMZ plus AT101 with stem-like cell-conditioned media.	('TMZ', 'Chemical', 'MESH:D000077204', (117, 120))	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('U251MG', 'CellLine', 'CVCL:0021', (60, 66))	('IL-6R', 'Gene', (14, 19))	('AT101', 'Chemical', 'MESH:C028178', (126, 131))	('U87MG', 'CellLine', 'CVCL:0022', (71, 76))	('upregulated', 'PosReg', (38, 49))	('U87MG', 'Var', (71, 76))	('AT101', 'Chemical', 'MESH:C028178', (108, 113))	('AT101', 'Var', (108, 113))	('IL-6R', 'Gene', '3570', (14, 19))
22274	33808494	Stem-like cell cultures were established and intensively characterized as described before by cultivating U251MG and U87MG cells in neurosphere medium (50% DMEM, 50% F12 medium (Thermo Fisher Scientific) containing the following supplements: 2 mM L-glutamine, 0.6% glucose (Roth, Karlsruhe, Germany), 9.5 ng/mL putrescine dihydrochloride (Sigma-Aldrich, St. Louis, MO, USA), 6.3 ng/mL progesterone (Sigma-Aldrich), 5.2 ng/mL sodium selenite (Sigma-Aldrich), 0.025 ng/mL insulin (Sigma-Aldrich), 2 mug/mL heparin (Sigma-Aldrich), and 4 mg/mL bovine serum albumin (Thermo Fisher Scientific)).	('U251MG', 'CellLine', 'CVCL:0021', (106, 112))	('heparin', 'Chemical', 'MESH:D006493', (504, 511))	('DMEM', 'Chemical', '-', (156, 160))	('6.3', 'Gene', '55558', (375, 378))	('6.3', 'Gene', (375, 378))	('serum albumin', 'Gene', '213', (548, 561))	('F12 medium', 'Chemical', '-', (166, 176))	('serum albumin', 'Gene', (548, 561))	('insulin', 'Gene', '3630', (470, 477))	('insulin', 'Gene', (470, 477))	('U87MG', 'CellLine', 'CVCL:0022', (117, 122))	('0.025', 'Var', (458, 463))	('glucose', 'Chemical', 'MESH:D005947', (265, 272))
22277	33808494	For the preparation of stem-like cell-conditioned media, 5.0 x 104/mL U251MG and U87MG stem-like cells were cultured over three days in 50% DMEM plus 50% F12 medium with all supplements indicated above.	('DMEM', 'Chemical', '-', (140, 144))	('U87MG', 'CellLine', 'CVCL:0022', (81, 86))	('U251MG', 'CellLine', 'CVCL:0021', (70, 76))	('U251MG', 'Var', (70, 76))	('U87MG', 'Var', (81, 86))	('F12 medium', 'Chemical', '-', (154, 164))
22291	33808494	DNase digestion, cDNA synthesis, and qRT-PCR were performed as described before using TaqMan primer probes (Applied Biosystems): CXCL11 (Hs00171138_m1), CXCL12 (Hs00171022_m1), CXCL16 (Hs00222859_m1), CX3CL1 (Hs00171086_m1), CXCR4 (Hs00237052_m1), CXCR6 (Hs00174843_m1), CXCR7 (Hs00664172_s1), CX3CR1 (Hs00365842_m1), GAPDH (Hs99999905_m1), interleukin-6 (IL-6) (Hs00985639_m1), interleukin-6 receptor (IL-6R) (Hs01075664_m1), kruppel-like factor 4 (KLF4) (Hs00358836_m1), Nestin (Hs00707120_s1), octamer binding transcription factor (OCT4) (Hs00999632_g1), transforming growth factor-beta (TGF-beta) (Hs00171257_m1), and TGF-beta receptor 1 (TGF-betaR1).	('Hs00171257_m1', 'Var', (602, 615))	('Nestin', 'Gene', '10763', (473, 479))	('transforming growth factor-beta', 'Gene', (558, 589))	('IL-6', 'Gene', '3569', (403, 407))	('IL-6', 'Gene', (356, 360))	('CX3CL1', 'Gene', (201, 207))	('CXCR6', 'Gene', '10663', (248, 253))	('TGF-beta', 'Gene', '7039', (591, 599))	('kruppel-like factor 4', 'Gene', '9314', (427, 448))	('CXCL16', 'Gene', '58191', (177, 183))	('IL-6', 'Gene', (403, 407))	('KLF4', 'Gene', (450, 454))	('CXCL11', 'Gene', (129, 135))	('kruppel-like factor 4', 'Gene', (427, 448))	('TGF-beta', 'Gene', (591, 599))	('TGF-beta', 'Gene', '7039', (622, 630))	('CXCL11', 'Gene', '6373', (129, 135))	('CXCL16', 'Gene', (177, 183))	('Nestin', 'Gene', (473, 479))	('interleukin-6 receptor', 'Gene', '3570', (379, 401))	('TGF-beta', 'Gene', '7039', (643, 651))	('CXCL12', 'Gene', '6387', (153, 159))	('CXCR4', 'Gene', '7852', (225, 230))	('interleukin-6', 'Gene', '3569', (341, 354))	('TGF-beta', 'Gene', (622, 630))	('CXCR4', 'Gene', (225, 230))	('interleukin-6 receptor', 'Gene', (379, 401))	('TGF-beta', 'Gene', (643, 651))	('CX3CL1', 'Gene', '6376', (201, 207))	('transforming growth factor-beta', 'Gene', '7124', (558, 589))	('CXCL12', 'Gene', (153, 159))	('interleukin-6', 'Gene', (341, 354))	('CXCR6', 'Gene', (248, 253))	('CX3CR1', 'Gene', '1524', (294, 300))	('OCT4', 'Gene', '5460', (535, 539))	('IL-6R', 'Gene', (403, 408))	('CXCR7', 'Gene', (271, 276))	('Hs00999632_g1', 'Var', (542, 555))	('interleukin-6', 'Gene', '3569', (379, 392))	('CX3CR1', 'Gene', (294, 300))	('CXCR7', 'Gene', '57007', (271, 276))	('IL-6R', 'Gene', '3570', (403, 408))	('KLF4', 'Gene', '9314', (450, 454))	('interleukin-6', 'Gene', (379, 392))	('Hs00707120_s1', 'Var', (481, 494))	('OCT4', 'Gene', (535, 539))	('IL-6', 'Gene', '3569', (356, 360))	('Hs00358836_m1', 'Var', (457, 470))
22292	33808494	In summary, we showed a high AT101-chemosensitivity of U251MG and U87MG GBM stem-like cells and native cells upon treatment with AT101 with a stem-like cell-conditioned medium.	('AT101', 'Chemical', 'MESH:C028178', (129, 134))	('AT101', 'Chemical', 'MESH:C028178', (29, 34))	('AT101-chemosensitivity', 'Gene', (29, 51))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('U251MG', 'CellLine', 'CVCL:0021', (55, 61))	('U251MG', 'Var', (55, 61))	('U87MG', 'CellLine', 'CVCL:0022', (66, 71))	('U87MG', 'Var', (66, 71))
22293	33808494	A specific inhibitory influence on the p-p42/44 signaling pathway, as well as a distinct regulation of the expression of individual stem cell markers, of the CXCR7 and the IL-6R upon AT101 and TMZ plus AT101 treatment, was found.	('AT101', 'Chemical', 'MESH:C028178', (183, 188))	('CXCR7', 'Gene', '57007', (158, 163))	('IL-6R', 'Gene', '3570', (172, 177))	('TMZ', 'Chemical', 'MESH:D000077204', (193, 196))	('expression', 'MPA', (107, 117))	('IL-6R', 'Gene', (172, 177))	('CXCR7', 'Gene', (158, 163))	('AT101', 'Chemical', 'MESH:C028178', (202, 207))	('AT101', 'Var', (183, 188))	('p-p42/44 signaling pathway', 'Pathway', (39, 65))
22295	33808494	Here, in our opinion, a local application of AT101 directly in the tumor resection cavity (e.g., by nanoparticles or (biodegradable) drug carrier devices) together with systemic treatment with TMZ will be the most promising approach.	('tumor', 'Disease', (67, 72))	('TMZ', 'Chemical', 'MESH:D000077204', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('AT101', 'Chemical', 'MESH:C028178', (45, 50))	('AT101', 'Var', (45, 50))
22297	33808494	Further, since it was shown that AT101 was a competent enhancer of radiation-induced apoptosis in head and neck squamous cell carcinoma in vitro, a combination of AT101 and radiation might also be feasible to treat glioblastomas more efficiently.	('AT101', 'Chemical', 'MESH:C028178', (163, 168))	('AT101', 'Chemical', 'MESH:C028178', (33, 38))	('glioblastomas', 'Phenotype', 'HP:0012174', (215, 228))	('enhancer', 'PosReg', (55, 63))	('glioblastoma', 'Phenotype', 'HP:0012174', (215, 227))	('glioblastomas', 'Disease', 'MESH:D005909', (215, 228))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('glioblastomas', 'Disease', (215, 228))	('neck squamous cell carcinoma', 'Disease', (107, 135))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (107, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('AT101', 'Var', (33, 38))
22303	33214683	Transgenic overexpression of Hoxb9 in the adrenal cortex of mice with activated Ctnnb1 led to larger adrenal tumours.	('larger adrenal', 'Phenotype', 'HP:0008221', (94, 108))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('Transgenic', 'Species', '10090', (0, 10))	('larger', 'PosReg', (94, 100))	('Hoxb9', 'Gene', (29, 34))	('Ctnnb1', 'Gene', (80, 86))	('activated', 'Var', (70, 79))	('Ctnnb1', 'Gene', '12387', (80, 86))	('Hoxb9', 'Gene', '15417', (29, 34))	('adrenal tumours', 'Disease', 'MESH:D000310', (101, 116))	('mice', 'Species', '10090', (60, 64))	('overexpression', 'PosReg', (11, 25))	('adrenal tumours', 'Disease', (101, 116))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
22310	33214683	These studies have identified mutations in the WNT signalling pathway to be one of the most frequent alterations, with CTNNB1-activating mutations present in up to 16% and inactivating changes in ZNRF3, a pathway repressor, in up to 21%.	('ZNRF3', 'Gene', '407821', (196, 201))	('CTNNB1-activating', 'Gene', (119, 136))	('mutations', 'Var', (137, 146))	('mutations', 'Var', (30, 39))	('WNT signalling pathway', 'Pathway', (47, 69))	('ZNRF3', 'Gene', (196, 201))	('inactivating changes', 'Var', (172, 192))
22311	33214683	Other pathways that are altered in ACC patients include epigenetic regulation and p53/RB1 and PKA signalling.	('RB1', 'Gene', (86, 89))	('ACC', 'Disease', (35, 38))	('altered', 'Reg', (24, 31))	('patients', 'Species', '9606', (39, 47))	('RB1', 'Gene', '5925', (86, 89))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('epigenetic regulation', 'Var', (56, 77))	('PKA signalling', 'Pathway', (94, 108))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))
22312	33214683	Studies in mice have shown that targeting an activating mutation in Ctnnb1 to the adrenal cortex leads to tumour formation, highlighting the relevance of this model to study this disease.	('Ctnnb1', 'Gene', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('Ctnnb1', 'Gene', '12387', (68, 74))	('mice', 'Species', '10090', (11, 15))	('activating', 'PosReg', (45, 55))	('leads to', 'Reg', (97, 105))	('tumour', 'Disease', (106, 112))	('mutation', 'Var', (56, 64))
22314	33214683	Genetic studies in mice have shown that a decrease in WNT signalling, either through deletion of Ctnnb1 or pathway inhibition, in adrenal cortical cells led to adrenal aplasia, degeneration and zonation defects, depending on the deletion stage and cell type.	('pathway', 'Pathway', (107, 114))	('adrenal aplasia', 'Phenotype', 'HP:0011743', (160, 175))	('WNT signalling', 'MPA', (54, 68))	('Ctnnb1', 'Gene', (97, 103))	('decrease', 'NegReg', (42, 50))	('deletion', 'Var', (85, 93))	('adrenal aplasia, degeneration and zonation defects', 'Disease', 'MESH:D057130', (160, 210))	('Ctnnb1', 'Gene', '12387', (97, 103))	('mice', 'Species', '10090', (19, 23))
22317	33214683	Emerging evidence has revealed that aberrant HOX gene expression in adult tissues can lead to malignancy, including in lung, ovarian, cervical, prostate and breast carcinoma, and can interact with other signalling pathways, such as WNT/beta-catenin, to promote tumour progression.	('breast carcinoma', 'Disease', (157, 173))	('malignancy', 'Disease', 'MESH:D009369', (94, 104))	('HOX gene', 'Gene', (45, 53))	('ovarian', 'Disease', (125, 132))	('prostate', 'Disease', (144, 152))	('lung', 'Disease', (119, 123))	('malignancy', 'Disease', (94, 104))	('promote', 'PosReg', (253, 260))	('breast carcinoma', 'Disease', 'MESH:D001943', (157, 173))	('beta-catenin', 'Gene', '12387', (236, 248))	('ovarian', 'Disease', 'MESH:D010049', (125, 132))	('aberrant', 'Var', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('beta-catenin', 'Gene', (236, 248))	('cervical', 'Disease', (134, 142))	('tumour', 'Phenotype', 'HP:0002664', (261, 267))	('breast carcinoma', 'Phenotype', 'HP:0003002', (157, 173))	('tumour', 'Disease', 'MESH:D009369', (261, 267))	('lead to', 'Reg', (86, 93))	('interact', 'Reg', (183, 191))	('tumour', 'Disease', (261, 267))
22320	33214683	Male mice with an activating Ctnnb1 mutation and Hoxb9 overexpression develop tumours with increased proliferation.	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('Hoxb9', 'Gene', (49, 54))	('Hoxb9', 'Gene', '15417', (49, 54))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumours', 'Disease', (78, 85))	('Ctnnb1', 'Gene', (29, 35))	('activating', 'PosReg', (18, 28))	('increased', 'PosReg', (91, 100))	('Ctnnb1', 'Gene', '12387', (29, 35))	('mice', 'Species', '10090', (5, 9))	('mutation', 'Var', (36, 44))
22321	33214683	The mutant Ctnnb1 mice were generated by breeding two previously described strains, Cyp11a1:Cre and the stabilised Ctnnb1 conditional allele.	('mutant', 'Var', (4, 10))	('Ctnnb1', 'Gene', (11, 17))	('mice', 'Species', '10090', (18, 22))	('Cyp11a1', 'Gene', '13070', (84, 91))	('Ctnnb1', 'Gene', (115, 121))	('Ctnnb1', 'Gene', '12387', (11, 17))	('Cyp11a1', 'Gene', (84, 91))	('Ctnnb1', 'Gene', '12387', (115, 121))
22337	33214683	ABC cells were derived from a mouse Ctnnb1 mutant adrenal gland tumour and grown in Y-media (DMEM/F12, 10% FBS, penicillin/streptomycin, L-Glutamine, 5 mug/ml Insulin, 0.4 mug/ml hydrocortisone, 10 ng/ml EGF, 10 mug/ml Gentamicin, 250 ng/ml amphotericin, 4.81 ng/ml Cholera toxin, 5 muM Y27632).	('penicillin', 'Chemical', 'MESH:D010406', (112, 122))	('adrenal gland tumour', 'Disease', (50, 70))	('ABC', 'Gene', '10058', (0, 3))	('streptomycin', 'Chemical', 'MESH:D013307', (123, 135))	('ABC', 'Gene', (0, 3))	('amphotericin', 'Chemical', 'MESH:D000666', (241, 253))	('adrenal gland tumour', 'Disease', 'MESH:D000310', (50, 70))	('mouse', 'Species', '10090', (30, 35))	('Ctnnb1', 'Gene', '12387', (36, 42))	('F12', 'Chemical', 'MESH:C007782', (98, 101))	('Gentamicin', 'Chemical', 'MESH:D005839', (219, 229))	('Ctnnb1', 'Gene', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('DMEM', 'Chemical', '-', (93, 97))	('L-Glutamine', 'Chemical', 'MESH:D005973', (137, 148))	('mutant', 'Var', (43, 49))	('Y27632', 'Chemical', 'MESH:C108830', (287, 293))	('Y-media', 'Species', '45504', (84, 91))	('hydrocortisone', 'Chemical', 'MESH:D006854', (179, 193))
22340	33214683	To perform gene knockdown, 6 x 105 H295R cells were seeded in six-well plates and the next day siRNA reagents non-targeting ON-TARGETplus SMARTpool (D-001810-10-05, Horizon Discovery, Cambridge, UK), PBX1 ON-TARGETplus SMARTpool (L-019680-00-0005), HOXA10 ON-TARGETplus SMARTpool (L-006336-00-0005), HOXA11 ON-TARGETplus SMARTpool (L-012108-00-0005), or HOXA13 ON-TARGETplus SMARTpool (L-011052-00-0005) were transfected with RNAiMAX (Thermo Fisher Scientific, Hemel Hempstead, UK) following the manufacturer's protocol.	('HOXA11', 'Gene', '3207', (300, 306))	('L-006336-00-0005', 'Var', (281, 297))	('HOXA11', 'Gene', (300, 306))	('HOXA10', 'Gene', (249, 255))	('L-011052-00-0005', 'Var', (386, 402))	('HOXA13', 'Gene', (354, 360))	('HOXA13', 'Gene', '3209', (354, 360))	('H295R', 'CellLine', 'CVCL:0458', (35, 40))	('L-019680-00-0005', 'Var', (230, 246))	('HOXA10', 'Gene', '3206', (249, 255))	('L-012108-00-0005', 'Var', (332, 348))
22344	33214683	The targeting HTL001 peptide sequence WYKWMKKAARRRRRRRRR and the CXR9 control peptide WYPAMKKHHRRRRRRRRR, both with D-isomer modification of C- and N-terminals were dissolved in DMSO.	('WYKWMKKAARRRRRRRRR', 'Var', (38, 56))	('HTL001', 'Gene', (14, 20))	('DMSO', 'Chemical', 'MESH:D004121', (178, 182))
22350	33214683	For RNA-seq analysis of adrenal tumours, mRNA libraries for were prepared using 500 ng of total RNA of each sample with NEBNext Ultra II Directional RNA Library Prep kit (E7760, NEB, Hitchin, UK) and NEBNext Poly(A) mRNA magnetic beads (E7490, NEB) following the manufacturer's protocol.	('NEB', 'Gene', (244, 247))	('E7760', 'Var', (171, 176))	('NEB', 'Gene', (200, 203))	('NEB', 'Gene', '17996', (244, 247))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('adrenal tumours', 'Disease', 'MESH:D000310', (24, 39))	('adrenal tumours', 'Disease', (24, 39))	('NEB', 'Gene', '17996', (200, 203))	('NEB', 'Gene', (178, 181))	('NEB', 'Gene', (120, 123))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('NEB', 'Gene', '17996', (178, 181))	('NEB', 'Gene', '17996', (120, 123))
22352	33214683	Gene set enrichment analysis (GSEA) was carried out with male Ctnnb1 mutant and double-mutant RNA-seq data using the Broad Institute Java plug-in with the Hallmarks gene set.	('Ctnnb1', 'Gene', (62, 68))	('Ctnnb1', 'Gene', '12387', (62, 68))	('double-mutant', 'Var', (80, 93))	('mutant', 'Var', (69, 75))
22353	33214683	STRING protein network analysis was carried out using the differentially expressed genes between male Ctnnb1 mutants and double mutants (genes with adjusted P < 0.1 and P < 0.05).	('Ctnnb1', 'Gene', (102, 108))	('Ctnnb1', 'Gene', '12387', (102, 108))	('mutants', 'Var', (109, 116))
22368	33214683	Quantitative RT-PCR (qRT-PCR) expression analysis showed an increase of Hoxb9 levels in the adult adrenals of transgenic mice (Fig.	('Hoxb9', 'Gene', (72, 77))	('transgenic mice', 'Species', '10090', (110, 125))	('transgenic', 'Var', (110, 120))	('Hoxb9', 'Gene', '15417', (72, 77))	('increase', 'PosReg', (60, 68))
22373	33214683	Ki67 staining revealed no difference in the number of proliferating cells between transgenic and wild-type animals (Fig.	('Ki67', 'Gene', (0, 4))	('transgenic', 'Var', (82, 92))	('Ki67', 'Gene', '17345', (0, 4))	('transgenic', 'Species', '10090', (82, 92))
22375	33214683	In both female and male adrenal glands from transgenic mice, Sf-1 expression was increased threefold, while there was no change in the expression of Shh, Patched (Ptch) or Axin2 (Fig.	('Patched', 'Gene', '19206', (154, 161))	('Patched', 'Gene', (154, 161))	('Shh', 'Gene', '20423', (149, 152))	('Sf-1', 'Gene', '22668', (61, 65))	('expression', 'MPA', (66, 76))	('Ptch', 'Gene', (163, 167))	('transgenic', 'Var', (44, 54))	('transgenic mice', 'Species', '10090', (44, 59))	('Axin2', 'Gene', '12006', (172, 177))	('Shh', 'Gene', (149, 152))	('increased', 'PosReg', (81, 90))	('Axin2', 'Gene', (172, 177))	('Ptch', 'Gene', '19206', (163, 167))	('Sf-1', 'Gene', (61, 65))
22378	33214683	These data showed that transgenic animals had no change in adrenal cortical ZG or ZF markers (Fig.	('adrenal cortical ZG', 'Disease', (59, 78))	('transgenic', 'Species', '10090', (23, 33))	('transgenic', 'Var', (23, 33))	('ZF markers', 'CPA', (82, 92))	('adrenal cortical ZG', 'Disease', 'MESH:D018268', (59, 78))
22381	33214683	To investigate if HOXB9 can promote tumour formation we bred Sf-1:Hoxb9 mice with mice containing the activating conditional Ctnnb1 deletion allele and a construct with Cre recombinase driven by Cyp11a1-regulatory sequences (Ctnnb1 mutant mice, referred to as ABC).	('Ctnnb1', 'Gene', '12387', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('ABC', 'Gene', '10058', (260, 263))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('Hoxb9', 'Gene', '15417', (66, 71))	('Ctnnb1', 'Gene', (125, 131))	('ABC', 'Gene', (260, 263))	('Sf-1', 'Gene', (61, 65))	('Cyp11a1', 'Gene', '13070', (195, 202))	('mice', 'Species', '10090', (82, 86))	('deletion', 'Var', (132, 140))	('Sf-1', 'Gene', '22668', (61, 65))	('mice', 'Species', '10090', (239, 243))	('Ctnnb1', 'Gene', '12387', (225, 231))	('Cyp11a1', 'Gene', (195, 202))	('mice', 'Species', '10090', (72, 76))	('Ctnnb1', 'Gene', (225, 231))	('Hoxb9', 'Gene', (66, 71))
22382	33214683	As expected, adrenals from Ctnnb1 mutant mice showed tumour formation characterised by increased organ size, which was larger in the female (Figs.	('increased', 'PosReg', (87, 96))	('organ size', 'CPA', (97, 107))	('tumour', 'Disease', (53, 59))	('mice', 'Species', '10090', (41, 45))	('Ctnnb1', 'Gene', (27, 33))	('Ctnnb1', 'Gene', '12387', (27, 33))	('larger', 'PosReg', (119, 125))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('mutant', 'Var', (34, 40))
22384	33214683	Six-month-old Ctnnb1 mutant mice that also carried the Sf-1:Hoxb9 transgene (double-mutant mice, referred to as ABC; Hoxb9 t/g) showed an increase in adrenal size, which was restricted to male mice (Fig.	('Hoxb9', 'Gene', (117, 122))	('increase', 'PosReg', (138, 146))	('mice', 'Species', '10090', (91, 95))	('ABC', 'Gene', '10058', (112, 115))	('mutant', 'Var', (21, 27))	('Hoxb9', 'Gene', '15417', (117, 122))	('mice', 'Species', '10090', (28, 32))	('Ctnnb1', 'Gene', (14, 20))	('Hoxb9', 'Gene', (60, 65))	('mice', 'Species', '10090', (193, 197))	('t/g', 'Var', (123, 126))	('adrenal size', 'CPA', (150, 162))	('ABC', 'Gene', (112, 115))	('Ctnnb1', 'Gene', '12387', (14, 20))	('Sf-1', 'Gene', '22668', (55, 59))	('Hoxb9', 'Gene', '15417', (60, 65))	('Sf-1', 'Gene', (55, 59))
22385	33214683	Haematoxylin and eosin staining showed no obvious morphological difference between Ctnnb1 and double mutants (Fig.	('Haematoxylin', 'Chemical', 'MESH:D006416', (0, 12))	('Ctnnb1', 'Gene', (83, 89))	('Ctnnb1', 'Gene', '12387', (83, 89))	('double mutants', 'Var', (94, 108))	('eosin', 'Chemical', 'MESH:D004801', (17, 22))
22386	33214683	As expected, antibody staining for beta-catenin and the WNT signalling downstream marker Lef1 in Ctnnb1 mutants showed high expression in the majority of cells (Fig.	('beta-catenin', 'Gene', (35, 47))	('mutants', 'Var', (104, 111))	('Lef1', 'Gene', '16842', (89, 93))	('beta-catenin', 'Gene', '12387', (35, 47))	('Ctnnb1', 'Gene', (97, 103))	('expression', 'MPA', (124, 134))	('Lef1', 'Gene', (89, 93))	('Ctnnb1', 'Gene', '12387', (97, 103))
22388	33214683	Proliferation, as measured by Ki67 staining, was higher in 6-month-old double-mutant male mice, with no changes in apoptosis, as measured by Caspase 3 staining (Fig.	('Caspase 3', 'Gene', '12367', (141, 150))	('higher', 'PosReg', (49, 55))	('Ki67', 'Gene', (30, 34))	('mice', 'Species', '10090', (90, 94))	('Caspase 3', 'Gene', (141, 150))	('Proliferation', 'CPA', (0, 13))	('Ki67', 'Gene', '17345', (30, 34))	('double-mutant', 'Var', (71, 84))
22389	33214683	No signs of invasive disease were observed in double-mutant animals (Fig.	('invasive disease', 'Disease', (12, 28))	('double-mutant', 'Var', (46, 59))	('invasive disease', 'Disease', 'MESH:D009361', (12, 28))
22392	33214683	qRT-PCR analysis showed that Sf-1 transcript was higher in both female and male double-mutant adrenal tumours relative to Ctnnb1 mutants, but there was no difference in the levels of SF-1 protein expression between the genotypes (Supplementary Fig.	('Ctnnb1', 'Gene', '12387', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('Sf-1', 'Gene', '22668', (29, 33))	('SF-1', 'Gene', '22668', (183, 187))	('transcript', 'MPA', (34, 44))	('Sf-1', 'Gene', (29, 33))	('SF-1', 'Gene', (183, 187))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('adrenal tumours', 'Disease', (94, 109))	('double-mutant', 'Var', (80, 93))	('adrenal tumours', 'Disease', 'MESH:D000310', (94, 109))	('mutants', 'Var', (129, 136))	('higher', 'PosReg', (49, 55))	('Ctnnb1', 'Gene', (122, 128))
22393	33214683	To investigate the pathways activated in the double mutants we performed RNA-seq on RNA derived from adrenal tumours from 3-month-old Ctnnb1 and double-mutant female and male mutant mice.	('Ctnnb1', 'Gene', (134, 140))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('Ctnnb1', 'Gene', '12387', (134, 140))	('mice', 'Species', '10090', (182, 186))	('double-mutant', 'Var', (145, 158))	('adrenal tumours', 'Disease', 'MESH:D000310', (101, 116))	('adrenal tumours', 'Disease', (101, 116))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
22394	33214683	Comparative analysis identified differentially expressed genes in the tumours of double-mutant mice compared to Ctnnb1 mutants, with a higher number in males (533 genes altered, Benjamini-Hochberg adjusted P < 0.1) than in the same comparison in females (66 genes altered, Benjamini-Hochberg adjusted P < 0.1) (Fig.	('double-mutant', 'Var', (81, 94))	('mice', 'Species', '10090', (95, 99))	('Ctnnb1', 'Gene', '12387', (112, 118))	('altered', 'Reg', (169, 176))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('Ctnnb1', 'Gene', (112, 118))	('tumours', 'Disease', (70, 77))	('mutants', 'Var', (119, 126))
22395	33214683	Comparative analysis of the differentially expressed genes between double mutants and Ctnnb1 mutant female and male tumours showed very few common genes altered in both sexes (three genes upregulated, and six genes downregulated in both females and males) (Fig.	('downregulated', 'NegReg', (215, 228))	('upregulated', 'PosReg', (188, 199))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('Ctnnb1', 'Gene', (86, 92))	('mutant', 'Var', (93, 99))	('Ctnnb1', 'Gene', '12387', (86, 92))	('male tumours', 'Disease', 'MESH:D018567', (111, 123))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('male tumours', 'Disease', (111, 123))
22396	33214683	Validating our qRT-PCR result, Sf-1 was increased in double mutants of both sexes.	('Sf-1', 'Gene', '22668', (31, 35))	('increased', 'PosReg', (40, 49))	('double mutants', 'Var', (53, 67))	('Sf-1', 'Gene', (31, 35))
22397	33214683	Interestingly, many genes that were differential between male double mutants and Ctnnb1 mutants were shared with those that were different between male and female Ctnnb1 mutant animals (52 upregulated genes and 30 downregulated genes) (Fig.	('Ctnnb1', 'Gene', '12387', (163, 169))	('Ctnnb1', 'Gene', '12387', (81, 87))	('Ctnnb1', 'Gene', (163, 169))	('upregulated', 'PosReg', (189, 200))	('mutant', 'Var', (170, 176))	('Ctnnb1', 'Gene', (81, 87))	('mutants', 'Var', (88, 95))	('downregulated', 'NegReg', (214, 227))
22399	33214683	Pathway analysis of the differentially expressed genes using the STRING protein-protein interaction database identified angiotensin signalling enriched in double-mutant male tumours compared to Ctnnb1 mutant tumours, including Agtr1b, Egr1, Nr4a1 and members of the Fos/Jun family Fos, Fosb and Junb (Fig.	('male tumours', 'Disease', 'MESH:D018567', (169, 181))	('Junb', 'Gene', '16477', (295, 299))	('Egr1', 'Gene', '13653', (235, 239))	('mutant', 'Var', (201, 207))	('Nr4a1', 'Gene', '15370', (241, 246))	('Fos', 'Gene', (266, 269))	('enriched', 'PosReg', (143, 151))	('Fosb', 'Gene', '14282', (286, 290))	('Fos', 'Gene', '14281', (266, 269))	('tumours', 'Disease', (208, 215))	('tumours', 'Disease', (174, 181))	('Egr1', 'Gene', (235, 239))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('Ctnnb1', 'Gene', '12387', (194, 200))	('Junb', 'Gene', (295, 299))	('tumours', 'Phenotype', 'HP:0002664', (208, 215))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('Fos', 'Gene', (281, 284))	('tumours', 'Disease', 'MESH:D009369', (208, 215))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('Ctnnb1', 'Gene', (194, 200))	('Fos', 'Gene', '14281', (281, 284))	('double-mutant', 'Var', (155, 168))	('Agtr1b', 'Gene', '11608', (227, 233))	('Agtr1b', 'Gene', (227, 233))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('male tumours', 'Disease', (169, 181))	('Nr4a1', 'Gene', (241, 246))	('Fosb', 'Gene', (286, 290))	('Fos', 'Gene', (286, 289))	('angiotensin signalling', 'MPA', (120, 142))	('Fos', 'Gene', '14281', (286, 289))
22401	33214683	qRT-PCR was used to validate these results for the Fos/Jun family, and antibody staining showed widespread expression of Fosb in double-mutant tumours (Fig.	('double-mutant', 'Var', (129, 142))	('Fosb', 'Gene', '14282', (121, 125))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('Fosb', 'Gene', (121, 125))	('tumours', 'Phenotype', 'HP:0002664', (143, 150))	('Fos', 'Gene', '14281', (121, 124))	('tumours', 'Disease', 'MESH:D009369', (143, 150))	('Fos', 'Gene', (121, 124))	('Fos', 'Gene', (51, 54))	('tumours', 'Disease', (143, 150))	('Fos', 'Gene', '14281', (51, 54))
22403	33214683	These data were validated using qRT-PCR for Cdk1, Ccnb1, Ccnb2, Ccne1 and Knstrn, which showed an increase in these genes in male double mutants but not in females (Fig.	('double mutants', 'Var', (130, 144))	('Knstrn', 'Gene', (74, 80))	('Cdk1', 'Gene', '12534', (44, 48))	('increase', 'PosReg', (98, 106))	('Ccnb2', 'Gene', (57, 62))	('Ccnb1', 'Gene', (50, 55))	('Cdk1', 'Gene', (44, 48))	('Ccnb2', 'Gene', '12442', (57, 62))	('Knstrn', 'Gene', '51944', (74, 80))	('Ccne1', 'Gene', (64, 69))	('Ccnb1', 'Gene', '268697', (50, 55))	('Ccne1', 'Gene', '12447', (64, 69))
22404	33214683	We next checked if the pathways we identified were also altered in female Ctnnb1 mutant tumours, compared to males of the same genotype, as these tumours shared a large number of altered genes with male double mutants (Fig.	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (146, 153))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('Ctnnb1', 'Gene', '12387', (74, 80))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('altered', 'Reg', (56, 63))	('tumours', 'Disease', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('mutant', 'Var', (81, 87))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('Ctnnb1', 'Gene', (74, 80))
22406	33214683	These data suggest a core set of cell cycle genes that are elevated in tumours with high Hoxb9 are also expressed at high levels in female Ctnnb1 tumours, compared to males.	('Hoxb9', 'Gene', '15417', (89, 94))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (146, 153))	('high', 'Var', (84, 88))	('tumours', 'Disease', (71, 78))	('cell cycle genes', 'Gene', (33, 49))	('Ctnnb1', 'Gene', (139, 145))	('Hoxb9', 'Gene', (89, 94))	('elevated', 'PosReg', (59, 67))	('Ctnnb1', 'Gene', '12387', (139, 145))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
22407	33214683	Our transgenic mouse data indicates that high Hoxb9 expression can promote cell proliferation within a tumour context.	('Hoxb9', 'Gene', (46, 51))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('high', 'Var', (41, 45))	('expression', 'MPA', (52, 62))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('Hoxb9', 'Gene', '15417', (46, 51))	('mouse', 'Species', '10090', (15, 20))	('tumour', 'Disease', (103, 109))	('transgenic', 'Species', '10090', (4, 14))	('promote', 'PosReg', (67, 74))
22421	33214683	Analysis of HOXA11 paralogues after HOXA11 knockdown showed a modest reduction in HOXC11 expression, while HOXD11 expression was not detected in H295R cells in control or siRNA-treated samples (Fig.	('HOXD11', 'Gene', (107, 113))	('knockdown', 'Var', (43, 52))	('HOXA11', 'Gene', '3207', (12, 18))	('HOXA11', 'Gene', (12, 18))	('HOXC11', 'Gene', (82, 88))	('HOXA11', 'Gene', '3207', (36, 42))	('HOXD11', 'Gene', '3237', (107, 113))	('HOXA11', 'Gene', (36, 42))	('H295R', 'CellLine', 'CVCL:0458', (145, 150))	('reduction', 'NegReg', (69, 78))
22425	33214683	siRNA knockdown of PBX1 in H295R cells led to reduced levels of expression and to a marked reduction in cell proliferation (Fig.	('cell proliferation', 'CPA', (104, 122))	('H295R', 'CellLine', 'CVCL:0458', (27, 32))	('reduction', 'NegReg', (91, 100))	('reduced', 'NegReg', (46, 53))	('knockdown', 'Var', (6, 15))	('levels of expression', 'MPA', (54, 74))	('PBX1', 'Gene', (19, 23))
22426	33214683	H295R cells harbour a CTNNB1-activating mutation, and our qRT-PCR studies showed that PBX1 knockdown had no effect on WNT signalling, as measured by the expression levels of downstream targets AXIN2 and LEF1 (Supplementary Fig.	('WNT signalling', 'MPA', (118, 132))	('mutation', 'Var', (40, 48))	('AXIN2', 'Gene', '8313', (193, 198))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('LEF1', 'Gene', '51176', (203, 207))	('knockdown', 'Var', (91, 100))	('LEF1', 'Gene', (203, 207))	('CTNNB1-activating', 'Gene', (22, 39))	('PBX1', 'Gene', (86, 90))	('AXIN2', 'Gene', (193, 198))
22429	33214683	To investigate if mouse adrenal tumours were also sensitive, we analysed three models: two cell lines derived from adrenal tumours driven by SV40 T antigen, ATC1 (containing an activating Ctnnb1 mutation) and ATC7; and primary cells derived from adrenal tissue from the Ctnnb1 mutant mice described above.	('Ctnnb1', 'Gene', (188, 194))	('Ctnnb1', 'Gene', '12387', (270, 276))	('mutant', 'Var', (277, 283))	('mouse', 'Species', '10090', (18, 23))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('Ctnnb1', 'Gene', '12387', (188, 194))	('adrenal tumours', 'Disease', 'MESH:D000310', (24, 39))	('mutation', 'Var', (195, 203))	('adrenal tumours', 'Disease', (24, 39))	('adrenal tumours', 'Disease', 'MESH:D000310', (115, 130))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('Ctnnb1', 'Gene', (270, 276))	('mice', 'Species', '10090', (284, 288))	('activating', 'PosReg', (177, 187))	('adrenal tumours', 'Disease', (115, 130))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
22436	33214683	Consistent with this, mice with Ctnnb1-activating mutations in the adrenal show a more aggressive and earlier phenotype in females, which we also observe in our Ctnnb1 mutant mice.	('Ctnnb1', 'Gene', '12387', (32, 38))	('mice', 'Species', '10090', (175, 179))	('Ctnnb1', 'Gene', (161, 167))	('more', 'PosReg', (82, 86))	('mutations', 'Var', (50, 59))	('Ctnnb1', 'Gene', '12387', (161, 167))	('Ctnnb1', 'Gene', (32, 38))	('mice', 'Species', '10090', (22, 26))
22438	33214683	Our RNA-seq analysis did not show changes in classic androgen receptor targets, such as Srd5a2, however, we did observe an increase in Frzb expression in double-mutant adrenals, which has been shown to be higher in female adrenals and upregulated in adrenals of castrated mice.	('Frzb', 'Gene', '20378', (135, 139))	('upregulated', 'PosReg', (235, 246))	('expression', 'MPA', (140, 150))	('Srd5a2', 'Gene', '94224', (88, 94))	('higher', 'PosReg', (205, 211))	('androgen receptor', 'Gene', '11835', (53, 70))	('Frzb', 'Gene', (135, 139))	('double-mutant', 'Var', (154, 167))	('mice', 'Species', '10090', (272, 276))	('androgen receptor', 'Gene', (53, 70))	('increase', 'PosReg', (123, 131))	('Srd5a2', 'Gene', (88, 94))
22441	33214683	Transgenic mice with increased foetal Sf-1 expression showed extra-adrenal formation and mice with a Sf-1 sumoylation mutation have a persistent X zone, suggesting that the bigger foetal derived X zone seen in the adrenal of the transgenic Sf-1:Hoxb9 mice could be due to the higher Sf-1 levels.	('mice', 'Species', '10090', (251, 255))	('Sf-1', 'Gene', '22668', (101, 105))	('foetal', 'MPA', (180, 186))	('Sf-1', 'Gene', (101, 105))	('mice', 'Species', '10090', (89, 93))	('Sf-1', 'Gene', '22668', (283, 287))	('Hoxb9', 'Gene', (245, 250))	('transgenic', 'Species', '10090', (229, 239))	('Sf-1', 'Gene', (283, 287))	('mice', 'Species', '10090', (11, 15))	('Hoxb9', 'Gene', '15417', (245, 250))	('mutation', 'Var', (118, 126))	('Sf-1', 'Gene', '22668', (240, 244))	('Sf-1', 'Gene', '22668', (38, 42))	('Sf-1', 'Gene', (240, 244))	('Transgenic mice', 'Species', '10090', (0, 15))	('Sf-1', 'Gene', (38, 42))
22443	33214683	Our data show an increase in cell cycle markers in double-mutant male tumours including Ccne1, a gene commonly amplified in ACC and thought to be a disease driver.	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('Ccne1', 'Gene', (88, 93))	('male tumours', 'Disease', 'MESH:D018567', (65, 77))	('Ccne1', 'Gene', '12447', (88, 93))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('male tumours', 'Disease', (65, 77))	('double-mutant', 'Var', (51, 64))	('increase', 'PosReg', (17, 25))	('cell', 'MPA', (29, 33))	('ACC', 'Phenotype', 'HP:0006744', (124, 127))
22450	33214683	Mice with Znrf3 mutations show an increase in proliferation of the ZF, which is thought to be due to moderate rather than high WNT signalling activation.	('mutations', 'Var', (16, 25))	('proliferation', 'CPA', (46, 59))	('increase', 'PosReg', (34, 42))	('Mice', 'Species', '10090', (0, 4))	('Znrf3', 'Gene', (10, 15))	('Znrf3', 'Gene', '407821', (10, 15))
22455	33214683	Consistent with this, analysis of the HOXA11 paralogues in H295R cells with HOXA11 knockdown only showed a mild reduction in HOXC11 expression.	('HOXC11 expression', 'MPA', (125, 142))	('HOXA11', 'Gene', '3207', (76, 82))	('HOXA11', 'Gene', (76, 82))	('H295R', 'CellLine', 'CVCL:0458', (59, 64))	('reduction', 'NegReg', (112, 121))	('HOXA11', 'Gene', '3207', (38, 44))	('knockdown', 'Var', (83, 92))	('HOXA11', 'Gene', (38, 44))
22460	33214683	Peptide-based therapeutics are being used in cancer treatment and a variant of HTL001 is being developed for clinical trials currently, as in vivo studies in mice showed growth inhibition in a range of tumour types, and the drug was well-tolerated.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mice', 'Species', '10090', (158, 162))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('variant', 'Var', (68, 75))	('HTL001', 'Gene', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', (202, 208))	('cancer', 'Disease', (45, 51))	('growth inhibition', 'CPA', (170, 187))
22548	32751066	We previously reported that yeast expressing human Patched (hPtch1) were able to grow in the presence of chemotherapeutic agents such as doxorubicin (dxr) and to efflux dxr out of cells using the proton motive force.	('dxr', 'Chemical', 'MESH:D004317', (150, 153))	('Patched', 'Var', (51, 58))	('hPtch1', 'Gene', (60, 66))	('doxorubicin', 'Chemical', 'MESH:D004317', (137, 148))	('human', 'Species', '9606', (45, 50))	('hPtch1', 'Gene', '5727', (60, 66))	('dxr', 'Chemical', 'MESH:D004317', (169, 172))	('yeast', 'Species', '4932', (28, 33))	('efflux dxr out', 'MPA', (162, 176))
22550	32751066	We measured the effect of 1200 compounds from the Prestwick Chemical drug library on the growth of hPtch1-expressing yeast in the presence of dxr, and we discovered that the methiothepin maleate (P375) significantly inhibited the resistance of hPtch1-expressing yeast to dxr in contrast to the other compounds such as P298 that did not affect it (Figure 1A).	('methiothepin maleate', 'Chemical', 'MESH:D008719', (174, 194))	('P375', 'Chemical', '-', (196, 200))	('hPtch1', 'Gene', '5727', (244, 250))	('hPtch1', 'Gene', (99, 105))	('inhibited', 'NegReg', (216, 225))	('dxr', 'Chemical', 'MESH:D004317', (271, 274))	('dxr', 'Chemical', 'MESH:D004317', (142, 145))	('P375', 'Var', (196, 200))	('hPtch1', 'Gene', '5727', (99, 105))	('yeast', 'Species', '4932', (117, 122))	('yeast', 'Species', '4932', (262, 267))	('resistance', 'MPA', (230, 240))	('hPtch1', 'Gene', (244, 250))	('P298', 'Chemical', '-', (318, 322))
22557	32751066	Remarkably, the presence of P136 in the efflux buffer increases the amount of dxr in hPtch1-expressing yeast significantly more than in control yeast (Figure 1B), indicating that P136 specifically inhibited dxr efflux activity mediated by hPtch1.	('dxr', 'Chemical', 'MESH:D004317', (78, 81))	('P136', 'Chemical', '-', (179, 183))	('inhibited', 'NegReg', (197, 206))	('amount of dxr', 'MPA', (68, 81))	('hPtch1', 'Gene', (85, 91))	('hPtch1', 'Gene', (239, 245))	('P136', 'Chemical', '-', (28, 32))	('P136', 'Var', (179, 183))	('yeast', 'Species', '4932', (144, 149))	('hPtch1', 'Gene', '5727', (85, 91))	('hPtch1', 'Gene', '5727', (239, 245))	('increases', 'PosReg', (54, 63))	('presence', 'Var', (16, 24))	('yeast', 'Species', '4932', (103, 108))	('P136', 'Var', (28, 32))	('dxr', 'Chemical', 'MESH:D004317', (207, 210))	('dxr efflux activity', 'MPA', (207, 226))
22594	32751066	The presence of numerous aromatic amino acids with polar groups such as tyrosine and tryptophan, as well as polar residues among the hydrophobic ones, also gives the ability to accommodate various ligands and provide a wide range of interactions.	('aromatic amino acids', 'Chemical', 'MESH:D024322', (25, 45))	('accommodate', 'Interaction', (177, 188))	('interactions', 'Interaction', (233, 245))	('provide', 'Reg', (209, 216))	('tyrosine', 'Chemical', 'MESH:D014443', (72, 80))	('ligands', 'Interaction', (197, 204))	('tyrosine', 'Var', (72, 80))	('tryptophan', 'Chemical', 'MESH:D014364', (85, 95))
22595	32751066	In view of the potential major role of this cavity in Ptch1 efflux activity, we have looked at whether some of the amino acids that compose it can be the cause of pathology in the case of mutation, which would underline their role in the transport of cholesterol.	('mutation', 'Var', (188, 196))	('cause', 'Reg', (154, 159))	('Ptch1 efflux activity', 'MPA', (54, 75))	('cholesterol', 'Chemical', 'MESH:D002784', (251, 262))
22596	32751066	Among those surrounding the cholesterol, five are conserved in the Patched family (between * in Table 2), two of which have side chains directed to the cholesterol (Leu427 and Ala497).	('Ala497', 'Var', (176, 182))	('cholesterol', 'Chemical', 'MESH:D002784', (28, 39))	('Leu427', 'Var', (165, 171))	('Ala497', 'Chemical', '-', (176, 182))	('Leu427', 'Chemical', '-', (165, 171))	('cholesterol', 'Chemical', 'MESH:D002784', (152, 163))
22600	32751066	Interestingly, three amino acids for which mutations are responsible for diseases, suggesting that they are important for Ptch1 function, are in the surrounding of cholesterol, dxr and astemizole: L128, D776, W1018.	('dxr', 'Disease', (177, 180))	('W1018', 'Var', (209, 214))	('D776', 'Var', (203, 207))	('astemizole', 'Chemical', 'MESH:D016589', (185, 195))	('cholesterol', 'Chemical', 'MESH:D002784', (164, 175))	('dxr', 'Chemical', 'MESH:D004317', (177, 180))	('cholesterol', 'Disease', (164, 175))	('L128', 'Var', (197, 201))
22601	32751066	From the 2D representation of the interaction between astemizole and Ptch1, we notice that most of them are hydrophobic interactions (W129, L777, I780, W1018) and one is a pi-stacking type (F1017).	('astemizole', 'Chemical', 'MESH:D016589', (54, 64))	('W129', 'Var', (134, 138))	('hydrophobic interactions', 'MPA', (108, 132))	('L777', 'Var', (140, 144))	('W1018', 'Var', (152, 157))	('I780', 'Var', (146, 150))
22607	32751066	The alteration of hERG by pharmacological inhibition produces long QT syndrome and the lethal cardiac arrhythmia torsade de pointes.	('cardiac arrhythmia torsade de pointes', 'Disease', 'MESH:D001145', (94, 131))	('rat', 'Species', '10116', (8, 11))	('long QT syndrome', 'Disease', (62, 78))	('hERG', 'Gene', (18, 22))	('torsade de pointes', 'Phenotype', 'HP:0001664', (113, 131))	('long QT syndrome', 'Phenotype', 'HP:0001657', (62, 78))	('cardiac arrhythmia torsade de pointes', 'Disease', (94, 131))	('alteration', 'Var', (4, 14))	('long QT syndrome', 'Disease', 'MESH:D008133', (62, 78))	('produces', 'Reg', (53, 61))	('cardiac arrhythmia', 'Phenotype', 'HP:0011675', (94, 112))
22610	32751066	IhERG "pulse" amplitude was monitored during repetitive application of the protocol presented in Figure 7, and we observed that 1microM astemizole induced about a 70% reduction in IhERG pulse amplitude, confirming the ability of astemizole to inhibit the hERG channel.	('astemizole', 'Chemical', 'MESH:D016589', (229, 239))	('astemizole', 'Chemical', 'MESH:D016589', (136, 146))	('reduction', 'NegReg', (167, 176))	('1microM', 'Var', (128, 135))	('inhibit', 'NegReg', (243, 250))	('astemizole', 'Gene', (136, 146))	('IhERG pulse amplitude', 'MPA', (180, 201))	('hERG channel', 'Pathway', (255, 267))
22702	30980285	We searched for possible TP53 gene defects and assessed nationwide incidence of ACC.	('TP53', 'Gene', '7157', (25, 29))	('TP53', 'Gene', (25, 29))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('defects', 'Var', (35, 42))
22703	30980285	Nonenhanced CT demonstrated > 20 Hounsfield Units (HU) for all tumours (median 34 (21-45)), median size 92 mm (20-196), Ki67 17% (1-40%), Weiss score 7 (4-9) and Helsinki score 24 (4-48).	('tumours', 'Disease', (63, 70))	('Ki67', 'Var', (120, 124))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
22704	30980285	One child had Beckwith-Wiedemann and one a TP53 mutation.	('Beckwith-Wiedemann', 'Disease', (14, 32))	('mutation', 'Var', (48, 56))	('child', 'Species', '9606', (4, 9))	('Beckwith-Wiedemann', 'Disease', 'MESH:D001506', (14, 32))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
22717	30980285	re-evaluated all tumours and determined Ki67, Weiss and Helsinki scores.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('tumours', 'Disease', (17, 24))	('Ki67', 'Var', (40, 44))
22743	30980285	Ten adult patients (age < 20 years (n = 3), concomitant other cancers (follicular lymphoma, earlier ACC and breast cancer, lung adenocarcinoma, prostate cancer (n = 4)) or strong family history of cancer (n = 3)) were screened for germline TP53 gene mutations, all were negative.	('TP53', 'Gene', '7157', (240, 244))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (153, 159))	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung adenocarcinoma', 'Disease', (123, 142))	('prostate cancer', 'Disease', 'MESH:D011471', (144, 159))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('follicular lymphoma', 'Disease', (71, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (144, 159))	('prostate cancer', 'Disease', (144, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('cancer', 'Disease', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('cancers', 'Disease', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (123, 142))	('TP53', 'Gene', (240, 244))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (197, 203))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (123, 142))	('patients', 'Species', '9606', (10, 18))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('ACC', 'Phenotype', 'HP:0006744', (100, 103))	('breast cancer', 'Disease', (108, 121))	('earlier ACC', 'Disease', (92, 103))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (250, 259))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('follicular lymphoma', 'Disease', 'MESH:D008224', (71, 90))
22775	30980285	Risk of death was higher in ENSAT stage III-IV compared to I-II (hazard ratio 9.29, 95% CI 2.56-33.66) (p = 0.001).	('ENSAT stage III-IV', 'Var', (28, 46))	('death', 'Disease', 'MESH:D003643', (8, 13))	('death', 'Disease', (8, 13))
22853	29506536	In some studies, the presence of inactivating TP53 mutations and activating beta-catenin mutations in ACC on transcriptome analysis was associated with worse prognosis.	('mutations', 'Var', (51, 60))	('beta-catenin', 'Gene', (76, 88))	('activating', 'PosReg', (65, 75))	('inactivating', 'Var', (33, 45))	('TP53', 'Gene', '7157', (46, 50))	('ACC', 'Phenotype', 'HP:0006744', (102, 105))	('TP53', 'Gene', (46, 50))	('mutations', 'Var', (89, 98))	('beta-catenin', 'Gene', '1499', (76, 88))
22887	28919755	In fact, in recent years, high SRB1 expression has emerged as an indicator of aggression in both prostate and breast cancers and a predictor of poor survival.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('high', 'Var', (26, 30))	('aggression in both prostate and breast cancers', 'Disease', 'MESH:D011471', (78, 124))	('SRB1', 'Gene', (31, 35))	('breast cancers', 'Phenotype', 'HP:0003002', (110, 124))	('aggression', 'Phenotype', 'HP:0000718', (78, 88))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('expression', 'MPA', (36, 46))
22962	28919755	Steroid hormone-synthesizing H295R cells were found to have much higher mRNA and protein expression levels of SRB1 compared to the other two human ACC cell lines, SW13 and RL251 (P<0.0001), which do not synthesize steroid hormones.	('SRB1', 'Gene', (110, 114))	('steroid hormones', 'Chemical', 'MESH:D013256', (214, 230))	('Steroid hormone', 'Chemical', 'MESH:D013256', (0, 15))	('human', 'Species', '9606', (141, 146))	('ACC', 'Phenotype', 'HP:0006744', (147, 150))	('SW13', 'CellLine', 'CVCL:0542', (163, 167))	('higher', 'PosReg', (65, 71))	('H295R', 'Var', (29, 34))
22966	28919755	It is clear from the image that SRB1-positive H295R cells effectively internalized DiO-labeled sHDL, in contrast to SW13 cells, which showed limited dye uptake.	('internalized', 'MPA', (70, 82))	('DiO', 'Chemical', '-', (83, 86))	('sHDL', 'Gene', (95, 99))	('DiO-labeled', 'Var', (83, 94))	('SW13', 'CellLine', 'CVCL:0542', (116, 120))
22981	28919755	H295R is a very aggressive and rapidly growing tumor with high animal-animal variability and rapid growth kinetics, making this tumor very difficult to cure.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('H295R', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', (47, 52))
22984	28919755	Although mice treated with both free WGA-TA and WGA-TA-HDL had lower body weights than other groups, it should be noted that part of the body weight decrease for WGA-TA-HDL can be ascribed to tumor volume decrease following treatment.	('tumor', 'Disease', (192, 197))	('lower', 'NegReg', (63, 68))	('mice', 'Species', '10090', (9, 13))	('lower body weights', 'Phenotype', 'HP:0004325', (63, 81))	('body weight decrease', 'Phenotype', 'HP:0004325', (137, 157))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('body', 'MPA', (137, 141))	('body weights', 'CPA', (69, 81))	('WGA-TA-HDL', 'Var', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('decrease', 'NegReg', (149, 157))	('decrease', 'NegReg', (205, 213))
23002	28919755	In addition, sHDL has been shown to cause cholesterol efflux and inhibition of cortisol production in noncancerous HAC16 adrenocortical cells.	('inhibition', 'NegReg', (65, 75))	('inhibition of cortisol production', 'Phenotype', 'HP:0008163', (65, 98))	('cortisol production', 'MPA', (79, 98))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('HAC16', 'CellLine', 'CVCL:8354', (115, 120))	('adrenocortical', 'Disease', (121, 135))	('adrenocortical', 'Disease', 'MESH:D018268', (121, 135))	('cholesterol efflux', 'MPA', (42, 60))	('cholesterol', 'Chemical', 'MESH:D002784', (42, 53))	('cortisol', 'Chemical', 'MESH:D006854', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('sHDL', 'Var', (13, 17))
23011	28919755	In addition, the same methodology has been used to prepare ETC642-blank sHDL, which has been examined in single- and multiple-dose clinical trials for treatment of cardiovascular diseases.	('ETC642', 'Chemical', 'MESH:C568357', (59, 65))	('cardiovascular diseases', 'Disease', (164, 187))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (164, 187))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (164, 187))	('ETC642-blank', 'Var', (59, 71))
23021	27374712	Two such frameshift mutations (p.Pro98Leufs*25, p.Pro27Leufs*17) were novel.	('p.Pro27Leufs*17', 'Var', (48, 63))	('p.Pro27Leufs*17', 'FRAMESHIFT', 'None', (48, 63))	('p.Pro98Leufs*25', 'Var', (31, 46))	('p.Pro98Leufs*25', 'FRAMESHIFT', 'None', (31, 46))
23022	27374712	The recurrent mutations were located at codons 31 (n=2; p.Val31Ile), 175 (n=3; p.Arg175His), and 273 (n=4; p.Arg273His and p.Arg273Cys).	('p.Arg175His', 'Var', (79, 90))	('p.Arg273Cys', 'Mutation', 'rs121913343', (123, 134))	('p.Arg273His', 'Var', (107, 118))	('p.Val31Ile', 'Mutation', 'rs201753350', (56, 66))	('p.Arg273His', 'Mutation', 'rs28934576', (107, 118))	('p.Arg273Cys', 'Var', (123, 134))	('p.Arg175His', 'Mutation', 'rs28934578', (79, 90))
23029	27374712	Li-Fraumeni syndrome (LFS, OMIM #151623) is an autosomal dominant cancer predisposition syndrome caused by a germline mutation in the TP53 tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('caused by', 'Reg', (97, 106))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('germline mutation', 'Var', (109, 126))	('TP53', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (47, 72))	('autosomal dominant cancer', 'Disease', (47, 72))	('TP53', 'Gene', '7157', (134, 138))
23033	27374712	LFS diagnosis can be confirmed by a genetic mutation in TP53.	('LFS', 'Disease', (0, 3))	('TP53', 'Gene', '7157', (56, 60))	('genetic mutation', 'Var', (36, 52))	('confirmed by', 'Reg', (21, 33))	('TP53', 'Gene', (56, 60))
23035	27374712	Furthermore, the spectrum of LFS-related TP53 mutations can be categorized into two groups: (1) gain of function mutations (missense mutations) conferring a dominant-negative effect or promoting an oncogenic effect and (2) loss of function mutations such as nonsense and frameshift mutations.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('oncogenic effect', 'CPA', (198, 214))	('loss of function', 'NegReg', (223, 239))	('gain of function', 'PosReg', (96, 112))	('mutations', 'Var', (113, 122))	('LFS-related', 'Gene', (29, 40))	('promoting', 'PosReg', (185, 194))	('frameshift mutations', 'Var', (271, 291))	('nonsense', 'Var', (258, 266))
23036	27374712	A previous study reported that missense mutations rather than nonsense or frameshift mutations are associated with an earlier onset of cancer.	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('missense mutations', 'Var', (31, 49))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('associated', 'Reg', (99, 109))
23050	27374712	The recurrent mutations were located at codons 31 (n=2; p.Val31Ile), 175 (n=3; p.Arg175His), and 273 [n=4; p.Arg273His (n=3), and p.Arg273Cys (n=1)] in TP53 (Fig.	('p.Arg273Cys', 'Mutation', 'rs121913343', (130, 141))	('p.Arg273His', 'Var', (107, 118))	('p.Val31Ile', 'Mutation', 'rs201753350', (56, 66))	('TP53', 'Gene', '7157', (152, 156))	('p.Arg273Cys', 'Var', (130, 141))	('p.Arg273His', 'Mutation', 'rs28934576', (107, 118))	('TP53', 'Gene', (152, 156))	('p.Arg175His', 'Mutation', 'rs28934578', (79, 90))
23051	27374712	Two novel frameshift mutations (p.Pro98Leufs*25 and p.Pro27Leufs*17) were identified (Table 1, Fig.	('p.Pro27Leufs*17', 'Var', (52, 67))	('p.Pro98Leufs*25', 'Var', (32, 47))	('p.Pro27Leufs*17', 'FRAMESHIFT', 'None', (52, 67))	('p.Pro98Leufs*25', 'FRAMESHIFT', 'None', (32, 47))
23052	27374712	The TP53 mutation carriers included three males and 11 females (male to female ratio of 0.3:1).	('mutation', 'Var', (9, 17))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
23060	27374712	One novel mutation, p.Pro98Leufs*25 was observed in patient 6, who was treated for ACC (at the age of 1 yr) and later developed osteosarcoma (4 yr), brain cancer (4 yr), and therapy-related neoplasm (10 yr) (Table 1).	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('neoplasm', 'Phenotype', 'HP:0002664', (190, 198))	('brain cancer', 'Phenotype', 'HP:0030692', (149, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('brain cancer', 'Disease', (149, 161))	('osteosarcoma', 'Disease', (128, 140))	('neoplasm', 'Disease', (190, 198))	('p.Pro98Leufs*25', 'FRAMESHIFT', 'None', (20, 35))	('osteosarcoma', 'Phenotype', 'HP:0002669', (128, 140))	('brain cancer', 'Disease', 'MESH:D001932', (149, 161))	('developed', 'PosReg', (118, 127))	('p.Pro98Leufs*25', 'Var', (20, 35))	('patient', 'Species', '9606', (52, 59))	('osteosarcoma', 'Disease', 'MESH:D012516', (128, 140))	('neoplasm', 'Disease', 'MESH:D009369', (190, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
23062	27374712	After the age of 28 yr, five primary tumors developed, including left breast cancer (28 yr), neurofibroma (33 yr), right breast cancer (38 yr), right nasal cavity squamous cell carcinoma (38 yr), and EGFR-mutated (p.Leu858Arg) lung adenocarcinoma (43 yr) in patient 7 (Table 1).	('neurofibroma', 'Disease', (93, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('squamous cell carcinoma', 'Disease', (163, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (227, 246))	('right breast cancer', 'Disease', 'MESH:D001943', (115, 134))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('EGFR', 'Gene', (200, 204))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (227, 246))	('breast cancer', 'Disease', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('neurofibroma', 'Disease', 'MESH:D009455', (93, 105))	('neurofibroma', 'Phenotype', 'HP:0001067', (93, 105))	('right breast cancer', 'Disease', (115, 134))	('primary tumors', 'Disease', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('p.Leu858Arg', 'Mutation', 'rs121434568', (214, 225))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 186))	('patient', 'Species', '9606', (258, 265))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('EGFR', 'Gene', '1956', (200, 204))	('p.Leu858Arg', 'Var', (214, 225))	('lung adenocarcinoma', 'Disease', (227, 246))	('primary tumors', 'Disease', 'MESH:D009369', (29, 43))
23069	27374712	Furthermore, missense mutations located at the loop, which were demonstrated to bind to the minor groove of DNA (L2: codons 164 to 194, L3: codons 237 to 250) and major groove of DNA (L1: codons 115 to 135, S2-S2-H2 motif: codons 273 to 286), were associated with brain cancer and ACC, respectively.	('brain cancer', 'Disease', (264, 276))	('bind', 'Interaction', (80, 84))	('brain cancer', 'Disease', 'MESH:D001932', (264, 276))	('brain cancer', 'Phenotype', 'HP:0030692', (264, 276))	('missense mutations', 'Var', (13, 31))	('associated with', 'Reg', (248, 263))	('ACC', 'Phenotype', 'HP:0006744', (281, 284))	('ACC', 'Disease', (281, 284))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))
23070	27374712	Here, we noted that the mutations of two brain cancer carriers and four breast cancer carriers were located at loop L2 and L3.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('brain cancer', 'Disease', 'MESH:D001932', (41, 53))	('brain cancer', 'Phenotype', 'HP:0030692', (41, 53))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (24, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('brain cancer', 'Disease', (41, 53))
23072	27374712	Despite the limited number of cases, identification of these frameshift mutations provides further insights into the TP53 mutation spectrum from Korean patients.	('TP53', 'Gene', '7157', (117, 121))	('frameshift mutations', 'Var', (61, 81))	('patients', 'Species', '9606', (152, 160))	('TP53', 'Gene', (117, 121))
23077	27374712	A previous study reported that missense variants appear to be associated with an earlier onset of cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('associated', 'Reg', (62, 72))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('missense variants', 'Var', (31, 48))
23078	27374712	However, this study demonstrated that missense mutations (e.g., p.Val31Ile) were identified in patients with a late-onset of cancer, while frameshift mutations (e.g.	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('p.Val31Ile', 'Var', (64, 74))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('p.Val31Ile', 'Mutation', 'rs201753350', (64, 74))
23079	27374712	p.Pro98Leufs*25) were identified in patients with an early-onset of cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patients', 'Species', '9606', (36, 44))	('p.Pro98Leufs*25', 'FRAMESHIFT', 'None', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('p.Pro98Leufs*25', 'Var', (0, 15))	('cancer', 'Disease', (68, 74))
23080	27374712	The age at tumor onset in TP53 mutation carriers could be influenced by genetic modifiers such as SNP309 (T>G), rs2279744 in MDM2 as well as PIN3 in TP53, together with environmental factors.	('SNP309 (T>G', 'Var', (98, 109))	('TP53', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('TP53', 'Gene', '7157', (26, 30))	('MDM2', 'Gene', '4193', (125, 129))	('tumor', 'Disease', (11, 16))	('TP53', 'Gene', '7157', (149, 153))	('rs2279744', 'Mutation', 'rs2279744', (112, 121))	('TP53', 'Gene', (149, 153))	('influenced', 'Reg', (58, 68))	('rs2279744', 'Var', (112, 121))	('MDM2', 'Gene', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
23081	27374712	There was a considerable heterogeneity in the relationship between TP53 mutations and tumor spectrum.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
23086	27374712	Previous studies reported that, when BRCA mutations are not identified in patients with breast cancer diagnosed before 30 yr, the likelihood of having a TP53 mutation is estimated to be 4-8%.	('patients', 'Species', '9606', (74, 82))	('TP53', 'Gene', '7157', (153, 157))	('mutation', 'Var', (158, 166))	('breast cancer', 'Disease', (88, 101))	('BRCA', 'Gene', '672', (37, 41))	('TP53', 'Gene', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BRCA', 'Gene', (37, 41))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
23089	27374712	Lastly, we reported patients with EGFR-mutated (p.Leu858Arg) lung adenocarcinoma (in patient 7) as well as therapy-related neoplasm.	('p.Leu858Arg', 'Var', (48, 59))	('patient', 'Species', '9606', (85, 92))	('neoplasm', 'Phenotype', 'HP:0002664', (123, 131))	('EGFR', 'Gene', (34, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('lung adenocarcinoma', 'Disease', (61, 80))	('patient', 'Species', '9606', (20, 27))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (61, 80))	('patients', 'Species', '9606', (20, 28))	('neoplasm', 'Disease', (123, 131))	('p.Leu858Arg', 'Mutation', 'rs121434568', (48, 59))	('EGFR', 'Gene', '1956', (34, 38))	('neoplasm', 'Disease', 'MESH:D009369', (123, 131))
23091	27374712	It is assumed that patient 7 had a germline TP53 mutation (p.Pro27Leufs*17) as the first genetic hit and a somatic EGFR mutation (p.Leu858Arg) as the second hit.	('patient', 'Species', '9606', (19, 26))	('EGFR', 'Gene', '1956', (115, 119))	('p.Leu858Arg', 'Mutation', 'rs121434568', (130, 141))	('p.Leu858Arg', 'Var', (130, 141))	('p.Pro27Leufs*17', 'FRAMESHIFT', 'None', (59, 74))	('EGFR', 'Gene', (115, 119))	('TP53', 'Gene', '7157', (44, 48))	('p.Pro27Leufs*17', 'Var', (59, 74))	('TP53', 'Gene', (44, 48))
23093	27374712	In addition, we did not compare clinical data between TP53 mutation-positive and -negative cases in the current study.	('TP53', 'Gene', '7157', (54, 58))	('mutation-positive', 'Var', (59, 76))	('TP53', 'Gene', (54, 58))
23096	27374712	There was a considerable heterogeneity in TP53 mutations and tumor spectrum among Korean patients.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
23129	26161274	Immunohistochemical analysis reported positivity to inhibin alpha and Melan-A (MART-1) and neuron specific enolase and synaptophysin and negativity to PS100 and chromogranin A, which confirmed the diagnosis of a neuroendocrine tumor.	('MART-1', 'Gene', '2315', (79, 85))	('chromogranin A', 'Gene', (161, 175))	('MART-1', 'Gene', (79, 85))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (212, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('positivity', 'Var', (38, 48))	('neuron specific enolase', 'Protein', (91, 114))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (212, 232))	('synaptophysin', 'Gene', (119, 132))	('neuroendocrine tumor', 'Disease', (212, 232))	('Melan-A', 'Gene', (70, 77))	('chromogranin A', 'Gene', '1113', (161, 175))	('synaptophysin', 'Gene', '6855', (119, 132))	('inhibin alpha', 'Protein', (52, 65))	('Melan-A', 'Gene', '2315', (70, 77))
23145	26161274	However, PTH could induce aldosterone secretion in a dose-dependent manner as previously observed in rat and human adrenocortical cells.	('PTH', 'Var', (9, 12))	('human', 'Species', '9606', (109, 114))	('rat', 'Species', '10116', (101, 104))	('aldosterone', 'Chemical', 'MESH:D000450', (26, 37))	('man', 'Species', '9606', (68, 71))	('adrenocortical', 'Disease', (115, 129))	('aldosterone secretion', 'MPA', (26, 47))	('adrenocortical', 'Disease', 'MESH:D018268', (115, 129))	('induce', 'Reg', (19, 25))	('man', 'Species', '9606', (111, 114))
23147	26161274	It seems that aldosterone production is directly enhanced with facilitated calcium entry in adrenal cells stimulated by PTH and indirectly enhanced through stimulation of renin release with a concomitant release of angiotensin II.	('facilitated calcium entry', 'MPA', (63, 88))	('aldosterone production', 'Phenotype', 'HP:0000859', (14, 36))	('aldosterone', 'Chemical', 'MESH:D000450', (14, 25))	('angiotensin II', 'Gene', '183', (215, 229))	('renin', 'Gene', '5972', (171, 176))	('enhanced', 'PosReg', (49, 57))	('PTH', 'Var', (120, 123))	('angiotensin II', 'Gene', (215, 229))	('calcium', 'Chemical', 'MESH:D002118', (75, 82))	('enhanced', 'PosReg', (139, 147))	('renin', 'Gene', (171, 176))	('aldosterone production', 'MPA', (14, 36))
23159	26161274	They detected a mutation at codon 541 in exon 10 with a loss of heterozygosity (LOH) in each contralateral allele in parathyroid adenoma and breast cancer tissue but not in adrenocortical adenoma tissue.	('heterozygosity', 'MPA', (64, 78))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (173, 195))	('parathyroid adenoma', 'Phenotype', 'HP:0002897', (117, 136))	('loss', 'NegReg', (56, 60))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (173, 195))	('mutation at codon 541', 'Var', (16, 37))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('parathyroid adenoma', 'Disease', 'MESH:D010282', (117, 136))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('adrenocortical adenoma', 'Disease', (173, 195))	('parathyroid adenoma', 'Disease', (117, 136))
23172	24755523	Extracellular activation of Wnt signaling through epigenetic dysregulation of Wnt inhibitory factor-1 (Wif-1) is associated with pathogenesis of adrenocortical tumor Wnt/beta-catenin signaling is considered to be an essential regulator of adrenocortical oncogenesis.	('Wnt inhibitory factor-1', 'Gene', '11197', (78, 101))	('Wif-1', 'Gene', '11197', (103, 108))	('adrenocortical tumor', 'Disease', (145, 165))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (145, 165))	('beta-catenin', 'Gene', (170, 182))	('adrenocortical oncogenesis', 'Disease', 'MESH:D063646', (239, 265))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('adrenocortical oncogenesis', 'Disease', (239, 265))	('beta-catenin', 'Gene', '1499', (170, 182))	('Wnt inhibitory factor-1', 'Gene', (78, 101))	('epigenetic dysregulation', 'Var', (50, 74))	('Wif-1', 'Gene', (103, 108))	('associated', 'Reg', (113, 123))
23173	24755523	Wnt inhibitory factor-1 (Wif-1), an extracellular regulator of Wnt signaling, is frequently down-regulated by hypermethylation of the promoter CpG.	('Wnt inhibitory factor-1', 'Gene', (0, 23))	('Wif-1', 'Gene', (25, 30))	('hypermethylation', 'Var', (110, 126))	('Wif-1', 'Gene', '11197', (25, 30))	('Wnt inhibitory factor-1', 'Gene', '11197', (0, 23))	('down-regulated', 'NegReg', (92, 106))
23176	24755523	Furthermore, a significant correlation was found between Wif-1 promoter methylation and mRNA transcription in the tumors.	('mRNA transcription', 'MPA', (88, 106))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Wif-1', 'Gene', (57, 62))	('methylation', 'Var', (72, 83))	('tumors', 'Disease', (114, 120))	('Wif-1', 'Gene', '11197', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
23180	24755523	However, despite the proposed activation of Wnt signaling in AC tumors, only 2 of 20 with intracellular beta-catenin accumulation showed beta-catenin mutations.	('tumors', 'Disease', (64, 70))	('beta-catenin', 'Gene', '1499', (137, 149))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('beta-catenin', 'Gene', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('beta-catenin', 'Gene', '1499', (104, 116))	('activation', 'PosReg', (30, 40))	('mutations', 'Var', (150, 159))	('Wnt', 'MPA', (44, 47))	('beta-catenin', 'Gene', (137, 149))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
23181	24755523	Thus, genetic alterations of beta-catenin and epigenetics-related Wif-1 promoter hypermethylation may be important mechanisms underlying AC tumor formation though aberrant canonical Wnt/beta-catenin signaling activation.	('Wif-1', 'Gene', '11197', (66, 71))	('mechanisms underlying', 'Reg', (115, 136))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('beta-catenin', 'Gene', (186, 198))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('beta-catenin', 'Gene', (29, 41))	('beta-catenin', 'Gene', '1499', (186, 198))	('activation', 'PosReg', (209, 219))	('beta-catenin', 'Gene', '1499', (29, 41))	('Wif-1', 'Gene', (66, 71))	('hypermethylation', 'Var', (81, 97))	('genetic alterations', 'Var', (6, 25))	('tumor', 'Disease', (140, 145))
23186	24755523	The canonical Wnt/beta-catenin pathway has been shown to play an important role in organ development, while dysregulation of Wnt signaling has been implicated as causative factor in some genitourinary malignancy cases.	('beta-catenin', 'Gene', (18, 30))	('implicated', 'Reg', (148, 158))	('organ development', 'CPA', (83, 100))	('beta-catenin', 'Gene', '1499', (18, 30))	('dysregulation', 'Var', (108, 121))	('genitourinary malignancy', 'Disease', (187, 211))	('genitourinary malignancy', 'Disease', 'MESH:D014564', (187, 211))
23188	24755523	Under inactivation of Wnt signaling, beta-catenin is normally phosphorylated at the NH2-terminal residues, in which a glycogen synthase kinase 3beta (GSK-3beta) consensus motif is present, with the aid of a scaffolding complex composed of axin and adenomatous polyposis proteins (APCs).	('glycogen synthase kinase 3beta', 'Gene', '2932', (118, 148))	('APC', 'Gene', '324', (280, 283))	('GSK-3beta', 'Gene', '2932', (150, 159))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (248, 269))	('inactivation', 'Var', (6, 18))	('adenomatous polyposis proteins', 'Disease', 'MESH:D011125', (248, 278))	('beta-catenin', 'Gene', '1499', (37, 49))	('beta-catenin', 'Gene', (37, 49))	('axin', 'Gene', '8312', (239, 243))	('axin', 'Gene', (239, 243))	('GSK-3beta', 'Gene', (150, 159))	('adenomatous polyposis proteins', 'Disease', (248, 278))	('glycogen synthase kinase 3beta', 'Gene', (118, 148))	('APC', 'Gene', (280, 283))
23194	24755523	However, despite the lack of definite beta-catenin mutations, the majority of AC tumors (70-85%) in those studies were found to be positive for beta-catenin accumulation, which suggests an additional mechanism of Wnt activation involving stabilization of beta-catenin.	('beta-catenin', 'Gene', (38, 50))	('beta-catenin', 'Gene', (255, 267))	('beta-catenin', 'Gene', (144, 156))	('tumors', 'Disease', (81, 87))	('mutations', 'Var', (51, 60))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('beta-catenin', 'Gene', '1499', (255, 267))	('beta-catenin', 'Gene', '1499', (144, 156))	('beta-catenin', 'Gene', '1499', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('positive', 'Reg', (131, 139))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
23199	24755523	The aim of the present study was to assess whether activation of the Wnt signaling pathway caused by epigenetics-related Wif-1 dysregulation has an association with the pathogenesis of AC tumors.	('Wif-1', 'Gene', (121, 126))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('Wif-1', 'Gene', '11197', (121, 126))	('Wnt signaling pathway', 'Pathway', (69, 90))	('dysregulation', 'Var', (127, 140))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('activation', 'PosReg', (51, 61))	('epigenetics-related', 'Var', (101, 120))
23209	24755523	A genetic alteration encompassing exon 3 of the beta-catenin gene was found in only 2 of the 20 AC tumors that showed intracellular beta-catenin accumulation (Table 1).	('genetic alteration', 'Var', (2, 20))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('beta-catenin', 'Gene', (48, 60))	('beta-catenin', 'Gene', (132, 144))	('beta-catenin', 'Gene', '1499', (48, 60))	('beta-catenin', 'Gene', '1499', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))
23210	24755523	These 2 tumors harboring a beta-catenin mutation were both the non-secreting phenotype of AC adenoma.	('mutation', 'Var', (40, 48))	('beta-catenin', 'Gene', '1499', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('adenoma', 'Disease', 'MESH:D000236', (93, 100))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('beta-catenin', 'Gene', (27, 39))	('adenoma', 'Disease', (93, 100))
23211	24755523	As shown in Figure 2A, there were 2 different mutations, resulting in proline to alanine (P44A) and serine to proline (S45P) in 1 of the tumors, while Figure 2B shows a mutation resulting in leucine to proline (L46P) that was found in the other.	('S45P', 'Mutation', 'rs121913407', (119, 123))	('P44A', 'Mutation', 'rs367773779', (90, 94))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('leucine', 'Var', (191, 198))	('proline', 'Chemical', 'MESH:D011392', (202, 209))	('serine', 'Chemical', 'MESH:D012694', (100, 106))	('proline', 'Chemical', 'MESH:D011392', (70, 77))	('proline', 'Chemical', 'MESH:D011392', (110, 117))	('leucine', 'Chemical', 'MESH:D007930', (191, 198))	('proline to alanine', 'MPA', (70, 88))	('L46P', 'Mutation', 'p.L46P', (211, 215))	('serine to proline', 'MPA', (100, 117))	('alanine', 'Chemical', 'MESH:D000409', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
23214	24755523	On the other hand, the majority of cytosines remained virtually unchanged after bisulfite modification in the AC tumor samples (Fig.	('tumor', 'Disease', (113, 118))	('modification', 'Var', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('bisulfite', 'Chemical', 'MESH:C042345', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('bisulfite', 'Var', (80, 89))	('cytosines', 'MPA', (35, 44))
23219	24755523	No significant association of Wif-1 methylation was found with tumor histology or tumor volume.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Wif-1', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Wif-1', 'Gene', '11197', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (82, 87))	('methylation', 'Var', (36, 47))
23232	24755523	Activation of a beta-catenin exon 3 mutation is one of the most frequent genetic alterations seen in association with activated Wnt signaling.	('beta-catenin', 'Gene', '1499', (16, 28))	('Activation', 'PosReg', (0, 10))	('mutation', 'Var', (36, 44))	('beta-catenin', 'Gene', (16, 28))
23234	24755523	Indeed, in our series, only 2 of 20 (10%) AC tumors with abnormal beta-catenin staining possessed beta-catenin mutations.	('mutations', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('beta-catenin', 'Gene', (66, 78))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('beta-catenin', 'Gene', '1499', (66, 78))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('beta-catenin', 'Gene', (98, 110))	('beta-catenin', 'Gene', '1499', (98, 110))
23235	24755523	In addition, bi-allelic inactivation of APC is rarely found in sporadic AC tumors, though patients with familial adenomatous polyposis APC mutation are common.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('APC', 'Gene', '324', (135, 138))	('familial adenomatous polyposis APC', 'Disease', 'MESH:D011125', (104, 138))	('APC', 'Gene', '324', (40, 43))	('familial adenomatous polyposis APC', 'Disease', (104, 138))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (113, 134))	('bi-allelic', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('APC', 'Gene', (135, 138))	('tumors', 'Disease', (75, 81))	('APC', 'Gene', (40, 43))	('patients', 'Species', '9606', (90, 98))
23238	24755523	In order to resolve the discrepancy between the low prevalence of genetic mutations affecting beta-catenin or APC and highly activated Wnt signaling in AC tumors, we speculate that canonical Wnt signaling involving adrenal oncogenesis is controlled by an upstream regulator of the Wnt pathway.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mutations', 'Var', (74, 83))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('beta-catenin', 'Gene', (94, 106))	('APC', 'Gene', (110, 113))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('beta-catenin', 'Gene', '1499', (94, 106))	('APC', 'Gene', '324', (110, 113))
23240	24755523	In bladder and kidney cancer, epigenetic promoter CpG hypermethylation of Wif-1 is attributable to its down-regulation.	('bladder and kidney cancer', 'Disease', 'MESH:D001749', (3, 28))	('Wif-1', 'Gene', (74, 79))	('Wif-1', 'Gene', '11197', (74, 79))	('epigenetic promoter CpG hypermethylation', 'Var', (30, 70))	('kidney cancer', 'Phenotype', 'HP:0009726', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('down-regulation', 'NegReg', (103, 118))
23241	24755523	In the present study, CpG methylation of Wif-1 was more common in the AC tumors than NA tissues (Fig.	('common', 'Reg', (56, 62))	('Wif-1', 'Gene', (41, 46))	('Wif-1', 'Gene', '11197', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('CpG methylation', 'Var', (22, 37))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
23244	24755523	Furthermore, we found an inverse correlation between mRNA transcription levels of beta-catenin and Wif-1 in AC tumors, which indicates that intracellular beta-catenin accumulation accelerating Wnt signaling is related to epigenetics-associated down-regulation of Wif-1, but not to posttranslational modification of beta-catenin.	('beta-catenin', 'Gene', (154, 166))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('beta-catenin', 'Gene', '1499', (154, 166))	('tumors', 'Disease', (111, 117))	('Wif-1', 'Gene', (99, 104))	('epigenetics-associated', 'Var', (221, 243))	('Wif-1', 'Gene', (263, 268))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('Wnt signaling', 'MPA', (193, 206))	('Wif-1', 'Gene', '11197', (99, 104))	('down-regulation', 'NegReg', (244, 259))	('Wif-1', 'Gene', '11197', (263, 268))	('beta-catenin', 'Gene', (315, 327))	('beta-catenin', 'Gene', '1499', (315, 327))	('mRNA', 'MPA', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('accelerating', 'PosReg', (180, 192))	('beta-catenin', 'Gene', (82, 94))	('beta-catenin', 'Gene', '1499', (82, 94))
23245	24755523	Therefore, it is quite possible that epigenetics-related functional impairment of Wif-1 may lead to constitutive beta-catenin activation and subsequent adrenal oncogenesis via cyclin D1 activation.	('lead', 'Reg', (92, 96))	('beta-catenin', 'Gene', '1499', (113, 125))	('epigenetics-related', 'Var', (37, 56))	('adrenal oncogenesis', 'CPA', (152, 171))	('activation', 'PosReg', (186, 196))	('Wif-1', 'Gene', (82, 87))	('activation', 'PosReg', (126, 136))	('beta-catenin', 'Gene', (113, 125))	('Wif-1', 'Gene', '11197', (82, 87))	('cyclin D1', 'Gene', '595', (176, 185))	('cyclin D1', 'Gene', (176, 185))
23249	24755523	In pigmented nodular-adrenocortical disease, the association of miR-449 with dysregulation of WNT1-inducible signaling pathway protein 2 has been discussed, while the probability of miR-29s in non-small-cell lung cancer as a mechanism of escape from epigenetic regulation of Wif-1 has also been noted.	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('Wif-1', 'Gene', (275, 280))	('pigmented nodular-adrenocortical disease', 'Disease', 'MESH:C566469', (3, 43))	('Wif-1', 'Gene', '11197', (275, 280))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('WNT1-inducible signaling pathway protein 2', 'Gene', '8839', (94, 136))	('miR-449', 'Var', (64, 71))	('WNT1-inducible signaling pathway protein 2', 'Gene', (94, 136))	('dysregulation', 'MPA', (77, 90))	('association', 'Interaction', (49, 60))	('pigmented nodular-adrenocortical disease', 'Disease', (3, 43))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('miR-29s', 'Var', (182, 189))	('-adrenocortical disease', 'Phenotype', 'HP:0008207', (20, 43))	('lung cancer', 'Disease', (208, 219))
23252	24755523	Dysregulation of the canonical Wnt/beta-catenin signaling pathway may be a minimum requirement in the initial step of adrenal tumorigenesis, though that appears to be insufficient for development of malignant transformation.	('beta-catenin', 'Gene', (35, 47))	('Dysregulation', 'Var', (0, 13))	('beta-catenin', 'Gene', '1499', (35, 47))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
23254	24755523	In conclusion, this is the first clinical study of inactivation of the Wif-1 gene via epigenetic pathways in AC tumors.	('inactivation', 'Var', (51, 63))	('Wif-1', 'Gene', (71, 76))	('tumors', 'Disease', (112, 118))	('clinical', 'Species', '191496', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('Wif-1', 'Gene', '11197', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
23255	24755523	In addition to genetic alterations of beta-catenin, the epigenetics of promoter CpG hypermethylation of Wif-1 may be an important mechanism associated with the initial process of adrenal oncogenesis via aberrant canonical Wnt/beta-catenin signaling activation.	('beta-catenin', 'Gene', (38, 50))	('beta-catenin', 'Gene', '1499', (226, 238))	('adrenal oncogenesis', 'Disease', (179, 198))	('associated', 'Reg', (140, 150))	('Wif-1', 'Gene', (104, 109))	('aberrant', 'Var', (203, 211))	('Wif-1', 'Gene', '11197', (104, 109))	('beta-catenin', 'Gene', '1499', (38, 50))	('activation', 'PosReg', (249, 259))	('epigenetics', 'Var', (56, 67))	('hypermethylation', 'Var', (84, 100))	('beta-catenin', 'Gene', (226, 238))
23404	19091123	This system supports that the presence of four or more of the following nine criteria (nuclear grade III-IV, mitotic rate >5/50 HPFs, atypical mitoses, clear cell tumour composition <= 25%, diffuse architecture, necrosis, venous, sinusoidal and capsular invasion) is indicative of malignancy.	('atypical mitoses', 'CPA', (134, 150))	('mitotic rate', 'CPA', (109, 121))	('<= 25', 'Var', (182, 187))	('necrosis', 'Disease', 'MESH:D009336', (212, 220))	('diffuse architecture', 'CPA', (190, 210))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('venous', 'CPA', (222, 228))	('malignancy', 'Disease', 'MESH:D009369', (281, 291))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('necrosis', 'Disease', (212, 220))	('malignancy', 'Disease', (281, 291))	('tumour', 'Disease', (163, 169))
23530	30269470	However, recent studies have reported that adjuvant mitotane may prolong recurrence-free survival in patients with radically resected adrenocortical carcinoma.	('patients', 'Species', '9606', (101, 109))	('prolong', 'PosReg', (65, 72))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (134, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('adrenocortical carcinoma', 'Disease', (134, 158))	('mitotane', 'Var', (52, 60))	('mitotane', 'Chemical', 'MESH:D008939', (52, 60))	('recurrence-free survival', 'CPA', (73, 97))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (134, 158))
23554	30279954	Indeed, the recent clinical trials on IGF1R inhibitors for ACC taught us a hard lesson on this regard.	('IGF1R', 'Gene', (38, 43))	('inhibitors', 'Var', (44, 54))	('IGF1R', 'Gene', '3480', (38, 43))
23562	29594118	Benign adrenal cortical tumors presenting with Cushing syndrome often have diverse mutations (PRKACA, PRKAR1A, GNAS, PDE11A, and PDE8B) involving the cyclic AMP signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('PRKACA', 'Gene', (94, 100))	('Benign adrenal cortical tumors', 'Disease', 'MESH:D000310', (0, 30))	('GNAS', 'Gene', (111, 115))	('PDE8B', 'Gene', '8622', (129, 134))	('GNAS', 'Gene', '2778', (111, 115))	('PRKAR1A', 'Gene', (102, 109))	('Cushing syndrome', 'Disease', 'MESH:D003480', (47, 63))	('PRKACA', 'Gene', '5566', (94, 100))	('PDE8B', 'Gene', (129, 134))	('cyclic AMP', 'Chemical', 'MESH:D000242', (150, 160))	('mutations', 'Var', (83, 92))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (47, 63))	('Cushing syndrome', 'Disease', (47, 63))	('PDE11A', 'Gene', (117, 123))	('PDE11A', 'Gene', '50940', (117, 123))	('adrenal cortical tumors', 'Phenotype', 'HP:0100641', (7, 30))	('PRKAR1A', 'Gene', '5573', (102, 109))	('Benign adrenal cortical tumors', 'Disease', (0, 30))
23564	29594118	The recent discovery of inactivating ARMC5 germline mutations in PBMAH has challenged the old belief that this disorder is mainly a sporadic disease.	('germline mutations', 'Var', (43, 61))	('ARMC5', 'Gene', '79798', (37, 42))	('ARMC5', 'Gene', (37, 42))	('PBMAH', 'Disease', (65, 70))	('inactivating', 'Var', (24, 36))
23587	29594118	At the molecular level, somatic mutations involving potassium channels (KCNJ5), ATPases (ATP1A1 and ATP2B3), and calcium channels (CACNA1D) account for approximately 60% of sporadic aldosterone-producing adenomas (Figure 2).	('adenomas', 'Disease', 'MESH:D000236', (204, 212))	('ATP', 'Chemical', 'MESH:D000255', (89, 92))	('CACNA1D', 'Gene', '776', (131, 138))	('KCNJ5', 'Gene', (72, 77))	('adenomas', 'Disease', (204, 212))	('CACNA1D', 'Gene', (131, 138))	('ATP1A1', 'Gene', '476', (89, 95))	('ATP2B3', 'Gene', '492', (100, 106))	('ATP2B3', 'Gene', (100, 106))	('aldosterone', 'Chemical', 'MESH:D000450', (182, 193))	('ATP1A1', 'Gene', (89, 95))	('ATP', 'Chemical', 'MESH:D000255', (100, 103))	('mutations', 'Var', (32, 41))	('KCNJ5', 'Gene', '3762', (72, 77))	('calcium', 'Chemical', 'MESH:D002118', (113, 120))	('potassium', 'Chemical', 'MESH:D011188', (52, 61))	('ATP', 'Chemical', 'MESH:D000255', (80, 83))
23588	29594118	Among these, activating KCNJ5 mutations implicating G1514 and L168R appear to be the most frequent.	('activating', 'PosReg', (13, 23))	('KCNJ5', 'Gene', '3762', (24, 29))	('G1514', 'Var', (52, 57))	('L168R', 'Mutation', 'rs386352318', (62, 67))	('L168R', 'Var', (62, 67))	('KCNJ5', 'Gene', (24, 29))
23589	29594118	KCNJ5 mutations were identified in approximately 40-50% (range, 30.2-76.8%) of aldosterone-producing adenomas.	('identified', 'Reg', (21, 31))	('adenomas', 'Disease', 'MESH:D000236', (101, 109))	('KCNJ5', 'Gene', '3762', (0, 5))	('adenomas', 'Disease', (101, 109))	('aldosterone', 'Chemical', 'MESH:D000450', (79, 90))	('KCNJ5', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
23590	29594118	Altered sodium permeability due to KCNJ5 (encoding Kir3.4) mutations results in cellular depolarization and increased intracytoplasmic calcium levels via voltage-gated calcium channels in affected tumor cells.	('Kir3.4', 'Gene', (51, 57))	('sodium', 'Chemical', 'MESH:D012964', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('calcium', 'Chemical', 'MESH:D002118', (135, 142))	('increased', 'PosReg', (108, 117))	('KCNJ5', 'Gene', (35, 40))	('increased intracytoplasmic calcium', 'Phenotype', 'HP:0003575', (108, 142))	('KCNJ5', 'Gene', '3762', (35, 40))	('Kir3.4', 'Gene', '3762', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('mutations', 'Var', (59, 68))	('calcium', 'Chemical', 'MESH:D002118', (168, 175))	('cellular depolarization', 'MPA', (80, 103))	('sodium permeability', 'MPA', (8, 27))	('tumor', 'Disease', (197, 202))	('intracytoplasmic calcium levels', 'MPA', (118, 149))
23591	29594118	The rates of ATP1A1 (overall rate ~4%, range, 0-25%), ATP2B3 (overall rate ~2%, range, 0-3.1%), and CACNA1D (overall rate ~5%, range, 0-14.3%) mutations were significantly lower in various series.	('CACNA1D', 'Gene', (100, 107))	('ATP2B3', 'Gene', (54, 60))	('ATP1A1', 'Gene', '476', (13, 19))	('CACNA1D', 'Gene', '776', (100, 107))	('ATP1A1', 'Gene', (13, 19))	('lower', 'NegReg', (172, 177))	('ATP2B3', 'Gene', '492', (54, 60))	('mutations', 'Var', (143, 152))
23592	29594118	ATP1A1 (Na+/K+ ATPase alpha-subunit) mutations result in cellular depolarization and subsequent calcium influx, whereas ATP2B3 (Ca2+ATPase) and CACNA1D (Cav1.3) mutations result in impaired intracellular calcium clearance and stimulation of the voltage-gated calcium channels at lower depolarization levels, respectively.	('ATP2B3', 'Gene', (120, 126))	('calcium', 'Chemical', 'MESH:D002118', (204, 211))	('calcium', 'Chemical', 'MESH:D002118', (259, 266))	('voltage-gated calcium channels', 'Pathway', (245, 275))	('ATP', 'Chemical', 'MESH:D000255', (132, 135))	('CACNA1D', 'Gene', '776', (144, 151))	('CACNA1D', 'Gene', (144, 151))	('calcium', 'Chemical', 'MESH:D002118', (96, 103))	('ATP2B3', 'Gene', '492', (120, 126))	('impaired intracellular calcium clearance', 'Phenotype', 'HP:0003575', (181, 221))	('Cav1.3', 'Gene', (153, 159))	('mutations', 'Var', (37, 46))	('ATP1A1', 'Gene', (0, 6))	('Ca2+ATPase', 'Gene', (128, 138))	('Cav1.3', 'Gene', '776', (153, 159))	('intracellular calcium clearance', 'MPA', (190, 221))	('stimulation', 'PosReg', (226, 237))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('ATP', 'Chemical', 'MESH:D000255', (120, 123))	('ATP1A1', 'Gene', '476', (0, 6))	('Ca2+ATPase', 'Gene', '760;1769', (128, 138))	('cellular depolarization', 'CPA', (57, 80))	('calcium influx', 'MPA', (96, 110))	('impaired', 'NegReg', (181, 189))	('ATP', 'Chemical', 'MESH:D000255', (15, 18))
23593	29594118	These four somatic alterations are thought to cause autonomous aldosterone production and cellular proliferation through aberrant activation of the calcium/calmodulin kinase signaling pathway, which is normally implicated in the physiology of aldosterone biosynthesis in ZG cells.	('calcium', 'Chemical', 'MESH:D002118', (148, 155))	('aldosterone production', 'MPA', (63, 85))	('aldosterone', 'Chemical', 'MESH:D000450', (243, 254))	('aldosterone production', 'Phenotype', 'HP:0000859', (63, 85))	('activation', 'PosReg', (130, 140))	('calcium/calmodulin kinase signaling pathway', 'Pathway', (148, 191))	('alterations', 'Var', (19, 30))	('aldosterone', 'Chemical', 'MESH:D000450', (63, 74))	('cause', 'Reg', (46, 51))	('cellular proliferation', 'CPA', (90, 112))
23603	29594118	The lack of somatic KCNJ5 mutations in unilateral hyperplasia and in the paradoxical ZG hyperplasia surrounding KCNJ5-mutant aldosterone-producing adenomas is of significance.	('hyperplasia', 'Disease', 'MESH:D006965', (88, 99))	('KCNJ5', 'Gene', '3762', (112, 117))	('KCNJ5', 'Gene', '3762', (20, 25))	('unilateral hyperplasia', 'Phenotype', 'HP:0001528', (39, 61))	('hyperplasia', 'Disease', 'MESH:D006965', (50, 61))	('hyperplasia', 'Disease', (50, 61))	('hyperplasia', 'Disease', (88, 99))	('mutations', 'Var', (26, 35))	('adenomas', 'Disease', 'MESH:D000236', (147, 155))	('aldosterone-producing', 'MPA', (125, 146))	('KCNJ5', 'Gene', (112, 117))	('adenomas', 'Disease', (147, 155))	('KCNJ5', 'Gene', (20, 25))	('aldosterone', 'Chemical', 'MESH:D000450', (125, 136))
23610	29594118	showed that aldosterone-producing adenomas with CACNA1D or ATP1A1 mutations were generally smaller than 1 cm.	('mutations', 'Var', (66, 75))	('aldosterone', 'Chemical', 'MESH:D000450', (12, 23))	('CACNA1D', 'Gene', (48, 55))	('CACNA1D', 'Gene', '776', (48, 55))	('ATP1A1', 'Gene', '476', (59, 65))	('adenomas', 'Disease', 'MESH:D000236', (34, 42))	('ATP1A1', 'Gene', (59, 65))	('adenomas', 'Disease', (34, 42))
23614	29594118	In that series, no ATP2B3 mutation was noted in adrenals with multiple nodules; however, a subsequent series identified a case with ATP2B3 mutation in one nodule and KCNJ5 and ATP2B3 mutation in another distinct nodule within the same adrenal gland.	('mutation', 'Var', (139, 147))	('ATP2B3', 'Gene', '492', (176, 182))	('KCNJ5', 'Gene', (166, 171))	('ATP2B3', 'Gene', '492', (132, 138))	('ATP2B3', 'Gene', (176, 182))	('KCNJ5', 'Gene', '3762', (166, 171))	('ATP2B3', 'Gene', (132, 138))	('ATP2B3', 'Gene', '492', (19, 25))	('ATP2B3', 'Gene', (19, 25))
23618	29594118	For instance, aldosterone-producing adenomas with KCNJ5 mutations are enriched in tumors that are predominantly composed of ZF-like clear cells (Figures 1A,B) that show higher CYP17A1 and CYP11B1 expression profiles and significantly lower expression profiles for CYP11B2.	('tumors', 'Disease', (82, 88))	('lower', 'NegReg', (234, 239))	('CYP17A1', 'Gene', (176, 183))	('CYP17A1', 'Gene', '1586', (176, 183))	('CYP11B2', 'Gene', (264, 271))	('CYP11B1', 'Gene', '1584', (188, 195))	('KCNJ5', 'Gene', '3762', (50, 55))	('adenomas', 'Disease', 'MESH:D000236', (36, 44))	('mutations', 'Var', (56, 65))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('adenomas', 'Disease', (36, 44))	('CYP11B1', 'Gene', (188, 195))	('aldosterone', 'Chemical', 'MESH:D000450', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('CYP11B2', 'Gene', '1585', (264, 271))	('higher', 'PosReg', (169, 175))	('expression profiles', 'MPA', (240, 259))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'MPA', (196, 206))	('KCNJ5', 'Gene', (50, 55))
23624	29594118	The significant differences between KCNJ5 mutant and wild-type tumors initiated a scientific discussion on the possibility that tumor formation and hyperfunctionality may represent independent processes.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mutant', 'Var', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('KCNJ5', 'Gene', (36, 41))	('KCNJ5', 'Gene', '3762', (36, 41))
23628	29594118	CTNNB1 mutations were reported in ~5% of these tumors.	('CTNNB1', 'Gene', '1499', (0, 6))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('CTNNB1', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (7, 16))
23629	29594118	Several studies have confirmed the tumorigenic role of this mutation as it was mutually exclusive to ion channel-related (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) mutations in primary aldosteronism.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('ATP2B3', 'Gene', (137, 143))	('ATP1A1', 'Gene', '476', (129, 135))	('ATP2B3', 'Gene', '492', (137, 143))	('KCNJ5', 'Gene', '3762', (122, 127))	('CACNA1D', 'Gene', '776', (149, 156))	('CACNA1D', 'Gene', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('ATP1A1', 'Gene', (129, 135))	('tumor', 'Disease', (35, 40))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (171, 192))	('KCNJ5', 'Gene', (122, 127))	('mutations', 'Var', (158, 167))	('primary aldosteronism', 'Disease', (171, 192))
23631	29594118	Aldosterone-producing adenomas with CTNNB1 mutations have been reported to have higher CYP11B2 mRNA and protein (by immunohistochemistry) expression levels compared to those harboring KCNJ5 mutations.	('CTNNB1', 'Gene', (36, 42))	('expression levels', 'MPA', (138, 155))	('CTNNB1', 'Gene', '1499', (36, 42))	('adenomas', 'Disease', 'MESH:D000236', (22, 30))	('KCNJ5', 'Gene', (184, 189))	('CYP11B2', 'Gene', (87, 94))	('mutations', 'Var', (43, 52))	('adenomas', 'Disease', (22, 30))	('KCNJ5', 'Gene', '3762', (184, 189))	('CYP11B2', 'Gene', '1585', (87, 94))	('higher', 'PosReg', (80, 86))
23637	29594118	Several researchers have hypothesized that CTNNB1 mutations likely play a role in tumorigenesis rather than in aldosterone production; however, others have proposed that CTNNB1 mutations play a role in aldosterone overproduction through aberrant activation of beta-catenin that can result in overexpression of AT1 receptor, as well as certain nuclear receptors (e.g., NURR1 and NURR7) and conversion of progesterone into 11beta-deoxycorticosterone.	('mutations', 'Var', (177, 186))	('CTNNB1', 'Gene', '1499', (170, 176))	('NURR1', 'Gene', '4929', (368, 373))	('AT1 receptor', 'Protein', (310, 322))	('tumor', 'Disease', (82, 87))	('aldosterone', 'Chemical', 'MESH:D000450', (111, 122))	('CTNNB1', 'Gene', (43, 49))	('NURR1', 'Gene', (368, 373))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('aldosterone production', 'Phenotype', 'HP:0000859', (111, 133))	('aldosterone overproduction', 'MPA', (202, 228))	('CTNNB1', 'Gene', (170, 176))	('activation', 'PosReg', (246, 256))	('11beta-deoxycorticosterone', 'Chemical', '-', (421, 447))	('aldosterone', 'Chemical', 'MESH:D000450', (202, 213))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('NURR7', 'Gene', (378, 383))	('beta-catenin', 'Gene', (260, 272))	('beta-catenin', 'Gene', '1499', (260, 272))	('progesterone', 'Chemical', 'MESH:D011374', (403, 415))	('CTNNB1', 'Gene', '1499', (43, 49))	('overexpression', 'PosReg', (292, 306))
23640	29594118	Of these, type 3 familial hyperaldosteronism is associated with germline KCNJ5 mutations; therefore, a small proportion of seemingly sporadic aldosterone-producing adenomas with KCNJ5 mutations may in fact be a harbinger of this condition.	('adenomas', 'Disease', (164, 172))	('KCNJ5', 'Gene', (178, 183))	('associated', 'Reg', (48, 58))	('mutations', 'Var', (184, 193))	('KCNJ5', 'Gene', '3762', (178, 183))	('KCNJ5', 'Gene', (73, 78))	('type 3 familial hyperaldosteronism', 'Phenotype', 'HP:0011739', (10, 44))	('adenomas', 'Disease', 'MESH:D000236', (164, 172))	('familial hyperaldosteronism', 'Disease', 'MESH:C580087', (17, 44))	('KCNJ5', 'Gene', '3762', (73, 78))	('familial hyperaldosteronism', 'Disease', (17, 44))	('aldosterone', 'Chemical', 'MESH:D000450', (142, 153))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (26, 44))	('mutations', 'Var', (79, 88))
23642	29594118	The identification of a novel germline CACNA1H (M1549V) mutation encoding the low voltage activated T-type calcium channel (Cav3.2) has broadened the genomic landscape of familial hyperaldosteronism; the adrenalectomy specimen of one affected individual showed ZG layer hyperplasia.	('CACNA1H', 'Gene', '8912', (39, 46))	('M1549V', 'SUBSTITUTION', 'None', (48, 54))	('Cav3.2', 'Gene', '8912', (124, 130))	('calcium', 'Chemical', 'MESH:D002118', (107, 114))	('men', 'Species', '9606', (223, 226))	('hyperplasia', 'Disease', 'MESH:D006965', (270, 281))	('familial hyperaldosteronism', 'Disease', (171, 198))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (180, 198))	('hyperplasia', 'Disease', (270, 281))	('familial hyperaldosteronism', 'Disease', 'MESH:C580087', (171, 198))	('CACNA1H', 'Gene', (39, 46))	('mutation', 'Var', (56, 64))	('Cav3.2', 'Gene', (124, 130))	('M1549V', 'Var', (48, 54))
23643	29594118	Interestingly, primary aldosteronism was also recently described in African American patients harboring germline mutations in the armadillo repeat containing 5 (ARMC5); however, a more recent study of predominantly Caucasian patients with primary aldosteronism did not identify a pathogenetic ARMC5 mutation.	('ARMC5', 'Gene', (293, 298))	('armadillo repeat containing 5', 'Gene', '79798', (130, 159))	('ARMC5', 'Gene', '79798', (293, 298))	('patients', 'Species', '9606', (225, 233))	('ARMC5', 'Gene', (161, 166))	('patients', 'Species', '9606', (85, 93))	('ARMC5', 'Gene', '79798', (161, 166))	('mutations', 'Var', (113, 122))	('primary aldosteronism', 'Disease', (15, 36))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (15, 36))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (239, 260))	('armadillo repeat containing 5', 'Gene', (130, 159))
23658	29594118	Consequently, PPNAD is further subdivided based on its association with Carney complex: (i) c-PPNAD for those associated with Carney complex, and (ii) i-PPNAD for isolated cases with may be either familial (due to germline mutations) or sporadic (due to somatic alterations).	('germline mutations', 'Var', (214, 232))	('familial', 'Disease', (197, 205))	('c-PPNAD', 'Chemical', '-', (92, 99))
23684	29594118	Alterations in the cyclic adenosine monophosphate (cAMP) or protein kinase A (PKA) signaling pathway have been linked to the pathogenesis of glucocorticoid-producing adrenal cortical neoplasms and bilateral adrenocortical micronodular disease (Figure 7).	('adrenal cortical neoplasms', 'Disease', (166, 192))	('bilateral adrenocortical micronodular disease', 'Disease', 'MESH:C566469', (197, 242))	('neoplasms', 'Phenotype', 'HP:0002664', (183, 192))	('linked', 'Reg', (111, 117))	('adrenal cortical neoplasms', 'Disease', 'MESH:D000310', (166, 192))	('cyclic adenosine monophosphate', 'Chemical', 'MESH:D000242', (19, 49))	('Alterations', 'Var', (0, 11))	('bilateral adrenocortical micronodular disease', 'Disease', (197, 242))	('neoplasm', 'Phenotype', 'HP:0002664', (183, 191))	('cyclic adenosine monophosphate', 'MPA', (19, 49))	('cAMP', 'Chemical', 'MESH:D000242', (51, 55))	('adrenal cortical neoplasms', 'Phenotype', 'HP:0100641', (166, 192))
23690	29594118	Activating mutations in the stimulatory G-protein alpha subunit (GNAS) and the catalytic subunit of PKA (PRKACA), as well as inactivating mutations in the type 1 alpha regulatory subunit of PKA (PRKAR1A) and cAMP-hydrolyzing PDEs (PDE11A and PDE8B), have been linked with various morphological correlates of ACTH-independent adrenal Cushing syndrome.	('GNAS', 'Gene', '2778', (65, 69))	('ACTH', 'Gene', '5443', (308, 312))	('adrenal Cushing syndrome', 'Disease', 'MESH:D003480', (325, 349))	('PRKAR1A', 'Gene', '5573', (195, 202))	('PDE8B', 'Gene', '8622', (242, 247))	('PRKACA', 'Gene', '5566', (105, 111))	('cAMP', 'Chemical', 'MESH:D000242', (208, 212))	('G-protein alpha subunit', 'Gene', '2778', (40, 63))	('adrenal Cushing syndrome', 'Disease', (325, 349))	('ACTH', 'Gene', (308, 312))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (333, 349))	('PDEs', 'Gene', '50940', (225, 229))	('PDE8B', 'Gene', (242, 247))	('linked', 'Reg', (260, 266))	('PRKACA', 'Gene', (105, 111))	('PDE11A', 'Gene', '50940', (231, 237))	('PDE11A', 'Gene', (231, 237))	('G-protein alpha subunit', 'Gene', (40, 63))	('inactivating mutations', 'Var', (125, 147))	('PRKAR1A', 'Gene', (195, 202))	('GNAS', 'Gene', (65, 69))	('PDEs', 'Gene', (225, 229))
23691	29594118	Mutations in CTNNB1 have also been described in glucocorticoid-producing adrenal cortical proliferations including adenomas.	('adenomas', 'Disease', 'MESH:D000236', (115, 123))	('described', 'Reg', (35, 44))	('adenomas', 'Disease', (115, 123))	('CTNNB1', 'Gene', (13, 19))	('glucocorticoid-producing', 'MPA', (48, 72))	('Mutations', 'Var', (0, 9))	('adrenal cortical proliferation', 'Phenotype', 'HP:0100641', (73, 103))	('CTNNB1', 'Gene', '1499', (13, 19))
23692	29594118	Aldosterone and glucocorticoid co-secreting adenomas have been reported to harbor KCNJ5 mutations.	('Aldosterone', 'Disease', (0, 11))	('adenomas', 'Disease', 'MESH:D000236', (44, 52))	('adenomas', 'Disease', (44, 52))	('mutations', 'Var', (88, 97))	('KCNJ5', 'Gene', (82, 87))	('KCNJ5', 'Gene', '3762', (82, 87))
23695	29594118	Among these, ACTH-independent steroidogenesis has been explained by the presence of ectopic hormone receptors (e.g., gastric inhibitory polypeptide receptors, beta-adrenergic, 5HT-7 serotonin receptor, V2-V3 vasopressin receptor, and angiotensin receptor "AT1R") or dysregulation of eutopic receptors (5-HT4 serotonin receptor, V1 vasopressin receptor, luteinizing hormone/human chorionic gonadotropin).	('V1 vasopressin receptor', 'Protein', (328, 351))	('dysregulation', 'Var', (266, 279))	('AT1R"', 'Gene', (256, 261))	('human', 'Species', '9606', (373, 378))	('ACTH', 'Gene', (13, 17))	('ACTH', 'Gene', '5443', (13, 17))	('5-HT4 serotonin receptor', 'Protein', (302, 326))	('luteinizing hormone/human chorionic gonadotropin', 'Protein', (353, 401))	('AT1R"', 'Gene', '185', (256, 261))
23699	29594118	that 55% of PBMAH cases harbor inactivating ARMC5 germline mutations has challenged the old belief that PBMAH is mainly a sporadic disease.	('ARMC5', 'Gene', '79798', (44, 49))	('PBMAH', 'Disease', (12, 17))	('ARMC5', 'Gene', (44, 49))	('inactivating', 'Var', (31, 43))
23707	29594118	This is also consistent with the finding that larger non-functional adenomas are frequently associated with CTNNB1 mutations.	('mutations', 'Var', (115, 124))	('CTNNB1', 'Gene', '1499', (108, 114))	('adenomas', 'Disease', 'MESH:D000236', (68, 76))	('adenomas', 'Disease', (68, 76))	('CTNNB1', 'Gene', (108, 114))	('associated', 'Reg', (92, 102))
23709	29594118	Somatic activating GNAS mutations and somatic allelic loses of PRKAR1A were seen in up to 17 and 23% of glucocorticoid-producing adenomas, respectively.	('GNAS', 'Gene', (19, 23))	('PRKAR1A', 'Gene', '5573', (63, 70))	('adenomas', 'Disease', 'MESH:D000236', (129, 137))	('adenomas', 'Disease', (129, 137))	('GNAS', 'Gene', '2778', (19, 23))	('PRKAR1A', 'Gene', (63, 70))	('mutations', 'Var', (24, 33))
23710	29594118	Interestingly, glucocorticoid-producing adenomas with somatic PRKAR1A alterations were more frequently associated with smaller tumor size and paradoxical increase in urinary cortisol levels following dexamethasone suppression.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('alterations', 'Var', (70, 81))	('increase in urinary cortisol', 'Phenotype', 'HP:0012030', (154, 182))	('smaller', 'NegReg', (119, 126))	('tumor', 'Disease', (127, 132))	('cortisol', 'Chemical', 'MESH:D006854', (174, 182))	('adenomas', 'Disease', 'MESH:D000236', (40, 48))	('PRKAR1A', 'Gene', (62, 69))	('adenomas', 'Disease', (40, 48))	('dexamethasone', 'Chemical', 'MESH:D003907', (200, 213))	('urinary cortisol levels', 'MPA', (166, 189))	('increase', 'PosReg', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('PRKAR1A', 'Gene', '5573', (62, 69))
23713	29594118	Mutations in PRKAR1A, PDE11A, and PDE8B have all been implicated in the pathogenesis of bilateral micronodular adrenocortical disease presenting with Cushing syndrome.	('PDE11A', 'Gene', (22, 28))	('adrenocortical disease', 'Disease', (111, 133))	('implicated in', 'Reg', (54, 67))	('PDE8B', 'Gene', (34, 39))	('adrenocortical disease', 'Disease', 'MESH:D018268', (111, 133))	('pathogenesis', 'Reg', (72, 84))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (150, 166))	('PRKAR1A', 'Gene', (13, 20))	('PDE8B', 'Gene', '8622', (34, 39))	('Cushing syndrome', 'Disease', (150, 166))	('Cushing syndrome', 'Disease', 'MESH:D003480', (150, 166))	('Mutations', 'Var', (0, 9))	('adrenocortical disease presenting', 'Phenotype', 'HP:0008207', (111, 144))	('PRKAR1A', 'Gene', '5573', (13, 20))	('PDE11A', 'Gene', '50940', (22, 28))
23717	29594118	Germline or sporadic inactivating PRKAR1A, PDE11A, and PDE8B mutations have also been described in i-PPNAD causing adrenal Cushing syndrome.	('PDE11A', 'Gene', (43, 49))	('adrenal Cushing syndrome', 'Disease', 'MESH:D003480', (115, 139))	('causing', 'Reg', (107, 114))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (123, 139))	('mutations', 'Var', (61, 70))	('PDE8B', 'Gene', (55, 60))	('PRKAR1A', 'Gene', (34, 41))	('PDE8B', 'Gene', '8622', (55, 60))	('inactivating', 'Var', (21, 33))	('adrenal Cushing syndrome', 'Disease', (115, 139))	('PDE11A', 'Gene', '50940', (43, 49))	('PRKAR1A', 'Gene', '5573', (34, 41))
23719	29594118	The role of PDE variants impacting the clinical manifestations of Carney complex patients has also been documented.	('Carney complex', 'Disease', (66, 80))	('men', 'Species', '9606', (108, 111))	('patients', 'Species', '9606', (81, 89))	('impacting', 'Reg', (25, 34))	('PDE', 'Gene', (12, 15))	('PDE', 'Gene', '8622', (12, 15))	('variants', 'Var', (16, 24))
23720	29594118	For instance, a higher frequency of PDE11A variants was noted in male patients with Carney complex presenting with large cell calcifying Sertoli cell tumor.	('patients', 'Species', '9606', (70, 78))	('Sertoli cell tumor', 'Phenotype', 'HP:0100619', (137, 155))	('Carney complex', 'Disease', (84, 98))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('variants', 'Var', (43, 51))	('tumor', 'Disease', (150, 155))	('PDE11A', 'Gene', (36, 42))	('PDE11A', 'Gene', '50940', (36, 42))
23721	29594118	Germline PDE11A variant mutation has also been described with adrenal enlargement but without evidence of Cushing syndrome.	('adrenal enlargement', 'Disease', (62, 81))	('adrenal enlargement', 'Disease', 'MESH:D006529', (62, 81))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (106, 122))	('PDE11A', 'Gene', '50940', (9, 15))	('adrenal enlargement', 'Phenotype', 'HP:0008221', (62, 81))	('Cushing syndrome', 'Disease', (106, 122))	('mutation', 'Var', (24, 32))	('Cushing syndrome', 'Disease', 'MESH:D003480', (106, 122))	('PDE11A', 'Gene', (9, 15))	('variant mutation', 'Var', (16, 32))
23722	29594118	The discovery of PDE11A variants in patients with Carney complex and genomic duplication of the locus of PRKACB (encoding the catalytic C-beta subunit of PKA) in a patient with Carney complex but without evidence of Cushing syndrome support the existence of versatile genomic alterations causing PKA dysregulation.	('PRKACB', 'Gene', (105, 111))	('patients', 'Species', '9606', (36, 44))	('variants', 'Var', (24, 32))	('C-beta', 'Species', '10703', (136, 142))	('patient', 'Species', '9606', (164, 171))	('PDE11A', 'Gene', '50940', (17, 23))	('PDE11A', 'Gene', (17, 23))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (216, 232))	('Cushing syndrome', 'Disease', 'MESH:D003480', (216, 232))	('PRKACB', 'Gene', '5567', (105, 111))	('Cushing syndrome', 'Disease', (216, 232))	('patient', 'Species', '9606', (36, 43))
23723	29594118	A recent study has broadened our knowledge of pathogenic PRKACA alterations in bilateral micronodular adrenocortical disease presenting with Cushing syndrome.	('PRKACA', 'Gene', '5566', (57, 63))	('Cushing syndrome', 'Disease', (141, 157))	('Cushing syndrome', 'Disease', 'MESH:D003480', (141, 157))	('adrenocortical disease presenting', 'Phenotype', 'HP:0008207', (102, 135))	('adrenocortical disease', 'Disease', (102, 124))	('adrenocortical disease', 'Disease', 'MESH:D018268', (102, 124))	('alterations', 'Var', (64, 75))	('PRKACA', 'Gene', (57, 63))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (141, 157))
23724	29594118	In this series, germline duplication of PRKACA was identified in 5 of 35 patients with bilateral nodular cortical disease lacking germline PRKAR1A, PDE11A, PDE8B, and somatic GNAS mutations (31 i-PPNAD, 2 i-MAD, and 2 macronodular type).	('PRKAR1A', 'Gene', (139, 146))	('PDE8B', 'Gene', (156, 161))	('PRKACA', 'Gene', (40, 46))	('PDE8B', 'Gene', '8622', (156, 161))	('mutations', 'Var', (180, 189))	('PRKACA', 'Gene', '5566', (40, 46))	('GNAS', 'Gene', '2778', (175, 179))	('GNAS', 'Gene', (175, 179))	('PRKAR1A', 'Gene', '5573', (139, 146))	('bilateral nodular cortical disease', 'Disease', (87, 121))	('bilateral nodular cortical disease', 'Disease', 'MESH:D020518', (87, 121))	('PDE11A', 'Gene', (148, 154))	('patients', 'Species', '9606', (73, 81))	('PDE11A', 'Gene', '50940', (148, 154))
23725	29594118	No significant phenotypic differences were reported between those carrying a germline PRKACA duplication and those lacking this molecular alteration.	('PRKACA', 'Gene', (86, 92))	('duplication', 'Var', (93, 104))	('PRKACA', 'Gene', '5566', (86, 92))
23728	29594118	Despite significant adrenal gland enlargement, PBMAH is characterized by relatively inefficient and low cortisol overproduction in comparison to its micronodular counterpart, an observation that has attracted interest from the scientific community.	('low cortisol', 'Phenotype', 'HP:0008163', (100, 112))	('adrenal gland enlargement', 'Disease', 'MESH:D000307', (20, 45))	('adrenal gland enlargement', 'Disease', (20, 45))	('adrenal gland enlargement', 'Phenotype', 'HP:0008221', (20, 45))	('cortisol', 'Chemical', 'MESH:D006854', (104, 112))	('cortisol overproduction', 'MPA', (104, 127))	('PBMAH', 'Var', (47, 52))
23731	29594118	Significant downregulation of genes encoding enzymes implicated in steroidogenesis (CYP11A, CYP17, and CYP21A2) has also been observed and used to explain this phenomenon in PBMAH.	('downregulation', 'NegReg', (12, 26))	('men', 'Species', '9606', (165, 168))	('CYP17', 'Gene', '1586', (92, 97))	('CYP21A2', 'Gene', '1589', (103, 110))	('genes', 'Gene', (30, 35))	('CYP21A2', 'Gene', (103, 110))	('CYP11A', 'Var', (84, 90))	('CYP17', 'Gene', (92, 97))
23733	29594118	characterized the ARMC5 heterogeneity of individual nodules in PBMAH by demonstrating distinctive secondary somatic mutations arising in the background of germline susceptibility in individual macronodular proliferations.	('mutations', 'Var', (116, 125))	('ARMC5', 'Gene', (18, 23))	('ARMC5', 'Gene', '79798', (18, 23))
23735	29594118	The discovery of frequent germline ARCM5 alterations in patients with adrenal Cushing syndrome has advanced our understanding of this disease, especially with regards to its inherent genotype-phenotype correlations.	('patients', 'Species', '9606', (56, 64))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (78, 94))	('adrenal Cushing syndrome', 'Disease', 'MESH:D003480', (70, 94))	('adrenal Cushing syndrome', 'Disease', (70, 94))	('ARCM5', 'Gene', (35, 40))	('alterations', 'Var', (41, 52))
23738	29594118	In addition, adrenals with ARMC5-driven PBMAH were significantly bigger and had more nodules than those with ARMC5-wild-type presentations.	('ARMC5', 'Gene', (109, 114))	('ARMC5', 'Gene', '79798', (109, 114))	('PBMAH', 'Var', (40, 45))	('ARMC5', 'Gene', (27, 32))	('more', 'PosReg', (80, 84))	('ARMC5', 'Gene', '79798', (27, 32))	('bigger', 'PosReg', (65, 71))	('nodules', 'CPA', (85, 92))
23939	26510907	The gains in 1-year CS over time were more pronounced in older patients (>53 years), those with an unhappy marital status (divorced, separated or widowed), or stage III or high-grade disease.	('high-grade disease', 'Var', (172, 190))	('stage', 'Disease', (159, 164))	('CS', 'Chemical', '-', (20, 22))	('patients', 'Species', '9606', (63, 71))
23951	26510907	For example, patients with advanced or poorly differentiated tumors have more pronounced gains than those with early-stage or well differentiated tumors.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('poorly differentiated', 'Var', (39, 60))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('gains', 'PosReg', (89, 94))	('tumors', 'Disease', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
23969	26510907	Based on the International Classification of Disease (ICD), patients with ACC were identified based on site (C74.0 or 74.9) and histologic subtype code (8370).	('C74.0 or 74.9', 'Var', (109, 122))	('8370', 'Var', (153, 157))	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('patients', 'Species', '9606', (60, 68))	('ACC', 'Disease', (74, 77))
24081	25889798	In Southern Brazil, the incidence of adrenocortical tumors is unusually high, coinciding with a high prevalence of the germ line TP53 mutation R337H which is present in up to 0.5% of newborns in specific regions of Southern Brazil.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('R337H', 'Var', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('R337H', 'Mutation', 'rs121912664', (143, 148))	('TP53', 'Gene', '7157', (129, 133))	('adrenocortical tumors', 'Disease', (37, 58))	('TP53', 'Gene', (129, 133))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (37, 58))
24082	25889798	Carriers of this particular mutation have been found to have a penetrance of 2.39% to 9.9% for adrenocortical tumors, with most tumors being carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (95, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('carcinomas', 'Disease', (141, 151))	('carcinomas', 'Disease', 'MESH:D002277', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (110, 116))	('mutation', 'Var', (28, 36))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('adrenocortical tumors', 'Disease', (95, 116))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('to 9', 'Species', '1214577', (83, 87))
24083	25889798	Interestingly, this particular TP53 mutation was not found to predispose to extra-adrenal cancers, although this relationship was not studied rigorously.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('extra-adrenal cancers', 'Disease', 'MESH:D000310', (76, 97))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('extra-adrenal cancers', 'Disease', (76, 97))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('mutation', 'Var', (36, 44))
24090	25889798	Patients with increased p53 staining tend to have higher grade tumors, reflected by higher Ki-67 expression, higher tumor stage, and poorer disease-free survival.	('increased', 'PosReg', (14, 23))	('poorer', 'NegReg', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('higher', 'PosReg', (84, 90))	('p53', 'Gene', '7157', (24, 27))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('expression', 'MPA', (97, 107))	('tumor', 'Disease', (63, 68))	('p53', 'Gene', (24, 27))	('disease-free survival', 'CPA', (140, 161))	('Ki-67', 'Gene', '17345', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Ki-67', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (116, 121))	('staining', 'Var', (28, 36))
24108	25889798	When accumulation is abnormally increased due to activating mutations, there is abnormal Wnt pathway activation resulting in tumor formation.	('accumulation', 'MPA', (5, 17))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Wnt pathway', 'Pathway', (89, 100))	('activation', 'PosReg', (101, 111))	('tumor', 'Disease', (125, 130))	('increased', 'PosReg', (32, 41))	('mutations', 'Var', (60, 69))
24117	25889798	However, later studies revealed that a proportion of adrenal tumors are immunonegative, and that negative staining does not exclude the diagnosis of ACC.	('adrenal tumors', 'Disease', 'MESH:D000310', (53, 67))	('adrenal tumor', 'Phenotype', 'HP:0100631', (53, 66))	('adrenal tumors', 'Disease', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('immunonegative', 'Var', (72, 86))
24121	25889798	Genetic alterations at the 11p15 chromosomal locus result in an overexpression of IGF-2 in adrenal cortex cells and are fairly specific to both sporadic and syndromic adrenocortical carcinomas but not adenomas.	('Genetic alterations', 'Var', (0, 19))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (167, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('adenomas', 'Disease', (201, 209))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('syndromic adrenocortical carcinomas', 'Disease', (157, 192))	('overexpression', 'PosReg', (64, 78))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (167, 192))	('IGF-2', 'Gene', (82, 87))	('syndromic adrenocortical carcinomas', 'Disease', 'MESH:D018268', (157, 192))	('IGF-2', 'Gene', '3481', (82, 87))	('adenomas', 'Disease', 'MESH:D000236', (201, 209))
24126	25889798	La-Fraumeni syndrome, associated with germ line mutations in the TP53 gene, is present in the majority of children with adrenocortical tumors but is seen less commonly in adults.	('La-Fraumeni syndrome', 'Disease', 'MESH:D049310', (0, 20))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (120, 141))	('TP53', 'Gene', '7157', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('TP53', 'Gene', (65, 69))	('La-Fraumeni syndrome', 'Disease', (0, 20))	('adrenocortical tumors', 'Disease', (120, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('children', 'Species', '9606', (106, 114))	('mutations', 'Var', (48, 57))
24128	25889798	This mutation is associated with tumors exclusive to childhood and frequently results in benign, and rarely malignant, adrenal tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Disease', (33, 39))	('associated', 'Reg', (17, 27))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('results in', 'Reg', (78, 88))	('adrenal tumor', 'Phenotype', 'HP:0100631', (119, 132))	('adrenal tumors', 'Disease', (119, 133))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('benign', 'Disease', (89, 95))	('mutation', 'Var', (5, 13))	('adrenal tumors', 'Disease', 'MESH:D000310', (119, 133))
24141	25889798	As discussed previously, loss of heterozygosity at 17p13 and SF-1 protein staining have been shown to be stage-independent prognostic factors, while p53 and Beta-catenin staining have not.	('p53', 'Gene', (149, 152))	('loss', 'Var', (25, 29))	('17p13', 'Protein', (51, 56))	('protein', 'Protein', (66, 73))	('p53', 'Gene', '7157', (149, 152))	('SF-1', 'Gene', (61, 65))	('SF-1', 'Gene', '2516', (61, 65))
24154	24012779	Spotty skin pigmentation, cardiac and other myxomas, and different types of endocrine tumors and other characterize Carney complex, which is caused largely by inactivating Protein Kinase A, Regulatory subunit, type I, Alpha (PRKAR1A) gene mutations.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('myxomas', 'Disease', 'MESH:D009232', (44, 51))	('cardiac', 'Disease', (26, 33))	('skin pigmentation', 'Phenotype', 'HP:0000953', (7, 24))	('endocrine tumors', 'Disease', 'MESH:D004701', (76, 92))	('endocrine tumors', 'Disease', (76, 92))	('myxomas', 'Disease', (44, 51))	('Spotty skin pigmentation', 'Disease', 'MESH:D056733', (0, 24))	('mutations', 'Var', (239, 248))	('PRKAR1A', 'Gene', '5573', (225, 232))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Carney complex', 'Disease', (116, 130))	('inactivating', 'NegReg', (159, 171))	('Spotty skin pigmentation', 'Disease', (0, 24))	('PRKAR1A', 'Gene', (225, 232))
24176	24012779	PRKAR1A has three transcript isoforms (NM_212471.1, NM_212472.1 and NM_002734.3) that differ at the 5'-untranslated region but share the same coding sequence (1143bp coding region, 384 amino acids).	('NM_002734.3', 'Var', (68, 79))	('PRKAR1A', 'Gene', (0, 7))	('NM_212471.1', 'Var', (39, 50))	('NM_212472.1', 'Var', (52, 63))	('PRKAR1A', 'Gene', '5573', (0, 7))
24177	24012779	To date, more than 120 disease-causing PRKAR1A mutations have been reported in Carney complex patients.	('patients', 'Species', '9606', (94, 102))	('disease-causing', 'Reg', (23, 38))	('PRKAR1A', 'Gene', (39, 46))	('mutations', 'Var', (47, 56))	('PRKAR1A', 'Gene', '5573', (39, 46))	('Carney complex', 'Disease', (79, 93))
24178	24012779	Recently large PRKAR1A deletions up to 4Kb in size were also reported.	('deletions', 'Var', (23, 32))	('PRKAR1A', 'Gene', '5573', (15, 22))	('PRKAR1A', 'Gene', (15, 22))
24179	24012779	PRKAR1A mutations are present in up to 70% of the patients diagnosed with Carney complex; the percentage of PRKAR1A mutations increases to 80% for those that present with Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD).	('PRKAR1A', 'Gene', '5573', (108, 115))	('patients', 'Species', '9606', (50, 58))	('primary pigmented nodular adrenocortical disease', 'Disease', (195, 243))	('Cushing syndrome', 'Disease', 'MESH:D003480', (171, 187))	('PRKAR1A', 'Gene', (0, 7))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (171, 187))	('mutations', 'Var', (116, 125))	('Carney complex', 'Disease', (74, 88))	('PP', 'Phenotype', 'HP:0000826', (245, 247))	('Cushing syndrome', 'Disease', (171, 187))	('PRKAR1A', 'Gene', (108, 115))	('primary pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (195, 243))	('PRKAR1A', 'Gene', '5573', (0, 7))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (203, 243))
24180	24012779	Among the types of PRKAR1A mutations described above, nonsense substitutions, small indels, variations of splicing sites and other abnormalities that are detected before the end of the last exon, may lead to frame shifts and premature stop codons (PSC).	('mutations', 'Var', (27, 36))	('lead to', 'Reg', (200, 207))	('PRKAR1A', 'Gene', (19, 26))	('PRKAR1A', 'Gene', '5573', (19, 26))	('frame shifts', 'MPA', (208, 220))	('nonsense substitutions', 'Var', (54, 76))	('variations', 'Var', (92, 102))	('premature stop codons', 'MPA', (225, 246))
24182	24012779	Thus, all mutations leading to a premature stop codon, regardless of the location or type of sequence defect, result in PRKAR1A haploinsufficiency.	('haploinsufficiency', 'Disease', (128, 146))	('PRKAR1A', 'Gene', (120, 127))	('PRKAR1A', 'Gene', '5573', (120, 127))	('haploinsufficiency', 'Disease', 'MESH:D058495', (128, 146))	('mutations', 'Var', (10, 19))	('result in', 'Reg', (110, 119))
24183	24012779	Missense mutations of the PRKAR1A gene, short in-frame indels and splice variants that do not lead to a frameshift and/or a nonsense mRNA are expressed at the protein level.	('PRKAR1A', 'Gene', '5573', (26, 33))	('PRKAR1A', 'Gene', (26, 33))	('Missense mutations', 'Var', (0, 18))
24185	24012779	For example, substitutions within the cAMP-binding domain (i.e.	('cAMP', 'Gene', '820', (38, 42))	('cAMP', 'Gene', (38, 42))	('substitutions', 'Var', (13, 26))
24186	24012779	D183Y, A213D), which can affect the affinity of the PRKAR1A protein to cAMP or the binding of the catalytic subunits of protein kinase A (PKA), seem to have the highest impact.	('cAMP', 'Gene', (71, 75))	('A213D', 'Var', (7, 12))	('cAMP', 'Gene', '820', (71, 75))	('affinity', 'Interaction', (36, 44))	('PRKAR1A', 'Gene', '5573', (52, 59))	('D183Y', 'Var', (0, 5))	('binding', 'Interaction', (83, 90))	('PRKAR1A', 'Gene', (52, 59))	('A213D', 'Mutation', 'rs281864786', (7, 12))	('D183Y', 'Mutation', 'p.D183Y', (0, 5))	('affect', 'Reg', (25, 31))
24187	24012779	Another mutation (R146S) has been shown to affect the catalytic subunit's binding to the PRKAR1A protein only.	('PRKAR1A', 'Gene', (89, 96))	('catalytic subunit', 'MPA', (54, 71))	('affect', 'Reg', (43, 49))	('R146S', 'Var', (18, 23))	('R146S', 'Mutation', 'p.R146S', (18, 23))	('PRKAR1A', 'Gene', '5573', (89, 96))	('binding', 'Interaction', (74, 81))
24188	24012779	A recurrent mutation at the start codon (M1V) leads to an alternate start codon 141bp downstream of the original; the mutant PRKAR1A binds less efficiently both cAMP and the catalytic subunits of the Protein kinase A tetramer.	('less', 'NegReg', (139, 143))	('PRKAR1A', 'Gene', '5573', (125, 132))	('cAMP', 'Gene', (161, 165))	('cAMP', 'Gene', '820', (161, 165))	('mutant', 'Var', (118, 124))	('binds', 'Interaction', (133, 138))	('PRKAR1A', 'Gene', (125, 132))
24190	24012779	For example the mutation c.709-7_709-2del causes a slight effect due to the small proportion that the mutant allele contributes to the total mRNA.	('mRNA', 'MPA', (141, 145))	('c.709-7_709-2del', 'Mutation', 'c.709-7_709-2del', (25, 41))	('c.709-7_709-2del', 'Var', (25, 41))
24191	24012779	Another type of PRKAR1A mutations leads to a longer but insufficiently expressed protein: four of these mutations have been detected to date at the last exon of the gene, resulting in loss of the normal stop codon, protein elongation, and the use of a new stop codon downstream within the 3' untranslated region.	('mutations', 'Var', (104, 113))	('PRKAR1A', 'Gene', '5573', (16, 23))	('stop codon', 'MPA', (203, 213))	('loss', 'NegReg', (184, 188))	('protein elongation', 'CPA', (215, 233))	('insufficiently', 'Disease', 'MESH:D000309', (56, 70))	('insufficiently', 'Disease', (56, 70))	('mutations', 'Var', (24, 33))	('PRKAR1A', 'Gene', (16, 23))
24197	24012779	Recent genome-wide studies in some sporadic cases of another form of bilateral adrenal hyperplasia (similar to primary pigmented nodular adrenocortical disease but not pigmented) isolated micronodular disease (iMAD) revealed mutations in two genes of the phosphodiesterase family, phosphodiesterase 11A (PDE11A) and phosphodiesterase 8B (PDE8B).	('PDE8B', 'Gene', '8622', (338, 343))	('phosphodiesterase 8B', 'Gene', (316, 336))	('PDE11A', 'Gene', (304, 310))	('PDE11A', 'Gene', '50940', (304, 310))	('phosphodiesterase 11A', 'Gene', (281, 302))	('bilateral adrenal hyperplasia', 'Disease', (69, 98))	('mutations', 'Var', (225, 234))	('phosphodiesterase 8B', 'Gene', '8622', (316, 336))	('primary pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (111, 159))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (119, 159))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (79, 98))	('MAD', 'Disease', 'None', (211, 214))	('PDE8B', 'Gene', (338, 343))	('primary pigmented nodular adrenocortical disease', 'Disease', (111, 159))	('MAD', 'Disease', (211, 214))	('bilateral adrenal hyperplasia', 'Disease', 'MESH:D000312', (69, 98))	('phosphodiesterase 11A', 'Gene', '50940', (281, 302))
24198	24012779	It should be noted that patients with PDE11A and PDE8B defects do not have Carney complex.	('defects', 'Var', (55, 62))	('PDE11A', 'Gene', '50940', (38, 44))	('PDE11A', 'Gene', (38, 44))	('PDE8B', 'Gene', (49, 54))	('Carney complex', 'Disease', (75, 89))	('PDE8B', 'Gene', '8622', (49, 54))	('patients', 'Species', '9606', (24, 32))
24199	24012779	Finally, some Carney complex patients that carry germline PRKAR1A defects may also develop somatic activating mutations of the beta-catenin gene (CTNNB1) in their adrenal lesions.	('defects', 'Var', (66, 73))	('activating', 'PosReg', (99, 109))	('patients', 'Species', '9606', (29, 37))	('Carney complex', 'Disease', (14, 28))	('CTNNB1', 'Gene', '1499', (146, 152))	('PRKAR1A', 'Gene', (58, 65))	('develop', 'PosReg', (83, 90))	('beta-catenin', 'Gene', (127, 139))	('PRKAR1A', 'Gene', '5573', (58, 65))	('CTNNB1', 'Gene', (146, 152))	('beta-catenin', 'Gene', '1499', (127, 139))
24206	24012779	Certainly activation of other pathways plays a role: Studies in lymphocytes from Carney complex patients with PRKAR1A mutations, for example, showed that higher PKA activity led to increased extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation and increased cell proliferation through the activation of the mitogen-activated protein kinase (MAPK) pathway.	('activity', 'MPA', (165, 173))	('extracellular signal-regulated kinases 1/2', 'Gene', (191, 233))	('MAPK', 'Gene', '5595;5594;5595', (356, 360))	('phosphorylation', 'MPA', (243, 258))	('PRKAR1A', 'Gene', '5573', (110, 117))	('MAPK', 'Gene', (356, 360))	('increased', 'PosReg', (181, 190))	('extracellular signal-regulated kinases 1/2', 'Gene', '5595', (191, 233))	('mutations', 'Var', (118, 127))	('higher', 'PosReg', (154, 160))	('increased', 'PosReg', (263, 272))	('ERK1/2', 'Gene', (235, 241))	('patients', 'Species', '9606', (96, 104))	('PRKAR1A', 'Gene', (110, 117))	('cell proliferation', 'CPA', (273, 291))	('ERK1/2', 'Gene', '5595;5594', (235, 241))	('PKA', 'Enzyme', (161, 164))
24208	24012779	Experiments in the H295 adrenocortical cells showed that PRKAR1A inactivation there leads to decreased expression of mothers against decapentaplegic homolog 3 (SMAD3) gene, which mediates the transforming growth factor beta (TGFbeta) receptor signaling.	('mothers against decapentaplegic homolog 3', 'Gene', (117, 158))	('adrenocortical', 'Disease', (24, 38))	('transforming growth factor beta', 'Gene', '7040', (192, 223))	('inactivation', 'Var', (65, 77))	('PRKAR1A', 'Gene', (57, 64))	('expression', 'MPA', (103, 113))	('TGFbeta', 'Gene', '7040', (225, 232))	('transforming growth factor beta', 'Gene', (192, 223))	('adrenocortical', 'Disease', 'MESH:D018268', (24, 38))	('decreased', 'NegReg', (93, 102))	('H295', 'CellLine', 'CVCL:0456', (19, 23))	('PRKAR1A', 'Gene', '5573', (57, 64))	('mothers against decapentaplegic homolog 3', 'Gene', '4088', (117, 158))	('SMAD3', 'Gene', '4088', (160, 165))	('SMAD3', 'Gene', (160, 165))	('TGFbeta', 'Gene', (225, 232))
24214	24012779	This is a rare finding: somatic CTNNB1 mutations in Carney complex have only been reported in adrenal adenomas developing in the context of primary pigmented adrenocortical disease.	('pigmented adrenocortical disease', 'Disease', (148, 180))	('adrenal adenomas', 'Disease', (94, 110))	('pigmented adrenocortical disease', 'Phenotype', 'HP:0001580', (148, 180))	('mutations', 'Var', (39, 48))	('CTNNB1', 'Gene', '1499', (32, 38))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (94, 110))	('pigmented adrenocortical disease', 'Disease', 'MESH:C566469', (148, 180))	('reported', 'Reg', (82, 90))	('CTNNB1', 'Gene', (32, 38))	('adrenal adenomas', 'Disease', 'MESH:D018246', (94, 110))
24217	24012779	Primary pigmented adrenocortical disease is the most common manifestation in Carney complex and familial and isolated (sporadic) PPNAD may be caused by the inactivating mutations in PRKAR1A gene.	('Primary pigmented adrenocortical disease', 'Disease', 'MESH:C566469', (0, 40))	('Primary pigmented adrenocortical disease', 'Disease', (0, 40))	('pigmented adrenocortical disease', 'Phenotype', 'HP:0001580', (8, 40))	('Carney complex', 'Disease', (77, 91))	('inactivating mutations', 'Var', (156, 178))	('PRKAR1A', 'Gene', (182, 189))	('PP', 'Phenotype', 'HP:0000826', (129, 131))	('PRKAR1A', 'Gene', '5573', (182, 189))	('caused by', 'Reg', (142, 151))
24219	24012779	Genome wide studies in sporadic both pigmented and non-pigmented adrenocortical hyperplasia cases (isolated micronodular disease, iMAD), that do not have Carney complex, revealed inactivating mutations of the phosphodiesterase gene 11A (PDE11A).	('non-pigmented adrenocortical hyperplasia', 'Disease', (51, 91))	('non-pigmented adrenocortical hyperplasia', 'Disease', 'MESH:C566469', (51, 91))	('PDE11A', 'Gene', '50940', (237, 243))	('pigmented adrenocortical hyperplasia', 'Phenotype', 'HP:0001580', (55, 91))	('MAD', 'Disease', 'None', (131, 134))	('PDE11A', 'Gene', (237, 243))	('MAD', 'Disease', (131, 134))	('inactivating mutations', 'Var', (179, 201))
24220	24012779	PDE11A inactivation leads to increased cAMP levels and increased protein kinase A signaling, an effect similar to that of PRKAR1A inactivating mutations.	('protein kinase A signaling', 'MPA', (65, 91))	('cAMP', 'Gene', (39, 43))	('cAMP', 'Gene', '820', (39, 43))	('inactivation', 'Var', (7, 19))	('increased', 'PosReg', (55, 64))	('PRKAR1A', 'Gene', (122, 129))	('increased', 'PosReg', (29, 38))	('PDE11A', 'Gene', (0, 6))	('PDE11A', 'Gene', '50940', (0, 6))	('PRKAR1A', 'Gene', '5573', (122, 129))
24221	24012779	Finally, a germline Phosphodiesterase 8B (PDE8B) missense substitution (c.914A>C/H305P) has been described in a patient with pigmented isolated micronodular disease unassociated with Carney complex.	('c.914A>C', 'Var', (72, 80))	('c.914A>C', 'SUBSTITUTION', 'None', (72, 80))	('H305P', 'SUBSTITUTION', 'None', (81, 86))	('pigmented isolated micronodular disease', 'Disease', (125, 164))	('patient', 'Species', '9606', (112, 119))	('H305P', 'Var', (81, 86))	('PDE8B', 'Gene', '8622', (42, 47))	('PDE8B', 'Gene', (42, 47))	('Phosphodiesterase 8B', 'Gene', '8622', (20, 40))	('Phosphodiesterase 8B', 'Gene', (20, 40))
24245	24012779	McCune-Albright Syndrome (MAS) is caused by mosaicism for a mutation in the Guanine Nucleotide-binding protein, Alpha-Stimulating activity polypeptide (GNAS) gene (Table 1).	('mutation', 'Var', (60, 68))	('caused by', 'Reg', (34, 43))	('GNAS', 'Gene', '2778', (152, 156))	('MAS', 'Disease', 'MESH:D005357', (26, 29))	('GNAS', 'Gene', (152, 156))	('MAS', 'Disease', (26, 29))	('McCune-Albright Syndrome', 'Disease', (0, 24))
24246	24012779	The GNAS mutated alleles are always in equal or less abundance than the wild type allele, proving that they act in a dominant way.	('GNAS', 'Gene', (4, 8))	('GNAS', 'Gene', '2778', (4, 8))	('mutated', 'Var', (9, 16))
24249	24012779	Mutations in GNAS were initially detected in growth hormone (GH)-producing tumors and later the same genetic defect was identified in McCune-Albright syndrome.	('genetic defect', 'Disease', 'MESH:D030342', (101, 115))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (134, 158))	('genetic defect', 'Disease', (101, 115))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('GNAS', 'Gene', (13, 17))	('detected', 'Reg', (33, 41))	('Mutations', 'Var', (0, 9))	('growth hormone', 'Gene', '2688', (45, 59))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('McCune-Albright syndrome', 'Disease', (134, 158))	('growth hormone', 'Gene', (45, 59))	('tumors', 'Disease', (75, 81))	('GNAS', 'Gene', '2778', (13, 17))
24250	24012779	The most common GNAS mutations in McCune-Albright syndrome are the ones who lead to the amino acid substitutions at Arg 201 (to Cys or His or Ser or Gly) and rarely at Gln 227 (to Arg or Lys).	('mutations', 'Var', (21, 30))	('Cys', 'Chemical', 'MESH:D003545', (128, 131))	('GNAS', 'Gene', (16, 20))	('Lys', 'Chemical', 'MESH:D008239', (187, 190))	('Arg', 'Chemical', 'MESH:D001120', (180, 183))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (34, 58))	('Ser', 'Chemical', 'MESH:D012694', (142, 145))	('Arg', 'Chemical', 'MESH:D001120', (116, 119))	('GNAS', 'Gene', '2778', (16, 20))	('His', 'Chemical', 'MESH:D006639', (135, 138))	('Gly', 'Chemical', 'MESH:D005998', (149, 152))	('Gln', 'Chemical', 'MESH:D005973', (168, 171))	('Arg 201', 'Var', (116, 123))	('McCune-Albright syndrome', 'Disease', (34, 58))	('lead to', 'Reg', (76, 83))
24251	24012779	These mutations cause a constitutively activated form of Gsa which lead to high adenyl cyclase activity and cAMP levels.	('adenyl cyclase', 'Gene', (80, 94))	('Gsa', 'Gene', (57, 60))	('cAMP', 'Gene', '820', (108, 112))	('adenyl cyclase', 'Gene', '107', (80, 94))	('high', 'PosReg', (75, 79))	('cAMP', 'Gene', (108, 112))	('Gsa', 'Gene', '2778', (57, 60))	('mutations', 'Var', (6, 15))	('cause', 'Reg', (16, 21))
24254	24012779	For example, McCune-Albright syndrome patients with growth hormone (GH)-secreting pituitary adenomas bear their GNAS mutations on the maternal allele; allele-biased mutations are not seen in other tissues where the GNAS gene is not subject to imprinting.	('mutations', 'Var', (117, 126))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (82, 100))	('GNAS', 'Gene', (112, 116))	('pituitary adenomas', 'Disease', (82, 100))	('growth hormone', 'Gene', '2688', (52, 66))	('GNAS', 'Gene', '2778', (215, 219))	('McCune-Albright syndrome', 'Disease', (13, 37))	('growth hormone', 'Gene', (52, 66))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (13, 37))	('patients', 'Species', '9606', (38, 46))	('GNAS', 'Gene', '2778', (112, 116))	('pituitary adenomas', 'Disease', 'MESH:D010911', (82, 100))	('GNAS', 'Gene', (215, 219))
24257	24012779	The reported GNAS mutations in Arg 201 and Gln 227 in McCune-Albright syndrome inhibit the guanosine triphosphate hydrolase (GTPase) catalytic ability of Gsa making impossible to control the Gsa activation and as a result there is excessive cAMP production, even in the absence of stimulating hormones (Figure 1).	('inhibit', 'NegReg', (79, 86))	('phosphate', 'Chemical', 'MESH:D010710', (104, 113))	('Arg', 'Chemical', 'MESH:D001120', (31, 34))	('GNAS', 'Gene', (13, 17))	('Gsa', 'Gene', (191, 194))	('Gsa', 'Gene', '2778', (154, 157))	('Gsa', 'Gene', (154, 157))	('excessive', 'PosReg', (231, 240))	('GNAS', 'Gene', '2778', (13, 17))	('Gln 227', 'Var', (43, 50))	('Gsa', 'Gene', '2778', (191, 194))	('McCune-Albright syndrome', 'Disease', (54, 78))	('Gln', 'Chemical', 'MESH:D005973', (43, 46))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (54, 78))	('mutations in Arg 201', 'Var', (18, 38))	('cAMP', 'Gene', (241, 245))	('guanosine triphosphate hydrolase', 'MPA', (91, 123))	('cAMP', 'Gene', '820', (241, 245))
24259	24012779	For example, the pathology of the pituitary in McCune-Albright syndrome patients that carry GNAS mutations and in Carney complex patients that carry PRKAR1A mutations is almost identical.	('mutations', 'Var', (97, 106))	('GNAS', 'Gene', (92, 96))	('PRKAR1A', 'Gene', '5573', (149, 156))	('patients', 'Species', '9606', (129, 137))	('pathology of the pituitary', 'Phenotype', 'HP:0011747', (17, 43))	('PRKAR1A', 'Gene', (149, 156))	('GNAS', 'Gene', '2778', (92, 96))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (47, 71))	('McCune-Albright syndrome', 'Disease', (47, 71))	('patients', 'Species', '9606', (72, 80))
24283	19372190	Furthermore, inhibition of PLD-mediated signal generation inhibits both AngII- and elevated [K+]e-elicited aldosterone secretion, suggesting the importance of this signaling enzyme to steroid hormone production.	('[K+]e-elicited aldosterone secretion', 'MPA', (92, 128))	('PLD', 'Gene', '2822', (27, 30))	('PLD', 'Gene', (27, 30))	('rat', 'Species', '10116', (51, 54))	('inhibits', 'NegReg', (58, 66))	('inhibition', 'Var', (13, 23))	('AngII', 'Gene', (72, 77))	('AngII', 'Gene', '24179', (72, 77))	('elevated', 'PosReg', (83, 91))	('aldosterone', 'Chemical', 'MESH:D000450', (107, 118))	('steroid hormone', 'Chemical', 'MESH:D013256', (184, 199))
24286	19372190	Investigators have shown an ability of cytosolic Ca2+ concentration to modulate PLD activity, with chelation of intracellular Ca2+ inhibiting PLD activation in response to some agonists and Ca2+ ionophores increasing enzyme activity [reviewed in ].	('chelation', 'Var', (99, 108))	('Ca2+', 'Chemical', 'MESH:D000069285', (126, 130))	('response', 'MPA', (160, 168))	('Ca2+', 'Chemical', 'MESH:D000069285', (49, 53))	('PLD', 'Gene', '2822', (142, 145))	('rat', 'Species', '10116', (61, 64))	('PLD', 'Gene', (142, 145))	('modulate', 'Reg', (71, 79))	('increasing', 'PosReg', (206, 216))	('activity', 'MPA', (84, 92))	('PLD', 'Gene', '2822', (80, 83))	('PLD', 'Gene', (80, 83))	('activation', 'MPA', (146, 156))	('inhibiting', 'NegReg', (131, 141))	('Ca2+', 'Chemical', 'MESH:D000069285', (190, 194))	('enzyme activity', 'MPA', (217, 232))
24292	19372190	In addition, we sought to compare the effects of modulating Ca2+ influx on PLD activation and acute aldosterone secretion in this bovine system with the responses observed in the NCI H295R human adrenocortical carcinoma cell line.	('modulating', 'Var', (49, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (195, 219))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (195, 219))	('aldosterone', 'Chemical', 'MESH:D000450', (100, 111))	('human', 'Species', '9606', (189, 194))	('H295R', 'CellLine', 'CVCL:0458', (183, 188))	('PLD', 'Gene', '2822', (75, 78))	('adrenocortical carcinoma', 'Disease', (195, 219))	('Ca2+', 'Chemical', 'MESH:D000069285', (60, 64))	('bovine', 'Species', '9913', (130, 136))	('PLD', 'Gene', (75, 78))
24329	19372190	We found that BTP2 had no effect on PLD activation elicited in response to AngII (Figure 6A).	('AngII', 'Gene', (75, 80))	('BTP2', 'Chemical', '-', (14, 18))	('PLD', 'Gene', '2822', (36, 39))	('PLD', 'Gene', (36, 39))	('AngII', 'Gene', '24179', (75, 80))	('BTP2', 'Var', (14, 18))
24335	19372190	As shown in Figure 7A, we found that tyrphostin A9 inhibited AngII-elicited PLD activation in primary bovine adrenal glomerulosa cells, without affecting basal PLD activity.	('tyrphostin', 'Var', (37, 47))	('AngII', 'Gene', (61, 66))	('PLD', 'Gene', (160, 163))	('bovine', 'Species', '9913', (102, 108))	('tyrphostin A9', 'Chemical', 'MESH:C406122', (37, 50))	('PLD', 'Gene', '2822', (76, 79))	('PLD', 'Gene', (76, 79))	('PLD', 'Gene', '2822', (160, 163))	('inhibited', 'NegReg', (51, 60))	('AngII', 'Gene', '24179', (61, 66))
24337	19372190	In experiments to determine the ability of tyrphostin A9 to modulate the aldosterone secretory response, we found that tyrphostin A9 completely blocked AngII- and elevated [K+]e-induced aldosterone secretion (data not shown).	('aldosterone', 'Chemical', 'MESH:D000450', (186, 197))	('elevated', 'PosReg', (163, 171))	('tyrphostin A9', 'Chemical', 'MESH:C406122', (119, 132))	('tyrphostin A9', 'Var', (119, 132))	('[K+]e-induced aldosterone secretion', 'MPA', (172, 207))	('AngII', 'Gene', '24179', (152, 157))	('blocked', 'NegReg', (144, 151))	('aldosterone', 'Chemical', 'MESH:D000450', (73, 84))	('tyrphostin A9', 'Chemical', 'MESH:C406122', (43, 56))	('AngII', 'Gene', (152, 157))
24338	19372190	However, we also observed that tyrphostin A9 significantly inhibited the ability of 22(R)-hydroxycholesterol to trigger steroidogenesis (Figure 7C).	('tyrphostin A9', 'Chemical', 'MESH:C406122', (31, 44))	('inhibited', 'NegReg', (59, 68))	('22(R)-hydroxycholesterol', 'Chemical', 'MESH:C003585', (84, 108))	('trigger steroidogenesis', 'MPA', (112, 135))	('tyrphostin', 'Var', (31, 41))
24339	19372190	Because 22(R)-hydroxycholesterol can directly enter mitochondria to access the rate-limiting enzyme of aldosterone synthesis, thereby bypassing signaling mechanisms, inhibitory effects on secretion induced by this compound indicate that tyrphostin A9 either inhibits aldosterone biosynthetic enzymes or affects cell health.	('cell health', 'CPA', (311, 322))	('inhibits', 'NegReg', (258, 266))	('aldosterone', 'Chemical', 'MESH:D000450', (267, 278))	('aldosterone biosynthetic enzymes', 'Enzyme', (267, 299))	('tyrphostin A9', 'Chemical', 'MESH:C406122', (237, 250))	('22(R)-hydroxycholesterol', 'Chemical', 'MESH:C003585', (8, 32))	('tyrphostin', 'Var', (237, 247))	('rat', 'Species', '10116', (79, 82))	('affects', 'Reg', (303, 310))	('aldosterone', 'Chemical', 'MESH:D000450', (103, 114))
24345	19372190	Similarly to the primary bovine adrenal glomerulosa cells (Figure 2), a lack of extracellular Ca2+ also inhibited AngII-elicited PLD activation in H295R cells (Figure 6).	('AngII', 'Gene', (114, 119))	('bovine', 'Species', '9913', (25, 31))	('H295R', 'CellLine', 'CVCL:0458', (147, 152))	('Ca2+', 'Chemical', 'MESH:D000069285', (94, 98))	('AngII', 'Gene', '24179', (114, 119))	('inhibited', 'NegReg', (104, 113))	('PLD', 'Gene', '2822', (129, 132))	('lack', 'Var', (72, 76))	('PLD', 'Gene', (129, 132))
24356	19372190	This finding is not particularly surprising considering that elevated [K+]e is thought to exert its effects on adrenal glomerulosa cells by depolarizing the cells, thereby opening voltage-dependent calcium channels [reviewed in (Rainey et al., In press)].	('voltage-dependent calcium channels', 'MPA', (180, 214))	('calcium', 'Chemical', 'MESH:D002118', (198, 205))	('depolarizing', 'NegReg', (140, 152))	('elevated [K+]e', 'Var', (61, 75))	('opening', 'Reg', (172, 179))	('[K+]e', 'Var', (70, 75))
24358	19372190	However, removal of extracellular Ca2+ inhibits AngII-elicited PLD activation in both primary bovine adrenal glomerulosa cells (Figure 3) and H295R cells (Figure 7), suggesting that Ca2+ influx plays some role in PLD activation.	('PLD', 'Gene', (213, 216))	('H295R', 'CellLine', 'CVCL:0458', (142, 147))	('activation', 'PosReg', (67, 77))	('Ca2+', 'Chemical', 'MESH:D000069285', (34, 38))	('Ca2+', 'Chemical', 'MESH:D000069285', (182, 186))	('AngII', 'Gene', '24179', (48, 53))	('PLD', 'Gene', '2822', (63, 66))	('PLD', 'Gene', (63, 66))	('removal', 'Var', (9, 16))	('AngII', 'Gene', (48, 53))	('bovine', 'Species', '9913', (94, 100))	('inhibits', 'NegReg', (39, 47))	('PLD', 'Gene', '2822', (213, 216))
24382	19372190	Although tyrphostin A9 completely inhibited AngII-induced aldosterone secretion, as well as that elicited in response to elevated [K+]e (data not shown), it also inhibited secretion in response to 22(R)-hydroxycholesterol (Figure 7C), indicating either effects on cell health or on one or more aldosterone biosynthetic enzymes.	('AngII', 'Gene', '24179', (44, 49))	('aldosterone', 'Chemical', 'MESH:D000450', (294, 305))	('inhibited', 'NegReg', (34, 43))	('AngII', 'Gene', (44, 49))	('secretion', 'MPA', (172, 181))	('aldosterone', 'Chemical', 'MESH:D000450', (58, 69))	('22(R)-hydroxycholesterol', 'Chemical', 'MESH:C003585', (197, 221))	('tyrphostin A9', 'Chemical', 'MESH:C406122', (9, 22))	('inhibited', 'NegReg', (162, 171))	('tyrphostin A9', 'Var', (9, 22))
24398	31447392	On multivariable analysis, DFI (OR=1.33, 95%CI=1.12-1.58, p=0.0012) and non-functioning tumor (OR=0.13, 95%CI=0.13-0.56, p=0.0056) were independently associated with prolonged survival.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('non-functioning', 'Var', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('prolonged', 'PosReg', (166, 175))	('DFI', 'Disease', (27, 30))	('tumor', 'Disease', (88, 93))
24453	31447392	After backward selection, only DFI (OR 1.33, CI 1.12 - 1.58, p=0.0012) and nonfunctioning primary tumor (OR 0.13, CI 0.03 - 0.56, p=0.0056) were independently associated with extended survival (Table 2).	('nonfunctioning', 'Var', (75, 89))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('DFI', 'Disease', (31, 34))
24464	31447392	While this study demonstrated a higher response rate in patients treated with EDP-M (23.2% vs 9.2%, p<0.001), there was no difference in OS between the groups (14.8 months vs 12.0 months, p=0.07), suggesting that this response was not a durable one.	('EDP-M', 'Chemical', '-', (78, 83))	('patients', 'Species', '9606', (56, 64))	('EDP-M', 'Var', (78, 83))	('higher', 'PosReg', (32, 38))
24505	32810311	These include an immune-inflamed phenotype, 15 ,  16  expression of T cell signaling pathway genes such as IFNgamma, 17  microsatellite instability, 18  somatic copy-number alterations, 19  human leukocyte antigen (HLA) class I diversity, 20  T cell repertoire clonality change, 21  WNT-beta-catenin signaling, 22  TGFbeta expression, 23  and even commensal microbiota.	('IFNgamma', 'Gene', '3458', (107, 115))	('beta-catenin', 'Gene', '1499', (287, 299))	('T cell signaling pathway genes', 'Gene', (68, 98))	('TGFbeta', 'Gene', (315, 322))	('alterations', 'Var', (173, 184))	('TGFbeta', 'Gene', '7039', (315, 322))	('beta-catenin', 'Gene', (287, 299))	('human', 'Species', '9606', (190, 195))	('IFNgamma', 'Gene', (107, 115))
24564	32810311	We analyzed RNA-Seq data of 28 pretreatment tumors from melanoma patients who received anti-PD-1 ICI.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('anti-PD-1', 'Var', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (65, 73))
24570	32810311	35  Axis 6 (Treg) and axis 7 (MDSC) were high in Pt25 and Pt16, respectively, suggesting that the strategies to deplete Treg or MDSC might be recommended to these patients.	('Treg', 'Chemical', '-', (12, 16))	('Pt16', 'Var', (58, 62))	('patients', 'Species', '9606', (163, 171))	('Pt25', 'Var', (49, 53))	('Treg', 'Chemical', '-', (120, 124))
24585	32810311	For example, immunograms for hallmarks of cancer could also be compiled by adopting gene sets for the eight hallmarks: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming of energy metabolism, and evading immune destruction.	('death', 'Disease', 'MESH:D003643', (198, 203))	('death', 'Disease', (198, 203))	('hallmarks of cancer', 'Disease', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('replicative immortality', 'CPA', (214, 237))	('immune destruction', 'CPA', (346, 364))	('evading', 'Var', (155, 162))	('invasion', 'CPA', (273, 281))	('activating', 'PosReg', (262, 272))	('enabling', 'PosReg', (205, 213))	('inducing', 'PosReg', (239, 247))	('reprogramming', 'Reg', (298, 311))	('angiogenesis', 'CPA', (248, 260))	('proliferative signaling', 'MPA', (130, 153))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (29, 48))	('sustaining', 'PosReg', (119, 129))
24592	33019484	A case report of neurological adverse events caused by short-term and low-dose treatment of mitotane Low-dose mitotane has been widely used for many decades in patients with advanced adrenocortical carcinoma (ACC), which exhibited good safety profiles compared with the high-dose regimen.	('adrenocortical carcinoma', 'Disease', (183, 207))	('mitotane', 'Chemical', 'MESH:D008939', (92, 100))	('patients', 'Species', '9606', (160, 168))	('mitotane', 'Gene', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (183, 207))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (183, 207))	('Low-dose', 'Var', (101, 109))	('ACC', 'Phenotype', 'HP:0006744', (209, 212))	('mitotane', 'Chemical', 'MESH:D008939', (110, 118))
24628	33019484	In addition, it exhibits tumor specificity as its adrenolytic effects seem to be enhanced by the presence of CYP11B activity in cortisol secreting tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('CYP11B', 'Gene', (109, 115))	('enhanced', 'PosReg', (81, 89))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('presence', 'Var', (97, 105))	('tumor', 'Disease', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('adrenolytic effects', 'MPA', (50, 69))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('activity', 'MPA', (116, 124))	('CYP11B', 'Gene', '1584', (109, 115))	('cortisol', 'Chemical', 'MESH:D006854', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
24629	33019484	The in vitro data also indicated that mitotane could alter mitochondrial respiratory chain activity by inducing cytochrome C oxidase defect in human ACC cells and inhibit Sterol-O-acyl transferase 1, inducing endoplasmic reticulum stress in ACC cells, in turn leading to apoptosis.	('stress', 'Disease', 'MESH:D000079225', (231, 237))	('apoptosis', 'CPA', (271, 280))	('inhibit', 'NegReg', (163, 170))	('cytochrome C', 'MPA', (112, 124))	('alter', 'Reg', (53, 58))	('human', 'Species', '9606', (143, 148))	('cytochrome C oxidase defect', 'Phenotype', 'HP:0003688', (112, 139))	('mitotane', 'Var', (38, 46))	('Sterol-O-acyl transferase 1', 'Gene', (171, 198))	('inducing', 'Reg', (103, 111))	('leading to', 'Reg', (260, 270))	('Sterol-O-acyl transferase 1', 'Gene', '6646', (171, 198))	('mitotane', 'Chemical', 'MESH:D008939', (38, 46))	('inducing', 'Reg', (200, 208))	('ACC', 'Phenotype', 'HP:0006744', (241, 244))	('mitochondrial', 'MPA', (59, 72))	('ACC', 'Phenotype', 'HP:0006744', (149, 152))	('stress', 'Disease', (231, 237))
24702	32116467	The effect of a mutation at each gene was allowed to vary by cancer type, whereas the mean effect of each gene was shared across cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutation', 'Var', (16, 24))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancer type', 'Disease', 'MESH:D009369', (61, 72))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer type', 'Disease', (61, 72))
24703	32116467	Through this we determined that mutations at TP53 and FAT4 were together the most useful for predicting patient survival.	('TP53', 'Gene', (45, 49))	('FAT4', 'Gene', (54, 58))	('FAT4', 'Gene', '79633', (54, 58))	('mutations', 'Var', (32, 41))	('patient', 'Species', '9606', (104, 111))	('TP53', 'Gene', '7157', (45, 49))
24712	32116467	This initiative has resulted in several studies across multiple cancer types that have revealed important shared molecular alterations for somatic mutations, copy number, messenger RNA, and protein abundance.	('protein abundance', 'MPA', (190, 207))	('cancer type', 'Disease', 'MESH:D009369', (64, 75))	('copy number', 'Var', (158, 169))	('messenger RNA', 'MPA', (171, 184))	('cancer type', 'Disease', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
24748	32116467	The multilayer nature of our model allows the effect of a mutation at each gene to vary by cancer type while simultaneously inferring the mean and variance of these effects.	('cancer type', 'Disease', 'MESH:D009369', (91, 102))	('vary', 'Reg', (83, 87))	('mutation', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer type', 'Disease', (91, 102))
24751	32116467	We consider 4 different likelihood models for survival: For each likelihood we consider a hierarchical linear model for : where  is the linear effect of age if  and mutation at gene  on survival if  for a patient with cancer type .	('cancer type', 'Disease', 'MESH:D009369', (218, 229))	('mutation', 'Var', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('patient', 'Species', '9606', (205, 212))	('cancer type', 'Disease', (218, 229))
24753	32116467	Under the assumption that a mutation at one gene or an increase in 1 year of age may affect survival differently depending on the type of cancer, the linear effect of age and each mutation, , was assumed to vary by cancer type.	('cancer type', 'Disease', 'MESH:D009369', (215, 226))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutation', 'Var', (28, 36))	('type of cancer', 'Disease', 'MESH:D009369', (130, 144))	('survival', 'MPA', (92, 100))	('affect', 'Reg', (85, 91))	('cancer type', 'Disease', (215, 226))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('type of cancer', 'Disease', (130, 144))
24770	32116467	Across all 27 cancers, TP53 was mutated in an average of 38.3% of patients, the highest of all genes, and FAT4 in 8.8% (Table 2).	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutated', 'Var', (32, 39))	('TP53', 'Gene', '7157', (23, 27))	('FAT4', 'Gene', (106, 110))	('TP53', 'Gene', (23, 27))	('FAT4', 'Gene', '79633', (106, 110))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('patients', 'Species', '9606', (66, 74))
24776	32116467	Of the patients in our study, 7.7% had a mutation at APOB.	('mutation', 'Var', (41, 49))	('APOB', 'Gene', '338', (53, 57))	('APOB', 'Gene', (53, 57))	('patients', 'Species', '9606', (7, 15))
24784	32116467	Similarly, Figure 2C shows the estimated effect of a TP53 mutation on survival across cancers, and the estimated effect was generally negative for most cancers.	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('survival', 'MPA', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutation', 'Var', (58, 66))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('TP53', 'Gene', '7157', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('effect', 'Reg', (41, 47))	('TP53', 'Gene', (53, 57))
24785	32116467	This, again, demonstrates a poorer prognosis for patients with a mutation at TP53.	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('mutation', 'Var', (65, 73))	('patients', 'Species', '9606', (49, 57))
24787	32116467	FAT4 mutation credible intervals (Figure 2D) appeared to be more positive than those of TP53, with some intervals entirely above 0.	('FAT4', 'Gene', '79633', (0, 4))	('mutation', 'Var', (5, 13))	('TP53', 'Gene', '7157', (88, 92))	('TP53', 'Gene', (88, 92))	('FAT4', 'Gene', (0, 4))
24793	32116467	To visualize the impact of age and a mutation at each of TP53 and FAT4, we show here survival curves computed based on each combination of predictor values.	('FAT4', 'Gene', (66, 70))	('FAT4', 'Gene', '79633', (66, 70))	('mutation', 'Var', (37, 45))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
24797	32116467	The mutation rates for patients with ACC are as follows: 50.6% had no mutations in FAT4 or TP53, 10.1% had mutations in just FAT4, 19.1% had mutations at just TP53, and 4.49% had mutations in both.	('FAT4', 'Gene', (83, 87))	('FAT4', 'Gene', (125, 129))	('mutations', 'Var', (70, 79))	('mutations', 'Var', (107, 116))	('mutations', 'Var', (141, 150))	('TP53', 'Gene', (91, 95))	('FAT4', 'Gene', '79633', (125, 129))	('ACC', 'Disease', 'MESH:D018268', (37, 40))	('patients', 'Species', '9606', (23, 31))	('TP53', 'Gene', '7157', (159, 163))	('ACC', 'Phenotype', 'HP:0006744', (37, 40))	('TP53', 'Gene', (159, 163))	('ACC', 'Disease', (37, 40))	('TP53', 'Gene', '7157', (91, 95))	('FAT4', 'Gene', '79633', (83, 87))
24798	32116467	The impact of the negative coefficient of TP53 is demonstrated in these plots, as prognosis seems to worsen over 5 years if a patient has such a mutation.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('patient', 'Species', '9606', (126, 133))	('mutation', 'Var', (145, 153))
24812	32116467	A potential explanation is that mutations in FAT4 contribute to the development of certain cancers, but these cancers are comparatively less aggressive than those that arise from mutations in TP53 or other driver genes.	('cancers', 'Disease', (110, 117))	('contribute', 'Reg', (50, 60))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (32, 41))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('FAT4', 'Gene', '79633', (45, 49))	('TP53', 'Gene', '7157', (192, 196))	('TP53', 'Gene', (192, 196))	('FAT4', 'Gene', (45, 49))
24820	32116467	These plots demonstrated the largely negative effect of increasing age and a TP53 mutation and the less noticeable effect of FAT4.	('FAT4', 'Gene', (125, 129))	('FAT4', 'Gene', '79633', (125, 129))	('mutation', 'Var', (82, 90))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('negative', 'NegReg', (37, 45))
24830	28894201	Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications.	('primary aldosteronism', 'Disease', (123, 144))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (123, 144))	('hypertension', 'Disease', 'MESH:D006973', (179, 191))	('CYP11B1', 'Gene', '1584', (56, 63))	('hormone excess', 'Phenotype', 'HP:0000845', (100, 114))	('PA', 'Phenotype', 'HP:0011736', (146, 148))	('DNA methylation', 'Var', (37, 52))	('hypertension', 'Disease', (179, 191))	('due to primary aldosteronism', 'Phenotype', 'HP:0011739', (116, 144))	('hypercortisolemia', 'Disease', (67, 84))	('hypercortisolemia', 'Disease', 'None', (67, 84))	('Adrenocortical hormone excess', 'Disease', 'MESH:C531600', (85, 114))	('CYP11B1', 'Gene', (56, 63))	('cardiovascular complications', 'Disease', 'MESH:D002318', (196, 224))	('Cortisol', 'Chemical', 'MESH:D006854', (0, 8))	('overproduction', 'PosReg', (9, 23))	('hypertension', 'Phenotype', 'HP:0000822', (179, 191))	('hypercortisolemia', 'Disease', (153, 170))	('hypercortisolemia', 'Disease', 'None', (153, 170))	('Adrenocortical hormone excess', 'Disease', (85, 114))	('Cortisol', 'MPA', (0, 8))	('causes', 'Reg', (172, 178))	('Adrenocortical hormone excess', 'Phenotype', 'HP:0011749', (85, 114))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (196, 224))	('hypercortisolemia Adrenocortical hormone', 'Phenotype', 'HP:0003118', (67, 107))	('cardiovascular complications', 'Disease', (196, 224))
24831	28894201	In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction.	('aldosterone synthase', 'Gene', (26, 46))	('hypomethylation', 'Var', (7, 22))	('aldosterone', 'Chemical', 'MESH:D000450', (26, 37))	('aldosterone synthase', 'Gene', '1585', (26, 46))	('hypomethylation of aldosterone', 'Phenotype', 'HP:0004319', (7, 37))	('CYP11B2', 'Gene', (48, 55))	('CYP11B2', 'Gene', '1585', (48, 55))	('aldosterone overproduction', 'MPA', (76, 102))	('aldosterone', 'Chemical', 'MESH:D000450', (76, 87))	('PA', 'Phenotype', 'HP:0011736', (3, 5))	('associated', 'Reg', (60, 70))
24835	28894201	Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated.	('CYP11B1', 'Gene', (177, 184))	('CYP11B1', 'Gene', '1584', (177, 184))	('GNAS', 'Gene', (161, 165))	('mutations', 'Var', (33, 42))	('PRKACA', 'Gene', (96, 102))	('PRKACA', 'Gene', '5566', (96, 102))	('CPA', 'Chemical', '-', (16, 19))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (111, 129))	('PA', 'Phenotype', 'HP:0011736', (17, 19))	('GNAS', 'Gene', '2778', (161, 165))
24836	28894201	In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay.	('methylation', 'Var', (17, 28))	('CYP11B1', 'Gene', (37, 44))	('reduced', 'NegReg', (29, 36))	('CYP11B1', 'Gene', '1584', (37, 44))	('DNA methylation', 'Var', (13, 28))
24837	28894201	Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter.	('expression', 'MPA', (113, 123))	('PA', 'Phenotype', 'HP:0011736', (200, 202))	('CPA', 'Chemical', '-', (151, 154))	('CPA', 'Chemical', '-', (199, 202))	('CYP11B1', 'Gene', (54, 61))	('PA', 'Phenotype', 'HP:0011736', (152, 154))	('CYP11B1', 'Gene', (105, 112))	('reduce', 'NegReg', (203, 209))	('CYP11B1', 'Gene', '1584', (54, 61))	('mutations', 'Var', (173, 182))	('cortisol production', 'MPA', (128, 147))	('regulation', 'MPA', (91, 101))	('DNA methylation', 'MPA', (210, 225))	('CYP11B1', 'Gene', '1584', (105, 112))	('CYP11B1', 'Gene', (233, 240))	('CYP11B1', 'Gene', '1584', (233, 240))	('CPA', 'Gene', (199, 202))	('cortisol', 'Chemical', 'MESH:D006854', (128, 136))
24844	28894201	Recently, exome sequencing revealed that CPAs frequently carry somatic mutations in the catalytic subunit of PKA (PRKACA) that leads to the activation of cAMP response element-binding protein (CREB), and the guanine nucleotide-binding protein subunit alpha (GNAS) gene, resulting in an activation of PKA.	('CREB', 'Gene', '1385', (193, 197))	('CPA', 'Chemical', '-', (41, 44))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (208, 226))	('PKA', 'Gene', '5566', (109, 112))	('PKA', 'Gene', (109, 112))	('GNAS', 'Gene', '2778', (258, 262))	('activation', 'PosReg', (140, 150))	('PRKACA', 'Gene', (114, 120))	('cAMP response element-binding protein', 'Gene', '1385', (154, 191))	('GNAS', 'Gene', (258, 262))	('mutations', 'Var', (71, 80))	('cAMP response element-binding protein', 'Gene', (154, 191))	('PKA', 'Gene', (300, 303))	('PA', 'Phenotype', 'HP:0011736', (42, 44))	('PRKACA', 'Gene', '5566', (114, 120))	('CREB', 'Gene', (193, 197))	('PKA', 'Gene', '5566', (300, 303))	('activation', 'PosReg', (286, 296))
24846	28894201	However, the molecular mechanism how these mutations affect CYP11B1 expression has not been well clarified.	('expression', 'MPA', (68, 78))	('CYP11B1', 'Gene', (60, 67))	('affect', 'Reg', (53, 59))	('CYP11B1', 'Gene', '1584', (60, 67))	('mutations', 'Var', (43, 52))
24847	28894201	Recent studies demonstrated that aldosterone synthase (cytochrome P450 family 11 subfamily B member 2: CYP11B2) in aldosterone-producing adenomas (APA) is upregulated by DNA hypomethylation of its promoter region.	('aldosterone', 'Chemical', 'MESH:D000450', (115, 126))	('aldosterone', 'Chemical', 'MESH:D000450', (33, 44))	('PA', 'Phenotype', 'HP:0011736', (148, 150))	('aldosterone synthase', 'Gene', (33, 53))	('cytochrome P450 family 11 subfamily B member 2', 'Gene', '1585', (55, 101))	('adenomas', 'Disease', 'MESH:D000236', (137, 145))	('rat', 'Species', '10116', (22, 25))	('DNA hypomethylation', 'Var', (170, 189))	('aldosterone synthase', 'Gene', '1585', (33, 53))	('upregulated', 'PosReg', (155, 166))	('CYP11B2', 'Gene', (103, 110))	('adenomas', 'Disease', (137, 145))	('CYP11B2', 'Gene', '1585', (103, 110))	('cytochrome P450 family 11 subfamily B member 2', 'Gene', (55, 101))
24856	28894201	In addition, we performed Western blot analysis and confirmed that CYP11B1 protein level was significantly higher in CPA than in AUAT (Figure S4).	('CYP11B1', 'Gene', (67, 74))	('PA', 'Phenotype', 'HP:0011736', (118, 120))	('CYP11B1', 'Gene', '1584', (67, 74))	('CPA', 'Chemical', '-', (117, 120))	('AUAT', 'Disease', 'None', (129, 133))	('higher', 'PosReg', (107, 113))	('CPA', 'Var', (117, 120))	('AUAT', 'Disease', (129, 133))
24858	28894201	Two patients had the p.L206R mutation of the PRKACA gene.	('p.L206R', 'Var', (21, 28))	('PRKACA', 'Gene', (45, 51))	('PRKACA', 'Gene', '5566', (45, 51))	('patients', 'Species', '9606', (4, 12))	('p.L206R', 'Mutation', 'rs386352352', (21, 28))
24859	28894201	Among six patients with GNAS gene mutations, three CPAs had p.R201H.	('p.R201H', 'Var', (60, 67))	('GNAS', 'Gene', '2778', (24, 28))	('CPA', 'Chemical', '-', (51, 54))	('CPAs', 'Disease', (51, 55))	('GNAS', 'Gene', (24, 28))	('patients', 'Species', '9606', (10, 18))	('PA', 'Phenotype', 'HP:0011736', (52, 54))	('p.R201H', 'Mutation', 'rs121913495', (60, 67))	('mutations', 'Var', (34, 43))
24860	28894201	The other three patients carried p.R201C, p.R201S, and p.Q227R mutations respectively.	('p.R201C', 'Var', (33, 40))	('p.R201S', 'Mutation', 'rs11554273', (42, 49))	('patients', 'Species', '9606', (16, 24))	('p.R201C', 'Mutation', 'rs11554273', (33, 40))	('p.R201S', 'Var', (42, 49))	('p.Q227R', 'Var', (55, 62))	('p.Q227R', 'Mutation', 'rs121913494', (55, 62))
24870	28894201	Additionally, CPAs that carried somatic mutations (n = 8) were significantly less methylated in the five CpG sites of the CYP11B1 promoter compared to those without mutations (n = 5) (Fig.	('CPA', 'Chemical', '-', (14, 17))	('PA', 'Phenotype', 'HP:0011736', (15, 17))	('methylated', 'MPA', (82, 92))	('less', 'NegReg', (77, 81))	('mutations', 'Var', (40, 49))	('CYP11B1', 'Gene', (122, 129))	('CYP11B1', 'Gene', '1584', (122, 129))
24871	28894201	Mutations in both PRKACA and GNAS facilitate phosphorylation of the transcription factor CREB, which then binds to the Ad1/ cAMP response element (CRE) site in the CYP11B1 promoter.	('cAMP', 'Chemical', 'MESH:D000242', (124, 128))	('CYP11B1', 'Gene', '1584', (164, 171))	('CREB', 'Gene', (89, 93))	('GNAS', 'Gene', '2778', (29, 33))	('Ad1', 'Gene', '351', (119, 122))	('phosphorylation', 'MPA', (45, 60))	('Mutations', 'Var', (0, 9))	('CYP11B1', 'Gene', (164, 171))	('PRKACA', 'Gene', (18, 24))	('PRKACA', 'Gene', '5566', (18, 24))	('CREB', 'Gene', '1385', (89, 93))	('Ad1', 'Gene', (119, 122))	('binds', 'Interaction', (106, 111))	('GNAS', 'Gene', (29, 33))	('facilitate', 'PosReg', (34, 44))
24873	28894201	In CPA, the somatic mutations reduced the methylation level of these two CpG sites significantly, while the methylation level of the other three CpG sites were not affected by somatic mutations (Fig.	('PA', 'Phenotype', 'HP:0011736', (4, 6))	('CPA', 'Chemical', '-', (3, 6))	('methylation level', 'MPA', (42, 59))	('reduced', 'NegReg', (30, 37))	('mutations', 'Var', (20, 29))
24880	28894201	Since mutations in both PRKACA and GNAS genes lead to the constitutive activation of the PKA pathway, we examined the effect of cAMP-induced PKA activation on DNA methylation using a cAMP analog, 2'-O-dibutyladenosine 3', 5'-cyclic monophosphate (dibutyric cAMP; dbcAMP).	('cAMP', 'Chemical', 'MESH:D000242', (265, 269))	('PRKACA', 'Gene', (24, 30))	('PKA', 'Gene', '5566', (89, 92))	('PKA', 'Gene', (89, 92))	('PRKACA', 'Gene', '5566', (24, 30))	('activation', 'PosReg', (71, 81))	('GNAS', 'Gene', '2778', (35, 39))	('dbcAMP', 'Chemical', 'MESH:D003994', (263, 269))	('PKA', 'Gene', '5566', (141, 144))	('cAMP', 'Chemical', 'MESH:D000242', (257, 261))	('PKA', 'Gene', (141, 144))	('GNAS', 'Gene', (35, 39))	('mutations', 'Var', (6, 15))	('cAMP', 'Chemical', 'MESH:D000242', (183, 187))	('cAMP', 'Chemical', 'MESH:D000242', (128, 132))
24891	28894201	Recent studies have reported that the CYP11B2 promoter in APA is hypomethylated, suggesting that the hypomethylated state is associated with aldosterone overproduction.	('hypomethylated', 'Var', (101, 115))	('CYP11B2', 'Gene', (38, 45))	('associated', 'Reg', (125, 135))	('aldosterone overproduction', 'MPA', (141, 167))	('aldosterone', 'Chemical', 'MESH:D000450', (141, 152))	('CYP11B2', 'Gene', '1585', (38, 45))	('PA', 'Phenotype', 'HP:0011736', (59, 61))
24897	28894201	DNA methylation in the CYP11B1 promoter reduced its activity.	('activity', 'MPA', (52, 60))	('CYP11B1', 'Gene', (23, 30))	('CYP11B1', 'Gene', '1584', (23, 30))	('methylation', 'Var', (4, 15))	('reduced', 'NegReg', (40, 47))
24898	28894201	We therefore conclude that DNA methylation interferes with the binding of transcription factors to the CYP11B1 promoter.	('CYP11B1', 'Gene', '1584', (103, 110))	('binding', 'Interaction', (63, 70))	('interferes', 'NegReg', (43, 53))	('methylation', 'Var', (31, 42))	('CYP11B1', 'Gene', (103, 110))
24899	28894201	Recent genetic analysis identified a mutation in the PRKACA gene that causes CPA.	('CPA', 'Disease', (77, 80))	('mutation', 'Var', (37, 45))	('PA', 'Phenotype', 'HP:0011736', (78, 80))	('causes', 'Reg', (70, 76))	('CPA', 'Chemical', '-', (77, 80))	('PRKACA', 'Gene', (53, 59))	('PRKACA', 'Gene', '5566', (53, 59))
24900	28894201	This mutation results in the release of PRKACA from the inhibitory R subunits, leading to the constitutive, cAMP-independent activation of PKA.	('PRKACA', 'Gene', (40, 46))	('activation', 'PosReg', (125, 135))	('PKA', 'Gene', '5566', (139, 142))	('release', 'MPA', (29, 36))	('PRKACA', 'Gene', '5566', (40, 46))	('cAMP', 'Chemical', 'MESH:D000242', (108, 112))	('results in', 'Reg', (14, 24))	('mutation', 'Var', (5, 13))	('PKA', 'Gene', (139, 142))
24901	28894201	Moreover, GNAS mutations that activate PKA through a constitutive increase in intracellular cAMP concentrations are also frequently identified in CPA.	('PKA', 'Gene', '5566', (39, 42))	('increase', 'PosReg', (66, 74))	('GNAS', 'Gene', '2778', (10, 14))	('PKA', 'Gene', (39, 42))	('cAMP', 'Chemical', 'MESH:D000242', (92, 96))	('mutations', 'Var', (15, 24))	('GNAS', 'Gene', (10, 14))	('intracellular cAMP concentrations', 'MPA', (78, 111))	('CPA', 'Chemical', '-', (146, 149))	('PA', 'Phenotype', 'HP:0011736', (147, 149))	('rat', 'Species', '10116', (104, 107))
24902	28894201	Thus, both PRKACA and GNAS mutations lead to activation of the cAMP/PKA signaling pathway.	('mutations', 'Var', (27, 36))	('PKA', 'Gene', '5566', (68, 71))	('PKA', 'Gene', (68, 71))	('GNAS', 'Gene', (22, 26))	('PRKACA', 'Gene', (11, 17))	('PRKACA', 'Gene', '5566', (11, 17))	('cAMP', 'Chemical', 'MESH:D000242', (63, 67))	('GNAS', 'Gene', '2778', (22, 26))	('activation', 'PosReg', (45, 55))
24904	28894201	A previous study reported that mutations in PRKACA and GNAS were associated with small tumors, young age at presentation, and a severe phenotype.	('mutations', 'Var', (31, 40))	('PRKACA', 'Gene', '5566', (44, 50))	('GNAS', 'Gene', '2778', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('small', 'Disease', (81, 86))	('associated', 'Reg', (65, 75))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('GNAS', 'Gene', (55, 59))	('tumors', 'Disease', (87, 93))	('PRKACA', 'Gene', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
24905	28894201	Another study also reported that patients with CPA containing PRKACA mutations had higher basal serum cortisol concentrations than patients without PRKACA mutations, which persisted after dexamethasone suppression tests.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (69, 78))	('PRKACA', 'Gene', (62, 68))	('rat', 'Species', '10116', (118, 121))	('dexamethasone', 'Chemical', 'MESH:D003907', (188, 201))	('patients', 'Species', '9606', (33, 41))	('basal serum cortisol concentrations', 'MPA', (90, 125))	('cortisol', 'Chemical', 'MESH:D006854', (102, 110))	('CPA', 'Chemical', '-', (47, 50))	('PRKACA', 'Gene', '5566', (62, 68))	('PRKACA', 'Gene', (148, 154))	('PRKACA', 'Gene', '5566', (148, 154))	('higher', 'PosReg', (83, 89))	('PA', 'Phenotype', 'HP:0011736', (48, 50))
24907	28894201	Mutations in KCNJ5 , ATP1A1 , ATP2B3 , and CACNA1D  upregulate CYP11B2.	('KCNJ5', 'Gene', (13, 18))	('KCNJ5', 'Gene', '3762', (13, 18))	('ATP1A1', 'Gene', '476', (21, 27))	('ATP1A1', 'Gene', (21, 27))	('Mutations', 'Var', (0, 9))	('CYP11B2', 'Gene', (63, 70))	('CACNA1D', 'Gene', '776', (43, 50))	('CACNA1D', 'Gene', (43, 50))	('upregulate', 'PosReg', (52, 62))	('CYP11B2', 'Gene', '1585', (63, 70))	('ATP2B3', 'Gene', '492', (30, 36))	('ATP2B3', 'Gene', (30, 36))
24908	28894201	However, in the case of CPA carrying PRKACA or GNAS mutations CYP11B1 promoters are significantly hypomethylated compared to wild-type CPA.	('mutations', 'Var', (52, 61))	('PRKACA', 'Gene', '5566', (37, 43))	('GNAS', 'Gene', (47, 51))	('CPA', 'Chemical', '-', (24, 27))	('CYP11B1', 'Gene', '1584', (62, 69))	('PA', 'Phenotype', 'HP:0011736', (136, 138))	('CPA', 'Chemical', '-', (135, 138))	('GNAS', 'Gene', '2778', (47, 51))	('PRKACA', 'Gene', (37, 43))	('CYP11B1', 'Gene', (62, 69))	('hypomethylated', 'PosReg', (98, 112))	('PA', 'Phenotype', 'HP:0011736', (25, 27))
24909	28894201	More interestingly, PRKACA or GNAS mutations reduced DNA methylation at the two CpG sites around the Ad1/CRE binding site significantly, but not at the other three CpG sites.	('reduced', 'NegReg', (45, 52))	('PRKACA', 'Gene', (20, 26))	('Ad1', 'Gene', '351', (101, 104))	('GNAS', 'Gene', '2778', (30, 34))	('PRKACA', 'Gene', '5566', (20, 26))	('GNAS', 'Gene', (30, 34))	('Ad1', 'Gene', (101, 104))	('DNA methylation', 'MPA', (53, 68))	('mutations', 'Var', (35, 44))
24910	28894201	Since these mutations result in the continuous PKA activation, to mimick the effect of these mutations, we treated H295R cells with dbcAMP, which activates PKA constitutively.	('PKA', 'Gene', '5566', (47, 50))	('PKA', 'Gene', '5566', (156, 159))	('dbcAMP', 'Chemical', 'MESH:D003994', (132, 138))	('mutations', 'Var', (12, 21))	('PKA', 'Gene', (47, 50))	('dbcAMP', 'Gene', (132, 138))	('H295R', 'CellLine', 'CVCL:0458', (115, 120))	('activation', 'PosReg', (51, 61))	('PKA', 'Gene', (156, 159))
24912	28894201	These data suggest that mutations in PRKACA or GNAS have an impact on the methylation status of the CYP11B1 promoter region, especially around the Ad1/CRE site.	('Ad1', 'Gene', (147, 150))	('PRKACA', 'Gene', '5566', (37, 43))	('GNAS', 'Gene', '2778', (47, 51))	('GNAS', 'Gene', (47, 51))	('impact', 'Reg', (60, 66))	('mutations', 'Var', (24, 33))	('Ad1', 'Gene', '351', (147, 150))	('methylation status', 'MPA', (74, 92))	('PRKACA', 'Gene', (37, 43))	('CYP11B1', 'Gene', (100, 107))	('CYP11B1', 'Gene', '1584', (100, 107))
24913	28894201	Since several studies have demonstrated that the binding of transcription factors affects DNA methylation status, these results suggest that somatic mutations commonly found in CPA that facilitate the binding of activated CREB to the Ad1/CRE site should influence DNA methylation of the CYP11B1 promoter.	('CREB', 'Gene', (222, 226))	('Ad1', 'Gene', (234, 237))	('mutations', 'Var', (149, 158))	('CREB', 'Gene', '1385', (222, 226))	('facilitate', 'PosReg', (186, 196))	('influence', 'Reg', (254, 263))	('CYP11B1', 'Gene', (287, 294))	('CYP11B1', 'Gene', '1584', (287, 294))	('binding', 'Interaction', (201, 208))	('DNA methylation', 'MPA', (264, 279))	('CPA', 'Chemical', '-', (177, 180))	('rat', 'Species', '10116', (34, 37))	('Ad1', 'Gene', '351', (234, 237))	('PA', 'Phenotype', 'HP:0011736', (178, 180))	('CPA', 'Gene', (177, 180))
24922	28894201	This raises the possibility that hypomethylation at the promoter regions of CYP11B1 and CYP11B2 might be associated with the production of cortisol in ZF and aldosterone in the zona glomerulosa.	('CYP11B1', 'Gene', (76, 83))	('CYP11B2', 'Gene', (88, 95))	('CYP11B1', 'Gene', '1584', (76, 83))	('aldosterone', 'Chemical', 'MESH:D000450', (158, 169))	('CYP11B2', 'Gene', '1585', (88, 95))	('production', 'MPA', (125, 135))	('cortisol', 'Chemical', 'MESH:D006854', (139, 147))	('hypomethylation', 'Var', (33, 48))	('associated', 'Reg', (105, 115))
24928	28894201	Furthermore, somatic mutations associated with CPA, which result in the activation of the cAMP/PKA signaling pathway, induce DNA hypomethylation at the CYP11B1 promoter.	('activation', 'PosReg', (72, 82))	('cAMP', 'Chemical', 'MESH:D000242', (90, 94))	('CYP11B1', 'Gene', (152, 159))	('PKA', 'Gene', '5566', (95, 98))	('PA', 'Phenotype', 'HP:0011736', (48, 50))	('CYP11B1', 'Gene', '1584', (152, 159))	('CPA', 'Gene', (47, 50))	('induce', 'Reg', (118, 124))	('DNA hypomethylation', 'MPA', (125, 144))	('CPA', 'Chemical', '-', (47, 50))	('PKA', 'Gene', (95, 98))	('mutations', 'Var', (21, 30))
24964	27585489	In gonadectomized B6D2F2 mice GLI1+ progenitors contributed to long-lived adrenal capsule cells and to adrenocortical neoplasms that expressed Gata4 and Foxl2, two prototypical gonadal markers.	('neoplasms', 'Phenotype', 'HP:0002664', (118, 127))	('GLI1', 'Gene', (30, 34))	('mice', 'Species', '10090', (25, 29))	('adrenocortical neoplasms', 'Disease', (103, 127))	('Gata4', 'Gene', (143, 148))	('Gata4', 'Gene', '14463', (143, 148))	('Foxl2', 'Gene', (153, 158))	('Foxl2', 'Gene', '26927', (153, 158))	('B6D2F2', 'Var', (18, 24))	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (103, 127))	('GLI1', 'Gene', '14632', (30, 34))
24985	27585489	C57Bl/6J mice harboring Gli1-creERT2 [Gli1tm3(cre/ESR1)Alj/J], Rosa26 loxP-stop-loxP lacZ [R26R-lacZ; Gt(ROSA)26Sortm1Sor/J], or R26R-confetti [B6.Cg-Gt(ROSA)26Sortm1(CAG-Brainbow2.1)Cle/J] transgenes were obtained from the Jackson Laboratory (Bar Harbor, ME).	('CAG-Brainbow2', 'Disease', 'MESH:D030342', (167, 180))	('Gli1', 'Gene', (24, 28))	('Rosa26', 'Gene', (63, 69))	('Gli1', 'Gene', '14632', (24, 28))	('Gli1', 'Gene', '14632', (38, 42))	('ESR1', 'Gene', '13982', (50, 54))	('CAG-Brainbow2', 'Disease', (167, 180))	('R26R-confetti', 'Var', (129, 142))	('ESR1', 'Gene', (50, 54))	('mice', 'Species', '10090', (9, 13))	('Rosa26', 'Gene', '14910', (63, 69))	('Gli1', 'Gene', (38, 42))
25054	27585489	Studies of mutant mice have shown that GLI1 is not required for hedgehog signaling, because GLI2 can rescue most GLI1 functions.	('mutant', 'Var', (11, 17))	('mice', 'Species', '10090', (18, 22))	('GLI2', 'Gene', (92, 96))	('functions', 'MPA', (118, 127))	('GLI1', 'Gene', (113, 117))	('GLI1', 'Gene', (39, 43))	('GLI1', 'Gene', '14632', (113, 117))	('GLI1', 'Gene', '14632', (39, 43))	('GLI2', 'Gene', '14633', (92, 96))
25063	27585489	Long-lived GLI1+ capsular progenitor cells give rise to adrenocortical neoplasms in gonadectomized B6D2F2 mice and to patches of subcapsular cell hyperplasia in older, non-gonadectomized B6D2F2 mice.	('B6D2F2', 'Var', (99, 105))	('hyperplasia', 'Disease', (146, 157))	('mice', 'Species', '10090', (106, 110))	('adrenocortical neoplasms', 'Disease', (56, 80))	('GLI1', 'Gene', (11, 15))	('neoplasms', 'Phenotype', 'HP:0002664', (71, 80))	('GLI1', 'Gene', '14632', (11, 15))	('mice', 'Species', '10090', (194, 198))	('hyperplasia', 'Disease', 'MESH:D006965', (146, 157))	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (56, 80))
25076	27585489	To our knowledge, this is the first article describing the use of the R26R-confetti reporter in adrenocortical tissue.	('adrenocortical', 'Disease', 'MESH:D018268', (96, 110))	('R26R-confetti', 'Var', (70, 83))	('adrenocortical', 'Disease', (96, 110))
25080	27585489	Such neoplasia-ready cells may be defined in part by epigenetic modifications that impact the phenotypic plasticity of adrenocortical stem/progenitor cells, allowing some to respond to the hormonal changes associated with GDX.	('adrenocortical', 'Disease', 'MESH:D018268', (119, 133))	('neoplasia-ready', 'Disease', 'MESH:D009369', (5, 20))	('neoplasia-ready', 'Disease', (5, 20))	('respond to', 'MPA', (174, 184))	('GDX', 'Gene', (222, 225))	('neoplasia', 'Phenotype', 'HP:0002664', (5, 14))	('phenotypic plasticity', 'CPA', (94, 115))	('allowing', 'Reg', (157, 165))	('impact', 'Reg', (83, 89))	('adrenocortical', 'Disease', (119, 133))	('epigenetic modifications', 'Var', (53, 77))	('GDX', 'Gene', '27643', (222, 225))
25081	27585489	Epigenetic variability among stem/progenitor cells may explain why GDX of susceptible mouse strains leads to discrete wedges of proliferating neoplastic cells in the adrenal cortex rather than uniform tumor formation along the periphery of the cortex.	('GDX', 'Gene', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('mouse', 'Species', '10090', (86, 91))	('GDX', 'Gene', '27643', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('Epigenetic variability', 'Var', (0, 22))
25103	27555782	Pediatric ACC is commonly reported in families with Li-Fraumeni syndrome, which are generally related with TP53 tumor-suppressor germ line mutations or inherent genetic and/or epigenetic changes affecting chromosome 11p15 (Beckwith-Wiedemann syndrome).	('reported', 'Reg', (26, 34))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (52, 72))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (223, 250))	('ACC', 'Phenotype', 'HP:0006744', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('Li-Fraumeni syndrome', 'Disease', (52, 72))	('Pediatric ACC', 'Disease', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Beckwith-Wiedemann syndrome', 'Disease', (223, 250))	('epigenetic changes', 'Var', (176, 194))	('tumor', 'Disease', (112, 117))
25109	27555782	Increased levels of insulin-like growth factor 2 (IGF-2) are found in 90% of pediatric ACC due to genetic or epigenetic changes in chromosome 11p15.	('genetic', 'Var', (98, 105))	('ACC', 'Phenotype', 'HP:0006744', (87, 90))	('Increased levels of insulin-like growth factor', 'Phenotype', 'HP:0030269', (0, 46))	('epigenetic changes', 'Var', (109, 127))	('insulin-like growth factor 2', 'Gene', '3481', (20, 48))	('insulin-like growth factor 2', 'Gene', (20, 48))	('Increased levels of insulin', 'Phenotype', 'HP:0000842', (0, 27))	('IGF-2', 'Gene', (50, 55))	('IGF-2', 'Gene', '3481', (50, 55))
25132	27555782	Eighty-two miRNAs such as TGGTGCT, MIR-29A, MIR-29B, MIR-29C, GTACTGT, MIR-101, GTGCCTT, and MIR-506 were found to be associated with DEGs.	('DEGs', 'Disease', (134, 138))	('MIR-101', 'Var', (71, 78))	('MIR-29B', 'Gene', '407024', (44, 51))	('MIR-29A', 'Gene', (35, 42))	('MIR-29A', 'Gene', '407021', (35, 42))	('MIR-506', 'Gene', '574511', (93, 100))	('MIR-29C', 'Gene', '407026', (53, 60))	('associated', 'Reg', (118, 128))	('MIR-29B', 'Gene', (44, 51))	('MIR-29C', 'Gene', (53, 60))	('MIR-506', 'Gene', (93, 100))
25145	27555782	Pinto et al reported that pediatric ACC based on TP53 and somatic ATRX mutations had shown high expression of genes associated with chromosome instability and deregulation of cell cycle control, such as CCNB1.	('chromosome instability', 'Phenotype', 'HP:0040012', (132, 154))	('CCNB1', 'Gene', '891', (203, 208))	('cell cycle control', 'CPA', (175, 193))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('ACC', 'Phenotype', 'HP:0006744', (36, 39))	('expression', 'MPA', (96, 106))	('ATRX', 'Gene', (66, 70))	('mutations', 'Var', (71, 80))	('ATRX', 'Gene', '546', (66, 70))	('CCNB1', 'Gene', (203, 208))
25246	26684865	However, 20HU may be an acceptable density cut-off value for a mass <4 cm in absence of malignancy history.	('malignancy', 'Disease', 'MESH:D009369', (88, 98))	('malignancy', 'Disease', (88, 98))	('20HU', 'Var', (9, 13))
25273	26131713	Silencing of GPER by a specific shRNA partially reversed G-1-mediated cell growth inhibition without affecting ERK activation.	('GPER', 'Gene', '2852', (13, 17))	('ERK', 'Gene', '5594', (111, 114))	('GPER', 'Gene', (13, 17))	('ERK', 'Gene', (111, 114))	('Silencing', 'Var', (0, 9))	('cell growth', 'CPA', (70, 81))
25284	26131713	Our in vitro experiments demonstrated that ESR1 knock down was more effective than an IGF1R antibody in controlling H295R cell proliferation.	('ESR1', 'Gene', (43, 47))	('H295R', 'CellLine', 'CVCL:0458', (116, 121))	('IGF1R', 'Gene', (86, 91))	('ESR1', 'Gene', '2099', (43, 47))	('IGF1R', 'Gene', '3480', (86, 91))	('knock down', 'Var', (48, 58))	('H295R cell proliferation', 'CPA', (116, 140))
25297	26131713	Knocking down of GPER gene expression, using a specific shRNA, (shGPER) was assessed by western blot analysis and revealed a substantial decrease in protein content compared to the control shRNA (insert, Fig.	('GPER', 'Gene', '2852', (17, 21))	('decrease', 'NegReg', (137, 145))	('GPER', 'Gene', (17, 21))	('GPER', 'Gene', '2852', (66, 70))	('protein content', 'MPA', (149, 164))	('GPER', 'Gene', (66, 70))	('Knocking', 'Var', (0, 8))
25298	26131713	However, GPER silencing was able to only partially abrogate the inhibitory effects exerted by G-1 on H295R cell proliferation (Fig.	('GPER', 'Gene', (9, 13))	('silencing', 'Var', (14, 23))	('H295R cell proliferation', 'CPA', (101, 125))	('GPER', 'Gene', '2852', (9, 13))	('H295R', 'CellLine', 'CVCL:0458', (101, 106))	('abrogate', 'NegReg', (51, 59))
25307	26131713	Ki-67 immunostaimning was significantly lower in G-1-treated tumors compared to control mice (value score control: 6, 6 +- 0, 89 (SD); value score G-1 treated cells: 3, 1 +- 0.55 * (SD) (*p < 0.05) (Fig.	('Ki-67', 'Gene', (0, 5))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('Ki-67', 'Gene', '17345', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mice', 'Species', '10090', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('G-1-treated', 'Var', (49, 60))	('lower', 'NegReg', (40, 45))
25312	26131713	In agreement with the observation that inappropriate accumulation of B type cyclins is associated with the initiation of apoptotic pathways, we found that G-1 caused cell death by apoptosis.	('cyclin', 'Gene', (76, 82))	('G-1', 'Var', (155, 158))	('cyclin', 'Gene', '5111', (76, 82))	('apoptosis', 'CPA', (180, 189))	('cell death', 'CPA', (166, 176))
25318	26131713	The presence of G-1 increased Bax expression while decreased Bcl-2 (Fig.	('increased', 'PosReg', (20, 29))	('Bax', 'Gene', (30, 33))	('decreased', 'NegReg', (51, 60))	('Bcl-2', 'Gene', (61, 66))	('Bcl-2', 'Gene', '596', (61, 66))	('Bax', 'Gene', '581', (30, 33))	('G-1', 'Gene', (16, 19))	('presence', 'Var', (4, 12))
25355	26131713	G-1 caused sustained ERK1/2 activation in H295R, this event was clearly involved in the induction of apoptosis, since chemical inhibition of MEK1/2 using PD98059 abrogated G-1 ability to induce the expression of proapoptotic factor Bax.	('Bax', 'Gene', (232, 235))	('MEK1/2', 'Gene', '5604;5605', (141, 147))	('ERK1/2', 'Gene', (21, 27))	('abrogated', 'NegReg', (162, 171))	('MEK1/2', 'Gene', (141, 147))	('ERK1/2', 'Gene', '5595;5594', (21, 27))	('PD98059', 'Chemical', 'MESH:C093973', (154, 161))	('H295R', 'Var', (42, 47))	('H295R', 'CellLine', 'CVCL:0458', (42, 47))	('activation', 'PosReg', (28, 38))	('Bax', 'Gene', '581', (232, 235))	('inhibition', 'NegReg', (127, 137))	('induce', 'PosReg', (187, 193))	('expression', 'MPA', (198, 208))
25357	26131713	Moreover, ERK activity has been shown to directly affect mitochondrial function by decreasing mitochondrial respiration and mitochondrial membrane potential, causing mitochondrial membrane disruption and Cytochrome c release.	('decreasing', 'NegReg', (83, 93))	('mitochondrial function', 'MPA', (57, 79))	('Cytochrome c', 'Gene', '54205', (204, 216))	('mitochondrial membrane potential', 'MPA', (124, 156))	('mitochondrial membrane disruption', 'MPA', (166, 199))	('activity', 'Var', (14, 22))	('affect', 'Reg', (50, 56))	('mitochondrial respiration', 'MPA', (94, 119))	('ERK', 'Gene', '5594', (10, 13))	('Cytochrome c', 'Gene', (204, 216))	('causing', 'Reg', (158, 165))	('ERK', 'Gene', (10, 13))
25358	26131713	Interestingly, GPER silencing was not able to prevent G-1 induced ERK phosphorylation, underlying the existence of alternative targets for G-1.	('GPER', 'Gene', (15, 19))	('ERK', 'Gene', '5594', (66, 69))	('GPER', 'Gene', '2852', (15, 19))	('silencing', 'Var', (20, 29))	('ERK', 'Gene', (66, 69))
25363	26131713	G-1 clearly causes cell-cycle arrest at the G2 phase and apoptosis through a mechanism that requires sustained ERK1/2 activation.	('causes', 'Reg', (12, 18))	('ERK1/2', 'Gene', (111, 117))	('apoptosis', 'CPA', (57, 66))	('G-1', 'Var', (0, 3))	('cell-cycle arrest at the G2 phase', 'CPA', (19, 52))	('ERK1/2', 'Gene', '5595;5594', (111, 117))
25375	26131713	TRizol RNA isolation system (Invitrogen, Carlsbad, CA, USA) was used to extract total RNA from H295R, SKBR3 and ACCs.	('H295R', 'Var', (95, 100))	('H295R', 'CellLine', 'CVCL:0458', (95, 100))	('SKBR3', 'CellLine', 'CVCL:0033', (102, 107))	('ACCs', 'Gene', (112, 116))	('TRizol', 'Chemical', 'MESH:C411644', (0, 6))	('ACCs', 'Gene', '84680', (112, 116))
25425	25924874	Reinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus resulting in copy number gains encompassing the entire PRKACA; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications.	('patients', 'Species', '9606', (252, 260))	('copy number', 'Var', (196, 207))	('gains', 'PosReg', (322, 327))	('gains', 'PosReg', (208, 213))	('patients', 'Species', '9606', (377, 385))	('PRKACA', 'Gene', (238, 244))	('duplications', 'Var', (344, 356))	('patients', 'Species', '9606', (55, 63))	('PRKACA', 'Gene', '5566', (238, 244))	('rearrangements', 'Var', (130, 144))
25428	25924874	Constitutional chromosomal PRKACA amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo.	('PRKACA', 'Gene', (27, 33))	('amplification', 'Var', (34, 47))	('PRKACA', 'Gene', '5566', (27, 33))	('CS', 'Phenotype', 'HP:0003118', (104, 106))	('associated', 'Reg', (88, 98))	('genetic defect', 'Disease', 'MESH:D030342', (73, 87))	('genetic defect', 'Disease', (73, 87))
25429	25924874	PRKACA amplification can lead to variable phenotypes clinically and pathologically, and both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.	('PRKACA', 'Gene', (0, 6))	('BAH', 'Chemical', '-', (118, 121))	('lead to', 'Reg', (25, 32))	('PRKACA', 'Gene', '5566', (0, 6))	('amplification', 'Var', (7, 20))
25430	25924874	Inactivating mutations of PRKAR1A, the main regulatory subunit (R1alpha) of protein kinase A (PKA), cause primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia (BAH) leading to Cushing syndrome (CS) .	('pigmented nodular adrenocortical disease', 'Disease', (114, 154))	('PRKAR1A', 'Gene', (26, 33))	('Cushing syndrome', 'Disease', (220, 236))	('CS', 'Phenotype', 'HP:0003118', (238, 240))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (114, 154))	('Inactivating mutations', 'Var', (0, 22))	('PKA', 'Gene', '34284', (94, 97))	('BAH', 'Chemical', '-', (204, 207))	('PRKAR1A', 'Gene', '5573', (26, 33))	('cause', 'Reg', (100, 105))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (220, 236))	('PKA', 'Gene', (94, 97))	('Cushing syndrome', 'Disease', 'MESH:D003480', (220, 236))	('bilateral adrenocortical hyperplasia', 'Disease', (166, 202))	('bilateral adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (166, 202))
25432	25924874	Inactivation of PRKAR1A leads to increased PKA activity that is due to lack of regulation of the PKA's main catalytic subunit (Calpha) coded by the PRKACA gene .	('PKA', 'Gene', '34284', (43, 46))	('PKA', 'Gene', (43, 46))	('PRKAR1A', 'Gene', '5573', (16, 23))	('PRKACA', 'Gene', (148, 154))	('increased', 'PosReg', (33, 42))	('PKA', 'Gene', (97, 100))	('PKA', 'Gene', '34284', (97, 100))	('PRKACA', 'Gene', '5566', (148, 154))	('Inactivation', 'Var', (0, 12))	('PRKAR1A', 'Gene', (16, 23))
25433	25924874	We recently reported gain of function mutations in PRKACA that lead to increased cyclic AMP (cAMP) signaling in adrenal CS associated with BAH (when PRKACA defects are present in the germline) and sporadic cortisol-producing adrenal adenomas (CPAs) (when PRKACA defects are present in the somatic state, i.e.	('PRKACA', 'Gene', '5566', (51, 57))	('PRKACA', 'Gene', (149, 155))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (225, 241))	('adrenal adenomas', 'Disease', (225, 241))	('cortisol', 'Chemical', 'MESH:D006854', (206, 214))	('PRKACA', 'Gene', '5566', (255, 261))	('BAH', 'Disease', (139, 142))	('adrenal CS', 'MPA', (112, 122))	('cyclic AMP', 'Chemical', 'MESH:D000242', (81, 91))	('CPA', 'Chemical', '-', (243, 246))	('mutations', 'Var', (38, 47))	('PRKACA', 'Gene', (51, 57))	('cAMP', 'Chemical', 'MESH:D000242', (93, 97))	('PRKACA', 'Gene', '5566', (149, 155))	('CS', 'Phenotype', 'HP:0003118', (120, 122))	('PRKACA', 'Gene', (255, 261))	('gain of function', 'PosReg', (21, 37))	('increased', 'PosReg', (71, 80))	('BAH', 'Chemical', '-', (139, 142))	('adrenal adenomas', 'Disease', 'MESH:D018246', (225, 241))
25435	25924874	Thus, gain of function of PRKACA appears to lead to benign adrenal tumors without any other manifestations of CNC (such as skin pigmentation, myxomas, and other neoplasms), suggesting that increased activity of this catalytic subunit of PKA is associated with abnormalities specific to adrenocortical tissue, whereas inactivating mutations of the PKA regulatory subunit R1alpha (encoded by PRKAR1A) result in the full spectrum of findings associated with CNC.	('neoplasms', 'Disease', (161, 170))	('PRKACA', 'Gene', '5566', (26, 32))	('PRKAR1A', 'Gene', (390, 397))	('activity', 'MPA', (199, 207))	('myxomas', 'Disease', (142, 149))	('skin pigmentation', 'Phenotype', 'HP:0000953', (123, 140))	('skin pigmentation', 'Disease', (123, 140))	('PKA', 'Gene', '34284', (237, 240))	('adrenocortical', 'Disease', 'MESH:D018268', (286, 300))	('neoplasms', 'Phenotype', 'HP:0002664', (161, 170))	('benign adrenal tumors', 'Disease', (52, 73))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('myxomas', 'Disease', 'MESH:D009232', (142, 149))	('adrenocortical', 'Disease', (286, 300))	('inactivating mutations', 'Var', (317, 339))	('PKA', 'Gene', (237, 240))	('skin pigmentation', 'Disease', 'MESH:D010859', (123, 140))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('PRKAR1A', 'Gene', '5573', (390, 397))	('PKA', 'Gene', '34284', (347, 350))	('PRKACA', 'Gene', (26, 32))	('neoplasms', 'Disease', 'MESH:D009369', (161, 170))	('benign adrenal tumors', 'Disease', 'MESH:D000310', (52, 73))	('PKA', 'Gene', (347, 350))	('increased', 'PosReg', (189, 198))
25436	25924874	In the present investigation, we first screened the patients for germline mutations in PRKAR1A, which was negative in all 5 patients.	('PRKAR1A', 'Gene', '5573', (87, 94))	('PRKAR1A', 'Gene', (87, 94))	('patients', 'Species', '9606', (124, 132))	('patients', 'Species', '9606', (52, 60))	('germline mutations', 'Var', (65, 83))
25438	25924874	Surprisingly, our new data suggest that there might be a dosage-dependent effect on the phenotype, as both duplications and triplications encompassing PRKACA were observed, and those patients with triplications presented at a younger age.	('triplications', 'Var', (124, 137))	('PRKACA', 'Gene', (151, 157))	('PRKACA', 'Gene', '5566', (151, 157))	('duplications', 'Var', (107, 119))	('patients', 'Species', '9606', (183, 191))
25502	25924874	The PRKACA gene resided on duplication segments in subject CAR54.03, while it was triplicated in subjects CAR696.01 and CAR767.03.	('CAR54.03', 'Var', (59, 67))	('CAR767.03', 'Var', (120, 129))	('PRKACA', 'Gene', '5566', (4, 10))	('PRKACA', 'Gene', (4, 10))
25505	25924874	These results might suggest potential invisible complexity underlying the rearrangement that generated the "dup-nml-dup" and "dup-trp" complex structure observed in subjects CAR54.03 and CAR696.01.	('trp', 'Chemical', 'MESH:D014364', (130, 133))	('CAR54.03', 'Var', (174, 182))	('CAR696.01', 'Var', (187, 196))
25510	25924874	As we have reported elsewhere  it appears that germline amplification of PRKACA leads to BAH, both macronodular and micronodular forms.	('PRKACA', 'Gene', (73, 79))	('leads to', 'Reg', (80, 88))	('germline amplification', 'Var', (47, 69))	('BAH', 'Chemical', '-', (89, 92))	('BAH', 'Disease', (89, 92))	('PRKACA', 'Gene', '5566', (73, 79))
25511	25924874	In this study, however, we reexamined the genetics and genomics of these patients with in-depth genomic analysis and found that there were differences in the degree of amplification: PRKACA triplications were identified in patients 2 and 3, both of whom had clinical presentation at a younger age, when compared to the other patients.	('identified', 'Reg', (209, 219))	('patients', 'Species', '9606', (325, 333))	('triplications', 'Var', (190, 203))	('PRKACA', 'Gene', (183, 189))	('patients', 'Species', '9606', (223, 231))	('patients', 'Species', '9606', (73, 81))	('PRKACA', 'Gene', '5566', (183, 189))
25512	25924874	A similar genomic dosage-dependent phenotype has been described in Charcot-Marie-Tooth disease type 1A (CMT1A): in CMT1A, patients with triplications presented with a more severe distal symmetric polyneurpopathy phenotype than those with duplications .	('Charcot-Marie-Tooth disease type 1A', 'Disease', (67, 102))	('Charcot-Marie-Tooth disease type 1A', 'Disease', 'MESH:D000699', (67, 102))	('patients', 'Species', '9606', (122, 130))	('CMT1A', 'CellLine', 'CVCL:X218', (104, 109))	('triplications', 'Var', (136, 149))	('polyneurpopathy', 'Disease', (196, 211))	('CMT1A', 'CellLine', 'CVCL:X218', (115, 120))	('polyneurpopathy', 'Disease', 'None', (196, 211))
25513	25924874	These data also demonstrate that amplifications of PRKACA at the genomic level, at least up to triplications are compatible with life.	('PRKACA', 'Gene', '5566', (51, 57))	('PRKACA', 'Gene', (51, 57))	('amplifications', 'Var', (33, 47))
25514	25924874	No PRKACA-activating mutations associated with CS has been identified in the germline whereas such mutations have now been confirmed in the somatic state by five more studies of hundreds of patients with adrenal CS .	('PRKACA', 'Gene', (3, 9))	('patients', 'Species', '9606', (190, 198))	('PRKACA', 'Gene', '5566', (3, 9))	('CS', 'Phenotype', 'HP:0003118', (47, 49))	('CS', 'Phenotype', 'HP:0003118', (212, 214))	('associated', 'Reg', (31, 41))	('mutations', 'Var', (21, 30))
25515	25924874	Likewise, in the only cancer where PRKACA is reported to be involved, its activation is also somatic and is caused by genomic rearrangements of the 19p13 locus resulting in recurrent DNAJB1-PRKACA chimeric transcripts found in fibrolamellar hepatocellular carcinoma .	('rearrangements', 'Var', (126, 140))	('fibrolamellar hepatocellular carcinoma', 'Disease', (227, 265))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('fibrolamellar hepatocellular carcinoma', 'Disease', 'MESH:C537258', (227, 265))	('PRKACA', 'Gene', (35, 41))	('DNAJB1', 'Gene', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('activation', 'PosReg', (74, 84))	('PRKACA', 'Gene', (190, 196))	('chimeric transcripts', 'MPA', (197, 217))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (241, 265))	('PRKACA', 'Gene', '5566', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('PRKACA', 'Gene', '5566', (190, 196))	('DNAJB1', 'Gene', '3337', (183, 189))
25516	25924874	The somatic PRKACA mutations identified to date  are all present in a location of the Calpha protein that is responsible for binding to the regulatory subunit(s).	('Calpha protein', 'Protein', (86, 100))	('PRKACA', 'Gene', (12, 18))	('mutations', 'Var', (19, 28))	('PRKACA', 'Gene', '5566', (12, 18))
25521	25924874	It should be noted that PRKACA mutations that were predicted to lose interaction with the regulatory subunit while maintaining enzymatic activity had been studied in vitro in the early 1990s .	('enzymatic', 'MPA', (127, 136))	('PRKACA', 'Gene', (24, 30))	('mutations', 'Var', (31, 40))	('PRKACA', 'Gene', '5566', (24, 30))	('lose', 'NegReg', (64, 68))	('interaction', 'Interaction', (69, 80))
25522	25924874	Additional PRKACA sequences that had similar effects in vitro were described recently, and the first PRKACA mutations in humans with predicted functional effects were reported in 2012 with no association with an obvious phenotype .	('PRKACA', 'Gene', '5566', (101, 107))	('mutations', 'Var', (108, 117))	('PRKACA', 'Gene', (11, 17))	('PRKACA', 'Gene', '5566', (11, 17))	('PRKACA', 'Gene', (101, 107))	('humans', 'Species', '9606', (121, 127))
25524	25924874	In addition, 92 specimens from sporadic somatotroph adenomas were screened for mutations at codon 206 of PRKACA or PRKACB, and none were identified.	('PRKACA', 'Gene', '5566', (105, 111))	('somatotroph adenomas', 'Disease', 'MESH:D049912', (40, 60))	('PRKACB', 'Gene', '5567', (115, 121))	('PRKACA', 'Gene', (105, 111))	('PRKACB', 'Gene', (115, 121))	('somatotroph adenomas', 'Disease', (40, 60))	('mutations', 'Var', (79, 88))
25525	25924874	The data presented here and those reported earlier  show that PRKACA is a relatively unique endocrine tumor gene: it causes rare forms of BAH leading to CS in children and young adults when it is part of increased dosage of chromosome 19p13.2p13.12 genomic material; triplications appear to convey a more severe phenotype than duplications.	('children', 'Species', '9606', (159, 167))	('endocrine tumor', 'Phenotype', 'HP:0100568', (92, 107))	('PRKACA', 'Gene', (62, 68))	('BAH', 'Chemical', '-', (138, 141))	('BAH', 'Disease', (138, 141))	('PRKACA', 'Gene', '5566', (62, 68))	('causes', 'Reg', (117, 123))	('triplications', 'Var', (267, 280))	('CS', 'Phenotype', 'HP:0003118', (153, 155))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('endocrine tumor', 'Disease', 'MESH:D004701', (92, 107))	('endocrine tumor', 'Disease', (92, 107))
25527	25924874	The Leu206Arg and the other activating PRKACA mutations identified to date  may not be compatible with life in human embryos and that is potentially why they have not been found in the germline.	('activating', 'PosReg', (28, 38))	('human', 'Species', '9606', (111, 116))	('Leu206Arg', 'Mutation', 'rs386352352', (4, 13))	('Leu206Arg', 'Var', (4, 13))	('PRKACA', 'Gene', (39, 45))	('PRKACA', 'Gene', '5566', (39, 45))
25535	25924874	Indeed, new animal models that will study Prkaca overexpression are essential to elucidate the pathophysiology of the described PRKACA defects and will be very useful for the development of molecular therapies for the treatment of cortisol-producing lesions in humans.	('PRKACA', 'Gene', '5566', (128, 134))	('PRKACA', 'Gene', (128, 134))	('defects', 'Var', (135, 142))	('humans', 'Species', '9606', (261, 267))	('cortisol', 'Chemical', 'MESH:D006854', (231, 239))
25553	24602387	Estrogen oversecretion may lead to gynecomastia in men and metrorrhagia in postmenopausal women.	('men', 'Species', '9606', (79, 82))	('oversecretion', 'Var', (9, 22))	('gynecomastia', 'Disease', 'MESH:D006177', (35, 47))	('men', 'Species', '9606', (51, 54))	('metrorrhagia in postmenopausal', 'Phenotype', 'HP:0008209', (59, 89))	('Estrogen', 'Protein', (0, 8))	('men', 'Species', '9606', (92, 95))	('gynecomastia', 'Phenotype', 'HP:0000771', (35, 47))	('gynecomastia', 'Disease', (35, 47))	('lead to', 'Reg', (27, 34))	('metrorrhagia', 'Disease', (59, 71))	('metrorrhagia', 'Disease', 'MESH:D008796', (59, 71))	('women', 'Species', '9606', (90, 95))	('metrorrhagia', 'Phenotype', 'HP:0100608', (59, 71))
25670	21897902	Virilization is due to dehydroepiandrosterone and dehydroepiandrosterone sulphate rather than testosterone.	('testosterone', 'Chemical', 'MESH:D013739', (94, 106))	('dehydroepiandrosterone sulphate', 'Chemical', 'MESH:D019314', (50, 81))	('dehydroepiandrosterone', 'Chemical', 'MESH:D003687', (23, 45))	('dehydroepiandrosterone', 'Var', (23, 45))	('dehydroepiandrosterone', 'Var', (50, 72))	('dehydroepiandrosterone', 'Chemical', 'MESH:D003687', (50, 72))	('Virilization', 'Disease', (0, 12))
25728	30760340	Factors associated with survival included disease-free interval greater than six months (after index adrenalectomy), nonfunctional tumor, surgical resection of recurrence, R0 resection, and solitary liver metastasis.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('disease-free', 'Disease', (42, 54))	('nonfunctional tumor', 'Disease', 'MESH:C565486', (117, 136))	('R0 resection', 'Var', (172, 184))	('nonfunctional tumor', 'Disease', (117, 136))
25802	33889224	In contrast, patients with non-functioning ACC may present with a variety of nonspecific symptoms, such as abdominal pain, fatigue, and symptoms related to mass effects.	('non-functioning', 'Var', (27, 42))	('fatigue', 'Phenotype', 'HP:0012378', (123, 130))	('pain', 'Phenotype', 'HP:0012531', (117, 121))	('abdominal pain', 'Phenotype', 'HP:0002027', (107, 121))	('patients', 'Species', '9606', (13, 21))	('abdominal pain', 'Disease', (107, 121))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('fatigue', 'Disease', 'MESH:D005221', (123, 130))	('abdominal pain', 'Disease', 'MESH:D015746', (107, 121))	('fatigue', 'Disease', (123, 130))
25862	31427568	Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity Oxysterol-binding protein like 2 (OSBPL2) was identified as a novel causal gene for autosomal dominant nonsyndromic hearing loss.	('AMPK', 'Gene', (132, 136))	('OSBPL2', 'Gene', (12, 18))	('OSBPL2', 'Gene', '334206', (12, 18))	('hearing loss', 'Phenotype', 'HP:0000365', (262, 274))	('Oxysterol-binding protein like 2', 'Gene', '334206', (146, 178))	('Oxysterol-binding protein like 2', 'Gene', (146, 178))	('cholesterol biosynthesis', 'MPA', (47, 71))	('reactive oxygen species production', 'MPA', (83, 117))	('increases cholesterol', 'Phenotype', 'HP:0003124', (37, 58))	('inhibiting', 'NegReg', (121, 131))	('autosomal dominant nonsyndromic hearing loss', 'Disease', (230, 274))	('AMPK', 'Gene', '5562', (132, 136))	('Deletion', 'Var', (0, 8))	('cholesterol', 'Chemical', 'MESH:D002784', (47, 58))	('autosomal dominant nonsyndromic hearing loss', 'Disease', 'MESH:C580334', (230, 274))	('OSBPL2', 'Gene', (180, 186))	('OSBPL2', 'Gene', '334206', (180, 186))	('increases', 'PosReg', (37, 46))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (83, 106))
25868	31427568	The levels of total cholesterol and ROS in OC1 cells or zebrafish inner ear were both increased in Osbpl2/osbpl2b-KO mutants and the mitochondrial damage was detected in Osbpl2-KO OC1 cells.	('OC1', 'Gene', (43, 46))	('increased', 'PosReg', (86, 95))	('OC1', 'Gene', '393545', (180, 183))	('Osbpl2', 'Gene', (170, 176))	('mutants', 'Var', (117, 124))	('Osbpl2', 'Gene', '334206', (170, 176))	('ROS', 'MPA', (36, 39))	('zebrafish', 'Species', '7955', (56, 65))	('Osbpl2', 'Gene', (99, 105))	('OC1', 'Gene', '393545', (43, 46))	('OC1', 'Gene', (180, 183))	('osbpl2b', 'Gene', (106, 113))	('Osbpl2', 'Gene', '334206', (99, 105))	('cholesterol', 'Chemical', 'MESH:D002784', (20, 31))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('osbpl2b', 'Gene', '334206', (106, 113))
25873	31427568	Increasing evidences suggest that deregulation of cholesterol-homeostasis is the causative or characteristic factor of numerous pathologies, including cardiovascular disease, cerebrovascular disease, metabolic diseases, tumourigenesis and neurodegenerative diseases.	('cardiovascular disease', 'Disease', (151, 173))	('cholesterol', 'Chemical', 'MESH:D002784', (50, 61))	('cholesterol-homeostasis', 'MPA', (50, 73))	('deregulation', 'Var', (34, 46))	('cerebrovascular disease', 'Disease', 'MESH:D002561', (175, 198))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (239, 265))	('metabolic diseases', 'Disease', (200, 218))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (151, 173))	('cardiovascular disease', 'Disease', 'MESH:D002318', (151, 173))	('cerebrovascular disease', 'Disease', (175, 198))	('tumourigenesis', 'Disease', (220, 234))	('neurodegenerative diseases', 'Disease', (239, 265))	('metabolic diseases', 'Disease', 'MESH:D008659', (200, 218))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (239, 265))
25876	31427568	Our previous work described the association of human mutations in OSBPL2 with autosomal dominant non-syndromic hearing loss (ADNSHL) in a large affected Chinese family, which was also reported in an affected German family by Thoenes et al.	('non-syndromic hearing loss', 'Disease', (97, 123))	('mutations', 'Var', (53, 62))	('association', 'Interaction', (32, 43))	('non-syndromic hearing loss', 'Disease', 'MESH:C537845', (97, 123))	('hearing loss', 'Phenotype', 'HP:0000365', (111, 123))	('human', 'Species', '9606', (47, 52))	('OSBPL2', 'Gene', (66, 72))
25880	31427568	It was suggested that the OSBPL2 deficits might result in the loss of tightly-regulated cholesterol-homeostasis response in inner ear and lead to the auditory dysfunction.	('loss', 'NegReg', (62, 66))	('auditory dysfunction', 'Disease', (150, 170))	('cholesterol', 'Chemical', 'MESH:D002784', (88, 99))	('OSBPL2', 'Gene', (26, 32))	('tightly-regulated cholesterol-homeostasis response', 'MPA', (70, 120))	('deficits', 'Var', (33, 41))	('lead to', 'Reg', (138, 145))	('auditory dysfunction', 'Disease', 'MESH:D006311', (150, 170))
25881	31427568	Considering the ubiquitous expression of OSBPL2 in diverse cell types and multiple cellular functions of this sterol sensor, the potential pathogenesis of OSBPL2 deficits in ADNSHL still needed to be further investigated in the functional or dysfunctional context of specific cell types in vitro and in vivo.	('OSBPL2', 'Gene', (155, 161))	('sterol', 'Chemical', 'MESH:D013261', (110, 116))	('deficits', 'Var', (162, 170))
25882	31427568	In this study, OC1 auditory cell and zebrafish as well as their Osbpl2/osbpl2b-knockout (KO) mutants were used to investigate the potential role of OSBPL2 in the regulation of cholesterol-homeostasis.	('osbpl2b', 'Gene', (71, 78))	('mutants', 'Var', (93, 100))	('OC1', 'Gene', '393545', (15, 18))	('Osbpl2', 'Gene', '334206', (64, 70))	('osbpl2b', 'Gene', '334206', (71, 78))	('Osbpl2', 'Gene', (64, 70))	('OC1', 'Gene', (15, 18))	('zebrafish', 'Species', '7955', (37, 46))	('cholesterol', 'Chemical', 'MESH:D002784', (176, 187))
25899	31427568	The protein levels of Srebp2, Hmgcr and Hmgcs1, key regulators in AMPK signaling pathway and cholesterol biosynthesis, were also measured in Osbpl2/osbpl2b-KO mutants.	('Hmgcs1', 'Gene', (40, 46))	('Osbpl2', 'Gene', (141, 147))	('Osbpl2', 'Gene', '334206', (141, 147))	('osbpl2b', 'Gene', (148, 155))	('protein levels', 'MPA', (4, 18))	('Srebp2', 'Gene', (22, 28))	('Hmgcr', 'Gene', (30, 35))	('Hmgcr', 'Gene', '559054', (30, 35))	('mutants', 'Var', (159, 166))	('Srebp2', 'Gene', '100037309', (22, 28))	('osbpl2b', 'Gene', '334206', (148, 155))	('Hmgcs1', 'Gene', '394060', (40, 46))	('AMPK', 'Gene', '5562', (66, 70))	('AMPK', 'Gene', (66, 70))	('cholesterol', 'Chemical', 'MESH:D002784', (93, 104))
25916	31427568	Silencing AMPK up-regulated the expression of nuclear Srebp2, Hmgcr, and Hmgcs1 (Fig.	('Srebp2', 'Gene', (54, 60))	('Hmgcs1', 'Gene', '394060', (73, 79))	('Silencing', 'Var', (0, 9))	('up-regulated', 'PosReg', (15, 27))	('Hmgcs1', 'Gene', (73, 79))	('AMPK', 'Gene', '5562', (10, 14))	('AMPK', 'Gene', (10, 14))	('Srebp2', 'Gene', '100037309', (54, 60))	('Hmgcr', 'Gene', (62, 67))	('Hmgcr', 'Gene', '559054', (62, 67))	('expression', 'MPA', (32, 42))
25921	31427568	Therefore, it was suggested that OSBPL2 plays an important role in the regulation on cholesterol biosynthesis through AMPK signaling pathway, and OSBPL2 deficit induced aberrant cholesterol biosynthesis/accumulation by inhibiting AMPK activity.	('AMPK', 'Gene', '5562', (118, 122))	('deficit', 'Var', (153, 160))	('AMPK', 'Gene', (118, 122))	('OSBPL2', 'Gene', (146, 152))	('inhibiting', 'NegReg', (219, 229))	('cholesterol', 'Chemical', 'MESH:D002784', (85, 96))	('cholesterol', 'Chemical', 'MESH:D002784', (178, 189))	('cholesterol biosynthesis/accumulation', 'MPA', (178, 215))	('AMPK', 'Gene', '5562', (230, 234))	('AMPK', 'Gene', (230, 234))	('induced', 'Reg', (161, 168))	('aberrant cholesterol biosynthesis', 'Phenotype', 'HP:0003107', (169, 202))
25937	31427568	To determine the effect of ATIC on AMPK activity, the AICAR levels were measured in the case of ATIC overexpression or knockdown.	('ATIC', 'Gene', (27, 31))	('AMPK', 'Gene', (35, 39))	('ATIC', 'Gene', (96, 100))	('knockdown', 'Var', (119, 128))	('ATIC', 'Gene', '140622', (27, 31))	('ATIC', 'Gene', '140622', (96, 100))	('AICAR', 'Chemical', 'MESH:C031143', (54, 59))	('AMPK', 'Gene', '5562', (35, 39))
25940	31427568	These results suggested that the OSBPL2 deficit led to the destruction of the OSBPL2-ATIC interaction, resulting in decreased levels of AICAR and inhibition of AMPK activity.	('ATIC', 'Gene', (85, 89))	('AMPK', 'Gene', (160, 164))	('inhibition', 'NegReg', (146, 156))	('OSBPL2', 'Gene', (33, 39))	('interaction', 'Interaction', (90, 101))	('deficit', 'Var', (40, 47))	('levels of AICAR', 'MPA', (126, 141))	('ATIC', 'Gene', '140622', (85, 89))	('decreased', 'NegReg', (116, 125))	('AMPK', 'Gene', '5562', (160, 164))	('AICAR', 'Chemical', 'MESH:C031143', (136, 141))
25953	31427568	On the other hand, OSBPL2 deficit interfered the OSBPL2-ATIC interaction and reduced the intracellular AICAR level as well as AMPK activity, which enhanced nuclear transfer of SREBP2 and upregulated the expression HMGCR and HMGCS1, resulting in excessive cholesterol biosynthesis and ROS accumulation (Fig.	('intracellular AICAR level', 'MPA', (89, 114))	('cholesterol', 'Chemical', 'MESH:D002784', (255, 266))	('excessive cholesterol', 'Phenotype', 'HP:0003124', (245, 266))	('upregulated', 'PosReg', (187, 198))	('HMGCS1', 'Gene', (224, 230))	('SREBP2', 'Gene', (176, 182))	('AICAR', 'Chemical', 'MESH:C031143', (103, 108))	('AMPK', 'Gene', '5562', (126, 130))	('ROS', 'Chemical', 'MESH:D017382', (284, 287))	('HMGCR', 'Gene', '559054', (214, 219))	('excessive', 'PosReg', (245, 254))	('reduced', 'NegReg', (77, 84))	('ROS accumulation', 'MPA', (284, 300))	('enhanced', 'PosReg', (147, 155))	('ATIC', 'Gene', '140622', (56, 60))	('SREBP2', 'Gene', '100037309', (176, 182))	('nuclear transfer', 'MPA', (156, 172))	('ATIC', 'Gene', (56, 60))	('deficit', 'Var', (26, 33))	('HMGCS1', 'Gene', '394060', (224, 230))	('AMPK', 'Gene', (126, 130))	('cholesterol biosynthesis', 'MPA', (255, 279))	('HMGCR', 'Gene', (214, 219))	('interfered', 'NegReg', (34, 44))
25959	31427568	These results strongly suggested that Osbpl2/osbpl2b deficits inhibited AMPK activity and enhanced cholesterol biosynthesis.	('AMPK', 'Gene', (72, 76))	('cholesterol biosynthesis', 'MPA', (99, 123))	('osbpl2b', 'Gene', '334206', (45, 52))	('cholesterol', 'Chemical', 'MESH:D002784', (99, 110))	('AMPK', 'Gene', '5562', (72, 76))	('deficits', 'Var', (53, 61))	('enhanced', 'PosReg', (90, 98))	('inhibited', 'NegReg', (62, 71))	('osbpl2b', 'Gene', (45, 52))	('Osbpl2', 'Gene', (38, 44))	('Osbpl2', 'Gene', '334206', (38, 44))	('enhanced cholesterol', 'Phenotype', 'HP:0003124', (90, 110))
25962	31427568	There was a strong correlation between low AMPK activation status with insulin resistance, obesity and sedentary lifestyle.	('insulin', 'Gene', (71, 78))	('AMPK', 'Gene', '5562', (43, 47))	('obesity', 'Disease', 'MESH:D009765', (91, 98))	('insulin resistance', 'Phenotype', 'HP:0000855', (71, 89))	('obesity', 'Disease', (91, 98))	('AMPK', 'Gene', (43, 47))	('low', 'Var', (39, 42))	('obesity', 'Phenotype', 'HP:0001513', (91, 98))	('sedentary lifestyle', 'Disease', (103, 122))	('insulin', 'Gene', '30262', (71, 78))
25969	31427568	In the present work, AMPK inhibition increased intracellular cholesterol synthesis, which was observed both in Osbpl2/osbpl2b-KO mutants.	('Osbpl2', 'Gene', (111, 117))	('osbpl2b', 'Gene', (118, 125))	('intracellular cholesterol synthesis', 'MPA', (47, 82))	('cholesterol', 'Chemical', 'MESH:D002784', (61, 72))	('osbpl2b', 'Gene', '334206', (118, 125))	('AMPK', 'Gene', '5562', (21, 25))	('AMPK', 'Gene', (21, 25))	('increased', 'PosReg', (37, 46))	('mutants', 'Var', (129, 136))	('Osbpl2', 'Gene', '334206', (111, 117))	('increased intracellular cholesterol', 'Phenotype', 'HP:0003575', (37, 72))
25980	31427568	The present data were consistent with a model in which OSBPL2 deficits led to the exposure of the AICARF domain, inhibited the cellular levels of AICAR, and suppressed AMPK activity.	('deficits', 'Var', (62, 70))	('OSBPL2', 'Gene', (55, 61))	('led', 'Reg', (71, 74))	('inhibited', 'NegReg', (113, 122))	('suppressed', 'NegReg', (157, 167))	('exposure', 'MPA', (82, 90))	('AICAR', 'Chemical', 'MESH:C031143', (146, 151))	('cellular levels of AICAR', 'MPA', (127, 151))	('AMPK', 'Gene', '5562', (168, 172))	('AMPK', 'Gene', (168, 172))	('AICAR', 'Chemical', 'MESH:C031143', (98, 103))
25996	31427568	Our findings contributed to elucidating the pathogenesis/physiopathology of OSBPL2 mutation and the potential linkage of deregulation of cholesterol-homeostasis and SNHL.	('OSBPL2', 'Gene', (76, 82))	('cholesterol', 'Chemical', 'MESH:D002784', (137, 148))	('SNHL', 'Disease', (165, 169))	('mutation', 'Var', (83, 91))
25997	31427568	Antibodies for adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK/Ampk) (#2793), Flag-Tag (#2368), His-Tag (#12698), GST-Tag (#2624), GAPDH (#5174) and phosphospecific antibodies for AMPK/Ampk -pThr172 (#2535) were purchased from Cell Signaling Technology (Danvers, MA, USA).	('#5174', 'Var', (154, 159))	('Ampk', 'Gene', '5562', (201, 205))	('GAPDH', 'Gene', (147, 152))	('AMP', 'Chemical', '-', (74, 77))	('AMPK', 'Gene', (74, 78))	('Thr172', 'Chemical', '-', (208, 214))	('AMPK', 'Gene', '5562', (196, 200))	('AMP', 'Chemical', '-', (43, 46))	('#2793', 'Var', (86, 91))	('#2368', 'Var', (104, 109))	('Ampk', 'Gene', (201, 205))	("adenosine 5'-monophosphate", 'Chemical', '-', (15, 41))	('Ampk', 'Gene', '5562', (79, 83))	('#12698', 'Var', (121, 127))	('#2624', 'Var', (139, 144))	('His', 'Chemical', 'MESH:D006639', (112, 115))	('AMPK', 'Gene', '5562', (74, 78))	('GAPDH', 'Gene', '317743', (147, 152))	('AMP', 'Chemical', '-', (196, 199))	('AMPK', 'Gene', (196, 200))	('Ampk', 'Gene', (79, 83))
25998	31427568	Antibodies for HMGCR/Hmgcr (#ab174830), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) (#ab188321), HA-Tag (#ab1424) and phosphospecific antibodies for acetyl-CoA carboxylase (ACC/Acc) pSer79 (#ab68191) were purchased from Abcam (Cambridge, UK).	('#ab174830', 'Var', (28, 37))	('HMGCR', 'Gene', '559054', (15, 20))	('#ab68191', 'Var', (254, 262))	('Ser79', 'Chemical', '-', (247, 252))	('ATIC', 'Gene', (142, 146))	('Hmgcr', 'Gene', (21, 26))	('Hmgcr', 'Gene', '559054', (21, 26))	('HMGCR', 'Gene', (15, 20))	('ATIC', 'Gene', '140622', (142, 146))
25999	31427568	Antibodies for ACC/Acc (#21923-1-AP), 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) (#17643-1-AP) and sterol regulatory element-binding protein 2 SREBP2/Srebp2 (#A13049) were from Proteintech (Chicago, IL, USA).	('SREBP2', 'Gene', '100037309', (151, 157))	('SREBP2', 'Gene', (151, 157))	('HMGCS1', 'Gene', '394060', (81, 87))	('#17643-1-AP', 'Var', (90, 101))	('sterol regulatory element-binding protein 2', 'Gene', (107, 150))	('Srebp2', 'Gene', (158, 164))	('sterol regulatory element-binding protein 2', 'Gene', '100037309', (107, 150))	('Srebp2', 'Gene', '100037309', (158, 164))	('HMGCS1', 'Gene', (81, 87))	('#21923-1-AP', 'Var', (24, 35))
26001	31427568	IRDye 800CW goat anti-Mouse IgG (#926-32213) and IRDye 680LT goat anti-Rabbit IgG (#926-68021) were purchased from LI-COR Biosciences (Lincoln, Nebraska, USA).	('#926-68021', 'Var', (83, 93))	('goat', 'Species', '9925', (12, 16))	('Rabbit', 'Species', '9986', (71, 77))	('goat', 'Species', '9925', (61, 65))	('Mouse', 'Species', '10090', (22, 27))	('#926-32213', 'Var', (33, 43))
26002	31427568	Cholesterol (#C8667) and methyl-beta-cyclodextrin (#C4555) were purchased from Sigma-ldrich (St. Louis, MO, USA).	('#C8667', 'Var', (13, 19))	('methyl-beta-cyclodextrin', 'Chemical', 'MESH:C108732', (25, 49))	('#C4555', 'Var', (51, 57))	('Cholesterol', 'Chemical', 'MESH:D002784', (0, 11))
26003	31427568	Aminoimidazole carboxamide ribonucleotide (AICAR) (#S1802) and Compound C (#S7840) were purchased from Selleckchem (Houston, TX, USA).	('#S1802', 'Var', (51, 57))	('#S7840', 'Var', (75, 81))	('AICAR', 'Chemical', 'MESH:C031143', (43, 48))	('Aminoimidazole carboxamide ribonucleotide', 'Chemical', 'MESH:C031143', (0, 41))
26039	30305978	In 2011, abiraterone acetate was approved for the treatment of metastatic CRPC; however abiraterone is known to cause mineralocorticoid excess syndrome characterized by hypokalemia, fluid retention, and hypertension.	('abiraterone acetate', 'Chemical', 'MESH:D000069501', (9, 28))	('hypokalemia', 'Disease', 'MESH:D007008', (169, 180))	('cause', 'Reg', (112, 117))	('abiraterone', 'Chemical', 'MESH:C089740', (88, 99))	('fluid retention', 'Phenotype', 'HP:0000969', (182, 197))	('hypokalemia', 'Phenotype', 'HP:0002900', (169, 180))	('hypertension', 'Disease', 'MESH:D006973', (203, 215))	('hypertension', 'Phenotype', 'HP:0000822', (203, 215))	('mineralocorticoid excess', 'Phenotype', 'HP:0000859', (118, 142))	('mineralocorticoid excess syndrome', 'Disease', 'MESH:D043204', (118, 151))	('abiraterone', 'Var', (88, 99))	('fluid', 'Disease', (182, 187))	('mineralocorticoid excess syndrome', 'Disease', (118, 151))	('hypertension', 'Disease', (203, 215))	('hypokalemia', 'Disease', (169, 180))	('abiraterone', 'Chemical', 'MESH:C089740', (9, 20))
26068	23714463	For this review, we focus on three rare syndromes and their associated genetic mutations including BAP1, TP53, and SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2).	('SDHC', 'Gene', (133, 137))	('BAP1', 'Gene', (99, 103))	('SDHD', 'Gene', (139, 143))	('SDH', 'Gene', '6390', (121, 124))	('SDHAF2', 'Gene', '54949', (145, 151))	('SDHAF2', 'Gene', (145, 151))	('SDH', 'Gene', (145, 148))	('SDHB', 'Gene', (127, 131))	('SDH', 'Gene', (115, 118))	('SDH', 'Gene', '6390', (127, 130))	('mutations', 'Var', (79, 88))	('SDH', 'Gene', (139, 142))	('SDH', 'Gene', (121, 124))	('TP53', 'Gene', (105, 109))	('SDH', 'Gene', '6390', (133, 136))	('SDHx', 'Chemical', '-', (115, 119))	('SDH', 'Gene', (127, 130))	('SDHC', 'Gene', '6391', (133, 137))	('BAP1', 'Gene', '8314', (99, 103))	('SDH', 'Gene', (133, 136))	('SDHD', 'Gene', '6392', (139, 143))	('SDH', 'Gene', '6390', (145, 148))	('SDHB', 'Gene', '6390', (127, 131))	('SDH', 'Gene', '6390', (115, 118))	('SDH', 'Gene', '6390', (139, 142))	('TP53', 'Gene', '7157', (105, 109))
26069	23714463	BAP1 encodes an enzyme that catalyzes the removal of ubiquitin from protein substrates, and germline mutations of BAP1 cause a novel cancer syndrome characterized by high incidence of benign atypical melanocytic tumors, uveal melanomas, cutaneous melanomas, malignant mesotheliomas, and potentially other cancers.	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('benign atypical melanocytic tumors', 'Disease', (184, 218))	('BAP1', 'Gene', (114, 118))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (237, 256))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (237, 256))	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('cancers', 'Disease', 'MESH:D009369', (305, 312))	('BAP1', 'Gene', (0, 4))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (237, 255))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('cause', 'Reg', (119, 124))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (258, 281))	('uveal melanomas', 'Disease', (220, 235))	('uveal melanomas', 'Phenotype', 'HP:0007716', (220, 235))	('cancer syndrome', 'Disease', 'MESH:D009369', (133, 148))	('melanomas', 'Phenotype', 'HP:0002861', (226, 235))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (258, 280))	('mutations', 'Var', (101, 110))	('cutaneous melanomas', 'Disease', (237, 256))	('cancer syndrome', 'Disease', (133, 148))	('malignant mesotheliomas', 'Disease', (258, 281))	('benign atypical melanocytic tumors', 'Disease', 'MESH:D009508', (184, 218))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('cancers', 'Disease', (305, 312))	('BAP1', 'Gene', '8314', (114, 118))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (258, 281))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('melanomas', 'Phenotype', 'HP:0002861', (247, 256))	('uveal melanomas', 'Disease', 'MESH:C536494', (220, 235))	('BAP1', 'Gene', '8314', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
26070	23714463	TP53 mutations cause Li-Fraumeni syndrome (LFS), a highly penetrant cancer syndrome associated with multiple tumors including but not limited to sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancers', 'Disease', 'MESH:D001943', (155, 169))	('breast cancers', 'Disease', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('brain tumors', 'Disease', (171, 183))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('cause', 'Reg', (15, 20))	('Li-Fraumeni syndrome', 'Disease', (21, 41))	('TP53', 'Gene', '7157', (0, 4))	('multiple tumors', 'Disease', 'MESH:D009369', (100, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (155, 169))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (21, 41))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (189, 214))	('adrenocortical carcinomas', 'Disease', (189, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('mutations', 'Var', (5, 14))	('cancer syndrome', 'Disease', 'MESH:D009369', (68, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('TP53', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('multiple tumors', 'Disease', (100, 115))	('brain tumors', 'Disease', 'MESH:D001932', (171, 183))	('sarcomas', 'Disease', 'MESH:D012509', (145, 153))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (189, 214))	('brain tumors', 'Phenotype', 'HP:0030692', (171, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('sarcomas', 'Disease', (145, 153))	('cancer syndrome', 'Disease', (68, 83))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
26072	23714463	SDH is a mitochondrial enzyme complex involved in the tricarboxylic acid (TCA) cycle, and germline SDHx mutations lead to increased succinate with subsequent paragangliomas, pheochromocytomas, renal cell carcinomas (RCCs), gastrointestinal stromal tumors (GISTs), and other rarer cancers.	('succinate', 'MPA', (132, 141))	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('SDH', 'Gene', (99, 102))	('cancers', 'Disease', (280, 287))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (223, 254))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (223, 254))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('SDH', 'Gene', '6390', (0, 3))	('TCA', 'Chemical', 'MESH:D014233', (74, 77))	('paragangliomas', 'Disease', 'MESH:D010235', (158, 172))	('paraganglioma', 'Phenotype', 'HP:0002668', (158, 171))	('paragangliomas', 'Phenotype', 'HP:0002668', (158, 172))	('mutations', 'Var', (104, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (193, 213))	('pheochromocytomas', 'Disease', 'MESH:D010673', (174, 191))	('pheochromocytomas', 'Disease', (174, 191))	('increased', 'PosReg', (122, 131))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('gastrointestinal stromal tumors', 'Disease', (223, 254))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (193, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('SDH', 'Gene', (0, 3))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (54, 72))	('cancers', 'Disease', 'MESH:D009369', (280, 287))	('SDHx', 'Chemical', '-', (99, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('increased succinate', 'Phenotype', 'HP:0020149', (122, 141))	('renal cell carcinomas', 'Disease', (193, 214))	('SDH', 'Gene', '6390', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (174, 191))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('paragangliomas', 'Disease', (158, 172))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (193, 214))	('succinate', 'Chemical', 'MESH:D019802', (132, 141))	('GISTs', 'Phenotype', 'HP:0100723', (256, 261))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (174, 190))	('RCCs', 'Phenotype', 'HP:0005584', (216, 220))
26080	23714463	Nearly 15 years later, Harbor and colleagues reported a high frequency of BAP1 mutations in metastasizing uveal melanoma (UM), including one that was germline in origin.	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('BAP1', 'Gene', '8314', (74, 78))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('UM', 'Phenotype', 'HP:0007716', (122, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('BAP1', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
26082	23714463	In one report, germline inactivating mutations of BAP1 were discovered in two families with high incidence of malignant mesothelioma (MM), UM, and other cancers.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (110, 132))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('germline inactivating mutations', 'Var', (15, 46))	('cancers', 'Disease', (153, 160))	('malignant mesothelioma', 'Disease', (110, 132))	('discovered', 'Reg', (60, 70))	('BAP1', 'Gene', '8314', (50, 54))	('UM', 'Phenotype', 'HP:0007716', (139, 141))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (110, 132))	('BAP1', 'Gene', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
26083	23714463	In the second report, two families were described in which germline mutations in BAP1 predisposed to multiple melanocytic tumors ranging from epithelioid nevi to atypical melanocytic tumors, with some mutation carriers developing UM or cutaneous melanoma (CM).	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('epithelioid nevi', 'Disease', (142, 158))	('multiple melanocytic tumors', 'Disease', (101, 128))	('BAP1', 'Gene', (81, 85))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('cutaneous melanoma', 'Disease', (236, 254))	('melanocytic tumors', 'Disease', 'MESH:D009508', (110, 128))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (236, 254))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (236, 254))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('predisposed to', 'Reg', (86, 100))	('melanocytic tumors', 'Disease', 'MESH:D009508', (171, 189))	('developing', 'PosReg', (219, 229))	('melanocytic tumors', 'Disease', (171, 189))	('nevi to atypical melanocytic tumors', 'Phenotype', 'HP:0000995', (154, 189))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('nevi', 'Phenotype', 'HP:0003764', (154, 158))	('UM', 'Phenotype', 'HP:0007716', (230, 232))	('germline mutations', 'Var', (59, 77))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('multiple melanocytic tumors', 'Disease', 'MESH:D009508', (101, 128))	('BAP1', 'Gene', '8314', (81, 85))	('CM', 'Phenotype', 'HP:0012056', (256, 258))
26084	23714463	Below, we focus on the involvement of BAP1 mutations in a new cancer predisposition disorder, now known as the BAP1 cancer syndrome.	('BAP1', 'Gene', '8314', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('BAP1', 'Gene', (38, 42))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('involvement', 'Reg', (23, 34))	('cancer syndrome', 'Disease', 'MESH:D009369', (116, 131))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('men', 'Species', '9606', (30, 33))	('cancer syndrome', 'Disease', (116, 131))	('BAP1', 'Gene', '8314', (38, 42))
26085	23714463	Notably, however, somatic BAP1 mutations have also been reported in various sporadic tumors including MM, RCC, and a rare, distinct subset of melanocytic tumors known as atypical Spitz tumors (ASTs).	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('BAP1', 'Gene', (26, 30))	('Spitz tumors', 'Disease', (179, 191))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('melanocytic tumors', 'Disease', (142, 160))	('melanocytic tumors', 'Disease', 'MESH:D009508', (142, 160))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', (85, 91))	('mutations', 'Var', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('reported', 'Reg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Disease', (154, 160))	('Spitz tumors', 'Disease', 'MESH:D018332', (179, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('BAP1', 'Gene', '8314', (26, 30))
26088	23714463	Historically, the understanding of MM pathogenesis was understood in the context of somatic genetic losses within chromosome arms 3p, 9p, and 22q, the latter two specifically affecting CDKN2A and NF2, suggesting a multistep cascade involving the inactivation of multiple tumor suppressors.	('genetic', 'Var', (92, 99))	('losses', 'NegReg', (100, 106))	('CDKN2A', 'Gene', '1029', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('affecting', 'Reg', (175, 184))	('NF2', 'Gene', '4771', (196, 199))	('tumor', 'Disease', (271, 276))	('CDKN2A', 'Gene', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('NF2', 'Gene', (196, 199))
26090	23714463	Bott and colleagues reported inactivating mutations in BAP1, a tumor suppressor gene located at 3p21.1, in 22% of sporadic MMs.	('tumor', 'Disease', (63, 68))	('BAP1', 'Gene', (55, 59))	('MMs', 'Disease', (123, 126))	('inactivating mutations', 'Var', (29, 51))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('BAP1', 'Gene', '8314', (55, 59))
26092	23714463	Moreover, heterozygous germline mutations of BAP1 were identified in two high-risk cancer families in which the predominant malignancy was MM; notably, one family also had two cases of UM, a tumor type previously shown to be associated with somatic BAP1 mutations.	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('BAP1', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('identified', 'Reg', (55, 65))	('BAP1', 'Gene', '8314', (45, 49))	('malignancy', 'Disease', 'MESH:D009369', (124, 134))	('BAP1', 'Gene', '8314', (249, 253))	('malignancy', 'Disease', (124, 134))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('BAP1', 'Gene', (249, 253))	('mutations', 'Var', (254, 263))	('cancer', 'Disease', (83, 89))
26098	23714463	Intriguingly, germline BAP1 mutations were also found in 2 of 26 sporadic MMs tested, and both patients with mutant BAP1 were previously diagnosed with UM.	('BAP1', 'Gene', (23, 27))	('BAP1', 'Gene', (116, 120))	('patients', 'Species', '9606', (95, 103))	('MMs', 'Disease', (74, 77))	('BAP1', 'Gene', '8314', (23, 27))	('UM', 'Phenotype', 'HP:0007716', (152, 154))	('found', 'Reg', (48, 53))	('mutant', 'Var', (109, 115))	('BAP1', 'Gene', '8314', (116, 120))	('mutations', 'Var', (28, 37))
26099	23714463	Concurrent work by Wiesner and colleagues revealed inactivating germline BAP1 mutations in two families with multiple benign melanocytic tumors; some affected individuals developed UM or CM, and one family member was subsequently diagnosed with MM.	('BAP1', 'Gene', '8314', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('BAP1', 'Gene', (73, 77))	('melanocytic tumors', 'Disease', (125, 143))	('mutations', 'Var', (78, 87))	('inactivating germline', 'Var', (51, 72))	('melanocytic tumors', 'Disease', 'MESH:D009508', (125, 143))	('CM', 'Phenotype', 'HP:0012056', (187, 189))	('developed', 'PosReg', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('UM', 'Phenotype', 'HP:0007716', (181, 183))	('germline', 'Var', (64, 72))
26100	23714463	The existence of a BAP1-related melanocytic disorder was confirmed by a report of germline BAP1 inactivation in families with metastatic UM or with both UM and CM; and some carriers also had atypical melanocytic tumors.	('BAP1', 'Gene', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('inactivation', 'Var', (96, 108))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('BAP1', 'Gene', '8314', (19, 23))	('melanocytic tumors', 'Disease', 'MESH:D009508', (200, 218))	('melanocytic disorder', 'Disease', 'MESH:D009508', (32, 52))	('melanocytic disorder', 'Disease', (32, 52))	('UM', 'Phenotype', 'HP:0007716', (137, 139))	('melanocytic tumors', 'Disease', (200, 218))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('BAP1', 'Gene', (19, 23))	('BAP1', 'Gene', '8314', (91, 95))	('metastatic UM', 'Disease', (126, 139))	('CM', 'Disease', (160, 162))	('CM', 'Phenotype', 'HP:0012056', (160, 162))
26101	23714463	Another group reported a germline BAP1 mutation in a family with a wide variety of cancers, including three MMs, three UMs, and three CMs.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('UM', 'Phenotype', 'HP:0007716', (119, 121))	('UMs', 'Disease', (119, 122))	('mutation', 'Var', (39, 47))	('BAP1', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('reported', 'Reg', (14, 22))	('germline', 'Var', (25, 33))	('CMs', 'Disease', (134, 137))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('BAP1', 'Gene', '8314', (34, 38))	('CM', 'Phenotype', 'HP:0012056', (134, 136))	('MMs', 'Disease', (108, 111))	('cancers', 'Disease', (83, 90))
26102	23714463	More recently, a germline BAP1 mutation was identified in a family in which MM was found in four members, none with a history of asbestos exposure; one member also had multiple melanocytic tumors.	('BAP1', 'Gene', (26, 30))	('multiple melanocytic tumors', 'Disease', 'MESH:D009508', (168, 195))	('multiple melanocytic tumors', 'Disease', (168, 195))	('mutation', 'Var', (31, 39))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('BAP1', 'Gene', '8314', (26, 30))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
26104	23714463	The full tumor spectrum associated with germline BAP1 mutations has yet to be established, as suggested by recent report of a germline BAP1 splice mutation and truncating frameshift in a family with UM, CM, suspected MM, as well as paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (232, 245))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('paraganglioma', 'Disease', (232, 245))	('BAP1', 'Gene', (49, 53))	('BAP1', 'Gene', '8314', (135, 139))	('truncating frameshift', 'Var', (160, 181))	('mutations', 'Var', (54, 63))	('CM', 'Phenotype', 'HP:0012056', (203, 205))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('paraganglioma', 'Disease', 'MESH:D010235', (232, 245))	('BAP1', 'Gene', (135, 139))	('UM', 'Phenotype', 'HP:0007716', (199, 201))	('BAP1', 'Gene', '8314', (49, 53))
26110	23714463	Inactivating somatic mutations of BAP1 were identified in 26/31 (84%) metastasizing tumors, including one that was germline in origin.	('BAP1', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('identified', 'Reg', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('BAP1', 'Gene', '8314', (34, 38))	('Inactivating somatic mutations', 'Var', (0, 30))
26114	23714463	Biallelic inactivation of BAP1 has been documented in multiple tumors from these high-risk families, strongly suggesting that BAP1 acts as a classical tumor suppressor gene.	('BAP1', 'Gene', (26, 30))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('BAP1', 'Gene', (126, 130))	('tumor', 'Disease', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('Biallelic inactivation', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('BAP1', 'Gene', '8314', (26, 30))	('men', 'Species', '9606', (44, 47))	('multiple tumors', 'Disease', 'MESH:D009369', (54, 69))	('multiple tumors', 'Disease', (54, 69))	('BAP1', 'Gene', '8314', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
26124	23714463	Mutations of BAP1 and potentially genes encoding other PR-DUB components may alter the function of the holo-complex leading to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('BAP1', 'Gene', (13, 17))	('alter', 'Reg', (77, 82))	('tumor', 'Disease', (127, 132))	('Mutations', 'Var', (0, 9))	('function', 'MPA', (87, 95))	('BAP1', 'Gene', '8314', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
26125	23714463	Germane to this, somatic ASXL1/2 alterations have been detected in human myelodysplastic disorders and solid tumors, and a conditional, systemic knockout model in which Bap1 was homozygously deleted in adult mice recapitulated features of human myelodysplastic syndrome.	('ASXL1/2', 'Gene', (25, 32))	('human', 'Species', '9606', (239, 244))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('solid tumors', 'Disease', 'MESH:D009369', (103, 115))	('myelodysplastic disorders', 'Disease', (73, 98))	('Bap1', 'Gene', '8314', (169, 173))	('Bap1', 'Gene', (169, 173))	('myelodysplastic syndrome', 'Disease', (245, 269))	('ASXL1/2', 'Gene', '171023;55252', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('alterations', 'Var', (33, 44))	('mice', 'Species', '10090', (208, 212))	('detected', 'Reg', (55, 63))	('myelodysplastic disorders', 'Phenotype', 'HP:0002863', (73, 98))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (245, 269))	('solid tumors', 'Disease', (103, 115))	('myelodysplastic disorders', 'Disease', 'MESH:D009190', (73, 98))	('human', 'Species', '9606', (67, 72))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (245, 269))
26126	23714463	While the first two reports of germline inactivating BAP1 mutations focused on different disease entities:that is, one on families with a high incidence of MM, and the other on families with multiple melanocytic tumors:both studies found recurrent UMs as well.	('mutations', 'Var', (58, 67))	('UM', 'Phenotype', 'HP:0007716', (248, 250))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('multiple melanocytic tumors', 'Disease', 'MESH:D009508', (191, 218))	('UMs', 'Disease', (248, 251))	('BAP1', 'Gene', '8314', (53, 57))	('multiple melanocytic tumors', 'Disease', (191, 218))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('focused', 'Reg', (68, 75))	('BAP1', 'Gene', (53, 57))
26127	23714463	As proposed by Goldstein, current evidence supports the notion that these initial reports of germline BAP1 mutations were describing a single syndrome consisting of a range of tumors with varying penetrance.	('BAP1', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutations', 'Var', (107, 116))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('BAP1', 'Gene', '8314', (102, 106))
26134	23714463	Moreover, why do BAP1 mutations predispose to cancer when present in the germ line, yet act as a late, somatic event in connection with UM metastasis?	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('predispose', 'Reg', (32, 42))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('BAP1', 'Gene', (17, 21))
26135	23714463	It is also unclear if variations in the number of melanocytic tumors and incidence of MM among BAP1 mutation carriers reflect differences in genetic background of affected individuals or differences in exposure to carcinogens.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BAP1', 'Gene', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('carriers', 'Reg', (109, 117))	('mutation', 'Var', (100, 108))	('BAP1', 'Gene', '8314', (95, 99))	('melanocytic tumors', 'Disease', (50, 68))	('melanocytic tumors', 'Disease', 'MESH:D009508', (50, 68))
26137	23714463	BAP1 mutation carriers should be regularly monitored for evidence of early malignancy, and preventive measures such as avoidance of exposure to asbestos and sun should be implemented.	('asbestos', 'Chemical', 'MESH:D001194', (144, 152))	('BAP1', 'Gene', (0, 4))	('men', 'Species', '9606', (176, 179))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('BAP1', 'Gene', '8314', (0, 4))	('malignancy', 'Disease', (75, 85))	('mutation', 'Var', (5, 13))
26140	23714463	In 1990, germline TP53 mutations were discovered to be the underlying cause of the majority of LFS cases.	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('cause', 'Reg', (70, 75))	('LFS', 'Disease', (95, 98))
26142	23714463	Approximately 1,800 different somatic and germline TP53 mutations have been reported, with most localized to the DNA binding domain (DBD) (http://p53.iarc.fr).	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('TP53', 'Gene', '7157', (51, 55))
26143	23714463	Mutant p53 loss-of-function, dominant-negative and gain-of-function properties are all important for tumorigenesis in humans, with gain-of-function activities being particularly relevant.	('humans', 'Species', '9606', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('p53', 'Gene', '7157', (7, 10))	('gain-of-function', 'PosReg', (51, 67))	('loss-of-function', 'NegReg', (11, 27))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
26152	23714463	Specific TP53 mutant genotype may influence age of onset and tumor spectrum.	('mutant', 'Var', (14, 20))	('age', 'MPA', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TP53', 'Gene', '7157', (9, 13))	('influence', 'Reg', (34, 43))	('TP53', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
26153	23714463	Birch and colleagues reported a significantly higher incidence and earlier age at cancer diagnosis for breast (p = 0.006) and brain cancers (p = 0.05) in families who carry missense mutations in the DBD.	('brain cancers', 'Disease', 'MESH:D001932', (126, 139))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('brain cancers', 'Disease', (126, 139))	('higher', 'PosReg', (46, 52))	('breast', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('missense mutations', 'Var', (173, 191))
26155	23714463	Furthermore, nonsense, frameshift, and splice mutations are associated with particularly early tumor onset.	('tumor', 'Disease', (95, 100))	('nonsense', 'Var', (13, 21))	('frameshift', 'Var', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('splice mutations', 'Var', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('associated', 'Reg', (60, 70))
26156	23714463	However, these genotype:phenotype correlations are not consistent, as numerous families carrying the same mutation express widely divergent clinical manifestations of age of onset and cancer type.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('mutation', 'Var', (106, 114))
26158	23714463	The sensitivity and specificity of the Chompret criteria are 82% and 58%, respectively, making it perhaps the most rigorous and relevant definition to justify TP53 mutation analysis.	('TP53', 'Gene', (159, 163))	('mutation', 'Var', (164, 172))	('TP53', 'Gene', '7157', (159, 163))
26164	23714463	Almost 50% of children with CPC harbor germline TP53 mutations even in the absence of a typical LFS family history.	('children', 'Species', '9606', (14, 22))	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('CPC', 'Disease', (28, 31))	('germline', 'Var', (39, 47))
26166	23714463	Approximately 20% to 30% of tumors in TP53 mutation carriers do not belong to the classical LFS tumor spectrum: Wilms tumor and phyllodes tumors of the breast are strongly associated, pancreatic cancer moderately associated, and neuroblastoma weakly associated with TP53 mutation carrier status.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TP53', 'Gene', (38, 42))	('LFS tumor', 'Disease', 'MESH:D016864', (92, 101))	('associated', 'Interaction', (172, 182))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('TP53', 'Gene', (266, 270))	('LFS tumor', 'Disease', (92, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (184, 201))	('mutation', 'Var', (43, 51))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('neuroblastoma', 'Disease', (229, 242))	('neuroblastoma', 'Phenotype', 'HP:0003006', (229, 242))	('Wilms tumor', 'Disease', 'MESH:D009396', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('neuroblastoma', 'Disease', 'MESH:D009447', (229, 242))	('TP53', 'Gene', '7157', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (28, 34))	('TP53', 'Gene', '7157', (266, 270))	('Wilms tumor', 'Phenotype', 'HP:0002667', (112, 123))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Disease', 'MESH:D010190', (184, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('pancreatic cancer', 'Disease', (184, 201))	('Wilms tumor', 'Disease', (112, 123))	('tumors', 'Disease', (138, 144))
26167	23714463	Carcinomas of the lung and gastrointestinal tract, lymphomas, and other neoplasms have been shown to occur in TP53 mutation carriers or first-degree relatives of carriers at much earlier ages than seen in the general population.	('carriers', 'Reg', (124, 132))	('lymphomas', 'Disease', (51, 60))	('TP53', 'Gene', '7157', (110, 114))	('lymphomas', 'Disease', 'MESH:D008223', (51, 60))	('TP53', 'Gene', (110, 114))	('Carcinomas of the lung and gastrointestinal tract', 'Disease', 'MESH:D004067', (0, 49))	('neoplasms', 'Disease', 'MESH:D009369', (72, 81))	('neoplasms', 'Disease', (72, 81))	('lymphomas', 'Phenotype', 'HP:0002665', (51, 60))	('mutation', 'Var', (115, 123))	('Carcinomas', 'Phenotype', 'HP:0030731', (0, 10))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))
26168	23714463	Approximately 1% of heritable breast cancers arise due to a germline TP53 mutation.	('mutation', 'Var', (74, 82))	('breast cancers', 'Disease', 'MESH:D001943', (30, 44))	('breast cancers', 'Disease', (30, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('arise due to', 'Reg', (45, 57))	('breast cancers', 'Phenotype', 'HP:0003002', (30, 44))	('germline', 'Var', (60, 68))
26169	23714463	However, 7% of women who develop breast cancer under 30 years of age and have no first- or second-degree relatives with cancer carry a TP53 mutation; presence of first- or second-degree relatives with cancer raises this likelihood to well over 75%.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('women', 'Species', '9606', (15, 20))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('TP53', 'Gene', '7157', (135, 139))	('mutation', 'Var', (140, 148))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('TP53', 'Gene', (135, 139))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
26172	23714463	In TP53 mutation carriers, the cumulative probability of a second cancer is 57% (+-10%) at 30 years.	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutation', 'Var', (8, 16))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
26174	23714463	A unique R337H mutation exclusively found in LFS families from southeastern Brazil is a risk allele for pediatric ACC and, until recently, was thought to represent a unique example of a tissue-specific predisposing mutation.	('R337H', 'Var', (9, 14))	('R337H', 'Mutation', 'rs121912664', (9, 14))	('pediatric ACC', 'Disease', (104, 117))
26175	23714463	Nonbiased ascertainment of families with the R337H mutation shows that the cancer risk encompasses the full spectrum of tumors associated with LFS, in particular early-onset breast cancer (mean age at diagnosis below 40 years) and CPC.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('breast cancer', 'Disease', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('CPC', 'Disease', (231, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('cancer', 'Disease', (75, 81))	('R337H', 'Mutation', 'rs121912664', (45, 50))	('R337H', 'Var', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('men', 'Species', '9606', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (181, 187))
26176	23714463	Additionally, current data on overall cancer penetrance suggest that the age-related cancer risk is somewhat lower than in LFS associated with other TP53 mutations, with tumors detected in approximately 25% of carriers at the age of 30 and a lifetime risk of approximately 80%.	('lower', 'NegReg', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('TP53', 'Gene', '7157', (149, 153))	('mutations', 'Var', (154, 163))	('cancer', 'Disease', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('TP53', 'Gene', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (38, 44))	('tumors', 'Disease', (170, 176))
26178	23714463	The PIN3 (16 bp duplication in intron 3) polymorphism has been associated with an increase in age of onset of tumors in TP53 mutation carriers.	('polymorphism', 'Var', (41, 53))	('PIN3', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('increase', 'PosReg', (82, 90))	('TP53', 'Gene', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('TP53', 'Gene', '7157', (120, 124))	('mutation', 'Var', (125, 133))
26179	23714463	A single nucleotide polymorphism (SNP) at codon 72 in exon 4 involves the substitution of an arginine for a proline base.	('arginine', 'MPA', (93, 101))	('proline', 'Chemical', 'MESH:D011392', (108, 115))	('arginine', 'Chemical', 'MESH:D001120', (93, 101))	('substitution', 'Var', (74, 86))
26180	23714463	The current consensus from a large number of studies is that R72 is more effective in inducing apoptosis than P72.	('P72', 'Gene', '10521', (110, 113))	('R72', 'Var', (61, 64))	('apoptosis', 'CPA', (95, 104))	('inducing', 'Reg', (86, 94))	('P72', 'Gene', (110, 113))
26181	23714463	On the other hand, the SNP309, rs2279744 T/G polymorphic substitution in the MDM2 gene appears to confer an earlier age of onset in LFS patients.	('rs2279744', 'Mutation', 'rs2279744', (31, 40))	('MDM2', 'Gene', '4193', (77, 81))	('MDM2', 'Gene', (77, 81))	('patients', 'Species', '9606', (136, 144))	('LFS', 'Disease', (132, 135))	('SNP309', 'Var', (23, 29))
26183	23714463	Interestingly, telomeres in peripheral blood leukocytes of TP53 mutation carriers are shorter than in normal individuals of corresponding age.	('mutation', 'Var', (64, 72))	('TP53', 'Gene', (59, 63))	('shorter', 'NegReg', (86, 93))	('telomeres', 'CPA', (15, 24))	('TP53', 'Gene', '7157', (59, 63))
26185	23714463	The accelerated telomere attrition in TP53 mutation carriers is postulated to lead to greater genomic instability and earlier age of cancer onset in successive generations.	('greater', 'PosReg', (86, 93))	('telomere', 'MPA', (16, 24))	('mutation', 'Var', (43, 51))	('TP53', 'Gene', (38, 42))	('genomic instability', 'CPA', (94, 113))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('accelerated', 'PosReg', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TP53', 'Gene', '7157', (38, 42))
26186	23714463	Global copy number variation frequency and total structural variation are significantly increased in individuals with germline TP53 mutations (p = 0.01).	('mutations', 'Var', (132, 141))	('increased', 'PosReg', (88, 97))	('structural variation', 'MPA', (49, 69))	('germline', 'Var', (118, 126))	('TP53', 'Gene', '7157', (127, 131))	('Global copy number variation frequency', 'MPA', (0, 38))	('TP53', 'Gene', (127, 131))
26188	23714463	These findings, together with the accelerated telomere attrition data, support the notion that TP53 mutation carriers have inherently unstable genomes and harbor other genetic and genomic alterations that can directly modify the age phenotype.	('mutation', 'Var', (100, 108))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))	('modify', 'Reg', (218, 224))
26189	23714463	Recent evidence suggests that the "early" germline presence of TP53 mutations in a cell may induce early critical telomere length shortening, which in turn may be involved in chromothripsis:an event of catastrophic chromosome rearrangement that is frequently seen in LFS-associated tumors.	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('telomere length shortening', 'Phenotype', 'HP:0031413', (114, 140))	('TP53', 'Gene', '7157', (63, 67))	('LFS-associated', 'Disease', (267, 281))	('TP53', 'Gene', (63, 67))	('tumors', 'Disease', (282, 288))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('mutations', 'Var', (68, 77))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('men', 'Species', '9606', (235, 238))	('involved', 'Reg', (163, 171))	('induce', 'Reg', (92, 98))	('chromothripsis', 'Disease', (175, 189))
26190	23714463	What the other genetic events are that modify the "driver" genotype conferred by the germline TP53 mutation are being actively explored and may ultimately lead to the development of more precise predictive algorithms of cancer phenotype and disease risk.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('algorithms of cancer', 'Disease', 'MESH:D009369', (206, 226))	('TP53', 'Gene', '7157', (94, 98))	('mutation', 'Var', (99, 107))	('lead', 'Reg', (155, 159))	('TP53', 'Gene', (94, 98))	('algorithms of cancer', 'Disease', (206, 226))	('men', 'Species', '9606', (174, 177))
26192	23714463	For female TP53 mutation carriers, the role of prophylactic mastectomy has not been carefully evaluated.	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('mutation', 'Var', (16, 24))
26195	23714463	Although FDG-PET/CT can identify new primary cancers in TP53 mutation carriers, repeated radiation exposure may accelerate the risk of secondary malignancies.	('malignancies', 'Disease', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('TP53', 'Gene', '7157', (56, 60))	('mutation', 'Var', (61, 69))	('TP53', 'Gene', (56, 60))	('malignancies', 'Disease', 'MESH:D009369', (145, 157))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('accelerate', 'PosReg', (112, 122))
26198	23714463	Studies to improve the predictive value of genetic and genomic modifier effects on the mutant TP53-associated phenotype will inform development of more refined tumor screening protocols and lead to improved understanding of the biologic mechanisms of tumor formation in these patients.	('patients', 'Species', '9606', (276, 284))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutant', 'Var', (87, 93))	('men', 'Species', '9606', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
26206	23714463	However, in the presence of an underlying germline SDHx mutation, the tumor rate may be extraordinarily high with a penetrance approaching 80%.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('germline', 'Var', (42, 50))	('SDHx', 'Gene', (51, 55))	('SDHx', 'Chemical', '-', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
26210	23714463	Over the past several years, we have learned that germline mutations in each of these SDHx genes may lead to development of paragangliomas or pheochromocytomas.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (142, 158))	('paragangliomas or pheochromocytomas', 'Disease', (124, 159))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (142, 159))	('germline mutations', 'Var', (50, 68))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('paragangliomas or pheochromocytomas', 'Disease', 'MESH:D010673', (124, 159))	('paraganglioma', 'Phenotype', 'HP:0002668', (124, 137))	('paragangliomas', 'Phenotype', 'HP:0002668', (124, 138))	('SDHx', 'Gene', (86, 90))	('men', 'Species', '9606', (116, 119))	('SDHx', 'Chemical', '-', (86, 90))	('lead to', 'Reg', (101, 108))
26213	23714463	Germline mutations in other genes such as NF1, VHL, RET, TMEM127, and MAX also have been associated with the development of paragangliomas and pheochromocytomas.	('Germline mutations', 'Var', (0, 18))	('associated with', 'Reg', (89, 104))	('VHL', 'Disease', 'MESH:D006623', (47, 50))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (124, 160))	('men', 'Species', '9606', (116, 119))	('VHL', 'Disease', (47, 50))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('RET', 'Gene', '5979', (52, 55))	('paraganglioma', 'Phenotype', 'HP:0002668', (124, 137))	('MAX', 'Gene', (70, 73))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (143, 160))	('TMEM127', 'Gene', (57, 64))	('paragangliomas', 'Phenotype', 'HP:0002668', (124, 138))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (143, 159))	('RET', 'Gene', (52, 55))	('NF1', 'Gene', '4763', (42, 45))	('TMEM127', 'Gene', '55654', (57, 64))	('NF1', 'Gene', (42, 45))
26214	23714463	Based on gene expression and pathway analysis, these tumors can be divided into two clusters corresponding to their underlying gene mutations: Cluster 1 (Cluster 1A: SDHx, Cluster 1B: VHL), associated with pseudohypoxia and aberrant VEGF signaling, and Cluster 2 (RET/NF1/TMEM127/MAX), associated with aberrant kinase signaling pathways.	('TMEM127', 'Gene', (272, 279))	('RET', 'Gene', '5979', (264, 267))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('associated', 'Reg', (190, 200))	('pseudohypoxia', 'Disease', (206, 219))	('pseudohypoxia', 'Disease', 'None', (206, 219))	('NF1', 'Gene', '4763', (268, 271))	('TMEM127', 'Gene', '55654', (272, 279))	('VEGF', 'Gene', '7422', (233, 237))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('RET', 'Gene', (264, 267))	('VEGF', 'Gene', (233, 237))	('VHL', 'Disease', (184, 187))	('tumors', 'Disease', (53, 59))	('NF1', 'Gene', (268, 271))	('kinase signaling pathways', 'Pathway', (311, 336))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (132, 141))	('SDHx', 'Chemical', '-', (166, 170))	('VHL', 'Disease', 'MESH:D006623', (184, 187))
26215	23714463	In the absence of SDHx mutations, paragangliomas (and sometimes pheochromocytomas) are benign and very slow growing tumors.	('SDHx', 'Chemical', '-', (18, 22))	('paragangliomas', 'Disease', (34, 48))	('paragangliomas', 'Disease', 'MESH:D010235', (34, 48))	('very slow growing tumors', 'Disease', 'MESH:D000326', (98, 122))	('paragangliomas', 'Phenotype', 'HP:0002668', (34, 48))	('paraganglioma', 'Phenotype', 'HP:0002668', (34, 47))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (64, 81))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (64, 80))	('SDHx', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('pheochromocytomas', 'Disease', (64, 81))	('very slow growing tumors', 'Disease', (98, 122))	('pheochromocytomas', 'Disease', 'MESH:D010673', (64, 81))
26217	23714463	However, when such tumors occur because of germline mutations in SDHx genes, paragangliomas and pheochromocytomas can transform to become highly aggressive and metastatic.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('germline mutations', 'Var', (43, 61))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (77, 113))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('metastatic', 'CPA', (160, 170))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('SDHx', 'Chemical', '-', (65, 69))	('SDHx', 'Gene', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('paragangliomas', 'Phenotype', 'HP:0002668', (77, 91))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (96, 112))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (96, 113))
26219	23714463	A recent study from the National Institutes of Health demonstrated that nearly 30% of nonmetastatic paragangliomas and pheochromocytomas are due to germline SDHx mutations, and that 44% of adults and 81% of children with metastatic disease are due to germline SDHx mutations.	('mutations', 'Var', (162, 171))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('children', 'Species', '9606', (207, 215))	('SDHx', 'Chemical', '-', (260, 264))	('SDHx', 'Chemical', '-', (157, 161))	('SDHx', 'Gene', (157, 161))	('paragangliomas', 'Phenotype', 'HP:0002668', (100, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (100, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (119, 135))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (119, 136))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (100, 136))	('due', 'Reg', (141, 144))
26220	23714463	In fact, this study did not test for all of the known SDHx genes, so the actual prevalence of germline SDHx mutations in this disease may be higher.	('SDHx', 'Chemical', '-', (54, 58))	('SDHx', 'Chemical', '-', (103, 107))	('SDHx', 'Gene', (103, 107))	('mutations', 'Var', (108, 117))
26222	23714463	Each SDHx gene mutation leads to a slightly different disease phenotype and clinical presentation (see Table 2).	('mutation', 'Var', (15, 23))	('SDHx', 'Chemical', '-', (5, 9))	('SDHx', 'Gene', (5, 9))
26223	23714463	Interestingly, PGL-1 disease related to germline SDHD mutations is inherited in a maternally imprinted fashion with only the children of fathers: but not mothers: developing disease.	('children', 'Species', '9606', (125, 133))	('mutations', 'Var', (54, 63))	('PGL-1 disease', 'Disease', (15, 28))	('SDHD', 'Gene', '6392', (49, 53))	('PGL-1 disease', 'Disease', 'MESH:D010235', (15, 28))	('SDHD', 'Gene', (49, 53))
26225	23714463	This is also true for germline SDHAF2 mutations (PGL-2), which are also inherited as a maternally imprinted disease.	('SDHAF2', 'Gene', '54949', (31, 37))	('SDHAF2', 'Gene', (31, 37))	('PGL-2', 'Gene', '54949', (49, 54))	('mutations', 'Var', (38, 47))	('PGL-2', 'Gene', (49, 54))
26226	23714463	Disease caused by germline SDHB mutations (PGL-4) seems to be the most common and malignant of the clinical phenotypes in "Familial Paraganglioma and Pheochromocytoma Syndrome."	('PGL-4', 'Gene', '6390', (43, 48))	('Paraganglioma', 'Phenotype', 'HP:0002668', (132, 145))	('caused', 'Reg', (8, 14))	('Familial Paraganglioma', 'Disease', 'MESH:D010235', (123, 145))	('Familial Paraganglioma', 'Disease', (123, 145))	('mutations', 'Var', (32, 41))	('Pheochromocytoma Syndrome', 'Disease', (150, 175))	('PGL-4', 'Gene', (43, 48))	('SDHB', 'Gene', '6390', (27, 31))	('Pheochromocytoma Syndrome', 'Disease', 'MESH:D010673', (150, 175))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (150, 166))	('SDHB', 'Gene', (27, 31))
26227	23714463	Every germline SDHx mutation (except SDHAF2) has been associated with GISTs.	('SDHx', 'Chemical', '-', (15, 19))	('SDHx', 'Gene', (15, 19))	('GISTs', 'Phenotype', 'HP:0100723', (70, 75))	('mutation', 'Var', (20, 28))	('GISTs', 'Disease', (70, 75))	('SDHAF2', 'Gene', '54949', (37, 43))	('SDHAF2', 'Gene', (37, 43))	('associated', 'Reg', (54, 64))
26229	23714463	Previously, clinical testing for the specific inherited SDHx mutations was based on disease presentation.	('SDHx', 'Gene', (56, 60))	('mutations', 'Var', (61, 70))	('SDHx', 'Chemical', '-', (56, 60))
26230	23714463	For instance, a patient with metastatic paraganglioma that secretes catecholamine would first be tested for SDHB mutations, whereas a young patient with just familial head and neck paragangliomas might first be screened for SDHD or SDHC mutations.	('tested', 'Reg', (97, 103))	('mutations', 'Var', (113, 122))	('SDHD', 'Gene', (224, 228))	('SDHB', 'Gene', '6390', (108, 112))	('patient', 'Species', '9606', (16, 23))	('paraganglioma', 'Phenotype', 'HP:0002668', (40, 53))	('paragangliomas', 'Disease', 'MESH:D010235', (181, 195))	('SDHC', 'Gene', '6391', (232, 236))	('paragangliomas', 'Phenotype', 'HP:0002668', (181, 195))	('paraganglioma', 'Phenotype', 'HP:0002668', (181, 194))	('secretes catecholamine', 'MPA', (59, 81))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('SDHB', 'Gene', (108, 112))	('catecholamine', 'Chemical', 'MESH:D002395', (68, 81))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (176, 195))	('just familial head', 'Phenotype', 'HP:0001357', (153, 171))	('SDHC', 'Gene', (232, 236))	('paragangliomas', 'Disease', (181, 195))	('paraganglioma', 'Disease', (40, 53))	('paraganglioma', 'Disease', (181, 194))	('patient', 'Species', '9606', (140, 147))	('paraganglioma', 'Disease', 'MESH:D010235', (40, 53))	('SDHD', 'Gene', '6392', (224, 228))	('paraganglioma', 'Disease', 'MESH:D010235', (181, 194))
26231	23714463	In order to identify patients at risk for underlying germline SDHx mutations, it was observed several years ago that tumor tissues could be stained by immunohistochemistry (IHC) for the SDHB protein.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('SDHB', 'Gene', (186, 190))	('tumor', 'Disease', (117, 122))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (21, 29))	('SDHx', 'Gene', (62, 66))	('SDHx', 'Chemical', '-', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('SDHB', 'Gene', '6390', (186, 190))
26238	23714463	Like LFS, we have learned that scheduled surveillance can detect early tumors in patients with underlying germline SDHx mutations.	('SDHx', 'Chemical', '-', (115, 119))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (120, 129))	('tumors', 'Disease', (71, 77))	('SDHx', 'Gene', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
26244	23714463	Fractionated metanephrines are nearly always abnormal in individuals with a hereditary syndrome characterized by secreting tumors (elevated metanephrines for RET and NF1 mutations and elevated normetanephrines for SDHx and VHL mutations).	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('SDHx', 'Chemical', '-', (214, 218))	('hereditary syndrome', 'Disease', (76, 95))	('NF1', 'Gene', '4763', (166, 169))	('normetanephrines', 'Chemical', 'MESH:D009647', (193, 209))	('VHL', 'Disease', 'MESH:D006623', (223, 226))	('hereditary syndrome', 'Disease', 'MESH:D009386', (76, 95))	('RET', 'Gene', '5979', (158, 161))	('metanephrines', 'MPA', (140, 153))	('elevated', 'PosReg', (131, 139))	('NF1', 'Gene', (166, 169))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('RET', 'Gene', (158, 161))	('elevated', 'PosReg', (184, 192))	('VHL', 'Disease', (223, 226))	('normetanephrines', 'MPA', (193, 209))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('metanephrines', 'Chemical', 'MESH:D008676', (140, 153))	('tumors', 'Disease', (123, 129))	('metanephrines', 'Chemical', 'MESH:D008676', (13, 26))	('SDHx', 'Gene', (214, 218))	('mutations', 'Var', (170, 179))	('metanephrines', 'Chemical', 'MESH:D008676', (196, 209))
26249	23714463	At the University of Utah, a recent prospective observational study of whole body, rapid sequence MRI in SDHx mutation carriers demonstrated MRI sensitivity of 88% and specificity of 95% to detect new tumors compared to biochemical testing sensitivity of 38% and specificity of 95% (K. Jasperson, personal communication, submitted).	('SDHx', 'Chemical', '-', (105, 109))	('SDHx', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mutation', 'Var', (110, 118))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))
26250	23714463	The University of Utah now recommends whole body MRI (5-mm slices from skull base to pelvis) at least every two years for patients with underlying SDHx mutations, followed by PET scans for patients with abnormal MRI results.	('mutations', 'Var', (152, 161))	('SDHx', 'Gene', (147, 151))	('men', 'Species', '9606', (32, 35))	('SDHx', 'Chemical', '-', (147, 151))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (189, 197))
26251	23714463	As testing for SDHx mutations has become more widespread, we have learned more about the spectrum of other SDH-related tumors, including GISTs, renal tumors (RCC, oncocytoma), papillary thyroid cancer, pituitary tumors, and even neuroblastoma.	('SDHx', 'Chemical', '-', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('renal tumors', 'Phenotype', 'HP:0009726', (144, 156))	('GISTs', 'Phenotype', 'HP:0100723', (137, 142))	('oncocytoma', 'Disease', 'MESH:D018249', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('papillary thyroid cancer', 'Disease', (176, 200))	('SDH', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('GISTs', 'Disease', (137, 142))	('neuroblastoma', 'Disease', (229, 242))	('SDH', 'Gene', '6390', (15, 18))	('neuroblastoma', 'Phenotype', 'HP:0003006', (229, 242))	('pituitary tumors', 'Disease', 'MESH:D010911', (202, 218))	('neuroblastoma', 'Disease', 'MESH:D009447', (229, 242))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('oncocytoma', 'Disease', (163, 173))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (176, 200))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('thyroid cancer', 'Phenotype', 'HP:0002890', (186, 200))	('tumors', 'Disease', (212, 218))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('renal tumors', 'Disease', (144, 156))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (176, 200))	('mutations', 'Var', (20, 29))	('SDH', 'Gene', (15, 18))	('SDH', 'Gene', '6390', (107, 110))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('pituitary tumors', 'Disease', (202, 218))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('renal tumors', 'Disease', 'MESH:D007674', (144, 156))
26252	23714463	In fact, wild-type GISTs lacking somatic KIT or PDFRA mutations have been shown to be 100% SDH-deficient as measured by SDHB IHC.	('SDH-deficient', 'Disease', 'MESH:D007153', (91, 104))	('mutations', 'Var', (54, 63))	('SDHB', 'Gene', '6390', (120, 124))	('PDFRA', 'Gene', (48, 53))	('GISTs', 'Phenotype', 'HP:0100723', (19, 24))	('SDHB', 'Gene', (120, 124))	('SDH-deficient', 'Disease', (91, 104))
26255	23714463	Many recent reports have demonstrated germline SDHA mutations associated with SDH-deficient (wild-type KIT/PDFRA) GISTs, which can be detected by SDHA IHC.	('mutations', 'Var', (52, 61))	('SDH-deficient', 'Disease', 'MESH:D007153', (78, 91))	('SDH', 'Gene', (78, 81))	('associated', 'Reg', (62, 72))	('SDH', 'Gene', (47, 50))	('SDH', 'Gene', '6390', (146, 149))	('GISTs', 'Phenotype', 'HP:0100723', (114, 119))	('SDH', 'Gene', '6390', (47, 50))	('SDH', 'Gene', '6390', (78, 81))	('SDH-deficient', 'Disease', (78, 91))	('SDH', 'Gene', (146, 149))
26256	23714463	Germline SDHx mutations still account for less than half of SDH-deficient GISTs, and the search for underlying SDH-related genes continues for the majority of patients with SDH-deficient GISTs.	('SDH', 'Gene', (60, 63))	('SDH', 'Gene', (111, 114))	('GISTs', 'Phenotype', 'HP:0100723', (187, 192))	('SDH-deficient', 'Disease', 'MESH:D007153', (173, 186))	('SDH', 'Gene', '6390', (111, 114))	('SDH', 'Gene', '6390', (9, 12))	('SDH', 'Gene', '6390', (173, 176))	('SDH-deficient', 'Disease', (173, 186))	('GISTs', 'Phenotype', 'HP:0100723', (74, 79))	('SDH', 'Gene', '6390', (60, 63))	('SDH-deficient', 'Disease', (60, 73))	('SDH', 'Gene', (173, 176))	('SDHx', 'Chemical', '-', (9, 13))	('patients', 'Species', '9606', (159, 167))	('mutations', 'Var', (14, 23))	('SDH', 'Gene', (9, 12))	('SDH-deficient', 'Disease', 'MESH:D007153', (60, 73))
26257	23714463	It is now recommended that patients with SDH-deficient GISTs be referred for genetic evaluation for underlying SDHx mutations.	('SDH-deficient', 'Disease', (41, 54))	('men', 'Species', '9606', (15, 18))	('SDH-deficient', 'Disease', 'MESH:D007153', (41, 54))	('GISTs', 'Phenotype', 'HP:0100723', (55, 60))	('patients', 'Species', '9606', (27, 35))	('mutations', 'Var', (116, 125))	('SDHx', 'Gene', (111, 115))	('SDHx', 'Chemical', '-', (111, 115))
26258	23714463	If germline SDHx mutations are identified in patients with GISTs, they should be considered for biochemical and imaging surveillance due to risk for other tumors.	('SDHx', 'Gene', (12, 16))	('GISTs', 'Phenotype', 'HP:0100723', (59, 64))	('SDHx', 'Chemical', '-', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (17, 26))
26259	23714463	As familial tumors due to inherited SDHx mutations become better recognized, we will begin to learn more about the genetic, epigenetic, and metabolic alterations related to cancer risk.	('SDHx', 'Gene', (36, 40))	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('SDHx', 'Chemical', '-', (36, 40))	('cancer', 'Disease', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('familial tumors', 'Disease', 'MESH:D009386', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('familial tumors', 'Disease', (3, 18))
26267	23714463	BAP1 encodes a catalyzing enzyme that removes ubiquitin from protein substrates, and germline BAP1 mutations cause a novel cancer syndrome characterized by high incidence of benign atypical melanocytic tumors, uveal melanoma, cutaneous melanoma, malignant mesothelioma, and potentially other cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (246, 268))	('benign atypical melanocytic tumors', 'Disease', 'MESH:D009508', (174, 208))	('uveal melanoma', 'Disease', 'MESH:C536494', (210, 224))	('BAP1', 'Gene', (0, 4))	('uveal melanoma', 'Disease', (210, 224))	('BAP1', 'Gene', '8314', (94, 98))	('malignant mesothelioma', 'Disease', (246, 268))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('cancers', 'Disease', (292, 299))	('cutaneous melanoma', 'Disease', (226, 244))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (226, 244))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (246, 268))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (226, 244))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('benign atypical melanocytic tumors', 'Disease', (174, 208))	('uveal melanoma', 'Phenotype', 'HP:0007716', (210, 224))	('cause', 'Reg', (109, 114))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('cancer syndrome', 'Disease', 'MESH:D009369', (123, 138))	('BAP1', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('mutations', 'Var', (99, 108))	('cancers', 'Disease', 'MESH:D009369', (292, 299))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('cancer syndrome', 'Disease', (123, 138))	('BAP1', 'Gene', '8314', (0, 4))
26268	23714463	BAP1 mutation carriers should have regular medical examinations in order to diagnose associated malignancies at an early, more treatable stage.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('BAP1', 'Gene', (0, 4))	('malignancies', 'Disease', (96, 108))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
26269	23714463	TP53 mutations cause Li-Fraumeni syndrome with extremely high risk for sarcomas, breast cancer, brain tumors, adrenocortical carcinomas, and other tumors.	('breast cancer', 'Disease', (81, 94))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('brain tumors', 'Disease', 'MESH:D001932', (96, 108))	('brain tumors', 'Phenotype', 'HP:0030692', (96, 108))	('sarcomas', 'Disease', 'MESH:D012509', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('cause', 'Reg', (15, 20))	('sarcomas', 'Disease', (71, 79))	('Li-Fraumeni syndrome', 'Disease', (21, 41))	('TP53', 'Gene', '7157', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('brain tumors', 'Disease', (96, 108))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (21, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (110, 135))	('mutations', 'Var', (5, 14))	('adrenocortical carcinomas', 'Disease', (110, 135))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('TP53', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (110, 135))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
26271	23714463	SDH is a mitochondrial enzyme complex involved in the tricarboxylic acid cycle, and SDHx mutations (SDHA, SDHB, SDHC, SDHD, and SDHAF2) lead to increased succinate and high risk for paragangliomas, pheochromocytomas, renal cell carcinoma (RCC), gastrointestinal stromal tumors (GISTs), and other tumors.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (217, 237))	('SDH', 'Gene', '6390', (128, 131))	('GISTs', 'Phenotype', 'HP:0100723', (278, 283))	('succinate', 'MPA', (154, 163))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (198, 214))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('pheochromocytomas', 'Disease', 'MESH:D010673', (198, 215))	('SDH', 'Gene', '6390', (112, 115))	('pheochromocytomas', 'Disease', (198, 215))	('SDH', 'Gene', '6390', (0, 3))	('tumors', 'Disease', (270, 276))	('SDHx', 'Chemical', '-', (84, 88))	('paragangliomas', 'Disease', 'MESH:D010235', (182, 196))	('SDH', 'Gene', (106, 109))	('SDHC', 'Gene', '6391', (112, 116))	('paraganglioma', 'Phenotype', 'HP:0002668', (182, 195))	('SDHAF2', 'Gene', (128, 134))	('SDH', 'Gene', '6390', (118, 121))	('paragangliomas', 'Phenotype', 'HP:0002668', (182, 196))	('SDHAF2', 'Gene', '54949', (128, 134))	('SDH', 'Gene', (128, 131))	('renal cell carcinoma', 'Disease', (217, 237))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (217, 237))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (245, 276))	('SDH', 'Gene', (112, 115))	('SDH', 'Gene', '6390', (100, 103))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (245, 276))	('SDHD', 'Gene', '6392', (118, 122))	('SDH', 'Gene', (0, 3))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (54, 72))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('SDHB', 'Gene', '6390', (106, 110))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (198, 215))	('RCC', 'Disease', (239, 242))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('increased succinate', 'Phenotype', 'HP:0020149', (144, 163))	('SDH', 'Gene', '6390', (84, 87))	('SDH', 'Gene', (118, 121))	('SDHC', 'Gene', (112, 116))	('increased', 'PosReg', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('paragangliomas', 'Disease', (182, 196))	('SDHD', 'Gene', (118, 122))	('SDH', 'Gene', (100, 103))	('tumors', 'Disease', (296, 302))	('gastrointestinal stromal tumors', 'Disease', (245, 276))	('RCC', 'Disease', 'MESH:C538614', (239, 242))	('succinate', 'Chemical', 'MESH:D019802', (154, 163))	('SDHB', 'Gene', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('SDH', 'Gene', (84, 87))	('SDH', 'Gene', '6390', (106, 109))
26272	23714463	Regular biochemical screening and imaging in patients with germline SDHx mutations can detect early cancer to improve patient outcome.	('SDHx', 'Chemical', '-', (68, 72))	('SDHx', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('improve', 'PosReg', (110, 117))	('patient', 'Species', '9606', (45, 52))	('patients', 'Species', '9606', (45, 53))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patient', 'Species', '9606', (118, 125))	('mutations', 'Var', (73, 82))
26280	29403152	An investigation for TP53 gene aberrations revealed the presence of a germline point mutation in exon 4 (c.215C>G (p.Pro72Arg)).	('TP53', 'Gene', (21, 25))	('c.215C>G', 'Mutation', 'rs1042522', (105, 113))	('p.Pro72Arg', 'Mutation', 'rs1042522', (115, 125))	('c.215C>G', 'Var', (105, 113))	('TP53', 'Gene', '7157', (21, 25))
26318	29403152	Metabolites of pregnenolone (P5), progesterone (P4), 17-OHP5, 17-OHP4, cortisol, and estrogens were also elevated (Fig.	('cortisol', 'MPA', (71, 79))	('pregnenolone', 'Chemical', 'MESH:D011284', (15, 27))	('elevated', 'PosReg', (105, 113))	('Metabolites', 'MPA', (0, 11))	('estrogens', 'MPA', (85, 94))	('progesterone', 'MPA', (34, 46))	('cortisol', 'Chemical', 'MESH:D006854', (71, 79))	('17-OHP4', 'Var', (62, 69))	('17-OHP5', 'MPA', (53, 60))	('17-OHP5', 'Chemical', '-', (53, 60))	('17-OHP4', 'Chemical', '-', (62, 69))	('progesterone', 'Chemical', 'MESH:D011374', (34, 46))
26325	29403152	A heterozygous point mutation was detected in exon 4 of the TP53 gene (c.215C>G (p.Pro72Arg)) (Fig.	('c.215C>G', 'Mutation', 'rs1042522', (71, 79))	('TP53', 'Gene', '7157', (60, 64))	('p.Pro72Arg', 'Mutation', 'rs1042522', (81, 91))	('c.215C>G', 'Var', (71, 79))	('TP53', 'Gene', (60, 64))
26340	29403152	Our ACC case has another specific feature, a germline mutation in the TP53 gene, the tumor suppressor gene that encodes the p53 protein.	('tumor', 'Disease', (85, 90))	('p53', 'Gene', (124, 127))	('TP53', 'Gene', '7157', (70, 74))	('p53', 'Gene', '7157', (124, 127))	('germline mutation', 'Var', (45, 62))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('TP53', 'Gene', (70, 74))	('ACC', 'Phenotype', 'HP:0006744', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
26342	29403152	have reported the presence of germline TP53 mutations in nearly 50% of the patients, although they did not present with clinical features, such as virilization and/or feminization.	('feminization', 'Disease', (167, 179))	('patients', 'Species', '9606', (75, 83))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('virilization', 'Disease', (147, 159))	('TP53', 'Gene', (39, 43))
26343	29403152	Similarly, a 52-yr-old man with ACC with the same mutation has been reported; however, his tumor was a non-functioning ACC, and clinical features including the existence of gynecomastia have not been described.	('ACC', 'Phenotype', 'HP:0006744', (32, 35))	('man', 'Species', '9606', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('ACC', 'Phenotype', 'HP:0006744', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('gynecomastia', 'Disease', 'MESH:D006177', (173, 185))	('gynecomastia', 'Disease', (173, 185))	('tumor', 'Disease', (91, 96))	('gynecomastia', 'Phenotype', 'HP:0000771', (173, 185))	('mutation', 'Var', (50, 58))
26344	29403152	Therefore, our case might be the first reported case with feminizing ACC accompanied by a TP53 mutation.	('ACC', 'Phenotype', 'HP:0006744', (69, 72))	('accompanied', 'Reg', (73, 84))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('mutation', 'Var', (95, 103))
26345	29403152	investigated the steroid metabolic pathway in ACC tissue obtained from a Brazilian boy with virilization and detected a TP53 gene mutation: p.Arg337His, common in South Brazil.	('investigated', 'Reg', (0, 12))	('ACC', 'Phenotype', 'HP:0006744', (46, 49))	('steroid', 'Chemical', 'MESH:D013256', (17, 24))	('steroid metabolic pathway', 'Enzyme', (17, 42))	('p.Arg337His', 'Var', (140, 151))	('p.Arg337His', 'Mutation', 'rs121912664', (140, 151))	('boy', 'Species', '9606', (83, 86))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
26347	29403152	This report confirms that androgen synthesis in ACC with TP53 mutation is regulated genetically to some extent.	('mutation', 'Var', (62, 70))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('ACC', 'Phenotype', 'HP:0006744', (48, 51))	('androgen synthesis', 'MPA', (26, 44))
26348	29403152	TP53 gene mutation in our case could be discussed in association with aromatase overexpression.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('aromatase', 'Gene', '1588', (70, 79))	('mutation', 'Var', (10, 18))	('aromatase', 'Gene', (70, 79))
26352	29403152	On the other hand, in breast tissue, mutations in the TP53 response elements increase aromatase activity, although normal p53 protein regulates the aromatase activity negatively via the connecting aromatase promoter II.	('aromatase', 'Gene', (86, 95))	('activity', 'MPA', (158, 166))	('aromatase', 'Gene', '1588', (148, 157))	('aromatase', 'Gene', (197, 206))	('aromatase', 'Gene', '1588', (86, 95))	('p53', 'Gene', '7157', (122, 125))	('aromatase', 'Gene', '1588', (197, 206))	('mutations', 'Var', (37, 46))	('TP53', 'Gene', '7157', (54, 58))	('increase', 'PosReg', (77, 85))	('TP53', 'Gene', (54, 58))	('aromatase', 'Gene', (148, 157))	('p53', 'Gene', (122, 125))
26353	29403152	Our case, together with these studies, could indicate that the TP53 gene mutation is associated with aromatase hyperactivity in ACC tissue and contributes to increase estrogen synthesis.	('ACC', 'Phenotype', 'HP:0006744', (128, 131))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('hyperactivity', 'Phenotype', 'HP:0000752', (111, 124))	('aromatase hyperactivity', 'Disease', (101, 124))	('aromatase hyperactivity', 'Disease', 'MESH:C537436', (101, 124))	('mutation', 'Var', (73, 81))	('increase', 'PosReg', (158, 166))	('estrogen synthesis', 'MPA', (167, 185))
26354	29403152	Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease associated with changes in the tumor suppressor gene, TP53, located on chromosome 17p.	('changes', 'Var', (80, 87))	('associated', 'Reg', (64, 74))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('autosomal dominant disease', 'Disease', (37, 63))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (37, 63))	('tumor', 'Disease', (95, 100))
26359	29403152	Although our patient was already diagnosed with ACC, there is a need for careful and regular follow-up, in accordance with the course of childhood LFS, for earlier detection of ACC relapse and other malignant diseases because of the presence of a higher Weiss's score and a TP53 gene mutation.	("Weiss's score", 'CPA', (254, 267))	('mutation', 'Var', (284, 292))	('ACC', 'Phenotype', 'HP:0006744', (177, 180))	('patient', 'Species', '9606', (13, 20))	('ACC relapse', 'Disease', (177, 188))	('higher', 'PosReg', (247, 253))	('TP53', 'Gene', '7157', (274, 278))	('malignant diseases', 'Disease', 'MESH:D009369', (199, 217))	('malignant diseases', 'Disease', (199, 217))	('TP53', 'Gene', (274, 278))	('ACC', 'Phenotype', 'HP:0006744', (48, 51))
26370	27940298	Over recent decades, several groups have demonstrated that dysregulation of the signaling pathways involved in organogenesis and homeostasis of the adrenal cortex plays a central role in human adrenocortical disease.	('adrenocortical disease', 'Disease', (193, 215))	('dysregulation', 'Var', (59, 72))	('adrenocortical disease', 'Disease', 'MESH:D018268', (193, 215))	('signaling pathways', 'Pathway', (80, 98))	('human', 'Species', '9606', (187, 192))	('rat', 'Species', '10116', (48, 51))
26391	27940298	Shh binding relieves Ptch1-mediated inhibition of the signal transducer smoothened homolog (Smo), thereby activating downstream signaling through the zinc finger glioma-associated oncogene family (Gli) of transcription factors.	('zinc finger glioma-associated oncogene family (Gli', 'Gene', (150, 200))	('activating', 'PosReg', (106, 116))	('downstream signaling', 'MPA', (117, 137))	('relieves', 'NegReg', (12, 20))	('Smo', 'Gene', (92, 95))	('zinc finger glioma-associated oncogene family (Gli)', 'Gene', '2735', (150, 201))	('Ptch1', 'Gene', '5727', (21, 26))	('inhibition', 'MPA', (36, 46))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('binding', 'Var', (4, 11))	('Ptch1', 'Gene', (21, 26))	('Smo', 'Gene', '6608', (92, 95))
26394	27940298	Moreover, defects in HH signaling have also been implicated in human diseases.	('human', 'Species', '9606', (63, 68))	('implicated', 'Reg', (49, 59))	('defects', 'Var', (10, 17))
26395	27940298	Pallister-Hall syndrome, a congenital syndrome caused by truncation mutations of GLI3, is associated with varying degrees of adrenal failure.	('Pallister-Hall syndrome', 'Disease', 'MESH:D054975', (0, 23))	('congenital syndrome', 'Disease', (27, 46))	('adrenal failure', 'Phenotype', 'HP:0000846', (125, 140))	('caused by', 'Reg', (47, 56))	('truncation mutations', 'Var', (57, 77))	('adrenal failure', 'Disease', 'MESH:D000312', (125, 140))	('adrenal failure', 'Disease', (125, 140))	('congenital syndrome', 'Disease', 'MESH:D000013', (27, 46))	('GLI3', 'Gene', '2737', (81, 85))	('Pallister-Hall syndrome', 'Disease', (0, 23))	('GLI3', 'Gene', (81, 85))
26396	27940298	Although recently debated, adrenal agenesis has also been reported in a mouse model of Pallister-Hall syndrome carrying a Gli3 mutation providing further support for a major role of Shh signaling in adrenal stem and progenitor cell biology and in homeostatic adrenocortical maintenance.	('Pallister-Hall syndrome', 'Disease', (87, 110))	('adrenal agenesis', 'Phenotype', 'HP:0011743', (27, 43))	('mutation', 'Var', (127, 135))	('mouse', 'Species', '10090', (72, 77))	('homeostatic adrenocortical', 'Disease', 'MESH:D018268', (247, 273))	('homeostatic adrenocortical', 'Disease', (247, 273))	('Pallister-Hall syndrome', 'Disease', 'MESH:D054975', (87, 110))	('adrenal', 'Disease', (27, 34))	('adrenocortical maintenance', 'Phenotype', 'HP:0008207', (259, 285))	('Gli3', 'Gene', (122, 126))
26398	27940298	While molecular data from the TCGA ACC cohort (https://gdc-portal.nci.nih.gov/projects/TCGA-ACC) do not support a global role of SHH signaling pathway in ACC, increased expression of several HH-associated genes has been observed in a subset of samples with ZNRF3 loss-of-function mutations (see Wnt section, below) (AM Lerario.	('mutations', 'Var', (280, 289))	('SHH', 'Gene', '6469', (129, 132))	('ACC', 'Phenotype', 'HP:0006744', (92, 95))	('ZNRF3', 'Gene', '84133', (257, 262))	('ACC', 'Phenotype', 'HP:0006744', (154, 157))	('ZNRF3', 'Gene', (257, 262))	('expression', 'MPA', (169, 179))	('SHH', 'Gene', (129, 132))	('loss-of-function', 'NegReg', (263, 279))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))
26400	27940298	Moreover, treatment of H295R human ACC cells with the SMO inhibitor cyclopamine inhibits cell proliferation,; furthermore, cyclopamine treatment of H295A human ACC cells diminishes viability and leads to a decrease in beta-catenin expression and nuclear localization.	('human', 'Species', '9606', (154, 159))	('beta-catenin expression', 'MPA', (218, 241))	('viability', 'CPA', (181, 190))	('cell proliferation', 'CPA', (89, 107))	('rat', 'Species', '10116', (101, 104))	('cyclopamine', 'Var', (123, 134))	('cyclopamine', 'Chemical', 'MESH:C000541', (68, 79))	('cyclopamine', 'Chemical', 'MESH:C000541', (123, 134))	('decrease', 'NegReg', (206, 214))	('nuclear localization', 'MPA', (246, 266))	('ACC', 'Phenotype', 'HP:0006744', (160, 163))	('inhibits', 'NegReg', (80, 88))	('SMO', 'Gene', '6608', (54, 57))	('SMO', 'Gene', (54, 57))	('human', 'Species', '9606', (29, 34))	('diminishes', 'NegReg', (170, 180))	('H295A', 'CellLine', 'CVCL:0457', (148, 153))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))
26408	27940298	Canonical Wnt signaling is extensively implicated in homeostatic adrenocortical function, and deregulation is involved in both adrenal adenomas and cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (127, 143))	('homeostatic adrenocortical function', 'Disease', 'MESH:D018268', (53, 88))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (127, 142))	('adrenal adenomas', 'Disease', 'MESH:D018246', (127, 143))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('deregulation', 'Var', (94, 106))	('involved', 'Reg', (110, 118))	('homeostatic adrenocortical function', 'Disease', (53, 88))	('adrenal adenomas', 'Disease', (127, 143))
26414	27940298	A connection between Wnt pathway deregulation and adrenal disease was first established based on observations made on familial adenomatous polyposis (FAP) families.	('FAP', 'Disease', 'MESH:C567782', (150, 153))	('adrenal disease', 'Phenotype', 'HP:0000834', (50, 65))	('Wnt pathway', 'Pathway', (21, 32))	('adrenal disease', 'Disease', 'MESH:D000309', (50, 65))	('adrenal disease', 'Disease', (50, 65))	('FAP', 'Disease', (150, 153))	('familial adenomatous polyposis', 'Disease', (118, 148))	('deregulation', 'Var', (33, 45))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (118, 148))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (127, 148))
26415	27940298	This autosomal dominant inherited disorder is caused by inactivating mutations in APC, a gene that encodes a structural protein of the destruction complex.	('caused by', 'Reg', (46, 55))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('APC', 'Disease', (82, 85))	('inactivating mutations', 'Var', (56, 78))	('inherited disorder', 'Disease', 'MESH:D030342', (24, 42))	('inherited disorder', 'Disease', (24, 42))
26418	27940298	In fact, later studies have shown that although APC inactivating mutations are rare in sporadic adrenocortical tumors (ACTs), CTNNB1 (beta-catenin) activating mutations are fairly common among both ACAs and ACCs .	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutations', 'Var', (159, 168))	('CTNNB1', 'Gene', (126, 132))	('ACC', 'Phenotype', 'HP:0006744', (207, 210))	('sporadic adrenocortical tumors', 'Disease', (87, 117))	('ACCs', 'Phenotype', 'HP:0006744', (207, 211))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('APC', 'Disease', 'MESH:D011125', (48, 51))	('ACAs', 'Phenotype', 'HP:0008256', (198, 202))	('sporadic adrenocortical tumors', 'Disease', 'MESH:D018268', (87, 117))	('CTNNB1', 'Gene', '1499', (126, 132))	('activating', 'PosReg', (148, 158))	('APC', 'Disease', (48, 51))
26419	27940298	Notably, activating mutations in CTNNB1 alter protein phosphorylation, preventing subsequent degradation, and potentiating nuclear transcriptional activity.	('nuclear transcriptional activity', 'MPA', (123, 155))	('alter', 'Reg', (40, 45))	('degradation', 'MPA', (93, 104))	('CTNNB1', 'Gene', '1499', (33, 39))	('protein phosphorylation', 'MPA', (46, 69))	('preventing', 'NegReg', (71, 81))	('CTNNB1', 'Gene', (33, 39))	('potentiating', 'PosReg', (110, 122))	('mutations', 'Var', (20, 29))
26420	27940298	Previous studies have shown that activating CTNNB1 mutations (affecting the phosphorylation residues in exon 3) occur in over 20% of both ACA and ACC .	('ACA', 'Disease', (138, 141))	('mutations', 'Var', (51, 60))	('ACC', 'Phenotype', 'HP:0006744', (146, 149))	('CTNNB1', 'Gene', (44, 50))	('affecting', 'Reg', (62, 71))	('CTNNB1', 'Gene', '1499', (44, 50))	('activating', 'PosReg', (33, 43))
26421	27940298	More recently, recurring homozygous deletions or inactivating mutations in ZNRF3 were identified in approximately 20% of ACCs by three different studies .	('ZNRF3', 'Gene', '84133', (75, 80))	('ACC', 'Phenotype', 'HP:0006744', (121, 124))	('identified', 'Reg', (86, 96))	('inactivating mutations', 'Var', (49, 71))	('ZNRF3', 'Gene', (75, 80))	('ACCs', 'Phenotype', 'HP:0006744', (121, 125))	('ACCs', 'Disease', (121, 125))
26422	27940298	Interestingly, ZNRF3 alterations are mutually exclusive with CTNNB1 and APC mutations, consistent with an activating effect of ZNRF3 loss on canonical Wnt signaling.	('ZNRF3', 'Gene', (15, 20))	('CTNNB1', 'Gene', (61, 67))	('canonical', 'MPA', (141, 150))	('mutations', 'Var', (76, 85))	('activating', 'PosReg', (106, 116))	('ZNRF3', 'Gene', '84133', (127, 132))	('loss', 'NegReg', (133, 137))	('CTNNB1', 'Gene', '1499', (61, 67))	('ZNRF3', 'Gene', (127, 132))	('rat', 'Species', '10116', (25, 28))	('APC', 'Disease', 'MESH:D011125', (72, 75))	('ZNRF3', 'Gene', '84133', (15, 20))	('alterations', 'Var', (21, 32))	('APC', 'Disease', (72, 75))
26423	27940298	Taken together, mutations affecting Wnt pathway components (ZNRF3, CTNNB1, and APC), occur in approximately 40% of ACCs, and represent the most frequently altered pathway.	('ACC', 'Phenotype', 'HP:0006744', (115, 118))	('altered', 'Reg', (155, 162))	('ZNRF3', 'Gene', '84133', (60, 65))	('APC', 'Disease', 'MESH:D011125', (79, 82))	('mutations', 'Var', (16, 25))	('CTNNB1', 'Gene', '1499', (67, 73))	('ZNRF3', 'Gene', (60, 65))	('ACCs', 'Phenotype', 'HP:0006744', (115, 119))	('APC', 'Disease', (79, 82))	('CTNNB1', 'Gene', (67, 73))
26424	27940298	The landscape of activating Wnt/beta-catenin mutations in pediatric ACT also reveals frequent mutations in beta-catenin, occurring in approximately 20% of tumors.	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mutations', 'Var', (94, 103))	('activating', 'PosReg', (17, 27))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('beta-catenin', 'Protein', (107, 119))
26425	27940298	ZNRF3 deletions and mutations, while observed in adult ACC, are not seen in pediatric ACC.	('ACC', 'Phenotype', 'HP:0006744', (55, 58))	('ZNRF3', 'Gene', '84133', (0, 5))	('deletions', 'Var', (6, 15))	('ZNRF3', 'Gene', (0, 5))	('ACC', 'Phenotype', 'HP:0006744', (86, 89))	('mutations', 'Var', (20, 29))
26427	27940298	A study of APAs shows Wnt/beta-catenin signaling activation charac-terized by a lack of activating beta-catenin mutations but down-regulation of SFRP2, a negative Wnt regulator .	('beta-catenin', 'Protein', (99, 111))	('mutations', 'Var', (112, 121))	('SFRP2', 'Gene', '6423', (145, 150))	('SFRP2', 'Gene', (145, 150))	('activating', 'MPA', (88, 98))	('down-regulation', 'NegReg', (126, 141))
26428	27940298	Though Wnt/beta-catenin signaling has been linked to aldosterone production in APAs and adrenal homeostasis, most ACAs with Wnt/beta-catenin pathway mutations are non-functioning.	('mutations', 'Var', (149, 158))	('aldosterone production', 'MPA', (53, 75))	('adrenal homeostasis', 'Disease', 'MESH:D000312', (88, 107))	('ACAs', 'Phenotype', 'HP:0008256', (114, 118))	('aldosterone production', 'Phenotype', 'HP:0000859', (53, 75))	('adrenal homeostasis', 'Disease', (88, 107))	('aldosterone', 'Chemical', 'MESH:D000450', (53, 64))
26429	27940298	Activating beta-catenin mutations were also found in macronodules (nodules >1 cm) but not micronodules (nodules <1 cm) formed in patients with primary pigmented nodular adrenocortical disease (PPNAD), suggesting that elevated Wnt/beta-catenin signaling participates primarily in the increased growth and not the increased steroidogenesis in this disorder.	('Activating', 'PosReg', (0, 10))	('beta-catenin', 'Gene', (11, 23))	('patients', 'Species', '9606', (129, 137))	('primary pigmented nodular adrenocortical disease', 'Disease', (143, 191))	('PPNAD', 'Chemical', '-', (193, 198))	('mutations', 'Var', (24, 33))	('primary pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (143, 191))
26431	27940298	H295R human ACC cells harbor an activating beta-catenin mutation.	('human', 'Species', '9606', (6, 11))	('ACC', 'Phenotype', 'HP:0006744', (12, 15))	('beta-catenin', 'Protein', (43, 55))	('mutation', 'Var', (56, 64))	('activating', 'PosReg', (32, 42))
26433	27940298	Small molecule antagonism of the TCF/beta-catenin complex also results in H295R growth inhibition.	('TCF', 'Gene', (33, 36))	('TCF', 'Gene', '3172', (33, 36))	('antagonism', 'Var', (15, 25))	('H295R growth inhibition', 'CPA', (74, 97))
26441	27940298	The data indicate a causative role for beta-catenin in adrenal tumorigenesis, though the broad range of phenotypes seen supports a need for additional mutations or epigenetic alterations for carcinoma development.	('tumor', 'Disease', (63, 68))	('carcinoma', 'Disease', 'MESH:D002277', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('beta-catenin', 'Protein', (39, 51))	('adrenal', 'Disease', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('epigenetic alterations', 'Var', (164, 186))	('causative role', 'Reg', (20, 34))	('carcinoma', 'Disease', (191, 200))	('rat', 'Species', '10116', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
26442	27940298	The prevalence and importance of Wnt pathway alterations in adrenal diseases suggest a prominent role of this pathway in development and homeostasis.	('Wnt pathway', 'Pathway', (33, 44))	('alterations', 'Var', (45, 56))	('adrenal disease', 'Phenotype', 'HP:0000834', (60, 75))	('adrenal diseases', 'Disease', (60, 76))	('adrenal diseases', 'Disease', 'MESH:D000309', (60, 76))	('rat', 'Species', '10116', (49, 52))
26448	27940298	In mouse adrenal development, when beta-catenin expression is lost in all steroidogenic cells, adrenals become aplastic are entirely absent by embryonic day (E) 18.5. beta-catenin inactivation in a subset of steroidogenic cells in the adult mouse adrenal cortex causes decreased cortical proliferation, and progressive cortical thinning and disorganization.	('disorganization', 'CPA', (341, 356))	('mouse', 'Species', '10090', (3, 8))	('mouse', 'Species', '10090', (241, 246))	('cortical proliferation', 'CPA', (279, 301))	('beta-catenin', 'Protein', (167, 179))	('decreased', 'NegReg', (269, 278))	('rat', 'Species', '10116', (295, 298))	('inactivation', 'Var', (180, 192))
26456	27940298	In human patients, a WNT4 homozygous loss-of-function mutation presents with severe developmental defects including adrenal hypoplasia.	('mutation', 'Var', (54, 62))	('loss-of-function', 'NegReg', (37, 53))	('patients', 'Species', '9606', (9, 17))	('adrenal hypoplasia', 'Disease', (116, 134))	('human', 'Species', '9606', (3, 8))	('developmental defects', 'Disease', (84, 105))	('WNT4', 'Gene', (21, 25))	('developmental defects', 'Disease', 'MESH:D003147', (84, 105))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (116, 134))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (116, 134))
26457	27940298	The marked increase in severity of the human WNT4 mutation compared to that in mice, which exhibit no striking difference in volume or morphology of the adrenal glands at birth, suggests that mouse models may be inadequate to reflect the actions of specific human Wnt ligands.	('increase', 'PosReg', (11, 19))	('mouse', 'Species', '10090', (192, 197))	('human', 'Species', '9606', (258, 263))	('mice', 'Species', '10090', (79, 83))	('WNT4', 'Gene', (45, 49))	('human', 'Species', '9606', (39, 44))	('mutation', 'Var', (50, 58))	('severity', 'MPA', (23, 31))
26460	27940298	Rspo3 appears to be especially crucial: it is expressed in Gli1-expressing stem/progenitor cells in the mouse adrenal capsule from E14.5 onwards, and knockout affects both development of the adrenal cortex and the adult adrenal.	('development of the adrenal cortex', 'CPA', (172, 205))	('knockout', 'Var', (150, 158))	('mouse', 'Species', '10090', (104, 109))	('affects', 'Reg', (159, 166))
26461	27940298	Rspo1 knockout on the other hand causes no obvious adrenal phenotype in the mouse.	('Rspo1', 'Gene', (0, 5))	('mouse', 'Species', '10090', (76, 81))	('Rspo1', 'Gene', '192199', (0, 5))	('knockout', 'Var', (6, 14))	('adrenal phenotype', 'MPA', (51, 68))
26471	27940298	Studies in mice reveal that FGF signaling is essential for adrenal development; knockout of Fgfr2 in mice results in embryonic adrenal hypoplasia or agenesis.	('knockout', 'Var', (80, 88))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (127, 145))	('embryonic adrenal hypoplasia', 'Disease', (117, 145))	('mice', 'Species', '10090', (11, 15))	('embryonic adrenal hypoplasia', 'Phenotype', 'HP:0008244', (117, 145))	('mice', 'Species', '10090', (101, 105))	('embryonic adrenal hypoplasia', 'Disease', 'MESH:D000312', (117, 145))	('Fgfr2', 'Gene', (92, 97))	('results in', 'Reg', (106, 116))	('agenesis', 'CPA', (149, 157))	('hypoplasia or agenesis', 'Phenotype', 'HP:0009115', (135, 157))
26473	27940298	Embryonically, loss of Fgfr2 IIIb causes reduced cortical proliferation  and additional studies support that FGF signaling is involved in adrenal growth in adulthood.	('reduced', 'NegReg', (41, 48))	('cortical proliferation', 'CPA', (49, 71))	('Fgfr2', 'Gene', (23, 28))	('loss', 'Var', (15, 19))	('Embryonically', 'CellLine', 'CVCL:M564', (0, 13))	('rat', 'Species', '10116', (65, 68))
26487	27940298	Mutations in the cAMP-PKA signaling pathway play etiologic roles in several endocrine tumors and syndromes.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cAMP-PKA signaling pathway', 'Pathway', (17, 43))	('endocrine tumors', 'Disease', 'MESH:D004701', (76, 92))	('endocrine tumors', 'Disease', (76, 92))	('cAMP', 'Chemical', 'MESH:D000242', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Mutations', 'Var', (0, 9))	('etiologic', 'Reg', (49, 58))	('syndromes', 'Disease', (97, 106))
26488	27940298	Somatic mutations in the Guanine Nucleotide Binding Protein Alpha Stimulating 1 (GNAS1) gene, which encodes for the stimulatory G protein subunit Gsalpha, result in constitutive stimulation of adenylate cyclase and subsequent PKA activation.	('PKA', 'Enzyme', (226, 229))	('Guanine Nucleotide Binding Protein Alpha Stimulating 1', 'Gene', '2778', (25, 79))	('Gsalpha', 'Gene', '2778', (146, 153))	('stimulation', 'PosReg', (178, 189))	('GNAS1', 'Gene', '2778', (81, 86))	('mutations', 'Var', (8, 17))	('Gsalpha', 'Gene', (146, 153))	('activation', 'PosReg', (230, 240))	('GNAS1', 'Gene', (81, 86))	('adenylate cyclase', 'MPA', (193, 210))
26489	27940298	Post-zygotic mosaicism for activating GNAS1 mutations are the cause of the McCune-Albright Syndrome, a disease characterized by cafe-au-lait spots, multifocal bone fibrous dysplasia and several endocrine hyperfunction syndromes, including cortisol-producing bilateral adrenocortical hyperplasia.	('cafe-au-lait spots', 'Phenotype', 'HP:0000957', (128, 146))	('a disease', 'Disease', 'MESH:D004194', (101, 110))	('GNAS1', 'Gene', (38, 43))	('cortisol', 'Chemical', 'MESH:D006854', (239, 247))	('GNAS1', 'Gene', '2778', (38, 43))	('activating', 'PosReg', (27, 37))	('McCune-Albright Syndrome', 'Disease', (75, 99))	('multifocal bone fibrous dysplasia', 'Disease', 'None', (148, 181))	('a disease', 'Disease', (101, 110))	('cause', 'Reg', (62, 67))	('McCune-Albright Syndrome', 'Disease', 'MESH:D005357', (75, 99))	('mutations', 'Var', (44, 53))	('bilateral adrenocortical hyperplasia', 'Disease', (258, 294))	('bilateral adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (258, 294))	('endocrine hyperfunction syndromes', 'Disease', 'MESH:D000308', (194, 227))	('multifocal bone fibrous dysplasia', 'Disease', (148, 181))	('endocrine hyperfunction syndromes', 'Disease', (194, 227))
26490	27940298	In addition, somatic activating GNAS1 mutations have been described in isolated ACTH-independent macronodular adrenal hyperplasia (AIMAH), also renamed as primary macronodular hyperplasia (PMAH), and cortisol producing adenomas.	('primary macronodular hyperplasia', 'Disease', (155, 187))	('described', 'Reg', (58, 67))	('macronodular adrenal hyperplasia', 'Disease', (97, 129))	('primary macronodular hyperplasia', 'Disease', 'MESH:C565662', (155, 187))	('cortisol', 'Chemical', 'MESH:D006854', (200, 208))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (97, 129))	('activating', 'PosReg', (21, 31))	('GNAS1', 'Gene', '2778', (32, 37))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (110, 129))	('GNAS1', 'Gene', (32, 37))	('adenomas', 'Disease', 'MESH:D000236', (219, 227))	('mutations', 'Var', (38, 47))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (97, 129))	('adenomas', 'Disease', (219, 227))
26491	27940298	More commonly, mutations in both regulatory and catalytic PKA subunits are observed in both familial and sporadic cortisol-producing adrenocortical diseases.	('adrenocortical diseases', 'Phenotype', 'HP:0008207', (133, 156))	('mutations', 'Var', (15, 24))	('observed', 'Reg', (75, 83))	('adrenocortical diseases', 'Disease', (133, 156))	('adrenocortical diseases', 'Disease', 'MESH:D018268', (133, 156))	('cortisol', 'Chemical', 'MESH:D006854', (114, 122))	('familial', 'Disease', (92, 100))
26492	27940298	10% of primary pigmented nodular adrenocortical disease (PPNAD) cases carry inactivating mutations of the PRKAR1A gene, which encodes for the PKA regulatory subunit Ialpha.	('primary pigmented nodular adrenocortical disease', 'Disease', (7, 55))	('PPNAD', 'Chemical', '-', (57, 62))	('inactivating mutations', 'Var', (76, 98))	('PRKAR1A', 'Gene', (106, 113))	('primary pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (7, 55))
26496	27940298	Inactivation of PRKAR1A in vitro promotes PKA activity and cAMP production.	('PRKAR1A', 'Gene', (16, 23))	('promotes', 'PosReg', (33, 41))	('cAMP', 'Chemical', 'MESH:D000242', (59, 63))	('cAMP production', 'CPA', (59, 74))	('Inactivation', 'Var', (0, 12))	('PKA activity', 'CPA', (42, 54))
26501	27940298	However, in mice with constitutively active beta-catenin, loss of PKA catalytic unit Prkaca accelerates tumorigenesis.	('Prkaca', 'Gene', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Prkaca', 'Gene', '5566', (85, 91))	('accelerates', 'PosReg', (92, 103))	('loss', 'Var', (58, 62))	('tumor', 'Disease', (104, 109))	('rat', 'Species', '10116', (98, 101))	('mice', 'Species', '10090', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
26504	27940298	Moreover, somatic mutations of the beta-catenin gene CTNNB1 have been found in a subset of PPNAD macronodules, consistent with cooperatively of these two signaling pathways in neoplastic adrenocortical growth.	('rat', 'Species', '10116', (132, 135))	('PPNAD', 'Chemical', '-', (91, 96))	('CTNNB1', 'Gene', '1499', (53, 59))	('neoplastic adrenocortical growth', 'Disease', (176, 208))	('neoplastic adrenocortical growth', 'Disease', 'MESH:D018268', (176, 208))	('CTNNB1', 'Gene', (53, 59))	('found', 'Reg', (70, 75))	('mutations', 'Var', (18, 27))
26506	27940298	In fact, a recent molecular profiling study has identified PRKAR1A inactivating somatic mutations in a significant proportion of ACCs, and some of these ACCs also harbor alterations in Wnt/beta-catenin signaling.	('ACCs', 'Disease', (129, 133))	('inactivating', 'NegReg', (67, 79))	('mutations', 'Var', (88, 97))	('alterations', 'Reg', (170, 181))	('ACC', 'Phenotype', 'HP:0006744', (153, 156))	('ACC', 'Phenotype', 'HP:0006744', (129, 132))	('ACCs', 'Phenotype', 'HP:0006744', (153, 157))	('rat', 'Species', '10116', (174, 177))	('PRKAR1A', 'Gene', (59, 66))	('ACCs', 'Phenotype', 'HP:0006744', (129, 133))	('Wnt/beta-catenin signaling', 'MPA', (185, 211))
26507	27940298	In addition to PRKAR1A mutations in PPNADs, mutations in other regulators of the PKA signaling pathway have been found to be associated with various adrenocortical neoplasms.	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (149, 173))	('PPNAD', 'Chemical', '-', (36, 41))	('associated', 'Reg', (125, 135))	('adrenocortical neoplasms', 'Disease', (149, 173))	('neoplasms', 'Phenotype', 'HP:0002664', (164, 173))	('mutations', 'Var', (44, 53))	('PPNADs', 'Gene', (36, 42))
26508	27940298	PRKAR2B protein is conspicuously absent in 50% of cortisol producing adenoma (CPA) samples analyzed by Western blot, despite the absence of genetic mutations in the PRKAR2B gene, perhaps due to protein degradation.	('mutations', 'Var', (148, 157))	('absence', 'NegReg', (129, 136))	('PRKAR2B', 'Gene', (0, 7))	('protein', 'Protein', (8, 15))	('PRKAR2B', 'Gene', (165, 172))	('adenoma', 'Disease', 'MESH:D000236', (69, 76))	('PRKAR2B', 'Gene', '5577', (0, 7))	('PRKAR2B', 'Gene', '5577', (165, 172))	('absent', 'NegReg', (33, 39))	('adenoma', 'Disease', (69, 76))	('CPA', 'Chemical', '-', (78, 81))	('cortisol', 'Chemical', 'MESH:D006854', (50, 58))
26509	27940298	Moreover, abnormal regulation of the PKA pathway has been associated with inactivating mutations in PDE11A and PDE8B, two major regulators of intracellular cAMP levels in the adrenal cortex.	('PKA pathway', 'Pathway', (37, 48))	('associated', 'Reg', (58, 68))	('abnormal', 'Reg', (10, 18))	('PDE11A', 'Gene', (100, 106))	('PDE8B', 'Gene', (111, 116))	('regulation', 'MPA', (19, 29))	('inactivating mutations', 'Var', (74, 96))	('PDE11A', 'Gene', '50940', (100, 106))	('PDE8B', 'Gene', '8622', (111, 116))	('cAMP', 'Chemical', 'MESH:D000242', (156, 160))
26512	27940298	More recently, somatic activating mutations in PRKACA (the most highly expressed catalytic PKA isoform in the human adrenal) have been observed in four different CPA cohorts.	('PRKACA', 'Gene', '5566', (47, 53))	('CPA', 'Chemical', '-', (162, 165))	('PRKACA', 'Gene', (47, 53))	('human', 'Species', '9606', (110, 115))	('mutations', 'Var', (34, 43))	('activating', 'PosReg', (23, 33))
26514	27940298	After the identification of the somatic PRKACA hotspot mutations in CPAs, germline amplifications in the catalytic subunits of PKA have been described in patients with cortisol-producing hyperplasias and adenomas.	('PRKACA', 'Gene', (40, 46))	('CPA', 'Chemical', '-', (68, 71))	('adenomas', 'Disease', 'MESH:D000236', (204, 212))	('hyperplasias', 'Disease', (187, 199))	('mutations', 'Var', (55, 64))	('adenomas', 'Disease', (204, 212))	('PRKACA', 'Gene', '5566', (40, 46))	('patients', 'Species', '9606', (154, 162))	('hyperplasias', 'Disease', 'MESH:D006965', (187, 199))	('cortisol', 'Chemical', 'MESH:D006854', (168, 176))	('CPAs', 'Gene', (68, 72))
26517	27940298	In addition to alterations in core constituents of the PKA pathway, molecular defects in upstream genes can also induce abnormal activation of the pathway.	('PKA pathway', 'Pathway', (55, 66))	('rat', 'Species', '10116', (19, 22))	('molecular defects', 'Var', (68, 85))	('activation', 'PosReg', (129, 139))
26518	27940298	In contrast to activating mutations in the TSH receptor, which are a common cause of Plummer syndrome, activating mutations of the MC2R have been rarely found in ACTH-independent adrenal Cushing syndrome.	('Cushing syndrome', 'Phenotype', 'HP:0003118', (187, 203))	('Plummer syndrome', 'Disease', 'MESH:D011004', (85, 101))	('found', 'Reg', (153, 158))	('mutations', 'Var', (114, 123))	('MC2R', 'Gene', (131, 135))	('adrenal Cushing syndrome', 'Disease', (179, 203))	('TSH receptor', 'Gene', '7253', (43, 55))	('Plummer syndrome', 'Disease', (85, 101))	('TSH receptor', 'Gene', (43, 55))	('MC2R', 'Gene', '4158', (131, 135))	('adrenal Cushing syndrome', 'Disease', 'MESH:D003480', (179, 203))
26519	27940298	On the other hand, ectopic expression of different classes of GPCRs (termed illicit receptors) are frequently described in bilateral macronodular adrenal hyperplasia (BMAH) and are thought to play a role in the abnormal activation of the PKA pathway.	('bilateral macronodular adrenal hyperplasia', 'Disease', (123, 165))	('GPCR', 'Gene', '151', (62, 66))	('ectopic expression', 'Var', (19, 37))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (146, 165))	('described', 'Reg', (110, 119))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (133, 165))	('PKA pathway', 'Pathway', (238, 249))	('bilateral macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (123, 165))	('GPCR', 'Gene', (62, 66))
26521	27940298	In summary, increased activation of the PKA pathway by several different molecular defects leads to different forms of adrenocortical hormonal hyperactivity and abnormal growth, highlighting the central role of the cAMP/PKA pathway in steroidogenesis, homeostatic maintenance, and pathologic proliferation.	('defects', 'Var', (83, 90))	('cAMP', 'Chemical', 'MESH:D000242', (215, 219))	('activation', 'PosReg', (22, 32))	('adrenocortical hormonal hyperactivity', 'Disease', 'MESH:D018268', (119, 156))	('abnormal growth', 'CPA', (161, 176))	('hyperactivity', 'Phenotype', 'HP:0000752', (143, 156))	('abnormal growth', 'Phenotype', 'HP:0001507', (161, 176))	('adrenocortical hormonal hyperactivity', 'Disease', (119, 156))	('PKA pathway', 'Pathway', (40, 51))	('rat', 'Species', '10116', (299, 302))
26522	27940298	Most vertebrate chromosomes encode repetitive nucleotide sequences at their ends that facilitate chromosomal stability, known as telomeres.	('facilitate', 'PosReg', (86, 96))	('repetitive nucleotide sequences', 'Var', (35, 66))	('chromosomal stability', 'CPA', (97, 118))	('rat', 'Species', '10116', (11, 14))
26529	27940298	Telomere shortening and potential dysfunction have also been observed in patients with Li-Fraumeni syndrome, a hereditary genetic condition most commonly caused by mutations of the TP53 gene, and characterized by predisposition to several cancers, included ACC.	('Telomere shortening', 'Phenotype', 'HP:0031413', (0, 19))	('TP53', 'Gene', (181, 185))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (87, 107))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('cancers', 'Disease', (239, 246))	('Li-Fraumeni syndrome', 'Disease', (87, 107))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('Telomere', 'MPA', (0, 8))	('observed', 'Reg', (61, 69))	('patients', 'Species', '9606', (73, 81))	('caused by', 'Reg', (154, 163))	('ACC', 'Phenotype', 'HP:0006744', (257, 260))	('mutations', 'Var', (164, 173))	('TP53', 'Gene', '7157', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
26530	27940298	Patients carrying TP53 mutations and associated malignancies have shorter telomeres compared to carriers with no cancer , consistent with an association between telomere shortening and the development of malignancies.	('malignancies', 'Disease', (204, 216))	('TP53', 'Gene', '7157', (18, 22))	('shorter', 'NegReg', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('telomeres', 'MPA', (74, 83))	('TP53', 'Gene', (18, 22))	('malignancies', 'Disease', 'MESH:D009369', (48, 60))	('cancer', 'Disease', (113, 119))	('mutations', 'Var', (23, 32))	('Patients', 'Species', '9606', (0, 8))	('telomere shortening', 'Phenotype', 'HP:0031413', (161, 180))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('malignancies', 'Disease', (48, 60))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
26533	27940298	It is well established that telomere dysfunction leads to genetic instability and promotes human carcinoma, whereas subsequent reactivation of telomere protective mechanisms promotes escape of senescence and subsequently immortality.	('telomere dysfunction', 'Var', (28, 48))	('carcinoma', 'Disease', 'MESH:D002277', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('promotes', 'PosReg', (82, 90))	('genetic instability', 'MPA', (58, 77))	('leads to', 'Reg', (49, 57))	('escape of senescence', 'CPA', (183, 203))	('carcinoma', 'Disease', (97, 106))	('human', 'Species', '9606', (91, 96))
26543	27940298	These findings demonstrate a contribution of telomere deprotection to adrenocortical tumorigenesis and genomic instability.	('telomere', 'Var', (45, 53))	('rat', 'Species', '10116', (22, 25))	('genomic instability', 'CPA', (103, 122))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (70, 98))	('adrenocortical tumorigenesis', 'Disease', (70, 98))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
26557	27940298	IGF2 and also H19, a long non-coding RNA, are imprinted genes inversely regulated by methylation of imprinting control region 1 (ICR1) (also called imprinting center 1, IC1, or differentially methylated region 1, DMR1) at the human 11p15 locus (mouse chromosome 7).	('methylation', 'Var', (85, 96))	('IC1', 'Gene', (169, 172))	('human', 'Species', '9606', (226, 231))	('H19', 'Gene', (14, 17))	('p15', 'Gene', (234, 237))	('p15', 'Gene', '1030', (234, 237))	('H19', 'CellLine', 'CVCL:H782', (14, 17))	('IC1', 'Gene', '105259599', (169, 172))	('mouse', 'Species', '10090', (245, 250))	('IGF2', 'Gene', (0, 4))
26560	27940298	BWS is molecularly characterized by alterations at chromosome 11p15 that involve mutation or deletion of imprinted genes, methylation alterations, or paternal uniparental disomy (UPD) (reviewed by).	('rat', 'Species', '10116', (138, 141))	('p15', 'Gene', (64, 67))	('p15', 'Gene', '1030', (64, 67))	('mutation', 'Var', (81, 89))	('imprinted genes', 'Gene', (105, 120))	('methylation alterations', 'Var', (122, 145))	('rat', 'Species', '10116', (40, 43))	('paternal uniparental disomy', 'Disease', (150, 177))	('BWS', 'Disease', 'MESH:D001506', (0, 3))	('BWS', 'Disease', (0, 3))	('deletion', 'Var', (93, 101))	('paternal uniparental disomy', 'Disease', 'MESH:C536471', (150, 177))
26561	27940298	Aberrations frequently result in a gain of imprinting (hypermethylation) at the ICR1 locus, either by aberrant methylation of the maternal chromosome, or paternal UPD, which results in overexpression of IGF2.	('IGF2', 'Gene', (203, 207))	('imprinting', 'MPA', (43, 53))	('ICR1', 'Gene', (80, 84))	('gain', 'PosReg', (35, 39))	('aberrant methylation', 'Var', (102, 122))	('overexpression', 'PosReg', (185, 199))	('rat', 'Species', '10116', (4, 7))	('Aberrations', 'Var', (0, 11))	('methylation', 'Var', (111, 122))
26563	27940298	It is curious that, in contrast to BWS, the IMAGe syndrome is caused by specific gain-of-function mutations in the maternal CDKN1C gene, which encodes the cell cycle regulator p57Kip2 and (like IGF2) is located within the chromosome 11p15 locus.	('IMAGe syndrome', 'Disease', (44, 58))	('CDKN1C', 'Gene', (124, 130))	('p15', 'Gene', '1030', (235, 238))	('CDKN1C', 'Gene', '1028', (124, 130))	('p57Kip2', 'Gene', '1028', (176, 183))	('gain-of-function', 'PosReg', (81, 97))	('mutations', 'Var', (98, 107))	('p57Kip2', 'Gene', (176, 183))	('BWS', 'Disease', 'MESH:D001506', (35, 38))	('BWS', 'Disease', (35, 38))	('p15', 'Gene', (235, 238))
26565	27940298	A recent study of BWS patients has found that only paternal UPD, as compared to other BWS genotypes, is associated with ACC specifically suggesting that other imprinted loci in addition to IGF2 on chromosome 11 are important contributors to pediatric ACC risk.	('BWS', 'Disease', 'MESH:D001506', (18, 21))	('ACC', 'Disease', (120, 123))	('paternal UPD', 'Var', (51, 63))	('patients', 'Species', '9606', (22, 30))	('associated', 'Reg', (104, 114))	('ACC', 'Phenotype', 'HP:0006744', (251, 254))	('ACC', 'Phenotype', 'HP:0006744', (120, 123))	('BWS', 'Disease', (86, 89))	('BWS', 'Disease', (18, 21))	('BWS', 'Disease', 'MESH:D001506', (86, 89))
26567	27940298	In an analysis of 37 pediatric ACTs, while only two patients were diagnosed with BWS, 100% of cases exhibited overexpression of IGF2 with 91% loss of heterozygosity at 11p due to maternal allele loss.	('loss', 'NegReg', (142, 146))	('IGF2', 'Gene', (128, 132))	('maternal allele loss', 'Var', (179, 199))	('BWS', 'Disease', 'MESH:D001506', (81, 84))	('BWS', 'Disease', (81, 84))	('patients', 'Species', '9606', (52, 60))	('overexpression', 'PosReg', (110, 124))
26568	27940298	Analysis of SNVs led authors to also conclude that loss of heterozygosity was an early event in pediatric adrenocortical tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('adrenocortical tumorigenesis', 'Disease', (106, 134))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (106, 134))	('loss of heterozygosity', 'Var', (51, 73))	('pediatric adrenocortical', 'Disease', 'MESH:C565973', (96, 120))	('pediatric adrenocortical', 'Disease', (96, 120))
26569	27940298	These observations strongly suggest a causal role for 11p15 alterations in pediatric ACC, albeit not routinely due to BWS.	('BWS', 'Disease', (118, 121))	('BWS', 'Disease', 'MESH:D001506', (118, 121))	('rat', 'Species', '10116', (64, 67))	('ACC', 'Phenotype', 'HP:0006744', (85, 88))	('p15', 'Gene', (56, 59))	('alterations', 'Var', (60, 71))	('p15', 'Gene', '1030', (56, 59))
26580	27940298	In this review we have highlighted discoveries that have elucidated signaling pathways critical to the stem/progenitor niche in the adrenal cortex and how mutations in these pathways contribute to human disease, most notably human neoplasias.	('neoplasias', 'Phenotype', 'HP:0002664', (231, 241))	('neoplasias', 'Disease', (231, 241))	('mutations', 'Var', (155, 164))	('neoplasia', 'Phenotype', 'HP:0002664', (231, 240))	('human', 'Species', '9606', (225, 230))	('human', 'Species', '9606', (197, 202))	('neoplasias', 'Disease', 'MESH:D009369', (231, 241))	('contribute', 'Reg', (183, 193))
26582	27940298	In adrenal neoplasia, the cell or cells of origin are unclear, as is the sequence by which mutations contribute to carcinoma (see Fig.	('contribute', 'Reg', (101, 111))	('neoplasia', 'Phenotype', 'HP:0002664', (11, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Disease', (115, 124))	('mutations', 'Var', (91, 100))	('adrenal neoplasia', 'Phenotype', 'HP:0100631', (3, 20))	('adrenal neoplasia', 'Disease', (3, 20))	('adrenal neoplasia', 'Disease', 'MESH:D009369', (3, 20))	('carcinoma', 'Disease', 'MESH:D002277', (115, 124))
26596	26537284	The physical exam revealed a rounded face, clavicular fatness, a fatty hump, BP= 200X100 mmHg, BMI=32.4 kg/m2.	('BP= 200X100 mmHg', 'Var', (77, 93))	('clavicular fatness', 'Disease', 'MESH:C536428', (43, 61))	('rounded face', 'Phenotype', 'HP:0000311', (29, 41))	('clavicular fatness', 'Disease', (43, 61))
26641	24062770	Laboratory tests of hypothalamic-pituitary-adrenal function in CS included measurement of baseline morning (0800 h to 0900 h) and afternoon (1600 h to 2200 h) plasma cortisol levels, baseline 24 h UFC, loss of plasma cortisol circadian rhythm (i.e., baseline afternoon plasma cortisol level greater than 7.5 mug/dL and greater than 50% of baseline morning plasma cortisol level), nonsuppression of morning 0800 h plasma cortisol level (i.e., greater than 5 mug/dL) after administration of 1 mg dexamethasone orally at 2300 h (overnight low-dose dexamethasone suppression test, overnight LDDST), and nonsuppression of 24 h UFC (>122 mug) or nonsuppression of morning 0800 h plasma cortisol level (>5 mug/dL) 48 h after 0.5 mg dexamethasone administered orally every 6 h for 2 days (2-day LDDST).	('nonsuppression', 'Var', (599, 613))	('dexamethasone', 'Chemical', 'MESH:D003907', (494, 507))	('dexamethasone', 'Chemical', 'MESH:D003907', (545, 558))	('cortisol', 'Chemical', 'MESH:D006854', (363, 371))	('hypothalamic-pituitary-adrenal function', 'Disease', (20, 59))	('loss of plasma cortisol', 'Phenotype', 'HP:0008163', (202, 225))	('cortisol', 'Chemical', 'MESH:D006854', (680, 688))	('cortisol', 'Chemical', 'MESH:D006854', (217, 225))	('CS', 'Phenotype', 'HP:0003118', (63, 65))	('dexamethasone', 'Chemical', 'MESH:D003907', (725, 738))	('cortisol', 'Chemical', 'MESH:D006854', (276, 284))	('men', 'Species', '9606', (82, 85))	('loss', 'NegReg', (202, 206))	('cortisol', 'Chemical', 'MESH:D006854', (166, 174))	('cortisol', 'Chemical', 'MESH:D006854', (420, 428))	('hypothalamic-pituitary-adrenal function', 'Disease', 'MESH:D007029', (20, 59))
26728	24062770	reported an association between laparoscopic adrenalectomy for adrenocortical carcinoma and a high risk of peritoneal carcinomatosis (83%) compared with open adrenalectomy (8%, P = 0.0001).	('peritoneal carcinomatosis', 'Disease', (107, 132))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (63, 87))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (63, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('laparoscopic', 'Var', (32, 44))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (107, 132))	('adrenocortical carcinoma', 'Disease', (63, 87))
26742	23671264	TARBP2 over-expression was not related to gene mutations; however, copy number gain of the TARBP2 gene was observed in 57% of the carcinomas analyzed.	('gain', 'PosReg', (79, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('carcinomas', 'Disease', (130, 140))	('carcinomas', 'Disease', 'MESH:D002277', (130, 140))	('TARBP2', 'Gene', (91, 97))	('copy number', 'Var', (67, 78))
26755	23671264	We further investigated the effect of TARBP2 deregulation on cell growth and apoptosis and explored possible mechanisms responsible for its deregulation in this tumor type.	('TARBP2', 'Gene', (38, 44))	('deregulation', 'Var', (45, 57))	('apoptosis', 'CPA', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))
26763	23671264	cDNA was synthesized from 100 ng of total RNA using High Capacity cDNA RT Kit (Applied Biosystems), and the mRNA expression was quantified for DICER (DICER1) (ID_00998578_m1), DROSHA (ID_01095029_m1), TARBP2 (ID_00998379_m1), DGCR8 (ID_00987089_m1), PRKRA (ID_00269379_m1), IGF2 (ID_00277496_s1), and H19 (ID_00399293_g1) using a 7900HT Real-Time PCR System (Applied Biosystems).	('ID_00987089_m1', 'Var', (233, 247))	('DGCR8', 'Gene', (226, 231))	('IGF2', 'Gene', (274, 278))	('PRKRA', 'Gene', (250, 255))	('H19', 'Gene', (301, 304))	('ID_00399293_g1', 'Var', (306, 320))	('DGCR8', 'Gene', '54487', (226, 231))	('DICER', 'Gene', (150, 155))	('PRKRA', 'Gene', '8575', (250, 255))	('DICER', 'Gene', (143, 148))	('ID_00998578_m1', 'Var', (159, 173))	('H19', 'Gene', '283120', (301, 304))	('DROSHA', 'Gene', '29102', (176, 182))	('DROSHA', 'Gene', (176, 182))	('IGF2', 'Gene', '3481', (274, 278))	('ID_00277496_s1', 'Var', (280, 294))	('DICER1', 'Gene', '23405', (150, 156))	('ID_01095029_m1', 'Var', (184, 198))	('DICER', 'Gene', '23405', (150, 155))	('ID_00998379_m1', 'Var', (209, 223))	('ID_00269379_m1', 'Var', (257, 271))	('DICER', 'Gene', '23405', (143, 148))	('DICER1', 'Gene', (150, 156))
26764	23671264	Expression levels of miR-497 (ID_001043) and miR-195 (ID_000494) were quantified in the NCI-H295R cells after transfection experiments to evaluate transfection efficiency.	('NCI-H295R', 'CellLine', 'CVCL:0458', (88, 97))	('miR-195', 'Gene', (45, 52))	('miR-497', 'Gene', (21, 28))	('ID_001043', 'Var', (30, 39))	('miR-497', 'Gene', '574456', (21, 28))	('miR-195', 'Gene', '406971', (45, 52))
26768	23671264	Whole cell lysates were prepared as described previously for detection of miRNA machinery proteins using primary antibody anti-TARBP2 (sc-100909; Santa Cruz Biotechnology, Inc.) at 1:1000 dilution, anti-DICER (ab14601; Abcam, Cambridge, UK) at 1:200 dilution, or anti-DROSHA (ab12286; Abcam) at 1:400 dilution.	('miR', 'Gene', (74, 77))	('DICER', 'Gene', (203, 208))	('miR', 'Gene', '220972', (74, 77))	('DROSHA', 'Gene', '29102', (268, 274))	('DICER', 'Gene', '23405', (203, 208))	('DROSHA', 'Gene', (268, 274))	('ab14601;', 'Var', (210, 218))
26774	23671264	Expression values for TARBP2 (HG-U133_Plus_2.0 probe set: 203677_s_at), DICER (213229_at, 206061_s_at), DROSHA (2218269_at), IGF2 (202409_at, 202410_x_at, 210881_s_at), and H19 (224646_x_at, 224997_x_at) were extracted from the microarray data.	('202409_at', 'Var', (131, 140))	('203677_s_at', 'Var', (58, 69))	('DICER', 'Gene', (72, 77))	('IGF2', 'Gene', (125, 129))	('H19', 'Gene', '283120', (173, 176))	('H19', 'Gene', (173, 176))	('DROSHA', 'Gene', '29102', (104, 110))	('224646_x_at', 'Var', (178, 189))	('2218269_at', 'Var', (112, 122))	('DROSHA', 'Gene', (104, 110))	('213229_at', 'Var', (79, 88))	('IGF2', 'Gene', '3481', (125, 129))	('210881_s_at', 'Var', (155, 166))	('DICER', 'Gene', '23405', (72, 77))
26775	23671264	NCI-H295R cells were transfected using Amaxa Nucleofector technology (Lonza, Basel, Switzerland) with pre-miR-195, pre-miR-497 (PM10827 and PM10490 respectively; Applied Biosystems/Ambion), or siTARBP2 (sc-106846; Santa Cruz Biotechnology, Inc.), as described previously.	('miR-195', 'Gene', (106, 113))	('miR-497', 'Gene', (119, 126))	('miR-195', 'Gene', '406971', (106, 113))	('miR-497', 'Gene', '574456', (119, 126))	('NCI-H295R', 'CellLine', 'CVCL:0458', (0, 9))	('PM10827', 'Var', (128, 135))	('PM10490', 'Var', (140, 147))
26838	23671264	As observed in our cohort, the combination of TARBP2, IGF2, and H19 could improve the overall prediction for ACC classification in both data sets (Supplementary Tables S4 and S5, see section on supplementary data given at the end of this article).	('IGF2', 'Gene', '3481', (54, 58))	('improve', 'PosReg', (74, 81))	('combination', 'Var', (31, 42))	('IGF2', 'Gene', (54, 58))	('TARBP2', 'Gene', (46, 52))	('H19', 'Gene', '283120', (64, 67))	('ACC classification', 'Disease', (109, 127))	('H19', 'Gene', (64, 67))
26841	23671264	We observed copy number gain in 57% of the carcinoma cases (16/28), but no changes among the adenomas and normal tissue samples (Supplementary Figure S10, see section on supplementary data given at the end of this article).	('copy number', 'Var', (12, 23))	('gain', 'PosReg', (24, 28))	('adenomas', 'Disease', (93, 101))	('carcinoma', 'Disease', 'MESH:D002277', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinoma', 'Disease', (43, 52))	('adenomas', 'Disease', 'MESH:D000236', (93, 101))
26842	23671264	For examples, four tumors (Ca3, Ca20, Ca22, and Ca25), showing TARBP2 copy number gain, were among the cases with relatively low TARBP2 expression (Supplementary Figure S10).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('expression', 'MPA', (136, 146))	('TARBP2', 'Gene', (63, 69))	('Ca22', 'CellLine', 'CVCL:1102', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('copy number', 'Var', (70, 81))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('gain', 'PosReg', (82, 86))
26851	23671264	Noteworthy, the four carcinomas with TARBP2 copy number gain and low TARBP2 expression exhibited high expression of miR-195 and miR-497.	('miR-195', 'Gene', (116, 123))	('miR-195', 'Gene', '406971', (116, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('carcinomas', 'Disease', (21, 31))	('carcinomas', 'Disease', 'MESH:D002277', (21, 31))	('expression', 'MPA', (102, 112))	('TARBP2', 'Gene', (69, 75))	('copy number', 'Var', (44, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('gain', 'PosReg', (56, 60))	('low', 'NegReg', (65, 68))	('expression', 'MPA', (76, 86))	('TARBP2', 'Gene', (37, 43))	('miR-497', 'Gene', (128, 135))	('miR-497', 'Gene', '574456', (128, 135))
26864	23671264	Disruption of miRNA machinery has been previously associated with tumorigenesis in several cancer types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('miR', 'Gene', '220972', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('miR', 'Gene', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('associated', 'Reg', (50, 60))	('Disruption', 'Var', (0, 10))
26884	23671264	TARBP2 gene mutations causing a loss of TARBP protein expression have been previously shown in colorectal and gastric cancers.	('expression', 'MPA', (54, 64))	('TARBP2', 'Gene', (0, 6))	('shown', 'Reg', (86, 91))	('loss', 'NegReg', (32, 36))	('mutations', 'Var', (12, 21))	('gastric cancers', 'Phenotype', 'HP:0012126', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('TARBP', 'Gene', (40, 45))	('protein', 'Protein', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (95, 125))
26885	23671264	On the other hand, we found TARBP2 gene copy number gain in 57% (16/28) of the carcinomas, suggesting that copy number gain of TARBP2 gene may be, at least partially, responsible for its over-expression in ACC.	('copy number', 'Var', (107, 118))	('TARBP2', 'Gene', (127, 133))	('carcinomas', 'Disease', 'MESH:D002277', (79, 89))	('carcinomas', 'Disease', (79, 89))	('TARBP2', 'Gene', (28, 34))	('gain', 'PosReg', (52, 56))	('over-expression', 'PosReg', (187, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('gain', 'PosReg', (119, 123))	('ACC', 'Disease', (206, 209))
26892	23671264	Together, it is intriguing to speculate that the phenotypic effect observed in ACC cell line upon alteration of miR-195 and miR-497 expression may be mediated through TARBP2 and DICER downregulation.	('TARBP2', 'Protein', (167, 173))	('miR-195', 'Gene', '406971', (112, 119))	('DICER', 'Gene', (178, 183))	('alteration', 'Var', (98, 108))	('miR-497', 'Gene', '574456', (124, 131))	('miR-497', 'Gene', (124, 131))	('downregulation', 'NegReg', (184, 198))	('DICER', 'Gene', '23405', (178, 183))	('miR-195', 'Gene', (112, 119))
26905	23756599	In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma primary cells and cell lines.	('pituitary adenoma', 'Disease', (146, 163))	('pituitary adenoma', 'Disease', 'MESH:D010911', (146, 163))	('SF-1', 'Gene', (77, 81))	('proliferation/survival', 'CPA', (116, 138))	('rat', 'Species', '10116', (123, 126))	('Cyp11a1', 'Var', (54, 61))	('promotes', 'PosReg', (107, 115))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (146, 163))	('rat', 'Species', '10116', (24, 27))	('rat', 'Species', '10116', (142, 145))
26914	23756599	MENX is caused by a biallelic loss-of-function mutation in Cdkn1b, encoding the cell cycle inhibitor p27, which results in a highly unstable protein.	('p27', 'Gene', '83571', (101, 104))	('loss-of-function', 'NegReg', (30, 46))	('Cdkn1b', 'Gene', (59, 65))	('mutation', 'Var', (47, 55))	('Cdkn1b', 'Gene', '83571', (59, 65))	('MENX', 'Disease', (0, 4))	('MENX', 'Chemical', '-', (0, 4))	('p27', 'Gene', (101, 104))
26920	23756599	CYP11A1 and NUSAP1) are highly expressed at both mRNA and protein level in human gonadotropinomas and may represent novel biomarkers of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('gonadotropinomas', 'Disease', 'None', (81, 97))	('CYP11A1', 'Var', (0, 7))	('gonadotropinomas', 'Disease', (81, 97))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('human', 'Species', '9606', (75, 80))	('NUSAP1', 'Gene', (12, 18))
26948	23756599	Primary pituitary tumor cells were isolated from mutant rat pituitaries and grown as previously described.	('pituitary tumor', 'Disease', 'MESH:D010911', (8, 23))	('rat', 'Species', '10116', (56, 59))	('mutant', 'Var', (49, 55))	('pituitary tumor', 'Disease', (8, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
26949	23756599	For infections, GH3 and primary tumor cells were plated on 96-well plates and 24 h later cells were infected by lentiviral vectors expressing the green fluorescence protein (GFP) or GFP and shRNA against Cyp11a1.	('infections', 'Disease', (4, 14))	('GFP', 'Var', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('GH', 'Gene', '81668', (16, 18))	('infections', 'Disease', 'MESH:D007239', (4, 14))	('Cyp11a1', 'Gene', (204, 211))	('tumor', 'Disease', (32, 37))
26963	23756599	In order to unravel the genetic changes associated with pituitary adenoma (PA) formation, we performed whole genome transcriptome analysis of 16 individual pituitary lesions from 11 adult MENX mutant rats (8 months of age) and compared them with 5 normal pituitaries.	('pituitary adenoma', 'Disease', (56, 73))	('pituitary adenoma', 'Disease', 'MESH:D010911', (56, 73))	('mutant', 'Var', (193, 199))	('MENX', 'Chemical', '-', (188, 192))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (56, 73))	('rats', 'Species', '10116', (200, 204))
26974	23756599	While the mRNA level Nr5a1 was up-regulated 2.7-fold in the adenomas (Dataset 1), its downstream targets were overexpressed up to 23-fold in the tumors, including Angpt2, Cyp11a1, Cyp11b1, Cyp11b2, Giot1, Gnrhr, Nos1, Nr0b1/Dax1, Nr0b2, Scarb1.	('up-regulated', 'PosReg', (31, 43))	('Scarb1', 'Gene', '25073', (237, 243))	('Dax1', 'Gene', (224, 228))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('Nos1', 'Gene', '24598', (212, 216))	('Gnrhr', 'Gene', '81668', (205, 210))	('Angpt2', 'Gene', '89805', (163, 169))	('adenomas', 'Disease', 'MESH:D000236', (60, 68))	('adenomas', 'Disease', (60, 68))	('Dax1', 'Gene', '58850', (224, 228))	('Nr0b2', 'Gene', (230, 235))	('Angpt2', 'Gene', (163, 169))	('Giot1', 'Gene', '171090', (198, 203))	('Cyp11b2', 'Gene', (189, 196))	('Nr0b2', 'Gene', '117274', (230, 235))	('Gnrhr', 'Gene', (205, 210))	('Nr0b1', 'Gene', '58850', (218, 223))	('Giot1', 'Gene', (198, 203))	('Cyp11b1', 'Gene', '500892', (180, 187))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('Scarb1', 'Gene', (237, 243))	('Nos1', 'Gene', (212, 216))	('Nr5a1', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Cyp11b1', 'Gene', (180, 187))	('Nr0b1', 'Gene', (218, 223))	('overexpressed', 'PosReg', (110, 123))	('tumors', 'Disease', (145, 151))	('Cyp11a1', 'Var', (171, 178))	('Cyp11b2', 'Gene', '24294', (189, 196))
27015	23756599	Quantification of the IHC results demonstrated that Ki-67-positive cells were more numerous than NuSAP-positive cells (Fig.	('NuSAP', 'Gene', (97, 102))	('Ki-67-positive', 'Var', (52, 66))	('rat', 'Species', '10116', (41, 44))	('NuSAP', 'Gene', '51203', (97, 102))
27020	23756599	To clarify the role of this gene in tumorigenesis, we first used Y1 cancer cells derived from a steroidogenic tissue and expressing Cyp11a1 at high level.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Cyp11a1', 'Var', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Disease', (68, 74))	('tumor', 'Disease', (36, 41))
27021	23756599	siRNA-mediated knock-down of Cyp11a1 reduced the ability of Y1 cells to proliferate when compared with cells transfected with scrambled siRNA oligos (Supplementary Fig.	('Cyp11a1', 'Gene', (29, 36))	('reduced', 'NegReg', (37, 44))	('rat', 'Species', '10116', (79, 82))	('knock-down', 'Var', (15, 25))
27025	23756599	We found that siRNA-mediated silencing of Cyp11a1 reduced GH3 cells proliferation, while scrambled siRNA oligos elicited no effect (Supplementary Fig.	('GH', 'Gene', '81668', (58, 60))	('Cyp11a1', 'Gene', (42, 49))	('silencing', 'Var', (29, 38))	('rat', 'Species', '10116', (75, 78))	('reduced', 'NegReg', (50, 57))
27030	23756599	In growth curve experiments, viral-mediated Cyp11a1 knock-down decreased the growth rate of GH3 cells, while infection with the mock vector had not effect on cell growth (Fig.	('rat', 'Species', '10116', (84, 87))	('decreased', 'NegReg', (63, 72))	('knock-down', 'Var', (52, 62))	('Cyp11a1', 'Gene', (44, 51))	('GH', 'Gene', '81668', (92, 94))
27033	23756599	We also assessed caspase-3/7 activity as a measure of apoptosis in GH3 cells infected with GFP or with sh-Cyp11a1.	('sh-Cyp11a1', 'Var', (103, 113))	('caspase-3', 'Gene', '25402', (17, 26))	('activity', 'MPA', (29, 37))	('GH', 'Gene', '81668', (67, 69))	('caspase-3', 'Gene', (17, 26))
27034	23756599	Caspase-3/7 activity is higher in cells infected by sh-Cyp11a1 compared with mock infected cells, suggesting that this process might also explain part of the reduced cell growth (Fig.	('Caspase-3', 'Gene', (0, 9))	('sh-Cyp11a1', 'Var', (52, 62))	('Caspase-3', 'Gene', '25402', (0, 9))	('cell growth', 'CPA', (166, 177))	('higher', 'PosReg', (24, 30))	('activity', 'MPA', (12, 20))	('reduced', 'NegReg', (158, 165))
27038	23756599	Rat PA cells express both Nr5a1 and Cyp11a1 and, noteworthy, in these cells SF-1 and P450scc co-localize, as determined by dual co-immunofluorescence (Fig.	('SF-1', 'Gene', (76, 80))	('Rat PA', 'CellLine', 'CVCL:0492', (0, 6))	('Cyp11a1', 'Var', (36, 43))	('P450scc', 'Enzyme', (85, 92))	('Nr5a1', 'Enzyme', (26, 31))
27042	23756599	We observed that knock-down of Nr5a1 in LbetaT2 cells, as demonstrated by western blotting (Fig.	('knock-down', 'Var', (17, 27))	('LbetaT2', 'CellLine', 'CVCL:0398', (40, 47))	('Nr5a1', 'Gene', (31, 36))	('rat', 'Species', '10116', (65, 68))
27050	23756599	DLK1 was found to be selectively silenced in NFPAs but not in other types of PA. DLK1 is located in the DLK1/MEG3 imprinted locus on human chromosome 14q32.3 and MEG3, coding for a maternally imprinted long noncoding RNA with tumor suppressive function, was also found to be specifically silenced through methylation in NFPAs, but not in other hypophyseal adenoma types.	('methylation', 'Var', (305, 316))	('MEG3', 'Gene', (109, 113))	('DLK1', 'Gene', (81, 85))	('MEG3', 'Gene', '55384', (162, 166))	('NFPAs', 'Disease', (320, 325))	('silenced', 'NegReg', (288, 296))	('hypophyseal adenoma', 'Disease', 'MESH:D000072659', (344, 363))	('MEG3', 'Gene', '55384', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('PAs', 'Chemical', 'MESH:D011478', (322, 325))	('PAs', 'Chemical', 'MESH:D011478', (47, 50))	('hypophyseal adenoma', 'Disease', (344, 363))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('human', 'Species', '9606', (133, 138))	('MEG3', 'Gene', (162, 166))	('tumor', 'Disease', (226, 231))
27054	23756599	PTTG1, the homologue of yeast securin, controls the faithful separation of sister chromatids, while deregulated expression of centrosome proteins (CENP) and Aurora kinases has been linked to defects in the mitotic machinery.	('linked', 'Reg', (181, 187))	('rat', 'Species', '10116', (65, 68))	('PTTG1', 'Gene', (0, 5))	('mitotic machinery', 'CPA', (206, 223))	('yeast', 'Species', '4932', (24, 29))	('faithful separation', 'CPA', (52, 71))	('deregulated', 'Var', (100, 111))	('securin', 'Gene', (30, 37))	('controls', 'Reg', (39, 47))	('securin', 'Gene', '851691', (30, 37))	('expression', 'MPA', (112, 122))
27075	23756599	Here we show that Cyp11a1 plays a pro-proliferative role in Y1 adrenocortical cancer cells, but also in GH3 somatotroph adenoma cells and in rat primary pituitary gonadotroph cells.	('primary pituitary gonadotroph', 'Phenotype', 'HP:0011759', (145, 174))	('somatotroph adenoma', 'Disease', 'MESH:D049912', (108, 127))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (63, 84))	('Cyp11a1', 'Var', (18, 25))	('GH', 'Gene', '81668', (104, 106))	('pro-proliferative', 'PosReg', (34, 51))	('somatotroph adenoma', 'Disease', (108, 127))	('adrenocortical cancer', 'Disease', (63, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rat', 'Species', '10116', (141, 144))	('rat', 'Species', '10116', (45, 48))
27077	23756599	The first one showed that overexpression of CYP11A1 in tumorigenic and non-tumorigenic mammalian cell lines can either inhibit or enhance cell viability in a cell type-specific manner.	('mammalian', 'Species', '9606', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CYP11A1', 'Var', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('overexpression', 'PosReg', (26, 40))	('cell viability', 'CPA', (138, 152))	('tumor', 'Disease', (55, 60))	('inhibit', 'NegReg', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('enhance', 'PosReg', (130, 137))	('tumor', 'Disease', (75, 80))
27078	23756599	In cells sensitive to CYP11A1, gene overexpression led to decreased cell proliferation through increase of p21 expression and induction of apoptosis.	('overexpression', 'PosReg', (36, 50))	('rat', 'Species', '10116', (80, 83))	('cell proliferation', 'CPA', (68, 86))	('increase', 'PosReg', (95, 103))	('decreased', 'NegReg', (58, 67))	('p21', 'Gene', (107, 110))	('p21', 'Gene', '24525', (107, 110))	('apoptosis', 'CPA', (139, 148))	('CYP11A1', 'Var', (22, 29))
27079	23756599	The authors did not investigate the molecular processes associated with CYP11A1-mediated increase in cell proliferation.	('CYP11A1-mediated', 'Var', (72, 88))	('cell proliferation', 'CPA', (101, 119))	('rat', 'Species', '10116', (113, 116))	('increase', 'PosReg', (89, 97))
27112	20396632	Pathogenesis was incompletely understood, mutation at the 17p13 locus, including the p53 tumor suppressor gene, is observed in about 25% of cases; furthermore, alterations of the 11p15 locus, leading to IGF-II overexpression are frequently observed compared to adenomas or normal adrenal cortex.	('IGF-II', 'Gene', (203, 209))	('IGF-II', 'Gene', '3481', (203, 209))	('p53', 'Gene', (85, 88))	('p15', 'Gene', (181, 184))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('alterations', 'Var', (160, 171))	('p53', 'Gene', '7157', (85, 88))	('p15', 'Gene', '1030', (181, 184))	('overexpression', 'PosReg', (210, 224))	('adenomas', 'Disease', 'MESH:D000236', (261, 269))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('adenomas', 'Disease', (261, 269))
27123	20396632	A recent clinical review by Allolio and colleagues that analyzed the efficacy of mitotane treatment in advanced ACC, concluded that mitotane leads to an objective tumor regression in about 25% of cases.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('mitotane', 'Chemical', 'MESH:D008939', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('ACC', 'Phenotype', 'HP:0006744', (112, 115))	('men', 'Species', '9606', (95, 98))	('tumor', 'Disease', (163, 168))	('mitotane', 'Var', (132, 140))	('mitotane', 'Chemical', 'MESH:D008939', (132, 140))
27135	19961896	Malfunction of this system results in pathophysiology, including hypertension, severe hypokalaemic alkalosis, pre-and post-natal growth failure, cardiac fibrosis and congestive heart failure.	('post-natal growth failure', 'Phenotype', 'HP:0008897', (118, 143))	('Malfunction', 'Var', (0, 11))	('hypokalaemic alkalosis', 'Disease', (86, 108))	('-natal growth failure', 'Phenotype', 'HP:0001511', (122, 143))	('hypokalaemic alkalosis', 'Disease', 'MESH:D000471', (86, 108))	('alkalosis', 'Phenotype', 'HP:0001948', (99, 108))	('growth failure', 'Disease', 'MESH:D006130', (129, 143))	('results in', 'Reg', (27, 37))	('hypertension', 'Disease', 'MESH:D006973', (65, 77))	('hypokalaemic alkalosis', 'Phenotype', 'HP:0001949', (86, 108))	('hypertension', 'Disease', (65, 77))	('congestive heart failure', 'Disease', (166, 190))	('heart failure', 'Phenotype', 'HP:0001635', (177, 190))	('growth failure', 'Disease', (129, 143))	('hypertension', 'Phenotype', 'HP:0000822', (65, 77))	('growth failure', 'Phenotype', 'HP:0001510', (129, 143))	('cardiac fibrosis', 'Disease', (145, 161))	('cardiac fibrosis', 'Disease', 'MESH:D005355', (145, 161))	('congestive heart failure', 'Phenotype', 'HP:0001635', (166, 190))	('congestive heart failure', 'Disease', 'MESH:D006333', (166, 190))
27148	19961896	Interestingly, adenovirus-meditated overexpression of dominant-negative PKD caused a reduction in acute AngII-induced aldosterone secretion, and overexpression of a constitutively-active PKD mutant enhanced aldosterone secretion in response to a one-hour AngII stimulation.	('aldosterone', 'Chemical', 'MESH:D000450', (207, 218))	('aldosterone secretion', 'MPA', (207, 228))	('PKD', 'Gene', (72, 75))	('PKD', 'Gene', (187, 190))	('PKD', 'Gene', '5587', (72, 75))	('AngII', 'Gene', '24179', (255, 260))	('PKD', 'Gene', '5587', (187, 190))	('reduction', 'NegReg', (85, 94))	('AngII', 'Gene', '24179', (104, 109))	('mutant', 'Var', (191, 197))	('enhanced aldosterone', 'Phenotype', 'HP:0000859', (198, 218))	('AngII', 'Gene', (255, 260))	('dominant-negative', 'Var', (54, 71))	('enhanced', 'PosReg', (198, 206))	('aldosterone', 'Chemical', 'MESH:D000450', (118, 129))	('overexpression', 'PosReg', (145, 159))	('AngII', 'Gene', (104, 109))
27184	19961896	As previously shown, all of the above agents induced aldosterone secretion (AngII, 20 +- 3.7-fold; PMA, 10 +- 1.9-fold; K+, 7.5 +- 1.6-fold; and ACTH, 22 +- 2.1-fold over the control value; Figure 1A).	('aldosterone secretion', 'MPA', (53, 74))	('PMA', 'Chemical', 'MESH:D013755', (99, 102))	('AngII', 'Gene', '24179', (76, 81))	('induced', 'Reg', (45, 52))	('PMA', 'Var', (99, 102))	('AngII', 'Gene', (76, 81))	('aldosterone', 'Chemical', 'MESH:D000450', (53, 64))
27187	19961896	In the primary cells AngII increased pPKDSer910 in a concentration-dependent manner (Figure 3A and B), comparable to its effects on aldosterone secretion.	('rat', 'Species', '10116', (60, 63))	('AngII', 'Gene', '24179', (21, 26))	('pPKDSer910', 'Var', (37, 47))	('AngII', 'Gene', (21, 26))	('aldosterone', 'Chemical', 'MESH:D000450', (132, 143))
27197	19961896	To this end we infected primary bovine adrenal glomerulosa cells with adenovirus containing no insert, a constitutively-active or a dominant-negative PKD construct, in which serines 738 and 742 are mutated to phosphorylation-mimicking glutamates (PKDS738/742E) or unphosphorylatable alanines (PKDS738/742A), respectively.	('PKD', 'Gene', (247, 250))	('bovine', 'Species', '9913', (32, 38))	('PKD', 'Gene', '5587', (247, 250))	('PKD', 'Gene', (293, 296))	('PKD', 'Gene', '5587', (293, 296))	('serines', 'Chemical', 'MESH:D012694', (174, 181))	('alanines', 'Chemical', 'MESH:D000409', (283, 291))	('PKD', 'Gene', '5587', (150, 153))	('PKD', 'Gene', (150, 153))	('serines 738', 'Var', (174, 185))	('glutamates', 'Protein', (235, 245))	('glutamates', 'Chemical', 'MESH:D005971', (235, 245))
27254	33479027	The cSCC CD8+ T-cell population contained a higher proportion of CD69+/CD103+ TRMs than that in non-lesional skin and blood.	('CD8', 'Gene', '925', (9, 12))	('CD8', 'Gene', (9, 12))	('CD69+/CD103+ TRMs', 'Var', (65, 82))
27255	33479027	These cSCC CD69+/CD103+ TRMs exhibited increased IL-10 production, and higher CD39, CTLA-4 and PD-1 expression compared with CD103- TRMs in the tumor.	('higher', 'PosReg', (71, 77))	('tumor', 'Disease', (144, 149))	('CD39', 'Gene', (78, 82))	('CD69+/CD103+', 'Var', (11, 23))	('PD-1', 'Gene', (95, 99))	('increased IL-10 production', 'Phenotype', 'HP:0030783', (39, 65))	('CTLA-4', 'Gene', (84, 90))	('expression', 'MPA', (100, 110))	('increased', 'PosReg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('IL-10 production', 'MPA', (49, 65))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
27256	33479027	CD103+ cells were more frequent in P-M than P-NM cSCCs.	('P-M', 'Disease', (35, 38))	('CD103+ cells', 'Var', (0, 12))	('cSCCs', 'Chemical', '-', (49, 54))
27258	33479027	Immunofluorescence microscopy showed that the majority of CD103 was present on CD8+ T cells and that CD8+CD103+ cells were significantly more frequent in P-M than P-NM cSCCs.	('CD8', 'Gene', '925', (101, 104))	('P-M', 'Var', (154, 157))	('CD8', 'Gene', (79, 82))	('CD103', 'Gene', (58, 63))	('CD8', 'Gene', '925', (79, 82))	('cSCCs', 'Chemical', '-', (168, 173))	('CD8', 'Gene', (101, 104))
27261	33479027	In genetically susceptible individuals, including those with variant MC1R genotype and/or fair skin, exposure to ultraviolet radiation induces alterations in cancer driver genes within keratinocytes, which enable the development of skin cancers and precancerous skin lesions.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('MC1R', 'Gene', '4157', (69, 73))	('skin cancers', 'Disease', (232, 244))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('skin cancers', 'Disease', 'MESH:D012878', (232, 244))	('MC1R', 'Gene', (69, 73))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', (237, 243))	('skin cancer', 'Phenotype', 'HP:0008069', (232, 243))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('enable', 'PosReg', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('fair skin', 'Phenotype', 'HP:0007513', (90, 99))	('cancer', 'Disease', (252, 258))	('precancerous skin lesions', 'Disease', 'MESH:D011230', (249, 274))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('precancerous skin lesions', 'Disease', (249, 274))	('variant', 'Var', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('alterations', 'Reg', (143, 154))	('skin cancers', 'Phenotype', 'HP:0008069', (232, 244))
27262	33479027	Dysfunctional cutaneous immunity is also a well-known risk factor for keratinocyte skin cancer, especially cutaneous squamous cell carcinoma (cSCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('cutaneous squamous cell carcinoma', 'Disease', (107, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('skin cancer', 'Disease', (83, 94))	('skin cancer', 'Phenotype', 'HP:0008069', (83, 94))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (107, 140))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 140))	('skin cancer', 'Disease', 'MESH:D012878', (83, 94))	('Dysfunctional', 'Var', (0, 13))
27310	33479027	CD69-CD103- T cells accounted for significantly lower proportions of the CD3+ population in cSCC and NS compared with blood (mean 44.2% and 35.7% vs 77.4%, respectively: p<0.0001 for both comparisons, n=36 tumors, figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('lower', 'NegReg', (48, 53))	('CD69-CD103- T cells', 'Var', (0, 19))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumors', 'Disease', (206, 212))	('cSCC', 'Disease', (92, 96))
27311	33479027	The percentage of CD3+ T cells that were CD69+CD103+ TRMs was also higher in cSCCs and NS than blood (mean 9.1% and 11.4% vs 0.3%, respectively, p<0.0001, n=36 tumors, figure 3B).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('higher', 'PosReg', (67, 73))	('cSCCs', 'Disease', (77, 82))	('cSCCs', 'Chemical', '-', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('CD69+CD103+ TRMs', 'Var', (41, 57))
27313	33479027	While greater numbers of CD69+CD103+ TRMs were present in the CD4+FOXP3- population (mean 7.9%, figure 3D), and in the total CD4+ population (mean 7.0%, figure 3E) than in the Treg group, CD69+CD103+ TRMs were present in greater amounts in the CD8+ population (mean 24.1%, figure 3F).	('CD69+CD103+ TRMs', 'Var', (25, 41))	('CD8', 'Gene', (244, 247))	('CD8', 'Gene', '925', (244, 247))
27314	33479027	Significantly higher percentages of tumor-infiltrating CD103+ T cells were CD8+ (mean 62.0%, figure 3G) than CD4+ (mean 34.8%, p<0.0001), CD4+FOXP3+ (mean 1.4%, p<0.0001) and CD4+FOXP3- (33.0%, p=0.0009).	('CD103+', 'Var', (55, 61))	('CD8', 'Gene', '925', (75, 78))	('CD4+FOXP3+', 'Var', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CD8', 'Gene', (75, 78))	('tumor', 'Disease', (36, 41))	('higher', 'PosReg', (14, 20))
27315	33479027	Although CD103+ TRMs accounted for similar percentages of the total lymphocyte and CD3+ T-cell populations in cSCC and NS, the percentage of CD4 T cells that were CD103+ TRMs was lower in cSCC than NS (p=0.0007, figure 3E, H, I), whereas, by contrast, cSCCs contained higher percentages of CD8 T cells that were CD103+ TRMs than NS (p=0.0039, figure 3F and I).	('CD8', 'Gene', (290, 293))	('lower', 'NegReg', (179, 184))	('CD8', 'Gene', '925', (290, 293))	('cSCCs', 'Chemical', '-', (252, 257))	('cSCC', 'Disease', (188, 192))	('CD103+ TRMs', 'Var', (163, 174))
27317	33479027	These CD103+ TRMs were predominantly located in the peritumoral stromal areas, although there were smaller frequencies that were present in the tumor nests, where the vast majority of CD8 T cells expressed CD103 (figure 4B).	('CD103+', 'Var', (6, 12))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CD103', 'Var', (206, 211))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CD8', 'Gene', (184, 187))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CD8', 'Gene', '925', (184, 187))
27319	33479027	In the cSCC CD8 T-cell population, CD103+ TRMs produced similar amounts of IFNgamma, TNFalpha and IL-2 compared with CD69- T cells and CD103- TRMs (figure 5A).	('CD8', 'Gene', '925', (12, 15))	('TNFalpha', 'Gene', (85, 93))	('IFNgamma', 'Gene', (75, 83))	('TNFalpha', 'Gene', '7124', (85, 93))	('IFNgamma', 'Gene', '3458', (75, 83))	('IL-2', 'Gene', '3558', (98, 102))	('CD103+ TRMs', 'Var', (35, 46))	('CD8', 'Gene', (12, 15))	('IL-2', 'Gene', (98, 102))
27321	33479027	While IL-10 production was detected in a relatively small proportion of the CD8+CD103+ cells, it suggested a possible upregulation of an immunosuppressive phenotype by tumor-infiltrating CD103+ TRM, therefore expression of the inhibitory markers CD39, CTLA-4 and PD-1 was investigated.	('CD103+', 'Var', (187, 193))	('tumor', 'Disease', (168, 173))	('upregulation', 'PosReg', (118, 130))	('immunosuppressive phenotype', 'MPA', (137, 164))	('CD8', 'Gene', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('CD8', 'Gene', '925', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
27323	33479027	Analysis of the tumor-infiltrating CD4+ T-cell population showed that CD4+CD103+ TRMs expressed IFNgamma in higher frequencies than CD69- T cells, and TNFalpha in greater percentages than CD69- T cells and CD103- TRMs, but there were no significant differences between the CD4+CD103+ TRMs and the other T-cell subsets in the expression of IL-2 (online supplemental figure 5A-C).	('TNFalpha', 'Gene', (151, 159))	('IL-2', 'Gene', '3558', (339, 343))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('IL-2', 'Gene', (339, 343))	('CD4+CD103+', 'Var', (70, 80))	('TNFalpha', 'Gene', '7124', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('IFNgamma', 'Gene', (96, 104))	('IFNgamma', 'Gene', '3458', (96, 104))
27324	33479027	Although more of the CD4+CD103+ TRMs expressed IL-10, this did not reach statistical significance (n=10 tumors), but there was a significantly higher proportion of CD4+CD103+ TRMs than CD69- T cells and CD103- TRMs expressing CD39 (online supplemental figure 5DE).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CD4+CD103+', 'Var', (164, 174))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))
27325	33479027	These results suggest that CD103+ TRMs, which are predominantly within the cSCC CD8 T-cell population, display a regulatory phenotype.	('CD103+', 'Var', (27, 33))	('CD8', 'Gene', (80, 83))	('CD8', 'Gene', '925', (80, 83))
27326	33479027	Consistent with this, immunofluorescence microscopy confirmed CD103+ immune cells in cSCC also expressed CD39 (n=5 tumors, figure 5B and online supplemental figure 6).	('CD39', 'Var', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('cSCC', 'Disease', (85, 89))
27331	33479027	CD103 was expressed on immune cells infiltrating the cSCC stroma (figure 6A), and P-M cSCCs contained significantly increased percentages of CD103+ cells in the immune infiltrate compared with P-NM cSCCs (median 12.1% vs 6.9%, respectively, p<0.0001, figure 6B).	('cSCCs', 'Chemical', '-', (86, 91))	('CD103+ cells', 'Var', (141, 153))	('cSCCs', 'Chemical', '-', (198, 203))	('P-M', 'Var', (82, 85))	('increased', 'PosReg', (116, 125))
27332	33479027	cSCCs were then characterized into two groups based on CD103 expression:CD103 low (below median expression; CD103 expressed by <9.24% of immune infiltrate, n=41 tumors) and CD103 high (above median expression; CD103 expressed by >=9.25% of immune infiltrate, n=41 tumors).	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('low', 'NegReg', (78, 81))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('CD103', 'Gene', (72, 77))	('CD103', 'Var', (173, 178))	('tumors', 'Disease', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cSCCs', 'Chemical', '-', (0, 5))
27334	33479027	To investigate the association between CD103 expression and survival in other cancer types, TCGA data were analyzed using TIMER2.0, demonstrating that high (greater than median) expression of ITGAE (encoding CD103) was associated with reduced survival in primary cutaneous melanoma, breast carcinoma, renal cell carcinoma, kidney chromophobe cancer and lower grade glioma, figure 6D, whereas two cancer types showed the opposite association (high ITGAE expression was associated with increased survival in cervical/endocervical cancer and pancreatic adenocarcinoma).	('cancer', 'Disease', 'MESH:D009369', (396, 402))	('cancer', 'Phenotype', 'HP:0002664', (528, 534))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (539, 564))	('cancer', 'Disease', (342, 348))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('breast carcinoma', 'Phenotype', 'HP:0003002', (283, 299))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('breast carcinoma', 'Disease', (283, 299))	('renal cell carcinoma, kidney chromophobe cancer', 'Disease', 'MESH:C538614', (301, 348))	('cancer', 'Disease', 'MESH:D009369', (528, 534))	('carcinoma', 'Phenotype', 'HP:0030731', (555, 564))	('expression', 'Var', (178, 188))	('glioma', 'Disease', (365, 371))	('pancreatic adenocarcinoma', 'Disease', (539, 564))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('cancer', 'Disease', (396, 402))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (301, 321))	('cancer', 'Disease', (78, 84))	('glioma', 'Disease', 'MESH:D005910', (365, 371))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('increased', 'PosReg', (484, 493))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('breast carcinoma', 'Disease', 'MESH:D001943', (283, 299))	('melanoma', 'Phenotype', 'HP:0002861', (273, 281))	('cutaneous melanoma', 'Disease', (263, 281))	('survival', 'MPA', (243, 251))	('cancer', 'Disease', (528, 534))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (263, 281))	('reduced', 'NegReg', (235, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('glioma', 'Phenotype', 'HP:0009733', (365, 371))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (263, 281))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (539, 564))
27338	33479027	There was no significant difference in CD8-CD103+ cell frequencies between P-M and P-NM cSCCs (2.0% vs 2.3% of immune infiltrate respectively, p=0.59, figure 6G).	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))	('P-M', 'Var', (75, 78))	('P-NM', 'Var', (83, 87))	('cSCCs', 'Chemical', '-', (88, 93))
27350	33479027	Non-recirculating TRMs express CD69 and include CD103- TRM and CD103+ TRM subgroups, which have potent effector functions, whereas recirculating T cells in skin include TCMs and TMMs.	('TMMs', 'Disease', 'None', (178, 182))	('TMMs', 'Disease', (178, 182))	('CD69', 'Var', (31, 35))	('CD103+', 'Var', (63, 69))
27353	33479027	Many tumor-infiltrating memory T cells expressed the TRM marker CD69, and TRMs were subcategorized as CD103+ or CD103-.	('CD69', 'Gene', (64, 68))	('tumor-infiltrating memory T', 'Disease', (5, 32))	('tumor-infiltrating memory T', 'Disease', 'MESH:D017254', (5, 32))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CD103-', 'Var', (112, 118))	('CD103+', 'Var', (102, 108))
27362	33479027	Extracellular ATP also activates the purinergic receptor P2Rx7, which is required for the generation and functionality of long-lived CD103+ TRMs in tissues.	('activates', 'PosReg', (23, 32))	('ATP', 'Chemical', 'MESH:D000255', (14, 17))	('CD103+', 'Var', (133, 139))	('P2Rx7', 'Gene', (57, 62))	('P2Rx7', 'Gene', '5027', (57, 62))
27366	33479027	Related to this, CD103+ TRM cells have been reported to have higher expression of inhibitory receptors such as CTLA4, Tim-3 and PD-1, as well as CD39.	('expression', 'MPA', (68, 78))	('higher', 'PosReg', (61, 67))	('Tim-3', 'Gene', (118, 123))	('CTLA4', 'Gene', (111, 116))	('PD-1', 'Gene', (128, 132))	('CD103+', 'Var', (17, 23))	('CD39', 'Gene', (145, 149))	('Tim-3', 'Gene', '84868', (118, 123))
27367	33479027	Likewise, CD103+CD39+ tumor-infiltrating CD8 T cells have been shown to be enriched for tumor-reactive cells and display exhausted gene signatures.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('CD103+CD39+', 'Var', (10, 21))	('gene signatures', 'MPA', (131, 146))	('CD8', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('CD8', 'Gene', '925', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', (88, 93))
27368	33479027	This suggests that the role of CD103 on tumor-infiltrating T cells in cancer may be more complex than previously thought, and that tumor-reactive CD103+ TRMs may boost or inhibit the antitumor immune response.	('boost', 'PosReg', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('CD103+', 'Var', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', (187, 192))	('inhibit', 'NegReg', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
27369	33479027	Indeed, we showed that CD103+ TRMs are associated with poorer clinical outcomes in cSCC, which is in contrast to some studies on other types of cancer.	('cSCC', 'Disease', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('CD103+ TRMs', 'Var', (23, 34))	('poorer', 'NegReg', (55, 61))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
27371	33479027	CD103+ TRMs have also been described as protective or conveying better prognosis in other tumor types, including oropharyngeal, head and neck, lung, breast and ovarian cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('better', 'PosReg', (64, 70))	('ovarian cancers', 'Phenotype', 'HP:0100615', (160, 175))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (149, 175))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('CD103+ TRMs', 'Var', (0, 11))	('oropharyngeal', 'Disease', (113, 126))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('lung', 'Disease', (143, 147))
27374	33479027	In addition, Gabriely and colleagues also demonstrated that high CD103 expression was associated with shorter survival in patients with glioma and glioblastoma.	('shorter', 'NegReg', (102, 109))	('expression', 'MPA', (71, 81))	('survival', 'MPA', (110, 118))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('high', 'Var', (60, 64))	('glioblastoma', 'Disease', (147, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (147, 159))	('CD103', 'Gene', (65, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('patients', 'Species', '9606', (122, 130))	('glioma', 'Disease', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
27377	33479027	Further evidence for the association between CD103 and poorer clinical outcome in cancer was demonstrated in TCGA data showing high ITGAE expression was associated with reduced survival in primary cutaneous melanoma, breast carcinoma, kidney chromophobe cancer, renal cell carcinoma, lower grade glioma and adrenocortical carcinoma.	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('high', 'Var', (127, 131))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (307, 331))	('reduced', 'NegReg', (169, 176))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', (254, 260))	('breast carcinoma', 'Disease', 'MESH:D001943', (217, 233))	('adrenocortical carcinoma', 'Disease', (307, 331))	('glioma', 'Disease', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (262, 282))	('glioma', 'Disease', 'MESH:D005910', (296, 302))	('cutaneous melanoma', 'Disease', (197, 215))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (197, 215))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (197, 215))	('breast carcinoma', 'Phenotype', 'HP:0003002', (217, 233))	('kidney chromophobe cancer', 'Disease', 'MESH:D007680', (235, 260))	('breast carcinoma', 'Disease', (217, 233))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (296, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('renal cell carcinoma', 'Disease', (262, 282))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (262, 282))	('kidney chromophobe cancer', 'Disease', (235, 260))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (307, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('CD103', 'Gene', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
27378	33479027	Based on the associations of CD103+ TRMs with metastases and survival in different types of cancer, it remains unclear how CD103+ TRMs influences outcome in different cancers and whether the pathogenic role of CD103+ TRMs in diverse cancer types is tumor or organ-dependent, or differs between primary and metastatic tumors in some cancer types.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('CD103+', 'Gene', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('tumor', 'Disease', (249, 254))	('influences', 'Reg', (135, 145))	('tumors', 'Phenotype', 'HP:0002664', (317, 323))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('CD103+', 'Var', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Disease', (167, 174))	('tumors', 'Disease', (317, 323))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Disease', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('cancer', 'Disease', (332, 338))	('tumors', 'Disease', 'MESH:D009369', (317, 323))	('metastases', 'Disease', 'MESH:D009362', (46, 56))	('associations', 'Interaction', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('metastases', 'Disease', (46, 56))	('cancer', 'Disease', (233, 239))	('cancers', 'Disease', 'MESH:D009369', (167, 174))
27382	33479027	CD4+CD103+ TRMs in cSCC were able to produce IFNgamma and TNFalpha (and also upregulated CD39 and PD-1, online supplemental figure 5), so it is possible that their reduction/suppression by Tregs is another mechanism for decreased immune surveillance in cSCC.	('PD-1', 'Gene', (98, 102))	('TNFalpha', 'Gene', (58, 66))	('upregulated', 'PosReg', (77, 88))	('CD39', 'Gene', (89, 93))	('decreased immune surveillance', 'Phenotype', 'HP:0002721', (220, 249))	('TNFalpha', 'Gene', '7124', (58, 66))	('immune', 'MPA', (230, 236))	('Tregs', 'Chemical', '-', (189, 194))	('CD4+CD103+ TRMs', 'Var', (0, 15))	('IFNgamma', 'Gene', (45, 53))	('IFNgamma', 'Gene', '3458', (45, 53))
27394	32373071	We exposed both NCI-H295R and MUC1 cell lines to palbociclib and found a concentration- and time-dependent reduction of cell viability, which was more pronounced in the NCI-H295R cells in line with higher CDK4 expression.	('CDK4', 'Gene', '1019', (205, 209))	('NCI-H295R', 'CellLine', 'CVCL:0458', (16, 25))	('palbociclib', 'Chemical', 'MESH:C500026', (49, 60))	('NCI-H295R', 'Var', (169, 178))	('cell viability', 'CPA', (120, 134))	('MUC1', 'Gene', (30, 34))	('MUC1', 'Gene', '4582', (30, 34))	('NCI-H295R', 'CellLine', 'CVCL:0458', (169, 178))	('reduction', 'NegReg', (107, 116))	('CDK4', 'Gene', (205, 209))
27403	32373071	For ACC, biomarkers such as specific transcriptomic profiles, copy number alteration patterns and methylation in certain promoter regions have been identified by genome-wide studies to be associated with tumor aggressiveness and clinical outcome.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (204, 224))	('associated', 'Reg', (188, 198))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('methylation', 'Var', (98, 109))	('copy number alteration patterns', 'Var', (62, 93))	('tumor aggressiveness', 'Disease', (204, 224))	('ACC', 'Phenotype', 'HP:0006744', (4, 7))	('aggressiveness', 'Phenotype', 'HP:0000718', (210, 224))
27417	32373071	RNA quality was determined by quantitative real-time PCR (RT-qPCR) for two housekeeping genes, ACTB (Hs9999903_m1) and GAPDH (Hs99999905_m1) (Applied Biosystems, Darmstadt, Germany), using the TaqMan Gene Expression Master Mix (Applied Biosystems), the CFX96 real-time thermocycler (Biorad, Hercules, CA, USA) and the Bio-Rad CFX Manager 2.0 software.	('GAPDH', 'Gene', (119, 124))	('Hs9999903_m1', 'Var', (101, 113))	('ACTB', 'Gene', (95, 99))	('ACTB', 'Gene', '60', (95, 99))	('Hs99999905_m1', 'Var', (126, 139))	('GAPDH', 'Gene', '2597', (119, 124))
27435	32373071	Seventy two hours post-transfection with siRNA or upon completion of the drug treatment, cells were collected for RT-qPCR analysis or western blot (WB) analysis to demonstrate knock-down of CDK4 or examine changes in RNA and protein expression in the CDK4/6 pathway.	('CDK4', 'Gene', (190, 194))	('CDK4/6', 'Gene', '1019;1021', (251, 257))	('CDK4', 'Gene', '1019', (190, 194))	('RNA and', 'MPA', (217, 224))	('knock-down', 'Var', (176, 186))	('changes', 'Reg', (206, 213))	('protein', 'Protein', (225, 232))	('CDK4', 'Gene', '1019', (251, 255))	('CDK4', 'Gene', (251, 255))	('CDK4/6', 'Gene', (251, 257))
27440	32373071	Inhibition of CDK4/6 and IGF1R achieved synergistic compromise of cell viability and proliferation while showing a correlation with reduced mammalian target of rapamycin complex 1 (mTORC1) activity.	('CDK4/6', 'Gene', (14, 20))	('rapamycin', 'Chemical', 'MESH:D020123', (160, 169))	('activity', 'MPA', (189, 197))	('cell viability', 'CPA', (66, 80))	('mTORC1', 'Gene', '382056', (181, 187))	('reduced', 'NegReg', (132, 139))	('Inhibition', 'Var', (0, 10))	('IGF1R', 'Gene', (25, 30))	('CDK4/6', 'Gene', '1019;1021', (14, 20))	('compromise', 'NegReg', (52, 62))	('mTORC1', 'Gene', (181, 187))	('mammalian', 'MPA', (140, 149))
27443	32373071	The membrane was further probed with antibodies against CDK4 (EPR4513-32-7, abcam, dilution 1:1000) and CDKN2A (G175-405, BD Pharmingen, San Jose, CA, USA, dilution 1:500).	('CDKN2A', 'Gene', '1029', (104, 110))	('G175-405', 'Var', (112, 120))	('CDK4', 'Gene', '1019', (56, 60))	('CDK4', 'Gene', (56, 60))	('CDKN2A', 'Gene', (104, 110))	('EPR4513-32-7', 'Var', (62, 74))
27445	32373071	Moreover, CDK4/6 inhibitors have been reported to reduce cell viability in ACC cell lines despite lack of pRb expression p130/RBL2 being already reported to be expressed in the NCI-H295R cell line.	('NCI-H295R', 'CellLine', 'CVCL:0458', (177, 186))	('reduce', 'NegReg', (50, 56))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('RBL2', 'Gene', '5934', (126, 130))	('RB', 'Phenotype', 'HP:0009919', (126, 128))	('CDK4/6', 'Gene', '1019;1021', (10, 16))	('p130', 'Gene', (121, 125))	('inhibitors', 'Var', (17, 27))	('CDK4/6', 'Gene', (10, 16))	('pRb', 'Gene', (106, 109))	('p130', 'Gene', '5934', (121, 125))	('pRb', 'Gene', '5925', (106, 109))	('cell viability', 'CPA', (57, 71))	('RBL2', 'Gene', (126, 130))
27456	32373071	Of note, CDK4 copy number (CN) gains, as well as losses of its regulator, CDKN2A, are frequently reported in ACC.	('CDK4', 'Gene', (9, 13))	('gains', 'PosReg', (31, 36))	('CDK4', 'Gene', '1019', (9, 13))	('CDKN2A', 'Gene', (74, 80))	('CDKN2A', 'Gene', '1029', (74, 80))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('copy number', 'Var', (14, 25))	('losses', 'NegReg', (49, 55))
27465	32373071	Considering the clinical outcome (n = 104 ACC), OS showed no relationship with CDK4 protein expression (p = 0.2013, data not shown), while PFS was slightly longer in patients with high CDK4 nuclear expression compared to patients with low expression (median=24 vs. 9 months, p = 0.0122, HR = 0.56, 95% CI = 0.36-0.88, Figure 2F).	('ACC', 'Phenotype', 'HP:0006744', (42, 45))	('CDK4', 'Gene', '1019', (185, 189))	('patients', 'Species', '9606', (221, 229))	('patients', 'Species', '9606', (166, 174))	('CDK4', 'Gene', (79, 83))	('CDK4', 'Gene', (185, 189))	('high', 'Var', (180, 184))	('PFS', 'MPA', (139, 142))	('CDK4', 'Gene', '1019', (79, 83))	('longer', 'PosReg', (156, 162))
27466	32373071	As expected, PFS was also significantly associated with ENSAT tumor stage (stage 1-2 vs. 3-4, p = 0.001, HR = 2.25, 95% CI = 1.39-3.64), Ki67 proliferation index (cut-off 15%, p < 0.001, HR = 3.53, 95% CI = 2.11-5.89), and resection status (R0-X vs. R1-2, p < 0.001, HR = 6.49, 95% CI 2.5-16.8).	('PFS', 'Var', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('R1-2', 'Gene', '2840;910;913', (250, 254))	('Ki67 proliferation index', 'CPA', (137, 161))	('tumor', 'Disease', (62, 67))	('resection status', 'CPA', (223, 239))	('associated', 'Reg', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('R1-2', 'Gene', (250, 254))
27468	32373071	Further investigation showed that high CDK4 protein expression was significantly associated with longer TTP during treatment with platinum-based chemotherapy (n = 53, median 6 vs. 4 months, p = 0.0156, HR = 3.1, 95% CI = 1.4-6.7) (Figure 2G).	('TTP', 'MPA', (104, 107))	('CDK4', 'Gene', '1019', (39, 43))	('CDK4', 'Gene', (39, 43))	('expression', 'MPA', (52, 62))	('high', 'Var', (34, 38))	('platinum', 'Chemical', 'MESH:D010984', (130, 138))	('protein', 'Protein', (44, 51))	('longer', 'PosReg', (97, 103))
27483	32373071	Whereas, CDK4 knockdown in NCI-H295R showed a significant decrease of cell viability when compared to the control (88.6 +- 9.3 vs. 100.0 +- 8.6, p < 0.0001) (Supplementary Figure 4C), no clear effect was detected in MUC1 cells (97.0 +- 7.6 vs. 100.0 +- 6.9, p = 0.175) (Supplementary Figure 4C).	('CDK4', 'Gene', (9, 13))	('CDK4', 'Gene', '1019', (9, 13))	('NCI-H295R', 'Var', (27, 36))	('cell viability', 'CPA', (70, 84))	('decrease', 'NegReg', (58, 66))	('MUC1', 'Gene', (216, 220))	('MUC1', 'Gene', '4582', (216, 220))	('knockdown', 'Var', (14, 23))	('NCI-H295R', 'CellLine', 'CVCL:0458', (27, 36))
27487	32373071	However, comparing the general effect of palbociclib in the two ACC cell lines, a stronger decrease in cell viability was observed in NCI-H295R which was obvious at higher drug concentrations or longer treatment times (Supplementary Figure 5A).	('cell viability', 'CPA', (103, 117))	('palbociclib', 'Chemical', 'MESH:C500026', (41, 52))	('NCI-H295R', 'CellLine', 'CVCL:0458', (134, 143))	('ACC', 'Phenotype', 'HP:0006744', (64, 67))	('NCI-H295R', 'Var', (134, 143))	('decrease', 'NegReg', (91, 99))
27504	32373071	High CDK4 expression could therefore be involved in better response to therapy with platinum compounds and thus explain at least in part the longer PFS observed in the entire cohort.	('High', 'Var', (0, 4))	('CDK4', 'Gene', (5, 9))	('platinum', 'Chemical', 'MESH:D010984', (84, 92))	('CDK4', 'Gene', '1019', (5, 9))	('expression', 'MPA', (10, 20))	('better', 'PosReg', (52, 58))	('response', 'MPA', (59, 67))
27510	32373071	Currently, they are also under investigation in phase I and II clinical trials on other solid tumors and in patients with amplification or overexpression of CDK4 at tumor level (NCT03242382).	('overexpression', 'PosReg', (139, 153))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('amplification', 'Var', (122, 135))	('CDK4', 'Gene', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('CDK4', 'Gene', '1019', (157, 161))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Disease', (165, 170))
27515	32373071	Of note, we observed that this effect was more evident in NCI-H295R than in MUC1 cell line.	('MUC1', 'Gene', (76, 80))	('MUC1', 'Gene', '4582', (76, 80))	('NCI-H295R', 'Var', (58, 67))	('NCI-H295R', 'CellLine', 'CVCL:0458', (58, 67))
27517	32373071	In terms of mechanisms, consistent with previous studies reporting the deletion of the RB gene and lack of RB1 in a subset of ACC tumors, we found no RB1 protein expression in neither NCI-H295R nor MUC1 cells, similarly to RB negative palbociclib sensitive hepatoma cells.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('RB', 'Gene', '5925', (87, 89))	('MUC1', 'Gene', (198, 202))	('MUC1', 'Gene', '4582', (198, 202))	('RB1', 'Gene', '5925', (150, 153))	('RB', 'Gene', '5925', (107, 109))	('RB negative palbociclib sensitive hepatoma', 'Disease', (223, 265))	('RB', 'Phenotype', 'HP:0009919', (223, 225))	('deletion', 'Var', (71, 79))	('RB negative palbociclib sensitive hepatoma', 'Disease', 'MESH:D012175', (223, 265))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('NCI-H295R', 'CellLine', 'CVCL:0458', (184, 193))	('RB', 'Phenotype', 'HP:0009919', (150, 152))	('RB1', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ACC', 'Phenotype', 'HP:0006744', (126, 129))	('RB', 'Phenotype', 'HP:0009919', (87, 89))	('protein', 'Protein', (154, 161))	('tumors', 'Disease', (130, 136))	('RB', 'Gene', '5925', (223, 225))	('RB1', 'Gene', '5925', (107, 110))	('expression', 'MPA', (162, 172))	('RB1', 'Gene', (150, 153))	('RB', 'Phenotype', 'HP:0009919', (107, 109))	('RB', 'Gene', '5925', (150, 152))
27534	32373071	Both palbociclib and linsitinib were reported to be mostly well-tolerated with the most common adverse events being hematologic toxicity under palbociclib and fatigue, nausea and hyperglycemia under linsitinib.	('fatigue', 'Disease', 'MESH:D005221', (159, 166))	('hematologic', 'Disease', (116, 127))	('hyperglycemia', 'Phenotype', 'HP:0003074', (179, 192))	('nausea', 'Phenotype', 'HP:0002018', (168, 174))	('nausea', 'Disease', (168, 174))	('fatigue', 'Disease', (159, 166))	('nausea', 'Disease', 'MESH:D009325', (168, 174))	('palbociclib', 'Var', (143, 154))	('hyperglycemia', 'Disease', 'MESH:D006943', (179, 192))	('toxicity', 'Disease', (128, 136))	('toxicity', 'Disease', 'MESH:D064420', (128, 136))	('fatigue', 'Phenotype', 'HP:0012378', (159, 166))	('linsitinib', 'Chemical', 'MESH:C551528', (199, 209))	('linsitinib', 'Chemical', 'MESH:C551528', (21, 31))	('palbociclib', 'Chemical', 'MESH:C500026', (5, 16))	('hyperglycemia', 'Disease', (179, 192))	('palbociclib', 'Chemical', 'MESH:C500026', (143, 154))
27543	32147670	A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence Genome-wide association studies (GWASs) have enriched the fields of genomics and drug development.	('men', 'Species', '9606', (202, 205))	('adrenocortical carcinoma', 'Disease', (60, 84))	('polymorphism', 'Var', (9, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('retinoic acid', 'Chemical', 'MESH:D014212', (29, 42))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (60, 84))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (60, 84))	('modifies', 'Reg', (51, 59))
27545	32147670	Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation.	('p.R337H (R337H', 'Var', (129, 143))	('p.R337H', 'Mutation', 'rs121912664', (129, 136))	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (124, 128))	('mutations', 'Var', (50, 59))	('R337H', 'Mutation', 'rs121912664', (138, 143))	('Paediatric ACC', 'Disease', (0, 14))	('TP53', 'Gene', (124, 128))	('R337H', 'Mutation', 'rs121912664', (131, 136))	('associated', 'Reg', (29, 39))	('ACC', 'Phenotype', 'HP:0006744', (11, 14))	('TP53', 'Gene', '7157', (45, 49))
27546	32147670	We analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients.	('patients', 'Species', '9606', (115, 123))	('R337H', 'Mutation', 'rs121912664', (85, 90))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('ACC', 'Phenotype', 'HP:0006744', (111, 114))	('ACC', 'Disease', (80, 83))	('R337H', 'Var', (85, 90))
27548	32147670	A SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts.	('alcohol dehydrogenase 7', 'Gene', '131', (24, 47))	('ACC', 'Phenotype', 'HP:0006744', (123, 126))	('ACC', 'Disease', (123, 126))	('rs971074', 'Mutation', 'rs971074', (7, 15))	('associated', 'Reg', (84, 94))	('rs971074', 'Var', (7, 15))	('alcohol dehydrogenase 7', 'Gene', (24, 47))
27554	32147670	Li-Fraumeni syndrome (LFS) families have a higher risk of developing paediatric ACC, with more than 50% of all children with ACC having a heritable TP53 mutation.	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('children', 'Species', '9606', (111, 119))	('ACC', 'Phenotype', 'HP:0006744', (125, 128))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('LFS', 'Disease', 'MESH:D016864', (22, 25))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('paediatric ACC', 'Disease', (69, 83))	('LFS', 'Disease', (22, 25))	('mutation', 'Var', (153, 161))
27560	32147670	The phenotypic heterogeneity among R337H carriers in terms of cancer risk and the variability in age-of-onset may indicate the involvement of environmental and/or genetic variants that are able to modulate cancer development.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('modulate', 'Reg', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('men', 'Species', '9606', (149, 152))	('R337H', 'Var', (35, 40))	('R337H', 'Mutation', 'rs121912664', (35, 40))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('men', 'Species', '9606', (220, 223))	('men', 'Species', '9606', (134, 137))
27561	32147670	The enormous heterogeneity in cancer development noted in families carrying the germline R337H mutation has prompted us to gain further insight into potential genetic factors cooperating to modify the age-dependent incidence of cancer onset in the adrenal cortex.	('R337H', 'Var', (89, 94))	('cancer', 'Disease', (228, 234))	('R337H', 'Mutation', 'rs121912664', (89, 94))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('men', 'Species', '9606', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
27566	32147670	For example, GWASs have identified over 900 SNPs significantly associated with cancer susceptibility traits.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SNPs', 'Var', (44, 48))	('associated', 'Reg', (63, 73))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
27568	32147670	The genetic data supporting the role of p53 in ACC has improved the early diagnosis of ACC in TP53 mutation carriers through asymptomatic screening.	('carriers', 'Reg', (108, 116))	('ACC', 'Phenotype', 'HP:0006744', (87, 90))	('improved', 'PosReg', (55, 63))	('ACC', 'Disease', (87, 90))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutation', 'Var', (99, 107))	('ACC', 'Phenotype', 'HP:0006744', (47, 50))
27569	32147670	The identification of other more druggable gene targets with genetic associations with ACC could prove useful, whereby SNPs in genes that associate with differential ACC cancer risk in TP53 mutation carriers could help to identify novel druggable genes and/or pathways.	('mutation', 'Var', (190, 198))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('ACC', 'Phenotype', 'HP:0006744', (87, 90))	('ACC', 'Phenotype', 'HP:0006744', (166, 169))	('cancer', 'Disease', (170, 176))	('TP53', 'Gene', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('TP53', 'Gene', '7157', (185, 189))
27570	32147670	SNPs in the p53 pathway have been clearly shown to associate with differential cancer risk.	('associate', 'Reg', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('p53 pathway', 'Pathway', (12, 23))	('SNPs', 'Var', (0, 4))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
27571	32147670	Indeed, SNPs in well-described p53 pathway genes have been frequently identified in GWASs of seemingly sporadic cancers.	('p53 pathway genes', 'Gene', (31, 48))	('SNPs', 'Var', (8, 12))	('identified', 'Reg', (70, 80))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('GWASs of', 'Disease', (84, 92))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
27572	32147670	In fact, one p53 pathway SNP, MDM2 SNP309 that associates with differential expression levels of a key regulator of p53, has been shown to modify cancer risk in TP53 mutation carriers with LFS.	('cancer', 'Disease', (146, 152))	('TP53', 'Gene', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('LFS', 'Disease', (189, 192))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('LFS', 'Disease', 'MESH:D016864', (189, 192))	('TP53', 'Gene', '7157', (161, 165))	('mutation', 'Var', (166, 174))	('modify', 'Reg', (139, 145))
27573	32147670	Specifically, LFS families with more penetrant TP53 mutations relative to the Brazilian R337H, are at higher risks of developing many types of cancer, such as sarcomas, breast, and brain cancers, as well as ACC.	('more', 'PosReg', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('ACC', 'Phenotype', 'HP:0006744', (207, 210))	('TP53', 'Gene', '7157', (47, 51))	('developing', 'PosReg', (118, 128))	('cancer', 'Disease', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('brain cancers', 'Disease', (181, 194))	('LFS', 'Disease', (14, 17))	('breast', 'Disease', (169, 175))	('LFS', 'Disease', 'MESH:D016864', (14, 17))	('brain cancers', 'Disease', 'MESH:D001932', (181, 194))	('mutations', 'Var', (52, 61))	('sarcomas', 'Disease', 'MESH:D012509', (159, 167))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('cancer', 'Disease', (187, 193))	('sarcomas', 'Disease', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('R337H', 'Mutation', 'rs121912664', (88, 93))	('TP53', 'Gene', (47, 51))
27574	32147670	MDM2 SNP309 has been shown to modify this cancer risk in multiple cohorts of TP53 mutation carriers in an age- and gender-dependent manner.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mutation', 'Var', (82, 90))	('MDM2', 'Var', (0, 4))	('modify', 'Reg', (30, 36))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
27575	32147670	Importantly, genetically engineered mouse models carrying either alleles of MDM2 SNP309 and a highly penetrant LFS p53 mutation demonstrated similar allele-specific differences in age-dependent cancer incidence.	('LFS', 'Disease', 'MESH:D016864', (111, 114))	('mutation', 'Var', (119, 127))	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('LFS', 'Disease', (111, 114))	('mouse', 'Species', '10090', (36, 41))
27577	32147670	Here, we studied two independent cohorts of ACC patients (paediatric and adult) to demonstrate that a SNP in a druggable gene and pathway significantly associates with ACC age-dependent incidence.	('ACC', 'Disease', (168, 171))	('ACC', 'Phenotype', 'HP:0006744', (44, 47))	('ACC', 'Phenotype', 'HP:0006744', (168, 171))	('associates with', 'Reg', (152, 167))	('patients', 'Species', '9606', (48, 56))	('SNP', 'Var', (102, 105))
27578	32147670	A cohort of children diagnosed with ACC with the R337H germline mutation was used in this study.	('ACC', 'Phenotype', 'HP:0006744', (36, 39))	('children', 'Species', '9606', (12, 20))	('ACC', 'Disease', (36, 39))	('R337H', 'Var', (49, 54))	('R337H', 'Mutation', 'rs121912664', (49, 54))
27606	32147670	In order to identify potential genetic modifiers underlying ACC development that could improve cancer risk management and treatment, we genotyped a total of 42 TP53 R337H carriers with ACC, divided into a discovery cohort (BRZ1, N = 26) and a validation cohort (BRZ2, N = 16).	('ACC', 'Disease', (185, 188))	('R337H', 'Mutation', 'rs121912664', (165, 170))	('R337H', 'Var', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('TP53', 'Gene', '7157', (160, 164))	('ACC', 'Phenotype', 'HP:0006744', (60, 63))	('cancer', 'Disease', (95, 101))	('men', 'Species', '9606', (71, 74))	('TP53', 'Gene', (160, 164))	('men', 'Species', '9606', (113, 116))	('BRZ', 'Chemical', '-', (223, 226))	('BRZ', 'Chemical', '-', (262, 265))	('ACC', 'Phenotype', 'HP:0006744', (185, 188))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('men', 'Species', '9606', (127, 130))
27613	32147670	In total, these SNPs were found to associate with differential risk of 33 different cancers.	('SNPs', 'Var', (16, 20))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
27623	32147670	One of these six SNPs, rs971074, significantly associated with differential age-of-onset (adj.	('rs971074', 'Var', (23, 31))	('rs971074', 'Mutation', 'rs971074', (23, 31))	('associated', 'Reg', (47, 57))
27624	32147670	rs971074 (C/T, chr4:100341861, Genome Reference Consortium Human Build 37 (GRCh37)/hg19) is a synonymous SNP located in exon 6 of the alcohol dehydrogenase 7 gene (ADH7) gene (Fig.	('Human', 'Species', '9606', (59, 64))	('rs971074', 'Mutation', 'rs971074', (0, 8))	('alcohol dehydrogenase 7', 'Gene', '131', (134, 157))	('alcohol dehydrogenase 7', 'Gene', (134, 157))	('rs971074', 'Var', (0, 8))	('ADH7', 'Gene', (164, 168))
27625	32147670	The TP53 mutation carriers with rs971074 minor allele (CT) were diagnosed at a median age of 0.85 year in the BRZ1 and at a median of 0.585 year in BRZ2 cohort.	('TP53', 'Gene', (4, 8))	('BRZ', 'Chemical', '-', (110, 113))	('rs971074 minor', 'Var', (32, 46))	('rs971074', 'Mutation', 'rs971074', (32, 40))	('BRZ', 'Chemical', '-', (148, 151))	('TP53', 'Gene', '7157', (4, 8))
27627	32147670	When the patients of BRZ1 and BRZ2 are combined (BRZ), CT patients were diagnosed at a median age of 0.67 years compared to a median age of 2.17 years for CC patients (p = 0.00068, Mann-Whitney U test) Table 1 and Fig.	('patients', 'Species', '9606', (9, 17))	('BRZ2', 'Var', (30, 34))	('BRZ', 'Chemical', '-', (30, 33))	('BRZ', 'Chemical', '-', (21, 24))	('BRZ', 'Chemical', '-', (49, 52))	('BRZ1', 'Var', (21, 25))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (158, 166))
27630	32147670	Altogether, these data show that the rs971074 SNP associates with differential ACC age-of-onset in both TP53 mutation carriers and non-carriers alike.	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('rs971074', 'Var', (37, 45))	('ACC age-of-onset', 'Disease', (79, 95))	('ACC', 'Phenotype', 'HP:0006744', (79, 82))	('rs971074', 'Mutation', 'rs971074', (37, 45))
27631	32147670	However, in ACC patients with no inherited TP53 mutations, the TP53 gene is known to be somatically mutated (19.6%, cBioPortal).	('ACC', 'Phenotype', 'HP:0006744', (12, 15))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('patients', 'Species', '9606', (16, 24))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
27632	32147670	In the adult cohort, 18 patients (19.6%) had known pathogenic TP53 mutations in their tumours, and 2 had the R337H germline mutation.	('R337H', 'Mutation', 'rs121912664', (109, 114))	('R337H', 'Var', (109, 114))	('TP53', 'Gene', '7157', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('TP53', 'Gene', (62, 66))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (24, 32))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))
27633	32147670	When we restrict our analyses to those 71 patients without either inherited or somatic TP53 mutations, and excluding the patient with no somatic mutation data, similar allelic differences in the age-of-onset were found (p = 0.00075, Kruskal-Wallis test, Table 2 and Supplementary Fig.	('men', 'Species', '9606', (272, 275))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('patient', 'Species', '9606', (42, 49))	('patients', 'Species', '9606', (42, 50))	('patient', 'Species', '9606', (121, 128))
27635	32147670	This corresponds to a 20.5 year earlier diagnosis for TT patients demonstrating the apparent TP53 mutation-independence of these associations.	('patients', 'Species', '9606', (57, 65))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('mutation-independence', 'Var', (98, 119))
27636	32147670	It is important to note that in a smaller paediatric ACC cohort (N = 21, The Hospital for Sick Children, Canada) of TP53 mutation carriers with more penetrant mutations and diagnosed at ages ranging from 1 to 17.83 years (Supplementary Table 3), no significant difference in ACC age-of-onset with the rs971074 SNP genotype was observed (Supplementary Table 4).	('TP53', 'Gene', (116, 120))	('ACC', 'Disease', (275, 278))	('rs971074', 'Mutation', 'rs971074', (301, 309))	('ACC', 'Phenotype', 'HP:0006744', (275, 278))	('mutations', 'Var', (159, 168))	('ACC', 'Phenotype', 'HP:0006744', (53, 56))	('men', 'Species', '9606', (228, 231))	('rs971074 SNP', 'Var', (301, 313))	('mutation', 'Var', (121, 129))	('Children', 'Species', '9606', (95, 103))	('TP53', 'Gene', '7157', (116, 120))	('men', 'Species', '9606', (343, 346))
27637	32147670	The rs971074 SNP was included in our list of cancer GWAS SNPs due to its association with differential cancer risk in the upper aerodigestive tract, particularly oesophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer GWAS SNPs', 'Disease', (45, 61))	('cancer GWAS SNPs', 'Disease', 'MESH:D009369', (45, 61))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('rs971074', 'Mutation', 'rs971074', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (174, 180))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('rs971074', 'Var', (4, 12))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
27663	32147670	We demonstrated that the minor allele of rs971074 in ADH7 associates with a significantly earlier age of paediatric ACC in R337H carriers (CT) and adult ACC (TT), relative to patients homozygous for the major allele (CC) in a manner that is seemingly independent of both inherited and somatic TP53 mutations.	('R337H', 'Var', (123, 128))	('R337H', 'Mutation', 'rs121912664', (123, 128))	('rs971074', 'Mutation', 'rs971074', (41, 49))	('TP53', 'Gene', '7157', (293, 297))	('TP53', 'Gene', (293, 297))	('ADH7', 'Gene', (53, 57))	('ACC', 'Phenotype', 'HP:0006744', (153, 156))	('earlier', 'PosReg', (90, 97))	('rs971074', 'Var', (41, 49))	('patients', 'Species', '9606', (175, 183))	('ACC', 'Phenotype', 'HP:0006744', (116, 119))
27666	32147670	For instance, amplification of chromosome 9q occurs in 90% of paediatric ACC tumours but not in adult tumours.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('ACC', 'Phenotype', 'HP:0006744', (73, 76))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('tumours', 'Disease', (77, 84))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('tumours', 'Disease', (102, 109))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('amplification', 'Var', (14, 27))
27667	32147670	Moreover, although upregulation of the Wnt/beta-catenin signalling is common in paediatric and adult ACC, mutations in ZNRF3 are only observed in adult tumours.	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('tumours', 'Disease', (152, 159))	('ACC', 'Phenotype', 'HP:0006744', (101, 104))	('ZNRF3', 'Gene', '84133', (119, 124))	('ZNRF3', 'Gene', (119, 124))	('upregulation', 'PosReg', (19, 31))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (106, 115))	('beta-catenin', 'Gene', (43, 55))	('beta-catenin', 'Gene', '1499', (43, 55))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))
27670	32147670	The rs971074 SNP is a synonymous SNP found in exon 6 of ADH7.	('ADH7', 'Gene', (56, 60))	('rs971074', 'Mutation', 'rs971074', (4, 12))	('rs971074 SNP', 'Var', (4, 16))
27682	32147670	Specifically, using a two-step validation strategy to identify transcripts that significantly and reproducibly associate with ACC progression, we clearly demonstrated that transcripts for multiple RA pathway genes associate with differential progression in both adult (five genes) and paediatric (three genes) ACC.	('RA', 'Chemical', 'MESH:D014212', (197, 199))	('ACC', 'Phenotype', 'HP:0006744', (310, 313))	('transcripts', 'Var', (172, 183))	('ACC', 'Phenotype', 'HP:0006744', (126, 129))	('progression', 'PosReg', (242, 253))	('ACC', 'Disease', (126, 129))	('RA pathway genes', 'Gene', (197, 213))
27695	32147670	Support of this came from experiments in both cell culture and murine xenografts, whereby treatment of ACC with 9-cis RA resulted in decreased cell viability, proliferation, and steroid hormone production.	('cell viability', 'CPA', (143, 157))	('ACC', 'Phenotype', 'HP:0006744', (103, 106))	('murine', 'Species', '10090', (63, 69))	('steroid', 'Chemical', 'MESH:D013256', (178, 185))	('proliferation', 'CPA', (159, 172))	('men', 'Species', '9606', (32, 35))	('steroid hormone production', 'MPA', (178, 204))	('men', 'Species', '9606', (95, 98))	('9-cis RA', 'Chemical', 'MESH:D000077556', (112, 120))	('decreased', 'NegReg', (133, 142))	('9-cis RA', 'Var', (112, 120))
27697	32147670	It is intriguing to note that a recent study of metastatic ACC tumours has identified an enrichment of driver mutations in RA pathway genes, possibly lending further support to the inactivation of this pathway being a crucial step in ACC progression.	('tumours', 'Disease', (63, 70))	('RA', 'Chemical', 'MESH:D014212', (123, 125))	('mutations', 'Var', (110, 119))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('men', 'Species', '9606', (95, 98))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('ACC', 'Phenotype', 'HP:0006744', (234, 237))	('ACC', 'Phenotype', 'HP:0006744', (59, 62))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
27700	32147670	These findings will impact the design of future studies using RA in pre-clinical studies and guide preventive actions following genetic counselling and testing for children carriers of R337H germline mutation.	('children', 'Species', '9606', (164, 172))	('R337H', 'Mutation', 'rs121912664', (185, 190))	('R337H', 'Var', (185, 190))	('RA', 'Chemical', 'MESH:D014212', (62, 64))	('impact', 'Reg', (20, 26))
27841	30416972	The ratio would be even lower in the pediatric setting, given that deficiency of TSH is as frequent as deficiency of other anterior pituitary hormones among children and adolescents with post-TBI hypopituitarism.	('hypopituitarism', 'Phenotype', 'HP:0040075', (196, 211))	('hypopituitarism', 'Disease', 'MESH:D007018', (196, 211))	('TSH', 'Gene', (81, 84))	('deficiency of other anterior pituitary', 'Disease', 'MESH:D010900', (103, 141))	('deficiency of TSH', 'Phenotype', 'HP:0031098', (67, 84))	('TSH', 'Chemical', '-', (81, 84))	('rat', 'Species', '10116', (4, 7))	('deficiency of other anterior pituitary', 'Disease', (103, 141))	('children', 'Species', '9606', (157, 165))	('deficiency', 'Var', (67, 77))	('hypopituitarism', 'Disease', (196, 211))
27913	30416972	However, the results of the TRH test in 37 survivors after cranial irradiation for childhood tumors and 33 matched controls demonstrated abnormalities in TSH dynamics of survivors representing subtle alteration of hypothalamus-pituitary-thyroid axis consisting of a shift in the timing of the peak and/or nadir TSH and not an actual loss of TSH diurnal rhythm.	('childhood tumors', 'Disease', 'MESH:D009369', (83, 99))	('nadir TSH', 'Phenotype', 'HP:0002925', (305, 314))	('rat', 'Species', '10116', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('alteration', 'Reg', (200, 210))	('childhood tumors', 'Disease', (83, 99))	('hypothalamus-pituitary-thyroid axis', 'Disease', 'MESH:D007029', (214, 249))	('rat', 'Species', '10116', (204, 207))	('TSH', 'Chemical', '-', (341, 344))	('TSH', 'Chemical', '-', (311, 314))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('hypothalamus-pituitary-thyroid axis', 'Disease', (214, 249))	('abnormalities', 'Var', (137, 150))	('TSH', 'Chemical', '-', (154, 157))	('TSH', 'MPA', (311, 314))	('TSH', 'MPA', (154, 157))
27997	30416972	Rarely, monoclonal anti-programmed cell death-1 receptor (anti-PD-1) antibodies, such as pembrolizumab and nivolumab cause hypophysitis.	('hypophysitis', 'Disease', (123, 135))	('anti-PD-1', 'Gene', (58, 67))	('cause', 'Reg', (117, 122))	('nivolumab', 'Chemical', 'MESH:D000077594', (107, 116))	('antibodies', 'Var', (69, 79))	('pembrolizumab', 'Chemical', 'MESH:C582435', (89, 102))	('hypophysitis', 'Disease', 'MESH:D000072659', (123, 135))
28000	30416972	Unlike anti-CTLA-4 antibodies, anti-PD1-induced hypophysitis is less frequent compared with thyroiditis.	('thyroiditis', 'Disease', (92, 103))	('CTLA-4', 'Gene', '1493', (12, 18))	('anti-PD1-induced', 'Var', (31, 47))	('hypophysitis', 'Disease', 'MESH:D000072659', (48, 60))	('thyroiditis', 'Phenotype', 'HP:0100646', (92, 103))	('thyroiditis', 'Disease', 'MESH:D013959', (92, 103))	('hypophysitis', 'Disease', (48, 60))	('CTLA-4', 'Gene', (12, 18))
28003	30416972	The difference in the rate of hypophysitis between anti-PD-1 antibodies and anti-CTLA-4 antibodies may be explained by different activation of T-cells and ectopic expression of CTLA-4 in pituitary cells.	('CTLA-4', 'Gene', '1493', (177, 183))	('antibodies', 'Var', (61, 71))	('CTLA-4', 'Gene', '1493', (81, 87))	('hypophysitis', 'Disease', (30, 42))	('rat', 'Species', '10116', (22, 25))	('CTLA-4', 'Gene', (177, 183))	('activation', 'PosReg', (129, 139))	('anti-PD-1 antibodies', 'Var', (51, 71))	('T-cells', 'CPA', (143, 150))	('CTLA-4', 'Gene', (81, 87))	('hypophysitis', 'Disease', 'MESH:D000072659', (30, 42))
28051	30089500	There are ten cancer types that have a TP53 mutation rate greater than 50% in total (Fig.	('cancer', 'Disease', (14, 20))	('mutation', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('TP53', 'Gene', (39, 43))
28052	30089500	Moreover, we can find a summary of the variant classification of TP53 mutations in cancers, e.g., in pancreatic adenocarcinoma (PAAD), 64 and 12% of TP53 mutations being missense and frame-shift insertion, respectively (Fig.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (101, 126))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('TP53', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('TP53', 'Gene', '7157', (149, 153))	('missense', 'Var', (170, 178))	('pancreatic adenocarcinoma', 'Disease', (101, 126))	('TP53', 'Gene', (149, 153))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (101, 126))	('mutations', 'Var', (154, 163))	('PAAD', 'Phenotype', 'HP:0006725', (128, 132))	('frame-shift insertion', 'Var', (183, 204))	('cancers', 'Disease', (83, 90))
28053	30089500	Importantly, we can find the associations of TP53 mutations with survival prognosis in cancers.	('cancers', 'Disease', (87, 94))	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('associations', 'Interaction', (29, 41))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('survival prognosis', 'CPA', (65, 83))	('TP53', 'Gene', '7157', (45, 49))
28054	30089500	For example, TP53 mutations are associated with worse survival (overall and disease free survival) prognosis in PAAD (Fig.	('TP53', 'Gene', (13, 17))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('PAAD', 'Disease', (112, 116))	('TP53', 'Gene', '7157', (13, 17))	('mutations', 'Var', (18, 27))
28056	30089500	In fact, previous studies have shown that PLK1 interacted with TP53, and that p53 dysfunction caused enhanced expression of PLK1 in cancers.	('PLK1', 'Gene', (124, 128))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('TP53', 'Gene', '7157', (63, 67))	('PLK1', 'Gene', '5347', (42, 46))	('TP53', 'Gene', (63, 67))	('PLK1', 'Gene', '5347', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('p53', 'Gene', (78, 81))	('enhanced', 'PosReg', (101, 109))	('expression', 'MPA', (110, 120))	('p53', 'Gene', '7157', (78, 81))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('PLK1', 'Gene', (42, 46))	('dysfunction', 'Var', (82, 93))
28081	30089500	In addition, TCOA shows that mir-1269, mir-10b, mir-224, and mir-183 are overexpressed in LIHC with more than 4-fold expression increase compared to normal tissue, while mir-1258, mir-675, mir-490, mir-424, mir-483, mir-1247, mir-199b, mir-199a-2, mir-139, mir-199a-1, mir-3607, and mir-451 are underexpressed in LIHC with more than 4-fold expression decrease compared to normal tissue (Fig.	('mir-183', 'Gene', '406959', (61, 68))	('mir-10b', 'Gene', '406903', (39, 46))	('mir-483', 'Gene', '619552', (207, 214))	('mir-675', 'Gene', '100033819', (180, 187))	('mir-199b', 'Gene', (226, 234))	('mir-451', 'Gene', '574411', (283, 290))	('TCOA', 'Chemical', '-', (13, 17))	('mir-139', 'Gene', '406931', (248, 255))	('mir-139', 'Gene', (248, 255))	('mir-199a-2', 'Gene', (236, 246))	('mir-10b', 'Gene', (39, 46))	('mir-451', 'Gene', (283, 290))	('mir-199a-2', 'Gene', '406977', (236, 246))	('mir-1269', 'Var', (29, 37))	('expression', 'MPA', (117, 127))	('mir-224', 'Gene', '407009', (48, 55))	('mir-483', 'Gene', (207, 214))	('mir-199b', 'Gene', '406978', (226, 234))	('mir-424', 'Gene', '494336', (198, 205))	('mir-424', 'Gene', (198, 205))	('decrease', 'NegReg', (351, 359))	('mir-183', 'Gene', (61, 68))	('mir-199a-1', 'Gene', (257, 267))	('increase', 'PosReg', (128, 136))	('mir-490', 'Gene', '574443', (189, 196))	('expression', 'MPA', (340, 350))	('mir-675', 'Gene', (180, 187))	('mir-490', 'Gene', (189, 196))	('mir-199a-1', 'Gene', '406976', (257, 267))	('mir-224', 'Gene', (48, 55))
28102	30089500	Kaplan-Meier survival curves were used to show the survival (OS or DFS) differences between gene-mutated cancer patients and gene-wildtype cancer patients, and between gene, miRNA or protein higher-expression-level patients and lower-expression-level patients.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('patients', 'Species', '9606', (215, 223))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('protein', 'Protein', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('patients', 'Species', '9606', (112, 120))	('gene-mutated', 'Var', (92, 104))	('higher-expression-level', 'PosReg', (191, 214))	('patients', 'Species', '9606', (251, 259))	('miRNA', 'Protein', (174, 179))	('OS', 'Chemical', '-', (61, 63))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Disease', (139, 145))
28215	27900213	Another study showed the likelihood of cancer to be 10%, 19%, and 47% for tumours >=4 cm, >=6 cm, and >=8 cm, respectively.	('>=8 cm', 'Var', (102, 108))	('>=6 cm', 'Var', (90, 96))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumours', 'Disease', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
28296	27241967	CS in children is often caused by germline or somatic mutations in an expanding list of genes with implications for the prognosis of the patients and for their families.	('children', 'Species', '9606', (6, 14))	('caused by', 'Reg', (24, 33))	('germline', 'Var', (34, 42))	('patients', 'Species', '9606', (137, 145))
28330	27241967	In some patients with PBMAH/MMAD, cortisol levels appear to increase with food ingestion, a condition that is known as food-dependent CS.	('cortisol levels', 'MPA', (34, 49))	('cortisol', 'Chemical', 'MESH:D006854', (34, 42))	('increase', 'PosReg', (60, 68))	('food ingestion', 'Disease', (74, 88))	('PBMAH/MMAD', 'Var', (22, 32))	('patients', 'Species', '9606', (8, 16))
28392	27241967	PBMAH/MMAD presents with massive enlargement of both adrenal glands, whereas PPNAD or iMAD, as mentioned above, is more difficult to diagnose radiologically because it is usually associated with normal or small-sized adrenal glands, despite the histologic presence of hyperplasia.	('hyperplasia', 'Disease', (268, 279))	('small-sized adrenal glands', 'Phenotype', 'HP:0000835', (205, 231))	('PBMAH/MMAD', 'Var', (0, 10))	('enlargement of both adrenal glands', 'Phenotype', 'HP:0008221', (33, 67))	('hyperplasia', 'Disease', 'MESH:D006965', (268, 279))	('enlargement', 'PosReg', (33, 44))
28431	27241967	Genetic and molecular mechanisms responsible for excess cortisol secretion by primary adrenal lesions have been identified, as outlined in this review.	('excess cortisol', 'Phenotype', 'HP:0003118', (49, 64))	('lesions', 'Var', (94, 101))	('cortisol secretion', 'MPA', (56, 74))	('cortisol', 'Chemical', 'MESH:D006854', (56, 64))	('excess', 'PosReg', (49, 55))
28463	27241967	Mifepristone (RU486), an effective oral glucocorticoid receptor antagonist, is now approved for use in adult patients with recurrent CD.	('RU486', 'Var', (14, 19))	('glucocorticoid receptor', 'Gene', '2908', (40, 63))	('Mifepristone', 'Chemical', 'MESH:D015735', (0, 12))	('RU486', 'Chemical', 'MESH:D015735', (14, 19))	('patients', 'Species', '9606', (109, 117))	('glucocorticoid receptor', 'Gene', (40, 63))
28474	27241967	As mentioned above, MAS was found to be due to postzygotic activating mutations in the alpha subunit of the gene for the stimulatory guanine-nucleotide- binding protein (Gsalpha) which leads to activation of the cAMP/PKA pathway by leading to increased cAMP levels.	('MAS', 'Disease', 'MESH:D005357', (20, 23))	('mutations', 'Var', (70, 79))	('MAS', 'Disease', (20, 23))	('activation', 'PosReg', (194, 204))	('Gsalpha', 'Gene', '2778', (170, 177))	('activating', 'PosReg', (59, 69))	('cAMP/PKA pathway', 'Pathway', (212, 228))	('cAMP', 'Chemical', 'MESH:D000242', (212, 216))	('cAMP', 'Chemical', 'MESH:D000242', (253, 257))	('increased', 'PosReg', (243, 252))	('Gsalpha', 'Gene', (170, 177))	('cAMP levels', 'MPA', (253, 264))
28475	27241967	Today somatic mutations of GNAS1 have been described in a small number of cortisol-producing AAs, and in PBMAH/MMAD, in addition to MAS.	('small number of cortisol', 'Phenotype', 'HP:0008163', (58, 82))	('cortisol', 'Chemical', 'MESH:D006854', (74, 82))	('GNAS1', 'Gene', (27, 32))	('cortisol-producing AAs', 'Disease', (74, 96))	('GNAS1', 'Gene', '2778', (27, 32))	('MAS', 'Disease', (132, 135))	('MAS', 'Disease', 'MESH:D005357', (132, 135))	('described', 'Reg', (43, 52))	('mutations', 'Var', (14, 23))
28476	27241967	Inactivating germline mutations of the PRKAR1A gene coding for the regulatory 1A subunit of PKA were then found to be responsible for PPNAD (and CNC).	('responsible', 'Reg', (118, 129))	('Inactivating germline mutations', 'Var', (0, 31))	('PRKAR1A', 'Gene', (39, 46))	('PRKAR1A', 'Gene', '5573', (39, 46))	('PPNAD', 'Disease', (134, 139))
28477	27241967	Inactivating PRKAR1A mutations lead to constitutive activation of the cAMP/PKA pathway by increasing the availability of the PKA catalytic subunit.	('cAMP', 'Chemical', 'MESH:D000242', (70, 74))	('mutations', 'Var', (21, 30))	('PRKAR1A', 'Gene', (13, 20))	('availability of', 'MPA', (105, 120))	('cAMP/PKA pathway', 'Pathway', (70, 86))	('PRKAR1A', 'Gene', '5573', (13, 20))	('increasing', 'PosReg', (90, 100))	('activation', 'PosReg', (52, 62))
28481	27241967	Genetic defects in cAMP-binding phosphodiesterases (PDEs) have been described in isolated PPNAD as well as in other forms of micronodular BAH, such as iMAD.	('cAMP', 'Chemical', 'MESH:D000242', (19, 23))	('BAH', 'Chemical', '-', (138, 141))	('Genetic defects', 'Var', (0, 15))	('isolated PPNAD', 'Disease', (81, 95))	('PDEs', 'Gene', '50940', (52, 56))	('PDEs', 'Gene', (52, 56))	('described', 'Reg', (68, 77))
28482	27241967	cAMP-binding PDEs decrease cAMP levels after stimulation of the cAMP/PKA pathway; inactivating PDE mutations lead to accumulation of cAMP and dysregulated activation of the PKA pathway.	('cAMP levels', 'MPA', (27, 38))	('PDE', 'Gene', (13, 16))	('PDEs', 'Gene', (13, 17))	('PDEs', 'Gene', '50940', (13, 17))	('cAMP', 'Chemical', 'MESH:D000242', (133, 137))	('accumulation', 'PosReg', (117, 129))	('cAMP', 'Chemical', 'MESH:D000242', (64, 68))	('cAMP', 'Chemical', 'MESH:D000242', (27, 31))	('PDE', 'Gene', '501', (95, 98))	('mutations', 'Var', (99, 108))	('cAMP', 'Chemical', 'MESH:D000242', (0, 4))	('PDE', 'Gene', (95, 98))	('activation', 'PosReg', (155, 165))	('PKA pathway', 'Pathway', (173, 184))	('PDE', 'Gene', '501', (13, 16))	('cAMP', 'MPA', (133, 137))
28483	27241967	Mutations in two different PDEs, PDE11A and PDE8B, are associated with iMAD.	('PDEs', 'Gene', '50940', (27, 31))	('PDE8B', 'Gene', '8622', (44, 49))	('PDE8B', 'Gene', (44, 49))	('iMAD', 'Disease', (71, 75))	('associated', 'Reg', (55, 65))	('PDE11A', 'Gene', '50940', (33, 39))	('PDEs', 'Gene', (27, 31))	('Mutations', 'Var', (0, 9))	('PDE11A', 'Gene', (33, 39))
28485	27241967	The catalytic subunit of PKA, PRKACA was found to be recurrently mutated: one hotspot mutation was the most frequent c.617A>G/p.Leu206Arg, a single amino acid change that leads to constitutive activation of PKA.	('p.Leu206Arg', 'Mutation', 'rs386352352', (126, 137))	('PRKACA', 'Gene', '5566', (30, 36))	('c.617A>G/p.Leu206Arg', 'Var', (117, 137))	('activation', 'PosReg', (193, 203))	('c.617A>G', 'Mutation', 'c.617A>G', (117, 125))	('PRKACA', 'Gene', (30, 36))
28486	27241967	Today, PRKACA-activating mutations have been identified in 42% of all AAs studied and additional mutations beyond the original one (p.Leu206Arg) -which to date remains the most frequent one- have been identified.	('p.Leu206Arg', 'Var', (132, 143))	('PRKACA', 'Gene', (7, 13))	('p.Leu206Arg', 'Mutation', 'rs386352352', (132, 143))	('PRKACA', 'Gene', '5566', (7, 13))	('AAs', 'Disease', (70, 73))
28487	27241967	Patients harboring a PRKACA mutation were typically younger at the time of the diagnosis of CS and presented with smaller tumors.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Disease', (122, 128))	('PRKACA', 'Gene', (21, 27))	('PRKACA', 'Gene', '5566', (21, 27))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
28488	27241967	Activating PRKACA mutations cluster at the interface of the regulatory and catalytic subunits, interfere with the formation of a stable PKA holoenzyme, and, thus, result in constitutive activation of PKA and increased cortisol production and altered proliferation in these tumors.	('formation', 'MPA', (114, 123))	('Activating', 'PosReg', (0, 10))	('increased cortisol', 'Phenotype', 'HP:0003118', (208, 226))	('activation', 'PosReg', (186, 196))	('tumors', 'Disease', 'MESH:D009369', (273, 279))	('cortisol', 'Chemical', 'MESH:D006854', (218, 226))	('PRKACA', 'Gene', (11, 17))	('altered', 'Reg', (242, 249))	('interfere', 'NegReg', (95, 104))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('PKA', 'Enzyme', (200, 203))	('cortisol production', 'MPA', (218, 237))	('increased', 'PosReg', (208, 217))	('PRKACA', 'Gene', '5566', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('proliferation', 'CPA', (250, 263))	('tumors', 'Disease', (273, 279))	('mutations', 'Var', (18, 27))
28490	27241967	We have recently reported five patients with BAH and CS caused by genetic rearrangements in in the chromosome 19p13 locus, resulting in copy number gains encompassing the entire PRKACA gene.	('copy', 'MPA', (136, 140))	('PRKACA', 'Gene', (178, 184))	('genetic rearrangements in', 'Var', (66, 91))	('BAH', 'Disease', (45, 48))	('gains', 'PosReg', (148, 153))	('BAH', 'Chemical', '-', (45, 48))	('PRKACA', 'Gene', '5566', (178, 184))	('patients', 'Species', '9606', (31, 39))	('caused by', 'Reg', (56, 65))
28492	27241967	The PRKACA copy number variation may be inherited in an autosomal dominant manner or occur de novo.	('copy number variation', 'Var', (11, 32))	('PRKACA', 'Gene', '5566', (4, 10))	('PRKACA', 'Gene', (4, 10))
28493	27241967	PRKACA amplification can lead to both micro- and macro-nodular BAH associated with CS that may have a milder or more severe clinical phenotype, depending on the gene dosage.	('BAH', 'Chemical', '-', (63, 66))	('PRKACA', 'Gene', (0, 6))	('lead to', 'Reg', (25, 32))	('PRKACA', 'Gene', '5566', (0, 6))	('associated', 'Reg', (67, 77))	('amplification', 'Var', (7, 20))
28494	27241967	PBMAH/MMAD may rarely be found as a feature of multiple tumor syndromes including familial adenomatous polyposis (caused by APC gene mutations), multiple endocrine neoplasia type 1 (caused by menin gene mutations), or hereditary leiomyomatosis and renal cell carcinoma (caused by fumarate hydratase FH gene mutations).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('multiple tumor', 'Disease', (47, 61))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (82, 112))	('FH', 'Disease', 'MESH:D006938', (299, 301))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (91, 112))	('APC', 'Gene', '324', (124, 127))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (154, 173))	('menin', 'Gene', '4221', (192, 197))	('mutations', 'Var', (133, 142))	('menin', 'Gene', (192, 197))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (248, 268))	('mutations', 'Var', (307, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('multiple endocrine neoplasia type', 'Disease', 'MESH:D018761', (145, 178))	('APC', 'Gene', (124, 127))	('mutations', 'Var', (203, 212))	('hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C535516', (218, 268))	('multiple endocrine neoplasia type', 'Disease', (145, 178))	('multiple tumor', 'Disease', 'MESH:D009369', (47, 61))	('familial adenomatous polyposis', 'Disease', (82, 112))	('neoplasia', 'Phenotype', 'HP:0002664', (164, 173))
28498	27241967	Inactivating ARMC5 mutations were detected in the tumors; in all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('carried', 'Reg', (94, 101))	('ARMC5', 'Gene', '79798', (88, 93))	('ARMC5', 'Gene', (88, 93))	('ARMC5', 'Gene', (13, 18))	('mutations', 'Var', (102, 111))	('ARMC5', 'Gene', '79798', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
28500	27241967	Subsequent studies have confirmed the high frequency of ARMC5 mutations in this disorder.	('ARMC5', 'Gene', (56, 61))	('mutations', 'Var', (62, 71))	('ARMC5', 'Gene', '79798', (56, 61))
28508	27241967	Both pituitary adenomas and adrenocortical tumors, including bilateral adrenocortical hypeprlasias are often caused by germline or somatic mutations in an ever expanding list of genes with implications for the family of the patients and the prognosis of the patients.	('pituitary adenoma', 'Phenotype', 'HP:0002893', (5, 22))	('pituitary adenomas', 'Disease', (5, 23))	('adrenocortical hypeprlasias', 'Disease', 'MESH:D018268', (71, 98))	('bilateral adrenocortical hypeprlasia', 'Disease', 'MESH:D018268', (61, 97))	('mutations', 'Var', (139, 148))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (28, 49))	('bilateral adrenocortical hypeprlasia', 'Disease', (61, 97))	('pituitary adenomas', 'Disease', 'MESH:D010911', (5, 23))	('caused by', 'Reg', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('patients', 'Species', '9606', (224, 232))	('patients', 'Species', '9606', (258, 266))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('adrenocortical hypeprlasias', 'Disease', (71, 98))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (5, 23))	('adrenocortical tumors', 'Disease', (28, 49))
28519	26812773	ACCs in children can occur as a component of a multisystem syndrome such as Beckwith-Wiedemann Syndrome, multiple endocrine neoplasia (MEN) type 1, Carney's complex, hemihypertrophy syndrome, Li-Fraumeni and other constitutional p53 mutations.	('hemihypertrophy', 'Phenotype', 'HP:0001528', (166, 181))	('neoplasia', 'Phenotype', 'HP:0002664', (124, 133))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (105, 133))	('multisystem syndrome', 'Disease', 'MESH:D004194', (47, 67))	('multiple endocrine neoplasia', 'Disease', (105, 133))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (114, 133))	('children', 'Species', '9606', (8, 16))	('Beckwith-Wiedemann Syndrome', 'Disease', (76, 103))	('p53', 'Gene', '7157', (229, 232))	("Carney's complex", 'Disease', (148, 164))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('MEN', 'Species', '9606', (135, 138))	('Beckwith-Wiedemann Syndrome', 'Disease', 'MESH:D001506', (76, 103))	('p53', 'Gene', (229, 232))	('multisystem syndrome', 'Disease', (47, 67))	('hemihypertrophy syndrome', 'Disease', 'MESH:C563014', (166, 190))	('Li-Fraumeni', 'Disease', (192, 203))	('hemihypertrophy syndrome', 'Disease', (166, 190))	('mutations', 'Var', (233, 242))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (192, 203))
28540	26812773	Our patient met criteria for stage II (completely resected, tumor >=100 g, or volume >=200 cm3, with normal postoperative hormone levels).	('>=100 g', 'Var', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
28550	26812773	This included assessment for defects in adrenal steroidogenesis causing adrenal hyperplasia or for adrenal tumors.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (72, 91))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (72, 91))	('defects', 'Var', (29, 36))	('adrenal tumors', 'Disease', (99, 113))	('steroid', 'Chemical', 'MESH:D013256', (48, 55))	('adrenal tumors', 'Disease', 'MESH:D000310', (99, 113))	('adrenal steroidogenesis', 'MPA', (40, 63))	('causing', 'Reg', (64, 71))	('adrenal hyperplasia', 'Disease', (72, 91))
28573	26812773	However, the likelihood of a TP53 pathogenic germ line variant is 50%-80% for children with ACC even in the absence of family history.	('variant', 'Var', (55, 62))	('ACC', 'Phenotype', 'HP:0006744', (92, 95))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('children', 'Species', '9606', (78, 86))	('pathogenic', 'Reg', (34, 44))
28576	26812773	Increasing surveillance based on a positive TP53 mutation can help detect cancers early.	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('mutation', 'Var', (49, 57))	('cancers', 'Disease', (74, 81))	('TP53', 'Gene', '7157', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('TP53', 'Gene', (44, 48))
28612	27022243	Growing evidence has shown that aberrant Beclin-1 expression is associated with several tumors, such as hepatocellular carcinoma, colonic carcinomas, and hypopharyngeal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('hepatocellular carcinoma', 'Disease', (104, 128))	('hypopharyngeal carcinoma', 'Disease', 'MESH:D007012', (154, 178))	('aberrant', 'Var', (32, 40))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('expression', 'MPA', (50, 60))	('associated', 'Reg', (64, 74))	('hypopharyngeal carcinoma', 'Disease', (154, 178))	('Beclin-1', 'Gene', '8678', (41, 49))	('colonic carcinomas', 'Disease', (130, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('colonic carcinomas', 'Disease', 'MESH:D015179', (130, 148))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (104, 128))	('Beclin-1', 'Gene', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('hypopharyngeal carcinoma', 'Phenotype', 'HP:0012182', (154, 178))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (104, 128))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))
28790	21111771	Among the down-regulated transcripts were several with functions in steroidogenesis that were affected to different degrees:i.e., Mc2r >Scarb1 > Star >= Hsd3b1 > Cyp11b1.	('steroid', 'Chemical', 'MESH:D013256', (68, 75))	('Scarb1', 'Gene', (136, 142))	('down-regulated', 'NegReg', (10, 24))	('steroidogenesis', 'MPA', (68, 83))	('Scarb1', 'Gene', '20778', (136, 142))	('Mc2r', 'Gene', '17200', (130, 134))	('Mc2r', 'Gene', (130, 134))	('Cyp11b1', 'Var', (162, 169))
28793	21111771	On a more global scale, SF-1 knockdown affects the accumulation of a large number of transcripts, most of which are not recognizably involved in steroid hormone biosynthesis.	('knockdown', 'Var', (29, 38))	('affects', 'Reg', (39, 46))	('steroid hormone', 'Chemical', 'MESH:D013256', (145, 160))	('accumulation of', 'MPA', (51, 66))	('SF-1', 'Gene', (24, 28))
28795	21111771	Indeed, manipulating SF-1 gene dosage in vivo raises some doubts about a master regulatory role for SF-1 in the expression of genes involved in adrenal steroidogenesis.	('SF-1', 'Gene', (21, 25))	('manipulating', 'Var', (8, 20))	('steroid', 'Chemical', 'MESH:D013256', (152, 159))
28797	21111771	In humans, heterozygous SF-1 mutations that disrupt its DNA binding activity sometimes cause adrenal insufficiency; in other cases, however, they have no effect on adrenal function while at the same time impairing gonadal function.	('adrenal insufficiency', 'Disease', (93, 114))	('gonadal function', 'CPA', (214, 230))	('impairing', 'NegReg', (204, 213))	('adrenal function', 'MPA', (164, 180))	('mutations', 'Var', (29, 38))	('cause', 'Reg', (87, 92))	('DNA binding', 'Interaction', (56, 67))	('humans', 'Species', '9606', (3, 9))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (93, 114))	('SF-1', 'Gene', (24, 28))	('disrupt', 'NegReg', (44, 51))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (93, 114))
28799	21111771	Similarly, manipulating SF-1 dosage in H295R human adrenocortical tumor cells by over-expressing wild-type SF-1, by transformation with a dominant negative SF-1 mutant or by knocking down SF-1 with siRNA has little or no effect on key enzymes in steroidogenesis such as STAR and CYP11A1.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('SF-1', 'Gene', (156, 160))	('mutant', 'Var', (161, 167))	('steroid', 'Chemical', 'MESH:D013256', (246, 253))	('over-expressing', 'PosReg', (81, 96))	('SF-1', 'Gene', (188, 192))	('human', 'Species', '9606', (45, 50))	('CYP11A1', 'Gene', '1583', (279, 286))	('STAR', 'Gene', '6770', (270, 274))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (51, 71))	('CYP11A1', 'Gene', (279, 286))	('knocking', 'Var', (174, 182))	('STAR', 'Gene', (270, 274))	('adrenocortical tumor', 'Disease', (51, 71))
28802	21111771	Given the concerns about the relative importance of SF-1 in situ discussed above, the present study was undertaken to determine the consequences of SF-1 knockdown on the steroidogenic potential of Y1 adrenocortical tumor cells.	('SF-1', 'Gene', (148, 152))	('knockdown', 'Var', (153, 162))	('adrenocortical tumor', 'Disease', (200, 220))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('steroid', 'Chemical', 'MESH:D013256', (170, 177))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (200, 220))	('steroidogenic potential', 'MPA', (170, 193))
28805	21111771	Transcripts encoding Cyp11a1 and Cyp11b1 are relatively resistant to SF-1 knockdown, whereas transcripts encoding StAR, Mc2r, Hsd3b1 and Scarb1 are considerably more sensitive.	('Cyp11a1', 'Gene', (21, 28))	('Cyp11b1', 'Var', (33, 40))	('StAR', 'Gene', '20845', (114, 118))	('Scarb1', 'Gene', (137, 143))	('Cyp11a1', 'Gene', '13070', (21, 28))	('Mc2r', 'Gene', '17200', (120, 124))	('StAR', 'Gene', (114, 118))	('SF-1', 'Gene', (69, 73))	('Scarb1', 'Gene', '20778', (137, 143))	('Mc2r', 'Gene', (120, 124))
28806	21111771	To determine if SF-1 has a more global role in the adrenal cortex extending beyond its role in steroidogenesis, we also have examined the genome-wide consequences of SF-1 knockdown in these cells.	('steroid', 'Chemical', 'MESH:D013256', (95, 102))	('knockdown', 'Var', (171, 180))	('SF-1', 'Gene', (166, 170))
28807	21111771	We observe that SF-1 knockdown alters the transcription landscape of Y1 adrenal cells by affecting the expression of slightly more than 2,000 transcripts, most of which are not recognizably involved in steroid hormone biosynthesis.	('expression', 'MPA', (103, 113))	('transcription', 'MPA', (42, 55))	('SF-1', 'Gene', (16, 20))	('affecting', 'Reg', (89, 98))	('steroid hormone', 'Chemical', 'MESH:D013256', (202, 217))	('alters', 'Reg', (31, 37))	('knockdown', 'Var', (21, 30))
28834	21111771	The two-class analysis controls for gene-specific variances in the data:e.g., variances caused by preferential labeling of transcripts with either the Cy5 or Cy3 dye.	('Cy3', 'Var', (158, 161))	('Cy3', 'Chemical', '-', (158, 161))	('Cy5', 'Var', (151, 154))	('preferential', 'PosReg', (98, 110))	('Cy5', 'Chemical', 'MESH:C085321', (151, 154))
28835	21111771	The set of transcripts significantly affected by SF-1 knockdown in microarray experiments was tested for enrichment in specific categories relative to their representation on the NIA 15K mouse cDNA array using a false discovery rate <= 0.05 as described in detail previously.	('SF-1', 'Gene', (49, 53))	('mouse', 'Species', '10090', (187, 192))	('affected', 'Reg', (37, 45))	('knockdown', 'Var', (54, 63))
28837	21111771	A control plasmid with a scrambled SF1 shRNA sequence did not affect SF-1 levels (data not shown), indicating that the knockdown of SF-1 was a specific effect of the SF-1 shRNA.	('SF-1', 'Gene', (132, 136))	('SF1', 'Gene', '26423', (35, 38))	('SF1', 'Gene', (35, 38))	('knockdown', 'Var', (119, 128))
28838	21111771	To evaluate the consequences of SF-1 knockdown in Y1 cells on steroidogenic potential, seven of the SF-1 shRNA transformants were examined by quantitative RT-PCR for transcripts derived from primary SF-1 targets in the adrenal cortex (reviewed in):i.e., Cyp11a1, Cyp11b1, Hsd3b1, Star, Mc2r and Scarb1.	('Cyp11a1', 'Gene', '13070', (254, 261))	('Mc2r', 'Gene', '17200', (286, 290))	('steroid', 'Chemical', 'MESH:D013256', (62, 69))	('Cyp11a1', 'Gene', (254, 261))	('Scarb1', 'Gene', (295, 301))	('Cyp11b1', 'Var', (263, 270))	('Mc2r', 'Gene', (286, 290))	('Scarb1', 'Gene', '20778', (295, 301))
28840	21111771	SF-1 knockdown was associated with a decrease in Mc2r transcripts to undetectable levels and with marked reductions in the levels of transcripts encoding StAR and Hsd3b1 (73% and 77% decreases, respectively) and Scarb1 (more than 90% reduction) (Fig.	('levels of transcripts', 'MPA', (123, 144))	('decrease', 'NegReg', (37, 45))	('Mc2r', 'Gene', '17200', (49, 53))	('Hsd3b1', 'Gene', (163, 169))	('StAR', 'Gene', (154, 158))	('Mc2r', 'Gene', (49, 53))	('knockdown', 'Var', (5, 14))	('reductions', 'NegReg', (105, 115))	('Scarb1', 'Gene', (212, 218))	('decreases', 'NegReg', (183, 192))	('SF-1', 'Gene', (0, 4))	('StAR', 'Gene', '20845', (154, 158))	('Scarb1', 'Gene', '20778', (212, 218))
28841	21111771	Transcripts encoding Cyp11b1 were reduced by only 30%, whereas Cyp11a1 transcripts were unaffected by the decrease in SF-1 (Fig.	('reduced', 'NegReg', (34, 41))	('Transcripts', 'MPA', (0, 11))	('Cyp11a1', 'Gene', '13070', (63, 70))	('SF-1', 'Gene', (118, 122))	('decrease', 'NegReg', (106, 114))	('Cyp11a1', 'Gene', (63, 70))	('Cyp11b1', 'Var', (21, 28))
28842	21111771	In contrast, transfection of the SF-1 knockdown clones with an expression vector encoding mouse SF-1 increased SF-1 transcript accumulation and also increased the accumulation of transcripts for StAR, Cyp11b1, Scarb1, Mc2r and Hsd3b1 (Fig.	('SF-1', 'Gene', (111, 115))	('transcripts', 'MPA', (179, 190))	('Cyp11b1', 'Var', (201, 208))	('Scarb1', 'Gene', '20778', (210, 216))	('StAR', 'Gene', (195, 199))	('increased', 'PosReg', (101, 110))	('increased', 'PosReg', (149, 158))	('mouse', 'Species', '10090', (90, 95))	('transcript accumulation', 'MPA', (116, 139))	('Mc2r', 'Gene', '17200', (218, 222))	('Mc2r', 'Gene', (218, 222))	('accumulation', 'MPA', (163, 175))	('StAR', 'Gene', '20845', (195, 199))	('SF-1', 'Gene', (96, 100))	('Scarb1', 'Gene', (210, 216))	('Hsd3b1', 'Gene', (227, 233))
28843	21111771	Cyp11a1, a transcript not significantly affected by SF-1 knockdown (Fig.	('Cyp11a1', 'Gene', (0, 7))	('Cyp11a1', 'Gene', '13070', (0, 7))	('knockdown', 'Var', (57, 66))	('SF-1', 'Gene', (52, 56))
28844	21111771	As shown in Table 1, SF-1 knockdown was accompanied by a more than 20-fold decrease in steroid output, whereas the restoration of SF-1 expression increased steroid output to levels seen in parental Y1 cells.	('decrease', 'NegReg', (75, 83))	('increased', 'PosReg', (146, 155))	('steroid output', 'MPA', (156, 170))	('steroid', 'Chemical', 'MESH:D013256', (87, 94))	('SF-1', 'Gene', (130, 134))	('knockdown', 'Var', (26, 35))	('restoration', 'Var', (115, 126))	('expression', 'MPA', (135, 145))	('SF-1', 'Gene', (21, 25))	('steroid', 'Chemical', 'MESH:D013256', (156, 163))	('steroid output', 'MPA', (87, 101))
28845	21111771	The very different effects of SF-1 knockdown on the accumulation of transcripts with functions in steroidogenesis (Fig.	('knockdown', 'Var', (35, 44))	('steroid', 'Chemical', 'MESH:D013256', (98, 105))	('SF-1', 'Gene', (30, 34))	('accumulation', 'MPA', (52, 64))
28846	21111771	To explore the basis for this difference, we compared the binding of SF-1 to the proximal promoter regions of Star, Cyp11a1 and Cyp11b1 by chromatin immunoprecipitation.	('Cyp11a1', 'Gene', (116, 123))	('Cyp11b1', 'Var', (128, 135))	('binding', 'Interaction', (58, 65))	('Cyp11a1', 'Gene', '13070', (116, 123))	('SF-1', 'Gene', (69, 73))	('compared', 'Reg', (45, 53))
28847	21111771	SF-1 antibodies precipitated greater amounts of promoter DNA from the Star, Cyp11b1 and Cyp11a1 genes in parent Y1 cells than did a control IgG (Fig.	('Cyp11a1', 'Gene', (88, 95))	('promoter DNA', 'MPA', (48, 60))	('Cyp11a1', 'Gene', '13070', (88, 95))	('Cyp11b1', 'Var', (76, 83))
28850	21111771	As shown in Figure 4B, the RNA polymerase II antibodies precipitated appreciably greater amounts of promoter DNA from the Star, Cyp11b1 and Cyp11a1 genes in parent Y1 cells than did the control IgG.	('Cyp11b1', 'Var', (128, 135))	('Cyp11a1', 'Gene', (140, 147))	('Cyp11a1', 'Gene', '13070', (140, 147))
28851	21111771	In the SF-1 knockdown clones, the binding of RNA polymerase II to the Star promoter was reduced by 70%, whereas the binding of RNA polymerase II to the Cyp11a1 and to the Cyp11b1 promoters were reduced by only 22% and 27%, respectively (Fig.	('binding', 'Interaction', (116, 123))	('binding', 'Interaction', (34, 41))	('Cyp11a1', 'Gene', '13070', (152, 159))	('knockdown', 'Var', (12, 21))	('Cyp11a1', 'Gene', (152, 159))	('SF-1', 'Gene', (7, 11))	('reduced', 'NegReg', (88, 95))
28854	21111771	Cyp11b1 was not represented on the arrays and variations in the signals for mc2r transcripts on the arrays resulted in changes that failed to reach statistical significance, despite the dramatic decrease in accumulation seen by RT-qPCR (Fig.	('mc2r', 'Gene', '17200', (76, 80))	('changes', 'Reg', (119, 126))	('mc2r', 'Gene', (76, 80))	('decrease', 'NegReg', (195, 203))	('accumulation', 'PosReg', (207, 219))	('variations', 'Var', (46, 56))
28855	21111771	Of these, 32 exhibited significant changes after SF- 1 knockdown confirming the microarray results; three transcripts in this set exhibited small changes that failed to reach statistical significance, possibly due to limitations in the sensitivity of quantitative PCR (Table 3).	('knockdown', 'Var', (55, 64))	('SF- 1', 'Gene', '22668', (49, 54))	('changes', 'Reg', (35, 42))	('SF- 1', 'Gene', (49, 54))
28858	21111771	Nonetheless, SF-1 knockdown did not affect each of these steroidogenic transcripts in the same way.	('knockdown', 'Var', (18, 27))	('SF-1', 'Gene', (13, 17))	('steroid', 'Chemical', 'MESH:D013256', (57, 64))
28859	21111771	Transcripts encoding the Mc2r were the most affected, with only traces remaining after SF-1 knockdown, Scarb1 was reduced to < 10% of its original level and Star and Hsd3b1 were each reduced to approximately 25% of their original levels.	('Scarb1', 'Gene', '20778', (103, 109))	('reduced', 'NegReg', (114, 121))	('knockdown', 'Var', (92, 101))	('Scarb1', 'Gene', (103, 109))	('SF-1', 'Gene', (87, 91))	('Mc2r', 'Gene', '17200', (25, 29))	('Mc2r', 'Gene', (25, 29))
28861	21111771	To test the latter possibility, the ability of the residual SF-1 in the knockdown clones to bind to the proximal promoter regions of Star, Cyp11a1 and Cyp11b1 was assessed by ChIP analysis (Fig.	('Cyp11b1', 'Var', (151, 158))	('Cyp11a1', 'Gene', (139, 146))	('Cyp11a1', 'Gene', '13070', (139, 146))	('bind', 'Interaction', (92, 96))
28862	21111771	On the other hand, the proximal promoters of Star and Cyp11a1 did not bind the residual SF-1, suggesting that the continued expression of these transcripts in the SF1 knockdown clones was due to the contribution of other transcription factors.	('SF1', 'Gene', (163, 166))	('knockdown', 'Var', (167, 176))	('Cyp11a1', 'Gene', '13070', (54, 61))	('SF1', 'Gene', '26423', (163, 166))	('expression', 'MPA', (124, 134))	('Cyp11a1', 'Gene', (54, 61))
28868	21111771	As determined by gene expression profiling, increasing SF-1 dosage in H295R adrenal cells results in the enrichment of transcript clusters with functions in lipid and steroid metabolism, apoptosis and cell cycle regulation, cell adhesion and extracellular matrix.	('dosage', 'Var', (60, 66))	('lipid', 'Chemical', 'MESH:D008055', (157, 162))	('apoptosis', 'CPA', (187, 196))	('cell adhesion', 'CPA', (224, 237))	('steroid', 'Chemical', 'MESH:D013256', (167, 174))	('SF-1', 'Gene', (55, 59))	('cell cycle regulation', 'CPA', (201, 222))	('functions', 'MPA', (144, 153))	('transcript clusters', 'MPA', (119, 138))
28872	21111771	The difference between ACTH stimulation and SF-1 knockdown with respect to steroidogenesis, at least in part, results from an ACTH-induced up-regulation of transcripts with functions in cholesterol biosynthesis; these transcripts are not affected in the SF-1 knockdown clones (Appendix B).	('cholesterol', 'Chemical', 'MESH:D002784', (186, 197))	('knockdown', 'Var', (49, 58))	('ACTH', 'Gene', '18976', (126, 130))	('up-regulation', 'PosReg', (139, 152))	('ACTH', 'Gene', (23, 27))	('steroidogenesis', 'MPA', (75, 90))	('ACTH', 'Gene', (126, 130))	('transcripts', 'MPA', (156, 167))	('steroid', 'Chemical', 'MESH:D013256', (75, 82))	('ACTH', 'Gene', '18976', (23, 27))
28875	21111771	In this example, disruption of a non-canonical SF-1 binding site in the proximal promoter region of mouse Adcy4 enhances Adcy4 promoter activity, over-expression of SF-1 inhibits Adcy4 promoter activity and shRNA-mediated knockdown of SF-1 increases endogenous Adcy4 expression.	('Adcy4', 'Gene', (121, 126))	('Adcy4', 'Gene', (261, 266))	('Adcy4', 'Gene', '104110', (106, 111))	('mouse', 'Species', '10090', (100, 105))	('enhances', 'PosReg', (112, 120))	('Adcy4', 'Gene', '104110', (179, 184))	('inhibits', 'NegReg', (170, 178))	('Adcy4', 'Gene', '104110', (261, 266))	('disruption', 'Var', (17, 27))	('Adcy4', 'Gene', '104110', (121, 126))	('endogenous', 'MPA', (250, 260))	('Adcy4', 'Gene', (106, 111))	('Adcy4', 'Gene', (179, 184))	('expression', 'MPA', (267, 277))
28877	21111771	The exception is Cyp11a1, which was not affected following SF-1 knockdown and thus seems not to require SF-1 for expression.	('Cyp11a1', 'Gene', (17, 24))	('SF-1', 'Gene', (59, 63))	('Cyp11a1', 'Gene', '13070', (17, 24))	('knockdown', 'Var', (64, 73))
28884	33729392	The epigenetic modification or activation and/or loss of TCF21 expression results in an imbalance in TCF21 signaling, which may lead to tumor initiation and, most likely, to progression and tumor metastasis.	('imbalance in TCF21 signaling', 'MPA', (88, 116))	('tumor initiation', 'Disease', (136, 152))	('loss', 'NegReg', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('progression', 'CPA', (174, 185))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('results in', 'Reg', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('imbalance', 'Phenotype', 'HP:0002172', (88, 97))	('epigenetic modification', 'Var', (4, 27))	('tumor', 'Disease', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor initiation', 'Disease', 'MESH:D009369', (136, 152))	('activation', 'PosReg', (31, 41))	('tumor', 'Disease', (136, 141))	('lead to', 'Reg', (128, 135))	('TCF21', 'Gene', (57, 62))
28888	33729392	These HLH proteins were named E proteins (E12, E47, E2-2, HEB, TCF4), since they bind to Ephrussi-box (E-box) sequences (CANNTG).	('TCF4', 'Gene', '6925', (63, 67))	('HEB', 'Gene', (58, 61))	('TCF4', 'Gene', (63, 67))	('E2-2', 'Gene', '6925;106478911', (52, 56))	('E47', 'CellLine', 'CVCL:L675', (47, 50))	('HEB', 'Gene', '6938', (58, 61))	('E2-2', 'Gene', (52, 56))	('bind', 'Interaction', (81, 85))	('E47', 'Var', (47, 50))
28905	33729392	TARID associates with the TCF21 promoter, forming an R-loop, a structure that acts as an anchoring support for adapter protein GADD45A, which recruits essential components of the base excision repair (BER) pathway, TDG and TET, responsible for promoting DNA demethylation by oxidation and replacement of 5-methylcytosine with 5-cytosine.	('TARID', 'Gene', '100507308', (0, 5))	('GADD45A', 'Gene', '1647', (127, 134))	('promoting', 'PosReg', (244, 253))	('TDG', 'Gene', '6996', (215, 218))	('replacement', 'Var', (289, 300))	('TARID', 'Gene', (0, 5))	('GADD45A', 'Gene', (127, 134))	('5-cytosine', 'Chemical', '-', (326, 336))	('TET', 'Chemical', 'MESH:C010349', (223, 226))	('DNA demethylation', 'MPA', (254, 271))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (304, 320))	('TDG', 'Gene', (215, 218))
28907	33729392	MicroRNAs (miRNAs), such as miRNA-21, miRNA-224, miRNA-205, miRNA-30-3p, and miR-3648, are also related to TCF21 regulation (Figure 1) and are involved in the silencing of genes in human tumors.	('human', 'Species', '9606', (181, 186))	('miRNA-21', 'Gene', (28, 36))	('miR-3648', 'Gene', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('miRNA-21', 'Gene', '406991', (28, 36))	('silencing', 'MPA', (159, 168))	('related', 'Reg', (96, 103))	('miRNA-224', 'Gene', '407009', (38, 47))	('miRNA-30-3p', 'Var', (60, 71))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('miR-3648', 'Gene', '100500862', (77, 85))	('miRNA-205', 'Var', (49, 58))	('miRNA-224', 'Gene', (38, 47))
28908	33729392	Inhibition of TCF21 expression was also associated with an increase of risk of coronary artery disease in a Chinese population.	('TCF21', 'Gene', (14, 19))	('coronary artery disease', 'Disease', 'MESH:D003324', (79, 102))	('Inhibition', 'Var', (0, 10))	('coronary artery disease', 'Disease', (79, 102))
28924	33729392	Depletion of Tcf21 results in disruption of pro-epicardial cell specification and in failure of mature epithelial epicardium formation during early stages of epicardial development in Xenopus.	('Tcf21', 'Gene', (13, 18))	('pro-epicardial cell specification', 'CPA', (44, 77))	('Xenopus', 'Species', '8355', (184, 191))	('failure', 'NegReg', (85, 92))	('Depletion', 'Var', (0, 9))	('disruption', 'NegReg', (30, 40))	('mature epithelial epicardium formation', 'CPA', (96, 134))
28929	33729392	TCF21 overexpression in primary neonatal pulmonary fibroblasts increases intracellular lipids responsible for activating the synthesis of surfactants and phospholipids in adult rat alveolar type II cells in culture.	('TCF21', 'Gene', (0, 5))	('increases', 'PosReg', (63, 72))	('intracellular lipids', 'MPA', (73, 93))	('rat', 'Species', '10116', (177, 180))	('overexpression', 'Var', (6, 20))	('lipids', 'Chemical', 'MESH:D008055', (87, 93))	('activating', 'PosReg', (110, 120))	('phospholipids', 'Chemical', 'MESH:D010743', (154, 167))	('lipids', 'Chemical', 'MESH:D008055', (161, 167))
28931	33729392	By E10.5 dpc, adrenal (AP) and gonadal primordium differentiate separately.	('AP', 'Gene', '16870', (23, 25))	('E10.5 dpc', 'Var', (3, 12))	('rat', 'Species', '10116', (68, 71))	('adrenal', 'CPA', (14, 21))
28933	33729392	Tcf21 knockout (KO) mice show gonadal failures, vascular abnormalities, and sex indistinction during embryogenesis, while mutant Tcf21 mice show gonadal dysgenesis.	('gonadal failures', 'CPA', (30, 46))	('vascular abnormalities', 'Disease', (48, 70))	('mice', 'Species', '10090', (20, 24))	('sex indistinction', 'CPA', (76, 93))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (145, 163))	('vascular abnormalities', 'Disease', 'MESH:D000783', (48, 70))	('mice', 'Species', '10090', (135, 139))	('vascular abnormalities', 'Phenotype', 'HP:0002597', (48, 70))	('mutant', 'Var', (122, 128))	('gonadal dysgenesis', 'CPA', (145, 163))	('Tcf21', 'Gene', (129, 134))
28948	33729392	Ectopic expression of WT1 prevents the differentiation locking of adrenocortical steroidogenic cells in progenitor status.	('steroid', 'Chemical', 'MESH:D013256', (81, 88))	('prevents', 'NegReg', (26, 34))	('Ectopic expression', 'Var', (0, 18))	('differentiation locking', 'CPA', (39, 62))	('WT1', 'Gene', (22, 25))
28960	33729392	In vitro, Tcf21 increased pre-adipocyte differentiation, whereas Tcf21 knockdown and overexpression attenuated and promoted pre-adipocyte differentiation, respectively, which changed lipid droplet accumulation.	('promoted', 'PosReg', (115, 123))	('lipid droplet accumulation', 'MPA', (183, 209))	('attenuated', 'NegReg', (100, 110))	('Tcf21', 'Gene', (65, 70))	('Tcf21', 'Gene', (10, 15))	('knockdown', 'Var', (71, 80))	('increased', 'PosReg', (16, 25))	('pre-adipocyte differentiation', 'CPA', (26, 55))	('lipid', 'Chemical', 'MESH:D008055', (183, 188))	('pre-adipocyte differentiation', 'CPA', (124, 153))	('changed', 'Reg', (175, 182))
28964	33729392	described for the first time that the promoter region on human chromosome 6q23-q24 of TCF21 was hypermethylated in non-small-cell lung cancers (NSCLC) and head and neck squamous cell carcinomas.	('lung cancers', 'Disease', (130, 142))	('NSCLC', 'Disease', (144, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('lung cancers', 'Disease', 'MESH:D008175', (130, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('TCF21', 'Gene', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancers', 'Phenotype', 'HP:0100526', (130, 142))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (164, 193))	('hypermethylated', 'Var', (96, 111))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (169, 193))	('human', 'Species', '9606', (57, 62))	('neck squamous cell carcinomas', 'Disease', (164, 193))
28966	33729392	In general, the proposition is that TCF21 is downregulated primarily by DNA hypermethylation, rather than genetic mutations, in malignant tumors.	('TCF21', 'Gene', (36, 41))	('rat', 'Species', '10116', (94, 97))	('hypermethylation', 'Var', (76, 92))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('downregulated', 'NegReg', (45, 58))	('malignant tumors', 'Disease', 'MESH:D009369', (128, 144))	('malignant tumors', 'Disease', (128, 144))	('DNA', 'MPA', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
28971	33729392	The prevalence of TCF21 methylation in primary lung adenocarcinoma samples was 81%, higher than other methylated genes found in the 6q12-q27 locus.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('TCF21', 'Gene', (18, 23))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('methylation', 'Var', (24, 35))	('lung adenocarcinoma', 'Disease', (47, 66))	('higher', 'PosReg', (84, 90))
28973	33729392	Moreover, exogenous expression of TCF21 in cells that have silenced endogenous TCF21 showed impaired tumorigenic properties in vitro and in vivo.	('exogenous', 'MPA', (10, 19))	('silenced', 'Var', (59, 67))	('TCF21', 'Gene', (34, 39))	('TCF21', 'Gene', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('impaired', 'NegReg', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
28974	33729392	concluded that TCF21 hypermethylation and impaired TCF21 expression are specific and frequent in NSCLC cells, even in early-stage disease, thereby making TCF21 a potential biomarker for early-stage NSCLC.	('hypermethylation', 'Var', (21, 37))	('expression', 'MPA', (57, 67))	('NSCLC', 'Disease', (97, 102))	('TCF21', 'Gene', (15, 20))	('TCF21', 'Gene', (51, 56))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('NSCLC', 'Disease', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('impaired', 'NegReg', (42, 50))
28975	33729392	Demethylation of the TCF21 promoter in H1299 cells (NSCLC cell line) by 5-aza-2'-deoxycytine (5-Aza) resulted in a higher level of TCF21 expression, leading to a loss of cell viability and invasion ability and an increase in cell apoptosis.	('cell apoptosis', 'CPA', (225, 239))	('expression', 'MPA', (137, 147))	('loss', 'NegReg', (162, 166))	('NSCLC', 'Disease', (52, 57))	('invasion ability', 'CPA', (189, 205))	('TCF21', 'Gene', (21, 26))	("5-aza-2'-deoxycytine", 'Chemical', '-', (72, 92))	('H1299', 'CellLine', 'CVCL:0060', (39, 44))	('Demethylation', 'Var', (0, 13))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('cell viability', 'CPA', (170, 184))	('TCF21', 'Gene', (131, 136))	('higher', 'PosReg', (115, 121))	('increase', 'PosReg', (213, 221))	('5-Aza', 'Chemical', '-', (94, 99))
28984	33729392	Moreover, siRNA-TCF21 downregulates the expression of KISS1 and the invasion ability in Cak-1 cells, suggesting that aberrantly expressed miR-21 regulates the invasion pathway through TCF21-KISS1 association in renal cell carcinoma.	('KISS1', 'Gene', (190, 195))	('renal cell carcinoma', 'Disease', (211, 231))	('miR-21', 'Gene', '406991', (138, 144))	('downregulates', 'NegReg', (22, 35))	('association', 'Interaction', (196, 207))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (211, 231))	('KISS1', 'Gene', (54, 59))	('KISS1', 'Gene', '3814', (190, 195))	('miR-21', 'Gene', (138, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('KISS1', 'Gene', '3814', (54, 59))	('invasion', 'CPA', (159, 167))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (211, 231))	('aberrantly', 'Var', (117, 127))	('regulates', 'Reg', (145, 154))
28988	33729392	TARID, the lncRNA responsible for TCF21 demethylation, was undetectable in most CCSK samples, suggesting that TCF21 hypermethylation and reduced TARID expression are involved in the pathogenic pathway of CCSK.	('TARID', 'Gene', '100507308', (0, 5))	('expression', 'MPA', (151, 161))	('TARID', 'Gene', '100507308', (145, 150))	('TARID', 'Gene', (0, 5))	('TCF21', 'Gene', (110, 115))	('CCSK', 'Disease', (204, 208))	('CCSK', 'Chemical', '-', (80, 84))	('involved', 'Reg', (166, 174))	('hypermethylation', 'Var', (116, 132))	('CCSK', 'Chemical', '-', (204, 208))	('TARID', 'Gene', (145, 150))	('reduced', 'NegReg', (137, 144))
28993	33729392	Moreover, TCF21 interferes with the MAPK pathway by reducing ERK levels in UCEC cells expressing higher levels of TCF21.	('TCF21', 'Var', (114, 119))	('AP', 'Gene', '16870', (37, 39))	('ERK', 'Gene', '5594', (61, 64))	('reducing', 'NegReg', (52, 60))	('interferes', 'NegReg', (16, 26))	('ERK', 'Gene', (61, 64))	('TCF21', 'Var', (10, 15))
28997	33729392	The SUMOylation of TCF21 at lysine residue 24 (K24) by the small ubiquitin-like modifier SUMO1 stabilizes the TCF21 protein and enhances its interaction with histone deacetylases (HDAC1/2).	('protein', 'Protein', (116, 123))	('HDAC1/2', 'Gene', '3065;3066', (180, 187))	('lysine', 'Chemical', 'MESH:D008239', (28, 34))	('SUMOylation', 'Var', (4, 15))	('interaction', 'Interaction', (141, 152))	('stabilizes', 'PosReg', (95, 105))	('SUMO1', 'Gene', '7341', (89, 94))	('HDAC1/2', 'Gene', (180, 187))	('K24', 'Gene', '192666', (47, 50))	('SUMO1', 'Gene', (89, 94))	('TCF21', 'Gene', (110, 115))	('TCF21', 'Gene', (19, 24))	('enhances', 'PosReg', (128, 136))	('K24', 'Gene', (47, 50))
28998	33729392	The SUMOylation of TCF21 represses the activity of Eralpha and decreases the percentage of S-phase cells.	('SUMOylation', 'Var', (4, 15))	('decreases', 'NegReg', (63, 72))	('represses', 'NegReg', (25, 34))	('percentage of S-phase cells', 'CPA', (77, 104))	('activity', 'MPA', (39, 47))	('Eralpha', 'Gene', '2099', (51, 58))	('TCF21', 'Gene', (19, 24))	('Eralpha', 'Gene', (51, 58))
28999	33729392	Analysis of the genetic polymorphism of TCF21 and the risk of breast cancer in Chinese women suggests that the TCF21 rs12190287 polymorphism can regulate TCF21 expression and may serve as a potential marker for genetic susceptibility to breast cancer.	('expression', 'MPA', (160, 170))	('TCF21', 'Gene', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (237, 250))	('breast cancer', 'Disease', (62, 75))	('TCF21', 'Gene', (111, 116))	('rs12190287', 'Var', (117, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('women', 'Species', '9606', (87, 92))	('rs12190287', 'Mutation', 'rs12190287', (117, 127))	('regulate', 'Reg', (145, 153))
29012	33729392	In agreement with the observation that pediatric ACT appear to have a biphasic age distribution with a poor clinical outcome in the group aged >5 years, it was found that the combination of TCF21 and SF1 was a good predictor of malignancy for children less than 5 years old.	('predictor', 'Reg', (215, 224))	('combination', 'Var', (175, 186))	('children', 'Species', '9606', (243, 251))	('malignancy', 'Disease', 'MESH:D009369', (228, 238))	('SF1', 'Gene', (200, 203))	('TCF21', 'Gene', (190, 195))	('malignancy', 'Disease', (228, 238))
29013	33729392	By using quantitative DNA methylation analysis in melanoma biopsies of patients and in their derived cell lines, it was demonstrated that TCF21 expression is downregulated in metastatic melanoma by promoter hypermethylation.	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('expression', 'MPA', (144, 154))	('downregulated', 'NegReg', (158, 171))	('TCF21', 'Gene', (138, 143))	('promoter hypermethylation', 'Var', (198, 223))	('melanoma', 'Disease', (50, 58))	('patients', 'Species', '9606', (71, 79))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('rat', 'Species', '10116', (127, 130))
29017	33729392	In colorectal and gastric cancer cells, downregulation of TCF21 by hypermethylation induces cell proliferation, migration, and invasion, probably through inactivation of PI3K/AKT signaling (Figure 1).	('colorectal and gastric cancer', 'Disease', 'MESH:D013274', (3, 32))	('inactivation', 'NegReg', (154, 166))	('TCF21', 'Gene', (58, 63))	('downregulation', 'NegReg', (40, 54))	('rat', 'Species', '10116', (115, 118))	('rat', 'Species', '10116', (104, 107))	('AKT', 'Gene', (175, 178))	('invasion', 'CPA', (127, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('hypermethylation', 'Var', (67, 83))	('AKT', 'Gene', '207', (175, 178))	('migration', 'CPA', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cell proliferation', 'CPA', (92, 110))	('induces', 'Reg', (84, 91))
29021	33729392	As the epigenetic regulation of TCF21 through different levels of methylation is a common observation in different malignancies, these data are summarized in Table 2.	('methylation', 'MPA', (66, 77))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('epigenetic regulation', 'Var', (7, 28))	('malignancies', 'Disease', (115, 127))	('TCF21', 'Gene', (32, 37))
29026	33024147	Frequency of the TP53 R337H variant in sporadic breast cancer and its impact on genomic instability The R337H is a TP53 germline pathogenic variant that has been associated with several types of cancers, including breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('R337H', 'Mutation', 'rs121912664', (104, 109))	('R337H', 'Var', (104, 109))	('associated with', 'Reg', (162, 177))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('breast cancer', 'Disease', (214, 227))	('TP53', 'Gene', (115, 119))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('R337H', 'Mutation', 'rs121912664', (22, 27))	('TP53', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (39, 61))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('TP53', 'Gene', '7157', (115, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('sporadic breast cancer', 'Disease', (39, 61))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancers', 'Disease', (195, 202))	('TP53', 'Gene', '7157', (17, 21))
29027	33024147	Our main objective was to determine the frequency of the R337H variant in sporadic breast cancer patients from Parana state, South Brazil, its association with prognosis and its impact in genomic instability.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('sporadic breast cancer', 'Disease', (74, 96))	('R337H', 'Var', (57, 62))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (74, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('R337H', 'Mutation', 'rs121912664', (57, 62))	('patients', 'Species', '9606', (97, 105))
29028	33024147	The genotyping of 805 breast cancer tissues revealed a genotypic and allelic frequency of the R337H variant of 2.36% and 1.18%, respectively.	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('R337H', 'Mutation', 'rs121912664', (94, 99))	('R337H', 'Var', (94, 99))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
29030	33024147	Array-CGH analysis showed that R337H+ patients presented a higher number of copy number alterations (CNAs), compared to the R337H-.	('R337H', 'Mutation', 'rs121912664', (31, 36))	('R337H', 'Mutation', 'rs121912664', (124, 129))	('copy', 'MPA', (76, 80))	('patients', 'Species', '9606', (38, 46))	('R337H+', 'Var', (31, 37))
29032	33024147	Furthermore, homozygous (R337H+/R337H+) fibroblasts presented increased levels of copy number variants when compared to heterozygous or R337H- cells.	('increased', 'PosReg', (62, 71))	('levels', 'MPA', (72, 78))	('R337H+/R337H+', 'Var', (25, 38))	('R337H', 'Mutation', 'rs121912664', (25, 30))	('R337H', 'Mutation', 'rs121912664', (136, 141))	('R337H', 'Mutation', 'rs121912664', (32, 37))	('copy', 'MPA', (82, 86))
29033	33024147	In conclusion, the R337H variant may contribute to 2.36% of the breast cancer cases without family cancer history in Parana.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('R337H', 'Var', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('R337H', 'Mutation', 'rs121912664', (19, 24))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', (64, 77))
29034	33024147	Among other mechanisms, R337H increases the level of genomic instability, as evidenced by a higher number of CNAs in the R337H+ cases compared to the R337H-.	('R337H', 'Mutation', 'rs121912664', (24, 29))	('R337H', 'Var', (24, 29))	('R337H', 'Mutation', 'rs121912664', (121, 126))	('CNAs', 'Disease', (109, 113))	('R337H+', 'Var', (121, 127))	('genomic instability', 'MPA', (53, 72))	('R337H', 'Mutation', 'rs121912664', (150, 155))
29035	33024147	The R337H is a germline pathogenic variant at codon 337 of exon 10 of the TP53 gene, which occurs outside the DNA binding region in the dimerization region of the p53 protein.	('R337H', 'Mutation', 'rs121912664', (4, 9))	('R337H', 'Var', (4, 9))	('p53', 'Gene', '7157', (163, 166))	('p53', 'Gene', (163, 166))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))
29036	33024147	The exchange of arginine by a histidine (R337H CGC   CAC) characterizes the variant, which affects the structure (tetramer formation) of the protein, leading to an unstable molecule with the eventual loss of function.	('affects', 'Reg', (91, 98))	('arginine', 'Chemical', 'MESH:D001120', (16, 24))	('loss', 'NegReg', (200, 204))	('R337H', 'Mutation', 'rs121912664', (41, 46))	('R337H', 'Var', (41, 46))	('CGC   CAC', 'Gene', (47, 56))	('exchange', 'Var', (4, 12))	('histidine', 'Chemical', 'MESH:D006639', (30, 39))	('arginine', 'Var', (16, 24))	('unstable molecule', 'MPA', (164, 181))
29037	33024147	The R337H was first reported in the southern region of Brazil as a germline variant in pediatric patients with adrenocortical tumors (ACTs), where it was identified in 95% of the cases.	('R337H', 'Mutation', 'rs121912664', (4, 9))	('adrenocortical tumors', 'Disease', (111, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('R337H', 'Var', (4, 9))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (111, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('patients', 'Species', '9606', (97, 105))
29044	33024147	These and other authors have found breast cancer cases and other tumors positive for R337H associated with Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome, hereditary and non-hereditary breast cancer, and/or asymptomatic high risk patients.	('LFS', 'Disease', (129, 132))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (137, 162))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('LFS', 'Disease', 'MESH:D016864', (129, 132))	('tumors', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('R337H', 'Var', (85, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))	('R337H', 'Mutation', 'rs121912664', (85, 90))	('Li-Fraumeni syndrome', 'Disease', (107, 127))	('Li-Fraumeni-like syndrome', 'Disease', (137, 162))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('associated', 'Reg', (91, 101))	('non-hereditary breast cancer', 'Disease', 'MESH:D061325', (179, 207))	('non-hereditary breast cancer', 'Disease', (179, 207))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (107, 127))	('patients', 'Species', '9606', (239, 247))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (35, 48))
29045	33024147	Despite the accumulating and compelling evidence of the association between R337H and breast cancer, few studies have investigated the cellular phenotype and/or the genomic "consequences" of the R337H variant in breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('breast cancer', 'Disease', (212, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('R337H', 'Mutation', 'rs121912664', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('R337H', 'Var', (76, 81))	('association', 'Interaction', (56, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('R337H', 'Mutation', 'rs121912664', (195, 200))
29048	33024147	The main objective of this study was to determine the frequency of the TP53 R337H variant in patients diagnosed with sporadic breast cancer from the state of Parana and its association with clinical and histopathological parameters to assess its potential prognostic value in this population.	('sporadic breast cancer', 'Disease', (117, 139))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (117, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('R337H', 'Mutation', 'rs121912664', (76, 81))	('R337H', 'Var', (76, 81))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
29049	33024147	To our knowledge, no studies have assessed the direct impact of the R337H variant on the genomic instability of these tumors.	('R337H', 'Mutation', 'rs121912664', (68, 73))	('R337H', 'Var', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
29050	33024147	In addition, to verify whether R337H+/R337H+ and Wt/R337H+ cells contribute equally to genomic instability, we generated normal cell cultures of fibroblasts from individuals with homozygous and heterozygous TP53 R337H variants exposed to a DNA damage agent and evaluated the patterns of their copy number variations (CNVs).	('R337H', 'Mutation', 'rs121912664', (212, 217))	('R337H variants', 'Var', (212, 226))	('R337H', 'Mutation', 'rs121912664', (38, 43))	('TP53', 'Gene', '7157', (207, 211))	('R337H', 'Mutation', 'rs121912664', (52, 57))	('R337H', 'Mutation', 'rs121912664', (31, 36))	('TP53', 'Gene', (207, 211))	('variants', 'Var', (218, 226))
29051	33024147	Nineteen patients were identified by real-time PCR as heterozygous carriers of TP53 R337H among 805 women with sporadic breast cancer.	('patients', 'Species', '9606', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('sporadic breast cancer', 'Disease', (111, 133))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (111, 133))	('R337H', 'Mutation', 'rs121912664', (84, 89))	('R337H', 'Var', (84, 89))	('women', 'Species', '9606', (100, 105))
29053	33024147	The breast cancer patients were subdivided into two groups according to the R337H variant status.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('R337H', 'Mutation', 'rs121912664', (76, 81))	('breast cancer', 'Disease', (4, 17))	('R337H', 'Var', (76, 81))	('patients', 'Species', '9606', (18, 26))
29056	33024147	The R337H+ group had a significantly lower mean age at diagnosis compared to the R337H- group (47.88 +- 11.56 and 58.52 +- 15.18 years, respectively; Student's t-test, t = 2.97, P < 0.05).	('R337H', 'Mutation', 'rs121912664', (81, 86))	('R337H', 'Mutation', 'rs121912664', (4, 9))	('R337H+', 'Var', (4, 10))	('lower', 'NegReg', (37, 42))
29057	33024147	In the living patients in the R337H+ group, a significantly lower mean age at diagnosis was observed compared to the R337H- group (47.90 +- 9.92 and 57.94 +- 15.9 years, respectively; Student's t-test, t = 2.22, P < 0.05).	('R337H', 'Mutation', 'rs121912664', (117, 122))	('R337H+', 'Var', (30, 36))	('patients', 'Species', '9606', (14, 22))	('R337H', 'Mutation', 'rs121912664', (30, 35))	('lower', 'NegReg', (60, 65))
29059	33024147	The analysis (multiple logistic regression) considering the R337H status and the clinical variables (age at diagnosis, tumor size, lymph node metastasis, ER, PR and HER2 receptor status), also did not show any significance.	('tumor', 'Disease', (119, 124))	('ER', 'Gene', '2069', (166, 168))	('ER', 'Gene', '2069', (154, 156))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('HER2', 'Gene', (165, 169))	('PR', 'Gene', '140738', (158, 160))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('HER2', 'Gene', '2064', (165, 169))	('R337H', 'Mutation', 'rs121912664', (60, 65))	('R337H', 'Var', (60, 65))
29061	33024147	To determine the patterns of CNAs that could be influenced by the TP53 R337H variant, we performed genome-wide array-comparative genomic hybridization (CGH) analysis using an oligonucleotide array-CGH platform (Agilent Technologies, Inc.).	('oligonucleotide', 'Chemical', 'MESH:D009841', (175, 190))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('CNAs', 'Disease', (29, 33))	('R337H', 'Var', (71, 76))	('R337H', 'Mutation', 'rs121912664', (71, 76))
29064	33024147	The main cytobands with CNAs (> 30% of cases) observed in this group were 8q11.1-q24.3 (89% of cases), 8p12-p11.21 (78%), and 1q21.1-q44 (67%), followed by 1p36.33-p36.32, 6p25.3-p21.1, 8q24.3, 11p15.5, 11q13.4-q25, 13q11-q34, 14q21.1-q32.33, 14q32.33, 17p13.3-p11.2, 19p13.3, 19p13.11, and 20q11.21 (44%).	('1q21.1-q44', 'Var', (126, 136))	('19p13.3', 'Var', (268, 275))	('p21', 'Gene', (179, 182))	('p36', 'Gene', (164, 167))	('p21', 'Gene', '644914', (179, 182))	('8q11.1-q24.3', 'Var', (74, 86))	('p36', 'Gene', (157, 160))	('p11', 'Gene', '6281', (261, 264))	('14q32.33', 'Var', (243, 251))	('p36', 'Gene', '302', (164, 167))	('p11', 'Gene', (261, 264))	('p11', 'Gene', (108, 111))	('14q21.1-q32.33', 'Var', (227, 241))	('p36', 'Gene', '302', (157, 160))	('19p13.11', 'Var', (277, 285))	('p11', 'Gene', '6281', (108, 111))
29065	33024147	Among these cytobands (except at 11q, 13q, and 14q21.1-q32.33, which were observed with loss of copy number), 8p12-p11.21 and 19p13.3 were observed with high levels of gain (log 2 > 2.0).	('gain', 'PosReg', (168, 172))	('p11', 'Gene', '6281', (115, 118))	('loss', 'NegReg', (88, 92))	('19p13.3', 'Var', (126, 133))	('p11', 'Gene', (115, 118))
29066	33024147	In the R337H- group, 204 CNAs were observed, with an average of 22.67 +- 16.78 alterations per case.	('R337H', 'Mutation', 'rs121912664', (7, 12))	('CNAs', 'Disease', (25, 29))	('R337H-', 'Var', (7, 13))
29067	33024147	The main cytobands with CNAs observed in this group were 14q32.33 (89% of cases), 8p11.22, 8q11.1-q24.3 and 22q11.22 (78%), 7p22.3 (67%), 1p36.33-p36.32 (56%), and 8q24.3, 10q26.3, 16p13.3-p11.1, and 17p13.3-p11.2.	('p36', 'Gene', '302', (146, 149))	('p36', 'Gene', (139, 142))	('8q11.1-q24.3', 'Var', (91, 103))	('22q11.22', 'Var', (108, 116))	('p11', 'Gene', '6281', (208, 211))	('p11', 'Gene', (189, 192))	('p36', 'Gene', '302', (139, 142))	('14q32.33', 'Var', (57, 65))	('p11', 'Gene', (83, 86))	('10q26.3', 'Var', (172, 179))	('p11', 'Gene', '6281', (189, 192))	('p36', 'Gene', (146, 149))	('p11', 'Gene', (208, 211))	('p11', 'Gene', '6281', (83, 86))	('8q24.3', 'Var', (164, 170))
29068	33024147	In these cytobands (except 17p, which was observed with loss of copy number), high levels of gains (log 2 > 2.0) were observed in 8p11.22 and 22q11.22.	('gains', 'PosReg', (93, 98))	('p11', 'Gene', (131, 134))	('22q11.22', 'Var', (142, 150))	('p11', 'Gene', '6281', (131, 134))
29069	33024147	Finally, the comparison of the total number of CNAs in both groups, which was measured by the comparison of the total "number of calls" in the Cytogenomics aberration interval base reports, revealed a significantly higher number of CNAs in the R337H+ group of patients (t = 2.35; P < 0.05).	('higher', 'PosReg', (215, 221))	('R337H', 'Mutation', 'rs121912664', (244, 249))	('patients', 'Species', '9606', (260, 268))	('CNAs', 'Disease', (232, 236))	('R337H+', 'Var', (244, 250))
29070	33024147	The findings indicated that genomic instability was more frequent in patients with the R337H variant.	('genomic instability', 'CPA', (28, 47))	('R337H', 'Mutation', 'rs121912664', (87, 92))	('R337H', 'Var', (87, 92))	('frequent', 'Reg', (57, 65))	('patients', 'Species', '9606', (69, 77))
29079	33024147	This analysis revealed 256 and 180 miRNA targets for the R337H+ and R337H- groups, respectively.	('R337H', 'Mutation', 'rs121912664', (68, 73))	('R337H', 'Mutation', 'rs121912664', (57, 62))	('R337H-', 'Var', (68, 74))	('R337H+', 'Var', (57, 63))
29081	33024147	Four genes (CCNE2, MTDH, RDH10, and SNAI2) were commonly observed in both the R337H+ and R337H- groups of patients.	('SNAI2', 'Gene', '6591', (36, 41))	('SNAI2', 'Gene', (36, 41))	('MTDH', 'Gene', '92140', (19, 23))	('RDH10', 'Gene', '157506', (25, 30))	('CCNE2', 'Gene', (12, 17))	('R337H+', 'Var', (78, 84))	('observed', 'Reg', (57, 65))	('CCNE2', 'Gene', '9134', (12, 17))	('R337H-', 'Var', (89, 95))	('MTDH', 'Gene', (19, 23))	('patients', 'Species', '9606', (106, 114))	('R337H', 'Mutation', 'rs121912664', (78, 83))	('RDH10', 'Gene', (25, 30))	('R337H', 'Mutation', 'rs121912664', (89, 94))
29083	33024147	Interestingly, in the R337H- group, all the genes identified in the integration analysis mapped at the 8q region, and were commonly affected in these cases in the array-CGH analysis.	('R337H', 'Mutation', 'rs121912664', (22, 27))	('affected', 'Reg', (132, 140))	('R337H-', 'Var', (22, 28))	('mapped', 'Reg', (89, 95))
29085	33024147	This analysis was performed by querying the database in all the groups of breast cancer cases available and in breast cancer cases based on the TP53 variants status.	('TP53', 'Gene', '7157', (144, 148))	('breast cancer', 'Disease', (74, 87))	('TP53', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('variants', 'Var', (149, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
29087	33024147	In the R337H+ group, 72.1% (31/43) of the genes were associated with survival.	('R337H', 'Mutation', 'rs121912664', (7, 12))	('R337H+', 'Var', (7, 13))	('associated', 'Reg', (53, 63))
29089	33024147	Five genes in this group were only observed in cases that presented with TP53 variants in the KMplot database.	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('variants', 'Var', (78, 86))
29090	33024147	Overexpression of three of these genes (ECM1, MMP16, and CTHRC) was associated with significantly worse survival.	('MMP16', 'Gene', '4325', (46, 51))	('MMP16', 'Gene', (46, 51))	('ECM1', 'Gene', '1893', (40, 44))	('CTHRC', 'Gene', (57, 62))	('Overexpression', 'Var', (0, 14))	('ECM1', 'Gene', (40, 44))	('worse', 'NegReg', (98, 103))
29092	33024147	Four other genes (ITGA6, HOXD10, FASN, and BUP1) were observed only in cases that were negative for TP53 variants in the KMplot database.	('FASN', 'Gene', '2194', (33, 37))	('TP53', 'Gene', '7157', (100, 104))	('HOXD10', 'Gene', '3236', (25, 31))	('TP53', 'Gene', (100, 104))	('ITGA6', 'Gene', '3655', (18, 23))	('variants', 'Var', (105, 113))	('ITGA6', 'Gene', (18, 23))	('FASN', 'Gene', (33, 37))	('HOXD10', 'Gene', (25, 31))	('BUP1', 'Gene', (43, 47))	('BUP1', 'Gene', '51733', (43, 47))
29095	33024147	In the R337H- group of patients, 85.7% (6/7) genes were associated with survival.	('patients', 'Species', '9606', (23, 31))	('R337H', 'Mutation', 'rs121912664', (7, 12))	('R337H-', 'Var', (7, 13))	('associated', 'Reg', (56, 66))
29096	33024147	Only SNAI2 (also found in the R337H+ group) was not associated with survival.	('R337H+', 'Var', (30, 36))	('SNAI2', 'Gene', '6591', (5, 10))	('SNAI2', 'Gene', (5, 10))	('R337H', 'Mutation', 'rs121912664', (30, 35))
29097	33024147	Overexpression of OXR1 was the only gene in this group that was significantly associated with TP53 status, conferring a higher survival rate in patients with no TP53 variants.	('associated', 'Reg', (78, 88))	('TP53', 'Gene', (161, 165))	('OXR1', 'Gene', (18, 22))	('higher', 'PosReg', (120, 126))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('patients', 'Species', '9606', (144, 152))	('OXR1', 'Gene', '55074', (18, 22))	('variants', 'Var', (166, 174))	('survival', 'MPA', (127, 135))	('TP53', 'Gene', '7157', (161, 165))
29098	33024147	Interestingly, in the R337H+ group, three genes (IGFBP5, MAF, and SMYD3) that were not associated with survival in the breast cancer cases in general were associated with survival specifically in cases with TP53 variants.	('MAF', 'Gene', '4094', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('MAF', 'Gene', (57, 60))	('breast cancer', 'Disease', (119, 132))	('R337H+', 'Var', (22, 28))	('TP53', 'Gene', '7157', (207, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('SMYD3', 'Gene', (66, 71))	('associated', 'Reg', (87, 97))	('associated with', 'Reg', (155, 170))	('SMYD3', 'Gene', '64754', (66, 71))	('TP53', 'Gene', (207, 211))	('R337H', 'Mutation', 'rs121912664', (22, 27))	('IGFBP5', 'Gene', (49, 55))	('IGFBP5', 'Gene', '3488', (49, 55))	('variants', 'Var', (212, 220))
29099	33024147	To further verify the differences in the level of genomic instability in R337H+ cells, we performed genome-wide CNVs analyses in homozygous (R337H+/R337H+) and heterozygous (Wt/R337H+) fibroblast cell cultures.	('R337H', 'Mutation', 'rs121912664', (148, 153))	('R337H', 'Mutation', 'rs121912664', (141, 146))	('R337H', 'Mutation', 'rs121912664', (73, 78))	('R337H+/R337H+', 'Var', (141, 154))	('R337H', 'Mutation', 'rs121912664', (177, 182))	('R337H+', 'Var', (73, 79))
29101	33024147	Statistically significantly increased levels of CNVs (all P < 0.05) in chromosomes 1, 2, 3, 6, 7, 8, 10, 11, 13, 14, 15, 16, and 22 were found only in homozygous R337H/R337H cells when compared to the other cells.	('increased', 'PosReg', (28, 37))	('R337H/R337H', 'Var', (162, 173))	('R337H', 'Mutation', 'rs121912664', (168, 173))	('CNVs', 'MPA', (48, 52))	('R337H', 'Mutation', 'rs121912664', (162, 167))	('levels', 'MPA', (38, 44))
29104	33024147	We also conducted a comprehensive computational analysis to determine the impact of the TP53 R337H variant on genomic instability, evaluating both the breast tumor tissue of the patients and homozygous (R337H+/R337H+) and heterozygous (Wt/R337H+) fibroblast cell cultures established from a patient with adrenocortical cancer and a variant carrier, respectively.	('breast tumor', 'Disease', (151, 163))	('R337H', 'Mutation', 'rs121912664', (239, 244))	('R337H', 'Mutation', 'rs121912664', (203, 208))	('adrenocortical cancer', 'Disease', (304, 325))	('patient', 'Species', '9606', (291, 298))	('R337H', 'Mutation', 'rs121912664', (93, 98))	('R337H+/R337H+', 'Var', (203, 216))	('R337H', 'Var', (93, 98))	('patients', 'Species', '9606', (178, 186))	('patient', 'Species', '9606', (178, 185))	('breast tumor', 'Phenotype', 'HP:0100013', (151, 163))	('R337H', 'Mutation', 'rs121912664', (210, 215))	('TP53', 'Gene', '7157', (88, 92))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (304, 325))	('breast tumor', 'Disease', 'MESH:D001943', (151, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('TP53', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))
29106	33024147	This is the first report on the R337H genotypic frequency in breast cancer tissue without family history of cancer in Parana state.	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('R337H', 'Mutation', 'rs121912664', (32, 37))	('cancer', 'Disease', (68, 74))	('R337H', 'Var', (32, 37))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
29107	33024147	Previous studies have evaluated the frequency of the R337H variant in women with and without breast cancer in different regions of Brazil.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('R337H', 'Var', (53, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('R337H', 'Mutation', 'rs121912664', (53, 58))	('women', 'Species', '9606', (70, 75))
29109	33024147	reported an R337H genotypic frequency of 0.5% (2/390) in women diagnosed with breast cancer in Rio de Janeiro in, southeast Brazil.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('women', 'Species', '9606', (57, 62))	('R337H', 'Mutation', 'rs121912664', (12, 17))	('R337H', 'Var', (12, 17))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
29111	33024147	reported a higher genotypic frequency (8.6%, 70/815) in a cohort of breast cancer patients from Rio Grande do Sul and Sao Paulo without family cancer history.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('patients', 'Species', '9606', (82, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('cancer', 'Disease', (75, 81))	('breast cancer', 'Disease', (68, 81))	('genotypic', 'Var', (18, 27))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
29113	33024147	Other possibilities are associations with other genetic variants that facilitate carcinogenesis among R337H carriers or their exposure to environmental factors in the regions where they live, as demonstrated for ACTs.	('R337H', 'Var', (102, 107))	('associations', 'Interaction', (24, 36))	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('facilitate', 'PosReg', (70, 80))	('carcinogenesis', 'Disease', (81, 95))	('R337H', 'Mutation', 'rs121912664', (102, 107))
29114	33024147	Interestingly, the frequency of the breast cancer patients with the R337H variant in our study varied according to the hospitals and regions, ranging from 1.57% in Curitiba, the capital of Parana, to 7.6% in the eastern Parana state, where agricultural activities are more prominent.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('R337H', 'Mutation', 'rs121912664', (68, 73))	('breast cancer', 'Disease', (36, 49))	('R337H', 'Var', (68, 73))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
29115	33024147	It is important to point out, however, that in this study only the TP53 R337H variant was genotyped.	('R337H', 'Mutation', 'rs121912664', (72, 77))	('TP53', 'Gene', '7157', (67, 71))	('R337H', 'Var', (72, 77))	('TP53', 'Gene', (67, 71))
29116	33024147	Therefore, it is very likely that both the R337H carriers and non-carriers groups, harbor other somatic and/or TP53 germline variants.	('TP53', 'Gene', (111, 115))	('TP53', 'Gene', '7157', (111, 115))	('R337H', 'Mutation', 'rs121912664', (43, 48))	('R337H', 'Var', (43, 48))
29117	33024147	The association of clinical parameters in the groups of breast cancer patients we studied based on the R337H variant revealed a lower average age (47.88 +- 11.56) at diagnosis of the R337H+ group compared to the R337H- group (47.88 +- 11.56 vs. 58.52 +- 15.18 years; P < 0.05).	('R337H', 'Mutation', 'rs121912664', (212, 217))	('patients', 'Species', '9606', (70, 78))	('R337H+', 'Var', (183, 189))	('R337H', 'Var', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('R337H', 'Mutation', 'rs121912664', (103, 108))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('lower', 'NegReg', (128, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('R337H', 'Mutation', 'rs121912664', (183, 188))	('breast cancer', 'Disease', (56, 69))
29118	33024147	in patients with breast cancer positive for the R337H variant.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('R337H', 'Mutation', 'rs121912664', (48, 53))	('R337H', 'Var', (48, 53))	('breast cancer', 'Disease', (17, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('patients', 'Species', '9606', (3, 11))
29120	33024147	The same was observed in the study by Gomes et al., in which two cases of breast cancer with the R337H variant had a lower age at diagnosis.	('breast cancer', 'Disease', (74, 87))	('R337H', 'Var', (97, 102))	('R337H', 'Mutation', 'rs121912664', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
29122	33024147	Altogether, the present and prior studies provide evidence of an association between the R337H variant and early age of diagnosis, regardless of a family history of cancer.	('R337H', 'Var', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('R337H', 'Mutation', 'rs121912664', (89, 94))
29123	33024147	To determine the impact of the R337H variant on the tumor genome stability of breast cancer patients, we performed a genome-wide evaluation of CNAs.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('tumor', 'Disease', (52, 57))	('patients', 'Species', '9606', (92, 100))	('R337H', 'Mutation', 'rs121912664', (31, 36))	('R337H', 'Var', (31, 36))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
29124	33024147	Genomic instability is a hallmark of cancer hallmark that can be evident as the presence of chromosome regions with copy number gains/amplifications and losses/deletions.	('hallmark of cancer hallmark', 'Disease', (25, 52))	('gains/amplifications', 'PosReg', (128, 148))	('copy number', 'Var', (116, 127))	('Genomic', 'MPA', (0, 7))	('losses/deletions', 'NegReg', (153, 169))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('hallmark of cancer hallmark', 'Disease', 'MESH:D009369', (25, 52))
29126	33024147	In our analysis, we observed a significantly higher frequency of CNAs in the R337H+ breast cancer patients than in the R337H-  group.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('R337H', 'Mutation', 'rs121912664', (119, 124))	('CNAs', 'Disease', (65, 69))	('R337H+', 'Var', (77, 83))	('patients', 'Species', '9606', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('higher', 'PosReg', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('R337H', 'Mutation', 'rs121912664', (77, 82))	('breast cancer', 'Disease', (84, 97))
29127	33024147	In addition, a significantly higher number of cases in the R337H+ group displayed the main affected cytobands compared to the R337H- group.	('R337H+', 'Var', (59, 65))	('R337H', 'Mutation', 'rs121912664', (126, 131))	('higher', 'PosReg', (29, 35))	('R337H', 'Mutation', 'rs121912664', (59, 64))
29128	33024147	These results showed a higher level of genomic instability in the R337H+ patients and a preferential involvement of the most affected cytobands.	('genomic instability', 'MPA', (39, 58))	('patients', 'Species', '9606', (73, 81))	('R337H+', 'Var', (66, 72))	('R337H', 'Mutation', 'rs121912664', (66, 71))
29131	33024147	Critical cancer-associated pathways among the top 15 most significantly affected, such as Proteoglycans in cancer, Pathways in cancer, ErbB, Hippo, and Ras pathways, were observed in both groups, likely not reflecting the presence of the R337H variant but the tumorigenic process itself.	('tumor', 'Disease', (260, 265))	('cancer', 'Disease', (9, 15))	('ErbB', 'Gene', (135, 139))	('Ras pathways', 'Pathway', (152, 164))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ErbB', 'Gene', '1956', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('R337H', 'Mutation', 'rs121912664', (238, 243))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('Hippo', 'Pathway', (141, 146))	('R337H', 'Var', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', (107, 113))
29132	33024147	Interestingly, in the R337H+ group, the TP53 and TGFB signaling pathways, which were not observed in the R337H- group, were among the pathways mostly affected by the miRNAs present in the cytobands with CNAs.	('affected', 'Reg', (150, 158))	('R337H+', 'Var', (22, 28))	('TGFB', 'Gene', (49, 53))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('R337H', 'Mutation', 'rs121912664', (22, 27))	('TGFB', 'Gene', '7040', (49, 53))	('R337H', 'Mutation', 'rs121912664', (105, 110))
29134	33024147	In the R337H+ and R337H- groups, we observed 43 and seven genes (four genes were common to both groups), respectively, which could be affected by these two distinct molecular mechanisms.	('R337H', 'Mutation', 'rs121912664', (18, 23))	('R337H', 'Mutation', 'rs121912664', (7, 12))	('R337H-', 'Var', (18, 24))	('R337H+', 'Var', (7, 13))
29139	33024147	However, little is known about the roles of miRNAs in patients with TP53 variants.	('TP53', 'Gene', '7157', (68, 72))	('patients', 'Species', '9606', (54, 62))	('TP53', 'Gene', (68, 72))	('variants', 'Var', (73, 81))
29140	33024147	A limited number of reports in cancer have shown the phenotypic consequences of variant's TP53 upon miRNA binding, such as gain of function of the R157H and miR-128, and R273H and miR-27a.	('miRNA', 'Protein', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('variant', 'Var', (80, 87))	('gain of function', 'PosReg', (123, 139))	('miR-27a', 'Gene', (180, 187))	('R273H', 'Var', (170, 175))	('miR-128', 'Chemical', '-', (157, 164))	('TP53', 'Gene', '7157', (90, 94))	('R273H', 'Mutation', 'rs28934576', (170, 175))	('TP53', 'Gene', (90, 94))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('miR-27a', 'Gene', '407018', (180, 187))	('miR-128', 'Protein', (157, 164))	('cancer', 'Disease', (31, 37))	('R157H', 'Var', (147, 152))	('R157H', 'Mutation', 'p.R157H', (147, 152))
29141	33024147	In our study, in the R337H+ group the miR-128 was among the miRNAs previously described in these studies.	('miR-128', 'Chemical', '-', (38, 45))	('R337H', 'Mutation', 'rs121912664', (21, 26))	('R337H+', 'Var', (21, 27))	('miR-128', 'Gene', (38, 45))
29142	33024147	However, no miRNA present in the R337H- group was previously associated with TP53 variants.	('variants', 'Var', (82, 90))	('R337H', 'Mutation', 'rs121912664', (33, 38))	('TP53', 'Gene', '7157', (77, 81))	('associated', 'Reg', (61, 71))	('TP53', 'Gene', (77, 81))
29143	33024147	One recent study has shown the association of a polymorphism in miR-605 with the occurrence of multiple primary tumours in R337H carriers that meet the LF criteria.	('R337H', 'Var', (123, 128))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('R337H', 'Mutation', 'rs121912664', (123, 128))	('polymorphism', 'Var', (48, 60))	('association', 'Interaction', (31, 42))	('miR-605', 'Gene', (64, 71))	('miR-605', 'Gene', '693190', (64, 71))
29146	33024147	The analysis in the R337H+ group revealed significant associations with 72.1% of the genes, five of which (CTHRC1, ECM1, MCL1, MMP16, and STAT1) were associated specifically in cases that presented with TP53 variants in the KMplot database.	('associated', 'Reg', (150, 160))	('R337H', 'Mutation', 'rs121912664', (20, 25))	('STAT1', 'Gene', (138, 143))	('TP53', 'Gene', '7157', (203, 207))	('CTHRC1', 'Gene', (107, 113))	('ECM1', 'Gene', '1893', (115, 119))	('MMP16', 'Gene', (127, 132))	('TP53', 'Gene', (203, 207))	('STAT1', 'Gene', '6772', (138, 143))	('associations', 'Interaction', (54, 66))	('MMP16', 'Gene', '4325', (127, 132))	('MCL1', 'Gene', '4170', (121, 125))	('variants', 'Var', (208, 216))	('ECM1', 'Gene', (115, 119))	('MCL1', 'Gene', (121, 125))	('CTHRC1', 'Gene', '115908', (107, 113))
29147	33024147	Four other genes (ITGA6, HOXD10, FASN, and BUP1) were observed only in the breast cancer cases in the database that were negative for TP53 variants.	('FASN', 'Gene', '2194', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('HOXD10', 'Gene', '3236', (25, 31))	('breast cancer', 'Disease', (75, 88))	('TP53', 'Gene', (134, 138))	('FASN', 'Gene', (33, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('ITGA6', 'Gene', '3655', (18, 23))	('ITGA6', 'Gene', (18, 23))	('variants', 'Var', (139, 147))	('HOXD10', 'Gene', (25, 31))	('BUP1', 'Gene', (43, 47))	('TP53', 'Gene', '7157', (134, 138))	('BUP1', 'Gene', '51733', (43, 47))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
29148	33024147	In addition, three genes (IGFBP5, MAF, and SMYD3) that were not associated with survival in breast cancer cases in general were associated with survival specifically in cases with TP53 variants.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('SMYD3', 'Gene', '64754', (43, 48))	('breast cancer', 'Disease', (92, 105))	('variants', 'Var', (185, 193))	('IGFBP5', 'Gene', (26, 32))	('IGFBP5', 'Gene', '3488', (26, 32))	('MAF', 'Gene', '4094', (34, 37))	('MAF', 'Gene', (34, 37))	('TP53', 'Gene', '7157', (180, 184))	('TP53', 'Gene', (180, 184))	('associated', 'Reg', (128, 138))	('SMYD3', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
29149	33024147	In the R337H- group of patients, only OXR1 was significantly associated with TP53 status.	('OXR1', 'Gene', (38, 42))	('patients', 'Species', '9606', (23, 31))	('R337H', 'Mutation', 'rs121912664', (7, 12))	('OXR1', 'Gene', '55074', (38, 42))	('TP53', 'Gene', '7157', (77, 81))	('associated', 'Reg', (61, 71))	('TP53', 'Gene', (77, 81))	('R337H-', 'Var', (7, 13))
29151	33024147	Altogether, these data indicated that OXR1 prevents genome instability and could function in the cases with R337H-.	('OXR1', 'Gene', (38, 42))	('R337H-', 'Var', (108, 114))	('prevents', 'NegReg', (43, 51))	('OXR1', 'Gene', '55074', (38, 42))	('R337H', 'Mutation', 'rs121912664', (108, 113))	('genome instability', 'CPA', (52, 70))
29152	33024147	It is important to point out, however, the limitation of the interpretation of the KMplot results in relation to the R337H variant impact on survival of breast cancer patients, considering that there was no description in the queried database of the type of TP53 variants in breast cancer cases.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('TP53', 'Gene', '7157', (258, 262))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('TP53', 'Gene', (258, 262))	('R337H', 'Var', (117, 122))	('patients', 'Species', '9606', (167, 175))	('R337H', 'Mutation', 'rs121912664', (117, 122))	('breast cancer', 'Disease', 'MESH:D001943', (275, 288))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', (275, 288))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (275, 288))	('breast cancer', 'Disease', (153, 166))
29153	33024147	Finally, to further verify the impact of the R337H variant on the level of genomic instability, CNVs were analyzed in homozygous (R337H+/R337H+) and heterozygous (Wt/R337H+) normal fibroblasts exposed to a DNA damage agent.	('R337H+/R337H+', 'Var', (130, 143))	('R337H', 'Mutation', 'rs121912664', (137, 142))	('R337H', 'Mutation', 'rs121912664', (45, 50))	('R337H', 'Var', (45, 50))	('R337H', 'Mutation', 'rs121912664', (166, 171))	('R337H', 'Mutation', 'rs121912664', (130, 135))
29154	33024147	These analyses revealed a significant increase in CNVs in the cells homozygous for the R337H variant compared to cells with one wild-type TP53 allele.	('increase', 'PosReg', (38, 46))	('TP53', 'Gene', '7157', (138, 142))	('R337H', 'Mutation', 'rs121912664', (87, 92))	('R337H', 'Var', (87, 92))	('TP53', 'Gene', (138, 142))	('CNVs', 'Disease', (50, 54))
29155	33024147	Although these variations were significant in several chromosomes, reflecting a genome-wide instability, our data revealed that chromosome 11p was the region most susceptible to CNV (> 10 kb, > 50 kb, and > 100 kb), which is consistent with the CNAs described in ACTs and breast cancer.	('CNV', 'Var', (178, 181))	('breast cancer', 'Disease', 'MESH:D001943', (272, 285))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('breast cancer', 'Disease', (272, 285))	('breast cancer', 'Phenotype', 'HP:0003002', (272, 285))
29156	33024147	At 11p15, in particular, a large cluster of imprinted genes that includes IGF2, a paternally expressed fetal growth factor, can be altered in ACTs, including those with the R337H variant.	('IGF2', 'Gene', '3481', (74, 78))	('altered', 'Reg', (131, 138))	('IGF2', 'Gene', (74, 78))	('R337H', 'Mutation', 'rs121912664', (173, 178))	('R337H', 'Var', (173, 178))
29157	33024147	Previous studies have shown the additional impact of CNVs on tumors harboring germline TP53 variants, such as R337H.	('tumors', 'Disease', (61, 67))	('TP53', 'Gene', '7157', (87, 91))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('TP53', 'Gene', (87, 91))	('R337H', 'Mutation', 'rs121912664', (110, 115))	('R337H', 'Var', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
29158	33024147	analyzed 25 ACT tumors, 13 of which with the R337H variant.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('R337H', 'Mutation', 'rs121912664', (45, 50))	('R337H', 'Var', (45, 50))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))
29159	33024147	The authors utilized high-resolution single nucleotide polymorphism analysis to demonstrate that the cases with the wild-type TP53 displayed distinct genomic profiles, with significantly fewer rearrangements, compared to the cases with the R337H variant.	('TP53', 'Gene', (126, 130))	('R337H', 'Mutation', 'rs121912664', (240, 245))	('R337H', 'Var', (240, 245))	('fewer', 'NegReg', (187, 192))	('TP53', 'Gene', '7157', (126, 130))	('rearrangements', 'MPA', (193, 207))
29160	33024147	This finding was also observed in patients with Li-Fraumeni, where an increased number of CNVs were observed in patients carrying germline variants in the TP53 gene, such as R337H.	('R337H', 'Mutation', 'rs121912664', (174, 179))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (48, 59))	('R337H', 'Var', (174, 179))	('TP53', 'Gene', '7157', (155, 159))	('patients', 'Species', '9606', (112, 120))	('TP53', 'Gene', (155, 159))	('Li-Fraumeni', 'Disease', (48, 59))	('patients', 'Species', '9606', (34, 42))
29162	33024147	Among other mechanisms, R337H increases the level of breast cancer genomic instability, as evidenced by the presence of a higher number of CNAs potentially affecting genes/miRNAs that regulate critical cancer signaling pathways.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('R337H', 'Mutation', 'rs121912664', (24, 29))	('R337H', 'Var', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('affecting', 'Reg', (156, 165))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('increases', 'PosReg', (30, 39))	('breast cancer', 'Disease', (53, 66))
29163	33024147	This instability was also observed in R337H+/R337H+ fibroblast cells, which showed a significant increase in CNVs compared to cells with one wild-type TP53 allele.	('increase', 'PosReg', (97, 105))	('R337H', 'Mutation', 'rs121912664', (38, 43))	('TP53', 'Gene', (151, 155))	('R337H+/R337H+', 'Var', (38, 51))	('R337H', 'Mutation', 'rs121912664', (45, 50))	('CNVs', 'MPA', (109, 113))	('TP53', 'Gene', '7157', (151, 155))
29164	33024147	Altogether, these results indicate that the presence of the R337H variant is associated with an increased level of genomic instability in the cells.	('genomic instability in', 'MPA', (115, 137))	('R337H', 'Mutation', 'rs121912664', (60, 65))	('R337H', 'Var', (60, 65))
29175	33024147	Genotyping for the TP53 R337H variant (NM_000546.6(TP53):c.1010G > A(p.Arg337His:National Center for Biotechnology Information.	('p.Arg337His', 'Mutation', 'rs121912664', (69, 80))	('R337H', 'Mutation', 'rs121912664', (24, 29))	('TP53', 'Gene', (51, 55))	('R337H', 'Var', (24, 29))	('c.1010G > A', 'Mutation', 'rs121912664', (57, 68))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('TP53', 'Gene', '7157', (51, 55))
29182	33024147	The association of the TP53 R337H variant and the clinical-histopathological parameters was performed between the R337H+ and R337H- groups of patients, considering tumor grade and size, lymph node metastasis, and estrogen, progesterone, and HER2 receptor status.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('R337H+', 'Var', (114, 120))	('HER2', 'Gene', '2064', (241, 245))	('R337H', 'Mutation', 'rs121912664', (28, 33))	('progesterone', 'Chemical', 'MESH:D011374', (223, 235))	('R337H', 'Var', (28, 33))	('R337H', 'Mutation', 'rs121912664', (114, 119))	('R337H', 'Mutation', 'rs121912664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('patients', 'Species', '9606', (142, 150))	('HER2', 'Gene', (241, 245))	('R337H-', 'Var', (125, 131))
29187	33024147	Multiple logistic regression analysis was performed using the software GraphPad Prim 8 and taking into consideration the clinical parameters (age at diagnosis, tumor size, lymph node metastasis, and ER, PR, and HER2 receptors as independent variables (X) and the patient R337H genotype (positive or negative for the R337H variant) as the single dependent (Y) variable.	('patient', 'Species', '9606', (263, 270))	('HER2', 'Gene', (211, 215))	('R337H', 'Var', (316, 321))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('HER2', 'Gene', '2064', (211, 215))	('R337H', 'Mutation', 'rs121912664', (271, 276))	('R337H', 'Mutation', 'rs121912664', (316, 321))	('ER', 'Gene', '2069', (199, 201))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('ER', 'Gene', '2069', (212, 214))	('Prim', 'Species', '13597', (80, 84))	('PR', 'Gene', '140738', (203, 205))	('tumor', 'Disease', (160, 165))
29188	33024147	To detect CNAs, as a measurement of genomic instability, the DNA from the breast cancer cases positive and negative for the TP53 R337H variant were profiled using the SurePrint G3 Human CGH Microarray (Agilent, Santa Clara, CA, USA) according to our previous protocol for FFPE samples.	('breast cancer', 'Disease', (74, 87))	('TP53', 'Gene', '7157', (124, 128))	('TP53', 'Gene', (124, 128))	('Human', 'Species', '9606', (180, 185))	('R337H', 'Var', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('R337H', 'Mutation', 'rs121912664', (129, 134))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
29191	33024147	Copy number gains and losses were defined as the minimum average absolute log2 ratio (intensity of the Cy5 dye (reference DNA)/intensity of the Cy3 dye (test DNA) value of >= 0.25 and <  - 0.25, respectively.	('Cy5', 'Chemical', 'MESH:C085321', (103, 106))	('gains', 'PosReg', (12, 17))	('losses', 'NegReg', (22, 28))	('Copy number', 'Var', (0, 11))	('Cy3', 'Chemical', '-', (144, 147))
29192	33024147	For both groups of breast cancer patients (TP53 R337H+ and R337H -) analyzed by array-CGH, the identification of the genes and miRNAs mapped in the cyto-bands that were mostly affected by CNAs was obtained from the Agilent Cytogenomics v.5.0 interval base reports (based on the analysis parameters described above).	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('patients', 'Species', '9606', (33, 41))	('R337H', 'Mutation', 'rs121912664', (59, 64))	('R337H -', 'Var', (59, 66))	('R337H', 'Mutation', 'rs121912664', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('TP53', 'Gene', '7157', (43, 47))	('affected', 'Reg', (176, 184))	('TP53', 'Gene', (43, 47))	('breast cancer', 'Disease', (19, 32))
29194	33024147	This analysis was performed in relation to survival in the aggregated breast cancer clinical studies extracted from The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases (breast cancer cases in general and selected for TP53 variants).	('TP53', 'Gene', (275, 279))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('aggregated breast cancer', 'Disease', 'MESH:D001943', (59, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('variants', 'Var', (280, 288))	('Cancer', 'Disease', 'MESH:D009369', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('TP53', 'Gene', '7157', (275, 279))	('Breast Cancer', 'Disease', 'MESH:D001943', (166, 179))	('Cancer', 'Disease', (120, 126))	('Cancer', 'Disease', (173, 179))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('breast cancer', 'Disease', (227, 240))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Breast Cancer', 'Disease', (166, 179))	('Cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Breast Cancer', 'Phenotype', 'HP:0003002', (166, 179))	('aggregated breast cancer', 'Disease', (59, 83))
29200	33024147	CNV analyses were performed for each of the chromosomes, or for specific cytobands (9q, 9q33-34, 11p, 11p15, 17p and 17p13) considering their relevance to the ACTs and breast cancer, as we previously described.	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('9q33-34', 'Var', (88, 95))	('breast cancer', 'Disease', (168, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
29205	32633024	In addition, inhibition of AKR1B1 has been shown to mostly have anti-cancer effects.	('AKR1B1', 'Gene', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('inhibition', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
29209	32633024	Thus, there is a need to conduct more clinical studies on the application of AKR1B1 inhibitors as adjuvant therapy on different cancers.	('inhibitors', 'Var', (84, 94))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('AKR1B1', 'Gene', (77, 83))
29220	32633024	Consequently, ectopic activation of the polyol pathway could result in different diabetic complications.	('polyol', 'Chemical', 'MESH:C024617', (40, 46))	('result in', 'Reg', (61, 70))	('ectopic', 'Var', (14, 21))	('polyol pathway', 'Pathway', (40, 54))	('diabetic complications', 'Disease', (81, 103))	('diabetic complications', 'Disease', 'MESH:D048909', (81, 103))
29228	32633024	23 ,  24  This may prove a point that AKR1B1 could have a role in cancer promotion through NFkappaB activation, which has the ability to promote tumorigenicity in several cancers.	('activation', 'PosReg', (100, 110))	('tumorigenicity', 'CPA', (145, 159))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('promote', 'PosReg', (137, 144))	('cancer', 'Disease', (171, 177))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('NFkappaB', 'Protein', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('AKR1B1', 'Var', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (66, 72))
29243	32633024	For example, in vivo studies have indicated higher AKR1B1 levels in invasive tumour cells in mice having colon cancer with Trp53 deletion in comparison with normal and non-invasive models.	('Trp53', 'Gene', (123, 128))	('AKR1B1 levels', 'MPA', (51, 64))	('colon cancer', 'Disease', 'MESH:D015179', (105, 117))	('higher', 'PosReg', (44, 50))	('colon cancer', 'Disease', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('deletion', 'Var', (129, 137))	('Trp53', 'Gene', '22059', (123, 128))	('invasive tumour', 'Disease', 'MESH:D009361', (68, 83))	('mice', 'Species', '10090', (93, 97))	('invasive tumour', 'Disease', (68, 83))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('colon cancer', 'Phenotype', 'HP:0003003', (105, 117))
29245	32633024	17 ,  31 ,  32  In another study conducted on HT-29 and SW480, AKR1B1 mRNA expression was seen in SW480 without any protein expression; however, no AKR1B1 mRNA expression was found in HT-29 while it was seen on protein level.	('SW480', 'CellLine', 'CVCL:0546', (98, 103))	('HT-29', 'CellLine', 'CVCL:0320', (46, 51))	('AKR1B1', 'Gene', (63, 69))	('SW480', 'CellLine', 'CVCL:0546', (56, 61))	('SW480', 'Var', (98, 103))	('HT-29', 'CellLine', 'CVCL:0320', (184, 189))
29248	32633024	31 ,  35  Furthermore, a significantly different expression of AKR1B1 and S100P was found between lymph nodes categorized as Dukes' stage B groups and controls.	('S100P', 'SUBSTITUTION', 'None', (74, 79))	('AKR1B1', 'Gene', (63, 69))	('expression', 'MPA', (49, 59))	('S100P', 'Var', (74, 79))	('different', 'Reg', (39, 48))
29250	32633024	29  Despite the fact that there is still no clear correlation between the expression of AKR1B1 and tumour creation in CRC tissues, several evidence suggest that AKR1B1 could play a role in the tumorigenesis of CRC.	('tumorigenesis', 'CPA', (193, 206))	('CRC', 'Phenotype', 'HP:0003003', (210, 213))	('tumour creation', 'Disease', (99, 114))	('tumour creation', 'Disease', 'MESH:D009369', (99, 114))	('CRC', 'Phenotype', 'HP:0003003', (118, 121))	('role', 'Reg', (181, 185))	('play', 'Reg', (174, 178))	('AKR1B1', 'Var', (161, 167))	('CRC', 'Disease', (210, 213))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
29251	32633024	It has been proposed that ROS creation could result in the activation of inflammatory TFs such as NFkappaB, resulting in carcinogenesis.	('NFkappaB', 'Gene', (98, 106))	('carcinogenesis', 'Disease', 'MESH:D063646', (121, 135))	('ROS', 'Var', (26, 29))	('activation', 'PosReg', (59, 69))	('ROS', 'Chemical', 'MESH:D017382', (26, 29))	('carcinogenesis', 'Disease', (121, 135))
29253	32633024	37  Consistently, ROS creation has been shown to be reduced after the knockdown of AKR1B1 in CRC.	('knockdown', 'Var', (70, 79))	('reduced', 'NegReg', (52, 59))	('CRC', 'Phenotype', 'HP:0003003', (93, 96))	('AKR1B1', 'Gene', (83, 89))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('ROS creation', 'CPA', (18, 30))
29255	32633024	29  Furthermore, silencing AKR1B1 in CRC cells has been found to cause a reduction in translocation of p65 and p50 NFkappaB subunits which were partially restored after renovating AKR1B1 expression.	('AKR1B1', 'Gene', (27, 33))	('p65', 'Gene', '5970', (103, 106))	('translocation', 'MPA', (86, 99))	('CRC', 'Phenotype', 'HP:0003003', (37, 40))	('silencing', 'Var', (17, 26))	('p65', 'Gene', (103, 106))	('reduction', 'NegReg', (73, 82))	('p50 NFkappaB', 'Protein', (111, 123))
29257	32633024	29  Along with this, inhibition of AKR1B1 with Fidarestat resulted in the inhibition of Cox-2 and iNOS in both ApcMin/+ mice under HFD and C57BL/KsJ-db/db obese mice which contributed to low NFkappaB levels in cells.	('obese', 'Disease', (155, 160))	('mice', 'Species', '10090', (161, 165))	('NFkappaB levels', 'MPA', (191, 206))	('iNOS', 'Gene', (98, 102))	('Fidarestat', 'Chemical', 'MESH:C077139', (47, 57))	('mice', 'Species', '10090', (120, 124))	('Cox-2', 'Gene', '4513', (88, 93))	('AKR1B1', 'Gene', (35, 41))	('inhibition', 'NegReg', (74, 84))	('Cox-2', 'Gene', (88, 93))	('obese', 'Disease', 'MESH:D009765', (155, 160))	('iNOS', 'Gene', '4843', (98, 102))	('C57BL/KsJ-db/db', 'Var', (139, 154))	('inhibition', 'NegReg', (21, 31))	('low', 'NegReg', (187, 190))
29259	32633024	40   Another evidence that suggests AKR1B1 has a role in CRC inflammation is the notion that AKR1B1 plays a role in the synthesis of prostaglandins.	('prostaglandins', 'Chemical', 'MESH:D011453', (133, 147))	('CRC', 'Phenotype', 'HP:0003003', (57, 60))	('role', 'Reg', (49, 53))	('AKR1B1', 'Var', (93, 99))	('CRC inflammation', 'Disease', 'MESH:D015179', (57, 73))	('AKR1B1', 'Var', (36, 42))	('CRC inflammation', 'Disease', (57, 73))	('synthesis of prostaglandins', 'MPA', (120, 147))
29265	32633024	41  Taken together, these data suggest that AKR1B1 could have a regulatory role on the inflammatory responses and the carcinogenesis through manipulation of ROS, NFkappaB and PGE2 synthesis in CRC.	('inflammatory responses', 'CPA', (87, 109))	('ROS', 'Chemical', 'MESH:D017382', (157, 160))	('carcinogenesis', 'Disease', (118, 132))	('PGE2', 'Chemical', 'MESH:D015232', (175, 179))	('ROS', 'Protein', (157, 160))	('CRC', 'Phenotype', 'HP:0003003', (193, 196))	('AKR1B1', 'Var', (44, 50))	('NFkappaB', 'Protein', (162, 170))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('PGE2 synthesis', 'MPA', (175, 189))	('manipulation', 'Reg', (141, 153))
29269	32633024	43  Cyclins D1 and E, cdk4, proliferating cell nuclear antigen (PCNA), E2F and C-Myc were also suppressed following AKR1B1 inhibition.	('C-Myc', 'Gene', '4609', (79, 84))	('suppressed', 'NegReg', (95, 105))	('PCNA', 'Gene', (64, 68))	('proliferating cell nuclear antigen', 'Gene', (28, 62))	('inhibition', 'Var', (123, 133))	('cdk4', 'Gene', (22, 26))	('C-Myc', 'Gene', (79, 84))	('E2F', 'MPA', (71, 74))	('PCNA', 'Gene', '5111', (64, 68))	('proliferating cell nuclear antigen', 'Gene', '5111', (28, 62))	('cdk4', 'Gene', '1019', (22, 26))	('D1 and E', 'Gene', '27241', (12, 20))	('AKR1B1', 'Gene', (116, 122))
29270	32633024	29  It has also been reported that AKR1B1 knockdown raised the cyclin E levels in CRC with the cells in the starved state experiencing elevation in cyclin E levels compared to the cells in the released state.	('cyclin', 'Gene', (148, 154))	('elevation', 'PosReg', (135, 144))	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('cyclin', 'Gene', '5111', (148, 154))	('AKR1B1', 'Gene', (35, 41))	('raised', 'PosReg', (52, 58))	('cyclin', 'Gene', '5111', (63, 69))	('cyclin', 'Gene', (63, 69))	('knockdown', 'Var', (42, 51))
29273	32633024	Since AKR1B1 could increase tumorigenesis by inducing cell cycle progression in CRC, its inhibition could be used as a therapeutic approach in the treatment of cancer.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('CRC', 'Disease', (80, 83))	('inducing', 'Reg', (45, 53))	('increase', 'PosReg', (19, 27))	('tumorigenesis', 'CPA', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))	('cell cycle progression', 'CPA', (54, 76))	('AKR1B1', 'Var', (6, 12))
29279	32633024	Interestingly, the Inhibition of AKR1B1 has been demonstrated to down-regulate mir-21 and abrogate these effects.	('mir-21', 'Gene', (79, 85))	('mir-21', 'Gene', '406991', (79, 85))	('abrogate', 'NegReg', (90, 98))	('rat', 'Species', '10116', (56, 59))	('Inhibition', 'Var', (19, 29))	('down-regulate', 'NegReg', (65, 78))	('AKR1B1', 'Gene', (33, 39))
29281	32633024	44  It has been reported that Forkhead box O3A (FOXO3a) expression could inhibit AP-1 activation and mir-21 expression.	('AP-1', 'Protein', (81, 85))	('FOXO3a', 'Gene', '2309', (48, 54))	('Forkhead box O3A', 'Gene', '2309', (30, 46))	('mir-21', 'Gene', (101, 107))	('FOXO3a', 'Gene', (48, 54))	('mir-21', 'Gene', '406991', (101, 107))	('expression', 'MPA', (108, 118))	('expression', 'Var', (56, 66))	('Forkhead box O3A', 'Gene', (30, 46))	('inhibit', 'NegReg', (73, 80))
29282	32633024	AKR1B1 inhibition not only could activate phosphatase and tensin homolog (PTEN) through the inhibition of phosphorylation but also could increase its expression.	('expression', 'MPA', (150, 160))	('AKR1B1', 'Gene', (0, 6))	('phosphorylation', 'MPA', (106, 121))	('inhibition', 'NegReg', (92, 102))	('phosphatase and tensin homolog', 'Gene', '5728', (42, 72))	('inhibition', 'Var', (7, 17))	('increase', 'PosReg', (137, 145))	('PTEN', 'Gene', (74, 78))	('activate', 'PosReg', (33, 41))
29285	32633024	24 ,  41   Alternatively, AKR1B1 inhibition could prevent activation of the mTOR pathway through 5' adenosine monophosphate-activated protein kinase (AMPK) activation as it prevents phosphorylation of mTOR, Raptor, eIF4E, S6K and 4E-BP1, thereby inhibiting tumour growth.	('adenosine', 'Chemical', 'MESH:D000241', (100, 109))	('AKR1B1', 'Gene', (26, 32))	('Raptor', 'Gene', '57521', (207, 213))	('inhibition', 'Var', (33, 43))	('prevents', 'NegReg', (173, 181))	('tumour', 'Phenotype', 'HP:0002664', (257, 263))	('phosphorylation', 'MPA', (182, 197))	('tumour', 'Disease', 'MESH:D009369', (257, 263))	('tumour', 'Disease', (257, 263))	('mTOR pathway', 'Pathway', (76, 88))	('eIF4E', 'Gene', (215, 220))	('inhibiting', 'NegReg', (246, 256))	('mTOR', 'Protein', (201, 205))	('Raptor', 'Gene', (207, 213))	('eIF4E', 'Gene', '1977', (215, 220))	('prevent', 'NegReg', (50, 57))	('S6K and 4E-BP1', 'Gene', '6198;1978', (222, 236))	('AMPK', 'Gene', (150, 154))	('AMPK', 'Gene', '5564', (150, 154))
29286	32633024	AKR1B1 inhibition has also been reported to increase P53 protein, a tumour suppressor, which could inhibit mTOR activity.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('P53', 'Gene', (53, 56))	('AKR1B1', 'Gene', (0, 6))	('P53', 'Gene', '7157', (53, 56))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('inhibit', 'NegReg', (99, 106))	('increase', 'PosReg', (44, 52))	('inhibition', 'Var', (7, 17))	('tumour', 'Disease', (68, 74))	('mTOR activity', 'MPA', (107, 120))
29288	32633024	49  In this regard, it has been shown that silencing AKR1B1 in HCT-116 cells resulted in a lower proliferation, migration and wound closure as well as a lower phosphorylation of ERK1/2 in MAP kinase cascade.	('lower', 'NegReg', (91, 96))	('rat', 'Species', '10116', (115, 118))	('rat', 'Species', '10116', (104, 107))	('MAP kinase cascade', 'Pathway', (188, 206))	('wound closure', 'CPA', (126, 139))	('phosphorylation', 'MPA', (159, 174))	('silencing', 'Var', (43, 52))	('HCT-116', 'CellLine', 'CVCL:0291', (63, 70))	('ERK1/2', 'Gene', '5595;5594', (178, 184))	('lower', 'NegReg', (153, 158))	('AKR1B1', 'Gene', (53, 59))	('ERK1/2', 'Gene', (178, 184))
29289	32633024	These data suggest that inhibition of aldose reductase could prevent tumour growth via mTOR inhibition by different mechanisms.	('tumour', 'Disease', (69, 75))	('aldose reductase', 'Gene', '231', (38, 54))	('prevent', 'NegReg', (61, 68))	('mTOR', 'MPA', (87, 91))	('inhibition', 'NegReg', (92, 102))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('inhibition', 'Var', (24, 34))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('aldose reductase', 'Gene', (38, 54))
29291	32633024	Inhibition of AKR1B1 led to down-regulation of inter-cellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and vascular endothelial-cadherin triggered by EGF or FGF.	('down-regulation', 'NegReg', (28, 43))	('vascular endothelial-cadherin', 'Gene', (139, 168))	('inter-cellular adhesion molecule-1', 'Gene', '3383', (47, 81))	('ICAM-1', 'Gene', '3383', (83, 89))	('vascular cell adhesion molecule-1', 'Gene', (92, 125))	('inter-cellular adhesion molecule-1', 'Gene', (47, 81))	('VCAM-1', 'Gene', '7412', (127, 133))	('EGF', 'Gene', (182, 185))	('AKR1B1', 'Gene', (14, 20))	('ICAM-1', 'Gene', (83, 89))	('vascular cell adhesion molecule-1', 'Gene', '7412', (92, 125))	('EGF', 'Gene', '1950', (182, 185))	('Inhibition', 'Var', (0, 10))	('FGF', 'Gene', (189, 192))	('FGF', 'Gene', '2247', (189, 192))	('vascular endothelial-cadherin', 'Gene', '1003', (139, 168))	('VCAM-1', 'Gene', (127, 133))
29294	32633024	40   Altogether, AKR1B1 could induce malignancy in CRC by affecting cell proliferation, migration and collagen expression.	('induce', 'PosReg', (30, 36))	('collagen expression', 'CPA', (102, 121))	('rat', 'Species', '10116', (91, 94))	('rat', 'Species', '10116', (80, 83))	('cell proliferation', 'CPA', (68, 86))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('affecting', 'Reg', (58, 67))	('migration', 'CPA', (88, 97))	('malignancy', 'Disease', 'MESH:D009369', (37, 47))	('AKR1B1', 'Var', (17, 23))	('malignancy', 'Disease', (37, 47))	('CRC', 'Disease', (51, 54))
29303	32633024	53  Although studies measuring AKR1B1 expression could not clearly highlight its effect on breast cancer, several evidence suggest that AKR1B1 could play a significant role in breast cancer tumorigenesis and epithelial to mesenchymal transition (EMT).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumorigenesis', 'CPA', (190, 203))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('AKR1B1', 'Var', (136, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('breast cancer', 'Disease', (176, 189))	('epithelial to mesenchymal transition', 'CPA', (208, 244))
29306	32633024	30  It has been also indicated that Twist2 is highly expressed in breast cancer and nuclear Twist2 plays a role in inducing EMT in breast cancer.	('Twist2', 'Gene', '117581', (36, 42))	('Twist2', 'Gene', '117581', (92, 98))	('nuclear', 'Var', (84, 91))	('EMT', 'CPA', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('inducing', 'Reg', (115, 123))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('Twist2', 'Gene', (36, 42))	('Twist2', 'Gene', (92, 98))
29311	32633024	51 ,  57  Furthermore, some evidence suggests that AKR1B1 might also play a role in inflammatory responses as its inhibition could be interrupted with inflammation, triggered by chemokines, growth factors and inflammatory cytokines such as TNF alpha.	('TNF alpha', 'Gene', (240, 249))	('AKR1B1', 'Var', (51, 57))	('inflammatory responses', 'CPA', (84, 106))	('inhibition', 'MPA', (114, 124))	('inflammation', 'Disease', 'MESH:D007249', (151, 163))	('TNF alpha', 'Gene', '7124', (240, 249))	('play', 'Reg', (69, 73))	('inflammation', 'Disease', (151, 163))
29316	32633024	Furthermore, their research has shown that the inhibition of AKR1B1 suppresses PGF2a, an NFkappaB activator, causing NFkappaB to decrease.	('NFkappaB', 'MPA', (117, 125))	('PGF2a', 'Gene', (79, 84))	('inhibition', 'Var', (47, 57))	('decrease', 'NegReg', (129, 137))	('suppresses', 'NegReg', (68, 78))	('PGF2a', 'Chemical', 'MESH:D015237', (79, 84))	('AKR1B1', 'Gene', (61, 67))
29328	32633024	Furthermore, AKR1B1 was more expressed in cells being in the S phase in comparison to cells in the G1 phase, supporting the evidence that AKR1B1 could promote proliferation and hinder apoptosis through ERK1/2 pathway.	('ERK1/2', 'Gene', (202, 208))	('ERK1/2', 'Gene', '5595;5594', (202, 208))	('AKR1B1', 'Var', (138, 144))	('rat', 'Species', '10116', (166, 169))	('proliferation', 'CPA', (159, 172))	('promote', 'PosReg', (151, 158))	('hinder', 'NegReg', (177, 183))	('apoptosis', 'CPA', (184, 193))
29330	32633024	Lower levels of AKR1B1 was seen in mice with pancreatic tumours after knockdown of ZEB1 in comparison with controls; however, no direct effect was found between AKR1B1 and ZEB1 suggesting an indirect interaction.	('knockdown', 'Var', (70, 79))	('pancreatic tumours', 'Disease', (45, 63))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('pancreatic tumours', 'Disease', 'MESH:D010190', (45, 63))	('mice', 'Species', '10090', (35, 39))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))
29333	32633024	There is evidence suggesting that AKR1B1 could promote tumour progression in lung cancer.	('tumour', 'Disease', (55, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('promote', 'PosReg', (47, 54))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('AKR1B1', 'Var', (34, 40))	('lung cancer', 'Disease', (77, 88))
29336	32633024	Further knockdown of AKR1B1 in the A549 lung cancer cell line resulted in the reduction of EMT phenotype.	('AKR1B1', 'Gene', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('knockdown', 'Var', (8, 17))	('reduction', 'NegReg', (78, 87))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('A549', 'CellLine', 'CVCL:0023', (35, 39))	('EMT phenotype', 'CPA', (91, 104))	('lung cancer', 'Disease', (40, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))
29340	32633024	Hence, inhibition of AKR1B1 could assist to treat cancer by reducing tumour growth.	('tumour', 'Disease', (69, 75))	('AKR1B1', 'Gene', (21, 27))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('inhibition', 'Var', (7, 17))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('reducing', 'NegReg', (60, 68))
29343	32633024	Inhibition of AKR1B1 caused hepatoma cells to become more sensitive to 3-deoxyglucosone and glyceraldehyde, suggesting a role for AKR1B1 in cancer resistance in hepatoma cells.	('hepatoma', 'Disease', (28, 36))	('hepatoma', 'Disease', 'MESH:D006528', (28, 36))	('glyceraldehyde', 'Chemical', 'MESH:D005985', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (140, 146))	('AKR1B1', 'Gene', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('3-deoxyglucosone', 'Chemical', 'MESH:C016350', (71, 87))	('Inhibition', 'Var', (0, 10))	('hepatoma', 'Disease', (161, 169))	('hepatoma', 'Disease', 'MESH:D006528', (161, 169))	('become more', 'PosReg', (46, 57))
29347	32633024	Ectopic expression of AKR1B1 in the Hep2G cell line has been demonstrated to increase cell proliferation, migration, invasion, colony formation and wound healing whereas suppression of AKR1B1 caused the opposite effects.	('Hep2G', 'CellLine', 'CVCL:0027', (36, 41))	('wound healing', 'CPA', (148, 161))	('Ectopic expression', 'Var', (0, 18))	('colony formation', 'CPA', (127, 143))	('rat', 'Species', '10116', (109, 112))	('cell proliferation', 'CPA', (86, 104))	('rat', 'Species', '10116', (68, 71))	('AKR1B1', 'Gene', (22, 28))	('increase', 'PosReg', (77, 85))	('rat', 'Species', '10116', (98, 101))	('migration', 'CPA', (106, 115))	('invasion', 'CPA', (117, 125))
29358	32633024	Mutations in the -1079/-1068 region of the AKR1B1 promoter could abrogate the activation of this gene by T3.	('T3', 'Chemical', 'MESH:D014284', (105, 107))	('activation', 'MPA', (78, 88))	('Mutations', 'Var', (0, 9))	('AKR1B1', 'Gene', (43, 49))	('abrogate', 'NegReg', (65, 73))
29361	32633024	Besides, induction of NRF2 could silence human monocytic leukaemia cell line U937 and cause an increase in AKR1B1 expression suggesting that NRF2 may regulate AKR1B1 expression in peripheral blood cells.	('leukaemia', 'Disease', (57, 66))	('NRF2', 'Gene', '4780', (141, 145))	('leukaemia', 'Disease', 'MESH:D007938', (57, 66))	('AKR1B1', 'Gene', (107, 113))	('increase', 'PosReg', (95, 103))	('NRF2', 'Gene', (141, 145))	('human', 'Species', '9606', (41, 46))	('regulate', 'Reg', (150, 158))	('NRF2', 'Gene', '4780', (22, 26))	('induction', 'Var', (9, 18))	('expression', 'MPA', (114, 124))	('U937', 'CellLine', 'CVCL:0007', (77, 81))	('expression', 'MPA', (166, 176))	('NRF2', 'Gene', (22, 26))	('silence', 'NegReg', (33, 40))
29370	32633024	However, inhibition of aldose reductase has been reported to cause elevated levels of HNE which could increase phosphorylation of CREB and cell proliferation.	('CREB', 'Gene', (130, 134))	('aldose reductase', 'Gene', '231', (23, 39))	('levels of HNE', 'MPA', (76, 89))	('CREB', 'Gene', '1385', (130, 134))	('phosphorylation', 'MPA', (111, 126))	('aldose reductase', 'Gene', (23, 39))	('HNE', 'Chemical', 'MESH:C027576', (86, 89))	('cell proliferation', 'CPA', (139, 157))	('increase', 'PosReg', (102, 110))	('rat', 'Species', '10116', (151, 154))	('inhibition', 'Var', (9, 19))
29373	32633024	DNA methylation has been presented as a diagnostic biomarker for cancer detection with the advent of FDA approved tests such as Epi proColon and Cologuard, which could screen methylation of SEPT9, NDRG4 and BMP3 in CRC.	('NDRG4', 'Gene', '65009', (197, 202))	('NDRG4', 'Gene', (197, 202))	('BMP3', 'Gene', '651', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('methylation', 'Var', (175, 186))	('CRC', 'Phenotype', 'HP:0003003', (215, 218))	('screen', 'Reg', (168, 174))	('BMP3', 'Gene', (207, 211))	('SEPT9', 'Gene', '10801', (190, 195))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('SEPT9', 'Gene', (190, 195))
29377	32633024	29 ,  83  Consistent with these data, in a study using public methylation dataset GSE48684, AKR1B1 methylation indicated an area under the roc curve (AUC) of 0.84 between normal and CRC tissues as well as an AUC of 0.874 between normal, adenoma and CRC tissues.	('methylation', 'Var', (99, 110))	('adenoma', 'Disease', 'MESH:D000236', (237, 244))	('AUC', 'MPA', (208, 211))	('adenoma', 'Disease', (237, 244))	('AKR1B1', 'Gene', (92, 98))	('CRC', 'Phenotype', 'HP:0003003', (249, 252))	('area', 'MPA', (124, 128))	('CRC', 'Phenotype', 'HP:0003003', (182, 185))
29383	32633024	84 ,  85 ,  86  Besides, a study has demonstrated that AKR1B1 methylation occurred specifically in epithelial breast cell lines.	('epithelial breast', 'Disease', (99, 116))	('AKR1B1', 'Gene', (55, 61))	('methylation', 'Var', (62, 73))	('rat', 'Species', '10116', (44, 47))	('occurred', 'Reg', (74, 82))
29391	32633024	88   Altogether, these data suggest that AKR1B1 methylation has the potential to be used as a diagnostic biomarker in breast cancer and CRC although further research with higher sample sizes is needed to provide more valid data.	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('AKR1B1', 'Gene', (41, 47))	('methylation', 'Var', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('CRC although', 'Disease', (136, 148))
29398	32633024	92 ,  93  DOX is classified as an anthracycline antibiotic that could be used in the treatment of cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('DOX', 'Chemical', 'MESH:D004317', (10, 13))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('anthracycline', 'Chemical', 'MESH:D018943', (34, 47))	('DOX', 'Var', (10, 13))
29408	32633024	92 ,  96  For example, induction of AKR1B1 which could reduce DRC to Daunorubicinol induced resistant to tumour cells in pancreatic cancer.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('pancreatic cancer', 'Disease', (121, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (121, 138))	('tumour', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Daunorubicinol', 'Chemical', 'MESH:C000847', (69, 83))	('AKR1B1', 'Gene', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('reduce', 'NegReg', (55, 61))	('DRC', 'Chemical', 'MESH:D003630', (62, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))	('induction', 'Var', (23, 32))
29410	32633024	96  Recently, it has been found that cyclin-dependent kinase inhibitors such as Dinaciclib, Roscovitine, Purvalanol A, AZD5438 and R547 could inhibit AKR1C1 and to some extent AKR1B10, therefore sensitizing resistant cells.	('inhibit', 'NegReg', (142, 149))	('cyclin', 'Gene', (37, 43))	('Purvalanol A', 'Chemical', 'MESH:C471843', (105, 117))	('Dinaciclib', 'Chemical', 'MESH:C553669', (80, 90))	('AKR1B10', 'Gene', '57016', (176, 183))	('Roscovitine', 'Chemical', 'MESH:D000077546', (92, 103))	('AKR1C1', 'Gene', '1645', (150, 156))	('AKR1B10', 'Gene', (176, 183))	('AKR1C1', 'Gene', (150, 156))	('AZD5438', 'Chemical', 'MESH:C521840', (119, 126))	('AZD5438', 'Var', (119, 126))	('R547', 'Var', (131, 135))	('cyclin', 'Gene', '5111', (37, 43))
29413	32633024	Thus, it was proposed that tumour cell lines with lower levels of AKR1B1 such as SW480 and HT29 were more resistant to 2DG than tumour cell lines with higher levels of AKR1B1 such as HepG2 and SKOV3.	('AKR1B1', 'Var', (66, 72))	('tumour', 'Disease', (128, 134))	('HepG2', 'CellLine', 'CVCL:0027', (183, 188))	('SKOV3', 'CellLine', 'CVCL:0532', (193, 198))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('2DG', 'Chemical', 'MESH:D003847', (119, 122))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('HT29', 'CellLine', 'CVCL:0320', (91, 95))	('tumour', 'Disease', (27, 33))	('resistant', 'MPA', (106, 115))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('SW480', 'CellLine', 'CVCL:0546', (81, 86))
29423	32633024	These data suggest that glyceraldehyde, diacetyl and 2DG could reduce the amount of GSH in AKR1B1 overexpressing cells, increasing the level of cytotoxicity.	('increasing', 'PosReg', (120, 130))	('2DG', 'Chemical', 'MESH:D003847', (53, 56))	('glyceraldehyde', 'Chemical', 'MESH:D005985', (24, 38))	('diacetyl', 'Chemical', 'MESH:D003931', (40, 48))	('2DG', 'Var', (53, 56))	('cytotoxicity', 'Disease', (144, 156))	('GSH', 'Chemical', '-', (84, 87))	('reduce', 'NegReg', (63, 69))	('AKR1B1', 'Gene', (91, 97))	('GSH', 'MPA', (84, 87))	('amount', 'MPA', (74, 80))	('cytotoxicity', 'Disease', 'MESH:D064420', (144, 156))
29426	32633024	In addition, N-acetyl-cysteine, a substance that could induce GSH production has shown the cells to become more resistant to glyceraldehyde and diacetyl.	('GSH', 'MPA', (62, 65))	('resistant', 'MPA', (112, 121))	('N-acetyl-cysteine', 'Var', (13, 30))	('glyceraldehyde', 'Chemical', 'MESH:D005985', (125, 139))	('diacetyl', 'Chemical', 'MESH:D003931', (144, 152))	('N-acetyl-cysteine', 'Chemical', 'MESH:D000111', (13, 30))	('GSH', 'Chemical', '-', (62, 65))
29427	32633024	These data propose that 2DG glyceraldehyde and diacetyl could kill tumour cells by lowering the amount of GSH, however, AKR1B1 depletion may provide more NADPH for the synthesis of GSH and this may promote cell resistance against these drugs.	('2DG glyceraldehyde', 'Chemical', '-', (24, 42))	('GSH', 'Chemical', '-', (181, 184))	('synthesis', 'MPA', (168, 177))	('promote', 'PosReg', (198, 205))	('GSH', 'MPA', (106, 109))	('amount', 'MPA', (96, 102))	('tumour', 'Disease', (67, 73))	('depletion', 'Var', (127, 136))	('NADPH for', 'MPA', (154, 163))	('lowering', 'NegReg', (83, 91))	('cell resistance', 'CPA', (206, 221))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('diacetyl', 'Chemical', 'MESH:D003931', (47, 55))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('AKR1B1', 'Gene', (120, 126))	('GSH', 'Chemical', '-', (106, 109))	('NADPH', 'Chemical', 'MESH:D009249', (154, 159))
29428	32633024	17  In another study including 39 cell lines and 64 anti-cancer drugs, AKR1B1 expression alteration induced the tumour cells to become more sensitive to 23 out of 64 drugs, suggesting that AKR1B1 expression could be a putative marker for chemosensitivity prediction.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (57, 63))	('tumour', 'Disease', (112, 118))	('alteration', 'Var', (89, 99))	('sensitive', 'MPA', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('AKR1B1', 'Gene', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('become more', 'PosReg', (128, 139))	('expression alteration', 'Var', (78, 99))	('rat', 'Species', '10116', (93, 96))
29430	32633024	Thus, there is an urge to conduct more clinical studies on the application of AKR1B1 inhibitors as adjuvant therapy on different cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('inhibitors', 'Var', (85, 95))	('cancers', 'Disease', (129, 136))	('AKR1B1', 'Gene', (78, 84))
29498	32342024	Patients also reported aversion toward taking their medication, including mitotane therapy, cortisol replacement therapy, and supportive medication.	('cortisol', 'Disease', (92, 100))	('cortisol', 'Chemical', 'MESH:D006854', (92, 100))	('Patients', 'Species', '9606', (0, 8))	('mitotane', 'Var', (74, 82))	('mitotane', 'Chemical', 'MESH:D008939', (74, 82))
29574	30475217	Most benign aldosterone-producing adenomas have mutations in ion channels affecting membrane conductance and polarization and subsequently intracellular calcium levels.	('calcium', 'Chemical', 'MESH:D002118', (153, 160))	('affecting', 'Reg', (74, 83))	('aldosterone', 'Chemical', 'MESH:D000450', (12, 23))	('membrane conductance', 'MPA', (84, 104))	('polarization', 'MPA', (109, 121))	('adenomas', 'Disease', 'MESH:D000236', (34, 42))	('adenomas', 'Disease', (34, 42))	('mutations', 'Var', (48, 57))
29575	30475217	In particular somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and a germline mutation in CACNA1H have been described.	('ATP1A1', 'Gene', '476', (42, 48))	('KCNJ5', 'Gene', (35, 40))	('CACNA1H', 'Gene', (93, 100))	('CACNA1D', 'Gene', '776', (58, 65))	('ATP1A1', 'Gene', (42, 48))	('KCNJ5', 'Gene', '3762', (35, 40))	('mutations', 'Var', (22, 31))	('CACNA1H', 'Gene', '8912', (93, 100))	('ATP2B3', 'Gene', '492', (50, 56))	('ATP2B3', 'Gene', (50, 56))	('CACNA1D', 'Gene', (58, 65))
29578	30475217	In this study our goal was to identify mutations in a set of genes known to confer aldosterone production in APA in ACCs associated with hyperaldosteronism.	('hyperaldosteronism', 'Disease', 'MESH:D006929', (137, 155))	('aldosterone production', 'Phenotype', 'HP:0000859', (83, 105))	('confer', 'Reg', (76, 82))	('associated', 'Reg', (121, 131))	('aldosterone production in APA', 'MPA', (83, 112))	('mutations', 'Var', (39, 48))	('hyperaldosteronism', 'Disease', (137, 155))	('aldosterone', 'Chemical', 'MESH:D000450', (83, 94))	('ACCs', 'Gene', '84680', (116, 120))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (137, 155))	('ACCs', 'Gene', (116, 120))
29590	30475217	APAv1 was designed to target genes previously shown to be mutated in APA or other adrenal hyperplasias/neoplasms, contains 310 independent primer pairs targeting the entire coding regions of genes with reported somatic mutations in APA (KCNJ5, ATP1A1, ATP2B3, CACNA1D), genes shown to harbor germline or somatic variants associated with adrenal hyperplasia (phosphodiesterase 11A [PDE11A], phosphodiesterase 8B [PDE8B], protein kinase, cAMP-dependent, regulatory, type 1, [PRKAR1A].	('ATP1A1', 'Gene', '476', (244, 250))	('PRKAR1A', 'Gene', '5573', (473, 480))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (337, 356))	('variants', 'Var', (312, 320))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (82, 101))	('KCNJ5', 'Gene', (237, 242))	('protein kinase', 'MPA', (420, 434))	('PDE8B', 'Gene', (412, 417))	('CACNA1D', 'Gene', '776', (260, 267))	('adrenal hyperplasias', 'Phenotype', 'HP:0008221', (82, 102))	('CACNA1D', 'Gene', (260, 267))	('ATP2B3', 'Gene', '492', (252, 258))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (337, 356))	('adrenal hyperplasias/neoplasms', 'Disease', (82, 112))	('ATP2B3', 'Gene', (252, 258))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (82, 101))	('KCNJ5', 'Gene', '3762', (237, 242))	('neoplasms', 'Phenotype', 'HP:0002664', (103, 112))	('mutations', 'Var', (219, 228))	('associated', 'Reg', (321, 331))	('phosphodiesterase 8B', 'Gene', '8622', (390, 410))	('adrenal hyperplasia', 'Disease', (337, 356))	('PRKAR1A', 'Gene', (473, 480))	('adrenal hyperplasias/neoplasms', 'Disease', 'MESH:D000312', (82, 112))	('PDE11A', 'Gene', '50940', (381, 387))	('phosphodiesterase 8B', 'Gene', (390, 410))	('PDE11A', 'Gene', (381, 387))	('PDE8B', 'Gene', '8622', (412, 417))	('phosphodiesterase 11A', 'Gene', '50940', (358, 379))	('phosphodiesterase 11A', 'Gene', (358, 379))	('ATP1A1', 'Gene', (244, 250))
29591	30475217	APAv2 contains 499 independent primer pairs targeting the entire coding regions of genes in APAv1 and genes shown to harbor germline or somatic variants associated with other adrenal diseases (protein kinase, cAMP-dependent, catalytic, [PRAKACA], and armadillo repeat containing 5 [ARMC5]), alpha-1H subunit of T-type voltage dependent Ca(2+) channels [CACNA1H]) and oncogene hot spots in guanine nucleotidebinding protein subunit [GNAS], beta-catenin [CTNNB1].	('beta-catenin', 'Gene', (439, 451))	('variants', 'Var', (144, 152))	('beta-catenin', 'Gene', '1499', (439, 451))	('CACNA1H', 'Gene', '8912', (353, 360))	('GNAS', 'Gene', (432, 436))	('armadillo repeat containing 5', 'Gene', '79798', (251, 280))	('CTNNB1', 'Gene', (453, 459))	('adrenal diseases', 'Disease', (175, 191))	('armadillo repeat containing 5', 'Gene', (251, 280))	('APAv1', 'Gene', (92, 97))	('CACNA1H', 'Gene', (353, 360))	('adrenal diseases', 'Disease', 'MESH:D000303', (175, 191))	('CTNNB1', 'Gene', '1499', (453, 459))	('GNAS', 'Gene', '2778', (432, 436))
29594	30475217	First, we reviewed charts of 422 patients with a pathologically confirmed diagnosis of ACC for features of hyperaldosteronism and second, we stained an ACC TMA for CYP11B2.	('patients', 'Species', '9606', (33, 41))	('ACC', 'Disease', (87, 90))	('ACC', 'Disease', (152, 155))	('hyperaldosteronism', 'Disease', 'MESH:D006929', (107, 125))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (107, 125))	('ACC', 'Disease', 'MESH:D018268', (87, 90))	('ACC', 'Disease', 'MESH:D018268', (152, 155))	('CYP11B2', 'Var', (164, 171))	('hyperaldosteronism', 'Disease', (107, 125))	('TMA', 'Chemical', '-', (156, 159))
29607	30475217	In the second separate approach, ACC TMAs, containing 141 different specimens, including specimens of 118 patients that were also part of the initial 422 patients available for chart review, were stained for CYP11B2 and full slides were used to confirm staining.	('TMAs', 'Chemical', '-', (37, 41))	('patients', 'Species', '9606', (154, 162))	('ACC', 'Disease', (33, 36))	('CYP11B2', 'Var', (208, 215))	('patients', 'Species', '9606', (106, 114))	('ACC', 'Disease', 'MESH:D018268', (33, 36))
29611	30475217	The remaining 5 patients showed only minimal focal staining or were entirely negative on CYP11B2 staining and therefore escaped identification by TMA staining.	('patients', 'Species', '9606', (16, 24))	('TMA', 'Chemical', '-', (146, 149))	('CYP11B2', 'Var', (89, 96))	('negative', 'NegReg', (77, 85))
29621	30475217	DNA was isolated from FFPE samples and subjected to two different NGS custom panels, a panel sequencing mutations in genes known to be associated with PA in adrenal adenomas (Supplementary Table 1) and the DNA component of the Oncomine Comprehensive Assay (OCP), a pan-cancer panel targeting ~135 genes recurrently altered through somatic mutation or high level copy number amplification/loss that is being used in the NCI MATCH trial (Supplementary Table 2).	('high level copy number amplification/loss', 'Var', (351, 392))	('mutations', 'Var', (104, 113))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (157, 173))	('adrenal adenomas', 'Disease', 'MESH:D018246', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (157, 172))	('associated', 'Reg', (135, 145))	('adrenal adenomas', 'Disease', (157, 173))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
29622	30475217	None of the ACCs, including the ACCs, which showed autonomous aldosterone production (true primary aldosteronism) (Table 2), harbored well-supported mutations in the aldosterone-production associated genes.	('aldosterone production', 'Phenotype', 'HP:0000859', (62, 84))	('aldosterone', 'Chemical', 'MESH:D000450', (166, 177))	('mutations', 'Var', (149, 158))	('true primary aldosteronism', 'Phenotype', 'HP:0011739', (86, 112))	('ACCs', 'Gene', (32, 36))	('aldosterone', 'Chemical', 'MESH:D000450', (62, 73))	('ACCs', 'Gene', '84680', (32, 36))	('ACCs', 'Gene', (12, 16))	('autonomous aldosterone production', 'MPA', (51, 84))	('ACCs', 'Gene', '84680', (12, 16))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (91, 112))
29623	30475217	One patient (ACC 14) had a likely germline variant of uncertain significance in ATP2B3 (c.3518T, p.A1173V, NM_001001344).	('ACC 1', 'Gene', (13, 18))	('NM_001001344', 'Var', (107, 119))	('ATP2B3', 'Gene', '492', (80, 86))	('p.A1173V', 'Mutation', 'rs149428057', (97, 105))	('patient', 'Species', '9606', (4, 11))	('ATP2B3', 'Gene', (80, 86))	('ACC 1', 'Gene', '597', (13, 18))	('c.3518T', 'Var', (88, 95))	('p.A1173V', 'Var', (97, 105))
29624	30475217	Using the OCP, 6 ACCs had activating CTNNB1 mutations and 4 ACCs displayed TP53 mutations (Figure 2A).	('activating', 'PosReg', (26, 36))	('TP53', 'Gene', '7157', (75, 79))	('ACCs', 'Gene', '84680', (60, 64))	('CTNNB1', 'Gene', (37, 43))	('CTNNB1', 'Gene', '1499', (37, 43))	('mutations', 'Var', (44, 53))	('ACCs', 'Gene', (60, 64))	('ACCs', 'Gene', (17, 21))	('TP53', 'Gene', (75, 79))	('ACCs', 'Gene', '84680', (17, 21))
29625	30475217	In accordance with recently published molecular landscape analysis, deleterious mutations in several other known tumor suppressors were found (e.g.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutations', 'Var', (80, 89))
29627	30475217	Somatic genomic losses and gains also mirrored recent publications with amplifications of TERT and PIK3R1 and losses of CDKN2A (Figure 2B).	('TERT', 'Gene', '7015', (90, 94))	('losses', 'NegReg', (110, 116))	('CDKN2A', 'Gene', (120, 126))	('losses', 'NegReg', (16, 22))	('amplifications', 'Var', (72, 86))	('CDKN2A', 'Gene', '1029', (120, 126))	('TERT', 'Gene', (90, 94))	('PIK3R1', 'Gene', '5295', (99, 105))	('gains', 'PosReg', (27, 32))	('PIK3R1', 'Gene', (99, 105))
29628	30475217	Interestingly, one tumor harbored a mutation in APEX1, which had been implied in regulation of the CYP11B2 locus.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('APEX1', 'Gene', '328', (48, 53))	('tumor', 'Disease', (19, 24))	('APEX1', 'Gene', (48, 53))	('mutation', 'Var', (36, 44))
29630	30475217	One of these patients in addition had the commonly observed CHEK2 founder mutation (c.1100delC).	('c.1100delC', 'Mutation', 'rs555607708', (84, 94))	('patients', 'Species', '9606', (13, 21))	('c.1100delC', 'Var', (84, 94))	('CHEK2', 'Gene', '11200', (60, 65))	('CHEK2', 'Gene', (60, 65))
29631	30475217	Other variants in genes associated with hereditary diseases were likely somatic mutations (e.g.	('hereditary diseases', 'Disease', (40, 59))	('variants', 'Var', (6, 14))	('hereditary diseases', 'Disease', 'MESH:D030342', (40, 59))
29642	30475217	HAC15 cells express CYP11B2 upon AngII stimulation and produce aldosterone.	('produce', 'Reg', (55, 62))	('CYP11B2', 'Var', (20, 27))	('AngII', 'Gene', (33, 38))	('aldosterone', 'MPA', (63, 74))	('AngII', 'Gene', '183', (33, 38))	('HAC15', 'CellLine', 'CVCL:S898', (0, 5))	('aldosterone', 'Chemical', 'MESH:D000450', (63, 74))
29647	30475217	The use of a TMA bears the risk of identifying ACCs with CYP11B2 staining, which do not have other prerequisites for aldosterone production (e.g.	('aldosterone production', 'Phenotype', 'HP:0000859', (117, 139))	('TMA', 'Chemical', '-', (13, 16))	('CYP11B2 staining', 'Var', (57, 73))	('aldosterone', 'Chemical', 'MESH:D000450', (117, 128))	('ACCs', 'Gene', (47, 51))	('ACCs', 'Gene', '84680', (47, 51))
29651	30475217	The observed mutations are well in accordance with prior publications, suggesting involvement of WNT-signaling and cell cycle regulation in the pathogenesis of ACC.	('mutations', 'Var', (13, 22))	('ACC', 'Disease', 'MESH:D018268', (160, 163))	('ACC', 'Disease', (160, 163))	('involvement', 'Reg', (82, 93))
29653	30475217	The majority of APAs (70-90%) carry specific mutations in genes altering cell membrane polarization and intracellular calcium levels.	('APAs', 'Disease', (16, 20))	('mutations', 'Var', (45, 54))	('cell membrane', 'MPA', (73, 86))	('calcium', 'Chemical', 'MESH:D002118', (118, 125))
29657	30475217	Although we cannot exclude that some subclones of aldosterone-producing ACC potentially carry mutations in the same genes as described in APA, our data is suggestive for a different mechanism of aldosterone production in aldosterone-producing ACCs.	('aldosterone', 'Chemical', 'MESH:D000450', (221, 232))	('aldosterone production', 'Phenotype', 'HP:0000859', (195, 217))	('ACC', 'Disease', 'MESH:D018268', (243, 246))	('aldosterone', 'MPA', (195, 206))	('aldosterone', 'Chemical', 'MESH:D000450', (50, 61))	('mutations', 'Var', (94, 103))	('ACC', 'Disease', (72, 75))	('aldosterone', 'Chemical', 'MESH:D000450', (195, 206))	('ACC', 'Disease', (243, 246))	('carry', 'Reg', (88, 93))	('ACC', 'Disease', 'MESH:D018268', (72, 75))	('ACCs', 'Gene', '84680', (243, 247))	('ACCs', 'Gene', (243, 247))
29663	31352437	Aberrant DNA methylation of synaptophysin is involved in adrenal cortisol-producing adenoma Cortisol-producing adenoma (CPA) is the main cause of Adrenal Cushing syndrome.	('adenoma', 'Disease', (84, 91))	('CPA', 'Chemical', '-', (120, 123))	('Aberrant', 'Var', (0, 8))	('Adrenal Cushing syndrome', 'Disease', (146, 170))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (154, 170))	('involved', 'Reg', (45, 53))	('adenoma', 'Disease', 'MESH:D000236', (111, 118))	('synaptophysin', 'Gene', (28, 41))	('adenoma', 'Disease', 'MESH:D000236', (84, 91))	('Adrenal Cushing syndrome', 'Disease', 'MESH:D003480', (146, 170))	('synaptophysin', 'Gene', '6855', (28, 41))	('adenoma', 'Disease', (111, 118))
29666	31352437	Our results showed that aberrant DNA methylation of SYP is involved in CPA progress.	('DNA', 'MPA', (33, 36))	('aberrant', 'Var', (24, 32))	('involved', 'Reg', (59, 67))	('CPA', 'Chemical', '-', (71, 74))	('CPA progress', 'Disease', (71, 83))	('SYP', 'Gene', (52, 55))
29669	31352437	Knock-down of TET3 resulted in hypermethylation of SYP which reducing the expression level of SYP in H295R cells.	('reducing', 'NegReg', (61, 69))	('expression level of SYP', 'MPA', (74, 97))	('hypermethylation', 'Var', (31, 47))	('Knock-down', 'Var', (0, 10))	('TET3', 'Gene', (14, 18))	('SYP', 'Protein', (51, 54))	('H295R', 'CellLine', 'CVCL:0458', (101, 106))
29681	31352437	One of the most important epigenetic modifications of the genome is DNA methylation, which occurs on cytosine residues at carbon 5 of the pyrimidine ring of simple sequences termed CpG dinucleotides, and subsequently controls gene expression.	('controls', 'Reg', (217, 225))	('gene expression', 'MPA', (226, 241))	('methylation', 'Var', (72, 83))	('carbon 5', 'Chemical', '-', (122, 130))	('DNA', 'Var', (68, 71))	('pyrimidine', 'Chemical', 'MESH:C030986', (138, 148))	('cytosine', 'Chemical', 'MESH:D003596', (101, 109))
29682	31352437	Thus, DNA methylation regulates expression of many genes and is involved in many human diseases.	('involved', 'Reg', (64, 72))	('regulates', 'Reg', (22, 31))	('human', 'Species', '9606', (81, 86))	('methylation', 'Var', (10, 21))	('expression', 'MPA', (32, 42))	('DNA', 'Var', (6, 9))
29684	31352437	Thus, we hypothesized that methylation of cytosine nucleotides in CpG islands of the SYP promoter may regulate SYP gene expression and contribute to the hyperfunction of the adrenal cortex in CPA.	('cytosine nucleotides', 'Chemical', 'MESH:D003597', (42, 62))	('CPA', 'Chemical', '-', (192, 195))	('expression', 'MPA', (120, 130))	('regulate', 'Reg', (102, 110))	('methylation', 'Var', (27, 38))	('hyperfunction', 'PosReg', (153, 166))	('SYP gene', 'Gene', (111, 119))	('contribute', 'Reg', (135, 145))
29686	31352437	Accordingly, numerous studies have suggested that aberrant expression of certain miRNAs is closely correlated with tumour phenotype, suggesting that miRNAs might function as oncogenes or tumour suppressors.	('tumour', 'Disease', (187, 193))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('function', 'Reg', (162, 170))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('expression', 'MPA', (59, 69))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('correlated', 'Reg', (99, 109))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('aberrant', 'Var', (50, 58))	('tumour', 'Disease', (115, 121))
29687	31352437	The pleiotropic nature of miRNAs suggests that multiple signalling pathways can be affected by aberrant miRNA expression, thereby significantly directing cancer cell biological behaviour.	('miRNA', 'Protein', (104, 109))	('directing', 'PosReg', (144, 153))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('affected', 'Reg', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('aberrant', 'Var', (95, 103))
29711	31352437	Not surprisingly, we found that knock-down of SYP results in decreased secretion of cortisol (Figure 2G).	('cortisol', 'Chemical', 'MESH:D006854', (84, 92))	('SYP', 'Gene', (46, 49))	('secretion of cortisol', 'MPA', (71, 92))	('decreased secretion of cortisol', 'Phenotype', 'HP:0008163', (61, 92))	('decreased', 'NegReg', (61, 70))	('knock-down', 'Var', (32, 42))
29730	31352437	To further determine whether miR-27a-5p directly binds TET3 mRNA and regulates its expression, a luciferase reporter construct containing the wild-type or mutant 3'-UTR coding sequences for TET3 was generated and introduced into miR-27a-5p mimics and H295R cells.	('miR-27a', 'Gene', (229, 236))	('miR-27a', 'Gene', (29, 36))	('mutant', 'Var', (155, 161))	('regulates', 'Reg', (69, 78))	('H295R', 'CellLine', 'CVCL:0458', (251, 256))	('expression', 'MPA', (83, 93))	('TET3', 'Gene', (55, 59))	('miR-27a', 'Gene', '407018', (229, 236))	('miR-27a', 'Gene', '407018', (29, 36))
29731	31352437	Overexpression of miR-27a-5p significantly decreased the relative luciferase activity of the WT-3'-UTR of TET3 reporter plasmids, but when the miR-27a-5p seed sequence in TET3 mRNA 3'-UTR was mutated, the inhibitory effect of miR-27a-5p on the relative luciferase activity was abrogated (Figure 4D).	('miR-27a', 'Gene', (18, 25))	('miR-27a', 'Gene', '407018', (143, 150))	('miR-27a', 'Gene', '407018', (226, 233))	('miR-27a', 'Gene', '407018', (18, 25))	('abrogated', 'NegReg', (277, 286))	('miR-27a', 'Gene', (143, 150))	('activity', 'MPA', (77, 85))	('mutated', 'Var', (192, 199))	('miR-27a', 'Gene', (226, 233))	('luciferase', 'Enzyme', (66, 76))
29732	31352437	Negative control miR-27a-5p mimics did not affect the wild-type or mutant constructs, confirming the specificity of the action.	('miR-27a', 'Gene', '407018', (17, 24))	('miR-27a', 'Gene', (17, 24))	('mutant', 'Var', (67, 73))
29751	31352437	Recent studies have shown that a common epigenetic aberration in cancer involves deregulated DNA methylation such as CpG island hypermethylation that leads to gene silencing of specific tumour-suppressor genes.	('tumour', 'Disease', (186, 192))	('deregulated', 'Var', (81, 92))	('gene', 'MPA', (159, 163))	('DNA', 'Protein', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
29752	31352437	Interestingly, a global hypomethylation has recently also been postulated to be an important contributor to tumourigenesis such as hepatocellular carcinoma.	('tumour', 'Disease', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('global hypomethylation', 'Var', (17, 39))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (131, 155))	('hepatocellular carcinoma', 'Disease', (131, 155))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (131, 155))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumour', 'Disease', 'MESH:D009369', (108, 114))
29753	31352437	Moreover, there are studies that demonstrated that primary and metastatic adrenocortical carcinoma samples have a global hypomethylation pattern compared with normal and benign adrenocortical tissue samples, whereas other studies clarified that some genes involved in cell cycle regulation, and apoptosis in the development of adrenal showed significant and frequent hypermethylation.	('benign adrenocortical', 'Disease', 'MESH:D018268', (170, 191))	('adrenocortical carcinoma', 'Disease', (74, 98))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (74, 98))	('hypomethylation', 'MPA', (121, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('benign adrenocortical', 'Disease', (170, 191))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (74, 98))	('hypermethylation', 'Var', (367, 383))
29757	31352437	We confirmed the presence of hypomethylation of the SYP promoter in CPA compared with normal adrenal cortex.	('SYP promoter', 'Gene', (52, 64))	('hypomethylation', 'Var', (29, 44))	('CPA', 'Disease', (68, 71))	('CPA', 'Chemical', '-', (68, 71))
29758	31352437	Moreover, demethylation treatment of the adrenocortical carcinoma cell line H295R using 5-aza resulted in increased expression of SYP, which also supports the finding that SYP expression is regulated by an epigenetic mechanism.	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (41, 65))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (41, 65))	('expression', 'MPA', (116, 126))	('5-aza', 'Chemical', 'MESH:D001374', (88, 93))	('SYP', 'Gene', (130, 133))	('demethylation', 'Var', (10, 23))	('adrenocortical carcinoma', 'Disease', (41, 65))	('increased', 'PosReg', (106, 115))	('H295R', 'CellLine', 'CVCL:0458', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
29759	31352437	These findings provide the first evidence of a mechanism by which SYP is upregulated in CPA through epigenetic regulation of this gene.	('CPA', 'Disease', (88, 91))	('epigenetic regulation', 'Var', (100, 121))	('SYP', 'MPA', (66, 69))	('upregulated', 'PosReg', (73, 84))	('CPA', 'Chemical', '-', (88, 91))
29763	31352437	For this reason, we detected whether the over-expression of SYP caused by DNA hypomethylation is related to the secretion of cortisol.	('secretion of cortisol', 'MPA', (112, 133))	('over-expression', 'PosReg', (41, 56))	('cortisol', 'Chemical', 'MESH:D006854', (125, 133))	('hypomethylation', 'Var', (78, 93))	('DNA', 'Gene', (74, 77))
29764	31352437	After demethylation treatment of the adrenocortical carcinoma cell line H295R with 5-aza, the secretion of cortisol increased compared with the control group.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('cortisol increased', 'Phenotype', 'HP:0003118', (107, 125))	('adrenocortical carcinoma', 'Disease', (37, 61))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (37, 61))	('demethylation', 'Var', (6, 19))	('5-aza', 'Var', (83, 88))	('cortisol', 'Chemical', 'MESH:D006854', (107, 115))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (37, 61))	('increased', 'PosReg', (116, 125))	('H295R', 'CellLine', 'CVCL:0458', (72, 77))	('secretion of cortisol', 'MPA', (94, 115))	('5-aza', 'Chemical', 'MESH:D001374', (83, 88))
29765	31352437	Then, we knocked-down the expression of SYP in H295R cells and demonstrated that the effect of SYP knock-down decreased the secretion of cortisol.	('knock-down', 'Var', (99, 109))	('H295R', 'CellLine', 'CVCL:0458', (47, 52))	('cortisol', 'Chemical', 'MESH:D006854', (137, 145))	('SYP', 'Gene', (95, 98))	('decreased', 'NegReg', (110, 119))	('secretion of cortisol', 'MPA', (124, 145))
29766	31352437	Moreover, the finding that SYP inhibits H295R cell proliferation was also confirmed.	('inhibits', 'NegReg', (31, 39))	('H295R', 'CellLine', 'CVCL:0458', (40, 45))	('SYP', 'Var', (27, 30))	('H295R cell proliferation', 'CPA', (40, 64))
29767	31352437	Numerous evidences have shown the association of aberrantly expressed miRNAs with tumour development and progression.	('association', 'Interaction', (34, 45))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('progression', 'CPA', (105, 116))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('miRNAs', 'Protein', (70, 76))	('aberrantly expressed', 'Var', (49, 69))
29771	31352437	TET1, TET2, and TET3, the ten eleven translocation (TET) family of methylcytosine dioxygenases, can transform 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), and eliminate extant methylation labels in cells.	('TET2', 'Gene', (6, 10))	('TET1', 'Gene', '80312', (0, 4))	('transform', 'MPA', (100, 109))	('TET3', 'Var', (16, 20))	('cytosine', 'Chemical', 'MESH:D003596', (73, 81))	('TET', 'Chemical', '-', (16, 19))	('cytosine', 'Chemical', 'MESH:D003596', (153, 161))	('TET', 'Chemical', '-', (0, 3))	('TET2', 'Gene', '54790', (6, 10))	('cytosine', 'Chemical', 'MESH:D003596', (118, 126))	('TET1', 'Gene', (0, 4))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (110, 126))	('extant methylation labels', 'MPA', (184, 209))	('TET', 'Chemical', '-', (6, 9))	('eliminate', 'NegReg', (174, 183))	('5hmC', 'Chemical', 'MESH:C011865', (163, 167))	('5mC', 'Chemical', 'MESH:D044503', (128, 131))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (138, 161))	('TET', 'Chemical', '-', (52, 55))
29776	31352437	Recently, a report showed that mutations of the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 can inactivate methylcytosine dioxygenase activity, resulting in DNA hypermethylation in acute myeloid leukemia cells.	('isocitrate dehydrogenase', 'Gene', (48, 72))	('IDH', 'Gene', '3417', (74, 77))	('IDH2', 'Gene', (94, 98))	('IDH', 'Gene', (94, 97))	('IDH2', 'Gene', '3418', (94, 98))	('acute myeloid leukemia', 'Disease', (188, 210))	('cytosine', 'Chemical', 'MESH:D003596', (120, 128))	('DNA hypermethylation', 'MPA', (164, 184))	('IDH', 'Gene', (85, 88))	('mutations', 'Var', (31, 40))	('methylcytosine dioxygenase activity', 'MPA', (114, 149))	('leukemia', 'Phenotype', 'HP:0001909', (202, 210))	('IDH', 'Gene', '3417', (94, 97))	('inactivate', 'NegReg', (103, 113))	('IDH1', 'Gene', (85, 89))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (188, 210))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (194, 210))	('isocitrate dehydrogenase', 'Gene', '3417', (48, 72))	('IDH', 'Gene', '3417', (85, 88))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (188, 210))	('IDH', 'Gene', (74, 77))	('IDH1', 'Gene', '3417', (85, 89))
29777	31352437	This conclusion further enhances the outlook that TET methylcytosine dioxygenase plays a critical role in aberrant epigenetic regulation in cancer progression.	('TET', 'Chemical', '-', (50, 53))	('cytosine', 'Chemical', 'MESH:D003596', (60, 68))	('aberrant', 'Var', (106, 114))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
29780	31352437	Our results further demonstrated that knock-down of TET3 can reduce the expression level of the SYP gene in H295R cell.	('reduce', 'NegReg', (61, 67))	('expression level', 'MPA', (72, 88))	('knock-down', 'Var', (38, 48))	('SYP gene', 'Gene', (96, 104))	('TET3', 'Gene', (52, 56))	('H295R', 'CellLine', 'CVCL:0458', (108, 113))
29781	31352437	Moreover, knock-down of TET3 results in decreased secretion of cortisol.	('TET3', 'Gene', (24, 28))	('knock-down', 'Var', (10, 20))	('cortisol', 'Chemical', 'MESH:D006854', (63, 71))	('decreased secretion of cortisol', 'Phenotype', 'HP:0008163', (40, 71))	('secretion of cortisol', 'MPA', (50, 71))	('decreased', 'NegReg', (40, 49))
29818	31352437	Endogenous peroxidase activity was blocked by using 3% H2O2 in methnal for 10min and then soaked with phosphate buffered saline (PBS) (pH 7.2-7.4) three times for 5 min.	('H2O2', 'Chemical', 'MESH:D006861', (55, 59))	('H2O2', 'Var', (55, 59))	('PBS', 'Chemical', '-', (129, 132))	('phosphate buffered saline', 'Chemical', '-', (102, 127))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('activity', 'MPA', (22, 30))	('blocked', 'NegReg', (35, 42))
29822	31352437	The TET3 mutants for the miR-27a-5p seed regions were prepared using the QuikChange Site-Directed Mutagenesis Kit (Stratagene, San Diego, CA, USA) to get mutant TET3 3'UTR (MUT-TET3-3'UTR).	('miR-27a', 'Gene', (25, 32))	('TET3', 'Gene', (161, 165))	('miR-27a', 'Gene', '407018', (25, 32))	('mutant', 'Var', (154, 160))
29918	30992996	As in case 1, aldosterone-secreting adrenal tumours producing excesses of one or more adrenocortical hormones (often progesterone) have been reported previously, caused by paraneoplastic aberrant steroid synthesis pathways or enzyme deficiencies resulting in proximal hormone precursors accumulating, or being redirected to other pathways.	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('aldosterone-secreting', 'Disease', (14, 35))	('caused', 'Reg', (162, 168))	('accumulating', 'PosReg', (287, 299))	('enzyme deficiencies', 'Disease', 'MESH:D008661', (226, 245))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('steroid', 'Pathway', (196, 203))	('aldosterone', 'Chemical', 'MESH:D000450', (14, 25))	('proximal hormone precursors', 'MPA', (259, 286))	('adrenal tumours', 'Disease', 'MESH:D000310', (36, 51))	('excesses', 'PosReg', (62, 70))	('steroid', 'Chemical', 'MESH:D013256', (196, 203))	('paraneoplastic', 'Disease', 'MESH:D010257', (172, 186))	('adrenocortical', 'Disease', 'MESH:D018268', (86, 100))	('aberrant', 'Var', (187, 195))	('progesterone', 'Chemical', 'MESH:D011374', (117, 129))	('adrenocortical', 'Disease', (86, 100))	('enzyme deficiencies', 'Disease', (226, 245))	('paraneoplastic', 'Disease', (172, 186))	('adrenal tumours', 'Disease', (36, 51))
29925	30774760	Modeling the prevalent germline TP53 R337H mutation in mouse The TP53 gene encoded protein p53 plays a critical role in tumor suppression, while its germline mutation causes Li-Fraumeni syndrome (LFS), an autosomal dominant cancer predisposition disorder.	('TP53', 'Gene', '22059', (65, 69))	('TP53', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('TP53', 'Gene', '22059', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (205, 230))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (174, 194))	('autosomal dominant cancer', 'Disease', (205, 230))	('TP53', 'Gene', (32, 36))	('R337H', 'Mutation', 'rs121912664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('R337H', 'Var', (37, 42))	('Li-Fraumeni syndrome', 'Disease', (174, 194))	('tumor', 'Disease', (120, 125))	('causes', 'Reg', (167, 173))
29926	30774760	LFS is generally considered to be a rare inherited condition, but the unique founder mutation TP53 R337H that gives rise to a variant of LFS is highly prevalent in southern and southeastern Brazil with an estimated mutation carrier frequency of ~0.3%, translating to hundreds of thousands of individuals.	('R337H', 'Mutation', 'rs121912664', (99, 104))	('LFS', 'Gene', (137, 140))	('variant', 'Var', (126, 133))	('TP53', 'Gene', (94, 98))
29927	30774760	Although its overall cancer penetrance is low compared with classic LFS mutations, TP53 R337H has been associated with an increased risk of pediatric adrenocortical carcinoma relative to other cancers typically associated with LFS.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('pediatric adrenocortical carcinoma', 'Disease', (140, 174))	('cancer', 'Disease', (193, 199))	('cancers', 'Disease', (193, 200))	('TP53', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cancer', 'Disease', (21, 27))	('pediatric adrenocortical carcinoma', 'Disease', 'MESH:C565973', (140, 174))	('R337H', 'Mutation', 'rs121912664', (88, 93))	('R337H', 'Var', (88, 93))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (150, 174))
29928	30774760	The majority of LFS mutations occur within the DNA binding domain of p53 that compromises the transactivation of its target genes, but the R337H mutation is located in the oligomerization domain of the carboxy terminus with grossly preserved p53 transcriptional activity by in vitro studies.	('transactivation', 'MPA', (94, 109))	('p53', 'Gene', (242, 245))	('compromises', 'NegReg', (78, 89))	('transcriptional activity', 'MPA', (246, 270))	('R337H', 'Mutation', 'rs121912664', (139, 144))	('R337H', 'Var', (139, 144))	('mutations', 'Var', (20, 29))
29929	30774760	Given the high prevalence of this mutation and paucity of information on its characteristics in vivo, we recently reported the generation of a mouse model with knockin of the p53 R334H mutation (human TP53 R337H homolog) and examined how it affects tumorigenesis as well as the oligomerization and activity of p53 in response to DNA damage under physiological conditions.	('human', 'Species', '9606', (195, 200))	('R334H', 'Var', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('mouse', 'Species', '10090', (143, 148))	('R334H', 'Mutation', 'p.R334H', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('R337H', 'Mutation', 'rs121912664', (206, 211))	('tumor', 'Disease', (249, 254))	('affects', 'Reg', (241, 248))	('p53', 'Gene', (175, 178))	('activity', 'MPA', (298, 306))	('oligomerization', 'MPA', (278, 293))
29931	30774760	On the other hand, exposure to the carcinogen diethylnitrosamine (DEN) caused significantly increased liver tumor development in p53334H/H mice with more malignant histopathologic features.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('DEN', 'Chemical', 'MESH:D004052', (66, 69))	('p53334H/H', 'Var', (129, 138))	('increased liver', 'Phenotype', 'HP:0002240', (92, 107))	('liver tumor', 'Disease', 'MESH:D008113', (102, 113))	('increased', 'PosReg', (92, 101))	('liver tumor', 'Phenotype', 'HP:0002896', (102, 113))	('liver tumor', 'Disease', (102, 113))	('mice', 'Species', '10090', (139, 143))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (46, 64))	('p53334H/H', 'Mutation', 'p.H53334H', (129, 138))
29932	30774760	In parallel, there was evidence of increased DNA damage and decreased transactivation of p53 target genes in the DEN-treated liver tissue of p53334H/H mice compared with that of wild-type mice.	('mice', 'Species', '10090', (188, 192))	('transactivation', 'MPA', (70, 85))	('decreased', 'NegReg', (60, 69))	('increased', 'PosReg', (35, 44))	('p53334H/H', 'Var', (141, 150))	('mice', 'Species', '10090', (151, 155))	('p53 target genes', 'Gene', (89, 105))	('p53334H/H', 'Mutation', 'p.H53334H', (141, 150))	('DEN', 'Chemical', 'MESH:D004052', (113, 116))	('DNA damage', 'MPA', (45, 55))
29933	30774760	Mechanistically, p53334H/H mouse liver tissue showed decreased levels of dimers and tetramers but increased monomers of p53 after DEN treatment, constituting the first in vivo demonstration of its diminished oligomerization capacity consistent with the observed decrease in its transcriptional activity (Figure 1).	('dimers', 'MPA', (73, 79))	('diminished', 'NegReg', (197, 207))	('levels', 'MPA', (63, 69))	('monomers', 'MPA', (108, 116))	('DEN', 'Chemical', 'MESH:D004052', (130, 133))	('p53334H/H', 'Mutation', 'p.H53334H', (17, 26))	('mouse', 'Species', '10090', (27, 32))	('oligomerization capacity', 'MPA', (208, 232))	('increased', 'PosReg', (98, 107))	('decreased', 'NegReg', (53, 62))	('p53', 'Gene', (120, 123))	('p53334H/H', 'Var', (17, 26))	('tetramers', 'MPA', (84, 93))
29934	30774760	Structural studies have suggested that arginine 337 within the alpha-helix motif of human p53 forms a salt bridge with aspartate 352 of another p53 molecule, helping to stabilize p53 homodimers that in turn dimerize to form tetramers.	('dimerize', 'MPA', (207, 215))	('p53', 'Gene', (179, 182))	('arginine', 'Chemical', 'MESH:D001120', (39, 47))	('tetramers', 'MPA', (224, 233))	('arginine 337', 'Var', (39, 51))	('aspartate', 'Chemical', 'MESH:D001224', (119, 128))	('homodimers', 'MPA', (183, 193))	('stabilize', 'MPA', (169, 178))	('human', 'Species', '9606', (84, 89))
29935	30774760	The substitution of arginine 337 to histidine, which has a lower pKa than arginine, has been proposed to disrupt the stabilization of these p53 homodimers due to the loss of protonation and salt bridge formation at physiologic pH.	('arginine', 'Chemical', 'MESH:D001120', (74, 82))	('arginine 337 to histidine', 'Mutation', 'rs121912664', (20, 45))	('loss', 'NegReg', (166, 170))	('arginine', 'Chemical', 'MESH:D001120', (20, 28))	('protonation', 'MPA', (174, 185))	('substitution', 'Var', (4, 16))	('arginine 337', 'Var', (20, 32))	('stabilization', 'MPA', (117, 130))	('disrupt', 'NegReg', (105, 112))	('salt bridge formation', 'MPA', (190, 211))
29936	30774760	Thus, the transcriptional activity of human p53 R337H may be more sensitive to intracellular pH than that of the wild-type protein.	('human', 'Species', '9606', (38, 43))	('R337H', 'Mutation', 'rs121912664', (48, 53))	('R337H', 'Var', (48, 53))	('transcriptional activity', 'MPA', (10, 34))	('p53', 'Gene', (44, 47))	('sensitive', 'MPA', (66, 75))
29937	30774760	In this regard, it is notable that the adrenal gland, which has very active uptake and the highest concentration of ascorbic acid (vitamin C) in the human body, is susceptible to cancer development in carriers of the R337H mutation.	('R337H', 'Mutation', 'rs121912664', (217, 222))	('ascorbic acid', 'Chemical', 'MESH:D001205', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('R337H', 'Var', (217, 222))	('susceptible', 'Reg', (164, 175))	('vitamin C', 'Chemical', 'MESH:D001205', (131, 140))	('human', 'Species', '9606', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('active uptake', 'MPA', (69, 82))	('cancer', 'Disease', (179, 185))
29938	30774760	Besides the adrenocortical carcinoma, another pediatric cancer observed in patients with the R337H mutation is carcinoma of the choroid plexus, which is involved in electrolyte transport and pH buffering of the cerebrospinal fluid.	('carcinoma of the choroid plexus', 'Disease', (111, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adrenocortical carcinoma', 'Disease', (12, 36))	('carcinoma of the choroid plexus', 'Phenotype', 'HP:0030392', (111, 142))	('R337H', 'Mutation', 'rs121912664', (93, 98))	('carcinoma of the choroid plexus', 'Disease', 'MESH:D020288', (111, 142))	('R337H', 'Var', (93, 98))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (12, 36))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (12, 36))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
29939	30774760	This raises the possibility that drugs or conditions that alter intracellular pH could affect the oligomerization of mutant p53 R337H, thereby ameliorating its defective transcriptional activity in vivo.	('p53', 'Gene', (124, 127))	('affect', 'Reg', (87, 93))	('defective', 'MPA', (160, 169))	('mutant', 'Var', (117, 123))	('oligomerization', 'MPA', (98, 113))	('R337H', 'Mutation', 'rs121912664', (128, 133))	('ameliorating', 'PosReg', (143, 155))	('R337H', 'Var', (128, 133))	('transcriptional activity', 'MPA', (170, 194))
29940	30774760	Because patients with the TP53 R337H mutation have also been reported to have decreased plasma ascorbic acid levels, it is tempting to speculate that modulating tissue vitamin C levels or pH may alter endogenous p53 activity in vivo and affect tumorigenesis.	('affect', 'Reg', (237, 243))	('TP53', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', (244, 249))	('ascorbic acid', 'Chemical', 'MESH:D001205', (95, 108))	('vitamin C', 'Chemical', 'MESH:D001205', (168, 177))	('R337H', 'Mutation', 'rs121912664', (31, 36))	('plasma ascorbic acid levels', 'MPA', (88, 115))	('alter', 'Reg', (195, 200))	('R337H', 'Var', (31, 36))	('endogenous', 'MPA', (201, 211))	('modulating', 'Var', (150, 160))	('decreased', 'NegReg', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('activity', 'MPA', (216, 224))	('patients', 'Species', '9606', (8, 16))
29943	30774760	With the availability of the p53 R334H mouse model, some of these questions could be addressed in the laboratory and may lead to insights for follow up by clinical investigation with the goal of improving the management of this large population of patients with a unique p53 mutation.	('R334H', 'Mutation', 'p.R334H', (33, 38))	('R334H', 'Var', (33, 38))	('lead', 'Reg', (121, 125))	('patients', 'Species', '9606', (248, 256))	('p53', 'Gene', (271, 274))	('mouse', 'Species', '10090', (39, 44))
29950	30349596	Mitotane therapy results in adrenal insufficiency, and glucocorticoid replacement therapy has to be administered at higher doses than those used in other aetiologies of primary adrenal insufficiency.	('Mitotane', 'Var', (0, 8))	('adrenal insufficiency', 'Disease', (28, 49))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (177, 198))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (177, 198))	('primary adrenal insufficiency', 'Phenotype', 'HP:0008207', (169, 198))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('men', 'Species', '9606', (77, 80))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (28, 49))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (28, 49))	('adrenal insufficiency', 'Disease', (177, 198))	('results in', 'Reg', (17, 27))
29969	30349596	At microscopic level, mitotane can cause the destruction of both the zona fasciculata and reticularis; however, its adrenocytolytic activity saves the zona glomerulosa, with selective loss of steroid secretion limited to hormones which are under the control of adrenocorticotropic hormone (ACTH) secretion.	('mitotane', 'Var', (22, 30))	('zona fasciculata', 'Disease', (69, 85))	('mitotane', 'Chemical', 'MESH:D008939', (22, 30))	('adrenocorticotropic hormone', 'Gene', (261, 288))	('zona fasciculata', 'Disease', 'MESH:D006562', (69, 85))	('steroid', 'Chemical', 'MESH:D013256', (192, 199))	('ACTH', 'Gene', (290, 294))	('loss', 'NegReg', (184, 188))	('ACTH', 'Gene', '5443', (290, 294))	('adrenocorticotropic hormone', 'Gene', '5443', (261, 288))	('adrenocytolytic activity', 'MPA', (116, 140))	('steroid secretion', 'MPA', (192, 209))
29974	30349596	In particular, mitotane induces an impairment of respiratory chain, decreasing aspartate and concomitantly increasing glutamate content in a time- and concentration-dependent manner.	('respiratory', 'MPA', (49, 60))	('aspartate', 'MPA', (79, 88))	('decreasing', 'NegReg', (68, 78))	('aspartate', 'Chemical', 'MESH:D001224', (79, 88))	('increasing', 'PosReg', (107, 117))	('mitotane', 'Var', (15, 23))	('glutamate', 'Chemical', 'MESH:D018698', (118, 127))	('men', 'Species', '9606', (41, 44))	('mitotane', 'Chemical', 'MESH:D008939', (15, 23))	('glutamate content', 'MPA', (118, 135))
29979	30349596	Furthermore, mitotane causes decreased mRNA levels of two cytochromes p450 (CYP11A1 and CYP17A1), encoding proteins involved in cortisol and dehydroepiandrosterone sulphate biosynthesis.	('mitotane', 'Chemical', 'MESH:D008939', (13, 21))	('CYP11A1', 'Gene', (76, 83))	('mRNA levels', 'MPA', (39, 50))	('CYP17A1', 'Gene', (88, 95))	('dehydroepiandrosterone sulphate', 'Chemical', 'MESH:D019314', (141, 172))	('decreased', 'NegReg', (29, 38))	('CYP17A1', 'Gene', '1586', (88, 95))	('p450', 'Gene', (70, 74))	('p450', 'Gene', '1555', (70, 74))	('cortisol', 'Chemical', 'MESH:D006854', (128, 136))	('CYP11A1', 'Gene', '1583', (76, 83))	('mitotane', 'Var', (13, 21))
29986	30349596	In addition to its inhibitory effects on multiple enzymatic steps of adrenocortical steroid biosynthesis, mitotane increases cortisol binding globulin (CBG) and sex hormone binding globulin (SHBG).	('SHBG', 'Gene', (191, 195))	('CBG', 'Gene', (152, 155))	('increases cortisol', 'Phenotype', 'HP:0003118', (115, 133))	('mitotane', 'Var', (106, 114))	('mitotane', 'Chemical', 'MESH:D008939', (106, 114))	('cortisol binding globulin', 'Gene', (125, 150))	('sex hormone binding globulin', 'Gene', '6462', (161, 189))	('increases', 'PosReg', (115, 124))	('sex hormone binding globulin', 'Gene', (161, 189))	('adrenocortical', 'Disease', (69, 83))	('adrenocortical', 'Disease', 'MESH:D018268', (69, 83))	('CBG', 'Gene', '866', (152, 155))	('steroid', 'Chemical', 'MESH:D013256', (84, 91))	('cortisol binding globulin', 'Gene', '866', (125, 150))	('SHBG', 'Gene', '6462', (191, 195))
29989	30349596	Finally, as mitotane is an inducer of hepatic cytochrome CYP34A, it can interfere with the metabolism of various drugs, including antihypertensives, statins, antibiotics, chemotherapeutic agents and coumarin-like anticoagulants.	('al', 'Chemical', 'MESH:D000535', (3, 5))	('antihypertensives', 'Disease', (130, 147))	('coumarin', 'Chemical', 'MESH:C030123', (199, 207))	('metabolism', 'MPA', (91, 101))	('mitotane', 'Var', (12, 20))	('mitotane', 'Chemical', 'MESH:D008939', (12, 20))	('interfere', 'NegReg', (72, 81))
29993	30349596	One of the most important contributions to this field is a retrospective analysis involving 177 patients from Italy and Germany treated with mitotane after radical surgery, showing that recurrence free survival (RFS) was significantly prolonged in the mitotane group (42 months) compared with the control groups (10 months and 25 months).	('mitotane', 'Chemical', 'MESH:D008939', (141, 149))	('mitotane', 'Chemical', 'MESH:D008939', (252, 260))	('al', 'Chemical', 'MESH:D000535', (161, 163))	('recurrence free survival', 'CPA', (186, 210))	('RFS', 'Disease', (212, 215))	('al', 'Chemical', 'MESH:D000535', (112, 114))	('RFS', 'Disease', 'MESH:D005198', (212, 215))	('al', 'Chemical', 'MESH:D000535', (208, 210))	('patients', 'Species', '9606', (96, 104))	('al', 'Chemical', 'MESH:D000535', (75, 77))	('prolonged', 'PosReg', (235, 244))	('mitotane', 'Var', (252, 260))
30054	30349596	Some authors suggest the use of mitotane in cases of poor prognosis, such as in p53 mutations carriers.	('carriers', 'Reg', (94, 102))	('p53', 'Gene', (80, 83))	('mutations', 'Var', (84, 93))	('p53', 'Gene', '7157', (80, 83))	('mitotane', 'Chemical', 'MESH:D008939', (32, 40))
30057	30349596	However, mitotane therapy results in adrenal insufficiency and some clinicians prefer to initiate cortisol replacement concomitantly with mitotane.	('cortisol', 'Chemical', 'MESH:D006854', (98, 106))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (37, 58))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (37, 58))	('results in', 'Reg', (26, 36))	('men', 'Species', '9606', (114, 117))	('adrenal insufficiency', 'Disease', (37, 58))	('mitotane', 'Chemical', 'MESH:D008939', (138, 146))	('mitotane', 'Var', (9, 17))	('mitotane', 'Chemical', 'MESH:D008939', (9, 17))
30067	30349596	However, in patients treated with mitotane, modified release hydrocortisone resulted in much lower total and free cortisol levels than immediate release hydrocortisone at the same dose.	('patients', 'Species', '9606', (12, 20))	('modified release', 'Var', (44, 60))	('al', 'Chemical', 'MESH:D000535', (102, 104))	('hydrocortisone', 'Chemical', 'MESH:D006854', (153, 167))	('mitotane', 'Chemical', 'MESH:D008939', (34, 42))	('lower total and free cortisol', 'Phenotype', 'HP:0008163', (93, 122))	('hydrocortisone', 'Chemical', 'MESH:D006854', (61, 75))	('lower', 'NegReg', (93, 98))	('cortisol', 'Chemical', 'MESH:D006854', (114, 122))
30073	30349596	Serum cortisol cannot be considered a valid parameter, since mitotane increases CBG which artificially raises total cortisol.	('mitotane', 'Var', (61, 69))	('total cortisol', 'MPA', (110, 124))	('CBG', 'Gene', (80, 83))	('mitotane', 'Chemical', 'MESH:D008939', (61, 69))	('raises total cortisol', 'Phenotype', 'HP:0003118', (103, 124))	('cortisol', 'Chemical', 'MESH:D006854', (116, 124))	('increases', 'PosReg', (70, 79))	('cortisol', 'Chemical', 'MESH:D006854', (6, 14))	('al', 'Chemical', 'MESH:D000535', (39, 41))	('raises', 'PosReg', (103, 109))	('al', 'Chemical', 'MESH:D000535', (98, 100))	('al', 'Chemical', 'MESH:D000535', (113, 115))	('CBG', 'Gene', '866', (80, 83))
30078	30349596	Moreover, mitotane can cause falsely elevated urinary free cortisol levels due to altered steroid clearance.	('steroid clearance', 'MPA', (90, 107))	('elevated', 'PosReg', (37, 45))	('elevated urinary free cortisol levels', 'Phenotype', 'HP:0012030', (37, 74))	('mitotane', 'Var', (10, 18))	('mitotane', 'Chemical', 'MESH:D008939', (10, 18))	('steroid', 'Chemical', 'MESH:D013256', (90, 97))	('cortisol', 'Chemical', 'MESH:D006854', (59, 67))	('al', 'Chemical', 'MESH:D000535', (30, 32))	('al', 'Chemical', 'MESH:D000535', (82, 84))	('altered', 'Reg', (82, 89))	('urinary free cortisol levels', 'MPA', (46, 74))
30081	30349596	Even if the more consistent consequence of mitotane on adrenal function is an increase of ACTH levels related to hypoadrenalism, studies in vitro have also documented a direct inhibitory effect of mitotane at pituitary level and hypothalamic levels.	('ACTH', 'Gene', '5443', (90, 94))	('mitotane', 'Chemical', 'MESH:D008939', (43, 51))	('hypoadrenalism', 'Phenotype', 'HP:0000846', (113, 127))	('hypoadrenalism', 'Disease', 'MESH:D000309', (113, 127))	('al', 'Chemical', 'MESH:D000535', (151, 153))	('increase of ACTH levels', 'Phenotype', 'HP:0003154', (78, 101))	('hypoadrenalism', 'Disease', (113, 127))	('increase', 'PosReg', (78, 86))	('inhibitory', 'NegReg', (176, 186))	('men', 'Species', '9606', (160, 163))	('al', 'Chemical', 'MESH:D000535', (122, 124))	('mitotane', 'Var', (197, 205))	('mitotane', 'Chemical', 'MESH:D008939', (197, 205))	('al', 'Chemical', 'MESH:D000535', (235, 237))	('al', 'Chemical', 'MESH:D000535', (60, 62))	('ACTH', 'Gene', (90, 94))
30085	30349596	Mitotane also acts on the hypothalamus-pituitary-thyroid axis, impairing thyroid-stimulating hormone expression and thyrotropin-releasing hormone responsivity in experimental models.	('impairing', 'NegReg', (63, 72))	('thyroid-stimulating hormone expression', 'MPA', (73, 111))	('Mitotane', 'Var', (0, 8))	('al', 'Chemical', 'MESH:D000535', (172, 174))	('thyrotropin-releasing hormone', 'Gene', (116, 145))	('hypothalamus-pituitary-thyroid axis', 'Disease', 'MESH:D007029', (26, 61))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('al', 'Chemical', 'MESH:D000535', (32, 34))	('thyrotropin-releasing hormone', 'Gene', '7200', (116, 145))	('hypothalamus-pituitary-thyroid axis', 'Disease', (26, 61))	('men', 'Species', '9606', (168, 171))	('al', 'Chemical', 'MESH:D000535', (9, 11))
30108	30349596	A larger randomised study conducted by Fassnacht et al., and including 304 patients, confirmed a significantly higher response and longer median progression-free survival in the group of patients treated with mitotane plus EDP compared to mitotane plus streptozocin.	('mitotane', 'Chemical', 'MESH:D008939', (239, 247))	('patients', 'Species', '9606', (187, 195))	('al', 'Chemical', 'MESH:D000535', (168, 170))	('al', 'Chemical', 'MESH:D000535', (52, 54))	('mitotane', 'Var', (209, 217))	('patients', 'Species', '9606', (75, 83))	('mitotane', 'Chemical', 'MESH:D008939', (209, 217))	('streptozocin', 'Chemical', 'MESH:D013311', (253, 265))	('higher', 'PosReg', (111, 117))	('response', 'MPA', (118, 126))	('EDP', 'Chemical', '-', (223, 226))
30118	30349596	In addition to activation of the beta catenin pathway, other findings include TP53 mutations found in Li-Fraumeni syndrome, the APC and CTNNB1 genes mutations in familial adenomatous polyposis coli, and the CDKN1C and IGF-2 genes mutations in Beckwith-Wiedemann syndrome as well as NF1, RB1 and menin gene mutations.	('al', 'Chemical', 'MESH:D000535', (168, 170))	('CDKN1C', 'Gene', '1028', (207, 213))	('mutations', 'Var', (230, 239))	('CTNNB1', 'Gene', '1499', (136, 142))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (243, 270))	('RB1', 'Gene', '5925', (287, 290))	('Li-Fraumeni syndrome', 'Disease', (102, 122))	('menin', 'Gene', '4221', (295, 300))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (102, 122))	('TP53', 'Gene', '7157', (78, 82))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (171, 197))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (171, 197))	('menin', 'Gene', (295, 300))	('adenomatous polyposis coli', 'Disease', (171, 197))	('NF1', 'Gene', '4763', (282, 285))	('mutations', 'Var', (149, 158))	('CTNNB1', 'Gene', (136, 142))	('CDKN1C', 'Gene', (207, 213))	('IGF-2', 'Gene', (218, 223))	('IGF-2', 'Gene', '3481', (218, 223))	('NF1', 'Gene', (282, 285))	('beta catenin pathway', 'Pathway', (33, 53))	('mutations', 'Var', (83, 92))	('mutations', 'Var', (306, 315))	('Beckwith-Wiedemann syndrome', 'Disease', (243, 270))	('APC', 'Disease', 'MESH:D011125', (128, 131))	('RB1', 'Gene', (287, 290))	('TP53', 'Gene', (78, 82))	('APC', 'Disease', (128, 131))
30131	29874863	In particular, the introduction of next-generation sequencing allowed the identification of somatic mutations in four genes differently involved in Ca2+ homeostasis (KCNJ5, ATP1A1, ATP2B3, and CACNA1D), unraveling the genetic basis of approximately 50% of sporadic APAs.	('mutations', 'Var', (100, 109))	('ATP1A1', 'Gene', (173, 179))	('ATP2B3', 'Gene', '492', (181, 187))	('CACNA1D', 'Gene', '776', (193, 200))	('CACNA1D', 'Gene', (193, 200))	('KCNJ5', 'Gene', (166, 171))	('ATP2B3', 'Gene', (181, 187))	('Ca2+', 'Chemical', 'MESH:D000069285', (148, 152))	('APAs', 'Disease', (265, 269))	('KCNJ5', 'Gene', '3762', (166, 171))	('ATP1A1', 'Gene', '476', (173, 179))
30141	29874863	In our cohort, the expression of both CRY genes was neither associated with the cellular composition of the APAs (CRY1 expression in ZG-like APAs: 1.46 [0.45-2.59], CRY1 expression in ZF-like APAs: 0.96 [0.49-1.58], p-value 0.291; CRY2 expression in ZG-like APAs: 1.24 [0.57-2.05], CRY2 expression in ZF-like APAs: 0.84 [0.62-1.28], p-value 0.170) nor with the mutational status (CRY1 expression in wild-type APAs: 1.39 [0.58-2.7], CRY1 expression in KCNJ5 mutant APAs: 0.89 [0.42-1.70], CRY1 expression in ATP1A1-ATP2B3 mutant APAs: 0.89 [0.49-1.09], CRY1 expression in CACNA1D mutant APAs: 1.4 [0.64-2.61], p-value = 0.417; CRY2 expression in wild-type APAs: 1.08 [0.61-1.98], CRY2 expression in KCNJ5 mutant APAs: 0.98 [0.54-1.41], CRY2 expression in ATP1A1-ATP2B3 mutant APAs: 0.89 [0.62-1.06], CRY2 expression in CACNA1D mutant APAs: 1.61 [0.80-2.87], p-value = 0.170).	('ATP1A1', 'Gene', '476', (507, 513))	('ATP2B3', 'Gene', (761, 767))	('CACNA1D', 'Gene', '776', (818, 825))	('CACNA1D', 'Gene', '776', (571, 578))	('CACNA1D', 'Gene', (818, 825))	('mutant', 'Var', (704, 710))	('ATP1A1', 'Gene', (507, 513))	('CACNA1D', 'Gene', (571, 578))	('KCNJ5', 'Gene', '3762', (698, 703))	('ATP1A1', 'Gene', (754, 760))	('KCNJ5', 'Gene', (451, 456))	('KCNJ5', 'Gene', '3762', (451, 456))	('ATP2B3', 'Gene', '492', (761, 767))	('ATP2B3', 'Gene', '492', (514, 520))	('ATP2B3', 'Gene', (514, 520))	('ATP1A1', 'Gene', '476', (754, 760))	('KCNJ5', 'Gene', (698, 703))
30142	29874863	No differences in the expression of HSD3B1 or HSD3B2, according to the mutational status (HSD3B1 expression in wild-type APAs: 1.37 [0.42-4.5], HSD3B1 expression in KCNJ5 mutant APAs: 0.51 [0.30-1.97], HSD3B1 expression in ATP1A1-ATP2B3 mutant APAs: 0.66 [0.27-1.63], HSD3B1 expression in CACNA1D mutant APAs: 2.27 [1.40-3.12], p-value = 0.212; HSD3B2 expression in wild-type APAs: 1.0 [0.75-2.37], HSD3B2 expression in KCNJ5 mutant APAs: 1.01 [0.68-2.18], HSD3B2 expression in ATP1A1-ATP2B3 mutant APAs: 0.69 [0.46-0.93], HSD3B2 expression in CACNA1D mutant APAs: 2.82 [1.16-3.19], p-value = 0.147) or the final diagnosis (HSD3B1 expression in APAs: 1.37 [0.30-3.00], HSD3B1 expression in UAHs: 0.66 [0.42-3.61], p-value 0.899; HSD3B2 expression in APAs: 1.17 [0.66-2.63], HSD3B2 expression in UAHs: 0.99 [0.71-1.63], p-value 0.523), were observed.	('ATP2B3', 'Gene', '492', (230, 236))	('CACNA1D', 'Gene', '776', (289, 296))	('ATP2B3', 'Gene', '492', (485, 491))	('KCNJ5', 'Gene', '3762', (165, 170))	('CACNA1D', 'Gene', (289, 296))	('ATP2B3', 'Gene', (230, 236))	('KCNJ5', 'Gene', (420, 425))	('ATP2B3', 'Gene', (485, 491))	('ATP1A1', 'Gene', '476', (223, 229))	('CACNA1D', 'Gene', '776', (544, 551))	('ATP1A1', 'Gene', '476', (478, 484))	('CACNA1D', 'Gene', (544, 551))	('ATP1A1', 'Gene', (223, 229))	('KCNJ5', 'Gene', '3762', (420, 425))	('mutant', 'Var', (552, 558))	('ATP1A1', 'Gene', (478, 484))	('KCNJ5', 'Gene', (165, 170))
30144	29874863	CRY1 and CRY2 genes were transcribed in HAC15 cells to a level comparable to that of a pooled set of APA samples, while HSD3B2 was 35-fold (25-61, p < 0.001) more expressed than HSD3B1.	('expressed', 'MPA', (163, 172))	('HAC15', 'CellLine', 'CVCL:S898', (40, 45))	('more', 'PosReg', (158, 162))	('HSD3B2', 'Var', (120, 126))	('CRY2', 'Gene', (9, 13))	('CRY1', 'Gene', (0, 4))
30160	29874863	A previous study showed that HSD3B1 (evaluated as H-score) was more expressed in APAs carrying somatic mutations in the KCNJ5 gene, while in our cohort we did not detect any significant association between the expression of HSD3B1 (evaluated by real-time PCR) and the mutational status of the samples.	('mutations', 'Var', (103, 112))	('KCNJ5', 'Gene', '3762', (120, 125))	('expressed', 'MPA', (68, 77))	('more', 'PosReg', (63, 67))	('KCNJ5', 'Gene', (120, 125))	('HSD3B1', 'Gene', (29, 35))
30161	29874863	On the contrary, we observed that both HSD3B1 expression and the relative HSD3B1/HSD3B2 ratio were significantly more elevated in APAs composed mainly of zona glomerulosa-like cells (while APAs carrying a mutation in KCNJ5 are composed mainly of zona fasciculata-like cells).	('HSD3B1', 'Gene', (39, 45))	('KCNJ5', 'Gene', (217, 222))	('fasciculata-', 'Phenotype', 'HP:0002380', (251, 263))	('zona fasciculata', 'Disease', (246, 262))	('KCNJ5', 'Gene', '3762', (217, 222))	('zona fasciculata', 'Disease', 'MESH:D006562', (246, 262))	('expression', 'MPA', (46, 56))	('mutation', 'Var', (205, 213))	('elevated', 'PosReg', (118, 126))	('HSD3B1/HSD3B2', 'Gene', (74, 87))
30167	29874863	Silencing PER1 in H295R cells was able to decrease the expression of HSD3B1 isoform by 58%, supporting the hypothesis that PER1 is involved in the modulation of serum aldosterone levels.	('aldosterone', 'Chemical', 'MESH:D000450', (167, 178))	('expression', 'MPA', (55, 65))	('H295R', 'CellLine', 'CVCL:0458', (18, 23))	('decrease', 'NegReg', (42, 50))	('HSD3B1', 'Protein', (69, 75))	('PER1', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))
30170	29874863	Contrary to what was expected from the Cry-null and the Per knock-out murine models, silencing CRY genes did not modify the expression of HSD3B1; however, we observed a mild upregulation of HSD3B2 in HAC15 cells transfected with CRY1 siRNA.	('HAC15', 'CellLine', 'CVCL:S898', (200, 205))	('HSD3B2', 'Gene', (190, 196))	('upregulation', 'PosReg', (174, 186))	('silencing', 'Var', (85, 94))	('murine', 'Species', '10090', (70, 76))
30183	29874863	Of the presented cohort of adrenal samples, 36 were included in the study by Fernandes-Rosa et al.. Of the included samples, 16 adrenal nodules carried a mutation in the KCNJ5 gene, six in the ATP1A1 or ATP2B3 genes, and five in the CACNA1D gene, while 19 samples had no mutations in any of these genes.	('ATP1A1', 'Gene', (193, 199))	('ATP2B3', 'Gene', (203, 209))	('mutation', 'Var', (154, 162))	('KCNJ5', 'Gene', (170, 175))	('ATP1A1', 'Gene', '476', (193, 199))	('CACNA1D', 'Gene', '776', (233, 240))	('KCNJ5', 'Gene', '3762', (170, 175))	('CACNA1D', 'Gene', (233, 240))	('ATP2B3', 'Gene', '492', (203, 209))
30193	29874863	For experiments, cells were plated at a density of 4 x 105 cells/well in a 12-well plate for 48 h. After overnight incubation in low-serum medium (DMEM/F-12 containing 0.1% cosmic calf serum, and antibiotics), cells were stimulated with 100 nM AngII (reference value in normotensive individuals 24 +- 17 pM) (Sigma #A9525) +- 1 microM irbesartan (Sigma #I2286) or forskolin (10 microM, Sigma #F6886) for 6, 12, and 24 h, and then harvested for RNA extraction, and gene-expression studies.	('forskolin', 'Chemical', 'MESH:D005576', (364, 373))	('irbesartan', 'Chemical', 'MESH:D000077405', (335, 345))	('Sigma #I2286', 'Var', (347, 359))	('Sigma #F6886', 'Var', (386, 398))	('Sigma #A9525) +-', 'Var', (309, 325))	('calf', 'Species', '9913', (180, 184))
30198	29874863	However, silencing CRY1 and CRY2 expression in HAC15 adrenocortical cells resulted only in a modest upregulation of the HSD3B2 gene, which was not consistent with the experimental observations in the Cry-null animal model.	('CRY1', 'Gene', (19, 23))	('HAC15', 'CellLine', 'CVCL:S898', (47, 52))	('silencing', 'Var', (9, 18))	('CRY2', 'Gene', (28, 32))	('HSD3B2', 'Gene', (120, 126))	('adrenocortical', 'Disease', (53, 67))	('upregulation', 'PosReg', (100, 112))	('adrenocortical', 'Disease', 'MESH:D018268', (53, 67))
30209	29383185	Finally, we observed that silencing EGR-1 gene expression reversed the main effects induced by G-1 in ACC cells, including upregulation of the negative regulator of cell cycle, p21Waf1/Cip1 and the positive regulator of mitochondrial apoptotic pathway, BAX, as well as the cell growth inhibition.	('BAX', 'Gene', (253, 256))	('cell growth inhibition', 'CPA', (273, 295))	('BAX', 'Gene', '581', (253, 256))	('EGR-1', 'Gene', (36, 41))	('upregulation', 'PosReg', (123, 135))	('Cip1', 'Gene', '1026', (185, 189))	('silencing', 'Var', (26, 35))	('Cip1', 'Gene', (185, 189))	('EGR-1', 'Gene', '1958', (36, 41))
30229	29383185	First, we performed immunofluorescence assay where untreated or G-1-treated cells were fixed and incubated with anti-Egr-1 antibody followed by an incubation with a secondary FITC-conjugated antibody.	('anti-Egr-1', 'Gene', (112, 122))	('anti-Egr-1', 'Var', (112, 122))	('FITC', 'Chemical', 'MESH:D016650', (175, 179))
30247	29383185	The results showed that pretreatment with PD98059 did abrogate G-1-induced Egr-1 expression.	('PD98059', 'Var', (42, 49))	('abrogate', 'NegReg', (54, 62))	('Egr-1', 'Gene', (75, 80))	('PD98059', 'Chemical', 'MESH:C093973', (42, 49))	('expression', 'MPA', (81, 91))
30251	29383185	In this experimental condition, we first examined the effect of gene silencing on the ability of G-1 to upregulate Egr-1 target genes such as p21Waf1/Cip1 and BAX.	('Egr-1', 'Gene', (115, 120))	('Cip1', 'Gene', '1026', (150, 154))	('gene silencing', 'Var', (64, 78))	('BAX', 'Gene', (159, 162))	('Cip1', 'Gene', (150, 154))	('BAX', 'Gene', '581', (159, 162))	('upregulate', 'PosReg', (104, 114))
30252	29383185	As show in Figure 5, silencing of Egr-1 gene expression (Figure 5A) abrogated the transcription of both p21Waf1/Cip1 (Figure 5B) and BAX (Figure 5C) genes following G-1 treatment.	('BAX', 'Gene', (133, 136))	('transcription', 'MPA', (82, 95))	('Cip1', 'Gene', '1026', (112, 116))	('BAX', 'Gene', '581', (133, 136))	('Cip1', 'Gene', (112, 116))	('abrogated', 'NegReg', (68, 77))	('Egr-1', 'Gene', (34, 39))	('silencing', 'Var', (21, 30))
30255	29383185	Since G-1 has been reported to be a selective GPER agonist, we expected that knockdown of GPER in H295R cells, might completely abrogate H295R cell growth inhibition.	('abrogate', 'NegReg', (128, 136))	('H295R cell growth inhibition', 'CPA', (137, 165))	('H295R', 'CellLine', 'CVCL:0458', (98, 103))	('H295R', 'CellLine', 'CVCL:0458', (137, 142))	('knockdown', 'Var', (77, 86))	('GPER', 'Gene', '2852', (90, 94))	('GPER', 'Gene', '2852', (46, 50))	('GPER', 'Gene', (90, 94))	('GPER', 'Gene', (46, 50))
30267	29383185	Indeed, we previously demonstrated that doses of G-1 1muM and onward elicit GPER-independent effects as supported by RNA interference experiments.	('muM', 'Gene', (54, 57))	('G-1', 'Gene', (49, 52))	('GPER', 'Gene', '2852', (76, 80))	('effects', 'MPA', (93, 100))	('elicit', 'Reg', (69, 75))	('muM', 'Gene', '56925', (54, 57))	('doses', 'Var', (40, 45))	('GPER', 'Gene', (76, 80))
30269	29383185	Therefore, we demonstrated that treatment of ACC cells with G-1 results in a significant increase in ROS production that was no longer detectable in the presence of the antioxidant NAC.	('increase in ROS production', 'Phenotype', 'HP:0025464', (89, 115))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('NAC', 'Chemical', 'MESH:D000111', (181, 184))	('ROS production', 'MPA', (101, 115))	('increase', 'PosReg', (89, 97))	('G-1', 'Var', (60, 63))
30277	29383185	Finally, after silencing Egr-1 we confirmed its involvement in cell cycle arrest and mitochondrial apoptotic process.	('involvement', 'Reg', (48, 59))	('silencing', 'Var', (15, 24))	('arrest', 'Disease', 'MESH:D006323', (74, 80))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))	('mitochondrial apoptotic process', 'CPA', (85, 116))	('arrest', 'Disease', (74, 80))	('Egr-1', 'Gene', (25, 30))
30278	29383185	In fact, the upregulation of p21Waf1/Cip1 and BAX expression seen under G-1 treatment, and consequently, the inhibitory effect on cell viability, were promptly reversed by silencing Egr-1 gene expression.	('Cip1', 'Gene', '1026', (37, 41))	('Cip1', 'Gene', (37, 41))	('upregulation', 'PosReg', (13, 25))	('BAX', 'Gene', (46, 49))	('Egr-1', 'Gene', (182, 187))	('BAX', 'Gene', '581', (46, 49))	('expression', 'MPA', (50, 60))	('silencing', 'Var', (172, 181))
30286	29383185	Inhibitors such as PD98059 (10muM), SB203580 (10muM), SP600125 (10 muM) (Calbiochem, Merck KGaA, Darmstadt, Germany) and ROS scavenge molecule NAC (N-acetyl cysteine, Sigma) (5mM) were used 1h prior to G-1.	('muM', 'Gene', (30, 33))	('SP600125', 'Chemical', 'MESH:C432165', (54, 62))	('PD98059', 'Chemical', 'MESH:C093973', (19, 26))	('muM', 'Gene', '56925', (48, 51))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111', (148, 165))	('muM', 'Gene', '56925', (67, 70))	('ROS', 'Chemical', 'MESH:D017382', (121, 124))	('muM', 'Gene', (48, 51))	('NAC', 'Chemical', 'MESH:D000111', (143, 146))	('muM', 'Gene', (67, 70))	('muM', 'Gene', '56925', (30, 33))	('SB203580', 'Chemical', 'MESH:C093642', (36, 44))	('1h', 'Chemical', '-', (190, 192))	('PD98059', 'Var', (19, 26))	('SB203580', 'Var', (36, 44))
30310	29383185	From our previous work we had access to 5 mm thick paraffin-embedded sections of H295R xenograft tumors from mice treated with vehicle and G-1.	('xenograft tumors', 'Disease', 'MESH:D009369', (87, 103))	('paraffin', 'Chemical', 'MESH:D010232', (51, 59))	('H295R', 'CellLine', 'CVCL:0458', (81, 86))	('H295R', 'Var', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('mice', 'Species', '10090', (109, 113))	('xenograft tumors', 'Disease', (87, 103))
30321	28969033	The immunohistochemical analysis showed a significant increase in plasma membrane expression of GLUT1 in malignant lesions, when compared to benign lesions (p=0.004), being the expression of this protein associated with shorter overall and disease-free survival (p=0.004 and p=0.001, respectively).	('overall', 'CPA', (228, 235))	('shorter', 'NegReg', (220, 227))	('plasma membrane expression', 'MPA', (66, 92))	('disease-free survival', 'CPA', (240, 261))	('increase', 'PosReg', (54, 62))	('expression', 'Var', (177, 187))	('GLUT1', 'Gene', (96, 101))	('GLUT1', 'Gene', '6513', (96, 101))
30331	28969033	Interestingly, Southern Brazil shows an unusually high incidence of pediatric ACTs, with values of 3.4-4.2 per million, a fact attributed to the high prevalence of the germline mutation p.R337H in TP53.	('p.R337H', 'Mutation', 'rs121912664', (186, 193))	('p.R337H', 'Var', (186, 193))	('TP53', 'Gene', '7157', (197, 201))	('pediatric ACTs', 'Disease', (68, 82))	('TP53', 'Gene', (197, 201))
30359	28969033	Also, GLUT1 expression was associated with shorter overall and disease-free survival, indicating this protein can contribute to predict malignancy in pediatric ACTs, as, presently, there is no adequate scoring system to predict clinical behavior in this type of tumor.	('malignancy', 'Disease', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('expression', 'Var', (12, 22))	('tumor', 'Disease', (262, 267))	('GLUT1', 'Gene', (6, 11))	('disease-free survival', 'CPA', (63, 84))	('GLUT1', 'Gene', '6513', (6, 11))	('malignancy', 'Disease', 'MESH:D009369', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('shorter', 'NegReg', (43, 50))
30366	28969033	Considering pediatric ACTs and adult ACTs show different genetic backgrounds, such as TP53 mutations, as well as different molecular mechanism involved in tumorigenesis, and oncogenes and tumor suppressors are important regulators of cancer cell metabolism, it is not surprising the expression of metabolism-related proteins in pediatric ACTs found in the present study shows some differences, when compared with a previous study with adult ACTs.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('TP53', 'Gene', '7157', (86, 90))	('tumor', 'Disease', (155, 160))	('TP53', 'Gene', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancer', 'Disease', (234, 240))
30371	28969033	Additionally, IGF1R knockdown inhibited anchorage-independent growth of glioma cells, associated with a decreased glycolytic phenotype.	('glioma', 'Disease', (72, 78))	('inhibited', 'NegReg', (30, 39))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('decreased', 'NegReg', (104, 113))	('glycolytic phenotype', 'MPA', (114, 134))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('IGF1R', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('IGF1R', 'Gene', '3480', (14, 19))
30408	28881628	Because of the lack of success of the previous protocols, we chose to inject H295R/TR SF-1 GFP-luc cells intrasplenically, to elicit formation of hepatic metastases.	('SF-1', 'Gene', (86, 90))	('hepatic metastases', 'Disease', (146, 164))	('hepatic metastases', 'Disease', 'MESH:D009362', (146, 164))	('H295R/TR', 'Var', (77, 85))	('elicit', 'Reg', (126, 132))	('H295R/T', 'Mutation', 'p.H295R,T', (77, 84))
30430	28881628	While retaining steroidogenic capacities, these cells have multiple features of a highly malignant phenotype, including among others a very complex karyotype (our unpublished observations), TP53 and CTNNB1 mutations.	('mutations', 'Var', (206, 215))	('steroidogenic capacities', 'MPA', (16, 40))	('CTNNB1', 'Gene', (199, 205))	('TP53', 'Gene', '22059', (190, 194))	('TP53', 'Gene', (190, 194))
30436	28881628	It has been reported that loss of beta-catenin induces reversal of EMT in H295R cells, as shown by downregulation of vimentin, N-cadherin and Slug upon CTNNB1 knockdown.	('vimentin', 'Protein', (117, 125))	('downregulation', 'NegReg', (99, 113))	('beta-catenin', 'Gene', '1499', (34, 46))	('Slug', 'Gene', '6591', (142, 146))	('EMT', 'CPA', (67, 70))	('N-cadherin', 'Protein', (127, 137))	('Slug', 'Gene', (142, 146))	('loss', 'Var', (26, 30))	('beta-catenin', 'Gene', (34, 46))
30462	28881628	When stated, mice underwent splenectomy through ligature of the pancreas and splenic vessels and complete resection of the spleen.	('mice', 'Species', '10090', (13, 17))	('pancreas', 'Disease', 'MESH:D010190', (64, 72))	('ligature', 'Var', (48, 56))	('splenectomy', 'Disease', (28, 39))	('pancreas', 'Disease', (64, 72))
30498	24803899	In 2008, a panel of international experts unanimously recommended adjuvant mitotane in patients with potential residual disease or a Ki67 positivity on pathologic examination of >10%.	('mitotane', 'Chemical', 'MESH:D008939', (75, 83))	('Ki67', 'Gene', (133, 137))	('positivity', 'Var', (138, 148))	('patients', 'Species', '9606', (87, 95))
30537	24441435	While some retrospective studies have shown no difference in recurrence rate, time to recurrence, or overall survival between laparoscopic and open approaches to ACC, others have found laparoscopic adrenalectomy to be associated with higher rates of peritoneal carcinomatosis, increased recurrence rates, incompleteness of resection and lowered overall survival.	('laparoscopic', 'Var', (185, 197))	('ACC', 'Phenotype', 'HP:0006744', (162, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('recurrence rates', 'CPA', (287, 303))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (250, 275))	('overall', 'MPA', (345, 352))	('peritoneal carcinomatosis', 'Disease', (250, 275))	('increased', 'PosReg', (277, 286))	('higher', 'PosReg', (234, 240))	('lowered', 'NegReg', (337, 344))
30568	19649631	Armed with our recent pre-clinical data that targeting the IGF-1R in human ACC cells effectively antagonizes downstream activation of AKT and has a marked inhibitory effect on tumor growth in human ACC xenograft models, we aimed to initiate a Phase I trial of IGF-1R inhibition in patients with ACC.	('AKT', 'Gene', (134, 137))	('human', 'Species', '9606', (192, 197))	('tumor', 'Disease', (176, 181))	('ACC', 'Phenotype', 'HP:0006744', (295, 298))	('ACC', 'Disease', (295, 298))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('antagonizes', 'NegReg', (97, 108))	('patients', 'Species', '9606', (281, 289))	('human', 'Species', '9606', (69, 74))	('IGF-1R', 'Gene', '3480', (260, 266))	('ACC', 'Phenotype', 'HP:0006744', (198, 201))	('IGF-1R', 'Gene', (260, 266))	('inhibitory', 'NegReg', (155, 165))	('AKT', 'Gene', '207', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('targeting', 'Var', (45, 54))	('IGF-1R', 'Gene', (59, 65))	('IGF-1R', 'Gene', '3480', (59, 65))
30582	19649631	Additional eligibility criteria included: adequate bone marrow, renal and hepatic function (absolute neutrophil count >=1000/mul, hemoglobin >=8 g/dl, platelets >75,000/mul, creatinine clearance >30 ml/min, total bilirubin <1.5 x the institution upper limit of normal [ULN], aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x ULN); fully recovered from prior anticancer treatments; and use of adequate contraception in patients with reproductive potential.	('creatinine clearance', 'MPA', (174, 194))	('>=1000/mul', 'Var', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('total bilirubin', 'MPA', (207, 222))	('alanine aminotransferase', 'Gene', (312, 336))	('aspartate aminotransferase', 'Gene', (275, 301))	('AST', 'Gene', (303, 306))	('alanine aminotransferase', 'Gene', '2875', (312, 336))	('cancer', 'Disease', (387, 393))	('renal', 'MPA', (64, 69))	('>=8', 'Var', (141, 144))	('hepatic', 'MPA', (74, 81))	('AST', 'Gene', '26503', (303, 306))	('patients', 'Species', '9606', (443, 451))	('cancer', 'Disease', 'MESH:D009369', (387, 393))	('aspartate aminotransferase', 'Gene', '26503', (275, 301))
30637	19649631	Due to our pre-clinical data indicating that antagonizing IGF-1R activation effectively blocked downstream AKT activation and tumor growth of ACC xenografts, we enrolled 14 patients with ACC in an expansion cohort of the phase I single agent study with anti-IGF-1R antibody antagonist, figitumumab.	('activation', 'PosReg', (111, 121))	('ACC', 'Phenotype', 'HP:0006744', (142, 145))	('ACC', 'Phenotype', 'HP:0006744', (187, 190))	('patients', 'Species', '9606', (173, 181))	('AKT', 'Gene', (107, 110))	('blocked', 'NegReg', (88, 95))	('antagonizing', 'Var', (45, 57))	('figitumumab', 'Chemical', 'MESH:C525021', (286, 297))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('IGF-1R', 'Gene', '3480', (258, 264))	('IGF-1R', 'Gene', '3480', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('IGF-1R', 'Gene', (258, 264))	('IGF-1R', 'Gene', (58, 64))	('AKT', 'Gene', '207', (107, 110))	('tumor', 'Disease', (126, 131))
30638	19649631	The purpose of accruing this cohort was to determine if targeting the IGF-1R in ACC patients was feasible, tolerable and had any evidence of anti-tumor activity that would warrant further investigation either as a single agent or in combination with additional therapies.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', (146, 151))	('targeting', 'Var', (56, 65))	('IGF-1R', 'Gene', (70, 76))	('IGF-1R', 'Gene', '3480', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
30660	19649631	Indeed in our pre-clinical studies, significantly enhanced efficacy, as measured by tumoral growth delay, was observed when IGF-1R antagonism was combined with mitotane in a human ACC xenograft model, compared to the single treatment modalities alone.	('IGF-1R', 'Gene', '3480', (124, 130))	('growth delay', 'Phenotype', 'HP:0001510', (92, 104))	('human', 'Species', '9606', (174, 179))	('IGF-1R', 'Gene', (124, 130))	('ACC', 'Phenotype', 'HP:0006744', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('combined', 'Interaction', (146, 154))	('tumoral growth delay', 'Disease', 'MESH:D006130', (84, 104))	('efficacy', 'MPA', (59, 67))	('enhanced', 'PosReg', (50, 58))	('antagonism', 'Var', (131, 141))	('tumoral growth delay', 'Disease', (84, 104))	('mitotane', 'Chemical', 'MESH:D008939', (160, 168))
30665	19649631	Further investigations will help us understand if blocking the IGF-1R in patients with ACC with help circumvent prosurvival pathways that will sensitize these highly refractory tumors to chemotherapy and other anti-tumor therapies.	('ACC', 'Phenotype', 'HP:0006744', (87, 90))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('ACC', 'Disease', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('patients', 'Species', '9606', (73, 81))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('sensitize', 'Reg', (143, 152))	('tumor', 'Disease', (215, 220))	('tumors', 'Disease', (177, 183))	('IGF-1R', 'Gene', '3480', (63, 69))	('tumor', 'Disease', (177, 182))	('blocking', 'Var', (50, 58))	('IGF-1R', 'Gene', (63, 69))
30674	26454676	SLC12A7 overexpression occurred predominantly in samples with amplifications (p<0.05), while amplifications were associated with non-functional tumors (p<0.05).	('overexpression', 'PosReg', (8, 22))	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('SLC12A7', 'Gene', (0, 7))	('amplifications', 'Var', (62, 76))	('SLC12A7', 'Gene', '10723', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
30687	26454676	Alteration of the canonical Wnt/beta-catenin signaling pathway occurs frequently in ACC via activating mutations of the proto-oncogene beta-catenin, which stabilizes beta-catenin and promotes its translocation to the nucleus.	('mutations', 'Var', (103, 112))	('Alteration', 'Reg', (0, 10))	('beta-catenin', 'Gene', (166, 178))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('beta-catenin', 'Gene', (32, 44))	('beta-catenin', 'Gene', (135, 147))	('translocation to the nucleus', 'MPA', (196, 224))	('beta-catenin', 'Gene', '1499', (135, 147))	('beta-catenin', 'Gene', '1499', (166, 178))	('promotes', 'PosReg', (183, 191))	('beta-catenin', 'Gene', '1499', (32, 44))
30690	26454676	In addition, Li-Fraumeni Syndrome, which is caused by germline TP53 mutations, is associated with childhood forms of ACC.	('ACC', 'Phenotype', 'HP:0006744', (117, 120))	('associated', 'Reg', (82, 92))	('TP53', 'Gene', '7157', (63, 67))	('Li-Fraumeni Syndrome', 'Disease', (13, 33))	('TP53', 'Gene', (63, 67))	('mutations', 'Var', (68, 77))	('caused', 'Reg', (44, 50))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (13, 33))
30693	26454676	In addition to these specified pathways, gene copy number variations (CNVs) occur frequently in ACC and are thought to be associated with the malignant behavior of these tumors.	('ACC', 'Disease', (96, 99))	('gene copy number variations', 'Var', (41, 68))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('associated with', 'Reg', (122, 137))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('ACC', 'Phenotype', 'HP:0006744', (96, 99))	('tumors', 'Disease', (170, 176))
30698	26454676	A meta-analysis of CNV studies demonstrated that genes involved in cell cycle regulation, retinoic acid signaling, the complement system, and antigen presentation are frequently affected by copy number changes.	('men', 'Species', '9606', (125, 128))	('affected', 'Reg', (178, 186))	('copy number changes', 'Var', (190, 209))	('retinoic acid', 'Chemical', 'MESH:D014212', (90, 103))	('cell', 'CPA', (67, 71))
30699	26454676	In addition, there still remains significant discrepancy among studies identifying genomic regions significantly affected by CNVs and the impact of these changes on tumor behavior.	('affected', 'Reg', (113, 121))	('CNVs', 'Var', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
30700	26454676	These studies identified novel genetic mutations previously not associated with ACC tumorigenesis and enabled a more precise, nucleotide level assessment of CNVs.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('men', 'Species', '9606', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', (84, 89))
30708	26454676	SCL12A7 was also shown to promote in vitro and in vivo tumor cell growth.	('promote', 'PosReg', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SCL12A7', 'Var', (0, 7))	('tumor', 'Disease', (55, 60))
30710	26454676	Overexpression of SLC12A7 has been associated with local tumor invasion, lymph node metastases, and poor clinical outcomes in cervical, ovarian, and breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cervical', 'Disease', (126, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('metastases', 'Disease', (84, 94))	('associated', 'Reg', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancers', 'Disease', 'MESH:D001943', (149, 163))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Overexpression', 'Var', (0, 14))	('SLC12A7', 'Gene', (18, 25))	('breast cancers', 'Disease', (149, 163))	('ovarian', 'Disease', (136, 143))	('ovarian', 'Disease', 'MESH:D010049', (136, 143))	('tumor', 'Disease', (57, 62))	('SLC12A7', 'Gene', '10723', (18, 25))
30726	26454676	The SLC12A7 locus was predicted to be one of the most amplified loci in ACC with 13 (68.4%) of 19 samples demonstrating copy gains.	('copy gains', 'Var', (120, 130))	('SLC12A7', 'Gene', (4, 11))	('SLC12A7', 'Gene', '10723', (4, 11))	('ACC', 'Phenotype', 'HP:0006744', (72, 75))
30727	26454676	An expanded cohort of 26 ACC samples was subsequently assessed for SLC12A7 CNVs and compared to normal adrenal tissue using the Taqman Copy Number Assays (Figure 1).	('CNVs', 'Var', (75, 79))	('ACC', 'Phenotype', 'HP:0006744', (25, 28))	('SLC12A7', 'Gene', (67, 74))	('SLC12A7', 'Gene', '10723', (67, 74))
30736	26454676	In contrast, a statistically significant association was observed between SLC12A7 gene amplifications and non-functional tumors and male patients (p<0.05; Figure 3B&C).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('SLC12A7', 'Gene', (74, 81))	('SLC12A7', 'Gene', '10723', (74, 81))	('non-functional', 'Disease', (106, 120))	('tumors', 'Disease', (121, 127))	('amplifications', 'Var', (87, 101))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (137, 145))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('significant association', 'Reg', (29, 52))
30737	26454676	No statistically significant association was observed between advanced tumors (ENSAT 3 and 4) and SLC12A7 amplifications.	('SLC12A7', 'Gene', (98, 105))	('amplifications', 'Var', (106, 120))	('SLC12A7', 'Gene', '10723', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
30738	26454676	Copy number alterations, including amplifications, have been shown to occur frequently in ACCs in multiple studies using comparative genomic hybridization (CGH) methods.	('ACCs', 'Gene', (90, 94))	('ACCs', 'Gene', '84680', (90, 94))	('ACC', 'Phenotype', 'HP:0006744', (90, 93))	('Copy number alterations', 'Var', (0, 23))
30740	26454676	Interestingly, three of these studies also identified low frequency 5p amplifications in adrenal adenomas, indicating that CNVs of chromosome 5 may be an early event in adrenocortical malignancy.	('5p amplifications', 'Var', (68, 85))	('adrenocortical malignancy', 'Disease', (169, 194))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (89, 105))	('adrenal adenomas', 'Disease', 'MESH:D000236', (89, 105))	('adrenocortical malignancy', 'Disease', 'MESH:D000306', (169, 194))	('CNVs', 'Var', (123, 127))	('adrenal adenomas', 'Disease', (89, 105))
30743	26454676	Thus, these findings possibly indicate that SLC12A7 amplifications in ACC may not represent a passenger event.	('ACC', 'Phenotype', 'HP:0006744', (70, 73))	('SLC12A7', 'Gene', (44, 51))	('SLC12A7', 'Gene', '10723', (44, 51))	('ACC', 'Disease', (70, 73))	('amplifications', 'Var', (52, 66))
30745	26454676	Furthermore transcriptome analyses have been shown to stratify tumors by prognosis and may also serve as a more reliable predictor of tumor aggressiveness than other commonly used markers, including the Weiss scoring system.	('tumor aggressiveness', 'Disease', (134, 154))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (134, 154))	('aggressiveness', 'Phenotype', 'HP:0000718', (140, 154))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('transcriptome', 'Var', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
30752	26454676	Similarly, SLC12A7 amplifications were associated with non-functional tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('SLC12A7', 'Gene', (11, 18))	('SLC12A7', 'Gene', '10723', (11, 18))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('associated', 'Reg', (39, 49))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('amplifications', 'Var', (19, 33))
30753	26454676	Since gene amplifications typically do not occur in benign adrenal adenomas, SLC12A7 copy gains may serve as a putative molecular marker of malignancy in indeterminate adrenal tumors, as well as a marker of non-functional tumors.	('SLC12A7', 'Gene', (77, 84))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (59, 75))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('adrenal tumors', 'Disease', (168, 182))	('malignancy', 'Disease', 'MESH:D009369', (140, 150))	('tumors', 'Disease', (222, 228))	('copy', 'Var', (85, 89))	('malignancy', 'Disease', (140, 150))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('SLC12A7', 'Gene', '10723', (77, 84))	('benign adrenal adenomas', 'Disease', 'MESH:D000236', (52, 75))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('benign adrenal adenomas', 'Disease', (52, 75))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('gains', 'PosReg', (90, 95))	('adrenal tumors', 'Disease', 'MESH:D000310', (168, 182))	('tumors', 'Disease', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))
30761	26454676	Furthermore, SLC12A7 amplifications are associated with non-functional tumors.	('SLC12A7', 'Gene', (13, 20))	('amplifications', 'Var', (21, 35))	('SLC12A7', 'Gene', '10723', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('associated', 'Reg', (40, 50))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
30825	31581360	Both miR-195 and miR-497 bind to the 3'-UTR of the SMURF2 mRNA and inhibit SMURF2 expression.	('miR-497', 'Var', (17, 24))	('expression', 'Species', '29278', (82, 92))	('SMURF2', 'Gene', (75, 81))	('inhibit', 'NegReg', (67, 74))	('expression', 'MPA', (82, 92))	('miR-195', 'Var', (5, 12))	('SMURF2', 'Gene', (51, 57))	('bind', 'Interaction', (25, 29))
30826	31581360	Furthermore, miR-195 and miR-497 regulate SMURF2-dependent TbetaRI ubiquitination and cause the activation of the TGF-beta signaling pathway in lung cancer cells.	('regulate', 'Reg', (33, 41))	('lung cancer', 'Disease', (144, 155))	('miR-497', 'Var', (25, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('TGF-beta', 'Gene', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('SMURF2-dependent', 'Gene', (42, 58))	('miR-195', 'Var', (13, 20))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('TGF-beta', 'Gene', '21803', (114, 122))	('TbetaRI', 'Protein', (59, 66))	('activation', 'PosReg', (96, 106))
30827	31581360	Upregulation of miR-195 and miR-497 significantly reduced cell viability and colony formation through the activation of TGF-beta signaling.	('TGF-beta', 'Gene', (120, 128))	('Upregulation', 'PosReg', (0, 12))	('cell viability', 'CPA', (58, 72))	('miR-497', 'Var', (28, 35))	('colony formation', 'CPA', (77, 93))	('TGF-beta', 'Gene', '21803', (120, 128))	('miR-195', 'Gene', (16, 23))	('reduced', 'NegReg', (50, 57))	('activation', 'PosReg', (106, 116))
30828	31581360	Interestingly, miR-195 and miR-497 also reduced the invasion ability of lung cancer cells when cells were treated with TGF-beta1.	('miR-497', 'Var', (27, 34))	('invasion ability of', 'CPA', (52, 71))	('TGF-beta', 'Gene', '21803', (119, 127))	('miR-195', 'Var', (15, 22))	('reduced', 'NegReg', (40, 47))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('TGF-beta', 'Gene', (119, 127))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
30829	31581360	Subsequent in vivo studies in xenograft nude mice model revealed that miR-195 and miR-497 repress tumor growth.	('Su', 'Chemical', 'MESH:C035067', (0, 2))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('nude mice', 'Species', '10090', (40, 49))	('repress', 'NegReg', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('miR-497', 'Var', (82, 89))	('miR-195', 'Var', (70, 77))
30830	31581360	These findings demonstrate that miR-195 and miR-497 act as a tumor suppressor by suppressing ubiquitination-mediated degradation of TGF-beta receptors through SMURF2, and suggest that miR-195 and miR-497 are potential therapeutic targets for lung cancer.	('suppressing', 'NegReg', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('miR-195', 'Var', (32, 39))	('ubiquitination-mediated degradation', 'MPA', (93, 128))	('SMURF2', 'Gene', (159, 165))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('TGF-beta', 'Gene', (132, 140))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('lung cancer', 'Disease', (242, 253))	('miR-497', 'Var', (44, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))	('TGF-beta', 'Gene', '21803', (132, 140))	('tumor', 'Disease', (61, 66))
30831	31581360	We demonstrated that ectopic expression of miR-195 and miR-497 by mimics suppressed TbetaR1 ubiquitination and degradation through the repression of SMURF2.	('degradation', 'MPA', (111, 122))	('miR-497', 'Var', (55, 62))	('TbetaR1', 'Protein', (84, 91))	('SMURF2', 'Gene', (149, 155))	('miR-195', 'Var', (43, 50))	('expression', 'Species', '29278', (29, 39))	('suppressed', 'NegReg', (73, 83))	('repression', 'NegReg', (135, 145))
30832	31581360	These results suggest that the reduction of SMURF2 gene expression by miR-195 or miR-497, which results in activation of transforming growth factor-beta signaling, has an important role in inhibiting lung cancer.	('transforming growth factor-beta signaling', 'MPA', (121, 162))	('reduction', 'NegReg', (31, 40))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('expression', 'Species', '29278', (56, 66))	('inhibiting', 'NegReg', (189, 199))	('expression', 'MPA', (56, 66))	('lung cancer', 'Disease', (200, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('miR-497', 'Var', (81, 88))	('activation', 'PosReg', (107, 117))	('SMURF2 gene', 'Gene', (44, 55))	('miR-195', 'Var', (70, 77))
30834	31581360	Dysregulation of the TGF-beta signaling pathway correlates with crucial roles in tumor initiation development and metastasis (Colak and Ten Dijke, 2017).	('metastasis', 'CPA', (114, 124))	('Dysregulation', 'Var', (0, 13))	('Di', 'Chemical', 'MESH:C076868', (140, 142))	('TGF-beta', 'Gene', '21803', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('TGF-beta', 'Gene', (21, 29))	('tumor', 'Disease', (81, 86))
30847	31581360	Conversely, induction of SMURF2 enhances tumor metastasis in a nude mouse model and increases invasion and migration of breast cancer cells (Jin et al., 2009) and inhibits cell apoptosis by promoting p53 degradation by stabilizing the E3 ligase MDM2 (Nie et al., 2010).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('degradation', 'MPA', (204, 215))	('MDM2', 'Gene', '17246', (245, 249))	('enhances', 'PosReg', (32, 40))	('p53', 'Gene', (200, 203))	('tumor metastasis', 'Disease', 'MESH:D009362', (41, 57))	('p53', 'Gene', '22060', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('E3 ligase', 'Protein', (235, 244))	('tumor metastasis', 'Disease', (41, 57))	('inhibits', 'NegReg', (163, 171))	('SMURF2', 'Gene', (25, 31))	('induction', 'Var', (12, 21))	('MDM2', 'Gene', (245, 249))	('mouse', 'Species', '10090', (68, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('promoting', 'PosReg', (190, 199))	('increases', 'PosReg', (84, 93))	('cell apoptosis', 'CPA', (172, 186))
30851	31581360	MiR-195 and miR-497 have been reported to inhibit cell cycle in HCC by directly binding to CCNE1, CDC25A, CDK4 and CDK6 (Furuta et al., 2013) and suppress breast cancer cell proliferation and invasion by regulating Raf-1 and CCND1 (Li et al., 2011).	('MiR-195', 'Gene', '406971', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('CCNE1', 'Gene', (91, 96))	('MiR-195', 'Gene', (0, 7))	('CCND1', 'Gene', (225, 230))	('Raf-1', 'Gene', (215, 220))	('suppress', 'NegReg', (146, 154))	('CDC25A', 'Gene', (98, 104))	('miR-497', 'Var', (12, 19))	('CDK4', 'Gene', (106, 110))	('invasion', 'CPA', (192, 200))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('binding', 'Interaction', (80, 87))	('breast cancer', 'Disease', (155, 168))	('inhibit', 'NegReg', (42, 49))	('cell cycle', 'CPA', (50, 60))	('CDK6', 'Gene', (115, 119))
30852	31581360	In addition, miR-195 and miR-497 have been reported to regulate TGF-beta signaling by inhibiting the components of TGF-beta signaling such as SMAD2, SMAD4 and SMAD7 (Duan and Chen, 2016; Hu et al., 2016; Jafarzadeh et al., 2016; Liu et al., 2016).	('TGF-beta', 'Gene', '21803', (115, 123))	('TGF-beta', 'Gene', '21803', (64, 72))	('miR-497', 'Var', (25, 32))	('TGF-beta', 'Gene', (115, 123))	('inhibiting', 'NegReg', (86, 96))	('TGF-beta', 'Gene', (64, 72))	('regulate', 'Reg', (55, 63))	('miR-195', 'Var', (13, 20))
30854	31581360	The current study demonstrated that miR-195 and miR-497 negatively regulate SMURF2 expression and SMURF2-dependent TbetaRI ubiquitination, thereby increasing the activation of TGF-beta signaling.	('TGF-beta', 'Gene', '21803', (176, 184))	('regulate', 'Reg', (67, 75))	('negatively', 'NegReg', (56, 66))	('TbetaRI ubiquitination', 'MPA', (115, 137))	('miR-195', 'Var', (36, 43))	('TGF-beta', 'Gene', (176, 184))	('miR-497', 'Var', (48, 55))	('expression', 'Species', '29278', (83, 93))	('increasing', 'PosReg', (147, 157))	('SMURF2', 'Gene', (76, 82))	('expression', 'MPA', (83, 93))
30855	31581360	In addition, miR-195 and miR-497 have inhibited cancer cell growth, colony formation, and invasion in cancer cell lines and attenuated tumorigenesis in a xenograft mouse model.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mouse', 'Species', '10090', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('miR-497', 'Var', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', (135, 140))	('colony formation', 'CPA', (68, 84))	('inhibited', 'NegReg', (38, 47))	('cancer', 'Disease', (102, 108))	('attenuated', 'NegReg', (124, 134))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (48, 54))	('miR-195', 'Var', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('invasion', 'CPA', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
30861	31581360	The expression levels of miR-195 and miR-497 were quantified 48 h after transfection and the cells were used for a western blot analysis.	('miR-497', 'Var', (37, 44))	('miR-195', 'Var', (25, 32))	('expression', 'Species', '29278', (4, 14))
30889	31581360	The SMURF2 primers were F-5'-TTG GCT CTG CAG AAA GGA TT-3' and R-5'-CCA CAG CTT TCC AGA ACC AT-3'.	("R-5'-CCA", 'Chemical', 'MESH:C027655', (63, 71))	("F-5'-TTG", 'Chemical', 'MESH:C033339', (24, 32))	("R-5'-CCA", 'Var', (63, 71))	("F-5'-TTG", 'Var', (24, 32))
30899	31581360	When the tumor volume reached approximately 100 mm3, different miRNA including miR-NC, miR-195, and miR-497, were administrated intratumorally at a dose of 4 mg kg-1.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('miR-497', 'Var', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('miR-NC', 'Var', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', (133, 138))	('miR-195', 'Var', (87, 94))
30909	31581360	Furthermore, miR-195 and miR-497 could be considered potential prognostic biomarkers in NSCLC, gastric cancer, osteosarcoma, renal cell carcinoma, pancreatic cancer and breast cancer (Igglezou et al., 2014; Shen et al., 2016; Su et al., 2016; Xu et al., 2014; Zhao et al., 2013).	('renal cell carcinoma', 'Disease', (125, 145))	('miR-497', 'Var', (25, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (125, 145))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('gastric cancer', 'Disease', (95, 109))	('miR-195', 'Var', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (95, 109))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('pancreatic cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (125, 145))	('Su', 'Chemical', 'MESH:C035067', (226, 228))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('NSCLC', 'Disease', (88, 93))	('osteosarcoma', 'Disease', (111, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (111, 123))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('breast cancer', 'Disease', (169, 182))
30910	31581360	However, the functions of miR-195 and miR-497 as well as their target genes have not yet been fully elucidated in lung cancer.	('miR-497', 'Var', (38, 45))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('miR-195', 'Gene', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
30912	31581360	We found that miR-195 and miR-497 expression levels were significantly downregulated in the tissue (Fig.	('downregulated', 'NegReg', (71, 84))	('miR-497', 'Gene', (26, 33))	('miR-195', 'Var', (14, 21))	('expression levels', 'MPA', (34, 51))	('expression', 'Species', '29278', (34, 44))
30914	31581360	Using target prediction databases such as TargetScan, miRanda and miRWalk 2.0, we found that the 3'-UTR of the SMURF2 mRNA has binding sequences for miR-195 and miR-497.	('miRanda', 'Disease', (54, 61))	('miR-195', 'Var', (149, 156))	('binding', 'Interaction', (127, 134))	('miR-497', 'Var', (161, 168))	('SMURF2', 'Gene', (111, 117))	('miRanda', 'Disease', 'MESH:C537402', (54, 61))
30918	31581360	Taken together, these data suggest that the low miR-195 and miR-497 expressions and high SMURF2 expression are associated with the biological process of tumorigenesis in lung cancer patients.	('expression', 'Species', '29278', (68, 78))	('low', 'NegReg', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('expression', 'Species', '29278', (96, 106))	('SMURF2', 'Gene', (89, 95))	('miR-195', 'Gene', (48, 55))	('associated', 'Reg', (111, 121))	('expression', 'MPA', (96, 106))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('miR-497 expressions', 'Var', (60, 79))	('patients', 'Species', '9606', (182, 190))	('lung cancer', 'Disease', (170, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
30920	31581360	S2A,B, the expression of miR-195 and miR-497 were upregulated or downregulated by transfection with its corresponding mimics or inhibitors, respectively.	('upregulated', 'PosReg', (50, 61))	('expression', 'Species', '29278', (11, 21))	('expression', 'MPA', (11, 21))	('downregulated', 'NegReg', (65, 78))	('miR-497', 'Var', (37, 44))	('miR-195', 'Var', (25, 32))
30921	31581360	Next, we examined whether miR-195 and miR-497 regulate the SMURF2 mRNA and protein expression in A549 cells.	('regulate', 'Reg', (46, 54))	('miR-497', 'Var', (38, 45))	('miR-195', 'Var', (26, 33))	('expression', 'Species', '29278', (83, 93))	('SMURF2', 'Gene', (59, 65))	('A549', 'CellLine', 'CVCL:0023', (97, 101))
30922	31581360	The inhibitors of miR-195 and miR-497 upregulated the expression of the SMURF2 gene relative to the negative control (Fig.	('expression', 'MPA', (54, 64))	('miR-195', 'Var', (18, 25))	('SMURF2 gene', 'Gene', (72, 83))	('upregulated', 'PosReg', (38, 49))	('miR-497', 'Var', (30, 37))	('expression', 'Species', '29278', (54, 64))
30923	31581360	2A), whereas the overexpression of miR-195 and miR-497 by the mimics significantly downregulated the SMURF2 mRNA (Fig.	('miR-497', 'Var', (47, 54))	('expression', 'Species', '29278', (21, 31))	('downregulated', 'NegReg', (83, 96))	('overexpression', 'PosReg', (17, 31))	('miR-195', 'Var', (35, 42))	('SMURF2 mRNA', 'MPA', (101, 112))
30925	31581360	Unfortunately, we observed that the effects of the inhibitors of miR-195 and miR-497 were insignificant on the TGF-beta1-induced SMURF2 protein expression (data not shown).	('miR-195', 'Var', (65, 72))	('expression', 'Species', '29278', (144, 154))	('SMURF2', 'Gene', (129, 135))	('expression', 'MPA', (144, 154))	('TGF-beta', 'Gene', (111, 119))	('miR-497', 'Var', (77, 84))	('TGF-beta', 'Gene', '21803', (111, 119))
30926	31581360	However, the overexpression of miR-195 and miR-497 by the mimics reduced TGF-beta1-induced SMURF2 protein (Fig.	('reduced', 'NegReg', (65, 72))	('expression', 'Species', '29278', (17, 27))	('TGF-beta', 'Gene', (73, 81))	('overexpression', 'PosReg', (13, 27))	('TGF-beta', 'Gene', '21803', (73, 81))	('miR-497', 'Var', (43, 50))	('miR-195', 'Var', (31, 38))
30927	31581360	These findings indicate that miR-195 and miR-497 directly regulate the SMURF2 gene expression through post-transcriptional repression.	('SMURF2', 'Gene', (71, 77))	('miR-497', 'Var', (41, 48))	('miR-195', 'Var', (29, 36))	('expression', 'Species', '29278', (83, 93))	('post-transcriptional repression', 'MPA', (102, 133))	('regulate', 'Reg', (58, 66))	('expression', 'MPA', (83, 93))
30929	31581360	Thus, we investigated whether the regulation of SMURF2 by miR-195 and miR-497 affects the TbetaRI levels in A549 cells.	('miR-497', 'Var', (70, 77))	('affects', 'Reg', (78, 85))	('SMURF2', 'Gene', (48, 54))	('A549', 'CellLine', 'CVCL:0023', (108, 112))	('miR-195', 'Var', (58, 65))	('TbetaRI levels', 'MPA', (90, 104))
30932	31581360	Polyubiquitination of TbetaRI has been reported to induce its turnover and degradation (Di Guglielmo et al., 2003).	('Polyubiquitination', 'Var', (0, 18))	('turnover', 'MPA', (62, 70))	('TbetaRI', 'Protein', (22, 29))	('Di', 'Chemical', 'MESH:C076868', (88, 90))	('induce', 'PosReg', (51, 57))	('degradation', 'MPA', (75, 86))
30933	31581360	HEK293T cells treated with inhibitors of miR-NC, miR-195 or miR-497 were co-transfected with the HA-TbetaRI and His-Ub vectors followed by the determination of TbetaRI ubiquitination using the Ni-NTA Pulldown Assay.	('miR-NC', 'Var', (41, 47))	('TbetaRI', 'MPA', (160, 167))	('Ni-NTA', 'Chemical', 'MESH:C088321', (193, 199))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('His', 'Chemical', 'MESH:C471213', (112, 115))	('miR-497', 'Var', (60, 67))	('miR-195', 'Var', (49, 56))
30935	31581360	3C), whereas the overexpression of miR-195 and miR-497 decreased the TbetaRI ubiquitination and SMURF2 mRNA level (Fig.	('miR-497', 'Var', (47, 54))	('TbetaRI ubiquitination', 'MPA', (69, 91))	('SMURF2 mRNA level', 'MPA', (96, 113))	('expression', 'Species', '29278', (21, 31))	('decreased', 'NegReg', (55, 64))	('miR-195', 'Var', (35, 42))
30937	31581360	As expected, the overexpression of SMURF2 resulted in the recovery of TbetaRI ubiquitination reduced by the miR-195 and miR-497 mimics (Fig.	('expression', 'Species', '29278', (21, 31))	('miR-195', 'Var', (108, 115))	('TbetaRI ubiquitination', 'MPA', (70, 92))	('miR-497 mimics', 'Var', (120, 134))
30938	31581360	Next, we examined whether miR-195 and miR-497 can also regulate the activation of TGF-beta signaling.	('TGF-beta', 'Gene', '21803', (82, 90))	('miR-497', 'Var', (38, 45))	('TGF-beta', 'Gene', (82, 90))	('miR-195', 'Var', (26, 33))
30940	31581360	Upon exposure to 5 ng mL-1 TGF-beta1 for 24 h, the TGF-beta1-induced luciferase activities in the cells transfected with the miR-195 or miR-497 mimics were significantly higher than in the cells transfected with miR-NC.	('higher', 'PosReg', (170, 176))	('TGF-beta', 'Gene', (51, 59))	('miR-195', 'Var', (125, 132))	('activities', 'MPA', (80, 90))	('TGF-beta', 'Gene', (27, 35))	('TGF-beta', 'Gene', '21803', (27, 35))	('mL-1', 'Gene', (22, 26))	('mL-1', 'Gene', '23961', (22, 26))	('TGF-beta', 'Gene', '21803', (51, 59))	('miR-497', 'Var', (136, 143))	('luciferase', 'Enzyme', (69, 79))
30941	31581360	In addition, the mimic of miR-195 or miR-497 induced the phosphorylation of SMAD2 and SMAD3 in A549 cells treated with TGF-beta1.	('TGF-beta', 'Gene', '21803', (119, 127))	('miR-195', 'Var', (26, 33))	('phospho', 'Chemical', 'MESH:C033601', (57, 64))	('SMAD3', 'Gene', '17127', (86, 91))	('SMAD3', 'Gene', (86, 91))	('TGF-beta', 'Gene', (119, 127))	('SMAD2', 'Protein', (76, 81))	('phosphorylation', 'MPA', (57, 72))	('miR-497', 'Var', (37, 44))	('induced', 'Reg', (45, 52))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
30942	31581360	However, this effect disappeared after treatment with TGF-beta signaling kinase inhibitor LY364947 (Fig.	('TGF-beta', 'Gene', '21803', (54, 62))	('LY364947', 'Var', (90, 98))	('LY364947', 'Chemical', 'MESH:C520284', (90, 98))	('TGF-beta', 'Gene', (54, 62))
30944	31581360	In contrast, following transfection with anti-miR-195 and anti-miR-497, the TGF-beta signaling pathway was slightly inhibited, which was reflected by the increased expression of SMURF2 and decreased phosphorylation of SMAD2 and SMAD3 compared with the negative control (Fig.	('SMAD3', 'Gene', (228, 233))	('anti-miR-497', 'Var', (58, 70))	('TGF-beta', 'Gene', '21803', (76, 84))	('expression', 'Species', '29278', (164, 174))	('decreased', 'NegReg', (189, 198))	('SMAD2', 'Protein', (218, 223))	('inhibited', 'NegReg', (116, 125))	('expression', 'MPA', (164, 174))	('phosphorylation', 'MPA', (199, 214))	('TGF-beta', 'Gene', (76, 84))	('anti-miR-195', 'Var', (41, 53))	('SMURF2', 'Protein', (178, 184))	('phospho', 'Chemical', 'MESH:C033601', (199, 206))	('increased', 'PosReg', (154, 163))	('SMAD3', 'Gene', '17127', (228, 233))
30947	31581360	Phospho-SMAD2 levels were decreased after a 2-h TGF-beta1 treatment of A549 cells transfected with miR-NC.	('TGF-beta', 'Gene', (48, 56))	('Phospho-SMAD2 levels', 'MPA', (0, 20))	('decreased', 'NegReg', (26, 35))	('TGF-beta', 'Gene', '21803', (48, 56))	('miR-NC', 'Var', (99, 105))	('A549', 'CellLine', 'CVCL:0023', (71, 75))
30950	31581360	Thus, the TGF-beta1-induced SMAD2 phosphorylation was prolonged in the miR-195 and miR-497 mimic-transfected cells.	('TGF-beta', 'Gene', (10, 18))	('phosphorylation', 'MPA', (34, 49))	('miR-497', 'Var', (83, 90))	('miR-195', 'Var', (71, 78))	('SMAD2', 'Protein', (28, 33))	('TGF-beta', 'Gene', '21803', (10, 18))	('phospho', 'Chemical', 'MESH:C033601', (34, 41))	('prolonged', 'PosReg', (54, 63))
30951	31581360	We next measured the expression of TGF-beta target genes such as cyclin-dependent kinase inhibitor 1A (CDKN1A) in A549 transfected with inhibitors or mimics of miR-NC, miR-195 and miR-497.	('TGF-beta', 'Gene', (35, 43))	('expression', 'Species', '29278', (21, 31))	('expression', 'MPA', (21, 31))	('miR-497', 'Var', (180, 187))	('miR-NC', 'Gene', (160, 166))	('CDKN1A', 'Gene', (103, 109))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('TGF-beta', 'Gene', '21803', (35, 43))	('miR-195', 'Var', (168, 175))
30952	31581360	To exclude the possibility of direct targeting of CDKN1A by miR-195 and miR-497, we examined this possibility using miRNA target prediction databases such as TargetScan, miRanda and miRWalk 2.0 but the results of the target prediction databases showed no binding sites for miR-195 and miR-497 in the 3'-UTR of CDKN1A.	('miR-497', 'Var', (285, 292))	('binding', 'Interaction', (255, 262))	('miR-195', 'Var', (273, 280))	('miRanda', 'Disease', 'MESH:C537402', (170, 177))	('miRanda', 'Disease', (170, 177))
30953	31581360	Figure S5B shows that anti-miR-195 and anti-miR-497 significantly repressed the TGF-beta1-induced CDKN1A gene; however, the overexpression of miR-195 and miR-497 by mimics induced CDKN1A expression (Fig.	('miR-195', 'Var', (142, 149))	('TGF-beta', 'Gene', '21803', (80, 88))	('induced', 'PosReg', (172, 179))	('TGF-beta', 'Gene', (80, 88))	('expression', 'Species', '29278', (128, 138))	('expression', 'Species', '29278', (187, 197))	('CDKN1A', 'Gene', (180, 186))	('expression', 'MPA', (187, 197))	('miR-497', 'Var', (154, 161))	('CDKN1A gene', 'Gene', (98, 109))	('overexpression', 'PosReg', (124, 138))
30954	31581360	Moreover, the p21 protein levels were regulated by the mimics and inhibitors of miR-195 and miR-497 (Figs 4C and S5C).	('miR-195', 'Var', (80, 87))	('p21', 'Gene', (14, 17))	('p21', 'Gene', '644914', (14, 17))	('S5C', 'Chemical', 'MESH:D013455', (113, 116))	('regulated', 'Reg', (38, 47))	('miR-497', 'Var', (92, 99))
30955	31581360	Indeed, miR-195- and miR-497-mediated induction of p21 protein levels was decreased by LY364947 treatment (Fig.	('LY364947', 'Chemical', 'MESH:C520284', (87, 95))	('p21', 'Gene', (51, 54))	('p21', 'Gene', '644914', (51, 54))	('induction', 'MPA', (38, 47))	('miR-497-mediated', 'Var', (21, 37))	('decreased', 'NegReg', (74, 83))	('miR-195-', 'Var', (8, 16))	('LY364947', 'Var', (87, 95))
30956	31581360	These results demonstrate that the sustained activation of TGF-beta signaling by miR-195 and miR-497 enhanced the activity and expression of TGF-beta target genes.	('TGF-beta', 'Gene', (59, 67))	('expression', 'Species', '29278', (127, 137))	('activity', 'MPA', (114, 122))	('expression', 'MPA', (127, 137))	('miR-497', 'Var', (93, 100))	('TGF-beta', 'Gene', (141, 149))	('miR-195', 'Var', (81, 88))	('enhanced', 'PosReg', (101, 109))	('TGF-beta', 'Gene', '21803', (59, 67))	('activation', 'PosReg', (45, 55))	('TGF-beta', 'Gene', '21803', (141, 149))
30957	31581360	Taken together, these data suggest that miR-195 and miR-497 function as positive regulators of TGF-beta signaling by inhibiting SMURF2-dependent TbetaRI ubiquitination.	('TGF-beta', 'Gene', '21803', (95, 103))	('SMURF2-dependent TbetaRI ubiquitination', 'MPA', (128, 167))	('miR-497', 'Var', (52, 59))	('miR-195', 'Var', (40, 47))	('inhibiting', 'NegReg', (117, 127))	('TGF-beta', 'Gene', (95, 103))
30960	31581360	To determine whether miR-195 and miR-497 influence the cancer phenotype of A549 cells, we carried out a series of biological experiments to determine the effects of miR-195 and miR-497 on cancer cell phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('miR-497', 'Var', (177, 184))	('influence', 'Reg', (41, 50))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('A549', 'CellLine', 'CVCL:0023', (75, 79))	('cancer', 'Disease', (55, 61))
30961	31581360	The WST assay revealed that the A549 cells transfected with the mimics of miR-195 and miR-497 had a dramatically inhibited cell proliferation compared with the negative control both in the absence and in the presence of TGF-beta1 (Fig.	('miR-497', 'Var', (86, 93))	('cell proliferation', 'CPA', (123, 141))	('inhibited', 'NegReg', (113, 122))	('miR-195', 'Var', (74, 81))	('TGF-beta', 'Gene', '21803', (220, 228))	('A549', 'CellLine', 'CVCL:0023', (32, 36))	('TGF-beta', 'Gene', (220, 228))
30962	31581360	Conversely, A549 cells transfected with the inhibitor of miR-195 or miR-497 showed a significant increase in cell proliferation (Fig.	('cell proliferation', 'CPA', (109, 127))	('miR-195', 'Gene', (57, 64))	('increase', 'PosReg', (97, 105))	('A549', 'CellLine', 'CVCL:0023', (12, 16))	('miR-497', 'Var', (68, 75))
30964	31581360	As expected, reduction of cell proliferation by miR-195 or miR-497 was restored by the overexpression of SMURF2, indicating that miR-195 and miR-497 inhibit cell proliferation by reducing SMURF2 levels in lung cancer cells (Fig.	('inhibit', 'NegReg', (149, 156))	('cell proliferation', 'CPA', (157, 175))	('reducing', 'NegReg', (179, 187))	('lung cancer', 'Disease', 'MESH:D008175', (205, 216))	('miR-497', 'Var', (141, 148))	('SMURF2 levels', 'MPA', (188, 201))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('miR-195', 'Var', (129, 136))	('lung cancer', 'Disease', (205, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('expression', 'Species', '29278', (91, 101))
30966	31581360	In control cells, TGF-beta1-induced suppression of cell proliferation was restored by treatment with LY364947 and this response also occurred identically with the mimic of miR-195- or miR-497-transfected cells (Fig.	('LY364947', 'Var', (101, 109))	('TGF-beta', 'Gene', (18, 26))	('LY364947', 'Chemical', 'MESH:C520284', (101, 109))	('suppression', 'NegReg', (36, 47))	('cell proliferation', 'CPA', (51, 69))	('TGF-beta', 'Gene', '21803', (18, 26))
30967	31581360	Several studies have reported on miR-195 and miR-497 as tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miR-497', 'Var', (45, 52))	('tumor', 'Disease', (56, 61))	('miR-195', 'Var', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
30968	31581360	The results show that the miR-195 and miR-497 mimics reduced the colony formation ability of the A549 cells compared with the negative control; these responses also occurred identically in the presence of TGF-beta1 (Fig.	('TGF-beta', 'Gene', '21803', (205, 213))	('colony formation ability of the A549 cells', 'CPA', (65, 107))	('reduced', 'NegReg', (53, 60))	('miR-497', 'Gene', (38, 45))	('TGF-beta', 'Gene', (205, 213))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('miR-195', 'Gene', (26, 33))	('mimics', 'Var', (46, 52))
30969	31581360	These data show that miR-195 and miR-497 inhibit cell proliferation and cell survival through activating TGF-beta signaling by suppression of SMURF2-induced TbetaRI ubiquitination.	('TGF-beta', 'Gene', '21803', (105, 113))	('cell survival', 'CPA', (72, 85))	('SMURF2-induced', 'Gene', (142, 156))	('TGF-beta', 'Gene', (105, 113))	('cell proliferation', 'CPA', (49, 67))	('TbetaRI ubiquitination', 'MPA', (157, 179))	('inhibit', 'NegReg', (41, 48))	('activating', 'PosReg', (94, 104))	('miR-497', 'Var', (33, 40))	('miR-195', 'Var', (21, 28))	('suppression', 'NegReg', (127, 138))
30970	31581360	The Matrigel invasion assay showed that miR-195 and miR-497 mimics reduced the invasive ability of lung cancer cells compared with control.	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('miR-195', 'Var', (40, 47))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('reduced', 'NegReg', (67, 74))	('miR-497', 'Gene', (52, 59))	('invasive ability of', 'CPA', (79, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
30972	31581360	In addition, despite the inhibition of TGF-beta signaling by LY364947 treatment, the invasive effects of the cells transfected with two miRNA were also decreased compared with control cells, suggesting that TGF-beta signaling does not contribute significantly to the effects of these miRNA on cell invasion (Fig.	('TGF-beta', 'Gene', '21803', (207, 215))	('TGF-beta', 'Gene', '21803', (39, 47))	('TGF-beta', 'Gene', (207, 215))	('decreased', 'NegReg', (152, 161))	('LY364947', 'Var', (61, 69))	('LY364947', 'Chemical', 'MESH:C520284', (61, 69))	('inhibition', 'NegReg', (25, 35))	('TGF-beta', 'Gene', (39, 47))	('invasive effects', 'CPA', (85, 101))
30973	31581360	In fact, the reduction of SMURF2 levels by siRNA or inhibitors leads to a decrease not only in cell survival/proliferation but also in migration and invasive abilities of cancer cells (David et al., 2014; Jin et al., 2009; Klupp et al., 2019).	('decrease', 'NegReg', (74, 82))	('SMURF2 levels', 'MPA', (26, 39))	('migration', 'CPA', (135, 144))	('cell survival/proliferation', 'CPA', (95, 122))	('reduction', 'NegReg', (13, 22))	('inhibitors', 'Var', (52, 62))	('invasive abilities of cancer', 'Disease', 'MESH:D009362', (149, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('invasive abilities of cancer', 'Disease', (149, 177))
30974	31581360	Hence, it is possible that miR-195 or miR-497 could decrease invasiveness of lung cancer cells by suppressing the expression of SMURF2 gene directly, although TGF-beta signaling was activated.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('invasiveness of lung cancer', 'Disease', (61, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('miR-497', 'Var', (38, 45))	('decrease', 'NegReg', (52, 60))	('TGF-beta', 'Gene', (159, 167))	('invasiveness of lung cancer', 'Disease', 'MESH:D008175', (61, 88))	('suppressing', 'NegReg', (98, 109))	('expression', 'Species', '29278', (114, 124))	('SMURF2', 'Gene', (128, 134))	('expression', 'MPA', (114, 124))	('TGF-beta', 'Gene', '21803', (159, 167))	('miR-195', 'Var', (27, 34))
30976	31581360	We also checked SMURF2 protein levels by the overexpression the mimic of miR-195 or miR-497, or Flag-SMURF2 (Fig.	('Flag-SMURF2', 'Var', (96, 107))	('expression', 'Species', '29278', (49, 59))	('miR-195', 'Gene', (73, 80))	('miR-497', 'Var', (84, 91))	('overexpression', 'PosReg', (45, 59))	('checked', 'Reg', (8, 15))
30977	31581360	Thus, miR-195 and miR-497 might regulate cell invasion in a SMURF2-dependent manner rather than the activation of TGF-beta signaling.	('regulate', 'Reg', (32, 40))	('cell invasion', 'CPA', (41, 54))	('miR-497', 'Var', (18, 25))	('TGF-beta', 'Gene', (114, 122))	('miR-195', 'Var', (6, 13))	('TGF-beta', 'Gene', '21803', (114, 122))
30978	31581360	Taken together, these results suggest that miR-195 and miR-497 have an important role as a potential tumor-suppressor in lung cancer by inhibiting cell growth and invasion.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('inhibiting', 'NegReg', (136, 146))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('miR-497', 'Var', (55, 62))	('tumor', 'Disease', (101, 106))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('miR-195', 'Var', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
30981	31581360	The results show that the overexpression group of miR-195 and miR-497 significantly suppressed the tumor size by 50% compared with miR-NC (Fig.	('tumor', 'Disease', (99, 104))	('miR-497', 'Var', (62, 69))	('miR-195', 'Var', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('expression', 'Species', '29278', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('suppressed', 'NegReg', (84, 94))
30983	31581360	Furthermore, TUNEL assay showed that miR-195 and miR-497 significantly increased the apoptosis rate of the xenograft tumors of mice transfected with miR-195 or miR-497 compared with the control (Fig.	('miR-195', 'Var', (149, 156))	('mice', 'Species', '10090', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('miR-497', 'Var', (49, 56))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('miR-195', 'Var', (37, 44))	('increased', 'PosReg', (71, 80))	('miR-497', 'Var', (160, 167))
30984	31581360	To assess whether miR-195 and miR-497 could regulate SMURF2 expression in vivo, we examined the expression levels of SMURF2.	('expression', 'MPA', (60, 70))	('regulate', 'Reg', (44, 52))	('expression', 'Species', '29278', (96, 106))	('miR-497', 'Var', (30, 37))	('expression', 'Species', '29278', (60, 70))	('SMURF2', 'Gene', (53, 59))
30985	31581360	Both protein levels and mRNA levels of SMURF2 were reduced in miR-195 and miR-497 overexpressed tumor tissues compared with the control (Fig.	('miR-497', 'Gene', (74, 81))	('reduced', 'NegReg', (51, 58))	('miR-195', 'Gene', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('protein levels', 'MPA', (5, 19))	('overexpressed', 'Var', (82, 95))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mRNA levels', 'MPA', (24, 35))
30986	31581360	In contrast to SMURF2 levels, TbetaRI and p-SMAD2 expression was significantly upregulated in the xenograft tumors of mice transfected with the miR-195 or miR-497 mimic compared with the control (Fig.	('miR-497', 'Var', (155, 162))	('p-SMAD2', 'Gene', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('TbetaRI', 'Gene', (30, 37))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('expression', 'Species', '29278', (50, 60))	('upregulated', 'PosReg', (79, 90))	('mice', 'Species', '10090', (118, 122))	('miR-195', 'Var', (144, 151))	('expression', 'MPA', (50, 60))
30987	31581360	These results indicate that overexpression of miR-195 and miR-497 significantly suppresses tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('miR-195', 'Var', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('expression', 'Species', '29278', (32, 42))	('overexpression', 'PosReg', (28, 42))	('tumor', 'Disease', (91, 96))	('suppresses', 'NegReg', (80, 90))	('miR-497', 'Var', (58, 65))
30988	31581360	In this study, we analyzed the expressions of miR-195 and miR-497 in the tissue and blood of lung cancer patients in the NCBI GEO database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE51853 and http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE1768) and in several lung cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', (277, 288))	('patients', 'Species', '9606', (105, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('blood of lung cancer', 'Disease', 'MESH:D008175', (84, 104))	('expression', 'Species', '29278', (31, 41))	('lung cancer', 'Disease', 'MESH:D008175', (277, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('blood of lung cancer', 'Disease', (84, 104))	('miR-497', 'Var', (58, 65))
30989	31581360	We found that miR-195 and miR-497 were significantly downregulated in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('miR-497', 'Var', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('miR-195', 'Var', (14, 21))	('downregulated', 'NegReg', (53, 66))
30990	31581360	Our results demonstrate that ectopic expression of miR-195 and miR-497 significantly suppressed lung cancer cell proliferation, colony formation and invasion in the cancer cells and tumor growth in a xenograft mouse model.	('miR-497', 'Gene', (63, 70))	('expression', 'Species', '29278', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('miR-195', 'Var', (51, 58))	('suppressed', 'NegReg', (85, 95))	('cancer', 'Disease', (165, 171))	('colony formation', 'CPA', (128, 144))	('tumor', 'Disease', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (101, 107))	('mouse', 'Species', '10090', (210, 215))	('lung cancer', 'Disease', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('invasion in the', 'CPA', (149, 164))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
30991	31581360	These findings indicate that miR-195 and miR-497 might act as tumor suppressors whose downregulation may contribute to the progression and prognosis of cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('miR-497', 'Var', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('contribute', 'Reg', (105, 115))	('tumor', 'Disease', (62, 67))	('miR-195', 'Var', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('downregulation', 'NegReg', (86, 100))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
30992	31581360	Some studies have shown that miR-195 and miR-497 have different functions in other types of cancer.	('miR-497', 'Var', (41, 48))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('miR-195', 'Var', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
30995	31581360	However, most studies have reported that miR-195 and miR-497 function as tumor suppressors in many types of cancer, consistent with our findings (Furuta et al., 2013; Li et al., 2011).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', (73, 78))	('miR-497', 'Var', (53, 60))	('miR-195', 'Var', (41, 48))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
30996	31581360	To identify the molecular mechanism of miR-195 and miR-497 in cancer, we selected the SMURF2 gene among the components of TGF-beta signaling as putative targets of miR-195 and miR-497 using prediction databases.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SMURF2 gene', 'Gene', (86, 97))	('miR-497', 'Var', (176, 183))	('TGF-beta', 'Gene', '21803', (122, 130))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('miR-195', 'Var', (164, 171))	('TGF-beta', 'Gene', (122, 130))
31003	31581360	Recent studies have also reported that the SMURF2 gene was inhibited by miR-322/503 in the intestinal epithelial cell (Cao et al., 2014) and by miR-15b in pancreatic cancer (Zhang et al., 2015).	('SMURF2 gene', 'Gene', (43, 54))	('miR-15b', 'Var', (144, 151))	('inhibited', 'NegReg', (59, 68))	('pancreatic cancer', 'Disease', (155, 172))	('pancreatic cancer', 'Disease', 'MESH:D010190', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))	('miR-322/503', 'Var', (72, 83))
31005	31581360	Therefore, we focused on the effects of miR-195 and miR-497 on the SMURF2 gene expression and their biological functions in lung cancer.	('expression', 'Species', '29278', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('expression', 'MPA', (79, 89))	('miR-497', 'Var', (52, 59))	('miR-195', 'Var', (40, 47))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('SMURF2', 'Gene', (67, 73))
31006	31581360	In our experiments, we observed that miR-195 and miR-497 downregulate the SMURF2 gene expression by direct targeting of the 3'-UTR of SMURF2 using the luciferase reporter assay.	('miR-497', 'Var', (49, 56))	('downregulate', 'NegReg', (57, 69))	('expression', 'Species', '29278', (86, 96))	('expression', 'MPA', (86, 96))	('miR-195', 'Var', (37, 44))	('SMURF2 gene', 'Gene', (74, 85))
31007	31581360	Many studies have reported that perturbation of TGF-beta signaling is often considered a pathogenic factor in tumor progression due to its tumor-promoting effects or tumor suppressor effects (Butz et al., 2012; Ikushima and Miyazono, 2010).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Miyazono', 'Chemical', 'None', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('TGF-beta', 'Gene', (48, 56))	('perturbation', 'Var', (32, 44))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('TGF-beta', 'Gene', '21803', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
31011	31581360	However, perturbations of this balance induce the transformation from normal cells to cancer cells.	('perturbations', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('transformation', 'CPA', (50, 64))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('induce', 'Reg', (39, 45))	('cancer', 'Disease', (86, 92))
31015	31581360	Although miR-195 and miR-497 did not directly regulate the TbetaRI expression, they can upregulate cell surface TbetaRI expression by regulation of SMURF2.	('upregulate', 'PosReg', (88, 98))	('expression', 'Species', '29278', (120, 130))	('miR-195', 'Var', (9, 16))	('cell surface TbetaRI expression', 'MPA', (99, 130))	('expression', 'Species', '29278', (67, 77))	('SMURF2', 'Gene', (148, 154))	('miR-497', 'Var', (21, 28))	('regulation', 'Reg', (134, 144))
31016	31581360	We demonstrated that ectopic expression of miR-195 and miR-497 by mimics suppressed TbetaRI ubiquitination and degradation through the repression of SMURF2 gene expression.	('expression', 'Species', '29278', (161, 171))	('degradation', 'MPA', (111, 122))	('TbetaRI ubiquitination', 'MPA', (84, 106))	('miR-497', 'Var', (55, 62))	('SMURF2', 'Gene', (149, 155))	('miR-195', 'Var', (43, 50))	('expression', 'Species', '29278', (29, 39))	('suppressed', 'NegReg', (73, 83))	('repression', 'NegReg', (135, 145))
31018	31581360	These results suggest that the reduction of the SMURF2 gene expression by miR-195 or miR-497, resulting in the activation of TGF-beta signaling, has an important role in inhibiting early-stage lung cancer (Fig.	('activation', 'PosReg', (111, 121))	('expression', 'MPA', (60, 70))	('reduction', 'NegReg', (31, 40))	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('TGF-beta', 'Gene', (125, 133))	('SMURF2 gene', 'Gene', (48, 59))	('miR-195', 'Var', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('miR-497', 'Var', (85, 92))	('expression', 'Species', '29278', (60, 70))	('lung cancer', 'Disease', (193, 204))	('inhibiting', 'NegReg', (170, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))	('TGF-beta', 'Gene', '21803', (125, 133))
31022	31581360	Subsequent studies are required to identify accurately the contribution of TGF-beta signaling to the functions of miR-195 and miR-497 during metastasis.	('miR-497', 'Var', (126, 133))	('Su', 'Chemical', 'MESH:C035067', (0, 2))	('TGF-beta', 'Gene', '21803', (75, 83))	('miR-195', 'Gene', (114, 121))	('TGF-beta', 'Gene', (75, 83))
31025	31581360	In conclusion, this study identified a group of miRNA predicted to be downregulated in lung cancer patients and selected the miR-195 and miR-497 cluster.	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('miR-195', 'Var', (125, 132))	('miRNA', 'MPA', (48, 53))	('patients', 'Species', '9606', (99, 107))	('downregulated', 'NegReg', (70, 83))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('miR-497', 'Var', (137, 144))
31026	31581360	We demonstrated that miR-195 and miR-497 directly target SMURF2 with the luciferase assay and regulate TGF-beta signaling in lung cancer cells.	('SMURF2', 'Gene', (57, 63))	('regulate', 'Reg', (94, 102))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('target', 'Reg', (50, 56))	('TGF-beta', 'Gene', (103, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('lung cancer', 'Disease', (125, 136))	('TGF-beta', 'Gene', '21803', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miR-497', 'Var', (33, 40))	('miR-195', 'Var', (21, 28))
31028	31581360	As a result, we observed that activated TGF-beta signaling by miR-195 and miR-497 significantly suppressed tumor growth in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('TGF-beta', 'Gene', '21803', (40, 48))	('suppressed', 'NegReg', (96, 106))	('activated', 'PosReg', (30, 39))	('TGF-beta', 'Gene', (40, 48))	('miR-497', 'Var', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('miR-195', 'Var', (62, 69))
31029	31581360	However, miR-195 and miR-497 also suppressed invasive ability of lung cancer cells, although the activation of TGF-beta signaling increased cell invasion.	('cell invasion', 'CPA', (140, 153))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('activation', 'PosReg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('suppressed', 'NegReg', (34, 44))	('TGF-beta', 'Gene', (111, 119))	('miR-195', 'Var', (9, 16))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('increased', 'PosReg', (130, 139))	('miR-497', 'Var', (21, 28))	('TGF-beta', 'Gene', '21803', (111, 119))
31030	31581360	This study expands the understanding of the mechanisms for the post-transcriptional regulation of SMURF2 by regulation of miR-195 and miR-497, and its ability to modulate TGF-beta signaling.	('modulate', 'Reg', (162, 170))	('SMURF2', 'Gene', (98, 104))	('TGF-beta', 'Gene', '21803', (171, 179))	('regulation', 'Reg', (108, 118))	('miR-497', 'Var', (134, 141))	('miR-195', 'Var', (122, 129))	('TGF-beta', 'Gene', (171, 179))
31031	31581360	Our study sheds light on further clinical benefits of miR-195 and miR-497 as diagnosis biomarkers and therapeutic targets for lung cancer.	('miR-497', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('miR-195', 'Var', (54, 61))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))
31036	30963136	She was recently diagnosed with MSH6 germline mutation after her sister presented with uterine carcinoma in the setting of LS.	('carcinoma', 'Disease', (95, 104))	('germline mutation', 'Var', (37, 54))	('MSH6', 'Gene', (32, 36))	('carcinoma', 'Disease', 'MESH:D002277', (95, 104))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (87, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('MSH6', 'Gene', '2956', (32, 36))
31043	30963136	LS-hereditary nonpolyposis colorectal cancer is an autosomal-dominant hereditary cancer predisposition syndrome caused by germline pathogenic variants in any of DNA mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2.	('MSH2', 'Gene', '4436', (204, 208))	('autosomal-dominant hereditary cancer', 'Disease', (51, 87))	('MLH1', 'Gene', '4292', (198, 202))	('PMS2', 'Gene', (220, 224))	('MLH1', 'Gene', (198, 202))	('nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (14, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('variants', 'Var', (142, 150))	('caused by', 'Reg', (112, 121))	('MSH6', 'Gene', '2956', (210, 214))	('PMS2', 'Gene', '5395', (220, 224))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (3, 44))	('autosomal-dominant hereditary cancer', 'Disease', 'MESH:D009386', (51, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('nonpolyposis colorectal cancer', 'Disease', (14, 44))	('MSH2', 'Gene', (204, 208))	('MSH6', 'Gene', (210, 214))
31045	30963136	Germline pathogenic variants in the MSH6 gene account for ~18% of LS cases.	('MSH6', 'Gene', '2956', (36, 40))	('variants', 'Var', (20, 28))	('MSH6', 'Gene', (36, 40))
31050	30963136	Notably, as a result of a recent diagnosis of LS in the patient's sister, our patient was tested positive for familial pathogenic variant in MSH6.	('patient', 'Species', '9606', (78, 85))	('MSH6', 'Gene', (141, 145))	('variant', 'Var', (130, 137))	('MSH6', 'Gene', '2956', (141, 145))	('patient', 'Species', '9606', (56, 63))
31067	30963136	In this study, five of 114 patients with ACC and LS had MSH2 (in three patients), MSH6 (one patient), and MLH1 (one patient) germline mutations, with four patients demonstrating microsatellite stability.	('MSH6', 'Gene', '2956', (82, 86))	('MSH2', 'Gene', '4436', (56, 60))	('patient', 'Species', '9606', (92, 99))	('ACC', 'Phenotype', 'HP:0006744', (41, 44))	('MLH1', 'Gene', '4292', (106, 110))	('patient', 'Species', '9606', (116, 123))	('patients', 'Species', '9606', (71, 79))	('MLH1', 'Gene', (106, 110))	('patient', 'Species', '9606', (155, 162))	('patient', 'Species', '9606', (27, 34))	('patients', 'Species', '9606', (27, 35))	('MSH2', 'Gene', (56, 60))	('patients', 'Species', '9606', (155, 163))	('MSH6', 'Gene', (82, 86))	('patient', 'Species', '9606', (71, 78))	('germline mutations', 'Var', (125, 143))
31068	30963136	More recently, two more case reports published in 2016 and 2018 again showed association between LS and ACC with MSH2 germline mutation.	('ACC', 'Disease', (104, 107))	('MSH2', 'Gene', '4436', (113, 117))	('germline mutation', 'Var', (118, 135))	('ACC', 'Phenotype', 'HP:0006744', (104, 107))	('association', 'Interaction', (77, 88))	('MSH2', 'Gene', (113, 117))
31081	30455725	We could previously report that PGRMC2 interacts with the nucleoporin ALADIN which when mutated results in the autosomal recessive disorder triple A syndrome.	('autosomal recessive disorder', 'Disease', (111, 139))	('A syndrome', 'Disease', (147, 157))	('PGRMC2', 'Gene', (32, 38))	('nucleoporin', 'Gene', '729857', (58, 69))	('A syndrome', 'Disease', 'MESH:D013577', (147, 157))	('mutated', 'Var', (88, 95))	('results in', 'Reg', (96, 106))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (111, 139))	('nucleoporin', 'Gene', (58, 69))
31092	30455725	Mutations in the human AAAS gene, coding for the protein ALADIN (alacrima-achalasia-adrenal insufficiency neurologic disorder), lead to the autosomal recessive disorder named triple A syndrome.	('achalasia', 'Phenotype', 'HP:0002571', (74, 83))	('alacrima', 'Phenotype', 'HP:0000522', (65, 73))	('alacrima-achalasia-adrenal insufficiency neurologic disorder', 'Gene', '8086', (65, 125))	('human', 'Species', '9606', (17, 22))	('A syndrome', 'Disease', (182, 192))	('AAAS', 'Gene', '8086', (23, 27))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (140, 168))	('autosomal recessive disorder', 'Disease', (140, 168))	('Mutations', 'Var', (0, 9))	('A syndrome', 'Disease', 'MESH:D013577', (182, 192))	('AAAS', 'Gene', (23, 27))	('neurologic disorder', 'Phenotype', 'HP:0000707', (106, 125))	('lead to', 'Reg', (128, 135))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (84, 105))
31094	30455725	Most mutations in AAAS result in a mis-localization of ALADIN to the cytoplasm.	('AAAS', 'Gene', (18, 22))	('AAAS', 'Gene', '8086', (18, 22))	('ALADIN', 'Protein', (55, 61))	('result in', 'Reg', (23, 32))	('mutations', 'Var', (5, 14))	('mis-localization', 'MPA', (35, 51))
31123	30455725	To test whether depletion of ALADIN also results in decreased cellular proliferation in adrenal cells we used inducible adrenocortical NCI-H295R1-TR cells stably expressing AAAS shRNA (AAAS knock-down) and monitored cellular proliferation using live cell imaging for at least 65 h. AAAS knock-down resulted in decreased proliferation in adrenal cells (growth constant k (slope of linear regression line) = 0.044) compared to control cells expressing a scrambled shRNA (k = 0.062) (wild-type cells: k = 0.2) (Fig.	('AAAS', 'Gene', '8086', (173, 177))	('knock-down', 'Var', (287, 297))	('AAAS', 'Gene', (282, 286))	('AAAS', 'Gene', '8086', (185, 189))	('AAAS', 'Gene', '8086', (282, 286))	('proliferation', 'CPA', (320, 333))	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (135, 148))	('decreased', 'NegReg', (310, 319))	('AAAS', 'Gene', (173, 177))	('adrenocortical', 'Disease', 'MESH:D018268', (120, 134))	('adrenocortical', 'Disease', (120, 134))	('AAAS', 'Gene', (185, 189))
31124	30455725	Surprisingly, in live cell imaging stable over-expression of N-terminal-GFP-tagged ALADIN in adrenocortical NCI-H295R cells also impaired cellular proliferation (k = 0.082) compared to over-expression of GFP alone in these cells (k = 0.305) (wild-type cells: k = 0.16) (Fig.	('ALADIN', 'Gene', (83, 89))	('over-expression', 'PosReg', (42, 57))	('N-terminal-GFP-tagged', 'Var', (61, 82))	('adrenocortical', 'Disease', (93, 107))	('impaired', 'NegReg', (129, 137))	('adrenocortical', 'Disease', 'MESH:D018268', (93, 107))	('cellular proliferation', 'CPA', (138, 160))	('NCI-H295R', 'CellLine', 'CVCL:0458', (108, 117))
31126	30455725	The same phenotype was seen in adrenocortical cells transiently over-expressing N-terminal-GFP-tagged PGRMC1 (k = 0.015) (Fig.	('over-expressing', 'PosReg', (64, 79))	('PGRMC1', 'Gene', (102, 108))	('adrenocortical', 'Disease', (31, 45))	('PGRMC1', 'Gene', '10857', (102, 108))	('adrenocortical', 'Disease', 'MESH:D018268', (31, 45))	('N-terminal-GFP-tagged', 'Var', (80, 101))
31127	30455725	AAAS knock-down) on proliferation.	('proliferation', 'CPA', (20, 33))	('AAAS', 'Gene', '8086', (0, 4))	('AAAS', 'Gene', (0, 4))	('knock-down', 'Var', (5, 15))
31140	30455725	For this purpose, we chose patient cells with three different, and in vivo frequently occurring homozygous mutations in the AAAS gene: a donor splice mutation IVS14 + 1G > A (IVS14), a point mutation c.787T > C leading to the missense mutation S263P and a point mutation c.884G > A leading to the nonsense mutation W295X.	('c.787T > C', 'Mutation', 'rs121918550', (200, 210))	('AAAS', 'Gene', (124, 128))	('1G > A', 'Var', (167, 173))	('c.884G > A', 'Mutation', 'rs565082206', (271, 281))	('c.884G > A', 'Var', (271, 281))	('IVS14 + 1G > A', 'Mutation', 'c.IVS14+1G>A', (159, 173))	('c.787T > C', 'Var', (200, 210))	('patient', 'Species', '9606', (27, 34))	('S263P', 'Mutation', 'rs121918550', (244, 249))	('W295X', 'Mutation', 'rs766542823', (315, 320))	('AAAS', 'Gene', '8086', (124, 128))	('W295X', 'Var', (315, 320))	('1G > A', 'SUBSTITUTION', 'None', (167, 173))	('S263P', 'Var', (244, 249))	('donor', 'Species', '9606', (137, 142))
31148	30455725	Here, we show in patient fibroblasts that ALADIN depletion resulted in poleward spread of Aurora kinase A onto metaphase spindles and moreover, in accumulation in the cytoplasm (Fig.	('Aurora kinase A', 'Gene', (90, 105))	('accumulation', 'PosReg', (147, 159))	('patient', 'Species', '9606', (17, 24))	('Aurora kinase A', 'Gene', '6790', (90, 105))	('poleward spread', 'CPA', (71, 86))	('depletion', 'Var', (49, 58))	('ALADIN', 'Protein', (42, 48))
31149	30455725	The highest accumulation of Aurora kinase A in the cytoplasm was seen in patient cells carrying the ALADIN missense mutation S263P and the nonsense mutation W295X (Fig.	('W295X', 'Var', (157, 162))	('W295X', 'Mutation', 'rs766542823', (157, 162))	('patient', 'Species', '9606', (73, 80))	('accumulation', 'PosReg', (12, 24))	('Aurora kinase A', 'Gene', '6790', (28, 43))	('S263P', 'Mutation', 'rs121918550', (125, 130))	('ALADIN', 'Gene', (100, 106))	('S263P', 'Var', (125, 130))	('Aurora kinase A', 'Gene', (28, 43))
31151	30455725	Nevertheless, PGRMC1 also accumulated in the cytosol of triple A fibroblasts with highest levels in patient cells carrying the ALADIN missense mutation S263P and the nonsense mutation W295X (Fig.	('W295X', 'Mutation', 'rs766542823', (184, 189))	('W295X', 'Var', (184, 189))	('patient', 'Species', '9606', (100, 107))	('S263P', 'Mutation', 'rs121918550', (152, 157))	('PGRMC1', 'Gene', '10857', (14, 20))	('PGRMC1', 'Gene', (14, 20))	('S263P', 'Var', (152, 157))
31152	30455725	Thus, immunofluorescence results in triple A patient fibroblasts verified our previous findings and patient cells even presented with a more profound phenotype regarding Aurora kinase A and PGRMC1 mis-localization than adrenocortical ALADIN knock-down cells.	('adrenocortical', 'Disease', (219, 233))	('mis-localization', 'Var', (197, 213))	('adrenocortical', 'Disease', 'MESH:D018268', (219, 233))	('Aurora kinase A', 'Gene', (170, 185))	('patient', 'Species', '9606', (100, 107))	('patient', 'Species', '9606', (45, 52))	('Aurora kinase A', 'Gene', '6790', (170, 185))	('PGRMC1', 'Gene', (190, 196))	('PGRMC1', 'Gene', '10857', (190, 196))
31155	30455725	Now, we show that fibroblasts from triple A patients carrying the ALADIN missense mutation S263P or the nonsense mutation W295X had about two-fold increased levels of PGRMC2 on mRNA and protein level compared to anonymized healthy control fibroblasts (Fig.	('S263P', 'Mutation', 'rs121918550', (91, 96))	('increased', 'PosReg', (147, 156))	('patients', 'Species', '9606', (44, 52))	('S263P', 'Var', (91, 96))	('PGRMC2', 'MPA', (167, 173))	('W295X', 'Mutation', 'rs766542823', (122, 127))	('W295X', 'Var', (122, 127))	('ALADIN', 'Gene', (66, 72))	('levels', 'MPA', (157, 163))
31170	30455725	5c the same immunofluorescence staining pattern can be seen in cold-treated skin fibroblasts from triple A patients carrying the donor splice mutation IVS14, the missense mutation S263P or the nonsense mutation W295X.	('W295X', 'Var', (211, 216))	('donor', 'Species', '9606', (129, 134))	('W295X', 'Mutation', 'rs766542823', (211, 216))	('S263P', 'Mutation', 'rs121918550', (180, 185))	('S263P', 'Var', (180, 185))	('patients', 'Species', '9606', (107, 115))
31176	30455725	In order to address the pathogenesis in adrenal tissue in the patients, we reported that loss of ALADIN leads to an impairment of glucocorticoid and mineralocorticoid synthesis in adrenal cells in vitro.	('patients', 'Species', '9606', (62, 70))	('impairment', 'NegReg', (116, 126))	('loss', 'Var', (89, 93))	('ALADIN', 'Gene', (97, 103))
31177	30455725	Thus, it can be assumed that an equilibrated level of ALADIN protein is prerequisite for successful cellular proliferation and that depletion or accumulation of the nucleoporin impairs cellular proliferation.	('depletion', 'Var', (132, 141))	('accumulation', 'PosReg', (145, 157))	('ALADIN', 'Protein', (54, 60))	('nucleoporin', 'Gene', '729857', (165, 176))	('cellular proliferation', 'CPA', (185, 207))	('impairs', 'NegReg', (177, 184))	('nucleoporin', 'Gene', (165, 176))
31222	30455725	Over-expression of PGRMC1 alone would probably also result in the same phenotype while targeting high amount of PGRMC1 to the cytoplasm.	('PGRMC1', 'Gene', (112, 118))	('PGRMC1', 'Gene', '10857', (112, 118))	('PGRMC1', 'Gene', (19, 25))	('PGRMC1', 'Gene', '10857', (19, 25))	('Over-expression', 'Var', (0, 15))
31226	30455725	Future research has to address in more detail whether the loss of regulation of PGRMC2 and Aurora kinase A is dependent on different levels in ALADIN protein and on different kinds of mutations in the AAAS gene.	('PGRMC2', 'Gene', (80, 86))	('loss', 'NegReg', (58, 62))	('mutations', 'Var', (184, 193))	('AAAS', 'Gene', (201, 205))	('AAAS', 'Gene', '8086', (201, 205))	('Aurora kinase A', 'Gene', (91, 106))	('ALADIN protein', 'MPA', (143, 157))	('Aurora kinase A', 'Gene', '6790', (91, 106))	('regulation', 'MPA', (66, 76))
31231	30455725	We hypothesize that the previously documented decreased stability of K-fibers upon ALADIN depletion is partly the result of a mis-regulated PGRMC2 which displaces PGRMC1 from K-fibers to the cytosol.	('mis-regulated', 'Var', (126, 139))	('stability', 'MPA', (56, 65))	('displaces', 'NegReg', (153, 162))	('PGRMC1', 'Gene', (163, 169))	('decreased', 'NegReg', (46, 55))	('PGRMC1', 'Gene', '10857', (163, 169))	('PGRMC2', 'Gene', (140, 146))
31233	30455725	Our new results shall be the basis for more extended research focusing on mis-regulated PGRMC2 and Aurora kinase A due to loss of ALADIN.	('Aurora kinase A', 'Gene', '6790', (99, 114))	('PGRMC2', 'Gene', (88, 94))	('mis-regulated', 'Var', (74, 87))	('ALADIN', 'Protein', (130, 136))	('Aurora kinase A', 'Gene', (99, 114))	('loss', 'NegReg', (122, 126))
31250	30455725	Fluorescence was imaged using the confocal laser scanning microscope Zeiss LSM 510 with Zeiss EC Plan-Neofluar 40x objective/1.3 Oil and the following lasers: diode 405 nm, Argon 488 nm and DPSS 561 nm (Carl Zeiss).	('DPSS', 'Chemical', '-', (190, 194))	('Argon', 'Chemical', 'MESH:D001128', (173, 178))	('DPSS 561', 'Var', (190, 198))	('diode', 'Var', (159, 164))
31306	26234285	NLR was also associated with an advanced AJCC tumor stage (OR 2.72, 95%CI 1.03-7.20; P =0.04) and a positive surgical margin (OR 3.61, 95%CI 1.29-10.1; P =0.01).	('AJCC tumor', 'Disease', (41, 51))	('AJCC tumor', 'Disease', 'MESH:D009369', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('NLR', 'Var', (0, 3))
31318	26234285	On the multivariate analysis, AJCC T (HR 3.91, 95% 1.76-8.73) and M status (HR 2.42, 95%CI 1.10-5.35), as well as NLR (HR 2.21, 95%CI 1.10-4.43) remained independent predictors of a shorter DSS (all P <0.05; Table III).	('AJCC T', 'Var', (30, 36))	('DSS', 'MPA', (190, 193))	('DSS', 'Chemical', '-', (190, 193))
31326	26234285	Furthermore, we found that a PLR >190 was associated with tumor recurrence after surgery.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('associated with', 'Reg', (42, 57))	('PLR', 'Var', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
31340	26234285	Interestingly, patients with a high NLR and PLR had a larger tumor (>5 cm) and were more likely to require an extended surgical resection that included other surrounding organs invaded by the ACC lesion.	('patients', 'Species', '9606', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('ACC', 'Phenotype', 'HP:0006744', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('high', 'Var', (31, 35))	('tumor', 'Disease', (61, 66))
31343	26234285	Similarly, patients with a PLR >190 had a shorter 5-year RFS compared with patients who had a PLR <= 190, with this association remaining significant on multivariate analysis (HR 1.7) (Table Ib).	('shorter', 'NegReg', (42, 49))	('patients', 'Species', '9606', (75, 83))	('RFS', 'MPA', (57, 60))	('patients', 'Species', '9606', (11, 19))	('PLR', 'Var', (27, 30))
31353	23355100	The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('TP53', 'Gene', (34, 38))	('mutation', 'Var', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('germline', 'Var', (25, 33))	('cancers', 'Disease', (174, 181))	('affects', 'Reg', (70, 77))	('develop', 'PosReg', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('child', 'Species', '9606', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('rare', 'Disease', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
31368	23355100	TP53 is the most frequently mutated gene in human cancer with the prevalence of acquired TP53 mutations highest in epithelial ovarian cancers (47%), colorectal (43%), head/neck (42%), and esophageal cancers (41%) (International Agency for Research on Cancer (IARC) database, R15 release).	('human', 'Species', '9606', (44, 49))	('epithelial ovarian cancers', 'Disease', (115, 141))	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('cancer', 'Disease', (50, 56))	('esophageal cancers', 'Disease', 'MESH:D004938', (188, 206))	('Cancer', 'Disease', (251, 257))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (115, 141))	('cancer', 'Disease', (134, 140))	('Cancer', 'Disease', 'MESH:D009369', (251, 257))	('highest', 'Reg', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('colorectal', 'Disease', (149, 159))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (94, 103))	('head/neck', 'Disease', (167, 176))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('TP53', 'Gene', (89, 93))	('esophageal cancers', 'Disease', (188, 206))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('ovarian cancers', 'Phenotype', 'HP:0100615', (126, 141))	('Cancer', 'Phenotype', 'HP:0002664', (251, 257))	('colorectal', 'Disease', 'MESH:D015179', (149, 159))
31369	23355100	Cancers with acquired TP53 mutations are also associated with diminished survival rates, increased resistance to chemotherapy and radiation, and elevated relapse rates.	('mutations', 'Var', (27, 36))	('TP53', 'Gene', (22, 26))	('survival rates', 'CPA', (73, 87))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('diminished', 'NegReg', (62, 72))	('resistance to chemotherapy', 'CPA', (99, 125))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('increased', 'PosReg', (89, 98))	('relapse rates', 'CPA', (154, 167))
31371	23355100	In 1989, Lavigueur and colleagues accelerated TP53 research when they reported that 20% of transgenic mice carrying a germline mutant TP53 gene developed lung adenocarcinomas, osteosarcomas, and lymphomas.	('TP53', 'Gene', (134, 138))	('osteosarcoma', 'Phenotype', 'HP:0002669', (176, 188))	('osteosarcomas', 'Disease', 'MESH:D012516', (176, 189))	('lymphomas', 'Disease', 'MESH:D008223', (195, 204))	('lymphomas', 'Phenotype', 'HP:0002665', (195, 204))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('germline mutant', 'Var', (118, 133))	('osteosarcomas', 'Disease', (176, 189))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (154, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('transgenic mice', 'Species', '10090', (91, 106))	('osteosarcomas', 'Phenotype', 'HP:0002669', (176, 189))	('lymphomas', 'Disease', (195, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (154, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('lung adenocarcinomas', 'Disease', (154, 174))	('lymphoma', 'Phenotype', 'HP:0002665', (195, 203))	('developed', 'PosReg', (144, 153))
31373	23355100	showed that TP53 pathway alterations could directly cause human cancer.	('alterations', 'Var', (25, 36))	('human', 'Species', '9606', (58, 63))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('TP53 pathway', 'Pathway', (12, 24))	('cause', 'Reg', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
31374	23355100	Using the active metabolite of benzo[a]pyrene (a byproduct of cigarette smoke), Pfeifer's group induced TP53 mutagenesis, causing malignant transformation with unique genetic alterations.	('causing', 'Reg', (122, 129))	('TP53', 'Gene', (104, 108))	('benzo[a]pyrene', 'Chemical', 'MESH:D001564', (31, 45))	('induced', 'Reg', (96, 103))	('mutagenesis', 'Var', (109, 120))	('malignant transformation', 'CPA', (130, 154))
31376	23355100	During a similar timeframe, Donehower and colleagues showed that TP53 did not appear to impair normal embryogenesis, growth, or development in genetically engineered mice.	('TP53', 'Var', (65, 69))	('growth', 'CPA', (117, 123))	('men', 'Species', '9606', (135, 138))	('mice', 'Species', '10090', (166, 170))	('impair', 'NegReg', (88, 94))	('development', 'CPA', (128, 139))
31377	23355100	Donehower's observations confirmed that germline mutations in the TP53 gene could be present without lethal consequences; making an inherited human disorder a plausible concept.	('TP53', 'Gene', (66, 70))	('inherited human disorder', 'Disease', (132, 156))	('inherited human disorder', 'Disease', 'MESH:D030342', (132, 156))	('germline mutations', 'Var', (40, 58))
31387	23355100	Breast cancer is most predictive of the presence of a germline TP53 mutation when it is diagnosed before age 30-35 in a woman with a family history of a first- or second-degree relative with a core LFS cancer (other than breast cancer).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('mutation', 'Var', (68, 76))	('TP53', 'Gene', (63, 67))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('woman', 'Species', '9606', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('LFS cancer', 'Disease', (198, 208))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('LFS cancer', 'Disease', 'MESH:D016864', (198, 208))	('breast cancer', 'Disease', (221, 234))	('germline', 'Var', (54, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('Breast cancer', 'Disease', (0, 13))
31389	23355100	Recent studies have begun to describe the phenotype of breast cancers in TP53 mutation carriers.	('mutation', 'Var', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancers', 'Phenotype', 'HP:0003002', (55, 69))	('TP53', 'Gene', (73, 77))	('breast cancers', 'Disease', 'MESH:D001943', (55, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('breast cancers', 'Disease', (55, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))
31391	23355100	found a significantly greater number of Her2Neu positive tumors among TP53 carriers than among non-carriers (p = 0.0001; table 1).	('Her2Neu', 'Gene', '2064', (40, 47))	('Her2Neu', 'Gene', (40, 47))	('TP53', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('greater', 'PosReg', (22, 29))	('carriers', 'Var', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
31395	23355100	compared sarcomas diagnosed in TP53 mutation carriers in the IARC TP53 database (n=236) to sarcoma diagnoses in the Surveillance, Epidemiology, and End Results (SEER) database (n=34,671).	('sarcoma', 'Disease', 'MESH:D012509', (9, 16))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcoma', 'Disease', 'MESH:D012509', (91, 98))	('TP53', 'Gene', (31, 35))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('sarcoma', 'Disease', (9, 16))	('sarcoma', 'Disease', (91, 98))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('sarcomas', 'Disease', (9, 17))	('mutation', 'Var', (36, 44))
31396	23355100	They found that 67% of sarcomas in TP53 mutation carriers occurred before the age of 20 compared with only 11.9% in the SEER database; in TP53 carriers only 4.4% of sarcomas occurred after age 50, while 62.7% were diagnosed after 50 in the SEER data.	('sarcomas', 'Phenotype', 'HP:0100242', (165, 173))	('mutation', 'Var', (40, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (165, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('sarcomas', 'Disease', (165, 173))	('TP53', 'Gene', (35, 39))	('sarcomas', 'Disease', 'MESH:D012509', (23, 31))	('sarcomas', 'Phenotype', 'HP:0100242', (23, 31))	('sarcomas', 'Disease', 'MESH:D012509', (165, 173))	('sarcomas', 'Disease', (23, 31))
31397	23355100	The age distribution of sarcomas in TP53 mutation carriers is biphasic, with one peak in childhood and another between ages 20 and 40.	('sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('sarcomas', 'Disease', (24, 32))	('mutation', 'Var', (41, 49))	('child', 'Species', '9606', (89, 94))	('TP53', 'Gene', (36, 40))
31398	23355100	Brain Tumors occur in 9-16% of individuals with TP53 mutations.	('Brain Tumors', 'Disease', (0, 12))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('Tumors', 'Phenotype', 'HP:0002664', (6, 12))	('Brain Tumors', 'Disease', 'MESH:D001932', (0, 12))	('Brain Tumors', 'Phenotype', 'HP:0030692', (0, 12))
31400	23355100	Despite limited sample sizes, a compelling body of evidence supports the association between choroid plexus tumors, particularly choroid plexus carcinomas (CPC) and TP53 germline mutations.	('TP53', 'Gene', (165, 169))	('choroid plexus tumors', 'Disease', (93, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('choroid plexus tumors', 'Phenotype', 'HP:0002190', (93, 114))	('choroid plexus tumors', 'Disease', 'MESH:D016545', (93, 114))	('choroid plexus carcinomas', 'Disease', (129, 154))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (129, 153))	('CPC', 'Phenotype', 'HP:0030392', (156, 159))	('choroid plexus carcinomas', 'Phenotype', 'HP:0030392', (129, 154))	('germline mutations', 'Var', (170, 188))	('choroid plexus carcinomas', 'Disease', 'MESH:D020288', (129, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
31401	23355100	reported that all 8 individuals in their cohort with choroid plexus tumor (type not specified) and no additional personal or family history reported were positive for a germline TP53 mutation.	('positive', 'Reg', (154, 162))	('TP53', 'Gene', (178, 182))	('mutation', 'Var', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('not specified', 'Species', '32644', (80, 93))	('choroid plexus tumor', 'Disease', 'MESH:D016545', (53, 73))	('choroid plexus tumor', 'Disease', (53, 73))
31403	23355100	As with sarcoma, there appears to be a biphasic age distribution of brain tumors in those with TP53 mutations, with highest prevalence rates before age 10 and after 20 years of age.	('mutations', 'Var', (100, 109))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('brain tumors', 'Phenotype', 'HP:0030692', (68, 80))	('brain tumors', 'Disease', 'MESH:D001932', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('sarcoma', 'Disease', (8, 15))	('brain tumors', 'Disease', (68, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('TP53', 'Gene', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
31404	23355100	Adrenocortical Carcinoma (ACC) accounts for 10-14% of cancers in TP53 mutation carriers overall.	('carriers', 'Reg', (79, 87))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (0, 24))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('TP53', 'Gene', (65, 69))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('ACC', 'Phenotype', 'HP:0006744', (26, 29))	('Adrenocortical Carcinoma', 'Disease', (0, 24))	('Carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (0, 24))	('mutation', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
31406	23355100	The highest prevalence rates of ACC are reported in carriers of the Brazilian founder mutation, TP53 R337H.	('R337H', 'Mutation', 'rs121912664', (101, 106))	('TP53 R337H', 'Var', (96, 106))	('ACC', 'Phenotype', 'HP:0006744', (32, 35))	('ACC', 'Disease', (32, 35))
31410	23355100	However, more recent studies have found that the R337H mutation can be found in families with a broad spectrum of LFS-associated cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('LFS-associated', 'Disease', (114, 128))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('found', 'Reg', (71, 76))	('R337H', 'Var', (49, 54))	('cancers', 'Disease', (129, 136))	('R337H', 'Mutation', 'rs121912664', (49, 54))
31417	23355100	Mutations in the DNA binding portion of the gene cause highly penetrant disease with very early onset cancers; mutations outside the core DNA binding domain are associated with slower rates of tumor development.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('highly penetrant disease', 'Disease', (55, 79))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('cause', 'Reg', (49, 54))	('tumor', 'Disease', (193, 198))	('men', 'Species', '9606', (206, 209))
31419	23355100	They (and others) have used yeast-based functional assays to show that TP53 mutant alleles with reduced transactivation capability (including dominant negative acting proteins that reduce the transactivation ability of the p53 wild-type protein) are associated with a higher frequency of multiple tumors and are more likely to be found in germline carriers with strong family histories of cancer.	('p53', 'Gene', (223, 226))	('p53', 'Gene', '7157', (223, 226))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('transactivation', 'MPA', (104, 119))	('mutant', 'Var', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('yeast', 'Species', '4932', (28, 33))	('TP53', 'Gene', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('transactivation', 'MPA', (192, 207))	('multiple tumors', 'Disease', (288, 303))	('multiple tumors', 'Disease', 'MESH:D009369', (288, 303))	('cancer', 'Disease', (389, 395))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('associated with', 'Reg', (250, 265))
31420	23355100	Inherited genetic variations (including single-nucleotide polymorphisms, SNPs) of the TP53 gene have been reported to impair p53 function in vitro and are associated with worse outcomes in specific subgroups of patients with cancer.	('function', 'MPA', (129, 137))	('patients', 'Species', '9606', (211, 219))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('associated', 'Reg', (155, 165))	('cancer', 'Disease', (225, 231))	('genetic variations', 'Disease', (10, 28))	('p53', 'Gene', (125, 128))	('single-nucleotide polymorphisms', 'Var', (40, 71))	('TP53', 'Gene', (86, 90))	('p53', 'Gene', '7157', (125, 128))	('genetic variations', 'Disease', 'MESH:D030342', (10, 28))	('impair', 'NegReg', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))
31422	23355100	Deleterious (disease causing) mutations in TP53 are only found in ~70% of the patients who meet the classic diagnostic criteria for LFS, underscoring the importance of clinical suspicion and astute diagnostic skills when trying to identify affected patients and families.	('patients', 'Species', '9606', (249, 257))	('patients', 'Species', '9606', (78, 86))	('mutations', 'Var', (30, 39))	('LFS', 'Disease', (132, 135))	('TP53', 'Gene', (43, 47))
31425	23355100	During the 3rd International p53 mutant workshop-LFS symposium in 2007, the Chompret criteria were modified to develop a set of Consensus-based criteria to identify TP53 carriers.	('p53', 'Gene', '7157', (29, 32))	('mutant', 'Var', (33, 39))	('TP53', 'Gene', (165, 169))	('p53', 'Gene', (29, 32))
31426	23355100	Breast Cancer < 30 Some, including the NCCN, advocate testing all individuals with breast cancer under age 30 who are negative for BRCA1 and BRCA2 mutations for TP53 mutations.	('mutations', 'Var', (147, 156))	('TP53', 'Gene', (161, 165))	('mutations', 'Var', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('BRCA2', 'Gene', '675', (141, 146))	('Breast Cancer', 'Disease', (0, 13))	('testing', 'Reg', (54, 61))	('BRCA1', 'Gene', '672', (131, 136))	('breast cancer', 'Disease', (83, 96))	('Breast Cancer', 'Disease', 'MESH:D001943', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast Cancer', 'Phenotype', 'HP:0003002', (0, 13))	('BRCA1', 'Gene', (131, 136))	('BRCA2', 'Gene', (141, 146))
31428	23355100	have suggested that a TP53 mutation is actually more likely than a BRCA1 or BRCA2 mutation in women with breast cancer diagnosed under age 30 without contributory family history.	('women', 'Species', '9606', (94, 99))	('BRCA2', 'Gene', (76, 81))	('BRCA2', 'Gene', '675', (76, 81))	('mutation', 'Var', (27, 35))	('BRCA1', 'Gene', '672', (67, 72))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('TP53', 'Gene', (22, 26))	('BRCA1', 'Gene', (67, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
31431	23355100	Based on the published literature, however, it appears that the probability of finding a TP53 mutation is higher in ACC diagnosed <40, especially those diagnosed in childhood.	('child', 'Species', '9606', (165, 170))	('ACC', 'Phenotype', 'HP:0006744', (116, 119))	('TP53', 'Gene', (89, 93))	('mutation', 'Var', (94, 102))
31433	23355100	GI Cancers TP53 mutation analysis should also be considered in cases of early onset gastrointestinal (GI) cancer who meet the classic LFS or LFL criteria if other more common hereditary GI syndromes have been ruled out.	('onset gastrointestinal (GI) cancer', 'Disease', 'MESH:D004067', (78, 112))	('mutation', 'Var', (16, 24))	('TP53', 'Gene', (11, 15))	('GI Cancers', 'Disease', 'MESH:D009369', (0, 10))	('Cancers', 'Phenotype', 'HP:0002664', (3, 10))	('Cancer', 'Phenotype', 'HP:0002664', (3, 9))	('GI Cancers', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
31437	23355100	Using clinical data from a TP53 clinical testing cohort of 525 patients submitted for testing, with 91 mutations identified, prevalence tables summarizing the individual and family characteristics associated with TP53 mutations were created.	('mutations', 'Var', (218, 227))	('patients', 'Species', '9606', (63, 71))	('TP53', 'Gene', (213, 217))
31438	23355100	Gonzalez and colleagues found that the highest germline TP53 mutation frequency rate (100%; n=5) was in patients who had at least one core cancer during childhood (prior to 18 years of age) and a positive family history for cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('child', 'Species', '9606', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mutation', 'Var', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('patients', 'Species', '9606', (104, 112))	('TP53', 'Gene', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', (139, 145))
31440	23355100	One of the most common and challenging clinical testing dilemmas is determining the most appropriate testing strategy for a woman who has tested negative for BRCA1 and BRCA2 mutations, but who has a family history consistent with a hereditary breast cancer syndrome.	('BRCA2', 'Gene', '675', (168, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('hereditary breast cancer syndrome', 'Disease', (232, 265))	('hereditary breast cancer syndrome', 'Disease', 'MESH:D001943', (232, 265))	('BRCA1', 'Gene', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('BRCA2', 'Gene', (168, 173))	('mutations', 'Var', (174, 183))	('woman', 'Species', '9606', (124, 129))	('BRCA1', 'Gene', '672', (158, 163))
31442	23355100	However, in the absence of very early age of breast cancer diagnosis, most families with breast cancer have an exceedingly low probability of carrying a TP53 mutation.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('mutation', 'Var', (158, 166))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('TP53', 'Gene', (153, 157))	('early age of breast', 'Phenotype', 'HP:0010314', (32, 51))
31447	23355100	Decisions regarding germline TP53 testing should be made by healthcare professionals with specialized training in clinical cancer genetics and experience interpreting complex, and potentially novel, variant gene mutations of uncertain clinical significance.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('variant gene mutations', 'Var', (199, 221))
31449	23355100	After identifying a mutation, the proband's parent with any pertinent cancer history or family history should be tested first to establish the lineage of the mutation; otherwise, both parents should be tested.	('pertinent cancer', 'Disease', (60, 76))	('mutation', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('pertinent cancer', 'Disease', 'MESH:D009369', (60, 76))
31457	23355100	Partners of patients with a high probability of carrying a TP53 germline mutation have been reported to have elevated levels of distress and have expressed a desire for psychosocial support services.	('patients', 'Species', '9606', (12, 20))	('psychosocial', 'Disease', (169, 181))	('TP53', 'Gene', (59, 63))	('germline mutation', 'Var', (64, 81))	('levels of distress', 'MPA', (118, 136))	('psychosocial', 'Disease', 'MESH:C535569', (169, 181))
31473	23355100	The thirty-three asymptomatic germline TP53 mutation carriers studied self-selected to be followed with enhanced surveillance (n=18) or routine institutional follow-up care (n=16; one LFS patient was in both groups).	('mutation', 'Var', (44, 52))	('TP53', 'Gene', (39, 43))	('patient', 'Species', '9606', (188, 195))
31480	23355100	For instance, genomic assessment of copy number variation (CNV) can yield a pattern associated with LFS-associated cancers compared to other cancers and may identify early stage disease in asymptomatic germline TP53 mutation carriers.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('men', 'Species', '9606', (28, 31))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('identify', 'Reg', (157, 165))	('associated', 'Reg', (84, 94))	('TP53', 'Gene', (211, 215))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))	('copy number variation', 'Var', (36, 57))
31485	23355100	In addition to limiting the effectiveness of mammography, increased mammographic densities have been associated with elevated breast cancer risk in women with hereditary and sporadic forms of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('increased', 'PosReg', (58, 67))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (192, 205))	('elevated breast cancer', 'Disease', (117, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('elevated breast cancer', 'Disease', 'MESH:D001943', (117, 139))	('mammographic densities', 'Var', (68, 90))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('women', 'Species', '9606', (148, 153))
31489	23355100	In this small series (n=6) of premenopausal women with germline BRCA1 mutations, mammographic density was significantly reduced at 12 months (median absolute decrease, 8.3%; P = 0.043; representing a 29.2% median reduction in mammographic percent density).	('BRCA1', 'Gene', '672', (64, 69))	('men', 'Species', '9606', (33, 36))	('mutations', 'Var', (70, 79))	('mammographic', 'MPA', (81, 93))	('BRCA1', 'Gene', (64, 69))	('men', 'Species', '9606', (46, 49))	('women', 'Species', '9606', (44, 49))	('decrease', 'NegReg', (158, 166))	('reduction', 'NegReg', (213, 222))	('reduced', 'NegReg', (120, 127))
31494	23355100	The proband had another child, a 4-year-old asymptomatic daughter, who was tested and found to carry the same TP53 mutation.	('child', 'Species', '9606', (24, 29))	('mutation', 'Var', (115, 123))	('TP53', 'Gene', (110, 114))
31495	23355100	Given the mutation and her brother's history, she underwent a brain MRI and two tumors were identified: a low grade glioma and a CPC.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('glioma', 'Disease', (116, 122))	('CPC', 'Disease', (129, 132))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mutation', 'Var', (10, 18))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('CPC', 'Phenotype', 'HP:0030392', (129, 132))
31499	23355100	As discussed above, testing for TP53 mutations in children has been quite controversial in the past, but is gaining acceptance due to recent data showing a benefit from screening regimens.	('mutations', 'Var', (37, 46))	('men', 'Species', '9606', (183, 186))	('TP53', 'Gene', (32, 36))	('children', 'Species', '9606', (50, 58))
31505	23355100	In a recent study of 64 choroid plexus tumors from children (with and without LFS), more than 90% of CPCs demonstrated TP53 dysfunction, either due to deleterious TP53 germline mutations (~50%) or due to somatic TP53 sequence variants involving TP53 codon 72 or MDM SNP 309.	('MDM', 'Disease', 'MESH:D007645', (262, 265))	('choroid plexus tumors', 'Disease', (24, 45))	('children', 'Species', '9606', (51, 59))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('choroid plexus tumors', 'Phenotype', 'HP:0002190', (24, 45))	('choroid plexus tumors', 'Disease', 'MESH:D016545', (24, 45))	('CPCs', 'Phenotype', 'HP:0030392', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('germline mutations', 'Var', (168, 186))	('TP53', 'Gene', (163, 167))	('CPC', 'Phenotype', 'HP:0030392', (101, 104))	('MDM', 'Disease', (262, 265))	('TP53', 'Gene', (119, 123))	('TP53', 'Gene', (212, 216))
31511	23355100	There is early evidence that PARP inhibition may be a therapeutic target that can trigger selective cell death in high-grade brain cancers (including choroid plexus carcinomas).	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('inhibition', 'Var', (34, 44))	('choroid plexus carcinomas', 'Disease', 'MESH:D020288', (150, 175))	('brain cancers', 'Disease', 'MESH:D001932', (125, 138))	('PARP', 'Gene', '142', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('brain cancers', 'Disease', (125, 138))	('choroid plexus carcinomas', 'Disease', (150, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (150, 174))	('choroid plexus carcinomas', 'Phenotype', 'HP:0030392', (150, 175))	('PARP', 'Gene', (29, 33))
31512	23355100	TP53 mutation carriers are 100 times more likely to develop leukemia; however, only three percent of LFS patients develop a hematopoietic malignancy.	('hematopoietic malignancy', 'Disease', (124, 148))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (105, 113))	('hematopoietic malignancy', 'Phenotype', 'HP:0004377', (124, 148))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))	('develop', 'PosReg', (52, 59))	('hematopoietic malignancy', 'Disease', 'MESH:D019337', (124, 148))	('leukemia', 'Disease', (60, 68))	('mutation', 'Var', (5, 13))	('leukemia', 'Disease', 'MESH:D007938', (60, 68))
31514	23355100	TP53 alterations were the first biological marker to become incorporated in risk stratification and upfront treatment decisions for chronic lymphocytic leukemia (CLL) patients treated on randomized clinical trials.	('CLL', 'Disease', 'MESH:D015451', (162, 165))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (167, 175))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (132, 160))	('CLL', 'Phenotype', 'HP:0005550', (162, 165))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('CLL', 'Disease', (162, 165))	('alterations', 'Var', (5, 16))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (132, 160))	('men', 'Species', '9606', (113, 116))	('chronic lymphocytic leukemia', 'Disease', (132, 160))
31515	23355100	TP53 inactivation in CLL predicts for an ultra high-risk group of patients with fludarabine-resistant disease and median survival times of less than 12 months.	('CLL', 'Disease', (21, 24))	('TP53', 'Gene', (0, 4))	('CLL', 'Disease', 'MESH:D015451', (21, 24))	('CLL', 'Phenotype', 'HP:0005550', (21, 24))	('inactivation', 'Var', (5, 17))	('fludarabine-resistant disease', 'Disease', (80, 109))	('patients', 'Species', '9606', (66, 74))	('fludarabine', 'Chemical', 'MESH:C024352', (80, 91))
31516	23355100	Therefore, the European Research Initiative on CLL, has recommended that TP53 mutation analysis be performed for all CLL patients and that those with TP53 mutations be considered for allogeneic stem cell transplantation in first remission.	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (155, 164))	('CLL', 'Phenotype', 'HP:0005550', (117, 120))	('CLL', 'Disease', (117, 120))	('TP53', 'Gene', (73, 77))	('CLL', 'Disease', 'MESH:D015451', (47, 50))	('men', 'Species', '9606', (61, 64))	('CLL', 'Phenotype', 'HP:0005550', (47, 50))	('CLL', 'Disease', 'MESH:D015451', (117, 120))	('CLL', 'Disease', (47, 50))	('patients', 'Species', '9606', (121, 129))
31518	23355100	A number of strategies have been explored to target TP53-associated cancers and improve outcomes for patients with somatic and germline TP53 mutations.	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (141, 150))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('TP53-associated', 'Gene', (52, 67))	('TP53', 'Gene', (136, 140))
31520	23355100	Monoclonal antibodies have been shown to improve outcomes in several disease types, including some promising laboratory and early-phase clinical trials showing an apoptotic affect against TP53-associated leukemia.	('leukemia', 'Disease', 'MESH:D007938', (204, 212))	('leukemia', 'Disease', (204, 212))	('leukemia', 'Phenotype', 'HP:0001909', (204, 212))	('Monoclonal antibodies', 'Var', (0, 21))
31526	23355100	Reactivation of wild-type TP53 activity can be a successful strategy and has caused regression of lymphoma and liver cancer in TP53 deficient in vivo model systems.	('lymphoma', 'Disease', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lymphoma', 'Disease', 'MESH:D008223', (98, 106))	('liver cancer', 'Phenotype', 'HP:0002896', (111, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (98, 106))	('Reactivation', 'Var', (0, 12))	('liver cancer', 'Disease', 'MESH:D006528', (111, 123))	('liver cancer', 'Disease', (111, 123))
31527	23355100	These small molecules (currently named PhiKan083, PRIMA-1, CP31398, WR1065, MIRA-1, STIMA-1, RETRA, Nutlin -3, and RITA) reactivate TP53 functional pathways using mechanisms such as raising the melting temperature of the mutant protein to trigger reactivation of function, normalizing the folding conformation of the mutant protein to restore its ability to bind to DNA, or reactivating TP53 wild-type function in TP53-associated cancers.	('TP53', 'Gene', (387, 391))	('cancers', 'Phenotype', 'HP:0002664', (430, 437))	('reactivating', 'NegReg', (374, 386))	('reactivation', 'MPA', (247, 259))	('cancers', 'Disease', (430, 437))	('bind', 'Interaction', (358, 362))	('TP53 functional pathways', 'Pathway', (132, 156))	('cancer', 'Phenotype', 'HP:0002664', (430, 436))	('protein', 'Protein', (324, 331))	('PRIMA-1', 'Gene', '145270', (50, 57))	('DNA', 'Interaction', (366, 369))	('wild-type function', 'MPA', (392, 410))	('mutant', 'Var', (317, 323))	('mutant', 'Var', (221, 227))	('cancers', 'Disease', 'MESH:D009369', (430, 437))	('folding conformation', 'MPA', (289, 309))	('restore', 'PosReg', (335, 342))	('PRIMA-1', 'Gene', (50, 57))	('ability', 'MPA', (347, 354))	('normalizing', 'Var', (273, 284))
31535	23355100	Similarly, studies of TP53 deficient mice have shown prolonged overall survival of more than 5 months when treated with Metformin.	('prolonged', 'PosReg', (53, 62))	('Metformin', 'Chemical', 'MESH:D008687', (120, 129))	('deficient', 'Var', (27, 36))	('TP53', 'Gene', (22, 26))	('mice', 'Species', '10090', (37, 41))
31550	22934112	In particular, the monoclonality analysis indicates that tumor progression is the final result of an intrinsic genetic mutation, whereas polyclonality suggests that tumor cells are affected by local or systemic stimuli.	('mutation', 'Var', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (165, 170))
31551	22934112	Molecular alterations lead to inactivation of the tumor suppressor genes and sequential activation of the oncogenes.	('activation', 'PosReg', (88, 98))	('alterations', 'Var', (10, 21))	('lead', 'Reg', (22, 26))	('oncogenes', 'Gene', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('inactivation', 'NegReg', (30, 42))	('tumor', 'Disease', (50, 55))
31553	22934112	Loss of heterozygosity (LOH) at chromosome region 11p15, associated with a higher risk of tumor recurrence, is more frequent in ACC than in adrenal adenomas.	('ACC', 'Phenotype', 'HP:0006744', (128, 131))	('ACC', 'Disease', (128, 131))	('Loss of heterozygosity', 'Var', (0, 22))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (140, 156))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('adrenal adenomas', 'Disease', 'MESH:D018246', (140, 156))	('adrenal adenomas', 'Disease', (140, 156))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
31554	22934112	The development of ACC may be due to an activation of the Wnt signaling pathway caused by germline mutations of the Adenomatous Polyposis Coli (APC) gene.	('Wnt signaling pathway', 'Pathway', (58, 79))	('Adenomatous Polyposis Coli', 'Phenotype', 'HP:0005227', (116, 142))	('APC', 'Phenotype', 'HP:0005227', (144, 147))	('ACC', 'Phenotype', 'HP:0006744', (19, 22))	('APC', 'Disease', 'MESH:D011125', (144, 147))	('activation', 'PosReg', (40, 50))	('APC', 'Disease', (144, 147))	('mutations', 'Var', (99, 108))	('ACC', 'Disease', (19, 22))	('Adenomatous Polyposis Coli', 'Disease', (116, 142))	('Adenomatous Polyposis Coli', 'Disease', 'MESH:D011125', (116, 142))
31555	22934112	Germline mutations in TP53 are identified in 70% of families with the Li-Fraumeni syndrome.	('Germline mutations', 'Var', (0, 18))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (70, 90))	('identified', 'Reg', (31, 41))	('Li-Fraumeni syndrome', 'Disease', (70, 90))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
31579	22934112	Overexpression of IGF-II and topoisomerase 2A (TOPO 2A) and loss of heterozygosity (LOH) on chromosome 11p15 and 17p13 loci were identified as factors could potentially be used to predict a grade of malignancy.	('malignancy', 'Disease', (199, 209))	('IGF-II', 'Gene', '3481', (18, 24))	('p13', 'Gene', (115, 118))	('IGF-II', 'Gene', (18, 24))	('loss', 'Var', (60, 64))	('malignancy', 'Disease', 'MESH:D009369', (199, 209))	('p13', 'Gene', '440926', (115, 118))
31607	22934112	Mitotane exerts a specific cytotoxic effect on adrenal cortex cells, resulting in focal degeneration of the fasciculata and reticularis areas while the effects on glomerular are relatively scarce.	('degeneration of the fasciculata', 'Disease', (88, 119))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('Mitotane', 'Var', (0, 8))	('degeneration of the fasciculata', 'Disease', 'MESH:D009410', (88, 119))
31617	22934112	Furthermore, mitotane inhibits the production of testicular androgens, acting as an antagonist on the progesterone and androgen receptors and as an agonist of the estrogen receptor.	('mitotane', 'Chemical', 'MESH:D008939', (13, 21))	('androgen receptors', 'Protein', (119, 137))	('progesterone', 'Protein', (102, 114))	('estrogen receptor', 'Gene', (163, 180))	('production', 'MPA', (35, 45))	('inhibits', 'NegReg', (22, 30))	('estrogen receptor', 'Gene', '2099', (163, 180))	('mitotane', 'Var', (13, 21))
31618	22934112	Beside its adrenolytic effects, mitotane inhibits MDR-1/P-glycoprotein, a multidrug resistance protein, thus enhancing the effect of different chemotherapy drugs.	('adrenolytic effects', 'MPA', (11, 30))	('inhibits', 'NegReg', (41, 49))	('P-glycoprotein', 'Gene', (56, 70))	('enhancing', 'PosReg', (109, 118))	('MDR-1', 'Gene', (50, 55))	('drug resistance', 'Phenotype', 'HP:0020174', (79, 94))	('effect', 'MPA', (123, 129))	('MDR-1', 'Gene', '5243', (50, 55))	('mitotane', 'Var', (32, 40))	('mitotane', 'Chemical', 'MESH:D008939', (32, 40))	('P-glycoprotein', 'Gene', '5243', (56, 70))
31645	22934112	In other studies, however, a response rate of approximately 42% of cases has been described; moreover, it has also been demonstrated that radiotherapy reduced the risk of local failure by 4.7 times in a clinical study involving 58 patients.	('reduced', 'NegReg', (151, 158))	('patients', 'Species', '9606', (231, 239))	('local failure', 'Disease', (171, 184))	('local failure', 'Disease', 'MESH:D012594', (171, 184))	('radiotherapy', 'Var', (138, 150))
31647	22934112	reported that the probability of recurrence risk reduction was significantly higher in a group of patients treated with 45-55 Gy for five weeks after surgery, than in patients who did not undergo radiotherapy (79% versus 12%).	('recurrence', 'CPA', (33, 43))	('reduction', 'NegReg', (49, 58))	('45-55 Gy', 'Var', (120, 128))	('patients', 'Species', '9606', (167, 175))	('patients', 'Species', '9606', (98, 106))
31664	22934112	IGF-2 hypersecretion translates in an unchecked cell proliferation, due to the activation of PI3K/Akt/mTOR pathway through IGF-1R.	('IGF-2', 'Gene', '3481', (0, 5))	('Akt', 'Gene', '207', (98, 101))	('IGF-1R', 'Gene', '3480', (123, 129))	('mTOR', 'Gene', (102, 106))	('Akt', 'Gene', (98, 101))	('activation', 'PosReg', (79, 89))	('IGF-1R', 'Gene', (123, 129))	('IGF-2', 'Gene', (0, 5))	('mTOR', 'Gene', '2475', (102, 106))	('hypersecretion', 'Var', (6, 20))
31665	22934112	Preclinical studies on cell and xenograft models demonstrated that NVP-AEW541, a small molecule inhibitor, and IMC-A12, a fully human monoclonal antibody, both targeting IGF-1R, were able to inhibit IGF-2 downstream pathway and to reduce cell proliferation.	('NVP-AEW541', 'Var', (67, 77))	('IGF-1R', 'Gene', '3480', (170, 176))	('reduce', 'NegReg', (231, 237))	('IGF-2', 'Gene', '3481', (199, 204))	('IGF-1R', 'Gene', (170, 176))	('inhibit', 'NegReg', (191, 198))	('human', 'Species', '9606', (128, 133))	('cell proliferation', 'CPA', (238, 256))	('IMC-A12', 'Gene', (111, 118))	('IGF-2', 'Gene', (199, 204))
31681	22934112	Sunitinib has been found to induce a strong adrenal toxicity in animal models, and a partial response to this treatment has been reported in a single patient with metastatic ACC, after failure of mitotane-based chemotherapy creating the necessary conditions for the beginning of a phase II trial with sunitinib as monotherapy for refractory ACCs.	('metastatic', 'Disease', (163, 173))	('patient', 'Species', '9606', (150, 157))	('mitotane', 'Chemical', 'MESH:D008939', (196, 204))	('ACC', 'Phenotype', 'HP:0006744', (341, 344))	('ACCs', 'Gene', '84680', (341, 345))	('ACCs', 'Gene', (341, 345))	('ACC', 'Phenotype', 'HP:0006744', (174, 177))	('Sunitinib', 'Chemical', 'MESH:D000077210', (0, 9))	('adrenal toxicity', 'Disease', 'MESH:D000312', (44, 60))	('Sunitinib', 'Var', (0, 9))	('sunitinib', 'Chemical', 'MESH:D000077210', (301, 310))	('adrenal toxicity', 'Disease', (44, 60))
31716	22934112	Preclinical in vitro studies evaluated the effect of PKF115-584, a small molecule inhibitor of the T-cell factor (Tcf)/beta-catenin complex, on beta-catenin-dependent transcription and proliferation in H295R ACC cells, harbouring mutations in CTNNB1 gene.	('T-cell factor', 'Gene', '3172', (99, 112))	('beta-catenin', 'Gene', (144, 156))	('beta-catenin', 'Gene', '1499', (119, 131))	('proliferation', 'CPA', (185, 198))	('beta-catenin', 'Gene', '1499', (144, 156))	('CTNNB1', 'Gene', (243, 249))	('ACC', 'Phenotype', 'HP:0006744', (208, 211))	('T-cell factor', 'Gene', (99, 112))	('mutations', 'Var', (230, 239))	('beta-catenin', 'Gene', (119, 131))	('CTNNB1', 'Gene', '1499', (243, 249))	('Tcf', 'Gene', '3172', (114, 117))	('H295R', 'CellLine', 'CVCL:0458', (202, 207))	('Tcf', 'Gene', (114, 117))
31717	22934112	Treatment with PKF115-584 inhibited cell proliferation and induced apoptosis in a dose-dependent way in H295R cells, but not in HeLa cells, thus indicating that targeting the Wnt/beta-catenin pathway might be useful in the treatment of adrenocortical tumors.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (236, 257))	('beta-catenin', 'Gene', '1499', (179, 191))	('apoptosis', 'CPA', (67, 76))	('HeLa', 'CellLine', 'CVCL:0030', (128, 132))	('inhibited', 'NegReg', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('adrenocortical tumors', 'Disease', (236, 257))	('induced', 'Reg', (59, 66))	('H295R', 'CellLine', 'CVCL:0458', (104, 109))	('PKF115-584', 'Var', (15, 25))	('beta-catenin', 'Gene', (179, 191))	('cell proliferation', 'CPA', (36, 54))
31718	22934112	CWP232291 is a compound which is able to promote beta-catenin degradation.	('promote', 'PosReg', (41, 48))	('beta-catenin', 'Gene', (49, 61))	('CWP232291', 'Var', (0, 9))	('beta-catenin', 'Gene', '1499', (49, 61))
31719	22934112	It also exhibited potent growth inhibitory activity in several multiple myeloma cell lines and a phase I clinical study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia is currently ongoing (http://www.clinicaltrials.gov/, trial ID NCT01398462).	('growth inhibitory activity', 'MPA', (25, 51))	('myeloma cell lines', 'Disease', 'MESH:D009101', (72, 90))	('myeloid leukemia', 'Disease', (179, 195))	('multiple myeloma', 'Phenotype', 'HP:0006775', (63, 79))	('myeloid leukemia', 'Disease', 'MESH:D007951', (179, 195))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (179, 195))	('patients', 'Species', '9606', (136, 144))	('leukemia', 'Phenotype', 'HP:0001909', (187, 195))	('myeloma cell lines', 'Disease', (72, 90))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (173, 195))	('CWP232291', 'Var', (123, 132))
31724	22934112	It has previously been found that increased SF-1 dosage stimulates proliferation, decreases apoptosis of human adrenocortical cells, and induces ACTs in transgenic mice.	('apoptosis', 'CPA', (92, 101))	('transgenic mice', 'Species', '10090', (153, 168))	('induces', 'Reg', (137, 144))	('adrenocortical', 'Disease', (111, 125))	('SF-1', 'Gene', '7536', (44, 48))	('SF-1', 'Gene', (44, 48))	('dosage', 'Var', (49, 55))	('ACTs', 'MPA', (145, 149))	('adrenocortical', 'Disease', 'MESH:D018268', (111, 125))	('proliferation', 'CPA', (67, 80))	('stimulates', 'PosReg', (56, 66))	('human', 'Species', '9606', (105, 110))	('decreases', 'NegReg', (82, 91))
31725	22934112	In vitro studies performed on H295R cells demonstrated that SF-1 gene silencing strongly affected TGF-beta and Wnt/beta-catenin signalling, suggesting the existence of a crosstalk between these pathways.	('silencing', 'NegReg', (70, 79))	('SF-1', 'Gene', (60, 64))	('beta-catenin', 'Gene', (115, 127))	('affected', 'Reg', (89, 97))	('gene', 'Var', (65, 69))	('H295R', 'CellLine', 'CVCL:0458', (30, 35))	('SF-1', 'Gene', '7536', (60, 64))	('TGF-beta', 'MPA', (98, 106))	('beta-catenin', 'Gene', '1499', (115, 127))	('crosstalk', 'Reg', (170, 179))
31726	22934112	Moreover, SF-1 knockdown induced a significant reduction of proliferation rate in treated cells compared to control cells and a reduction of cells in the S-phase.	('knockdown', 'Var', (15, 24))	('reduction', 'NegReg', (128, 137))	('reduction', 'NegReg', (47, 56))	('proliferation rate', 'CPA', (60, 78))	('SF-1', 'Gene', (10, 14))	('cells in the S-phase', 'CPA', (141, 161))	('SF-1', 'Gene', '7536', (10, 14))
31728	22934112	Two members of the alkyloxyphenol class, AC-45594 and OOP, were shown to inhibit proliferation of H295R and SW-13 cells through a mechanism which did not seem to be selective for SF-1.	('AC-45594', 'Var', (41, 49))	('H295R', 'CellLine', 'CVCL:0458', (98, 103))	('alkyloxyphenol', 'Chemical', '-', (19, 33))	('SF-1', 'Gene', '7536', (179, 183))	('AC-45594', 'Chemical', 'MESH:C527833', (41, 49))	('SF-1', 'Gene', (179, 183))	('SW-13', 'CellLine', 'CVCL:0542', (108, 113))	('proliferation', 'CPA', (81, 94))	('inhibit', 'NegReg', (73, 80))
31729	22934112	On the contrary, members of the IsoQ class, SID7969543 (IsoQ A), and the number 31 and 32 compounds, selectively inhibited cell proliferation in conditions of increased SF-1 expression, strongly suggesting that the IsoQ drugs selectively target the activity of SF-1-related genes, thus representing a potential new class of compounds to be used in ACC treatment.	('SF-1', 'Gene', '7536', (261, 265))	('SF-1', 'Gene', (169, 173))	('expression', 'MPA', (174, 184))	('inhibited', 'NegReg', (113, 122))	('cell proliferation', 'CPA', (123, 141))	('SF-1', 'Gene', '7536', (169, 173))	('ACC', 'Phenotype', 'HP:0006744', (348, 351))	('increased', 'PosReg', (159, 168))	('activity', 'MPA', (249, 257))	('SID7969543', 'Var', (44, 54))	('SF-1', 'Gene', (261, 265))
31761	18587089	The ectopic production of sex steroids and their progenitors by neoplastic adrenocortical tissue causes a syndrome known as adrenal-associated endocrinopathy (AAE) or hyperadrenocorticism.	('hyperadrenocorticism', 'Disease', (167, 187))	('neoplastic adrenocortical tissue', 'Disease', (64, 96))	('endocrinopathy', 'Disease', 'MESH:C567425', (143, 157))	('ectopic', 'Var', (4, 11))	('causes', 'Reg', (97, 103))	('neoplastic adrenocortical tissue', 'Disease', 'MESH:D018268', (64, 96))	('hyperadrenocorticism', 'Disease', 'MESH:D000308', (167, 187))	('endocrinopathy', 'Disease', (143, 157))	('steroids', 'Chemical', 'MESH:D013256', (30, 38))
31886	33875173	For patients with stage 1 or 2 disease (Table 5) with low-grade Ki67 (less than 10%) following an R0 resection, there is no evidence-based data on whether adjuvant mitotane may be beneficial due to a lack of prospective and retrospective studies.	('Ki67', 'Chemical', '-', (64, 68))	('stage 1', 'Disease', (18, 25))	('low-grade Ki67', 'Var', (54, 68))	('mitotane', 'Chemical', 'MESH:D008939', (164, 172))	('patients', 'Species', '9606', (4, 12))	('Ki67', 'Var', (64, 68))
31894	33875173	Although it remains a matter of debate for which patients radiation therapy should be entertained, and low-level evidence suggests a potential benefit for all stages, radiation is more commonly recommended for patients with high-risk features, particularly those with stage 3 disease and R1 or R2 status.	('men', 'Species', '9606', (199, 202))	('patients', 'Species', '9606', (210, 218))	('patients', 'Species', '9606', (49, 57))	('stage 3 disease', 'Disease', (268, 283))	('R2 status', 'Var', (294, 303))
31905	33875173	Lynch syndrome is characterized by germline pathogenic variants in DNA mismatch-repair genes associated with endometrial and colorectal cancer, but also other malignancies.	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('variants', 'Var', (55, 63))	('malignancies', 'Disease', 'MESH:D009369', (159, 171))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('associated', 'Reg', (93, 103))	('DNA mismatch-repair genes', 'Gene', (67, 92))	('endometrial', 'Disease', (109, 120))	('Lynch syndrome', 'Disease', (0, 14))	('malignancies', 'Disease', (159, 171))	('colorectal cancer', 'Disease', (125, 142))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('endometrial', 'Disease', 'MESH:D014591', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
31906	33875173	Roughly 2 to 4% of ACCs arise in patients with Lynch syndrome, and tumors can be screened by immunohistochemistry for DNA mismatch-repair proteins and microsatellite instability.	('Lynch syndrome', 'Disease', 'MESH:D003123', (47, 61))	('microsatellite instability', 'Var', (151, 177))	('patients', 'Species', '9606', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ACCs', 'Gene', (19, 23))	('Lynch syndrome', 'Disease', (47, 61))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('ACCs', 'Gene', '84680', (19, 23))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
31909	33875173	LFS is associated with germline pathogenic variants in TP53 and, predisposing to multiple different cancers, including early onset breast cancer, sarcoma and brain cancer.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('LFS', 'Disease', (0, 3))	('TP53', 'Gene', '7157', (55, 59))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('TP53', 'Gene', (55, 59))	('associated', 'Reg', (7, 17))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('brain cancer', 'Phenotype', 'HP:0030692', (158, 170))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('LFS', 'Disease', 'MESH:D016864', (0, 3))	('sarcoma and brain cancer', 'Disease', 'MESH:D001932', (146, 170))	('breast cancer', 'Disease', (131, 144))	('variants', 'Var', (43, 51))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('cancers', 'Disease', (100, 107))
31911	33875173	The Chompret testing criteria for TP53 (LFS) suggest testing everyone with a diagnosis of ACC, which is justified because a significant proportion of patients carry de novo mutations, and a family history can be negative.	('TP53', 'Gene', (34, 38))	('ACC', 'Disease', (90, 93))	('LFS', 'Disease', 'MESH:D016864', (40, 43))	('mutations', 'Var', (173, 182))	('patients', 'Species', '9606', (150, 158))	('LFS', 'Disease', (40, 43))	('TP53', 'Gene', '7157', (34, 38))
31915	33875173	Currently, there is not enough evidence to support any detailed molecular analysis of the tumor, with the exception of overall mutation load and/or microsatellite instability, both of which can be used to justify immunotherapy.	('microsatellite instability', 'MPA', (148, 174))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mutation load', 'Var', (127, 140))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
31963	33875173	These observational studies demonstrated that adjuvant mitotane therapy was associated with prolonged recurrence-free survival and possibly greater overall survival when compared to no adjuvant therapy amongst patients with locoregional/stage 3 ACC (Table 5).	('greater', 'PosReg', (140, 147))	('recurrence-free survival', 'CPA', (102, 126))	('overall survival', 'CPA', (148, 164))	('mitotane', 'Var', (55, 63))	('adjuvant', 'Var', (46, 54))	('mitotane', 'Chemical', 'MESH:D008939', (55, 63))	('patients', 'Species', '9606', (210, 218))	('prolonged', 'PosReg', (92, 101))
31974	33875173	While side effect of mitotane include common systemic adverse effects such as fatigue and gastrointestinal disturbances, mitotane is also associated with multiple endocrinopathies (adrenal insufficiency, hypothyroidism, hypercholesterolemia, and reproductive dysfunction), which need to be closely monitored and treated.	('hypothyroidism', 'Disease', 'MESH:D007037', (204, 218))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (220, 240))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (220, 240))	('hypothyroidism', 'Phenotype', 'HP:0000821', (204, 218))	('mitotane', 'Gene', (21, 29))	('multiple endocrinopathies', 'Disease', 'MESH:C567425', (154, 179))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (181, 202))	('mitotane', 'Chemical', 'MESH:D008939', (121, 129))	('fatigue', 'Disease', (78, 85))	('hypercholesterolemia', 'Disease', (220, 240))	('fatigue', 'Phenotype', 'HP:0012378', (78, 85))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (181, 202))	('multiple endocrinopathies', 'Disease', (154, 179))	('gastrointestinal disturbances', 'Disease', (90, 119))	('mitotane', 'Chemical', 'MESH:D008939', (21, 29))	('fatigue', 'Disease', 'MESH:D005221', (78, 85))	('gastrointestinal disturbances', 'Disease', 'MESH:D005767', (90, 119))	('adrenal insufficiency', 'Disease', (181, 202))	('hypothyroidism', 'Disease', (204, 218))	('mitotane', 'Var', (121, 129))	('associated', 'Reg', (138, 148))
31979	33875173	Mitotane can cause substantial hypercholesterolemia, bone marrow suppression, and drug-induced rash.	('hypercholesterolemia', 'Disease', (31, 51))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (31, 51))	('Mitotane', 'Var', (0, 8))	('rash', 'Disease', 'MESH:D005076', (95, 99))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (53, 76))	('cause', 'Reg', (13, 18))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('rash', 'Phenotype', 'HP:0000988', (95, 99))	('rash', 'Disease', (95, 99))	('bone marrow suppression', 'Disease', (53, 76))	('bone marrow suppression', 'Disease', 'MESH:D001855', (53, 76))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (31, 51))
31980	33875173	In addition, mitotane is known to cause several complicated endocrinopathies, which are discussed below.	('endocrinopathies', 'Disease', 'MESH:C567425', (60, 76))	('endocrinopathies', 'Disease', (60, 76))	('mitotane', 'Chemical', 'MESH:D008939', (13, 21))	('cause', 'Reg', (34, 39))	('mitotane', 'Var', (13, 21))
31985	33875173	Mitotane can induce an increase in hepatic synthesis of cortisol-binding globulin (as well as other globulins, discussed below), thereby resulting in a greater requirement of glucocorticoid dosing and false reassurance when measuring total serum cortisol levels.	('cortisol', 'Chemical', 'MESH:D006854', (246, 254))	('requirement', 'MPA', (160, 171))	('Mitotane', 'Var', (0, 8))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('glucocorticoid dosing', 'MPA', (175, 196))	('increase', 'PosReg', (23, 31))	('cortisol', 'Chemical', 'MESH:D006854', (56, 64))	('hepatic synthesis', 'MPA', (35, 52))	('men', 'Species', '9606', (167, 170))
31986	33875173	In addition, and more important, mitotane increases activity of CYP3A4, which metabolizes exogenous glucocorticoids, thereby further necessitating a higher glucocorticoid dose (and other hormone replacement, discussed below).	('mitotane', 'Var', (33, 41))	('mitotane', 'Chemical', 'MESH:D008939', (33, 41))	('men', 'Species', '9606', (202, 205))	('increases', 'PosReg', (42, 51))	('glucocorticoid dose', 'MPA', (156, 175))	('activity', 'MPA', (52, 60))	('CYP3A4', 'Gene', '1576', (64, 70))	('higher', 'PosReg', (149, 155))	('CYP3A4', 'Gene', (64, 70))
31996	33875173	Mitotane can induce male hypogonadism and gynecomastia.	('Mitotane', 'Var', (0, 8))	('induce', 'Reg', (13, 19))	('gynecomastia', 'Disease', 'MESH:D006177', (42, 54))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('gynecomastia', 'Disease', (42, 54))	('male hypogonadism', 'Disease', (20, 37))	('gynecomastia', 'Phenotype', 'HP:0000771', (42, 54))	('male hypogonadism', 'Phenotype', 'HP:0000026', (20, 37))	('hypogonadism', 'Phenotype', 'HP:0000135', (25, 37))	('male hypogonadism', 'Disease', 'MESH:D005058', (20, 37))
31998	33875173	Furthermore, mitotane increases sex hormone-binding globulin levels and reduces 5-alpha reductase activity; therefore, replacement therapy with testosterone in men can be challenging.	('men', 'Species', '9606', (126, 129))	('increases sex hormone-binding globulin', 'Phenotype', 'HP:0031419', (22, 60))	('sex hormone-binding globulin', 'Gene', '6462', (32, 60))	('mitotane', 'Chemical', 'MESH:D008939', (13, 21))	('reduces', 'NegReg', (72, 79))	('testosterone', 'Chemical', 'MESH:D013739', (144, 156))	('sex hormone-binding globulin', 'Gene', (32, 60))	('men', 'Species', '9606', (160, 163))	('increases', 'PosReg', (22, 31))	('mitotane', 'Var', (13, 21))	('5-alpha reductase activity', 'MPA', (80, 106))
32091	33875173	Over the past decade, cancer therapy has changed with the introduction small-molecule tyrosine kinase inhibitors.	('small-molecule', 'Var', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (22, 28))
32143	33875173	There are several pharmacologic options to control effects of hypercortisolism, through enzyme inhibitors or direct antagonism on the glucocorticoid receptor.	('antagonism', 'Var', (116, 126))	('glucocorticoid receptor', 'Gene', '2908', (134, 157))	('hypercortisolism', 'Phenotype', 'HP:0003118', (62, 78))	('glucocorticoid receptor', 'Gene', (134, 157))	('hypercortisolism', 'Disease', 'MESH:D003480', (62, 78))	('hypercortisolism', 'Disease', (62, 78))
32165	33875173	Even in patients with high risk for adrenal malignancy (history of extra-adrenal malignancy) referred for adrenal biopsy, 0% of adrenal tumors with HU <10 were malignant or pheochromocytomas.	('adrenal tumor', 'Phenotype', 'HP:0100631', (128, 141))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('adrenal malignancy', 'Disease', (73, 91))	('adrenal malignancy', 'Phenotype', 'HP:0100631', (36, 54))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (173, 189))	('adrenal tumors', 'Disease', (128, 142))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (173, 190))	('adrenal malignancy', 'Disease', 'MESH:D000310', (73, 91))	('adrenal malignancy', 'Disease', (36, 54))	('pheochromocytomas', 'Disease', 'MESH:D010673', (173, 190))	('adrenal malignancy', 'Phenotype', 'HP:0100631', (73, 91))	('adrenal tumors', 'Disease', 'MESH:D000310', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('adrenal malignancy', 'Disease', 'MESH:D000310', (36, 54))	('pheochromocytomas', 'Disease', (173, 190))	('HU <10', 'Var', (148, 154))	('patients', 'Species', '9606', (8, 16))
32205	33875173	It is notable that in one of the studies, patients with OAC treated with mitotane (presumably for higher-stage disease) also had improved survival compared to patients with other ACCs on the same treatment.	('OAC', 'Chemical', '-', (56, 59))	('ACCs', 'Gene', (179, 183))	('survival', 'MPA', (138, 146))	('mitotane', 'Chemical', 'MESH:D008939', (73, 81))	('men', 'Species', '9606', (201, 204))	('mitotane', 'Var', (73, 81))	('OAC', 'Disease', (56, 59))	('patients', 'Species', '9606', (42, 50))	('improved', 'PosReg', (129, 137))	('patients', 'Species', '9606', (159, 167))	('ACCs', 'Gene', '84680', (179, 183))
32210	33810240	Methiothepin Increases Chemotherapy Efficacy against Resistant Melanoma Cells We previously reported that methiothepin, a small molecule known as a nonselective serotonin 5-HT receptor antagonist, inhibited the doxorubicin efflux activity of the Hedgehog receptor Ptch1 and enhanced the cytotoxic, pro-apoptotic, anti-proliferative, and anti-clonogenic effects of doxorubicin on adrenocortical carcinoma cells.	('inhibited', 'NegReg', (197, 206))	('Melanoma', 'Disease', 'MESH:D008545', (63, 71))	('anti-proliferative', 'CPA', (313, 331))	('methiothepin', 'Var', (106, 118))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (379, 403))	('adrenocortical carcinoma', 'Disease', (379, 403))	('anti-clonogenic effects', 'CPA', (337, 360))	('Methiothepin', 'Chemical', 'MESH:D008719', (0, 12))	('Melanoma', 'Disease', (63, 71))	('cytotoxic', 'CPA', (287, 296))	('Ptch1', 'Gene', (264, 269))	('serotonin', 'Chemical', 'MESH:D012701', (161, 170))	('doxorubicin efflux activity', 'MPA', (211, 238))	('Melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('5-HT', 'Chemical', 'MESH:D012701', (171, 175))	('doxorubicin', 'Chemical', 'MESH:D004317', (364, 375))	('carcinoma', 'Phenotype', 'HP:0030731', (394, 403))	('enhanced', 'PosReg', (274, 282))	('pro-apoptotic', 'CPA', (298, 311))	('doxorubicin', 'Chemical', 'MESH:D004317', (211, 222))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (379, 403))	('methiothepin', 'Chemical', 'MESH:D008719', (106, 118))
32212	33810240	Melanoma patients having the BRAFV600E mutation are treated with vemurafenib, an inhibitor of BRAFV600E, often in combination with trametinib, an inhibitor of MEK.	('patients', 'Species', '9606', (9, 17))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('BRAFV600E', 'Var', (94, 103))	('BRAFV600E', 'Mutation', 'rs113488022', (94, 103))	('Melanoma', 'Disease', (0, 8))	('BRAFV600E', 'Var', (29, 38))	('vemurafenib', 'Chemical', 'MESH:D000077484', (65, 76))	('MEK', 'Gene', (159, 162))	('BRAFV600E', 'Mutation', 'rs113488022', (29, 38))	('MEK', 'Gene', '5609', (159, 162))	('trametinib', 'Chemical', 'MESH:C560077', (131, 141))
32219	33810240	Nearly half of patients with metastatic melanomas harbor a valine to glutamine substitution in codon 600 of the serine/threonine kinase BRAF.	('melanomas', 'Disease', (40, 49))	('patients', 'Species', '9606', (15, 23))	('BRAF', 'Gene', '673', (136, 140))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('BRAF', 'Gene', (136, 140))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('serine', 'Chemical', 'MESH:D012694', (112, 118))	('valine to glutamine', 'Var', (59, 78))	('valine to glutamine substitution in codon 600', 'Mutation', 'p.V600Q', (59, 104))
32229	33810240	In this cohort, the Kaplan-Meier analysis for a subset of patients with metastatic disease who did not receive immunotherapy indicated that a high level of Ptch1 in patient samples significantly correlated with a lower overall survival time.	('lower', 'NegReg', (213, 218))	('metastatic disease', 'Disease', 'MESH:C538445', (72, 90))	('patient', 'Species', '9606', (58, 65))	('Ptch1', 'Var', (156, 161))	('patient', 'Species', '9606', (165, 172))	('metastatic disease', 'Disease', (72, 90))	('patients', 'Species', '9606', (58, 66))	('overall survival time', 'CPA', (219, 240))
32236	33810240	Western blots were carried out on extracts from melanoma cell lines sensitive (A375, SKMEL28, MeWo, WM9S) or rendered resistant to chemotherapy (A375RIV, SKMELV3, MeWoR, MW9R) (Figure 1A), from melanoma cells derived from patients sensitive (Patient#1S) or resistant (Patient#1R, Patient#2R) to chemotherapy (Figure 1B), and from melanocytes (Figure 1C).	('melanoma', 'Disease', (48, 56))	('Patient', 'Species', '9606', (268, 275))	('A375', 'CellLine', 'CVCL:0132', (79, 83))	('SKMEL28', 'CellLine', 'CVCL:0526', (85, 92))	('Patient', 'Species', '9606', (242, 249))	('melanoma', 'Disease', (194, 202))	('patients', 'Species', '9606', (222, 230))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('Patient', 'Species', '9606', (280, 287))	('A375RIV', 'Var', (145, 152))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('A375', 'CellLine', 'CVCL:0132', (145, 149))	('WM9S', 'CellLine', 'CVCL:6806', (100, 104))	('SKMELV3', 'CellLine', 'CVCL:L992', (154, 161))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
32243	33810240	The amount of dxr accumulated was drastically reduced after 30 min of incubation with a physiological buffer, and the presence of methiothepin in the buffer allowed the cells to retain a significant amount of dxr.	('dxr', 'Chemical', 'MESH:D004317', (209, 212))	('presence', 'Var', (118, 126))	('amount of dxr accumulated', 'MPA', (4, 29))	('dxr', 'MPA', (209, 212))	('dxr', 'Chemical', 'MESH:D004317', (14, 17))	('reduced', 'NegReg', (46, 53))	('methiothepin', 'Chemical', 'MESH:D008719', (130, 142))
32252	33810240	Two of the binding poses with the lowest predicted binding energy (Figure 3D and E) are close to key amino-acids previously highlighted as interacting with other inhibitors of Ptch1 or cholesterol, and either are responsible of damaging phenotypes when mutated or highly conserved within the Ptch family proteins (L128, L427, L431, I567, D776, W1018, Q1020, V1081).	('L431', 'Var', (326, 330))	('D776', 'Var', (338, 342))	('interacting', 'Interaction', (139, 150))	('Q1020', 'Var', (351, 356))	('L128', 'Var', (314, 318))	('L427', 'Var', (320, 324))	('W1018', 'Var', (344, 349))	('V1081', 'Var', (358, 363))	('cholesterol', 'Chemical', 'MESH:D002784', (185, 196))	('L431', 'CellLine', 'CVCL:0037', (326, 330))	('I567', 'Var', (332, 336))
32257	33810240	Remarkably, our results show that WM9R cells, known to be resistant to vemurafenib, are also resistant to dxr, and that methiothepin also increases drx cytotoxicity in these resistant cells.	('increases', 'PosReg', (138, 147))	('dxr', 'Chemical', 'MESH:D004317', (106, 109))	('cytotoxicity', 'Disease', 'MESH:D064420', (152, 164))	('resistant', 'MPA', (93, 102))	('WM9R', 'Chemical', '-', (34, 38))	('methiothepin', 'Var', (120, 132))	('vemurafenib', 'Chemical', 'MESH:D000077484', (71, 82))	('methiothepin', 'Chemical', 'MESH:D008719', (120, 132))	('cytotoxicity', 'Disease', (152, 164))
32263	33810240	Our results clearly show that methiothepin significantly increased the cytotoxic, anti-proliferative, pro-apoptotic, and anti-clonogenic effects of dxr against melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('methiothepin', 'Var', (30, 42))	('anti-proliferative', 'CPA', (82, 100))	('anti-clonogenic effects', 'CPA', (121, 144))	('dxr', 'Chemical', 'MESH:D004317', (148, 151))	('increased', 'PosReg', (57, 66))	('methiothepin', 'Chemical', 'MESH:D008719', (30, 42))	('cytotoxic', 'CPA', (71, 80))	('pro-apoptotic', 'CPA', (102, 115))
32267	33810240	Vemurafenib is a targeted chemotherapy which interrupts the BRAF/MEK step in the BRAF/MEK/ERK pathway when BRAF has the V600E mutation.	('BRAF', 'Gene', (107, 111))	('ERK', 'Gene', (90, 93))	('MEK', 'Gene', (86, 89))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('MEK', 'Gene', (65, 68))	('BRAF', 'Gene', '673', (81, 85))	('MEK', 'Gene', '5609', (65, 68))	('V600E', 'Mutation', 'rs113488022', (120, 125))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('MEK', 'Gene', '5609', (86, 89))	('BRAF', 'Gene', (81, 85))	('interrupts', 'NegReg', (45, 55))	('V600E', 'Var', (120, 125))	('ERK', 'Gene', '5594', (90, 93))	('BRAF', 'Gene', '673', (107, 111))
32271	33810240	We also observed that methiothepin increased the cytotoxicity of the inhibitor of MEK kinase trametinib (Figure 7B), and of the combined treatment vemurafenib/trametinib, which is currently used on patients with BRAFV600E melanoma (Figure 7C).	('increased', 'PosReg', (35, 44))	('vemurafenib', 'Chemical', 'MESH:D000077484', (147, 158))	('BRAFV600E', 'Mutation', 'rs113488022', (212, 221))	('MEK', 'Gene', '5609', (82, 85))	('patients', 'Species', '9606', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('cytotoxicity', 'Disease', (49, 61))	('melanoma', 'Disease', (222, 230))	('trametinib', 'Chemical', 'MESH:C560077', (93, 103))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('trametinib', 'Chemical', 'MESH:C560077', (159, 169))	('BRAFV600E', 'Var', (212, 221))	('methiothepin', 'Chemical', 'MESH:D008719', (22, 34))	('cytotoxicity', 'Disease', 'MESH:D064420', (49, 61))	('MEK', 'Gene', (82, 85))
32273	33810240	Indeed, 48 h after performing a wound on a mat of melanoma cells, the closing area was significantly larger when methiothepin was added to vemurafenib indicating that the presence of methiothepin delays or inhibits the closure of the wound and therefore the migration of cells (Figure 8).	('methiothepin', 'Var', (183, 195))	('delays', 'NegReg', (196, 202))	('methiothepin', 'Chemical', 'MESH:D008719', (183, 195))	('closing', 'MPA', (70, 77))	('inhibits', 'NegReg', (206, 214))	('migration of cells', 'CPA', (258, 276))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('larger', 'PosReg', (101, 107))	('melanoma', 'Disease', (50, 58))	('methiothepin', 'Chemical', 'MESH:D008719', (113, 125))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('vemurafenib', 'Chemical', 'MESH:D000077484', (139, 150))	('presence', 'Var', (171, 179))	('closure of the wound', 'CPA', (219, 239))
32279	33810240	Accordingly, we observed that Ptch1 is endogenously expressed in various melanoma cell lines carrying or not a BRAF mutation.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('mutation', 'Var', (116, 124))	('Ptch1', 'Gene', (30, 35))	('BRAF', 'Gene', (111, 115))	('BRAF', 'Gene', '673', (111, 115))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
32280	33810240	We previously found that decreased Ptch1 expression in MeWo and A375 melanoma cells using silencing RNA against Ptch1 strongly inhibited the efflux of doxorubicin, indicating that Ptch1 is involved in doxorubicin efflux in melanoma cells carrying or not the BRAF mutation.	('melanoma', 'Disease', (223, 231))	('A375', 'CellLine', 'CVCL:0132', (64, 68))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('silencing', 'Var', (90, 99))	('decreased', 'NegReg', (25, 34))	('Ptch1', 'Gene', (112, 117))	('inhibited', 'NegReg', (127, 136))	('doxorubicin', 'Chemical', 'MESH:D004317', (151, 162))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('BRAF', 'Gene', '673', (258, 262))	('efflux of doxorubicin', 'MPA', (141, 162))	('Ptch1', 'Gene', (35, 40))	('BRAF', 'Gene', (258, 262))	('doxorubicin', 'Chemical', 'MESH:D004317', (201, 212))	('melanoma', 'Disease', (69, 77))
32286	33810240	Indeed, our results demonstrate that the binding of methiothepin to Ptch1 increases the cytotoxicity of five different chemotherapeutic drugs (doxorubicin, cisplatin, oxaliplatin, vemurafenib and trametinib) against various melanoma cell lines carrying or not a BRAF mutation.	('cytotoxicity', 'Disease', (88, 100))	('mutation', 'Var', (267, 275))	('methiothepin', 'Chemical', 'MESH:D008719', (52, 64))	('binding', 'Interaction', (41, 48))	('doxorubicin', 'Chemical', 'MESH:D004317', (143, 154))	('BRAF', 'Gene', '673', (262, 266))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('trametinib', 'Chemical', 'MESH:C560077', (196, 206))	('cytotoxicity', 'Disease', 'MESH:D064420', (88, 100))	('Ptch1', 'Gene', (68, 73))	('increases', 'PosReg', (74, 83))	('vemurafenib', 'Chemical', 'MESH:D000077484', (180, 191))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (167, 178))	('BRAF', 'Gene', (262, 266))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('melanoma', 'Disease', (224, 232))
32289	33810240	Moreover, these effects were obtained at a concentration of chemotherapeutic drugs or methiothepin that did not affect by itself, suggesting that the use of methiothepin could allow to decrease the concentration of chemotherapeutic agents, and, therefore, of side effects for patients.	('concentration of chemotherapeutic agents', 'MPA', (198, 238))	('patients', 'Species', '9606', (276, 284))	('methiothepin', 'Chemical', 'MESH:D008719', (86, 98))	('decrease', 'NegReg', (185, 193))	('methiothepin', 'Var', (157, 169))	('methiothepin', 'Chemical', 'MESH:D008719', (157, 169))
32296	33810240	Actually, we observed that the amount of doxorubicin in the tumors of mice treated with the combination of methiothepin and doxorubicin was significantly higher (three times) than in tumors from mice treated with doxorubicin alone, which was not the case in the heart of animals.	('methiothepin', 'Var', (107, 119))	('methiothepin', 'Chemical', 'MESH:D008719', (107, 119))	('mice', 'Species', '10090', (195, 199))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('higher', 'PosReg', (154, 160))	('doxorubicin', 'Chemical', 'MESH:D004317', (213, 224))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('doxorubicin', 'Chemical', 'MESH:D004317', (41, 52))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('doxorubicin', 'Chemical', 'MESH:D004317', (124, 135))	('tumors', 'Disease', (183, 189))	('tumors', 'Disease', (60, 66))
32297	33810240	From these results, for melanoma treatment, we can expect that methiothepin will increase chemotherapy concentration and efficacy only in melanoma cells and not in healthy tissues preventing the increase of side effects such as those observed in clinical trials with inhibitors of ABC transporters.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('chemotherapy concentration', 'MPA', (90, 116))	('methiothepin', 'Var', (63, 75))	('methiothepin', 'Chemical', 'MESH:D008719', (63, 75))	('increase', 'PosReg', (81, 89))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('efficacy', 'MPA', (121, 129))	('melanoma', 'Disease', (24, 32))
32317	33810240	Finally, the best poses were analyzed by assessing the distance with the key amino acids L128, L427, L431, I567, D776, W1018, Q1020, V1081.	('Q1020', 'Var', (126, 131))	('L427', 'Var', (95, 99))	('L128', 'Var', (89, 93))	('I567', 'Var', (107, 111))	('W1018', 'Var', (119, 124))	('L431', 'CellLine', 'CVCL:0037', (101, 105))	('D776', 'Var', (113, 117))	('L431', 'Var', (101, 105))	('V1081', 'Var', (133, 138))
32322	33810240	Titration of methiothepin results in a gradual change in MST signal, which is plotted against the methiothepin concentration to yield a dose-response curve, which has been fitted to derive the methiothepin binding constant (Kd).	('change', 'Reg', (47, 53))	('Titration', 'Var', (0, 9))	('methiothepin', 'Chemical', 'MESH:D008719', (193, 205))	('methiothepin', 'Chemical', 'MESH:D008719', (13, 25))	('methiothepin', 'Chemical', 'MESH:D008719', (98, 110))	('MST signal', 'MPA', (57, 67))
32338	33810240	The present study provides one more proof of concept that the use of inhibitors of Ptch1 drug efflux activity as adjuvant to classical or targeted chemotherapy could be a novel way to circumvent drug resistance, recurrence and metastasis of tumors expressing Ptch1 with very limited side effects for patients.	('Ptch1', 'Gene', (259, 264))	('drug resistance', 'Phenotype', 'HP:0020174', (195, 210))	('circumvent', 'NegReg', (184, 194))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('recurrence', 'CPA', (212, 222))	('metastasis of tumors', 'Disease', 'MESH:D009362', (227, 247))	('drug resistance', 'MPA', (195, 210))	('inhibitors', 'Var', (69, 79))	('metastasis of tumors', 'Disease', (227, 247))	('Ptch1', 'Gene', (83, 88))	('patients', 'Species', '9606', (300, 308))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
32351	33138000	Finally, stratifying patients in high and low pre-surgery CTC number groups, assuming the 75th percentile CTC value as cut-off, CTCs significantly predicted patients' overall survival (log rank = 0.005), also in a multivariate analysis adjusted for age and tumor stage.	('tumor', 'Disease', (257, 262))	('predicted', 'Reg', (147, 156))	('patients', 'Species', '9606', (157, 165))	('patients', 'Species', '9606', (21, 29))	('overall survival', 'MPA', (167, 183))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('CTCs', 'Var', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))
32407	33138000	The presence of CTMs and CAMLs has been described to be associated with malignancy and poor prognosis in breast cancer and other solid tumors.	('solid tumors', 'Disease', (129, 141))	('malignancy', 'Disease', 'MESH:D009369', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('CTMs', 'Var', (16, 20))	('solid tumors', 'Disease', 'MESH:D009369', (129, 141))	('malignancy', 'Disease', (72, 82))	('associated', 'Reg', (56, 66))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('CTMs', 'Chemical', 'MESH:C083633', (16, 20))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
32480	33228607	The Weiss score is comprised of nine histological criteria: (i) high nuclear grade, (ii) mitotic rate greater than five per 50 high power fields (HPF), (iii) atypical mitotic figures, (iv) eosinophilic tumor cell cytoplasm (greater than 75% of tumor cells), (v) diffuse architecture (greater than 33% of the tumor), (vi) necrosis, (vii) venous invasion, (viii) sinusoidal invasion, and (ix) capsular invasion.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('sinusoidal invasion', 'CPA', (361, 380))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (244, 249))	('venous invasion', 'CPA', (337, 352))	('eosinophilic tumor', 'Disease', 'MESH:D004802', (189, 207))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('eosinophilic tumor', 'Disease', (189, 207))	('mitotic rate', 'CPA', (89, 101))	('capsular invasion', 'CPA', (391, 408))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('necrosis', 'Disease', (321, 329))	('atypical', 'Var', (158, 166))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', (308, 313))	('necrosis', 'Disease', 'MESH:D009336', (321, 329))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
32564	32183347	Additionally, FATE1 silencing increased sensitivity of the NCI-H1155 non-small lung cancer cell line to paclitaxel and reduced viability of a variety of other cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('lung cancer', 'Disease', (79, 90))	('FATE1', 'Gene', '89885', (14, 19))	('increased', 'PosReg', (30, 39))	('cancer', 'Disease', (159, 165))	('FATE1', 'Gene', (14, 19))	('viability', 'CPA', (127, 136))	('non-small lung cancer', 'Phenotype', 'HP:0030358', (69, 90))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('reduced', 'NegReg', (119, 126))	('silencing', 'Var', (20, 29))	('sensitivity', 'MPA', (40, 51))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('cancer', 'Disease', (84, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('small lung', 'Phenotype', 'HP:0002089', (73, 83))
32570	32183347	Our study aimed to investigate the prevalence of circulating antibodies present in patients with both benign and malignant adrenocortical tumors (ACT) using three different methods (immunofluorescence (IF), ELISA and Western blot (WB)) and to identify transcripts significantly associated with low and high FATE1 expression in ACC.	('ACC', 'Phenotype', 'HP:0006744', (327, 330))	('FATE1', 'Gene', '89885', (307, 312))	('FATE1', 'Gene', (307, 312))	('malignant adrenocortical tumors', 'Disease', 'MESH:D009369', (113, 144))	('malignant adrenocortical tumors', 'Disease', (113, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('expression', 'MPA', (313, 323))	('patients', 'Species', '9606', (83, 91))	('high', 'Var', (302, 306))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
32572	32183347	Using immunohistochemistry (IHC), we investigated FATE1 expression in a series of 27 children ACT (all positive for the TP53 R337H mutation).	('R337H', 'Var', (125, 130))	('children', 'Species', '9606', (85, 93))	('FATE1', 'Gene', '89885', (50, 55))	('FATE1', 'Gene', (50, 55))	('R337H', 'SUBSTITUTION', 'None', (125, 130))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
32576	32183347	Furthermore, FATE1 mRNA expression levels were significantly higher in a different cohort of 28 pediatric ACC cases (eight with WT TP53, 10 bearing the R337H and 10 other TP53 mutations; Table 1) than in age-matched normal adrenal glands (Figure 1C).	('TP53', 'Gene', (171, 175))	('higher', 'PosReg', (61, 67))	('R337H', 'Var', (152, 157))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('FATE1', 'Gene', '89885', (13, 18))	('ACC', 'Phenotype', 'HP:0006744', (106, 109))	('ACC', 'Disease', (106, 109))	('R337H', 'SUBSTITUTION', 'None', (152, 157))	('TP53', 'Gene', '7157', (171, 175))	('FATE1', 'Gene', (13, 18))
32578	32183347	We also measured the prevalence of circulating anti-FATE1 autoantibodies in a cohort of 12 children with ACT (all positive for TP53 R337H).	('FATE1', 'Gene', (52, 57))	('children', 'Species', '9606', (91, 99))	('FATE1', 'Gene', '89885', (52, 57))	('R337H', 'Var', (132, 137))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('R337H', 'SUBSTITUTION', 'None', (132, 137))
32589	32183347	High FATE1 expression was significantly correlated to excess steroid hormone secretion and MKI67 mRNA expression (Table 2).	('excess', 'Disease', 'MESH:D015835', (54, 60))	('steroid hormone secretion', 'MPA', (61, 86))	('MKI67', 'Gene', (91, 96))	('High', 'Var', (0, 4))	('MKI67', 'Gene', '4288', (91, 96))	('FATE1', 'Gene', '89885', (5, 10))	('expression', 'MPA', (11, 21))	('mRNA expression', 'MPA', (97, 112))	('FATE1', 'Gene', (5, 10))	('excess', 'Disease', (54, 60))	('steroid hormone', 'Chemical', 'MESH:D013256', (61, 76))
32610	32183347	Mutations in the beta-catenin and TP53 pathways, which are frequently found in ACC, may also contribute to the impairment of anti-tumor immune response.	('contribute', 'Reg', (93, 103))	('beta-catenin', 'Gene', '1499', (17, 29))	('TP53', 'Gene', (34, 38))	('impairment', 'NegReg', (111, 121))	('ACC', 'Phenotype', 'HP:0006744', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('TP53', 'Gene', '7157', (34, 38))	('beta-catenin', 'Gene', (17, 29))
32633	32183347	The H295R/TR N-Flag FATE1 stable cell line was established and cultured as described and can express N-terminally flagged FATE1 in a doxycycline-inducible manner.	('H295R/T', 'Mutation', 'p.H295R,T', (4, 11))	('TR N', 'Gene', '3842', (10, 14))	('FATE1', 'Gene', '89885', (122, 127))	('TR N', 'Gene', (10, 14))	('FATE1', 'Gene', '89885', (20, 25))	('N-terminally flagged', 'Var', (101, 121))	('doxycycline', 'Chemical', 'MESH:D004318', (133, 144))	('FATE1', 'Gene', (122, 127))	('FATE1', 'Gene', (20, 25))
32672	32183347	High FATE1 expression is negatively correlated to DFS and OS in adult patients with ACC and associated with increased steroidogenic and decreased immune response gene expression.	('DFS', 'Disease', (50, 53))	('patients', 'Species', '9606', (70, 78))	('negatively', 'NegReg', (25, 35))	('High', 'Var', (0, 4))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('FATE1', 'Gene', '89885', (5, 10))	('steroidogenic', 'MPA', (118, 131))	('increased', 'PosReg', (108, 117))	('expression', 'MPA', (11, 21))	('ACC', 'Disease', (84, 87))	('FATE1', 'Gene', (5, 10))	('steroid', 'Chemical', 'MESH:D013256', (118, 125))	('immune response gene expression', 'MPA', (146, 177))	('decreased immune response', 'Phenotype', 'HP:0002721', (136, 161))	('decreased', 'NegReg', (136, 145))
32769	31665449	Although mitotane appeared to blunt the magnitude of the increases in ACC-specific steroid biomarkers in recurred patients, it also suppressed the random sample-to-sample variability, which can be diagnostically helpful.	('ACC-specific steroid biomarkers', 'MPA', (70, 101))	('ACC', 'Phenotype', 'HP:0006744', (70, 73))	('blunt', 'NegReg', (30, 35))	('steroid', 'Chemical', 'MESH:D013256', (83, 90))	('random sample-to-sample variability', 'MPA', (147, 182))	('mitotane', 'Var', (9, 17))	('increases', 'PosReg', (57, 66))	('patients', 'Species', '9606', (114, 122))	('mitotane', 'Chemical', 'MESH:D008939', (9, 17))	('suppressed', 'NegReg', (132, 142))
32781	31665449	We also did not systematically compare the results of routine biochemical analysis of serum steroids to the 24-hour urine analysis by GC-MS; however, we previously demonstrated that routine serum biochemistry only identified abnormalities in 73% of ACC patients (n = 47), while urine steroid metabolomics by GC-MS found abnormalities in 95%.	('steroid', 'Chemical', 'MESH:D013256', (92, 99))	('steroids', 'Chemical', 'MESH:D013256', (92, 100))	('GC-MS found abnormalities', 'Disease', 'MESH:D009103', (308, 333))	('GC-MS found abnormalities', 'Disease', (308, 333))	('ACC', 'Phenotype', 'HP:0006744', (249, 252))	('patients', 'Species', '9606', (253, 261))	('abnormalities', 'Var', (225, 238))	('ACC', 'Disease', (249, 252))	('steroid', 'Chemical', 'MESH:D013256', (284, 291))
32797	31998569	Almost 50% of ACT cases are associated with syndromes, and the two main syndromes that were reported included the Li-Fraumeni syndrome that resulted from alterations of the tumor suppressor gene p53 in chromosome 17 and the Beckwith-Weidman syndrome that resulted from the effect of the region located in chromosome 11p15 .	('p53', 'Gene', (195, 198))	('p53', 'Gene', '7157', (195, 198))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (114, 134))	('Beckwith-Weidman syndrome', 'Disease', 'MESH:D001506', (224, 249))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('Li-Fraumeni syndrome', 'Disease', (114, 134))	('tumor', 'Disease', (173, 178))	('alterations', 'Var', (154, 165))	('Beckwith-Weidman syndrome', 'Disease', (224, 249))	('resulted from', 'Reg', (140, 153))
32810	31998569	There are several causes of pseudo-precocious puberty, including adrenal tumors, non-classical congenital adrenal hyperplasia, testicular tumors, germ cell tumors, McCune-Albright syndrome, familial male-limited precocious puberty (testotoxicosis), or exogenous sex steroid hormone usage.	('McCune-Albright syndrome', 'Disease', 'MESH:D005359', (164, 188))	('precocious puberty', 'Phenotype', 'HP:0000826', (35, 53))	('testicular tumors', 'Disease', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('McCune-Albright syndrome', 'Disease', (164, 188))	('tumors', 'Disease', (73, 79))	('exogenous sex', 'Var', (252, 265))	('adrenal tumors', 'Disease', (65, 79))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (95, 125))	('congenital adrenal hyperplasia', 'Disease', (95, 125))	('testotoxicosis', 'Disease', 'MESH:C536961', (232, 246))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('testicular tumors', 'Disease', 'MESH:D013736', (127, 144))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('testotoxicosis', 'Disease', (232, 246))	('adrenal tumor', 'Phenotype', 'HP:0100631', (65, 78))	('testicular tumors', 'Phenotype', 'HP:0010788', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (95, 125))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (106, 125))	('male-limited precocious puberty', 'Phenotype', 'HP:0008185', (199, 230))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('precocious puberty', 'Phenotype', 'HP:0000826', (212, 230))	('tumors', 'Disease', (156, 162))	('steroid', 'Chemical', 'MESH:D013256', (266, 273))	('familial male-limited precocious puberty', 'Disease', (190, 230))	('pseudo-precocious puberty', 'Disease', (28, 53))	('germ cell tumors', 'Phenotype', 'HP:0100728', (146, 162))	('adrenal tumors', 'Disease', 'MESH:D000310', (65, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
32825	31196171	Aberrant methylation-mediated downregulation of lncRNA SSTR5-AS1 promotes progression and metastasis of laryngeal squamous cell carcinoma Laryngeal squamous cell carcinoma (LSCC) is among the most common malignant tumors with poor prognosis.	('progression', 'CPA', (74, 85))	('malignant tumors', 'Disease', 'MESH:D018198', (204, 220))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('metastasis of laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 137))	('Aberrant methylation-mediated', 'Var', (0, 29))	('Laryngeal squamous cell carcinoma', 'Disease', (138, 171))	('malignant tumors', 'Disease', (204, 220))	('metastasis of laryngeal squamous cell carcinoma', 'Disease', (90, 137))	('downregulation', 'NegReg', (30, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinoma Laryngeal squamous cell carcinoma', 'Phenotype', 'HP:0012118', (128, 171))	('SSTR5-AS1', 'Gene', (55, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('promotes', 'PosReg', (65, 73))	('methylation-mediated', 'Var', (9, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('Laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 171))	('SSTR5-AS1', 'Gene', '146336;6755;5729', (55, 64))
32854	31196171	There are two transcripts of SSTR5, and the main transcript (NM_001053) is located at chr16: 1078781-1081454 (GRCh38/hg38).	('SSTR5', 'Gene', '6755', (29, 34))	('SSTR5', 'Gene', (29, 34))	('hg38', 'Gene', (117, 121))	('hg38', 'Gene', '8549', (117, 121))	('NM_001053', 'Var', (61, 70))
32873	31196171	3b, c, the expression levels of SSTR5 and SSTR5-AS1 were significantly increased in the 5-Aza-dC-, TSA-, 5-Aza-dC/TSA-treated laryngeal carcinoma cells, and the effect was more apparent in the 5-Aza-dC/TSA-treated cells, indicating that the expression of SSTR5 and SSTR5-AS1 might be co-regulated by DNA methylation and histone modification.	('SSTR5', 'Gene', (255, 260))	('SSTR5', 'Gene', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('SSTR5', 'Gene', '6755', (255, 260))	('5-Aza-dC-', 'Var', (88, 97))	('TSA', 'Chemical', 'MESH:C012589', (99, 102))	('SSTR5', 'Gene', '6755', (32, 37))	('TSA', 'Chemical', 'MESH:C012589', (202, 205))	('laryngeal carcinoma', 'Disease', (126, 145))	('5-Aza-dC/TSA-treated', 'Var', (105, 125))	('TSA', 'Chemical', 'MESH:C012589', (114, 117))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (193, 201))	('TSA-', 'Var', (99, 103))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (105, 113))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (126, 145))	('SSTR5', 'Gene', (42, 47))	('SSTR5', 'Gene', (265, 270))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (88, 96))	('expression levels', 'MPA', (11, 28))	('SSTR5', 'Gene', '6755', (42, 47))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (126, 145))	('increased', 'PosReg', (71, 80))	('SSTR5', 'Gene', '6755', (265, 270))
32875	31196171	3d, frequent CpG sites methylation was observed in the exon 1 region of SSTR5, while frequent methylated CpG sites were located in the promoter region of SSTR5-AS1 (Fig.	('methylation', 'Var', (23, 34))	('SSTR5', 'Gene', '6755', (154, 159))	('SSTR5', 'Gene', (154, 159))	('SSTR5', 'Gene', '6755', (72, 77))	('SSTR5', 'Gene', (72, 77))
32882	31196171	The methylation status of promoter region of SSTR5 in LSCC tissues was not associated with any clinicopathologic characteristics, while the methylation status of exon 1 in LSCC tissues was associated with TNM stage and lymph node metastasis (P < 0.05) (Table 1).	('methylation', 'Var', (140, 151))	('TNM stage', 'CPA', (205, 214))	('associated', 'Reg', (189, 199))	('SSTR5', 'Gene', '6755', (45, 50))	('lymph node metastasis', 'CPA', (219, 240))	('SSTR5', 'Gene', (45, 50))
32883	31196171	The mRNA expression level of SSTR5 in LSCC tissues with hypermethylation of exon 1 was significantly decreased than that with unmethylation of this region (P < 0.05); however, the expression level of SSTR5 was not associated with methylation status of promoter region (P > 0.05) (Fig.	('SSTR5', 'Gene', (200, 205))	('mRNA expression level', 'MPA', (4, 25))	('SSTR5', 'Gene', '6755', (29, 34))	('SSTR5', 'Gene', (29, 34))	('hypermethylation', 'Var', (56, 72))	('decreased', 'NegReg', (101, 110))	('SSTR5', 'Gene', '6755', (200, 205))
32885	31196171	To determine the potential role of histone modifications on SSTR5 downregulation, the presence of active (H3K4me3, H3K9ac) and inactive (H3K9me2) histone modifications at SSTR5 promoter was further examined by chromatin immunoprecipitation assay in AMC-HN-8 cells (Fig.	('SSTR5', 'Gene', '6755', (171, 176))	('SSTR5', 'Gene', '6755', (60, 65))	('H3K4me3', 'Var', (106, 113))	('SSTR5', 'Gene', (171, 176))	('SSTR5', 'Gene', (60, 65))	('H3K9ac', 'Var', (115, 121))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (249, 257))
32887	31196171	Increased enrichment of H3K4me3 and decreased enrichment of H3K9me2 were detected in 5-Aza-dC-treated AMC-HN-8 cells, and significant increased enrichment of H3K9ac was detected in TSA-treated AMC-HN-8 cells, indicating that in addition to DNA methylation, histone modification is also involved in the regulation of SSTR5 expression.	('SSTR5', 'Gene', (316, 321))	('TSA', 'Chemical', 'MESH:C012589', (181, 184))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (102, 110))	('5-Aza-dC-treated', 'Var', (85, 101))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (85, 93))	('H3K4me3', 'Var', (24, 31))	('involved', 'Reg', (286, 294))	('enrichment', 'MPA', (10, 20))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (193, 201))	('enrichment', 'MPA', (46, 56))	('SSTR5', 'Gene', '6755', (316, 321))	('decreased', 'NegReg', (36, 45))
32915	31196171	Promoter CpG sites hypermethylation of E-cadherin is a recognized mechanism of its inactivation in numerous cancers.	('numerous cancers', 'Disease', 'MESH:D009369', (99, 115))	('inactivation', 'NegReg', (83, 95))	('E-cadherin', 'Gene', '999', (39, 49))	('E-cadherin', 'Gene', (39, 49))	('numerous cancers', 'Disease', (99, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('hypermethylation', 'Var', (19, 35))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))
32919	31196171	The hMeDIP-qPCR assay was used to track the 5hmC change in the CpG-rich regions of E-cadherin promoters, and co-expression of SSTR5-AS1 and TET1 in AMC-HN-8 cells significantly increased 5hmC levels at the promoter regions of E-cadherin (Fig.	('E-cadherin', 'Gene', (83, 93))	('E-cadherin', 'Gene', '999', (83, 93))	('TET1', 'Gene', '80312', (140, 144))	('SSTR5-AS1', 'Var', (126, 135))	('5hmC', 'Chemical', '-', (187, 191))	('increased', 'PosReg', (177, 186))	('5hmC levels', 'MPA', (187, 198))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (148, 156))	('E-cadherin', 'Gene', (226, 236))	('5hmC', 'Chemical', '-', (44, 48))	('E-cadherin', 'Gene', '999', (226, 236))	('TET1', 'Gene', (140, 144))
32931	31196171	AChE-AS represses AChE expression via epigenetic modification of the AChE promoter region and demonstrates an anti-apoptotic effect in hepatocellular carcinoma cells.	('AChE', 'Gene', '43', (0, 4))	('AChE', 'Gene', (18, 22))	('AChE', 'Gene', '43', (18, 22))	('AChE', 'Gene', '43', (69, 73))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (135, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('hepatocellular carcinoma', 'Disease', (135, 159))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (135, 159))	('epigenetic', 'Var', (38, 48))	('AChE', 'Gene', (0, 4))	('anti-apoptotic', 'CPA', (110, 124))	('AChE', 'Gene', (69, 73))
32933	31196171	Moreover, by genomic sequence analysis, obvious CpG islands were found in the promoter and exon 1 regions of SSTR5 and SSTR5-AS1, indicating the possible epigenetic regulation mechanisms on their expression regulation.	('SSTR5', 'Gene', '6755', (109, 114))	('SSTR5', 'Gene', '6755', (119, 124))	('SSTR5', 'Gene', (109, 114))	('CpG islands', 'Var', (48, 59))	('SSTR5', 'Gene', (119, 124))
32937	31196171	In the present study, we verified the tumor suppressor role of SSTR5 and SSTR5-AS1 in LSCC progression; DNA hypermethylation and histone modification may co-regulate the expression of SSTR5 and SSTR5-AS1.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('SSTR5', 'Gene', '6755', (184, 189))	('SSTR5', 'Gene', '6755', (73, 78))	('SSTR5', 'Gene', (184, 189))	('SSTR5', 'Gene', (73, 78))	('SSTR5', 'Gene', '6755', (194, 199))	('SSTR5', 'Gene', (194, 199))	('SSTR5', 'Gene', '6755', (63, 68))	('co-regulate', 'Reg', (154, 165))	('DNA hypermethylation', 'Var', (104, 124))	('histone modification', 'Var', (129, 149))	('LSCC', 'Disease', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('SSTR5', 'Gene', (63, 68))	('expression', 'MPA', (170, 180))
32950	31196171	In the process of laryngeal squamous cell carcinogenesis, when CpG sites hypermethylation occurs in the promoter region of E-cadherin, SSTR5-AS1 may also act as a tumor suppressor gene to upregulate the expression of E-cadherin by recruiting TET1 to E-cadherin to hydrolyze 5'-mc to 5'-hmc, thus inhibiting the occurrence of EMT.	('hypermethylation', 'Var', (73, 89))	('laryngeal squamous cell carcinogenesis', 'Disease', 'MESH:D063646', (18, 56))	('TET1', 'Gene', (242, 246))	('tumor', 'Disease', (163, 168))	('laryngeal squamous cell carcinogenesis', 'Disease', (18, 56))	("hydrolyze 5'-mc to 5'-hmc", 'MPA', (264, 289))	('SSTR5-AS1', 'Gene', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('E-cadherin', 'Gene', (250, 260))	('E-cadherin', 'Gene', '999', (250, 260))	('E-cadherin', 'Gene', (123, 133))	('E-cadherin', 'Gene', '999', (123, 133))	('inhibiting', 'NegReg', (296, 306))	('upregulate', 'PosReg', (188, 198))	('E-cadherin', 'Gene', (217, 227))	('E-cadherin', 'Gene', '999', (217, 227))	("5'-mc", 'Chemical', 'MESH:D044503', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TET1', 'Gene', '80312', (242, 246))	('recruiting', 'PosReg', (231, 241))	('expression', 'MPA', (203, 213))	("5'-hmc", 'Chemical', 'MESH:C011865', (283, 289))
32951	31196171	SSTR5 may act as a tumor suppressor gene in LSCC, and aberrant DNA hypermethylation of the CpG sites clustered in the exon 1 and histone modification on its promoter region may be epigenetic mechanisms for its inactivation.	('LSCC', 'Disease', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('CpG', 'Gene', (91, 94))	('SSTR5', 'Gene', '6755', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('SSTR5', 'Gene', (0, 5))	('histone modification', 'Var', (129, 149))	('aberrant', 'Var', (54, 62))
32952	31196171	SSTR5-AS1 may play anti-tumor role in LSCC and may be regulated by hypermethylation of the same CpG sites with SSTR5.	('SSTR5', 'Gene', '6755', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('SSTR5', 'Gene', (111, 116))	('tumor', 'Disease', (24, 29))	('LSCC', 'Disease', (38, 42))	('SSTR5', 'Gene', '6755', (0, 5))	('hypermethylation', 'Var', (67, 83))	('SSTR5', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
32989	31196171	Antibodies against H3K4me3, H3K9ac, H3K9me2, MLL3, and TET1 (Upstate, Millipore, MA, USA) were used for immunoprecipitation.	('H3K9me2', 'Var', (36, 43))	('TET1', 'Gene', (55, 59))	('H3K4me3', 'Var', (19, 26))	('H3K9ac', 'Var', (28, 34))	('MLL3', 'Gene', (45, 49))	('TET1', 'Gene', '80312', (55, 59))	('MLL3', 'Gene', '58508', (45, 49))
33147	26843863	Downregulation of VDR gene expression may result from epigenetics events, that is, methylation of cytosine nucleotide of CpG islands in VDR gene promoter.	('Downregulation', 'NegReg', (0, 14))	('expression', 'MPA', (27, 37))	('VDR', 'Gene', (136, 139))	('methylation', 'Var', (83, 94))	('VDR gene', 'Gene', (18, 26))	('cytosine nucleotide', 'Chemical', 'MESH:D003597', (98, 117))
33151	26843863	Methylation in the promoter region of VDR gene was found in 3/8 ACCs, while no VDR gene methylation was observed in normal adrenals and adrenocortical adenomas.	('ACCs', 'Disease', (64, 68))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (136, 159))	('adrenocortical adenomas', 'Disease', (136, 159))	('Methylation', 'Var', (0, 11))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (136, 159))	('ACC', 'Phenotype', 'HP:0006744', (64, 67))	('VDR gene', 'Gene', (38, 46))	('ACCs', 'Phenotype', 'HP:0006744', (64, 68))	('found', 'Reg', (51, 56))
33153	26843863	The association between VDR gene promoter methylation and reduced VDR gene expression is not a rare event in ACC, suggesting that VDR epigenetic inactivation may have a role in adrenocortical carcinogenesis.	('epigenetic inactivation', 'Var', (134, 157))	('adrenocortical carcinogenesis', 'Disease', (177, 206))	('role', 'Reg', (169, 173))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('VDR', 'Gene', (130, 133))	('VDR gene', 'Gene', (66, 74))	('VDR', 'Gene', (24, 27))	('reduced', 'NegReg', (58, 65))	('expression', 'MPA', (75, 85))	('adrenocortical carcinogenesis', 'Disease', 'MESH:D063646', (177, 206))
33190	26843863	Methylation in the VDR promoter was observed in 3/8 ACCs specimens, which included two cortisol-producing and 1 nonfunctioning carcinoma patients (C3, C4, and C6 patients in Table 1).	('VDR promoter', 'Gene', (19, 31))	('observed', 'Reg', (36, 44))	('carcinoma', 'Disease', (127, 136))	('patients', 'Species', '9606', (162, 170))	('ACC', 'Phenotype', 'HP:0006744', (52, 55))	('ACCs', 'Phenotype', 'HP:0006744', (52, 56))	('Methylation', 'Var', (0, 11))	('patients', 'Species', '9606', (137, 145))	('cortisol', 'Chemical', 'MESH:D006854', (87, 95))	('carcinoma', 'Disease', 'MESH:D002277', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
33195	26843863	A somatic VDR gene mutation could occur, reflecting a mechanism (i.e., loss of tumor-suppressor function) implicated in the malignant transformation of adrenocortical cells.	('tumor-suppressor', 'Gene', (79, 95))	('mutation', 'Var', (19, 27))	('tumor-suppressor', 'Gene', '7248', (79, 95))	('VDR gene', 'Gene', (10, 18))	('adrenocortical', 'Disease', (152, 166))	('loss', 'NegReg', (71, 75))	('adrenocortical', 'Disease', 'MESH:D018268', (152, 166))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
33197	26843863	Epigenetic inactivation of human VDR, reducing its mRNA and protein expression, has been shown in various cancer types, supporting the loss of an antiproliferative role of VDR, and may potentially occur in ACCs.	('ACCs', 'Phenotype', 'HP:0006744', (206, 210))	('loss', 'NegReg', (135, 139))	('antiproliferative', 'CPA', (146, 163))	('reducing', 'NegReg', (38, 46))	('human', 'Species', '9606', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('VDR', 'Gene', (33, 36))	('cancer', 'Disease', (106, 112))	('ACC', 'Phenotype', 'HP:0006744', (206, 209))	('Epigenetic inactivation', 'Var', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
33198	26843863	Disruption of promoter activity by DNA methylation is an epigenetic inactivating mechanism frequently observed in tumor-suppressor genes.	('Disruption', 'NegReg', (0, 10))	('tumor-suppressor', 'Gene', (114, 130))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor-suppressor', 'Gene', '7248', (114, 130))	('promoter activity', 'MPA', (14, 31))	('DNA methylation', 'Var', (35, 50))
33205	26843863	There is also evidence that a number of short noncoding RNAs may repress VDR posttranscriptional regulation in cancer, and their specific role as VDR regulators in adrenocortical tumors is possible.	('repress', 'NegReg', (65, 72))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (164, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('short noncoding RNAs', 'Var', (40, 60))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('VDR posttranscriptional regulation', 'MPA', (73, 107))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('adrenocortical tumors', 'Disease', (164, 185))
33207	26843863	This suggests a potential role of VDR epigenetic inactivation in malignant adrenocortical tumorigenesis.	('adrenocortical tumor', 'Disease', 'MESH:D018268', (75, 95))	('epigenetic inactivation', 'Var', (38, 61))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('adrenocortical tumor', 'Disease', (75, 95))	('malignant adrenocortical', 'Disease', 'MESH:D018268', (65, 89))	('VDR', 'Gene', (34, 37))	('malignant adrenocortical', 'Disease', (65, 89))
33334	23390454	Other features indicating a malignant adrenal tumour (adrenal carcinoma) in our patient (according to Weineke's definition of malignancy) included large atypical cells, pleomorphism, atypical nuclei, prominent nucleoli, moderate oeosinophilic cytoplasm arranged in a lobular and solid pattern, and finally capsular and vascular invasion (Figure 3).	('adrenal carcinoma', 'Phenotype', 'HP:0006744', (54, 71))	('adrenal carcinoma', 'Disease', 'MESH:D000310', (54, 71))	('malignancy', 'Disease', (126, 136))	('adrenal carcinoma', 'Disease', (54, 71))	('malignant adrenal tumour', 'Disease', (28, 52))	('atypical nuclei', 'CPA', (183, 198))	('malignancy', 'Disease', 'MESH:D009369', (126, 136))	('malignant adrenal tumour', 'Disease', 'MESH:D000310', (28, 52))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('patient', 'Species', '9606', (80, 87))	('pleomorphism', 'Var', (169, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
33338	23390454	Mutation in the p53 gene is estimated to occur in 80%-90% of all paediatric ACTs.	('p53', 'Gene', (16, 19))	('Mutation', 'Var', (0, 8))	('occur', 'Reg', (41, 46))	('p53', 'Gene', '7157', (16, 19))	('paediatric ACTs', 'Disease', (65, 80))
33339	23390454	Mutation of TP53 R337H, a distinct germline of p53, s described in Brazilian patients with ACT.	('R337H', 'Mutation', 'rs121912664', (17, 22))	('TP53', 'Gene', (12, 16))	('R337H', 'Var', (17, 22))	('TP53', 'Gene', '7157', (12, 16))	('patients', 'Species', '9606', (77, 85))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
33377	23087853	In many patients with pheochromocytoma, especially in those with extra-adrenal pheochromocytoma, adrenal pheochromocytoma larger than 5 cm, or mutations of genes encoding mainly subunits B and D of the mitochondrial enzyme succinate dehydrogenase [SDHB and SDHD], the possibility of metastatic disease or multiple tumors should be considered.	('SDHB', 'Gene', (248, 252))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (97, 121))	('pheochromocytoma', 'Disease', (22, 38))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (71, 95))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (22, 38))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (97, 121))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (71, 95))	('adrenal pheochromocytoma', 'Disease', (97, 121))	('pheochromocytoma', 'Disease', 'MESH:D010673', (105, 121))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('multiple tumors', 'Disease', 'MESH:D009369', (305, 320))	('mutations', 'Var', (143, 152))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (79, 95))	('pheochromocytoma', 'Disease', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('extra-adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (65, 95))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (105, 121))	('SDHD', 'Gene', '6392', (257, 261))	('SDHB', 'Gene', '6390', (248, 252))	('patients', 'Species', '9606', (8, 16))	('extra-adrenal pheochromocytoma', 'Disease', (65, 95))	('pheochromocytoma', 'Disease', 'MESH:D010673', (79, 95))	('pheochromocytoma', 'Disease', 'MESH:D010673', (22, 38))	('SDHD', 'Gene', (257, 261))	('extra-adrenal pheochromocytoma', 'Phenotype', 'HP:0006737', (65, 95))	('pheochromocytoma', 'Disease', (79, 95))	('multiple tumors', 'Disease', (305, 320))
33385	23087853	Scintigraphy imaging with I-123 MIBG, compared with I-131 MIBG, is advantageous because of its optimal delta-emissions and lack of ss-particles that result in a lower absorbed dose.	('delta-emissions', 'MPA', (103, 118))	('absorbed dose', 'MPA', (167, 180))	('MIBG', 'Var', (32, 36))	('I-131 MIBG', 'Chemical', 'MESH:D019797', (52, 62))	('I-123 MIBG', 'Var', (26, 36))	('I-123 MIBG', 'Chemical', '-', (26, 36))
33386	23087853	Importantly, the normal adrenal medullary may show physiological uptake of both I-131and I-123 MIBG.	('I-123 MIBG', 'Chemical', '-', (89, 99))	('I-131and', 'Var', (80, 88))	('I-123', 'Var', (89, 94))	('I-131and', 'Chemical', '-', (80, 88))
33390	23087853	SPECT with I-123MIBG improves the identification of lesions in case of lesions with limited uptake or those with central necrosis.	('I-123MIBG', 'Chemical', '-', (11, 20))	('necrosis', 'Disease', (121, 129))	('improves', 'PosReg', (21, 29))	('necrosis', 'Disease', 'MESH:D009336', (121, 129))	('I-123MIBG', 'Var', (11, 20))
33473	23087853	I123/I131-MIBG with or without SPECT-CT is routinely employed for imaging pheochromocytomas.	('MIBG', 'Chemical', 'MESH:D019797', (10, 14))	('I123/I131-MIBG', 'Var', (0, 14))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (74, 91))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (74, 90))	('pheochromocytomas', 'Disease', (74, 91))	('pheochromocytomas', 'Disease', 'MESH:D010673', (74, 91))
33522	32871646	Endocrinologic tests suggested ACTH-independent CS due to adrenocortical tumor with the following findings: elevated 24-hour urinary free cortisol (UFC), 1529.2 mug/day (normal, 58.0-403.0 mug/day); elevated midnight serum cortisol level, 26.4 mug/dL (normal, <2.0 mug/dL); and unsuppressed serum cortisol level after low-dose dexamethasone suppression test (DST), 30.9 mug/dL (normal, <5.0 mug/dL).	('adrenocortical tumor', 'Disease', (58, 78))	('ACTH', 'Gene', '5443', (31, 35))	('midnight serum cortisol level', 'MPA', (208, 237))	('cortisol', 'Chemical', 'MESH:D006854', (297, 305))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('CS', 'Phenotype', 'HP:0003118', (48, 50))	('dexamethasone', 'Chemical', 'MESH:D003907', (327, 340))	('cortisol', 'Chemical', 'MESH:D006854', (223, 231))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (58, 78))	('1529.2 mug/day', 'Var', (154, 168))	('CS', 'Gene', '1431', (48, 50))	('elevated', 'PosReg', (199, 207))	('cortisol', 'Chemical', 'MESH:D006854', (138, 146))	('elevated', 'PosReg', (108, 116))	('unsuppressed serum cortisol', 'Phenotype', 'HP:0008163', (278, 305))	('ACTH', 'Gene', (31, 35))
33606	32283844	It has been observed that trabectedin interferes with FUS-CHOP and EWS-CHOP fusion proteins, inhibiting their ability to induce the transcription of different oncogenes Furthermore, in vitro studies demonstrate that trabectedin downregulates the Wnt/beta-catenin pathway in cell cultures of biliary tract adenocarcinoma.	('downregulates', 'NegReg', (228, 241))	('trabectedin', 'Var', (216, 227))	('inhibiting', 'NegReg', (93, 103))	('CHOP', 'Gene', (58, 62))	('CHOP', 'Gene', '1649', (71, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('EWS', 'Gene', '2130', (67, 70))	('trabectedin', 'Chemical', 'MESH:D000077606', (26, 37))	('trabectedin', 'Chemical', 'MESH:D000077606', (216, 227))	('oncogenes', 'Gene', (159, 168))	('induce', 'MPA', (121, 127))	('adenocarcinoma', 'Disease', (305, 319))	('CHOP', 'Gene', (71, 75))	('beta-catenin', 'Gene', (250, 262))	('transcription', 'MPA', (132, 145))	('ability', 'MPA', (110, 117))	('beta-catenin', 'Gene', '1499', (250, 262))	('EWS', 'Gene', (67, 70))	('CHOP', 'Gene', '1649', (58, 62))	('adenocarcinoma', 'Disease', 'MESH:D000230', (305, 319))
33610	32283844	Exposure of NCI-H295R cells to increasing concentrations of trabectedin (0.0625-0.750 nM) for four days led to a concentration-dependent reduction of cell viability.	('0.0625-0.750 nM', 'Var', (73, 88))	('reduction', 'NegReg', (137, 146))	('trabectedin', 'Chemical', 'MESH:D000077606', (60, 71))	('cell viability', 'CPA', (150, 164))	('NCI-H295R', 'CellLine', 'CVCL:0458', (12, 21))
33626	32283844	When cells were exposed to the IC50 trabectedin for three days and then transferred in drug-free medium, the cytotoxic insult elicited by trabectedin induced cell death.	('trabectedin', 'Chemical', 'MESH:D000077606', (138, 149))	('IC50', 'Var', (31, 35))	('trabectedin', 'Chemical', 'MESH:D000077606', (36, 47))	('trabectedin', 'Var', (138, 149))	('cytotoxic', 'CPA', (109, 118))	('death', 'Disease', 'MESH:D003643', (163, 168))	('death', 'Disease', (163, 168))
33634	32283844	Based on these findings, we investigated whether trabectedin could influence beta-catenin expression and function in NCI-H29R cells.	('influence', 'Reg', (67, 76))	('trabectedin', 'Chemical', 'MESH:D000077606', (49, 60))	('H29R', 'SUBSTITUTION', 'None', (121, 125))	('H29R', 'Var', (121, 125))	('expression', 'MPA', (90, 100))	('beta-catenin', 'Gene', (77, 89))	('function', 'MPA', (105, 113))	('beta-catenin', 'Gene', '1499', (77, 89))
33648	32283844	These data suggest that the damage induced by trabectedin was not repaired upon withdrawal, and this is consistent with the trabectedin capability to inhibit the transcription-dependent nucleotide excision repair pathways, leading to p53-independent apoptosis.	('p53', 'Gene', (234, 237))	('p53', 'Gene', '7157', (234, 237))	('inhibit', 'NegReg', (150, 157))	('trabectedin', 'Chemical', 'MESH:D000077606', (124, 135))	('trabectedin', 'Var', (124, 135))	('trabectedin', 'Chemical', 'MESH:D000077606', (46, 57))	('leading to', 'Reg', (223, 233))
33730	32079166	Dysregulation of miRNA expression is considered to be an early step of tumor formation.	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
33738	32079166	Germline and somatic mutations in the TP53 (tumor protein p53) gene, activation of Wnt/ss-catenin pathway through somatic CTNNB1 (catenin beta 1) mutations, overexpression of IGF-2 (insulin-like growth factor 2) and SF1 (steroidogenic factor-1) genes, and mutations in mismatch repair genes are all related to ACC formation.	('IGF-2', 'Gene', (175, 180))	('IGF-2', 'Gene', '3481', (175, 180))	('TP53', 'Gene', (38, 42))	('overexpression', 'PosReg', (157, 171))	('mutations', 'Var', (256, 265))	('steroidogenic factor-1', 'Gene', '2516', (221, 243))	('related', 'Reg', (299, 306))	('steroidogenic factor-1', 'Gene', (221, 243))	('SF1', 'Gene', (216, 219))	('tumor', 'Disease', (44, 49))	('CTNNB1', 'Gene', (122, 128))	('insulin-like growth factor 2', 'Gene', (182, 210))	('SF1', 'Gene', '2516', (216, 219))	('catenin beta 1', 'Gene', '1499', (130, 144))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Wnt/ss-catenin pathway', 'Pathway', (83, 105))	('TP53', 'Gene', '7157', (38, 42))	('ACC', 'Phenotype', 'HP:0006744', (310, 313))	('ACC', 'Disease', 'MESH:D000306', (310, 313))	('ACC', 'Disease', (310, 313))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutations', 'Var', (21, 30))	('p53', 'Gene', '7157', (58, 61))	('mutations', 'Var', (146, 155))	('insulin-like growth factor 2', 'Gene', '3481', (182, 210))	('CTNNB1', 'Gene', '1499', (122, 128))	('p53', 'Gene', (58, 61))	('catenin beta 1', 'Gene', (130, 144))	('activation', 'PosReg', (69, 79))
33775	32079166	Overexpression of miR-205 could induce apoptosis, block proliferation in cell culture (SW-13 adrenocortical cancer cell line) and also inhibit in vivo tumor growth, suggesting a tumor suppressor role for this miRNA.	('apoptosis', 'CPA', (39, 48))	('miR', 'Gene', '220972', (209, 212))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (93, 114))	('proliferation', 'CPA', (56, 69))	('SW-13', 'CellLine', 'CVCL:0542', (87, 92))	('Overexpression', 'Var', (0, 14))	('miR-205', 'Gene', (18, 25))	('tumor', 'Disease', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('inhibit', 'NegReg', (135, 142))	('miR', 'Gene', (209, 212))	('miR', 'Gene', '220972', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('induce', 'PosReg', (32, 38))	('adrenocortical cancer', 'Disease', (93, 114))	('miR', 'Gene', (18, 21))	('block', 'NegReg', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('miR-205', 'Gene', '406988', (18, 25))	('tumor', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
33828	32079166	All studies confirmed the significant overexpression of miR-483-5p in ACC versus ACA.	('ACA', 'Phenotype', 'HP:0008256', (81, 84))	('ACC', 'Phenotype', 'HP:0006744', (70, 73))	('ACC', 'Disease', 'MESH:D000306', (70, 73))	('ACC', 'Disease', (70, 73))	('miR-483-5p', 'Chemical', '-', (56, 66))	('ACA', 'Disease', (81, 84))	('miR-483-5p', 'Var', (56, 66))	('overexpression', 'PosReg', (38, 52))	('ACA', 'Disease', 'MESH:D018246', (81, 84))
33831	32079166	Furthermore, they found a correlation between the expression of miR-483-5p and the aggressiveness of ACC.	('miR-483-5p', 'Var', (64, 74))	('aggressiveness', 'Disease', 'MESH:D001523', (83, 97))	('ACC', 'Phenotype', 'HP:0006744', (101, 104))	('ACC', 'Disease', 'MESH:D000306', (101, 104))	('ACC', 'Disease', (101, 104))	('correlation', 'Reg', (26, 37))	('aggressiveness', 'Disease', (83, 97))	('aggressiveness', 'Phenotype', 'HP:0000718', (83, 97))	('miR-483-5p', 'Chemical', '-', (64, 74))
33832	32079166	They detected miR-483-5p only in the serum of patients with aggressive ACC.	('patients', 'Species', '9606', (46, 54))	('ACC', 'Phenotype', 'HP:0006744', (71, 74))	('miR-483-5p', 'Chemical', '-', (14, 24))	('miR-483-5p', 'Var', (14, 24))	('ACC', 'Disease', (71, 74))	('ACC', 'Disease', 'MESH:D000306', (71, 74))	('detected', 'Reg', (5, 13))
33833	32079166	Shorter overall and shorter recurrence-free survival were associated with increased miR-483-5p and decreased miR-195 expression in the circulation.	('miR-195', 'Gene', '406971', (109, 116))	('decreased', 'NegReg', (99, 108))	('expression', 'MPA', (117, 127))	('shorter', 'NegReg', (20, 27))	('miR-483-5p', 'Chemical', '-', (84, 94))	('increased', 'PosReg', (74, 83))	('miR-195', 'Gene', (109, 116))	('miR-483-5p', 'Var', (84, 94))	('recurrence-free survival', 'CPA', (28, 52))	('Shorter', 'NegReg', (0, 7))
33837	32079166	Moreover, a correlation between the level of miR-483-5p and the number of circulating tumor cells was also revealed.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('miR-483-5p', 'Chemical', '-', (45, 55))	('tumor', 'Disease', (86, 91))	('miR-483-5p', 'Var', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
33844	32079166	The diagnostic accuracy of EV-associated miR-483-5p was higher than in previous studies on unfractionated plasma or serum (87.5 % and 94.4 %, respectively, area under curve: 0,965).	('higher', 'PosReg', (56, 62))	('miR-483-5p', 'Var', (41, 51))	('miR-483-5p', 'Chemical', '-', (41, 51))	('EV-associated', 'Disease', (27, 40))
33845	32079166	(Table 4) Therefore, EV-associated miR-483-5p appears to be a promising minimally invasive biomarker of ACC.	('ACC', 'Disease', (104, 107))	('miR-483-5p', 'Chemical', '-', (35, 45))	('miR-483-5p', 'Var', (35, 45))	('ACC', 'Phenotype', 'HP:0006744', (104, 107))	('ACC', 'Disease', 'MESH:D000306', (104, 107))
33876	32079166	The most down-regulated potential target gene of miR-483-5p was the N-myc downstream-regulated gene 2 (NDRG2), whereas the most downregulated target gene for miR-139-5p was NDRG4.	('miR-139', 'Gene', (158, 165))	('NDRG2', 'Gene', (103, 108))	('N-myc downstream-regulated gene 2', 'Gene', '57447', (68, 101))	('miR-483-5p', 'Chemical', '-', (49, 59))	('miR-483-5p', 'Var', (49, 59))	('NDRG4', 'Gene', '65009', (173, 178))	('miR-139', 'Gene', '406931', (158, 165))	('5p', 'Chemical', '-', (57, 59))	('5p', 'Chemical', '-', (166, 168))	('N-myc downstream-regulated gene 2', 'Gene', (68, 101))	('down-regulated', 'NegReg', (9, 23))	('NDRG2', 'Gene', '57447', (103, 108))	('NDRG4', 'Gene', (173, 178))
33880	32079166	The inhibition of miR-483-5p and miR-139-5p and the restoration of the two genes suppressed the invasive potential of ACC cell lines in vitro.	('suppressed', 'NegReg', (81, 91))	('ACC', 'Phenotype', 'HP:0006744', (118, 121))	('miR-139', 'Gene', '406931', (33, 40))	('ACC', 'Disease', 'MESH:D000306', (118, 121))	('ACC', 'Disease', (118, 121))	('miR-483-5p', 'Chemical', '-', (18, 28))	('5p', 'Chemical', '-', (26, 28))	('miR-483-5p', 'Var', (18, 28))	('inhibition', 'NegReg', (4, 14))	('miR-139', 'Gene', (33, 40))	('5p', 'Chemical', '-', (41, 43))
33884	32079166	It was demonstrated that the overexpression of miR-497 and the silencing of MALAT1 down-regulates eIF4E, and thus suppress cellular proliferation and induces cell cycle arrest.	('cell cycle arrest', 'CPA', (158, 175))	('overexpression', 'PosReg', (29, 43))	('MALAT1', 'Gene', '378938', (76, 82))	('miR-497', 'Gene', (47, 54))	('suppress', 'NegReg', (114, 122))	('miR-497', 'Gene', '574456', (47, 54))	('eIF4E', 'Gene', '1977', (98, 103))	('MALAT1', 'Gene', (76, 82))	('eIF4E', 'Gene', (98, 103))	('down-regulates', 'NegReg', (83, 97))	('cellular proliferation', 'CPA', (123, 145))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (158, 175))	('induces', 'Reg', (150, 157))	('silencing', 'Var', (63, 72))
33900	32079166	Both miRNAs and lncRNAs are able to function as tumor suppressors or oncogenes, and their aberrant expression can lead to tumorigenesis.	('miR', 'Gene', '220972', (5, 8))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('miR', 'Gene', (5, 8))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('aberrant expression', 'Var', (90, 109))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (122, 127))	('lead to', 'Reg', (114, 121))
33904	32079166	This manuscript was written and formatted by A.D., P.P., P.I.T.	('P.I.T', 'Disease', (57, 62))	('P.P.', 'Var', (51, 55))	('P.I.T', 'Disease', 'MESH:C537241', (57, 62))
33970	29855779	When comparing medical agents, a relatively high percentage of patients using mitotane showed normalization of cortisol (81.8%), whereas treatment with cabergoline and pasireotide less often normalized cortisol secretion (35.7 and 41.1%).	('normalization', 'MPA', (94, 107))	('mitotane', 'Var', (78, 86))	('mitotane', 'Chemical', 'MESH:D008939', (78, 86))	('cortisol', 'MPA', (111, 119))	('cortisol secretion', 'MPA', (202, 220))	('cortisol', 'Chemical', 'MESH:D006854', (202, 210))	('cabergoline', 'Chemical', 'MESH:D000077465', (152, 163))	('patients', 'Species', '9606', (63, 71))	('cortisol', 'Chemical', 'MESH:D006854', (111, 119))
34058	29468134	In the First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) in 2012 of 304 patients, there was no significance difference in the overall survival between EDP-M vs M-S (14.8 mo and 12.0 mo, respectively, P = 0.07), but the response rates (23.2% vs 9.2%, P < 0.001) and progression-free survival (5.0 mo vs 2.1 mo, P < 0.001) were significantly better with EDP-M.	('EDP-M', 'Chemical', '-', (219, 224))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (79, 103))	('progression-free survival', 'CPA', (333, 358))	('EDP-M', 'Var', (420, 425))	('better', 'PosReg', (408, 414))	('EDP-M', 'Chemical', '-', (420, 425))	('Metastatic Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (68, 103))	('M-S', 'Chemical', '-', (228, 231))	('Metastatic Adrenocortical Carcinoma', 'Disease', (68, 103))	('patients', 'Species', '9606', (140, 148))	('Carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('response rates', 'CPA', (287, 301))
34109	29029450	In a multivariate Cox analysis (HR 16.2, 95%CI[1.39-188.6, P<0.026]), miR483-5p was the only variable that significantly predicted recurrence, but not overall survival.	('Cox', 'Gene', '1351', (18, 21))	('predicted', 'Reg', (121, 130))	('Cox', 'Gene', (18, 21))	('miR483-5p', 'Var', (70, 79))	('recurrence', 'CPA', (131, 141))
34110	29029450	In addition, miR483 and miR483-5p levels correlated with the number of circulating tumor cells (CTCs) detected in the same blood samples, independently of the timing of sampling.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR483', 'MPA', (13, 19))	('tumor', 'Disease', (83, 88))	('miR483-5p', 'Var', (24, 33))	('correlated', 'Reg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
34111	29029450	In conclusion, we demonstrated that miR483-5p absolute plasma levels in ACC patients are powerful molecular markers that may help in the follow-up of patients after surgery and chemotherapy, and contribute to more accurately classify and predict tumor progression.	('ACC', 'Phenotype', 'HP:0006744', (72, 75))	('miR483-5p', 'Var', (36, 45))	('patients', 'Species', '9606', (76, 84))	('ACC', 'Disease', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('patients', 'Species', '9606', (150, 158))	('tumor', 'Disease', (246, 251))	('help', 'Reg', (125, 129))
34120	29029450	In particular, the two mature sequences of miR483, miR483-5p and miR483-3p, mapping in the second intron of the insulin-like growth factor 2 (IGF2) gene, have proved to be overexpressed both in the primary tumor and the bloodstream, with a diagnostic and prognostic value.	('miR483', 'Var', (43, 49))	('overexpressed', 'PosReg', (172, 185))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('IGF2', 'Gene', (142, 146))	('tumor', 'Disease', (206, 211))	('miR483-5p', 'Var', (51, 60))	('miR483-3p', 'Var', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
34122	29029450	We measured miR483 and miR483-5p absolute plasma levels of a cohort of 27 ACC patients before and after surgery, uncovering correlations with disease stage and predictive values particularly for the -5p variant.	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('patients', 'Species', '9606', (78, 86))	('ACC', 'Disease', (74, 77))	('miR483', 'MPA', (12, 18))	('miR483-5p', 'Var', (23, 32))
34126	29029450	A significant difference was found between the two stage groups in both miR483 values of pre-S (0.089+-0.079 ng/ml and 0.210+-0.113 ng/ml, St 1/2 and St 3/4, P=0.016, respectively) and post-S (0.066+-0.0640 ng/ml and 0.150+-0.102 ng/ml, St 1/2 and St 3/4, P=0.001, respectively) samples.	('0.066+-0.0640 ng/ml', 'Var', (193, 212))	('St 3/4', 'Gene', (248, 254))	('St 3/4', 'Gene', '6762;6484', (248, 254))	('St 1/2', 'Gene', (237, 243))	('St 1/2', 'Gene', '1316;6386;6761', (237, 243))	('0.150+-0.102 ng/ml', 'Var', (217, 235))	('St 3/4', 'Gene', '6762;6484', (150, 156))	('St 1/2', 'Gene', (139, 145))	('St 3/4', 'Gene', (150, 156))	('St 1/2', 'Gene', '1316;6386;6761', (139, 145))	('miR483', 'Gene', (72, 78))	('0.210+-0.113 ng/ml', 'Var', (119, 137))
34130	29029450	We confirmed the presence of a significant difference between the two stage groups in both pre-S [miR483-5p (ng/ml):0.110+-0.053 and 0.364+-0.234, St 1/2 and St 3/4, P=0.002] and post-S [miR483-5p (ng/ml): 0.100+-0.053 and 0.290+-0.270, St 1/2 and St 3/4, P=0.03] levels, Figure 1B.	('0.364+-0.234', 'Var', (133, 145))	('St 3/4', 'Gene', (248, 254))	('St 3/4', 'Gene', '6762;6484', (248, 254))	('St 1/2', 'Gene', (147, 153))	('St 1/2', 'Gene', (237, 243))	('St 1/2', 'Gene', '1316;6386;6761', (147, 153))	('St 1/2', 'Gene', '1316;6386;6761', (237, 243))	('St 3/4', 'Gene', (158, 164))	('St 3/4', 'Gene', '6762;6484', (158, 164))
34132	29029450	To assess the prognostic ability of miR483-5p and miR483 to predict recurrence-free and overall survival, we constructed Kaplan-Meier curves stratifying patients into two groups on the basis of the cut-off values determined by ROC analysis (0.101 ng/ml for miR483 and 0.221 ng/ml for miR483-5p).	('0.221 ng/ml', 'Var', (268, 279))	('miR483', 'Var', (257, 263))	('patients', 'Species', '9606', (153, 161))
34134	29029450	After adjustments for age and sex, the patients with circulating levels of miR483-5p >= 0.221 ng/ml, maintained a significantly higher risk of recurrence (HR, 16.20; 95% confidence interval [CI], 1.39 to 188.6, P=0.026), Table 3.	('miR483-5p >= 0.221 ng/ml', 'Var', (75, 99))	('recurrence', 'CPA', (143, 153))	('patients', 'Species', '9606', (39, 47))
34139	29029450	Among those miRs differentially expressed in malignant and benign adrenal cortical tumor tissues,, miR483 and its mature variant miR483-5p, are detected at higher levels in blood from patients with ACC compared to ACA.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('higher', 'PosReg', (156, 162))	('benign adrenal cortical tumor', 'Disease', (59, 88))	('patients', 'Species', '9606', (184, 192))	('adrenal cortical tumor', 'Phenotype', 'HP:0100641', (66, 88))	('miR483', 'Var', (99, 105))	('ACC', 'Phenotype', 'HP:0006744', (198, 201))	('benign adrenal cortical tumor', 'Disease', 'MESH:D000310', (59, 88))	('ACC', 'Disease', (198, 201))	('miR483-5p', 'Var', (129, 138))
34141	29029450	However, the sensitivity of the miR quantification technique used was low, as miR483-5p in serum samples of non-aggressive tumors was under the detection limit of the method and no cut-off value derived from ROC curves and used for recurrence or survival analysis was given.	('miR483-5p', 'Var', (78, 87))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('aggressive tumor', 'Disease', (112, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('aggressive tumor', 'Disease', 'MESH:D001523', (112, 128))
34145	29029450	In a Cox multivariate regression analysis, miR483-5p remained the best prognostic variable for recurrence risk.	('Cox', 'Gene', (5, 8))	('Cox', 'Gene', '1351', (5, 8))	('miR483-5p', 'Var', (43, 52))
34146	29029450	Notably, miR483 maps at 11p15.5 within the second intron of the insulin-like growth factor 2 (IGF2) gene, which is one of the most hyper-expressed genes in ACC, and is involved, although apparently not being sufficient in promoting ACC in the mouse, in the multistep progression process underlying the carcinoma development.	('mouse', 'Species', '10090', (243, 248))	('miR483', 'Var', (9, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('ACC', 'Phenotype', 'HP:0006744', (156, 159))	('ACC', 'Phenotype', 'HP:0006744', (232, 235))	('IGF2', 'Gene', (94, 98))	('carcinoma', 'Disease', (302, 311))	('carcinoma', 'Disease', 'MESH:D002277', (302, 311))
34147	29029450	Thus, miR483-5p represents one of the best markers for maintaining the self-fueling oncogenic activation of adrenocortical cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('miR483-5p', 'Var', (6, 15))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (108, 129))	('adrenocortical cancer', 'Disease', (108, 129))
34148	29029450	Among the clinicopathologic parameters of ACC, only the tumor stage and diameter showed a positive correlation with miR483-5p.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miR483-5p', 'Var', (116, 125))	('tumor', 'Disease', (56, 61))	('ACC', 'Phenotype', 'HP:0006744', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('ACC', 'Disease', (42, 45))
34151	29029450	These findings validate not only the specific release of miR483 from the tumor mass (correlation with the diameter), but also the strict relationship between the corpuscular and the acellular part of the liquid biopsy.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('miR483', 'Var', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (73, 78))
34156	29029450	However, ACC is a rare cancer, and our cohort of patients is well characterized according to the clinical data, and to date is the largest series analyzed for circulating miR483 and miR483-5p.	('miR483', 'Var', (171, 177))	('ACC', 'Phenotype', 'HP:0006744', (9, 12))	('ACC', 'Disease', (9, 12))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('miR483-5p', 'Var', (182, 191))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
34176	29029450	Receiver operating characteristic (ROC) curve analysis was performed to calculate AUC and select the miR483 and miR483-5p values showing the best sensitivity and specificity for discriminating between low (St 1/2) and high (St 3/4) disease stages.	('miR483-5p', 'Var', (112, 121))	('St 1/2', 'Gene', '1316;6386;6761', (206, 212))	('miR483', 'Var', (101, 107))	('St 1/2', 'Gene', (206, 212))	('St 3/4', 'Gene', '6762;6484', (224, 230))	('St 3/4', 'Gene', (224, 230))
34177	29029450	A Cox proportional-hazards regression analysis was used in univariate and multivariate analyses to assess the predictive role of miR483 or miR483-5p cut-off values on disease recurrence and overall survival.	('Cox', 'Gene', (2, 5))	('miR483-5p', 'Var', (139, 148))	('Cox', 'Gene', '1351', (2, 5))	('miR483', 'Var', (129, 135))
34203	28943972	Furthermore, we sought to detect the most predominant patterns of non-coding RNA expression along with their corresponding molecular pathways that may be involved in the development of ACC and could serve as biomarkers for this type of cancer.	('ACC', 'Disease', (185, 188))	('RNA', 'Gene', (77, 80))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('non-coding', 'Var', (66, 76))	('involved', 'Reg', (154, 162))	('cancer', 'Disease', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('ACC', 'Phenotype', 'HP:0006744', (185, 188))
34213	28943972	While miR-497 (4 fold, p<3x10-10), miR-195 (3.6 fold, p<1x10-9), miR-335 (3 fold, p<1x10-9), miR-214 (2.7 fold, p<1x10-6), and miR-199 (2.5 fold, multiple forms identified, p<9x10-6) were substantially downregulated in ACC samples (Figure 1C).	('miR-335', 'Gene', (65, 72))	('miR-214', 'Gene', (93, 100))	('miR-199', 'Var', (127, 134))	('miR-195', 'Gene', (35, 42))	('miR-195', 'Gene', '406971', (35, 42))	('miR-214', 'Gene', '406996', (93, 100))	('ACC samples', 'Disease', (219, 230))	('miR-497', 'Gene', (6, 13))	('downregulated', 'NegReg', (202, 215))	('miR-497', 'Gene', '574456', (6, 13))	('miR-335', 'Gene', '442904', (65, 72))	('ACC', 'Phenotype', 'HP:0006744', (219, 222))
34217	28943972	miR-153 has oncogenic function in prostate cancer tissue, with knockdown of miR-153 shown to upregulate tumor suppressor genes.	('miR-153', 'Chemical', '-', (76, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('miR-153', 'Gene', (76, 83))	('tumor', 'Disease', (104, 109))	('prostate cancer', 'Disease', (34, 49))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('miR-153', 'Chemical', '-', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (34, 49))	('knockdown', 'Var', (63, 72))	('miR-153', 'Gene', (0, 7))	('upregulate', 'PosReg', (93, 103))
34241	28943972	Commonly enriched miRNAs in a pathway map showed the majority of the miRNAs were involved in various cancers (Figures 2D-G).	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('involved', 'Reg', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('miRNAs', 'Var', (69, 75))
34256	28943972	Remapping small RNA sequencing data to identify differentially expressed lncRNAs in ACC tissue samples showed 48 lncRNAs (p<0.05; Figure 4A) were significantly expressed where 31 lncRNAs were upregulated including the top five listed here: lnc-BHLHHE22-1:14 (16.7 fold, p<0.0007), lnc-C11orf35-1:1 (15.7 fold, p<0.000000001), lnc-RP1L1-5:2 (12.6 fold, p<0.0001), lnc-C11orf88-1:1 (7.2 fold, p<0.000006), and lnc-TRPC4AP-1:2 (6 fold, p<0.0005; Figure 4B) and 17 were downregulated.	('downregulated', 'NegReg', (466, 479))	('C11orf88', 'Gene', (367, 375))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('lnc-BHLHHE22-1:14', 'Var', (240, 257))	('C11orf88', 'Gene', '399949', (367, 375))	('upregulated', 'PosReg', (192, 203))	('C11orf35', 'Gene', '256329', (285, 293))	('TRPC4AP', 'Gene', (412, 419))	('RP1L1', 'Gene', '94137', (330, 335))	('RP1L1', 'Gene', (330, 335))	('TRPC4AP', 'Gene', '26133', (412, 419))	('C11orf35', 'Gene', (285, 293))
34259	28943972	The small nucleolar RNAs (snoRNAs) are another subclass of snRNAs that localize in the nucleolus and play a role in maturation of RNA molecules through chemical modifications targeting mainly rRNAs, tRNAs and snRNAs.	('snoRNA', 'Gene', '84546', (26, 32))	('snoRNA', 'Gene', (26, 32))	('chemical modifications', 'Var', (152, 174))	('rRNAs', 'Protein', (192, 197))
34276	28943972	Specifically, miR-483, miR-153, miR-135, miR-514, lnc-BHLHHE22-1:14, lnc-C11orf351:1, lnc-RP1L1-5:2, RNU2-6P, RNU2-48P, RNU2-36P, and RNU2-61P showed greater than 10 fold expression in ACC versus ACA samples.	('C11orf35', 'Gene', (73, 81))	('RNU2-48P', 'Gene', (110, 118))	('RNU2', 'Gene', (134, 138))	('RNU2', 'Gene', (101, 105))	('RP1L1', 'Gene', '94137', (90, 95))	('C11orf35', 'Gene', '256329', (73, 81))	('ACC', 'Phenotype', 'HP:0006744', (185, 188))	('lnc-BHLHHE22-1:14', 'Var', (50, 67))	('RP1L1', 'Gene', (90, 95))	('ACC', 'Disease', (185, 188))	('RNU2-48P', 'Gene', '106481649', (110, 118))	('miR-514', 'Chemical', '-', (41, 48))	('RNU2-6P', 'Gene', (101, 108))	('miR-153', 'Chemical', '-', (23, 30))	('ACA', 'Phenotype', 'HP:0008256', (196, 199))	('RNU2', 'Gene', '6066', (120, 124))	('miR-135', 'Var', (32, 39))	('RNU2', 'Gene', '6066', (110, 114))	('miR-135', 'Chemical', '-', (32, 39))	('RNU2', 'Gene', '6066', (134, 138))	('expression', 'MPA', (171, 181))	('RNU2', 'Gene', (120, 124))	('miR-483', 'Gene', (14, 21))	('RNU2', 'Gene', '6066', (101, 105))	('RNU2', 'Gene', (110, 114))	('miR-153', 'Var', (23, 30))	('miR-514', 'Var', (41, 48))	('RNU2-6P', 'Gene', '100873825', (101, 108))	('miR-483', 'Gene', '619552', (14, 21))
34289	28009746	Patients with less favorable prognosis at baseline demonstrated the greatest increase in CDFS3 over time (eg, capsular invasion: 28%-88%, Delta60% vs no capsular invasion: 51%-87%, Delta36%).	('capsular invasion', 'CPA', (110, 127))	('Delta36', 'Mutation', 'c.del36', (181, 188))	('Delta60%', 'Var', (138, 146))	('Delta60', 'Mutation', 'c.del60', (138, 145))	('CDFS', 'Chemical', '-', (89, 93))	('Patients', 'Species', '9606', (0, 8))	('increase', 'PosReg', (77, 85))	('CDFS3', 'Gene', (89, 94))
34345	28009746	For example, larger changes in CDFS3 were seen among patients with capsular invasion (28%-88%, Delta60%) vs without capsular invasion (51%-87%, Delta36%).	('Delta60', 'Mutation', 'c.del60', (95, 102))	('CDFS3', 'Gene', (31, 36))	('patients', 'Species', '9606', (53, 61))	('Delta36', 'Mutation', 'c.del36', (144, 151))	('Delta60', 'Var', (95, 102))	('changes', 'Reg', (20, 27))	('CDFS', 'Chemical', '-', (31, 35))
34346	28009746	Similarly, patients with functional tumors (20%-83%, Delta63%) had larger differences in CDFS3 vs patients without functional tumors (43%-78%, Delta35%).	('Delta35%', 'Var', (143, 151))	('functional tumors', 'Disease', (115, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('functional tumors', 'Disease', 'MESH:D009369', (115, 132))	('differences', 'Reg', (74, 85))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('patients', 'Species', '9606', (98, 106))	('Delta63%', 'Var', (53, 61))	('functional tumors', 'Disease', 'MESH:D009369', (25, 42))	('Delta35', 'Mutation', 'c.del35', (143, 150))	('CDFS', 'Chemical', '-', (89, 93))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('patients', 'Species', '9606', (11, 19))	('functional tumors', 'Disease', (25, 42))	('CDFS3', 'Gene', (89, 94))	('Delta63', 'Mutation', 'c.del63', (53, 60))
34347	28009746	These patterns were also seen in CDFS3 among patients with T3/T4 (22%-80%, Delta58%) vs T1/T2 (45%-76%, Delta31%) tumors, as well as among patients with high mitotic index (>10/50 HPF) (21%-100%, Delta79%) vs low mitotic index (<=10/50 HPF) (33%-69%, Delta36%) disease (all P < 0.001).	('Delta31', 'Mutation', 'c.del31', (104, 111))	('T3/T4', 'Var', (59, 64))	('CDFS', 'Chemical', '-', (33, 37))	('Delta36', 'Mutation', 'c.del36', (251, 258))	('patients', 'Species', '9606', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Delta79', 'Mutation', 'c.del79', (196, 203))	('CDFS3', 'Gene', (33, 38))	('Delta36', 'Var', (251, 258))	('patients', 'Species', '9606', (45, 53))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('Delta58', 'Mutation', 'c.del58', (75, 82))
34391	24571724	We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('adrenal adenomas', 'Disease', (97, 113))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (202, 223))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('patients', 'Species', '9606', (64, 72))	('cortisol', 'Chemical', 'MESH:D006854', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('patients', 'Species', '9606', (188, 196))	('adrenocortical tumors', 'Disease', (202, 223))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (97, 112))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', (33, 38))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (97, 113))	('adrenal adenomas', 'Disease', 'MESH:D018246', (97, 113))	('mutations', 'Var', (138, 147))
34394	24571724	Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617A C in 7 and c.595_596insCAC in 1).	('cyclic AMP', 'Chemical', 'MESH:D000242', (94, 104))	('c.595_596insCAC', 'Var', (195, 210))	('c.595_596insCAC', 'Mutation', 'c.595_596insCAC', (195, 210))	('adenomas', 'Disease', 'MESH:D000236', (167, 175))	('PRKACA', 'Gene', (47, 53))	('adenomas', 'Disease', (167, 175))	('c.617A C', 'Var', (177, 185))	('mutations', 'Var', (34, 43))
34395	24571724	Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('hypercortisolism', 'Phenotype', 'HP:0003118', (201, 217))	('mutations', 'Var', (24, 33))	('adrenal tumors', 'Disease', (247, 261))	('patients', 'Species', '9606', (93, 101))	('unilateral adenoma', 'Disease', 'MESH:D000236', (62, 80))	('hypercortisolism', 'Disease', (201, 217))	('identified', 'Reg', (39, 49))	('hypercortisolism', 'Disease', 'MESH:D003480', (201, 217))	('patients', 'Species', '9606', (227, 235))	('unilateral adenoma', 'Disease', (62, 80))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (113, 131))	('PRKACA', 'Gene', (9, 15))	('adenomas', 'Disease', 'MESH:D000236', (73, 81))	('adenomas', 'Disease', (73, 81))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (113, 131))	('adrenal tumors', 'Disease', 'MESH:D000310', (247, 261))	("Cushing's syndrome", 'Disease', (113, 131))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('patients', 'Species', '9606', (175, 183))
34396	24571724	Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA.	('gain', 'PosReg', (126, 130))	('cortisol', 'Chemical', 'MESH:D006854', (23, 31))	('patients', 'Species', '9606', (9, 17))	('hyperplasias', 'Disease', 'MESH:D006965', (42, 54))	('copy-number', 'Var', (114, 125))	('hyperplasias', 'Disease', (42, 54))
34397	24571724	In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased.	('activity', 'MPA', (264, 272))	('protein levels', 'MPA', (190, 204))	('increased', 'PosReg', (180, 189))	('PKA', 'Gene', (52, 55))	('increased', 'PosReg', (277, 286))	('inhibition', 'MPA', (33, 43))	('mutants', 'Var', (74, 81))	('PKA', 'Enzyme', (260, 263))	('patients', 'Species', '9606', (132, 140))	('impaired', 'NegReg', (24, 32))
34398	24571724	Genetic alterations of the catalytic subunit of PKA were found to be associated with human disease.	('Genetic alterations', 'Var', (0, 19))	('human disease', 'Disease', (85, 98))	('associated', 'Reg', (69, 79))	('PKA', 'Gene', (48, 51))	('human', 'Species', '9606', (85, 90))
34399	24571724	Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas.	('bilateral adrenal hyperplasias', 'Disease', (47, 77))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (154, 170))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (154, 169))	('adrenal hyperplasias', 'Phenotype', 'HP:0008221', (57, 77))	('bilateral adrenal hyperplasias', 'Disease', 'MESH:D000312', (47, 77))	('resulted in', 'Reg', (112, 123))	('adrenal adenomas', 'Disease', 'MESH:D018246', (154, 170))	('mutations', 'Var', (102, 111))	('resulted in', 'Reg', (35, 46))	('cortisol', 'Chemical', 'MESH:D006854', (135, 143))	('adrenal adenomas', 'Disease', (154, 170))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (57, 76))
34405	24571724	Whereas somatic mutations in the gene encoding beta-catenin (CTNNB1) have been found primarily in nonsecreting adrenocortical adenomas, there is some evidence that increased endocrine activity may be linked to aberrant cyclic AMP (cAMP) signaling.	('cAMP', 'Gene', (231, 235))	('CTNNB1', 'Gene', (61, 67))	('adrenocortical adenomas', 'Disease', (111, 134))	('endocrine activity', 'MPA', (174, 192))	('cyclic AMP', 'Chemical', 'MESH:D000242', (219, 229))	('cAMP', 'Gene', '820', (231, 235))	('beta-catenin', 'Gene', '1499', (47, 59))	('nonsecreting adrenocortical adenomas', 'Phenotype', 'HP:0011745', (98, 134))	('aberrant', 'Var', (210, 218))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (111, 134))	('CTNNB1', 'Gene', '1499', (61, 67))	('beta-catenin', 'Gene', (47, 59))	('found', 'Reg', (79, 84))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (111, 134))	('increased', 'PosReg', (164, 173))
34406	24571724	For instance, ectopic expression of G-protein-coupled receptors for neuroendocrine hormones or neurotransmitters that mediate their effects through cAMP has been implicated in syndromes such as food-dependent hypercortisolism and related conditions that are caused by cortisol-producing adenomas or bilateral hyperplasias of the adrenal cortex.	('implicated', 'Reg', (162, 172))	('G-protein-coupled receptors', 'Protein', (36, 63))	('bilateral hyperplasias of the adrenal cortex', 'Disease', (299, 343))	('hyperplasias of the adrenal', 'Phenotype', 'HP:0008221', (309, 336))	('food-dependent hypercortisolism', 'Disease', (194, 225))	('food-dependent hypercortisolism', 'Disease', 'MESH:D047748', (194, 225))	('dependent hypercortisolism', 'Phenotype', 'HP:0011744', (199, 225))	('bilateral hyperplasias of the adrenal cortex', 'Disease', 'MESH:D001477', (299, 343))	('adenomas', 'Disease', 'MESH:D000236', (287, 295))	('neuroendocrine', 'Disease', 'MESH:D018358', (68, 82))	('neuroendocrine', 'Disease', (68, 82))	('cAMP', 'Gene', (148, 152))	('adenomas', 'Disease', (287, 295))	('cAMP', 'Gene', '820', (148, 152))	('cortisol', 'Chemical', 'MESH:D006854', (268, 276))	('ectopic expression', 'Var', (14, 32))	('hypercortisolism', 'Phenotype', 'HP:0003118', (209, 225))	('cortisol', 'Chemical', 'MESH:D006854', (214, 222))
34408	24571724	Finally, mutations in the genes encoding the cAMP-degrading phosphodiesterase 11A (PDE11A) and phosphodiesterase 8B (PDE8B) and in the gene encoding the regulatory subunit of the cAMP-dependent protein kinase (protein kinase A [PKA]) (PRKAR1A) have been identified in patients with Cushing's syndrome due to primary pigmented nodular adrenocortical disease and in a small number of cortisol-producing adrenal adenomas.	('adrenal adenomas', 'Phenotype', 'HP:0008256', (401, 417))	('mutations', 'Var', (9, 18))	('cAMP', 'Gene', (45, 49))	('PRKAR1A', 'Gene', '5573', (235, 242))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (282, 300))	('cortisol', 'Chemical', 'MESH:D006854', (382, 390))	('adrenal adenomas', 'Disease', (401, 417))	('patients', 'Species', '9606', (268, 276))	('identified', 'Reg', (254, 264))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (282, 300))	('cAMP', 'Gene', (179, 183))	('PDE8B', 'Gene', (117, 122))	("Cushing's syndrome", 'Disease', (282, 300))	('PDE11A', 'Gene', (83, 89))	('PDE11A', 'Gene', '50940', (83, 89))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (316, 356))	('cAMP', 'Gene', '820', (45, 49))	('phosphodiesterase 8B', 'Gene', '8622', (95, 115))	('pigmented nodular adrenocortical disease', 'Disease', (316, 356))	('small number of cortisol', 'Phenotype', 'HP:0008163', (366, 390))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (316, 356))	('PRKAR1A', 'Gene', (235, 242))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (401, 416))	('adrenal adenomas', 'Disease', 'MESH:D018246', (401, 417))	('cAMP', 'Gene', '820', (179, 183))	('PDE8B', 'Gene', '8622', (117, 122))	('phosphodiesterase 8B', 'Gene', (95, 115))
34422	24571724	The PRKACA-containing plasmid was used for site-directed mutagenesis, with the c.617A C and the c.595_596insCAC mutation introduced with the use of the QuikChange II Site-Directed Mutagenesis Kit (Agilent Technologies), according to the manufacturer's protocol.	('c.595_596insCAC', 'Mutation', 'c.595_596insCAC', (96, 111))	('c.617A C', 'Var', (79, 87))	('c.595_596insCAC', 'Var', (96, 111))
34427	24571724	For transfections including both PKA Calpha (nonmutant or Leu206Arg variant) and RIIbeta subunits, a molar ratio of 1:8 was used.	('Leu206Arg', 'Var', (58, 67))	('Leu206Arg', 'SUBSTITUTION', 'None', (58, 67))	('PKA Calpha', 'Gene', '5566', (33, 43))	('RIIbeta', 'Chemical', '-', (81, 88))	('PKA Calpha', 'Gene', (33, 43))
34431	24571724	Within this small set of genetic alterations, somatic variants in PRKACA, encoding the PKA Calpha subunit, were found in 8 of 10 tumors (c.617A C, p.Leu206Arg in 7 and c.595_596insCAC, Leu199_Cys200insTrp in 1).	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('c.595_596insCAC', 'Mutation', 'c.595_596insCAC', (168, 183))	('p.Leu206Arg', 'Mutation', 'rs386352352', (147, 158))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('found', 'Reg', (112, 117))	('Leu199_Cys200insTrp', 'Var', (185, 204))	('PRKACA', 'Gene', (66, 72))	('Leu199_Cys200insTrp', 'Mutation', 'p.L,C199,200W', (185, 204))	('PKA Calpha', 'Gene', '5566', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('p.Leu206Arg', 'Var', (147, 158))	('PKA Calpha', 'Gene', (87, 97))	('c.617A C', 'Var', (137, 145))	('c.595_596insCAC', 'Var', (168, 183))
34433	24571724	The Leu206Arg variant was identified in 14 of these 129 adenomas, and all 14 patients with this variant also had overt Cushing's syndrome, according to the predefined criteria.	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (119, 137))	('adenomas', 'Disease', (56, 64))	("Cushing's syndrome", 'Disease', (119, 137))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (119, 137))	('Leu206Arg', 'Var', (4, 13))	('Leu206Arg', 'SUBSTITUTION', 'None', (4, 13))	('patients', 'Species', '9606', (77, 85))	('adenomas', 'Disease', 'MESH:D000236', (56, 64))
34434	24571724	Whole-exome and targeted sequencing indicated that both the nonmutated and mutated alleles were present in tumor tissue, consistent with a heterozygous state of PRKACA mutations (Fig.	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (168, 177))
34435	24571724	In the affected patients, there were no PRKACA mutations in DNA derived from leukocytes (19 patients) or fat tissue (1 patient) or in adjacent normal adrenal tissue (6 patients).	('PRKACA', 'Gene', (40, 46))	('patient', 'Species', '9606', (119, 126))	('patient', 'Species', '9606', (92, 99))	('patients', 'Species', '9606', (16, 24))	('patient', 'Species', '9606', (168, 175))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (168, 176))	('patient', 'Species', '9606', (16, 23))
34436	24571724	Comparative genomic hybridization of samples from 35 patients with cortisol-secreting bilateral adrenal hyperplasias and overt Cushing's syndrome identified 5 patients (4 kindreds) with copy-number gains (duplications) of the genomic region on chromosome 19p that includes PRKACA (Fig.	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (127, 145))	('bilateral adrenal hyperplasias', 'Disease', 'MESH:D000312', (86, 116))	('cortisol', 'Chemical', 'MESH:D006854', (67, 75))	('patients', 'Species', '9606', (53, 61))	("Cushing's syndrome", 'Disease', (127, 145))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (127, 145))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (96, 115))	('bilateral adrenal hyperplasias', 'Disease', (86, 116))	('adrenal hyperplasias', 'Phenotype', 'HP:0008221', (96, 116))	('patients', 'Species', '9606', (159, 167))	('copy-number gains', 'Var', (186, 203))
34445	24571724	Exchanging Leu206 with the bulky and positively charged amino acid Arg in silico yields steric hindrance between the side chain of the mutated Arg206 in the Calpha subunit and Val115 and Tyr228 in the RIIbeta subunit (Fig.	('Val115', 'Var', (176, 182))	('Leu206', 'Var', (11, 17))	('mutated Arg206', 'Var', (135, 149))	('Arg206', 'Chemical', '-', (143, 149))	('Tyr228', 'Var', (187, 193))	('Arg', 'Chemical', 'MESH:D001120', (67, 70))	('Arg', 'Chemical', 'MESH:D001120', (143, 146))	('Arg206', 'Var', (143, 149))	('RIIbeta', 'Chemical', '-', (201, 208))	('steric hindrance', 'MPA', (88, 104))	('Leu206', 'Chemical', '-', (11, 17))	('Tyr228', 'Chemical', '-', (187, 193))	('Val115', 'Chemical', '-', (176, 182))
34446	24571724	The functional consequences of the two detected variants (Leu206Arg and Leu199_Cys200insTrp) were investigated in intact cells by means of FRET microscopy with the use of a sensor for PKA activity (AKAR4-NES).	('Leu199_Cys200insTrp', 'Var', (72, 91))	('Leu206Arg', 'SUBSTITUTION', 'None', (58, 67))	('Leu206Arg', 'Var', (58, 67))	('NES', 'Gene', '10763', (204, 207))	('Leu199_Cys200insTrp', 'Mutation', 'p.L,C199,200W', (72, 91))	('NES', 'Gene', (204, 207))
34447	24571724	The PKA activity in cells transfected only with either nonmutant Calpha or the variants was high and was not further stimulated by cAMP analogues, indicating preservation of the catalytic activity in the mutants (Fig.	('PKA', 'Enzyme', (4, 7))	('cAMP', 'Gene', '820', (131, 135))	('activity', 'MPA', (8, 16))	('mutants', 'Var', (204, 211))	('catalytic activity', 'MPA', (178, 196))	('cAMP', 'Gene', (131, 135))
34448	24571724	However, after cotransfection with excess nonmutant RIIbeta, basal PKA activity was decreased in cells transfected with nonmutant Calpha and became responsive to cAMP analogues, whereas PKA activity in the cells transfected with the mutants remained high and was not responsive to cAMP analogues (Fig.	('nonmutant', 'Var', (120, 129))	('cAMP', 'Gene', (281, 285))	('responsive', 'MPA', (148, 158))	('cAMP', 'Gene', '820', (281, 285))	('RIIbeta', 'Chemical', '-', (52, 59))	('PKA', 'Enzyme', (67, 70))	('cAMP', 'Gene', (162, 166))	('activity', 'MPA', (71, 79))	('cAMP', 'Gene', '820', (162, 166))	('decreased', 'NegReg', (84, 93))
34449	24571724	Similarly, transfection of the mutant Calpha Leu206Arg variant caused a profound increase in PKA activity under basal conditions so that PKA activity was in the same range as that in cells transfected with the nonmutant Calpha on cAMP stimulation, and this activity was not suppressed by cotransfection with RIIbeta, indicating again a lack of suppression of the activity of the mutant catalytic subunit by the regulatory subunit (Fig.	('Calpha', 'Gene', (38, 44))	('activity', 'MPA', (141, 149))	('activity', 'MPA', (97, 105))	('PKA', 'Enzyme', (93, 96))	('cAMP', 'Gene', (230, 234))	('cAMP', 'Gene', '820', (230, 234))	('Leu206Arg', 'Var', (45, 54))	('increase', 'PosReg', (81, 89))	('Leu206Arg', 'SUBSTITUTION', 'None', (45, 54))	('RIIbeta', 'Chemical', '-', (308, 315))
34450	24571724	Consistent with these findings, basal PKA activity in tumor tissue was found to be higher in adenoma samples with PRKACA mutations than in those without such mutations (Fig.	('mutations', 'Var', (121, 130))	('adenoma', 'Disease', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('basal PKA activity', 'MPA', (32, 50))	('PRKACA', 'Gene', (114, 120))	('adenoma', 'Disease', 'MESH:D000236', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('higher', 'PosReg', (83, 89))
34452	24571724	As compared with tumor-tissue samples from patients without any known genetic defects, tumor-tissue samples from patients with duplications of PRKACA had higher PKA Calpha messenger RNA and protein levels (Fig.	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('PRKACA', 'Gene', (143, 149))	('PKA Calpha', 'Gene', '5566', (161, 171))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (113, 121))	('duplications', 'Var', (127, 139))	('tumor', 'Disease', (87, 92))	('higher', 'PosReg', (154, 160))	('PKA Calpha', 'Gene', (161, 171))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('genetic defects', 'Disease', 'MESH:D030342', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('genetic defects', 'Disease', (70, 85))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
34456	24571724	Furthermore, in the group of patients with overt Cushing's syndrome, the presence of PRKACA mutations was associated with a more severe phenotype (Table 1).	('PRKACA', 'Gene', (85, 91))	('patients', 'Species', '9606', (29, 37))	('associated', 'Reg', (106, 116))	('mutations', 'Var', (92, 101))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (49, 67))	("Cushing's syndrome", 'Disease', (49, 67))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (49, 67))
34457	24571724	Accordingly, expression levels of a variety of steroidogenic enzymes in mutant adenoma tissues were higher in the presence of a PRKACA mutation (Table S5 in the Supplementary Appendix).	('expression levels', 'MPA', (13, 30))	('mutant', 'Var', (72, 78))	('steroidogenic enzymes', 'Enzyme', (47, 68))	('PRKACA', 'Gene', (128, 134))	('adenoma', 'Disease', 'MESH:D000236', (79, 86))	('adenoma', 'Disease', (79, 86))	('higher', 'PosReg', (100, 106))	('mutation', 'Var', (135, 143))
34458	24571724	There were no obvious phenotypic differences between patients with germline PRKACA duplications and those without duplications, although the number of patients with duplications was small.	('patients', 'Species', '9606', (53, 61))	('duplications', 'Var', (83, 95))	('PRKACA', 'Gene', (76, 82))	('patients', 'Species', '9606', (151, 159))
34460	24571724	The three young boys presenting with Cushing's syndrome due to bilateral hyperplasia (two with micronodular disease and one with macronodular disease) (Table S4 in the Supplementary Appendix) had severe disease similar to that of patients with somatic PRKACA mutations.	("Cushing's syndrome", 'Disease', (37, 55))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (37, 55))	('macronodular disease', 'Disease', 'MESH:C565662', (129, 149))	('bilateral hyperplasia', 'Disease', (63, 84))	('mutations', 'Var', (259, 268))	('macronodular disease', 'Disease', (129, 149))	('patients', 'Species', '9606', (230, 238))	('bilateral hyperplasia', 'Disease', 'MESH:D006965', (63, 84))	('boys', 'Species', '9606', (16, 20))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (37, 55))	('PRKACA', 'Gene', (252, 258))
34461	24571724	One patient with PRKACA duplication had a paradoxical increase in cortisol secretion after administration of dexamethasone, whereas the other four patients did not undergo a long-term dexamethasone suppression test (Liddle's test) before surgery.	('dexamethasone', 'Chemical', 'MESH:D003907', (109, 122))	('PRKACA', 'Gene', (17, 23))	('patient', 'Species', '9606', (147, 154))	('increase', 'PosReg', (54, 62))	('patient', 'Species', '9606', (4, 11))	('increase in cortisol', 'Phenotype', 'HP:0003118', (54, 74))	('cortisol secretion', 'MPA', (66, 84))	('patients', 'Species', '9606', (147, 155))	('duplication', 'Var', (24, 35))	('dexamethasone', 'Chemical', 'MESH:D003907', (184, 197))	('cortisol', 'Chemical', 'MESH:D006854', (66, 74))
34463	24571724	The current study suggests that more than one third of cortisol-producing adenomas associated with overt Cushing's syndrome have unique somatic mutations in PRKACA (which encodes the main catalytic subunit of PKA), resulting in constitutive PKA activation.	('activation', 'PosReg', (245, 255))	('PKA', 'Enzyme', (241, 244))	("Cushing's syndrome", 'Disease', (105, 123))	('adenomas', 'Disease', 'MESH:D000236', (74, 82))	('PRKACA', 'Gene', (157, 163))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (105, 123))	('adenomas', 'Disease', (74, 82))	('cortisol', 'Chemical', 'MESH:D006854', (55, 63))	('associated', 'Reg', (83, 93))	('constitutive', 'MPA', (228, 240))	('mutations', 'Var', (144, 153))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (105, 123))
34466	24571724	All the patients with PRKACA defects, whether germline or somatic, had overt Cushing's syndrome, and none of the patients with subclinical Cushing's syndrome or other adrenal tumors had genetic PRKACA alterations.	('adrenal tumors', 'Disease', 'MESH:D000310', (167, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	("Cushing's syndrome", 'Disease', (77, 95))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (77, 95))	('patients', 'Species', '9606', (113, 121))	('adrenal tumors', 'Disease', (167, 181))	('defects', 'Var', (29, 36))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (139, 157))	("Cushing's syndrome", 'Disease', (139, 157))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (139, 157))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (77, 95))	('PRKACA', 'Gene', (22, 28))	('patients', 'Species', '9606', (8, 16))
34469	24571724	Because PRKACA mediates most of the effects of inactivating PRKAR1A mutations and because mutations of PRKAR1A are associated with a variety of tumors in humans and mice, we would speculate that somatic PRKACA defects might also play a role in other forms of endocrine and nonendocrine tumors.	('tumors', 'Disease', (144, 150))	('mutations', 'Var', (90, 99))	('mice', 'Species', '10090', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('PRKAR1A', 'Gene', '5573', (60, 67))	('tumors', 'Disease', (286, 292))	('nonendocrine tumors', 'Disease', (273, 292))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('play', 'Reg', (229, 233))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('nonendocrine tumors', 'Disease', 'MESH:D009369', (273, 292))	('role', 'Reg', (236, 240))	('PRKAR1A', 'Gene', (103, 110))	('humans', 'Species', '9606', (154, 160))	('associated', 'Reg', (115, 125))	('inactivating', 'Var', (47, 59))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('PRKAR1A', 'Gene', '5573', (103, 110))	('PRKAR1A', 'Gene', (60, 67))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('mutations', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
34473	24571724	Although some randomly introduced mutations in PRKACA have been shown to result in unopposed catalytic activation in vitro, such alterations have not been linked to human disease.	('mutations', 'Var', (34, 43))	('unopposed catalytic activation', 'MPA', (83, 113))	('PRKACA', 'Gene', (47, 53))	('human', 'Species', '9606', (165, 170))
34474	24571724	The only naturally found gain-of-function PRKACA mutations are those described in the Cos1(A1) drosophila mutant.	('mutations', 'Var', (49, 58))	('PRKACA', 'Gene', (42, 48))	('gain-of-function', 'PosReg', (25, 41))	('Cos1', 'Gene', (86, 90))	('drosophila', 'Species', '7227', (95, 105))
34475	24571724	The two PRKACA mutants identified in the current study alter the structure of the catalytic subunit at a site that is essential for interaction with the regulatory subunit, thus maintaining high activity of the catalytic subunit in the absence of cAMP.	('cAMP', 'Gene', (247, 251))	('cAMP', 'Gene', '820', (247, 251))	('structure', 'MPA', (65, 74))	('mutants', 'Var', (15, 22))	('high activity', 'MPA', (190, 203))	('PRKACA', 'Gene', (8, 14))	('maintaining', 'Reg', (178, 189))	('alter', 'Reg', (55, 60))
34477	24571724	In conclusion, the current study links genetic variants of the main catalytic subunit of PKA with both hyperplasias and adenomas of the adrenal cortex leading to corticotropin-independent Cushing's syndrome.	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (188, 206))	('variants', 'Var', (47, 55))	('genetic variants', 'Var', (39, 55))	("Cushing's syndrome", 'Disease', (188, 206))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (188, 206))	('hyperplasias and adenomas of the adrenal cortex', 'Disease', 'MESH:D001477', (103, 150))
34486	24784157	For 9 families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (9 minor children and 4 adult children).	('variant', 'Var', (83, 90))	('children', 'Species', '9606', (124, 132))	('children', 'Species', '9606', (145, 153))	('transmitted', 'Reg', (67, 78))	('children', 'Species', '9606', (106, 114))
34491	24784157	In 9 families with parental sequence data, a parent transmitted the variant to one or more children.	('transmitted', 'Reg', (52, 63))	('children', 'Species', '9606', (91, 99))	('variant', 'Var', (68, 75))
34502	24784157	The LSDBs and catalogs of clinically-relevant variants such as HGMD and ClinVar catalog variants identified in a gene together with annotations of each variant as "pathogenic," "probable pathogenic," "variant of unknown significance," "probable non-pathogenic," or "non-pathogenic" (or similar categories).	('LSDBs', 'Chemical', '-', (4, 9))	('variants', 'Var', (88, 96))	('variants', 'Var', (46, 54))
34506	24784157	Our minimum acceptable segregation patterns for autosomal dominant disorders were either a confirmed de novo variant in an affected child with two unaffected parents or segregation of the variant to three affected family members in two generations.	('autosomal dominant disorders', 'Disease', 'MESH:D030342', (48, 76))	('variant', 'Var', (109, 116))	('child', 'Species', '9606', (132, 137))	('autosomal dominant disorders', 'Disease', (48, 76))
34507	24784157	Briefly, these include mutations leading to premature translation termination, loss of a translation termination codon, loss of a translation initiation codon, and alteration of canonical splice donor or acceptor sites.	('loss', 'NegReg', (79, 83))	('mutations', 'Var', (23, 32))	('alteration', 'Reg', (164, 174))	('donor', 'Species', '9606', (195, 200))	('premature translation termination', 'MPA', (44, 77))	('loss', 'NegReg', (120, 124))	('translation initiation codon', 'MPA', (130, 158))	('translation termination codon', 'MPA', (89, 118))
34514	24784157	Of the 5928 variants that remained, 4932 were judged highly unlikely to be reportable under ACMG recommendations because they were not present in LSDBs and localized to introns outside of the canonical spice sites (67%), resided in 3' untranslated regions (UTR) (13%), encoded synonymous amino acid changes (7.5%), or resided in other non protein-coding regions such as 5' UTRs or the kilobase flanking the gene (6%) (Figure 1).	('encoded', 'Reg', (269, 276))	('variants', 'Var', (12, 20))	('resided', 'Reg', (221, 228))	('LSDBs', 'Chemical', '-', (146, 151))
34516	24784157	Each of the remaining 996 variants was then annotated with information available from HGMD, ClinVar and LSDBs and for the predicted consequence (e.g., frameshift, splicing and termination).	('LSDBs', 'Chemical', '-', (104, 109))	('splicing', 'MPA', (163, 171))	('frameshift', 'Var', (151, 161))
34519	24784157	For all 9 families (9 minor children and 4 adult children), one parent transmitted the variant to one or more children.	('children', 'Species', '9606', (28, 36))	('children', 'Species', '9606', (110, 118))	('transmitted', 'Reg', (71, 82))	('variant', 'Var', (87, 94))	('children', 'Species', '9606', (49, 57))
34522	24784157	An adult subject with an SCN5A mutation had a history of exercise-induced fatigue and a first degree relative with an unspecified early onset cardiac condition; this relative was not enrolled in our study and, therefore, we could not evaluate segregation of the variant or verify phenotypic relevance.	('cardiac condition', 'Disease', (142, 159))	('mutation', 'Var', (31, 39))	('unspecified', 'Species', '32644', (118, 129))	('fatigue', 'Disease', 'MESH:D005221', (74, 81))	('SCN5A', 'Gene', '6331', (25, 30))	('cardiac condition', 'Disease', 'MESH:D006331', (142, 159))	('SCN5A', 'Gene', (25, 30))	('exercise-induced fatigue', 'Phenotype', 'HP:0030973', (57, 81))	('fatigue', 'Disease', (74, 81))	('fatigue', 'Phenotype', 'HP:0012378', (74, 81))
34523	24784157	Another adult subject had an APOB mutation with a normal lipid profile: serum cholesterol 161 mg/dL (normal <200), LDL 93 mg/dL (normal <100) and HDL 56 mg/dL (high risk <40, low risk >=60).	('APOB', 'Gene', (29, 33))	('cholesterol', 'Chemical', 'MESH:D002784', (78, 89))	('mutation', 'Var', (34, 42))	('LDL', 'MPA', (115, 118))	('serum cholesterol', 'MPA', (72, 89))	('lipid', 'Chemical', 'MESH:D008055', (57, 62))	('HDL', 'MPA', (146, 149))	('APOB', 'Gene', '338', (29, 33))
34527	24784157	patch-clamp) evidence likely led to their classification of three variants that we considered as "known pathogenic" as "variants of unknown significance", i.e., CACNA1S p.T1354S, SCN5A p.T220I, and SCN5A p.E428K.	('SCN5A', 'Gene', '6331', (198, 203))	('CACNA1S', 'Gene', '779', (161, 168))	('SCN5A', 'Gene', (198, 203))	('p.T1354S', 'Mutation', 'rs145910245', (169, 177))	('SCN5A', 'Gene', (179, 184))	('p.T220I', 'Mutation', 'rs45620037', (185, 192))	('p.T220I', 'Var', (185, 192))	('SCN5A', 'Gene', '6331', (179, 184))	('p.E428K', 'Var', (204, 211))	('p.E428K', 'Mutation', 'rs199473111', (204, 211))	('p.T1354S', 'Var', (169, 177))	('CACNA1S', 'Gene', (161, 168))
34539	24784157	For SCN5A, this may reflect the fact that more variants are entered in databases because 1) both gain and loss of function variants in SCN5A can cause disease and 2) functional testing for pathogenicity is relatively accessible using patch-clamping experiments.	('disease', 'Disease', (151, 158))	('loss of function', 'NegReg', (106, 122))	('SCN5A', 'Gene', '6331', (4, 9))	('SCN5A', 'Gene', (4, 9))	('gain', 'PosReg', (97, 101))	('SCN5A', 'Gene', (135, 140))	('SCN5A', 'Gene', '6331', (135, 140))	('variants', 'Var', (123, 131))
34540	24784157	For example, we identified a TP53 variant (p.R337H/chr17:g.7574017C>T, see Table 3) with 2.5-9.9% penetrance for pediatric adrenocortical carcinoma (ACC), and newborn screening programs in Brazil have shown that screening for carriers of this mutation reduces morbidity and mortality.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('p.R337H', 'Mutation', 'rs121912664', (43, 50))	('pediatric adrenocortical carcinoma', 'Disease', 'MESH:C565973', (113, 147))	('chr17:g.7574017C>T', 'SUBSTITUTION', 'None', (51, 69))	('pediatric adrenocortical carcinoma', 'Disease', (113, 147))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('chr17:g.7574017C>T', 'Var', (51, 69))	('reduces', 'NegReg', (252, 259))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (123, 147))	('morbidity', 'MPA', (260, 269))
34543	24784157	Regarding delineation of the pathogenicity of variants deposited by clinical laboratories, BRCA1 and BRCA2 variants provide an excellent illustration.	('BRCA1', 'Gene', (91, 96))	('BRCA2', 'Gene', (101, 106))	('variants', 'Var', (107, 115))	('BRCA2', 'Gene', '675', (101, 106))	('BRCA1', 'Gene', '672', (91, 96))
34544	24784157	Although our criteria for pathogenicity are scientifically sound, many BRCA1 and BRCA2 variants in public databases lack information on segregation with disease or experimental functional assays.	('BRCA1', 'Gene', (71, 76))	('variants', 'Var', (87, 95))	('BRCA2', 'Gene', (81, 86))	('man', 'Species', '9606', (66, 69))	('BRCA1', 'Gene', '672', (71, 76))	('BRCA2', 'Gene', '675', (81, 86))
34545	24784157	Because variants lacking this information would not be considered pathogenic in our paradigm, our approach may well under-report the BRCA1 and BRCA2 associated cancer risks.	('BRCA2', 'Gene', '675', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('variants', 'Var', (8, 16))	('BRCA1', 'Gene', '672', (133, 138))	('under-report', 'NegReg', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('BRCA2', 'Gene', (143, 148))	('BRCA1', 'Gene', (133, 138))
34546	24784157	The subject, in whom we identified a pathogenic APOB mutation (p.R3527W/chr2:g. 21229161G>A), a conclusion supported by functional assays demonstrating reduced LDLR binding, had a favorable serum cholesterol and lipoprotein profile.	('LDLR', 'Gene', '3949', (160, 164))	('p.R3527W', 'Mutation', 'rs144467873', (63, 71))	('pathogenic', 'Reg', (37, 47))	('binding', 'Interaction', (165, 172))	('21229161G>A', 'SUBSTITUTION', 'None', (80, 91))	('reduced', 'NegReg', (152, 159))	('APOB', 'Gene', '338', (48, 52))	('cholesterol', 'Chemical', 'MESH:D002784', (196, 207))	('APOB', 'Gene', (48, 52))	('serum cholesterol', 'MPA', (190, 207))	('LDLR', 'Gene', (160, 164))	('p.R3527W/chr2', 'Var', (63, 76))	('21229161G>A', 'Var', (80, 91))
34548	24784157	For example, the person with an SCN5A variant and exercise-induced fatigue had a brother with an unspecified early-onset cardiac condition.	('SCN5A', 'Gene', '6331', (32, 37))	('cardiac condition', 'Disease', (121, 138))	('SCN5A', 'Gene', (32, 37))	('exercise-induced fatigue', 'Phenotype', 'HP:0030973', (50, 74))	('cardiac condition', 'Disease', 'MESH:D006331', (121, 138))	('fatigue', 'Disease', 'MESH:D005221', (67, 74))	('fatigue', 'Disease', (67, 74))	('unspecified', 'Species', '32644', (97, 108))	('variant', 'Var', (38, 45))	('person', 'Species', '9606', (17, 23))	('fatigue', 'Phenotype', 'HP:0012378', (67, 74))
34551	24784157	We found that variants were listed occasionally as mutations or known pathogenic alleles in LSDBs without published evidence of segregation with disease or functional assays to support pathogenicity.	('variants', 'Var', (14, 22))	('LSDBs', 'Disease', (92, 97))	('LSDBs', 'Chemical', '-', (92, 97))
34563	23097668	Several studies have also revealed that the blockade of MR by an MR antagonist (MRA), such as spironolactone or eplerenone, offers an effective approach to treat cardiac disease, especially cardiac failure.	('eplerenone', 'Chemical', 'MESH:D000077545', (112, 122))	('blockade', 'Var', (44, 52))	('cardiac failure', 'Disease', (190, 205))	('spironolactone', 'Chemical', 'MESH:D013148', (94, 108))	('MR', 'Gene', '4306', (56, 58))	('MR', 'Gene', '4306', (65, 67))	('cardiac disease', 'Disease', (162, 177))	('MR', 'Gene', '4306', (80, 82))	('cardiac failure', 'Phenotype', 'HP:0001635', (190, 205))	('cardiac failure', 'Disease', 'MESH:D006333', (190, 205))	('cardiac disease', 'Disease', 'MESH:D006331', (162, 177))
34586	23097668	Both the expression of StAR at mRNA and protein levels and its activity were shown to be increased by nifedipine and efonidipine in MA-10 mouse Leydig cells and NCI-H295R human adrenocortical carcinoma cells, but decreased by amlodipine, azelnidipine, or R(-)-efonidipine.	('StAR', 'Gene', (23, 27))	('activity', 'MPA', (63, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('adrenocortical carcinoma', 'Disease', (177, 201))	('mouse', 'Species', '10090', (138, 143))	('NCI-H295R', 'CellLine', 'CVCL:0458', (161, 170))	('efonidipine', 'Chemical', 'MESH:C066425', (260, 271))	('nifedipine', 'Chemical', 'MESH:D009543', (102, 112))	('expression', 'MPA', (9, 19))	('efonidipine', 'Var', (117, 128))	('efonidipine', 'Chemical', 'MESH:C066425', (117, 128))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (177, 201))	('R(-)-efonidipine', 'Chemical', '-', (255, 271))	('azelnidipine', 'Chemical', 'MESH:C061679', (238, 250))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (177, 201))	('increased', 'PosReg', (89, 98))	('amlodipine', 'Chemical', 'MESH:D017311', (226, 236))	('human', 'Species', '9606', (171, 176))
34603	23097668	In this way, in vivo studies with benidipine and cilnidipine were found to reduce the plasma aldosterone concentration (PAC) in stroke-prone spontaneously hypertensive rats, in the ischemia reperfusion mouse model, and in male SHR/Izm rats.	('rat', 'Species', '10116', (112, 115))	('ischemia', 'Disease', (181, 189))	('hypertensive', 'Disease', 'MESH:D006973', (155, 167))	('PAC', 'Phenotype', 'HP:0000859', (120, 123))	('stroke', 'Phenotype', 'HP:0001297', (128, 134))	('aldosterone', 'Chemical', 'MESH:D000450', (93, 104))	('ischemia', 'Disease', 'MESH:D007511', (181, 189))	('stroke', 'Disease', 'MESH:D020521', (128, 134))	('PAC', 'Phenotype', 'HP:0006699', (120, 123))	('reduce', 'NegReg', (75, 81))	('benidipine', 'Var', (34, 44))	('rat', 'Species', '10116', (235, 238))	('rats', 'Species', '10116', (168, 172))	('stroke', 'Disease', (128, 134))	('reduce the plasma aldosterone concentration', 'Phenotype', 'HP:0004319', (75, 118))	('cilnidipine', 'Var', (49, 60))	('mouse', 'Species', '10090', (202, 207))	('hypertensive', 'Disease', (155, 167))	('benidipine', 'Chemical', 'MESH:C061004', (34, 44))	('rat', 'Species', '10116', (168, 171))	('plasma aldosterone concentration', 'Phenotype', 'HP:0000859', (86, 118))	('plasma aldosterone concentration', 'MPA', (86, 118))	('rats', 'Species', '10116', (235, 239))	('cilnidipine', 'Chemical', 'MESH:C065927', (49, 60))
34604	23097668	In clinical studies, azelnidipine, benidipine, and efonidipine were shown to exert suppressive actions on PAC in hypertensive patients with type 2 diabetes mellitus, in patients with mild-to-moderate stage chronic kidney disease with albuminuria, in patients with chronic glomerulonephritis, and in patients with essential hypertension.	('diabetes mellitus', 'Disease', 'MESH:D003920', (147, 164))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (147, 164))	('PAC', 'Phenotype', 'HP:0000859', (106, 109))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (299, 307))	('hypertensive', 'Disease', (113, 125))	('hypertension', 'Phenotype', 'HP:0000822', (323, 335))	('glomerulonephritis', 'Disease', (272, 290))	('PAC', 'Protein', (106, 109))	('PAC', 'Phenotype', 'HP:0006699', (106, 109))	('kidney disease', 'Disease', (214, 228))	('kidney disease', 'Disease', 'MESH:D007674', (214, 228))	('glomerulonephritis', 'Phenotype', 'HP:0000099', (272, 290))	('patients', 'Species', '9606', (250, 258))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (140, 155))	('hypertensive', 'Disease', 'MESH:D006973', (113, 125))	('rat', 'Species', '10116', (195, 198))	('benidipine', 'Var', (35, 45))	('diabetes mellitus', 'Disease', (147, 164))	('efonidipine', 'Chemical', 'MESH:C066425', (51, 62))	('albuminuria', 'Disease', 'MESH:D000419', (234, 245))	('albuminuria', 'Phenotype', 'HP:0012592', (234, 245))	('azelnidipine', 'Chemical', 'MESH:C061679', (21, 33))	('patients', 'Species', '9606', (169, 177))	('moderate stage chronic kidney', 'Phenotype', 'HP:0003774', (191, 220))	('albuminuria', 'Disease', (234, 245))	('hypertension', 'Disease', 'MESH:D006973', (323, 335))	('glomerulonephritis', 'Disease', 'MESH:D005921', (272, 290))	('benidipine', 'Chemical', 'MESH:C061004', (35, 45))	('hypertension', 'Disease', (323, 335))	('suppressive', 'NegReg', (83, 94))	('kidney disease', 'Phenotype', 'HP:0000112', (214, 228))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (206, 228))
34613	23097668	Recent studies have revealed that dihydropyridine CCBs, such as azelnidipine, benidipine, cilnidipine, efonidipine, and nifedipine, have inhibitory actions on adrenal aldosterone biosynthesis in vitro.	('dihydropyridine CCBs', 'Chemical', '-', (34, 54))	('efonidipine', 'Chemical', 'MESH:C066425', (103, 114))	('adrenal aldosterone', 'Phenotype', 'HP:0000859', (159, 178))	('cilnidipine', 'Var', (90, 101))	('inhibitory actions', 'MPA', (137, 155))	('aldosterone', 'Chemical', 'MESH:D000450', (167, 178))	('nifedipine', 'Chemical', 'MESH:D009543', (120, 130))	('benidipine', 'Chemical', 'MESH:C061004', (78, 88))	('adrenal aldosterone biosynthesis', 'MPA', (159, 191))	('cilnidipine', 'Chemical', 'MESH:C065927', (90, 101))	('azelnidipine', 'Chemical', 'MESH:C061679', (64, 76))
34616	21750201	Phase I Trial of Cixutumumab Combined with Temsirolimus in Patients with Advanced Cancer Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism.	('Temsirolimus', 'Chemical', 'MESH:C401859', (43, 55))	('IGF-1R', 'Gene', '3480', (214, 220))	('insulin', 'Gene', (177, 184))	('Cixutumumab', 'Chemical', 'MESH:C557414', (17, 28))	('IGF-1R', 'Gene', (214, 220))	('inhibitors', 'Var', (126, 136))	('AKT', 'Gene', (145, 148))	('insulin', 'Gene', '3630', (177, 184))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer', 'Disease', (82, 88))	('Mammalian target of rapamycin', 'Gene', '2475', (89, 118))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Mammalian target of rapamycin', 'Gene', (89, 118))	('mTOR', 'Gene', (120, 124))	('Patients', 'Species', '9606', (59, 67))	('mTOR', 'Gene', '2475', (120, 124))	('AKT', 'Gene', '207', (145, 148))	('activation', 'PosReg', (149, 159))
34617	21750201	Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human IgG1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition.	('mTOR', 'Gene', '2475', (14, 18))	('mTOR', 'Gene', (210, 214))	('modulating', 'Reg', (185, 195))	('enhance', 'PosReg', (140, 147))	('cancer', 'Disease', (166, 172))	('mTOR', 'Gene', (148, 152))	('human', 'Species', '9606', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('mTOR', 'Gene', '2475', (148, 152))	('IGF-1R', 'Gene', '3480', (116, 122))	('cixutumumab', 'Var', (47, 58))	('IGF-1R', 'Gene', (116, 122))	('temsirolimus', 'Chemical', 'MESH:C401859', (29, 41))	('cixutumumab', 'Chemical', 'MESH:C557414', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mTOR', 'Gene', '2475', (210, 214))	('mTOR', 'Gene', (14, 18))
34626	21750201	PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGFBP3.	('increased', 'PosReg', (69, 78))	('IGFBP3', 'Gene', (96, 102))	('temsirolimus', 'Chemical', 'MESH:C401859', (56, 68))	('PD', 'Disease', 'MESH:D010300', (0, 2))	('cixutumumab', 'Var', (21, 32))	('increased plasma IGF-1', 'Phenotype', 'HP:0030269', (69, 91))	('IGFBP3', 'Gene', '3486', (96, 102))	('cixutumumab', 'Chemical', 'MESH:C557414', (21, 32))	('IGF-1', 'Gene', '3479', (86, 91))	('IGF-1', 'Gene', (86, 91))
34630	21750201	Recent studies in in vitro and in vivo models as well as using tumor biopsies from patients have demonstrated that treatment with mTOR inhibitors leads to upregulation of AKT phosphorylation in tumors, which may antagonize the antiproliferative effects of mTOR inhibition.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('AKT', 'Gene', '207', (171, 174))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('mTOR', 'Gene', '2475', (256, 260))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('mTOR', 'Gene', (130, 134))	('tumor', 'Disease', (194, 199))	('mTOR', 'Gene', (256, 260))	('patients', 'Species', '9606', (83, 91))	('mTOR', 'Gene', '2475', (130, 134))	('tumors', 'Disease', (194, 200))	('upregulation', 'PosReg', (155, 167))	('AKT', 'Gene', (171, 174))	('inhibitors', 'Var', (135, 145))
34631	21750201	Several studies have shown that mTOR inhibitors mediate AKT activation through an IGF-1R-dependent mechanism and that IGF-1R inhibitors may abrogate or reduce AKT phosphorylation induced by mTOR inhibitors.	('AKT', 'Gene', '207', (56, 59))	('IGF-1R', 'Gene', (118, 124))	('reduce', 'NegReg', (152, 158))	('AKT', 'Gene', (159, 162))	('mTOR', 'Gene', '2475', (190, 194))	('mTOR', 'Gene', '2475', (32, 36))	('mTOR', 'Gene', (190, 194))	('AKT', 'Gene', (56, 59))	('mTOR', 'Gene', (32, 36))	('activation', 'PosReg', (60, 70))	('IGF-1R', 'Gene', '3480', (82, 88))	('abrogate', 'NegReg', (140, 148))	('IGF-1R', 'Gene', (82, 88))	('inhibitors', 'Var', (125, 135))	('AKT', 'Gene', '207', (159, 162))	('IGF-1R', 'Gene', '3480', (118, 124))
34637	21750201	Patients must have absolute neutrophil count >= 1500/mL; platelets >= 100,000/mL; creatinine <= 2x ULN; bilirubin <= 1.5 x ULN; AST(SGOT) and/or ALT(SGPT) <= 5x ULN.	('AST', 'MPA', (128, 131))	('>= 1500/mL', 'Var', (45, 55))	('absolute neutrophil', 'MPA', (19, 38))	('creatinine', 'Chemical', 'MESH:D003404', (82, 92))	('bilirubin', 'MPA', (104, 113))	('ALT', 'MPA', (145, 148))	('bilirubin', 'Chemical', 'MESH:D001663', (104, 113))	('platelets', 'CPA', (57, 66))	('Patients', 'Species', '9606', (0, 8))	('creatinine', 'MPA', (82, 92))
34638	21750201	There was no limit to prior numbers of treatment, including IGF-1R inhibitors or mTOR inhibitors.	('inhibitors', 'Var', (67, 77))	('IGF-1R', 'Gene', '3480', (60, 66))	('IGF-1R', 'Gene', (60, 66))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))
34709	21750201	Among 17 patients with available SUV changes from Day 0 to Day 3, seven patients had a decrease in SUV in all locations, five patients had a mixture of SUV decrease/increase in different locations, and five patients had increased SUV in all disease sites.	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (207, 215))	('SUV', 'MPA', (99, 102))	('changes', 'Var', (37, 44))	('decrease', 'NegReg', (87, 95))	('patients', 'Species', '9606', (126, 134))	('decrease/increase', 'PosReg', (156, 173))	('patients', 'Species', '9606', (72, 80))
34710	21750201	Among 14 patients with SUV changes available from Day 0 to Day 11, five patients had a decrease in all sites, five patients had a mixture of SUV decrease/increase in different sites, and four patients had increased SUV in all locations.	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (192, 200))	('changes', 'Var', (27, 34))	('decrease', 'NegReg', (87, 95))	('patients', 'Species', '9606', (72, 80))
34711	21750201	Among nine patients with available SUV changes from Day 0 to Day 56, five patients had a decrease in all sites, one patient had a mixture of SUV decrease/increase in different locations, and three patients had an increased SUV in all sites where there was tumor.	('patient', 'Species', '9606', (74, 81))	('patients', 'Species', '9606', (197, 205))	('patient', 'Species', '9606', (116, 123))	('changes', 'Var', (39, 46))	('patients', 'Species', '9606', (74, 82))	('decrease', 'NegReg', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('patient', 'Species', '9606', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('patients', 'Species', '9606', (11, 19))	('patient', 'Species', '9606', (197, 204))	('tumor', 'Disease', (256, 261))
34733	21750201	Overall, the plasma IGF-1 and IGFBP3 levels suggest that cixutumumab and its combination with temsirolimus facilitates upregulation of IGF-1 and IGFBP3.	('IGF-1', 'Gene', (135, 140))	('cixutumumab', 'Var', (57, 68))	('IGFBP3', 'Gene', '3486', (30, 36))	('cixutumumab', 'Chemical', 'MESH:C557414', (57, 68))	('IGFBP3', 'Gene', (145, 151))	('temsirolimus', 'Chemical', 'MESH:C401859', (94, 106))	('IGF-1', 'Gene', '3479', (20, 25))	('IGF-1', 'Gene', (20, 25))	('IGFBP3', 'Gene', '3486', (145, 151))	('IGFBP3', 'Gene', (30, 36))	('facilitates upregulation', 'PosReg', (107, 131))	('IGF-1', 'Gene', '3479', (135, 140))	('upregulation of IGF-1', 'Phenotype', 'HP:0030269', (119, 140))
34770	18793695	have shown that ANP decreases the amount of cholesterol found in mitochondrial contact sites (sites at which the outer and inner mitochondrial membranes are closely apposed) in AngII-stimulated bovine adrenal glomerulosa cells, although these authors suggest that this effect is the result of ANP-induced inhibition of StAR expression and cholesterol transport to contact sites.	('decreases', 'NegReg', (20, 29))	('AngII', 'Gene', (177, 182))	('cholesterol', 'Chemical', 'MESH:D002784', (44, 55))	('ANP', 'Var', (16, 19))	('cholesterol', 'Chemical', 'MESH:D002784', (339, 350))	('inhibition', 'NegReg', (305, 315))	('AngII', 'Gene', '183', (177, 182))	('bovine', 'Species', '9913', (194, 200))	('mitochondrial contact sites', 'MPA', (65, 92))	('decreases the amount of cholesterol', 'Phenotype', 'HP:0003146', (20, 55))
34772	18793695	We also show, for the first time, that PKC-activating phorbol 12-myristate 13-acetate (PMA) increases the mitochondrial cholesterol content in and aldosterone secretion from these cells.	('PMA', 'Chemical', 'MESH:D013755', (87, 90))	('phorbol 12-myristate 13-acetate', 'Chemical', 'MESH:D013755', (54, 85))	('mitochondrial cholesterol content', 'MPA', (106, 139))	('cholesterol', 'Chemical', 'MESH:D002784', (120, 131))	('aldosterone', 'Chemical', 'MESH:D000450', (147, 158))	('aldosterone secretion', 'MPA', (147, 168))	('phorbol', 'Var', (54, 61))	('increases', 'PosReg', (92, 101))
34774	18793695	Finally, ANP inhibits these effects, again highlighting the ability of this hormone to block various aspects of steroid hormone biosynthesis.	('ANP', 'Var', (9, 12))	('inhibits', 'NegReg', (13, 21))	('steroid hormone', 'Chemical', 'MESH:D013256', (112, 127))
34798	18793695	In previous experiments we and others have demonstrated that the PKC-activating phorbol ester, phorbol 12-myristate 13-acetate (PMA), can increase aldosterone secretion from bovine adrenal glomerulosa cells, although other investigators have failed to observe such an effect in rat or bovine adrenal glomerulosa cells or the H295 cell line.	('PMA', 'Chemical', 'MESH:D013755', (128, 131))	('increase', 'PosReg', (138, 146))	('phorbol 12-myristate 13-acetate', 'Var', (95, 126))	('rat', 'Species', '10116', (50, 53))	('phorbol ester', 'Chemical', 'MESH:D010703', (80, 93))	('phorbol 12-myristate 13-acetate', 'Chemical', 'MESH:D013755', (95, 126))	('increase aldosterone', 'Phenotype', 'HP:0000859', (138, 158))	('aldosterone', 'Chemical', 'MESH:D000450', (147, 158))	('aldosterone secretion', 'MPA', (147, 168))	('bovine', 'Species', '9913', (285, 291))	('rat', 'Species', '10116', (278, 281))	('bovine', 'Species', '9913', (174, 180))
34799	18793695	In our hands, 10 nM PMA significantly stimulated aldosterone secretion from the H295R cells by about 1.6-fold over control (Figure 1).	('PMA', 'Var', (20, 23))	('stimulated aldosterone', 'Phenotype', 'HP:0000859', (38, 60))	('aldosterone secretion from', 'MPA', (49, 75))	('stimulated', 'PosReg', (38, 48))	('aldosterone', 'Chemical', 'MESH:D000450', (49, 60))	('PMA', 'Chemical', 'MESH:D013755', (20, 23))	('H295R', 'CellLine', 'CVCL:0458', (80, 85))
34800	18793695	We also investigated the effect of PMA on mitochondrial cholesterol content and found that PMA also induced a significant increase in mitochondrial cholesterol content (Figure 1).	('mitochondrial cholesterol content', 'MPA', (134, 167))	('PMA', 'Chemical', 'MESH:D013755', (91, 94))	('PMA', 'Var', (91, 94))	('cholesterol', 'Chemical', 'MESH:D002784', (148, 159))	('cholesterol', 'Chemical', 'MESH:D002784', (56, 67))	('increase', 'PosReg', (122, 130))	('PMA', 'Chemical', 'MESH:D013755', (35, 38))	('mitochondrial', 'MPA', (42, 55))
34807	18793695	PMA induced a significant elevation in the aldosterone secretory rate and this increase was returned to a value not significantly different from the control value with simultaneous exposure to ANP (Figure 3A).	('PMA', 'Var', (0, 3))	('elevation', 'PosReg', (26, 35))	('aldosterone', 'Chemical', 'MESH:D000450', (43, 54))	('aldosterone secretory rate', 'MPA', (43, 69))	('PMA', 'Chemical', 'MESH:D013755', (0, 3))	('rat', 'Species', '10116', (65, 68))
34809	18793695	Experiments demonstrated that ANP alone also decreased basal aldosterone secretion by approximately 30% (to a value of 0.7 +- 0.1-fold over the control of 1.0; n=4, p<0.02 using a one-sample t test) and mitochondrial cholesterol content by roughly 40% (to a value of 0.6 +- 0.1-fold over the control of 1.0; n=4, p=0.054 versus the control of 1.0 using a one-sample t test), with a mean relative enrichment of citrate synthase activity of 9.1 +- 2.6-fold.	('citrate synthase', 'Gene', '1431', (410, 426))	('aldosterone', 'Chemical', 'MESH:D000450', (61, 72))	('rat', 'Species', '10116', (413, 416))	('decreased basal aldosterone', 'Phenotype', 'HP:0004319', (45, 72))	('decreased', 'NegReg', (45, 54))	('cholesterol', 'Chemical', 'MESH:D002784', (217, 228))	('rat', 'Species', '10116', (19, 22))	('ANP', 'Var', (30, 33))	('mitochondrial cholesterol content', 'MPA', (203, 236))	('citrate synthase', 'Gene', (410, 426))	('basal aldosterone secretion', 'MPA', (55, 82))
34810	18793695	Together these results suggest that one of the mechanisms by which ANP may function to inhibit steroidogenesis elicited by multiple agonists may be through an ability to reduce cholesterol transport to the mitochondria.	('reduce', 'NegReg', (170, 176))	('steroid', 'Chemical', 'MESH:D013256', (95, 102))	('cholesterol', 'Chemical', 'MESH:D002784', (177, 188))	('ANP', 'Var', (67, 70))	('cholesterol transport to the mitochondria', 'MPA', (177, 218))	('steroidogenesis', 'MPA', (95, 110))	('reduce cholesterol', 'Phenotype', 'HP:0003146', (170, 188))	('inhibit', 'NegReg', (87, 94))
34813	18793695	ANP was shown to decrease cholesterol in these contact sites, perhaps as a result of the capacity of ANP to reduce StAR expression.	('cholesterol', 'Chemical', 'MESH:D002784', (26, 37))	('decrease', 'NegReg', (17, 25))	('decrease cholesterol', 'Phenotype', 'HP:0003146', (17, 37))	('reduce', 'NegReg', (108, 114))	('StAR expression', 'MPA', (115, 130))	('ANP', 'Var', (0, 3))	('cholesterol', 'MPA', (26, 37))
34814	18793695	In this report, we show for the first time that ANP also inhibited cholesterol mobilization to the mitochondria of a human adrenocorticocarcinoma cell line, the NCI H295R cells, in response to AngII (Figure 2) and the phorbol ester PMA (Figure 3).	('ANP', 'Var', (48, 51))	('cholesterol', 'Chemical', 'MESH:D002784', (67, 78))	('human', 'Species', '9606', (117, 122))	('inhibited', 'NegReg', (57, 66))	('AngII', 'Gene', (193, 198))	('adrenocorticocarcinoma', 'Disease', 'None', (123, 145))	('cholesterol mobilization to the mitochondria', 'MPA', (67, 111))	('AngII', 'Gene', '183', (193, 198))	('adrenocorticocarcinoma', 'Disease', (123, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('NCI H295R', 'CellLine', 'CVCL:0458', (161, 170))	('phorbol ester PMA', 'Chemical', '-', (218, 235))
34815	18793695	This effect correlated with an ability of ANP to also reduce aldosterone secretion from these cells (Figure 2 and Figure 3), such that in both cases ANP decreased the PMA-stimulated parameter to a value not significantly different from the control.	('reduce aldosterone', 'Phenotype', 'HP:0004319', (54, 72))	('ANP', 'Var', (149, 152))	('aldosterone', 'Chemical', 'MESH:D000450', (61, 72))	('reduce', 'NegReg', (54, 60))	('aldosterone secretion', 'MPA', (61, 82))	('decreased', 'NegReg', (153, 162))	('PMA', 'Chemical', 'MESH:D013755', (167, 170))	('PMA-stimulated parameter', 'MPA', (167, 191))
34818	18793695	Indeed, these results argue that ANP exerts its action on aldosterone secretion and cholesterol transport via a pathway independent from that induced by PMA.	('cholesterol', 'Chemical', 'MESH:D002784', (84, 95))	('PMA', 'Chemical', 'MESH:D013755', (153, 156))	('aldosterone secretion', 'MPA', (58, 79))	('aldosterone', 'Chemical', 'MESH:D000450', (58, 69))	('ANP', 'Var', (33, 36))	('cholesterol transport', 'MPA', (84, 105))
34822	18793695	The reason for the discrepancy is unclear but likely relates to the fact that the magnitude of the increase in aldosterone secretion in response to PMA is much less than that to AngII, thus requiring a larger number of experiments to demonstrate statistical significance.	('less', 'NegReg', (160, 164))	('PMA', 'Chemical', 'MESH:D013755', (148, 151))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (99, 122))	('PMA', 'Var', (148, 151))	('AngII', 'Gene', (178, 183))	('AngII', 'Gene', '183', (178, 183))	('rat', 'Species', '10116', (241, 244))	('aldosterone', 'Chemical', 'MESH:D000450', (111, 122))	('aldosterone secretion', 'MPA', (111, 132))
34829	18793695	This idea is consistent with the fact that elevated potassium is thought to function by depolarizing the plasma membrane, activating voltage-dependent calcium channel and increasing calcium influx [reviewed in ], as well as the finding that calcium can elicit transfer of cholesterol from the outer to inner mitochondrial membranes.	('elevated potassium', 'Phenotype', 'HP:0002153', (43, 61))	('activating', 'PosReg', (122, 132))	('calcium', 'Var', (241, 248))	('increasing', 'PosReg', (171, 181))	('elicit', 'Reg', (253, 259))	('depolarizing', 'NegReg', (88, 100))	('calcium influx', 'MPA', (182, 196))	('voltage-dependent calcium channel', 'MPA', (133, 166))	('transfer', 'MPA', (260, 268))	('plasma membrane', 'MPA', (105, 120))	('calcium', 'Chemical', 'MESH:D002118', (182, 189))	('calcium', 'Chemical', 'MESH:D002118', (241, 248))	('cholesterol', 'Chemical', 'MESH:D002784', (272, 283))	('potassium', 'Chemical', 'MESH:D011188', (52, 61))	('calcium', 'Chemical', 'MESH:D002118', (151, 158))
34836	18670617	The analysis of the main intracellular signaling pathways downstream of the activated IGF-IR, phosphatidyl inositol 3-kinase (PI3K)-Akt, and extracellular signal-regulated kinase (ERK1/2) cascades reveals that RGZ rapidly interferes with the Akt and ERK1/2 phosphorylation/activation which mediates IGF-I stimulated proliferation.	('RGZ', 'Var', (210, 213))	('ERK1/2', 'Gene', (180, 186))	('Akt', 'Gene', (132, 135))	('ERK1/2', 'Gene', '5595;5594', (180, 186))	('Akt', 'Gene', (242, 245))	('ERK1/2', 'Gene', (250, 256))	('phosphatidyl inositol 3-kinase', 'Gene', '5293', (94, 124))	('interferes', 'NegReg', (222, 232))	('IGF-IR', 'Gene', (86, 92))	('phosphatidyl inositol 3-kinase', 'Gene', (94, 124))	('Akt', 'Gene', '207', (132, 135))	('ERK1/2', 'Gene', '5595;5594', (250, 256))	('IGF-IR', 'Gene', '3480', (86, 92))	('Akt', 'Gene', '207', (242, 245))	('phosphorylation/activation', 'MPA', (257, 283))
34858	18670617	In this study, we investigate two different cell models of ACC, namely, SW13 and H295R lines, whether the TZD RGZ may exert its antiproliferative action on human ACC cell lines by interfering with the intracellular pathways activated by IGF-IR.	('TZD', 'Var', (106, 109))	('ACC', 'Phenotype', 'HP:0006744', (162, 165))	('H295R', 'Chemical', '-', (81, 86))	('antiproliferative action', 'CPA', (128, 152))	('TZD', 'Chemical', 'MESH:C089946', (106, 109))	('interfering', 'NegReg', (180, 191))	('IGF-IR', 'Gene', (237, 243))	('SW13', 'CellLine', 'CVCL:0542', (72, 76))	('IGF-IR', 'Gene', '3480', (237, 243))	('intracellular pathways', 'Pathway', (201, 223))	('human', 'Species', '9606', (156, 161))	('ACC', 'Phenotype', 'HP:0006744', (59, 62))
34859	18670617	Anti-phospho [Akt (Ser473), ERK1/2 (T202/Y204)] and anti-Akt antibodies were from Cell Signaling Technology, Inc. (Danvers, Mass, USA).	('ERK1/2', 'Gene', (28, 34))	('Akt', 'Gene', (14, 17))	('Akt', 'Gene', '207', (57, 60))	('ERK1/2', 'Gene', '5595;5594', (28, 34))	('Ser473', 'Var', (19, 25))	('Ser473', 'Chemical', '-', (19, 25))	('T202/Y204)]', 'Var', (36, 47))	('Akt', 'Gene', '207', (14, 17))	('Akt', 'Gene', (57, 60))
34871	18670617	H295R need DMEM/F-12 medium enriched with a mixture of insulin/transferrin/selenium (Sigma-Aldrich).	('transferrin', 'Gene', '7018', (63, 74))	('H295R', 'Var', (0, 5))	('H295R', 'Chemical', '-', (0, 5))	('transferrin', 'Gene', (63, 74))	('selenium', 'Chemical', 'MESH:D012643', (75, 83))	('insulin', 'Gene', '3630', (55, 62))	('insulin', 'Gene', (55, 62))	('DMEM/F-12', 'Chemical', '-', (11, 20))
34899	18670617	Following 24-hour treatment, RGZ reduces cell viability in a dose-dependent manner in SW13 cells treated (Figure 2(b)) or not (Figure 2(a)) with 10 nM IGF-I, showing an IC50 of 22.48 +- 1.54 muM (coefficient of variation 6.9%) as calculated with ALLFIT program, Figure 2(c).	('reduces', 'NegReg', (33, 40))	('cell viability', 'CPA', (41, 55))	('muM', 'Gene', '56925', (191, 194))	('SW13', 'CellLine', 'CVCL:0542', (86, 90))	('muM', 'Gene', (191, 194))	('RGZ', 'Var', (29, 32))
34904	18670617	Conversely, in H295R cells where the effect of RGZ requires longer times to become evident, RGZ is also able to revert IGF-I-stimulation (Figures 3(f)-3(h)).	('IGF-I-stimulation', 'MPA', (119, 136))	('revert', 'NegReg', (112, 118))	('RGZ', 'Var', (92, 95))	('H295R', 'Chemical', '-', (15, 20))
34907	18670617	Rapid stimulation (15 minutes) of SW13 (Figure 4(a)) and H295R (Figure 4(b)) cells with 10 nM IGF-I determines an increased phosphorylation of Akt in Ser473, resulting in the activation of the enzyme (Figure 4, upper and lower panels).	('IGF-I', 'Gene', (94, 99))	('SW13', 'CellLine', 'CVCL:0542', (34, 38))	('increased', 'PosReg', (114, 123))	('activation', 'PosReg', (175, 185))	('Ser473', 'Var', (150, 156))	('Akt', 'Gene', '207', (143, 146))	('phosphorylation', 'MPA', (124, 139))	('Ser473', 'Chemical', '-', (150, 156))	('Akt', 'Gene', (143, 146))	('enzyme', 'Enzyme', (193, 199))	('H295R', 'Chemical', '-', (57, 62))
34909	18670617	The inhibitory effect of RGZ is statistically significant versus IGF-I only, but this trend is also present on active Akt in basal conditions (Figure 4 lower panels).	('Akt', 'Gene', '207', (118, 121))	('Akt', 'Gene', (118, 121))	('inhibitory', 'NegReg', (4, 14))	('RGZ', 'Var', (25, 28))
34910	18670617	The in vitro immunokinase assay for PI3K performed on SW13 (Figure 5(a)) and on H295R (Figure 5(b)) lysates demonstrates a rapid activation (15 minutes) of the enzyme by IGF-I, which is reverted by co-incubation with RGZ.	('H295R', 'Chemical', '-', (80, 85))	('SW13', 'CellLine', 'CVCL:0542', (54, 58))	('PI3K', 'Var', (36, 40))	('activation', 'PosReg', (129, 139))
34912	18670617	Similarly, RGZ interferes with IGF-I-rapid stimulation of phosphorylation/activation of ERK1/2 in SW13 (Figure 6(a)) and H295R (Figure 6(b)), but, conversely, the effect of RGZ in basal conditions is evident in SW13 cells only (Figures 6(a), 6(b)).	('SW13', 'CellLine', 'CVCL:0542', (98, 102))	('phosphorylation/activation', 'PosReg', (58, 84))	('SW13', 'CellLine', 'CVCL:0542', (211, 215))	('ERK1/2', 'Gene', (88, 94))	('ERK1/2', 'Gene', '5595;5594', (88, 94))	('H295R', 'Chemical', '-', (121, 126))	('H295R', 'Var', (121, 126))	('phosphorylation/activation', 'MPA', (58, 84))
34915	18670617	The block of the IGF-IR system by NVP results in inhibition of IGF-I-stimulated cell proliferation evaluated at 2 and 4 days of treatment in SW13 (Figure 7(b)) and H295R, respectively, (Figure 7(c)).	('IGF-IR', 'Gene', (17, 23))	('H295R', 'Var', (164, 169))	('H295R', 'Chemical', '-', (164, 169))	('cell proliferation', 'CPA', (80, 98))	('SW13', 'CellLine', 'CVCL:0542', (141, 145))	('IGF-IR', 'Gene', '3480', (17, 23))	('inhibition', 'NegReg', (49, 59))	('IGF-I-stimulated', 'Gene', (63, 79))
34916	18670617	Moreover, a further addition of RGZ to the inhibitor results in no significant reduction of cell proliferation in the presence of IGF-I compared to NVP + IGF-I (Figures 7(b), 7(c)) suggesting that RGZ growth inhibition is mediated via IGF-IR signaling.	('IGF-IR', 'Gene', (235, 241))	('IGF-I', 'Var', (130, 135))	('IGF-IR', 'Gene', '3480', (235, 241))	('cell proliferation', 'CPA', (92, 110))	('reduction', 'NegReg', (79, 88))
34927	18670617	Moreover, in these cells, RGZ and PIO induce a more differentiated phenotype where steroidogenesis is increased due to a significant upregulation of MC2-R and Star expression.	('PIO', 'Chemical', 'MESH:D000077205', (34, 37))	('steroidogenesis', 'MPA', (83, 98))	('PIO', 'Var', (34, 37))	('MC2-R', 'Gene', (149, 154))	('upregulation', 'PosReg', (133, 145))	('MC2-R', 'Gene', '4158', (149, 154))	('increased', 'PosReg', (102, 111))	('Star expression', 'MPA', (159, 174))
34938	18670617	In SW13 as well as in H295R cells, RGZ was able to significantly reduce cell proliferation in a dose- and time-dependent manner as evaluated by different techniques (MTS, thymidine uptake and cell counting), with a calculated IC50 of 22.48 +- 1.54 muM.	('H295R', 'Chemical', '-', (22, 27))	('muM', 'Gene', '56925', (248, 251))	('SW13', 'CellLine', 'CVCL:0542', (3, 7))	('MTS', 'Gene', '8201', (166, 169))	('RGZ', 'Var', (35, 38))	('cell proliferation', 'CPA', (72, 90))	('muM', 'Gene', (248, 251))	('reduce', 'NegReg', (65, 71))	('MTS', 'Gene', (166, 169))	('thymidine', 'Chemical', 'MESH:D013936', (171, 180))
34944	18670617	However, the inhibitory effect of RGZ was reached more slowly in H295R (4-7 days) than in SW13 (1-2 days), probably due to the differences in the kinetic of duplication between the two cell lines.	('H295R', 'Chemical', '-', (65, 70))	('H295R', 'Var', (65, 70))	('SW13', 'CellLine', 'CVCL:0542', (90, 94))	('inhibitory effect', 'MPA', (13, 30))	('slowly', 'NegReg', (55, 61))
34945	18670617	Moreover, in H295R RGZ inhibition increases with the dose of IGF-I, while in SW13, the effect was similar independently of the dose of the growth factor.	('SW13', 'CellLine', 'CVCL:0542', (77, 81))	('H295R', 'Chemical', '-', (13, 18))	('H295R', 'Var', (13, 18))	('inhibition', 'NegReg', (23, 33))	('IGF-I', 'Gene', (61, 66))	('increases', 'PosReg', (34, 43))
34953	18670617	Interestingly, among the anticancer action exerted by RGZ in H295R, both PPARgamma dependent and independent effects seem to coexist in these cells, since the PPARgamma antagonist GW9662 has been demonstrated to block RGZ induction of MC2R expression and cortisol secretion but not RGZ inhibition of cell proliferation (Betz et al., 2005).	('cancer', 'Disease', (29, 35))	('H295R', 'Chemical', '-', (61, 66))	('PPARgamma', 'Gene', '5468', (159, 168))	('PPARgamma', 'Gene', '5468', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('GW9662', 'Var', (180, 186))	('cortisol secretion', 'MPA', (255, 273))	('expression', 'MPA', (240, 250))	('GW9662', 'Chemical', 'MESH:C457499', (180, 186))	('MC2R', 'Gene', (235, 239))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('PPARgamma', 'Gene', (73, 82))	('block', 'NegReg', (212, 217))	('MC2R', 'Gene', '4158', (235, 239))	('PPARgamma', 'Gene', (159, 168))
34956	18670617	In accordance, Betz and colleagues described that IGF-II production increased with time despite the clear growth-suppressive effects of RGZ and PIO in H295R.	('growth-suppressive', 'CPA', (106, 124))	('PIO', 'Chemical', 'MESH:D000077205', (144, 147))	('H295R', 'Chemical', '-', (151, 156))	('H295R', 'Var', (151, 156))	('IGF-II', 'Gene', '3481', (50, 56))	('IGF-II', 'Gene', (50, 56))	('increased', 'PosReg', (68, 77))
34984	33373169	16  Other studies have been carried out to examine the proliferation, overexpression or mutation of TFAP4 in specific types of cancer, but those studies had low sample sizes and diverse methods.	('mutation', 'Var', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('overexpression', 'PosReg', (70, 84))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('TFAP4', 'Gene', (100, 105))	('TFAP4', 'Gene', '7023', (100, 105))
35010	33373169	TMB measures the mutation number in a specific cancer genome.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('TMB', 'Chemical', '-', (0, 3))	('cancer', 'Disease', (47, 53))	('mutation', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
35029	33373169	In the OS analysis, Cox regression identified that high TFAP4 expression was a risk factor for ACC (P = .049), KIRC (P < .001), KIRP (P < .001), SKCM (P = .026) and LIHC (P < .001); however, it appeared to be a protective factor in UVM (P = .009), READ (P = .012), STAD (P = .046) and LGG (P = .008), as shown in Figure 3A and Table 1.	('TFAP4', 'Gene', '7023', (56, 61))	('ACC', 'Disease', (95, 98))	('high', 'Var', (51, 55))	('UVM', 'Disease', (232, 235))	('TFAP4', 'Gene', (56, 61))
35030	33373169	KM analysis showed that patients with higher TFAP4 levels had a shorter OS compared with patients with lower TFAP4 levels in KIRC (P = .010), KIRP (P < .001), LIHC (P = .050) and UCEC (P = .015), whereas those with increased TFAP4 levels showed a superior OS to those with decreased TFAP4 levels in READ (P = .045), THYM (P = .038) and UVM (P = .004), as seen in Figure 3B-H. Cox regression analysis of DSS identified that high TFAP4 expression was a risk factor in KIRC (P < .001), LIHC (P = .019), KIRP (P < .001), SKCM (P = .019) and THCA (P = .014).	('KIRC', 'Disease', (466, 470))	('SKCM', 'Disease', (517, 521))	('DSS', 'Chemical', '-', (403, 406))	('high', 'Var', (423, 427))	('THCA', 'Chemical', '-', (537, 541))	('TFAP4', 'Gene', (428, 433))	('TFAP4', 'Gene', '7023', (428, 433))	('TFAP4', 'Gene', (283, 288))	('TFAP4', 'Gene', (109, 114))	('TFAP4', 'Gene', '7023', (283, 288))	('LIHC', 'Disease', (483, 487))	('TFAP4', 'Gene', '7023', (109, 114))	('TFAP4', 'Gene', (45, 50))	('TFAP4', 'Gene', (225, 230))	('TFAP4', 'Gene', '7023', (45, 50))	('TFAP4', 'Gene', '7023', (225, 230))	('lower TFAP4 levels', 'Phenotype', 'HP:0040209', (103, 121))	('KIRP', 'Disease', (500, 504))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (24, 32))	('THCA', 'Disease', (537, 541))
35032	33373169	Patients with increased TFAP4 levels showed superior DSS to those with decreased TFAP4 levels in BRCA (P = .046) and UVM (P < .001), as seen in Figure 4B-G. Cox regression analysis of PFI identified high TFAP4 expression as a risk factor in ACC (P = .010), KIRP (P = .032), KIRC (P < .001), PRAD (P = .001), LIHC (P < .001), THCA (P = .004) and UCEC (P = .008), while it was a protective factor in GBM (P = .004), LGG (P < .001) and LUSC (P = .017) (Figure 5A).	('PRAD', 'Disease', (291, 295))	('KIRC', 'Disease', (274, 278))	('TFAP4', 'Gene', (81, 86))	('LGG', 'Disease', (414, 417))	('high', 'Var', (199, 203))	('TFAP4', 'Gene', (24, 29))	('TFAP4', 'Gene', '7023', (81, 86))	('THCA', 'Chemical', '-', (325, 329))	('TFAP4', 'Gene', '7023', (24, 29))	('Patients', 'Species', '9606', (0, 8))	('KIRP', 'Disease', (257, 261))	('decreased TFAP4 levels in BRCA', 'Phenotype', 'HP:0040209', (71, 101))	('TFAP4', 'Gene', (204, 209))	('DSS', 'Chemical', '-', (53, 56))	('UCEC', 'Disease', (345, 349))	('TFAP4', 'Gene', '7023', (204, 209))	('LIHC', 'Disease', (308, 312))	('THCA', 'Disease', (325, 329))	('ACC', 'Disease', (241, 244))
35060	33373169	We also found that most cancer types had a higher number of TFAP4 alternations, and that abnormal TFAP4 expression served as a prognostic factor in some types of cancer, based on both Cox and KM survival analyses.	('alternations', 'Var', (66, 78))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('abnormal', 'Var', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (162, 168))	('TFAP4', 'Gene', (98, 103))	('TFAP4', 'Gene', (60, 65))	('TFAP4', 'Gene', '7023', (98, 103))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('TFAP4', 'Gene', '7023', (60, 65))	('expression', 'MPA', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
35082	33373169	32  Specific gene mutations may predict patient prognosis and treatment response.	('patient', 'Species', '9606', (40, 47))	('predict', 'Reg', (32, 39))	('mutations', 'Var', (18, 27))
35109	33013829	Their functions in immune regulation include acting against pathogen invasion, removing mutant cells, and triggering inflammation.	('inflammation', 'Disease', 'MESH:D007249', (117, 129))	('mutant', 'Var', (88, 94))	('triggering', 'Reg', (106, 116))	('inflammation', 'Disease', (117, 129))
35114	33013829	Reactive oxygen/nitrogen species (ROS/RNS) produced by immune cells and epithelial cells fight against microbial invasion and eliminate the mutant cell.	('nitrogen', 'Chemical', 'MESH:D009584', (16, 24))	('ROS', 'Chemical', '-', (34, 37))	('RNS', 'Chemical', 'MESH:D011886', (38, 41))	('microbial invasion', 'CPA', (103, 121))	('eliminate', 'NegReg', (126, 135))	('mutant', 'Var', (140, 146))
35180	33013829	The dysfunction of the PI3K/AKT/mTOR pathway interferes with the normal cell-cycle and causes tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('AKT', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mTOR', 'Gene', '2475', (32, 36))	('interferes', 'NegReg', (45, 55))	('dysfunction', 'Var', (4, 15))	('normal cell-cycle', 'CPA', (65, 82))	('mTOR', 'Gene', (32, 36))	('tumor', 'Disease', (94, 99))	('causes', 'Reg', (87, 93))	('AKT', 'Gene', '207', (28, 31))
35181	33013829	Similarly, NPTX1 and NPTX2 can inhibit cyclin A2 and CDK2 through the Rb/E2F signaling pathway, respectively, thus inducing G0/G1 arrest in pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('CDK2', 'Gene', '1017', (53, 57))	('NPTX1', 'Gene', (11, 16))	('NPTX1', 'Gene', '4884', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('arrest', 'Disease', 'MESH:D006323', (130, 136))	('cyclin A2', 'Gene', (39, 48))	('inducing', 'Reg', (115, 123))	('NPTX2', 'Var', (21, 26))	('Rb/E2F signaling pathway', 'Pathway', (70, 94))	('cyclin A2', 'Gene', '890', (39, 48))	('inhibit', 'NegReg', (31, 38))	('CDK2', 'Gene', (53, 57))	('arrest', 'Disease', (130, 136))	('pancreatic cancer', 'Disease', (140, 157))
35182	33013829	Overexpression of NPTX2 has been identified as a prognosis factor in clear cell renal cell carcinoma, and its interaction with AMPA-selective glutamate receptor-4 affects tumor cell viability and metastasis.	('AMPA-selective glutamate receptor-4', 'Gene', '2893', (127, 162))	('clear cell renal cell carcinoma', 'Disease', (69, 100))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (80, 100))	('AMPA-selective glutamate receptor-4', 'Gene', (127, 162))	('interaction', 'Interaction', (110, 121))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (69, 100))	('Overexpression', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('affects', 'Reg', (163, 170))	('metastasis', 'CPA', (196, 206))	('NPTX2', 'Gene', (18, 23))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (69, 100))
35185	33013829	On the contrary, a low level of NPTX2 showed better response to neoadjuvant chemoradiation (CRT) treatment in rectal adenocarcinomas.	('adenocarcinomas', 'Disease', 'MESH:D000230', (117, 132))	('NPTX2', 'Gene', (32, 37))	('better', 'PosReg', (45, 51))	('adenocarcinomas', 'Disease', (117, 132))	('low level', 'Var', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('response', 'MPA', (52, 60))
35205	33013829	Furthermore, the N-terminal domain of PTX3 enhances tissue repair and remodeling functions.	('N-terminal domain', 'Var', (17, 34))	('enhances', 'PosReg', (43, 51))	('tissue repair', 'CPA', (52, 65))	('PTX3', 'Gene', (38, 42))	('PTX3', 'Gene', '5806', (38, 42))	('remodeling functions', 'CPA', (70, 90))
35222	33013829	For short pentraxins, low expression of CRP showed better survival outcomes in kidney renal papillary cell carcinoma (KIRP) than high CRP expression (Figure 4A).	('low expression', 'Var', (22, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (79, 116))	('CRP', 'Gene', (40, 43))	('CRP', 'Gene', '1401', (40, 43))	('CRP', 'Gene', (134, 137))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (86, 116))	('CRP', 'Gene', '1401', (134, 137))	('kidney renal papillary cell carcinoma', 'Disease', (79, 116))	('pentraxins', 'Chemical', '-', (10, 20))
35225	33013829	We revealed that low NPTX1 expression improved the survival outcomes in patients with adrenocortical carcinoma (ACC), urothelial bladder carcinoma (BCLA), kidney renal papillary cell carcinoma (KIRP), stomach adenocarcinoma (STAD) and uveal melanoma (UVM), (Figures 4D-H).	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('NPTX1', 'Gene', '4884', (21, 26))	('expression', 'MPA', (27, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (235, 249))	('uveal melanoma', 'Disease', (235, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('ACC', 'Phenotype', 'HP:0006744', (112, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (235, 249))	('low', 'Var', (17, 20))	('AD', 'Disease', (227, 229))	('AD', 'Phenotype', 'HP:0002511', (227, 229))	('survival outcomes', 'CPA', (51, 68))	('improved', 'PosReg', (38, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (155, 192))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (86, 110))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (162, 192))	('UVM', 'Phenotype', 'HP:0007716', (251, 254))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (118, 146))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (201, 223))	('AD', 'Disease', 'MESH:D000544', (227, 229))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (86, 110))	('urothelial bladder carcinoma', 'Disease', (118, 146))	('stomach adenocarcinoma', 'Disease', (201, 223))	('NPTX1', 'Gene', (21, 26))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (129, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('adrenocortical carcinoma', 'Disease', (86, 110))	('kidney renal papillary cell carcinoma', 'Disease', (155, 192))	('patients', 'Species', '9606', (72, 80))
35226	33013829	Patients that showed high expression of NPTX2 frequently exhibited worse survival outcomes for glioblastoma multiforme (GBM), kidney renal papillary cell carcinoma (KIRP), lung squamous cell carcinoma (LUSC) and uveal melanoma (UVM), (Figures 4I-L).	('glioblastoma multiforme', 'Disease', (95, 118))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (95, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (212, 226))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (133, 163))	('uveal melanoma', 'Disease', (212, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('NPTX2', 'Gene', (40, 45))	('Patients', 'Species', '9606', (0, 8))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (126, 163))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (172, 200))	('UVM', 'Phenotype', 'HP:0007716', (228, 231))	('LUSC', 'Phenotype', 'HP:0030359', (202, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 200))	('lung squamous cell carcinoma', 'Disease', (172, 200))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('high expression', 'Var', (21, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('kidney renal papillary cell carcinoma', 'Disease', (126, 163))	('uveal melanoma', 'Disease', 'MESH:C536494', (212, 226))
35248	30897760	A Systematic Pan-Cancer Analysis of Genetic Heterogeneity Reveals Associations with Epigenetic Modifiers Intratumor genetic heterogeneity (ITH) is the main obstacle to effective cancer treatment and a major mechanism of drug resistance.	('Epigenetic Modifiers', 'Var', (84, 104))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('drug resistance', 'Phenotype', 'HP:0020174', (220, 235))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('Associations', 'Interaction', (66, 78))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
35251	30897760	Integration of ITH scores and somatic variants detected in each tumor sample revealed that mutations in epigenetic modifier genes are associated with higher ITH levels.	('associated', 'Reg', (134, 144))	('tumor', 'Disease', (64, 69))	('higher', 'PosReg', (150, 156))	('ITH levels', 'MPA', (157, 167))	('mutations', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
35252	30897760	Indeed, the knockout of histone methyltransferase SETD2 or DNA methyltransferase DNMT3A using the CRISPR/Cas9 system on cancer cells led to significant expansion of genetically-distinct clones and culminated in highly heterogeneous cell populations.	('genetically-distinct clones', 'CPA', (165, 192))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('knockout', 'Var', (12, 20))	('expansion', 'PosReg', (152, 161))	('SETD2', 'Gene', '29072', (50, 55))	('DNMT3A', 'Gene', (81, 87))	('DNMT3A', 'Gene', '1788', (81, 87))	('culminated in', 'Reg', (197, 210))	('SETD2', 'Gene', (50, 55))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
35259	30897760	By facilitating the emergence of nucleotide sequence mutations, copy-number alterations, chromosomal translocations or aneuploidies, genomic instability has been regarded as the major source of ITH.	('copy-number alterations', 'Var', (64, 87))	('aneuploidies', 'Disease', (119, 131))	('aneuploidies', 'Disease', 'MESH:D000782', (119, 131))	('nucleotide sequence mutations', 'Var', (33, 62))	('chromosomal translocations', 'Var', (89, 115))
35261	30897760	Besides mutations, cancer cells invariably present with some degree of epigenetic alterations that contribute to the acquisition of the cancer hallmarks.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer hallmarks', 'Disease', 'MESH:D009369', (136, 152))	('cancer', 'Disease', (19, 25))	('epigenetic alterations', 'Var', (71, 93))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer hallmarks', 'Disease', (136, 152))
35262	30897760	Indeed, there is evidence that epigenomic reprogramming plays a seminal role in tumorigenesis by creating a progenitor-like cell state that facilitates expression of driver mutations and tumor initiation.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('driver mutations', 'Var', (166, 182))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (187, 192))	('epigenomic reprogramming', 'Var', (31, 55))	('expression', 'MPA', (152, 162))	('facilitates', 'PosReg', (140, 151))
35263	30897760	For instance, acute monocytic leukemias frequently (20.5%) carry mutations in the de novo DNA methyltransferase gene DNMT3A, displaying aberrant genome-wide DNA methylation profiles.	('monocytic leukemias', 'Disease', (20, 39))	('leukemias', 'Phenotype', 'HP:0001909', (30, 39))	('acute monocytic leukemias', 'Phenotype', 'HP:0004845', (14, 39))	('DNMT3A', 'Gene', (117, 123))	('DNMT3A', 'Gene', '1788', (117, 123))	('monocytic leukemias', 'Disease', 'MESH:D007951', (20, 39))	('mutations', 'Var', (65, 74))
35264	30897760	Ten percent of kidney renal clear cell carcinomas (KIRC) have mutations in SETD2, the methyltransferase responsible for trimethylation of Lys36 in histone H3 (H3K36me3), which is necessary for accurate gene expression and DNA repair.	('kidney renal clear cell carcinomas', 'Disease', (15, 49))	('kidney renal clear cell carcinomas', 'Disease', 'MESH:C538614', (15, 49))	('SETD2', 'Gene', '29072', (75, 80))	('SETD2', 'Gene', (75, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('mutations', 'Var', (62, 71))	('Lys36', 'Chemical', '-', (138, 143))
35265	30897760	H3K36me3 is also involved in targeting DNMT3A to chromatin, highlighting the finely tuned epigenetic interplay between histone and DNA methylation that is needed for normal cell function and is frequently disrupted in cancer cells.	('DNMT3A', 'Gene', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('DNMT3A', 'Gene', '1788', (39, 45))	('H3K36me3', 'Var', (0, 8))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
35266	30897760	While epigenetic deregulation in cancer arises primarily as a consequence of DNA mutations, the view that altered epigenomes may also change DNA mutation rates highlights reciprocal interactions that contribute to cancer development.	('change', 'Reg', (134, 140))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('DNA', 'Gene', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (81, 90))	('DNA', 'Gene', (77, 80))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
35267	30897760	Accordingly, epigenomic disruption should favor the development of genetically-diverse tumor cell populations, fueling ITH.	('favor', 'PosReg', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('epigenomic disruption', 'Var', (13, 34))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('development', 'CPA', (52, 63))
35270	30897760	Our integrative pan-cancer characterization of somatic variants and ITH identified mutations in epigenetic modifier genes that display an association with increased clonal evolution across several cancer types.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('variants', 'Var', (55, 63))	('cancer', 'Disease', (197, 203))	('epigenetic modifier genes', 'Gene', (96, 121))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
35275	30897760	The ITH score was obtained using the mutant-allele tumor heterogeneity (MATH) method (Figure 1A and Table S1).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutant-allele', 'Var', (37, 50))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
35280	30897760	Individual analysis of each cancer type revealed that only thyroid carcinoma (THCA), pancreatic adenocarcinoma (PAAD) and kidney renal clear cell carcinoma (KIRC) exhibited a statistically significant positive correlation between genomic instability and ITH (Figure 1B).	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('only thyroid carcinoma', 'Disease', 'MESH:D013964', (54, 76))	('kidney renal clear cell carcinoma', 'Disease', (122, 155))	('ITH', 'Disease', (254, 257))	('pancreatic adenocarcinoma', 'Disease', (85, 110))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (85, 110))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('only thyroid carcinoma', 'Disease', (54, 76))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (85, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('genomic', 'Var', (230, 237))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (59, 76))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (122, 155))	('THCA', 'Phenotype', 'HP:0002890', (78, 82))
35283	30897760	To investigate whether epigenomic deregulation drives the development of tumors with high levels of ITH, we focused our analysis on KIRC, the cancer type with the highest frequency of mutations in epigenetic modifiers (Figure 2A).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('mutations', 'Var', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (142, 148))
35284	30897760	The important role of epigenomic deregulation in the development and progression of KIRC is illustrated by the finding that patients with mutations in epigenetic modifiers have worse overall survival compared to those without mutations in these genes (p < 0.05, log-rank test; Figure 2B).	('overall survival', 'MPA', (183, 199))	('worse', 'NegReg', (177, 182))	('mutations', 'Var', (138, 147))	('patients', 'Species', '9606', (124, 132))	('epigenetic', 'Gene', (151, 161))
35285	30897760	Moreover, the presence of mutations in epigenetic modifier genes correlates positively with increased ITH across different cancer types (Figure 2D and Table S2).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('epigenetic modifier genes', 'Gene', (39, 64))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('mutations', 'Var', (26, 35))	('increased', 'PosReg', (92, 101))	('cancer', 'Disease', (123, 129))	('ITH', 'Disease', (102, 105))
35286	30897760	The strongest predictor of high ITH in both KIRC alone or across several cancer types was the presence of mutations in SETD2, DNMT1 and DNTM3A (Figure 2E).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('SETD2', 'Gene', '29072', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('SETD2', 'Gene', (119, 124))	('DNMT1', 'Gene', (126, 131))	('mutations', 'Var', (106, 115))	('DNMT1', 'Gene', '1786', (126, 131))	('DNTM3A', 'Gene', (136, 142))
35287	30897760	Importantly, we could model 32% of variability in KIRC ITH using only mutations in SETD2, DNMT1 and DNTM3A (Figure 2F).	('mutations', 'Var', (70, 79))	('DNMT1', 'Gene', (90, 95))	('DNTM3A', 'Gene', (100, 106))	('DNMT1', 'Gene', '1786', (90, 95))	('SETD2', 'Gene', '29072', (83, 88))	('SETD2', 'Gene', (83, 88))
35289	30897760	These data suggest that epigenomic deregulation is an important determinant of ITH and identify mutations in SETD2, DNMT1 and DNTM3A as candidate drivers of ITH.	('ITH', 'Disease', (79, 82))	('SETD2', 'Gene', '29072', (109, 114))	('DNMT1', 'Gene', (116, 121))	('SETD2', 'Gene', (109, 114))	('DNMT1', 'Gene', '1786', (116, 121))	('mutations', 'Var', (96, 105))	('DNTM3A', 'Gene', (126, 132))
35290	30897760	We next sought to experimentally validate the role of SETD2, DNMT1 and DNMT3A mutations in driving the emergence of genetically-distinct subclonal cell populations.	('DNMT3A', 'Gene', (71, 77))	('DNMT3A', 'Gene', '1788', (71, 77))	('SETD2', 'Gene', '29072', (54, 59))	('DNMT1', 'Gene', (61, 66))	('SETD2', 'Gene', (54, 59))	('mutations', 'Var', (78, 87))	('DNMT1', 'Gene', '1786', (61, 66))
35293	30897760	Importantly, knockout of DNMT1 rendered KIRC cells senescent (Figure 3B), in contrast to DNMT3A and SETD2 depletion, which were well tolerated and did not significantly affect cell proliferation (Figure 3C).	('DNMT1', 'Gene', '1786', (25, 30))	('knockout', 'Var', (13, 21))	('DNMT3A', 'Gene', (89, 95))	('DNMT3A', 'Gene', '1788', (89, 95))	('senescent', 'CPA', (51, 60))	('SETD2', 'Gene', '29072', (100, 105))	('DNMT1', 'Gene', (25, 30))	('SETD2', 'Gene', (100, 105))
35294	30897760	This finding suggests that additional compensatory mutations are required to allow the proliferation of DNMT1 mutant cells within tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('DNMT1', 'Gene', (104, 109))	('DNMT1', 'Gene', '1786', (104, 109))	('mutant', 'Var', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
35295	30897760	Alternatively, DNMT1 mutant clones could be selected during tumor evolution due their ability to promote carcinogenesis through the senescence-associated secretory phenotype.	('carcinogenesis', 'Disease', 'MESH:D063646', (105, 119))	('mutant', 'Var', (21, 27))	('DNMT1', 'Gene', (15, 20))	('carcinogenesis', 'Disease', (105, 119))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('DNMT1', 'Gene', '1786', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('senescence-associated secretory phenotype', 'MPA', (132, 173))	('promote', 'PosReg', (97, 104))
35296	30897760	To investigate whether loss of DNMT3A or SETD2 drives the acquisition of genetically-heterogeneous cell populations over time, we performed whole-exome sequencing of control and knockout cells cultured during 1, 3 and 6 months (Figure 4A).	('DNMT3A', 'Gene', (31, 37))	('SETD2', 'Gene', '29072', (41, 46))	('DNMT3A', 'Gene', '1788', (31, 37))	('loss', 'Var', (23, 27))	('SETD2', 'Gene', (41, 46))
35298	30897760	Compared to control cells, loss of either SETD2 or DNMT3A resulted in significantly increased and comparable levels of ITH after just one month (Figure 4B and Table S4).	('loss', 'Var', (27, 31))	('ITH', 'MPA', (119, 122))	('SETD2', 'Gene', '29072', (42, 47))	('increased', 'PosReg', (84, 93))	('DNMT3A', 'Gene', (51, 57))	('DNMT3A', 'Gene', '1788', (51, 57))	('SETD2', 'Gene', (42, 47))
35299	30897760	However, while ITH rose for up to three months after SETD2 depletion, it remained constant through time in DNMT3A knockout cells (Figure 4B).	('SETD2', 'Gene', (53, 58))	('depletion', 'Var', (59, 68))	('rose', 'PosReg', (19, 23))	('DNMT3A', 'Gene', (107, 113))	('DNMT3A', 'Gene', '1788', (107, 113))	('SETD2', 'Gene', '29072', (53, 58))
35302	30897760	Altogether, these data suggest that loss of SETD2 or DNMT3A drives specific patterns of clonal evolution that culminate in tumors with increased levels of ITH.	('DNMT3A', 'Gene', (53, 59))	('tumors', 'Disease', (123, 129))	('DNMT3A', 'Gene', '1788', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('SETD2', 'Gene', '29072', (44, 49))	('loss', 'Var', (36, 40))	('increased', 'PosReg', (135, 144))	('SETD2', 'Gene', (44, 49))	('culminate in', 'Reg', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
35303	30897760	The increased ITH observed knockout of SETD2 or DNMT3A knockout suggests that new clones carrying phenotypic traits that confer selective advantage within the cell populations have expanded and were selected.	('SETD2', 'Gene', (39, 44))	('DNMT3A', 'Gene', (48, 54))	('DNMT3A', 'Gene', '1788', (48, 54))	('knockout', 'Var', (55, 63))	('SETD2', 'Gene', '29072', (39, 44))
35307	30897760	Basal mitochondrial respiration in knockout and parental cells was equally efficient (Figure 5B), indicating that no major intrinsic metabolic alterations were caused upon loss of either SETD2 or DNMT3A.	('SETD2', 'Gene', (187, 192))	('loss', 'Var', (172, 176))	('DNMT3A', 'Gene', (196, 202))	('DNMT3A', 'Gene', '1788', (196, 202))	('SETD2', 'Gene', '29072', (187, 192))
35309	30897760	Both parameters were significantly increased in SETD2 and DNMT3A knockout cells when compared to parental cells under similar conditions (Figure 5C,D).	('increased', 'PosReg', (35, 44))	('DNMT3A', 'Gene', (58, 64))	('SETD2', 'Gene', '29072', (48, 53))	('DNMT3A', 'Gene', '1788', (58, 64))	('knockout', 'Var', (65, 73))	('SETD2', 'Gene', (48, 53))
35310	30897760	Analysis of SETD2 and DNMT3A knockout cells revealed mutations in genes involved in mitochondria biogenesis and function (Table S5); however, inspection of mitochondria network in knockout cells using fluorescence confocal microscopy did not reveal any major alterations (Figure 5E).	('SETD2', 'Gene', '29072', (12, 17))	('SETD2', 'Gene', (12, 17))	('DNMT3A', 'Gene', (22, 28))	('DNMT3A', 'Gene', '1788', (22, 28))	('mutations', 'Var', (53, 62))
35317	30897760	Recently, high concordance was observed between the evolution of genetic and epigenetic diversification in esophageal squamous cell carcinoma and in glioma, disclosing possible relationships between genomic and epigenomic alterations during the clonal evolution of tumors.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('glioma', 'Disease', (149, 155))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (107, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('epigenetic', 'Var', (77, 87))	('tumors', 'Disease', (265, 271))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('esophageal squamous cell carcinoma', 'Disease', (107, 141))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (149, 155))
35318	30897760	An interesting hypothesis linking DNA mutations and epigenetics in cancer is that altered DNA methylation or chromatin modifications may accelerate mutation rates.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('accelerate', 'PosReg', (137, 147))	('chromatin', 'MPA', (109, 118))	('DNA', 'Protein', (90, 93))	('mutation rates', 'MPA', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('altered', 'Var', (82, 89))
35319	30897760	For example, abnormal DNA hypomethylation near guanine quadruplexes (G4s)-rich regions is a common signature for many DNA breakpoints associated with somatic copy-number alterations.	('G4s', 'Gene', (69, 72))	('DNA', 'Disease', (118, 121))	('abnormal', 'Var', (13, 21))	('guanine', 'Chemical', 'MESH:D006147', (47, 54))	('G4s', 'Gene', '411', (69, 72))
35320	30897760	This finding suggests that DNA hypomethylation in genomic regions enriched for G4s acts as a mutagenic factor in cancer.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('hypomethylation', 'Var', (31, 46))	('cancer', 'Disease', (113, 119))	('mutagenic', 'Reg', (93, 102))	('G4s', 'Gene', '411', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('G4s', 'Gene', (79, 82))
35322	30897760	Together, these data establish a strong association between epigenomic deregulation:namely, DNA and histone methylation and genomic mutations, which we show play important roles during clonal evolution and genetic diversification of tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Disease', (233, 239))	('mutations', 'Var', (132, 141))
35323	30897760	Particularly, we identified and validated mutations in the methyltransferase genes SETD2 and DNMT3A as potent drivers of ITH.	('ITH', 'Disease', (121, 124))	('SETD2', 'Gene', '29072', (83, 88))	('SETD2', 'Gene', (83, 88))	('mutations', 'Var', (42, 51))	('DNMT3A', 'Gene', (93, 99))	('DNMT3A', 'Gene', '1788', (93, 99))
35328	30897760	We thus reasoned that the increased ITH observed upon SETD2 or DNMT3A knockout likely underpins phenotypic variations in mitochondrial metabolism upon which natural selection could act.	('ITH', 'MPA', (36, 39))	('SETD2', 'Gene', '29072', (54, 59))	('mitochondrial metabolism', 'MPA', (121, 145))	('SETD2', 'Gene', (54, 59))	('increased', 'PosReg', (26, 35))	('DNMT3A', 'Gene', (63, 69))	('DNMT3A', 'Gene', '1788', (63, 69))	('knockout', 'Var', (70, 78))
35329	30897760	In agreement with this, we observed that both SETD2 and DNMT3A depleted cell populations have increased bioenergetic performance under stress conditions, a phenotype that was accompanied by mutations in genes involved in mitochondria function.	('SETD2', 'Gene', (46, 51))	('mutations', 'Var', (190, 199))	('increased', 'PosReg', (94, 103))	('bioenergetic', 'MPA', (104, 116))	('DNMT3A', 'Gene', (56, 62))	('DNMT3A', 'Gene', '1788', (56, 62))	('SETD2', 'Gene', '29072', (46, 51))
35330	30897760	Caki-2 cells (Cell Line Services, Eppelheim, Germany) that do not have SETD2 mutations were selected as a cellular model of KIRC.	('SETD2', 'Gene', (71, 76))	('SETD2', 'Gene', '29072', (71, 76))	('mutations', 'Var', (77, 86))	('Caki-2', 'CellLine', 'CVCL:0235', (0, 6))
35339	30897760	After 1 h blocking with 5% non-fat dry milk in 1x PBS, 0.1% Tween20 at room temperature, membranes were incubated with antibodies as follows: anti-DNMT1 (2 microg/mL, Active Motif, Carlsbad, CA, USA), anti-DNMT3A (1:1000, Cell Signaling), anti-H3K36me3 (1:500, Abcam, Cambridge, UK), alpha-tubulin (1:15,000, Sigma-Aldrich) and anti-histone H3 (1:1000, Abcam).	('DNMT1', 'Gene', '1786', (147, 152))	('alpha-tubulin', 'Protein', (284, 297))	('anti-H3K36me3', 'Var', (239, 252))	('DNMT3A', 'Gene', (206, 212))	('DNMT3A', 'Gene', '1788', (206, 212))	('anti-histone', 'Var', (328, 340))	('DNMT1', 'Gene', (147, 152))	('PBS', 'Chemical', 'MESH:D007854', (50, 53))
35358	30897760	Genomic instability was calculated as the absolute number of mutations and INDEL observed in each tumor sample.	('INDEL', 'Var', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mutations', 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
35361	30897760	To identify driver-gene mutations, a binary matrix was produced representing the presence/absence of mutations for each gene on each tumor sample, eliminating the bias introduced by hypermutated genes.	('mutations', 'Var', (24, 33))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
35374	30897760	Single-nucleotide variants reported in dbSNP150 were filtered out from VCF output files, unless they were also present in COSMICv85.	('dbSNP150', 'Gene', (39, 47))	('Single-nucleotide variants', 'Var', (0, 26))	('dbSNP150', 'Chemical', '-', (39, 47))
35375	30897760	The ITH from control and knockout cell lines was determined using the mutant-allele tumor heterogeneity (MATH) approach.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (84, 89))	('mutant-allele', 'Var', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
35377	30897760	Our pan-cancer analyses revealed that mutations in epigenetic modifiers, namely SETD2 and DNMT3A, are major determinants of ITH.	('SETD2', 'Gene', (80, 85))	('cancer', 'Disease', (8, 14))	('ITH', 'Disease', (124, 127))	('determinants', 'Reg', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('DNMT3A', 'Gene', (90, 96))	('DNMT3A', 'Gene', '1788', (90, 96))	('mutations', 'Var', (38, 47))	('SETD2', 'Gene', '29072', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
35379	30897760	For instance, SETD2 mutations are found in 10% of KIRC, 9% of non-small cell lung carcinomas, 15% of pediatric high-grade gliomas and 8% of adult high-grade gliomas, whereas mutations in DNMT3A are observed in over 20% acute monocytic leukemias.	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (62, 92))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('DNMT3A', 'Gene', (187, 193))	('leukemias', 'Phenotype', 'HP:0001909', (235, 244))	('monocytic leukemias', 'Disease', 'MESH:D007951', (225, 244))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('gliomas', 'Disease', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('cell lung carcinomas', 'Disease', (72, 92))	('cell lung carcinomas', 'Disease', 'MESH:D055752', (72, 92))	('acute monocytic leukemias', 'Phenotype', 'HP:0004845', (219, 244))	('monocytic leukemias', 'Disease', (225, 244))	('SETD2', 'Gene', (14, 19))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('mutations', 'Var', (20, 29))	('DNMT3A', 'Gene', '1788', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('SETD2', 'Gene', '29072', (14, 19))	('gliomas', 'Disease', (157, 164))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (66, 92))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))
35381	30897760	Our experimental validation of the role of specific epigenetic modifier genes in driving ITH reveals novel biomarkers and/or therapeutic targets that may contribute to more effective cancer prognoses and treatment.	('cancer', 'Disease', (183, 189))	('epigenetic modifier genes', 'Var', (52, 77))	('contribute', 'Reg', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
35382	30897760	The following are available online at , Method S1: Pan-Cancer Data Sets, Method S2: Intratumor heterogeneity score using mutant-allele tumor heterogeneity (MATH) score, Method S3: Identification of deregulated cancer pathways associated with ITH, Method S4: Pan-cancer discovery of driver-gene mutations of ITH, Method S5: Whole-exome sequencing and variant calling for human cancer cell lines, Method S6: Clonality analyses.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Disease', (376, 382))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('deregulated', 'MPA', (198, 209))	('Pan-cancer', 'Disease', 'MESH:C537931', (258, 268))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('mutations', 'Var', (294, 303))	('tumor', 'Disease', (89, 94))	('cancer', 'Disease', (262, 268))	('cancer', 'Disease', 'MESH:D009369', (376, 382))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('tumor', 'Disease', (135, 140))	('ITH', 'Gene', (307, 310))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('human', 'Species', '9606', (370, 375))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('cancer', 'Disease', (210, 216))	('Pan-cancer', 'Disease', (258, 268))
35383	30897760	This file contains the description of the computational methods used in this study, Table S1: Clinical data and genomic features (genomic instability and MATH values) for samples from 16 different TCGA cancer types, Table S2: Linear models associating mutations in functional groups and ITH for each cancer type, Table S3: Predicted effect of DNMT1, DNMT3A and SETD2 mutations in KIRC samples from cBioportal, Table S4: ITH values (MATH) estimated for control, DNTM3A and SETD2 KO cell lines, Table S5: Mutations generated after SETD2 and DNMT3A knockouts (not present in controls), including the mutations with GO terms associated with mitochondria, Table S6: Material and Methods Table (e.g., plasmids, gRNAs, antibodies, primers and other products), Table S7: Read length, total reads and mapped reads for each condition.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('SETD2', 'Gene', (361, 366))	('SETD2', 'Gene', (472, 477))	('DNMT3A', 'Gene', '1788', (350, 356))	('SETD2', 'Gene', '29072', (361, 366))	('SETD2', 'Gene', '29072', (472, 477))	('DNMT3A', 'Gene', '1788', (539, 545))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('DNMT1', 'Gene', '1786', (343, 348))	('cancer', 'Disease', (300, 306))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('DNMT3A', 'Gene', (350, 356))	('SETD2', 'Gene', (529, 534))	('DNMT3A', 'Gene', (539, 545))	('DNMT1', 'Gene', (343, 348))	('SETD2', 'Gene', '29072', (529, 534))	('mutations', 'Var', (367, 376))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (300, 306))
35388	30709931	Landscape of germline and somatic mitochondrial DNA mutations in pediatric malignancies Little is known about the spectrum of mitochondrial DNA (mtDNA) mutations across pediatric malignancies.	('mutations', 'Var', (52, 61))	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('malignancies', 'Disease', (75, 87))	('malignancies', 'Disease', (179, 191))	('mitochondrial DNA', 'Gene', (34, 51))
35390	30709931	We identified 391 mtDNA mutations in 284 tumors including 45 loss-of-function mutations, which clustered at 4 statistically significant hotspots in MT-COX3, MT-ND4, and MT-ND5, and at a mutation hotspot in MT-tRNA-MET.	('MT-ND4', 'Gene', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('MT-ND4', 'Gene', '4538', (157, 163))	('COX3', 'Gene', (151, 155))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('MT-ND5', 'Gene', '4540', (169, 175))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (78, 87))	('COX3', 'Gene', '4514', (151, 155))	('mutations', 'Var', (24, 33))	('mtDNA', 'Gene', (18, 23))	('loss-of-function', 'NegReg', (61, 77))	('MT-ND5', 'Gene', (169, 175))
35391	30709931	A skewed ratio (4.83) of non-synonymous versus synonymous (dN/dS) mtDNA mutations with high statistical significance was identified based on Monte Carlo simulations in the tumors.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mtDNA', 'Gene', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Disease', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('dN', 'Chemical', '-', (59, 61))	('dS', 'Chemical', 'MESH:D003903', (62, 64))
35393	30709931	mtDNA mutations varied by cancer type and mtDNA haplogroup.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mtDNA', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
35394	30709931	Collectively, these results suggest that deleterious mtDNA mutations play a role in the development and progression of pediatric cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('role', 'Reg', (76, 80))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('mtDNA', 'Gene', (53, 58))	('cancers', 'Disease', (129, 136))	('mutations', 'Var', (59, 68))
35398	30709931	Many aspects of mitochondrial biology are important in cancer, including mitochondrial biogenesis and turnover, fission and fusion dynamics, oxidative stress, metabolism, bioenergetics, signaling, and variation in mitochondrial DNA (mtDNA) sequence and abundance.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('variation', 'Var', (201, 210))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('oxidative stress', 'Phenotype', 'HP:0025464', (141, 157))	('cancer', 'Disease', (55, 61))
35401	30709931	At least 8.5% of pediatric cancer patients have germline mutations in cancer predisposition genes.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Disease', (27, 33))	('germline mutations', 'Var', (48, 66))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))
35404	30709931	Epigenetic factors, such as chromatin remodeling and histone modifications, also appear to play a more critical role in pediatric compared to adult cancers.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('pediatric', 'Disease', (120, 129))	('adult cancers', 'Disease', (142, 155))	('histone modifications', 'Var', (53, 74))	('adult cancers', 'Disease', 'MESH:D009369', (142, 155))
35406	30709931	The importance of mtDNA mutations in cancer has been less well recognized, despite several large-scale studies showing significant numbers of mtDNA mutations in a variety of adult tumors.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (148, 157))	('mtDNA', 'Gene', (142, 147))	('adult tumors', 'Disease', (174, 186))	('cancer', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('adult tumors', 'Disease', 'MESH:C538052', (174, 186))
35407	30709931	These mtDNA mutations, to a large extent, have been dismissed as passenger events during tumorigenesis.	('mutations', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mtDNA', 'Gene', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
35408	30709931	mtDNA mutations have been reported in a few pediatric cancer subtypes, e.g.	('reported', 'Reg', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('mtDNA', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (6, 15))
35409	30709931	medulloblastoma, glioma, acute myelogenous leukemia (AML), and neuroblastoma, but little is known regarding the spectrum of mtDNA mutations across pediatric malignancies and its contribution to tumorigenesis.	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (31, 51))	('medulloblastoma', 'Disease', 'MESH:D008527', (0, 15))	('medulloblastoma', 'Phenotype', 'HP:0002885', (0, 15))	('tumor', 'Disease', (194, 199))	('medulloblastoma', 'Disease', (0, 15))	('neuroblastoma', 'Disease', (63, 76))	('neuroblastoma', 'Phenotype', 'HP:0003006', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('neuroblastoma', 'Disease', 'MESH:D009447', (63, 76))	('glioma', 'Disease', (17, 23))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (25, 51))	('malignancies', 'Disease', 'MESH:D009369', (157, 169))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('mtDNA', 'Gene', (124, 129))	('acute myelogenous leukemia', 'Disease', (25, 51))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('malignancies', 'Disease', (157, 169))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))	('AML', 'Disease', 'MESH:D015470', (53, 56))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (25, 51))	('AML', 'Disease', (53, 56))	('mutations', 'Var', (130, 139))	('AML', 'Phenotype', 'HP:0004808', (53, 56))
35419	30709931	All tumor-only mtDNA mutations are listed in Supplementary Table 1.	('tumor', 'Disease', (4, 9))	('mtDNA', 'Gene', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutations', 'Var', (21, 30))
35423	30709931	Since there are 12 classes of possible point substitutions (SC1, ..., SC12), the probability of observing substitution SCx leading to a synonymous mutation in a set of observed mutations can be defined as  where P(syn SCx) is the frequency at which the substitution class SCx leads to a synonymous mutation and P(SCx) is the frequency of this substitution class in the data, i.e., mutational signature.	('SCx', 'Gene', (272, 275))	('SCx', 'Gene', '642658', (218, 221))	('SCx', 'Gene', '642658', (119, 122))	('SCx', 'Gene', '642658', (272, 275))	('substitution', 'Var', (106, 118))	('SCx', 'Gene', (218, 221))	('leads to', 'Reg', (276, 284))	('synonymous mutation', 'MPA', (287, 306))	('SCx', 'Gene', (119, 122))	('SCx', 'Gene', '642658', (313, 316))	('SCx', 'Gene', (313, 316))
35425	30709931	For both pediatric and adult tumor-only mtDNA mutations, we created one million simulated datasets with the number of mutations and the mutational signature identical to the original empirical dataset, but with randomly assigned positions.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('mtDNA', 'Gene', (40, 45))
35430	30709931	All adult cancer mutations are included in Supplementary Table 3.	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))
35437	30709931	For comparison with adult cancers, we reanalyzed mtDNA genome mutations previously reported in 2,202 adult cancers.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('adult cancers', 'Disease', 'MESH:D009369', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('adult cancers', 'Disease', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('adult cancers', 'Disease', 'MESH:D009369', (20, 33))	('mtDNA genome', 'Gene', (49, 61))	('mutations', 'Var', (62, 71))	('adult cancers', 'Disease', (101, 114))
35440	30709931	Three hundred and ninety-one tumor-only mtDNA mutations were detected in 284 (45.7%) of the 616 remaining cancers (Supplementary Table 1).	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('tumor', 'Disease', (29, 34))	('mtDNA', 'Gene', (40, 45))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
35441	30709931	The mean number of tumor-only mtDNA mutations seen across all subtypes was 0.63 +- 0.84, ranging from a significantly lower number of 0.36 mtDNA mutations per tumor in low-grade gliomas (LGG) compared to other subtypes (p = 0.017, Mann-Whitney rank test) to 1.15 mtDNA mutations per tumor in adrenocortical carcinomas (ACC) (Fig.	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('mutations', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('ACC', 'Phenotype', 'HP:0006744', (319, 322))	('tumor', 'Disease', (19, 24))	('gliomas', 'Disease', (178, 185))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('gliomas', 'Disease', 'MESH:D005910', (178, 185))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (292, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('adrenocortical carcinomas', 'Disease', (292, 317))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (159, 164))	('gliomas', 'Phenotype', 'HP:0009733', (178, 185))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (292, 317))	('mutations', 'Var', (36, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (307, 317))	('tumor', 'Disease', (283, 288))	('lower', 'NegReg', (118, 123))
35442	30709931	Nearly all tumor-only mtDNA mutations (99.2%) were present in a heteroplasmic state, with levels ranging from 2.5% to almost 100% (near-homoplasmy), but significantly skewed toward low-level heteroplasmy (skewness = 2.38, Pearson's kurtosis = 5.23), with the average heteroplasmy at 17.7% (Fig.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('mtDNA', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('mutations', 'Var', (28, 37))
35444	30709931	In total, we identified 158 missense, 71 rRNA, 45 LoF, 43 D-loop, 36 synonymous, and 35 tRNA tumor-only mtDNA mutations with varied heteroplasmy levels (Fig.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('missense', 'Var', (28, 36))	('LoF', 'NegReg', (50, 53))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
35447	30709931	However, the majority (68.4%) of pediatric, tumor-only mtDNA mutations were detected at heteroplasmy levels below 10% with a median heteroplasmy of 7.2% (Fig.	('mtDNA', 'Gene', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutations', 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
35448	30709931	2a), while the distribution of adult tumor-only mtDNA mutations was more uniform across all heteroplasmy levels (Fig.	('mtDNA', 'Gene', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
35449	30709931	We did not observe significant difference in heteroplasmy levels of different classes of tumor-only mtDNA mutations, in either pediatric cancers (Supplementary Figure 1a) or adult cancers (Supplementary Figure 1b).	('heteroplasmy levels', 'MPA', (45, 64))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mtDNA', 'Gene', (100, 105))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('adult cancers', 'Disease', (174, 187))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('adult cancers', 'Disease', 'MESH:D009369', (174, 187))	('mutations', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
35450	30709931	We observed a significant number of missense and LoF mutations at high heteroplasmy in both pediatric and adult cancers, as well as low heteroplasmy tumor-only mtDNA mutations.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('adult cancers', 'Disease', (106, 119))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mutations', 'Var', (53, 62))	('adult cancers', 'Disease', 'MESH:D009369', (106, 119))	('tumor', 'Disease', (149, 154))	('missense', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('LoF', 'NegReg', (49, 52))
35452	30709931	Reanalysis of data from Corces et al revealed that tumor cells from the same patient harbored frameshift variants which, while rare in the bulk population, were nearly homoplasmic within some cells and absent in others.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('frameshift variants', 'Var', (94, 113))	('patient', 'Species', '9606', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
35453	30709931	This intra-tumor variability, while apparent at single-cell level, was obscured in bulk samples; due to averaging of VAF, these mutations appear to have low heteroplasmy (Supplementary Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('low', 'NegReg', (153, 156))	('mutations', 'Var', (128, 137))	('intra-tumor', 'Disease', 'MESH:D009369', (5, 16))	('intra-tumor', 'Disease', (5, 16))	('AF', 'Disease', 'MESH:D001281', (118, 120))	('heteroplasmy', 'MPA', (157, 169))
35454	30709931	These results support our hypothesis that LoF mtDNA mutations can arise in distinct or individual tumor cells.	('mutations', 'Var', (52, 61))	('mtDNA', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
35455	30709931	Low observed heteroplasmy of mtDNA mutations in tumors can thus result from individual cells harboring different mtDNA mutations, suggesting that LoF mtDNA mutations in individual tumor cells may in fact have a functional role in tumor development or progression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutations', 'Var', (156, 165))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Disease', (180, 185))	('mtDNA', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('mtDNA', 'Gene', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mtDNA', 'Gene', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('mutations', 'Var', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (35, 44))
35456	30709931	The composition of heteroplasmic mtDNA variants in matched normal blood from pediatric cancer patients and in our non-cancer pediatric control samples was dramatically different from the observed pediatric tumor-only mtDNA mutations.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('patients', 'Species', '9606', (94, 102))	('different', 'Reg', (168, 177))	('tumor', 'Disease', (206, 211))	('mtDNA', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('variants', 'Var', (39, 47))
35457	30709931	A chi-square test showed that the composition of the tumor-only mtDNA mutations was significantly different from that of the heteroplasmic mtDNA variants in non-cancer control samples (p-value < 2.2e-16).	('mutations', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('different', 'Reg', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', (161, 167))	('mtDNA', 'Gene', (64, 69))
35458	30709931	Specifically, 51.6% of all tumor-only mtDNA mutations were either missense or LoF, which is significantly higher than 6.2% found in the non-cancer control samples (Z-score = 16.4, p < 0.001, Z-test).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('missense', 'Var', (66, 74))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('LoF', 'NegReg', (78, 81))	('mutations', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('mtDNA', 'Gene', (38, 43))
35459	30709931	In both the matched normal and non-cancer control datasets and in direct contrast to tumor-only mtDNA mutations, the most frequent heteroplasmic variants were within the D-loop region (43.8% in matched normal and 41.5% in non-cancer), followed by synonymous variants with uneven heteroplasmy levels (Fig.	('tumor', 'Disease', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('variants', 'Var', (145, 153))	('cancer', 'Disease', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
35460	30709931	Nearly 85% of all heteroplasmic variants in both datasets were known to be benign, haplogroup-defining markers (Supplementary Tables 9 & 10), which demonstrated evidence of intensive purifying selection against deleterious variants in non-cancer cells.	('cancer', 'Disease', (239, 245))	('variants', 'Var', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
35461	30709931	Missense variants were largely confined to low heteroplasmy levels and only two LoF variants were detected at very low heteroplasmy in matched normal tissues: m.12384T>TC, an MT-ND5 frameshift variant in a hyperdiploid B-cell leukemia patient at 4.8% heteroplasmy, and m.14527A>AC, an MT-ND6 frameshift variant, in an ependymoma patient at 3.1% heteroplasmy.	('patient', 'Species', '9606', (235, 242))	('m.14527A>AC', 'Var', (269, 280))	('patient', 'Species', '9606', (329, 336))	('MT-ND5', 'Gene', (175, 181))	('hyperdiploid B-cell leukemia', 'Disease', (206, 234))	('ependymoma', 'Phenotype', 'HP:0002888', (318, 328))	('leukemia', 'Phenotype', 'HP:0001909', (226, 234))	('ependymoma', 'Disease', (318, 328))	('MT-ND5', 'Gene', '4540', (175, 181))	('m.12384T>TC', 'Mutation', 'm.12384T>TC', (159, 170))	('ependymoma', 'Disease', 'MESH:D004806', (318, 328))	('MT-ND6', 'Gene', '4541', (285, 291))	('MT-ND6', 'Gene', (285, 291))	('m.14527A>AC', 'Mutation', 'm.14527A>AC', (269, 280))	('hyperdiploid B-cell leukemia', 'Disease', 'MESH:D015448', (206, 234))	('m.12384T>TC', 'Var', (159, 170))
35462	30709931	Interestingly, four pediatric cancer patients harbored homoplasmic variants (ependymoma, m.14484T>C; Ewing sarcoma, m.1555A>G; hyperdiploid B-cell acute lymphoblastic leukemia (ALL), m.14484T>C; and neuroblastoma, m.11778G>A) in their matched tumor and normal samples that are causal of Leber's Hereditary Optic Neuropathy (LHON) and hearing loss.	('m.14484T>C', 'Mutation', 'm.14484T>C', (89, 99))	('m.1555A>G', 'Var', (116, 125))	('hyperdiploid B-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (127, 175))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('m.14484T>C', 'Mutation', 'm.14484T>C', (183, 193))	('ependymoma', 'Disease', (77, 87))	('neuroblastoma', 'Disease', (199, 212))	('tumor', 'Disease', (243, 248))	('neuroblastoma', 'Phenotype', 'HP:0003006', (199, 212))	('patients', 'Species', '9606', (37, 45))	('hearing loss', 'Disease', 'MESH:D034381', (334, 346))	('ependymoma', 'Phenotype', 'HP:0002888', (77, 87))	('m.11778G>A', 'Mutation', 'm.11778G>A', (214, 224))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('neuroblastoma', 'Disease', 'MESH:D009447', (199, 212))	('Optic Neuropathy', 'Phenotype', 'HP:0001138', (306, 322))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (147, 175))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (101, 114))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (101, 114))	('Neuropathy', 'Phenotype', 'HP:0009830', (312, 322))	('cancer', 'Disease', (30, 36))	('ependymoma', 'Disease', 'MESH:D004806', (77, 87))	('hearing loss', 'Disease', (334, 346))	('m.11778G>A', 'Var', (214, 224))	('hyperdiploid B-cell acute lymphoblastic leukemia', 'Disease', (127, 175))	('m.1555A>G', 'Mutation', 'm.1555A>G', (116, 125))	('m.14484T>C', 'Var', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (153, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('hearing loss', 'Phenotype', 'HP:0000365', (334, 346))	("Leber's Hereditary Optic Neuropathy", 'Disease', (287, 322))	('m.14484T>C', 'Var', (183, 193))	('ALL', 'Phenotype', 'HP:0006721', (177, 180))	('Ewing sarcoma', 'Disease', (101, 114))	("Leber's Hereditary Optic Neuropathy", 'Disease', 'MESH:D029242', (287, 322))	('leukemia', 'Phenotype', 'HP:0001909', (167, 175))
35463	30709931	Three cancer patients' matched tumor and normal samples had heteroplasmic mtDNA variants known to cause classic mitochondrial diseases: ACC, m.3243A>G (5.0%); B-cell ALL, m.9185T>C (4.9%); neuroblastoma, m.8363G>A (53.4%) (Supplementary Table 11).	('patients', 'Species', '9606', (13, 21))	('m.3243A>G', 'Mutation', 'm.3243A>G', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mitochondrial diseases', 'Disease', (112, 134))	('m.8363G>A', 'Var', (204, 213))	('mitochondrial diseases', 'Disease', 'MESH:D028361', (112, 134))	('m.8363G>A', 'Mutation', 'm.8363G>A', (204, 213))	('ACC', 'Phenotype', 'HP:0006744', (136, 139))	('ALL', 'Phenotype', 'HP:0006721', (166, 169))	('neuroblastoma', 'Disease', (189, 202))	('m.9185T>C', 'Var', (171, 180))	('neuroblastoma', 'Phenotype', 'HP:0003006', (189, 202))	('mtDNA', 'Gene', (74, 79))	('neuroblastoma', 'Disease', 'MESH:D009447', (189, 202))	('cancer', 'Disease', (6, 12))	('m.9185T>C', 'Mutation', 'm.9185T>C', (171, 180))	('cause', 'Reg', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('m.3243A>G', 'Var', (141, 150))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
35464	30709931	Compared to the low prevalence rate (1 in 5000) of mitochondrial disorders in the general population, these results are suggestive of increased cancer risk associated with known pathogenic mtDNA variants, contrary to an earlier report.	('variants', 'Var', (195, 203))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (51, 74))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('mitochondrial disorders', 'Disease', (51, 74))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
35465	30709931	Clinical data for these patients were not available due to the de-identified nature of this dataset, so it is unclear whether these patients suffered from symptomatic mitochondrial disorders associated with these mtDNA variants.	('mitochondrial disorders', 'Disease', (167, 190))	('variants', 'Var', (219, 227))	('suffered', 'Reg', (141, 149))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (132, 140))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (167, 190))
35467	30709931	For statistical power, we focused on macro-haplogroups with at least 20 patients: A (20), B (20), H (207), J (47), K (30), L (102), T (43) and U (57).	('U (57', 'Var', (143, 148))	('patients', 'Species', '9606', (72, 80))	('B (20', 'Var', (90, 95))	('H (207', 'Var', (98, 104))	('J (47', 'Var', (107, 112))	('T (43', 'Var', (132, 137))	('K (30', 'Var', (115, 120))	('L (102', 'Var', (123, 129))
35469	30709931	However, we observed that the number of tumor-only mtDNA mutations per sample differed significantly between the two largest macro-haplogroups: 0.66 for H, which is mostly Eurasian-specific, and 0.47 for L, which is mostly African-specific (p = 0.03, Kruskal-Wallis test).	('mtDNA', 'Gene', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('0.47', 'Var', (195, 199))
35473	30709931	We observed a highly skewed dN/dS ratio (4.83) of non-synonymous mutations (including missense, stop-gain and stop-loss) versus synonymous tumor-only mutations in pediatric cancers.	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('stop-loss', 'Var', (110, 119))	('cancers', 'Disease', (173, 180))	('dN', 'Chemical', '-', (28, 30))	('missense', 'Var', (86, 94))	('synonymous tumor', 'Disease', 'MESH:D009369', (128, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('dS', 'Chemical', 'MESH:D003903', (31, 33))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('synonymous tumor', 'Disease', (128, 144))	('stop-gain', 'Disease', (96, 105))
35474	30709931	If we include the LoF mutations in the non-synonymous category, the dN/dS ratio was even higher (5.64).	('dN', 'Chemical', '-', (68, 70))	('dS', 'Chemical', 'MESH:D003903', (71, 73))	('dN/dS ratio', 'MPA', (68, 79))	('higher', 'PosReg', (89, 95))	('mutations', 'Var', (22, 31))
35475	30709931	Interestingly, the dN/dS ratio was higher for the tumor-only mtDNA mutations between 0.1 and 0.5 heteroplasmy (7.3) than at less than 0.1 heteroplasmy (5.2), although this is not statistically significant.	('dS', 'Chemical', 'MESH:D003903', (22, 24))	('dN/dS ratio', 'MPA', (19, 30))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mtDNA', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('higher', 'PosReg', (35, 41))	('tumor', 'Disease', (50, 55))	('dN', 'Chemical', '-', (19, 21))
35478	30709931	Using the mutational signature shown for tumor-only mtDNA mutations in this study, we calculated an expected dN/dS ratio of 3.11 (Supplementary Table 2), which is significantly lower than the observed ratios of 4.83 (Z = 3.28, p = 5.19x10-4) (Fig.	('dN', 'Chemical', '-', (109, 111))	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('dS', 'Chemical', 'MESH:D003903', (112, 114))	('mtDNA', 'Gene', (52, 57))	('tumor', 'Disease', (41, 46))	('dN/dS ratio', 'MPA', (109, 120))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
35480	30709931	Similarly, a lower dN/dS ratio of 0.93 was observed in the heteroplasmic mtDNA variants found in control samples with no history of cancer.	('cancer', 'Disease', (132, 138))	('lower', 'NegReg', (13, 18))	('mtDNA', 'Gene', (73, 78))	('dS', 'Chemical', 'MESH:D003903', (22, 24))	('dN/dS ratio', 'MPA', (19, 30))	('variants', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('dN', 'Chemical', '-', (19, 21))
35482	30709931	Combined, these analyses provide strong statistical evidence that non-synonymous tumor-only mtDNA mutations are under positive selection, hence enriched in tumors, but subjected to strong purifying selection, thus diminished, in non-tumor tissues (Fig.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutations', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mtDNA', 'Gene', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('synonymous tumor', 'Disease', 'MESH:D009369', (70, 86))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumors', 'Disease', (156, 162))	('tumor', 'Disease', (81, 86))	('synonymous tumor', 'Disease', (70, 86))
35483	30709931	We performed a similar analysis using only high-quality tumor-only mtDNA mutations found in adult cancers from the Ju et al.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('adult cancers', 'Disease', (92, 105))	('tumor', 'Disease', (56, 61))	('adult cancers', 'Disease', 'MESH:D009369', (92, 105))	('mtDNA', 'Gene', (67, 72))	('mutations', 'Var', (73, 82))
35485	30709931	This indicates that the tumor-only mtDNA mutations in adult cancer are likely under similar strong positive selection.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mtDNA', 'Gene', (35, 40))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
35486	30709931	Loss-of-function mutations are the most striking group of mtDNA mutations in tumor vs. control comparisons.	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', (77, 82))	('mutations', 'Var', (17, 26))	('mtDNA', 'Gene', (58, 63))
35487	30709931	We identified a total of 45 tumor-only mtDNA LoF (frameshift and nonsense) mutations, with heteroplasmy ranging from 2.5% to 73% (Table 2, Supplementary Table 1).	('LoF', 'NegReg', (45, 48))	('tumor', 'Disease', (28, 33))	('mtDNA', 'Gene', (39, 44))	('frameshift', 'Var', (50, 60))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
35488	30709931	Similarly, LoF mutations were frequently observed in Ewing sarcomas (EWS) (11.4%) and osteosarcomas (OS) (13.5%).	('OS', 'Phenotype', 'HP:0002669', (101, 103))	('EWS', 'Gene', '2130', (69, 72))	('EWS', 'Gene', (69, 72))	('sarcomas', 'Phenotype', 'HP:0100242', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('Ewing sarcomas', 'Disease', (53, 67))	('mutations', 'Var', (15, 24))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (53, 67))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (53, 66))	('osteosarcomas', 'Disease', (86, 99))	('osteosarcomas', 'Phenotype', 'HP:0002669', (86, 99))	('osteosarcomas', 'Disease', 'MESH:D012516', (86, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('LoF', 'NegReg', (11, 14))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (53, 67))	('EWS', 'Phenotype', 'HP:0012254', (69, 72))
35489	30709931	Combined, these three cancer subtypes had significantly more LoF mutations compared to other subtypes (p = 2.41x10-4).	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('LoF', 'NegReg', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('mutations', 'Var', (65, 74))
35490	30709931	For example, we observed LoF mutations in only 2 of 45 neuroblastoma samples (4.4%), and in 5 of 157 CNS tumors combined (3.2%).	('neuroblastoma', 'Disease', (55, 68))	('CNS tumors', 'Disease', (101, 111))	('mutations', 'Var', (29, 38))	('neuroblastoma', 'Phenotype', 'HP:0003006', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('LoF', 'NegReg', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('neuroblastoma', 'Disease', 'MESH:D009447', (55, 68))	('CNS tumors', 'Disease', 'MESH:D016543', (101, 111))
35491	30709931	In hematologic malignancies, 19 of 302 (6.3%) B-ALL and 2 out of 20 (10%) acute myeloid leukemia (AML) cases harbored a LoF mutation in the cancer sample.	('malignancies', 'Disease', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('acute myeloid leukemia', 'Disease', (74, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (80, 96))	('AML', 'Disease', 'MESH:D015470', (98, 101))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (74, 96))	('B-ALL and 2', 'Gene', '28907', (46, 57))	('mutation', 'Var', (124, 132))	('AML', 'Disease', (98, 101))	('malignancies', 'Disease', 'MESH:D009369', (15, 27))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (74, 96))	('LoF', 'NegReg', (120, 123))	('ALL', 'Phenotype', 'HP:0006721', (48, 51))	('AML', 'Phenotype', 'HP:0004808', (98, 101))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))
35493	30709931	The majority of LoF mutations were within the mitochondrial complex I genes, particularly, with the most (11) in MT-ND5.	('LoF', 'NegReg', (16, 19))	('MT-ND5', 'Gene', (113, 119))	('mutations', 'Var', (20, 29))	('MT-ND5', 'Gene', '4540', (113, 119))
35494	30709931	We observed three recurrent tumor-only LoF mutations, including m.12417C>CA in MT-ND5 in four cases (ependymoma, Ewing sarcoma, ETV6-RUNX1 B-ALL, Ph-positive ALL), m.10191TC>T in MT-ND3 in two cases (B-ALL and high-grade glioma (HGG)), and m.9531A>AC in MT-CO3 in two cases (OS and Ph-positive ALL).	('tumor', 'Disease', (28, 33))	('MT-ND5', 'Gene', '4540', (79, 85))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (113, 126))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (113, 126))	('m.9531A>AC', 'Var', (240, 250))	('MT-ND5', 'Gene', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('OS', 'Phenotype', 'HP:0002669', (275, 277))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('m.10191TC>T', 'Var', (164, 175))	('ALL', 'Phenotype', 'HP:0006721', (294, 297))	('ALL', 'Phenotype', 'HP:0006721', (158, 161))	('ependymoma', 'Disease', (101, 111))	('ALL', 'Phenotype', 'HP:0006721', (141, 144))	('ETV6', 'Gene', '2120', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('m.9531A>AC', 'Mutation', 'm.9531A>AC', (240, 250))	('Ewing sarcoma', 'Disease', (113, 126))	('MT-ND3', 'Gene', (179, 185))	('ependymoma', 'Phenotype', 'HP:0002888', (101, 111))	('m.10191TC>T', 'Mutation', 'm.10191TC>T', (164, 175))	('LoF', 'NegReg', (39, 42))	('MT-ND3', 'Gene', '4537', (179, 185))	('m.12417C>CA', 'Var', (64, 75))	('MT-CO3', 'Gene', (254, 260))	('m.12417C>CA', 'Mutation', 'm.12417C>CA', (64, 75))	('glioma', 'Disease', (221, 227))	('ETV6', 'Gene', (128, 132))	('RUNX1', 'Gene', (133, 138))	('ependymoma', 'Disease', 'MESH:D004806', (101, 111))	('MT-CO3', 'Gene', '4514', (254, 260))	('glioma', 'Disease', 'MESH:D005910', (221, 227))	('ALL', 'Phenotype', 'HP:0006721', (202, 205))	('RUNX1', 'Gene', '861', (133, 138))
35495	30709931	To further explore possible mutational hotspots, we conducted a meta-analysis of pediatric tumor-only mutations, in combination with previously published tumor-only mtDNA mutations from 2,202 primarily adult cancers (Supplementary Table 3).	('adult cancers', 'Disease', 'MESH:D009369', (202, 215))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('adult cancers', 'Disease', (202, 215))	('mutations', 'Var', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (154, 159))
35496	30709931	Four windows (9445-9544, 10960-11059, 11768-11867, 12374-12473) within MT-ND4, MT-ND5 and MT-CO3 genes exhibited a substantial and significant enrichment of frameshift indels (p = 5.9x10-3 to 1.8x10-28, Bonferroni correction, Supplementary Table 15), indicating the presence of mutational hotspots (Fig 5a).	('MT-CO3', 'Gene', (90, 96))	('MT-ND5', 'Gene', '4540', (79, 85))	('MT-ND4', 'Gene', '4538', (71, 77))	('MT-ND4', 'Gene', (71, 77))	('MT-ND5', 'Gene', (79, 85))	('MT-CO3', 'Gene', '4514', (90, 96))	('frameshift indels', 'Var', (157, 174))
35497	30709931	After restricting the analysis to 20 long homopolymers within coding regions, hotspots in MT-ND4 (polyA 11032-11038 and polyC 11867-11872) and MT-ND5 (polyA 12418-12425) remained significant (p = 3.1x10-3 - 9.2x10-11, Bonferroni correction, Supplementary Table 16).	('MT-ND4', 'Gene', '4538', (90, 96))	('MT-ND4', 'Gene', (90, 96))	('polyA 12418-12425', 'Var', (151, 168))	('polyC 11867-11872', 'Var', (120, 137))	('MT-ND5', 'Gene', (143, 149))	('polyA 11032-11038', 'Var', (98, 115))	('MT-ND5', 'Gene', '4540', (143, 149))
35498	30709931	We used the same approach to test for clustering of probable pathogenic tumor-only tRNA mutations (as defined by predicted MitoTIP score >= 16.25).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('pathogenic', 'Reg', (61, 71))	('mutations', 'Var', (88, 97))	('tRNA', 'Gene', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
35499	30709931	One 20bp window located in MT-TM (TRNM), encoding the mitochondrial tRNA for methionine, was significantly enriched for pathogenic mutations (p = 2.361x10-5, Bonferroni correction, Supplementary Table 17).	('mutations', 'Var', (131, 140))	('methionine', 'Chemical', 'MESH:D008715', (77, 87))	('TRNM', 'Gene', '4569', (34, 38))	('TRNM', 'Gene', (34, 38))	('MT-TM', 'Gene', '4569', (27, 32))	('MT-TM', 'Gene', (27, 32))	('pathogenic', 'Reg', (120, 130))
35500	30709931	Identification of a MT-TM mutational hotspot is novel and may lead to important insights into tumor pathogenesis, since the mitochondrial tRNA genes are hotspots for pathogenic mutations that also cause mitochondrial disorders.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('MT-TM', 'Gene', '4569', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutations', 'Var', (177, 186))	('mitochondrial disorders', 'Disease', (203, 226))	('MT-TM', 'Gene', (20, 25))	('tumor', 'Disease', (94, 99))	('mitochondrial tRNA', 'Gene', (124, 142))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (203, 226))	('cause', 'Reg', (197, 202))
35502	30709931	We observed a statistically significant enrichment of highly pathogenic variants in the MT-TM gene in adult samples (p = 2.78x10-4, Welch's t-test) compared to all other tRNA genes (Supplementary Figure 4d), which is in agreement with the presence of a hotspot for pathogenic mutations in this gene in both pediatric and adult cancers.	('MT-TM', 'Gene', '4569', (88, 93))	('MT-TM', 'Gene', (88, 93))	('adult cancers', 'Disease', (321, 334))	('pathogenic', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('variants', 'Var', (72, 80))	('adult cancers', 'Disease', 'MESH:D009369', (321, 334))	('cancers', 'Phenotype', 'HP:0002664', (327, 334))
35504	30709931	Fifteen to 29 tumor-only mtDNA mutations per sample were found in 5 mtDNA-hypermutated samples (Supplementary Table 18).	('mutations', 'Var', (31, 40))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mtDNA', 'Gene', (25, 30))
35506	30709931	We observed a strong correlation between the number of missense mutations in the nuclear genome and the number of mutations in the mitochondrial genome (Pearson correlation coefficient = 0.43, p = 1.33x10-7), suggesting potentially common mechanisms underlying the increased number of nuclear and mtDNA tumor-only mutations.	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('missense mutations', 'Var', (55, 73))	('tumor', 'Disease', (303, 308))
35509	30709931	We have demonstrated the spectrum of the mtDNA mutations that are both shared by and unique to individual pediatric cancer subtypes.	('mtDNA', 'Gene', (41, 46))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
35510	30709931	While different pediatric cancer subtypes showed different mean numbers of tumor-only mtDNA mutations, the types of mtDNA mutations seen also varied among different subtypes.	('mtDNA', 'Gene', (86, 91))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('mutations', 'Var', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
35511	30709931	For example, LGGs had the fewest number of tumor-only mtDNA mutations, lacked any LoF mutations, and any mtDNA mutations present in these tumors occurred at very low heteroplasmy levels.	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('mtDNA', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
35512	30709931	In contrast, a total of six LoF mutations were identified in 5 of 20 (25%) ACC samples, which is significantly higher than in any other subtype of pediatric malignancy.	('malignancy', 'Disease', 'MESH:D009369', (157, 167))	('malignancy', 'Disease', (157, 167))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('ACC', 'Disease', (75, 78))	('mutations', 'Var', (32, 41))	('LoF', 'NegReg', (28, 31))
35513	30709931	15-70% of ACCs and the vast majority of osteosarcomas have inactivating TP53 alterations.	('osteosarcomas', 'Disease', (40, 53))	('osteosarcomas', 'Phenotype', 'HP:0002669', (40, 53))	('osteosarcomas', 'Disease', 'MESH:D012516', (40, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (45, 53))	('TP53', 'Gene', '7157', (72, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('TP53', 'Gene', (72, 76))	('alterations', 'Var', (77, 88))	('ACCs', 'Disease', (10, 14))	('ACC', 'Phenotype', 'HP:0006744', (10, 13))	('inactivating', 'Var', (59, 71))
35514	30709931	previously reported that MT-ND5 somatic mutations down regulate mitochondrial electron transport chain complex I enzyme activity and increase reactive oxygen species, also epigenetically upregulate nuclear anti-apoptotic genes in p53 deficient cells.	('MT-ND5', 'Gene', '4540', (25, 31))	('upregulate', 'PosReg', (187, 197))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (142, 165))	('MT-ND5', 'Gene', (25, 31))	('p53', 'Gene', '7157', (230, 233))	('mutations', 'Var', (40, 49))	('reactive oxygen species', 'MPA', (142, 165))	('epigenetically', 'Var', (172, 186))	('down regulate', 'NegReg', (50, 63))	('increase', 'PosReg', (133, 141))	('activity', 'MPA', (120, 128))	('p53', 'Gene', (230, 233))	('nuclear anti-apoptotic genes', 'Gene', (198, 226))
35515	30709931	Based on this finding we initially postulated that a link between TP53 mutations and complex I activity could explain why LoF mutations in ACC and OS were observed at such high frequency relative to the rest of the pediatric tumors studied.	('TP53', 'Gene', '7157', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('TP53', 'Gene', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('ACC', 'Phenotype', 'HP:0006744', (139, 142))	('mutations', 'Var', (71, 80))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('mutations', 'Var', (126, 135))	('OS', 'Phenotype', 'HP:0002669', (147, 149))	('tumors', 'Disease', (225, 231))
35516	30709931	However, only 2 of the 20 ACC tumors in our dataset had a nuclear TP53 mutation.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('mutation', 'Var', (71, 79))	('ACC', 'Phenotype', 'HP:0006744', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
35517	30709931	Similarly, while CPCs also harbor TP53 mutations, no LoF mutations were observed in the four CPC samples that we studied.	('CPC', 'Phenotype', 'HP:0030392', (17, 20))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))	('CPC', 'Phenotype', 'HP:0030392', (93, 96))	('TP53', 'Gene', '7157', (34, 38))
35520	30709931	both observed a skewed dN/dS ratio (indicating an increase in non-synonymous tumor-only mtDNA mutations compared to synonymous mtDNA mutations) in adult cancers.	('dN', 'Chemical', '-', (23, 25))	('dS', 'Chemical', 'MESH:D003903', (26, 28))	('mutations', 'Var', (94, 103))	('synonymous tumor', 'Disease', 'MESH:D009369', (66, 82))	('adult cancers', 'Disease', (147, 160))	('mtDNA', 'Gene', (88, 93))	('increase', 'PosReg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('adult cancers', 'Disease', 'MESH:D009369', (147, 160))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('synonymous tumor', 'Disease', (66, 82))
35522	30709931	Sequencing and analyzing the mtDNA genome in a large number of children without cancer provided further support for this conclusion.	('Sequencing', 'Var', (0, 10))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('children', 'Species', '9606', (63, 71))
35523	30709931	Our analysis clearly demonstrated that non-synonymous or deleterious mtDNA mutations were under strong negative selection in normal cells, but under strong positive selection in tumor cells.	('tumor', 'Disease', (178, 183))	('non-synonymous', 'Var', (39, 53))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mtDNA', 'Gene', (69, 74))
35524	30709931	Thus, we have demonstrated for the first time that the highly skewed dN/dS ratio of tumor-only mtDNA mutations is a strong indicator that mtDNA mutations have broad contributions to tumor development not only in pediatric cancers but also in adult cancers.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('adult cancers', 'Disease', 'MESH:D009369', (242, 255))	('mtDNA', 'Gene', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('mutations', 'Var', (144, 153))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('cancers', 'Disease', (248, 255))	('adult cancers', 'Disease', (242, 255))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('mtDNA', 'Gene', (138, 143))	('mutations', 'Var', (101, 110))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancers', 'Disease', (222, 229))	('contributions', 'Reg', (165, 178))	('dN', 'Chemical', '-', (69, 71))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (84, 89))	('dS', 'Chemical', 'MESH:D003903', (72, 74))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
35525	30709931	We postulate that a significant fraction of the observed non-synonymous or deleterious mtDNA mutations provide the tumor cells with a significant selective advantage.	('mtDNA', 'Gene', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (93, 102))	('tumor', 'Disease', (115, 120))	('non-synonymous', 'Var', (57, 71))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
35526	30709931	While LoF tumor-only mtDNA mutations in a variety of cancers have previously been reported, including several recurrent mutations, we discovered clustering of LoF mtDNA mutations in MT-CO3, MT-ND4, and MT-ND5, predominantly in the Complex I (ND) subunit genes (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('mutations', 'Var', (169, 178))	('LoF tumor', 'Disease', 'MESH:D009369', (6, 15))	('mtDNA', 'Gene', (163, 168))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('MT-ND4', 'Gene', (190, 196))	('LoF tumor', 'Disease', (6, 15))	('MT-ND4', 'Gene', '4538', (190, 196))	('MT-ND5', 'Gene', (202, 208))	('MT-CO3', 'Gene', '4514', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('MT-CO3', 'Gene', (182, 188))	('MT-ND5', 'Gene', '4540', (202, 208))	('LoF', 'NegReg', (159, 162))
35527	30709931	Rather, these hotspot mtDNA mutations were shared by diverse childhood and adult cancers as demonstrated by our meta-analysis.	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('adult cancers', 'Disease', (75, 88))	('adult cancers', 'Disease', 'MESH:D009369', (75, 88))	('mtDNA', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (28, 37))
35528	30709931	While the observed LoF mutations were spread across all 13 mtDNA protein-coding genes, the existence of hotspots of LoF mtDNA mutations in childhood and adult cancers indicates that defects in specific mitochondrial genes, function, and related pathways such as mitochondrial apoptosis may play a more important role than previously appreciated for tumorigenesis of childhood and adult cancers.	('adult cancers', 'Disease', (153, 166))	('cancers', 'Phenotype', 'HP:0002664', (386, 393))	('adult cancers', 'Disease', 'MESH:D009369', (153, 166))	('adult cancers', 'Disease', (380, 393))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('mutations', 'Var', (23, 32))	('function', 'MPA', (223, 231))	('mtDNA', 'Gene', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('adult cancers', 'Disease', 'MESH:D009369', (380, 393))	('LoF', 'NegReg', (116, 119))	('mutations', 'Var', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('mitochondrial genes', 'Gene', (202, 221))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('defects', 'Var', (182, 189))	('tumor', 'Disease', (349, 354))
35529	30709931	This is supported by the high predicted pathogenicity scores of tumor-only mutations in some of the mtDNA genes.	('tumor', 'Disease', (64, 69))	('mtDNA', 'Gene', (100, 105))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
35530	30709931	The importance of individual LoF mtDNA mutations to tumor development, especially those occurring within complex I genes, is supported by previous studies.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('mtDNA', 'Gene', (33, 38))	('LoF', 'NegReg', (29, 32))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
35531	30709931	experimentally demonstrated that mitochondrial complex I dysfunction, caused by a heteroplasmic nonsense MT-ND5 mutation, promoted tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('MT-ND5', 'Gene', (105, 111))	('mutation', 'Var', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('promoted', 'PosReg', (122, 130))	('tumor', 'Disease', (131, 136))	('MT-ND5', 'Gene', '4540', (105, 111))	('caused by', 'Reg', (70, 79))
35532	30709931	This result is similar to that reported by Ishikawa et al., who demonstrated complex I deficiencies caused by a MT-ND6 frameshift mutation contributed to tumor progression and metastasis.	('metastasis', 'CPA', (176, 186))	('I deficiencies', 'Disease', (85, 99))	('I deficiencies', 'Disease', 'MESH:C537728', (85, 99))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('frameshift mutation', 'Var', (119, 138))	('MT-ND6', 'Gene', '4541', (112, 118))	('MT-ND6', 'Gene', (112, 118))	('tumor', 'Disease', (154, 159))
35533	30709931	Recently, Gopal et al reported that LoF mutations in the complex I genes lead to rewiring of glutathione metabolism in renal oncocytoma and are early genetic events that contribute to tumor formation.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('rewiring of glutathione metabolism', 'MPA', (81, 115))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('LoF', 'NegReg', (36, 39))	('renal oncocytoma', 'Disease', 'MESH:C537750', (119, 135))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', (184, 189))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (119, 135))	('renal oncocytoma', 'Disease', (119, 135))	('glutathione', 'Chemical', 'MESH:D005978', (93, 104))
35534	30709931	Notably, 13 and 8 of these 45 LoF mutations that we found were above 15% and 40% heteroplasmy, respectively, with the highest observed at 73% in a neuroblastoma tumor (Supplementary Table 1).	('neuroblastoma tumor', 'Disease', (147, 166))	('LoF', 'NegReg', (30, 33))	('heteroplasmy', 'MPA', (81, 93))	('neuroblastoma tumor', 'Disease', 'MESH:D009447', (147, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mutations', 'Var', (34, 43))	('neuroblastoma', 'Phenotype', 'HP:0003006', (147, 160))
35535	30709931	High heteroplasmy levels support a contributing role for a mtDNA mutation in tumorigenesis, consistent with the Park et al study demonstrating that a LoF MT-ND5 mutation promoted tumorigenesis at high-level heteroplasmy but not at homoplasmy.	('MT-ND5', 'Gene', (154, 160))	('mutation', 'Var', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('LoF', 'NegReg', (150, 153))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('MT-ND5', 'Gene', '4540', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (77, 82))	('promoted', 'PosReg', (170, 178))	('tumor', 'Disease', (179, 184))
35536	30709931	Conversely, tumor heterogeneity may lead to skewed lower heteroplasmy levels observed for other LoF mutations, as we illustrated in the single-cell ATACseq data from two acute myeloid leukemia patients.	('mutations', 'Var', (100, 109))	('acute myeloid leukemia', 'Disease', (170, 192))	('patients', 'Species', '9606', (193, 201))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (170, 192))	('heteroplasmy levels', 'MPA', (57, 76))	('lower', 'NegReg', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (170, 192))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (176, 192))	('tumor', 'Disease', (12, 17))	('leukemia', 'Phenotype', 'HP:0001909', (184, 192))
35537	30709931	We have demonstrated clustering of tumor-only mtDNA mutations in the MT-TM gene encoding the tRNA for methionine (Fig.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('methionine', 'Chemical', 'MESH:D008715', (102, 112))	('tumor', 'Disease', (35, 40))	('MT-TM', 'Gene', '4569', (69, 74))	('MT-TM', 'Gene', (69, 74))
35538	30709931	A heteroplasmic pathogenic MT-TM mutation was first reported in a patient with splenic lymphoma, with deficient mitochondrial respiratory chain enzyme activities and Complex IV COX2 subunit expression.	('splenic lymphoma', 'Disease', (79, 95))	('COX2', 'Gene', (177, 181))	('mutation', 'Var', (33, 41))	('splenic lymphoma', 'Disease', 'MESH:D013158', (79, 95))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('deficient mitochondrial respiratory', 'Disease', (102, 137))	('activities', 'MPA', (151, 161))	('pathogenic', 'Reg', (16, 26))	('COX2', 'Gene', '4513', (177, 181))	('MT-TM', 'Gene', '4569', (27, 32))	('patient', 'Species', '9606', (66, 73))	('MT-TM', 'Gene', (27, 32))	('deficient mitochondrial respiratory', 'Disease', 'MESH:D012131', (102, 137))
35540	30709931	Of note, the 22 mitochondrial tRNA genes are also hotspots for pathogenic mutations that cause classical mitochondrial disorders.	('mitochondrial tRNA genes', 'Gene', (16, 40))	('mutations', 'Var', (74, 83))	('mitochondrial disorders', 'Disease', (105, 128))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (105, 128))
35541	30709931	Mitochondrial haplogroups, as defined by common fixed (homoplasmic) mtDNA polymorphisms, have long been found to be associated with varied risks for diverse cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('polymorphisms', 'Var', (74, 87))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('mtDNA', 'Gene', (68, 73))	('associated', 'Reg', (116, 126))
35542	30709931	For example, the mtDNA haplogroup M7B2 was found to be a risk factor for leukemia, while haplogroup U was found to increase the risk for both renal and prostate cancers.	('renal and prostate cancers', 'Disease', 'MESH:D011471', (142, 168))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('increase', 'PosReg', (115, 123))	('leukemia', 'Phenotype', 'HP:0001909', (73, 81))	('leukemia', 'Disease', 'MESH:D007938', (73, 81))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('M7B2', 'Var', (34, 38))	('leukemia', 'Disease', (73, 81))	('prostate cancers', 'Phenotype', 'HP:0012125', (152, 168))
35544	30709931	However, we observed significantly fewer tumor-only mtDNA mutations occurring in patients belonging to the L (African) macro-haplogroup compared to the H (Eurasian macro-haplogroup).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (58, 67))	('fewer', 'NegReg', (35, 40))	('mtDNA', 'Gene', (52, 57))	('tumor', 'Disease', (41, 46))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
35546	30709931	There is significant mitochondrial heterogeneity in different cells and microenvironments which, while highlighting the tumor extraordinary metabolic plasticity during tumorigenesis, makes it extremely challenging to select a single representative or appropriate assay to assess the functional significance of the candidate mtDNA mutation.	('tumor', 'Disease', (168, 173))	('mtDNA', 'Gene', (324, 329))	('mutation', 'Var', (330, 338))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (120, 125))
35547	30709931	A thorough characterization of the likely functional significance of a mtDNA mutation would likely require a suite of assays targeting all aspects of tumorigenesis.	('mutation', 'Var', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mtDNA', 'Gene', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
35548	30709931	Determining the functional significance of tumor-only mtDNA mutations is complicated by heteroplasmy and intra-tumor heterogeneity and, in some cases, tumor percentage.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('intra-tumor', 'Disease', 'MESH:D009369', (105, 116))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (111, 116))	('intra-tumor', 'Disease', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mtDNA', 'Gene', (54, 59))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
35549	30709931	A tumor-only mtDNA mutation may be observed at low VAF from next-generation sequencing of a tumor sample.	('mutation', 'Var', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('AF', 'Disease', 'MESH:D001281', (52, 54))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (2, 7))	('mtDNA', 'Gene', (13, 18))	('tumor', 'Disease', (92, 97))
35553	30709931	Similarly, our analysis of the single-cell ATACseq data from two acute myeloid leukemia patients also supports this hypothesis, since individual tumor cells had near-homoplasmy levels of some LoF mtDNA mutations that were observed at low heteroplasmy at bulk cell populations.	('mtDNA', 'Gene', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (71, 87))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (65, 87))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('patients', 'Species', '9606', (88, 96))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (65, 87))	('LoF', 'NegReg', (192, 195))	('tumor', 'Disease', (145, 150))	('acute myeloid leukemia', 'Disease', (65, 87))	('mutations', 'Var', (202, 211))
35554	30709931	If the near homoplasmy state of LoF mutations in single cells translates to a selective disadvantage, these tumor cells are expected to be purified away, so that they would represent lower fractions of all mtDNA mutations at higher heteroplasmy levels when the bulk tumor cells are sequenced.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('LoF', 'NegReg', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('mtDNA', 'Gene', (206, 211))
35555	30709931	However, our data showed that the likely functionally deleterious tumor-only mtDNA mutations, including the LoF mutations, occurred at comparable if not higher heteroplasmy levels than the likely functionally neutral tumor-only mtDNA mutations, such as the synonymous and D-loop region mutations (Supplementary Figure 6).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', (66, 71))	('mtDNA', 'Gene', (77, 82))	('mutations', 'Var', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
35556	30709931	This is true for tumor-only mtDNA mutations found in both pediatric and adult cancers.	('mtDNA', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('adult cancers', 'Disease', 'MESH:D009369', (72, 85))	('tumor', 'Disease', (17, 22))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('adult cancers', 'Disease', (72, 85))	('mutations', 'Var', (34, 43))
35557	30709931	Furthermore, although most of the tumor-only mtDNA mutations were seen at low heteroplasmy, the composition of these mutations across different heteroplasmy levels remained similar (Figure 2a &2b, Supplementary Figure 6), which argues that the deleterious mtDNA mutations were not selected against.	('mtDNA', 'Gene', (45, 50))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
35558	30709931	Combined with single-cell ATACseq data, we should not dismiss the likely functional significance of a tumor-only mtDNA mutation because of low heteroplasmy.	('mutation', 'Var', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mtDNA', 'Gene', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
35559	30709931	The most intriguing observation from this study was our novel finding that four childhood cancer patients harbored homoplasmic or heteroplasmic mtDNA germline variants that are known to cause classical mitochondrial disorders, which have not been previously linked to a cancer phenotype.	('mitochondrial disorders', 'Disease', 'MESH:D028361', (202, 225))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('variants', 'Var', (159, 167))	('mitochondrial disorders', 'Disease', (202, 225))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cause', 'Reg', (186, 191))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('mtDNA', 'Gene', (144, 149))	('patients', 'Species', '9606', (97, 105))
35562	30709931	Park et al reported that homoplasmic MT-ND5 mutations prevents tumor development.	('tumor', 'Disease', (63, 68))	('prevents', 'NegReg', (54, 62))	('MT-ND5', 'Gene', '4540', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('MT-ND5', 'Gene', (37, 43))
35565	30709931	It is also intriguing that there are four pediatric cancer patients with homoplasmic pathogenic variants that cause primary mitochondrial diseases, yet, it was shown by Park et al that the homoplasmic MT-ND5 mutations prevents tumor development.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('variants', 'Var', (96, 104))	('prevents', 'NegReg', (218, 226))	('tumor', 'Disease', (227, 232))	('mutations', 'Var', (208, 217))	('MT-ND5', 'Gene', '4540', (201, 207))	('mitochondrial diseases', 'Disease', 'MESH:D028361', (124, 146))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mitochondrial diseases', 'Disease', (124, 146))	('MT-ND5', 'Gene', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
35566	30709931	To explain this, we speculate that there is residual mitochondrial function in cells with these homoplasmic pathogenic mtDNA variants or they would cause death or miscarriage instead of mitochondrial diseases only.	('mitochondrial function', 'MPA', (53, 75))	('miscarriage', 'Disease', (163, 174))	('death', 'Disease', 'MESH:D003643', (154, 159))	('death', 'Disease', (154, 159))	('mitochondrial diseases', 'Disease', 'MESH:D028361', (186, 208))	('miscarriage', 'Phenotype', 'HP:0005268', (163, 174))	('variants', 'Var', (125, 133))	('mitochondrial diseases', 'Disease', (186, 208))	('cause', 'Reg', (148, 153))	('mtDNA', 'Gene', (119, 124))
35567	30709931	We found five samples that were mtDNA-hypermutated, with significantly more tumor-only mtDNA mutations than other samples (15-29 vs. 0.63 +- 0.84).	('mtDNA', 'Gene', (87, 92))	('mutations', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
35569	30709931	It is possible that the same underlying mechanism causes somatic nuclear DNA and mtDNA mutations in cancer.	('nuclear DNA', 'Disease', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mtDNA', 'Gene', (81, 86))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('mutations', 'Var', (87, 96))
35570	30709931	These data provide further support for tumor-only mtDNA mutations contributing to diverse cancer development.	('mutations', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('contributing', 'Reg', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mtDNA', 'Gene', (50, 55))	('tumor', 'Disease', (39, 44))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
35571	30709931	In conclusion, the present study establishes the broad landscape of germline and tumor-only mtDNA genome mutations across numerous subtypes of childhood leukemias, brain tumors, and solid tumors.	('tumor', 'Disease', (188, 193))	('childhood leukemias', 'Disease', 'MESH:D007938', (143, 162))	('mtDNA genome', 'Gene', (92, 104))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mutations', 'Var', (105, 114))	('brain tumors', 'Disease', (164, 176))	('childhood leukemias', 'Disease', (143, 162))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (81, 86))	('tumors', 'Disease', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('leukemias', 'Phenotype', 'HP:0001909', (153, 162))	('brain tumors', 'Disease', 'MESH:D001932', (164, 176))	('brain tumors', 'Phenotype', 'HP:0030692', (164, 176))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('leukemia', 'Phenotype', 'HP:0001909', (153, 161))	('tumors', 'Disease', (170, 176))
35572	30709931	We utilized a highly powered public dataset, combined with additional data from pediatric controls with no history of cancer, to demonstrate that deleterious mtDNA mutations contribute significantly to the tumorigenesis of pediatric cancers.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (233, 239))	('mtDNA', 'Gene', (158, 163))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('mutations', 'Var', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
35573	30709931	The highly skewed dN/dS ratio clearly indicates non-synonymous mtDNA mutations in general, rather than a few isolated mutations, provide tumor cells a selective advantage.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', (137, 142))	('advantage', 'PosReg', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('dN', 'Chemical', '-', (18, 20))	('dS', 'Chemical', 'MESH:D003903', (21, 23))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mtDNA', 'Gene', (63, 68))	('non-synonymous', 'Var', (48, 62))
35575	30709931	This is highlighted by the discoveries of hotspots for mtDNA LoF and likely pathogenic tRNA mutations shared between pediatric and adult cancers, which suggests that certain mitochondrial genes and pathways may play a bigger role in tumorigenesis than others.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('mtDNA', 'Gene', (55, 60))	('adult cancers', 'Disease', 'MESH:D009369', (131, 144))	('tumor', 'Disease', (233, 238))	('mutations', 'Var', (92, 101))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('LoF', 'NegReg', (61, 64))	('tRNA', 'Gene', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('adult cancers', 'Disease', (131, 144))
35576	30709931	Future functional studies are required to determine the effect of specific mutations on mitochondrial function and their role in cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (75, 84))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
35577	30709931	Statement of Significance: This pan-cancer mtDNA study establishes the landscape of germline and tumor mtDNA mutations and identifies hotspots of tumor mtDNA mutations to pinpoint key mitochondrial functions in pediatric malignancies.	('malignancies', 'Disease', (221, 233))	('mtDNA', 'Gene', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Disease', (36, 42))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mutations', 'Var', (109, 118))	('malignancies', 'Disease', 'MESH:D009369', (221, 233))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('mutations', 'Var', (158, 167))	('mtDNA', 'Gene', (103, 108))
35586	29625048	These integrated subtypes shared mutations, copy-number alterations, pathway commonalities, and micro-environment characteristics that appeared influential in the new molecular taxonomy, beyond any phenotypic contributions from tumor stage or tissue of origin.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('copy-number alterations', 'Var', (44, 67))
35600	29625048	Using aneuploidy (AN), CpG hypermethylation (METH), mRNA (MRNA), miRNA (MIR), and protein (P), the resultant number of groups ranged from 10 to 25 (Figure 1).	('hypermethylation', 'Var', (27, 43))	('METH', 'Chemical', '-', (45, 49))	('miRNA', 'MPA', (65, 70))	('mRNA', 'MPA', (52, 56))	('aneuploidy', 'Var', (6, 16))
35604	29625048	Over one-third of the samples displayed relatively sparse aneuploidy in AN7; these were enriched for THCA, LAML, PRAD, and THYM.	('aneuploidy', 'Var', (58, 68))	('amp', 'Chemical', 'MESH:D000249', (23, 26))	('AN7', 'Gene', (72, 75))	('THCA', 'Disease', (101, 105))
35607	29625048	Consistent with previous results, squamous (lung, head and neck, and esophageal) tumors clustered together by aneuploidy patterns, particularly 3p loss and 3q gain (AN3).	('3p loss', 'Var', (144, 151))	('3q gain', 'Var', (156, 163))	('esophageal) tumors clustered', 'Disease', 'MESH:D004938', (69, 97))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
35609	29625048	Despite the exclusion of loci known to be involved in tissue-specific DNA methylation, tumors originating from the same organ often aggregated by cancer-type-specific hypermethylation (Figure 1B; Table S2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('hypermethylation', 'Var', (167, 183))
35625	29625048	We used clustering of cluster assignments (COCA) algorithm to assess the overlap of platform-specific memberships from each of the five molecular platforms (aneuploidy, mRNA, miRNA, DNA methylation, and RPPA) (Figure 2A).	('COCA', 'Species', '289672', (43, 47))	('miRNA', 'MPA', (175, 180))	('mRNA', 'MPA', (169, 173))	('DNA', 'MPA', (182, 185))	('aneuploidy', 'Var', (157, 167))
35636	29625048	Eight iClusters were dominated by a single tumor type (C24:LAML, C11:LGG [IDH1 mut], C6:OV, C8:UCEC, C12:THCA, C16:PRAD, C26:LIHC, C14:LUAD).	('C26', 'CellLine', 'CVCL:0240', (121, 124))	('IDH1', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('C11', 'Gene', '51728', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('C24:', 'Var', (55, 59))	('IDH1', 'Gene', '3417', (74, 78))	('C12:THCA', 'Var', (101, 109))	('tumor', 'Disease', (43, 48))	('C11', 'Gene', (65, 68))
35637	29625048	Others contained tumors from similar or related cells or tissues: C28:pan-kidney (KIRC, KIRP), C15:SKCM/UVM-melanoma of the skin (SKCM) and eye (UVM), C23:GBM/LGG (IDH1wt), and C5:CNS/ endocrine.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('C15', 'Gene', '51316', (95, 98))	('C23:GBM/LGG', 'Gene', '4691', (151, 162))	('UVM-melanoma of the skin', 'Disease', (104, 128))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('C15', 'Gene', (95, 98))	('C28', 'Var', (66, 69))	('IDH1', 'Gene', '3417', (164, 168))	('IDH1', 'Gene', (164, 168))	('UVM-melanoma of the skin', 'Disease', 'MESH:D008545', (104, 128))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('C23:GBM/LGG', 'Gene', (151, 162))
35641	29625048	C4:pan-GI (CRC) was predominantly COAD and READ with chromosomal instability (CIN) and a distinct aneuploidy profile (Figure 2B).	('CIN', 'Disease', (78, 81))	('COAD', 'Disease', (34, 38))	('pan-GI', 'Var', (3, 9))	('CIN', 'Disease', 'MESH:D007674', (78, 81))	('COAD', 'Disease', 'MESH:D029424', (34, 38))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('chromosomal instability', 'Disease', (53, 76))
35642	29625048	The pan-squamous cohort formed three iClusters (C10, C25, and C27).	('C10', 'Gene', '3226', (48, 51))	('C10', 'Gene', (48, 51))	('C25', 'Var', (53, 56))	('C27', 'Var', (62, 65))
35644	29625048	Even though all squamous iClusters were characterized by chromosome 3q amplification, unique features defined C10:pan-SCC (9p deletion) and C25:pan-SCC (Chr11 amp) (Figure 2B).	('amp', 'Chemical', 'MESH:D000249', (71, 74))	('SCC', 'Gene', (118, 121))	('C10', 'Gene', (110, 113))	('SCC', 'Gene', (148, 151))	('C10', 'Gene', '3226', (110, 113))	('SCC', 'Gene', '6317', (118, 121))	('SCC', 'Gene', '6317', (148, 151))	('amp', 'Chemical', 'MESH:D000249', (159, 162))	('9p deletion', 'Var', (123, 134))
35645	29625048	Among mixed tumor type iClusters, three were defined by copy-number alterations.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('copy-number alterations', 'Var', (56, 79))
35646	29625048	C7:mixed was characterized by chr9 deletion, C2:BRCA (HER2 amp) mainly consisted of ERBB2-amplified tumors (BRCA, BLCA, and STAD), and C13:mixed (Chr8 del) contained highly aneuploid tumors, including a mixture of BRCA-Basal, UCEC (CN-high subtype), UCS, and BLCA.	('BRCA', 'Gene', '672', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('BRCA', 'Gene', (48, 52))	('amp', 'Chemical', 'MESH:D000249', (59, 62))	('BRCA', 'Gene', (214, 218))	('amp', 'Chemical', 'MESH:D000249', (90, 93))	('tumors', 'Disease', (183, 189))	('BLCA', 'Disease', (259, 263))	('aneuploid tumors', 'Disease', 'MESH:D000782', (173, 189))	('BRCA', 'Gene', (108, 112))	('UCEC', 'Disease', (226, 230))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('HER2', 'Gene', '2064', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('ERBB2', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('C13', 'Gene', (135, 138))	('tumors', 'Disease', (100, 106))	('deletion', 'Var', (35, 43))	('ERBB2', 'Gene', '2064', (84, 89))	('UCS', 'Disease', (250, 253))	('C13', 'Gene', '3229', (135, 138))	('BRCA', 'Gene', '672', (48, 52))	('HER2', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('BRCA', 'Gene', '672', (214, 218))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('aneuploid tumors', 'Disease', (173, 189))
35654	29625048	The silhouette widths ranged from -0.05 to 0.59, with the highest silhouette widths belonging to single-cancer-type-dominant iClusters (C11:LGG [IDH1 mut], C12:THCA, C16:PRAD, and C24:LAML).	('IDH1', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IDH1', 'Gene', '3417', (145, 149))	('C11', 'Gene', '51728', (136, 139))	('C16:PRAD', 'Var', (166, 174))	('C24:LAML', 'Var', (180, 188))	('cancer', 'Disease', (104, 110))	('C12:THCA', 'Var', (156, 164))	('C11', 'Gene', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
35655	29625048	Interestingly, 6 of the 7 pan-organ system iClusters (pan-GI: C1, C4, C18; pan-SCC: C25, C27, and pan-kidney: C28) had similar ranges of silhouette widths to those of single cancer-type dominant iClusters, suggesting that these were as robust as the cancer-type-dominant iClusters.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('C27', 'Var', (89, 92))	('SCC', 'Gene', (79, 82))	('C18', 'Gene', (70, 73))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('C18', 'Gene', '27241', (70, 73))	('SCC', 'Gene', '6317', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
35656	29625048	iClusters driven by a shared specific chromosomal alteration (e.g., C13:mixed [chr8 del]) tended to compose multiple tumor types and appeared to have among the lowest silhouette widths, suggesting substantial molecular heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mixed [chr8 del]', 'Var', (72, 88))	('tumor', 'Disease', (117, 122))	('C13', 'Gene', (68, 71))	('C13', 'Gene', '3229', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
35673	29625048	Melanomas and lung adenocarcinomas have been shown to have relatively high mutation rates, and we observed similar results with C15:SKCM/UVM and C14:LUAD.	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('C15', 'Gene', (128, 131))	('C14:LUAD', 'Var', (145, 153))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (14, 34))	('mutation', 'MPA', (75, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('Melanomas and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (0, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('C15', 'Gene', '51316', (128, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
35674	29625048	Mutation frequencies varied widely within the two iClusters with the most diverse tumor compositions: C3:mesenchymal (immune) and C20:mixed (stromal/immune).	('C20', 'Var', (130, 133))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
35681	29625048	Despite having very different cancer type compositions, the pan-squamous iClusters C10:pan-SCC, C25:pan-SCC (chr11 amp), and C27:pan-SCC (HPV) shared many pathway characteristics.	('amp', 'Chemical', 'MESH:D000249', (115, 118))	('SCC', 'Gene', '6317', (133, 136))	('SCC', 'Gene', '6317', (91, 94))	('C10', 'Gene', (83, 86))	('HPV', 'Species', '10566', (138, 141))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('SCC', 'Gene', (104, 107))	('C10', 'Gene', '3226', (83, 86))	('C25', 'Var', (96, 99))	('SCC', 'Gene', (91, 94))	('SCC', 'Gene', '6317', (104, 107))	('SCC', 'Gene', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('C27', 'Var', (125, 128))
35685	29625048	In addition, C20:mixed (stromal/immune) contained 32% Pan-GI samples and also displayed strong immune-related signaling.	('amp', 'Chemical', 'MESH:D000249', (62, 65))	('C20:mixed', 'Var', (13, 22))	('Pan-GI', 'Protein', (54, 60))
35686	29625048	Beta-catenin/cell-cell adhesion signaling appeared high in C4:pan-GI (CRC), C18:pan-GI (MSI), and C20:mixed (stromal/immune), but not in the smaller C1:STAD (EBV-CIMP).	('SI', 'Disease', 'None', (89, 91))	('C18', 'Gene', (76, 79))	('C4:pan-GI', 'Var', (59, 68))	('Beta-catenin/cell-cell adhesion signaling', 'MPA', (0, 41))	('C20:mixed', 'Var', (98, 107))	('C18', 'Gene', '27241', (76, 79))	('EBV', 'Species', '10376', (158, 161))	('high', 'PosReg', (51, 55))
35704	29625048	Interrogation of individual iClusters for their differentiating PARADIGM pathway features, canonical pathways, and gene programs amenable to drug targeting identified strong immune-related signaling features for both C3:mesenchymal (immune) and C20:mixed (stromal/immune) tumors, suggesting that they may share potential susceptibility to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('C20', 'Var', (245, 248))	('tumors', 'Disease', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('C3', 'Var', (217, 219))	('immune-related signaling', 'MPA', (174, 198))	('AR', 'Gene', '367', (65, 67))
35707	29625048	Compared to the seemingly discohesive groupings of the 17 heterogeneous iClusters, the 11 most homogeneous iClusters (C6:OV, C8:UCEC, C11:LGG [IDH1 mut], C12:THCA, C14:LUAD, C15:SKCM/UVM, C16:PRAD, C19:BRCA [luminal], C21:DLBC, C24:LAML, C26:LIHC) had higher silhouette widths, uniform tumor types, and histopathologies, but showed surprising degrees of spatial discohesion in the TumorMap.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('C21', 'Gene', (218, 221))	('IDH1', 'Gene', (143, 147))	('C11', 'Gene', (134, 137))	('C24:LAML', 'Var', (228, 236))	('higher', 'PosReg', (252, 258))	('Tumor', 'Phenotype', 'HP:0002664', (381, 386))	('C16:PRAD', 'Var', (188, 196))	('C21', 'Gene', '79718', (218, 221))	('C19:BRCA', 'Gene', (198, 206))	('IDH1', 'Gene', '3417', (143, 147))	('tumor', 'Disease', (286, 291))	('C15', 'Gene', '51316', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('C15', 'Gene', (174, 177))	('C26', 'CellLine', 'CVCL:0240', (238, 241))	('silhouette widths', 'CPA', (259, 276))	('C11', 'Gene', '51728', (134, 137))	('C19:BRCA', 'Gene', '672', (198, 206))
35710	29625048	However, exceptions that challenge this concept have also become apparent from such notable examples as the unpredictable clinical responses to a potent BRAF inhibitor across diverse malignancies all expressing the same BRAF mutation.	('BRAF', 'Gene', '673', (153, 157))	('BRAF', 'Gene', (153, 157))	('BRAF', 'Gene', '673', (220, 224))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('BRAF', 'Gene', (220, 224))	('amp', 'Chemical', 'MESH:D000249', (94, 97))	('mutation', 'Var', (225, 233))	('malignancies', 'Disease', (183, 195))
35735	29625048	Cervical squamous tumors clustered in high aneuploidy clusters AN1 and AN5.	('squamous tumors', 'Disease', (9, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('squamous tumors', 'Disease', 'MESH:D002294', (9, 24))	('AN1', 'Var', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
35736	29625048	These clusters were also enriched for other Pan-gyn tumors, including ovarian, high-copy number endometrial, and uterine carcinosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('high-copy number', 'Var', (79, 95))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('carcinosarcoma', 'Disease', 'MESH:D002296', (121, 135))	('ovarian', 'Disease', (70, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (113, 135))	('carcinosarcoma', 'Disease', (121, 135))
35737	29625048	Gynecologic tumors with fewer copy-number alterations including Luminal breast cancers and other endometrial tumors grouped separately in low aneuploidy clusters AN7 and AN8, respectively.	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('low aneuploidy clusters', 'Disease', 'MESH:D000782', (138, 161))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('copy-number alterations', 'Var', (30, 53))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('low aneuploidy clusters', 'Disease', (138, 161))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('breast cancers', 'Disease', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('endometrial tumors', 'Disease', 'MESH:D016889', (97, 115))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('AN7', 'Var', (162, 165))	('endometrial tumors', 'Disease', (97, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
35748	29625048	To minimize the influence of variable tumor purity levels on a clustering result, we dichotomized the data using a beta-value of >= 0.3 to define positive DNA methylation and < 0.3 to specify lack of methylation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('positive DNA methylation', 'Var', (146, 170))
35750	29625048	For clustering analysis of tumors, we selected 3,139 CpG sites that were methylated at a beta-value of >= 0.3 in more than 10% of tumors within any of the 33 cancer types.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('methylated', 'Var', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
35753	29625048	The heatmap was generated using the original beta-values for the top one-third (n = 1,035) of the most variability methylated CpGs across tumors (Figure 1B).	('CpGs', 'Gene', (126, 130))	('methylated', 'Var', (115, 125))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
35754	29625048	We noted that a fraction of ESCA and STAD was found in METH9 with LUAD and PAAD, a result that may be related to the low tumor cellularity of the cancers in this cluster.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('METH', 'Chemical', '-', (55, 59))	('low tumor', 'Disease', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ESCA', 'Disease', (28, 32))	('METH9', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('low tumor', 'Disease', 'MESH:D009800', (117, 126))
35778	29625048	MIR5 contained OV, MIR8 BRCA, MIR12 LGG, MIR13 LIHC, MIR14 THCA, and MIR15 PRAD.	('MIR1', 'Gene', '79187', (69, 73))	('MIR1', 'Gene', (69, 73))	('BRCA', 'Gene', '672', (24, 28))	('BRCA', 'Gene', (24, 28))	('MIR12', 'Gene', (30, 35))	('MIR8', 'Var', (19, 23))	('MIR1', 'Gene', '79187', (53, 57))	('MIR12', 'Gene', '406905', (30, 35))	('MIR1', 'Gene', (53, 57))	('MIR1', 'Gene', '79187', (41, 45))	('MIR1', 'Gene', '79187', (30, 34))	('MIR1', 'Gene', (41, 45))	('MIR1', 'Gene', (30, 34))
35786	29625048	MIR6, the Pan-GI group, was largely COAD and STAD, but also had substantial PAAD, READ and ESCA, with smaller numbers of CHOL and LIHC.	('MIR6', 'Var', (0, 4))	('COAD', 'Disease', (36, 40))	('COAD', 'Disease', 'MESH:D029424', (36, 40))
35869	28386245	It has since been demonstrated that after extinguishing FAdE-dependent SF1 expression, some cells become embedded within the coalescing capsule and later reemerge as FAdE-independent SF1-expressing cells during the formation of the definitive cortex.	('SF1', 'Gene', (183, 186))	('cortex', 'Gene', '33937', (243, 249))	('cortex', 'Gene', (243, 249))	('SF1', 'Gene', (71, 74))	('SF1', 'Gene', '22668', (183, 186))	('rat', 'Species', '10116', (25, 28))	('SF1', 'Gene', '22668', (71, 74))	('FAdE-dependent', 'Var', (56, 70))
35875	28386245	Studies examining the consequences of genetic loss of DAX1 in the adrenal revealed an unexpectedly hyper-functional zF in younger mice, characterized by an increase in cell proliferation and steroid production.	('mice', 'Species', '10090', (130, 134))	('rat', 'Species', '10116', (180, 183))	('DAX1', 'Gene', (54, 58))	('cell proliferation', 'CPA', (168, 186))	('steroid production', 'MPA', (191, 209))	('increase', 'PosReg', (156, 164))	('DAX1', 'Gene', '11614', (54, 58))	('steroid', 'Chemical', 'MESH:D013256', (191, 198))	('genetic loss', 'Var', (38, 50))	('hyper-functional', 'PosReg', (99, 115))
35893	28386245	In the mouse adrenal gland, beta-catenin expression is first observed at E12.5 in Sf1+ cells of the definitive cortex in a scattered fashion beneath the newly formed capsule.	('beta-catenin', 'Gene', (28, 40))	('Sf1', 'Gene', (82, 85))	('mouse', 'Species', '10090', (7, 12))	('beta-catenin', 'Gene', '12387', (28, 40))	('E12.5', 'Var', (73, 78))	('cortex', 'Gene', (111, 117))	('cortex', 'Gene', '33937', (111, 117))	('Sf1', 'Gene', '22668', (82, 85))
35894	28386245	After E18.5 and throughout life, beta-catenin protein expression becomes more enriched in cells of the zG, which have also been demonstrated to bear active canonical Wnt signaling.	('beta-catenin', 'Gene', '12387', (33, 45))	('beta-catenin', 'Gene', (33, 45))	('rat', 'Species', '10116', (135, 138))	('E18.5', 'Var', (6, 11))
35926	28386245	After E14.5, Tcf21 expression becomes predominately restricted to the capsule and further diminishes over time, leaving only a small population of capsular Tcf21+ cells through adulthood.	('Tcf21', 'Gene', (156, 161))	('Tcf21', 'Gene', (13, 18))	('Tcf21', 'Gene', '21412', (13, 18))	('E14.5', 'Var', (6, 11))	('leaving', 'Reg', (112, 119))	('Tcf21', 'Gene', '21412', (156, 161))
35930	28386245	The proper balance of progenitor proliferation and differentiation is crucial, as dysregulation of the mechanisms that regulate the differentiation, proliferation, and self-maintenance of progenitor cells throughout life can result in organ failure.	('rat', 'Species', '10116', (156, 159))	('dysregulation', 'Var', (82, 95))	('result in', 'Reg', (225, 234))	('rat', 'Species', '10116', (40, 43))	('organ failure', 'Disease', (235, 248))	('organ failure', 'Disease', 'MESH:D009102', (235, 248))
35935	28386245	In humans, WNT4 mutations underlie the defects in Serkal syndrome, an autosomal recessive disorder characterized by multiple malformations including adrenal hypoplasia and male-to-female sexual reversion.	('Serkal syndrome', 'Disease', (50, 65))	('multiple malformations', 'Disease', 'MESH:D000015', (116, 138))	('Serkal syndrome', 'Disease', 'OMIM:611812', (50, 65))	('mutations', 'Var', (16, 25))	('multiple malformations', 'Disease', (116, 138))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (70, 98))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (149, 167))	('humans', 'Species', '9606', (3, 9))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (149, 167))	('adrenal hypoplasia', 'Disease', (149, 167))	('autosomal recessive disorder', 'Disease', (70, 98))	('WNT4', 'Gene', (11, 15))
35936	28386245	In mice, while Wnt4 expression is observed in the developing adrenal glands as early as E11.5, by E14.5 it is restricted to the outer cortex.	('E14.5', 'Var', (98, 103))	('mice', 'Species', '10090', (3, 7))	('cortex', 'Gene', (134, 140))	('cortex', 'Gene', '33937', (134, 140))	('Wnt4', 'Gene', '22417', (15, 19))	('Wnt4', 'Gene', (15, 19))
35937	28386245	Additionally, a mouse model of Wnt4 inactivation suggests that this ligand is required for proper zG differentiation and aldosterone production.	('aldosterone production', 'Phenotype', 'HP:0000859', (121, 143))	('Wnt4', 'Gene', '22417', (31, 35))	('Wnt4', 'Gene', (31, 35))	('aldosterone', 'Chemical', 'MESH:D000450', (121, 132))	('mouse', 'Species', '10090', (16, 21))	('inactivation', 'Var', (36, 48))
35938	28386245	In these mice, genetic loss of Wnt4 decreases Cyp11b2 expression, leading to a diminished production of aldosterone.	('expression', 'MPA', (54, 64))	('Wnt4', 'Gene', '22417', (31, 35))	('Wnt4', 'Gene', (31, 35))	('production of aldosterone', 'MPA', (90, 115))	('Cyp11b2', 'Gene', (46, 53))	('diminished production of aldosterone', 'Phenotype', 'HP:0004319', (79, 115))	('diminished', 'NegReg', (79, 89))	('aldosterone', 'Chemical', 'MESH:D000450', (104, 115))	('Cyp11b2', 'Gene', '13072', (46, 53))	('mice', 'Species', '10090', (9, 13))	('loss', 'Var', (23, 27))	('decreases', 'NegReg', (36, 45))
35942	28386245	Additionally, according to our own analysis on a recently published molecular profiling study on adrenocortical carcinomas, samples with activating exon 3 CTNNB1 mutations exhibit increased expression of WNT4 in comparison to samples without somatic alterations in components of the Wnt pathway (fold change = 17.5, FDR-adjusted p-value <0.001).	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (97, 122))	('mutations', 'Var', (162, 171))	('activating', 'PosReg', (137, 147))	('increased', 'PosReg', (180, 189))	('adrenocortical carcinomas', 'Disease', (97, 122))	('CTNNB1', 'Gene', '12387', (155, 161))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (97, 121))	('CTNNB1', 'Gene', (155, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (97, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('expression', 'MPA', (190, 200))	('rat', 'Species', '10116', (254, 257))
35984	28386245	The global Fgfr2-IIIb knockout results in embryonic lethality due to severe malformations, including adrenal hypoplasia.	('Fgfr2', 'Gene', (11, 16))	('embryonic lethality', 'Disease', 'MESH:D020964', (42, 61))	('malformations', 'Disease', 'MESH:D000014', (76, 89))	('malformations', 'Disease', (76, 89))	('embryonic lethality', 'Disease', (42, 61))	('knockout', 'Var', (22, 30))	('Fgfr2', 'Gene', '14183', (11, 16))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (101, 119))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (101, 119))	('adrenal hypoplasia', 'Disease', (101, 119))
35985	28386245	The same adrenal phenotype was recapitulated by a Sf1-driven specific knockout of both Fgfr2-IIIb and Fgfr2-IIIc.	('knockout', 'Var', (70, 78))	('Fgfr2', 'Gene', (87, 92))	('Fgfr2', 'Gene', '14183', (102, 107))	('Fgfr2', 'Gene', '14183', (87, 92))	('Fgfr2', 'Gene', (102, 107))	('Sf1', 'Gene', (50, 53))	('Sf1', 'Gene', '22668', (50, 53))
36005	28386245	Clinical evidence suggests an important role of R-Spondins in stem cell biology and morphogenesis since inactivating mutations in R-Spondin genes are associated with syndromes characterized by stem cell failure and developmental abnormalities.	('associated', 'Reg', (150, 160))	('syndromes', 'Disease', (166, 175))	('R-Spondin', 'Gene', '192199', (130, 139))	('developmental abnormalities', 'Disease', (215, 242))	('R-Spondin', 'Gene', (48, 57))	('R-Spondin', 'Gene', '192199', (48, 57))	('inactivating mutations', 'Var', (104, 126))	('developmental abnormalities', 'Disease', 'MESH:D006130', (215, 242))	('R-Spondin', 'Gene', (130, 139))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (215, 242))
36012	28386245	Interestingly, while the genetic loss of Rspo1 had no observable effects on the adrenals, loss of Rspo3 was associated with remarkable phenotypes.	('Rspo3', 'Gene', (98, 103))	('loss', 'Var', (90, 94))	('Rspo1', 'Gene', (41, 46))	('genetic loss', 'Var', (25, 37))	('Rspo3', 'Gene', '72780', (98, 103))	('Rspo1', 'Gene', '192199', (41, 46))
36013	28386245	By using different crosses of a Rspo3flox allele and several CreERT drivers, the authors demonstrated that (a) loss of Rspo3 results in cortical atrophy both during development and postnatally; (b) these changes are accompanied by a dramatic decrease in canonical Wnt signaling, which results in loss of the expression of canonical Wnt target genes such as Axin2 and Wnt4; (c) loss of a functional zG, characterized by profound morphological changes and loss of expression of zG markers (while retaining zF differentiation); (d) loss of cortical Shh-expressing cells and capsular Gli1-expressing cells; and (e) a significant decrease in the mitotic activity of the cortex.	('Rspo3', 'Gene', (32, 37))	('Cre', 'Gene', '39441', (61, 64))	('loss', 'Var', (111, 115))	('Rspo3', 'Gene', (119, 124))	('decrease', 'NegReg', (625, 633))	('Rspo3', 'Gene', '72780', (32, 37))	('Wnt4', 'Gene', '22417', (367, 371))	('loss', 'NegReg', (377, 381))	('Rspo3', 'Gene', '72780', (119, 124))	('decrease', 'NegReg', (242, 250))	('cortex', 'Gene', (665, 671))	('Axin2', 'Gene', '12006', (357, 362))	('Axin2', 'Gene', (357, 362))	('loss', 'NegReg', (296, 300))	('cortical Shh-expressing cells', 'CPA', (537, 566))	('cortical atrophy', 'Phenotype', 'HP:0002120', (136, 152))	('cortical atrophy', 'Disease', (136, 152))	('expression', 'MPA', (308, 318))	('cortical atrophy', 'Disease', 'MESH:D001284', (136, 152))	('cortex', 'Gene', '33937', (665, 671))	('Cre', 'Gene', (61, 64))	('rat', 'Species', '10116', (96, 99))	('Wnt4', 'Gene', (367, 371))	('loss', 'NegReg', (529, 533))
36018	28386245	Supporting this observation, genetic ablation of beta1 integrin favors a symmetric pattern of cell division in the mammary stem cell niche, leading to exhaustion of the stem cell compartment.	('exhaustion', 'CPA', (151, 161))	('beta1', 'Gene', (49, 54))	('favors', 'PosReg', (64, 70))	('symmetric pattern', 'CPA', (73, 90))	('beta1', 'Gene', '97440', (49, 54))	('genetic ablation', 'Var', (29, 45))
36041	26087193	Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('TARBP2', 'Gene', '6895', (70, 76))	('truncating mutations', 'Var', (77, 97))	('tumor', 'Disease', (101, 106))	('TARBP2', 'Gene', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('ovarian tumors', 'Disease', (50, 64))	('mutations', 'Var', (26, 35))	('ovarian tumors', 'Phenotype', 'HP:0100615', (50, 64))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('DICER1', 'Gene', (19, 25))	('DICER1', 'Gene', '23405', (19, 25))	('hot-spot', 'PosReg', (10, 18))	('ovarian tumors', 'Disease', 'MESH:D010051', (50, 64))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
36044	26087193	Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors.	('TARBP2', 'Gene', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('mutations', 'Var', (30, 39))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('metal', 'Chemical', 'MESH:D008670', (43, 48))	('TARBP2', 'Gene', '6895', (126, 132))	('DICER1', 'Gene', (98, 104))	('DICER1', 'Gene', '23405', (98, 104))
36059	26087193	We have recently demonstrated that expression of LIN28, a highly conserved RNA-binding protein that has emerged as a modulator of the processing of let-7, was associated with recurrence in ACCs.	('ACCs', 'Gene', (189, 193))	('ACCs', 'Gene', '84680', (189, 193))	('associated with', 'Reg', (159, 174))	('LIN28', 'Gene', (49, 54))	('LIN28', 'Gene', '79727', (49, 54))	('ACC', 'Phenotype', 'HP:0006744', (189, 192))	('expression', 'Var', (35, 45))
36064	26087193	Recently, DICER1 mutations in the RNase IIIb domain were found in 29% of nonepithelial ovarian tumors, predominantly in Sertoli-Leydig cell tumors (60%).	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (128, 146))	('ovarian tumors', 'Phenotype', 'HP:0100615', (87, 101))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('Sertoli-Leydig cell tumors', 'Disease', (120, 146))	('DICER1', 'Gene', (10, 16))	('DICER1', 'Gene', '23405', (10, 16))	('ovarian tumors', 'Disease', 'MESH:D010051', (87, 101))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (120, 146))	('found', 'Reg', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (120, 146))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutations', 'Var', (17, 26))	('ovarian tumors', 'Disease', (87, 101))
36067	26087193	In mouse models of cancer, the loss of a single Dicer1 allele (haploinsufficiency) reduced the time to tumor onset or survival time.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('haploinsufficiency', 'Disease', (63, 81))	('Dicer1', 'Gene', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('mouse', 'Species', '10090', (3, 8))	('reduced', 'NegReg', (83, 90))	('tumor', 'Disease', (103, 108))	('loss', 'Var', (31, 35))	('cancer', 'Disease', (19, 25))	('haploinsufficiency', 'Disease', 'MESH:D058495', (63, 81))	('Dicer1', 'Gene', '192119', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('survival time', 'CPA', (118, 131))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
36069	26087193	Truncating mutations in TARBP2 gene, encoding the TRBP protein, were identified in sporadic and hereditary carcinomas with microsatellite instability.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('hereditary carcinomas', 'Disease', (96, 117))	('TARBP2', 'Gene', (24, 30))	('Truncating mutations', 'Var', (0, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('identified', 'Reg', (69, 79))	('sporadic', 'Disease', (83, 91))	('TRBP', 'Gene', (50, 54))	('TRBP', 'Gene', '6895', (50, 54))	('hereditary carcinomas', 'Disease', 'MESH:C565972', (96, 117))	('TARBP2', 'Gene', '6895', (24, 30))
36070	26087193	Two frameshift mutations in TARBP2 were identified: the deletion of a C in a (C)5 coding microsatellite repeat of exon 5 in the colorectal cancer cell line Co115 and the insertion of a C in a (C)7 coding microsatellite repeat of exon 5 in the endometrial cancer cell line SKUT-1B.	('deletion', 'Var', (56, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (128, 145))	('TARBP2', 'Gene', '6895', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('endometrial cancer', 'Phenotype', 'HP:0012114', (243, 261))	('TARBP2', 'Gene', (28, 34))	('SKUT-1', 'CellLine', 'CVCL:0533', (272, 278))	('endometrial cancer', 'Disease', 'MESH:D016889', (243, 261))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('colorectal cancer', 'Disease', (128, 145))	('endometrial cancer', 'Disease', (243, 261))
36071	26087193	The presence of TARBP2 frameshift mutations causes diminished TRBP protein expression and a defect in the processing of miRNAs.	('TRBP', 'Gene', (62, 66))	('TRBP', 'Gene', '6895', (62, 66))	('TARBP2', 'Gene', '6895', (16, 22))	('frameshift mutations', 'Var', (23, 43))	('TARBP2', 'Gene', (16, 22))	('diminished', 'NegReg', (51, 61))	('defect', 'NegReg', (92, 98))	('processing of miRNAs', 'MPA', (106, 126))	('expression', 'MPA', (75, 85))
36072	26087193	The reintroduction of TRBP in the deficient cells restores the efficient production of miRNAs and inhibits tumor growth.	('reintroduction', 'Var', (4, 18))	('restores', 'PosReg', (50, 58))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('efficient production of miRNAs', 'MPA', (63, 93))	('TRBP', 'Gene', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('inhibits', 'NegReg', (98, 106))	('TRBP', 'Gene', '6895', (22, 26))
36075	26087193	Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the (C)5 coding microsatellite repeat of TARBP2 exon 5.	('TARBP2', 'Gene', '6895', (153, 159))	('TARBP2', 'Gene', (153, 159))	('mutations', 'Var', (30, 39))	('metal', 'Chemical', 'MESH:D008670', (43, 48))	('DICER1', 'Gene', (98, 104))	('DICER1', 'Gene', '23405', (98, 104))
36091	26087193	In multivariate analysis, a weak DICER1 expression (HR 2.6, 95% CI 1.1-6.7; p = 0.048) and a Ki67 >= 10% (HR 6.2, 95% CI 2.5-15.6; p = 0.0001) remained as independent predictors of recurrence (Table 3).	('expression', 'MPA', (40, 50))	('weak', 'NegReg', (28, 32))	('DICER1', 'Gene', (33, 39))	('Ki67', 'Chemical', '-', (93, 97))	('Ki67 >= 10%', 'Var', (93, 104))	('DICER1', 'Gene', '23405', (33, 39))
36121	26087193	demonstrated DICER1 SUMOylation by the UBC9 enzyme, which promotes DICER1 post-translational degradation.	('UBC9', 'Gene', '7329', (39, 43))	('DICER1', 'Gene', '23405', (13, 19))	('SUMOylation', 'Var', (20, 31))	('post-translational degradation', 'MPA', (74, 104))	('promotes', 'PosReg', (58, 66))	('DICER1', 'Gene', (67, 73))	('UBC9', 'Gene', (39, 43))	('DICER1', 'Gene', '23405', (67, 73))	('DICER1', 'Gene', (13, 19))
36122	26087193	In this study, the loss of DICER1 protein expression was a molecular predictor of local recurrence and/or metastasis.	('DICER1', 'Gene', (27, 33))	('local recurrence', 'CPA', (82, 98))	('protein', 'Protein', (34, 41))	('DICER1', 'Gene', '23405', (27, 33))	('expression', 'MPA', (42, 52))	('loss', 'Var', (19, 23))	('metastasis', 'CPA', (106, 116))
36124	26087193	Additionaly, we could not conclude if the loss of DICER1 protein expression has a direct role in cancer progression or is an epiphenomenon reflecting underlying abnormalities.	('loss', 'Var', (42, 46))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('DICER1', 'Gene', (50, 56))	('DICER1', 'Gene', '23405', (50, 56))	('protein', 'Protein', (57, 64))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
36125	26087193	In other cancers, low expression of DICER1 has been associated with inactivating DICER1 mutations and miR-107/103 deregulation.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('DICER1', 'Gene', '23405', (81, 87))	('cancers', 'Disease', (9, 16))	('mutations', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('inactivating', 'Var', (68, 80))	('miR-107', 'Gene', '406901', (102, 109))	('DICER1', 'Gene', '23405', (36, 42))	('DICER1', 'Gene', (36, 42))	('DICER1', 'Gene', (81, 87))	('deregulation', 'NegReg', (114, 126))	('low', 'NegReg', (18, 21))	('miR-107', 'Gene', (102, 109))	('expression', 'MPA', (22, 32))
36127	26087193	It was recently shown that hot-spot DICER1 mutations were highly prevalent in Sertoli-Leydig cell tumors.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (78, 104))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (78, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutations', 'Var', (43, 52))	('DICER1', 'Gene', (36, 42))	('DICER1', 'Gene', '23405', (36, 42))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (86, 104))	('prevalent', 'Reg', (65, 74))	('Sertoli-Leydig cell tumors', 'Disease', (78, 104))
36128	26087193	DICER1 hot-spot mutations were also found in a single high-grade ovarian sarcoma, one testicular germ-cell and two embryonal rhabdomyosarcomas.	('embryonal rhabdomyosarcomas', 'Phenotype', 'HP:0006743', (115, 142))	('DICER1', 'Gene', (0, 6))	('DICER1', 'Gene', '23405', (0, 6))	('embryonal rhabdomyosarcomas', 'Disease', 'MESH:D018233', (115, 142))	('ovarian sarcoma', 'Disease', 'MESH:D010051', (65, 80))	('ovarian sarcoma', 'Disease', (65, 80))	('mutations', 'Var', (16, 25))	('found', 'Reg', (36, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('embryonal rhabdomyosarcomas', 'Disease', (115, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('hot-spot', 'PosReg', (7, 15))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (125, 142))
36133	26087193	identified TARBP2 truncating mutations in sporadic and hereditary carcinomas with microsatellite instability.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('hereditary carcinomas', 'Disease', 'MESH:C565972', (55, 76))	('hereditary carcinomas', 'Disease', (55, 76))	('TARBP2', 'Gene', (11, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('TARBP2', 'Gene', '6895', (11, 17))	('sporadic', 'Disease', (42, 50))	('truncating mutations', 'Var', (18, 38))
36162	26087193	The assays for target genes were DICER1 (Hs00998580_m1) and TARBP2 (Hs00998379_m1).	('Hs00998379_m1', 'Var', (68, 81))	('Hs00998580_m1', 'Var', (41, 54))	('DICER1', 'Gene', (33, 39))	('DICER1', 'Gene', '23405', (33, 39))	('TARBP2', 'Gene', '6895', (60, 66))	('TARBP2', 'Gene', (60, 66))
36165	26087193	The following TaqMan MicroRNA Assays were used: miR-103 (000439) and miR-107 (00443).	('000439', 'Var', (57, 63))	('miR-107', 'Gene', (69, 76))	('miR-103', 'Var', (48, 55))	('miR-103', 'Chemical', '-', (48, 55))	('miR-107', 'Gene', '406901', (69, 76))
36254	19451403	hypothesized that congenital anomalies brought about by thalidomide were secondary to its effect on vasculogenesis.	('congenital anomalies', 'Disease', 'MESH:D000013', (18, 38))	('thalidomide', 'Chemical', 'MESH:D013792', (56, 67))	('thalidomide', 'Var', (56, 67))	('congenital anomalies', 'Disease', (18, 38))
36255	19451403	While the precise mechanism by which thalidomide exerts its anti-angiogenic effects remain to be elucidated, thalidomide has been shown to have promising results in a variety of cancers, with multiple myeloma at the forefront.	('multiple myeloma', 'Disease', (192, 208))	('thalidomide', 'Chemical', 'MESH:D013792', (109, 120))	('thalidomide', 'Chemical', 'MESH:D013792', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('multiple myeloma', 'Phenotype', 'HP:0006775', (192, 208))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('thalidomide', 'Var', (109, 120))	('anti-angiogenic', 'MPA', (60, 75))	('multiple myeloma', 'Disease', 'MESH:D009101', (192, 208))
36344	19451403	Renal functional status of patients were defined by use of either group 0, with normal CLCr > 80 mL/min (n=29), and 1 for mild renal impairment (RI) with 50 <= CLCr <= 80 mL/min.	('mild renal impairment', 'Disease', (122, 143))	('patients', 'Species', '9606', (27, 35))	('mild renal impairment', 'Disease', 'MESH:D007674', (122, 143))	('CLCr', 'Chemical', '-', (87, 91))	('50 <=', 'Var', (154, 159))	('renal impairment', 'Phenotype', 'HP:0000083', (127, 143))	('CLCr', 'Chemical', '-', (160, 164))
36347	19451403	Therefore, clearance was estimated separately for groups of patients with respect to renal function, normal or mild RI, thereby resulting in reduction of objective function value of 16, which meets the pre-defined criteria.	('objective function value of 16', 'MPA', (154, 184))	('patients', 'Species', '9606', (60, 68))	('rat', 'Species', '10116', (39, 42))	('clearance', 'MPA', (11, 20))	('mild RI', 'Var', (111, 118))	('reduction', 'NegReg', (141, 150))
36356	19451403	Serum cytokine tests which were performed to determine clinical concentrations of IFN-gamma, IL-2, IL-4, IL-10, IL-12p70, IL-13, and TNF-alpha indicated that the concentrations were mostly below the limit of quantification, and hence not evaluable.	('IL-13', 'Gene', '3596', (122, 127))	('rat', 'Species', '10116', (169, 172))	('rat', 'Species', '10116', (71, 74))	('IL-4', 'Gene', (99, 103))	('IL-10', 'Gene', (105, 110))	('IL-2', 'Gene', '3558', (93, 97))	('IL-4', 'Gene', '3565', (99, 103))	('IFN-gamma', 'Gene', '3458', (82, 91))	('IFN-gamma', 'Gene', (82, 91))	('TNF-alpha', 'Gene', '7124', (133, 142))	('IL-2', 'Gene', (93, 97))	('IL-12p70', 'Var', (112, 120))	('TNF-alpha', 'Gene', (133, 142))	('IL-13', 'Gene', (122, 127))	('IL-10', 'Gene', '3586', (105, 110))
36375	19451403	In this study, clearance for patients with mild RI was about 50% of that for individuals with normal renal function, resulting in greater lenalidomide exposure in the renally impaired subjects.	('lenalidomide exposure', 'MPA', (138, 159))	('patients', 'Species', '9606', (29, 37))	('mild', 'Var', (43, 47))	('lenalidomide', 'Chemical', 'MESH:D000077269', (138, 150))	('renally impaired', 'Phenotype', 'HP:0000083', (167, 183))	('greater', 'PosReg', (130, 137))
36376	19451403	Similarly, it has been reported that in patients with multiple myeloma lenalidomide exposure in those with mild RI is 56% greater than those with normal function.	('greater', 'PosReg', (122, 129))	('patients', 'Species', '9606', (40, 48))	('multiple myeloma', 'Phenotype', 'HP:0006775', (54, 70))	('multiple myeloma', 'Disease', 'MESH:D009101', (54, 70))	('mild RI', 'Var', (107, 114))	('multiple myeloma', 'Disease', (54, 70))	('lenalidomide', 'Chemical', 'MESH:D000077269', (71, 83))
36409	33889439	CA209-538 is a multicentre open label phase 2 study conducted at five Australia sites (Austin Health, Peter McCallum Cancer Center and Monash Health, Melbourne; Blacktown Hospital, Sydney; and Border Medical Oncology, Albury/Wodonga, local sponsor was the Olivia Newton-John Cancer Research Institute, Melbourne).	('Oncology', 'Phenotype', 'HP:0002664', (208, 216))	('Olivia Newton-John Cancer', 'Disease', (256, 281))	('Peter McCallum Cancer', 'Disease', (102, 123))	('Peter McCallum Cancer', 'Disease', 'MESH:D009369', (102, 123))	('CA209-538', 'Var', (0, 9))	('Cancer', 'Phenotype', 'HP:0002664', (275, 281))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Olivia Newton-John Cancer', 'Disease', 'MESH:D009369', (256, 281))
36449	33889439	The two patients obtaining an objective response had tumors with an MSH2 mutation in keeping with a microsatellite instable phenotype (MSI-H), one patient on the background of a MSH2 germline mutation.	('MSI', 'Gene', (135, 138))	('MSH2', 'Gene', '4436', (68, 72))	('patient', 'Species', '9606', (147, 154))	('MSI', 'Gene', '5928', (135, 138))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('MSH2', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('MSH2', 'Gene', '4436', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('patient', 'Species', '9606', (8, 15))	('mutation', 'Var', (73, 81))	('tumors', 'Disease', (53, 59))	('MSH2', 'Gene', (68, 72))	('patients', 'Species', '9606', (8, 16))
36450	33889439	The tumor of this patient demonstrated a high TMB of 145 mutations per megabase (MB) whilst the second MSI-H tumor demonstrated only a TMB of 5.05/MB.	('tumor', 'Disease', (4, 9))	('MSI-H tumor', 'Disease', (103, 114))	('MSI-H tumor', 'Disease', 'MESH:D009369', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('TMB', 'Chemical', '-', (46, 49))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('patient', 'Species', '9606', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('TMB', 'Chemical', '-', (135, 138))	('tumor', 'Disease', (109, 114))
36451	33889439	The TMB range of the remaining four patients has been 0-170/MB; the patient with the tumor demonstrating the highest TMB had stable disease as her best response to study treatment with a reduction of target lesions that has just fallen short of an objective response, it carried a biallelic RB1 deletion.	('tumor', 'Disease', (85, 90))	('RB1', 'Gene', '5925', (291, 294))	('TMB', 'Chemical', '-', (4, 7))	('patients', 'Species', '9606', (36, 44))	('patient', 'Species', '9606', (68, 75))	('TMB', 'Chemical', '-', (117, 120))	('fallen', 'Phenotype', 'HP:0002527', (229, 235))	('deletion', 'Var', (295, 303))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('RB1', 'Gene', (291, 294))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('patient', 'Species', '9606', (36, 43))
36453	33889439	The tumors of both responders harbored next to a MSH-2 mutation, an inactivating TP53 mutation.	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('TP53', 'Gene', (81, 85))	('mutation', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutation', 'Var', (55, 63))	('TP53', 'Gene', '7157', (81, 85))	('MSH-2', 'Gene', (49, 54))	('MSH-2', 'Gene', '4436', (49, 54))
36454	33889439	Current systemic treatment options for patients with advanced ACC include mitotane which is associated with a response rate of 23%, median time to progression of 5.5 months and high toxicity.	('patients', 'Species', '9606', (39, 47))	('toxicity', 'Disease', 'MESH:D064420', (182, 190))	('toxicity', 'Disease', (182, 190))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('mitotane', 'Var', (74, 82))	('mitotane', 'Chemical', 'MESH:D008939', (74, 82))
36478	33889439	The tumor with the highest TMB next to an MSI-H tumor was mismatch repair protein proficient and harbored a biallelic RB1 deletion.	('tumor', 'Disease', (4, 9))	('MSI-H tumor', 'Disease', (42, 53))	('tumor', 'Disease', (48, 53))	('TMB', 'Chemical', '-', (27, 30))	('MSI-H tumor', 'Disease', 'MESH:D009369', (42, 53))	('RB1', 'Gene', (118, 121))	('deletion', 'Var', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('RB1', 'Gene', '5925', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('biallelic', 'Var', (108, 117))
36479	33889439	Preclinical studies have shown that RB1 deletions can lead to increased DNA damage by impaired homologous recombination repair potentially explaining the high TMB in this patient.	('increased', 'PosReg', (62, 71))	('impaired', 'NegReg', (86, 94))	('patient', 'Species', '9606', (171, 178))	('deletions', 'Var', (40, 49))	('TMB', 'Chemical', '-', (159, 162))	('RB1', 'Gene', (36, 39))	('homologous recombination repair', 'MPA', (95, 126))	('RB1', 'Gene', '5925', (36, 39))	('DNA damage', 'MPA', (72, 82))
36480	33889439	We identified in the tumor tissue of our patient cohort several oncogenic mutations that are well recognized as oncogenic aberrations in ACC.	('tumor', 'Disease', (21, 26))	('mutations', 'Var', (74, 83))	('patient', 'Species', '9606', (41, 48))	('ACC', 'Phenotype', 'HP:0006744', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
36481	33889439	Of interest the tumor of one responder had an activating CTNNB1 and an inactivating STK11 mutation both of which have been associated with primary resistance to anti-PD-1 therapy in patients with melanoma and non-small cell lung cancer respectively suggesting that combination immunotherapy may overcome this resistance.	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('CTNNB1', 'Gene', '1499', (57, 63))	('patients', 'Species', '9606', (182, 190))	('STK11', 'Gene', '6794', (84, 89))	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('inactivating', 'NegReg', (71, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('mutation', 'Var', (90, 98))	('activating', 'PosReg', (46, 56))	('CTNNB1', 'Gene', (57, 63))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (209, 235))	('tumor', 'Disease', (16, 21))	('PD-1', 'Gene', (166, 170))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (213, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('PD-1', 'Gene', '5133', (166, 170))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('lung cancer', 'Disease', (224, 235))	('STK11', 'Gene', (84, 89))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))
36491	33889439	This may suggest that checkpoint inhibition in ACC patients reinvigorates anti-tumor immune responses that are directed against shared antigens expressed by liver and adrenal gland.	('inhibition', 'Var', (33, 43))	('reinvigorates', 'PosReg', (60, 73))	('tumor', 'Disease', (79, 84))	('ACC', 'Phenotype', 'HP:0006744', (47, 50))	('patients', 'Species', '9606', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
36503	33181667	Thus, high expression of TGF-beta2 not only facilitates the prognosis in CRC patients, but also may provide a new target for the treatment of CRC.	('CRC', 'Disease', (73, 76))	('TGF-beta2', 'Gene', '7042', (25, 34))	('patients', 'Species', '9606', (77, 85))	('high', 'Var', (6, 10))	('prognosis', 'CPA', (60, 69))	('facilitates', 'PosReg', (44, 55))	('TGF-beta2', 'Gene', (25, 34))	('CRC', 'Disease', (142, 145))
36506	33181667	Immunotherapy has provided antitumor effects in malignant melanoma and non-small cell lung cancer by targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4), and inhibitors of programmed death 1 (PD-1) receptor, and programmed death ligand 1 (PD-L1).	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))	('PD-1', 'Gene', (202, 206))	('PD-1', 'Gene', '5133', (202, 206))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('inhibitors', 'Var', (168, 178))	('lung cancer', 'Disease', (86, 97))	('malignant melanoma', 'Phenotype', 'HP:0002861', (48, 66))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('programmed death 1', 'Gene', '5133', (182, 200))	('programmed death ligand 1', 'Gene', (222, 247))	('malignant melanoma', 'Disease', 'MESH:D008545', (48, 66))	('programmed death 1', 'Gene', (182, 200))	('CTLA4', 'Gene', '1493', (156, 161))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', (111, 154))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', '1493', (111, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('CTLA4', 'Gene', (156, 161))	('PD-L1', 'Gene', (249, 254))	('programmed death ligand 1', 'Gene', '29126', (222, 247))	('tumor', 'Disease', (31, 36))	('malignant melanoma', 'Disease', (48, 66))	('PD-L1', 'Gene', '29126', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
36518	33181667	Inhibition of TGF-beta signaling prevents metastasis or further development of certain advanced tumors such as CRC and gastric cancer, while TGF-beta1 can impair immune cell responsiveness and promote angiogenesis.	('promote', 'PosReg', (193, 200))	('angiogenesis', 'CPA', (201, 213))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TGF-beta', 'Gene', (14, 22))	('tumors', 'Disease', (96, 102))	('gastric cancer', 'Disease', (119, 133))	('TGF-beta', 'Gene', (141, 149))	('impair', 'NegReg', (155, 161))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('TGF-beta1', 'Gene', (141, 150))	('Inhibition', 'Var', (0, 10))	('immune cell responsiveness', 'CPA', (162, 188))	('metastasis', 'CPA', (42, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('prevents', 'NegReg', (33, 41))	('CRC', 'Disease', (111, 114))	('TGF-beta1', 'Gene', '7040', (141, 150))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('TGF-beta', 'Gene', '7039', (14, 22))	('TGF-beta', 'Gene', '7039', (141, 149))	('further development', 'CPA', (56, 75))
36553	33181667	This analysis documented that upregulation of TGF- beta2 was strongly related to the poor prognosis of patients with gastric cancer (OS HR = 1.88 (95%CI: 1.57-2.24), P < .0001; PPS HR = 2.51 (95%CI: 2.01-3.15), P < .0001; 209908_s_at), breast cancer (OS HR = 0.77 (95%CI: 0.61-0.99), P = .039; no-distance survival HR = 0.78 (95%CI: 0.62-0.99), P = .043; 209908_s_at) (2K-L), lung cancer (OS HR = 1.23 (1.08-1.4), P = .0013, 220407_s_at; PPS HR = 1.34 (1.04-1.73), P = .025, 220406_at), and Ovarian cancer (OS HR = 1.18 (1.04-1.34), P = .013, 209909_s_at; progression-free survival, progression-free survival, HR = 1.22 (1.07-1.39), P = .0036, 220407_s_at;) (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (376, 387))	('TGF- beta2', 'Gene', '7042', (46, 56))	('patients', 'Species', '9606', (103, 111))	('gastric cancer', 'Disease', (117, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (376, 387))	('220407_s_at', 'Var', (644, 655))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('209909_s_at', 'Var', (543, 554))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (491, 505))	('TGF- beta2', 'Gene', (46, 56))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', (381, 387))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('cancer', 'Disease', (499, 505))	('breast cancer', 'Disease', (236, 249))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (499, 505))	('upregulation', 'PosReg', (30, 42))	('lung cancer', 'Disease', (376, 387))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (499, 505))
36554	33181667	Conversely, the expression of TGF-beta2 appeared as a protective factor in the prostate, breast cancer, colorectal, blood cancer, brain, gastric, lung, and ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (156, 171))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Disease', (89, 102))	('TGF-beta2', 'Gene', (30, 39))	('prostate', 'Disease', (79, 87))	('gastric', 'Disease', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TGF-beta2', 'Gene', '7042', (30, 39))	('blood cancer', 'Phenotype', 'HP:0001909', (116, 128))	('ovarian cancers', 'Disease', (156, 171))	('ovarian cancers', 'Disease', 'MESH:D010051', (156, 171))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('expression', 'Var', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung', 'Disease', (146, 150))	('brain', 'Disease', (130, 135))	('colorectal, blood cancer', 'Disease', 'MESH:D015179', (104, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
36572	33181667	Data on the expression of markers of DCs (CD1C, NRP1, and ITGAX) indicate that high TGF-beta2 expression increases DC infiltration in COAD.	('CD1C', 'Gene', '911', (42, 46))	('DC infiltration', 'MPA', (115, 130))	('TGF-beta2', 'Gene', '7042', (84, 93))	('TGF-beta2', 'Gene', (84, 93))	('ITGAX', 'Gene', (58, 63))	('NRP1', 'Gene', '8829', (48, 52))	('NRP1', 'Gene', (48, 52))	('high', 'Var', (79, 83))	('ITGAX', 'Gene', '3687', (58, 63))	('CD1C', 'Gene', (42, 46))	('increases', 'PosReg', (105, 114))
36577	33181667	The present work demonstrated that TGF-beta2 expression correlates with the prognosis of patients with multiple types of cancer, and particularly strong correlation is present between high TGF-beta2 expression and the prognosis of CRC patients.	('TGF-beta2', 'Gene', '7042', (35, 44))	('TGF-beta2', 'Gene', (35, 44))	('expression', 'MPA', (199, 209))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (235, 243))	('CRC', 'Disease', (231, 234))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('TGF-beta2', 'Gene', '7042', (189, 198))	('cancer', 'Disease', (121, 127))	('TGF-beta2', 'Gene', (189, 198))	('high', 'Var', (184, 188))
36585	33181667	Variations in TGF-beta2 expression in a range of different cancers may be related to discrepancies in data collection methods between individual studies or differences in underlying biological mechanisms.	('related', 'Reg', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Variations', 'Var', (0, 10))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('TGF-beta2', 'Gene', (14, 23))	('cancers', 'Disease', (59, 66))	('TGF-beta2', 'Gene', '7042', (14, 23))
36586	33181667	In the database used in the current work, a correlation between high TGF-beta2 expression and poor prognosis of CRC was observed.	('high', 'Var', (64, 68))	('expression', 'MPA', (79, 89))	('CRC', 'Disease', (112, 115))	('TGF-beta2', 'Gene', '7042', (69, 78))	('TGF-beta2', 'Gene', (69, 78))
36603	33195415	However, the characterization of aberrant ACE2 expression in malignant tumors has not been elucidated.	('malignant tumors', 'Disease', (61, 77))	('malignant tumors', 'Disease', 'MESH:D009369', (61, 77))	('ACE2', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('aberrant', 'Var', (33, 41))	('ACE2', 'Gene', '59272', (42, 46))
36616	33195415	GSEA analysis which was carried out to determine the effect of ACE2 on tumors indicated that several cancer-associated pathways and immune-related pathways were hyperactivated in the high ACE2 expression group of most tumors.	('hyperactivated', 'PosReg', (161, 175))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('expression', 'MPA', (193, 203))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('GSEA', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('ACE2', 'Gene', '59272', (63, 67))	('tumors', 'Disease', (218, 224))	('cancer', 'Disease', (101, 107))	('ACE2', 'Gene', '59272', (188, 192))	('ACE2', 'Gene', (63, 67))	('immune-related pathways', 'Pathway', (132, 155))	('ACE2', 'Gene', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('high', 'Var', (183, 187))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
36651	33195415	Neoantigen is a neonatal antigen that is encoded by a mutant gene of a tumor cell.	('mutant', 'Var', (54, 60))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
36653	33195415	Neoantigen vaccines can be developed using the immune activity of tumor neoantigens, according to a specific mutation in the tumor cells, then administered to patients to achieve the required therapeutic effect.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('patients', 'Species', '9606', (159, 167))	('mutation', 'Var', (109, 117))
36656	33195415	The Tumor Mutational Burden (TMB) is usually measured by the number of somatic mutations that occur within an average of 1 Mb in the coding region (exon region) of the tumor cell genome (non-synonymous mutations).	('Tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('TMB', 'Chemical', '-', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mutations', 'Var', (79, 88))
36660	33195415	Microsatellite Instability (MSI) refers to any change in the length of a microsatellite due to the insertion or deletion of a repeating unit in a tumor compared to normal tissue.	('change', 'Reg', (47, 53))	('S', 'Gene', '43740568', (29, 30))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('length', 'MPA', (61, 67))	('insertion', 'Var', (99, 108))	('tumor', 'Disease', (146, 151))	('deletion', 'Var', (112, 120))	('Microsatellite Instability', 'Disease', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
36666	33195415	We visualized the tumor with the most ACE2 mutations using an R data package, maftools.	('tumor', 'Disease', (18, 23))	('ACE2', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('ACE2', 'Gene', '59272', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
36667	33195415	Therefore, TCGA expression profiling was used to evaluate the relationship between ACE2 and five MMRs genes: MLH1, MSH2, MSH6, PMS2, and EPCAM mutations.	('PMS2', 'Gene', (127, 131))	('MLH1', 'Gene', '4292', (109, 113))	('MLH1', 'Gene', (109, 113))	('MSH6', 'Gene', (121, 125))	('PMS2', 'Gene', '5395', (127, 131))	('ACE2', 'Gene', (83, 87))	('MMRs genes', 'Gene', (97, 107))	('EPCAM', 'Gene', (137, 142))	('MSH6', 'Gene', '2956', (121, 125))	('MSH2', 'Gene', (115, 119))	('ACE2', 'Gene', '59272', (83, 87))	('MSH2', 'Gene', '4436', (115, 119))	('EPCAM', 'Gene', '4072', (137, 142))	('mutations', 'Var', (143, 152))
36713	33195415	We regularly collect and synthesize neoantigen vaccines, according to mutations in specific tumor cells, and using the immune activity of tumor neoantigens we immunize patients to achieve the required therapeutic effect.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('patients', 'Species', '9606', (168, 176))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
36726	33195415	A schematic diagram of the tumor with the highest number of mutations is shown in Figure 12.	('tumor', 'Disease', (27, 32))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
36727	33195415	Notably, ACE2 mutations were only observed in BLCA, BRCA, COAD, HNSC, LAML, LGG, LUAD, LUSC, OV, SKCM, STAD, and UCEC.	('S', 'Gene', '43740568', (66, 67))	('S', 'Gene', '43740568', (97, 98))	('S', 'Gene', '43740568', (103, 104))	('ACE2', 'Gene', '59272', (9, 13))	('BRCA', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (52, 56))	('COAD', 'Disease', (58, 62))	('S', 'Gene', '43740568', (89, 90))	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('mutations', 'Var', (14, 23))	('ACE2', 'Gene', (9, 13))
36728	33195415	These findings indicate that ACE2 mutations seldom occur in most tumors.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('ACE2', 'Gene', '59272', (29, 33))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (34, 43))	('ACE2', 'Gene', (29, 33))
36733	33195415	DNA hypermethylation in the promoter region of a tumor suppressor gene leads to gene silencing, which in turn leads to dysregulation of multiple signaling pathways associated with human malignancy.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('multiple signaling pathways', 'Pathway', (136, 163))	('gene', 'MPA', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('malignancy', 'Disease', 'MESH:D009369', (186, 196))	('leads to', 'Reg', (110, 118))	('human', 'Species', '9606', (180, 185))	('tumor', 'Disease', (49, 54))	('malignancy', 'Disease', (186, 196))	('dysregulation', 'MPA', (119, 132))	('hypermethylation', 'Var', (4, 20))
36773	33195415	It has been demonstrated that overexpressed ACE2 may inhibit cell growth and vascular endothelial growth factor production in lung cancer, breast cancer, colon cancer, and pancreatic cancer.	('ACE2', 'Gene', '59272', (44, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ACE2', 'Gene', (44, 48))	('inhibit', 'NegReg', (53, 60))	('vascular endothelial growth factor', 'Gene', '7422', (77, 111))	('pancreatic cancer', 'Disease', 'MESH:D010190', (172, 189))	('lung cancer', 'Disease', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colon cancer', 'Disease', 'MESH:D015179', (154, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('vascular endothelial growth factor', 'Gene', (77, 111))	('pancreatic cancer', 'Disease', (172, 189))	('cell growth', 'CPA', (61, 72))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Disease', (139, 152))	('overexpressed', 'Var', (30, 43))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('colon cancer', 'Disease', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (172, 189))
36774	33195415	On the other hand, overexpressed ACE2 may promote the migration and invasion of human renal carcinoma cells.	('ACE2', 'Gene', '59272', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('renal carcinoma', 'Disease', 'MESH:C538614', (86, 101))	('migration', 'CPA', (54, 63))	('promote', 'PosReg', (42, 49))	('overexpressed', 'Var', (19, 32))	('human', 'Species', '9606', (80, 85))	('renal carcinoma', 'Disease', (86, 101))	('ACE2', 'Gene', (33, 37))	('renal carcinoma', 'Phenotype', 'HP:0005584', (86, 101))
36787	33195415	We found that increased ACE2 expression correlates with immune infiltration levels in most tumors and that higher ACE2 expression was related to immune neoantigen, TMB, and microsatellite instability.	('tumors', 'Disease', (91, 97))	('increased', 'PosReg', (14, 23))	('expression', 'MPA', (119, 129))	('TMB', 'Chemical', '-', (164, 167))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('ACE2', 'Gene', '59272', (114, 118))	('related', 'Reg', (134, 141))	('ACE2', 'Gene', (24, 28))	('microsatellite', 'Var', (173, 187))	('expression', 'MPA', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ACE2', 'Gene', '59272', (24, 28))	('higher', 'PosReg', (107, 113))	('ACE2', 'Gene', (114, 118))	('immune infiltration levels', 'MPA', (56, 82))
36833	32175564	First, cell markers of T cells CD4 memory were identified by Cell Marker database as CCR7, CD27 (Gene symbol: BTLA), CXCR5, IL7R, and cell markers of macrophages M0 as CD68, CD163, CD14, CD11b (Gene symbol: ITGAM) and CD206 (Gene symbol: MRC1).	('CD163', 'Var', (174, 179))	('CD4', 'Gene', (31, 34))	('CD14', 'Gene', (181, 185))	('CD27', 'Gene', '939', (91, 95))	('CD4', 'Gene', '920', (31, 34))	('CD27', 'Gene', (91, 95))	('MRC1', 'Gene', '4360', (238, 242))	('CD14', 'Gene', '929', (181, 185))	('CD11b', 'Gene', (187, 192))	('BTLA', 'Gene', (110, 114))	('CXCR5', 'Gene', (117, 122))	('CD11b', 'Gene', '3684', (187, 192))	('CXCR5', 'Gene', '643', (117, 122))	('CD206', 'Gene', (218, 223))	('CD206', 'Gene', '4360', (218, 223))	('BTLA', 'Gene', '151888', (110, 114))	('MRC1', 'Gene', (238, 242))
36835	32175564	Besides, comprehensive analysis of genomics and clinical data in cBioPortal database showed that CCR7, CXCR5, IL7R CD68, CD163, CD14, ITGAM, MRC1 and H2AFX had genomic alteration in primary ACC (Supplementary Figure S5A).	('MRC1', 'Gene', '4360', (141, 145))	('CD14', 'Gene', (128, 132))	('CD163', 'Var', (121, 126))	('CXCR5', 'Gene', (103, 108))	('CXCR5', 'Gene', '643', (103, 108))	('CD14', 'Gene', '929', (128, 132))	('MRC1', 'Gene', (141, 145))	('primary ACC', 'Disease', (182, 193))
36894	31354635	Conclusions: Our study identified abnormally methylated DEGs and potentially affected pathways in ACCs, from which we could begin to understand the basic molecular mechanisms of these alterations.	('DEGs', 'Protein', (56, 60))	('affected', 'Reg', (77, 85))	('abnormally methylated', 'Var', (34, 55))	('pathways', 'Pathway', (86, 94))	('ACCs', 'Gene', (98, 102))	('ACCs', 'Gene', '84680', (98, 102))
36895	31354635	Moreover, these abnormally methylated genes might serve as therapeutic targets and biomarkers to allow ACC patients to be more precisely diagnosed and effectively treated.	('abnormally', 'Var', (16, 26))	('patients', 'Species', '9606', (107, 115))	('ACC', 'Disease', (103, 106))
36899	31354635	ACCs are generally discovered in grown-ups aged 40-50 years, while it may also happen to children, especially those with a typical germline mutation in tumor protein p53.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('ACCs', 'Gene', (0, 4))	('ACCs', 'Gene', '84680', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('tumor', 'Disease', (152, 157))	('children', 'Species', '9606', (89, 97))	('germline mutation', 'Var', (131, 148))
36903	31354635	In recent years, many studies identified genetic and epigenetic alterations in ACCs and suggested them to be key factors for the occurrence and development of ACCs.	('ACCs', 'Gene', '84680', (79, 83))	('epigenetic alterations', 'Var', (53, 75))	('ACCs', 'Gene', (79, 83))	('genetic', 'Var', (41, 48))	('ACCs', 'Gene', '84680', (159, 163))	('ACCs', 'Gene', (159, 163))
36908	31354635	The abnormal DNA methylation can impact tumorigenesis and tumor progression by influencing the regulatory patterns of oncogenes and anti-oncogenes, as well as the structure of chromatin at the level of transcription.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('abnormal', 'Var', (4, 12))	('influencing', 'Reg', (79, 90))	('regulatory patterns', 'MPA', (95, 114))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('structure', 'MPA', (163, 172))	('DNA', 'Protein', (13, 16))	('tumor', 'Disease', (40, 45))	('impact', 'Reg', (33, 39))
36910	31354635	Additionally, there is evidence showing the intimate relationship between tumorigenesis and GpG-island hyper-methylation which causes the silencing of downstream genes.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('GpG-island', 'Protein', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('silencing', 'MPA', (138, 147))	('tumor', 'Disease', (74, 79))	('hyper-methylation', 'Var', (103, 120))
36915	31354635	This current study thus, seeks to identify abnormally methylated DEGs, along with alterations in signaling pathways and GO among normal and tumor samples and using this information elucidate the molecular mechanisms of ACCs.	('abnormally methylated', 'Var', (43, 64))	('ACCs', 'Gene', (219, 223))	('ACCs', 'Gene', '84680', (219, 223))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('alterations', 'Reg', (82, 93))	('signaling pathways', 'Pathway', (97, 115))	('tumor', 'Disease', (140, 145))
36916	31354635	Datasets GSE12368 and GSE19750 were performed on the same platform Affymetrix Human Genome U133 Plus 2.0 Array (HG U133 Plus 2.0).	('GSE12368', 'Var', (9, 17))	('Human', 'Species', '9606', (78, 83))	('GSE19750', 'Var', (22, 30))
36917	31354635	Dataset GSE14922, GSE75415, and GSE90713 were performed on the platform Agilent-014850 Whole Human Genome Microarray 4x44K, Affymetrix Human Genome U133A Array and Affymetrix Human Gene Expression Array, respectively.	('GSE90713', 'Var', (32, 40))	('Human', 'Species', '9606', (175, 180))	('Human', 'Species', '9606', (135, 140))	('Human', 'Species', '9606', (93, 98))	('GSE75415', 'Var', (18, 26))
36921	31354635	The cut-off standards for DMGs and DEGs were beta > 0.2, p <0.05 and  logFC  > 1, p <0.05, respectively.	('logFC  >', 'Var', (70, 78))	('beta > 0.2', 'Var', (45, 55))	('DMGs', 'Chemical', '-', (26, 30))
36928	31354635	NCI-H296R was grown and maintained in DMEM media supplemented with 1% insulin transferrin selenium (Gibco, China) and 2.5% Nu-Serum I (Gibco, China) in a standard humidified incubator at 37 C in a 5% CO2 atmosphere.	('selenium', 'Chemical', 'MESH:D012643', (90, 98))	('DMEM', 'Chemical', '-', (38, 42))	('CO2', 'Chemical', '-', (200, 203))	('H296R', 'Var', (4, 9))	('transferrin', 'Gene', '7018', (78, 89))	('H296R', 'SUBSTITUTION', 'None', (4, 9))	('transferrin', 'Gene', (78, 89))
36950	31354635	As shown in Figures 4, 5, significant differences were identified and determined to be identical to those differences found between tumor and normal samples in both databases regarding the expression of the six downregulated hyper-methylated genes and the one upregulated hypo-methylated gene.	('hyper-methylated', 'Var', (225, 241))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('downregulated', 'NegReg', (211, 224))
36951	31354635	As shown in Figure 6A, it was observed that 40 out of the total 79 cases having genic alterations, such as missense, amplification, etc., occurred most often in PTGER4, CYP11B1, and NR2F1 (13, 15, and 21%, respectively).	('CYP11B1', 'Gene', (169, 176))	('CYP11B1', 'Gene', '1584', (169, 176))	('PTGER4', 'Gene', '5734', (161, 167))	('missense', 'Var', (107, 115))	('NR2F1', 'Gene', '7025', (182, 187))	('PTGER4', 'Gene', (161, 167))	('amplification', 'Var', (117, 130))	('occurred', 'Reg', (138, 146))	('NR2F1', 'Gene', (182, 187))
36958	31354635	When their expression and methylation were combined, the overall rates of survival significantly negatively correlated with hypermethylation and low expression of five genes (CD14, HOXA5, KCNQ1, and NR2F1) along with hypomethylation and high expression of ESM1 (Figure 8C).	('hypermethylation', 'Var', (124, 140))	('CD14', 'Gene', (175, 179))	('NR2F1', 'Gene', '7025', (199, 204))	('ESM1', 'Gene', '11082', (256, 260))	('ESM1', 'Gene', (256, 260))	('CD14', 'Gene', '929', (175, 179))	('negatively', 'NegReg', (97, 107))	('KCNQ1', 'Gene', (188, 193))	('expression', 'MPA', (149, 159))	('low', 'NegReg', (145, 148))	('NR2F1', 'Gene', (199, 204))	('HOXA5', 'Gene', '3202', (181, 186))	('HOXA5', 'Gene', (181, 186))	('KCNQ1', 'Gene', '3784', (188, 193))
36959	31354635	In order to confirm the methylation of the six hyper-methylated gene promoters in ACC, bisulfite sequence analyses were performed on three ACC samples and three adjacent normal ones, demonstrating that methylation of all CpG sites of five gene promoters were more frequent in ACC rather than in normal samples (Figures 10A-E).	('ACC', 'Disease', (276, 279))	('frequent', 'Reg', (264, 272))	('bisulfite', 'Chemical', 'MESH:C042345', (87, 96))	('methylation', 'Var', (202, 213))
36972	31354635	Therefore, hyper-methylation could lead to gene downregulation, functionally similar to a tumor suppressor gene, while hypo-methylation could result in gene upregulation, functionally similar to oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('gene', 'MPA', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('upregulation', 'PosReg', (157, 169))	('downregulation', 'NegReg', (48, 62))	('hypo-methylation', 'Var', (119, 135))	('hyper-methylation', 'Var', (11, 28))
36982	31354635	Although the specific functions of these seven genes in ACC have never been demonstrated, their mutation and expression dysregulation may have impacts on tumorigenesis, staging, and prognosis of ACC.	('expression', 'MPA', (109, 119))	('dysregulation', 'Var', (120, 133))	('impacts', 'Reg', (143, 150))	('mutation', 'Var', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('staging', 'CPA', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('ACC', 'Disease', (195, 198))	('tumor', 'Disease', (154, 159))
36984	31354635	Consistently, our study showed hypermethylation of two genes (PTGER4 and NR2F1) led to a higher pathology stage.	('NR2F1', 'Gene', (73, 78))	('hypermethylation', 'Var', (31, 47))	('led to', 'Reg', (80, 86))	('PTGER4', 'Gene', '5734', (62, 68))	('higher', 'PosReg', (89, 95))	('PTGER4', 'Gene', (62, 68))	('NR2F1', 'Gene', '7025', (73, 78))
36988	31354635	When their expression and methylation were combined, the overall rates of survival significantly negatively correlated with hypermethylation and low expression of five genes (CD14, HOXA5, KCNQ1, and NR2F1) along with hypomethylation and high expression of ESM1.	('hypermethylation', 'Var', (124, 140))	('CD14', 'Gene', (175, 179))	('NR2F1', 'Gene', '7025', (199, 204))	('ESM1', 'Gene', '11082', (256, 260))	('ESM1', 'Gene', (256, 260))	('CD14', 'Gene', '929', (175, 179))	('negatively', 'NegReg', (97, 107))	('KCNQ1', 'Gene', (188, 193))	('expression', 'MPA', (149, 159))	('low', 'NegReg', (145, 148))	('NR2F1', 'Gene', (199, 204))	('HOXA5', 'Gene', '3202', (181, 186))	('HOXA5', 'Gene', (181, 186))	('KCNQ1', 'Gene', '3784', (188, 193))
36994	31354635	In our study, we found that ESM1 was hypomethylated and upregulated in ACCs, indicating that aberrant methylation in ACCs might lead to the upregulation of ESM1, resulting in ACC tumorigenesis.	('methylation', 'MPA', (102, 113))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('ESM1', 'Gene', (156, 160))	('ACCs', 'Gene', '84680', (117, 121))	('ACCs', 'Gene', (117, 121))	('aberrant', 'Var', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('ACC', 'Disease', (175, 178))	('ACCs', 'Gene', (71, 75))	('ESM1', 'Gene', '11082', (28, 32))	('upregulation', 'PosReg', (140, 152))	('ACCs', 'Gene', '84680', (71, 75))	('ESM1', 'Gene', (28, 32))	('ESM1', 'Gene', '11082', (156, 160))	('tumor', 'Disease', (179, 184))
36996	31354635	Besides the methylation, other genetic alterations, such as missense mutation, amplification and deep deletion could also contribute to tumorogenesis.	('deep deletion', 'Var', (97, 110))	('contribute', 'Reg', (122, 132))	('tumorogenesis', 'Disease', (136, 149))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('missense mutation', 'Var', (60, 77))	('tumorogenesis', 'Disease', 'MESH:D002471', (136, 149))	('amplification', 'Var', (79, 92))
37000	31354635	However, we have noticed that hypermethylation of the CYP11B1 gene and the loss of its expression may be related to the occurrence of hypercortisolemia.	('hypermethylation', 'Var', (30, 46))	('CYP11B1', 'Gene', (54, 61))	('related', 'Reg', (105, 112))	('hypercortisolemia', 'Disease', 'None', (134, 151))	('CYP11B1', 'Gene', '1584', (54, 61))	('expression', 'MPA', (87, 97))	('loss', 'NegReg', (75, 79))	('hypercortisolemia', 'Disease', (134, 151))
37004	31354635	In conclusion, we identified seven genes hypo/hyper methylated and dysregulated, which could play important roles in the development and progression of ACCs.	('ACCs', 'Gene', (152, 156))	('ACCs', 'Gene', '84680', (152, 156))	('hypo/hyper methylated', 'Var', (41, 62))	('play', 'Reg', (93, 97))	('roles', 'Reg', (108, 113))
37007	31354635	Our novel data suggests these abnormally methylated genes could be used as therapeutic targets and biomarkers for ACC patients to be precisely diagnosed and effectively treated.	('patients', 'Species', '9606', (118, 126))	('ACC', 'Disease', (114, 117))	('abnormally', 'Var', (30, 40))
37018	29164414	LVI positivity further stratified patients with T2 and T3 disease (T2: 37 mo vs. median not reached; T3: 36 mo vs. 96 mo; p = 0.03) but did not influence survival in patients with T1 or T4 disease.	('T3 disease', 'Disease', (55, 65))	('positivity', 'Var', (4, 14))	('patients', 'Species', '9606', (34, 42))	('LVI', 'Chemical', '-', (0, 3))	('patients', 'Species', '9606', (166, 174))
37064	29164414	There was no difference in recurrence between LVI-positive and LVI-negative tumors (63% vs. 57%, p = 0.064), although LVI-positivity was associated with less locoregional recurrence (20% vs. 55%) and more distant recurrence (80% vs. 45%) compared with LVI-negativity (p = 0.003).	('less', 'NegReg', (153, 157))	('LVI', 'Chemical', '-', (46, 49))	('LVI', 'Chemical', '-', (118, 121))	('LVI', 'Chemical', '-', (252, 255))	('locoregional recurrence', 'CPA', (158, 181))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('LVI-positivity', 'Var', (118, 132))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('distant recurrence', 'CPA', (205, 223))	('LVI', 'Chemical', '-', (63, 66))
37112	29471873	Here, we used the query options in the control panel to enter the TCGA identifiers for adrenocortical carcinoma (ACC) and bladder urothelial carcinoma (BLCA) studies, and the miRBase IDs for has-let-7b and has-let-7c.	('bladder urothelial carcinoma', 'Disease', (122, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('let-7b', 'Gene', '406884', (195, 201))	('has-let-7c', 'Var', (206, 216))	('let-7b', 'Gene', (195, 201))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (87, 111))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (87, 111))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (122, 150))	('adrenocortical carcinoma', 'Disease', (87, 111))
37186	27770290	MIS has also been correlated with earlier recurrence rates, increased the risk of tumor spillage, or positive margins.	('MIS', 'Var', (0, 3))	('tumor spillage', 'Disease', 'MESH:D009369', (82, 96))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('earlier recurrence rates', 'CPA', (34, 58))	('positive margins', 'CPA', (101, 117))	('tumor spillage', 'Disease', (82, 96))
37235	27770290	On univariable analysis, the cases completed using MIS techniques had significantly lower BMI (median: 25.5 kg/m2, range: 19.0 - 50.0, non-converted MIS vs. 34.0 kg/m2, range: 25.4 - 64.0, converted MIS; p=0.020), smaller tumor size (median: 6.5 cm, range: 3.0 - 15.0, non-converted MIS vs. 11.0 cm, range: 7.0 - 15.0, converted MIS; p<0.001), lower EBL (median: 100 mL, range: 25 - 450, non-converted MIS vs. 800 mL, range: 400 - 1400, converted MIS; p<0.001) and shorter operative times (156 min, range: 79 - 318, non-converted MIS vs. 358 min, range: 205 - 780, converted MIS; p=0.001).	('operative times', 'CPA', (473, 488))	('BMI', 'MPA', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('lower', 'NegReg', (344, 349))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('converted', 'Var', (189, 198))	('lower', 'NegReg', (84, 89))	('tumor', 'Disease', (222, 227))	('lower BMI', 'Phenotype', 'HP:0045082', (84, 93))
37247	27770290	This is a critical finding, as the importance of achieving a margin-negative resection was reinforced in a large analysis of nearly 4,000 patients identified from the National Cancer Data Base, which revealed a clear improvement in survival among margin-negative patients,.	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('patients', 'Species', '9606', (263, 271))	('survival', 'MPA', (232, 240))	('Cancer', 'Disease', (176, 182))	('Cancer', 'Disease', 'MESH:D009369', (176, 182))	('improvement', 'PosReg', (217, 228))	('patients', 'Species', '9606', (138, 146))	('margin-negative', 'Var', (247, 262))
37272	27119750	The 10-fold increase in incidence in Southern Brazil is accounted for by the highly prevalent R337H germline mutation of the TP53 gene.	('TP53', 'Gene', (125, 129))	('R337H', 'Mutation', 'rs121912664', (94, 99))	('R337H', 'Var', (94, 99))	('TP53', 'Gene', '7157', (125, 129))
37285	27119750	Retrospective studies have suggested that mitotane has a narrow therapeutic window with sustained maintenance of a serum level >=14 mg/L predicting a better recurrence-free survival (RFS) in the adjuvant setting, while improving tumor response and survival in advanced ACC.	('better', 'PosReg', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('recurrence-free survival', 'CPA', (157, 181))	('mitotane', 'Var', (42, 50))	('mitotane', 'Chemical', 'MESH:D008939', (42, 50))	('tumor', 'Disease', (229, 234))	('improving', 'PosReg', (219, 228))	('serum level', 'MPA', (115, 126))	('ACC', 'Phenotype', 'HP:0006744', (269, 272))
37299	27119750	The First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) evaluated the efficacy of first-line EDP-M versus Sz-M in these patients.	('Metastatic Adrenocortical Carcinoma', 'Disease', (65, 100))	('Carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Sz-M', 'Chemical', '-', (172, 176))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (76, 100))	('EDP-M', 'Chemical', '-', (159, 164))	('Metastatic Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (65, 100))	('patients', 'Species', '9606', (186, 194))	('EDP-M', 'Var', (159, 164))
37300	27119750	The EDP-M arm had significantly higher objective responses and progression-free survival (PFS) when compared to the Sz-M arm, in addition to a 21% reduction in the risk of death in the former arm in the intent-to-treat analysis.	('higher', 'PosReg', (32, 38))	('progression-free survival', 'CPA', (63, 88))	('EDP-M', 'Var', (4, 9))	('Sz-M', 'Chemical', '-', (116, 120))	('reduction', 'NegReg', (147, 156))	('objective responses', 'CPA', (39, 58))	('EDP-M', 'Chemical', '-', (4, 9))
37352	27119750	Analysis of mRNA expression patterns and mutation patterns in ACC has also revealed potential targets for ACC therapy, including the FGF receptor and c-MET.	('c-MET', 'Gene', '4233', (150, 155))	('mutation', 'Var', (41, 49))	('c-MET', 'Gene', (150, 155))	('ACC', 'Phenotype', 'HP:0006744', (106, 109))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('ACC', 'Disease', (106, 109))	('mRNA expression', 'MPA', (12, 27))
37356	27119750	Analysis of tumors has demonstrated that mutations in beta-catenin (encoded by CTNNB1) are seen in cancers, and expression analyses have confirmed a Wnt/beta-catenin expression pattern, generally associated with more aggressive tumor behavior.	('beta-catenin', 'Gene', (153, 165))	('beta-catenin', 'Gene', '1499', (153, 165))	('mutations', 'Var', (41, 50))	('aggressive tumor', 'Disease', 'MESH:D001523', (217, 233))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('beta-catenin', 'Gene', (54, 66))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('beta-catenin', 'Gene', '1499', (54, 66))	('CTNNB1', 'Gene', '1499', (79, 85))	('more', 'PosReg', (212, 216))	('aggressive tumor', 'Disease', (217, 233))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('associated with', 'Reg', (196, 211))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('CTNNB1', 'Gene', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
37360	27119750	Because beta-catenin can be activated directly by mutations, agents that target the pathway at the post-receptor level may be necessary for efficacy.	('beta-catenin', 'Gene', (8, 20))	('activated', 'PosReg', (28, 37))	('beta-catenin', 'Gene', '1499', (8, 20))	('mutations', 'Var', (50, 59))
37361	27119750	CWP232291 is a drug that appears to suppress Wnt signaling by promoting beta-catenin degradation, and this agent is currently in early phase I trials for leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (154, 162))	('leukemia', 'Disease', 'MESH:D007938', (154, 162))	('promoting', 'PosReg', (62, 71))	('beta-catenin', 'Gene', (72, 84))	('leukemia', 'Disease', (154, 162))	('suppress', 'NegReg', (36, 44))	('beta-catenin', 'Gene', '1499', (72, 84))	('Wnt signaling', 'Pathway', (45, 58))	('CWP232291', 'Var', (0, 9))
37364	27119750	It is important to note however that 27% of benign adrenocortical tumors harbor beta-catenin mutations; therefore, whether this is a targetable therapy for adrenal malignancies is challenging to decipher.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (93, 102))	('benign adrenocortical tumors', 'Disease', 'MESH:D018268', (44, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('beta-catenin', 'Gene', (80, 92))	('benign adrenocortical tumors', 'Disease', (44, 72))	('adrenal malignancies', 'Disease', (156, 176))	('beta-catenin', 'Gene', '1499', (80, 92))	('adrenal malignancies', 'Phenotype', 'HP:0100631', (156, 176))	('adrenal malignancies', 'Disease', 'MESH:D009369', (156, 176))
37367	27119750	Although inverse agonists of SF1 have been demonstrated to be successful at reducing the proliferation of ACC cell lines, this line of study has not yet engendered clinical trials.	('proliferation', 'CPA', (89, 102))	('inverse agonists', 'Var', (9, 25))	('ACC', 'Phenotype', 'HP:0006744', (106, 109))	('SF1', 'Gene', (29, 32))	('reducing', 'NegReg', (76, 84))	('SF1', 'Gene', '7536', (29, 32))
37370	27119750	Inhibitors of the enzyme were initially developed as potential therapeutics for cardiovascular disease targeted towards reducing building of cholesterol esters in macrophages.	('building of cholesterol esters in', 'MPA', (129, 162))	('cholesterol esters', 'Chemical', 'MESH:D002788', (141, 159))	('reducing', 'NegReg', (120, 128))	('cardiovascular disease', 'Disease', (80, 102))	('Inhibitors', 'Var', (0, 10))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (80, 102))	('cardiovascular disease', 'Disease', 'MESH:D002318', (80, 102))
37372	27119750	Although no results from the trial are yet available, mechanistic studies have suggested that inhibition of ACAT1 in the presence of cholesterol causes ER stress and calcium release in adrenocortical cells, leading to cell death.	('ACAT1', 'Gene', (108, 113))	('cell death', 'CPA', (218, 228))	('ER stress', 'MPA', (152, 161))	('adrenocortical', 'Disease', (185, 199))	('calcium', 'Chemical', 'MESH:D002118', (166, 173))	('ACAT1', 'Gene', '38', (108, 113))	('adrenocortical', 'Disease', 'MESH:D018268', (185, 199))	('cholesterol', 'Chemical', 'MESH:D002784', (133, 144))	('calcium release', 'MPA', (166, 181))	('inhibition', 'Var', (94, 104))	('causes', 'Reg', (145, 151))
37380	27119750	Tyrosine Kinase inhibitors have largely been ineffective as monotherapy The Wnt signaling pathway remains a viable target, and tools to target this pathway are now coming online Inhibition of ACAT1 (acetyl-coA cholesterol acetyl transferase 1) is a promising new avenue of research Further research is needed for the identification of additional targets and the means to block them	('acetyl-coA cholesterol acetyl transferase 1', 'Gene', (199, 242))	('acetyl-coA cholesterol acetyl transferase 1', 'Gene', '38', (199, 242))	('Inhibition', 'Var', (178, 188))	('Tyrosine Kinase', 'Gene', '7294', (0, 15))	('ACAT1', 'Gene', (192, 197))	('ACAT1', 'Gene', '38', (192, 197))	('Tyrosine Kinase', 'Gene', (0, 15))
37432	26282907	Similarly, 3- and 5-year survival was worse among patients with locoregional and distant metastasis (39.5 and 19.7 %, respectively) compared to patients who had locoregional recurrence only (81.4 and 64.1 %, respectively) or distant metastasis only (55.1 and 43.3 %, respectively) (p = 0.01).	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (50, 58))	('worse', 'NegReg', (38, 43))	('locoregional', 'Var', (64, 76))
37495	27213037	Microsatellite instability is the hallmark of Lynch syndrome, and while there is an increased risk of all malignancies in patients with this syndrome, endometrial carcinoma and colorectal carcinoma are most often associated with this disease.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('Microsatellite', 'Var', (0, 14))	('associated', 'Reg', (213, 223))	('endometrial carcinoma', 'Disease', (151, 172))	('colorectal carcinoma', 'Disease', (177, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('malignancies', 'Disease', (106, 118))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (177, 197))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (151, 172))	('Lynch syndrome', 'Disease', (46, 60))	('patients', 'Species', '9606', (122, 130))	('Lynch syndrome', 'Disease', 'MESH:D003123', (46, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (151, 172))
37531	27213037	Another French study of 51 patients confirmed these findings, also noting that the SUVmax of the tumor was correlated with Weiss score greater than or equal to 3, IGF-2 expression and loss of heterozygosity (LOH) of the tumor-suppressor gene TP53, all pathologic indicators of malignancy.	('malignancy', 'Disease', (277, 287))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', (97, 102))	('IGF-2', 'Gene', (163, 168))	('patients', 'Species', '9606', (27, 35))	('IGF-2', 'Gene', '3481', (163, 168))	('loss of heterozygosity', 'Var', (184, 206))	('expression', 'MPA', (169, 179))	('TP53', 'Gene', (242, 246))	('malignancy', 'Disease', 'MESH:D009369', (277, 287))	('TP53', 'Gene', '7157', (242, 246))	('SUVmax', 'Disease', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
37561	27213037	In addition to its role in ascertaining malignancy in histopathologic analysis of adrenocortical tumors, Ki-67 can be used to aid in prognosis for patients with ACC.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (82, 103))	('adrenocortical tumors', 'Disease', (82, 103))	('aid', 'Gene', (126, 129))	('patients', 'Species', '9606', (147, 155))	('ACC', 'Phenotype', 'HP:0006744', (161, 164))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Ki-', 'Chemical', 'MESH:C066186', (105, 108))	('Ki-67', 'Var', (105, 110))	('malignancy', 'Disease', 'MESH:D009369', (40, 50))	('aid', 'Gene', '57379', (126, 129))	('malignancy', 'Disease', (40, 50))
37572	27213037	Genome-wide analysis has revealed that less common variants of TP53 polymorphisms were associated with a decreased OS in ACC.	('ACC', 'Phenotype', 'HP:0006744', (121, 124))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('variants', 'Var', (51, 59))	('polymorphisms', 'Var', (68, 81))	('decreased', 'NegReg', (105, 114))	('OS in ACC', 'Disease', (115, 124))
37614	27213037	There is also some evidence that mitotane sensitizes ACC tumor cells to radiation, but this is not well studied.	('mitotane', 'Var', (33, 41))	('mitotane', 'Chemical', 'MESH:D008939', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('ACC', 'Phenotype', 'HP:0006744', (53, 56))	('sensitizes', 'Reg', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
37617	27213037	Univariate and multivariate analysis showed significantly longer survival at 119 months for plasma concentrations greater than or equal to 14 mg/l compared with 18 months for patients receiving mitotane monotherapy in whom a plasma mitotane concentration was less than 14 mg/l.	('mitotane', 'Chemical', 'MESH:D008939', (194, 202))	('mitotane', 'Chemical', 'MESH:D008939', (232, 240))	('longer', 'PosReg', (58, 64))	('survival', 'CPA', (65, 73))	('greater than', 'Var', (114, 126))	('patients', 'Species', '9606', (175, 183))
37621	27213037	Indeed, mitotane therapy is associated with a range of significant toxicity, characterized most commonly by gastrointestinal symptoms and more rarely, by significant neurologic side effects.	('gastrointestinal symptoms', 'Disease', 'MESH:D012817', (108, 133))	('mitotane', 'Var', (8, 16))	('mitotane', 'Chemical', 'MESH:D008939', (8, 16))	('gastrointestinal symptoms', 'Disease', (108, 133))	('toxicity', 'Disease', 'MESH:D064420', (67, 75))	('toxicity', 'Disease', (67, 75))
37631	27213037	When treated with the regimen as first-line therapy, patients in the EDP-mitotane group had an objective response rate of 23.2% and a median progression-free survival of 5 months, compared with 9.2% response and 2-month progression-free survival for the streptozocin-mitotane group.	('mitotane', 'Chemical', 'MESH:D008939', (267, 275))	('streptozocin', 'Chemical', 'MESH:D013311', (254, 266))	('EDP-mitotane', 'Chemical', '-', (69, 81))	('patients', 'Species', '9606', (53, 61))	('men', 'Species', '9606', (26, 29))	('mitotane', 'Chemical', 'MESH:D008939', (73, 81))	('progression-free', 'CPA', (141, 157))	('EDP-mitotane', 'Var', (69, 81))
37725	26538381	In the left adrenal gland, aldosterone levels from LD1 and LD2 were as high as 25444 and 10187 ng dl-1, respectively, and A/C of both LD1 (32.05) and LD2 (12.47) were higher than that of EIV (3.74; Table 2).	('LD2', 'Var', (59, 62))	('aldosterone levels', 'MPA', (27, 45))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('25444', 'Var', (79, 84))	('LD1', 'Var', (51, 54))	('aldosterone', 'Chemical', 'MESH:D000450', (27, 38))	('10187', 'Var', (89, 94))
37771	26538381	In our experience, the incidence of adrenal haemorrhage during sampling procedures has been higher in case of S-AVS when compared with C-AVS.	('C', 'Chemical', 'MESH:D002244', (135, 136))	('S-AVS', 'Var', (110, 115))	('adrenal haemorrhage', 'Disease', (36, 55))	('adrenal haemorrhage', 'Disease', 'MESH:D006470', (36, 55))
37772	26538381	Therefore, we must acknowledge that S-AVS is considered to have inherent risks of complications, such as adrenal haemorrhage and resultant partial adrenal infarct, whose incidence is expected to be higher than that seen in C-AVS.	('C', 'Chemical', 'MESH:D002244', (223, 224))	('S-AVS', 'Var', (36, 41))	('adrenal haemorrhage', 'Disease', (105, 124))	('adrenal haemorrhage', 'Disease', 'MESH:D006470', (105, 124))	('adrenal infarct', 'Disease', (147, 162))	('adrenal infarct', 'Disease', 'MESH:D007238', (147, 162))
37791	26580448	Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families.	('patient', 'Species', '9606', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('patient', 'Species', '9606', (83, 90))	('improve', 'PosReg', (32, 39))	('tumor', 'Disease', (61, 66))	('mutations', 'Var', (18, 27))
37794	26580448	The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome.	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (235, 240))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
37796	26580448	Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('persons', 'Species', '9606', (147, 154))	('autism', 'Disease', (219, 225))	('participants', 'Species', '9606', (199, 211))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('autism', 'Disease', 'MESH:D001321', (219, 225))	('autism', 'Phenotype', 'HP:0000717', (219, 225))
37798	26580448	A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('protein-truncating mutations', 'Var', (38, 66))	('tumor', 'Disease', (70, 75))	('patients', 'Species', '9606', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
37799	26580448	Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutation', 'Var', (39, 47))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('patients', 'Species', '9606', (10, 18))
37800	26580448	Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', (109, 115))	('identified', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('children', 'Species', '9606', (79, 87))
37802	26580448	The frequency of germline mutations in cancer-predisposition genes in children and adolescents with cancer and the implications of such mutations are largely unknown.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('children', 'Species', '9606', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('germline mutations', 'Var', (17, 35))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
37803	26580448	To better determine the contribution of germline predisposition mutations to childhood cancer, we used next-generation sequencing, including whole-genome and whole-exome sequencing, to analyze the genomes of 1120 children and adolescents with cancer.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('childhood cancer', 'Disease', 'MESH:C536928', (77, 93))	('childhood cancer', 'Disease', (77, 93))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('children', 'Species', '9606', (213, 221))
37804	26580448	We describe the prevalence and spectrum of germline variants among 565 cancer-associated genes, with an emphasis on the analysis of 60 genes that have been associated with autosomal dominant cancer-predisposition syndromes.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', (71, 77))	('variants', 'Var', (52, 60))	('associated', 'Reg', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
37805	26580448	We also reviewed records of patients with mutations and those without mutations in these 60 genes for information on family history of cancer.	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('patients', 'Species', '9606', (28, 36))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
37808	26580448	To verify predictions of aberrant splicing caused by variants affecting splice junctions, we sequenced the RNA transcripts extracted from 522 samples of tumor tissue obtained from 522 patients.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('splice junctions', 'MPA', (72, 88))	('variants', 'Var', (53, 61))
37815	26580448	The first category included genes that have been associated with autosomal dominant cancer-predisposition syndromes, and it consisted of 49 classical genes (including 23 genes from the ACMG gene list) and 11 genes that have been implicated in genetic syndromes associated with RAS mutations (sometimes called RASopathies; these include the cardiofaciocutaneous syndrome, Costello's syndrome [also called the faciocutaneoskeletal syndrome], Noonan's syndrome, and the multiple lentigines syndrome).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('RASopathies', 'Disease', (309, 320))	('associated', 'Reg', (49, 59))	('multiple lentigines syndrome', 'Disease', 'MESH:D044542', (467, 495))	('faciocutaneoskeletal syndrome', 'Disease', 'MESH:D056685', (408, 437))	('RAS', 'Gene', (277, 280))	('cardiofaciocutaneous syndrome', 'Disease', 'MESH:C535579', (340, 369))	("Costello's syndrome", 'Disease', 'MESH:D056685', (371, 390))	('multiple lentigines syndrome', 'Disease', (467, 495))	("Noonan's syndrome", 'Disease', (440, 457))	('cancer', 'Disease', (84, 90))	('multiple lentigines', 'Phenotype', 'HP:0001003', (467, 486))	('genetic syndrome', 'Disease', (243, 259))	('RASopathies', 'Disease', 'None', (309, 320))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	("Noonan's syndrome", 'Disease', 'MESH:D009634', (440, 457))	('cardiofaciocutaneous syndrome', 'Disease', (340, 369))	('mutations', 'Var', (281, 290))	('faciocutaneoskeletal syndrome', 'Disease', (408, 437))	('genetic syndrome', 'Disease', 'MESH:D030342', (243, 259))	("Costello's syndrome", 'Disease', (371, 390))
37818	26580448	Variants detected in the 89 genes that have been associated with autosomal dominant or autosomal recessive cancer-predisposition syndromes were reviewed by a multidisciplinary panel for classification and reporting.	('autosomal recessive cancer', 'Disease', (87, 113))	('Variants', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('autosomal dominant', 'Disease', (65, 83))	('autosomal recessive cancer', 'Disease', 'MESH:D009369', (87, 113))
37821	26580448	Our analyses of the genes in these three categories focused on known hotspot-activating mutations in genes encoding kinases and on truncation mutations in genes encoding tumor-suppressor proteins and in other cancer genes.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('truncation mutations', 'Var', (131, 151))	('tumor', 'Disease', (170, 175))	('cancer', 'Disease', (209, 215))	('hotspot-activating', 'PosReg', (69, 87))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
37827	26580448	In the 60 genes that have been associated with autosomal dominant cancer-predisposition syndromes, we identified 633 nonsilent germline variants, of which 78 (12%) were deemed to be pathogenic, 17 (3%) probably pathogenic, 226 (36%) of uncertain significance, 273 (43%) probably benign, and 39 (6%) benign (Table S4A in Supplementary Appendix 2).	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('variants', 'Var', (136, 144))	('cancer', 'Disease', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))
37830	26580448	One patient (Patient HGG111) with cafe au lait spots and a high-grade glioma had 2 distinct PMS2 truncation mutations, which indicated a diagnosis of biallelic mismatch-repair deficiency that was corroborated by the somatic hypermutation observed in the genome of the high-grade glioma.	('PMS2', 'Gene', '5395', (92, 96))	('glioma', 'Disease', (279, 285))	('glioma', 'Disease', (70, 76))	('truncation mutations', 'Var', (97, 117))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('patient', 'Species', '9606', (4, 11))	('glioma', 'Disease', 'MESH:D005910', (279, 285))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (279, 285))	('cafe au lait spots', 'Phenotype', 'HP:0000957', (34, 52))	('Patient', 'Species', '9606', (13, 20))	('PMS2', 'Gene', (92, 96))	('indicated', 'Reg', (125, 134))
37831	26580448	The most common cancer types that were associated with germline TP53 mutations included adrenocortical tumors (in 27 of 39 patients [69%]), hypodiploid acute lymphoblastic leukemia (in 9 of 47 [19%]), and choroid plexus carcinoma (in 1 of 4 [25%]) : findings that were consistent with those in previous reports.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('hypodiploid acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (140, 180))	('adrenocortical tumors', 'Disease', (88, 109))	('TP53', 'Gene', '7157', (64, 68))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (158, 180))	('hypodiploid acute lymphoblastic leukemia', 'Disease', (140, 180))	('cancer', 'Disease', (16, 22))	('choroid plexus carcinoma', 'Disease', (205, 229))	('patients', 'Species', '9606', (123, 131))	('germline', 'Var', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('mutations', 'Var', (69, 78))	('leukemia', 'Phenotype', 'HP:0001909', (172, 180))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (205, 229))	('TP53', 'Gene', (64, 68))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (88, 109))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (152, 180))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (205, 229))
37833	26580448	One patient with retinoblastoma had a mosaic RB1 mutation, and three patients with hypodiploid acute lymphoblastic leukemia had a mosaic TP53 mutation (Table S4A in Supplementary Appendix 2).	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (101, 123))	('RB1', 'Gene', (45, 48))	('retinoblastoma', 'Phenotype', 'HP:0009919', (17, 31))	('mosaic', 'Var', (38, 44))	('patient', 'Species', '9606', (4, 11))	('mutation', 'Var', (49, 57))	('RB1', 'Gene', '5925', (45, 48))	('patients', 'Species', '9606', (69, 77))	('hypodiploid acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (83, 123))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (95, 123))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('patient', 'Species', '9606', (69, 76))	('hypodiploid acute lymphoblastic leukemia', 'Disease', (83, 123))	('mutation', 'Var', (142, 150))	('TP53', 'Gene', '7157', (137, 141))	('retinoblastoma', 'Disease', 'MESH:D012175', (17, 31))	('retinoblastoma', 'Disease', (17, 31))	('TP53', 'Gene', (137, 141))
37834	26580448	The mutant allele fraction in matching tumor specimens ranged from 0.76 to 0.90, a finding that is consistent with the presence of a second hit within the tumors.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('mutant', 'Var', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Disease', (39, 44))
37836	26580448	In the first control data set, from the 1000 Genomes Project, we identified 11 pathogenic or probably pathogenic mutations in the 60 genes that have been associated with autosomal dominant cancer-predisposition syndromes; mutations were found in APC (in one person), BRCA1 (in one), BRCA2 (in four), MSH6 (in one), SDHA (in one), SDHB (in one), and TP53 (in two) (Table S6 in Supplementary Appendix 1).	('APC', 'Disease', (246, 249))	('mutations', 'Var', (113, 122))	('SDHB', 'Gene', '6390', (330, 334))	('TP53', 'Gene', '7157', (349, 353))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('MSH6', 'Gene', (300, 304))	('mutations', 'Var', (222, 231))	('MSH6', 'Gene', '2956', (300, 304))	('SDHB', 'Gene', (330, 334))	('BRCA2', 'Gene', (283, 288))	('associated', 'Reg', (154, 164))	('person', 'Species', '9606', (258, 264))	('TP53', 'Gene', (349, 353))	('SDHA', 'Gene', (315, 319))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('BRCA1', 'Gene', '672', (267, 272))	('SDHA', 'Gene', '6389', (315, 319))	('BRCA2', 'Gene', '675', (283, 288))	('APC', 'Disease', 'MESH:D011125', (246, 249))	('BRCA1', 'Gene', (267, 272))
37840	26580448	Combining data from this single patient, who had ataxia telangiectasia caused by biallelic mutations in ATM (Fig.	('telangiectasia', 'Phenotype', 'HP:0001009', (56, 70))	('patient', 'Species', '9606', (32, 39))	('biallelic mutations', 'Var', (81, 100))	('ATM', 'Gene', '472', (104, 107))	('caused by', 'Reg', (71, 80))	('ataxia', 'Phenotype', 'HP:0001251', (49, 55))	('ataxia telangiectasia', 'Disease', (49, 70))	('ATM', 'Gene', (104, 107))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (49, 70))
37841	26580448	S4 in Supplementary Appendix 1), with data from the 94 patients who had pathogenic mutations in the 60 autosomal dominant cancer-predisposition genes, we observed an 8.5% prevalence (95 of 1120 patients) of germline mutations that were pathogenic or probably pathogenic in the sample we analyzed.	('mutations', 'Var', (83, 92))	('patients', 'Species', '9606', (194, 202))	('germline mutations', 'Var', (207, 225))	('pathogenic', 'Reg', (236, 246))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('patients', 'Species', '9606', (55, 63))
37842	26580448	A total of 61 of the 93 patients (66%) with monoallelic germline mutations had a second hit within the tumor genome (Table S4 in Supplementary Appendix 2), as shown by loss of heterozygosity (in 57 patients) or mutational inactivation of the second allele (in 4).	('loss', 'NegReg', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('patients', 'Species', '9606', (198, 206))	('tumor', 'Disease', (103, 108))	('mutational', 'Var', (211, 221))	('patients', 'Species', '9606', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('mutations', 'Var', (65, 74))
37844	26580448	S5 and S6 in Supplementary Appendix 1) The prevalence of germline mutations that were pathogenic or probably pathogenic was greatest among patients with non-CNS solid tumors (48 of 287 patients [16.7%]), followed by those with CNS tumors (21 of 245 [8.6%], including the patient with biallelic loss of ATM) or leukemia (26 of 588 [4.4%]) (Fig.	('mutations', 'Var', (66, 75))	('ATM', 'Gene', '472', (302, 305))	('germline', 'Gene', (57, 65))	('patient', 'Species', '9606', (271, 278))	('patient', 'Species', '9606', (185, 192))	('leukemia', 'Phenotype', 'HP:0001909', (310, 318))	('CNS tumor', 'Phenotype', 'HP:0100006', (227, 236))	('leukemia', 'Disease', 'MESH:D007938', (310, 318))	('leukemia', 'Disease', (310, 318))	('ATM', 'Gene', (302, 305))	('patients', 'Species', '9606', (139, 147))	('loss', 'NegReg', (294, 298))	('patients', 'Species', '9606', (185, 193))	('CNS tumors', 'Disease', 'MESH:D009369', (227, 237))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('CNS tumors', 'Disease', (227, 237))	('non-CNS solid tumors', 'Disease', (153, 173))	('non-CNS solid tumors', 'Disease', 'MESH:D009369', (153, 173))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('patient', 'Species', '9606', (139, 146))
37846	26580448	The histologic subtypes of CNS tumor that were most often associated with germline mutations included choroid plexus carcinoma (in 1 of 4 patients [25%]), medulloblastoma (in 5 of 37 [13.5%]), high-grade glioma (in 9 of 99 [9.1%]), low-grade glioma (in 3 of 38 [7.9%]), and ependymoma (in 4 of 67 [6.0%]).	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (102, 126))	('glioma', 'Disease', (242, 248))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('glioma', 'Disease', 'MESH:D005910', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('medulloblastoma', 'Disease', 'MESH:D008527', (155, 170))	('ependymoma', 'Disease', (274, 284))	('medulloblastoma', 'Phenotype', 'HP:0002885', (155, 170))	('choroid plexus carcinoma', 'Disease', (102, 126))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('patients', 'Species', '9606', (138, 146))	('medulloblastoma', 'Disease', (155, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('ependymoma', 'Phenotype', 'HP:0002888', (274, 284))	('CNS tumor', 'Phenotype', 'HP:0100006', (27, 36))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (102, 126))	('mutations', 'Var', (83, 92))	('associated', 'Reg', (58, 68))	('glioma', 'Disease', (204, 210))	('tumor', 'Disease', (31, 36))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('ependymoma', 'Disease', 'MESH:D004806', (274, 284))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
37849	26580448	The known associations included the association of TP53 mutations with classic Li-Fraumeni syndrome-associated component cancers such as rhabdomyosarcomas, osteosarcomas, adrenocortical tumors, CNS tumors, and leukemia; NF1 mutations with CNS tumors; RB1 mutations with retinoblastoma and osteosarcoma; and ALK mutations with neuroblastoma (Fig.	('Li-Fraumeni syndrome-associated component cancers', 'Disease', 'MESH:D016864', (79, 128))	('retinoblastoma', 'Phenotype', 'HP:0009919', (270, 284))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (137, 154))	('ALK', 'Gene', '238', (307, 310))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('neuroblastoma', 'Disease', (326, 339))	('osteosarcomas', 'Phenotype', 'HP:0002669', (156, 169))	('mutations', 'Var', (311, 320))	('ALK', 'Gene', (307, 310))	('RB1', 'Gene', (251, 254))	('NF1', 'Gene', '4763', (220, 223))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (171, 192))	('mutations', 'Var', (255, 264))	('neuroblastoma', 'Phenotype', 'HP:0003006', (326, 339))	('sarcoma', 'Phenotype', 'HP:0100242', (294, 301))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('associations', 'Interaction', (10, 22))	('neuroblastoma', 'Disease', 'MESH:D009447', (326, 339))	('CNS tumors', 'Disease', 'MESH:D009369', (239, 249))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('CNS tumors', 'Disease', (239, 249))	('NF1', 'Gene', (220, 223))	('association', 'Interaction', (36, 47))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (137, 153))	('CNS tumor', 'Phenotype', 'HP:0100006', (194, 203))	('Li-Fraumeni syndrome-associated component cancers', 'Disease', (79, 128))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('RB1', 'Gene', '5925', (251, 254))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('leukemia', 'Phenotype', 'HP:0001909', (210, 218))	('adrenocortical tumors', 'Disease', (171, 192))	('retinoblastoma and osteosarcoma', 'Disease', 'MESH:C566714', (270, 301))	('osteosarcoma', 'Phenotype', 'HP:0002669', (156, 168))	('osteosarcomas', 'Disease', 'MESH:D012516', (156, 169))	('TP53', 'Gene', '7157', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('CNS tumor', 'Phenotype', 'HP:0100006', (239, 248))	('CNS tumors', 'Disease', (194, 204))	('CNS tumors', 'Disease', 'MESH:D009369', (194, 204))	('leukemia', 'Disease', (210, 218))	('osteosarcoma', 'Phenotype', 'HP:0002669', (289, 301))	('leukemia', 'Disease', 'MESH:D007938', (210, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('osteosarcomas', 'Disease', (156, 169))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('mutations', 'Var', (224, 233))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (137, 154))	('rhabdomyosarcomas', 'Disease', (137, 154))
37850	26580448	New associations included the association of germline TP53, PMS2, and RET mutations with Ewing's sarcoma; APC and SDHB mutations with neuroblastoma; and a variety of mutations (APC, VHL, CDH1, PTCH1, or SDHA) with leukemia.	('VHL', 'Disease', 'MESH:D006623', (182, 185))	('SDHB', 'Gene', (114, 118))	('CDH1', 'Gene', '999', (187, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('leukemia', 'Phenotype', 'HP:0001909', (214, 222))	('PMS2', 'Gene', (60, 64))	('association', 'Interaction', (30, 41))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (89, 104))	('CDH1', 'Gene', (187, 191))	('SDHA', 'Gene', '6389', (203, 207))	('TP53', 'Gene', '7157', (54, 58))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (89, 104))	('neuroblastoma', 'Disease', (134, 147))	('mutations', 'Var', (119, 128))	('leukemia', 'Disease', 'MESH:D007938', (214, 222))	('neuroblastoma', 'Phenotype', 'HP:0003006', (134, 147))	('leukemia', 'Disease', (214, 222))	('RET', 'Gene', '5979', (70, 73))	('VHL', 'Disease', (182, 185))	('neuroblastoma', 'Disease', 'MESH:D009447', (134, 147))	('PTCH1', 'Gene', '5727', (193, 198))	('APC', 'Disease', 'MESH:D011125', (177, 180))	("Ewing's sarcoma", 'Disease', (89, 104))	('APC', 'Disease', (177, 180))	('PMS2', 'Gene', '5395', (60, 64))	('SDHA', 'Gene', (203, 207))	('SDHB', 'Gene', '6390', (114, 118))	('APC', 'Disease', 'MESH:D011125', (106, 109))	('mutations', 'Var', (74, 83))	('APC', 'Disease', (106, 109))	('TP53', 'Gene', (54, 58))	('PTCH1', 'Gene', (193, 198))	('RET', 'Gene', (70, 73))	('associations', 'Interaction', (4, 16))
37851	26580448	A total of eight children had germline mutations in the adult-onset cancer-predisposition genes BRCA1, BRCA2, and PALB2.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PALB2', 'Gene', (114, 119))	('BRCA2', 'Gene', '675', (103, 108))	('BRCA1', 'Gene', '672', (96, 101))	('children', 'Species', '9606', (17, 25))	('germline mutations', 'Var', (30, 48))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('BRCA1', 'Gene', (96, 101))	('cancer', 'Disease', (68, 74))	('BRCA2', 'Gene', (103, 108))	('PALB2', 'Gene', '79728', (114, 119))
37853	26580448	Although biallelic mutations of BRCA1/2 and PALB2 are known to cause Fanconi's anemia, there were no germline mutations or deletions involving the second alleles of these genes in any of the affected patients.	('patients', 'Species', '9606', (200, 208))	('cause', 'Reg', (63, 68))	('BRCA1/2', 'Gene', (32, 39))	('PALB2', 'Gene', '79728', (44, 49))	("Fanconi's anemia", 'Disease', (69, 85))	('anemia', 'Phenotype', 'HP:0001903', (79, 85))	('PALB2', 'Gene', (44, 49))	("Fanconi's anemia", 'Disease', 'MESH:D005199', (69, 85))	('BRCA1/2', 'Gene', '672;675', (32, 39))	("Fanconi's anemia", 'Phenotype', 'HP:0001994', (69, 85))	('biallelic mutations', 'Var', (9, 28))
37857	26580448	Of these 2 patients, 1 had an adrenocortical tumor tested for TP53 (TP53 p.I332F in Patient ACT001) and 1 had retinoblastoma that was tested for RB1 (mosaic RB1 p.R445* in Patient RB002); both lesions were identified by means of the next-generation sequencing approaches used in this study.	('adrenocortical tumor', 'Disease', 'MESH:D018268', (30, 50))	('TP53', 'Gene', (62, 66))	('retinoblastoma', 'Phenotype', 'HP:0009919', (110, 124))	('TP53', 'Gene', (68, 72))	('Patient', 'Species', '9606', (172, 179))	('RB1', 'Gene', (157, 160))	('retinoblastoma', 'Disease', (110, 124))	('Patient', 'Species', '9606', (84, 91))	('p.R445*', 'Var', (161, 168))	('RB1', 'Gene', (145, 148))	('RB1', 'Gene', '5925', (157, 160))	('TP53', 'Gene', '7157', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mosaic', 'Var', (150, 156))	('p.R445*', 'Mutation', 'p.R445*', (161, 168))	('p.I332F', 'Mutation', 'p.I332F', (73, 80))	('TP53', 'Gene', '7157', (68, 72))	('patients', 'Species', '9606', (11, 19))	('p.I332F', 'Var', (73, 80))	('retinoblastoma', 'Disease', 'MESH:D012175', (110, 124))	('RB1', 'Gene', '5925', (145, 148))	('adrenocortical tumor', 'Disease', (30, 50))
37859	26580448	Furthermore, among these 23 patients, only 13 (57%) had a history that was consistent with the underlying genetic syndrome, including 8 patients with TP53 mutations (and thus the Li-Fraumeni syndrome), 2 with APC mutations (familial adenomatous polyposis), 2 with BRCA2 mutations (hereditary breast and ovarian cancer; the pedigrees are shown in Fig.	('TP53', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (233, 254))	('genetic syndrome', 'Disease', 'MESH:D030342', (106, 122))	('BRCA2', 'Gene', '675', (264, 269))	('mutations', 'Var', (270, 279))	('familial adenomatous polyposis', 'Disease', (224, 254))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (224, 254))	('patients', 'Species', '9606', (28, 36))	('TP53', 'Gene', '7157', (150, 154))	('APC', 'Disease', 'MESH:D011125', (209, 212))	('Li-Fraumeni syndrome', 'Disease', (179, 199))	('APC', 'Disease', (209, 212))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (179, 199))	('mutations', 'Var', (155, 164))	('ovarian cancer', 'Phenotype', 'HP:0100615', (303, 317))	('patients', 'Species', '9606', (136, 144))	('genetic syndrome', 'Disease', (106, 122))	('BRCA2', 'Gene', (264, 269))	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (281, 317))
37860	26580448	S8 in Supplementary Appendix 1), and 1 with PMS2 mutations (hereditary nonpolyposis colorectal cancer, also known as the Lynch syndrome).	('PMS2', 'Gene', '5395', (44, 48))	('Lynch syndrome', 'Disease', (121, 135))	('mutations', 'Var', (49, 58))	('nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (71, 101))	('Lynch syndrome', 'Disease', 'MESH:D003123', (121, 135))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (60, 101))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('hereditary nonpolyposis colorectal cancer', 'Disease', (60, 101))	('PMS2', 'Gene', (44, 48))
37864	26580448	These included 114 heterozygous truncation mutations, in 109 patients, that involved tumor-suppressor genes, tyrosine kinase genes, or other cancer genes (Fig.	('tumor', 'Disease', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('truncation mutations', 'Var', (32, 52))	('patients', 'Species', '9606', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', (141, 147))
37866	26580448	A total of 18 patients who did not have pathogenic mutations in genes that have been associated with cancer-predisposition syndromes had protein-truncating mutations in tumor-suppressor genes.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Disease', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (169, 174))	('patients', 'Species', '9606', (14, 22))	('protein-truncating mutations', 'Var', (137, 165))
37867	26580448	Two known hotspots of somatic activating mutations in EGFR, T790 and H773, were identified once each in the germline of 2 patients with leukemia (Fig.	('activating', 'PosReg', (30, 40))	('T790', 'Var', (60, 64))	('leukemia', 'Disease', (136, 144))	('leukemia', 'Disease', 'MESH:D007938', (136, 144))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('H773', 'Var', (69, 73))	('patients', 'Species', '9606', (122, 130))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (54, 58))
37869	26580448	First, we included mutations that were pathogenic or probably pathogenic in 60 genes that have been associated with clinically relevant autosomal dominant cancer-predisposition syndromes, and we did not include other genes that, when mutated, may contribute toward a patient's susceptibility to cancer.	('patient', 'Species', '9606', (267, 274))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (295, 301))	('pathogenic', 'Reg', (39, 49))	('associated', 'Reg', (100, 110))	('mutations', 'Var', (19, 28))	('contribute', 'Reg', (247, 257))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
37871	26580448	Moreover, 109 children (9.7%) had germline-truncating mutations in other cancer-associated genes, although non-hotspot missense mutations in these genes were not fully characterized, some of which may eventually be considered to be cancer-susceptibility genes.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('children', 'Species', '9606', (14, 22))	('cancer', 'Disease', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('germline-truncating mutations', 'Var', (34, 63))
37872	26580448	Second, among the 226 variants of uncertain significance that were identified in the 60 genes that have been associated with autosomal dominant cancer-predisposition syndromes, 119 (52.7%) were predicted to be deleterious by at least two computational methods, and some of these could, in fact, confer susceptibility to cancer.	('associated', 'Reg', (109, 119))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('susceptibility', 'Reg', (302, 316))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('variants', 'Var', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (320, 326))
37873	26580448	Finally, as we learn more about how certain genetic alterations (e.g., structural variations, changes in noncoding regions, and epigenetic modifications) influence cellular function, new cancer-predisposing lesions in these and other newly discovered cancer-associated genes will be identified.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', (187, 193))	('influence', 'Reg', (154, 163))	('epigenetic modifications', 'Var', (128, 152))	('cellular function', 'MPA', (164, 181))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('structural', 'MPA', (71, 81))	('cancer', 'Disease', (251, 257))
37874	26580448	We found several unexpected germline mutations in patients with Ewing's sarcoma, neuroblastoma, osteosarcoma, or leukemia.	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (64, 79))	('osteosarcoma', 'Disease', (96, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('patients', 'Species', '9606', (50, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (96, 108))	('neuroblastoma', 'Disease', 'MESH:D009447', (81, 94))	('osteosarcoma', 'Disease', 'MESH:D012516', (96, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('neuroblastoma', 'Disease', (81, 94))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (64, 79))	('germline mutations', 'Var', (28, 46))	('leukemia', 'Phenotype', 'HP:0001909', (113, 121))	('neuroblastoma', 'Phenotype', 'HP:0003006', (81, 94))	("Ewing's sarcoma", 'Disease', (64, 79))	('leukemia', 'Disease', (113, 121))	('leukemia', 'Disease', 'MESH:D007938', (113, 121))
37880	26580448	described a high prevalence of childhood cancer in families with germline BRCA2 mutations, and Brooks et al.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (80, 89))	('BRCA2', 'Gene', (74, 79))	('germline', 'Var', (65, 73))	('BRCA2', 'Gene', '675', (74, 79))	('childhood cancer', 'Disease', 'MESH:C536928', (31, 47))	('childhood cancer', 'Disease', (31, 47))
37881	26580448	reported 20 cases of pediatric cancer among 379 families, members of which had a mutation in either BRCA1 or BRCA2.	('pediatric cancer', 'Disease', 'MESH:D009369', (21, 37))	('BRCA1', 'Gene', '672', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('mutation', 'Var', (81, 89))	('BRCA2', 'Gene', (109, 114))	('BRCA1', 'Gene', (100, 105))	('pediatric cancer', 'Disease', (21, 37))	('BRCA2', 'Gene', '675', (109, 114))
37882	26580448	These reports suggest that pathogenic mutations in BRCA1 and BRCA2 are more common in pediatric cancer than has been recognized previously and that they potentially underpin a broader spectrum of cancer phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('common', 'Reg', (76, 82))	('BRCA2', 'Gene', '675', (61, 66))	('pediatric cancer', 'Disease', 'MESH:D009369', (86, 102))	('BRCA1', 'Gene', '672', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('BRCA2', 'Gene', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('BRCA1', 'Gene', (51, 56))	('pediatric cancer', 'Disease', (86, 102))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (38, 47))	('underpin', 'Reg', (165, 173))	('cancer', 'Disease', (96, 102))
37884	26580448	However, only 40% of our patients with germline mutations that were pathogenic or probably pathogenic and that could be evaluated had a family history of cancer.	('germline mutations', 'Var', (39, 57))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
37891	26580448	Observation of pathogenic mutations in the controls may indicate uncharacterized cancer phenotypes in the people enrolled, rather than refuting the pathogenicity of these mutations in cancer predisposition (Tables S6 and S7 in Supplementary Appendix 1).	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (81, 87))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('people', 'Species', '9606', (106, 112))
37892	26580448	Moreover, by adjusting for the distribution of cancer subtypes observed in the SEER program and by applying previously reported mutation frequencies for those not included in this study, we predicted an overall mutation prevalence of 7.3 to 9.8% in the SEER pediatric cancer population (Table S10 in Supplementary Appendix 2).	('cancer', 'Disease', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('pediatric cancer', 'Disease', 'MESH:D009369', (258, 274))	('to 9', 'Species', '1214577', (238, 242))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('pediatric cancer', 'Disease', (258, 274))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('mutation', 'Var', (211, 219))
37893	26580448	Second, we did not study the parents or relatives of the patients in our cohort and hence could not assess whether variants were new or segregated with a cancer phenotype among family members.	('patients', 'Species', '9606', (57, 65))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('variants', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
37896	26580448	Additional family, epidemiologic, and functional studies are warranted to better understand the cancer risks associated with each of these variants.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('variants', 'Var', (139, 147))
37897	26580448	In conclusion, germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer who participated in this study.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', (37, 43))	('children', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('identified', 'Reg', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('germline mutations', 'Var', (15, 33))
37900	26214578	Combined transcriptome studies identify AFF3 as a mediator of the oncogenic effects of beta-catenin in adrenocortical carcinoma Adrenocortical cancer (ACC) is a very aggressive tumor, and genomics studies demonstrate that the most frequent alterations of driver genes in these cancers activate the Wnt/beta-catenin signaling pathway.	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('AFF3', 'Gene', (40, 44))	('Wnt', 'Gene', '35975', (298, 301))	('beta-catenin', 'Gene', (87, 99))	('beta-catenin', 'Gene', (302, 314))	('Adrenocortical cancer', 'Disease', (128, 149))	('Adrenocortical cancer', 'Disease', 'MESH:D000306', (128, 149))	('Wnt', 'Gene', (298, 301))	('beta-catenin', 'Gene', '1499', (87, 99))	('beta-catenin', 'Gene', '1499', (302, 314))	('very aggressive tumor', 'Disease', (161, 182))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('alterations', 'Var', (240, 251))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (103, 127))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('cancers', 'Disease', (277, 284))	('AFF3', 'Gene', '3899', (40, 44))	('very aggressive tumor', 'Disease', 'MESH:D000326', (161, 182))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (103, 127))	('activate', 'PosReg', (285, 293))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('adrenocortical carcinoma', 'Disease', (103, 127))
37902	26214578	A combined transcriptomic analysis from two series of human tumors and the human ACC cell line H295R harboring a spontaneous beta-catenin activating mutation was done to identify the Wnt/beta-catenin targets.	('H295R', 'CellLine', 'CVCL:0458', (95, 100))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('Wnt', 'Gene', '35975', (183, 186))	('human', 'Species', '9606', (75, 80))	('mutation', 'Var', (149, 157))	('Wnt', 'Gene', (183, 186))	('human', 'Species', '9606', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
37905	26214578	AFF3 silencing decreases cell proliferation and increases apoptosis in the ACC cell line H295R.	('increases', 'PosReg', (48, 57))	('AFF3', 'Gene', (0, 4))	('silencing', 'Var', (5, 14))	('cell proliferation', 'CPA', (25, 43))	('H295R', 'CellLine', 'CVCL:0458', (89, 94))	('AFF3', 'Gene', '3899', (0, 4))	('decreases', 'NegReg', (15, 24))	('apoptosis', 'CPA', (58, 67))
37912	26214578	Several studies show the importance of the Wnt/beta-catenin signaling pathway in the development and maintenance of numerous organs, and that alterations of the Wnt/beta-catenin signaling are involved in a wide range of human diseases, and especially malignancies.	('malignancies', 'Disease', 'MESH:D009369', (251, 263))	('Wnt', 'Gene', '35975', (43, 46))	('alterations', 'Var', (142, 153))	('Wnt', 'Gene', (43, 46))	('involved', 'Reg', (192, 200))	('Wnt', 'Gene', '35975', (161, 164))	('human', 'Species', '9606', (220, 225))	('malignancies', 'Disease', (251, 263))	('Wnt', 'Gene', (161, 164))
37913	26214578	The Wnt/beta-catenin pathway is required for normal adrenal (NA) gland formation, and adrenocortical cell-specific knockout of Ctnnb1 in mice results in adrenal gland aplasia.	('results in', 'Reg', (142, 152))	('Ctnnb1', 'Gene', (127, 133))	('knockout', 'Var', (115, 123))	('adrenocortical', 'Disease', (86, 100))	('Wnt', 'Gene', '35975', (4, 7))	('Ctnnb1', 'Gene', '12387', (127, 133))	('adrenal gland aplasia', 'Phenotype', 'HP:0011743', (153, 174))	('adrenocortical', 'Disease', 'MESH:D018268', (86, 100))	('Wnt', 'Gene', (4, 7))	('adrenal gland aplasia', 'Disease', (153, 174))	('mice', 'Species', '10090', (137, 141))	('adrenal gland aplasia', 'Disease', 'MESH:D000307', (153, 174))
37915	26214578	Inhibition of the Wnt/beta-catenin pathway in the adrenocortical cell line H295R by PKF115-584 or a shRNA against beta-catenin messenger RNA (mRNA) increases apoptosis and is associated with a complete absence of tumor growth in a xenograft model.	('tumor', 'Disease', (213, 218))	('PKF115-584', 'Var', (84, 94))	('H295R', 'CellLine', 'CVCL:0458', (75, 80))	('increases', 'PosReg', (148, 157))	('apoptosis', 'CPA', (158, 167))	('Wnt', 'Gene', '35975', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('adrenocortical', 'Disease', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('Wnt', 'Gene', (18, 21))	('adrenocortical', 'Disease', 'MESH:D018268', (50, 64))
37916	26214578	These observations implicate alterations of Wnt/beta-catenin in ACC pathogenesis.	('Wnt', 'Gene', '35975', (44, 47))	('Wnt', 'Gene', (44, 47))	('alterations', 'Var', (29, 40))	('ACC', 'Disease', (64, 67))	('implicate', 'Reg', (19, 28))
37918	26214578	A better understanding of the biological processes affected by Wnt/beta-catenin pathway alterations in ACC may allow the identification of therapeutic targets and thereby contribute to the development of new therapeutic strategies.	('ACC', 'Disease', (103, 106))	('contribute', 'Reg', (171, 181))	('alterations', 'Var', (88, 99))	('Wnt', 'Gene', '35975', (63, 66))	('Wnt', 'Gene', (63, 66))
37920	26214578	We performed a combined transcriptomic analysis on cohorts of ACC and on human cell models to identify alterations of gene expression due to aberrant Wnt/beta-catenin pathway activation.	('Wnt', 'Gene', '35975', (150, 153))	('alterations', 'Reg', (103, 114))	('Wnt', 'Gene', (150, 153))	('activation', 'PosReg', (175, 185))	('human', 'Species', '9606', (73, 78))	('aberrant', 'Var', (141, 149))	('gene expression', 'MPA', (118, 133))
37922	26214578	We used the H295R cell line, human adrenocortical cells, harboring a heterozygous CTNNB1 (beta-catenin) gene mutation affecting the GSK3beta phosphorylation site (S45P) and leading to constitutive transcriptional activity of beta-catenin-lymphoid enhancer binding factor (LEF)/T-cell factor (TCF).	('TCF', 'Gene', (292, 295))	('affecting', 'Reg', (118, 127))	('H295R', 'CellLine', 'CVCL:0458', (12, 17))	('TCF', 'Gene', '3172', (292, 295))	('human', 'Species', '9606', (29, 34))	('adrenocortical', 'Disease', (35, 49))	('CTNNB1', 'Gene', (82, 88))	('adrenocortical', 'Disease', 'MESH:D018268', (35, 49))	('constitutive transcriptional activity', 'MPA', (184, 221))	('CTNNB1', 'Gene', '1499', (82, 88))	('S45P', 'Mutation', 'rs121913407', (163, 167))	('GSK3beta', 'MPA', (132, 140))	('mutation', 'Var', (109, 117))
37926	26214578	We thereby identified 44 genes significantly downregulated (adjusted P-value<0.05 and log2 ratio<-1) and 29 genes significantly upregulated (adjusted P-value<0.05 and log2 ratio>1) by specific CTNNB1 inactivation (Figure 1b, Supplementary Figure S1-B and Supplementary Table S1).	('CTNNB1', 'Gene', '1499', (193, 199))	('downregulated', 'NegReg', (45, 58))	('inactivation', 'Var', (200, 212))	('upregulated', 'PosReg', (128, 139))	('CTNNB1', 'Gene', (193, 199))
37929	26214578	We validated the Wnt/beta-catenin pathway-dependent expression of all these six genes by real time-PCR in H295R-shbeta cells in parental H295R cells transiently transfected with a small interfering RNA construct targeting another region of the CTNNB1 mRNA, and in established tumors with CTNNB1 inactivation from a subcutaneous xenograft model (Figures 2b and c and Supplementary Figure S2-A and B).	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('CTNNB1', 'Gene', (288, 294))	('CTNNB1', 'Gene', '1499', (244, 250))	('inactivation', 'Var', (295, 307))	('Wnt', 'Gene', '35975', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('H295R', 'CellLine', 'CVCL:0458', (106, 111))	('H295R', 'CellLine', 'CVCL:0458', (137, 142))	('Wnt', 'Gene', (17, 20))	('CTNNB1', 'Gene', '1499', (288, 294))	('CTNNB1', 'Gene', (244, 250))	('tumors', 'Disease', (276, 282))
37931	26214578	LEF1 silencing had similar effects to CTNNB1 silencing on apoptosis, as expected since LEF1 is involved in nuclear response of Wnt/beta-catenin pathway.	('Wnt', 'Gene', '35975', (127, 130))	('CTNNB1', 'Gene', (38, 44))	('silencing', 'Var', (5, 14))	('Wnt', 'Gene', (127, 130))	('apoptosis', 'CPA', (58, 67))	('LEF1', 'Gene', (0, 4))	('silencing', 'NegReg', (45, 54))	('CTNNB1', 'Gene', '1499', (38, 44))
37934	26214578	The dysregulation of Wnt/beta-catenin pathways allows beta-catenin to accumulate and translocate to the nucleus, where it may activate the transcription of target genes.	('accumulate', 'PosReg', (70, 80))	('activate', 'PosReg', (126, 134))	('dysregulation', 'Var', (4, 17))	('Wnt', 'Gene', '35975', (21, 24))	('beta-catenin', 'Protein', (54, 66))	('Wnt', 'Gene', (21, 24))	('transcription', 'MPA', (139, 152))
37944	26214578	LEF1 silencing had a similar effect and led to decreases AFF3 mRNA levels (Figure 5b).	('AFF3', 'Gene', '3899', (57, 61))	('silencing', 'Var', (5, 14))	('LEF1', 'Gene', (0, 4))	('decreases', 'NegReg', (47, 56))	('AFF3', 'Gene', (57, 61))
37945	26214578	Two copies of the putative AFF3 WRE (wild type or mutant) were inserted in tandem into the reporter plasmid, pGL3Tk, where luciferase expression is driven by the minimal Tk promoter (2xWT or 2xMut).	('luciferase', 'Enzyme', (123, 133))	('AFF3', 'Gene', '3899', (27, 31))	('mutant', 'Var', (50, 56))	('AFF3', 'Gene', (27, 31))
37947	26214578	Doxycyclin treatment did not affect activity of the 2xMut construct with mutated LEF/TCF sites.	('TCF', 'Gene', (85, 88))	('TCF', 'Gene', '3172', (85, 88))	('Doxycyclin', 'Chemical', 'MESH:D004318', (0, 10))	('mutated', 'Var', (73, 80))
37957	26214578	The effect of AFF3 silencing on H295R cell proliferation was measured by MTT (3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) and colony-formation assays: silencing significantly decreased proliferation (-75% at 16 days, P<0.001, Figure 6c) and reduced the rate of colony formation (Figure 6d), with respect to the shAFF3 cell line without AFF3 silencing (-dox) or the control line.	('H295R', 'CellLine', 'CVCL:0458', (32, 37))	('proliferation', 'CPA', (203, 216))	('AFF3', 'Gene', (14, 18))	('silencing', 'Var', (169, 178))	('AFF3', 'Gene', '3899', (331, 335))	('AFF3', 'Gene', (354, 358))	('dox', 'Chemical', 'MESH:D004318', (371, 374))	('AFF3', 'Gene', (331, 335))	('reduced', 'NegReg', (259, 266))	('MTT', 'Chemical', 'MESH:C070243', (73, 76))	('AFF3', 'Gene', '3899', (14, 18))	('colony formation', 'CPA', (279, 295))	('3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (78, 138))	('decreased', 'NegReg', (193, 202))	('AFF3', 'Gene', '3899', (354, 358))
37979	26214578	This expression pattern is consistent with mesomelic dysplasia and central nervous system abnormalities observed in a female infant with a microdeletion on chromosome 2, only affecting the AFF3 gene.	('mesomelic dysplasia', 'Phenotype', 'HP:0008845', (43, 62))	('mesomelic dysplasia and central nervous system abnormalities', 'Disease', 'MESH:D009421', (43, 103))	('AFF3', 'Gene', (189, 193))	('affecting', 'Reg', (175, 184))	('infant', 'Species', '9606', (125, 131))	('central nervous system abnormalities', 'Phenotype', 'HP:0002011', (67, 103))	('AFF3', 'Gene', '3899', (189, 193))	('nervous system abnormalities', 'Phenotype', 'HP:0000707', (75, 103))	('microdeletion', 'Var', (139, 152))
37980	26214578	A recent study identified a CGG repeat expansion, associated with intellectual disability, in the promoter of AFF3 at an autosomal folate-sensitive fragile site named FRA2A.	('intellectual disability', 'Phenotype', 'HP:0001249', (66, 89))	('FRA2A', 'Gene', (167, 172))	('AFF3', 'Gene', (110, 114))	('CGG repeat expansion', 'Var', (28, 48))	('folate', 'Chemical', 'MESH:D005492', (131, 137))	('FRA2A', 'Gene', '2373', (167, 172))	('folate-sensitive fragile site', 'Phenotype', 'HP:0003564', (131, 160))	('intellectual disability', 'Disease', (66, 89))	('AFF3', 'Gene', '3899', (110, 114))
37991	26214578	AFF3 and P-TEFb form the SEC-like 3 recently described in HEK293 cells.	('TEFb', 'Chemical', '-', (11, 15))	('AFF3', 'Gene', (0, 4))	('P-TEFb', 'Var', (9, 15))	('AFF3', 'Gene', '3899', (0, 4))	('HEK293', 'CellLine', 'CVCL:0045', (58, 64))
37992	26214578	The SEC consists of the RNA polymerase II elongation factors eleven-nineteen Lys-rich leukemia (ELL) proteins, EAF1/2 (ELL-associated factor) proteins, P-TEFb and several frequent myeloid/lymphoid or mixed-lineage leukemia translocation partners, such as AF9, ENL, AFF1, AFF4 and AFF3.	('ELL', 'Gene', (119, 122))	('lymphoid or mixed-lineage leukemia', 'Phenotype', 'HP:0005531', (188, 222))	('AF9', 'Gene', '4300', (255, 258))	('EAF1/2', 'Gene', '85403;55840', (111, 117))	('Lys-rich leukemia', 'Disease', 'MESH:D000080203', (77, 94))	('leukemia', 'Phenotype', 'HP:0001909', (214, 222))	('EAF1/2', 'Gene', (111, 117))	('Lys-rich leukemia', 'Disease', (77, 94))	('AFF4', 'Gene', '27125', (271, 275))	('AFF4', 'Gene', (271, 275))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('leukemia', 'Disease', 'MESH:D007938', (214, 222))	('TEFb', 'Chemical', '-', (154, 158))	('AFF3', 'Gene', '3899', (280, 284))	('leukemia', 'Disease', (214, 222))	('AFF1', 'Gene', (265, 269))	('ENL', 'Gene', (260, 263))	('AFF1', 'Gene', '4299', (265, 269))	('leukemia', 'Disease', (86, 94))	('leukemia', 'Disease', 'MESH:D007938', (86, 94))	('ELL', 'Gene', '8178', (96, 99))	('AF9', 'Gene', (255, 258))	('ELL', 'Gene', (96, 99))	('P-TEFb', 'Var', (152, 158))	('AFF3', 'Gene', (280, 284))	('ENL', 'Gene', '4298', (260, 263))	('ELL', 'Gene', '8178', (119, 122))
38006	26214578	S45P CTNNB1 (beta-catenin) gene activating mutation, previously identified in the parental H295R cell line, was confirmed by direct sequencing in all Ctr and shAFF3 clones (data not shown).	('CTNNB1', 'Gene', (5, 11))	('S45P', 'Var', (0, 4))	('H295R', 'CellLine', 'CVCL:0458', (91, 96))	('S45P', 'Mutation', 'rs121913407', (0, 4))	('CTNNB1', 'Gene', '1499', (5, 11))	('AFF3', 'Gene', (160, 164))	('activating', 'PosReg', (32, 42))	('AFF3', 'Gene', '3899', (160, 164))
38008	26214578	The AFF3-Flag-tagged vector from origene (RC221621, Origene, Rockville, MD, USA) was used to overexpress AFF3.	('AFF3', 'Gene', '3899', (105, 109))	('AFF3', 'Gene', (4, 8))	('RC221621', 'Var', (42, 50))	('AFF3', 'Gene', '3899', (4, 8))	('AFF3', 'Gene', (105, 109))
38020	26214578	The elution was made with the peptide 3X Flag (sigma F4799) at 4  C for 30 min without agitation.	('sigma', 'Var', (47, 52))	('agitation', 'Phenotype', 'HP:0000713', (87, 96))	('agitation', 'Disease', 'MESH:D011595', (87, 96))	('agitation', 'Disease', (87, 96))
38032	26214578	Gene set enrichment analysis were performed with several data sets from breast cancers (ArrayExpress data set E-MTAB-365; Gene Expression Omnibus (GEO) data sets GSE6532, GSE4922 and GSE1456; and The Cancer Genome Atlas breast carcinoma data set) and with a data set with inhibition of CDK9 by Flavopiridol.	('GSE6532', 'Chemical', '-', (162, 169))	('CDK9', 'Gene', '1025', (286, 290))	('Cancer Genome Atlas breast carcinoma', 'Disease', 'MESH:D001943', (200, 236))	('Cancer', 'Phenotype', 'HP:0002664', (200, 206))	('GSE4922', 'Var', (171, 178))	('Cancer Genome Atlas breast carcinoma', 'Disease', (200, 236))	('GSE1456', 'Var', (183, 190))	('GSE6532', 'Var', (162, 169))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('GSE1456', 'Chemical', '-', (183, 190))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('breast cancers', 'Disease', (72, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('CDK9', 'Gene', (286, 290))	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('GSE4922', 'Chemical', '-', (171, 178))	('Flavopiridol', 'Chemical', 'MESH:C077990', (294, 306))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('breast carcinoma', 'Phenotype', 'HP:0003002', (220, 236))
38036	25992224	Additionally, such findings have led to the development of small molecule IGF-1R inhibitors which also co-inhibit additional targets such as insulin receptor and epidermal growth factor receptor.	('epidermal growth factor receptor', 'Gene', '1956', (162, 194))	('inhibitors', 'Var', (81, 91))	('insulin receptor', 'Gene', (141, 157))	('IGF-1R', 'Gene', (74, 80))	('epidermal growth factor receptor', 'Gene', (162, 194))	('insulin receptor', 'Gene', '3643', (141, 157))
38043	25992224	The importance of IGF-1R signaling for the treatment of cancer is further underscored by the potential for IGF-1R signaling to promote resistance to both cytotoxic chemotherapies and radiation, as well as other molecular targeted therapies (Figure 1).	('promote', 'PosReg', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('resistance', 'CPA', (135, 145))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('IGF-1R', 'Var', (107, 113))
38051	25992224	One of the major concerns during the initial discovery and development of IGF-1R inhibitors centered around potential toxicity which was speculated to arise from targeting the highly homologous insulin receptor (IR).	('inhibitors', 'Var', (81, 91))	('IR', 'Gene', '3643', (212, 214))	('toxicity', 'Disease', 'MESH:D064420', (118, 126))	('IGF-1R', 'Gene', (74, 80))	('insulin receptor', 'Gene', (194, 210))	('toxicity', 'Disease', (118, 126))	('insulin receptor', 'Gene', '3643', (194, 210))
38052	25992224	The IR supports critical physiological functions in regulating glucose homeostasis and, therefore, inhibition of IR could potentially lead to undesired toxicities such as hyperglycemia and hyperinsulinemia.	('glucose homeostasis', 'Disease', 'MESH:D018149', (63, 82))	('IR', 'Gene', '3643', (113, 115))	('glucose homeostasis', 'Disease', (63, 82))	('lead to', 'Reg', (134, 141))	('hyperglycemia', 'Disease', 'MESH:D006943', (171, 184))	('hyperglycemia', 'Phenotype', 'HP:0003074', (171, 184))	('inhibition', 'Var', (99, 109))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (189, 205))	('toxicities', 'Disease', (152, 162))	('IR', 'Gene', '3643', (4, 6))	('hyperinsulinemia', 'Disease', (189, 205))	('hyperglycemia', 'Disease', (171, 184))	('toxicities', 'Disease', 'MESH:D064420', (152, 162))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (189, 205))
38055	25992224	Although the early disclosures for figitumumab reported encouraging clinical response, two phase III trials evaluating figitumumab in NSCLC, NCT00596830 (figitumumab in combination with paclitaxel and carboplatin) and NCT00673049 (figitumumab in combination with erlotinib) were discontinued in 2010 as independent data analysis indicated both trials were unlikely to meet the primary end points.	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('erlotinib', 'Chemical', 'MESH:D000069347', (263, 272))	('figitumumab', 'Chemical', 'MESH:C525021', (35, 46))	('paclitaxel', 'Chemical', 'MESH:D017239', (186, 196))	('NCT00596830', 'Var', (141, 152))	('carboplatin', 'Chemical', 'MESH:D016190', (201, 212))	('figitumumab', 'Chemical', 'MESH:C525021', (231, 242))	('figitumumab', 'Chemical', 'MESH:C525021', (119, 130))	('NSCLC', 'Disease', (134, 139))	('figitumumab', 'Chemical', 'MESH:C525021', (154, 165))
38098	25992224	For example, disruption of IGF-1R in osteoblasts enhances insulin signaling and action, and insulin-stimulated IRS-1 phosphorylation is elevated in IGF-1R knockout cells.	('insulin', 'Gene', (92, 99))	('insulin', 'Gene', (58, 65))	('disruption', 'Var', (13, 23))	('action', 'MPA', (80, 86))	('IRS', 'Gene', '3376', (111, 114))	('insulin', 'Gene', '3630', (92, 99))	('insulin', 'Gene', '3630', (58, 65))	('elevated', 'PosReg', (136, 144))	('IGF-1R', 'Gene', (27, 33))	('enhances', 'PosReg', (49, 57))	('IRS', 'Gene', (111, 114))
38100	25992224	For example, treatment with an IGF-1R specific antibody is associated with elevated signaling through IR, which may limit sustained inhibition of AKT signaling (Figure 4).	('AKT', 'Gene', '207', (146, 149))	('IR', 'Gene', '3643', (102, 104))	('elevated', 'PosReg', (75, 83))	('AKT', 'Gene', (146, 149))	('antibody', 'Var', (47, 55))	('IGF-1R', 'Gene', (31, 37))	('signaling', 'MPA', (84, 93))
38103	25992224	Taken together, these data strongly suggest that co-targeting both IGF-1R and IR is critical to achieve superior and broader anti-tumor efficacy as compared to targeting IGF-1R alone.	('IR', 'Gene', '3643', (78, 80))	('IGF-1R', 'Gene', (67, 73))	('co-targeting', 'Var', (49, 61))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
38144	25992224	The CDK2 activity was successfully dialed out with the retention of IGF-1R activity as a result of modifications to the aniline pharmacophore (compound 23).	('CDK2', 'Gene', (4, 8))	('aniline', 'Chemical', 'MESH:C023650', (120, 127))	('CDK2', 'Gene', '1017', (4, 8))	('activity', 'MPA', (75, 83))	('modifications', 'Var', (99, 112))
38145	25992224	Substitutions on the pyrimidine moiety especially with halogens significantly increased potency.	('pyrimidine', 'Chemical', 'MESH:C030986', (21, 31))	('increased', 'PosReg', (78, 87))	('Substitutions', 'Var', (0, 13))	('potency', 'MPA', (88, 95))
38153	25992224	Reciprocal interaction between IGF-1R and EGFR has also been described in a variety of other tumor types, including breast cancer, CRC, pancreatic cancer (PaCa) and HCC, where inhibition of either receptor can promote the activation of the other receptor.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('inhibition', 'Var', (176, 186))	('described', 'Reg', (61, 70))	('PaCa', 'CellLine', 'CVCL:1U09', (155, 159))	('CRC', 'Disease', (131, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('EGFR', 'Gene', (42, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('HCC', 'Disease', (165, 168))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('IGF-1R', 'Gene', (31, 37))	('breast cancer', 'Disease', (116, 129))	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('EGFR', 'Gene', '1956', (42, 46))	('tumor', 'Disease', (93, 98))	('promote', 'PosReg', (210, 217))	('activation', 'MPA', (222, 232))	('pancreatic cancer', 'Disease', (136, 153))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
38155	25992224	In pre-clinical studies, co-targeting EGFR and IGF-1R was shown to produce superior efficacy compared to treatment with the respective monotherapies in multiple models.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (38, 42))	('co-targeting', 'Var', (25, 37))	('IGF-1R', 'Gene', (47, 53))
38169	25992224	Compound 28 also showed anti-proliferative sensitivity in H1975 cells with a GI50 of 1.3 M, a cell line that harbors an EGFR mutation (T790M) and reported to be resistant to erlotinib (GI50 of 47 M).	('H1975', 'CellLine', 'CVCL:1511', (58, 63))	('T790M', 'Var', (135, 140))	('rat', 'Species', '10116', (36, 39))	('anti-proliferative sensitivity', 'MPA', (24, 54))	('erlotinib', 'Chemical', 'MESH:D000069347', (174, 183))	('EGFR', 'Gene', '1956', (120, 124))	('T790M', 'Mutation', 'rs121434569', (135, 140))	('EGFR', 'Gene', (120, 124))
38170	25992224	The authors attributed the observed efficacy to the unique multi-targeted profile of compound 28, although it is not clear if compound 28 directly inhibits EGFR with the T790M mutation.	('T790M', 'Mutation', 'rs121434569', (170, 175))	('T790M', 'Var', (170, 175))	('EGFR', 'Gene', '1956', (156, 160))	('EGFR', 'Gene', (156, 160))	('inhibits', 'NegReg', (147, 155))
38175	25992224	Within the field of dual IGF-1R/EGFR inhibitors, what appears to be lacking is a head-to-head in vivo comparison of selective dual IGF-1R/EGFR inhibitors to selective compounds only targeting IGF-1R and/or EGFR in respect to both efficacy and tolerability.	('EGFR', 'Gene', (206, 210))	('EGFR', 'Gene', '1956', (138, 142))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (138, 142))	('inhibitors', 'Var', (143, 153))	('EGFR', 'Gene', (32, 36))	('EGFR', 'Gene', '1956', (206, 210))
38179	25992224	Since inhibition of IGF-1R leads to downregulation of AKT signaling, it was then hypothesized that inhibiting both mTORC1 and IGF-1R may counteract this feedback loop and produce a superior therapeutic response compared to mTORC1 inhibition alone.	('mTORC1', 'Gene', (115, 121))	('downregulation', 'NegReg', (36, 50))	('mTORC1', 'Gene', '382056', (223, 229))	('AKT', 'Gene', '207', (54, 57))	('IGF-1R', 'Gene', (126, 132))	('mTORC1', 'Gene', '382056', (115, 121))	('inhibition', 'Var', (6, 16))	('therapeutic response', 'CPA', (190, 210))	('AKT', 'Gene', (54, 57))	('IGF-1R', 'Gene', (20, 26))	('mTORC1', 'Gene', (223, 229))	('inhibiting', 'Var', (99, 109))
38185	25992224	Based on similar biological rationale, R1507, an IGF-1R mAb is also being evaluated in a phase I study in combination with mTORC1 inhibitor everolimus.	('mTORC1', 'Gene', '382056', (123, 129))	('everolimus', 'Chemical', 'MESH:D000068338', (140, 150))	('mTORC1', 'Gene', (123, 129))	('R1507', 'Var', (39, 44))	('rat', 'Species', '10116', (28, 31))
38188	25992224	Loss of LKB1 leads to activation of the mTOR and IGF-1R pathways.	('LKB1', 'Gene', '6794', (8, 12))	('LKB1', 'Gene', (8, 12))	('activation', 'PosReg', (22, 32))	('IGF-1R pathways', 'Pathway', (49, 64))	('Loss', 'Var', (0, 4))
38199	25992224	XL228 was progressed into two phase I clinical trials (NCT00464113, NCT00526838) and early clinical data showed evidence of IGF-1R and SRC kinase pathway inhibition, as supported by phospho-protein analysis in circulating leukocytes, hair follicles and skin biopsy samples, and by transient upregulation of plasma glucose and insulin.	('NCT00526838', 'Var', (68, 79))	('SRC', 'Gene', '6714', (135, 138))	('SRC', 'Gene', (135, 138))	('IGF-1R', 'Gene', (124, 130))	('XL228', 'Chemical', '-', (0, 5))	('glucose', 'Chemical', 'MESH:D005947', (314, 321))	('insulin', 'Gene', (326, 333))	('insulin', 'Gene', '3630', (326, 333))	('NCT00464113', 'Var', (55, 66))	('inhibition', 'NegReg', (154, 164))	('upregulation', 'PosReg', (291, 303))
38218	25992224	Nonetheless, drug combinations have become a common approach in clinical development, with examples in the oncology kinase field including the ongoing clinical evaluation of drug combinations co-targeting IGF-1R and EGFR, as well as MEK and EGFR, just to name a few.	('EGFR', 'Gene', (216, 220))	('MEK', 'Gene', (233, 236))	('co-targeting', 'Var', (192, 204))	('EGFR', 'Gene', '1956', (241, 245))	('MEK', 'Gene', '5609', (233, 236))	('combinations co-targeting', 'Var', (179, 204))	('IGF-1R', 'Gene', (205, 211))	('EGFR', 'Gene', (241, 245))	('oncology', 'Phenotype', 'HP:0002664', (107, 115))	('EGFR', 'Gene', '1956', (216, 220))
38233	22427350	Dysregulation of developmental signal transduction pathways is found in an increasing number of cancers including ACC.	('developmental signal transduction pathways', 'Pathway', (17, 59))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('found', 'Reg', (63, 68))	('cancers', 'Disease', (96, 103))
38235	22427350	While its dysregulation is a common molecular event in a variety of cancers, its role in adrenal development and ACC is unknown.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('dysregulation', 'Var', (10, 23))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))
38242	22427350	Probe sets for JAG1, JAG2, DLL1, DLL3, and DLL4 were presented in a heatmap with clustering delineated by tumor type; individual samples were ordered based on JAG1 expression as determined by probe sets 216268_s_at and 209099_x_at.	('209099_x_at', 'Var', (219, 230))	('DLL1', 'Gene', (27, 31))	('expression', 'Species', '29278', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('JAG2', 'Gene', (21, 25))	('DLL1', 'Gene', '28514', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('JAG1', 'Gene', (159, 163))	('JAG2', 'Gene', '3714', (21, 25))	('tumor', 'Disease', (106, 111))	('216268_s_at', 'Var', (203, 214))
38269	22427350	The btan20 (Notch1) and C651.6DbHN (Notch2) monoclonal antibodies were developed by Spyros Artavanis-Tsakonas and were obtained from the Developmental Studies Hybridoma Bank under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, IA, 52242.	('Notch2', 'Gene', (36, 42))	('C651.6DbHN', 'Var', (24, 34))	('NICHD', 'Disease', (200, 205))	('Notch2', 'Gene', '4853', (36, 42))	('NICHD', 'Disease', 'None', (200, 205))	('Notch1', 'Gene', (12, 18))	('Notch1', 'Gene', '4851', (12, 18))
38279	22427350	While both JAG1 and JAG2 were significantly different in ACC vs ACA/NL, JAG1 is expressed at a higher level and a greater increase in ACC than JAG2.	('JAG2', 'Gene', '3714', (20, 24))	('ACC', 'Disease', (134, 137))	('JAG1', 'Var', (72, 76))	('JAG2', 'Gene', (143, 147))	('JAG2', 'Gene', '3714', (143, 147))	('JAG2', 'Gene', (20, 24))	('increase', 'PosReg', (122, 130))
38294	22427350	Following EDTA treatment, an increase in the expression of the Notch luciferase reporter was observed (EDTA-Notch versus Vehicle-Notch = 2.3 fold increase, bottom panel, Fig 2D).	('EDTA-Notch', 'Var', (103, 113))	('EDTA', 'Chemical', 'MESH:D004492', (10, 14))	('EDTA', 'Chemical', 'MESH:D004492', (103, 107))	('increase', 'PosReg', (146, 154))	('expression', 'Species', '29278', (45, 55))	('increase', 'PosReg', (29, 37))	('expression', 'MPA', (45, 55))
38300	22427350	No statistically significant difference in Hes1 expression was observed on Day 4 in wildtype Y1 (Red+) cells cultured with GFP+ (Control or DNMaml) cells indicating DNMaml is not affecting Notch signaling in adjacent wildtype Y1 (Red+) cells (Right panel, Fig 5C).	('DNMaml', 'Var', (165, 171))	('Notch signaling', 'MPA', (189, 204))	('expression', 'Species', '29278', (48, 58))
38310	22427350	In breast cancer, JAG1 is correlated with poor prognosis and lower survival rates in women with late stage, aggressive cancer.	('lower', 'NegReg', (61, 66))	('JAG1', 'Var', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('survival', 'MPA', (67, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Disease', (119, 125))	('women', 'Species', '9606', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
38312	22427350	Overexpression of Jag1 has been shown to cell-autonomously induce transformation of RKE cells independent of Notch receptors but dependent on intracellular interaction between the cytoplasmic tail of Jag1 and Affadin, a cell adherens junction protein.	('Jag1', 'Gene', (18, 22))	('transformation', 'CPA', (66, 80))	('Jag1', 'Gene', (200, 204))	('expression', 'Species', '29278', (4, 14))	('induce', 'Reg', (59, 65))	('Overexpression', 'Var', (0, 14))
38314	22427350	In this report, knockdown of Jag1 in mouse adrenocortical cancer cells employing specific shRNAs resulted in a density-dependent reduction in proliferation.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('proliferation', 'CPA', (142, 155))	('adrenocortical cancer', 'Disease', (43, 64))	('reduction', 'NegReg', (129, 138))	('Jag1', 'Gene', (29, 33))	('knockdown', 'Var', (16, 25))	('mouse', 'Species', '10090', (37, 42))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (43, 64))
38410	22540324	Additionally, the size of the tumor by MRI is underestimated by 20% in comparison to 16% to 47% by CT scans.	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('MRI', 'Var', (39, 42))
38448	22540324	Mass effect may, however, result in upper abdominal and/or flank pain.	('flank pain', 'Phenotype', 'HP:0030157', (59, 69))	('pain', 'Phenotype', 'HP:0012531', (65, 69))	('flank pain', 'Disease', (59, 69))	('flank pain', 'Disease', 'MESH:D021501', (59, 69))	('result in', 'Reg', (26, 35))	('upper abdominal', 'Disease', (36, 51))	('Mass effect', 'Var', (0, 11))
38516	21897901	The tumor did not exhibit the remaining criteria: sinusoidal invasion, atypical mitotic figure, and capsular invasion.	('tumor', 'Disease', (4, 9))	('capsular invasion', 'CPA', (100, 117))	('atypical', 'Var', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('sinusoidal invasion', 'CPA', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
38544	21266030	Bilateral adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1 (MEN1) and a novel mutation in the MEN1 gene The incidence of adrenal involvement in MEN1 syndrome has been reported between 9 and 45%, while the incidence of adrenocortical carcinoma (ACC) in MEN1 patients has been reported between 2.6 and 6%.	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('MEN1', 'Gene', (90, 94))	('Bilateral adrenocortical carcinoma', 'Disease', 'MESH:D018268', (0, 34))	('adrenal involvement', 'Disease', 'MESH:D000312', (151, 170))	('MEN1', 'Gene', '4221', (174, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('patient', 'Species', '9606', (40, 47))	('patient', 'Species', '9606', (287, 294))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (10, 34))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (248, 272))	('MEN1', 'Gene', '4221', (124, 128))	('MEN1 syndrome', 'Disease', (174, 187))	('MEN1', 'Gene', (174, 178))	('Bilateral adrenocortical carcinoma', 'Disease', (0, 34))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (10, 34))	('MEN1', 'Gene', (124, 128))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (248, 272))	('MEN1', 'Gene', '4221', (282, 286))	('neoplasia', 'Phenotype', 'HP:0002664', (72, 81))	('MEN1 syndrome', 'Disease', 'MESH:D018761', (174, 187))	('adrenal involvement', 'Disease', (151, 170))	('adrenocortical carcinoma', 'Disease', (248, 272))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (62, 81))	('multiple endocrine neoplasia type 1', 'Gene', (53, 88))	('MEN1', 'Gene', (282, 286))	('multiple endocrine neoplasia type 1', 'Gene', '4221', (53, 88))	('ACC', 'Phenotype', 'HP:0006744', (274, 277))	('patients', 'Species', '9606', (287, 295))	('MEN1', 'Gene', '4221', (90, 94))	('mutation', 'Var', (108, 116))
38547	21266030	Interestingly, a not previously described in the literature data, novel germline mutation (p.E45V) in exon 2 of MEN1 gene, was detected.	('MEN1', 'Gene', (112, 116))	('p.E45V) in', 'Var', (91, 101))	('MEN1', 'Gene', '4221', (112, 116))	('p.E45V', 'Mutation', 'p.E45V', (91, 97))
38554	21266030	The incidence of adrenal lesions in MEN1 patients varies between 9 and 45% and they usually develop in patients with mutations in exons 2 and 10.	('develop', 'Reg', (92, 99))	('mutations in exons 2', 'Var', (117, 137))	('adrenal lesions', 'Disease', 'MESH:D000307', (17, 32))	('adrenal lesions', 'Disease', (17, 32))	('patients', 'Species', '9606', (41, 49))	('MEN1', 'Gene', (36, 40))	('MEN1', 'Gene', '4221', (36, 40))	('patients', 'Species', '9606', (103, 111))
38559	21266030	Interestingly enough, a novel germline mutation in exon 2 of MEN1 gene, was detected.	('germline mutation in', 'Var', (30, 50))	('MEN1', 'Gene', '4221', (61, 65))	('MEN1', 'Gene', (61, 65))
38592	21266030	A germline p.E45V mutation in exon 2 of the MEN1 gene was detected, while none of the rest members of the family expressed any genetic abnormality.	('p.E45V', 'Var', (11, 17))	('genetic abnormality', 'Disease', (127, 146))	('genetic abnormality', 'Disease', 'MESH:D030342', (127, 146))	('MEN1', 'Gene', '4221', (44, 48))	('p.E45V', 'Mutation', 'p.E45V', (11, 17))	('MEN1', 'Gene', (44, 48))
38595	21266030	A not previously described, novel germline mutation (p.E45V) in exon 2 of MEN1 gene was detected in the postoperative genetic test for MEN1.	('p.E45V) in', 'Var', (53, 63))	('p.E45V', 'Mutation', 'p.E45V', (53, 59))	('MEN1', 'Gene', (135, 139))	('MEN1', 'Gene', '4221', (135, 139))	('MEN1', 'Gene', (74, 78))	('MEN1', 'Gene', '4221', (74, 78))
38597	21266030	Various types of mutations scattered throughout the 10 coding exons of the MEN1 gene inactivate the MEN1 gene.	('MEN1', 'Gene', (100, 104))	('MEN1', 'Gene', '4221', (100, 104))	('inactivate', 'NegReg', (85, 95))	('MEN1', 'Gene', (75, 79))	('MEN1', 'Gene', '4221', (75, 79))	('mutations', 'Var', (17, 26))
38599	21266030	The mutations are distributed across the MEN1 reading frame, resulting in a great deal of novel mutations, approximately 50%, in the index cases.	('mutations', 'Var', (4, 13))	('MEN1', 'Gene', '4221', (41, 45))	('MEN1', 'Gene', (41, 45))	('mutations', 'Var', (96, 105))
38628	21266030	Both NLS-1 (amino acid 479-497) and NLS-2 (amino acids 588-608) are present in the C-fourth of menin.	('NLS-1', 'Gene', (5, 10))	('menin', 'Gene', '4221', (95, 100))	('amino', 'Var', (12, 17))	('NLS-2', 'Gene', '29968', (36, 41))	('NLS-2', 'Gene', (36, 41))	('menin', 'Gene', (95, 100))	('NLS-1', 'Gene', '84879', (5, 10))
38633	21266030	The patient we describe harbors the germline p.E45V mutation of the MEN1 gene which, to the best of our knowledge, has not been previously described in the literature data.	('p.E45V', 'Var', (45, 51))	('patient', 'Species', '9606', (4, 11))	('MEN1', 'Gene', (68, 72))	('p.E45V', 'Mutation', 'p.E45V', (45, 51))	('MEN1', 'Gene', '4221', (68, 72))
38635	21266030	Although, pathogenetic mutations of glutamic acid either to lysine (p.E45K) or glykine (p.E45G) or alanine (p.E45A), have been previously described, the close proximity of this amino acid (amino acid 45) to the area (amino acids 1-40) of menin molecule responsive for Menin-JunD interaction, poses a possible explanation of the present tumorgenesis by disrupting Menin-JunD interaction, finally affecting the tumor suppression function.	('disrupting', 'NegReg', (352, 362))	('JunD', 'Gene', (274, 278))	('tumor', 'Disease', (409, 414))	('affecting', 'Reg', (395, 404))	('tumor', 'Disease', 'MESH:D009369', (409, 414))	('tumor', 'Disease', (336, 341))	('JunD', 'Gene', (369, 373))	('p.E45G', 'Var', (88, 94))	('Menin', 'Gene', '4221', (363, 368))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('glutamic acid', 'Chemical', 'MESH:D018698', (36, 49))	('mutations', 'Var', (23, 32))	('lysine', 'Chemical', 'MESH:D008239', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('Menin', 'Gene', '4221', (268, 273))	('menin', 'Gene', '4221', (238, 243))	('JunD', 'Gene', '3727', (274, 278))	('p.E45A', 'Mutation', 'p.E45A', (108, 114))	('menin', 'Gene', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('Menin', 'Gene', (363, 368))	('p.E45A', 'Var', (108, 114))	('JunD', 'Gene', '3727', (369, 373))	('p.E45G', 'Mutation', 'p.E45G', (88, 94))	('Menin', 'Gene', (268, 273))	('alanine', 'Chemical', 'MESH:D000409', (99, 106))	('p.E45K', 'Mutation', 'rs1114167491', (68, 74))
38636	21266030	In conclusion, we present a MEN1 patient with the novel p.E45V mutation in the exon 2 of the MEN1 gene, in whom bilateral ACC was detected.	('patient', 'Species', '9606', (33, 40))	('MEN1', 'Gene', (28, 32))	('MEN1', 'Gene', (93, 97))	('MEN1', 'Gene', '4221', (28, 32))	('MEN1', 'Gene', '4221', (93, 97))	('p.E45V', 'Var', (56, 62))	('p.E45V', 'Mutation', 'p.E45V', (56, 62))	('ACC', 'Phenotype', 'HP:0006744', (122, 125))
38637	21266030	Whether this novel mutation predisposed to bilateral ACC development or whether bilateral ACC can also occur in MEN1 patients, remains to be proved.	('mutation', 'Var', (19, 27))	('predisposed', 'Reg', (28, 39))	('ACC', 'Phenotype', 'HP:0006744', (90, 93))	('ACC', 'Phenotype', 'HP:0006744', (53, 56))	('patients', 'Species', '9606', (117, 125))	('MEN1', 'Gene', (112, 116))	('bilateral ACC', 'Disease', (43, 56))	('MEN1', 'Gene', '4221', (112, 116))
38668	33667214	We constructed a combined risk score by logistic regression modelling for ACC survival according to tumor stage, NDRG4 expression, and CKS2 expression.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('NDRG4', 'Gene', (113, 118))	('tumor', 'Disease', (100, 105))	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('CKS2', 'Gene', (135, 139))	('expression', 'Var', (119, 129))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
38677	33667214	The infiltration of CD8+ T cells, dendritic cells, natural killer T cells, regulatory T cells, macrophages, and fibroblasts was significantly more abundant in NDRG4 high-expression samples, while the infiltration of Th1 and Th2 cells was more abundant in NDRG4 low-expression samples (Figure 7A).	('NDRG4', 'Gene', (159, 164))	('CD8', 'Gene', (20, 23))	('more abundant', 'PosReg', (142, 155))	('CD8', 'Gene', '925', (20, 23))	('infiltration', 'CPA', (4, 16))	('high-expression', 'Var', (165, 180))
38686	33667214	Our study found a relationship between high expression of NDRG4 and favorable survival in ACC (Figure 5A-5C), suggesting that it may be a potential tumor suppressor.	('expression', 'MPA', (44, 54))	('high', 'Var', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('ACC', 'Disease', (90, 93))	('tumor', 'Disease', (148, 153))	('NDRG4', 'Gene', (58, 63))	('ACC', 'Phenotype', 'HP:0006744', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
38688	33667214	Moreover, Agosta et al (2018) found that NDRG4 may be a potential target of miR-139-5p, and that the miR-139-5p/NDRG4 pathway promotes ACC aggressiveness by mediating epithelial-to-mesenchymal transition, which results in tumor cell invasiveness and anchorage-independent growth.	('aggressiveness', 'Phenotype', 'HP:0000718', (139, 153))	('anchorage-independent growth', 'CPA', (250, 278))	('ACC', 'Phenotype', 'HP:0006744', (135, 138))	('results in', 'Reg', (211, 221))	('promotes', 'PosReg', (126, 134))	('miR-139-5p/NDRG4', 'Var', (101, 117))	('mediating', 'Reg', (157, 166))	('aggressiveness', 'Disease', 'MESH:D001523', (139, 153))	('tumor cell invasiveness', 'Disease', (222, 245))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('aggressiveness', 'Disease', (139, 153))	('epithelial-to-mesenchymal transition', 'CPA', (167, 203))	('tumor cell invasiveness', 'Disease', 'MESH:D009361', (222, 245))
38693	33667214	According to these studies, we speculate that miRNAs might play an important role in the regulation of NDRG4 and CKS2, resulting in tumor cell proliferation and aggressiveness, as well as ACC progression.	('aggressiveness', 'Disease', 'MESH:D001523', (161, 175))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('miRNAs', 'Var', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('NDRG4', 'Gene', (103, 108))	('aggressiveness', 'Disease', (161, 175))	('tumor', 'Disease', (132, 137))	('CKS2', 'Gene', (113, 117))	('ACC', 'Phenotype', 'HP:0006744', (188, 191))	('aggressiveness', 'Phenotype', 'HP:0000718', (161, 175))	('ACC progression', 'CPA', (188, 203))	('resulting in', 'Reg', (119, 131))
38703	28073588	Recent comprehensive genetic analyses of ACCs demonstrated recurrent copy number gains in multiple CYP genes prompting investigation into whether CYP overexpression potentiates ACC chemoresistance.	('ACCs', 'Gene', '84680', (41, 45))	('ACC', 'Phenotype', 'HP:0006744', (177, 180))	('ACCs', 'Gene', (41, 45))	('ACC', 'Disease', (177, 180))	('CYP', 'Gene', (99, 102))	('copy number gains', 'Var', (69, 86))	('CYP', 'Gene', '4051', (146, 149))	('CYP', 'Gene', '4051', (99, 102))	('ACC', 'Phenotype', 'HP:0006744', (41, 44))	('CYP', 'Gene', (146, 149))	('potentiates', 'PosReg', (165, 176))	('chemoresistance', 'CPA', (181, 196))
38707	28073588	Copy gains of CYP2A6 were found in 26% (7/27) of ACC specimens.	('CYP2A6', 'Gene', (14, 20))	('ACC', 'Disease', (49, 52))	('Copy gains', 'Var', (0, 10))	('CYP2A6', 'Gene', '1548', (14, 20))	('ACC', 'Phenotype', 'HP:0006744', (49, 52))
38708	28073588	Silencing of CYP2A6 in NCI-H295R cells resulted in decreased cell viability and increased chemosensitivity (P < .05).	('chemosensitivity', 'CPA', (90, 106))	('NCI-H295R', 'CellLine', 'CVCL:0458', (23, 32))	('increased', 'PosReg', (80, 89))	('decreased', 'NegReg', (51, 60))	('CYP2A6', 'Gene', '1548', (13, 19))	('cell viability', 'CPA', (61, 75))	('CYP2A6', 'Gene', (13, 19))	('Silencing', 'Var', (0, 9))
38709	28073588	Frequent upregulation in ACCs and the reversal of chemoresistance in ACC cells via enforced silencing, suggest a role for CYP2A6 in adrenocortical malignancy.	('ACC', 'Phenotype', 'HP:0006744', (69, 72))	('ACCs', 'Gene', (25, 29))	('ACCs', 'Gene', '84680', (25, 29))	('upregulation', 'PosReg', (9, 21))	('adrenocortical malignancy', 'Disease', 'MESH:D000306', (132, 157))	('CYP2A6', 'Gene', '1548', (122, 128))	('silencing', 'Var', (92, 101))	('CYP2A6', 'Gene', (122, 128))	('ACC', 'Phenotype', 'HP:0006744', (25, 28))	('enforced', 'PosReg', (83, 91))	('adrenocortical malignancy', 'Disease', (132, 157))
38711	28073588	Gene-level analyses of loci with abnormal copy numbers revealed multiple cytochrome P450 (CYP) genes to be overrepresented in the cohort.	('CYP', 'Gene', '4051', (90, 93))	('cytochrome P450', 'Gene', (73, 88))	('abnormal copy numbers', 'Var', (33, 54))	('cytochrome P450', 'Gene', '4051', (73, 88))	('overrepresented', 'PosReg', (107, 122))	('CYP', 'Gene', (90, 93))
38715	28073588	In addition to their roles in metabolism, abnormal expression and function of CYP enzymes have been linked to lung, colon, pancreatic, and adrenal cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung', 'Disease', (110, 114))	('colon', 'Disease', (116, 121))	('linked', 'Reg', (100, 106))	('abnormal', 'Var', (42, 50))	('CYP', 'Gene', (78, 81))	('adrenal cancer', 'Disease', (139, 153))	('pancreatic', 'Disease', 'MESH:D010195', (123, 133))	('function', 'MPA', (66, 74))	('adrenal cancer', 'Disease', 'MESH:D000310', (139, 153))	('CYP', 'Gene', '4051', (78, 81))	('pancreatic', 'Disease', (123, 133))
38724	28073588	The copy number gains of CYP genes in ACC predicted by Rubinstein et al.	('ACC', 'Disease', (38, 41))	('copy number gains', 'Var', (4, 21))	('CYP', 'Gene', (25, 28))	('CYP', 'Gene', '4051', (25, 28))	('ACC', 'Phenotype', 'HP:0006744', (38, 41))
38731	28073588	Twenty ng aliquots of genomic DNA isolated from fresh frozen tissue samples were subjected to quadruplicate multiplex reactions containing individual CYP TaqMan copy number assays and RNase P TaqMan copy number reference assay (all from Life Technologies, Carlsbad, CA) as previously described.	('copy', 'Var', (161, 165))	('CYP', 'Gene', '4051', (150, 153))	('CYP', 'Gene', (150, 153))
38763	28073588	To determine if the observed copy number gains resulted in changes in transcriptional amplification, expression of the CYP genes was tested.	('copy number', 'Var', (29, 40))	('CYP', 'Gene', (119, 122))	('tested', 'Reg', (133, 139))	('CYP', 'Gene', '4051', (119, 122))	('changes', 'Reg', (59, 66))	('transcriptional amplification', 'MPA', (70, 99))
38787	28073588	However, the apparent absence of overexpression of other CYP genes co-amplified via copy gains and the near global increase in expression in tumors without copy gains suggest a more pointed or directional upregulation evolved for metabolic support of survival networks.	('overexpression', 'PosReg', (33, 47))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('CYP', 'Gene', (57, 60))	('upregulation', 'PosReg', (205, 217))	('expression', 'MPA', (127, 137))	('tumors', 'Disease', (141, 147))	('increase', 'PosReg', (115, 123))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('CYP', 'Gene', '4051', (57, 60))	('copy gains', 'Var', (84, 94))
38794	28073588	Intriguingly, CYP2A6 silencing reduced cell viability, an effect that has not been previously described in the literature.	('CYP2A6', 'Gene', (14, 20))	('reduced', 'NegReg', (31, 38))	('cell viability', 'CPA', (39, 53))	('silencing', 'Var', (21, 30))	('CYP2A6', 'Gene', '1548', (14, 20))
38849	32517679	Tumor size in patients undergoing RLA was significantly smaller compared to patients who underwent TLA/RATLA.	('patients', 'Species', '9606', (76, 84))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TLA', 'Chemical', '-', (105, 108))	('RLA', 'Var', (34, 37))	('TLA', 'Chemical', '-', (99, 102))	('Tumor size', 'CPA', (0, 10))	('smaller', 'NegReg', (56, 63))	('patients', 'Species', '9606', (14, 22))
38866	32290321	In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('alter', 'Reg', (53, 58))	('dysfunctions', 'Var', (26, 38))	('tumor', 'Disease', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('epigenetic modifications', 'Var', (94, 118))	('genetic', 'Var', (79, 86))	('expression', 'MPA', (65, 75))	('cancer', 'Disease', (3, 9))	('PRDM genes', 'Gene', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
38867	32290321	They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed.	('imbalance', 'Phenotype', 'HP:0002172', (152, 161))	('alternative splicing', 'Var', (29, 49))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
38880	32290321	Some evidence suggests that PRDMs are involved in human malignancy through modulation of several processes such as epigenetic modifications, genetic reprogramming, inflammation, and metabolic homeostasis.	('inflammation', 'Disease', (164, 176))	('malignancy', 'Disease', 'MESH:D009369', (56, 66))	('modulation', 'Reg', (75, 85))	('involved', 'Reg', (38, 46))	('PRDMs', 'Chemical', '-', (28, 33))	('malignancy', 'Disease', (56, 66))	('genetic reprogramming', 'CPA', (141, 162))	('inflammation', 'Disease', 'MESH:D007249', (164, 176))	('metabolic homeostasis', 'CPA', (182, 203))	('epigenetic modifications', 'Var', (115, 139))	('human', 'Species', '9606', (50, 55))
38881	32290321	These two isoforms, generated by either alternative splicing or alternative use of different promoters, play opposite roles, particularly in cancer.	('alternative splicing', 'Var', (40, 60))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
38883	32290321	The imbalance in favor of PR- is observed in many human malignancies and it can be due to inactivating mutations or silencing of the complete form and/or to increased expression of the PR- form.	('inactivating mutations', 'Var', (90, 112))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('human', 'Species', '9606', (50, 55))	('increased', 'PosReg', (157, 166))	('silencing', 'Var', (116, 125))	('malignancies', 'Disease', (56, 68))	('expression', 'MPA', (167, 177))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
38885	32290321	An overview of cancer-specific alterations affecting PRDM family members, taking into account putative causes, produced effects, and underlying molecular mechanisms, is detailed below and summarized in Table 1.	('alterations', 'Var', (31, 42))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('PRDM', 'Gene', (53, 57))
38892	32290321	Particularly, disruption of PRDM1/BLIMP1 function is frequently observed in the activated B-cell-like (ABC) subtype of DLBCL by distinct mechanisms including inactivating mutations, chromosomal deletion, and epigenetic silencing.	('BCL', 'Phenotype', 'HP:0012191', (121, 124))	('inactivating mutations', 'Var', (158, 180))	('BLIMP1', 'Gene', '639', (34, 40))	('function', 'MPA', (41, 49))	('ABC', 'Gene', (103, 106))	('ABC', 'Gene', '10058', (103, 106))	('activated B-cell-like', 'Disease', (80, 101))	('epigenetic silencing', 'Var', (208, 228))	('BLIMP1', 'Gene', (34, 40))	('chromosomal deletion', 'Var', (182, 202))	('disruption', 'NegReg', (14, 24))
38893	32290321	Of note, a more recent study demonstrated that its genetic loss could contribute to the overall poor prognosis for ABC-DLBCL but not germinal center B-cell-like (GCB)-DLBCLs.	('BCL', 'Phenotype', 'HP:0012191', (121, 124))	('BCL', 'Phenotype', 'HP:0012191', (169, 172))	('ABC', 'Gene', (115, 118))	('ABC', 'Gene', '10058', (115, 118))	('genetic loss', 'Var', (51, 63))
38894	32290321	Furthermore, the lack of BLIMP1 expression correlated with an impaired p53 signaling pathway and Myc overexpression; gene expression profiling data also indicated that inactivated BLIMP1 could facilitate DLBCL progression through Myc and BCR (B cell receptor) signaling, which are essential for ABC-DLBCL survival.	('DLBCL', 'Disease', (204, 209))	('BLIMP1', 'Gene', (25, 31))	('BCL', 'Phenotype', 'HP:0012191', (301, 304))	('BLIMP1', 'Gene', (180, 186))	('ABC', 'Gene', '10058', (295, 298))	('BLIMP1', 'Gene', '639', (25, 31))	('BLIMP1', 'Gene', '639', (180, 186))	('BCL', 'Phenotype', 'HP:0012191', (206, 209))	('inactivated', 'Var', (168, 179))	('facilitate', 'PosReg', (193, 203))	('Myc', 'MPA', (230, 233))	('ABC', 'Gene', (295, 298))
38897	32290321	In addition, PRDM1 ectopic expression in a DLBCL-derived cell line triggered cell cycle arrest.	('PRDM1', 'Gene', (13, 18))	('ectopic expression', 'Var', (19, 37))	('arrest', 'Disease', 'MESH:D006323', (88, 94))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (77, 94))	('arrest', 'Disease', (88, 94))	('BCL', 'Phenotype', 'HP:0012191', (45, 48))	('triggered', 'Reg', (67, 76))
38899	32290321	Consistently, an in vivo study showed that mouse Prdm1 deletion cooperated with constitutive activation of the NF-kappaB pathway to support a neoplastic phenotype.	('activation', 'PosReg', (93, 103))	('support', 'PosReg', (132, 139))	('Prdm1', 'Gene', '12142', (49, 54))	('NF-kappaB', 'Gene', '18033', (111, 120))	('Prdm1', 'Gene', (49, 54))	('deletion', 'Var', (55, 63))	('neoplastic phenotype', 'CPA', (142, 162))	('mouse', 'Species', '10090', (43, 48))	('NF-kappaB', 'Gene', (111, 120))
38901	32290321	For instance, array comparative genomic hybridization and gene expression profiling in extranodal NK/T-cell lymphoma (EN-NK/T) revealed that the most frequently deleted chromosomal region 6q21-6q25, induced a downregulation of several tumor-suppressor genes including PRDM1.	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (101, 116))	('NK/T-cell lymphoma', 'Disease', 'MESH:D054391', (98, 116))	('NK/T-cell lymphoma', 'Disease', (98, 116))	('downregulation', 'NegReg', (209, 223))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cell lymphoma', 'Phenotype', 'HP:0012191', (103, 116))	('tumor-suppressor', 'Gene', (235, 251))	('PRDM1', 'Gene', (268, 273))	('6q21-6q25', 'Var', (188, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (108, 116))	('tumor-suppressor', 'Gene', '7248', (235, 251))
38905	32290321	PRDM1 mutations occurred in patients with plasmablastic lymphoma; interestingly, in this rare neoplasm, PRDM1 genetic alterations did not impair terminal B-cell differentiation, but contributed to the oncogenicity of MYC, which is usually dysregulated by translocation or amplification.	('lymphoma', 'Phenotype', 'HP:0002665', (56, 64))	('plasmablastic lymphoma', 'Disease', (42, 64))	('MYC', 'Gene', '4609', (217, 220))	('genetic alterations', 'Var', (110, 129))	('MYC', 'Gene', (217, 220))	('neoplasm', 'Disease', (94, 102))	('plasmablastic lymphoma', 'Disease', 'MESH:D000069293', (42, 64))	('PRDM1', 'Gene', (104, 109))	('oncogenicity', 'MPA', (201, 213))	('neoplasm', 'Disease', 'MESH:D009369', (94, 102))	('neoplasm', 'Phenotype', 'HP:0002664', (94, 102))	('patients', 'Species', '9606', (28, 36))	('contributed to', 'Reg', (182, 196))
38918	32290321	In colorectal tumor cells, PRDM1 knockdown by small-interfering RNA (siRNA) results in both apoptosis and growth arrest through regulation of p53 transcription.	('apoptosis', 'CPA', (92, 101))	('p53', 'Gene', (142, 145))	('growth arrest', 'Disease', (106, 119))	('knockdown', 'Var', (33, 42))	('growth arrest', 'Disease', 'MESH:D006323', (106, 119))	('PRDM1', 'Gene', (27, 32))	('regulation', 'Reg', (128, 138))	('growth arrest', 'Phenotype', 'HP:0001510', (106, 119))	('transcription', 'MPA', (146, 159))	('colorectal tumor', 'Disease', (3, 19))	('colorectal tumor', 'Disease', 'MESH:D015179', (3, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('small-interfering', 'Var', (46, 63))
38919	32290321	Interestingly, both p53 mRNA and protein levels are considerably increased after PRDM1/BLIMP1 depletion, which is accompanied by the induction of p53 target genes.	('BLIMP1', 'Gene', (87, 93))	('BLIMP1', 'Gene', '639', (87, 93))	('depletion', 'Var', (94, 103))	('increased', 'PosReg', (65, 74))
38926	32290321	In addition, PRDM1 reduced the expression of DKK1 thus exerting its antitumor effect via antagonizing the activity of Wnt/beta-catenin pathway (Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('beta-catenin', 'Gene', '1499', (122, 134))	('antagonizing', 'NegReg', (89, 101))	('tumor', 'Disease', (72, 77))	('DKK1', 'Gene', '22943', (45, 49))	('DKK1', 'Gene', (45, 49))	('activity', 'MPA', (106, 114))	('expression', 'MPA', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('reduced', 'NegReg', (19, 26))	('PRDM1', 'Var', (13, 18))	('beta-catenin', 'Gene', (122, 134))
38928	32290321	Specifically, the ectopic expression of the transcription factor Aiolos induced anoikis resistance to cancer cells by downregulating PRDM1.	('Aiolos', 'Gene', (65, 71))	('Aiolos', 'Gene', '22806', (65, 71))	('ectopic expression', 'Var', (18, 36))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('induced', 'PosReg', (72, 79))	('cancer', 'Disease', (102, 108))	('downregulating', 'NegReg', (118, 132))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('PRDM1', 'Gene', (133, 138))
38931	32290321	Additionally, mutations were revealed in some solid tumors, such as skin cutaneous melanoma and uterine carcinosarcoma, which displayed more than 5% of patients carrying PRDM1 mutations.	('revealed', 'Reg', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('skin cutaneous melanoma', 'Disease', (68, 91))	('mutations', 'Var', (176, 185))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('carcinosarcoma', 'Disease', 'MESH:D002296', (104, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (96, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('PRDM1', 'Gene', (170, 175))	('carcinosarcoma', 'Disease', (104, 118))	('mutations', 'Var', (14, 23))	('patients', 'Species', '9606', (152, 160))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (68, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
38937	32290321	Indeed, both genetic inactivation or epigenetic silencing of RIZ1 and/or an increase of RIZ2 expression levels were frequently revealed in many human cancer tissues and cell lines.	('increase', 'PosReg', (76, 84))	('human', 'Species', '9606', (144, 149))	('revealed', 'Reg', (127, 135))	('genetic inactivation', 'Var', (13, 33))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('expression levels', 'MPA', (93, 110))	('cancer', 'Disease', (150, 156))	('RIZ2', 'Gene', '7799', (88, 92))	('RIZ2', 'Gene', (88, 92))	('RIZ1', 'Gene', (61, 65))	('epigenetic silencing', 'Var', (37, 57))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
38941	32290321	Riz1 knockout mice, carrying normal Riz2, were tumor prone in both wild-type and mutant p53 genetic backgrounds.	('prone', 'PosReg', (53, 58))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('p53', 'Gene', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutant', 'Var', (81, 87))	('Riz2', 'Gene', '7799', (36, 40))	('Riz2', 'Gene', (36, 40))	('tumor', 'Disease', (47, 52))
38942	32290321	Indeed, an accelerated tumorigenesis was associated with Riz1 deficiency (Riz1-/-) on the p53+/- background.	('Riz1', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('deficiency', 'Var', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('accelerated', 'PosReg', (11, 22))	('tumor', 'Disease', (23, 28))
38945	32290321	Indeed, frameshift mutations of microsatellite repeats localized in the C-terminal coding region were frequently detected in colorectal, gastric, endometrial, and pancreatic microsatellite instability (MIN) positive cancers.	('colorectal', 'Disease', (125, 135))	('gastric', 'Disease', (137, 144))	('endometrial', 'Disease', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('frameshift mutations', 'Var', (8, 28))	('pancreatic microsatellite instability (MIN) positive cancers', 'Disease', 'MESH:D053842', (163, 223))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('detected', 'Reg', (113, 121))
38949	32290321	Despite their high occurrence, the functional significance in tumorigenesis of these C-terminal PRDM2 truncated forms induced by frameshift mutations is still unknown and deserves investigation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('PRDM2', 'Gene', (96, 101))	('frameshift mutations', 'Var', (129, 149))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('induced', 'Reg', (118, 125))
38950	32290321	Interestingly, the restoration of the wild-type PRDM2 gene sequence of one mutant c.4467delA allele by genome editing in homozygous mutant human colorectal cancer cells, repaired its H3K9me2 activity, impaired tumor cell growth, reduced anchorage-independent growth, cellular migration, and colony forming ability in vitro, as well as decreased the tumor growth in a mouse xenograft model.	('colony forming ability in vitro', 'CPA', (291, 322))	('colorectal cancer', 'Disease', 'MESH:D015179', (145, 162))	('mouse', 'Species', '10090', (367, 372))	('activity', 'MPA', (191, 199))	('impaired tumor', 'Disease', 'MESH:D060825', (201, 215))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('colorectal cancer', 'Disease', (145, 162))	('decreased', 'NegReg', (335, 344))	('tumor', 'Disease', (210, 215))	('H3K9me2', 'Protein', (183, 190))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('c.4467delA', 'Var', (82, 92))	('PRDM2', 'Gene', (48, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('reduced', 'NegReg', (229, 236))	('repaired', 'NegReg', (170, 178))	('cellular migration', 'CPA', (267, 285))	('tumor', 'Disease', (349, 354))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('mutant', 'Var', (132, 138))	('anchorage-independent growth', 'CPA', (237, 265))	('impaired tumor', 'Disease', (201, 215))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('human', 'Species', '9606', (139, 144))	('c.4467delA', 'Mutation', 'rs57173229', (82, 92))
38951	32290321	Furthermore, H3K9me2 activity restoration determined the downregulation of several genes involved in cancer pathways, mostly of EMT, thus contributing to a more aggressive cancer phenotype (Figure 1E).	('downregulation', 'NegReg', (57, 71))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('H3K9me2', 'Protein', (13, 20))	('cancer', 'Disease', (101, 107))	('aggressive cancer', 'Disease', 'MESH:D009369', (161, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('restoration', 'Var', (30, 41))	('cancer', 'Disease', (172, 178))	('aggressive cancer', 'Disease', (161, 178))	('more', 'PosReg', (156, 160))
38952	32290321	In addition, frameshift mutations in the (A)9 tract were also found in samples of malignant melanoma and nevi and in leukemia cell lines.	('nevi', 'Disease', (105, 109))	('malignant melanoma', 'Disease', 'MESH:D008545', (82, 100))	('malignant melanoma', 'Disease', (82, 100))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('leukemia', 'Disease', 'MESH:D007938', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('nevi', 'Phenotype', 'HP:0003764', (105, 109))	('leukemia', 'Disease', (117, 125))	('frameshift mutations', 'Var', (13, 33))	('found', 'Reg', (62, 67))	('malignant melanoma', 'Phenotype', 'HP:0002861', (82, 100))	('A)9', 'Gene', (42, 45))
38953	32290321	Interestingly, in most cases of MIN pathway cancers these frameshift mutations were biallelic or homozygous/hemizygous, indicating that PRDM2 follows the two-hit model of tumor suppressor genes, with one hit achieved either by mutations/deletions affecting the PR domain or by frameshift mutations in the 3' end affecting the interactions between the N-terminal PR domain of RIZ1 and its C-terminal region, including the PR-binding motif.	('affecting', 'Reg', (312, 321))	('RIZ1', 'Gene', (375, 379))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('mutations/deletions', 'Var', (227, 246))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('frameshift mutations', 'Var', (277, 297))	('interactions', 'Interaction', (326, 338))
38955	32290321	Interestingly, some PRDM2 polymorphisms have also been associated with carcinogenesis.	('polymorphisms', 'Var', (26, 39))	('PRDM2', 'Gene', (20, 25))	('carcinogenesis', 'Disease', (71, 85))	('associated', 'Reg', (55, 65))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
38957	32290321	A CpG island in the PRDM2/RIZ1 promoter is frequently methylated in many cancer types, such as breast carcinomas and liver tumors, as well as in colon and lung cancer cell lines.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', (160, 166))	('liver tumors', 'Disease', 'MESH:D008113', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('liver tumors', 'Phenotype', 'HP:0002896', (117, 129))	('breast carcinomas', 'Disease', 'MESH:D001943', (95, 112))	('methylated', 'Var', (54, 64))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('breast carcinomas', 'Disease', (95, 112))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('liver tumors', 'Disease', (117, 129))	('PRDM2/RIZ1', 'Gene', (20, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('breast carcinomas', 'Phenotype', 'HP:0003002', (95, 112))	('colon and lung cancer', 'Disease', 'MESH:D008175', (145, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))
38958	32290321	Additionally, epigenetic silencing of RIZ1 expression was also detected in pituitary adenomas and nasopharyngeal carcinoma specimens.	('detected', 'Reg', (63, 71))	('epigenetic silencing', 'Var', (14, 34))	('carcinoma', 'Disease', 'MESH:D009369', (113, 122))	('men', 'Species', '9606', (128, 131))	('pituitary adenomas', 'Disease', 'MESH:D010911', (75, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (98, 122))	('RIZ1', 'Gene', (38, 42))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (75, 93))	('carcinoma', 'Disease', (113, 122))	('pituitary adenomas', 'Disease', (75, 93))
38965	32290321	Noteworthy, a later study demonstrated that estradiol induced the preferential synthesis of transcripts with exon 9a, whereas it reduced those containing exons 9b and 10.	('synthesis', 'MPA', (79, 88))	('preferential', 'PosReg', (66, 78))	('exon 9a', 'Var', (109, 116))	('reduced', 'NegReg', (129, 136))	('estradiol', 'Chemical', 'MESH:D004958', (44, 53))
38974	32290321	Specifically, tumor suppressor function requires the establishment of the H4K20me1-H3K9me1 trans-tail 'histone code' at specific loci through the direct interaction of RIZ1 PR-binding motif to PR-Set7 monomethyltransferase, an essential component of the mammalian cell cycle, which is needed for proper DNA replication and mitosis, thus hypothesizing an additional mechanism of action.	('men', 'Species', '9606', (62, 65))	('mitosis', 'Disease', 'None', (323, 330))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('interaction', 'Interaction', (153, 164))	('mammalian', 'Species', '9606', (254, 263))	('PR-Set7', 'Gene', (193, 200))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('H4K20me1-H3K9me1', 'Var', (74, 90))	('PR-Set7', 'Gene', '387893', (193, 200))	('RIZ1', 'Gene', (168, 172))	('mitosis', 'Disease', (323, 330))
38976	32290321	Since the loss of PR-Set7 produced persistent DNA double-strand breaks (DSBs), it was conceivable that H4K20me1, and possibly Riz1-mediated H3K9me1, had a role in DNA repair.	('loss', 'Var', (10, 14))	('DNA double-strand breaks', 'MPA', (46, 70))	('DSBs', 'Chemical', '-', (72, 76))	('H4K20me1', 'Var', (103, 111))	('PR-Set7', 'Gene', (18, 25))	('PR-Set7', 'Gene', '387893', (18, 25))
38987	32290321	It is well established that chromosomal rearrangements or proviral insertion at the PRDM3 locus gene, MECOM, are found in up to 10% of acute myeloid leukemia (AML) cases with poor survival outcomes.	('men', 'Species', '9606', (49, 52))	('AML', 'Phenotype', 'HP:0004808', (159, 162))	('AML', 'Disease', (159, 162))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (135, 157))	('MECOM', 'Gene', (102, 107))	('found', 'Reg', (113, 118))	('leukemia', 'Phenotype', 'HP:0001909', (149, 157))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (141, 157))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (135, 157))	('AML', 'Disease', 'MESH:D015470', (159, 162))	('acute myeloid leukemia', 'Disease', (135, 157))	('chromosomal rearrangements', 'Var', (28, 54))
38991	32290321	Later, in ovarian tumors a high frequency of aberrant EVI1 splicing, generating novel isoforms, could contribute to the pathophysiology of these cancers.	('cancers', 'Disease', (145, 152))	('ovarian tumors', 'Disease', (10, 24))	('EVI1', 'Gene', (54, 58))	('ovarian tumors', 'Phenotype', 'HP:0100615', (10, 24))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('aberrant', 'Var', (45, 53))	('ovarian tumors', 'Disease', 'MESH:D010051', (10, 24))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('isoforms', 'MPA', (86, 94))	('contribute', 'Reg', (102, 112))	('EVI1', 'Gene', '14013', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
38992	32290321	EVI1 is usually upregulated through the generation of oncogenic fusion proteins as a consequence of rearrangements; alternatively, it can also be upregulated by leukemogenic factors at the transcriptional level.	('upregulated', 'PosReg', (16, 27))	('rearrangements', 'Var', (100, 114))	('EVI1', 'Gene', (0, 4))	('upregulated', 'PosReg', (146, 157))	('men', 'Species', '9606', (109, 112))	('EVI1', 'Gene', '14013', (0, 4))
39003	32290321	For instance, the proximal set of EVI1 zinc fingers is able to bind the N-terminal domain of the zinc finger transcription factor hypermethylated in cancer 1 (HIC1); in turn, this interaction deregulates the DNA binding and transcriptional activity of EVI1 on the BCL-XL promoter, thus compromising the anti-apoptotic activity of EVI1 (Figure 2).	('transcriptional', 'MPA', (224, 239))	('hypermethylated in cancer 1', 'Gene', (130, 157))	('EVI1', 'Gene', (252, 256))	('EVI1', 'Gene', '14013', (252, 256))	('BCL-XL', 'Gene', (264, 270))	('compromising', 'NegReg', (286, 298))	('anti-apoptotic activity', 'CPA', (303, 326))	('EVI1', 'Gene', (34, 38))	('deregulates', 'NegReg', (192, 203))	('HIC1', 'Gene', (159, 163))	('EVI1', 'Gene', '14013', (34, 38))	('BCL-XL', 'Gene', '598', (264, 270))	('hypermethylated in cancer 1', 'Gene', '3090', (130, 157))	('interaction', 'Var', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DNA binding', 'Interaction', (208, 219))	('HIC1', 'Gene', '3090', (159, 163))	('EVI1', 'Gene', (330, 334))	('BCL', 'Phenotype', 'HP:0012191', (264, 267))	('EVI1', 'Gene', '14013', (330, 334))
39006	32290321	EVI1 knockdown impaired PC cell proliferation through a cell cycle progression blockade.	('blockade', 'NegReg', (79, 87))	('cell cycle progression', 'CPA', (56, 78))	('impaired', 'NegReg', (15, 23))	('knockdown', 'Var', (5, 14))	('PC', 'Phenotype', 'HP:0012125', (24, 26))	('EVI1', 'Gene', (0, 4))	('EVI1', 'Gene', '14013', (0, 4))
39007	32290321	Mechanistically, these changes might be at least in part mediated by reactivation of SMAD3, a known transcriptional target of EVI1.	('SMAD3', 'Gene', '4088', (85, 90))	('SMAD3', 'Gene', (85, 90))	('EVI1', 'Gene', (126, 130))	('reactivation', 'Var', (69, 81))	('EVI1', 'Gene', '14013', (126, 130))
39008	32290321	EVI1 knockdown in PC cells also reduced migratory potential and anchorage-independent growth while enhancing apoptosis sensitivity.	('enhancing', 'PosReg', (99, 108))	('anchorage-independent growth', 'CPA', (64, 92))	('apoptosis sensitivity', 'CPA', (109, 130))	('migratory potential', 'CPA', (40, 59))	('knockdown', 'Var', (5, 14))	('reduced', 'NegReg', (32, 39))	('EVI1', 'Gene', (0, 4))	('PC', 'Phenotype', 'HP:0012125', (18, 20))	('EVI1', 'Gene', '14013', (0, 4))
39019	32290321	In addition, EVI1 knockdown demonstrated its requirement for metastasis of colon cancer cells.	('knockdown', 'Var', (18, 27))	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('men', 'Species', '9606', (52, 55))	('EVI1', 'Gene', (13, 17))	('metastasis of colon cancer', 'Disease', (61, 87))	('EVI1', 'Gene', '14013', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('metastasis of colon cancer', 'Disease', 'MESH:D015179', (61, 87))
39024	32290321	Recent findings have suggested MECOM as a novel candidate gene for hereditary hematological malignancies; indeed, a novel germline mutation within the ninth zinc finger motif was reported in a family with developed myeloid malignancies.	('reported', 'Reg', (179, 187))	('myeloid malignancies', 'Disease', 'MESH:D009369', (215, 235))	('hematological malignancies', 'Phenotype', 'HP:0004377', (78, 104))	('hereditary hematological malignancies', 'Disease', (67, 104))	('myeloid malignancies', 'Disease', (215, 235))	('hereditary hematological malignancies', 'Disease', 'MESH:D019337', (67, 104))	('germline mutation within', 'Var', (122, 146))
39025	32290321	As for PRDM2 gene, a mononucleotide repeat (A7) in exon 8 of MECOM coding sequences was found to be a target for frameshift mutation (loss-of-function mutation) in colorectal cancers with MIN.	('colorectal cancer', 'Phenotype', 'HP:0003003', (164, 181))	('colorectal cancers', 'Disease', 'MESH:D015179', (164, 182))	('mononucleotide', 'Chemical', '-', (21, 35))	('colorectal cancers', 'Disease', (164, 182))	('PRDM2', 'Gene', (7, 12))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('frameshift mutation', 'Var', (113, 132))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
39026	32290321	In the same study, the authors also observed intratumor heterogeneity (an important cancer hallmark) of MECOM mutations in four of 16 analyzed cases (25%).	('MECOM', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('cancer hallmark', 'Disease', (84, 99))	('cancer hallmark', 'Disease', 'MESH:D009369', (84, 99))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
39034	32290321	PRDM5 is silenced in human breast, ovarian, and liver cancers by CpG island methylation of its promoter region.	('ovarian', 'Disease', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('breast', 'Disease', (27, 33))	('liver cancer', 'Phenotype', 'HP:0002896', (48, 60))	('human', 'Species', '9606', (21, 26))	('silenced', 'NegReg', (9, 17))	('liver cancers', 'Phenotype', 'HP:0002896', (48, 61))	('liver cancers', 'Disease', (48, 61))	('liver cancers', 'Disease', 'MESH:D006528', (48, 61))	('methylation', 'Var', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('PRDM5', 'Gene', (0, 5))
39036	32290321	Later, epigenetic PRDM5 silencing was also shown in gastric and colorectal cancers, where its ectopic expression determined a cell growth suppression.	('colorectal cancers', 'Disease', 'MESH:D015179', (64, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('colorectal cancers', 'Disease', (64, 82))	('suppression', 'NegReg', (138, 149))	('epigenetic PRDM5', 'Var', (7, 23))	('gastric', 'Disease', (52, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('silencing', 'NegReg', (24, 33))	('cell growth', 'CPA', (126, 137))
39037	32290321	Of note, PRDM5 promoter methylation was detected in both primary colorectal and gastric cancers but not in noncancerous tissue specimens collected from areas adjacent to the tumors.	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('cancerous', 'Disease', (110, 119))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (65, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('detected', 'Reg', (40, 48))	('methylation', 'Var', (24, 35))	('men', 'Species', '9606', (132, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('PRDM5', 'Gene', (9, 14))	('cancerous', 'Disease', 'MESH:D009369', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('gastric cancers', 'Phenotype', 'HP:0012126', (80, 95))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
39040	32290321	Recently, a significant PRDM5 promoter methylation was observed in BRAF mutant cancers of the serrated pathway whereas minimal levels of methylation were detected in the BRAF wild-type cancers of the traditional pathway; moreover, PRDM5 methylation was evident in a small proportion of serrated type polyps indicating that this may be an early event in tumorigenesis.	('polyps', 'Disease', (300, 306))	('serrated pathway', 'Pathway', (94, 110))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('tumor', 'Disease', (353, 358))	('mutant', 'Var', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('serrated type', 'Disease', (286, 299))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('polyps', 'Disease', 'MESH:D011127', (300, 306))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PRDM5', 'Gene', (231, 236))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('BRAF', 'Gene', '673', (170, 174))	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', (170, 174))	('PRDM5', 'Gene', (24, 29))	('serrated type polyps', 'Phenotype', 'HP:0032222', (286, 306))	('BRAF', 'Gene', (67, 71))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
39042	32290321	For example, aberrant DNA methylation reduced PRDM5 expression in about 40.5% of cervical cancers, whereas normal tissues were unmethylated.	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cervical cancers', 'Disease', (81, 97))	('PRDM5', 'Gene', (46, 51))	('cervical cancers', 'Disease', 'MESH:D002583', (81, 97))	('expression', 'MPA', (52, 62))	('aberrant DNA methylation', 'Var', (13, 37))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))
39043	32290321	Similarly, PRDM5 was frequently silenced by promoter methylation in multiple cancer cell lines and tumor specimens, including nasopharyngeal, esophageal, gastric, cervical, and hepatocellular carcinoma.	('tumor', 'Disease', (99, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('silenced', 'NegReg', (32, 40))	('men', 'Species', '9606', (110, 113))	('cancer', 'Disease', (77, 83))	('PRDM5', 'Gene', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (177, 201))	('promoter methylation', 'Var', (44, 64))	('nasopharyngeal', 'Disease', (126, 140))	('hepatocellular carcinoma', 'Disease', (177, 201))	('cervical', 'Disease', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (177, 201))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('esophageal', 'Disease', (142, 152))	('gastric', 'Disease', (154, 161))
39049	32290321	Accordingly, this concept is also supported by a study in which repression of PRDM5 function, due to deletions in its locus along with miR-182 sequence amplification, was shown to play a co-operative role in ovarian cancers.	('ovarian cancers', 'Disease', 'MESH:D010051', (208, 223))	('miR-182', 'Gene', '406958', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('ovarian cancers', 'Disease', (208, 223))	('repression', 'NegReg', (64, 74))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (208, 222))	('PRDM5', 'Gene', (78, 83))	('ovarian cancers', 'Phenotype', 'HP:0100615', (208, 223))	('deletions', 'Var', (101, 110))	('miR-182', 'Gene', (135, 142))
39055	32290321	Noteworthy, a meta-analysis of genome-wide association studies correlated a single nucleotide polymorphism in PRDM6 gene with both mammographic density and breast cancer susceptibility.	('PRDM6', 'Gene', (110, 115))	('PRDM6', 'Gene', '93166', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('single nucleotide polymorphism', 'Var', (76, 106))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('mammographic density', 'Disease', (131, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))
39059	32290321	A whole-exome sequencing analysis on a small group of pituitary adenomas revealed genetic variants in several genes, including PRDM8.	('pituitary adenomas', 'Disease', (54, 72))	('PRDM8', 'Gene', (127, 132))	('variants', 'Var', (90, 98))	('pituitary adenomas', 'Disease', 'MESH:D010911', (54, 72))	('PRDM8', 'Gene', '56978', (127, 132))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (54, 72))
39071	32290321	Indeed, meiotic recombination is crucial for accurate chromosomal disjunction and genomic stability maintenance during meiosis; likewise, homologous recombination also promotes genomic stability by repairing DSBs in cells undergoing mitosis.	('homologous recombination', 'Var', (138, 162))	('DSBs', 'Disease', (208, 212))	('meiosis', 'Disease', 'MESH:C536875', (119, 126))	('DSBs', 'Chemical', '-', (208, 212))	('promotes', 'PosReg', (168, 176))	('genomic stability', 'CPA', (177, 194))	('mitosis', 'Disease', (233, 240))	('repairing', 'NegReg', (198, 207))	('mitosis', 'Disease', 'None', (233, 240))	('meiosis', 'Disease', (119, 126))
39072	32290321	Furthermore, the two processes involve overlapping molecular machinery and comparable mechanisms whose dysregulation can often lead to diseases, including cancer.	('diseases', 'Disease', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lead to', 'Reg', (127, 134))	('dysregulation', 'Var', (103, 116))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
39078	32290321	Since PRDM9 variability has been suggested to influence genomic instability, the authors of this study argued that these rare allelic forms could be involved in the development of preleukemic clones in B-ALL patients and proposed that an altered PRDM9 function in the parental germline could lead to the genomic instability associated with childhood ALL.	('PRDM9', 'Gene', '56979', (6, 11))	('function', 'MPA', (252, 260))	('LL', 'Phenotype', 'HP:0005526', (351, 353))	('patients', 'Species', '9606', (208, 216))	('childhood ALL', 'Disease', (340, 353))	('LL', 'Phenotype', 'HP:0005526', (205, 207))	('genomic instability', 'MPA', (304, 323))	('B-ALL', 'Phenotype', 'HP:0004812', (202, 207))	('altered', 'Var', (238, 245))	('PRDM9', 'Gene', (246, 251))	('lead to', 'Reg', (292, 299))	('PRDM9', 'Gene', '56979', (246, 251))	('involved', 'Reg', (149, 157))	('PRDM9', 'Gene', (6, 11))	('men', 'Species', '9606', (172, 175))
39079	32290321	PRDM9 mutations have also been correlated with specific solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('PRDM9', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('correlated', 'Reg', (31, 41))	('PRDM9', 'Gene', '56979', (0, 5))
39080	32290321	Indeed, in a study defining a landscape of non-coding RNA (ncRNA) in the head and neck squamous cell carcinoma (HNSCC), 307 non-coding transcripts differentially expressed in HNSCC were significantly correlated with patient survival, and associated with known gene mutations and chromosome alterations, including PRDM9 mutations; particularly, piR-34736 was upregulated two-fold in HNSCC and correlated to patient survival and PRDM9 mutation.	('neck squamous cell carcinoma', 'Disease', (82, 110))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (82, 110))	('HNSCC', 'Disease', (382, 387))	('mutation', 'Var', (433, 441))	('PRDM9', 'Gene', (427, 432))	('patient', 'Species', '9606', (216, 223))	('mutations', 'Var', (319, 328))	('PRDM9', 'Gene', '56979', (427, 432))	('patient', 'Species', '9606', (406, 413))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('PRDM9', 'Gene', (313, 318))	('PRDM9', 'Gene', '56979', (313, 318))	('correlated', 'Reg', (200, 210))	('HNSCC', 'Phenotype', 'HP:0012288', (382, 387))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))	('HNSCC', 'Phenotype', 'HP:0012288', (175, 180))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (73, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('upregulated', 'PosReg', (358, 369))	('piR-34736', 'Var', (344, 353))
39081	32290321	Very recently, a mutation analysis of histone lysine methyltransferases in bladder cancer from TCGA datasets identified PRDM9 among the six genes with a potential critical role in oncogenesis and prognosis of this cancer type.	('PRDM9', 'Gene', '56979', (120, 125))	('cancer', 'Disease', (214, 220))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutation', 'Var', (17, 25))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('lysine', 'Chemical', 'MESH:D008239', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('PRDM9', 'Gene', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
39082	32290321	Noteworthy, our pan-cancer mutation analysis recognized PRDM9 as one of the most mutated genes of the PRDM family with frequencies ranging from 0.5% to 15.4% and higher than 5% in multiple cancers, such as DLBCL, HNSCC, endometrial, esophageal, stomach, and colon carcinomas, kidney and lung tumors, and melanoma.	('colon carcinomas', 'Disease', (258, 274))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('BCL', 'Phenotype', 'HP:0012191', (208, 211))	('lung tumors', 'Phenotype', 'HP:0100526', (287, 298))	('multiple cancers', 'Disease', (180, 196))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('mutation', 'Var', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('colon carcinomas', 'Disease', 'MESH:D003110', (258, 274))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('lung tumors', 'Disease', (287, 298))	('melanoma', 'Disease', 'MESH:D008545', (304, 312))	('DLBCL', 'Disease', (206, 211))	('HNSCC', 'Disease', (213, 218))	('esophageal', 'Disease', (233, 243))	('cancer', 'Disease', (20, 26))	('multiple cancers', 'Disease', 'MESH:D009369', (180, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('HNSCC', 'Phenotype', 'HP:0012288', (213, 218))	('endometrial', 'Disease', (220, 231))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('PRDM9', 'Gene', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('melanoma', 'Disease', (304, 312))	('PRDM9', 'Gene', '56979', (56, 61))	('lung tumors', 'Disease', 'MESH:D008175', (287, 298))	('stomach', 'Disease', (245, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('carcinomas', 'Phenotype', 'HP:0030731', (264, 274))
39083	32290321	In a newly published pan-cancer analysis of TCGA data the authors revealed that aberrant expression of PRDM9 was associated with an enrichment of somatic structural variants at sites of binding and activity in several cancer types, thus hypothesizing a novel mechanism underlying genomic instability during tumorigenesis based on the possibility that there are putative uncharacterized genomic features and binding sites leading to these variants.	('PRDM9', 'Gene', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('expression', 'MPA', (89, 99))	('variants', 'Var', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', (218, 224))	('men', 'Species', '9606', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('PRDM9', 'Gene', '56979', (103, 108))	('tumor', 'Disease', (307, 312))	('activity', 'MPA', (198, 206))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('binding', 'Interaction', (186, 193))	('cancer', 'Disease', (25, 31))	('aberrant', 'Var', (80, 88))	('associated', 'Reg', (113, 123))
39085	32290321	Using RNA-seq and other methodologies, analysis of 84 soft tissue sarcomas revealed that a significant subset of low-grade undifferentiated pleomorphic sarcoma (UPS) showed a gene fusion of PRDM10 either with MED12 or CITED2, suggesting that these rearrangements were specific for this less aggressive UPS subset.	('undifferentiated pleomorphic sarcoma', 'Disease', (123, 159))	('men', 'Species', '9606', (257, 260))	('aggressive UPS', 'Disease', 'MESH:D017118', (291, 305))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('CITED2', 'Gene', '10370', (218, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('gene fusion', 'Var', (175, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('MED12', 'Gene', (209, 214))	('PRDM10', 'Gene', '56980', (190, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (54, 74))	('sarcomas', 'Disease', (66, 74))	('MED12', 'Gene', '9968', (209, 214))	('PRDM10', 'Gene', (190, 196))	('aggressive UPS', 'Disease', (291, 305))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (123, 159))	('CITED2', 'Gene', (218, 224))
39089	32290321	In childhood ALL, whole-exome-sequencing and whole-genome-sequencing revealed that homozygous non-synonymous coding mutations negatively affected PRDM11 function.	('non-synonymous coding mutations', 'Var', (94, 125))	('PRDM11', 'Gene', (146, 152))	('LL', 'Phenotype', 'HP:0005526', (14, 16))	('affected', 'Reg', (137, 145))	('PRDM11', 'Chemical', '-', (146, 152))	('negatively', 'NegReg', (126, 136))	('function', 'MPA', (153, 161))
39091	32290321	Indeed, deletion of PRDM11 accelerated Myc-driven lymphomagenesis, while its overexpression induced apoptosis and delayed lymphoma onset.	('PRDM11', 'Chemical', '-', (20, 26))	('lymphoma', 'Disease', 'MESH:D008223', (50, 58))	('overexpression', 'PosReg', (77, 91))	('lymphoma', 'Disease', (122, 130))	('delayed lymphoma', 'Disease', (114, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('PRDM11', 'Gene', (20, 26))	('lymphoma', 'Disease', 'MESH:D008223', (122, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('accelerated', 'PosReg', (27, 38))	('delayed lymphoma', 'Disease', 'MESH:D008223', (114, 130))	('lymphoma', 'Disease', (50, 58))	('apoptosis', 'CPA', (100, 109))	('deletion', 'Var', (8, 16))
39096	32290321	Several studies indicated that PRDM12 might act as a tumor suppressor gene in human chronic myeloid leukemia with derivative chromosome 9 deletions or rearrangements.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (92, 108))	('chronic myeloid leukemia', 'Disease', (84, 108))	('rearrangements', 'Var', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('PRDM12', 'Gene', '59335', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PRDM12', 'Gene', (31, 37))	('deletions', 'Var', (138, 147))	('tumor', 'Disease', (53, 58))	('men', 'Species', '9606', (160, 163))	('human', 'Species', '9606', (78, 83))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (84, 108))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (84, 108))
39111	32290321	The analysis of gene copy number suggested that the mechanism could be gene amplification on chromosome 8q13, a region frequently altered in a wide variety of human tumors.	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('gene amplification', 'Var', (71, 89))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
39113	32290321	In vitro experiments showed that while ectopic PRDM14 expression enhanced cancer cell growth and resistance to chemotherapeutic drugs, PRDM14 knockdown was able to induce apoptosis and increase sensitivity to chemotherapeutic drugs.	('increase', 'PosReg', (185, 193))	('PRDM14', 'Gene', (47, 53))	('sensitivity to chemotherapeutic drugs', 'MPA', (194, 231))	('ectopic', 'Var', (39, 46))	('induce', 'PosReg', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('apoptosis', 'CPA', (171, 180))	('enhanced', 'PosReg', (65, 73))	('resistance to chemotherapeutic drugs', 'MPA', (97, 133))	('cancer', 'Disease', (74, 80))	('men', 'Species', '9606', (15, 18))	('PRDM14', 'Gene', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('knockdown', 'Var', (142, 151))
39114	32290321	More recently, in vitro and in vivo experiments were set up to ascertain whether and how PRDM14 could also confer stem cell-like properties and epigenetic changes to cancer cells.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('men', 'Species', '9606', (42, 45))	('stem cell-like properties', 'CPA', (114, 139))	('confer', 'Reg', (107, 113))	('epigenetic changes', 'Var', (144, 162))	('PRDM14', 'Gene', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
39118	32290321	PRDM14 silencing strongly reduced the stem cell phenotype and inhibited breast cancer cell line proliferation, tumorsphere formation, and suppressed cell growth in the presence of low concentrations of anticancer drugs.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('PRDM14', 'Gene', (0, 6))	('reduced', 'NegReg', (26, 33))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('silencing', 'Var', (7, 16))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', (79, 85))	('cell growth', 'CPA', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('stem cell phenotype', 'CPA', (38, 57))	('inhibited', 'NegReg', (62, 71))	('suppressed', 'NegReg', (138, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
39121	32290321	In particular, miR-424 knockdown induces cdc42 expression that in turn positively regulates PRDM14 through the activation of p-21-activated kinase 1 (pak1) and stat5 (Figure 1F).	('activation', 'PosReg', (111, 121))	('pak1', 'Gene', '5058', (150, 154))	('regulates', 'Reg', (82, 91))	('knockdown', 'Var', (23, 32))	('p-21-activated kinase 1', 'Gene', '5058', (125, 148))	('stat5', 'Gene', (160, 165))	('cdc42', 'Gene', '998', (41, 46))	('p-21-activated kinase 1', 'Gene', (125, 148))	('pak1', 'Gene', (150, 154))	('miR-424', 'Gene', '494336', (15, 22))	('cdc42', 'Gene', (41, 46))	('miR-424', 'Gene', (15, 22))	('induces', 'PosReg', (33, 40))	('stat5', 'Gene', '6776', (160, 165))	('expression', 'MPA', (47, 57))	('PRDM14', 'Gene', (92, 98))
39128	32290321	As in human ALL, mice with LL induced by Prdm14 aberrant expression showed widespread aneuploidy and copy number alterations, indicating significant chromosomal damage due to failure to activate genes involved in chromosomal stability and DNA repair pathways.	('human', 'Species', '9606', (6, 11))	('mice', 'Species', '10090', (17, 21))	('aneuploidy', 'Disease', (86, 96))	('LL', 'Phenotype', 'HP:0005526', (13, 15))	('aneuploidy', 'Disease', 'MESH:D000782', (86, 96))	('aberrant expression', 'Var', (48, 67))	('copy number alterations', 'CPA', (101, 124))	('activate', 'PosReg', (186, 194))	('Prdm14', 'Gene', (41, 47))	('LL', 'Phenotype', 'HP:0005526', (27, 29))
39136	32290321	Consistently, PRDM14 overexpression promoted cell migration through extracellular matrix degradation in a human lung cancer cell line.	('human', 'Species', '9606', (106, 111))	('overexpression', 'Var', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('cell migration', 'CPA', (45, 59))	('extracellular matrix degradation', 'CPA', (68, 100))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('PRDM14', 'Gene', (14, 20))	('promoted', 'PosReg', (36, 44))
39139	32290321	More recently, overexpression of PRDM14 was observed also in pancreatic cancer, where it could sustain cell pluripotency; indeed, PRDM14 knockdown suppressed cancer stem-like phenotypes, including liver metastasis, via miR-125a-3p regulating Fyn expression (Figure 1F).	('PRDM14', 'Gene', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('suppressed', 'NegReg', (147, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('cancer', 'Disease', (158, 164))	('knockdown', 'Var', (137, 146))	('Fyn', 'Gene', (242, 245))	('liver metastasis', 'Disease', 'MESH:D009362', (197, 213))	('Fyn', 'Gene', '2534', (242, 245))	('expression', 'MPA', (246, 256))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('liver metastasis', 'Disease', (197, 213))	('pancreatic cancer', 'Disease', (61, 78))	('cancer', 'Disease', (72, 78))
39141	32290321	Alterations of the 8q13.2 region with PRDM14 copy number gain were also found in intracranial germ cell tumors and in head and neck cancer.	('head and neck cancer', 'Disease', 'MESH:D006258', (118, 138))	('found', 'Reg', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('head and neck cancer', 'Phenotype', 'HP:0012288', (118, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PRDM14', 'Gene', (38, 44))	('tumors', 'Disease', (104, 110))	('copy number', 'Var', (45, 56))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('germ cell tumors', 'Phenotype', 'HP:0100728', (94, 110))	('gain', 'PosReg', (57, 61))
39147	32290321	Later, PRDM14 silencing was found through hypermethylation of its promoter in HPV-positive cancers, and ectopic expression of PRDM14 in HPV16-positive cancer cell lines induced apoptosis, possibly due to a direct upregulation of the pro-apoptotic genes NOXA and PUMA.	('hypermethylation', 'Var', (42, 58))	('PRDM14', 'Gene', (126, 132))	('PUMA', 'Gene', '27113', (262, 266))	('PRDM14', 'Gene', (7, 13))	('HPV-positive cancers', 'Disease', 'MESH:D030361', (78, 98))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', (151, 157))	('upregulation', 'PosReg', (213, 225))	('PUMA', 'Gene', (262, 266))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('HPV16', 'Species', '333760', (136, 141))	('HPV-positive cancers', 'Disease', (78, 98))	('NOXA', 'Gene', '5366', (253, 257))	('ectopic expression', 'Var', (104, 122))	('apoptosis', 'CPA', (177, 186))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Disease', (91, 97))	('induced', 'PosReg', (169, 176))	('NOXA', 'Gene', (253, 257))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('silencing', 'NegReg', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
39154	32290321	PRDM15 was identified as a candidate tumor suppressor gene, since localized homozygous deletions were revealed at 21q22 chromosome region in several pancreatic cancer cell lines.	('PRDM15', 'Gene', (0, 6))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('tumor', 'Disease', (37, 42))	('deletions', 'Var', (87, 96))	('pancreatic cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('PRDM15', 'Gene', '63977', (0, 6))
39163	32290321	Moreover, the aberrant expression of MEL1S/sPRDM16, associated with DNA hypomethylation, was correlated with dysregulation of TGF-beta-mediated signaling suggesting that MEL1S might be responsible for TGF-beta resistance in leukemogenesis of adult T-cell leukemia.	('TGF-beta', 'Gene', (126, 134))	('leukemogenesis of adult T-cell leukemia', 'Disease', (224, 263))	('MEL1', 'Gene', (170, 174))	('MEL1', 'Gene', '63976', (170, 174))	('leukemogenesis of adult T-cell leukemia', 'Disease', 'MESH:D015459', (224, 263))	('correlated', 'Reg', (93, 103))	('leukemia', 'Phenotype', 'HP:0001909', (255, 263))	('TGF-beta', 'Gene', '7039', (126, 134))	('MEL1', 'Gene', (37, 41))	('associated', 'Reg', (52, 62))	('TGF-beta', 'Gene', (201, 209))	('MEL1', 'Gene', '63976', (37, 41))	('aberrant', 'Var', (14, 22))	('dysregulation', 'MPA', (109, 122))	('TGF-beta', 'Gene', '7039', (201, 209))	('expression', 'MPA', (23, 33))
39167	32290321	In addition, cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion were detected in a case of progressive CML suggesting that different mechanisms of chromosomal rearrangement may occur in these malignancies.	('CML', 'Phenotype', 'HP:0005506', (154, 157))	('men', 'Species', '9606', (219, 222))	('malignancies', 'Disease', (243, 255))	('CML', 'Disease', (154, 157))	('t(1;21)(p36;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (71, 87))	('cryptic', 'Gene', '55997', (13, 20))	('RUNX1', 'Gene', (57, 62))	('PRDM16', 'Gene', (46, 52))	('cryptic', 'Gene', (13, 20))	('partial deletions', 'Var', (25, 42))	('RUNX1', 'Gene', (95, 100))	('RUNX1', 'Gene', '861', (57, 62))	('RUNX1', 'Gene', '861', (95, 100))	('detected', 'Reg', (120, 128))	('malignancies', 'Disease', 'MESH:D009369', (243, 255))
39168	32290321	Successively, additional PRDM16 translocation partners, fusion transcripts and other rearrangements have been detected in leukemia cases with a poor prognosis, most of them showing an upregulation of this gene as a common feature.	('detected', 'Reg', (110, 118))	('PRDM16', 'Gene', (25, 31))	('leukemia', 'Disease', (122, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('men', 'Species', '9606', (94, 97))	('upregulation', 'PosReg', (184, 196))	('fusion transcripts', 'Var', (56, 74))
39169	32290321	Actually, several studies have established that high PRDM16 expression is independently associated with adverse outcomes in both adult and pediatric AML patients.	('expression', 'MPA', (60, 70))	('AML', 'Disease', (149, 152))	('AML', 'Phenotype', 'HP:0004808', (149, 152))	('patients', 'Species', '9606', (153, 161))	('PRDM16', 'Gene', (53, 59))	('AML', 'Disease', 'MESH:D015470', (149, 152))	('high', 'Var', (48, 52))	('associated with', 'Reg', (88, 103))
39174	32290321	The mouse model of conditional Prdm16 deletion elucidated the role of these two isoforms in normal and leukemic hematopoiesis and identified sPrdm16 as one of the drivers of prognostically adverse inflammation in leukemia.	('leukemic hematopoiesis', 'Disease', (103, 125))	('mouse', 'Species', '10090', (4, 9))	('inflammation', 'Disease', 'MESH:D007249', (197, 209))	('leukemia', 'Disease', (213, 221))	('leukemia', 'Phenotype', 'HP:0001909', (213, 221))	('leukemia', 'Disease', 'MESH:D007938', (213, 221))	('inflammation', 'Disease', (197, 209))	('leukemic hematopoiesis', 'Disease', 'MESH:C536227', (103, 125))	('Prdm16', 'Gene', (31, 37))	('deletion', 'Var', (38, 46))
39175	32290321	To date, rearrangements of the chromosomal region encompassing PRDM16 have been observed not only in hematopoietic malignancies but also in several solid tumors though with different and/or conflicting results, which altogether indicate this gene may function as both oncogene and tumor suppressor gene.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('PRDM16', 'Gene', (63, 69))	('observed', 'Reg', (80, 88))	('men', 'Species', '9606', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('rearrangements', 'Var', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('malignancies', 'Disease', (115, 127))	('tumor', 'Disease', (281, 286))	('tumor', 'Disease', (154, 159))
39176	32290321	For instance, genome-wide array based comparative genomic hybridization (array-CGH) defined distinct amplifications in osteosarcoma, involving PRDM16.	('osteosarcoma', 'Disease', 'MESH:D012516', (119, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('amplifications', 'Var', (101, 115))	('osteosarcoma', 'Disease', (119, 131))	('osteosarcoma', 'Phenotype', 'HP:0002669', (119, 131))	('PRDM16', 'Gene', (143, 149))
39177	32290321	Otherwise, array-CGH integrated with gene expression analysis of leiomyosarcoma revealed a frequent loss at 1p36, which contains PRDM16, suggesting that this defect could promote muscle differentiation in this context.	('p36', 'Gene', (109, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (65, 79))	('p36', 'Gene', '51251', (109, 112))	('promote', 'PosReg', (171, 178))	('leiomyosarcoma', 'Disease', (65, 79))	('muscle differentiation', 'CPA', (179, 201))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (65, 79))	('defect', 'Var', (158, 164))	('loss', 'NegReg', (100, 104))	('PRDM16', 'Gene', (129, 135))
39178	32290321	Similarly, integrated analysis of uterine leiomyosarcoma revealed PRDM16 deletions and/or reduced expression.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('reduced', 'NegReg', (90, 97))	('PRDM16', 'Gene', (66, 72))	('deletions', 'Var', (73, 82))	('leiomyosarcoma', 'Disease', (42, 56))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (34, 56))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (42, 56))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (42, 56))	('expression', 'MPA', (98, 108))
39184	32290321	A possible role as a tumor suppressor gene has been proposed in lung cancer where PRDM16 is aberrantly methylated and its expression is low or absent.	('PRDM16', 'Gene', (82, 88))	('lung cancer', 'Disease', (64, 75))	('absent', 'NegReg', (143, 149))	('expression', 'MPA', (122, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('tumor', 'Disease', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('aberrantly methylated', 'Var', (92, 113))	('low', 'NegReg', (136, 139))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
39185	32290321	Accordingly, the median overall survival of both non-small cell lung cancer and LUAD patients with high levels of PRDM16 was significantly longer than that of cases with low levels of this gene.	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('longer', 'PosReg', (139, 145))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PRDM16', 'Gene', (114, 120))	('patients', 'Species', '9606', (85, 93))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (49, 75))	('high levels', 'Var', (99, 110))	('non-small cell lung cancer', 'Disease', (49, 75))
39190	32290321	Altogether, these findings indicate that PRDM16 methylation status, both hypermethylation and hypomethylation, is often affected in distinct cancers, where this gene can play alternatively a role as an oncogene or as a tumor suppressor gene.	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('PRDM16', 'Gene', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('hypermethylation', 'Var', (73, 89))	('tumor', 'Disease', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('affected', 'Reg', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('hypomethylation', 'MPA', (94, 109))	('methylation', 'Var', (48, 59))	('cancers', 'Disease', (141, 148))
39192	32290321	Additionally, PRDM16 is highly overexpressed also in atypical teratoid/rhabdoid tumor, a highly malignant brain tumor predominantly arising in infants; moreover, it could have a functional role in human rhabdoid tumor cells since PRDM16 knockdown resulted in reduced metabolic activity and proliferation.	('rhabdoid tumor', 'Disease', 'MESH:D018335', (71, 85))	('rhabdoid tumor', 'Disease', (71, 85))	('PRDM16', 'Gene', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('infants', 'Species', '9606', (143, 150))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (203, 217))	('brain tumor', 'Phenotype', 'HP:0030692', (106, 117))	('malignant brain tumor', 'Disease', 'MESH:D001932', (96, 117))	('malignant brain tumor', 'Disease', (96, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('metabolic activity', 'CPA', (267, 285))	('proliferation', 'CPA', (290, 303))	('reduced', 'NegReg', (259, 266))	('knockdown', 'Var', (237, 246))	('rhabdoid tumor', 'Disease', (203, 217))	('human', 'Species', '9606', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))
39200	32290321	Moreover, knockdown of ciRS-133 reduced cancer cachexia in tumor-implanted mice, decreasing oxygen consumption and heat production.	('oxygen consumption', 'MPA', (92, 110))	('mice', 'Species', '10090', (75, 79))	('tumor', 'Disease', (59, 64))	('ciRS-133 reduced cancer cachexia', 'Disease', (23, 55))	('decreasing', 'NegReg', (81, 91))	('heat production', 'MPA', (115, 130))	('cachexia', 'Phenotype', 'HP:0004326', (47, 55))	('ciRS-133 reduced cancer cachexia', 'Disease', 'MESH:D002100', (23, 55))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))	('knockdown', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
39202	32290321	Our TCGA analysis found that PRDM16 gene was mutated in about 6-7% of DLBCL and it was frequently altered in many cases of skin cutaneous melanoma (7.8%) and endometrial carcinoma (5.6%).	('endometrial carcinoma', 'Disease', 'MESH:D016889', (158, 179))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('BCL', 'Phenotype', 'HP:0012191', (72, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('skin cutaneous melanoma', 'Disease', (123, 146))	('endometrial carcinoma', 'Disease', (158, 179))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (158, 179))	('PRDM16', 'Gene', (29, 35))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (128, 146))	('DLBCL', 'Disease', (70, 75))	('altered', 'Reg', (98, 105))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (123, 146))	('mutated', 'Var', (45, 52))
39222	32290321	Moreover, high expression of ZFPM1 was related with good prognosis of LUAD through the analysis of RNA-seq, DNA methylation, and miRNA-seq data of squamous cell cancer samples downloaded from TCGA.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('related', 'Reg', (39, 46))	('LUAD', 'Disease', (70, 74))	('LUAD', 'Phenotype', 'HP:0030078', (70, 74))	('expression', 'MPA', (15, 25))	('squamous cell cancer', 'Disease', (147, 167))	('high', 'Var', (10, 14))	('ZFPM1', 'Gene', (29, 34))	('squamous cell cancer', 'Disease', 'MESH:D002294', (147, 167))	('ZFPM1', 'Gene', '161882', (29, 34))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (147, 167))
39224	32290321	Indeed, our pan-cancer analysis revealed ZFPM1/FOG1 mutation occurrence in about 50% of ACC patients.	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('ZFPM1', 'Gene', (41, 46))	('patients', 'Species', '9606', (92, 100))	('ACC', 'Disease', (88, 91))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('ZFPM1', 'Gene', '161882', (41, 46))	('mutation', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
39225	32290321	Interestingly, these mutations were localized in a hotspot region and OncodriveCLUST results suggested it could be putatively considered a cancer driver gene in this malignancy.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('malignancy', 'Disease', 'MESH:D009369', (166, 176))	('cancer', 'Disease', (139, 145))	('malignancy', 'Disease', (166, 176))	('mutations', 'Var', (21, 30))
39226	32290321	These results were confirmed by a complete analysis of the mutational data of ACC, which was performed on the same public database and validated through further algorithms (Mutsig and 20/20 rule); this study identified a new ACC-specific gene mutation signature, also comprising ZFPM1 among the six genes.	('ACC', 'Phenotype', 'HP:0006744', (225, 228))	('mutation', 'Var', (243, 251))	('ACC-specific', 'Disease', (225, 237))	('ZFPM1', 'Gene', (279, 284))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('ZFPM1', 'Gene', '161882', (279, 284))
39227	32290321	In addition, in our analysis we found that ZFPM1 is mutated also in colorectal cancers at relatively high frequencies.	('colorectal cancers', 'Disease', 'MESH:D015179', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutated', 'Var', (52, 59))	('colorectal cancers', 'Disease', (68, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('ZFPM1', 'Gene', '161882', (43, 48))	('ZFPM1', 'Gene', (43, 48))
39234	32290321	It is known that GATA3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation; FOG2 was shown to act during mammary development even though the consequences of Gata3 gene ablation in murine models were more severe than that of Fog2, whose excision induced premature mammary gland involution.	('induced', 'Reg', (283, 290))	('murine', 'Species', '10090', (218, 224))	('Fog2', 'Gene', '22762', (262, 266))	('Fog2', 'Gene', (262, 266))	('gene', 'Var', (201, 205))	('Gata3', 'Gene', (195, 200))	('Gata3', 'Gene', '14462', (195, 200))	('men', 'Species', '9606', (158, 161))
39238	32290321	Bioinformatics analysis of microarray data and genotyping of a ZFPM2 polymorphism indicated its possible role in glioma and glioblastoma.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('polymorphism', 'Var', (69, 81))	('ZFPM2', 'Gene', (63, 68))	('role', 'Reg', (105, 109))	('glioma', 'Disease', (113, 119))	('glioblastoma', 'Disease', (124, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))
39245	32290321	Indeed, we found that, after PRDM9, ZFPM2/FOG2 was the most mutated PRDM gene with pan-cancer frequencies of protein-affecting mutations higher than 1%; specifically, we detected mutation frequencies higher than 5% in patients with skin cutaneous melanoma, lung tumors, uterine carcinosarcoma, esophageal carcinoma, and stomach and rectum adenocarcinomas.	('skin cutaneous melanoma', 'Disease', (232, 255))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (344, 353))	('PRDM9', 'Gene', (29, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (344, 354))	('mutation', 'Var', (179, 187))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('PRDM9', 'Gene', '56979', (29, 34))	('lung tumors', 'Disease', (257, 268))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (294, 314))	('sarcoma', 'Phenotype', 'HP:0100242', (285, 292))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (270, 292))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (237, 255))	('mutations', 'Var', (127, 136))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (232, 255))	('cancer', 'Disease', (87, 93))	('rectum adenocarcinomas', 'Disease', 'MESH:D012004', (332, 354))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('carcinosarcoma', 'Disease', (278, 292))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (294, 314))	('carcinosarcoma', 'Disease', 'MESH:D002296', (278, 292))	('lung tumors', 'Disease', 'MESH:D008175', (257, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('lung tumors', 'Phenotype', 'HP:0100526', (257, 268))	('esophageal carcinoma', 'Disease', (294, 314))	('rectum adenocarcinomas', 'Disease', (332, 354))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
39250	32290321	In this scenario, being involved in a multitude of pathways regulating several cancer-related processes, ranging from cell metabolism to stemness, the pharmacological control of PRDM epigenetic modulators represent a potential multi-target approach in cancer therapy (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (252, 258))	('epigenetic modulators', 'Var', (183, 204))	('PRDM', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
39251	32290321	A hallmark of cancer is the genomic instability that accounts for the increase in mutation frequency.	('cancer', 'Disease', (14, 20))	('increase', 'PosReg', (70, 78))	('mutation', 'Var', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('genomic', 'MPA', (28, 35))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
39255	32290321	For instance, PRDM2a/RIZ1 was shown to counteract the IGF-1 receptor and the downstream components ERK1/2 and AKT (Figure 3B).	('AKT', 'Gene', (110, 113))	('IGF-1', 'Gene', '3479', (54, 59))	('IGF-1', 'Gene', (54, 59))	('ERK1/2', 'Gene', '5595;5594', (99, 105))	('ERK1/2', 'Gene', (99, 105))	('PRDM2a/RIZ1', 'Var', (14, 25))	('AKT', 'Gene', '207', (110, 113))
39279	32290321	PRDM14 knockdown decreased cancer stem-like phenotypes through upregulation of miR-125a-3p that subsequently downregulated Fyna mechanism that is reported to regulate tumor phenotypes in pancreatic cancer (Figure 1F).	('Fyn', 'Gene', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (187, 204))	('PRDM14', 'Gene', (0, 6))	('upregulation', 'PosReg', (63, 75))	('decreased', 'NegReg', (17, 26))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('pancreatic cancer', 'Disease', 'MESH:D010190', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', (167, 172))	('Fyn', 'Gene', '2534', (123, 126))	('miR-125a-3p', 'Gene', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('pancreatic cancer', 'Disease', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('downregulated', 'NegReg', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Disease', (27, 33))	('knockdown', 'Var', (7, 16))
39287	32290321	Indeed, its silencing in breast cancer cells reduces cancer stem cells phenotype and tumorsphere formation (Table 1 and Figure 1).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (32, 38))	('reduces', 'NegReg', (45, 52))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('silencing', 'Var', (12, 21))	('breast cancer', 'Disease', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
39291	32290321	MAGL blockade impairs migration, invasiveness, and tumorigenicity in aggressive human cancer.	('blockade', 'Var', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MAGL', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (51, 56))	('invasiveness', 'CPA', (33, 45))	('migration', 'CPA', (22, 31))	('impairs', 'NegReg', (14, 21))	('human', 'Species', '9606', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancer', 'Disease', (86, 92))
39296	32290321	Additionally, since some PRDMs (e.g., PRDM1, 9, 11, 14, 16) are able to orchestrate the differentiation of B and T lymphocytes, their involvement in the control of a more incisive immune response to neoplasia cannot be excluded.	('PRDM1', 'Var', (38, 43))	('neoplasia', 'Phenotype', 'HP:0002664', (199, 208))	('men', 'Species', '9606', (141, 144))	('neoplasia', 'Disease', 'MESH:D009369', (199, 208))	('neoplasia', 'Disease', (199, 208))	('PRDMs', 'Chemical', '-', (25, 30))
39298	32290321	Currently, as reported for other families, many studies have highlighted the consequences of aberrant isoform expression in triggering tumorigenesis and drug resistance, suggesting that dysregulation of alternative transcription may be a key mechanism leading to cancer progression and drug resistance.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Disease', (263, 269))	('tumor', 'Disease', (135, 140))	('drug resistance', 'CPA', (286, 301))	('leading', 'Reg', (252, 259))	('drug resistance', 'CPA', (153, 168))	('aberrant', 'Var', (93, 101))	('drug resistance', 'Phenotype', 'HP:0020174', (153, 168))	('drug resistance', 'Phenotype', 'HP:0020174', (286, 301))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('dysregulation', 'Var', (186, 199))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
39300	32190803	IDH1 Expression via the R132H Mutation-Specific Antibody in Adrenocortical Neoplasias:Prognostic Impact in Carcinomas Mutations to isocitrate dehydrogenase (IDH) appear to play a prognostic or predictive role in several neoplasias.	('Adrenocortical Neoplasias', 'Disease', (60, 85))	('neoplasias', 'Phenotype', 'HP:0002664', (220, 230))	('neoplasias', 'Disease', (220, 230))	('IDH1', 'Gene', (0, 4))	('Carcinomas', 'Disease', (107, 117))	('IDH', 'Gene', (0, 3))	('isocitrate dehydrogenase', 'Gene', '3417', (131, 155))	('R132H', 'Mutation', 'rs121913500', (24, 29))	('Adrenocortical Neoplasias', 'Disease', 'MESH:D009369', (60, 85))	('Carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('IDH1', 'Gene', '3417', (0, 4))	('IDH', 'Gene', (157, 160))	('IDH', 'Gene', '3417', (0, 3))	('neoplasias', 'Disease', 'MESH:D009369', (220, 230))	('Neoplasias', 'Phenotype', 'HP:0002664', (75, 85))	('Mutations', 'Var', (118, 127))	('isocitrate dehydrogenase', 'Gene', (131, 155))	('IDH', 'Gene', '3417', (157, 160))	('Carcinomas', 'Disease', 'MESH:D002277', (107, 117))
39301	32190803	Immunohistochemical staining designed to detect a specific R132H mutation to IDH1 showed expression in the normal adrenal cortex, raising interest to study the potential role of IDH1 in the pathogenesis of adrenocortical tumors.	('expression', 'MPA', (89, 99))	('R132H', 'Mutation', 'rs121913500', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (206, 227))	('IDH1', 'Gene', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('adrenocortical tumors', 'Disease', (206, 227))	('R132H', 'Var', (59, 64))
39307	32190803	We were unable to identify IDH1 mutations among our adrenocortical tumors using a targeted next-generation sequencing panel or via exon sequencing.	('adrenocortical tumors', 'Disease', (52, 73))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (52, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mutations', 'Var', (32, 41))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('IDH1', 'Gene', (27, 31))
39308	32190803	Among adrenocortical carcinomas, IDH1 R132H immunopositivity correlated with a better prognosis.	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (6, 30))	('R132H', 'Mutation', 'rs121913500', (38, 43))	('adrenocortical carcinomas', 'Disease', (6, 31))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (6, 31))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (6, 31))	('IDH1 R132H', 'Var', (33, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))
39315	32190803	Mutations of IDH isoforms 1 and 2 were first identified in gliomas, and have since been reported in several neoplasias.	('IDH', 'Gene', '3417', (13, 16))	('identified', 'Reg', (45, 55))	('Mutations', 'Var', (0, 9))	('neoplasias', 'Disease', 'MESH:D009369', (108, 118))	('reported', 'Reg', (88, 96))	('neoplasias', 'Phenotype', 'HP:0002664', (108, 118))	('neoplasias', 'Disease', (108, 118))	('gliomas', 'Disease', (59, 66))	('IDH', 'Gene', (13, 16))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
39316	32190803	The mutated form of IDH gains neomorphic activity, resulting in the conversion of alpha-ketoglutarate to an oncometabolite, D-2-hydroxyglutarate.	('mutated', 'Var', (4, 11))	('IDH', 'Gene', (20, 23))	('D-2-hydroxyglutarate', 'MPA', (124, 144))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (124, 144))	('IDH', 'Gene', '3417', (20, 23))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (82, 101))	('gains', 'PosReg', (24, 29))	('conversion of alpha-ketoglutarate', 'MPA', (68, 101))	('neomorphic activity', 'CPA', (30, 49))
39319	32190803	IDH mutations occur in most lower-grade gliomas and secondary glioblastomas, indicative of a distinctive pathogenesis and a better prognosis compared to primary glioblastomas.	('IDH', 'Gene', (0, 3))	('glioblastomas', 'Phenotype', 'HP:0012174', (161, 174))	('occur', 'Reg', (14, 19))	('IDH', 'Gene', '3417', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('glioblastomas', 'Disease', 'MESH:D005909', (161, 174))	('glioblastomas', 'Phenotype', 'HP:0012174', (62, 75))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('glioblastomas', 'Disease', (161, 174))	('glioblastomas', 'Disease', 'MESH:D005909', (62, 75))	('mutations', 'Var', (4, 13))	('glioblastomas', 'Disease', (62, 75))
39320	32190803	A specific R132H mutation to IDH1 accompanies approximately 80% of all IDH mutations in gliomas, and can be depicted from formalin-fixed, paraffin-embedded (FFPE) tissues through immunohistochemistry using an antibody against the mutated protein.	('R132H', 'Var', (11, 16))	('paraffin', 'Chemical', 'MESH:D010232', (138, 146))	('R132H', 'Mutation', 'rs121913500', (11, 16))	('gliomas', 'Disease', (88, 95))	('formalin', 'Chemical', 'MESH:D005557', (122, 130))	('IDH', 'Gene', (29, 32))	('IDH', 'Gene', (71, 74))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('mutations', 'Var', (75, 84))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('IDH', 'Gene', '3417', (29, 32))	('IDH', 'Gene', '3417', (71, 74))
39321	32190803	In adrenocortical tumors, IDH1 and IDH2 mutations have thus far remained unreported.	('IDH2', 'Gene', '3418', (35, 39))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (3, 24))	('IDH1', 'Gene', (26, 30))	('mutations', 'Var', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('adrenocortical tumors', 'Disease', (3, 24))	('IDH2', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
39323	32190803	This finding piqued our interest in examining the IDH1 R132H expression in adrenocortical tumors.	('IDH1', 'Gene', (50, 54))	('R132H', 'Var', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('R132H', 'Mutation', 'rs121913500', (55, 60))	('adrenocortical tumors', 'Disease', (75, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (75, 96))
39333	32190803	To identify mutations of IDH1 at Arg132 using amplicon-based hot spot panel sequencing, we chose 10 tumors with Weiss scores of 3 to 9, 5 of which exhibited strong positive and 5 exhibited negative IDH1 R132H immunohistochemical staining (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('R132H', 'Mutation', 'rs121913500', (203, 208))	('mutations', 'Var', (12, 21))	('tumors', 'Disease', (100, 106))	('negative', 'NegReg', (189, 197))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('to 9', 'Species', '1214577', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('IDH1', 'Gene', (25, 29))	('Arg132', 'Chemical', '-', (33, 39))
39334	32190803	For IDH1 gene sequencing from the FFPE tumor material, we chose an additional 10 tumors, 5 tumors with Weiss scores of 0 to 2 with positive IDH1 R132H immunohistochemistry, and 5 tumors with Weiss scores of 3 to 9 with low positivity.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('R132H', 'Mutation', 'rs121913500', (145, 150))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('to 9', 'Species', '1214577', (209, 213))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('R132H', 'Var', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('IDH1', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumors', 'Disease', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Disease', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (179, 184))
39349	32190803	The intensity of the cytoplasmic staining of IDH1 R132H, that is the amount of positively staining granules, was scored on a scale from 0 to 3.	('IDH1', 'Gene', (45, 49))	('R132H', 'Mutation', 'rs121913500', (50, 55))	('R132H', 'Var', (50, 55))
39354	32190803	DNA was subjected to library preparation using the Ion AmpliSeq Cancer Hotspot Panel version 2, designed to target 2800 COSMIC mutations from 50 oncogenes and tumor suppressor genes, and sequenced on the Ion Torrent PGM System (Thermo Fisher Scientific).	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Disease', (159, 164))	('mutations', 'Var', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
39364	32190803	In histologically malignant tumors (Weiss score 3-9), the IDH1 R132H staining (negative vs positive) correlated with the Helsinki score (< 8.5 vs >= 8.5; R2 = -0.437, P = .012).	('R132H', 'Var', (63, 68))	('R132H', 'Mutation', 'rs121913500', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('Helsinki score', 'Disease', (121, 135))	('malignant tumors', 'Disease', (18, 34))	('malignant tumors', 'Disease', 'MESH:D009369', (18, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('IDH1', 'Gene', (58, 62))
39365	32190803	Aldosterone secretion of the tumor correlated with a weak IDH1 R132H staining (R2 = -0.163, P = .023), whereas cortisol secretion correlated with a strong IDH1 R132H staining (R2 = 0.243, P = .001).	('IDH1 R132H', 'Var', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('R132H', 'Mutation', 'rs121913500', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Aldosterone secretion', 'MPA', (0, 21))	('cortisol secretion', 'MPA', (111, 129))	('tumor', 'Disease', (29, 34))	('weak', 'NegReg', (53, 57))	('R132H', 'Mutation', 'rs121913500', (160, 165))
39366	32190803	We found no correlation between the IDH1 R132H staining and testosterone secretion (R2 = 0.071, P = .326) or with hormonal inactivity (R2 = -0.132, P = .066).	('IDH1', 'Gene', (36, 40))	('R132H', 'Var', (41, 46))	('R132H', 'Mutation', 'rs121913500', (41, 46))	('testosterone secretion', 'MPA', (60, 82))	('testosterone', 'Chemical', 'MESH:D013739', (60, 72))
39368	32190803	Patients with a positive IDH1 R132H staining survived longer than patients with a negative staining (P = .031; Fig.	('R132H', 'Var', (30, 35))	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', (25, 29))	('R132H', 'Mutation', 'rs121913500', (30, 35))	('patients', 'Species', '9606', (66, 74))
39369	32190803	The data analysis of the hot-spot mutations revealed no mutations in the IDH1 or IDH2 genes, with a sensitivity of 2%.	('mutations', 'Var', (56, 65))	('IDH2', 'Gene', (81, 85))	('IDH2', 'Gene', '3418', (81, 85))	('IDH1', 'Gene', (73, 77))	('mutations', 'Var', (34, 43))
39370	32190803	In a large cohort of adrenocortical tumors, we found that mutation-specific IDH1 R132H immunopositivity correlated with a better prognosis among adrenocortical carcinoma patients, suggesting a distinct pathogenic pathway among these tumors.	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (145, 169))	('R132H', 'Mutation', 'rs121913500', (81, 86))	('better', 'PosReg', (122, 128))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (145, 169))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (21, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('adrenocortical carcinoma', 'Disease', (145, 169))	('patients', 'Species', '9606', (170, 178))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('R132H', 'Var', (81, 86))	('adrenocortical tumors', 'Disease', (21, 42))	('tumors', 'Disease', (36, 42))	('IDH1', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (36, 42))
39371	32190803	However, IDH1 R132H immunohistochemistry did not correlate with the prognostic scoring systems used for adrenocortical tumors, such as the Weiss score or the Helsinki score, nor did it distinguish between local and metastasized disease.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('metastasized disease', 'Disease', (215, 235))	('adrenocortical tumors', 'Disease', (104, 125))	('R132H', 'Mutation', 'rs121913500', (14, 19))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (104, 125))	('IDH1', 'Var', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('metastasized disease', 'Disease', 'MESH:D009362', (215, 235))
39372	32190803	However, through genetic analysis, we failed to identify any known or novel IDH1 mutations in our adrenocortical tumor cohort.	('IDH1', 'Gene', (76, 80))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (98, 118))	('adrenocortical tumor', 'Disease', (98, 118))	('mutations', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
39373	32190803	The IDH1 R132H antibody used for the immunohistochemical staining was developed to specifically recognize the R132H mutated form of the IDH1 protein, the most frequent mutation seen in secondary glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (195, 208))	('R132H', 'Var', (110, 115))	('glioblastomas', 'Disease', 'MESH:D005909', (195, 208))	('IDH1', 'Gene', (136, 140))	('R132H', 'Mutation', 'rs121913500', (9, 14))	('R132H', 'Mutation', 'rs121913500', (110, 115))	('glioblastomas', 'Disease', (195, 208))
39374	32190803	These most often occur at codon 132 by replacing arginine with another amino acid.	('occur', 'Reg', (17, 22))	('replacing', 'Var', (39, 48))	('arginine', 'MPA', (49, 57))	('arginine', 'Chemical', 'MESH:D001120', (49, 57))
39376	32190803	This mutation-specific antibody does not detect other mutated forms of IDH1, such as R132S, R132C, R132G, or R132L, nor does it bind to or cross-react with wild-type IDH1.	('bind', 'Interaction', (128, 132))	('R132G', 'Mutation', 'rs121913499', (99, 104))	('R132S', 'Mutation', 'rs121913499', (85, 90))	('R132C', 'Mutation', 'rs121913499', (92, 97))	('IDH1', 'Gene', (71, 75))	('R132L', 'Mutation', 'rs121913500', (109, 114))	('R132G', 'Var', (99, 104))	('R132L', 'Var', (109, 114))	('R132S', 'Var', (85, 90))	('R132C', 'Var', (92, 97))
39377	32190803	We found only one study that reported any positivity in tumor cells using the IDH1 R132H antibody in tumors negative for the R132H mutation through DNA sequencing.	('R132H', 'Var', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('R132H', 'Mutation', 'rs121913500', (83, 88))	('IDH1', 'Gene', (78, 82))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('R132H', 'Mutation', 'rs121913500', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumors', 'Disease', (101, 107))
39378	32190803	Amary and colleagues studied IDH1 and 2 mutations in cartilaginous tumors, finding 5 R132H immunopositive tumors in which the mutation remained undetected through sequencing.	('R132H', 'Mutation', 'rs121913500', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('cartilaginous tumors', 'Disease', 'MESH:D015831', (53, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cartilaginous tumors', 'Disease', (53, 73))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('IDH1 and 2', 'Gene', '3417;3418', (29, 39))	('R132H', 'Var', (85, 90))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
39379	32190803	They assumed that the amount and proportion of tumor cell DNA in the sample was too low for sequencing, concluding that the IDH1 R132H immunohistochemical staining was, in fact, more sensitive in identifying the mutation than sequencing.	('mutation', 'Var', (212, 220))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('R132H', 'Mutation', 'rs121913500', (129, 134))	('tumor', 'Disease', (47, 52))
39381	32190803	Furthermore, we observed a granular cytosolic staining similar to that in IDH1 R132H-mutated gliomas, although less intensive.	('gliomas', 'Disease', (93, 100))	('gliomas', 'Disease', 'MESH:D005910', (93, 100))	('R132H', 'Mutation', 'rs121913500', (79, 84))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('IDH1', 'Gene', (74, 78))	('R132H-mutated', 'Var', (79, 92))
39382	32190803	To verify the specific R132H mutation of IDH1in these tumors, we performed a next-generation sequencing mutational analysis of codon 132, but failed to detect any of the previously reported mutations.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('IDH1in', 'Gene', (41, 47))	('R132H', 'Var', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('R132H', 'Mutation', 'rs121913500', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
39386	32190803	Mutated IDH offers a distinct target for specific, individualized therapies.	('IDH', 'Gene', (8, 11))	('Mutated', 'Var', (0, 7))	('IDH', 'Gene', '3417', (8, 11))
39388	32190803	Binding of the IDH1 R132H antibody to a proportion of adrenocortical tumors indicates that the new IDH-targeted therapies could benefit this subset of tumor patients.	('IDH', 'Gene', '3417', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('R132H', 'Mutation', 'rs121913500', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (151, 156))	('adrenocortical tumors', 'Disease', (54, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('patients', 'Species', '9606', (157, 165))	('IDH', 'Gene', (15, 18))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (54, 75))	('IDH', 'Gene', '3417', (15, 18))	('IDH', 'Gene', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('R132H', 'Var', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
39392	32190803	One weakness of our study stems from our inability to identify the epitope that the IDH1 R132H antibody binds to in adrenocortical tumors.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (116, 137))	('R132H', 'Mutation', 'rs121913500', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('IDH1', 'Gene', (84, 88))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('adrenocortical tumors', 'Disease', (116, 137))	('R132H', 'Var', (89, 94))
39393	32190803	In conclusion, among adrenocortical carcinomas, IDH1 R132H immunopositivity correlated with a better prognosis.	('adrenocortical carcinomas', 'Disease', (21, 46))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (21, 46))	('IDH1 R132H', 'Var', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (21, 46))	('R132H', 'Mutation', 'rs121913500', (53, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (21, 45))
39397	32051792	In this study, we focused on the pathological and radiological properties of nonfunctional AI(NFAI) and the association with malignancy risk in our clinical series.	('AI', 'Disease', 'MESH:C538238', (96, 98))	('malignancy', 'Disease', 'MESH:D009369', (125, 135))	('malignancy', 'Disease', (125, 135))	('nonfunctional', 'Var', (77, 90))	('AI', 'Disease', 'MESH:C538238', (91, 93))
39415	32051792	These statements recommend adrenalectomy for tumors that are hypersecretory, are >4-6 cm in size, or have suspicious radiological signs (e.g., irregular borders, heterogeneity, hemorrhage, central necrosis, or calcification).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('heterogeneity', 'CPA', (162, 175))	('central', 'Disease', (189, 196))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('calcification', 'Disease', (210, 223))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('necrosis', 'Disease', (197, 205))	('hemorrhage', 'Disease', (177, 187))	('irregular', 'Var', (143, 152))	('hemorrhage', 'Disease', 'MESH:D006470', (177, 187))	('necrosis', 'Disease', 'MESH:D009336', (197, 205))	('calcification', 'Disease', 'MESH:D002114', (210, 223))
39477	31949384	Most of the malignant thrombus had a SUVmax of >6.0, and in our case also, SUVmax of 7.6 was suggestive of a malignant tumor thrombus.	('malignant tumor thrombus', 'Disease', (109, 133))	('malignant thrombus', 'Disease', (12, 30))	('malignant thrombus', 'Disease', 'MESH:D013927', (12, 30))	('malignant tumor thrombus', 'Disease', 'MESH:D013927', (109, 133))	('SUVmax', 'MPA', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('SUVmax', 'Var', (75, 81))
39479	29872083	Comprehensive analysis of CTNNB1 in adrenocortical carcinomas: Identification of novel mutations and correlation to survival The Wnt/beta-Catenin signaling pathway is one of the most frequently altered pathways in adrenocortical carcinomas (ACCs).	('CTNNB1', 'Gene', (26, 32))	('ACCs', 'Phenotype', 'HP:0006744', (241, 245))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (214, 239))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (36, 61))	('adrenocortical carcinomas', 'Disease', (214, 239))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('CTNNB1', 'Gene', '1499', (26, 32))	('adrenocortical carcinomas', 'Disease', (36, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (229, 239))	('altered', 'Reg', (194, 201))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (214, 239))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (36, 61))	('ACC', 'Phenotype', 'HP:0006744', (241, 244))	('mutations', 'Var', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
39481	29872083	Mutations in APC, CTNNB1, ZNRF3 and homozygous deletions in ZNRF3 were observed in 3.8% (2/52), 11.5% (6/52), 1.9% (1/52) and 17.3% (9/52) of the cohort respectively.	('CTNNB1', 'Gene', '1499', (18, 24))	('deletions', 'Var', (47, 56))	('APC', 'Gene', (13, 16))	('ZNRF3', 'Gene', '84133', (60, 65))	('ZNRF3', 'Gene', '84133', (26, 31))	('APC', 'Gene', '324', (13, 16))	('observed', 'Reg', (71, 79))	('ZNRF3', 'Gene', (26, 31))	('ZNRF3', 'Gene', (60, 65))	('Mutations', 'Var', (0, 9))	('CTNNB1', 'Gene', (18, 24))
39482	29872083	Novel interstitial deletions in CTNNB1 spanning intron 1 to exon 3/intron 3 were also found in 7.7% (4/52) of the tumours.	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('found', 'Reg', (86, 91))	('tumours', 'Disease', (114, 121))	('CTNNB1', 'Gene', '1499', (32, 38))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('deletions', 'Var', (19, 28))	('CTNNB1', 'Gene', (32, 38))
39483	29872083	Nuclear accumulation of beta-Catenin, increased expression of Cyclin D1 and significantly higher expression of AXIN2 (p = 0.0039), ZNRF3 (p = 0.0032) and LEF1(p = 0.0090) observed in the tumours harbouring the deletion in comparison to tumours without CTNNB1 mutation demonstrates that the truncated beta-Catenin is functionally active and erroneously activates the downstream targets.	('tumours', 'Disease', 'MESH:D009369', (187, 194))	('truncated', 'Var', (290, 299))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('AXIN2', 'Gene', (111, 116))	('beta-Catenin', 'Protein', (24, 36))	('Nuclear accumulation', 'MPA', (0, 20))	('expression', 'MPA', (48, 58))	('beta-Catenin', 'Protein', (300, 312))	('Cyclin D1', 'Gene', '595', (62, 71))	('expression', 'MPA', (97, 107))	('Cyclin D1', 'Gene', (62, 71))	('tumours', 'Disease', (236, 243))	('CTNNB1', 'Gene', '1499', (252, 258))	('AXIN2', 'Gene', '8313', (111, 116))	('ZNRF3', 'Gene', '84133', (131, 136))	('deletion', 'Var', (210, 218))	('higher', 'PosReg', (90, 96))	('ZNRF3', 'Gene', (131, 136))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))	('tumours', 'Phenotype', 'HP:0002664', (236, 243))	('tumours', 'Disease', 'MESH:D009369', (236, 243))	('activates', 'PosReg', (352, 361))	('tumours', 'Disease', (187, 194))	('tumour', 'Phenotype', 'HP:0002664', (236, 242))	('increased', 'PosReg', (38, 47))	('CTNNB1', 'Gene', (252, 258))
39484	29872083	Significantly lower overall survival rate in patients with tumours harbouring alterations in APC/CTNNB1/ZNRF3 in comparison to those without mutation was observed.	('ZNRF3', 'Gene', (104, 109))	('lower', 'NegReg', (14, 19))	('CTNNB1', 'Gene', '1499', (97, 103))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('APC', 'Gene', (93, 96))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('alterations', 'Var', (78, 89))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('patients', 'Species', '9606', (45, 53))	('ZNRF3', 'Gene', '84133', (104, 109))	('CTNNB1', 'Gene', (97, 103))	('APC', 'Gene', '324', (93, 96))	('tumours', 'Disease', (59, 66))	('overall survival', 'MPA', (20, 36))
39485	29872083	In conclusion, the discovery of novel large deletions in addition to the point mutations in CTNNB1 infers that activation of Wnt/beta-Catenin pathway via alterations in CTNNB1 occurs frequently in ACCs.	('activation', 'PosReg', (111, 121))	('CTNNB1', 'Gene', (92, 98))	('ACC', 'Phenotype', 'HP:0006744', (197, 200))	('Wnt/beta-Catenin pathway', 'Pathway', (125, 149))	('CTNNB1', 'Gene', '1499', (169, 175))	('CTNNB1', 'Gene', '1499', (92, 98))	('ACCs', 'Phenotype', 'HP:0006744', (197, 201))	('alterations', 'Var', (154, 165))	('CTNNB1', 'Gene', (169, 175))
39486	29872083	We also confirm that alterations in Wnt/beta-Catenin signaling pathway members have a negative effect on overall survival of patients.	('overall survival', 'CPA', (105, 121))	('negative', 'NegReg', (86, 94))	('Wnt/beta-Catenin signaling pathway', 'Pathway', (36, 70))	('alterations', 'Var', (21, 32))	('patients', 'Species', '9606', (125, 133))
39494	29872083	Mutations in exon 3 of the CTNNB1 gene (encoding beta-Catenin) causing loss of serine/threonine residues are the most frequent mechanism of an erroneously activated Wnt/beta-Catenin signaling pathway.	('Wnt/beta-Catenin signaling pathway', 'Pathway', (165, 199))	('threonine', 'Chemical', 'MESH:D013912', (86, 95))	('serine/threonine residues', 'MPA', (79, 104))	('serine', 'Chemical', 'MESH:D012694', (79, 85))	('Mutations', 'Var', (0, 9))	('CTNNB1', 'Gene', (27, 33))	('loss', 'NegReg', (71, 75))	('CTNNB1', 'Gene', '1499', (27, 33))
39497	29872083	CTNNB1 mutations have been observed in approximately 10-15% of ACCs, although aberrant activation of Wnt/beta-Catenin signaling is observed in a much higher proportion of ACC tumours, most of them are not caused by known CTNNB1 mutations.	('CTNNB1', 'Gene', '1499', (0, 6))	('activation', 'PosReg', (87, 97))	('ACC tumours', 'Disease', 'MESH:D004476', (171, 182))	('ACCs', 'Phenotype', 'HP:0006744', (63, 67))	('CTNNB1', 'Gene', '1499', (221, 227))	('CTNNB1', 'Gene', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (175, 182))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('ACC', 'Phenotype', 'HP:0006744', (63, 66))	('ACCs', 'Disease', (63, 67))	('observed', 'Reg', (27, 35))	('ACC', 'Phenotype', 'HP:0006744', (171, 174))	('ACC tumours', 'Disease', (171, 182))	('Wnt/beta-Catenin signaling', 'MPA', (101, 127))	('CTNNB1', 'Gene', (221, 227))	('mutations', 'Var', (7, 16))
39498	29872083	Recent pan-genomic studies of ACCs have shown that alterations in other members of Wnt/beta-Catenin signaling pathway such as ZNRF3 and APC could also lead to activation of the pathway.	('activation', 'PosReg', (159, 169))	('alterations', 'Var', (51, 62))	('ACCs', 'Phenotype', 'HP:0006744', (30, 34))	('APC', 'Gene', (136, 139))	('Wnt/beta-Catenin signaling pathway', 'Pathway', (83, 117))	('ZNRF3', 'Gene', '84133', (126, 131))	('ZNRF3', 'Gene', (126, 131))	('ACC', 'Phenotype', 'HP:0006744', (30, 33))	('APC', 'Gene', '324', (136, 139))
39499	29872083	Furthermore, benign adrenal tumours with aberrant beta-Catenin nuclear accumulation have been associated with a larger size and malignant adrenal tumours with aberrant beta-Catenin nuclear accumulation defined poor prognosis.	('malignant adrenal tumours', 'Disease', (128, 153))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('aberrant', 'Var', (41, 49))	('malignant adrenal tumours', 'Disease', 'MESH:D000310', (128, 153))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('benign adrenal tumours', 'Disease', (13, 35))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('benign adrenal tumours', 'Disease', 'MESH:D000310', (13, 35))	('beta-Catenin', 'Protein', (50, 62))
39501	29872083	We also describe novel interstitial deletions in CTNNB1 and their functional impact in ACCs.	('ACC', 'Phenotype', 'HP:0006744', (87, 90))	('deletions', 'Var', (36, 45))	('CTNNB1', 'Gene', '1499', (49, 55))	('ACCs', 'Phenotype', 'HP:0006744', (87, 91))	('impact', 'Reg', (77, 83))	('CTNNB1', 'Gene', (49, 55))	('ACCs', 'Disease', (87, 91))
39502	29872083	We have screened 61 tumours originating from 52 patients for mutations in members of Wnt/beta-catenin signaling pathway; APC, AXIN2, CTNNB1, and ZNRF3.	('AXIN2', 'Gene', (126, 131))	('AXIN2', 'Gene', '8313', (126, 131))	('CTNNB1', 'Gene', (133, 139))	('tumours', 'Disease', 'MESH:D009369', (20, 27))	('beta-catenin', 'Gene', '1499', (89, 101))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (61, 70))	('APC', 'Gene', (121, 124))	('tumours', 'Phenotype', 'HP:0002664', (20, 27))	('patients', 'Species', '9606', (48, 56))	('ZNRF3', 'Gene', '84133', (145, 150))	('CTNNB1', 'Gene', '1499', (133, 139))	('APC', 'Gene', '324', (121, 124))	('beta-catenin', 'Gene', (89, 101))	('tumours', 'Disease', (20, 27))	('ZNRF3', 'Gene', (145, 150))
39503	29872083	Mutations in APC, CTNNB1, and ZNRF3 genes were found in two, six and one sample respectively whereas none of the analyzed samples harboured any mutations in AXIN2.	('AXIN2', 'Gene', (157, 162))	('CTNNB1', 'Gene', '1499', (18, 24))	('APC', 'Gene', (13, 16))	('ZNRF3', 'Gene', '84133', (30, 35))	('AXIN2', 'Gene', '8313', (157, 162))	('APC', 'Gene', '324', (13, 16))	('ZNRF3', 'Gene', (30, 35))	('found', 'Reg', (47, 52))	('Mutations', 'Var', (0, 9))	('CTNNB1', 'Gene', (18, 24))
39504	29872083	One of the APC mutations was germline, c.4666_4667insA (p.T1556NfsTer3), and the other was a somatic mutation, c.4391_4394del (p.E1464GfsTer8) (Supplementary Fig.	('APC', 'Gene', (11, 14))	('c.4666_4667insA', 'Mutation', 'rs1114167560', (39, 54))	('c.4391_4394del', 'Var', (111, 125))	('APC', 'Gene', '324', (11, 14))	('p.E1464G', 'Var', (127, 135))	('p.T1556N', 'SUBSTITUTION', 'None', (56, 64))	('p.E1464G', 'SUBSTITUTION', 'None', (127, 135))	('p.T1556N', 'Var', (56, 64))	('c.4666_4667insA', 'Var', (39, 54))	('c.4391_4394del', 'Mutation', 'c.4391_4394del', (111, 125))
39505	29872083	The patient with the tumour harbouring somatic mutation, c.4391_4394del, also harboured a 16.6 kb large germline duplication spanning over exon 2 and 3.	('c.4391_4394del', 'Mutation', 'c.4391_4394del', (57, 71))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('patient', 'Species', '9606', (4, 11))	('tumour', 'Disease', (21, 27))	('c.4391_4394del', 'Var', (57, 71))
39506	29872083	Missense mutations in exon 3 of CTNNB1, c.133T > C (p.S45P), c.104T > A (p.I35N), c.136C > A (p.S45Y), c.109C > G (p.S37C), c.105G > A (p.G34R) and c.134C > T (p.S45F) were found in 6 individual tumours (Supplementary Fig.	('p.S45Y', 'Mutation', 'rs121913409', (94, 100))	('p.S45P', 'Mutation', 'rs121913407', (52, 58))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('p.I35N', 'Mutation', 'p.I35N', (73, 79))	('p.G34R', 'Mutation', 'rs121913399', (136, 142))	('c.133T > C', 'Var', (40, 50))	('c.105G > A', 'Var', (124, 134))	('CTNNB1', 'Gene', '1499', (32, 38))	('p.S45F', 'Mutation', 'rs121913409', (160, 166))	('p.S37C', 'Mutation', 'rs121913403', (115, 121))	('c.104T > A', 'Mutation', 'c.104T>A', (61, 71))	('c.109C > G', 'Mutation', 'rs121913403', (103, 113))	('c.109C > G', 'Var', (103, 113))	('CTNNB1', 'Gene', (32, 38))	('c.136C > A', 'Mutation', 'rs121913409', (82, 92))	('c.136C > A', 'Var', (82, 92))	('c.134C > T', 'Var', (148, 158))	('c.104T > A', 'Var', (61, 71))	('c.105G > A', 'Mutation', 'rs121913399', (124, 134))	('c.133T > C', 'Mutation', 'rs121913407', (40, 50))	('c.134C > T', 'Mutation', 'rs121913409', (148, 158))	('tumours', 'Disease', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
39507	29872083	All the observed mutations in CTNNB1 occurred in established hotspot residues.	('CTNNB1', 'Gene', '1499', (30, 36))	('occurred', 'Reg', (37, 45))	('mutations', 'Var', (17, 26))	('CTNNB1', 'Gene', (30, 36))
39508	29872083	A novel missense mutation, c.646C > T (p.H216Y), was found in ZNRF3 (Supplementary Fig.	('c.646C > T', 'Var', (27, 37))	('ZNRF3', 'Gene', '84133', (62, 67))	('c.646C > T', 'Mutation', 'rs369470752', (27, 37))	('p.H216Y', 'Mutation', 'rs369470752', (39, 46))	('ZNRF3', 'Gene', (62, 67))
39509	29872083	S2), and in silico analysis using Polyphen-2, SIFT and PROVEAN predicted these mutations as deleterious (Supplementary Table S1).	('SIFT', 'Disease', 'None', (46, 50))	('SIFT', 'Disease', (46, 50))	('mutations', 'Var', (79, 88))
39510	29872083	Allele comparison of the SNP (rs11564435) in CTNNB1 found in our cohort showed similar allele frequency (chi2 = 2.0517, P = 0.1520) to that of European subpopulations.	('CTNNB1', 'Gene', '1499', (45, 51))	('rs11564435', 'Var', (30, 40))	('rs11564435', 'Mutation', 'rs11564435', (30, 40))	('CTNNB1', 'Gene', (45, 51))
39511	29872083	cDNA-specific PCR amplification using primers spanning exon 1 to 6 of CTNNB1 was performed on cDNA of all 61 ACC tumours to identify deletions spanning exon 3.	('CTNNB1', 'Gene', '1499', (70, 76))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('deletions', 'Var', (133, 142))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('ACC tumours', 'Disease', (109, 120))	('CTNNB1', 'Gene', (70, 76))	('ACC tumours', 'Disease', 'MESH:D004476', (109, 120))
39513	29872083	Sanger sequencing of gel-excised and purified products revealed a mutation r.-48_241del leading to deletion of the entire exon 2 and 3 (here forth called  (2 + 3) deletion) in all four samples (Supplementary Fig.	('deletion', 'MPA', (99, 107))	('r.-48_241del leading', 'Var', (75, 95))	('r.-48_241del', 'Mutation', 'r.-48_241del', (75, 87))
39514	29872083	If such exclusion was caused by genomic deletion, the exclusion of exon 2 and 3 of CTNNB1 could be caused by deletions occurring anywhere from intron 1 to intron 3.	('CTNNB1', 'Gene', '1499', (83, 89))	('CTNNB1', 'Gene', (83, 89))	('deletions', 'Var', (109, 118))
39518	29872083	The other three tumours, ACC18, 21 and 37, harboured deletion mutations g.41217632_g.41224675del ( 7044 bp), g.41220754_g.41224725delinsA ( 3972 bp) and g.41218557_g.	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('g.41224675del', 'Var', (83, 96))	('tumours', 'Disease', (16, 23))	('g.41224675del', 'DELETION', 'None', (83, 96))	('g.41224725del', 'DELETION', 'None', (120, 133))	('ACC', 'Phenotype', 'HP:0006744', (25, 28))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('g.41218557_g', 'Var', (153, 165))	('g.41224725del', 'Var', (120, 133))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))
39519	29872083	The deletions in all four tumours occurred at overlapping loci (Fig.	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumours', 'Disease', (26, 33))	('deletions', 'Var', (4, 13))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
39521	29872083	Deletion of exon 2 and 3 eliminates the natural transcription start site of CTNNB1.	('CTNNB1', 'Gene', '1499', (76, 82))	('natural transcription start site', 'MPA', (40, 72))	('eliminates', 'NegReg', (25, 35))	('CTNNB1', 'Gene', (76, 82))	('Deletion', 'Var', (0, 8))
39523	29872083	Exclusion of exon 2 and 3 leads to partial deletion of the N-terminal, which harbours GSK3beta, CK1 phosphorylation and beta-TrCP recognition sites (Supplementary Fig S4).	('GSK3beta', 'Gene', (86, 94))	('beta-TrCP', 'Gene', '8945', (120, 129))	('GSK3beta', 'Gene', '2932', (86, 94))	('CK1', 'Species', '2498238', (96, 99))	('partial deletion', 'Var', (35, 51))	('beta-TrCP', 'Gene', (120, 129))
39524	29872083	Analysis of Cyclin D1 protein expression showed significantly higher expression (p = 0.0095) in the samples with the deletion in comparison to analyzed tumours without CTNNB1 mutation (Fig.	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('tumours', 'Disease', (152, 159))	('Cyclin D1', 'Gene', '595', (12, 21))	('CTNNB1', 'Gene', (168, 174))	('Cyclin D1', 'Gene', (12, 21))	('expression', 'MPA', (69, 79))	('higher', 'PosReg', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('CTNNB1', 'Gene', '1499', (168, 174))	('deletion', 'Var', (117, 125))
39525	29872083	mRNA expression analyses revealed high expression levels of AXIN2 and LEF1 in samples harbouring CTNNB1 mutations and deletions.	('mutations', 'Var', (104, 113))	('AXIN2', 'Gene', '8313', (60, 65))	('CTNNB1', 'Gene', '1499', (97, 103))	('deletions', 'Var', (118, 127))	('expression levels', 'MPA', (39, 56))	('CTNNB1', 'Gene', (97, 103))	('AXIN2', 'Gene', (60, 65))	('LEF1', 'Gene', (70, 74))
39526	29872083	The expression of AXIN2 and LEF1 was significantly higher in tumours harbouring a  (2 + 3) deletion in comparison to those without mutations in analyzed genes (ACC wildtype (n = 39) vs  (2 + 3) deletion (n = 4), p = 0.0039 and p = 0.0090 respectively) and was comparable to the tumours harbouring CTNNB1 missense mutations (ACC wildtype (n = 39) vs CTNNB1 mutants (n = 5), p = 0.0211 and p = 0.0451 respectively; Fig.	('missense mutations', 'Var', (304, 322))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('expression', 'MPA', (4, 14))	('LEF1', 'Gene', (28, 32))	('CTNNB1', 'Gene', (297, 303))	('AXIN2', 'Gene', '8313', (18, 23))	('ACC', 'Phenotype', 'HP:0006744', (160, 163))	('CTNNB1', 'Gene', '1499', (349, 355))	('ACC', 'Phenotype', 'HP:0006744', (324, 327))	('tumours', 'Disease', (278, 285))	('deletion', 'Var', (91, 99))	('tumour', 'Phenotype', 'HP:0002664', (278, 284))	('tumours', 'Phenotype', 'HP:0002664', (278, 285))	('higher', 'PosReg', (51, 57))	('tumours', 'Disease', 'MESH:D009369', (278, 285))	('CTNNB1', 'Gene', (349, 355))	('AXIN2', 'Gene', (18, 23))	('CTNNB1', 'Gene', '1499', (297, 303))	('tumours', 'Disease', (61, 68))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
39527	29872083	Expression levels of ZNRF3 mRNA were significantly higher in tumours harbouring the  (2 + 3) deletion (p = 0.0032) and missense mutations (p = 0.0210) in comparison to those without CTNNB1 mutations (Fig.	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('missense mutations', 'Var', (119, 137))	('CTNNB1', 'Gene', (182, 188))	('Expression levels', 'MPA', (0, 17))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('ZNRF3', 'Gene', '84133', (21, 26))	('ZNRF3', 'Gene', (21, 26))	('tumours', 'Disease', (61, 68))	('higher', 'PosReg', (51, 57))	('CTNNB1', 'Gene', '1499', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
39528	29872083	A trend towards higher expression of Cyclin D1 mRNA was observed in samples harbouring CTNNB1 mutations and deletions in comparison to those without but did not reach statistical significance (Supplementary Fig.	('higher', 'PosReg', (16, 22))	('mutations', 'Var', (94, 103))	('CTNNB1', 'Gene', '1499', (87, 93))	('Cyclin D1', 'Gene', '595', (37, 46))	('Cyclin D1', 'Gene', (37, 46))	('deletions', 'Var', (108, 117))	('CTNNB1', 'Gene', (87, 93))	('expression', 'MPA', (23, 33))
39529	29872083	GISTIC analysis of SNP array data (n = 52) showed significant deletions occurring at ZNRF3 locus (q < 0.01).	('ZNRF3', 'Gene', '84133', (85, 90))	('deletions', 'Var', (62, 71))	('ZNRF3', 'Gene', (85, 90))
39531	29872083	Analysis of SNP array data from recurrent tumours available for 4/9 cases with ZNRF3 deletion in the primary tumour showed presence of ZNRF3 deletion in all four recurrent tumours.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('ZNRF3', 'Gene', '84133', (79, 84))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Disease', (109, 115))	('tumour', 'Disease', (172, 178))	('ZNRF3', 'Gene', (79, 84))	('ZNRF3', 'Gene', '84133', (135, 140))	('ZNRF3', 'Gene', (135, 140))	('tumours', 'Disease', (42, 49))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', (42, 48))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('deletion', 'Var', (141, 149))	('deletion', 'Var', (85, 93))	('tumours', 'Disease', (172, 179))	('tumours', 'Phenotype', 'HP:0002664', (172, 179))	('tumours', 'Disease', 'MESH:D009369', (172, 179))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
39532	29872083	The deletions found in ZNRF3 were mutually exclusive to APC, CTNNB1 and ZNRF3 mutations.	('CTNNB1', 'Gene', (61, 67))	('ZNRF3', 'Gene', (23, 28))	('deletions', 'Var', (4, 13))	('mutations', 'Var', (78, 87))	('ZNRF3', 'Gene', '84133', (72, 77))	('CTNNB1', 'Gene', '1499', (61, 67))	('APC', 'Gene', (56, 59))	('ZNRF3', 'Gene', (72, 77))	('APC', 'Gene', '324', (56, 59))	('ZNRF3', 'Gene', '84133', (23, 28))
39533	29872083	Samples with ZNRF3 deletions showed significantly lower expression of ZNRF3 (p = 0.0001) and higher expression of AXIN2 (p = 0.0274) and LEF1 (0.0081) in comparison to the samples devoid of mutations in investigated genes (Supplementary Fig.	('higher', 'PosReg', (93, 99))	('lower', 'NegReg', (50, 55))	('LEF1', 'Gene', (137, 141))	('ZNRF3', 'Gene', '84133', (13, 18))	('ZNRF3', 'Gene', (13, 18))	('expression', 'MPA', (100, 110))	('expression', 'MPA', (56, 66))	('AXIN2', 'Gene', (114, 119))	('AXIN2', 'Gene', '8313', (114, 119))	('ZNRF3', 'Gene', '84133', (70, 75))	('ZNRF3', 'Gene', (70, 75))	('deletions', 'Var', (19, 28))
39535	29872083	In ACCs without any CTNNB1 mutation (n = 51), 15 samples harboured loss, nine harboured gain, 11 harboured copy neutral loss of heterozygosity (cnLOH), five harboured loss with allelic imbalance whereas 11 were diploid at the CTNNB1 locus 3p22.1 (Supplementary Fig.	('ACCs', 'Phenotype', 'HP:0006744', (3, 7))	('CTNNB1', 'Gene', (226, 232))	('CTNNB1', 'Gene', (20, 26))	('imbalance', 'Phenotype', 'HP:0002172', (185, 194))	('mutation', 'Var', (27, 35))	('loss', 'NegReg', (167, 171))	('loss', 'NegReg', (67, 71))	('CTNNB1', 'Gene', '1499', (20, 26))	('gain', 'PosReg', (88, 92))	('ACC', 'Phenotype', 'HP:0006744', (3, 6))	('CTNNB1', 'Gene', '1499', (226, 232))	('loss of heterozygosity', 'NegReg', (120, 142))
39536	29872083	Amongst tumours with CTNNB1 missense mutation, one harboured gain and three harboured cnLOH.	('missense mutation', 'Var', (28, 45))	('tumours', 'Disease', (8, 15))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('CTNNB1', 'Gene', (21, 27))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('CTNNB1', 'Gene', '1499', (21, 27))	('gain', 'PosReg', (61, 65))	('tumours', 'Disease', 'MESH:D009369', (8, 15))
39537	29872083	Out of the four tumours harbouring a CTNNB1  (2 + 3) deletion, two harboured gain and one harboured cnLOH (Supplementary Fig.	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('tumours', 'Disease', (16, 23))	('deletion', 'Var', (53, 61))	('CTNNB1', 'Gene', '1499', (37, 43))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('gain', 'PosReg', (77, 81))	('CTNNB1', 'Gene', (37, 43))
39540	29872083	Both tumours with APC mutation and all six tumours harbouring beta-Catenin missense mutations showed expression of active beta-Catenin at varied levels.	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('missense mutations', 'Var', (75, 93))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('tumours', 'Disease', (5, 12))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('APC', 'Gene', (18, 21))	('tumours', 'Disease', (43, 50))	('APC', 'Gene', '324', (18, 21))	('active beta-Catenin', 'MPA', (115, 134))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('beta-Catenin', 'Gene', (62, 74))
39542	29872083	Hence quantification of active beta-Catenin for four tumours harbouring the  (2 + 3) deletion was not possible due to the lack of epitope.	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('deletion', 'Var', (85, 93))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))
39544	29872083	Amongst the analyzed samples harbouring ZNRF3 alterations (8 deletions and 1 mutation), only three samples showed expression of the active beta-Catenin.	('ZNRF3', 'Gene', '84133', (40, 45))	('deletions', 'Var', (61, 70))	('ZNRF3', 'Gene', (40, 45))	('alterations', 'Var', (46, 57))	('expression', 'MPA', (114, 124))
39547	29872083	Nuclear expression of beta-Catenin was observed in all six tumours harbouring beta-Catenin missense mutations and in 3/4 tumours harbouring the  (2 + 3) deletion (Supplementary Table S7).	('missense mutations', 'Var', (91, 109))	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('beta-Catenin', 'Protein', (78, 90))	('tumours', 'Disease', (121, 128))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('observed', 'Reg', (39, 47))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('Nuclear expression', 'MPA', (0, 18))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('tumours', 'Disease', (59, 66))
39548	29872083	Hence on the basis of beta-Catenin mutation and corresponding nuclear expression status, the tumours could be divided into tumours (1) with CTNNB1 mutation and nuclear expression (n = 9), (2) with CTNNB1 mutation but without nuclear expression (n = 1), (3) with wildtype CTNNB1 and without nuclear expression (n = 23) and (4) with wildtype CTNNB1 and nuclear expression (n = 16) (Figs 4 and S10 and S11).	('CTNNB1', 'Gene', (197, 203))	('mutation', 'Var', (204, 212))	('CTNNB1', 'Gene', (140, 146))	('mutation', 'Var', (147, 155))	('S10', 'Gene', '6204', (391, 394))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('CTNNB1', 'Gene', (340, 346))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('CTNNB1', 'Gene', '1499', (271, 277))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('S11', 'Gene', '6267', (399, 402))	('S10', 'Gene', (391, 394))	('CTNNB1', 'Gene', (271, 277))	('CTNNB1', 'Gene', '1499', (197, 203))	('CTNNB1', 'Gene', '1499', (140, 146))	('CTNNB1', 'Gene', '1499', (340, 346))	('tumours', 'Disease', (93, 100))	('S11', 'Gene', (399, 402))	('tumours', 'Disease', (123, 130))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumours', 'Disease', 'MESH:D009369', (93, 100))
39549	29872083	Amongst 16 CTNNB1 wildtype tumours with the presence of nuclear accumulation, five harboured ZNRF3 deletion and one harboured APC mutation.	('CTNNB1', 'Gene', '1499', (11, 17))	('APC', 'Gene', (126, 129))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('APC', 'Gene', '324', (126, 129))	('CTNNB1', 'Gene', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('ZNRF3', 'Gene', '84133', (93, 98))	('deletion', 'Var', (99, 107))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumours', 'Disease', (27, 34))	('ZNRF3', 'Gene', (93, 98))
39557	29872083	Median age at operation and tumour size for the group of tumours with APC/CTNNB1/ZNRF3 alterations were 52.5 years and 10 cm respectively and were not significantly different from those without mutations (46 yrs, p = 0.3517, and 10 cm, p = 0.5731; Supplementary Fig.	('ZNRF3', 'Gene', '84133', (81, 86))	('tumour', 'Disease', (57, 63))	('CTNNB1', 'Gene', (74, 80))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('alterations', 'Var', (87, 98))	('ZNRF3', 'Gene', (81, 86))	('CTNNB1', 'Gene', '1499', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('tumours', 'Disease', (57, 64))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('APC', 'Gene', (70, 73))	('tumour', 'Disease', (28, 34))	('APC', 'Gene', '324', (70, 73))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
39558	29872083	There were no significant differences in any analyzed clinical parameters between groups of tumours with and without APC/CTNNB1/ZNRF3 alterations, nuclear beta-Catenin expression or active beta-Catenin expression (Supplemental Table S8).	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('CTNNB1', 'Gene', '1499', (121, 127))	('ZNRF3', 'Gene', (128, 133))	('nuclear beta-Catenin expression', 'MPA', (147, 178))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('CTNNB1', 'Gene', (121, 127))	('APC', 'Gene', (117, 120))	('alterations', 'Var', (134, 145))	('APC', 'Gene', '324', (117, 120))	('ZNRF3', 'Gene', '84133', (128, 133))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('active beta-Catenin expression', 'MPA', (182, 212))
39560	29872083	The median overall survival rate for patients with a tumour harbouring APC/CTNNB1/ZNRF3 alteration was significantly lower compared to the ones without (43 vs 114 months, log rank p = 0.0141, Fig.	('CTNNB1', 'Gene', (75, 81))	('APC', 'Gene', '324', (71, 74))	('ZNRF3', 'Gene', '84133', (82, 87))	('ZNRF3', 'Gene', (82, 87))	('tumour', 'Disease', (53, 59))	('patients', 'Species', '9606', (37, 45))	('lower', 'NegReg', (117, 122))	('CTNNB1', 'Gene', '1499', (75, 81))	('APC', 'Gene', (71, 74))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('alteration', 'Var', (88, 98))
39562	29872083	Univariate analysis on the cohort based on the mutational status of APC/CTNNB1/ZNRF3 also showed a significant prognostic value (Supplementary Table S9) in the entire cohort (HR = 2.493, P = 0.013) as well as in adult ACCs (HR = 2.481, P = 0.014).	('adult ACCs', 'Disease', (212, 222))	('APC', 'Gene', (68, 71))	('APC', 'Gene', '324', (68, 71))	('ZNRF3', 'Gene', '84133', (79, 84))	('ACC', 'Phenotype', 'HP:0006744', (218, 221))	('CTNNB1', 'Gene', (72, 78))	('ZNRF3', 'Gene', (79, 84))	('mutational status', 'Var', (47, 64))	('ACCs', 'Phenotype', 'HP:0006744', (218, 222))	('prognostic value', 'Reg', (111, 127))	('CTNNB1', 'Gene', '1499', (72, 78))
39564	29872083	The median overall survival rate for patients with tumours harbouring CTNNB1 mutations and deletions alone was significantly lower compared to the ones without (12.5 vs 77 months, log rank p = 0.0331, Fig.	('CTNNB1', 'Gene', '1499', (70, 76))	('patients', 'Species', '9606', (37, 45))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('mutations', 'Var', (77, 86))	('lower', 'NegReg', (125, 130))	('CTNNB1', 'Gene', (70, 76))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('tumours', 'Disease', (51, 58))
39565	29872083	The difference in disease-free survival between the group of patients with and without CTNNB1 mutations alone did not reach statistical significance (8 vs 41 months, log rank p = 0.1148, Supplementary Fig.	('CTNNB1', 'Gene', '1499', (87, 93))	('patients', 'Species', '9606', (61, 69))	('CTNNB1', 'Gene', (87, 93))	('mutations', 'Var', (94, 103))
39567	29872083	Mutations and deletions in genes involved in the Wnt/beta-Catenin signaling pathway are observed in approximately 40% of ACCs and mutations in CTNNB1 alone accounts for up to 15% of studied tumours.	('ACC', 'Phenotype', 'HP:0006744', (121, 124))	('tumours', 'Disease', 'MESH:D009369', (190, 197))	('tumours', 'Disease', (190, 197))	('CTNNB1', 'Gene', (143, 149))	('ACCs', 'Phenotype', 'HP:0006744', (121, 125))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (130, 139))	('deletions', 'Var', (14, 23))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('ACCs', 'Disease', (121, 125))	('CTNNB1', 'Gene', '1499', (143, 149))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))
39568	29872083	Missense mutations or deletions in/of exon 3 affecting serine/threonine phosphorylation sites of beta-Catenin have been observed in these types of tumours and were observed in 11.5% of our cohort.	('threonine', 'Chemical', 'MESH:D013912', (62, 71))	('deletions', 'Var', (22, 31))	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('observed', 'Reg', (120, 128))	('affecting', 'Reg', (45, 54))	('serine/threonine phosphorylation sites', 'MPA', (55, 93))	('serine', 'Chemical', 'MESH:D012694', (55, 61))	('tumours', 'Disease', (147, 154))	('tumours', 'Disease', 'MESH:D009369', (147, 154))	('beta-Catenin', 'Protein', (97, 109))	('Missense mutations', 'Var', (0, 18))
39570	29872083	To our knowledge, such interstitial deletions leading to skipping of exon 2 and 3 have not been reported in adrenal tumours.	('skipping of exon 2', 'MPA', (57, 75))	('deletions', 'Var', (36, 45))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('adrenal tumours', 'Disease', (108, 123))	('adrenal tumours', 'Disease', 'MESH:D000310', (108, 123))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
39571	29872083	Deletion of exon 2 and 3 in CTNNB1 was previously observed in one melanoma cell line and in one malignant melanoma.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('observed', 'Reg', (50, 58))	('malignant melanoma', 'Phenotype', 'HP:0002861', (96, 114))	('CTNNB1', 'Gene', '1499', (28, 34))	('CTNNB1', 'Gene', (28, 34))	('malignant melanoma', 'Disease', (96, 114))	('malignant melanoma', 'Disease', 'MESH:D008545', (96, 114))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('Deletion', 'Var', (0, 8))
39572	29872083	Whole genome sequencing allowed us to map interstitial deletions spanning intron 1 to exon 3/intron3 of CTNNB1.	('CTNNB1', 'Gene', (104, 110))	('CTNNB1', 'Gene', '1499', (104, 110))	('deletions', 'Var', (55, 64))
39573	29872083	Interestingly, deletions occurred at similar regions in all four tumours leading to deletion of exon 2 and either whole (n = 1/4) or fractions of exon 3 (n = 3/4).	('deletion', 'Var', (84, 92))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('exon 2', 'Gene', (96, 102))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('tumours', 'Disease', (65, 72))
39574	29872083	Despite deletion of exon 2 carrying the transcription start site, and complete exclusion of exon 3, expression of an in-frame truncated protein was observed in all four tumours.	('tumours', 'Disease', (169, 176))	('expression', 'MPA', (100, 110))	('deletion', 'Var', (8, 16))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('tumours', 'Disease', 'MESH:D009369', (169, 176))
39579	29872083	Constitutively active beta-Catenin occurring via deletion of exon 3 alone was shown to induce adrenal hyperplasia in female mice, which had advanced to cancer in some cases.	('cancer', 'Disease', (152, 158))	('adrenal hyperplasia', 'Disease', (94, 113))	('exon 3', 'Gene', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('beta-Catenin', 'Protein', (22, 34))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (94, 113))	('induce', 'Reg', (87, 93))	('mice', 'Species', '10090', (124, 128))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (94, 113))	('deletion', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
39581	29872083	Such N-terminally deleted beta-Catenin, lacking the first 86 and 89 amino acids ( N86 and  N89 beta-Catenin) was shown to cause increased LEF1 mediated transcription in vitro and increased proliferation, apoptosis and decreased migration in mouse intestinal epithelial cells.	('lacking', 'NegReg', (40, 47))	('N89', 'Var', (91, 94))	('proliferation', 'CPA', (189, 202))	('beta-Catenin', 'Protein', (26, 38))	('mouse', 'Species', '10090', (241, 246))	('increased', 'PosReg', (128, 137))	('migration', 'CPA', (228, 237))	('transcription', 'MPA', (152, 165))	('increased LEF1', 'Phenotype', 'HP:0030269', (128, 142))	('LEF1', 'Gene', (138, 142))	('decreased', 'NegReg', (218, 227))	('increased', 'PosReg', (179, 188))	('apoptosis', 'CPA', (204, 213))
39582	29872083	N89 beta-Catenin expression in mouse mammary glands was shown to cause development of aggressive adenocarcinomas in 100% of the studied female mice.	('aggressive adenocarcinomas', 'Disease', 'MESH:D000230', (86, 112))	('mouse', 'Species', '10090', (31, 36))	('beta-Catenin', 'Protein', (4, 16))	('cause', 'Reg', (65, 70))	('N89', 'Var', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('aggressive adenocarcinomas', 'Disease', (86, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('mice', 'Species', '10090', (143, 147))
39583	29872083	Immunohistochemical analysis of the tumours with mutant beta-Catenin showed nuclear and cytoplasmic accumulation of beta-Catenin in all but one tumour with the  (2 + 3) deletion.	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('mutant', 'Var', (49, 55))	('tumour', 'Disease', (36, 42))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('tumours', 'Disease', (36, 43))	('tumour', 'Disease', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('beta-Catenin', 'Protein', (56, 68))
39584	29872083	An absence of nuclear accumulation of beta-Catenin in adrenocortical tumours harbouring activating beta-Catenin mutations has been observed before.	('adrenocortical tumours', 'Disease', 'MESH:D000306', (54, 76))	('adrenocortical tumours', 'Disease', (54, 76))	('mutations', 'Var', (112, 121))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('activating', 'PosReg', (88, 98))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('nuclear accumulation', 'MPA', (14, 34))
39588	29872083	Our findings of high expression of Cyclin D1 and significantly higher expression of AXIN2, LEF1 and ZNRF3 mRNA in tumours harbouring the  (2 + 3) deletion at a similar level to those with hot spot mutations suggest the activating nature of these deleterious mutations in ACCs.	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('deletion', 'Var', (146, 154))	('Cyclin D1', 'Gene', (35, 44))	('tumours', 'Disease', (114, 121))	('LEF1', 'Gene', (91, 95))	('expression', 'MPA', (21, 31))	('AXIN2', 'Gene', '8313', (84, 89))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('expression', 'MPA', (70, 80))	('ZNRF3', 'Gene', '84133', (100, 105))	('AXIN2', 'Gene', (84, 89))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('ACC', 'Phenotype', 'HP:0006744', (271, 274))	('ZNRF3', 'Gene', (100, 105))	('higher', 'PosReg', (63, 69))	('Cyclin D1', 'Gene', '595', (35, 44))	('ACCs', 'Phenotype', 'HP:0006744', (271, 275))
39589	29872083	Association of CTNNB1 mutation with low survival observed in our cohort confirms and validates the previous observations.	('CTNNB1', 'Gene', (15, 21))	('low survival', 'MPA', (36, 48))	('mutation', 'Var', (22, 30))	('CTNNB1', 'Gene', '1499', (15, 21))
39590	29872083	In our study, the association was even more evident in the group of patients with tumour harbouring alterations in APC/CTNNB1/ZNRF3.	('APC', 'Gene', '324', (115, 118))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('CTNNB1', 'Gene', (119, 125))	('ZNRF3', 'Gene', '84133', (126, 131))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('ZNRF3', 'Gene', (126, 131))	('patients', 'Species', '9606', (68, 76))	('tumour', 'Disease', (82, 88))	('APC', 'Gene', (115, 118))	('CTNNB1', 'Gene', '1499', (119, 125))	('alterations', 'Var', (100, 111))
39591	29872083	While aberrations in Wnt/beta-Catenin signaling pathway and nuclear accumulation of beta-Catenin are observed with similar frequency (40%) in ACCs, the presence of aberrancy (CTNNB1 missense mutation and ZNRF3 deletion) and accumulation of beta-Catenin do not always occur together.	('ZNRF3', 'Gene', (204, 209))	('missense mutation', 'Var', (182, 199))	('ACC', 'Phenotype', 'HP:0006744', (142, 145))	('CTNNB1', 'Gene', (175, 181))	('ACCs', 'Phenotype', 'HP:0006744', (142, 146))	('Wnt/beta-Catenin signaling pathway', 'Pathway', (21, 55))	('nuclear accumulation', 'MPA', (60, 80))	('CTNNB1', 'Gene', '1499', (175, 181))	('deletion', 'Var', (210, 218))	('ZNRF3', 'Gene', '84133', (204, 209))
39593	29872083	Tumour heterogeneity and complexity of malignant tumours like a culmination of whole genome hypo- or hyperploidy, accumulation of mutations and alterations in methylation, RNA expression and miRNA expression which is also observed in ACCs might lead to different phenotypic observations in tumours than expected by just a presence of the single mutations.	('lead to', 'Reg', (245, 252))	('tumours', 'Phenotype', 'HP:0002664', (290, 297))	('malignant tumours', 'Disease', 'MESH:D009369', (39, 56))	('malignant tumours', 'Disease', (39, 56))	('tumours', 'Disease', 'MESH:D009369', (290, 297))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('RNA', 'MPA', (172, 175))	('tumour', 'Phenotype', 'HP:0002664', (290, 296))	('tumours', 'Disease', (49, 56))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('ACCs', 'Phenotype', 'HP:0006744', (234, 238))	('methylation', 'MPA', (159, 170))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('alterations', 'Reg', (144, 155))	('miRNA', 'Protein', (191, 196))	('tumours', 'Disease', (290, 297))	('mutations', 'Var', (130, 139))	('ACC', 'Phenotype', 'HP:0006744', (234, 237))
39594	29872083	The interstitial deletion in CTNNB1, as well as the alterations in APC and ZNRF3, observed in our cohort adds to the spectrum of aberrancies occurring in ACCs with activated Wnt/beta-Catenin pathway.	('ZNRF3', 'Gene', '84133', (75, 80))	('CTNNB1', 'Gene', '1499', (29, 35))	('ZNRF3', 'Gene', (75, 80))	('ACC', 'Phenotype', 'HP:0006744', (154, 157))	('deletion', 'Var', (17, 25))	('APC', 'Gene', (67, 70))	('CTNNB1', 'Gene', (29, 35))	('ACCs', 'Phenotype', 'HP:0006744', (154, 158))	('APC', 'Gene', '324', (67, 70))
39624	29872083	Possible deletion/insertion overlapping the CTNNB1 locus was manually inspected.	('CTNNB1', 'Gene', '1499', (44, 50))	('deletion/insertion', 'Var', (9, 27))	('CTNNB1', 'Gene', (44, 50))
39627	29872083	Western blotting was performed on the PVDF membrane as described before and probed for beta-Catenin (1:200, cat#sc-376959, Santa Cruz Biotechnology, TX, USA), active beta-Catenin (cat#05-665, Merck Millipore, MA, USA), Cyclin D1 (cat#sc-6281, Santa Cruz Biotechnology, TX, USA) and Actin (cat#sc-1616, Santa Cruz Biotechnology, TX, USA).	('active beta-Catenin', 'Protein', (159, 178))	('PVDF', 'Chemical', 'MESH:C024865', (38, 42))	('cat#sc-1616', 'Var', (289, 300))	('Cyclin D1', 'Gene', '595', (219, 228))	('Cyclin D1', 'Gene', (219, 228))	('Actin', 'Protein', (282, 287))	('cat#05-665', 'Var', (180, 190))
39750	28685511	Hypersecretion of glucocorticoid, mineralocorticoid, sex steroids, and catecholamines not only causes clinical syndromes but can also be related to morbidity and premature mortality.	('causes', 'Reg', (95, 101))	('clinical syndromes', 'Disease', (102, 120))	('catecholamines', 'Chemical', 'MESH:D002395', (71, 85))	('related', 'Reg', (137, 144))	('Hypersecretion', 'Var', (0, 14))	('steroids', 'Chemical', 'MESH:D013256', (57, 65))
39769	28685511	APW=100x(EA-DA)/(EA-PA) RPW=100x(EA-DA)/EA (EA, attenuation coefficient 60 to 70 seconds after contrast administration; DA, attenuation coefficient 10 or 15 minutes after contrast administration; PA, attenuation coefficient before contrast administration) Generally, adrenal adenomas show typical rapid washout after contrast administration, whereas malignant lesions usually show fast contrast enhancement but slow contrast washout.	('men', 'Species', '9606', (402, 405))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (267, 282))	('adrenal adenomas', 'Disease', 'MESH:D018246', (267, 283))	('EA-PA', 'Chemical', '-', (17, 22))	('APW=100x', 'Var', (0, 8))	('EA-DA', 'Chemical', '-', (9, 14))	('adrenal adenomas', 'Disease', (267, 283))	('EA-DA', 'Chemical', '-', (33, 38))	('washout', 'MPA', (303, 310))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (267, 283))
39790	28685511	In a study that involved adenomas with little fat and >=10 HU on a CT scan before contrast administration, the sensitivity was 67% when all tumors >=10 HU were included in the study, and sensitivity and specificity were 89% and 100%, respectively, when only tumors with HU values of 10 to 30 were included.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('adenomas', 'Disease', 'MESH:D000236', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('>=10', 'Var', (54, 58))	('adenomas', 'Disease', (25, 33))
39792	28685511	Chemical shift MRI is better at diagnosing adrenal incidentaloma than conventional MRI, with findings such as reduced T1 signal and increased T2 signal suggestive of malignancy or pheochromocytoma.	('malignancy or pheochromocytoma', 'Disease', (166, 196))	('reduced', 'NegReg', (110, 117))	('adrenal incidentaloma', 'Disease', (43, 64))	('T2 signal', 'MPA', (142, 151))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (180, 196))	('malignancy or pheochromocytoma', 'Disease', 'MESH:D010673', (166, 196))	('increased', 'PosReg', (132, 141))	('adrenal incidentaloma', 'Disease', 'MESH:C538238', (43, 64))	('T1 signal', 'MPA', (118, 127))	('Chemical shift', 'Var', (0, 14))
39869	28685511	Metyrosine inhibits the synthesis of catecholamines and can thus be used preoperatively with alpha-blockers to reduce blood loss and volume deficiency during surgery and to stabilize blood pressure.	('synthesis of catecholamines', 'MPA', (24, 51))	('blood loss', 'Disease', 'MESH:D006473', (118, 128))	('volume deficiency', 'Disease', 'MESH:D016055', (133, 150))	('volume deficiency', 'Disease', (133, 150))	('catecholamines', 'Chemical', 'MESH:D002395', (37, 51))	('inhibits', 'NegReg', (11, 19))	('blood loss', 'Disease', (118, 128))	('reduce', 'NegReg', (111, 117))	('Metyrosine', 'Chemical', 'MESH:D019805', (0, 10))	('Metyrosine', 'Var', (0, 10))
39950	25945745	In Brazil, the p.R337H TP53 founder mutation causes the variant form of LFS, Li-Fraumeni-like syndrome.	('LFS', 'Disease', 'MESH:D016864', (72, 75))	('p.R337H', 'Mutation', 'rs121912664', (15, 22))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (77, 102))	('causes', 'Reg', (45, 51))	('LFS', 'Disease', (72, 75))	('Li-Fraumeni-like syndrome', 'Disease', (77, 102))	('p.R337H', 'Var', (15, 22))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))
39951	25945745	The occurrence of cancer and age of disease onset are known to vary, even in patients carrying the same mutation, and several mechanisms such as genetic and epigenetic alterations may be involved in this variability.	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('patients', 'Species', '9606', (77, 85))	('mutation', 'Var', (104, 112))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
39954	25945745	We also evaluated TDG expression in patients with adrenocortical tumors (ADR) with and without the p.R337H TP53 mutation.	('p.R337H', 'Mutation', 'rs121912664', (99, 106))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('adrenocortical tumors', 'Disease', (50, 71))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('TDG', 'Gene', (18, 21))	('evaluated', 'Reg', (8, 17))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (50, 71))	('TDG', 'Gene', '6996', (18, 21))	('p.R337H', 'Var', (99, 106))
39955	25945745	However, increased TDG expression was observed by quantitative reverse transcription PCR in p.R337H carriers with ADR.	('TDG', 'Gene', (19, 22))	('p.R337H', 'Mutation', 'rs121912664', (92, 99))	('TDG', 'Gene', '6996', (19, 22))	('increased', 'PosReg', (9, 18))	('p.R337H', 'Var', (92, 99))
39958	25945745	The main molecular mechanism underlying LFS is germline mutations in TP53, which predominantly occur in the central DNA-binding domain.	('TP53', 'Gene', '7157', (69, 73))	('germline mutations', 'Var', (47, 65))	('TP53', 'Gene', (69, 73))	('LFS', 'Disease', 'MESH:D016864', (40, 43))	('LFS', 'Disease', (40, 43))
39959	25945745	In Southern Brazil, a variant form of LFS, Li-Fraumeni-like syndrome (LFL), occurs as a result of a founder mutation in exon 10 of TP53, replacing an arginine with histidine at codon 337 (p.R337H), which falls within the oligomerization domain .	('p.R337H', 'Mutation', 'rs121912664', (188, 195))	('LFL', 'Disease', 'MESH:D016864', (70, 73))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (43, 68))	('LFS', 'Disease', (38, 41))	('replacing', 'Var', (137, 146))	('TP53', 'Gene', '7157', (131, 135))	('Li-Fraumeni-like syndrome', 'Disease', (43, 68))	('TP53', 'Gene', (131, 135))	('falls', 'Phenotype', 'HP:0002527', (204, 209))	('LFS', 'Disease', 'MESH:D016864', (38, 41))	('arginine with histidine at codon 337', 'Mutation', 'rs121912664', (150, 186))	('LFL', 'Disease', (70, 73))	('p.R337H', 'Var', (188, 195))
39960	25945745	The p.R337H mutation alters the functional properties of the p53 protein at elevated intracellular pH values (above 7.0) and/or temperatures above 36.5C.	('elevated', 'PosReg', (76, 84))	('functional properties', 'MPA', (32, 53))	('p.R337H', 'Var', (4, 11))	('protein', 'Protein', (65, 72))	('elevated intracellular pH', 'Phenotype', 'HP:0003575', (76, 101))	('alters', 'Reg', (21, 27))	('p.R337H', 'Mutation', 'rs121912664', (4, 11))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))
39961	25945745	Recent reports have indicated that TP53 mutations indirectly alter the levels of several transcripts, including the specialized base excision repair enzyme thymine-DNA glycosylase (TDG).	('thymine-DNA glycosylase', 'Gene', '6996', (156, 179))	('thymine-DNA glycosylase', 'Gene', (156, 179))	('alter', 'Reg', (61, 66))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('TDG', 'Gene', (181, 184))	('mutations', 'Var', (40, 49))	('TDG', 'Gene', '6996', (181, 184))	('levels of several transcripts', 'MPA', (71, 100))
39963	25945745	demonstrated that the introduction of a P65A point mutation in TDGled to a significant loss of TDG/CREB-binding protein/retinoic acid receptor ternary complex stability, resulting in the deregulation of networks associated with DNA replication, recombination, and repair.	('loss', 'NegReg', (87, 91))	('TDG', 'Gene', '6996', (63, 66))	('CREB-binding protein', 'Gene', '1387', (99, 119))	('P65A point', 'Var', (40, 50))	('TDG', 'Gene', '6996', (95, 98))	('deregulation', 'PosReg', (187, 199))	('P65A', 'Mutation', 'p.P65A', (40, 44))	('TDG', 'Gene', (63, 66))	('CREB-binding protein', 'Gene', (99, 119))	('TDG', 'Gene', (95, 98))	('DNA', 'MPA', (228, 231))	('networks', 'MPA', (203, 211))
39965	25945745	Cells lacking TDG activity exhibit two major alterations: a decreased capacity for base excision repair, leading to increased sensitivity to mutagenic damage and the accumulation of mutations, and an impaired ability to maintain wild-type promoter region methylation patterns, resulting in inappropriate gene expression.	('TDG', 'Gene', '6996', (14, 17))	('decreased', 'NegReg', (60, 69))	('gene expression', 'MPA', (304, 319))	('impaired', 'NegReg', (200, 208))	('inappropriate', 'Reg', (290, 303))	('TDG', 'Gene', (14, 17))	('sensitivity to mutagenic damage', 'MPA', (126, 157))	('base excision repair', 'MPA', (83, 103))	('increased', 'PosReg', (116, 125))	('mutations', 'Var', (182, 191))
39967	25945745	Alterations in the normal methylation patterns of TDG-regulated genes may be one mechanism underlying the occurrence of early age tumors in patients with germline TP53 mutations.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('TDG', 'Gene', (50, 53))	('methylation patterns', 'MPA', (26, 46))	('TP53', 'Gene', '7157', (163, 167))	('TDG', 'Gene', '6996', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('TP53', 'Gene', (163, 167))	('patients', 'Species', '9606', (140, 148))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('Alterations', 'Reg', (0, 11))	('mutations', 'Var', (168, 177))
39969	25945745	Epigenetic alterations, particularly DNA methylation, are a plausible molecular mechanism that may contribute to the diversity of tumors described in LFS/LFL patients.	('tumors', 'Disease', (130, 136))	('Epigenetic alterations', 'Var', (0, 22))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('contribute', 'Reg', (99, 109))	('LFL', 'Disease', (154, 157))	('LFS', 'Disease', 'MESH:D016864', (150, 153))	('LFL', 'Disease', 'MESH:D016864', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('patients', 'Species', '9606', (158, 166))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('LFS', 'Disease', (150, 153))
39971	25945745	Our objective for the present study was therefore to evaluate the methylation patterns of six genes that are likely to be dependent on TDG activity, aiming to verify its relevance in patients carrying the p.R337H mutation.	('TDG', 'Gene', '6996', (135, 138))	('p.R337H', 'Var', (205, 212))	('TDG', 'Gene', (135, 138))	('patients', 'Species', '9606', (183, 191))	('p.R337H', 'Mutation', 'rs121912664', (205, 212))
39973	25945745	Fifty individuals recruited from the Oncogenetics Department of the A.C. Camargo Cancer Center (So Paulo, SP, Brazil) were selected for methylation analysis and divided into five groups: 1) 10 patient p.R337H carriers that had developed cancer, 2) 10 patient p.R337H carriers without cancer, 3) 10 individuals with cancer and carrying germline TP53 mutations other than p.R337H, 4) 10 individuals with wild-type TP53 and relatives who are carriers of germline TP53 mutations, and 5) 10 healthy individuals with no personal or family history of cancer (Supplementary Table S1).	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('TP53', 'Gene', (412, 416))	('TP53', 'Gene', '7157', (344, 348))	('cancer', 'Disease', 'MESH:D009369', (544, 550))	('TP53', 'Gene', '7157', (460, 464))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (237, 243))	('TP53', 'Gene', '7157', (412, 416))	('Cancer', 'Disease', (81, 87))	('p.R337H', 'Var', (370, 377))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('patient', 'Species', '9606', (251, 258))	('cancer', 'Disease', (284, 290))	('cancer', 'Disease', (315, 321))	('TP53', 'Gene', (344, 348))	('p.R337H', 'Var', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('p.R337H', 'Mutation', 'rs121912664', (259, 266))	('cancer', 'Disease', (544, 550))	('TP53', 'Gene', (460, 464))	('Cancer', 'Disease', 'MESH:D009369', (81, 87))	('p.R337H', 'Mutation', 'rs121912664', (370, 377))	('cancer', 'Phenotype', 'HP:0002664', (544, 550))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('patient', 'Species', '9606', (193, 200))	('p.R337H', 'Mutation', 'rs121912664', (201, 208))
39974	25945745	Adrenocortical carcinomas from two patients with the p.R337H mutation and six patients without it were selected for gene expression analysis (Supplementary Table S2).	('Adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (0, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (15, 25))	('patients', 'Species', '9606', (78, 86))	('p.R337H', 'Mutation', 'rs121912664', (53, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('p.R337H', 'Var', (53, 60))	('patients', 'Species', '9606', (35, 43))	('Adrenocortical carcinomas', 'Disease', 'MESH:D018268', (0, 25))	('Adrenocortical carcinomas', 'Disease', (0, 25))
39980	25945745	In addition to the p.R337H mutation, we also examined TP53 exons 2-11, including the flanking intronic regions containing splice sites using protocols from the International Agency for Research on Cancer (http://p53.iarc.fr/Download/TP53DirectSequencingIARC.pdf).	('p.R337H', 'Mutation', 'rs121912664', (19, 26))	('p53', 'Gene', '7157', (212, 215))	('Cancer', 'Disease', (197, 203))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('TP53', 'Gene', (54, 58))	('TP53', 'Gene', (233, 237))	('Cancer', 'Disease', 'MESH:D009369', (197, 203))	('TP53', 'Gene', '7157', (54, 58))	('p.R337H', 'Var', (19, 26))	('p53', 'Gene', (212, 215))	('TP53', 'Gene', '7157', (233, 237))
39990	25945745	We identified 20 TP53 p.R337H carrier patients, 10 patients with other TP53 mutations, and 20 patients with wild-type TP53.	('p.R337H', 'Mutation', 'rs121912664', (22, 29))	('patients', 'Species', '9606', (94, 102))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('patients', 'Species', '9606', (51, 59))	('TP53', 'Gene', (71, 75))	('patients', 'Species', '9606', (38, 46))	('TP53', 'Gene', '7157', (71, 75))	('p.R337H', 'Var', (22, 29))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
39997	25945745	In the adrenocortical carcinoma samples, two of the eight tumors possessed the p.R337H mutation (Supplementary Table S2).	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (7, 31))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('p.R337H', 'Var', (79, 86))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('adrenocortical carcinoma', 'Disease', (7, 31))	('p.R337H', 'Mutation', 'rs121912664', (79, 86))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (7, 31))
39998	25945745	RT-qPCR also revealed higher TDG expression in both p.R337H-positive cases however, this finding could not be tested for statistical significance because of the small sample size.	('higher', 'PosReg', (22, 28))	('p.R337H-positive', 'Var', (52, 68))	('TDG', 'Gene', '6996', (29, 32))	('p.R337H', 'Mutation', 'rs121912664', (52, 59))	('TDG', 'Gene', (29, 32))
40000	25945745	According to Chompret criteria, germline mutations in TP53 are found in 70 of LFS cases and in 29 of LFL families.	('LFS', 'Disease', (78, 81))	('germline mutations', 'Var', (32, 50))	('LFL', 'Disease', 'MESH:D016864', (101, 104))	('LFS', 'Disease', 'MESH:D016864', (78, 81))	('TP53', 'Gene', '7157', (54, 58))	('found', 'Reg', (63, 68))	('TP53', 'Gene', (54, 58))	('LFL', 'Disease', (101, 104))
40001	25945745	The TP53 p.R337H founder mutation was reported to be associated with Brazilian families with LFL in 2007, and has an estimated population frequency of 0.3 in Southern and Southeastern regions of Brazil, where the incidence of adrenocortical carcinoma is 10- to 15-fold greater than in other countries.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (226, 250))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (226, 250))	('TP53', 'Gene', (4, 8))	('LFL', 'Disease', 'MESH:D016864', (93, 96))	('adrenocortical carcinoma', 'Disease', (226, 250))	('associated', 'Reg', (53, 63))	('p.R337H', 'Var', (9, 16))	('LFL', 'Disease', (93, 96))	('p.R337H', 'Mutation', 'rs121912664', (9, 16))	('TP53', 'Gene', '7157', (4, 8))
40002	25945745	reported that TDG expression is directly regulated by wild-type p53 protein, suggesting that the loss of p53 function may affect TDG-mediated processes.	('TDG', 'Gene', '6996', (14, 17))	('TDG', 'Gene', (129, 132))	('loss', 'Var', (97, 101))	('TDG', 'Gene', '6996', (129, 132))	('TDG', 'Gene', (14, 17))	('p53', 'Gene', (105, 108))	('affect', 'Reg', (122, 128))	('p53', 'Gene', '7157', (105, 108))	('function', 'MPA', (109, 117))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
40005	25945745	reported that TDG hypermethylation and the consequent reduction of transcript expression led to an impairment of repair in multiple myeloma cell lines.	('TDG', 'Gene', '6996', (14, 17))	('multiple myeloma', 'Disease', (123, 139))	('hypermethylation', 'Var', (18, 34))	('reduction', 'NegReg', (54, 63))	('multiple myeloma', 'Phenotype', 'HP:0006775', (123, 139))	('TDG', 'Gene', (14, 17))	('repair', 'MPA', (113, 119))	('multiple myeloma', 'Disease', 'MESH:D009101', (123, 139))	('transcript expression', 'MPA', (67, 88))
40010	25945745	TDG is also very active during development, and epigenetically regulates several genes associated with development and cell determination such as the homeobox family genes and other transcription factors.	('epigenetically', 'Var', (48, 62))	('TDG', 'Gene', (0, 3))	('regulates', 'Reg', (63, 72))	('homeobox family genes', 'Gene', (150, 171))	('TDG', 'Gene', '6996', (0, 3))
40011	25945745	The present study evaluated the methylation patterns of CDKN2A, FOXA1, HOXD8, OCT4, SOX2, and SOX17 in peripheral blood samples from patients with germline TP53 mutations and healthy individuals.	('FOXA1', 'Gene', (64, 69))	('patients', 'Species', '9606', (133, 141))	('OCT4', 'Gene', '5460', (78, 82))	('SOX2', 'Gene', '6657', (84, 88))	('TP53', 'Gene', '7157', (156, 160))	('SOX17', 'Gene', (94, 99))	('SOX2', 'Gene', (84, 88))	('HOXD8', 'Gene', (71, 76))	('methylation', 'MPA', (32, 43))	('mutations', 'Var', (161, 170))	('TP53', 'Gene', (156, 160))	('OCT4', 'Gene', (78, 82))	('FOXA1', 'Gene', '3169', (64, 69))	('CDKN2A', 'Gene', (56, 62))	('HOXD8', 'Gene', '3234', (71, 76))	('CDKN2A', 'Gene', '1029', (56, 62))	('SOX17', 'Gene', '64321', (94, 99))
40017	25945745	Alterations to the methylation patterns of genes potentially regulated by TDG could act as risk modifiers, and could explain the differences in the ages of tumor onset and tumor subtypes described in this syndrome however, we were unable to confirm the differences in the methylation patterns of the tested genes and samples (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('Alterations', 'Var', (0, 11))	('TDG', 'Gene', '6996', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('methylation', 'MPA', (19, 30))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('TDG', 'Gene', (74, 77))
40021	25945745	Although increased TDG expression was observed in two adrenocortical carcinomas from patients who were positive for the p.R337H mutation, it was not possible to infer the relationship between the p.R337H mutation and TDG levels because of the small number of cases.	('TDG', 'Gene', (19, 22))	('p.R337H', 'Var', (120, 127))	('p.R337H', 'Var', (196, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('p.R337H', 'Mutation', 'rs121912664', (120, 127))	('p.R337H', 'Mutation', 'rs121912664', (196, 203))	('TDG', 'Gene', '6996', (19, 22))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (54, 79))	('increased', 'PosReg', (9, 18))	('patients', 'Species', '9606', (85, 93))	('TDG', 'Gene', (217, 220))	('adrenocortical carcinomas', 'Disease', (54, 79))	('TDG', 'Gene', '6996', (217, 220))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (54, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (54, 79))	('expression', 'MPA', (23, 33))
40048	25664881	This has led to major scientific discoveries including the identification of a unique TP53-R337H germline mutation, which is highly prevalent in Southern Brazil and predisposes to pediatric adrenocortical carcinoma; identification of DICER1 germline mutations in familial pleuropulmonary blastoma, which has subsequently led to characterization of the DICER1 syndrome; and discovery of BRD4-NUT-mediated oncogenic and epigenetic mechanisms in NUT midline carcinoma.	('pediatric adrenocortical carcinoma', 'Disease', 'MESH:C565973', (180, 214))	('TP53', 'Gene', (86, 90))	('BRD4', 'Gene', '23476', (386, 390))	('pediatric adrenocortical carcinoma', 'Disease', (180, 214))	('NUT', 'Gene', (391, 394))	('mutation', 'Var', (106, 114))	('NUT', 'Gene', '256646', (391, 394))	('DICER1', 'Gene', '23405', (234, 240))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (272, 296))	('DICER1', 'Gene', '23405', (352, 358))	('DICER1', 'Gene', (234, 240))	('NUT', 'Gene', '256646', (443, 446))	('TP53', 'Gene', '7157', (86, 90))	('NUT', 'Gene', (443, 446))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('DICER1', 'Gene', (352, 358))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (190, 214))	('R337H', 'Mutation', 'rs121912664', (91, 96))	('BRD4', 'Gene', (386, 390))	('NUT midline carcinoma', 'Disease', (443, 464))	('familial pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (263, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (455, 464))	('familial pleuropulmonary blastoma', 'Disease', (263, 296))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (443, 464))
40087	24790294	Virilizing Adrenocortical Carcinoma Invading the Right Atrium with Histological High-Grade Malignancy and p53 Mutation in a 3-Year-Old Child: Indication of Post Operative Adjuvant Chemotherapy We present a 3-yr-old girl with a virilizing adrenocortical carcinoma invading into the right atrium with histological high-grade malignancy and p53 mutation.	('p53', 'Gene', '7157', (106, 109))	('p53', 'Gene', (106, 109))	('malignancy', 'Disease', 'MESH:D009369', (323, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (238, 262))	('Virilizing Adrenocortical Carcinoma', 'Disease', (0, 35))	('girl', 'Species', '9606', (215, 219))	('Malignancy', 'Disease', (91, 101))	('mutation', 'Var', (342, 350))	('p53', 'Gene', '7157', (338, 341))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (238, 262))	('malignancy', 'Disease', (323, 333))	('Child', 'Species', '9606', (135, 140))	('adrenocortical carcinoma', 'Disease', (238, 262))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (11, 35))	('Carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('p53', 'Gene', (338, 341))	('Malignancy', 'Disease', 'MESH:D009369', (91, 101))	('Virilizing Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (0, 35))
40092	24790294	A heterozygous mutation of the p53 tumor-suppressor gene (codon 248 CGC TGG) was found.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('codon 248', 'Var', (58, 67))	('tumor', 'Disease', (35, 40))	('CGC TGG', 'Gene', (68, 75))
40094	24790294	In this type of patient with histological high-grade malignancy and p53 mutations, postoperative adjuvant chemotherapy is indicated even if macroscopic total surgical removal had been performed.	('mutations', 'Var', (72, 81))	('malignancy', 'Disease', 'MESH:D009369', (53, 63))	('malignancy', 'Disease', (53, 63))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('patient', 'Species', '9606', (16, 23))
40101	24790294	Li-Fraumeni syndrome is associated with changes in the tumor suppressor gene p53 on chromosome 17p.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('changes', 'Var', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))
40110	24790294	At a local hospital, she was diagnosed as having a simple virilizing type CAH on the ground of high 17OHP (5.6 ng/ml) and T (986 ng/dl).	('CAH', 'Disease', (74, 77))	('T (986 ng/dl', 'Var', (122, 134))	('CAH', 'Disease', 'None', (74, 77))	('17OHP', 'Chemical', 'MESH:D019326', (100, 105))	('CAH', 'Phenotype', 'HP:0008258', (74, 77))	('5.6', 'Var', (107, 110))
40168	24790294	On the other hand, ACT in childhood cancer is associated with the highest frequency of germline p53 mutations.	('mutations', 'Var', (100, 109))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('child', 'Species', '9606', (26, 31))	('germline', 'Var', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
40169	24790294	We found a mutation of the p53 tumor-suppressor gene (codon 248 CGC TGG).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('p53', 'Gene', '7157', (27, 30))	('tumor', 'Disease', (31, 36))	('codon 248', 'Var', (54, 63))	('CGC TGG', 'Gene', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('p53', 'Gene', (27, 30))
40171	24790294	P53 mutations in children with sporadic ACT suggest that children may represent probands with which to ascertain Li-Fraumeni syndrome families.	('children', 'Species', '9606', (17, 25))	('children', 'Species', '9606', (57, 65))	('P53', 'Gene', (0, 3))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (113, 133))	('P53', 'Gene', '7157', (0, 3))	('mutations', 'Var', (4, 13))	('Li-Fraumeni syndrome', 'Disease', (113, 133))
40172	24790294	In children, p53 positivity has been associated with clinically malignant ACT and p53 negativity has been associated with clinically benign ACT.	('children', 'Species', '9606', (3, 11))	('associated with', 'Reg', (37, 52))	('positivity', 'Var', (17, 27))	('p53', 'Gene', (82, 85))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (82, 85))	('clinically', 'Disease', (53, 63))	('p53', 'Gene', '7157', (13, 16))
40184	23589626	Methylation most often occurs at the cytosine of a cytosine-guanine dinucleotide (CpG) and acts to down-regulate gene expression.	('cytosine', 'Chemical', 'MESH:D003596', (37, 45))	('gene expression', 'MPA', (113, 128))	('Methylation', 'Var', (0, 11))	('down-regulate', 'NegReg', (99, 112))	('cytosine', 'Chemical', 'MESH:D003596', (51, 59))	('cytosine-guanine dinucleotide', 'Chemical', 'MESH:C015772', (51, 80))
40185	23589626	Disruption of the DNA methylation machinery can lead to imprinting disorders, repeat-instability disease and neurological defects.	('repeat-instability disease', 'Disease', 'MESH:D016388', (78, 104))	('neurological defects', 'Disease', (109, 129))	('neurological defects', 'Phenotype', 'HP:0000707', (109, 129))	('repeat-instability disease', 'Disease', (78, 104))	('neurological defects', 'Disease', 'MESH:D009422', (109, 129))	('imprinting disorders', 'Disease', (56, 76))	('lead to', 'Reg', (48, 55))	('Disruption', 'Var', (0, 10))
40187	23589626	Tumors often display a global loss of methylation, or hypomethylation, at repetitive elements, which is thought to destabilize the genome through transposon-mediated rearrangements, activate growth-promoting oncogenes and cause de-differentiation through the loss of imprinting.	('methylation', 'MPA', (38, 49))	('de-differentiation', 'CPA', (228, 246))	('loss', 'NegReg', (259, 263))	('activate', 'PosReg', (182, 190))	('growth-promoting oncogenes', 'CPA', (191, 217))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('loss', 'NegReg', (30, 34))	('hypomethylation', 'Var', (54, 69))	('cause', 'Reg', (222, 227))
40188	23589626	An abnormal gain of methylation, or hypermethylation, at gene regulatory elements also contributes to tumorigenesis by silencing tumor suppressor genes involved in DNA damage repair, cell cycle control and other processes.	('methylation', 'MPA', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('hypermethylation', 'Var', (36, 52))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('gain', 'PosReg', (12, 16))	('silencing', 'NegReg', (119, 128))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
40189	23589626	This aberrant methylation may be due, at least in part, to recurring mutations in genes that are involved in epigenetic regulation, such as DNA methyltransferases, which are commonly mutated in acute myeloid leukemia, and chromatin remodelling enzymes, which are frequently mutated in renal carcinomas and pancreatic neuroendocrine tumors.	('mutations', 'Var', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (332, 338))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (306, 338))	('pancreatic neuroendocrine tumors', 'Disease', (306, 338))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (194, 216))	('renal carcinomas', 'Phenotype', 'HP:0005584', (285, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (194, 216))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (317, 338))	('renal carcinomas', 'Disease', 'MESH:C538614', (285, 301))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (200, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (291, 301))	('leukemia', 'Phenotype', 'HP:0001909', (208, 216))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('renal carcinomas', 'Disease', (285, 301))	('acute myeloid leukemia', 'Disease', (194, 216))
40199	23589626	The molecular basis of GDX-induced adrenocortical neoplasia is unknown, but it has been hypothesized that DNA methylation and other epigenetic modifications may impact the phenotypic plasticity of adrenocortical stem/progenitor cells, allowing them to respond to the rise in circulating gonadotropins.	('adrenocortical neoplasia', 'Disease', (35, 59))	('phenotypic plasticity', 'CPA', (172, 193))	('rise in circulating gonadotropins', 'Phenotype', 'HP:0000837', (267, 300))	('adrenocortical', 'Disease', (35, 49))	('DNA', 'Gene', (106, 109))	('respond to', 'MPA', (252, 262))	('allowing', 'Reg', (235, 243))	('adrenocortical', 'Disease', 'MESH:D018268', (35, 49))	('neoplasia', 'Phenotype', 'HP:0002664', (50, 59))	('impact', 'Reg', (161, 167))	('methylation', 'Var', (110, 121))	('adrenocortical', 'Disease', (197, 211))	('epigenetic modifications', 'Var', (132, 156))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (35, 59))	('adrenocortical', 'Disease', 'MESH:D018268', (197, 211))
40217	23589626	Pre-annealed methylated paired-end Illumina indexing adapters (Adap1: ACACTCTTTCCCTACACGACGCTCTTCCGATCT; Adap2: P-GATCGGAAGAGCACACGTCTGAACTCCAGTCAC, P = phosphate) at a concentration of 0.26 mM were ligated overnight at 16 C to the ends of the DNA fragments using 1200 U of T4 DNA Ligase (M0202L, NEB) in 1x Ligase Buffer to a final volume of 28.9 mul.	('phosphate', 'Chemical', 'MESH:D010710', (153, 162))	('Adap1', 'Gene', '231821', (63, 68))	('EB', 'Chemical', 'MESH:C004912', (298, 300))	('Adap2', 'Gene', (105, 110))	('Adap2', 'Gene', '216991', (105, 110))	('Adap1', 'Gene', (63, 68))	('M0202L', 'Var', (289, 295))	('M0202L', 'Mutation', 'p.M0202L', (289, 295))
40278	23589626	The observed methylation changes suggest the neoplastic tissue may arise owing to aberrant gene expression of genes normally silent in adrenocortical cells or the silencing of adrenal-specific markers.	('methylation', 'MPA', (13, 24))	('gene expression', 'MPA', (91, 106))	('silencing', 'NegReg', (163, 172))	('adrenocortical', 'Disease', (135, 149))	('adrenocortical', 'Disease', 'MESH:D018268', (135, 149))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (45, 62))	('aberrant', 'Var', (82, 90))	('neoplastic', 'Disease', (45, 55))
40293	23589626	Conditional mutagenesis of the mouse Dnmt1 gene, which encodes the maintenance DNA methyltransferase, converts insulin-producing pancreatic beta-cells into glucagon-producing alpha-cells.	('Dnmt1', 'Gene', (37, 42))	('insulin-producing', 'MPA', (111, 128))	('mouse', 'Species', '10090', (31, 36))	('Dnmt1', 'Gene', '13433', (37, 42))	('mutagenesis', 'Var', (12, 23))	('converts', 'Reg', (102, 110))
40327	22629514	Abnormalities in the insulin-like growth factor II (IGF II), p53 tumor suppressor gene, steroidogenic factor 1 overexpression, and mutations of the beta catenin gene have been implicated.	('insulin-like growth factor II (IGF II', 'Gene', '3481', (21, 58))	('mutations', 'Var', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Abnormalities', 'Var', (0, 13))	('tumor', 'Disease', (65, 70))	('steroidogenic factor 1', 'Gene', (88, 110))	('steroidogenic factor 1', 'Gene', '2516', (88, 110))	('p53', 'Gene', '7157', (61, 64))	('beta catenin', 'Gene', '1499', (148, 160))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('p53', 'Gene', (61, 64))	('overexpression', 'PosReg', (111, 125))	('beta catenin', 'Gene', (148, 160))
40414	33657992	Moreover, DHA, but not saturated fatty acid, can significantly increase the levels of specific microRNAs in a dose-dependent fashion.	('increase', 'PosReg', (63, 71))	('n', 'Chemical', 'MESH:D009584', (19, 20))	('DHA', 'Var', (10, 13))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('DHA', 'Chemical', 'MESH:D004281', (10, 13))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('levels of specific microRNAs', 'MPA', (76, 104))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('saturated fatty acid', 'Chemical', 'MESH:D005227', (23, 43))	('n', 'Chemical', 'MESH:D009584', (131, 132))
40415	33657992	In addition, it has been reported that microRNAs are involved in adipocyte differentiation and show differences in adipogenesis between lean and obese subjects.	('obese', 'Disease', (145, 150))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('obese', 'Disease', 'MESH:D009765', (145, 150))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('adipocyte differentiation', 'CPA', (65, 90))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (134, 135))	('adipogenesis', 'MPA', (115, 127))	('microRNAs', 'Var', (39, 48))	('differences', 'Reg', (100, 111))	('involved', 'Reg', (53, 61))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('n', 'Chemical', 'MESH:D009584', (139, 140))
40459	33657992	Thereof, based on bioinformatics and published literature, microRNAs miR-30d, miR-99a, miR-100, and miR-320 were selected for further analyses due to their seed-sites in potential mRNA targets (Table 2) and putative involvement in nutrient sensing and transport, e.g.	('n', 'Chemical', 'MESH:D009584', (249, 250))	('n', 'Chemical', 'MESH:D009584', (242, 243))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('miR-99a', 'Gene', (78, 85))	('n', 'Chemical', 'MESH:D009584', (217, 218))	('miR-30d', 'Gene', '407033', (69, 76))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('n', 'Chemical', 'MESH:D009584', (231, 232))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('n', 'Chemical', 'MESH:D009584', (255, 256))	('involvement', 'Reg', (216, 227))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('miR-320', 'Var', (100, 107))	('n', 'Chemical', 'MESH:D009584', (245, 246))	('mRNA targets', 'MPA', (180, 192))	('n', 'Chemical', 'MESH:D009584', (229, 230))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('miR-99a', 'Gene', '407055', (78, 85))	('miR-100', 'Gene', (87, 94))	('n', 'Chemical', 'MESH:D009584', (174, 175))	('miR-320', 'Chemical', '-', (100, 107))	('n', 'Chemical', 'MESH:D009584', (237, 238))	('n', 'Chemical', 'MESH:D009584', (204, 205))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('miR-30d', 'Gene', (69, 76))	('miR-100', 'Gene', '406892', (87, 94))	('n', 'Chemical', 'MESH:D009584', (225, 226))
40469	33657992	Table 2 lists predicted 5' seed-sites with a complete match or matches with 1 or 2 mismatches in the respective target genes and the putative MRE-sites.	('mismatches', 'Var', (83, 93))	('matches', 'Interaction', (63, 70))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (121, 122))
40471	33657992	A miR-99a seed-site with two mismatches for SLC6A6, predicted by the microRNA target prediction algorithm rna22, was found in the 3'-UTR of SLC6A6.	('miR-99a', 'Gene', (2, 9))	('SLC6A6', 'Gene', '6533', (140, 146))	('mismatches', 'Var', (29, 39))	('SLC6A6', 'Gene', '6533', (44, 50))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('miR-99a', 'Gene', '407055', (2, 9))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('SLC6A6', 'Gene', (44, 50))	('n', 'Chemical', 'MESH:D009584', (94, 95))	('SLC6A6', 'Gene', (140, 146))
40473	33657992	In addition, we detected two sequence elements in the coding sequence reflecting 5' seed-sites with two mismatches and sequence elements with a potential for a moderate 3'-site base-pairing MRE with miR-99a in exon 1 of SLC7A5.	('mismatches', 'Var', (104, 114))	('n', 'Chemical', 'MESH:D009584', (148, 149))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('n', 'Chemical', 'MESH:D009584', (66, 67))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (208, 209))	('SLC7A5', 'Gene', (220, 226))	('miR-99a', 'Gene', '407055', (199, 206))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (213, 214))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('miR-99a', 'Gene', (199, 206))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('SLC7A5', 'Gene', '8140', (220, 226))	('n', 'Chemical', 'MESH:D009584', (187, 188))
40486	33657992	Our expression analyses and exploratory pairwise comparisons of the regression analyses revealed: sex-specific expression differences in the control group and in all placentas from both groups (without the factor treatment), n-3 LCPUFA treatment effects between control and intervention group, and sex-dependent effects following n-3 LCPUFA treatment (Table 3).	('LCPUFA', 'Gene', '9933', (229, 235))	('n', 'Chemical', 'MESH:D009584', (156, 157))	('LCPUFA', 'Gene', (334, 340))	('n', 'Chemical', 'MESH:D009584', (281, 282))	('n', 'Chemical', 'MESH:D009584', (243, 244))	('effects', 'Reg', (246, 253))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (264, 265))	('n', 'Chemical', 'MESH:D009584', (327, 328))	('n', 'Chemical', 'MESH:D009584', (295, 296))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('expression', 'MPA', (111, 121))	('n', 'Chemical', 'MESH:D009584', (309, 310))	('n', 'Chemical', 'MESH:D009584', (271, 272))	('LCPUFA', 'Gene', (229, 235))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (160, 161))	('n-3', 'Var', (225, 228))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('LCPUFA', 'Gene', '9933', (334, 340))	('n', 'Chemical', 'MESH:D009584', (285, 286))	('n', 'Chemical', 'MESH:D009584', (348, 349))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('n', 'Chemical', 'MESH:D009584', (260, 261))	('n', 'Chemical', 'MESH:D009584', (171, 172))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('n', 'Chemical', 'MESH:D009584', (275, 276))	('n', 'Chemical', 'MESH:D009584', (306, 307))	('n', 'Chemical', 'MESH:D009584', (220, 221))	('n', 'Chemical', 'MESH:D009584', (330, 331))	('n', 'Chemical', 'MESH:D009584', (225, 226))
40510	33657992	Comparing female placentas between the intervention and control group, E2/T ratios were significantly increased in the presence of n-3 LCPUFA supplementation.	('n', 'Chemical', 'MESH:D009584', (156, 157))	('E2/T ratios', 'MPA', (71, 82))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('LCPUFA', 'Gene', (135, 141))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('n-3', 'Var', (131, 134))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('LCPUFA', 'Gene', '9933', (135, 141))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('increased', 'PosReg', (102, 111))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('E2', 'Chemical', 'MESH:D004958', (71, 73))	('n', 'Chemical', 'MESH:D009584', (131, 132))
40519	33657992	Moreover, E2/T tended to significantly correlate with miR-99a in male placentas (p = 0.073).	('miR-99a', 'Gene', (54, 61))	('correlate', 'Reg', (39, 48))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('n', 'Chemical', 'MESH:D009584', (34, 35))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('E2', 'Chemical', 'MESH:D004958', (10, 12))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('n', 'Chemical', 'MESH:D009584', (17, 18))	('miR-99a', 'Gene', '407055', (54, 61))	('E2/T', 'Var', (10, 14))
40523	33657992	Hypothesizing that the observed placental expression differences for mTOR mRNA, SLC7A5 mRNA, SLC6A6 mRNA, and LAT1 have changed the respective protein levels and/or activities and thereby the amino acid substrates of LAT1 (His, Ile, Leu, Met, Phe, Trp, Tyr, and Val) and TauT (Tau) in maternal and fetal compartments, we analyzed respective amino acid levels in the maternal plasma at week-15 and week-32 of gestation (Table 6) and in the offspring the chorionic villous portion of the placenta as well as cord plasma (Table 7).	('n', 'Chemical', 'MESH:D009584', (60, 61))	('Tau', 'Gene', '6533', (277, 280))	('activities', 'MPA', (165, 175))	('n', 'Chemical', 'MESH:D009584', (290, 291))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('n', 'Chemical', 'MESH:D009584', (360, 361))	('SLC6A6', 'Gene', (93, 99))	('n', 'Chemical', 'MESH:D009584', (416, 417))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('Trp', 'Chemical', 'MESH:D014364', (248, 251))	('protein levels', 'MPA', (143, 157))	('n', 'Chemical', 'MESH:D009584', (344, 345))	('n', 'Chemical', 'MESH:D009584', (177, 178))	('n', 'Chemical', 'MESH:D009584', (295, 296))	('n', 'Chemical', 'MESH:D009584', (429, 430))	('differences', 'Var', (53, 64))	('n', 'Chemical', 'MESH:D009584', (446, 447))	('n', 'Chemical', 'MESH:D009584', (477, 478))	('SLC7A5', 'Gene', '8140', (80, 86))	('SLC6A6', 'Gene', '6533', (93, 99))	('n', 'Chemical', 'MESH:D009584', (459, 460))	('n', 'Chemical', 'MESH:D009584', (159, 160))	('Tau', 'Gene', (271, 274))	('TauT', 'Gene', (271, 275))	('Tau', 'Gene', '6533', (271, 274))	('n', 'Chemical', 'MESH:D009584', (268, 269))	('n', 'Chemical', 'MESH:D009584', (491, 492))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('n', 'Chemical', 'MESH:D009584', (259, 260))	('changed', 'Reg', (120, 127))	('n', 'Chemical', 'MESH:D009584', (283, 284))	('mTOR', 'Gene', (69, 73))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (322, 323))	('TauT', 'Gene', '6533', (271, 275))	('SLC7A5', 'Gene', (80, 86))	('n', 'Chemical', 'MESH:D009584', (433, 434))	('n', 'Chemical', 'MESH:D009584', (195, 196))	('n', 'Chemical', 'MESH:D009584', (371, 372))	('n', 'Chemical', 'MESH:D009584', (313, 314))	('n', 'Chemical', 'MESH:D009584', (394, 395))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('Tau', 'Gene', (277, 280))	('mTOR', 'Gene', '2475', (69, 73))
40535	33657992	Moreover, alterations in mTOR signaling and levels of essential amino acids, such as Trp, may affect protein synthesis and thereby muscle mass, and fetal plasma Tau levels are associated with intrauterine growth restriction.	('n', 'Chemical', 'MESH:D009584', (19, 20))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('affect', 'Reg', (94, 100))	('n', 'Chemical', 'MESH:D009584', (202, 203))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('mTOR', 'Gene', (25, 29))	('n', 'Chemical', 'MESH:D009584', (193, 194))	('n', 'Chemical', 'MESH:D009584', (145, 146))	('Trp', 'Gene', (85, 88))	('muscle mass', 'CPA', (131, 142))	('protein synthesis', 'MPA', (101, 118))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('growth restriction', 'Phenotype', 'HP:0001510', (205, 223))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('mTOR', 'Gene', '2475', (25, 29))	('intrauterine growth restriction', 'Phenotype', 'HP:0001511', (192, 223))	('Tau', 'Gene', (161, 164))	('alterations', 'Var', (10, 21))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (222, 223))	('Tau', 'Gene', '6533', (161, 164))	('Trp', 'Chemical', 'MESH:D014364', (85, 88))	('intrauterine growth restriction', 'Disease', (192, 223))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('essential amino acids', 'Chemical', 'MESH:D000601', (54, 75))	('associated', 'Reg', (176, 186))	('n', 'Chemical', 'MESH:D009584', (107, 108))
40554	33657992	SLC7A5 mRNA was significantly positively associated with both bodyweight and lean mass at 1 year, and with fat mass at 3 years of age, showing substantially increased beta-coefficient values in the unadjusted models.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (19, 20))	('SLC7A5', 'Gene', (0, 6))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('mRNA', 'Var', (7, 11))	('n', 'Chemical', 'MESH:D009584', (199, 200))	('n', 'Chemical', 'MESH:D009584', (192, 193))	('lean mass', 'CPA', (77, 86))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('n', 'Chemical', 'MESH:D009584', (181, 182))	('n', 'Chemical', 'MESH:D009584', (158, 159))	('associated', 'Interaction', (41, 51))	('positively', 'PosReg', (30, 40))	('SLC7A5', 'Gene', '8140', (0, 6))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('bodyweight', 'Disease', (62, 72))	('n', 'Chemical', 'MESH:D009584', (140, 141))	('increased', 'PosReg', (157, 166))
40589	33657992	Our data on sex-specific and n-3 LCPUFA-responsive expression changes and associations between miR-99a and target genes will give new insights into regulatory mechanisms of amino acid transport in the placenta.	('n', 'Chemical', 'MESH:D009584', (60, 61))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('n', 'Chemical', 'MESH:D009584', (176, 177))	('associations', 'Interaction', (74, 86))	('miR-99a', 'Gene', '407055', (95, 102))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('n', 'Chemical', 'MESH:D009584', (144, 145))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('LCPUFA', 'Gene', '9933', (33, 39))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('n', 'Chemical', 'MESH:D009584', (206, 207))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('n', 'Chemical', 'MESH:D009584', (84, 85))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('miR-99a', 'Gene', (95, 102))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('changes', 'Var', (62, 69))	('n', 'Chemical', 'MESH:D009584', (195, 196))	('LCPUFA', 'Gene', (33, 39))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (187, 188))
40597	33657992	Inhibition of mTORC1 reduces the mRNA levels of SLC6A6 and SLC7A5, but discrepancies between SLC7A5 mRNA and LAT1 protein expression were also reported.	('mTORC1', 'Gene', (14, 20))	('SLC7A5', 'Gene', '8140', (93, 99))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('mTORC1', 'Gene', '382056', (14, 20))	('SLC7A5', 'Gene', '8140', (59, 65))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('SLC7A5', 'Gene', (93, 99))	('mRNA levels', 'MPA', (33, 44))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('SLC6A6', 'Gene', (48, 54))	('SLC7A5', 'Gene', (59, 65))	('Inhibition', 'Var', (0, 10))	('reduces', 'NegReg', (21, 28))	('SLC6A6', 'Gene', '6533', (48, 54))	('n', 'Chemical', 'MESH:D009584', (131, 132))
40624	33657992	Interestingly, n-3 LCPUFA EPA reduces indoleamine 2,3-dioxygenase, which catalyzes Trp to kynurenine conversion in tumor cells.	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n-3', 'Var', (15, 18))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('kynurenine', 'Chemical', 'MESH:D007737', (90, 100))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('LCPUFA', 'Gene', '9933', (19, 25))	('n', 'Chemical', 'MESH:D009584', (15, 16))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('reduces', 'NegReg', (30, 37))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('LCPUFA', 'Gene', (19, 25))	('Trp', 'Chemical', 'MESH:D014364', (83, 86))
40635	33657992	Moreover, long-term Tau supplementation in mildly obese mice can inhibit adipogenesis in muscle and white adipose tissue, but not brown adipose tissue.	('n', 'Chemical', 'MESH:D009584', (12, 13))	('obese', 'Disease', (50, 55))	('n', 'Chemical', 'MESH:D009584', (66, 67))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('adipogenesis in muscle', 'MPA', (73, 95))	('obese', 'Disease', 'MESH:D009765', (50, 55))	('Tau', 'Gene', (20, 23))	('Tau', 'Gene', '6533', (20, 23))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (134, 135))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('mice', 'Species', '10090', (56, 60))	('supplementation', 'Var', (24, 39))	('inhibit', 'NegReg', (65, 72))
40794	33604380	In particular, evaluation of the mutations in immune cells is capable of predicting the outcome of patients with cancerous tumors.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous tumors', 'Disease', 'MESH:D009369', (113, 129))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (99, 107))	('cancerous tumors', 'Disease', (113, 129))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
40804	33604380	We discovered that the related immune cell infiltration signatures were differently expressed between low and high CDCA3 expression groups.	('CDCA3', 'Gene', (115, 120))	('high', 'Var', (110, 114))	('CDCA3', 'Gene', '83461', (115, 120))
40805	33604380	We also found that the higher proportion of CD8+ T cells, CD4+ T cells, and B cells appeared in the high CDCA3 expression group.	('CD8', 'Gene', (44, 47))	('CD8', 'Gene', '925', (44, 47))	('CD4', 'Gene', '920', (58, 61))	('CDCA3', 'Gene', '83461', (105, 110))	('high', 'Var', (100, 104))	('CDCA3', 'Gene', (105, 110))	('CD4', 'Gene', (58, 61))
40806	33604380	Our data suggested that the high CDCA3 expression promoted the infiltration of T cells and exhausted these cells, and the patients with high CDCA3 expression might have poorer outcomes by analyzing the information of HCC patients obtained from The Cancer Genome Atlas (TCGA) database.	('CDCA3', 'Gene', '83461', (141, 146))	('patients', 'Species', '9606', (221, 229))	('promoted', 'PosReg', (50, 58))	('CDCA3', 'Gene', (141, 146))	('expression', 'Var', (39, 49))	('CDCA3', 'Gene', '83461', (33, 38))	('CDCA3', 'Gene', (33, 38))	('patients', 'Species', '9606', (122, 130))	('Cancer', 'Phenotype', 'HP:0002664', (248, 254))	('Cancer', 'Disease', (248, 254))	('high', 'Var', (28, 32))	('Cancer', 'Disease', 'MESH:D009369', (248, 254))	('HCC', 'Phenotype', 'HP:0001402', (217, 220))	('infiltration of T cells', 'CPA', (63, 86))
40816	33604380	Significance of HR referred to the ratio of risk rate produced by high CDCA3 expression to the risk rate produced by low CDCA3 expression, on the premise that p < 0.05.	('expression', 'MPA', (77, 87))	('CDCA3', 'Gene', (121, 126))	('CDCA3', 'Gene', '83461', (71, 76))	('CDCA3', 'Gene', (71, 76))	('high', 'Var', (66, 70))	('CDCA3', 'Gene', '83461', (121, 126))
40817	33604380	The higher the HR value, the bigger the ratio of risk rate produced by high CDCA3 expression on survival.	('HR value', 'MPA', (15, 23))	('CDCA3', 'Gene', (76, 81))	('CDCA3', 'Gene', '83461', (76, 81))	('high', 'Var', (71, 75))
40828	33604380	Here, we established a standard to describe the association between CDCA3 expression and gene markers of infiltrating immune cells, where 0.00-0.29 was considered weak, 0.30-0.59 was considered moderate, 0.60-0.79 was considered strong, and 0.80-1.00 was considered very strong expression.	('CDCA3', 'Gene', '83461', (68, 73))	('0.30-0.59', 'Var', (169, 178))	('association', 'Interaction', (48, 59))	('CDCA3', 'Gene', (68, 73))
40834	33604380	Here, logrank p < 0.05 was statistically significant, and significance of HR referred to the ratio of risk rate produced by the application of high expression of CDCA3 to the risk rate produced by low expression of CDCA3.	('CDCA3', 'Gene', '83461', (162, 167))	('high expression', 'Var', (143, 158))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (215, 220))	('CDCA3', 'Gene', '83461', (215, 220))
40856	33604380	As revealed by PPS (HR = 0.67, 95%CI = 0.54-0.84, p = 0.00038) (Figure 2(j)), the high CDCA3 expression was associated with the better prognosis in gastric cancer because the HR < 1 and p < 0.05.	('PPS', 'Chemical', '-', (15, 18))	('CDCA3', 'Gene', (87, 92))	('gastric cancer', 'Disease', (148, 162))	('high', 'Var', (82, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('expression', 'MPA', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CDCA3', 'Gene', '83461', (87, 92))
40859	33604380	These results indicated that a high expression of CDCA3 had a strong association with poor outcomes for patients with various cancers, especially in HCC, and the correlation depended on the type of tumor.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HCC', 'Phenotype', 'HP:0001402', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('CDCA3', 'Gene', '83461', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancers', 'Disease', (126, 133))	('CDCA3', 'Gene', (50, 55))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('high', 'Var', (31, 35))	('tumor', 'Disease', (198, 203))	('patients', 'Species', '9606', (104, 112))	('expression', 'MPA', (36, 46))	('HCC', 'Disease', (149, 152))
40866	33604380	p < 0.05 was statistically significant, and the hazard ratio > 1 represented the higher risk factors produced by high CDCA3 expression affected in the prognosis of patients with different clinicopathologic features.	('high', 'Var', (113, 117))	('CDCA3', 'Gene', '83461', (118, 123))	('CDCA3', 'Gene', (118, 123))	('expression', 'MPA', (124, 134))	('patients', 'Species', '9606', (164, 172))	('affected', 'Reg', (135, 143))
40870	33604380	It was remarkable that the hazard ratio (HR) of CDCA3 expression in univariate analysis equaled to 2.075, the value of HR and the p < 0.001 both indicated that CDCA3 can predict the prognosis in HCC, and the hazard ratio revealed that the patients with high CDCA3 expression had 2.075 times of higher risk in poor OS than the patients with low CDCA3 expression in univariate analysis.	('CDCA3', 'Gene', (258, 263))	('high', 'Var', (253, 257))	('CDCA3', 'Gene', (48, 53))	('CDCA3', 'Gene', '83461', (344, 349))	('poor OS', 'Disease', (309, 316))	('CDCA3', 'Gene', (344, 349))	('patients', 'Species', '9606', (239, 247))	('patients', 'Species', '9606', (326, 334))	('CDCA3', 'Gene', '83461', (160, 165))	('CDCA3', 'Gene', (160, 165))	('HCC', 'Disease', (195, 198))	('HCC', 'Phenotype', 'HP:0001402', (195, 198))	('expression', 'Var', (264, 274))	('CDCA3', 'Gene', '83461', (258, 263))	('CDCA3', 'Gene', '83461', (48, 53))
40872	33604380	The results showed that high expression of CDCA3 was associated with poor outcomes in HCC patients, and it could act as a potential independent predictor of survival (HR = 2.037; 95%CI = 1.484-2.796; p < 0.001; Figure 3(d)) by excluding confounding factors.	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('high', 'Var', (24, 28))	('HCC', 'Disease', (86, 89))	('patients', 'Species', '9606', (90, 98))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
40873	33604380	Besides, the value of the hazard ratio revealed that the patients with high CDCA3 expression had 2.037 times of higher risk in poor OS than the patients with low CDCA3 expression.	('poor OS', 'Disease', (127, 134))	('CDCA3', 'Gene', '83461', (162, 167))	('CDCA3', 'Gene', '83461', (76, 81))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (76, 81))	('expression', 'Var', (82, 92))	('patients', 'Species', '9606', (144, 152))
40880	33604380	The results showed that high expression of CDCA3 was associated with poor prognosis of patients, high levels of infiltrating immune cells, and tumor purity in HCC and ACC.	('tumor', 'Disease', (143, 148))	('patients', 'Species', '9606', (87, 95))	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('ACC', 'Phenotype', 'HP:0006744', (167, 170))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('expression', 'MPA', (29, 39))	('HCC', 'Disease', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
40883	33604380	The high CDCA3 expression was also correlated with a poorer survival (OS: HR = 2.5, p = 6.4E - 07; DFS: HR = 1.8, p = 0.00026) (Figure S1 ac-ad) but was positively related to the infiltrating levels of B cells (partial cor = 0.252, p = 2.42E - 08), CD4+ T cells (partial cor = 0.222, p = 1.01E - 06), macrophages (partial cor = 0.207, p = 5.93E - 06), neutrophils (partial cor = 0.174, p = 1.35E - 04), and dendritic cells (partial cor = 0.229, p = 4.54E - 07) in LGG (Figure S2 s).	('CDCA3', 'Gene', '83461', (9, 14))	('CDCA3', 'Gene', (9, 14))	('related', 'Reg', (164, 171))	('expression', 'MPA', (15, 25))	('high', 'Var', (4, 8))	('CD4', 'Gene', (249, 252))	('CD4', 'Gene', '920', (249, 252))
40911	33604380	According to the univariate and multivariate analyses, we identified that T stage, M stage, and CDCA3 expression had significant prognostic values for predicting the survival of patients with HCC; in fact, the high expression determined poor OS of patients with HCC and suggested that increased CDCA3 expression deteriorated the state of patients with HCC.	('HCC', 'Phenotype', 'HP:0001402', (262, 265))	('HCC', 'Disease', (352, 355))	('CDCA3', 'Gene', (96, 101))	('increased', 'PosReg', (285, 294))	('HCC', 'Phenotype', 'HP:0001402', (352, 355))	('patients', 'Species', '9606', (178, 186))	('determined', 'Reg', (226, 236))	('HCC', 'Phenotype', 'HP:0001402', (192, 195))	('high', 'Var', (210, 214))	('CDCA3', 'Gene', '83461', (295, 300))	('patients', 'Species', '9606', (338, 346))	('patients', 'Species', '9606', (248, 256))	('HCC', 'Disease', (262, 265))	('CDCA3', 'Gene', (295, 300))	('CDCA3', 'Gene', '83461', (96, 101))
40915	33604380	Thus, CDCA3 expression can potentially influence the immunosuppressive effect in HCC.	('influence', 'Reg', (39, 48))	('HCC', 'Disease', (81, 84))	('expression', 'Var', (12, 22))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('immunosuppressive', 'MPA', (53, 70))	('CDCA3', 'Gene', '83461', (6, 11))	('CDCA3', 'Gene', (6, 11))
40926	33604380	According to the results of the univariate and multivariate analyses, T stage, M stage, and CDCA3 expression were important prognostic factors for the survival of patients with HCC; importantly, high CDCA3 expression had the potential to be an independent predictor for poor outcome for patients with HCC according to the results of multivariate analyses.	('patients', 'Species', '9606', (163, 171))	('HCC', 'Disease', (301, 304))	('CDCA3', 'Gene', '83461', (200, 205))	('expression', 'MPA', (206, 216))	('HCC', 'Phenotype', 'HP:0001402', (177, 180))	('HCC', 'Phenotype', 'HP:0001402', (301, 304))	('patients', 'Species', '9606', (287, 295))	('CDCA3', 'Gene', (200, 205))	('CDCA3', 'Gene', '83461', (92, 97))	('high', 'Var', (195, 199))	('CDCA3', 'Gene', (92, 97))
40952	32436117	Related studies have found that the loss of mammalian PCL2 leads to increased self-renewal and delayed differentiation of ESCs.	('self-renewal', 'CPA', (78, 90))	('loss', 'Var', (36, 40))	('mammalian', 'Species', '9606', (44, 53))	('delayed differentiation', 'CPA', (95, 118))	('increased', 'PosReg', (68, 77))
40955	32436117	Cases of GBM with H3F3AK27 mutations show high frequency of TP53 mutations, hypomethylation of DNA, midline location and spread of diffuse pontine glioma, and poor prognosis.	('mutations', 'Var', (27, 36))	('H3F3A', 'Gene', '3020', (18, 23))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('hypomethylation', 'Var', (76, 91))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('TP53', 'Gene', '7157', (60, 64))	('H3F3A', 'Gene', (18, 23))	('glioma', 'Disease', (147, 153))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
40956	32436117	Mutations in these genes are closely related to the alternate expansions of specific gene expression profiles, leading to the formation of gliomas.	('leading to', 'Reg', (111, 121))	('gliomas', 'Disease', (139, 146))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))
41009	32436117	In the colony formation experiment, we could obviously see that the number of colonies was reduced after DZNeP treatment (Fig.	('DZNeP treatment', 'Var', (105, 120))	('reduced', 'NegReg', (91, 98))	('DZNeP', 'Chemical', 'MESH:C048460', (105, 110))
41010	32436117	We demonstrated that in U87 cells, DZNeP reduced the increases in the EZH2 protein level caused by hPCL2 expressions and the protein expression of SUZ12 and EED in PRC2 were reduced compared to that in the control (Fig.	('hPCL2', 'Gene', '22823', (99, 104))	('reduced', 'NegReg', (41, 48))	('SUZ12', 'Gene', '23512', (147, 152))	('PRC2', 'Gene', (164, 168))	('hPCL2', 'Gene', (99, 104))	('U87', 'Gene', '641648', (24, 27))	('DZNeP', 'Chemical', 'MESH:C048460', (35, 40))	('SUZ12', 'Gene', (147, 152))	('protein expression', 'MPA', (125, 143))	('reduced', 'NegReg', (174, 181))	('EZH2', 'Gene', (70, 74))	('EZH2', 'Gene', '2146', (70, 74))	('increases', 'PosReg', (53, 62))	('DZNeP', 'Var', (35, 40))	('expressions', 'MPA', (105, 116))	('U87', 'Gene', (24, 27))
41017	32436117	The phenotypes associated with PCL mutations in Drosophila and Xenopus, as well as the colocalization and interaction of PCLs and PRC2, suggest that PCL proteins play a crucial role in PRC2 function.	('Xenopus', 'Species', '8355', (63, 70))	('interaction', 'Interaction', (106, 117))	('PCL', 'Gene', (31, 34))	('Drosophila', 'Species', '7227', (48, 58))	('mutations', 'Var', (35, 44))
41030	32436117	Studies have shown that the absence of EED can lead to abnormal differentiation and functional defects of hematopoietic stem cells (HSPCs).It has been reported in the literature that CRISPR/Cas9-mediated SUZ12 inactivation and mutant JAK3 synergistically drive T cell transformation and T-cell acute lymphoblastic leukemia (T-ALL) development.	('T cell transformation', 'CPA', (261, 282))	('mutant', 'Var', (227, 233))	('inactivation', 'NegReg', (210, 222))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (294, 322))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (287, 322))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (287, 322))	('T-cell acute lymphoblastic leukemia', 'Disease', (287, 322))	('SUZ12', 'Gene', '23512', (204, 209))	('SUZ12', 'Gene', (204, 209))	('drive', 'PosReg', (255, 260))	('leukemia', 'Phenotype', 'HP:0001909', (314, 322))	('JAK3', 'Gene', (234, 238))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (300, 322))	('JAK3', 'Gene', '3718', (234, 238))
41031	32436117	In contrast, in the study of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC), it was found that shRNA-mediated SUZ12 knock-down significantly inhibited tumor cell proliferation, migration and invasion.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (83, 105))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (29, 66))	('inhibited', 'NegReg', (179, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (79, 105))	('SUZ12', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('SUZ12', 'Gene', '23512', (148, 153))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('non-small cell lung cancer', 'Disease', (79, 105))	('knock-down', 'Var', (154, 164))	('NSCLC', 'Disease', (107, 112))	('neck squamous cell carcinoma', 'Disease', (38, 66))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (38, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('HNSC', 'Disease', 'None', (68, 72))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (79, 105))	('tumor', 'Disease', (189, 194))	('invasion', 'CPA', (229, 237))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('HNSC', 'Disease', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
41036	32436117	H3K9 and H3K27 methylation are related to gene silencing, while H3K4 methylation can activate genes.	('gene', 'MPA', (42, 46))	('H3', 'Gene', '126961', (9, 11))	('methylation', 'Var', (15, 26))	('H3', 'Gene', '126961', (64, 66))	('activate', 'PosReg', (85, 93))	('H3', 'Gene', '126961', (0, 2))
41041	32436117	It has been suggested in the latest research that the mutant H3K27, which is a lethal subunit of glioma, appears in the normal H3.	('H3', 'Gene', '126961', (61, 63))	('glioma', 'Disease', (97, 103))	('H3', 'Gene', '126961', (127, 129))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('mutant', 'Var', (54, 60))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
41042	32436117	The ability, recruiting target genes on chromatin by PRC2, does not seem to be affected by the H3K27 mutation, but the transcription will be restricted if the deposition of H3K27me3 and me2 in the whole genome is depleted, and results in affecting gene expression of regulating neurogenesis.	('affecting', 'Reg', (238, 247))	('regulating neurogenesis', 'CPA', (267, 290))	('restricted', 'NegReg', (141, 151))	('me2', 'Gene', '4200', (186, 189))	('deposition', 'MPA', (159, 169))	('H3', 'Gene', '126961', (95, 97))	('me2', 'Gene', (186, 189))	('transcription', 'MPA', (119, 132))	('me3', 'Gene', '109264', (178, 181))	('depleted', 'NegReg', (213, 221))	('gene expression', 'MPA', (248, 263))	('mutation', 'Var', (101, 109))	('H3', 'Gene', '126961', (173, 175))	('me3', 'Gene', (178, 181))
41051	32436117	We found that the expression of PCL2 increased the protein level of EZH2, while DZNeP inhibited the expression of EZH2.	('EZH2', 'Gene', (68, 72))	('DZNeP', 'Chemical', 'MESH:C048460', (80, 85))	('PCL2', 'Gene', (32, 36))	('protein level', 'MPA', (51, 64))	('increased', 'PosReg', (37, 46))	('inhibited', 'NegReg', (86, 95))	('EZH2', 'Gene', '2146', (68, 72))	('EZH2', 'Gene', '2146', (114, 118))	('expression', 'Var', (18, 28))	('EZH2', 'Gene', (114, 118))
41106	32181392	Cell biology; Proteins; Biochemistry; Molecular biology; Biomolecules; MKP-3, DUSP6, FOXO1, p21, H295R, ERK1/2 Multiple biological processes are regulated by the action of mitogen-activated protein kinases (MAPK), such as ERK1/2, JNK1/2 and p38 proteins.	('ERK1', 'Gene', '5595', (222, 226))	('ERK1', 'Gene', (222, 226))	('p38', 'Gene', '5594', (241, 244))	('FOXO1', 'Gene', (85, 90))	('ERK1', 'Gene', '5595', (104, 108))	('ERK1', 'Gene', (104, 108))	('DUSP6', 'Gene', (78, 83))	('DUSP6', 'Gene', '1848', (78, 83))	('H295R', 'Var', (97, 102))	('p38', 'Gene', (241, 244))
41111	32181392	While MKP-1 and MKP-2 (DUSP1 and DUSP4, respectively) are nuclear enzymes induced by different stimuli, MKP-3 or DUSP6 is an ERK-selective cytoplasmic phosphatase induced mainly by proliferative stimuli.	('ERK', 'Gene', '5594', (125, 128))	('DUSP4', 'Gene', '1846', (33, 38))	('DUSP4', 'Gene', (33, 38))	('ERK', 'Gene', (125, 128))	('MKP-2', 'Gene', '1846', (16, 21))	('DUSP1', 'Gene', (23, 28))	('rat', 'Species', '10116', (188, 191))	('DUSP6', 'Gene', (113, 118))	('DUSP6', 'Gene', '1848', (113, 118))	('DUSP1', 'Gene', '1843', (23, 28))	('MKP-3', 'Var', (104, 109))	('MKP-2', 'Gene', (16, 21))
41112	32181392	In addition, splice variants of MKP-2 and MKP-3 have been described in human tissues.	('splice variants', 'Var', (13, 28))	('MKP-2', 'Gene', '1846', (32, 37))	('MKP-3', 'Gene', (42, 47))	('MKP-2', 'Gene', (32, 37))	('human', 'Species', '9606', (71, 76))
41131	32181392	PCR products were resolved on a 1.5% (wt/vol) agarose gel containing 0.5 mug/ml of ethidium bromide to determine the molecular sizes of the amplicons: 830 bp for MKP-3L and 403 bp for MKP-3S.	('MKP-3S', 'Var', (184, 190))	('ethidium bromide', 'Chemical', 'MESH:D004996', (83, 99))	('MKP-3L', 'Var', (162, 168))	('agarose', 'Chemical', 'MESH:D012685', (46, 53))
41136	32181392	In order to detect bound antibodies we used goat anti-rabbit or goat anti-mouse horseradish peroxidase-conjugated as secondary antibodies (Bio-Rad Cat# 170-6515, RRID: AB_11125142 and Cat# 170-6516,RRID:AB_11125547) and the enhanced chemiluminescence detection reagent Bio-Lumina (Kalium Technologies SRL, Buenos Aires, Argentina).	('horseradish', 'Species', '3704', (80, 91))	('Cat# 170-6516', 'Var', (184, 197))	('goat', 'Species', '9925', (44, 48))	('goat', 'Species', '9925', (64, 68))	('rabbit', 'Species', '9986', (54, 60))	('mouse', 'Species', '10090', (74, 79))	('Cat# 170-6515', 'Var', (147, 160))
41149	32181392	As previously reported, Ang II increased P-ERK1/2 levels.	('P-ERK', 'Gene', (41, 46))	('ERK1', 'Gene', '5595', (43, 47))	('ERK1', 'Gene', (43, 47))	('Ang II', 'Var', (24, 30))	('increased', 'PosReg', (31, 40))	('P-ERK', 'Gene', '9451', (41, 46))
41169	32181392	It has been reported that MKP-3 dephosphorylates the non-MAPK substrate transcription factor FOXO1, an effect which leads to the activation of FOXO1-dependent genes encoding for gluconeogenic enzymes.	('rat', 'Species', '10116', (67, 70))	('MKP-3', 'Var', (26, 31))	('FOXO1-dependent genes', 'Gene', (143, 164))	('activation', 'PosReg', (129, 139))	('FOXO1', 'Gene', (93, 98))
41263	31384714	AMH has been thought to be diagnostic of MEN2 syndrome; however, NF1, SDHB, and MAX mutations have all been associated with AMH.	('SDHB', 'Gene', '6390', (70, 74))	('AMH', 'Phenotype', 'HP:0008239', (124, 127))	('MEN2 syndrome', 'Disease', 'MESH:D013577', (41, 54))	('SDHB', 'Gene', (70, 74))	('AMH', 'Disease', (124, 127))	('MEN2 syndrome', 'Disease', (41, 54))	('AMH', 'Chemical', '-', (0, 3))	('mutations', 'Var', (84, 93))	('AMH', 'Chemical', '-', (124, 127))	('associated', 'Reg', (108, 118))	('MAX', 'Gene', (80, 83))	('AMH', 'Phenotype', 'HP:0008239', (0, 3))	('NF1', 'Gene', (65, 68))	('NF1', 'Gene', '4763', (65, 68))
41270	31384714	Moreover, to identify PCCs, all patients with an International Classification of Diseases (ICD) 10th revision code of E27.5 (adrenomedullary hyperfunction) and/or C74.1 (malignant neoplasm of medulla of adrenal gland) being admitted and/or attending the outpatient clinic between 2000 and 2018 at the Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden, were screened.	('PCC', 'Gene', (22, 25))	('E27.5', 'Var', (118, 123))	('patients', 'Species', '9606', (32, 40))	('PCCs', 'Phenotype', 'HP:0002666', (22, 26))	('malignant neoplasm', 'Disease', (170, 188))	('ICD', 'Disease', 'OMIM:252500', (91, 94))	('malignant neoplasm', 'Disease', 'MESH:D009369', (170, 188))	('neoplasm of medulla of adrenal', 'Phenotype', 'HP:0100642', (180, 210))	('ICD', 'Disease', (91, 94))	('neoplasm', 'Phenotype', 'HP:0002664', (180, 188))	('C74.1', 'Var', (163, 168))	('outpatient', 'Species', '9606', (254, 264))	('PCC', 'Gene', '1421', (22, 25))	('Metabolism and Diabetes', 'Disease', 'MESH:D003920', (330, 353))
41278	31384714	An HbA1c 42 to 47 mmol/mol and/or fasting plasma glucose 6 to 6.9 mmol/L and/or random plasma glucose 7.8 to 11 mmol/L was defined as prediabetes; levels above these were defined as diabetes.	('diabetes', 'Disease', 'MESH:D003920', (137, 145))	('glucose', 'Chemical', 'MESH:D005947', (49, 56))	('diabetes', 'Disease', (182, 190))	('glucose', 'Chemical', 'MESH:D005947', (94, 101))	('HbA1c', 'Var', (3, 8))	('diabetes', 'Disease', 'MESH:D003920', (182, 190))	('diabetes', 'Disease', (137, 145))
41282	31384714	As controls, 95 patients with PCC without AMH were identified; however, two patients with adrenocortical cancers and concomitant catecholamine excess but without an eligible ICD code (E275 or C741) were known to us as well, were not included, but have been presented elsewhere.	('patients', 'Species', '9606', (76, 84))	('catecholamine', 'MPA', (129, 142))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('PCC', 'Gene', (30, 33))	('E275', 'Var', (184, 188))	('catecholamine excess', 'Phenotype', 'HP:0003334', (129, 149))	('patients', 'Species', '9606', (16, 24))	('AMH', 'Chemical', '-', (42, 45))	('adrenocortical cancers', 'Disease', (90, 112))	('PCC', 'Gene', '1421', (30, 33))	('ICD', 'Disease', 'OMIM:252500', (174, 177))	('catecholamine', 'Chemical', 'MESH:D002395', (129, 142))	('adrenocortical cancers', 'Disease', 'MESH:D000306', (90, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('C741', 'Var', (192, 196))	('ICD', 'Disease', (174, 177))	('AMH', 'Phenotype', 'HP:0008239', (42, 45))
41335	31384714	However, 20% (2 out of 11) of our hereditary AMH cases were associated with NF1 mutations, which has rarely been described previously.	('NF1', 'Gene', '4763', (76, 79))	('AMH', 'Disease', (45, 48))	('mutations', 'Var', (80, 89))	('AMH', 'Chemical', '-', (45, 48))	('associated', 'Reg', (60, 70))	('AMH', 'Phenotype', 'HP:0008239', (45, 48))	('NF1', 'Gene', (76, 79))
41384	31384714	Not all AMH cases had had a genetic evaluation for all new mutations that are constantly being reported in the field of PCCs.	('AMH', 'Phenotype', 'HP:0008239', (8, 11))	('PCCs', 'Phenotype', 'HP:0002666', (120, 124))	('PCC', 'Gene', (120, 123))	('AMH', 'Chemical', '-', (8, 11))	('mutations', 'Var', (59, 68))	('PCC', 'Gene', '1421', (120, 123))
41398	31122251	Necroptosis can elicit strong adaptive immune responses that may defend against tumor progression; however, the recruited inflammatory response may also promote tumorigenesis and cancer metastasis, and necroptosis may generate an immunosuppressive tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer metastasis', 'Disease', (179, 196))	('tumor', 'Disease', (248, 253))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer metastasis', 'Disease', 'MESH:D009362', (179, 196))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (80, 85))	('immunosuppressive tumor', 'Disease', (230, 253))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (230, 253))	('necroptosis', 'Var', (202, 213))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('promote', 'PosReg', (153, 160))	('tumor', 'Disease', (161, 166))
41405	31122251	However, the evasion of and resistance to apoptosis are also considered indisputable hallmarks of cancer, and resistance to apoptosis is often responsible for both tumorigenesis and drug resistance, resulting in chemotherapy failure.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('drug resistance', 'Phenotype', 'HP:0020174', (182, 197))	('tumor', 'Disease', (164, 169))	('evasion of', 'MPA', (13, 23))	('failure', 'Disease', 'MESH:D017093', (225, 232))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('responsible', 'Reg', (143, 154))	('cancer', 'Disease', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('failure', 'Disease', (225, 232))	('resistance to apoptosis', 'Var', (110, 133))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
41418	31122251	This membrane-bound multimeric protein complex is named complex I, and within this complex, RIPK1, which is a crucial regulator of cell fate, is polyubiquitinated by cIAP1/2, which, in turn, induces the canonical NF-kappaB (nuclear factor kappa B) pathway, which transactivates cytoprotective genes and facilitates cell survival.	('RIPK1', 'Gene', (92, 97))	('nuclear factor kappa B', 'Gene', '4790', (224, 246))	('transactivates', 'PosReg', (263, 277))	('cIAP1', 'Gene', (166, 171))	('cytoprotective genes', 'Gene', (278, 298))	('facilitates', 'PosReg', (303, 314))	('induces', 'PosReg', (191, 198))	('cIAP1', 'Gene', '329', (166, 171))	('polyubiquitinated', 'Var', (145, 162))	('cell survival', 'CPA', (315, 328))	('nuclear factor kappa B', 'Gene', (224, 246))
41432	31122251	When RIPK1 is polyubiquitinated by cIAP1/2, NF-kappaB pathway is activated and cell survival prevails.	('cell survival', 'CPA', (79, 92))	('cIAP1', 'Gene', (35, 40))	('cIAP1', 'Gene', '329', (35, 40))	('polyubiquitinated', 'Var', (14, 31))	('NF-kappaB pathway', 'Pathway', (44, 61))	('activated', 'PosReg', (65, 74))	('RIPK1', 'Gene', (5, 10))
41433	31122251	When RIPK1 is deubiquitinated by CYLD, NF-kappaB pathway was limited and complex II composed of RIPK1, TRADD, caspase 8 and FADD was formed.	('limited', 'NegReg', (61, 68))	('RIPK1', 'Var', (96, 101))	('caspase 8', 'Gene', '841', (110, 119))	('NF-kappaB pathway', 'Pathway', (39, 56))	('caspase 8', 'Gene', (110, 119))	('FADD', 'Gene', '8772', (124, 128))	('FADD', 'Gene', (124, 128))	('CYLD', 'Gene', (33, 37))	('CYLD', 'Gene', '1540', (33, 37))
41442	31122251	Autophagy reportedly saves ATP- depleted cells from necrosis/necroptosis by restoring energy, and the inhibition of autophagy may incur a metabolic crisis and promote necroptosis.	('necrosis/necroptosis', 'Disease', (52, 72))	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('restoring', 'PosReg', (76, 85))	('inhibition', 'Var', (102, 112))	('necrosis/necroptosis', 'Disease', 'MESH:D009336', (52, 72))	('Autophagy', 'CPA', (0, 9))	('incur', 'NegReg', (130, 135))	('promote', 'PosReg', (159, 166))	('autophagy', 'CPA', (116, 125))	('metabolic crisis', 'CPA', (138, 154))	('energy', 'MPA', (86, 92))	('necroptosis', 'CPA', (167, 178))
41445	31122251	showed that in the background of Map3k7 deletion, the autophagic pathway may switch the cell death mode to from apoptosis to necroptosis by acting as a scaffold allowing the necrosome to be more efficiently activated, which is mediated by the p62-dependent recruitment of RIPK1 to the autophagic machinery.	('p62', 'Gene', (243, 246))	('Map3k7', 'Gene', (33, 39))	('switch', 'Reg', (77, 83))	('Map3k7', 'Gene', '6885', (33, 39))	('deletion', 'Var', (40, 48))	('autophagic pathway', 'Pathway', (54, 72))	('p62', 'Gene', '23636', (243, 246))
41449	31122251	Moreover, RIPK3 can also promote the activity of glutamate-ammonia ligase (GLUL) and glutamate dehydrogenase 1 (GLUD1), two enzymes involved in glutaminolysis, which may as well contribute to elevated ROS generation.	('glutamate-ammonia ligase', 'Gene', '2752', (49, 73))	('GLUD1', 'Gene', '2746', (112, 117))	('GLUD1', 'Gene', (112, 117))	('glutamate-ammonia ligase', 'Gene', (49, 73))	('elevated', 'PosReg', (192, 200))	('RIPK3', 'Var', (10, 15))	('promote', 'PosReg', (25, 32))	('activity', 'MPA', (37, 45))	('ROS', 'Chemical', 'MESH:D017382', (201, 204))	('ROS generation', 'MPA', (201, 215))	('elevated ROS generation', 'Phenotype', 'HP:0025464', (192, 215))
41463	31122251	Nevertheless, as a necrotic cell death modality, necroptosis can trigger inflammatory responses and reportedly promotes cancer metastasis and immunosuppression.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer metastasis', 'Disease', 'MESH:D009362', (120, 137))	('necrotic cell death modality', 'Disease', (19, 47))	('inflammatory responses', 'CPA', (73, 95))	('necrotic cell death modality', 'Disease', 'MESH:D003643', (19, 47))	('promotes', 'PosReg', (111, 119))	('trigger', 'Reg', (65, 72))	('cancer metastasis', 'Disease', (120, 137))	('necroptosis', 'Var', (49, 60))
41467	31122251	reported that leukemogenesis was markedly accelerated following the knockout of RIPK3 in mice transplanted with bone marrow cells bearing a mutated AML driver gene and that the survival of the RIPK3 knockout mice was poorer than that of the wild-type mice.	('mice', 'Species', '10090', (251, 255))	('RIPK3', 'Gene', (80, 85))	('AML', 'Phenotype', 'HP:0004808', (148, 151))	('mice', 'Species', '10090', (89, 93))	('knockout', 'Var', (68, 76))	('AML', 'Disease', (148, 151))	('leukemogenesis', 'Disease', (14, 28))	('accelerated', 'PosReg', (42, 53))	('AML', 'Disease', 'MESH:D015470', (148, 151))	('mice', 'Species', '10090', (208, 212))
41469	31122251	In a cohort study involving more than one hundred patients, low RIPK3 expression was found to independently prognosticate a reduced DFS (disease-free survival) and OS (overall survival).	('reduced', 'NegReg', (124, 131))	('patients', 'Species', '9606', (50, 58))	('DFS', 'CPA', (132, 135))	('low', 'Var', (60, 63))	('expression', 'MPA', (70, 80))	('RIPK3', 'Gene', (64, 69))	('OS', 'Chemical', '-', (164, 166))
41470	31122251	Furthermore, RIPK3 knockout mice were reportedly at a higher risk of developing colitis-associated colorectal cancer and producing a higher number of pro-inflammatory or tumor-promoting factors.	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('knockout', 'Var', (19, 27))	('colorectal cancer', 'Disease', (99, 116))	('mice', 'Species', '10090', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('higher', 'PosReg', (133, 139))	('colitis', 'Disease', 'MESH:D003092', (80, 87))	('tumor', 'Disease', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('colitis', 'Disease', (80, 87))	('RIPK3', 'Gene', (13, 18))	('colitis', 'Phenotype', 'HP:0002583', (80, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
41476	31122251	The authors suggested that the downregulation of RIPK1 expression promoted by epigenetic changes during tumor progression enables tumor cells to evade anoikis, which may stimulate tumorigenesis by enhancing the metastatic abilities of the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('epigenetic changes', 'Var', (78, 96))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', (180, 185))	('expression', 'MPA', (55, 65))	('RIPK1', 'Gene', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (239, 244))	('downregulation', 'NegReg', (31, 45))	('stimulate', 'PosReg', (170, 179))	('tumor', 'Disease', (130, 135))	('enhancing', 'PosReg', (197, 206))
41504	31122251	Necroptosis has also been shown to generate an immunosuppressive tumor microenvironment in vivo in PDA and, thus, promote the oncogenesis of pancreatic cancer.	('PDA', 'Phenotype', 'HP:0006725', (99, 102))	('PDA', 'Disease', (99, 102))	('immunosuppressive tumor', 'Disease', (47, 70))	('pancreatic cancer', 'Disease', (141, 158))	('oncogenesis', 'CPA', (126, 137))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (47, 70))	('PDA', 'Chemical', '-', (99, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Necroptosis', 'Var', (0, 11))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (141, 158))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('promote', 'PosReg', (114, 121))
41505	31122251	In RIPK3 knockout p48Cre;KrasG12D pancreases, the percentages of B cells and T cells were elevated, the percentages of peritumoral myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), both of which can not only inhibit antitumor immune reactions but also stimulate tumor growth and metastasis, were reduced and the expression of programmed death-ligand 1(PD-L1), a ligand which negatively regulates T cell antigen receptor signaling through interacting with its receptor PD-1, in macrophages was decreased.	('KrasG12D', 'Var', (25, 33))	('TAMs', 'Chemical', '-', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('expression', 'MPA', (344, 354))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('reduced', 'NegReg', (328, 335))	('decreased', 'NegReg', (525, 534))	('stimulate', 'PosReg', (284, 293))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', (176, 181))	('T cell antigen receptor signaling', 'MPA', (428, 461))	('T cells', 'CPA', (77, 84))	('thr', 'Chemical', 'MESH:D013912', (462, 465))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('PD-1', 'Gene', (500, 504))	('PD-1', 'Gene', '5133', (500, 504))	('RIPK3', 'Gene', (3, 8))	('elevated', 'PosReg', (90, 98))	('p48Cre', 'Var', (18, 24))	('PD-L1', 'Gene', '29126', (384, 389))	('B cells', 'CPA', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('PD-L1', 'Gene', (384, 389))	('knockout p48Cre', 'Var', (9, 24))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('inhibit', 'NegReg', (240, 247))	('tumor', 'Disease', (252, 257))
41506	31122251	Furthermore, the blockade of necroptosis may expand and activate T cells, which is a promising avenue for ameliorating the unsatisfactory efficacy of checkpoint-based immunotherapeutics in pancreatic cancer.	('pancreatic cancer', 'Disease', (189, 206))	('pancreatic cancer', 'Disease', 'MESH:D010190', (189, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('blockade', 'Var', (17, 25))	('expand', 'PosReg', (45, 51))	('activate', 'PosReg', (56, 64))	('necroptosis', 'Gene', (29, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (189, 206))	('T cells', 'CPA', (65, 72))
41508	31122251	demonstrated that in several breast cancer cell lines, the knockout of the RIPK1, RIPK3, or MLKL genes in cancer cells markedly reduced their tumorigenicity and appeared to sensitize breast cancer cells to radiotherapy.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Disease', (106, 112))	('knockout', 'Var', (59, 67))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('breast cancer', 'Disease', (183, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('RIPK1', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('reduced', 'NegReg', (128, 135))	('RIPK3', 'Gene', (82, 87))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('MLKL', 'Gene', (92, 96))	('breast cancer', 'Disease', (29, 42))	('tumor', 'Disease', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('radiotherapy', 'CPA', (206, 218))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('sensitize', 'Reg', (173, 182))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
41511	31122251	reported that the in vivo deletion of RIPK3 or RIPK1 attenuated tumor progression and immunosuppression in mice and explained these results by suggesting that necroptosis promoted pancreatic oncogenesis because CXCL1 (chemokine (C-X-C motif) ligand 1), which is a chemokine attractant, and Mincle signaling induced by necroptosis promotes the induction of adaptive immunosuppression by myeloid cells.	('CXCL1', 'Gene', (211, 216))	('chemokine (C-X-C motif) ligand 1', 'Gene', '14825', (218, 250))	('pancreatic oncogenesis', 'Disease', (180, 202))	('RIPK1 attenuated tumor', 'Disease', (47, 69))	('adaptive immunosuppression', 'CPA', (356, 382))	('promotes', 'PosReg', (330, 338))	('promoted', 'PosReg', (171, 179))	('deletion', 'Var', (26, 34))	('RIPK1 attenuated tumor', 'Disease', 'MESH:C538265', (47, 69))	('Mincle', 'Gene', (290, 296))	('mice', 'Species', '10090', (107, 111))	('CXCL1', 'Gene', '14825', (211, 216))	('Mincle', 'Gene', '56619', (290, 296))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('pancreatic oncogenesis', 'Disease', 'MESH:D063646', (180, 202))	('RIPK3', 'Gene', (38, 43))
41519	31122251	However, contrasting evidence indicates that under certain circumstances, necroptosis may promote cancer cell metastasis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('necroptosis', 'Var', (74, 85))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('promote', 'PosReg', (90, 97))	('cancer', 'Disease', (98, 104))
41525	31122251	explained that endothelial cells subjected to necroptotic death provide a tunnel through which tumor cells can pass and start to extravasate and/or the DAMP (damage-associated molecular pattern) molecules generated by necroptotic cells exert effects on tumor cells and adjacent endothelial cells, thus promoting the extravasation and metastasis of cancer cells.	('metastasis of cancer', 'Disease', (334, 354))	('metastasis of cancer', 'Disease', 'MESH:D009362', (334, 354))	('promoting', 'PosReg', (302, 311))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('necroptotic', 'Var', (218, 229))	('extravasation', 'MPA', (316, 329))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('tumor', 'Disease', (253, 258))	('thr', 'Chemical', 'MESH:D013912', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
41528	31122251	Whether necroptosis facilitates or suppresses tumor growth and metastasis cannot be conclusively determined.	('necroptosis', 'Var', (8, 19))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('facilitates', 'PosReg', (20, 31))	('tumor', 'Disease', (46, 51))	('suppresses', 'NegReg', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
41531	31122251	Additionally, the pharmacological or genetic inhibition of necroptosis reverts the necroptosis-dominated microenvironment and converts ICC to HCC, which further substantiates the role of necroptosis in determining liver cancer subtypes.	('liver cancer', 'Disease', (214, 226))	('ICC', 'Disease', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('reverts', 'NegReg', (71, 78))	('HCC', 'Gene', '619501', (142, 145))	('necroptosis-dominated microenvironment', 'MPA', (83, 121))	('HCC', 'Phenotype', 'HP:0001402', (142, 145))	('HCC', 'Gene', (142, 145))	('pharmacological', 'Var', (18, 33))	('liver cancer', 'Phenotype', 'HP:0002896', (214, 226))	('liver cancer', 'Disease', 'MESH:D006528', (214, 226))	('converts', 'Reg', (126, 134))
41533	31122251	Inducing and/or manipulating necroptosis in anti-cancer therapies represent a promising therapeutic approach for bypassing acquired or intrinsic apoptosis-resistance, serving as an alternative way to eliminate apoptosis- resistant cancer cells.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (231, 237))	('necroptosis', 'Gene', (29, 40))	('ser', 'Chemical', 'MESH:D012694', (167, 170))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('manipulating', 'Var', (16, 28))	('cancer', 'Disease', (49, 55))
41569	31122251	CD95L has been reported to induce necroptosis upon the downregulation of cIAPs, which polyubiquitinate RIPK1 to steer the pathway towards NF-kappaB signaling.	('cIAPs', 'Gene', (73, 78))	('steer', 'Reg', (112, 117))	('polyubiquitinate', 'Var', (86, 102))	('RIPK1', 'Gene', (103, 108))	('CD95L', 'Gene', (0, 5))	('induce', 'PosReg', (27, 33))	('CD95L', 'Gene', '356', (0, 5))	('necroptosis', 'Disease', (34, 45))	('NF-kappaB signaling', 'Pathway', (138, 157))	('downregulation', 'NegReg', (55, 69))
41574	31122251	For instance, in ovarian cancer cells, vaccinia virus can cause necroptosis.	('vaccinia virus', 'Var', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (17, 31))	('cause', 'Reg', (58, 63))	('ovarian cancer', 'Disease', 'MESH:D010051', (17, 31))	('ovarian cancer', 'Disease', (17, 31))	('necroptosis', 'Disease', (64, 75))
41590	31122251	reported that proteasome inhibitors MG132 and bortezomib can trigger the RIPK3/MLKL dependent necroptosis in both fibroblasts in mouse models and human leukemia cells.	('trigger', 'Reg', (61, 68))	('mouse', 'Species', '10090', (129, 134))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('human', 'Species', '9606', (146, 151))	('leukemia', 'Disease', 'MESH:D007938', (152, 160))	('leukemia', 'Disease', (152, 160))	('RIPK3/MLKL', 'Protein', (73, 83))	('MG132', 'Var', (36, 41))	('MG132', 'Chemical', 'MESH:C072553', (36, 41))	('bortezomib', 'Chemical', 'MESH:D000069286', (46, 56))
41594	31122251	Polyinosinic:polycytidylic acid (PolyI:C), which is a viral dsRNA analog, was reported to trigger necroptosis in cervical cancer, which strictly depended on the expression of RIPK3.	('Polyinosinic', 'Var', (0, 12))	('necroptosis in cervical cancer', 'Disease', (98, 128))	('trigger', 'PosReg', (90, 97))	('PolyI:C', 'Chemical', 'MESH:D011070', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Polyinosinic:polycytidylic acid', 'Chemical', 'MESH:D011070', (0, 31))	('necroptosis in cervical cancer', 'Disease', 'MESH:D002583', (98, 128))
41596	31122251	In colon carcinoma cell lines, in addition to inducing immune or macrophage activation, PolyI:C can trigger necroptosis alone or combined with the pan-caspase inhibitor zVAD, supporting tumor retardation mediated by immune effectors in vivo.	('colon carcinoma', 'Disease', 'MESH:D015179', (3, 18))	('PolyI:C', 'Var', (88, 95))	('colon carcinoma', 'Disease', (3, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor retardation', 'Disease', 'MESH:D009369', (186, 203))	('tumor retardation', 'Disease', (186, 203))	('supporting', 'PosReg', (175, 185))	('necroptosis', 'CPA', (108, 119))	('inducing', 'Reg', (46, 54))	('zVAD', 'Chemical', '-', (169, 173))	('trigger', 'Reg', (100, 107))	('PolyI:C', 'Chemical', 'MESH:D011070', (88, 95))
41617	31122251	The current knowledge and evidence are inadequate to determine whether necroptosis generally promotes or suppresses tumor cell growth and/or cancer metastasis.	('necroptosis', 'Var', (71, 82))	('suppresses', 'NegReg', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer metastasis', 'Disease', (141, 158))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer metastasis', 'Disease', 'MESH:D009362', (141, 158))	('promotes', 'PosReg', (93, 101))	('tumor', 'Disease', (116, 121))
41746	28516062	IP3R activity can be suppressed by compounds like xestospongin B, which directly inhibits IP3Rs, or U73122, which inhibits PLC activity.	('inhibits', 'NegReg', (81, 89))	('U73122', 'Chemical', 'MESH:C060229', (100, 106))	('IP3R', 'Gene', '3710', (90, 94))	('inhibits', 'NegReg', (114, 122))	('suppressed', 'NegReg', (21, 31))	('U73122', 'Var', (100, 106))	('PLC activity', 'MPA', (123, 135))	('IP3R', 'Gene', '3710', (0, 4))	('IP3R', 'Gene', (0, 4))	('IP3R', 'Gene', (90, 94))	('xestospongin B', 'Chemical', 'MESH:C078549', (50, 64))
41771	28516062	This locally released H2O2 sensitizes IP3Rs to low concentrations of agonists and stimulates Ca2+ oscillations, thereby further boosting mitochondrial bioenergetics.	('Ca2', 'Gene', '760', (93, 96))	('mitochondrial bioenergetics', 'MPA', (137, 164))	('stimulates', 'PosReg', (82, 92))	('Ca2', 'Gene', (93, 96))	('IP3R', 'Gene', (38, 42))	('IP3R', 'Gene', '3710', (38, 42))	('H2O2', 'Var', (22, 26))	('H2O2', 'Chemical', 'MESH:D006861', (22, 26))	('boosting', 'PosReg', (128, 136))
41775	28516062	As a consequence, changes in the ER Ca2+-store content will eventually impact the level of Ca2+ transfer from the ER to the mitochondria and thus eventually cell death and survival decisions.	('changes', 'Var', (18, 25))	('Ca2', 'Gene', '760', (36, 39))	('Ca2', 'Gene', '760', (91, 94))	('cell death', 'CPA', (157, 167))	('Ca2', 'Gene', (36, 39))	('Ca2', 'Gene', (91, 94))	('impact', 'NegReg', (71, 77))	('survival decisions', 'CPA', (172, 190))
41779	28516062	The decrease in [Ca2+]ER can either induce autophagy due to an impaired basal mitochondrial Ca2+ transfer or suppress autophagy due to diminished [Ca2+]cyt increases.	('Ca2', 'Gene', (17, 20))	('Ca2', 'Gene', (92, 95))	('Ca2', 'Gene', '760', (92, 95))	('suppress', 'NegReg', (109, 117))	('autophagy', 'CPA', (118, 127))	('Ca2', 'Gene', '760', (147, 150))	('Ca2', 'Gene', '760', (17, 20))	('autophagy', 'CPA', (43, 52))	('decrease', 'Var', (4, 12))	('diminished', 'NegReg', (135, 145))	('induce', 'Reg', (36, 42))	('impaired', 'NegReg', (63, 71))	('Ca2', 'Gene', (147, 150))
41782	28516062	This is supported by observations made in DT40 B-lymphocytes in which all three IP3R isoforms have been deleted.	('IP3R', 'Gene', (80, 84))	('IP3R', 'Gene', '3710', (80, 84))	('deleted', 'Var', (104, 111))
41789	28516062	It was proposed that antiapoptotic Bcl-2, by lowering the ER Ca2+ levels, could suppress cytosolic Ca2+ signals evoked by various pharmacological and physiological agents, thereby counteracting the activation of CaMKKbeta-controlled autophagy.	('Bcl-2', 'Gene', (35, 40))	('Bcl-2', 'Gene', '596', (35, 40))	('suppress', 'NegReg', (80, 88))	('antiapoptotic', 'Var', (21, 34))	('Ca2', 'Gene', '760', (99, 102))	('Ca2', 'Gene', '760', (61, 64))	('lowering', 'NegReg', (45, 53))	('Ca2', 'Gene', (99, 102))	('Ca2', 'Gene', (61, 64))
41798	28516062	Many cell death-inducing agents, like H2O2, arachidonic acid, ceramide, and menadione have been shown to act at the ER by triggering Ca2+ release through IP3Rs and subsequently provoking mitochondrial Ca2+ rises.	('H2O2', 'Var', (38, 42))	('triggering', 'Reg', (122, 132))	('menadione', 'Chemical', 'MESH:D024483', (76, 85))	('ceramide', 'Chemical', 'MESH:D002518', (62, 70))	('provoking', 'Reg', (177, 186))	('IP3R', 'Gene', '3710', (154, 158))	('Ca2', 'Gene', (201, 204))	('arachidonic acid', 'Chemical', 'MESH:D016718', (44, 60))	('Ca2', 'Gene', '760', (133, 136))	('IP3R', 'Gene', (154, 158))	('Ca2', 'Gene', (133, 136))	('Ca2', 'Gene', '760', (201, 204))	('H2O2', 'Chemical', 'MESH:D006861', (38, 42))
41806	28516062	This mechanism has been shown to be responsible for the sustained proliferation of cells deficient in promyelocytic leukemia protein (PML), a tumor suppressor present at the MAMs that augments ER-mitochondrial Ca2+ flux on the one hand and excessive chemotherapeutic resistance on the other hand.	('Ca2', 'Gene', (210, 213))	('PML', 'Gene', '5371', (134, 137))	('augments', 'PosReg', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('MAM', 'Gene', (174, 177))	('tumor', 'Disease', (142, 147))	('promyelocytic leukemia protein', 'Gene', '5371', (102, 132))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (102, 124))	('deficient', 'Var', (89, 98))	('Ca2', 'Gene', '760', (210, 213))	('PML', 'Gene', (134, 137))	('MAM', 'Gene', '6445', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('leukemia', 'Phenotype', 'HP:0001909', (116, 124))	('promyelocytic leukemia protein', 'Gene', (102, 132))
41807	28516062	Indeed, loss of PML reduced basal ER-mitochondrial Ca2+ transfers, thereby inducing sustained autophagy, promoting malignant cell survival and reduced chemotherapy-induced apoptosis contributing to poor chemotherapeutic efficacy (Table 1).	('reduced', 'NegReg', (20, 27))	('Ca2', 'Gene', (51, 54))	('PML', 'Gene', (16, 19))	('autophagy', 'CPA', (94, 103))	('loss', 'Var', (8, 12))	('promoting', 'PosReg', (105, 114))	('malignant cell survival', 'CPA', (115, 138))	('chemotherapy-induced apoptosis', 'CPA', (151, 181))	('Ca2', 'Gene', '760', (51, 54))	('PML', 'Gene', '5371', (16, 19))	('inducing', 'Reg', (75, 83))	('reduced', 'NegReg', (143, 150))
41809	28516062	Mitochondrial fragmentation leads to Bax-dependent apoptosis, while hyperfusion of mitochondria in response to a decline in Drp1 results in proliferation.	('hyperfusion', 'PosReg', (68, 79))	('proliferation', 'CPA', (140, 153))	('Bax', 'Gene', (37, 40))	('leads to', 'Reg', (28, 36))	('Drp1', 'Gene', '10059', (124, 128))	('decline', 'NegReg', (113, 120))	('Drp1', 'Gene', (124, 128))	('apoptosis', 'CPA', (51, 60))	('Bax', 'Gene', '581', (37, 40))	('Mitochondrial', 'Var', (0, 13))
41811	28516062	Mitochondrial hyperfusion may also render cells more sensitive to apoptotic stimuli due to hyperpolarization of the mitochondrial membrane and thus an increased driving force for mitochondrial Ca2+ uptake.	('Ca2', 'Gene', '760', (193, 196))	('increased', 'PosReg', (151, 160))	('sensitive', 'MPA', (53, 62))	('hyperfusion', 'Var', (14, 25))	('Ca2', 'Gene', (193, 196))	('hyperpolarization', 'MPA', (91, 108))	('driving force', 'MPA', (161, 174))
41817	28516062	Inhibition of IP3Rs and thus spontaneous Ca2+ signals lead to reduced mitochondrial bioenergetics and increased autophagy, allowing cell survival.	('increased', 'PosReg', (102, 111))	('Ca2', 'Gene', (41, 44))	('mitochondrial bioenergetics', 'CPA', (70, 97))	('IP3R', 'Gene', '3710', (14, 18))	('Inhibition', 'Var', (0, 10))	('allowing', 'PosReg', (123, 131))	('IP3R', 'Gene', (14, 18))	('Ca2', 'Gene', '760', (41, 44))	('autophagy', 'CPA', (112, 121))	('reduced', 'NegReg', (62, 69))
41821	28516062	Strikingly, inhibition of IP3R activity, knockdown of IP3R or MCU led in both normal and cancer cells to a so-called "bioenergetic crisis" characterized by a decreased basal and maximal oxygen consumption rate and increased AMPK phosphorylation, subsequently resulting in an increased autophagic flux.	('MCU', 'Gene', (62, 65))	('increased', 'PosReg', (275, 284))	('decreased', 'NegReg', (158, 167))	('autophagic flux', 'CPA', (285, 300))	('IP3R', 'Gene', '3710', (54, 58))	('MCU', 'Gene', '90550', (62, 65))	('IP3R', 'Gene', (26, 30))	('IP3R', 'Gene', (54, 58))	('IP3R', 'Gene', '3710', (26, 30))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('AMPK', 'Gene', '5562', (224, 228))	('increased', 'PosReg', (214, 223))	('cancer', 'Disease', (89, 95))	('AMPK', 'Gene', (224, 228))	('oxygen', 'Chemical', 'MESH:D010100', (186, 192))	('knockdown', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
41822	28516062	However, these interventions resulted in cell death in the cancer cells but not in the normal cells, indicating that autophagy upregulation induced upon IP3R inhibition was sufficient to sustain cell survival in the normal cells but not in cancer cells.	('cell survival', 'CPA', (195, 208))	('IP3R', 'Gene', (153, 157))	('autophagy', 'CPA', (117, 126))	('cancer', 'Disease', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('inhibition', 'Var', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('upregulation', 'PosReg', (127, 139))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('IP3R', 'Gene', '3710', (153, 157))
41835	28516062	Instead, nucleoside complementation could rescue the death of the cancer cells induced by IP3R inhibition, indicating that constitutive ER-mitochondrial Ca2+ fluxes are required for cancer cell survival by sustaining an adequate source of mitochondrial substrates for nucleotide synthesis.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('IP3R', 'Gene', '3710', (90, 94))	('inhibition', 'Var', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Ca2', 'Gene', '760', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('Ca2', 'Gene', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('death of the cancer', 'Disease', 'MESH:D003643', (53, 72))	('cancer', 'Disease', (182, 188))	('nucleoside', 'Chemical', 'MESH:D009705', (9, 19))	('IP3R', 'Gene', (90, 94))	('cancer', 'Disease', (66, 72))	('death of the cancer', 'Disease', (53, 72))
41845	28516062	Strikingly, silencing of MCU blunted cell invasiveness without affecting cell viability.	('cell invasiveness', 'CPA', (37, 54))	('MCU', 'Gene', (25, 28))	('blunted', 'NegReg', (29, 36))	('MCU', 'Gene', '90550', (25, 28))	('silencing', 'Var', (12, 21))
41846	28516062	The in vivo growth of breast cancer cells in which MCU was deleted was severely impaired, correlating with an altered cellular redox state and impaired mitochondrial production of ATP.	('breast cancer', 'Disease', (22, 35))	('deleted', 'Var', (59, 66))	('cellular redox state', 'MPA', (118, 138))	('MCU', 'Gene', (51, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('altered', 'Reg', (110, 117))	('impaired', 'NegReg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mitochondrial production', 'MPA', (152, 176))	('MCU', 'Gene', '90550', (51, 54))	('impaired', 'NegReg', (143, 151))	('ATP', 'Chemical', 'MESH:D000255', (180, 183))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
41858	28516062	However, in cancer cells, the G1/S checkpoint control appears to be lost despite the fact that IP3R inhibition still leads to activation of AMPK, implying defects in the mechanisms linking AMPK to the G1/S checkpoint arrest, for example, mutations impairing p53 activity or hyperactivating CDKs.	('CDKs', 'Gene', (290, 294))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('impairing', 'NegReg', (248, 257))	('p53', 'Gene', (258, 261))	('p53', 'Gene', '7157', (258, 261))	('activity', 'MPA', (262, 270))	('cancer', 'Disease', (12, 18))	('IP3R', 'Gene', '3710', (95, 99))	('mutations', 'Var', (238, 247))	('CDKs', 'Gene', '1017;1019', (290, 294))	('activation', 'PosReg', (126, 136))	('IP3R', 'Gene', (95, 99))	('AMPK', 'Gene', '5562', (140, 144))	('AMPK', 'Gene', (140, 144))	('AMPK', 'Gene', '5562', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('AMPK', 'Gene', (189, 193))	('hyperactivating', 'PosReg', (274, 289))
41859	28516062	Previous work indicated that p53 mutations could result in a bypass of G1/S arrest.	('result in', 'Reg', (49, 58))	('S arrest', 'Disease', 'MESH:D006323', (74, 82))	('mutations', 'Var', (33, 42))	('p53', 'Gene', (29, 32))	('p53', 'Gene', '7157', (29, 32))	('bypass', 'MPA', (61, 67))	('S arrest', 'Disease', (74, 82))
41860	28516062	Thus, re-expression of p53 may restore the G1/S checkpoint control in a number of these cancer cell types exposed to IP3R inhibition, thereby slowing down cell cycle progression and proliferation and preventing cell death by mitotic catastrophe.	('proliferation', 'CPA', (182, 195))	('cancer', 'Disease', (88, 94))	('preventing', 'NegReg', (200, 210))	('cell death', 'CPA', (211, 221))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cell cycle progression', 'CPA', (155, 177))	('restore', 'PosReg', (31, 38))	('IP3R', 'Gene', (117, 121))	('re-expression', 'Var', (6, 19))	('p53', 'Gene', (23, 26))	('IP3R', 'Gene', '3710', (117, 121))	('p53', 'Gene', '7157', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('G1/S checkpoint control', 'MPA', (43, 66))	('mitotic catastrophe', 'CPA', (225, 244))	('slowing down', 'NegReg', (142, 154))
41863	28516062	Upon palmitoylation, TMX1 is recruited to the MAMs, where it binds and inhibits SERCA2b.	('SERCA2b', 'Gene', '11938', (80, 87))	('SERCA2b', 'Gene', (80, 87))	('MAM', 'Gene', '6445', (46, 49))	('TMX1', 'Gene', (21, 25))	('binds', 'Interaction', (61, 66))	('palmitoylation', 'Var', (5, 19))	('TMX1', 'Gene', '81542', (21, 25))	('MAM', 'Gene', (46, 49))	('inhibits', 'NegReg', (71, 79))
41864	28516062	As such, loss of TMX1 accelerates SERCA2b-mediated ER Ca2+ accumulation, particularly in the MAMs.	('accelerates', 'PosReg', (22, 33))	('MAM', 'Gene', '6445', (93, 96))	('TMX1', 'Gene', (17, 21))	('Ca2', 'Gene', '760', (54, 57))	('SERCA2b', 'Gene', (34, 41))	('loss', 'Var', (9, 13))	('Ca2', 'Gene', (54, 57))	('SERCA2b', 'Gene', '11938', (34, 41))	('TMX1', 'Gene', '81542', (17, 21))	('MAM', 'Gene', (93, 96))
41865	28516062	As a consequence, loss of TMX1 in HeLa and A375P, a malignant melanoma cell line, increased ER Ca2+ retention and reduced ER-mitochondrial Ca2+ transfer.	('Ca2', 'Gene', '760', (95, 98))	('loss', 'Var', (18, 22))	('TMX1', 'Gene', (26, 30))	('malignant melanoma', 'Phenotype', 'HP:0002861', (52, 70))	('reduced', 'NegReg', (114, 121))	('Ca2', 'Gene', '760', (139, 142))	('malignant melanoma', 'Disease', 'MESH:D008545', (52, 70))	('TMX1', 'Gene', '81542', (26, 30))	('Ca2', 'Gene', (139, 142))	('Ca2', 'Gene', (95, 98))	('malignant melanoma', 'Disease', (52, 70))	('HeLa', 'CellLine', 'CVCL:0030', (34, 38))	('increased', 'PosReg', (82, 91))	('A375', 'CellLine', 'CVCL:0132', (43, 47))
41867	28516062	Consistent with the work of Foskett and others, loss of TMX1 resulted in increased cell death and increased ROS production in vitro (Table 1).	('increased', 'PosReg', (73, 82))	('TMX1', 'Gene', '81542', (56, 60))	('loss', 'Var', (48, 52))	('ROS', 'Chemical', 'MESH:D017382', (108, 111))	('increased', 'PosReg', (98, 107))	('ROS production', 'MPA', (108, 122))	('increased ROS production', 'Phenotype', 'HP:0025464', (98, 122))	('cell death', 'CPA', (83, 93))	('TMX1', 'Gene', (56, 60))
41868	28516062	Furthermore, while loss of TMX1 in these cancer cell lines accelerated tumor growth, TMX1 overexpression had the opposite effect.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('TMX1', 'Gene', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TMX1', 'Gene', (27, 31))	('TMX1', 'Gene', '81542', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('loss', 'Var', (19, 23))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('accelerated', 'PosReg', (59, 70))	('tumor', 'Disease', (71, 76))	('TMX1', 'Gene', '81542', (27, 31))
41874	28516062	In particular, the differences between IP3R inhibition and loss of TMX1,which both impair mitochondrial bioenergetics and result in spontaneous cell death in vitro but lead to an opposite effect in in vivo tumor growth experiments (impaired upon IP3R inhibition versus accelerated upon TMX1 loss) require further research.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('IP3R', 'Gene', '3710', (39, 43))	('TMX1', 'Gene', (67, 71))	('IP3R', 'Gene', '3710', (246, 250))	('TMX1', 'Gene', '81542', (286, 290))	('IP3R', 'Gene', (39, 43))	('tumor', 'Disease', (206, 211))	('IP3R', 'Gene', (246, 250))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('TMX1', 'Gene', '81542', (67, 71))	('impair', 'NegReg', (83, 89))	('mitochondrial bioenergetics', 'MPA', (90, 117))	('loss', 'NegReg', (291, 295))	('TMX1', 'Gene', (286, 290))	('accelerated', 'PosReg', (269, 280))	('loss', 'Var', (59, 63))
41875	28516062	It is important to note that alterations in ER-mitochondrial Ca2+ transfers will not only impact mitochondrial bioenergetics but also cancer cell senescence and sensitivity toward chemotherapeutic drugs (Figure 1).	('mitochondrial bioenergetics', 'MPA', (97, 124))	('cancer', 'Disease', (134, 140))	('sensitivity', 'CPA', (161, 172))	('alterations', 'Var', (29, 40))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('Ca2', 'Gene', '760', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('impact', 'Reg', (90, 96))	('Ca2', 'Gene', (61, 64))
41877	28516062	Cancer cells in which IP3R2, the most sensitive isoform to its ligand IP3, or MCU were knocked down could escape cellular senescence.	('MCU', 'Gene', '90550', (78, 81))	('cellular senescence', 'CPA', (113, 132))	('IP3', 'Chemical', 'MESH:D015544', (70, 73))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('IP3R2', 'Gene', '3709', (22, 27))	('IP3', 'Chemical', 'MESH:D015544', (22, 25))	('knocked down', 'Var', (87, 99))	('IP3R2', 'Gene', (22, 27))	('MCU', 'Gene', (78, 81))	('escape', 'NegReg', (106, 112))
41879	28516062	Strikingly, cells undergoing oncogene-induced senescence displayed an increase in basal mitochondrial Ca2+ and IP3-induced mitochondrial Ca2+ accumulation.	('Ca2', 'Gene', (137, 140))	('increase', 'PosReg', (70, 78))	('IP3', 'Chemical', 'MESH:D015544', (111, 114))	('Ca2', 'Gene', '760', (102, 105))	('Ca2', 'Gene', '760', (137, 140))	('oncogene-induced', 'Var', (29, 45))	('Ca2', 'Gene', (102, 105))
41886	28516062	Cells that lack p53 or that express oncogenic p53 mutations failed to upregulate SERCA2b activity and display ER-mitochondrial Ca2+ transfers and cell death.	('Ca2', 'Gene', (127, 130))	('mutations', 'Var', (50, 59))	('p53', 'Gene', (46, 49))	('SERCA2b', 'Gene', '11938', (81, 88))	('p53', 'Gene', (16, 19))	('Ca2', 'Gene', '760', (127, 130))	('p53', 'Gene', '7157', (46, 49))	('p53', 'Gene', '7157', (16, 19))	('upregulate', 'PosReg', (70, 80))	('cell death', 'CPA', (146, 156))	('SERCA2b', 'Gene', (81, 88))	('activity', 'MPA', (89, 97))
42033	26353009	Metyrapone increases cortisol metabolites in the serum and urine due to the predominant inhibition of 11beta-hydroxylase, and to a lesser extent the other steroidogenesis enzymes.	('Metyrapone', 'Var', (0, 10))	('inhibition', 'NegReg', (88, 98))	('cortisol', 'Chemical', 'MESH:D006854', (21, 29))	('increases', 'PosReg', (11, 20))	('steroid', 'Chemical', 'MESH:D013256', (155, 162))	('Metyrapone', 'Chemical', 'MESH:D008797', (0, 10))	('increases cortisol', 'Phenotype', 'HP:0003118', (11, 29))	('11beta-hydroxylase', 'Enzyme', (102, 120))	('cortisol metabolites', 'MPA', (21, 41))
42053	25087088	MET abnormalities in patients with genitourinary malignancies and outcomes with c-MET inhibitors To determine the prevalence of MET amplification and mutation among genitourinary (GU) malignancies and its association with clinical factors and responses to c-MET inhibitors.	('malignancies', 'Disease', (184, 196))	('c-MET', 'Gene', (80, 85))	('c-MET', 'Gene', '4233', (256, 261))	('genitourinary malignancies', 'Disease', 'MESH:D014564', (35, 61))	('mutation', 'Var', (150, 158))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('genitourinary', 'Disease', (165, 178))	('genitourinary malignancies', 'Disease', (35, 61))	('patients', 'Species', '9606', (21, 29))	('c-MET', 'Gene', (256, 261))	('malignancies', 'Disease', 'MESH:D009369', (184, 196))	('c-MET', 'Gene', '4233', (80, 85))	('malignancies', 'Disease', (49, 61))
42055	25087088	MET amplification was found in 7 of 97 (7.2%) patients (4/27 renal [all clear cell], 1/18 urothelial and 2/12 adrenocortical carcinoma), with MET mutation/variant in 3 of 54 (5.6%) (2/20 RCC [1 clear cell and 1 papillary] and 1/16 prostate cancer).	('patients', 'Species', '9606', (46, 54))	('RCC', 'Disease', (187, 190))	('prostate cancer', 'Disease', (231, 246))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cell], 1', 'Gene', '1057', (78, 86))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (110, 134))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (110, 134))	('prostate cancer', 'Disease', 'MESH:D011471', (231, 246))	('adrenocortical carcinoma', 'Disease', (110, 134))	('MET mutation/variant', 'Var', (142, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (231, 246))	('renal', 'Disease', (61, 66))
42056	25087088	No demographic characteristics were associated with specific MET abnormalities, but patients testing positive for mutation or amplification had more metastatic sites (median, 4 vs. 3 for wild-type MET).	('metastatic sites', 'CPA', (149, 165))	('mutation', 'Var', (114, 122))	('amplification', 'Var', (126, 139))	('patients', 'Species', '9606', (84, 92))
42063	25087088	MET mutation and/or amplification can be found in diverse GU malignancies, and is potentially targetable.	('found', 'Reg', (41, 46))	('MET mutation', 'Var', (0, 12))	('GU malignancies', 'Phenotype', 'HP:0007379', (58, 73))	('amplification', 'MPA', (20, 33))	('GU malignancies', 'Disease', 'MESH:D009369', (58, 73))	('GU malignancies', 'Disease', (58, 73))
42064	25087088	We explored the prevalence of MET abnormalities and its association with demographics and targeted therapy response in patients with GU tumors.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('GU tumors', 'Disease', 'MESH:D009369', (133, 142))	('patients', 'Species', '9606', (119, 127))	('GU tumors', 'Disease', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('GU tumors', 'Phenotype', 'HP:0007379', (133, 142))	('MET abnormalities', 'Var', (30, 47))
42068	25087088	Recent data have shown that many solid tumors display MET/HGF pathway deregulation, actuated by various mechanisms, including c-MET overexpression, MET mutation, amplification and increased HGF secretion by the tumor microenvironment.	('HGF', 'Gene', (58, 61))	('increased', 'PosReg', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (211, 216))	('tumors', 'Disease', (39, 45))	('overexpression', 'PosReg', (132, 146))	('c-MET', 'Gene', '4233', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('MET mutation', 'Var', (148, 160))	('c-MET', 'Gene', (126, 131))	('deregulation', 'Reg', (70, 82))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('mutation', 'Var', (152, 160))	('HGF', 'Gene', '3082', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (39, 44))	('HGF', 'Gene', (190, 193))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('HGF', 'Gene', '3082', (58, 61))	('amplification', 'MPA', (162, 175))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
42069	25087088	Genitourinary (GU) malignancies frequently involve c-MET deregulation.	('c-MET', 'Gene', (51, 56))	('malignancies', 'Disease', (19, 31))	('Genitourinary', 'Disease', (0, 13))	('c-MET', 'Gene', '4233', (51, 56))	('malignancies', 'Disease', 'MESH:D009369', (19, 31))	('deregulation', 'Var', (57, 69))
42071	25087088	MET mutations are described both in hereditary and sporadic papillary renal cell carcinoma (RCC); in addition, MET amplification and overexpression is a newly described mechanism of resistance in RCC patients undergoing VEGFR inhibitor treatment.	('sporadic papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (51, 90))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (60, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('patients', 'Species', '9606', (200, 208))	('MET', 'Var', (111, 114))	('sporadic papillary renal cell carcinoma', 'Disease', (51, 90))	('VEGFR', 'Gene', '3791', (220, 225))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('overexpression', 'PosReg', (133, 147))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('VEGFR', 'Gene', (220, 225))	('mutations', 'Var', (4, 13))	('RCC', 'Disease', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))
42072	25087088	In bladder cancers, phosphorylation of HGF/c-MET is associated with the development of metastasis and poor survival.	('c-MET', 'Gene', '4233', (43, 48))	('HGF', 'Gene', (39, 42))	('bladder cancers', 'Disease', 'MESH:D001749', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HGF', 'Gene', '3082', (39, 42))	('associated', 'Reg', (52, 62))	('c-MET', 'Gene', (43, 48))	('bladder cancers', 'Disease', (3, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('phosphorylation', 'Var', (20, 35))	('bladder cancers', 'Phenotype', 'HP:0009725', (3, 18))
42074	25087088	Although much of the available data highlight the importance of protein overexpression as a mechanism of c-MET deregulation in GU malignancies, genetic abnormalities, including mutation and amplification, may also play a role.	('mutation', 'Var', (177, 185))	('c-MET', 'Gene', '4233', (105, 110))	('GU malignancies', 'Phenotype', 'HP:0007379', (127, 142))	('amplification', 'Var', (190, 203))	('genetic abnormalities', 'Disease', 'MESH:D030342', (144, 165))	('c-MET', 'Gene', (105, 110))	('GU malignancies', 'Disease', 'MESH:D009369', (127, 142))	('genetic abnormalities', 'Disease', (144, 165))	('deregulation', 'PosReg', (111, 123))	('GU malignancies', 'Disease', (127, 142))
42077	25087088	We investigated MET status, including mutation and amplification, in patients with advanced RCC, prostate cancer, urothelial cancer and adrenocortical carcinoma referred to our Phase I Clinical Trials Program.	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (136, 160))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (136, 160))	('urothelial cancer', 'Disease', 'MESH:D014523', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('investigated', 'Reg', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('adrenocortical carcinoma', 'Disease', (136, 160))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('patients', 'Species', '9606', (69, 77))	('urothelial cancer', 'Disease', (114, 131))	('prostate cancer', 'Disease', (97, 112))	('amplification', 'Var', (51, 64))
42086	25087088	Patient characteristics including demographics, tumor type, MET mutation and/or amplification status and associated genetic abnormalities were summarized using frequency distributions and percentages.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('genetic abnormalities', 'Disease', 'MESH:D030342', (116, 137))	('amplification status', 'Var', (80, 100))	('tumor', 'Disease', (48, 53))	('genetic abnormalities', 'Disease', (116, 137))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('MET mutation', 'Var', (60, 72))	('Patient', 'Species', '9606', (0, 7))
42088	25087088	A total of 118 patients with advanced RCC, prostate cancer, urothelial and adrenocortical cancers were analyzed for MET mutation/variant (53 patients) or amplification (97 patients).	('RCC', 'Disease', (38, 41))	('patients', 'Species', '9606', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('urothelial and adrenocortical cancers', 'Disease', 'MESH:D000306', (60, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('MET mutation/variant', 'Var', (116, 136))	('prostate cancer', 'Disease', (43, 58))	('amplification', 'Var', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('patients', 'Species', '9606', (172, 180))	('prostate cancer', 'Disease', 'MESH:D011471', (43, 58))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('patients', 'Species', '9606', (141, 149))	('prostate cancer', 'Phenotype', 'HP:0012125', (43, 58))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
42093	25087088	The prevalence of MET amplification was 14.8% (4 out of 27) in RCC (all clear cell), 5.5% (1 out of 18) in urothelial cancer and 17% (2 out of 12) in adrenocortical cancer.	('RCC', 'Disease', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('urothelial cancer', 'Disease', (107, 124))	('adrenocortical cancer', 'Disease', (150, 171))	('MET amplification', 'Var', (18, 35))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (150, 171))	('urothelial cancer', 'Disease', 'MESH:D014523', (107, 124))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
42101	25087088	Patients harboring a MET abnormality had a median of 4 (3-5) metastatic sites compared to 3 (0-6) sites in wild-type patients; of note, all patients with a MET variant presented with bone metastasis and 2 out of 3 (67%) had brain metastasis, while only 2 out of 50 (4%) in the MET wild-type group developed central metastasis.	('variant', 'Var', (160, 167))	('brain metastasis', 'Disease', (224, 240))	('Patients', 'Species', '9606', (0, 8))	('brain metastasis', 'Disease', 'MESH:D009362', (224, 240))	('patients', 'Species', '9606', (140, 148))	('patients', 'Species', '9606', (117, 125))	('MET variant', 'Var', (156, 167))	('bone metastasis', 'CPA', (183, 198))
42104	25087088	Five out of 10 patients with MET abnormalities had concomitant mutations, including p53 mutations (2 patients), PTEN loss (3 patients) and a VHL mutation (1 patient with RCC) (Table 2).	('patients', 'Species', '9606', (15, 23))	('loss', 'NegReg', (117, 121))	('mutations', 'Var', (88, 97))	('patients', 'Species', '9606', (125, 133))	('patients', 'Species', '9606', (101, 109))	('VHL', 'Gene', '7428', (141, 144))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('mutation', 'Var', (145, 153))	('patient', 'Species', '9606', (15, 22))	('patient', 'Species', '9606', (157, 164))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('p53', 'Gene', '7157', (84, 87))	('PTEN', 'Gene', (112, 116))	('patient', 'Species', '9606', (125, 132))	('patient', 'Species', '9606', (101, 108))	('p53', 'Gene', (84, 87))	('PTEN', 'Gene', '5728', (112, 116))	('VHL', 'Gene', (141, 144))
42106	25087088	The prevalence of mutations in other important oncogenes in the overall patient population was: 0 out of 81 patients for KRAS, 1 out of 66 (1.5%) for EGFR; 2 out of 77 (2.6%) for BRAF; and 5 out of 101 (5%) for PIK3CA.	('PIK3CA', 'Gene', (211, 217))	('PIK3CA', 'Gene', '5290', (211, 217))	('BRAF', 'Gene', '673', (179, 183))	('KRAS, 1', 'Gene', '3845', (121, 128))	('patient', 'Species', '9606', (72, 79))	('BRAF', 'Gene', (179, 183))	('patient', 'Species', '9606', (108, 115))	('patients', 'Species', '9606', (108, 116))	('mutations', 'Var', (18, 27))
42107	25087088	None of the patients positive for those mutations had a MET genetic abnormality, although not all of them were tested for both mutation and amplification.	('genetic abnormality', 'Disease', 'MESH:D030342', (60, 79))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (12, 20))	('genetic abnormality', 'Disease', (60, 79))
42108	25087088	For survival analysis we compared the group of patients who tested positive for either a MET mutation/variant or amplification (MET positive group, 10 patients) with patients who tested negative for both abnormalities (MET negative group, 28 patients).	('amplification', 'MPA', (113, 126))	('patients', 'Species', '9606', (47, 55))	('MET mutation/variant', 'Var', (89, 109))	('patients', 'Species', '9606', (151, 159))	('patients', 'Species', '9606', (166, 174))	('patients', 'Species', '9606', (242, 250))
42109	25087088	Patients with MET mutation and MET amplification were grouped altogether after considering that individual survival data was similar between both groups (Table 2).	('Patients', 'Species', '9606', (0, 8))	('MET mutation', 'Var', (14, 26))	('MET', 'Var', (31, 34))
42121	25087088	Three out of four (75%) of patients with PD on a c-MET protocol and tested for TP53 alteration were positive for mutation, while none of the four patients with SD or PR tested positive.	('mutation', 'Var', (113, 121))	('c-MET', 'Gene', (49, 54))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('positive', 'Reg', (100, 108))	('tested', 'Reg', (68, 74))	('patients', 'Species', '9606', (27, 35))	('c-MET', 'Gene', '4233', (49, 54))	('alteration', 'Var', (84, 94))	('patients', 'Species', '9606', (146, 154))
42122	25087088	We detected MET gene amplification in 7.2% of 97 patients and a MET genetic mutation/variant in 5.6% of 54 patients with GU malignancies.	('GU malignancies', 'Phenotype', 'HP:0007379', (121, 136))	('MET', 'Var', (12, 15))	('patients', 'Species', '9606', (49, 57))	('GU malignancies', 'Disease', 'MESH:D009369', (121, 136))	('patients', 'Species', '9606', (107, 115))	('GU malignancies', 'Disease', (121, 136))
42123	25087088	The prevalence of MET amplification was highest in RCC (14.8%) and adrenocortical carcinoma (17%), whereas a genetic variant was more frequent in RCC (10%).	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('adrenocortical carcinoma', 'Disease', (67, 91))	('highest', 'Reg', (40, 47))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (67, 91))	('MET amplification', 'Var', (18, 35))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (67, 91))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
42126	25087088	Data from the Catalog of Somatic Mutations in Cancer (COSMIC) database revealed a low prevalence of MET mutations in prostate cancer (3.6%), in which c-MET activation was especially mediated by c-MET overexpression in the setting of androgen deprivation.	('Cancer', 'Disease', (46, 52))	('overexpression', 'PosReg', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('c-MET', 'Gene', '4233', (150, 155))	('mutations', 'Var', (104, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('Cancer', 'Disease', 'MESH:D009369', (46, 52))	('activation', 'PosReg', (156, 166))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('c-MET', 'Gene', (194, 199))	('c-MET', 'Gene', (150, 155))	('prostate cancer', 'Disease', (117, 132))	('c-MET', 'Gene', '4233', (194, 199))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))
42127	25087088	In addition, there was a 2.3% prevalence of MET mutations in urothelial cancers, 3% in RCC and none in adrenocortical carcinomas.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('MET mutations', 'Var', (44, 57))	('RCC', 'Disease', (87, 90))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (103, 128))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (103, 127))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('adrenocortical carcinomas', 'Disease', (103, 128))	('urothelial cancers', 'Disease', (61, 79))	('urothelial cancers', 'Disease', 'MESH:D014523', (61, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (103, 128))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
42130	25087088	Trisomy of chromosome 7, where the MET gene is located, has been detected in some patients with PRCC.	('detected', 'Reg', (65, 73))	('PRCC', 'Gene', '5546', (96, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('patients', 'Species', '9606', (82, 90))	('PRCC', 'Gene', (96, 100))	('Trisomy', 'Var', (0, 7))	('PRCC', 'Phenotype', 'HP:0006766', (96, 100))
42132	25087088	All mutations described here were N375S, which occurs in the extracellular semaphorin domain of the MET gene.	('N375S', 'SUBSTITUTION', 'None', (34, 39))	('MET', 'Gene', (100, 103))	('N375S', 'Var', (34, 39))
42136	25087088	It is important to note that only one of the 2 patients with RCC and a N375S mutation/variant had a papillary subtype.	('papillary', 'Disease', (100, 109))	('patients', 'Species', '9606', (47, 55))	('N375S', 'Var', (71, 76))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('N375S', 'SUBSTITUTION', 'None', (71, 76))
42139	25087088	A retrospective series of patients with gastroesophageal tumors showed MET amplification associated with a higher tumor grade and worse survival.	('gastroesophageal tumors', 'Phenotype', 'HP:0100751', (40, 63))	('associated', 'Reg', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('MET amplification', 'Var', (71, 88))	('gastroesophageal tumors', 'Disease', (40, 63))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Disease', (114, 119))	('gastroesophageal tumors', 'Disease', 'MESH:D005764', (40, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', (57, 62))
42142	25087088	Our series also demonstrated a shorter OS for patients with either a MET mutation/variant or amplification compared to wild-type patients (6.1 months vs. 11.5 months) after they presented to our Phase I Clinic.	('amplification', 'Var', (93, 106))	('MET mutation/variant', 'Var', (69, 89))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (129, 137))
42145	25087088	As demonstrated in preclinical models, the N375S mutation may confer resistance to c-MET inhibitors  and our data suggest that resistance might also occur in vivo.	('c-MET', 'Gene', '4233', (83, 88))	('N375S', 'Var', (43, 48))	('c-MET', 'Gene', (83, 88))	('N375S', 'SUBSTITUTION', 'None', (43, 48))
42146	25087088	Additionally, two patients with MET amplification were treated with c-MET inhibitors and both presented tumor progression as best response.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('c-MET', 'Gene', '4233', (68, 73))	('tumor', 'Disease', (104, 109))	('c-MET', 'Gene', (68, 73))	('patients', 'Species', '9606', (18, 26))	('MET amplification', 'Var', (32, 49))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
42151	25087088	In the same study, MET germline mutations were greatly associated with better activity of the drug, but they were all considered activating mutations of MET gene, which are different than N375S variant as previously discussed.	('germline mutations', 'Var', (23, 41))	('N375S', 'SUBSTITUTION', 'None', (188, 193))	('activity of the drug', 'MPA', (78, 98))	('N375S', 'Var', (188, 193))	('better', 'PosReg', (71, 77))	('activating', 'PosReg', (129, 139))
42161	25087088	These limitations notwithstanding, we showed that abnormalities of MET gene might be detected in GU malignancies and that patients with them had a worse prognosis, especially those being treated in a phase I setting.	('GU malignancies', 'Disease', 'MESH:D009369', (97, 112))	('GU malignancies', 'Disease', (97, 112))	('abnormalities', 'Var', (50, 63))	('patients', 'Species', '9606', (122, 130))	('MET gene', 'Gene', (67, 75))	('GU malignancies', 'Phenotype', 'HP:0007379', (97, 112))	('detected', 'Reg', (85, 93))
42170	24958272	In this population, germline mutations of the TP53 tumor suppressor gene (R337H) have been detected in 34% of the patients.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TP53', 'Gene', '7157', (46, 50))	('tumor', 'Disease', (51, 56))	('detected', 'Reg', (91, 99))	('TP53', 'Gene', (46, 50))	('R337H', 'Mutation', 'rs121912664', (74, 79))	('R337H', 'Var', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('patients', 'Species', '9606', (114, 122))
42174	24958272	Chromosome imbalances (losses and gains) in specific loci of DNA have been reported with impact on several genes such as TP53, insulin-like growth factor type II (IGF-2), steroidogenic factor 1(SF1) and beta-catenin.	('DNA', 'Gene', (61, 64))	('beta-catenin', 'Gene', (203, 215))	('TP53', 'Gene', '7157', (121, 125))	('imbalances', 'Phenotype', 'HP:0002172', (11, 21))	('impact', 'Reg', (89, 95))	('TP53', 'Gene', (121, 125))	('beta-catenin', 'Gene', '1499', (203, 215))	('IGF-2', 'Gene', (163, 168))	('IGF-2', 'Gene', '3481', (163, 168))	('gains', 'PosReg', (34, 39))	('imbalances', 'Var', (11, 21))	('steroidogenic factor 1(SF1', 'Gene', '7536', (171, 197))
42204	24958272	Mitotane is an adrenal-specfic cytotoxic agent, which can also lead to necrosis of the adrenal gland.	('Mitotane', 'Var', (0, 8))	('necrosis', 'Disease', 'MESH:D009336', (71, 79))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('lead to', 'Reg', (63, 70))	('necrosis', 'Disease', (71, 79))
42220	24958272	Since the vast majority of medications are metabolized or altered by hepatic CYP3A4, mitotane therefore has a significant impact on drug metabolism and drug-drug interactions.	('drug interaction', 'Phenotype', 'HP:0020172', (157, 173))	('CYP3A4', 'Gene', '1576', (77, 83))	('impact', 'Reg', (122, 128))	('drug metabolism', 'MPA', (132, 147))	('mitotane', 'Chemical', 'MESH:D008939', (85, 93))	('drug-drug interactions', 'Phenotype', 'HP:0020172', (152, 174))	('hepatic', 'Var', (69, 76))	('interactions', 'Interaction', (162, 174))	('metabolized', 'MPA', (43, 54))	('CYP3A4', 'Gene', (77, 83))	('altered', 'Reg', (58, 65))
42224	24958272	In addition, mitotane increase hepatic production of globulins (such as cortisol binding globulin [CBG] and thyroid binding globulin [TBG]), thereby further lowering the free concentrations of circulating cortisol.	('thyroid binding globulin', 'MPA', (108, 132))	('CBG', 'Gene', '866', (99, 102))	('mitotane', 'Chemical', 'MESH:D008939', (13, 21))	('hepatic production of globulins', 'MPA', (31, 62))	('cortisol binding globulin', 'Gene', (72, 97))	('TBG', 'Chemical', '-', (134, 137))	('free concentrations of circulating cortisol', 'MPA', (170, 213))	('increase', 'PosReg', (22, 30))	('lowering', 'NegReg', (157, 165))	('CBG', 'Gene', (99, 102))	('cortisol', 'Chemical', 'MESH:D006854', (72, 80))	('cortisol binding globulin', 'Gene', '866', (72, 97))	('cortisol', 'Chemical', 'MESH:D006854', (205, 213))	('mitotane', 'Var', (13, 21))
42225	24958272	Patients on mitotane should be empirically treated with low dose hydrocortisone to prevent adrenal crises, and treating physicians must be aware that patients may require increasing doses of glucocorticoids (well into the supraphysiologic range) to achieve normal adrenal replacement.	('men', 'Species', '9606', (279, 282))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (150, 158))	('mitotane', 'Var', (12, 20))	('mitotane', 'Chemical', 'MESH:D008939', (12, 20))	('low dose hydrocortisone', 'Phenotype', 'HP:0008163', (56, 79))	('adrenal crises', 'Disease', (91, 105))	('hydrocortisone', 'Chemical', 'MESH:D006854', (65, 79))
42229	24958272	Mitotane induces hypercholesterolemia (primary high LDL and triglycerides) via unclear mechanisms.	('triglycerides', 'MPA', (60, 73))	('Mitotane', 'Var', (0, 8))	('induces', 'Reg', (9, 16))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('triglycerides', 'Chemical', 'MESH:D014280', (60, 73))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (17, 37))	('high LDL', 'Phenotype', 'HP:0003141', (47, 55))	('hypercholesterolemia', 'Disease', (17, 37))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (17, 37))
42234	24958272	Mitotane can cause a central hypothyroidism and inhibits the conversion of testosterone to dihydrotestosterone; both of these effects can further compound fatigue and systemic symptoms.	('testosterone', 'Chemical', 'MESH:D013739', (98, 110))	('Mitotane', 'Var', (0, 8))	('testosterone', 'Chemical', 'MESH:D013739', (75, 87))	('inhibits', 'NegReg', (48, 56))	('fatigue', 'Disease', (155, 162))	('hypothyroidism', 'Disease', 'MESH:D007037', (29, 43))	('hypothyroidism', 'Phenotype', 'HP:0000821', (29, 43))	('cause', 'Reg', (13, 18))	('hypothyroidism', 'Disease', (29, 43))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('fatigue', 'Phenotype', 'HP:0012378', (155, 162))	('central hypothyroidism', 'Phenotype', 'HP:0011787', (21, 43))	('conversion of testosterone to dihydrotestosterone', 'MPA', (61, 110))	('systemic symptoms', 'Disease', (167, 184))	('dihydrotestosterone', 'Chemical', 'MESH:D013196', (91, 110))	('fatigue', 'Disease', 'MESH:D005221', (155, 162))
42241	24958272	The best outcomes in advanced ACC were achieved by etoposide, doxorubicin, and cisplatin (EDP) or streptozotocin, both in combination with mitotane.	('EDP', 'Chemical', '-', (90, 93))	('mitotane', 'Chemical', 'MESH:D008939', (139, 147))	('etoposide', 'Chemical', 'MESH:D005047', (51, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('etoposide', 'Var', (51, 60))	('doxorubicin', 'Chemical', 'MESH:D004317', (62, 73))	('cisplatin', 'Var', (79, 88))	('doxorubicin', 'Var', (62, 73))	('streptozotocin', 'Chemical', 'MESH:D013311', (98, 112))
42247	24958272	The progression-free survival (PFS) was significantly longer in the M/EDP than SM groups (5.0 vs 2.1 months).	('progression-free survival', 'CPA', (4, 29))	('longer', 'PosReg', (54, 60))	('M/EDP', 'Var', (68, 73))	('SM', 'Chemical', '-', (79, 81))	('M/EDP', 'Chemical', '-', (68, 73))
42248	24958272	The response rate was also higher in the M/EDP group (23.2% vs 9.2%) and the toxicity profile was similar.	('toxicity', 'Disease', 'MESH:D064420', (77, 85))	('toxicity', 'Disease', (77, 85))	('M/EDP', 'Chemical', '-', (41, 46))	('M/EDP', 'Var', (41, 46))	('higher', 'PosReg', (27, 33))	('response', 'MPA', (4, 12))
42284	24958272	Inhibition of EGFR pathway results in clinical benefit in several malignancies like non small cell lung cancer (NSCLC) and pancreatic cancer.	('benefit', 'PosReg', (47, 54))	('EGFR', 'Gene', '1956', (14, 18))	('pancreatic cancer', 'Disease', (123, 140))	('EGFR', 'Gene', (14, 18))	('NSCLC', 'Disease', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('pancreatic cancer', 'Disease', 'MESH:D010190', (123, 140))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (84, 110))	('small cell lung cancer', 'Disease', 'MESH:D055752', (88, 110))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (88, 110))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('Inhibition', 'Var', (0, 10))	('malignancies', 'Disease', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('small cell lung cancer', 'Disease', (88, 110))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
42285	24958272	Recently, Fassnatch and colleagues reported that 78% of ACCs express EGFR by immunohistochemistry, though none of the tumors harbored EGFR mutations in exons 19-21, .	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'Gene', (134, 138))	('mutations in', 'Var', (139, 151))	('EGFR', 'Gene', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('ACCs', 'Gene', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('ACCs', 'Gene', '84680', (56, 60))	('tumors', 'Disease', (118, 124))	('EGFR', 'Gene', '1956', (134, 138))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
42291	24958272	The IGF-1R phosphorylation activates PI3K/AKT signaling pathway leading to cell survival.	('IGF-1R', 'Gene', '3480', (4, 10))	('AKT', 'Gene', (42, 45))	('phosphorylation', 'Var', (11, 26))	('cell survival', 'CPA', (75, 88))	('AKT', 'Gene', '207', (42, 45))	('IGF-1R', 'Gene', (4, 10))	('activates', 'PosReg', (27, 36))
42302	24958272	Pre-clinical studies have shown the anti-proliferative effect of the dual PI3K/mTOR inhibition in adrenocortical cell lines and xenograft models.	('mTOR', 'Gene', (79, 83))	('anti-proliferative effect', 'CPA', (36, 61))	('mTOR', 'Gene', '2475', (79, 83))	('dual', 'Var', (69, 73))	('inhibition', 'NegReg', (84, 94))	('adrenocortical', 'Disease', (98, 112))	('adrenocortical', 'Disease', 'MESH:D018268', (98, 112))
42311	24958272	Mutations in APC and CTNNB1genes, which encode this protein, have been described in several malignancies.	('malignancies', 'Disease', (92, 104))	('APC', 'Disease', 'MESH:D011125', (13, 16))	('APC', 'Disease', (13, 16))	('Mutations', 'Var', (0, 9))	('described', 'Reg', (71, 80))	('CTNNB1', 'Gene', (21, 27))	('malignancies', 'Disease', 'MESH:D009369', (92, 104))	('CTNNB1', 'Gene', '1499', (21, 27))
42345	24958272	As an example, blocking programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, results in significant antitumor activity in several malignancies.	('PD-1', 'Gene', (44, 48))	('PD-1', 'Gene', '5133', (44, 48))	('malignancies', 'Disease', 'MESH:D009369', (159, 171))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('programmed death-1', 'Gene', (24, 42))	('programmed death-1', 'Gene', '5133', (24, 42))	('malignancies', 'Disease', (159, 171))	('tumor', 'Disease', (133, 138))	('blocking', 'Var', (15, 23))
42347	20351491	Familial Micronodular Adrenocortical Disease, Cushing Syndrome, and Mutations of the Gene Encoding Phosphodiesterase 11A4 (PDE11A) We present the pathologic findings in the adrenal glands of 4 patients, aged 10 to 38 years, with Cushing syndrome and germline inactivating mutations of the gene PDE11A4 that encodes phosphodiesterase11A4.	('Familial Micronodular Adrenocortical Disease', 'Disease', 'MESH:C566469', (0, 44))	('PDE11A', 'Gene', '50940', (294, 300))	('patients', 'Species', '9606', (193, 201))	('phosphodiesterase', 'Gene', '50940', (315, 332))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (229, 245))	('PDE11A', 'Gene', '50940', (123, 129))	('PDE11A', 'Gene', (294, 300))	('Cushing syndrome', 'Disease', (229, 245))	('Phosphodiesterase 11A4', 'Gene', '50940', (99, 121))	('PDE11A', 'Gene', (123, 129))	('Mutations', 'Var', (68, 77))	('Cushing Syndrome', 'Disease', (46, 62))	('Cushing Syndrome', 'Disease', 'MESH:D003480', (46, 62))	('phosphodiesterase', 'Gene', (315, 332))	('Familial Micronodular Adrenocortical Disease', 'Disease', (0, 44))	('Cushing syndrome', 'Disease', 'MESH:D003480', (229, 245))	('Phosphodiesterase 11A4', 'Gene', (99, 121))	('Cushing Syndrome', 'Phenotype', 'HP:0003118', (46, 62))
42350	20351491	Three of the group, including the mother and daughter, had the same pathology, primary pigmented nodular adrenocortical disease, a disorder known to be caused by inactivating mutations of the PRKAR1A gene.	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (87, 127))	('caused by', 'Reg', (152, 161))	('pigmented nodular adrenocortical disease', 'Disease', (87, 127))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (87, 127))	('PRKAR1A', 'Gene', (192, 199))	('inactivating mutations', 'Var', (162, 184))	('PRKAR1A', 'Gene', '5573', (192, 199))
42358	20351491	The nodular hyperplasia of the McCune-Albright syndrome is caused by postzygotic somatic mutations in the GNAS gene.	('GNAS', 'Gene', (106, 110))	('GNAS', 'Gene', '2778', (106, 110))	('mutations', 'Var', (89, 98))	('nodular hyperplasia', 'Disease', 'MESH:D020518', (4, 23))	('caused by', 'Reg', (59, 68))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (31, 55))	('nodular hyperplasia', 'Disease', (4, 23))	('McCune-Albright syndrome', 'Disease', (31, 55))
42359	20351491	This gene encodes the alpha subunit of the stimulatory G protein and mutation results in activation of the Gsalpha subunit, uninterrupted stimulation of adenylyl cyclase, and persistently high levels of cyclic adenosine monophosphate (cAMP).	('Gsalpha', 'Gene', '2778', (107, 114))	('cAMP', 'Chemical', 'MESH:D000242', (235, 239))	('high', 'PosReg', (188, 192))	('mutation', 'Var', (69, 77))	('adenylyl cyclase', 'MPA', (153, 169))	('activation', 'PosReg', (89, 99))	('Gsalpha', 'Gene', (107, 114))	('cyclic adenosine monophosphate', 'Chemical', 'MESH:D000242', (203, 233))
42360	20351491	Primary pigmented nodular adrenocortical disease (PPNAD), another primary bilateral adrenal cause of the Cushing syndrome, is caused by inactivating germline mutations of the PRKAR1A gene.	('Cushing syndrome', 'Phenotype', 'HP:0003118', (105, 121))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (8, 48))	('PPNAD', 'Chemical', '-', (50, 55))	('PRKAR1A', 'Gene', (175, 182))	('Cushing syndrome', 'Disease', (105, 121))	('Cushing syndrome', 'Disease', 'MESH:D003480', (105, 121))	('caused by', 'Reg', (126, 135))	('inactivating', 'Var', (136, 148))	('Primary pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (0, 48))	('Primary pigmented nodular adrenocortical disease', 'Disease', (0, 48))	('PRKAR1A', 'Gene', '5573', (175, 182))
42361	20351491	PRKAR1A encodes the type 1A regulatory subunit of cAMP-dependent protein kinase; its inactivation results in increased cAMP signaling.	('inactivation', 'Var', (85, 97))	('cAMP', 'Chemical', 'MESH:D000242', (50, 54))	('cAMP signaling', 'MPA', (119, 133))	('cAMP', 'Chemical', 'MESH:D000242', (119, 123))	('PRKAR1A', 'Gene', (0, 7))	('increased', 'PosReg', (109, 118))	('PRKAR1A', 'Gene', '5573', (0, 7))
42364	20351491	A genome-wide scan of patients with primary adrenal disease and their tissues identified inactivating mutations disrupting the expression of a third gene, phosphodiesterase11A4 (PDE11A4), in 4 of them.	('phosphodiesterase', 'Gene', (155, 172))	('adrenal disease', 'Phenotype', 'HP:0000834', (44, 59))	('expression', 'MPA', (127, 137))	('PDE11A', 'Gene', (178, 184))	('primary adrenal disease', 'Disease', (36, 59))	('PDE11A', 'Gene', '50940', (178, 184))	('patients', 'Species', '9606', (22, 30))	('phosphodiesterase', 'Gene', '50940', (155, 172))	('primary adrenal disease', 'Disease', 'MESH:D000310', (36, 59))	('primary adrenal disease', 'Phenotype', 'HP:0008207', (36, 59))	('inactivating mutations', 'Var', (89, 111))	('disrupting', 'NegReg', (112, 122))
42368	20351491	The mutations of the GNAS, PRKAR1A, PDE11A, and PDE8B genes all result in increased AMP signaling.	('PRKAR1A', 'Gene', '5573', (27, 34))	('AMP', 'Chemical', 'MESH:D000249', (84, 87))	('GNAS', 'Gene', (21, 25))	('PDE8B', 'Gene', '8622', (48, 53))	('PDE8B', 'Gene', (48, 53))	('increased', 'PosReg', (74, 83))	('PRKAR1A', 'Gene', (27, 34))	('mutations', 'Var', (4, 13))	('AMP signaling', 'MPA', (84, 97))	('GNAS', 'Gene', '2778', (21, 25))	('PDE11A', 'Gene', (36, 42))	('PDE11A', 'Gene', '50940', (36, 42))
42369	20351491	Herein, we describe the adrenal findings in the 4 patients with the PDE11A4 gene mutation, 1 PPNAD, the other indeterminate, possibly a variant of PPNAD.	('patients', 'Species', '9606', (50, 58))	('PDE11A', 'Gene', (68, 74))	('PDE11A', 'Gene', '50940', (68, 74))	('mutation', 'Var', (81, 89))	('adrenal findings', 'MPA', (24, 40))	('PPNAD', 'Chemical', '-', (147, 152))	('PPNAD', 'Chemical', '-', (93, 98))	('adrenal findings', 'Phenotype', 'HP:0000834', (24, 40))
42372	20351491	The fourth patient (case 4) inherited the mutation from her father; he had an enlarged adrenal gland but normal results of adrenocortical testing and no Cushing syndrome.	('enlarged adrenal gland', 'Phenotype', 'HP:0008221', (78, 100))	('adrenocortical', 'Disease', (123, 137))	('adrenocortical', 'Disease', 'MESH:D018268', (123, 137))	('Cushing syndrome', 'Disease', (153, 169))	('Cushing syndrome', 'Disease', 'MESH:D003480', (153, 169))	('patient', 'Species', '9606', (11, 18))	('mutation', 'Var', (42, 50))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (153, 169))
42393	20351491	We have presented the pathology in the adrenal glands of 4 patients with Cushing syndrome caused by inactivating mutations of the PDE11A4 gene.	('PDE11A', 'Gene', (130, 136))	('PDE11A', 'Gene', '50940', (130, 136))	('Cushing syndrome', 'Disease', 'MESH:D003480', (73, 89))	('inactivating mutations', 'Var', (100, 122))	('patients', 'Species', '9606', (59, 67))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (73, 89))	('Cushing syndrome', 'Disease', (73, 89))	('caused by', 'Reg', (90, 99))
42397	20351491	More recently, a series of inactivating mutations of the PRKAR1A gene were identified as causative of PPNAD, a different Cushing syndrome-associated pathologic phenotype.	('causative', 'Reg', (89, 98))	('Cushing syndrome', 'Disease', (121, 137))	('Cushing syndrome', 'Disease', 'MESH:D003480', (121, 137))	('inactivating mutations', 'Var', (27, 49))	('PRKAR1A', 'Gene', (57, 64))	('PPNAD', 'Chemical', '-', (102, 107))	('PRKAR1A', 'Gene', '5573', (57, 64))	('PPNAD', 'Disease', (102, 107))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (121, 137))
42398	20351491	It seemed possible that the Cushing syndrome associated with the PDE11A4 gene mutations might result in 1 of the foregoing pathologies.	('result in', 'Reg', (94, 103))	('Cushing syndrome', 'Disease', 'MESH:D003480', (28, 44))	('mutations', 'Var', (78, 87))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (28, 44))	('PDE11A', 'Gene', (65, 71))	('PDE11A', 'Gene', '50940', (65, 71))	('Cushing syndrome', 'Disease', (28, 44))
42399	20351491	In fact, 3 of the 4 patients (cases 1, 2, and 3) had PPNAD, a mother and her daughter with the same PDE11A4 gene mutation, and a third unrelated patient with a different PDE11A4 mutation.	('PPNAD', 'Chemical', '-', (53, 58))	('mutation', 'Var', (113, 121))	('PDE11A', 'Gene', '50940', (170, 176))	('PPNAD', 'Disease', (53, 58))	('PDE11A', 'Gene', (100, 106))	('patient', 'Species', '9606', (145, 152))	('patient', 'Species', '9606', (20, 27))	('PDE11A', 'Gene', '50940', (100, 106))	('patients', 'Species', '9606', (20, 28))	('PDE11A', 'Gene', (170, 176))
42405	20351491	The patient inherited the PDE11A4 mutation from her father who had an enlarged right adrenal gland but no Cushing syndrome and normal total glucocorticoid secretion.	('PDE11A', 'Gene', (26, 32))	('PDE11A', 'Gene', '50940', (26, 32))	('mutation', 'Var', (34, 42))	('patient', 'Species', '9606', (4, 11))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (106, 122))	('Cushing syndrome', 'Disease', (106, 122))	('total glucocorticoid secretion', 'MPA', (134, 164))	('Cushing syndrome', 'Disease', 'MESH:D003480', (106, 122))	('inherited', 'Reg', (12, 21))
42409	20351491	As different mutations in the PRKARIA gene result in different clinical phenotypes, it is possible that different PDE11A4 mutations could cause different pathologic phenotypes.	('result', 'Reg', (43, 49))	('PDE11A', 'Gene', '50940', (114, 120))	('PRKARIA', 'Gene', (30, 37))	('cause', 'Reg', (138, 143))	('mutations', 'Var', (122, 131))	('PDE11A', 'Gene', (114, 120))
42439	23178798	The goat anti-rabbit (phosphoserine916PKD and total PKD secondary antibody), and rabbit anti-goat (actin secondary antibody) were from Sigma.	('phosphoserine916PKD', 'Var', (22, 41))	('actin', 'Gene', '100342017', (99, 104))	('goat', 'Species', '9925', (4, 8))	('actin', 'Gene', (99, 104))	('goat', 'Species', '9925', (93, 97))
42448	23178798	Actin was used for normalization because both the total PKD and phosphoserine910PKD antibodies were raised in rabbit, necessitating stripping and reprobing of the blot, with possibly nonhomogeneous loss of immunoreactivity, if total PKD were to be used for normalization.	('phosphoserine910', 'Chemical', '-', (64, 80))	('Actin', 'Gene', (0, 5))	('phosphoserine910PKD', 'Chemical', '-', (64, 83))	('loss', 'NegReg', (198, 202))	('serine910', 'Chemical', '-', (71, 80))	('phosphoserine910PKD', 'Var', (64, 83))	('Actin', 'Gene', '100342017', (0, 5))
42605	19417029	Although 11 cytochrome P-450s that can metabolize xenobiotics are expressed in the human liver, only 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 seem to be involved in drug metabolism, and the drug-drug interactions of commonly used drugs.	('1A2', 'Var', (101, 104))	('2D6', 'Var', (122, 125))	('2C19', 'Var', (116, 120))	('human', 'Species', '9606', (83, 88))	('cytochrome P-450s', 'Enzyme', (12, 29))	('interactions', 'Interaction', (193, 205))	('involved', 'Reg', (146, 154))
42616	19417029	Zosuquidar (LY335979) a potent inhibitor containing a cyclopropyldibenzosuberane moiety has shown promising activity in vivo.	('activity', 'MPA', (108, 116))	('Zosuquidar', 'Chemical', '-', (0, 10))	('LY335979', 'Chemical', 'MESH:C095179', (12, 20))	('cyclopropyldibenzosuberane', 'Chemical', '-', (54, 80))	('LY335979', 'Var', (12, 20))
42638	19417029	A 2-fold reduction may be sufficient to significantly affect activity:for example, bcr-abl mutations in imatinibrefractory chronic myelogenous leukemia and c-KIT mutations in gastrointestinal stromal tumor often affect drug binding ~ 2-fold as evidenced by both in vitro studies and clinical observations that increasing the dose by 50% to 100% often rescues activity.	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('activity', 'MPA', (359, 367))	('bcr-abl', 'Gene', (83, 90))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (131, 151))	('affect', 'Reg', (212, 218))	('drug binding', 'Interaction', (219, 231))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (175, 205))	('c-KIT', 'Gene', (156, 161))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (175, 205))	('c-KIT', 'Gene', '3815', (156, 161))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (131, 151))	('gastrointestinal stromal tumor', 'Disease', (175, 205))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (123, 151))	('mutations', 'Var', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('myelogenous leukemia', 'Disease', (131, 151))	('mutations', 'Var', (91, 100))	('rescues', 'PosReg', (351, 358))	('bcr-abl', 'Gene', '25', (83, 90))
42699	32377128	III: Non-functional tumors with malignancy risk: For non-functional adrenal tumors, the indication for surgery is the risk of malignancy-related to the size of the lesion.	('malignancy', 'Disease', 'MESH:D009369', (126, 136))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('malignancy', 'Disease', (126, 136))	('adrenal tumors', 'Disease', 'MESH:D000310', (68, 82))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('adrenal tumor', 'Phenotype', 'HP:0100631', (68, 81))	('tumors', 'Disease', (76, 82))	('adrenal tumors', 'Disease', (68, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('malignancy', 'Disease', 'MESH:D009369', (32, 42))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('malignancy', 'Disease', (32, 42))	('non-functional', 'Var', (53, 67))
42718	32377128	In the right adrenalectomy, there are some specific side-related problems as follows: liver injury, duodenum injury, vena cava injury, hepatic vein Injury, right adrenal vein Injury, kidney Injury, division of a polar renal artery, rupture of the adrenal capsule and injury of the diaphragm.	('liver injury', 'Disease', (86, 98))	('vena cava injury', 'Disease', (117, 133))	('kidney Injury', 'Disease', (183, 196))	('duodenum injury', 'Disease', (100, 115))	('liver injury', 'Disease', 'MESH:D017093', (86, 98))	('hepatic vein Injury', 'Disease', 'MESH:D056486', (135, 154))	('kidney Injury', 'Disease', 'MESH:D058186', (183, 196))	('adrenal vein Injury', 'Disease', 'MESH:D000312', (162, 181))	('hepatic vein Injury', 'Disease', (135, 154))	('rupture', 'Disease', 'MESH:D012421', (232, 239))	('rupture', 'Disease', (232, 239))	('vena cava injury', 'Disease', 'MESH:D013479', (117, 133))	('adrenal vein Injury', 'Disease', (162, 181))	('division', 'Var', (198, 206))	('duodenum injury', 'Disease', 'MESH:D004379', (100, 115))	('injury', 'Disease', (267, 273))
42875	32158565	Previous in vitro and animal model studies suggest that high aldosterone levels can cause oxidative stress, leading to DNA damage.	('oxidative stress', 'MPA', (90, 106))	('aldosterone', 'Chemical', 'MESH:D000450', (61, 72))	('high', 'Var', (56, 60))	('oxidative stress', 'Phenotype', 'HP:0025464', (90, 106))	('DNA damage', 'MPA', (119, 129))	('aldosterone levels', 'MPA', (61, 79))	('cause', 'Reg', (84, 89))	('high aldosterone', 'Phenotype', 'HP:0000859', (56, 72))	('leading to', 'Reg', (108, 118))
42891	32158565	Some MN cases have common genetic mutations in CACNA1D, ATP1A1, ATP2B3, and KCNJ5 to those found in APA cases.	('ATP2B3', 'Gene', (64, 70))	('KCNJ5', 'Gene', (76, 81))	('ATP1A1', 'Gene', '476', (56, 62))	('KCNJ5', 'Gene', '3762', (76, 81))	('CACNA1D', 'Gene', (47, 54))	('ATP1A1', 'Gene', (56, 62))	('ATP2B3', 'Gene', '492', (64, 70))	('CACNA1D', 'Gene', '776', (47, 54))	('PA', 'Disease', 'MESH:D006929', (101, 103))	('mutations', 'Var', (34, 43))
43038	30444046	Simultaneously, tumor suppressor genes (TSGs) can be inactivated by promoter hypermethylation (Llinas-Arias and Esteller, 2017).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('promoter hypermethylation', 'Var', (68, 93))	('Llinas-Arias', 'Disease', (95, 107))	('inactivated', 'NegReg', (53, 64))	('tumor', 'Disease', (16, 21))	('Llinas-Arias', 'Disease', 'MESH:D005878', (95, 107))
43039	30444046	CpG island hypermethylation in cancer cells is associated with a decrease in histone active marks: histone H3 and H4 acetylation, H3K4 trimethylation, and gain of repressive marks: H3K9me3 and H3K27me3 (Llinas-Arias and Esteller, 2017).	('H3K27me3', 'Var', (193, 201))	('H3K4', 'Protein', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('histone H3', 'Protein', (99, 109))	('H3K9me3', 'Protein', (181, 188))	('hypermethylation', 'Var', (11, 27))	('Llinas-Arias', 'Disease', 'MESH:D005878', (203, 215))	('gain', 'PosReg', (155, 159))	('histone', 'MPA', (77, 84))	('decrease', 'NegReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('repressive', 'MPA', (163, 173))	('cancer', 'Disease', (31, 37))	('Llinas-Arias', 'Disease', (203, 215))
43054	30444046	This KRAB-ZNF is upregulated in bladder cancer, while its knockdown induces apoptosis and reduces the viability of cancer cells in in vitro and in vivo experiments (Kawahara et al., 2016).	('induces', 'Reg', (68, 75))	('cancer', 'Disease', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('upregulated', 'PosReg', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('reduces', 'NegReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ZNF', 'Gene', (10, 13))	('apoptosis', 'CPA', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('knockdown', 'Var', (58, 67))	('ZNF', 'Gene', '284390', (10, 13))
43084	30444046	For breast cancer, we used nine different cell lines representing distinct molecular subtypes: luminal A (MCF7, T47D), luminal B (BT474), basal (BT20, BT549, HS578T, MDA-MB231, MDA-MB468), and HER2 positive (SKBR3).	('T47D', 'CellLine', 'CVCL:0553', (112, 116))	('HER2', 'Gene', (193, 197))	('MDA-MB231', 'CellLine', 'CVCL:0062', (166, 175))	('MDA-MB231', 'Var', (166, 175))	('BT549', 'CellLine', 'CVCL:1092', (151, 156))	('MDA-MB468', 'Var', (177, 186))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('HS578T', 'CellLine', 'CVCL:0332', (158, 164))	('HER2', 'Gene', '2064', (193, 197))	('SKBR3', 'CellLine', 'CVCL:0033', (208, 213))	('MDA-MB468', 'CellLine', 'CVCL:0419', (177, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MCF7', 'CellLine', 'CVCL:0031', (106, 110))	('BT20', 'Var', (145, 149))	('HS578T', 'Var', (158, 164))
43106	30444046	Interestingly, the majority of the KRAB-ZNFs with an altered mRNA level exhibited reduced expression, while only a small but distinct cluster of 16 KRAB-ZNFs showed upregulation in multiple cancer types (Fig.	('ZNFs', 'Chemical', '-', (40, 44))	('multiple cancer', 'Disease', (181, 196))	('altered', 'Var', (53, 60))	('expression', 'MPA', (90, 100))	('ZNFs', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('reduced', 'NegReg', (82, 89))	('mRNA level', 'MPA', (61, 71))	('multiple cancer', 'Disease', 'MESH:D009369', (181, 196))	('upregulation', 'PosReg', (165, 177))
43140	30444046	As aberrant splicing is a frequent event in carcinogenesis, we wanted to explore the isoform signature for cancer-associated KRAB-ZNFs in TCGA datasets.	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('aberrant', 'Var', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinogenesis', 'Disease', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('ZNFs', 'Chemical', '-', (130, 134))	('cancer', 'Disease', (107, 113))
43143	30444046	As expected, we found that a majority of splicing variants (84.5%) were overexpressed in cancer tissues compared to their normal counterparts (Fig.	('splicing variants', 'Var', (41, 58))	('overexpressed', 'PosReg', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
43144	30444046	Out of 490 significant isoforms, 21 variants (4.3%) showed expression only in cancer tissues, 220 variants (44.9%) were strongly overexpressed in cancer compared to normal (>= 2-fold overexpression, with the highest level reaching 652-fold change), and 173 variants (35.3%) showed mild overexpression (FC < 2 and >= 1.2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('expression', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('overexpression', 'PosReg', (286, 300))	('overexpressed', 'PosReg', (129, 142))	('variants', 'Var', (98, 106))
43145	30444046	It is of note that 21 isoforms that fell below the detection threshold in normal samples included mainly truncated and nonsense variants of ZNF695.	('ZNF695', 'Gene', '57116', (140, 146))	('nonsense', 'Var', (119, 127))	('ZNF695', 'Gene', (140, 146))
43150	30444046	ZNF273, the isoform with a 5' partial deletion of the KRAB domain, was switched to three other isoforms, which could be translated to a full-length protein, a variant with a C-terminal partial deletion of the KRAB domain, and a protein devoid of the zinc finger domain.	('ZNF273', 'Gene', (0, 6))	('partial deletion', 'Var', (30, 46))	('ZNF273', 'Gene', '10793', (0, 6))
43155	30444046	Four out of five ZNF273 variants (Fig.	('ZNF273', 'Gene', '10793', (17, 23))	('ZNF273', 'Gene', (17, 23))	('variants', 'Var', (24, 32))
43213	30444046	Finally, our survival analysis indicated that the expression of KRAB-ZNFs may act as a risk factor.	('KRAB-ZNFs', 'Gene', (64, 73))	('ZNFs', 'Chemical', '-', (69, 73))	('expression', 'Var', (50, 60))
43214	30444046	Patients with high expression of five out of 10 analyzed KRAB-ZNFs presented significantly shorter overall survival than those with low expression (Fig.	('ZNFs', 'Chemical', '-', (62, 66))	('overall survival', 'MPA', (99, 115))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('KRAB-ZNFs', 'Gene', (57, 66))	('shorter', 'NegReg', (91, 98))
43216	30444046	In contrast, high expression was associated with better prognosis in the case of ZNF205 (P < 0.001, hazard ratio = 0.5), ZNF707 (P = 0.001, hazard ratio = 0.5), and ZNF789 (P = 0.017, hazard ratio = 0.5) (Fig.	('ZNF205', 'Gene', (81, 87))	('high', 'Var', (13, 17))	('ZNF707', 'Gene', '286075', (121, 127))	('ZNF789', 'Gene', (165, 171))	('ZNF789', 'Gene', '285989', (165, 171))	('better', 'PosReg', (49, 55))	('ZNF205', 'Gene', '7755', (81, 87))	('ZNF707', 'Gene', (121, 127))
43231	30444046	We observed that the majority of variants was detected both in normal and cancer tissues, but as expected, they had a higher level in tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('variants', 'Var', (33, 41))
43232	30444046	The differential expression of KRAB-ZNF splicing isoforms in cancer was reported only by Juarez-Mendez and colleagues (Juarez-Mendez et al., 2013), who demonstrated a specific increase of ZNF695 variants in ovarian cancer compared to normal cells.	('ZNF', 'Gene', (36, 39))	('variants', 'Var', (195, 203))	('increase', 'PosReg', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ovarian cancer', 'Disease', (207, 221))	('cancer', 'Disease', (61, 67))	('ZNF', 'Gene', (188, 191))	('ZNF', 'Gene', '284390', (36, 39))	('ZNF695', 'Gene', '57116', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZNF', 'Gene', '284390', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))	('ZNF695', 'Gene', (188, 194))
43243	30444046	Furthermore, we have previously shown that ZNF695 was upregulated in pluripotent stem cells compared to more specialized cell types, whereas its knockdown resulted in the loss of self-renewal properties and differentiation of pluripotent stem cells (Oleksiewicz et al., 2017).	('ZNF695', 'Gene', '57116', (43, 49))	('knockdown', 'Var', (145, 154))	('upregulated', 'PosReg', (54, 65))	('self-renewal properties', 'CPA', (179, 202))	('differentiation', 'CPA', (207, 222))	('ZNF695', 'Gene', (43, 49))	('loss', 'NegReg', (171, 175))
43469	25129428	Patients with pheos had a significantly lower BMI when compared to patients with BT (27 vs. 30 kg/m2, p <0.001).	('pheos', 'Phenotype', 'HP:0002666', (14, 19))	('patients', 'Species', '9606', (67, 75))	('BT', 'Chemical', '-', (81, 83))	('BMI', 'MPA', (46, 49))	('Patients', 'Species', '9606', (0, 8))	('pheos', 'Var', (14, 19))	('lower BMI', 'Phenotype', 'HP:0045082', (40, 49))	('lower', 'NegReg', (40, 45))
43483	25129428	Our data show that patients with pheos had a lower BMI when compared to patients with BT.	('BMI', 'MPA', (51, 54))	('patients', 'Species', '9606', (19, 27))	('lower BMI', 'Phenotype', 'HP:0045082', (45, 54))	('patients', 'Species', '9606', (72, 80))	('pheos', 'Phenotype', 'HP:0002666', (33, 38))	('lower', 'NegReg', (45, 50))	('BT', 'Chemical', '-', (86, 88))	('pheos', 'Var', (33, 38))
43511	25129428	In conclusion, adrenal pathology influences intraoperative blood loss and procedure time during adrenalectomy but does not affect transfusion requirement, LOS or complication rates.	('adrenal', 'Disease', (15, 22))	('intraoperative blood loss', 'Disease', (44, 69))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (44, 69))	('influences', 'Reg', (33, 43))	('pathology', 'Var', (23, 32))
43578	33807178	In our study, patients who had liver resections had decreased OS compared to those who did not.	('decreased', 'NegReg', (52, 61))	('liver resections', 'Var', (31, 47))	('patients', 'Species', '9606', (14, 22))
43630	32266384	The nuclear receptor steroidogenic factor-1 (SF1 also known as NR5A1) is a pivotal factor for the initiation and fetal maturation of the adrenal cortex, with its absence resulting in adrenal aplasia.	('SF1', 'Gene', (45, 48))	('NR5A1', 'Gene', '2516', (63, 68))	('adrenal aplasia', 'Disease', (183, 198))	('steroid', 'Chemical', 'MESH:D013256', (21, 28))	('SF1', 'Gene', '7536', (45, 48))	('NR5A1', 'Gene', (63, 68))	('resulting in', 'Reg', (170, 182))	('adrenal aplasia', 'Phenotype', 'HP:0011743', (183, 198))	('absence', 'Var', (162, 169))	('adrenal aplasia', 'Disease', 'MESH:D000310', (183, 198))
43701	32266384	However, aberrant expression and activation of G-protein coupled receptors have been implicated as a possible mechanism explaining cortisol hypersecretion (and in primary hyperaldosteronism).	('activation', 'PosReg', (33, 43))	('G-protein coupled receptors', 'Protein', (47, 74))	('primary hyperaldosteronism', 'Phenotype', 'HP:0011736', (163, 189))	('cortisol', 'MPA', (131, 139))	('primary hyperaldosteronism', 'Disease', (163, 189))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (171, 189))	('cortisol', 'Chemical', 'MESH:D006854', (131, 139))	('aberrant expression', 'Var', (9, 28))	('primary hyperaldosteronism', 'Disease', 'MESH:D003480', (163, 189))
43714	32266384	Mutations in beta -catenin (CTNNB1) leading to constitutive activation of the Wnt signaling pathway is a frequent finding in benign and malignant adrenocortical tumors.	('benign', 'Disease', (125, 131))	('beta -catenin', 'Gene', (13, 26))	('malignant adrenocortical tumors', 'Disease', 'MESH:D009369', (136, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('malignant adrenocortical tumors', 'Disease', (136, 167))	('CTNNB1', 'Gene', (28, 34))	('activation', 'PosReg', (60, 70))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('CTNNB1', 'Gene', '1499', (28, 34))	('beta -catenin', 'Gene', '1499', (13, 26))	('Wnt signaling pathway', 'Pathway', (78, 99))
43717	32266384	In 1 study of 100 adrenal adenomas that had been surgically excised, 36% were found to contain CTNNB1 mutations.	('CTNNB1', 'Gene', (95, 101))	('adrenal adenomas', 'Disease', (18, 34))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (18, 34))	('adrenal adenomas', 'Disease', 'MESH:D000236', (18, 34))	('mutations', 'Var', (102, 111))	('CTNNB1', 'Gene', '1499', (95, 101))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (18, 33))
43718	32266384	Somatic activating mutations of GNAS, which encodes the alpha-subunit of the stimulatory G protein (GSalpha), occur in 5% to 17% of adrenal adenomas which are cortisol secreting.	('adrenal adenomas', 'Disease', (132, 148))	('mutations', 'Var', (19, 28))	('GSalpha', 'Gene', (100, 107))	('GNAS', 'Gene', '2778', (32, 36))	('GSalpha', 'Gene', '2778', (100, 107))	('cortisol', 'Chemical', 'MESH:D006854', (159, 167))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (132, 147))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (132, 148))	('activating', 'PosReg', (8, 18))	('adrenal adenomas', 'Disease', 'MESH:D000236', (132, 148))	('GNAS', 'Gene', (32, 36))
43719	32266384	An example of this is constitutive activation of adenylyl cyclase as a result of somatic GNAS mutations in McCune-Albright syndrome.	('adenylyl cyclase', 'Enzyme', (49, 65))	('McCune-Albright syndrome', 'Disease', (107, 131))	('mutations', 'Var', (94, 103))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (107, 131))	('GNAS', 'Gene', (89, 93))	('GNAS', 'Gene', '2778', (89, 93))	('activation', 'PosReg', (35, 45))
43720	32266384	Inactivating mutations in PRKAR1A have been described in cortisol-producing adrenal tumors.	('cortisol', 'Chemical', 'MESH:D006854', (57, 65))	('PRKAR1A', 'Gene', (26, 33))	('adrenal tumors', 'Disease', (76, 90))	('adrenal tumor', 'Phenotype', 'HP:0100631', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Inactivating mutations', 'Var', (0, 22))	('adrenal tumors', 'Disease', 'MESH:D000310', (76, 90))	('PRKAR1A', 'Gene', '5573', (26, 33))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('described', 'Reg', (44, 53))
43721	32266384	PRKAR1A gene encodes for a regulatory subunit of PKA, and inactivating mutations lead to constitutive activation of the cAMP-PKA pathway.	('inactivating mutations', 'Var', (58, 80))	('constitutive', 'MPA', (89, 101))	('cAMP', 'Chemical', '-', (120, 124))	('PRKAR1A', 'Gene', (0, 7))	('activation', 'PosReg', (102, 112))	('PRKAR1A', 'Gene', '5573', (0, 7))	('cAMP-PKA pathway', 'Pathway', (120, 136))
43722	32266384	Although mutations in this gene were first described in Carney complex, somatic mutations of PRKAR1A have been described in some sporadic adrenocortical tumors.	('adrenocortical tumors', 'Disease', (138, 159))	('PRKAR1A', 'Gene', '5573', (93, 100))	('mutations', 'Var', (80, 89))	('described', 'Reg', (111, 120))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (138, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('PRKAR1A', 'Gene', (93, 100))	('Carney complex', 'Disease', (56, 70))
43724	32266384	Mutations in PRKACA may be associated with smaller adenomas but higher levels of cortisol production than adenomas where this mutation is not present.	('PRKACA', 'Gene', (13, 19))	('cortisol', 'Chemical', 'MESH:D006854', (81, 89))	('PRKACA', 'Gene', '5566', (13, 19))	('higher', 'PosReg', (64, 70))	('levels of cortisol production', 'MPA', (71, 100))	('adenomas', 'Disease', 'MESH:D000236', (106, 114))	('Mutations', 'Var', (0, 9))	('adenomas', 'Disease', 'MESH:D000236', (51, 59))	('adenomas', 'Disease', (106, 114))	('adenomas', 'Disease', (51, 59))
43725	32266384	The lower frequency of these mutations in adenomas which produce less cortisol may be an explanation for the lack of progression in these patients to a clinically apparent Cushing's syndrome.	('adenomas', 'Disease', (42, 50))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (172, 190))	('mutations', 'Var', (29, 38))	("Cushing's syndrome", 'Disease', (172, 190))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (172, 190))	('cortisol', 'Chemical', 'MESH:D006854', (70, 78))	('adenomas', 'Disease', 'MESH:D000236', (42, 50))	('patients', 'Species', '9606', (138, 146))
43726	32266384	Mutations in cyclic nucleotide phosphodiesterase have also been noted in cortisol-producing ACAs.	('Mutations', 'Var', (0, 9))	('cortisol', 'Chemical', 'MESH:D006854', (73, 81))	('cyclic nucleotide phosphodiesterase', 'Gene', (13, 48))	('cyclic nucleotide phosphodiesterase', 'Gene', '5140', (13, 48))	('noted', 'Reg', (64, 69))	('cortisol-producing ACAs', 'Disease', (73, 96))
43728	32266384	Mutations in PDE11A and PDE8B genes are the most commonly reported.	('PDE11A', 'Gene', (13, 19))	('PDE11A', 'Gene', '50940', (13, 19))	('PDE8B', 'Gene', (24, 29))	('PDE8B', 'Gene', '8622', (24, 29))	('Mutations', 'Var', (0, 9))
43729	32266384	Mutations in KCNJ5 (potassium channel) have been documented in patients with aldosterone-producing adenomas in approximately 40% of patients from European cohorts, though much higher rates are reported in patients from Japan and Asia.	('patients', 'Species', '9606', (205, 213))	('KCNJ5', 'Gene', '3762', (13, 18))	('aldosterone', 'Chemical', 'MESH:D000450', (77, 88))	('potassium', 'Chemical', 'MESH:D011188', (20, 29))	('adenomas', 'Disease', 'MESH:D000236', (99, 107))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (63, 71))	('adenomas', 'Disease', (99, 107))	('men', 'Species', '9606', (53, 56))	('patients', 'Species', '9606', (132, 140))	('KCNJ5', 'Gene', (13, 18))
43731	32266384	Adenomas with KCNJ5 mutations tend to be larger than those which do not carry the mutation and appear to be more common in women than men.	('KCNJ5', 'Gene', (14, 19))	('men', 'Species', '9606', (125, 128))	('KCNJ5', 'Gene', '3762', (14, 19))	('Adenomas', 'Disease', 'MESH:D000236', (0, 8))	('women', 'Species', '9606', (123, 128))	('Adenomas', 'Disease', (0, 8))	('mutations', 'Var', (20, 29))	('men', 'Species', '9606', (134, 137))
43733	32266384	In aldosterone-producing adenomas that did not have KCNJ5 mutations, abnormalities in ATP1A1 (encoding a Na+/K+ ATPase alpha subunit) were found in 5.2% and of ATP2B3 (encoding a Ca2+ ATPase) in 1.6%, with these mutations associated with increased plasma aldosterone concentrations and lower potassium concentrations than cases without the mutation.	('mutations', 'Var', (58, 67))	('Ca2+', 'Chemical', 'MESH:D000069285', (179, 183))	('increased plasma aldosterone', 'Phenotype', 'HP:0000859', (238, 266))	('potassium concentrations', 'MPA', (292, 316))	('potassium', 'Chemical', 'MESH:D011188', (292, 301))	('ATP2B3', 'Gene', '492', (160, 166))	('ATP2B3', 'Gene', (160, 166))	('plasma aldosterone concentrations', 'MPA', (248, 281))	('mutations', 'Var', (212, 221))	('lower potassium concentrations', 'Phenotype', 'HP:0002900', (286, 316))	('plasma aldosterone concentrations', 'Phenotype', 'HP:0000859', (248, 281))	('KCNJ5', 'Gene', (52, 57))	('aldosterone', 'Chemical', 'MESH:D000450', (3, 14))	('lower', 'NegReg', (286, 291))	('adenomas', 'Disease', 'MESH:D000236', (25, 33))	('adenomas', 'Disease', (25, 33))	('ATP1A1', 'Gene', (86, 92))	('ATP1A1', 'Gene', '476', (86, 92))	('aldosterone', 'Chemical', 'MESH:D000450', (255, 266))	('increased', 'PosReg', (238, 247))	('KCNJ5', 'Gene', '3762', (52, 57))
43734	32266384	Additionally, mutations in the CACNA1D gene have been identified and recently gain of function mutations in the CLCN2 chloride channel gene has also been described.	('CACNA1D', 'Gene', '776', (31, 38))	('CLCN2', 'Gene', (112, 117))	('CACNA1D', 'Gene', (31, 38))	('gain of function', 'PosReg', (78, 94))	('CLCN2', 'Gene', '1181', (112, 117))	('mutations', 'Var', (95, 104))	('mutations', 'Var', (14, 23))
43735	32266384	This gene encodes a voltage-gated calcium channel and 11% of aldosterone-producing adenomas without mutations in KCNJ5 have been reported to carry mutations in this gene.	('mutations', 'Var', (147, 156))	('KCNJ5', 'Gene', '3762', (113, 118))	('aldosterone', 'Chemical', 'MESH:D000450', (61, 72))	('KCNJ5', 'Gene', (113, 118))	('adenomas', 'Disease', 'MESH:D000236', (83, 91))	('calcium', 'Chemical', 'MESH:D002118', (34, 41))	('adenomas', 'Disease', (83, 91))
43736	32266384	Mutations in KCNJ5, CACNA1H, ATP1A1, ATP2B3, and CACNA1D account for approximately 50% of aldosterone-producing adrenal adenomas in patients from Europe; this is likely to be higher in Asian patients.	('CACNA1D', 'Gene', (49, 56))	('adrenal adenomas', 'Disease', 'MESH:D000236', (112, 128))	('patients', 'Species', '9606', (191, 199))	('CACNA1H', 'Gene', (20, 27))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (112, 127))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (112, 128))	('KCNJ5', 'Gene', '3762', (13, 18))	('CACNA1H', 'Gene', '8912', (20, 27))	('Mutations', 'Var', (0, 9))	('ATP2B3', 'Gene', '492', (37, 43))	('aldosterone', 'Chemical', 'MESH:D000450', (90, 101))	('adrenal adenomas', 'Disease', (112, 128))	('ATP1A1', 'Gene', '476', (29, 35))	('CACNA1D', 'Gene', '776', (49, 56))	('ATP2B3', 'Gene', (37, 43))	('patients', 'Species', '9606', (132, 140))	('ATP1A1', 'Gene', (29, 35))	('KCNJ5', 'Gene', (13, 18))
43742	32266384	However, only one-third of these ACCs have a mutation of TP53.	('mutation', 'Var', (45, 53))	('ACCs', 'Gene', (33, 37))	('ACCs', 'Gene', '84680', (33, 37))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
43743	32266384	As previously described, mutations in CTNNB1 are also present in ACCs and may be associated with poor outcome.	('mutations', 'Var', (25, 34))	('ACCs', 'Gene', '84680', (65, 69))	('ACCs', 'Gene', (65, 69))	('CTNNB1', 'Gene', (38, 44))	('associated', 'Reg', (81, 91))	('CTNNB1', 'Gene', '1499', (38, 44))
43745	32266384	Mutations in this gene were identified in 21% of 123 ACCs following genomic characterization.	('identified', 'Reg', (28, 38))	('Mutations', 'Var', (0, 9))	('ACCs', 'Gene', (53, 57))	('ACCs', 'Gene', '84680', (53, 57))
43746	32266384	Loss of heterozygosity at the 11p15 locus can lead to insulin-like growth factor-2 overexpression which is associated with malignant ACCs.	('lead to', 'Reg', (46, 53))	('insulin-like growth factor-2', 'Gene', '3481', (54, 82))	('Loss of heterozygosity', 'Var', (0, 22))	('insulin-like growth factor-2', 'Gene', (54, 82))	('overexpression', 'PosReg', (83, 97))	('11p15', 'Gene', (30, 35))	('ACCs', 'Gene', (133, 137))	('ACCs', 'Gene', '84680', (133, 137))
43753	32266384	Whole-genome sequencing, along with single nucleotide polymorphism array analyses, identified recurrent mutations in an armadillo repeat containing 5 (ARMC5) gene, located in chromosome 16p, in 50% of BMAH patients who underwent surgery.	('ARMC5', 'Gene', '79798', (151, 156))	('mutations', 'Var', (104, 113))	('armadillo repeat containing 5', 'Gene', '79798', (120, 149))	('patients', 'Species', '9606', (206, 214))	('armadillo repeat containing 5', 'Gene', (120, 149))	('ARMC5', 'Gene', (151, 156))
43754	32266384	Patients with ARMC5 mutations tend to display adrenal hyperplasia associated with multiple nodules.	('adrenal hyperplasia', 'Disease', (46, 65))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (46, 65))	('Patients', 'Species', '9606', (0, 8))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (46, 65))	('ARMC5', 'Gene', '79798', (14, 19))	('ARMC5', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
43755	32266384	Discovering ARMC5 mutations was the first evidence of BMAH as a genetic disease.	('genetic disease', 'Disease', (64, 79))	('mutations', 'Var', (18, 27))	('ARMC5', 'Gene', '79798', (12, 17))	('ARMC5', 'Gene', (12, 17))	('BMAH', 'Disease', (54, 58))	('genetic disease', 'Disease', 'MESH:D030342', (64, 79))
43757	32266384	The penetrance of ARMC5 mutations is variable.	('mutations', 'Var', (24, 33))	('ARMC5', 'Gene', '79798', (18, 23))	('ARMC5', 'Gene', (18, 23))
43763	32266384	Other mutations have been associated with sporadic pheochromocytoma clustering to 2 common pathways: hypoxic signaling and kinase signaling genes.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (51, 67))	('pheochromocytoma', 'Disease', (51, 67))	('pheochromocytoma', 'Disease', 'MESH:D010673', (51, 67))	('associated', 'Reg', (26, 36))	('mutations', 'Var', (6, 15))
43766	32266384	Cluster 2 gene mutations are more likely to result in adrenal pheochromocytomas, whereas those in Cluster 1 mostly result in extra-adrenal noradrenergic paragangliomas (except for mutations in VHL).	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (54, 79))	('VHL', 'Gene', (193, 196))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (62, 78))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (54, 79))	('VHL', 'Gene', '7428', (193, 196))	('mutations', 'Var', (15, 24))	('paragangliomas', 'Disease', (153, 167))	('adrenal pheochromocytomas', 'Disease', (54, 79))	('paragangliomas', 'Disease', 'MESH:D010235', (153, 167))	('result in', 'Reg', (44, 53))	('extra-adrenal noradrenergic', 'MPA', (125, 152))	('paragangliomas', 'Phenotype', 'HP:0002668', (153, 167))	('paraganglioma', 'Phenotype', 'HP:0002668', (153, 166))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (62, 79))	('result in', 'Reg', (115, 124))
43767	32266384	Mutations in VHL, RET, NF1, SDHB, and SDHD account for 90% of all pheochromocytomas and paragangliomas.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (66, 83))	('RET', 'Gene', '5979', (18, 21))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (66, 82))	('NF1', 'Gene', (23, 26))	('VHL', 'Gene', (13, 16))	('NF1', 'Gene', '4763', (23, 26))	('Mutations', 'Var', (0, 9))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (66, 102))	('SDHD', 'Gene', (38, 42))	('VHL', 'Gene', '7428', (13, 16))	('SDHD', 'Gene', '6392', (38, 42))	('RET', 'Gene', (18, 21))	('SDHB', 'Gene', '6390', (28, 32))	('paraganglioma', 'Phenotype', 'HP:0002668', (88, 101))	('paragangliomas', 'Phenotype', 'HP:0002668', (88, 102))	('SDHB', 'Gene', (28, 32))
43770	32266384	SDHB (10.3%) and SDHD (8.9%) mutations are the most frequent germline mutations in pheochromocytoma and paragangliomas.	('pheochromocytoma and paragangliomas', 'Disease', 'MESH:D010673', (83, 118))	('mutations', 'Var', (29, 38))	('SDHD', 'Gene', '6392', (17, 21))	('SDHD', 'Gene', (17, 21))	('SDHB', 'Gene', '6390', (0, 4))	('paragangliomas', 'Phenotype', 'HP:0002668', (104, 118))	('paraganglioma', 'Phenotype', 'HP:0002668', (104, 117))	('SDHB', 'Gene', (0, 4))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (83, 99))
43772	32266384	In 1 large study of patients with pheochromocytoma and/or paraganglioma, patients with NF1 and MEN2 mutations could be discriminated from those with VHL and SDH mutations in 99% of cases by the relative concentrations of normetanephrine and metanephrine, as all patients with NF1 and MEN2 presented with tumors characterized by increased plasma concentrations of metanephrine, in contrast to patients with VHL and SDH mutations, usually presenting with increases in normetanephrine or methoxytyramine.	('tumors', 'Disease', (304, 310))	('metanephrine', 'Chemical', 'MESH:D008676', (224, 236))	('NF1', 'Gene', '4763', (87, 90))	('NF1', 'Gene', '4763', (276, 279))	('VHL', 'Gene', '7428', (406, 409))	('metanephrine', 'Chemical', 'MESH:D008676', (241, 253))	('SDH', 'Gene', '6390', (414, 417))	('metanephrine', 'Chemical', 'MESH:D008676', (469, 481))	('NF1', 'Gene', (87, 90))	('VHL', 'Gene', '7428', (149, 152))	('NF1', 'Gene', (276, 279))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('increased plasma concentrations', 'Phenotype', 'HP:0020170', (328, 359))	('MEN2', 'Var', (284, 288))	('paraganglioma', 'Disease', (58, 71))	('patients', 'Species', '9606', (20, 28))	('increased', 'PosReg', (328, 337))	('SDH', 'Gene', (414, 417))	('pheochromocytoma', 'Disease', 'MESH:D010673', (34, 50))	('paraganglioma', 'Disease', 'MESH:D010235', (58, 71))	('SDH', 'Gene', '6390', (157, 160))	('patients', 'Species', '9606', (392, 400))	('metanephrine', 'Chemical', 'MESH:D008676', (363, 375))	('methoxytyramine', 'Chemical', 'MESH:C001746', (485, 500))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('pheochromocytoma', 'Disease', (34, 50))	('patients', 'Species', '9606', (73, 81))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (34, 50))	('plasma concentrations of metanephrine', 'MPA', (338, 375))	('VHL', 'Gene', (406, 409))	('normetanephrine', 'Chemical', 'MESH:D009647', (221, 236))	('normetanephrine', 'Chemical', 'MESH:D009647', (466, 481))	('paraganglioma', 'Phenotype', 'HP:0002668', (58, 71))	('SDH', 'Gene', (157, 160))	('patients', 'Species', '9606', (262, 270))	('VHL', 'Gene', (149, 152))
43773	32266384	Additionally, measurements of plasma methoxytyramine discriminated patients with SDH mutations from those with VHL mutations in a further 78% of cases.	('VHL', 'Gene', (111, 114))	('patients', 'Species', '9606', (67, 75))	('VHL', 'Gene', '7428', (111, 114))	('discriminated', 'Reg', (53, 66))	('mutations', 'Var', (85, 94))	('SDH', 'Gene', '6390', (81, 84))	('men', 'Species', '9606', (21, 24))	('methoxytyramine', 'Chemical', 'MESH:C001746', (37, 52))	('SDH', 'Gene', (81, 84))
43807	32266384	A HU <= 10 is consistent with a benign adrenal adenoma or other benign lesions (eg, myelolipomas, lipomas).	('lipomas', 'Phenotype', 'HP:0012032', (89, 96))	('lipomas', 'Phenotype', 'HP:0012032', (98, 105))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (39, 54))	('myelolipomas', 'Disease', (84, 96))	('adrenal adenoma', 'Disease', 'MESH:D000236', (39, 54))	('lipomas', 'Disease', 'MESH:D008067', (89, 96))	('adrenal adenoma', 'Disease', (39, 54))	('lipomas', 'Disease', 'MESH:D008067', (98, 105))	('lipomas', 'Disease', (89, 96))	('lipomas', 'Disease', (98, 105))	('HU <= 10', 'Var', (2, 10))	('myelolipomas', 'Disease', 'MESH:D018209', (84, 96))
43830	32266384	Despite the absence of florid signs and symptoms, ACS in patients AI has been associated with hypertension, insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome, and increased mortality.	('mortality', 'Disease', (197, 206))	('ACS', 'Var', (50, 53))	('obesity', 'Disease', (154, 161))	('type 2 diabetes', 'Disease', (128, 143))	('insulin', 'Gene', (108, 115))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (128, 143))	('hypertension', 'Phenotype', 'HP:0000822', (94, 106))	('insulin resistance', 'Phenotype', 'HP:0000855', (108, 126))	('type 2 diabetes', 'Disease', 'MESH:D003924', (128, 143))	('obesity', 'Disease', 'MESH:D009765', (154, 161))	('diabetes mellitus', 'Disease', (135, 152))	('mortality', 'Disease', 'MESH:D003643', (197, 206))	('associated', 'Reg', (78, 88))	('metabolic syndrome', 'Disease', (163, 181))	('diabetes mellitus', 'Disease', 'MESH:D003920', (135, 152))	('insulin', 'Gene', '3630', (108, 115))	('obesity', 'Phenotype', 'HP:0001513', (154, 161))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (135, 152))	('patients', 'Species', '9606', (57, 65))	('metabolic syndrome', 'Disease', 'MESH:D024821', (163, 181))	('hypertension', 'Disease', 'MESH:D006973', (94, 106))	('hypertension', 'Disease', (94, 106))
43845	32266384	Increased cardiovascular disease has been linked to the post-1-mg DST cortisol level as an independent cardiovascular risk factor.	('cardiovascular disease', 'Phenotype', 'HP:0001626', (10, 32))	('cardiovascular risk factor', 'Phenotype', 'HP:0001626', (103, 129))	('cardiovascular disease', 'Disease', 'MESH:D002318', (10, 32))	('post-1-mg DST', 'Var', (56, 69))	('cortisol', 'Chemical', 'MESH:D006854', (70, 78))	('cardiovascular disease', 'Disease', (10, 32))
43849	32266384	Impaired glucose tolerance or diabetes has been reported to occur in 10% to 69% of patients with ACS and improved glycemic control (and in some cases reversal of diabetes) following surgery is reported in some studies but not others (Table 7).	('ACS', 'Var', (97, 100))	('diabetes', 'Disease', 'MESH:D003920', (30, 38))	('glycemic control', 'MPA', (114, 130))	('patients', 'Species', '9606', (83, 91))	('Impaired glucose tolerance', 'Disease', (0, 26))	('Impaired glucose tolerance', 'Disease', 'MESH:D018149', (0, 26))	('diabetes', 'Disease', (162, 170))	('diabetes', 'Disease', 'MESH:D003920', (162, 170))	('improved', 'PosReg', (105, 113))	('Impaired glucose tolerance', 'Phenotype', 'HP:0040270', (0, 26))	('diabetes', 'Disease', (30, 38))
43885	32266384	However, normotensive patients with suppressible aldosterone/renin ratios may frequently develop hypertension and PA. Brown and colleagues reported that populations with suppressed plasma renin activity (<=0.5 ng/mL/h) and high aldosterone levels were at increased risk of hypertension (HR 1.18; 95% CI 1.03-1.36).	('hypertension', 'Disease', (97, 109))	('suppressed plasma renin activity', 'Phenotype', 'HP:0003351', (170, 202))	('renin', 'Gene', (188, 193))	('<=0.5 ng/mL/h', 'Var', (204, 217))	('suppressed', 'NegReg', (170, 180))	('renin', 'Gene', '5972', (61, 66))	('hypertension', 'Phenotype', 'HP:0000822', (97, 109))	('hypertension', 'Phenotype', 'HP:0000822', (273, 285))	('patients', 'Species', '9606', (22, 30))	('hypertension', 'Disease', (273, 285))	('renin', 'Gene', '5972', (188, 193))	('hypertension', 'Disease', 'MESH:D006973', (97, 109))	('aldosterone levels', 'MPA', (228, 246))	('aldosterone', 'Chemical', 'MESH:D000450', (49, 60))	('high aldosterone', 'Phenotype', 'HP:0000859', (223, 239))	('renin', 'Gene', (61, 66))	('aldosterone', 'Chemical', 'MESH:D000450', (228, 239))	('hypertension', 'Disease', 'MESH:D006973', (273, 285))
43896	32266384	There is a correlation between tumor size and risk of adrenocortical cancer: 2% risk in AIs <4 cm, 6% in AIs 4.1 to 6 cm, and 25% in AIs >6 cm.	('adrenocortical cancer', 'Disease', (54, 75))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (31, 36))	('AIs <4 cm', 'Var', (88, 97))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (54, 75))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
43976	32266384	It should only be undertaken following detailed discussion at an adrenal tumor multidisciplinary meeting and if the lesion is not conclusively benign on imaging and, most importantly, the outcome will affect the therapeutic management of the patient (eg, if the patient has an extra-adrenal primary and a lesion in the adrenal would affect the staging and further management of the patient).	('men', 'Species', '9606', (230, 233))	('adrenal tumor', 'Disease', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('adrenal tumor', 'Disease', 'MESH:D000310', (65, 78))	('affect', 'Reg', (201, 207))	('patient', 'Species', '9606', (382, 389))	('staging', 'CPA', (344, 351))	('affect', 'Reg', (333, 339))	('patient', 'Species', '9606', (242, 249))	('patient', 'Species', '9606', (262, 269))	('adrenal tumor', 'Phenotype', 'HP:0100631', (65, 78))	('lesion', 'Var', (305, 311))	('men', 'Species', '9606', (370, 373))
44011	32266384	Based on the available data and clinical experience, the European guidelines suggest that laparoscopic adrenalectomy may be justified for adrenal tumors <=6 cm with radiological signs of malignancy and without evidence of local invasion.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('<=6', 'Var', (153, 156))	('malignancy', 'Disease', 'MESH:D009369', (187, 197))	('adrenal tumor', 'Phenotype', 'HP:0100631', (138, 151))	('adrenal tumors', 'Disease', 'MESH:D000310', (138, 152))	('malignancy', 'Disease', (187, 197))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('adrenal tumors', 'Disease', (138, 152))
44093	32266384	124I-MIBG has been evaluated as a potential PET imaging tracer but this undergoes complex decay with emission of high energy gamma radiation leading to poorer image quality and unfavorable dosimetry.	('image', 'MPA', (159, 164))	('poorer', 'NegReg', (152, 158))	('MIBG', 'Chemical', 'MESH:D019797', (5, 9))	('124I-MIBG', 'Var', (0, 9))
44113	32438306	Overall, 1559 identical variants coexisted in parts of adrenal cortical adenoma and pheochromocytoma, which mainly (85.8%) originated from germline mutations.	('variants', 'Var', (24, 32))	('pheochromocytoma', 'Disease', (84, 100))	('originated from', 'Reg', (123, 138))	('pheochromocytoma', 'Disease', 'MESH:D010673', (84, 100))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (84, 100))	('adrenal cortical adenoma', 'Disease', 'MESH:D018246', (55, 79))	('coexisted', 'Reg', (33, 42))	('adrenal cortical adenoma', 'Disease', (55, 79))
44114	32438306	These enriched mutations were engaged in stemness control, coherent with substantial expression of the stemness markers (SOX2, CD44 and OCT4) in both parts.	('SOX2', 'Gene', (121, 125))	('CD44', 'Gene', '960', (127, 131))	('mutations', 'Var', (15, 24))	('CD44', 'Gene', (127, 131))	('OCT4', 'Gene', (136, 140))
44116	32438306	The germline mutations were also enriched in signaling involving cancer proliferation, hypoxia inducible factor-1, focal adhesion and extracellular matrix receptor interaction.	('focal adhesion', 'MPA', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('germline mutations', 'Var', (4, 22))	('hypoxia', 'Disease', 'MESH:D000860', (87, 94))	('cancer', 'Disease', (65, 71))	('hypoxia', 'Disease', (87, 94))
44117	32438306	Somatic mutations affecting mitogen-activated protein kinase signaling, glycolysis and the citrate cycle were found in some tumor elements.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mitogen-activated protein kinase signaling', 'MPA', (28, 70))	('tumor', 'Disease', (124, 129))	('mutations', 'Var', (8, 17))	('citrate', 'Chemical', 'MESH:D019343', (91, 98))	('affecting', 'Reg', (18, 27))	('citrate', 'Enzyme', (91, 98))	('glycolysis', 'MPA', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
44119	32438306	Germline mutations involving the stemness regulation and cancer proliferative signaling may drive intermixed tumor formation.	('Germline mutations', 'Var', (0, 18))	('stemness', 'CPA', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('drive', 'Reg', (92, 97))	('tumor', 'Disease', (109, 114))
44140	32438306	The further pathway enrichment analysis, illustrated by the Kyoto Encyclopedia of Genes and Genomes (KEGG) using DAVID web (https://david.ncifcrf.gov/), demonstrated the top 6 enriched pathways sequentially linked to cancer pathway (hsa05200; 3.2%), endocytosis (hsa04144; 2.1%), focal adhesion (hsa04510; 1.8%), protein digestion and absorption (hsa04974; 1.7%), extracellular matrix (ECM)-receptor interaction (hsa04512; 1.3%), and hypoxia-inducible factors-1 (HIF-1) signaling pathway (hsa04066; 1.3%).	('HIF-1', 'Gene', '3091', (463, 468))	('HIF-1', 'Gene', (463, 468))	('endocytosis', 'MPA', (250, 261))	('protein', 'Protein', (313, 320))	('hypoxia-inducible factors-1', 'Gene', '3091', (434, 461))	('cancer', 'Disease', (217, 223))	('linked', 'Reg', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('hypoxia-inducible factors-1', 'Gene', (434, 461))	('focal adhesion', 'MPA', (280, 294))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('hsa04512', 'Var', (413, 421))
44141	32438306	Furthermore, the 32 genes enriched in "pathways in cancer" were clarified by the KEGG system to demonstrate signaling involving PI3K-Akt (map04151, 34.85%), 3',5' cyclic adenosine monophosphate (cAMP) (map04024, 17.4%), Rap1 (map04015,17.4%), Hedgehog (map04340, 13%), apoptosis (map04210, 13%), HIFs (map04066, 13%), and pathways regulating pluripotency of stem cells (Wnt, mammalian wingless-type integration) signaling (map04550, 13%) (https://ppt.cc/fH7DEx, supplementary Table 1).	('Rap1', 'Gene', '5906', (220, 224))	('map04550', 'Var', (423, 431))	('map04066', 'Var', (302, 310))	('HIFs', 'Disease', (296, 300))	('map04015,17.4', 'Var', (226, 239))	('adenosine', 'Chemical', 'MESH:D000241', (170, 179))	('Akt', 'Gene', '207', (133, 136))	('map04024', 'Var', (202, 210))	('map04340', 'Var', (253, 261))	('mammalian', 'Species', '9606', (375, 384))	('map04210', 'Var', (280, 288))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Rap1', 'Gene', (220, 224))	('Akt', 'Gene', (133, 136))	('cAMP', 'Chemical', 'MESH:D000242', (195, 199))	('HIFs', 'Disease', 'None', (296, 300))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
44144	32438306	These mutants were previously found to regulate expression of the stemness markers, SOX2, OCT4, and CD44, in a direct or indirect manner.	('regulate', 'Reg', (39, 47))	('mutants', 'Var', (6, 13))	('expression', 'MPA', (48, 58))	('OCT4', 'Gene', (90, 94))	('SOX2', 'Gene', (84, 88))	('CD44', 'Gene', '960', (100, 104))	('CD44', 'Gene', (100, 104))
44145	32438306	Our results displayed a greater mutation burden in the ACA than in the PHEO part, which were linked to three function processes: kinase signaling, energy metabolism involving glycolysis and the citrate cycle, and focal adhesion/ECM-receptor interaction.	('citrate', 'Chemical', 'MESH:D019343', (194, 201))	('mutation', 'Var', (32, 40))	('glycolysis', 'MPA', (175, 185))
44146	32438306	Analysis of the enriched KEGG pathways mapped the ACA-specific somatic mutations to the PI3K-Akt signaling pathway (hsa04151; 5.7%), Carbon metabolism (hsa01200; 4.4%), Focal adhesion (hsa04510; 4.4%), Biosynthesis of amino acids (hsa01230; 3.8%), and ECM-receptor interaction (hsa04512; 3.8%) (https://ppt.cc/fH7DEx, Supplementary Table 2).	('Carbon', 'MPA', (133, 139))	('Akt', 'Gene', (93, 96))	('hsa01200', 'Var', (152, 160))	('hsa04151', 'Var', (116, 124))	('hsa04512;', 'Var', (278, 287))	('mutations', 'Var', (71, 80))	('hsa01230;', 'Var', (231, 240))	('Akt', 'Gene', '207', (93, 96))
44148	32438306	Only one PHEO-specific missense mutation (MAPKAPK2, NM_032960.3, c.46G>C, p.A16P) was detected involving mitogen-activated protein kinase (MAPK) signaling (https://ppt.cc/fH7DEx, Supplementary Table 3).	('c.46G>C', 'Var', (65, 72))	('MAPKAPK2', 'Gene', '9261', (42, 50))	('MAPKAPK2', 'Gene', (42, 50))	('p.A16P', 'Mutation', 'p.A16P', (74, 80))	('c.46G>C', 'Mutation', 'c.46G>C', (65, 72))
44154	32438306	Overall, 35 proteins from 29 germline mutations were involved in stemness regulation, which may be the "first hit" driving ACA and PHEO tumor formation.	('involved', 'Reg', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('stemness', 'CPA', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('germline mutations', 'Var', (29, 47))
44155	32438306	Additional mutations affecting kinase signaling, focal adhesion/ECM-receptor interaction, and HIF-1 signaling pathway may accelerate tumor growth and intimately admix ACA and PHEO together.	('mutations', 'Var', (11, 20))	('HIF-1', 'Gene', '3091', (94, 99))	('accelerate', 'PosReg', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('HIF-1', 'Gene', (94, 99))	('affecting', 'Reg', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('kinase', 'Pathway', (31, 37))	('tumor', 'Disease', (133, 138))	('focal adhesion/ECM-receptor interaction', 'Protein', (49, 88))
44171	32438306	Since beta-catenin mutation is found in both aldosterone- and cortisol-producing adenoma, Wnt/beta-catenin signaling is critical for adrenal tumorigenesis.	('mutation', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('adenoma', 'Disease', (81, 88))	('adrenal tumor', 'Disease', (133, 146))	('beta-catenin', 'Gene', '1499', (6, 18))	('adrenal tumor', 'Phenotype', 'HP:0100631', (133, 146))	('beta-catenin', 'Gene', (94, 106))	('aldosterone-', 'Disease', (45, 57))	('aldosterone', 'Chemical', 'MESH:D000450', (45, 56))	('beta-catenin', 'Gene', '1499', (94, 106))	('cortisol', 'Chemical', 'MESH:D006854', (62, 70))	('adrenal tumor', 'Disease', 'MESH:D000310', (133, 146))	('adenoma', 'Disease', 'MESH:D000236', (81, 88))	('beta-catenin', 'Gene', (6, 18))
44176	32438306	Aberrant cAMP-PKA signaling correlates with many proliferative adrenocortical diseases both in human and mouse models.	('cAMP', 'Chemical', 'MESH:D000242', (9, 13))	('adrenocortical diseases', 'Disease', 'MESH:D018268', (63, 86))	('human', 'Species', '9606', (95, 100))	('Aberrant', 'Var', (0, 8))	('cAMP-PKA', 'Gene', (9, 17))	('adrenocortical diseases', 'Phenotype', 'HP:0008207', (63, 86))	('mouse', 'Species', '10090', (105, 110))	('adrenocortical diseases', 'Disease', (63, 86))
44177	32438306	Both ACA and PHEO tissues in MCT had enriched gene mutations involving the above pathways, suggesting that abnormal paracrine regulation in adrenocortical stem cells may cause greater tumor outgrowth and hypercortisolism.	('paracrine regulation', 'MPA', (116, 136))	('hypercortisolism', 'Disease', (204, 220))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('abnormal', 'Var', (107, 115))	('greater', 'PosReg', (176, 183))	('tumor', 'Disease', (184, 189))	('hypercortisolism', 'Phenotype', 'HP:0003118', (204, 220))	('cause', 'Reg', (170, 175))	('hypercortisolism', 'Disease', 'MESH:D003480', (204, 220))
44178	32438306	The Cancer Genome Atlas (TCGA) project recognized a driver mutation in 73% of pheochromocytoma, 27% harboring a germline mutation with autosomal dominant inheritance, and 46% as a somatic mutation in sporadic cases.	('pheochromocytoma', 'Disease', (78, 94))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('mutation', 'Var', (59, 67))	('Cancer', 'Disease', (4, 10))	('pheochromocytoma', 'Disease', 'MESH:D010673', (78, 94))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
44184	32438306	One European study, assembling a tissue array of 166 pheochromocytomas and 42 paragangliomas, documented expression of stem cell markers (SOX2, LIN28, NGFR, THY1) in more than 10% of tumors, significantly associated with SDHx mutation.	('paragangliomas', 'Disease', (78, 92))	('mutation', 'Var', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Disease', (183, 189))	('LIN28', 'Gene', (144, 149))	('LIN28', 'Gene', '79727', (144, 149))	('NGFR', 'Gene', '4804', (151, 155))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (53, 69))	('pheochromocytomas', 'Disease', 'MESH:D010673', (53, 70))	('associated', 'Reg', (205, 215))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('pheochromocytomas', 'Disease', (53, 70))	('paragangliomas', 'Disease', 'MESH:D010235', (78, 92))	('paragangliomas', 'Phenotype', 'HP:0002668', (78, 92))	('SDHx', 'Gene', (221, 225))	('NGFR', 'Gene', (151, 155))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (53, 70))	('THY1', 'Gene', '7070', (157, 161))	('THY1', 'Gene', (157, 161))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))
44185	32438306	However, PHEO tumorigenesis could be coherently attributable to the germline mutations involving HIF-1, Wnt- and PI3k-Akt kinase signaling as well as stemness activation.	('HIF-1', 'Gene', '3091', (97, 102))	('tumor', 'Disease', (14, 19))	('PHEO', 'Disease', (9, 13))	('Akt', 'Gene', (118, 121))	('HIF-1', 'Gene', (97, 102))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('Akt', 'Gene', '207', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
44192	32438306	To elucidate the mechanism of the closely intermixed ACA and PHEO tissues in MCT, we assumed coordinating all these mutations involving cAMP, Rap 1, apoptosis, and focal adhesion/ECM-receptor interaction may cause aberrant cellular proliferation, adhesion and cell junction behavior to develop MCT.	('adhesion', 'CPA', (247, 255))	('cell junction behavior', 'CPA', (260, 282))	('apoptosis', 'CPA', (149, 158))	('MCT', 'Disease', (294, 297))	('focal adhesion/ECM-receptor', 'Protein', (164, 191))	('cAMP', 'Gene', (136, 140))	('develop', 'PosReg', (286, 293))	('Rap 1', 'Gene', (142, 147))	('cAMP', 'Chemical', 'MESH:D000242', (136, 140))	('mutations', 'Var', (116, 125))	('Rap 1', 'Gene', '5906', (142, 147))	('cellular proliferation', 'CPA', (223, 245))	('cause', 'Reg', (208, 213))
44207	32438306	These missense mutations may alter the tumor metabolism and accelerate greater tumor burden.	('accelerate', 'PosReg', (60, 70))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('missense mutations', 'Var', (6, 24))	('tumor metabolism', 'Disease', (39, 55))	('tumor metabolism', 'Disease', 'MESH:D008659', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('alter', 'Reg', (29, 34))
44209	32438306	This dedifferentiation capacity of cancer cells may be either inherited (hierarchical theory) or acquired via mutations that lead to a stem-cell-like permissive epigenome (stochastic theory).	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('stem-cell-like permissive epigenome', 'MPA', (135, 170))	('dedifferentiation capacity', 'CPA', (5, 31))	('lead to', 'Reg', (125, 132))	('cancer', 'Disease', (35, 41))
44215	32438306	This study provided a speculative tumorigenesis for MCT that germline mutations involved in stemness activation and cancer proliferative signaling may drive the intermixed tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('stemness', 'CPA', (92, 100))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (172, 177))	('cancer', 'Disease', (116, 122))	('germline mutations', 'Var', (61, 79))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('drive', 'PosReg', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
44243	32237064	ab32149; Abcam, Cambridge, London, UK) and an anti-phospho-LCK (Tyr394) polyclonal antibody (Cat No.	('LCK', 'Gene', '3932', (59, 62))	('Tyr394', 'Chemical', '-', (64, 70))	('LCK', 'Gene', (59, 62))	('Tyr394', 'Var', (64, 70))
44244	32237064	The percentage of LCK and phosphor LCK (Tyr394)-positive cells were calculated subsequently.	('LCK', 'Gene', (18, 21))	('LCK', 'Gene', (35, 38))	('LCK', 'Gene', '3932', (18, 21))	('LCK', 'Gene', '3932', (35, 38))	('Tyr394', 'Chemical', '-', (40, 46))	('Tyr394', 'Var', (40, 46))
44269	32237064	Because phosphorylation of Tyr-394 activates LCK, we further analyzed the activity of LCK in PCNSL and GBM by using an anti-phosphotyrosine 394 antibody (Fig.	('phosphotyrosine', 'Chemical', 'MESH:D019000', (124, 139))	('phosphorylation', 'Var', (8, 23))	('activates', 'PosReg', (35, 44))	('LCK', 'Gene', (86, 89))	('PCNSL', 'Phenotype', 'HP:0030069', (93, 98))	('LCK', 'Gene', (45, 48))	('LCK', 'Gene', '3932', (86, 89))	('LCK', 'Gene', '3932', (45, 48))	('PCNSL', 'Chemical', '-', (93, 98))	('Tyr', 'Chemical', 'MESH:D014443', (27, 30))
44285	32237064	Consistent with this notion, it has been reported that LCK-targeted inhibitors can regulate human glioma cell migration, tumor growth, and stemness gene expression [18].	('stemness', 'Disease', 'MESH:D020295', (139, 147))	('stemness', 'Disease', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('tumor', 'Disease', (121, 126))	('LCK', 'Gene', (55, 58))	('inhibitors', 'Var', (68, 78))	('regulate', 'Reg', (83, 91))	('glioma', 'Disease', (98, 104))	('LCK', 'Gene', '3932', (55, 58))	('human', 'Species', '9606', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
44301	32098326	The main predictors of ACC recurrence include advanced disease stage, incomplete surgical resection, cortisol production, certain genetic alterations, and high proliferation rate (Ki-67 proliferation index).	('ACC', 'Disease', 'MESH:D018268', (23, 26))	('genetic alterations', 'Var', (130, 149))	('high proliferation rate', 'CPA', (155, 178))	('cortisol production', 'MPA', (101, 120))	('ACC', 'Disease', (23, 26))	('Ki-67', 'Chemical', '-', (180, 185))	('cortisol', 'Chemical', 'MESH:D006854', (101, 109))
44320	32098326	For example, the estimated risk of recurrence in patients with triple-negative breast cancer is approximately 43%, and 25% in patients with non-triple-negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('triple-negative', 'Var', (63, 78))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('patients', 'Species', '9606', (126, 134))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
44321	32098326	A meta-analysis performed by Early Breast Cancer Trialists' Collaborative Group found that patients with breast cancer treated with adjuvant anthracycline-based regimen (8575 patients) had a 10 year recurrence rate of 39.4% compared to 47.4% in those who did not receive any adjuvant chemotherapy (risk ratio [RR], 0.73; 95% confidence interval [CI], 0.68-0.79), translating into a number needed to treat (NNT) of 13 (i.e., one recurrence is prevented for each 13 patients treated).	('Breast Cancer', 'Disease', 'MESH:D001943', (35, 48))	('anthracycline-based regimen', 'Var', (141, 168))	('patients', 'Species', '9606', (91, 99))	('anthracycline', 'Chemical', 'MESH:D018943', (141, 154))	('Breast Cancer', 'Phenotype', 'HP:0003002', (35, 48))	('patients', 'Species', '9606', (464, 472))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('patients', 'Species', '9606', (175, 183))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('Breast Cancer', 'Disease', (35, 48))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
44346	32098326	A meta-analysis of more than 1500 patients identified from the National Cancer Database found that patients with R0 margins had a median OS of 57.6 months (95% CI, 48.5-66.0), which was significantly longer than that of patients with microscopically positive (R1) margins (22.4 months; 95% CI, 17.6-33.5), and that of patients with macroscopically positive (R2) margins (13.7 months; 95% CI, 5.8-26.8).	('patients', 'Species', '9606', (318, 326))	('patients', 'Species', '9606', (99, 107))	('R0 margins', 'Var', (113, 123))	('patients', 'Species', '9606', (220, 228))	('patients', 'Species', '9606', (34, 42))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Cancer', 'Disease', (72, 78))	('Cancer', 'Disease', 'MESH:D009369', (72, 78))	('OS', 'Chemical', '-', (137, 139))
44354	32098326	In another analysis, laparoscopic resection was associated with higher recurrence rates (p < 0.0001) but shorter operative time, less estimated blood loss, and shorter postoperative hospital stay compared to open approach.	('blood loss', 'Disease', (144, 154))	('blood loss', 'Disease', 'MESH:D006473', (144, 154))	('recurrence', 'MPA', (71, 81))	('shorter', 'NegReg', (105, 112))	('laparoscopic', 'Var', (21, 33))
44357	32098326	Another study, which compared 319 patients from the German ACC Registry with 250 patients in a validation cohort found Ki-67 to be the single best prognostic value for RFS (HR for recurrence, 1.042 per 1% increase; p < 0.0001) and OS (HR for death, 1.051; p < 0.0001).	('Ki-67', 'Var', (119, 124))	('death', 'Disease', (242, 247))	('death', 'Disease', 'MESH:D003643', (242, 247))	('RFS', 'Disease', (168, 171))	('increase', 'PosReg', (205, 213))	('Ki-67', 'Chemical', '-', (119, 124))	('patients', 'Species', '9606', (81, 89))	('ACC', 'Disease', 'MESH:D018268', (59, 62))	('patients', 'Species', '9606', (34, 42))	('OS', 'Chemical', '-', (231, 233))	('ACC', 'Disease', (59, 62))
44359	32098326	Patients with Ki-67 <10%, 10%-19%, and >=20% had median RFS of 53.2, 31.6, and 9.4 months, respectively, and median OS of 180.5, 113.5, and 42.0 months, respectively.	('Ki-67 <10%', 'Var', (14, 24))	('RFS', 'MPA', (56, 59))	('Patients', 'Species', '9606', (0, 8))	('Ki-67', 'Chemical', '-', (14, 19))	('OS', 'Chemical', '-', (116, 118))	('<10%', 'Var', (20, 24))
44394	32098326	Mitotane directly interacts with lipid membranes and inhibits sterol-O-acyl-transferase activity, resulting in an excess of free cholesterol and other fatty acids that are toxic to hormone-producing adrenal cells.	('fatty acids', 'Chemical', 'MESH:D005227', (151, 162))	('Mitotane', 'Var', (0, 8))	('sterol-O-acyl-transferase activity', 'Enzyme', (62, 96))	('excess of free cholesterol', 'Phenotype', 'HP:0003124', (114, 140))	('cholesterol', 'Chemical', 'MESH:D002784', (129, 140))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('fatty acids', 'MPA', (151, 162))	('free cholesterol', 'MPA', (124, 140))	('lipid', 'Chemical', 'MESH:D008055', (33, 38))	('inhibits', 'NegReg', (53, 61))	('excess', 'PosReg', (114, 120))
44395	32098326	Mitotane affects the proteins involved in stress response, tumorigenesis, and cellular metabolism and structure.	('Mitotane', 'Var', (0, 8))	('tumor', 'Disease', (59, 64))	('stress response', 'CPA', (42, 57))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('cellular metabolism', 'CPA', (78, 97))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('proteins', 'Protein', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('affects', 'Reg', (9, 16))
44396	32098326	As mitotane inhibits steroidogenesis by multiple mechanisms, it also induces CYP3A4 expression, leading to increased steroid clearance; thus, patients who receive mitotane often require higher steroid doses than usual.	('mitotane', 'Chemical', 'MESH:D008939', (163, 171))	('CYP3A4', 'Gene', '1576', (77, 83))	('steroidogenesis', 'MPA', (21, 36))	('mitotane', 'Var', (3, 11))	('increased', 'PosReg', (107, 116))	('steroid', 'Chemical', 'MESH:D013256', (21, 28))	('mitotane', 'Chemical', 'MESH:D008939', (3, 11))	('induces', 'Reg', (69, 76))	('steroid', 'Chemical', 'MESH:D013256', (193, 200))	('steroid', 'Chemical', 'MESH:D013256', (117, 124))	('inhibits', 'NegReg', (12, 20))	('higher', 'PosReg', (186, 192))	('expression', 'MPA', (84, 94))	('patients', 'Species', '9606', (142, 150))	('CYP3A4', 'Gene', (77, 83))	('steroid clearance', 'MPA', (117, 134))
44409	32098326	Median RFS was significantly longer in the mitotane group (42 months), compared with 10 months in control group 1 (HR, 2.91; 95% CI, 1.77-4.78), and 25 months in control group 2 (HR, 1.97 (95% CI, 1.21-3.20).	('longer', 'PosReg', (29, 35))	('mitotane', 'Chemical', 'MESH:D008939', (43, 51))	('mitotane', 'Var', (43, 51))	('RFS', 'MPA', (7, 10))
44412	32098326	A systematic review and meta-analysis in 2018 including 5 retrospective studies and 1249 patients found that adjuvant mitotane was associated with longer RFS (HR, 0.62; 95% CI, 0.42-0.94) and OS (HR, 0.69; 95% CI, 0.55-0.88).	('patients', 'Species', '9606', (89, 97))	('RFS', 'MPA', (154, 157))	('adjuvant', 'Var', (109, 117))	('mitotane', 'Chemical', 'MESH:D008939', (118, 126))	('OS', 'Chemical', '-', (192, 194))	('mitotane', 'Gene', (118, 126))
44437	32098326	A study of 20 matched patients showed that adjuvant XRT conferred a statistically significant benefit in local control (HR, 12.59; 95% CI, 1.62-97.88) without an effect on OS (HR, 1.97; 95% CI, 0.57-6.77).	('OS', 'Chemical', '-', (172, 174))	('local control', 'CPA', (105, 118))	('benefit', 'PosReg', (94, 101))	('patients', 'Species', '9606', (22, 30))	('adjuvant', 'Var', (43, 51))
44460	31325906	We show that PBK is regulated by FOXM1 and targeting PBK via shRNA decreased cell proliferation, clonogenicity, and anchorage independent growth in ACC cell lines.	('targeting', 'Var', (43, 52))	('PBK', 'Gene', (53, 56))	('FOXM1', 'Gene', (33, 38))	('anchorage independent growth', 'CPA', (116, 144))	('FOXM1', 'Gene', '2305', (33, 38))	('clonogenicity', 'CPA', (97, 110))	('decreased', 'NegReg', (67, 76))	('cell proliferation', 'CPA', (77, 95))
44461	31325906	PBK silencing inhibited pAkt, pp38MAPK, and pH3 altering the cell cycle.	('pH3', 'Gene', (44, 47))	('pp38MAPK', 'Var', (30, 38))	('Akt', 'Gene', '207', (25, 28))	('inhibited', 'NegReg', (14, 23))	('PBK', 'Gene', (0, 3))	('cell cycle', 'CPA', (61, 71))	('Akt', 'Gene', (25, 28))	('silencing', 'Var', (4, 13))
44462	31325906	Therapeutically, targeting PBK with the small molecule inhibitor HITOPK032 phenocopied PBK specific modulation of pAkt and pH3, but also induced apoptosis via activation of JNK.	('Akt', 'Gene', '207', (115, 118))	('activation', 'PosReg', (159, 169))	('JNK', 'Gene', (173, 176))	('Akt', 'Gene', (115, 118))	('HITOPK032', 'Var', (65, 74))	('modulation', 'MPA', (100, 110))	('JNK', 'Gene', '5599', (173, 176))	('induced', 'Reg', (137, 144))
44471	31325906	Integrated genomic studies have revealed that 60% of ACC tissues harbor frequent mutations in TP53, ATM, CTNNB1, none of which have been successfully targeted up to date.	('ATM', 'Gene', '472', (100, 103))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('ACC', 'Disease', (53, 56))	('CTNNB1', 'Gene', '1499', (105, 111))	('mutations', 'Var', (81, 90))	('ATM', 'Gene', (100, 103))	('CTNNB1', 'Gene', (105, 111))
44481	31325906	Treatment with the PBK inhibitor, HITOPK032, blocked proliferation and triggered apoptosis in ACC cells, and decreased tumor growth in our newly established in vivo ACC PDX mouse model.	('PBK', 'Gene', (19, 22))	('HITOPK032', 'Var', (34, 43))	('apoptosis', 'CPA', (81, 90))	('mouse', 'Species', '10090', (173, 178))	('proliferation', 'CPA', (53, 66))	('triggered', 'Reg', (71, 80))	('decreased tumor', 'Disease', (109, 124))	('blocked', 'NegReg', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('decreased tumor', 'Disease', 'MESH:D002303', (109, 124))
44488	31325906	The following primary antibodies were used for immunoblot analysis: PARP (#9542S), pH3 (Ser10) (#9701S), H3 (# 4499S), pAkt (Ser473) (#9271), Akt ( #9272 ), pERK (p42/44) (9101S), ERK (#9102), pp38MAPK (#9211), p38MAPK (# 9212), pJNK (#9251S), JNK (# 9252) from Cell Signaling (Danvers, MA); FOXM1 (# SC-500) from Santa Cruz; beta tubulin (#ab6046), PBK (# ab75983) from Abcam.	('Akt', 'Gene', (142, 145))	('ERK', 'Gene', (180, 183))	('Akt', 'Gene', '207', (120, 123))	('#ab6046', 'Var', (340, 347))	('JNK', 'Gene', (230, 233))	('Akt', 'Gene', '207', (142, 145))	('JNK', 'Gene', '5599', (230, 233))	('9701S', 'CellLine', 'CVCL:Z231', (97, 102))	('FOXM1', 'Gene', (292, 297))	('ERK', 'Gene', '5594', (158, 161))	('JNK', 'Gene', (244, 247))	('FOXM1', 'Gene', '2305', (292, 297))	('JNK', 'Gene', '5599', (244, 247))	('# SC-500', 'Var', (299, 307))	('ERK', 'Gene', (158, 161))	('ERK', 'Gene', '5594', (180, 183))	('pERK', 'Gene', '9451', (157, 161))	('pERK', 'Gene', (157, 161))	('Akt', 'Gene', (120, 123))
44508	31325906	Cells were plated in 96-well in quadruplicates and treated with either HITOPK032 (2uM) (Sigma) or HITOPK032 in combination with SP600125 (10uM) (Selleckchem), a JNK inhibitor.	('JNK', 'Gene', (161, 164))	('JNK', 'Gene', '5599', (161, 164))	('SP600125', 'Chemical', 'MESH:C432165', (128, 136))	('HITOPK032', 'Var', (98, 107))
44517	31325906	Kaplan-Meier estimate of overall survival (OS) in the 75 cases available through cBioPortal revealed that high PBK expression in the tumor was associated with significantly poorer overall survival (OS) (p < 0.001) with a median OS of 16.1 months (Fig.	('PBK', 'Gene', (111, 114))	('overall survival', 'MPA', (180, 196))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('high', 'Var', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('poorer', 'NegReg', (173, 179))
44524	31325906	Silencing or targeting MELK or PBK in renal cancer cells decreased FOXM1 expression indicating a feedback loop.	('renal cancer', 'Disease', (38, 50))	('MELK', 'Gene', '9833', (23, 27))	('MELK', 'Gene', (23, 27))	('renal cancer', 'Phenotype', 'HP:0009726', (38, 50))	('FOXM1', 'Gene', '2305', (67, 72))	('FOXM1', 'Gene', (67, 72))	('expression', 'MPA', (73, 83))	('renal cancer', 'Disease', 'MESH:D007680', (38, 50))	('targeting', 'Var', (13, 22))	('PBK', 'Gene', (31, 34))	('Silencing', 'Var', (0, 9))	('decreased', 'NegReg', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
44531	31325906	In contrast to studies in renal carcinoma, PBK silencing did not decrease FOXM1 protein expression (Supplementary Fig.	('renal carcinoma', 'Disease', (26, 41))	('FOXM1', 'Gene', (74, 79))	('FOXM1', 'Gene', '2305', (74, 79))	('PBK', 'Gene', (43, 46))	('renal carcinoma', 'Phenotype', 'HP:0005584', (26, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('protein', 'Protein', (80, 87))	('silencing', 'Var', (47, 56))	('decrease', 'NegReg', (65, 73))	('expression', 'MPA', (88, 98))	('renal carcinoma', 'Disease', 'MESH:C538614', (26, 41))
44536	31325906	2A) demonstrated that, by day 10, there was on average a 6-fold decrease in proliferation with shPBK1 and shPBK3 in CU-ACC1 cells (p<0.01) , whereas a 2.6-fold decrease with shPBK1 and 1.9-fold decrease with shPBK3 (p <0.01) was observed in H295R cell lines compared to controls (Fig.	('decrease', 'NegReg', (64, 72))	('shPBK3', 'Var', (106, 112))	('shPBK1', 'Var', (95, 101))	('CU', 'Chemical', 'MESH:D003300', (116, 118))	('proliferation', 'CPA', (76, 89))
44537	31325906	There was also on average 2.2-fold decrease (p < 0.01) in 2D colony numbers with shPBK1 and shPBK3 in CU-ACC1 cells (Fig.	('shPBK3', 'Var', (92, 98))	('decrease', 'NegReg', (35, 43))	('CU', 'Chemical', 'MESH:D003300', (102, 104))	('shPBK1', 'Var', (81, 87))	('2D colony numbers', 'CPA', (58, 75))
44539	31325906	The CU-ACC2 cell line, which compared to CU-ACC2 PDX has lower expression of PBK, appeared most resilient to PBK knockdown, and showed no significant change in proliferative rates with PBK silencing (Supplementary Fig.	('silencing', 'Var', (189, 198))	('PBK', 'Gene', (77, 80))	('expression', 'MPA', (63, 73))	('PBK', 'Gene', (185, 188))	('CU', 'Chemical', 'MESH:D003300', (4, 6))	('CU', 'Chemical', 'MESH:D003300', (41, 43))	('lower', 'NegReg', (57, 62))
44541	31325906	Since PBK has been implicated in modulation of PI3K and MAPK downstream pathways in other cancers, we next assessed the activation of downstream effectors including pAkt (S473), p38MAPK (Thr180/Tyr182), and pERK (p42/44) in ACC cell lines.	('cancers', 'Disease', (90, 97))	('Thr180', 'Chemical', '-', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('PBK', 'Gene', (6, 9))	('MAPK', 'Pathway', (56, 60))	('Akt', 'Gene', '207', (166, 169))	('Thr180/Tyr182', 'Var', (187, 200))	('Akt', 'Gene', (166, 169))	('Tyr182', 'Chemical', '-', (194, 200))	('pERK', 'Gene', (207, 211))	('pERK', 'Gene', '9451', (207, 211))	('S473', 'Var', (171, 175))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('p38MAPK (Thr180/Tyr182', 'Var', (178, 200))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
44542	31325906	PBK silencing resulted on average in a 2-fold decrease in pAkt and 1.8-3 fold decrease in p38MAPK (p<0.05) with no effects on ERK activation (Fig.	('Akt', 'Gene', (59, 62))	('decrease', 'NegReg', (78, 86))	('p38MAPK', 'MPA', (90, 97))	('Akt', 'Gene', '207', (59, 62))	('ERK', 'Gene', '5594', (126, 129))	('PBK', 'Gene', (0, 3))	('ERK', 'Gene', (126, 129))	('decrease', 'NegReg', (46, 54))	('silencing', 'Var', (4, 13))
44544	31325906	We found that in non-synchronized cells, silencing PBK decreased pH3 on average by 5-fold in CU-ACC1 (p <0.01), 2-fold in H295R cells (p <0.05), and 1.5 fold in CU-ACC2 cell lines (Figure 3A, Supplementary Fig.	('silencing', 'Var', (41, 50))	('CU', 'Chemical', 'MESH:D003300', (93, 95))	('decreased', 'NegReg', (55, 64))	('pH3', 'Gene', (65, 68))	('CU', 'Chemical', 'MESH:D003300', (161, 163))	('PBK', 'Gene', (51, 54))
44546	31325906	Examination of pH3 through mitotic progression post block release showed that PBK knockdown completely inhibited induction of pH3 in synchronized CU-ACC1 cell (Supplementary Fig.	('CU', 'Chemical', 'MESH:D003300', (146, 148))	('PBK', 'Gene', (78, 81))	('pH3', 'Gene', (126, 129))	('knockdown', 'Var', (82, 91))	('inhibited', 'NegReg', (103, 112))
44547	31325906	Flow cytometry was performed to specifically analyze if PBK silencing affects cell cycle progression in CU-ACC1 cells.	('CU', 'Chemical', 'MESH:D003300', (104, 106))	('affects', 'Reg', (70, 77))	('silencing', 'Var', (60, 69))	('cell cycle progression', 'CPA', (78, 100))	('PBK', 'Gene', (56, 59))
44552	31325906	Since prolonged mitosis has been shown to induce apoptosis, we analyzed whether stable PBK knockdown induced apoptosis in ACC tumor cells.	('mitosis', 'Disease', (16, 23))	('mitosis', 'Disease', 'None', (16, 23))	('ACC tumor', 'Disease', 'MESH:D004476', (122, 131))	('knockdown', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ACC tumor', 'Disease', (122, 131))	('PBK', 'Gene', (87, 90))
44557	31325906	HITOPK032 treatment decreased phosphorylation of Akt and histone 3 in all cell lines (Fig.	('HITOPK032', 'Var', (0, 9))	('phosphorylation', 'MPA', (30, 45))	('decreased', 'NegReg', (20, 29))	('Akt', 'Gene', '207', (49, 52))	('histone 3', 'Protein', (57, 66))	('Akt', 'Gene', (49, 52))
44560	31325906	CU-ACC1 and H295R cells appeared more sensitive to HITOPK032 than CU-ACC2 with both cell lines exhibiting a 3-fold average decrease in histone 3 phosphorylation (p<0.05) (Fig.	('decrease', 'NegReg', (123, 131))	('HITOPK032', 'Var', (51, 60))	('CU', 'Chemical', 'MESH:D003300', (0, 2))	('histone 3 phosphorylation', 'MPA', (135, 160))	('CU', 'Chemical', 'MESH:D003300', (66, 68))
44561	31325906	CU-ACC1 cells were more sensitive to HITOPK032 treatment with increased PARP and caspase-3 cleavages at a dose of 1uM as early as 24 hours (p< 0.01).	('increased', 'PosReg', (62, 71))	('PARP', 'Enzyme', (72, 76))	('caspase-3', 'Enzyme', (81, 90))	('CU', 'Chemical', 'MESH:D003300', (0, 2))	('HITOPK032', 'Var', (37, 46))	('cleavages', 'MPA', (91, 100))
44562	31325906	In nasopharyngeal carcinoma, HITOPK032 has been implicated in stress induction via activation of JNK.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('JNK', 'Gene', (97, 100))	('JNK', 'Gene', '5599', (97, 100))	('carcinoma', 'Disease', (18, 27))	('carcinoma', 'Disease', 'MESH:D009369', (18, 27))	('HITOPK032', 'Var', (29, 38))	('implicated', 'Reg', (48, 58))	('activation', 'PosReg', (83, 93))
44563	31325906	We observed similar activation of JNK/SAPK in CU-ACC1 and H295R cell lines treated with HITOPK032 at doses from 0-4uM.	('CU', 'Chemical', 'MESH:D003300', (46, 48))	('JNK/SAPK', 'Gene', (34, 42))	('activation', 'PosReg', (20, 30))	('JNK/SAPK', 'Gene', '5599;5601', (34, 42))	('HITOPK032', 'Var', (88, 97))
44566	31325906	Treatment with HITOPK032 induced a 2-fold increase in caspase activation in CU-ACC1 and H295R cells compared to controls (Fig.	('caspase', 'Protein', (54, 61))	('CU', 'Chemical', 'MESH:D003300', (76, 78))	('activation', 'MPA', (62, 72))	('HITOPK032', 'Var', (15, 24))	('increase', 'PosReg', (42, 50))
44567	31325906	Combination treatment with the JNK inhibitor SP600125 (10uM) with HITOPK032 (4uM) resulted in 1.2-fold decrease in caspase activation in CU-ACC1 and a 1.5-fold reduction in H295R cell lines compared to only HITOPK032 (4uM) treated cells, suggesting that induction of apoptosis in ACC cell lines in response to HITOPK032 treatment is in part through JNK activation.	('activation', 'MPA', (123, 133))	('reduction', 'NegReg', (160, 169))	('JNK', 'Gene', '5599', (31, 34))	('SP600125', 'Var', (45, 53))	('JNK', 'Gene', (349, 352))	('HITOPK032', 'Var', (310, 319))	('CU', 'Chemical', 'MESH:D003300', (137, 139))	('SP600125', 'Chemical', 'MESH:C432165', (45, 53))	('JNK', 'Gene', '5599', (349, 352))	('decrease', 'NegReg', (103, 111))	('JNK', 'Gene', (31, 34))	('caspase', 'Enzyme', (115, 122))
44572	31325906	Figure 6A shows significant decreases in the rate of tumor growth by day 14 and 17 in the HITOPK032 group compared to controls (p<0.01) with representative images of tumors harvested at the completion of the study (Fig.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('decreases', 'NegReg', (28, 37))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('HITOPK032', 'Var', (90, 99))	('tumor', 'Disease', (53, 58))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
44576	31325906	Cleaved PARP and caspase-3 was higher in 6 out 7 treated tumors compared to 1 out of 5 tumors in the control group, suggesting that HITOPK032 treatment induced an apoptotic response in ACC PDX tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('apoptotic', 'MPA', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('HITOPK032', 'Var', (132, 141))	('tumors', 'Disease', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
44583	31325906	For an indirect target such as Akt, PBK silencing decreased Akt activation in CU-ACC1 and H295R cells but not in CU-ACC2 cell lines.	('PBK', 'Gene', (36, 39))	('Akt', 'Gene', (31, 34))	('activation', 'MPA', (64, 74))	('Akt', 'Gene', '207', (60, 63))	('CU', 'Chemical', 'MESH:D003300', (113, 115))	('Akt', 'Gene', (60, 63))	('decreased', 'NegReg', (50, 59))	('Akt', 'Gene', '207', (31, 34))	('CU', 'Chemical', 'MESH:D003300', (78, 80))	('silencing', 'Var', (40, 49))
44585	31325906	In breast cancer, PBK silencing inhibited pH3 and led to dysfunction of cytokinesis promoting apoptosis.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cytokinesis', 'MPA', (72, 83))	('inhibited', 'NegReg', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('pH3', 'Protein', (42, 45))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('silencing', 'Var', (22, 31))	('dysfunction', 'MPA', (57, 68))	('PBK', 'Gene', (18, 21))	('apoptosis', 'CPA', (94, 103))
44586	31325906	In the prototype CU-ACC1 cells, PBK knockdown caused a greatly delayed G2/M phase and, the initial G1 accumulation upon thymidine treatment.	('G1 accumulation upon thymidine', 'MPA', (99, 129))	('G2/M phase', 'CPA', (71, 81))	('knockdown', 'Var', (36, 45))	('delayed', 'NegReg', (63, 70))	('CU', 'Chemical', 'MESH:D003300', (17, 19))	('thymidine', 'Chemical', 'MESH:D013936', (120, 129))	('PBK', 'Gene', (32, 35))
44588	31325906	Moreover, the initial G1 accumulation increased through 18 hours post release suggesting that PBK silencing in CU-ACC1 allowed more cells to accumulate at G1 at any given time.	('CU', 'Chemical', 'MESH:D003300', (111, 113))	('CU-ACC1', 'Gene', (111, 118))	('silencing', 'Var', (98, 107))
44589	31325906	This observation was also in agreement with the severe growth restricted phenotype observed upon PBK knockdown in CU-ACC1 cell lines.	('severe growth restricted', 'Phenotype', 'HP:0008850', (48, 72))	('PBK', 'Gene', (97, 100))	('CU', 'Chemical', 'MESH:D003300', (114, 116))	('knockdown', 'Var', (101, 110))
44590	31325906	Hence, rather than triggering apoptosis, PBK silencing restricted the ability of the cell lines, especially CU-ACC1, to proliferate as evidenced by the growth curves shown in Figure 2A.	('silencing', 'Var', (45, 54))	('restricted', 'NegReg', (55, 65))	('PBK', 'Gene', (41, 44))	('proliferate', 'CPA', (120, 131))	('CU', 'Chemical', 'MESH:D003300', (108, 110))
44591	31325906	H295R cells, which have a non-functional p53 and activated beta catenin appeared to be resilient to cell cycle alteration with PBK knockdown and also exhibited less alterations in rates proliferation than CU-ACC1.	('non-functional', 'Var', (26, 40))	('p53', 'Gene', '7157', (41, 44))	('knockdown', 'Var', (131, 140))	('rates proliferation', 'CPA', (180, 199))	('CU', 'Chemical', 'MESH:D003300', (205, 207))	('PBK', 'Gene', (127, 130))	('cell cycle alteration', 'Phenotype', 'HP:0011018', (100, 121))	('beta catenin', 'Gene', (59, 71))	('beta catenin', 'Gene', '1499', (59, 71))	('activated', 'PosReg', (49, 58))	('p53', 'Gene', (41, 44))
44592	31325906	HITOPK032 recapitulated shPBK specific effects by inhibiting pH3 and pAkt in H295R, CU-ACC1, and CU-ACC2 cell lines, but in addition, induced apoptosis via activation of JNK.	('HITOPK032', 'Var', (0, 9))	('inhibiting', 'NegReg', (50, 60))	('CU', 'Chemical', 'MESH:D003300', (97, 99))	('JNK', 'Gene', (170, 173))	('activation', 'PosReg', (156, 166))	('CU', 'Chemical', 'MESH:D003300', (84, 86))	('Akt', 'Gene', (70, 73))	('induced', 'Reg', (134, 141))	('shPBK', 'Gene', (24, 29))	('pH3', 'Enzyme', (61, 64))	('JNK', 'Gene', '5599', (170, 173))	('apoptosis', 'CPA', (142, 151))	('Akt', 'Gene', '207', (70, 73))
44593	31325906	Although further studies are required to determine causes behind JNK activation, we hypothesize that a component of the HITOPK032 mediated effects may be dependent on a DNA damage response in ACC tumors.	('ACC tumor', 'Disease', (192, 201))	('HITOPK032', 'Var', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('JNK', 'Gene', '5599', (65, 68))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('ACC tumor', 'Disease', 'MESH:D004476', (192, 201))	('JNK', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
44594	31325906	Another possibility is that similar to nasopharyngeal carcinoma, HITOPK032 treatment of ACC induced reactive oxygen species and ER stress.	('carcinoma', 'Disease', 'MESH:D009369', (54, 63))	('ER stress', 'MPA', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('induced', 'Reg', (92, 99))	('reactive oxygen species', 'MPA', (100, 123))	('carcinoma', 'Disease', (54, 63))	('HITOPK032 treatment', 'Var', (65, 84))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (39, 63))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (100, 123))
44596	31325906	We showed that HITOPK032 effectively inhibited tumor growth using the first PDX model in the field of adult ACC.	('inhibited', 'NegReg', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('HITOPK032', 'Var', (15, 24))	('tumor', 'Disease', (47, 52))
44598	31325906	Treatment responses in PDX are more reflective of the clinical drug's effectiveness than xenograft in vivo studies.We have also validated downstream effectors of HITOPK032 in the harvested PDX tumor tissues demonstrating that the in vivo responses closely recapitulated effects of in vitro experiments, which is encouraging for future target development.	('HITOPK032', 'Var', (162, 171))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
44599	31325906	In summary, we have shown that targeting PBK, both genomically and pharmacologically, inhibits tumorigenic growth in preclinical models of ACC.	('inhibits', 'NegReg', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('PBK', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('targeting', 'Var', (31, 40))	('tumor', 'Disease', (95, 100))
44600	31325906	Mitotane, an adrenolytic drug used to treat patients with ACC has been shown to cause ER stress.	('Mitotane', 'Var', (0, 8))	('patients', 'Species', '9606', (44, 52))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('cause', 'Reg', (80, 85))	('ER stress', 'Disease', (86, 95))
44602	31325906	Future investigations will test in our new preclinical models the hypothesis that disruption of specific components of the cell the cycle such as PBK in conjunction with Mitotane, a known ER stress inducer, will enhance the anti-tumorigenic responses in ACC and provide new treatment strategies for our patients with ACC.	('patients', 'Species', '9606', (303, 311))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('enhance', 'PosReg', (212, 219))	('disruption', 'Var', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('PBK', 'Gene', (146, 149))	('tumor', 'Disease', (229, 234))	('Mitotane', 'Chemical', 'MESH:D008939', (170, 178))	('ACC', 'Disease', (254, 257))
44626	31561459	Obesity-related alterations in the amounts and/or spectrum of adipokine release have been linked to metabolic disorders such as hyperlipidemia and type 2 diabetes and are increasingly recognized as a key factor linking obesity with cancer.	('metabolic disorders', 'Disease', (100, 119))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('obesity', 'Phenotype', 'HP:0001513', (219, 226))	('Obesity', 'Disease', 'MESH:D009765', (0, 7))	('linked', 'Reg', (90, 96))	('hyperlipidemia and type 2 diabetes', 'Disease', 'MESH:D003924', (128, 162))	('cancer', 'Disease', (232, 238))	('hyperlipidemia', 'Phenotype', 'HP:0003077', (128, 142))	('alterations', 'Var', (16, 27))	('Obesity', 'Disease', (0, 7))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('amounts', 'MPA', (35, 42))	('obesity', 'Disease', 'MESH:D009765', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('metabolic disorders', 'Disease', 'MESH:D008659', (100, 119))	('obesity', 'Disease', (219, 226))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (147, 162))	('rat', 'Species', '10116', (20, 23))
44659	31561459	These results were validated in an in vivo xenograft model, where BALB/c nu/nu mice injected S.C. with OE21 human esophageal carcinoma cells along with CAMs had more infiltrated MSCs than those mice injected with OE21 cells alone.	('infiltrated MSCs', 'CPA', (166, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('OE21', 'Var', (103, 107))	('more', 'PosReg', (161, 165))	('mice', 'Species', '10090', (79, 83))	('esophageal carcinoma', 'Disease', (114, 134))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (114, 134))	('human', 'Species', '9606', (108, 113))	('rat', 'Species', '10116', (172, 175))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (114, 134))	('mice', 'Species', '10090', (194, 198))
44667	31561459	Conditioned media from CAMs, more so than conditioned media from ATMs and NTMs, stimulated migration and Matrigel invasion of OE21 cells, which could be partially blocked by chemerin neutralization, siRNA knockdown of chemerin or chemerin1, or pharmacological antagonism of chemerin1 with CCX832.	('stimulated', 'PosReg', (80, 90))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('rat', 'Species', '10116', (94, 97))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('NTM', 'Gene', (74, 77))	('knockdown', 'Var', (205, 214))	('migration', 'CPA', (91, 100))	('NTM', 'Gene', '50863', (74, 77))
44671	31561459	In the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus (BE) to high-grade dysplasia BE and esophageal carcinoma, a significant increase in myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) density was observed that coincided with increased expression of their respective chemotactic factors, macrophage inflammatory protein-3 alpha (MIP3alpha), and chemerin in the same regions.	('macrophage inflammatory protein-3 alpha', 'Gene', '6364', (324, 363))	('increase', 'PosReg', (142, 150))	('expression', 'MPA', (272, 282))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (106, 126))	('mDC', 'Gene', (178, 181))	('mDC', 'Gene', '20299', (178, 181))	('BE', 'Phenotype', 'HP:0100580', (99, 101))	('MIP3alpha', 'Gene', '6364', (365, 374))	('dysplasia', 'Disease', (18, 27))	("Barrett's esophagus", 'Disease', (50, 69))	('BE', 'Disease', 'MESH:D001471', (99, 101))	('dysplasia', 'Disease', (89, 98))	('high-grade', 'Var', (78, 88))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (50, 69))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (50, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('myeloid dendritic', 'Disease', 'MESH:D007635', (154, 171))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (106, 126))	('BE', 'Phenotype', 'HP:0100580', (71, 73))	('myeloid dendritic', 'Disease', (154, 171))	('metaplasia-dysplasia-carcinoma', 'Disease', (7, 37))	('metaplasia-dysplasia-carcinoma', 'Disease', 'MESH:D008679', (7, 37))	('dysplasia', 'Disease', 'MESH:D015792', (18, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('BE', 'Disease', 'MESH:D001471', (71, 73))	('increased', 'PosReg', (262, 271))	('esophageal carcinoma', 'Disease', (106, 126))	('dysplasia', 'Disease', 'MESH:D015792', (89, 98))	('MIP3alpha', 'Gene', (365, 374))	('macrophage inflammatory protein-3 alpha', 'Gene', (324, 363))
44705	31561459	While CCRL2 expression was detectable in several colorectal cell lines (SW480, SW620, LS174T, Caco2), siRNA-mediated knockdown of CCRL2 mRNA reduced proliferation, colony formation and migration only in LS174T cells.	('rat', 'Species', '10116', (156, 159))	('reduced', 'NegReg', (141, 148))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('migration', 'CPA', (185, 194))	('proliferation', 'CPA', (149, 162))	('N', 'Chemical', 'MESH:D009584', (138, 139))	('rat', 'Species', '10116', (188, 191))	('colony formation', 'CPA', (164, 180))	('CCRL2', 'Gene', (130, 135))	('knockdown', 'Var', (117, 126))	('CCRL2', 'Gene', (6, 11))
44720	31561459	Localized chemerin expression in melanoma has been demonstrated to decrease the presence of pDCs in the tumor microenvironment, ultimately inhibiting immune escape mechanisms.	('presence', 'MPA', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('decrease', 'NegReg', (67, 75))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('tumor', 'Disease', (104, 109))	('expression', 'Var', (19, 29))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('rat', 'Species', '10116', (58, 61))	('immune escape mechanisms', 'CPA', (150, 174))	('pDCs', 'Protein', (92, 96))	('inhibiting', 'NegReg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
44728	31561459	Similarly, mice injected hepatically with PVTT-1-Che cells exhibited reduced liver tumor foci development, a 1.3-fold increase in survival (54 days versus 41 days) compared to mice injected with control PVTT-1 cells.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('survival', 'CPA', (130, 138))	('reduced', 'NegReg', (69, 76))	('increase', 'PosReg', (118, 126))	('liver tumor', 'Disease', 'MESH:D008113', (77, 88))	('PVTT-1-Che', 'Var', (42, 52))	('men', 'Species', '9606', (101, 104))	('liver tumor', 'Disease', (77, 88))	('mice', 'Species', '10090', (11, 15))	('mice', 'Species', '10090', (176, 180))	('liver tumor', 'Phenotype', 'HP:0002896', (77, 88))
44756	31561459	detected no significant difference in recurrence-free survival or disease-free survival between patients classified with having low (<= 130.5 ng/mL) and high (> 130.5 ng/mL) serum chemerin concentration.	('> 130.5 ng/mL', 'Var', (159, 172))	('<= 130.5 ng/mL', 'Var', (133, 147))	('patients', 'Species', '9606', (96, 104))	('rat', 'Species', '10116', (196, 199))	('serum chemerin concentration', 'MPA', (174, 202))
44772	31561459	Interestingly, mice transplanted with human chemerin-expressing H295R tumors had higher serum concentrations of human chemerin but proportionally lower mouse serum chemerin suggesting a type of negative regulatory feedback mechanism.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('rat', 'Species', '10116', (101, 104))	('human', 'Species', '9606', (38, 43))	('higher', 'PosReg', (81, 87))	('H295R', 'Var', (64, 69))	('mouse', 'Species', '10090', (152, 157))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('lower', 'NegReg', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mouse serum chemerin', 'MPA', (152, 172))	('mice', 'Species', '10090', (15, 19))	('human', 'Species', '9606', (112, 117))	('serum concentrations of human chemerin', 'MPA', (88, 126))
44782	31561459	In further support of a direct tumor suppressive (rather than immune-mediated) effect of chemerin, H295R cells with stable expression of human chemerin had decreased colony formation and invasion in in vitro assays and formed smaller tumors when xenografted into the flanks immunodeficient T-cell deficient athymic nude and T, B, and NK-cell deficient and macrophage and dendritic cell-impaired NOD Scid gamma mice.	('colony formation', 'CPA', (166, 182))	('tumor', 'Disease', (234, 239))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('chemerin', 'Gene', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('mice', 'Species', '10090', (410, 414))	('human', 'Species', '9606', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('H295R', 'Var', (99, 104))	('flanks immunodeficient T-cell deficient athymic nude', 'Disease', 'MESH:D021501', (267, 319))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('smaller', 'NegReg', (226, 233))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('decreased', 'NegReg', (156, 165))	('N', 'Chemical', 'MESH:D009584', (334, 335))	('rat', 'Species', '10116', (50, 53))	('tumor', 'Disease', (31, 36))	('N', 'Chemical', 'MESH:D009584', (395, 396))	('tumors', 'Disease', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
44794	31561459	In the study by Krawczyk et al., foamy macrophages were histologically identified in 82% of pRCC tumors and the macrophages expressed cell surface markers CD689 and CD163 that are characteristic of the M2 anti-inflammatory phenotype.	('CD163', 'Var', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('foamy macrophages', 'Phenotype', 'HP:0003651', (33, 50))	('pRCC', 'Disease', 'MESH:D002292', (92, 96))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('pRCC', 'Disease', (92, 96))	('CD689', 'Var', (155, 160))	('pRCC', 'Phenotype', 'HP:0006766', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
44827	31561459	Depletion experiments indicated a critical role of NK cells and CD8+ T cells in the tumor suppression response to chemerin, while the depletion of CD4+ T regulatory cells enhanced tumor suppression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('enhanced', 'PosReg', (171, 179))	('CD8', 'Gene', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('CD4', 'Gene', '920', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('depletion', 'Var', (134, 143))	('CD8', 'Gene', '925', (64, 67))	('tumor', 'Disease', (180, 185))	('men', 'Species', '9606', (16, 19))	('tumor', 'Disease', (84, 89))	('N', 'Chemical', 'MESH:D009584', (51, 52))	('CD4', 'Gene', (147, 150))
44868	31561459	However, while serum chemerin concentrations increased with Gleason score, the opposite effect was observed for chemerin expression in prostate tumor tissue.	('prostate tumor', 'Phenotype', 'HP:0100787', (135, 149))	('increased', 'PosReg', (45, 54))	('rat', 'Species', '10116', (37, 40))	('prostate tumor', 'Disease', 'MESH:D011471', (135, 149))	('serum chemerin concentrations', 'MPA', (15, 44))	('Gleason', 'Var', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('prostate tumor', 'Disease', (135, 149))
44894	28146118	Mutations of cAMP response elements on Mc2r promoter disrupts JDP2 effect.	('disrupts', 'NegReg', (53, 61))	('Mutations', 'Var', (0, 9))	('JDP2 effect', 'MPA', (62, 73))	('cAMP', 'Chemical', '-', (13, 17))
44910	28146118	Mutations in MC2R have been associated with familial glucocorticoid deficiency.	('familial glucocorticoid deficiency', 'Disease', (44, 78))	('familial glucocorticoid deficiency', 'Disease', 'MESH:C564577', (44, 78))	('associated', 'Reg', (28, 38))	('Mutations', 'Var', (0, 9))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (53, 78))	('MC2R', 'Gene', (13, 17))
44921	28146118	These results indicate that adrenal glands express JDP2 protein and JDP2 enhances MC2R expression in Y1 adrenocortical cancer cells.	('adrenocortical cancer', 'Disease', (104, 125))	('expression', 'Species', '29278', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (104, 125))	('JDP2 protein', 'Protein', (51, 63))	('JDP2', 'Var', (68, 72))	('MC2R', 'Protein', (82, 86))	('enhances', 'PosReg', (73, 81))
44923	28146118	As shown in Figure 2A-E, JDP2 dose-dependently activated Mc2r gene transcription in a LUC assay using HEPG2, JEG3, Ishikawa, Y1, and MCF7 cells.	('activated', 'PosReg', (47, 56))	('Mc2r gene', 'Gene', (57, 66))	('MCF7', 'CellLine', 'CVCL:0031', (133, 137))	('JDP2', 'Var', (25, 29))	('transcription', 'MPA', (67, 80))
44925	28146118	Deletion of the promoter region which contains distal cAMP response elements, as shown in the -720 promoter, resulted in a significant loss (approximately 50%) of JDP2-mediated transcriptional activity in both HepG2 and JEG3 cells.	('cAMP', 'Chemical', '-', (54, 58))	('loss', 'NegReg', (135, 139))	('Deletion', 'Var', (0, 8))	('JDP2-mediated', 'Gene', (163, 176))	('HepG2', 'CellLine', 'CVCL:0027', (210, 215))
44927	28146118	To further determine whether the cAMP response elements are required for JDP2-mediated activation, we next generated 15 cAMP response element mutations (TGA or TCA were mutated to ACC) in -1320-bp Mc2r promoter-LUC plasmids.	('mutations', 'Var', (142, 151))	('TGA', 'Gene', (153, 156))	('cAMP', 'Chemical', '-', (33, 37))	('cAMP', 'Chemical', '-', (120, 124))	('TCA', 'Gene', (160, 163))
44928	28146118	Consistent with the previous results, mutations of 15 cAMP response elements dramatically reduced (approximately 90% loss) JDP-mediated Mc2r promoter activity in HepG2 cells (Figure 4A).	('JDP-mediated Mc2r promoter activity', 'MPA', (123, 158))	('reduced', 'NegReg', (90, 97))	('cAMP', 'Chemical', '-', (54, 58))	('loss', 'NegReg', (117, 121))	('mutations', 'Var', (38, 47))	('HepG2', 'CellLine', 'CVCL:0027', (162, 167))
44932	28146118	We cotransfected Mc2r-LUC reporter gene with either wild-type, T148A (mimicking de-phosphorylated), or T148D (mimicking phosphorylated) Jdp2 expression plasmid and determined LUC activity 48 h post-transfection.	('T148A', 'Var', (63, 68))	('T148A', 'Mutation', 'c.148T>A', (63, 68))	('Jdp2', 'Gene', (136, 140))	('T148D', 'Var', (103, 108))	('expression', 'Species', '29278', (141, 151))	('T148D', 'Mutation', 'p.T148D', (103, 108))	('Jdp2', 'Gene', '122953', (136, 140))
44933	28146118	As shown in Figure 5, while wild-type and T148D JDP2 enhanced Mc2r promoter activity eight-fold, T148A JDP2 significantly reduced this effect (approximately 38% loss).	('JDP2', 'Gene', (103, 107))	('JDP2', 'Gene', (48, 52))	('T148D', 'Var', (42, 47))	('T148A', 'Var', (97, 102))	('T148A', 'Mutation', 'c.148T>A', (97, 102))	('Mc2r', 'Protein', (62, 66))	('T148D', 'Mutation', 'p.T148D', (42, 47))	('reduced', 'NegReg', (122, 129))	('enhanced', 'PosReg', (53, 61))
44935	28146118	Previously, we have shown that ATF3 can be SUMOylated and SUMOylation/deSUMOylation of ATF3 regulates TP53 gene activity and trans-activation of p53.	('regulates', 'Reg', (92, 101))	('ATF3', 'Gene', (31, 35))	('TP53', 'Gene', (102, 106))	('ATF3', 'Gene', (87, 91))	('SUMOylation/deSUMOylation', 'Var', (58, 83))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('ATF3', 'Gene', '467', (87, 91))	('trans-activation', 'MPA', (125, 141))	('ATF3', 'Gene', '467', (31, 35))	('TP53', 'Gene', '7157', (102, 106))	('activity', 'MPA', (112, 120))
44937	28146118	GST-JDP2 protein was incubated with E1 and E2 enzymes and either wild-type or mutated SUMO-1 at 30  C for 3 h followed by western blot analysis.	('SUMO-1', 'Gene', '7341', (86, 92))	('SUMO-1', 'Gene', (86, 92))	('E1 and E', 'Gene', '6080', (36, 44))	('mutated', 'Var', (78, 85))
44940	28146118	As shown in Figure 7A, expression of wild-type JDP2 leads to an increase (seven to eight fold) in the activity of Mc2r promoter-driven LUC reporters.	('expression', 'Var', (23, 33))	('increase', 'PosReg', (64, 72))	('JDP2', 'Gene', (47, 51))	('activity', 'MPA', (102, 110))	('Mc2r promoter-driven', 'Gene', (114, 134))	('expression', 'Species', '29278', (23, 33))
44942	28146118	Though JDP2 binds to ATF proteins, JDP2 suppresses the transcription of its homologue immediate early gene counterpart, ATF3.	('JDP2', 'Var', (35, 39))	('ATF3', 'Gene', '467', (120, 124))	('suppresses', 'NegReg', (40, 50))	('binds', 'Interaction', (12, 17))	('ATF3', 'Gene', (120, 124))	('transcription', 'MPA', (55, 68))	('ATF', 'Gene', '2668', (120, 123))	('ATF', 'Gene', '2668', (21, 24))	('ATF', 'Gene', (120, 123))	('ATF', 'Gene', (21, 24))
44945	28146118	Interestingly, we observed that both expression of T148A mutant protein and SUMO1-JDP2 fusion protein relieved the reduction by 20% and 10%, respectively.	('T148A', 'Var', (51, 56))	('T148A', 'Mutation', 'c.148T>A', (51, 56))	('expression', 'Species', '29278', (37, 47))	('SUMO1', 'Gene', '7341', (76, 81))	('SUMO1', 'Gene', (76, 81))
44958	28146118	In the present work, we demonstrate that loss of phosphorylation on JDP2 T148 significantly reduces its activity in regulating Mc2r promoter.	('activity', 'MPA', (104, 112))	('regulating Mc2r promoter', 'MPA', (116, 140))	('JDP2', 'Gene', (68, 72))	('T148', 'Var', (73, 77))	('phosphorylation', 'MPA', (49, 64))	('T148', 'Chemical', 'MESH:C029383', (73, 77))	('reduces', 'NegReg', (92, 99))	('loss', 'NegReg', (41, 45))
44961	28146118	Previously, we have reported that ATF3 is a novel substrate for SUMOylation and that SUMOylation of ATF3 alters p53 trans-activation and stability as well as prostate cancer proliferation.	('prostate cancer', 'Phenotype', 'HP:0012125', (158, 173))	('alters', 'Reg', (105, 111))	('trans-activation', 'MPA', (116, 132))	('prostate cancer', 'Disease', (158, 173))	('ATF3', 'Gene', '467', (100, 104))	('ATF3', 'Gene', '467', (34, 38))	('p53', 'Gene', (112, 115))	('stability', 'MPA', (137, 146))	('prostate cancer', 'Disease', 'MESH:D011471', (158, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('SUMOylation', 'Var', (85, 96))	('ATF3', 'Gene', (100, 104))	('p53', 'Gene', '7157', (112, 115))	('ATF3', 'Gene', (34, 38))
44963	28146118	The reason why T48A mutation or SUMO-JDP2 fusion constructs from the present study still retain the ability to suppress ATF3 activation with albeit weaker reduction may be due to the strong interaction of JDP2-HDACs.	('suppress', 'NegReg', (111, 119))	('SUMO-JDP2', 'Gene', (32, 41))	('ATF3', 'Gene', '467', (120, 124))	('T48A', 'Mutation', 'c.48T>A', (15, 19))	('activation', 'MPA', (125, 135))	('SUMO-JDP2', 'Gene', '122953', (32, 41))	('ATF3', 'Gene', (120, 124))	('interaction', 'Interaction', (190, 201))	('HD', 'Disease', 'MESH:D006816', (210, 212))	('T48A mutation', 'Var', (15, 28))
44972	28146118	T148A, T148D, and 1-100 Jdp2 expression plasmids were created by PCR-based mutagenesis (QuikChange Lightning site-directed mutagenesis kit, Agilent/Strategene, La Jolla, CA, USA).	('T148A', 'Mutation', 'c.148T>A', (0, 5))	('Jdp2', 'Gene', '122953', (24, 28))	('T148D', 'Var', (7, 12))	('expression', 'Species', '29278', (29, 39))	('T148D', 'Mutation', 'p.T148D', (7, 12))	('Jdp2', 'Gene', (24, 28))
44990	28146118	The samples were advanced to immunoblotting using anti-SUMO1 (or anti-SUMO3) or anti-JDP2 antibodies.	('SUMO3', 'Gene', (70, 75))	('anti-JDP2', 'Var', (80, 89))	('SUMO3', 'Gene', '6612', (70, 75))	('SUMO1', 'Gene', (55, 60))	('SUMO1', 'Gene', '7341', (55, 60))
44996	27098837	Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) CaV1.3.	('Zona glomerulosa', 'Disease', 'MESH:D006562', (0, 16))	('calcium', 'Chemical', 'MESH:D002118', (71, 78))	('CaV1.3', 'Gene', '776', (94, 100))	('Zona glomerulosa', 'Disease', (0, 16))	('CaV1.3', 'Gene', (94, 100))	('mutations', 'Var', (48, 57))
44999	27098837	In H295R cells transfected with wild-type or mutant CaV1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 muM of compound 8.	('muM', 'Gene', '56925', (151, 154))	('mutant', 'Var', (45, 51))	('CaV1.3', 'Gene', '776', (52, 58))	('aldosterone', 'MPA', (94, 105))	('muM', 'Gene', (151, 154))	('H295R', 'CellLine', 'CVCL:0458', (3, 8))	('CaV1.3', 'Gene', (52, 58))	('aldosterone', 'Chemical', 'MESH:D000450', (94, 105))
45001	27098837	Selective CaV1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of CaV1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of CaV1.3.	('primary hyperaldosteronism', 'Disease', (60, 86))	('primary hyperaldosteronism', 'Disease', 'MESH:D003480', (60, 86))	('CaV1.3', 'Gene', (214, 220))	('CaV1.2', 'Gene', (130, 136))	('mutations', 'Var', (201, 210))	('CaV1.3', 'Gene', '776', (10, 16))	('CaV1.2', 'Gene', '775', (130, 136))	('CaV1.3', 'Gene', '776', (214, 220))	('primary hyperaldosteronism', 'Phenotype', 'HP:0011736', (60, 86))	('men', 'Species', '9606', (174, 177))	('CaV1.3', 'Gene', (10, 16))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (68, 86))
45005	27098837	We previously reported somatic gain-of-function mutations in two genes that regulate Na+, K+ and Ca2+ transport in APAs with a zona glomerulosa (ZG)-like phenotype.	('mutations', 'Var', (48, 57))	('Ca2+', 'Chemical', 'MESH:D000069285', (97, 101))	('gain-of-function', 'PosReg', (31, 47))	('Na+', 'MPA', (85, 88))
45006	27098837	Whole exome sequencing of small-cell APAs with a ZG-like gene expression profile found five out of ten to harbour one of four different somatic mutations in the voltage dependent L-type Ca2+ channel, CaV1.3 (encoded by the gene CACNA1D).	('CaV1.3', 'Gene', '776', (200, 206))	('CACNA1D', 'Gene', '776', (228, 235))	('CACNA1D', 'Gene', (228, 235))	('Ca2+', 'Chemical', 'MESH:D000069285', (186, 190))	('mutations', 'Var', (144, 153))	('CaV1.3', 'Gene', (200, 206))
45007	27098837	These four substitution mutations, V259D, G403R, I750M, and P1336R, cluster around the Ca2+ pore between the S5 and S6 domains that line the inner pore surface.	('V259D', 'Mutation', 'p.V259D', (35, 40))	('V259D', 'Var', (35, 40))	('I750M', 'Mutation', 'rs41276445', (49, 54))	('Ca2+', 'Chemical', 'MESH:D000069285', (87, 91))	('P1336R', 'Var', (60, 66))	('G403R', 'Var', (42, 47))	('I750M', 'Var', (49, 54))	('G403R', 'Mutation', 'rs386834263', (42, 47))	('P1336R', 'Mutation', 'p.P1336R', (60, 66))
45008	27098837	The mutations occur in conserved sites within functional domains such as the voltage-sensing domain to the pore (V259D and P1336R) and the channel activation gate (G403R and I750M).	('I750M', 'Var', (174, 179))	('I750M', 'Mutation', 'rs41276445', (174, 179))	('P1336R', 'Mutation', 'p.P1336R', (123, 129))	('G403R', 'Var', (164, 169))	('P1336R', 'Var', (123, 129))	('G403R', 'Mutation', 'rs386834263', (164, 169))	('V259D', 'Mutation', 'p.V259D', (113, 118))	('V259D', 'Var', (113, 118))
45009	27098837	The G403R and I750M mutations were simultaneously reported as rare de novo germline mutations presenting at birth, together with several patients having somatic mutations of the same residues in sporadic APAs.	('I750M', 'Mutation', 'rs41276445', (14, 19))	('I750M', 'Var', (14, 19))	('G403R', 'Var', (4, 9))	('G403R', 'Mutation', 'rs386834263', (4, 9))	('patients', 'Species', '9606', (137, 145))
45011	27098837	Patch clamping of HEK293 cells has shown that at least 6 of the 19 mutations affect the CaV1.3 channel function and allow for increased Ca2+ influx through either shifting voltage-dependent activation towards more negative voltages, decelerating inactivation, and/or increasing currents through a higher open channel probability.	('CaV1.3', 'Gene', (88, 94))	('activation', 'PosReg', (190, 200))	('higher', 'PosReg', (297, 303))	('Ca2+ influx', 'MPA', (136, 147))	('mutations', 'Var', (67, 76))	('affect', 'Reg', (77, 83))	('currents', 'MPA', (278, 286))	('increasing', 'PosReg', (267, 277))	('CaV1.3', 'Gene', '776', (88, 94))	('HEK293', 'CellLine', 'CVCL:0045', (18, 24))	('increased', 'PosReg', (126, 135))	('decelerating inactivation', 'MPA', (233, 258))	('Ca2+', 'Chemical', 'MESH:D000069285', (136, 140))
45012	27098837	The current medical treatment of primary hyperaldosteronism is blockade of the mineralocorticoid receptor, which can lead to an increase in aldosterone secretion.	('increase in aldosterone', 'Phenotype', 'HP:0000859', (128, 151))	('increase', 'PosReg', (128, 136))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (41, 59))	('aldosterone', 'Chemical', 'MESH:D000450', (140, 151))	('primary hyperaldosteronism', 'Disease', 'MESH:D003480', (33, 59))	('mineralocorticoid receptor', 'Gene', (79, 105))	('primary hyperaldosteronism', 'Phenotype', 'HP:0011736', (33, 59))	('aldosterone secretion', 'MPA', (140, 161))	('primary hyperaldosteronism', 'Disease', (33, 59))	('blockade', 'Var', (63, 71))	('mineralocorticoid receptor', 'Gene', '4306', (79, 105))	('men', 'Species', '9606', (25, 28))
45013	27098837	Therefore, blockade of calcium entry through selective antagonism of CaV1.3 might present a valuable therapeutic target.	('antagonism', 'Var', (55, 65))	('CaV1.3', 'Gene', (69, 75))	('CaV1.3', 'Gene', '776', (69, 75))	('calcium', 'Chemical', 'MESH:D002118', (23, 30))
45014	27098837	We therefore aimed to investigate whether CaV1.3 mutations cause the postulated increase in aldosterone secretion from human adrenocortical cells, and whether blockade of calcium entry reverses this.	('CaV1.3', 'Gene', '776', (42, 48))	('aldosterone', 'Chemical', 'MESH:D000450', (92, 103))	('mutations', 'Var', (49, 58))	('adrenocortical', 'Disease', (125, 139))	('increase', 'PosReg', (80, 88))	('CaV1.3', 'Gene', (42, 48))	('adrenocortical', 'Disease', 'MESH:D018268', (125, 139))	('calcium', 'Chemical', 'MESH:D002118', (171, 178))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (80, 103))	('human', 'Species', '9606', (119, 124))
45018	27098837	To study the role of CaV1.3 on aldosterone secretion, we first investigated the substitution mutations near the voltage-sensing domain, P1336R and V259D, on 24-h aldosterone production in transiently transfected H295R cells to find if the different changes seen in our electrophysiology data translated to changes in aldosterone secretion.	('P1336R', 'Mutation', 'p.P1336R', (136, 142))	('h aldosterone', 'Phenotype', 'HP:0000859', (160, 173))	('changes', 'Reg', (306, 313))	('CaV1.3', 'Gene', '776', (21, 27))	('aldosterone', 'Chemical', 'MESH:D000450', (162, 173))	('aldosterone production', 'Phenotype', 'HP:0000859', (162, 184))	('P1336R', 'Var', (136, 142))	('H295R', 'CellLine', 'CVCL:0458', (212, 217))	('aldosterone', 'Chemical', 'MESH:D000450', (31, 42))	('CaV1.3', 'Gene', (21, 27))	('aldosterone secretion', 'MPA', (317, 338))	('V259D', 'Var', (147, 152))	('V259D', 'Mutation', 'p.V259D', (147, 152))	('aldosterone', 'Chemical', 'MESH:D000450', (317, 328))
45019	27098837	We then contrasted the aldosterone secretion of cells transfected with mutant CaV1.3 channels to those transfected with wild-type CaV1.3 channel in the presence of compound 8 or nifedipine to study if blockade of calcium entry affects APAs with a CaV1.3 mutation differently.	('aldosterone', 'Chemical', 'MESH:D000450', (23, 34))	('aldosterone secretion', 'MPA', (23, 44))	('CaV1.3', 'Gene', (130, 136))	('CaV1.3', 'Gene', (78, 84))	('CaV1.3', 'Gene', (247, 253))	('nifedipine', 'Chemical', 'MESH:D009543', (178, 188))	('mutant', 'Var', (71, 77))	('CaV1.3', 'Gene', '776', (130, 136))	('calcium', 'Chemical', 'MESH:D002118', (213, 220))	('CaV1.3', 'Gene', '776', (78, 84))	('CaV1.3', 'Gene', '776', (247, 253))
45020	27098837	Transfection of H295R cells with exogenous CaV1.3 was performed with beta3 and alpha2delta accessory subunits, the subunits we used previously to show gain-of function effects of the mutations on Ca2+ currents.	('Ca2+', 'Chemical', 'MESH:D000069285', (196, 200))	('H295R', 'CellLine', 'CVCL:0458', (16, 21))	('mutations', 'Var', (183, 192))	('CaV1.3', 'Gene', (43, 49))	('beta3', 'Gene', (69, 74))	('Ca2+ currents', 'MPA', (196, 209))	('CaV1.3', 'Gene', '776', (43, 49))	('gain-of', 'PosReg', (151, 158))	('beta3', 'Gene', '1934', (69, 74))
45022	27098837	Transfection of H295R cells with CaV1.3 mutants P1336R and V259D caused a 2.4 +- 0.2 (P = 0.0004) and 2.1 +- 0.2 (P = 0.002) fold increase, respectively, in basal aldosterone production compared to wild-type transfected H295R cells (Fig.	('aldosterone', 'Chemical', 'MESH:D000450', (163, 174))	('CaV1.3', 'Gene', (33, 39))	('H295R', 'CellLine', 'CVCL:0458', (16, 21))	('P1336R', 'Mutation', 'p.P1336R', (48, 54))	('aldosterone production', 'Phenotype', 'HP:0000859', (163, 185))	('H295R', 'CellLine', 'CVCL:0458', (220, 225))	('basal aldosterone production', 'MPA', (157, 185))	('increase', 'PosReg', (130, 138))	('P1336R', 'Var', (48, 54))	('V259D', 'Mutation', 'p.V259D', (59, 64))	('CaV1.3', 'Gene', '776', (33, 39))	('V259D', 'Var', (59, 64))
45025	27098837	In cells transiently transfected with wild-type, P1336R, or V259D CaV1.3, there was a similar biphasic effect of compound 8 on aldosterone secretion from the mutant P1336R cells, as that seen in wild-type CaV1.3.	('CaV1.3', 'Gene', '776', (66, 72))	('CaV1.3', 'Gene', (205, 211))	('P1336R', 'Mutation', 'p.P1336R', (165, 171))	('P1336R', 'Mutation', 'p.P1336R', (49, 55))	('aldosterone', 'Chemical', 'MESH:D000450', (127, 138))	('V259D', 'Var', (60, 65))	('CaV1.3', 'Gene', '776', (205, 211))	('V259D', 'Mutation', 'p.V259D', (60, 65))	('P1336R', 'Var', (165, 171))	('aldosterone secretion', 'MPA', (127, 148))	('CaV1.3', 'Gene', (66, 72))	('P1336R', 'Var', (49, 55))
45026	27098837	In mutant V259D cells, compound 8 was inhibitory only at 100 muM (Fig.	('muM', 'Gene', (61, 64))	('mutant V259D', 'Var', (3, 15))	('V259D', 'Mutation', 'p.V259D', (10, 15))	('V259D', 'Var', (10, 15))	('muM', 'Gene', '56925', (61, 64))
45028	27098837	In wild-type CaV1.3 transfected cells, after treatment with 1 muM, 10 muM or 100 muM nifedipine, a 35 +- 12% decrease of aldosterone secretion was observed only at the highest concentration of nifedipine interrogated (100 muM)(P = 0.0001, Fig.	('decrease', 'NegReg', (109, 117))	('muM', 'Gene', '56925', (62, 65))	('muM', 'Gene', (222, 225))	('nifedipine', 'Chemical', 'MESH:D009543', (193, 203))	('decrease of aldosterone', 'Phenotype', 'HP:0004319', (109, 132))	('nifedipine', 'Var', (85, 95))	('muM', 'Gene', (62, 65))	('muM', 'Gene', '56925', (70, 73))	('CaV1.3', 'Gene', (13, 19))	('nifedipine', 'Chemical', 'MESH:D009543', (85, 95))	('men', 'Species', '9606', (50, 53))	('muM', 'Gene', '56925', (81, 84))	('aldosterone', 'Chemical', 'MESH:D000450', (121, 132))	('muM', 'Gene', '56925', (222, 225))	('muM', 'Gene', (70, 73))	('aldosterone secretion', 'MPA', (121, 142))	('muM', 'Gene', (81, 84))	('CaV1.3', 'Gene', '776', (13, 19))
45030	27098837	In P1336R and V259D transfected cells, despite the increased aldosterone secretion compared to that of wild-type cells (as seen at 0 muM), the presence of high concentration of nifedipine (100 muM) decreased aldosterone production similarly across all genotypes (Fig.	('muM', 'Gene', (133, 136))	('aldosterone', 'Chemical', 'MESH:D000450', (208, 219))	('aldosterone', 'Chemical', 'MESH:D000450', (61, 72))	('nifedipine', 'Chemical', 'MESH:D009543', (177, 187))	('increased', 'PosReg', (51, 60))	('P1336R', 'Mutation', 'p.P1336R', (3, 9))	('aldosterone secretion', 'MPA', (61, 82))	('aldosterone production', 'MPA', (208, 230))	('muM', 'Gene', '56925', (193, 196))	('increased aldosterone', 'Phenotype', 'HP:0000859', (51, 72))	('decreased aldosterone', 'Phenotype', 'HP:0004319', (198, 219))	('aldosterone production', 'Phenotype', 'HP:0000859', (208, 230))	('P1336R', 'Var', (3, 9))	('V259D', 'Mutation', 'p.V259D', (14, 19))	('muM', 'Gene', '56925', (133, 136))	('muM', 'Gene', (193, 196))	('V259D', 'Var', (14, 19))	('decreased', 'NegReg', (198, 207))
45032	27098837	In primary human adrenal cells cultured from the normal adjacent adrenals of patients with an APA, 10 and 100 muM of compound 8 inhibited aldosterone production by 35 +- 10 and 43 +- 11%, respectively (P < 0.05; Fig.	('aldosterone production', 'Phenotype', 'HP:0000859', (138, 160))	('human', 'Species', '9606', (11, 16))	('inhibited aldosterone production', 'Phenotype', 'HP:0004319', (128, 160))	('muM', 'Gene', '56925', (110, 113))	('patients', 'Species', '9606', (77, 85))	('muM', 'Gene', (110, 113))	('APA', 'Var', (94, 97))	('aldosterone', 'Chemical', 'MESH:D000450', (138, 149))	('inhibited', 'NegReg', (128, 137))	('aldosterone production', 'MPA', (138, 160))
45042	27098837	In a large multi-centre study of 474 APAs, the frequency of CaV1.3 mutation was estimated to be 9.3%.	('CaV1.3', 'Gene', '776', (60, 66))	('mutation', 'Var', (67, 75))	('CaV1.3', 'Gene', (60, 66))
45043	27098837	Although no particular histological phenotype was found in the multi-centre study, one centre within the study did subsequently report that of their 71 APAs, CaV1.3 mutant APAs (3 of 71) were composed mainly of ZG-like cells.	('CaV1.3', 'Gene', '776', (158, 164))	('mutant', 'Var', (165, 171))	('CaV1.3', 'Gene', (158, 164))
45044	27098837	Thus the current approximation could be a substantial underestimation since (a) half of our selected ZG-like APAs that were exome sequenced had a CaV1.3 mutation; and (b) our experience is that such tumours are frequently too small to be detected by conventional adrenal imaging.	('CaV1.3', 'Gene', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('CaV1.3', 'Gene', '776', (146, 152))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('tumours', 'Disease', (199, 206))	('mutation', 'Var', (153, 161))
45045	27098837	We therefore wished to show whether the mutations are likely to increase aldosterone production, rather than trigger development of the adenoma, and whether this increase could be reversed by blockade of calcium entry.	('adenoma', 'Disease', (136, 143))	('men', 'Species', '9606', (124, 127))	('calcium', 'Chemical', 'MESH:D002118', (204, 211))	('aldosterone production', 'MPA', (73, 95))	('aldosterone production', 'Phenotype', 'HP:0000859', (73, 95))	('mutations', 'Var', (40, 49))	('increase', 'PosReg', (64, 72))	('aldosterone', 'Chemical', 'MESH:D000450', (73, 84))	('increase aldosterone', 'Phenotype', 'HP:0000859', (64, 84))	('adenoma', 'Disease', 'MESH:D000236', (136, 143))
45047	27098837	Herein we report that the two CaV1.3 mutations studied, selected for having different electrophysiological effects, do increase aldosterone secretion of transfected human adrenocortical cells (Fig.	('adrenocortical', 'Disease', 'MESH:D018268', (171, 185))	('human', 'Species', '9606', (165, 170))	('CaV1.3', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('do increase aldosterone', 'Phenotype', 'HP:0000859', (116, 139))	('increase', 'PosReg', (119, 127))	('increase aldosterone', 'Phenotype', 'HP:0000859', (119, 139))	('aldosterone secretion', 'MPA', (128, 149))	('adrenocortical', 'Disease', (171, 185))	('CaV1.3', 'Gene', '776', (30, 36))	('aldosterone', 'Chemical', 'MESH:D000450', (128, 139))
45049	27098837	The inhibition of aldosterone secretion was seen in the presence of the highest concentration of compound 8 interrogated in this study (100 muM) in H295R cells transfected with CaV1.3 mutants (Fig.	('CaV1.3', 'Gene', (177, 183))	('muM', 'Gene', '56925', (140, 143))	('aldosterone', 'Chemical', 'MESH:D000450', (18, 29))	('muM', 'Gene', (140, 143))	('mutants', 'Var', (184, 191))	('CaV1.3', 'Gene', '776', (177, 183))	('H295R', 'CellLine', 'CVCL:0458', (148, 153))	('inhibition', 'NegReg', (4, 14))	('aldosterone secretion', 'MPA', (18, 39))
45051	27098837	We also postulate that regardless of whether a given APA has a somatic mutation of CaV1.3, the channel is often more active than in normal ZG cells, where immunohistochemistry suggests CaV1.3 is mainly internalised (Fig.	('CaV1.3', 'Gene', '776', (185, 191))	('active', 'MPA', (117, 123))	('more', 'PosReg', (112, 116))	('CaV1.3', 'Gene', '776', (83, 89))	('mutation', 'Var', (71, 79))	('internalised', 'MPA', (202, 214))	('CaV1.3', 'Gene', (185, 191))	('CaV1.3', 'Gene', (83, 89))
45064	27098837	This cell line was used mainly due to the ease of transfecting exogenous mutant CaV1.3.	('mutant', 'Var', (73, 79))	('CaV1.3', 'Gene', (80, 86))	('CaV1.3', 'Gene', '776', (80, 86))
45068	27098837	Previous studies have shown a number of dihydropyridines to reduce aldosterone secretion from adrenocortical cells.	('reduce aldosterone', 'Phenotype', 'HP:0004319', (60, 78))	('reduce', 'NegReg', (60, 66))	('adrenocortical', 'Disease', (94, 108))	('adrenocortical', 'Disease', 'MESH:D018268', (94, 108))	('dihydropyridines', 'Chemical', 'MESH:D004095', (40, 56))	('dihydropyridines', 'Var', (40, 56))	('aldosterone', 'Chemical', 'MESH:D000450', (67, 78))
45071	27098837	At the lowest concentration of nifedipine that we had interrogated (1 muM), a concentration which should have easily blocked CaV1.2, only some inhibition of aldosterone could be seen in non-transfected H295R and primary adrenal cells and none at all in H295R cells transfected with CaV1.3 mutants (Figs 2 and 3).	('aldosterone', 'MPA', (157, 168))	('CaV1.3', 'Gene', '776', (282, 288))	('nifedipine', 'Chemical', 'MESH:D009543', (31, 41))	('mutants', 'Var', (289, 296))	('aldosterone', 'Chemical', 'MESH:D000450', (157, 168))	('muM', 'Gene', '56925', (70, 73))	('CaV1.2', 'Gene', (125, 131))	('CaV1.3', 'Gene', (282, 288))	('H295R', 'CellLine', 'CVCL:0458', (202, 207))	('muM', 'Gene', (70, 73))	('CaV1.2', 'Gene', '775', (125, 131))	('inhibition', 'NegReg', (143, 153))	('H295R', 'CellLine', 'CVCL:0458', (253, 258))
45083	27098837	Although no evidence exists in humans, there is an additional theoretical benefit from blocking aldosterone synthesis rather than response - that such a drug could cause involution of aldosterone-producing cells.	('involution of aldosterone-producing cells', 'MPA', (170, 211))	('blocking', 'NegReg', (87, 95))	('cause', 'Reg', (164, 169))	('drug', 'Var', (153, 157))	('aldosterone', 'Chemical', 'MESH:D000450', (96, 107))	('humans', 'Species', '9606', (31, 37))	('aldosterone synthesis', 'MPA', (96, 117))	('aldosterone', 'Chemical', 'MESH:D000450', (184, 195))
45084	27098837	This is suggested by the observation that genetic deletion of the enzyme aldosterone synthase leads to apoptosis of the normal ZG cells.	('aldosterone synthase', 'Gene', '1585', (73, 93))	('genetic deletion', 'Var', (42, 58))	('leads to', 'Reg', (94, 102))	('apoptosis', 'CPA', (103, 112))	('aldosterone synthase', 'Gene', (73, 93))
45085	27098837	In summary, we previously reported ZG-like APAs to have CaV1.3 mutations.	('mutations', 'Var', (63, 72))	('CaV1.3', 'Gene', '776', (56, 62))	('CaV1.3', 'Gene', (56, 62))
45087	27098837	By blocking endogenous CaV1.3 in primary human adrenal and transfecting mutant CaV1.3 in the human adrenocortical cell line, H295R, we have also confirmed that CaV1.3 plays a role in human adrenal steroidogenesis.	('adrenocortical', 'Disease', 'MESH:D018268', (99, 113))	('CaV1.3', 'Gene', (160, 166))	('mutant', 'Var', (72, 78))	('CaV1.3', 'Gene', '776', (79, 85))	('human', 'Species', '9606', (93, 98))	('CaV1.3', 'Gene', (23, 29))	('human', 'Species', '9606', (41, 46))	('CaV1.3', 'Gene', '776', (160, 166))	('human', 'Species', '9606', (183, 188))	('H295R', 'CellLine', 'CVCL:0458', (125, 130))	('CaV1.3', 'Gene', (79, 85))	('adrenocortical', 'Disease', (99, 113))	('CaV1.3', 'Gene', '776', (23, 29))	('blocking', 'NegReg', (3, 11))	('human adrenal steroidogenesis', 'MPA', (183, 212))
45088	27098837	Taken together, these discoveries suggest that CaV1.3 can provide a novel mechanism and target for regulating excess aldosterone secretion and may be a novel way of treating hyperaldosteronism, especially those caused by ZG-like APAs with a CaV1.3 mutation.	('CaV1.3', 'Gene', '776', (241, 247))	('CaV1.3', 'Gene', (47, 53))	('excess aldosterone secretion', 'MPA', (110, 138))	('hyperaldosteronism', 'Disease', (174, 192))	('aldosterone', 'Chemical', 'MESH:D000450', (117, 128))	('mutation', 'Var', (248, 256))	('caused', 'Reg', (211, 217))	('CaV1.3', 'Gene', (241, 247))	('CaV1.3', 'Gene', '776', (47, 53))	('excess aldosterone', 'Phenotype', 'HP:0000859', (110, 128))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (174, 192))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (174, 192))
45091	27098837	For transient transfection, wild-type or mutant P1336R or V259D CaV1.3 GFP-tagged constructs were co-transfected together with constructs for beta3 and alpha2delta auxiliary subunits of CaV1.3 into H295R cells using Amaxa Nucleofector kit R (Lonza, Germany) with electroporation program P20.	('H295R', 'CellLine', 'CVCL:0458', (198, 203))	('P20', 'Gene', '51673', (287, 290))	('P20', 'Gene', (287, 290))	('mutant P1336R', 'Var', (41, 54))	('beta3', 'Gene', '1934', (142, 147))	('beta3', 'Gene', (142, 147))	('CaV1.3', 'Gene', (64, 70))	('P1336R', 'Mutation', 'p.P1336R', (48, 54))	('CaV1.3', 'Gene', '776', (186, 192))	('P1336R', 'Var', (48, 54))	('V259D', 'Var', (58, 63))	('V259D', 'Mutation', 'p.V259D', (58, 63))	('CaV1.3', 'Gene', (186, 192))	('CaV1.3', 'Gene', '776', (64, 70))
45150	15239841	Mutations of the p53 tumor suppressor (TP53) gene have been associated with hereditary (Li-Fraumeni syndrome) and sporadic adrenocortical tumors.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', (138, 143))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (88, 108))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('sporadic adrenocortical tumors', 'Disease', (114, 144))	('associated', 'Reg', (60, 70))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('p53', 'Gene', '7157', (17, 20))	('TP53', 'Gene', '7157', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('p53', 'Gene', (17, 20))	('Li-Fraumeni syndrome', 'Disease', (88, 108))	('TP53', 'Gene', (39, 43))	('sporadic adrenocortical tumors', 'Disease', 'MESH:D018268', (114, 144))
45160	15239841	High GATA-4 expression has been suggested to promote cell proliferation through an anti-apoptotic effect in mouse and human granulosa cells.	('GATA-4', 'Gene', (5, 11))	('High', 'Var', (0, 4))	('mouse', 'Species', '10090', (108, 113))	('anti-apoptotic effect', 'CPA', (83, 104))	('promote', 'PosReg', (45, 52))	('human', 'Species', '9606', (118, 123))	('cell proliferation', 'CPA', (53, 71))
45186	15239841	Cycling conditions for PCR were: 95 C, 3 min, followed by 40 cycles at 95 C, 30 sec, 56 C, 30 sec, 72 C, 30 sec, and a final extension cycle of 7 min at 72 C. Amplification of a 234 bp fragment from the human luteinizing hormone receptor (LHR) transcript was accomplished using oligonucleotides eLHR: 5'-AGACATTCCAAAGAGATTTC-3' and LHR2101R: 5'-GCAGTTACTGATGTAACAGTTAACAC-3'.	('LHR', 'Gene', (239, 242))	('luteinizing hormone receptor', 'Gene', '3973', (209, 237))	('luteinizing hormone receptor', 'Gene', (209, 237))	('human', 'Species', '9606', (203, 208))	('LHR2101R', 'Var', (332, 340))
45236	26064108	We reported the first evidence that orexin-A stimulated p70S6K and 4EBP1 in human H295R adrenocortical cells in a concentration and time-dependent manner.	('H295R', 'CellLine', 'CVCL:0458', (82, 87))	('p70S6K', 'Var', (56, 62))	('orexin-A', 'Gene', (36, 44))	('human', 'Species', '9606', (76, 81))	('4EBP1', 'Gene', (67, 72))	('adrenocortical', 'Disease', (88, 102))	('orexin-A', 'Gene', '25723', (36, 44))	('adrenocortical', 'Disease', 'MESH:D018268', (88, 102))	('stimulated', 'PosReg', (45, 55))	('rat', 'Species', '10116', (121, 124))
45238	26064108	Our results also indicated that p70S6K and 4EBP1 kinases participated in controlling cortisol secretion via OX1 receptor in H295R cells, which implied important role of p70S6K and 4EBP1 kinases in regulating adrenal function induced by orexin-A.	('orexin-A', 'Gene', '25723', (236, 244))	('participated', 'Reg', (57, 69))	('controlling cortisol secretion', 'MPA', (73, 103))	('OX1', 'Gene', (108, 111))	('cortisol', 'Chemical', 'MESH:D006854', (85, 93))	('p70S6K', 'Var', (32, 38))	('p70S6K', 'Var', (169, 175))	('OX1', 'Gene', '18104', (108, 111))	('orexin-A', 'Gene', (236, 244))	('H295R', 'CellLine', 'CVCL:0458', (124, 129))	('adrenal function', 'MPA', (208, 224))
45252	26064108	Both p70S6K and 4EBP1 are regulators of mRNA translation and stimulate the synthesis of several proteins involved in cell growth, proliferation, cell survival, and tumorigenesis.	('tumor', 'Disease', (164, 169))	('stimulate', 'PosReg', (61, 70))	('synthesis of several proteins', 'MPA', (75, 104))	('rat', 'Species', '10116', (137, 140))	('4EBP1', 'Gene', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('p70S6K', 'Var', (5, 11))	('mRNA translation', 'MPA', (40, 56))
45253	26064108	According to the study of Nardella et al., 25% (4 out of 16) pheochromocytomas showed very high levels of S6K1 (the p70S6K family consists of two kinases, S6K1 and S6K2).	('pheochromocytomas', 'Disease', (61, 78))	('S6K2', 'Gene', '6199', (164, 168))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (61, 78))	('S6K1', 'Var', (106, 110))	('S6K2', 'Gene', (164, 168))	('pheochromocytomas', 'Disease', 'MESH:D010673', (61, 78))
45254	26064108	They also found that deletion of S6K1 markedly reduced the proliferation of the chromaffin cells.	('deletion', 'Var', (21, 29))	('chromaffin', 'Chemical', '-', (80, 90))	('S6K1', 'Gene', (33, 37))	('proliferation of the chromaffin cells', 'CPA', (59, 96))	('rat', 'Species', '10116', (66, 69))	('reduced', 'NegReg', (47, 54))
45255	26064108	Similarly, moderate to high staining of phosph-S6K1 and/or phosph-4EBP1 was observed in most human primary cultures of adrenocortical tumors.	('4EBP1', 'Gene', '1978', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('rat', 'Species', '10116', (15, 18))	('4EBP1', 'Gene', (66, 71))	('human', 'Species', '9606', (93, 98))	('adrenocortical tumors', 'Disease', (119, 140))	('phosph-S6K1', 'Var', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (119, 140))
45262	26064108	Despite AKT signaling pathway described in the literature, the role of orexin in activation of p70S6K and 4EBP1-downstream effectors of AKT/mTOR pathway is at present largely unknown.	('orexin', 'Gene', '3060', (71, 77))	('orexin', 'Gene', (71, 77))	('AKT signaling pathway', 'Pathway', (8, 29))	('p70S6K', 'Var', (95, 101))	('rat', 'Species', '10116', (51, 54))
45269	26064108	The cells were grown in a humidified atmosphere containing 5% CO2 at 37 C. Before an experiment, cells (5 x 105 cells/well in six-well plates) were grown in Petri dishes in serum-free medium for 24 h. The next day, cells were treated with different concentrations of orexin-A (10-9 M, 10-8 M, 10-7 M, and 10-6 M) or 10-6 M orexin-A with PF-04691502.	('orexin-A', 'Gene', (323, 331))	('rat', 'Species', '10116', (256, 259))	('PF-04691502', 'Var', (337, 348))	('10-9', 'Var', (277, 281))	('orexin-A', 'Gene', '25723', (323, 331))	('orexin-A', 'Gene', (267, 275))	('PF-04691502', 'Chemical', 'MESH:C570662', (337, 348))	('CO2', 'Chemical', '-', (62, 65))	('orexin-A', 'Gene', '25723', (267, 275))
45274	26064108	Membranes were incubated in nonfat dry milk for 120 min at room temperature and then washed three times with TBST for 30 min and then incubated with primary antibody against phospho/total-p70S6K at a 1 : 1000 dilution and phospho/total-4EBP1 at a 1 : 1000 dilution in TBST overnight at 4 C. The membranes were washed and incubated with a secondary antibody for 1.5 h at room temperature and then washed three times with TBST for 30 min.	('TBST', 'Chemical', '-', (420, 424))	('TBST', 'Chemical', '-', (109, 113))	('phospho/total-p70S6K', 'Var', (174, 194))	('rat', 'Species', '10116', (380, 383))	('4EBP1', 'Gene', '1978', (236, 241))	('4EBP1', 'Gene', (236, 241))	('rat', 'Species', '10116', (69, 72))	('TBST', 'Chemical', '-', (268, 272))
45280	26064108	Similarly to p70S6K, orexin-A (10-6 M) induced a significant increase of 4EBP1 phosphorylation compared with the control, with 1 h of treatment of orexin-A being the most potent.	('p70S6K', 'Var', (13, 19))	('orexin-A', 'Gene', '25723', (21, 29))	('orexin-A', 'Gene', '25723', (147, 155))	('4EBP1', 'Gene', '1978', (73, 78))	('4EBP1', 'Gene', (73, 78))	('increase', 'PosReg', (61, 69))	('orexin-A', 'Gene', (147, 155))	('orexin-A', 'Gene', (21, 29))
45284	26064108	The data showed a specific increase in the p70S6K or 4EBP1 protein in H295R cells treated with 10-6 M orexin-A, increasing by 2.4-fold or 2.6-fold, compared to untreated controls (Figures 3(a) and 3(b)).	('orexin-A', 'Gene', '25723', (102, 110))	('4EBP1', 'Gene', '1978', (53, 58))	('p70S6K', 'Var', (43, 49))	('4EBP1', 'Gene', (53, 58))	('H295R', 'CellLine', 'CVCL:0458', (70, 75))	('orexin-A', 'Gene', (102, 110))	('increase', 'PosReg', (27, 35))
45290	26064108	This effect disappeared in the presence of PF-04691502 (10-6 M), SB674042 (10-6 M), and the combination of both (Figure 4).	('SB674042', 'Chemical', 'MESH:C492260', (65, 73))	('SB674042', 'Var', (65, 73))	('PF-04691502', 'Var', (43, 54))	('PF-04691502', 'Chemical', 'MESH:C570662', (43, 54))
45298	26064108	In different types of adrenal cells, the p70S6K/4EBP1 pathway played crucial role in mediating survival signals, and altering p70S6K and/or 4EBP1 function have been associated with many pathologies.	('4EBP1', 'Gene', (48, 53))	('altering p70S6K', 'Var', (117, 132))	('mediating', 'MPA', (85, 94))	('associated', 'Reg', (165, 175))	('4EBP1', 'Gene', '1978', (140, 145))	('function', 'MPA', (146, 154))	('4EBP1', 'Gene', '1978', (48, 53))	('4EBP1', 'Gene', (140, 145))	('p70S6K', 'Var', (126, 132))
45299	26064108	Compared with normal adrenal zona glomerulosa, the levels of phosphorylation of p70S6K were significantly upregulated in aldosterone-producing adenomas (APAs) and idiopathic hyperaldosteronism (IHA).	('levels of phosphorylation', 'MPA', (51, 76))	('upregulated', 'PosReg', (106, 117))	('p70S6K', 'Var', (80, 86))	('adenomas', 'Disease', 'MESH:D000236', (143, 151))	('idiopathic hyperaldosteronism', 'Disease', (163, 192))	('adenomas', 'Disease', (143, 151))	('idiopathic hyperaldosteronism', 'Disease', 'MESH:D003480', (163, 192))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (174, 192))
45301	26064108	in mouse indicated a pivotal role for p70S6K in the proliferation of the adrenal medulla, deletion of S6K1 showed a dramatic reduction in the proliferation of the chromaffin cells.	('reduction', 'NegReg', (125, 134))	('p70S6K', 'Var', (38, 44))	('deletion', 'Var', (90, 98))	('rat', 'Species', '10116', (149, 152))	('S6K1', 'Gene', (102, 106))	('mouse', 'Species', '10090', (3, 8))	('chromaffin', 'Chemical', '-', (163, 173))	('proliferation of the adrenal medulla', 'CPA', (52, 88))	('rat', 'Species', '10116', (59, 62))	('proliferation of the chromaffin cells', 'CPA', (142, 179))
45302	26064108	Similarly, PI3K-mTOR dual inhibitor (NVP-BEZ235) was able to significantly inhibit phosphorylation of p70S6K in H295R cells and subsequently reduce proliferation in vitro and xenograft growth in vivo.	('proliferation', 'CPA', (148, 161))	('p70S6K', 'Protein', (102, 108))	('PI3K-mTOR', 'Var', (11, 20))	('inhibit', 'NegReg', (75, 82))	('H295R', 'CellLine', 'CVCL:0458', (112, 117))	('BEZ235', 'Chemical', 'MESH:C531198', (41, 47))	('phosphorylation', 'MPA', (83, 98))	('xenograft growth in vivo', 'CPA', (175, 199))	('reduce', 'NegReg', (141, 147))	('rat', 'Species', '10116', (155, 158))
45315	26064108	In this experiment, orexin-A stimulated cortisol secretion in H295R cells, while the effect was partly abolished in the presence of mTOR inhibitor PF-04691502, OX1 receptor-specific antagonist of SB674042, and the combination of both.	('OX1', 'Gene', '18104', (160, 163))	('cortisol secretion', 'MPA', (40, 58))	('orexin-A', 'Gene', (20, 28))	('cortisol', 'Chemical', 'MESH:D006854', (40, 48))	('stimulated', 'PosReg', (29, 39))	('orexin-A', 'Gene', '25723', (20, 28))	('PF-04691502', 'Chemical', 'MESH:C570662', (147, 158))	('stimulated cortisol', 'Phenotype', 'HP:0003118', (29, 48))	('H295R', 'CellLine', 'CVCL:0458', (62, 67))	('OX1', 'Gene', (160, 163))	('SB674042', 'Chemical', 'MESH:C492260', (196, 204))	('PF-04691502', 'Var', (147, 158))
45338	22952916	Loss of imprinting (LOI) at 11p15 causes Beckwith-Wiedmann syndrome (BWS) characterised by embryonic overgrowth and predisposition to tumour development, among which adrenocortical carcinomas.	('overgrowth', 'Phenotype', 'HP:0001548', (101, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('causes', 'Reg', (34, 40))	('embryonic overgrowth', 'Disease', (91, 111))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (166, 191))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (166, 190))	('tumour', 'Disease', (134, 140))	('adrenocortical carcinomas', 'Disease', (166, 191))	('Beckwith-Wiedmann syndrome', 'Disease', (41, 67))	('BWS', 'Disease', 'MESH:D001506', (69, 72))	('embryonic overgrowth', 'Disease', 'MESH:D019214', (91, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (166, 191))	('Loss', 'Var', (0, 4))	('Beckwith-Wiedmann syndrome', 'Disease', 'MESH:D001506', (41, 67))	('BWS', 'Disease', (69, 72))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
45342	22952916	Consistent with this idea, IGF1R antagonists can inhibit proliferation of the human adrenocortical carcinoma H295R cell line both in culture and in xenograft experiments.	('human', 'Species', '9606', (78, 83))	('adrenocortical carcinoma', 'Disease', (84, 108))	('H295R', 'CellLine', 'CVCL:0458', (109, 114))	('antagonists', 'Var', (33, 44))	('IGF1R', 'Gene', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('proliferation', 'CPA', (57, 70))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (84, 108))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (84, 108))	('inhibit', 'NegReg', (49, 56))
45350	22952916	Our analysis of these models shows that Igf2 overexpression does not induce adrenal tumour development although it triggers aberrant recruitment of adrenal progenitors cells in a hedgehog independent manner.	('Igf2', 'Gene', (40, 44))	('triggers', 'Reg', (115, 123))	('adrenal tumour', 'Disease', 'MESH:D000310', (76, 90))	('overexpression', 'Var', (45, 59))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('recruitment', 'MPA', (133, 144))	('adrenal tumour', 'Disease', (76, 90))
45380	22952916	Five hundred ng of mRNAs were reverse transcribed for 1 hour at 42 C with 5 pmol of random hexamer primers (U1240; Promega), 200 units reverse transcriptase (M1701; Promega), 2mM dNTPs and 20 units RNAsin (N2615; Promega).	('N2615', 'CellLine', 'CVCL:D425', (206, 211))	('dNTPs', 'Chemical', 'MESH:D010278', (179, 184))	('rev', 'Gene', '19714', (135, 138))	('M1701', 'Var', (158, 163))	('rev', 'Gene', (135, 138))	('U1240', 'Var', (108, 113))	('rev', 'Gene', '19714', (30, 33))	('rev', 'Gene', (30, 33))
45385	22952916	Taqman gene expression assay probes that were used in the study are: Ppib Mm00478295_m1, Gli1 Mm004494645_m1, Patched1 Mm00436026_m1, Pod1 Mm00448961_m1, Shh Mm00436527_m1, Axin2 Mm00443610_m1, Lef-1 mM00550265_m1, Vegf-A Mm01281449_m1, Nov/Ccn3 Mm00456855_m1, Connexin-alpha43 (Gja1) Mm00439105_m1.	('Nov', 'Gene', (237, 240))	('Vegf-A', 'Gene', (215, 221))	('Mm00436527_m1', 'Var', (158, 171))	('Gja1', 'Gene', (279, 283))	('Mm00439105_m1', 'Var', (285, 298))	('Mm00448961_m1', 'Var', (139, 152))	('mM00550265_m1', 'Var', (200, 213))	('Gli1', 'Gene', '14632', (89, 93))	('Mm00456855_m1', 'Var', (246, 259))	('Ccn3', 'Gene', '18133', (241, 245))	('Mm00443610_m1', 'Var', (179, 192))	('Axin2', 'Gene', '12006', (173, 178))	('Mm004494645_m1', 'Var', (94, 108))	('Axin2', 'Gene', (173, 178))	('Shh', 'Gene', (154, 157))	('Lef-1', 'Gene', '16842', (194, 199))	('Mm01281449_m1', 'Var', (222, 235))	('Ppib', 'Gene', '19035', (69, 73))	('Gli1', 'Gene', (89, 93))	('Gja1', 'Gene', '14609', (279, 283))	('Ppib', 'Gene', (69, 73))	('Mm00436026_m1', 'Var', (119, 132))	('Patched1', 'Gene', (110, 118))	('Nov', 'Gene', '18133', (237, 240))	('Lef-1', 'Gene', (194, 199))	('Shh', 'Gene', '20423', (154, 157))	('Vegf-A', 'Gene', '22339', (215, 221))	('Patched1', 'Gene', '19206', (110, 118))	('Ccn3', 'Gene', (241, 245))
45407	22952916	Further characterisation of the AdIgf2 transgenic line by RTqPCR showed a 6.8-fold increase in Igf2 in the adrenal cortex of transgenics compared with WT (Figure 1A).	('increase', 'PosReg', (83, 91))	('transgenic', 'Species', '10090', (39, 49))	('Igf2', 'Gene', (95, 99))	('transgenics', 'Var', (125, 136))	('transgenic', 'Species', '10090', (125, 135))
45434	22952916	As expected, expression levels of both Axin2 and Lef1 were markedly increased in DeltaCat adrenals (Figure 2B).	('expression levels', 'MPA', (13, 30))	('Axin2', 'Gene', '12006', (39, 44))	('Axin2', 'Gene', (39, 44))	('DeltaCat', 'Var', (81, 89))	('Lef1', 'Gene', '16842', (49, 53))	('Lef1', 'Gene', (49, 53))	('increased', 'PosReg', (68, 77))
45450	22952916	This suggests that alterations in both pathways may accelerate malignant tumour progression.	('malignant tumour', 'Disease', 'MESH:D009369', (63, 79))	('malignant tumour', 'Disease', (63, 79))	('alterations', 'Var', (19, 30))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('accelerate', 'PosReg', (52, 62))
45451	22952916	We thus tested this hypothesis by mating AdIgf2 mice with DeltaCat mice to generate DeltaCat;AdIgf2 compound transgenics.	('tested', 'Reg', (8, 14))	('DeltaCat', 'Var', (84, 92))	('mice', 'Species', '10090', (48, 52))	('transgenic', 'Species', '10090', (109, 119))	('mice', 'Species', '10090', (67, 71))
45453	22952916	As expected, constitutive activation of beta-catenin through deletion of the third exon of the Ctnnb1 gene, resulted in benign adrenal hyperplasia, accumulation of basophilic sub-capsular cells (Figure 3A, b inset, black arrows) and ectopic differentiation of zona glomerulosa cells, shown by expansion of the domain of Disabled2 (Dab2) expression throughout the cortex and inside the medulla (Figure 3A, e).	('expansion', 'Var', (293, 302))	('Ctnnb1', 'Gene', '12387', (95, 101))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (127, 146))	('deletion', 'Var', (61, 69))	('ectopic differentiation', 'CPA', (233, 256))	('benign adrenal hyperplasia', 'Disease', (120, 146))	('Disabled2', 'Gene', '13132', (320, 329))	('Dab2', 'Gene', '13132', (331, 335))	('activation', 'PosReg', (26, 36))	('accumulation', 'PosReg', (148, 160))	('Disabled2', 'Gene', (320, 329))	('Dab2', 'Gene', (331, 335))	('benign adrenal hyperplasia', 'Disease', 'MESH:D000312', (120, 146))	('Ctnnb1', 'Gene', (95, 101))
45454	22952916	Surprisingly, overexpression of Igf2 in the context of constitutive beta-catenin activation did not significantly alter adrenal histology (Figure 3A, c) or Dab2 expression (Figure 3A, f and Figure S4) in the majority of double transgenics when compared with DeltaCat mice.	('Igf2', 'Gene', (32, 36))	('expression', 'MPA', (161, 171))	('Dab2', 'Gene', '13132', (156, 160))	('double transgenics', 'Var', (220, 238))	('Dab2', 'Gene', (156, 160))	('adrenal', 'MPA', (120, 127))	('mice', 'Species', '10090', (267, 271))	('alter', 'Reg', (114, 119))	('transgenic', 'Species', '10090', (227, 237))
45456	22952916	Analysis of the proliferative parameters by Ki67 staining, showed that the number of proliferating cells was significantly increased in the cortex and medulla of DeltaCat (Figure 3B, b & Figure 3C, a) and DeltaCat;AdIgf2 (Figure 3B, c & Figure 3C, a) adrenals when compared with wild-type (Figure 3B, a & Figure 3C, a).	('DeltaCat', 'Var', (162, 170))	('increased', 'PosReg', (123, 132))	('Ki67', 'Gene', (44, 48))	('number of proliferating cells', 'CPA', (75, 104))	('and DeltaCat', 'Var', (201, 213))	('Ki67', 'Gene', '17345', (44, 48))
45469	22952916	Compound transgenics had histological features reminiscent of 14 month-old DeltaCat adrenals, characterised by massive cortical dysplasia (Figure 4A, c-d), accumulation of basophilic spindle-shaped cells (Fig 4Ac) and cortical and medullary invasion by Dab2-positive zona glomerulosa cells (Figure 4A, g-h).	('transgenics', 'Var', (9, 20))	('transgenic', 'Species', '10090', (9, 19))	('cortical dysplasia', 'Disease', (119, 137))	('massive cortical dysplasia', 'Phenotype', 'HP:0032046', (111, 137))	('cortical dysplasia', 'Phenotype', 'HP:0002539', (119, 137))	('accumulation', 'PosReg', (156, 168))	('Dab2', 'Gene', (253, 257))	('Dab2', 'Gene', '13132', (253, 257))	('cortical dysplasia', 'Disease', 'MESH:D054220', (119, 137))
45473	22952916	The relative acceleration of tumour progression in response to Igf2 overexpression was also associated with a significant increase in Cyclin D1 expression in DeltaCat;AdIgf2 when compared with DeltaCat adrenals (Figure 4B, b), but did not result in further deregulation of malignancy markers expression (Figure S6 compared with Figure 3D).	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('Cyclin D1', 'Gene', '12443', (134, 143))	('malignancy', 'Disease', 'MESH:D009369', (273, 283))	('tumour', 'Disease', (29, 35))	('expression', 'MPA', (144, 154))	('overexpression', 'PosReg', (68, 82))	('Cyclin D1', 'Gene', (134, 143))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('DeltaCat;AdIgf2', 'Var', (158, 173))	('Igf2', 'Gene', (63, 67))	('malignancy', 'Disease', (273, 283))	('acceleration', 'PosReg', (13, 25))	('increase', 'PosReg', (122, 130))
45485	22952916	One ACTH-treated DeltaCat;AdIgf2 adrenal presented as an overt carcinoma in situ (Weiss 3) with diffuse architecture (Figure 4D, c) high grade nuclear alterations, oedematous remodelling (Figure 4D, f, dashed line) and large areas of necrosis (Figure 4D, f, inset).	('necrosis', 'Disease', (234, 242))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (63, 80))	('ACTH', 'Gene', '18976', (4, 8))	('necrosis', 'Disease', 'MESH:D009336', (234, 242))	('AdIgf2', 'Var', (26, 32))	('oedematous remodelling', 'Disease', (164, 186))	('carcinoma in situ', 'Disease', 'MESH:D002278', (63, 80))	('ACTH', 'Gene', (4, 8))	('oedematous remodelling', 'Disease', 'MESH:D020257', (164, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('carcinoma in situ', 'Disease', (63, 80))
45502	22952916	However, our analysis of beta-catenin expression by immunohistochemistry, and of Wnt target genes expression by RTqPCR, failed to show activation of the Wnt/beta-catenin pathway in Igf2 transgenic adrenals (Figure 2).	('transgenic', 'Var', (186, 196))	('Igf2', 'Gene', (181, 185))	('Wnt/beta-catenin pathway', 'Pathway', (153, 177))	('transgenic', 'Species', '10090', (186, 196))
45505	22952916	Indeed, increasing Igf2 levels through LOI (heterozygous deletion of H19) or with a keratin 10 promoter increases the number and size of colon adenomas as well as malignant progression in APCMin/+ mice.	('colon adenomas', 'Disease', (137, 151))	('malignant progression', 'CPA', (163, 184))	('H19', 'Gene', (69, 72))	('increases', 'PosReg', (104, 113))	('LOI', 'Var', (39, 42))	('colon adenomas', 'Disease', 'MESH:D000236', (137, 151))	('mice', 'Species', '10090', (197, 201))	('increasing', 'PosReg', (8, 18))
45506	22952916	Conversely, the reduction of Igf2 expression resulting from deletion of the transcriptionally active paternal allele or from the use of a soluble form of the scavenger IGF2R receptor, is associated with reduced number of adenomas and decreased malignant progression.	('Igf2', 'Gene', (29, 33))	('adenomas', 'Disease', 'MESH:D000236', (221, 229))	('expression', 'MPA', (34, 44))	('decreased', 'NegReg', (234, 243))	('deletion', 'Var', (60, 68))	('adenomas', 'Disease', (221, 229))	('reduced', 'NegReg', (203, 210))	('reduction', 'NegReg', (16, 25))	('malignant progression', 'CPA', (244, 265))
45517	22952916	Indeed, a vast majority (6/7) of the tumour tissue from DeltaCat;AdIgf2 mice had a Weiss score of 1 whereas the majority of DeltaCat adrenals (4/5) displayed features consistent with a Weiss score of 0.	('Weiss score', 'MPA', (83, 94))	('tumour', 'Disease', (37, 43))	('mice', 'Species', '10090', (72, 76))	('DeltaCat', 'Var', (56, 64))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
45534	22952916	This resulted in overall aggravation of the tumour phenotype in DeltaCat;AdIgf2 adrenals, with one tumour presenting as an overt carcinoma in situ (Weiss 3).	('DeltaCat', 'Var', (64, 72))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('carcinoma in situ', 'Disease', 'MESH:D002278', (129, 146))	('tumour', 'Disease', (99, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('tumour', 'Disease', (44, 50))	('aggravation', 'PosReg', (25, 36))	('carcinoma in situ', 'Disease', (129, 146))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (129, 146))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
45538	22952916	However, one caveat of these experiments is the observation that tumours in the DeltaCat group switch from Weiss 0 or 1 to Weiss 2 and show a significant increase in Ki67 labelling index after ACTH treatment (Figure 4).	('Ki67', 'Gene', (166, 170))	('DeltaCat', 'Var', (80, 88))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('Ki67', 'Gene', '17345', (166, 170))	('ACTH', 'Gene', '18976', (193, 197))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('tumours', 'Disease', (65, 72))	('increase', 'PosReg', (154, 162))	('ACTH', 'Gene', (193, 197))
45546	22952916	One interesting observation of our studies is the accumulation of Pod-1 positive subcapsular progenitor cells in the adrenal cortex of AdIgf2 transgenic mice (Figure 1).	('transgenic mice', 'Species', '10090', (142, 157))	('transgenic', 'Var', (142, 152))	('AdIgf2', 'Gene', (135, 141))	('Pod-1', 'Gene', (66, 71))	('accumulation', 'PosReg', (50, 62))
45556	22952916	These observations obviously have implications for normal adrenal homeostasis but also suggest that aberrant recruitment of progenitor cells, resulting from deregulated Wnt, Hedgehog or IGF signalling, may participate in the development of adrenal cortex tumours.	('aberrant', 'Var', (100, 108))	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('adrenal cortex tumours', 'Disease', 'MESH:D000306', (240, 262))	('IGF', 'Protein', (186, 189))	('tumours', 'Phenotype', 'HP:0002664', (255, 262))	('Wnt', 'Pathway', (169, 172))	('deregulated', 'Var', (157, 168))	('Hedgehog', 'Protein', (174, 182))	('adrenal cortex tumours', 'Disease', (240, 262))	('participate', 'Reg', (206, 217))	('recruitment', 'CPA', (109, 120))
45590	22542918	Recently overexpression of IGF-II and H19 genes in Beckwith-Wiedemann syndrome, mutations in the APC gene and p53 tumor suppressor gene in familial adenomatous polyposis and Li-Fraumeni syndrome, respectively, have been proposed for genesis of adrenocortical carcinomas.	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (139, 169))	('IGF-II', 'Gene', '3481', (27, 33))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (174, 194))	('APC', 'Gene', (97, 100))	('IGF-II', 'Gene', (27, 33))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (51, 78))	('mutations', 'Var', (80, 89))	('p53', 'Gene', '7157', (110, 113))	('tumor', 'Disease', (114, 119))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (244, 269))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('overexpression', 'PosReg', (9, 23))	('p53', 'Gene', (110, 113))	('H19', 'Gene', (38, 41))	('adrenocortical carcinomas', 'Disease', (244, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('carcinomas', 'Phenotype', 'HP:0030731', (259, 269))	('APC', 'Gene', '324', (97, 100))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (148, 169))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (244, 268))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (244, 269))	('familial adenomatous polyposis', 'Disease', (139, 169))	('Li-Fraumeni syndrome', 'Disease', (174, 194))	('Beckwith-Wiedemann syndrome', 'Disease', (51, 78))
45616	19477426	Genetic p53 deficiency partially rescues the adrenocortical dysplasia (acd) phenotype at the expense of increased tumorigenesis Telomere dysfunction and shortening induce chromosomal instability and tumorigenesis.	('tumor', 'Disease', (199, 204))	('adrenocortical dysplasia', 'Gene', (45, 69))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('p53', 'Gene', (8, 11))	('increased', 'PosReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('acd', 'Gene', (71, 74))	('chromosomal instability', 'Phenotype', 'HP:0040012', (171, 194))	('shortening', 'Var', (153, 163))	('adrenocortical dysplasia', 'Gene', '497652', (45, 69))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('rescues', 'PosReg', (33, 40))	('p53', 'Gene', '22060', (8, 11))	('acd', 'Gene', '497652', (71, 74))	('chromosomal instability', 'MPA', (171, 194))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('deficiency', 'Var', (12, 22))
45617	19477426	In this study, we analyze the adrenocortical dysplasia (acd) mouse, harboring a mutation in Tpp1/Acd.	('Tpp1', 'Gene', '12751', (92, 96))	('adrenocortical dysplasia', 'Gene', (30, 54))	('mouse', 'Species', '10090', (61, 66))	('mutation', 'Var', (80, 88))	('Tpp1', 'Gene', (92, 96))	('adrenocortical dysplasia', 'Gene', '497652', (30, 54))
45618	19477426	Additional loss of p53 dramatically rescues the acd phenotype in an organ-specific manner, including skin hyperpigmentation and adrenal morphology, but not germ cell atrophy.	('p53', 'Gene', '22060', (19, 22))	('skin hyperpigmentation', 'Phenotype', 'HP:0000953', (101, 123))	('atrophy', 'Disease', (166, 173))	('loss', 'Var', (11, 15))	('adrenal morphology', 'CPA', (128, 146))	('p53', 'Gene', (19, 22))	('acd', 'Disease', (48, 51))	('skin hyperpigmentation', 'Disease', (101, 123))	('rescues', 'PosReg', (36, 43))	('skin hyperpigmentation', 'Disease', 'MESH:D017495', (101, 123))	('atrophy', 'Disease', 'MESH:D001284', (166, 173))
45625	19477426	By studying the acd mouse, we show that telomere deprotection without significant telomere shortening is sufficient to induce tumor formation in the context of p53 absence.	('mouse', 'Species', '10090', (20, 25))	('p53', 'Gene', '22060', (160, 163))	('absence', 'NegReg', (164, 171))	('telomere shortening', 'Phenotype', 'HP:0031413', (82, 101))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('p53', 'Gene', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('telomere', 'Var', (40, 48))	('deprotection', 'NegReg', (49, 61))	('induce', 'Reg', (119, 125))	('tumor', 'Disease', (126, 131))
45627	19477426	In some tissues and cancers, this problem is overcome by the activity of telomerase, a ribonucleoprotein that adds telomeric repeats to the 3' end of the leading strand (reviewed by).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('telomeric', 'Var', (115, 124))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
45629	19477426	While some parts of the shelterin complex directly bind to either double-stranded (TRF1, TRF2) or single-stranded (POT1) telomere repeats, TIN2, RAP1 and TPP1/ACD serve as critical interconnectors of the shelterin complex.	('TRF2', 'Gene', (89, 93))	('TRF1', 'Gene', (83, 87))	('RAP1', 'Gene', (145, 149))	('POT1', 'Gene', (115, 119))	('single-stranded', 'Var', (98, 113))	('RAP1', 'Gene', '57321', (145, 149))	('shelterin', 'Chemical', '-', (24, 33))	('TRF1', 'Gene', '21749', (83, 87))	('POT1', 'Gene', '101185', (115, 119))	('TRF2', 'Gene', '21750', (89, 93))	('shelterin', 'Chemical', '-', (204, 213))	('TIN2', 'Gene', '28113', (139, 143))	('TIN2', 'Gene', (139, 143))	('bind', 'Interaction', (51, 55))
45632	19477426	Concurrent with the cloning of human TPP1/ACD, we had identified a recessive mutation (Acdacd) in the mouse ortholog of the gene encoding TPP1 as the genetic cause of the adrenocortical dysplasia (acd) phenotype, hence termed Acd.	('TPP1', 'Gene', (138, 142))	('adrenocortical dysplasia', 'Gene', '497652', (171, 195))	('mutation', 'Var', (77, 85))	('cause', 'Reg', (158, 163))	('human', 'Species', '9606', (31, 36))	('mouse', 'Species', '10090', (102, 107))	('adrenocortical dysplasia', 'Gene', (171, 195))
45638	19477426	With continued telomere shortening, cells from Terc-/- mice exhibit cytogenetic abnormalities, including chromosomal fusions, presumably due to the ligation of unprotected telomeres by the DNA repair machinery.	('chromosomal fusions', 'CPA', (105, 124))	('cytogenetic abnormalities', 'CPA', (68, 93))	('telomere shortening', 'Phenotype', 'HP:0031413', (15, 34))	('mice', 'Species', '10090', (55, 59))	('telomere', 'Var', (15, 23))	('Terc', 'Gene', '21748', (47, 51))	('Terc', 'Gene', (47, 51))
45647	19477426	With the exception of the Pot1b-/- mouse, attempts to create deletions of components of the shelterin complex in whole murine organisms have led to phenotypes with early embryonic lethality.	('embryonic lethality', 'Disease', (170, 189))	('led to', 'Reg', (141, 147))	('deletions', 'Var', (61, 70))	('shelterin', 'Chemical', '-', (92, 101))	('Pot1b', 'Gene', (26, 31))	('mouse', 'Species', '10090', (35, 40))	('murine', 'Species', '10090', (119, 125))	('embryonic lethality', 'Disease', 'MESH:D020964', (170, 189))	('Pot1b', 'Gene', '72836', (26, 31))
45664	19477426	Relative testicular weights were lower in Acdacd/acd animals regardless of their genetic p53 status when compared to their Acd+/+ littermates (Fig.	('p53', 'Gene', '22060', (89, 92))	('Acdacd/acd', 'Var', (42, 52))	('Relative testicular weights', 'CPA', (0, 27))	('p53', 'Gene', (89, 92))	('lower', 'NegReg', (33, 38))
45674	19477426	As telomere dysfunction in general and loss of Tpp1/Acd in particular is known to activate p53 signaling leading to cellular senescence, we examined whether p53-mediated cellular senescence contributed to the adrenal phenotype observed in Acdacd/acd mice.	('activate', 'PosReg', (82, 90))	('Tpp1', 'Gene', '12751', (47, 51))	('p53', 'Gene', '22060', (157, 160))	('p53', 'Gene', (91, 94))	('adrenal', 'MPA', (209, 216))	('loss', 'Var', (39, 43))	('mice', 'Species', '10090', (250, 254))	('p53', 'Gene', (157, 160))	('Tpp1', 'Gene', (47, 51))	('p53', 'Gene', '22060', (91, 94))
45710	19477426	There were significantly more chromosomes with at least one copy number change in Acdacd/acd than Acd+/+ tumors.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('copy number', 'Var', (60, 71))	('more', 'PosReg', (25, 29))	('Acdacd/acd', 'Disease', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
45711	19477426	Notably, several of the observed amplifications encompass loci that may contribute to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('amplifications', 'Var', (33, 47))	('contribute', 'Reg', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
45712	19477426	This includes amplifications of potential or proven oncogenes such as the cluster of Wnt genes on chromosome 11 and the Kras locus on chromosome 6, which has recently been shown to be amplified in tumors from Terc-/- mice.	('Terc', 'Gene', '21748', (209, 213))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('Terc', 'Gene', (209, 213))	('mice', 'Species', '10090', (217, 221))	('Kras', 'Gene', (120, 124))	('Kras', 'Gene', '16653', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('amplifications', 'Var', (14, 28))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))
45715	19477426	In this study we show that the ablation of p53 both profoundly rescues a number of characteristics of the acd phenotype and increases tumorigenesis.	('p53', 'Gene', '22060', (43, 46))	('increases', 'PosReg', (124, 133))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('rescues', 'PosReg', (63, 70))	('p53', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('ablation', 'Var', (31, 39))	('tumor', 'Disease', (134, 139))
45721	19477426	Phenotypic rescue through the ablation of p53 in the Acdacd/acd mice was most profound in the skin where hyperpigmention was macroscopically completely absent in Acdacd/acd p53-/- mice.	('p53', 'Gene', (42, 45))	('p53', 'Gene', (173, 176))	('p53', 'Gene', '22060', (42, 45))	('ablation', 'Var', (30, 38))	('mice', 'Species', '10090', (180, 184))	('p53', 'Gene', '22060', (173, 176))	('mice', 'Species', '10090', (64, 68))
45726	19477426	Overall it seems more likely that skin hyperpigmentation is induced by telomere deprotection and direct activation of p53-sensitive pathways in melanocytes as it has been shown for other mouse models.	('skin hyperpigmentation', 'Disease', (34, 56))	('activation', 'PosReg', (104, 114))	('deprotection', 'NegReg', (80, 92))	('p53', 'Gene', '22060', (118, 121))	('p53', 'Gene', (118, 121))	('skin hyperpigmentation', 'Disease', 'MESH:D017495', (34, 56))	('mouse', 'Species', '10090', (187, 192))	('telomere', 'Var', (71, 79))	('skin hyperpigmentation', 'Phenotype', 'HP:0000953', (34, 56))
45728	19477426	We did not observe any rescue of the testicular Acdacd/acd phenotype through p53 ablation in Acdacd/acd animals, which is in contrast to the moderate rescue observed in late generation Terc-/- p53-/- mice.	('testicular Acdacd/acd', 'Disease', (37, 58))	('Terc', 'Gene', '21748', (185, 189))	('Terc', 'Gene', (185, 189))	('p53', 'Gene', (193, 196))	('ablation', 'Var', (81, 89))	('p53', 'Gene', (77, 80))	('mice', 'Species', '10090', (200, 204))	('rat', 'Species', '10116', (178, 181))	('p53', 'Gene', '22060', (193, 196))	('rat', 'Species', '10116', (145, 148))	('p53', 'Gene', '22060', (77, 80))
45736	19477426	The majority of humans with cytomegalic AHC (with hypogonadotropic hypogonadism) have a germ line mutation in NR0B1 (DAX1).	('hypogonadotropic hypogonadism', 'Disease', (50, 79))	('hypogonadotropic hypogonadism', 'Phenotype', 'HP:0000044', (50, 79))	('mutation', 'Var', (98, 106))	('AHC', 'Disease', 'MESH:D000312', (40, 43))	('humans', 'Species', '9606', (16, 22))	('hypogonadism', 'Phenotype', 'HP:0000135', (67, 79))	('DAX1', 'Gene', '190', (117, 121))	('AHC', 'Disease', (40, 43))	('NR0B1', 'Gene', (110, 115))	('DAX1', 'Gene', (117, 121))	('hypogonadotropic hypogonadism', 'Disease', 'MESH:D007006', (50, 79))
45738	19477426	In summary, ablation of p53 rescues the Acdacd/acd phenotype to varying degrees and in an organ-specific manner.	('p53', 'Gene', (24, 27))	('ablation', 'Var', (12, 20))	('Acdacd/acd', 'Disease', (40, 50))	('rescues', 'PosReg', (28, 35))	('p53', 'Gene', '22060', (24, 27))
45739	19477426	The differences of the Acdacd/acd and the Terc-/- phenotype and their different rescue by p53 ablation can be explained by distinct molecular mechanisms induced by either short telomeres or deprotected telomeres.	('ablation', 'Var', (94, 102))	('p53', 'Gene', (90, 93))	('short telomere', 'Phenotype', 'HP:0031413', (171, 185))	('short telomeres', 'Var', (171, 186))	('Terc', 'Gene', '21748', (42, 46))	('Terc', 'Gene', (42, 46))	('p53', 'Gene', '22060', (90, 93))	('Acdacd/acd', 'Disease', (23, 33))	('short telomeres', 'Phenotype', 'HP:0031413', (171, 186))
45740	19477426	Alternatively, telomere dysfunction induced by deprotection in Acdacd/acd mice could be more severe than telomere dysfunction induced by telomere shortening in Terc-/- mice and therefore not as readily rescued by simple p53 ablation.	('p53', 'Gene', (220, 223))	('telomere dysfunction', 'Disease', (15, 35))	('deprotection', 'Var', (47, 59))	('mice', 'Species', '10090', (168, 172))	('p53', 'Gene', '22060', (220, 223))	('telomere shortening', 'Phenotype', 'HP:0031413', (137, 156))	('Terc', 'Gene', '21748', (160, 164))	('Terc', 'Gene', (160, 164))	('mice', 'Species', '10090', (74, 78))
45746	19477426	Some degree of telomere shortening was inconsistently observed comparing tumor tissue and normal tissue (liver) from the same animal and was independent of the Acd genotype.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('telomere shortening', 'Phenotype', 'HP:0031413', (15, 34))	('telomere', 'Var', (15, 23))	('tumor', 'Disease', (73, 78))
45788	19477426	Isolated high molecular weight genomic DNA (#13343, Qiagen, Hilden, Germany) from 6 acd tumors and 4 wt tumors was run on a 1% agarose gel and spectrophotometric measurements at 230nm, 260nm and 280nm were conducted to exclude samples with significant degradation or contamination.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('#13343', 'Var', (44, 50))	('acd tumors', 'Disease', 'MESH:D009369', (84, 94))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('agarose', 'Chemical', 'MESH:D012685', (127, 134))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('acd tumors', 'Disease', (84, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
45793	19477426	We combined neighboring selected segments that were all estimated to have copy numbers greater than 2, or all less than 2, into "runs", and counted the number of distinct runs in each tumor.	('tumor', 'Disease', (184, 189))	('copy numbers', 'Var', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (184, 189))
45802	33464382	Specifically, mice deficient in HIF1alpha in adrenocortical cells displayed enhanced levels of enzymes responsible for steroidogenesis and a cognate increase in circulatory steroid levels.	('increase', 'PosReg', (149, 157))	('mice', 'Species', '10090', (14, 18))	('levels of enzymes responsible for steroidogenesis', 'MPA', (85, 134))	('enhanced', 'PosReg', (76, 84))	('steroid', 'Chemical', 'MESH:D013256', (173, 180))	('circulatory steroid levels', 'MPA', (161, 187))	('steroid', 'Chemical', 'MESH:D013256', (119, 126))	('HIF1alpha', 'Gene', (32, 41))	('deficient', 'Var', (19, 28))
45804	33464382	Based on these results, we propose HIF1alpha to be a vital regulator of steroidogenesis as its modulation in adrenocortical cells dramatically impacts hormone synthesis with systemic consequences.	('hormone synthesis', 'MPA', (151, 168))	('steroid', 'Chemical', 'MESH:D013256', (72, 79))	('impacts', 'Reg', (143, 150))	('modulation', 'Var', (95, 105))
45809	33464382	Accordingly, it has been suggested that inappropriately low pO2, or hypoxia, can lead to both structural changes in the adrenal cortex and interfere with hormone production.	('interfere', 'NegReg', (139, 148))	('lead to', 'Reg', (81, 88))	('hypoxia', 'Disease', (68, 75))	('hormone production', 'MPA', (154, 172))	('hypoxia', 'Disease', 'MESH:D000860', (68, 75))	('pO2', 'Chemical', 'MESH:C093415', (60, 63))	('pO2', 'Var', (60, 63))	('structural changes', 'CPA', (94, 112))
45857	33464382	Taken together, P2H1 mice exhibit markedly opposite expression levels of Hif1alpha and Hif2alpha confined to adrenocortical cells, which we were even able to define in whole adrenal glands.	('Hif1alpha', 'Gene', (73, 82))	('mice', 'Species', '10090', (21, 25))	('P2H1', 'Chemical', '-', (16, 20))	('Hif2alpha', 'Gene', (87, 96))	('P2H1', 'Var', (16, 20))	('expression', 'MPA', (52, 62))	('Hif2alpha', 'Gene', '13819', (87, 96))	('Hif1alpha', 'Gene', '15251', (73, 82))
45858	33464382	To evaluate the impact of changes in HIF1alpha and/or HIF2alpha activity in adrenocortical cells, we analyzed adrenal gland morphology using H&E staining on paraffin sections but found no differences between P2H1 mice and WT littermates in the structure of the adrenal gland, especially, at the side of the cortex of P2H1 mice in comparison to WT littermates (Fig.	('between', 'Var', (200, 207))	('P2H1', 'Chemical', '-', (208, 212))	('mice', 'Species', '10090', (213, 217))	('HIF2alpha', 'Gene', (54, 63))	('H&E', 'Chemical', '-', (141, 144))	('HIF2alpha', 'Gene', '13819', (54, 63))	('mice', 'Species', '10090', (322, 326))	('P2H1', 'Chemical', '-', (317, 321))	('paraffin', 'Chemical', 'MESH:D010232', (157, 165))
45859	33464382	As we detected a significant increase in Vegfa in the adrenal glands of P2H1 mice, we used CD31 staining to quantify endothelial cells but detected no significant differences between P2H1 and WT mice (Fig.	('mice', 'Species', '10090', (77, 81))	('mice', 'Species', '10090', (195, 199))	('Vegfa', 'Gene', '22339', (41, 46))	('CD31', 'Gene', '18613', (91, 95))	('increase', 'PosReg', (29, 37))	('CD31', 'Gene', (91, 95))	('Vegfa', 'Gene', (41, 46))	('P2H1', 'Chemical', '-', (183, 187))	('P2H1', 'Chemical', '-', (72, 76))	('P2H1', 'Var', (72, 76))
45862	33464382	Next, to verify if the observed changes in lipid droplets indeed led to changes in steroidogenesis, we quantified steroid hormones and their precursor levels by LC-MS/MS in the adrenal gland and in plasma.	('steroidogenesis', 'MPA', (83, 98))	('precursor levels', 'MPA', (141, 157))	('steroid hormones', 'MPA', (114, 130))	('steroid', 'Chemical', 'MESH:D013256', (83, 90))	('steroid', 'Chemical', 'MESH:D013256', (114, 121))	('changes', 'Reg', (72, 79))	('lipid', 'Chemical', 'MESH:D008055', (43, 48))	('changes', 'Var', (32, 39))
45863	33464382	Quantification revealed a significant increase in virtually all the hormones tested in P2H1 adrenal glands compared to WT littermates (Fig.	('P2H1', 'Chemical', '-', (87, 91))	('increase', 'PosReg', (38, 46))	('P2H1', 'Var', (87, 91))
45868	33464382	Further, although increased steroid levels often result in other systemic changes, P2H1 mice displayed no difference in serum potassium levels or blood glucose levels compared to WT littermates (Supplementary Fig.	('increased', 'PosReg', (18, 27))	('glucose', 'Chemical', 'MESH:D005947', (152, 159))	('systemic changes', 'MPA', (65, 81))	('steroid levels', 'MPA', (28, 42))	('steroid', 'Chemical', 'MESH:D013256', (28, 35))	('potassium', 'Chemical', 'MESH:D011188', (126, 135))	('P2H1', 'Chemical', '-', (83, 87))	('result', 'Reg', (49, 55))	('P2H1', 'Var', (83, 87))	('mice', 'Species', '10090', (88, 92))	('serum potassium levels', 'MPA', (120, 142))	('blood glucose levels', 'MPA', (146, 166))
45869	33464382	Taken together, in contrast to the systemic effects induced by acute and high levels of circulatory cortical hormones (e.g., corticosterone, aldosterone), the P2H1 mice display moderate but chronically enhanced levels of cortical hormones at the described time points.	('P2H1', 'Var', (159, 163))	('corticosterone', 'Chemical', 'MESH:D003345', (125, 139))	('enhanced', 'PosReg', (202, 210))	('mice', 'Species', '10090', (164, 168))	('aldosterone', 'Chemical', 'MESH:D000450', (141, 152))	('levels of cortical hormones', 'MPA', (211, 238))	('P2H1', 'Chemical', '-', (159, 163))
45870	33464382	Previous in vitro studies and reports on HIF1alpha alterations in zebrafish larvae have suggested negative regulation of Star, the mitochondrial cholesterol transporter.	('regulation', 'MPA', (107, 117))	('alterations', 'Var', (51, 62))	('negative', 'NegReg', (98, 106))	('zebrafish', 'Species', '7955', (66, 75))	('HIF1alpha', 'Gene', (41, 50))	('mitochondrial cholesterol transporter', 'MPA', (131, 168))	('cholesterol', 'Chemical', 'MESH:D002784', (145, 156))	('Star', 'MPA', (121, 125))
45879	33464382	Furthermore, P2H1 cortical cells also displayed a positive signature related to the regulation of nuclear beta-catenin signaling, which is known to be primarily activated in the zona glomerulosa with potential hyperplasic effects (Fig.	('regulation', 'MPA', (84, 94))	('beta-catenin', 'Gene', '12387', (106, 118))	('P2H1', 'Chemical', '-', (13, 17))	('P2H1', 'Var', (13, 17))	('activated', 'PosReg', (161, 170))	('zona glomerulosa', 'Disease', (178, 194))	('zona glomerulosa', 'Disease', 'MESH:D006562', (178, 194))	('beta-catenin', 'Gene', (106, 118))
45884	33464382	Therefore, we enumerated the various white blood cell (WBC) fractions in P2H1 mice and compared it with that of their WT littermates, which revealed a significant reduction in both lymphocyte and eosinophil fractions (Fig.	('reduction', 'NegReg', (163, 172))	('P2H1', 'Chemical', '-', (73, 77))	('P2H1', 'Var', (73, 77))	('mice', 'Species', '10090', (78, 82))	('eosin', 'Chemical', 'MESH:D004801', (196, 201))
45887	33464382	Intriguingly and in contrast to hormone levels in the adrenal glands of the P2H1 mice, P2P3 adrenal glands displayed a marked decrease in corticosterone and aldosterone levels, along with a cognate reduction in their precursors, both in the adrenal gland (Fig.	('P2P3', 'Var', (87, 91))	('mice', 'Species', '10090', (81, 85))	('reduction', 'NegReg', (198, 207))	('aldosterone', 'Chemical', 'MESH:D000450', (157, 168))	('decrease', 'NegReg', (126, 134))	('corticosterone', 'Chemical', 'MESH:D003345', (138, 152))	('decrease in corticosterone', 'Phenotype', 'HP:0032363', (126, 152))	('P2H1', 'Chemical', '-', (76, 80))
45888	33464382	These results clearly suggest that steroidogenesis is dependent on HIF1alpha but not HIF2alpha.	('steroidogenesis', 'MPA', (35, 50))	('HIF1alpha', 'Var', (67, 76))	('HIF2alpha', 'Gene', '13819', (85, 94))	('steroid', 'Chemical', 'MESH:D013256', (35, 42))	('HIF2alpha', 'Gene', (85, 94))
45890	33464382	This observation is contrary to that seen in the P2H1 mice but fits neatly with the observed reduction in steroid levels in the P2P3 mice, thereby underscoring the central role of HIF1alpha (Fig.	('fits', 'Disease', 'MESH:D012640', (63, 67))	('mice', 'Species', '10090', (133, 137))	('reduction', 'NegReg', (93, 102))	('steroid levels', 'MPA', (106, 120))	('steroid', 'Chemical', 'MESH:D013256', (106, 113))	('P2P3', 'Var', (128, 132))	('fits', 'Disease', (63, 67))	('P2H1', 'Chemical', '-', (49, 53))	('mice', 'Species', '10090', (54, 58))
45892	33464382	In line with all previous results, we show an overall increase in cytokines in the plasma of P2P3 mice versus their WT littermate controls (Fig.	('P2P3 mice', 'Var', (93, 102))	('cytokines in', 'MPA', (66, 78))	('increase', 'PosReg', (54, 62))	('mice', 'Species', '10090', (98, 102))
45899	33464382	Ablation of HIF1alpha revealed an important role for this transcription factor in steroidogenesis, which concurs with results from previous studies.	('Ablation', 'Var', (0, 8))	('steroid', 'Chemical', 'MESH:D013256', (82, 89))	('steroidogenesis', 'MPA', (82, 97))	('HIF1alpha', 'Gene', (12, 21))
45900	33464382	Our findings that HIF1alpha deletion results in the upregulation of mRNA of a vast majority of steroid-related enzymes appear counterintuitive.	('steroid', 'Chemical', 'MESH:D013256', (95, 102))	('upregulation', 'PosReg', (52, 64))	('steroid-related', 'Enzyme', (95, 110))	('mRNA of a vast majority of', 'MPA', (68, 94))	('HIF1alpha', 'Gene', (18, 27))	('deletion', 'Var', (28, 36))
45908	33464382	Glucocorticoids and aldosterone are both essential for homeostasis and their substantial increase in P2H1 mice was intriguing, given their pivotal role in immune suppression and blood pressure regulation, respectively.	('P2H1', 'Var', (101, 105))	('mice', 'Species', '10090', (106, 110))	('aldosterone', 'Chemical', 'MESH:D000450', (20, 31))	('increase', 'PosReg', (89, 97))	('P2H1', 'Chemical', '-', (101, 105))
45910	33464382	Such glucocorticoid elevation can eventually even result in dramatic immune deficiency, for example, as seen in Cushing's disease.	('glucocorticoid', 'Var', (5, 19))	('result in', 'Reg', (50, 59))	("Cushing's disease", 'Disease', 'MESH:D003480', (112, 129))	("Cushing's disease", 'Disease', (112, 129))	('immune deficiency', 'MPA', (69, 86))	('immune deficiency', 'Phenotype', 'HP:0002721', (69, 86))
45911	33464382	Intriguingly, we found serum CXCL1 to be significantly enhanced in P2H1 mice, probably because as a central neutrophil attractant it was associated with the massive increase in circulatory neutrophils seen in these mice.	('increase', 'PosReg', (165, 173))	('CXCL1', 'Gene', (29, 34))	('P2H1', 'Var', (67, 71))	('enhanced', 'PosReg', (55, 63))	('P2H1', 'Chemical', '-', (67, 71))	('CXCL1', 'Gene', '14825', (29, 34))	('mice', 'Species', '10090', (72, 76))	('mice', 'Species', '10090', (215, 219))	('circulatory neutrophils', 'MPA', (177, 200))
45913	33464382	Specifically, compared to P2H1 mice, the expression profile of virtually all steroidogenesis-regulating enzymes was dramatically inverted in the P2P3 mice, which resulted in an overall impairment of the steroidogenesis pathway (Fig.	('steroidogenesis pathway', 'Pathway', (203, 226))	('mice', 'Species', '10090', (150, 154))	('steroidogenesis-regulating', 'Enzyme', (77, 103))	('steroid', 'Chemical', 'MESH:D013256', (203, 210))	('P2H1', 'Chemical', '-', (26, 30))	('inverted', 'NegReg', (129, 137))	('P2P3', 'Var', (145, 149))	('mice', 'Species', '10090', (31, 35))	('expression profile', 'MPA', (41, 59))	('steroid', 'Chemical', 'MESH:D013256', (77, 84))	('impairment', 'NegReg', (185, 195))
45974	32570871	The number of CD4+ and CD8+ T cells has also been associated in increased vascular density.	('CD8', 'Gene', (23, 26))	('CD8', 'Gene', '925', (23, 26))	('CD4+', 'Var', (14, 18))	('vascular density', 'CPA', (74, 90))	('increased', 'PosReg', (64, 73))	('increased vascular density', 'Phenotype', 'HP:0002634', (64, 90))
45977	32570871	In pancreatic cancer, CTCs and neutrophils are found together and the presence of neutrophils predicts metastasis-free survival in patients.	('patients', 'Species', '9606', (131, 139))	('presence', 'Var', (70, 78))	('pancreatic cancer', 'Disease', (3, 20))	('predicts', 'Reg', (94, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('metastasis-free survival', 'CPA', (103, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))
45979	32570871	Also, CTCs have been suggested to induce apoptosis of T helper cells via FAS-ligand pathway, leading to tumor immune escape and induction of dormancy.	('leading to', 'Reg', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('FAS-ligand', 'Pathway', (73, 83))	('CTCs', 'Var', (6, 10))	('induction', 'CPA', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
46034	32570871	At 22 weeks, almost 80% of CD45+ cells are CD3+ T cells, 10% CD20+ B cells and the remaining 10% myeloid and NK cells.	('CD20', 'Gene', '54474', (61, 65))	('CD20', 'Gene', (61, 65))	('CD45+', 'Var', (27, 32))
46041	32570871	When these mice are engrafted with human CD34+ HSCs they also develop into CD33+ myeloid cells, CD33+CD14+ monocytes and CD163+ TAMs that can also secrete more immunosuppressive cytokines such as arginase-1 than in NOG mice engrafted with the same cells.	('CD33', 'Gene', (96, 100))	('mice', 'Species', '10090', (219, 223))	('arginase-1', 'Gene', '383', (196, 206))	('human', 'Species', '9606', (35, 40))	('HSC', 'Gene', (47, 50))	('HSC', 'Gene', '2523', (47, 50))	('TAMs', 'Chemical', '-', (128, 132))	('mice', 'Species', '10090', (11, 15))	('CD163', 'Gene', '9332', (121, 126))	('arginase-1', 'Gene', (196, 206))	('CD34+', 'Var', (41, 46))	('CD163', 'Gene', (121, 126))	('CD14', 'Gene', (101, 105))	('CD33', 'Gene', '945', (75, 79))	('secrete', 'MPA', (147, 154))	('CD33', 'Gene', (75, 79))	('CD33', 'Gene', '945', (96, 100))	('CD14', 'Gene', '929', (101, 105))
46042	32570871	Besides an increased number of myeloid cells, these mice have a slightly higher rate of CD45+ cells in the circulation, spleen and bone marrow compared to NOG mice.	('CD45+', 'Var', (88, 93))	('mice', 'Species', '10090', (159, 163))	('mice', 'Species', '10090', (52, 56))	('higher', 'PosReg', (73, 79))
46047	32570871	Limitations related to immune responses observed in these mice may include the lack of certain human cytokines that cause immune activation, and incomplete HLA-matching that causes a non-specific immune reaction especially in tumors with low antigen presentation.	('incomplete', 'Var', (145, 155))	('human', 'Species', '9606', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumors', 'Disease', (226, 232))	('causes', 'Reg', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('mice', 'Species', '10090', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('HLA-matching', 'Protein', (156, 168))	('non-specific immune', 'MPA', (183, 202))
46067	32570871	However, the model with CD34+ cells resulted in lower number of metastases to hTEB and overall lower tumor burden to hTEB compared to a model with no prior injection of CD34+ cells.	('metastases', 'Disease', 'MESH:D009362', (64, 74))	('lower', 'NegReg', (95, 100))	('CD34+ cells', 'Var', (24, 35))	('lower', 'NegReg', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('metastases', 'Disease', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
46078	32570871	Inhibition of the PI3K signaling pathway by BKM120 inhibited tumor growth and lung metastasis by enhancing anti-tumor immunity by decreasing the number of CD4+ TILs, increasing the number of activated CD4+CD69+ T cells, and decreasing the number of CD20+ B cells.	('BKM120', 'Chemical', 'MESH:C571178', (44, 50))	('increasing', 'PosReg', (166, 176))	('CD20', 'Gene', '54474', (249, 253))	('PI3K signaling pathway', 'Pathway', (18, 40))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('decreasing', 'NegReg', (130, 140))	('lung metastasis', 'CPA', (78, 93))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('enhancing', 'PosReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('BKM120', 'Var', (44, 50))	('decreasing', 'NegReg', (224, 234))	('tumor', 'Disease', (112, 117))	('inhibited', 'NegReg', (51, 60))	('CD20', 'Gene', (249, 253))	('tumor', 'Disease', (61, 66))
46092	32570871	All models that expressed PD-L1 developed lung metastases from primary tumors and the formation of metastases in all molecular subtypes of human primary and relapsed NMIBCs could be inhibited by treatment with the anti-PD-L1 antibody durvalumab.	('PD-L1', 'Var', (26, 31))	('metastases', 'Disease', (47, 57))	('metastases', 'Disease', (99, 109))	('durvalumab', 'Chemical', 'MESH:C000613593', (234, 244))	('human', 'Species', '9606', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('metastases', 'Disease', 'MESH:D009362', (47, 57))	('lung metastases', 'Disease', (42, 57))	('metastases', 'Disease', 'MESH:D009362', (99, 109))	('lung metastases', 'Disease', 'MESH:D009362', (42, 57))
46104	32570871	Corresponding with this observation, higher number of CD4+ and CD8+ cells were observed in lung metastases of nivolumab-treated mice, whereas no differences were observed in the number of these cells in primary subcutaneous tumors, and in immunohistochemical analysis of PD-L1 and PD-1 in tumors and lung metastases.	('lung metastases', 'Disease', (300, 315))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('lung metastases', 'Disease', 'MESH:D009362', (91, 106))	('CD8', 'Gene', '925', (63, 66))	('PD-L1', 'Gene', (271, 276))	('higher', 'PosReg', (37, 43))	('PD-1', 'Gene', (281, 285))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('lung metastases', 'Disease', (91, 106))	('CD4+', 'Var', (54, 58))	('nivolumab', 'Chemical', 'MESH:D000077594', (110, 119))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (211, 230))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('mice', 'Species', '10090', (128, 132))	('CD8', 'Gene', (63, 66))	('lung metastases', 'Disease', 'MESH:D009362', (300, 315))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (211, 229))	('tumors', 'Disease', (289, 295))
46128	32570871	Muromonab increased levels of human TNF-alpha, IFN-gamma, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A, IL12/23p40 and GM-CSF, and caused significant T-cell activation.	('GM-CSF', 'Gene', '1437', (113, 119))	('IFN-gamma', 'Gene', '3458', (47, 56))	('IFN-gamma', 'Gene', (47, 56))	('IL-8', 'Gene', '3576', (70, 74))	('IL-13', 'Gene', (83, 88))	('IL-17A', 'Gene', '3605', (90, 96))	('TNF-alpha', 'Gene', '7124', (36, 45))	('TNF-alpha', 'Gene', (36, 45))	('T-cell activation', 'CPA', (144, 161))	('increased', 'PosReg', (10, 19))	('IL-6', 'Gene', '3569', (64, 68))	('IL-8', 'Gene', (70, 74))	('human', 'Species', '9606', (30, 35))	('GM-CSF', 'Gene', (113, 119))	('IL-17A', 'Gene', (90, 96))	('IL12/23p40', 'Var', (98, 108))	('IL-6', 'Gene', (64, 68))	('IL-13', 'Gene', '3596', (83, 88))	('Muromonab', 'Gene', (0, 9))
46209	30533000	Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h, P = 0.014), and 2.5-fold higher than that in reference population not treated with mitotane (1.81 L/h).	('higher', 'PosReg', (33, 39))	('mitotane', 'Chemical', 'MESH:D008939', (57, 65))	('Etoposide clearance', 'MPA', (0, 19))	('mitotane', 'Chemical', 'MESH:D008939', (207, 215))	('higher', 'PosReg', (149, 155))	('mitotane', 'Chemical', 'MESH:D008939', (88, 96))	('mitotane', 'Var', (57, 65))	('Etoposide', 'Chemical', 'MESH:D005047', (0, 9))
46217	30533000	Furthermore, lower rates of severe hematological toxicities are observed with EDP-mitotane regimen than with platinum-etoposide in small-cell lung cancer (SCLC) patients (11 vs 53% of grade 3-4 neutropenia).	('SCLC', 'Disease', (155, 159))	('neutropenia', 'Phenotype', 'HP:0001875', (194, 205))	('SCLC', 'Disease', 'MESH:D018288', (155, 159))	('platinum-etoposide', 'Chemical', '-', (109, 127))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lower', 'NegReg', (13, 18))	('hematological toxicities', 'Disease', (35, 59))	('hematological toxicities', 'Disease', 'MESH:D006402', (35, 59))	('EDP-mitotane', 'Var', (78, 90))	('SCLC', 'Phenotype', 'HP:0030357', (155, 159))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (131, 153))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('neutropenia', 'Disease', (194, 205))	('patients', 'Species', '9606', (161, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('small-cell lung cancer', 'Disease', (131, 153))	('EDP-mitotane', 'Chemical', '-', (78, 90))	('neutropenia', 'Disease', 'MESH:D009503', (194, 205))
46219	30533000	Indeed, mitotane is a strong inducer of cytochrome P450 3A4 (CYP3A4) and ATP-binding cassette (ABC) multidrug transporters, while etoposide is a substrate of these proteins.	('cytochrome P450 3A4', 'Gene', '1576', (40, 59))	('CYP3A4', 'Gene', '1576', (61, 67))	('ATP-binding cassette', 'Gene', (73, 93))	('ATP-binding cassette', 'Gene', '10058', (73, 93))	('cytochrome P450 3A4', 'Gene', (40, 59))	('ABC', 'Gene', (95, 98))	('inducer', 'PosReg', (29, 36))	('mitotane', 'Var', (8, 16))	('mitotane', 'Chemical', 'MESH:D008939', (8, 16))	('etoposide', 'Chemical', 'MESH:D005047', (130, 139))	('ABC', 'Gene', '10058', (95, 98))	('CYP3A4', 'Gene', (61, 67))
46241	30533000	Etoposide clearance was 2-fold higher in patients concomitantly treated with mitotane (median 4.95 L/h (2.67-6.20)) than after mitotane discontinuation (median 2.53 L/h (2.02-2.78), P = 0.014, Fig.	('mitotane', 'Var', (77, 85))	('mitotane', 'Chemical', 'MESH:D008939', (77, 85))	('mitotane', 'Chemical', 'MESH:D008939', (127, 135))	('patients', 'Species', '9606', (41, 49))	('Etoposide clearance', 'MPA', (0, 19))	('higher', 'PosReg', (31, 37))	('Etoposide', 'Chemical', 'MESH:D005047', (0, 9))
46249	30533000	Etoposide clearance was 2.5-fold higher in patients concomitantly treated with mitotane than in reference population not treated with mitotane.	('higher', 'PosReg', (33, 39))	('mitotane', 'Var', (79, 87))	('patients', 'Species', '9606', (43, 51))	('mitotane', 'Chemical', 'MESH:D008939', (134, 142))	('mitotane', 'Chemical', 'MESH:D008939', (79, 87))	('Etoposide clearance', 'MPA', (0, 19))	('Etoposide', 'Chemical', 'MESH:D005047', (0, 9))
46251	30533000	Mitotane could induce both CYP3A4 and ABC transporters, notably breast resistance cancer protein (BCRP) and P-gp.	('ABC', 'Gene', (38, 41))	('Mitotane', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('P-gp', 'Gene', '5243', (108, 112))	('CYP3A4', 'Gene', (27, 33))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CYP3A4', 'Gene', '1576', (27, 33))	('ABC', 'Gene', '10058', (38, 41))	('P-gp', 'Gene', (108, 112))	('induce', 'PosReg', (15, 21))
46253	30533000	Thus, mitotane could increase both the metabolic clearance and excretion of etoposide, resulting in infra-therapeutic drug plasma exposure.	('mitotane', 'Var', (6, 14))	('etoposide', 'Chemical', 'MESH:D005047', (76, 85))	('mitotane', 'Chemical', 'MESH:D008939', (6, 14))	('infra-therapeutic drug plasma exposure', 'MPA', (100, 138))	('excretion', 'MPA', (63, 72))	('metabolic clearance', 'MPA', (39, 58))	('increase', 'PosReg', (21, 29))
46258	30533000	Mitotane could even increase the expression of these proteins in tumor cells, thus limiting the intra-tumor diffusion of etoposide, and thereby conferring chemotherapy resistance.	('Mitotane', 'Var', (0, 8))	('etoposide', 'Chemical', 'MESH:D005047', (121, 130))	('intra-tumor', 'Disease', (96, 107))	('limiting', 'NegReg', (83, 91))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('chemotherapy resistance', 'MPA', (155, 178))	('intra-tumor', 'Disease', 'MESH:D009369', (96, 107))	('expression', 'MPA', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('conferring', 'Reg', (144, 154))	('increase', 'PosReg', (20, 28))
46294	30402590	The two largest studies on adjuvant mitotane are retrospective, and they suggest it prolongs time to recurrence with no impact on overall survival.	('mitotane', 'Var', (36, 44))	('time to recurrence', 'CPA', (93, 111))	('mitotane', 'Chemical', 'MESH:D008939', (36, 44))	('prolongs', 'PosReg', (84, 92))
46312	30402590	Although many ACC exhibited complex genomic patterns of gains and losses, select copy number alterations were remarkably recurrent across tumors, including gains in 9q34 and 5p, which respectively encompass NR5A1 (encoding steroidogenic factor 1, the master regulator of steroidogenesis) and oncogene TERT; and losses in 11q, 13q, and 17p, which respectively encompass known tumor suppressor genes MEN1, RB1, and TP53.	('TERT', 'Gene', (301, 305))	('TERT', 'Gene', '7015', (301, 305))	('tumor', 'Disease', (138, 143))	('MEN1', 'Gene', '4221', (398, 402))	('steroid', 'Chemical', 'MESH:D013256', (271, 278))	('TP53', 'Gene', '7157', (413, 417))	('RB1', 'Gene', (404, 407))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('steroidogenic factor 1', 'Gene', '2516', (223, 245))	('steroidogenic factor 1', 'Gene', (223, 245))	('losses', 'NegReg', (66, 72))	('MEN1', 'Gene', (398, 402))	('steroid', 'Chemical', 'MESH:D013256', (223, 230))	('tumor', 'Disease', (375, 380))	('RB1', 'Gene', '5925', (404, 407))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('NR5A1', 'Gene', (207, 212))	('gains', 'PosReg', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('TP53', 'Gene', (413, 417))	('losses', 'Var', (311, 317))	('ACC', 'Phenotype', 'HP:0006744', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('9q34', 'Gene', (165, 169))	('tumors', 'Disease', (138, 144))	('NR5A1', 'Gene', '2516', (207, 212))	('gains', 'PosReg', (56, 61))
46317	30402590	These clinical observations informed targeted approaches in the pregenomics era evaluating the prevalence of somatic alterations in loci encompassing IGF2, TP53, MEN1, APC, and CTNNB1.	('alterations', 'Var', (117, 128))	('APC', 'Disease', 'MESH:D011125', (168, 171))	('MEN1', 'Gene', '4221', (162, 166))	('CTNNB1', 'Gene', '1499', (177, 183))	('MEN1', 'Gene', (162, 166))	('APC', 'Disease', (168, 171))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('IGF2', 'Gene', '3481', (150, 154))	('IGF2', 'Gene', (150, 154))	('CTNNB1', 'Gene', (177, 183))
46320	30402590	Finally, targeted sequencing approaches identified that somatic APC mutations are somewhat rare, but mutations in CTNNB1 are common, present in <=30% of ACC.	('mutations', 'Var', (101, 110))	('APC', 'Disease', 'MESH:D011125', (64, 67))	('CTNNB1', 'Gene', '1499', (114, 120))	('APC', 'Disease', (64, 67))	('ACC', 'Phenotype', 'HP:0006744', (153, 156))	('CTNNB1', 'Gene', (114, 120))
46330	30402590	demonstrated that C1A tumors are enriched for somatic mutations in CTNNB1 or TP53, supported by immunohistochemical evidence of nuclear accumulation of p53 or nuclear localization of beta-catenin.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('C1A', 'Gene', '100862690', (18, 21))	('nuclear accumulation', 'MPA', (128, 148))	('beta-catenin', 'Gene', (183, 195))	('p53', 'Gene', (152, 155))	('mutations', 'Var', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('p53', 'Gene', '7157', (152, 155))	('CTNNB1', 'Gene', '1499', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('TP53', 'Gene', (77, 81))	('beta-catenin', 'Gene', '1499', (183, 195))	('C1A', 'Gene', (18, 21))	('CTNNB1', 'Gene', (67, 73))	('TP53', 'Gene', '7157', (77, 81))	('tumors', 'Disease', (22, 28))
46334	30402590	Select differentially methylated genes in ACC included transcriptionally silenced tumor suppressors, such as CDKN2A, GATA4, and PYCARD, giving rise to the hypothesis that dysregulated epigenetic programming in ACC promotes tumorigenesis partially through tumor suppressor silencing.	('promotes', 'PosReg', (214, 222))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('CDKN2A', 'Gene', '1029', (109, 115))	('PYCARD', 'Gene', (128, 134))	('tumor', 'Disease', (82, 87))	('ACC', 'Phenotype', 'HP:0006744', (42, 45))	('GATA4', 'Gene', '2626', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('dysregulated epigenetic programming', 'Var', (171, 206))	('PYCARD', 'Gene', '29108', (128, 134))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('GATA4', 'Gene', (117, 122))	('CDKN2A', 'Gene', (109, 115))	('ACC', 'Phenotype', 'HP:0006744', (210, 213))
46335	30402590	A subsequent genomic methylation study supported these findings, identifying that hypermethylated CpGs in ACC are largely restricted to CpG islands, whereas hypomethylated CpGs are present in open sea regions.	('open sea', 'Disease', 'MESH:D009041', (192, 200))	('hypermethylated', 'Var', (82, 97))	('ACC', 'Phenotype', 'HP:0006744', (106, 109))	('open sea', 'Disease', (192, 200))	('CpGs', 'Gene', (98, 102))
46346	30402590	Confirming previously identified alterations in CTNNB1, TP53, CDKN2A, RB1, and MEN1, the authors also identified novel somatic alterations in ZNRF3, DAXX, TERT, and MED12.	('MEN1', 'Gene', '4221', (79, 83))	('ZNRF3', 'Gene', '84133', (142, 147))	('DAXX', 'Gene', (149, 153))	('ZNRF3', 'Gene', (142, 147))	('CTNNB1', 'Gene', '1499', (48, 54))	('RB1', 'Gene', (70, 73))	('MEN1', 'Gene', (79, 83))	('TP53', 'Gene', '7157', (56, 60))	('DAXX', 'Gene', '1616', (149, 153))	('MED12', 'Gene', '9968', (165, 170))	('TERT', 'Gene', (155, 159))	('TERT', 'Gene', '7015', (155, 159))	('CTNNB1', 'Gene', (48, 54))	('CDKN2A', 'Gene', (62, 68))	('alterations', 'Var', (33, 44))	('RB1', 'Gene', '5925', (70, 73))	('alterations', 'Var', (127, 138))	('MED12', 'Gene', (165, 170))	('TP53', 'Gene', (56, 60))	('CDKN2A', 'Gene', '1029', (62, 68))
46347	30402590	The gene most frequently targeted for somatic alteration (biallelic deletion or loss of function mutation) was ZNRF3, altered in 21% of ACC and mutually exclusive with mutations in CTNNB1.	('CTNNB1', 'Gene', '1499', (181, 187))	('biallelic deletion', 'Var', (58, 76))	('CTNNB1', 'Gene', (181, 187))	('altered', 'Reg', (118, 125))	('ZNRF3', 'Gene', '84133', (111, 116))	('ACC', 'Phenotype', 'HP:0006744', (136, 139))	('mutation', 'Var', (97, 105))	('loss of function', 'NegReg', (80, 96))	('ACC', 'Disease', (136, 139))	('ZNRF3', 'Gene', (111, 116))
46350	30402590	Finally, the authors demonstrated that C1A ACC have higher mutation rate and higher incidence of recurrent mutations, and a subset of C1A exclusively bears intermediate or high levels of CpG island methylation.	('C1A', 'Gene', (39, 42))	('mutations', 'Var', (107, 116))	('C1A', 'Gene', (134, 137))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('C1A', 'Gene', '100862690', (39, 42))	('higher', 'PosReg', (52, 58))	('C1A', 'Gene', '100862690', (134, 137))	('mutation rate', 'MPA', (59, 72))
46352	30402590	's findings were validated by Juhlin et al., who also identified frequent ZNRF3 deletions.	('ZNRF3', 'Gene', (74, 79))	('ZNRF3', 'Gene', '84133', (74, 79))	('deletions', 'Var', (80, 89))
46355	30402590	ACC-TCGA identified additional recurrent somatic alterations in PRKAR1A, RPL22, TERF2, and CCNE1 and somatic alterations in epigenetic modifiers including MLL family members, SETD2, TET1, and SMARCA4.	('TERF2', 'Gene', (80, 85))	('TET1', 'Gene', (182, 186))	('SMARCA4', 'Gene', (192, 199))	('CCNE1', 'Gene', '898', (91, 96))	('alterations', 'Var', (49, 60))	('CCNE1', 'Gene', (91, 96))	('TERF2', 'Gene', '7014', (80, 85))	('PRKAR1A', 'Gene', (64, 71))	('SMARCA4', 'Gene', '6597', (192, 199))	('RPL22', 'Gene', '6146', (73, 78))	('SETD2', 'Gene', '29072', (175, 180))	('TET1', 'Gene', '80312', (182, 186))	('alterations', 'Reg', (109, 120))	('SETD2', 'Gene', (175, 180))	('PRKAR1A', 'Gene', '5573', (64, 71))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('RPL22', 'Gene', (73, 78))
46356	30402590	The identification of recurrent loss of function alterations in PRKAR1A, the regulatory subunit that mitigates protein kinase A activity, implicated protein kinase A signaling for the first time in sporadic ACC.	('implicated', 'Reg', (138, 148))	('alterations', 'Var', (49, 60))	('PRKAR1A', 'Gene', (64, 71))	('ACC', 'Phenotype', 'HP:0006744', (207, 210))	('protein kinase A', 'MPA', (149, 165))	('PRKAR1A', 'Gene', '5573', (64, 71))
46366	30402590	Finally, COC3 tumors have a higher frequency of somatic alterations leading to cell cycle activation and are steroid-high + proliferative, genomically noisy +- WGD, and CIMP-high.	('cell cycle', 'CPA', (79, 89))	('steroid', 'Chemical', 'MESH:D013256', (109, 116))	('activation', 'PosReg', (90, 100))	('alterations', 'Var', (56, 67))	('CIMP', 'Chemical', '-', (169, 173))	('COC3 tumors', 'Disease', 'MESH:D009369', (9, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('leading to', 'Reg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('COC3 tumors', 'Disease', (9, 20))
46372	30402590	Preclinical studies including xenograft models of ACC were promising, suggesting that inhibition of IGF2/IGF1R signaling may indeed be therapeutically efficacious in ACC.	('IGF2', 'Gene', (100, 104))	('ACC', 'Phenotype', 'HP:0006744', (166, 169))	('IGF1R', 'Gene', (105, 110))	('ACC', 'Disease', (166, 169))	('ACC', 'Phenotype', 'HP:0006744', (50, 53))	('IGF1R', 'Gene', '3480', (105, 110))	('IGF2', 'Gene', '3481', (100, 104))	('inhibition', 'Var', (86, 96))
46377	30402590	Though disappointing for most patients, the demonstration that a subset of patients with ACC respond to IGF2/IGF1R therapy suggests that acquired genetic and molecular alterations secondary to LOH of the IGF2 locus may restrict tumor response to therapy.	('IGF2', 'Gene', '3481', (204, 208))	('IGF2', 'Gene', (104, 108))	('restrict', 'NegReg', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('IGF1R', 'Gene', (109, 114))	('patients', 'Species', '9606', (75, 83))	('ACC', 'Phenotype', 'HP:0006744', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('IGF2', 'Gene', (204, 208))	('patients', 'Species', '9606', (30, 38))	('IGF1R', 'Gene', '3480', (109, 114))	('IGF2', 'Gene', '3481', (104, 108))	('LOH', 'Var', (193, 196))	('tumor', 'Disease', (228, 233))
46378	30402590	This possibility is supported not only by the complex landscape of molecular alterations identified in ACC-TCGA and other studies but also by in vivo work demonstrating that overexpression of IGF2 is insufficient to initiate adrenocortical tumorigenesis but probably collaborates with other events, such as activation of beta-catenin signaling.	('ACC', 'Phenotype', 'HP:0006744', (103, 106))	('tumor', 'Disease', (240, 245))	('IGF2', 'Gene', '3481', (192, 196))	('beta-catenin', 'Gene', (321, 333))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('adrenocortical', 'Disease', (225, 239))	('beta-catenin', 'Gene', '1499', (321, 333))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('IGF2', 'Gene', (192, 196))	('adrenocortical', 'Disease', 'MESH:D018268', (225, 239))	('overexpression', 'Var', (174, 188))
46383	30402590	Studies using the NCI-H295R model have demonstrated that inhibition of beta-catenin-dependent transcription impairs proliferation and steroidogenesis and promotes apoptosis, supporting the evaluation of such therapeutic approaches in preclinical and clinical studies.	('apoptosis', 'CPA', (163, 172))	('steroid', 'Chemical', 'MESH:D013256', (134, 141))	('inhibition', 'Var', (57, 67))	('promotes', 'PosReg', (154, 162))	('NCI-H295R', 'CellLine', 'CVCL:0458', (18, 27))	('proliferation', 'CPA', (116, 129))	('impairs', 'NegReg', (108, 115))	('beta-catenin', 'Gene', (71, 83))	('beta-catenin', 'Gene', '1499', (71, 83))
46384	30402590	Together, these findings suggest that pharmacological inhibition of beta-catenin-dependent transcription or of autocrine/paracrine Wnt signaling in tumors with ZNRF3 alterations may be therapeutically efficacious.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('ZNRF3', 'Gene', '84133', (160, 165))	('ZNRF3', 'Gene', (160, 165))	('alterations', 'Var', (166, 177))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('beta-catenin', 'Gene', (68, 80))	('autocrine/paracrine Wnt signaling', 'MPA', (111, 144))	('beta-catenin', 'Gene', '1499', (68, 80))
46386	30402590	beta-catenin is a critical regulator of development and homeostasis of numerous tissues including the adrenal cortex; not surprisingly, many inhibitors of beta-catenin-dependent transcription cause on-target toxicity in Wnt-dependent tissues such as the intestine.	('beta-catenin', 'Gene', (155, 167))	('toxicity', 'Disease', (208, 216))	('beta-catenin', 'Gene', '1499', (0, 12))	('beta-catenin', 'Gene', '1499', (155, 167))	('cause', 'Reg', (192, 197))	('inhibitors', 'Var', (141, 151))	('toxicity', 'Disease', 'MESH:D064420', (208, 216))	('beta-catenin', 'Gene', (0, 12))
46387	30402590	New ligand-based therapies are under development, including inhibitors of Porcupine (an acyltransferase enzyme whose activity is essential for the secretion of all Wnt ligands) and Frizzled proteins, which may be more effective in potentially ligand-fueled malignancies such as ACC with somatic alterations in ZNRF3.	('ACC', 'Phenotype', 'HP:0006744', (278, 281))	('ZNRF3', 'Gene', (310, 315))	('malignancies', 'Disease', 'MESH:D009369', (257, 269))	('ACC', 'Disease', (278, 281))	('Porcupine', 'Gene', (74, 83))	('malignancies', 'Disease', (257, 269))	('Frizzled', 'Protein', (181, 189))	('ZNRF3', 'Gene', '84133', (310, 315))	('alterations', 'Var', (295, 306))
46407	30402590	It will be essential to consider rational application of this therapy in patients with mismatch repair deficiency and prominent immune infiltrate.	('mismatch repair', 'Protein', (87, 102))	('patients', 'Species', '9606', (73, 81))	('deficiency', 'Var', (103, 113))
46415	30402590	In other solid tumors, pharmacological modulation of epigenetic programs has improved efficacy of standard-of-care cytotoxic agents and may be a promising therapeutic strategy for ACC.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('solid tumors', 'Disease', 'MESH:D009369', (9, 21))	('ACC', 'Phenotype', 'HP:0006744', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('epigenetic programs', 'Var', (53, 72))	('solid tumors', 'Disease', (9, 21))	('improved', 'PosReg', (77, 85))	('efficacy', 'MPA', (86, 94))
46596	25691058	We can assume that activation of PKM2 depletes intermediates, thus resulting in a reduced proliferation rate of cancer cells.	('activation', 'Var', (19, 29))	('PKM2', 'Gene', '5315', (33, 37))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('reduced', 'NegReg', (82, 89))	('depletes intermediates', 'MPA', (38, 60))	('PKM2', 'Gene', (33, 37))
46652	26106367	Most ACAs are associated with abnormalities of the cAMP signaling pathway, whereas most ACCs are linked to alterations in IGF2, TP53, or the Wnt/betacatenin pathways.	('TP53', 'Gene', '7157', (128, 132))	('alterations', 'Var', (107, 118))	('TP53', 'Gene', (128, 132))	('IGF2', 'Gene', '3481', (122, 126))	('associated', 'Reg', (14, 24))	('betacatenin', 'Gene', (145, 156))	('linked', 'Reg', (97, 103))	('ACAs', 'Phenotype', 'HP:0008256', (5, 9))	('cAMP signaling pathway', 'Pathway', (51, 73))	('cAMP', 'Chemical', '-', (51, 55))	('abnormalities', 'Var', (30, 43))	('IGF2', 'Gene', (122, 126))	('betacatenin', 'Gene', '1499', (145, 156))
46653	26106367	Among these are somatic mutations of PKA catalytic subunit alpha gene (PRKACA) in ACA, germline, and somatic mutations of armadillo repeat containing 5 gene (ARMC5) in primary bilateral macronodular adrenal hyperplasia and somatic alterations of the E3 ubiquitin ligase gene ZNRF3 in ACC.	('PRKACA', 'Gene', '5566', (71, 77))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (186, 218))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (199, 218))	('armadillo repeat containing 5', 'Gene', '79798', (122, 151))	('alterations', 'Reg', (231, 242))	('primary bilateral macronodular adrenal hyperplasia', 'Disease', (168, 218))	('primary bilateral macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (168, 218))	('ARMC5', 'Gene', (158, 163))	('mutations', 'Var', (109, 118))	('ARMC5', 'Gene', '79798', (158, 163))	('armadillo repeat containing 5', 'Gene', (122, 151))	('mutations', 'Var', (24, 33))	('PRKACA', 'Gene', (71, 77))	('ZNRF3', 'Gene', (275, 280))
46661	26106367	Till now, the majority of genetic and molecular alterations of benign tumors has been closely linked to abnormalities in the cAMP signaling pathway.	('abnormalities', 'Var', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('alterations', 'Var', (48, 59))	('benign tumors', 'Disease', (63, 76))	('linked', 'Reg', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('benign tumors', 'Disease', 'MESH:D009369', (63, 76))	('cAMP signaling pathway', 'Pathway', (125, 147))	('cAMP', 'Chemical', '-', (125, 129))
46662	26106367	Somatic and germline mutations were identified in actors of the cAMP pathway as the PRKAR1A gene (regulatory subunit of the cAMP-dependent protein kinase A), GNAS gene (alpha subunit of the stimulatory G protein), and the PDE11A/8B genes (cAMP-degrading phosphodiesterase 11A and 8B, respectively).	('PRKAR1A', 'Gene', (84, 91))	('GNAS', 'Gene', '2778', (158, 162))	('PDE11A', 'Gene', (222, 228))	('phosphodiesterase 11A', 'Enzyme', (254, 275))	('cAMP', 'Chemical', '-', (239, 243))	('cAMP', 'Chemical', '-', (64, 68))	('GNAS', 'Gene', (158, 162))	('PRKAR1A', 'Gene', '5573', (84, 91))	('cAMP', 'Chemical', '-', (124, 128))	('PDE11A', 'Gene', '50940', (222, 228))	('mutations', 'Var', (21, 30))
46664	26106367	For example, ectopic expression of the gastric inhibitory polypeptide receptor (GIPR) in the human adrenal gland causes significant hypercortisolemia after meal ingestion and leads to Cushing's syndrome.	('leads to', 'Reg', (175, 183))	('GIPR', 'Gene', (80, 84))	('hypercortisolemia after meal ingestion', 'Phenotype', 'HP:0011744', (132, 170))	('hypercortisolemia', 'Disease', (132, 149))	('causes', 'Reg', (113, 119))	('human', 'Species', '9606', (93, 98))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (184, 202))	('hypercortisolemia', 'Disease', 'None', (132, 149))	('ectopic expression', 'Var', (13, 31))	("Cushing's syndrome", 'Disease', (184, 202))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (184, 202))
46669	26106367	For example, a hotspot somatic mutation in the PKA catalytic subunit alpha gene (PRKACA) has been identified in ACA, germline, and somatic mutations of armadillo repeat containing 5 gene (ARMC5) have been described in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH), and somatic alterations in the E3 ubiquitin ligase gene ZNRF3 were recently identified in ACC.	('primary bilateral macronodular adrenal hyperplasia', 'Disease', (232, 282))	('primary bilateral macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (232, 282))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (250, 282))	('armadillo repeat containing 5', 'Gene', (152, 181))	('ZNRF3', 'Gene', (348, 353))	('PRKACA', 'Gene', '5566', (81, 87))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (263, 282))	('mutations', 'Var', (139, 148))	('PBMAH', 'Chemical', '-', (284, 289))	('patients', 'Species', '9606', (218, 226))	('mutation', 'Var', (31, 39))	('described', 'Reg', (205, 214))	('ARMC5', 'Gene', '79798', (188, 193))	('ARMC5', 'Gene', (188, 193))	('armadillo repeat containing 5', 'Gene', '79798', (152, 181))	('PRKACA', 'Gene', (81, 87))
46671	26106367	Prior to the introduction of next-generation sequencing, mutations in some genes such as GNAS or PRKAR1A had been reported in ACA-S. Activating mutations of the GNAS alpha subunit and PRKAR1A-inactivating mutations promote the cAMP pathway activation.	('PRKAR1A', 'Gene', (97, 104))	('PRKAR1A', 'Gene', (184, 191))	('promote', 'PosReg', (215, 222))	('PRKAR1A', 'Gene', '5573', (97, 104))	('PRKAR1A', 'Gene', '5573', (184, 191))	('GNAS', 'Gene', '2778', (161, 165))	('GNAS', 'Gene', (161, 165))	('GNAS', 'Gene', (89, 93))	('cAMP', 'Chemical', '-', (227, 231))	('mutations', 'Var', (144, 153))	('activation', 'PosReg', (240, 250))	('cAMP pathway', 'Pathway', (227, 239))	('GNAS', 'Gene', '2778', (89, 93))
46672	26106367	CTNNB1-activating mutations had been found in ACA-NS and ACA-S but their prevalence was higher among ACA-NS.	('CTNNB1', 'Gene', '1499', (0, 6))	('higher', 'PosReg', (88, 94))	('CTNNB1', 'Gene', (0, 6))	('ACA-S', 'Disease', (57, 62))	('ACA-NS', 'Disease', (46, 52))	('mutations', 'Var', (18, 27))
46673	26106367	Recently, Beuschlein and collaborators identified a hotspot mutation in PRKACA gene through whole-exome sequencing in ACA-S.	('mutation', 'Var', (60, 68))	('ACA-S', 'Disease', (118, 123))	('PRKACA', 'Gene', (72, 78))	('hotspot', 'PosReg', (52, 59))	('PRKACA', 'Gene', '5566', (72, 78))
46674	26106367	The somatic mutation, p.L206R/c.617A > G was present in more than one-third of the examined tumors.	('p.L206R/c.617A > G', 'Var', (22, 40))	('c.617A > G', 'Mutation', 'rs769817752', (30, 40))	('p.L206R', 'Mutation', 'rs386352352', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
46677	26106367	The p.L206R point mutation results in the introduction of a voluminous and positively charged amino acid that inhibits the formation of stable complexes between subunits of PKA.	('inhibits', 'NegReg', (110, 118))	('formation', 'MPA', (123, 132))	('p.L206R', 'Var', (4, 11))	('results in', 'Reg', (27, 37))	('p.L206R', 'Mutation', 'rs386352352', (4, 11))
46678	26106367	This mutation prevents the interaction of the catalytic subunit of PKA with the regulatory subunit, resulting in an increased phosphorylation of substrates and finally, in an excessive steroidogenic activity (Figure 2A).	('interaction', 'Interaction', (27, 38))	('steroidogenic activity', 'MPA', (185, 207))	('steroid', 'Chemical', 'MESH:D013256', (185, 192))	('phosphorylation of substrates', 'MPA', (126, 155))	('increased', 'PosReg', (116, 125))	('excessive', 'PosReg', (175, 184))	('prevents', 'NegReg', (14, 22))	('mutation', 'Var', (5, 13))
46680	26106367	L206R mutation of PRKACA in ACA-S was associated with more severe phenotypes (Cushing's syndrome).	('associated', 'Reg', (38, 48))	("Cushing's syndrome", 'Disease', (78, 96))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (78, 96))	('L206R', 'Mutation', 'rs386352352', (0, 5))	('L206R', 'Var', (0, 5))	('PRKACA', 'Gene', (18, 24))	('PRKACA', 'Gene', '5566', (18, 24))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (78, 96))
46681	26106367	Another mutation in the PRKACA gene, Leu199_Cys200insTrp, identified only in one study, has the same effect on the stability of the PKA complex (Figures 1A and 2A).	('Leu199_Cys200insTrp', 'Var', (37, 56))	('PRKACA', 'Gene', (24, 30))	('Leu199_Cys200insTrp', 'Mutation', 'p.L,C199,200W', (37, 56))	('PRKACA', 'Gene', '5566', (24, 30))	('stability of the PKA complex', 'CPA', (115, 143))
46682	26106367	Adrenal cortex and cortisol-secreting adenomas are characterized by a high occurrence of PRKACA-activating mutations.	('PRKACA', 'Gene', (89, 95))	('mutations', 'Var', (107, 116))	('PRKACA', 'Gene', '5566', (89, 95))	('adenomas', 'Disease', 'MESH:D000236', (38, 46))	('adenomas', 'Disease', (38, 46))
46683	26106367	However, other mutations in GNAS and CTNNB1 genes are found in some ACA-S without PRKACA mutations and are mutually exclusive.	('GNAS', 'Gene', '2778', (28, 32))	('PRKACA', 'Gene', (82, 88))	('PRKACA', 'Gene', '5566', (82, 88))	('mutations', 'Var', (15, 24))	('CTNNB1', 'Gene', '1499', (37, 43))	('found', 'Reg', (54, 59))	('GNAS', 'Gene', (28, 32))	('ACA-S', 'Disease', (68, 73))	('CTNNB1', 'Gene', (37, 43))
46684	26106367	The hotspot mutation in the PRKACA gene seems to be sufficient to alter the endocrine and proliferative systems in ACA-S and represents the main genetic risk factor associated with this type of tumor.	('ACA-S', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('PRKACA', 'Gene', (28, 34))	('PRKACA', 'Gene', '5566', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('hotspot', 'PosReg', (4, 11))	('alter', 'Reg', (66, 71))	('tumor', 'Disease', (194, 199))	('mutation', 'Var', (12, 20))
46691	26106367	Mutations or variants of some genes involved in the cAMP signaling pathway have been identified as in GNAS, PDE11A, and PDE8B genes but are only present in a limited fraction of PBMAH cases.	('PDE8B', 'Gene', (120, 125))	('variants', 'Var', (13, 21))	('GNAS', 'Gene', (102, 106))	('PDE8B', 'Gene', '8622', (120, 125))	('PBMAH', 'Chemical', '-', (178, 183))	('PDE11A', 'Gene', (108, 114))	('PDE11A', 'Gene', '50940', (108, 114))	('cAMP', 'Chemical', '-', (52, 56))	('GNAS', 'Gene', '2778', (102, 106))
46694	26106367	ARMC5 alterations were detected in tumors obtained from 18 of 33 patients who had undergone surgery (55%).	('alterations', 'Var', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('ARMC5', 'Gene', '79798', (0, 5))	('ARMC5', 'Gene', (0, 5))	('tumors', 'Disease', (35, 41))	('detected', 'Reg', (23, 31))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('patients', 'Species', '9606', (65, 73))
46697	26106367	In each case, the same germline mutation was detected in all nodules and associated with a nodule-specific second somatic ARMC5 alteration (LOH, nonsense or missense mutation).	('ARMC5', 'Gene', '79798', (122, 127))	('ARMC5', 'Gene', (122, 127))	('associated with', 'Reg', (73, 88))	('nonsense', 'Var', (145, 153))
46698	26106367	The discovery of ARMC5 alterations establishes the first direct genetic link to PBMAH.	('PBMAH', 'Chemical', '-', (80, 85))	('alterations', 'Var', (23, 34))	('ARMC5', 'Gene', '79798', (17, 22))	('ARMC5', 'Gene', (17, 22))	('PBMAH', 'Disease', (80, 85))
46699	26106367	The pattern of mutations suggests a "two-hit" model of a tumor suppressor gene, responsible for a hereditary predisposition syndrome.	('tumor', 'Disease', (57, 62))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))
46700	26106367	Subsequent studies confirm the recurrent mutation of ARMC5 in family members with PBMAH.	('PBMAH', 'Chemical', '-', (82, 87))	('ARMC5', 'Gene', (53, 58))	('PBMAH', 'Disease', (82, 87))	('ARMC5', 'Gene', '79798', (53, 58))	('mutation', 'Var', (41, 49))
46701	26106367	In these various studies, the percentage of ARMC5 mutations reaches 25% in index cases of PBMAH.	('PBMAH', 'Disease', (90, 95))	('mutations', 'Var', (50, 59))	('ARMC5', 'Gene', (44, 49))	('ARMC5', 'Gene', '79798', (44, 49))	('PBMAH', 'Chemical', '-', (90, 95))
46702	26106367	Recently, the high frequency of alterations in the ARMC5 gene has been confirmed in a large cohort of 98 patients with PBMAH, including operated and non-operated patients.	('ARMC5', 'Gene', '79798', (51, 56))	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (105, 113))	('PBMAH', 'Chemical', '-', (119, 124))	('alterations', 'Var', (32, 43))	('PBMAH', 'Disease', (119, 124))	('ARMC5', 'Gene', (51, 56))
46703	26106367	Up to now, these recent studies identified - in patients with PBMAH - in addition to LOH and a microdeletion, a total of 61 different mutations in ARMC5: 27 germinal, 30 somatic, two which have been identified at somatic and germline levels in different cases (p.R315 and p.R619X) and two without status available (Figure 1B).	('p.R619X', 'Mutation', 'rs766717248', (272, 279))	('ARMC5', 'Gene', '79798', (147, 152))	('PBMAH', 'Chemical', '-', (62, 67))	('ARMC5', 'Gene', (147, 152))	('patients', 'Species', '9606', (48, 56))	('p.R315', 'Var', (261, 267))	('p.R619X', 'Var', (272, 279))
46704	26106367	Two of the germline mutations are found in several index cases and in at least three studies suggesting a founder effect: p.R267X and p.R898W.	('p.R898W', 'Mutation', 'rs587777659', (134, 141))	('p.R267X', 'Var', (122, 129))	('p.R898W', 'Var', (134, 141))	('p.R267X', 'Mutation', 'rs369721476', (122, 129))
46707	26106367	Recent functional study on ARMC5 gene, performed in the human adrenocortical cells H295R, showed that ARMC5 gene silencing alters the expression of genes involved in steroidogenesis leading to a global decreased of cortisol secretion (Figure 2B).	('cortisol secretion', 'MPA', (215, 233))	('adrenocortical', 'Disease', (62, 76))	('expression', 'MPA', (134, 144))	('alters', 'Reg', (123, 129))	('decreased', 'NegReg', (202, 211))	('adrenocortical', 'Disease', 'MESH:D018268', (62, 76))	('gene', 'Var', (108, 112))	('ARMC5', 'Gene', '79798', (102, 107))	('ARMC5', 'Gene', (102, 107))	('steroid', 'Chemical', 'MESH:D013256', (166, 173))	('silencing', 'NegReg', (113, 122))	('human', 'Species', '9606', (56, 61))	('ARMC5', 'Gene', (27, 32))	('decreased of cortisol', 'Phenotype', 'HP:0008163', (202, 223))	('ARMC5', 'Gene', '79798', (27, 32))
46708	26106367	All data describing ARMC5 mutations show that patients suffering from PBMAH have a phenotype more severe than patients without ARMC5 mutation.	('patients', 'Species', '9606', (46, 54))	('mutations', 'Var', (26, 35))	('ARMC5', 'Gene', '79798', (20, 25))	('ARMC5', 'Gene', (20, 25))	('ARMC5', 'Gene', '79798', (127, 132))	('PBMAH', 'Chemical', '-', (70, 75))	('ARMC5', 'Gene', (127, 132))	('PBMAH', 'Disease', (70, 75))	('patients', 'Species', '9606', (110, 118))
46709	26106367	Patients with ARMC5 mutations present with larger tumor volumes, increased numbers of tumor nodules, and more severe hypercortisolism.	('hypercortisolism', 'Disease', 'MESH:D003480', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor nodules', 'Disease', 'MESH:D016606', (86, 99))	('Patients', 'Species', '9606', (0, 8))	('ARMC5', 'Gene', '79798', (14, 19))	('tumor', 'Disease', (50, 55))	('increased', 'PosReg', (65, 74))	('tumor nodules', 'Disease', (86, 99))	('larger', 'PosReg', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mutations', 'Var', (20, 29))	('tumor', 'Disease', (86, 91))	('increased numbers of tumor nodules', 'Phenotype', 'HP:0032536', (65, 99))	('hypercortisolism', 'Phenotype', 'HP:0003118', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('hypercortisolism', 'Disease', (117, 133))	('ARMC5', 'Gene', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('more severe hypercortisolism', 'Phenotype', 'HP:0011744', (105, 133))
46710	26106367	Recently, ARMC5 mutations have been associated with another steroid hypersecretion.	('another steroid hypersecretion', 'MPA', (52, 82))	('mutations', 'Var', (16, 25))	('ARMC5', 'Gene', '79798', (10, 15))	('ARMC5', 'Gene', (10, 15))	('associated', 'Reg', (36, 46))	('steroid', 'Chemical', 'MESH:D013256', (60, 67))
46713	26106367	The genomic and functional data indicate that ARMC5 has a role of tumor suppressor gene because two inactivating mutations seem necessary to develop PBMAH and human cells (H295R and HeLa) transfected with non-mutated ARMC5 resulted in cell death (Figure 2B).	('non-mutated', 'Var', (205, 216))	('ARMC5', 'Gene', '79798', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('ARMC5', 'Gene', (46, 51))	('tumor', 'Disease', (66, 71))	('cell death', 'CPA', (235, 245))	('human', 'Species', '9606', (159, 164))	('ARMC5', 'Gene', '79798', (217, 222))	('ARMC5', 'Gene', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('HeLa', 'CellLine', 'CVCL:0030', (182, 186))	('PBMAH', 'Chemical', '-', (149, 154))
46717	26106367	These data suggest that genetic alterations of the ARMC5 gene may cause the development of different associated tumors with PBMAH.	('ARMC5', 'Gene', '79798', (51, 56))	('genetic alterations', 'Var', (24, 43))	('PBMAH', 'Disease', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cause', 'Reg', (66, 71))	('PBMAH', 'Chemical', '-', (124, 129))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('ARMC5', 'Gene', (51, 56))	('tumors', 'Disease', (112, 118))
46718	26106367	With the recent advances in the genetic methods, it is possible to imagine that future studies will reveal cases with ARMC5 mutations in other types of tumors without PBMAH.	('mutations', 'Var', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('ARMC5', 'Gene', '79798', (118, 123))	('PBMAH', 'Chemical', '-', (167, 172))	('ARMC5', 'Gene', (118, 123))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
46720	26106367	Mutations in the DOT1L (DOT1-like histone H3K79 methyltransferase) and HDAC9 (histone deacetylase 9) genes have also been found in patients with PBMAH.	('patients', 'Species', '9606', (131, 139))	('PBMAH', 'Disease', (145, 150))	('DOT1L', 'Gene', '84444', (17, 22))	('DOT1-like histone H3K79 methyltransferase', 'Gene', (24, 65))	('HDAC9', 'Gene', (71, 76))	('HDAC9', 'Gene', '9734', (71, 76))	('DOT1-like histone H3K79 methyltransferase', 'Gene', '84444', (24, 65))	('DOT1L', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (122, 127))	('histone deacetylase 9', 'Gene', (78, 99))	('PBMAH', 'Chemical', '-', (145, 150))	('histone deacetylase 9', 'Gene', '9734', (78, 99))
46721	26106367	Unlike ARMC5 mutations, their frequency is lower and appeared only in two and one cases, respectively.	('mutations', 'Var', (13, 22))	('ARMC5', 'Gene', '79798', (7, 12))	('ARMC5', 'Gene', (7, 12))
46722	26106367	These new mutations seem to define a little subgroup of PBMAH without ARMC5 mutations.	('PBMAH', 'Chemical', '-', (56, 61))	('mutations', 'Var', (10, 19))	('ARMC5', 'Gene', (70, 75))	('PBMAH', 'Disease', (56, 61))	('ARMC5', 'Gene', '79798', (70, 75))
46724	26106367	In regard to the high frequency (20%) of mutations in ARMC5 gene in all index cases analyzed, its systematic genetic screening appears to be important for patients with PBMAH or Cushing syndrome.	('mutations', 'Var', (41, 50))	('PBMAH', 'Chemical', '-', (169, 174))	('PBMAH', 'Disease', (169, 174))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (178, 194))	('ARMC5', 'Gene', '79798', (54, 59))	('ARMC5', 'Gene', (54, 59))	('Cushing syndrome', 'Disease', (178, 194))	('patients', 'Species', '9606', (155, 163))	('Cushing syndrome', 'Disease', 'MESH:D003480', (178, 194))
46732	26106367	This work confirmed recurrent alterations in the known drivers CTNNB1 and TP53 and revealed new genes not previously reported to be altered in ACC.	('CTNNB1', 'Gene', '1499', (63, 69))	('CTNNB1', 'Gene', (63, 69))	('alterations', 'Var', (30, 41))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))
46743	26106367	Recurrent deletion of three regions in chromosome 22 was identified in osteoblastoma, one of these regions contains ZNRF3.	('osteoblastoma', 'Phenotype', 'HP:0011846', (71, 84))	('ZNRF3', 'Gene', (116, 121))	('osteoblastoma', 'Disease', (71, 84))	('deletion', 'Var', (10, 18))	('osteoblastoma', 'Disease', 'MESH:D018215', (71, 84))
46744	26106367	Moreover, the deletion of ZNRF3 and RNF43 in the intestinal epithelium in mouse induces the development of adenoma with an increased nuclear beta-catenin and an increased expression of Wnt/beta-catenin target genes.	('expression', 'MPA', (171, 181))	('increased', 'PosReg', (123, 132))	('RNF43', 'Gene', (36, 41))	('ZNRF3', 'Gene', (26, 31))	('adenoma', 'Disease', 'MESH:D000236', (107, 114))	('increased', 'PosReg', (161, 170))	('mouse', 'Species', '10090', (74, 79))	('adenoma', 'Disease', (107, 114))	('deletion', 'Var', (14, 22))	('nuclear beta-catenin', 'MPA', (133, 153))	('induces', 'Reg', (80, 87))
46745	26106367	Interestingly alterations of ZNRF3 and CTNNB1 are completely exclusive in ACC, suggesting that ZNRF3 alterations might play a crucial role in tumorigenesis by activating also the Wnt/beta-catenin signaling pathway.	('Wnt/beta-catenin signaling pathway', 'Pathway', (179, 213))	('ZNRF3', 'Gene', (29, 34))	('CTNNB1', 'Gene', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('alterations', 'Var', (101, 112))	('tumor', 'Disease', (142, 147))	('ZNRF3', 'Gene', (95, 100))	('activating', 'Reg', (159, 169))	('ACC', 'Disease', (74, 77))	('CTNNB1', 'Gene', '1499', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
46747	26106367	ACC with altered ZNRF3 showed transcriptional activation of beta-catenin targets, but this activation was weaker than in CTNNB1-mutated tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('CTNNB1', 'Gene', '1499', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('activation', 'PosReg', (46, 56))	('CTNNB1', 'Gene', (121, 127))	('ZNRF3', 'Gene', (17, 22))	('altered', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('transcriptional', 'MPA', (30, 45))	('beta-catenin targets', 'MPA', (60, 80))
46748	26106367	However, till now, ACCs are the cancers described with the most frequent ZNRF3 alterations, suggesting a specific mechanism of tumorigenesis into the adrenal cortex tissue.	('ZNRF3', 'Gene', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('alterations', 'Var', (79, 90))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('tumor', 'Disease', (127, 132))	('cancers', 'Disease', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
46751	26106367	Alterations in genes not previously reported were identified: somatic mutations of PRKACA gene in ACA, germline and somatic mutations of ARMC5 gene in PBMAH, and somatic alterations of ZNRF3 gene in ACC.	('mutations', 'Var', (70, 79))	('mutations', 'Var', (124, 133))	('alterations', 'Var', (170, 181))	('PRKACA', 'Gene', (83, 89))	('ARMC5', 'Gene', (137, 142))	('ZNRF3', 'Gene', (185, 190))	('PRKACA', 'Gene', '5566', (83, 89))	('PBMAH', 'Chemical', '-', (151, 156))	('ARMC5', 'Gene', '79798', (137, 142))
46753	25075217	Repurposing Drugs in Oncology (ReDO):mebendazole as an anti-cancer agent Mebendazole, a well-known anti-helminthic drug in wide clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical studies across a number of different cancer types.	('mebendazole', 'Chemical', 'MESH:D008463', (37, 48))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('Oncology', 'Phenotype', 'HP:0002664', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('Mebendazole', 'Var', (73, 84))	('as', 'Chemical', 'MESH:D001151', (143, 145))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('as', 'Chemical', 'MESH:D001151', (49, 51))	('cancer', 'Disease', (265, 271))	('Mebendazole', 'Chemical', 'MESH:D008463', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
46784	25075217	In 2002, Mukhopadhyay and colleagues showed that MBZ induced a dose- and time-dependant apoptotic response in a range of lung cancer cell lines, with an IC50 of ~0.16 muM.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('MBZ', 'Var', (49, 52))	('muM', 'Gene', (167, 170))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('MBZ', 'Chemical', 'MESH:D008463', (49, 52))	('apoptotic response', 'CPA', (88, 106))	('muM', 'Gene', '56925', (167, 170))
46786	25075217	Just as importantly, MBZ had no effect on normal HUVECs or WI38 fibroblasts, even at a concentration of 1 muM.	('muM', 'Gene', '56925', (106, 109))	('MBZ', 'Var', (21, 24))	('as', 'Chemical', 'MESH:D001151', (71, 73))	('as', 'Chemical', 'MESH:D001151', (5, 7))	('muM', 'Gene', (106, 109))	('MBZ', 'Chemical', 'MESH:D008463', (21, 24))
46787	25075217	Overall, the in vitro results showed that MBZ inhibited lung cancer cell growth 5-fold compared to controls.	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('MBZ', 'Var', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('MBZ', 'Chemical', 'MESH:D008463', (42, 45))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('inhibited', 'NegReg', (46, 55))
46792	25075217	The experiment was also repeated with C3H mice and the K1735 mouse cell line, and MBZ inhibited tumour growth in this syngeneic mouse model also.	('as', 'Chemical', 'MESH:D001151', (16, 18))	('mice', 'Species', '10090', (42, 46))	('MBZ', 'Chemical', 'MESH:D008463', (82, 85))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour growth', 'Disease', (96, 109))	('mouse', 'Species', '10090', (128, 133))	('mouse', 'Species', '10090', (61, 66))	('tumour growth', 'Disease', 'MESH:D006130', (96, 109))	('inhibited', 'NegReg', (86, 95))	('MBZ', 'Var', (82, 85))
46794	25075217	Finally, the investigators also assessed whether MBZ might inhibit the formation of lung metastases and injected A549 cells into the tail vein of mice.	('as', 'Chemical', 'MESH:D001151', (32, 34))	('as', 'Chemical', 'MESH:D001151', (92, 94))	('as', 'Chemical', 'MESH:D001151', (95, 97))	('MBZ', 'Var', (49, 52))	('lung metastases', 'Disease', (84, 99))	('lung metastases', 'Disease', 'MESH:D009362', (84, 99))	('mice', 'Species', '10090', (146, 150))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('MBZ', 'Chemical', 'MESH:D008463', (49, 52))	('inhibit', 'NegReg', (59, 66))
46799	25075217	H295R, SW-13 and WI-38 (normal fibroblast) cells lines were treated with different concentrations of MBZ in vitro, and the two cancer cells lines showed dose-dependent growth arrest, with IC50 of 0.23 muM for H295R and 0.27 muM for SW-13 cells, with no effect on the normal fibroblast cells.	('MBZ', 'Chemical', 'MESH:D008463', (101, 104))	('growth arrest', 'Phenotype', 'HP:0001510', (168, 181))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('muM', 'Gene', '56925', (224, 227))	('muM', 'Gene', '56925', (201, 204))	('H295R', 'Var', (209, 214))	('as', 'Chemical', 'MESH:D001151', (38, 40))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('as', 'Chemical', 'MESH:D001151', (281, 283))	('SW-13', 'CellLine', 'CVCL:0542', (7, 12))	('muM', 'Gene', (224, 227))	('growth arrest', 'Disease', 'MESH:D006323', (168, 181))	('growth arrest', 'Disease', (168, 181))	('cancer', 'Disease', (127, 133))	('muM', 'Gene', (201, 204))	('SW-13', 'CellLine', 'CVCL:0542', (232, 237))
46807	25075217	MBZ was shown to induce dose-dependent apoptosis in both cell lines with an average IC50 of 0.32 muM, while the equivalent for the non-cancerous melanocyte cell line was IC50 of 1.9 muM.	('cancer', 'Disease', (135, 141))	('apoptosis', 'CPA', (39, 48))	('MBZ', 'Var', (0, 3))	('muM', 'Gene', (182, 185))	('as', 'Chemical', 'MESH:D001151', (167, 169))	('as', 'Chemical', 'MESH:D001151', (5, 7))	('muM', 'Gene', '56925', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('MBZ', 'Chemical', 'MESH:D008463', (0, 3))	('muM', 'Gene', (97, 100))	('muM', 'Gene', '56925', (182, 185))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
46826	25075217	MBZ reduced cell survival by 63.1% at a dose of 0.5 muM.	('MBZ', 'Var', (0, 3))	('reduced', 'NegReg', (4, 11))	('muM', 'Gene', '56925', (52, 55))	('MBZ', 'Chemical', 'MESH:D008463', (0, 3))	('muM', 'Gene', (52, 55))	('cell survival', 'CPA', (12, 25))
46865	25075217	Subsequent work on melanoma confirmed this result, and also showed that MBZ decreased the levels of X-linked inhibitor of apoptosis (XIAP), but to date this has not been confirmed in non-melanoma cell lines.	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('X-linked inhibitor of apoptosis', 'Gene', '331', (100, 131))	('as', 'Chemical', 'MESH:D001151', (81, 83))	('melanoma', 'Disease', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('as', 'Chemical', 'MESH:D001151', (158, 160))	('melanoma', 'Disease', (19, 27))	('decreased', 'NegReg', (76, 85))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('MBZ', 'Var', (72, 75))	('non-melanoma', 'Disease', (183, 195))	('X-linked inhibitor of apoptosis', 'Gene', (100, 131))	('XIAP', 'Gene', (133, 137))	('XIAP', 'Gene', '331', (133, 137))	('MBZ', 'Chemical', 'MESH:D008463', (72, 75))	('non-melanoma', 'Disease', 'MESH:D008545', (183, 195))
46872	25075217	This independence of p53 status is also evident in the analysis of melanoma cells, where wild-type and mutant p53 cell lines were sensitive to MBZ.	('p53', 'Gene', (110, 113))	('mutant', 'Var', (103, 109))	('p53', 'Gene', '7157', (110, 113))	('p53', 'Gene', '7157', (21, 24))	('melanoma', 'Disease', (67, 75))	('MBZ', 'Chemical', 'MESH:D008463', (143, 146))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('p53', 'Gene', (21, 24))
46886	25075217	Additional cancer types, which should be further investigated in animal studies include:  As with other anti-cancer agents, it is most likely that MBZ will be more effective in combination with other drugs or treatment modalities.	('MBZ', 'Var', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('MBZ', 'Chemical', 'MESH:D008463', (147, 150))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
46887	25075217	It should be noted that the first two clinical trials are using MBZ with current standard of care treatment in glioma, which in this case means a combination protocol with other drugs, principally temozolomide.	('glioma', 'Disease', (111, 117))	('as', 'Chemical', 'MESH:D001151', (134, 136))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('MBZ', 'Chemical', 'MESH:D008463', (64, 67))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('temozolomide', 'Chemical', 'MESH:D000077204', (197, 209))	('MBZ', 'Var', (64, 67))
46908	25075217	Metformin: There is pre-clinical evidence that metformin potentiates the action of existing microtubule disrupting drugs in a range of cancer types, including endometrial cancers and paediatric sarcomas.	('cancer', 'Disease', (135, 141))	('metformin', 'Chemical', 'MESH:D008687', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('potentiates', 'PosReg', (57, 68))	('cancer', 'Disease', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('sarcomas', 'Disease', 'MESH:D012509', (194, 202))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('endometrial cancers', 'Disease', 'MESH:D016889', (159, 178))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('action', 'MPA', (73, 79))	('endometrial cancers', 'Disease', (159, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (194, 202))	('sarcomas', 'Disease', (194, 202))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('metformin', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('microtubule disrupting drugs', 'MPA', (92, 120))
46933	25075217	As was mentioned previously, there is also evidence that cimetidine can increase the plasma levels of MBZ.	('MBZ', 'MPA', (102, 105))	('increase', 'PosReg', (72, 80))	('as', 'Chemical', 'MESH:D001151', (77, 79))	('MBZ', 'Chemical', 'MESH:D008463', (102, 105))	('plasma levels', 'MPA', (85, 98))	('as', 'Chemical', 'MESH:D001151', (4, 6))	('cimetidine', 'Chemical', 'MESH:D002927', (57, 67))	('as', 'Chemical', 'MESH:D001151', (87, 89))	('cimetidine', 'Var', (57, 67))
46960	25075217	There is also limited clinical evidence that oral supplementation with EPA/DHA can improve outcomes in colorectal and advanced non-small cell lung cancer.	('DHA', 'Chemical', 'MESH:D004281', (75, 78))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (127, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('EPA/DHA', 'Var', (71, 78))	('colorectal', 'Disease', 'MESH:D015179', (103, 113))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (127, 153))	('improve', 'PosReg', (83, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('non-small cell lung cancer', 'Disease', (127, 153))	('EPA', 'Chemical', 'MESH:D015118', (71, 74))	('colorectal', 'Disease', (103, 113))
46963	24936644	Prevalence of the TP53 p.R337H Mutation in Breast Cancer Patients in Brazil Germline TP53 mutations predispose individuals to multiple cancers and are associated with Li-Fraumeni/Li-Fraumeni-Like Syndromes (LFS/LFL).	('predispose', 'Reg', (100, 110))	('mutations', 'Var', (90, 99))	('Li-Fraumeni', 'Disease', (167, 178))	('TP53', 'Gene', '7157', (18, 22))	('Breast Cancer', 'Disease', 'MESH:D001943', (43, 56))	('LFS', 'Disease', (207, 210))	('p.R337H', 'Var', (23, 30))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (167, 178))	('TP53', 'Gene', (85, 89))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Breast Cancer', 'Disease', (43, 56))	('LFS', 'Disease', 'MESH:D016864', (207, 210))	('Patients', 'Species', '9606', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Breast Cancer', 'Phenotype', 'HP:0003002', (43, 56))	('p.R337H', 'Mutation', 'rs121912664', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('Li-Fraumeni', 'Disease', (179, 190))	('multiple cancers', 'Disease', 'MESH:D009369', (126, 142))	('associated with', 'Reg', (151, 166))	('TP53', 'Gene', (18, 22))	('TP53', 'Gene', '7157', (85, 89))	('Li-Fraumeni-Like Syndrome', 'Disease', (179, 204))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (179, 190))	('Li-Fraumeni-Like Syndrome', 'Disease', 'MESH:C567189', (179, 204))	('multiple cancers', 'Disease', (126, 142))
46964	24936644	The founder mutation TP53 p.R337H is detected in 0.3% of the general population in southern Brazil.	('TP53', 'Gene', (21, 25))	('p.R337H', 'Mutation', 'rs121912664', (26, 33))	('p.R337H', 'Var', (26, 33))	('TP53', 'Gene', '7157', (21, 25))
46966	24936644	Breast Cancer (BC) is one of the most common cancers diagnosed in TP53 mutation carriers.	('TP53', 'Gene', '7157', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('TP53', 'Gene', (66, 70))	('mutation', 'Var', (71, 79))	('BC', 'Phenotype', 'HP:0003002', (15, 17))	('Breast Cancer', 'Disease', (0, 13))	('Breast Cancer', 'Disease', 'MESH:D001943', (0, 13))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('Breast Cancer', 'Phenotype', 'HP:0003002', (0, 13))
46967	24936644	We have assessed the prevalence of p.R337H in two groups: (1) 59 BC affected women with a familial history (FH) suggestive of hereditary cancer syndrome but no LFS/LFL features; (2) 815 BC affected women unselected for cancer FH, diagnosed with BC at or before age 45 or at age 55 or older.	('cancer FH', 'Disease', 'MESH:D006938', (219, 228))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer FH', 'Disease', (219, 228))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('hereditary cancer syndrome', 'Disease', (126, 152))	('FH', 'Disease', 'MESH:D006938', (226, 228))	('LFS', 'Disease', 'MESH:D016864', (160, 163))	('BC', 'Phenotype', 'HP:0003002', (245, 247))	('women', 'Species', '9606', (198, 203))	('p.R337H', 'Var', (35, 42))	('women', 'Species', '9606', (77, 82))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (126, 152))	('FH', 'Disease', 'MESH:D006938', (108, 110))	('p.R337H', 'Mutation', 'rs121912664', (35, 42))	('BC', 'Phenotype', 'HP:0003002', (65, 67))	('BC', 'Phenotype', 'HP:0003002', (186, 188))	('LFS', 'Disease', (160, 163))
46971	24936644	These results suggest that inheritance of p.R337H may significantly contribute to the high incidence of BC in Brazil, in addition to its recently demonstrated impact on the risk of childhood ACC.	('ACC', 'Phenotype', 'HP:0006744', (191, 194))	('p.R337H', 'Var', (42, 49))	('contribute', 'Reg', (68, 78))	('p.R337H', 'Mutation', 'rs121912664', (42, 49))	('child', 'Species', '9606', (181, 186))	('BC', 'Phenotype', 'HP:0003002', (104, 106))
46972	24936644	Germline TP53 mutations are the underlying genetic defect in Li-Fraumeni Syndrome (LFS) and its variant, Li-Fraumeni-Like Syndrome (LFL), autosomal dominant disorders characterised by a predisposition to multiple early-onset cancers.	('autosomal dominant disorders', 'Disease', 'MESH:D030342', (138, 166))	('genetic defect', 'Disease', (43, 57))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('genetic defect', 'Disease', 'MESH:D030342', (43, 57))	('Li-Fraumeni Syndrome', 'Disease', (61, 81))	('cancers', 'Disease', (225, 232))	('Li-Fraumeni-Like Syndrome', 'Disease', 'MESH:C567189', (105, 130))	('TP53', 'Gene', '7157', (9, 13))	('Li-Fraumeni-Like Syndrome', 'Disease', (105, 130))	('TP53', 'Gene', (9, 13))	('LFS', 'Disease', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('autosomal dominant disorders', 'Disease', (138, 166))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (61, 81))	('LFS', 'Disease', 'MESH:D016864', (83, 86))	('mutations', 'Var', (14, 23))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
46974	24936644	BC is the most common cancer in adult TP53 mutation carriers, representing over 25% of all cancer diagnoses.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('TP53', 'Gene', (38, 42))	('mutation', 'Var', (43, 51))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', (22, 28))	('common', 'Reg', (15, 21))	('BC', 'Phenotype', 'HP:0003002', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('TP53', 'Gene', '7157', (38, 42))
46975	24936644	In Europe and North America, germline TP53 mutations have been estimated to occur in 1 of 5,000-20,000 live births.	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', '7157', (38, 42))
46976	24936644	Among BC-affected women, mutations have been described in no more than 0.25% of those diagnosed with BC at any age and unselected for familial history of cancer (FHC), and in up to 7% of those with very early-onset BC (diagnosis before age 30), independent of FHC.	('mutations', 'Var', (25, 34))	('FHC', 'Gene', (162, 165))	('BC', 'Phenotype', 'HP:0003002', (215, 217))	('FHC', 'Gene', (260, 263))	('cancer', 'Disease', (154, 160))	('to 7', 'Species', '1214577', (178, 182))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('FHC', 'Gene', '3949', (162, 165))	('BC', 'Phenotype', 'HP:0003002', (6, 8))	('FHC', 'Gene', '3949', (260, 263))	('women', 'Species', '9606', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('BC', 'Phenotype', 'HP:0003002', (101, 103))
46977	24936644	A recent study in a cohort of 100 BC patients diagnosed at or before age 35 identified germline BRCA1, BRCA2 and TP53 mutations in 11, 6, and 5% of the patients, respectively, supporting that the TP53 mutation screening should be offered together with BRCA1/2 testing in women with early-onset BC.	('BRCA1', 'Gene', (252, 257))	('TP53', 'Gene', (196, 200))	('early-onset BC', 'Disease', (282, 296))	('BC', 'Phenotype', 'HP:0003002', (34, 36))	('BRCA2', 'Gene', (103, 108))	('women', 'Species', '9606', (271, 276))	('patients', 'Species', '9606', (37, 45))	('TP53', 'Gene', '7157', (196, 200))	('TP53', 'Gene', (113, 117))	('BRCA2', 'Gene', '675', (103, 108))	('BC', 'Phenotype', 'HP:0003002', (294, 296))	('BRCA1', 'Gene', '672', (96, 101))	('mutations', 'Var', (118, 127))	('BRCA1/2', 'Gene', (252, 259))	('BRCA1', 'Gene', (96, 101))	('patients', 'Species', '9606', (152, 160))	('TP53', 'Gene', '7157', (113, 117))	('BRCA1', 'Gene', '672', (252, 257))	('BRCA1/2', 'Gene', '672;675', (252, 259))
46978	24936644	In southern and southeastern regions of Brazil, a specific mutation that occurs in codon 337 (g.16901G>A; p.R337H), has been reported to occur at a high frequency.	('p.R337H', 'Mutation', 'rs121912664', (106, 113))	('p.R337H', 'Var', (106, 113))	('g.16901G>A', 'Mutation', 'rs121912664', (94, 104))	('g.16901G>A; p.R337H', 'Var', (94, 113))
46979	24936644	The arginine residue at codon 337 is part of an alpha-helix motif involved in p53 oligomerisation and structural studies have shown that replacement of arginine by histidine disrupts oligomerisation in a pH-dependent manner, making the domain unable to oligomerise in conditions of slightly elevated pH.	('elevated pH', 'Phenotype', 'HP:0008151', (291, 302))	('disrupts', 'NegReg', (174, 182))	('replacement', 'Var', (137, 148))	('arginine', 'Var', (152, 160))	('arginine', 'Chemical', 'MESH:D001120', (4, 12))	('p53', 'Gene', (78, 81))	('histidine', 'Chemical', 'MESH:D006639', (164, 173))	('p53', 'Gene', '7157', (78, 81))	('arginine', 'Chemical', 'MESH:D001120', (152, 160))	('oligomerisation', 'MPA', (183, 198))
46982	24936644	Since wild-type p53 activity represses several components of glycolysis it is plausible that the dependency of p.R337H activity upon pH may facilitate the metabolic adaptation of cancer cells to aerobic glycolysis, a well-defined cancer hallmark.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('components', 'MPA', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('p53', 'Gene', (16, 19))	('p.R337H activity', 'Var', (111, 127))	('glycolysis', 'MPA', (61, 71))	('represses', 'NegReg', (29, 38))	('p53', 'Gene', '7157', (16, 19))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('metabolic adaptation', 'MPA', (155, 175))	('p.R337H', 'Mutation', 'rs121912664', (111, 118))	('cancer', 'Disease', (179, 185))	('facilitate', 'PosReg', (140, 150))
46984	24936644	Haplotype studies have shown that the mutation occurs on the same TP53 haplotype in all Brazilian p.R337H carriers, providing evidence of a founder effect.	('TP53', 'Gene', (66, 70))	('p.R337H', 'Mutation', 'rs121912664', (98, 105))	('mutation', 'Var', (38, 46))	('TP53', 'Gene', '7157', (66, 70))
46985	24936644	A mass newborn screening program conducted in the State of Parana (2005-2010) had tested 171,641 newborns, unselected for FHC, and 461 (0.27%) were found to be carriers of p.R337H and 11 of them (2.4%) had developed ACC.	('p.R337H', 'Var', (172, 179))	('FHC', 'Gene', '3949', (122, 125))	('p.R337H', 'Mutation', 'rs121912664', (172, 179))	('FHC', 'Gene', (122, 125))	('ACC', 'Phenotype', 'HP:0006744', (216, 219))
46986	24936644	Evaluation of FHC in mutation carriers reported that 27.4% had FHC matching LFL criteria and 41.6% had FHC that fitted no clinical criteria for a cancer syndrome.	('cancer syndrome', 'Disease', 'MESH:D009369', (146, 161))	('FHC', 'Gene', '3949', (14, 17))	('cancer syndrome', 'Disease', (146, 161))	('FHC', 'Gene', '3949', (63, 66))	('mutation', 'Var', (21, 29))	('FHC', 'Gene', '3949', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('FHC', 'Gene', (63, 66))	('FHC', 'Gene', (103, 106))	('FHC', 'Gene', (14, 17))
46987	24936644	Aside from this mass screening initiative, patients carrying the p.R337H mutation have been identified in families recruited in high risk cancer clinics and matching clinical definitions of LFS/LFL with ACC, soft tissue sarcoma, osteosarcoma, brain tumors and BC.	('cancer', 'Disease', (138, 144))	('brain tumors', 'Disease', (243, 255))	('p.R337H', 'Mutation', 'rs121912664', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('sarcoma', 'Disease', 'MESH:D012509', (220, 227))	('sarcoma', 'Disease', (220, 227))	('sarcoma', 'Disease', 'MESH:D012509', (234, 241))	('osteosarcoma', 'Phenotype', 'HP:0002669', (229, 241))	('LFS', 'Disease', (190, 193))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('sarcoma', 'Disease', (234, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('patients', 'Species', '9606', (43, 51))	('LFS', 'Disease', 'MESH:D016864', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (208, 227))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('BC', 'Phenotype', 'HP:0003002', (260, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (234, 241))	('p.R337H', 'Var', (65, 72))	('brain tumors', 'Disease', 'MESH:D001932', (243, 255))	('brain tumors', 'Phenotype', 'HP:0030692', (243, 255))	('osteosarcoma', 'Disease', (229, 241))	('ACC', 'Phenotype', 'HP:0006744', (203, 206))	('ACC', 'Disease', (203, 206))	('osteosarcoma', 'Disease', 'MESH:D012516', (229, 241))
46988	24936644	The p.R337H mutation has also been reported in individual cases with choroid plexus tumors (CPT), osteosarcoma and BC.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('osteosarcoma', 'Disease', 'MESH:D012516', (98, 110))	('reported', 'Reg', (35, 43))	('choroid plexus tumors', 'Phenotype', 'HP:0002190', (69, 90))	('p.R337H', 'Var', (4, 11))	('choroid plexus tumors', 'Disease', (69, 90))	('choroid plexus tumors', 'Disease', 'MESH:D016545', (69, 90))	('CPT', 'Phenotype', 'HP:0002190', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('p.R337H', 'Mutation', 'rs121912664', (4, 11))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('osteosarcoma', 'Disease', (98, 110))	('BC', 'Phenotype', 'HP:0003002', (115, 117))
46989	24936644	Compared with mutations that alter the DNA binding domain of p53, which represent over 90% of missense TP53 mutations in LFS/LFL families outside Brazil, the p.R337H mutation appears to be less penetrant.	('TP53', 'Gene', '7157', (103, 107))	('p.R337H', 'Mutation', 'rs121912664', (158, 165))	('mutations', 'Var', (108, 117))	('TP53', 'Gene', (103, 107))	('LFS', 'Disease', (121, 124))	('missense', 'Var', (94, 102))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('LFS', 'Disease', 'MESH:D016864', (121, 124))	('p.R337H', 'Var', (158, 165))
46990	24936644	BC represents 28.6% of all cancers in families with germline p.R337H mutation, compared to 27.2% and 27.8% in families with germline TP53 mutations from Northern America and in Western Europe, respectively.	('p.R337H', 'Var', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('p.R337H', 'Mutation', 'rs121912664', (61, 68))	('BC', 'Phenotype', 'HP:0003002', (0, 2))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('germline', 'Var', (52, 60))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))	('cancers', 'Disease', (27, 34))
46991	24936644	Interestingly, in two small-size case-control studies of BC-affected women recruited from southeastern Brazil, p.R337H was detected in 2.4% (3/123) and 0.5% (2/390) in BC cases but was not detected in the controls.	('BC', 'Phenotype', 'HP:0003002', (57, 59))	('BC-affected', 'Disease', (57, 68))	('p.R337H', 'Var', (111, 118))	('BC', 'Phenotype', 'HP:0003002', (168, 170))	('p.R337H', 'Mutation', 'rs121912664', (111, 118))	('women', 'Species', '9606', (69, 74))
46992	24936644	In the present study, we assessed the prevalence of germline p.R337H in women diagnosed with BC at different ages, with or without a documented FHC and recruited from different regions of Brazil.	('p.R337H', 'Var', (61, 68))	('BC', 'Phenotype', 'HP:0003002', (93, 95))	('FHC', 'Gene', '3949', (144, 147))	('p.R337H', 'Mutation', 'rs121912664', (61, 68))	('FHC', 'Gene', (144, 147))	('women', 'Species', '9606', (72, 77))
46995	24936644	The decision of studying TP53 p.R337H prevalence in families with the HBOC and HBCC phenotypes was influenced by recent reports describing germline mutations in TP53 among families with breast and/or ovarian and breast and/or colorectal cancer.	('p.R337H', 'Mutation', 'rs121912664', (30, 37))	('TP53', 'Gene', (161, 165))	('TP53', 'Gene', (25, 29))	('breast and/or', 'Disease', (212, 225))	('colorectal cancer', 'Disease', (226, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('breast and/or ovarian', 'Disease', (186, 207))	('colorectal cancer', 'Disease', 'MESH:D015179', (226, 243))	('breast and/or ovarian', 'Disease', 'MESH:D010051', (186, 207))	('BC', 'Phenotype', 'HP:0003002', (80, 82))	('p.R337H', 'Var', (30, 37))	('TP53', 'Gene', '7157', (161, 165))	('TP53', 'Gene', '7157', (25, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (226, 243))
47006	24936644	Genotyping of the tumour DNA was performed to assess loss of heterozygosity (LOH) at the p.R337H locus whenever possible.	('p.R337H', 'Mutation', 'rs121912664', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('loss', 'NegReg', (53, 57))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('p.R337H', 'Var', (89, 96))	('tumour', 'Disease', (18, 24))
47007	24936644	The presence of the Brazilian founder p.R337H haplotype was confirmed in the mutation-positive samples by ASO-PCR and nested-PCR analysing SNP 15 (rs1642785) and SNP28 (rs9894946) from a panel of 29 intragenic SNPs, as described elsewhere.	('p.R337H', 'Var', (38, 45))	('rs9894946', 'Var', (169, 178))	('p.R337H', 'Mutation', 'rs121912664', (38, 45))	('rs1642785', 'Mutation', 'rs1642785', (147, 156))	('rs9894946', 'Mutation', 'rs9894946', (169, 178))	('rs1642785', 'Var', (147, 156))
47015	24936644	Both probands were tested for germline BRCA1 and BRCA2 mutations and found to be negative.	('mutations', 'Var', (55, 64))	('BRCA2', 'Gene', '675', (49, 54))	('BRCA1', 'Gene', '672', (39, 44))	('BRCA1', 'Gene', (39, 44))	('BRCA2', 'Gene', (49, 54))
47016	24936644	Interestingly, however, a pathogenic BRCA2 mutation was found in a second-degree relative of the first proband (Figure 1).	('mutation', 'Var', (43, 51))	('BRCA2', 'Gene', (37, 42))	('BRCA2', 'Gene', '675', (37, 42))	('pathogenic', 'Reg', (26, 36))
47023	24936644	In two cases, only mutant alleles were detected, suggesting that these patients were constitutive mutant homozygotes or hemizygotes (CNV with LOH at the TP53 p.R337H locus cannot be excluded).	('p.R337H', 'Mutation', 'rs121912664', (158, 165))	('patients', 'Species', '9606', (71, 79))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', (153, 157))	('p.R337H', 'Var', (158, 165))
47024	24936644	In 23 of the TP53 p.R337H carriers available biological materials enabled mutation screening in all coding exons (2-11) of the gene and no other deleterious mutations were identified.	('TP53', 'Gene', (13, 17))	('mutation', 'Var', (74, 82))	('p.R337H', 'Var', (18, 25))	('p.R337H', 'Mutation', 'rs121912664', (18, 25))	('TP53', 'Gene', '7157', (13, 17))
47031	24936644	Given that BC represents the most common cancer in female TP53 mutation carriers, this study has been designed to determine whether, similar as ACC, p.R337H may be a risk factor for BC, the main sentinel cancer for adult LFS/LFL.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('p.R337H', 'Mutation', 'rs121912664', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('LFS', 'Disease', 'MESH:D016864', (221, 224))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('BC', 'Phenotype', 'HP:0003002', (182, 184))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BC', 'Phenotype', 'HP:0003002', (11, 13))	('p.R337H', 'Var', (149, 156))	('LFS', 'Disease', (221, 224))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('ACC', 'Phenotype', 'HP:0006744', (144, 147))	('risk', 'Reg', (166, 170))
47032	24936644	Studies in families reporting to high-risk cancer clinics have shown that BC represents 28.6% of all cancers diagnosed in p.R337H carriers.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('BC', 'Phenotype', 'HP:0003002', (74, 76))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (43, 49))	('cancers', 'Disease', (101, 108))	('p.R337H', 'Mutation', 'rs121912664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('p.R337H', 'Var', (122, 129))
47033	24936644	However, given the partial penetrance and the wide variations in the patterns of inherited cancer in carriers of this mutation, it is plausible that a significant proportion of BC in Brazilian women may occur in a background of germline p.R337H carriers.	('p.R337H', 'Var', (237, 244))	('BC', 'Phenotype', 'HP:0003002', (177, 179))	('p.R337H', 'Mutation', 'rs121912664', (237, 244))	('cancer', 'Disease', (91, 97))	('women', 'Species', '9606', (193, 198))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
47034	24936644	In this study, we have identified the germline TP53 mutation in a high percentage (8.6%) of BC-affected women unselected for a FHC.	('FHC', 'Gene', '3949', (127, 130))	('BC-affected', 'Disease', (92, 103))	('BC', 'Phenotype', 'HP:0003002', (92, 94))	('germline', 'Var', (38, 46))	('FHC', 'Gene', (127, 130))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))	('women', 'Species', '9606', (104, 109))
47037	24936644	On the other hand, even in a series of women with nosological definitions of BC syndromes other than LFS/LFL (group 1), p.R337H was detected at a significant frequency for a single mutation (of 3.4%).	('p.R337H', 'Var', (120, 127))	('BC', 'Phenotype', 'HP:0003002', (77, 79))	('LFS', 'Disease', 'MESH:D016864', (101, 104))	('p.R337H', 'Mutation', 'rs121912664', (120, 127))	('women', 'Species', '9606', (39, 44))	('BC syndromes', 'Disease', (77, 89))	('LFS', 'Disease', (101, 104))
47038	24936644	These findings identify p.R337H as the most common germline TP53 mutation associated with cancer described in any population and as the single most prevalent cancer-associated founder alleles identified to date.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('p.R337H', 'Var', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('p.R337H', 'Mutation', 'rs121912664', (24, 31))	('cancer', 'Disease', (90, 96))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('associated', 'Reg', (74, 84))
47039	24936644	The association between p.R337H and early, pre-menopausal BC is consistent with the tumour patterns observed in subjects who carry other germline mutant TP53 alleles.	('menopausal BC', 'Phenotype', 'HP:0008209', (47, 60))	('tumour', 'Disease', (84, 90))	('p.R337H', 'Var', (24, 31))	('TP53', 'Gene', '7157', (153, 157))	('BC', 'Phenotype', 'HP:0003002', (58, 60))	('p.R337H', 'Mutation', 'rs121912664', (24, 31))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', (153, 157))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
47043	24936644	Several studies have investigated the prevalence of germline TP53 mutations in non-Brazilian BC patients selected or not selected for a FHC, providing evidence that germline TP53 mutations are associated with a fraction of early BC diagnoses irrespective of a FHC.	('BC', 'Phenotype', 'HP:0003002', (93, 95))	('FHC', 'Gene', '3949', (136, 139))	('BC', 'Phenotype', 'HP:0003002', (229, 231))	('TP53', 'Gene', (174, 178))	('FHC', 'Gene', (260, 263))	('FHC', 'Gene', (136, 139))	('early BC diagnoses', 'Disease', (223, 241))	('associated with', 'Reg', (193, 208))	('patients', 'Species', '9606', (96, 104))	('mutations', 'Var', (179, 188))	('FHC', 'Gene', '3949', (260, 263))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('TP53', 'Gene', '7157', (174, 178))
47044	24936644	However, it should be noted that in all these studies, the mutations identified are different and primarily, if not exclusively, occur in the DNA-binding domain of the p53 protein.	('p53', 'Gene', (168, 171))	('p53', 'Gene', '7157', (168, 171))	('mutations', 'Var', (59, 68))	('occur', 'Reg', (129, 134))
47045	24936644	Therefore, our study is unique in demonstrating the prevalence of a single mutation in Brazilian patients with early-onset BC that is greater than the reported prevalence of all other TP53 mutations worldwide.	('early-onset BC', 'Disease', (111, 125))	('mutation', 'Var', (75, 83))	('BC', 'Phenotype', 'HP:0003002', (123, 125))	('TP53', 'Gene', '7157', (184, 188))	('TP53', 'Gene', (184, 188))	('patients', 'Species', '9606', (97, 105))
47047	24936644	However, early-onset BC, regardless of FH, could be considered a sentinel phenotype for the identification of subjects who are carriers of germline p.R337H in Brazilian patients.	('patients', 'Species', '9606', (169, 177))	('BC', 'Phenotype', 'HP:0003002', (21, 23))	('p.R337H', 'Var', (148, 155))	('FH', 'Disease', 'MESH:D006938', (39, 41))	('early-onset', 'Disease', (9, 20))	('p.R337H', 'Mutation', 'rs121912664', (148, 155))
47055	24936644	Another important question involves the mechanisms of breast carcinogenesis related to the p.R337H mutation because tumour genotyping revealed that loss of the wild-type allele (LOH) at the mutation locus is not common in these cases.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (54, 75))	('tumour', 'Disease', (116, 122))	('p.R337H', 'Var', (91, 98))	('breast carcinogenesis', 'Disease', (54, 75))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('p.R337H', 'Mutation', 'rs121912664', (91, 98))
47056	24936644	In contrast, in virtually all ACC and CPT of paediatric p.R337H carriers, LOH has been described at the mutation locus with the loss of the wild-type allele, consistent with the classic two-hit model proposed for carcinogenesis associated with tumour suppressor genes.	('LOH', 'Disease', (74, 77))	('carcinogenesis', 'Disease', 'MESH:D063646', (213, 227))	('ACC', 'Phenotype', 'HP:0006744', (30, 33))	('p.R337H', 'Var', (56, 63))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('p.R337H', 'Mutation', 'rs121912664', (56, 63))	('carcinogenesis', 'Disease', (213, 227))	('tumour', 'Disease', 'MESH:D009369', (244, 250))	('CPT', 'Phenotype', 'HP:0002190', (38, 41))	('tumour', 'Disease', (244, 250))
47057	24936644	Thus, the mechanism of p.R337H-associated carcinogenesis may depend on the tissue and the patients age when the tumour diagnosis was made.	('p.R337H', 'Mutation', 'rs121912664', (23, 30))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (112, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (42, 56))	('carcinogenesis', 'Disease', (42, 56))	('p.R337H-associated', 'Var', (23, 41))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('patients', 'Species', '9606', (90, 98))
47058	24936644	It should be kept in mind, however, that p.R337H is a oligomerization domain mutant, and not a DNA-binding domain mutation.	('oligomerization', 'MPA', (54, 69))	('p.R337H', 'Mutation', 'rs121912664', (41, 48))	('p.R337H', 'Var', (41, 48))
47060	24936644	This hypothesis may also account for the observation that tumor patterns in subjects who have inherited two mutant alleles are not more severe than in heterozygote carriers.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutant', 'Var', (108, 114))
47061	24936644	While the exact disease-causing mechanism of the p.R337H mutation remains elusive, alternative hypotheses should be considered, such as the influence of environmental changes onto pH and occurrence of constant, more subtle changes to oligomerisation in vivo without the requirement for drastic pH changes.	('oligomerisation', 'MPA', (234, 249))	('p.R337H', 'Var', (49, 56))	('p.R337H', 'Mutation', 'rs121912664', (49, 56))	('changes', 'Reg', (223, 230))
47062	24936644	In conclusion, the germline p.R337H may contribute to a significant proportion of the health burden associated with BC in Brazil, and its identification may have important implications for disease management and cancer risk counselling not only in childhood, due to the risk for ACC, but also in adults, due to its association with BC and possibly other adult onset tumors.	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('tumors', 'Disease', (366, 372))	('tumors', 'Disease', 'MESH:D009369', (366, 372))	('implications', 'Reg', (172, 184))	('p.R337H', 'Var', (28, 35))	('BC', 'Phenotype', 'HP:0003002', (116, 118))	('association', 'Reg', (315, 326))	('BC', 'Phenotype', 'HP:0003002', (332, 334))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('p.R337H', 'Mutation', 'rs121912664', (28, 35))	('child', 'Species', '9606', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('ACC', 'Phenotype', 'HP:0006744', (279, 282))	('tumors', 'Phenotype', 'HP:0002664', (366, 372))	('ACC', 'Disease', (279, 282))
47108	20525431	Using a fibrinogen/thrombin mixture as described above, we compared the results of orthotopic transplantion of either 1x105 or 3x105 tumorigenic bovine adrenocortical cells expressing SV40 TAg in female immunodeficient (RAG2-/-, gammac-/-) mice.	('fibrinogen', 'Gene', '2244', (8, 18))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('fibrinogen', 'Gene', (8, 18))	('mice', 'Species', '10090', (240, 244))	('SV40 TAg', 'Var', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('bovine', 'Species', '9913', (145, 151))	('immunodeficient', 'Disease', 'MESH:D007153', (203, 218))	('adrenocortical', 'Disease', (152, 166))	('tumor', 'Disease', (133, 138))	('immunodeficient', 'Disease', (203, 218))	('adrenocortical', 'Disease', 'MESH:D018268', (152, 166))
47136	19047010	Because of the low proliferative rate of primary human adrenocortical (pHAC) cells, a lentiviral system is ideal for transducing these cells with genes that may alter their characteristics or cause them to acquire benign or malignant tumorigenicity.	('tumor', 'Disease', (234, 239))	('alter', 'Reg', (161, 166))	('human', 'Species', '9606', (49, 54))	('characteristics', 'MPA', (173, 188))	('cause', 'Reg', (192, 197))	('adrenocortical', 'Disease', (55, 69))	('transducing', 'Var', (117, 128))	('adrenocortical', 'Disease', 'MESH:D018268', (55, 69))	('acquire', 'PosReg', (206, 213))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('genes', 'Var', (146, 151))
47142	19047010	The major questions that we wish to address are (a) the experimental determination of the potential of various genes to confer on normal human adrenocortical cells the ability to form a range of tissue structures (corresponding to nodules, adenomas, and carcinomas) and (b) the potential for progression of cells from a benign to a malignant state, i.e.	('carcinomas', 'Phenotype', 'HP:0030731', (254, 264))	('human', 'Species', '9606', (137, 142))	('carcinomas', 'Disease', (254, 264))	('carcinomas', 'Disease', 'MESH:D002277', (254, 264))	('adrenocortical', 'Disease', (143, 157))	('nodules', 'Disease', (231, 238))	('adrenocortical', 'Disease', 'MESH:D018268', (143, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('adenomas', 'Disease', 'MESH:D000236', (240, 248))	('genes', 'Var', (111, 116))	('adenomas', 'Disease', (240, 248))
47153	19047010	Previously, we showed that pBAC (primary bovine adrenocortical) and pHAC (primary human adrenocortical) cells co-transduced with retroviruses encoding RasG12V and SV40 T antigen can produce malignant tumors when transplanted in the subrenal capsule of immunodeficient mice.	('adrenocortical', 'Disease', 'MESH:D018268', (88, 102))	('malignant tumors', 'Disease', 'MESH:D018198', (190, 206))	('adrenocortical', 'Disease', (48, 62))	('bovine', 'Species', '9913', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('mice', 'Species', '10090', (268, 272))	('adrenocortical', 'Disease', 'MESH:D018268', (48, 62))	('human', 'Species', '9606', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('immunodeficient', 'Disease', 'MESH:D007153', (252, 267))	('adrenocortical', 'Disease', (88, 102))	('SV40 T', 'Var', (163, 169))	('RasG12V', 'Var', (151, 158))	('malignant tumors', 'Disease', (190, 206))	('produce', 'PosReg', (182, 189))	('immunodeficient', 'Disease', (252, 267))
47177	19047010	Thus, the model provides a way to investigate what genetic changes can convert normal adrenocortical cells into a benign, as well as a malignant, lesion, or produce a tissue structure with no detectable abnormalities.	('convert', 'Reg', (71, 78))	('adrenocortical', 'Disease', (86, 100))	('adrenocortical', 'Disease', 'MESH:D018268', (86, 100))	('produce', 'Reg', (157, 164))	('changes', 'Var', (59, 66))
47185	19047010	In summary, a suite of methods is in place that allows us to investigate the genetic modifications that may convert primary human or bovine adrenocortical cells to a fully malignant state or to various forms of benign lesions with properties of nodules or adenomas.	('bovine', 'Species', '9913', (133, 139))	('adrenocortical', 'Disease', 'MESH:D018268', (140, 154))	('adenomas', 'Disease', 'MESH:D000236', (256, 264))	('human', 'Species', '9606', (124, 129))	('adenomas', 'Disease', (256, 264))	('modifications', 'Var', (85, 98))	('convert', 'Reg', (108, 115))	('adrenocortical', 'Disease', (140, 154))
47189	30988622	The adverse effects of anti-PD-1 antibodies relating to autoimmunity are different from traditional chemotherapeutic drugs and may involve many organs including the endocrine system.	('involve', 'Reg', (131, 138))	('PD-1', 'Gene', (28, 32))	('PD-1', 'Gene', '5133', (28, 32))	('autoimmunity', 'Phenotype', 'HP:0002960', (56, 68))	('antibodies', 'Var', (33, 43))
47197	30988622	Although clinically effective, anti-PD-1 antibodies may cause organ- or tissue-specific immune reactions involving gastrointestinal tract, liver, lung, skin, endocrine system, etc.	('gastrointestinal tract', 'Disease', 'MESH:D004067', (115, 137))	('liver', 'CPA', (139, 144))	('lung', 'Disease', (146, 150))	('antibodies', 'Var', (41, 51))	('organ- or tissue-specific immune reactions', 'CPA', (62, 104))	('cause', 'Reg', (56, 61))	('endocrine', 'CPA', (158, 167))	('PD-1', 'Gene', (36, 40))	('PD-1', 'Gene', '5133', (36, 40))	('gastrointestinal tract', 'Disease', (115, 137))
47201	30988622	Laboratory tests indicated the diagnosis of adrenocorticotropic hormone (ACTH) deficiency, probably caused by nivolumab-induced hypophysitis.	('ACTH', 'Gene', '5443', (73, 77))	('deficiency', 'Var', (79, 89))	('adrenocorticotropic hormone', 'Gene', (44, 71))	('adrenocorticotropic hormone', 'Gene', '5443', (44, 71))	('hypophysitis', 'Disease', 'MESH:D000072659', (128, 140))	('ACTH', 'Gene', (73, 77))	('nivolumab', 'Chemical', 'MESH:D000077594', (110, 119))	('hypophysitis', 'Disease', (128, 140))
47221	30988622	After oxygen inhalation and treatments of dopamine, antibiotic drug, low molecular weight heparin, sodium, and glucocorticoid, his symptoms of fever, dyspnea, and somnolence alleviated, with SaO2 >95%.	('dyspnea', 'Phenotype', 'HP:0002094', (150, 157))	('low', 'Var', (69, 72))	('sodium', 'Chemical', 'MESH:D012964', (99, 105))	('dyspnea', 'Disease', (150, 157))	('dopamine', 'Chemical', 'MESH:D004298', (42, 50))	('oxygen', 'Chemical', 'MESH:D010100', (6, 12))	('fever', 'Disease', 'MESH:D005334', (143, 148))	('fever', 'Disease', (143, 148))	('SaO2', 'Chemical', '-', (191, 195))	('dyspnea', 'Disease', 'MESH:D004417', (150, 157))	('somnolence', 'Disease', (163, 173))	('alleviated', 'NegReg', (174, 184))	('heparin', 'Chemical', 'MESH:D006493', (90, 97))	('somnolence', 'Disease', 'MESH:D006970', (163, 173))	('fever', 'Phenotype', 'HP:0001945', (143, 148))
47250	30988622	Anti-PD-1 antibodies also showed excellent effects on other malignancies including advanced non-small-cell lung cancer (NSCLC), melanoma, renal-cell carcinoma (RCC), bladder cancer, head and neck cancer, and hepatocellular carcinoma.	('renal-cell carcinoma', 'Disease', (138, 158))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('head and neck cancer', 'Disease', 'MESH:D006258', (182, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('hepatocellular carcinoma', 'Disease', (208, 232))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('renal-cell carcinoma', 'Disease', 'MESH:C538614', (138, 158))	('bladder cancer', 'Disease', (166, 180))	('bladder cancer', 'Disease', 'MESH:D001749', (166, 180))	('antibodies', 'Var', (10, 20))	('bladder cancer', 'Phenotype', 'HP:0009725', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('SCLC', 'Phenotype', 'HP:0030357', (121, 125))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('renal-cell carcinoma', 'Phenotype', 'HP:0005584', (138, 158))	('non-small-cell lung cancer', 'Disease', (92, 118))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (208, 232))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (92, 118))	('head and neck cancer', 'Phenotype', 'HP:0012288', (182, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('malignancies', 'Disease', (60, 72))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('effects', 'Reg', (43, 50))	('PD-1', 'Gene', (5, 9))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (208, 232))	('PD-1', 'Gene', '5133', (5, 9))	('NSCLC', 'Disease', (120, 125))	('melanoma', 'Disease', (128, 136))
47253	30988622	Although exhibiting impressive efficacy, anti-PD-1 antibodies may manifest unique side effects related to autoimmune responses involving various organs including endocrine system.	('antibodies', 'Var', (51, 61))	('PD-1', 'Gene', '5133', (46, 50))	('PD-1', 'Gene', (46, 50))
47258	30988622	The clinical characteristics of hypophysitis induced by anti-CTLA-4 antibodies are different from that induced by anti-PD-1 antibodies.	('PD-1', 'Gene', '5133', (119, 123))	('CTLA-4', 'Gene', '1493', (61, 67))	('antibodies', 'Var', (68, 78))	('hypophysitis', 'Disease', 'MESH:D000072659', (32, 44))	('CTLA-4', 'Gene', (61, 67))	('hypophysitis', 'Disease', (32, 44))	('PD-1', 'Gene', (119, 123))
47269	30988622	The pathological differences between hypophysitis induced by anti-CTLA-4 antibodies and anti-PD-1 antibodies are unclear.	('CTLA-4', 'Gene', (66, 72))	('hypophysitis', 'Disease', 'MESH:D000072659', (37, 49))	('PD-1', 'Gene', '5133', (93, 97))	('CTLA-4', 'Gene', '1493', (66, 72))	('antibodies', 'Var', (73, 83))	('PD-1', 'Gene', (93, 97))	('hypophysitis', 'Disease', (37, 49))
47270	30988622	CTLA-4 antigen is found expressed on pituitary endocrine cells, and high expression of CTLA-4 is associated with severe hypophysitis through type II and type IV hypersensitivities in cancer patients treated with anti-CTLA-4 antibodies.	('hypophysitis', 'Disease', 'MESH:D000072659', (120, 132))	('hypersensitivities', 'Disease', 'MESH:D004342', (161, 179))	('cancer', 'Disease', (183, 189))	('CTLA-4', 'Gene', (0, 6))	('hypophysitis', 'Disease', (120, 132))	('patients', 'Species', '9606', (190, 198))	('high expression', 'Var', (68, 83))	('CTLA-4', 'Gene', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('associated with', 'Reg', (97, 112))	('CTLA-4', 'Gene', '1493', (217, 223))	('CTLA-4', 'Gene', '1493', (0, 6))	('CTLA-4', 'Gene', '1493', (87, 93))	('CTLA-4', 'Gene', (217, 223))	('hypersensitivities', 'Disease', (161, 179))
47302	28738949	On univariate Cox regression, transfusion, stage IV, hormonal hypersecretion, and adjuvant therapy were associated with decreased RFS.	('decreased', 'NegReg', (120, 129))	('transfusion', 'Var', (30, 41))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('RFS', 'MPA', (130, 133))
47332	28738949	Transfusion was associated with more advanced stage disease (stage IV: 45.6% vs 24.4%, P = 0.007), and transfused patients compared to nontransfused were more likely to have an open surgical approach (98.2% vs 68.5%, P < 0.001), other organs resected during surgery (78.9% vs 36.3%, P < 0.001), inferior vena cava involvement or thrombus (24.6% vs 5.4%, P = 0.002), intraoperative tumor rupture (20.0% vs 6.0%, P = 0.03), and larger tumor size (15.8 vs 10.2 cm, P < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('intraoperative tumor rupture', 'Disease', (366, 394))	('tumor', 'Disease', 'MESH:D009369', (433, 438))	('tumor', 'Disease', (433, 438))	('inferior vena cava involvement', 'Phenotype', 'HP:0031041', (295, 325))	('tumor', 'Disease', (381, 386))	('intraoperative tumor rupture', 'Disease', 'MESH:D012421', (366, 394))	('tumor', 'Disease', 'MESH:D009369', (381, 386))	('inferior vena cava involvement or thrombus', 'Disease', 'MESH:C563013', (295, 337))	('advanced', 'Disease', (37, 45))	('transfused', 'Var', (103, 113))	('Transfusion', 'Var', (0, 11))	('patients', 'Species', '9606', (114, 122))	('inferior vena cava involvement or thrombus', 'Disease', (295, 337))	('open surgical approach', 'CPA', (177, 199))	('tumor', 'Phenotype', 'HP:0002664', (433, 438))
47333	28738949	Additionally, transfused patients had higher operative blood loss (2000 vs 250 mL, P < 0.001), longer operative time (312 vs 181 minutes, P < 0.001), and longer hospital stay (8 vs 5 days, P < 0.001).	('blood loss', 'Disease', 'MESH:D006473', (55, 65))	('blood loss', 'Disease', (55, 65))	('transfused', 'Var', (14, 24))	('patients', 'Species', '9606', (25, 33))	('higher', 'PosReg', (38, 44))
47337	28738949	On univariate Cox regression, transfusion, stage IV disease, hormonal hypersecretion, and postoperative therapy were found to be associated with decreased RFS (Table 2).	('transfusion', 'Var', (30, 41))	('RFS', 'MPA', (155, 158))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('decreased', 'NegReg', (145, 154))	('stage IV disease', 'Disease', (43, 59))
47341	28738949	These data corroborate other studies that have reported transfusion to be associated with worse oncological outcomes in a number of other cancers.	('transfusion', 'Var', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
47344	28738949	The mainstay of treatment is complete surgical resection, and although its efficacy is minimal, current practice guidelines recommend adjuvant mitotane therapy for high-risk disease: defined as increased tumor size, positive margins, high grade, and capsular rupture.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('positive', 'Var', (216, 224))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mitotane', 'Chemical', 'MESH:D008939', (143, 151))	('high', 'Var', (234, 238))	('increased', 'PosReg', (194, 203))	('tumor', 'Disease', (204, 209))
47356	28738949	Another study on pancreatic adenocarcinoma demonstrated that postoperative transfusion and >2 units of intraoperative transfusion were independent predictors of decreased disease-free survival, further supporting a possible role of timing and volume.	('disease-free survival', 'CPA', (171, 192))	('pancreatic adenocarcinoma', 'Disease', (17, 42))	('postoperative transfusion', 'Var', (61, 86))	('decreased', 'NegReg', (161, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (17, 42))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (17, 42))
47361	28738949	This study demonstrated an association between transfusion and decreased RFS and OS for patients undergoing resection of ACC even when accounting for other known poor prognostic factors.	('ACC', 'Phenotype', 'HP:0006744', (121, 124))	('ACC', 'Disease', (121, 124))	('RFS', 'MPA', (73, 76))	('decreased', 'NegReg', (63, 72))	('transfusion', 'Var', (47, 58))	('patients', 'Species', '9606', (88, 96))
47364	28738949	In conclusion, allogenic red blood cell transfusion is independently associated with decreased RFS and OS in patients undergoing curative-intent resection for ACC, even after accounting for other adverse clinico-pathologic factors.	('decreased', 'NegReg', (85, 94))	('patients', 'Species', '9606', (109, 117))	('blood cell transfusion', 'Phenotype', 'HP:0011888', (29, 51))	('RFS', 'MPA', (95, 98))	('ACC', 'Phenotype', 'HP:0006744', (159, 162))	('allogenic', 'Var', (15, 24))
47372	29622661	These cells expressed cell-surface MSC markers (CD44, CD90, CD105 and CD166) but did not express the haematopoietic, lymphocytic or HLA-DR markers.	('CD166', 'Gene', '214', (70, 75))	('CD90', 'Gene', '7070', (54, 58))	('CD44', 'Gene', '960', (48, 52))	('CD90', 'Gene', (54, 58))	('CD166', 'Gene', (70, 75))	('CD105', 'Var', (60, 65))	('CD44', 'Gene', (48, 52))
47379	29622661	Bone marrow-derived MSCs exhibit the ability to adhere to plastic dishes in a standard culture condition and express a set of phenotypic markers on their surface, including CD44, CD90, CD105 and CD166.	('CD44', 'Gene', '960', (173, 177))	('CD105', 'Var', (185, 190))	('adhere', 'CPA', (48, 54))	('CD44', 'Gene', (173, 177))	('CD166', 'Gene', (195, 200))	('CD166', 'Gene', '214', (195, 200))	('CD90', 'Gene', (179, 183))	('CD90', 'Gene', '7070', (179, 183))
47429	29622661	Flow cytometry immunoprofiling demonstrated that cell populations in both MGPM and CM harboured cells expressing mesenchymal markers CD44, CD90, CD105 and CD166 but lacked expression of the haematopoetic and lymphocytic markers: CD19, CD45 and HLA-DR (Fig.	('CD44', 'Gene', '960', (133, 137))	('CD19', 'Gene', (229, 233))	('CD166', 'Gene', '214', (155, 160))	('lacked', 'NegReg', (165, 171))	('CD105', 'Var', (145, 150))	('CD90', 'Gene', '7070', (139, 143))	('CD44', 'Gene', (133, 137))	('CD90', 'Gene', (139, 143))	('CD45', 'Gene', (235, 239))	('expression', 'MPA', (172, 182))	('CD19', 'Gene', '930', (229, 233))	('CD45', 'Gene', '5788', (235, 239))	('CD166', 'Gene', (155, 160))
47431	29622661	There was a non-significant trend towards a higher mean fluorescence intensity for DAX1 among cells seeded in MGPM compared to CM.	('DAX1', 'Gene', '190', (83, 87))	('higher', 'PosReg', (44, 50))	('MGPM', 'Var', (110, 114))	('fluorescence intensity', 'MPA', (56, 78))	('DAX1', 'Gene', (83, 87))
47446	29622661	OCT4 expression was significantly higher in cells harvested in MGPM (P = 0.024, 95% CI for mean fold-change difference: 1.07-8.71).	('expression', 'MPA', (5, 15))	('MGPM', 'Var', (63, 67))	('higher', 'PosReg', (34, 40))	('OCT4', 'Gene', '5460', (0, 4))	('OCT4', 'Gene', (0, 4))
47474	29406000	Many of the ACTs develop in the context of a TP53 gene mutation, which causes Li-Fraumeni syndrome.	('TP53', 'Gene', (45, 49))	('causes', 'Reg', (71, 77))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (78, 98))	('mutation', 'Var', (55, 63))	('TP53', 'Gene', '7157', (45, 49))	('Li-Fraumeni syndrome', 'Disease', (78, 98))
47520	29406000	In rare occasions, ACTH-dependent CS may result from ectopic ACTH and/or CRH production, where the source of the ectopic hormone production is located in the lungs, the liver, the thymus, the pancreas or other neuroendocrine tumors.	('ectopic', 'Var', (53, 60))	('pancreas', 'Disease', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('ACTH', 'Gene', (19, 23))	('CRH', 'Gene', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('ACTH', 'Gene', '5443', (19, 23))	('CS', 'Phenotype', 'HP:0003118', (34, 36))	('ACTH', 'Gene', (61, 65))	('result from', 'Reg', (41, 52))	('CRH', 'Gene', '1392', (73, 76))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (210, 231))	('ACTH', 'Gene', '5443', (61, 65))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (210, 231))	('pancreas', 'Disease', 'MESH:D010190', (192, 200))	('neuroendocrine tumors', 'Disease', (210, 231))
47522	29406000	TP53 gene mutations are the most common cause of adrenocortical tumors and are identified in almost 70% of ACTs.	('TP53', 'Gene', '7157', (0, 4))	('cause', 'Reg', (40, 45))	('TP53', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (49, 70))	('mutations', 'Var', (10, 19))	('adrenocortical tumors', 'Disease', (49, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
47523	29406000	This percentage is higher in pediatric patients with ACTs from Southern Brazil, where a point mutation of TP53 gene (Arg337His) has been reported in 78 - 97% of cases.	('patients', 'Species', '9606', (39, 47))	('TP53', 'Gene', (106, 110))	('Arg337His', 'Var', (117, 126))	('TP53', 'Gene', '7157', (106, 110))	('Arg337His', 'SUBSTITUTION', 'None', (117, 126))
47524	29406000	Germline TP53 gene mutations may cause Li-Fraumeni syndrome (LFS) which is an autosomal dominant inherited syndrome predisposing to various cancers.	('cause', 'Reg', (33, 38))	('LFS', 'Disease', (61, 64))	('autosomal dominant inherited syndrome', 'Disease', (78, 115))	('mutations', 'Var', (19, 28))	('LFS', 'Disease', 'MESH:D016864', (61, 64))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (39, 59))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('autosomal dominant inherited syndrome', 'Disease', 'None', (78, 115))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Li-Fraumeni syndrome', 'Disease', (39, 59))
47526	29406000	The penetrance of the germline mutations is variable and it has been suggested that any child with ACT should be assessed for TP53 mutations, irrespective of the family history.	('mutations', 'Var', (131, 140))	('child', 'Species', '9606', (88, 93))	('TP53', 'Gene', (126, 130))	('TP53', 'Gene', '7157', (126, 130))
47529	29406000	MAS results from postzygotic somatic mutations of the GNAS gene, which codes for the Gsa subunit of the G-protein coupled receptors, causing their constitutive activation which leads to elevated levels of the intracellular cAMP, irrespective of the ligand concentration.	('MAS', 'Disease', 'MESH:D005357', (0, 3))	('levels of the intracellular cAMP', 'MPA', (195, 227))	('MAS', 'Disease', (0, 3))	('GNAS', 'Gene', (54, 58))	('activation', 'PosReg', (160, 170))	('Gsa', 'Gene', (85, 88))	('mutations', 'Var', (37, 46))	('GNAS', 'Gene', '2778', (54, 58))	('cAMP', 'Chemical', '-', (223, 227))	('Gsa', 'Gene', '2778', (85, 88))	('constitutive', 'MPA', (147, 159))	('elevated', 'PosReg', (186, 194))
47534	29406000	Additional defects of the cAMP/PKA pathway include mutations in the PRKAR1A gene, which codes for the regulatory subunit R1a of the PKA, and are the leading cause of Carney Complex (CNC).	('cAMP/PKA pathway', 'Pathway', (26, 42))	('cause', 'Reg', (157, 162))	('mutations', 'Var', (51, 60))	('Carney Complex', 'Disease', (166, 180))	('PRKAR1A', 'Gene', (68, 75))	('cAMP', 'Chemical', '-', (26, 30))	('PRKAR1A', 'Gene', '5573', (68, 75))
47538	29406000	Defects of the 11p15 locus involving IGF2, H9 and CDKI genes, either in the somatic state in the adrenal tumors or identified as germline defects, as in patients with Beckwith-Wiedemann syndrome (BWS), have also been associated with the presence of adrenal dependent CS in the neonatal period.	('CDKI', 'Gene', (50, 54))	('patients', 'Species', '9606', (153, 161))	('associated', 'Reg', (217, 227))	('adrenal tumors', 'Disease', (97, 111))	('CD', 'Chemical', 'MESH:D002104', (50, 52))	('IGF2', 'Gene', '3481', (37, 41))	('Beckwith-Wiedemann syndrome', 'Disease', (167, 194))	('Defects', 'Var', (0, 7))	('IGF2', 'Gene', (37, 41))	('BWS', 'Disease', 'MESH:D001506', (196, 199))	('adrenal dependent CS', 'Disease', (249, 269))	('BWS', 'Disease', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (167, 194))	('adrenal tumor', 'Phenotype', 'HP:0100631', (97, 110))	('adrenal tumors', 'Disease', 'MESH:D000310', (97, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('CS', 'Phenotype', 'HP:0003118', (267, 269))
47544	29406000	Other genetic defects that cause ACTs and CS, include MEN1 gene mutations causing multiple endocrine neoplasia type 1 (MEN1), APC gene defects causing familial adenomatous polyposis (FAP), and others such as SF1, PRKACA, PDE11A, PDE8B, and ARMC5 genetic changes.	('FAP', 'Disease', (183, 186))	('PRKACA', 'Gene', (213, 219))	('PDE11A', 'Gene', '50940', (221, 227))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (91, 110))	('FAP', 'Disease', 'MESH:C567782', (183, 186))	('MEN1', 'Gene', (119, 123))	('MEN1', 'Gene', '4221', (54, 58))	('PDE8B', 'Gene', (229, 234))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (160, 181))	('APC', 'Disease', 'MESH:D011125', (126, 129))	('APC', 'Disease', (126, 129))	('SF1', 'Gene', (208, 211))	('ARMC5', 'Gene', (240, 245))	('mutations', 'Var', (64, 73))	('MEN1', 'Gene', (54, 58))	('genetic defects', 'Disease', (6, 21))	('multiple endocrine neoplasia type 1', 'Gene', (82, 117))	('multiple endocrine neoplasia type 1', 'Gene', '4221', (82, 117))	('genetic defects', 'Disease', 'MESH:D030342', (6, 21))	('SF1', 'Gene', '7536', (208, 211))	('PRKACA', 'Gene', '5566', (213, 219))	('CS', 'Phenotype', 'HP:0003118', (42, 44))	('familial adenomatous polyposis', 'Disease', (151, 181))	('defects', 'Var', (135, 142))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (151, 181))	('PDE8B', 'Gene', '8622', (229, 234))	('PDE11A', 'Gene', (221, 227))	('neoplasia', 'Phenotype', 'HP:0002664', (101, 110))	('ARMC5', 'Gene', '79798', (240, 245))	('MEN1', 'Gene', '4221', (119, 123))	('causing', 'Reg', (143, 150))
47550	29406000	On the contrary, pituitary blastomas represent the majority of the ACTH-dependent CS in infancy and most of these patients present with a germiline or somatic DICER1 gene mutation.	('mutation', 'Var', (171, 179))	('CS', 'Phenotype', 'HP:0003118', (82, 84))	('ACTH', 'Gene', (67, 71))	('DICER1', 'Gene', (159, 165))	('DICER1', 'Gene', '23405', (159, 165))	('ACTH', 'Gene', '5443', (67, 71))	('pituitary blastomas', 'Disease', 'MESH:D018202', (17, 36))	('patients', 'Species', '9606', (114, 122))	('pituitary blastomas', 'Disease', (17, 36))
47552	29406000	Germline mutations of the DICER1 gene cause the pleuropulmonary blastoma familial tumor and dysplasia syndrome, which involves the presence of multiple benign and malignant tumors in addition to pituitary blastomas.	('Germline mutations', 'Var', (0, 18))	('pleuropulmonary blastoma familial tumor', 'Disease', 'MESH:C537516', (48, 87))	('dysplasia syndrome', 'Disease', 'MESH:D005348', (92, 110))	('dysplasia syndrome', 'Disease', (92, 110))	('DICER1', 'Gene', '23405', (26, 32))	('cause', 'Reg', (38, 43))	('pituitary blastomas', 'Disease', 'MESH:D018202', (195, 214))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('DICER1', 'Gene', (26, 32))	('pleuropulmonary blastoma familial tumor', 'Disease', (48, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (48, 72))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('malignant tumors', 'Disease', (163, 179))	('pituitary blastomas', 'Disease', (195, 214))	('malignant tumors', 'Disease', 'MESH:D018198', (163, 179))
47588	29406000	Given the possibility of pituitary hormone deficiencies as a result of the manipulation of the pituitary gland and their long-term effects in the developing child, referral to a center with neurosurgeon specialized in pediatric tumors is highly recommended.	('pituitary hormone deficiencies', 'Disease', 'MESH:C580003', (25, 55))	('pediatric tumors', 'Disease', 'MESH:D063766', (218, 234))	('pituitary hormone deficiencies', 'Disease', (25, 55))	('manipulation', 'Var', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('pediatric tumors', 'Disease', (218, 234))	('child', 'Species', '9606', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))
47602	29406000	Neonatal CS may present as part of a genetic syndrome, such as Li-Fraumeni syndrome (LFS), McCune-Albright syndrome (MAS), Beckwith-Wiedemann syndrome (BWS), and DICER1 mutations.	('CS', 'Phenotype', 'HP:0003118', (9, 11))	('BWS', 'Disease', 'MESH:D001506', (152, 155))	('BWS', 'Disease', (152, 155))	('mutations', 'Var', (169, 178))	('Li-Fraumeni syndrome', 'Disease', (63, 83))	('MAS', 'Disease', (117, 120))	('Beckwith-Wiedemann syndrome', 'Disease', (123, 150))	('McCune-Albright syndrome', 'Disease', (91, 115))	('LFS', 'Disease', 'MESH:D016864', (85, 88))	('MAS', 'Disease', 'MESH:D005357', (117, 120))	('DICER1', 'Gene', (162, 168))	('genetic syndrome', 'Disease', (37, 53))	('DICER1', 'Gene', '23405', (162, 168))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (91, 115))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (63, 83))	('genetic syndrome', 'Disease', 'MESH:D030342', (37, 53))	('LFS', 'Disease', (85, 88))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (123, 150))
47764	27489549	Consistently, MC2R antagonists were found to partially inhibit in vitro the cortisol response evoked by GIP in perifused BMAH samples.	('MC2R', 'Gene', (14, 18))	('cortisol response evoked by GIP', 'MPA', (76, 107))	('antagonists', 'Var', (19, 30))	('cortisol', 'Chemical', 'MESH:D006854', (76, 84))	('inhibit', 'NegReg', (55, 62))
47768	27489549	The disease is caused in most patients by germline inactivating mutations that affect the PRKAR1A gene, resulting in constitutive activation of protein kinase A (PKA) in adrenocortical cells.	('protein', 'Enzyme', (144, 151))	('PRKAR1A', 'Gene', '5573', (90, 97))	('activation', 'PosReg', (130, 140))	('constitutive', 'MPA', (117, 129))	('germline inactivating mutations', 'Var', (42, 73))	('adrenocortical', 'Disease', (170, 184))	('adrenocortical', 'Disease', 'MESH:D018268', (170, 184))	('patients', 'Species', '9606', (30, 38))	('PRKAR1A', 'Gene', (90, 97))
47769	27489549	Since MC2R are positively coupled to the cAMP/PKA pathway, it can be considered that PRKAR1A mutations partly mimic the action of ACTH on adrenal steroidogenic cells.	('PRKAR1A', 'Gene', (85, 92))	('mutations', 'Var', (93, 102))	('cAMP/PKA pathway', 'Pathway', (41, 57))	('PRKAR1A', 'Gene', '5573', (85, 92))	('cAMP', 'Chemical', '-', (41, 45))	('steroid', 'Chemical', 'MESH:D013256', (146, 153))
47771	27489549	It is now well established that the development of macronodular adrenal hyperplasia requires inactivation of the two ARMC5 alleles, respectively, by the first germline mutation and a secondary somatic genetic event.	('macronodular adrenal hyperplasia', 'Disease', (51, 83))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (64, 83))	('inactivation', 'Var', (93, 105))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (51, 83))	('ARMC5', 'Gene', (117, 122))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (51, 83))
47772	27489549	Surprisingly, inactivation of ARMC5 expression in the human adrenocortical cell line H295R, which reproduces the molecular defects observed in adrenocortical cells of patients with BMAH, results in a decrease in expression of steroidogenic enzymes.	('adrenocortical', 'Disease', (60, 74))	('adrenocortical', 'Disease', 'MESH:D018268', (60, 74))	('adrenocortical', 'Disease', (143, 157))	('adrenocortical', 'Disease', 'MESH:D018268', (143, 157))	('steroid', 'Chemical', 'MESH:D013256', (226, 233))	('H295R', 'CellLine', 'CVCL:0458', (85, 90))	('ARMC5', 'Gene', (30, 35))	('expression', 'MPA', (212, 222))	('patients', 'Species', '9606', (167, 175))	('inactivation', 'Var', (14, 26))	('steroidogenic enzymes', 'MPA', (226, 247))	('human', 'Species', '9606', (54, 59))	('decrease', 'NegReg', (200, 208))
47774	27489549	We hypothesize that ARMC5 mutations may alter differentiation and/or separation of the adrenogonadal primordium leading to the presence of pseudo-gonadal cells in the adrenal areas.	('presence of pseudo-gonadal cells', 'Phenotype', 'HP:0010459', (127, 159))	('alter', 'Reg', (40, 45))	('rat', 'Species', '10116', (73, 76))	('mutations', 'Var', (26, 35))	('differentiation', 'CPA', (46, 61))	('ARMC5', 'Gene', (20, 25))	('pseudo-gonadal cells', 'CPA', (139, 159))	('separation of the adrenogonadal primordium', 'CPA', (69, 111))
47788	24832650	Mutations responsible for a number of familial cancer syndromes (Beckwith-Wiedemann syndrome, Li-Fraumeni syndrome, Multiple Endocrine Neoplasia type 1) have also been shown to present as somatic mutations in sporadic ACC.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (94, 114))	('Neoplasia', 'Phenotype', 'HP:0002664', (135, 144))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (65, 92))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (38, 63))	('Li-Fraumeni syndrome', 'Disease', (94, 114))	('sporadic ACC', 'Disease', (209, 221))	('Mutations', 'Var', (0, 9))	('Multiple Endocrine Neoplasia type 1', 'Gene', '4221', (116, 151))	('Multiple Endocrine Neoplasia type 1', 'Gene', (116, 151))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Endocrine Neoplasia', 'Phenotype', 'HP:0100568', (125, 144))	('Beckwith-Wiedemann syndrome', 'Disease', (65, 92))	('familial cancer syndromes', 'Disease', (38, 63))
47789	24832650	Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome that results from a germline mutation in the TP53 gene located on chromosome 17p13.	('TP53', 'Gene', (122, 126))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('results from', 'Reg', (82, 94))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (27, 52))	('autosomal dominant cancer', 'Disease', (27, 52))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('TP53', 'Gene', '7157', (122, 126))	('germline mutation', 'Var', (97, 114))
47791	24832650	Germline TP53 mutations have been identified in 70% of families with Li-Fraumeni syndrome.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (69, 89))	('Li-Fraumeni syndrome', 'Disease', (69, 89))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('identified', 'Reg', (34, 44))	('mutations', 'Var', (14, 23))
47793	24832650	Germline TP53 mutations have also been observed in 50%-80% of children and 30%-35% of adults with apparent sporadic ACC.	('children', 'Species', '9606', (62, 70))	('observed', 'Reg', (39, 47))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
47794	24832650	However, a recent study has demonstrated that TP53 germline mutations may be rare in adult patients, and approximates a prevalence of 13% in patients under 40 years old with ACC.	('patients', 'Species', '9606', (91, 99))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('patients', 'Species', '9606', (141, 149))	('germline mutations', 'Var', (51, 69))
47795	24832650	Inactivating somatic mutations in TP53 have also been observed in sporadic ACC in exons 5-8 and exons 2-11.	('TP53', 'Gene', (34, 38))	('observed', 'Reg', (54, 62))	('ACC', 'Disease', (75, 78))	('TP53', 'Gene', '7157', (34, 38))	('Inactivating somatic mutations', 'Var', (0, 30))
47796	24832650	A specific germline mutation (Arg337His) located on exon 10, affecting residues on the C-terminal domain of the p53 protein responsible for oligomerization was identified in 77%-97% of children with benign or malignant sporadic ACT and 13.5% of adults with sporadic ACT in southern Brazil, and was associated with an unfavorable prognosis in adults, but not in children with ACT.	('affecting', 'Reg', (61, 70))	('children', 'Species', '9606', (361, 369))	('Arg337His', 'Var', (30, 39))	('Arg337His', 'SUBSTITUTION', 'None', (30, 39))	('p53', 'Gene', (112, 115))	('p53', 'Gene', '7157', (112, 115))	('children', 'Species', '9606', (185, 193))
47797	24832650	The presence of inactivating TP53 mutations in ACC was associated with worse prognosis on transcriptome analysis.	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('inactivating', 'Reg', (16, 28))
47800	24832650	Defects in the imprinted 11p15 region increase IGF-2 expression in patients with Beckwith-Wiedemann syndrome.	('increase', 'PosReg', (38, 46))	('Beckwith-Wiedemann syndrome', 'Disease', (81, 108))	('p15', 'Gene', (27, 30))	('patients', 'Species', '9606', (67, 75))	('increase IGF-2', 'Phenotype', 'HP:0030269', (38, 52))	('Defects', 'Var', (0, 7))	('p15', 'Gene', '1030', (27, 30))	('expression', 'MPA', (53, 63))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (81, 108))	('IGF-2', 'Gene', (47, 52))	('IGF-2', 'Gene', '3481', (47, 52))
47806	24832650	MEN1 is caused by an inactivating mutation in the menin gene, a tumor suppressor located on chromosome 11q13.	('MEN1', 'Gene', '4221', (0, 4))	('tumor', 'Disease', (64, 69))	('caused by', 'Reg', (8, 17))	('menin', 'Gene', '4221', (50, 55))	('inactivating mutation', 'Var', (21, 42))	('menin', 'Gene', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('MEN1', 'Gene', (0, 4))
47809	24832650	While somatic mutations of MEN1 are very rare in ACT, LOH at 11q13 has been described in over 90% of informative ACCs and 20% of ACAs.	('MEN1', 'Gene', '4221', (27, 31))	('LOH at 11q13', 'Var', (54, 66))	('MEN1', 'Gene', (27, 31))	('ACCs', 'Gene', (113, 117))	('ACCs', 'Gene', '84680', (113, 117))
47812	24832650	The net effect of disruption of this complex is stabilization of beta-catenin, which translocates to the nucleus to enhance gene expression through interactions with various transcription factors and coactivators.	('enhance', 'PosReg', (116, 123))	('beta-catenin', 'Gene', '1499', (65, 77))	('interactions', 'Interaction', (148, 160))	('disruption', 'Var', (18, 28))	('gene expression', 'MPA', (124, 139))	('beta-catenin', 'Gene', (65, 77))
47815	24832650	This suggests that beta-catenin mutation maybe an early step in a common multistep progression of ACA and ACC.	('ACA', 'Disease', (98, 101))	('beta-catenin', 'Gene', (19, 31))	('ACC', 'Disease', (106, 109))	('beta-catenin', 'Gene', '1499', (19, 31))	('mutation', 'Var', (32, 40))
47816	24832650	The presence of activating beta-catenin mutations in ACC was associated with worse prognosis on transcriptome analysis.	('beta-catenin', 'Gene', '1499', (27, 39))	('mutations', 'Var', (40, 49))	('beta-catenin', 'Gene', (27, 39))	('activating', 'PosReg', (16, 26))	('ACC', 'Gene', (53, 56))
47817	24832650	Carney Complex is an autosomal dominant disorder that results from inactivating mutations in the protein kinase A regulatory subunity (PRKAR1A) gene, that encodes the type 1alpha regulatory subunit of cAMP dependent PKA.	('results from', 'Reg', (54, 66))	('autosomal dominant disorder', 'Disease', (21, 48))	('PRKAR1A', 'Gene', (135, 142))	('PRKAR1A', 'Gene', '5573', (135, 142))	('inactivating mutations', 'Var', (67, 89))	('Carney Complex', 'Disease', (0, 14))	('cAMP', 'Chemical', '-', (201, 205))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (21, 48))
47819	24832650	Isolated PPNAD and CNC have both been associated with inactivating mutations in PRKAR1A located on chromosome 17q22-24.	('Isolated PPNAD', 'Disease', (0, 14))	('CNC', 'Disease', (19, 22))	('associated', 'Reg', (38, 48))	('PRKAR1A', 'Gene', '5573', (80, 87))	('inactivating mutations', 'Var', (54, 76))	('PRKAR1A', 'Gene', (80, 87))
47820	24832650	Somatic inactivating mutations or allele losses of PRKAR1A locus are also seen in sporadic ACA and ACC.	('allele losses', 'Var', (34, 47))	('ACC', 'Disease', (99, 102))	('PRKAR1A', 'Gene', (51, 58))	('seen', 'Reg', (74, 78))	('PRKAR1A', 'Gene', '5573', (51, 58))
47821	24832650	Gardner syndrome is an autosomal dominant disorder that results from mutations in the APC gene on chromosome 5q21.	('mutations', 'Var', (69, 78))	('Gardner syndrome', 'Disease', (0, 16))	('APC', 'Gene', (86, 89))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (23, 50))	('APC', 'Gene', '324', (86, 89))	('Gardner syndrome', 'Disease', 'MESH:D005736', (0, 16))	('results from', 'Reg', (56, 68))	('autosomal dominant disorder', 'Disease', (23, 50))
47824	24832650	We recently demonstrated that somatic KCNJ5 mutations occur frequently in aldosterone producing ACA, but have not been identified in other ACTs.	('KCNJ5', 'Gene', '3762', (38, 43))	('mutations', 'Var', (44, 53))	('aldosterone producing ACA', 'Disease', (74, 99))	('KCNJ5', 'Gene', (38, 43))
47827	24832650	However studies suggest that a significant number of distinct genetic alterations in adenomas are also seen in carcinomas, and cases have been reported which demonstrate both benign and malignant pathological areas of the same tumor.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('seen', 'Reg', (103, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('tumor', 'Disease', (227, 232))	('carcinomas', 'Disease', 'MESH:D002277', (111, 121))	('carcinomas', 'Disease', (111, 121))	('adenomas', 'Disease', 'MESH:D000236', (85, 93))	('adenomas', 'Disease', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('genetic alterations', 'Var', (62, 81))
47829	24832650	suggested that activation of a protooncogene on chromosome 4 may be an early event, with progression from ACA to ACC involving activation of oncogenes on chromosomes 5 and 12 and inactivation of tumor suppressor genes on chromosome arms 1p and 17p.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('inactivation', 'Var', (179, 191))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('activation', 'PosReg', (127, 137))	('ACA', 'Disease', (106, 109))	('oncogenes', 'Gene', (141, 150))
47830	24832650	Studies also suggest a positive correlation between the number of CGH alterations and tumor size.	('alterations', 'Var', (70, 81))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))
47854	24832650	There is a growing body of evidence to suggest that epigenetic abnormalities including DNA methylation and histone modification play a key role, in conjunction with genetic modifications, to cause altered patterns of gene expression, resulting in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('DNA methylation', 'Var', (87, 102))	('resulting in', 'Reg', (234, 246))	('tumor', 'Disease', (247, 252))	('patterns of gene expression', 'MPA', (205, 232))	('epigenetic abnormalities', 'Var', (52, 76))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('histone', 'Protein', (107, 114))	('cause', 'Reg', (191, 196))
47855	24832650	DNA hypermethylation of the promoter cytosine in cytosine phosphate guanine islands (CpG islands) causing downstream gene silencing has been shown to be intimately involved in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cytosine', 'Chemical', 'MESH:D003596', (37, 45))	('tumor', 'Disease', (176, 181))	('involved', 'Reg', (164, 172))	('cytosine', 'Chemical', 'MESH:D003596', (49, 57))	('silencing', 'NegReg', (122, 131))	('cytosine phosphate guanine', 'Chemical', '-', (49, 75))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('hypermethylation', 'Var', (4, 20))
47856	24832650	Altered DNA methylation of the H19 promoter has been shown to be involved in the abnormal expression of both H19 and IGF-2 genes in adrenocortical carcinomas.	('H19', 'Gene', '283120', (31, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('IGF-2', 'Gene', (117, 122))	('adrenocortical carcinomas', 'Disease', (132, 157))	('H19', 'Gene', (31, 34))	('IGF-2', 'Gene', '3481', (117, 122))	('Altered', 'Var', (0, 7))	('involved', 'Reg', (65, 73))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (132, 157))	('expression', 'MPA', (90, 100))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (132, 156))	('H19', 'Gene', '283120', (109, 112))	('H19', 'Gene', (109, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (132, 157))
47860	24832650	miRNAs regulate approximately one third of coding genes, therefore changes in miRNA expression may be associated with cancer development and progression.	('cancer', 'Disease', (118, 124))	('changes', 'Var', (67, 74))	('associated', 'Reg', (102, 112))	('miRNA expression', 'MPA', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('progression', 'CPA', (141, 152))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
47872	24832650	Mutations found in familial cancer syndromes have contributed significantly to our understanding of the pathogenesis of sporadic ACTs.	('familial cancer syndromes', 'Disease', 'MESH:D009386', (19, 44))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Mutations', 'Var', (0, 9))	('familial cancer syndromes', 'Disease', (19, 44))	('sporadic ACTs', 'Disease', (120, 133))
47900	24790306	Immunoreactivities with P450scc and P450c17 were seen in almost all tumor cells in 1996; reactivities with P450c21, 3beta HSD, P450c11, and DHEA-ST, though seen, were not as prevalent (Fig.	('tumor', 'Disease', (68, 73))	('P450c11', 'Gene', '1584', (127, 134))	('P450c17', 'Gene', (36, 43))	('P450c21', 'Var', (107, 114))	('P450scc', 'Gene', (24, 31))	('P450scc', 'Gene', '1583', (24, 31))	('DHEA-ST', 'Gene', '6822', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('3beta HSD', 'Gene', (116, 125))	('3beta HSD', 'Gene', '3283', (116, 125))	('P450c11', 'Gene', (127, 134))	('DHEA-ST', 'Gene', (140, 147))	('P450c17', 'Gene', '1586', (36, 43))
47917	24012403	Knowledge of mutations in sporadic cancer, such as BRAF in thyroid cancer, has led to rapid progress in small-molecule kinase inhibitor strategies.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('rat', 'Species', '10116', (138, 141))	('cancer', 'Disease', (67, 73))	('thyroid cancer', 'Disease', 'MESH:D013964', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('thyroid cancer', 'Phenotype', 'HP:0002890', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (35, 41))	('thyroid cancer', 'Disease', (59, 73))
47930	24012403	Apart from its physiologic role in thyroid differentiation, growth, and function, the MAPK pathway can also contribute to development of thyroid cancer by aberrant activation at several points.	('thyroid cancer', 'Disease', 'MESH:D013964', (137, 151))	('MAPK pathway', 'Pathway', (86, 98))	('aberrant', 'Var', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('activation', 'PosReg', (164, 174))	('thyroid cancer', 'Phenotype', 'HP:0002890', (137, 151))	('thyroid cancer', 'Disease', (137, 151))	('contribute', 'Reg', (108, 118))
47931	24012403	In sporadic and hereditary medullary thyroid cancer (MTC), mutant RET activates RAS, causing constitutive MAPK signaling, while mutations in both RET and RAS are common in follicular thyroid cancer.	('thyroid cancer', 'Phenotype', 'HP:0002890', (183, 197))	('mutant', 'Var', (59, 65))	('RET', 'Gene', (66, 69))	('thyroid cancer', 'Disease', 'MESH:D013964', (37, 51))	('RET', 'Gene', (146, 149))	('causing', 'Reg', (85, 92))	('activates', 'PosReg', (70, 79))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (27, 51))	('thyroid cancer', 'Phenotype', 'HP:0002890', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('MTC', 'Phenotype', 'HP:0002865', (53, 56))	('follicular thyroid cancer', 'Disease', (172, 197))	('constitutive MAPK signaling', 'MPA', (93, 120))	('RAS', 'Protein', (80, 83))	('RET', 'Gene', '5979', (66, 69))	('follicular thyroid cancer', 'Disease', 'MESH:C572845', (172, 197))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('RET', 'Gene', '5979', (146, 149))	('thyroid cancer', 'Disease', (37, 51))	('thyroid cancer', 'Disease', 'MESH:D013964', (183, 197))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (172, 197))
47932	24012403	Downstream in the pathway, mutation in the BRAF serine/threonine kinase has emerged as the most common genetic abnormality in papillary thyroid cancer (PTC), and is also present in anaplastic thyroid cancer (ATC).	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (126, 150))	('mutation', 'Var', (27, 35))	('anaplastic thyroid cancer', 'Disease', (181, 206))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PTC', 'Gene', (152, 155))	('PTC', 'Phenotype', 'HP:0002895', (152, 155))	('PTC', 'Gene', '5979', (152, 155))	('ATC', 'Phenotype', 'HP:0011779', (208, 211))	('papillary thyroid cancer', 'Disease', (126, 150))	('anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (181, 206))	('abnormality in papillary', 'Phenotype', 'HP:0025445', (111, 135))	('genetic abnormality', 'Disease', 'MESH:D030342', (103, 122))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (181, 206))	('BRAF', 'Gene', (43, 47))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (126, 150))	('thyroid cancer', 'Phenotype', 'HP:0002890', (136, 150))	('genetic abnormality', 'Disease', (103, 122))	('thyroid cancer', 'Phenotype', 'HP:0002890', (192, 206))
47933	24012403	In total, mutation in some element of the MAPK pathway is present in over 70% of thyroid cancers, marking this as the central cellular control element in thyroid oncogenesis.	('present', 'Reg', (58, 65))	('thyroid cancers', 'Disease', 'MESH:D013964', (81, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('mutation', 'Var', (10, 18))	('MAPK', 'Gene', (42, 46))	('thyroid cancer', 'Phenotype', 'HP:0002890', (81, 95))	('thyroid cancers', 'Disease', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
47941	24012403	In 1993, linkage narrowed the MEN2A locus to a small area near the RET proto-oncogene, and RET was identified as the causative gene in MEN2A and FMTC, with two groups reporting heterozygous germline mutations in affected patients, but not in normal controls and unaffected family members.	('RET', 'Gene', (91, 94))	('MEN2A', 'Gene', '5979', (30, 35))	('patients', 'Species', '9606', (221, 229))	('MTC', 'Phenotype', 'HP:0002865', (146, 149))	('RET', 'Gene', '5979', (67, 70))	('MEN2A', 'Gene', '5979', (135, 140))	('RET', 'Gene', '5979', (91, 94))	('MEN2A', 'Gene', (135, 140))	('germline', 'Var', (190, 198))	('RET', 'Gene', (67, 70))	('MEN2A', 'Gene', (30, 35))
47942	24012403	Description of RET mutations in MEN2B kindreds followed soon thereafter.	('mutations', 'Var', (19, 28))	('RET', 'Gene', '5979', (15, 18))	('MEN2B', 'Gene', (32, 37))	('RET', 'Gene', (15, 18))	('MEN2B', 'Gene', '5979', (32, 37))
47943	24012403	Genetic tests to presymptomatically identify affected individuals in families with MEN2 and FMTC became more directed after identification of these mutations.	('MEN2', 'Gene', (83, 87))	('mutations', 'Var', (148, 157))	('MTC', 'Phenotype', 'HP:0002865', (93, 96))	('MEN', 'Species', '9606', (83, 86))
47944	24012403	became the first to use a genetic test to recommend prophylactic surgery, performing total thyroidectomy and parathyroidectomy in asymptomatic patients within MEN2A families found to carry RET mutations.	('RET', 'Gene', '5979', (189, 192))	('rat', 'Species', '10116', (111, 114))	('MEN2A', 'Gene', '5979', (159, 164))	('patients', 'Species', '9606', (143, 151))	('mutations', 'Var', (193, 202))	('MEN2A', 'Gene', (159, 164))	('RET', 'Gene', (189, 192))
47947	24012403	reported that MEN2A families with parathyroid hyperplasia and pheochromocytoma carried the C634R RET mutation much more frequently than families lacking these disease features.	('pheochromocytoma', 'Disease', 'MESH:D010673', (62, 78))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (62, 78))	('carried', 'Reg', (79, 86))	('MEN2A', 'Gene', (14, 19))	('MEN2A', 'Gene', '5979', (14, 19))	('parathyroid hyperplasia', 'Disease', (34, 57))	('RET', 'Gene', '5979', (97, 100))	('parathyroid hyperplasia', 'Phenotype', 'HP:0008208', (34, 57))	('C634R', 'Var', (91, 96))	('C634R', 'Mutation', 'rs75076352', (91, 96))	('RET', 'Gene', (97, 100))	('pheochromocytoma', 'Disease', (62, 78))	('parathyroid hyperplasia', 'Disease', 'MESH:D006965', (34, 57))
47949	24012403	This revealed that codon 634 mutations accounted for 85% of MEN2A cases, and that the C634R mutation was significantly more likely to lead to hyperparathyroidism and pheochromocytoma.	('MEN2A', 'Gene', (60, 65))	('lead to', 'Reg', (134, 141))	('hyperparathyroidism and pheochromocytoma', 'Disease', 'MESH:D010673', (142, 182))	('C634R', 'Mutation', 'rs75076352', (86, 91))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (166, 182))	('codon 634 mutations', 'Var', (19, 38))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (142, 161))	('C634R', 'Var', (86, 91))	('MEN2A', 'Gene', '5979', (60, 65))
47950	24012403	Families with the less aggressive FMTC had mutations in several codons including 634, but none carried the C634R mutation.	('634', 'Var', (81, 84))	('C634R', 'Mutation', 'rs75076352', (107, 112))	('MTC', 'Phenotype', 'HP:0002865', (35, 38))	('mutations', 'Var', (43, 52))	('C634R', 'Var', (107, 112))
47951	24012403	Finally, 75 of 79 MEN2B families had the same M918T mutation.	('MEN2B', 'Gene', (18, 23))	('M918T', 'Mutation', 'rs74799832', (46, 51))	('MEN2B', 'Gene', '5979', (18, 23))	('M918T', 'Var', (46, 51))
47953	24012403	For the highest risk MEN2B mutations, thyroidectomy is recommended as soon as possible and ideally before 1 month of age, with central node dissection recommended if surgery is delayed beyond 1 year of age (Table 2).	('MEN2B', 'Gene', (21, 26))	('mutations', 'Var', (27, 36))	('MEN2B', 'Gene', '5979', (21, 26))
47955	24012403	Certain MEN2A mutations, such as C609Y, lead to MTC usually only after age 20-40, and thyroidectomy between ages 5 and 10 for these patients can be acceptable under the ATA guidelines.	('C609Y', 'Mutation', 'rs77939446', (33, 38))	('lead to', 'Reg', (40, 47))	('MTC', 'Phenotype', 'HP:0002865', (48, 51))	('MTC', 'Disease', (48, 51))	('C609Y', 'Var', (33, 38))	('MEN2A', 'Gene', (8, 13))	('MEN2A', 'Gene', '5979', (8, 13))	('patients', 'Species', '9606', (132, 140))
47956	24012403	Still, rare examples of MTC in very young patients with mutations thought to confer lower risk exist, and therefore early thyroidectomy (before age 5) remains a reasonable option for these groups, .With the high sensitivity and specificity of genetic testing, and the fact that 98% of MEN2 patients have a known RET mutation, genetic testing is now the standard to determine prophylactic surgical therapy in MEN2.	('MEN', 'Species', '9606', (408, 411))	('patients', 'Species', '9606', (290, 298))	('MTC', 'Phenotype', 'HP:0002865', (24, 27))	('RET', 'Gene', (312, 315))	('MEN2', 'Gene', (285, 289))	('mutation', 'Var', (316, 324))	('MEN', 'Species', '9606', (285, 288))	('patients', 'Species', '9606', (42, 50))	('RET', 'Gene', '5979', (312, 315))
47957	24012403	RET mutations are found with high frequency in sporadic MTC.	('mutations', 'Var', (4, 13))	('RET', 'Gene', '5979', (0, 3))	('MTC', 'Phenotype', 'HP:0002865', (56, 59))	('RET', 'Gene', (0, 3))
47958	24012403	A study of 100 sporadic MTC patients with 10 year median follow-up identified somatic RET mutations in 43%, and found that their presence strongly correlated with lymph node and distant metastases (70 and 30% vs. 26 and 12% in RET+ and - patients, p<0.0001).	('RET', 'Gene', '5979', (86, 89))	('mutations', 'Var', (90, 99))	('RET', 'Gene', '5979', (227, 230))	('metastases', 'Disease', (186, 196))	('MTC', 'Phenotype', 'HP:0002865', (24, 27))	('correlated with', 'Reg', (147, 162))	('metastases', 'Disease', 'MESH:D009362', (186, 196))	('RET', 'Gene', (86, 89))	('RET', 'Gene', (227, 230))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (238, 246))
47959	24012403	Of patients with mutations, 79% had the same M918T mutation found in most MEN2B cases.	('M918T', 'Var', (45, 50))	('patients', 'Species', '9606', (3, 11))	('MEN2B', 'Gene', (74, 79))	('MEN2B', 'Gene', '5979', (74, 79))	('mutations', 'Var', (17, 26))	('M918T', 'Mutation', 'rs74799832', (45, 50))
47960	24012403	Sporadic RET mutations also independently predicted worse outcomes, with significantly reduced disease-free, and overall survival.	('mutations', 'Var', (13, 22))	('reduced', 'NegReg', (87, 94))	('RET', 'Gene', '5979', (9, 12))	('overall survival', 'CPA', (113, 129))	('disease-free', 'CPA', (95, 107))	('RET', 'Gene', (9, 12))
47965	24012403	In 2002, a genome-level screen for cancer-related mutations found activating somatic BRAF mutations in many human tumor cell types, including 59% of melanoma lines studied.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mutations', 'Var', (90, 99))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('melanoma', 'Disease', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BRAF', 'Gene', (85, 89))	('activating', 'PosReg', (66, 76))	('tumor', 'Disease', (114, 119))	('human', 'Species', '9606', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
47966	24012403	Although over 30 BRAF mutations have been described, a single base-pair substitution (T1799A) replacing valine with glutamate at residue 600 (V600E) is both the most common and most potent mutation, leading to 700-fold increased kinase activity, constitutive activation of the MAPK pathway, transformation of cells in vitro, and growth of tumors in mice in vivo Soon after the initial report of BRAF mutations in human cancer, the V600E mutation was reported in a high percentage of human papillary thyroid cancers.	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (489, 513))	('kinase activity', 'MPA', (229, 244))	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (489, 514))	('cancer', 'Disease', 'MESH:D009369', (419, 425))	('increased', 'PosReg', (219, 228))	('tumors', 'Phenotype', 'HP:0002664', (339, 345))	('thyroid cancer', 'Phenotype', 'HP:0002890', (499, 513))	('T1799A', 'Mutation', 'rs113488022', (86, 92))	('cancer', 'Disease', (507, 513))	('papillary thyroid cancers', 'Disease', 'MESH:D000077273', (489, 514))	('human', 'Species', '9606', (483, 488))	('human', 'Species', '9606', (413, 418))	('cancer', 'Phenotype', 'HP:0002664', (507, 513))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('valine with glutamate at residue 600', 'Mutation', 'rs113488022', (104, 140))	('tumors', 'Disease', (339, 345))	('papillary thyroid cancers', 'Disease', (489, 514))	('V600E', 'Mutation', 'rs113488022', (431, 436))	('cancers', 'Phenotype', 'HP:0002664', (507, 514))	('mutations', 'Var', (22, 31))	('MAPK pathway', 'Pathway', (277, 289))	('cancer', 'Disease', (419, 425))	('mice', 'Species', '10090', (349, 353))	('V600E', 'Mutation', 'rs113488022', (142, 147))	('activation', 'PosReg', (259, 269))	('cancer', 'Disease', 'MESH:D009369', (507, 513))	('tumors', 'Disease', 'MESH:D009369', (339, 345))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('V600E', 'Var', (431, 436))	('to 7', 'Species', '1214577', (207, 211))
47967	24012403	found the BRAF mutation in 28/78 (36%) of adult, non-radiation exposed PTC specimens, while RET and RAS mutations accounted for only 16% of cases each.	('mutation', 'Var', (15, 23))	('PTC', 'Gene', (71, 74))	('PTC', 'Gene', '5979', (71, 74))	('RET', 'Gene', (92, 95))	('PTC', 'Phenotype', 'HP:0002895', (71, 74))	('BRAF', 'Gene', (10, 14))	('RET', 'Gene', '5979', (92, 95))
47968	24012403	Concurrently, another group reported the V600E mutation in 24/35 (69%) of PTC specimens in a screen of 476 samples from diverse types of primary tumors.	('primary tumors', 'Disease', (137, 151))	('PTC', 'Gene', (74, 77))	('primary tumors', 'Disease', 'MESH:D009369', (137, 151))	('V600E', 'Var', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('PTC', 'Gene', '5979', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('PTC', 'Phenotype', 'HP:0002895', (74, 77))	('V600E', 'Mutation', 'rs113488022', (41, 46))
47969	24012403	BRAF mutation was determined to occur more frequently in tall cell and less commonly in follicular variants of PTC, and a recent meta-analysis established a 45% overall prevalence of the V600E mutation in papillary thyroid cancer (1,118 of 2,470 published cases).	('PTC', 'Gene', (111, 114))	('PTC', 'Gene', '5979', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('V600E', 'Mutation', 'rs113488022', (187, 192))	('PTC', 'Phenotype', 'HP:0002895', (111, 114))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (205, 229))	('thyroid cancer', 'Phenotype', 'HP:0002890', (215, 229))	('V600E', 'Var', (187, 192))	('papillary thyroid cancer', 'Disease', (205, 229))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (205, 229))
47970	24012403	While medullary thyroid cancers do not carry BRAF mutations, 24-40% of anaplastic thyroid cancers do, and BRAF mutations are common in poorly differentiated, recurrent, and radioiodine-resistant thyroid cancers.	('common', 'Reg', (125, 131))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (6, 30))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('anaplastic thyroid cancers', 'Phenotype', 'HP:0011779', (71, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (16, 30))	('anaplastic thyroid cancer', 'Disease', (71, 96))	('thyroid cancers', 'Disease', (16, 31))	('mutations', 'Var', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('thyroid cancers', 'Disease', 'MESH:D013964', (195, 210))	('thyroid cancer', 'Phenotype', 'HP:0002890', (195, 209))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('thyroid cancers', 'Disease', 'MESH:D013964', (82, 97))	('medullary thyroid cancers', 'Phenotype', 'HP:0002865', (6, 31))	('anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (71, 96))	('thyroid cancers', 'Disease', 'MESH:D013964', (16, 31))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (71, 96))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('radioiodine', 'Chemical', 'MESH:C000614965', (173, 184))	('thyroid cancers', 'Disease', (195, 210))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (82, 96))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('thyroid cancers', 'Disease', (82, 97))
47971	24012403	Determination of the crystal structure of mutant BRAF protein showed how the V600E mutation, nestled between activating phosphorylation sites at T599 and S602, disrupts the hydrophobic interactions that stabilize the inactive form of the protein, and mimics the conformation of a phosphorylated state.	('stabilize', 'MPA', (203, 212))	('S602', 'Var', (154, 158))	('inactive form', 'MPA', (217, 230))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('hydrophobic interactions', 'MPA', (173, 197))	('protein', 'Protein', (238, 245))	('V600E', 'Var', (77, 82))	('BRAF', 'Gene', (49, 53))	('disrupts', 'NegReg', (160, 168))
47972	24012403	This change creates a pseudo-phosphorylated conformation and leads to constitutive pathway activation and tumorigenic behavior.	('constitutive pathway', 'Pathway', (70, 90))	('pseudo-phosphorylated conformation', 'MPA', (22, 56))	('activation', 'PosReg', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('creates', 'Reg', (12, 19))	('tumor', 'Disease', (106, 111))	('change', 'Var', (5, 11))
47973	24012403	Consistent with this model, invasiveness of thyroid cancer cell cultures expressing BRAF V600E was found to require signaling via the MAP kinase pathway.	('MAP', 'Pathway', (134, 137))	('invasiveness of thyroid cancer', 'Disease', 'MESH:D013964', (28, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('BRAF V600E', 'Var', (84, 94))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('invasiveness of thyroid cancer', 'Disease', (28, 58))	('thyroid cancer', 'Phenotype', 'HP:0002890', (44, 58))
47974	24012403	Thyroid cells with the V600E mutation also show reduced markers of differentiation.	('V600E', 'Mutation', 'rs113488022', (23, 28))	('reduced', 'NegReg', (48, 55))	('V600E', 'Var', (23, 28))	('markers of differentiation', 'CPA', (56, 82))
47975	24012403	Using inducible BRAF V600E mutant rat thyroid cell lines, Mitsutake and colleagues showed suppressed expression of genes necessary for iodine handling and thyroid differentiation, such as thyrotropin receptor (TSHR), sodium-iodine symporter (NIS), and thyroglobulin (Tg), as well as increased chromosomal instability.	('mutant', 'Var', (27, 33))	('increased', 'PosReg', (283, 292))	('V600E', 'Mutation', 'rs113488022', (21, 26))	('thyroglobulin', 'Gene', '24826', (252, 265))	('BRAF', 'Gene', (16, 20))	('TSHR', 'Gene', (210, 214))	('sodium-iodine', 'Chemical', '-', (217, 230))	('NIS', 'Chemical', 'MESH:D009532', (242, 245))	('thyrotropin receptor', 'Gene', (188, 208))	('chromosomal instability', 'CPA', (293, 316))	('iodine', 'Chemical', 'MESH:D007455', (135, 141))	('iodine', 'Chemical', 'MESH:D007455', (224, 230))	('TSHR', 'Gene', '25360', (210, 214))	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (283, 316))	('thyroglobulin', 'Gene', (252, 265))	('thyrotropin receptor', 'Gene', '25360', (188, 208))	('rat', 'Species', '10116', (34, 37))	('suppressed', 'NegReg', (90, 100))	('expression', 'MPA', (101, 111))
47979	24012403	Similarly, Liu showed that while a MEK kinase inhibitor led to reduced invasiveness and cell cycle arrest in thyroid lines harboring BRAF mutations, this effect was potentiated by concurrent blockade of the NF-kappaB pathway.	('invasiveness', 'Disease', (71, 83))	('NF-kappaB', 'Gene', '4790', (207, 216))	('NF-kappaB', 'Gene', (207, 216))	('reduced', 'NegReg', (63, 70))	('MEK', 'Gene', (35, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (88, 105))	('MEK', 'Gene', '5609', (35, 38))	('BRAF', 'Gene', (133, 137))	('blockade', 'NegReg', (191, 199))	('potentiated', 'PosReg', (165, 176))	('cell cycle arrest', 'CPA', (88, 105))	('invasiveness', 'Disease', 'MESH:D009362', (71, 83))	('mutations', 'Var', (138, 147))
47981	24012403	In contrast, BRAF V600E is always active, and forms homo or heterodimers in the absence of RAS signaling, and can additionally activate MEK as a monomer.	('homo', 'MPA', (52, 56))	('BRAF V600E', 'Var', (13, 23))	('activate', 'PosReg', (127, 135))	('MEK', 'Gene', (136, 139))	('MEK', 'Gene', '5609', (136, 139))	('heterodimers', 'MPA', (60, 72))	('V600E', 'Mutation', 'rs113488022', (18, 23))
47982	24012403	Monomers and homodimers of mutant BRAF as well as heterodimers with wild-type RAF proteins may participate in MEK-independent signaling with the PI3K/AKT/mTOR, NF-kappaB, and other pathways.	('mTOR', 'Gene', (154, 158))	('NF-kappaB', 'Gene', (160, 169))	('mutant', 'Var', (27, 33))	('BRAF', 'Gene', (34, 38))	('AKT', 'Gene', '207', (150, 153))	('participate', 'Reg', (95, 106))	('MEK', 'Gene', (110, 113))	('MEK', 'Gene', '5609', (110, 113))	('NF-kappaB', 'Gene', '4790', (160, 169))	('AKT', 'Gene', (150, 153))	('mTOR', 'Gene', '2475', (154, 158))
47984	24012403	As data accumulated to elucidate the molecular effects of the BRAF V600E mutation in thyroid cancer, clinical data has similarly accrued to support a picture of uncontrolled pro-malignant signaling.	('V600E', 'Mutation', 'rs113488022', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('thyroid cancer', 'Phenotype', 'HP:0002890', (85, 99))	('thyroid cancer', 'Disease', (85, 99))	('V600E', 'Var', (67, 72))	('BRAF', 'Gene', (62, 66))	('thyroid cancer', 'Disease', 'MESH:D013964', (85, 99))
47986	24012403	In one study, 76% (24/34) of BRAF V600E positive (BRAF+) PTC primary tumors had positive sentinel lymph nodes, while only 17% (12/69) of BRAF V600E negative (BRAF-) primary tumors did.	('V600E', 'Mutation', 'rs113488022', (142, 147))	('primary tumors', 'Disease', 'MESH:D009369', (61, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('primary tumors', 'Disease', (165, 179))	('PTC', 'Gene', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('primary tumors', 'Disease', 'MESH:D009369', (165, 179))	('PTC', 'Phenotype', 'HP:0002895', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('PTC', 'Gene', '5979', (57, 60))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('primary tumors', 'Disease', (61, 75))	('BRAF V600E positive', 'Var', (29, 48))
47987	24012403	In another series, correlation of outcomes with retrospective BRAF testing of 190 PTC fine-needle aspiration (FNA) specimens showed that patients with BRAF+ FNAs had higher rates of unfavorable pathologic characteristics, with more frequent recurrence (36 vs. 12%), more lymph node metastases (39 vs. 19%), and more capsular invasion (29 vs. 16%) than BRAF- FNAs.	('BRAF+ FNAs', 'Var', (151, 161))	('rat', 'Species', '10116', (173, 176))	('metastases', 'Disease', 'MESH:D009362', (282, 292))	('PTC', 'Gene', (82, 85))	('patients', 'Species', '9606', (137, 145))	('aspiration', 'Phenotype', 'HP:0002835', (98, 108))	('PTC', 'Phenotype', 'HP:0002895', (82, 85))	('PTC', 'Gene', '5979', (82, 85))	('rat', 'Species', '10116', (102, 105))	('recurrence', 'CPA', (241, 251))	('metastases', 'Disease', (282, 292))	('capsular invasion', 'CPA', (316, 333))
47990	24012403	Overall, BRAF positivity was associated with significantly higher relative risk (RR) of tumor recurrence (24.9 vs. 12.6%, RR 1.93), lymph node metastasis (54.1% vs. 36.8%, RR 1.32), stage III or IV disease (35.4% vs. 19.6%, RR 1.70), and extrathyroidal extension (46.2% vs. 23.6%, RR 1.71) compared to BRAF- PTCs.	('stage III', 'Disease', (182, 191))	('lymph node metastasis', 'CPA', (132, 153))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('PTC', 'Gene', (308, 311))	('PTC', 'Gene', '5979', (308, 311))	('positivity', 'Var', (14, 24))	('IV disease', 'Disease', 'MESH:D020432', (195, 205))	('PTC', 'Phenotype', 'HP:0002895', (308, 311))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('IV disease', 'Disease', (195, 205))	('rat', 'Species', '10116', (241, 244))	('tumor', 'Disease', (88, 93))	('extrathyroidal extension', 'CPA', (238, 262))
47991	24012403	Testing for BRAF mutation informs risk estimates for resected thyroid cancer, and inclusion of BRAF status modestly improves performance of the AMES, MACIS, TNM, and ATA risk scores.	('BRAF status', 'Gene', (95, 106))	('BRAF', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('thyroid cancer', 'Disease', 'MESH:D013964', (62, 76))	('mutation', 'Var', (17, 25))	('improves', 'PosReg', (116, 124))	('TNM', 'Gene', (157, 160))	('TNM', 'Gene', '10178', (157, 160))	('thyroid cancer', 'Phenotype', 'HP:0002890', (62, 76))	('thyroid cancer', 'Disease', (62, 76))
47994	24012403	While knowledge of mutations in resected cancers improves prognostication, some have sought to apply molecular testing to prospective surgical decision-making.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (19, 28))	('improves', 'PosReg', (49, 57))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('prognostication', 'MPA', (58, 73))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
47995	24012403	Based on their results correlating BRAF+ FNAs with higher recurrence risk even after correcting for unfavorable tumor characteristics, Xing et al.	('tumor', 'Disease', (112, 117))	('BRAF+ FNAs', 'Var', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))
48000	24012403	One study (n=51) found that BRAF positivity in excised tumors did not correlate with nodal metastases, but did not test for BRAF preoperatively and had a low rate of BRAF mutation (29%).	('nodal metastases', 'Disease', (85, 101))	('rat', 'Species', '10116', (135, 138))	('mutation', 'Var', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('nodal metastases', 'Disease', 'MESH:D009362', (85, 101))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('rat', 'Species', '10116', (158, 161))	('tumors', 'Disease', 'MESH:D009369', (55, 61))
48001	24012403	A larger study (n=148) found that BRAF+ FNA specimens were significantly associated with occult lymph node metastases after prophylactic central neck dissection, and concluded that BRAF status may be helpful in the decision whether to perform nodal dissection in a clinically node-negative neck.	('metastases', 'Disease', 'MESH:D009362', (107, 117))	('associated with', 'Reg', (73, 88))	('metastases', 'Disease', (107, 117))	('BRAF+ FNA', 'Var', (34, 43))
48004	24012403	In BRAF-mutated metastatic melanoma, a phase-III trial of the MEK inhibitor trametinib demonstrated significantly prolonged progression-free and overall survival in the treatment group.	('rat', 'Species', '10116', (94, 97))	('MEK', 'Gene', (62, 65))	('MEK', 'Gene', '5609', (62, 65))	('overall survival', 'CPA', (145, 161))	('trametinib', 'Chemical', 'MESH:C560077', (76, 86))	('progression-free', 'CPA', (124, 140))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('prolonged', 'PosReg', (114, 123))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('BRAF-mutated', 'Var', (3, 15))
48009	24012403	Cancers with RAS mutations responded best to selumetinib (5/5), while only 1/9 cancers with BRAF V600E had enough uptake to warrant treatment with 131I.	('131I', 'Chemical', 'MESH:C000614965', (147, 151))	('cancers', 'Disease', (79, 86))	('Cancers', 'Disease', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('RAS', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('selumetinib', 'Chemical', 'MESH:C517975', (45, 56))	('V600E', 'Mutation', 'rs113488022', (97, 102))
48016	24012403	Response did correspond to expression of mutant RET, where mutation positive patients enjoyed higher response rates than those with BRAF or RAS mutations, providing further enthusiasm for prospective genetic profiling of thyroid cancers in future trials.	('rat', 'Species', '10116', (110, 113))	('mutation positive', 'Var', (59, 76))	('RET', 'Gene', '5979', (48, 51))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('thyroid cancer', 'Phenotype', 'HP:0002890', (221, 235))	('higher', 'PosReg', (94, 100))	('patients', 'Species', '9606', (77, 85))	('RET', 'Gene', (48, 51))	('thyroid cancers', 'Disease', (221, 236))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('response rates', 'MPA', (101, 115))	('thyroid cancers', 'Disease', 'MESH:D013964', (221, 236))
48019	24012403	One such is PLX4720, which inserts into the ATP-binding site of mutant BRAF, stabilizing its inactive state.	('inactive state', 'MPA', (93, 107))	('BRAF', 'Gene', (71, 75))	('stabilizing', 'MPA', (77, 88))	('mutant', 'Var', (64, 70))	('ATP', 'Chemical', 'MESH:D000255', (44, 47))
48020	24012403	In a mouse model, Nehs and colleagues injected V600E anaplastic thyroid cancer cells into mouse thyroids, and then treated with PLX4720.	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (53, 78))	('anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (53, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('mouse', 'Species', '10090', (90, 95))	('anaplastic thyroid cancer', 'Disease', (53, 78))	('V600E', 'Var', (47, 52))	('thyroid cancer', 'Phenotype', 'HP:0002890', (64, 78))	('mouse', 'Species', '10090', (5, 10))
48023	24012403	Based on these studies and data in melanoma with the similar but orally available BRAF inhibitor vemurafenib, Rosove and colleagues reported a complete response to vemurafenib in a critically ill patient with metastatic BRAF+ ATC, providing clinical evidence of the promise of this approach in human ATC.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('human', 'Species', '9606', (294, 299))	('BRAF+', 'Var', (220, 225))	('patient', 'Species', '9606', (196, 203))	('vemurafenib', 'Chemical', 'MESH:D000077484', (97, 108))	('ATC', 'Phenotype', 'HP:0011779', (226, 229))	('ATC', 'Phenotype', 'HP:0011779', (300, 303))	('vemurafenib', 'Chemical', 'MESH:D000077484', (164, 175))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
48031	24012403	They reported that testing for mutations in RET, RAS, BRAF, and PAX8/PPAR-gamma (a fusion of the thyroid transcription factor PAX8 promoter with the peroxisome proliferator-activated receptor-gamma1 gene, which is found in some follicular thyroid cancers) identified mutations in 15% of indeterminate or nondiagnostic FNAs.	('RET', 'Gene', (44, 47))	('PAX8', 'Gene', '7849', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('PPAR-gamma', 'Gene', (69, 79))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (228, 253))	('mutations', 'Var', (267, 276))	('PAX8', 'Gene', (126, 130))	('PPAR-gamma', 'Gene', '5468', (69, 79))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('RET', 'Gene', '5979', (44, 47))	('follicular thyroid cancers', 'Disease', (228, 254))	('thyroid cancer', 'Phenotype', 'HP:0002890', (239, 253))	('rat', 'Species', '10116', (167, 170))	('follicular thyroid cancers', 'Phenotype', 'HP:0006731', (228, 254))	('PAX8', 'Gene', '7849', (64, 68))	('follicular thyroid cancers', 'Disease', 'MESH:C572845', (228, 254))	('indeterminate', 'Disease', (287, 300))	('PAX8', 'Gene', (64, 68))
48036	24012403	Overall, detecting a known malignant mutation on thyroid FNA has a positive predictive value for malignancy of nearly 100% for BRAF, RET, or PAX8/PPAR-gamma and 74-87% for RAS, and these patients should undergo total thyroidectomy.	('patients', 'Species', '9606', (187, 195))	('BRAF', 'Disease', (127, 131))	('mutation', 'Var', (37, 45))	('RET', 'Gene', (133, 136))	('PAX8', 'Gene', '7849', (141, 145))	('PPAR-gamma', 'Gene', (146, 156))	('malignancy', 'Disease', 'MESH:D009369', (97, 107))	('PPAR-gamma', 'Gene', '5468', (146, 156))	('PAX8', 'Gene', (141, 145))	('RET', 'Gene', '5979', (133, 136))	('malignancy', 'Disease', (97, 107))	('RAS', 'Disease', (172, 175))
48037	24012403	While testing for mutations of known malignant potential can identify patients who should undergo total thyroidectomy, with its low negative predictive value, it cannot rule out malignancy.	('malignancy', 'Disease', (178, 188))	('patients', 'Species', '9606', (70, 78))	('malignancy', 'Disease', 'MESH:D009369', (178, 188))	('mutations', 'Var', (18, 27))
48043	24012403	At least one study funded by the company reported that the rate of surgery in indeterminate nodules classified as benign by the gene expression test fell to 7% among patients of participating endocrinologists, compared to 74% overall for indeterminate nodules prior to adoption of the test.	('to 7', 'Species', '1214577', (154, 158))	('to 7', 'Species', '1214577', (219, 223))	('gene', 'Var', (128, 132))	('rat', 'Species', '10116', (59, 62))	('fell', 'NegReg', (149, 153))	('patients', 'Species', '9606', (166, 174))
48046	24012403	An industry-sponsored study claiming cost-effectiveness of this $3,200 test used a cost model which assumed very high 30 and 44% complication rates for hemi and total thyroidectomy and did not account for the costs and quality-of-life impact of missed cancer diagnoses.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', (252, 258))	('rat', 'Species', '10116', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('hemi', 'Var', (152, 156))
48054	24012403	Germline HRPT2 mutations cause familial hyperparathyroidism/jaw-tumor syndrome and somatic mutation of HRPT2 is found in over 75% of sporadic parathyroid carcinomas.	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (40, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('HRPT2', 'Gene', '79577', (103, 108))	('mutations', 'Var', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('HRPT2', 'Gene', (103, 108))	('HRPT2', 'Gene', '79577', (9, 14))	('cause', 'Reg', (25, 30))	('familial hyperparathyroidism/jaw-tumor syndrome', 'Disease', 'MESH:C563273', (31, 78))	('HRPT2', 'Gene', (9, 14))	('parathyroid carcinomas', 'Phenotype', 'HP:0006780', (142, 164))	('sporadic parathyroid carcinomas', 'Disease', (133, 164))	('parathyroid carcinoma', 'Phenotype', 'HP:0006780', (142, 163))	('sporadic parathyroid carcinomas', 'Disease', 'MESH:D010282', (133, 164))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('familial hyperparathyroidism/jaw-tumor syndrome', 'Disease', (31, 78))
48055	24012403	Some patients with seemingly sporadic parathyroid carcinoma will be found to have germline HRPT2 mutations, making genetic testing of parathyroid carcinoma patients potentially helpful by identifying related gene carriers who will benefit from serum calcium screening.	('parathyroid carcinoma', 'Disease', (134, 155))	('mutations', 'Var', (97, 106))	('patients', 'Species', '9606', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('parathyroid carcinoma', 'Disease', 'MESH:D010282', (38, 59))	('patients', 'Species', '9606', (5, 13))	('HRPT2', 'Gene', '79577', (91, 96))	('parathyroid carcinoma', 'Phenotype', 'HP:0006780', (134, 155))	('parathyroid carcinoma', 'Disease', (38, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('calcium', 'Chemical', 'MESH:D002118', (250, 257))	('parathyroid carcinoma', 'Phenotype', 'HP:0006780', (38, 59))	('parathyroid carcinoma', 'Disease', 'MESH:D010282', (134, 155))	('HRPT2', 'Gene', (91, 96))
48058	24012403	Hyperparathyroidism (HPT) occurs in a minority of MEN2A patients, with the risk strongly influenced by the specific RET mutation present (Table 1).	('MEN2A', 'Gene', '5979', (50, 55))	('patients', 'Species', '9606', (56, 64))	('mutation', 'Var', (120, 128))	('RET', 'Gene', (116, 119))	('influenced', 'Reg', (89, 99))	('Hyperparathyroidism', 'Phenotype', 'HP:0000843', (0, 19))	('Hyperparathyroidism', 'Disease', (0, 19))	('Hyperparathyroidism', 'Disease', 'MESH:D006961', (0, 19))	('HPT', 'Phenotype', 'HP:0000843', (21, 24))	('RET', 'Gene', '5979', (116, 119))	('MEN2A', 'Gene', (50, 55))
48059	24012403	The incidence of HPT in MEN2A is known to be 20-35%, and is much more common with mutations of codon 634, although HPT also occurs in 1-5% of patients with codon 609, 611, 618, and 620 mutations.	('MEN2A', 'Gene', '5979', (24, 29))	('HPT', 'Phenotype', 'HP:0000843', (17, 20))	('MEN2A', 'Gene', (24, 29))	('HPT', 'Phenotype', 'HP:0000843', (115, 118))	('mutations', 'Var', (82, 91))	('codon', 'Gene', (95, 100))	('patients', 'Species', '9606', (142, 150))	('HPT', 'Disease', (17, 20))
48063	24012403	Unlike MEN2 mutations, which cluster at particular codons, MEN1 mutations are highly variable, with over 1,100 distinct germline mutations described and the most common occurring in only 4.5% of families (as opposed to 85% of MEN2A families having RET codon 634 mutations).	('MEN1', 'Gene', (59, 63))	('MEN2A', 'Gene', (226, 231))	('MEN2A', 'Gene', '5979', (226, 231))	('MEN1', 'Gene', '4221', (59, 63))	('MEN', 'Species', '9606', (226, 229))	('RET', 'Gene', '5979', (248, 251))	('mutations', 'Var', (129, 138))	('MEN', 'Species', '9606', (7, 10))	('MEN', 'Species', '9606', (59, 62))	('RET', 'Gene', (248, 251))
48065	24012403	Thus, while genetic testing for MEN1 mutations is available, identifying carriers does not suggest a specific prophylactic surgical therapy, as in MEN2, but rather identifies those who require screening for development of different manifestations of the disease.	('MEN', 'Species', '9606', (147, 150))	('MEN1', 'Gene', (32, 36))	('mutations', 'Var', (37, 46))	('MEN1', 'Gene', '4221', (32, 36))	('rat', 'Species', '10116', (157, 160))	('MEN', 'Species', '9606', (32, 35))
48066	24012403	found that genetic testing for MEN1 helped identify biochemical changes 5-10 years before the development of clinically apparent tumors, allowing for early surgical intervention in some cases.	('biochemical', 'MPA', (52, 63))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('MEN1', 'Gene', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('genetic testing', 'Var', (11, 26))	('MEN1', 'Gene', '4221', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))
48069	24012403	The importance of the MEN1 gene to parathyroid disease is highlighted by the frequency of somatic MEN1 mutation in sporadic parathyroid adenomas.	('parathyroid adenomas', 'Disease', 'MESH:D010282', (124, 144))	('MEN1', 'Gene', (22, 26))	('parathyroid disease', 'Disease', (35, 54))	('parathyroid adenomas', 'Disease', (124, 144))	('parathyroid disease', 'Disease', 'MESH:D010279', (35, 54))	('parathyroid adenomas', 'Phenotype', 'HP:0002897', (124, 144))	('mutation', 'Var', (103, 111))	('MEN1', 'Gene', (98, 102))	('MEN1', 'Gene', '4221', (22, 26))	('MEN1', 'Gene', '4221', (98, 102))	('parathyroid disease', 'Phenotype', 'HP:0000828', (35, 54))
48071	24012403	Screening 185 additional sporadic parathyroid adenomas for these by direct sequencing revealed MEN1 mutations in 35.2% of the validation cohort, while only 1 of the other mutations (occurring in 1/185 patients) was found.	('mutations', 'Var', (100, 109))	('patients', 'Species', '9606', (201, 209))	('parathyroid adenomas', 'Disease', (34, 54))	('parathyroid adenomas', 'Phenotype', 'HP:0002897', (34, 54))	('parathyroid adenomas', 'Disease', 'MESH:D010282', (34, 54))	('MEN1', 'Gene', (95, 99))	('MEN1', 'Gene', '4221', (95, 99))
48072	24012403	Thus, while the exact mechanisms by which RET and MEN1 lead to parathyroid disease remain unknown, somatic MEN1 mutation is a frequent event in sporadic and heritable parathyroid disease.	('RET', 'Gene', '5979', (42, 45))	('mutation', 'Var', (112, 120))	('MEN1', 'Gene', (107, 111))	('MEN1', 'Gene', '4221', (107, 111))	('parathyroid disease', 'Disease', (167, 186))	('parathyroid disease', 'Phenotype', 'HP:0000828', (167, 186))	('parathyroid disease', 'Disease', (63, 82))	('parathyroid disease', 'Disease', 'MESH:D010279', (167, 186))	('MEN1', 'Gene', (50, 54))	('parathyroid disease', 'Disease', 'MESH:D010279', (63, 82))	('RET', 'Gene', (42, 45))	('MEN1', 'Gene', '4221', (50, 54))	('parathyroid disease', 'Phenotype', 'HP:0000828', (63, 82))
48084	24012403	Activation of mTOR in NF1-mutated tumors is influenced by inactivation of tuberin, the product of the Tuberous Sclerosis Complex gene TSC2.	('mTOR', 'Gene', '2475', (14, 18))	('NF1', 'Gene', (22, 25))	('TSC2', 'Gene', (134, 138))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('NF1', 'Gene', '4763', (22, 25))	('tuberin', 'Gene', '7249', (74, 81))	('inactivation', 'Var', (58, 70))	('tuberin', 'Gene', (74, 81))	('Activation', 'PosReg', (0, 10))	('Tuberous Sclerosis Complex', 'Disease', (102, 128))	('Tuberous Sclerosis Complex', 'Disease', 'MESH:D014402', (102, 128))	('TSC2', 'Gene', '7249', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('mTOR', 'Gene', (14, 18))
48089	24012403	found PCCs were significantly more common (penetrance ~60% by 50 years versus 5-20% in other groups) and occured earlier (mean 21.7 vs. 27.8 years, p=0.012) in patients with missense mutations of surface residues of the VHL protein, compared to those with deletions, truncations, or missense mutations of core residues.	('patients', 'Species', '9606', (160, 168))	('missense mutations', 'Var', (174, 192))	('VHL', 'Gene', (220, 223))	('PCCs', 'Disease', (6, 10))	('VHL', 'Gene', '7428', (220, 223))
48090	24012403	This genotypic distinction between mutations with low and high risk of PCC correlates closely with the earlier clinical designation of vHL type 1 and 2.	('PCC', 'Disease', (71, 74))	('vHL', 'Gene', '7428', (135, 138))	('vHL', 'Gene', (135, 138))	('mutations', 'Var', (35, 44))
48092	24012403	Mutant proteins may fail to cause degradation of HIF proteins, leading to pro-malignant signaling, but as some patients with mutations that do not disrupt HIF interactions still develop PCC, additional mechanisms, such as failure of normal apoptosis of adrenal progenitor cells, may be responsible for PCC features of vHL syndrome.	('mutations', 'Var', (125, 134))	('develop', 'Reg', (178, 185))	('vHL syndrome', 'Disease', (318, 330))	('degradation of HIF proteins', 'Disease', 'MESH:D055959', (34, 61))	('PCC', 'Disease', (186, 189))	('degradation of HIF proteins', 'Disease', (34, 61))	('vHL syndrome', 'Disease', 'MESH:D013577', (318, 330))	('patients', 'Species', '9606', (111, 119))
48095	24012403	SDHD was first identified as a cause of Familial Paraganglioma syndrome, and SDHD mutations were soon reported in sporadic PGLs and hereditary and sporadic PCCs.	('Paraganglioma', 'Phenotype', 'HP:0002668', (49, 62))	('Familial Paraganglioma syndrome', 'Disease', (40, 71))	('SDHD', 'Gene', '6392', (77, 81))	('Familial Paraganglioma syndrome', 'Disease', 'MESH:D010235', (40, 71))	('SDHD', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('SDHD', 'Gene', '6392', (0, 4))	('cause', 'Reg', (31, 36))	('SDHD', 'Gene', (0, 4))
48098	24012403	After identification of the SDHD mutation, reports of mutations causing the syndrome in the A, B, and C SDH subunits, as well as in the SDH assembly-factor 2 (SDHAF2) gene followed.	('SDHD', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))	('SDH', 'Gene', '6390', (159, 162))	('SDH', 'Gene', '6390', (28, 31))	('SDH', 'Gene', '6390', (104, 107))	('SDH', 'Gene', (136, 139))	('syndrome', 'Disease', (76, 84))	('SDH', 'Gene', '6390', (136, 139))	('mutations', 'Var', (54, 63))	('SDHAF2', 'Gene', '54949', (159, 165))	('SDHAF2', 'Gene', (159, 165))	('SDH', 'Gene', (159, 162))	('SDH assembly-factor 2', 'Gene', (136, 157))	('SDH', 'Gene', (104, 107))	('SDH', 'Gene', (28, 31))	('SDH assembly-factor 2', 'Gene', '54949', (136, 157))	('SDHD', 'Gene', '6392', (28, 32))	('causing', 'Reg', (64, 71))
48100	24012403	As with HIF-stabilization in vHL syndrome, the SDHx mutations inactivate the SDH complex, leading to a defect in electron transport, accumulation of succinate, and induction of a pseudo-hypoxic state with consequent persistence of HIF factors.	('mutations', 'Var', (52, 61))	('SDH', 'Gene', (77, 80))	('induction', 'Reg', (164, 173))	('SDH', 'Gene', (47, 50))	('vHL syndrome', 'Disease', (29, 41))	('SDHx', 'Chemical', '-', (47, 51))	('defect', 'NegReg', (103, 109))	('succinate', 'Chemical', 'MESH:D019802', (149, 158))	('electron transport', 'MPA', (113, 131))	('SDH', 'Gene', '6390', (77, 80))	('accumulation of succinate', 'MPA', (133, 158))	('inactivate', 'NegReg', (62, 72))	('SDH', 'Gene', '6390', (47, 50))	('vHL syndrome', 'Disease', 'MESH:D013577', (29, 41))	('pseudo-hypoxic state', 'MPA', (179, 199))
48104	24012403	Malignant PCCs occur more commonly in families with SDHB mutations, while SDHD PCCs are more often benign.	('SDHB', 'Gene', (52, 56))	('SDHD', 'Gene', (74, 78))	('SDHD', 'Gene', '6392', (74, 78))	('Malignant PCCs', 'Disease', (0, 14))	('mutations', 'Var', (57, 66))	('SDHB', 'Gene', '6390', (52, 56))
48105	24012403	In malignant PCC/PGL, SDHB mutations also portend a worse prognosis, and are associated with lower 5-year survival when compared to tumors without SDHB mutations.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('SDHB', 'Gene', '6390', (22, 26))	('SDHB', 'Gene', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('lower', 'NegReg', (93, 98))	('SDHB', 'Gene', '6390', (147, 151))	('5-year survival', 'MPA', (99, 114))	('SDHB', 'Gene', (147, 151))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
48106	24012403	Mutations of the other SDHx genes rarely lead to PCCs, and these syndromes are marked mostly by head and neck paragangliomas.	('SDHx', 'Chemical', '-', (23, 27))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (105, 124))	('SDHx', 'Gene', (23, 27))	('Mutations', 'Var', (0, 9))	('neck paragangliomas', 'Disease', 'MESH:D010235', (105, 124))	('lead to', 'Reg', (41, 48))	('paragangliomas', 'Phenotype', 'HP:0002668', (110, 124))	('PCCs', 'Disease', (49, 53))	('neck paragangliomas', 'Disease', (105, 124))
48108	24012403	reported autosomal dominant inheritance of 6 distinct germline TMEM127 mutations in 7 families, representing 30% of familial and 3% of apparently sporadic PCCs out of 102 screened.	('TMEM127', 'Gene', (63, 70))	('mutations', 'Var', (71, 80))	('TMEM127', 'Gene', '55654', (63, 70))
48110	24012403	It co-localizes with mTORC1, and siRNA knockdown of TMEM127 increases mTORC1 signaling, which is likewise observed with NF1 mutations.	('mutations', 'Var', (124, 133))	('mTORC1', 'Gene', '382056', (21, 27))	('TMEM127', 'Gene', (52, 59))	('TMEM127', 'Gene', '55654', (52, 59))	('knockdown', 'Var', (39, 48))	('mTORC1', 'Gene', '382056', (70, 76))	('NF1', 'Gene', (120, 123))	('NF1', 'Gene', '4763', (120, 123))	('mTORC1', 'Gene', (21, 27))	('mTORC1', 'Gene', (70, 76))	('increases', 'PosReg', (60, 69))
48111	24012403	Screening of 642 sporadic PCCs found TMEM127 mutations in only six patients (0.9%), making TMEM127 the least common PCC susceptibility gene.	('mutations', 'Var', (45, 54))	('patients', 'Species', '9606', (67, 75))	('TMEM127', 'Gene', '55654', (91, 98))	('TMEM127', 'Gene', (91, 98))	('TMEM127', 'Gene', (37, 44))	('TMEM127', 'Gene', '55654', (37, 44))
48112	24012403	MAX mutations causing loss of protein expression were discovered in three kindreds by exome sequencing, and then confirmed to affect 1.12% of 1,694 sporadic and hereditary PCC patients without a known mutation.	('patients', 'Species', '9606', (176, 184))	('MAX', 'Gene', (0, 3))	('affect', 'Reg', (126, 132))	('PCC', 'Disease', (172, 175))	('mutations', 'Var', (4, 13))	('protein expression', 'MPA', (30, 48))
48114	24012403	Like SDHAF2 and SDHD, transmission of familial MAX mutation is preferentially paternal, with tumors of affected patients expressing only the paternal allele either through uniparental disomy or loss of heterozygosity for chromosome 14q.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('SDHD', 'Gene', '6392', (16, 20))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('patients', 'Species', '9606', (112, 120))	('SDHD', 'Gene', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('mutation', 'Var', (51, 59))	('uniparental disomy or loss', 'Disease', (172, 198))	('SDHAF2', 'Gene', '54949', (5, 11))	('tumors', 'Disease', (93, 99))	('uniparental disomy or loss', 'Disease', 'MESH:D024182', (172, 198))	('SDHAF2', 'Gene', (5, 11))	('familial MAX', 'Gene', (38, 50))
48115	24012403	Despite the host of mutations predisposing to PCCS and PGLs, there is an increasing understanding that the affected genes cluster into only a few pathways and relate to other forms of neuroendocrine cancer.	('PCCS', 'Disease', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('neuroendocrine cancer', 'Disease', (184, 205))	('neuroendocrine cancer', 'Disease', 'MESH:D018358', (184, 205))	('endocrine cancer', 'Phenotype', 'HP:0100568', (189, 205))	('relate', 'Reg', (159, 165))	('neuroendocrine cancer', 'Phenotype', 'HP:0100634', (184, 205))	('mutations', 'Var', (20, 29))
48118	24012403	Analysis of 78 sporadic tumors which grouped to these same clusters uncovered somatic mutations of RET and VHL in 17, loss of SDH heterozygosity in 2/2 sporadic tumors that clustered with familial SDHx tumors, and loss of heterozygosity of the VHL locus in 16/16 tumors clustering with familial vHL tumors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', (161, 167))	('RET', 'Gene', (99, 102))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('loss', 'Var', (214, 218))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('VHL', 'Gene', (244, 247))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('sporadic tumors', 'Disease', (152, 167))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('SDH', 'Gene', '6390', (197, 200))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('loss', 'Var', (118, 122))	('VHL', 'Gene', (107, 110))	('sporadic tumors', 'Disease', 'MESH:D009369', (152, 167))	('SDH', 'Gene', '6390', (126, 129))	('mutations', 'Var', (86, 95))	('VHL', 'Gene', '7428', (244, 247))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('sporadic tumors', 'Disease', (15, 30))	('tumors', 'Disease', (299, 305))	('familial SDHx tumors', 'Disease', 'MESH:D009386', (188, 208))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('RET', 'Gene', '5979', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('SDH', 'Gene', (197, 200))	('familial SDHx tumors', 'Disease', (188, 208))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('sporadic tumors', 'Disease', 'MESH:D009369', (15, 30))	('VHL', 'Gene', '7428', (107, 110))	('familial vHL tumors', 'Disease', (286, 305))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('SDH', 'Gene', (126, 129))	('tumors', 'Disease', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('familial vHL tumors', 'Disease', 'MESH:D009386', (286, 305))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('tumors', 'Disease', (263, 269))
48122	24012403	The FIRM-ACT trial, which randomized patients with advanced ACC to treatment with mitotane plus either streptozocin (Sz+M) or etoposide, doxorubicin, and cisplatin (EDP+M), established EDP+M as the standard of care due to its higher objective response rate (23.2 vs. 9.2%, p<0.001) and similar toxicity.	('toxicity', 'Disease', (294, 302))	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))	('EDP+M', 'Var', (185, 190))	('rat', 'Species', '10116', (252, 255))	('streptozocin', 'Chemical', 'MESH:D013311', (103, 115))	('mitotane', 'Chemical', 'MESH:D008939', (82, 90))	('patients', 'Species', '9606', (37, 45))	('doxorubicin', 'Chemical', 'MESH:D004317', (137, 148))	('ACC', 'Phenotype', 'HP:0006744', (60, 63))	('toxicity', 'Disease', 'MESH:D064420', (294, 302))	('EDP', 'Chemical', '-', (165, 168))	('EDP', 'Chemical', '-', (185, 188))	('etoposide', 'Chemical', 'MESH:D005047', (126, 135))
48123	24012403	Despite higher response rates with EDP+M, overall survival remained disappointing, with no significant difference between the two treatment groups (median 14.8 vs. 12.0 months, p=0.07).	('response', 'MPA', (15, 23))	('EDP+M', 'Var', (35, 40))	('higher', 'PosReg', (8, 14))	('rat', 'Species', '10116', (24, 27))	('EDP', 'Chemical', '-', (35, 38))
48127	24012403	At this parentally-imprinted locus, duplications, deletions, gene methylation, chromosomal loss, and uniparental disomy cause variations in the effective copy number of IGF2, with increased gene dosage driving proliferation and malignancy in neural-crest derived tissues.	('duplications', 'Var', (36, 48))	('variations', 'Var', (126, 136))	('IGF2', 'Gene', '3481', (169, 173))	('proliferation', 'CPA', (210, 223))	('increased', 'PosReg', (180, 189))	('IGF2', 'Gene', (169, 173))	('gene methylation', 'Var', (61, 77))	('malignancy', 'Disease', 'MESH:D009369', (228, 238))	('uniparental disomy', 'Disease', (101, 119))	('rat', 'Species', '10116', (217, 220))	('malignancy', 'Disease', (228, 238))	('deletions', 'Var', (50, 59))	('uniparental disomy', 'Disease', 'MESH:D024182', (101, 119))
48133	24012403	Combination therapy with sunitinib and the ERK inhibitor PD98059 resulted in greater proliferation inhibition (68% with both vs. 23% and 19% inhibition with sunitinib or PD98059 alone).	('PD98059', 'Var', (57, 64))	('PD98059', 'Chemical', 'MESH:C093973', (170, 177))	('sunitinib', 'Chemical', 'MESH:D000077210', (25, 34))	('PD98059', 'Chemical', 'MESH:C093973', (57, 64))	('ERK', 'Gene', '5594', (43, 46))	('ERK', 'Gene', (43, 46))	('rat', 'Species', '10116', (92, 95))	('proliferation inhibition', 'CPA', (85, 109))	('sunitinib', 'Chemical', 'MESH:D000077210', (157, 166))
48135	24012403	As in other areas of endocrine dysfunction, exome sequencing has proven a powerful tool for identifying specific mutations in both familial and sporadic functional adrenal adenomas.	('sporadic functional adrenal adenomas', 'Disease', 'MESH:D018246', (144, 180))	('endocrine dysfunction', 'Disease', 'MESH:D004700', (21, 42))	('endocrine dysfunction', 'Disease', (21, 42))	('endocrine dysfunction', 'Phenotype', 'HP:0000818', (21, 42))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (164, 180))	('familial', 'Disease', (131, 139))	('mutations', 'Var', (113, 122))	('sporadic functional adrenal adenomas', 'Disease', (144, 180))
48138	24012403	The KCNJ5 gene encodes a potassium channel that causes depolarization and excessive aldosterone release when mutated.	('aldosterone', 'Chemical', 'MESH:D000450', (84, 95))	('KCNJ5', 'Gene', '3762', (4, 9))	('aldosterone release', 'MPA', (84, 103))	('excessive aldosterone', 'Phenotype', 'HP:0000859', (74, 95))	('causes', 'Reg', (48, 54))	('aldosterone release', 'Phenotype', 'HP:0000859', (84, 103))	('mutated', 'Var', (109, 116))	('depolarization', 'MPA', (55, 69))	('KCNJ5', 'Gene', (4, 9))
48139	24012403	Mutations in the Na+/K+ ATPase ATPA1 and the Ca2+ ATPase ATP2B3 likewise cause depolarization with aldosterone release, and somatic mutations in these genes occur in 7% of APAs.	('Ca2+ ATPase', 'Gene', (45, 56))	('aldosterone release', 'Phenotype', 'HP:0000859', (99, 118))	('ATPase', 'Gene', (50, 56))	('cause', 'Reg', (73, 78))	('ATPase', 'Gene', (24, 30))	('ATPase', 'Gene', '1769', (50, 56))	('Mutations', 'Var', (0, 9))	('ATPase', 'Gene', '1769', (24, 30))	('ATP', 'Chemical', 'MESH:D000255', (50, 53))	('occur', 'Reg', (157, 162))	('aldosterone', 'Chemical', 'MESH:D000450', (99, 110))	('depolarization', 'MPA', (79, 93))	('APAs', 'Disease', (172, 176))	('Ca2+ ATPase', 'Gene', '760;1769', (45, 56))	('ATP', 'Chemical', 'MESH:D000255', (57, 60))	('mutations', 'Var', (132, 141))	('ATP', 'Chemical', 'MESH:D000255', (24, 27))	('ATP', 'Chemical', 'MESH:D000255', (31, 34))	('ATP2B3', 'Gene', '492', (57, 63))	('ATP2B3', 'Gene', (57, 63))
48140	24012403	Notably, a screen of 380 APAs found KCNJ5 mutations in 49% of females but only 19% of males (p<.001), while 17/21 (81%) of ATPase mutations occurred in males.	('ATPase', 'Gene', (123, 129))	('ATPase', 'Gene', '1769', (123, 129))	('KCNJ5', 'Gene', (36, 41))	('mutations', 'Var', (42, 51))	('KCNJ5', 'Gene', '3762', (36, 41))
48141	24012403	Knowledge of these APA-causing mutations has not yet altered surgical management, but medical therapies targeting these genes could someday reduce the need for adrenalectomy in these patients.	('mutations', 'Var', (31, 40))	('patients', 'Species', '9606', (183, 191))	('APA-causing', 'Disease', (19, 30))
48151	24012403	Early reports indicated no association between tumor size and outcomes, but more recently, larger, non-functional pancreatic tumors were found to be significantly associated with poorer survival and higher rates of metastasis in a long-term study of more than 500 MEN1 patients.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('MEN1', 'Gene', (264, 268))	('metastasis', 'CPA', (215, 225))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('rat', 'Species', '10116', (206, 209))	('patients', 'Species', '9606', (269, 277))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('pancreatic tumors', 'Disease', 'MESH:D010190', (114, 131))	('poorer', 'NegReg', (179, 185))	('pancreatic tumors', 'Disease', (114, 131))	('survival', 'CPA', (186, 194))	('tumor', 'Disease', (47, 52))	('non-functional', 'Var', (99, 113))	('MEN1', 'Gene', '4221', (264, 268))	('higher', 'PosReg', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (125, 130))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (114, 131))
48176	24012403	Unlike in MTC where mutations in RET lead to constitutive activation, providing a mechanism for tumorigenesis, the overexpressed receptors in PNETs are not mutated, suggesting that their overexpression does not drive malignancy, but rather represents an upregulatory reaction to primary mutations in other genes.	('RET', 'Gene', (33, 36))	('MTC', 'Phenotype', 'HP:0002865', (10, 13))	('malignancy', 'Disease', 'MESH:D009369', (217, 227))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('malignancy', 'Disease', (217, 227))	('tumor', 'Disease', (96, 101))	('RET', 'Gene', '5979', (33, 36))	('rat', 'Species', '10116', (233, 236))	('PNETs', 'Gene', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mutations', 'Var', (20, 29))
48180	24012403	TSC2 and PTEN function to negatively regulate the PI3K/Akt/mTOR pathway, with mutations in either leading to increased proliferation and loss of hypoxia-induced growth inhibition (Fig.	('Akt', 'Gene', (55, 58))	('TSC2', 'Gene', '7249', (0, 4))	('TSC2', 'Gene', (0, 4))	('regulate', 'Reg', (37, 45))	('mTOR', 'Gene', '2475', (59, 63))	('PTEN', 'Gene', (9, 13))	('PTEN', 'Gene', '5728', (9, 13))	('mutations', 'Var', (78, 87))	('loss', 'NegReg', (137, 141))	('hypoxia', 'Disease', (145, 152))	('negatively', 'NegReg', (26, 36))	('hypoxia', 'Disease', 'MESH:D000860', (145, 152))	('Akt', 'Gene', '207', (55, 58))	('rat', 'Species', '10116', (126, 129))	('increased', 'PosReg', (109, 118))	('mTOR', 'Gene', (59, 63))
48185	24012403	This, along with the finding of ATRX mutations in additional cancer types with the ALT phenotype implies that DAXX and ATRX play important roles in telomere maintenance.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('mutations', 'Var', (37, 46))	('ATRX', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
48186	24012403	Testing for these mutations promises to provide important prognostic information and further investigation of DAXX/ATRX function may uncover new insights into the pathogenesis of PNETs and other cancers.	('mutations', 'Var', (18, 27))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('PNETs', 'Disease', (179, 184))	('cancers', 'Disease', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
48187	24012403	Recognition that genes in the mTOR pathway are mutated in at least 16% of PNETs and that the pathway's function may be impaired in up to 85% of tumors has spurred the use of mTOR inhibitors in PNETs.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PNETs', 'Disease', (74, 79))	('function', 'MPA', (103, 111))	('mutated', 'Var', (47, 54))	('mTOR', 'Gene', '2475', (30, 34))	('mTOR', 'Gene', (174, 178))	('mTOR', 'Gene', '2475', (174, 178))	('mTOR', 'Gene', (30, 34))
48195	24012403	Grade 3 or 4 neutropenia and hypertension occurred in >10% of patients receiving sunitinib, while a 7% rate of grade 3 or 4 stomatitis was the most frequent serious complication in patients taking everolimus.	('hypertension', 'Disease', (29, 41))	('neutropenia', 'Disease', 'MESH:D009503', (13, 24))	('rat', 'Species', '10116', (103, 106))	('hypertension', 'Phenotype', 'HP:0000822', (29, 41))	('neutropenia', 'Phenotype', 'HP:0001875', (13, 24))	('stomatitis', 'Disease', 'MESH:D013280', (124, 134))	('Grade 3', 'Disease', (0, 7))	('everolimus', 'Chemical', 'MESH:D000068338', (197, 207))	('stomatitis', 'Disease', (124, 134))	('patients', 'Species', '9606', (181, 189))	('stomatitis', 'Phenotype', 'HP:0010280', (124, 134))	('neutropenia', 'Disease', (13, 24))	('sunitinib', 'Chemical', 'MESH:D000077210', (81, 90))	('hypertension', 'Disease', 'MESH:D006973', (29, 41))	('patients', 'Species', '9606', (62, 70))	('sunitinib', 'Var', (81, 90))
48202	24012403	Genetic testing for these mutations allows identification of at-risk individuals for screening prior to the onset of symptoms and in some cases permits prophylactic surgery.. Mutations in genes of the MAP-kinase signaling pathway (most commonly RET or BRAF) are found in most familial and sporadic thyroid cancers and cause constitutive proliferative signaling, leading to malignancy.. Small-molecule kinase inhibitors block aberrant pro-malignant signaling in several endocrine cancers and represent an active area of research with great potential.	('cancers', 'Phenotype', 'HP:0002664', (306, 313))	('block', 'NegReg', (419, 424))	('cancers', 'Phenotype', 'HP:0002664', (479, 486))	('endocrine cancers', 'Disease', (469, 486))	('cancer', 'Phenotype', 'HP:0002664', (479, 485))	('malignancy', 'Disease', (373, 383))	('endocrine cancers', 'Disease', 'MESH:D004701', (469, 486))	('RET', 'Gene', '5979', (245, 248))	('pro-malignant signaling', 'MPA', (434, 457))	('sporadic thyroid cancers', 'Disease', (289, 313))	('Small-molecule', 'Var', (386, 400))	('endocrine cancer', 'Phenotype', 'HP:0100568', (469, 485))	('aberrant', 'MPA', (425, 433))	('sporadic thyroid cancers', 'Disease', 'MESH:D013964', (289, 313))	('thyroid cancer', 'Phenotype', 'HP:0002890', (298, 312))	('rat', 'Species', '10116', (344, 347))	('RET', 'Gene', (245, 248))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('malignancy', 'Disease', 'MESH:D009369', (373, 383))
48204	24012403	In pancreatic neuroendocrine tumors, drugs targeting somatostatin receptors alleviatesymptoms, are useful for imaging, and can prolong life.	('somatostatin', 'Gene', '6750', (53, 65))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (3, 35))	('alleviatesymptoms', 'NegReg', (76, 93))	('endocrine tumor', 'Phenotype', 'HP:0100568', (19, 34))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (14, 34))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (14, 35))	('alleviatesymptoms', 'Disease', (76, 93))	('somatostatin', 'Gene', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (3, 34))	('life', 'CPA', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('prolong', 'PosReg', (127, 134))	('drugs', 'Var', (37, 42))	('pancreatic neuroendocrine tumors', 'Disease', (3, 35))
48387	32711725	The best diagnostic performance was provided by the combination of tumour diameter greater than 4 cm, unenhanced CT tumour attenuation greater than 20 HU, and urine steroid metabolomics indicating a high risk of ACC, which provided a PPV of 76 4% and a negative predictive value of 99 7% for ACC.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumour', 'Disease', (67, 73))	('steroid', 'Chemical', 'MESH:D013256', (165, 172))	('tumour', 'Disease', (116, 122))	('ACC', 'Phenotype', 'HP:0006744', (212, 215))	('greater', 'Var', (83, 90))	('ACC', 'Phenotype', 'HP:0006744', (292, 295))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('ACC', 'Disease', (212, 215))
48489	32711725	We anticipate that these changes would substantially lessen the burden on and morbidity in patients with benign adrenal tumours and suspicious imaging findings, and lead to reductions in health-care costs due to decreased numbers of imaging procedures, time to surgery in ACC, and numbers of unnecessary surgeries.	('decreased', 'NegReg', (212, 221))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('patients', 'Species', '9606', (91, 99))	('reductions', 'NegReg', (173, 183))	('burden on', 'MPA', (64, 73))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('lessen', 'NegReg', (53, 59))	('benign adrenal tumours', 'Disease', (105, 127))	('benign adrenal tumours', 'Disease', 'MESH:D000310', (105, 127))	('changes', 'Var', (25, 32))	('health-care costs', 'MPA', (187, 204))	('ACC', 'Phenotype', 'HP:0006744', (272, 275))
48495	32698135	Somatic mutations of p53/Rb and Wnt/beta-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12).	('mutations', 'Var', (8, 17))	('beta-catenin', 'Gene', (36, 48))	('p53/Rb', 'Gene', '7157;5925', (21, 27))	('p53/Rb', 'Gene', (21, 27))	('beta-catenin', 'Gene', '1499', (36, 48))
48504	32698135	A first subtype associates a 'C1A' transcriptome profile, characterized by upregulation of proliferative genes, a CpG island hypermethylation, a 'Noisy' chromosome alteration profile - that is, numerous and anarchic alterations - and an accumulation of mutations in p53/Rb and Wnt/beta-catenin-related genes.	('beta-catenin', 'Gene', '1499', (281, 293))	('mutations', 'Var', (253, 262))	('upregulation', 'PosReg', (75, 87))	('beta-catenin', 'Gene', (281, 293))	('p53/Rb', 'Gene', '7157;5925', (266, 272))	("'C1A'", 'Disease', (29, 34))	('p53/Rb', 'Gene', (266, 272))
48520	32698135	In the Wuerzburg cohort, sequence variants were called using targeted NGS with the GeneRead DNAseq Human Comprehensive Cancer Panel V2 and the GeneRead DNAseq Panel PCR Kit V2 (Qiagen and NextSeq500, Illumina) and Sanger sequencing for ZNRF3 for 20/24 samples, as previously reported, and with a QIAseq Targeted DNA Custom Panel (Qiagen and NextSeq500, Illumina) for 4/24 samples.	('variants', 'Var', (34, 42))	('Human', 'Species', '9606', (99, 104))	('ZNRF3', 'Gene', '84133', (236, 241))	('Cancer', 'Disease', (119, 125))	('ZNRF3', 'Gene', (236, 241))	('Cancer', 'Disease', 'MESH:D009369', (119, 125))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))
48521	32698135	In case of subclonal variant - called in one tumor region but not in the other - the coverage depth of the negative region was also checked.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('subclonal', 'Var', (11, 20))
48543	32698135	Intratumor heterogeneity of chromosome alterations was observed to a variable extent in all matched tumor samples (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (100, 105))	('chromosome alterations', 'Var', (28, 50))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
48550	32698135	The association between intratumor heterogeneity of gene alterations (sequence mutations and copy number alterations in p53/Rb and Wnt/beta-catenin pathways) and clinical and genomic features was tested in the 18 patients with at least one gene alteration in one of the two tumor samples.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('p53/Rb', 'Gene', (120, 126))	('p53/Rb', 'Gene', '7157;5925', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('beta-catenin', 'Gene', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tested', 'Reg', (196, 202))	('beta-catenin', 'Gene', '1499', (135, 147))	('tumor', 'Disease', (29, 34))	('copy number alterations', 'Var', (93, 116))	('patients', 'Species', '9606', (213, 221))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))
48553	32698135	Intratumor heterogeneity of gene alterations was neither associated with clinical prognostic factors, such as age (P = 0.90), ENSAT stage (P = 0.72) or Ki67 proliferation index (P = 0.44, Supplementary Table 3), nor with tumor purity (80 vs 88% in samples without intratumor heterogeneity, P = 0.49), nor with other genomic alterations, such as proportion of altered genome (62 vs 38% in samples without intratumor heterogeneity, P = 0.16), average methylation of four genes (22 vs 11% in samples without intratumor heterogeneity, P = 0.48), chromosome alterations or methylation profiles (P = 1, data not shown).	('methylation', 'Var', (449, 460))	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Disease', (409, 414))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (510, 515))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (409, 414))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', (510, 515))	('tumor', 'Phenotype', 'HP:0002664', (510, 515))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
48555	32698135	Intratumor heterogeneity of gene alterations and methylation profiles was identified in 8/26 (31%) and 2/12 (17%) patients, respectively.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('patients', 'Species', '9606', (114, 122))	('gene alterations', 'Var', (28, 44))
48559	32698135	Germline mutations of TP53 are also known to predispose to ACC in part of Li Fraumeni syndrome.	('Germline mutations', 'Var', (0, 18))	('predispose', 'Reg', (45, 55))	('Li Fraumeni syndrome', 'Disease', 'MESH:D016864', (74, 94))	('Li Fraumeni syndrome', 'Disease', (74, 94))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))	('ACC', 'Disease', (59, 62))
48560	32698135	Moreover, the role of CTNNB1 mutations in adrenocortical tumorigenesis has been validated by functional experiments in cell lines and mouse models.	('CTNNB1', 'Gene', (22, 28))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('mouse', 'Species', '10090', (134, 139))
48561	32698135	Therefore, intratumor heterogeneity of such gene alterations appears to go against the hypothesis of early clonal events that drive the tumorigenesis.	('alterations', 'Var', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', (136, 141))
48562	32698135	First, p53/Rb or Wnt/beta-catenin alterations could be drivers of aggressive subclones, associated with metastatic spread and therefore predominant in poor prognosis tumors.	('metastatic spread', 'CPA', (104, 121))	('beta-catenin', 'Gene', (21, 33))	('beta-catenin', 'Gene', '1499', (21, 33))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('p53/Rb', 'Gene', (7, 13))	('p53/Rb', 'Gene', '7157;5925', (7, 13))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('alterations', 'Var', (34, 45))	('associated with', 'Reg', (88, 103))
48574	32698135	Several pan-cancer studies support a variable chronological timing of CTNNB1 mutations.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('mutations', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('CTNNB1', 'Gene', (70, 76))
48575	32698135	Conversely, TP53 mutations are usually described as early clonal events.	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
48576	32698135	In a whole-exome analysis of paired primary tumors and metastases in 136 colorectal, lung or breast cancer patients, almost all TP53 mutations (79/85, 93%) were fully clonal.	('metastases', 'Disease', (55, 65))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('metastases', 'Disease', 'MESH:D009362', (55, 65))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('mutations', 'Var', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('patients', 'Species', '9606', (107, 115))
48577	32698135	In the TCGA ACC study, all 7 TP53 mutations occurred before whole-genome doubling.	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('occurred', 'Reg', (44, 52))	('mutations', 'Var', (34, 43))
48578	32698135	In the present study, 2/6 TP53 mutations showed intratumor heterogeneity.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('TP53', 'Gene', '7157', (26, 30))
48579	32698135	showing 3/7 private TP53 mutations in matched primary and recurrent/metastatic samples.	('mutations', 'Var', (25, 34))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (20, 24))
48580	32698135	These results could be random due to the small number of patients, could suggest a technical artifact - for instance, all heterogeneous TP53 mutations were found in FFPE samples - or unique biology in ACC.	('patients', 'Species', '9606', (57, 65))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))	('mutations', 'Var', (141, 150))
48581	32698135	Finally, the hypothesis of revertant alleles may explain some cases of intratumor heterogeneity with alterations in 'driver' genes found in the primary tumor, but not in recurrence.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('alterations', 'Var', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
48582	32698135	Some deletions of BRCA2 mutation with the restoration of the open reading frame have indeed been described as a mechanism of resistance to therapy in ovarian cancers.	('BRCA2', 'Gene', '675', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('ovarian cancers', 'Phenotype', 'HP:0100615', (150, 165))	('ovarian cancers', 'Disease', (150, 165))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('ovarian cancers', 'Disease', 'MESH:D010051', (150, 165))	('open reading frame', 'MPA', (61, 79))	('mutation', 'Var', (24, 32))	('BRCA2', 'Gene', (18, 23))	('deletions', 'Var', (5, 14))
48586	32698135	In the last two cases, CIMP is related to the accumulation of an oncometabolite due to mutations in genes coding for metabolic enzymes, whereas in ACC the origin of CIMP is still unknown.	('CIMP', 'Disease', (23, 27))	('CIMP', 'Chemical', '-', (23, 27))	('accumulation', 'PosReg', (46, 58))	('CIMP', 'Chemical', '-', (165, 169))	('mutations', 'Var', (87, 96))
48587	32698135	In a study evaluating the methylation profiles of four different tumor regions in glioblastoma patients, the global methylation profile, corresponding to IDH mutational status and its association to CIMP, was stable across the different tumor regions of the same patient.	('methylation', 'MPA', (116, 127))	('patient', 'Species', '9606', (263, 270))	('mutational status', 'Var', (158, 175))	('tumor', 'Disease', (237, 242))	('patient', 'Species', '9606', (95, 102))	('tumor', 'Disease', (65, 70))	('glioblastoma', 'Disease', (82, 94))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('patients', 'Species', '9606', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('IDH', 'Gene', (154, 157))	('CIMP', 'Chemical', '-', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('IDH', 'Gene', '3417', (154, 157))
48593	32698135	For instance, ZNRF3 mutations were identified by Sanger sequencing in 20/52 samples, whereas NGS was used for all remaining samples and other genes.	('ZNRF3', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))	('ZNRF3', 'Gene', '84133', (14, 19))
48594	32698135	Since Sanger sequencing has a lower sensitivity than NGS for detecting variants at low allelic ratio, this could have led to overestimating intratumor heterogeneity in patients with ZNRF3 mutations.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ZNRF3', 'Gene', '84133', (182, 187))	('tumor', 'Disease', (145, 150))	('ZNRF3', 'Gene', (182, 187))	('patients', 'Species', '9606', (168, 176))	('mutations', 'Var', (188, 197))	('overestimating', 'PosReg', (125, 139))	('sensitivity', 'MPA', (36, 47))
48603	32698135	This work was supported by the Programme de Recherche Translationnelle en Cancerologie to the COMETE network (PRT-K COMETE-TACTIC), the ITMO Cancer AVIESAN (Alliance pour les Sciences de la Vie et de la Sante) as part of the Plan Cancer 2014-2019 (A J received a PhD grant), the Deutsche Krebshilfe (70112969 to C L R and M F) and Deutsche Forschungsgemeinschaft (#314061271 - CRC/TRR 205) to M F. G A and J B jointly supervised the work.	('70112969', 'Var', (300, 308))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Disease', (74, 80))	('Cancer 2014-2019', 'Disease', 'MESH:C000657245', (230, 246))	('Cancer', 'Disease', (230, 236))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('Cancer 2014-2019', 'Disease', (230, 246))	('Cancer', 'Disease', 'MESH:D009369', (230, 236))	('Cancer', 'Disease', (141, 147))	('Cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('#314061271 - CRC/TRR', 'Var', (364, 384))	('Cancer', 'Disease', 'MESH:D009369', (141, 147))
48634	31783819	Based on the large number of ACC cases, we further compared the prognostic difference between patients with high- and low- FSCN1/FOXM1 expression.	('patients', 'Species', '9606', (94, 102))	('FSCN1', 'Gene', '6624', (123, 128))	('ACC', 'Phenotype', 'HP:0006744', (29, 32))	('FSCN1', 'Gene', (123, 128))	('FOXM1', 'Gene', (129, 134))	('FOXM1', 'Gene', '2305', (129, 134))	('high-', 'Var', (108, 113))	('ACC', 'Disease', (29, 32))	('ACC', 'Disease', 'MESH:D018268', (29, 32))
48649	31783819	The cut-off value distinguishing high or low expression of candidate markers was H score >= 1 or < 1 (FSCN1) and H score > 1 or = 1 (FoxM1) in this research.	('FSCN1', 'Gene', (102, 107))	('FSCN1', 'Gene', '6624', (102, 107))	('FoxM1', 'Gene', (133, 138))	('expression', 'MPA', (45, 55))	('H score > 1 or = 1', 'Var', (113, 131))	('H score >= 1', 'Var', (81, 93))	('FoxM1', 'Gene', '2305', (133, 138))
48659	31783819	In addition, based on the microarray data (GSE12368) in ACCs (n = 12) and ACAs (n = 16), we also checked the different expression levels of FSCN1 and FOXM1.	('ACC', 'Phenotype', 'HP:0006744', (56, 59))	('ACA', 'Phenotype', 'HP:0008256', (74, 77))	('FSCN1', 'Gene', (140, 145))	('GSE12368', 'Var', (43, 51))	('ACCs', 'Gene', (56, 60))	('ACAs', 'Chemical', 'MESH:C562042', (74, 78))	('ACCs', 'Gene', '84680', (56, 60))	('FOXM1', 'Gene', '2305', (150, 155))	('FOXM1', 'Gene', (150, 155))	('checked', 'Reg', (97, 104))	('FSCN1', 'Gene', '6624', (140, 145))
48680	31783819	In the TCGA ACC cohort, patients with a high expression level of FOXM1 and FSCN1 had worse overall survival (OS, n = 76, HR = 4.9, P = 4e-04 and HR = 9.4, P = 4.1e-05, respectively, Fig.	('FSCN1', 'Gene', '6624', (75, 80))	('ACC', 'Phenotype', 'HP:0006744', (12, 15))	('FOXM1', 'Gene', '2305', (65, 70))	('ACC', 'Disease', (12, 15))	('overall survival', 'MPA', (91, 107))	('patients', 'Species', '9606', (24, 32))	('high expression level', 'Var', (40, 61))	('FOXM1', 'Gene', (65, 70))	('FSCN1', 'Gene', (75, 80))	('ACC', 'Disease', 'MESH:D018268', (12, 15))	('worse', 'NegReg', (85, 90))
48684	31783819	As a result, high Fascin expression and high FoxM1 expression in the tumour tissues were both remarkably correlated with worse OS (HR = 4.69, P = 0.002 and HR = 3.95, P = 0.001, respectively) and DFS (HR = 3.92, P = 0.007 and HR = 3.34, P = 0.009, respectively).	('tumour', 'Disease', (69, 75))	('high', 'Var', (40, 44))	('worse OS', 'Disease', (121, 129))	('expression', 'MPA', (25, 35))	('high', 'PosReg', (13, 17))	('Fascin', 'Gene', '6624', (18, 24))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('DFS', 'Disease', (196, 199))	('expression', 'MPA', (51, 61))	('Fascin', 'Gene', (18, 24))	('FoxM1', 'Gene', '2305', (45, 50))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('FoxM1', 'Gene', (45, 50))
48737	30362899	These findings suggest aberrant TRHR expression in human pituitary adenomatous ACTH-producing cells.	('pituitary adenomatous', 'Disease', (57, 78))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (57, 74))	('pituitary adenomatous ACTH', 'Phenotype', 'HP:0008291', (57, 83))	('human', 'Species', '9606', (51, 56))	('TRHR', 'Gene', (32, 36))	('pituitary adenomatous', 'Disease', 'MESH:D011125', (57, 78))	('aberrant', 'Var', (23, 31))
48806	30362899	Aberrant expression of several hormone receptors in the adrenal cortex, particularly G-protein coupled receptors, has been reported as a regulating mechanism of cortisol production when ACTH of pituitary origin is suppressed (El Ghorayeb et al.).	('cortisol production', 'MPA', (161, 180))	('Aberrant', 'Var', (0, 8))	('G-protein coupled receptors', 'Protein', (85, 112))	('cortisol', 'Chemical', 'MESH:D006854', (161, 169))	('expression', 'MPA', (9, 19))
48807	30362899	The best-characterized example to date is the aberrant expression of the gastric-inhibitory polypeptide receptor (GIPR) that may cause food-dependent hypercortisolism (N'Diaye et al.	('dependent hypercortisolism', 'Phenotype', 'HP:0011744', (140, 166))	('GIPR', 'Gene', (114, 118))	('cause', 'Reg', (129, 134))	('food-dependent hypercortisolism', 'Disease', 'MESH:D047748', (135, 166))	('food-dependent hypercortisolism', 'Disease', (135, 166))	('hypercortisolism', 'Phenotype', 'HP:0003118', (150, 166))	('aberrant expression', 'Var', (46, 65))
48808	30362899	Next, to GIP, steroidogenesis can be driven by the expression of ectopic receptors such as serotonin, glucagon, beta-adrenergic receptors, and vasopressin receptors V2 and V3, as well as malfunction of eutopic luteinizing hormone receptors vasopressin receptor V1, or serotonin receptor (El Ghorayeb et al.).	('serotonin', 'Chemical', 'MESH:D012701', (268, 277))	('steroidogenesis', 'CPA', (14, 29))	('malfunction', 'Var', (187, 198))	('serotonin', 'Chemical', 'MESH:D012701', (91, 100))	('dog', 'Species', '9615', (20, 23))	('driven by', 'Reg', (37, 46))
48809	30362899	In humans, ectopic TRHR expression has been detected in aldosterone-secreting adrenal tumors and aldosterone responsiveness to TRH has been demonstrated in a subset of patients with primary aldosteronism (Zwermann et al.).	('adrenal tumors', 'Disease', 'MESH:D000310', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (182, 203))	('aldosteronism', 'Disease', (190, 203))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('detected', 'Reg', (44, 52))	('ectopic', 'Var', (11, 18))	('humans', 'Species', '9606', (3, 9))	('TRHR', 'Gene', (19, 23))	('adrenal tumors', 'Disease', (78, 92))	('patients', 'Species', '9606', (168, 176))	('aldosteronism', 'Disease', 'MESH:D006929', (190, 203))	('aldosterone', 'Chemical', 'MESH:D000450', (97, 108))	('aldosterone', 'Chemical', 'MESH:D000450', (56, 67))
48817	31252396	For diagnosis of PCC with 100% specificity, PAE value >=100% and EAP attenuation >=100 HU had 78.8 and 63.6% sensitivity respectively.	('>=100 HU', 'Var', (81, 89))	('PCC', 'Disease', (17, 20))	('PAE', 'Chemical', '-', (44, 47))
48818	31252396	Peak enhancement in EAP, PAE value >=100% and EAP attenuation >=100 HU differentiate PCC from other malignant adrenal masses with high specificity.	('enhancement', 'PosReg', (5, 16))	('PCC', 'Disease', (85, 88))	('>=100', 'Var', (62, 67))	('PAE', 'Chemical', '-', (25, 28))
48861	31252396	Thus, based on the observation that higher proportion of PCC with PAE <100% and EAP HU <100 were metanephrine-secreting, sub-group analysis was done to compare CT characteristics of PCC with these secretory subtypes (Table 3).	('metanephrine', 'Chemical', 'MESH:D008676', (97, 109))	('PAE <100%', 'Var', (66, 75))	('metanephrine-secreting', 'MPA', (97, 119))	('EAP HU <100', 'Var', (80, 91))	('PAE', 'Chemical', '-', (66, 69))
48863	31252396	Additionally, proportion of the PCC with peak enhancement in EAP or EAP HU >=100 were significantly lower in the metanephrine-secreting PCC group.	('enhancement', 'PosReg', (46, 57))	('lower', 'NegReg', (100, 105))	('metanephrine-secreting PCC', 'Disease', (113, 139))	('EAP HU >=100', 'Var', (68, 80))	('metanephrine', 'Chemical', 'MESH:D008676', (113, 125))
48931	26527083	Despite the presence of bilateral adrenal masses and lack of tumor within kidney parenchyma, the diagnosis of RCC was substantiated by immunohistochemistry (RCC+/PAX2+/PAX8+/Melan-A-/SF-1- among others) and molecular genetic analysis, harboring mutations in VHL, TP53, KDM5C, and PBRM1.	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('PBRM1', 'Gene', '55193', (280, 285))	('tumor within kidney parenchyma', 'Disease', 'MESH:D001929', (61, 91))	('PAX2', 'Gene', '5076', (162, 166))	('TP53', 'Gene', '7157', (263, 267))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('tumor within kidney parenchyma', 'Disease', (61, 91))	('tumor within kidney', 'Phenotype', 'HP:0009726', (61, 80))	('PBRM1', 'Gene', (280, 285))	('KDM5C', 'Gene', (269, 274))	('mutations', 'Var', (245, 254))	('renal masses', 'Phenotype', 'HP:0009726', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('VHL', 'Gene', (258, 261))	('PAX2', 'Gene', (162, 166))	('PAX8', 'Gene', (168, 172))	('TP53', 'Gene', (263, 267))	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('VHL', 'Gene', '7428', (258, 261))	('KDM5C', 'Gene', '8242', (269, 274))	('PAX8', 'Gene', '7849', (168, 172))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('RCC', 'Disease', (157, 160))
48949	26527083	Tumor mutation screening was performed and identified the following mutations in the tumor tissue: VHL (W88 fs*44), TP53 (R337H), KDM5C (R68*), PBRM1 (R1160*), KIT (P467S), and NOTCH1 (P1236L).	('NOTCH1', 'Gene', '4851', (177, 183))	('tumor', 'Disease', (85, 90))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('R1160*', 'SUBSTITUTION', 'None', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('PBRM1', 'Gene', '55193', (144, 149))	('KDM5C', 'Gene', '8242', (130, 135))	('TP53', 'Gene', (116, 120))	('VHL', 'Gene', (99, 102))	('PBRM1', 'Gene', (144, 149))	('R1160*', 'Var', (151, 157))	('P467S', 'Var', (165, 170))	('P467S', 'Mutation', 'p.P467S', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('R68*', 'Var', (137, 141))	('P1236L', 'Var', (185, 191))	('P1236L', 'Mutation', 'rs1241855040', (185, 191))	('KDM5C', 'Gene', (130, 135))	('VHL', 'Gene', '7428', (99, 102))	('KIT', 'Gene', (160, 163))	('R68*', 'SUBSTITUTION', 'None', (137, 141))	('TP53', 'Gene', '7157', (116, 120))	('R337H', 'Mutation', 'rs121912664', (122, 127))	('R337H', 'Var', (122, 127))	('NOTCH1', 'Gene', (177, 183))	('W88 fs*44', 'Mutation', 'p.W88fsX44', (104, 113))
48953	26527083	Based on the diagnosis of RCC and the molecular genetic finding of a VHL mutation, the patient was subsequently started on the tyrosine kinase inhibitor sunitinib 50 mg per day (4 weeks on, 2 weeks off).	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('patient', 'Species', '9606', (87, 94))	('sunitinib', 'Chemical', 'MESH:D000077210', (153, 162))	('VHL', 'Gene', (69, 72))	('mutation', 'Var', (73, 81))	('VHL', 'Gene', '7428', (69, 72))
48972	26527083	Mutations in the von Hippel-Lindau gene (VHL), a tumor suppressor gene whose discovery arose out of investigations into the pathogenesis of the inherited von Hippel-Lindau cancer syndrome, have also been frequently identified in non-hereditary ccRCCs and are believed to play a role in oncogenesis.	('von Hippel-Lindau', 'Disease', (17, 34))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('RCC', 'Phenotype', 'HP:0005584', (246, 249))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (154, 171))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (246, 249))	('RCC', 'Disease', (246, 249))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (17, 34))	('inherited von Hippel-Lindau cancer syndrome', 'Disease', (144, 187))	('tumor', 'Disease', (49, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (244, 249))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (215, 225))	('inherited von Hippel-Lindau cancer syndrome', 'Disease', 'MESH:D006623', (144, 187))	('VHL', 'Gene', (41, 44))	('VHL', 'Gene', '7428', (41, 44))
48973	26527083	According to The Cancer Research Genome Atlas Network (TCGA) study involving molecular characterization of more than 400 nephrectomy specimens with known ccRCC, somatic mutations in the VHL gene were identified in 43.5 % of cases.	('VHL', 'Gene', (186, 189))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('mutations', 'Var', (169, 178))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('RCC', 'Disease', (156, 159))	('identified', 'Reg', (200, 210))	('Cancer', 'Disease', (17, 23))	('VHL', 'Gene', '7428', (186, 189))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))
48974	26527083	The same study identified PBRM1 and KDM5C mutations in 27.7 % and 5.6 % of cases, respectively.	('PBRM1', 'Gene', (26, 31))	('KDM5C', 'Gene', (36, 41))	('PBRM1', 'Gene', '55193', (26, 31))	('KDM5C', 'Gene', '8242', (36, 41))	('mutations', 'Var', (42, 51))
48975	26527083	In contrast, according to provisional data available through the TCGA, the respective mutation rates of VHL, PBRM1, and KDM5C were 0.0, 1.1, and 0.0 %, respectively, in a set of 88 patient cases of adrenocortical carcinoma.	('VHL', 'Gene', '7428', (104, 107))	('PBRM1', 'Gene', (109, 114))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (198, 222))	('adrenocortical carcinoma', 'Disease', (198, 222))	('patient', 'Species', '9606', (181, 188))	('KDM5C', 'Gene', (120, 125))	('PBRM1', 'Gene', '55193', (109, 114))	('KDM5C', 'Gene', '8242', (120, 125))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (198, 222))	('mutation', 'Var', (86, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('VHL', 'Gene', (104, 107))
48976	26527083	Although a comparison of the two data sets reveals that TP53 mutations tend to occur more frequently in adrenocortical carcinoma compared to ccRCC (18.5 % vs 1.8 %), functional loss of this tumor suppressor gene is common in many forms of aggressive advanced cancers.	('aggressive advanced cancers', 'Disease', (239, 266))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('occur', 'Reg', (79, 84))	('TP53', 'Gene', '7157', (56, 60))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (104, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (104, 128))	('mutations', 'Var', (61, 70))	('loss', 'NegReg', (177, 181))	('tumor', 'Disease', (190, 195))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('adrenocortical carcinoma', 'Disease', (104, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('RCC', 'Disease', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('aggressive advanced cancers', 'Disease', 'MESH:D006223', (239, 266))	('TP53', 'Gene', (56, 60))	('RCC', 'Disease', 'MESH:C538614', (143, 146))
48989	25635221	Although a debulking surgery (R2 resection) did not significantly improve PFS, R2 resection did provide a modest benefit in overall survival compared with patients who did not undergo surgery (22 month vs 11 month).	('PFS', 'MPA', (74, 77))	('patients', 'Species', '9606', (155, 163))	('R2 resection', 'Var', (79, 91))	('overall survival', 'MPA', (124, 140))
49011	25635221	In total, 23.2% of patients with M-EDP had tumor response compared with 9.2% of patients with M-Sz.	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (80, 88))	('M-Sz', 'Chemical', '-', (94, 98))	('M-EDP', 'Chemical', '-', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('M-EDP', 'Var', (33, 38))	('tumor', 'Disease', (43, 48))
49013	25635221	Despite an improvement in response rates with M-EDP, it was a toxic regime with 58.1% of patients experiencing serious adverse events.	('M-EDP', 'Chemical', '-', (46, 51))	('response', 'MPA', (26, 34))	('patients', 'Species', '9606', (89, 97))	('M-EDP', 'Var', (46, 51))	('improvement', 'PosReg', (11, 22))
49015	25635221	reported a significantly prolonged recurrence-free survival in patients receiving mitotane compared with the two control groups without treatment (42 months vs 10 months and 25 months, respectively).	('mitotane', 'Var', (82, 90))	('mitotane', 'Chemical', 'MESH:D008939', (82, 90))	('prolonged', 'PosReg', (25, 34))	('recurrence-free survival', 'CPA', (35, 59))	('patients', 'Species', '9606', (63, 71))
49017	25635221	Fassnacht and colleagues reported an improved 5-year survival among patients treated with adjuvant mitotane compared with patients not treated with mitotane (87% vs 53%, p = 0.04).	('mitotane', 'Var', (99, 107))	('mitotane', 'Chemical', 'MESH:D008939', (99, 107))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (122, 130))	('improved', 'PosReg', (37, 45))	('mitotane', 'Chemical', 'MESH:D008939', (148, 156))
49019	25635221	Recently, Else and colleagues retrospectively analyzed a large cohort (n = 391) and found that patients who received adjuvant mitotane (n = 105) had a significantly improved recurrence-free survival with no impact on overall survival.	('improved', 'PosReg', (165, 173))	('patients', 'Species', '9606', (95, 103))	('mitotane', 'Var', (126, 134))	('mitotane', 'Chemical', 'MESH:D008939', (126, 134))	('recurrence-free survival', 'CPA', (174, 198))
49026	25635221	These advances indicate the importance of genetic dysregulation in ACC development Pan-genomic analysis of genetic mutations, chromosomal aberrations, DNA methylation, gene expression or microRNA dysregulation can provide essential data that are key to improving the application of personalized treatment for patients with ACC and other cancers.	('cancers', 'Disease', 'MESH:D009369', (337, 344))	('cancers', 'Phenotype', 'HP:0002664', (337, 344))	('ACC', 'Disease', (323, 326))	('mutations', 'Var', (115, 124))	('cancers', 'Disease', (337, 344))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (126, 149))	('genetic dysregulation', 'Disease', 'MESH:D030342', (42, 63))	('genetic dysregulation', 'Disease', (42, 63))	('patients', 'Species', '9606', (309, 317))
49027	25635221	using hot spot gene sequencing and comparative genomic hybridization identified copy number alterations or genetic mutations in 47.5% of ACC patients.	('copy number alterations', 'Var', (80, 103))	('ACC', 'Disease', (137, 140))	('genetic mutations', 'Var', (107, 124))	('patients', 'Species', '9606', (141, 149))
49036	25635221	On a multivariate Cox regression model gene expression remained a significant prognostic indicator of survival that was independent of tumor stage.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('Cox', 'Gene', '1351', (18, 21))	('tumor', 'Disease', (135, 140))	('gene expression', 'Var', (39, 54))	('Cox', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
49037	25635221	Recently, alterations in the retinoblastoma gene (RB1) have been described in ACC and may play a role in determining the aggressiveness of the tumor biology.	('play', 'Reg', (90, 94))	('alterations', 'Var', (10, 21))	('described', 'Reg', (65, 74))	('retinoblastoma', 'Disease', 'MESH:D012175', (29, 43))	('retinoblastoma', 'Disease', (29, 43))	('aggressiveness of the tumor', 'Disease', (121, 148))	('aggressiveness of the tumor', 'Disease', 'MESH:D001523', (121, 148))	('RB1', 'Gene', (50, 53))	('ACC', 'Disease', (78, 81))	('RB1', 'Gene', '5925', (50, 53))	('retinoblastoma', 'Phenotype', 'HP:0009919', (29, 43))	('aggressiveness', 'Phenotype', 'HP:0000718', (121, 135))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
49059	25635221	demonstrated that inhibition of mTOR signaling reduces adrenocortical tumor growth.	('adrenocortical tumor', 'Disease', (55, 75))	('reduces', 'NegReg', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (55, 75))	('mTOR signaling', 'Pathway', (32, 46))	('inhibition', 'Var', (18, 28))
49083	25635221	Several studies have shown that mitotane induces the CYP3A4 system making it difficult to achieve appropriate serum drug levels.	('CYP3A4', 'Gene', '1576', (53, 59))	('induces', 'Reg', (41, 48))	('mitotane', 'Var', (32, 40))	('CYP3A4', 'Gene', (53, 59))	('mitotane', 'Chemical', 'MESH:D008939', (32, 40))
49085	25635221	The CTNNB1 gene, which encodes beta-catenin, is mutated in adrenal tumors.	('mutated', 'Var', (48, 55))	('adrenal tumors', 'Disease', 'MESH:D000310', (59, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('CTNNB1', 'Gene', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('CTNNB1', 'Gene', '1499', (4, 10))	('adrenal tumors', 'Disease', (59, 73))
49087	25635221	Furthermore, PKF115-584, a small molecule inhibitor of T-cell factor/beta-catenin complex, has inhibited cell proliferation and induced apoptosis in NCI-H295R ACC cell lines.	('NCI-H295R', 'CellLine', 'CVCL:0458', (149, 158))	('apoptosis', 'CPA', (136, 145))	('inhibited', 'NegReg', (95, 104))	('PKF115-584', 'Var', (13, 23))	('induced', 'Reg', (128, 135))	('cell proliferation', 'CPA', (105, 123))
49127	25635221	The FIRM-ACT trial revealed that mitotane plus etoposide, doxorubicin and cisplatin had an improvement in progression-free survival (PFS) compared with mitotane plus streptozosin.	('mitotane', 'Var', (33, 41))	('progression-free survival', 'CPA', (106, 131))	('mitotane', 'Chemical', 'MESH:D008939', (33, 41))	('doxorubicin', 'Chemical', 'MESH:D004317', (58, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('streptozosin', 'Chemical', '-', (166, 178))	('etoposide', 'Chemical', 'MESH:D005047', (47, 56))	('improvement', 'PosReg', (91, 102))	('mitotane', 'Chemical', 'MESH:D008939', (152, 160))
49185	23255219	Experiments with primary human retinoblastoma samples have revealed novel therapeutic targets, MDM2 and MDMX, which regulate the p53 pathway; inactivation of MDM2/MDMX via Nutlin, a small molecule inhibitor, can result in p53-mediated apoptosis.	('retinoblastoma', 'Gene', '5925', (31, 45))	('MDMX', 'Gene', (104, 108))	('MDMX', 'Gene', '4194', (163, 167))	('MDM2', 'Gene', '4193', (95, 99))	('retinoblastoma', 'Gene', (31, 45))	('MDM2', 'Gene', (95, 99))	('result in', 'Reg', (212, 221))	('human', 'Species', '9606', (25, 30))	('MDM2', 'Gene', '4193', (158, 162))	('MDM2', 'Gene', (158, 162))	('inactivation', 'Var', (142, 154))	('p53', 'Gene', (129, 132))	('MDMX', 'Gene', (163, 167))	('p53', 'Gene', '7157', (129, 132))	('p53', 'Gene', (222, 225))	('p53', 'Gene', '7157', (222, 225))	('retinoblastoma', 'Phenotype', 'HP:0009919', (31, 45))	('MDMX', 'Gene', '4194', (104, 108))
49188	23255219	Importantly, SYK inhibitors have been shown to induce apoptosis of retinoblastoma cells in the preclinical models.	('apoptosis', 'CPA', (54, 63))	('induce', 'PosReg', (47, 53))	('SYK', 'Gene', (13, 16))	('SYK', 'Gene', '6850', (13, 16))	('inhibitors', 'Var', (17, 27))	('retinoblastoma', 'Gene', '5925', (67, 81))	('retinoblastoma', 'Gene', (67, 81))	('retinoblastoma', 'Phenotype', 'HP:0009919', (67, 81))
49189	23255219	These standard cytogenetic studies were expanded to include oligonucleotide array comparative genomic hybridization (oaCGH) in a series of 220 tumors; this approach has defined an area of amplification on 2q24 that may be associated with a poor prognosis.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('amplification', 'Var', (188, 201))	('oligonucleotide', 'Chemical', 'MESH:D009841', (60, 75))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
49199	23255219	A second line of research is related to bone morphogenetic protein (BMP) signaling; GCT resembling germinomas arise in the zebrafish model due to a mutation in a BMP receptor.	('zebrafish', 'Species', '7955', (123, 132))	('germinomas', 'Disease', (99, 109))	('BMP', 'Gene', '649', (68, 71))	('BMP', 'Gene', (162, 165))	('BMP', 'Gene', '649', (162, 165))	('due to', 'Reg', (139, 145))	('germinomas', 'Disease', 'MESH:D018237', (99, 109))	('mutation', 'Var', (148, 156))	('BMP', 'Gene', (68, 71))
49207	23255219	This study showed that treatment with cisplatin/carboplatin resulted in higher risk for disease progression when compared with standard C5V therapy for patients with advanced disease.	('C5V', 'Chemical', '-', (136, 139))	('carboplatin', 'Chemical', 'MESH:D016190', (48, 59))	('patients', 'Species', '9606', (152, 160))	('disease progression', 'CPA', (88, 107))	('cisplatin/carboplatin', 'Var', (38, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))
49240	23255219	While genome-wide studies are ongoing, a more pragmatic approach will be taken with the use of the SequenomOncoCarta Panel, a mass spectrometry-based assay, to detect single nucleotide variants (SNVs) and insertions/deletions in key cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('insertions/deletions', 'Var', (205, 225))	('single nucleotide variants', 'Var', (167, 193))
49264	23255219	The goals of the protocol will be: (1) to evaluate whether a watch and wait strategy can maintain an overall survival rate of >95% for patients with stage I; (2) to evaluate whether the substitution of carboplatin for cisplatin will maintain a high EFS for children in the intermediate risk category; and (3) to increase EFS to >70% for patients with high-risk GCT by exploring the impact of therapy intensification.	('substitution', 'Var', (186, 198))	('patients', 'Species', '9606', (135, 143))	('EFS', 'MPA', (321, 324))	('EFS', 'MPA', (249, 252))	('carboplatin', 'Chemical', 'MESH:D016190', (202, 213))	('increase', 'PosReg', (312, 320))	('cisplatin', 'Chemical', 'MESH:D002945', (218, 227))	('patients', 'Species', '9606', (337, 345))	('children', 'Species', '9606', (257, 265))
49304	23135296	Both Yersinia pseudotuberculosis and Y. enterocolitica can induce severe suppurative and necrotizing enteritis with serositis, along with abscesses especially prominent in the liver but also found in spleen and mesenteric lymph nodes.	('Yersinia pseudotuberculosis', 'Species', '633', (5, 32))	('serositis', 'Phenotype', 'HP:0045073', (116, 125))	('suppurative', 'Disease', (73, 84))	('Y. enterocolitica', 'Var', (37, 54))	('necrotizing enteritis', 'Disease', 'MESH:D004751', (89, 110))	('induce', 'Reg', (59, 65))	('rat', 'Species', '10116', (78, 81))	('abscesses', 'Phenotype', 'HP:0025615', (138, 147))	('serositis', 'Disease', (116, 125))	('necrotizing enteritis', 'Disease', (89, 110))	('serositis', 'Disease', 'MESH:D012700', (116, 125))	('Y. enterocolitica', 'Species', '630', (37, 54))
49424	23135296	Lung: abscesses, thrombosis, vasculitis, pleuritis, and intralesional bacillus-shaped bacteria, multifocal, severe.	('thrombosis', 'Disease', (17, 27))	('pleuritis', 'Phenotype', 'HP:0002102', (41, 50))	('abscesses', 'Disease', (6, 15))	('vasculitis', 'Phenotype', 'HP:0002633', (29, 39))	('pleuritis', 'Disease', (41, 50))	('vasculitis', 'Disease', 'MESH:D014657', (29, 39))	('abscesses', 'Phenotype', 'HP:0025615', (6, 15))	('thrombosis', 'Disease', 'MESH:D013927', (17, 27))	('intralesional bacillus-shaped bacteria', 'Var', (56, 94))	('vasculitis', 'Disease', (29, 39))	('pleuritis', 'Disease', 'MESH:D010998', (41, 50))
49429	23135296	Septicemia in pateints with low CD4 T cells is further evidence suggesting that an immunocompromised immune system may be involved in chromobacteriosis.	('CD4', 'Species', '1151252', (32, 35))	('involved', 'Reg', (122, 130))	('Septicemia', 'Disease', (0, 10))	('Septicemia', 'Disease', 'MESH:D018805', (0, 10))	('low CD4 T cells', 'Var', (28, 43))
49512	23135296	Diabetic nephropathy is a multifactorial progressive kidney disease resulting from alterations in hemodynamic and fibrotic cytokines, such as transforming growth factor beta1 and angiotensin II, respectively, leading to angiopathy of capillaries in the kidney glomeruli, diffuse glomerulosclerosis, and nephrotic syndrome.	('Diabetic nephropathy', 'Disease', (0, 20))	('Diabetic nephropathy', 'Disease', 'MESH:D003928', (0, 20))	('beta1', 'Gene', '10678', (169, 174))	('angiotensin II', 'Gene', '183', (179, 193))	('glomerulosclerosis', 'Disease', (279, 297))	('angiopathy of capillaries in the kidney glomeruli', 'Disease', 'MESH:D007674', (220, 269))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (279, 297))	('glomerulosclerosis', 'Disease', 'MESH:D005921', (279, 297))	('rat', 'Species', '10116', (87, 90))	('kidney disease', 'Phenotype', 'HP:0000112', (53, 67))	('alterations', 'Var', (83, 94))	('nephrotic syndrome', 'Disease', 'MESH:D009404', (303, 321))	('angiopathy of capillaries in the kidney glomeruli', 'Disease', (220, 269))	('kidney disease', 'Disease', (53, 67))	('nephrotic syndrome', 'Disease', (303, 321))	('angiotensin II', 'Gene', (179, 193))	('nephropathy', 'Phenotype', 'HP:0000112', (9, 20))	('kidney disease', 'Disease', 'MESH:D007674', (53, 67))	('beta1', 'Gene', (169, 174))	('progressive kidney', 'Phenotype', 'HP:0012622', (41, 59))	('leading to', 'Reg', (209, 219))	('nephrotic syndrome', 'Phenotype', 'HP:0000100', (303, 321))
49591	23135296	About 15% of patients with chronic renal failure have hyperplastic Brunner's glands detected at endoscopy as multiple polyps in the duodenal bulb.	('chronic renal failure', 'Disease', 'MESH:D007676', (27, 48))	('polyps', 'Disease', 'MESH:D011127', (118, 124))	('renal failure', 'Phenotype', 'HP:0000083', (35, 48))	('hyperplastic', 'Var', (54, 66))	('patients', 'Species', '9606', (13, 21))	('chronic renal failure', 'Phenotype', 'HP:0003774', (27, 48))	('polyps', 'Disease', (118, 124))	('chronic renal failure', 'Disease', (27, 48))	("Brunner's glands", 'Disease', (67, 83))
49598	21163858	Disruption of SF-1 can lead to disorders of adrenal development, while increased SF-1 dosage has been associated with adrenocortical tumorigenesis.	('disorders', 'CPA', (31, 40))	('lead to', 'Reg', (23, 30))	('adrenocortical tumor', 'Disease', (118, 138))	('associated', 'Reg', (102, 112))	('Disruption', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('SF-1', 'Gene', (81, 85))	('increased', 'PosReg', (71, 80))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (118, 138))	('dosage', 'MPA', (86, 92))	('SF-1', 'Gene', (14, 18))	('adrenal development', 'CPA', (44, 63))
49605	21163858	SF-1 is expressed during early adrenal development in mice and humans, and disruption of SF-1 can be associated with adrenal agenesis or hypoplasia in both species.	('disruption', 'Var', (75, 85))	('adrenal agenesis', 'Phenotype', 'HP:0011743', (117, 133))	('adrenal agenesis or hypoplasia', 'Disease', (117, 147))	('adrenal agenesis or hypoplasia', 'Disease', 'MESH:D000312', (117, 147))	('SF-1', 'Gene', (89, 93))	('associated', 'Reg', (101, 111))	('mice', 'Species', '10090', (54, 58))	('humans', 'Species', '9606', (63, 69))	('agenesis or hypoplasia', 'Phenotype', 'HP:0009115', (125, 147))
49623	21163858	Expression vectors (pCMX) containing SF-1 (NR5A1) [wild-type (WT) and mutant G35E] cDNAs have been described previously.	('Expression vectors', 'Species', '29278', (0, 18))	('NR5A1', 'Gene', (43, 48))	('NR5A1', 'Gene', '2516', (43, 48))	('mutant G35E]', 'Var', (70, 82))	('G35E', 'Mutation', 'rs121918654', (77, 81))
49625	21163858	To analyze the effects of SF-1 on CITED2 and ANGPT2 regulation according to promoter length, individual pGL4.10-luc reporter constructs (100 ng/well) were cotransfected with pCMXWT or mutant SF-1 expression vectors (50 ng/well).	('CITED2', 'Gene', (34, 40))	('SF-1', 'Gene', (191, 195))	('pGL4', 'Gene', (104, 108))	('ANGPT2', 'Gene', '285', (45, 51))	('mutant', 'Var', (184, 190))	('ANGPT2', 'Gene', (45, 51))	('CITED2', 'Gene', '10370', (34, 40))	('expression vectors', 'Species', '29278', (196, 214))	('pGL4', 'Gene', '6390', (104, 108))
49626	21163858	Activation of the 4.5 kb ANGPT2 promoter by SF-1 was studied further with increasing amounts of pCMXWT or mutant SF-1 expression vectors (10, 50, and 100 ng/well).	('expression vectors', 'Species', '29278', (118, 136))	('mutant', 'Var', (106, 112))	('ANGPT2', 'Gene', '285', (25, 31))	('ANGPT2', 'Gene', (25, 31))	('SF-1', 'Gene', (113, 117))
49646	21163858	Ang2 (encoded by ANGPT2; MIM 601922) emerged as a common factor in all these datasets and within a GeneGo angiogenic process network.	('ANGPT2', 'Gene', '285', (17, 23))	('ANGPT2', 'Gene', (17, 23))	('MIM 601922', 'Var', (25, 35))	('Ang2', 'Gene', (0, 4))	('Ang2', 'Gene', '285', (0, 4))
49652	21163858	This activation was lost when the functionally impaired G35E mutant SF-1 construct was used.	('SF-1', 'Gene', (68, 72))	('G35E mutant', 'Var', (56, 67))	('G35E', 'Mutation', 'rs121918654', (56, 60))
49670	21163858	In particular, NR4A1 (Nur77, NGFI-B) has been shown to drive the transcription of the plasminogen activator inhibitor 1 (PAI-1) in human umbilical vein endothelial cells and to act as a transcriptional mediator for VEGF-A-induced angiogenesis, with distinct proangiogenic effects in vivo.	('VEGF-A', 'Gene', (215, 221))	('PAI-1', 'Gene', '5054', (121, 126))	('Nur77', 'Gene', '3164', (22, 27))	('NR4A1', 'Var', (15, 20))	('NGFI-B', 'Gene', '3164', (29, 35))	('plasminogen activator inhibitor 1', 'Gene', (86, 119))	('transcription', 'MPA', (65, 78))	('NGFI-B', 'Gene', (29, 35))	('human', 'Species', '9606', (131, 136))	('angiogenesis', 'CPA', (230, 242))	('PAI-1', 'Gene', (121, 126))	('drive', 'PosReg', (55, 60))	('VEGF-A', 'Gene', '7422', (215, 221))	('plasminogen activator inhibitor 1', 'Gene', '5054', (86, 119))	('Nur77', 'Gene', (22, 27))
49673	21163858	In some cases, loss of function changes in key transcriptional regulators or signaling pathways results in hypoplasia of developing glands and hormone deficiency syndromes.	('signaling pathways', 'Pathway', (77, 95))	('hormone deficiency syndromes', 'Disease', (143, 171))	('hormone deficiency', 'Phenotype', 'HP:0000824', (143, 161))	('hypoplasia', 'Disease', 'MESH:C535916', (107, 117))	('hormone deficiency syndromes', 'Disease', 'MESH:D009384', (143, 171))	('hypoplasia', 'Disease', (107, 117))	('loss of function', 'NegReg', (15, 31))	('changes', 'Var', (32, 39))
49674	21163858	Conversely, overactivity or increased expression of these factors and/or pathways has been associated with tumorigenesis.	('increased', 'PosReg', (28, 37))	('expression', 'Species', '29278', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('overactivity', 'Var', (12, 24))	('tumor', 'Disease', (107, 112))	('expression', 'MPA', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('associated', 'Reg', (91, 101))
49680	21115159	Inactivating mutations of the PRKAR1A gene coding for the regulatory type I-alpha (RIalpha) subunit of protein kinase A (PKA) are responsible for the disease in most CNC patients.	('patients', 'Species', '9606', (170, 178))	('PRKAR1A', 'Gene', (30, 37))	('responsible', 'Reg', (130, 141))	('RIalpha', 'Chemical', '-', (83, 90))	('Inactivating mutations', 'Var', (0, 22))	('PRKAR1A', 'Gene', '5573', (30, 37))	('CNC', 'Disease', (166, 169))
49681	21115159	The overall penetrance of CNC among PRKAR1A mutation carriers is near 98%.	('PRKAR1A', 'Gene', (36, 43))	('mutation', 'Var', (44, 52))	('CNC', 'Disease', (26, 29))	('PRKAR1A', 'Gene', '5573', (36, 43))
49682	21115159	Most PRKAR1A mutations result in premature stop codon generation and lead to nonsense-mediated mRNA decay.	('PRKAR1A', 'Gene', (5, 12))	('premature stop codon generation', 'MPA', (33, 64))	('result in', 'Reg', (23, 32))	('PRKAR1A', 'Gene', '5573', (5, 12))	('lead to', 'Reg', (69, 76))	('nonsense-mediated mRNA decay', 'MPA', (77, 105))	('mutations', 'Var', (13, 22))
49683	21115159	Phosphodiesterase-11A (the PDE11A gene) and -8B (the PDE8B gene) mutations were found in patients with isolated adrenal hyperplasia and Cushing syndrome, as well in patients with PPNAD.	('found', 'Reg', (80, 85))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (136, 152))	('Phosphodiesterase-11A', 'Gene', (0, 21))	('Cushing syndrome', 'Disease', 'MESH:D003480', (136, 152))	('PDE11A gene) and -8B', 'Gene', '8622', (27, 47))	('isolated adrenal hyperplasia', 'Disease', 'MESH:C537027', (103, 131))	('PPNAD', 'Chemical', '-', (179, 184))	('Cushing syndrome', 'Disease', (136, 152))	('isolated adrenal hyperplasia', 'Disease', (103, 131))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (165, 173))	('PPNAD', 'Disease', (179, 184))	('Phosphodiesterase-11A', 'Gene', '50940', (0, 21))	('PDE8B', 'Gene', (53, 58))	('PDE8B', 'Gene', '8622', (53, 58))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (112, 131))	('mutations', 'Var', (65, 74))
49684	21115159	Recent evidences demonstrated that dysregulation of cAMP/PKA pathway can modulate other signaling pathways and contributes to adrenocortical tumorigenesis.	('modulate', 'Reg', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('adrenocortical tumorigenesis', 'Disease', (126, 154))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (126, 154))	('cAMP', 'Gene', '820', (52, 56))	('dysregulation', 'Var', (35, 48))	('contributes', 'Reg', (111, 122))	('cAMP', 'Gene', (52, 56))
49691	21115159	Alternatively, the diagnosis may be made if one major criterion is present and a first-degree relative has CNC or an inactivating mutation of the gene encoding protein kinase A regulatory subunit 1alpha (PRKAR1A).	('CNC', 'Disease', (107, 110))	('PRKAR1A', 'Gene', (204, 211))	('inactivating mutation', 'Var', (117, 138))	('PRKAR1A', 'Gene', '5573', (204, 211))
49713	21115159	Inactivating mutations of PRKAR1A gene were identified in patients mapping to chromosome 17.	('patients', 'Species', '9606', (58, 66))	('PRKAR1A', 'Gene', '5573', (26, 33))	('PRKAR1A', 'Gene', (26, 33))	('Inactivating mutations', 'Var', (0, 22))
49714	21115159	To date, at least 117 pathogenic variants in PRKAR1A have been identified.	('PRKAR1A', 'Gene', '5573', (45, 52))	('variants', 'Var', (33, 41))	('PRKAR1A', 'Gene', (45, 52))
49719	21115159	The overall penetrance of CNC among PRKAR1A mutation carriers was near 98%.	('PRKAR1A', 'Gene', (36, 43))	('mutation', 'Var', (44, 52))	('CNC', 'Disease', (26, 29))	('PRKAR1A', 'Gene', '5573', (36, 43))
49720	21115159	The mutations in PRKAR1A are spread along the whole coding sequence and most of them are unique.	('mutations', 'Var', (4, 13))	('PRKAR1A', 'Gene', '5573', (17, 24))	('PRKAR1A', 'Gene', (17, 24))
49721	21115159	To date, only 3 mutations have been found in more than three unrelated families: c.82C>T, c.491_492delTG and c.709-7del6.	('c.709-7del6', 'Var', (109, 120))	('c.82C>T', 'Var', (81, 88))	('c.491_492delTG', 'Var', (90, 104))	('c.491_492delTG', 'Mutation', 'rs281864790', (90, 104))	('c.82C>T', 'Mutation', 'rs281864780', (81, 88))	('c.709-7del6', 'Mutation', 'c.709-7del6', (109, 120))
49722	21115159	Mutant mRNAs containing a premature stop codon are unstable, as a result of nonsense-mediated mRNA decay (NMD).	('Mutant', 'Var', (0, 6))	('nonsense-mediated', 'MPA', (76, 93))	('NMD', 'Disease', 'None', (106, 109))	('NMD', 'Disease', (106, 109))
49723	21115159	Thus, at the molecular level, most of mutations have the same effect: absence of detectable mutant protein and a reduction of RIalpha protein levels by 50%.	('RIalpha', 'Chemical', '-', (126, 133))	('RIalpha protein levels', 'MPA', (126, 148))	('reduction', 'NegReg', (113, 122))	('absence', 'NegReg', (70, 77))	('mutant', 'Var', (92, 98))	('protein', 'Protein', (99, 106))	('mutations', 'Var', (38, 47))
49724	21115159	Germ-line PRKAR1A deletions were found in two patients with sporadic CNC.	('PRKAR1A', 'Gene', '5573', (10, 17))	('patients', 'Species', '9606', (46, 54))	('found', 'Reg', (33, 38))	('PRKAR1A', 'Gene', (10, 17))	('deletions', 'Var', (18, 27))
49725	21115159	In the first patient, the deletion was expected to lead to PRKAR1A haploinsufficiency, consistent with the majority of PRKAR1A mutations causing CNC.	('haploinsufficiency', 'Disease', 'MESH:D058495', (67, 85))	('PRKAR1A', 'Gene', (119, 126))	('patient', 'Species', '9606', (13, 20))	('haploinsufficiency', 'Disease', (67, 85))	('deletion', 'Var', (26, 34))	('CNC', 'Disease', (145, 148))	('lead to', 'Reg', (51, 58))	('PRKAR1A', 'Gene', '5573', (119, 126))	('PRKAR1A', 'Gene', (59, 66))	('mutations', 'Var', (127, 136))	('PRKAR1A', 'Gene', '5573', (59, 66))	('causing', 'Reg', (137, 144))
49726	21115159	In the second patient, the deletion led to in-frame elimination of exon 3 and the expression of a shorter protein, lacking the primary site for interaction with the catalytic PKA subunit.	('expression', 'MPA', (82, 92))	('exon', 'Protein', (67, 71))	('elimination', 'NegReg', (52, 63))	('deletion', 'Var', (27, 35))	('patient', 'Species', '9606', (14, 21))	('lacking', 'NegReg', (115, 122))
49727	21115159	In vitro transfection studies of this PRKAR1A mutation showed impaired ability to bind cyclic AMP and a high PKA activity.	('impaired', 'NegReg', (62, 70))	('PRKAR1A', 'Gene', '5573', (38, 45))	('PKA', 'CPA', (109, 112))	('PRKAR1A', 'Gene', (38, 45))	('bind', 'Interaction', (82, 86))	('activity', 'MPA', (113, 121))	('mutation', 'Var', (46, 54))	('ability', 'MPA', (71, 78))
49728	21115159	The patient bearing this expressed PRKAR1A mutation presented a more severe CNC-phenotype.	('PRKAR1A', 'Gene', '5573', (35, 42))	('mutation', 'Var', (43, 51))	('patient', 'Species', '9606', (4, 11))	('PRKAR1A', 'Gene', (35, 42))	('CNC-phenotype', 'Disease', (76, 89))
49729	21115159	Recently, the pathogenic effects of seven missense substitutions in PRKAR1A were investigated.	('missense substitutions', 'Var', (42, 64))	('PRKAR1A', 'Gene', (68, 75))	('PRKAR1A', 'Gene', '5573', (68, 75))
49730	21115159	These missense PRKAR1A defects (c.26G>A, c.178_348del171, c.220C>T, c.438A>T, c.547G>T, c.638C>A, c.865G>T), whose mRNAs escaped NMD and lead to the expression of a mutant RIalpha protein, increase PKA activity and PKA-specific activation due to decreased binding of RIalpha to cAMP or the C subunit, as well as conformational changes that prevent normal enzymatic functioning.	('c.638C>A', 'Mutation', 'rs281864786', (88, 96))	('c.26G>A', 'Mutation', 'c.26G>A', (32, 39))	('RIalpha', 'Protein', (267, 274))	('c.438A>T', 'Var', (68, 76))	('c.547G>T', 'Var', (78, 86))	('increase', 'PosReg', (189, 197))	('PKA-specific', 'Enzyme', (215, 227))	('cAMP', 'Gene', '820', (278, 282))	('c.220C>T', 'Mutation', 'rs137853303', (58, 66))	('binding', 'Interaction', (256, 263))	('NMD', 'Disease', (129, 132))	('decreased', 'NegReg', (246, 255))	('PKA', 'Enzyme', (198, 201))	('C subunit', 'Protein', (290, 299))	('PRKAR1A', 'Gene', (15, 22))	('c.220C>T', 'Var', (58, 66))	('c.638C>A', 'Var', (88, 96))	('expression', 'MPA', (149, 159))	('c.865G>T', 'Mutation', 'c.865G>T', (98, 106))	('activity', 'MPA', (202, 210))	('RIalpha', 'Chemical', '-', (172, 179))	('conformational', 'MPA', (312, 326))	('NMD', 'Disease', 'None', (129, 132))	('mutant', 'Var', (165, 171))	('activation', 'PosReg', (228, 238))	('RIalpha protein', 'Protein', (172, 187))	('c.178_348del171', 'Mutation', 'c.178_348del171', (41, 56))	('c.438A>T', 'Mutation', 'rs761320023', (68, 76))	('cAMP', 'Gene', (278, 282))	('c.26G>A', 'Var', (32, 39))	('PRKAR1A', 'Gene', '5573', (15, 22))	('RIalpha', 'Chemical', '-', (267, 274))	('c.547G>T', 'Mutation', 'c.547G>T', (78, 86))
49733	21115159	CNC patients with PRKAR1A mutation presented with clinically disease at a younger age and had more myxomas, schwannomas, and thyroid and gonadal tumors than patients without PRKAR1A mutations.	('schwannomas', 'Phenotype', 'HP:0100008', (108, 119))	('patients', 'Species', '9606', (157, 165))	('PRKAR1A', 'Gene', (18, 25))	('gonadal tumors', 'Disease', (137, 151))	('gonadal tumors', 'Disease', 'MESH:D006058', (137, 151))	('PRKAR1A', 'Gene', (174, 181))	('schwannomas', 'Disease', 'MESH:D009442', (108, 119))	('patients', 'Species', '9606', (4, 12))	('schwannomas', 'Disease', (108, 119))	('PRKAR1A', 'Gene', '5573', (18, 25))	('mutation', 'Var', (26, 34))	('myxomas', 'Disease', (99, 106))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('thyroid', 'Disease', (125, 132))	('PRKAR1A', 'Gene', '5573', (174, 181))	('more', 'PosReg', (94, 98))	('gonadal tumors', 'Phenotype', 'HP:0010785', (137, 151))	('myxomas', 'Disease', 'MESH:D009232', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))
49734	21115159	In this group, the c.491-492delTG defect was more frequently associated with patients with cardiac myxomas, lentigines, and thyroid tumors.	('lentigines', 'Disease', (108, 118))	('cardiac myxomas', 'Disease', (91, 106))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cardiac myxomas', 'Phenotype', 'HP:0011672', (91, 106))	('cardiac myxomas', 'Disease', 'MESH:D009232', (91, 106))	('patients', 'Species', '9606', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('thyroid tumors', 'Disease', (124, 138))	('thyroid tumors', 'Disease', 'MESH:D013959', (124, 138))	('associated', 'Reg', (61, 71))	('c.491-492delTG', 'Var', (19, 33))	('c.491-492delTG', 'Mutation', 'rs281864790', (19, 33))
49735	21115159	Although a small number of PRKAR1A missense mutations were identified so far, the clinical follow-up of this subgroup suggests that expressed RIalpha mutant proteins are associated with a more severe and aggressive CNC phenotype.	('PRKAR1A', 'Gene', '5573', (27, 34))	('RIalpha', 'Gene', (142, 149))	('proteins', 'Protein', (157, 165))	('RIalpha', 'Chemical', '-', (142, 149))	('PRKAR1A', 'Gene', (27, 34))	('associated with', 'Reg', (170, 185))	('mutant', 'Var', (150, 156))	('CNC', 'Disease', (215, 218))
49738	21115159	There were no differences in the prevalence of lentigines and other pigmented skin lesions between this group and the patients with PRKAR1A mutations.	('PRKAR1A', 'Gene', '5573', (132, 139))	('lentigines', 'Disease', (47, 57))	('mutations', 'Var', (140, 149))	('pigmented skin lesions', 'Disease', (68, 90))	('pigmented skin lesions', 'Disease', 'MESH:D012871', (68, 90))	('patients', 'Species', '9606', (118, 126))	('PRKAR1A', 'Gene', (132, 139))
49740	21115159	These patients were diagnosed before 8 yr of age and most of them were carriers of either the c.709-7del6 mutation or the c.1A>G / p.M1V substitution in the PRKAR1A gene.	('PRKAR1A', 'Gene', (157, 164))	('c.1A>G', 'Mutation', 'rs281864779', (122, 128))	('c.1A>G / p.M1V', 'Var', (122, 136))	('c.709-7del6', 'Mutation', 'c.709-7del6', (94, 105))	('c.709-7del6', 'Var', (94, 105))	('patients', 'Species', '9606', (6, 14))	('PRKAR1A', 'Gene', '5573', (157, 164))	('p.M1V', 'Mutation', 'rs281864779', (131, 136))
49741	21115159	Therefore, the association of these two PRKAR1A mutations with PPNAD and mostly mild Cushing syndrome has important implications for genetic counseling.	('PRKAR1A', 'Gene', (40, 47))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (85, 101))	('Cushing syndrome', 'Disease', (85, 101))	('PPNAD', 'Chemical', '-', (63, 68))	('PRKAR1A', 'Gene', '5573', (40, 47))	('Cushing syndrome', 'Disease', 'MESH:D003480', (85, 101))	('PPNAD', 'Disease', (63, 68))	('association', 'Interaction', (15, 26))	('mutations', 'Var', (48, 57))
49745	21115159	Recently, a genome-wide screen of 10 kindreds with Cushing syndrome and adrenocortical hyperplasia, who did not have PRKAR1A mutations, identified a strong association between the disease and inactivating mutations in phosphodiesterase 11A (PDE11A).	('adrenocortical hyperplasia', 'Disease', (72, 98))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (72, 98))	('inactivating mutations', 'Var', (192, 214))	('phosphodiesterase 11A', 'Gene', (218, 239))	('PRKAR1A', 'Gene', '5573', (117, 124))	('PDE11A', 'Gene', (241, 247))	('PDE11A', 'Gene', '50940', (241, 247))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (51, 67))	('Cushing syndrome', 'Disease', (51, 67))	('PRKAR1A', 'Gene', (117, 124))	('phosphodiesterase 11A', 'Gene', '50940', (218, 239))	('Cushing syndrome', 'Disease', 'MESH:D003480', (51, 67))
49748	21115159	Five different PDE11A mutations were identified so far in the patients with isolated MAD or PPNAD; three of them resulted in premature stop codon generation and the other two were single base substitutions in the catalytic domain of the protein, significantly affecting the ability of PDE11A to degrade cAMP in vitro.	('PDE11A', 'Gene', (15, 21))	('premature stop codon generation', 'MPA', (125, 156))	('PDE11A', 'Gene', '50940', (15, 21))	('ability', 'MPA', (274, 281))	('affecting', 'Reg', (260, 269))	('PPNAD', 'Chemical', '-', (92, 97))	('resulted in', 'Reg', (113, 124))	('cAMP', 'Gene', (303, 307))	('PDE11A', 'Gene', (285, 291))	('cAMP', 'Gene', '820', (303, 307))	('mutations', 'Var', (22, 31))	('PDE11A', 'Gene', '50940', (285, 291))	('MAD', 'Disease', 'None', (85, 88))	('patients', 'Species', '9606', (62, 70))	('MAD', 'Disease', (85, 88))
49749	21115159	Cyclic AMP and cGMP levels in adrenocortical tumors from individuals with inactivating PDE11A mutations were significantly elevated.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (30, 51))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutations', 'Var', (94, 103))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('elevated', 'PosReg', (123, 131))	('adrenocortical tumors', 'Disease', (30, 51))	('PDE11A', 'Gene', '50940', (87, 93))	('PDE11A', 'Gene', (87, 93))	('cGMP', 'Chemical', 'MESH:D006152', (15, 19))
49753	21115159	Sequencing of the PDE8B-coding regions identified a single base substitution (c.914A>T, p.H305P) in a young girl with Cushing syndrome.	('girl', 'Species', '9606', (108, 112))	('Cushing syndrome', 'Disease', 'MESH:D003480', (118, 134))	('Cushing syndrome', 'Disease', (118, 134))	('PDE8B', 'Gene', (18, 23))	('c.914A>T', 'Var', (78, 86))	('PDE8B', 'Gene', '8622', (18, 23))	('c.914A>T', 'Mutation', 'rs121918360', (78, 86))	('p.H305P', 'Var', (88, 95))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (118, 134))	('p.H305P', 'Mutation', 'rs121918360', (88, 95))
49754	21115159	The patient inherited the mutation from her father, who presented with a very mild-to-indistinguishable adrenocortical phenotype.	('adrenocortical', 'Disease', (104, 118))	('patient', 'Species', '9606', (4, 11))	('adrenocortical', 'Disease', 'MESH:D018268', (104, 118))	('mutation', 'Var', (26, 34))
49755	21115159	In vitro studies indicated an impaired ability of the mutant protein to degrade cAMP.	('cAMP', 'Gene', (80, 84))	('mutant', 'Var', (54, 60))	('cAMP', 'Gene', '820', (80, 84))
49759	21115159	Furthermore, E2F1 mediates proliferative effects of defective RIalpha in a human cell line harboring a PRKAR1A-inactivating mutation.	('RIalpha', 'Chemical', '-', (62, 69))	('PRKAR1A', 'Gene', '5573', (103, 110))	('human', 'Species', '9606', (75, 80))	('defective', 'Var', (52, 61))	('proliferative effects', 'MPA', (27, 48))	('E2F1', 'Gene', '1869', (13, 17))	('E2F1', 'Gene', (13, 17))	('RIalpha', 'Protein', (62, 69))	('PRKAR1A', 'Gene', (103, 110))
49760	21115159	Recently, it was demonstrated that inactivating mutations of PRKAR1A observed in adrenocortical tumors affect SMAD3 function, leading to resistance to TGFbeta-induced apoptosis.	('function', 'MPA', (116, 124))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (81, 102))	('resistance', 'CPA', (137, 147))	('PRKAR1A', 'Gene', (61, 68))	('inactivating mutations', 'Var', (35, 57))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('SMAD3', 'Gene', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('SMAD3', 'Gene', '4088', (110, 115))	('leading to', 'Reg', (126, 136))	('TGFbeta', 'Gene', (151, 158))	('PRKAR1A', 'Gene', '5573', (61, 68))	('adrenocortical tumors', 'Disease', (81, 102))	('TGFbeta', 'Gene', '7040', (151, 158))	('affect', 'Reg', (103, 109))
49762	21115159	Somatic mutations of the CTNNB1 gene have been found in adrenal tumors from patients with PPNAD, Carney complex and germline PRKAR1A-inactivating mutations.	('CTNNB1', 'Gene', '1499', (25, 31))	('PPNAD', 'Chemical', '-', (90, 95))	('patients', 'Species', '9606', (76, 84))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('PRKAR1A', 'Gene', '5573', (125, 132))	('Carney complex', 'Disease', (97, 111))	('found', 'Reg', (47, 52))	('CTNNB1', 'Gene', (25, 31))	('mutations', 'Var', (8, 17))	('adrenal tumors', 'Disease', 'MESH:D000310', (56, 70))	('PRKAR1A', 'Gene', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('adrenal tumors', 'Disease', (56, 70))
49764	21115159	Our previous study demonstrated that mouse Prkar1a haploinsufficiency leads to an increase in tumors in the Trp53+/- or Rb1+/- backgrounds and chemically-induced skin papillomas by dysregulation of the cell cycle and Wnt signaling.	('skin papillomas', 'Disease', 'MESH:D010212', (162, 177))	('cell cycle', 'CPA', (202, 212))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('haploinsufficiency', 'Disease', 'MESH:D058495', (51, 69))	('Rb1', 'Gene', (120, 123))	('papillomas', 'Phenotype', 'HP:0012740', (167, 177))	('dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (181, 212))	('haploinsufficiency', 'Disease', (51, 69))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Prkar1a', 'Gene', (43, 50))	('mouse', 'Species', '10090', (37, 42))	('tumors', 'Disease', (94, 100))	('Trp53', 'Gene', '22059', (108, 113))	('Trp53', 'Gene', (108, 113))	('increase', 'PosReg', (82, 90))	('Prkar1a', 'Gene', '19084', (43, 50))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('dysregulation', 'Var', (181, 194))	('skin papillomas', 'Disease', (162, 177))	('Rb1', 'Gene', '19645', (120, 123))
49767	21115159	Phosphodiesterase-11A (PDE11A) and -8B (PDE8B) mutations were found in patients with isolated adrenal hyperplasia and Cushing syndrome, as well in patients with PPNAD.	('isolated adrenal hyperplasia', 'Disease', 'MESH:C537027', (85, 113))	('PDE8B', 'Gene', (40, 45))	('PDE11A) and -8B', 'Gene', '50940;8622', (23, 38))	('Cushing syndrome', 'Disease', (118, 134))	('Cushing syndrome', 'Disease', 'MESH:D003480', (118, 134))	('PDE8B', 'Gene', '8622', (40, 45))	('isolated adrenal hyperplasia', 'Disease', (85, 113))	('patients', 'Species', '9606', (71, 79))	('Phosphodiesterase-11A', 'Gene', (0, 21))	('PPNAD', 'Chemical', '-', (161, 166))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (147, 155))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (94, 113))	('Phosphodiesterase-11A', 'Gene', '50940', (0, 21))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (118, 134))	('found', 'Reg', (62, 67))
49770	21115159	Furthermore, dysregulation of this pathway can modulate other signaling pathways and contributes to adrenocortical tumorigenesis.	('contributes', 'Reg', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('dysregulation', 'Var', (13, 26))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (100, 128))	('adrenocortical tumorigenesis', 'Disease', (100, 128))	('modulate', 'Reg', (47, 55))
49772	21115159	Patients with isolated PPNAD were diagnosed before 8 yr of age and most of them were carriers of either the c.709-7del6 mutation or the c.1A>G / p.M1V substitution in the PRKAR1A gene.	('PPNAD', 'Chemical', '-', (23, 28))	('c.1A>G / p.M1V', 'Var', (136, 150))	('PRKAR1A', 'Gene', (171, 178))	('c.709-7del6', 'Mutation', 'c.709-7del6', (108, 119))	('c.1A>G', 'Mutation', 'rs281864779', (136, 142))	('Patients', 'Species', '9606', (0, 8))	('c.709-7del6 mutation', 'Var', (108, 128))	('isolated PPNAD', 'Disease', (14, 28))	('PRKAR1A', 'Gene', '5573', (171, 178))	('p.M1V', 'Mutation', 'rs281864779', (145, 150))
49774	21115159	PDE11A mutations are associated with isolated MAD or PPNAD and significantly affect the ability of PDE11A to degrade cAMP in vitro.	('PDE11A', 'Gene', (99, 105))	('PDE11A', 'Gene', '50940', (99, 105))	('PPNAD', 'Chemical', '-', (53, 58))	('associated', 'Reg', (21, 31))	('PPNAD', 'Disease', (53, 58))	('affect', 'Reg', (77, 83))	('PDE11A', 'Gene', (0, 6))	('MAD', 'Disease', 'None', (46, 49))	('cAMP', 'Gene', (117, 121))	('PDE11A', 'Gene', '50940', (0, 6))	('MAD', 'Disease', (46, 49))	('cAMP', 'Gene', '820', (117, 121))	('mutations', 'Var', (7, 16))
49777	21115159	Since most of the PRKAR1A mutations lead to NMD and produce no mutant protein, additional studies are needed to understand what molecular mechanisms may explain phenotypic differences.	('NMD', 'Disease', (44, 47))	('lead to', 'Reg', (36, 43))	('PRKAR1A', 'Gene', '5573', (18, 25))	('mutations', 'Var', (26, 35))	('mutant protein', 'MPA', (63, 77))	('PRKAR1A', 'Gene', (18, 25))	('NMD', 'Disease', 'None', (44, 47))
49778	21115159	PRKAR1A and mutations in PDE genes (PDE11A and PDE8B) represent a unique model that can be used to understand the function and complex interactions of the cAMP/PKA signaling pathway and may be exploited pharmacologically for the benefit of patients with CNC, PPNAD, MAD and related disorders.	('PDE', 'Gene', (47, 50))	('PPNAD', 'Disease', (259, 264))	('PDE', 'Gene', (36, 39))	('PDE11A', 'Gene', (36, 42))	('PDE11A', 'Gene', '50940', (36, 42))	('MAD', 'Disease', (266, 269))	('PDE8B', 'Gene', (47, 52))	('PRKAR1A', 'Gene', (0, 7))	('PDE', 'Gene', '5152;50940', (47, 50))	('cAMP', 'Gene', (155, 159))	('PPNAD', 'Chemical', '-', (259, 264))	('PDE', 'Gene', '5152;50940', (36, 39))	('PDE', 'Gene', (25, 28))	('CNC', 'Disease', (254, 257))	('patients', 'Species', '9606', (240, 248))	('MAD', 'Disease', 'None', (266, 269))	('PRKAR1A', 'Gene', '5573', (0, 7))	('PDE8B', 'Gene', '8622', (47, 52))	('mutations', 'Var', (12, 21))	('PDE', 'Gene', '5152;50940', (25, 28))	('cAMP', 'Gene', '820', (155, 159))
49783	20179500	Its ability to enhance wild-type alpha1beta2gamma2L and etomidate-insensitive mutant alpha1beta2(M286W)gamma2L human gamma-aminobutyric acid type A receptor activities was assessed using electrophysiological techniques.	('activities', 'MPA', (157, 167))	('etomidate', 'Chemical', 'MESH:D005045', (56, 65))	('M286W', 'Mutation', 'p.M286W', (97, 102))	('human', 'Species', '9606', (111, 116))	('M286W', 'Var', (97, 102))	('enhance', 'PosReg', (15, 22))	('alpha1beta2gamma2L', 'Enzyme', (33, 51))	('alpha1beta2', 'Protein', (85, 96))
49891	20179500	Rats given carboetomidate had serum corticosterone concentrations that were significantly higher than those given an equi-hypnotic dose of etomidate and not significantly different from those given vehicle.	('Rats', 'Species', '10116', (0, 4))	('etomidate', 'Chemical', 'MESH:D005045', (139, 148))	('etomidate', 'Chemical', 'MESH:D005045', (16, 25))	('corticosterone', 'Chemical', 'MESH:D003345', (36, 50))	('carboetomidate', 'Chemical', 'MESH:C548177', (11, 25))	('rat', 'Species', '10116', (58, 61))	('higher', 'PosReg', (90, 96))	('serum corticosterone concentrations', 'MPA', (30, 65))	('carboetomidate', 'Var', (11, 25))
49900	20179500	Similarly, imidazole-containing antifungal agents bind within the active sites of CYP130 and CYP121 where they form a coordination bond between their basic nitrogens and the enzymes' heme iron.	('nitrogens', 'Chemical', 'MESH:D009584', (156, 165))	('C', 'Chemical', 'MESH:D002244', (93, 94))	('bind', 'Interaction', (50, 54))	('CYP121', 'Var', (93, 99))	('imidazole', 'Chemical', 'MESH:C029899', (11, 20))	('coordination bond', 'Interaction', (118, 135))	('C', 'Chemical', 'MESH:D002244', (82, 83))	('iron', 'Chemical', 'MESH:D007501', (188, 192))	('heme', 'Chemical', 'MESH:D006418', (183, 187))
49912	20179500	Previous electrophysiological studies of the GABAA receptor have shown that a mutation in the beta subunit at the putative etomidate binding site (M286W) nearly completely abolishes etomidate enhancement.	('M286W', 'Mutation', 'p.M286W', (147, 152))	('mutation', 'Var', (78, 86))	('etomidate enhancement', 'MPA', (182, 203))	('GABA', 'Chemical', 'MESH:D005680', (45, 49))	('M286W', 'Var', (147, 152))	('etomidate', 'Chemical', 'MESH:D005045', (123, 132))	('etomidate', 'Chemical', 'MESH:D005045', (182, 191))	('abolishes', 'NegReg', (172, 181))
49913	20179500	Our studies show that this mutation also abolishes enhancement by carboetomidate, suggesting that carboetomidate modulates GABAA receptor function by binding to the same site on the GABAA receptor as etomidate.	('modulates', 'Reg', (113, 122))	('carboetomidate', 'Chemical', 'MESH:C548177', (98, 112))	('GABA', 'Chemical', 'MESH:D005680', (123, 127))	('etomidate', 'Chemical', 'MESH:D005045', (71, 80))	('function', 'MPA', (138, 146))	('GABA', 'Chemical', 'MESH:D005680', (182, 186))	('mutation', 'Var', (27, 35))	('carboetomidate', 'Chemical', 'MESH:C548177', (66, 80))	('etomidate', 'Chemical', 'MESH:D005045', (200, 209))	('GABAA receptor', 'Protein', (123, 137))	('etomidate', 'Chemical', 'MESH:D005045', (103, 112))	('binding', 'Interaction', (150, 157))
49922	20179500	Methoxycarbonyl etomidate is very rapidly metabolized by esterases and, therefore, produces hypnosis of extremely short duration and does not cause prolonged suppression of adrenocortical function following administration.	('Methoxycarbonyl', 'Var', (0, 15))	('Methoxycarbonyl etomidate', 'Chemical', 'MESH:C543057', (0, 25))	('rat', 'Species', '10116', (215, 218))	('prolonged suppression of adrenocortical function', 'Phenotype', 'HP:0008207', (148, 196))	('hypnosis', 'Disease', 'None', (92, 100))	('suppression of adrenocortical function', 'Disease', 'MESH:D018268', (158, 196))	('hypnosis', 'Disease', (92, 100))	('rat', 'Species', '10116', (122, 125))	('suppression of adrenocortical function', 'Disease', (158, 196))
49933	32592449	 TP53 p.Arg337His geographic distribution correlates with adrenocortical tumor occurrence The p.Arg337His mutation of the TP53 is the most frequent germline missense variant associated with cancer described so far in this gene.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('TP53', 'Gene', (122, 126))	('associated', 'Reg', (174, 184))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('TP53', 'Gene', '7157', (122, 126))	('TP53', 'Gene', '7157', (1, 5))	('tumor', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('TP53', 'Gene', (1, 5))	('p.Arg337His', 'Mutation', 'rs121912664', (94, 105))	('p.Arg337His', 'Var', (94, 105))	('p.Arg337His', 'Mutation', 'rs121912664', (6, 17))
49942	32592449	ACT was found to be a good sentinel cancer to suppose p.Arg337His presence in our region.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('p.Arg337His', 'Mutation', 'rs121912664', (54, 65))	('cancer', 'Disease', (36, 42))	('p.Arg337His', 'Var', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
49943	32592449	The study presents a reliable and efficient method for high-throughput TP53 p.Arg337His genotyping, what allowed authors to determine the frequency and geographic distribution of this mutation in a cohort from the most populous state in Brazil.	('TP53', 'Gene', '7157', (71, 75))	('p.Arg337His', 'Var', (76, 87))	('TP53', 'Gene', (71, 75))	('p.Arg337His', 'Mutation', 'rs121912664', (76, 87))
49944	32592449	In addition, adrenocortical tumor was found to be a good sentinel cancer to suppose p.Arg337His presence in the region analyzed.	('p.Arg337His', 'Mutation', 'rs121912664', (84, 95))	('p.Arg337His', 'Var', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (13, 33))	('adrenocortical tumor', 'Disease', (13, 33))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Disease', (66, 72))
49946	32592449	Germline mutations in this gene are usually associated with Li-Fraumeni Syndrome (LFS), an inherited disorder characterized by predisposition to a broad spectrum of tumors.	('associated', 'Reg', (44, 54))	('Germline mutations', 'Var', (0, 18))	('Li-Fraumeni Syndrome', 'Disease', (60, 80))	('LFS', 'Disease', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('LFS', 'Disease', 'MESH:D016864', (82, 85))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('inherited disorder', 'Disease', 'MESH:D030342', (91, 109))	('inherited disorder', 'Disease', (91, 109))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (60, 80))
49948	32592449	The p.Arg337His mutation of the TP53 (NG_017013.2:g.21852G>A) is known to contribute to the development of several types of cancer, such as adrenocortical tumors (ACT), choroid plexus carcinoma, osteosarcoma, breast cancer, and neuroblastoma (Assumpcao et al., 2008; Seidinger et al., 2010; Seidinger, et al., 2015).	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('TP53', 'Gene', '7157', (32, 36))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (169, 193))	('cancer', 'Disease', (216, 222))	('p.Arg337His', 'Mutation', 'rs121912664', (4, 15))	('p.Arg337His', 'Var', (4, 15))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (140, 161))	('osteosarcoma', 'Disease', (195, 207))	('osteosarcoma', 'Disease', 'MESH:D012516', (195, 207))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (169, 193))	('NG_017013.2:g.21852G>A', 'Mutation', 'rs121912664', (38, 60))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('neuroblastoma', 'Disease', (228, 241))	('contribute', 'Reg', (74, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('neuroblastoma', 'Phenotype', 'HP:0003006', (228, 241))	('TP53', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('adrenocortical tumors', 'Disease', (140, 161))	('neuroblastoma', 'Disease', 'MESH:D009447', (228, 241))	('cancer', 'Disease', (124, 130))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('osteosarcoma', 'Phenotype', 'HP:0002669', (195, 207))	('breast cancer', 'Disease', (209, 222))	('choroid plexus carcinoma', 'Disease', (169, 193))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
49951	32592449	Genotype analysis based on a series of SNPs loci near in or around the TP53 revealed that p.Arg337His carriers share the same relatively rare haplotype, raising the hypothesis of a founder effect (Garritano et al., 2010).	('TP53', 'Gene', '7157', (71, 75))	('p.Arg337His', 'Var', (90, 101))	('TP53', 'Gene', (71, 75))	('p.Arg337His', 'Mutation', 'rs121912664', (90, 101))
49952	32592449	Although different tumors have been linked to the p.Arg337His, ACT presents the most striking association with the mutation.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('p.Arg337His', 'Var', (50, 61))	('p.Arg337His', 'Mutation', 'rs121912664', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
49953	32592449	More than 90% of Brazilian patients diagnosed with ACT are carriers of this missense variant, a finding that explained the reason why Brazil has the highest incidence in the world for this type of tumor (Ribeiro et al., 2001).	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('missense', 'Var', (76, 84))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))
49959	32592449	In addition, first evidence on the geographic superposition of this mutation and pediatric adrenocortical cancer is presented.	('mutation', 'Var', (68, 76))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
49962	32592449	After the routine testing for hemoglobinopathies, 31,612 samples consecutively collected from January to September of 2005 were analyzed for the p.Arg337His mutation.	('hemoglobinopathies', 'Disease', 'MESH:D006453', (30, 48))	('hemoglobinopathies', 'Disease', (30, 48))	('p.Arg337His', 'Mutation', 'rs121912664', (145, 156))	('p.Arg337His', 'Var', (145, 156))
49967	32592449	The allelic discrimination by real-time polymerase chain reaction (PCR) consisted of amplification of exon 10 from the TP53 (NG_017013.2), using primers flanking the region of the p.Arg337His mutation: (CCTCCTCTGTTGCTGCAGATC) and (CCTCATTCAGATCTCTCGGAAC).	('p.Arg337His', 'Var', (180, 191))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('p.Arg337His', 'Mutation', 'rs121912664', (180, 191))
49969	32592449	The sensitivity in detecting the p.Arg337His allele decreased, but was still possible, when attempting to find a mutant among four or five samples per well.	('p.Arg337His', 'Mutation', 'rs121912664', (33, 44))	('p.Arg337His', 'Var', (33, 44))	('decreased', 'NegReg', (52, 61))
49971	32592449	Of these, six were positive for the p.Arg337His allele both by pooled and individual analysis.	('p.Arg337His', 'Mutation', 'rs121912664', (36, 47))	('p.Arg337His', 'Var', (36, 47))	('positive', 'Reg', (19, 27))
49972	32592449	The presence of haplotype A3 was examined in p.Arg337His positive samples by using allele-specific oligonucleotide PCR, followed by nested-PCR to detect the SNP rs9894946, as previously described by Garritano et al., 2010.	('oligonucleotide', 'Chemical', 'MESH:D009841', (99, 114))	('rs9894946', 'Mutation', 'rs9894946', (161, 170))	('p.Arg337His', 'Mutation', 'rs121912664', (45, 56))	('p.Arg337His', 'Var', (45, 56))	('rs9894946', 'Var', (161, 170))
49973	32592449	Furthermore, all cases were genotyped by direct sequencing of SNPs rs1642785 and rs1800370 to distinguish between the haplotypes A1 and A3, as described by Giacomazzi, Selistre, Duarte, et al., 2013.	('rs1800370', 'Var', (81, 90))	('rs1642785', 'Mutation', 'rs1642785', (67, 76))	('rs1800370', 'Mutation', 'rs1800370', (81, 90))	('rs1642785', 'Var', (67, 76))	('SNPs', 'Gene', (62, 66))
49975	32592449	After observe that the distribution of p.Arg337His carriers was uneven and to better explore the distribution pattern of carriers along our region, we conducted statistical analysis to detect potential deviations from the expected random occurrence of p.Arg337His.	('p.Arg337His', 'Mutation', 'rs121912664', (39, 50))	('p.Arg337His', 'Var', (39, 50))	('p.Arg337His', 'Mutation', 'rs121912664', (252, 263))	('p.Arg337His', 'Var', (252, 263))
49976	32592449	Since ACT is strongly associated with p.Arg337His in our region (Seidinger et al., 2010), we matched the geographic occurrence of p.Arg337His mutation within the RHB-VII with that of ACT.	('p.Arg337His', 'Var', (130, 141))	('p.Arg337His', 'Var', (38, 49))	('p.Arg337His', 'Mutation', 'rs121912664', (130, 141))	('p.Arg337His', 'Mutation', 'rs121912664', (38, 49))	('associated', 'Reg', (22, 32))	('ACT', 'Disease', (6, 9))
49980	32592449	No association could be found between p.Arg337His and gender, ethnicity, premature birth or twinning (Table 1).	('premature birth', 'Disease', (73, 88))	('premature birth', 'Phenotype', 'HP:0001622', (73, 88))	('p.Arg337His', 'Mutation', 'rs121912664', (38, 49))	('p.Arg337His', 'Var', (38, 49))
49981	32592449	Haplotyping of mutation carriers with available DNA sample revealed the presence of haplotype A3 in all p.Arg337His carriers tested (n = 63).	('p.Arg337His', 'Var', (104, 115))	('presence', 'Reg', (72, 80))	('p.Arg337His', 'Mutation', 'rs121912664', (104, 115))
49982	32592449	After analyzing 31,612 samples, we noticed that some cities had a p.Arg337His frequency much higher than the overall average.	('higher', 'PosReg', (93, 99))	('p.Arg337His', 'Mutation', 'rs121912664', (66, 77))	('p.Arg337His', 'Var', (66, 77))
49997	32592449	The method currently employed to analyze the p.Arg337His mutation has been PCR followed by restriction fragment length polymorphism analysis (PCR-RFLP) of an HhaI site abolished by the p.Arg337His mutation (Ribeiro et al., 2001).	('p.Arg337His', 'Var', (45, 56))	('p.Arg337His', 'Mutation', 'rs121912664', (185, 196))	('p.Arg337His', 'Var', (185, 196))	('p.Arg337His', 'Mutation', 'rs121912664', (45, 56))
50001	32592449	We have no explanation for this uneven distribution, though it may be related to lower population migration rates or a potential diffusion center for p.Arg337His.	('p.Arg337His', 'Var', (150, 161))	('lower', 'NegReg', (81, 86))	('p.Arg337His', 'Mutation', 'rs121912664', (150, 161))	('population migration rates', 'CPA', (87, 113))
50002	32592449	Adrenocortical tumors was found to be a good sentinel cancer to suppose p.Arg337His presence in our region.	('Adrenocortical tumors', 'Disease', (0, 21))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Adrenocortical tumors', 'Disease', 'MESH:D018268', (0, 21))	('p.Arg337His', 'Mutation', 'rs121912664', (72, 83))	('p.Arg337His', 'Var', (72, 83))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
50003	32592449	We observed a pronounced correlation between the occurrence of this tumor and p.Arg337His mutation, a finding that reinforces the predominant role of genetic predisposition over environmental risk factors on ACT tumorigenesis.	('tumor', 'Disease', (68, 73))	('p.Arg337His', 'Var', (78, 89))	('p.Arg337His', 'Mutation', 'rs121912664', (78, 89))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (212, 217))
50008	32592449	A prospective study conducted in the Brazilian state of Parana found that p.Arg337His children enrolled in an ACT surveillance program had earlier diagnosis and better prognosis than those who did not adhere to the cancer surveillance program (Custodio et al., 2013).	('children', 'Species', '9606', (86, 94))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('p.Arg337His', 'Mutation', 'rs121912664', (74, 85))	('p.Arg337His', 'Var', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
50011	32592449	Additionally, considering the increased susceptibility of p.Arg337His carriers to multiple cancers, both during childhood (Custodio et al., 2013; Giacomazzi, Selistre, Rossi, et al., 2013; Seidinger et al., 2010; Seidinger, et al., 2015) and adulthood (Achatz et al., 2007; Assumpcao et al., 2008; Cury, Ferraz, & Silva, 2014; Giacomazzi, Graudenz, et al., 2014; Mastellaro et al., 2017), there would be a further increase in the number of people who could benefit from early detection of the p.Arg337His mutation.	('people', 'Species', '9606', (440, 446))	('multiple cancers', 'Disease', 'MESH:D009369', (82, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('the', 'Var', (489, 492))	('p.Arg337His', 'Mutation', 'rs121912664', (493, 504))	('p.Arg337His', 'Mutation', 'rs121912664', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('multiple cancers', 'Disease', (82, 98))
50012	32592449	Newborn screening of the p.Arg337His mutation has the potential for improving early diagnosis and prognosis of ACT patients (Custodio et al., 2013).	('patients', 'Species', '9606', (115, 123))	('improving', 'PosReg', (68, 77))	('p.Arg337His', 'Mutation', 'rs121912664', (25, 36))	('p.Arg337His', 'Var', (25, 36))
50014	32592449	For genetic counseling purposes, it remains to be determined the full spectrum of cancer associated with p.Arg337His mutation, both in childhood and adulthood and, perhaps most importantly, the psychological consequences of knowing it beforehand.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('p.Arg337His', 'Var', (105, 116))	('p.Arg337His', 'Mutation', 'rs121912664', (105, 116))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
50015	32592449	The authors have a patent application related to this study to declare: JAY, IPC, ALS and CSG are inventors of the application BR 10 2012 031182 8 A2, submitted on December 7th, 2012 to Brazilian National Institute of Industrial Property (Instituto Nacional da Propriedade Industrial - INPI), covering the high-throughput method for p.Arg337His genotyping, which is fully described in the manuscript.	('ALS', 'Disease', 'MESH:D008113', (82, 85))	('p.Arg337His', 'Mutation', 'rs121912664', (333, 344))	('ALS', 'Disease', (82, 85))	('p.Arg337His', 'Var', (333, 344))
50021	32059362	All but one (64/65; 98%) NETs and all (54/54; 100%) NECs revealed STX1 positivity in at least 50% of the tumor cells.	('revealed', 'Reg', (57, 65))	('STX1', 'Gene', (66, 70))	('NETs', 'Disease', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('NETs', 'Disease', 'MESH:D018358', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('STX1', 'Gene', '6804', (66, 70))	('positivity', 'Var', (71, 81))	('tumor', 'Disease', (105, 110))
50061	32059362	All 20 (100%) pituitary adenoma cases and 14/16 (88%) of pheochromocytoma cases showed STX1 positivity (Table 1, Figure 6).	('pituitary adenoma', 'Disease', (14, 31))	('pituitary adenoma', 'Disease', 'MESH:D010911', (14, 31))	('STX1', 'Gene', (87, 91))	('pheochromocytoma', 'Disease', (57, 73))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (14, 31))	('STX1', 'Gene', '6804', (87, 91))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (57, 73))	('pheochromocytoma', 'Disease', 'MESH:D010673', (57, 73))	('positivity', 'Var', (92, 102))
50140	31717612	In our previous in vitro study, we reported that MTT interferes with the modulation of both MSH1 and MSH2 enzymes belonging to Mismatch Repair Systems (MMRs), which could explain the radiosensitizing properties of MTT.	('MTT', 'Var', (49, 52))	('MTT', 'Chemical', 'MESH:D008939', (49, 52))	('interferes', 'NegReg', (53, 63))	('modulation', 'MPA', (73, 83))	('MSH2', 'Gene', (101, 105))	('di', 'Disease', 'MESH:D003643', (185, 187))	('MSH1', 'Gene', (92, 96))	('MSH2', 'Gene', '4436', (101, 105))	('MTT', 'Chemical', 'MESH:D008939', (214, 217))
50152	31717612	In particular, we observed an early volume reduction in the tumor masses treated with MTT/IR in combination compared to those from the control (p < 0.0001) and also a strong effect on tumors treated with IR alone (p < 0.0001), according to the RECIST criteria.	('di', 'Disease', 'MESH:D003643', (232, 234))	('MTT/IR', 'Var', (86, 92))	('volume', 'MPA', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('MTT', 'Chemical', 'MESH:D008939', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('reduction', 'NegReg', (43, 52))	('combination', 'Var', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Disease', (60, 65))
50158	31717612	MTT reduced the corticosterone level in mice after 7 and 14 days of treatment by 53% and 56%, respectively, compared to the untreated control (p < 0.005), confirming its antisteroidogenic properties.	('MTT', 'Var', (0, 3))	('steroid', 'Chemical', 'MESH:D013256', (174, 181))	('corticosterone', 'Chemical', 'MESH:D003345', (16, 30))	('reduced', 'NegReg', (4, 11))	('MTT', 'Chemical', 'MESH:D008939', (0, 3))	('mice', 'Species', '10090', (40, 44))	('corticosterone level', 'MPA', (16, 36))	('reduced the corticosterone level', 'Phenotype', 'HP:0032363', (4, 36))
50181	31717612	On the contrary, in both siMSH2 cell lines treated with MTT/IR, we observed temporary G2 arrest, which progressively decreased to 4% and 11% in the siMSH2 H295R and SW13 cell lines at 72 h of treatment, respectively.	('arrest', 'Disease', (89, 95))	('MTT/IR', 'Var', (56, 62))	('MSH2', 'Gene', (150, 154))	('SW13', 'CellLine', 'CVCL:0542', (165, 169))	('MSH2', 'Gene', '4436', (150, 154))	('decreased', 'NegReg', (117, 126))	('MSH2', 'Gene', (27, 31))	('MSH2', 'Gene', '4436', (27, 31))	('MTT', 'Chemical', 'MESH:D008939', (56, 59))	('H295R', 'Chemical', '-', (155, 160))	('arrest', 'Disease', 'MESH:D006323', (89, 95))
50198	31717612	Interestingly, only histological samples belonging to tumors treated with MTT/IR showed the presence of necrotic tissue and the absence of neoplastic cells after 14 days of treatment.	('necrotic', 'Disease', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('MTT/IR', 'Var', (74, 80))	('necrotic', 'Disease', 'MESH:D009336', (104, 112))	('tumors', 'Disease', (54, 60))	('MTT', 'Chemical', 'MESH:D008939', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
50200	31717612	The antisteroidogenic effect on the corticosterone level from MTT/IR treatment is significantly higher compared to that of MTT or IR alone (Figure 4).	('MTT', 'Chemical', 'MESH:D008939', (62, 65))	('higher', 'PosReg', (96, 102))	('corticosterone', 'Chemical', 'MESH:D003345', (36, 50))	('MTT/IR treatment', 'Var', (62, 78))	('antisteroidogenic effect', 'MPA', (4, 28))	('steroid', 'Chemical', 'MESH:D013256', (8, 15))	('corticosterone level', 'MPA', (36, 56))	('MTT', 'Chemical', 'MESH:D008939', (123, 126))
50206	31717612	Surprisingly, the cells from tumors treated with MTT/IR, after a block in the G2 phase, underwent cell death.	('MTT/IR', 'Var', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('MTT', 'Chemical', 'MESH:D008939', (49, 52))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('death', 'Disease', 'MESH:D003643', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('death', 'Disease', (103, 108))	('tumors', 'Disease', (29, 35))
50210	31717612	Similarly, we observed an increased G2 phase block in the cell cycle and cell death in H295R and SW13 adrenocortical cell lines after silencing MSH2, an enzyme belonging to the MMR family.	('death', 'Disease', 'MESH:D003643', (78, 83))	('death', 'Disease', (78, 83))	('MSH2', 'Gene', (144, 148))	('MSH2', 'Gene', '4436', (144, 148))	('H295R', 'Chemical', '-', (87, 92))	('silencing', 'Var', (134, 143))	('SW13', 'CellLine', 'CVCL:0542', (97, 101))	('G2 phase block', 'CPA', (36, 50))
50213	31717612	Furthermore, in the control sample, the absence of MSH2 protein caused cell death and a consistent accumulation of the cell proliferative compartment, indicating a pivotal role of this protein in ACC.	('absence', 'Var', (40, 47))	('MSH2', 'Gene', (51, 55))	('MSH2', 'Gene', '4436', (51, 55))	('protein', 'Protein', (56, 63))	('di', 'Disease', 'MESH:D003643', (153, 155))	('death', 'Disease', 'MESH:D003643', (76, 81))	('ACC', 'Phenotype', 'HP:0006744', (196, 199))	('accumulation', 'PosReg', (99, 111))	('death', 'Disease', (76, 81))
50214	31717612	Mimicking a genetic condition, we speculate that MTT reduces MSH2 activity, allowing IR to induce cell death.	('MTT', 'Var', (49, 52))	('MSH2', 'Gene', (61, 65))	('activity', 'MPA', (66, 74))	('MSH2', 'Gene', '4436', (61, 65))	('di', 'Disease', 'MESH:D003643', (23, 25))	('MTT', 'Chemical', 'MESH:D008939', (49, 52))	('death', 'Disease', 'MESH:D003643', (103, 108))	('death', 'Disease', (103, 108))	('reduces', 'NegReg', (53, 60))
50230	31717612	H295R-xenografted tumors showed characteristics and histological features similar to those of the original tumor, constituting a useful in vivo ACC model.	('ACC', 'Phenotype', 'HP:0006744', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (18, 23))	('H295R', 'Chemical', '-', (0, 5))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('H295R-xenografted', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
50254	31717612	Cells were transfected with a negative control siGENOME by non-targeting siRNA MSH2 (Dharmacon, Lafayette, CO, USA) by Fugene HD (Promega, Madison, WI, USA), according to the manufacturer's protocol.	('HD', 'Disease', 'MESH:D006816', (126, 128))	('MSH2', 'Gene', (79, 83))	('MSH2', 'Gene', '4436', (79, 83))	('di', 'Disease', 'MESH:D003643', (141, 143))	('non-targeting', 'Var', (59, 72))	('di', 'Disease', 'MESH:D003643', (163, 165))
50266	31202631	Here we present CHASMplus, a computational method, that is uniquely capable of identifying driver missense mutations, including those specific to a cancer type, as evidenced by significantly superior performance on diverse benchmarks.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('missense mutations', 'Var', (98, 116))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('CHASMplus', 'Disease', (16, 25))	('CHASMplus', 'Disease', 'None', (16, 25))
50267	31202631	Applied to 8,657 tumor samples across 32 cancer types in The Cancer Genome Atlas, CHASMplus identifies over 4,000 unique driver missense mutations in 240 genes, supporting a prominent role for rare driver mutations.	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', (61, 67))	('tumor', 'Disease', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (41, 47))	('CHASMplus', 'Disease', (82, 91))	('missense mutations', 'Var', (128, 146))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('CHASMplus', 'Disease', 'None', (82, 91))
50270	31202631	Their analysis revealed that most driver mutations occur only in a few patients, presenting a challenge for precision medicine, and several cancer types will benefit from additional sequencing to identify these rare driver mutations.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
50271	31202631	Cancer is a disease of the genome where certain somatic mutations drive the neoplastic process of cancer, while the majority of mutations are benign passengers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (56, 65))	('neoplastic process', 'CPA', (76, 94))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (98, 104))	('drive', 'PosReg', (66, 71))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
50272	31202631	Missense mutations are the most common protein-coding mutation found in cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Missense mutations', 'Var', (0, 18))	('cancer', 'Disease', (72, 78))
50273	31202631	However, due to the large number of somatic mutations identified in DNA sequencing of human tumors, it has been logistically impossible to experimentally validate driver mutations at sufficiently large scale.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('human', 'Species', '9606', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutations', 'Var', (44, 53))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
50274	31202631	The task of identifying putative drivers from cancer sequencing studies has therefore depended on statistical models to identify genes with an excess number of mutations over expectation.	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('mutations', 'Var', (160, 169))
50275	31202631	The rationale is that because driver mutations provide a fitness advantage to cancer cells, they will be observed more often than expected by chance due to their contribution to carcinogenesis and, as such, leave a statistically detectable signal.	('cancer', 'Disease', (78, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (178, 192))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (37, 46))	('fitness', 'Disease', (57, 64))	('carcinogenesis', 'Disease', (178, 192))	('fitness', 'Disease', 'MESH:D012640', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
50276	31202631	Based on such gene-level analyses, it has been hypothesized that cancer driver mutations exhibit a long tail phenomenon with few common drivers and many rare drivers, suggesting that numerous rare drivers remain to be discovered.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('long tail', 'Phenotype', 'HP:0002831', (99, 108))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (79, 88))
50279	31202631	Overall, this highlights the critical importance of new methods that can identify putative driver missense mutations and separate them from passenger mutations even within known cancer genes, which could spur effective experimental validation.	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('missense mutations', 'Var', (98, 116))
50280	31202631	While many computational methods have been developed to predict whether a missense mutation is generally deleterious or pathogenic, there has not previously been a method to score the oncogenic impact of a missense mutation specifically by cancer type.	('missense mutation', 'Var', (206, 223))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('missense mutation', 'Var', (74, 91))	('cancer', 'Disease', (240, 246))
50281	31202631	Although it is well known that missense mutations have different impacts in different cancer types, currently available computational methods either do not take it into consideration or fail at the task of distinguishing the differences.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('missense mutations', 'Var', (31, 49))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('impacts', 'Reg', (65, 72))	('cancer', 'Disease', (86, 92))
50282	31202631	This indicates an unmet need, given the clinical relevance of mutations is increasingly understood to depend both on the particular mutation and cancer type.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mutations', 'Var', (62, 71))
50283	31202631	In this work, we introduce a machine learning method, CHASMplus, to predict the driver status of missense mutations in a cancer type-specific manner.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CHASMplus', 'Disease', (54, 63))	('CHASMplus', 'Disease', 'None', (54, 63))	('cancer', 'Disease', (121, 127))	('missense mutations', 'Var', (97, 115))
50285	31202631	We explore the emerging role for rare driver missense mutations in cancer and, when possible, relate predictions to supporting functional evidence.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('missense mutations', 'Var', (45, 63))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
50286	31202631	We provide an interactive resource for exploring driver missense mutations identified from the TCGA (http://karchinlab.github.io/CHASMplus) and a user-friendly tool (http://chasmplus.readthedocs.io/) to predict whether newly observed mutations from further sequencing are likely cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('CHASMplus', 'Disease', (129, 138))	('CHASMplus', 'Disease', 'None', (129, 138))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('mutations', 'Var', (234, 243))
50287	31202631	Lastly, we examine the diversity of driver missense mutations across various types of cancer, which leads to a refined understanding of the likely trajectory of driver missense mutation discovery with further sequencing.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('missense mutations', 'Var', (43, 61))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))
50288	31202631	We have developed a method named CHASMplus that uses machine learning to discriminate somatic missense mutations (referred to hereafter as missense mutations) as either cancer drivers or passengers (Figure 1a, Methods).	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('CHASMplus', 'Disease', (33, 42))	('CHASMplus', 'Disease', 'None', (33, 42))	('missense mutations', 'Var', (94, 112))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
50293	31202631	In contrast, most previous methods provide a single impact score for each missense mutation, regardless of cancer type.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('missense mutation', 'Var', (74, 91))
50296	31202631	First, a cancer type-specific model should accurately predict oncogenic effects of missense mutations in an appropriate cell line.	('missense mutations', 'Var', (83, 101))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
50297	31202631	We therefore compared predictions of breast cancer-specific CHASMplus, CHASM, and CanDrA models in known breast cancer driver genes to a previous large-scale validation of 698 missense mutations in MCF10A (breast epithelium) cells that measured cell viability (Figure 2a, Methods).	('breast cancer', 'Disease', (37, 50))	('CHASM', 'Gene', '219537', (60, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('CHASMplus', 'Disease', 'None', (60, 69))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('MCF10A', 'CellLine', 'CVCL:0598', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CHASM', 'Gene', (60, 65))	('CHASM', 'Gene', (71, 76))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('missense mutations', 'Var', (176, 194))	('CHASM', 'Gene', '219537', (71, 76))	('MCF10A', 'Gene', (198, 204))	('CHASMplus', 'Disease', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
50307	31202631	It has been previously documented that lung adenocarcinoma (LUAD) missense mutations in EGFR appear predominantly in its kinase domain, while GBM missense mutations appear in its extracellular domain.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('missense mutations', 'Var', (66, 84))	('EGFR', 'Gene', '1956', (88, 92))	('lung adenocarcinoma', 'Disease', (39, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))	('EGFR', 'Gene', (88, 92))
50308	31202631	We therefore scored TCGA missense mutations in the gene EGFR from LUAD patients and from GBM patients with CHASMplus, CanDrA, and CHASM (Figure 2c).	('CHASM', 'Gene', (107, 112))	('CHASM', 'Gene', '219537', (130, 135))	('CHASMplus', 'Disease', (107, 116))	('patients', 'Species', '9606', (71, 79))	('EGFR', 'Gene', '1956', (56, 60))	('CHASM', 'Gene', '219537', (107, 112))	('missense mutations', 'Var', (25, 43))	('CHASMplus', 'Disease', 'None', (107, 116))	('EGFR', 'Gene', (56, 60))	('CHASM', 'Gene', (130, 135))	('patients', 'Species', '9606', (93, 101))
50309	31202631	The CHASMplus GBM model correctly scores the missense mutations from GBM patients significantly higher than those from LUAD patients (p=0.004, two-sided t-test), and vice versa for the CHASMplus LUAD model (p=0.003, two-sided t-test).	('CHASMplus', 'Disease', (185, 194))	('CHASMplus', 'Disease', (4, 13))	('GBM', 'Disease', (69, 72))	('CHASMplus LUAD', 'Disease', 'None', (185, 199))	('CHASMplus', 'Disease', 'None', (185, 194))	('CHASMplus', 'Disease', 'None', (4, 13))	('CHASMplus LUAD', 'Disease', (185, 199))	('missense mutations', 'Var', (45, 63))	('higher', 'PosReg', (96, 102))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (124, 132))
50310	31202631	In contrast, the CHASM GBM model and the CHASM LUAD model both score the mutations from LUAD patients higher than those from GBM patients (p=1e-5 and 5e-5, respectively, two-sided t-test).	('CHASM', 'Gene', (41, 46))	('score', 'PosReg', (63, 68))	('patients', 'Species', '9606', (129, 137))	('CHASM', 'Gene', '219537', (17, 22))	('higher', 'PosReg', (102, 108))	('CHASM', 'Gene', '219537', (41, 46))	('patients', 'Species', '9606', (93, 101))	('mutations', 'Var', (73, 82))	('CHASM', 'Gene', (17, 22))
50311	31202631	CanDrA does not have a LUAD model, but its GBM model scores mutations from LUAD patients higher than those from GBM patients (p=0.0002, two-sided t-test), which is significant in the wrong direction.	('mutations', 'Var', (60, 69))	('higher', 'PosReg', (89, 95))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (80, 88))
50314	31202631	This approach is useful because some cancer driver mutations do occur in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
50315	31202631	The power to detect these mutations, particularly when they occur at low frequency in many cancer types, is increased when many cancer types are aggregated, known as a pan-cancer analysis.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (91, 97))	('increased', 'PosReg', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (128, 134))
50318	31202631	A range of benchmarks was critical because missense mutations with the most established experimental support for a driver role tend to be in a few well-understood cancer driver genes.	('missense mutations', 'Var', (43, 61))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
50320	31202631	These results suggest that CHASMplus improves on previous methods to predict driver missense mutations in a pan-cancer setting, as well as in a cancer type-specific manner.	('driver missense mutations', 'Var', (77, 102))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('CHASMplus', 'Disease', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('CHASMplus', 'Disease', 'None', (27, 36))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
50323	31202631	Using cancer type-specific models, we found a wide range of putative driver missense mutations in various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('missense mutations', 'Var', (76, 94))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
50325	31202631	In total, 479 unique driver missense mutations were identified by the cancer type-specific analyses but missed by pan-cancer analysis.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('missense mutations', 'Var', (28, 46))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
50326	31202631	The pan-cancer analysis identified 3,527 unique missense mutations as putative drivers (Table S3) and had substantial overlap with our earlier pan-cancer analysis (p<2.2e-16, one-sided Fisher's exact test).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('missense mutations', 'Var', (48, 66))	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
50327	31202631	Given the substantially different methodology, the overlap suggests the CHASMplus pan-cancer analysis identifies a core set of driver mutations with multiple distinct sources of evidence.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CHASMplus pan-cancer', 'Disease', 'MESH:D009369', (72, 92))	('CHASMplus pan-cancer', 'Disease', (72, 92))	('mutations', 'Var', (134, 143))
50329	31202631	Notably, the cancer type-specific analysis identified a substantial number of putative driver mutations not previously characterized in OncoKB (median overlap 53%).	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (94, 103))
50330	31202631	Altogether across the pan-cancer and cancer type-specific analyses, 4,006 unique driver missense mutations were identified by CHASMplus, of which 2,037 were neither found by OncoKB nor our earlier pan-cancer analysis, indicating a potentially expanded landscape of putative driver missense mutations of interest for further examination.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('CHASMplus', 'Disease', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('CHASMplus', 'Disease', 'None', (126, 135))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('missense mutations', 'Var', (88, 106))
50335	31202631	These results suggest that CHASMplus has potential to discriminate driver and passenger mutations in both well-known and putative cancer driver genes, although follow up experiments are required for confirmation.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('CHASMplus', 'Disease', (27, 36))	('mutations', 'Var', (88, 97))	('CHASMplus', 'Disease', 'None', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
50336	31202631	Based on our mutation-level analysis, we observed that the spectrum of rare (<1% of cancer samples), intermediate (1-5%), and common (>5%) frequency driver missense mutations varied substantially among cancer types (Figure 3a).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (202, 208))	('missense mutations', 'Var', (156, 174))
50337	31202631	For example, uveal melanoma was dominated by common driver missense mutations (88%), while head and neck squamous cell carcinoma (HNSC) was dominated by rare driver missense mutations (63%).	('uveal melanoma', 'Disease', (13, 27))	('neck squamous cell carcinoma', 'Disease', (100, 128))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('missense mutations', 'Var', (59, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (100, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (13, 27))
50338	31202631	However, when we considered all cancer types together (pan-cancer), the overall proportion of rare driver missense mutations considered rare was slightly greater than for common (35.5% and 35.4%, respectively) and 4-fold greater than found by the cancer hotspots method (8%, P<2.2e-16, Fisher's exact test).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('missense mutations', 'Var', (106, 124))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
50339	31202631	These results suggest that rare driver missense mutations have a greater role in many cancer types than previously suggested, but that this might not be the case for every cancer type.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('missense mutations', 'Var', (39, 57))	('cancer', 'Disease', (86, 92))
50340	31202631	We observed, after adjusting for sample size, that the average tumor mutation burden for a cancer type positively correlated with the prevalence of rare (but not common) driver missense mutations (R=0.63, P=4.7e-5, likelihood ratio test, Figure 3b).	('tumor', 'Disease', (63, 68))	('missense mutations', 'Var', (177, 195))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
50341	31202631	While cancer types appear to have different proportions of rare, intermediate and common driver missense mutations across cancer types, this result could be confounded by differences in subtypes or cell-of-origin.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('missense mutations', 'Var', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (6, 12))
50344	31202631	Fifty-five out of 223 genes (24.7%) contained putative driver missense mutations that were enriched in particular cancer subtypes (q-value<=0.1, chi-squared test, Figure 3c, Table S5, Figure S4).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('missense mutations', 'Var', (62, 80))	('cancer', 'Disease', (114, 120))
50345	31202631	Several genes showed strong specificity, consistent with prior literature, such as NFE2L2 mutations in esophageal cancers of squamous cell-of-origin, TP53 mutations in Human Papillomavirus-negative tumors in head and neck cancer, KIT mutations in testicular seminomas and PIK3CA mutations in the Luminal A subtype of breast cancer.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (90, 99))	('cancers', 'Disease', (114, 121))	('breast cancer', 'Disease', 'MESH:D001943', (317, 330))	('breast cancer', 'Disease', (317, 330))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('KIT', 'Gene', '3815', (230, 233))	('testicular seminomas', 'Phenotype', 'HP:0100617', (247, 267))	('Papillomavirus-negative tumors', 'Disease', 'MESH:D030361', (174, 204))	('mutations', 'Var', (279, 288))	('Papillomavirus-negative tumors', 'Disease', (174, 204))	('PIK3CA', 'Gene', (272, 278))	('NFE2L2', 'Gene', '4780', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('neck cancer', 'Disease', 'MESH:D006258', (217, 228))	('neck cancer', 'Disease', (217, 228))	('TP53', 'Gene', '7157', (150, 154))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('seminomas', 'Disease', 'MESH:D018239', (258, 267))	('seminomas', 'Disease', (258, 267))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('head and neck cancer', 'Phenotype', 'HP:0012288', (208, 228))	('NFE2L2', 'Gene', (83, 89))	('mutations', 'Var', (234, 243))	('KIT', 'Gene', (230, 233))	('mutations', 'Var', (155, 164))	('PIK3CA', 'Gene', '5290', (272, 278))	('breast cancer', 'Phenotype', 'HP:0003002', (317, 330))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
50346	31202631	It should be noted that in some cases these differences are confounded by the fact that subtypes were originally defined by mutation status (GBM or LGG with IDH1/IDH2 mutations).	('IDH2', 'Gene', '3418', (162, 166))	('IDH2', 'Gene', (162, 166))	('mutations', 'Var', (167, 176))	('IDH1', 'Gene', (157, 161))	('IDH1', 'Gene', '3417', (157, 161))
50347	31202631	For example, the protein phosphatase PPP2R1A, which has been implicated as a tumor suppressor gene in many tumor types, contained common driver missense mutations in our pan-cancer analysis at residue positions 179 and 183, which is located at the protein interface composing the phosphatase 2A complex (Figure 3d).	('PPP2R1A', 'Gene', '5518', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('missense mutations', 'Var', (144, 162))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('PPP2R1A', 'Gene', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (77, 82))
50348	31202631	It also had a much broader set of rare driver mutations throughout the protein interface, such as R105Q and R459C.	('R105Q', 'Var', (98, 103))	('R105Q', 'Mutation', 'rs1489963266', (98, 103))	('R459C', 'Mutation', 'p.R459C', (108, 113))	('R459C', 'Var', (108, 113))
50349	31202631	Similarly, CHASMplus identified common driver missense mutations (S310A/F/Y) in the extracellular domain of the well-known oncogene ERBB2, but also finds rare driver missense mutations in both the extracellular and kinase domain (e.g., L313V and R678Q) (Figure 3e).	('R678Q', 'Var', (246, 251))	('ERBB2', 'Gene', (132, 137))	('S310A/F/Y', 'Var', (66, 75))	('S310A/F/Y', 'Mutation', 'rs1057519816', (66, 75))	('L313V', 'Mutation', 'p.L313V', (236, 241))	('CHASMplus', 'Disease', (11, 20))	('CHASMplus', 'Disease', 'None', (11, 20))	('L313V', 'Var', (236, 241))	('ERBB2', 'Gene', '2064', (132, 137))	('R678Q', 'Mutation', 'rs1057519862', (246, 251))
50350	31202631	This is supportive of previous experimental work implicating rare cancer driver mutations in commonly mutated cancer driver genes.	('cancer', 'Disease', (110, 116))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (66, 72))
50351	31202631	Truncating or likely loss-of-function mutations are typical hallmarks of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('loss-of-function', 'NegReg', (21, 37))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('Truncating', 'Var', (0, 10))	('mutations', 'Var', (38, 47))
50352	31202631	However, the role of driver missense mutations may be under-characterized in tumor suppressor genes, since these mutations are more diverse and occur over a larger region than in oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('missense mutations', 'Var', (28, 46))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))
50353	31202631	As a case in point, the tumor suppressor gene CASP8 contains many truncating variants, while all of the putative driver missense mutations identified by CHASMplus were considered rare (Figure 3f).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('variants', 'Var', (77, 85))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('CHASMplus', 'Disease', (153, 162))	('CASP8', 'Gene', (46, 51))	('CHASMplus', 'Disease', 'None', (153, 162))	('CASP8', 'Gene', '841', (46, 51))	('truncating', 'MPA', (66, 76))
50355	31202631	We explored functional evidence to support whether the rare driver missense mutations in CASP8, predicted by CHASMplus, behaved similarly to truncating variants.	('CHASMplus', 'Disease', 'None', (109, 118))	('CASP8', 'Gene', (89, 94))	('CASP8', 'Gene', '841', (89, 94))	('CHASMplus', 'Disease', (109, 118))	('missense mutations', 'Var', (67, 85))
50357	31202631	For 12 immune-related markers, we compared tumor samples with driver missense mutations or truncating mutations in CASP8 to control samples with no mutations in CASP8.	('CASP8', 'Gene', (161, 166))	('truncating mutations', 'Var', (91, 111))	('CASP8', 'Gene', '841', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('CASP8', 'Gene', (115, 120))	('CASP8', 'Gene', '841', (115, 120))	('missense mutations', 'Var', (69, 87))	('tumor', 'Disease', (43, 48))
50359	31202631	Conventional wisdom has suggested that because rare missense mutations in tumor suppressor genes do not tend to cluster in protein sequence, they are solely passenger events.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('missense mutations', 'Var', (52, 70))
50360	31202631	However, our work suggests that rare driver missense mutations in CASP8 and perhaps in other tumor suppressor genes may be relevant to tumor immune-related phenotypes.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('missense mutations', 'Var', (44, 62))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (135, 140))	('CASP8', 'Gene', (66, 71))	('CASP8', 'Gene', '841', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
50365	31202631	Because PTEN mutations are found in many cancer types, we used CHASMplus pan-cancer predictions.	('CHASMplus pan-cancer', 'Disease', 'MESH:D009369', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('CHASMplus pan-cancer', 'Disease', (63, 83))	('found', 'Reg', (27, 32))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
50369	31202631	Next, we examined the lipid phosphatase activity and protein abundance for the PTEN mutations that we predicted as drivers in the TCGA.	('mutations', 'Var', (84, 93))	('PTEN', 'Gene', (79, 83))	('PTEN', 'Gene', '5728', (79, 83))
50370	31202631	We observed that these driver missense mutations, regardless of frequency, had significantly lower lipid phosphatase activity than other missense mutations in PTEN (common: p=0.008; intermediate: p=1.9e-9; rare: p=1.6e-18; Mann-Whitney U test, Figure 5e).	('PTEN', 'Gene', (159, 163))	('missense mutations', 'Var', (30, 48))	('PTEN', 'Gene', '5728', (159, 163))	('lipid phosphatase activity', 'MPA', (99, 125))	('lower', 'NegReg', (93, 98))
50371	31202631	A likely explanation is that greater decreases in PTEN lipid phosphatase activity may promote tumor growth and tumor clones with these mutations are positively selected in many patients.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('activity', 'MPA', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patients', 'Species', '9606', (177, 185))	('mutations', 'Var', (135, 144))	('PTEN', 'Gene', (50, 54))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (111, 116))	('promote', 'PosReg', (86, 93))	('PTEN', 'Gene', '5728', (50, 54))	('decreases', 'NegReg', (37, 46))
50379	31202631	Based on our cancer type-specific models from CHASMplus, we found that the diversity and prevalence of driver missense mutations varied considerably across TCGA cancer types (Figure 6a, Methods).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('CHASMplus', 'Disease', (46, 55))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('CHASMplus', 'Disease', 'None', (46, 55))	('cancer', 'Disease', (161, 167))	('missense mutations', 'Var', (110, 128))	('TCGA', 'Disease', (156, 160))
50384	31202631	Are there substantially more cancer driver missense mutations yet to be discovered?	('missense mutations', 'Var', (43, 61))	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))
50387	31202631	Subsampling analysis showed all cancer types had a linear increase in the number of unique driver missense mutations identified (R2 > 0.5) with no evidence of saturation at current sample sizes (Figure S7a).	('S7', 'Gene', '6264', (202, 204))	('increase', 'PosReg', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('missense mutations', 'Var', (98, 116))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
50388	31202631	However, discovery of driver missense mutations, which occur in aggregate at a given prevalence (average number per cancer sample), varied substantially among cancer types (Figure 6b).	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('missense mutations', 'Var', (29, 47))
50390	31202631	This resulted in only marginal increases in the overall prevalence of identified driver missense mutations, consistent with our predicted trajectory based only on TCGA samples (Methods, Table S7, Figure S7b).	('S7', 'Gene', '6264', (192, 194))	('missense mutations', 'Var', (88, 106))	('increases', 'PosReg', (31, 40))	('S7', 'Gene', '6264', (203, 205))
50391	31202631	In contrast, thymoma (THYM), uveal melanoma (UVM), and pancreatic ductal adenocarcinoma (PAAD) contained common driver missense mutations that could be detected based on only a few samples from the cohort, e.g., GTF2I L424H in THYM.	('thymoma', 'Gene', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('GTF2I', 'Gene', (212, 217))	('thymoma', 'Gene', '7063', (13, 20))	('thymoma', 'Phenotype', 'HP:0100522', (13, 20))	('GTF2I', 'Gene', '2969', (212, 217))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (55, 87))	('missense', 'Var', (119, 127))	('L424H', 'Mutation', 'p.L424H', (218, 223))	('pancreatic ductal adenocarcinoma', 'Disease', (55, 87))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (55, 87))
50392	31202631	In contrast, the prevalence of rare driver missense mutations increased substantially with sample size in breast cancer (BRCA), head and neck squamous cell carcinoma (HNSC), and colon adenocarcinoma (COAD).	('missense mutations', 'Var', (43, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (137, 165))	('colon adenocarcinoma', 'Disease', (178, 198))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (178, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('neck squamous cell carcinoma', 'Disease', (137, 165))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
50393	31202631	These results suggest cancer types can be clustered by patterns of driver missense mutation diversity and prevalence (Figure 6a), in addition to well-established approaches to define cancer subtypes, such as by cell-of-origin.	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('driver missense mutation', 'Var', (67, 91))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
50395	31202631	Future insights into cancer evolution and its relevance for clinical care will increasingly rely on the precise interpretation of whether individual mutations are cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
50397	31202631	The long tail hypothesis posits that there are many rare driver mutations in human cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('long tail', 'Phenotype', 'HP:0002831', (4, 13))	('mutations', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
50400	31202631	The observed diversity of driver mutations across patients' tumors may be influenced by tumor mutation burden, the type of gene (i.e., tumor suppressor genes), the functional strength of the mutation, and the mutation's subtype specificity.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('influenced', 'Reg', (74, 84))	('tumor', 'Disease', (135, 140))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (88, 93))	('tumors', 'Disease', (60, 66))
50401	31202631	The diversity of driver missense mutations supports the critical role of understanding the origins and overall contribution of rare driver mutations -- failure to capture and identify rare driver mutations, which occur in aggregate at reasonable prevalence, may result in crucial missed opportunities for interpreting a patient's cancer.	('missense mutations', 'Var', (24, 42))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('patient', 'Species', '9606', (320, 327))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', (330, 336))
50403	31202631	We therefore have precomputed the score of every possible missense mutation across the genome, effectively an in silico saturation mutagenesis across all genes to score as of yet unobserved mutations that are potential cancer drivers.	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('missense mutation', 'Var', (58, 75))	('cancer', 'Disease', (219, 225))
50404	31202631	Although missense mutations are the most frequent protein-coding somatic alteration in cancer, CHASMplus only predicts missense mutations; but, in principle, our approach could be extended to other types of alterations.	('cancer', 'Disease', (87, 93))	('CHASMplus', 'Disease', (95, 104))	('CHASMplus', 'Disease', 'None', (95, 104))	('missense mutations', 'Var', (119, 137))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('missense mutations', 'Var', (9, 27))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
50405	31202631	Lastly, while our study leverages the large sized TCGA cohorts to make informed judgements about driver missense mutations, inevitably these tumors may still miss important contexts for understanding cancer.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('missense mutations', 'Var', (104, 122))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
50407	31202631	For example, it is well known EGFR mutations in lung adenocarcinoma are more highly prevalent in Asian compared to Caucasian populations.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('EGFR', 'Gene', (30, 34))	('lung adenocarcinoma', 'Disease', (48, 67))	('prevalent', 'Reg', (84, 93))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('EGFR', 'Gene', '1956', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('mutations', 'Var', (35, 44))
50409	31202631	We expect that an increasingly complete catalog of driver missense mutations will be generated by a combination of improved computational methods and cumulative growth of available samples from cancer sequencing studies.	('missense mutations', 'Var', (58, 76))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
50410	31202631	However, for some cancer types in some populations, discovery of driver missense mutations may already be effectively saturated.	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('missense mutations', 'Var', (72, 90))
50411	31202631	By analyzing the trajectory of discovery at the level of driver missense mutations, we identified a more complicated pattern which depends on the cancer type.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('missense mutations', 'Var', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
50412	31202631	Future work will further elucidate a broader range of driver mutations, including those within non-coding regions of the genome, at different stages of carcinogenesis, such as in pre-cancerous lesions, and in response to therapeutic treatment.	('carcinogenesis', 'Disease', (152, 166))	('cancerous lesions', 'Disease', 'MESH:D009369', (183, 200))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancerous lesions', 'Disease', (183, 200))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))
50415	31202631	We collected a set of 1,225,917 somatic mutations in 8,657 samples from The Cancer Genome Atlas (TCGA) somatic mutation calls from whole-exome sequencing (v0.2.8, https://synapse.org/MC3).	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MC3', 'Gene', (183, 186))	('MC3', 'Gene', '4159', (183, 186))	('mutations', 'Var', (40, 49))	('Cancer', 'Disease', (76, 82))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))
50417	31202631	We identified hypermutated samples as having more mutations than 1.5 times the interquartile range above the third quartile (Tukey's condition) of samples within the same cancer type.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (171, 177))
50420	31202631	Previous machine learning approaches for predicting driver mutations have been trained on a small positive class of bona fide driver missense mutations, which are highly prevalent in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('missense mutations', 'Var', (133, 151))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (188, 194))
50422	31202631	Driver genes have been labeled but the labels of missense mutations are inferred by cluster assumptions, e.g., driver missense mutations may occur together in known driver genes and in significantly mutated genes for a particular cancer type.	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('occur', 'Reg', (141, 146))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('missense mutations', 'Var', (118, 136))
50423	31202631	Mutations are assigned to the 'positive' class (driver-like) for a cancer type based on these assumptions, and all other mutations are assigned to the 'negative' class (passenger-like).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
50424	31202631	To extend this approach to a pan-cancer prediction, all mutations from the positive class were merged into one group and a single classifier was trained.	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (56, 65))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))
50426	31202631	To test the assumptions of our training procedure, we rigorously evaluated CHASMplus on orthogonally labeled mutations based on in vitro experiments, in vivo experiments, and literature curation.	('CHASMplus', 'Disease', (75, 84))	('CHASMplus', 'Disease', 'None', (75, 84))	('mutations', 'Var', (109, 118))
50429	31202631	The positive class (likely-driver missense mutations) was selected by the following criteria: 1) missense mutations had to occur in a curated set of 125 pan-cancer driver genes; 2) for each of the 32 TCGA cancer types, missense mutations found in that cancer type had to occur in a significantly mutated gene for that cancer type according to MutSigCV v1.4.	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (318, 324))	('v1.4', 'Gene', '28815', (352, 356))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', (205, 211))	('missense mutations', 'Var', (219, 237))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('v1.4', 'Gene', (352, 356))
50431	31202631	Notably, MutSigCV v1.4 only assess the total number of mutations in a gene, and not any characteristics of those mutations; thus, we avoid making strong assumptions about the properties of a particular driver mutation; 3) missense mutations had to occur in samples with relatively low mutation rate (less than 500 mutations, half the minimum hypermutator threshold as defined above).	('missense mutations', 'Var', (222, 240))	('v1.4', 'Gene', '28815', (18, 22))	('v1.4', 'Gene', (18, 22))
50441	31202631	We used random forests, a machine learning technique, to predict whether a missense mutation is a cancer driver.	('missense mutation', 'Var', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
50443	31202631	Since missense mutations in the same gene may have overlapping feature representations which result in classifier overfitting, we performed prediction using a 10-fold gene hold-out cross-validation procedure for both CHASMplus and 20/20+.	('overfitting', 'PosReg', (114, 125))	('CHASMplus', 'Disease', (217, 226))	('CHASMplus', 'Disease', 'None', (217, 226))	('missense mutations', 'Var', (6, 24))	('result in', 'Reg', (93, 102))
50445	31202631	The CHASMplus score represents the fraction of decision trees which vote for the mutation being a driver.	('CHASMplus', 'Disease', (4, 13))	('mutation', 'Var', (81, 89))	('CHASMplus', 'Disease', 'None', (4, 13))
50450	31202631	Next, each simulated missense mutation and gene was scored with the CHASMplus and 20/20+ models that were previously trained on the observed data.	('missense mutation', 'Var', (21, 38))	('CHASMplus', 'Disease', (68, 77))	('CHASMplus', 'Disease', 'None', (68, 77))
50452	31202631	We compared CHASMplus to 12 other methods that were designed to prioritize likely cancer driver missense mutations or have been used for that purpose (VEST, CADD, FATHMM cancer, SIFT, MutationAssessor, REVEL, MCAP, ParsSNP, CHASM, Polyphen2, transFIC and CanDrA).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MCAP', 'Gene', (209, 213))	('cancer', 'Disease', (170, 176))	('CHASM', 'Gene', (224, 229))	('CHASM', 'Gene', (12, 17))	('CHASM', 'Gene', '219537', (224, 229))	('cancer', 'Disease', (82, 88))	('CADD', 'Disease', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('missense mutations', 'Var', (96, 114))	('CHASMplus', 'Disease', (12, 21))	('CHASMplus', 'Disease', 'None', (12, 21))	('CHASM', 'Gene', '219537', (12, 17))	('MCAP', 'Gene', '23476', (209, 213))
50463	31202631	Mutations were scored using the corresponding cancer type models of CHASMplus, CanDrA, and CHASM, along with two high-performing methods which are not cancer type-specific (ParsSNP and REVEL).	('CHASMplus', 'Disease', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('CHASMplus', 'Disease', 'None', (68, 77))	('CHASM', 'Gene', '219537', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (46, 52))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (151, 157))	('CHASM', 'Gene', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CHASM', 'Gene', (68, 73))	('CHASM', 'Gene', '219537', (91, 96))
50465	31202631	To assess each method's ability to distinguish breast cancer-specific driver mutations, mutations that increased cell viability in known breast cancer driver genes were labeled as positive class.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Disease', (137, 150))	('increased', 'PosReg', (103, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('mutations', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cell viability', 'CPA', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
50466	31202631	Mutations that did not increase cell viability or increased cell viability but were not found in breast cancer-specific genes were labeled as negative class.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))
50468	31202631	Breast cancer-specific genes were labeled based on the Cancer Gene Census (CGC, genes marked as relevant to "breast" cancer and somatic missense mutations, COSMIC v79) or The Cancer Genome Atlas (TCGA).	('Cancer', 'Disease', (175, 181))	('missense mutations', 'Var', (136, 154))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Cancer', 'Disease', 'MESH:D009369', (175, 181))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Cancer', 'Disease', (55, 61))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Disease', (117, 123))	('Breast cancer', 'Disease', (0, 13))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))
50470	31202631	We obtained all missense mutations from targeted sequencing with the MSK-IMPACT gene panel of 414 cancer-related genes originating from approximately 10,000 patients' tumors.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('missense mutations', 'Var', (16, 34))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Disease', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
50472	31202631	For each cancer type, mutations were labeled as 'positive' class if they occurred in a cancer driver gene implicated for that cancer type and also a tumor of the same type.	('cancer', 'Disease', (87, 93))	('occurred', 'Reg', (73, 81))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
50479	31202631	We obtained all missense mutations from targeted sequencing with the MSK-IMPACT gene panel of 414 cancer-related genes, originating from approximately 10,000 patients' tumors.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('missense mutations', 'Var', (16, 34))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
50481	31202631	The study selected mutations based on their presence in sequenced human tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('human', 'Species', '9606', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('mutations', 'Var', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (72, 78))
50484	31202631	We assessed each method's ability to distinguish TP53 mutations with low transactivation (positive class) versus all other TP53 mutations (negative class).	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('transactivation', 'MPA', (73, 88))	('mutations', 'Var', (54, 63))	('low', 'NegReg', (69, 72))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
50485	31202631	We evaluated all missense mutations (n=2,314) for TP53 from the IARC TP53 database.	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('missense mutations', 'Var', (17, 35))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))
50486	31202631	Low transactivation was considered as less than 50% wildtype, as indicated by the median of 8 different targets (WAF1, MDM2, BAX, h1433s, AIP1, GADD45, NOXA, and P53R2).	('WAF1', 'Gene', (113, 117))	('transactivation', 'MPA', (4, 19))	('MDM2', 'Gene', '4193', (119, 123))	('NOXA', 'Gene', (152, 156))	('GADD45', 'Gene', (144, 150))	('MDM2', 'Gene', (119, 123))	('h1433s', 'Var', (130, 136))	('P53R2', 'Gene', '50484', (162, 167))	('NOXA', 'Gene', '5366', (152, 156))	('AIP1', 'Gene', '23204', (138, 142))	('BAX', 'Gene', (125, 128))	('WAF1', 'Gene', '1026', (113, 117))	('BAX', 'Gene', '581', (125, 128))	('GADD45', 'Gene', '1647', (144, 150))	('P53R2', 'Gene', (162, 167))	('AIP1', 'Gene', (138, 142))
50488	31202631	The experiment assumes that mutations that provide a growth advantage to cells with growth factors withdrawn reflect cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('growth', 'MPA', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('mutations', 'Var', (28, 37))
50489	31202631	We compared (pan-cancer) CHASMplus to the cancer hotspots method (v0.6), with respect to its sensitivity to identify driver missense mutations.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('CHASMplus', 'Disease', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('CHASMplus', 'Disease', 'None', (25, 34))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('missense mutations', 'Var', (124, 142))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
50491	31202631	The sensitivity of CHASMplus to detect the OncoKB-labeled mutations was 0.83, which was significantly higher than the hotspot method (0.46, p<2.2e-16, McNemar's test, n=896).	('mutations', 'Var', (58, 67))	('CHASMplus', 'Disease', (19, 28))	('CHASMplus', 'Disease', 'None', (19, 28))	('higher', 'PosReg', (102, 108))
50492	31202631	To minimize potential gene bias, we also repeated the analysis after excluding all 389 TP53 mutations, yielding sensitivity of 0.76 for CHASMplus and 0.49 for hotspot detection, a difference which is still statistically significant (p<2.2e-16, McNemar's test, n=507) (Figure 7b).	('CHASMplus', 'Disease', 'None', (136, 145))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('CHASMplus', 'Disease', (136, 145))
50499	31202631	We performed gene ontology analysis on the set of 75 genes (Table S4) containing at least one driver missense mutation from CHASMplus that did not overlap with previous genes from the Cancer Gene Census (COSMIC v79, annotated with somatic missense) or any driver genes from the TCGA PancanAtlas analysis.	('CHASMplus', 'Disease', (124, 133))	('CHASMplus', 'Disease', 'None', (124, 133))	('mutation', 'Var', (110, 118))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Cancer', 'Disease', (184, 190))	('Cancer', 'Disease', 'MESH:D009369', (184, 190))
50500	31202631	Mutation frequency was calculated based on the fraction of cancer samples that contained a driver mutation in a particular cancer type.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutation', 'Var', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
50502	31202631	All mutations within a codon are then classified as rare (<1% of cancer samples), intermediate (1-5%), or common (>5%).	('mutations', 'Var', (4, 13))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
50508	31202631	gwCHASMplus scores were computed for each of these missense mutations.	('missense mutations', 'Var', (51, 69))	('gwCHASMplus', 'Disease', 'None', (0, 11))	('gwCHASMplus', 'Disease', (0, 11))
50511	31202631	We extended our comparison of the PTEN saturation mutagenesis experiment of lipid phosphatase activity to the two "runner-up" methods (CanDrA and ParsSNP), assessed in the five benchmarks in Figure 2d.	('activity', 'MPA', (94, 102))	('mutagenesis', 'Var', (50, 61))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
50512	31202631	CHASMplus, CanDrA and ParsSNP were then compared to each other based on their specificity, sensitivity, precision and F1 score to identify mutations damaging to lipid phosphatase activity in PTEN.	('CHASMplus', 'Disease', (0, 9))	('CHASMplus', 'Disease', 'None', (0, 9))	('damaging', 'Reg', (149, 157))	('mutations', 'Var', (139, 148))	('PTEN', 'Gene', (191, 195))	('PTEN', 'Gene', '5728', (191, 195))	('lipid phosphatase activity', 'MPA', (161, 187))
50513	31202631	Most driver missense mutation prediction methods do not report p-values, but CHASMplus does compute a p-value.	('CHASMplus', 'Disease', 'None', (77, 86))	('missense mutation', 'Var', (12, 29))	('CHASMplus', 'Disease', (77, 86))
50516	31202631	We clustered TCGA cancer types according to two features, prevalence (fraction of samples mutated) and normalized diversity (normalized entropy) among predicted missense mutation drivers (q <= 0.01).	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('missense mutation', 'Var', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))
50518	31202631	To evaluate this possibility, we correlated the mean Variant Allele Fraction (VAF) for mutations in tumor samples in each cancer type with a variety of metrics summarizing our results.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (87, 96))
50520	31202631	We found no significant correlation between mean VAF for cancer types with: average number of predicted driver mutations per sample (Pearson r=0.26, p=0.14, correlation test), fraction of samples with predicted driver mutations (Pearson r=0.2, p=0.28, correlation test), unique number of significant mutations (Pearson r=0.04, p=0.82, correlation test), and normalized driver diversity (Pearson r=0.33, p=0.07, correlation test).	('mutations', 'Var', (111, 120))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
50521	31202631	We performed driver missense mutation predictions on random subsamples of each of 9 representative cancer types (ACC, SARC, PRAD, THYM, UVM, PAAD, BRCA, HNSC, and COAD), using CHASMplus.	('missense mutation', 'Var', (20, 37))	('UVM', 'Disease', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('HNSC', 'Disease', (153, 157))	('CHASMplus', 'Disease', (176, 185))	('cancer', 'Disease', (99, 105))	('PRAD', 'Disease', (124, 128))	('THYM', 'Disease', (130, 134))	('BRCA', 'Disease', (147, 151))	('CHASMplus', 'Disease', 'None', (176, 185))	('ACC', 'Disease', (113, 116))	('SARC', 'Disease', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('PAAD', 'Disease', (141, 145))
50524	31202631	The number of unique driver missense mutations and overall driver prevalence (average number of driver missense mutations per cancer sample) were then calculated based on significant CHASMplus predictions (q<=0.01).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('CHASMplus', 'Disease', (183, 192))	('missense mutations', 'Var', (28, 46))	('CHASMplus', 'Disease', 'None', (183, 192))
50525	31202631	Results were then ordered by increasing sample size to observe trends in the identification of driver missense mutations by CHASMplus.	('CHASMplus', 'Disease', (124, 133))	('CHASMplus', 'Disease', 'None', (124, 133))	('driver missense mutations', 'Var', (95, 120))
50528	31202631	Similar to statistical methods for driver gene detection, hotspot detection identifies an excess number of mutations compared to expectation using a large number of cancer samples.	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', (165, 171))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))
50529	31202631	We assessed the number of samples required to detect driver missense mutations across a range of frequencies (proportion of tumor samples in which a mutation occurs) and somatic background mutation rates.	('missense mutations', 'Var', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
50530	31202631	In Figure 7a, each of the 32 TCGA cancer types is placed according to its sample size and background mutation rate, relative to six curves which represent the required sample size to detect driver missense mutations of a certain frequency, with 90% power, using hotspot detection (see Statistical Power Analysis).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('missense mutations', 'Var', (197, 215))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))
50532	31202631	At current TCGA sample sizes, we found codon-based hotspot detection approaches were not well powered to identify driver missense mutations that occurred at less than 1% frequency in most cancer types.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('missense mutations', 'Var', (121, 139))	('cancer', 'Disease', (188, 194))
50535	31202631	For these mutations, pan-cancer analysis using ~10,000 TCGA samples should enable detection of driver mutations at frequency as low as 0.1%.	('mutations', 'Var', (10, 19))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))
50537	31202631	Interactive portal for exploring driver missense mutations in TCGA: https://karchinlab.github.io/CHASMplus.	('missense mutations', 'Var', (40, 58))	('CHASMplus', 'Disease', (97, 106))	('CHASMplus', 'Disease', 'None', (97, 106))
50538	31202631	Missense mutations are the most frequent type of protein-coding alteration in cancers and the most difficult to interpret.	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Missense mutations', 'Var', (0, 18))
50539	31202631	While many computational methods have been developed to predict whether genes are cancer drivers or whether missense mutations are generally deleterious or pathogenic, there has not previously been a method to score the oncogenic impact of a missense mutation specifically by cancer type, limiting adoption of computational missense mutation predictors in the clinic.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('missense', 'Var', (242, 250))
50542	31202631	We introduce a machine learning method honed for each cancer type, and a resource for fast lookup of the cancer-specific driver propensity of every possible missense mutation in the human exome.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('human', 'Species', '9606', (182, 187))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('missense mutation', 'Var', (157, 174))
50543	31202631	CHASMplus identifies driver missense mutations in a cancer type-specific manner Rare driver mutations are common in cancer when considered as a group In some cancers, further sequencing will yield insight into rare driver mutations Comprehensive resource of driver propensity for all possible missense mutations	('CHASMplus', 'Disease', (0, 9))	('CHASMplus', 'Disease', 'None', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('missense mutations', 'Var', (28, 46))	('cancer', 'Disease', (158, 164))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
50563	30352417	Mitotane is associated with various side effects that are always dose-dependent and are related to its pharmacodynamic properties in some cases (modification of lipid profile, hepatic cytolysis, cholestasis, adrenal insufficiency) but not in others (neurological disorders, leucopenia, nausea and vomiting).	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (208, 229))	('lipid profile', 'MPA', (161, 174))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('neurological disorders', 'Disease', (250, 272))	('nausea', 'Phenotype', 'HP:0002018', (286, 292))	('lipid', 'Chemical', 'MESH:D008055', (161, 166))	('cholestasis', 'Disease', 'MESH:D002779', (195, 206))	('nausea', 'Disease', (286, 292))	('adrenal insufficiency', 'Disease', (208, 229))	('hepatic cytolysis', 'MPA', (176, 193))	('Mitotane', 'Var', (0, 8))	('neurological disorders', 'Disease', 'MESH:D009422', (250, 272))	('vomiting', 'Disease', 'MESH:D014839', (297, 305))	('nausea', 'Disease', 'MESH:D009325', (286, 292))	('modification', 'Reg', (145, 157))	('hepatic cytolysis', 'Phenotype', 'HP:0002605', (176, 193))	('vomiting', 'Phenotype', 'HP:0002013', (297, 305))	('vomiting', 'Disease', (297, 305))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (208, 229))	('leucopenia', 'Disease', (274, 284))	('cholestasis', 'Disease', (195, 206))	('leucopenia', 'Disease', 'MESH:C536227', (274, 284))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (286, 305))	('cholestasis', 'Phenotype', 'HP:0001396', (195, 206))
50632	30352417	In children given mitotane, we observed an improvement in GV, despite not normalizing UFC (UFC levels did not always drop below 80 microg/24 h).	('mitotane', 'Var', (18, 26))	('mitotane', 'Chemical', 'MESH:D008939', (18, 26))	('children', 'Species', '9606', (3, 11))	('improvement', 'PosReg', (43, 54))
50633	30352417	In addition, mitotane may facilitate an increase in adenoma volume through the stimulation of pituitary ACTH secretion driven by the adrenal insufficiency.	('mitotane', 'Chemical', 'MESH:D008939', (13, 21))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (133, 154))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (133, 154))	('increase', 'PosReg', (40, 48))	('adenoma', 'Disease', 'MESH:D000236', (52, 59))	('adrenal insufficiency', 'Disease', (133, 154))	('mitotane', 'Var', (13, 21))	('ACTH', 'Gene', (104, 108))	('ACTH', 'Gene', '5443', (104, 108))	('adenoma', 'Disease', (52, 59))
50650	30301885	We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes.	('ACC', 'Disease', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('mutations', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))
50658	30301885	Molecular studies have demonstrated that TP53 inactivating mutations, CTNNB1 activating mutations, IGF2 overexpression, damaging mutations in ZNRF3, and high-level amplification of TERT are common and key drivers of ACC.	('TP53', 'Gene', '7157', (41, 45))	('CTNNB1', 'Gene', '1499', (70, 76))	('TP53', 'Gene', (41, 45))	('TERT', 'Gene', (181, 185))	('mutations', 'Var', (129, 138))	('mutations', 'Var', (88, 97))	('IGF2', 'Gene', '3481', (99, 103))	('TERT', 'Gene', '7015', (181, 185))	('ZNRF3', 'Gene', '84133', (142, 147))	('CTNNB1', 'Gene', (70, 76))	('ZNRF3', 'Gene', (142, 147))	('activating', 'PosReg', (77, 87))	('overexpression', 'PosReg', (104, 118))	('IGF2', 'Gene', (99, 103))
50660	30301885	Multiple studies have reported that activating and inactivating alterations in the TP53/Rb and WNT pathways are key molecular events in the pathogenesis of ACC.	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('ACC', 'Disease', (156, 159))	('activating', 'PosReg', (36, 46))	('WNT pathways', 'Pathway', (95, 107))	('inactivating alterations', 'Var', (51, 75))
50667	30301885	We identified 15,321 somatic mutations in the coding region of the genome in 33 tumors; 5928 nonsynonymous mutations and 9393 silent mutations (Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutations', 'Var', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('nonsynonymous mutations', 'Var', (93, 116))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))
50674	30301885	Similar to primary ACC from the TCGA data and most other solid tumors, metastatic ACC were characterized by a predominance of C > T transitions (Fig.	('solid tumors', 'Disease', (57, 69))	('metastatic ACC', 'Disease', (71, 85))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('solid tumors', 'Disease', 'MESH:D009369', (57, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('C > T transitions', 'Var', (126, 143))
50677	30301885	Similar to primary ACC, we observed that CTNNB1, DNHD1, and TTN were frequently mutated in metastatic ACC.	('TTN', 'Gene', (60, 63))	('DNHD1', 'Gene', (49, 54))	('TTN', 'Gene', '7273', (60, 63))	('metastatic ACC', 'Disease', (91, 105))	('CTNNB1', 'Gene', (41, 47))	('mutated', 'Var', (80, 87))	('DNHD1', 'Gene', '144132', (49, 54))	('CTNNB1', 'Gene', '1499', (41, 47))
50678	30301885	Nevertheless, we have also identified genes such as ENTHD1, HELZ2, PCDH12, SHANK1, and WDR66 that were more frequently mutated in metastatic ACC but not in primary tumors (Fig.	('primary tumors', 'Disease', 'MESH:D009369', (156, 170))	('HELZ2', 'Gene', (60, 65))	('SHANK1', 'Gene', (75, 81))	('ENTHD1', 'Gene', '150350', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('PCDH12', 'Gene', (67, 73))	('metastatic ACC', 'Disease', (130, 144))	('WDR66', 'Gene', (87, 92))	('ENTHD1', 'Gene', (52, 58))	('PCDH12', 'Gene', '51294', (67, 73))	('mutated', 'Var', (119, 126))	('SHANK1', 'Gene', '50944', (75, 81))	('primary tumors', 'Disease', (156, 170))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('HELZ2', 'Gene', '85441', (60, 65))	('WDR66', 'Gene', '144406', (87, 92))
50679	30301885	In addition, we noticed that two metastatic ACCs from the same patient (Case 1) had a strong hypermutation phenotype (Supplementary Table 1), and two additional patients had > /10 single-nucleotide polymorphisms (SNPs) per megabase compared to a median of 2.63 SNPs per megabase for all metastatic ACCs in our data set.	('single-nucleotide polymorphisms', 'Var', (180, 211))	('patient', 'Species', '9606', (161, 168))	('hypermutation phenotype', 'MPA', (93, 116))	('patients', 'Species', '9606', (161, 169))	('patient', 'Species', '9606', (63, 70))	('ACCs', 'Gene', (44, 48))	('ACCs', 'Gene', (298, 302))	('ACCs', 'Gene', '84680', (44, 48))	('ACCs', 'Gene', '84680', (298, 302))
50680	30301885	For the two tumor samples with the highest mutation rates, the only LoF mutation shared between both tumors is a heterozygous 9-base germline insertion in exon 1of MSH3 (Supplementary Table 2 and Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('mutation', 'Var', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('MSH3', 'Gene', (164, 168))	('LoF', 'NegReg', (68, 71))	('mutation', 'Var', (72, 80))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('MSH3', 'Gene', '4437', (164, 168))	('tumors', 'Disease', (101, 107))
50683	30301885	We detected a focal homozygous deletion of MSH6 (Supplementary Table 2 and Supplementary Fig.	('MSH6', 'Gene', (43, 47))	('deletion', 'Var', (31, 39))	('MSH6', 'Gene', '2956', (43, 47))
50685	30301885	In addition, we detected a frameshift mutation in ATM that has become homozygous through an LoH event (Supplementary Table 2 and Supplementary Fig.	('ATM', 'Gene', '472', (50, 53))	('ATM', 'Gene', (50, 53))	('frameshift mutation', 'Var', (27, 46))
50687	30301885	Interestingly, a single sample from the TCGA ACC primary tumors (TCGA-OR-A5K4-01) also possessed LoF mutations in MSH6 and ATM (although both were nonsense mutations, Supplementary Fig.	('mutations', 'Var', (101, 110))	('LoF', 'NegReg', (97, 100))	('primary tumors', 'Disease', (49, 63))	('ATM', 'Gene', (123, 126))	('MSH6', 'Gene', (114, 118))	('primary tumors', 'Disease', 'MESH:D009369', (49, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('MSH6', 'Gene', '2956', (114, 118))	('ATM', 'Gene', '472', (123, 126))
50688	30301885	5), and had the eighth-highest mutation rate of that sample of 92 primary tumors (24), suggesting compound LoF in these two genes may be driving hypermutation.	('LoF', 'Var', (107, 110))	('primary tumors', 'Disease', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('primary tumors', 'Disease', 'MESH:D009369', (66, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
50689	30301885	The final patient with hypermutating ACC metastases had no detected LoF mutations in any DNA repair genes that were present in all three of the metastases sampled for that patient.	('mutations', 'Var', (72, 81))	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('patient', 'Species', '9606', (172, 179))	('DNA repair genes', 'Gene', (89, 105))	('patient', 'Species', '9606', (10, 17))	('ACC', 'Disease', (37, 40))	('metastases', 'Disease', (41, 51))	('metastases', 'Disease', (144, 154))	('metastases', 'Disease', 'MESH:D009362', (144, 154))
50690	30301885	However, there were two rare germline ATM missense mutations that rose to fixation in all three of the tumor samples from that patient through complete LoH (Supplementary Table 2 and Supplementary Fig.	('ATM', 'Gene', '472', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('patient', 'Species', '9606', (127, 134))	('tumor', 'Disease', (103, 108))	('missense mutations', 'Var', (42, 60))	('ATM', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('LoH', 'NegReg', (152, 155))
50691	30301885	To understand the nature of metastatic ACC, we selected all the somatic mutations within the coding regions of each tumor sample site and performed principal component analysis (PCA) on the entire patient cohort.	('mutations', 'Var', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('patient', 'Species', '9606', (197, 204))
50697	30301885	Nevertheless, we observed that genes such as DNAH6, MUC5B, HELZ2, and KIAA0100 were frequently mutated in three of six lung ACC metastases (Supplementary Table 3).	('metastases', 'Disease', (128, 138))	('KIAA0100', 'Gene', (70, 78))	('HELZ2', 'Gene', '85441', (59, 64))	('KIAA0100', 'Gene', '9703', (70, 78))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('lung ACC', 'Disease', (119, 127))	('HELZ2', 'Gene', (59, 64))	('mutated', 'Var', (95, 102))	('MUC5B', 'Gene', '727897', (52, 57))	('MUC5B', 'Gene', (52, 57))	('DNAH6', 'Gene', '1768', (45, 50))	('DNAH6', 'Gene', (45, 50))
50698	30301885	In addition, CTNNB1 was mutated in both ACC liver metastases (Fig.	('mutated', 'Var', (24, 31))	('liver metastases', 'Disease', 'MESH:D009362', (44, 60))	('CTNNB1', 'Gene', (13, 19))	('CTNNB1', 'Gene', '1499', (13, 19))	('liver metastases', 'Disease', (44, 60))
50699	30301885	Genes such as ARHGEF28 and PPL were mutated in three of six ACC samples classified as other tumor sites (Fig.	('PPL', 'Gene', (27, 30))	('ARHGEF28', 'Gene', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('ACC', 'Disease', (60, 63))	('PPL', 'Gene', '5493', (27, 30))	('mutated', 'Var', (36, 43))	('ARHGEF28', 'Gene', '64283', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
50702	30301885	We selected four patients with metastases to more than one tumor site and found that most mutated genes were common within a patient regardless of the site of metastases (Fig.	('metastases', 'Disease', (159, 169))	('tumor', 'Disease', (59, 64))	('mutated', 'Var', (90, 97))	('metastases', 'Disease', 'MESH:D009362', (31, 41))	('patient', 'Species', '9606', (17, 24))	('metastases', 'Disease', 'MESH:D009362', (159, 169))	('patients', 'Species', '9606', (17, 25))	('patient', 'Species', '9606', (125, 132))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('metastases', 'Disease', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
50707	30301885	At the genome-wide scale, copy number variation in metastatic tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('metastatic tumors', 'Disease', 'MESH:C538445', (51, 68))	('copy number variation', 'Var', (26, 47))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('metastatic tumors', 'Disease', (51, 68))
50710	30301885	However, in contrast to primary tumors, we detected no whole-genome doubling (WGD) events in the ABSOLUTE analysis of our ACC metastases, in spite of the fact that the proportion of CNV-altered genomes ranged from 0.17 to 0.96 (Supplementary Table 1).	('primary tumors', 'Disease', (24, 38))	('primary tumors', 'Disease', 'MESH:D009369', (24, 38))	('metastases', 'Disease', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('CNV-altered', 'Var', (182, 193))	('metastases', 'Disease', 'MESH:D009362', (126, 136))
50711	30301885	At the gene level, the TERT amplification, CHEK2/ZNRF3 deletion, and CDKN2A deletion previously identified as being common in primary ACC were also identified in our metastatic sample.	('deletion', 'Var', (76, 84))	('primary ACC', 'Disease', (126, 137))	('TERT', 'Gene', (23, 27))	('CDKN2A', 'Gene', '1029', (69, 75))	('TERT', 'Gene', '7015', (23, 27))	('ZNRF3', 'Gene', (49, 54))	('CHEK2', 'Gene', '11200', (43, 48))	('deletion', 'Var', (55, 63))	('ZNRF3', 'Gene', '84133', (49, 54))	('CDKN2A', 'Gene', (69, 75))	('CHEK2', 'Gene', (43, 48))
50714	30301885	However, we found common homozygous deletions in CDK11A/B, STK4/TOMM34, and CDKN2A/MTAP (Supplementary Figs.	('CDKN2A', 'Gene', '1029', (76, 82))	('MTAP', 'Gene', '4507', (83, 87))	('deletions', 'Var', (36, 45))	('MTAP', 'Gene', (83, 87))	('STK4', 'Gene', '6789', (59, 63))	('STK4', 'Gene', (59, 63))	('TOMM34', 'Gene', '10953', (64, 70))	('TOMM34', 'Gene', (64, 70))	('CDK11A/B', 'Gene', (49, 57))	('CDKN2A', 'Gene', (76, 82))	('CDK11A/B', 'Gene', '728642;984', (49, 57))
50717	30301885	In agreement with the patterns observed for SNPs, copy number variation in metastatic tumors was also highly homogenous within patients but divergent between metastases in the same site (or different sites) from different patients.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('patients', 'Species', '9606', (222, 230))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('patients', 'Species', '9606', (127, 135))	('metastases', 'Disease', (158, 168))	('metastatic tumors', 'Disease', 'MESH:C538445', (75, 92))	('metastatic tumors', 'Disease', (75, 92))	('copy number variation', 'Var', (50, 71))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
50718	30301885	We analyzed the entire gene list of recurrent mutations in metastatic ACC through ingenuity pathway analysis (IPA) to identify molecular pathways associated with these tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (46, 55))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (168, 174))	('metastatic ACC', 'Gene', (59, 73))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
50721	30301885	We analyzed targetable recurrent mutations in ACC metastases using commercially available and FDA-approved drugs through the IPA database.	('metastases', 'Disease', 'MESH:D009362', (50, 60))	('ACC', 'Gene', (46, 49))	('metastases', 'Disease', (50, 60))	('mutations', 'Var', (33, 42))
50726	30301885	Collectively, based on whole-exome sequencing mutations identified in metastatic ACC, 9 of 14 patients could have treatment using commercially available and approved drugs that target alterations in their tumors.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('mutations', 'Var', (46, 55))	('patients', 'Species', '9606', (94, 102))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))
50733	30301885	Multiple genes such as CSMD2 (CUB and Sushi Multiple Domains 2), LRP1b (LDL Receptor related Protein 1B) and KIAA0100, which have been suggested to have tumor suppressor function in the literature were also found to be mutated in metastatic ACC tumors.	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('KIAA0100', 'Gene', '9703', (109, 117))	('ACC tumors', 'Disease', (241, 251))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('mutated', 'Var', (219, 226))	('CSMD2', 'Gene', (23, 28))	('LRP1b', 'Gene', '53353', (65, 70))	('tumor', 'Disease', (153, 158))	('LDL Receptor related Protein 1B', 'Gene', (72, 103))	('CSMD2', 'Gene', '114784', (23, 28))	('ACC tumors', 'Disease', 'MESH:D004476', (241, 251))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('LRP1b', 'Gene', (65, 70))	('LDL Receptor related Protein 1B', 'Gene', '53353', (72, 103))	('tumor', 'Disease', (245, 250))	('CUB', 'Gene', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('KIAA0100', 'Gene', (109, 117))	('CUB', 'Gene', '64478', (30, 33))
50734	30301885	Particularly, CSMD2, a candidate tumor suppressor gene in colorectal cancer and breast cancer patients was mutated in three metastatic ACC samples (Fig.	('patients', 'Species', '9606', (94, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (58, 75))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutated', 'Var', (107, 114))	('CSMD2', 'Gene', '114784', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('colorectal cancer', 'Disease', (58, 75))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('CSMD2', 'Gene', (14, 19))	('breast cancer', 'Disease', (80, 93))	('tumor', 'Disease', (33, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (58, 75))
50735	30301885	LRP1b, a candidate tumor suppressor gene that is frequently inactivated in non-small lung cancer cells was also mutated in three metastatic ACC samples (Fig.	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('LRP1b', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('tumor', 'Disease', (19, 24))	('small lung', 'Phenotype', 'HP:0002089', (79, 89))	('mutated', 'Var', (112, 119))	('LRP1b', 'Gene', '53353', (0, 5))
50737	30301885	Primary ACC are enriched for mutations in CTNNB1, TP53, ZNRF3, DAXX, and MEN1 genes, including homozygous deletions or high-level amplifications.	('deletions', 'Var', (106, 115))	('MEN1', 'Gene', (73, 77))	('MEN1', 'Gene', '4221', (73, 77))	('DAXX', 'Gene', (63, 67))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (50, 54))	('CTNNB1', 'Gene', (42, 48))	('ZNRF3', 'Gene', '84133', (56, 61))	('TP53', 'Gene', (50, 54))	('ZNRF3', 'Gene', (56, 61))	('CTNNB1', 'Gene', '1499', (42, 48))	('DAXX', 'Gene', '1616', (63, 67))
50738	30301885	Although we observed a higher frequency of mutations in the CTNNB1 (p.D32G, p.G34R, p.S45P, and p.S45F) in metastatic ACC, there were no mutations observed in TP53, ZNRF3, MEN1, and DAXX.	('DAXX', 'Gene', '1616', (182, 186))	('MEN1', 'Gene', (172, 176))	('CTNNB1', 'Gene', (60, 66))	('p.S45F', 'Var', (96, 102))	('MEN1', 'Gene', '4221', (172, 176))	('p.G34R', 'Mutation', 'rs121913399', (76, 82))	('ZNRF3', 'Gene', '84133', (165, 170))	('p.S45F', 'Mutation', 'rs121913409', (96, 102))	('p.D32G', 'Mutation', 'rs121913396', (68, 74))	('TP53', 'Gene', '7157', (159, 163))	('DAXX', 'Gene', (182, 186))	('TP53', 'Gene', (159, 163))	('ZNRF3', 'Gene', (165, 170))	('p.S45P', 'Mutation', 'rs121913407', (84, 90))	('CTNNB1', 'Gene', '1499', (60, 66))	('p.G34R', 'Var', (76, 82))	('p.D32G', 'Var', (68, 74))	('p.S45P', 'Var', (84, 90))
50740	30301885	It appears that metastatic ACCs do adapt and gain mutations in other genes that are different than primary ACCs.	('ACCs', 'Gene', '84680', (27, 31))	('ACCs', 'Gene', (27, 31))	('gain', 'PosReg', (45, 49))	('mutations', 'Var', (50, 59))	('ACCs', 'Gene', '84680', (107, 111))	('ACCs', 'Gene', (107, 111))
50741	30301885	Although, we found frameshift-, nonsense- or splice site mutations in metastatic ACC tumors, the majority of them were not recurrent (present in multiple metastatic samples) and are, therefore, not discussed here.	('frameshift-', 'Var', (19, 30))	('ACC tumors', 'Disease', (81, 91))	('nonsense- or splice site mutations', 'Var', (32, 66))	('ACC tumors', 'Disease', 'MESH:D004476', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
50744	30301885	Particularly, loss of CSMD3 has been shown to increase the proliferation of airway epithelial cells.	('loss', 'Var', (14, 18))	('increase', 'PosReg', (46, 54))	('proliferation of airway epithelial cells', 'CPA', (59, 99))	('CSMD3', 'Gene', '114788', (22, 27))	('CSMD3', 'Gene', (22, 27))
50746	30301885	Homozygous LoF mutations in RLTPR (CARMIL2) has been associated with disseminated EBV + smooth muscle tumors.	('RLTPR', 'Gene', '146206', (28, 33))	('muscle tumors', 'Disease', (95, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('CARMIL2', 'Gene', (35, 42))	('mutations', 'Var', (15, 24))	('CARMIL2', 'Gene', '146206', (35, 42))	('RLTPR', 'Gene', (28, 33))	('LoF', 'NegReg', (11, 14))	('muscle tumors', 'Disease', 'MESH:D009217', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
50748	30301885	However, some of these variants are present in the TCGA data set of other cancer types.	('variants', 'Var', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))
50749	30301885	For example, the P1772S variant in the HELZ2 gene is present in cutaneous melanoma and colorectal adenocarcinoma, the C1183S variant in PCDH12 is present in renal cell carcinoma and colorectal adenocarcinoma.	('P1772S', 'Mutation', 'rs1232421413', (17, 23))	('colorectal adenocarcinoma', 'Disease', (87, 112))	('C1183S', 'Mutation', 'rs200120809', (118, 124))	('cutaneous melanoma', 'Disease', (64, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (64, 82))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (64, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('HELZ2', 'Gene', (39, 44))	('colorectal adenocarcinoma', 'Disease', (182, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('present', 'Reg', (53, 60))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (87, 112))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (157, 177))	('C1183S', 'Var', (118, 124))	('P1772S', 'Var', (17, 23))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (182, 207))	('PCDH12', 'Gene', (136, 142))	('HELZ2', 'Gene', '85441', (39, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (157, 177))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('present', 'Reg', (146, 153))	('renal cell carcinoma', 'Disease', (157, 177))	('PCDH12', 'Gene', '51294', (136, 142))
50753	30301885	Nevertheless, our results provide evidence that metastatic ACCs do evolve and gain mutations that are different than primary ACCs.	('mutations', 'Var', (83, 92))	('ACCs', 'Gene', (59, 63))	('ACCs', 'Gene', '84680', (59, 63))	('ACCs', 'Gene', (125, 129))	('ACCs', 'Gene', '84680', (125, 129))	('gain', 'PosReg', (78, 82))
50755	30301885	Although we do not provide any evidence that chemotherapy resistance driver genes are common in metastatic tumors and moreover it is very difficult to make a connection between heterogeneity and primary resistance, it is tempting to speculate high heterogeneity in tumors could lead to rapid acquired resistance because of the higher probability of pre-existing drug-resistant subclones, which may explain resistance to systemic chemotherapy that are common in ACC.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('high', 'Var', (243, 247))	('tumors', 'Disease', (107, 113))	('acquired resistance', 'CPA', (292, 311))	('metastatic tumors', 'Disease', (96, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', (265, 271))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('lead to', 'Reg', (278, 285))	('metastatic tumors', 'Disease', 'MESH:C538445', (96, 113))
50758	30301885	Although many metastatic ACC tumor samples harbored mutations in the beta-catenin gene like primary ACC, other genes involving molecular pathways such as ERBB4, GPCR, RAR, and PDGFR signaling were also frequently mutated in metastatic ACC.	('mutations', 'Var', (52, 61))	('PDGFR', 'Gene', (176, 181))	('PDGFR', 'Gene', '5159', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('RAR', 'Gene', '5914', (167, 170))	('beta-catenin', 'Gene', (69, 81))	('ERBB4', 'Gene', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('metastatic ACC', 'Disease', (224, 238))	('beta-catenin', 'Gene', '1499', (69, 81))	('GPCR', 'Gene', (161, 165))	('tumor', 'Disease', (29, 34))	('primary ACC', 'Disease', (92, 103))	('metastatic ACC', 'Disease', (14, 28))	('ERBB4', 'Gene', '2066', (154, 159))	('RAR', 'Gene', (167, 170))	('GPCR', 'Gene', '9170', (161, 165))
50759	30301885	Activating mutations in ERBB4 have recently been reported in non-small cell lung cancer.	('cell lung cancer', 'Disease', (71, 87))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (65, 87))	('ERBB4', 'Gene', '2066', (24, 29))	('Activating mutations', 'Var', (0, 20))	('reported', 'Reg', (49, 57))	('cell lung cancer', 'Disease', 'MESH:D008175', (71, 87))	('ERBB4', 'Gene', (24, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (61, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
50760	30301885	In melanoma, ERBB4 mutations have been shown to be the major oncogenic driver with both aberrant ERBB4 and PI3K-AKT signaling.	('ERBB4', 'Gene', '2066', (13, 18))	('mutations', 'Var', (19, 28))	('ERBB4', 'Gene', '2066', (97, 102))	('melanoma', 'Disease', (3, 11))	('ERBB4', 'Gene', (13, 18))	('PI3K-AKT signaling', 'Pathway', (107, 125))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('aberrant', 'Var', (88, 96))	('ERBB4', 'Gene', (97, 102))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
50761	30301885	Likewise, we observed mutations in ERBB4 and PI3K-AKT signaling genes in metastatic ACC.	('metastatic ACC', 'Disease', (73, 87))	('PI3K-AKT signaling genes', 'Gene', (45, 69))	('ERBB4', 'Gene', '2066', (35, 40))	('mutations', 'Var', (22, 31))	('ERBB4', 'Gene', (35, 40))
50763	30301885	Activating mutations of G-protein-coupled receptor are mutated in approximately 20% of all cancers including skin, prostate, breast, thyroid, liver, kidney, pancreas, skin, ovary, and large intestine.	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (11, 20))	('G-protein-coupled receptor', 'Gene', '9170', (24, 50))	('pancreas', 'Disease', (157, 165))	('breast', 'Disease', (125, 131))	('mutated', 'Var', (55, 62))	('skin', 'Disease', (167, 171))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('skin', 'Disease', (109, 113))	('pancreas', 'Disease', 'MESH:D010190', (157, 165))	('kidney', 'Disease', (149, 155))	('thyroid', 'Disease', (133, 140))	('G-protein-coupled receptor', 'Gene', (24, 50))	('ovary', 'Disease', (173, 178))	('prostate', 'Disease', (115, 123))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('large intestine', 'Disease', (184, 199))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('liver', 'Disease', (142, 147))
50764	30301885	Particularly, the glutamate family of G-protein-linked receptors (GRM1-8) that were seen in our cohort was mutated in 8% of non-small cell lung cancers.	('lung cancers', 'Phenotype', 'HP:0100526', (139, 151))	('GRM1-8', 'Gene', (66, 72))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (128, 150))	('cell lung cancers', 'Disease', (134, 151))	('mutated', 'Var', (107, 114))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (124, 150))	('glutamate', 'Chemical', 'MESH:D018698', (18, 27))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (124, 151))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('GRM1-8', 'Gene', '2911;2912;2913;2914;2915;2916;2917;2918', (66, 72))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (128, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('glutamate family of G-protein-linked receptors', 'Protein', (18, 64))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cell lung cancers', 'Disease', 'MESH:D008175', (134, 151))
50766	30301885	We found the druggable target ERBB4 to be frequently mutated in metastatic ACC and we propose exploring the possibility of targeting this class of molecules.	('mutated', 'Var', (53, 60))	('ERBB4', 'Gene', '2066', (30, 35))	('ERBB4', 'Gene', (30, 35))	('metastatic ACC', 'Disease', (64, 78))
50767	30301885	For instance, lapatinib is already under clinical trial in patients with stage IV melanoma with ERBB4 mutations.	('ERBB4', 'Gene', '2066', (96, 101))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('mutations', 'Var', (102, 111))	('patients', 'Species', '9606', (59, 67))	('ERBB4', 'Gene', (96, 101))	('lapatinib', 'Chemical', 'MESH:D000077341', (14, 23))
50770	30301885	Another case report of metastatic ACC with aberrant vascular endothelial growth factor (VEGF) expression showed significant antitumor activity following sunitinib treatment.	('vascular endothelial growth factor', 'Gene', '7422', (52, 86))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('metastatic ACC', 'Disease', (23, 37))	('VEGF', 'Gene', (88, 92))	('vascular endothelial growth factor', 'Gene', (52, 86))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('sunitinib', 'Chemical', 'MESH:D000077210', (153, 162))	('tumor', 'Disease', (128, 133))	('VEGF', 'Gene', '7422', (88, 92))	('aberrant', 'Var', (43, 51))
50786	30301885	The list of genes that carry missense, nonsense and splice site mutations and also mutated in at least two samples from the pairwise tumor and germline data of metastatic adrenocortical tumors was uploaded into the IPA software (Qiagen).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (186, 191))	('adrenocortical tumors', 'Disease', (171, 192))	('tumor', 'Disease', (133, 138))	('missense', 'Var', (29, 37))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (171, 192))
50790	27057163	The model includes cellular proliferation, intracellular cholesterol translocation, diffusional transport of steroids, and metabolic pathways of adrenal steroidogenesis, which serially involve steroidogenic proteins and enzymes such as StAR, CYP11A1, CYP17A1, HSD3B2, CYP21A2, CYP11B1, CYP11B2, HSD17B3, and CYP19A1.	('CYP19A1', 'Gene', (308, 315))	('CYP11B1', 'Gene', '1584', (277, 284))	('CYP11A1', 'Var', (242, 249))	('CYP11B1', 'Gene', (277, 284))	('steroids', 'Chemical', 'MESH:D013256', (109, 117))	('CYP17A1', 'Gene', (251, 258))	('CYP17A1', 'Gene', '1586', (251, 258))	('steroid', 'Chemical', 'MESH:D013256', (109, 116))	('diffusional transport', 'MPA', (84, 105))	('CYP11B2', 'Var', (286, 293))	('CYP21A2', 'Gene', (268, 275))	('steroidogenesis', 'Chemical', '-', (153, 168))	('HSD17B3', 'Gene', '3293', (295, 302))	('CYP21A2', 'Gene', '1589', (268, 275))	('CYP19A1', 'Gene', '1588', (308, 315))	('steroid', 'Chemical', 'MESH:D013256', (153, 160))	('HSD17B3', 'Gene', (295, 302))	('steroid', 'Chemical', 'MESH:D013256', (193, 200))	('cholesterol', 'Chemical', 'MESH:D002784', (57, 68))
50801	27057163	H295R cells have the physiological characteristics of zonally undifferentiated human fetal adrenal cells and the ability to produce steroid hormones found in the adult adrenal cortex.	('human', 'Species', '9606', (79, 84))	('H295R', 'Var', (0, 5))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('produce steroid hormones', 'MPA', (124, 148))	('steroid hormones', 'Chemical', 'MESH:D013256', (132, 148))
50826	27057163	The cells were maintained in a 1 : 1 mixture of Dulbecco's modified Eagle's medium (DMEM, GIBCO, Life Technologies, Carlsbad, CA) and F-12 medium (MP Biomedicals Inc., Irvine, CA) supplemented with 15 mM HEPES (Dojindo Laboratories, Kumamoto, Japan), 0.00625 mg/mL insulin (Sigma-Aldrich, Inc., St. Louis, MO), 0.00625 mg/mL transferrin (Sigma-Aldrich Inc., St. Louis, MO), 30 nM sodium selenite (Wako Pure Chemical Industries Ltd., Osaka, Japan), 1.25 mg/mL bovine serum albumin (BSA, Sigma-Aldrich Inc., St. Louis, MO), 0.00535 mg/mL linoleic acid (Sigma-Aldrich Inc., St. Louis, MO), 2.5% Nu Serum (Becton, Dickinson and Company, Franklin Lakes, NJ), 100 U/mL penicillin (Meiji Seika Pharma, Tokyo, Japan), and 100 mg/L streptomycin (Meiji Seika Pharma, Tokyo, Japan).	('serum albumin', 'Gene', '213', (466, 479))	('0.00535 mg/mL', 'Var', (522, 535))	('serum albumin', 'Gene', (466, 479))	('insulin', 'Gene', (265, 272))	('transferrin', 'Gene', '7018', (325, 336))	('MP', 'Chemical', 'MESH:D008797', (147, 149))	('transferrin', 'Gene', (325, 336))	('insulin', 'Gene', '3630', (265, 272))	('bovine', 'Species', '9913', (459, 465))
50840	27057163	The transitions in MRM were as follows: PREG m/z 317   299, HPREG m/z 315   297, DHEA m/z 289   271, PROG m/z 315   109, HPROG m/z 331   109, DIONE m/z 287   97, DCORT m/z 331   123, DCORTICO m/z 347   161, CORTICO m/z 347   100, CORT m/z 363   309, ALDO m/z 361   343, and TESTO m/z 289   109.	('ALDO', 'Chemical', 'MESH:D000450', (250, 254))	('CORTICO', 'Chemical', 'MESH:D003345', (184, 191))	('CORT', 'Gene', '1325', (230, 234))	('CORTICO', 'Chemical', 'MESH:D003345', (207, 214))	('m/z 289   109', 'Var', (280, 293))	('PROG', 'Chemical', 'MESH:D011374', (101, 105))	('CORT', 'Gene', (207, 211))	('CORT', 'Gene', (163, 167))	('CORT', 'Gene', (184, 188))	('CORT', 'Gene', '1325', (207, 211))	('CORT', 'Gene', '1325', (163, 167))	('PROG', 'Chemical', 'MESH:D011374', (122, 126))	('CORT', 'Gene', '1325', (184, 188))	('DHEA', 'Chemical', 'MESH:D003687', (81, 85))	('m/z 287', 'Var', (148, 155))	('CORT', 'Gene', (230, 234))	('m/z 315   297', 'Var', (66, 79))	('m/z 347   161', 'Var', (192, 205))
50905	27057163	The highly sensitive parameters for fitting the NLSD score were the extracted nine kinetic parameters, k Cholesterol  Transport, k f acc, k f loc, k b loc, V max CYP11A1, K m CYP11A1, V maxA CYP17H, V maxA HSD3B2, and V maxA CYP21A2, which had higher than 3.0 fitting sensitivity.	('Cholesterol', 'Chemical', 'MESH:D002784', (105, 116))	('CYP17', 'Gene', '1586', (191, 196))	('CYP21A2', 'Gene', (225, 232))	('k Cholesterol  Transport', 'MPA', (103, 127))	('CYP21A2', 'Gene', '1589', (225, 232))	('CYP17', 'Gene', (191, 196))	('CYP11A1', 'Var', (162, 169))
50911	27057163	AGT has been reported to inhibit CYP11A1, CYP21A2, CYP11B1, and CYP11B2.	('CYP11B1', 'Gene', '1584', (51, 58))	('CYP21A2', 'Gene', '1589', (42, 49))	('CYP11A1', 'Var', (33, 40))	('AGT', 'Chemical', 'MESH:D000616', (0, 3))	('CYP21A2', 'Gene', (42, 49))	('inhibit', 'NegReg', (25, 32))	('CYP11B1', 'Gene', (51, 58))	('CYP11B2', 'Var', (64, 71))
50916	27057163	Inhibition of AGT by CYP11B2 has been shown using sheep adrenal homogenates as well as a human adrenal homogenate from a patient with Cushing's syndrome.	('human', 'Species', '9606', (89, 94))	("Cushing's syndrome", 'Disease', (134, 152))	('Inhibition', 'NegReg', (0, 10))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (134, 152))	('AGT', 'Protein', (14, 17))	('AGT', 'Chemical', 'MESH:D000616', (14, 17))	('sheep', 'Species', '9940', (50, 55))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (134, 152))	('patient', 'Species', '9606', (121, 128))	('CYP11B2', 'Var', (21, 28))
50917	27057163	The activity of 18-hydroxylase induced by CYP11B2 was determined as the conversion of corticosterone to 18-hydroxycorticosterone in the previous study.	('corticosterone', 'Chemical', 'MESH:D003345', (86, 100))	('CYP11B2', 'Var', (42, 49))	('corticosterone', 'Chemical', 'MESH:D003345', (114, 128))	('18-hydroxycorticosterone', 'Chemical', 'MESH:D015069', (104, 128))	('activity', 'MPA', (4, 12))
50918	27057163	The cause of the discrepancy regarding the effect of AGT on CYP11B2 was suggested to be substrate inhibition, because the intracellular concentration of CORTICO was increased by over 10 times of that in the culture medium to reach 50 muM.	('CORTICO', 'Chemical', 'MESH:D003345', (153, 160))	('intracellular concentration of CORTICO', 'MPA', (122, 160))	('muM', 'Gene', (234, 237))	('CYP11B2', 'Var', (60, 67))	('muM', 'Gene', '56925', (234, 237))	('increased', 'PosReg', (165, 174))	('AGT', 'Chemical', 'MESH:D000616', (53, 56))
50920	27057163	Hecker and colleagues reported that 3 muM AGT decreases PREG and PROG concentrations and increases the TESTO concentration.	('muM', 'Gene', '56925', (38, 41))	('TESTO concentration', 'MPA', (103, 122))	('AGT', 'Chemical', 'MESH:D000616', (42, 45))	('muM', 'Gene', (38, 41))	('AGT', 'Var', (42, 45))	('decreases', 'NegReg', (46, 55))	('PROG', 'Chemical', 'MESH:D011374', (65, 69))	('increases', 'PosReg', (89, 98))
50923	27057163	The mechanism of action of DDD in adrenal steroidogenesis was estimated by dose-dependent inhibition of CYP11A1, HSD3B2, CYP21A2, and CYP11B1 (estimated inhibitions at 25 muM were 87.0%, 86.9%, 76.9%, and 84.9%, resp.)	('adrenal steroidogenesis', 'MPA', (34, 57))	('inhibition', 'NegReg', (90, 100))	('muM', 'Gene', (171, 174))	('steroidogenesis', 'Chemical', '-', (42, 57))	('CYP21A2', 'Gene', '1589', (121, 128))	('CYP11B1', 'Gene', (134, 141))	('CYP21A2', 'Gene', (121, 128))	('DDD', 'Chemical', 'MESH:D003632', (27, 30))	('HSD3B2', 'Gene', (113, 119))	('CYP11A1', 'Var', (104, 111))	('CYP11B1', 'Gene', '1584', (134, 141))	('muM', 'Gene', '56925', (171, 174))
50924	27057163	DDD has been reported to inhibit CYP11A1, HSD3B2, CYP21A2, CYP11B1, and CYP11B2.	('CYP11B2', 'Var', (72, 79))	('CYP11B1', 'Gene', '1584', (59, 66))	('CYP11A1', 'Gene', (33, 40))	('DDD', 'Chemical', 'MESH:D003632', (0, 3))	('CYP21A2', 'Gene', (50, 57))	('CYP21A2', 'Gene', '1589', (50, 57))	('HSD3B2', 'Gene', (42, 48))	('inhibit', 'NegReg', (25, 32))	('CYP11B1', 'Gene', (59, 66))
50927	27057163	Inhibition of DDD by CYP11B2 has been shown using mitochondrial and microsomal fractions prepared by standard centrifugation procedures from a bovine adrenal cortex homogenate.	('DDD', 'Gene', (14, 17))	('bovine', 'Species', '9913', (143, 149))	('Inhibition', 'NegReg', (0, 10))	('DDD', 'Chemical', 'MESH:D003632', (14, 17))	('CYP11B2', 'Var', (21, 28))
50928	27057163	The cause of the discrepancy regarding the inhibition of DDD by CYP11B2 could not be explained by same effect in the case of AGT.	('exp', 'Gene', (85, 88))	('DDD', 'MPA', (57, 60))	('DDD', 'Chemical', 'MESH:D003632', (57, 60))	('AGT', 'Chemical', 'MESH:D000616', (125, 128))	('exp', 'Gene', '4154', (85, 88))	('CYP11B2', 'Var', (64, 71))
50930	27057163	SP has been reported to inhibit CYP17H, CYP17L, CYP11B1, and CYP11B2.	('CYP11B1', 'Gene', (48, 55))	('CYP17', 'Gene', '1586', (32, 37))	('CYP11B1', 'Gene', '1584', (48, 55))	('CYP17', 'Gene', '1586', (40, 45))	('SP', 'Chemical', 'MESH:D013148', (0, 2))	('CYP11B2', 'Var', (61, 68))	('CYP17', 'Gene', (32, 37))	('inhibit', 'NegReg', (24, 31))	('CYP17', 'Gene', (40, 45))
50939	27057163	Regarding CYP11B1 and CYP11B2, our results were unclear compared with a previous study.	('CYP11B1', 'Gene', (10, 17))	('CYP11B2', 'Var', (22, 29))	('CYP11B1', 'Gene', '1584', (10, 17))
50940	27057163	It has been shown that 30 muM SP inhibits CYP11B1 and CYP11B2 in human and bovine adrenal mitochondria.	('muM', 'Gene', (26, 29))	('CYP11B1', 'Gene', '1584', (42, 49))	('human', 'Species', '9606', (65, 70))	('SP', 'Chemical', 'MESH:D013148', (30, 32))	('inhibits', 'NegReg', (33, 41))	('CYP11B2', 'Var', (54, 61))	('muM', 'Gene', '56925', (26, 29))	('CYP11B1', 'Gene', (42, 49))	('bovine', 'Species', '9913', (75, 81))
50949	27057163	The mechanism of action of KC in adrenal steroidogenesis was estimated by inhibition of CYP11A1, CYP17H, CYP17L, HSD3B2, CYP21A2, CYP11B1, and CYP11B2 (estimated inhibitions at 10 muM were 92.6%, 94.3%, 51.8%, 83.0%, 88.2%, 97.4%, and 79.8%, resp.)	('steroidogenesis', 'Chemical', '-', (41, 56))	('CYP11B1', 'Gene', (130, 137))	('CYP21A2', 'Gene', '1589', (121, 128))	('CYP17', 'Gene', '1586', (105, 110))	('CYP17', 'Gene', '1586', (97, 102))	('CYP17', 'Gene', (97, 102))	('inhibition', 'NegReg', (74, 84))	('CYP21A2', 'Gene', (121, 128))	('adrenal steroidogenesis', 'MPA', (33, 56))	('KC', 'Chemical', 'MESH:D007654', (27, 29))	('CYP11B1', 'Gene', '1584', (130, 137))	('muM', 'Gene', '56925', (180, 183))	('CYP17', 'Gene', (105, 110))	('muM', 'Gene', (180, 183))	('CYP11B2', 'Var', (143, 150))
50950	27057163	KC has been reported to inhibit CYP11A1, CYP17H, CYP17L, HSD3B2, CYP21A2, and CYP11B1.	('CYP21A2', 'Gene', '1589', (65, 72))	('CYP11A1', 'Var', (32, 39))	('CYP21A2', 'Gene', (65, 72))	('HSD3B2', 'Gene', (57, 63))	('CYP17', 'Gene', (41, 46))	('CYP17', 'Gene', (49, 54))	('KC', 'Chemical', 'MESH:D007654', (0, 2))	('CYP11B1', 'Gene', (78, 85))	('CYP11B1', 'Gene', '1584', (78, 85))	('CYP17', 'Gene', '1586', (49, 54))	('CYP17', 'Gene', '1586', (41, 46))	('inhibit', 'NegReg', (24, 31))
50953	27057163	Regarding CYP11B2 and HSD17B3, we considered that these estimated inhibitions of KC did have sufficient reliability in terms of quantitative prediction precision, because ALDO and TESTO concentrations were less than the lower limit of quantification at 10 muM KC.	('ALDO', 'Chemical', 'MESH:D000450', (171, 175))	('CYP11B2', 'Var', (10, 17))	('HSD17B3', 'Gene', (22, 29))	('KC', 'Chemical', 'MESH:D007654', (81, 83))	('KC', 'Chemical', 'MESH:D007654', (260, 262))	('HSD17B3', 'Gene', '3293', (22, 29))	('muM', 'Gene', '56925', (256, 259))	('muM', 'Gene', (256, 259))	('ALDO', 'MPA', (171, 175))
50955	27057163	MC has been reported to inhibit not only CYP17H and CYP17L but also CYP11A1, CYP21A2, and CYP11B1.	('CYP11B1', 'Gene', '1584', (90, 97))	('CYP17', 'Gene', '1586', (52, 57))	('CYP11A1', 'Var', (68, 75))	('CYP17', 'Gene', (52, 57))	('CYP17', 'Gene', (41, 46))	('CYP17', 'Gene', '1586', (41, 46))	('CYP21A2', 'Gene', '1589', (77, 84))	('CYP21A2', 'Gene', (77, 84))	('CYP11B1', 'Gene', (90, 97))	('inhibit', 'NegReg', (24, 31))	('MC', 'Chemical', 'MESH:D008825', (0, 2))
50964	27057163	The mechanism of action of DZ in adrenal steroidogenesis was estimated by inhibition of CYP11A1, HSD3B2, CYP21A2, CYP11B1, and HSD17B3 (estimated inhibitions at 100 muM were 58.6%, 94.1%, 96.5%, 87.2%, and 98.1%, resp.)	('muM', 'Gene', '56925', (165, 168))	('CYP11A1', 'Var', (88, 95))	('CYP11B1', 'Gene', (114, 121))	('CYP11B1', 'Gene', '1584', (114, 121))	('steroidogenesis', 'Chemical', '-', (41, 56))	('HSD3B2', 'Gene', (97, 103))	('muM', 'Gene', (165, 168))	('inhibition', 'NegReg', (74, 84))	('adrenal steroidogenesis', 'MPA', (33, 56))	('HSD17B3', 'Gene', (127, 134))	('CYP21A2', 'Gene', '1589', (105, 112))	('DZ', 'Chemical', 'MESH:C004742', (27, 29))	('HSD17B3', 'Gene', '3293', (127, 134))	('CYP21A2', 'Gene', (105, 112))
50972	27057163	Cholesterol uptake (k Cholesterol  Transport), StAR protein (k f loc), and CYP11A1 (V max CYP11A1), which are determining factors of the capacity for steroidogenesis, promoted the production of mineralocorticoids (DCORTICO, CORTICO, and ALDO) and restrained the synthesis of glucocorticoids (DCORT and CORT) and sex steroids (DIONE, TESTO, and E1) because of the accumulation of intermediate molecules in steroidogenesis (PREG, HPREG, DHEA, PROG, and HPROG) only by self-activation.	('steroidogenesis', 'Chemical', '-', (150, 165))	('steroidogenesis', 'Chemical', '-', (405, 420))	('PROG', 'Chemical', 'MESH:D011374', (441, 445))	('promoted', 'PosReg', (167, 175))	('synthesis', 'MPA', (262, 271))	('Cholesterol', 'Chemical', 'MESH:D002784', (0, 11))	('Cholesterol', 'Chemical', 'MESH:D002784', (22, 33))	('CORT', 'Gene', (224, 228))	('CYP11A1', 'Var', (75, 82))	('CORT', 'Gene', '1325', (224, 228))	('DHEA', 'Chemical', 'MESH:D003687', (435, 439))	('CORT', 'Gene', (215, 219))	('CORT', 'Gene', '1325', (215, 219))	('production', 'MPA', (180, 190))	('mineralocorticoids', 'MPA', (194, 212))	('CORT', 'Gene', (293, 297))	('CORT', 'Gene', (302, 306))	('CORT', 'Gene', '1325', (293, 297))	('CORT', 'Gene', '1325', (302, 306))	('steroids', 'Chemical', 'MESH:D013256', (316, 324))	('CORTICO', 'Chemical', 'MESH:D003345', (224, 231))	('restrained', 'NegReg', (247, 257))	('CORTICO', 'Chemical', 'MESH:D003345', (215, 222))	('PROG', 'Chemical', 'MESH:D011374', (452, 456))	('ALDO', 'Chemical', 'MESH:D000450', (237, 241))
50979	27057163	On the other hand, inhibition of CYP17H and/or HSD3B2 induced the metabolic shift that enhanced the mineralocorticoid biosynthesis and deviated from the glucocorticoid biosynthesis.	('metabolic shift', 'MPA', (66, 81))	('inhibition', 'Var', (19, 29))	('CYP17', 'Gene', '1586', (33, 38))	('HSD3B2', 'Gene', (47, 53))	('enhanced', 'PosReg', (87, 95))	('CYP17', 'Gene', (33, 38))	('mineralocorticoid biosynthesis', 'MPA', (100, 130))
50994	27057163	However, the relationship is unclear and disputed in a small-scale clinical study indicating that genetic variation in HSD3B1 affects blood pressure and hypertension in APA patients.	('hypertension', 'Disease', (153, 165))	('hypertension', 'Phenotype', 'HP:0000822', (153, 165))	('blood pressure', 'MPA', (134, 148))	('HSD3B1', 'Gene', '3283', (119, 125))	('patients', 'Species', '9606', (173, 181))	('HSD3B1', 'Gene', (119, 125))	('hypertension', 'Disease', 'MESH:D006973', (153, 165))	('affects', 'Reg', (126, 133))	('genetic variation', 'Var', (98, 115))
50998	27057163	Mineralocorticoids, such as DCORTICO, CORTICO, and ALDO, and intermediate steroids upstream of the adrenal steroidogenesis pathway, such as PREG, HPREG, DHEA, PROG, and HPROG, were accelerated by reactions of cholesterol import (k Cholesterol  Transport), StAR protein (k f MTR and k f loc), and CYP11A1 (V max CYP11A1).	('PROG', 'Chemical', 'MESH:D011374', (159, 163))	('PROG', 'Chemical', 'MESH:D011374', (170, 174))	('DHEA', 'Chemical', 'MESH:D003687', (153, 157))	('ALDO', 'Chemical', 'MESH:D000450', (51, 55))	('CORTICO', 'Chemical', 'MESH:D003345', (29, 36))	('CYP11A1', 'Var', (296, 303))	('cholesterol', 'Chemical', 'MESH:D002784', (209, 220))	('steroidogenesis', 'Chemical', '-', (107, 122))	('accelerated', 'PosReg', (181, 192))	('cholesterol import', 'MPA', (209, 227))	('steroids', 'Chemical', 'MESH:D013256', (74, 82))	('CORTICO', 'Chemical', 'MESH:D003345', (38, 45))	('Cholesterol', 'Chemical', 'MESH:D002784', (231, 242))
50999	27057163	On the other hand, glucocorticoids, such as DCORT and CORT, and sex hormones, such as DIONE, TESTO, and E1, were suppressed by these model parameters.	('CORT', 'Gene', '1325', (45, 49))	('parameters', 'Var', (139, 149))	('suppressed', 'NegReg', (113, 123))	('TESTO', 'Disease', (93, 98))	('CORT', 'Gene', (54, 58))	('CORT', 'Gene', '1325', (54, 58))	('glucocorticoids', 'MPA', (19, 34))	('CORT', 'Gene', (45, 49))
51003	27057163	This suggestion partially supports a comparative animal study in which molecular and cellular variations in CYP17H activity dramatically affect acute cortisol production, resulting in distinct physiological and behavioral responses.	('cortisol', 'Chemical', 'MESH:D006854', (150, 158))	('CYP17', 'Gene', (108, 113))	('variations', 'Var', (94, 104))	('acute cortisol production', 'MPA', (144, 169))	('affect', 'Reg', (137, 143))	('CYP17', 'Gene', '1586', (108, 113))
51033	26548814	JAG1 mutations have been associated with several disorders including the multisystem dominant disorder Alagille syndrome, and some cases of tetralogy of Fallot (although these may represent variable expressivity of Alagille syndrome).	('tetralogy of Fallot', 'Phenotype', 'HP:0001636', (140, 159))	('multisystem dominant disorder Alagille syndrome', 'Disease', (73, 120))	('multisystem dominant disorder Alagille syndrome', 'Disease', 'MESH:D016738', (73, 120))	('associated', 'Reg', (25, 35))	('tetralogy of Fallot', 'Disease', (140, 159))	('JAG1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('Alagille syndrome', 'Disease', (215, 232))	('Alagille syndrome', 'Disease', 'MESH:D016738', (103, 120))	('Alagille syndrome', 'Disease', 'MESH:D016738', (215, 232))
51034	26548814	In addition, variations in JAG1 have been found to be associated with multiple types of cancer including breast cancer and adrenocortical carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('variations', 'Var', (13, 23))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('JAG1', 'Gene', (27, 31))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (123, 147))	('adrenocortical carcinoma', 'Disease', (123, 147))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('associated', 'Reg', (54, 64))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (123, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
51035	26548814	Alagille syndrome, which primarily affects the liver, heart, skeleton, eye, face, kidney and vasculature is caused by loss of function mutations in JAG1, demonstrating that haploinsufficiency for JAG1 is disease causing, at least in these tissues.	('Alagille syndrome', 'Disease', 'MESH:D016738', (0, 17))	('mutations', 'Var', (135, 144))	('haploinsufficiency', 'Disease', (173, 191))	('JAG1', 'Gene', (148, 152))	('loss of function', 'NegReg', (118, 134))	('rat', 'Species', '10116', (161, 164))	('haploinsufficiency', 'Disease', 'MESH:D058495', (173, 191))	('Alagille syndrome', 'Disease', (0, 17))
51039	26548814	Further work on Drosophila with NOTCH mutations revealed that Notch locus deficiencies also lead to abnormal embryonic development, with hypertrophy of the nervous system.	('Drosophila', 'Species', '7227', (16, 26))	('lead to', 'Reg', (92, 99))	('NOTCH', 'Gene', (32, 37))	('hypertrophy of the nervous system', 'Disease', (137, 170))	('NOTCH', 'Gene', '31293', (32, 37))	('Notch locus', 'Gene', (62, 73))	('hypertrophy of the nervous system', 'Disease', 'MESH:D006984', (137, 170))	('mutations', 'Var', (38, 47))	('deficiencies', 'Var', (74, 86))
51044	26548814	In 1997 the human homolog (JAG1) of the rat Jagged1 gene was cloned and mapped within a region of the short arm of chromosome 20, which coincided with the critical region for the autosomal dominant disorder, Alagille syndrome (ALGS) and immediately following this discovery, mutations within JAG1 were found to be associated with ALGS.	('mutations', 'Var', (275, 284))	('ALGS', 'Disease', 'MESH:D016738', (330, 334))	('autosomal dominant disorder', 'Disease', (179, 206))	('ALGS', 'Disease', 'MESH:D016738', (227, 231))	('ALGS', 'Disease', (227, 231))	('ALGS', 'Disease', (330, 334))	('rat', 'Species', '10116', (40, 43))	('short arm', 'Phenotype', 'HP:0009824', (102, 111))	('JAG1', 'Gene', (292, 296))	('associated', 'Reg', (314, 324))	('Alagille syndrome', 'Disease', (208, 225))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (179, 206))	('human', 'Species', '9606', (12, 17))	('Alagille syndrome', 'Disease', 'MESH:D016738', (208, 225))
51045	26548814	Nine years later, some patients with ALGS were also identified who had mutations in the NOTCH2 receptor, although the percentage of patients with JAG1 mutations is much higher (94% have JAG1 mutations, and 1-2% have NOTCH2 mutations).	('NOTCH2', 'Gene', (216, 222))	('NOTCH2', 'Gene', '4853', (88, 94))	('patients', 'Species', '9606', (23, 31))	('mutations', 'Var', (191, 200))	('NOTCH2', 'Gene', (88, 94))	('JAG1', 'Gene', (146, 150))	('mutations', 'Var', (71, 80))	('NOTCH2', 'Gene', '4853', (216, 222))	('JAG1', 'Gene', (186, 190))	('ALGS', 'Disease', 'MESH:D016738', (37, 41))	('patients', 'Species', '9606', (132, 140))	('mutations', 'Var', (151, 160))	('ALGS', 'Disease', (37, 41))
51061	26548814	In cancer, high levels of JAG1 mRNA and protein have been shown to be a marker for poor overall outcome in breast cancer and possibly enhance adrenocortical carcinoma cell proliferation and tumor aggressiveness  ALGS, which is caused by mutations in JAG1 or more rarely NOTCH2, is an autosomal dominant, multi-system disorder.	('JAG1', 'Gene', (26, 30))	('multi-system disorder', 'Disease', 'MESH:D015140', (304, 325))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('ALGS', 'Disease', (212, 216))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (190, 210))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('mutations', 'Var', (237, 246))	('multi-system disorder', 'Disease', (304, 325))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('NOTCH2', 'Gene', '4853', (270, 276))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (142, 166))	('breast cancer', 'Disease', (107, 120))	('rat', 'Species', '10116', (179, 182))	('JAG1', 'Gene', (250, 254))	('mRNA', 'MPA', (31, 35))	('caused', 'Reg', (227, 233))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (142, 166))	('cancer', 'Disease', (3, 9))	('tumor aggressiveness', 'Disease', (190, 210))	('aggressiveness', 'Phenotype', 'HP:0000718', (196, 210))	('NOTCH2', 'Gene', (270, 276))	('adrenocortical carcinoma', 'Disease', (142, 166))	('enhance', 'PosReg', (134, 141))	('ALGS', 'Disease', 'MESH:D016738', (212, 216))	('cancer', 'Disease', (114, 120))
51064	26548814	The spectrum of JAG1 mutations in ALGS includes full gene deletions, and other protein truncating mutations including nonsense, frameshift and splice site as well as missense mutations, suggesting that the clinical phenotype is caused by haploinsufficiency for JAG1.	('nonsense', 'Var', (118, 126))	('ALGS', 'Disease', 'MESH:D016738', (34, 38))	('haploinsufficiency', 'Disease', (238, 256))	('protein', 'Protein', (79, 86))	('ALGS', 'Disease', (34, 38))	('JAG1', 'Gene', (261, 265))	('full gene deletions', 'Var', (48, 67))	('missense mutations', 'Var', (166, 184))	('haploinsufficiency', 'Disease', 'MESH:D058495', (238, 256))	('JAG1', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
51065	26548814	In some cases, missense mutations have been shown to be pathogenic because they are not properly trafficked to the cell membrane, which also supports haploinsufficiency as the disease mechanism for ALGS.	('haploinsufficiency', 'Disease', 'MESH:D058495', (150, 168))	('ALGS', 'Disease', 'MESH:D016738', (198, 202))	('haploinsufficiency', 'Disease', (150, 168))	('missense mutations', 'Var', (15, 33))	('ALGS', 'Disease', (198, 202))
51068	26548814	detected a missense mutation in JAG1 (p.G274D) within a large family with multiple individuals with cardiac disease, most notably TOF.	('cardiac disease', 'Disease', (100, 115))	('cardiac disease', 'Disease', 'MESH:D006331', (100, 115))	('p.G274D', 'Var', (38, 45))	('TOF', 'Disease', (130, 133))	('TOF', 'Phenotype', 'HP:0001636', (130, 133))	('TOF', 'Disease', 'MESH:D013771', (130, 133))	('JAG1', 'Gene', (32, 36))	('p.G274D', 'Mutation', 'rs28939668', (38, 45))
51070	26548814	In 2010 a larger cohort of individuals with TOF or pulmonic stenosis/peripheral pulmonary stenosis (PS/PPS) were screened for JAG1 mutations.	('mutations', 'Var', (131, 140))	('JAG1', 'Gene', (126, 130))	('peripheral pulmonary stenosis', 'Disease', (69, 98))	('pulmonic stenosis', 'Disease', (51, 68))	('TOF', 'Disease', (44, 47))	('pulmonic stenosis', 'Disease', 'MESH:D011666', (51, 68))	('TOF', 'Phenotype', 'HP:0001636', (44, 47))	('TOF', 'Disease', 'MESH:D013771', (44, 47))	('pulmonic stenosis', 'Phenotype', 'HP:0001642', (51, 68))	('peripheral pulmonary stenosis', 'Phenotype', 'HP:0004969', (69, 98))	('peripheral pulmonary stenosis', 'Disease', 'MESH:D016738', (69, 98))	('pulmonary stenosis', 'Phenotype', 'HP:0001642', (80, 98))
51071	26548814	Within this cohort 2% of TOF and 4% of PS/PPS individuals had a JAG1 mutation.	('JAG1', 'Gene', (64, 68))	('mutation', 'Var', (69, 77))	('TOF', 'Disease', (25, 28))	('TOF', 'Phenotype', 'HP:0001636', (25, 28))	('TOF', 'Disease', 'MESH:D013771', (25, 28))
51072	26548814	As JAG1 has been shown to be expressed in critical vascular structures of heart development, and the cardiac disease in these individuals is similar to that seen in ALGS patients, the mutations detected in this cohort are likely the cause of the cardiac disease.	('patients', 'Species', '9606', (170, 178))	('ALGS', 'Disease', (165, 169))	('mutations', 'Var', (184, 193))	('JAG1', 'Gene', (3, 7))	('cardiac disease', 'Disease', (101, 116))	('cardiac disease', 'Disease', (246, 261))	('cause', 'Reg', (233, 238))	('cardiac disease', 'Disease', 'MESH:D006331', (246, 261))	('cardiac disease', 'Disease', 'MESH:D006331', (101, 116))	('ALGS', 'Disease', 'MESH:D016738', (165, 169))
51082	26548814	Mice heterozygous for mutations in Notch2 and Jag1 have a renal phenotype, including glomerular vascularization defects.	('Jag1', 'Gene', (46, 50))	('Notch2', 'Gene', (35, 41))	('mutations', 'Var', (22, 31))	('glomerular vascularization defects', 'CPA', (85, 119))	('Mice', 'Species', '10090', (0, 4))	('renal', 'MPA', (58, 63))
51086	26548814	An endothelial-specific knockout of Jag1 results in embryonic lethality resulting from severely impaired vascular smooth muscle and cardiovascular development.	('vascular smooth muscle', 'CPA', (105, 127))	('cardiovascular development', 'CPA', (132, 158))	('Jag1', 'Gene', (36, 40))	('embryonic lethality', 'Disease', 'MESH:D020964', (52, 71))	('embryonic lethality', 'Disease', (52, 71))	('knockout', 'Var', (24, 32))	('impaired', 'NegReg', (96, 104))
51087	26548814	Further work demonstrated that when Jag1 is deleted in the endothelium, disruption of the endothelial-to-mesenchymal transition occurs resulting in valve calcification and congenital heart defects similar to those present in ALGS.	('valve calcification', 'Phenotype', 'HP:0005146', (148, 167))	('congenital heart defects', 'Disease', 'MESH:D006330', (172, 196))	('valve calcification', 'Disease', (148, 167))	('Jag1', 'Gene', (36, 40))	('endothelial-to-mesenchymal transition', 'CPA', (90, 127))	('ALGS', 'Disease', 'MESH:D016738', (225, 229))	('heart defects', 'Phenotype', 'HP:0030680', (183, 196))	('congenital heart defects', 'Phenotype', 'HP:0001627', (172, 196))	('resulting in', 'Reg', (135, 147))	('congenital heart defects', 'Disease', (172, 196))	('valve calcification', 'Disease', 'MESH:C562942', (148, 167))	('ALGS', 'Disease', (225, 229))	('deleted', 'Var', (44, 51))	('rat', 'Species', '10116', (20, 23))
51088	26548814	Deletion of Jag1 in the cranial neural crest (CNC) cells cause midface anomalies as well as other craniofacial growth problems correlating with the classic inverted triangular facial features present in individuals with ALGS.	('midface anomalies', 'Phenotype', 'HP:0000309', (63, 80))	('cause', 'Reg', (57, 62))	('ALGS', 'Disease', 'MESH:D016738', (220, 224))	('growth problems', 'Phenotype', 'HP:0001510', (111, 126))	('ALGS', 'Disease', (220, 224))	('anomalies', 'Disease', 'MESH:D000014', (71, 80))	('Jag1', 'Gene', (12, 16))	('anomalies', 'Disease', (71, 80))	('craniofacial', 'Disease', (98, 110))	('craniofacial', 'Disease', 'MESH:D019465', (98, 110))	('triangular facial features', 'Phenotype', 'HP:0000325', (165, 191))	('Deletion', 'Var', (0, 8))
51089	26548814	JAG1 mutations are responsible for Alagille syndrome and other disorders.	('responsible', 'Reg', (19, 30))	('Alagille syndrome', 'Disease', (35, 52))	('JAG1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('other disorders', 'Disease', 'MESH:C535332', (57, 72))	('other disorders', 'Disease', (57, 72))	('Alagille syndrome', 'Disease', 'MESH:D016738', (35, 52))
51111	26068307	This expression pattern is partially due to epigenetic deregulation of retinal development; epigenetic perturbations also contribute to tumor progression.	('retinal development', 'CPA', (71, 90))	('epigenetic perturbations', 'Var', (92, 116))	('contribute', 'Reg', (122, 132))	('epigenetic deregulation', 'Var', (44, 67))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
51118	26068307	Amplification of the MYCN oncogene is one of the most frequent genetic lesions in neuroblastoma and is associated with poor outcome.	('Amplification', 'Var', (0, 13))	('associated', 'Reg', (103, 113))	('neuroblastoma', 'Disease', 'MESH:D009447', (82, 95))	('neuroblastoma', 'Disease', (82, 95))	('neuroblastoma', 'Phenotype', 'HP:0003006', (82, 95))	('MYCN oncogene', 'Gene', (21, 34))
51119	26068307	Germline mutations in the transcription factor PHOX2B, which normally coordinates proliferation and differentiation of the sympathoadrenal lineage during development, can predispose children to neuroblastoma.	('Germline mutations', 'Var', (0, 18))	('neuroblastoma', 'Disease', 'MESH:D009447', (194, 207))	('PHOX2B', 'Gene', '8929', (47, 53))	('neuroblastoma', 'Disease', (194, 207))	('neuroblastoma', 'Phenotype', 'HP:0003006', (194, 207))	('predispose', 'Reg', (171, 181))	('children', 'Species', '9606', (182, 190))	('PHOX2B', 'Gene', (47, 53))
51120	26068307	Similarly, germline mutations in the ALK gene can lead to perturbations in signal transduction pathways in the same lineage and predispose children to neuroblastoma.	('signal transduction pathways', 'Pathway', (75, 103))	('lead to', 'Reg', (50, 57))	('ALK', 'Gene', (37, 40))	('neuroblastoma', 'Phenotype', 'HP:0003006', (151, 164))	('predispose', 'Reg', (128, 138))	('children', 'Species', '9606', (139, 147))	('ALK', 'Gene', '238', (37, 40))	('germline mutations', 'Var', (11, 29))	('neuroblastoma', 'Disease', 'MESH:D009447', (151, 164))	('perturbations', 'MPA', (58, 71))	('neuroblastoma', 'Disease', (151, 164))
51123	26068307	The recent discovery of recurrent somatic mutations in the ARID1A/1B genes, which encode chromatin remodeling proteins, and in the ATRX gene, which encodes an ATP-dependent helicase, points to a role for epigenetics in neuroblastoma initiation and progression.	('ATRX', 'Gene', '546', (131, 135))	('neuroblastoma', 'Phenotype', 'HP:0003006', (219, 232))	('ARID1A/1B', 'Gene', (59, 68))	('ARID1A/1B', 'Gene', '8289;57492', (59, 68))	('neuroblastoma initiation', 'Disease', 'MESH:D009447', (219, 243))	('neuroblastoma initiation', 'Disease', (219, 243))	('ATRX', 'Gene', (131, 135))	('mutations', 'Var', (42, 51))
51126	26068307	ATRX mutations are associated with the older age group, but it is unclear whether they directly contribute to the poor outcome in this patient population.	('associated', 'Reg', (19, 29))	('patient', 'Species', '9606', (135, 142))	('ATRX', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('ATRX', 'Gene', '546', (0, 4))
51134	26068307	Recent genomic analysis showed that most pediatric conventional melanomas are very similar to adult melanomas, with oncogenic BRAF mutations, TERT promoter mutations, and UV-induced DNA damage.	('mutations', 'Var', (131, 140))	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('melanomas', 'Disease', (64, 73))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('melanomas', 'Disease', (100, 109))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('TERT', 'Gene', (142, 146))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('TERT', 'Gene', '7015', (142, 146))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))
51137	26068307	Although most cases are sporadic, the risk of osteosarcoma is increased in those with various genetic diseases, including hereditary retinoblastoma, Li Fraumeni syndrome, and germline mutations of RecQL4.	('RecQL4', 'Gene', '9401', (197, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('genetic diseases', 'Disease', 'MESH:D030342', (94, 110))	('genetic diseases', 'Disease', (94, 110))	('retinoblastoma', 'Phenotype', 'HP:0009919', (133, 147))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (122, 147))	('germline mutations', 'Var', (175, 193))	('osteosarcoma', 'Disease', (46, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (46, 58))	('Fraumeni syndrome', 'Disease', (152, 169))	('Fraumeni syndrome', 'Disease', 'MESH:D016864', (152, 169))	('RecQL4', 'Gene', (197, 203))	('osteosarcoma', 'Disease', 'MESH:D012516', (46, 58))	('hereditary retinoblastoma', 'Disease', (122, 147))
51142	26068307	Interestingly, children who have germline mutations in the RB1 gene and develop retinoblastoma as infants are predisposed to develop osteosarcoma in adolescence.	('infants', 'Species', '9606', (98, 105))	('RB1', 'Gene', (59, 62))	('germline mutations', 'Var', (33, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (133, 145))	('retinoblastoma', 'Disease', 'MESH:D012175', (80, 94))	('retinoblastoma', 'Disease', (80, 94))	('children', 'Species', '9606', (15, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('develop', 'PosReg', (125, 132))	('RB1', 'Gene', '5925', (59, 62))	('retinoblastoma', 'Phenotype', 'HP:0009919', (80, 94))	('osteosarcoma', 'Disease', (133, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))
51143	26068307	Virtually all osteosarcomas have initiating mutations in the TP53 tumor suppressor gene, which is important for DNA repair, stress response, and cell cycle progression.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('osteosarcomas', 'Disease', (14, 27))	('osteosarcomas', 'Phenotype', 'HP:0002669', (14, 27))	('osteosarcoma', 'Phenotype', 'HP:0002669', (14, 26))	('osteosarcomas', 'Disease', 'MESH:D012516', (14, 27))	('mutations', 'Var', (44, 53))	('sarcomas', 'Phenotype', 'HP:0100242', (19, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
51145	26068307	Importantly, the mechanism of TP53 gene inactivation is unique among human cancers: many osteosarcoma tumors have translocations in the first intron of the gene that separate the promoter of the TP53 gene from the coding region, generating an inactive allele.	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', (195, 199))	('osteosarcoma tumors', 'Disease', 'MESH:D012516', (89, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('translocations', 'Var', (114, 128))	('cancers', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('inactive', 'MPA', (243, 251))	('osteosarcoma tumors', 'Disease', (89, 108))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TP53', 'Gene', '7157', (30, 34))	('TP53', 'Gene', '7157', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
51152	26068307	Most Ewing sarcoma tumors have a translocation involving the EWS gene on chromosome 22 and the FLI gene on chromosome 11 (EWS-FLI).	('FLI', 'Gene', (95, 98))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (5, 25))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (5, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (11, 18))	('FLI', 'Gene', '2314', (126, 129))	('FLI', 'Gene', (126, 129))	('FLI', 'Gene', '2314', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('EWS', 'Gene', '2130', (61, 64))	('EWS', 'Gene', (61, 64))	('translocation', 'Var', (33, 46))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('Ewing sarcoma tumors', 'Disease', (5, 25))	('EWS', 'Gene', '2130', (122, 125))	('EWS', 'Gene', (122, 125))
51156	26068307	Indeed, in addition to TP53, the only other significant recurrent mutations in EWS are in STAG2 (17%), which encodes part of the cohesion complex important for sister chromatid cohesion during M-phase of the cell cycle, and CDKN2A (11%), which encodes the cell cycle regulation proteins p16INK4a and p14ARF.	('mutations', 'Var', (66, 75))	('EWS', 'Gene', (79, 82))	('CDKN2A', 'Gene', '1029', (224, 230))	('p14ARF', 'Gene', '1029', (300, 306))	('EWS', 'Gene', '2130', (79, 82))	('STAG2', 'Gene', (90, 95))	('STAG2', 'Gene', '10735', (90, 95))	('p16INK4a', 'Gene', (287, 295))	('p14ARF', 'Gene', (300, 306))	('p16INK4a', 'Gene', '1029', (287, 295))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('CDKN2A', 'Gene', (224, 230))
51157	26068307	Patients with tumors harboring both STAG2 and TP53 mutations have a poor clinical outcome.	('mutations', 'Var', (51, 60))	('TP53', 'Gene', '7157', (46, 50))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('STAG2', 'Gene', (36, 41))	('TP53', 'Gene', (46, 50))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('STAG2', 'Gene', '10735', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
51166	26068307	In contrast, patients with ARMS have an inferior clinical outcome, and their tumors often contain a translocation between the FOXO1A gene on chromosome 13q14 and either PAX3 on chromosome 2q35 or PAX7 on chromosome 1p36.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('PAX3', 'Gene', (169, 173))	('ARMS', 'Phenotype', 'HP:0006779', (27, 31))	('PAX7', 'Gene', (196, 200))	('FOXO1A', 'Gene', (126, 132))	('patients', 'Species', '9606', (13, 21))	('translocation', 'Var', (100, 113))	('contain', 'Reg', (90, 97))	('FOXO1A', 'Gene', '2308', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('PAX7', 'Gene', '5081', (196, 200))	('PAX3', 'Gene', '5077', (169, 173))
51167	26068307	Recent results suggest that translocation-negative ARMS tumors have molecular profiles more similar to those of ERMS tumors, so the current trend is to classify rhabdomyosarcoma as being translocation-positive or translocation-negative rather than in the histopathologic terms of ARMS and ERMS.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (161, 177))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('ARMS', 'Phenotype', 'HP:0006779', (51, 55))	('ARMS tumors', 'Disease', (51, 62))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('ERMS tumors', 'Disease', (112, 123))	('ERMS', 'Phenotype', 'HP:0006743', (289, 293))	('ERMS', 'Phenotype', 'HP:0006743', (112, 116))	('rhabdomyosarcoma', 'Disease', (161, 177))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('ARMS', 'Phenotype', 'HP:0006779', (280, 284))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (161, 177))	('ERMS tumors', 'Disease', 'MESH:D009369', (112, 123))	('translocation-negative', 'Var', (28, 50))	('ARMS tumors', 'Disease', 'MESH:D009369', (51, 62))
51171	26068307	Translocation-positive rhabdomyosarcoma tumors have stable genomes similar to those of the Ewing sarcoma tumors described above, and they lack high rates of recurrent mutations in known cancer or developmental pathways.	('Ewing sarcoma tumors', 'Disease', (91, 111))	('rhabdomyosarcoma tumors', 'Disease', (23, 46))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (23, 39))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('Translocation-positive', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('Ewing sarcoma tumors', 'Disease', 'MESH:C563168', (91, 111))	('rhabdomyosarcoma tumors', 'Disease', 'MESH:D012208', (23, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (91, 104))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
51172	26068307	In contrast, the translocation-negative tumors have features of an unstable genome, with the most recurrently mutated pathway being the RAS signal transduction pathway.	('RAS signal transduction pathway', 'Pathway', (136, 167))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('translocation-negative', 'Var', (17, 39))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
51173	26068307	Those mutations are associated with high-risk disease but their correlation with outcome in translocation-negative rhabdomyosarcoma is unknown.	('rhabdomyosarcoma', 'Disease', (115, 131))	('associated', 'Reg', (20, 30))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (115, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (115, 131))	('mutations', 'Var', (6, 15))
51178	26068307	However, patients with familial adenomatous polyposis, Beckwith-Wiedemann syndrome, and trisomy 18 and infants with very low birth weight (< 1500 grams) are at increased risk for hepatoblastoma.	('patients', 'Species', '9606', (9, 17))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (179, 193))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (23, 53))	('low birth weight', 'Phenotype', 'HP:0001518', (121, 137))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (55, 82))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (32, 53))	('increased risk for hepatoblastoma', 'Phenotype', 'HP:0001402', (160, 193))	('infants', 'Species', '9606', (103, 110))	('hepatoblastoma', 'Disease', 'MESH:D018197', (179, 193))	('familial adenomatous polyposis', 'Disease', (23, 53))	('trisomy 18', 'Var', (88, 98))	('Beckwith-Wiedemann syndrome', 'Disease', (55, 82))	('hepatoblastoma', 'Disease', (179, 193))
51179	26068307	Beta-catenin mutations and deletions are common in embryonal and mixed subtypes of sporadic hepatoblastoma.	('hepatoblastoma', 'Phenotype', 'HP:0002884', (92, 106))	('sporadic hepatoblastoma', 'Disease', (83, 106))	('mixed subtypes', 'Species', '384619', (65, 79))	('deletions', 'Var', (27, 36))	('Beta-catenin', 'Protein', (0, 12))	('mutations', 'Var', (13, 22))	('sporadic hepatoblastoma', 'Disease', 'MESH:D018197', (83, 106))	('common', 'Reg', (41, 47))
51220	26068307	All models use the same retinal progenitor cell-specific Cre-transgene (Chx10-Cre) and different combinations of null or floxed alleles of the Rb family with p53 pathway inactivation:  Ostx-Cre; Rblox/Lox;p53Lox/Lox Ostx-Cre; Rblox/Lox;p53Lox/Lox;p107-/- Ostx-Cre; Rblox/Lox;p53Lox/Lox;ATRXLox/Lox The genetically engineered mouse models of osteosarcoma are based on conditional inactivation of the Rb and p53 pathways in osteoblasts.	('conditional inactivation', 'Var', (367, 391))	('osteosarcoma', 'Disease', 'MESH:D012516', (341, 353))	('lox', 'Gene', '4015', (267, 270))	('Lox', 'Gene', (208, 211))	('Lox', 'Gene', (239, 242))	('p107', 'Gene', '5933', (247, 251))	('Lox', 'Gene', '4015', (290, 293))	('Lox', 'Gene', (294, 297))	('lox', 'Gene', (197, 200))	('lox', 'Gene', (228, 231))	('Lox', 'Gene', '4015', (243, 246))	('mouse', 'Species', '10090', (325, 330))	('Lox', 'Gene', (278, 281))	('Chx10', 'Gene', (72, 77))	('Lox', 'Gene', '4015', (201, 204))	('Lox', 'Gene', '4015', (282, 285))	('Lox', 'Gene', '4015', (232, 235))	('lox', 'Gene', '4015', (122, 125))	('Lox', 'Gene', (212, 215))	('osteosarcoma', 'Phenotype', 'HP:0002669', (341, 353))	('Lox', 'Gene', '4015', (271, 274))	('lox', 'Gene', (267, 270))	('Chx10', 'Gene', '338917', (72, 77))	('Lox', 'Gene', (290, 293))	('Lox', 'Gene', (243, 246))	('Lox', 'Gene', '4015', (208, 211))	('Lox', 'Gene', '4015', (239, 242))	('Lox', 'Gene', '4015', (212, 215))	('Lox', 'Gene', '4015', (294, 297))	('sarcoma', 'Phenotype', 'HP:0100242', (346, 353))	('Lox', 'Gene', (201, 204))	('Lox', 'Gene', (282, 285))	('lox', 'Gene', '4015', (197, 200))	('lox', 'Gene', (122, 125))	('lox', 'Gene', '4015', (228, 231))	('Lox', 'Gene', '4015', (278, 281))	('Lox', 'Gene', (232, 235))	('osteosarcoma', 'Disease', (341, 353))	('Lox', 'Gene', (271, 274))	('p107', 'Gene', (247, 251))	('p53 pathways', 'Pathway', (406, 418))
51222	26068307	More recently, new models of neuroblastoma have been developed that include mutations in Alk and Lin28b.	('Alk', 'Gene', (89, 92))	('mutations', 'Var', (76, 85))	('neuroblastoma', 'Disease', (29, 42))	('Alk', 'Gene', '238', (89, 92))	('Lin28b', 'Gene', (97, 103))	('neuroblastoma', 'Phenotype', 'HP:0003006', (29, 42))	('Lin28b', 'Gene', '389421', (97, 103))	('neuroblastoma', 'Disease', 'MESH:D009447', (29, 42))
51223	26068307	We have also included Atrx mutations to model the indolent form of disease in Stage 4 patients older than 12 years.	('mutations', 'Var', (27, 36))	('Atrx', 'Gene', (22, 26))	('Atrx', 'Gene', '546', (22, 26))	('patients', 'Species', '9606', (86, 94))
51236	26068307	For example, RB1 inactivation contributes to retinoblastoma initiation by promoting cell-cycle progression, but the RB1 protein is also required for rod photoreceptor differentiation.	('inactivation', 'Var', (17, 29))	('RB1', 'Gene', '5925', (13, 16))	('RB1', 'Gene', '5925', (116, 119))	('RB1', 'Gene', (116, 119))	('retinoblastoma initiation', 'Disease', 'MESH:D012175', (45, 70))	('retinoblastoma', 'Phenotype', 'HP:0009919', (45, 59))	('promoting', 'PosReg', (74, 83))	('RB1', 'Gene', (13, 16))	('retinoblastoma initiation', 'Disease', (45, 70))	('cell-cycle progression', 'CPA', (84, 106))
51240	26068307	When a tumor-initiating mutation occurs in those distinct progenitor cell populations, the result may vary dramatically depending on the competence of that cell at that particular stage of development.	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('mutation', 'Var', (24, 32))	('tumor', 'Disease', (7, 12))
51241	26068307	In one cell population, an oncogenic mutation may result in a tumor with cellular features of skeletal muscle such as rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', (118, 134))	('result in', 'Reg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutation', 'Var', (37, 45))	('tumor', 'Disease', (62, 67))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (118, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (118, 134))
51242	26068307	In another cell population, the same oncogenic mutation may lead to rapid cell death or, alternatively, to a tumor with osteogenic features.	('lead to', 'Reg', (60, 67))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('rapid cell death', 'CPA', (68, 84))	('tumor', 'Disease', (109, 114))
51243	26068307	Thus, the competence of individual progenitor cells combined with the specific oncogenic mutations influence when and where pediatric solid tumors arise during development.	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('pediatric solid tumors', 'Disease', (124, 146))	('influence', 'Reg', (99, 108))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (124, 146))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
51251	26452166	Occurrence of Neuroblastoma among TP53 p.R337H Carriers The high incidence of adrenocortical tumors and choroid plexus carcinoma in children from South and Southeastern regions of Brazil is associated with the germline p.R337H mutation of TP53 gene.	('choroid plexus carcinoma', 'Disease', (104, 128))	('TP53', 'Gene', '7157', (239, 243))	('associated', 'Reg', (190, 200))	('Neuroblastoma', 'Disease', 'MESH:D009447', (14, 27))	('p.R337H', 'Var', (39, 46))	('TP53', 'Gene', '7157', (34, 38))	('p.R337H', 'Var', (219, 226))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (104, 128))	('adrenocortical tumors', 'Disease', (78, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('p.R337H', 'Mutation', 'rs121912664', (39, 46))	('TP53', 'Gene', (34, 38))	('p.R337H', 'Mutation', 'rs121912664', (219, 226))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (104, 128))	('TP53', 'Gene', (239, 243))	('Neuroblastoma', 'Disease', (14, 27))	('children', 'Species', '9606', (132, 140))	('Neuroblastoma', 'Phenotype', 'HP:0003006', (14, 27))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (78, 99))
51252	26452166	The concomitant occurrence of neuroblastoma and adrenocortical tumors in pediatric patients harboring the p.R337H mutation at our institution prompted us to investigate the putative association between p.R337H and pediatric neuroblastoma.	('p.R337H', 'Var', (106, 113))	('pediatric neuroblastoma', 'Disease', (214, 237))	('neuroblastoma', 'Phenotype', 'HP:0003006', (224, 237))	('p.R337H', 'Var', (202, 209))	('p.R337H', 'Mutation', 'rs121912664', (106, 113))	('p.R337H', 'Mutation', 'rs121912664', (202, 209))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('pediatric neuroblastoma', 'Disease', 'MESH:D009447', (214, 237))	('neuroblastoma', 'Disease', 'MESH:D009447', (30, 43))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (48, 69))	('neuroblastoma', 'Disease', 'MESH:D009447', (224, 237))	('neuroblastoma', 'Disease', (30, 43))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('neuroblastoma', 'Disease', (224, 237))	('adrenocortical tumors', 'Disease', (48, 69))	('neuroblastoma', 'Phenotype', 'HP:0003006', (30, 43))
51253	26452166	Genomic DNA samples from 83 neuroblastoma patients referred to a single institution during the period of 2000-2014 were screened for the p.R337H mutation.	('p.R337H', 'Var', (137, 144))	('neuroblastoma', 'Phenotype', 'HP:0003006', (28, 41))	('p.R337H', 'Mutation', 'rs121912664', (137, 144))	('neuroblastoma', 'Disease', 'MESH:D009447', (28, 41))	('patients', 'Species', '9606', (42, 50))	('neuroblastoma', 'Disease', (28, 41))
51255	26452166	Seven out 83 neuroblastoma patients (8.4%) were carriers of the TP53 p.R337H mutation in our cohort.	('neuroblastoma', 'Phenotype', 'HP:0003006', (13, 26))	('p.R337H', 'Var', (69, 76))	('patients', 'Species', '9606', (27, 35))	('p.R337H', 'Mutation', 'rs121912664', (69, 76))	('neuroblastoma', 'Disease', 'MESH:D009447', (13, 26))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('neuroblastoma', 'Disease', (13, 26))
51256	26452166	Immunohistochemical analysis of p.R337H-positive tumors revealed nuclear p53 accumulation.	('accumulation', 'PosReg', (77, 89))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('p.R337H-positive', 'Var', (32, 48))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('p.R337H', 'Mutation', 'rs121912664', (32, 39))
51258	26452166	Our data indicate that in addition to adrenocortical tumors, choroid plexus carcinoma, breast cancer and osteosarcoma, genetic counseling and clinical surveillance should consider neuroblastoma as a potential neoplasia affecting p.R337H carriers.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (38, 59))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('breast cancer', 'Disease', (87, 100))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('neoplasia', 'Phenotype', 'HP:0002664', (209, 218))	('p.R337H carriers', 'Var', (229, 245))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (61, 85))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('osteosarcoma', 'Disease', (105, 117))	('adrenocortical tumors', 'Disease', (38, 59))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))	('neuroblastoma', 'Disease', (180, 193))	('p.R337H', 'Mutation', 'rs121912664', (229, 236))	('neuroblastoma', 'Phenotype', 'HP:0003006', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('neuroblastoma', 'Disease', 'MESH:D009447', (180, 193))	('choroid plexus carcinoma', 'Disease', (61, 85))	('neoplasia', 'Disease', 'MESH:D009369', (209, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('neoplasia', 'Disease', (209, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (61, 85))
51260	26452166	Germline mutations in this gene are usually found in families presenting Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (LFLS).	('Germline mutations', 'Var', (0, 18))	('Li-Fraumeni-like syndrome', 'Disease', (103, 128))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (73, 93))	('LFS', 'Disease', 'MESH:D016864', (95, 98))	('Li-Fraumeni syndrome', 'Disease', (73, 93))	('found', 'Reg', (44, 49))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (103, 128))	('LFS', 'Disease', (95, 98))
51262	26452166	The germline mutation p.R337H of TP53 gene has an unusually high prevalence in Brazil, reaching 0.3% of the healthy population from Southern region.	('p.R337H', 'Mutation', 'rs121912664', (22, 29))	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (33, 37))	('Brazil', 'Disease', (79, 85))	('p.R337H', 'Var', (22, 29))
51265	26452166	In a preliminary study at our institution we identified two carriers of p.R337H mutation presenting concomitant ACT and neuroblastoma (NB) (data presented hereafter), indicating a putative role for p.R337H on NB tumorigenesis.	('p.R337H', 'Mutation', 'rs121912664', (198, 205))	('NB', 'Phenotype', 'HP:0003006', (209, 211))	('p.R337H', 'Var', (72, 79))	('p.R337H', 'Mutation', 'rs121912664', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('neuroblastoma', 'Disease', 'MESH:D009447', (120, 133))	('NB', 'Phenotype', 'HP:0003006', (135, 137))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('neuroblastoma', 'Disease', (120, 133))	('neuroblastoma', 'Phenotype', 'HP:0003006', (120, 133))	('p.R337H', 'Var', (198, 205))	('tumor', 'Disease', (212, 217))
51266	26452166	The surveillance program developed in Southern Brazil for the early diagnosis of cancer among children carriers of the p.R337H, reported, as expected, occurrence of ACT and choroid plexus carcinoma, and less frequently glioblastoma multiforme, Burkitt lymphoma and neuroblastoma.	('ACT and', 'Disease', (165, 172))	('neuroblastoma', 'Disease', (265, 278))	('cancer', 'Disease', (81, 87))	('neuroblastoma', 'Phenotype', 'HP:0003006', (265, 278))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('neuroblastoma', 'Disease', 'MESH:D009447', (265, 278))	('p.R337H', 'Mutation', 'rs121912664', (119, 126))	('choroid plexus carcinoma', 'Disease', (173, 197))	('glioblastoma multiforme', 'Disease', (219, 242))	('Burkitt lymphoma', 'Disease', (244, 260))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (219, 242))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (244, 260))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (173, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (252, 260))	('children', 'Species', '9606', (94, 102))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (244, 260))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (173, 197))	('p.R337H', 'Var', (119, 126))
51272	26452166	NB is not commonly associated with TP53 mutations.	('mutations', 'Var', (40, 49))	('NB', 'Phenotype', 'HP:0003006', (0, 2))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))
51273	26452166	Recently, a single nucleotide polymorphism (SNP) that maps to 3' UTR of TP53 (rs78378222) was found to be associated with neuroblastoma susceptibility.	('rs78378222', 'Var', (78, 88))	('rs78378222', 'Mutation', 'rs78378222', (78, 88))	('associated with', 'Reg', (106, 121))	('TP53', 'Gene', '7157', (72, 76))	('neuroblastoma', 'Disease', 'MESH:D009447', (122, 135))	('TP53', 'Gene', (72, 76))	('neuroblastoma', 'Disease', (122, 135))	('neuroblastoma', 'Phenotype', 'HP:0003006', (122, 135))
51274	26452166	This germline variant impairs proper termination and polyadenylation of TP53 transcripts and besides NB, it was also found to confer susceptibility to cutaneous basal cell carcinoma, prostate cancer, glioma and colorectal adenomas.	('polyadenylation', 'MPA', (53, 68))	('susceptibility', 'Reg', (133, 147))	('NB', 'Phenotype', 'HP:0003006', (101, 103))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('glioma', 'Disease', (200, 206))	('TP53', 'Gene', '7157', (72, 76))	('prostate cancer', 'Disease', 'MESH:D011471', (183, 198))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('prostate cancer', 'Phenotype', 'HP:0012125', (183, 198))	('cutaneous basal cell carcinoma', 'Disease', (151, 181))	('colorectal adenomas', 'Disease', 'MESH:D015179', (211, 230))	('prostate cancer', 'Disease', (183, 198))	('cutaneous basal cell carcinoma', 'Disease', 'MESH:D002280', (151, 181))	('colorectal adenomas', 'Disease', (211, 230))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('termination', 'MPA', (37, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('variant', 'Var', (14, 21))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (161, 181))	('TP53', 'Gene', (72, 76))	('impairs', 'NegReg', (22, 29))
51275	26452166	Although the role of TP53 on neuroblastoma tumorigenesis is still under debate, our preliminary findings prompted us to investigate the association between the highly prevalent p.R337H mutation and pediatric neuroblastoma.	('TP53', 'Gene', (21, 25))	('neuroblastoma', 'Disease', 'MESH:D009447', (208, 221))	('neuroblastoma', 'Disease', (29, 42))	('p.R337H', 'Mutation', 'rs121912664', (177, 184))	('neuroblastoma', 'Disease', (208, 221))	('pediatric neuroblastoma', 'Disease', (198, 221))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('neuroblastoma', 'Phenotype', 'HP:0003006', (29, 42))	('p.R337H', 'Var', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('neuroblastoma', 'Phenotype', 'HP:0003006', (208, 221))	('pediatric neuroblastoma', 'Disease', 'MESH:D009447', (198, 221))	('TP53', 'Gene', '7157', (21, 25))	('tumor', 'Disease', (43, 48))	('association', 'Interaction', (136, 147))	('neuroblastoma', 'Disease', 'MESH:D009447', (29, 42))
51288	26452166	Briefly, genomic DNA was subjected to qPCR using primers that flank the region of the p.R337H mutation: 5'-CCTCCTCTGTTGCTGCAGATC-3' and 5'-CCTCATTCAGATCTCTCGGAAC-3' in conjunction with two MGB probes: 5'-VIC-CGTGAGCGCTTCGAG-3' and 5'-FAM-CGTGAGCACTTCGAG-3', that bind to the wild-type and mutant allele, respectively.	('mutant', 'Var', (289, 295))	('p.R337H', 'Mutation', 'rs121912664', (86, 93))	('p.R337H', 'Var', (86, 93))
51290	26452166	Tumor samples from patients with p.R337H were screened for other possible mutations in exons 5 to 9 of TP53 gene according to IARC protocol, available in http://p53.iarc.fr/ProtocolsAndTools.aspx.	('p.R337H', 'Mutation', 'rs121912664', (33, 40))	('TP53', 'Gene', '7157', (103, 107))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (19, 27))	('TP53', 'Gene', (103, 107))	('to 9', 'Species', '1214577', (95, 99))	('p53', 'Gene', (161, 164))	('p.R337H', 'Var', (33, 40))	('p53', 'Gene', '7157', (161, 164))
51291	26452166	This hypomorphic allele is characterized by an A to C transversion at the 3'UTR of TP53 (NM_000546.5:c.*1175A>C).	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('NM_000546.5:c.*1175A>C', 'Mutation', 'rs78378222', (89, 111))	('A to C transversion', 'Phenotype', 'HP:0011540', (47, 66))	('NM_000546.5', 'Var', (89, 100))
51292	26452166	In order to genotype the patients included in our cohort, we amplified the correspondent region with primers rs78378222F: 5'- GTAAAACGACGGCCAGTGGGTCAACATCTTTTACATTC-3' and rs78378222R: 5'- TAATACGACTCACTATAGGGCCAGCACCTCCTCACTCAC-3' by using standard PCR conditions.	('rs78378222', 'Mutation', 'rs78378222', (109, 119))	('rs78378222', 'Mutation', 'rs78378222', (172, 182))	('patients', 'Species', '9606', (25, 33))	('rs78378222R', 'Var', (172, 183))	('rs78378222F', 'Var', (109, 120))
51296	26452166	This antibody is specific for an N-terminal epitope and reacts with both wild-type and mutant human p53 proteins.	('reacts', 'Reg', (56, 62))	('proteins', 'Protein', (104, 112))	('N-terminal epitope', 'Disease', 'OMIM:300855', (33, 51))	('mutant', 'Var', (87, 93))	('p53', 'Gene', '7157', (100, 103))	('human', 'Species', '9606', (94, 99))	('N-terminal epitope', 'Disease', (33, 51))	('p53', 'Gene', (100, 103))
51297	26452166	Ten NB tumors negative for p.R337H were stained in parallel as negative controls.	('p.R337H', 'Var', (27, 34))	('NB tumors', 'Disease', (4, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('NB', 'Phenotype', 'HP:0003006', (4, 6))	('p.R337H', 'Mutation', 'rs121912664', (27, 34))	('NB tumors', 'Disease', 'MESH:D009369', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
51300	26452166	The association between p.R337H presence and gender, age at diagnosis, tumor stage at diagnosis, primary site of disease, MYCN amplification and outcome was assessed by the Mann Whitney test, Chi-square test for trend or Fisher Exact test.	('MYCN', 'Gene', (122, 126))	('MYCN', 'Gene', '4613', (122, 126))	('p.R337H', 'Var', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('p.R337H', 'Mutation', 'rs121912664', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
51301	26452166	Patients diagnosed with adrenocortical tumor at our institution are invited to do the p.R337H testing due the strong association of this mutation with ACT at our geographic region.	('p.R337H', 'Var', (86, 93))	('p.R337H', 'Mutation', 'rs121912664', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Patients', 'Species', '9606', (0, 8))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (24, 44))	('association', 'Reg', (117, 128))	('adrenocortical tumor', 'Disease', (24, 44))
51302	26452166	Two p.R337H heterozygous ACT patients were found to present synchronous neuroblastoma (Figs 1 and 2).	('patients', 'Species', '9606', (29, 37))	('synchronous neuroblastoma', 'Disease', (60, 85))	('p.R337H', 'Var', (4, 11))	('neuroblastoma', 'Phenotype', 'HP:0003006', (72, 85))	('p.R337H', 'Mutation', 'rs121912664', (4, 11))	('synchronous neuroblastoma', 'Disease', 'MESH:D009378', (60, 85))
51304	26452166	This finding led us to hypothesize that p.R337H could be actively associated to NB tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('p.R337H', 'Mutation', 'rs121912664', (40, 47))	('tumor', 'Disease', (83, 88))	('associated', 'Reg', (66, 76))	('p.R337H', 'Var', (40, 47))	('NB', 'Phenotype', 'HP:0003006', (80, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
51305	26452166	We investigated therefore the presence of p.R337H in an additional group of 81 pediatric patients diagnosed exclusively with neuroblastoma.	('neuroblastoma', 'Disease', (125, 138))	('p.R337H', 'Var', (42, 49))	('neuroblastoma', 'Phenotype', 'HP:0003006', (125, 138))	('patients', 'Species', '9606', (89, 97))	('p.R337H', 'Mutation', 'rs121912664', (42, 49))	('neuroblastoma', 'Disease', 'MESH:D009447', (125, 138))
51308	26452166	None of 77 tested patients from our cohort (p.R337H positive n = 7 / p.R337H negative n = 70) was found to carry the hypomorphic allele (C) for SNP rs78378222.	('p.R337H', 'Mutation', 'rs121912664', (44, 51))	('SNP', 'Var', (144, 147))	('p.R337H', 'Mutation', 'rs121912664', (69, 76))	('patients', 'Species', '9606', (18, 26))	('rs78378222', 'Var', (148, 158))	('p.R337H', 'Var', (44, 51))	('rs78378222', 'Mutation', 'rs78378222', (148, 158))
51309	26452166	TP53 mutations in NB may arise as a consequence of tumor progression or be induced by chemotherapy.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('mutations', 'Var', (5, 14))	('NB', 'Phenotype', 'HP:0003006', (18, 20))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
51310	26452166	In our cohort, only two out seven p.R337H positive tumors were subjected to chemotherapy before mutation genotyping.	('p.R337H positive', 'Var', (34, 50))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('p.R337H', 'Mutation', 'rs121912664', (34, 41))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))
51312	26452166	Direct sequencing of exons 5-9 of TP53 gene revealed no additional mutation on p.R337H positive tumors (Table 1).	('TP53', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('p.R337H positive', 'Var', (79, 95))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('p.R337H', 'Mutation', 'rs121912664', (79, 86))	('TP53', 'Gene', '7157', (34, 38))
51313	26452166	Although LOH was not found among the p.R337H NB patients available for this analysis, immunohistochemistry against p53 revealed nuclear protein accumulation on p.R337H positive tumors, reinforcing the hypothesis of p53 inactivation on NB cells (Table 1; Fig 3).	('NB', 'Phenotype', 'HP:0003006', (235, 237))	('p.R337H', 'Mutation', 'rs121912664', (37, 44))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('nuclear protein accumulation', 'MPA', (128, 156))	('p53', 'Gene', (215, 218))	('p53', 'Gene', (115, 118))	('p.R337H positive', 'Var', (160, 176))	('p53', 'Gene', '7157', (115, 118))	('p53', 'Gene', '7157', (215, 218))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('NB', 'Phenotype', 'HP:0003006', (45, 47))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))	('patients', 'Species', '9606', (48, 56))	('p.R337H', 'Mutation', 'rs121912664', (160, 167))
51314	26452166	The median expression pattern of the 10 negative p.R337H NB tumors, used as a reference for this assay, was 15% of NB cells presenting immunopositivity for p53.	('NB', 'Phenotype', 'HP:0003006', (57, 59))	('NB tumors', 'Disease', (57, 66))	('expression', 'MPA', (11, 21))	('p.R337H', 'Var', (49, 56))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('NB tumors', 'Disease', 'MESH:D009369', (57, 66))	('p.R337H', 'Mutation', 'rs121912664', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('NB', 'Phenotype', 'HP:0003006', (115, 117))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
51316	26452166	No significant association was observed between p.R337H presence and gender, age at diagnosis, primary site of disease, MYCN amplification and outcome.	('MYCN', 'Gene', (120, 124))	('MYCN', 'Gene', '4613', (120, 124))	('p.R337H', 'Mutation', 'rs121912664', (48, 55))	('p.R337H', 'Var', (48, 55))
51317	26452166	p.R337H was statistically associated with increased proportion of stage I tumors.	('p.R337H', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('p.R337H', 'Mutation', 'rs121912664', (0, 7))	('I tumors', 'Disease', (72, 80))	('I tumors', 'Disease', 'MESH:D009369', (72, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
51321	26452166	Among p.R337H negative patients with available information (n = 61), 39 patients mentioned sporadic cases in family members, while no family met the criteria for LFS or LFLS (Table 3).	('p.R337H negative', 'Var', (6, 22))	('LFS', 'Disease', 'MESH:D016864', (162, 165))	('patients', 'Species', '9606', (23, 31))	('p.R337H', 'Mutation', 'rs121912664', (6, 13))	('LFS', 'Disease', (162, 165))	('patients', 'Species', '9606', (72, 80))
51322	26452166	Among the p.R337H positive patients (n = 7), 4 reported sporadic cases in family members and one met the criteria for LFLS (Birch) associated with the parental side segregating the p.R337H mutation (Table 3).	('p.R337H positive', 'Var', (10, 26))	('p.R337H', 'Var', (181, 188))	('p.R337H', 'Mutation', 'rs121912664', (181, 188))	('patients', 'Species', '9606', (27, 35))	('p.R337H', 'Mutation', 'rs121912664', (10, 17))
51324	26452166	Since its description in 2001 by Ribeiro and colleagues, continuous efforts have been devoted to better understand how the p.R337H mutation contributes to carcinogenesis.	('p.R337H', 'Var', (123, 130))	('carcinogenesis', 'CPA', (155, 169))	('p.R337H', 'Mutation', 'rs121912664', (123, 130))	('contributes', 'Reg', (140, 151))
51326	26452166	Strongly associated with ACT and CPC, the 337H allele is thought to be responsible for the high incidence of these tumors in the Southern and Southeastern regions of Brazil.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('337H', 'Var', (42, 46))	('associated', 'Reg', (9, 19))	('CPC', 'Disease', (33, 36))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('ACT', 'Disease', (25, 28))
51327	26452166	Besides ACT and CPC, osteosarcoma and breast cancer, including phyllodes tumors of the breast, are also associated with p.R337H, in a lesser extent though.	('tumors of the breast', 'Phenotype', 'HP:0100013', (73, 93))	('p.R337H', 'Var', (120, 127))	('osteosarcoma', 'Phenotype', 'HP:0002669', (21, 33))	('osteosarcoma', 'Disease', (21, 33))	('osteosarcoma', 'Disease', 'MESH:D012516', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('p.R337H', 'Mutation', 'rs121912664', (120, 127))	('CPC', 'Disease', (16, 19))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors of the breast', 'Disease', (73, 93))	('tumors of the breast', 'Disease', 'MESH:D001943', (73, 93))	('breast cancer', 'Disease', (38, 51))	('associated', 'Reg', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('phyllodes', 'Chemical', '-', (63, 72))
51328	26452166	In the present work, we describe the identification of p.R337H carriers among neuroblastoma pediatric patients.	('neuroblastoma pediatric', 'Disease', 'MESH:D009447', (78, 101))	('patients', 'Species', '9606', (102, 110))	('p.R337H', 'Var', (55, 62))	('neuroblastoma pediatric', 'Disease', (78, 101))	('p.R337H', 'Mutation', 'rs121912664', (55, 62))	('neuroblastoma', 'Phenotype', 'HP:0003006', (78, 91))
51330	26452166	This frequency is about 28 to 42 times higher than the estimated 0.2 to 0.3% frequency for p.R337H in people not selected by cancer diagnosis from our region, suggesting that carriers of the p.R337H are at increased risk of developing NB than the general population.	('NB', 'Phenotype', 'HP:0003006', (235, 237))	('p.R337H', 'Mutation', 'rs121912664', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('p.R337H', 'Var', (191, 198))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('people', 'Species', '9606', (102, 108))	('p.R337H', 'Mutation', 'rs121912664', (91, 98))
51331	26452166	Although cancer in general does not arise from a single gene defect, populations in which p.R337H was identified should consider neuroblastoma as a potential neoplasia affecting carriers.	('cancer', 'Disease', (9, 15))	('neoplasia', 'Disease', 'MESH:D009369', (158, 167))	('neuroblastoma', 'Disease', 'MESH:D009447', (129, 142))	('p.R337H', 'Var', (90, 97))	('neuroblastoma', 'Disease', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('neoplasia', 'Disease', (158, 167))	('neuroblastoma', 'Phenotype', 'HP:0003006', (129, 142))	('p.R337H', 'Mutation', 'rs121912664', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('neoplasia', 'Phenotype', 'HP:0002664', (158, 167))
51332	26452166	In accordance with our findings, Custodio and colleagues have also identified a neuroblastoma patient in a surveillance program for p.R337H carriers in Southern Brazil (Table 4).	('neuroblastoma', 'Disease', (80, 93))	('neuroblastoma', 'Phenotype', 'HP:0003006', (80, 93))	('p.R337H', 'Var', (132, 139))	('patient', 'Species', '9606', (94, 101))	('p.R337H', 'Mutation', 'rs121912664', (132, 139))	('neuroblastoma', 'Disease', 'MESH:D009447', (80, 93))
51333	26452166	Nuclear p53 accumulation on NB cells suggests p53 inactivation in p.R337H-positive tumors (Fig 3).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('p53', 'Gene', (8, 11))	('p.R337H-positive', 'Var', (66, 82))	('p53', 'Gene', (46, 49))	('p53', 'Gene', '7157', (8, 11))	('tumors', 'Disease', (83, 89))	('p.R337H', 'Mutation', 'rs121912664', (66, 73))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('p53', 'Gene', '7157', (46, 49))	('NB', 'Phenotype', 'HP:0003006', (28, 30))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('inactivation', 'NegReg', (50, 62))
51335	26452166	LOH with retention of the mutated allele was identified in virtually all cases of ACT and CPC associated with p.R337H.	('CPC', 'Disease', (90, 93))	('p.R337H', 'Var', (110, 117))	('associated', 'Reg', (94, 104))	('p.R337H', 'Mutation', 'rs121912664', (110, 117))	('ACT', 'Disease', (82, 85))
51336	26452166	On the other hand, the mechanism of breast carcinogenesis associated with p.R337H mutation appears to be not related to the classical two-hit model involving tumor suppressor genes, since LOH at the mutation locus is not common in these cases.	('tumor', 'Disease', (158, 163))	('p.R337H', 'Mutation', 'rs121912664', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('breast carcinogenesis', 'Disease', (36, 57))	('p.R337H', 'Var', (74, 81))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (36, 57))
51337	26452166	It is important to note that p.R337H is a dominant negative mutation that affects the oligomerization domain of p53, so it can interfere with normal function of wild-type allele through the impaired tetramer conformation of the protein.	('p.R337H', 'Mutation', 'rs121912664', (29, 36))	('impaired', 'NegReg', (190, 198))	('affects', 'Reg', (74, 81))	('normal function', 'MPA', (142, 157))	('interfere', 'NegReg', (127, 136))	('p53', 'Gene', (112, 115))	('protein', 'Protein', (228, 235))	('p.R337H', 'Var', (29, 36))	('tetra', 'Species', '42554', (199, 204))	('p53', 'Gene', '7157', (112, 115))	('oligomerization domain', 'MPA', (86, 108))	('tetramer conformation', 'MPA', (199, 220))
51340	26452166	The presence of p.R337H mutation was statistically associated with increased proportion of stage I tumors.	('I tumors', 'Disease', (97, 105))	('p.R337H', 'Var', (16, 23))	('I tumors', 'Disease', 'MESH:D009369', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('p.R337H', 'Mutation', 'rs121912664', (16, 23))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
51342	26452166	Although we had no access to the majority of pathology reports, data obtained on cancer family history of p.R337H positive NB patients showed that only one out of 7 families presented features consistent with LFS/LFLS (Table 3).	('LFS', 'Disease', (209, 212))	('p.R337H', 'Var', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('p.R337H', 'Mutation', 'rs121912664', (106, 113))	('NB', 'Phenotype', 'HP:0003006', (123, 125))	('cancer', 'Disease', (81, 87))	('LFS', 'Disease', 'MESH:D016864', (209, 212))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
51343	26452166	This finding is in accordance with the broad phenotypic variation observed among families with p.R337H, i.e., a large proportion of families without any history of cancer while some families presenting with clear LFS/LFLS.	('p.R337H', 'Mutation', 'rs121912664', (95, 102))	('LFS', 'Disease', (213, 216))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('LFS', 'Disease', 'MESH:D016864', (213, 216))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('p.R337H', 'Var', (95, 102))
51344	26452166	Recently, a polymorphism that maps to 3' UTR of TP53 (rs78378222) was found to be associated with neuroblastoma susceptibility (Table 4).	('rs78378222', 'Var', (54, 64))	('rs78378222', 'Mutation', 'rs78378222', (54, 64))	('TP53', 'Gene', '7157', (48, 52))	('associated', 'Reg', (82, 92))	('neuroblastoma', 'Disease', 'MESH:D009447', (98, 111))	('TP53', 'Gene', (48, 52))	('neuroblastoma', 'Disease', (98, 111))	('neuroblastoma', 'Phenotype', 'HP:0003006', (98, 111))
51346	26452166	From our extensive literature revision on TP53 polymorphisms studied in the context of NB, we found rs1042522 as the most commonly SNP studied among NB patients (Table 4).	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('rs1042522', 'Var', (100, 109))	('rs1042522', 'Mutation', 'rs1042522', (100, 109))	('NB', 'Phenotype', 'HP:0003006', (87, 89))	('NB', 'Phenotype', 'HP:0003006', (149, 151))	('patients', 'Species', '9606', (152, 160))
51348	26452166	Interestingly, the allele that codifies for an arginine was consistently overrepresented among neuroblastoma patients (Table 4).	('patients', 'Species', '9606', (109, 117))	('neuroblastoma', 'Disease', 'MESH:D009447', (95, 108))	('arginine', 'Chemical', 'MESH:D001120', (47, 55))	('neuroblastoma', 'Disease', (95, 108))	('overrepresented', 'PosReg', (73, 88))	('arginine', 'Var', (47, 55))	('neuroblastoma', 'Phenotype', 'HP:0003006', (95, 108))
51349	26452166	To our knowledge, 34 patients with neuroblastic tumors harboring TP53 mutations have been described until now (summarized in Table 5).	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('neuroblastic tumors', 'Disease', 'MESH:D009369', (35, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (21, 29))	('neuroblastic tumors', 'Phenotype', 'HP:0004376', (35, 54))	('neuroblastic tumors', 'Disease', (35, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('neuroblastic tumor', 'Phenotype', 'HP:0004376', (35, 53))
51350	26452166	Considering the cases with somatic alterations, a significant proportion of mutations may have arisen as a consequence of tumor progression or induced by chemotherapy.	('mutations', 'Var', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('arisen', 'Reg', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
51351	26452166	With respect to 18 patients with germline mutations, we found that p.R337H is the most common inherited TP53 mutation associated with NB (n = 7).	('TP53', 'Gene', '7157', (104, 108))	('patients', 'Species', '9606', (19, 27))	('TP53', 'Gene', (104, 108))	('NB', 'Phenotype', 'HP:0003006', (134, 136))	('p.R337H', 'Var', (67, 74))	('associated', 'Reg', (118, 128))	('p.R337H', 'Mutation', 'rs121912664', (67, 74))
51353	26452166	Whether neuroblastic tissue present a marked susceptibility to alterations at codon 248 of p53 remains to be investigated.	('p53', 'Gene', '7157', (91, 94))	('p53', 'Gene', (91, 94))	('alterations at codon', 'Var', (63, 83))
51354	26452166	Tissue-specificity of TP53 mutations has been considerably discussed.	('mutations', 'Var', (27, 36))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
51355	26452166	Missense TP53 mutations located in the DNA-binding loop that contact the minor groove of DNA were associated with brain tumors, whereas mutations in the non DNA-binding loops, beta-sheets and oligomerization domain were associated with adrenocortical tumors.	('brain tumors', 'Disease', (114, 126))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (236, 257))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('brain tumors', 'Disease', 'MESH:D001932', (114, 126))	('associated', 'Reg', (220, 230))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('adrenocortical tumors', 'Disease', (236, 257))	('associated', 'Reg', (98, 108))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('brain tumors', 'Phenotype', 'HP:0030692', (114, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('mutations', 'Var', (14, 23))	('Missense', 'Var', (0, 8))
51356	26452166	Mutations affecting TP53 splicing sites were strongly associated with Wilm's tumor, while null mutations were not associated with a specific type of tumor, but were associated with early onset tumors, in particular brain tumors.	('particular brain tumors', 'Disease', 'MESH:D001932', (204, 227))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('brain tumors', 'Phenotype', 'HP:0030692', (215, 227))	('TP53', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	("Wilm's tumor", 'Disease', (70, 82))	('tumors', 'Disease', (221, 227))	("Wilm's tumor", 'Disease', 'MESH:D009396', (70, 82))	('tumor', 'Disease', (193, 198))	('associated', 'Reg', (54, 64))	('associated', 'Reg', (165, 175))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (221, 226))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('TP53', 'Gene', '7157', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (70, 82))	('particular brain tumors', 'Disease', (204, 227))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (149, 154))	('tumors', 'Disease', (193, 199))	('tumor', 'Disease', (77, 82))
51357	26452166	Apparently, mutations affecting different domains of the protein may exert different impact on protein function or protein-protein interactions, culminating in different tissue-susceptibility to cancer.	('mutations', 'Var', (12, 21))	('impact', 'Reg', (85, 91))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('interactions', 'Interaction', (131, 143))	('protein-protein', 'Protein', (115, 130))	('protein', 'Protein', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
51358	26452166	From this perspective, it is well accepted that p.R337H predisposes carriers to a broad spectrum of cancer.	('predisposes', 'Reg', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('p.R337H', 'Var', (48, 55))	('p.R337H', 'Mutation', 'rs121912664', (48, 55))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
51359	26452166	The spectrum of tumors found in p.R337H families may, eventually, overlap that found in LFS or LFLS.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('LFS', 'Disease', 'MESH:D016864', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('p.R337H', 'Var', (32, 39))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('LFS', 'Disease', (88, 91))	('p.R337H', 'Mutation', 'rs121912664', (32, 39))
51360	26452166	Therefore, the clinical criteria for LFS and LFLS are not suitable for suspecting p.R337H.	('LFS', 'Disease', (37, 40))	('p.R337H', 'Mutation', 'rs121912664', (82, 89))	('p.R337H', 'Var', (82, 89))	('LFS', 'Disease', 'MESH:D016864', (37, 40))
51361	26452166	The challenge in identify individuals carrying the p.R337H mutation and, therefore, family members at high risk of developing cancer, has motivated several efforts to define the exact spectrum of tumors associated to this mutation.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('p.R337H', 'Var', (51, 58))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('p.R337H', 'Mutation', 'rs121912664', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
51362	26452166	The present work shows that in addition to ACT, CPC, breast cancer and osteosarcoma, genetic counseling and clinical surveillance should consider neuroblastoma as a potential disease affecting p.R337H carriers.	('neuroblastoma', 'Disease', 'MESH:D009447', (146, 159))	('osteosarcoma', 'Disease', 'MESH:D012516', (71, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('neuroblastoma', 'Disease', (146, 159))	('neuroblastoma', 'Phenotype', 'HP:0003006', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('p.R337H', 'Var', (193, 200))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('breast cancer', 'Disease', (53, 66))	('p.R337H', 'Mutation', 'rs121912664', (193, 200))	('osteosarcoma', 'Disease', (71, 83))	('CPC', 'Disease', (48, 51))
51405	25798129	Cells in the adrenal cortex of adult mice and rats lack CYP17A1, so corticosterone is the principal glucocorticoid secreted, and adrenal androgens are not produced.	('lack', 'NegReg', (51, 55))	('CYP17A1', 'Var', (56, 63))	('corticosterone', 'Chemical', 'MESH:D003345', (68, 82))	('rats', 'Species', '10116', (46, 50))	('mice', 'Species', '10090', (37, 41))
51426	25798129	The Fz expresses CYP17A1 and CYB5 and produces large amounts of DHEA and DHEA-S, which are converted by the sequential actions of the liver and placenta into estrogens.	('DHEA-S', 'Chemical', 'MESH:D003687', (73, 79))	('DHEA', 'Disease', (64, 68))	('DHEA', 'Chemical', 'MESH:D003687', (64, 68))	('DHEA', 'Chemical', 'MESH:D003687', (73, 77))	('DHEA-S', 'Disease', (73, 79))	('CYB5', 'Var', (29, 33))	('CYP17A1', 'Var', (17, 24))
51463	25798129	Cleavage of the extracellular domain of DLK1 by TNF-alpha converting enzyme produces a biologically active soluble peptide that inhibits the differentiation of preadipocytes into mature adipocytes.	('Cleavage', 'Var', (0, 8))	('TNF-alpha', 'Gene', (48, 57))	('inhibits', 'NegReg', (128, 136))	('TNF-alpha', 'Gene', '21926', (48, 57))	('DLK1', 'Gene', (40, 44))
51479	25798129	Targeted mutagenesis of beta-catenin in SF1+ cells causes late onset adrenal hypoplasia, presumed to be the result of stem/progenitor cell pool depletion.	('beta-catenin', 'Gene', (24, 36))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (69, 87))	('beta-catenin', 'Gene', '12387', (24, 36))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (69, 87))	('Targeted mutagenesis', 'Var', (0, 20))	('causes', 'Reg', (51, 57))	('SF1', 'Gene', (40, 43))	('SF1', 'Gene', '22668', (40, 43))	('adrenal hypoplasia', 'Disease', (69, 87))
51482	25798129	Stem cell self-renewal mechanisms are frequently co-opted to drive oncogenesis, and WNT signaling is the pathway most frequently mutated in adrenocortical carcinomas (Table 5).	('adrenocortical carcinomas', 'Disease', (140, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (140, 164))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (140, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('mutated', 'Var', (129, 136))	('WNT signaling', 'Pathway', (84, 97))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (140, 165))
51497	25798129	Inactivating mutations in the protein kinase-A regulatory subunit gene (PRKAR1A) lead to excessive cAMP production.	('PRKAR1A', 'Gene', '19084', (72, 79))	('lead', 'Reg', (81, 85))	('cAMP', 'Chemical', '-', (99, 103))	('Inactivating mutations', 'Var', (0, 22))	('PRKAR1A', 'Gene', (72, 79))	('excessive', 'PosReg', (89, 98))	('cAMP production', 'MPA', (99, 114))
51498	25798129	Such mutations cause Carney complex, a syndrome associated with pituitary-independent Cushing syndrome and adrenocortical neoplasia.	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (107, 131))	('adrenocortical neoplasia', 'Disease', (107, 131))	('pituitary-independent Cushing syndrome', 'Disease', 'MESH:D047748', (64, 102))	('mutations', 'Var', (5, 14))	('pituitary-independent Cushing syndrome', 'Disease', (64, 102))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (86, 102))	('neoplasia', 'Phenotype', 'HP:0002664', (122, 131))	('Carney complex', 'Disease', (21, 35))	('cause', 'Reg', (15, 20))
51518	25798129	The loss of Inha results in constitutive TGF-beta2 activation in adrenocortical progenitor cells, with subsequent expansion of cells that express Gata4 and other gonadal-like markers.	('TGF-beta2', 'Gene', (41, 50))	('expansion', 'PosReg', (114, 123))	('Inha', 'Gene', (12, 16))	('adrenocortical', 'Disease', (65, 79))	('adrenocortical', 'Disease', 'MESH:D018268', (65, 79))	('Gata4', 'Gene', (146, 151))	('Gata4', 'Gene', '14463', (146, 151))	('Inha', 'Gene', '16322', (12, 16))	('activation', 'PosReg', (51, 61))	('TGF-beta2', 'Gene', '21808', (41, 50))	('loss', 'Var', (4, 8))
51538	25798129	Similarly, targeted mutagenesis of transcription factors that activate Sf1 expression, such as Wt1, Pbx1, and Cited, severely impairs adrenal gland development [reviewed in Ref.	('mutagenesis', 'Var', (20, 31))	('adrenal gland development [', 'CPA', (134, 161))	('Wt1', 'Gene', (95, 98))	('men', 'Species', '9606', (155, 158))	('Pbx1', 'Gene', (100, 104))	('activate', 'PosReg', (62, 70))	('impairs', 'NegReg', (126, 133))	('Wt1', 'Gene', '22431', (95, 98))	('Pbx1', 'Gene', '18514', (100, 104))	('Sf1', 'Gene', '26423', (71, 74))	('Sf1', 'Gene', (71, 74))
51540	25798129	Individuals with mutations in the DNA-binding domain of SF1 exhibit primary adrenal failure and gonadal dysgenesis.	('primary adrenal failure', 'Disease', 'MESH:D000310', (68, 91))	('gonadal dysgenesis', 'Disease', (96, 114))	('SF1', 'Gene', (56, 59))	('primary adrenal failure', 'Disease', (68, 91))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (96, 114))	('adrenal failure', 'Phenotype', 'HP:0000846', (76, 91))	('SF1', 'Gene', '22668', (56, 59))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (96, 114))	('mutations in', 'Var', (17, 29))
51544	25798129	Intriguingly, genetic ablation of the SF1 target gene Vnn1, encoding the gonadal-like marker Vanin-1, has been shown to reduce the severity of neoplastic lesions in the Sf1 transgenic mice.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (143, 161))	('SF1', 'Gene', (38, 41))	('Vanin-1', 'Gene', (93, 100))	('transgenic mice', 'Species', '10090', (173, 188))	('reduce', 'NegReg', (120, 126))	('Vnn1', 'Gene', (54, 58))	('SF1', 'Gene', '22668', (38, 41))	('Vnn1', 'Gene', '22361', (54, 58))	('genetic ablation', 'Var', (14, 30))	('Vanin-1', 'Gene', '22361', (93, 100))	('Sf1', 'Gene', '26423', (169, 172))	('neoplastic lesions', 'Disease', (143, 161))	('neoplastic lesions', 'Disease', 'MESH:D051437', (143, 161))	('Sf1', 'Gene', (169, 172))
51545	25798129	Similarly, mice in which the endogenous Sf1 gene of the mouse has been replaced with a mutant lacking a key SUMOylation site exhibit abnormal cell fate specification in steroidogenic tissues, including ectopic expression of gonadal markers.	('cell fate specification in steroidogenic tissues', 'CPA', (142, 190))	('Sf1', 'Gene', '26423', (40, 43))	('mouse', 'Species', '10090', (56, 61))	('mice', 'Species', '10090', (11, 15))	('mutant', 'Var', (87, 93))	('gonadal markers', 'CPA', (224, 239))	('ectopic', 'CPA', (202, 209))	('Sf1', 'Gene', (40, 43))
51549	25798129	DAX1 deficiency in humans and mice leads to excessive differentiation of subcapsular progenitors and eventual depletion of the stem/progenitor cell compartment.	('depletion of', 'MPA', (110, 122))	('DAX1', 'Gene', '190', (0, 4))	('mice', 'Species', '10090', (30, 34))	('deficiency', 'Var', (5, 15))	('subcapsular progenitors', 'CPA', (73, 96))	('humans', 'Species', '9606', (19, 25))	('DAX1', 'Gene', (0, 4))	('excessive', 'PosReg', (44, 53))
51550	25798129	Cytomegaly, a hallmark of adrenal dysfunction associated with Dax1 deficiency, is thought to be a compensatory response to a reduced number of cortical cells or to progenitor cell exhaustion.	('Cytomegaly', 'Disease', (0, 10))	('Dax1', 'Gene', '11614', (62, 66))	('hallmark of adrenal dysfunction', 'Disease', 'MESH:D000312', (14, 45))	('adrenal dysfunction', 'Phenotype', 'HP:0000846', (26, 45))	('Dax1', 'Gene', (62, 66))	('hallmark of adrenal dysfunction', 'Disease', (14, 45))	('deficiency', 'Var', (67, 77))
51561	25798129	Ectopic expression of a transcriptionally active isoform of WT1 in SF1+ progenitors causes adrenocortical hypoplasia, increased expression of Gata4, Gli1, and Tcf21, and contraction of the X-zone.	('WT1', 'Gene', (60, 63))	('WT1', 'Gene', '22431', (60, 63))	('adrenocortical hypoplasia', 'Disease', 'MESH:D018268', (91, 116))	('adrenocortical hypoplasia', 'Phenotype', 'HP:0008182', (91, 116))	('Gata4', 'Gene', (142, 147))	('Ectopic expression', 'Var', (0, 18))	('SF1', 'Gene', (67, 70))	('increased', 'PosReg', (118, 127))	('Gli1', 'Gene', (149, 153))	('Gata4', 'Gene', '14463', (142, 147))	('Tcf21', 'Gene', '21412', (159, 164))	('adrenocortical hypoplasia', 'Disease', (91, 116))	('contraction of the X-zone', 'CPA', (170, 195))	('expression', 'MPA', (128, 138))	('Tcf21', 'Gene', (159, 164))	('SF1', 'Gene', '22668', (67, 70))	('causes', 'Reg', (84, 90))	('Gli1', 'Gene', '14632', (149, 153))
51562	25798129	WT1 directly regulates the expression of Gli1 in adrenal tissue suggesting that ectopic expression of Wt1 prevents differentiation into SF1+ adrenocortical steroidogenic cells by maintaining cells in a GLI1+ progenitor state.	('Wt1', 'Gene', (102, 105))	('SF1', 'Gene', '22668', (136, 139))	('WT1', 'Gene', '22431', (0, 3))	('SF1', 'Gene', (136, 139))	('adrenocortical', 'Disease', (141, 155))	('adrenocortical', 'Disease', 'MESH:D018268', (141, 155))	('WT1', 'Gene', (0, 3))	('Gli1', 'Gene', '14632', (41, 45))	('prevents', 'NegReg', (106, 114))	('differentiation', 'MPA', (115, 130))	('Wt1', 'Gene', '22431', (102, 105))	('Gli1', 'Gene', (41, 45))	('ectopic expression', 'Var', (80, 98))
51567	25798129	Gata6 mutant mice also exhibit abnormal adrenocortical zonation: virgin females lack an X-zone, and castrate males lack a secondary X-zone (Figures 10A,B).	('mice', 'Species', '10090', (13, 17))	('adrenocortical zonation', 'Disease', 'MESH:D018268', (40, 63))	('mutant', 'Var', (6, 12))	('adrenocortical zonation', 'Disease', (40, 63))	('Gata6', 'Chemical', '-', (0, 5))	('X-zone', 'MPA', (88, 94))	('Gata6', 'Gene', (0, 5))	('lack', 'NegReg', (80, 84))	('lack', 'NegReg', (115, 119))	('rat', 'Species', '10116', (104, 107))
51572	25798129	Hindlimb buds express Gata6 in an anterior-posterior gradient, and conditional deletion of Gata6 in limb bud mesenchyme of mice leads to ectopic expression of Shh and its target gene Gli1.	('Gli1', 'Gene', (183, 187))	('Gata6', 'Gene', (91, 96))	('ectopic expression', 'MPA', (137, 155))	('Gata6', 'Chemical', '-', (22, 27))	('Shh', 'Protein', (159, 162))	('Gata6', 'Chemical', '-', (91, 96))	('leads to', 'Reg', (128, 136))	('Gli1', 'Gene', '14632', (183, 187))	('deletion', 'Var', (79, 87))	('mice', 'Species', '10090', (123, 127))
51573	25798129	The mutant mice develop hindlimb preaxial polydactyly.	('mutant', 'Var', (4, 10))	('mice', 'Species', '10090', (11, 15))	('preaxial polydactyly', 'Phenotype', 'HP:0100258', (33, 53))	('hindlimb preaxial polydactyly', 'CPA', (24, 53))	('polydactyly', 'Phenotype', 'HP:0010442', (42, 53))
51578	25798129	Disruption of these pathways can lead to neoplasia.	('lead to', 'Reg', (33, 40))	('neoplasia', 'Disease', 'MESH:D009369', (41, 50))	('neoplasia', 'Phenotype', 'HP:0002664', (41, 50))	('neoplasia', 'Disease', (41, 50))	('Disruption', 'Var', (0, 10))
51586	23570263	In Brazil, a particular mutation, occurring in the tetramerisation domain of the gene, p.R337H, is exceedingly common due to a founder effect and is strongly associated with ACC.	('Brazil', 'Gene', (3, 9))	('associated with', 'Reg', (158, 173))	('p.R337H', 'Var', (87, 94))	('ACC', 'Phenotype', 'HP:0006744', (174, 177))	('ACC', 'Disease', (174, 177))	('p.R337H', 'Mutation', 'rs121912664', (87, 94))
51587	23570263	In this report, we describe the phenotype and long-term clinical follow-up of a female child diagnosed with ACC and homozygous for the TP53 p.R337H founder mutation.	('ACC', 'Phenotype', 'HP:0006744', (108, 111))	('p.R337H', 'Var', (140, 147))	('ACC', 'Disease', (108, 111))	('p.R337H', 'Mutation', 'rs121912664', (140, 147))	('TP53', 'Gene', (135, 139))	('child', 'Species', '9606', (87, 92))
51589	23570263	Family history was consistent with an LFL tumour pattern, and genotyping identified the TP53 p.R337H mutation in both alleles in genomic DNA from lymphocytes and fibroblasts.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('LFL tumour', 'Disease', 'MESH:D016864', (38, 48))	('p.R337H', 'Var', (93, 100))	('p.R337H', 'Mutation', 'rs121912664', (93, 100))	('TP53', 'Gene', (88, 92))	('LFL tumour', 'Disease', (38, 48))
51593	23570263	This is the first clinical and aerobic functional capacity documentation of a patient who carries two mutant TP53 alleles and no wild-type allele.	('TP53', 'Gene', (109, 113))	('patient', 'Species', '9606', (78, 85))	('mutant', 'Var', (102, 108))
51594	23570263	Our results support the hypothesis that TP53 p.R337H, the most common TP53 mutation ever described in any population, is a conditional mutant.	('p.R337H', 'Var', (45, 52))	('TP53', 'Gene', (70, 74))	('TP53 p.R337H', 'Var', (40, 52))	('p.R337H', 'Mutation', 'rs121912664', (45, 52))
51595	23570263	Furthermore, our observations over a long period of clinical follow-up suggest that TP53 p.R337H homozygotes do not have a more severe disease phenotype than do heterozygote carriers of the same mutation.	('severe disease', 'Disease', 'MESH:D056729', (128, 142))	('severe disease', 'Disease', (128, 142))	('p.R337H', 'Mutation', 'rs121912664', (89, 96))	('TP53', 'Gene', (84, 88))	('p.R337H', 'Var', (89, 96))
51596	23570263	Patients with the homozygous TP53 p.R337H genotype will require careful surveillance for lifetime cancer risk and for effects on metabolic capacity later in life.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('p.R337H', 'Var', (34, 41))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('p.R337H', 'Mutation', 'rs121912664', (34, 41))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', (29, 33))	('metabolic', 'MPA', (129, 138))	('cancer', 'Disease', (98, 104))
51603	23570263	The only known genetic defect associated with LFS and LFL is the inheritance of a mutation in the tumour suppressor gene TP53.	('genetic defect', 'Disease', 'MESH:D030342', (15, 29))	('genetic defect', 'Disease', (15, 29))	('LFL', 'Disease', (54, 57))	('LFS', 'Disease', 'MESH:D016864', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('mutation', 'Var', (82, 90))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('TP53', 'Gene', (121, 125))	('tumour', 'Disease', (98, 104))	('LFS', 'Disease', (46, 49))
51604	23570263	Mutations occur in up to 80% of the classical forms of LFS.	('Mutations', 'Var', (0, 9))	('LFS', 'Disease', (55, 58))	('LFS', 'Disease', 'MESH:D016864', (55, 58))	('occur', 'Reg', (10, 15))
51605	23570263	TP53 encodes a 53 kD nuclear phosphoprotein, p53, that acts as a growth suppressor transcription factor, which is inactivated by somatic mutations in many forms of cancer.	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutations', 'Var', (137, 146))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))
51606	23570263	The most frequent TP53 germline mutations are missense substitutions that cluster in highly conserved regions of the DNA-binding domain of the protein (codons 125-300), with hotspots at highly mutable CpG motifs that are also found in somatic mutations in sporadic cancers.	('germline mutations', 'Var', (23, 41))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('TP53', 'Gene', (18, 22))	('missense', 'Var', (46, 54))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('cancers', 'Disease', (265, 272))	('cancers', 'Disease', 'MESH:D009369', (265, 272))
51607	23570263	In Brazil, a particular mutation has been reported in a significant proportion of the LFS families presenting germline TP53 mutations.	('LFS', 'Disease', (86, 89))	('mutations', 'Var', (124, 133))	('LFS', 'Disease', 'MESH:D016864', (86, 89))	('TP53', 'Gene', (119, 123))
51608	23570263	This mutation, p.R337H (c.1010 G > A, genomic nucleotide number 16901; CGC to CAC at codon 337), occurs in exon 10 and was initially identified in Brazilian children with ACC and no documented familial history of other cancers.	('CGC to CAC at codon 337', 'Mutation', 'c.337CGC>CAC', (71, 94))	('ACC', 'Phenotype', 'HP:0006744', (171, 174))	('p.R337H', 'Mutation', 'rs121912664', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('c.1010 G > A', 'Var', (24, 36))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('c.1010 G > A', 'Mutation', 'rs121912664', (24, 36))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('children', 'Species', '9606', (157, 165))	('cancers', 'Disease', (219, 226))	('ACC', 'Disease', (171, 174))
51610	23570263	Structural studies on the p53 oligomerisation domain have shown that replacement of arginine by histidine disrupts oligomerisation in a pH-dependent manner, making the domain unable to oligomerise in conditions of slightly elevated pH.	('oligomerisation', 'MPA', (115, 130))	('disrupts', 'NegReg', (106, 114))	('elevated pH', 'Phenotype', 'HP:0008151', (223, 234))	('replacement', 'Var', (69, 80))	('histidine', 'Chemical', 'MESH:D006639', (96, 105))	('arginine', 'Chemical', 'MESH:D001120', (84, 92))
51611	23570263	Although biological dependence upon pH has not been demonstrated thus far, it is plausible that the p.R337H mutant protein operates as a conditional mutant that loses its function only in cells undergoing a small increase in intracellular pH.	('loses', 'NegReg', (161, 166))	('p.R337H', 'Mutation', 'rs121912664', (100, 107))	('p.R337H', 'Var', (100, 107))	('function', 'MPA', (171, 179))
51612	23570263	Subsequent to the initial studies on childhood ACC, studies of families with LFS traits have shown that the mutation predisposes individuals to a wide range of cancers.	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('LFS', 'Disease', 'MESH:D016864', (77, 80))	('cancers', 'Disease', (160, 167))	('child', 'Species', '9606', (37, 42))	('ACC', 'Phenotype', 'HP:0006744', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mutation', 'Var', (108, 116))	('predisposes', 'Reg', (117, 128))	('LFS', 'Disease', (77, 80))
51613	23570263	Similar to the canonical forms of LFS, the most common cancers in p.R337H carriers are pre-menopausal breast cancer and sarcoma before age 45.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('breast cancer', 'Disease', (102, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('p.R337H', 'Var', (66, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('LFS', 'Disease', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('p.R337H', 'Mutation', 'rs121912664', (66, 73))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('LFS', 'Disease', 'MESH:D016864', (34, 37))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('pre-menopausal breast cancer', 'Phenotype', 'HP:0008209', (87, 115))	('sarcoma', 'Disease', (120, 127))	('cancers', 'Disease', (55, 62))
51614	23570263	However, the penetrance of the disease in p.R337H carriers appears to be significantly lower than in carriers of germline TP53 mutations occurring in the DNA-binding domain.	('penetrance', 'MPA', (13, 23))	('lower', 'NegReg', (87, 92))	('p.R337H', 'Mutation', 'rs121912664', (42, 49))	('p.R337H', 'Var', (42, 49))
51618	23570263	However, no information is currently available on the impact of TP53 deficiency on the exercise capacity of patients with germline TP53 mutations.	('deficiency', 'Disease', (69, 79))	('TP53', 'Gene', (131, 135))	('deficiency', 'Disease', 'MESH:D007153', (69, 79))	('mutations', 'Var', (136, 145))	('TP53', 'Gene', (64, 68))	('patients', 'Species', '9606', (108, 116))
51619	23570263	Here we report the diagnosis, follow-up and monitoring of exercise capacity in a young patient homozygous for the germline TP53 p.R337H mutation.	('patient', 'Species', '9606', (87, 94))	('p.R337H', 'Mutation', 'rs121912664', (128, 135))	('p.R337H', 'Var', (128, 135))	('TP53', 'Gene', (123, 127))
51629	23570263	The patient was found to be homozygous for a germline TP53 mutation (p.R337H) (detailed genotypic analysis is described below).	('TP53', 'Gene', (54, 58))	('p.R337H', 'Mutation', 'rs121912664', (69, 76))	('p.R337H', 'Var', (69, 76))	('patient', 'Species', '9606', (4, 11))
51647	23570263	DNA from lymphocytes was screened for the TP53 p.R337H mutation with allele-specific TaqMan  probes (Applied Biosystems, Foster City, CA, USA) using a MX 3000P qPCR System - Stratagene (Agilent Technologies Inc., Santa Clara, CA, USA) and analysed using the Stratagene MxPro qPCR Software.	('p.R337H', 'Var', (47, 54))	('TP53', 'Gene', (42, 46))	('p.R337H', 'Mutation', 'rs121912664', (47, 54))
51649	23570263	Both the father and mother were found to be heterozygous TP53 p.R337H carriers (Figure 2).	('p.R337H', 'Mutation', 'rs121912664', (62, 69))	('p.R337H', 'Var', (62, 69))	('TP53', 'Gene', (57, 61))
51650	23570263	Allele-specific PCR (ASO PCR) for TP53 SNP179 identified the proband as well as both parents as carriers of the p.R337H Brazilian founder allele described by Garritano et al.	('p.R337H', 'Mutation', 'rs121912664', (112, 119))	('p.R337H', 'Var', (112, 119))	('TP53', 'Gene', (34, 38))
51651	23570263	The presence of the Brazilian founder p.R337H haplotype (A3) was verified in mutation-positive samples, as previously described, by both ASO-PCR and Nested-PCR used to analyse SNP28 (rs9894946) from a panel of 29 intragenic SNPs.	('rs9894946', 'Var', (183, 192))	('p.R337H', 'Var', (38, 45))	('p.R337H', 'Mutation', 'rs121912664', (38, 45))	('rs9894946', 'Mutation', 'rs9894946', (183, 192))	('SNP28', 'Gene', (176, 181))
51652	23570263	Because this SNP is identical in haplotypes A1 and A3, all cases were further genotyped for SNP15 (rs1642785) and SNP18 (rs1800370) by direct sequencing.	('rs1800370', 'Mutation', 'rs1800370', (121, 130))	('rs1642785', 'Mutation', 'rs1642785', (99, 108))	('rs1642785', 'Var', (99, 108))	('rs1800370', 'Var', (121, 130))
51655	23570263	We describe a patient who is a homozygous carrier of a germline TP53 mutation, p.R337H, having inherited the same mutant allele from both parents.	('p.R337H', 'Var', (79, 86))	('p.R337H', 'Mutation', 'rs121912664', (79, 86))	('patient', 'Species', '9606', (14, 21))	('TP53', 'Gene', (64, 68))
51658	23570263	Approximately 50% of mutation carriers develop cancer by age 30.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('mutation', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('develop', 'PosReg', (39, 46))
51659	23570263	In Brazil, however, the existence of a founder mutation, p.R337H, which is present in approximately 0.3% of the dense population in the southern and southeastern regions of the country, make the occurrence of homozygosity for germline TP53 mutations more likely than anywhere else in the world.	('TP53', 'Gene', (235, 239))	('p.R337H', 'Mutation', 'rs121912664', (57, 64))	('p.R337H', 'Var', (57, 64))
51662	23570263	Several studies have shown that germline mutations in cancer predisposition genes may have a dose effect, resulting in a more severe phenotype in homozygotes than in heterozygotes.	('germline mutations', 'Var', (32, 50))	('severe phenotype', 'MPA', (126, 142))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('resulting', 'Reg', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
51664	23570263	Furthermore, several cancer-predisposing mutations in tumour-suppressor genes display different phenotypes in heterozygotes and homozygotes.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
51665	23570263	This is the case for mutations in the PALB2, BRIP1 and ATM genes, where heterozygotes have an increased lifetime risk of breast cancer, and homozygotes are diagnosed with multisystemic genetic syndromes (Fanconi's anaemia for the first 2 genes and ataxia-telangiectasia for the latter).	('BRIP1', 'Gene', (45, 50))	('ATM', 'Gene', '472', (55, 58))	('PALB2', 'Gene', (38, 43))	("Fanconi's anaemia", 'Phenotype', 'HP:0001994', (204, 221))	('telangiectasia', 'Phenotype', 'HP:0001009', (255, 269))	('multisystemic genetic syndromes', 'Disease', (171, 202))	('ataxia-telangiectasia', 'Disease', (248, 269))	('PALB2', 'Gene', '79728', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ATM', 'Gene', (55, 58))	('multisystemic genetic syndromes', 'Disease', 'MESH:D030342', (171, 202))	('BRIP1', 'Gene', '83990', (45, 50))	('ataxia', 'Phenotype', 'HP:0001251', (248, 254))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('mutations', 'Var', (21, 30))	("Fanconi's anaemia", 'Disease', (204, 221))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('anaemia', 'Phenotype', 'HP:0001903', (214, 221))	('breast cancer', 'Disease', (121, 134))	('ataxia-telangiectasia', 'Disease', 'MESH:D001260', (248, 269))	("Fanconi's anaemia", 'Disease', 'MESH:D005199', (204, 221))
51666	23570263	There are also situations where homozygous and heterozygous states for a mutation in the same gene are each associated with different genetic syndromes, such as the Lynch (LS) and Childhood Cancer (CCS) syndromes associated with heterozygous and homozygous germline mutations in the MMR genes.	('associated', 'Reg', (213, 223))	('Childhood Cancer', 'Disease', (180, 196))	('Childhood Cancer', 'Disease', 'MESH:C536928', (180, 196))	('Lynch', 'Disease', (165, 170))	('MMR', 'Gene', (283, 286))	('associated', 'Reg', (108, 118))	('germline mutations', 'Var', (257, 275))	('mutation', 'Var', (73, 81))	('Cancer', 'Phenotype', 'HP:0002664', (190, 196))
51669	23570263	Based on the structural analysis of a peptide encoding the oligomerisation domain, it has been shown that replacement of arginine by histidine at position 377 perturbs the formation of a hydrogen bond that links R377 on one p53 monomer to D352 on another p53 monomer, thus forming a dimer.	('forming', 'Reg', (273, 280))	('replacement', 'Var', (106, 117))	('R377', 'Var', (212, 216))	('perturbs', 'NegReg', (159, 167))	('D352', 'Chemical', '-', (239, 243))	('formation', 'MPA', (172, 181))	('hydrogen bond', 'MPA', (187, 200))	('D352', 'Var', (239, 243))	('arginine by histidine at position 377', 'Mutation', 'p.R377H', (121, 158))	('hydrogen', 'Chemical', 'MESH:D006859', (187, 195))
51671	23570263	In the present case, we speculate that the proteins encoded by the two mutant alleles can form dimers in neutral pH conditions, which also occurs between one mutant and one wild-type monomer in patients who inherit only one mutant p.R337H allele.	('p.R337H', 'Mutation', 'rs121912664', (231, 238))	('patients', 'Species', '9606', (194, 202))	('dimers', 'MPA', (95, 101))	('form', 'Reg', (90, 94))	('proteins', 'Protein', (43, 51))	('p.R337H', 'Var', (231, 238))
51673	23570263	In the mouse, lack of p53 leads to impaired cardiorespiratory fitness and loss of aerobic competence.	('mouse', 'Species', '10090', (7, 12))	('p53', 'Gene', (22, 25))	('loss', 'NegReg', (74, 78))	('impaired cardiorespiratory fitness', 'Disease', (35, 69))	('lack', 'Var', (14, 18))	('aerobic competence', 'CPA', (82, 100))	('impaired cardiorespiratory fitness', 'Disease', 'MESH:D004827', (35, 69))
51676	23570263	The results of the cardiopulmonary exercise test performed here indicate that, despite carrying two TP53 mutant alleles, our patient has preserved functional capacity, as demonstrated by peak power output, peak oxygen uptake, and an anaerobic threshold within the limits of normality.	('peak oxygen uptake', 'MPA', (206, 224))	('TP53', 'Gene', (100, 104))	('functional capacity', 'MPA', (147, 166))	('patient', 'Species', '9606', (125, 132))	('peak power output', 'MPA', (187, 204))	('anaerobic threshold', 'MPA', (233, 252))	('mutant', 'Var', (105, 111))	('oxygen', 'Chemical', 'MESH:D010100', (211, 217))
51680	23570263	Therefore, the cardiopulmonary exercise test results for our patient indicate that inheritance of two mutant TP53 p.R337H alleles does not appear to affect energy metabolism in humans by the age of 10 years.	('humans', 'Species', '9606', (177, 183))	('patient', 'Species', '9606', (61, 68))	('affect', 'Reg', (149, 155))	('p.R337H', 'Var', (114, 121))	('TP53', 'Gene', (109, 113))	('p.R337H', 'Mutation', 'rs121912664', (114, 121))	('energy metabolism', 'MPA', (156, 173))
51681	23570263	The current report is the first clinical description and documentation of aerobic functional capacity of a patient who carries two mutant TP53 alleles and no wild-type allele.	('mutant', 'Var', (131, 137))	('patient', 'Species', '9606', (107, 114))	('TP53', 'Gene', (138, 142))
51682	23570263	Furthermore, our observations over a long period of clinical follow-up do not support the hypothesis that p.R337H homozygotes may have a more severe disease phenotype than heterozygote carriers of the same mutation.	('p.R337H', 'Mutation', 'rs121912664', (106, 113))	('p.R337H', 'Var', (106, 113))	('severe disease', 'Disease', 'MESH:D056729', (142, 156))	('severe disease', 'Disease', (142, 156))
51702	33490685	Aberrant expression of some transcription factors regulating organ development is known to promote hyperplasia and neoplasia, that is why investigation of tumorigenesis requires elucidation of transcriptional factors mediating normal postnatal development.	('hyperplasia', 'Disease', 'MESH:D006965', (99, 110))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('Aberrant expression', 'Var', (0, 19))	('neoplasia', 'Disease', (115, 124))	('promote', 'PosReg', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('neoplasia', 'Disease', 'MESH:D009369', (115, 124))	('tumor', 'Disease', (155, 160))	('neoplasia', 'Phenotype', 'HP:0002664', (115, 124))	('hyperplasia', 'Disease', (99, 110))
51715	33490685	It significantly complicates evaluation of Wnt signaling function in wild-type laboratory animals, since transcriptional regulation represents a network of cooperating factors, and impaired function of one regulator may change activity of other factors.	('rat', 'Species', '10116', (83, 86))	('transcriptional regulation', 'MPA', (105, 131))	('Wnt', 'Gene', (43, 46))	('activity', 'MPA', (227, 235))	('change', 'Reg', (220, 226))	('Wnt', 'Gene', '114487', (43, 46))	('rat', 'Species', '10116', (161, 164))	('impaired function', 'Var', (181, 198))
51824	33490685	Disregulation of Wnt signaling also has been shown to initiate adrenocortical tumorigenesis.	('Disregulation', 'Var', (0, 13))	('initiate', 'PosReg', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Wnt', 'Gene', (17, 20))	('tumor', 'Disease', (78, 83))	('Wnt', 'Gene', '114487', (17, 20))
51840	31294783	Although alterations in the steroid metabolome have been used to diagnose inborn errors in steroidogenesis for several decades, recent advances have refocused attention on the capabilities of steroid metabolome profiling.	('inborn errors', 'Disease', (74, 87))	('steroid', 'Chemical', 'MESH:D013256', (192, 199))	('steroid', 'Chemical', 'MESH:D013256', (28, 35))	('alterations', 'Var', (9, 20))	('inborn errors', 'Disease', 'MESH:D008661', (74, 87))	('steroid', 'Chemical', 'MESH:D013256', (91, 98))
51857	31294783	The variants of congenital adrenal hyperplasia (CAH) comprise five autosomal recessive inborn disorders defined by glucocorticoid deficiency resulting from inactivating mutations in enzymes involved in adrenal steroidogenesis.	('autosomal recessive inborn disorders', 'Disease', (67, 103))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (16, 46))	('CAH', 'Disease', 'MESH:D000312', (48, 51))	('variants', 'Var', (4, 12))	('congenital adrenal hyperplasia', 'Disease', (16, 46))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (27, 46))	('CAH', 'Phenotype', 'HP:0008258', (48, 51))	('inactivating mutations', 'Var', (156, 178))	('steroid', 'Chemical', 'MESH:D013256', (210, 217))	('glucocorticoid deficiency', 'Disease', (115, 140))	('autosomal recessive inborn disorders', 'Disease', 'MESH:D030342', (67, 103))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (115, 140))	('CAH', 'Disease', (48, 51))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (16, 46))	('glucocorticoid deficiency', 'Disease', 'MESH:C565974', (115, 140))
51860	31294783	More than 90% of CAH cases are caused by mutant 21-hydroxylase (CYP21A2), a key enzyme in glucocorticoid and mineralocorticoid biosynthesis (Fig.	('CAH', 'Phenotype', 'HP:0008258', (17, 20))	('mutant', 'Var', (41, 47))	('CYP21A2', 'Gene', '1589', (64, 71))	('CAH', 'Disease', (17, 20))	('CYP21A2', 'Gene', (64, 71))	('CAH', 'Disease', 'MESH:D000312', (17, 20))	('caused by', 'Reg', (31, 40))
51861	31294783	1); the presence and severity of loss of cortisol and aldosterone production CYP21A2 deficiency is 17OHP, but 17OHPreg, Prog, and Preg are also increased.	('deficiency', 'Var', (85, 95))	('aldosterone', 'Chemical', 'MESH:D000450', (54, 65))	('17OHP', 'Chemical', 'MESH:C037605', (110, 115))	('loss', 'NegReg', (33, 37))	('cortisol', 'Chemical', 'MESH:D006854', (41, 49))	('aldosterone production', 'MPA', (54, 76))	('CYP21A2', 'Gene', '1589', (77, 84))	('aldosterone production', 'Phenotype', 'HP:0000859', (54, 76))	('CYP21A2', 'Gene', (77, 84))	('17OHP', 'Chemical', 'MESH:C037605', (99, 104))
51863	31294783	Therefore, diagnostic ratios of the urinary metabolites of 21-deoxycortisol (PTONE) or 17OHP (PT and 17HP) over glucocorticoid metabolites are invaluable for the diagnosis of CYP21A2 deficiency [Fig.	('CYP21A2', 'Gene', '1589', (175, 182))	('17OHP', 'Chemical', 'MESH:C037605', (87, 92))	('21-deoxycortisol', 'Chemical', 'MESH:C003556', (59, 75))	('17HP', 'Chemical', 'MESH:C104697', (101, 105))	('17OHP', 'MPA', (87, 92))	('deficiency', 'Var', (183, 193))	('glucocorticoid metabolites', 'MPA', (112, 138))	('CYP21A2', 'Gene', (175, 182))
51864	31294783	In the past, diagnosis of CYP21A2 deficiency has been challenging in neonates and preterm infants, as 17OHP radioimmunoassay results are compromised by cross-reactivity of abundant neonatal 3beta-OH-Delta5 steroids.	('deficiency', 'Var', (34, 44))	('infants', 'Species', '9606', (90, 97))	('CYP21A2', 'Gene', (26, 33))	('17OHP', 'Chemical', 'MESH:C037605', (102, 107))	('CYP21A2', 'Gene', '1589', (26, 33))	('3beta-OH-Delta5 steroids', 'Chemical', 'MESH:D013256', (190, 214))
51866	31294783	Biologically active androgens are increased in CYP21A2 deficiency, driven by the accumulation of precursor steroids prior to the enzymatic block, feeding into all three major androgen biosynthesis pathways: the classic androgen pathway, the alternative pathway to DHT, and the 11-oxygenated androgen pathway (Fig.	('classic androgen pathway', 'Pathway', (211, 235))	('CYP21A2', 'Gene', (47, 54))	('Biologically active androgens', 'MPA', (0, 29))	('androgens', 'Chemical', 'MESH:D000728', (20, 29))	('11-oxygenated androgen pathway', 'Pathway', (277, 307))	('CYP21A2', 'Gene', '1589', (47, 54))	('steroids', 'Chemical', 'MESH:D013256', (107, 115))	('deficiency', 'Var', (55, 65))	('androgen', 'Chemical', 'MESH:D000728', (291, 299))	('androgen', 'Chemical', 'MESH:D000728', (175, 183))	('androgen', 'Chemical', 'MESH:D000728', (20, 28))	('androgen', 'Chemical', 'MESH:D000728', (219, 227))	('increased', 'PosReg', (34, 43))	('DHT', 'Chemical', 'MESH:C478856', (264, 267))	('feeding', 'Reg', (146, 153))	('11-oxygenated androgen', 'Chemical', 'MESH:D000728', (277, 299))
51867	31294783	The accumulation of 17OHP increases atypical conversion of 17OHP to androstenedione (A4) by CYP17A1 17,20-lyase activity, which physiologically has a much higher preference for the conversion of 17OHPreg to DHEA.	('17OHP', 'Chemical', 'MESH:C037605', (59, 64))	('DHEA', 'Chemical', 'MESH:D003687', (207, 211))	('17OHP', 'Chemical', 'MESH:C037605', (20, 25))	('17OHP', 'Var', (20, 25))	('atypical conversion', 'MPA', (36, 55))	('CYP17A1', 'Gene', (92, 99))	('androstenedione', 'Chemical', 'MESH:D000735', (68, 83))	('CYP17A1', 'Gene', '1586', (92, 99))	('17OHP', 'Chemical', 'MESH:C037605', (195, 200))	('increases', 'PosReg', (26, 35))
51870	31294783	Alternative DHT pathway activity is reflected by 5alpha17HP and An, whereas increased 11-oxygenated pathway activity is reflected by the major metabolite of 11OHA4, 11beta-OHAn (Figs.	('Alternative DHT pathway', 'Pathway', (0, 23))	('11-oxygenated pathway', 'Pathway', (86, 107))	('activity', 'MPA', (24, 32))	('activity', 'MPA', (108, 116))	('DHT', 'Chemical', 'MESH:C478856', (12, 15))	('increased', 'PosReg', (76, 85))	('5alpha17HP', 'Var', (49, 59))	('11OHA4, 11beta-OHAn', 'Chemical', 'MESH:C014594', (157, 176))	('5alpha17HP', 'Chemical', 'MESH:C104697', (49, 59))
51872	31294783	Therefore, CYP17A1 deficiency mostly presents with combined glucocorticoid and sex steroid deficiency; HPA axis upregulation drives increased mineralocorticoid production via the only remaining functional adrenocortical biosynthesis pathway.	('sex steroid deficiency', 'Disease', 'MESH:D012735', (79, 101))	('increased mineralocorticoid', 'Phenotype', 'HP:0000859', (132, 159))	('CYP17A1', 'Gene', (11, 18))	('deficiency', 'Var', (19, 29))	('HPA', 'Disease', 'MESH:D007029', (103, 106))	('increased', 'PosReg', (132, 141))	('upregulation', 'PosReg', (112, 124))	('functional adrenocortical biosynthesis', 'Phenotype', 'HP:0008207', (194, 232))	('mineralocorticoid production', 'MPA', (142, 170))	('sex steroid deficiency', 'Disease', (79, 101))	('HPA', 'Disease', (103, 106))	('CYP17A1', 'Gene', '1586', (11, 18))	('PA', 'Phenotype', 'HP:0011736', (104, 106))
51873	31294783	Glucocorticoid deficiency is rarely life-threatening in CYP17A1 deficiency, as increased corticosterone exerts some glucocorticoid receptor activation.	('increased', 'PosReg', (79, 88))	('deficiency', 'Var', (64, 74))	('Glucocorticoid deficiency', 'Disease', (0, 25))	('CYP17A1', 'Gene', (56, 63))	('Glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (0, 25))	('corticosterone exerts', 'MPA', (89, 110))	('CYP17A1', 'Gene', '1586', (56, 63))	('corticosterone', 'Chemical', 'MESH:D003345', (89, 103))	('increased corticosterone', 'Phenotype', 'HP:0032362', (79, 103))	('Glucocorticoid deficiency', 'Disease', 'MESH:C565974', (0, 25))	('glucocorticoid receptor activation', 'MPA', (116, 150))
51876	31294783	In CYP17A1 deficiency, serum DHEA and A4 are low at baseline and after adrenal cosyntropin stimulation.	('DHEA', 'Chemical', 'MESH:D003687', (29, 33))	('deficiency', 'Var', (11, 21))	('serum DHEA', 'MPA', (23, 33))	('low', 'NegReg', (45, 48))	('CYP17A1', 'Gene', (3, 10))	('CYP17A1', 'Gene', '1586', (3, 10))
51879	31294783	Although milder forms of CYP17A1 deficiency have been reported, where only sex steroid production seems to be present (so-called "isolated 17,20-lyase deficiency"), stimulated cortisol levels do not rise sufficiently in these patients, indicating glucocorticoid deficiency.	('stimulated', 'MPA', (165, 175))	('CYP17A1', 'Gene', (25, 32))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (247, 272))	('CYP17A1', 'Gene', '1586', (25, 32))	('glucocorticoid deficiency', 'Disease', 'MESH:C565974', (247, 272))	('steroid', 'Chemical', 'MESH:D013256', (79, 86))	('stimulated cortisol levels', 'Phenotype', 'HP:0003118', (165, 191))	('patients', 'Species', '9606', (226, 234))	('deficiency', 'Var', (33, 43))	('cortisol', 'Chemical', 'MESH:D006854', (176, 184))	('glucocorticoid deficiency', 'Disease', (247, 272))	('cortisol levels', 'MPA', (176, 191))
51881	31294783	In classic forms with severe CYP17A1 deficiency, DOC and corticosterone metabolites are markedly increased, with mildly increased Preg and Prog metabolites.	('increased', 'PosReg', (97, 106))	('corticosterone', 'Chemical', 'MESH:D003345', (57, 71))	('CYP17A1', 'Gene', (29, 36))	('CYP17A1', 'Gene', '1586', (29, 36))	('increased', 'PosReg', (120, 129))	('deficiency', 'Var', (37, 47))	('DOC', 'Chemical', 'MESH:C060842', (49, 52))
51883	31294783	In neonates with CYP17A1 deficiency, the 11-keto corticosterone metabolite 11-dehydrocorticosterone is dominant in newborns and, therefore, urine steroid metabolites increased in CYP17A1 deficiency include THA, 5alpha-THA, and 6alpha-hydroxy-11-dehydro-tetrahydrocorticosterone (6alpha-OHTHA), with the latter the most important quantitative marker.	('CYP17A1', 'Gene', '1586', (179, 186))	('5alpha-THA', 'Chemical', 'MESH:D013619', (211, 221))	('11-dehydrocorticosterone', 'Chemical', 'MESH:C003552', (75, 99))	('increased', 'PosReg', (166, 175))	('deficiency', 'Var', (25, 35))	('steroid', 'Chemical', 'MESH:D013256', (146, 153))	('6alpha-OHTHA', 'Chemical', 'MESH:C023888', (279, 291))	('deficiency', 'Var', (187, 197))	('11-keto corticosterone', 'Chemical', 'MESH:D003345', (41, 63))	('CYP17A1', 'Gene', (17, 24))	('CYP17A1', 'Gene', (179, 186))	('CYP17A1', 'Gene', '1586', (17, 24))
51898	31294783	POR mutations allowing for significant residual alternative pathway activity present with 46,XY DSD and normal male genitalia in individuals with 46,XY, whereas major loss-of-function POR mutations result in normal female phenotype and 46,XY DSD.	('POR', 'Gene', (0, 3))	('alternative pathway', 'Pathway', (48, 67))	('mutations', 'Var', (188, 197))	('loss-of-function', 'NegReg', (167, 183))	('POR', 'Gene', '5447', (0, 3))	('POR', 'Gene', (184, 187))	('mutations', 'Var', (4, 13))	('POR', 'Gene', '5447', (184, 187))
51905	31294783	CYP11B1 deficiency results in cortisol deficiency, mineralocorticoid excess, and androgen excess.	('cortisol deficiency', 'Phenotype', 'HP:0008163', (30, 49))	('mineralocorticoid excess', 'Phenotype', 'HP:0000859', (51, 75))	('androgen', 'CPA', (81, 89))	('results in', 'Reg', (19, 29))	('androgen', 'Chemical', 'MESH:D000728', (81, 89))	('mineralocorticoid', 'MPA', (51, 68))	('cortisol deficiency', 'Disease', 'MESH:C535280', (30, 49))	('deficiency', 'Var', (8, 18))	('excess', 'PosReg', (69, 75))	('excess', 'PosReg', (90, 96))	('CYP11B1', 'Gene', '1584', (0, 7))	('cortisol deficiency', 'Disease', (30, 49))	('CYP11B1', 'Gene', (0, 7))
51911	31294783	In contrast to CYP21A2 deficiency, PTONE is low in CYP11B1 deficiency, as 17OHP cannot be 11beta-hydroxylated.	('low', 'NegReg', (44, 47))	('CYP11B1', 'Gene', '1584', (51, 58))	('17OHP', 'Chemical', 'MESH:C037605', (74, 79))	('deficiency', 'Var', (59, 69))	('CYP21A2', 'Gene', (15, 22))	('CYP21A2', 'Gene', '1589', (15, 22))	('CYP11B1', 'Gene', (51, 58))	('PTONE', 'MPA', (35, 40))
51912	31294783	In neonates, high 6alpha-hydroxylase activity increases 6alpha-hydroxytetrahydrotetrahydro-11-deoxycortisol (6alpha-OHTHS) excretion, which adds diagnostic value.	('6alpha-hydroxylase', 'Enzyme', (18, 36))	('high', 'Var', (13, 17))	('6alpha-OHTHS', 'Chemical', 'MESH:D003350', (109, 121))	('increases', 'PosReg', (46, 55))	('6alpha-hydroxytetrahydrotetrahydro-11-deoxycortisol', 'Chemical', 'MESH:D003350', (56, 107))
51914	31294783	Deficiency of HSD3B2, therefore, leads to reduced mineralocorticoid, glucocorticoid, and sex steroid production.	('mineralocorticoid', 'MPA', (50, 67))	('HSD3B2', 'Gene', (14, 20))	('reduced', 'NegReg', (42, 49))	('HSD3B2', 'Gene', '3284', (14, 20))	('glucocorticoid', 'MPA', (69, 83))	('steroid', 'Chemical', 'MESH:D013256', (93, 100))	('sex steroid production', 'MPA', (89, 111))	('reduced mineralocorticoid', 'Phenotype', 'HP:0004319', (42, 67))	('Deficiency', 'Var', (0, 10))
51920	31294783	Surprisingly, excretion rates of PT, 17HP, and PD are elevated, similar to CYP21A2 deficiency; however, in CYP21A2 deficiency, the 5PT/PTONE ratio is typically low (<1.5), whereas it is high (>35) in HSD3B2 deficiency (Table 2).	('low', 'NegReg', (160, 163))	('HSD3B2', 'Gene', (200, 206))	('HSD3B2', 'Gene', '3284', (200, 206))	('CYP21A2', 'Gene', '1589', (107, 114))	('5PT/PTONE ratio', 'MPA', (131, 146))	('CYP21A2', 'Gene', (107, 114))	('17HP', 'Chemical', 'MESH:C104697', (37, 41))	('CYP21A2', 'Gene', (75, 82))	('deficiency', 'Var', (115, 125))	('excretion', 'MPA', (14, 23))	('CYP21A2', 'Gene', '1589', (75, 82))
51923	31294783	In chromosomally male individuals, SRD5A2 deficiency presents with undermasculinization, that is, ambiguous genitalia at birth (46,XY DSD).	('ambiguous genitalia', 'Disease', 'MESH:D012734', (98, 117))	('deficiency', 'Var', (42, 52))	('ambiguous genitalia', 'Disease', (98, 117))	('SRD5A2', 'Gene', (35, 41))	('ambiguous genitalia', 'Phenotype', 'HP:0000062', (98, 117))	('SRD5A2', 'Gene', '6716', (35, 41))	('genitalia at birth', 'Phenotype', 'HP:0000078', (108, 126))
51924	31294783	SRD5A2 deficiency has elucidated the crucial role of DHT in male genital skin, as in its absence, external genital masculinization does not occur.	('DHT', 'Chemical', 'MESH:C478856', (53, 56))	('SRD5A2', 'Gene', (0, 6))	('deficiency', 'Var', (7, 17))	('male genital skin', 'Disease', (60, 77))	('SRD5A2', 'Gene', '6716', (0, 6))
51930	31294783	Inactivating HSD17B3 mutations results in failure to convert A4 to T in the fetal testis, causing male undermasculinization (46,XY DSD).	('male undermasculinization', 'Disease', (98, 123))	('failure', 'Disease', (42, 49))	('causing', 'Reg', (90, 97))	('Inactivating', 'Var', (0, 12))	('HSD17B3', 'Gene', (13, 20))	('HSD17B3', 'Gene', '3293', (13, 20))	('A4 to T', 'Mutation', 'c.4A>T', (61, 68))	('convert A4 to T', 'MPA', (53, 68))	('failure', 'Disease', 'MESH:D017093', (42, 49))	('mutations', 'Var', (21, 30))
51934	31294783	There is a paucity of published data on urine steroid profiling in HSD17B3 deficiency.	('HSD17B3', 'Gene', (67, 74))	('steroid', 'Chemical', 'MESH:D013256', (46, 53))	('HSD17B3', 'Gene', '3293', (67, 74))	('deficiency', 'Var', (75, 85))
51941	31294783	Individuals with 46,XY with inactivating CYB5A mutations present with 46,XY DSD at birth, and girls with 46,XX present with lack of adrenarche, pubertal development, and primary gonadal failure in adolescence.	('CYB5A', 'Gene', (41, 46))	('CYB5A', 'Gene', '1528', (41, 46))	('lack', 'NegReg', (124, 128))	('mutations', 'Var', (47, 56))	('girls', 'Species', '9606', (94, 99))	('pubertal development', 'CPA', (144, 164))	('primary gonadal failure', 'Disease', 'MESH:D006058', (170, 193))	('primary gonadal failure', 'Phenotype', 'HP:0008193', (170, 193))	('primary gonadal failure', 'Disease', (170, 193))	('adrenarche', 'CPA', (132, 142))	('inactivating', 'Var', (28, 40))
51963	31294783	PAPSS2 deficiency is a rare monogenic form of androgen excess caused by impaired DHEA sulfation, resulting in an increased downstream activation of unconjugated DHEA to androgens.	('downstream activation', 'MPA', (123, 144))	('androgen', 'Chemical', 'MESH:D000728', (46, 54))	('androgen', 'Chemical', 'MESH:D000728', (169, 177))	('impaired DHEA sulfation', 'Disease', (72, 95))	('PAPSS2', 'Gene', '9060', (0, 6))	('PAPSS2', 'Gene', (0, 6))	('deficiency', 'Var', (7, 17))	('DHEA', 'Chemical', 'MESH:D003687', (161, 165))	('impaired DHEA sulfation', 'Disease', 'MESH:D009084', (72, 95))	('DHEA', 'Chemical', 'MESH:D003687', (81, 85))	('increased', 'PosReg', (113, 122))	('androgens', 'Chemical', 'MESH:D000728', (169, 178))	('PA', 'Phenotype', 'HP:0011736', (0, 2))	('unconjugated DHEA to androgens', 'MPA', (148, 178))
51964	31294783	The seminal case of PAPSS2 deficiency was a girl with early-onset androgen excess who clinically presented with premature adrenarche at the age of 6 years, thereafter progressing to a polycystic ovary syndrome (PCOS)-like phenotype in adolescence.	('PAPSS2', 'Gene', '9060', (20, 26))	('PAPSS2', 'Gene', (20, 26))	('ovary syndrome', 'Phenotype', 'HP:0000137', (195, 209))	('girl', 'Species', '9606', (44, 48))	('polycystic ovary syndrome', 'Disease', (184, 209))	('deficiency', 'Var', (27, 37))	('PA', 'Phenotype', 'HP:0011736', (20, 22))	('polycystic ovary syndrome', 'Disease', 'MESH:D011085', (184, 209))	('premature adrenarche', 'Phenotype', 'HP:0012412', (112, 132))	('PCOS', 'Disease', 'MESH:D011085', (211, 215))	('PCOS', 'Disease', (211, 215))	('progressing', 'PosReg', (167, 178))	('polycystic ovary', 'Phenotype', 'HP:0000147', (184, 200))	('androgen', 'Chemical', 'MESH:D000728', (66, 74))
51966	31294783	Low serum DHEAS is a common finding in patients with PAPSS2 deficiency.	('DHEAS', 'Gene', '6822', (10, 15))	('deficiency', 'Var', (60, 70))	('patients', 'Species', '9606', (39, 47))	('PA', 'Phenotype', 'HP:0011736', (53, 55))	('PAPSS2', 'Gene', '9060', (53, 59))	('PAPSS2', 'Gene', (53, 59))	('DHEAS', 'Gene', (10, 15))
51967	31294783	Detailed investigations of steroid metabolism are available from two brothers with compound heterozygous PAPSS2 mutations and their heterozygous parents.	('steroid', 'Chemical', 'MESH:D013256', (27, 34))	('PA', 'Phenotype', 'HP:0011736', (105, 107))	('mutations', 'Var', (112, 121))	('PAPSS2', 'Gene', '9060', (105, 111))	('PAPSS2', 'Gene', (105, 111))
51969	31294783	Of note, this mother and the mother of the first reported case were carriers of major loss-of-function PAPSS2 mutations and presented clinically with PCOS.	('PCOS', 'Disease', (150, 154))	('mutations', 'Var', (110, 119))	('PAPSS2', 'Gene', '9060', (103, 109))	('PAPSS2', 'Gene', (103, 109))	('loss-of-function', 'NegReg', (86, 102))	('PCOS', 'Disease', 'MESH:D011085', (150, 154))	('PA', 'Phenotype', 'HP:0011736', (103, 105))
51972	31294783	CRD is caused by HSD11B1 deficiency whereas ACRD results form a deficiency in the activity of H6PDH, which is essential for maintaining the reductive activity of HSD11B1 in vivo by the reduced form of NAD phosphate provision to the enzyme.	('HSD11B1', 'Gene', '3290', (17, 24))	('reductive activity', 'MPA', (140, 158))	('deficiency', 'Var', (25, 35))	('CRD', 'Disease', (45, 48))	('CRD', 'Disease', 'MESH:C536447', (0, 3))	('CRD', 'Disease', 'MESH:C536447', (45, 48))	('deficiency', 'NegReg', (64, 74))	('HSD11B1', 'Gene', (17, 24))	('H6PDH', 'Gene', (94, 99))	('HSD11B1', 'Gene', '3290', (162, 169))	('activity', 'MPA', (82, 90))	('CRD', 'Disease', (0, 3))	('NAD phosphate', 'Chemical', 'MESH:D009243', (201, 214))	('caused by', 'Reg', (7, 16))	('HSD11B1', 'Gene', (162, 169))
51981	31294783	Therefore, HSD11B2 deficiency caused by inborn mutations or excess consumption of HSD11B2 inhibitors (carbenoxolone, licorice) leads to unwanted excess MR activation by cortisol, resulting in apparent mineralocorticoid excess (AME).	('HSD11B2', 'Gene', (82, 89))	('deficiency', 'Var', (19, 29))	('cortisol', 'Chemical', 'MESH:D006854', (169, 177))	('carbenoxolone', 'Chemical', 'MESH:D002229', (102, 115))	('inborn', 'Disease', 'MESH:D030342', (40, 46))	('mutations', 'Var', (47, 56))	('HSD11B2', 'Gene', (11, 18))	('mineralocorticoid excess', 'Phenotype', 'HP:0000859', (201, 225))	('HSD11B2', 'Gene', '3291', (82, 89))	('MR', 'Gene', '4306', (152, 154))	('HSD11B2', 'Gene', '3291', (11, 18))	('inborn', 'Disease', (40, 46))	('mineralocorticoid excess', 'MPA', (201, 225))	('activation', 'PosReg', (155, 165))
51982	31294783	Clinically, HSD11B2 deficiency manifests with hypertension, hypokalemia, and low renin levels, but no evidence of excess mineralocorticoid secretion, with subnormal levels of aldosterone.	('hypertension', 'Phenotype', 'HP:0000822', (46, 58))	('excess mineralocorticoid', 'Phenotype', 'HP:0000859', (114, 138))	('renin', 'Gene', '5972', (81, 86))	('deficiency', 'Var', (20, 30))	('hypokalemia', 'Disease', (60, 71))	('HSD11B2', 'Gene', '3291', (12, 19))	('hypokalemia', 'Disease', 'MESH:D007008', (60, 71))	('aldosterone', 'Chemical', 'MESH:D000450', (175, 186))	('hypertension', 'Disease', 'MESH:D006973', (46, 58))	('HSD11B2', 'Gene', (12, 19))	('renin', 'Gene', (81, 86))	('hypokalemia', 'Phenotype', 'HP:0002900', (60, 71))	('hypertension', 'Disease', (46, 58))	('low renin levels', 'Phenotype', 'HP:0003351', (77, 93))
51996	31294783	CYP11B2 mutations invariably result in loss of 18-oxidase activity, whereas the 18-hydroxylase activity can be either preserved or lost.	('18-hydroxylase', 'MPA', (80, 94))	('18-oxidase activity', 'MPA', (47, 66))	('CYP11B2', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('CYP11B2', 'Gene', '1585', (0, 7))	('loss', 'NegReg', (39, 43))
51999	31294783	As the two-step conversion of corticosterone to aldosterone was initially considered to be catalyzed by two different enzymes:corticosterone methyloxidase I (CMO I, 18-hydroxylase) and corticosterone methyloxidase II (CMO II, 18-oxidase):a biochemical categorization of CYP11B2 deficiencies as CMO I and CMO II is still widely accepted.	('CYP11B2', 'Gene', '1585', (270, 277))	('corticosterone', 'Chemical', 'MESH:D003345', (30, 44))	('corticosterone', 'Chemical', 'MESH:D003345', (126, 140))	('corticosterone', 'Chemical', 'MESH:D003345', (185, 199))	('deficiencies', 'Var', (278, 290))	('aldosterone', 'Chemical', 'MESH:D000450', (48, 59))	('CYP11B2', 'Gene', (270, 277))
52000	31294783	18-hydroxylase deficiency results in low serum 18-hydroxycorticosterone (18OHB) and low to undetectable aldosterone, with concomitant accumulation of corticosterone.	('18-hydroxylase', 'Protein', (0, 14))	('low', 'NegReg', (37, 40))	('aldosterone', 'MPA', (104, 115))	('accumulation', 'PosReg', (134, 146))	('undetectable aldosterone', 'Phenotype', 'HP:0004319', (91, 115))	('corticosterone', 'Chemical', 'MESH:D003345', (57, 71))	('serum 18-hydroxycorticosterone', 'MPA', (41, 71))	('corticosterone', 'Chemical', 'MESH:D003345', (150, 164))	('accumulation of corticosterone', 'Phenotype', 'HP:0032362', (134, 164))	('18-hydroxycorticosterone', 'Chemical', 'MESH:D015069', (47, 71))	('aldosterone', 'Chemical', 'MESH:D000450', (104, 115))	('18OHB', 'Chemical', 'MESH:C501453', (73, 78))	('deficiency', 'Var', (15, 25))
52004	31294783	In 18-oxidase deficiency, aldosterone levels are low whereas 18OHB levels are increased, in contrast to low 18OHB in CMO I. Serum corticosterone is normal to high, depending on the severity of 18-oxidase deficiency.	('18OHB levels', 'MPA', (61, 73))	('18-oxidase', 'Enzyme', (3, 13))	('aldosterone', 'Chemical', 'MESH:D000450', (26, 37))	('corticosterone', 'Chemical', 'MESH:D003345', (130, 144))	('18OHB', 'Chemical', 'MESH:C501453', (108, 113))	('increased', 'PosReg', (78, 87))	('aldosterone levels', 'MPA', (26, 44))	('deficiency', 'Var', (14, 24))	('low', 'NegReg', (49, 52))	('18OHB', 'Chemical', 'MESH:C501453', (61, 66))
52018	31294783	Most cases of Cushing syndrome are due to excess stimulation of the adrenals by ACTH, either due to a pituitary tumor (= Cushing disease; 70% to 75%) or ectopic ACTH secretion (10% to 15%).	('ACTH', 'Gene', (80, 84))	('Cushing syndrome', 'Disease', 'MESH:D003480', (14, 30))	('ACTH', 'Gene', '5443', (80, 84))	('pituitary tumor', 'Disease', (102, 117))	('Cushing disease', 'Disease', (121, 136))	('Cushing disease', 'Disease', 'MESH:D047748', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Cushing disease', 'Phenotype', 'HP:0003118', (121, 136))	('pituitary tumor', 'Disease', 'MESH:D010911', (102, 117))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (14, 30))	('stimulation', 'PosReg', (49, 60))	('ACTH', 'Gene', (161, 165))	('ectopic', 'Var', (153, 160))	('ACTH', 'Gene', '5443', (161, 165))	('Cushing syndrome', 'Disease', (14, 30))
52020	31294783	More rarely, autonomous adrenal cortisol hypersecretion is caused by primary bilateral macronodular adrenal hyperplasia, due to AMRC5 mutations, or primary pigmented nodular adrenocortical disease due to inactivating PRKAR1A mutations, affecting the regulatory subunit of the cAMP-dependent protein kinase A. Mutations in the PRKACA gene, encoding the catalytic subunit of protein kinase A, have been identified as a frequent cause of cortisol excess in unilateral adrenal adenomas due to somatic driver mutations, but also as a rare germline mutation underlying bilateral macronodular adrenal hyperplasia.	('unilateral adrenal adenomas', 'Disease', 'MESH:D018246', (454, 481))	('PRKACA', 'Gene', (326, 332))	('pigmented nodular adrenocortical disease', 'Disease', (156, 196))	('autonomous adrenal cortisol hypersecretion', 'Disease', 'MESH:C536845', (13, 55))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (586, 605))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (100, 119))	('PRKAR1A', 'Gene', '5573', (217, 224))	('cortisol', 'Chemical', 'MESH:D006854', (32, 40))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (87, 119))	('cortisol', 'MPA', (435, 443))	('adrenal hyperplasia', 'Disease', (586, 605))	('Mutations', 'Var', (309, 318))	('adrenal hyperplasia', 'Disease', (100, 119))	('cAMP', 'Chemical', 'MESH:D000242', (276, 280))	('unilateral adrenal adenomas', 'Disease', (454, 481))	('adrenocortical disease due', 'Phenotype', 'HP:0008207', (174, 200))	('ACA', 'Phenotype', 'HP:0008256', (329, 332))	('PRKACA', 'Gene', '5566', (326, 332))	('cause', 'Reg', (426, 431))	('autonomous adrenal cortisol hypersecretion', 'Disease', (13, 55))	('MR', 'Gene', '4306', (129, 131))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (586, 605))	('cortisol excess', 'Phenotype', 'HP:0003118', (435, 450))	('PRKAR1A', 'Gene', (217, 224))	('cortisol', 'Chemical', 'MESH:D006854', (435, 443))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (100, 119))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (156, 196))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (573, 605))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (465, 481))
52033	31294783	Rare familial forms of PA have been shown to be associated with germline mutations in KCNJ5, CACNA1D, CACNA1H, and CLCN2.	('CACNA1D', 'Gene', '776', (93, 100))	('CACNA1H', 'Gene', (102, 109))	('CACNA1D', 'Gene', (93, 100))	('KCNJ5', 'Gene', (86, 91))	('associated', 'Reg', (48, 58))	('CLCN2', 'Gene', '1181', (115, 120))	('CACNA1H', 'Gene', '8912', (102, 109))	('familial forms', 'Disease', (5, 19))	('KCNJ5', 'Gene', '3762', (86, 91))	('PA', 'Phenotype', 'HP:0011736', (23, 25))	('CLCN2', 'Gene', (115, 120))	('germline', 'Var', (64, 72))
52034	31294783	Similarly, somatic driver mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 have been discovered in APA tissue, altogether accounting for most cases.	('PA', 'Phenotype', 'HP:0011736', (107, 109))	('CTNNB1', 'Gene', (75, 81))	('ATP2B3', 'Gene', (54, 60))	('ATP1A1', 'Gene', (46, 52))	('CACNA1D', 'Gene', '776', (62, 69))	('mutations', 'Var', (26, 35))	('CTNNB1', 'Gene', '1499', (75, 81))	('KCNJ5', 'Gene', (39, 44))	('KCNJ5', 'Gene', '3762', (39, 44))	('ATP2B3', 'Gene', '492', (54, 60))	('ATP1A1', 'Gene', '476', (46, 52))	('CACNA1D', 'Gene', (62, 69))
52035	31294783	Most of these ion channel mutations lead to enhanced calcium influx into zona glomerulosa cells, thereby stimulating aldosterone synthase (CYP11B2) expression.	('aldosterone synthase', 'Gene', '1585', (117, 137))	('CYP11B2', 'Gene', '1585', (139, 146))	('calcium', 'Chemical', 'MESH:D002118', (53, 60))	('stimulating', 'Reg', (105, 116))	('mutations', 'Var', (26, 35))	('stimulating aldosterone', 'Phenotype', 'HP:0000859', (105, 128))	('calcium influx into zona glomerulosa cells', 'MPA', (53, 95))	('expression', 'MPA', (148, 158))	('aldosterone synthase', 'Gene', (117, 137))	('CYP11B2', 'Gene', (139, 146))	('enhanced', 'PosReg', (44, 52))
52040	31294783	Serum and urinary 18-hydroxycortisol, 18-oxocortisol, and 18-oxo-THF excretion are highest in FHA type 1 (= GRA, see "Glucocorticoid-remediable aldosteronism" above) and FHA type 3 (germline KCNJ5 mutations); they also tend to be higher in APA than in bilateral hyperaldosteronism, albeit with considerable overlap.	('FHA', 'Disease', (170, 173))	('hyperaldosteronism', 'Disease', 'MESH:D006929', (262, 280))	('KCNJ5', 'Gene', (191, 196))	('higher', 'PosReg', (230, 236))	('FHA', 'Disease', 'MESH:C580087', (94, 97))	('18-hydroxycortisol', 'Chemical', 'MESH:C033689', (18, 36))	('urinary 18-hydroxycortisol', 'MPA', (10, 36))	('hyperaldosteronism', 'Disease', (262, 280))	('KCNJ5', 'Gene', '3762', (191, 196))	('FHA', 'Disease', (94, 97))	('18-oxocortisol', 'MPA', (38, 52))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (262, 280))	('APA', 'Disease', (240, 243))	('18-oxo-THF', 'Chemical', 'MESH:C006461', (58, 68))	('mutations', 'Var', (197, 206))	('FHA', 'Disease', 'MESH:C580087', (170, 173))	('18-oxo-THF excretion', 'MPA', (58, 78))	('18-oxocortisol', 'Chemical', 'MESH:C038135', (38, 52))	('PA', 'Phenotype', 'HP:0011736', (241, 243))
52041	31294783	No distinct steroid metabolome signature has been identified for other PA-causing mutations yet, mostly due to the rarity of cases.	('PA-causing', 'Disease', (71, 81))	('mutations', 'Var', (82, 91))	('PA', 'Phenotype', 'HP:0011736', (71, 73))	('steroid', 'Chemical', 'MESH:D013256', (12, 19))
52061	31294783	Additionally, urine steroid metabolome analysis revealed that mitotane strongly inhibits 5alpha-reductase activity in ACC patients, explaining treatment-related male hypogonadism, and acts as a strong inducer of CYP3A4, resulting in significantly accelerated cortisol inactivation.	('male hypogonadism', 'Phenotype', 'HP:0000026', (161, 178))	('inducer', 'PosReg', (201, 208))	('inhibits', 'NegReg', (80, 88))	('cortisol inactivation', 'MPA', (259, 280))	('male hypogonadism', 'Disease', (161, 178))	('mitotane', 'Var', (62, 70))	('5alpha-reductase', 'Enzyme', (89, 105))	('hypogonadism', 'Phenotype', 'HP:0000135', (166, 178))	('ACC', 'Phenotype', 'HP:0006744', (118, 121))	('ACC', 'Disease', (118, 121))	('CYP3A4', 'Gene', '1576', (212, 218))	('mitotane', 'Chemical', 'MESH:D008939', (62, 70))	('patients', 'Species', '9606', (122, 130))	('male hypogonadism', 'Disease', 'MESH:D005058', (161, 178))	('cortisol', 'Chemical', 'MESH:D006854', (259, 267))	('CYP3A4', 'Gene', (212, 218))	('steroid', 'Chemical', 'MESH:D013256', (20, 27))	('accelerated', 'PosReg', (247, 258))	('ACC', 'Disease', 'MESH:D018268', (118, 121))
52068	31294783	3beta5alpha-PD 5alpha-pregnane-3beta,20alpha-diol 6alpha-OHTHA 6alpha-hydroxy-11-dehydro-tetrahydrocorticosterone; 18OHB 18-hydroxycorticosterone A4 androstenedione ACA adrenocortical adenoma ACC adrenocortical carcinoma ACRD apparent cortisone reductase deficiency AME apparent mineralocorticoid excess An androgen APA aldosterone-producing adenoma CAH congenital adrenal hyperplasia CMO I corticosterone methyloxidase I CMO II corticosterone methyloxidase II CRD cortisone reductase deficiency CYB5A cytochrome b5 CYP cytochrome P450 DOC deoxycorticosterone DSD disorder of sex development FHA familial hyperaldosteronism GC-MS gas chromatography-mass spectrometry GRA glucocorticoid-remediable aldosteronism hCG human chorionic gonadotropin HPA hypothalamic-pituitary-adrenal MACE mild autonomous cortisol excess MR mineralocorticoid receptor PA primary aldosteronism PCOS polycystic ovary syndrome PHA pseudohypoaldosteronism POR cytochrome P450 oxidoreductase PORD POR deficiency STS steroid sulfatase STSD steroid sulfatase deficiency T testosterone UHPLC-MS/MS ultra-HPLC-tandem mass spectrometry	('MR', 'Gene', '4306', (816, 818))	('testosterone', 'Chemical', 'MESH:D013739', (1043, 1055))	('5alpha-pregnane-3beta,20alpha-diol', 'Chemical', 'MESH:C016836', (15, 49))	('POR', 'Gene', (970, 973))	('hypoaldosteronism', 'Phenotype', 'HP:0004319', (912, 929))	('adenoma', 'Disease', (184, 191))	('hypothalamic-pituitary-adrenal', 'Disease', 'MESH:D007029', (748, 778))	('sulfatase deficiency', 'Disease', 'MESH:D052517', (1020, 1040))	('adenoma', 'Disease', (342, 349))	('ACA', 'Disease', 'MESH:D018246', (165, 168))	('POR', 'Gene', '5447', (965, 968))	('adenoma', 'Disease', 'MESH:D000236', (184, 191))	('POR', 'Gene', (930, 933))	('ovary syndrome', 'Phenotype', 'HP:0000137', (887, 901))	('CAH', 'Phenotype', 'HP:0008258', (350, 353))	('PA', 'Phenotype', 'HP:0011736', (317, 319))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (365, 384))	('mineralocorticoid receptor', 'Gene', (819, 845))	('POR', 'Gene', (965, 968))	('pseudohypoaldosteronism', 'Disease', 'MESH:D011546', (906, 929))	('POR', 'Gene', '5447', (970, 973))	('steroid', 'Chemical', 'MESH:D013256', (989, 996))	('corticosterone', 'Chemical', 'MESH:D003345', (545, 559))	('PA primary aldosteronism', 'Phenotype', 'HP:0011739', (846, 870))	('CYP', 'Gene', (516, 519))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (196, 220))	('cytochrome P450', 'Gene', (934, 949))	('POR', 'Gene', '5447', (930, 933))	('HPA', 'Disease', (744, 747))	('polycystic ovary syndrome', 'Disease', 'MESH:D011085', (876, 901))	('corticosterone', 'Chemical', 'MESH:D003345', (99, 113))	('autonomous cortisol excess', 'Disease', (789, 815))	('ACC', 'Disease', (192, 195))	('CYB5A', 'Gene', (496, 501))	('CRD', 'Disease', 'MESH:C536447', (461, 464))	('6alpha-OHTHA', 'Chemical', 'MESH:C023888', (50, 62))	('cytochrome P450', 'Gene', (520, 535))	('deficiency', 'Var', (974, 984))	('mineralocorticoid receptor', 'Gene', '4306', (819, 845))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (605, 623))	('ACA', 'Phenotype', 'HP:0008256', (165, 168))	('autonomous cortisol excess', 'Disease', 'MESH:C535280', (789, 815))	('corticosterone', 'Chemical', 'MESH:D003345', (391, 405))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (849, 870))	('PA', 'Phenotype', 'HP:0011736', (745, 747))	('FHA', 'Disease', 'MESH:C580087', (592, 595))	('hypothalamic-pituitary-adrenal', 'Disease', (748, 778))	('adenoma', 'Disease', 'MESH:D000236', (342, 349))	('ACC', 'Disease', 'MESH:D018268', (192, 195))	('familial hyperaldosteronism', 'Disease', 'MESH:C580087', (596, 623))	('mineralocorticoid excess', 'Phenotype', 'HP:0000859', (279, 303))	('deoxycorticosterone', 'Chemical', 'MESH:D003900', (540, 559))	('congenital adrenal hyperplasia', 'Disease', (354, 384))	('cytochrome b', 'Gene', '4519', (502, 514))	('DOC', 'Chemical', 'MESH:C060842', (536, 539))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (196, 220))	('steroid', 'Chemical', 'MESH:D013256', (1012, 1019))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('CAH', 'Disease', (350, 353))	('pseudohypoaldosteronism', 'Disease', (906, 929))	('CRD', 'Disease', (222, 225))	('pseudohypoaldosteronism', 'Phenotype', 'HP:0008242', (906, 929))	('STSD', 'Disease', (1007, 1011))	('P450 oxidoreductase', 'Gene', '5447', (945, 964))	('adrenocortical carcinoma', 'Disease', (196, 220))	('18OHB', 'Chemical', 'MESH:C501453', (115, 120))	('ACC', 'Phenotype', 'HP:0006744', (192, 195))	('PHA', 'Disease', (902, 905))	('PHA', 'Disease', 'MESH:D011546', (902, 905))	('cortisone reductase deficiency', 'Disease', 'MESH:C536447', (235, 265))	('cortisone reductase deficiency', 'Disease', 'MESH:C536447', (465, 495))	('familial hyperaldosteronism GC', 'Phenotype', 'HP:0011740', (596, 626))	('human', 'Species', '9606', (715, 720))	('CYP', 'Gene', '4051', (516, 519))	('HPA', 'Disease', 'MESH:D007029', (744, 747))	('cytochrome P450', 'Gene', '4051', (520, 535))	('FHA', 'Disease', (592, 595))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (354, 384))	('androgen', 'Chemical', 'MESH:D000728', (307, 315))	('hCG', 'Gene', (711, 714))	('excess MR mineralocorticoid', 'Phenotype', 'HP:0000859', (809, 836))	('deficiency T testosterone', 'Phenotype', 'HP:0040171', (1030, 1055))	('PCOS', 'Disease', 'MESH:D011085', (871, 875))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (169, 191))	('cortisol excess', 'Phenotype', 'HP:0003118', (800, 815))	('ACA', 'Disease', (165, 168))	('corticosterone', 'Chemical', 'MESH:D003345', (131, 145))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (169, 191))	('androstenedione', 'Chemical', 'MESH:D000735', (149, 164))	('polycystic ovary syndrome', 'Disease', (876, 901))	('polycystic ovary', 'Phenotype', 'HP:0000147', (876, 892))	('adrenocortical adenoma', 'Disease', (169, 191))	('CYB5A', 'Gene', '1528', (496, 501))	('PHA', 'Phenotype', 'HP:0008242', (902, 905))	('CRD', 'Disease', 'MESH:C536447', (222, 225))	('corticosterone', 'Chemical', 'MESH:D003345', (429, 443))	('cytochrome P450', 'Gene', '4051', (934, 949))	('hCG', 'Gene', '93659', (711, 714))	('STSD', 'Disease', 'MESH:D016114', (1007, 1011))	('CAH', 'Disease', 'MESH:D000312', (350, 353))	('P450 oxidoreductase', 'Gene', (945, 964))	('cortisone reductase deficiency', 'Disease', (235, 265))	('cortisone reductase deficiency', 'Disease', (465, 495))	('cytochrome b', 'Gene', (502, 514))	('aldosterone', 'Chemical', 'MESH:D000450', (320, 331))	('PCOS', 'Disease', (871, 875))	('3beta5alpha-PD', 'Chemical', 'MESH:C082619', (0, 14))	('CRD', 'Disease', (461, 464))	('PA', 'Phenotype', 'HP:0011736', (846, 848))	('familial hyperaldosteronism', 'Disease', (596, 623))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (354, 384))	('sulfatase deficiency', 'Disease', (1020, 1040))	('18-hydroxycorticosterone', 'Chemical', 'MESH:D015069', (121, 145))
52093	31370263	Inhibition of ACE exerts antihypertensive effects and lowers serum and renal chemerin protein.	('hypertensive', 'Disease', 'MESH:D006973', (29, 41))	('ACE', 'Gene', '1636', (14, 17))	('Inhibition', 'Var', (0, 10))	('lowers', 'NegReg', (54, 60))	('hypertensive', 'Disease', (29, 41))	('ACE', 'Gene', (14, 17))
52122	31370263	In a melanoma model, chemerin transfected cancer cells exhibited a growth inhibitory immune cell distribution in the tumor microenvironment, which was characterized by a higher number of NK and T cells and a relative decline of MDSC and pDCs.	('pDC', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('higher', 'PosReg', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('tumor', 'Disease', (117, 122))	('melanoma', 'Disease', (5, 13))	('MDSC', 'MPA', (228, 232))	('T cells', 'CPA', (194, 201))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('pDC', 'Gene', '5132', (237, 240))	('decline', 'NegReg', (217, 224))	('transfected', 'Var', (30, 41))	('growth inhibitory immune', 'MPA', (67, 91))
52133	31370263	Chemerin binding to CMKLR1, but not to GPR1 or CCRL2, strongly increases intracellular calcium concentration, decreases cyclic AMP levels and induces the phosphorylation of p42-p44 MAP kinases, through the Gi class of G proteins.	('decreases', 'NegReg', (110, 119))	('induces', 'Reg', (142, 149))	('GPR1', 'Gene', (39, 43))	('p42', 'Gene', '23552', (173, 176))	('cyclic AMP levels', 'MPA', (120, 137))	('Chemerin', 'Gene', (0, 8))	('cyclic AMP', 'Chemical', 'MESH:D000242', (120, 130))	('increases intracellular calcium concentration', 'Phenotype', 'HP:0003575', (63, 108))	('intracellular calcium concentration', 'MPA', (73, 108))	('Chemerin', 'Gene', '5919', (0, 8))	('increases', 'PosReg', (63, 72))	('CCRL2', 'Gene', '9034', (47, 52))	('G proteins', 'Protein', (218, 228))	('GPR1', 'Gene', '2825', (39, 43))	('binding', 'Interaction', (9, 16))	('CCRL2', 'Gene', (47, 52))	('calcium', 'Chemical', 'MESH:D002118', (87, 94))	('phosphorylation', 'MPA', (154, 169))	('CMKLR1', 'Var', (20, 26))	('p42', 'Gene', (173, 176))
52159	31370263	These results were supported by a study observing the same effect of chemerin on angiogenesis and even more demonstrated that chemerin mediated the formation of blood vessels to a similar extent as VEGF.	('angiogenesis', 'CPA', (81, 93))	('chemerin', 'Var', (126, 134))	('VEGF', 'Gene', (198, 202))	('formation of blood vessels', 'CPA', (148, 174))	('VEGF', 'Gene', '7422', (198, 202))
52163	31370263	Knockdown of chemerin receptor CMKLR1, but not of CCRL2, completely inhibited the chemerin-induced migration and angiogenesis of HUVECs, which indicated that chemerin promoted the migration and angiogenic activities mainly through CMKLR1.	('CCRL2', 'Gene', '9034', (50, 55))	('CMKLR1', 'Var', (231, 237))	('chemerin-induced', 'MPA', (82, 98))	('migration', 'CPA', (180, 189))	('promoted', 'PosReg', (167, 175))	('angiogenesis', 'CPA', (113, 125))	('inhibited', 'NegReg', (68, 77))	('angiogenic activities', 'CPA', (194, 215))	('chemerin receptor', 'Gene', '1240', (13, 30))	('chemerin receptor', 'Gene', (13, 30))	('CCRL2', 'Gene', (50, 55))
52174	31370263	In contrast to this study on a small patients  collective, in a metaanalysis of publicly available DNA microarray data of 3951 breast cancer patients, chemerin expression was observed to be significantly lower in breast cancer tissue than in a normal breast (p = 2.17 x 10-7) and use of Kaplan-Meier plotter software revealed that high chemerin expression in breast cancer tissue did not affect overall survival (OS), but turned out to negatively affect relapse-free survival (RFS; p = 0.015; Figure 2).	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('breast cancer', 'Disease', (359, 372))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('patients', 'Species', '9606', (141, 149))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('patients', 'Species', '9606', (37, 45))	('OS', 'Chemical', '-', (413, 415))	('breast cancer', 'Disease', (213, 226))	('breast cancer', 'Disease', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('affect', 'Reg', (447, 453))	('high', 'Var', (331, 335))	('relapse-free survival', 'CPA', (454, 475))	('expression', 'MPA', (160, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (359, 372))	('negatively', 'NegReg', (436, 446))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Disease', 'MESH:D001943', (359, 372))	('lower', 'NegReg', (204, 209))
52175	31370263	In contrast, high CMKLR1 expression, which did not significantly differ between normal and tumorigenic breast, had robust beneficial effects on RFS of breast cancer patients, but did not affect OS.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('high CMKLR1', 'Var', (13, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('OS', 'Chemical', '-', (194, 196))	('patients', 'Species', '9606', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('beneficial effects', 'PosReg', (122, 140))	('tumor', 'Disease', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('RFS', 'MPA', (144, 147))
52176	31370263	Chemerin receptor GPR1 was found to be up-regulated in cancer tissue (p = 0.002), and high expression of GPR1 also led to prolonged RFS (p = 0.00082), but did not affect OS of breast cancer patients.	('patients', 'Species', '9606', (190, 198))	('GPR1', 'Gene', '2825', (105, 109))	('OS', 'Chemical', '-', (170, 172))	('up-regulated', 'PosReg', (39, 51))	('GPR1', 'Gene', '2825', (18, 22))	('cancer', 'Disease', (183, 189))	('Chemerin receptor', 'Gene', '1240', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', (55, 61))	('RFS', 'MPA', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('high expression', 'Var', (86, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('GPR1', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('prolonged', 'PosReg', (122, 131))	('GPR1', 'Gene', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('breast cancer', 'Disease', (176, 189))	('Chemerin receptor', 'Gene', (0, 17))
52197	31370263	The prolonged OS of patients with high expression of CMKLR1 and CCRL2 clearly suggested an anti-tumoral effect of serum chemerin being activated in ovarian cancer tissue.	('activated', 'PosReg', (135, 144))	('OS', 'Chemical', '-', (14, 16))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ovarian cancer', 'Disease', (148, 162))	('high expression', 'Var', (34, 49))	('CCRL2', 'Gene', '9034', (64, 69))	('tumor', 'Disease', (96, 101))	('CMKLR1', 'Gene', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('ovarian cancer', 'Phenotype', 'HP:0100615', (148, 162))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('ovarian cancer', 'Disease', 'MESH:D010051', (148, 162))	('CCRL2', 'Gene', (64, 69))
52209	31370263	Multi-variable Cox regression analysis suggested expression of chemerin to be an independent predictor of a better prognosis for patients with NSCLC.	('NSCLC', 'Disease', (143, 148))	('patients', 'Species', '9606', (129, 137))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('expression', 'Var', (49, 59))
52227	31370263	In line with these studies, the analysis of publicly available DNA microarray data of 876 gastric cancer patients by means of the Kaplan-Meier plotter software demonstrated that high chemerin tumor expression reduced OS of gastric cancer patients (p = 0.0059; Figure 5) and also higher tissue expression of CMKLR1 and GPR1 significantly decreased OS of gastric cancer patients (p = 0.0085 or p = 1.7 x 10-7, respectively).	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (223, 237))	('high', 'Var', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (353, 367))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('GPR1', 'Gene', '2825', (318, 322))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('patients', 'Species', '9606', (368, 376))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', (192, 197))	('patients', 'Species', '9606', (105, 113))	('gastric cancer', 'Phenotype', 'HP:0012126', (223, 237))	('OS', 'Chemical', '-', (347, 349))	('gastric cancer', 'Disease', (353, 367))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patients', 'Species', '9606', (238, 246))	('gastric cancer', 'Disease', (90, 104))	('CMKLR1', 'Gene', (307, 313))	('decreased', 'NegReg', (337, 346))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('reduced', 'NegReg', (209, 216))	('gastric cancer', 'Disease', (223, 237))	('higher', 'PosReg', (279, 285))	('gastric cancer', 'Disease', 'MESH:D013274', (353, 367))	('GPR1', 'Gene', (318, 322))	('OS', 'Chemical', '-', (217, 219))
52242	31370263	Supporting the mentioned studies suggesting a tumor-suppressive role of chemerin, the metaanalysis of publicly available gene expression data of 364 patients with HCC by means of the Kaplan-Meier plotter software revealed that high chemerin expression in cancer tissue significantly increased patients' OS (p = 0.00027) and progression-free survival (PFS; p = 0.012).	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('patients', 'Species', '9606', (149, 157))	('HCC', 'Phenotype', 'HP:0001402', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('OS', 'Chemical', '-', (303, 305))	('patients', 'Species', '9606', (293, 301))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('chemerin', 'Protein', (232, 240))	('tumor', 'Disease', (46, 51))	('expression', 'MPA', (241, 251))	('increased', 'PosReg', (283, 292))	('progression-free survival', 'CPA', (324, 349))	("patients' OS", 'CPA', (293, 305))	('cancer', 'Disease', (255, 261))	('high', 'Var', (227, 231))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
52253	31370263	It was shown that chemerin was independently able to prognosticate AML patients, and high chemerin expression was associated with positive prognosis.	('AML', 'Disease', 'MESH:D015470', (67, 70))	('AML', 'Phenotype', 'HP:0004808', (67, 70))	('patients', 'Species', '9606', (71, 79))	('AML', 'Disease', (67, 70))	('high', 'Var', (85, 89))
52256	31370263	Chemerin was found to be down-regulated in melanoma and high chemerin mRNA expression in tumors correlated with improved outcome in human melanoma.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('tumors', 'Disease', (89, 95))	('melanoma', 'Disease', (138, 146))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('chemerin', 'Gene', (61, 69))	('melanoma', 'Disease', (43, 51))	('Chemerin', 'Gene', (0, 8))	('down-regulated', 'NegReg', (25, 39))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('human', 'Species', '9606', (132, 137))	('mRNA expression', 'MPA', (70, 85))	('improved', 'PosReg', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('Chemerin', 'Gene', '5919', (0, 8))	('high', 'Var', (56, 60))
52269	28369373	Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage Li-Fraumeni Syndrome (LFS) results from heterozygous germline mutations of TP53, encoding a key transcriptional factor activated in response to DNA damage.	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (120, 140))	('TP53', 'Gene', (195, 199))	('Li-Fraumeni Syndrome', 'Disease', (120, 140))	('defect', 'NegReg', (51, 57))	('TP53', 'Gene', '7157', (9, 13))	('transcriptional', 'MPA', (81, 96))	('TP53', 'Gene', (9, 13))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('TP53', 'Gene', '7157', (195, 199))	('mutations', 'Var', (14, 23))	('mutations', 'Var', (182, 191))
52270	28369373	Then, to compare the impact of the different types of germline TP53 mutations on DNA binding, we performed chromatin immunoprecipitation-sequencing (ChIP-Seq) in lymphocytes exposed to doxorubicin.	('mutations', 'Var', (68, 77))	('doxorubicin', 'Chemical', 'MESH:D004317', (185, 196))	('TP53', 'Gene', (63, 67))
52272	28369373	ChIP-Seq analysis of LFS lymphocytes carrying TP53 null mutations (p.P152Rfs*18 or complete deletion) or the low penetrant 'Brazilian' p.R337H mutation revealed a moderate decrease of p53-binding sites (949, 580 and 620, respectively) and of ChIP-Seq peak depths.	('p53-binding', 'Protein', (184, 195))	('ChIP-Seq peak depths', 'MPA', (242, 262))	('p.P152Rfs*18', 'Mutation', 'p.P152RfsX18', (67, 79))	('decrease', 'NegReg', (172, 180))	('TP53', 'Gene', (46, 50))	('p.R337H', 'Var', (135, 142))	('complete deletion', 'Var', (83, 100))	('p.P152Rfs*18', 'Var', (67, 79))	('p.R337H', 'Mutation', 'rs121912664', (135, 142))
52273	28369373	In contrast, analysis of LFS lymphocytes with TP53 dominant-negative missense mutations p.R273H or p.R248W revealed only 310 and 143 p53-binding sites, respectively, and the depths of the corresponding peaks were drastically reduced.	('depths', 'MPA', (174, 180))	('p.R248W', 'Var', (99, 106))	('p53-binding', 'Protein', (133, 144))	('reduced', 'NegReg', (225, 232))	('p.R273H', 'Mutation', 'rs28934576', (88, 95))	('p.R248W', 'Mutation', 'rs121912651', (99, 106))	('TP53', 'Gene', (46, 50))	('p.R273H', 'Var', (88, 95))
52277	28369373	If germline TP53 mutations are identified in familial aggregations of childhood and adult tumours, they can also be detected in patients and families who have developed only adult cancers and in patients without a familial history of cancer.	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('TP53', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('patients', 'Species', '9606', (128, 136))	('familial aggregations of childhood and adult tumours', 'Disease', 'MESH:C536928', (45, 97))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('patients', 'Species', '9606', (195, 203))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (234, 240))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (180, 186))
52278	28369373	With the exponential use, in cancer patients, of TP53 tests performed with gene panels, it is likely that the percentage of germline TP53 mutations detected in such patients or families will increase.	('cancer', 'Disease', (29, 35))	('patients', 'Species', '9606', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (165, 173))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('TP53', 'Gene', (133, 137))	('mutations', 'Var', (138, 147))
52279	28369373	The diversity of the clinical presentations associated with germline TP53 mutations suggests that it should be appropriate to include Li-Fraumeni syndrome within an expanded category designated 'TP53-related inherited cancers' characterized by a broader tumour spectrum and age of tumour onset.	('inherited cancers', 'Disease', (208, 225))	('tumour', 'Disease', 'MESH:D009369', (281, 287))	('Li-Fraumeni syndrome', 'Disease', (134, 154))	('inherited cancers', 'Disease', 'MESH:D009386', (208, 225))	('TP53', 'Gene', (69, 73))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('mutations', 'Var', (74, 83))	('tumour', 'Disease', (281, 287))	('tumour', 'Disease', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (134, 154))	('tumour', 'Phenotype', 'HP:0002664', (281, 287))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))
52280	28369373	LFS animal models and clinical data support the existence of genotype-phenotype correlations in LFS: (i) mouse models of LFS have shown the phenotypic severity of dominant-negative mutations, as compared with null mutations; (ii) from a large series of 415 TP53 mutation carriers, we have recently reported that the mean age of tumour onset was statistically lower in carriers harbouring dominant-negative missense mutations than in carriers with loss of function mutations and that dominant-negative missense mutations represent the predominant germline alterations in carriers who developed childhood cancers, except ACC.	('dominant-negative missense mutations', 'Var', (483, 519))	('tumour', 'Phenotype', 'HP:0002664', (328, 334))	('cancers', 'Phenotype', 'HP:0002664', (603, 610))	('dominant-negative missense mutations', 'Var', (388, 424))	('tumour', 'Disease', 'MESH:D009369', (328, 334))	('cancer', 'Phenotype', 'HP:0002664', (603, 609))	('tumour', 'Disease', (328, 334))	('lower', 'NegReg', (359, 364))	('childhood cancers', 'Disease', 'MESH:C536928', (593, 610))	('mouse', 'Species', '10090', (105, 110))	('childhood cancers', 'Disease', (593, 610))
52281	28369373	In contrast, null mutations such as nonsense mutations, frameshift mutations or genomic rearrangements are predominantly detected in pedigrees characterized by cancers occurring in adulthood.	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('frameshift mutations', 'Var', (56, 76))	('cancers', 'Disease', (160, 167))	('detected', 'Reg', (121, 129))	('nonsense mutations', 'Var', (36, 54))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
52282	28369373	Indeed, analysis of the p53 transcriptional response after doxorubicin exposure of lymphocytes derived from three TP53 wild-type control subjects, 3 carriers of dominant-negative missense mutations and 3 carriers of null mutations, revealed that in lymphocytes with germline dominant-negative missense mutations, the number of induced genes and the level of p53 target gene induction were drastically reduced, as compared to controls and LFS lymphocytes with null mutations.	('dominant-negative missense mutations', 'Var', (275, 311))	('reduced', 'NegReg', (401, 408))	('doxorubicin', 'Chemical', 'MESH:D004317', (59, 70))
52283	28369373	It can alternatively be used to determine the functionality of p53 protein in LFS patients harbouring germline TP53 mutations.	('TP53', 'Gene', (111, 115))	('patients', 'Species', '9606', (82, 90))	('LFS', 'Disease', (78, 81))	('mutations', 'Var', (116, 125))
52284	28369373	To confirm the results obtained in our previous study performed on a limited number of samples and showing that dominant-negative missense mutations had a more drastic impact on p53 transcriptional response compared to null mutations, we selected 35 EBV-immortalized lymphocytes from 5 control subjects with wild-type TP53 genotype, 14 LFS patients with TP53 null mutations and 16 LFS patients with missense mutations previously classified as dominant-negative mutations according to the IARC (International Agency for Research on Cancer) TP53 database (http://p53.iarc.fr/; date last accessed March 22, 2017) (Table 1).	('Cancer', 'Disease', (531, 537))	('Cancer', 'Disease', 'MESH:D009369', (531, 537))	('mutations', 'Var', (139, 148))	('Cancer', 'Phenotype', 'HP:0002664', (531, 537))	('TP53', 'Gene', (354, 358))	('patients', 'Species', '9606', (340, 348))	('patients', 'Species', '9606', (385, 393))
52287	28369373	These results therefore confirm our previous results showing that germline TP53 mutations detected in LFS patients result in a constitutive reduction of p53 transcriptional activity and that dominant-negative missense mutations have a more severe impact on this transcriptional activity than null mutations.	('p53 transcriptional activity', 'MPA', (153, 181))	('LFS', 'Disease', (102, 105))	('mutations', 'Var', (80, 89))	('missense mutations', 'Var', (209, 227))	('patients', 'Species', '9606', (106, 114))	('reduction', 'NegReg', (140, 149))	('TP53', 'Gene', (75, 79))
52288	28369373	We then extended this functional analysis to 26 patients suspected to present with LFS and harbouring 15 additional different missense mutations.	('LFS', 'Disease', (83, 86))	('patients', 'Species', '9606', (48, 56))	('missense mutations', 'Var', (126, 144))
52289	28369373	The first group corresponded to 3 mutations (p.R290H, p.G302R, p.T304A) previously classified as 'supertrans or functional' in a yeast-based functional assay.	('yeast', 'Species', '4932', (129, 134))	('p.R290H', 'Var', (45, 52))	('p.T304A', 'Var', (63, 70))	('p.G302R', 'Mutation', 'rs863224686', (54, 61))	('p.T304A', 'Mutation', 'rs587782654', (63, 70))	('p.G302R', 'Var', (54, 61))	('p.R290H', 'Mutation', 'rs55819519', (45, 52))
52290	28369373	When we looked at the TP53 missense mutations p.R158H and p.R337H associated with adrenocortical carcinoma or adult tumours, we obtained scores close to the ones of the null mutations (mean score = 5.6 +- 0.4) (Fig.	('adult tumours', 'Disease', (110, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('p.R158H', 'Mutation', 'rs587782144', (46, 53))	('p.R158H', 'Var', (46, 53))	('adrenocortical carcinoma', 'Disease', (82, 106))	('associated', 'Reg', (66, 76))	('p.R337H', 'Mutation', 'rs121912664', (58, 65))	('adult tumours', 'Disease', 'MESH:D006528', (110, 123))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (82, 106))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (82, 106))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('TP53', 'Gene', (22, 26))	('p.R337H', 'Var', (58, 65))
52291	28369373	Finally, when we analysed the other missense mutations (p.E11Q, p.G108D, p.T125M, p.R175G, p.H193D, p.H193P, p.V216M, p.C229R, p.I254T, p.R282P), we observed a drastic alteration of the p53 transcriptional activity (mean score = 3.8 +- 0.2), similar to that observed with well characterized dominant-negative missense mutations suggesting that most of these mutations are also bona fide dominant-negative mutations (Fig.	('p.G108D', 'Mutation', 'p.G108D', (64, 71))	('p.I254T', 'Var', (127, 134))	('p53', 'Gene', (186, 189))	('p.V216M', 'Var', (109, 116))	('p.C229R', 'Mutation', 'rs1064794312', (118, 125))	('p.H193P', 'Mutation', 'rs786201838', (100, 107))	('p.R175G', 'Var', (82, 89))	('p.H193P', 'Var', (100, 107))	('p.T125M', 'Mutation', 'rs786201057', (73, 80))	('p.C229R', 'Var', (118, 125))	('p.H193D', 'Mutation', 'rs876658468', (91, 98))	('p.H193D', 'Var', (91, 98))	('p.G108D', 'Var', (64, 71))	('alteration', 'Reg', (168, 178))	('p.R282P', 'Mutation', 'rs730882008', (136, 143))	('p.R282P', 'Var', (136, 143))	('p.V216M', 'Mutation', 'rs730882025', (109, 116))	('p.E11Q', 'Mutation', 'rs201382018', (56, 62))	('p.E11Q', 'Var', (56, 62))	('p.R175G', 'Mutation', 'rs138729528', (82, 89))	('p.T125M', 'Var', (73, 80))	('transcriptional activity', 'MPA', (190, 214))	('p.I254T', 'Mutation', 'p.I254T', (127, 134))
52292	28369373	In order to evaluate the impact of germline TP53 mutations on p53 DNA binding, we did a genome-wide mapping of p53-binding sites in response to DNA damage, by performing ChIP-Seq in control EBV-immortalized lymphocytes exposed to doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (230, 241))	('TP53', 'Gene', (44, 48))	('mutations', 'Var', (49, 58))
52299	28369373	Colonies of YPH500 strains cultured on media containing a limited amount of adenine are spontaneously red, whereas colonies expressing ADE2 turn white (Supplementary Material, Fig.	('adenine', 'Chemical', 'MESH:D000225', (76, 83))	('YPH500', 'Gene', (12, 18))	('ADE2', 'Var', (135, 139))
52301	28369373	As a positive control, we used the p53-binding site within MDM2 and, as a negative control, a sequence from the USH1G gene [MIM*607696, NM_173477] without any signal detected in the p53 ChIP-Seq experiments.	('USH1G', 'Gene', '124590', (112, 117))	('USH1G', 'Gene', (112, 117))	('MDM2', 'Gene', '4193', (59, 63))	('MDM2', 'Gene', (59, 63))	('[MIM*607696', 'Var', (123, 134))
52304	28369373	In lymphocytes harbouring the TP53 p.R248W mutation, the up-regulation of these genes was significantly reduced, demonstrating the specificity of the regulation by p53 (Supplementary Materials, Fig.	('reduced', 'NegReg', (104, 111))	('TP53 p.R248W', 'Var', (30, 42))	('p.R248W', 'Var', (35, 42))	('up-regulation', 'PosReg', (57, 70))	('p.R248W', 'Mutation', 'rs121912651', (35, 42))
52305	28369373	In order to study the functional consequences of germline TP53 mutations on p53 DNA binding in presence of DNA damage, we performed a ChIP-Seq analysis of EBV-immortalized lymphocytes from LFS patients harbouring heterozygous TP53 mutations, after exposure to doxorubicin.	('mutations', 'Var', (231, 240))	('patients', 'Species', '9606', (193, 201))	('doxorubicin', 'Chemical', 'MESH:D004317', (260, 271))	('TP53', 'Gene', (226, 230))
52306	28369373	a frameshift mutation (p.P152Rfs*18) and a complete deletion, both resulting into p53 haplodeficiency, (ii) two canonical missense mutations, classified as dominant-negative (p.R248W, p.R273H), according to the IARC TP53 database and (iii) the p.R337H mutation, a low penetrance TP53 mutation associated with adrenocortical carcinomas or adulthood tumours (Table 1).	('p.R248W', 'Mutation', 'rs121912651', (175, 182))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (309, 334))	('resulting into', 'Reg', (67, 81))	('p.R337H', 'Var', (244, 251))	('p.R248W', 'Var', (175, 182))	('associated', 'Reg', (293, 303))	('p.P152Rfs*18', 'Var', (23, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (309, 333))	('carcinomas', 'Phenotype', 'HP:0030731', (324, 334))	('p.P152Rfs*18', 'Mutation', 'p.P152RfsX18', (23, 35))	('TP53', 'Gene', (279, 283))	('p.R273H', 'Var', (184, 191))	('p.R337H', 'Mutation', 'rs121912664', (244, 251))	('tumours', 'Phenotype', 'HP:0002664', (348, 355))	('adrenocortical carcinomas or adulthood tumours', 'Disease', (309, 355))	('adrenocortical carcinomas or adulthood tumours', 'Disease', 'MESH:D018268', (309, 355))	('p.R273H', 'Mutation', 'rs28934576', (184, 191))	('tumour', 'Phenotype', 'HP:0002664', (348, 354))
52307	28369373	As shown in Figure 3A, the total number of ChIP-Seq peaks detected was reduced approximately by half in LFS lymphocytes harbouring the p.P152Rfs*18 mutation or the complete TP53 deletion compared to the two controls.	('p.P152Rfs*18', 'Mutation', 'p.P152RfsX18', (135, 147))	('p.P152Rfs*18', 'Var', (135, 147))	('ChIP-Seq peaks', 'MPA', (43, 57))	('reduced', 'NegReg', (71, 78))	('TP53', 'Gene', (173, 177))
52309	28369373	We identified 845, 562, 532, 239 and 139 peaks in common between control lymphocytes and LFS lymphocytes harbouring p.P152Rfs*18, complete deletion, p.R337H, p.R273H and p.R248W mutations, respectively (Fig.	('p.R337H', 'Mutation', 'rs121912664', (149, 156))	('p.R248W', 'Mutation', 'rs121912651', (170, 177))	('p.R337H', 'Var', (149, 156))	('complete deletion', 'Var', (130, 147))	('p.P152Rfs*18', 'Mutation', 'p.P152RfsX18', (116, 128))	('p.R273H', 'Mutation', 'rs28934576', (158, 165))	('p.R273H', 'Var', (158, 165))	('p.R248W', 'Var', (170, 177))	('p.P152Rfs*18', 'Var', (116, 128))
52312	28369373	Because some studies have shown that some dominant-negative missense mutations, such as the p.R248W mutation, may result in GOF by modulating expression of target genes involved in oncogenesis, we explored thanks to the ChIP-Seq data, the putative GOF activity of the p.R248W mutant in lymphocytes not exposed to doxorubicin.	('p.R248W', 'Var', (268, 275))	('missense mutations', 'Var', (60, 78))	('p.R248W', 'Mutation', 'rs121912651', (268, 275))	('modulating', 'Reg', (131, 141))	('p.R248W', 'Mutation', 'rs121912651', (92, 99))	('expression', 'MPA', (142, 152))	('doxorubicin', 'Chemical', 'MESH:D004317', (313, 324))	('result', 'Reg', (114, 120))	('p.R248W mutation', 'Var', (92, 108))
52315	28369373	In TP53 mutation carriers, this constitutive alteration of the transcriptional response to DNA damage, detectable in non-tumour cells, constitutes an endophenotype before the occurrence of cancer and confirms that germline TP53 mutations represent a genetic permissive context facilitating the malignant transformation of cells in which DNA damage has occurred.	('TP53', 'Gene', (3, 7))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('TP53', 'Gene', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('mutations', 'Var', (228, 237))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('mutation', 'Var', (8, 16))	('malignant transformation', 'CPA', (294, 318))	('transcriptional response to', 'MPA', (63, 90))	('tumour', 'Disease', (121, 127))	('cancer', 'Disease', (189, 195))
52316	28369373	This suggests that the core LFS tumour spectrum is probably explained by the differential sensitivities of tissues to oncogenic stresses and that the tumour spectrum associated with germline TP53 mutations is much broader than initially considered.	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Disease', (32, 38))	('tumour', 'Disease', (150, 156))	('TP53', 'Gene', (191, 195))	('LFS tumour', 'Disease', (28, 38))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('LFS tumour', 'Disease', 'MESH:D016864', (28, 38))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('mutations', 'Var', (196, 205))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
52319	28369373	We anticipate that this challenge will increase with the detection of such germline TP53 variants in patients with atypical clinical presentations, performed in the context of next-generation sequencing (NGS) cancer gene panels.	('patients', 'Species', '9606', (101, 109))	('variants', 'Var', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (209, 215))	('TP53', 'Gene', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
52328	28369373	The differences between both studies might be explained by the numerous genetic and epigenetic modifications occurring in cancer cell lines, which deeply modify the landscape of p53-binding sites.	('landscape', 'MPA', (165, 174))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('modify', 'Reg', (154, 160))	('p53-binding', 'Protein', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('epigenetic modifications', 'Var', (84, 108))
52330	28369373	In lymphocytes from LFS patients harbouring null mutations, the p53 functionality scores obtained with the p53 functional assay, the number and scores of ChIP-Seq peaks were reduced by half in average, as compared to control lymphocytes (Figs 1 and 3).	('null mutations', 'Var', (44, 58))	('reduced', 'NegReg', (174, 181))	('p53', 'Gene', (64, 67))	('patients', 'Species', '9606', (24, 32))
52331	28369373	This probably explains why TP53 null mutations are associated with later tumour-onset and why in tumours with such mutations, LOH affecting the wild-type allele is more commonly observed than in tumours with other types of TP53 mutations.	('TP53', 'Gene', (27, 31))	('mutations', 'Var', (115, 124))	('tumours', 'Disease', 'MESH:D009369', (97, 104))	('tumours', 'Disease', (97, 104))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('associated', 'Reg', (51, 61))	('tumour-onset', 'Disease', (73, 85))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumours', 'Disease', (195, 202))	('tumour-onset', 'Disease', 'MESH:D009369', (73, 85))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('null mutations', 'Var', (32, 46))
52332	28369373	The second part of the explanation probably corresponds to the gain of multiple neomorphic properties, TP53 missense mutations being able to transform the tumour suppressor protein into an oncogenic protein, providing a selective advantage during cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('advantage', 'PosReg', (230, 239))	('TP53', 'Gene', (103, 107))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('missense mutations', 'Var', (108, 126))	('tumour', 'Disease', (155, 161))
52333	28369373	A recent study, also based on ChIP-Seq but performed in cancer cell lines, has reported that missense mutations with GOF cause aberrant DNA binding and upregulation of genes involved in chromatin conformation.	('upregulation', 'PosReg', (152, 164))	('genes', 'Gene', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('missense mutations', 'Var', (93, 111))	('DNA binding', 'Interaction', (136, 147))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
52334	28369373	As previously shown by transcriptomic analyses performed in non-cancer tissues from p53-/-and p53 mutant/mutant mice, which did not reveal any significant changes, our study confirms that GOF is not observed in non-malignant cells and suggests that GOF occurs when cells are transformed.	('p53', 'Gene', (94, 97))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mutant/mutant', 'Var', (98, 111))	('mice', 'Species', '10090', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
52335	28369373	The clinical management of LFS represents a real challenge for physicians, considering the wide tumour spectrum associated with germline TP53 mutations, and the diversity of the clinical severity and age of tumour onset observed among families.	('mutations', 'Var', (142, 151))	('tumour', 'Disease', (207, 213))	('LFS', 'Disease', (27, 30))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('tumour', 'Disease', (96, 102))	('TP53', 'Gene', (137, 141))
52336	28369373	The 'Toronto protocol' including annual total body MRI and brain MRI, from the first year of life, has recently been elaborated to ensure early tumour detection in germline TP53 mutation carriers.	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('mutation', 'Var', (178, 186))	('tumour', 'Disease', (144, 150))	('TP53', 'Gene', (173, 177))
52337	28369373	EBV-Immortalized lymphocytes from wild-type TP53 control individuals and from germline TP53 mutation carriers (Table 1) were cultured in RPMI 1640 medium (GIBCO, Invitrogen), supplemented with 10% heat-inactivated fetal bovine serum (Invitrogen) at 37  C with 5% CO2.	('bovine', 'Species', '9913', (220, 226))	('CO2', 'Chemical', '-', (263, 266))	('TP53', 'Gene', (87, 91))	('mutation', 'Var', (92, 100))
52341	28369373	Briefly, starting from 100 ng of total RNA,cRNA was synthesized and labelled using the low input Quick Amp Labeling Kit (Agilent), with Cy3 (for untreated cells) and Cy5 (for treated cells).	('Cy3', 'Var', (136, 139))	('Cy5', 'Chemical', 'MESH:C085321', (166, 169))	('Cy3', 'Chemical', '-', (136, 139))	('Amp', 'Chemical', 'MESH:D000249', (103, 106))	('Cy5', 'Var', (166, 169))
52345	28369373	The comparative Ct method was used for quantification of MDM2 [MIM*164785, NM_002392], GCNT3 [MIM*606836, NM_004751], LINC01480 [NR_110724], PLXNB1 [MIM*601053, NM_002673] and SRSF8 [MIM*603269, NM_032102] gene expression compared to that of the GAPDH [MIM*138400, NM_002046] gene, used as control.	('SRSF8', 'Gene', (176, 181))	('LINC01480', 'Gene', (118, 127))	('LINC01480', 'Gene', '101927931', (118, 127))	('MDM2', 'Gene', '4193', (57, 61))	('MDM2', 'Gene', (57, 61))	('NM_004751]', 'Var', (106, 116))	('PLXNB1', 'Gene', '5364', (141, 147))	('SRSF8', 'Gene', '10929', (176, 181))	('GCNT3', 'Gene', (87, 92))	('GCNT3', 'Gene', '9245', (87, 92))	('PLXNB1', 'Gene', (141, 147))
52352	28369373	Transformed yeast cells were plated on a synthetic minimal medium minus leucine and histidine, to select for cells containing the pLS76 or pSS16 and pRS313 vectors, respectively, plus a limited amount of adenine (10 microg/ml) and incubated for 2 days at 30  C (Supplementary Material, Fig.	('yeast', 'Species', '4932', (12, 17))	('leucine', 'Chemical', 'MESH:D007930', (72, 79))	('pLS76', 'Var', (130, 135))	('histidine', 'Chemical', 'MESH:D006639', (84, 93))	('adenine', 'Chemical', 'MESH:D000225', (204, 211))	('pRS313', 'Chemical', '-', (149, 155))	('pRS313', 'Var', (149, 155))
52353	28369373	EBV-immortalized lymphocytes from wild-type TP53 subjects or from germline TP53 mutation carriers were seeded in duplicates in 15cm dishes, at a density of 20 x 106 cells/dish and treated with 0.3 microM of doxorubicin for 8h (Sigma-Aldrich).	('mutation', 'Var', (80, 88))	('TP53', 'Gene', (75, 79))	('doxorubicin', 'Chemical', 'MESH:D004317', (207, 218))
52363	29299119	Such alterations were very likely linked to the previously described, mitotane-induced respiratory chain defect.	('respiratory chain defect', 'Disease', (87, 111))	('respiratory chain defect', 'Phenotype', 'HP:0200125', (87, 111))	('alterations', 'Var', (5, 16))	('mitotane', 'Chemical', 'MESH:D008939', (70, 78))	('respiratory chain defect', 'Disease', 'MESH:D028361', (87, 111))	('linked', 'Reg', (34, 40))
52364	29299119	Lipidomic studies of intracellular and intramitochondrial phospholipids revealed that mitotane exposure markedly reduced the phosphatidylserine/phosphatidylethanolamine ratio, indicative of a dysfunction of phosphatidylserine decarboxylase located in Mitochondria-Associated Membranes.	('phosphatidylethanolamine', 'Chemical', 'MESH:C483858', (144, 168))	('phosphatidylserine', 'Chemical', 'MESH:D010718', (125, 143))	('phosphatidylserine/phosphatidylethanolamine ratio', 'MPA', (125, 174))	('phosphatidylserine', 'Chemical', 'MESH:D010718', (207, 225))	('phosphatidylserine decarboxylase', 'Gene', '23761', (207, 239))	('mitotane', 'Var', (86, 94))	('mitotane', 'Chemical', 'MESH:D008939', (86, 94))	('phosphatidylserine decarboxylase', 'Gene', (207, 239))	('Lipid', 'Chemical', 'MESH:D008055', (0, 5))	('reduced', 'NegReg', (113, 120))	('phospholipids', 'Chemical', 'MESH:D010743', (58, 71))
52365	29299119	Expression levels of Mitochondria-Associated Membranes proteins phosphatidylserine decarboxylase, DRP1, ATAD3A or TSPO were greatly reduced by mitotane as assessed by western blot analyses.	('phosphatidylserine decarboxylase', 'Gene', (64, 96))	('mitotane', 'Var', (143, 151))	('TSPO', 'Gene', (114, 118))	('Expression levels', 'MPA', (0, 17))	('mitotane', 'Chemical', 'MESH:D008939', (143, 151))	('DRP1', 'Gene', (98, 102))	('reduced', 'NegReg', (132, 139))	('Mitochondria-Associated Membranes', 'MPA', (21, 54))	('ATAD3A', 'Gene', '55210', (104, 110))	('DRP1', 'Gene', '10059', (98, 102))	('ATAD3A', 'Gene', (104, 110))	('phosphatidylserine decarboxylase', 'Gene', '23761', (64, 96))
52367	29299119	Finally, we showed that PK11195, a pharmacological inhibitor of the cholesterol translocator TSPO, embedded in Mitochondria-Associated Membranes, exerts a synergetic effect with mitotane in inducing Mitochondria-Associated Membranes disruption, apoptosis and in inhibiting steroid secretion.	('steroid', 'Chemical', 'MESH:D013256', (273, 280))	('PK11195', 'Var', (24, 31))	('mitotane', 'Chemical', 'MESH:D008939', (178, 186))	('inhibiting', 'NegReg', (262, 272))	('cholesterol', 'Chemical', 'MESH:D002784', (68, 79))	('inducing', 'PosReg', (190, 198))	('steroid secretion', 'MPA', (273, 290))	('apoptosis', 'CPA', (245, 254))	('Mitochondria-Associated Membranes disruption', 'MPA', (199, 243))
52389	29299119	In this present study, several preclinical in vitro studies including metabolomic and lipidomic approaches as well as apoptosis and steroidogenic production assessments and cell imaging indicate that MAM formation and function are markedly inhibited by mitotane exposure, synergistically with the concomitant use of a TSPO inhibitor.	('mitotane', 'Var', (253, 261))	('mitotane', 'Chemical', 'MESH:D008939', (253, 261))	('MAM', 'Gene', '6445', (200, 203))	('lipid', 'Chemical', 'MESH:D008055', (86, 91))	('inhibited', 'NegReg', (240, 249))	('steroid', 'Chemical', 'MESH:D013256', (132, 139))	('MAM', 'Gene', (200, 203))	('function', 'CPA', (218, 226))
52393	29299119	As illustrated in Figure 1A, HRMAS spectra of untreated or mitotane-treated H295R cells demonstrated that aspartate content was drastically reduced upon mitotane exposure.	('mitotane', 'Chemical', 'MESH:D008939', (153, 161))	('aspartate', 'Chemical', 'MESH:D001224', (106, 115))	('mitotane', 'Chemical', 'MESH:D008939', (59, 67))	('aspartate content', 'MPA', (106, 123))	('mitotane', 'Var', (153, 161))	('H295R', 'CellLine', 'CVCL:0458', (76, 81))	('reduced', 'NegReg', (140, 147))
52396	29299119	Mitotane therefore induced a robust decrease in intracellular aspartate/glutamate ratio (Figure 2A).	('Mitotane', 'Var', (0, 8))	('intracellular aspartate/glutamate ratio', 'MPA', (48, 87))	('glutamate', 'Chemical', 'MESH:D018698', (72, 81))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('aspartate', 'Chemical', 'MESH:D001224', (62, 71))	('decrease', 'NegReg', (36, 44))
52400	29299119	Thus, the defect in oxidation of NADH by complex I causes major dysfunction of the tricarboxylic acid cycle because of the depletion of the intracellular content of NAD+.	('dysfunction of the tricarboxylic acid cycle', 'Phenotype', 'HP:0000816', (64, 107))	('tricarboxylic acid cycle', 'MPA', (83, 107))	('dysfunction', 'MPA', (64, 75))	('NADH', 'Gene', (33, 37))	('NAD+', 'Chemical', 'MESH:D009243', (165, 169))	('oxidation', 'MPA', (20, 29))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (83, 101))	('depletion of the intracellular content of NAD+', 'MPA', (123, 169))	('NADH', 'Chemical', 'MESH:D009243', (33, 37))	('defect', 'Var', (10, 16))
52420	29299119	Our results demonstrate that mitotane significantly reduces the fraction of COX2 that colocalizes with Calnexin (Figure 6B, Manders' and Pearsons' coefficients).	('COX2', 'Gene', '4513', (76, 80))	('colocalizes', 'MPA', (86, 97))	('reduces', 'NegReg', (52, 59))	('Calnexin', 'Gene', (103, 111))	('Calnexin', 'Gene', '821', (103, 111))	('mitotane', 'Var', (29, 37))	('COX2', 'Gene', (76, 80))	('mitotane', 'Chemical', 'MESH:D008939', (29, 37))
52424	29299119	To further explore this possibility, we incubated H295R cells with a combination of both mitotane and PK11195, a high affinity and selective pharmacological inhibitor of TSPO, in order to check whether this antagonist may rather increase the efficiency of mitotane and induce mitochondrial fragmentation.	('H295R', 'CellLine', 'CVCL:0458', (50, 55))	('mitotane', 'Chemical', 'MESH:D008939', (256, 264))	('induce', 'Reg', (269, 275))	('increase', 'PosReg', (229, 237))	('mitotane', 'Chemical', 'MESH:D008939', (89, 97))	('efficiency', 'MPA', (242, 252))	('mitotane', 'CPA', (256, 264))	('PK11195', 'Var', (102, 109))	('mitochondrial fragmentation', 'CPA', (276, 303))
52426	29299119	PK11195, at relatively low concentrations (50 muM) did not induce major morphological changes in the mitochondrial network of H295R cells nor decrease the colocalization with calnexin (Figure 7A and 7B).	('colocalization', 'MPA', (155, 169))	('H295R', 'CellLine', 'CVCL:0458', (126, 131))	('muM', 'Gene', '56925', (46, 49))	('decrease', 'NegReg', (142, 150))	('calnexin', 'Gene', '821', (175, 183))	('muM', 'Gene', (46, 49))	('PK11195', 'Var', (0, 7))	('calnexin', 'Gene', (175, 183))
52428	29299119	In sharp contrast, a combination of the same concentration of mitotane in addition with 50 muM PK11195 dramatically induced a marked punctiform pattern of mitochondria as well as of the reticular ER network (Figure 7A Mitotane/PK11195 condition and Figure 7B.	('Mitotane', 'Chemical', 'MESH:D008939', (218, 226))	('induced', 'Reg', (116, 123))	('mitotane', 'Chemical', 'MESH:D008939', (62, 70))	('punctiform pattern of mitochondria', 'MPA', (133, 167))	('PK11195', 'Var', (95, 102))	('muM', 'Gene', '56925', (91, 94))	('muM', 'Gene', (91, 94))
52430	29299119	In the presence of 50 muM mitotane, PK11195 could not further disrupt the mitochondrial network and MAM interactions (Supplementary Figure 2A and 2B).	('MAM', 'Gene', '6445', (100, 103))	('mitotane', 'Chemical', 'MESH:D008939', (26, 34))	('PK11195', 'Var', (36, 43))	('MAM', 'Gene', (100, 103))	('muM', 'Gene', '56925', (22, 25))	('mitochondrial network', 'CPA', (74, 95))	('disrupt', 'Reg', (62, 69))	('muM', 'Gene', (22, 25))
52432	29299119	Furthermore, given that MAM are major contributor regulating cellular homeostasis such as apoptosis, we also showed that the two compounds PK11195 and mitotane disclosed synergistic effects on apoptosis (Figure 8).	('apoptosis', 'CPA', (193, 202))	('mitotane', 'Chemical', 'MESH:D008939', (151, 159))	('PK11195', 'Var', (139, 146))	('MAM', 'Gene', (24, 27))	('MAM', 'Gene', '6445', (24, 27))
52433	29299119	PK11195 alone did not induce Caspase 3/7 activity as a marker of apoptosis in H295R cells whereas mitotane dose-dependently increases Caspase 3/7 activity.	('mitotane', 'Chemical', 'MESH:D008939', (98, 106))	('Caspase 3', 'Gene', (29, 38))	('H295R', 'CellLine', 'CVCL:0458', (78, 83))	('activity', 'MPA', (146, 154))	('Caspase 3', 'Gene', (134, 143))	('Caspase 3', 'Gene', '836', (29, 38))	('increases', 'PosReg', (124, 133))	('Caspase 3', 'Gene', '836', (134, 143))	('PK11195', 'Var', (0, 7))
52434	29299119	Combining 50 muM PK11195 and 10 muM of mitotane did not increase Caspase 3/7 activity thus excluding that MAM dysfunction upon mitotane exposure at a low concentration of 10 muM is a consequence of cell apoptosis.	('mitotane', 'Chemical', 'MESH:D008939', (39, 47))	('mitotane', 'Chemical', 'MESH:D008939', (127, 135))	('muM', 'Gene', (174, 177))	('muM', 'Gene', (13, 16))	('MAM', 'Gene', (106, 109))	('muM', 'Gene', '56925', (32, 35))	('Caspase 3', 'Gene', '836', (65, 74))	('MAM', 'Gene', '6445', (106, 109))	('Caspase 3', 'Gene', (65, 74))	('muM', 'Gene', (32, 35))	('muM', 'Gene', '56925', (174, 177))	('muM', 'Gene', '56925', (13, 16))	('PK11195', 'Var', (17, 24))
52435	29299119	Combining 50 muM PK11195 and 100 muM mitotane significantly potentiates the activation of caspase 3/7 activity, consistent with a synergistic effect of both drugs on H295 cells.	('muM', 'Gene', (33, 36))	('mitotane', 'Chemical', 'MESH:D008939', (37, 45))	('muM', 'Gene', (13, 16))	('caspase 3', 'Gene', (90, 99))	('caspase 3', 'Gene', '836', (90, 99))	('H295', 'CellLine', 'CVCL:0456', (166, 170))	('potentiates', 'PosReg', (60, 71))	('activity', 'MPA', (102, 110))	('muM', 'Gene', '56925', (33, 36))	('activation', 'PosReg', (76, 86))	('muM', 'Gene', '56925', (13, 16))	('PK11195', 'Var', (17, 24))
52437	29299119	Using measurements of cortisol production in H295R cell supernatants with the highly specific and sensitive LC-MS/MS method, we finally demonstrated the synergy between PK11195 and mitotane on steroid secretion (Figure 9).	('cortisol', 'Chemical', 'MESH:D006854', (22, 30))	('PK11195', 'Var', (169, 176))	('mitotane', 'Chemical', 'MESH:D008939', (181, 189))	('steroid secretion', 'MPA', (193, 210))	('H295R', 'CellLine', 'CVCL:0458', (45, 50))	('steroid', 'Chemical', 'MESH:D013256', (193, 200))
52438	29299119	While mitotane alone, at a low 10 muM concentration, did not significantly modify cortisol secretion, addition of PK11195 significantly reduced cortisol release by more than 80% as compared to PK11195 alone which also inhibited cortisol release.	('muM', 'Gene', '56925', (34, 37))	('cortisol', 'Chemical', 'MESH:D006854', (228, 236))	('cortisol', 'Chemical', 'MESH:D006854', (82, 90))	('cortisol release', 'MPA', (144, 160))	('PK11195', 'Var', (114, 121))	('muM', 'Gene', (34, 37))	('cortisol', 'Chemical', 'MESH:D006854', (144, 152))	('inhibited cortisol release', 'Phenotype', 'HP:0008163', (218, 244))	('mitotane', 'Chemical', 'MESH:D008939', (6, 14))	('reduced', 'NegReg', (136, 143))	('cortisol release', 'MPA', (228, 244))	('reduced cortisol', 'Phenotype', 'HP:0008163', (136, 152))
52439	29299119	Collectively, these findings provided first evidence that o,p'DDD and TSPO inhibitor synergistically inhibited cortisol synthesis in human adrenocortical H295 cells.	('cortisol synthesis', 'MPA', (111, 129))	("o,p'DDD", 'Chemical', 'MESH:D008939', (58, 65))	('adrenocortical', 'Disease', (139, 153))	('adrenocortical', 'Disease', 'MESH:D018268', (139, 153))	('TSPO inhibitor', 'Gene', (70, 84))	('cortisol', 'Chemical', 'MESH:D006854', (111, 119))	('human', 'Species', '9606', (133, 138))	('inhibited', 'NegReg', (101, 110))	("p'DDD", 'Var', (60, 65))	('H295', 'CellLine', 'CVCL:0456', (154, 158))	('inhibited cortisol synthesis', 'Phenotype', 'HP:0008163', (101, 129))
52443	29299119	We previously showed by immunocytochemistry that mitotane induces a fragmentation of the mitochondrial network and demonstrated that this was accompanied by a specific inhibition of respiratory chain complexes I and IV activities.	('respiratory chain complexes', 'MPA', (182, 209))	('fragmentation', 'CPA', (68, 81))	('mitotane', 'Var', (49, 57))	('mitotane', 'Chemical', 'MESH:D008939', (49, 57))	('inhibition', 'NegReg', (168, 178))	('IV activities', 'MPA', (216, 229))	('mitochondrial network', 'CPA', (89, 110))
52445	29299119	Because of these similar phenotypes, we studied the impact of mitotane on PISD with complementary approaches and confirmed that mitotane inhibits both PISD protein expression by Western Blot and function by lipidomic studies in human adrenocortical H295R cells.	('H295R', 'CellLine', 'CVCL:0458', (249, 254))	('PISD', 'Gene', (151, 155))	('PISD', 'Gene', '23761', (151, 155))	('adrenocortical', 'Disease', (234, 248))	('function', 'MPA', (195, 203))	('adrenocortical', 'Disease', 'MESH:D018268', (234, 248))	('mitotane', 'Var', (128, 136))	('PISD', 'Gene', '23761', (74, 78))	('mitotane', 'Chemical', 'MESH:D008939', (62, 70))	('mitotane', 'Chemical', 'MESH:D008939', (128, 136))	('human', 'Species', '9606', (228, 233))	('PISD', 'Gene', (74, 78))	('inhibits', 'NegReg', (137, 145))	('lipid', 'Chemical', 'MESH:D008055', (207, 212))
52448	29299119	Likewise, mitotane reduces DRP1 protein steady state levels in H295R cells.	('mitotane', 'Var', (10, 18))	('mitotane', 'Chemical', 'MESH:D008939', (10, 18))	('DRP1', 'Gene', (27, 31))	('H295R', 'CellLine', 'CVCL:0458', (63, 68))	('DRP1', 'Gene', '10059', (27, 31))	('reduces', 'NegReg', (19, 26))
52451	29299119	Yet, the compensatory effect reported here for adrenocortical cells with mitotane remains to be further characterized.	('adrenocortical', 'Disease', 'MESH:D018268', (47, 61))	('mitotane', 'Chemical', 'MESH:D008939', (73, 81))	('adrenocortical', 'Disease', (47, 61))	('mitotane', 'Var', (73, 81))
52452	29299119	Our findings also demonstrated that mitotane directly inhibits the expression of some but not all structural MAM resident proteins.	('MAM', 'Gene', (109, 112))	('MAM', 'Gene', '6445', (109, 112))	('inhibits', 'NegReg', (54, 62))	('expression', 'MPA', (67, 77))	('mitotane', 'Var', (36, 44))	('mitotane', 'Chemical', 'MESH:D008939', (36, 44))
52454	29299119	We showed using immunocytochemistry and high resolution deconvolution microscopy followed by quantification of Manders and Pearson colocalization coefficients that mitotane induces a disruption of MAM and its functional consequences are summarized in Figure 10.	('mitotane', 'Var', (164, 172))	('MAM', 'Gene', '6445', (197, 200))	('mitotane', 'Chemical', 'MESH:D008939', (164, 172))	('disruption', 'MPA', (183, 193))	('MAM', 'Gene', (197, 200))
52458	29299119	The observed features including disruption of mitochondrial network and dysfunction in calcium, phospholipid and cholesterol metabolism are very similar to the effects demonstrated in H295R cells upon mitotane exposure.	('calcium', 'MPA', (87, 94))	('mitochondrial network', 'MPA', (46, 67))	('calcium', 'Chemical', 'MESH:D002118', (87, 94))	('cholesterol metabolism', 'MPA', (113, 135))	('cholesterol', 'Chemical', 'MESH:D002784', (113, 124))	('disruption', 'Reg', (32, 42))	('dysfunction', 'Var', (72, 83))	('phospholipid', 'Chemical', 'MESH:D010743', (96, 108))	('mitotane', 'Chemical', 'MESH:D008939', (201, 209))	('H295R', 'CellLine', 'CVCL:0458', (184, 189))
52459	29299119	Interestingly, neurological side effects in patients treated with mitotane resembled certain Alzheimer disease symptoms, providing support for a similar pathogenic mechanism.	('patients', 'Species', '9606', (44, 52))	('Alzheimer disease', 'Disease', 'MESH:D000544', (93, 110))	('Alzheimer disease', 'Disease', (93, 110))	('mitotane', 'Var', (66, 74))	('mitotane', 'Chemical', 'MESH:D008939', (66, 74))	('Alzheimer disease', 'Phenotype', 'HP:0002511', (93, 110))
52479	29299119	O,p'-DDD or mitotane (HRA Pharma) and PK 11195 (Sigma-Aldrich, St. Louis, MO) were solubilized in dimethyl sulfoxide (DMSO, Sigma-Aldrich) and used at the indicated concentrations ranging from 0 to 100 mM.	('PK 11195', 'Var', (38, 46))	('mitotane', 'Gene', (12, 20))	('DMSO', 'Chemical', 'MESH:D004121', (118, 122))	("p'-DDD", 'Chemical', '-', (2, 8))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (98, 116))	('mitotane', 'Chemical', 'MESH:D008939', (12, 20))
52493	29299119	Two measurements of model quality were reported for PLS-DA: R2Y and Q2 representing respectively, the goodness of fit (i.e.	('goodness of fit', 'Disease', (102, 117))	('R2Y', 'Var', (60, 63))	('goodness of fit', 'Disease', 'MESH:D012640', (102, 117))
52507	29299119	PC species were detected as product ions of m/z 184, PE, PS and PA as neutral losses of respectively m/z 141, 185 and 115.	('PE', 'Chemical', 'MESH:C483858', (53, 55))	('m/z 184', 'Var', (44, 51))	('m/z 141', 'Var', (101, 108))	('losses', 'NegReg', (78, 84))	('PS', 'Chemical', 'MESH:D010718', (57, 59))	('PA', 'Chemical', 'MESH:D011478', (64, 66))	('115', 'MPA', (118, 121))
52521	29299119	H295R cells seeded 6-well plates, were incubated for 48 h with vehicle (DMSO, control group); 50 muM PK 11195; 10 muM mitotane (o,p'DDD) or a combination of both PK 11195 (50 muM) + o,p'DDD (10 muM).	('muM', 'Gene', '56925', (194, 197))	('PK 11195', 'Var', (162, 170))	('PK 11195', 'Var', (101, 109))	("o,p'DDD", 'Chemical', 'MESH:D008939', (182, 189))	('muM', 'Gene', (175, 178))	('muM', 'Gene', '56925', (97, 100))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('muM', 'Gene', '56925', (114, 117))	("o,p'DDD", 'Chemical', 'MESH:D008939', (128, 135))	('muM', 'Gene', (97, 100))	('muM', 'Gene', (114, 117))	('mitotane', 'Chemical', 'MESH:D008939', (118, 126))	('muM', 'Gene', (194, 197))	('DMSO', 'Chemical', 'MESH:D004121', (72, 76))	('muM', 'Gene', '56925', (175, 178))
52587	28851942	Combining STR profiling with species identification by PCR, more than 20.5% (99/482) of tumor cell lines were revealed as having been incorrectly identified, including intra-species (14.5%), inter-species (4.4%) cross-contamination and contaminating cell lines (1.7%).	('tumor', 'Disease', (88, 93))	('cross-contamination', 'Var', (212, 231))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
52607	28851942	Among the cells established by Chinese scholars, more than 65.5% (19/29) were replaced by HeLa cells, concluding human liver cancer cell lines BEL7402, QGY7701, QGY7703 and SMMC7721, esophageal squamous Cell Carcinoma cell EC9706, gastric cancer cells BGC823, MGC803 and SGC7901, lung cancer cells SPC-A1 and GLC-82, oral squamous cell carcinoma Tca-8113, ovarian carcinoma cells Ho8910 and Ho8910PM, nasopharyngeal carcinoma tumor lines CNE-1, CNE-2Z and 4 derivatives.	('carcinoma', 'Phenotype', 'HP:0030731', (416, 425))	('EC9706', 'CellLine', 'CVCL:E307', (223, 229))	('gastric cancer', 'Disease', (231, 245))	('squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('lung cancer', 'Disease', 'MESH:D008175', (280, 291))	('BEL7402', 'CellLine', 'CVCL:5492', (143, 150))	('esophageal squamous Cell Carcinoma', 'Disease', (183, 217))	('Chinese', 'Species', '10029', (31, 38))	('human', 'Species', '9606', (113, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (280, 291))	('HeLa', 'CellLine', 'CVCL:0030', (90, 94))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (401, 425))	('oral squamous cell carcinoma Tca-8113, ovarian carcinoma cells Ho8910', 'Disease', 'MESH:D002294', (317, 386))	('gastric cancer', 'Disease', 'MESH:D013274', (231, 245))	('BGC823', 'CellLine', 'CVCL:3360', (252, 258))	('CNE-2Z', 'CellLine', 'CVCL:6890', (445, 451))	('liver cancer', 'Disease', 'MESH:D006528', (119, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (364, 373))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (426, 431))	('carcinoma tumor', 'Disease', (416, 431))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (322, 345))	('carcinoma tumor', 'Disease', 'MESH:D009369', (416, 431))	('SPC-A1', 'Gene', (298, 304))	('SPC-A1', 'Gene', '27032', (298, 304))	('QGY7703', 'Var', (161, 168))	('gastric cancer', 'Phenotype', 'HP:0012126', (231, 245))	('CNE-1', 'CellLine', 'CVCL:6888', (438, 443))	('liver cancer', 'Phenotype', 'HP:0002896', (119, 131))	('lung cancer', 'Disease', (280, 291))	('Carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('liver cancer', 'Disease', (119, 131))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (356, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('SMMC7721', 'CellLine', 'CVCL:0534', (173, 181))	('esophageal squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (183, 217))
52609	28851942	Additionally, 2 (THP-21 and K562-21) of the 29 cross-contaminated cell lines may be caused by mislabeling.	('THP-21', 'CellLine', 'CVCL:0006', (17, 23))	('K562-21', 'Var', (28, 35))	('caused by', 'Reg', (84, 93))	('K562', 'CellLine', 'CVCL:0004', (28, 32))
52615	28851942	When analyzed by STR profiling, 3 cell lines (803-Luc2-TdT, 803-mCherry and 786-0) had 3 or 4 types of copy numbers in more than 5 STR loci (Fig.	('copy numbers', 'Var', (103, 115))	('TdT', 'Gene', '1791', (55, 58))	('TdT', 'Gene', (55, 58))	('STR', 'Gene', (131, 134))
52660	28851942	STR loci and the amelogenin sex-determining marker were amplified using the AmpFlSTR  Identifiler  Plus PCR Amplification Kit (Applied Biosystems, USA) (detecting amelogenin, D5S818, D21S11, D7S820, CSF1PO, D2S1338, D3S1358, vWA, D8S1179, D16S539, TPOX, TH01, D19S433, D18S51, FGA and D13S317) or the DNA TyperTM15 plus direct kit (Institute of Forensic Science, Ministry of Public Security, China)(detecting the loci listed above plus Penta E, D6S1043 and D12S391) according to the manufacturer's instructions in a GeneAmp PCR system 9700.	('D8S1179', 'Var', (230, 237))	('FGA', 'Gene', '2243', (277, 280))	('D2S1338', 'Var', (207, 214))	('FGA', 'Gene', (277, 280))	('D16S539', 'Var', (239, 246))	('D18S51', 'Var', (269, 275))	('D19S433', 'Var', (260, 267))	('D12S391', 'Var', (457, 464))	('D21S11', 'Var', (183, 189))	('D13S317', 'Var', (285, 292))	('D7S820', 'Var', (191, 197))	('D3S1358', 'Var', (216, 223))	('D6S1043', 'Var', (445, 452))
52671	28135248	Five percent of cases, mostly with undetectable TERT, harbored ATRX or DAXX alterations, demonstrated elongated telomeres and increased telomeric repeat containing RNA (TERRA).	('alterations', 'Var', (76, 87))	('elongated', 'PosReg', (102, 111))	('ATRX', 'Gene', (63, 67))	('DAXX', 'Gene', '1616', (71, 75))	('TERT', 'Gene', (48, 52))	('telomeric repeat containing RNA', 'MPA', (136, 167))	('ATRX', 'Gene', '546', (63, 67))	('TERT', 'Gene', '7015', (48, 52))	('increased', 'PosReg', (126, 135))	('DAXX', 'Gene', (71, 75))	('telomeres', 'CPA', (112, 121))
52673	28135248	In this group, telomere length positively correlated with TP53 and RB1 mutations.	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('RB1', 'Gene', (67, 70))	('mutations', 'Var', (71, 80))	('correlated', 'Reg', (42, 52))	('telomere length', 'MPA', (15, 30))
52678	28135248	The telomerase enzymatic subunit is encoded by TERT, and while it is transcriptionally silent in most non-neoplastic cells, reactivation may endow a small population of cells with the ability to survive crisis, at which point they become immortalized.	('TERT', 'Gene', (47, 51))	('reactivation', 'Var', (124, 136))	('TERT', 'Gene', '7015', (47, 51))	('ran', 'Gene', (70, 73))	('ran', 'Gene', '5901', (70, 73))
52682	28135248	Deactivating mutations in ATRX and its binding partner DAXX were found tightly correlated with long telomeres in pancreatic neuroendocrine tumors and glioma.	('ATRX', 'Gene', (26, 30))	('DAXX', 'Gene', '1616', (55, 59))	('long telomeres', 'MPA', (95, 109))	('DAXX', 'Gene', (55, 59))	('Deactivating mutations', 'Var', (0, 22))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (124, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ATRX', 'Gene', '546', (26, 30))	('glioma', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))	('correlated', 'Reg', (79, 89))	('pancreatic neuroendocrine tumors', 'Disease', (113, 145))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (113, 145))
52683	28135248	Recent evidence suggested that loss of ATRX may contribute to ALT by promoting sustained sister telomere cohesion and chromatid exchange.	('ATRX', 'Gene', (39, 43))	('promoting', 'PosReg', (69, 78))	('ATRX', 'Gene', '546', (39, 43))	('loss', 'Var', (31, 35))	('contribute', 'Reg', (48, 58))	('ALT', 'Disease', (62, 65))	('chromatid exchange', 'CPA', (118, 136))
52695	28135248	We curated a core sample set that consisted of 473 T/N pairs with the most comprehensive molecular profiling and an extended set that consisted of 6,835 T/N pairs with varying numbers of cases profiled by each individual platform (Figure 1a, Online Methods).	('835 T/N', 'Var', (149, 156))	('835 T/N', 'SUBSTITUTION', 'None', (149, 156))	('473 T/N', 'Var', (47, 54))	('473 T/N', 'SUBSTITUTION', 'None', (47, 54))
52696	28135248	TERT promoter (TERTp) mutations, predominantly C250T and C228T, were detected in 27% of the extended set for the cases where TERTp status could be determined (n=1,581).	('C250T', 'Var', (47, 52))	('TERT', 'Gene', '7015', (15, 19))	('C250T', 'Mutation', 'c.250C>T', (47, 52))	('C228T', 'Mutation', 'c.228C>T', (57, 62))	('TERTp', 'Gene', (125, 130))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERTp', 'Gene', '7015', (125, 130))	('TERT', 'Gene', (125, 129))	('C228T', 'Var', (57, 62))	('TERTp', 'Gene', (15, 20))	('TERTp', 'Gene', '7015', (15, 20))	('TERT', 'Gene', '7015', (125, 129))	('TERT', 'Gene', (15, 19))
52697	28135248	In agreement with previous reports; high incidence of TERTp mutations was found in bladder cancer (42/60, 70%), liver cancer (73/162, 45%), melanoma (93/129, 72%), lower grade glioma (127/285, 45%) and glioblastoma (25/28, 89%, Supplementary Figure 4a).	('glioblastoma', 'Disease', 'MESH:D005909', (202, 214))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('TERTp', 'Gene', (54, 59))	('TERTp', 'Gene', '7015', (54, 59))	('glioma', 'Disease', (176, 182))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioblastoma', 'Disease', (202, 214))	('glioblastoma', 'Phenotype', 'HP:0012174', (202, 214))	('liver cancer', 'Disease', 'MESH:D006528', (112, 124))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('liver cancer', 'Phenotype', 'HP:0002896', (112, 124))	('bladder cancer', 'Disease', (83, 97))	('liver cancer', 'Disease', (112, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (60, 69))
52703	28135248	In the majority of TERTp structural variants (65%), at least one predicted super enhancer was found to directly overlap with the juxtaposed position (Supplementary Table 3).	('TERTp', 'Gene', (19, 24))	('TERTp', 'Gene', '7015', (19, 24))	('variants', 'Var', (36, 44))
52712	28135248	Taken together, we found somatic TERT alterations including TERTp mutations, TERT amplifications and TERT structural variants involving gene promoter or gene body in 32% of core set samples.	('TERT', 'Gene', '7015', (101, 105))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (77, 81))	('TERT', 'Gene', '7015', (60, 64))	('variants', 'Var', (117, 125))	('TERT', 'Gene', (101, 105))	('TERTp', 'Gene', (60, 65))	('TERTp', 'Gene', '7015', (60, 65))	('TERT', 'Gene', (60, 64))
52718	28135248	As previously described in pediatric brain tumors, TERT promoter probe cg11625005 demonstrated a strong correlation with TERT expression (Rho=0.52, FDR<0.0001).	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('brain tumors', 'Phenotype', 'HP:0030692', (37, 49))	('pediatric brain tumors', 'Disease', (27, 49))	('TERT', 'Gene', (51, 55))	('correlation', 'Interaction', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cg11625005', 'Var', (71, 81))	('TERT', 'Gene', '7015', (51, 55))	('TERT', 'Gene', (121, 125))	('TERT', 'Gene', '7015', (121, 125))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (27, 49))
52723	28135248	TERTp methylation (two-sided t-test P<0.05) and TERTp mutations (two-sided t-test P<0.0001) were associated with relative TL shortening compared to other types of TERT alterations (Supplementary Figure 5c).	('TERTp', 'Gene', '7015', (0, 5))	('TERT', 'Gene', '7015', (163, 167))	('TERTp', 'Gene', (48, 53))	('TERTp', 'Gene', '7015', (48, 53))	('mutations', 'Var', (54, 63))	('TERT', 'Gene', (0, 4))	('shortening', 'NegReg', (125, 135))	('TERT', 'Gene', (48, 52))	('TERT', 'Gene', '7015', (0, 4))	('methylation', 'Var', (6, 17))	('TERT', 'Gene', (163, 167))	('TERT', 'Gene', '7015', (48, 52))	('TERTp', 'Gene', (0, 5))
52727	28135248	Focal TERC amplifications were associated with increased TERC expression (two-sided t-test P<0.0001) (Supplementary Figure 5d), and were enriched in TERT expressing samples (Odds Ratio (OR) 2.59, Fisher's Exact P<0.0001).	('TERT', 'Gene', '7015', (149, 153))	('TERC', 'Gene', (57, 61))	('TERC', 'Gene', (6, 10))	('amplifications', 'Var', (11, 25))	('TERC', 'Gene', '7012', (57, 61))	('increased', 'PosReg', (47, 56))	('TERT', 'Gene', (149, 153))	('TERC', 'Gene', '7012', (6, 10))
52737	28135248	TERC amplification was additionally associated with higher telomerase signature scores compared to non-amplified samples (two-sided t-test, P<0.0001), which may in part be explained by the co-expression patterns of TERT and TERC.	('TERT', 'Gene', '7015', (215, 219))	('amplification', 'Var', (5, 18))	('TERC', 'Gene', (0, 4))	('TERC', 'Gene', (224, 228))	('higher', 'PosReg', (52, 58))	('telomerase signature scores', 'MPA', (59, 86))	('TERC', 'Gene', '7012', (0, 4))	('TERT', 'Gene', (215, 219))	('TERC', 'Gene', '7012', (224, 228))
52740	28135248	We found alterations of ATRX and IDH1 as the most significantly associated with relative TL elongation (both FDR<0.0001; Figure 3a).	('associated', 'Reg', (64, 74))	('IDH1', 'Gene', (33, 37))	('ATRX', 'Gene', (24, 28))	('alterations', 'Var', (9, 20))	('IDH1', 'Gene', '3417', (33, 37))	('ATRX', 'Gene', '546', (24, 28))
52741	28135248	Since IDH1 mutations frequently co-occur with ATRX in glioma, we tested a model with both tumor type and IDH1 as covariates, and found IDH1 no longer associated with TL ratio (two-sided t-test P=0.15).	('associated', 'Reg', (150, 160))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('mutations', 'Var', (11, 20))	('IDH1', 'Gene', '3417', (6, 10))	('ATRX', 'Gene', '546', (46, 50))	('IDH1', 'Gene', (135, 139))	('IDH1', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH1', 'Gene', '3417', (135, 139))	('IDH1', 'Gene', '3417', (105, 109))	('glioma', 'Disease', (54, 60))	('ATRX', 'Gene', (46, 50))	('IDH1', 'Gene', (6, 10))	('TL ratio', 'MPA', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
52743	28135248	Alterations of the VHL were found to be associated with relative TL shortening (TL ratio 0.7, 95%CI 0.61-0.8, FDR<0.0001).	('relative TL shortening', 'MPA', (56, 78))	('Alterations', 'Var', (0, 11))	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('VHL', 'Disease', (19, 22))
52746	28135248	A linear regression model showed that in addition to older age, positive TERRA expression, TP53 deletion, TP53 mutations, ATRX deletion, ATRX structural variants and absent/undetectable TERT expression were all independently associated with relative TL elongation (Figure 3b-c).	('mutations', 'Var', (111, 120))	('TP53', 'Gene', (91, 95))	('ATRX', 'Gene', (137, 141))	('positive', 'PosReg', (64, 72))	('TP53', 'Gene', '7157', (106, 110))	('ATRX', 'Gene', (122, 126))	('ATRX', 'Gene', '546', (122, 126))	('TP53', 'Gene', '7157', (91, 95))	('ATRX', 'Gene', '546', (137, 141))	('deletion', 'Var', (127, 135))	('deletion', 'Var', (96, 104))	('variants', 'Var', (153, 161))	('associated', 'Reg', (225, 235))	('TERT', 'Gene', (186, 190))	('relative TL elongation', 'CPA', (241, 263))	('TERT', 'Gene', '7015', (186, 190))	('TP53', 'Gene', (106, 110))
52747	28135248	Although DAXX has been linked to telomere length and ALT, DAXX mutations (n=51/6,835) and deletions (n=5/6,835) did not associate with TL.	('mutations', 'Var', (63, 72))	('DAXX', 'Gene', (58, 62))	('DAXX', 'Gene', '1616', (9, 13))	('deletions', 'Var', (90, 99))	('DAXX', 'Gene', (9, 13))	('DAXX', 'Gene', '1616', (58, 62))
52749	28135248	In addition to non-synonymous mutations and deletions, we detected ATRX structural variants from WGS data in 5% of the core set samples (n=26/473).	('variants', 'Var', (83, 91))	('ATRX', 'Gene', (67, 71))	('ATRX', 'Gene', '546', (67, 71))
52755	28135248	We observed a significant decrease in ATRX expression in samples showing mutations, deletions, fusions and structural variants compared to cases with wild type ATRX (Figure 4a).	('ATRX', 'Gene', '546', (160, 164))	('decrease', 'NegReg', (26, 34))	('structural variants', 'Var', (107, 126))	('ATRX', 'Gene', (38, 42))	('fusions', 'Var', (95, 102))	('ATRX', 'Gene', (160, 164))	('ATRX', 'Gene', '546', (38, 42))	('expression', 'MPA', (43, 53))	('mutations', 'Var', (73, 82))	('deletions', 'Var', (84, 93))
52756	28135248	We found that all of types of ATRX alteration associated with significantly longer TL compared to wild type ATRX, consistent with the previously established association between ATRX deactivation and ALT (Figure 4b).	('ATRX', 'Gene', (30, 34))	('ATRX', 'Gene', '546', (177, 181))	('ATRX', 'Gene', (108, 112))	('longer', 'PosReg', (76, 82))	('ATRX', 'Gene', '546', (30, 34))	('alteration', 'Var', (35, 45))	('ATRX', 'Gene', '546', (108, 112))	('ATRX', 'Gene', (177, 181))
52757	28135248	Recent studies found that ATRX knockdown resulted in elevated levels of telomeric repeat containing RNA (TERRA).	('ATRX', 'Gene', '546', (26, 30))	('ATRX', 'Gene', (26, 30))	('knockdown', 'Var', (31, 40))	('elevated', 'PosReg', (53, 61))
52758	28135248	Our results demonstrate a significantly higher fraction of TERRA expressing samples in all groups of ATRX altered samples (Figure 4c, Fisher's Exact test P<0.05) compared to the group of ATRX wild type samples.	('ATRX', 'Gene', '546', (187, 191))	('higher', 'PosReg', (40, 46))	('TERRA expressing', 'MPA', (59, 75))	('ATRX', 'Gene', (187, 191))	('ATRX', 'Gene', (101, 105))	('ATRX', 'Gene', '546', (101, 105))	('altered', 'Var', (106, 113))
52762	28135248	ATRX/DAXX mutations were found in 210 TERT expressing samples, representing 3% of the cohort.	('ATRX', 'Gene', (0, 4))	('DAXX', 'Gene', '1616', (5, 9))	('TERT', 'Gene', (38, 42))	('DAXX', 'Gene', (5, 9))	('ATRX', 'Gene', '546', (0, 4))	('TERT', 'Gene', '7015', (38, 42))	('mutations', 'Var', (10, 19))
52763	28135248	These events were in majority non-truncating, while ATRX/DAXX mutations in TERT-negative cases were mostly truncating (Supplementary Methods, Supplementary Figure 9a).	('non-truncating', 'MPA', (30, 44))	('mutations', 'Var', (62, 71))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('DAXX', 'Gene', '1616', (57, 61))	('ATRX', 'Gene', (52, 56))	('ATRX', 'Gene', '546', (52, 56))	('DAXX', 'Gene', (57, 61))
52764	28135248	TERT-expressing ATRX/DAXX mutants showed higher telomerase signature scores compared to ATRX/DAXX altered samples lacking TERT expression (Supplementary Figure 9b).	('TERT', 'Gene', (122, 126))	('DAXX', 'Gene', '1616', (93, 97))	('TERT', 'Gene', '7015', (122, 126))	('DAXX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (88, 92))	('ATRX', 'Gene', '546', (16, 20))	('TERT', 'Gene', (0, 4))	('DAXX', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (0, 4))	('mutants', 'Var', (26, 33))	('telomerase signature scores', 'MPA', (48, 75))	('higher', 'PosReg', (41, 47))	('DAXX', 'Gene', '1616', (21, 25))	('ATRX', 'Gene', (88, 92))	('ATRX', 'Gene', (16, 20))
52778	28135248	In addition to IDH1 and TP53, RB1 (TL ratio 1.5, 95%CI 1.2-1.87, FDR=0.001) and MDM2 (TL ratio 1.51, 95%CI 1.14-2, FDR=0.01) were revealed to associate with relatively long TLs.	('MDM2', 'Gene', (80, 84))	('IDH1', 'Gene', (15, 19))	('TP53', 'Gene', (24, 28))	('IDH1', 'Gene', '3417', (15, 19))	('RB1', 'Var', (30, 33))	('MDM2', 'Gene', '4193', (80, 84))	('TP53', 'Gene', '7157', (24, 28))
52779	28135248	The finding of RB1 is consistent with experimental data demonstrating markedly elongated telomeres in Rb1 deficient mice independent of telomerase.	('mice', 'Species', '10090', (116, 120))	('telomeres', 'CPA', (89, 98))	('deficient', 'Var', (106, 115))	('elongated', 'PosReg', (79, 88))	('Rb1', 'Gene', (102, 105))	('Rb1', 'Gene', '19645', (102, 105))
52780	28135248	In the opposite direction, somatic alterations in PBRM1 (TL ratio 0.67, 95%CI 0.55-0.83, FDR=0.001), NRAS (TL ratio 0.68, 95%CI 0.52-0.9, FDR=0.02) and VHL (TL ratio 0.7, 95%CI 0.57-0.85, FDR=0.002) were associated with relative TL shortening (Figure 5d).	('NRAS', 'Gene', (101, 105))	('PBRM1', 'Gene', (50, 55))	('alterations', 'Var', (35, 46))	('PBRM1', 'Gene', '55193', (50, 55))	('NRAS', 'Gene', '4893', (101, 105))	('VHL', 'Disease', (152, 155))	('VHL', 'Disease', 'MESH:D006623', (152, 155))
52790	28135248	This paradoxical association between TERT promoter methylation and increased TERT expression may result from loss of CTCF binding, a transcriptional repressor reported to bind to the unmethylated TERT promoter.	('TERT', 'Gene', (37, 41))	('binding', 'Interaction', (122, 129))	('TERT', 'Gene', (77, 81))	('ran', 'Gene', (134, 137))	('TERT', 'Gene', '7015', (37, 41))	('TERT', 'Gene', '7015', (77, 81))	('ran', 'Gene', '5901', (134, 137))	('CTCF', 'Gene', (117, 121))	('loss', 'NegReg', (109, 113))	('TERT', 'Gene', (196, 200))	('TERT', 'Gene', '7015', (196, 200))	('increased', 'PosReg', (67, 76))	('methylation', 'Var', (51, 62))	('CTCF', 'Gene', '10664', (117, 121))
52791	28135248	Structural TERT variants have been documented and we detected these across several novel cancer types, including sarcoma, prostate and liver carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('liver carcinoma', 'Phenotype', 'HP:0001402', (135, 150))	('liver carcinoma', 'Disease', (135, 150))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('prostate', 'Disease', (122, 130))	('liver carcinoma', 'Disease', 'MESH:D006528', (135, 150))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('sarcoma', 'Disease', (113, 120))	('cancer', 'Disease', (89, 95))	('detected', 'Reg', (53, 61))	('TERT', 'Gene', (11, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('TERT', 'Gene', '7015', (11, 15))	('variants', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
52792	28135248	Hepatitis B virus and adeno-associated virus type 2 integration in TERT was found in about 5% of hepatocellular carcinomas.	('TERT', 'Gene', (67, 71))	('integration', 'Var', (52, 63))	('found', 'Reg', (76, 81))	('TERT', 'Gene', '7015', (67, 71))	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (97, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (97, 121))	('Hepatitis B virus', 'Species', '10407', (0, 17))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (97, 122))	('adeno-associated virus type 2', 'Species', '10804', (22, 51))	('hepatocellular carcinomas', 'Disease', (97, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('Hepatitis B virus', 'Disease', (0, 17))
52797	28135248	An estimated 5-10% of TERC and TERRA carry the poly-A tails required for oligo-dT primer based RNA sequencing quantification.	('poly-A', 'Chemical', 'MESH:D011061', (47, 53))	('TERC', 'Gene', '7012', (22, 26))	('TERC', 'Gene', (22, 26))	('poly-A tails', 'Var', (47, 59))
52802	28135248	Deactivation of ATRX and/or DAXX has been related to ALT, and was observed in five percent of the cases in our core set.	('Deactivation', 'Var', (0, 12))	('ATRX', 'Gene', '546', (16, 20))	('DAXX', 'Gene', (28, 32))	('ALT', 'Disease', (53, 56))	('DAXX', 'Gene', '1616', (28, 32))	('related', 'Reg', (42, 49))	('ATRX', 'Gene', (16, 20))
52803	28135248	A detailed review of ATRX somatic changes revealed a large spectrum of potentially protein truncating changes, including inactivating mutations, deletions and structural variants.	('inactivating mutations', 'Var', (121, 143))	('structural variants', 'Var', (159, 178))	('protein truncating changes', 'MPA', (83, 109))	('ATRX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (21, 25))	('deletions', 'Var', (145, 154))
52805	28135248	Our analysis reinforced the association of inactivate ATRX/DAXX and ALT, demonstrating relative TL elongation in samples affected by somatic alterations in one of these two genes and a higher frequency of TERRA expression in tumors with these alterations.	('alterations', 'Var', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('DAXX', 'Gene', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('ATRX', 'Gene', '546', (54, 58))	('TL elongation', 'CPA', (96, 109))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('affected', 'Reg', (121, 129))	('DAXX', 'Gene', '1616', (59, 63))	('tumors', 'Disease', (225, 231))	('ATRX', 'Gene', (54, 58))	('inactivate', 'Var', (43, 53))
52808	28135248	Such mechanisms may involve some RB1 and TP53 alterations, as somatic changes in these genes were associated with telomere elongation within this group.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('telomere elongation', 'CPA', (114, 133))	('RB1', 'Gene', (33, 36))	('changes', 'Var', (70, 77))	('associated', 'Reg', (98, 108))
52827	28135248	There was sufficient coverage for TERTp mutation calling in 903 samples, and we detected TERTp mutations in n=183, including C228T (n=128), C250T (n=49), C242/243T (n=5) and C169T (n=1).	('TERTp', 'Gene', '7015', (89, 94))	('C250T', 'Var', (140, 145))	('C250T', 'Mutation', 'c.250C>T', (140, 145))	('TERTp', 'Gene', '7015', (34, 39))	('C228T', 'Var', (125, 130))	('C169T', 'Var', (174, 179))	('detected', 'Reg', (80, 88))	('C169T', 'Mutation', 'c.169C>T', (174, 179))	('C242/243T', 'Var', (154, 163))	('C228T', 'Mutation', 'c.228C>T', (125, 130))	('TERTp', 'Gene', (89, 94))	('TERTp', 'Gene', (34, 39))
52830	28135248	Because we were only interested in variants involving TERT (chr5:1253287-1315162, including 20kb upstream of the TSS) and ATRX (chrX:76760356-77041719), variants not overlapping one of these regions were excluded.	('ATRX', 'Gene', (122, 126))	('TERT', 'Gene', '7015', (54, 58))	('variants', 'Var', (35, 43))	('chr5:1253287-1315162', 'STRUCTURAL_ABNORMALITY', 'None', (60, 80))	('chrX:76760356-77041719', 'STRUCTURAL_ABNORMALITY', 'None', (128, 150))	('ATRX', 'Gene', '546', (122, 126))	('TERT', 'Gene', (54, 58))
52841	28135248	This analysis found overlapping super-enhancers in 11/17 TERTp structural variants, and this was significantly more than expected by chance (Chi-Square test P=0.001).	('super-enhancers', 'PosReg', (32, 47))	('variants', 'Var', (74, 82))	('TERTp', 'Gene', (57, 62))	('TERTp', 'Gene', '7015', (57, 62))
52842	28135248	For each structural variant proximal (adjacent to the TERT promoter) and distal breakpoint (juxtaposed to the TERT promoter) we calculated the number of reads mapping to each of three histone marks (H3K27ac, H3K27me3 and H3Kme1) individually within each tissue and cell/type.	('H3Kme1', 'Var', (221, 227))	('H3K27ac', 'Var', (199, 206))	('H3K27me3', 'Var', (208, 216))	('TERT', 'Gene', '7015', (54, 58))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', '7015', (110, 114))	('TERT', 'Gene', (54, 58))
52854	28135248	Spearman correlation was used to associate TERT expression and methylation, and to correlate gene expression and TL.	('TERT', 'Gene', (43, 47))	('methylation', 'Var', (63, 74))	('TERT', 'Gene', '7015', (43, 47))
52858	24625245	TP53 p.R337H prevalence in a series of Brazilian hereditary breast cancer families Approximately 5-10% of breast cancers are hereditary.	('p.R337H', 'Mutation', 'rs121912664', (5, 12))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('breast cancers', 'Disease', 'MESH:D001943', (106, 120))	('breast cancers', 'Disease', (106, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('hereditary breast cancer', 'Disease', (49, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancers', 'Phenotype', 'HP:0003002', (106, 120))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (49, 73))	('p.R337H', 'Var', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
52860	24625245	HBOC is due to mutations in the BRCA1 and BRCA2 genes and is characterized by breast adenocarcinoma and/or epithelial ovarian carcinoma.	('BRCA1', 'Gene', (32, 37))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (78, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('BRCA2', 'Gene', '675', (42, 47))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (118, 135))	('breast adenocarcinoma and/or epithelial ovarian carcinoma', 'Disease', 'MESH:D000077216', (78, 135))	('mutations', 'Var', (15, 24))	('BRCA1', 'Gene', '672', (32, 37))	('HBOC', 'Disease', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('due to', 'Reg', (8, 14))	('BRCA2', 'Gene', (42, 47))
52861	24625245	LFS is associated with germline mutations in TP53; the most frequent cancer types associated with this syndrome are sarcoma, breast cancer, leukemia, brain tumors and adrenocortical carcinomas.	('germline mutations', 'Var', (23, 41))	('TP53', 'Gene', (45, 49))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (167, 192))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('adrenocortical carcinomas', 'Disease', (167, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('LFS', 'Disease', (0, 3))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('sarcoma', 'Disease', 'MESH:D012509', (116, 123))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('LFS', 'Disease', 'MESH:D016864', (0, 3))	('breast cancer', 'Disease', (125, 138))	('sarcoma', 'Disease', (116, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (167, 191))	('TP53', 'Gene', '7157', (45, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (167, 192))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('brain tumors', 'Disease', 'MESH:D001932', (150, 162))	('brain tumors', 'Phenotype', 'HP:0030692', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('cancer', 'Disease', (69, 75))	('cancer', 'Disease', (132, 138))	('leukemia', 'Disease', (140, 148))	('leukemia', 'Disease', 'MESH:D007938', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('brain tumors', 'Disease', (150, 162))
52863	24625245	In Brazil, especially in the southern part of the country, a specific mutation in the TP53 gene, TP53 p.R337H, occurs at a high frequency in childhood adrenocortical tumors.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (151, 172))	('p.R337H', 'Var', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', '7157', (97, 101))	('p.R337H', 'Mutation', 'rs121912664', (102, 109))	('TP53', 'Gene', (86, 90))	('TP53', 'Gene', (97, 101))	('adrenocortical tumors', 'Disease', (151, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
52865	24625245	We carried out a case-control study to determine the prevalence of the TP53 p.R337H mutation in 28 female cancer patients attended at the Cancer Genetic Counseling Service of the General Hospital of the University of Sao Paulo Medical School of Ribeirao Preto who fulfilled Hereditary Breast and Ovary Cancer Syndrome genetic test criteria compared to healthy woman (controls).	('Hereditary Breast and Ovary Cancer', 'Disease', 'MESH:D061325', (274, 308))	('patients', 'Species', '9606', (113, 121))	('Cancer', 'Phenotype', 'HP:0002664', (302, 308))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('woman', 'Species', '9606', (360, 365))	('p.R337H', 'Var', (76, 83))	('TP53', 'Gene', '7157', (71, 75))	('Cancer', 'Phenotype', 'HP:0002664', (138, 144))	('TP53', 'Gene', (71, 75))	('Ovary Cancer', 'Phenotype', 'HP:0100615', (296, 308))	('p.R337H', 'Mutation', 'rs121912664', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
52866	24625245	TP53 p.R337H mutation status was determined using the High Resolution Melting (HRM) method, followed by DNA sequencing.	('p.R337H', 'Mutation', 'rs121912664', (5, 12))	('p.R337H', 'Var', (5, 12))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))
52867	24625245	Fisher's test was used to compare the prevalence of TP53 p.R337H in the patient and control groups.	('p.R337H', 'Mutation', 'rs121912664', (57, 64))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))	('patient', 'Species', '9606', (72, 79))	('p.R337H', 'Var', (57, 64))
52868	24625245	Two of the breast cancer cases (7.1%) and none of the controls carried the TP53 p.R337H mutation.	('p.R337H', 'Mutation', 'rs121912664', (80, 87))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Disease', (11, 24))	('p.R337H', 'Var', (80, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
52870	24625245	We suggest that genetic screening of Brazilian breast cancer patients who fulfill Hereditary Breast and Ovary Cancer Syndrome criteria and have a family history that includes other tumors of the LFS/LFL spectrum be tested for the TP53 p.R337H mutation.	('breast cancer', 'Disease', (47, 60))	('p.R337H', 'Mutation', 'rs121912664', (235, 242))	('LFS', 'Disease', (195, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('tumors', 'Disease', (181, 187))	('TP53', 'Gene', (230, 234))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('Hereditary Breast and Ovary Cancer', 'Disease', 'MESH:D061325', (82, 116))	('patients', 'Species', '9606', (61, 69))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('LFS', 'Disease', 'MESH:D016864', (195, 198))	('Ovary Cancer', 'Phenotype', 'HP:0100615', (104, 116))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('p.R337H', 'Var', (235, 242))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('TP53', 'Gene', '7157', (230, 234))
52875	24625245	HBOC is due to mutations in the BRCA1 and BRCA2 genes; it is characterized by ductal or lobular breast adenocarcinoma and epithelial ovarian carcinoma.	('BRCA1', 'Gene', (32, 37))	('lobular breast adenocarcinoma and epithelial ovarian carcinoma', 'Disease', 'MESH:D000077216', (88, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('BRCA2', 'Gene', '675', (42, 47))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (133, 150))	('mutations', 'Var', (15, 24))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (96, 117))	('BRCA1', 'Gene', '672', (32, 37))	('HBOC', 'Disease', (0, 4))	('due to', 'Reg', (8, 14))	('BRCA2', 'Gene', (42, 47))
52876	24625245	In 1990, LFS was found to be associated with germline mutations in TP53.	('LFS', 'Disease', 'MESH:D016864', (9, 12))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('associated', 'Reg', (29, 39))	('LFS', 'Disease', (9, 12))	('germline mutations', 'Var', (45, 63))
52877	24625245	Pathogenic mutation carriers for this gene have a cumulative risk of up to 90% for the development of a cancer spectrum, which is usually diagnosed before the age of 45.	('mutation', 'Var', (11, 19))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
52884	24625245	(2013) estimated an overall frequency of 0.2-0.3% for TP53 p.R337H in a southern Brazil state.	('p.R337H', 'Var', (59, 66))	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', (54, 58))	('p.R337H', 'Mutation', 'rs121912664', (59, 66))
52886	24625245	It also has been proposed that this mutation increases breast cancer risk in women, especially in southern Brazil.	('increases', 'PosReg', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('women', 'Species', '9606', (77, 82))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('mutation', 'Var', (36, 44))
52887	24625245	The frequency of TP53 p.R337H in women with breast cancer has been reported as 2.4%, while in healthy women it is only 0.3%.	('p.R337H', 'Mutation', 'rs121912664', (22, 29))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('women', 'Species', '9606', (33, 38))	('breast cancer', 'Disease', (44, 57))	('women', 'Species', '9606', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('p.R337H', 'Var', (22, 29))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
52888	24625245	Given this potential association with breast cancer and the high frequency of TP53 p.R337H in southern Brazil, we conducted a case-control study to compare TP53 p.R337H mutation prevalence in healthy controls with that in female breast cancer patients in Ribeirao Preto, Sao Paulo state, located in southeast Brazil.	('p.R337H', 'Var', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('patients', 'Species', '9606', (243, 251))	('association', 'Interaction', (21, 32))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('p.R337H', 'Var', (83, 90))	('p.R337H', 'Mutation', 'rs121912664', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('breast cancer', 'Disease', (38, 51))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('p.R337H', 'Mutation', 'rs121912664', (83, 90))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('breast cancer', 'Disease', (229, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))
52895	24625245	The HRM method was used to detect the TP53 p.R337H mutation.	('TP53', 'Gene', (38, 42))	('p.R337H', 'Mutation', 'rs121912664', (43, 50))	('p.R337H', 'Var', (43, 50))	('TP53', 'Gene', '7157', (38, 42))
52900	24625245	The TP53 p.R337H mutation frequency in breast cancer patients and controls was compared using Fisher's exact test with GraphPad Prism 5 software to calculate odds ratios (OR), with confidence intervals (CIs) of 95%.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('patients', 'Species', '9606', (53, 61))	('TP53', 'Gene', (4, 8))	('p.R337H', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('p.R337H', 'Mutation', 'rs121912664', (9, 16))	('TP53', 'Gene', '7157', (4, 8))	('breast cancer', 'Disease', (39, 52))
52901	24625245	The TP53 p.R337H frequency in breast cancer patients was compared to the estimated Brazilian population frequency, which we assumed to be the true prevalence rate for the Brazilian population, using the one-sided exact test for binomial proportions.	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('patients', 'Species', '9606', (44, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('TP53', 'Gene', (4, 8))	('breast cancer', 'Disease', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('p.R337H', 'Var', (9, 16))	('p.R337H', 'Mutation', 'rs121912664', (9, 16))	('TP53', 'Gene', '7157', (4, 8))
52902	24625245	Twenty-eight women diagnosed with breast cancer were tested for TP53 mutations; two of them (7.1%) were found to carry a pathogenic mutation, heterozygous TP53 p.R337H (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('TP53', 'Gene', '7157', (155, 159))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('TP53', 'Gene', (155, 159))	('p.R337H', 'Var', (160, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('women', 'Species', '9606', (13, 18))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('p.R337H', 'Mutation', 'rs121912664', (160, 167))
52903	24625245	Both are negative for BRCA1 and BRCA2 pathogenic mutations.	('mutations', 'Var', (49, 58))	('BRCA2', 'Gene', (32, 37))	('BRCA1', 'Gene', '672', (22, 27))	('BRCA2', 'Gene', '675', (32, 37))	('BRCA1', 'Gene', (22, 27))
52904	24625245	TP53 p.R337H is known to be more frequent in women with breast cancer, especially in families in southern Brazil suspected to have Li-Fraumeni Syndrome.	('p.R337H', 'Mutation', 'rs121912664', (5, 12))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('p.R337H', 'Var', (5, 12))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (131, 151))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('women', 'Species', '9606', (45, 50))	('Li-Fraumeni Syndrome', 'Disease', (131, 151))
52911	24625245	Both had the same TP53 mutation; they were heterozygous for TP53 p.R337H.	('TP53', 'Gene', '7157', (18, 22))	('p.R337H', 'Var', (65, 72))	('TP53', 'Gene', (18, 22))	('p.R337H', 'Mutation', 'rs121912664', (65, 72))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))
52921	24625245	In comparison with the two of 28 HBOC breast cancer women patients who had the TP53 p.R337H mutation, none of the 120 healthy women without family history of cancer had this mutation.	('p.R337H', 'Mutation', 'rs121912664', (84, 91))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('women', 'Species', '9606', (126, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('p.R337H', 'Var', (84, 91))	('women', 'Species', '9606', (52, 57))	('HBOC breast cancer', 'Disease', (33, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('patients', 'Species', '9606', (58, 66))	('HBOC breast cancer', 'Disease', 'MESH:D061325', (33, 51))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
52922	24625245	We found a significant association of TP53 p.R337H mutation with breast cancer (p = 0.0347; Table 5).	('p.R337H', 'Mutation', 'rs121912664', (43, 50))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('TP53', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('p.R337H', 'Var', (43, 50))	('TP53', 'Gene', '7157', (38, 42))
52923	24625245	Comparing our results with the overall frequency of TP53 p.R337H in southern Brazil, assumed by Custodio et al.	('p.R337H', 'Mutation', 'rs121912664', (57, 64))	('p.R337H', 'Var', (57, 64))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))
52924	24625245	(2013) to be in the range of 0.2-0.3%, we found that the TP53 p.R337H mutation frequency was significantly higher among breast cancer women with HBOC than in the general Brazilian population (p = 0.001 and 0.003 in comparison to 0.2 and 0.3%, respectively; one-sided exact binomial test).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('p.R337H', 'Var', (62, 69))	('women', 'Species', '9606', (134, 139))	('p.R337H', 'Mutation', 'rs121912664', (62, 69))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('higher', 'PosReg', (107, 113))
52925	24625245	Based on our study, we suggest that TP53 p.R337H mutation prevalence in breast cancer patients suspected of HBOC in Ribeirao Preto, Sao Paulo, Brazil is high (7.1%).	('p.R337H', 'Var', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TP53', 'Gene', (36, 40))	('TP53', 'Gene', '7157', (36, 40))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('p.R337H', 'Mutation', 'rs121912664', (41, 48))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('patients', 'Species', '9606', (86, 94))
52931	24625245	However, the pathogenicity of TP53 p.R337H is still questionable due to the low number of functional studies.	('TP53', 'Gene', (30, 34))	('p.R337H', 'Mutation', 'rs121912664', (35, 42))	('p.R337H', 'Var', (35, 42))	('TP53', 'Gene', '7157', (30, 34))
52932	24625245	(2007) screened for the TP53 p.R337H mutation in 45 Brazilian subjects from unrelated families with cancer histories suggestive of LFS.	('LFS', 'Disease', 'MESH:D016864', (131, 134))	('p.R337H', 'Mutation', 'rs121912664', (29, 36))	('TP53', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('p.R337H', 'Var', (29, 36))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('LFS', 'Disease', (131, 134))	('TP53', 'Gene', '7157', (24, 28))
52935	24625245	Three of the cases (2.4%) and none of the controls were carriers of the TP53 p.R337H mutation (P = 0.04).	('p.R337H', 'Var', (77, 84))	('TP53', 'Gene', (72, 76))	('TP53', 'Gene', '7157', (72, 76))	('p.R337H', 'Mutation', 'rs121912664', (77, 84))
52937	24625245	The role of the TP53 p.R337H mutation in breast carcinogenesis is still unclear.	('p.R337H', 'Var', (21, 28))	('breast carcinogenesis', 'Disease', (41, 62))	('p.R337H', 'Mutation', 'rs121912664', (21, 28))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (41, 62))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))
52938	24625245	(2007) found that, in an invasive ductal breast adenocarcinoma sample, the TP53 p.R337H mutation was homozygous in tumor tissue and heterozygous in peripheral blood, suggesting a role in tumor development.	('p.R337H', 'Mutation', 'rs121912664', (80, 87))	('invasive ductal breast adenocarcinoma', 'Disease', (25, 62))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('TP53', 'Gene', '7157', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (115, 120))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (41, 62))	('tumor', 'Disease', (187, 192))	('p.R337H', 'Var', (80, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('invasive ductal breast adenocarcinoma', 'Disease', 'MESH:D018270', (25, 62))	('TP53', 'Gene', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
52939	24625245	(2008) found the mutant TP53 p.R337H allele to be absent in the three breast tumors examined.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('breast tumors', 'Disease', (70, 83))	('p.R337H', 'Mutation', 'rs121912664', (29, 36))	('TP53', 'Gene', (24, 28))	('breast tumors', 'Phenotype', 'HP:0100013', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('p.R337H', 'Var', (29, 36))	('breast tumors', 'Disease', 'MESH:D001943', (70, 83))	('TP53', 'Gene', '7157', (24, 28))
52940	24625245	(2012) evaluated TP53 p.R337H mutation frequency in 390 unselected breast cases and 324 controls from Rio de Janeiro state.	('p.R337H', 'Mutation', 'rs121912664', (22, 29))	('breast', 'Disease', (67, 73))	('p.R337H', 'Var', (22, 29))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
52943	24625245	Our study shows that TP53 p.R337H is found in women who fulfill HBOC genetic testing criteria but not the LFS criteria, according to NCCN Clinical Practice Guidelines in Oncology v.1.2010.	('TP53', 'Gene', (21, 25))	('p.R337H', 'Mutation', 'rs121912664', (26, 33))	('LFS', 'Disease', (106, 109))	('Oncology', 'Phenotype', 'HP:0002664', (170, 178))	('p.R337H', 'Var', (26, 33))	('LFS', 'Disease', 'MESH:D016864', (106, 109))	('women', 'Species', '9606', (46, 51))	('TP53', 'Gene', '7157', (21, 25))
52946	24625245	This fact, associated with the apparently high frequency of TP53 p.R337H mutation in the population that we analyzed, reinforces the necessity of adjusting genetic testing criteria for hereditary syndromes according to local populations characteristics.	('hereditary syndromes', 'Disease', (185, 205))	('p.R337H', 'Var', (65, 72))	('p.R337H', 'Mutation', 'rs121912664', (65, 72))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('hereditary syndromes', 'Disease', 'MESH:D009386', (185, 205))
52947	24625245	It has been suggested that TP53 genetic testing should be considered for women diagnosed with breast cancer under age 30 after they have previously tested negative for mutations in BRCA1 and BRCA2.	('BRCA1', 'Gene', '672', (181, 186))	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('women', 'Species', '9606', (73, 78))	('BRCA1', 'Gene', (181, 186))	('BRCA2', 'Gene', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRCA2', 'Gene', '675', (191, 196))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('mutations', 'Var', (168, 177))
52951	24625245	Nevertheless, the association of TP53 p.R337H mutation with breast cancer that we found is enough to lead us to suggest that TP53 p.R337H mutation screening should be conducted at the same time as BRCA testing and not necessarily only after patients have previously tested negative for BRCA gene mutations.	('breast cancer', 'Disease', (60, 73))	('TP53', 'Gene', '7157', (125, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('BRCA', 'Gene', '672', (286, 290))	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (125, 129))	('BRCA', 'Gene', (286, 290))	('p.R337H', 'Mutation', 'rs121912664', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TP53', 'Gene', (33, 37))	('BRCA', 'Gene', '672', (197, 201))	('p.R337H', 'Var', (130, 137))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('patients', 'Species', '9606', (241, 249))	('BRCA', 'Gene', (197, 201))	('p.R337H', 'Mutation', 'rs121912664', (130, 137))
52953	24625245	Our study shows that TP53 p.R337H mutation prevalence in breast cancer patients suspected of Hereditary Breast and Ovary Cancer Syndrome in Ribeirao Preto, Sao Paulo, Brazil is high (7.1%) and could play an important role in predisposition to breast cancer in this population.	('breast cancer', 'Disease', (243, 256))	('TP53', 'Gene', (21, 25))	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('p.R337H', 'Mutation', 'rs121912664', (26, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('patients', 'Species', '9606', (71, 79))	('Cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Hereditary Breast and Ovary Cancer', 'Disease', 'MESH:D061325', (93, 127))	('p.R337H', 'Var', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('Ovary Cancer', 'Phenotype', 'HP:0100615', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('TP53', 'Gene', '7157', (21, 25))
52955	24625245	We propose that TP53 p.R337H mutation screening be conducted in Brazilian women who have been diagnosed with breast cancer at any age, who fulfill Hereditary Breast and Ovary Cancer Syndrome genetic testing criteria and have a family history that includes other tumors of the LFS/LFL spectrum.	('LFS', 'Disease', 'MESH:D016864', (276, 279))	('p.R337H', 'Var', (21, 28))	('breast cancer', 'Disease', (109, 122))	('women', 'Species', '9606', (74, 79))	('Ovary Cancer', 'Phenotype', 'HP:0100615', (169, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('p.R337H', 'Mutation', 'rs121912664', (21, 28))	('tumors', 'Disease', (262, 268))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('Hereditary Breast and Ovary Cancer', 'Disease', 'MESH:D061325', (147, 181))	('LFS', 'Disease', (276, 279))	('TP53', 'Gene', '7157', (16, 20))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TP53', 'Gene', (16, 20))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
52995	24499519	CNC is characterized by two or more major manifestations of the syndrome, including lentigines, cutaneous and/or cardiac myxomas, breast myxomatosis, breast ductal adenoma, testicular Sertoli cell tumors, breast tumors, PPNAD, acromegaly, blue nevus, osteochondromyxoma, thyroid carcinoma and mutation of the PRKAR1a gene .	('cardiac myxomas', 'Disease', 'MESH:D009232', (113, 128))	('acromegaly', 'Phenotype', 'HP:0000845', (227, 237))	('breast ductal adenoma', 'Disease', 'MESH:D000236', (150, 171))	('PRKAR1a', 'Gene', (309, 316))	('acromegaly', 'Disease', (227, 237))	('cardiac myxoma', 'Phenotype', 'HP:0011672', (113, 127))	('lentigines', 'Disease', (84, 94))	('PRKAR1a', 'Gene', '5573', (309, 316))	('osteochondromyxoma', 'Disease', 'None', (251, 269))	('man', 'Species', '9606', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('testicular Sertoli cell tumors', 'Disease', 'MESH:D012707', (173, 203))	('blue nevus', 'Disease', (239, 249))	('blue nevus', 'Phenotype', 'HP:0100814', (239, 249))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('PPNAD', 'Disease', (220, 225))	('breast tumors', 'Disease', (205, 218))	('breast tumors', 'Disease', 'MESH:D001943', (205, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('cardiac myxomas', 'Disease', (113, 128))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (271, 288))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (184, 203))	('cardiac myxomas', 'Phenotype', 'HP:0011672', (113, 128))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('nevus', 'Phenotype', 'HP:0003764', (244, 249))	('breast tumors', 'Phenotype', 'HP:0100013', (205, 218))	('thyroid carcinoma', 'Disease', (271, 288))	('breast myxomatosis', 'Disease', 'MESH:D009234', (130, 148))	('PPNAD', 'Chemical', '-', (220, 225))	('osteochondromyxoma', 'Disease', (251, 269))	('mutation', 'Var', (293, 301))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (271, 288))	('breast myxomatosis', 'Disease', (130, 148))	('testicular Sertoli cell tumors', 'Disease', (173, 203))	('acromegaly', 'Disease', 'MESH:D000172', (227, 237))	('breast ductal adenoma', 'Disease', (150, 171))
53015	24499519	In most cases, CNC is caused by inactivating mutations in the gene encoding for the protein kinase A type 1A regulatory subunit (PRKAR1A), which is a tumor suppressor.	('PRKAR1A', 'Gene', (129, 136))	('protein kinase A type 1A regulatory subunit', 'Gene', (84, 127))	('protein kinase A type 1A regulatory subunit', 'Gene', '5573', (84, 127))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('caused by', 'Reg', (22, 31))	('PRKAR1A', 'Gene', '5573', (129, 136))	('inactivating mutations', 'Var', (32, 54))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('CNC', 'Disease', (15, 18))
53016	24499519	Mutations in this gene also cause endocrine tumors in CNC .	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cause', 'Reg', (28, 33))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('endocrine tumors', 'Disease', 'MESH:D004701', (34, 50))	('endocrine tumors', 'Disease', (34, 50))
53017	24499519	Over 70% of patients with CNC with a classical phenotype show a PRKAR1A mutation .	('patients', 'Species', '9606', (12, 20))	('PRKAR1A', 'Gene', (64, 71))	('PRKAR1A', 'Gene', '5573', (64, 71))	('mutation', 'Var', (72, 80))	('CNC', 'Disease', (26, 29))
53018	24499519	PRKAR1A mutations were observed in 80% of the familial cases compared to 37% of the sporadic CNC cases.	('observed', 'Reg', (23, 31))	('PRKAR1A', 'Gene', '5573', (0, 7))	('PRKAR1A', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))
53019	24499519	The overall penetrance of CNC in patients with PRKAR1A mutations is 97.5% .	('patients', 'Species', '9606', (33, 41))	('PRKAR1A', 'Gene', (47, 54))	('mutations', 'Var', (55, 64))	('PRKAR1A', 'Gene', '5573', (47, 54))	('CNC', 'Disease', (26, 29))
53053	22209747	In cases of classical familial cancer susceptibility syndromes, single gene mutations confer tumor susceptibility.	('familial cancer', 'Disease', 'MESH:D009369', (22, 37))	('single gene mutations', 'Var', (64, 85))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('familial cancer', 'Disease', (22, 37))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
53063	22209747	Indeed, it is estimated that a significant amount of TP53 mutation-caused childhood ACCs are due to de novo germline TP53 mutations.	('mutation-caused', 'Var', (58, 73))	('child', 'Species', '9606', (74, 79))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('mutations', 'Var', (122, 131))	('ACCs', 'Gene', (84, 88))	('TP53', 'Gene', '7157', (53, 57))	('ACCs', 'Gene', '84680', (84, 88))	('TP53', 'Gene', (53, 57))	('due', 'Reg', (93, 96))
53065	22209747	Syndrome-associated gene mutations are generally inherited in a dominant fashion, resulting in a 50% chance for offspring to inherit the cancer susceptibility mutation.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('Syndrome-associated gene', 'Gene', (0, 24))
53070	22209747	In general, it is estimated that ~10% of all cancers are caused by single germline mutations conferring increased cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('germline mutations', 'Var', (74, 92))	('caused', 'Reg', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('cancer', 'Disease', (114, 120))
53089	22209747	It is estimated that germline TP53 mutations can be detected in 80% of children with ACC.	('TP53', 'Gene', '7157', (30, 34))	('TP53', 'Gene', (30, 34))	('children', 'Species', '9606', (71, 79))	('mutations', 'Var', (35, 44))
53095	22209747	As mentioned above, the majority of childhood ACC occurs in patients with germline TP53 mutations (~80%), but only 6.5-9.9% of all LFS patients will be diagnosed with ACC.	('occurs', 'Reg', (50, 56))	('TP53', 'Gene', '7157', (83, 87))	('patients', 'Species', '9606', (135, 143))	('LFS', 'Disease', 'MESH:D016864', (131, 134))	('childhood ACC', 'Disease', (36, 49))	('TP53', 'Gene', (83, 87))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (88, 97))	('child', 'Species', '9606', (36, 41))	('LFS', 'Disease', (131, 134))	('germline', 'Var', (74, 82))
53096	22209747	In the United States, mutations in TP53 in affected children are diverse.	('children', 'Species', '9606', (52, 60))	('TP53', 'Gene', '7157', (35, 39))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (35, 39))
53098	22209747	It was initially believed, that the R337H mutation exclusively causes pediatric ACC as a relatively low penetrance allele.	('R337H', 'Mutation', 'rs121912664', (36, 41))	('R337H', 'Var', (36, 41))	('pediatric ACC', 'Disease', (70, 83))	('causes', 'Reg', (63, 69))
53099	22209747	However, over recent years it has become clear that this mutation is due to a founder effect and segregates with tumor development in LFS or LFS-like families, although its penetrance is lower than that of most other LFS causing TP53 mutations (.	('mutation', 'Var', (57, 65))	('tumor', 'Disease', (113, 118))	('LFS', 'Disease', 'MESH:D016864', (217, 220))	('LFS', 'Disease', (134, 137))	('LFS', 'Disease', (217, 220))	('TP53', 'Gene', '7157', (229, 233))	('LFS', 'Disease', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('LFS', 'Disease', 'MESH:D016864', (134, 137))	('TP53', 'Gene', (229, 233))	('LFS', 'Disease', 'MESH:D016864', (141, 144))	('mutations', 'Var', (234, 243))
53100	22209747	It is unclear to what extent germline TP53 mutations contribute to ACC development in the adult population.	('contribute', 'Reg', (53, 63))	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('ACC development', 'CPA', (67, 82))	('TP53', 'Gene', '7157', (38, 42))
53101	22209747	in which they analyzed all patient samples sent to their institution for TP53 gene testing, 14/21 (66%) ACC patients carried germline TP53 mutations.	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('TP53', 'Gene', (73, 77))	('patient', 'Species', '9606', (27, 34))	('patient', 'Species', '9606', (108, 115))	('patients', 'Species', '9606', (108, 116))	('TP53', 'Gene', '7157', (134, 138))
53104	22209747	Furthermore, the study may well have a referral bias, as it may be assumed that physicians sent samples for germline DNA testing based not only on the ACC diagnosis, but also on other clinical findings that suggest LFS or TP53 mutations.	('LFS', 'Disease', 'MESH:D016864', (215, 218))	('TP53', 'Gene', '7157', (222, 226))	('LFS', 'Disease', (215, 218))	('TP53', 'Gene', (222, 226))	('mutations', 'Var', (227, 236))
53106	22209747	This disease is caused by mutations of a genetic locus on chromosome 11p15, which harbors the IGF2 gene, as well as several other genes.	('mutations', 'Var', (26, 35))	('IGF2', 'Gene', (94, 98))	('IGF2', 'Gene', '3481', (94, 98))	('caused by', 'Reg', (16, 25))
53107	22209747	Commonly, mutations result in a relative increase in IGF2 expression.	('IGF2', 'Gene', '3481', (53, 57))	('expression', 'MPA', (58, 68))	('IGF2', 'Gene', (53, 57))	('mutations', 'Var', (10, 19))	('increase', 'PosReg', (41, 49))
53139	22209747	The only general genetic screening recommendation that can be deduced from the current literature is testing for alterations of the TP53 gene.	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('alterations', 'Var', (113, 124))
53141	22209747	Testing should be encouraged until more evidence accumulates regarding germline TP53 mutations in the adult ACC population.	('mutations', 'Var', (85, 94))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))
53155	22209747	While there had not been extensive studies addressing the question of screening for cancers in LFS patients, a very recent study showed that a screening program is feasible and that screening related early detection of tumors may translate into decreased mortality amongst TP53 mutation carriers.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mortality', 'MPA', (255, 264))	('tumors', 'Disease', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('LFS', 'Disease', 'MESH:D016864', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('cancers', 'Disease', (84, 91))	('patients', 'Species', '9606', (99, 107))	('decreased', 'NegReg', (245, 254))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (273, 277))	('mutation', 'Var', (278, 286))	('LFS', 'Disease', (95, 98))	('TP53', 'Gene', (273, 277))
53159	22209747	In accordance with this recommendation children with known germline TP53 mutation should be followed for abnormal sexual development, precocious puberty as a possible manifestation of excess sex steroid secretion, or symptoms and signs of Cushing syndrome.	('abnormal sexual development', 'Phenotype', 'HP:0100000', (105, 132))	('TP53', 'Gene', (68, 72))	('abnormal sexual development', 'CPA', (105, 132))	('excess sex steroid secretion', 'Disease', (184, 212))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (239, 255))	('Cushing syndrome', 'Disease', (239, 255))	('precocious puberty', 'CPA', (134, 152))	('precocious puberty', 'Phenotype', 'HP:0000826', (134, 152))	('Cushing syndrome', 'Disease', 'MESH:D003480', (239, 255))	('children', 'Species', '9606', (39, 47))	('TP53', 'Gene', '7157', (68, 72))	('mutation', 'Var', (73, 81))	('excess sex steroid secretion', 'Disease', 'MESH:D012735', (184, 212))
53211	32751564	Afterwards, slices were incubated overnight with both primary antibodies anti-CYP11B1 (1:30) and anti-CYP11B2 (1:200) at 4  C. Slides were then incubated for 2 h with a cocktail containing a fluorescent secondary antibody goat anti-rat (1:200, #4417, Cell Signaling Technology, Danvers, MA, USA) and goat anti-mouse (1:750, #4408S, Cell Signaling Technology, Danvers, MA, United States).	('CYP11B2', 'Gene', (102, 109))	('1:750', 'Var', (317, 322))	('CYP11B2', 'Gene', '1585', (102, 109))	('CYP11B1', 'Gene', (78, 85))	('CYP11B1', 'Gene', '1584', (78, 85))	('1:200', 'Var', (111, 116))
53258	32287321	CCNB2 and AURKA overexpression may cause atypical mitosis in Japanese cortisol-producing adrenocortical carcinoma with TP53 somatic variant Many genomic analyses of cortisol-producing adrenocortical carcinoma (ACC) have been reported, but very few have come from East Asia.	('CCNB2', 'Gene', (0, 5))	('AURKA', 'Gene', '6790', (10, 15))	('TP53', 'Gene', '7157', (119, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('AURKA', 'Gene', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (184, 208))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (89, 113))	('mitosis', 'MPA', (50, 57))	('cortisol', 'Chemical', 'MESH:D006854', (165, 173))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (184, 208))	('atypical', 'MPA', (41, 49))	('CCNB2', 'Gene', '9133', (0, 5))	('cortisol', 'Chemical', 'MESH:D006854', (70, 78))	('TP53', 'Gene', (119, 123))	('adrenocortical carcinoma', 'Disease', (184, 208))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (89, 113))	('variant', 'Var', (132, 139))	('overexpression', 'PosReg', (16, 30))	('adrenocortical carcinoma', 'Disease', (89, 113))	('cause', 'Reg', (35, 40))
53261	32287321	The hypothesis was obtained by integrating the somatic variant findings with clinical and pathological data, and it was further verified using The Cancer Genome Atlas (TCGA) dataset for ACC.	('variant', 'Var', (55, 62))	('Cancer', 'Disease', 'MESH:D009369', (147, 153))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Cancer', 'Disease', (147, 153))
53262	32287321	Six possible pathogenic and one uncertain significance somatic variants including a novel PRKAR1A (NM_002734.4):c.545C>A (p.T182K) variant were found in five of seven cases.	('p.T182K', 'Mutation', 'p.T182K', (122, 129))	('PRKAR1A', 'Gene', '5573', (90, 97))	('c.545C>A', 'Mutation', 'c.545C>A', (112, 120))	('PRKAR1A', 'Gene', (90, 97))	('c.545C>A', 'Var', (112, 120))
53263	32287321	By integrating these data with pathological findings, we hypothesized that cases with TP53 variants were more likely to show atypical mitotic figures.	('TP53', 'Gene', (86, 90))	('variants', 'Var', (91, 99))	('TP53', 'Gene', '7157', (86, 90))
53264	32287321	Using TCGA dataset, we found that atypical mitotic figures were associated with TP53 somatic variant, and mRNA expression of CCNB2 and AURKA was significantly high in TP53 mutated cases and atypical mitotic figure cases.	('CCNB2', 'Gene', '9133', (125, 130))	('associated', 'Reg', (64, 74))	('high', 'PosReg', (159, 163))	('AURKA', 'Gene', '6790', (135, 140))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('AURKA', 'Gene', (135, 140))	('mRNA expression', 'MPA', (106, 121))	('atypical mitotic figures', 'CPA', (34, 58))	('TP53', 'Gene', '7157', (167, 171))	('CCNB2', 'Gene', (125, 130))	('mutated', 'Var', (172, 179))	('TP53', 'Gene', (167, 171))
53266	32287321	We presumed that overexpression of CCNB2 and AURKA mRNA may cause atypical mitosis in TP53 somatic mutated cases.	('cause', 'Reg', (60, 65))	('AURKA', 'Gene', '6790', (45, 50))	('TP53', 'Gene', '7157', (86, 90))	('AURKA', 'Gene', (45, 50))	('TP53', 'Gene', (86, 90))	('mutated', 'Var', (99, 106))	('overexpression', 'PosReg', (17, 31))	('CCNB2', 'Gene', (35, 40))	('CCNB2', 'Gene', '9133', (35, 40))
53279	32287321	However, how the somatic variant in TP53 or CTNNB1 affects clinical and pathological findings and leads to poor prognosis of ACC is not fully elucidated.	('CTNNB1', 'Gene', (44, 50))	('ACC', 'Disease', (125, 128))	('TP53', 'Gene', '7157', (36, 40))	('CTNNB1', 'Gene', '1499', (44, 50))	('variant', 'Var', (25, 32))	('TP53', 'Gene', (36, 40))	('affects', 'Reg', (51, 58))
53281	32287321	Previous studies suggested that the low-prevalence somatic variants affect tumorigenesis; therefore, high-sensitivity variant screening methods are required for cancer genome analysis.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('variants', 'Var', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', (161, 167))	('affect', 'Reg', (68, 74))	('tumor', 'Disease', (75, 80))
53283	32287321	Ten genes (APC, CCNE1, CDK4, CDKN2A, CTNNB1, MDM2, MEN1, RB1, TP53, and ZNRF3) involved in TP53-RB1 and Wnt pathways were selected because TP53 and CTNNB1 somatic variants have been reported as poor prognostic factors in ACC.	('CCNE1', 'Gene', (16, 21))	('CDKN2A', 'Gene', '1029', (29, 35))	('RB1', 'Gene', '5925', (96, 99))	('TP53', 'Gene', (62, 66))	('MDM2', 'Gene', '4193', (45, 49))	('CDK4', 'Gene', '1019', (23, 27))	('variants', 'Var', (163, 171))	('ZNRF3', 'Gene', '84133', (72, 77))	('ZNRF3', 'Gene', (72, 77))	('CTNNB1', 'Gene', (148, 154))	('CCNE1', 'Gene', '898', (16, 21))	('RB1', 'Gene', '5925', (57, 60))	('TP53', 'Gene', (139, 143))	('TP53', 'Gene', (91, 95))	('TP53', 'Gene', '7157', (62, 66))	('MEN1', 'Gene', '4221', (51, 55))	('APC', 'Disease', 'MESH:D011125', (11, 14))	('ACC', 'Disease', (221, 224))	('CTNNB1', 'Gene', '1499', (37, 43))	('APC', 'Disease', (11, 14))	('RB1', 'Gene', (96, 99))	('CDKN2A', 'Gene', (29, 35))	('MEN1', 'Gene', (51, 55))	('CTNNB1', 'Gene', '1499', (148, 154))	('CDK4', 'Gene', (23, 27))	('TP53', 'Gene', '7157', (139, 143))	('MDM2', 'Gene', (45, 49))	('RB1', 'Gene', (57, 60))	('TP53', 'Gene', '7157', (91, 95))	('CTNNB1', 'Gene', (37, 43))
53308	32287321	These 83 cases were evaluated for somatic variants of 12 candidate genes in this study and the presence or absence of cortisol production.	('variants', 'Var', (42, 50))	('cortisol', 'MPA', (118, 126))	('cortisol', 'Chemical', 'MESH:D006854', (118, 126))
53311	32287321	Associations between TP53 or CTNNB1 somatic variants and atypical mitotic figures were evaluated using the Fisher's exact test.	('TP53', 'Gene', (21, 25))	('Associations', 'Interaction', (0, 12))	('CTNNB1', 'Gene', '1499', (29, 35))	('CTNNB1', 'Gene', (29, 35))	('variants', 'Var', (44, 52))	('TP53', 'Gene', '7157', (21, 25))
53322	32287321	In other cases, we searched for possible pathogenic variants in tumor tissues using following exclusion criteria: 1) variants on mutant alleles with less than 1% in the tumor tissue; 2) variants registered in the gnomAD and 3.5KJPN databases; 3) variants observed in our 218 in-house control exomes; 4) synonymous variants; and 5) variants predicted to likely be benign by multiple prediction tools.	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('variants', 'Var', (52, 60))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
53323	32287321	A total of seven somatic variants, two variants in TP53 (c.375G>A:p.T125 = and c.749C>T:p.P250L), three variants in CTNNB1 (c.110C>G:p.S37C, c.121A>G:p.T41A and c.133T>C:p.S45P), one variant in PRKAR1A (c.545C>A:p.T182K) and one variant in ZNRF3 (c.433C>T:p.R145X), were identified in five of the seven ACC cases (71.4%, Fig 1).	('PRKAR1A', 'Gene', (194, 201))	('p.T182K', 'Mutation', 'p.T182K', (212, 219))	('c.121A>G', 'Mutation', 'rs121913412', (141, 149))	('c.133T>C', 'Mutation', 'rs121913407', (161, 169))	('c.545C>A', 'Mutation', 'c.545C>A', (203, 211))	('TP53', 'Gene', (51, 55))	('c.110C>G:p.S37C', 'Var', (124, 139))	('p.S37C', 'Mutation', 'rs121913403', (133, 139))	('p.T41A', 'Mutation', 'rs121913412', (150, 156))	('PRKAR1A', 'Gene', '5573', (194, 201))	('p.R145X', 'Mutation', 'rs1188411932', (256, 263))	('c.375G>A', 'Mutation', 'rs55863639', (57, 65))	('p.S45P', 'Mutation', 'rs121913407', (170, 176))	('c.375G>A:p.T125 =', 'Var', (57, 74))	('c.749C>T', 'Mutation', 'rs1064794311', (79, 87))	('p.P250L', 'Mutation', 'rs1064794311', (88, 95))	('CTNNB1', 'Gene', '1499', (116, 122))	('c.433C>T', 'Mutation', 'rs1188411932', (247, 255))	('TP53', 'Gene', '7157', (51, 55))	('c.133T>C:p.S45P', 'Var', (161, 176))	('c.121A>G:p.T41A', 'Var', (141, 156))	('ZNRF3', 'Gene', '84133', (240, 245))	('c.110C>G', 'Mutation', 'rs121913403', (124, 132))	('T125', 'Chemical', '-', (68, 72))	('ZNRF3', 'Gene', (240, 245))	('c.749C>T', 'Var', (79, 87))	('CTNNB1', 'Gene', (116, 122))
53324	32287321	Somatic variants in TP53, CTNNB1, and ZNRF3 had been reported as pathogenic variants in cases of ACC or other cancers.	('pathogenic', 'Reg', (65, 75))	('cancers', 'Disease', (110, 117))	('CTNNB1', 'Gene', (26, 32))	('TP53', 'Gene', (20, 24))	('ACC', 'Disease', (97, 100))	('ZNRF3', 'Gene', '84133', (38, 43))	('variants', 'Var', (8, 16))	('CTNNB1', 'Gene', '1499', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('variants', 'Var', (76, 84))	('ZNRF3', 'Gene', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('TP53', 'Gene', '7157', (20, 24))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
53325	32287321	Although the somatic variant in PRKAR1A (NM_002734.4):c.545C>A (p.T182K) is a novel missense variant.	('c.545C>A', 'Mutation', 'c.545C>A', (54, 62))	('PRKAR1A', 'Gene', '5573', (32, 39))	('c.545C>A', 'Var', (54, 62))	('PRKAR1A', 'Gene', (32, 39))	('p.T182K', 'Mutation', 'p.T182K', (64, 71))
53332	32287321	From these results, we hypothesized that in cases with TP53 somatic variants, an abnormality occurred in the M phase of the cell cycle, causing an atypical mitotic figure to appear.	('variants', 'Var', (68, 76))	('occurred', 'Reg', (93, 101))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('appear', 'PosReg', (174, 180))	('atypical', 'MPA', (147, 155))	('causing', 'Reg', (136, 143))	('M phase of the cell cycle', 'CPA', (109, 134))
53336	32287321	We identified nine CTNNB1 variant cases, seven TP53 variant cases, five MEN1 variant cases, three PRKAR1A variant cases, two ZNRF3 variant cases, one APC variant case, one CDK2A variant case, one MDM2 variant case, and one RB1 variant case (S2 Fig).	('CTNNB1', 'Gene', (19, 25))	('RB1', 'Gene', (223, 226))	('APC', 'Disease', 'MESH:D011125', (150, 153))	('APC', 'Disease', (150, 153))	('MDM2', 'Gene', '4193', (196, 200))	('PRKAR1A', 'Gene', (98, 105))	('MEN1', 'Gene', (72, 76))	('variant', 'Var', (26, 33))	('RB1', 'Gene', '5925', (223, 226))	('MEN1', 'Gene', '4221', (72, 76))	('MDM2', 'Gene', (196, 200))	('CTNNB1', 'Gene', '1499', (19, 25))	('ZNRF3', 'Gene', '84133', (125, 130))	('TP53', 'Gene', '7157', (47, 51))	('PRKAR1A', 'Gene', '5573', (98, 105))	('TP53', 'Gene', (47, 51))	('ZNRF3', 'Gene', (125, 130))
53337	32287321	Thirteen cases (35.1%) harboring either CTNNB1, ZNRF3, or PRKAR1A somatic variants involved cortisol production.	('CTNNB1', 'Gene', (40, 46))	('cortisol', 'Chemical', 'MESH:D006854', (92, 100))	('PRKAR1A', 'Gene', (58, 65))	('involved', 'Reg', (83, 91))	('ZNRF3', 'Gene', '84133', (48, 53))	('ZNRF3', 'Gene', (48, 53))	('CTNNB1', 'Gene', '1499', (40, 46))	('variants', 'Var', (74, 82))	('PRKAR1A', 'Gene', '5573', (58, 65))	('cortisol production', 'MPA', (92, 111))
53341	32287321	Next, associations between TP53 or CTNNB1 somatic variants and atypical mitotic figures were evaluated using Fisher's exact test.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('associations', 'Interaction', (6, 18))	('CTNNB1', 'Gene', '1499', (35, 41))	('CTNNB1', 'Gene', (35, 41))	('variants', 'Var', (50, 58))
53345	32287321	Five cases had CTNNB1 somatic variant and atypical mitotic figures, of which three cases also harbored TP53 somatic variants and one case had observed copy-number alterations of the gene belonging to the TP53-RB1 pathway.	('RB1', 'Gene', '5925', (209, 212))	('TP53', 'Gene', '7157', (103, 107))	('CTNNB1', 'Gene', (15, 21))	('TP53', 'Gene', (103, 107))	('variant', 'Var', (30, 37))	('CTNNB1', 'Gene', '1499', (15, 21))	('TP53', 'Gene', '7157', (204, 208))	('RB1', 'Gene', (209, 212))	('TP53', 'Gene', (204, 208))	('harbored', 'Reg', (94, 102))
53346	32287321	In the TP53 somatic variant cases, the results were consistent with the hypothesis that atypical mitotic figures appear through M phase abnormalities.	('TP53', 'Gene', '7157', (7, 11))	('variant', 'Var', (20, 27))	('TP53', 'Gene', (7, 11))
53347	32287321	Though both TP53 and CTNNB1 variants have been reported as poor prognostic factors, we speculated that the two somatic variants produced different abnormal cell cycle phases.	('variants', 'Var', (28, 36))	('TP53', 'Gene', '7157', (12, 16))	('CTNNB1', 'Gene', (21, 27))	('abnormal cell cycle phases', 'Phenotype', 'HP:0011018', (147, 173))	('TP53', 'Gene', (12, 16))	('CTNNB1', 'Gene', '1499', (21, 27))
53351	32287321	Analysis of the ACC-TCGA dataset revealed that the TP53 mutated group had significantly higher mRNA expression in CDK1 (p < 0.001), CCNB1 (p < 0.001), CCNB2 (p < 0.001), and AURKA (p < 0.001) compared with the TP53 wild group (Fig 3A, 3B, 3C and 3D).	('higher', 'PosReg', (88, 94))	('CDK1', 'Gene', (114, 118))	('mRNA expression', 'MPA', (95, 110))	('AURKA', 'Gene', (174, 179))	('TP53', 'Gene', (51, 55))	('TP53', 'Gene', (210, 214))	('CCNB1', 'Gene', (132, 137))	('mutated', 'Var', (56, 63))	('CCNB1', 'Gene', '891', (132, 137))	('CCNB2', 'Gene', (151, 156))	('AURKA', 'Gene', '6790', (174, 179))	('CCNB2', 'Gene', '9133', (151, 156))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', '7157', (210, 214))	('CDK1', 'Gene', '983', (114, 118))
53352	32287321	Compared with the wild group, the CTNNB1 mutated group showed significantly higher mRNA expression levels only in the CCNB2 (p = 0.046) group, but no significant difference in the CDK1 (p = 0.116), CCNB1 (p = 0.194), and AURAKA (p = 0.126) groups (Fig 3E, 3F, 3G and 3H).	('CDK1', 'Gene', (180, 184))	('mutated', 'Var', (41, 48))	('CCNB1', 'Gene', (198, 203))	('CTNNB1', 'Gene', (34, 40))	('CCNB2', 'Gene', '9133', (118, 123))	('AURAKA', 'Gene', (221, 227))	('mRNA expression levels', 'MPA', (83, 105))	('CCNB1', 'Gene', '891', (198, 203))	('CTNNB1', 'Gene', '1499', (34, 40))	('AURAKA', 'Gene', '6790', (221, 227))	('3H', 'Chemical', 'MESH:D014316', (267, 269))	('higher', 'PosReg', (76, 82))	('CCNB2', 'Gene', (118, 123))	('CDK1', 'Gene', '983', (180, 184))
53353	32287321	Furthermore, a significant difference in the mRNA expression level of CCNB2 was absent in the CTNNB1 mutated group when the four cases with simultaneous TP53 variants were excluded (p = 0.191) (S3 Fig).	('CCNB2', 'Gene', '9133', (70, 75))	('CTNNB1', 'Gene', '1499', (94, 100))	('mRNA expression level', 'MPA', (45, 66))	('absent', 'NegReg', (80, 86))	('mutated', 'Var', (101, 108))	('TP53', 'Gene', '7157', (153, 157))	('CCNB2', 'Gene', (70, 75))	('TP53', 'Gene', (153, 157))	('CTNNB1', 'Gene', (94, 100))
53354	32287321	TP53 mutated cases are likely to have abnormalities in the M phase, but CTNNB1 mutated cases are likely not to have abnormalities in the M phase.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('CTNNB1', 'Gene', (72, 78))	('mutated', 'Var', (5, 12))	('M phase', 'CPA', (59, 66))	('CTNNB1', 'Gene', '1499', (72, 78))	('abnormalities', 'Var', (38, 51))
53362	32287321	Overall survival was significantly shorter in the high-expression group than in the low-expression group in all CDK1, CCNB2, and AURKA groups (p < 0.001).	('CDK1', 'Gene', '983', (112, 116))	('high-expression', 'Var', (50, 65))	('CCNB2', 'Gene', '9133', (118, 123))	('CDK1', 'Gene', (112, 116))	('AURKA', 'Gene', '6790', (129, 134))	('shorter', 'NegReg', (35, 42))	('AURKA', 'Gene', (129, 134))	('Overall survival', 'MPA', (0, 16))	('CCNB2', 'Gene', (118, 123))
53374	32287321	The five cases in which somatic variants were identified in this study harbored somatic variants in either CTNNB1, ZNRF3, or PRKAR1A, which are involved in cortisol production.	('ZNRF3', 'Gene', (115, 120))	('CTNNB1', 'Gene', '1499', (107, 113))	('PRKAR1A', 'Gene', '5573', (125, 132))	('CTNNB1', 'Gene', (107, 113))	('cortisol', 'Chemical', 'MESH:D006854', (156, 164))	('ZNRF3', 'Gene', '84133', (115, 120))	('PRKAR1A', 'Gene', (125, 132))	('variants', 'Var', (88, 96))
53375	32287321	These somatic variants related to cortisol production may be involved in the poor prognosis of cortisol-producing ACC.	('cortisol', 'Chemical', 'MESH:D006854', (95, 103))	('cortisol-producing ACC', 'Disease', (95, 117))	('involved', 'Reg', (61, 69))	('variants', 'Var', (14, 22))	('cortisol', 'Chemical', 'MESH:D006854', (34, 42))
53376	32287321	Although the CTNNB1 variant has been studied, further verification is required for the ZNRF3 and PRAKR1A variants.	('PRAKR1A', 'Gene', (97, 104))	('CTNNB1', 'Gene', (13, 19))	('ZNRF3', 'Gene', '84133', (87, 92))	('variants', 'Var', (105, 113))	('CTNNB1', 'Gene', '1499', (13, 19))	('ZNRF3', 'Gene', (87, 92))
53378	32287321	One possible reason for the high frequency of somatic variants involved in cortisol production in our study is that the cortisol level of the cases we analyzed was higher, although it was difficult to compare because no cortisol levels are reported in the ACC-TCGA dataset.	('cortisol', 'Chemical', 'MESH:D006854', (75, 83))	('involved', 'Reg', (63, 71))	('cortisol', 'Chemical', 'MESH:D006854', (120, 128))	('cortisol', 'Chemical', 'MESH:D006854', (220, 228))	('cortisol level', 'MPA', (120, 134))	('higher', 'PosReg', (164, 170))	('variants', 'Var', (54, 62))
53381	32287321	In PRKAR1A variants, 80% of variants, such as frameshift or nonsense variants (with premature stop codon), are subject to mRNA nonsense-mediated decay (NMD), which prevents translation of proteins.	('translation', 'MPA', (173, 184))	('variants', 'Var', (11, 19))	('subject', 'Reg', (111, 118))	('frameshift', 'Var', (46, 56))	('PRKAR1A', 'Gene', (3, 10))	('nonsense variants', 'Var', (60, 77))	('mRNA', 'MPA', (122, 126))	('PRKAR1A', 'Gene', '5573', (3, 10))	('prevents', 'NegReg', (164, 172))	('proteins', 'Protein', (188, 196))	('nonsense-mediated', 'Var', (127, 144))
53382	32287321	However, 20% of the variants that escaped NMD and were translated into a protein have been reported to cause more aggressive tumors due to the dominant-negative effect.	('variants', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('aggressive tumors', 'Disease', (114, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('cause', 'Reg', (103, 108))	('aggressive tumors', 'Disease', 'MESH:D001523', (114, 131))	('more', 'PosReg', (109, 113))
53383	32287321	The c.545C>A (p.T182K) somatic variant located at the cAMP binding domain A of PRKAR1A protein is likely to escape NDM.	('PRKAR1A', 'Gene', '5573', (79, 86))	('cAMP', 'Chemical', '-', (54, 58))	('c.545C>A', 'Var', (4, 12))	('p.T182K', 'Mutation', 'p.T182K', (14, 21))	('PRKAR1A', 'Gene', (79, 86))	('c.545C>A', 'Mutation', 'c.545C>A', (4, 12))
53384	32287321	reported that a germline c.439A>G (p.S147G) variant in the cAMP binding domain A caused ACC in a woman.	('c.439A>G', 'Var', (25, 33))	('p.S147G', 'Mutation', 'rs1307692323', (35, 42))	('ACC', 'Disease', (88, 91))	('cAMP', 'Chemical', '-', (59, 63))	('c.439A>G', 'Mutation', 'rs1307692323', (25, 33))	('caused', 'Reg', (81, 87))	('woman', 'Species', '9606', (97, 102))
53385	32287321	In addition, three germline PRKAR1A variants in the cAMP binding domain A (c.547G>T (p.A183Y), c.638C>A (p.213D), and c.438A>T (p.R146S)) had been reported and the functional studies in vitro have demonstrated that these missense variants might enhance the PKA activity leading to accelerating the tumor genesis.	('c.638C>A', 'Mutation', 'rs281864786', (95, 103))	('cAMP', 'Chemical', '-', (52, 56))	('enhance', 'PosReg', (245, 252))	('PRKAR1A', 'Gene', '5573', (28, 35))	('tumor', 'Disease', (298, 303))	('activity', 'MPA', (261, 269))	('accelerating', 'PosReg', (281, 293))	('p.A183Y', 'Mutation', 'rs373972476', (85, 92))	('c.547G>T', 'Mutation', 'rs373972476', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('c.438A>T', 'Mutation', 'rs761320023', (118, 126))	('c.638C>A', 'Var', (95, 103))	('p.R146S', 'Mutation', 'rs761320023', (128, 135))	('c.547G>T', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('PKA', 'Enzyme', (257, 260))	('c.438A>T', 'Var', (118, 126))	('PRKAR1A', 'Gene', (28, 35))	('missense variants', 'Var', (221, 238))
53387	32287321	Although the PRKAR1A:c.545C>A (p.T182K) variant is considered as "variant of uncertain significance" at this time, we hypothesized that the c.545C>A (p.T182K) variant was also likely to cause the upregulation of PKA activity and involve in ACC carcinogenesis.	('PKA', 'Enzyme', (212, 215))	('p.T182K', 'Mutation', 'p.T182K', (31, 38))	('PRKAR1A:c.545C>A', 'SUBSTITUTION', 'None', (13, 29))	('PRKAR1A:c.545C>A', 'Var', (13, 29))	('ACC carcinogenesis', 'Disease', (240, 258))	('c.545C>A', 'Mutation', 'c.545C>A', (140, 148))	('p.T182K', 'Mutation', 'p.T182K', (150, 157))	('c.545C>A', 'Mutation', 'c.545C>A', (21, 29))	('involve in', 'Reg', (229, 239))	('upregulation', 'PosReg', (196, 208))	('activity', 'MPA', (216, 224))
53391	32287321	Inhibition of ZNRF3 enhances Wnt pathway signaling and is involved in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('Wnt pathway signaling', 'Pathway', (29, 50))	('involved', 'Reg', (58, 66))	('ZNRF3', 'Gene', '84133', (14, 19))	('enhances', 'PosReg', (20, 28))	('ZNRF3', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
53393	32287321	The ZNRF3:c.433C>T (p.R145X) variant identified in this study is also a nonsense variant located at a site presumed to affect the sequence upstream of the transmembrane domain.	('ZNRF3:c.433C>T', 'SUBSTITUTION', 'None', (4, 18))	('ZNRF3:c.433C>T', 'Var', (4, 18))	('p.R145X', 'Mutation', 'rs1188411932', (20, 27))	('affect', 'Reg', (119, 125))
53394	32287321	The ZNRF3:c.433C>T (p.R145X) variant is speculated to be involved in carcinogenesis by upregulating the Wnt pathways.	('p.R145X', 'Mutation', 'rs1188411932', (20, 27))	('ZNRF3:c.433C>T', 'SUBSTITUTION', 'None', (4, 18))	('ZNRF3:c.433C>T', 'Var', (4, 18))	('Wnt pathways', 'Pathway', (104, 116))	('upregulating', 'PosReg', (87, 99))
53398	32287321	The analysis using the ACC-TCGA dataset showed that the appearance of atypical mitotic figures in CTNNB1 mutated cases was likely to be affected by TP53-RB1 pathway alterations.	('CTNNB1', 'Gene', (98, 104))	('affected', 'Reg', (136, 144))	('TP53', 'Gene', (148, 152))	('TP53', 'Gene', '7157', (148, 152))	('RB1', 'Gene', (153, 156))	('mutated', 'Var', (105, 112))	('RB1', 'Gene', '5925', (153, 156))	('CTNNB1', 'Gene', '1499', (98, 104))
53399	32287321	In addition, verification of mRNA expression by the ACC-TCGA dataset suggested that abnormalities in genes related to the M phase were not involved in the poor prognosis of CTNNB1 mutated cases.	('CTNNB1', 'Gene', (173, 179))	('mutated cases', 'Var', (180, 193))	('CTNNB1', 'Gene', '1499', (173, 179))
53400	32287321	While CTNNB1 mutated ACC is considered to be a poor prognostic factor, it has been reported that cortisol-producing ACA also has CTNNB1 variants with the same frequency as that for ACC.	('CTNNB1', 'Gene', '1499', (6, 12))	('variants', 'Var', (136, 144))	('CTNNB1', 'Gene', (129, 135))	('CTNNB1', 'Gene', (6, 12))	('CTNNB1', 'Gene', '1499', (129, 135))	('cortisol', 'Chemical', 'MESH:D006854', (97, 105))
53401	32287321	In this study, the mechanism of the poor prognosis of CTNNB1 mutated cases could not be clarified.	('CTNNB1', 'Gene', (54, 60))	('mutated', 'Var', (61, 68))	('CTNNB1', 'Gene', '1499', (54, 60))
53402	32287321	However, if the mechanism of poor prognosis in CTNNB1 mutated ACC cases is elucidated in the future, the pathogenesis of ACC will be clarified, and the development of personalized ACC medicine can be expected to advance.	('CTNNB1', 'Gene', (47, 53))	('men', 'Species', '9606', (159, 162))	('mutated', 'Var', (54, 61))	('CTNNB1', 'Gene', '1499', (47, 53))	('ACC', 'Disease', (62, 65))
53403	32287321	In contrast, in the cases with TP53 somatic variant in which the frequency of atypical mitotic figures significantly increases, it was found that the mRNA of CDK1, CCNB1, CCNB2, and AURKA, which are involved in the regulation of the M phase, was significantly highly expresed.	('CCNB2', 'Gene', (171, 176))	('variant', 'Var', (44, 51))	('AURKA', 'Gene', (182, 187))	('TP53', 'Gene', '7157', (31, 35))	('increases', 'PosReg', (117, 126))	('TP53', 'Gene', (31, 35))	('CDK1', 'Gene', (158, 162))	('CCNB2', 'Gene', '9133', (171, 176))	('CDK1', 'Gene', '983', (158, 162))	('CCNB1', 'Gene', (164, 169))	('CCNB1', 'Gene', '891', (164, 169))	('AURKA', 'Gene', '6790', (182, 187))
53409	32287321	In particular, expression was higher in TP53 somatic variant cases.	('higher', 'PosReg', (30, 36))	('TP53', 'Gene', '7157', (40, 44))	('somatic variant', 'Var', (45, 60))	('expression', 'MPA', (15, 25))	('TP53', 'Gene', (40, 44))
53412	32287321	This antagonistic AURKA-mediated relationship between CCNB2 and P53 may explain why TP53 somatic variants were associated with increased atypical mitotic figures in our study and may also point to a new treatment strategy for some ACC cases.	('CCNB2', 'Gene', (54, 59))	('AURKA', 'Gene', '6790', (18, 23))	('P53', 'Gene', (64, 67))	('atypical mitotic figures', 'CPA', (137, 161))	('P53', 'Gene', (85, 88))	('AURKA', 'Gene', (18, 23))	('P53', 'Gene', '7157', (85, 88))	('variants', 'Var', (97, 105))	('men', 'Species', '9606', (208, 211))	('TP53', 'Gene', '7157', (84, 88))	('P53', 'Gene', '7157', (64, 67))	('CCNB2', 'Gene', '9133', (54, 59))	('TP53', 'Gene', (84, 88))	('increased', 'PosReg', (127, 136))
53413	32287321	reported that overexpression of AURKA occurs in pediatric ACC with the TP53 p.R337H variant, and that AMG900, an Aurora kinase inhibitor, acted synergistically with mitotane and doxorubicin in the inhibition of H295R cell proliferation.	('AURKA', 'Gene', '6790', (32, 37))	('AMG900', 'Chemical', 'MESH:C555658', (102, 108))	('doxorubicin', 'Chemical', 'MESH:D004317', (178, 189))	('mitotane', 'Chemical', 'MESH:D008939', (165, 173))	('H295R cell proliferation', 'CPA', (211, 235))	('AURKA', 'Gene', (32, 37))	('p.R337H', 'Var', (76, 83))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('overexpression', 'PosReg', (14, 28))	('p.R337H', 'Mutation', 'rs121912664', (76, 83))
53416	32287321	In aggressive cases with TP53 variants, it may be more effective to administer an AURKA inhibitor in combination with conventional mitotane and combined etoposide, doxorubicin, and cisplatin therapy as adjuvant therapy.	('variants', 'Var', (30, 38))	('TP53', 'Gene', (25, 29))	('doxorubicin', 'Chemical', 'MESH:D004317', (164, 175))	('AURKA', 'Gene', '6790', (82, 87))	('etoposide', 'Chemical', 'MESH:D005047', (153, 162))	('AURKA', 'Gene', (82, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (181, 190))	('TP53', 'Gene', '7157', (25, 29))	('mitotane', 'Chemical', 'MESH:D008939', (131, 139))
53418	32287321	In adult ACC, TP53 variants do not have an identified hotspot and are not concentrated in specific exons, so it is currently challenging to confirm the presence or absence of TP53 variants for all cases in clinical practice.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (175, 179))	('TP53', 'Gene', (14, 18))	('TP53', 'Gene', '7157', (175, 179))	('variants', 'Var', (19, 27))
53419	32287321	In the future, if it is possible to measure the serum circulating mRNA of CCNB2 easily, this may be useful for selecting cases to be screened for TP53 variants in ACC, determining therapeutic effects, and predicting recurrence.	('TP53', 'Gene', '7157', (146, 150))	('variants', 'Var', (151, 159))	('CCNB2', 'Gene', '9133', (74, 79))	('TP53', 'Gene', (146, 150))	('CCNB2', 'Gene', (74, 79))
53422	32287321	In this study, we showed that ACC with atypical mitosis harbored TP53 somatic variants and is likely to be associated with AURKA-mediated M phase deregulation due to overexpression of CCNB2.	('AURKA', 'Gene', (123, 128))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('mitosis harbored', 'Disease', (48, 64))	('CCNB2', 'Gene', '9133', (184, 189))	('AURKA', 'Gene', '6790', (123, 128))	('CCNB2', 'Gene', (184, 189))	('M phase deregulation', 'MPA', (138, 158))	('variants', 'Var', (78, 86))	('mitosis harbored', 'Disease', 'MESH:C537062', (48, 64))	('overexpression', 'PosReg', (166, 180))
53424	32287321	In cancer, low-frequency allelic variant may affect carcinogenicity.	('affect', 'Reg', (45, 51))	('low-frequency allelic variant', 'Var', (11, 40))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('carcinogenicity', 'CPA', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
53425	32287321	Furthermore, because this study mainly focused on somatic variants of the TP53-RB1 and Wnt pathways, crosstalk of alterations with other pathways has not been fully verified.	('RB1', 'Gene', (79, 82))	('RB1', 'Gene', '5925', (79, 82))	('variants', 'Var', (58, 66))	('Wnt pathways', 'Pathway', (87, 99))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))
53430	32287321	We identified a novel somatic variant of PRKAR1A c.545C>A (p.T182K).	('PRKAR1A', 'Gene', '5573', (41, 48))	('p.T182K', 'Mutation', 'p.T182K', (59, 66))	('c.545C>A', 'Var', (49, 57))	('PRKAR1A', 'Gene', (41, 48))	('c.545C>A', 'Mutation', 'c.545C>A', (49, 57))
53431	32287321	In addition, we reported, for what we believe to be the first time, that ACC with TP53 somatic variants is frequently associated with atypical mitotic figures and a higher expression of CCNB2 and AURKA.	('TP53', 'Gene', (82, 86))	('associated', 'Reg', (118, 128))	('CCNB2', 'Gene', '9133', (186, 191))	('AURKA', 'Gene', (196, 201))	('atypical mitotic figures', 'CPA', (134, 158))	('expression', 'MPA', (172, 182))	('higher', 'PosReg', (165, 171))	('CCNB2', 'Gene', (186, 191))	('variants', 'Var', (95, 103))	('TP53', 'Gene', '7157', (82, 86))	('AURKA', 'Gene', '6790', (196, 201))
53433	32287321	25 Feb 2020  PONE-D-20-01265 CCNB2 and AURKA overexpression may cause atypical mitosis in Japanese cortisol-producing adrenocortical carcinoma with TP53 somatic variant PLOS ONE Dear Dr. Ikeya, Thank you for submitting your manuscript to PLOS ONE.	('PONE-D-20-01265', 'Var', (13, 28))	('cause', 'Reg', (64, 69))	('TP53', 'Gene', '7157', (148, 152))	('AURKA', 'Gene', '6790', (39, 44))	('TP53', 'Gene', (148, 152))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (118, 142))	('CCNB2', 'Gene', '9133', (29, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('cortisol', 'Chemical', 'MESH:D006854', (99, 107))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (118, 142))	('AURKA', 'Gene', (39, 44))	('atypical mitosis', 'MPA', (70, 86))	('CCNB2', 'Gene', (29, 34))	('overexpression', 'PosReg', (45, 59))	('adrenocortical carcinoma', 'Disease', (118, 142))
53467	32287321	Line 293-299: I did not find supporting evidence in literature to attribute pathogenicity to PRKAR1A c.545C>A (p.T182K) variant.	('c.545C>A', 'Mutation', 'c.545C>A', (101, 109))	('PRKAR1A', 'Gene', '5573', (93, 100))	('p.T182K', 'Mutation', 'p.T182K', (111, 118))	('PRKAR1A', 'Gene', (93, 100))	('c.545C>A', 'Var', (101, 109))
53468	32287321	As suggested, since PRKAR1A:c.545C>T and c.545C>A are not the same, the text describing references to variants of Clinvar has been deleted.	('c.545C>A', 'Mutation', 'c.545C>A', (41, 49))	('PRKAR1A:c.545C>T', 'Var', (20, 36))	('PRKAR1A:c.545C>T', 'SUBSTITUTION', 'None', (20, 36))	('c.545C', 'Var', (41, 47))
53471	32287321	The pathogenicity of some missense variants of the cAMP binding domain A, such as c.547G>T (p.A183Y), c.638C>A (p.213D), and c.438A>T (p.R146S) have been demonstrated in vitro, as shown in the new reference 41 and 42.	('p.R146S', 'Mutation', 'rs761320023', (135, 142))	('c.638C>A', 'Mutation', 'rs281864786', (102, 110))	('p.A183Y', 'Mutation', 'rs373972476', (92, 99))	('c.438A>T', 'Var', (125, 133))	('c.638C>A', 'Var', (102, 110))	('c.547G>T', 'Mutation', 'rs373972476', (82, 90))	('cAMP', 'Chemical', '-', (51, 55))	('c.547G>T', 'Var', (82, 90))	('c.438A>T', 'Mutation', 'rs761320023', (125, 133))
53472	32287321	The PRKAR1A:c.545C>A (p.T182K) variant is likely to affect cAMP binding domain A and which will affect the enzyme function of PRKAR1A through conformational changes.	('cAMP binding domain A', 'MPA', (59, 80))	('enzyme function', 'MPA', (107, 122))	('affect', 'Reg', (96, 102))	('PRKAR1A', 'Gene', '5573', (126, 133))	('PRKAR1A', 'Gene', (126, 133))	('PRKAR1A', 'Gene', (4, 11))	('conformational changes', 'MPA', (142, 164))	('PRKAR1A:c.545C>A', 'Var', (4, 20))	('cAMP', 'Chemical', '-', (59, 63))	('PRKAR1A:c.545C>A', 'SUBSTITUTION', 'None', (4, 20))	('p.T182K', 'Mutation', 'p.T182K', (22, 29))	('affect', 'Reg', (52, 58))	('PRKAR1A', 'Gene', '5573', (4, 11))
53473	32287321	It is presumed that the change enhances PKA activity and affects tumor formations.	('tumor', 'Disease', (65, 70))	('PKA activity', 'CPA', (40, 52))	('change', 'Var', (24, 30))	('affects', 'Reg', (57, 64))	('enhances', 'PosReg', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
53474	32287321	The PRKAR1A gene is one of the ACC driver genes, and variants in this gene are presumed to be clinically significant, especially in ACC.	('PRKAR1A', 'Gene', (4, 11))	('PRKAR1A', 'Gene', '5573', (4, 11))	('variants', 'Var', (53, 61))	('ACC', 'Disease', (132, 135))
53475	32287321	Based on the above, we have identified the PRKAR1A:c.545C>A (p.T182K) variant in this study as a potential variant of carcinogenesis.	('PRKAR1A:c.545C>A', 'SUBSTITUTION', 'None', (43, 59))	('PRKAR1A:c.545C>A', 'Var', (43, 59))	('p.T182K', 'Mutation', 'p.T182K', (61, 68))	('carcinogenesis', 'CPA', (118, 132))
53478	32287321	In accordance with Reviewer #1 comment, we have added a detailed discussion of the clinical significance and role in the pathogenicity of ZNRF3: c.433C>T (p.R145X) variant at LINE 576-588 in the revised manuscript.	('c.433C>T', 'Var', (145, 153))	('c.433C>T', 'Mutation', 'rs1188411932', (145, 153))	('p.R145X', 'Mutation', 'rs1188411932', (155, 162))	('ZNRF3', 'Gene', '84133', (138, 143))	('ZNRF3', 'Gene', (138, 143))	('men', 'Species', '9606', (34, 37))
53479	32287321	The ZNRF3:c.433C>T (p.R145X) variant was a nonsense variant of the transmembrane domain that has been reported to have a high potential for affecting pathogenicity in previous reports.	('ZNRF3:c.433C>T', 'Var', (4, 18))	('p.R145X', 'Mutation', 'rs1188411932', (20, 27))	('affecting', 'Reg', (140, 149))	('ZNRF3:c.433C>T', 'SUBSTITUTION', 'None', (4, 18))
53486	32287321	1 Apr 2020  PONE-D-20-01265R1  CCNB2 and AURKA overexpression may cause atypical mitosis in Japanese cortisol-producing adrenocortical carcinoma with TP53 somatic variant  Dear Dr. Yamashita: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE.	('AURKA', 'Gene', '6790', (41, 46))	('CCNB2', 'Gene', '9133', (31, 36))	('TP53', 'Gene', (150, 154))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (120, 144))	('overexpression', 'PosReg', (47, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('Apr', 'Gene', (2, 5))	('AURKA', 'Gene', (41, 46))	('PONE-D-20-01265R1', 'Var', (12, 29))	('Apr', 'Gene', '5366', (2, 5))	('adrenocortical carcinoma', 'Disease', (120, 144))	('cause', 'Reg', (66, 71))	('CCNB2', 'Gene', (31, 36))	('TP53', 'Gene', '7157', (150, 154))	('cortisol', 'Chemical', 'MESH:D006854', (101, 109))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (120, 144))
53505	22504887	Furthermore, inactivating mutations in tumor suppressor genes and activating mutations in oncogenes responsible for these familial cancer syndromes have also been found to be present as somatic mutations in sporadic cases of ACC.	('inactivating mutations', 'Var', (13, 35))	('ACC', 'Phenotype', 'HP:0006744', (225, 228))	('ACC', 'Disease', 'MESH:D000306', (225, 228))	('ACC', 'Disease', (225, 228))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (122, 147))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('familial cancer syndromes', 'Disease', (122, 147))
53507	22504887	Li-Fraumeni syndrome results from a germ-line mutation in the TP53 gene (17p13.1).	('TP53', 'Gene', '7157', (62, 66))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('results from', 'Reg', (21, 33))	('TP53', 'Gene', (62, 66))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('mutation', 'Var', (46, 54))
53509	22504887	In addition, inactivating somatic mutations in the TP53 gene have also been observed in sporadic ACC in 20-33% in exons 5-8 and in 25% in exons 2-11.	('ACC', 'Phenotype', 'HP:0006744', (97, 100))	('ACC', 'Disease', 'MESH:D000306', (97, 100))	('TP53', 'Gene', (51, 55))	('ACC', 'Disease', (97, 100))	('inactivating', 'Var', (13, 25))	('TP53', 'Gene', '7157', (51, 55))	('observed', 'Reg', (76, 84))
53510	22504887	In addition, a substitution of histidine for arginine at codon 337 has been shown in the development of childhood ACC in 1 in 10 carriers of this missense mutation.	('ACC', 'Phenotype', 'HP:0006744', (114, 117))	('ACC', 'Disease', 'MESH:D000306', (114, 117))	('ACC', 'Disease', (114, 117))	('substitution', 'Var', (15, 27))	('histidine for arginine at codon 337', 'Mutation', 'rs121912664', (31, 66))	('shown', 'Reg', (76, 81))
53511	22504887	The outcome of the resulting mutation is the inability of the p53 protein to initiate cell growth arrest, DNA repair and apoptosis in response to severe cellular DNA damage.	('mutation', 'Var', (29, 37))	('protein', 'Protein', (66, 73))	('p53', 'Gene', (62, 65))	('cell growth arrest', 'CPA', (86, 104))	('growth arrest', 'Phenotype', 'HP:0001510', (91, 104))	('inability', 'NegReg', (45, 54))	('p53', 'Gene', '7157', (62, 65))
53513	22504887	Screening for germline TP53 mutations in patients with apparently sporadic ACC is recommended, especially in pediatric cases but also in adults as 4% were recently reported to have a germline mutation.	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('ACC', 'Disease', 'MESH:D000306', (75, 78))	('ACC', 'Disease', (75, 78))	('patients', 'Species', '9606', (41, 49))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
53520	22504887	Carney complex results from inactivating mutations in the protein kinase A regulatory subunit (PRKAR1A) gene.	('results from', 'Reg', (15, 27))	('inactivating mutations', 'Var', (28, 50))	('PRKAR1A', 'Gene', (95, 102))	('PRKAR1A', 'Gene', '5573', (95, 102))	('Carney complex', 'Disease', (0, 14))
53522	22504887	Somatic inactivating mutations or allelic losses of the PRKAR1A locus at 17q22-24 are also seen in sporadic cases of adrenocortical adenoma and ACCs.	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (117, 139))	('ACCs', 'Gene', '84680', (144, 148))	('PRKAR1A', 'Gene', '5573', (56, 63))	('ACCs', 'Gene', (144, 148))	('allelic losses', 'Var', (34, 48))	('adrenocortical adenoma', 'Disease', (117, 139))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (117, 139))	('ACC', 'Phenotype', 'HP:0006744', (144, 147))	('PRKAR1A', 'Gene', (56, 63))	('seen', 'Reg', (91, 95))
53523	22504887	Mutations in the adenomatous polyposis coli (APC) gene are known to cause hereditary colorectal cancer.	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (17, 43))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (17, 43))	('APC', 'Phenotype', 'HP:0005227', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cause', 'Reg', (68, 73))	('adenomatous polyposis coli', 'Disease', (17, 43))	('APC', 'Gene', (45, 48))	('hereditary colorectal cancer', 'Disease', (74, 102))	('Mutations', 'Var', (0, 9))	('APC', 'Gene', '324', (45, 48))	('hereditary colorectal cancer', 'Disease', 'MESH:D015179', (74, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
53524	22504887	Several genetic changes in 5q21 of this gene are associated with Gardner syndrome.	('Gardner syndrome', 'Disease', 'MESH:D005736', (65, 81))	('associated', 'Reg', (49, 59))	('genetic changes', 'Var', (8, 23))	('Gardner syndrome', 'Disease', (65, 81))
53529	22504887	ACCs have altered beta-catenin localization as a result of activation mutations which are present in approximately one-fourth of tumors.	('ACCs', 'Gene', (0, 4))	('mutations', 'Var', (70, 79))	('tumors', 'Disease', (129, 135))	('altered', 'Reg', (10, 17))	('beta-catenin', 'Gene', (18, 30))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('ACCs', 'Gene', '84680', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('beta-catenin', 'Gene', '1499', (18, 30))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('activation', 'PosReg', (59, 69))
53530	22504887	The presence of activating mutations in the beta-catenin (CTNNB1) gene is associated with worse outcome and alterations in the Wnt/beta-catenin pathway may serve as prognostic markers for ACC.	('mutations', 'Var', (27, 36))	('alterations', 'Reg', (108, 119))	('beta-catenin', 'Gene', (131, 143))	('CTNNB1', 'Gene', (58, 64))	('beta-catenin', 'Gene', (44, 56))	('ACC', 'Phenotype', 'HP:0006744', (188, 191))	('ACC', 'Disease', 'MESH:D000306', (188, 191))	('ACC', 'Disease', (188, 191))	('beta-catenin', 'Gene', '1499', (131, 143))	('beta-catenin', 'Gene', '1499', (44, 56))	('activating', 'PosReg', (16, 26))	('CTNNB1', 'Gene', '1499', (58, 64))
53531	22504887	MEN 1 is caused by inactivating mutations in the MEN1 gene located in the chromosomal region 11q13.	('MEN1', 'Gene', (49, 53))	('caused by', 'Reg', (9, 18))	('MEN1', 'Gene', '4221', (49, 53))	('MEN 1', 'Gene', '4221', (0, 5))	('inactivating mutations', 'Var', (19, 41))	('MEN 1', 'Gene', (0, 5))
53552	22504887	Soon and colleagues, also showed the combination of IGF-2 and MAD2L1 had high accuracy for distinguishing between benign and malignant tumors with a 100% sensitivity and 95% specificity.	('IGF-2', 'Gene', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('IGF-2', 'Gene', '3481', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('MAD2L1', 'Gene', (62, 68))	('malignant tumors', 'Disease', (125, 141))	('malignant tumors', 'Disease', 'MESH:D009369', (125, 141))	('combination', 'Var', (37, 48))	('MAD2L1', 'Gene', '4085', (62, 68))
53569	22504887	Ki67 (also referred to MIB1) has been shown to be a prognostic marker for several malignancies.	('MIB1', 'Gene', '57534', (23, 27))	('malignancies', 'Disease', (82, 94))	('Ki67', 'Var', (0, 4))	('MIB1', 'Gene', (23, 27))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
53575	22504887	Survival was also associated with the expression of Snail in ACC samples with a median survival of 127 months in patients with Snail-negative tumors as compared to 34 months in patients with Snail-positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('Snail', 'Gene', (52, 57))	('associated', 'Reg', (18, 28))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('Snail', 'Gene', '6615', (191, 196))	('tumors', 'Disease', (206, 212))	('Snail', 'Gene', '6615', (127, 132))	('tumors', 'Disease', (142, 148))	('patients', 'Species', '9606', (113, 121))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('Snail', 'Gene', '6615', (52, 57))	('Snail', 'Gene', (191, 196))	('Snail', 'Gene', (127, 132))	('patients', 'Species', '9606', (177, 185))	('expression', 'Var', (38, 48))	('ACC', 'Phenotype', 'HP:0006744', (61, 64))	('ACC', 'Disease', 'MESH:D000306', (61, 64))	('ACC', 'Disease', (61, 64))
53584	22504887	In adult ACCs, they found a Deltact cutoff of <=3.2 and <=3.14 accurately predicted disease-free survival (AUC = 0.92) and overall survival (AUC = 0.90).	('overall survival', 'CPA', (123, 139))	('ACC', 'Phenotype', 'HP:0006744', (9, 12))	('ACCs', 'Gene', '84680', (9, 13))	('ACCs', 'Gene', (9, 13))	('disease-free survival', 'CPA', (84, 105))	('predicted', 'Reg', (74, 83))	('<=3.14', 'Var', (56, 62))
53594	22504887	Underexpression of miR-195 was also associated with worse overall survival and miR-483-5p had a high diagnostic accuracy for distinguishing benign from malignant adrenocortical tumors.	('overall', 'MPA', (58, 65))	('malignant adrenocortical tumors', 'Disease', 'MESH:D018268', (152, 183))	('malignant adrenocortical tumors', 'Disease', (152, 183))	('miR-483', 'Gene', (79, 86))	('worse', 'NegReg', (52, 57))	('Underexpression', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('miR-195', 'Gene', (19, 26))	('benign', 'Disease', (140, 146))	('miR-483', 'Gene', '619552', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('miR-195', 'Gene', '406971', (19, 26))
53601	22504887	Lastly, miR-139-5p has been reported to be overexpressed in ACC and is associated with poor outcome.	('ACC', 'Phenotype', 'HP:0006744', (60, 63))	('ACC', 'Disease', 'MESH:D000306', (60, 63))	('ACC', 'Disease', (60, 63))	('miR-139-5p', 'Var', (8, 18))	('overexpressed', 'PosReg', (43, 56))	('associated', 'Reg', (71, 81))
53602	22504887	Specifically, miR-139-5p was upregulated in recurrent ACCs, suggesting that this miRNA may be a marker of recurrent ACCs.	('upregulated', 'PosReg', (29, 40))	('ACC', 'Phenotype', 'HP:0006744', (54, 57))	('ACC', 'Phenotype', 'HP:0006744', (116, 119))	('miR-139-5p', 'Var', (14, 24))	('ACCs', 'Gene', (54, 58))	('ACCs', 'Gene', '84680', (54, 58))	('ACCs', 'Gene', '84680', (116, 120))	('ACCs', 'Gene', (116, 120))
53606	22504887	Recent studies have also shown that specific genetic aberrations in ACC tumor samples are associated with prognosis in patients with ACC.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('genetic aberrations', 'Var', (45, 64))	('tumor', 'Disease', (72, 77))	('patients', 'Species', '9606', (119, 127))	('associated', 'Reg', (90, 100))	('ACC', 'Phenotype', 'HP:0006744', (68, 71))	('ACC', 'Disease', 'MESH:D000306', (68, 71))	('ACC', 'Phenotype', 'HP:0006744', (133, 136))	('ACC', 'Disease', (68, 71))	('ACC', 'Disease', 'MESH:D000306', (133, 136))	('ACC', 'Disease', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
53611	22504887	Based on tumor DNA from 21 tumors two prognostic groups were identified based on chromosomal alterations and one group had a worse survival which was validated in an independent cohort of 25 tumors samples (P < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumors', 'Disease', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('chromosomal alterations', 'Var', (81, 104))
53612	22504887	Epigenetic changes have been implicated in the development of cancer and such changes have been found to have diagnostic, prognostic, and therapeutic implications.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('implicated', 'Reg', (29, 39))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Epigenetic changes', 'Var', (0, 18))
53615	22504887	DNA methylation has been implicated in affecting a number of different cellular processes including apoptosis, the cell cycle, DNA damage repair, growth factor response, signal transduction, and tumor architecture, all of which can contribute to the initiation and progression of cancer.	('growth', 'MPA', (146, 152))	('contribute', 'Reg', (232, 242))	('methyl', 'Chemical', 'MESH:C031105', (4, 10))	('tumor', 'Disease', (195, 200))	('affecting', 'Reg', (39, 48))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Disease', (280, 286))	('methylation', 'Var', (4, 15))	('cell cycle', 'CPA', (115, 125))	('signal', 'CPA', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('cellular processes', 'CPA', (71, 89))	('implicated', 'Reg', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('apoptosis', 'CPA', (100, 109))
53628	31689287	Prognostic analysis showed that ENST00000489707.5 had independent prognostic value in progression-free survival (PFS) (HR: 1.227, 95%CI: 1.077-1.398, p=0.002) and disease-specific survival (DSS) (HR: 1.419, 95%CI: 1.154-1.745, p=0.001) after adjustment of other risk factors.	('DSS', 'Gene', (190, 193))	('DSS', 'Gene', '5376', (190, 193))	('progression-free survival', 'CPA', (86, 111))	('disease-specific survival', 'CPA', (163, 188))	('ENST00000489707.5', 'Var', (32, 49))
53629	31689287	ENST00000489707.5 is a preferred alternative splicing product of PTK7, with a significantly increased proportion in ACC compared with other cancers.	('ENST00000489707.5', 'Var', (0, 17))	('PTK7', 'Gene', (65, 69))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('ACC', 'Disease', 'MESH:D000306', (116, 119))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ACC', 'Disease', (116, 119))
53652	31689287	Results showed that PTK7 has complex alternative transcripts in both tumor and normal tissues, among which ENST00000489707.5 has the strongest expression (Figure 1A, 1B).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('expression', 'MPA', (143, 153))	('PTK7', 'Gene', (20, 24))	('ENST00000489707.5', 'Var', (107, 124))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
53662	31689287	Log-rank test results indicated that patients with high ENST00000489707.5 expression had significantly worse PFS compared with the low expression group (p=0.012, Figure 3A).	('worse', 'NegReg', (103, 108))	('patients', 'Species', '9606', (37, 45))	('high', 'Var', (51, 55))	('ENST00000489707.5', 'Gene', (56, 73))	('PFS', 'MPA', (109, 112))
53666	31689287	ENST00000489707.5 expression was also independently associated with unfavorable DSS after adjustment for the other 5 factors (HR: 1.419, 95%CI: 1.154-1.745, p=0.001) (Table 2).	('associated with', 'Reg', (52, 67))	('DSS', 'Gene', '5376', (80, 83))	('ENST00000489707.5 expression', 'Var', (0, 28))	('DSS', 'Gene', (80, 83))
53668	31689287	Since ENST00000489707.5 is the dominant transcript of PTK7 in ACC, we confirmed a strong positive correlation between ENST00000489707.5 and PTK7 expression (Figure 4A).	('PTK7', 'Gene', (140, 144))	('expression', 'MPA', (145, 155))	('ENST00000489707.5', 'Var', (118, 135))	('ACC', 'Disease', 'MESH:D000306', (62, 65))	('ACC', 'Disease', (62, 65))	('PTK7', 'Gene', (54, 58))
53677	31689287	We infer that the expression of certain variants rather than total PTK7 expression could be specific biomarkers in typical cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Disease', (123, 130))	('variants', 'Var', (40, 48))
53681	31689287	Prognostic analysis showed that ENST00000489707.5 had independent prognostic value in PFS (HR: 1.227, 95%CI: 1.077-1.398, p=0.002) and DSS (HR: 1.419, 95%CI: 1.154-1.745, p=0.001) after adjustment for other risk factors.	('PFS', 'Disease', (86, 89))	('DSS', 'Gene', '5376', (135, 138))	('ENST00000489707.5', 'Var', (32, 49))	('DSS', 'Gene', (135, 138))
53682	31689287	Therefore, ENST00000489707.5 expression might serve as a specific prognostic marker in ACC patients.	('ENST00000489707.5', 'Var', (11, 28))	('patients', 'Species', '9606', (91, 99))	('ACC', 'Disease', (87, 90))	('ACC', 'Disease', 'MESH:D000306', (87, 90))
53687	31689287	By using DNA methylation data in TCGA-ACC, we also identified a critical CpG site (cg20819617) that showed a moderately negative correlation with ENST00000489707.5 expression and total PTK7 expression.	('ACC', 'Disease', 'MESH:D000306', (38, 41))	('ACC', 'Disease', (38, 41))	('PTK7', 'Gene', (185, 189))	('expression', 'MPA', (164, 174))	('negative', 'NegReg', (120, 128))	('expression', 'MPA', (190, 200))	('cg20819617', 'Var', (83, 93))
53696	31363169	These alterations include inactivating mutations of the TP53 gene associated with loss of heterozygosity of the locus in 25-35% of ACC, suggesting that P53 is involved in ACC pathogenesis.	('ACC', 'Phenotype', 'HP:0006744', (131, 134))	('TP53', 'Gene', '7157', (56, 60))	('ACC', 'Disease', (131, 134))	('TP53', 'Gene', (56, 60))	('ACC', 'Phenotype', 'HP:0006744', (171, 174))	('inactivating mutations', 'Var', (26, 48))
53697	31363169	Consistent with this idea, inactivation of both P53 and RB in the adrenal cortex of mice expressing the simian virus 40 (SV40) large T antigen (AdTAg mice) results in metastatic ACC development.	('SV40', 'Species', '1891767', (121, 125))	('mice', 'Species', '10090', (150, 154))	('inactivation', 'Var', (27, 39))	('P53', 'Protein', (48, 51))	('results in', 'Reg', (156, 166))	('metastatic ACC development', 'CPA', (167, 193))	('ACC', 'Phenotype', 'HP:0006744', (178, 181))	('mice', 'Species', '10090', (84, 88))	('simian virus 40', 'Species', '1891767', (104, 119))
53699	31363169	However, using transgenic mouse models, we have shown that these alterations, even when combined together, were not sufficient to induce malignant progression, indicating that further alterations are required to allow ACC progression.	('ACC', 'Phenotype', 'HP:0006744', (218, 221))	('alterations', 'Var', (65, 76))	('mouse', 'Species', '10090', (26, 31))	('malignant progression', 'CPA', (137, 158))
53733	31363169	To further refine the list of relevant EZH2 targets in the adrenal gland, we made use of transcriptome data obtained by analysis of a mouse model of adrenal-specific Ezh2 knockout.	('Ezh2', 'Gene', (166, 170))	('knockout', 'Var', (171, 179))	('mouse', 'Species', '10090', (134, 139))
53734	31363169	This model, which relies on excision of Ezh2 exons 16 to 19 by Sf1:Cre mediated recombination was recently characterised.	('Sf1', 'Gene', (63, 66))	('excision', 'Var', (28, 36))	('Ezh2', 'Gene', (40, 44))	('Sf1', 'Gene', '7536', (63, 66))
53737	31363169	2d) and was positively correlated with EZH2 and E2F1 in all three cohorts of patients (Fig.	('patients', 'Species', '9606', (77, 85))	('correlated', 'Reg', (23, 33))	('E2F1', 'Var', (48, 52))
53749	31363169	Interestingly, these E2F1 binding peaks were also associated with the H3K4me3 mark (active chromatin) and EZH2, in the absence of the H3K27me3 mark (inactive chromatin) in HeLa cells.	('EZH2', 'Gene', (106, 110))	('H3K4me3 mark', 'Var', (70, 82))	('binding', 'Interaction', (26, 33))	('E2F1', 'Gene', (21, 25))	('HeLa', 'CellLine', 'CVCL:0030', (172, 176))
53751	31363169	Treatment with 5 microM DZNep for 24, 48 and 72 h resulted in a strong reduction in the accumulation of RRM2, PRC1 and PTTG1 mRNA and protein, suggesting that EZH2 controlled their expression positively (Fig.	('accumulation', 'MPA', (88, 100))	('DZNep', 'Chemical', '-', (24, 29))	('DZNep', 'Var', (24, 29))	('PRC1', 'Gene', (110, 114))	('RRM2', 'Gene', (104, 108))	('PTTG1', 'Gene', (119, 124))	('reduction', 'NegReg', (71, 80))
53756	31363169	Consistent with our previously published data, inhibition of E2F with HLM resulted in decreased expression of EZH2 (Supplementary Fig.	('HLM', 'Gene', '23762', (70, 73))	('inhibition', 'Var', (47, 57))	('expression', 'MPA', (96, 106))	('EZH2', 'Gene', (110, 114))	('HLM', 'Gene', (70, 73))	('decreased', 'NegReg', (86, 95))
53763	31363169	Whereas drugs targeting PTTG1 and PRC1 are scarce, recent data have shown that RRM2 can be inhibited by compounds such as GW8510.	('inhibited', 'NegReg', (91, 100))	('RRM2', 'Protein', (79, 83))	('GW8510', 'Chemical', 'MESH:C500810', (122, 128))	('GW8510', 'Var', (122, 128))
53781	31363169	This was further amplified by the combination of 20 microM mitotane and 10 microM GW which resulted in the death of almost all cells after 5 days of incubation (Fig.	('mitotane', 'Var', (59, 67))	('death', 'Disease', 'MESH:D003643', (107, 112))	('10 microM', 'Var', (72, 81))	('mitotane', 'Chemical', 'MESH:D008939', (59, 67))	('death', 'Disease', (107, 112))	('GW', 'Chemical', 'MESH:C500810', (82, 84))
53788	31363169	This showed that mitotane did not cooperate with GW8510 but rather prevented its pro-apoptotic effects.	('prevented', 'NegReg', (67, 76))	('pro-apoptotic effects', 'CPA', (81, 102))	('GW8510', 'Var', (49, 55))	('mitotane', 'Chemical', 'MESH:D008939', (17, 25))	('GW8510', 'Chemical', 'MESH:C500810', (49, 55))
53794	31363169	This is in sharp contrast with normal mouse adrenal, in which Ezh2 ablation is associated with up-regulation of PRC2 target genes (Fig.	('mouse', 'Species', '10090', (38, 43))	('ablation', 'Var', (67, 75))	('Ezh2', 'Gene', (62, 66))	('up-regulation', 'PosReg', (95, 108))
53795	31363169	Indeed, whereas knockdown of EZH2 in H295R cells results in decreased proliferation and induction of apoptosis, inactivation of Ezh2 in the adrenal cortex does not alter proliferation but rather modulates differentiation of steroidogenic cells.	('H295R', 'CellLine', 'CVCL:0458', (37, 42))	('inactivation', 'Var', (112, 124))	('decreased', 'NegReg', (60, 69))	('differentiation of steroidogenic cells', 'CPA', (205, 243))	('modulates', 'Reg', (195, 204))	('EZH2', 'Gene', (29, 33))	('proliferation', 'CPA', (70, 83))	('Ezh2', 'Gene', (128, 132))	('apoptosis', 'CPA', (101, 110))
53802	31363169	Interestingly, collaboration between EZH2 and E2F1 was also found to regulate the majority of these genes in diffuse large B-cell lymphomas, suggesting that this activity was generally found in cancer.	('lymphomas', 'Phenotype', 'HP:0002665', (130, 139))	('cancer', 'Disease', (194, 200))	('E2F1', 'Gene', (46, 50))	('collaboration', 'Var', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lymphomas', 'Disease', (130, 139))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (123, 139))	('regulate', 'Reg', (69, 77))	('lymphomas', 'Disease', 'MESH:D008223', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('EZH2', 'Gene', (37, 41))
53805	31363169	By combining patients' data with transcriptome analysis of our mouse model of adrenal-specific Ezh2 deletion, we identified PTTG1, PRC1 and RRM2 as three robust positive target genes.	('RRM2', 'Gene', (140, 144))	('mouse', 'Species', '10090', (63, 68))	('Ezh2', 'Gene', (95, 99))	('patients', 'Species', '9606', (13, 21))	('PRC1', 'Gene', (131, 135))	('deletion', 'Var', (100, 108))	('PTTG1', 'Gene', (124, 129))
53808	31363169	Consistent with this idea, we show that pharmacological inhibition and/or siRNA-mediated knockdown of RRM2, which is required for the catalytic activity of the ribonucleotide reductase, is associated with decreased cell growth, G2/M arrest, increased apoptosis and inhibition of cell migration.	('inhibition', 'NegReg', (265, 275))	('increased', 'PosReg', (241, 250))	('pharmacological', 'Var', (40, 55))	('arrest', 'Disease', (233, 239))	('cell migration', 'CPA', (279, 293))	('cell growth', 'CPA', (215, 226))	('decreased', 'NegReg', (205, 214))	('knockdown', 'Var', (89, 98))	('apoptosis', 'CPA', (251, 260))	('arrest', 'Disease', 'MESH:D006323', (233, 239))	('RRM2', 'Gene', (102, 106))
53810	31363169	Interestingly, a number of compounds that can inhibit ribonucleotide reductase activity, such as Triapine (https://clinicaltrials.gov/ct2/results?term=triapine) or COH-29 (NCT02112565) have undergone or are undergoing phase I and II clinical trials and may prove interesting in the context of ACC.	('ribonucleotide reductase activity', 'MPA', (54, 87))	('ACC', 'Phenotype', 'HP:0006744', (293, 296))	('inhibit', 'NegReg', (46, 53))	('NCT02112565', 'Var', (172, 183))	('COH-29', 'Gene', (164, 170))	('triapine', 'Chemical', 'MESH:C078157', (151, 159))	('Triapine', 'Chemical', '-', (97, 105))
53816	31363169	Gene expression data from patients cohorts are readily available from GEO (GSE49820 and GSE10927) and Broad GDAC (TCGA ACC data).	('GSE49820', 'Var', (75, 83))	('GSE10927', 'Var', (88, 96))	('ACC', 'Phenotype', 'HP:0006744', (119, 122))	('patients', 'Species', '9606', (26, 34))
53887	30225430	A subgroup analysis of patients with available work-up for hypercortisolism (n=393) revealed that the presence of cortisol excess was a significant predictor of ACC (OR, 3.5 [1.7-7.6]; P<.001).	('hypercortisolism', 'Phenotype', 'HP:0003118', (59, 75))	('cortisol', 'Chemical', 'MESH:D006854', (64, 72))	('patients', 'Species', '9606', (23, 31))	('hypercortisolism', 'Disease', 'MESH:D003480', (59, 75))	('cortisol', 'MPA', (114, 122))	('presence', 'Var', (102, 110))	('hypercortisolism', 'Disease', (59, 75))	('cortisol excess', 'Phenotype', 'HP:0003118', (114, 129))	('cortisol', 'Chemical', 'MESH:D006854', (114, 122))
53955	29403275	Some aromatic and insoluble antitumor drugs such as SN38 and camptothecin as well as small molecule fluorescent dyes have been shown to be loaded onto nanosized GO surfaces through pi-pi stacking interactions and hydrogen bonds.	('SN38', 'Chemical', 'MESH:D000077146', (52, 56))	('pi-pi', 'Var', (181, 186))	('GO', 'Chemical', 'MESH:C000628730', (161, 163))	('camptothecin', 'Gene', (61, 73))	('hydrogen bonds', 'CPA', (213, 227))	('SN38', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('hydrogen', 'Chemical', 'MESH:D006859', (213, 221))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('camptothecin', 'Chemical', 'MESH:D002166', (61, 73))
53964	29403275	Human serum albumin (HSA) as the second carrier was used as a shell to encapsulate the PTX-GO forming a nanodrug, which is surface functionalized with a tumor targeting molecule, monoclonal antibodies against vascular endothelial growth factor (VEGF; denoted as mAbVEGF) via a polyethylene glycol (PEG) "bridge" (PTX-GHP-VEGF).	('Human', 'Species', '9606', (0, 5))	('serum albumin', 'Gene', '213', (6, 19))	('PTX-GHP', 'Chemical', '-', (313, 320))	('VEGF', 'Gene', '7422', (321, 325))	('tumor', 'Disease', (153, 158))	('PTX-GO', 'Chemical', '-', (87, 93))	('VEGF', 'Gene', (321, 325))	('VEGF', 'Gene', '7422', (265, 269))	('serum albumin', 'Gene', (6, 19))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('VEGF', 'Gene', (265, 269))	('vascular endothelial growth factor', 'Gene', '7422', (209, 243))	('PEG', 'Chemical', 'MESH:D011092', (298, 301))	('VEGF', 'Gene', '7422', (245, 249))	('polyethylene glycol', 'Chemical', 'MESH:D011092', (277, 296))	('VEGF', 'Gene', (245, 249))	('vascular endothelial growth factor', 'Gene', (209, 243))	('monoclonal', 'Var', (179, 189))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
53995	29403275	PTX-GHP-VEGF (0.8 mL, in PBS) at predetermined concentrations (25, 50, 100, 200, and 400 mug/mL) was first mixed with 0.2 mL RBCs.	('VEGF', 'Gene', (8, 12))	('25', 'Var', (63, 65))	('PBS', 'Chemical', '-', (25, 28))	('PTX-GHP', 'Chemical', '-', (0, 7))	('VEGF', 'Gene', '7422', (8, 12))
54066	29403275	These may be caused by the PEG coating of the nanoparticles that can improve blood circulation duration and effectively decrease macrophage clearance of nanoparticles by the reticuloendothelial system, the enhanced permeability and retention (EPR) effect of solid tumor, as well as the mAbVEGF tumor targeting effect enhancing tumor accumulation.	('enhancing', 'PosReg', (317, 326))	('VEGF', 'Gene', '7422', (289, 293))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('solid tumor', 'Disease', 'MESH:D009369', (258, 269))	('VEGF', 'Gene', (289, 293))	('macrophage clearance', 'MPA', (129, 149))	('tumor', 'Disease', (264, 269))	('enhanced', 'PosReg', (206, 214))	('tumor', 'Disease', (327, 332))	('improve blood circulation', 'Phenotype', 'HP:0011028', (69, 94))	('improve', 'PosReg', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('blood', 'MPA', (77, 82))	('PEG', 'Var', (27, 30))	('PEG', 'Chemical', 'MESH:D011092', (27, 30))	('tumor', 'Disease', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('permeability', 'MPA', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('decrease', 'NegReg', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('solid tumor', 'Disease', (258, 269))
54070	29403275	Because of the EPR effect, PTX-GHP without targeting moiety under NIR irradiation displayed in vivo tumor inhibition but not completely, indicating that active targeting of nanoparticles plays an important role in tumor therapy.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('PTX-GHP', 'Var', (27, 34))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('PTX-GHP', 'Chemical', '-', (27, 34))
54089	27344185	Recent analyses verify that miR-497 mainly suppresses tumors; however, it also acts as an oncogene in several cancers.	('cancers', 'Disease', (110, 117))	('suppresses', 'NegReg', (43, 53))	('miR-497', 'Var', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
54099	27344185	A recent study that profiled miRNAs in male breast cancer found that miR-497 was among the most prominently down-regulated miRNAs.	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('miR-497', 'Var', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('male breast cancer', 'Disease', 'MESH:D018567', (39, 57))	('down-regulated', 'NegReg', (108, 122))	('male breast cancer', 'Disease', (39, 57))
54102	27344185	These results suggest that miR-497 has a tumor-suppressive role.	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('miR-497', 'Var', (27, 34))
54120	27344185	The hypoxia-induced increase in luciferase activity was significantly inhibited with a mutated HRE1 in the core binding site; this eliminated HIF-1alpha binding and indicated that HIF-1alpha activates miR-497 transcription by directly binding to the HRE1 element upstream of the promoter.	('eliminated', 'NegReg', (131, 141))	('HIF-1alpha', 'Gene', (180, 190))	('transcription', 'MPA', (209, 222))	('mutated', 'Var', (87, 94))	('HIF-1alpha', 'Gene', '3091', (142, 152))	('luciferase', 'Enzyme', (32, 42))	('activates', 'PosReg', (191, 200))	('HIF-1alpha', 'Gene', (142, 152))	('hypoxia', 'Disease', 'MESH:D000860', (4, 11))	('binding', 'Interaction', (153, 160))	('activity', 'MPA', (43, 51))	('hypoxia', 'Disease', (4, 11))	('inhibited', 'NegReg', (70, 79))	('HIF-1alpha', 'Gene', '3091', (180, 190))	('miR-497', 'Gene', (201, 208))	('binding', 'Interaction', (235, 242))
54127	27344185	Indeed, DNA methylation at CpG dinucleotides can affect miRNAs expression.	('affect', 'Reg', (49, 55))	('DNA', 'Var', (8, 11))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (27, 44))	('miRNAs expression', 'MPA', (56, 73))	('methylation', 'Var', (12, 23))
54133	27344185	In addition to TFs and epigenetic modification, genomic alterations have also been reported to control miR-497 expression in cancer cells.	('epigenetic modification', 'Var', (23, 46))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('control', 'Reg', (95, 102))	('expression', 'MPA', (111, 121))	('miR-497', 'Gene', (103, 110))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
54135	27344185	In a large cohort of 131 paired CRC tissues, ~71% of colon cancers exhibited DNA copy number reduction at this segment.	('reduction', 'NegReg', (93, 102))	('colon cancers', 'Disease', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('DNA', 'Var', (77, 80))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('colon cancers', 'Phenotype', 'HP:0003003', (53, 66))	('colon cancers', 'Disease', 'MESH:D015179', (53, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (53, 65))
54140	27344185	Several studies have reported that increasing miR-497 expression via pre-miR-497 transfection suppresses proliferation and increases apoptosis in ACC and pancreatic cancer and inhibits migration and invasion in bladder cancer and nasopharyngeal carcinoma.	('ACC', 'Phenotype', 'HP:0006744', (146, 149))	('ACC', 'Disease', (146, 149))	('apoptosis', 'CPA', (133, 142))	('transfection', 'Var', (81, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('miR-497', 'Gene', (46, 53))	('increases', 'PosReg', (123, 132))	('nasopharyngeal carcinoma', 'Disease', (230, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('CC', 'Phenotype', 'HP:0002664', (147, 149))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (230, 254))	('pancreatic cancer', 'Disease', 'MESH:D010190', (154, 171))	('increasing', 'PosReg', (35, 45))	('suppresses', 'NegReg', (94, 104))	('pancreatic cancer', 'Disease', (154, 171))	('expression', 'MPA', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (230, 254))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Disease', 'MESH:D001749', (211, 225))	('bladder cancer', 'Disease', (211, 225))	('inhibits', 'NegReg', (176, 184))	('pre-miR-497 transfection', 'Var', (69, 93))	('bladder cancer', 'Phenotype', 'HP:0009725', (211, 225))
54142	27344185	miR-497 up-regulation by lentivirus LV-miR-497 transfection also significantly represses tumor angiogenesis in HCC and OC.	('HCC', 'Disease', (111, 114))	('CC', 'Phenotype', 'HP:0002664', (112, 114))	('HCC', 'Phenotype', 'HP:0001402', (111, 114))	('represses', 'NegReg', (79, 88))	('LV-miR-497', 'Var', (36, 46))	('miR-497', 'Gene', (0, 7))	('OC', 'Phenotype', 'HP:0100615', (119, 121))	('up-regulation', 'PosReg', (8, 21))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
54145	27344185	Our lab found that in pancreatic cancer, enhanced miR-497 could suppress cell proliferation, induce cycle arrest, attenuate migration and invasion capacities and inhibit tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('inhibit', 'NegReg', (162, 169))	('cycle arrest', 'CPA', (100, 112))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('enhanced', 'PosReg', (41, 49))	('suppress', 'NegReg', (64, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (22, 39))	('induce', 'Reg', (93, 99))	('tumor', 'Disease', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('miR-497', 'Var', (50, 57))	('cell proliferation', 'CPA', (73, 91))	('attenuate', 'NegReg', (114, 123))	('pancreatic cancer', 'Disease', (22, 39))	('pancreatic cancer', 'Disease', 'MESH:D010190', (22, 39))
54146	27344185	In addition to a tumor suppressor role, miR-497 may also act as an oncogene.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (17, 22))	('miR-497', 'Var', (40, 47))
54149	27344185	Therefore, miR-497 largely functions as a tumor suppressor in cancer, but it also acts as an oncogene by inhibiting or activating multiple biological processes, including division, proliferation, apoptosis, angiogenesis, migration, and invasion.	('proliferation', 'CPA', (181, 194))	('inhibiting', 'NegReg', (105, 115))	('division', 'CPA', (171, 179))	('tumor', 'Disease', (42, 47))	('angiogenesis', 'CPA', (207, 219))	('miR-497', 'Var', (11, 18))	('migration', 'CPA', (221, 230))	('invasion', 'CPA', (236, 244))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('apoptosis', 'CPA', (196, 205))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('activating', 'Reg', (119, 129))
54151	27344185	found that Bcl-w reduced apoptosis in tumor cells and that miR-497 could significantly inhibit its expression at both the mRNA and protein levels in breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('expression', 'MPA', (99, 109))	('miR-497', 'Var', (59, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('Bcl-w', 'Gene', '599', (11, 16))	('breast cancer', 'Disease', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('apoptosis', 'CPA', (25, 34))	('Bcl-w', 'Gene', (11, 16))	('inhibit', 'NegReg', (87, 94))
54152	27344185	used a luciferase reporter assay to demonstrate that miR-497 could directly bind to the 3'-UTR of Bcl-w.	('Bcl-w', 'Gene', (98, 103))	('Bcl-w', 'Gene', '599', (98, 103))	('miR-497', 'Var', (53, 60))	('bind', 'Interaction', (76, 80))
54153	27344185	In addition, Bcl-2, an anti-apoptosis factor that contributes to tumorigenesis and chemoresistance, was found to be a target of miR-497 in breast cancer, GC and CLL.	('CLL', 'Disease', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('miR-497', 'Var', (128, 135))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('CLL', 'Disease', 'MESH:D015451', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('CLL', 'Phenotype', 'HP:0005550', (161, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('Bcl-2', 'Gene', (13, 18))	('GC', 'Phenotype', 'HP:0012126', (154, 156))	('Bcl-2', 'Gene', '596', (13, 18))
54157	27344185	It is responsible for angiogenesis via a VEGF receptor 2 (VEGFR-2)-dependent signaling pathway and is important for tumor growth, invasiveness and metastasis.miR-497 regulation of VEGF-A expression has been confirmed in several cancers.	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('VEGF receptor 2', 'Gene', (41, 56))	('VEGFR-2', 'Gene', '3791', (58, 65))	('cancers', 'Disease', (228, 235))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('VEGFR-2', 'Gene', (58, 65))	('VEGF receptor 2', 'Gene', '3791', (41, 56))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('VEGF-A', 'Gene', '7422', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('metastasis.miR-497', 'Var', (147, 165))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('VEGF-A', 'Gene', (180, 186))	('tumor', 'Disease', (116, 121))
54159	27344185	revealed that VEGF-A over-expression induced by miR-497 inhibitors increased the protein level of phospho-AKT, which subsequently up-regulates Bcl- 2 and Cyclin D 1 (CCND1) protein and promoted cell growth in SAOS-2 osteosarcoma cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (216, 228))	('over-expression', 'PosReg', (21, 36))	('cell growth', 'CPA', (194, 205))	('inhibitors', 'Var', (56, 66))	('miR-497', 'Gene', (48, 55))	('AKT', 'Gene', '207', (106, 109))	('protein', 'Protein', (173, 180))	('CCND1', 'Gene', '595', (166, 171))	('VEGF-A', 'Gene', '7422', (14, 20))	('SAOS-2', 'CellLine', 'CVCL:0548', (209, 215))	('increased', 'PosReg', (67, 76))	('Bcl- 2', 'Gene', (143, 149))	('CCND1', 'Gene', (166, 171))	('Cyclin D 1', 'Gene', (154, 164))	('up-regulates', 'PosReg', (130, 142))	('osteosarcoma', 'Disease', (216, 228))	('osteosarcoma', 'Disease', 'MESH:D012516', (216, 228))	('Cyclin D 1', 'Gene', '595', (154, 164))	('Bcl- 2', 'Gene', '596', (143, 149))	('AKT', 'Gene', (106, 109))	('VEGF-A', 'Gene', (14, 20))	('promoted', 'PosReg', (185, 193))	('CC', 'Phenotype', 'HP:0002664', (166, 168))
54160	27344185	demonstrated that levels of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2), signaling molecules downstream of VEGF-A, are significantly decreased in miR-497-transfected OC cells, which inhibits angiogenesis.	('VEGF-A', 'Gene', (122, 128))	('AKT', 'Gene', (28, 31))	('ERK1/2', 'Gene', (79, 85))	('levels', 'MPA', (18, 24))	('ERK1/2', 'Gene', '5595;5594', (79, 85))	('decreased', 'NegReg', (148, 157))	('inhibits', 'NegReg', (197, 205))	('extracellular signal-regulated kinase 1/2', 'Gene', '5595', (36, 77))	('OC', 'Phenotype', 'HP:0100615', (181, 183))	('angiogenesis', 'CPA', (206, 218))	('extracellular signal-regulated kinase 1/2', 'Gene', (36, 77))	('miR-497-transfected', 'Var', (161, 180))	('VEGF-A', 'Gene', '7422', (122, 128))	('AKT', 'Gene', '207', (28, 31))
54161	27344185	discovered that miR-497 also targets VEGFR-2 to inhibit HUVEC apoptosis and tumor angiogenesis in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('HUVEC apoptosis', 'CPA', (56, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('VEGFR-2', 'Gene', (37, 44))	('breast cancer', 'Disease', (98, 111))	('HUVEC', 'CellLine', 'CVCL:2959', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('miR-497', 'Var', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('VEGFR-2', 'Gene', '3791', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('inhibit', 'NegReg', (48, 55))
54162	27344185	These results suggest that miR-497 may inhibit angiogenesis and tumor growth by reducing VEGF-A and VEGFR-2 expression through PI3K/AKT and mitogen-activated protein kinase (MAPK)/ERK pathways.	('ERK', 'Gene', '5594', (180, 183))	('tumor', 'Disease', (64, 69))	('VEGF-A', 'Gene', (89, 95))	('miR-497', 'Var', (27, 34))	('AKT', 'Gene', '207', (132, 135))	('VEGFR-2', 'Gene', '3791', (100, 107))	('inhibit', 'NegReg', (39, 46))	('ERK', 'Gene', (180, 183))	('VEGFR-2', 'Gene', (100, 107))	('AKT', 'Gene', (132, 135))	('angiogenesis', 'CPA', (47, 59))	('expression', 'MPA', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('reducing', 'NegReg', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('VEGF-A', 'Gene', '7422', (89, 95))
54165	27344185	Recent studies showed that miR-497 targeted IGF-1R to inhibit proliferation, invasion and metastasis by regulating PI3K/AKT signaling pathway activation in colorectal cancer and to function as an oncogene in cervical cancer.	('AKT', 'Gene', (120, 123))	('cervical cancer', 'Disease', (208, 223))	('colorectal cancer', 'Disease', 'MESH:D015179', (156, 173))	('miR-497', 'Var', (27, 34))	('inhibit', 'NegReg', (54, 61))	('activation', 'PosReg', (142, 152))	('proliferation', 'CPA', (62, 75))	('IGF-1R', 'Gene', '3480', (44, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (156, 173))	('IGF-1R', 'Gene', (44, 50))	('AKT', 'Gene', '207', (120, 123))	('regulating', 'Reg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('colorectal cancer', 'Disease', (156, 173))	('cervical cancer', 'Disease', 'MESH:D002583', (208, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
54171	27344185	Over-expression of CCNE1 has been detected in various cancers, and recent studies have revealed that miR-497 can directly reduce the CCNE1 protein level to suppress tumor growth by inducing G1 arrest in breast cancer and HCC.	('CCNE1', 'Gene', (133, 138))	('CC', 'Phenotype', 'HP:0002664', (133, 135))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('G1 arrest', 'CPA', (190, 199))	('CCNE1', 'Gene', '898', (133, 138))	('HCC', 'Phenotype', 'HP:0001402', (221, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('CCNE1', 'Gene', (19, 24))	('CC', 'Phenotype', 'HP:0002664', (19, 21))	('inducing', 'Reg', (181, 189))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('reduce', 'NegReg', (122, 128))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('breast cancer', 'Disease', (203, 216))	('miR-497', 'Var', (101, 108))	('protein level', 'MPA', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('CCNE1', 'Gene', '898', (19, 24))	('tumor', 'Disease', (165, 170))	('CC', 'Phenotype', 'HP:0002664', (222, 224))	('suppress', 'NegReg', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (165, 170))
54173	27344185	Several other genes encoding cell cycle activators, including cyclins, cyclin-dependent kinase 4 (CDK4), eukaryotic translation initiation factor 4E (eIF4E) and cell cycle division factors (CDC25a), are also known targets of miR-497.	('CDC25a', 'Gene', '993', (190, 196))	('eukaryotic translation initiation factor 4E', 'Gene', '1977', (105, 148))	('cyclin', 'Gene', (71, 77))	('eukaryotic translation initiation factor 4E', 'Gene', (105, 148))	('eIF4E', 'Gene', '1977', (150, 155))	('CDK4', 'Gene', (98, 102))	('cyclin', 'Gene', '5111', (62, 68))	('miR-497', 'Var', (225, 232))	('cyclin-dependent kinase 4', 'Gene', '1019', (71, 96))	('eIF4E', 'Gene', (150, 155))	('CDK4', 'Gene', '1019', (98, 102))	('CDC25a', 'Gene', (190, 196))	('cyclin', 'Gene', (62, 68))	('cyclin-dependent kinase 4', 'Gene', (71, 96))	('cyclin', 'Gene', '5111', (71, 77))
54174	27344185	Inhibitors of NF-kappa B kinase beta (IKKbeta), which is the key kinase in the canonical NF-kappa B signaling pathway, is involved in cell proliferation, metastasis, invasion and the epithelial-mesenchymal transition (EMT).	('NF-kappa B', 'Gene', (89, 99))	('NF-kappa B', 'Gene', '4790', (14, 24))	('involved', 'Reg', (122, 130))	('IKKbeta', 'Gene', (38, 45))	('Inhibitors', 'Var', (0, 10))	('NF-kappa B', 'Gene', (14, 24))	('NF-kappa B', 'Gene', '4790', (89, 99))	('IKKbeta', 'Gene', '3551', (38, 45))	('epithelial-mesenchymal', 'CPA', (183, 205))
54176	27344185	used a luciferase reporter assay to confirm that IKKbeta mRNA 3'-UTR harbors a miR-497 binding site, and miR-497 transfection into C6TA4 cells resulted in a notable reduction in IKKbeta protein level.	('transfection', 'Var', (113, 125))	('IKKbeta', 'Gene', '3551', (178, 185))	('miR-497 transfection', 'Var', (105, 125))	('IKKbeta', 'Gene', (49, 56))	('IKKbeta', 'Gene', '3551', (49, 56))	('reduction', 'NegReg', (165, 174))	('IKKbeta', 'Gene', (178, 185))
54180	27344185	reported that miR-497 could down-regulate these factors in NCI-H295R ACC cells.	('ACC', 'Phenotype', 'HP:0006744', (69, 72))	('miR-497', 'Var', (14, 21))	('NCI-H295R', 'CellLine', 'CVCL:0458', (59, 68))	('down-regulate', 'NegReg', (28, 41))	('CC', 'Phenotype', 'HP:0002664', (70, 72))
54183	27344185	Several other genes critical to cancer genesis and progression are exclusive targets of miR-497.	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('miR-497', 'Var', (88, 95))
54184	27344185	These genes include Nrdp1, CHEK1, FGF2, FGFR1, BIRC5, WNT7A, HDGF, MEK1, SMURF1, WEE1, ANLN and HSPA4 L, PDCD4, AMOT, YAP1, mTOR and p70S6K1.	('mTOR', 'Gene', '2475', (124, 128))	('HDGF', 'Gene', '3068', (61, 65))	('FGF2', 'Gene', (34, 38))	('CHEK1', 'Gene', (27, 32))	('AMOT', 'Gene', (112, 116))	('WEE1', 'Gene', '7465', (81, 85))	('Nrdp1', 'Gene', (20, 25))	('MEK1', 'Gene', '5604', (67, 71))	('PDCD4', 'Gene', (105, 110))	('SMURF1', 'Gene', (73, 79))	('FGFR1', 'Gene', (40, 45))	('HSPA4 L', 'Gene', '22824', (96, 103))	('YAP1', 'Gene', '10413', (118, 122))	('WNT7A', 'Gene', '7476', (54, 59))	('HSPA4 L', 'Gene', (96, 103))	('Nrdp1', 'Gene', '10193', (20, 25))	('WNT7A', 'Gene', (54, 59))	('PDCD4', 'Gene', '27250', (105, 110))	('ANLN', 'Gene', '54443', (87, 91))	('p70S6K1', 'Var', (133, 140))	('YAP1', 'Gene', (118, 122))	('WEE1', 'Gene', (81, 85))	('FGF2', 'Gene', '2247', (34, 38))	('mTOR', 'Gene', (124, 128))	('MEK1', 'Gene', (67, 71))	('FGFR1', 'Gene', '2260', (40, 45))	('ANLN', 'Gene', (87, 91))	('BIRC5', 'Gene', '332', (47, 52))	('BIRC5', 'Gene', (47, 52))	('HDGF', 'Gene', (61, 65))	('AMOT', 'Gene', '154796', (112, 116))	('CHEK1', 'Gene', '1111', (27, 32))	('SMURF1', 'Gene', '57154', (73, 79))
54186	27344185	Because miR-497 influences a wide range of tumor processes and is often deregulated in various cancers, it has potential use as a diagnostic biomarker.	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('miR-497', 'Var', (8, 15))	('influences', 'Reg', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (43, 48))
54189	27344185	confirmed that a combination of miR-34a and miR-497, both under-expressed in ACC, can discriminate these tumors from adrenocortical adenomas with a sensitivity of 89% and specificity of 100%.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('CC', 'Phenotype', 'HP:0002664', (78, 80))	('miR-34a', 'Gene', '407040', (32, 39))	('discriminate', 'Reg', (86, 98))	('miR-34a', 'Gene', (32, 39))	('ACC', 'Phenotype', 'HP:0006744', (77, 80))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (117, 140))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('adrenocortical adenomas', 'Disease', (117, 140))	('miR-497', 'Var', (44, 51))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (117, 140))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
54190	27344185	Except for in tumor tissues, the circulating miR-497 level can also serve as a biomarker.	('miR-497', 'Var', (45, 52))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
54191	27344185	In general, more advanced or malignant tumors express lower levels of miR-497.	('miR-497', 'Var', (70, 77))	('malignant tumors', 'Disease', 'MESH:D018198', (29, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('levels', 'MPA', (60, 66))	('malignant tumors', 'Disease', (29, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('lower', 'NegReg', (54, 59))
54193	27344185	So its clinical diagnostic worth of miR-497 should be reconsidered, because its level in plasma may be influenced by a lot of physiological or pathological factors besides cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('miR-497', 'Var', (36, 43))	('level', 'MPA', (80, 85))	('cancer', 'Disease', (172, 178))	('influenced', 'Reg', (103, 113))
54197	27344185	found that patients with high miR-497 expression had better 5-year disease-free and overall survival compared with patients with low miR-497 expression.	('patients', 'Species', '9606', (115, 123))	('overall survival', 'CPA', (84, 100))	('high miR-497', 'Var', (25, 37))	('patients', 'Species', '9606', (11, 19))	('miR-497', 'Var', (30, 37))	('better', 'PosReg', (53, 59))
54200	27344185	These data support an inspiring idea that elevated miR-497 can provide a novel therapeutic approach to inhibiting multiple proteins involved in the formation and progression of cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('miR-497', 'Var', (51, 58))	('inhibiting', 'NegReg', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('proteins', 'Protein', (123, 131))	('elevated', 'PosReg', (42, 50))
54203	27344185	Moreover, when LV-miR-497-transfected Huh7 hepatoma cells were injected into the tail vein of nude mice, the number of metastatic lung nodules decreased markedly after four weeks compared with controls.	('nude mice', 'Species', '10090', (94, 103))	('Huh7', 'Gene', (38, 42))	('decreased', 'NegReg', (143, 152))	('Huh7', 'Gene', '284424', (38, 42))	('hepatoma', 'Disease', (43, 51))	('LV-miR-497-transfected', 'Var', (15, 37))	('hepatoma', 'Disease', 'MESH:D006528', (43, 51))
54204	27344185	In prostate cancer, knocking down the expression of IKK beta, a direct target of miR-497, can suppress cell proliferation, migration and invasion in vitro; this indicates that miR-497 targets also have therapeutic potential.	('knocking', 'Var', (20, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('suppress', 'NegReg', (94, 102))	('cell proliferation', 'CPA', (103, 121))	('IKK beta', 'Gene', '3551', (52, 60))	('IKK beta', 'Gene', (52, 60))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
54206	27344185	miR-497 can also increase the sensitivity and response of tumor cells to drugs, and several reports suggest using it with chemotherapeutic agents.	('miR-497', 'Var', (0, 7))	('sensitivity', 'CPA', (30, 41))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('increase', 'PosReg', (17, 25))
54209	27344185	Mice that received miR-497 and cisplatin combination therapy had smaller tumors than those given cisplatin alone, with reductions of more than 50%.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('smaller', 'NegReg', (65, 72))	('reductions', 'NegReg', (119, 129))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Disease', (73, 79))	('miR-497', 'Var', (19, 26))
54214	27344185	miR-497 is dysregulated in various cancers via a variety of mechanisms, including TFs, epigenetic alterations and genomic alterations.	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('genomic alterations', 'Var', (114, 133))	('miR-497', 'Gene', (0, 7))	('TFs', 'Disease', (82, 85))	('dysregulated', 'Reg', (11, 23))	('cancers', 'Disease', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('epigenetic alterations', 'Var', (87, 109))
54219	26042218	Inactivating mutations of the PRKAR1A gene, coding for the type 1A regulatory subunit of PKA, are responsible for Carney complex and primary pigmented nodular adrenocortical disease (PPNAD).	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (141, 181))	('PRKAR1A', 'Gene', (30, 37))	('Carney complex', 'Disease', (114, 128))	('Inactivating mutations', 'Var', (0, 22))	('responsible', 'Reg', (98, 109))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (141, 181))	('pigmented nodular adrenocortical disease', 'Disease', (141, 181))	('PPNAD', 'Chemical', '-', (183, 188))
54220	26042218	PRKAR1A inactivation and PKA dysregulation have been implicated in various types of adrenocortical pathologies associated with ACTH-independent Cushing syndrome (AICS) from PPNAD to adrenocortical adenomas and cancer, and other forms of bilateral adrenocortical hyperplasias (BAH).	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (182, 205))	('associated', 'Reg', (111, 121))	('adrenocortical adenomas', 'Disease', (182, 205))	('bilateral adrenocortical hyperplasias', 'Disease', 'MESH:D018268', (237, 274))	('adrenocortical', 'Disease', 'MESH:D018268', (247, 261))	('CS', 'Phenotype', 'HP:0003118', (164, 166))	('PRKAR1A', 'Gene', (0, 7))	('BAH', 'Chemical', '-', (276, 279))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('bilateral adrenocortical hyperplasias', 'Disease', (237, 274))	('Cushing syndrome', 'Disease', 'MESH:D003480', (144, 160))	('adrenocortical', 'Disease', (247, 261))	('PPNAD', 'Chemical', '-', (173, 178))	('adrenocortical', 'Disease', 'MESH:D018268', (182, 196))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (144, 160))	('inactivation', 'Var', (8, 20))	('Cushing syndrome', 'Disease', (144, 160))	('adrenocortical', 'Disease', 'MESH:D018268', (84, 98))	('implicated', 'Reg', (53, 63))	('adrenocortical', 'Disease', (182, 196))	('adrenocortical', 'Disease', (84, 98))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (182, 205))	('cancer', 'Disease', (210, 216))	('dysregulation', 'Var', (29, 42))
54221	26042218	More recently, mutations of PRKACA, the gene coding for the catalytic subunit C alpha (Calpha), were also identified in the pathogenesis of adrenocortical tumors.	('identified', 'Reg', (106, 116))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (140, 161))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mutations', 'Var', (15, 24))	('PRKACA', 'Gene', (28, 34))	('PRKACA', 'Gene', '5566', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('ACA', 'Phenotype', 'HP:0008256', (31, 34))	('adrenocortical tumors', 'Disease', (140, 161))
54222	26042218	PRKACA copy number gain was found in the germline of several patients with cortisol-producing BAH, whereas the somatic Leu206Arg (c.617A>C) recurrent PRKACA mutation was found in as many as half of all adrenocortical adenomas associated with AICS.	('ACA', 'Phenotype', 'HP:0008256', (153, 156))	('c.617A>C', 'Mutation', 'rs386352352', (130, 138))	('PRKACA', 'Gene', (150, 156))	('PRKACA', 'Gene', '5566', (150, 156))	('cortisol', 'Chemical', 'MESH:D006854', (75, 83))	('BAH', 'Chemical', '-', (94, 97))	('PRKACA', 'Gene', (0, 6))	('patients', 'Species', '9606', (61, 69))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (202, 225))	('ACA', 'Phenotype', 'HP:0008256', (3, 6))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (202, 225))	('PRKACA', 'Gene', '5566', (0, 6))	('Leu206Arg', 'Var', (119, 128))	('adrenocortical adenomas', 'Disease', (202, 225))	('Leu206Arg', 'Chemical', '-', (119, 128))	('CS', 'Phenotype', 'HP:0003118', (244, 246))
54247	26042218	In McCune-Albright syndrome (MAS), which is caused by mutations in the GNAS gene that encodes the stimulatory subunit alpha of the G protein (Weinstein et al.,), ACAs or, more frequently, BAH are common.	('GNAS', 'Gene', (71, 75))	('mutations', 'Var', (54, 63))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (3, 27))	('caused by', 'Reg', (44, 53))	('BAH', 'Chemical', '-', (188, 191))	('GNAS', 'Gene', '2778', (71, 75))	('MAS', 'Disease', 'MESH:D005357', (29, 32))	('MAS', 'Disease', (29, 32))	('ACA', 'Phenotype', 'HP:0008256', (162, 165))	('McCune-Albright syndrome', 'Disease', (3, 27))
54248	26042218	In CNC, inactivating mutations of the PRKAR1A gene (encoding the RIalpha subunit of PKA) (Kirschner et al.,) lead to PPNAD.	('lead to', 'Reg', (109, 116))	('inactivating mutations', 'Var', (8, 30))	('PRKAR1A', 'Gene', (38, 45))	('PPNAD', 'Chemical', '-', (117, 122))	('PPNAD', 'Disease', (117, 122))
54249	26042218	Mutations of the PRKAR1A gene have also been identified in sporadic cases of PPNAD (not associated with CNC), as well as in ACAs (Groussin et al.,; Bertherat et al.,).	('identified', 'Reg', (45, 55))	('PPNAD', 'Chemical', '-', (77, 82))	('PRKAR1A', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('PPNAD', 'Disease', (77, 82))	('ACA', 'Phenotype', 'HP:0008256', (124, 127))
54250	26042218	In addition, a number of in vitro and transgenic mouse studies have demonstrated that PRKAR1A is an adrenocortical tumor suppressor gene and its inactivation leads to ACTH-independent cortisol secretion (Sahut-Barnola et al.,; Almeida and Stratakis,).	('cortisol', 'Chemical', 'MESH:D006854', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('leads to', 'Reg', (158, 166))	('ACTH-independent cortisol secretion', 'MPA', (167, 202))	('mouse', 'Species', '10090', (49, 54))	('PRKAR1A', 'Gene', (86, 93))	('inactivation', 'Var', (145, 157))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (100, 120))	('adrenocortical tumor', 'Disease', (100, 120))
54251	26042218	In an initial cohort of 10 cortisol-producing ACAs associated with overt AICS, the Leu206Arg (c.617A>C) PRKACA recurrent mutation was identified in 70% of these cases; with one ACA having another PRKACA defect, Leu199_Cys200insTrp (Beuschlein et al.,).	('PRKACA', 'Gene', (196, 202))	('PRKACA', 'Gene', (104, 110))	('PRKACA', 'Gene', '5566', (196, 202))	('Leu199', 'Chemical', '-', (211, 217))	('ACA', 'Phenotype', 'HP:0008256', (177, 180))	('ACA', 'Phenotype', 'HP:0008256', (199, 202))	('cortisol', 'Chemical', 'MESH:D006854', (27, 35))	('Leu206Arg', 'Chemical', '-', (83, 92))	('PRKACA', 'Gene', '5566', (104, 110))	('c.617A>C', 'Mutation', 'rs386352352', (94, 102))	('ACA', 'Phenotype', 'HP:0008256', (107, 110))	('Leu206Arg (c.617A>C', 'Var', (83, 102))	('CS', 'Phenotype', 'HP:0003118', (75, 77))	('ACA', 'Phenotype', 'HP:0008256', (46, 49))	('Leu199_Cys200insTrp', 'Var', (211, 230))
54252	26042218	Both of these mutations affect residues that are highly conserved across species from invertebrates to humans suggesting the major role played by these amino acids is in protein function (Beuschlein et al.,; Goh et al.,).	('residues', 'MPA', (31, 39))	('affect', 'Reg', (24, 30))	('humans', 'Species', '9606', (103, 109))	('mutations', 'Var', (14, 23))	('protein function', 'MPA', (170, 186))
54253	26042218	Dalmazi and collaborators have also identified two additional mutations: the insertion Cys200_Gly201insVal (c.600_601insGTG) and the missense Ser213Arg (c.639C>G) associated with 12 base pair duplication Leu212_Lys214insIleIleLeuArg (c.638_640insATTATCCTGAGG), in respectively 13.4% (3/22) and 4.5% (1/22) of their cortisol-producing ACA cohort (Di Dalmazi et al.,).	('c.600_601insGTG', 'Mutation', 'c.600_601insGTG', (108, 123))	('c.639C>G', 'Mutation', 'rs1187481745', (153, 161))	('c.638_640insATTATCCTGAGG', 'Mutation', 'c.638_640insATTATCCTGAGG', (234, 258))	('Ser213Arg', 'Mutation', 'rs1187481745', (142, 151))	('cortisol', 'Chemical', 'MESH:D006854', (315, 323))	('Leu212_Lys214insIleIleLeuArg', 'Var', (204, 232))	('c.600_601insGTG', 'Var', (108, 123))	('c.639C>G', 'Var', (153, 161))	('ACA', 'Phenotype', 'HP:0008256', (334, 337))
54255	26042218	The Leu206Arg variant has been identified at a frequency that ranges from 14.2 to 65.5% of cortisol-producing ACA depending on the studies (Beuschlein et al.,; Cao et al.,; Di Dalmazi et al.,; Goh et al.,; Nakajima et al.,; Sato et al.,).	('Leu206Arg', 'Var', (4, 13))	('Leu206Arg', 'Chemical', '-', (4, 13))	('ACA', 'Phenotype', 'HP:0008256', (110, 113))	('cortisol-producing', 'MPA', (91, 109))	('cortisol', 'Chemical', 'MESH:D006854', (91, 99))
54256	26042218	No PRKACA mutations were found either in 1600 in-house exomes or in the 1000 Genomes Project data set or in blood of patients harboring PRKACA mutations in tumors.	('ACA', 'Phenotype', 'HP:0008256', (139, 142))	('PRKACA', 'Gene', (136, 142))	('PRKACA', 'Gene', (3, 9))	('PRKACA', 'Gene', '5566', (136, 142))	('PRKACA', 'Gene', '5566', (3, 9))	('ACA', 'Phenotype', 'HP:0008256', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('patients', 'Species', '9606', (117, 125))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('mutations', 'Var', (10, 19))	('tumors', 'Disease', (156, 162))	('mutations', 'Var', (143, 152))
54257	26042218	The Leu206Arg substitution likely alters the function of the Calpha subunit at the heterozygote state, since both the wild type and mutant alleles were expressed in the tumor tissue (Beuschlein et al.,; Goh et al.,).	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('alters', 'Reg', (34, 40))	('function', 'MPA', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Leu206Arg', 'Var', (4, 13))	('Leu206Arg', 'Chemical', '-', (4, 13))	('tumor', 'Disease', (169, 174))	('Calpha subunit', 'Protein', (61, 75))
54258	26042218	PRKACA encodes the most highly expressed catalytic PKA isoform in the human adrenal and the functional consequences of two mutant variants have been predicted using different modeling approaches based on mouse PKA crystal structure (Beuschlein et al.,; Cao et al.,; Goh et al.,; Sato et al.,).	('variants', 'Var', (130, 138))	('PRKACA', 'Gene', (0, 6))	('ACA', 'Phenotype', 'HP:0008256', (3, 6))	('human', 'Species', '9606', (70, 75))	('PRKACA', 'Gene', '5566', (0, 6))	('mouse', 'Species', '10090', (204, 209))
54259	26042218	In the absence of cAMP, the regulatory subunit fits into a highly conserved hydrophobic cleft in the catalytic subunit formed by Leu206 and Leu199.	('fits', 'Disease', (47, 51))	('Leu199', 'Var', (140, 146))	('Leu206', 'Chemical', '-', (129, 135))	('fits', 'Disease', 'MESH:D012640', (47, 51))	('cAMP', 'Gene', (18, 22))	('Leu199', 'Chemical', '-', (140, 146))	('Leu206', 'Var', (129, 135))	('cAMP', 'Gene', '820', (18, 22))
54260	26042218	Therefore, the substitution from the small hydrophobic leucine to a large positively charge hydrophilic arginine in position 206 should abolish the interaction between the catalytic and regulatory subunit leading then to cAMP-independent PKA activation (Figure 1) (Beuschlein et al.,; Cao et al.,; Goh et al.,; Sato et al.,).	('substitution', 'Var', (15, 27))	('interaction between the', 'Interaction', (148, 171))	('activation', 'PosReg', (242, 252))	('cAMP', 'Gene', '820', (221, 225))	('leucine', 'Chemical', 'MESH:D007930', (55, 62))	('PKA', 'Enzyme', (238, 241))	('arginine', 'Chemical', 'MESH:D001120', (104, 112))	('abolish', 'NegReg', (136, 143))	('cAMP', 'Gene', (221, 225))
54261	26042218	Similar consequences are predicted for each one of the pathogenic PRKACA variants that have been identified so far in ACAs (Di Dalmazi et al.,).	('variants', 'Var', (73, 81))	('PRKACA', 'Gene', (66, 72))	('ACA', 'Phenotype', 'HP:0008256', (69, 72))	('PRKACA', 'Gene', '5566', (66, 72))	('ACA', 'Phenotype', 'HP:0008256', (118, 121))
54262	26042218	The activating effect of the novel PRKACA mutations in ACA predicted by what is known about the structural biology of the PKA tetramer has been validated by in vitro experiments in HEK293 cells for the most frequent variant, Leu206Arg (Beuschlein et al.,; Cao et al.,; Goh et al.,; Sato et al.,).	('Leu206Arg', 'Chemical', '-', (225, 234))	('activating', 'MPA', (4, 14))	('HEK293', 'CellLine', 'CVCL:0045', (181, 187))	('PRKACA', 'Gene', (35, 41))	('ACA', 'Phenotype', 'HP:0008256', (38, 41))	('ACA', 'Phenotype', 'HP:0008256', (55, 58))	('PRKACA', 'Gene', '5566', (35, 41))	('Leu206Arg', 'Var', (225, 234))
54263	26042218	The expression of Leu206Arg PRKACA increases the PKA activity and the level of CREB phosphorylation at Ser133 in basal conditions compared to the wild type PRKACA in two independent studies; the Leu206Arg did not interfere with the catalytic activity (Beuschlein et al.,; Cao et al.,; Goh et al.,).	('increases', 'PosReg', (35, 44))	('PRKACA', 'Gene', (156, 162))	('PKA', 'Enzyme', (49, 52))	('CREB', 'Gene', (79, 83))	('PRKACA', 'Gene', (28, 34))	('Leu206Arg', 'Var', (195, 204))	('Leu206Arg', 'Chemical', '-', (195, 204))	('PRKACA', 'Gene', '5566', (28, 34))	('activity', 'MPA', (53, 61))	('Ser133', 'Chemical', '-', (103, 109))	('CREB', 'Gene', '1385', (79, 83))	('ACA', 'Phenotype', 'HP:0008256', (31, 34))	('ACA', 'Phenotype', 'HP:0008256', (159, 162))	('Leu206Arg', 'Var', (18, 27))	('Leu206Arg', 'Chemical', '-', (18, 27))	('PRKACA', 'Gene', '5566', (156, 162))
54264	26042218	In contrast with cells transfected with the wild-type sequence, the Leu206Arg is not responsive to cAMP stimulation and its activity is not reduced by the co-expression with excess wild-type regulatory subunit (Beuschlein et al.,).	('activity', 'MPA', (124, 132))	('cAMP', 'Gene', (99, 103))	('cAMP', 'Gene', '820', (99, 103))	('Leu206Arg', 'Var', (68, 77))	('Leu206Arg', 'Chemical', '-', (68, 77))
54266	26042218	Consistent with these conclusions, basal PKA activity in ACA with PRKACA mutations compared to those without mutations is increased (Beuschlein et al.,; Cao et al.,).	('activity', 'MPA', (45, 53))	('PKA', 'Enzyme', (41, 44))	('ACA', 'Phenotype', 'HP:0008256', (57, 60))	('PRKACA', 'Gene', (66, 72))	('ACA', 'Phenotype', 'HP:0008256', (69, 72))	('PRKACA', 'Gene', '5566', (66, 72))	('increased', 'PosReg', (122, 131))	('mutations', 'Var', (73, 82))
54267	26042218	Similarly, Goh and collaborators demonstrated by immunohistochemistry a higher staining of the phosphorylation of CREB at Ser133 in 8 PRKACA mutant ACA vs. 5 ACA without identified mutations (Goh et al.,).	('Ser133', 'Chemical', '-', (122, 128))	('CREB', 'Gene', '1385', (114, 118))	('mutant', 'Var', (141, 147))	('PRKACA', 'Gene', '5566', (134, 140))	('ACA', 'Phenotype', 'HP:0008256', (137, 140))	('ACA', 'Phenotype', 'HP:0008256', (158, 161))	('staining', 'MPA', (79, 87))	('higher', 'PosReg', (72, 78))	('ACA', 'Phenotype', 'HP:0008256', (148, 151))	('CREB', 'Gene', (114, 118))	('phosphorylation', 'MPA', (95, 110))	('PRKACA', 'Gene', (134, 140))
54270	26042218	Thus, the overall frequency of the PRKACA hotspot mutation is 38.2% and it has been identified in cortisol-producing adenomas only (Table 1).	('adenomas', 'Disease', (117, 125))	('cortisol', 'Chemical', 'MESH:D006854', (98, 106))	('PRKACA', 'Gene', (35, 41))	('ACA', 'Phenotype', 'HP:0008256', (38, 41))	('PRKACA', 'Gene', '5566', (35, 41))	('adenomas', 'Disease', 'MESH:D000236', (117, 125))	('mutation', 'Var', (50, 58))
54271	26042218	One study described a predominance of PRKACA mutations in females (Cao et al.,).	('PRKACA', 'Gene', (38, 44))	('ACA', 'Phenotype', 'HP:0008256', (41, 44))	('mutations', 'Var', (45, 54))	('PRKACA', 'Gene', '5566', (38, 44))
54272	26042218	Patients harboring tumors with PRKACA mutations were diagnosed with CS at younger ages (45.3 +- 13.5 vs. 52.5 +- 11.9 years) (Goh et al.,).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('CS', 'Phenotype', 'HP:0003118', (68, 70))	('PRKACA', 'Gene', (31, 37))	('ACA', 'Phenotype', 'HP:0008256', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Patients', 'Species', '9606', (0, 8))	('PRKACA', 'Gene', '5566', (31, 37))	('mutations', 'Var', (38, 47))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
54273	26042218	In five studies including both overt and subclinical CS (Beuschlein et al.,; Di Dalmazi et al.,; Goh et al.,; Nakajima et al.,; Sato et al.,), PRKACA mutations are significantly associated with overt CS and higher serum cortisol level after 1 mg of dexamethasone, increased urinary free cortisol and midnight cortisol levels compared to patients without mutations (Beuschlein et al.,).	('dexamethasone', 'Chemical', 'MESH:D003907', (249, 262))	('midnight cortisol levels', 'MPA', (300, 324))	('PRKACA', 'Gene', (143, 149))	('increased', 'PosReg', (264, 273))	('cortisol', 'Chemical', 'MESH:D006854', (287, 295))	('cortisol', 'Chemical', 'MESH:D006854', (220, 228))	('PRKACA', 'Gene', '5566', (143, 149))	('urinary free cortisol', 'MPA', (274, 295))	('cortisol', 'Chemical', 'MESH:D006854', (309, 317))	('mutations', 'Var', (150, 159))	('increased urinary free cortisol', 'Phenotype', 'HP:0012030', (264, 295))	('higher serum cortisol level', 'Phenotype', 'HP:0003118', (207, 234))	('CS', 'Phenotype', 'HP:0003118', (200, 202))	('patients', 'Species', '9606', (337, 345))	('serum cortisol level', 'MPA', (214, 234))	('CS', 'Phenotype', 'HP:0003118', (53, 55))	('ACA', 'Phenotype', 'HP:0008256', (146, 149))	('higher', 'PosReg', (207, 213))
54274	26042218	These results highlight a direct link between PRKACA mutations and cortisol production, which is expected knowing the physiological function of PKA.	('PRKACA', 'Gene', '5566', (46, 52))	('cortisol', 'Chemical', 'MESH:D006854', (67, 75))	('mutations', 'Var', (53, 62))	('ACA', 'Phenotype', 'HP:0008256', (49, 52))	('cortisol production', 'MPA', (67, 86))	('PRKACA', 'Gene', (46, 52))
54276	26042218	have found 11% (3/27) and 22% (2/9) of PRKACA mutations, respectively, at position 206 in subclinical CS patients (Table 1) (Goh et al.,; Sato et al.,).	('patients', 'Species', '9606', (105, 113))	('mutations', 'Var', (46, 55))	('CS', 'Phenotype', 'HP:0003118', (102, 104))	('ACA', 'Phenotype', 'HP:0008256', (42, 45))	('PRKACA', 'Gene', (39, 45))	('PRKACA', 'Gene', '5566', (39, 45))
54278	26042218	Interestingly, in transcriptomic data from 25 wild-type ACA and 11 mutant ACA, 232 genes are differentially expressed and pathway analysis demonstrates an enrichment in "biosynthesis and metabolism of steroid and cholesterol" and "response to chemical stimulus" (Cao et al.,).	('ACA', 'Phenotype', 'HP:0008256', (74, 77))	('cholesterol', 'Chemical', 'MESH:D002784', (213, 224))	('steroid', 'Chemical', 'MESH:D013256', (201, 208))	('mutant', 'Var', (67, 73))	('ACA', 'Phenotype', 'HP:0008256', (56, 59))	('metabolism of steroid', 'MPA', (187, 208))
54280	26042218	Altogether these results demonstrate that PRKACA mutations constitutively activate PKA leading to cortisol-producing adenomas, thereby suggesting that PRKACA is a main contributor to adrenocortical tumorigenesis.	('adenomas', 'Disease', (117, 125))	('leading to', 'Reg', (87, 97))	('ACA', 'Phenotype', 'HP:0008256', (154, 157))	('mutations', 'Var', (49, 58))	('cortisol', 'Chemical', 'MESH:D006854', (98, 106))	('PRKACA', 'Gene', (42, 48))	('PRKACA', 'Gene', (151, 157))	('PRKACA', 'Gene', '5566', (42, 48))	('PRKACA', 'Gene', '5566', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('ACA', 'Phenotype', 'HP:0008256', (45, 48))	('PKA', 'Gene', (83, 86))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (183, 211))	('adrenocortical tumorigenesis', 'Disease', (183, 211))	('adenomas', 'Disease', 'MESH:D000236', (117, 125))	('activate', 'PosReg', (74, 82))
54282	26042218	Activating mutations have also been identified in CTNNB1 and GNAS genes at lower frequency (Cao et al.,; Goh et al.,; Sato et al.,).	('CTNNB1', 'Gene', (50, 56))	('mutations', 'Var', (11, 20))	('GNAS', 'Gene', (61, 65))	('CTNNB1', 'Gene', '1499', (50, 56))	('GNAS', 'Gene', '2778', (61, 65))
54287	26042218	However, the second ACA group, which included the ACA with PRKACA mutations, appears to have a distinct tumorigenesis mechanism.	('mutations', 'Var', (66, 75))	('ACA', 'Phenotype', 'HP:0008256', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('PRKACA', 'Gene', (59, 65))	('tumor', 'Disease', (104, 109))	('ACA', 'Phenotype', 'HP:0008256', (20, 23))	('ACA', 'Phenotype', 'HP:0008256', (62, 65))	('PRKACA', 'Gene', '5566', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
54288	26042218	This is supported by the observation of three studies that tumors with mutations in PRKACA were significantly smaller than the non-mutant ones (Di Dalmazi et al.,; Goh et al.,; Sato et al.,).	('smaller', 'NegReg', (110, 117))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (71, 80))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('ACA', 'Phenotype', 'HP:0008256', (87, 90))	('PRKACA', 'Gene', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('PRKACA', 'Gene', '5566', (84, 90))
54290	26042218	Most recently, genomic duplication of the locus of PRKACB encoding for the Cbeta catalytic subunit have also been described in a patient with CNC without CS (Forlino et al.,).	('CS', 'Phenotype', 'HP:0003118', (154, 156))	('PRKACB', 'Gene', '5567', (51, 57))	('described', 'Reg', (114, 123))	('genomic duplication', 'Var', (15, 34))	('PRKACB', 'Gene', (51, 57))	('CNC without', 'Disease', (142, 153))	('patient', 'Species', '9606', (129, 136))
54291	26042218	Comparative genomic hybridization of 35 BAH with overt CS demonstrated copy number gain at chr19p locus that included PRKACA gene in 5 patients (Beuschlein et al.,; Stratakis,; Carney et al.,).	('copy number', 'Var', (71, 82))	('patients', 'Species', '9606', (135, 143))	('chr19p', 'Gene', (91, 97))	('gain', 'PosReg', (83, 87))	('BAH', 'Chemical', '-', (40, 43))	('PRKACA', 'Gene', (118, 124))	('ACA', 'Phenotype', 'HP:0008256', (121, 124))	('CS', 'Phenotype', 'HP:0003118', (55, 57))	('PRKACA', 'Gene', '5566', (118, 124))
54296	26042218	This phenotype is comparable with PKA activation through PRKAR1A inactivation or PDEs mutations causing PPNAD (Almeida and Stratakis,).	('mutations', 'Var', (86, 95))	('PPNAD', 'Disease', (104, 109))	('causing', 'Reg', (96, 103))	('inactivation', 'Var', (65, 77))	('PDEs', 'Gene', (81, 85))	('PPNAD', 'Chemical', '-', (104, 109))
54299	26042218	Whereas somatic mutations that lead to overactivity cause ACAs (Stratakis,), germline defects cause BAH depending on genetic dosage (Lodish et al.,).	('BAH', 'Chemical', '-', (100, 103))	('BAH', 'Disease', (100, 103))	('ACAs', 'Disease', (58, 62))	('ACA', 'Phenotype', 'HP:0008256', (58, 61))	('mutations', 'Var', (16, 25))	('cause', 'Reg', (94, 99))
54300	26042218	PRKACA mutations have been described in almost 40% of cortisol-producing ACA and are therefore, the most frequent genetic alteration in these tumors (Table 1).	('cortisol', 'Chemical', 'MESH:D006854', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('described', 'Reg', (27, 36))	('PRKACA', 'Gene', (0, 6))	('cortisol-producing ACA', 'Disease', (54, 76))	('ACA', 'Phenotype', 'HP:0008256', (3, 6))	('PRKACA', 'Gene', '5566', (0, 6))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('ACA', 'Phenotype', 'HP:0008256', (73, 76))	('mutations', 'Var', (7, 16))
54302	26042218	Two inhibitors H89 and KT5720 have successfully decreased PKA activity induced by the transfection of Leu206Arg variant in HEK293 cells (Sato et al.,).	('HEK293', 'CellLine', 'CVCL:0045', (123, 129))	('Leu206Arg', 'Var', (102, 111))	('Leu206Arg', 'Chemical', '-', (102, 111))	('decreased', 'NegReg', (48, 57))	('PKA', 'CPA', (58, 61))
54305	26042218	The PKA inhibitor (PKI) is an endogenous thermostable peptide that interacts with the catalytic domain and is able to inhibit Leu206Arg variant in vitro (Cao et al.,).	('inhibit', 'NegReg', (118, 125))	('interacts', 'Interaction', (67, 76))	('Leu206Arg', 'Chemical', '-', (126, 135))	('Leu206Arg', 'Var', (126, 135))
54326	25593820	Mean thickness of gland is 5-6 mm with maximum width of 10 mm and approximate length is 2-4 cm in one section of CT. Paucity of retroperitoneal fat may render visualization of adrenals difficult due to overlap of surrounding structures.	('Paucity', 'Var', (117, 124))	('fat', 'Gene', '2195', (144, 147))	('fat', 'Gene', (144, 147))
54370	25593820	Isolated cases of macroscopic fat within the tumor mimicking myelolipoma have also been reported.	('fat', 'Gene', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('fat', 'Gene', '2195', (30, 33))	('tumor', 'Disease', (45, 50))	('macroscopic', 'Var', (18, 29))	('myelolipoma', 'Disease', 'MESH:D018209', (61, 72))	('myelolipoma', 'Disease', (61, 72))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
54407	24836548	Although most studies regarding adjuvant therapy are small and retrospective in nature, there is good evidence that radiation therapy prevents local recurrence and mitotane prolongs recurrence-free survival .	('local recurrence', 'CPA', (143, 159))	('prolongs', 'PosReg', (173, 181))	('mitotane', 'Var', (164, 172))	('mitotane', 'Chemical', 'MESH:D008939', (164, 172))	('recurrence-free survival', 'CPA', (182, 206))
54542	33650791	2  Molecular studies identified a correlation between ACC onset and genetic mutations, particularly involving TP53, CTNNB1 (beta-catenin) and IGF-II genes.	('ACC onset', 'Disease', (54, 63))	('TP53', 'Gene', '7157', (110, 114))	('beta-catenin', 'Gene', (124, 136))	('TP53', 'Gene', (110, 114))	('beta-catenin', 'Gene', '1499', (124, 136))	('IGF-II', 'Gene', (142, 148))	('genetic mutations', 'Var', (68, 85))	('IGF-II', 'Gene', '3481', (142, 148))	('CTNNB1', 'Gene', '1499', (116, 122))	('CTNNB1', 'Gene', (116, 122))
54543	33650791	3  Recently, genomic characterizations of ACC expanded the list of known mutations including also those on PRKAR1A (protein kinase cAMP-dependent regulatory type I alpha), RPL22 (ribosomal protein L22), TERF2 (telomere specific protein 2), CCNE1 (cyclin E1) and NF1 (neurofibromatosis type 1) genes  4  and revealed high heterogeneity and histotype-specific genomic profiles.	('NF1', 'Gene', '4763', (262, 265))	('cyclin E1', 'Gene', '898', (247, 256))	('mutations', 'Var', (73, 82))	('NF1', 'Gene', (262, 265))	('telomere specific protein 2', 'Gene', '7014', (210, 237))	('neurofibromatosis type 1', 'Gene', (267, 291))	('PRKAR1A', 'Gene', '5573', (107, 114))	('ribosomal protein L22', 'Gene', '6146', (179, 200))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (267, 284))	('telomere specific protein 2', 'Gene', (210, 237))	('cyclin E1', 'Gene', (247, 256))	('RPL22', 'Gene', '6146', (172, 177))	('CCNE1', 'Gene', (240, 245))	('RPL22', 'Gene', (172, 177))	('neurofibromatosis type 1', 'Gene', '4763', (267, 291))	('protein kinase cAMP-dependent regulatory type I alpha', 'Gene', '5573', (116, 169))	('ribosomal protein L22', 'Gene', (179, 200))	('CCNE1', 'Gene', '898', (240, 245))	('TERF2', 'Gene', (203, 208))	('TERF2', 'Gene', '7014', (203, 208))	('PRKAR1A', 'Gene', (107, 114))
54601	33650791	Sirt1 silencing was able to inhibit H295R (Figure 1E) and SW13 (Figure 1F) cell proliferation by 50% and 40%, respectively.	('H295R', 'Chemical', '-', (36, 41))	('SW13', 'CPA', (58, 62))	('H295R', 'Var', (36, 41))	('SW13', 'CellLine', 'CVCL:0542', (58, 62))	('Sirt1', 'Gene', (0, 5))	('Sirt1', 'Gene', '23411', (0, 5))	('silencing', 'Var', (6, 15))	('inhibit', 'NegReg', (28, 35))
54612	33650791	In addition, sirt1 silencing led to parp-1 cleavage (Figure S1D).	('sirt1', 'Gene', '23411', (13, 18))	('silencing', 'Var', (19, 28))	('parp-1', 'Gene', '142', (36, 42))	('parp-1', 'Gene', (36, 42))	('sirt1', 'Gene', (13, 18))
54615	33650791	N-cadherin and vimentin were reduced by sirtinol (Figure 3C) and siRNA for sirt1 (Figure 3D).	('vimentin', 'Gene', '7431', (15, 23))	('N-cadherin', 'Gene', (0, 10))	('vimentin', 'Gene', (15, 23))	('reduced', 'NegReg', (29, 36))	('sirt1', 'Gene', (75, 80))	('N-cadherin', 'Gene', '1000', (0, 10))	('siRNA', 'Var', (65, 70))	('sirtinol', 'Chemical', 'MESH:C439060', (40, 48))	('sirt1', 'Gene', '23411', (75, 80))
54621	33650791	Using a quantitative real-time PCR analysis, we observed that inhibition of sirt1 reduces mRNA levels of ERalpha and CCND1, a major ERalpha target gene involved in cell cycle regulation, 35  in H295R (Figure 4A) as well as in SW13 cells (Figure S2A).	('mRNA levels', 'MPA', (90, 101))	('SW13', 'CellLine', 'CVCL:0542', (226, 230))	('ERalpha', 'Gene', '2099', (105, 112))	('sirt1', 'Gene', (76, 81))	('H295R', 'Chemical', '-', (194, 199))	('CCND1', 'Gene', '595', (117, 122))	('ERalpha', 'Gene', (105, 112))	('sirt1', 'Gene', '23411', (76, 81))	('ERalpha', 'Gene', '2099', (132, 139))	('inhibition', 'Var', (62, 72))	('ERalpha', 'Gene', (132, 139))	('H295R', 'Var', (194, 199))	('CCND1', 'Gene', (117, 122))	('reduces', 'NegReg', (82, 89))
54642	33650791	We demonstrated that pharmacological inhibition of sirt1 by sirtinol reduced H295R and SW13 cell viability in a time- and dose-dependent manner and decreased cell ability to form colonies.	('H295R', 'Chemical', '-', (77, 82))	('H295R', 'Var', (77, 82))	('sirt1', 'Gene', (51, 56))	('reduced', 'NegReg', (69, 76))	('decreased', 'NegReg', (148, 157))	('SW13', 'CellLine', 'CVCL:0542', (87, 91))	('sirt1', 'Gene', '23411', (51, 56))	('sirtinol', 'Chemical', 'MESH:C439060', (60, 68))	('cell ability to form colonies', 'CPA', (158, 187))
54643	33650791	In support to its oncogenic role, it has been reported that sirt1 deacetylates and inactivates tumour suppressors promoting cell proliferation and angiogenesis and blocking apoptosis.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('blocking', 'NegReg', (164, 172))	('deacetylates', 'Var', (66, 78))	('apoptosis', 'CPA', (173, 182))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('angiogenesis', 'CPA', (147, 159))	('tumour', 'Disease', (95, 101))	('promoting', 'PosReg', (114, 123))	('sirt1', 'Gene', (60, 65))	('cell proliferation', 'CPA', (124, 142))	('sirt1', 'Gene', '23411', (60, 65))	('inactivates', 'NegReg', (83, 94))
54646	33650791	39  Additionally, another paper reported how in human epithelial cancer cells derived from colorectal, breast and cervical carcinomas, sirt1 silencing induces growth arrest and/or apoptosis.	('carcinomas', 'Disease', (123, 133))	('silencing', 'Var', (141, 150))	('epithelial cancer', 'Phenotype', 'HP:0031492', (54, 71))	('growth arrest', 'Phenotype', 'HP:0001510', (159, 172))	('sirt1', 'Gene', (135, 140))	('human', 'Species', '9606', (48, 53))	('cancer', 'Disease', (65, 71))	('induces', 'Reg', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('sirt1', 'Gene', '23411', (135, 140))	('carcinomas', 'Disease', 'MESH:D009369', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('growth arrest', 'Disease', (159, 172))	('apoptosis', 'CPA', (180, 189))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('growth arrest', 'Disease', 'MESH:D006323', (159, 172))
54647	33650791	40  Similarly, in cutaneous T-cell lymphoma sirt1 knockdown resulted in reduced cellular metabolism and proliferation, increased apoptosis and PARP-1 inactivation.	('sirt1', 'Gene', '23411', (44, 49))	('inactivation', 'NegReg', (150, 162))	('reduced', 'NegReg', (72, 79))	('cutaneous T-cell lymphoma', 'Disease', 'MESH:D016410', (18, 43))	('PARP-1', 'Gene', '142', (143, 149))	('apoptosis', 'CPA', (129, 138))	('cutaneous T-cell lymphoma', 'Phenotype', 'HP:0012192', (18, 43))	('cellular', 'CPA', (80, 88))	('proliferation', 'CPA', (104, 117))	('knockdown', 'Var', (50, 59))	('cutaneous T-cell lymphoma', 'Disease', (18, 43))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (28, 43))	('lymphoma', 'Phenotype', 'HP:0002665', (35, 43))	('sirt1', 'Gene', (44, 49))	('PARP-1', 'Gene', (143, 149))	('increased', 'PosReg', (119, 128))	('cell lymphoma', 'Phenotype', 'HP:0012191', (30, 43))
54651	33650791	Sirt1 inhibition allows the increase of bax expression, cytochrome c release, decrease of bcl-2 and activation of apoptosis.	('bcl-2', 'Gene', '596', (90, 95))	('bax', 'Gene', '581', (40, 43))	('decrease', 'NegReg', (78, 86))	('cytochrome c', 'Gene', (56, 68))	('cytochrome c', 'Gene', '54205', (56, 68))	('bax', 'Gene', (40, 43))	('Sirt1', 'Gene', (0, 5))	('inhibition', 'Var', (6, 16))	('bcl-2', 'Gene', (90, 95))	('Sirt1', 'Gene', '23411', (0, 5))	('apoptosis', 'CPA', (114, 123))	('increase', 'PosReg', (28, 36))
54652	33650791	42 ,  43  In this paper, we also confirmed a role for sirt1 in the EMT, a process in which the loss of non-mobile epithelial phenotype allows cells to dissolve their cellular junctions and transform into individual and mobile mesenchymal cells leading tumour metastasis.	('sirt1', 'Gene', '23411', (54, 59))	('tumour metastasis', 'Disease', 'MESH:D009362', (252, 269))	('transform', 'Reg', (189, 198))	('sirt1', 'Gene', (54, 59))	('EMT', 'Disease', (67, 70))	('tumour metastasis', 'Disease', (252, 269))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('loss', 'Var', (95, 99))
54653	33650791	44  We demonstrated that the lack of sirt1 interferes with H295R cell motility and migration reducing the expression of some EMT markers such as N-cadherin and vimentin.	('lack', 'Var', (29, 33))	('H295R', 'Chemical', '-', (59, 64))	('expression', 'MPA', (106, 116))	('vimentin', 'Gene', '7431', (160, 168))	('H295R cell motility', 'CPA', (59, 78))	('sirt1', 'Gene', (37, 42))	('reducing', 'NegReg', (93, 101))	('vimentin', 'Gene', (160, 168))	('N-cadherin', 'Gene', (145, 155))	('interferes', 'NegReg', (43, 53))	('sirt1', 'Gene', '23411', (37, 42))	('N-cadherin', 'Gene', '1000', (145, 155))	('migration', 'CPA', (83, 92))
54662	33650791	53  beta-tubulin depletion reduces metastasis via down-regulation of signalling molecules such as beta3 Integrin, p-FAK and p-Src in MDA-MB231 cells.	('metastasis', 'CPA', (35, 45))	('reduces', 'NegReg', (27, 34))	('beta3 Integrin', 'Protein', (98, 112))	('Src', 'Gene', (126, 129))	('Src', 'Gene', '6714', (126, 129))	('MDA-MB231', 'CellLine', 'CVCL:0062', (133, 142))	('down-regulation', 'NegReg', (50, 65))	('FAK', 'Gene', (116, 119))	('FAK', 'Gene', '5747', (116, 119))	('depletion', 'Var', (17, 26))	('beta-tubulin', 'Protein', (4, 16))
54669	33650791	8  Here, we demonstrated that loss of sirt1 down-regulated ERalpha and its target gene CCND1.	('down-regulated', 'NegReg', (44, 58))	('sirt1', 'Gene', '23411', (38, 43))	('CCND1', 'Gene', '595', (87, 92))	('ERalpha', 'Gene', (59, 66))	('ERalpha', 'Gene', '2099', (59, 66))	('loss', 'Var', (30, 34))	('CCND1', 'Gene', (87, 92))	('sirt1', 'Gene', (38, 43))
54681	33650791	60   Overall, our study proves that targeting sirt1 is sufficient to reduce activity of two major players in ACC: oestrogens and IGF-II.	('activity', 'MPA', (76, 84))	('sirt1', 'Gene', (46, 51))	('targeting', 'Var', (36, 45))	('oestrogens', 'MPA', (114, 124))	('sirt1', 'Gene', '23411', (46, 51))	('reduce', 'NegReg', (69, 75))	('IGF-II', 'Gene', (129, 135))	('IGF-II', 'Gene', '3481', (129, 135))
54684	33650791	In particular, we revealed that both sirt1 pharmacological inhibition (sirtinol) and gene silencing reduce proliferation of H295R and SW13 adrenocortical cancer cells by interfering with E2/ERalpha and IGF1R pathways through the inhibition of several proteins, such as ERalpha, CCND1 and IGF1R (Figure 6) and activating apoptosis.	('activating', 'PosReg', (309, 319))	('gene silencing', 'Var', (85, 99))	('sirt1', 'Gene', (37, 42))	('IGF1R', 'Gene', '3480', (288, 293))	('sirt1', 'Gene', '23411', (37, 42))	('IGF1R', 'Gene', (202, 207))	('E2/ERalpha', 'Gene', '106478911;2099', (187, 197))	('SW13', 'CellLine', 'CVCL:0542', (134, 138))	('CCND1', 'Gene', '595', (278, 283))	('IGF1R', 'Gene', (288, 293))	('inhibition', 'NegReg', (229, 239))	('ERalpha', 'Gene', (269, 276))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (139, 160))	('reduce', 'NegReg', (100, 106))	('ERalpha', 'Gene', (190, 197))	('CCND1', 'Gene', (278, 283))	('sirtinol', 'Chemical', 'MESH:C439060', (71, 79))	('proliferation', 'CPA', (107, 120))	('E2/ERalpha', 'Gene', (187, 197))	('interfering', 'NegReg', (170, 181))	('ERalpha', 'Gene', '2099', (269, 276))	('ERalpha', 'Gene', '2099', (190, 197))	('apoptosis', 'CPA', (320, 329))	('adrenocortical cancer', 'Disease', (139, 160))	('H295R', 'Chemical', '-', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('IGF1R', 'Gene', '3480', (202, 207))	('proteins', 'Protein', (251, 259))
54696	31523056	In addition, COMMD6 may modulate the ubiquitination and degradation of NF-kappaB subunits and regulate ribonucleoprotein and spliceosome complex biogenesis in tumours.	('regulate', 'Reg', (94, 102))	('tumours', 'Disease', (159, 166))	('degradation', 'MPA', (56, 67))	('NF-kappaB', 'Gene', (71, 80))	('COMMD6', 'Var', (13, 19))	('NF-kappaB', 'Gene', '4790', (71, 80))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('ubiquitination', 'MPA', (37, 51))	('modulate', 'Reg', (24, 32))
54710	31523056	It is also found that nuclear expression of COMMD1 sensitises ovarian cancer to cisplatin, and downregulation COMMD1 promotes tumour development by modulating a positive feedback loop that amplifies inflammatory- and stemness-associated properties of cancer cells.	('positive feedback loop', 'MPA', (161, 183))	('sensitises ovarian cancer', 'Disease', (51, 76))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('COMMD1', 'Gene', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('promotes', 'PosReg', (117, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('cancer', 'Disease', (70, 76))	('downregulation', 'Var', (95, 109))	('COMMD1', 'Gene', '150684', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('amplifies', 'PosReg', (189, 198))	('cancer', 'Disease', (251, 257))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('COMMD1', 'Gene', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('sensitises ovarian cancer', 'Disease', 'MESH:D010051', (51, 76))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('modulating', 'Reg', (148, 158))	('COMMD1', 'Gene', '150684', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
54711	31523056	In addition, COMMD5 inhibits renal cell carcinoma by promoting de-phosphorylation of ErbB2/HER2 and epigenetic gene silencing of EGFR and ErbB3 via promoter methylation.	('de-phosphorylation', 'MPA', (63, 81))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (29, 49))	('inhibits', 'NegReg', (20, 28))	('ErbB2', 'Gene', (85, 90))	('epigenetic gene silencing', 'Var', (100, 125))	('renal cell carcinoma', 'Disease', (29, 49))	('COMMD5', 'Gene', (13, 19))	('COMMD5', 'Gene', '28991', (13, 19))	('ErbB3', 'Gene', (138, 143))	('ErbB3', 'Gene', '2065', (138, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (29, 49))	('EGFR', 'Gene', '1956', (129, 133))	('promoting', 'PosReg', (53, 62))	('HER2', 'Gene', (91, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('ErbB2', 'Gene', '2064', (85, 90))	('HER2', 'Gene', '2064', (91, 95))	('EGFR', 'Gene', (129, 133))
54713	31523056	It has also been found that inhibition of COMMD7 suppresses invasion of pancreatic ductal adenocarcinoma by decreasing MMP2 secretion.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (72, 104))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (72, 104))	('invasion', 'CPA', (60, 68))	('MMP2', 'Gene', '4313', (119, 123))	('inhibition', 'Var', (28, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('COMMD7', 'Gene', '149951', (42, 48))	('COMMD7', 'Gene', (42, 48))	('pancreatic ductal adenocarcinoma', 'Disease', (72, 104))	('decreasing', 'NegReg', (108, 118))	('MMP2', 'Gene', (119, 123))	('suppresses', 'NegReg', (49, 59))
54717	31523056	Moreover, COMMD6 has also been reported to be involved in the inhibition of NF-kappaB pathway activity in HEK-293 cells.	('NF-kappaB', 'Gene', (76, 85))	('activity', 'MPA', (94, 102))	('NF-kappaB', 'Gene', '4790', (76, 85))	('COMMD6', 'Var', (10, 16))	('inhibition', 'NegReg', (62, 72))	('HEK-293', 'CellLine', 'CVCL:0045', (106, 113))
54718	31523056	The activation of NF-kappaB could be completely abolished by the mutation of the amino acid residues Trp24 and Pro41 in the COMM domain of COMMD6.	('Trp24', 'Gene', (101, 106))	('abolished', 'NegReg', (48, 57))	('NF-kappaB', 'Gene', '4790', (18, 27))	('mutation', 'Var', (65, 73))	('NF-kappaB', 'Gene', (18, 27))	('Trp24', 'Chemical', 'MESH:C509690', (101, 106))	('activation', 'PosReg', (4, 14))
54742	31523056	The mutation of COMMD6 in human tumour cell lines evaluated by COSMIC database (https://cancer.sanger.ac.uk/cosmic).	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('COMMD6', 'Gene', (16, 22))	('tumour', 'Disease', (32, 38))	('mutation', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('human', 'Species', '9606', (26, 31))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
54774	31523056	High expression of COMMD6 was associated with shorter overall survival (OS) and disease free survival (DFS) in patients with head and neck squamous cell carcinoma (HNSC, P = 0.0084 and HR = 1.7 for OS; P = 0.0056 and HR = 2.0 for DFS), cholangiocarcinoma (CHOL, P = 0.05 and HR = 2.7 for OS; P = 0.029 and HR = 2.8 for DFS) and adrenocortical carcinoma (ACC, P = 0.0077 and HR = 2.9 for OS; P = 0.0053 and HR = 2.6 for DFS) (Fig.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (125, 162))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (236, 254))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (328, 352))	('High', 'Var', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (125, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (236, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('disease free survival', 'CPA', (80, 101))	('adrenocortical carcinoma', 'Disease', (328, 352))	('overall survival', 'CPA', (54, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('COMMD6', 'Gene', (19, 25))	('shorter', 'NegReg', (46, 53))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (328, 352))	('cholangiocarcinoma', 'Disease', (236, 254))	('patients', 'Species', '9606', (111, 119))
54775	31523056	In contrast, high expression of COMMD6 was associated with longer OS and DFS in patients with brain lower grade glioma (LGG, P = 0.0016 and HR = 0.56 for OS; P = 0.0096 and HR = 0.66 for DFS) and uveal melanoma (UVM, P = 0.0085 and HR = 0.30 for OS; P = 0.028 and HR = 0.35 for DFS) (Fig.	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('patients', 'Species', '9606', (80, 88))	('high expression', 'Var', (13, 28))	('COMMD6', 'Gene', (32, 38))	('glioma', 'Disease', (112, 118))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('uveal melanoma', 'Disease', 'MESH:C536494', (196, 210))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('DFS', 'MPA', (73, 76))	('uveal melanoma', 'Phenotype', 'HP:0007716', (196, 210))	('uveal melanoma', 'Disease', (196, 210))
54776	31523056	In addition, high expression of COMMD6 was associated with longer OS in patients with testicular germ cell tumours (TGCT, P = 0.05, HR = 1.7E-09), longer DFS in patients with thyroid carcinoma (THCA, P = 0.017, HR = 0.48) and uterine corpus endometrial carcinoma (UCEC, P = 0.029, HR = 0.47) (Fig.	('TGCT', 'Disease', (116, 120))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('THCA', 'Disease', 'MESH:D013964', (194, 198))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('THCA', 'Disease', (194, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('endometrial carcinoma', 'Disease', (241, 262))	('longer', 'PosReg', (147, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('DFS', 'MPA', (154, 157))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (175, 192))	('patients', 'Species', '9606', (161, 169))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (241, 262))	('thyroid carcinoma', 'Disease', (175, 192))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (241, 262))	('high expression', 'Var', (13, 28))	('TGCT', 'Disease', 'MESH:C563236', (116, 120))	('COMMD6', 'Gene', (32, 38))	('testicular germ cell tumours', 'Disease', 'MESH:C563236', (86, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (175, 192))	('testicular germ cell tumours', 'Disease', (86, 114))	('patients', 'Species', '9606', (72, 80))
54799	31523056	COMMD6 has been reported to completely abolish NF-kappaB pathway activity by the mutation of the amino acid residues Trp24 and Pro41 in the COMM domain in HEK293 cells, indicating that COMMD6 may also play a vital role in the tumorigenesis and malignant progression.	('Trp24', 'Gene', (117, 122))	('activity', 'MPA', (65, 73))	('NF-kappaB', 'Gene', (47, 56))	('mutation', 'Var', (81, 89))	('Trp24', 'Chemical', 'MESH:C509690', (117, 122))	('abolish', 'NegReg', (39, 46))	('HEK293', 'CellLine', 'CVCL:0045', (155, 161))	('NF-kappaB', 'Gene', '4790', (47, 56))
54803	31523056	Phylogenetic analysis results showed that COMMD6 was clustered with COMMD7, COMMD8 and COMMD10 rather than other COMMD family members, indicating that these four COMMD members might play familiar roles during evolution.	('COMMD10', 'Gene', '51397', (87, 94))	('COMMD7', 'Gene', '149951', (68, 74))	('COMMD7', 'Gene', (68, 74))	('COMMD8', 'Gene', (76, 82))	('COMMD6', 'Var', (42, 48))	('COMMD10', 'Gene', (87, 94))	('COMMD8', 'Gene', '54951', (76, 82))
54848	31523056	Mutations of ribosome genes have been detected in various tumours, such as endometrial cancer, colorectal cancer and glioma.	('detected', 'Reg', (38, 46))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('ribosome genes', 'Gene', (13, 27))	('Mutations', 'Var', (0, 9))	('endometrial cancer', 'Phenotype', 'HP:0012114', (75, 93))	('colorectal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('endometrial cancer', 'Disease', (75, 93))	('glioma', 'Disease', (117, 123))	('endometrial cancer', 'Disease', 'MESH:D016889', (75, 93))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('rectal cancer', 'Phenotype', 'HP:0100743', (99, 112))	('tumours', 'Disease', (58, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))
54850	31523056	Inhibition of the spliceosome impairs survival, tumorigenicity and metastasis of MYC-dependent breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumorigenicity', 'CPA', (48, 62))	('impairs', 'NegReg', (30, 37))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('metastasis', 'CPA', (67, 77))	('survival', 'CPA', (38, 46))	('Inhibition', 'Var', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
54852	31523056	More importantly, the expression of COMMD6 could predict the survival of cancer patients, indicating the significant role of COMMD6 in tumour development and progression.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('patients', 'Species', '9606', (80, 88))	('expression', 'Var', (22, 32))	('COMMD6', 'Gene', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('tumour', 'Disease', (135, 141))	('predict', 'Reg', (49, 56))
54854	31523056	In addition, we found that COMMD6 may modulate the ubiquitination and degradation of NF-kappaB subunits and regulate ribonucleoprotein and spliceosome complex biogenesis in tumours.	('degradation', 'MPA', (70, 81))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumours', 'Disease', (173, 180))	('NF-kappaB', 'Gene', '4790', (85, 94))	('ubiquitination', 'MPA', (51, 65))	('NF-kappaB', 'Gene', (85, 94))	('COMMD6', 'Var', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('regulate', 'Reg', (108, 116))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('modulate', 'Reg', (38, 46))
54862	31301403	While 5-oxo-ETE did not affect the growth of H295R cells, overexpression of OXE receptor caused an increase in cell proliferation, which was further increased by 5-oxo-ETE and blocked by 5-lipoxygenase inhibition.	('5-oxo-ETE', 'Chemical', '-', (162, 171))	('5-oxo-ETE', 'Var', (162, 171))	('OXE receptor', 'Gene', '165140', (76, 88))	('increased', 'PosReg', (149, 158))	('OXE receptor', 'Gene', (76, 88))	('cell proliferation', 'CPA', (111, 129))	('overexpression', 'PosReg', (58, 72))	('5-lipoxygenase', 'Gene', '240', (187, 201))	('5-lipoxygenase', 'Gene', (187, 201))	('H295R', 'CellLine', 'CVCL:0458', (45, 50))	('increase', 'PosReg', (99, 107))	('5-oxo-ETE', 'Chemical', '-', (6, 15))
54863	31301403	5-oxo-ETE increased the migratory capacity of H295R cells in wound healing assays, but it did not induce the production of metalloproteases MMP-1, MMP-2, MMP-9 and MMP-10.	('MMP-9', 'Gene', (154, 159))	('MMP-1', 'Gene', '4312', (140, 145))	('MMP-1', 'Gene', '4312', (164, 169))	('MMP-2', 'Gene', (147, 152))	('MMP-1', 'Gene', (140, 145))	('MMP-10', 'Gene', (164, 170))	('MMP-1', 'Gene', (164, 169))	('MMP-10', 'Gene', '4319', (164, 170))	('migratory capacity', 'CPA', (24, 42))	('5-oxo-ETE', 'Var', (0, 9))	('MMP-2', 'Gene', '4313', (147, 152))	('MMP-9', 'Gene', '4318', (154, 159))	('H295R', 'CellLine', 'CVCL:0458', (46, 51))	('increased', 'PosReg', (10, 19))	('5-oxo-ETE', 'Chemical', '-', (0, 9))
54864	31301403	The pro-migratory effect of 5-oxo-ETE was reduced by pharmacological inhibition of the MEK/ERK1/2, p38 and PKC pathways.	('reduced', 'NegReg', (42, 49))	('p38', 'Gene', '5594', (99, 102))	('pro-migratory effect', 'CPA', (4, 24))	('PKC', 'Gene', (107, 110))	('PKC', 'Gene', '112476', (107, 110))	('MEK', 'Gene', (87, 90))	('p38', 'Gene', (99, 102))	('MEK', 'Gene', '5609', (87, 90))	('ERK1/2', 'Gene', (91, 97))	('ERK1/2', 'Gene', '5595;5594', (91, 97))	('5-oxo-ETE', 'Chemical', '-', (28, 37))	('5-oxo-ETE', 'Var', (28, 37))
54866	31301403	ERK activation by the eicosanoid was reduced by the "pan" PKC inhibitor GF109203X but not by the classical PKC inhibitor Go6976, suggesting the involvement of novel PKCs in this effect.	('PKC', 'Gene', (58, 61))	('Go6976', 'Chemical', 'MESH:C081021', (121, 127))	('GF109203X', 'Chemical', 'MESH:C070515', (72, 81))	('PKC', 'Gene', (165, 168))	('PKC', 'Gene', '112476', (58, 61))	('PKC', 'Gene', '112476', (165, 168))	('eicosanoid', 'Chemical', 'MESH:D015777', (22, 32))	('PKC', 'Gene', (107, 110))	('PKC', 'Gene', '112476', (107, 110))	('ERK', 'Gene', '5594', (0, 3))	('reduced', 'NegReg', (37, 44))	('ERK', 'Gene', (0, 3))	('GF109203X', 'Var', (72, 81))	('activation', 'PosReg', (4, 14))
54867	31301403	Although H295R cells display detectable phosphorylation of Ser299 in PKCdelta, a readout for the activation of this novel PKC, treatment with 5-oxo-ETE per se was unable to induce additional PKCdelta activation.	('PKCdelta', 'Gene', (69, 77))	('PKC', 'Gene', (122, 125))	('5-oxo-ETE', 'Chemical', '-', (142, 151))	('PKC', 'Gene', '112476', (122, 125))	('PKC', 'Gene', (69, 72))	('PKC', 'Gene', '112476', (69, 72))	('Ser299', 'Var', (59, 65))	('PKCdelta', 'Gene', '5580', (191, 199))	('PKCdelta', 'Gene', (191, 199))	('Ser299', 'Chemical', '-', (59, 65))	('PKC', 'Gene', (191, 194))	('PKC', 'Gene', '112476', (191, 194))	('H295R', 'CellLine', 'CVCL:0458', (9, 14))	('PKCdelta', 'Gene', '5580', (69, 77))	('phosphorylation', 'MPA', (40, 55))
54868	31301403	Our results revealed signaling effectors activated by 5-oxo-ETE in H295R cells and may have significant implications for our understanding of OXE receptor in adrenocortical cell pathophysiology.	('OXE receptor', 'Gene', '165140', (142, 154))	('H295R', 'CellLine', 'CVCL:0458', (67, 72))	('5-oxo-ETE', 'Chemical', '-', (54, 63))	('5-oxo-ETE', 'Var', (54, 63))	('OXE receptor', 'Gene', (142, 154))	('activated', 'PosReg', (41, 50))	('signaling effectors', 'MPA', (21, 40))
54887	31301403	Our studies revealed that 5-oxo-ETE stimulates the migratory capacity of H295R cells, without having significant effects on proliferation.	('stimulates', 'PosReg', (36, 46))	('5-oxo-ETE', 'Chemical', '-', (26, 35))	('5-oxo-ETE', 'Var', (26, 35))	('migratory capacity of H295R cells', 'CPA', (51, 84))	('H295R', 'CellLine', 'CVCL:0458', (73, 78))
54892	31301403	The following reagents were used: 5-oxo-ETE (Santa Cruz), 8Br-cAMP (Sigma), angiotensin II (Sigma), phorbol 12-myristate 13-acetate (PMA, LC Laboratories), zileuton (5-LOX inhibitor, Cayman Chemical), H89 (PKA inhibitor, Calbiochem), PD98059 (MEK1/2 inhibitor, Calbiochem), SB203580 (p38 inhibitor, Cell Signaling Technology), wortmannin (PI3K inhibitor, Sigma), Go6976 (inhibitor of classical PKCs, Tocris Bioscience), GF109203X ("pan" PKC inhibitor, Tocris Bioscience).	('GF109203X', 'Chemical', 'MESH:C070515', (420, 429))	('PD98059', 'Chemical', 'MESH:C093973', (234, 241))	('H89', 'Chemical', 'MESH:C063509', (201, 204))	('angiotensin II', 'Gene', '183', (76, 90))	('wortmannin', 'Chemical', 'MESH:D000077191', (327, 337))	('GF109203X', 'Var', (420, 429))	('p38', 'Gene', '5594', (284, 287))	('PD98059', 'Var', (234, 241))	('Go6976', 'Chemical', 'MESH:C081021', (363, 369))	('PKC', 'Gene', '112476', (437, 440))	('5-LOX', 'Gene', (166, 171))	('MEK1/2', 'Gene', '5604;5605', (243, 249))	('Go6976', 'Var', (363, 369))	('5-oxo-ETE', 'Chemical', '-', (34, 43))	('MEK1/2', 'Gene', (243, 249))	('5-LOX', 'Gene', '240', (166, 171))	('PKC', 'Gene', (437, 440))	('PKC', 'Gene', '112476', (394, 397))	('angiotensin II', 'Gene', (76, 90))	('8Br-cAMP', 'Chemical', '-', (58, 66))	('zileuton', 'Chemical', 'MESH:C063449', (156, 164))	('p38', 'Gene', (284, 287))	('PMA', 'Chemical', 'MESH:D013755', (133, 136))	('SB203580', 'Chemical', 'MESH:C093642', (274, 282))	('PKC', 'Gene', (394, 397))
54906	31301403	For Western blotting, the primary antibodies used were: anti-phospho-ERK1/2 (Thr202/Tyr204), anti-total ERK1/2, anti-PKCdelta, anti-PKCalpha, anti-PKCepsilon , anti-PKCeta, anti-PKCzeta, anti-PKCiota, anti-phospho-p38, anti-total p38, anti-phospho-Akt, anti-total Akt (Cell Signaling Technology), anti-phospho-Ser299-PKCdelta (Abcam), anti-actin and anti-vinculin (Bio-Rad Laboratories).	('PKC', 'Gene', '112476', (147, 150))	('PKC', 'Gene', '112476', (178, 181))	('PKC', 'Gene', (165, 168))	('PKCdelta', 'Gene', '5580', (117, 125))	('PKC', 'Gene', (117, 120))	('PKCdelta', 'Gene', (117, 125))	('PKCalpha', 'Gene', '5578', (132, 140))	('p38', 'Gene', '5594', (230, 233))	('Ser299', 'Chemical', '-', (310, 316))	('PKC', 'Gene', (132, 135))	('PKC', 'Gene', (178, 181))	('anti-total', 'Var', (219, 229))	('PKC', 'Gene', (147, 150))	('PKCepsilon', 'Gene', '5581', (147, 157))	('PKC', 'Gene', '112476', (192, 195))	('p38', 'Gene', '5594', (214, 217))	('ERK1/2', 'Gene', (104, 110))	('PKCalpha', 'Gene', (132, 140))	('ERK1/2', 'Gene', '5595;5594', (104, 110))	('vinculin', 'Gene', (355, 363))	('PKC', 'Gene', (192, 195))	('PKCzeta', 'Gene', '5590', (178, 185))	('PKC', 'Gene', '112476', (317, 320))	('PKCzeta', 'Gene', (178, 185))	('p38', 'Gene', (230, 233))	('Akt', 'Gene', (264, 267))	('Akt', 'Gene', (248, 251))	('PKCepsilon', 'Gene', (147, 157))	('PKCdelta', 'Gene', '5580', (317, 325))	('PKC', 'Gene', '112476', (165, 168))	('PKCdelta', 'Gene', (317, 325))	('ERK1/2', 'Gene', (69, 75))	('ERK1/2', 'Gene', '5595;5594', (69, 75))	('PKC', 'Gene', (317, 320))	('PKC', 'Gene', '112476', (117, 120))	('vinculin', 'Gene', '7414', (355, 363))	('PKC', 'Gene', '112476', (132, 135))	('p38', 'Gene', (214, 217))	('Akt', 'Gene', '207', (264, 267))	('Akt', 'Gene', '207', (248, 251))
54921	31301403	Given that PKA- and PKC-dependent pathways are known to play relevant roles in adrenocortical cell physiology, we examined the effects of 8Br-cAMP, which directly activates PKA, and angiotensin II, which couples to the DAG/Ca/PKC pathway.	('PKC', 'Gene', (20, 23))	('PKC', 'Gene', (226, 229))	('8Br-cAMP', 'Var', (138, 146))	('activates', 'PosReg', (163, 172))	('PKC', 'Gene', '112476', (226, 229))	('PKC', 'Gene', '112476', (20, 23))	('8Br-cAMP', 'Chemical', '-', (138, 146))	('angiotensin II', 'Gene', '183', (182, 196))	('DAG', 'Chemical', 'MESH:D004075', (219, 222))	('angiotensin II', 'Gene', (182, 196))
54922	31301403	We found that treatment of H295R cells with 8Br-cAMP markedly reduced cell number (Fig.	('H295R', 'CellLine', 'CVCL:0458', (27, 32))	('8Br-cAMP', 'Var', (44, 52))	('cell number', 'CPA', (70, 81))	('8Br-cAMP', 'Chemical', '-', (44, 52))	('reduced', 'NegReg', (62, 69))
54923	31301403	Along the same line, we observed significant inhibition by 8Br-cAMP in BrdU incorporation (Fig 1B) and crystal violet assays (Fig.	('inhibition', 'NegReg', (45, 55))	('8Br-cAMP', 'Var', (59, 67))	('BrdU', 'Chemical', 'MESH:D001973', (71, 75))	('8Br-cAMP', 'Chemical', '-', (59, 67))	('crystal', 'CPA', (103, 110))	('BrdU incorporation', 'MPA', (71, 89))	('crystal violet', 'Chemical', 'MESH:D005840', (103, 117))
54927	31301403	Interestingly, we found that 5-oxo-ETE caused a significant increase in cell migration relative to control (vehicle-treated).	('cell migration', 'CPA', (72, 86))	('5-oxo-ETE', 'Chemical', '-', (29, 38))	('5-oxo-ETE', 'Var', (29, 38))	('increase', 'PosReg', (60, 68))
54931	31301403	8Br-cAMP caused a slight inhibition in cell migration, but this effect was not statistically significant (Fig.	('inhibition', 'NegReg', (25, 35))	('8Br-cAMP', 'Var', (0, 8))	('8Br-cAMP', 'Chemical', '-', (0, 8))	('cell migration', 'CPA', (39, 53))
54933	31301403	PD98059, an inhibitor of MEK (the kinase responsible for ERK activation), caused a major inhibition (~70%) of migration stimulated by 5-oxo-ETE, thus implying the involvement of the MEK/ERK pathway in this effect.	('ERK', 'Gene', '5594', (186, 189))	('MEK', 'Gene', (182, 185))	('MEK', 'Gene', '5609', (182, 185))	('MEK', 'Gene', (25, 28))	('migration', 'CPA', (110, 119))	('PD98059', 'Var', (0, 7))	('ERK', 'Gene', (186, 189))	('MEK', 'Gene', '5609', (25, 28))	('PD98059', 'Chemical', 'MESH:C093973', (0, 7))	('ERK', 'Gene', '5594', (57, 60))	('inhibition', 'NegReg', (89, 99))	('ERK', 'Gene', (57, 60))	('5-oxo-ETE', 'Chemical', '-', (134, 143))
54934	31301403	We also observed a significant inhibition (~45%) by SB203580, an inhibitor of the MAPK p38.	('inhibition', 'NegReg', (31, 41))	('p38', 'Gene', (87, 90))	('SB203580', 'Var', (52, 60))	('p38', 'Gene', '5594', (87, 90))	('SB203580', 'Chemical', 'MESH:C093642', (52, 60))
54937	31301403	Since PKC isozymes have been widely implicated in cell motility in a number of cancer cells, we examined the effects of two PKC inhibitors, GF109203X (a 'pan" PKC inhibitor) and Go6976 (which preferentially inhibits classical PKCs).	('PKC', 'Gene', (6, 9))	('PKC', 'Gene', (226, 229))	('PKC', 'Gene', '112476', (226, 229))	('PKC', 'Gene', '112476', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PKC', 'Gene', (159, 162))	('PKC', 'Gene', '112476', (159, 162))	('PKC', 'Gene', (124, 127))	('implicated', 'Reg', (36, 46))	('PKC', 'Gene', '112476', (124, 127))	('GF109203X', 'Var', (140, 149))	('GF109203X', 'Chemical', 'MESH:C070515', (140, 149))	('Go6976', 'Chemical', 'MESH:C081021', (178, 184))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('Go6976', 'Var', (178, 184))
54938	31301403	These experiments revealed that GF109203X reduced cell migration induced by 5-oxo-ETE by ~40%, whereas Go6976 had no effect.	('reduced', 'NegReg', (42, 49))	('GF109203X', 'Chemical', 'MESH:C070515', (32, 41))	('GF109203X', 'Var', (32, 41))	('5-oxo-ETE', 'Chemical', '-', (76, 85))	('Go6976', 'Chemical', 'MESH:C081021', (103, 109))	('cell migration', 'CPA', (50, 64))
54941	31301403	These experiments showed that 5-oxo-ETE caused a time-dependent increase in ERK1/2 and p38 phosphorylation without any effect on Akt phosphorylation (Fig.	('Akt', 'Gene', '207', (129, 132))	('ERK1/2', 'Gene', (76, 82))	('p38', 'Gene', (87, 90))	('ERK1/2', 'Gene', '5595;5594', (76, 82))	('increase', 'PosReg', (64, 72))	('5-oxo-ETE', 'Var', (30, 39))	('Akt', 'Gene', (129, 132))	('p38', 'Gene', '5594', (87, 90))	('5-oxo-ETE', 'Chemical', '-', (30, 39))
54943	31301403	3B, ERK1/2 phosphorylation was totally inhibited by GF109203X, whereas Go6976 had no effect on 5-oxo-ETE.	('ERK1/2', 'Gene', (4, 10))	('inhibited', 'NegReg', (39, 48))	('Go6976', 'Chemical', 'MESH:C081021', (71, 77))	('ERK1/2', 'Gene', '5595;5594', (4, 10))	('GF109203X', 'Chemical', 'MESH:C070515', (52, 61))	('phosphorylation', 'MPA', (11, 26))	('5-oxo-ETE', 'Chemical', '-', (95, 104))	('GF109203X', 'Var', (52, 61))
54949	31301403	4B shows that H259R cells display detectable basal levels PKCdelta phosphorylation in position Ser299, suggesting an elevated endogenous basal activation.	('PKCdelta', 'Gene', (58, 66))	('H259R', 'Mutation', 'p.H259R', (14, 19))	('endogenous basal activation', 'MPA', (126, 153))	('Ser299', 'Var', (95, 101))	('Ser299', 'Chemical', '-', (95, 101))	('elevated', 'PosReg', (117, 125))	('PKCdelta', 'Gene', '5580', (58, 66))
54971	31301403	5-oxo-ETE promotes cell growth and survival in breast and prostate cancer cells, while silencing the OXE-R decreases cell viability.	('breast and prostate cancer', 'Disease', 'MESH:D001943', (47, 73))	('silencing', 'Var', (87, 96))	('cell viability', 'CPA', (117, 131))	('OXE-R', 'Gene', (101, 106))	('OXE-R', 'Gene', '165140', (101, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (58, 73))	('cell growth', 'CPA', (19, 30))	('promotes', 'PosReg', (10, 18))	('survival', 'CPA', (35, 43))	('decreases', 'NegReg', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('5-oxo-ETE', 'Chemical', '-', (0, 9))
54973	31301403	It is interesting that enhanced cell proliferation could be observed in H295R cells that overexpress OXE-R, an effect that is further increased by 5-oxo-ETE and reduced by the inhibitor of the 5-LOX pathway zileuton.	('enhanced', 'PosReg', (23, 31))	('reduced', 'NegReg', (161, 168))	('5-LOX', 'Gene', (193, 198))	('5-oxo-ETE', 'Var', (147, 156))	('OXE-R', 'Gene', (101, 106))	('5-oxo-ETE', 'Chemical', '-', (147, 156))	('overexpress', 'PosReg', (89, 100))	('OXE-R', 'Gene', '165140', (101, 106))	('zileuton', 'Chemical', 'MESH:C063449', (207, 215))	('5-LOX', 'Gene', '240', (193, 198))	('H295R', 'CellLine', 'CVCL:0458', (72, 77))	('increased', 'PosReg', (134, 143))	('cell proliferation', 'CPA', (32, 50))
54978	31301403	Pro-migratory effects of 5-oxo-ETE, 5-HETE and 5-HPETE have been previously described in some models.	('5-oxo-ETE', 'Chemical', '-', (25, 34))	('Pro-migratory', 'CPA', (0, 13))	('5-HPETE', 'Var', (47, 54))	('5-HETE', 'Chemical', 'MESH:C022022', (36, 42))	('5-HPETE', 'Chemical', '-', (47, 54))
54980	31301403	More recently, it was reported that 5-oxo-ETE rearranges the actin cytoskeleton and induces migration in prostate cancer cells.	('actin cytoskeleton', 'MPA', (61, 79))	('prostate cancer', 'Disease', (105, 120))	('5-oxo-ETE', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('migration', 'CPA', (92, 101))	('induces', 'PosReg', (84, 91))	('5-oxo-ETE', 'Chemical', '-', (36, 45))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('rearranges', 'Reg', (46, 56))
54988	31301403	highlighted the potential of modulating the ERK pathway for the targeting of adrenal cancer.	('ERK', 'Gene', '5594', (44, 47))	('modulating', 'Var', (29, 39))	('adrenal cancer', 'Disease', (77, 91))	('ERK', 'Gene', (44, 47))	('adrenal cancer', 'Disease', 'MESH:D000310', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
54989	31301403	We found that ERK activation by 5-oxo-ETE is dependent on PKC activity, since it is impaired by the "pan" PKC inhibitor GF109203X.	('PKC', 'Gene', (58, 61))	('ERK', 'Gene', (14, 17))	('PKC', 'Gene', (106, 109))	('PKC', 'Gene', '112476', (106, 109))	('PKC', 'Gene', '112476', (58, 61))	('GF109203X', 'Chemical', 'MESH:C070515', (120, 129))	('impaired', 'NegReg', (84, 92))	('GF109203X', 'Var', (120, 129))	('5-oxo-ETE', 'Chemical', '-', (32, 41))	('ERK', 'Gene', '5594', (14, 17))	('activation', 'PosReg', (18, 28))
54990	31301403	The lack of effect of Go6976, an inhibitor of the classical PKCs is indicative of the involvement of novel PKCs.	('Go6976', 'Chemical', 'MESH:C081021', (22, 28))	('PKC', 'Gene', (107, 110))	('PKC', 'Gene', '112476', (107, 110))	('Go6976', 'Var', (22, 28))	('PKC', 'Gene', (60, 63))	('PKC', 'Gene', '112476', (60, 63))
54994	31301403	It is likely that novel PKCs are basally activated in H295R cells, which is consistent with the high phospho-Ser299-PKCdelta signal detected in these cells under basal conditions (see Fig.	('PKC', 'Gene', '112476', (116, 119))	('H295R', 'Var', (54, 59))	('PKC', 'Gene', (24, 27))	('PKC', 'Gene', '112476', (24, 27))	('H295R', 'CellLine', 'CVCL:0458', (54, 59))	('PKCdelta', 'Gene', '5580', (116, 124))	('Ser299', 'Chemical', '-', (109, 115))	('PKCdelta', 'Gene', (116, 124))	('PKC', 'Gene', (116, 119))
55128	29967789	Of patients taking mitotane, approximately 50%-74% have gastrointestinal discomfort, about 38%-60% may have symptoms in neuromuscular system, and a minority may present with elevated aminotransferase or alkaline phosphatase, or reduced peripheral blood cells.	('neuromuscular system', 'Disease', (120, 140))	('mitotane', 'Var', (19, 27))	('alkaline phosphatase', 'MPA', (203, 223))	('gastrointestinal discomfort', 'Disease', (56, 83))	('elevated', 'PosReg', (174, 182))	('neuromuscular system', 'Disease', 'MESH:D009468', (120, 140))	('gastrointestinal discomfort', 'Phenotype', 'HP:0002027', (56, 83))	('aminotransferase', 'MPA', (183, 199))
55129	29967789	Besides, mitotane can reduce the synthesis of corticosteroids, leading to adrenocortical insufficiency.	('reduce', 'NegReg', (22, 28))	('adrenocortical insufficiency', 'Phenotype', 'HP:0008207', (74, 102))	('adrenocortical insufficiency', 'Disease', 'MESH:D000224', (74, 102))	('mitotane', 'Var', (9, 17))	('adrenocortical insufficiency', 'Disease', (74, 102))	('synthesis of corticosteroids', 'MPA', (33, 61))	('leading to', 'Reg', (63, 73))
55172	29034071	Carcinogenesis is a multistage process and involves a series of genetic and epigenetic changes that lead to the initiation, promotion and progression of cancer.	('Carcinogenesis', 'Disease', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('promotion', 'PosReg', (124, 133))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('epigenetic changes', 'Var', (76, 94))	('lead to', 'Reg', (100, 107))
55182	29034071	In prostate cancer therapy, treatment of the androgen-refractory human prostate cancer cell lines PC-3 and DU145 with apigenin resulted in apoptosis and a reduction in cell viability caused by a decrease in Bcl-2 and Bcl-xL and an increase in the active form of the Bax protein, accompanied by dose-dependent suppression of XIAP, c-IAP1, c-IAP2 and survivin proteins.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('human', 'Species', '9606', (65, 70))	('Bcl-xL', 'Gene', (217, 223))	('Bcl-2', 'Gene', '596', (207, 212))	('XIAP', 'Gene', (324, 328))	('prostate cancer', 'Disease', (3, 18))	('PC-3', 'CellLine', 'CVCL:0035', (98, 102))	('DU145', 'CellLine', 'CVCL:0105', (107, 112))	('survivin', 'Gene', (349, 357))	('reduction', 'NegReg', (155, 164))	('Bcl-xL', 'Gene', '598', (217, 223))	('suppression', 'NegReg', (309, 320))	('cell viability', 'CPA', (168, 182))	('c-IAP1', 'Gene', '329', (330, 336))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('decrease', 'NegReg', (195, 203))	('survivin', 'Gene', '11799', (349, 357))	('apigenin', 'Chemical', 'MESH:D047310', (118, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('apoptosis', 'CPA', (139, 148))	('c-IAP1', 'Gene', (330, 336))	('apigenin', 'Gene', (118, 126))	('prostate cancer', 'Disease', (71, 86))	('c-IAP2', 'Gene', (338, 344))	('c-IAP2', 'Gene', '330', (338, 344))	('DU145', 'Var', (107, 112))	('XIAP', 'Gene', '331', (324, 328))	('Bax', 'Gene', (266, 269))	('increase', 'PosReg', (231, 239))	('Bcl-2', 'Gene', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('active form', 'MPA', (247, 258))	('Bax', 'Gene', '581', (266, 269))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
55189	29034071	In addition to cases where apigenin triggered the intrinsic apoptotic pathway, apigenin was found to induce cell apoptosis via the extrinsic pathway or both the extrinsic and intrinsic pathways.	('intrinsic apoptotic pathway', 'Pathway', (50, 77))	('apigenin', 'Chemical', 'MESH:D047310', (27, 35))	('extrinsic pathway', 'Pathway', (131, 148))	('apigenin', 'Chemical', 'MESH:D047310', (79, 87))	('apigenin', 'Var', (79, 87))	('cell apoptosis', 'CPA', (108, 122))	('induce', 'PosReg', (101, 107))
55202	29034071	In addition, in renal cell carcinoma cells, apigenin caused DNA damage in ACHN cells in a time- and dose-dependent manner and induced G2/M phase cell cycle arrest through ataxia telangiectasia mutated (ATM) signal modulation.	('ataxia', 'Phenotype', 'HP:0001251', (171, 177))	('ATM', 'Gene', '472', (202, 205))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (145, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('apigenin', 'Var', (44, 52))	('renal cell carcinoma', 'Disease', (16, 36))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (16, 36))	('ataxia telangiectasia mutated', 'Gene', (171, 200))	('DNA damage', 'MPA', (60, 70))	('ataxia telangiectasia mutated', 'Gene', '472', (171, 200))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (16, 36))	('G2/M phase cell cycle arrest', 'CPA', (134, 162))	('ATM', 'Gene', (202, 205))	('telangiectasia', 'Phenotype', 'HP:0001009', (178, 192))	('apigenin', 'Chemical', 'MESH:D047310', (44, 52))
55205	29034071	Moreover, apigenin can induce cell cycle arrest at the G0/G1 or S checkpoints as well.	('apigenin', 'Chemical', 'MESH:D047310', (10, 18))	('apigenin', 'Var', (10, 18))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (30, 47))	('S checkpoints', 'CPA', (64, 77))	('induce', 'Reg', (23, 29))	('cell cycle arrest at the G0/G1', 'CPA', (30, 60))
55206	29034071	In human prostate cancer LNCaP cells, apigenin resulted in G1 arrest of cell cycle progression.	('prostate cancer', 'Disease', (9, 24))	('human', 'Species', '9606', (3, 8))	('apigenin', 'Chemical', 'MESH:D047310', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (9, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (9, 24))	('apigenin', 'Var', (38, 46))	('G1 arrest of cell cycle progression', 'CPA', (59, 94))	('LNCaP', 'CellLine', 'CVCL:0395', (25, 30))
55266	29034071	In addition, studies have shown that TC-1 tumor-bearing mice that were treated with apigenin combined with E7-HSP70 DNA were found to generate significant effector and memory E7-specific CD8+ T cell immune responses, thus generating strong therapeutic anti-tumor effects.	('rat', 'Species', '10116', (138, 141))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('mice', 'Species', '10090', (56, 60))	('CD8', 'Gene', (187, 190))	('rat', 'Species', '10116', (226, 229))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('CD8', 'Gene', '925', (187, 190))	('TC-1', 'CellLine', 'CVCL:1F93', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('apigenin', 'Chemical', 'MESH:D047310', (84, 92))	('E7-HSP70 DNA', 'Var', (107, 119))
55287	29034071	Aberrant activation of these pathways has been linked to cancer development and is frequently detected in malignancies.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('activation', 'PosReg', (9, 19))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (57, 63))	('malignancies', 'Disease', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('linked', 'Reg', (47, 53))
55318	29034071	The modulation of MAPKs by apigenin contributed to apigenin-induced cell cycle arrest at G0/G1 phase.	('modulation', 'Var', (4, 14))	('apigenin', 'Chemical', 'MESH:D047310', (27, 35))	('cell cycle arrest at G0/G1 phase', 'CPA', (68, 100))	('apigenin', 'Chemical', 'MESH:D047310', (51, 59))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('MAPKs', 'Gene', (18, 23))
55350	29034071	Dysregulation of this signaling pathway leads to the accumulation of beta-catenin in the nucleus and is linked to several human diseases, including cancer.	('cancer', 'Disease', (148, 154))	('human', 'Species', '9606', (122, 127))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('linked', 'Reg', (104, 110))	('Dysregulation', 'Var', (0, 13))	('beta-catenin', 'Gene', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('beta-catenin', 'Gene', '1499', (69, 81))	('accumulation', 'PosReg', (53, 65))
55376	29034071	Further, silencing of ANT2 by siRNA lowered the enhancement of DR5 expression by apigenin, indicating that ANT2 inhibition is needed for apigenin to enhance DR5 expression and Apo2L/TRAIL-induced apoptosis.	('lowered', 'NegReg', (36, 43))	('ANT2', 'Gene', '293', (22, 26))	('Apo2L', 'Gene', (176, 181))	('enhance', 'PosReg', (149, 156))	('ANT2', 'Gene', '293', (107, 111))	('DR5', 'Gene', '8795', (63, 66))	('apigenin', 'Chemical', 'MESH:D047310', (81, 89))	('enhancement', 'PosReg', (48, 59))	('apoptosis', 'CPA', (196, 205))	('DR5', 'Gene', (63, 66))	('DR5', 'Gene', '8795', (157, 160))	('TRAIL', 'Gene', '8743', (182, 187))	('DR5', 'Gene', (157, 160))	('Apo2L', 'Gene', '8743', (176, 181))	('ANT2', 'Gene', (22, 26))	('silencing', 'Var', (9, 18))	('TRAIL', 'Gene', (182, 187))	('ANT2', 'Gene', (107, 111))	('apigenin', 'Chemical', 'MESH:D047310', (137, 145))
55380	29034071	Aberrant miRNA expression may affect a multitude of transcripts and profoundly influence cancer-related signaling pathways.	('multitude of transcripts', 'MPA', (39, 63))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('influence', 'Reg', (79, 88))	('cancer', 'Disease', (89, 95))	('miRNA expression', 'Protein', (9, 25))	('affect', 'Reg', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
55382	29034071	Modulation of miRNA expression could also enhance apigenin-induced antitumor effects.	('Modulation', 'Var', (0, 10))	('miRNA expression', 'Protein', (14, 30))	('enhance', 'PosReg', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('apigenin', 'Chemical', 'MESH:D047310', (50, 58))
55383	29034071	miR-423-5p is overexpressed in glioblastomas and contributes to glioma stem cells.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('overexpressed', 'PosReg', (14, 27))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('glioblastomas', 'Phenotype', 'HP:0012174', (31, 44))	('miR-423-5p', 'Var', (0, 10))	('glioma', 'Disease', (64, 70))	('contributes', 'PosReg', (49, 60))	('glioblastomas', 'Disease', 'MESH:D005909', (31, 44))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('glioblastomas', 'Disease', (31, 44))
55384	29034071	The downregulation of miR-423-5p enhances apigenin-induced cell apoptosis in glioma stem cells with a shift in the Bax/Bcl-2 ratio, an increased cytochrome c level, Apaf-1 induction and caspase-3 activation.	('Bax', 'Gene', (115, 118))	('apigenin', 'Chemical', 'MESH:D047310', (42, 50))	('Bax', 'Gene', '581', (115, 118))	('cytochrome c', 'Gene', '54205', (145, 157))	('Bcl-2', 'Gene', '596', (119, 124))	('cell apoptosis', 'CPA', (59, 73))	('Apaf-1', 'Gene', '317', (165, 171))	('Apaf-1', 'Gene', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('enhances', 'PosReg', (33, 41))	('shift', 'Reg', (102, 107))	('rat', 'Species', '10116', (125, 128))	('cytochrome c', 'Gene', (145, 157))	('caspase-3', 'Gene', '836', (186, 195))	('downregulation', 'NegReg', (4, 18))	('miR-423-5p', 'Var', (22, 32))	('caspase-3', 'Gene', (186, 195))	('induction', 'PosReg', (172, 181))	('increased', 'PosReg', (135, 144))	('glioma', 'Disease', (77, 83))	('activation', 'PosReg', (196, 206))	('Bcl-2', 'Gene', (119, 124))	('glioma', 'Disease', 'MESH:D005910', (77, 83))
55440	28154203	Even so, numerous studies in breast cancer cell lines have shown that metformin directly affects growth and proliferation through inhibition of mammalian target of rapamycin complex I (mTORC1) in both AMPK-dependent and independent processes.	('n', 'Chemical', 'MESH:D009584', (194, 195))	('n', 'Chemical', 'MESH:D009584', (217, 218))	('n', 'Chemical', 'MESH:D009584', (3, 4))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (210, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('mammalian', 'Species', '9606', (144, 153))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('growth', 'CPA', (97, 103))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('breast cancer', 'Disease', (29, 42))	('mTORC1', 'Gene', (185, 191))	('n', 'Chemical', 'MESH:D009584', (229, 230))	('n', 'Chemical', 'MESH:D009584', (221, 222))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('affects', 'Reg', (89, 96))	('mTORC1', 'Gene', '382056', (185, 191))	('n', 'Chemical', 'MESH:D009584', (213, 214))	('inhibition', 'NegReg', (130, 140))	('proliferation', 'CPA', (108, 121))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('rat', 'Species', '10116', (115, 118))	('n', 'Chemical', 'MESH:D009584', (226, 227))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('metformin', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('metformin', 'Chemical', 'MESH:D008687', (70, 79))	('n', 'Chemical', 'MESH:D009584', (139, 140))	('n', 'Chemical', 'MESH:D009584', (131, 132))
55452	28154203	We hypothesized that metformin would decrease tumor volume by targeting tumor cells directly, and that the degree of efficacy would be dependent on intratumoral metformin accumulation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('metformin', 'Var', (21, 30))	('metformin', 'Chemical', 'MESH:D008687', (21, 30))	('rat', 'Species', '10116', (151, 154))	('decrease', 'NegReg', (37, 45))	('n', 'Chemical', 'MESH:D009584', (169, 170))	('metformin', 'Chemical', 'MESH:D008687', (161, 170))	('tumor', 'Disease', (153, 158))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (72, 77))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('tumor', 'Disease', (46, 51))	('n', 'Chemical', 'MESH:D009584', (182, 183))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('n', 'Chemical', 'MESH:D009584', (146, 147))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('n', 'Chemical', 'MESH:D009584', (139, 140))
55472	28154203	Colorimetric assays were used to measure free fatty acids (Wako Chemicals), glucose, triglycerides, and total cholesterol (#TR15421, TR22321, and TR13521, respectively; Thermo-Fisher).	('#TR15421', 'Var', (123, 131))	('TR13521', 'Var', (146, 153))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('triglycerides', 'Chemical', 'MESH:D014280', (85, 98))	('triglycerides', 'MPA', (85, 98))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('free fatty acids', 'Chemical', 'MESH:D005230', (41, 57))	('free fatty acids', 'MPA', (41, 57))	('TR22321', 'Var', (133, 140))	('cholesterol', 'Chemical', 'MESH:D002784', (110, 121))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('glucose', 'MPA', (76, 83))
55523	28154203	Although not statistically significant, metformin treated rats tended to have a higher study completion percentage relative to controls (72.7% vs. 45.5%; Fig.	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('metformin', 'Chemical', 'MESH:D008687', (40, 49))	('rats', 'Species', '10116', (58, 62))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('study completion', 'CPA', (87, 103))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('higher', 'PosReg', (80, 86))	('metformin', 'Var', (40, 49))
55548	28154203	4A); however, within the metformin treated group, tumors responding to metformin had a greater percentage of cells that stained positive for OCT2 (p<0.001) relative to the non-responding tumors (Fig.	('n', 'Chemical', 'MESH:D009584', (19, 20))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('n', 'Chemical', 'MESH:D009584', (184, 185))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('n', 'Chemical', 'MESH:D009584', (181, 182))	('n', 'Chemical', 'MESH:D009584', (174, 175))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('tumors', 'Disease', (187, 193))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('metformin', 'Var', (71, 80))	('metformin', 'Chemical', 'MESH:D008687', (71, 80))	('OCT2', 'Gene', '29503', (141, 145))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('OCT2', 'Gene', (141, 145))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('tumors', 'Disease', (50, 56))
55552	28154203	These results implicate OCT2 expression as a critical mediator of cellular metformin uptake in mammary tumors, and suggest that low or no expression could significantly impair or prevent the anti-cancer activity of metformin on neoplastic tissue.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (228, 245))	('tumors', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('n', 'Chemical', 'MESH:D009584', (184, 185))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('implicate', 'Reg', (14, 23))	('metformin', 'Chemical', 'MESH:D008687', (75, 84))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('n', 'Chemical', 'MESH:D009584', (192, 193))	('n', 'Chemical', 'MESH:D009584', (223, 224))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('n', 'Chemical', 'MESH:D009584', (198, 199))	('low', 'Var', (128, 131))	('OCT2', 'Gene', '29503', (24, 28))	('prevent', 'NegReg', (179, 186))	('n', 'Chemical', 'MESH:D009584', (158, 159))	('OCT2', 'Gene', (24, 28))	('cancer', 'Disease', (196, 202))	('impair', 'NegReg', (169, 175))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('n', 'Chemical', 'MESH:D009584', (228, 229))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('metformin', 'Chemical', 'MESH:D008687', (215, 224))	('n', 'Chemical', 'MESH:D009584', (226, 227))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('n', 'Chemical', 'MESH:D009584', (164, 165))
55597	28154203	Gene variants of cation transporters may also play a role in determining subpopulation responsiveness to drug treatment in a cancer setting.	('n', 'Chemical', 'MESH:D009584', (68, 69))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('play', 'Reg', (46, 50))	('n', 'Chemical', 'MESH:D009584', (137, 138))	('role', 'Reg', (53, 57))	('cancer', 'Disease', (125, 131))	('determining', 'Reg', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('Gene variants', 'Var', (0, 13))
55598	28154203	Genetic polymorphisms in SLC22A1 (OCT1) and SLC22A2 (OCT2) are associated with variability in metformin response in diabetics.	('metformin', 'Chemical', 'MESH:D008687', (94, 103))	('OCT2', 'Gene', (53, 57))	('diabetics', 'Disease', (116, 125))	('SLC22A2', 'Gene', '29503', (44, 51))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('SLC22A2', 'Gene', (44, 51))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('SLC22A1', 'Gene', (25, 32))	('polymorphisms', 'Var', (8, 21))	('diabetics', 'Disease', 'MESH:D003920', (116, 125))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('associated with', 'Reg', (63, 78))	('SLC22A1', 'Gene', '24904', (25, 32))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('metformin response', 'MPA', (94, 112))	('OCT2', 'Gene', '29503', (53, 57))
55601	28154203	Consistent with a direct metformin and AMPK-dependent mechanism, our findings indicate metformin-mediated mammary tumor regression was correlated with a reduced proliferative index (Ki67), increased AMPK activation, and subsequent inhibitory phosphorylation of ACC.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('reduced', 'NegReg', (153, 160))	('n', 'Chemical', 'MESH:D009584', (217, 218))	('n', 'Chemical', 'MESH:D009584', (176, 177))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('inhibitory phosphorylation', 'MPA', (231, 257))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('proliferative index', 'CPA', (161, 180))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('n', 'Chemical', 'MESH:D009584', (232, 233))	('n', 'Chemical', 'MESH:D009584', (256, 257))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('tumor', 'Disease', (114, 119))	('ACC', 'Protein', (261, 264))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('n', 'Chemical', 'MESH:D009584', (190, 191))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('n', 'Chemical', 'MESH:D009584', (213, 214))	('Ki67', 'Chemical', '-', (182, 186))	('metformin', 'Chemical', 'MESH:D008687', (87, 96))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))	('n', 'Chemical', 'MESH:D009584', (228, 229))	('AMPK activation', 'MPA', (199, 214))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('metformin-mediated', 'Var', (87, 105))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('rat', 'Species', '10116', (168, 171))	('increased', 'PosReg', (189, 198))
55729	25765741	Her serum potassium levels were (2.6 mEq/L), and arterial blood gas examination indicated metabolic alkalosis (pH 7.47, pCO2 = 58.6 mmHg, HCO3 = 42.1 mEq/L).	('serum potassium levels', 'MPA', (4, 26))	('HCO3', 'Chemical', 'MESH:D001639', (138, 142))	('alkalosis', 'Phenotype', 'HP:0001948', (100, 109))	('potassium', 'Chemical', 'MESH:D011188', (10, 19))	('metabolic alkalosis', 'Phenotype', 'HP:0200114', (90, 109))	('metabolic alkalosis', 'Disease', (90, 109))	('pCO2', 'Chemical', '-', (120, 124))	('pH', 'Var', (111, 113))	('metabolic alkalosis', 'Disease', 'MESH:D000471', (90, 109))	('indicated', 'Reg', (80, 89))
55758	25111790	Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation Adrenocortical carcinoma (ACC) is a rare, but highly malignant tumor of unknown origin.	('tumor', 'Disease', (188, 193))	('INHA', 'Gene', '3623', (23, 27))	('INHA', 'Gene', (101, 105))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('Adrenocortical Cancer', 'Disease', (43, 64))	('Epigenetic', 'Var', (90, 100))	('INHA', 'Gene', '3623', (101, 105))	('ACC', 'Phenotype', 'HP:0006744', (151, 154))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (125, 149))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Inhibin Alpha-Subunit', 'Gene', '3623', (0, 21))	('Linked', 'Reg', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('Promoter Variation', 'Var', (106, 124))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (125, 149))	('Inhibin Alpha-Subunit', 'Gene', (0, 21))	('INHA', 'Gene', (23, 27))	('Adrenocortical Cancer', 'Disease', 'MESH:D000306', (43, 64))	('Adrenocortical carcinoma', 'Disease', (125, 149))
55761	25111790	We investigated whether genetic and epigenetic changes of the INHA gene in human ACC cause loss or variation of INHA expression.	('variation', 'Var', (99, 108))	('expression', 'MPA', (117, 127))	('INHA', 'Gene', (62, 66))	('INHA', 'Gene', '3623', (112, 116))	('ACC', 'Phenotype', 'HP:0006744', (81, 84))	('INHA', 'Gene', (112, 116))	('loss', 'NegReg', (91, 95))	('INHA', 'Gene', '3623', (62, 66))	('human', 'Species', '9606', (75, 80))	('epigenetic changes', 'Var', (36, 54))
55765	25111790	Of the 3 coding bases affected, one variant was synonymous and two were missense variants: S72F and S184F.	('S184F', 'Var', (100, 105))	('S184F', 'Mutation', 'p.S184F', (100, 105))	('S72F', 'Var', (91, 95))	('S72F', 'Mutation', 'p.S72F', (91, 95))
55766	25111790	The minor allele of rs11893842 at -124 bp was observed at a low frequency (24%) in ACC samples and was associated with decreased INHA mRNA levels: 4.7+-1.9 arbitrary units for AA, compared to 26+-11 for AG/GG genotypes (P = 0.034).	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('INHA', 'Gene', '3623', (129, 133))	('decreased', 'NegReg', (119, 128))	('rs11893842', 'Mutation', 'rs11893842', (20, 30))	('INHA', 'Gene', (129, 133))	('rs11893842 at -124 bp', 'Var', (20, 41))
55768	25111790	CpG methylation was inversely correlated to INHA mRNA levels in ACCs (r = -0.701, p = 0.0036), but not associated with serum inhibin pro-alphaC levels.	('INHA', 'Gene', '3623', (44, 48))	('CpG', 'Var', (0, 3))	('methylation', 'Var', (4, 15))	('INHA', 'Gene', (44, 48))	('correlated', 'Reg', (30, 40))	('inversely', 'NegReg', (20, 29))	('ACC', 'Phenotype', 'HP:0006744', (64, 67))	('ACCs', 'Gene', '84680', (64, 68))	('ACCs', 'Gene', (64, 68))
55769	25111790	In conclusion, aberrant methylation and common genetic variation in the INHA promoter occur in human ACCs and are associated with decreased INHA expression.	('human', 'Species', '9606', (95, 100))	('INHA', 'Gene', (72, 76))	('methylation', 'MPA', (24, 35))	('ACC', 'Phenotype', 'HP:0006744', (101, 104))	('ACCs', 'Gene', (101, 105))	('expression', 'MPA', (145, 155))	('INHA', 'Gene', '3623', (140, 144))	('ACCs', 'Gene', '84680', (101, 105))	('aberrant', 'Var', (15, 23))	('INHA', 'Gene', (140, 144))	('INHA', 'Gene', '3623', (72, 76))	('decreased', 'NegReg', (130, 139))
55773	25111790	Mutations in genes underlying these disorders have also been linked to sporadic ACC formation, especially in the case of TP53 .	('sporadic ACC formation', 'Disease', (71, 93))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('Mutations', 'Var', (0, 9))	('linked', 'Reg', (61, 67))
55775	25111790	More recently, mutations in the Wnt/beta-catenin pathway have been shown to occur during adrenocortical tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutations', 'Var', (15, 24))	('beta-catenin', 'Gene', (36, 48))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (89, 109))	('occur', 'Reg', (76, 81))	('beta-catenin', 'Gene', '1499', (36, 48))	('adrenocortical tumor', 'Disease', (89, 109))
55782	25111790	Inha-related carcinogenesis in mice has also been attributed to decreased activin signalling potential and aberrant expression and effects of TGF-beta2.	('expression', 'MPA', (116, 126))	('Inha', 'Gene', '16322', (0, 4))	('activin', 'Gene', (74, 81))	('carcinogenesis', 'Disease', 'MESH:D063646', (13, 27))	('aberrant', 'Var', (107, 115))	('carcinogenesis', 'Disease', (13, 27))	('mice', 'Species', '10090', (31, 35))	('Inha', 'Gene', (0, 4))	('activin', 'Gene', '83729', (74, 81))	('TGF-beta2', 'Gene', (142, 151))	('decreased', 'NegReg', (64, 73))
55788	25111790	Several DNA alterations are known to influence gene expression during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('influence', 'Reg', (37, 46))	('alterations', 'Var', (12, 23))	('gene expression', 'MPA', (47, 62))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
55789	25111790	Apart from the genetic changes causing aberrant or absent expression, epigenetic alterations, such as chromatin remodelling and CpG methylation, can affect gene transcription and frequently occur in cancer.	('gene transcription', 'MPA', (156, 174))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('affect', 'Reg', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('occur', 'Reg', (190, 195))	('methylation', 'Var', (132, 143))	('epigenetic', 'Var', (70, 80))
55792	25111790	Sequencing of the INHA gene was undertaken to search for genetic variants that could affect gene function or expression levels.	('INHA', 'Gene', (18, 22))	('variants', 'Var', (65, 73))	('affect', 'Reg', (85, 91))	('expression levels', 'MPA', (109, 126))	('INHA', 'Gene', '3623', (18, 22))	('gene function', 'MPA', (92, 105))
55823	25111790	In total, sequencing of the INHA gene in 37 ACCs revealed 10 novel rare genetic variants in 8 ACCs.	('ACC', 'Phenotype', 'HP:0006744', (94, 97))	('ACC', 'Phenotype', 'HP:0006744', (44, 47))	('ACCs', 'Gene', '84680', (94, 98))	('ACCs', 'Gene', (94, 98))	('variants', 'Var', (80, 88))	('INHA', 'Gene', '3623', (28, 32))	('ACCs', 'Gene', (44, 48))	('ACCs', 'Gene', '84680', (44, 48))	('INHA', 'Gene', (28, 32))
55825	25111790	In the coding region of INHA we detected 1 synonymous nucleotide change (75C>T, Ala25Ala) and 2 missense variants, in 3 distinct ACCs.	('Ala25Ala', 'Chemical', '-', (80, 88))	('75C>T', 'Var', (73, 78))	('ACC', 'Phenotype', 'HP:0006744', (129, 132))	('INHA', 'Gene', '3623', (24, 28))	('ACCs', 'Gene', (129, 133))	('ACCs', 'Gene', '84680', (129, 133))	('INHA', 'Gene', (24, 28))	('75C>T', 'Mutation', 'rs1187137552', (73, 78))
55827	25111790	In our complete series of ACC samples, the -124A>G SNP, rs11893842, was the most prevalent genetic variation with a minor allele frequency (MAF) of 24%, compared to 44% in a reference population (www.1000genomes.org ).	('-124A>G', 'Mutation', 'rs11893842', (43, 50))	('ACC', 'Phenotype', 'HP:0006744', (26, 29))	('rs11893842', 'Var', (56, 66))	('rs11893842', 'Mutation', 'rs11893842', (56, 66))	('prevalent', 'Reg', (81, 90))
55828	25111790	Furthermore, the minor allele of the intronic SNP IVS1-87G>A (rs116399602) was present in 16% of ACC samples, seemingly higher than in healthy individuals (2.8% MAF).	('ACC', 'Phenotype', 'HP:0006744', (97, 100))	('ACC', 'Disease', (97, 100))	('higher', 'PosReg', (120, 126))	('IVS1-87G>A', 'Mutation', 'rs116399602', (50, 60))	('rs116399602', 'Var', (62, 73))	('rs116399602', 'Mutation', 'rs116399602', (62, 73))
55832	25111790	Rs144941390, rs374972575 and rs148455844 within the INHA gene were each detected in one ACC sample.	('rs374972575', 'Mutation', 'rs374972575', (13, 24))	('rs148455844', 'Mutation', 'rs148455844', (29, 40))	('INHA', 'Gene', (52, 56))	('Rs144941390', 'Mutation', 'Rs144941390', (0, 11))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('rs148455844', 'Var', (29, 40))	('INHA', 'Gene', '3623', (52, 56))	('rs374972575', 'Var', (13, 24))	('Rs144941390', 'Var', (0, 11))
55846	25111790	Of the 3 ACC samples with rare genetic variants in the INHA exons, only one was available for expression analysis; this ACC harbouring the S184F change showed a normal level of INHA mRNA (15 A.U., Figure 3A, open circle).	('INHA', 'Gene', (55, 59))	('INHA', 'Gene', '3623', (177, 181))	('ACC', 'Phenotype', 'HP:0006744', (9, 12))	('INHA', 'Gene', (177, 181))	('S184F', 'Mutation', 'p.S184F', (139, 144))	('INHA', 'Gene', '3623', (55, 59))	('ACC', 'Phenotype', 'HP:0006744', (120, 123))	('S184F', 'Var', (139, 144))
55847	25111790	When stratified for the five common SNPs, only the rs11893842 gene variation was associated with changes in INHA mRNA: mean expression in tissues with the AA genotype was 4.7+-1.9 A.U., compared to 26+-11 A.U.	('INHA', 'Gene', (108, 112))	('rs11893842', 'Var', (51, 61))	('rs11893842', 'Mutation', 'rs11893842', (51, 61))	('expression', 'MPA', (124, 134))	('INHA', 'Gene', '3623', (108, 112))
55850	25111790	Inhibin pro-alphaC levels were only available for one ACC patient with rare INHA variants: this premenopausal female patient with three rare variants in the 5'UTR of INHA had highly increased inhibin pro-alphaC levels at 3000 ng/l (normal<780 ng/l).	('INHA', 'Gene', '3623', (166, 170))	('increased', 'PosReg', (182, 191))	('highly increased inhibin pro-alphaC levels', 'Phenotype', 'HP:0030234', (175, 217))	('INHA', 'Gene', (76, 80))	('INHA', 'Gene', (166, 170))	('patient', 'Species', '9606', (58, 65))	('ACC', 'Phenotype', 'HP:0006744', (54, 57))	('variants', 'Var', (141, 149))	('patient', 'Species', '9606', (117, 124))	('INHA', 'Gene', '3623', (76, 80))	('inhibin pro-alphaC levels', 'MPA', (192, 217))
55853	25111790	This is the first study showing that the large variation in INHA expression in ACCs is partly caused by methylation and common genetic variation of the INHA promoter and is not due to rare genetic variants.	('INHA', 'Gene', '3623', (152, 156))	('caused by', 'Reg', (94, 103))	('INHA', 'Gene', '3623', (60, 64))	('ACCs', 'Gene', '84680', (79, 83))	('INHA', 'Gene', (152, 156))	('ACCs', 'Gene', (79, 83))	('INHA', 'Gene', (60, 64))	('methylation', 'Var', (104, 115))	('ACC', 'Phenotype', 'HP:0006744', (79, 82))
55858	25111790	Whether local knockdown of INHA in human adrenocortical cells contributes to adrenocortical tumorigenesis is unknown.	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (77, 105))	('adrenocortical', 'Disease', (41, 55))	('contributes', 'Reg', (62, 73))	('human', 'Species', '9606', (35, 40))	('INHA', 'Gene', '3623', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('adrenocortical', 'Disease', 'MESH:D018268', (41, 55))	('knockdown', 'Var', (14, 23))	('adrenocortical', 'Disease', 'MESH:D018268', (77, 91))	('adrenocortical', 'Disease', (77, 91))	('INHA', 'Gene', (27, 31))	('adrenocortical tumorigenesis', 'Disease', (77, 105))
55865	25111790	studied pediatric ACC patients with germline TP53 mutations and found 3 rare, heterozygous INHA variants in 6 out of 46 (13%) patients.	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (22, 30))	('INHA', 'Gene', '3623', (91, 95))	('INHA', 'Gene', (91, 95))	('patients', 'Species', '9606', (126, 134))	('TP53', 'Gene', '7157', (45, 49))	('ACC', 'Phenotype', 'HP:0006744', (18, 21))
55866	25111790	Of these three novel variants, one (G227A, rs12720061) was subsequently shown to be a common SNP and did not occur in our ACC cohort.	('G227A', 'Var', (36, 41))	('rs12720061', 'Mutation', 'rs12720061', (43, 53))	('rs12720061', 'Var', (43, 53))	('ACC', 'Phenotype', 'HP:0006744', (122, 125))	('G227A', 'Mutation', 'rs12720061', (36, 41))
55867	25111790	Implications of the other two genetic variants (P43A and A257T) are unknown; they were not found in the current investigation of sporadic ACCs.	('A257T', 'Mutation', 'c.257A>T', (57, 62))	('P43A', 'Mutation', 'p.P43A', (48, 52))	('A257T', 'Var', (57, 62))	('ACCs', 'Gene', (138, 142))	('ACCs', 'Gene', '84680', (138, 142))	('P43A', 'Var', (48, 52))	('ACC', 'Phenotype', 'HP:0006744', (138, 141))
55868	25111790	Interestingly, the above mentioned study found loss of heterozygosity (LOH) in the vicinity of the INHA gene in eight out of nine ACCs studied, suggesting that LOH could cause decreased expression levels.	('INHA', 'Gene', '3623', (99, 103))	('decreased', 'NegReg', (176, 185))	('heterozygosity', 'MPA', (55, 69))	('expression levels', 'MPA', (186, 203))	('loss', 'NegReg', (47, 51))	('ACC', 'Phenotype', 'HP:0006744', (130, 133))	('INHA', 'Gene', (99, 103))	('ACCs', 'Gene', '84680', (130, 134))	('LOH', 'Var', (160, 163))	('ACCs', 'Gene', (130, 134))
55869	25111790	Furthermore, comparative genomic hybridization analyses of human ACCs described sporadic chromosomal loss of the INHA region at 2q33-36, with a predominance in childhood tumors.	('human', 'Species', '9606', (59, 64))	('tumors', 'Disease', (170, 176))	('chromosomal loss', 'Var', (89, 105))	('INHA', 'Gene', '3623', (113, 117))	('ACCs', 'Gene', '84680', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('ACCs', 'Gene', (65, 69))	('INHA', 'Gene', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('ACC', 'Phenotype', 'HP:0006744', (65, 68))
55871	25111790	The serine to phenylalanine substitutions at amino acids 72 and 184 might affect the activity of the resulting inhibin alpha-subunit, but since the function of inhibin in the human adrenal gland is unknown, it is difficult to investigate the consequences of potentially altered activity.	('human', 'Species', '9606', (175, 180))	('inhibin alpha-subunit', 'Gene', '3623', (111, 132))	('phenylalanine', 'Chemical', 'MESH:D010649', (14, 27))	('serine', 'Chemical', 'MESH:D012694', (4, 10))	('affect', 'Reg', (74, 80))	('inhibin alpha-subunit', 'Gene', (111, 132))	('activity', 'MPA', (85, 93))	('substitutions', 'Var', (28, 41))
55872	25111790	The tumor harbouring the S184F change expressed a normal level of INHA mRNA, but function or protein degradation could still be affected by the introduction of the benzyl side ring.	('tumor', 'Disease', (4, 9))	('INHA', 'Gene', (66, 70))	('function', 'MPA', (81, 89))	('protein degradation', 'MPA', (93, 112))	('S184F', 'Mutation', 'p.S184F', (25, 30))	('S184F', 'Var', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('affected', 'Reg', (128, 136))	('INHA', 'Gene', '3623', (66, 70))
55873	25111790	The genetic variants located 179, 72 and 9 bps upstream of the intron-exon border might lead to alternative splicing of the INHA gene.	('INHA', 'Gene', (124, 128))	('lead to', 'Reg', (88, 95))	('variants', 'Var', (12, 20))	('INHA', 'Gene', '3623', (124, 128))	('alternative splicing', 'MPA', (96, 116))
55875	25111790	Unfortunately, we had only one patient with INHA variants and concomitantly available serum inhibin pro-alphaC levels.	('INHA', 'Gene', (44, 48))	('patient', 'Species', '9606', (31, 38))	('INHA', 'Gene', '3623', (44, 48))	('variants', 'Var', (49, 57))
55876	25111790	Given the low frequency of INHA genetic variants in sporadic and familial ACCs, these DNA changes might only be involved in adrenocortical tumorigenesis in a small subset of ACC patients.	('involved', 'Reg', (112, 120))	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('patients', 'Species', '9606', (178, 186))	('INHA', 'Gene', '3623', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('adrenocortical tumorigenesis', 'Disease', (124, 152))	('ACC', 'Phenotype', 'HP:0006744', (174, 177))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (124, 152))	('ACCs', 'Gene', (74, 78))	('variants', 'Var', (40, 48))	('ACCs', 'Gene', '84680', (74, 78))	('INHA', 'Gene', (27, 31))
55878	25111790	Minor alleles of rs11893842 and rs758807 were found to occur in ACC patients at lower frequencies than previously reported in healthy cohorts, which might suggest that the major alleles of these SNPs play a role in adrenal oncogenesis.	('rs758807', 'Var', (32, 40))	('rs11893842', 'Var', (17, 27))	('rs758807', 'Mutation', 'rs758807', (32, 40))	('rs11893842', 'Mutation', 'rs11893842', (17, 27))	('ACC', 'Phenotype', 'HP:0006744', (64, 67))	('patients', 'Species', '9606', (68, 76))	('adrenal oncogenesis', 'Disease', (215, 234))	('ACC', 'Disease', (64, 67))
55879	25111790	Intriguingly, the minor allele of rs11893842, located in the promoter region in close proximity to crucial regulatory sequences, was associated with lower levels of INHA mRNA expression.	('lower', 'NegReg', (149, 154))	('rs11893842', 'Mutation', 'rs11893842', (34, 44))	('INHA', 'Gene', '3623', (165, 169))	('INHA', 'Gene', (165, 169))	('rs11893842', 'Var', (34, 44))
55881	25111790	Methylation of promoter regions of tumor suppressor genes is a common mechanism involved in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('carcinogenesis', 'Disease', (92, 106))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (35, 40))	('involved', 'Reg', (80, 88))
55886	25111790	This epigenetic modification in the INHA promoter and rs11893842 might also be involved in regulatory control of INHA expression in the other INHA-expressing tissues, i.e.	('rs11893842', 'Mutation', 'rs11893842', (54, 64))	('INHA', 'Gene', '3623', (36, 40))	('INHA', 'Gene', (142, 146))	('INHA', 'Gene', '3623', (113, 117))	('INHA', 'Gene', (36, 40))	('INHA', 'Gene', (113, 117))	('involved', 'Reg', (79, 87))	('INHA', 'Gene', '3623', (142, 146))	('rs11893842', 'Var', (54, 64))
55890	25111790	Given the very low incidence of INHA genetic variants in this substantial set of 37 ACCs, it is very unlikely that INHA mutations play a significant role in ACC formation in man.	('INHA', 'Gene', (115, 119))	('INHA', 'Gene', (32, 36))	('man', 'Species', '9606', (174, 177))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('variants', 'Var', (45, 53))	('ACCs', 'Gene', (84, 88))	('ACC', 'Phenotype', 'HP:0006744', (157, 160))	('ACCs', 'Gene', '84680', (84, 88))	('INHA', 'Gene', '3623', (115, 119))	('INHA', 'Gene', '3623', (32, 36))
55891	25111790	Although LOH was not studied directly in these samples, the occurrence of heterozygous variants in the ACCs pleads against complete knockout of the gene.	('ACC', 'Phenotype', 'HP:0006744', (103, 106))	('ACCs', 'Gene', '84680', (103, 107))	('variants', 'Var', (87, 95))	('ACCs', 'Gene', (103, 107))
55894	25111790	Knockdown of the inhibin alpha-subunit during ACC formation through methylation might predispose to unopposed paracrine TGF-beta or activin action on adrenocortical proliferation or steroidogenesis.	('TGF-beta', 'Gene', (120, 128))	('inhibin alpha-subunit', 'Gene', '3623', (17, 38))	('predispose', 'Reg', (86, 96))	('action', 'MPA', (140, 146))	('ACC', 'Phenotype', 'HP:0006744', (46, 49))	('Knockdown', 'Var', (0, 9))	('adrenocortical proliferation', 'Phenotype', 'HP:0008186', (150, 178))	('methylation', 'Var', (68, 79))	('adrenocortical proliferation', 'Disease', 'MESH:D018268', (150, 178))	('activin', 'Gene', '83729', (132, 139))	('inhibin alpha-subunit', 'Gene', (17, 38))	('adrenocortical proliferation', 'Disease', (150, 178))	('paracrine', 'MPA', (110, 119))	('TGF-beta', 'Gene', '7040', (120, 128))	('steroidogenesis', 'CPA', (182, 197))	('activin', 'Gene', (132, 139))
55896	25111790	In conclusion, aberrant methylation and common genetic variation within the promoter region of the INHA gene are associated with INHA mRNA expression in human ACC.	('aberrant methylation', 'Var', (15, 35))	('associated with', 'Reg', (113, 128))	('INHA', 'Gene', '3623', (129, 133))	('INHA', 'Gene', (129, 133))	('INHA', 'Gene', '3623', (99, 103))	('INHA', 'Gene', (99, 103))	('human', 'Species', '9606', (153, 158))	('common genetic variation', 'Var', (40, 64))	('ACC', 'Phenotype', 'HP:0006744', (159, 162))
55897	25111790	These genetic and epigenetic INHA changes could contribute to human adrenocortical tumorigenesis, similar to the situation in the murine Inha knockout model.	('epigenetic', 'Var', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('adrenocortical tumorigenesis', 'Disease', (68, 96))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (68, 96))	('human', 'Species', '9606', (62, 67))	('murine', 'Species', '10090', (130, 136))	('INHA', 'Gene', (29, 33))	('genetic', 'Var', (6, 13))	('Inha', 'Gene', (137, 141))	('contribute', 'Reg', (48, 58))	('changes', 'Var', (34, 41))	('INHA', 'Gene', '3623', (29, 33))	('Inha', 'Gene', '16322', (137, 141))
55898	25111790	Rare INHA variants do not appear to be involved in the pathophysiology of sporadic ACC.	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('INHA', 'Gene', '3623', (5, 9))	('sporadic ACC', 'Disease', (74, 86))	('variants', 'Var', (10, 18))	('INHA', 'Gene', (5, 9))
56028	32258822	These studies confirmed that 90% of ACC exhibit loss of heterozygosity of the IGF2 locus leading to upregulation of IGF2/IGF1R signaling.	('loss', 'NegReg', (48, 52))	('IGF1R', 'Gene', '3480', (121, 126))	('IGF2', 'Gene', '3481', (78, 82))	('ACC', 'Phenotype', 'HP:0006744', (36, 39))	('IGF2', 'Gene', '3481', (116, 120))	('heterozygosity', 'Var', (56, 70))	('IGF2', 'Gene', (78, 82))	('IGF1R', 'Gene', (121, 126))	('IGF2', 'Gene', (116, 120))	('upregulation', 'PosReg', (100, 112))
56044	32258822	Our group recently demonstrated that uniform hypermethylation and silencing of the gene G0S2 accurately captures a subgroup of patients with homogeneously dismal disease course akin to patients with COC3/CIMP-high tumors in ACC-TCGA.	('G0S2', 'Gene', (88, 92))	('hypermethylation', 'Var', (45, 61))	('ACC', 'Phenotype', 'HP:0006744', (224, 227))	('COC3', 'Chemical', '-', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('patients', 'Species', '9606', (127, 135))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('patients', 'Species', '9606', (185, 193))	('CIMP-high tumors', 'Disease', (204, 220))	('silencing', 'NegReg', (66, 75))	('CIMP-high tumors', 'Disease', 'MESH:D009369', (204, 220))
56063	32258822	This, combined with identification of recurrent mutations leading to constitutive activation of both pathways in ACC and strong association between cortisol production and Wnt/beta-catenin pathway alterations, suggests that components of the ACTH signaling pathway may contribute to Wnt/beta-catenin-dependent adrenocortical carcinogenesis.	('contribute', 'Reg', (269, 279))	('activation', 'PosReg', (82, 92))	('association', 'Interaction', (128, 139))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('adrenocortical carcinogenesis', 'Disease', 'MESH:D063646', (310, 339))	('cortisol', 'Chemical', 'MESH:D006854', (148, 156))	('adrenocortical carcinogenesis', 'Disease', (310, 339))	('mutations', 'Var', (48, 57))
56064	32258822	This is strongly supported by a recent study from our group demonstrating that adrenocortical deletion of a negative regulator of ligand-dependent Wnt signaling, ZNRF3, leads to functional zF hyperplasia.	('deletion', 'Var', (94, 102))	('leads to', 'Reg', (169, 177))	('ZNRF3', 'Gene', '84133', (162, 167))	('ZNRF3', 'Gene', (162, 167))	('zF hyperplasia', 'Disease', (189, 203))	('zF hyperplasia', 'Disease', 'MESH:D006965', (189, 203))
56066	32258822	Intriguingly, these lesions also exhibited E2F-dependent upregulation of histone methyltransferase EZH2, akin to cell cycle-avid ACC.	('EZH2', 'Gene', '2146', (99, 103))	('EZH2', 'Gene', (99, 103))	('histone methyltransferase', 'Gene', (73, 98))	('ACC', 'Phenotype', 'HP:0006744', (129, 132))	('upregulation', 'PosReg', (57, 69))	('histone methyltransferase', 'Gene', '56979', (73, 98))	('E2F-dependent', 'Var', (43, 56))
56067	32258822	The recent demonstration that adrenocortical deletion of EZH2 leads to zF aplasia and glucocorticoid insufficiency suggests that the integrity of ACTH signaling in the adrenal cortex is exquisitely reliant on this pharmacologically targetable epigenetic modifier.	('EZH2', 'Gene', (57, 61))	('glucocorticoid insufficiency', 'Phenotype', 'HP:0008163', (86, 114))	('leads to', 'Reg', (62, 70))	('zF aplasia', 'Disease', (71, 81))	('EZH2', 'Gene', '2146', (57, 61))	('glucocorticoid', 'MPA', (86, 100))	('insufficiency', 'Disease', 'MESH:D000309', (101, 114))	('deletion', 'Var', (45, 53))	('zF aplasia', 'Disease', 'MESH:C563261', (71, 81))	('insufficiency', 'Disease', (101, 114))
56068	32258822	The steroidogenic NCI-H295R cell line has long been the classical, most established model of ACC, possessing high expression of SF1, constitutively active beta-catenin, and inactivation of pRb and p53.	('ACC', 'Phenotype', 'HP:0006744', (93, 96))	('SF1', 'Gene', (128, 131))	('p53', 'Gene', (197, 200))	('NCI-H295R', 'CellLine', 'CVCL:0458', (18, 27))	('SF1', 'Gene', '7536', (128, 131))	('inactivation', 'Var', (173, 185))	('pRb', 'Gene', (189, 192))
56071	32258822	Kiseljak-Vassiliades and colleagues also developed two new adult ACC-derived cell lines and xenograft models, CU-ACC1 and CU-ACC2; CU-ACC1 is a cortisol-producing cell line bearing constitutively active beta-catenin, whereas CU-ACC2 is a mismatch repair-deficient cell line bearing a mutation in TP53.	('TP53', 'Gene', '7157', (296, 300))	('ACC1', 'Gene', (113, 117))	('mutation', 'Var', (284, 292))	('ACC', 'Phenotype', 'HP:0006744', (125, 128))	('ACC', 'Phenotype', 'HP:0006744', (228, 231))	('cortisol', 'Chemical', 'MESH:D006854', (144, 152))	('TP53', 'Gene', (296, 300))	('ACC2', 'Gene', '32', (125, 129))	('ACC1', 'Gene', (134, 138))	('ACC2', 'Gene', '32', (228, 232))	('ACC1', 'Gene', '597', (113, 117))	('ACC2', 'Gene', (125, 129))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('ACC', 'Phenotype', 'HP:0006744', (134, 137))	('ACC2', 'Gene', (228, 232))	('ACC1', 'Gene', '597', (134, 138))	('ACC', 'Phenotype', 'HP:0006744', (65, 68))
56078	32258822	Those tumors with ZNRF3 deficiency are likely reliant on Porcupine-dependent Wnt ligand secretion and may be responsive to Porcupine inhibitors currently in phase I trials (e.g.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('deficiency', 'Var', (24, 34))	('tumors', 'Disease', (6, 12))	('ZNRF3', 'Gene', '84133', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('ZNRF3', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
56079	32258822	Tumors with mutations in CTNNB1 leading to constitutive stabilization of beta-catenin may instead be responsive to therapies targeting the oncogenic beta-catenin/CBP transcriptional program, which have recently completed phase I trials for solid tumors (e.g.	('CTNNB1', 'Gene', '1499', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('CBP', 'Gene', '1977', (162, 165))	('mutations', 'Var', (12, 21))	('CBP', 'Gene', (162, 165))	('CTNNB1', 'Gene', (25, 31))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('responsive', 'Reg', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('tumors', 'Disease', (246, 252))
56246	31266387	 ARMC5 Variants and Risk of Hypertension in Blacks: MH-GRID Study We recently found that ARMC5 variants may be associated with primary aldosteronism in blacks.	('primary aldosteronism', 'Phenotype', 'HP:0011736', (127, 148))	('ARMC5', 'Gene', (1, 6))	('Hypertension', 'Disease', (28, 40))	('MH-GRID', 'Disease', 'MESH:C535694', (52, 59))	('primary aldosteronism', 'Disease', (127, 148))	('MH-GRID', 'Disease', (52, 59))	('ARMC5', 'Gene', '79798', (1, 6))	('associated', 'Reg', (111, 121))	('ARMC5', 'Gene', '79798', (89, 94))	('ARMC5', 'Gene', (89, 94))	('Hypertension', 'Phenotype', 'HP:0000822', (28, 40))	('variants', 'Var', (95, 103))	('Hypertension', 'Disease', 'MESH:D006973', (28, 40))
56247	31266387	We investigated a cohort from the MH-GRID (Minority Health Genomics and Translational Research Bio-Repository Database) and tested the association between ARMC5 variants and blood pressure in blacks.	('variants', 'Var', (161, 169))	('ARMC5', 'Gene', '79798', (155, 160))	('blood pressure', 'Disease', (174, 188))	('ARMC5', 'Gene', (155, 160))	('MH-GRID', 'Disease', 'MESH:C535694', (34, 41))	('association', 'Interaction', (135, 146))	('MH-GRID', 'Disease', (34, 41))	('tested', 'Reg', (124, 130))
56249	31266387	Sixteen rare variants were significantly associated with hypertension (P=0.0402) in the gene-based (optimized sequenced kernel association test) analysis; the 16 and one other, rs116201073, together, showed a strong association (P=0.0003) with blood pressure in this data set.	('hypertension', 'Disease', 'MESH:D006973', (57, 69))	('associated', 'Reg', (41, 51))	('rs116201073', 'Var', (177, 188))	('hypertension', 'Disease', (57, 69))	('hypertension', 'Phenotype', 'HP:0000822', (57, 69))	('blood pressure', 'Disease', (244, 258))	('rs116201073', 'Mutation', 'rs116201073', (177, 188))
56250	31266387	The presence of the rs116201073 variant was associated with lower blood pressure.	('rs116201073', 'Mutation', 'rs116201073', (20, 31))	('lower blood pressure', 'Phenotype', 'HP:0002615', (60, 80))	('blood pressure', 'MPA', (66, 80))	('rs116201073', 'Var', (20, 31))	('lower', 'NegReg', (60, 65))
56251	31266387	We then used human embryonic kidney 293 and adrenocortical H295R cells transfected with an ARMC5 construct containing rs116201073 (c.*920T>C).	('embryonic kidney', 'Disease', 'MESH:D007674', (19, 35))	('adrenocortical', 'Disease', 'MESH:D018268', (44, 58))	('human', 'Species', '9606', (13, 18))	('ARMC5', 'Gene', (91, 96))	('H295R', 'CellLine', 'CVCL:0458', (59, 64))	('ARMC5', 'Gene', '79798', (91, 96))	('rs116201073 (c.*920T>C', 'Var', (118, 140))	('embryonic kidney', 'Disease', (19, 35))	('c.*920T>C', 'Mutation', 'rs116201073', (131, 140))	('rs116201073', 'Mutation', 'rs116201073', (118, 129))	('adrenocortical', 'Disease', (44, 58))	('c.*920T>C', 'Var', (131, 140))
56253	31266387	The allele carrying rs116201073 increased levels of ARMC5  mRNA, consistent with its protective effect in the epidemiological data.	('levels', 'MPA', (42, 48))	('rs116201073', 'Mutation', 'rs116201073', (20, 31))	('increased', 'PosReg', (32, 41))	('rs116201073', 'Var', (20, 31))	('ARMC5', 'Gene', '79798', (52, 57))	('ARMC5', 'Gene', (52, 57))
56255	31266387	We also identified a protective variant of the ARMC5 gene with an effect on ARMC5 expression confirmed in vitro.	('ARMC5', 'Gene', '79798', (76, 81))	('ARMC5', 'Gene', (76, 81))	('variant', 'Var', (32, 39))	('effect', 'Reg', (66, 72))	('expression', 'MPA', (82, 92))	('ARMC5', 'Gene', (47, 52))	('ARMC5', 'Gene', '79798', (47, 52))
56257	31266387	Germline variants in ARMC5 may in part be responsible for regulation of blood pressure in blacks through their in adrenocortical function.	('ARMC5', 'Gene', '79798', (21, 26))	('ARMC5', 'Gene', (21, 26))	('blood pressure', 'MPA', (72, 86))	('regulation', 'MPA', (58, 68))	('adrenocortical function', 'Disease', (114, 137))	('adrenocortical function', 'Disease', 'MESH:D018268', (114, 137))	('Germline variants', 'Var', (0, 17))	('responsible', 'Reg', (42, 53))
56266	31266387	Blacks are more likely to have PA because of bilateral adrenocortical hyperplasia,4, 11, 12, 13, 14, 15, 16, 17 although one report suggests a similar prevalence in whites and blacks.18 Several genetic defects have been identified in PA, although their link to the increased ethnic predisposition to hypertension has not been fully studied or understood.	('identified', 'Reg', (220, 230))	('hypertension', 'Disease', 'MESH:D006973', (300, 312))	('bilateral adrenocortical hyperplasia', 'Disease', (45, 81))	('bilateral adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (45, 81))	('genetic defects', 'Var', (194, 209))	('hypertension', 'Disease', (300, 312))	('hypertension', 'Phenotype', 'HP:0000822', (300, 312))
56268	31266387	We identified 12 germline ARMC5 genetic alterations in 20 unrelated and 2 related individuals (39.3%), in which all affected patients carrying a variant predicted to be damaging were black.	('ARMC5', 'Gene', '79798', (26, 31))	('genetic alterations', 'Var', (32, 51))	('ARMC5', 'Gene', (26, 31))	('variant', 'Var', (145, 152))	('patients', 'Species', '9606', (125, 133))
56286	31266387	Therefore, to investigate the relationship between a common ARMC5 variant and PRA, a smaller data set of 299 samples was used from the GENE-FORECAST (Genomics, Environmental Factors and the Social Determinants of Cardiovascular Disease in African Americans Study).	('ARMC5', 'Gene', '79798', (60, 65))	('Cardiovascular Disease', 'Disease', 'MESH:D002318', (213, 235))	('ARMC5', 'Gene', (60, 65))	('Cardiovascular Disease', 'Phenotype', 'HP:0001626', (213, 235))	('Cardiovascular Disease', 'Disease', (213, 235))	('variant', 'Var', (66, 73))	('men', 'Species', '9606', (167, 170))
56293	31266387	We used 1377 patients and 44 variants within ARMC5 (3 common, 4 low frequency, and 37 rare variants) for analysis.	('variants', 'Var', (29, 37))	('ARMC5', 'Gene', (45, 50))	('patients', 'Species', '9606', (13, 21))	('ARMC5', 'Gene', '79798', (45, 50))
56299	31266387	The DNA sequence of ARMC5-203 isoform (NM_024742) was cloned in pUCminusMCS plasmid (Blue Heron).	('ARMC5', 'Gene', '79798', (20, 25))	('ARMC5', 'Gene', (20, 25))	('NM_024742', 'Var', (39, 48))
56300	31266387	The rs116201073 (c.*920T>C) DNA change was introduced by targeted mutagenesis following the manufacturer's instructions (200555-12, Agilent Technologies UK Ltd).	('rs116201073', 'Mutation', 'rs116201073', (4, 15))	('c.*920T>C', 'Mutation', 'rs116201073', (17, 26))	('mutagenesis', 'Var', (66, 77))	('rs116201073 (c.*920T>C', 'Var', (4, 26))
56301	31266387	Human embryonic kidney 293 (HEK293) cells were grown in Dulbecco's modified Eagle medium (DMEM) (11995, Gibco) enriched with 10% fetal bovine serum (FBS) (900, Gemini Bio-Products Inc), GlutaMAX (35050, Gibco), and Anti (15240, Gibco), whereas human adrenocarcinoma (H295R) cells were maintained in DMEM-F12 (11320, Gibco) containing 10% FBS (900, Gemini Bio-Products Inc), GlutaMAX (35050, Gibco), Anti (15240, Gibco), and Insulin-Transferrin-Selenium (41400, Thermo Fisher Scientific).	('Human', 'Species', '9606', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('embryonic kidney', 'Disease', 'MESH:D007674', (6, 22))	('293 (HEK293)', 'CellLine', 'CVCL:0045', (23, 35))	('adrenocarcinoma', 'Disease', 'None', (250, 265))	('adrenocarcinoma', 'Disease', (250, 265))	('Insulin', 'Gene', (424, 431))	('bovine', 'Species', '9913', (135, 141))	('35050', 'Var', (384, 389))	('human', 'Species', '9606', (244, 249))	('FBS', 'Disease', (149, 152))	('FBS', 'Disease', 'MESH:D005198', (149, 152))	('Transferrin', 'Gene', (432, 443))	('H295R', 'CellLine', 'CVCL:0458', (267, 272))	('embryonic kidney', 'Disease', (6, 22))	('FBS', 'Disease', (338, 341))	('Insulin', 'Gene', '3630', (424, 431))	('FBS', 'Disease', 'MESH:D005198', (338, 341))	('Transferrin', 'Gene', '7018', (432, 443))
56309	31266387	In the discovery analysis (MH-GRID data), ARMC5 variant rs116201073 reached nominal significance (P=0.044; odds ratio, 0.7), suggesting a protective effect for this variant (Table 2).	('MH-GRID', 'Disease', (27, 34))	('rs116201073', 'Var', (56, 67))	('ARMC5', 'Gene', (42, 47))	('ARMC5', 'Gene', '79798', (42, 47))	('rs116201073', 'Mutation', 'rs116201073', (56, 67))	('MH-GRID', 'Disease', 'MESH:C535694', (27, 34))
56310	31266387	For the replication analysis (GENE-FORECAST data), the variant rs116201073 was imputed with high confidence (R 2=0.96) and its MAF (0.077) was similar to what was observed in MH-GRID.	('MH-GRID', 'Disease', 'MESH:C535694', (175, 182))	('rs116201073', 'Mutation', 'rs116201073', (63, 74))	('rs116201073', 'Var', (63, 74))	('MH-GRID', 'Disease', (175, 182))
56313	31266387	That process identified 16 rare variants that together are associated with hypertension (P=0.0011).	('hypertension', 'Disease', (75, 87))	('associated with', 'Reg', (59, 74))	('hypertension', 'Phenotype', 'HP:0000822', (75, 87))	('variants', 'Var', (32, 40))	('hypertension', 'Disease', 'MESH:D006973', (75, 87))
56314	31266387	SKAT-O of a set that consists of those 16 variants and the common variant identified in the single-variant analysis was more strongly associated with hypertension (Table 3).	('associated', 'Reg', (134, 144))	('hypertension', 'Disease', 'MESH:D006973', (150, 162))	('variants', 'Var', (42, 50))	('hypertension', 'Disease', (150, 162))	('hypertension', 'Phenotype', 'HP:0000822', (150, 162))
56316	31266387	All of the 16 rare variants associated with hypertension in the SKAT-O and outlined in Table 4 have the same effect as the common variant rs116201073 and this explains the stronger association for the set of 17 (16 rare+1 common).	('rs116201073', 'Var', (138, 149))	('hypertension', 'Disease', (44, 56))	('hypertension', 'Phenotype', 'HP:0000822', (44, 56))	('associated with', 'Reg', (28, 43))	('rs116201073', 'Mutation', 'rs116201073', (138, 149))	('hypertension', 'Disease', 'MESH:D006973', (44, 56))
56327	31266387	Then we estimated the association between the variant and PRA dichotomized using a cutoff of 0.65 ng/mL per hour54 to have, respectively, 82 and 134 patients in the low and high renin groups across the 216 samples for which genotype data were available in GENE-FORECAST.	('PRA', 'Disease', (58, 61))	('patients', 'Species', '9606', (149, 157))	('renin', 'Gene', (178, 183))	('variant', 'Var', (46, 53))	('high renin', 'Phenotype', 'HP:0000848', (173, 183))	('renin', 'Gene', '5972', (178, 183))
56329	31266387	The rs116201073 variant is a synonymous variant in most of the ARMC5 isoforms except in the NM_024742 isoform (referred to as ARMC5-203 in the Ensembl database) in which it is located in the 3'-untranslated transcribed region (UTR).	('ARMC5', 'Gene', (126, 131))	('rs116201073', 'Mutation', 'rs116201073', (4, 15))	('ARMC5', 'Gene', '79798', (126, 131))	('ARMC5', 'Gene', '79798', (63, 68))	('ARMC5', 'Gene', (63, 68))	('rs116201073', 'Var', (4, 15))
56330	31266387	To determine its potential effect on ARMC5's expression, we transfected wild-type and mutant ARMC5-203 plasmids in HEK293 cells and analyzed ARMC5 presence by real-time quantitative polymerase chain reaction, 24 and 48 hours after transfection.	('ARMC5', 'Gene', '79798', (141, 146))	('ARMC5', 'Gene', '79798', (37, 42))	('ARMC5', 'Gene', (37, 42))	('mutant', 'Var', (86, 92))	('HEK293', 'CellLine', 'CVCL:0045', (115, 121))	('ARMC5', 'Gene', '79798', (93, 98))	('ARMC5', 'Gene', (93, 98))	('ARMC5', 'Gene', (141, 146))
56331	31266387	Whereas at 24 hours, no difference was observed between the 2 groups, at 48 hours, there was a significant increase in ARMC5 mRNA accumulation when ARMC5 carried the variant allele (Figure 2).	('ARMC5', 'Gene', (148, 153))	('increase', 'PosReg', (107, 115))	('ARMC5', 'Gene', (119, 124))	('variant', 'Var', (166, 173))	('ARMC5', 'Gene', '79798', (119, 124))	('ARMC5', 'Gene', '79798', (148, 153))
56333	31266387	The treatment of the transfected cells with a translation inhibitor, cycloheximide, for 2 or 3 hours before collection led to a normalization of the ratio of ARMC5-203 mutant and wild-type mRNA demonstrating that the elevation of mutant ARMC5 mRNA was the result of a decrease of its translation rate.	('cycloheximide', 'Chemical', 'MESH:D003513', (69, 82))	('mutant', 'Var', (168, 174))	('mutant', 'Var', (230, 236))	('men', 'Species', '9606', (9, 12))	('mRNA', 'MPA', (243, 247))	('elevation', 'PosReg', (217, 226))	('ARMC5', 'Gene', (158, 163))	('decrease', 'NegReg', (268, 276))	('ARMC5', 'Gene', '79798', (158, 163))	('translation rate', 'MPA', (284, 300))	('ARMC5', 'Gene', '79798', (237, 242))	('ARMC5', 'Gene', (237, 242))
56334	31266387	A similar elevation of ARMC5-203 mRNA was found at 48 and 72 hours after transfection in an adrenocortical cell line H295R, but this increase was not significant (Figure S4).	('ARMC5', 'Gene', '79798', (23, 28))	('ARMC5', 'Gene', (23, 28))	('adrenocortical', 'Disease', (92, 106))	('H295R', 'CellLine', 'CVCL:0458', (117, 122))	('elevation', 'PosReg', (10, 19))	('adrenocortical', 'Disease', 'MESH:D018268', (92, 106))	('transfection', 'Var', (73, 85))
56335	31266387	Analysis of our data identified one common variant (rs116201073) located in the 3'UTR end of the ARMC5 gene that was associated with decreased risk of hypertension (odds ratio, 0.7) in a sample set of 1377 blacks from the MH-GRID study.	('rs116201073', 'Var', (52, 63))	('ARMC5', 'Gene', '79798', (97, 102))	('hypertension', 'Disease', 'MESH:D006973', (151, 163))	('MH-GRID', 'Disease', 'MESH:C535694', (222, 229))	('hypertension', 'Phenotype', 'HP:0000822', (151, 163))	('hypertension', 'Disease', (151, 163))	('rs116201073', 'Mutation', 'rs116201073', (52, 63))	('MH-GRID', 'Disease', (222, 229))	('decreased', 'NegReg', (133, 142))	('ARMC5', 'Gene', (97, 102))
56337	31266387	Gene-based SKAT-O analysis, in MH-GRID, also revealed a set of 16 rare variants associated with hypertension in blacks with the same protective effect as the common variant rs116201073.	('variants', 'Var', (71, 79))	('rs116201073', 'Var', (173, 184))	('hypertension', 'Disease', 'MESH:D006973', (96, 108))	('hypertension', 'Disease', (96, 108))	('associated', 'Reg', (80, 90))	('hypertension', 'Phenotype', 'HP:0000822', (96, 108))	('MH-GRID', 'Disease', 'MESH:C535694', (31, 38))	('rs116201073', 'Mutation', 'rs116201073', (173, 184))	('MH-GRID', 'Disease', (31, 38))
56338	31266387	These results confirm our previous report of ARMC5's possible involvement in regulating BP in blacks, possibly as a result of its role in determining the presence of bilateral adrenocortical hyperplasia and/or hyperaldosteronism.19  The ARMC5 gene is a putative tumor suppressor that is located on chromosome 16p11.2 and belongs to the family of armadillo-repeat-containing proteins.55, 56 In humans, ARMC5 consists of 8 exons and has an unknown function,19, 49 although recent evidence suggests that it plays a critical role for fetal development and immune responses through interactions with proteins from different pathways.57, 58 Four ARMC5 isoforms exist, with a different pattern of expression, although all 4 are expressed in the adrenal glands.55 The ARMC5 gene has been recently implicated in endogenous hypercortisolemia due to primary macronodular adrenal hyperplasia,59, 60, 61, 62, 63, 64 which is characterized by multiple nodules (>1 cm) in the adrenal cortex and hypercortisolemia.19 Biallelic inactivation of ARMC5 (germline and somatic) is required for the development of adrenocortical hyperplasia, which is consistent with the 2-hit hypothesis of tumorigenesis.59 Most disease-causing variants in ARMC5 are frameshift and/or nonsense, and lead to loss of function of the gene.62 Overexpression of ARMC5 in adrenocortical carcinoma cell line H295R leads to increased cell death59 while silencing of the gene in nonmutated primary macronodular adrenal hyperplasia cell cultures leads to a decrease of apoptosis.65  Genetic variants in ARMC5 have rarely been implicated in PA.	('death', 'Disease', (1392, 1397))	('hypercortisolemia', 'Disease', (814, 831))	('men', 'Species', '9606', (543, 546))	('ARMC5', 'Gene', (640, 645))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('hypercortisolemia', 'Disease', 'None', (814, 831))	('ARMC5', 'Gene', (401, 406))	('hypercortisolemia', 'Disease', (980, 997))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (1091, 1117))	('carcinoma', 'Phenotype', 'HP:0030731', (1342, 1351))	('hypercortisolemia', 'Disease', 'None', (980, 997))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (1327, 1351))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (860, 879))	('men', 'Species', '9606', (1083, 1086))	('ARMC5', 'Gene', '79798', (1318, 1323))	('ARMC5', 'Gene', (45, 50))	('bilateral adrenocortical hyperplasia', 'Disease', (166, 202))	('hyperaldosteronism', 'Disease', (210, 228))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (176, 202))	('macronodular adrenal', 'Phenotype', 'HP:0008231', (847, 867))	('macronodular adrenal', 'Phenotype', 'HP:0008231', (1450, 1470))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (847, 879))	('ARMC5', 'Gene', '79798', (1554, 1559))	('tumor', 'Disease', (1168, 1173))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (1463, 1482))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (210, 228))	('ARMC5', 'Gene', (1218, 1223))	('variants', 'Var', (1542, 1550))	('ARMC5', 'Gene', (1027, 1032))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (1327, 1351))	('death', 'Disease', 'MESH:D003643', (1392, 1397))	('tumor', 'Disease', 'MESH:D009369', (1168, 1173))	('ARMC5', 'Gene', '79798', (237, 242))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (860, 879))	('ARMC5', 'Gene', '79798', (760, 765))	('adrenocortical carcinoma', 'Disease', (1327, 1351))	('humans', 'Species', '9606', (393, 399))	('ARMC5', 'Gene', '79798', (640, 645))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (1450, 1482))	('tumor', 'Disease', (262, 267))	('ARMC5', 'Gene', '79798', (401, 406))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (1463, 1482))	('ARMC5', 'Gene', (1318, 1323))	('bilateral adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (166, 202))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('ARMC5', 'Gene', '79798', (45, 50))	('H295R', 'CellLine', 'CVCL:0458', (1362, 1367))	('adrenal hyperplasia', 'Disease', (1463, 1482))	('men', 'Species', '9606', (69, 72))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (210, 228))	('tumor', 'Phenotype', 'HP:0002664', (1168, 1173))	('ARMC5', 'Gene', (1554, 1559))	('adrenal hyperplasia', 'Disease', (860, 879))	('adrenocortical hyperplasia', 'Disease', (1091, 1117))	('endogenous hypercortisolemia', 'Phenotype', 'HP:0011744', (803, 831))	('ARMC5', 'Gene', '79798', (1218, 1223))	('ARMC5', 'Gene', '79798', (1027, 1032))	('ARMC5', 'Gene', (237, 242))	('ARMC5', 'Gene', (760, 765))
56339	31266387	The largest study to date examined 56 patients with PA and found 12 different germline variants in ARMC5 (6 predicted to be damaging by in silico analysis) in 20 unrelated and 2 related individuals (39%).19 These variants were exclusively found in black individuals and silencing of ARMC5 in H295R cells decreased CYP11B2 expression.19  A recent study in a different cohort of patients with PA reported 18 ARMC5 variants (5 rare with an allele frequency <1%) and 2 new variants that were not predicted to be damaging.66 Variants in ARMC5 are difficult to identify as pathogenic because ARMC5's function remains unclear; however, some missense variants fail to induce apoptosis after transfection in a human adrenocortical cancer cell line H295R.59 Although the link between ARMC5 and PA is yet to be explained, our data support a potential link between ARMC5 variants and hypertension in people of African descent.	('ARMC5', 'Gene', (283, 288))	('ARMC5', 'Gene', '79798', (406, 411))	('human', 'Species', '9606', (701, 706))	('patients', 'Species', '9606', (38, 46))	('adrenocortical cancer', 'Disease', (707, 728))	('ARMC5', 'Gene', (774, 779))	('variants', 'Var', (859, 867))	('ARMC5', 'Gene', (853, 858))	('patients', 'Species', '9606', (377, 385))	('ARMC5', 'Gene', (99, 104))	('people', 'Species', '9606', (888, 894))	('H295R', 'CellLine', 'CVCL:0458', (739, 744))	('ARMC5', 'Gene', '79798', (586, 591))	('ARMC5', 'Gene', '79798', (532, 537))	('link', 'Interaction', (840, 844))	('CYP11B2', 'Gene', '1585', (314, 321))	('ARMC5', 'Gene', (406, 411))	('hypertension', 'Disease', 'MESH:D006973', (872, 884))	('ARMC5', 'Gene', '79798', (283, 288))	('cancer', 'Phenotype', 'HP:0002664', (722, 728))	('hypertension', 'Disease', (872, 884))	('H295R', 'CellLine', 'CVCL:0458', (292, 297))	('ARMC5', 'Gene', '79798', (774, 779))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (707, 728))	('ARMC5', 'Gene', '79798', (853, 858))	('ARMC5', 'Gene', (586, 591))	('hypertension', 'Phenotype', 'HP:0000822', (872, 884))	('ARMC5', 'Gene', (532, 537))	('ARMC5', 'Gene', '79798', (99, 104))	('CYP11B2', 'Gene', (314, 321))
56341	31266387	Although these results were not significant, perhaps because of small sample size, the directions of the relationships were consistent with the seemingly protective effect of the variant (rs116201073) reported in the genetic associations' analyses of MH-GRID and UK Biobank data sets.	('rs116201073', 'Mutation', 'rs116201073', (188, 199))	('rs116201073', 'Var', (188, 199))	('MH-GRID', 'Disease', (251, 258))	('MH-GRID', 'Disease', 'MESH:C535694', (251, 258))
56343	31266387	Given the significantly higher prevalence of the variant in the control we can hypothesize that either the minor C allele has a direct protective effect against hypertension in this population predisposed to low-renin hypertension or this variant is a genetic marker of a protector factor.	('renin', 'Gene', (212, 217))	('hypertension', 'Disease', 'MESH:D006973', (218, 230))	('hypertension', 'Disease', 'MESH:D006973', (161, 173))	('hypertension', 'Disease', (218, 230))	('hypertension', 'Disease', (161, 173))	('renin', 'Gene', '5972', (212, 217))	('hypertension', 'Phenotype', 'HP:0000822', (218, 230))	('hypertension', 'Phenotype', 'HP:0000822', (161, 173))	('variant', 'Var', (49, 56))
56345	31266387	In the ARMC5-203 isoform, which is ubiquitously expressed49 and even overexpressed in our hypertensive cohort compared with controls, the rs116201073 variant is located in the 3'-UTR.	('rs116201073', 'Var', (138, 149))	('hypertensive', 'Disease', 'MESH:D006973', (90, 102))	('hypertensive', 'Disease', (90, 102))	('ARMC5', 'Gene', (7, 12))	('rs116201073', 'Mutation', 'rs116201073', (138, 149))	('ARMC5', 'Gene', '79798', (7, 12))
56346	31266387	The 3'-UTR region is essential for the regulation of mRNA stability, expression, and localization.67 Indeed, our in vitro experiments in HEK293 cells demonstrate that the ARMC5-203 carrying the variant mRNA is accumulated compared with the wild-type mRNA and this is the result, at least in part, of a reduction in its translation rate.	('translation rate', 'MPA', (319, 335))	('accumulated', 'PosReg', (210, 221))	('reduction', 'NegReg', (302, 311))	('HEK293', 'CellLine', 'CVCL:0045', (137, 143))	('men', 'Species', '9606', (128, 131))	('variant', 'Var', (194, 201))	('ARMC5', 'Gene', '79798', (171, 176))	('ARMC5', 'Gene', (171, 176))
56348	31266387	This suggests a specific and nonredundant role between this isoform and the 3 other ARMC5 isoforms.49 Altogether, these data suggest that the ARMC5-203 protein would promote hypertension, as the variant decreasing its protein translation is protective against hypertension.	('hypertension', 'Disease', 'MESH:D006973', (260, 272))	('hypertension', 'Disease', 'MESH:D006973', (174, 186))	('protein translation', 'MPA', (218, 237))	('ARMC5', 'Gene', '79798', (84, 89))	('ARMC5', 'Gene', (84, 89))	('hypertension', 'Disease', (174, 186))	('hypertension', 'Phenotype', 'HP:0000822', (174, 186))	('hypertension', 'Disease', (260, 272))	('protein', 'Protein', (152, 159))	('hypertension', 'Phenotype', 'HP:0000822', (260, 272))	('decreasing', 'NegReg', (203, 213))	('variant', 'Var', (195, 202))	('ARMC5', 'Gene', (142, 147))	('promote', 'PosReg', (166, 173))	('ARMC5', 'Gene', '79798', (142, 147))
56356	31266387	Fourth, we have limited data on the biochemical phenotype of the participants: the association between the common genetic variant and low renin could not be reliably established because of the small sample.	('renin', 'Gene', (138, 143))	('low renin', 'Phenotype', 'HP:0003351', (134, 143))	('participants', 'Species', '9606', (65, 77))	('variant', 'Var', (122, 129))	('renin', 'Gene', '5972', (138, 143))
56358	31266387	Finally, we did not consider other variants/loci of interest for an additive effect on hypertension.	('hypertension', 'Disease', 'MESH:D006973', (87, 99))	('hypertension', 'Phenotype', 'HP:0000822', (87, 99))	('variants/loci', 'Var', (35, 48))	('hypertension', 'Disease', (87, 99))
56359	31266387	We identified one common variant (rs116201073) of the ARMC5 gene that was associated with a decreased risk of hypertension in blacks and a set of 16 rare variants associated with hypertension.	('hypertension', 'Disease', 'MESH:D006973', (179, 191))	('rs116201073', 'Mutation', 'rs116201073', (34, 45))	('ARMC5', 'Gene', '79798', (54, 59))	('hypertension', 'Disease', 'MESH:D006973', (110, 122))	('hypertension', 'Disease', (179, 191))	('ARMC5', 'Gene', (54, 59))	('rs116201073', 'Var', (34, 45))	('hypertension', 'Phenotype', 'HP:0000822', (179, 191))	('hypertension', 'Disease', (110, 122))	('decreased', 'NegReg', (92, 101))	('hypertension', 'Phenotype', 'HP:0000822', (110, 122))
56360	31266387	These results extend our previous report of germline ARMC5 variants that may be linked to hypertension in blacks.	('hypertension', 'Disease', (90, 102))	('ARMC5', 'Gene', (53, 58))	('linked', 'Reg', (80, 86))	('variants', 'Var', (59, 67))	('ARMC5', 'Gene', '79798', (53, 58))	('hypertension', 'Disease', 'MESH:D006973', (90, 102))	('hypertension', 'Phenotype', 'HP:0000822', (90, 102))
56361	31266387	Although not conclusive, the evaluation of the main variant with respect to PRA may suggest a link to low-renin hypertension.	('renin', 'Gene', (106, 111))	('variant', 'Var', (52, 59))	('link', 'Reg', (94, 98))	('hypertension', 'Disease', (112, 124))	('hypertension', 'Phenotype', 'HP:0000822', (112, 124))	('renin', 'Gene', '5972', (106, 111))	('hypertension', 'Disease', 'MESH:D006973', (112, 124))
56366	30760718	Here we comprehensively analyze the genomic alterations of the genes encoding histone acetylation modulator proteins (HAMPs) in the Cancer Genome Atlas cohort and observe that HAMPs have a high frequency of focal copy number alterations and recurrent mutations, whereas transcript fusions of HAMPs are relatively rare genomic events in common adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('mutations', 'Var', (251, 260))	('Cancer Genome Atlas cohort', 'Disease', 'MESH:D009369', (132, 158))	('cancers', 'Phenotype', 'HP:0002664', (349, 356))	('Cancer Genome Atlas cohort', 'Disease', (132, 158))	('focal', 'MPA', (207, 212))	('adult cancers', 'Disease', (343, 356))	('adult cancers', 'Disease', 'MESH:C535836', (343, 356))	('HAMP', 'Gene', '57817', (292, 296))	('HAMP', 'Gene', (292, 296))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('HAMP', 'Gene', '57817', (176, 180))	('HAMP', 'Gene', '57817', (118, 122))	('HAMP', 'Gene', (176, 180))	('HAMP', 'Gene', (118, 122))
56368	30760718	For example, the recurrent focal amplification of BRD9 is observed in 9 cancer types and genetic depletion of BRD9 inhibits tumor growth.	('genetic depletion', 'Var', (89, 106))	('BRD9', 'Gene', '65980', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('BRD9', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (124, 129))	('BRD9', 'Gene', (50, 54))	('inhibits', 'NegReg', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('BRD9', 'Gene', '65980', (110, 114))	('cancer', 'Disease', (72, 78))
56416	30760718	BRD9, BRD4, KAT6A, ATAD2, CLOCK, ASH1L, and BPTF showed high overall G-scores for copy number gain, whereas HDAC4, BRD1, SIRT3, HDAC10, SP100, SP140L, SP110, and PBRM1 had high overall G-scores for copy number loss (overall G-score > 0.9; Fig.	('BRD4', 'Gene', '23476', (6, 10))	('BPTF', 'Gene', (44, 48))	('SP140L', 'Gene', (143, 149))	('SP110', 'Gene', '3431', (151, 156))	('ATAD2', 'Gene', (19, 24))	('SP100', 'Gene', (136, 141))	('KAT6A', 'Gene', '7994', (12, 17))	('HDAC10', 'Gene', '83933', (128, 134))	('SIRT3', 'Gene', (121, 126))	('ASH1L', 'Gene', (33, 38))	('SIRT3', 'Gene', '23410', (121, 126))	('copy number gain', 'Disease', 'MESH:D015430', (82, 98))	('CLOCK', 'Gene', '9575', (26, 31))	('CLOCK', 'Gene', (26, 31))	('BRD1', 'Gene', (115, 119))	('HDAC4', 'Gene', '9759', (108, 113))	('copy number', 'Var', (198, 209))	('ASH1L', 'Gene', '55870', (33, 38))	('copy number gain', 'Disease', (82, 98))	('KAT6A', 'Gene', (12, 17))	('SP110', 'Gene', (151, 156))	('SP100', 'Gene', '6672', (136, 141))	('BRD4', 'Gene', (6, 10))	('SP140L', 'Gene', '93349', (143, 149))	('BRD9', 'Gene', (0, 4))	('PBRM1', 'Gene', '55193', (162, 167))	('ATAD2', 'Gene', '29028', (19, 24))	('BRD1', 'Gene', '23774', (115, 119))	('HDAC10', 'Gene', (128, 134))	('HDAC4', 'Gene', (108, 113))	('BPTF', 'Gene', '2186', (44, 48))	('PBRM1', 'Gene', (162, 167))	('BRD9', 'Gene', '65980', (0, 4))
56418	30760718	3b); in contrast, high-level alterations (GISTIC status = - 2) were markedly less frequent in HAMPs with copy number loss (0.8-9.4%; Fig.	('HAMP', 'Gene', (94, 98))	('HAMP', 'Gene', '57817', (94, 98))	('copy number loss', 'Var', (105, 121))
56422	30760718	The mutation call set was generated via an ensemble calling strategy by the MC3 (Multi-Center Mutation Calling in Multiple Cancers) project, then we integrated five complementary methods to identify the genes with mutations that have significant signs of positive selection during tumor evolution (Fig.	('Multiple Cancers', 'Disease', (114, 130))	('MC3', 'Gene', (76, 79))	('Multiple Cancers', 'Disease', 'MESH:D009369', (114, 130))	('MC3', 'Gene', '4159', (76, 79))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cancers', 'Phenotype', 'HP:0002664', (123, 130))	('mutations', 'Var', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (281, 286))
56423	30760718	Collectively, across 33 cancer types, we identified 34 HAMPs that have recurrent mutations in at least one cancer type (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('HAMP', 'Gene', '57817', (55, 59))	('HAMP', 'Gene', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (107, 113))
56425	30760718	3b), the recurrent mutations of HAMPs were largely cancer type-specific (Fig.	('HAMP', 'Gene', '57817', (32, 36))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('HAMP', 'Gene', (32, 36))
56426	30760718	4b): 17 of 34 (50%) HAMPs with recurrent mutations were only observed in one cancer type and no recurrent mutation of HAMPs was found in more than 7 cancer types.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('HAMP', 'Gene', '57817', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HAMP', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('HAMP', 'Gene', '57817', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('HAMP', 'Gene', (118, 122))
56428	30760718	UCEC (n = 20), SKCM (n = 8), BLCA (n = 6), cervical squamous cell carcinoma, and endocervical adenocarcinoma (CESC; n = 6), and HNSC (n = 6) had the largest numbers of recurrent mutations in HAMPs, whereas ACC, DLBC, ESCA, KICH, LAML, LGG, mesothelioma (MESO), OV, PAAD, PCPG, READ, SARC, TGCT, THCA, THYM, UCS, and UVM had none (Fig.	('READ', 'Disease', 'None', (277, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('KICH', 'Disease', (223, 227))	('PAAD', 'Phenotype', 'HP:0006725', (265, 269))	('cervical squamous cell carcinoma', 'Disease', (43, 75))	('UCS', 'Phenotype', 'HP:0002891', (307, 310))	('OV', 'Phenotype', 'HP:0012887', (261, 263))	('mesothelioma', 'Disease', (240, 252))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (81, 108))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 75))	('HAMP', 'Gene', '57817', (191, 195))	('mesothelioma', 'Disease', 'MESH:D008654', (240, 252))	('ACC', 'Phenotype', 'HP:0006744', (206, 209))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('ESCA', 'Phenotype', 'HP:0011459', (217, 221))	('READ', 'Disease', (277, 281))	('KICH', 'Disease', 'None', (223, 227))	('HAMP', 'Gene', (191, 195))	('THYM', 'Phenotype', 'HP:0100522', (301, 305))	('THCA', 'Phenotype', 'HP:0002890', (295, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('mutations', 'Var', (178, 187))	('endocervical adenocarcinoma', 'Disease', (81, 108))
56429	30760718	Among the three types of HAMPs, BRD proteins and HATs had the highest frequencies of recurrent mutations and HDACs had few recurrent events (Fig.	('HAMP', 'Gene', '57817', (25, 29))	('HDAC', 'Gene', (109, 113))	('HAMP', 'Gene', (25, 29))	('HDAC', 'Gene', '9734', (109, 113))	('mutations', 'Var', (95, 104))
56431	30760718	Among eight HAMPs with M-scores > 0.4, EP300, PBRM1, and CREBBP had the largest overall M-scores across the 33 cancer types (Fig.	('CREBBP', 'Gene', (57, 63))	('HAMP', 'Gene', '57817', (12, 16))	('HAMP', 'Gene', (12, 16))	('M-scores', 'MPA', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CREBBP', 'Gene', '1387', (57, 63))	('PBRM1', 'Gene', (46, 51))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('EP300', 'Gene', (39, 44))	('EP300', 'Gene', '2033', (39, 44))	('PBRM1', 'Gene', '55193', (46, 51))	('M-scores > 0.4', 'Var', (23, 37))
56433	30760718	At a pan-cancer level, except for PBRM1, the most common mutation category of HAMPs was missense mutation (53.0-77.5%; Fig.	('cancer', 'Disease', (9, 15))	('HAMP', 'Gene', (78, 82))	('PBRM1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('PBRM1', 'Gene', '55193', (34, 39))	('missense mutation', 'Var', (88, 105))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('HAMP', 'Gene', '57817', (78, 82))
56434	30760718	In contrast, PBRM1 was most commonly affected by truncating mutations (49.1%; Fig.	('affected', 'Reg', (37, 45))	('PBRM1', 'Gene', (13, 18))	('PBRM1', 'Gene', '55193', (13, 18))	('truncating mutations', 'Var', (49, 69))
56435	30760718	Using the ABSOLUTE algorithm, we also determined the timing of the mutational processes and the clonal statuses of the mutations in HAMPs.	('HAMP', 'Gene', (132, 136))	('mutations', 'Var', (119, 128))	('HAMP', 'Gene', '57817', (132, 136))
56436	30760718	More than 50% of mutations in HAMPs were early genomic events (Fig.	('HAMP', 'Gene', '57817', (30, 34))	('mutations', 'Var', (17, 26))	('HAMP', 'Gene', (30, 34))
56437	30760718	5d and Supplementary Data 15) and more than 65% of mutations in HAMPs were clonal mutations (Fig.	('HAMP', 'Gene', (64, 68))	('mutations', 'Var', (51, 60))	('HAMP', 'Gene', '57817', (64, 68))
56439	30760718	We also analyzed the distributions of the mutations across the gene bodies and found that mutations in HAMPs were widely spatially distributed along the entire coding sequences, not concentrated within a specific local region (Fig.	('HAMP', 'Gene', '57817', (103, 107))	('mutations', 'Var', (90, 99))	('HAMP', 'Gene', (103, 107))
56442	30760718	Notably, we observed that PBRM1 mutations showed a unique pattern in KIRC and cholangiocarcinoma (CHOL).	('CHOL', 'Phenotype', 'HP:0030153', (98, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('mutations', 'Var', (32, 41))	('KIRC', 'Disease', (69, 73))	('cholangiocarcinoma', 'Disease', (78, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
56443	30760718	Compared with other cancer types, KIRC and CHOL showed higher frequencies of PBRM1 mutations (40.1% in KIRC and 19.4% in CHOL vs. an average of 2.3% among other cancer types).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (83, 92))	('PBRM1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PBRM1', 'Gene', '55193', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('CHOL', 'Phenotype', 'HP:0030153', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', (161, 167))	('CHOL', 'Phenotype', 'HP:0030153', (43, 47))
56444	30760718	Importantly, the dominant PBRM1 mutation category and type in KIRC and CHOL were truncating (83.9% and 85.7%, respectively) and homozygous (85.2% and 71.4%, respectively) mutations, which were remarkably higher than the averages in other cancer types (30.3% and 19.4%, respectively).	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('truncating', 'MPA', (81, 91))	('mutation', 'Var', (32, 40))	('CHOL', 'Phenotype', 'HP:0030153', (71, 75))
56445	30760718	Interestingly, we observed that, in both the CREBBP and EP300 genes, the most frequent mutations were located within the catalytic domain, although the mutations were not statistically significant hotspot mutations at the individual gene level based on OncodriveCLUST analysis (Fig.	('CREBBP', 'Gene', '1387', (45, 51))	('EP300', 'Gene', (56, 61))	('EP300', 'Gene', '2033', (56, 61))	('CREBBP', 'Gene', (45, 51))	('mutations', 'Var', (87, 96))
56448	30760718	Consistent with our analysis, one of the hotspot mutations that we identified in the HAT_KAT11 domain was also recently reported in a pan-cancer analysis of protein domain mutations in 5496 tumors.	('cancer', 'Disease', (138, 144))	('mutations', 'Var', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
56452	30760718	6a and Supplementary Data 18), which suggests that transcript fusion is a rare genetic alteration compared with SCNAs and mutations in HAMPs in common adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('adult cancers', 'Disease', 'MESH:C535836', (151, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('adult cancers', 'Disease', (151, 164))	('transcript fusion', 'Var', (51, 68))	('HAMP', 'Gene', '57817', (135, 139))	('HAMP', 'Gene', (135, 139))
56456	30760718	KAT6B-ADK (n = 6), BPTF-PITPNC1 (n = 5), and NCOA3-EYA2 (n = 5) were the most frequent fusions among the common cancer types examined in our study (Fig.	('fusions', 'Var', (87, 94))	('PITPNC1', 'Gene', '26207', (24, 31))	('BPTF', 'Gene', (19, 23))	('cancer', 'Disease', (112, 118))	('PITPNC1', 'Gene', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('BPTF', 'Gene', '2186', (19, 23))	('EYA2', 'Gene', '2139', (51, 55))	('NCOA3', 'Gene', '8202', (45, 50))	('EYA2', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('NCOA3', 'Gene', (45, 50))
56460	30760718	Taken together, these results suggest that, although certain HAMP transcript fusions may be actionable for clinical cancer care, transcript fusion is a rare genomic alteration compared with SCNAs and mutations of HAMPs in common cancers.	('HAMP', 'Gene', '57817', (61, 65))	('cancer', 'Disease', (229, 235))	('HAMP', 'Gene', (61, 65))	('transcript fusion', 'Var', (129, 146))	('cancer', 'Disease', (116, 122))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancers', 'Disease', (229, 236))	('HAMP', 'Gene', '57817', (213, 217))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('HAMP', 'Gene', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
56464	30760718	Across the different lineages of cancers, three types of alterations were observed: (1) consistent, putative gain-of-function (such as for KAT6A and CLOCK, which were focally amplified in six and five cancer types, respectively); (2) consistent, putative loss-of-function (such as for PBRM1, which is mutated in four and focally deleted in five cancer types, and for CREBBP, which is mutated in four and focally deleted in two cancer types); and (3) diverse alterations (such as for ATAD2, which is mutated in three and focally amplified in five cancer types, and for BPTF, which is mutated in three and focally amplified in five cancer types).	('gain-of-function', 'PosReg', (109, 125))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', (630, 636))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (427, 433))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('KAT6A', 'Gene', '7994', (139, 144))	('ATAD2', 'Gene', '29028', (483, 488))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('loss-of-function', 'NegReg', (255, 271))	('cancers', 'Disease', (33, 40))	('CREBBP', 'Gene', (367, 373))	('cancer', 'Disease', (546, 552))	('PBRM1', 'Gene', '55193', (285, 290))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (630, 636))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (427, 433))	('KAT6A', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (546, 552))	('ATAD2', 'Gene', (483, 488))	('PBRM1', 'Gene', (285, 290))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('BPTF', 'Gene', '2186', (568, 572))	('CREBBP', 'Gene', '1387', (367, 373))	('cancer', 'Disease', (345, 351))	('CLOCK', 'Gene', '9575', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('CLOCK', 'Gene', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (546, 552))	('BPTF', 'Gene', (568, 572))	('deleted', 'Var', (329, 336))
56465	30760718	This suggests that a large fraction of HAMP alterations may be commonly shared by multiple cancer types, whereas others may be tumor-lineage dependent.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('HAMP', 'Gene', (39, 43))	('HAMP', 'Gene', '57817', (39, 43))	('multiple cancer', 'Disease', (82, 97))	('tumor', 'Disease', (127, 132))	('alterations', 'Var', (44, 55))	('multiple cancer', 'Disease', 'MESH:D009369', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
56494	30760718	Consistent with the GBA prediction, knocking down BRD9 expression dramatically inhibited cancer cell growth in vitro (Fig.	('BRD9', 'Gene', '65980', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('BRD9', 'Gene', (50, 54))	('expression', 'MPA', (55, 65))	('cancer', 'Disease', (89, 95))	('inhibited', 'NegReg', (79, 88))	('knocking down', 'Var', (36, 49))	('GBA', 'Chemical', '-', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
56495	30760718	Finally, we demonstrated that the expression of BRD9 shRNAs significantly suppressed the growth of subcutaneous tumors formed by MDA-MB-231 or OVCAR8 cells in nude mice (Fig.	('subcutaneous tumors', 'Disease', (99, 118))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (129, 139))	('BRD9', 'Gene', (48, 52))	('nude mice', 'Species', '10090', (159, 168))	('OV', 'Phenotype', 'HP:0012887', (143, 145))	('suppressed', 'NegReg', (74, 84))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (99, 118))	('expression', 'Var', (34, 44))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (99, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('growth', 'CPA', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('BRD9', 'Gene', '65980', (48, 52))
56496	30760718	Collectively, our results demonstrate that genetic depletion of BDR9 expression significantly represses tumor cell growth in vitro and in vivo, suggesting that small molecular compounds targeting BRD9 may have strong clinical application potentials.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('BDR9', 'Gene', (64, 68))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('represses', 'NegReg', (94, 103))	('BRD9', 'Gene', '65980', (196, 200))	('BRD9', 'Gene', (196, 200))	('genetic depletion', 'Var', (43, 60))
56504	30760718	A HAMP with a high score indicates its recurrent alterations are common genomic events across multiple adult cancer types.	('HAMP', 'Gene', '57817', (2, 6))	('alterations', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('HAMP', 'Gene', (2, 6))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
56517	30760718	Furthermore, genetic depletion of HDACs in tumor cells leads to cell cycle arrest, apoptosis, and senescence, suggesting that HDACs are required for the survival and growth of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('genetic depletion', 'Var', (13, 30))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('HDAC', 'Gene', (126, 130))	('senescence', 'CPA', (98, 108))	('HDAC', 'Gene', '9734', (34, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('apoptosis', 'CPA', (83, 92))	('tumor', 'Disease', (43, 48))	('HDAC', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('cell cycle arrest', 'CPA', (64, 81))	('HDAC', 'Gene', '9734', (126, 130))
56520	30760718	For example, CREBBP and EP300 were widely mutated across multiple cancer types at relatively low frequencies; most of these mutations were heterozygous missense mutations.	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('EP300', 'Gene', (24, 29))	('EP300', 'Gene', '2033', (24, 29))	('multiple cancer', 'Disease', 'MESH:D009369', (57, 72))	('CREBBP', 'Gene', (13, 19))	('multiple cancer', 'Disease', (57, 72))	('CREBBP', 'Gene', '1387', (13, 19))
56521	30760718	In contrast, PBRM1 showed high-frequency, cancer type-specific mutations in KIRC (40.1%).	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('PBRM1', 'Gene', (13, 18))	('PBRM1', 'Gene', '55193', (13, 18))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
56527	30760718	Collectively, our comprehensive genomic analysis identified 63 putative cancer-causing HAMPs driven by SCNAs and/or mutations (recurrent score >= 1).	('SCNAs', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (116, 125))	('HAMP', 'Gene', '57817', (87, 91))	('HAMP', 'Gene', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
56530	30760718	For example, the breast and ovarian cancer patients with BRD4 amplifications may be potential candidates for treatment with BET inhibitors that have been successfully developed to the preclinical stage.	('BET', 'Gene', '92737', (124, 127))	('BET', 'Gene', (124, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (28, 42))	('patients', 'Species', '9606', (43, 51))	('BRD4', 'Gene', (57, 61))	('amplifications', 'Var', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('BRD4', 'Gene', '23476', (57, 61))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (17, 42))
56531	30760718	In addition, eight HAMPs focally lost copy numbers (overall G-score > 0.9) and eight HAMPs showed high frequencies of mutations (overall M-score > 0.4), which indicates that their functions may be reduced and/or deficient due to partial loss of wild-type alleles during cancer development.	('HAMP', 'Gene', (19, 23))	('deficient', 'NegReg', (212, 221))	('copy', 'MPA', (38, 42))	('HAMP', 'Gene', '57817', (85, 89))	('functions', 'MPA', (180, 189))	('mutations', 'Var', (118, 127))	('cancer', 'Disease', (270, 276))	('HAMP', 'Gene', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('lost', 'NegReg', (33, 37))	('HAMP', 'Gene', '57817', (19, 23))
56533	30760718	For example, mutations of the BRD-containing protein SMARCA4 in tumor cells results in a unique functional dependence on SMARCA2.	('tumor', 'Disease', (64, 69))	('functional dependence', 'MPA', (96, 117))	('SMARCA4', 'Gene', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutations', 'Var', (13, 22))	('SMARCA2', 'Gene', (121, 128))	('SMARCA2', 'Gene', '6595', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('results in', 'Reg', (76, 86))	('SMARCA4', 'Gene', '6597', (53, 60))
56535	30760718	Notably, very few homozygous deletions or mutations of HAMPs (except for PBRM1) were observed in cancer, suggesting that HAMPs may be essential for tumor growth, and that complete loss may be lethal.	('deletions', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', (148, 153))	('HAMP', 'Gene', '57817', (55, 59))	('PBRM1', 'Gene', '55193', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('HAMP', 'Gene', (55, 59))	('HAMP', 'Gene', '57817', (121, 125))	('HAMP', 'Gene', (121, 125))	('PBRM1', 'Gene', (73, 78))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
56549	30760718	Our genomic and functional studies demonstrated that: (1) BRD9 is recurrently and focally amplified in nine cancer types with the highest recurrent score; (2) the expression of BRD9 is significantly increased in cancer specimens compared with that in corresponding normal tissues; (3) computational prediction suggests that BRD9 expression is associated with cell cycle, DNA damage repair, and RNA metabolic pathways in cancer; and (4) genetic depletion of BRD9 by shRNAs reduced cancer cell growth in vitro and in vivo.	('associated', 'Reg', (343, 353))	('genetic depletion', 'Var', (436, 453))	('BRD9', 'Gene', (324, 328))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (480, 486))	('cancer', 'Disease', (420, 426))	('BRD9', 'Gene', '65980', (324, 328))	('BRD9', 'Gene', (457, 461))	('cancer', 'Phenotype', 'HP:0002664', (420, 426))	('BRD9', 'Gene', '65980', (457, 461))	('BRD9', 'Gene', (58, 62))	('BRD9', 'Gene', (177, 181))	('cancer', 'Disease', (212, 218))	('BRD9', 'Gene', '65980', (58, 62))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (420, 426))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Disease', (480, 486))	('reduced', 'NegReg', (472, 479))	('BRD9', 'Gene', '65980', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (480, 486))
56560	30760718	The gene expression data of 2012 cancer cell lines were downloaded through the Expression Atlas (https://www.ebi.ac.uk/gxa/download.html) under the accessions E-MTAB-2770, E-MTAB-3983, and E-MTAB-2706.	('E-MTAB-2770', 'Var', (159, 170))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('MTAB-2706', 'CellLine', 'CVCL:A552', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('E-MTAB-2706', 'Var', (189, 200))
56584	30760718	ABSOLUTE calculated the purity, ploidy, and absolute DNA copy numbers from the segmented copy number alterations and mutation profiles of tumor samples.	('alterations', 'Var', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', (138, 143))
56587	30760718	The cancer cell fraction of each somatic single-nucleotide variant was extracted from the output.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('single-nucleotide variant', 'Var', (41, 66))
56704	22335482	Identification of novel genetic variants in phosphodiesterase 8B (PDE8B), a cAMP specific phosphodiesterase highly expressed in the adrenal cortex, in a cohort of patients with adrenal tumors Genetic aberrations in various components of cAMP signalling pathway predispose to endocrine tumors.	('adrenal tumors', 'Disease', (177, 191))	('endocrine tumor', 'Phenotype', 'HP:0100568', (275, 290))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('cAMP', 'Gene', (237, 241))	('phosphodiesterase 8B', 'Gene', '8622', (44, 64))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('phosphodiesterase 8B', 'Gene', (44, 64))	('variants', 'Var', (32, 40))	('PDE8B', 'Gene', '8622', (66, 71))	('cAMP', 'Gene', (76, 80))	('patients', 'Species', '9606', (163, 171))	('adrenal tumor', 'Phenotype', 'HP:0100631', (177, 190))	('cAMP', 'Gene', '820', (237, 241))	('endocrine tumors', 'Disease', 'MESH:D004701', (275, 291))	('adrenal tumors', 'Disease', 'MESH:D000310', (177, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('endocrine tumors', 'Disease', (275, 291))	('predispose', 'Reg', (261, 271))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('PDE8B', 'Gene', (66, 71))	('cAMP', 'Gene', '820', (76, 80))
56705	22335482	Growing evidence has shown that mutations in the phosphodiesterases (PDEs) are involved in the predisposition to adrenocortical neoplastic conditions.	('adrenocortical neoplastic conditions', 'Disease', (113, 149))	('PDEs', 'Gene', '50940', (69, 73))	('involved', 'Reg', (79, 87))	('mutations', 'Var', (32, 41))	('phosphodiesterases', 'Gene', (49, 67))	('PDEs', 'Gene', (69, 73))	('adrenocortical neoplastic', 'Phenotype', 'HP:0100631', (113, 138))	('adrenocortical neoplastic conditions', 'Disease', 'MESH:D018268', (113, 149))	('phosphodiesterases', 'Gene', '50940', (49, 67))
56709	22335482	Two of the variations, seen only in the patient group, showed significant potential to impair protein function, both in vitro and in silico.	('variations', 'Var', (11, 21))	('patient', 'Species', '9606', (40, 47))	('impair', 'NegReg', (87, 93))	('protein', 'Protein', (94, 101))
56710	22335482	PDE8B is another gene in which variations may contribute to predisposition of adrenocortical tumors.	('contribute', 'Reg', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('PDE8B', 'Gene', (0, 5))	('adrenocortical tumors', 'Disease', (78, 99))	('variations', 'Var', (31, 41))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (78, 99))
56711	22335482	Genetic aberrations in various components of the adenosine 3',5'-cyclic monophosphate (cAMP) signalling pathway have been found to predispose to different types of adrenocortical tumors.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (164, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('predispose', 'Reg', (131, 141))	('Genetic aberrations', 'Var', (0, 19))	('cAMP', 'Gene', (87, 91))	('cAMP', 'Gene', '820', (87, 91))	("adenosine 3',5'-cyclic monophosphate", 'Chemical', 'MESH:D000242', (49, 85))	('adrenocortical tumors', 'Disease', (164, 185))
56713	22335482	Among the numerous phosphodiesterases, PDE8B is known to hydrolyze cAMP with the highest affinity, and PDE8B mutations have been recently implicated in adrenal tumorigenesis.	('cAMP', 'Gene', (67, 71))	('hydrolyze', 'MPA', (57, 66))	('phosphodiesterases', 'Gene', '50940', (19, 37))	('implicated', 'Reg', (138, 148))	('cAMP', 'Gene', '820', (67, 71))	('PDE8B', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('adrenal tumor', 'Disease', 'MESH:D000310', (152, 165))	('mutations', 'Var', (109, 118))	('adrenal tumor', 'Disease', (152, 165))	('phosphodiesterases', 'Gene', (19, 37))	('adrenal tumor', 'Phenotype', 'HP:0100631', (152, 165))
56715	22335482	Pde8b knockout mouse models have demonstrated significantly higher corticosterone levels; shRNA silencing of the Pde8b leads to increased corticosterone synthesis in an adrenal cell line.	('silencing', 'Var', (96, 105))	('higher', 'PosReg', (60, 66))	('corticosterone', 'Chemical', 'MESH:D003345', (67, 81))	('increased', 'PosReg', (128, 137))	('corticosterone levels', 'MPA', (67, 88))	('Pde8b', 'Gene', (113, 118))	('Pde8b', 'Gene', (0, 5))	('increased corticosterone', 'Phenotype', 'HP:0032362', (128, 152))	('mouse', 'Species', '10090', (15, 20))	('higher corticosterone levels', 'Phenotype', 'HP:0032362', (60, 88))	('corticosterone', 'Chemical', 'MESH:D003345', (138, 152))	('Pde8b', 'Gene', '218461', (113, 118))	('corticosterone synthesis in an adrenal cell line', 'MPA', (138, 186))	('Pde8b', 'Gene', '218461', (0, 5))
56716	22335482	Next, another cAMP-hydrolyzing phosphodiesterase, PDE11A, has been recently found mutant in adrenocortical and other endocrine tumors, including testicular germ cell tumors (TGCT) and prostate cancer (PCa).	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cAMP', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('mutant', 'Var', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (184, 199))	('prostate cancer', 'Phenotype', 'HP:0012125', (184, 199))	('PDE11A', 'Gene', '50940', (50, 56))	('PDE11A', 'Gene', (50, 56))	('prostate cancer', 'Disease', (184, 199))	('cAMP', 'Gene', '820', (14, 18))	('germ cell tumors', 'Phenotype', 'HP:0100728', (156, 172))	('germ cell tumors', 'Disease', 'MESH:D009373', (156, 172))	('adrenocortical', 'Disease', 'MESH:D018268', (92, 106))	('endocrine tumors', 'Disease', 'MESH:D004701', (117, 133))	('endocrine tumors', 'Disease', (117, 133))	('endocrine tumor', 'Phenotype', 'HP:0100568', (117, 132))	('germ cell tumors', 'Disease', (156, 172))	('adrenocortical', 'Disease', (92, 106))
56718	22335482	Finally, a severe case of adrenocortical hyperplasia and cortisol hypersecretion leading to Cushing syndrome due to inactivating PDE8B mutation has been reported.	('cortisol', 'Chemical', 'MESH:D006854', (57, 65))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (92, 108))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (26, 52))	('Cushing syndrome', 'Disease', (92, 108))	('adrenocortical hyperplasia', 'Disease', (26, 52))	('inactivating', 'Var', (116, 128))	('Cushing syndrome', 'Disease', 'MESH:D003480', (92, 108))	('cortisol', 'MPA', (57, 65))	('mutation', 'Var', (135, 143))	('PDE8B', 'Gene', (129, 134))
56719	22335482	Herein, we report two novel damaging PDE8B genetic variations in patients with adrenocortical tumors.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (79, 100))	('genetic variations', 'Var', (43, 61))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (65, 73))	('PDE8B', 'Gene', (37, 42))	('adrenocortical tumors', 'Disease', (79, 100))
56724	22335482	Prior to the study, all patients or tumor tissue were tested and found negative for mutations in PRKAR1A, PDE11A and GNAS - the three genes from the cAMP signalling pathway that have been associated with adrenocortical tumors.	('tumor', 'Disease', (219, 224))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (204, 225))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cAMP', 'Gene', (149, 153))	('tumor', 'Disease', (36, 41))	('PRKAR1A', 'Gene', (97, 104))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('GNAS', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('adrenocortical tumors', 'Disease', (204, 225))	('associated', 'Reg', (188, 198))	('PRKAR1A', 'Gene', '5573', (97, 104))	('PDE11A', 'Gene', (106, 112))	('GNAS', 'Gene', '2778', (117, 121))	('PDE11A', 'Gene', '50940', (106, 112))	('mutations', 'Var', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cAMP', 'Gene', '820', (149, 153))	('patients', 'Species', '9606', (24, 32))
56728	22335482	In the PDE8B mutation carriers, tumor DNA, when available, was sequenced to look for possible Loss of heterozygosity in the locus of identified genetic change, as previously described.	('PDE8B', 'Gene', (7, 12))	('mutation', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
56730	22335482	For transfection experiments, the PDE8B open reading frame was cloned into pCR3.1, and the missense mutations (R121H, H391A, P660L, V697I and D755N) were introduced by overlapping PCR, as described previously.	('H391A', 'Var', (118, 123))	('D755N', 'Mutation', 'rs116027371', (142, 147))	('R121H', 'Var', (111, 116))	('R121H', 'Mutation', 'rs115599001', (111, 116))	('V697I', 'Var', (132, 137))	('D755N', 'Var', (142, 147))	('V697I', 'Mutation', 'rs376318658', (132, 137))	('H391A', 'Mutation', 'p.H391A', (118, 123))	('P660L', 'Var', (125, 130))	('P660L', 'Mutation', 'p.P660L', (125, 130))
56732	22335482	Cells were transfected with 6 microg of plasmid DNA expressing either the wild-type (WT) or the mutated form of PDE8B, harvested 48 hours after the transfection, and subjected to cAMP level and PDE activity assays as previously described.	('mutated', 'Var', (96, 103))	('PDE', 'Gene', (112, 115))	('cAMP', 'Gene', (179, 183))	('cAMP', 'Gene', '820', (179, 183))	('PDE', 'Gene', '501', (194, 197))	('PDE', 'Gene', '501', (112, 115))	('PDE', 'Gene', (194, 197))
56735	22335482	We identified six PDE8B coding sequence alterations in eight unrelated individuals from our cohort of 216 patients with adrenal tumors; one individual presented with two different mutations.	('adrenal tumors', 'Disease', 'MESH:D000310', (120, 134))	('PDE8B', 'Gene', (18, 23))	('adrenal tumor', 'Phenotype', 'HP:0100631', (120, 133))	('alterations', 'Var', (40, 51))	('adrenal tumors', 'Disease', (120, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('patients', 'Species', '9606', (106, 114))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
56736	22335482	Five of the variations were missense and resulted in aminoacid substitutions: c.362G>A/p.R121H, c.1171C>A/p.H391A, c.1979C>T/p.P660L, c.2089G>A/p.V697I, and c.2263G>T/p.D755N, and one was a splice variant located five nucleotides upstream of exon 14 (c.1365-5g/a).	('c.2089G>A/p.V697I', 'Var', (134, 151))	('c.362G>A', 'Mutation', 'rs115599001', (78, 86))	('c.2089G>A', 'Mutation', 'rs376318658', (134, 143))	('p.R121H', 'Mutation', 'rs115599001', (87, 94))	('c.1365-5g/a', 'Mutation', 'c.1365-5G>A', (251, 262))	('c.2263G>T', 'Mutation', 'c.2263G>T', (157, 166))	('p.H391A', 'Mutation', 'p.H391A', (106, 113))	('c.1979C>T/p.P660L', 'Var', (115, 132))	('c.362G>A/p.R121H', 'Var', (78, 94))	('p.P660L', 'Mutation', 'p.P660L', (125, 132))	('resulted in', 'Reg', (41, 52))	('p.V697I', 'Mutation', 'rs376318658', (144, 151))	('c.1979C>T', 'Mutation', 'rs202138455', (115, 124))	('p.D755N', 'Mutation', 'rs116027371', (167, 174))	('c.1171C>A/p.H391A', 'Var', (96, 113))	('c.2263G>T/p.D755N', 'Var', (157, 174))	('c.1171C>A', 'Mutation', 'c.1171C>A', (96, 105))
56737	22335482	Two of the five missense variants (R121H and D755N) were previously described in the public databases, and three were novel.	('D755N', 'Mutation', 'rs116027371', (45, 50))	('R121H', 'Var', (35, 40))	('D755N', 'Var', (45, 50))	('R121H', 'Mutation', 'rs115599001', (35, 40))
56738	22335482	Three additional PDE8B sequence variations were identified in the control group - one reported polymorphic variant (c.1267A>G/p.I423V), and 2 previously unknown missense substitutions (c.971G>A/p.R324Q and c.1032G>A/p.V344I), each of the three present in one control individual in a heterozygote state.	('c.1267A>G', 'Mutation', 'rs61999348', (116, 125))	('c.1032G>A/p.V344I', 'Var', (206, 223))	('p.R324Q', 'Mutation', 'rs770351038', (194, 201))	('c.971G>A', 'Mutation', 'rs770351038', (185, 193))	('PDE8B', 'Gene', (17, 22))	('c.971G>A/p.R324Q', 'Var', (185, 201))	('p.I423V', 'Mutation', 'rs61999348', (126, 133))	('c.1032G>A', 'Mutation', 'rs1253489761', (206, 215))	('c.1267A>G/p.I423V', 'Var', (116, 133))	('p.V344I', 'Mutation', 'rs369585238', (216, 223))
56739	22335482	Of the six PDE8B variants identified in the patients with adrenal tumors, only one, R121H, was seen among the controls; it was present in 4 out of the 192 unrelated control individuals studied.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('variants', 'Var', (17, 25))	('patients', 'Species', '9606', (44, 52))	('adrenal tumors', 'Disease', 'MESH:D000310', (58, 72))	('PDE8B', 'Gene', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('R121H', 'Mutation', 'rs115599001', (84, 89))	('adrenal tumors', 'Disease', (58, 72))	('adrenal tumor', 'Phenotype', 'HP:0100631', (58, 71))
56740	22335482	The total allelic frequency of variant PDE8B alleles was comparable in the patients with adrenocortical tumors and the controls (1.85% vs 1.56%, respectively).	('adrenocortical tumors', 'Disease', 'MESH:D018268', (89, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('patients', 'Species', '9606', (75, 83))	('adrenocortical tumors', 'Disease', (89, 110))	('PDE8B', 'Gene', (39, 44))	('variant', 'Var', (31, 38))
56741	22335482	Three independent in silico models (Polyphen2, SIFT and SeattleSeqAnnotation) predicted mild or no effect on the PDE8B protein function for the two known (R121H and D755N) and one of the novel missense variants (V697I) in the patient group, as well as for all three missense substitutions found only in the control group 'R324Q, V344I and I423V).	('function', 'MPA', (127, 135))	('PDE8B', 'Gene', (113, 118))	('R121H', 'Var', (155, 160))	('R121H', 'Mutation', 'rs115599001', (155, 160))	('SIFT', 'Disease', 'None', (47, 51))	('V697I', 'Mutation', 'rs376318658', (212, 217))	('V344I', 'Var', (329, 334))	('D755N', 'Var', (165, 170))	('patient', 'Species', '9606', (226, 233))	('I423V', 'Var', (339, 344))	('D755N', 'Mutation', 'rs116027371', (165, 170))	('I423V', 'Mutation', 'rs61999348', (339, 344))	('SIFT', 'Disease', (47, 51))	("'R324Q", 'Var', (321, 327))	('V697I', 'Var', (212, 217))	('protein', 'Protein', (119, 126))	('R324Q', 'Mutation', 'rs770351038', (322, 327))	('V344I', 'Mutation', 'rs369585238', (329, 334))
56742	22335482	The H391A and P660L mutations that were seen only in the patient group were predicted respectively as possibly damaging and probably damaging.	('H391A', 'Mutation', 'p.H391A', (4, 9))	('H391A', 'Var', (4, 9))	('patient', 'Species', '9606', (57, 64))	('P660L', 'Var', (14, 19))	('P660L', 'Mutation', 'p.P660L', (14, 19))
56743	22335482	The splice site variant modelling (SplicePort) predicted a 20% decrease in the probability of the mutant junction sequence to serve as a donor site (Table 1).	('decrease', 'NegReg', (63, 71))	('donor', 'Species', '9606', (137, 142))	('mutant', 'Var', (98, 104))	('variant', 'Var', (16, 23))
56744	22335482	Seven of the mutation-positive individuals carried a single PDE8B change, and one patient - with ACC - presented with 2 mutations: R121H and c.1365 -5 g/a.	('c.1365 -5 g/a', 'Var', (141, 154))	('PDE8B', 'Gene', (60, 65))	('R121H', 'Var', (131, 136))	('R121H', 'Mutation', 'rs115599001', (131, 136))	('patient', 'Species', '9606', (82, 89))	('c.1365 -5 g/a', 'Mutation', 'c.1365-5G>A', (141, 154))	('mutation-positive', 'Reg', (13, 30))
56747	22335482	The c.1365-5g/a splice variation was seen in two more patients - one with AIMAH, and one with a cortisol-producing adrenocortical adenoma.	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (115, 137))	('patients', 'Species', '9606', (54, 62))	('c.1365-5g/a', 'Mutation', 'c.1365-5G>A', (4, 15))	('c.1365-5g/a', 'Var', (4, 15))	('cortisol', 'Chemical', 'MESH:D006854', (96, 104))	('adrenocortical adenoma', 'Disease', (115, 137))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (115, 137))
56748	22335482	The reported missense variation, D755N, and the novel H391A were each seen in one female with AIMAH, the P660L variant was identified in a male patient with a non-secreting adrenal adenoma and the V697I variant in a patient with a cortisol-producing adenoma.	('D755N', 'Mutation', 'rs116027371', (33, 38))	('P660L', 'Mutation', 'p.P660L', (105, 110))	('patient', 'Species', '9606', (216, 223))	('secreting adrenal adenoma', 'Phenotype', 'HP:0011746', (163, 188))	('V697I', 'Mutation', 'rs376318658', (197, 202))	('cortisol', 'Chemical', 'MESH:D006854', (231, 239))	('non-secreting', 'Disease', (159, 172))	('adrenal adenoma', 'Disease', 'MESH:D018246', (173, 188))	('P660L', 'Var', (105, 110))	('non-secreting adrenal adenoma', 'Phenotype', 'HP:0011745', (159, 188))	('patient', 'Species', '9606', (144, 151))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (173, 188))	('V697I', 'Var', (197, 202))	('adenoma', 'Disease', (181, 188))	('D755N', 'Var', (33, 38))	('H391A', 'Mutation', 'p.H391A', (54, 59))	('adenoma', 'Disease', (250, 257))	('adrenal adenoma', 'Disease', (173, 188))	('adenoma', 'Disease', 'MESH:D000236', (181, 188))	('adenoma', 'Disease', 'MESH:D000236', (250, 257))
56749	22335482	To look for potential loss of heterozygosity, we sequenced 4 tumor DNAs that were available - 2 cortisol-producing adenomas (one with the c.1365 -5 g/a splice site variant and one with the V697I substitution), one AIMAH samples (with the c.1365 -5 g/a splice site variant) and one ACC (with both R121H and V697 mutations).	('c.1365 -5 g/a', 'Mutation', 'c.1365-5G>A', (238, 251))	('R121H', 'Var', (296, 301))	('adenomas', 'Disease', 'MESH:D000236', (115, 123))	('R121H', 'Mutation', 'rs115599001', (296, 301))	('V697I', 'Mutation', 'rs376318658', (189, 194))	('adenomas', 'Disease', (115, 123))	('c.1365 -5 g/a splice', 'Var', (238, 258))	('c.1365 -5 g/a splice', 'Var', (138, 158))	('cortisol', 'Chemical', 'MESH:D006854', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('c.1365 -5 g/a', 'Mutation', 'c.1365-5G>A', (138, 151))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('V697I', 'Var', (189, 194))	('tumor', 'Disease', (61, 66))	('V697 mutations', 'Var', (306, 320))
56750	22335482	Loss of the wild type allele was detected in the two cortisol-producing adenomas; the AIMAH and ACC retained both the normal and the mutant PDE8B alleles.	('adenomas', 'Disease', 'MESH:D000236', (72, 80))	('PDE8B', 'Gene', (140, 145))	('adenomas', 'Disease', (72, 80))	('cortisol', 'Chemical', 'MESH:D006854', (53, 61))	('cortisol-producing', 'Disease', (53, 71))	('mutant', 'Var', (133, 139))
56751	22335482	To assess the potential effect on the PDE8B protein function, transfection experiments with expression vectors harbouring the R121H, H391A, P660L, V697I and D755N substitutions were conducted on HEK293 cell line (Fig.	('H391A', 'Mutation', 'p.H391A', (133, 138))	('H391A', 'Var', (133, 138))	('D755N', 'Var', (157, 162))	('expression vectors', 'Species', '29278', (92, 110))	('HEK293', 'CellLine', 'CVCL:0045', (195, 201))	('P660L', 'Var', (140, 145))	('P660L', 'Mutation', 'p.P660L', (140, 145))	('V697I', 'Mutation', 'rs376318658', (147, 152))	('R121H', 'Mutation', 'rs115599001', (126, 131))	('D755N', 'Mutation', 'rs116027371', (157, 162))	('V697I', 'Var', (147, 152))	('R121H', 'Var', (126, 131))
56752	22335482	A statistically significant decrease in PDE activity and an increase in cAMP levels relative to the WT were measured in the H391A and P660L transfected cells, indicating a reduced ability of the mutant PDE8B protein to degrade cAMP.	('reduced', 'NegReg', (172, 179))	('PDE', 'Gene', '501', (202, 205))	('PDE', 'Gene', (40, 43))	('P660L', 'Mutation', 'p.P660L', (134, 139))	('PDE', 'Gene', (202, 205))	('protein', 'Protein', (208, 215))	('increase', 'PosReg', (60, 68))	('activity', 'MPA', (44, 52))	('decrease', 'NegReg', (28, 36))	('PDE', 'Gene', '501', (40, 43))	('cAMP', 'Gene', (227, 231))	('H391A', 'Mutation', 'p.H391A', (124, 129))	('cAMP', 'Gene', (72, 76))	('cAMP', 'Gene', '820', (72, 76))	('mutant', 'Var', (195, 201))	('cAMP', 'Gene', '820', (227, 231))
56753	22335482	The most significant reduction of PDE activity and increase in cAMP levels was observed after transfection with the P660L-harbouring construct.	('increase', 'PosReg', (51, 59))	('activity', 'MPA', (38, 46))	('P660L', 'Mutation', 'p.P660L', (116, 121))	('PDE', 'Gene', (34, 37))	('PDE', 'Gene', '501', (34, 37))	('cAMP', 'Gene', (63, 67))	('cAMP', 'Gene', '820', (63, 67))	('reduction', 'NegReg', (21, 30))	('P660L-harbouring', 'Var', (116, 132))
56754	22335482	This observation is concordant with the in silico prediction of a high potential for the P660L substitution to impair the protein function.	('protein', 'Protein', (122, 129))	('impair', 'NegReg', (111, 117))	('P660L', 'Var', (89, 94))	('P660L', 'Mutation', 'p.P660L', (89, 94))
56755	22335482	In order to determine if alternative splice isoforms were caused by the intronic variant (c.1365-5 g/a) we performed RT-PCR in 2 tumor samples harbouring the splice site variant and 3 WT tumor samples, as controls.	('caused', 'Reg', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('c.1365-5 g/a', 'Mutation', 'c.1365-5G>A', (90, 102))	('WT tumor', 'Disease', 'MESH:C536751', (184, 192))	('WT tumor', 'Disease', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('c.1365-5 g/a', 'Var', (90, 102))	('tumor', 'Disease', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))
56758	22335482	In this study of 216 patients with adrenal tumors, we identified four novel variations affecting the coding sequence of PDE8B: three missense substitutions H391A, p.P660L and V697I and the c.1365-5 g/a splice variant; none of them were present among the 192 controls negative for endocrine disorders.	('adrenal tumors', 'Disease', (35, 49))	('PDE8B', 'Gene', (120, 125))	('H391A', 'Mutation', 'p.H391A', (156, 161))	('H391A', 'Var', (156, 161))	('V697I', 'Mutation', 'rs376318658', (175, 180))	('c.1365-5 g/a', 'Var', (189, 201))	('endocrine disorders', 'Disease', (280, 299))	('p.P660L', 'Mutation', 'p.P660L', (163, 170))	('patients', 'Species', '9606', (21, 29))	('endocrine disorders', 'Disease', 'MESH:D004700', (280, 299))	('adrenal tumors', 'Disease', 'MESH:D000310', (35, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('endocrine disorders', 'Phenotype', 'HP:0000818', (280, 299))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('V697I', 'Var', (175, 180))	('c.1365-5 g/a', 'Mutation', 'c.1365-5G>A', (189, 201))	('p.P660L', 'Var', (163, 170))	('adrenal tumor', 'Phenotype', 'HP:0100631', (35, 48))
56760	22335482	In consistence with our prior findings, damaging germline PDE8B mutations were present in patients with adrenocortical tumors, including AIMAH, PPNAD, secreting and non-secreting adrenal adenomas, and adrenocortical carcinomas.	('AIMAH', 'Disease', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (179, 195))	('secreting', 'Disease', (151, 160))	('non-secreting adrenal adenomas', 'Phenotype', 'HP:0011745', (165, 195))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (201, 225))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (201, 226))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('adrenal adenomas', 'Disease', (179, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (216, 226))	('adrenocortical tumors', 'Disease', (104, 125))	('mutations', 'Var', (64, 73))	('secreting adrenal adenoma', 'Phenotype', 'HP:0011746', (169, 194))	('non-secreting adrenal adenoma', 'Phenotype', 'HP:0011745', (165, 194))	('PPNAD', 'Disease', (144, 149))	('patients', 'Species', '9606', (90, 98))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (201, 226))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (179, 194))	('PDE8B', 'Gene', (58, 63))	('adrenocortical carcinomas', 'Disease', (201, 226))	('adrenal adenomas', 'Disease', 'MESH:D018246', (179, 195))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (104, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('secreting adrenal adenomas', 'Phenotype', 'HP:0011746', (169, 195))
56761	22335482	The frequency of PDE8B variant alleles was comparable among the controls and the patients.	('variant', 'Var', (23, 30))	('patients', 'Species', '9606', (81, 89))	('PDE8B', 'Gene', (17, 22))
56763	22335482	We have previously reported PDE genetic variations in individuals with mild or no obvious adrenal phenotype, likely due to the PDE redundancy.	('PDE', 'Gene', (127, 130))	('PDE', 'Gene', '501', (127, 130))	('PDE', 'Gene', '501', (28, 31))	('genetic variations', 'Var', (32, 50))	('PDE', 'Gene', (28, 31))	('reported', 'Reg', (19, 27))
56764	22335482	From the evolutionary point of view, PDE redundancy, through compensatory action, can potentially protect the cell from possible fatal consequences of single deleterious events affecting such an essential process as the cAMP degradation.	('PDE', 'Gene', (37, 40))	('redundancy', 'Var', (41, 51))	('cAMP', 'Gene', '820', (220, 224))	('cAMP', 'Gene', (220, 224))	('PDE', 'Gene', '501', (37, 40))
56765	22335482	While a significant difference in the distribution of PDE8B variants between the patient and control groups was not seen, a difference in the pathogenic potential of the identified variants was apparent: only the H391A and P660L variants were seen exclusively in the patients' group and these mutations showed a potential to impair the protein function, both in silico and in vitro.	('PDE8B', 'Gene', (54, 59))	('patient', 'Species', '9606', (267, 274))	('H391A', 'Mutation', 'p.H391A', (213, 218))	('patient', 'Species', '9606', (81, 88))	('patients', 'Species', '9606', (267, 275))	('H391A', 'Var', (213, 218))	('P660L', 'Var', (223, 228))	('P660L', 'Mutation', 'p.P660L', (223, 228))	('impair', 'NegReg', (325, 331))	('protein', 'Protein', (336, 343))
56767	22335482	Genetic changes in another phosphodiesterase, PDE11A, may act as a modifying genetic factor toward the development of testicular and adrenal tumors in Carney complex patients with PRKAR1A -inactivating mutations.	('PDE11A', 'Gene', (46, 52))	('changes', 'Var', (8, 15))	('adrenal tumors', 'Disease', 'MESH:D000310', (133, 147))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('adrenal tumor', 'Phenotype', 'HP:0100631', (133, 146))	('PRKAR1A', 'Gene', '5573', (180, 187))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('adrenal tumors', 'Disease', (133, 147))	('testicular and adrenal tumors', 'Phenotype', 'HP:0100631', (118, 147))	('PDE11A', 'Gene', '50940', (46, 52))	('patients', 'Species', '9606', (166, 174))	('PRKAR1A', 'Gene', (180, 187))	('Carney complex', 'Disease', (151, 165))
56768	22335482	Interestingly, the only patient who presented with two different PDE8B variations - the missense R121H and the splice c.1365-5 g/a - had adrenocortical carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('missense R121H', 'Var', (88, 102))	('c.1365-5 g/a', 'Mutation', 'c.1365-5G>A', (118, 130))	('R121H', 'Mutation', 'rs115599001', (97, 102))	('PDE8B', 'Gene', (65, 70))	('patient', 'Species', '9606', (24, 31))	('adrenocortical carcinoma', 'Disease', (137, 161))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (137, 161))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (137, 161))
56769	22335482	R121H and c.1365-5 g/a are the two most frequent PDE8B variations in our cohort of patients and controls, and, apart from this patient, they have never been seen together, thus likely being carried by different alleles.	('R121H', 'Mutation', 'rs115599001', (0, 5))	('patient', 'Species', '9606', (127, 134))	('c.1365-5 g/a', 'Var', (10, 22))	('PDE8B', 'Gene', (49, 54))	('patient', 'Species', '9606', (83, 90))	('patients', 'Species', '9606', (83, 91))	('c.1365-5 g/a', 'Mutation', 'c.1365-5G>A', (10, 22))	('R121H', 'Var', (0, 5))
56772	22335482	The PDE8B splice variant (c.1365-5 g/a) did not lead to the generation of detectable alternative mRNA, as shown by RT-PCR and sequencing of the resulting amplified cDNA products.	('PDE8B', 'Gene', (4, 9))	('c.1365-5 g/a', 'Mutation', 'c.1365-5G>A', (26, 38))	('c.1365-5 g/a', 'Var', (26, 38))
56773	22335482	Such alternative mRNA was expected based on the length of exon 14 (165bp), which was predicted to be spliced out leading to an in-frame deletion end expression of shorter PDE8B isoform.	('deletion', 'Var', (136, 144))	('PDE8B', 'Gene', (171, 176))	('expression', 'Species', '29278', (149, 159))
56774	22335482	Strong support for the involvement of impaired PDE8B functioning in adrenococrtical tumorigenesis comes from a recent study of a knockout mouse model and shRNA silencing.	('mouse', 'Species', '10090', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('silencing', 'Var', (160, 169))	('adrenococrtical tumorigenesis', 'Disease', (68, 97))	('adrenococrtical tumorigenesis', 'Disease', 'MESH:D063646', (68, 97))	('impaired', 'NegReg', (38, 46))	('PDE8B', 'Gene', (47, 52))
56775	22335482	The authors demonstrated that both genetic ablation and chemical/pharmacological inhibition of PDE8B potentiate adrenocortical steroidogenesis and that PDE8B has its greatest effect under low ACTH conditions.	('PDE8B', 'Gene', (95, 100))	('genetic ablation', 'Var', (35, 51))	('ACTH', 'Gene', (192, 196))	('ACTH', 'Gene', '5443', (192, 196))	('adrenocortical', 'Disease', (112, 126))	('adrenocortical', 'Disease', 'MESH:D018268', (112, 126))	('potentiate', 'PosReg', (101, 111))
56776	22335482	This phenomenon is likely related to the high affinity of PDE8B to cAMP and implies its involvement in fine cAMP regulation; the authors demonstrated that PDE8B is a major regulator of one or more pools of cAMP that promote steroidogenesis, via both acute and chronic mechanisms.	('cAMP', 'Gene', (67, 71))	('steroidogenesis', 'MPA', (224, 239))	('cAMP', 'Gene', '820', (67, 71))	('cAMP', 'Gene', '820', (108, 112))	('cAMP', 'Gene', (206, 210))	('cAMP', 'Gene', '820', (206, 210))	('promote', 'PosReg', (216, 223))	('PDE8B', 'Var', (155, 160))	('cAMP', 'Gene', (108, 112))
56778	22335482	In summary, we identified two novel damaging PDE8B variants (H391A and P660L) in two patients with respectively AIMAH and a non-secreting adrenal tumor.	('H391A', 'Mutation', 'p.H391A', (61, 66))	('P660L', 'Var', (71, 76))	('H391A', 'Var', (61, 66))	('P660L', 'Mutation', 'p.P660L', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('non-secreting adrenal tumor', 'Phenotype', 'HP:0011745', (124, 151))	('adrenal tumor', 'Disease', 'MESH:D000310', (138, 151))	('adrenal tumor', 'Disease', (138, 151))	('patients', 'Species', '9606', (85, 93))	('PDE8B', 'Gene', (45, 50))	('adrenal tumor', 'Phenotype', 'HP:0100631', (138, 151))
56814	20540918	Ablation may also play an important palliative role by debulking to decrease the overall catecholamine burden.	('catecholamine', 'Chemical', 'MESH:D002395', (89, 102))	('decrease', 'NegReg', (68, 76))	('Ablation', 'Var', (0, 8))	('debulking', 'Var', (55, 64))	('catecholamine burden', 'MPA', (89, 109))
56832	20540918	Thus, ablation of adrenal tumors has the propensity to result in the release of large amounts of these hormones into the bloodstream, resulting in acute hypertensive crisis and potentially even cardiac and cerebral ischemia or infarction.	('resulting in', 'Reg', (134, 146))	('result in', 'Reg', (55, 64))	('infarction', 'Disease', 'MESH:D007238', (227, 237))	('cerebral ischemia', 'Disease', (206, 223))	('adrenal tumors', 'Disease', (18, 32))	('cerebral ischemia', 'Disease', 'MESH:D002545', (206, 223))	('renal tumors', 'Phenotype', 'HP:0009726', (20, 32))	('hypertensive crisis', 'Phenotype', 'HP:0100735', (153, 172))	('infarction', 'Disease', (227, 237))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('hypertensive', 'Disease', 'MESH:D006973', (153, 165))	('adrenal tumors', 'Disease', 'MESH:D000310', (18, 32))	('cardiac and', 'CPA', (194, 205))	('hypertensive', 'Disease', (153, 165))	('release of', 'MPA', (69, 79))	('ablation', 'Var', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('cerebral ischemia', 'Phenotype', 'HP:0002637', (206, 223))
56905	20540918	Munver and colleagues have also described laparoscopic adrenal cryoablation of an aldosteronoma in a patient with bilateral adrenal hyperplasia.	('bilateral adrenal hyperplasia', 'Disease', 'MESH:D000312', (114, 143))	('bilateral adrenal hyperplasia', 'Disease', (114, 143))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (124, 143))	('patient', 'Species', '9606', (101, 108))	('aldosteronoma', 'Disease', 'None', (82, 95))	('cryoablation', 'Var', (63, 75))	('aldosteronoma', 'Disease', (82, 95))
56926	20540918	As has been described for renal ablation, communication with the anesthesiologist to coordinate breathing can also help avoid transgression of the pleura and enable movement of a target lesion off of an intervening rib.	('transgression', 'CPA', (126, 139))	('pleura', 'Disease', (147, 153))	('avoid', 'NegReg', (120, 125))	('pleura', 'Disease', 'MESH:D054363', (147, 153))	('communication', 'Var', (42, 55))
56930	20540918	Hydrodissection is most useful in protecting the bowel and pancreas and may also facilitate protection of the lung, kidney or hemidiaphragm and chest wall (including intercostal nerves).	('bowel and pancreas', 'Disease', 'MESH:D010190', (49, 67))	('Hydrodissection', 'Var', (0, 15))	('kidney or hemidiaphragm', 'Disease', 'MESH:D065630', (116, 139))	('facilitate', 'PosReg', (81, 91))	('kidney or hemidiaphragm', 'Disease', (116, 139))
56937	20540918	Damage to the adrenal gland can also result in adrenal insufficiency in certain patient populations, typically those with a history of prior nephrectomy with unilateral adrenalectomy.	('result in', 'Reg', (37, 46))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (47, 68))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (47, 68))	('Damage', 'Var', (0, 6))	('adrenal insufficiency', 'Disease', (47, 68))	('patient', 'Species', '9606', (80, 87))
56962	20540918	Enhancement or enlargement on subsequent imaging after initial negative imaging is considered indicative of tumor recurrence, and patients should be counseled about additional treatments, if appropriate, including repeat ablation, surgery, chemotherapy or observation.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('patients', 'Species', '9606', (130, 138))	('Enhancement', 'Var', (0, 11))	('enlargement', 'PosReg', (15, 26))
56995	33112833	Morning blood samples were drawn as part of a longitudinal observational study of baseline DHEAS data from children enrolled in the Surveillance Cohort Study for Cancer Risk (SCSCR) (Clinal trials: Brazilian registry (Rebec) U1111-1196-4533) following parental or guardian consent.	('children', 'Species', '9606', (107, 115))	('Cancer', 'Disease', 'MESH:D009369', (162, 168))	('DHEAS', 'Gene', (91, 96))	('DHEAS', 'Gene', '6822', (91, 96))	('U1111-1196-4533', 'Var', (225, 240))	('Cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Cancer', 'Disease', (162, 168))
56996	33112833	Girls were eligible for the SCSCR study if they met the following criteria: tested positive for a low penetrance germline TP53 p.R337H variant, underwent periodical medical, DHEAS, and imaging exams.	('DHEAS', 'Gene', '6822', (174, 179))	('Girls', 'Species', '9606', (0, 5))	('TP53', 'Gene', (122, 126))	('positive', 'Reg', (83, 91))	('p.R337H', 'Mutation', 'rs121912664', (127, 134))	('DHEAS', 'Gene', (174, 179))	('TP53', 'Gene', '7157', (122, 126))	('p.R337H', 'Var', (127, 134))
57049	33112833	Similarly, changes in the ZR were reported previously as a reduced mass in older American men (54-90 years) in relation to that of younger men (20-29 years).	('mass', 'MPA', (67, 71))	('reduced', 'NegReg', (59, 66))	('men', 'Species', '9606', (90, 93))	('men', 'Species', '9606', (139, 142))	('changes', 'Var', (11, 18))
57057	33112833	Ethnicity influence was highlighted by the work of Crawford et al., showing different DHEAS levels in women of the same age albeit different ethnicities and higher threshold: African American (<2440 nmol/L), Hispanic (<2990 nmol/L), Japanese (<3530 nmol/L), Caucasians (<3940 nmol/L) and Chinese women (<5160 nmol/L).	('DHEAS', 'Gene', '6822', (86, 91))	('<2990 nmol/L', 'Var', (218, 230))	('<2440 nmol/L', 'Var', (193, 205))	('<3940 nmol/L', 'Var', (270, 282))	('women', 'Species', '9606', (102, 107))	('<3530 nmol/L', 'Var', (243, 255))	('women', 'Species', '9606', (296, 301))	('DHEAS', 'Gene', (86, 91))
57078	30564891	PD-L1 expression on tumor cells can be a result of viral activation, oncogene expression, genomic changes in the tumor, such as gene amplification or disruption of the 3' untranslated region.	('tumor', 'Disease', (113, 118))	('oncogene', 'Gene', (69, 77))	('expression', 'Species', '29278', (6, 16))	('disruption', 'Var', (150, 160))	('activation', 'PosReg', (57, 67))	('PD-L1', 'Gene', (0, 5))	('gene amplification', 'Var', (128, 146))	('result', 'Reg', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('expression', 'Species', '29278', (78, 88))	('tumor', 'Disease', (20, 25))
57085	30564891	This secreted variant of PD-L1 may be an additional means by which cells can regulate T-cell function in the tumor microenvironment without requiring cell-cell interaction.	('regulate', 'Reg', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('variant', 'Var', (14, 21))	('PD-L1', 'Gene', (25, 30))	('tumor', 'Disease', (109, 114))
57090	30564891	To amplify the secPD-L1 mRNA qualitatively, PCR products after 30 cycles of amplification with O-3806 [crosses exon 3-4] (F1:ACTGTGAAAGTCAATGCCCC) and O-3816 [within the intron after exon 4] (R1: GCTAGGGGACAGTGTTAGAC, product 354 bp) or O-3818 [more 3' within the intron after exon 4] (R2: GGATGAATGGAGGTGAGGAA, product 465 bp) were analyzed; under the same conditions we amplified the full-length PD-L1 mRNA with O-3808 [crosses exon 4-5 junction] (F2: ACAGCTGAATTGGTCATCCC) and O-3820 (R3: CTTGGAGGCTCCTTGTTCAG, product 505 bp) or O-3822 (R4: AGGGATTCTCAACCCGTCTT, product 550 bp) (Supplemental Fig.	('N', 'Chemical', 'MESH:D009584', (26, 27))	('ACC', 'Phenotype', 'HP:0006744', (556, 559))	('O-3822', 'Var', (533, 539))	('O-3808 [crosses', 'Var', (414, 429))	('N', 'Chemical', 'MESH:D009584', (406, 407))
57091	30564891	Quantitative PCR requires a shorter secPD-L1 PCR product for parallel PCR efficiency, which could also result in amplification of genomic DNA; thus RNA was treated with DNAse prior to cDNA production.	('N', 'Chemical', 'MESH:D009584', (139, 140))	('genomic', 'Var', (130, 137))	('amplification', 'MPA', (113, 126))	('N', 'Chemical', 'MESH:D009584', (186, 187))	('N', 'Chemical', 'MESH:D009584', (170, 171))	('result in', 'Reg', (103, 112))	('N', 'Chemical', 'MESH:D009584', (149, 150))
57092	30564891	TaqMan PD-L1 primers were used to detect mRNA expression of the transmembrane domain containing form of full-length PD-L1 or the unique 3' sequence of secPD-L1, respectively: full-length PD-L1 (cat# Hs01125299_m1) and secPD-L1 (Cat# 4331348; ID: AI0IYL3) (schema in Supplemental Fig.	('N', 'Chemical', 'MESH:D009584', (43, 44))	('Cat# 4331348;', 'Var', (228, 241))	('schema', 'Disease', (256, 262))	('expression', 'Species', '29278', (46, 56))	('cat# Hs01125299_m1', 'Var', (194, 212))	('mers', 'Species', '1335626', (16, 20))	('schema', 'Disease', 'None', (256, 262))
57118	30564891	Mutation of cysteine 239 to serine in the recombinant secPD-L1 largely abrogated multimerization of the isoform (Supplemental Fig.	('Mutation', 'Var', (0, 8))	('multimerization', 'MPA', (81, 96))	('abrogated', 'NegReg', (71, 80))	('cysteine 239 to serine', 'Mutation', 'p.C239S', (12, 34))	('cysteine', 'Var', (12, 20))
57119	30564891	Given that the secPD-L1 variant can naturally dimerize, we compared the functional activity of recombinant secPD-L1 and a recombinant PD-L1 containing only the extracellular domain without the sec-specific carboxyl terminus and similarly purified with a His tag, rather than an Fc fusion, to determine whether secPD-L1 has immunosuppressive activity.	('variant', 'Var', (24, 31))	('dimerize', 'MPA', (46, 54))	('His', 'Chemical', 'MESH:D006639', (254, 257))
57123	30564891	A challenge in developing an antibody specific for the secPD-L1 variant may be due to the C-terminal region of secPD-L1 having an N-linked glycosylation motif (NVS, underlined in Fig.	('N', 'Chemical', 'MESH:D009584', (130, 131))	('N-linked glycosylation motif', 'Disease', (130, 158))	('N', 'Chemical', 'MESH:D009584', (160, 161))	('secPD-L1', 'Gene', (55, 63))	('variant', 'Var', (64, 71))	('secPD-L1', 'Gene', (111, 119))	('N-linked glycosylation motif', 'Disease', 'MESH:D018981', (130, 158))
57124	30564891	However, since there is a distinct 3' nucleotide sequence in the carboxyl terminus and 3'UTR that differ between the full-length and secPD-L1, we were able to measure mRNA expression of the secPD-L1 variant in a series of cell lines by RT-PCR.	('expression', 'Species', '29278', (172, 182))	('mRNA expression', 'MPA', (167, 182))	('variant', 'Var', (199, 206))	('secPD-L1', 'Gene', (190, 198))	('N', 'Chemical', 'MESH:D009584', (169, 170))
57126	30564891	We screened a series of cell lines with established positive or negative PD-L1 protein status by flow cytometry and western blot analysis, including lymphomas [HDLM-2(+) and OC1-LY1(-)], renal cell carcinoma [Caki-2(+), UMRC6(-)], and breast cancer cell lines [MDA231(+), SKBR3(+), and BT474(-)] to determine whether the secPD-L1 variant mRNA expression was associated with expression of the full-length PD-L1 by RT-PCR analysis.	('renal cell carcinoma', 'Disease', (187, 207))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (187, 207))	('lymphomas', 'Disease', 'MESH:D008223', (149, 158))	('lymphomas', 'Phenotype', 'HP:0002665', (149, 158))	('secPD-L1', 'Gene', (321, 329))	('breast cancer', 'Phenotype', 'HP:0003002', (235, 248))	('UMRC6', 'CellLine', 'CVCL:2741', (220, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('breast cancer', 'Disease', 'MESH:D001943', (235, 248))	('Caki-2', 'CellLine', 'CVCL:0235', (209, 215))	('SKBR3', 'CellLine', 'CVCL:0033', (272, 277))	('breast cancer', 'Disease', (235, 248))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (187, 207))	('lymphomas', 'Disease', (149, 158))	('expression', 'Species', '29278', (343, 353))	('expression', 'Species', '29278', (374, 384))	('variant', 'Var', (330, 337))	('lymphoma', 'Phenotype', 'HP:0002665', (149, 157))	('N', 'Chemical', 'MESH:D009584', (340, 341))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('MDA231', 'CellLine', 'CVCL:0062', (261, 267))
57142	30564891	When we analyzed data from two small cohorts of previously reported patients with melanoma treated with immune checkpoint therapy, we found nearly all melanoma specimens (98.5%) in both immune check point inhibitor-treated cohorts expressed some full-length PD-L1 (ipilimumab n = 40, PD-1 blocker n = 28), which was comparable to that (98.9%) in the cohort of cutaneous melanoma specimens in the TCGA (Supplemental Fig.	('ipilimumab', 'Chemical', 'MESH:D000074324', (265, 275))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('patients', 'Species', '9606', (68, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (360, 378))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('melanoma', 'Disease', (151, 159))	('PD-L1', 'Var', (258, 263))	('melanoma', 'Phenotype', 'HP:0002861', (370, 378))	('melanoma', 'Disease', (370, 378))	('cutaneous melanoma', 'Disease', (360, 378))	('melanoma', 'Disease', 'MESH:D008545', (370, 378))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (360, 378))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))
57157	30564891	Targeting PD-1 and its ligand PD-L1 has shown outstanding clinical benefit in clinical trials, and has significantly less toxicity than IL-2 or CTLA-4 blockade, leading to their FDA approval for numerous indications, including not only melanoma and non-small cell lung cancer, but also kidney and bladder cancer, as well as others including refractory Hodgkin's lymphoma.	("Hodgkin's lymphoma", 'Disease', (352, 370))	('toxicity', 'Disease', (122, 130))	('non-small cell lung cancer', 'Disease', (249, 275))	('kidney', 'Disease', (286, 292))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('bladder cancer', 'Phenotype', 'HP:0009725', (297, 311))	('CTLA-4', 'Gene', '1493', (144, 150))	('PD-1', 'Gene', (10, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (249, 275))	('CTLA-4', 'Gene', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (352, 370))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (253, 275))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('PD-L1', 'Var', (30, 35))	('melanoma', 'Disease', (236, 244))	('lymphoma', 'Phenotype', 'HP:0002665', (362, 370))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (249, 275))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (352, 370))	('bladder cancer', 'Disease', 'MESH:D001749', (297, 311))	('toxicity', 'Disease', 'MESH:D064420', (122, 130))	('bladder cancer', 'Disease', (297, 311))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
57164	30564891	For example in Hodgkin's lymphoma, while PD-L1 is highly expressed on Hodgkin Reed-Sternberg cells due to a chromosomal amplification of the PD-L1 gene, the bulk of the tumor mass is normal immune cells.	('PD-L1', 'Gene', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (15, 33))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('chromosomal amplification', 'Var', (108, 133))	('lymphoma', 'Phenotype', 'HP:0002665', (25, 33))	('tumor', 'Disease', (169, 174))	('PD-L1', 'Gene', (41, 46))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (15, 33))	("Hodgkin's lymphoma", 'Disease', (15, 33))
57165	30564891	Furthermore different cell-surface PD-L1 mRNA variants can produce higher levels of protein expression on the tumor cells' surface, as shown by the effect of structural variations in the 3' UTR region of PD-L1 mRNA found in a small subset of tumors.	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('higher', 'PosReg', (67, 73))	('N', 'Chemical', 'MESH:D009584', (43, 44))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('protein expression', 'MPA', (84, 102))	('variants', 'Var', (46, 54))	('N', 'Chemical', 'MESH:D009584', (212, 213))	('levels', 'MPA', (74, 80))	('tumor', 'Disease', (242, 247))	('expression', 'Species', '29278', (92, 102))	('PD-L1', 'Gene', (35, 40))	('tumors', 'Disease', (242, 248))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
57174	30564891	Recently we reported additional splice variants of PD-L1 in melanoma tumors, which have the PD-1 binding domain and cytoplasmic exons but do not include the transmembrane domain.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('melanoma tumors', 'Disease', (60, 75))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('binding', 'Interaction', (97, 104))	('splice variants', 'Var', (32, 47))	('melanoma tumors', 'Disease', 'MESH:D008545', (60, 75))	('PD-L1', 'Gene', (51, 56))
57175	30564891	Despite analyzing multiple thresholds of positive secPD-L1 and full-length PD-L1 in the clinical cohorts that we had access to, we did not find that secPD-L1 expression predicted clinical outcomes better than full-length PD-L1 expression.	('expression', 'Species', '29278', (227, 237))	('predicted', 'Reg', (169, 178))	('expression', 'Species', '29278', (158, 168))	('secPD-L1', 'Var', (149, 157))
57182	30564891	However, soluble PD-L1 in peripheral blood is not associated with worse prognosis in patients with pancreatic cancer; nor are soluble PD-L1 levels associated with PD-L1 expression on pancreatic tumor cells; but soluble PD-L1 levels are associated with markers of inflammation, such as C-reactive protein (CRP) and strong infiltration of T cells into the tumor.	('pancreatic tumor', 'Disease', 'MESH:D010190', (183, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('tumor', 'Disease', (354, 359))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('soluble', 'Var', (211, 218))	('patients', 'Species', '9606', (85, 93))	('C-reactive protein', 'MPA', (285, 303))	('associated', 'Reg', (236, 246))	('pancreatic cancer', 'Disease', 'MESH:D010190', (99, 116))	('inflammation', 'Disease', 'MESH:D007249', (263, 275))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('expression', 'Species', '29278', (169, 179))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (183, 199))	('pancreatic cancer', 'Disease', (99, 116))	('inflammation', 'Disease', (263, 275))	('pancreatic tumor', 'Disease', (183, 199))
57188	30564891	The integration of human papilloma virus upstream of the transmembrane domain-encoding region favors the expression of the secreted form of PD-L1 and their analysis substantiates the expression of this secreted isoform of PD-L1 across numerous cancers.	('human papilloma virus', 'Species', '10566', (19, 40))	('integration', 'Var', (4, 15))	('favors', 'PosReg', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('expression', 'Species', '29278', (183, 193))	('PD-L1', 'Gene', (140, 145))	('expression', 'Species', '29278', (105, 115))	('PD-L1 across numerous cancers', 'Disease', (222, 251))	('expression', 'MPA', (105, 115))	('papilloma', 'Phenotype', 'HP:0012740', (25, 34))	('PD-L1 across numerous cancers', 'Disease', 'MESH:D010300', (222, 251))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))
57197	30564891	ACC Adrenocortical carcinoma ATCC American Type Culture Collection B7-1 First of the B7-family of immunomodulatory proteins CCLE The Cancer Cell Line Encyclopedia CHO Chinese hamster ovarian cells CRP C-reactive protein CTLA-4 Cytotoxic T-Lymphocyte-Associated Protein 4 ECD-PD-L1 Extracellular domain of PD-L1 (Met 1-Thr 239) GTEx Genotype-Tissue Expression database IFN-gamma Interferon-gamma IgC domain Protein domain structurally similar to the constant region of immunoglobulins IgV domain Protein domain structurally similar to the variable region of immunoglobulins IRB Internal Review Board LAML Acute myeloid leukemia LIHC Liver hepatocellular carcinoma mRNA Messenger RNA NVS N-linked glycosylation motif PD-L1 Programmed death ligand-1 PD-1 Programmed cell death-1 RCC Renal cell carcinoma secPD-L1 Secreted splice variant of PD-L1 TCGA The Cancer Genome Atlas UCEC Uterine corpus endometrial carcinoma USC Uterine endometrial carcinoma VEGF Vascular endothelial growth factor KMM:conception and design, acquisition of data, analysis and interpretation of results, writing and revising of the paper.	('endometrial carcinoma', 'Disease', (926, 947))	('Cytotoxic', 'Disease', (227, 236))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (604, 626))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (604, 626))	('CTLA-4', 'Gene', (220, 226))	('GTEx', 'Chemical', '-', (327, 331))	('N', 'Chemical', 'MESH:D009584', (370, 371))	('N', 'Chemical', 'MESH:D009584', (665, 666))	('Cancer', 'Phenotype', 'HP:0002664', (852, 858))	('Cytotoxic', 'Disease', 'MESH:D064420', (227, 236))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (638, 662))	('RCC', 'Disease', 'MESH:C538614', (776, 779))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (610, 626))	('Expression', 'Species', '29278', (348, 358))	('endometrial carcinoma', 'Disease', (892, 913))	('Chinese hamster', 'Species', '10029', (167, 182))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (926, 947))	('leukemia', 'Phenotype', 'HP:0001909', (618, 626))	('N-linked glycosylation motif', 'Disease', 'MESH:D018981', (686, 714))	('N', 'Chemical', 'MESH:D009584', (686, 687))	('N', 'Chemical', 'MESH:D009584', (679, 680))	('Liver hepatocellular carcinoma', 'Disease', (632, 662))	('N-linked glycosylation motif', 'Disease', (686, 714))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (632, 662))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (926, 947))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (133, 162))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('Met 1-Thr', 'SUBSTITUTION', 'None', (312, 321))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (892, 913))	('carcinoma', 'Phenotype', 'HP:0030731', (791, 800))	('Renal cell carcinoma', 'Disease', (780, 800))	('carcinoma', 'Phenotype', 'HP:0030731', (904, 913))	('LIHC', 'Disease', (627, 631))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (852, 871))	('CCLE', 'Chemical', '-', (124, 128))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (892, 913))	('Met 1-Thr', 'Var', (312, 321))	('N', 'Chemical', 'MESH:D009584', (682, 683))	('Cancer Cell Line Encyclopedia', 'Disease', (133, 162))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (780, 800))	('LIHC', 'Disease', 'None', (627, 631))	('Cancer Genome Atlas', 'Disease', (852, 871))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('CTLA-4', 'Gene', '1493', (220, 226))	('RCC', 'Disease', (776, 779))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (780, 800))	('carcinoma', 'Phenotype', 'HP:0030731', (653, 662))	('carcinoma', 'Phenotype', 'HP:0030731', (938, 947))	('Acute myeloid leukemia', 'Disease', (604, 626))
57201	30564891	This work was supported by the Claudia Adams Barr Program for Innovative Cancer Research (Mahoney), the 2014 American Association for Cancer Research Basic Cancer Research Fellowship, Grant Number 14-40-01-MAHO (Mahoney), and the 2014 American Society of Clinical Oncology Young Investigator Award supported by Kidney Cancer Association (Mahoney), as well as by the Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Programs of Research Excellence (SPORE) P50CA101942 (Freeman and Mahoney), R50CA211482 (Shukla), U54CA163125 and P01AI056299 (Freeman).	('Cancer', 'Phenotype', 'HP:0002664', (386, 392))	('U54CA163125', 'Var', (523, 534))	('Kidney Cancer', 'Phenotype', 'HP:0009726', (400, 413))	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Cancer', 'Disease', 'MESH:D009369', (134, 140))	('Cancer', 'Disease', (156, 162))	('Cancer', 'Phenotype', 'HP:0002664', (318, 324))	('Cancer', 'Disease', (386, 392))	('Kidney Cancer', 'Disease', 'MESH:D007680', (400, 413))	('Kidney Cancer', 'Disease', (311, 324))	('R50CA211482', 'Var', (501, 512))	('Kidney Cancer', 'Phenotype', 'HP:0009726', (311, 324))	('Claudia Adams Barr', 'Disease', 'MESH:D000219', (31, 49))	('Harvard Cancer Center Kidney Cancer', 'Disease', 'MESH:D009369', (378, 413))	('Cancer', 'Disease', (318, 324))	('Cancer', 'Disease', (407, 413))	('Cancer', 'Disease', 'MESH:D009369', (386, 392))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Cancer', 'Disease', 'MESH:D009369', (156, 162))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('Kidney Cancer', 'Disease', 'MESH:D007680', (311, 324))	('Cancer', 'Disease', (73, 79))	('Claudia Adams Barr', 'Disease', (31, 49))	('N', 'Chemical', 'MESH:D009584', (190, 191))	('Cancer', 'Disease', (134, 140))	('Cancer', 'Disease', 'MESH:D009369', (318, 324))	('Cancer', 'Disease', 'MESH:D009369', (407, 413))	('Oncology', 'Phenotype', 'HP:0002664', (264, 272))	('P01AI056299', 'Var', (539, 550))	('Harvard Cancer Center Kidney Cancer', 'Disease', (378, 413))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))
57214	30159150	In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults.	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (46, 67))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (46, 67))	('gynecomastia', 'Disease', 'MESH:D006177', (96, 108))	('gynecomastia', 'Disease', (96, 108))	('gynecomastia', 'Phenotype', 'HP:0000771', (96, 108))	('mitotane', 'Var', (69, 77))	('adrenal insufficiency', 'Disease', (46, 67))	('hypothyroidism', 'Disease', 'MESH:D007037', (113, 127))	('hypothyroidism', 'Phenotype', 'HP:0000821', (113, 127))	('mitotane', 'Chemical', 'MESH:D008939', (69, 77))	('cause', 'Reg', (90, 95))	('hypothyroidism', 'Disease', (113, 127))
57242	30159150	As mitotane is known to cause adrenal insufficiency, the patient was started on a relatively low physiological replacement hydrocortisone (6 mg/m2/day, oral).	('mitotane', 'Var', (3, 11))	('patient', 'Species', '9606', (57, 64))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (30, 51))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (30, 51))	('men', 'Species', '9606', (118, 121))	('mitotane', 'Chemical', 'MESH:D008939', (3, 11))	('hydrocortisone', 'Chemical', 'MESH:D006854', (123, 137))	('adrenal insufficiency', 'Disease', (30, 51))
57252	30159150	As it was likely that this was due to mitotane interfering with steroid metabolism, supra-physiological doses of hydrocortisone were continued.	('steroid', 'Chemical', 'MESH:D013256', (64, 71))	('mitotane', 'Var', (38, 46))	('hydrocortisone', 'Chemical', 'MESH:D006854', (113, 127))	('mitotane', 'Chemical', 'MESH:D008939', (38, 46))	('steroid metabolism', 'MPA', (64, 82))	('interfering', 'NegReg', (47, 58))
57261	30159150	We report the case of a child with ACC who suffered multiple endocrinopathies as a result of mitotane chemotherapy.	('endocrinopathies', 'Disease', 'MESH:C567425', (61, 77))	('endocrinopathies', 'Disease', (61, 77))	('mitotane', 'Var', (93, 101))	('result', 'Reg', (83, 89))	('child', 'Species', '9606', (24, 29))	('mitotane', 'Chemical', 'MESH:D008939', (93, 101))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))
57264	30159150	Furthermore, we report the first case of mitotane causing PPP which subsequently triggered CPP.	('PPP', 'Disease', (58, 61))	('mitotane', 'Var', (41, 49))	('mitotane', 'Chemical', 'MESH:D008939', (41, 49))
57266	30159150	Not only does mitotane decrease endogenous levels of glucocorticoid and mineralocorticoid through its cytotoxic effect on the adrenal cortex, it also reduces the efficacy of exogenous steroid replacement by increasing CYP34A-mediated hepatic clearance of glucocorticoids and production of cortisol-binding globulin.	('decrease endogenous levels of glucocorticoid', 'Phenotype', 'HP:0008163', (23, 67))	('decrease', 'NegReg', (23, 31))	('efficacy', 'MPA', (162, 170))	('increasing', 'PosReg', (207, 217))	('men', 'Species', '9606', (199, 202))	('cytotoxic effect', 'MPA', (102, 118))	('production of cortisol-binding globulin', 'MPA', (275, 314))	('CYP34A-mediated', 'Enzyme', (218, 233))	('mitotane', 'Var', (14, 22))	('mitotane', 'Chemical', 'MESH:D008939', (14, 22))	('steroid', 'Chemical', 'MESH:D013256', (184, 191))	('reduces', 'NegReg', (150, 157))
57298	27557938	On the other hand, tier-based variant call sets that inherently attach uncertainties will be helpful when evaluating the behavior of low variant allele fraction (VAF) mutations and seeking to understand the effect of tumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('mutations', 'Var', (167, 176))
57323	27557938	Different from the DREAM challenge data, in this data set, Tier 1 cutoffs showed the biggest improvement in sensitivity compared to one level up, PASS, and moved closer to the top left corners of the ROC curves in all simulation scenarios from 30x to 60x coverage, except for 30x and VAF of 0.05.	('improvement', 'PosReg', (93, 104))	('cutoffs', 'Var', (66, 73))	('DREAM', 'Gene', '30818', (19, 24))	('sensitivity', 'MPA', (108, 119))	('DREAM', 'Gene', (19, 24))
57338	27557938	3c; black in oval 1), and all trunk mutation calls that occurred at the same genomic locus in all tumor regions of one patient (Fig.	('patient', 'Species', '9606', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('mutation', 'Var', (36, 44))
57339	27557938	The  (0.9468) and  (0.9717) scores acquired by MuSE were higher than those of Caller A.	('higher', 'PosReg', (57, 63))	('MuSE', 'Gene', (47, 51))	('MuSE', 'Gene', '399806', (47, 51))	('scores', 'MPA', (28, 34))	('0.9717', 'Var', (20, 26))
57347	27557938	The pisomatic,tumor associated ROC curve is shown to stand above that from Caller A, suggesting a good ability to discriminate mutations from references of the MuSE pipeline.	('tumor', 'Disease', (14, 19))	('MuSE', 'Gene', '399806', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mutations', 'Var', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('MuSE', 'Gene', (160, 164))
57351	27557938	We demonstrate the reliable performance of MuSE using both synthetic and real data, such as the ICGC-TCGA DREAM Mutation Calling challenge WGS data, the virtual-tumor benchmarking approach, TCGA ACC WES data, the multi-region lung adenocarcinoma WES data, and the ICGC PanCancer Pilot-63 WGS data.	('DREAM', 'Gene', (106, 111))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (226, 245))	('Mutation', 'Var', (112, 120))	('MuSE', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('MuSE', 'Gene', '399806', (43, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (226, 245))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('DREAM', 'Gene', '30818', (106, 111))	('ACC', 'Phenotype', 'HP:0006744', (195, 198))	('tumor', 'Disease', (161, 166))	('lung adenocarcinoma', 'Disease', (226, 245))
57352	27557938	We demonstrate the superior sensitivity of MuSE, especially to low VAF mutations, and its capacity to identify an appropriate balance of sensitivity and specificity in each sample with varying levels of heterogeneity.	('MuSE', 'Gene', '399806', (43, 47))	('low VAF', 'Protein', (63, 70))	('mutations', 'Var', (71, 80))	('MuSE', 'Gene', (43, 47))
57355	27557938	Copy number aberration (CNA), tumor purity, and tumor subclonality commonly exist in our data, both synthetic and real.	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Copy number aberration', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
57356	27557938	All influences of CNA, tumor purity, and tumor subclonality on the mutant chromosome content of a tumor reduce to the same question of VAF, and the mechanism of creating or changing the VAF is not as important as the VAF itself in terms of somatic mutation calling.	('VAF', 'MPA', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutant chromosome', 'Var', (67, 84))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
57357	27557938	Our pisomatic,tumor is directly related with the configuration of local copy number variation, purity, and subclonality of the position.	('local copy number variation', 'Var', (66, 93))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
57359	27557938	Therefore, we aim to deconvolute two log(2pisomatic,tumor) distributions, one from true mutations that represent tumor growth dynamics and one from reference positions that arise from sequencing machine errors or mapping errors.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (52, 57))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
57364	27557938	We will further validate MuSE through participation in the ICGC-TCGA DREAM Mutation Calling challenge and the ICGC Pilot-63 study, both of which have promised independent experimental validations.	('DREAM', 'Gene', '30818', (69, 74))	('Mutation', 'Var', (75, 83))	('DREAM', 'Gene', (69, 74))	('MuSE', 'Gene', (25, 29))	('MuSE', 'Gene', '399806', (25, 29))
57375	27557938	Because of the time-reversible characteristic of the F81 model, m can be any point along the evolutionary distance nu that connects the h and k tips without affecting the final result.	('tips', 'Disease', 'MESH:D060725', (144, 148))	('tips', 'Disease', (144, 148))	('F81', 'Var', (53, 56))
57378	27557938	By plotting the densities of log(2pisomatic,tumor) from MuSE on all positions (see Additional file 1: Figure S3), we observed that (1) the density of log-transformed pisomatic,tumor showed a bimodal behavior that could be approximated using a Gaussian mixture distribution; (2) the true positives (red) and reference positions (blue) correspond to each of the modes so that a cutoff can be identified to separate the two types of calls; (3) as expected, the separation of two modes becomes easier at higher coverage and higher variant allele fraction (VAF).	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('MuSE', 'Gene', '399806', (56, 60))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('variant', 'Var', (527, 534))	('tumor', 'Disease', (44, 49))	('MuSE', 'Gene', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
57384	27557938	For the virtual-tumor benchmarking data, we measured sensitivity and specificity by applying MuSE and MuTect to the combination of 24 spike-in BAMs (4 different variant allele fractions x 6 distinct depths) with the same depth non-spike-in WGS BAMs.	('MuSE', 'Gene', '399806', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('spike-in', 'Var', (134, 142))	('MuSE', 'Gene', (93, 97))
57388	27557938	Here, a trunk mutation was a somatic variant call that all tumor regions of one patient had at the same genomic locus.	('tumor', 'Disease', (59, 64))	('mutation', 'Var', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('patient', 'Species', '9606', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
57389	27557938	To validate variants identified by MuSE and Caller A in the ACC data, we selected 550 patient-specific positions and designed NimbleGen probes correspondingly for the purpose of targeted capture enrichment and deep sequencing.	('MuSE', 'Gene', (35, 39))	('MuSE', 'Gene', '399806', (35, 39))	('ACC', 'Phenotype', 'HP:0006744', (60, 63))	('patient', 'Species', '9606', (86, 93))	('variants', 'Var', (12, 20))
57449	25619516	To determine whether inactivating mutations of PTEN or activating mutations of PIK3CA might be responsible for activation of the PI3K pathway, mutation analysis was performed.	('inactivating mutations', 'Var', (21, 43))	('activating', 'PosReg', (55, 65))	('PI3', 'Gene', (129, 132))	('PIK3CA', 'Gene', (79, 85))	('PTEN', 'Gene', (47, 51))	('PI3', 'Gene', '477241', (129, 132))
57452	25619516	Mutation analysis of PIK3CA identified the presence of 3 different heterozygous silent mutations (codon 149 CCA>CCC, codon 438 TCT>TCA and codon 842 GTG>GTT) in 3 different ATs.	('AT', 'Disease', 'None', (173, 175))	('codon 149 CCA>CCC', 'Mutation', 'c.CODON149CCA>CCC', (98, 115))	('codon 842 GTG>GTT', 'Mutation', 'c.CODON842GTG>GTT', (139, 156))	('codon 438 TCT>TCA', 'Var', (117, 134))	('PIK3CA', 'Gene', (21, 27))	('codon 438 TCT>TCA', 'Mutation', 'c.CODON438TCT>TCA', (117, 134))	('codon 149 CCA>CCC', 'Var', (98, 115))
57464	25619516	The IGFBPs function as regulatory components of IGF signaling,39 and some studies have indicated that high IGFBP2 expression may contribute to ACC pathogenesis.	('IGFBP2', 'Gene', (107, 113))	('high', 'Var', (102, 106))	('IGFBPs', 'Gene', '3485;488516;16008;100855619;608158;3488;610316;607374', (4, 10))	('ACC', 'Phenotype', 'HP:0006744', (143, 146))	('contribute', 'Reg', (129, 139))	('IGFBPs', 'Gene', (4, 10))	('expression', 'MPA', (114, 124))	('ACC', 'Disease', (143, 146))
57466	25619516	Theoretically, high IGFBP2 expression could lead to higher IGF-II availability and thus increase IGFR1/PI3K signaling.	('high', 'Var', (15, 19))	('PI3', 'Gene', (103, 106))	('IGF-II', 'Protein', (59, 65))	('IGFR1', 'Gene', (97, 102))	('IGFR1', 'Gene', '100132417', (97, 102))	('increase', 'PosReg', (88, 96))	('expression', 'MPA', (27, 37))	('PI3', 'Gene', '477241', (103, 106))	('increase IGFR1', 'Phenotype', 'HP:0030269', (88, 102))	('availability', 'MPA', (66, 78))	('higher', 'PosReg', (52, 58))	('IGFBP2', 'Gene', (20, 26))
57509	20687934	The gross specimen consisted of a centrally necrotic, peripherally viable appearing, heterogenous gray to pink-yellow friable suprarenal mass, 17.0 x 6.0 x 6.0 cm, 2974 grams, completely effacing the adrenal gland (Fig.	('effacing', 'NegReg', (187, 195))	('2974', 'Var', (164, 168))	('necrotic', 'Disease', (44, 52))	('necrotic', 'Disease', 'MESH:D009336', (44, 52))
57560	20687934	Malignant peripheral nerve sheet tumor with rhabdomyoblastic elements (Triton tumor) can be excluded by morphology as well as negativity of Melan-A, synaptophysin, and calretinin and positivity of S-100.	('synaptophysin', 'Gene', (149, 162))	('Malignant peripheral nerve sheet tumor', 'Disease', (0, 38))	('synaptophysin', 'Gene', '6855', (149, 162))	('Malignant peripheral nerve sheet tumor', 'Disease', 'MESH:D010524', (0, 38))	('negativity', 'Var', (126, 136))	('Triton tumor', 'Disease', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('calretinin', 'Gene', '794', (168, 178))	('Malignant peripheral nerve', 'Phenotype', 'HP:0100697', (0, 26))	('positivity', 'Var', (183, 193))	('Triton tumor', 'Disease', 'MESH:D009369', (71, 83))	('Melan-A', 'Gene', (140, 147))	('Melan-A', 'Gene', '2315', (140, 147))	('calretinin', 'Gene', (168, 178))	('S-100', 'Protein', (197, 202))
57562	20687934	This can be distinguished from an adrenocortical tumor by positivity for other melanocytic makers such as S-100, HMB-45, tyrosinase and negativity of calretinin, synaptophysin and inhibin.	('inhibin', 'Protein', (180, 187))	('synaptophysin', 'Gene', '6855', (162, 175))	('tyrosinase', 'Gene', '7299', (121, 131))	('calretinin', 'Gene', '794', (150, 160))	('positivity', 'Var', (58, 68))	('HMB-45', 'Gene', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('negativity', 'Var', (136, 146))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (34, 54))	('tyrosinase', 'Gene', (121, 131))	('calretinin', 'Gene', (150, 160))	('adrenocortical tumor', 'Disease', (34, 54))	('synaptophysin', 'Gene', (162, 175))
57590	33953990	Immunohistochemical investigation showed strong positive staining for SF-1, P450c17, P450c21, 3betaHSD2, CYP11B1, and CYP11B2 and partial positive staining for P450scc and 3betaHSD1 in both the ACC and the liver metastases (Figure 2); these findings indicated synthetic capability for aldosterone and cortisol.	('CYP11B2', 'Gene', '1585', (118, 125))	('P450c17', 'Gene', (76, 83))	('3betaHSD', 'Gene', '3283', (172, 180))	('ACC', 'Phenotype', 'HP:0006744', (194, 197))	('3betaHSD', 'Gene', (94, 102))	('CYP', 'Gene', '9360', (105, 108))	('P450c21', 'Var', (85, 92))	('3betaHSD', 'Gene', (172, 180))	('P450c17', 'Gene', '1586', (76, 83))	('P450scc', 'Gene', '1583', (160, 167))	('CYP11B2', 'Gene', (118, 125))	('P450scc', 'Gene', (160, 167))	('CYP', 'Gene', (105, 108))	('indicated', 'Reg', (250, 259))	('CYP11B1', 'Gene', '1584', (105, 112))	('CYP', 'Gene', '9360', (118, 121))	('SF-1', 'Gene', (70, 74))	('P450scc and 3betaHSD1', 'Gene', '26871', (160, 181))	('SF-1', 'Gene', '7536', (70, 74))	('CYP11B1', 'Gene', (105, 112))	('3betaHSD', 'Gene', '3283', (94, 102))	('CYP', 'Gene', (118, 121))
57600	33615670	Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that originates in the outer layer of the adrenal gland.	('adrenocortical carcinoma', 'Disease', (15, 39))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (98, 122))	('carcinoma', 'Disease', 'MESH:D009369', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinoma', 'Disease', (113, 122))	('associated', 'Reg', (40, 50))	('aggressive malignancy', 'Disease', (139, 160))	('RET', 'Gene', '5979', (94, 97))	('Adrenocortical carcinoma', 'Disease', (98, 122))	('aggressive malignancy', 'Disease', 'MESH:D009369', (139, 160))	('double germline mutations', 'Var', (56, 81))	('MSH2', 'Gene', (85, 89))	('carcinoma', 'Disease', 'MESH:D009369', (113, 122))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (15, 39))	('RET', 'Gene', (94, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('ACC', 'Phenotype', 'HP:0006744', (124, 127))	('carcinoma', 'Disease', (30, 39))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (98, 122))	('MSH2', 'Gene', '4436', (85, 89))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (15, 39))
57609	33615670	Some genotype-phenotype correlations have been noted; for example, patients with MSH2 mutations carry a higher risk of extracolonic cancers or multiple malignancies (Cohen & Leininger, 2014; Lynch et al., 2009).	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('mutations', 'Var', (86, 95))	('extracolonic cancers', 'Disease', (119, 139))	('patients', 'Species', '9606', (67, 75))	('MSH2', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('extracolonic cancers', 'Disease', 'MESH:D009369', (119, 139))	('malignancies', 'Disease', (152, 164))
57610	33615670	The patient described here had the p.Val804Met (Figure 1; low to moderate risk for MTC) mutation in the RET gene.	('RET', 'Gene', (104, 107))	('p.Val804Met', 'Mutation', 'rs79658334', (35, 46))	('p.Val804Met', 'Var', (35, 46))	('MTC', 'Phenotype', 'HP:0002865', (83, 86))
57611	33615670	She carried a deleterious germline mutation in the MSH2 gene (c.211+1G>T splice variant; Figure 2) and had a family history of LS.	('MSH2', 'Gene', (51, 55))	('c.211+1G>T splice', 'Var', (62, 79))	('c.211+1G>T', 'Mutation', 'rs1114167883', (62, 72))
57614	33615670	Clinical analysis of a somatic gene panel of 523 cancer genes (TruSight Oncology 500 (TSO500), Illumina) performed on the patient's tumor (estimated tumor content of 70%) revealed the presence of a pathogenic mutation in the RET gene (c.2410G>A; p.Val804Met) with a VAF of 90%.	('RET', 'Gene', (225, 228))	('p.Val804Met', 'SUBSTITUTION', 'None', (246, 257))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('pathogenic', 'Reg', (198, 208))	('c.2410G>A', 'Mutation', 'rs79658334', (235, 244))	('p.Val804Met', 'Var', (246, 257))	('Oncology', 'Phenotype', 'HP:0002664', (72, 80))
57616	33615670	In addition, TSO 500 identified the MSH2 c.211+1G>T splice site mutation with a VAF of 88% which is consistent with loss of heterozygosity (LOH).	('c.211+1G>T', 'SUBSTITUTION', 'None', (41, 51))	('MSH2', 'Gene', (36, 40))	('c.211+1G>T', 'Var', (41, 51))
57618	33615670	The patient's sister (39 years old) was diagnosed with colon cancer at 28 years of age; she was the initial proband found to have a deleterious germline mutation in the MSH2 gene (c.211+1G>T, IVS1+1G>T).	('c.211+1G>T', 'SUBSTITUTION', 'None', (180, 190))	('c.211+1G>T', 'Var', (180, 190))	('colon cancer', 'Phenotype', 'HP:0003003', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('MSH2', 'Gene', (169, 173))	('colon cancer', 'Disease', (55, 67))	('IVS1+1G>T', 'Mutation', 'c.IVS1+1G>T', (192, 201))
57619	33615670	In addition, her paternal half-brother (60 years old), also found to have the familial MSH2 mutation, was diagnosed with renal (papillary grade II) cancer, bladder cancer, and primary urethra low-grade carcinoma.	('mutation', 'Var', (92, 100))	('diagnosed', 'Reg', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('bladder cancer', 'Disease', 'MESH:D001749', (156, 170))	('bladder cancer', 'Disease', (156, 170))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('bladder cancer', 'Phenotype', 'HP:0009725', (156, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('primary urethra low-grade carcinoma', 'Disease', (176, 211))
57622	33615670	In general, MSH2 mutations are associated with 48% risk of colorectal cancer, 21% risk of endometrial cancer, and 24% ovarian cancer; the risk of any cancer with MSH2 mutations range from 14.3% by age of 40 to 80.4% by age of 75 (Perez-Cabornero et al., 2013).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ovarian cancer', 'Disease', (118, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('endometrial cancer', 'Disease', (90, 108))	('colorectal cancer', 'Disease', (59, 76))	('endometrial cancer', 'Phenotype', 'HP:0012114', (90, 108))	('ovarian cancer', 'Disease', 'MESH:D010051', (118, 132))	('endometrial cancer', 'Disease', 'MESH:D016889', (90, 108))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('MSH2', 'Gene', (162, 166))	('mutations', 'Var', (17, 26))	('MSH2', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
57623	33615670	Upon enrollment in the NIH protocol (NCT03739827), the patient's tumor was found to be positive for the pathogenic RET mutation (c.2410G>A, p.Val804Met) with an allele fraction (VAF) of 90% (tumor content 70%).	('c.2410G>A', 'SUBSTITUTION', 'None', (129, 138))	('pathogenic', 'Reg', (104, 114))	('p.Val804Met', 'Var', (140, 151))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('c.2410G>A', 'Var', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('p.Val804Met', 'SUBSTITUTION', 'None', (140, 151))	('RET', 'Gene', (115, 118))
57624	33615670	The p.Val804Met mutation is one of the most common mutations in the RET gene; the American Thyroid Association (ATA) classifies this mutation as moderate risk in the guidelines for the management of MTC (Loveday et al., 2008; Moller et al., 2017; Romei et al., 2016).	('MTC', 'Phenotype', 'HP:0002865', (199, 202))	('p.Val804Met', 'Var', (4, 15))	('RET', 'Gene', (68, 71))	('p.Val804Met', 'SUBSTITUTION', 'None', (4, 15))
57625	33615670	The manifestation of disease from carriers of the p.Val804Met mutation ranges from metastatic MTC at an early age to no evidence of disease by age 80 (Feldman et al., 2000; Wells et al., 2015) and includes several reports of pheochromocytoma (Hoie et al., 2000; Nilsson et al., 1999), papillary thyroid carcinoma (Brauckhoff et al., 2002; Gibelin et al., 2004), and concomitant papillary and medullary carcinoma (Shifrin et al., 2009).	('papillary thyroid carcinoma', 'Disease', (285, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (402, 411))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (285, 312))	('pheochromocytoma', 'Disease', (225, 241))	('MTC', 'Phenotype', 'HP:0002865', (94, 97))	('p.Val804Met', 'SUBSTITUTION', 'None', (50, 61))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (225, 241))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (285, 312))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (295, 312))	('metastatic MTC', 'Disease', (83, 97))	('p.Val804Met', 'Var', (50, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))
57627	33615670	The confirmation of a secondary germline cancer-predisposing mutation generated significant anxiety in this patient, mostly due to concerns for her son.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('anxiety', 'Disease', 'MESH:D001007', (92, 99))	('mutation', 'Var', (61, 69))	('anxiety', 'Phenotype', 'HP:0000739', (92, 99))	('anxiety', 'Disease', (92, 99))
57714	31597261	Furthermore, radiotherapy provides pain relief, especially for vertebral and bone metastases, and can therefore have a potential positive effect on HRQoL.	('pain', 'Phenotype', 'HP:0012531', (35, 39))	('pain', 'Disease', 'MESH:D010146', (35, 39))	('HRQoL', 'Disease', (148, 153))	('radiotherapy', 'Var', (13, 25))	('pain', 'Disease', (35, 39))	('metastases', 'Disease', (82, 92))	('metastases', 'Disease', 'MESH:D009362', (82, 92))
57725	31597261	At higher serum concentrations, mitotane can cause neuropsychological adverse effects including vertigo, ataxia, impaired speech, and lethargy.	('ataxia', 'Disease', (105, 111))	('vertigo', 'Phenotype', 'HP:0002321', (96, 103))	('ataxia', 'Disease', 'MESH:D001259', (105, 111))	('lethargy', 'Phenotype', 'HP:0001254', (134, 142))	('lethargy', 'Disease', 'MESH:D053609', (134, 142))	('impaired speech', 'Disease', (113, 128))	('cause', 'Reg', (45, 50))	('mitotane', 'Var', (32, 40))	('mitotane', 'Chemical', 'MESH:D008939', (32, 40))	('vertigo', 'Disease', 'MESH:D014717', (96, 103))	('ataxia', 'Phenotype', 'HP:0001251', (105, 111))	('vertigo', 'Disease', (96, 103))	('lethargy', 'Disease', (134, 142))
57757	31597261	They discovered that the EDP-mitotane regime had a better progression-free and overall survival, while HRQoL did not differ between the groups.	('overall survival', 'CPA', (79, 95))	('better', 'PosReg', (51, 57))	('progression-free', 'CPA', (58, 74))	('EDP-mitotane', 'Var', (25, 37))	('mitotane', 'Chemical', 'MESH:D008939', (29, 37))
57857	27445985	However, the critical role of gap junctions as channels for communication was established by experiments in which it was demonstrated that hepatocytes and myocardial cells only passed current if gap junctions were observed and if gap junctions were not present, current did not pass between cells.	('passed current', 'MPA', (177, 191))	('gap', 'Var', (195, 198))	('rat', 'Species', '10116', (128, 131))
57887	27445985	In further support of the biological role of gap junctions in adrenal cortical function, inhibition of gap-junctional communication with 18-alpha glycyrrhetinic acid (18-alpha GA) treatment decreased the steroidogenic responsiveness of bovine adrenal cells in culture to ACTH.	('18-alpha glycyrrhetinic acid', 'Chemical', 'MESH:C119129', (137, 165))	('bovine', 'Species', '9913', (236, 242))	('inhibition', 'Var', (89, 99))	('decreased', 'NegReg', (190, 199))	('steroid', 'Chemical', 'MESH:D013256', (204, 211))	('steroidogenic responsiveness', 'MPA', (204, 232))
57891	27445985	Cell populations expressing Cx43 antisense grew faster, had decreased capacity for cell-cell communication, and had a diminished steroidogenic responsiveness to ACTH treatment compared with null transfected control populations.	('steroid', 'Chemical', 'MESH:D013256', (129, 136))	('cell-cell communication', 'CPA', (83, 106))	('faster', 'PosReg', (48, 54))	('decreased', 'NegReg', (60, 69))	('antisense', 'Var', (33, 42))	('steroidogenic responsiveness to ACTH treatment', 'MPA', (129, 175))	('grew', 'CPA', (43, 47))	('Cx43', 'Gene', (28, 32))	('diminished', 'NegReg', (118, 128))
57893	27445985	It has been suggested that gap junction communication of cAMP signaling, and subsequent PKA activation in the recipient cell, may increase the efficiency of hormone response by facilitating amplification of ACTH signaling throughout the population.	('ACTH signaling', 'MPA', (207, 221))	('cAMP', 'Chemical', 'MESH:D000242', (57, 61))	('gap', 'Var', (27, 30))	('hormone response', 'MPA', (157, 173))	('increase', 'PosReg', (130, 138))	('amplification', 'MPA', (190, 203))
57909	27445985	In a number of studies of adrenal cells in culture, ACTH has been demonstrated to increase gap junction protein expression and to increase the size and number of surface gap junction plaques.	('ACTH', 'Var', (52, 56))	('increase', 'PosReg', (82, 90))	('increase', 'PosReg', (130, 138))	('gap junction protein', 'Protein', (91, 111))	('rat', 'Species', '10116', (73, 76))	('expression', 'MPA', (112, 122))
57911	27445985	Specifically, an increase in gap junction plaque size and number at the cell surface as well as the decrease in gap junction plaque disassembly (internalization to form annular gap junctions) was reported following DbcAMP treatment.	('gap junction plaque size', 'MPA', (29, 53))	('gap junction plaque disassembly', 'MPA', (112, 143))	('decrease', 'NegReg', (100, 108))	('increase', 'PosReg', (17, 25))	('DbcAMP', 'Var', (215, 221))	('DbcAMP', 'Chemical', 'MESH:D003994', (215, 221))
57919	27445985	Specifically, PKA activation results in the phosphorylation of serines (S364, S365, S369, and S373) on the C-terminal tail of Cx43.	('S365', 'Var', (78, 82))	('phosphorylation', 'MPA', (44, 59))	('S373', 'Var', (94, 98))	('serines', 'Chemical', 'MESH:D012694', (63, 70))	('S369', 'Var', (84, 88))	('S364', 'Var', (72, 76))
57923	27445985	Specifically, there are at least 11 serine and 2 tyrosine residues on the C-terminal tail of Cx43 (Cx43-C-terminus) that, when phosphorylated, result in either an increase in gap junction function (S325, S328, S330, S364/365, and S373) or the downregulation of gap junction activity (Y247, S255, S262, Y265, S279/282, and S368).	('S255', 'Var', (290, 294))	('Y265', 'Var', (302, 306))	('gap junction activity', 'MPA', (261, 282))	('Y247', 'Var', (284, 288))	('serine', 'Chemical', 'MESH:D012694', (36, 42))	('gap junction function', 'MPA', (175, 196))	('S279/282', 'Var', (308, 316))	('S325', 'Var', (198, 202))	('S328', 'Var', (204, 208))	('increase', 'PosReg', (163, 171))	('downregulation', 'NegReg', (243, 257))	('S364/365', 'Var', (216, 224))	('Cx43-C-terminus', 'Gene', (99, 114))	('S373', 'Var', (230, 234))	('Cx43-C-terminus', 'Gene', '2697', (99, 114))	('tyrosine', 'Chemical', 'MESH:D014443', (49, 57))	('S368', 'Var', (322, 326))	('S262', 'Var', (296, 300))	('S330', 'Var', (210, 214))
57924	27445985	These observations have been made mainly from studies in clonal lines of murine fibroblasts (L929 cells), fibroblasts derived from Cx43 knockout and wild-type mice, rat liver epithelial cells (T51B), HeLa cells, and rat primary granulosa cells.	('T51B', 'Var', (193, 197))	('murine', 'Species', '10090', (73, 79))	('HeLa', 'CellLine', 'CVCL:0030', (200, 204))	('Cx43', 'Gene', (131, 135))	('L929', 'CellLine', 'CVCL:0462', (93, 97))	('knockout', 'Var', (136, 144))	('mice', 'Species', '10090', (159, 163))	('rat', 'Species', '10116', (165, 168))	('rat', 'Species', '10116', (216, 219))	('T51B', 'SUBSTITUTION', 'None', (193, 197))
57927	27445985	In the case of PKC-mediated hyperphosphorylation of Cx43, it is thought that phosphorylation makes this connexin more vulnerable to proteolytic degradation, thus decreasing gap junction-mediated communication.	('Cx43', 'Gene', (52, 56))	('phosphorylation', 'Var', (77, 92))	('vulnerable', 'MPA', (118, 128))	('connexin', 'Gene', (104, 112))	('gap junction-mediated communication', 'MPA', (173, 208))	('connexin', 'Gene', '100128922', (104, 112))	('decreasing', 'NegReg', (162, 172))
57940	27445985	Interestingly, exogenous Cx43 can decrease cell proliferation and contribute to reversion of the transformed phenotype.	('decrease', 'NegReg', (34, 42))	('exogenous', 'Var', (15, 24))	('Cx43', 'Protein', (25, 29))	('reversion', 'CPA', (80, 89))	('rat', 'Species', '10116', (55, 58))	('cell proliferation', 'CPA', (43, 61))
57955	27445985	In the medulla, several different connexin types (Cx29, Cx36, Cx43, and Cx50) have been reported to be expressed, depending on the species.	('Cx50', 'Gene', (72, 76))	('Cx36', 'Gene', (56, 60))	('connexin', 'Gene', '100128922', (34, 42))	('connexin', 'Gene', (34, 42))	('Cx50', 'Gene', '2703', (72, 76))	('Cx29', 'Gene', '349149', (50, 54))	('Cx43', 'Var', (62, 66))	('Cx36', 'Gene', '57369', (56, 60))	('Cx29', 'Gene', (50, 54))
57967	27445985	Gap junctions in a similar way could potentially retard the migration of cells from one area to another (centripetal migration) by tethering the cells to one another.	('migration of cells from', 'CPA', (60, 83))	('retard', 'NegReg', (49, 55))	('rat', 'Species', '10116', (120, 123))	('rat', 'Species', '10116', (63, 66))	('tethering', 'NegReg', (131, 140))	('Gap junctions', 'Var', (0, 13))
57968	27445985	Inhibiting cell migration through the granulosa cell layer of the follicle, in the case of the ovary, or as cells migrate in the adrenal gland could keep cells connected to one another if gap junctions fail to internalize.	('rat', 'Species', '10116', (117, 120))	('Inhibiting', 'Var', (0, 10))	('cell migration through the', 'CPA', (11, 37))	('cells connected', 'MPA', (154, 169))	('rat', 'Species', '10116', (19, 22))
57971	27445985	There is dramatic remodeling and relocation of gap junction plaques in the diabetic heart.	('diabetic heart', 'Disease', (75, 89))	('diabetic heart', 'Disease', 'MESH:D003920', (75, 89))	('gap', 'Var', (47, 50))
58009	26329697	There is a female predominance but only prior to adolescence (F/M 2:1 in young children, F/M 1:1 in adolescence).	('F/M 1', 'SUBSTITUTION', 'None', (89, 94))	('F/M 1', 'Var', (89, 94))	('F/M 2', 'Var', (62, 67))	('children', 'Species', '9606', (79, 87))	('F/M 2', 'SUBSTITUTION', 'None', (62, 67))
58023	26329697	Recently several, molecular markers have been investigated as a diagnostic aid: overexpression of IGF-2, IGF-1R, somatic p53 mutations, ki67 index and loss of heterozygosity of 11q13.	('overexpression', 'PosReg', (80, 94))	('mutations', 'Var', (125, 134))	('IGF-1R', 'Gene', '3480', (105, 111))	('loss of heterozygosity', 'Var', (151, 173))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('IGF-1R', 'Gene', (105, 111))	('IGF-2', 'Gene', (98, 103))	('IGF-2', 'Gene', '3481', (98, 103))
58114	26314582	Thompson has suggested that tumours with a PASS >= 6 were biologically more aggressive than tumours with a PASS <4.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('PASS >= 6', 'Var', (43, 52))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('aggressive', 'CPA', (76, 86))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))
58159	22266826	The aldosterone production by the NCI-H295, H295A, H295R-S1, H295R-S2, H295R-S3, HAC13, HAC15 and HAC50 were 119, 1, 6, 826, 18, 139, 412, and 1334 (pmol/mg protein/48h), respectively.	('H295R-S2', 'Var', (61, 69))	('H295R-S1', 'Var', (51, 59))	('HAC13', 'Var', (81, 86))	('H295A', 'Var', (44, 49))	('HAC15', 'Var', (88, 93))	('NCI-H295', 'CellLine', 'CVCL:0456', (34, 42))	('H295A', 'CellLine', 'CVCL:0457', (44, 49))	('HAC50', 'Var', (98, 103))	('aldosterone', 'Chemical', 'MESH:D000450', (4, 15))	('aldosterone production', 'MPA', (4, 26))	('H295R-S3', 'Var', (71, 79))	('aldosterone production', 'Phenotype', 'HP:0000859', (4, 26))
58160	22266826	H295A and H295R-S1 expressed less CYP11B2 than the commonly used H295R-S3 cells; while NCI-H295, H295R-S2, HAC13, HAC15 and HAC50 expressed 24, 14, 3, 10 and 35 fold higher CYP11B2 compared with the H295R-S3 cells.	('higher', 'PosReg', (166, 172))	('CYP11B2', 'Gene', (34, 41))	('CYP11B2', 'Gene', '1585', (34, 41))	('H295A', 'CellLine', 'CVCL:0457', (0, 5))	('H295R-S2', 'Var', (97, 105))	('NCI-H295', 'CellLine', 'CVCL:0456', (87, 95))	('CYP11B2', 'Gene', (173, 180))	('CYP11B2', 'Gene', '1585', (173, 180))
58161	22266826	When treated with Ang II, NCI-H295, H295R-S2, HAC13, HAC15 and HAC50 showed significantly higher aldosterone production than the basal level (p<0.05).	('aldosterone production', 'MPA', (97, 119))	('HAC50', 'Var', (63, 68))	('aldosterone production', 'Phenotype', 'HP:0000859', (97, 119))	('HAC15', 'Var', (53, 58))	('NCI-H295', 'CellLine', 'CVCL:0456', (26, 34))	('NCI-H295', 'Var', (26, 34))	('Ang II', 'Gene', '183', (18, 24))	('HAC13', 'Var', (46, 51))	('Ang II', 'Gene', (18, 24))	('higher aldosterone', 'Phenotype', 'HP:0000859', (90, 108))	('higher', 'PosReg', (90, 96))	('H295R-S2', 'Var', (36, 44))	('aldosterone', 'Chemical', 'MESH:D000450', (97, 108))
58162	22266826	A comparison of the available human adrenal cell lines indicates that the H295R-S2 and the clonal cell lines, HAC13, HAC15 and HAC50 produced the highest levels of aldosterone and responded well to Ang II.	('human', 'Species', '9606', (30, 35))	('HAC50', 'Var', (127, 132))	('highest levels of aldosterone', 'Phenotype', 'HP:0000859', (146, 175))	('responded', 'MPA', (180, 189))	('aldosterone', 'Chemical', 'MESH:D000450', (164, 175))	('Ang II', 'Gene', '183', (198, 204))	('levels', 'MPA', (154, 160))	('Ang II', 'Gene', (198, 204))	('HAC13', 'Var', (110, 115))	('aldosterone', 'MPA', (164, 175))
58181	22266826	H295R cells were selected from NCI-H295 to grow as monolayer cells, our group used different culture conditions and selected 3 substrains: H295R-S1, H295R-S2 and H295R-S3.	('H295R-S3', 'Var', (162, 170))	('H295R-S1', 'Var', (139, 147))	('NCI-H295', 'CellLine', 'CVCL:0456', (31, 39))	('H295R-S2', 'Var', (149, 157))
58207	22266826	In addition, we have observed that long term culture of the H295R-S2 leads to a drop in absolute aldosterone production (data not shown).	('aldosterone production', 'Phenotype', 'HP:0000859', (97, 119))	('absolute aldosterone production', 'MPA', (88, 119))	('drop in absolute aldosterone production', 'Phenotype', 'HP:0004319', (80, 119))	('drop', 'NegReg', (80, 84))	('aldosterone', 'Chemical', 'MESH:D000450', (97, 108))	('H295R-S2', 'Var', (60, 68))
58215	22266826	In addition to the steroidogenic genes, the microarray analysis showed that the NCI-H295, H295R-S1, H295R-S2, H295R-S3, HAC13, HAC15 and HAC50 expressed high level of the type 1 angiotensin II receptor (AT1 receptor; AGTR1), while the CAR47, SW13 and H295A cells expressed much lower level of AT1 receptor (Figure 3B).	('AT1', 'Gene', (293, 296))	('NCI-H295', 'CellLine', 'CVCL:0456', (80, 88))	('HAC13', 'Var', (120, 125))	('AT1', 'Gene', '185', (293, 296))	('H295R-S3', 'Var', (110, 118))	('AGTR1', 'Gene', (217, 222))	('AGTR1', 'Gene', '185', (217, 222))	('type 1 angiotensin II receptor', 'Gene', (171, 201))	('type 1 angiotensin II receptor', 'Gene', '185', (171, 201))	('AT1', 'Gene', (203, 206))	('H295A', 'CellLine', 'CVCL:0457', (251, 256))	('SW13', 'CellLine', 'CVCL:0542', (242, 246))	('AT1', 'Gene', '185', (203, 206))	('HAC50', 'Var', (137, 142))	('steroid', 'Chemical', 'MESH:D013256', (19, 26))
58222	22266826	Further ACTH treatment of the H295R-S2, HAC13, HAC15, and HAC50 cell lines showed a significant increase of aldosterone production only in the HAC15 cells (data not show), which is consistent with our previous study.	('aldosterone production', 'MPA', (108, 130))	('ACTH', 'Gene', (8, 12))	('aldosterone production', 'Phenotype', 'HP:0000859', (108, 130))	('ACTH', 'Gene', '5443', (8, 12))	('increase of aldosterone', 'Phenotype', 'HP:0000859', (96, 119))	('HAC15', 'Var', (143, 148))	('increase', 'PosReg', (96, 104))	('aldosterone', 'Chemical', 'MESH:D000450', (108, 119))
58227	22266826	This patient has inactivating mutation in PRKAR1A gene that encodes the regulatory subunit type 1A (RIalpha) of cAMP dependent protein kinase PKA.	('PRKAR1A', 'Gene', '5573', (42, 49))	('patient', 'Species', '9606', (5, 12))	('cAMP', 'Chemical', '-', (112, 116))	('inactivating mutation', 'Var', (17, 38))	('PRKAR1A', 'Gene', (42, 49))
58228	22266826	CAR47 is a first immortalized human cell line carrying an inactivating PRKAR1A mutation.	('human', 'Species', '9606', (30, 35))	('PRKAR1A', 'Gene', '5573', (71, 78))	('mutation', 'Var', (79, 87))	('inactivating', 'Var', (58, 70))	('PRKAR1A', 'Gene', (71, 78))
58237	22266826	In this study, NCI-H295, H295R-S2, HAC13, HAC15 and HAC50 cell lines produced more aldosterone and had higher CYP11B2 expression than the other cell lines.	('more', 'PosReg', (78, 82))	('H295R-S2', 'Var', (25, 33))	('HAC50', 'Var', (52, 57))	('aldosterone', 'MPA', (83, 94))	('CYP11B2', 'Gene', '1585', (110, 117))	('CYP11B2', 'Gene', (110, 117))	('aldosterone', 'Chemical', 'MESH:D000450', (83, 94))	('higher', 'PosReg', (103, 109))	('produced', 'MPA', (69, 77))	('NCI-H295', 'CellLine', 'CVCL:0456', (15, 23))	('expression', 'MPA', (118, 128))
58240	22266826	Compared to the H295R-S2 cell strain which represents a mixed population of tumor cells, HAC13, HAC15 and HAC50 cells are clonal which may provide a more stable steroidogenic phenotype.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('steroid', 'Chemical', 'MESH:D013256', (161, 168))	('steroidogenic phenotype', 'MPA', (161, 184))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('HAC50', 'Var', (106, 111))	('more', 'PosReg', (149, 153))	('HAC15', 'Var', (96, 101))
58241	22266826	Among the clonal cell lines, the HAC50 produced the most aldosterone and expressed the highest levels of CYP11B2 mRNA.	('CYP11B2', 'Gene', (105, 112))	('aldosterone', 'Chemical', 'MESH:D000450', (57, 68))	('CYP11B2', 'Gene', '1585', (105, 112))	('most', 'PosReg', (52, 56))	('HAC50', 'Var', (33, 38))	('levels', 'MPA', (95, 101))	('aldosterone', 'MPA', (57, 68))
58243	22266826	Our microarray analysis showed that NCI-H295, H295R-S1, H295R-S2, H295R-S3, HAC13, HAC15 and HAC50 expressed high levels of AT1 receptor.	('AT1', 'Gene', '185', (124, 127))	('AT1', 'Gene', (124, 127))	('HAC50', 'Var', (93, 98))	('H295R-S3', 'Var', (66, 74))	('H295R-S1', 'Var', (46, 54))	('H295R-S2', 'Var', (56, 64))	('HAC13', 'Var', (76, 81))	('HAC15', 'Var', (83, 88))	('NCI-H295', 'CellLine', 'CVCL:0456', (36, 44))
58244	22266826	Accordingly, we found that NCI-H295, H295R-S2, HAC13, HAC15 and HAC50 cells produced more aldosterone when stimulated by Ang II compared with their basal level.	('produced', 'MPA', (76, 84))	('aldosterone', 'MPA', (90, 101))	('more', 'PosReg', (85, 89))	('Ang II', 'Gene', '183', (121, 127))	('NCI-H295', 'CellLine', 'CVCL:0456', (27, 35))	('Ang II', 'Gene', (121, 127))	('aldosterone', 'Chemical', 'MESH:D000450', (90, 101))	('H295R-S2', 'Var', (37, 45))
58260	21971485	Nicotine Induced CpG methylation of Pax6 binding motif in StAR promoter reduces the gene expression and cortisol production Steroidogenic acute regulatory protein (StAR) mediates the rate-limiting step in the synthesis of steroid hormones, essential to fetal development.	('Pax6', 'Gene', '5080', (36, 40))	('rat', 'Species', '10116', (183, 186))	('gene expression', 'MPA', (84, 99))	('reduces', 'NegReg', (72, 79))	('StAR', 'Gene', (58, 62))	('cortisol production', 'MPA', (104, 123))	('StAR', 'Gene', (164, 168))	('Nicotine', 'Chemical', 'MESH:D009538', (0, 8))	('methylation', 'Var', (21, 32))	('steroid hormones', 'Chemical', 'MESH:D013256', (222, 238))	('cortisol', 'Chemical', 'MESH:D006854', (104, 112))	('StAR', 'Gene', '6770', (164, 168))	('StAR', 'Gene', '6770', (58, 62))	('Pax6', 'Gene', (36, 40))
58262	21971485	Here using primary human fetal adrenal cortex (pHFAC) cells and a human fetal adrenal cell line NCI-H295A, we show that nicotine inhibits StAR expression and cortisol production in a dose- and time-dependent manner, and prolongs the inhibitory effect on cells proliferating over 5 passages after termination of nicotine treatment.	('nicotine', 'Var', (120, 128))	('human', 'Species', '9606', (66, 71))	('rat', 'Species', '10116', (267, 270))	('cortisol', 'Chemical', 'MESH:D006854', (158, 166))	('nicotine', 'Chemical', 'MESH:D009538', (311, 319))	('NCI-H295A', 'CellLine', 'CVCL:0457', (96, 105))	('StAR expression', 'MPA', (138, 153))	('nicotine', 'Chemical', 'MESH:D009538', (120, 128))	('human', 'Species', '9606', (19, 24))	('prolongs', 'PosReg', (220, 228))	('inhibits', 'NegReg', (129, 137))	('cortisol production', 'MPA', (158, 177))
58263	21971485	Methylation detection within the StAR promoter region uncovers a single site CpG methylation at nt -377 that is sensitive to nicotine treatment.	('nicotine', 'Chemical', 'MESH:D009538', (125, 133))	('nt -377', 'Gene', (96, 103))	('methylation', 'Var', (81, 92))
58266	21971485	The luciferase activity assays validate that Pax6 increases StAR gene expression by binding to the glucagon G3-like motif (CGCCTGA) and methylation of this site blocks Pax6 binding and thus suppresses StAR expression.	('methylation', 'Var', (136, 147))	('blocks', 'NegReg', (161, 167))	('StAR gene', 'Gene', (60, 69))	('Pax6', 'Gene', (45, 49))	('Pax6', 'Gene', '5080', (45, 49))	('increases', 'PosReg', (50, 59))	('expression', 'MPA', (70, 80))	('Pax6', 'Gene', (168, 172))	('binding', 'Interaction', (173, 180))	('Pax6', 'Gene', '5080', (168, 172))	('StAR expression', 'MPA', (201, 216))	('binding', 'Interaction', (84, 91))	('suppresses', 'NegReg', (190, 200))
58274	21971485	Long term consequences of low birth weight on adrenal cortisol secretion contribute to increased risks for the metabolic syndrome in later life, suggesting a central role for adrenocortical steroidogenesis in intrauterine fetal programming.	('adrenal cortisol secretion', 'MPA', (46, 72))	('metabolic syndrome', 'Disease', 'MESH:D008659', (111, 129))	('cortisol', 'Chemical', 'MESH:D006854', (54, 62))	('adrenocortical', 'Disease', 'MESH:D018268', (175, 189))	('metabolic syndrome', 'Disease', (111, 129))	('low', 'Var', (26, 29))	('low birth weight', 'Phenotype', 'HP:0001518', (26, 42))	('steroid', 'Chemical', 'MESH:D013256', (190, 197))	('adrenocortical', 'Disease', (175, 189))
58280	21971485	Experimental data in rodents and recent observations in humans suggest that epigenetic changes in growth-related genes play a significant role in fetal programming.	('fetal programming', 'CPA', (146, 163))	('humans', 'Species', '9606', (56, 62))	('epigenetic changes', 'Var', (76, 94))	('growth-related genes', 'Gene', (98, 118))
58283	21971485	Studies have shown that aberrant DNA methylation occurs in human adrenocortical tumorigenesis that is often accompanied by abnormal hormone production.	('human', 'Species', '9606', (59, 64))	('aberrant', 'Var', (24, 32))	('adrenocortical', 'Disease', (65, 79))	('adrenocortical', 'Disease', 'MESH:D018268', (65, 79))	('abnormal hormone production', 'Phenotype', 'HP:0032367', (123, 150))	('DNA', 'Protein', (33, 36))
58284	21971485	Maternal nicotine exposure increases fetal incidence of adult cardiomyopathy, which has a direct relationship with abnormal regulated gene expression caused by the altered pattern of DNA methylation.	('cardiomyopathy', 'Disease', 'MESH:D009202', (62, 76))	('fetal incidence', 'CPA', (37, 52))	('nicotine', 'Chemical', 'MESH:D009538', (9, 17))	('increases', 'PosReg', (27, 36))	('cardiomyopathy', 'Disease', (62, 76))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (62, 76))	('altered', 'Var', (164, 171))
58290	21971485	We have identified a nicotine-sensitive CpG site of methylation at a potential Pax6 binding motif in the StAR promoter that may down-regulate StAR expression.	('Pax6', 'Gene', (79, 83))	('nicotine', 'Chemical', 'MESH:D009538', (21, 29))	('methylation', 'Var', (52, 63))	('StAR expression', 'MPA', (142, 157))	('Pax6', 'Gene', '5080', (79, 83))	('down-regulate', 'NegReg', (128, 141))
58330	21971485	CpG methylation of the StAR/Pax6 reporter was generated by incubation of the reporter plasmid with M.SssI by following the enzyme instruction.	('rat', 'Species', '10116', (50, 53))	('Pax6', 'Gene', (28, 32))	('Pax6', 'Gene', '5080', (28, 32))	('methylation', 'Var', (4, 15))
58373	21971485	Fig 7 shows that the frequency of the single point CpG methylation at nt -377 remained high level (85.5%) over the first 5 passages (15 days) and dropped to 45% over the second 5 passages after treatment with nicotine for 10 days.	('nicotine', 'Chemical', 'MESH:D009538', (209, 217))	('nt -377', 'Gene', (70, 77))	('methylation', 'Var', (55, 66))
58375	21971485	To determine whether Pax6 binding could promote the StAR gene expression and the methylation at nt -377 could block Pax6 binding, the siRNA approach and luciferase activity assay were employed.	('promote', 'PosReg', (40, 47))	('nt -377', 'Gene', (96, 103))	('methylation', 'Var', (81, 92))	('Pax6', 'Gene', (21, 25))	('Pax6', 'Gene', (116, 120))	('block', 'NegReg', (110, 115))	('Pax6', 'Gene', '5080', (116, 120))	('Pax6', 'Gene', '5080', (21, 25))	('binding', 'Interaction', (121, 128))	('StAR gene', 'Gene', (52, 61))
58378	21971485	This magnitude of decrease in StAR expression caused by Pax6 knock-down is even greater than that caused by treatment with 100 muM nicotine for 7 days.	('knock-down', 'Var', (61, 71))	('nicotine', 'Chemical', 'MESH:D009538', (131, 139))	('StAR expression', 'MPA', (30, 45))	('muM', 'Gene', (127, 130))	('decrease', 'NegReg', (18, 26))	('Pax6', 'Gene', (56, 60))	('Pax6', 'Gene', '5080', (56, 60))	('muM', 'Gene', '56925', (127, 130))
58379	21971485	Fig 8C shows that pre-treatment of the StAR/Pax6 reporters with M.SssI significantly reduced the luciferase activities in both absence (62%) and presence (71%) of Pax6 expression (P<0.01), suggesting that CpG methylation in the binding motif of Pax6 regulates StAR expression.	('StAR expression', 'MPA', (260, 275))	('Pax6', 'Gene', '5080', (245, 249))	('luciferase', 'Enzyme', (97, 107))	('Pax6', 'Gene', (44, 48))	('regulates', 'Reg', (250, 259))	('Pax6', 'Gene', '5080', (44, 48))	('presence', 'Var', (145, 153))	('activities', 'MPA', (108, 118))	('reduced', 'NegReg', (85, 92))	('Pax6', 'Gene', (163, 167))	('Pax6', 'Gene', '5080', (163, 167))	('Pax6', 'Gene', (245, 249))
58380	21971485	Expression of Pax6 significantly increased luciferase activities to 4 and 2.9 folds from baseline (mock) for the StAR/Pax6 reporters pre-treated with and without M.SssI, respectively (P<0.01), suggesting that Pax6 activates StAR gene expression by binding to the glucagon G3-like motif (CGCCTGA) and the methylation of this site partially blocks StAR expression.	('Pax6', 'Gene', '5080', (118, 122))	('methylation', 'Var', (304, 315))	('expression', 'MPA', (234, 244))	('Pax6', 'Gene', (209, 213))	('StAR expression', 'MPA', (346, 361))	('activates', 'PosReg', (214, 223))	('blocks', 'NegReg', (339, 345))	('binding', 'Interaction', (248, 255))	('Pax6', 'Gene', '5080', (209, 213))	('StAR gene', 'Gene', (224, 233))	('increased', 'PosReg', (33, 42))	('Pax6', 'Gene', (14, 18))	('Pax6', 'Gene', '5080', (14, 18))	('activities', 'MPA', (54, 64))	('Pax6', 'Gene', (118, 122))
58389	21971485	Future study will be necessary to determine if the CpG methylation at the Pax6 binding motif of StAR gene promoter would also occur in smoking humans with typically long term exposure at physiologically relevant plasma levels.	('Pax6', 'Gene', (74, 78))	('Pax6', 'Gene', '5080', (74, 78))	('humans', 'Species', '9606', (143, 149))	('methylation', 'Var', (55, 66))
58390	21971485	In this study, we have demonstrated that a single CpG site methylation at nt -377 of StAR promoter associates highly with suppression of the gene expression.	('methylation', 'Var', (59, 70))	('gene expression', 'MPA', (141, 156))	('rat', 'Species', '10116', (30, 33))	('suppression', 'NegReg', (122, 133))
58394	21971485	Expression of hypoxic marker CA IX is regulated by site-specific DNA methylation and is associated with the histology of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('DNA methylation', 'Var', (65, 80))	('CA IX', 'Gene', (29, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('CA IX', 'Gene', '768', (29, 34))	('Expression', 'MPA', (0, 10))	('regulated', 'Reg', (38, 47))	('associated', 'Reg', (88, 98))	('gastric cancer', 'Disease', (121, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
58395	21971485	Methylation of a single intronic CpG mediates expression silencing of the PMP24 gene in prostate cancer.	('PMP24', 'Gene', (74, 79))	('prostate cancer', 'Disease', (88, 103))	('Methylation', 'Var', (0, 11))	('PMP24', 'Gene', '11264', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('expression', 'MPA', (46, 56))
58396	21971485	A variant in the CHEK2 promoter at a methylation site relieves transcriptional repression and confers reduced risk of lung cancer.	('CHEK2', 'Gene', '11200', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('CHEK2', 'Gene', (17, 22))	('variant', 'Var', (2, 9))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('relieves', 'NegReg', (54, 62))	('transcriptional repression', 'MPA', (63, 89))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('reduced', 'NegReg', (102, 109))
58399	21971485	Pax6 is a critical transcription factor in the development of eye, pancreas, and central nervous system and variations in the Pax6 binding motif are reported.	('Pax6', 'Gene', (0, 4))	('Pax6', 'Gene', '5080', (0, 4))	('Pax6', 'Gene', (126, 130))	('Pax6', 'Gene', '5080', (126, 130))	('pancreas', 'Disease', 'MESH:D010190', (67, 75))	('variations', 'Var', (108, 118))	('pancreas', 'Disease', (67, 75))
58409	21971485	CpG methylation at the minimal binding motif of Pax6 (CGCCTGA) caused inhibition of StAR expression to certain degree, but not complete abolishment.	('inhibition', 'NegReg', (70, 80))	('methylation', 'Var', (4, 15))	('CGCCTGA', 'Gene', (54, 61))	('Pax6', 'Gene', (48, 52))	('Pax6', 'Gene', '5080', (48, 52))	('StAR expression', 'MPA', (84, 99))
58415	21971485	Identification and correction of critical epigenetic modification may hold key for developing early diagnosis and treatment of some adult diseases or disorders.	('epigenetic modification', 'Var', (42, 65))	('adult diseases or disorders', 'Disease', (132, 159))	('adult diseases or disorders', 'Disease', 'MESH:C538052', (132, 159))
58416	21971485	In our studies, nicotine-induced CpG methylation of Pax6 binding motif in StAR promotor reduces the StAR gene expression and cortisol production.	('StAR gene expression', 'MPA', (100, 120))	('methylation', 'Var', (37, 48))	('cortisol production', 'MPA', (125, 144))	('nicotine', 'Chemical', 'MESH:D009538', (16, 24))	('Pax6', 'Gene', (52, 56))	('Pax6', 'Gene', '5080', (52, 56))	('cortisol', 'Chemical', 'MESH:D006854', (125, 133))	('reduces', 'NegReg', (88, 95))
58419	21971485	The close correlation between sustained suppression of StAR expression and persistent CpG methylation at nt -377 after termination of nicotine treatment provided an inheritable epigenetic mechanism for nicotine-induced intrauterine programming of HPA axis and onset of adult diseases or disorders.	('adult diseases or disorders', 'Disease', 'MESH:C538052', (269, 296))	('suppression', 'NegReg', (40, 51))	('nt -377', 'Gene', (105, 112))	('methylation', 'Var', (90, 101))	('nicotine', 'Chemical', 'MESH:D009538', (134, 142))	('StAR expression', 'MPA', (55, 70))	('adult diseases or disorders', 'Disease', (269, 296))	('nicotine', 'Chemical', 'MESH:D009538', (202, 210))
58423	21971485	Single CpG methylation located at Pax6 binding motif regulates StAR expression.	('regulates', 'Reg', (53, 62))	('Pax6', 'Gene', (34, 38))	('Pax6', 'Gene', '5080', (34, 38))	('StAR expression', 'MPA', (63, 78))	('methylation', 'Var', (11, 22))
58433	20833336	Multiple endocrine neoplasia type I (MEN1), also known as Wermer syndrome, is an autosomal dominant tumor predisposition caused by mutations in the MEN1 gene.	('caused by', 'Reg', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (131, 140))	('autosomal dominant tumor', 'Disease', 'MESH:D030342', (81, 105))	('Multiple endocrine neoplasia type I', 'Disease', (0, 35))	('Wermer syndrome', 'Disease', 'MESH:D018761', (58, 73))	('Wermer syndrome', 'Disease', (58, 73))	('MEN1', 'Gene', '4221', (148, 152))	('Multiple endocrine neoplasia type I', 'Disease', 'MESH:D018761', (0, 35))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (9, 28))	('MEN1', 'Gene', (148, 152))	('neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('MEN1', 'Gene', (37, 41))	('MEN1', 'Gene', '4221', (37, 41))	('autosomal dominant tumor', 'Disease', (81, 105))
58440	20833336	A second Men1 conventional KO model confirmed that disruption of Men1 causes 100% embryonic lethality at E11.5-E13.5, showing that Menin plays an important role in cell differentiation and/or senescence.	('embryonic lethality', 'Disease', 'MESH:D020964', (82, 101))	('embryonic lethality', 'Disease', (82, 101))	('Men1', 'Gene', '4221', (65, 69))	('Men1', 'Gene', (65, 69))	('disruption', 'Var', (51, 61))	('Men1', 'Gene', '4221', (9, 13))	('Men1', 'Gene', (9, 13))
58441	20833336	Based on the findings from these two conventional models, and owing to the role of Menin in cell cycle regulation, it was hypothesized that the absence of Menin may arrest cell replication, thereby allowing cells to acquire genetic alterations that may predispose them to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', (272, 277))	('rat', 'Species', '10116', (236, 239))	('cell replication', 'CPA', (172, 188))	('absence', 'Var', (144, 151))	('Menin', 'Gene', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('predispose', 'Reg', (253, 263))	('arrest', 'NegReg', (165, 171))
58442	20833336	Another KO mouse model that more closely resembled the human MEN1 syndrome was developed by deleting exon 2, including the translational start site of Men1 .	('MEN1 syndrome', 'Disease', (61, 74))	('mouse', 'Species', '10090', (11, 16))	('deleting', 'Var', (92, 100))	('Men1', 'Gene', '4221', (151, 155))	('MEN1 syndrome', 'Disease', 'MESH:D018761', (61, 74))	('Men1', 'Gene', (151, 155))	('human', 'Species', '9606', (55, 60))
58450	20833336	Thus, developing tissue specific KO of Men1 was necessary to establish the direct effect of menin inactivation and endocrine tumor development.	('Men1', 'Gene', '4221', (39, 43))	('inactivation', 'Var', (98, 110))	('Men1', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('menin', 'Gene', '4221', (92, 97))	('menin', 'Gene', (92, 97))	('endocrine tumor', 'Disease', 'MESH:D004701', (115, 130))	('endocrine tumor', 'Disease', (115, 130))	('endocrine tumor', 'Phenotype', 'HP:0100568', (115, 130))
58451	20833336	In order to overcome homozygous lethality, a conditional KO model was developed which used cre-mediated recombination to cause deletion of exons 3-8 of Men1.	('deletion of exons', 'Var', (127, 144))	('Men1', 'Gene', (152, 156))	('Men1', 'Gene', '4221', (152, 156))
58466	20833336	MEN2 mutations convert the RET (REarranged during Transfection) protooncogene to a dominantly acting oncogene as a consequence of the ligand-independent activation of the tyrosine kinase.	('activation', 'PosReg', (153, 163))	('MEN2', 'Gene', (0, 4))	('RET', 'Gene', (27, 30))	('mutations', 'Var', (5, 14))	('MEN', 'Species', '9606', (0, 3))	('tyrosine kinase', 'Enzyme', (171, 186))
58473	20833336	Mutations in one of the PKA regulatory subunit genes, PRKAR1A, causes the majority of CNC cases, although a second unidentified gene has been localized to chromosome 2.	('PRKAR1A', 'Gene', (54, 61))	('Mutations', 'Var', (0, 9))	('causes', 'Reg', (63, 69))	('PRKAR1A', 'Gene', '19084', (54, 61))	('CNC cases', 'Disease', (86, 95))
58474	20833336	In an effort to model the disease, mice were generated that harbored a targeted deletion of this gene, resulting in dysregulated PKA activity.	('dysregulated PKA activity', 'MPA', (116, 141))	('rat', 'Species', '10116', (49, 52))	('deletion', 'Var', (80, 88))	('mice', 'Species', '10090', (35, 39))
58475	20833336	Prkar1a-/- mice died early in embryogenesis, but Prkar1a+/- mice survived and exhibited tumor formation in a range of cAMP-responsive tissues.	('cAMP', 'Chemical', 'MESH:D000242', (118, 122))	('Prkar1a+/-', 'Var', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('exhibited', 'Reg', (78, 87))	('mice', 'Species', '10090', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mice', 'Species', '10090', (60, 64))	('tumor', 'Disease', (88, 93))
58477	20833336	In terms of morbidity, most mutant mice required early euthanasia due to rapid progression of solid tumors found on the head, limbs, or rump.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutant', 'Var', (28, 34))	('solid tumors', 'Disease', 'MESH:D009369', (94, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('mice', 'Species', '10090', (35, 39))	('solid tumors', 'Disease', (94, 106))
58494	20833336	Pituitary tumors were found in about 50% of pitKO mice at 18 months of age, compared to less than 20% in control animals.	('Pituitary tumors', 'Disease', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('pitKO', 'Var', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('mice', 'Species', '10090', (50, 54))	('Pituitary tumors', 'Disease', 'MESH:D010911', (0, 16))
58499	20833336	Nearly 80% of the TEC3KO animals developed solid myxomatous lesions, which bore similarity to those seen in Prkar1a+/- animals, either uni- or bilaterally on the face by 10 months of age.	('TEC3KO', 'Var', (18, 24))	('myxomatous lesions', 'Phenotype', 'HP:0031461', (49, 67))	('solid myxomatous lesions', 'Disease', (43, 67))	('solid myxomatous lesions', 'Phenotype', 'HP:0031461', (43, 67))	('solid myxomatous lesions', 'Disease', 'MESH:D008945', (43, 67))
58504	20833336	Inactivating mutations in the PTEN gene have been identified as the cause of CD, and PTEN deletions have been identified in sporadic tumors of these tissues as well.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('sporadic tumors', 'Disease', (124, 139))	('identified', 'Reg', (110, 120))	('cause', 'Reg', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Inactivating mutations', 'Var', (0, 22))	('PTEN', 'Gene', '19211', (30, 34))	('sporadic tumors', 'Disease', 'MESH:D009369', (124, 139))	('PTEN', 'Gene', '19211', (85, 89))	('PTEN', 'Gene', (85, 89))	('PTEN', 'Gene', (30, 34))	('deletions', 'Var', (90, 99))
58515	20833336	It was also found that tumors formed in these mice were accompanied by LOH of the Pten allele, suggesting that in order to facilitate tumor formation, a secondary inactivating event must occur to effectively delete Pten in these tissues.	('Pten', 'Gene', (215, 219))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('Pten', 'Gene', '19211', (215, 219))	('delete', 'Var', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('Pten', 'Gene', (82, 86))	('Pten', 'Gene', '19211', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', (134, 139))
58518	20833336	This suggested that genetic background or type of Pten mutation may play a role in the variety of tumor spectrum seen in the mice as well as in human CD patients.	('Pten', 'Gene', (50, 54))	('Pten', 'Gene', '19211', (50, 54))	('human', 'Species', '9606', (144, 149))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mice', 'Species', '10090', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutation', 'Var', (55, 63))	('tumor', 'Disease', (98, 103))
58519	20833336	The question of genetic background has been addressed, and it was shown that different mutations had no effect on tumor burden/onset in the same genetic background.	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutations', 'Var', (87, 96))
58520	20833336	However, the same mutation in differing genetic backgrounds showed a large difference in tumor incidence.	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutation', 'Var', (18, 26))	('tumor', 'Disease', (89, 94))
58524	20833336	Further supporting the activation of Akt as the mechanism of tumorgenesis in these tissues, mice deficient for both Pten and Akt1 showed decreased tumor burden as compared with mice deficient for Pten alone, indicating that Pten's effects occur through activation of Akt.	('Pten', 'Gene', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Pten', 'Gene', '19211', (116, 120))	('mice', 'Species', '10090', (92, 96))	('tumor', 'Disease', (147, 152))	('Akt', 'Gene', (125, 128))	('Akt', 'Gene', (37, 40))	('Pten', 'Gene', (224, 228))	('Akt', 'Gene', (267, 270))	('decreased tumor', 'Disease', 'MESH:D009369', (137, 152))	('Pten', 'Gene', '19211', (224, 228))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Akt', 'Gene', '11651', (125, 128))	('Akt', 'Gene', '11651', (267, 270))	('Akt', 'Gene', '11651', (37, 40))	('Akt1', 'Gene', (125, 129))	('deficient', 'Var', (97, 106))	('mice', 'Species', '10090', (177, 181))	('decreased tumor', 'Disease', (137, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('Akt1', 'Gene', '11651', (125, 129))	('Pten', 'Gene', (196, 200))	('Pten', 'Gene', '19211', (196, 200))	('tumor', 'Disease', (61, 66))
58528	20833336	Of note, invasive tumors were not observed in these animals, indicating that although deletion of Pten lays the groundwork for thyroid neoplasia and hyperproliferation, additional genetic changes must occur in order to potentiate the development of true malignant cancers.	('malignant cancers', 'Disease', 'MESH:D009369', (254, 271))	('thyroid neoplasia', 'Phenotype', 'HP:0100031', (127, 144))	('potentiate', 'PosReg', (219, 229))	('Pten', 'Gene', (98, 102))	('invasive tumors', 'Disease', (9, 24))	('thyroid neoplasia', 'Disease', 'MESH:D013959', (127, 144))	('Pten', 'Gene', '19211', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('malignant cancers', 'Disease', (254, 271))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('neoplasia', 'Phenotype', 'HP:0002664', (135, 144))	('invasive tumors', 'Disease', 'MESH:D009369', (9, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('rat', 'Species', '10116', (161, 164))	('thyroid neoplasia', 'Disease', (127, 144))	('deletion', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
58530	20833336	Mice harboring mutations of the thyroid hormone receptor beta (TRbeta) develop follicular thyroid cancer, but when loss of Pten accompanied the TRbeta mutation, the tumor phenotype was significantly enhanced and survival decreased.	('TRbeta', 'Gene', (63, 69))	('TRbeta', 'Gene', '21834', (63, 69))	('Pten', 'Gene', (123, 127))	('Pten', 'Gene', '19211', (123, 127))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('thyroid cancer', 'Disease', (90, 104))	('loss', 'NegReg', (115, 119))	('enhanced', 'PosReg', (199, 207))	('mutations', 'Var', (15, 24))	('decreased', 'NegReg', (221, 230))	('Rb', 'Phenotype', 'HP:0009919', (145, 147))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (79, 104))	('mutation', 'Var', (151, 159))	('thyroid hormone receptor beta', 'Gene', (32, 61))	('thyroid cancer', 'Disease', 'MESH:D013964', (90, 104))	('TRbeta', 'Gene', (144, 150))	('TRbeta', 'Gene', '21834', (144, 150))	('tumor', 'Disease', (165, 170))	('thyroid cancer', 'Phenotype', 'HP:0002890', (90, 104))	('Rb', 'Phenotype', 'HP:0009919', (64, 66))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('thyroid hormone receptor beta', 'Gene', '21834', (32, 61))
58533	20833336	Genetic analysis of sporadic papillary thyroid cancer (PTC) demonstrated fusion of the RET proto-oncogene to other sequences, which came to be known as PTC genes.	('PTC', 'Gene', '19713', (55, 58))	('PTC', 'Gene', (152, 155))	('rat', 'Species', '10116', (67, 70))	('PTC', 'Phenotype', 'HP:0002895', (152, 155))	('thyroid cancer', 'Phenotype', 'HP:0002890', (39, 53))	('PTC', 'Gene', '19713', (152, 155))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (29, 53))	('sporadic papillary thyroid cancer', 'Disease', (20, 53))	('sporadic papillary thyroid cancer', 'Disease', 'MESH:D000077273', (20, 53))	('PTC', 'Gene', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('fusion', 'Var', (73, 79))	('PTC', 'Phenotype', 'HP:0002895', (55, 58))
58544	20833336	Finally, aberrant TSH signaling plays an important role in benign thyroid tumorigenesis, including in hyperfunctioning models.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('aberrant', 'Var', (9, 17))	('TSH', 'Protein', (18, 21))
58546	20833336	This pathway has been explored in transgenic mice by ectopically expressing the Adenosine A2 receptor in the thyroid, by expressing a mutated (activated) form of the Gsalpha subunit, or by expressing the cholera toxin A1 subunit.	('mutated', 'Var', (134, 141))	('Gsalpha', 'Gene', '14683', (166, 173))	('Gsalpha', 'Gene', (166, 173))	('transgenic mice', 'Species', '10090', (34, 49))
58550	20833336	Activating GNAS1 mutations are observed in over 25% of pituitary tumors, although no mouse model of this phenomenon has yet been observed.	('Activating', 'PosReg', (0, 10))	('mouse', 'Species', '10090', (85, 90))	('pituitary tumors', 'Disease', 'MESH:D010911', (55, 71))	('GNAS1', 'Gene', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('pituitary tumors', 'Disease', (55, 71))	('GNAS1', 'Gene', '14683', (11, 16))	('mutations', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
58553	20833336	A mouse model of PTTG overexpression targeted to the pituitary by the alpha-glycoprotein subunit promoter showed hyperplasia of pituitary lineages where the transgene was expressed, an effect which was enhanced by loss of the Rb gene.	('hyperplasia', 'Disease', 'MESH:D006965', (113, 124))	('PTTG', 'Gene', '30939', (17, 21))	('PTTG', 'Gene', (17, 21))	('pituitary lineages', 'CPA', (128, 146))	('hyperplasia', 'Disease', (113, 124))	('Rb', 'Phenotype', 'HP:0009919', (226, 228))	('loss', 'Var', (214, 218))	('mouse', 'Species', '10090', (2, 7))
58554	20833336	It was recently reported that mutations in the AIP gene predispose to familial pituitary tumors.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('predispose', 'Reg', (56, 66))	('AIP', 'Gene', '11632', (47, 50))	('familial pituitary tumors', 'Disease', (70, 95))	('familial pituitary tumors', 'Disease', 'MESH:D010911', (70, 95))	('AIP', 'Gene', (47, 50))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
58563	20833336	Although mutations in the phosphodiesterase genes PDE11A and PDE8B and beta-catenin appear to cause adrenal hyperplasia and/or tumors in humans , the corresponding mouse phenotype has not (yet) been described.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('phosphodiesterase', 'Gene', '50940;241489', (26, 43))	('PDE8B', 'Gene', '8622', (61, 66))	('mouse', 'Species', '10090', (164, 169))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (9, 18))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (100, 119))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (100, 119))	('phosphodiesterase', 'Gene', (26, 43))	('humans', 'Species', '9606', (137, 143))	('cause', 'Reg', (94, 99))	('PDE11A', 'Gene', '50940', (50, 56))	('PDE11A', 'Gene', (50, 56))	('adrenal hyperplasia', 'Disease', (100, 119))	('PDE8B', 'Gene', (61, 66))
58568	20833336	Moreover, loss of E2F1 and E2F4, transcription factors inhibited by Rb, interfered with the pituitary tumor incidence that occurred in Rb-deficient mice.	('loss', 'Var', (10, 14))	('E2F1', 'Gene', (18, 22))	('pituitary tumor', 'Disease', (92, 107))	('interfered', 'NegReg', (72, 82))	('Rb', 'Phenotype', 'HP:0009919', (68, 70))	('pituitary tumor', 'Disease', 'MESH:D010911', (92, 107))	('Rb', 'Phenotype', 'HP:0009919', (135, 137))	('mice', 'Species', '10090', (148, 152))	('E2F4', 'Gene', '104394', (27, 31))	('E2F1', 'Gene', '13555', (18, 22))	('E2F4', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
58571	20833336	Previous reports showed a series of novel phenotypes including increased body size, multiple organ hyperplasia, and pituitary tumors in mice deficient for p27KIP1.	('hyperplasia', 'Disease', 'MESH:D006965', (99, 110))	('mice', 'Species', '10090', (136, 140))	('increased', 'PosReg', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('pituitary tumors', 'Disease', (116, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('hyperplasia', 'Disease', (99, 110))	('p27KIP1', 'Var', (155, 162))	('deficient', 'Var', (141, 150))	('pituitary tumors', 'Disease', 'MESH:D010911', (116, 132))	('body size', 'CPA', (73, 82))
58572	20833336	Nevertheless, Rb-null and p27KIP1-null pituitary tumors were significantly different in both their genetic and pathological characteristics.	('pituitary tumors', 'Disease', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('p27KIP1-null', 'Var', (26, 38))	('Rb', 'Phenotype', 'HP:0009919', (14, 16))	('Rb-null', 'Var', (14, 21))	('pituitary tumors', 'Disease', 'MESH:D010911', (39, 55))
58573	20833336	More recently, germline mutations in CDKN1B, which encodes the p27KIP1 protein, have been reported to predispose human patients to the development of pituitary tumors.	('pituitary tumors', 'Disease', (150, 166))	('predispose', 'Reg', (102, 112))	('CDKN1B', 'Gene', '1027', (37, 43))	('patients', 'Species', '9606', (119, 127))	('pituitary tumors', 'Disease', 'MESH:D010911', (150, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('CDKN1B', 'Gene', (37, 43))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('germline', 'Var', (15, 23))	('human', 'Species', '9606', (113, 118))
58576	20833336	The implication of the cell cycle regulators in pituitary tumorigenesis is validated by the mouse models discussed above; however, the results from the combined deletions of some of these mutations in the mouse may put forward a more convoluted molecular network.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('deletions', 'Var', (161, 170))	('mouse', 'Species', '10090', (92, 97))	('pituitary tumor', 'Disease', (48, 63))	('mouse', 'Species', '10090', (205, 210))	('mutations', 'Var', (188, 197))	('pituitary tumor', 'Disease', 'MESH:D010911', (48, 63))
58577	20833336	For example, the combination of Rb and p27KIP1 deletions accelerated the formation of pituitary tumors in mice, suggesting cooperation of these pathways in pituitary tumorigenesis.	('Rb', 'Phenotype', 'HP:0009919', (32, 34))	('pituitary tumor', 'Disease', 'MESH:D010911', (156, 171))	('rat', 'Species', '10116', (63, 66))	('deletions', 'Var', (47, 56))	('mice', 'Species', '10090', (106, 110))	('pituitary tumors', 'Disease', 'MESH:D010911', (86, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('accelerated', 'PosReg', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('pituitary tumors', 'Disease', (86, 102))	('p27KIP1 deletions', 'Var', (39, 56))	('pituitary tumor', 'Disease', (156, 171))	('pituitary tumor', 'Disease', 'MESH:D010911', (86, 101))	('rat', 'Species', '10116', (128, 131))	('formation of', 'CPA', (73, 85))
58579	20833336	Similarly, the simultaneous loss of both p27KIP1 and p18INK4c exaggerated the phenotype caused by deficiency of either gene alone, indicating that these two genes mediate two separate pathways to collaboratively regulate cell growth.	('rat', 'Species', '10116', (179, 182))	('phenotype', 'MPA', (78, 87))	('p27KIP1', 'Var', (41, 48))	('p18INK4c', 'Gene', '12580', (53, 61))	('rat', 'Species', '10116', (68, 71))	('p18INK4c', 'Gene', (53, 61))	('exaggerated', 'PosReg', (62, 73))	('rat', 'Species', '10116', (203, 206))	('loss', 'NegReg', (28, 32))
58580	20833336	Additionally, growth suppression by p18INK4c combined with the wild-type Rb function may suggest that Rb is the common theme of both p27KIP1- and p18INK4c-mediated tumor suppression in the pituitary  Similar to the models of CD, the interpretation of the findings in these pituitary tumor models may be complicated by strain-specific effects.	('tumor', 'Disease', (164, 169))	('p27KIP1-', 'Var', (133, 141))	('pituitary tumor', 'Disease', (273, 288))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('Rb', 'Phenotype', 'HP:0009919', (73, 75))	('p18INK4c', 'Gene', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('pituitary tumor', 'Disease', 'MESH:D010911', (273, 288))	('Rb', 'Phenotype', 'HP:0009919', (102, 104))	('tumor', 'Disease', (283, 288))	('p18INK4c', 'Gene', (36, 44))	('p18INK4c', 'Gene', '12580', (146, 154))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('growth', 'MPA', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('p18INK4c', 'Gene', '12580', (36, 44))
58581	20833336	It has been reported that the 129Sv background significantly enhanced both the initiation and progression of tumorigenesis in the intermediate lobe of the pituitary in Rb+/- mice, while a Rb-null mutation bred in to the C57 background resulted in highly-penetrant tumor formation in the anterior lobe of the pituitary.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('129Sv background', 'Var', (30, 46))	('129Sv', 'Species', '10090', (30, 35))	('enhanced', 'PosReg', (61, 69))	('mice', 'Species', '10090', (174, 178))	('tumor', 'Disease', (264, 269))	('Rb', 'Phenotype', 'HP:0009919', (188, 190))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('Rb', 'Phenotype', 'HP:0009919', (168, 170))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', (109, 114))
58582	20833336	Furthermore, the 129S4 background decreased the latency of pituitary tumors and survival time in p27KIP1-deficient mice.	('pituitary tumors', 'Disease', 'MESH:D010911', (59, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('decreased', 'NegReg', (34, 43))	('latency', 'MPA', (48, 55))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('129S4', 'Var', (17, 22))	('pituitary tumors', 'Disease', (59, 75))	('survival time', 'CPA', (80, 93))	('mice', 'Species', '10090', (115, 119))
58585	20833336	These models should provide valuable models for the future as they allow researchers to identify downstream targets affected by these tumorigenic mutations.	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('mutations', 'Var', (146, 155))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
58620	33383673	Consequently, it was proposed that the blockade of PD-1/PD-L1 interaction could be a means to induce the reacquisition of antitumour activity by T cells.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('interaction', 'Interaction', (62, 73))	('blockade', 'Var', (39, 47))	('PD-1/PD-L1', 'Gene', (51, 61))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))
58637	33383673	Anti-PD-1 and anti-PD-L1 monoclonal antibodies, such as avelumab, are supposed to boost up and enhance said immune response.	('anti-PD-L1', 'Var', (14, 24))	('avelumab', 'Chemical', 'MESH:C000609138', (56, 64))	('boost', 'PosReg', (82, 87))	('Anti-PD-1', 'Var', (0, 9))	('immune response', 'CPA', (108, 123))	('enhance', 'PosReg', (95, 102))
58670	33383673	According to the protocol, participants aged 18 years and older with histologically confirmed unresectable/metastatic adrenocortical carcinoma (ACC), or unresectable malignant PHEO/PGL, are grouped in five different cohorts and receive EO2401 in combination with nivolumab at standard dose.	('nivolumab', 'Chemical', 'MESH:D000077594', (263, 272))	('EO2401', 'Var', (236, 242))	('participants', 'Species', '9606', (27, 39))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (118, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('EO2401', 'Chemical', '-', (236, 242))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (118, 142))	('adrenocortical carcinoma', 'Disease', (118, 142))
58671	33383673	The recommended dose of EO2401 is to be found in Cohort 1 and will be administered to the other cohorts of patients, respectively composed by previously treated ACCs, previously untreated ACCs, previously treated PHEO/PGL, and previously untreated PHEO/PGL.	('ACCs', 'Gene', (161, 165))	('ACCs', 'Gene', '84680', (161, 165))	('EO2401', 'Var', (24, 30))	('EO2401', 'Chemical', '-', (24, 30))	('ACCs', 'Gene', '84680', (188, 192))	('patients', 'Species', '9606', (107, 115))	('ACCs', 'Gene', (188, 192))
58725	33383673	As a final point, we should consider that PHEO/PGL patients harboring specific mutations might benefit the most from ICIs therapy.	('benefit', 'PosReg', (95, 102))	('patients', 'Species', '9606', (51, 59))	('mutations', 'Var', (79, 88))
58727	33383673	These mutations are classified in three clinically-relevant subgroups: pseudohypoxia, kinase signaling, and Wnt signaling.	('hypoxia', 'Disease', (77, 84))	('kinase signaling', 'Disease', (86, 102))	('Wnt signaling', 'Disease', (108, 121))	('mutations', 'Var', (6, 15))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))
58728	33383673	The pseudohypoxia subgroup includes mutations in a highly significant number of genes, including succinate subunits A, B, C, D, fumarate hydratase, and von Hippel-Lindau tumour suppressor gene, encoding for proteins involved in the cell response induced by conditions of hypoxia.	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (152, 176))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('mutations', 'Var', (36, 45))	('hypoxia', 'Disease', 'MESH:D000860', (271, 278))	('von Hippel-Lindau tumour', 'Disease', (152, 176))	('hypoxia', 'Disease', 'MESH:D000860', (10, 17))	('succinate subunits A', 'Gene', (97, 117))	('hypoxia', 'Disease', (271, 278))	('hypoxia', 'Disease', (10, 17))	('fumarate hydratase', 'Gene', (128, 146))
58729	33383673	Of note, mutations in this subgroup of genes, although acting at different metabolic levels and on different substrates, ultimately cause the stabilization of the hypoxia-inducible factor (HIF).	('stabilization', 'MPA', (142, 155))	('mutations', 'Var', (9, 18))	('hypoxia', 'Disease', 'MESH:D000860', (163, 170))	('cause', 'Reg', (132, 137))	('hypoxia', 'Disease', (163, 170))
58731	33383673	Thus, the engagement of PD-1 signaling represents a novel pathway of T-cell suppression promoted by pseudohypoxia, and provides the rational basis for a more effective use of ICIs in the specific subgroup of PHEO/PGL patients bearing the above mentioned pseudohypoxia-related gene mutations.	('T-cell suppression', 'CPA', (69, 87))	('hypoxia', 'Disease', 'MESH:D000860', (260, 267))	('hypoxia', 'Disease', (260, 267))	('hypoxia', 'Disease', (106, 113))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('mutations', 'Var', (281, 290))	('patients', 'Species', '9606', (217, 225))
58783	32483162	In fact, cosyntropin produces cortisol and adrenaline by stimulating the adrenal glands and has traditionally only been used to diagnose and resolve adrenal gland problems (e.g., Addison's disease, adrenal insufficiency caused by the use of steroids or from tumors).	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors', 'Disease', (258, 264))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (198, 219))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (198, 219))	("Addison's disease", 'Disease', 'MESH:D000224', (179, 196))	('cortisol', 'Chemical', 'MESH:D006854', (30, 38))	('steroids', 'Chemical', 'MESH:D013256', (241, 249))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('adrenal gland problems', 'Disease', (149, 171))	('adrenal gland problems', 'Phenotype', 'HP:0000834', (149, 171))	("Addison's disease", 'Phenotype', 'HP:0008207', (179, 196))	('adrenal insufficiency', 'Disease', (198, 219))	('cosyntropin', 'Var', (9, 20))	('adrenaline', 'Chemical', 'MESH:D004837', (43, 53))	("Addison's disease", 'Disease', (179, 196))	('stimulating', 'PosReg', (57, 68))
58784	32483162	On the other hand, mitotane, which is the first known therapeutic option for ACC patients, causes adrenal insufficiency and, due to its adverse effects on adrenocortical cells, often requires hydrocortisone replacement therapy (https://clinicaltrials.gov/).	('mitotane', 'Var', (19, 27))	('mitotane', 'Chemical', 'MESH:D008939', (19, 27))	('causes', 'Reg', (91, 97))	('requires', 'Reg', (183, 191))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (98, 119))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (98, 119))	('patients', 'Species', '9606', (81, 89))	('adrenal insufficiency', 'Disease', (98, 119))	('hydrocortisone', 'Chemical', 'MESH:D006854', (192, 206))
58801	32483162	MC2R and MRAP are mainly involved in the adrenal cortex, and it has been proven that patients with cortisol deficiency have mutant lesions in MC2R and MRAP [11].	('cortisol deficiency', 'Disease', (99, 118))	('MC2R', 'Gene', (142, 146))	('MRAP', 'Gene', (151, 155))	('MC2R', 'Gene', '4158', (0, 4))	('mutant lesions', 'Var', (124, 138))	('MRAP', 'Gene', '56246', (9, 13))	('MC2R', 'Gene', '4158', (142, 146))	('patients', 'Species', '9606', (85, 93))	('MRAP', 'Gene', '56246', (151, 155))	('MRAP', 'Gene', (9, 13))	('cortisol deficiency', 'Disease', 'MESH:C535280', (99, 118))	('MC2R', 'Gene', (0, 4))	('cortisol deficiency', 'Phenotype', 'HP:0008163', (99, 118))
58811	32483162	As mentioned in Table 2, DT-Hybrid predicted only two novel targets associated with ACC: hsa:6409 (SEN2) and hsa:595 (CCND1); no other relations were predicted by DT-Hybrid for ACC and there is no overlap between the predictions of DT-Hybrid and Heter-LP.	('hsa:595', 'Var', (109, 116))	('CCND1', 'Gene', (118, 123))	('hsa', 'Chemical', 'MESH:D006585', (89, 92))	('hsa', 'Chemical', 'MESH:D006585', (109, 112))	('DT', 'Chemical', 'MESH:D013936', (25, 27))	('SEN2', 'Gene', (99, 103))	('ACC', 'Disease', (84, 87))	('SEN2', 'Gene', '6409', (99, 103))	('CCND1', 'Gene', '595', (118, 123))	('DT', 'Chemical', 'MESH:D013936', (163, 165))	('Heter-LP', 'Chemical', '-', (246, 254))	('DT', 'Chemical', 'MESH:D013936', (232, 234))
58837	30770352	We show that CIMP-high ACC is characterized by upregulation of cell cycle and DNA damage response programs, and identify that hypermethylation and silencing of G0S2 distinguishes this subgroup.	('G0S2', 'Gene', (160, 164))	('ACC', 'Gene', '31', (23, 26))	('silencing', 'MPA', (147, 156))	('DNA damage response programs', 'Pathway', (78, 106))	('upregulation', 'PosReg', (47, 59))	('cell', 'CPA', (63, 67))	('ACC', 'Phenotype', 'HP:0006744', (23, 26))	('CIMP', 'Chemical', '-', (13, 17))	('G0S2', 'Gene', '50486', (160, 164))	('CIMP-high', 'Var', (13, 22))	('hypermethylation', 'Var', (126, 142))	('ACC', 'Gene', (23, 26))
58838	30770352	We confirmed G0S2 hypermethylation and silencing is exclusive to 40% of ACC, and independently predicts shorter disease-free and overall survival (median 14 and 17 months, respectively).	('ACC', 'Phenotype', 'HP:0006744', (72, 75))	('G0S2', 'Gene', '50486', (13, 17))	('hypermethylation', 'Var', (18, 34))	('G0S2', 'Gene', (13, 17))	('shorter', 'NegReg', (104, 111))	('ACC', 'Gene', (72, 75))	('overall survival', 'CPA', (129, 145))	('disease-free', 'CPA', (112, 124))	('silencing', 'MPA', (39, 48))	('ACC', 'Gene', '31', (72, 75))
58839	30770352	Finally, G0S2 methylation combined with validated molecular markers (BUB1B-PINK1) stratifies ACC into three groups, with uniformly favorable, intermediate, and uniformly dismal outcomes.	('G0S2', 'Gene', (9, 13))	('BUB1B', 'Gene', '701', (69, 74))	('ACC', 'Phenotype', 'HP:0006744', (93, 96))	('BUB1B', 'Gene', (69, 74))	('methylation', 'Var', (14, 25))	('ACC', 'Gene', (93, 96))	('PINK1', 'Gene', '65018', (75, 80))	('G0S2', 'Gene', '50486', (9, 13))	('ACC', 'Gene', '31', (93, 96))	('PINK1', 'Gene', (75, 80))
58840	30770352	G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal ACC, amenable to targeted assessment using routine molecular diagnostics.	('G0S2', 'Gene', '50486', (0, 4))	('ACC', 'Gene', (66, 69))	('ACC', 'Gene', '31', (66, 69))	('G0S2', 'Gene', (0, 4))	('hypermethylation', 'Var', (5, 21))	('ACC', 'Phenotype', 'HP:0006744', (66, 69))
58841	30770352	Assessing G0S2 methylation is straightforward, feasible for clinical decision-making, and will enable the direction of efficacious adjuvant therapies for patients with aggressive ACC.	('methylation', 'Var', (15, 26))	('ACC', 'Gene', (179, 182))	('G0S2', 'Gene', '50486', (10, 14))	('patients', 'Species', '9606', (154, 162))	('G0S2', 'Gene', (10, 14))	('ACC', 'Gene', '31', (179, 182))	('ACC', 'Phenotype', 'HP:0006744', (179, 182))
58846	30770352	Retrospective studies suggest adjuvant mitotane prolongs recurrence free survival, but its efficacy is limited by its poor pharmacokinetic properties and dose-limiting toxicities.	('mitotane', 'Var', (39, 47))	('mitotane', 'Chemical', 'MESH:D008939', (39, 47))	('toxicities', 'Disease', 'MESH:D064420', (168, 178))	('recurrence free survival', 'CPA', (57, 81))	('toxicities', 'Disease', (168, 178))	('prolongs', 'PosReg', (48, 56))
58854	30770352	Recent studies have implicated aberrant epigenetic patterning in ACC pathogenesis, highlighting that aggressive carcinomas bear widespread promoter CpG island hypermethylation.	('hypermethylation', 'Var', (159, 175))	('ACC', 'Gene', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('ACC', 'Gene', '31', (65, 68))	('aggressive carcinomas', 'Disease', 'MESH:D009369', (101, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('aggressive carcinomas', 'Disease', (101, 122))	('ACC', 'Phenotype', 'HP:0006744', (65, 68))
58861	30770352	Here, we present a new analysis of ACC-TCGA data in which we demonstrate that CIMP-high ACC is a unique, rapidly recurrent ACC molecular subtype, bearing upregulation of cell cycle- and DNA damage-associated cellular programs.	('ACC', 'Gene', '31', (88, 91))	('CIMP-high', 'Var', (78, 87))	('ACC', 'Gene', (35, 38))	('ACC', 'Gene', '31', (123, 126))	('CIMP', 'Chemical', '-', (78, 82))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('cell cycle-', 'CPA', (170, 181))	('ACC', 'Phenotype', 'HP:0006744', (123, 126))	('ACC', 'Gene', '31', (35, 38))	('upregulation', 'PosReg', (154, 166))	('ACC', 'Gene', (88, 91))	('ACC', 'Gene', (123, 126))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))
58862	30770352	We identify that uniform hypermethylation and silencing of the gene G0S2 (G0/G1 Switch 2) is largely exclusive to CIMP-high ACC.	('G0S2', 'Gene', '50486', (68, 72))	('hypermethylation', 'Var', (25, 41))	('G0S2', 'Gene', (68, 72))	('CIMP', 'Chemical', '-', (114, 118))	('ACC', 'Gene', (124, 127))	('silencing', 'MPA', (46, 55))	('ACC', 'Gene', '31', (124, 127))	('G0/G1 Switch 2', 'Gene', (74, 88))	('ACC', 'Phenotype', 'HP:0006744', (124, 127))	('G0/G1 Switch 2', 'Gene', '50486', (74, 88))
58863	30770352	We show in an independent cohort that targeted assessment of G0S2 methylation using an overnight assay independently identifies a subgroup of ACC patients with rapidly progressive or fatal disease course.	('ACC', 'Phenotype', 'HP:0006744', (142, 145))	('G0S2', 'Gene', '50486', (61, 65))	('G0S2', 'Gene', (61, 65))	('ACC', 'Gene', (142, 145))	('methylation', 'Var', (66, 77))	('ACC', 'Gene', '31', (142, 145))	('patients', 'Species', '9606', (146, 154))
58868	30770352	We used limma to nominate differentially expressed genes (Benjamini-Hochberg FDR-corrected p-value<0.05) between CIMP-high and non CIMP-high ACC.	('CIMP', 'Chemical', '-', (131, 135))	('CIMP', 'Chemical', '-', (113, 117))	('ACC', 'Gene', (141, 144))	('CIMP-high', 'Var', (113, 122))	('ACC', 'Gene', '31', (141, 144))	('ACC', 'Phenotype', 'HP:0006744', (141, 144))
58888	30770352	Quantitative real-time polymerase chain reaction (qPCR) was performed in the QuantStudio 3 Real-Time PCR System (Applied Biosciences/Thermo Fisher Scientific, USA; A28136), using TaqMan Fast Advanced Master Mix (Applied Biosciences/Thermo Fisher Scientific, USA; 4444557) and FAM-MGB-labeled TaqMan Gene Expression Assays (Applied Biosciences/Thermo Fisher Scientific, USA) to evaluate expression of G0S2 (Hs00274783_s1), BUB1B (Hs01084828_m1), PINK1 (Hs00260868_m1), and housekeeping gene GUSB (Hs00939627_m1).	('BUB1B', 'Gene', '701', (422, 427))	('PINK1', 'Gene', (445, 450))	('BUB1B', 'Gene', (422, 427))	('Hs00939627_m1', 'Var', (496, 509))	('Hs01084828_m1', 'Var', (429, 442))	('GUSB', 'Gene', (490, 494))	('Hs00260868_m1', 'Var', (452, 465))	('GUSB', 'Gene', '2990', (490, 494))	('G0S2', 'Gene', '50486', (400, 404))	('PINK1', 'Gene', '65018', (445, 450))	('G0S2', 'Gene', (400, 404))	('Hs00274783_s1', 'Var', (406, 419))
58907	30770352	We performed gene ontology analysis on differentially expressed genes and identified that CIMP-high ACC exhibited transcriptional upregulation of numerous cell cycle- and DNA damage-associated biological processes, consistent with the enrichment of cell cycle-activating somatic alterations and chromosomal "noisiness" in this subgroup (Figure 1C, left panel).	('cell cycle-', 'CPA', (155, 166))	('CIMP', 'Chemical', '-', (90, 94))	('ACC', 'Gene', (100, 103))	('ACC', 'Gene', '31', (100, 103))	('upregulation', 'PosReg', (130, 142))	('ACC', 'Phenotype', 'HP:0006744', (100, 103))	('CIMP-high', 'Var', (90, 99))
58909	30770352	The convergence of this unique transcriptional program, somatic alterations targeting the cell cycle, and "noisy" chromosomal landscape in CIMP-high carcinomas demonstrates that CIMP-high status defines a distinct molecular subtype of ACC characterized by rapidly recurrent or fatal disease course.	('CIMP-high status', 'Var', (178, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('ACC', 'Gene', '31', (235, 238))	('CIMP', 'Chemical', '-', (139, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('CIMP-high carcinomas', 'Disease', 'MESH:D009369', (139, 159))	('ACC', 'Phenotype', 'HP:0006744', (235, 238))	('ACC', 'Gene', (235, 238))	('CIMP-high carcinomas', 'Disease', (139, 159))	('CIMP', 'Chemical', '-', (178, 182))
58911	30770352	We sought to identify a single biomarker with strong discriminatory power between CIMP-high and non-CIMP-high ACC, straightforward to measure and interpret without reference samples or extensive data manipulation.	('ACC', 'Gene', '31', (110, 113))	('CIMP-high', 'Var', (82, 91))	('ACC', 'Gene', (110, 113))	('CIMP', 'Chemical', '-', (82, 86))	('CIMP', 'Chemical', '-', (100, 104))	('ACC', 'Phenotype', 'HP:0006744', (110, 113))
58916	30770352	These results suggested G0S2 is silenced by hypermethylation in a subgroup of ACC as reported in a smaller ACC cohort, and that low G0S2 expression and hypermethylation predict CIMP-high status.	('CIMP-high status', 'Disease', (177, 193))	('expression', 'MPA', (137, 147))	('ACC', 'Phenotype', 'HP:0006744', (107, 110))	('silenced', 'NegReg', (32, 40))	('G0S2', 'Gene', '50486', (24, 28))	('ACC', 'Gene', (107, 110))	('hypermethylation', 'Var', (152, 168))	('CIMP', 'Chemical', '-', (177, 181))	('ACC', 'Gene', '31', (78, 81))	('G0S2', 'Gene', (24, 28))	('G0S2', 'Gene', '50486', (132, 136))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('hypermethylation', 'Var', (44, 60))	('low', 'NegReg', (128, 131))	('ACC', 'Gene', '31', (107, 110))	('G0S2', 'Gene', (132, 136))	('ACC', 'Gene', (78, 81))
58924	30770352	This analysis identified two distinct clusters of samples: one cluster with samples bearing either no or low levels of G0S2 methylation ("G0S2 Unmethylated") corresponding to 2/3 of ACC-TCGA, and one with samples bearing high levels of uniform or heterogeneous G0S2 methylation ("G0S2 Methylated") corresponding to 1/3 of ACC-TCGA.	('ACC', 'Gene', (322, 325))	('G0S2', 'Gene', (280, 284))	('G0S2', 'Gene', '50486', (119, 123))	('ACC', 'Gene', '31', (322, 325))	('G0S2', 'Gene', (119, 123))	('ACC', 'Phenotype', 'HP:0006744', (182, 185))	('G0S2', 'Gene', '50486', (138, 142))	('G0S2', 'Gene', '50486', (261, 265))	('ACC', 'Gene', '31', (182, 185))	('methylation', 'MPA', (266, 277))	('ACC', 'Phenotype', 'HP:0006744', (322, 325))	('G0S2', 'Gene', '50486', (280, 284))	('G0S2', 'Gene', (138, 142))	('G0S2', 'Gene', (261, 265))	('methylation', 'Var', (124, 135))	('ACC', 'Gene', (182, 185))
58927	30770352	At average G0S2 methylation >0.5200819 (measured by 450k array), we can predict assignment to CIMP-high using G0S2 methylation alone at 94.87% accuracy, with 94.74% sensitivity, 94.92% specificity, 85.71% positive predictive value and 98.25% negative predictive value.	('CIMP', 'Chemical', '-', (94, 98))	('>0.5200819', 'Var', (28, 38))	('G0S2', 'Gene', '50486', (110, 114))	('G0S2', 'Gene', '50486', (11, 15))	('G0S2', 'Gene', (110, 114))	('G0S2', 'Gene', (11, 15))
58932	30770352	We performed targeted bisulfite sequencing of G0S2 and determined that uniform hypermethylation throughout the locus is pathological, exclusive to a subset of primary ACC and non-primary/recurrent ACC (Figure 3A, Supplementary Table S5).	('G0S2', 'Gene', (46, 50))	('ACC', 'Gene', '31', (197, 200))	('hypermethylation', 'Var', (79, 95))	('ACC', 'Gene', (167, 170))	('bisulfite', 'Chemical', 'MESH:C042345', (22, 31))	('ACC', 'Phenotype', 'HP:0006744', (197, 200))	('ACC', 'Gene', '31', (167, 170))	('G0S2', 'Gene', '50486', (46, 50))	('ACC', 'Gene', (197, 200))	('ACC', 'Phenotype', 'HP:0006744', (167, 170))
58936	30770352	The uniform pattern of G0S2 methylation in ACC-TCGA and our cohort indicated that locus methylation may be accurately measured by methylation-sensitive restriction digestion/qPCR-based methods instead of bisulfite-based approaches.	('G0S2', 'Gene', '50486', (23, 27))	('G0S2', 'Gene', (23, 27))	('ACC', 'Gene', '31', (43, 46))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('methylation', 'Var', (28, 39))	('ACC', 'Gene', (43, 46))	('bisulfite', 'Chemical', 'MESH:C042345', (204, 213))
58938	30770352	EpiTect and targeted bisulfite sequencing were highly concordant (Figure 3B, Supplementary Figure S5C), demonstrating that ACA have no measurable G0S2 methylation, while ACC have a bimodal distribution (Figure 3C; 40% of ACC in FMUSP+UM Primary ACC Cohort have G0S2 hypermethylation).	('ACC', 'Gene', '31', (221, 224))	('ACC', 'Gene', '31', (245, 248))	('ACC', 'Phenotype', 'HP:0006744', (245, 248))	('ACA', 'Phenotype', 'HP:0008256', (123, 126))	('ACC', 'Phenotype', 'HP:0006744', (170, 173))	('ACC', 'Phenotype', 'HP:0006744', (221, 224))	('ACC', 'Gene', (170, 173))	('G0S2', 'Gene', '50486', (146, 150))	('G0S2', 'Gene', '50486', (261, 265))	('bisulfite', 'Chemical', 'MESH:C042345', (21, 30))	('ACC', 'Gene', (221, 224))	('hypermethylation', 'Var', (266, 282))	('ACC', 'Gene', (245, 248))	('G0S2', 'Gene', (261, 265))	('G0S2', 'Gene', (146, 150))	('ACC', 'Gene', '31', (170, 173))
58942	30770352	These analyses demonstrate that EpiTect enables accurate assessment of binary G0S2 methylation status defined by gold-standard targeted bisulfite sequencing, reinforcing its potential clinical utility.	('bisulfite', 'Chemical', 'MESH:C042345', (136, 145))	('G0S2', 'Gene', '50486', (78, 82))	('G0S2', 'Gene', (78, 82))	('methylation', 'Var', (83, 94))
58943	30770352	As in ACC-TCGA, tumors with G0S2 hypermethylation have minimal transcript expression compared to ACA or ACC without G0S2 methylation (Figure 3D).	('G0S2', 'Gene', '50486', (116, 120))	('ACC', 'Gene', (6, 9))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('ACC', 'Gene', '31', (104, 107))	('G0S2', 'Gene', (116, 120))	('G0S2', 'Gene', '50486', (28, 32))	('ACC', 'Gene', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('transcript expression', 'MPA', (63, 84))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('ACC', 'Gene', '31', (6, 9))	('hypermethylation', 'Var', (33, 49))	('ACA', 'Phenotype', 'HP:0008256', (97, 100))	('tumors', 'Disease', (16, 22))	('G0S2', 'Gene', (28, 32))	('ACC', 'Phenotype', 'HP:0006744', (6, 9))	('ACC', 'Phenotype', 'HP:0006744', (104, 107))	('minimal', 'NegReg', (55, 62))
58947	30770352	Together with ACC-TCGA, these data illustrate that uniform G0S2 hypermethylation and silencing is exclusive to a subset of ACC, and that G0S2 methylation can be accurately measured using restriction digest/qPCR-based methods or inferred from G0S2 expression when gDNA is unavailable.	('silencing', 'MPA', (85, 94))	('G0S2', 'Gene', (242, 246))	('ACC', 'Gene', '31', (123, 126))	('G0S2', 'Gene', (137, 141))	('G0S2', 'Gene', '50486', (59, 63))	('ACC', 'Gene', (14, 17))	('ACC', 'Phenotype', 'HP:0006744', (123, 126))	('G0S2', 'Gene', (59, 63))	('hypermethylation', 'Var', (64, 80))	('ACC', 'Gene', '31', (14, 17))	('ACC', 'Phenotype', 'HP:0006744', (14, 17))	('G0S2', 'Gene', '50486', (242, 246))	('ACC', 'Gene', (123, 126))	('G0S2', 'Gene', '50486', (137, 141))
58951	30770352	In striking contrast, stratification by G0S2 methylation (measured by EpiTect or inferred from G0S2 expression when gDNA unavailable) demonstrates that patients with tumors bearing G0S2 hypermethylation homogeneously exhibited rapidly recurrent or fatal disease course (median DFS following R0/RX resection of 14 months and median OS of 17 months; Figure 4B-C).	('G0S2', 'Gene', (40, 44))	('exhibited', 'Reg', (217, 226))	('G0S2', 'Gene', '50486', (181, 185))	('G0S2', 'Gene', '50486', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('G0S2', 'Gene', (95, 99))	('hypermethylation', 'Var', (186, 202))	('G0S2', 'Gene', (181, 185))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Disease', (166, 172))	('G0S2', 'Gene', '50486', (40, 44))	('fatal disease course', 'CPA', (248, 268))	('patients', 'Species', '9606', (152, 160))
58953	30770352	Finally, carcinomas with G0S2 hypermethylation were identified at comparable frequency in patients with localized ACC (ENSAT I-II), localized ACC with locoregional invasion or lymph node involvement (ENSAT III), and ACC with distal metastases (ENSAT IV) at diagnosis (p=0.31, Chi-square test; Figure 4E).	('ACC', 'Phenotype', 'HP:0006744', (114, 117))	('G0S2', 'Gene', '50486', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('carcinomas', 'Disease', 'MESH:D009369', (9, 19))	('carcinomas', 'Phenotype', 'HP:0030731', (9, 19))	('metastases', 'Disease', 'MESH:D009362', (232, 242))	('ACC', 'Phenotype', 'HP:0006744', (216, 219))	('ACC', 'Gene', '31', (114, 117))	('metastases', 'Disease', (232, 242))	('ACC', 'Gene', '31', (216, 219))	('ACC', 'Gene', (114, 117))	('G0S2', 'Gene', (25, 29))	('ACC', 'Phenotype', 'HP:0006744', (142, 145))	('ACC', 'Gene', (216, 219))	('carcinomas', 'Disease', (9, 19))	('ACC', 'Gene', '31', (142, 145))	('hypermethylation', 'Var', (30, 46))	('patients', 'Species', '9606', (90, 98))	('ACC', 'Gene', (142, 145))
58954	30770352	Notably, among 17 ENSAT I-III patients with R0/RX resection and G0S2 hypermethylation, only 1 patient remains disease free at >24 months.	('patient', 'Species', '9606', (30, 37))	('G0S2', 'Gene', (64, 68))	('hypermethylation', 'Var', (69, 85))	('patients', 'Species', '9606', (30, 38))	('patient', 'Species', '9606', (94, 101))	('G0S2', 'Gene', '50486', (64, 68))
58955	30770352	We performed Cox proportional hazards regression analysis to evaluate the significance of G0S2 hypermethylation at predicting recurrence and death compared to other clinical metrics in the FMUSP+UM Primary ACC Cohort (Table 1).	('ACC', 'Phenotype', 'HP:0006744', (206, 209))	('ACC', 'Gene', (206, 209))	('death', 'Disease', 'MESH:D003643', (141, 146))	('ACC', 'Gene', '31', (206, 209))	('G0S2', 'Gene', '50486', (90, 94))	('hypermethylation', 'Var', (95, 111))	('death', 'Disease', (141, 146))	('G0S2', 'Gene', (90, 94))
58958	30770352	G0S2 hypermethylation remained significant in all multivariate models (Table 1).	('G0S2', 'Gene', (0, 4))	('G0S2', 'Gene', '50486', (0, 4))	('hypermethylation', 'Var', (5, 21))
58959	30770352	These observations demonstrate that G0S2 hypermethylation independently predicts rapidly recurrent disease course prior to detection of macroscopic disease spread, and routinely fatal disease course in the setting of disseminated disease.	('predicts', 'Reg', (72, 80))	('hypermethylation', 'Var', (41, 57))	('rapidly recurrent disease', 'Disease', (81, 106))	('G0S2', 'Gene', '50486', (36, 40))	('G0S2', 'Gene', (36, 40))
58960	30770352	Though G0S2 hypermethylation independently predicts uniformly dismal disease course, patients without G0S2 methylation exhibited heterogeneous outcomes (Figure 4B-C).	('G0S2', 'Gene', '50486', (102, 106))	('G0S2', 'Gene', (102, 106))	('predicts', 'Reg', (43, 51))	('hypermethylation', 'Var', (12, 28))	('G0S2', 'Gene', '50486', (7, 11))	('patients', 'Species', '9606', (85, 93))	('G0S2', 'Gene', (7, 11))
58972	30770352	In patients with G0S2 Unmethylated carcinomas, we could now distinguish those who remain disease free and alive (ACC I) from those with history of recurrence and death (ACC II).	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('carcinomas', 'Disease', 'MESH:D009369', (35, 45))	('Unmethylated', 'Var', (22, 34))	('G0S2', 'Gene', '50486', (17, 21))	('ACC', 'Phenotype', 'HP:0006744', (169, 172))	('ACC', 'Gene', '31', (113, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('carcinomas', 'Disease', (35, 45))	('G0S2', 'Gene', (17, 21))	('ACC', 'Gene', (169, 172))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('patients', 'Species', '9606', (3, 11))	('death', 'Disease', 'MESH:D003643', (162, 167))	('death', 'Disease', (162, 167))	('ACC', 'Gene', (113, 116))	('ACC', 'Gene', '31', (169, 172))
58973	30770352	These results demonstrate the combined utility of G0S2 methylation and BUB1B-PINK1 score in stratifying patients into three groups, two of which have uniformly favorable or dismal outcomes.	('PINK1', 'Gene', (77, 82))	('G0S2', 'Gene', '50486', (50, 54))	('BUB1B', 'Gene', '701', (71, 76))	('PINK1', 'Gene', '65018', (77, 82))	('methylation', 'Var', (55, 66))	('BUB1B', 'Gene', (71, 76))	('patients', 'Species', '9606', (104, 112))	('G0S2', 'Gene', (50, 54))
58977	30770352	We noted that the genomes of rapidly recurrent carcinomas are characterized by aberrant methylation directed to promoter CpG islands, "CIMP-high."	('rapidly', 'Disease', (29, 36))	('CIMP', 'Chemical', '-', (135, 139))	('aberrant', 'Var', (79, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Disease', 'MESH:D009369', (47, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('methylation', 'MPA', (88, 99))	('carcinomas', 'Disease', (47, 57))
58979	30770352	Here, we identified that hypermethylation and silencing of G0S2 is a hallmark of ACC-TCGA CIMP-high carcinomas.	('hypermethylation', 'Var', (25, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('G0S2', 'Gene', '50486', (59, 63))	('silencing', 'NegReg', (46, 55))	('ACC', 'Gene', '31', (81, 84))	('CIMP-high carcinomas', 'Disease', 'MESH:D009369', (90, 110))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('ACC', 'Phenotype', 'HP:0006744', (81, 84))	('CIMP-high carcinomas', 'Disease', (90, 110))	('G0S2', 'Gene', (59, 63))	('ACC', 'Gene', (81, 84))
58980	30770352	In an independent cohort, we determined that G0S2 hypermethylation is restricted to 40% of ACC, absent from ACA and physiological tissues.	('ACC', 'Gene', '31', (91, 94))	('G0S2', 'Gene', '50486', (45, 49))	('ACC', 'Phenotype', 'HP:0006744', (91, 94))	('hypermethylation', 'Var', (50, 66))	('G0S2', 'Gene', (45, 49))	('ACA', 'Phenotype', 'HP:0008256', (108, 111))	('ACC', 'Gene', (91, 94))
58983	30770352	G0S2 hypermethylation almost invariably predicts rapidly recurrent and fatal disease in patients with localized, locoregional and disseminated ACC, including one third of patients with low grade disease.	('G0S2', 'Gene', '50486', (0, 4))	('ACC', 'Gene', (143, 146))	('patients', 'Species', '9606', (88, 96))	('predicts', 'Reg', (40, 48))	('ACC', 'Gene', '31', (143, 146))	('patients', 'Species', '9606', (171, 179))	('rapidly', 'Disease', (49, 56))	('G0S2', 'Gene', (0, 4))	('hypermethylation', 'Var', (5, 21))	('ACC', 'Phenotype', 'HP:0006744', (143, 146))
58984	30770352	Interestingly, we observed only one patient with tumor G0S2 hypermethylation who remains disease free >24 months following R0/RX resection.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('G0S2', 'Gene', '50486', (55, 59))	('hypermethylation', 'Var', (60, 76))	('G0S2', 'Gene', (55, 59))	('patient', 'Species', '9606', (36, 43))
58985	30770352	Given that adjuvant mitotane therapy is the standard of care at FMUSP and UM, our data suggests that G0S2 hypermethylation predicts short-lived remission regardless, reinforcing the need to develop improved adjuvant therapies for high risk patients.	('mitotane', 'Chemical', 'MESH:D008939', (20, 28))	('predicts', 'Reg', (123, 131))	('G0S2', 'Gene', '50486', (101, 105))	('patients', 'Species', '9606', (240, 248))	('G0S2', 'Gene', (101, 105))	('hypermethylation', 'Var', (106, 122))
58987	30770352	Our study suggests that prospective assessment of G0S2 methylation would objectively identify uniformly high risk patients.	('G0S2', 'Gene', (50, 54))	('patients', 'Species', '9606', (114, 122))	('G0S2', 'Gene', '50486', (50, 54))	('methylation', 'Var', (55, 66))
58989	30770352	The major ongoing clinical trial evaluating the efficacy of adjuvant mitotane in low-intermediate risk ACC ("ADIUVO," NCT00777244) defines risk using grade; our study suggests this criterion is inadequate, as up to one third of these patients will have tumor G0S2 hypermethylation and likely recur on adjuvant mitotane.	('ACC', 'Phenotype', 'HP:0006744', (103, 106))	('hypermethylation', 'Var', (264, 280))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('ACC', 'Gene', (103, 106))	('patients', 'Species', '9606', (234, 242))	('mitotane', 'Chemical', 'MESH:D008939', (69, 77))	('tumor', 'Disease', (253, 258))	('G0S2', 'Gene', '50486', (259, 263))	('ACC', 'Gene', '31', (103, 106))	('mitotane', 'Chemical', 'MESH:D008939', (310, 318))	('G0S2', 'Gene', (259, 263))
58991	30770352	High risk CIMP-high/G0S2 Methylated ACC is associated with a unique transcriptional, copy number and mutational landscape in ACC-TCGA, suggesting a common biological program underlies this aggressive ACC subtype.	('ACC', 'Gene', '31', (200, 203))	('G0S2', 'Gene', '50486', (20, 24))	('ACC', 'Phenotype', 'HP:0006744', (200, 203))	('ACC', 'Phenotype', 'HP:0006744', (36, 39))	('ACC', 'Phenotype', 'HP:0006744', (125, 128))	('ACC', 'Gene', '31', (36, 39))	('G0S2', 'Gene', (20, 24))	('ACC', 'Gene', (200, 203))	('ACC', 'Gene', (125, 128))	('Methylated', 'Var', (25, 35))	('ACC', 'Gene', (36, 39))	('CIMP', 'Chemical', '-', (10, 14))	('ACC', 'Gene', '31', (125, 128))
58994	30770352	While there is currently little data to support a clinical trial evaluating utility of demethylating agents alone in ACC, studies in other solid tumors demonstrate that epigenetic priming with demethylating agents may increase efficacy of cytotoxic therapies and targeted DNA repair inhibitors.	('demethylating', 'Var', (193, 206))	('ACC', 'Phenotype', 'HP:0006744', (117, 120))	('solid tumors', 'Disease', 'MESH:D009369', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('efficacy', 'CPA', (227, 235))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('ACC', 'Gene', (117, 120))	('increase', 'PosReg', (218, 226))	('ACC', 'Gene', '31', (117, 120))	('solid tumors', 'Disease', (139, 151))	('cytotoxic therapies', 'CPA', (239, 258))	('epigenetic priming', 'Var', (169, 187))
58995	30770352	Together, these observations suggest that therapies targeting the cell cycle, DNA repair, and epigenetics may be efficacious in patients with CIMP-high/G0S2 Methylated ACC and warrant future study.	('ACC', 'Gene', '31', (168, 171))	('Methylated', 'Var', (157, 167))	('G0S2', 'Gene', '50486', (152, 156))	('ACC', 'Phenotype', 'HP:0006744', (168, 171))	('patients', 'Species', '9606', (128, 136))	('CIMP', 'Chemical', '-', (142, 146))	('G0S2', 'Gene', (152, 156))	('ACC', 'Gene', (168, 171))
58999	30770352	While G0S2 has been best characterized as a regulator of lipid metabolism, recent studies have demonstrated that methylation-dependent silencing of G0S2 in breast cancer augments oncogenic PI3K/mTOR signaling and MYC transcriptional activity.	('oncogenic', 'CPA', (179, 188))	('augments', 'PosReg', (170, 178))	('silencing', 'Var', (135, 144))	('G0S2', 'Gene', '50486', (6, 10))	('MYC', 'Gene', '4609', (213, 216))	('mTOR', 'Gene', (194, 198))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mTOR', 'Gene', '2475', (194, 198))	('G0S2', 'Gene', '50486', (148, 152))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('G0S2', 'Gene', (6, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('breast cancer', 'Disease', (156, 169))	('G0S2', 'Gene', (148, 152))	('methylation-dependent', 'Var', (113, 134))	('lipid', 'Chemical', 'MESH:D008055', (57, 62))	('MYC', 'Gene', (213, 216))
59001	30770352	In conclusion, our study is the first to reduce the complex genome-wide CpG island hypermethylation signature from ACC-TCGA to a single, binary molecular marker, amenable to targeted assessment using routine molecular diagnostics.	('CpG island', 'Gene', (72, 82))	('ACC', 'Gene', '31', (115, 118))	('ACC', 'Phenotype', 'HP:0006744', (115, 118))	('hypermethylation', 'Var', (83, 99))	('reduce', 'NegReg', (41, 47))	('ACC', 'Gene', (115, 118))
59002	30770352	Assessing G0S2 methylation as we have here is inexpensive, straightforward, compatible with a timeline feasible for clinical decision-making, and will enable the direction of efficacious adjuvant therapies for patients with uniformly aggressive ACC.	('methylation', 'Var', (15, 26))	('ACC', 'Gene', '31', (245, 248))	('ACC', 'Phenotype', 'HP:0006744', (245, 248))	('G0S2', 'Gene', '50486', (10, 14))	('G0S2', 'Gene', (10, 14))	('patients', 'Species', '9606', (210, 218))	('ACC', 'Gene', (245, 248))
59003	30770352	Future studies will be directed towards evaluating G0S2 methylation prospectively, in circulating tumor DNA, and in readily available clinical samples including formalin-fixed paraffin-embedded tissues.	('G0S2', 'Gene', '50486', (51, 55))	('paraffin', 'Chemical', 'MESH:D010232', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('formalin', 'Chemical', 'MESH:D005557', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('G0S2', 'Gene', (51, 55))	('tumor', 'Disease', (98, 103))	('methylation', 'Var', (56, 67))
59006	30770352	The Cancer Genome Atlas project on ACC (ACC-TCGA) revealed that aberrant promoter CpG island hypermethylation ("CIMP-high") independently predicts rapidly recurrent or fatal disease course.	('ACC', 'Gene', (35, 38))	('ACC', 'Gene', '31', (40, 43))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('ACC', 'Phenotype', 'HP:0006744', (40, 43))	('rapidly', 'Disease', (147, 154))	('CIMP', 'Chemical', '-', (112, 116))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('ACC', 'Gene', '31', (35, 38))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))	('ACC', 'Gene', (40, 43))	('aberrant', 'Var', (64, 72))	('predicts', 'Reg', (138, 146))
59007	30770352	In this study, we analyze ACC-TCGA data and identify that uniform hypermethylation and silencing of G0S2 is a hallmark of CIMP-high ACC.	('ACC', 'Phenotype', 'HP:0006744', (132, 135))	('hypermethylation', 'Var', (66, 82))	('ACC', 'Gene', '31', (26, 29))	('G0S2', 'Gene', '50486', (100, 104))	('silencing', 'MPA', (87, 96))	('ACC', 'Phenotype', 'HP:0006744', (26, 29))	('G0S2', 'Gene', (100, 104))	('ACC', 'Gene', (132, 135))	('CIMP', 'Chemical', '-', (122, 126))	('ACC', 'Gene', (26, 29))	('ACC', 'Gene', '31', (132, 135))
59008	30770352	We demonstrate in an independent cohort that G0S2 hypermethylation is exclusive to ACC, amenable to binary targeted assessment, and independently predictive of recurrence and death.	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('G0S2', 'Gene', '50486', (45, 49))	('death', 'Disease', 'MESH:D003643', (175, 180))	('death', 'Disease', (175, 180))	('hypermethylation', 'Var', (50, 66))	('ACC', 'Gene', (83, 86))	('G0S2', 'Gene', (45, 49))	('recurrence', 'Disease', (160, 170))	('ACC', 'Gene', '31', (83, 86))	('predictive of', 'Reg', (146, 159))
59010	30770352	Taken together, we demonstrate that evaluation of tumor G0S2 methylation identifies a subgroup of patients with rapidly progressive disease course who may benefit from aggressive adjuvant and surveillance approaches.	('methylation', 'Var', (61, 72))	('patients', 'Species', '9606', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('G0S2', 'Gene', '50486', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('G0S2', 'Gene', (56, 60))	('tumor', 'Disease', (50, 55))
59029	30208164	The deletion of exon 2 of Dax1 resulted in animals with normal adrenal function; however, adrenal insufficiency develops with time in aging Dax1-deleted mice.	('Dax1', 'Gene', (26, 30))	('adrenal insufficiency', 'Disease', (90, 111))	('adrenal function', 'MPA', (63, 79))	('deletion', 'Var', (4, 12))	('mice', 'Species', '10090', (153, 157))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (90, 111))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (90, 111))
59049	30208164	Moreover, the presence of fibronectin in the substrate enhanced the secretion of DHEA-S but impaired that of cortisol.	('cortisol', 'Chemical', 'MESH:D006854', (109, 117))	('fibronectin', 'Gene', '2335', (26, 37))	('presence', 'Var', (14, 22))	('secretion of DHEA-S', 'MPA', (68, 87))	('enhanced', 'PosReg', (55, 63))	('impaired', 'NegReg', (92, 100))	('DHEA-S', 'Chemical', 'MESH:D019314', (81, 87))	('fibronectin', 'Gene', (26, 37))
59073	30208164	ACTH increases aldosterone by stimulating the early steps of the steroidogenesis pathway, contributing to increased aldosterone.	('aldosterone', 'MPA', (116, 127))	('aldosterone', 'MPA', (15, 26))	('stimulating', 'PosReg', (30, 41))	('aldosterone', 'Chemical', 'MESH:D000450', (15, 26))	('increased aldosterone', 'Phenotype', 'HP:0000859', (106, 127))	('ACTH', 'Var', (0, 4))	('steroidogenesis pathway', 'Pathway', (65, 88))	('ACTH increases', 'Phenotype', 'HP:0011749', (0, 14))	('aldosterone', 'Chemical', 'MESH:D000450', (116, 127))	('increases', 'PosReg', (5, 14))	('increased', 'PosReg', (106, 115))	('increases aldosterone', 'Phenotype', 'HP:0000859', (5, 26))
59087	30208164	Other findings involving the loss of SHH in the adrenal cortex have shown reduced proliferation of capsular cells and decreases of 50-70% in the adrenal size of SF-1-Cre mice, who remain smaller as adults.	('SF-1-Cre', 'Gene', (161, 169))	('adrenal size', 'CPA', (145, 157))	('SF-1-Cre', 'Gene', '22668', (161, 169))	('loss', 'Var', (29, 33))	('decreases', 'NegReg', (118, 127))	('proliferation', 'CPA', (82, 95))	('mice', 'Species', '10090', (170, 174))	('SHH', 'Gene', (37, 40))	('reduced', 'NegReg', (74, 81))
59088	30208164	In a recently created mouse model, the transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), both effectors of the Hippo signaling pathway, were conditionally deleted in steroidogenic cells.	('Yes-associated protein', 'Gene', (71, 93))	('Yes-associated protein', 'Gene', '22601', (71, 93))	('TAZ', 'Gene', (99, 102))	('YAP', 'Gene', (66, 69))	('deleted', 'Var', (223, 230))	('mouse', 'Species', '10090', (22, 27))
59090	30208164	To investigate the role of the Wnt/beta-catenin pathway in the maintenance of the adrenal cortex, mouse Sf1/Cre transgenes were used to inactivate conditional beta-catenin alleles.	('inactivate', 'Var', (136, 146))	('conditional beta-catenin', 'Protein', (147, 171))	('Sf1', 'Gene', '22668', (104, 107))	('Sf1', 'Gene', (104, 107))	('mouse', 'Species', '10090', (98, 103))
59091	30208164	The analysis of fetal adrenal development after the complete inactivation of beta-catenin showed decreased proliferation in presumed progenitor cells of the adrenal cortex and adrenal aplasia.	('inactivation', 'Var', (61, 73))	('adrenal aplasia', 'Disease', 'MESH:D000310', (176, 191))	('proliferation', 'CPA', (107, 120))	('adrenal aplasia', 'Disease', (176, 191))	('decreased', 'NegReg', (97, 106))	('beta-catenin', 'Protein', (77, 89))	('adrenal aplasia', 'Phenotype', 'HP:0011743', (176, 191))
59092	30208164	In animals with lesser degrees of beta-catenin inactivation, age-dependent degeneration of the adrenal cortex occurred, demonstrating the role of the Wnt/beta-catenin pathway in maintaining the fetal and adult adrenal cortex.	('inactivation', 'Var', (47, 59))	('degeneration of the adrenal cortex', 'Disease', (75, 109))	('degeneration of the adrenal cortex', 'Disease', 'MESH:D000303', (75, 109))	('beta-catenin', 'Protein', (34, 46))
59093	30208164	In contrast, overactivation of beta-catenin produced an increase in progenitor-like cells and tumor formation.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('increase', 'PosReg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('progenitor-like cells', 'CPA', (68, 89))	('overactivation', 'Var', (13, 27))	('beta-catenin', 'Protein', (31, 43))
59095	30208164	Yaswen et al., using mice lacking POMC-derived peptides (i.e., POMC-null mutant mice), showed defective adrenal development and undetectable plasma steroids.	('mice', 'Species', '10090', (21, 25))	('adrenal development', 'CPA', (104, 123))	('mutant', 'Var', (73, 79))	('mice', 'Species', '10090', (80, 84))	('steroids', 'Chemical', 'MESH:D013256', (148, 156))	('undetectable', 'NegReg', (128, 140))	('plasma steroids', 'MPA', (141, 156))	('defective', 'NegReg', (94, 103))
59111	30208164	Four forms of congenital adrenal hypoplasia have been identified, as follows: 1) an X-linked form is caused by a mutation or deletion of the DAX1 gene on the X chromosome; 2) the autosomal recessive form is due to a mutation or deletion of the SF-1 gene on chromosome 9q33; 3) a rare autosomal form includes IMAGE syndrome and SERKAL syndrome, caused by mutations in CDKN1C and WNT4, respectively; and 4) ACTH resistance syndrome and familial isolated glucocorticoid deficiency syndromes are autosomal recessive diseases caused by mutations in genes related to ACTH function and signaling, such as MC2R and MRAP.	('caused', 'Reg', (344, 350))	('MC2R', 'Gene', (598, 602))	('IMAGE syndrome', 'Disease', 'MESH:C564543', (308, 322))	('MC2R', 'Gene', '4158', (598, 602))	('MRAP', 'Gene', '56246', (607, 611))	('DAX1', 'Gene', (141, 145))	('autosomal recessive diseases', 'Disease', (492, 520))	('IMAGE syndrome', 'Disease', (308, 322))	('mutations', 'Var', (531, 540))	('familial isolated glucocorticoid deficiency syndromes', 'Disease', 'MESH:C565974', (434, 487))	('mutation', 'Var', (216, 224))	('congenital adrenal hypoplasia', 'Disease', 'MESH:D000312', (14, 43))	('CDKN1C', 'Gene', (367, 373))	('ACTH resistance syndrome', 'Disease', (405, 429))	('SERKAL syndrome', 'Disease', (327, 342))	('congenital adrenal hypoplasia', 'Disease', (14, 43))	('SF-1', 'Gene', (244, 248))	('congenital adrenal hypoplasia', 'Phenotype', 'HP:0008244', (14, 43))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (452, 477))	('MRAP', 'Gene', (607, 611))	('SERKAL syndrome', 'Disease', 'OMIM:611812', (327, 342))	('mutations', 'Var', (354, 363))	('DAX1', 'Gene', '190', (141, 145))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (25, 43))	('autosomal recessive diseases', 'Disease', 'MESH:D030342', (492, 520))	('caused by', 'Reg', (521, 530))	('CDKN1C', 'Gene', '1028', (367, 373))	('ACTH resistance syndrome', 'Phenotype', 'HP:0008259', (405, 429))	('WNT4', 'Gene', (378, 382))	('WNT4', 'Gene', '54361', (378, 382))
59112	30208164	Mutations in two other genes have also been associated with ACTH resistance syndrome, the nicotinamide nucleotide transhydrogenase (NNT) gene and the minichromosome maintenance-deficient 4 (MCM4) gene.	('associated', 'Reg', (44, 54))	('MCM4', 'Gene', '4173', (190, 194))	('NNT', 'Gene', (132, 135))	('MCM4', 'Gene', (190, 194))	('nicotinamide nucleotide transhydrogenase', 'Gene', '23530', (90, 130))	('ACTH resistance syndrome', 'Phenotype', 'HP:0008259', (60, 84))	('Mutations', 'Var', (0, 9))	('ACTH resistance syndrome', 'Disease', (60, 84))	('minichromosome maintenance-deficient 4', 'Gene', (150, 188))	('NNT', 'Gene', '23530', (132, 135))	('minichromosome maintenance-deficient 4', 'Gene', '4173', (150, 188))	('nicotinamide nucleotide transhydrogenase', 'Gene', (90, 130))
59116	30208164	The deficiency in cortisol production results in excessive secretion of ACTH, which in turn cannot block cortisol synthesis, leading to enlargement of the adrenal gland.	('secretion of ACTH', 'MPA', (59, 76))	('deficiency', 'Var', (4, 14))	('enlargement', 'PosReg', (136, 147))	('cortisol', 'Chemical', 'MESH:D006854', (18, 26))	('adrenal gland', 'CPA', (155, 168))	('deficiency in cortisol', 'Phenotype', 'HP:0008163', (4, 26))	('cortisol', 'Chemical', 'MESH:D006854', (105, 113))
59120	30208164	Nonclassic CYP21A2 deficiency does not produce adrenal insufficiency but is associated with premature puberty, hirsutism, acne, and irregular menses due to excess androgen.	('CYP21A2', 'Gene', '1589', (11, 18))	('excess', 'PosReg', (156, 162))	('irregular', 'Disease', (132, 141))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (47, 68))	('hirsutism', 'Disease', (111, 120))	('irregular menses', 'Phenotype', 'HP:0000858', (132, 148))	('premature puberty', 'Disease', (92, 109))	('acne', 'Phenotype', 'HP:0001061', (122, 126))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (47, 68))	('acne', 'Disease', (122, 126))	('associated', 'Reg', (76, 86))	('acne', 'Disease', 'MESH:D000152', (122, 126))	('adrenal insufficiency', 'Disease', (47, 68))	('androgen', 'CPA', (163, 171))	('premature puberty', 'Phenotype', 'HP:0000826', (92, 109))	('deficiency', 'Var', (19, 29))	('CYP21A2', 'Gene', (11, 18))	('premature puberty', 'Disease', 'MESH:D011628', (92, 109))	('hirsutism', 'Disease', 'MESH:D006628', (111, 120))	('hirsutism', 'Phenotype', 'HP:0001007', (111, 120))
59122	30208164	Complete deletions, large gene conversions, and nonsense or frameshift mutations result in compromised CYP21A2 and the classic form of CYP21A2 deficiency.	('compromised', 'NegReg', (91, 102))	('CYP21A2', 'Gene', '1589', (103, 110))	('CYP21A2', 'Gene', (103, 110))	('CYP21A2', 'Gene', '1589', (135, 142))	('nonsense or frameshift mutations', 'Var', (48, 80))	('CYP21A2', 'Gene', (135, 142))
59123	30208164	In nonclassic CYP21A2 deficiency, the alleles preserve some enzyme activity as well as cortisol and aldosterone production.	('aldosterone production', 'MPA', (100, 122))	('aldosterone production', 'Phenotype', 'HP:0000859', (100, 122))	('CYP21A2', 'Gene', (14, 21))	('CYP21A2', 'Gene', '1589', (14, 21))	('enzyme activity', 'MPA', (60, 75))	('cortisol', 'Chemical', 'MESH:D006854', (87, 95))	('aldosterone', 'Chemical', 'MESH:D000450', (100, 111))	('deficiency', 'Var', (22, 32))
59124	30208164	The other form of CAH is 11beta-hydroxylase (CYP11B1) deficiency, which represents approximately 8% of all CAH cases.	('CYP11B1', 'Gene', (45, 52))	('deficiency', 'Var', (54, 64))	('CYP11B1', 'Gene', '1584', (45, 52))
59126	30208164	In contrast to CYP21A2, patients with CYP11B1 deficiency present with hypertension and sometimes hypokalemia.	('hypokalemia', 'Disease', 'MESH:D007008', (97, 108))	('hypertension', 'Phenotype', 'HP:0000822', (70, 82))	('hypokalemia', 'Phenotype', 'HP:0002900', (97, 108))	('CYP11B1', 'Gene', (38, 45))	('hypertension', 'Disease', 'MESH:D006973', (70, 82))	('CYP21A2', 'Gene', (15, 22))	('patients', 'Species', '9606', (24, 32))	('CYP21A2', 'Gene', '1589', (15, 22))	('hypertension', 'Disease', (70, 82))	('deficiency', 'Var', (46, 56))	('CYP11B1', 'Gene', '1584', (38, 45))	('hypokalemia', 'Disease', (97, 108))
59131	30208164	Mutations (nonsense and frameshift) eliminate enzyme transcription and function, resulting in salt-wasting forms of 3betaHSD2 deficiency, while single amino acid substitution decreases the affinity of the enzyme for substrate, leading to non-salt-wasting forms of 3betaHSD2 deficiency.	('3betaHSD2 deficiency', 'Disease', 'MESH:D007153', (264, 284))	('enzyme transcription', 'MPA', (46, 66))	('salt-wasting', 'MPA', (94, 106))	('non-salt-wasting', 'MPA', (238, 254))	('eliminate', 'NegReg', (36, 45))	('resulting in', 'Reg', (81, 93))	('3betaHSD2 deficiency', 'Disease', (264, 284))	('affinity', 'MPA', (189, 197))	('frameshift', 'Var', (24, 34))	('function', 'MPA', (71, 79))	('-salt-wasting', 'Phenotype', 'HP:0000127', (241, 254))	('salt', 'Chemical', 'MESH:D012492', (94, 98))	('3betaHSD2 deficiency', 'Disease', 'MESH:D007153', (116, 136))	('single amino acid substitution', 'Var', (144, 174))	('decreases', 'NegReg', (175, 184))	('salt-wasting', 'Phenotype', 'HP:0000127', (94, 106))	('salt-wasting', 'Phenotype', 'HP:0000127', (242, 254))	('salt', 'Chemical', 'MESH:D012492', (242, 246))	('3betaHSD2 deficiency', 'Disease', (116, 136))
59145	30208164	For example, mutations in the GNAS and MC2R genes have been reported, but they are present in only a limited number of cases.	('MC2R', 'Gene', '4158', (39, 43))	('GNAS', 'Gene', (30, 34))	('MC2R', 'Gene', (39, 43))	('mutations', 'Var', (13, 22))	('GNAS', 'Gene', '2778', (30, 34))
59146	30208164	The ARMC5 gene is located on chromosome 16p11.2, and because germline mutations are associated with nodule-specific somatic mutations, this gene is hypothesized to be a tumor suppressor gene.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('ARMC5', 'Gene', (4, 9))	('associated', 'Reg', (84, 94))	('tumor', 'Disease', (169, 174))
59153	30208164	Mutations in the gene encoding the alpha catalytic subunit of protein kinase A (PRKACA) have been reported in 30-65% of adenomas causing overt CS.	('adenomas', 'Disease', 'MESH:D000236', (120, 128))	('PRKACA', 'Gene', (80, 86))	('Mutations', 'Var', (0, 9))	('adenomas', 'Disease', (120, 128))	('PRKACA', 'Gene', '5566', (80, 86))	('reported', 'Reg', (98, 106))
59154	30208164	The most frequent mutation described in this gene, p.Leu206Arg, leads to the replacement of a leucine residue at position 206 by arginine.	('p.Leu206Arg', 'Var', (51, 62))	('leads to', 'Reg', (64, 72))	('leucine residue at position 206 by arginine', 'Mutation', 'rs386352352', (94, 137))	('p.Leu206Arg', 'Mutation', 'rs386352352', (51, 62))
59155	30208164	These mutations constitutively activate the cAMP pathway, resulting in abnormal PKA activity, increased cortisol production, and tumor development.	('activate', 'PosReg', (31, 39))	('cAMP', 'Gene', (44, 48))	('cAMP', 'Gene', '820', (44, 48))	('increased', 'PosReg', (94, 103))	('cortisol production', 'MPA', (104, 123))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('PKA', 'Enzyme', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('activity', 'MPA', (84, 92))	('cortisol', 'Chemical', 'MESH:D006854', (104, 112))	('tumor', 'Disease', (129, 134))	('mutations', 'Var', (6, 15))	('increased cortisol', 'Phenotype', 'HP:0003118', (94, 112))
59156	30208164	According to Lacroix and coworkers, the absence of mutations in the PRKACA gene in cases of low-cortisol-producing adenomas may explain why they rarely lead to CS over time.	('absence', 'NegReg', (40, 47))	('adenomas', 'Disease', 'MESH:D000236', (115, 123))	('mutations', 'Var', (51, 60))	('PRKACA', 'Gene', (68, 74))	('PRKACA', 'Gene', '5566', (68, 74))	('adenomas', 'Disease', (115, 123))	('cortisol', 'Chemical', 'MESH:D006854', (96, 104))	('low-cortisol', 'Phenotype', 'HP:0008163', (92, 104))
59157	30208164	Adrenocortical adenomas have also been associated with postzygotic mutations in the gene encoding the alpha subunit of the stimulatory guanine nucleotide-binding protein (GNAS).	('Adrenocortical adenomas', 'Disease', (0, 23))	('GNAS', 'Gene', (171, 175))	('mutations', 'Var', (67, 76))	('associated', 'Reg', (39, 49))	('GNAS', 'Gene', '2778', (171, 175))	('Adrenocortical adenomas', 'Phenotype', 'HP:0008256', (0, 23))	('Adrenocortical adenomas', 'Disease', 'MESH:D018246', (0, 23))
59158	30208164	These mutations are normally associated with McCune-Albright syndrome (MAS), where mosaic gain-of-function GNAS mutations in patients with MAS lead to the constitutive activation of adenylyl cyclase and to clinical features such as fibrous dysplasia and cafe-au-lait skin pigmentation.	('fibrous dysplasia', 'Disease', (232, 249))	('mutations', 'Var', (112, 121))	('au-lait skin', 'Phenotype', 'HP:0000957', (259, 271))	('skin pigmentation', 'Disease', 'MESH:D010859', (267, 284))	('McCune-Albright syndrome', 'Disease', (45, 69))	('patients', 'Species', '9606', (125, 133))	('fibrous dysplasia', 'Disease', 'MESH:D005357', (232, 249))	('gain-of-function', 'PosReg', (90, 106))	('activation', 'PosReg', (168, 178))	('lait skin', 'Phenotype', 'HP:0000973', (262, 271))	('MAS', 'Disease', 'MESH:D005357', (139, 142))	('MAS', 'Disease', (139, 142))	('GNAS', 'Gene', (107, 111))	('adenylyl cyclase', 'MPA', (182, 198))	('GNAS', 'Gene', '2778', (107, 111))	('MAS', 'Disease', 'MESH:D005357', (71, 74))	('MAS', 'Disease', (71, 74))	('skin pigmentation', 'Phenotype', 'HP:0000953', (267, 284))	('skin pigmentation', 'Disease', (267, 284))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (45, 69))
59159	30208164	Although the mechanisms leading to the development of adrenocortical adenomas have not yet been completely identified, mutations in the PRKACA gene are considered the primary genetic alterations involved in the formation of these tumors through the cAMP/PKA signaling pathway, stimulating both cortisol secretion and cell proliferation.	('PRKACA', 'Gene', (136, 142))	('cAMP', 'Gene', '820', (249, 253))	('adrenocortical adenomas', 'Disease', (54, 77))	('cortisol', 'Chemical', 'MESH:D006854', (294, 302))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (54, 77))	('stimulating', 'PosReg', (277, 288))	('cortisol secretion', 'MPA', (294, 312))	('cell proliferation', 'CPA', (317, 335))	('tumors', 'Disease', (230, 236))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (54, 77))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('PRKACA', 'Gene', '5566', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('mutations', 'Var', (119, 128))	('cAMP', 'Gene', (249, 253))
59161	30208164	The mutations found in APAs are mostly related to the regulation of calcium and potassium channels, such as the somatic mutations found in ATPA1A, a gene encoding the alpha subunit of the sodium/potassium ATPase, and ATP2B3, a gene encoding the plasma membrane calcium-transporting ATPase3.	('APAs', 'Gene', (23, 27))	('ATP2B3', 'Gene', (217, 223))	('related', 'Reg', (39, 46))	('potassium', 'Chemical', 'MESH:D011188', (195, 204))	('sodium', 'Chemical', 'MESH:D012964', (188, 194))	('mutations', 'Var', (120, 129))	('mutations', 'Var', (4, 13))	('potassium', 'Chemical', 'MESH:D011188', (80, 89))	('ATPA1A', 'Gene', (139, 145))	('ATP2B3', 'Gene', '492', (217, 223))
59162	30208164	Additionally, mutations in KCNJ5, which encodes potassium channels, were found in both sporadic and familial APA cases.	('found', 'Reg', (73, 78))	('KCNJ5', 'Gene', (27, 32))	('KCNJ5', 'Gene', '3762', (27, 32))	('familial APA', 'Disease', (100, 112))	('potassium', 'Chemical', 'MESH:D011188', (48, 57))	('mutations', 'Var', (14, 23))
59163	30208164	These mutations damage the channel's permeability, allowing the entrance of sodium:instead of potassium:into the cell, resulting in depolarization.	('permeability', 'MPA', (37, 49))	('sodium', 'MPA', (76, 82))	('entrance', 'MPA', (64, 72))	('depolarization', 'MPA', (132, 146))	('damage', 'Reg', (16, 22))	('potassium', 'Chemical', 'MESH:D011188', (94, 103))	('sodium', 'Chemical', 'MESH:D012964', (76, 82))	('mutations', 'Var', (6, 15))
59166	30208164	ACCs are differentiated from ACAs by the presence of 3 or more Weiss criteria, including nuclear grade, mitotic rate, the presence of atypical mitoses, <25% clear cells, necrosis, >33% diffuse architecture, and vascular, sinusoid and capsule invasion.	('diffuse architecture', 'CPA', (185, 205))	('necrosis', 'Disease', (170, 178))	('<25', 'Var', (152, 155))	('necrosis', 'Disease', 'MESH:D009336', (170, 178))	('mitotic rate', 'CPA', (104, 116))	('vascular', 'CPA', (211, 219))
59174	30208164	Inhibition of the IGF signaling pathway has been proposed as a promising treatment, and in combination with the administration of mitotane, it reduces tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mitotane', 'Chemical', 'MESH:D008939', (130, 138))	('tumor', 'Disease', (151, 156))	('IGF signaling pathway', 'Pathway', (18, 39))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('Inhibition', 'Var', (0, 10))	('reduces', 'NegReg', (143, 150))
59175	30208164	Alterations in the Wnt/beta-catenin signaling pathway are associated with gastric and ovarian cancer, gastrointestinal stromal and myeloid tumors and teratocarcinosarcomas.	('gastric and ovarian cancer', 'Disease', 'MESH:D013274', (74, 100))	('associated', 'Reg', (58, 68))	('Alterations', 'Var', (0, 11))	('teratocarcinosarcomas', 'Disease', (150, 171))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Wnt/beta-catenin signaling pathway', 'Pathway', (19, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('teratocarcinosarcomas', 'Disease', 'MESH:C535701', (150, 171))	('gastrointestinal stromal and myeloid tumors', 'Disease', 'MESH:D046152', (102, 145))
59177	30208164	However, inhibition of the Wnt/beta-catenin signaling pathway reduces cell viability and could be a treatment option for ACC patients.	('Wnt/beta-catenin signaling pathway', 'Pathway', (27, 61))	('reduces', 'NegReg', (62, 69))	('ACC', 'Disease', (121, 124))	('cell viability', 'CPA', (70, 84))	('inhibition', 'Var', (9, 19))	('patients', 'Species', '9606', (125, 133))
59179	30208164	The ZNRF3 gene is amplified and exhibits homozygous deletions and mutations in ACCs.	('mutations', 'Var', (66, 75))	('ZNRF3', 'Gene', '84133', (4, 9))	('ACCs', 'Gene', (79, 83))	('ZNRF3', 'Gene', (4, 9))
59182	30208164	The R337H germline mutation in the TP53 gene is an important molecular marker in pediatric tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('R337H', 'Mutation', 'rs121912664', (4, 9))	('R337H', 'Var', (4, 9))	('TP53', 'Gene', '7157', (35, 39))	('pediatric tumors', 'Disease', 'MESH:D063766', (81, 97))	('TP53', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('pediatric tumors', 'Disease', (81, 97))
59194	30208164	Moreover, upon demethylation treatment in H295R adrenocortical carcinoma cells, the hypermethylated genes showed increased gene expression.	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (48, 72))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (48, 72))	('gene expression', 'MPA', (123, 138))	('adrenocortical carcinoma', 'Disease', (48, 72))	('increased', 'PosReg', (113, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('demethylation', 'Var', (15, 28))
59214	30208164	LFS is a familial cancer predisposition disorder caused by germline mutations in the tumor suppressor gene TP53.	('caused by', 'Reg', (49, 58))	('tumor', 'Disease', (85, 90))	('familial cancer', 'Disease', 'MESH:D009369', (9, 24))	('LFS', 'Disease', (0, 3))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('germline mutations', 'Var', (59, 77))	('familial cancer', 'Disease', (9, 24))
59215	30208164	LOH on chromosomes 11 and 17 is the hallmark of pediatric adrenocortical tumors associated with germline TP53 mutations.	('mutations', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('pediatric adrenocortical tumors', 'Disease', (48, 79))	('associated', 'Reg', (80, 90))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('pediatric adrenocortical tumors', 'Disease', 'MESH:C565973', (48, 79))
59216	30208164	However, approximately 50% of pediatric ACTs do not harbor TP53 mutations.	('pediatric ACTs', 'Disease', (30, 44))	('TP53', 'Gene', '7157', (59, 63))	('TP53', 'Gene', (59, 63))	('mutations', 'Var', (64, 73))
59217	30208164	showed that CTNNB1 mutations occurred almost exclusively in pediatric ACTs without germline TP53 mutations.	('occurred', 'Reg', (29, 37))	('mutations', 'Var', (19, 28))	('CTNNB1', 'Gene', '1499', (12, 18))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('CTNNB1', 'Gene', (12, 18))
59218	30208164	The high incidence of childhood ACT in LFS suggests that the absence of TP53 may lead to increased proliferative capability, promoting further mutations, clonal expansion and tumorigenesis.	('tumor', 'Disease', (175, 180))	('proliferative capability', 'CPA', (99, 123))	('TP53', 'Gene', '7157', (72, 76))	('promoting', 'PosReg', (125, 134))	('clonal expansion', 'CPA', (154, 170))	('absence', 'Var', (61, 68))	('TP53', 'Gene', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('increased', 'PosReg', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('mutations', 'CPA', (143, 152))	('childhood ACT', 'Disease', (22, 35))
59219	30208164	In southern Brazil, the incidence of TP53 germline mutations is estimated to be between 3.4 and 4.2 per million children.	('TP53', 'Gene', (37, 41))	('children', 'Species', '9606', (112, 120))	('TP53', 'Gene', '7157', (37, 41))	('germline mutations', 'Var', (42, 60))
59220	30208164	demonstrated that a TP53-specific mutation, p.R337H, was related to a high prevalence of these tumors.	('p.R337H', 'Mutation', 'rs121912664', (44, 51))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('TP53', 'Gene', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p.R337H', 'Var', (44, 51))	('tumors', 'Disease', (95, 101))	('TP53', 'Gene', '7157', (20, 24))
59222	30208164	Although pediatric adrenocortical tumors are highly associated with germline TP53 mutations, only approximately 4% of these cases develop tumors, suggesting other genetic alterations.	('pediatric adrenocortical tumors', 'Disease', 'MESH:C565973', (9, 40))	('germline', 'Var', (68, 76))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('associated', 'Reg', (52, 62))	('mutations', 'Var', (82, 91))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('pediatric adrenocortical tumors', 'Disease', (9, 40))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
59223	30208164	A genomic study showed that select cases with an R337H mutation presented with secondary genetic events, such as initial LOH on chromosomes 11 and 17p, followed by dysregulation of IGF2 expression and the acquisition of ATRX (a DNA helicase) mutations.	('ATRX', 'Gene', (220, 224))	('presented', 'Reg', (64, 73))	('R337H', 'Var', (49, 54))	('R337H', 'Mutation', 'rs121912664', (49, 54))	('ATRX', 'Gene', '546', (220, 224))	('expression', 'MPA', (186, 196))	('IGF2', 'Gene', (181, 185))
59225	30208164	The most common alteration found in pediatric adrenocortical tumors was the amplification and gain of chromosome 9q34 close to where the NR5A1/SF-1 gene is situated.	('pediatric adrenocortical tumors', 'Disease', (36, 67))	('pediatric adrenocortical tumors', 'Disease', 'MESH:C565973', (36, 67))	('gain', 'PosReg', (94, 98))	('NR5A1', 'Gene', '2516', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('NR5A1', 'Gene', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('amplification', 'Var', (76, 89))
59237	30208164	In the future, these findings may make it possible to target molecular alterations in a subset of patients with particular molecular profiles and thus control the abnormal growth of these adrenal masses.	('alterations', 'Var', (71, 82))	('patients', 'Species', '9606', (98, 106))	('abnormal growth', 'Phenotype', 'HP:0001507', (163, 178))	('molecular alterations', 'Var', (61, 82))
59245	26673009	In vitro siRNA knockdown of SphK1 in two ACC cell lines (H295R and SW13) was used to determine its effect on cellular proliferation and invasion.	('H295R', 'CellLine', 'CVCL:0458', (57, 62))	('knockdown', 'Var', (15, 24))	('SphK1', 'Gene', '8877', (28, 33))	('invasion', 'CPA', (136, 144))	('cellular proliferation', 'CPA', (109, 131))	('SphK1', 'Gene', (28, 33))	('ACC', 'Phenotype', 'HP:0006744', (41, 44))	('SW13', 'CellLine', 'CVCL:0542', (67, 71))
59248	26673009	Functionally, konckdown of SphK1 gene expression in ACC cell lines significantly decreased cell proliferation and invasion.	('decreased', 'NegReg', (81, 90))	('ACC', 'Phenotype', 'HP:0006744', (52, 55))	('konckdown', 'Var', (14, 23))	('SphK1', 'Gene', '8877', (27, 32))	('SphK1', 'Gene', (27, 32))	('invasion', 'CPA', (114, 122))	('cell proliferation', 'CPA', (91, 109))
59249	26673009	FTY720 could result in a decreased cell proliferation and induction of apoptosis, and the combination of mitotane and FTY720 resulted in a greater anti-proliferative effect over single agent treatment in SW13 cells.	('mitotane', 'Chemical', 'MESH:D008939', (105, 113))	('apoptosis', 'CPA', (71, 80))	('decreased', 'NegReg', (25, 34))	('anti-proliferative effect', 'CPA', (147, 172))	('FTY720', 'Var', (0, 6))	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('cell proliferation', 'CPA', (35, 53))	('greater', 'PosReg', (139, 146))	('FTY720', 'Chemical', 'MESH:D000068876', (118, 124))	('FTY720', 'Var', (118, 124))	('combination', 'Interaction', (90, 101))	('SW13', 'CellLine', 'CVCL:0542', (204, 208))
59250	26673009	Furthermore, FTY720 could markedly inhibit tumor growth in ACC xenografts.	('FTY720', 'Var', (13, 19))	('FTY720', 'Chemical', 'MESH:D000068876', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('inhibit', 'NegReg', (35, 42))	('ACC', 'Phenotype', 'HP:0006744', (59, 62))
59261	26673009	Consistently, interference with SphK1 activity by dominant-negative mutants or competitive inhibitors, as well as inhibition of S1P by mAbs or S1P receptors antagonists, could significantly reduce cell proliferation, angiogenesis, and invasion, and increased apoptosis in some cancer cell lines.	('SphK1', 'Gene', (32, 37))	('activity', 'MPA', (38, 46))	('invasion', 'CPA', (235, 243))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('SphK1', 'Gene', '8877', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('increased', 'PosReg', (249, 258))	('interference', 'NegReg', (14, 26))	('mutants', 'Var', (68, 75))	('reduce', 'NegReg', (190, 196))	('angiogenesis', 'CPA', (217, 229))	('apoptosis', 'CPA', (259, 268))	('cell proliferation', 'CPA', (197, 215))
59262	26673009	Moreover, recent studies showed that SphK1 may be involved in resistance to both chemotherapeutics and targeted agents, suggesting that inhibitors of SphK1 in combination with chemotherapeutic treatments can synergistically act to induce tumor cell death.	('SphK1', 'Gene', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('SphK1', 'Gene', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('inhibitors', 'Var', (136, 146))	('tumor', 'Disease', (238, 243))	('SphK1', 'Gene', '8877', (37, 42))	('induce', 'PosReg', (231, 237))	('SphK1', 'Gene', '8877', (150, 155))
59263	26673009	However, no data are currently available on the efficacy of inhibitors of SphK1 in ACC, and the role of SphK1 in ACC progression remains unknown.	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('ACC', 'Disease', (83, 86))	('inhibitors', 'Var', (60, 70))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('SphK1', 'Gene', '8877', (104, 109))	('SphK1', 'Gene', '8877', (74, 79))	('SphK1', 'Gene', (104, 109))	('SphK1', 'Gene', (74, 79))
59274	26673009	As shown in Figure 1D, the length of survival time was significantly different between patients with low and high SphK1 expression (P = 0.03), with the low SphK1 group having a longer overall survival time.	('SphK1', 'Gene', '8877', (156, 161))	('low', 'Var', (101, 104))	('high', 'Var', (109, 113))	('expression', 'MPA', (120, 130))	('SphK1', 'Gene', (156, 161))	('patients', 'Species', '9606', (87, 95))	('SphK1', 'Gene', '8877', (114, 119))	('SphK1', 'Gene', (114, 119))	('longer', 'PosReg', (177, 183))
59276	26673009	To confirm whether SphK1 regulates cell proliferation in ACC, we using siRNA to knockdown SphK1 expression in the two adrenal cancer cell lines, SW13 and H295R.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('knockdown', 'Var', (80, 89))	('adrenal cancer', 'Disease', (118, 132))	('H295R', 'CellLine', 'CVCL:0458', (154, 159))	('ACC', 'Phenotype', 'HP:0006744', (57, 60))	('adrenal cancer', 'Disease', 'MESH:D000310', (118, 132))	('SW13', 'CellLine', 'CVCL:0542', (145, 149))	('SphK1', 'Gene', '8877', (90, 95))	('SphK1', 'Gene', '8877', (19, 24))	('SphK1', 'Gene', (90, 95))	('SphK1', 'Gene', (19, 24))
59282	26673009	We found that knockdown of Sphk1 inhibited cell invasive ability in H295R and SW13 cells, suggesting that overexpression of Sphk1 in ACC could promote metastasis in vitro (Figure 3A and 3B).	('metastasis', 'CPA', (151, 161))	('Sphk1', 'Gene', '8877', (124, 129))	('promote', 'PosReg', (143, 150))	('overexpression', 'PosReg', (106, 120))	('H295R', 'CellLine', 'CVCL:0458', (68, 73))	('cell invasive ability in', 'CPA', (43, 67))	('Sphk1', 'Gene', (27, 32))	('ACC', 'Phenotype', 'HP:0006744', (133, 136))	('knockdown', 'Var', (14, 23))	('SW13', 'CellLine', 'CVCL:0542', (78, 82))	('Sphk1', 'Gene', '8877', (27, 32))	('inhibited', 'NegReg', (33, 42))	('Sphk1', 'Gene', (124, 129))
59283	26673009	FTY720 is a sphingosine analogue and was previously shown to inhibit enzymatic activity of recombinant SphK1.	('enzymatic activity', 'MPA', (69, 87))	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('SphK1', 'Gene', '8877', (103, 108))	('FTY720', 'Var', (0, 6))	('inhibit', 'NegReg', (61, 68))	('SphK1', 'Gene', (103, 108))	('sphingosine', 'Chemical', 'MESH:D013110', (12, 23))
59284	26673009	H295R and SW13 cells were treated with 2.5, 5, 7.5, 10 muM of FTY720 for 24, 48 or 72 hrs, respectively.	('muM', 'Gene', '56925', (55, 58))	('FTY720', 'Var', (62, 68))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('SW13', 'CellLine', 'CVCL:0542', (10, 14))	('FTY720', 'Chemical', 'MESH:D000068876', (62, 68))	('muM', 'Gene', (55, 58))
59285	26673009	The results of MTT assay showed that FTY720 induced a dose and time-dependent decrease of cell viability in these two cell lines (Figure 3C and 3D), with IC50 values of 6.09 muM and 5.18 muM in SW13 and H295R cells at 48 h of treatment, respectively.	('decrease', 'NegReg', (78, 86))	('muM', 'Gene', (174, 177))	('cell viability', 'CPA', (90, 104))	('muM', 'Gene', '56925', (187, 190))	('H295R', 'CellLine', 'CVCL:0458', (203, 208))	('muM', 'Gene', (187, 190))	('SW13', 'CellLine', 'CVCL:0542', (194, 198))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('FTY720', 'Chemical', 'MESH:D000068876', (37, 43))	('muM', 'Gene', '56925', (174, 177))	('FTY720', 'Var', (37, 43))
59286	26673009	FTY720 at a concentration of 10 muM could induce a rapid inhibition of SphK1 enzymatic activity in SW13 and H295R cells (-36 +- 3% and -42 +- 5% in SW13 and H295R cells, respectively, at 6 hours; Figure 3E and 3F).	('SphK1', 'Gene', (71, 76))	('SW13', 'CellLine', 'CVCL:0542', (99, 103))	('H295R', 'CellLine', 'CVCL:0458', (157, 162))	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('FTY720', 'Var', (0, 6))	('inhibition', 'NegReg', (57, 67))	('SW13', 'CellLine', 'CVCL:0542', (148, 152))	('muM', 'Gene', '56925', (32, 35))	('muM', 'Gene', (32, 35))	('SphK1', 'Gene', '8877', (71, 76))	('H295R', 'CellLine', 'CVCL:0458', (108, 113))
59288	26673009	When the H295R and SW13 cells were treated with 2.5, 5, 10 muM of FTY720 for 48 h, and the results of western blot revealed that FTY720 significantly reduced the levels of p-PI3K, p-AKT and p-ERK, indicating that FTY720 specifically attenuated the PI3K/AKT and MAPK signaling pathways (Figure 4A and 4B).	('FTY720', 'Chemical', 'MESH:D000068876', (129, 135))	('attenuated', 'NegReg', (233, 243))	('FTY720', 'Var', (213, 219))	('MAPK', 'Gene', '5594', (261, 265))	('muM', 'Gene', '56925', (59, 62))	('p-PI3K', 'MPA', (172, 178))	('muM', 'Gene', (59, 62))	('AKT', 'Gene', (253, 256))	('H295R', 'CellLine', 'CVCL:0458', (9, 14))	('FTY720', 'Chemical', 'MESH:D000068876', (213, 219))	('p-ERK', 'Gene', '9451', (190, 195))	('p-ERK', 'Gene', (190, 195))	('AKT', 'Gene', '207', (182, 185))	('reduced', 'NegReg', (150, 157))	('AKT', 'Gene', '207', (253, 256))	('SW13', 'CellLine', 'CVCL:0542', (19, 23))	('FTY720', 'Var', (129, 135))	('MAPK', 'Gene', (261, 265))	('FTY720', 'Chemical', 'MESH:D000068876', (66, 72))	('AKT', 'Gene', (182, 185))
59290	26673009	The combination of mitotane and FTY720 showed a significant synergistic anti-proliferative effect in SW13 cells (CI = 0.90 +- 0.08) that potentiated the cytotoxic effect observed by using FTY720 alone, but not in H295R cells.	('mitotane', 'Chemical', 'MESH:D008939', (19, 27))	('FTY720', 'Chemical', 'MESH:D000068876', (188, 194))	('anti-proliferative', 'NegReg', (72, 90))	('H295R', 'CellLine', 'CVCL:0458', (213, 218))	('potentiated', 'PosReg', (137, 148))	('SW13', 'CellLine', 'CVCL:0542', (101, 105))	('cytotoxic effect', 'CPA', (153, 169))	('FTY720', 'Chemical', 'MESH:D000068876', (32, 38))	('FTY720', 'Var', (32, 38))
59293	26673009	Moreover, the combination of FTY720 and mitotane had a significant influence on the apoptotic rate in SW13 cells, but there is no obvious enhancement effect of the combination of FTY720 and mitotane on the apoptosis of H295R (Figure 5C and 5D).	('influence', 'Reg', (67, 76))	('SW13', 'CellLine', 'CVCL:0542', (102, 106))	('FTY720', 'Chemical', 'MESH:D000068876', (179, 185))	('FTY720', 'Var', (179, 185))	('apoptotic rate', 'CPA', (84, 98))	('H295R', 'CellLine', 'CVCL:0458', (219, 224))	('FTY720', 'Chemical', 'MESH:D000068876', (29, 35))	('mitotane', 'Chemical', 'MESH:D008939', (190, 198))	('mitotane', 'Chemical', 'MESH:D008939', (40, 48))
59294	26673009	Given the potent inhibitory effects of FTY720 on ACC growth in vitro, it is believed that FTY720 has the potential to be highly effective in treating ACC in vivo.	('FTY720', 'Gene', (39, 45))	('inhibitory', 'NegReg', (17, 27))	('ACC', 'Phenotype', 'HP:0006744', (150, 153))	('FTY720', 'Chemical', 'MESH:D000068876', (90, 96))	('ACC', 'Disease', (150, 153))	('FTY720', 'Var', (90, 96))	('FTY720', 'Chemical', 'MESH:D000068876', (39, 45))	('ACC', 'Phenotype', 'HP:0006744', (49, 52))
59295	26673009	Thus, we sought to determine the inhibition effect of FTY720 on the tumor growth of H295R cell xenograft.	('tumor', 'Disease', (68, 73))	('H295R', 'CellLine', 'CVCL:0458', (84, 89))	('FTY720', 'Chemical', 'MESH:D000068876', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('FTY720', 'Var', (54, 60))
59296	26673009	When tumors reached 70-100 mm3, saline or FTY720 (10 mg/kg) was administered by IP injection per day for 10 days and tumor growth was observed for more 10 days after the termination of treatment.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('FTY720', 'Var', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (117, 122))	('FTY720', 'Chemical', 'MESH:D000068876', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('saline', 'Chemical', 'MESH:D012965', (32, 38))
59298	26673009	Tumor volume was significantly lower in FTY720-treated mice as compared with control mice (Figure 6A and 6B; P < 0.05).	('mice', 'Species', '10090', (85, 89))	('Tumor volume', 'CPA', (0, 12))	('FTY720', 'Chemical', 'MESH:D000068876', (40, 46))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('FTY720-treated', 'Var', (40, 54))	('mice', 'Species', '10090', (55, 59))	('lower', 'NegReg', (31, 36))
59300	26673009	Compared with control group, the mean tumor weight was significantly less in FTY720-treated group without affecting body weight obviously (P < 0.01; Figure 6C and 6D).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('FTY720-treated', 'Var', (77, 91))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('FTY720', 'Chemical', 'MESH:D000068876', (77, 83))	('less', 'NegReg', (69, 73))
59306	26673009	We found that SphK1 is upregulated in ACC and that high expression of SphK1 significantly associated with advanced stage and poorer overall survival in ACC patients.	('patients', 'Species', '9606', (156, 164))	('ACC', 'Disease', (38, 41))	('upregulated', 'PosReg', (23, 34))	('ACC', 'Phenotype', 'HP:0006744', (152, 155))	('poorer', 'NegReg', (125, 131))	('overall', 'MPA', (132, 139))	('SphK1', 'Gene', '8877', (14, 19))	('SphK1', 'Gene', '8877', (70, 75))	('associated', 'Reg', (90, 100))	('SphK1', 'Gene', (14, 19))	('advanced stage', 'CPA', (106, 120))	('high', 'Var', (51, 55))	('SphK1', 'Gene', (70, 75))	('ACC', 'Phenotype', 'HP:0006744', (38, 41))
59309	26673009	In contrast, inhibition of SphK1 could attenuate lung cancer cell growth in vitro as well as in vivo.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('SphK1', 'Gene', '8877', (27, 32))	('inhibition', 'Var', (13, 23))	('SphK1', 'Gene', (27, 32))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('attenuate', 'NegReg', (39, 48))
59310	26673009	Consistent with previous studies, our results found that knockdown of SphK1 by siRNA markedly surpressed the ability of cell proliferation and invasion of two ACC cell lines, SW13 and H295R cells.	('cell proliferation', 'CPA', (120, 138))	('SW13', 'CellLine', 'CVCL:0542', (175, 179))	('invasion', 'CPA', (143, 151))	('knockdown', 'Var', (57, 66))	('SphK1', 'Gene', '8877', (70, 75))	('surpressed', 'NegReg', (94, 104))	('SphK1', 'Gene', (70, 75))	('H295R', 'CellLine', 'CVCL:0458', (184, 189))	('ACC', 'Phenotype', 'HP:0006744', (159, 162))
59313	26673009	FTY720 was originally developed as an immunosuppressive agent, which induces lymphopenia via an inhibition of lymphocytes' egress from lymphoid organs through its antagonist function on the lymphocytes' S1P receptors.	('lymphopenia', 'Phenotype', 'HP:0001888', (77, 88))	('lymphopenia', 'Disease', (77, 88))	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('FTY720', 'Var', (0, 6))	("lymphocytes' egress from lymphoid organs", 'CPA', (110, 150))	('lymphopenia', 'Disease', 'MESH:D008231', (77, 88))	('inhibition', 'NegReg', (96, 106))
59314	26673009	In addition, FTY720 could act as a SphK1 inhibitor to exhibit the antiproliferative effect in various cancers in a manner independent of S1P receptors.	('antiproliferative effect', 'CPA', (66, 90))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('FTY720', 'Var', (13, 19))	('FTY720', 'Chemical', 'MESH:D000068876', (13, 19))	('SphK1', 'Gene', '8877', (35, 40))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('SphK1', 'Gene', (35, 40))	('cancers', 'Disease', (102, 109))
59315	26673009	In the present study, we demonstrated for the first time that FTY720 is able to inhibit ACC cell growth not only in vitro, but also in vivo in a xenograft model.	('FTY720', 'Var', (62, 68))	('inhibit', 'NegReg', (80, 87))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('FTY720', 'Chemical', 'MESH:D000068876', (62, 68))	('ACC cell growth', 'CPA', (88, 103))
59316	26673009	In a mouse model of ACC, administration of FTY720 at 10 mg/kg/day inhibited tumor growth without causing detectable toxicity in vital organs.	('toxicity', 'Disease', 'MESH:D064420', (116, 124))	('toxicity', 'Disease', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('ACC', 'Phenotype', 'HP:0006744', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('inhibited', 'NegReg', (66, 75))	('mouse', 'Species', '10090', (5, 10))	('FTY720', 'Chemical', 'MESH:D000068876', (43, 49))	('FTY720', 'Var', (43, 49))	('ACC', 'Disease', (20, 23))
59317	26673009	FTY720 also has a capacity to inhibit SphK1 enzymatic activity, suggesting that FTY720 is a SphK1 inhibitor and may be a new anticancer agent candidate for ACC.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('SphK1', 'Gene', (92, 97))	('ACC', 'Phenotype', 'HP:0006744', (156, 159))	('inhibit', 'NegReg', (30, 37))	('SphK1', 'Gene', '8877', (38, 43))	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('cancer', 'Disease', (129, 135))	('SphK1', 'Gene', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('FTY720', 'Chemical', 'MESH:D000068876', (80, 86))	('FTY720', 'Var', (80, 86))	('SphK1', 'Gene', '8877', (92, 97))
59318	26673009	Although the evidence has highlighted the potent antitumor effect of FTY720 on ACC, the molecular mechanism is still unclear.	('ACC', 'Disease', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('FTY720', 'Chemical', 'MESH:D000068876', (69, 75))	('FTY720', 'Var', (69, 75))	('tumor', 'Disease', (53, 58))	('ACC', 'Phenotype', 'HP:0006744', (79, 82))
59319	26673009	To explore the mechanisms underlying the antitumor effects of FTY720, we tested the effect of FTY720 on the MAPK and PI3K/AKT pathways, which have been demonstrated to be involved in tumor progression.	('tested', 'Reg', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MAPK', 'Gene', '5594', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('MAPK', 'Gene', (108, 112))	('FTY720', 'Chemical', 'MESH:D000068876', (62, 68))	('FTY720', 'Var', (94, 100))	('AKT', 'Gene', '207', (122, 125))	('tumor', 'Disease', (183, 188))	('FTY720', 'Chemical', 'MESH:D000068876', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('AKT', 'Gene', (122, 125))
59321	26673009	It was consistent with our finding that FTY720 significantly inhibited the activity of the MAPK and PI3K/AKT pathways.	('MAPK', 'Gene', (91, 95))	('FTY720', 'Chemical', 'MESH:D000068876', (40, 46))	('inhibited', 'NegReg', (61, 70))	('AKT', 'Gene', '207', (105, 108))	('AKT', 'Gene', (105, 108))	('activity', 'MPA', (75, 83))	('FTY720', 'Var', (40, 46))	('MAPK', 'Gene', '5594', (91, 95))
59322	26673009	FTY720 strongly inhibited phosphorylation of PI3K and AKT as well as ERK expression.	('inhibited', 'NegReg', (16, 25))	('AKT', 'Gene', '207', (54, 57))	('FTY720', 'Chemical', 'MESH:D000068876', (0, 6))	('FTY720', 'Var', (0, 6))	('expression', 'MPA', (73, 83))	('PI3K', 'Pathway', (45, 49))	('AKT', 'Gene', (54, 57))	('ERK', 'Gene', '5594', (69, 72))	('ERK', 'Gene', (69, 72))	('phosphorylation', 'MPA', (26, 41))
59324	26673009	Mitotane is effective at inducing a reduction of cell viability in H295R but not in SW13 cells.	('H295R', 'Var', (67, 72))	('H295R', 'CellLine', 'CVCL:0458', (67, 72))	('cell viability', 'CPA', (49, 63))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('reduction', 'NegReg', (36, 45))	('SW13', 'CellLine', 'CVCL:0542', (84, 88))
59325	26673009	In this study, we investigated the effect of combining mitotane with FTY720 in ACC cells, and the results showed that the combination only resulted in a greater anti-proliferative effect over single agent treatment in SW13 cells, indicating that the combined therapy of SphK1 inhibition and mitotane may not be always favorable for ACC patients.	('SphK1', 'Gene', (270, 275))	('mitotane', 'Chemical', 'MESH:D008939', (291, 299))	('anti-proliferative effect', 'CPA', (161, 186))	('greater', 'PosReg', (153, 160))	('ACC', 'Phenotype', 'HP:0006744', (332, 335))	('patients', 'Species', '9606', (336, 344))	('FTY720', 'Chemical', 'MESH:D000068876', (69, 75))	('FTY720', 'Var', (69, 75))	('mitotane', 'Chemical', 'MESH:D008939', (55, 63))	('ACC', 'Disease', (332, 335))	('ACC', 'Phenotype', 'HP:0006744', (79, 82))	('SW13', 'CellLine', 'CVCL:0542', (218, 222))	('SphK1', 'Gene', '8877', (270, 275))
59326	26673009	Accumulating evidences have indicated that upreguration of SphK1 could induce cancer cells resistance to apoptosis, and FTY720 has also been shown to be a potent apoptosis inducer in various cancer cells.	('FTY720', 'Chemical', 'MESH:D000068876', (120, 126))	('FTY720', 'Var', (120, 126))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('SphK1', 'Gene', '8877', (59, 64))	('cancer', 'Disease', (78, 84))	('SphK1', 'Gene', (59, 64))	('resistance to apoptosis', 'CPA', (91, 114))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('upreguration', 'PosReg', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('induce', 'PosReg', (71, 77))
59327	26673009	In the present study, inhibition of SphK activity by FTY720 could induce apoptosis in ACC in vitro, and the combination of FTY720 and mitotane had a significant enhancement effect on the apoptotic rate in SW13 cells.	('FTY720', 'Var', (123, 129))	('SphK', 'Gene', '8877', (36, 40))	('FTY720', 'Chemical', 'MESH:D000068876', (123, 129))	('mitotane', 'Chemical', 'MESH:D008939', (134, 142))	('SphK', 'Gene', (36, 40))	('induce', 'Reg', (66, 72))	('inhibition', 'NegReg', (22, 32))	('apoptosis', 'CPA', (73, 82))	('SW13', 'CellLine', 'CVCL:0542', (205, 209))	('apoptotic rate', 'CPA', (187, 201))	('FTY720', 'Chemical', 'MESH:D000068876', (53, 59))	('ACC', 'Phenotype', 'HP:0006744', (86, 89))	('FTY720', 'Var', (53, 59))	('combination', 'Interaction', (108, 119))	('enhancement', 'PosReg', (161, 172))
59329	26673009	In addition, inhibition of SphK1, using both FTY720 and siRNA, could suppress ACC progression in vitro and in vivo, suggesting that SphK1 inhibition might represent new and potential strategies against human ACC.	('SphK1', 'Gene', (132, 137))	('SphK1', 'Gene', '8877', (27, 32))	('inhibition', 'Var', (13, 23))	('human', 'Species', '9606', (202, 207))	('FTY720', 'Chemical', 'MESH:D000068876', (45, 51))	('ACC', 'Phenotype', 'HP:0006744', (208, 211))	('FTY720', 'Var', (45, 51))	('SphK1', 'Gene', (27, 32))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('SphK1', 'Gene', '8877', (132, 137))	('ACC', 'Disease', (78, 81))	('suppress', 'NegReg', (69, 77))
59345	26673009	The membranes were blocked and then incubated overnight at 4 C with primary antibodies: anti-SphK1, anti-PI3K, antiphospho-PI3K (Y607), anti-AKT, antiphospho-AKT (S473), anti-ERK, antiphospho-ERK (pT202/pY204 + pT185/pY187) and beta-actin (Abcam, Cambridge, MA, USA).	('beta-actin', 'Gene', '728378', (228, 238))	('beta-actin', 'Gene', (228, 238))	('S473', 'Var', (163, 167))	('anti-PI3K', 'Var', (100, 109))	('AKT', 'Gene', (141, 144))	('ERK', 'Gene', '5594', (175, 178))	('ERK', 'Gene', '5594', (192, 195))	('SphK1', 'Gene', '8877', (93, 98))	('AKT', 'Gene', '207', (158, 161))	('SphK1', 'Gene', (93, 98))	('AKT', 'Gene', '207', (141, 144))	('ERK', 'Gene', (175, 178))	('ERK', 'Gene', (192, 195))	('AKT', 'Gene', (158, 161))
59422	26475302	However, a positive nuclear staining against EG-VEGF was associated with a significantly higher mortality in patients with ACC (hazard ratio (HR) for death 2.78; 95 % confidence interval (CI) 1.27-6.08; p = 0.01) (Fig.	('mortality', 'MPA', (96, 105))	('death', 'Disease', 'MESH:D003643', (150, 155))	('death', 'Disease', (150, 155))	('patients', 'Species', '9606', (109, 117))	('EG-VEGF', 'Gene', (45, 52))	('ACC', 'Phenotype', 'HP:0006744', (123, 126))	('higher', 'PosReg', (89, 95))	('positive', 'Var', (11, 19))
59423	26475302	Similarly, patients with a positive nuclear staining against PKR1 were more likely to die compared to patients with a negative nuclear expression of PKR1 (HR 2.22; 95 % CI 1.23-4.03; p < 0.01) (Fig.	('die', 'Disease', (86, 89))	('PKR1', 'Gene', (61, 65))	('patients', 'Species', '9606', (102, 110))	('positive nuclear staining', 'Var', (27, 52))	('patients', 'Species', '9606', (11, 19))
59424	26475302	The prognostic value was even higher when either EG-VEGF or PKR1 protein or both were expressed in the nucleus of ACC cells compared to patients with none of these factors in the nucleus (HR 5.65; 95 % CI 1.38-23.12; p = 0.02) (Fig.	('ACC', 'Phenotype', 'HP:0006744', (114, 117))	('PKR1', 'Gene', (60, 64))	('EG-VEGF', 'Var', (49, 56))	('higher', 'PosReg', (30, 36))	('patients', 'Species', '9606', (136, 144))
59427	26475302	The key finding of our study is the strong prognostic potential of nuclear staining of EG-VEGF and its receptor PKR1 for patient outcome in ACC.	('nuclear staining', 'Var', (67, 83))	('EG-VEGF', 'Gene', (87, 94))	('ACC', 'Phenotype', 'HP:0006744', (140, 143))	('ACC', 'Disease', (140, 143))	('patient', 'Species', '9606', (121, 128))
59435	26475302	Of note, if either EG-VEGF or PKR1 or both of them are present in the nucleus, the likelihood that patients die from ACC is more than five times higher than if none of these factors are detectable.	('ACC', 'Phenotype', 'HP:0006744', (117, 120))	('ACC', 'Disease', (117, 120))	('PKR1', 'Var', (30, 34))	('patients', 'Species', '9606', (99, 107))	('EG-VEGF', 'Var', (19, 26))	('higher', 'PosReg', (145, 151))
59504	24761076	In our study, duration of surgery was longer and blood loss was slightly larger in patients with tumors >6 cm as compared to patients with smaller adrenal masses.	('blood loss', 'Disease', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('>6 cm', 'Var', (104, 109))	('blood loss', 'Disease', 'MESH:D006473', (49, 59))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('patients', 'Species', '9606', (83, 91))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('smaller adrenal', 'Phenotype', 'HP:0000835', (139, 154))	('patients', 'Species', '9606', (125, 133))
59510	24761076	Causes of bleeding can be: Injuries to adrenal capsule, problems to close the adrenal vein or tears in the inferior cava or renal vein [Table 4].	('renal vein', 'Disease', (124, 134))	('tears', 'Phenotype', 'HP:0009926', (94, 99))	('renal vein', 'Disease', (80, 90))	('renal vein', 'Disease', 'MESH:D007674', (80, 90))	('bleeding', 'Disease', 'MESH:D006470', (10, 18))	('tears', 'Var', (94, 99))	('bleeding', 'Disease', (10, 18))	('renal vein', 'Disease', 'MESH:D007674', (124, 134))
59723	32357912	Gene amplification, gene mutation, and abnormalities in upstream and downstream regulators of cyclin D, CDK4, and CDK6 can all lead to abnormal activation of the cyclin D-CDK4/6-Rb pathway.	('CDK6', 'Gene', (114, 118))	('CDK6', 'Gene', '1021', (114, 118))	('CDK4/6', 'Gene', '1019;1021', (171, 177))	('cyclin', 'Gene', (94, 100))	('cyclin', 'Gene', (162, 168))	('Rb', 'Phenotype', 'HP:0009919', (178, 180))	('abnormalities', 'Var', (39, 52))	('lead to', 'Reg', (127, 134))	('CDK4/6', 'Gene', (171, 177))	('CDK4', 'Gene', (171, 175))	('gene mutation', 'Var', (20, 33))	('activation', 'PosReg', (144, 154))	('cyclin', 'Gene', '5111', (162, 168))	('CDK4', 'Gene', (104, 108))	('CDK4', 'Gene', '1019', (171, 175))	('cyclin', 'Gene', '5111', (94, 100))	('CDK4', 'Gene', '1019', (104, 108))
59733	32357912	Moreover, the cdk4, cdk6, and e2f1 genes show extensive gene amplification and gene mutation in various tumors; deep deletion and gene mutation of the rb1 gene were observed in various tumors, while gene fusion and multiple alterations in these four genes are rare (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cdk4', 'Gene', (14, 18))	('gene mutation', 'Var', (130, 143))	('tumors', 'Disease', (185, 191))	('tumors', 'Disease', (104, 110))	('rb1', 'Gene', '5925', (151, 154))	('cdk4', 'Gene', '1019', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('observed', 'Reg', (165, 173))	('cdk6', 'Gene', '1021', (20, 24))	('e2f1', 'Gene', (30, 34))	('deep deletion', 'Var', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('cdk6', 'Gene', (20, 24))	('rb1', 'Gene', (151, 154))	('e2f1', 'Gene', '1869', (30, 34))
59734	32357912	These gene changes may explain the difference in the clinical efficacy of and drug resistance to CDK4/6 inhibitors in different tumors.	('CDK4/6', 'Gene', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('changes', 'Var', (11, 18))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('CDK4/6', 'Gene', '1019;1021', (97, 103))	('drug resistance', 'Phenotype', 'HP:0020174', (78, 93))
59735	32357912	Based on the analysis from the UALCAN cancer database, moderate expression of the cdk4 gene in KIRC, LGG, KIRP, MESO, KICH, and SKCM was significantly negatively related to overall survival (p < 0.05); high expression of the cdk4 gene in LIHC was closely related to worse overall survival than low expression and may be a sensitive marker for predicting the prognosis of LIHC.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('negatively', 'NegReg', (151, 161))	('cdk4', 'Gene', '1019', (225, 229))	('high', 'Var', (202, 206))	('LIHC', 'Disease', (371, 375))	('cdk4', 'Gene', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('cdk4', 'Gene', '1019', (82, 86))	('cdk4', 'Gene', (82, 86))
59741	32357912	CDK4/6 inhibitors hinder the transition from G1 phase to S phase by inhibiting Rb phosphorylation and E2F release and induce tumor cycle arrest at G1 phase, which can inhibit tumor cell growth and cause tumor regression.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (203, 208))	('inhibit', 'NegReg', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('CDK4/6', 'Gene', (0, 6))	('inhibiting', 'NegReg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('inhibitors', 'Var', (7, 17))	('cause', 'Reg', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (175, 180))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('induce', 'Reg', (118, 124))	('hinder', 'NegReg', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('arrest', 'Disease', (137, 143))	('tumor', 'Disease', (125, 130))	('Rb', 'Phenotype', 'HP:0009919', (79, 81))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('E2F release', 'MPA', (102, 113))
59747	32357912	The mutation rate of cell cycle-related genes in breast cancer is as high as 38%.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutation', 'Var', (4, 12))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cell cycle-related genes', 'Gene', (21, 45))
59748	32357912	Increased expression of cyclin D causes continuous phosphorylation of Rb and leads to continuous proliferation of breast cancer cells; blocking CDK4/6 exerts a lethal effect on breast cancer cells.	('breast cancer', 'Disease', (177, 190))	('CDK4/6', 'Gene', '1019;1021', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('cyclin', 'Gene', '5111', (24, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('CDK4/6', 'Gene', (144, 150))	('phosphorylation', 'MPA', (51, 66))	('Rb', 'Phenotype', 'HP:0009919', (70, 72))	('cyclin', 'Gene', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('blocking', 'Var', (135, 143))	('breast cancer', 'Disease', (114, 127))	('leads to', 'Reg', (77, 85))
59767	32357912	The major adverse effects of CDK4/6 inhibitors are leukopenia and neutropenia, mainly caused by palbociclib and ribociclib.	('CDK4/6', 'Gene', (29, 35))	('leukopenia', 'Disease', 'MESH:D007970', (51, 61))	('leukopenia', 'Disease', (51, 61))	('ribociclib', 'Chemical', 'MESH:C000589651', (112, 122))	('palbociclib', 'Chemical', 'MESH:C500026', (96, 107))	('neutropenia', 'Disease', 'MESH:D009503', (66, 77))	('neutropenia', 'Phenotype', 'HP:0001875', (66, 77))	('palbociclib', 'Var', (96, 107))	('CDK4/6', 'Gene', '1019;1021', (29, 35))	('leukopenia', 'Phenotype', 'HP:0001882', (51, 61))	('neutropenia', 'Disease', (66, 77))
59768	32357912	CDK4/6 inhibitors can also cause gastrointestinal side effects such as diarrhea, nausea, and vomiting.	('nausea', 'Disease', (81, 87))	('nausea', 'Disease', 'MESH:D009325', (81, 87))	('diarrhea', 'Disease', (71, 79))	('diarrhea', 'Disease', 'MESH:D003967', (71, 79))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('diarrhea', 'Phenotype', 'HP:0002014', (71, 79))	('inhibitors', 'Var', (7, 17))	('cause', 'Reg', (27, 32))	('vomiting', 'Phenotype', 'HP:0002013', (93, 101))	('CDK4/6', 'Gene', (0, 6))	('vomiting', 'Disease', (93, 101))	('vomiting', 'Disease', 'MESH:D014839', (93, 101))	('gastrointestinal side effects', 'MPA', (33, 62))	('nausea', 'Phenotype', 'HP:0002018', (81, 87))
59776	32357912	CDK4/6 inhibitors may have the potential to be widely applied in multiple cancers, similar to traditional chemotherapy drugs such as cisplatin or paclitaxel.	('multiple cancers', 'Disease', (65, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('paclitaxel', 'Chemical', 'MESH:D017239', (146, 156))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('multiple cancers', 'Disease', 'MESH:D009369', (65, 81))	('inhibitors', 'Var', (7, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('CDK4/6', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
59778	32357912	Yang's study showed that CDK4/6 inhibitors increased the sensitivity of acute myeloid leukemia cells to cytotoxic drugs.	('acute myeloid leukemia', 'Disease', (72, 94))	('inhibitors', 'Var', (32, 42))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (72, 94))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (78, 94))	('CDK4/6', 'Gene', '1019;1021', (25, 31))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (72, 94))	('increased', 'PosReg', (43, 52))	('sensitivity', 'MPA', (57, 68))	('CDK4/6', 'Gene', (25, 31))
59779	32357912	Patnaik and Taylor's study showed that CDK4/6 inhibitors achieved disease control rates of 49% and 44%, respectively, in non-small-cell lung cancer patients (n = 68) and melanoma patients (n = 18).	('patients', 'Species', '9606', (148, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('inhibitors', 'Var', (46, 56))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('CDK4/6', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('disease control', 'CPA', (66, 81))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('patients', 'Species', '9606', (179, 187))	('CDK4/6', 'Gene', '1019;1021', (39, 45))	('lung cancer', 'Disease', (136, 147))
59780	32357912	Adkins' study indicated an objective response rate of 39% for CDK4/6 inhibitors in patients with head and neck squamous cell carcinoma (n = 62).	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('neck squamous cell carcinoma', 'Disease', (106, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (106, 134))	('CDK4/6', 'Gene', '1019;1021', (62, 68))	('patients', 'Species', '9606', (83, 91))	('CDK4/6', 'Gene', (62, 68))	('inhibitors', 'Var', (69, 79))
59791	32357912	First, CDK4/6 inhibitors downregulate E2F transcription factor-related gene expression and upregulate major histocompatibility complex class I molecule expression in breast cancer cell lines; CDK4/6 inhibitors activate endogenous retroviral components in tumor cells, stimulating the production of type III interferons to promote tumor antigen presentation.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('E2F transcription factor-related gene', 'Gene', (38, 75))	('tumor', 'Disease', (330, 335))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('inhibitors', 'Var', (199, 209))	('breast cancer', 'Disease', (166, 179))	('CDK4/6', 'Gene', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('activate', 'PosReg', (210, 218))	('CDK4/6', 'Gene', '1019;1021', (192, 198))	('stimulating', 'PosReg', (268, 279))	('expression', 'MPA', (152, 162))	('production', 'MPA', (284, 294))	('upregulate', 'PosReg', (91, 101))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('CDK4/6', 'Gene', '1019;1021', (7, 13))	('downregulate', 'NegReg', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('promote', 'PosReg', (322, 329))	('expression', 'MPA', (76, 86))	('CDK4/6', 'Gene', (192, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))
59792	32357912	Second, CDK4/6 inhibitors inhibit the proliferation of regulatory T (Treg) cells and DNA methyltransferase 1 expression in Treg cells, resulting in promoter hypomethylation and suppression of E2F release; other studies demonstrated that the expression of CDK6 in Treg cells was higher than that of other T cell subtypes.	('E2F release', 'MPA', (192, 203))	('proliferation', 'CPA', (38, 51))	('expression', 'MPA', (109, 119))	('promoter hypomethylation', 'MPA', (148, 172))	('CDK4/6', 'Gene', (8, 14))	('CDK6', 'Gene', (255, 259))	('inhibit', 'NegReg', (26, 33))	('expression', 'MPA', (241, 251))	('DNA methyltransferase 1', 'Gene', '1786', (85, 108))	('CDK6', 'Gene', '1021', (255, 259))	('suppression', 'NegReg', (177, 188))	('CDK4/6', 'Gene', '1019;1021', (8, 14))	('DNA methyltransferase 1', 'Gene', (85, 108))	('higher', 'PosReg', (278, 284))	('inhibitors', 'Var', (15, 25))
59794	32357912	Furthermore, CDK4/6 inhibitors promote tumor cell clearance by enhancing cytotoxic T cells (CTLs).	('cytotoxic T cells', 'CPA', (73, 90))	('CDK4/6', 'Gene', '1019;1021', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('enhancing', 'PosReg', (63, 72))	('inhibitors', 'Var', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('CDK4/6', 'Gene', (13, 19))	('promote', 'PosReg', (31, 38))	('tumor', 'Disease', (39, 44))
59795	32357912	CDK6 is an upstream regulatory element of nuclear factor of activated T cells (NFAT), and CDK4/6 inhibitors suppress NFAT phosphorylation, the activation of CTLs, and its ability to kill tumor cells.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('phosphorylation', 'CPA', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('NFAT', 'Protein', (117, 121))	('CDK6', 'Gene', (0, 4))	('CDK6', 'Gene', '1021', (0, 4))	('tumor', 'Disease', (187, 192))	('CTLs', 'Protein', (157, 161))	('CDK4/6', 'Gene', '1019;1021', (90, 96))	('activation', 'PosReg', (143, 153))	('CDK4/6', 'Gene', (90, 96))	('suppress', 'NegReg', (108, 116))	('inhibitors', 'Var', (97, 107))
59796	32357912	Finally, the Cyclin D1-CDK4 complex directly phosphorylates speckle-type POZ protein (SPOP), and CDK4/6 inhibitors can enhance the immune escape of tumors by decreasing the ubiquitination of SPOP and reducing the degradation of PD-L1.	('enhance', 'PosReg', (119, 126))	('CDK4/6', 'Gene', (97, 103))	('speckle-type POZ protein', 'Gene', '8405', (60, 84))	('SPOP', 'Gene', (86, 90))	('CDK4', 'Gene', '1019', (23, 27))	('reducing', 'NegReg', (200, 208))	('inhibitors', 'Var', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SPOP', 'Gene', '8405', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('CDK4/6', 'Gene', '1019;1021', (97, 103))	('CDK4', 'Gene', (97, 101))	('PD-L1', 'Gene', (228, 233))	('speckle-type POZ protein', 'Gene', (60, 84))	('SPOP', 'Gene', (191, 195))	('ubiquitination', 'MPA', (173, 187))	('PD-L1', 'Gene', '29126', (228, 233))	('tumors', 'Disease', (148, 154))	('Cyclin D1', 'Gene', '595', (13, 22))	('Cyclin D1', 'Gene', (13, 22))	('SPOP', 'Gene', '8405', (86, 90))	('CDK4', 'Gene', '1019', (97, 101))	('CDK4', 'Gene', (23, 27))	('decreasing', 'NegReg', (158, 168))	('degradation', 'MPA', (213, 224))	('tumors', 'Disease', 'MESH:D009369', (148, 154))
59801	32357912	Teo's study showed that CDK4/6 inhibitors combined with PI3K inhibitors increased the apoptosis of triple-negative breast cancer cell lines and induced persistent tumor regression in vivo.	('PI3', 'Gene', (56, 59))	('increased', 'PosReg', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('CDK4/6', 'Gene', '1019;1021', (24, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CDK4/6', 'Gene', (24, 30))	('induced', 'Reg', (144, 151))	('tumor', 'Disease', (163, 168))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PI3', 'Gene', '5266', (56, 59))	('breast cancer', 'Disease', (115, 128))	('inhibitors', 'Var', (31, 41))	('apoptosis', 'CPA', (86, 95))
59803	32357912	EGFR/HER2 inhibitors combined with CDK4/6 inhibitors may increase the sensitivity to EGFR inhibitor-resistant lung cancer cells.	('EGFR', 'Gene', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('EGFR', 'Gene', (0, 4))	('HER2', 'Gene', (5, 9))	('HER2', 'Gene', '2064', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('sensitivity', 'MPA', (70, 81))	('lung cancer', 'Disease', (110, 121))	('CDK4/6', 'Gene', '1019;1021', (35, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('increase', 'PosReg', (57, 65))	('inhibitors', 'Var', (10, 20))	('EGFR', 'Gene', '1956', (85, 89))	('EGFR', 'Gene', '1956', (0, 4))	('CDK4/6', 'Gene', (35, 41))
59804	32357912	Goel's study demonstrated that CDK4/6 inhibitors augmented the efficacy of EGFR inhibitors in esophageal squamous cell carcinoma and reversed drug resistance.	('reversed', 'Reg', (133, 141))	('augmented', 'PosReg', (49, 58))	('CDK4/6', 'Gene', (31, 37))	('inhibitors', 'Var', (38, 48))	('CDK4/6', 'Gene', '1019;1021', (31, 37))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (94, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('EGFR', 'Gene', '1956', (75, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('efficacy', 'MPA', (63, 71))	('drug resistance', 'Phenotype', 'HP:0020174', (142, 157))	('drug resistance', 'MPA', (142, 157))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))	('EGFR', 'Gene', (75, 79))	('inhibitors', 'Var', (80, 90))
59808	32357912	Chen's study showed that RAF inhibitors combined with CDK4/6 inhibitors improve the therapeutic effects of RAS or BRAF mutant tumors.	('RAS', 'Disease', (107, 110))	('RAF', 'Gene', '22882', (25, 28))	('BRAF', 'Gene', (114, 118))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('therapeutic effects', 'CPA', (84, 103))	('BRAF', 'Gene', '673', (114, 118))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('improve', 'PosReg', (72, 79))	('CDK4/6', 'Gene', (54, 60))	('RAF', 'Gene', '22882', (115, 118))	('RAF', 'Gene', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutant', 'Var', (119, 125))	('CDK4/6', 'Gene', '1019;1021', (54, 60))	('RAF', 'Gene', (25, 28))
59811	32357912	Ribociclib combined with the ALK inhibitor ceritinib showed excellent therapeutic effects in ALK mutant neuroblastoma.	('ALK', 'Gene', (29, 32))	('neuroblastoma', 'Disease', (104, 117))	('ALK', 'Gene', '238', (93, 96))	('neuroblastoma', 'Phenotype', 'HP:0003006', (104, 117))	('mutant', 'Var', (97, 103))	('ceritinib', 'Chemical', 'MESH:C586847', (43, 52))	('ALK', 'Gene', '238', (29, 32))	('ALK', 'Gene', (93, 96))	('neuroblastoma', 'Disease', 'MESH:D009447', (104, 117))
59814	32357912	Vijayaraghavan's research showed that CDK4/6 inhibitors combined with autophagy inhibitors can maintain the integrity of the G1/S checkpoint and may be a new therapeutic pattern for multiple solid tumors.	('maintain', 'PosReg', (95, 103))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('integrity', 'CPA', (108, 117))	('CDK4/6', 'Gene', '1019;1021', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('inhibitors', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('CDK4/6', 'Gene', (38, 44))	('tumors', 'Disease', (197, 203))
59815	32357912	Francis's study confirmed that CDK4/6 inhibitors resensitize Rb-positive sarcoma cells to the Weel kinase inhibitor AZD1775.	('Rb', 'Phenotype', 'HP:0009919', (61, 63))	('AZD1775', 'Chemical', 'MESH:C549567', (116, 123))	('sarcoma', 'Disease', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('CDK4/6', 'Gene', '1019;1021', (31, 37))	('inhibitors', 'Var', (38, 48))	('CDK4/6', 'Gene', (31, 37))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
59818	32357912	Some researchers believe that CCNE1 amplification causes acquired resistance to CDK4/6 inhibitors, and that sensitivity can be restored by targeting CDK2.	('CDK2', 'Gene', '1017', (149, 153))	('CCNE1', 'Gene', '898', (30, 35))	('CCNE1', 'Gene', (30, 35))	('amplification', 'Var', (36, 49))	('CDK2', 'Gene', (149, 153))	('causes', 'Reg', (50, 56))	('CDK4/6', 'Gene', '1019;1021', (80, 86))	('CDK4/6', 'Gene', (80, 86))
59819	32357912	In addition, activating cyclin D gene mutations may enhance sensitivity to CDK4/6 inhibitors, while cyclin D deficiency is associated with CDK4/6 inhibitor resistance.	('CDK4/6', 'Gene', (139, 145))	('CDK4/6', 'Gene', '1019;1021', (75, 81))	('activating', 'PosReg', (13, 23))	('CDK4/6', 'Gene', (75, 81))	('cyclin', 'Gene', '5111', (24, 30))	('enhance', 'PosReg', (52, 59))	('CDK4/6', 'Gene', '1019;1021', (139, 145))	('cyclin', 'Gene', '5111', (100, 106))	('cyclin', 'Gene', (24, 30))	('mutations', 'Var', (38, 47))	('cyclin', 'Gene', (100, 106))
59823	32357912	A recent study revealed that amplification of fibroblast growth factor receptor 1 (FGFR1) might cause resistance to CDK4/6 inhibitors.	('fibroblast growth factor receptor 1', 'Gene', (46, 81))	('amplification', 'Var', (29, 42))	('CDK4/6', 'Gene', (116, 122))	('cause', 'Reg', (96, 101))	('FGFR1', 'Gene', (83, 88))	('fibroblast growth factor receptor 1', 'Gene', '2260', (46, 81))	('FGFR1', 'Gene', '2260', (83, 88))	('CDK4/6', 'Gene', '1019;1021', (116, 122))
59825	32357912	Studies have shown that deletion of p16 decreases the endogenous inhibition of CDK4/6 and that low levels of p16 may suggest that cells are sensitive to CDK4/6 inhibitors.	('p16', 'Gene', (109, 112))	('CDK4/6', 'Gene', (153, 159))	('endogenous inhibition', 'MPA', (54, 75))	('p16', 'Gene', '1029', (36, 39))	('CDK4/6', 'Gene', '1019;1021', (79, 85))	('p16', 'Gene', '1029', (109, 112))	('CDK4/6', 'Gene', '1019;1021', (153, 159))	('deletion', 'Var', (24, 32))	('decreases', 'NegReg', (40, 49))	('CDK4/6', 'Gene', (79, 85))	('p16', 'Gene', (36, 39))
59827	32357912	However, Wang's study showed that approximately 85% of breast cancer cells have normal Rb status, but due to the rare Rb deletion in ER+ breast cancer, it is less sensitive as a predictive marker.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('Rb', 'Phenotype', 'HP:0009919', (118, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Rb status', 'MPA', (87, 96))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('Rb', 'Phenotype', 'HP:0009919', (87, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('deletion', 'Var', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
59832	32357912	CDK4/6 inhibitors achieve striking antitumor effects by regulating the cell cycle.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('inhibitors', 'Var', (7, 17))	('regulating', 'Reg', (56, 66))	('tumor', 'Disease', (39, 44))	('CDK4/6', 'Gene', (0, 6))	('cell cycle', 'CPA', (71, 81))
59835	32357912	CDK4/6 inhibitors have great potential to become broad-spectrum antitumor drugs.	('tumor', 'Disease', (68, 73))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('inhibitors', 'Var', (7, 17))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CDK4/6', 'Gene', (0, 6))
59862	31775884	For instance, germline TP53 mutations are less common in adults with ACC, and IGF2 overexpression is a marker of poor prognosis in adult ACC patients, but not in pediatric patients.	('ACC', 'Disease', (69, 72))	('TP53', 'Gene', (23, 27))	('IGF2', 'Gene', '3481', (78, 82))	('ACC', 'Disease', 'MESH:D018268', (137, 140))	('ACC', 'Disease', 'MESH:D018268', (69, 72))	('overexpression', 'PosReg', (83, 97))	('IGF2', 'Gene', (78, 82))	('TP53', 'Gene', '7157', (23, 27))	('patients', 'Species', '9606', (172, 180))	('ACC', 'Disease', (137, 140))	('mutations', 'Var', (28, 37))	('patients', 'Species', '9606', (141, 149))
59905	31775884	Some have reported that there were no correlations between age, sex, tumor size to the outcome of ACC, while others showed that age, sex, high tumor grade, and tumor size were significantly associated with prognosis.	('ACC', 'Disease', 'MESH:D018268', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('associated', 'Reg', (190, 200))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('ACC', 'Disease', (98, 101))	('tumor', 'Disease', (160, 165))	('high', 'Var', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
59952	31169702	In order to distinguish the tumor between the HCC and other hepatic tumors, gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) was performed, which also depicted a 1.5-cm well-demarcated round subcapsular mass with typical imaging findings of HCC such as hyper-arterial enhancement, delayed washout, and hypointensity on hepatobiliary phase on gadoxetic acid-enhanced MR images (Fig.	('gadoxetic acid', 'Chemical', 'MESH:C073590', (76, 90))	('tumor', 'Disease', (28, 33))	('hepatic tumors', 'Disease', (60, 74))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('hepatobiliary', 'Disease', (333, 346))	('delayed washout', 'MPA', (295, 310))	('tumor', 'Disease', (68, 73))	('hepatic tumor', 'Phenotype', 'HP:0002896', (60, 73))	('subcapsular mass', 'Phenotype', 'HP:0000523', (205, 221))	('HCC', 'Phenotype', 'HP:0001402', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('gadoxetic acid', 'Chemical', 'MESH:C073590', (356, 370))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('hepatobiliary', 'Disease', 'MESH:D004066', (333, 346))	('HCC', 'Disease', (255, 258))	('HCC', 'Phenotype', 'HP:0001402', (255, 258))	('hypointensity', 'Var', (316, 329))	('hepatic tumors', 'Disease', 'MESH:D056486', (60, 74))
60012	30107644	The results showed that recurrent mutations in MUC genes were significantly associated with better survival prognosis.	('better', 'PosReg', (92, 98))	('MUC', 'Gene', '100508689', (47, 50))	('MUC', 'Gene', (47, 50))	('associated', 'Reg', (76, 86))	('mutations', 'Var', (34, 43))
60013	30107644	Only a small part of RMGs was differentially expressed due to their own mutations and most of them were downregulated.	('RMGs', 'Chemical', '-', (21, 25))	('mutations', 'Var', (72, 81))	('RMGs', 'Gene', (21, 25))	('downregulated', 'NegReg', (104, 117))
60020	30107644	Mutations in cancer genome can influence molecular function of genes and signaling pathways, leading to cell differentiation, proliferation, and survival (Hanahan & Weinberg Robert, 2011; Watson, Takahashi, Futreal, & Chin, 2013).	('genes', 'Pathway', (63, 68))	('proliferation', 'CPA', (126, 139))	('leading to', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cell differentiation', 'CPA', (104, 124))	('influence', 'Reg', (31, 40))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Mutations', 'Var', (0, 9))	('signaling pathways', 'Pathway', (73, 91))	('survival', 'CPA', (145, 153))	('molecular function', 'MPA', (41, 59))
60024	30107644	TP53 (OMIM *191170) was reported as the most frequently mutated gene in diverse cancers, and patients with TP53 mutation tend to have worse prognosis (Wang & Sun, 2017).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (112, 120))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('patients', 'Species', '9606', (93, 101))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
60025	30107644	investigated 127 significantly mutated genes in 12 cancers and categorized them into 20 cellular processes, including Wnt/beta-catenin, MAPK, and PI3K signaling pathways (Kandoth et al., 2013).	('PI3K signaling pathways', 'Pathway', (146, 169))	('cancers', 'Disease', (51, 58))	('beta-catenin', 'Gene', '1499', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('beta-catenin', 'Gene', (122, 134))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('mutated', 'Var', (31, 38))
60027	30107644	For instance, 10 RMGs including KRAS (* 190070), TP53, CDKN2A (* 600160), and RREB1 (* 602209) were identified in Pancreatic Ductal Adenocarcinoma (PDAC), and it was revealed that the frequent disruptions in RAS-MAPK pathway played a pivotal role in this cancer (Network, 2014).	('CDKN2A', 'Gene', '1029', (55, 61))	('TP53', 'Gene', '7157', (49, 53))	('RMGs', 'Chemical', '-', (17, 21))	('cancer', 'Disease', (255, 261))	('* 600160', 'Var', (63, 71))	('PDAC', 'Phenotype', 'HP:0006725', (148, 152))	('disruptions', 'Reg', (193, 204))	('Pancreatic Ductal Adenocarcinoma', 'Disease', (114, 146))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('KRAS', 'Gene', '3845', (32, 36))	('Pancreatic Ductal Adenocarcinoma', 'Phenotype', 'HP:0006725', (114, 146))	('TP53', 'Gene', (49, 53))	('KRAS', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('RREB1', 'Gene', '6239', (78, 83))	('Pancreatic Ductal Adenocarcinoma', 'Disease', 'MESH:D021441', (114, 146))	('CDKN2A', 'Gene', (55, 61))	('RAS-MAPK pathway', 'Pathway', (208, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('RREB1', 'Gene', (78, 83))	('* 602209', 'Var', (85, 93))
60028	30107644	Besides, dozens of significantly mutated genes in various canonical signaling pathways were identified in Muscle-Invasive Bladder Cancer (BLCA), which highlighted the importance of these pathways in the disease (Robertson et al., 2017).	('Muscle-Invasive Bladder Cancer', 'Disease', 'MESH:D001749', (106, 136))	('Invasive Bladder', 'Phenotype', 'HP:0100645', (113, 129))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (122, 136))	('mutated', 'Var', (33, 40))	('Muscle-Invasive Bladder Cancer', 'Disease', (106, 136))	('BLCA', 'Phenotype', 'HP:0009725', (138, 142))
60031	30107644	Besides, it was reported that the mutations of six RMGs including TP53, KDR (* 191306), PIK3CA (* 171834), ATM (* 607585), AKT1 (* 164730), and KIT (* 164920) were associated with a poor prognosis in sporadic triple negative breast cancer (Pop et al., 2018).	('PIK3CA', 'Gene', '5290', (88, 94))	('TP53', 'Gene', '7157', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('* 191306', 'Var', (77, 85))	('AKT1', 'Gene', '207', (123, 127))	('KDR', 'Gene', '3791', (72, 75))	('* 164730', 'Var', (129, 137))	('* 171834', 'Var', (96, 104))	('PIK3CA', 'Gene', (88, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('* 164920', 'Var', (149, 157))	('AKT1', 'Gene', (123, 127))	('ATM', 'Gene', '472', (107, 110))	('TP53', 'Gene', (66, 70))	('* 607585', 'Var', (112, 120))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Disease', (225, 238))	('KIT', 'Gene', (144, 147))	('KDR', 'Gene', (72, 75))	('RMGs', 'Chemical', '-', (51, 55))	('ATM', 'Gene', (107, 110))
60032	30107644	The diagnostic and prognostic impacts of RMGs (e.g., EZH2 (* 601573), ELP3 (* 612722), and IDH2 (* 147650)) in lymphoma were surveyed for better clinical decision making (Rosenquist et al., 2016).	('* 601573', 'Var', (59, 67))	('* 147650', 'Var', (97, 105))	('ELP3', 'Gene', '55140', (70, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))	('IDH2', 'Gene', (91, 95))	('lymphoma', 'Disease', 'MESH:D008223', (111, 119))	('lymphoma', 'Disease', (111, 119))	('RMGs', 'Chemical', '-', (41, 45))	('IDH2', 'Gene', '3418', (91, 95))	('ELP3', 'Gene', (70, 74))	('* 612722', 'Var', (76, 84))	('EZH2', 'Gene', (53, 57))	('EZH2', 'Gene', '2146', (53, 57))
60033	30107644	Moreover, RMGs (e.g., TET2 (* 612839), DNMT3A (* 602769), BAP1 (* 603089), and ASXL1 (* 612990)) involved in histone modification, chromatin remodeling and DNA methylation were associated with adverse outcome in thymic carcinoma (Wang et al., 2014).	('DNMT3A', 'Gene', (39, 45))	('DNMT3A', 'Gene', '1788', (39, 45))	('* 612839', 'Var', (28, 36))	('BAP1', 'Gene', (58, 62))	('TET2', 'Gene', '54790', (22, 26))	('thymic carcinoma', 'Disease', 'MESH:D013945', (212, 228))	('thymic carcinoma', 'Disease', (212, 228))	('* 602769', 'Var', (47, 55))	('ASXL1', 'Gene', '171023', (79, 84))	('RMGs', 'Chemical', '-', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('associated', 'Reg', (177, 187))	('TET2', 'Gene', (22, 26))	('BAP1', 'Gene', '8314', (58, 62))	('* 603089', 'Var', (64, 72))	('ASXL1', 'Gene', (79, 84))	('* 612990', 'Var', (86, 94))
60049	30107644	The differences of overall survival time between RMG-mutation, RMG-MS or RMG-NS patients and RMG wild-type patients were shown by KM survival curves (log-rank test).	('RMG-NS', 'Disease', (73, 79))	('patients', 'Species', '9606', (80, 88))	('RMG-mutation', 'Var', (49, 61))	('RMG-NS', 'Disease', 'MESH:D009404', (73, 79))	('patients', 'Species', '9606', (107, 115))
60052	30107644	As a result, we identified 897 unique RMGs across 31 cancer types (Supporting Information Table S1).	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('RMGs', 'Var', (38, 42))	('RMGs', 'Chemical', '-', (38, 42))
60054	30107644	There were more than 100 RMGs in SKCM, STAD, LUSC, LUAD, ACC, and DLBC (see the abbreviations of cancer types in method section), indicating that these cancers were closely related to gene recurrent mutations.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('cancer', 'Disease', (152, 158))	('cancers', 'Disease', (152, 159))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('LUSC', 'Phenotype', 'HP:0030359', (45, 49))	('ACC', 'Phenotype', 'HP:0006744', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('RMGs', 'Chemical', '-', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (199, 208))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
60067	30107644	In addition, we identified 624 specifically mutated RMGs (smRMGs) that were only in a single cancer type (Figure 1d and Supporting Information Table S2).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('RMGs', 'Chemical', '-', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutated', 'Var', (44, 51))	('RMGs', 'Chemical', '-', (52, 56))
60071	30107644	We also detected another five smRMGs that mutated in nearly half of the samples in corresponding cancers, including PCDHAC2 in SKCM (53%), ZFPM1 in ACC (52%), VHL in KIRC (49%), GNAQ in UVM (49%), and ADAM6 in LUSC (45%).	('PCDHAC2', 'Gene', '56134', (116, 123))	('UVM', 'Phenotype', 'HP:0007716', (186, 189))	('ADAM6', 'Gene', '8755', (201, 206))	('PCDHAC2', 'Gene', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('RMGs', 'Chemical', '-', (32, 36))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('VHL', 'Disease', (159, 162))	('GNAQ', 'Gene', '2776', (178, 182))	('GNAQ', 'Gene', (178, 182))	('ZFPM1', 'Gene', '161882', (139, 144))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('LUSC', 'Phenotype', 'HP:0030359', (210, 214))	('ACC', 'Phenotype', 'HP:0006744', (148, 151))	('mutated', 'Var', (42, 49))	('ADAM6', 'Gene', (201, 206))	('VHL', 'Disease', 'MESH:D006623', (159, 162))	('ZFPM1', 'Gene', (139, 144))
60074	30107644	PI3K-Akt signaling pathway had the most number of RMGs (n = 47) and were disrupted in 23 cancer types.	('Akt', 'Gene', '207', (5, 8))	('RMGs', 'Var', (50, 54))	('RMGs', 'Chemical', '-', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('Akt', 'Gene', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
60078	30107644	It was also shown that BLCA had the greatest proportion of RMGs in cell cycle.	('cell cycle', 'CPA', (67, 77))	('RMGs', 'Var', (59, 63))	('BLCA', 'Phenotype', 'HP:0009725', (23, 27))	('RMGs', 'Chemical', '-', (59, 63))
60084	30107644	For most cRMGs, missense mutation accounts for the largest proportion (>50%), especially for PIK3CA.	('PIK3CA', 'Gene', (93, 99))	('PIK3CA', 'Gene', '5290', (93, 99))	('RMGs', 'Chemical', '-', (10, 14))	('missense mutation', 'Var', (16, 33))
60085	30107644	Specially, KMT2C in LUSC and CHOL as well as DNAH5 in CHOL were more frequently disrupted by nonsense mutation.	('DNAH5', 'Gene', (45, 50))	('DNAH5', 'Gene', '1767', (45, 50))	('disrupted', 'Reg', (80, 89))	('CHOL', 'Phenotype', 'HP:0030153', (29, 33))	('KMT2C', 'Gene', (11, 16))	('nonsense mutation', 'Var', (93, 110))	('KMT2C', 'Gene', '58508', (11, 16))	('CHOL', 'Phenotype', 'HP:0030153', (54, 58))	('LUSC', 'Phenotype', 'HP:0030359', (20, 24))
60086	30107644	In addition, frame shift insertion was also found to be a key mutation for MUC5B in KICH, which occupied a relatively large proportion.	('MUC5B', 'Gene', '727897', (75, 80))	('frame shift insertion', 'Var', (13, 34))	('MUC5B', 'Gene', (75, 80))
60087	30107644	To analyze the functional effects of mutations, we identified differentially expressed genes (DEGs) potentially affected by each cRMG, whereas these DEGs showed a relatively low overlap across different cancer types, except for the DEGs affected by TP53 mutations.	('affected', 'Reg', (112, 120))	('differentially expressed genes', 'MPA', (62, 92))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (203, 209))	('TP53', 'Gene', (249, 253))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('TP53', 'Gene', '7157', (249, 253))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
60089	30107644	It was observed that TP53 was more frequently disrupted by nonsense mutations, frame-shift indels and splice site mutations compared with other cRMGs (Figure 3a), which results in the initiation and progression of cancers (Payne & Kemp, 2005; Wojnarowicz et al., 2012).	('TP53', 'Gene', (21, 25))	('RMGs', 'Chemical', '-', (145, 149))	('frame-shift indels', 'Var', (79, 97))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('splice site mutations', 'Var', (102, 123))	('results in', 'Reg', (169, 179))	('nonsense mutations', 'Var', (59, 77))	('cancers', 'Disease', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('progression', 'PosReg', (199, 210))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('disrupted', 'Reg', (46, 55))	('TP53', 'Gene', '7157', (21, 25))
60091	30107644	To assess the functional impacts of TP53 mutations, we identified 87 DEGs shared by more than one-quarter of the 21 cancer types.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('TP53', 'Gene', '7157', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TP53', 'Gene', (36, 40))
60097	30107644	Surprisingly, patients with MUC3A, MUC4, MUC5B, MUC6, and MUC16 mutations had significantly better OS prognoses compared with those without mutations in several cancer types (Figure 4a).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('MUC6', 'Gene', (48, 52))	('better', 'PosReg', (92, 98))	('MUC4', 'Gene', '4585', (35, 39))	('MUC16', 'Gene', '94025', (58, 63))	('MUC4', 'Gene', (35, 39))	('MUC6', 'Gene', '4588', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('mutations', 'Var', (64, 73))	('OS prognoses', 'CPA', (99, 111))	('MUC5B', 'Gene', (41, 46))	('cancer', 'Disease', (161, 167))	('MUC3A', 'Gene', '4584', (28, 33))	('MUC3A', 'Gene', (28, 33))	('MUC5B', 'Gene', '727897', (41, 46))	('MUC16', 'Gene', (58, 63))	('patients', 'Species', '9606', (14, 22))
60099	30107644	Results showed that there was a greater proportion of in-frame deletion of MUC4 in KIPAN and KIRC (Figure 3a), where the mutations of MUC4 were significantly associated with prognosis.	('MUC4', 'Gene', (75, 79))	('MUC4', 'Gene', (134, 138))	('associated with', 'Reg', (158, 173))	('mutations', 'Var', (121, 130))	('MUC4', 'Gene', '4585', (134, 138))	('in-frame deletion', 'Var', (54, 71))	('MUC4', 'Gene', '4585', (75, 79))
60100	30107644	Similarly, we found a greater proportion of frame-shift deletion of MUC5B in STAD and STES.	('STES', 'Chemical', '-', (86, 90))	('MUC5B', 'Gene', '727897', (68, 73))	('MUC5B', 'Gene', (68, 73))	('STAD', 'Disease', (77, 81))	('frame-shift deletion', 'Var', (44, 64))	('STES', 'Disease', (86, 90))
60104	30107644	There were more recurrently mutated MUC family genes in SKCM, DLBC, CHOL, ACC, ESCA, KICH, and STAD compared with other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('STAD', 'Disease', (95, 99))	('KICH', 'Disease', (85, 89))	('mutated', 'Var', (28, 35))	('SKCM', 'Disease', (56, 60))	('CHOL', 'Disease', (68, 72))	('ESCA', 'Phenotype', 'HP:0011459', (79, 83))	('DLBC', 'Disease', (62, 66))	('ESCA', 'Disease', (79, 83))	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('cancer', 'Disease', (120, 126))	('ACC', 'Disease', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('MUC', 'Gene', '100508689', (36, 39))	('CHOL', 'Phenotype', 'HP:0030153', (68, 72))	('MUC', 'Gene', (36, 39))
60106	30107644	As a result, the better OS prognosis were observed in SKCM and STAD (Supporting Information Figure S3), which further suggested that mutations of MUC family genes were frequently associated with better survival prognosis in cancers.	('associated', 'Reg', (179, 189))	('better', 'PosReg', (195, 201))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancers', 'Disease', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mutations', 'Var', (133, 142))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('MUC', 'Gene', '100508689', (146, 149))	('MUC', 'Gene', (146, 149))
60107	30107644	To explore the impacts of mutation types on gene expression, we firstly identified 37 RMGs which were differentially expressed caused by their own mutations (Supporting Information Table S3).	('RMGs', 'Chemical', '-', (86, 90))	('mutations', 'Var', (147, 156))	('caused', 'Reg', (127, 133))
60110	30107644	We further categorized the mutations into two groups: MS (including missense and in-frame mutations) and NS (including nonsense, frame-shift, and splice site mutations).	('NS', 'Disease', 'MESH:D009404', (105, 107))	('frame-shift', 'Var', (129, 140))	('nonsense', 'Var', (119, 127))	('splice site mutations', 'Var', (146, 167))	('missense', 'Var', (68, 76))
60113	30107644	When comparing RMG-NS cancers to RMG wild-type cancers, we found all the 20 differentially expressed RMGs are downregulated (Supporting Information Figure S4), which may mainly due to nonsense-mediated mRNA decay (Noensie & Dietz, 2001).	('RMGs', 'Chemical', '-', (101, 105))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('RMG-NS cancers', 'Disease', 'MESH:D009369', (15, 29))	('downregulated', 'NegReg', (110, 123))	('cancers', 'Disease', (22, 29))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('RMG-NS cancers', 'Disease', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('nonsense-mediated mRNA decay', 'Var', (184, 212))	('RMGs', 'Gene', (101, 105))
60118	30107644	Similarly, to study the influences of mutation types on prognosis, we identified 13 cRMGs that mutated in sufficient samples (n >= 5) in each respective group (MS and NS) excluding TP53 that have been widely explored (Freed-Pastor & Prives, 2012).	('NS', 'Disease', 'MESH:D009404', (167, 169))	('TP53', 'Gene', (181, 185))	('mutated', 'Var', (95, 102))	('RMGs', 'Chemical', '-', (85, 89))	('TP53', 'Gene', '7157', (181, 185))
60120	30107644	The results showed that six cRMGs including OBSCN, CDKN2A, CSMD3, DMD, DNAH5, and KMT2Cwith MS or NS mutations have significant associations with prognosis in several cancer types (Figure 5c).	('DMD', 'Gene', '1756', (66, 69))	('CDKN2A', 'Gene', '1029', (51, 57))	('RMGs', 'Chemical', '-', (29, 33))	('mutations', 'Var', (101, 110))	('NS', 'Disease', 'MESH:D009404', (98, 100))	('OBSCN', 'Gene', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('OBSCN', 'Gene', '84033', (44, 49))	('cancer', 'Disease', (167, 173))	('KMT2C', 'Gene', (82, 87))	('DNAH5', 'Gene', '1767', (71, 76))	('KMT2C', 'Gene', '58508', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('DNAH5', 'Gene', (71, 76))	('DMD', 'Gene', (66, 69))	('CDKN2A', 'Gene', (51, 57))	('CSMD3', 'Gene', (59, 64))	('CSMD3', 'Gene', '114788', (59, 64))
60121	30107644	Patients with NS mutations in CDKN2A (PAAD), CSMD3 (STAD), and DMD (STAD and STES) had worse survival.	('CSMD3', 'Gene', (45, 50))	('CSMD3', 'Gene', '114788', (45, 50))	('DMD', 'Gene', '1756', (63, 66))	('CDKN2A', 'Gene', (30, 36))	('NS', 'Disease', 'MESH:D009404', (14, 16))	('CDKN2A', 'Gene', '1029', (30, 36))	('Patients', 'Species', '9606', (0, 8))	('PAAD', 'Phenotype', 'HP:0006725', (38, 42))	('STES', 'Chemical', '-', (77, 81))	('DMD', 'Gene', (63, 66))	('mutations', 'Var', (17, 26))
60124	30107644	The NS mutations downregulated its mRNA expression, therefore, dysregulated transcription, chromatin architecture or cellular differentiation.	('downregulated', 'NegReg', (17, 30))	('cellular differentiation', 'CPA', (117, 141))	('NS', 'Disease', 'MESH:D009404', (4, 6))	('transcription', 'MPA', (76, 89))	('mRNA expression', 'MPA', (35, 50))	('dysregulated', 'Reg', (63, 75))	('chromatin architecture', 'CPA', (91, 113))	('mutations', 'Var', (7, 16))
60125	30107644	Whereas, both OBSCN (in STAD) and DNAH5 (in SKCM) with MS mutations had better survival.	('OBSCN', 'Gene', '84033', (14, 19))	('mutations', 'Var', (58, 67))	('DNAH5', 'Gene', '1767', (34, 39))	('OBSCN', 'Gene', (14, 19))	('better', 'PosReg', (72, 78))	('DNAH5', 'Gene', (34, 39))
60130	30107644	Of which, mutations in ARID1A and PIK3CA were co-occurred (p-value < 0.01), which was consistent with the previous study (Liang et al., 2012).	('PIK3CA', 'Gene', (34, 40))	('ARID1A', 'Gene', '8289', (23, 29))	('ARID1A', 'Gene', (23, 29))	('PIK3CA', 'Gene', '5290', (34, 40))	('mutations', 'Var', (10, 19))
60133	30107644	Mutations in ARID1A could activate the PI3K pathway activity, and the concordance of mutations in ARID1A and PI3K pathway contributed to tumorigenesis (Liang et al., 2012).	('ARID1A', 'Gene', '8289', (98, 104))	('tumor', 'Disease', (137, 142))	('ARID1A', 'Gene', (98, 104))	('activate', 'PosReg', (26, 34))	('ARID1A', 'Gene', '8289', (13, 19))	('ARID1A', 'Gene', (13, 19))	('activity', 'MPA', (52, 60))	('PI3K pathway', 'Pathway', (39, 51))	('PI3K pathway', 'Pathway', (109, 121))	('mutations', 'Var', (85, 94))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('contributed', 'Reg', (122, 133))
60136	30107644	The co-occurred mutations in RNF43 and FAT3/FAT4 disrupted the Wnt signaling and thus promoted the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('FAT3', 'Gene', (39, 43))	('RNF43', 'Gene', (29, 34))	('RNF43', 'Gene', '54894', (29, 34))	('FAT3', 'Gene', '120114', (39, 43))	('mutations', 'Var', (16, 25))	('FAT4', 'Gene', (44, 48))	('Wnt signaling', 'Pathway', (63, 76))	('FAT4', 'Gene', '79633', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('disrupted', 'NegReg', (49, 58))	('promoted', 'PosReg', (86, 94))	('cancer', 'Disease', (114, 120))
60141	30107644	Moreover, we found MUC family genes were enriched in RMGs, and mutations of five MUC family genes were associated with better OS prognosis.	('MUC', 'Gene', (81, 84))	('mutations', 'Var', (63, 72))	('MUC', 'Gene', '100508689', (19, 22))	('MUC', 'Gene', '100508689', (81, 84))	('MUC', 'Gene', (19, 22))	('associated', 'Reg', (103, 113))	('RMGs', 'Chemical', '-', (53, 57))	('RMGs', 'Disease', (53, 57))
60142	30107644	In addition, we assessed the impacts of mutations in RMGs on gene expression and survival, as well as the pairwise mutation patterns among RMGs.	('mutations', 'Var', (40, 49))	('gene expression', 'MPA', (61, 76))	('RMGs', 'Chemical', '-', (139, 143))	('RMGs', 'Chemical', '-', (53, 57))
60143	30107644	In this study, we showed that the RMGs with mutation rates greater than 25% were enriched in hydrolases.	('mutation', 'Var', (44, 52))	('RMGs', 'Chemical', '-', (34, 38))	('hydrolases', 'Enzyme', (93, 103))
60144	30107644	Among these genes, PTEN was a tumor suppressor gene encoding a phosphatase and its mutation may lead to decreased sensitivity to apoptosis stimulating thus promote tumorigenesis (Farrow & Mark Evers, 2003; Stambolic et al., 1998; Zhong et al., 2000).	('tumor', 'Disease', (164, 169))	('sensitivity to apoptosis stimulating', 'MPA', (114, 150))	('PTEN', 'Gene', (19, 23))	('decreased', 'NegReg', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mutation', 'Var', (83, 91))	('PTEN', 'Gene', '5728', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (30, 35))	('promote', 'PosReg', (156, 163))
60146	30107644	Mutations in PTPRD abrogated its function to regulate STAT3 and promoted cancer progression (Funato, Yamazumi, Oda, & Akiyama, 2011; Zhao et al., 2010).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('PTPRD', 'Gene', '5789', (13, 18))	('promoted', 'PosReg', (64, 72))	('PTPRD', 'Gene', (13, 18))	('STAT3', 'Gene', '6774', (54, 59))	('abrogated', 'NegReg', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Mutations', 'Var', (0, 9))	('STAT3', 'Gene', (54, 59))	('function', 'MPA', (33, 41))
60147	30107644	In addition, the alterations in cathepsins may disrupt lysosomal trafficking and autophagy, thus led to tumor invasion (Dielschneider, Henson, & Gibson, 2017; White, Mehnert, & Chan, 2015).	('disrupt', 'NegReg', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('led to', 'Reg', (97, 103))	('cathepsins', 'Protein', (32, 42))	('tumor', 'Disease', (104, 109))	('autophagy', 'CPA', (81, 90))	('lysosomal trafficking', 'CPA', (55, 76))	('alterations', 'Var', (17, 28))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
60148	30107644	Recurrent mutations in hydrolases may cause uncontrolled proliferation, differentiation and metastasis, so target tumor cell hydrolases is a good way to treat cancer.	('cancer', 'Disease', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('differentiation', 'CPA', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cause', 'Reg', (38, 43))	('metastasis', 'CPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (114, 119))	('uncontrolled', 'MPA', (44, 56))	('hydrolases', 'Gene', (23, 33))	('mutations', 'Var', (10, 19))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
60152	30107644	The recurrent mutations of MUC4 were detected only in ESCA (16%), whereas not in STAD.	('MUC4', 'Gene', (27, 31))	('detected', 'Reg', (37, 45))	('ESCA', 'Phenotype', 'HP:0011459', (54, 58))	('ESCA', 'Disease', (54, 58))	('MUC4', 'Gene', '4585', (27, 31))	('mutations', 'Var', (14, 23))
60155	30107644	Our results suggested recurrent mutations of MUC family genes are closely associated with survival in diverse cancers, so the mutations of MUC4 may cause the increase in mRNA expression and further protect epithelial surfaces in ESCA and STAD.	('cancers', 'Disease', (110, 117))	('MUC', 'Gene', '100508689', (139, 142))	('MUC4', 'Gene', '4585', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MUC', 'Gene', '100508689', (45, 48))	('MUC4', 'Gene', (139, 143))	('mutations', 'Var', (126, 135))	('MUC', 'Gene', (45, 48))	('ESCA', 'Disease', (229, 233))	('protect', 'PosReg', (198, 205))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('ESCA', 'Phenotype', 'HP:0011459', (229, 233))	('increase', 'PosReg', (158, 166))	('mRNA expression', 'MPA', (170, 185))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('MUC', 'Gene', (139, 142))
60156	30107644	Similarly, PTEN was frequently mutated in GBM and the combined data, GBMLGG, which could also indicate the mutated PTEN lost its cancer suppressing property thus promote tumorigenesis in GBM.	('PTEN', 'Gene', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lost', 'NegReg', (120, 124))	('PTEN', 'Gene', '5728', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('PTEN', 'Gene', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('PTEN', 'Gene', '5728', (115, 119))	('mutated', 'Var', (107, 114))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', (170, 175))	('promote', 'PosReg', (162, 169))
60158	30107644	Mutant p53 protein encoded by TP53 with MS mutations could inactivate p53-related proteins and acquire new oncogenic functions (Freed-Pastor & Prives, 2012), so the upregulation of TP53 helped the tumor cells evade apoptosis and senescence.	('oncogenic functions', 'CPA', (107, 126))	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', (181, 185))	('TP53', 'Gene', '7157', (181, 185))	('p53', 'Gene', (70, 73))	('protein', 'Protein', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('p53', 'Gene', '7157', (70, 73))	('cells evade apoptosis and', 'CPA', (203, 228))	('p53', 'Gene', '7157', (7, 10))	('mutations', 'Var', (43, 52))	('the', 'PosReg', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Mutant', 'Var', (0, 6))	('TP53', 'Gene', '7157', (30, 34))	('inactivate', 'NegReg', (59, 69))	('tumor', 'Disease', (197, 202))	('p53', 'Gene', (7, 10))
60160	30107644	The mutated CDKN2A proteins failed to bind to cdk4, which promoted the development of cancer (Lilischkis, Sarcevic, Kennedy, Warlters, & Sutherland, 1996; Liu et al., 1995; Ranade et al., 1995).	('mutated', 'Var', (4, 11))	('CDKN2A', 'Gene', (12, 18))	('cdk4', 'Gene', '1019', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CDKN2A', 'Gene', '1029', (12, 18))	('cdk4', 'Gene', (46, 50))	('promoted', 'PosReg', (58, 66))	('proteins', 'Protein', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
60163	30107644	Whereas NS mutations could only downregulate gene expression (Supporting Information Figure S4).	('downregulate', 'NegReg', (32, 44))	('gene expression', 'MPA', (45, 60))	('mutations', 'Var', (11, 20))	('NS', 'Disease', 'MESH:D009404', (8, 10))
60169	30107644	Strong correlation between recurrently mutated MUC family genes and human survival were revealed.	('human survival', 'CPA', (68, 82))	('human', 'Species', '9606', (68, 73))	('MUC', 'Gene', '100508689', (47, 50))	('MUC', 'Gene', (47, 50))	('mutated', 'Var', (39, 46))
60445	26715866	In all, 35% of cases had a mutation in the canonical Wnt signaling pathway (either CTNNB1 or APC) and 48% had a mutation in TP53.	('TP53', 'Gene', '7157', (124, 128))	('CTNNB1', 'Gene', '1499', (83, 89))	('TP53', 'Gene', (124, 128))	('mutation', 'Var', (27, 35))	('CTNNB1', 'Gene', (83, 89))	('APC', 'Disease', 'MESH:D011125', (93, 96))	('canonical Wnt signaling pathway', 'Pathway', (43, 74))	('APC', 'Disease', (93, 96))
60446	26715866	Biomarker alterations in ACC may be used to direct therapies, including recommendations for and potential resistance of some patients to traditional chemotherapies, which may explain the low response rate in the unselected population.	('ACC', 'Gene', (25, 28))	('alterations', 'Var', (10, 21))	('patients', 'Species', '9606', (125, 133))
60477	26715866	Prior to the availability of Clinical Laboratory Improvement Amendments (CLIA) certified NGS, mutation analysis by Sanger sequencing included selected regions of BRAF, KRAS, cKIT, EGFR, and PIK3CA genes and was performed using M13-linked PCR primers designed to amplify targeted sequences.	('PIK3CA', 'Gene', '5290', (190, 196))	('cKIT', 'Gene', (174, 178))	('KRAS', 'Gene', '3845', (168, 172))	('mutation', 'Var', (94, 102))	('EGFR', 'Gene', '1956', (180, 184))	('CLIA', 'Disease', 'None', (73, 77))	('EGFR', 'Gene', (180, 184))	('cKIT', 'Gene', '3815', (174, 178))	('CLIA', 'Disease', (73, 77))	('PIK3CA', 'Gene', (190, 196))	('BRAF', 'Gene', '673', (162, 166))	('KRAS', 'Gene', (168, 172))	('BRAF', 'Gene', (162, 166))
60489	26715866	Seven of the 29 patients with low TOPO2A were treated with doxorubicin, which is predicted to be associated with a lack of benefit.	('doxorubicin', 'Chemical', 'MESH:D004317', (59, 70))	('TOPO2A', 'Gene', (34, 40))	('patients', 'Species', '9606', (16, 24))	('low', 'Var', (30, 33))
60496	26715866	Analysis of immune checkpoint biomarkers, PD-1 and PD-L1, identified PD-1 TILs in 20% of cases (9/46), overexpression of PD-L1 in 30% of cases (14/46), concurrence of PD-1/PD-L1 in 9% of cases (4/46), and occurrence of either PD-1 or PD-L1 in 41% of cases (19/46; Fig.	('PD-1', 'Gene', (167, 171))	('PD-L1', 'Gene', (121, 126))	('PD-L1', 'Gene', '29126', (172, 177))	('PD-1', 'Gene', '5133', (167, 171))	('PD-L1', 'Gene', '29126', (121, 126))	('PD-1', 'Gene', (226, 230))	('PD-L1', 'Gene', '29126', (51, 56))	('concurrence', 'Var', (152, 163))	('PD-1', 'Gene', (69, 73))	('PD-1', 'Gene', '5133', (226, 230))	('PD-1', 'Gene', (42, 46))	('PD-1', 'Gene', '5133', (69, 73))	('PD-1', 'Gene', '5133', (42, 46))	('overexpression', 'PosReg', (103, 117))	('PD-L1', 'Gene', (234, 239))	('PD-L1', 'Gene', '29126', (234, 239))	('PD-L1', 'Gene', (172, 177))	('PD-L1', 'Gene', (51, 56))
60505	26715866	Together, EGFR protein overexpression or gene amplification of EGFR in 21% of cases suggests consideration of treatment targeting EGFR.	('EGFR', 'Gene', '1956', (10, 14))	('EGFR', 'Gene', '1956', (63, 67))	('overexpression', 'PosReg', (23, 37))	('gene amplification', 'Var', (41, 59))	('EGFR', 'Gene', (10, 14))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))
60507	26715866	CTNNB1 mutations were identified in 35% of cases, and a mutation in APC was identified in one case tested.	('CTNNB1', 'Gene', '1499', (0, 6))	('APC', 'Disease', 'MESH:D011125', (68, 71))	('APC', 'Disease', (68, 71))	('CTNNB1', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
60508	26715866	CTNNB1 mutations have been reported in ACC at 25% (amino acid S45) and 31%.	('CTNNB1', 'Gene', '1499', (0, 6))	('CTNNB1', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
60509	26715866	Five of the 10 CTNNB1 mutations identified in our cohort were specific to S45; all others were within 20 codons, in exon 3.	('CTNNB1', 'Gene', (15, 21))	('mutations', 'Var', (22, 31))	('CTNNB1', 'Gene', '1499', (15, 21))
60510	26715866	Additionally, mutations in TP53 were identified in 47% of cases tested, which is higher than previously reported levels of 20%-27% and 33%, and may reflect the advanced disease stage of this study cohort, with a poorer prognosis.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('mutations', 'Var', (14, 23))	('identified', 'Reg', (37, 47))
60511	26715866	Also, the median age of those with TP53 mutations was 46 years, compared to 49 years for non-TP53 mutated.	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (93, 97))	('TP53', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))
60512	26715866	Mutations of BRCA2, AKT1, ATM, cKIT, cMET, EGFR, ERBB4, JAK3, and KDR were all identified in single tumors in 32 cases tested.	('ATM', 'Gene', (26, 29))	('ERBB4', 'Gene', '2066', (49, 54))	('cMET', 'Gene', '4233', (37, 41))	('cKIT', 'Gene', '3815', (31, 35))	('ERBB4', 'Gene', (49, 54))	('EGFR', 'Gene', (43, 47))	('identified', 'Reg', (79, 89))	('JAK3', 'Gene', (56, 60))	('AKT1', 'Gene', '207', (20, 24))	('KDR', 'Gene', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('JAK3', 'Gene', '3718', (56, 60))	('AKT1', 'Gene', (20, 24))	('tumors', 'Disease', (100, 106))	('cKIT', 'Gene', (31, 35))	('cMET', 'Gene', (37, 41))	('EGFR', 'Gene', '1956', (43, 47))	('ATM', 'Gene', '472', (26, 29))	('KDR', 'Gene', '3791', (66, 69))	('BRCA2', 'Gene', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('BRCA2', 'Gene', '675', (13, 18))
60526	26715866	However, we found decreased overall survival in low TOPO2A patients compared to the overall study population.	('decreased', 'NegReg', (18, 27))	('patients', 'Species', '9606', (59, 67))	('overall survival', 'MPA', (28, 44))	('low TOPO2A', 'Var', (48, 58))
60528	26715866	Patients with high levels of PGP have been shown to have higher levels of resistance to doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (88, 99))	('higher', 'PosReg', (57, 63))	('high levels', 'Var', (14, 25))	('Patients', 'Species', '9606', (0, 8))	('levels of resistance to doxorubicin', 'MPA', (64, 99))	('PGP', 'Gene', '283871', (29, 32))	('PGP', 'Gene', (29, 32))
60530	26715866	Cisplatin, a platinum-based agent in EDP-M kills tumor cells by binding and cross-linking DNA strands, causing DNA damage and triggering cell death pathways.	('binding', 'Interaction', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('DNA damage', 'MPA', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('triggering', 'Reg', (126, 136))	('causing', 'Reg', (103, 110))	('DNA strands', 'Protein', (90, 101))	('cell death', 'CPA', (137, 147))	('tumor', 'Disease', (49, 54))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('EDP-M', 'Chemical', '-', (37, 42))	('platinum', 'Chemical', 'MESH:D010984', (13, 21))	('cross-linking', 'Var', (76, 89))
60533	26715866	In ACC, Ronchi et al showed that high ERCC1 expression was an indicator of poor responses in platinum-treated patients.	('platinum', 'Chemical', 'MESH:D010984', (93, 101))	('expression', 'MPA', (44, 54))	('high', 'Var', (33, 37))	('ERCC1', 'Gene', '2067', (38, 43))	('ERCC1', 'Gene', (38, 43))	('patients', 'Species', '9606', (110, 118))
60534	26715866	Our findings are supportive of this conclusion, in that patients with high expression of ERCC1 who received platinum therapy had significantly shorter survival than patients with normal ERCC1 expression receiving platinum therapy.	('ERCC1', 'Gene', '2067', (89, 94))	('ERCC1', 'Gene', (89, 94))	('patients', 'Species', '9606', (56, 64))	('platinum', 'Chemical', 'MESH:D010984', (108, 116))	('shorter', 'NegReg', (143, 150))	('ERCC1', 'Gene', '2067', (186, 191))	('ERCC1', 'Gene', (186, 191))	('patients', 'Species', '9606', (165, 173))	('high expression', 'Var', (70, 85))	('platinum', 'Chemical', 'MESH:D010984', (213, 221))	('survival', 'MPA', (151, 159))
60548	26715866	Our study identified several biomarkers aberrantly expressed in ACC that have proven helpful in other cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('aberrantly', 'Var', (40, 50))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('ACC', 'Disease', (64, 67))
60553	26715866	While no currently FDA approved drugs target aberrations in the Wnt pathway, the finding of mutations in the beta-catenin gene and/or APC in 38% of ACC suggests that Wnt inhibitors under development, such as PRI-174, should be studied in patients with ACC.	('APC', 'Disease', 'MESH:D011125', (134, 137))	('ACC', 'Disease', (148, 151))	('APC', 'Disease', (134, 137))	('PR', 'Gene', '5241', (208, 210))	('mutations', 'Var', (92, 101))	('beta-catenin', 'Gene', (109, 121))	('beta-catenin', 'Gene', '1499', (109, 121))	('patients', 'Species', '9606', (238, 246))
60554	26715866	Similarly, clinical trials targeting TP53 might be warranted, as ~50% of ACC patients in our cohort of refractory ACC, presented with TP53 mutations.	('presented with', 'Reg', (119, 133))	('TP53', 'Gene', (134, 138))	('ACC', 'Disease', (73, 76))	('mutations', 'Var', (139, 148))	('patients', 'Species', '9606', (77, 85))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('TP53', 'Gene', '7157', (134, 138))
60555	26715866	Another area for clinical trials might be the PI3 kinase pathway; 57% of cases had a loss of PTEN and a single case had an AKT1 mutation, despite no mutations being found in either PTEN or PIK3CA.	('AKT1', 'Gene', (123, 127))	('PTEN', 'Gene', (93, 97))	('PTEN', 'Gene', '5728', (93, 97))	('PIK3CA', 'Gene', (189, 195))	('loss', 'NegReg', (85, 89))	('mutation', 'Var', (128, 136))	('PIK3CA', 'Gene', '5290', (189, 195))	('PTEN', 'Gene', (181, 185))	('PTEN', 'Gene', '5728', (181, 185))	('AKT1', 'Gene', '207', (123, 127))
60564	26715866	Furthermore, an evaluation of the percent of patients with germline versus somatic incidence of TP53 may be relevant, as germline TP53 mutations (Li-Fraumeni syndrome) are more common than somatic mutations in ACCs.	('ACCs', 'Gene', (210, 214))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (146, 166))	('TP53', 'Gene', (96, 100))	('ACCs', 'Gene', '84680', (210, 214))	('common', 'Reg', (177, 183))	('mutations', 'Var', (135, 144))	('Li-Fraumeni syndrome', 'Disease', (146, 166))	('patients', 'Species', '9606', (45, 53))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('TP53', 'Gene', '7157', (96, 100))
60576	23848572	The patient underwent germline genetic testing, revealing a deleterious mutation in exon 11 of FLCN (c.1252delC; p.Leu418TrpfsX50) leading to a premature stop codon and confirming the diagnosis of BHD.	('c.1252delC; p.Leu418TrpfsX50', 'Var', (101, 129))	('p.Leu418TrpfsX50', 'Var', (113, 129))	('FLCN', 'Gene', '201163', (95, 99))	('patient', 'Species', '9606', (4, 11))	('c.1252delC', 'Mutation', 'rs864622651', (101, 111))	('p.Leu418TrpfsX50', 'Mutation', 'rs864622651', (113, 129))	('premature stop codon', 'MPA', (144, 164))	('BHD', 'Disease', (197, 200))	('BHD', 'Disease', 'MESH:D058249', (197, 200))	('FLCN', 'Gene', (95, 99))
60584	23848572	BHD is caused by mutations in FLCN (Online Mendelian Inheritance in Man #13510, http://omim.org/entry/135150, for photograph of typical skin lesions see Ref.).	('FLCN', 'Gene', (30, 34))	('BHD', 'Disease', (0, 3))	('BHD', 'Disease', 'MESH:D058249', (0, 3))	('FLCN', 'Gene', '201163', (30, 34))	('Man', 'Species', '9606', (68, 71))	('caused by', 'Reg', (7, 16))	('mutations', 'Var', (17, 26))
60586	23848572	In order to explore an adrenal phenotype in BHD patients, we identified 14 patients from 11 unique families with genetically confirmed FLCN mutations in the University of Michigan Cancer Genetics Registry.	('BHD', 'Disease', (44, 47))	('FLCN', 'Gene', '201163', (135, 139))	('patients', 'Species', '9606', (75, 83))	('Cancer', 'Phenotype', 'HP:0002664', (180, 186))	('FLCN', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))	('BHD', 'Disease', 'MESH:D058249', (44, 47))	('patients', 'Species', '9606', (48, 56))
60593	23848572	No patient fulfilled clinical criteria for BHD, had undergone germline genetic testing for FLCN mutations, or had a reported family history of BHD.	('BHD', 'Disease', 'MESH:D058249', (43, 46))	('BHD', 'Disease', (43, 46))	('BHD', 'Disease', 'MESH:D058249', (143, 146))	('FLCN', 'Gene', '201163', (91, 95))	('BHD', 'Disease', (143, 146))	('patient', 'Species', '9606', (3, 10))	('FLCN', 'Gene', (91, 95))	('mutations', 'Var', (96, 105))
60596	23848572	First, a study of 23 BHD patients with confirmed FLCN mutations presenting with lung cysts reported one patient with an adrenal nodule.	('lung cysts', 'Phenotype', 'HP:0032445', (80, 90))	('BHD', 'Disease', 'MESH:D058249', (21, 24))	('FLCN', 'Gene', (49, 53))	('BHD', 'Disease', (21, 24))	('mutations', 'Var', (54, 63))	('patient', 'Species', '9606', (25, 32))	('patient', 'Species', '9606', (104, 111))	('patients', 'Species', '9606', (25, 33))	('lung cysts', 'Disease', (80, 90))	('FLCN', 'Gene', '201163', (49, 53))
60597	23848572	reported a large oncocytic adrenal tumor in a 36 year old female patient with BHD and confirmed FLCN mutation .	('oncocytic adrenal tumor', 'Disease', (17, 40))	('BHD', 'Disease', (78, 81))	('oncocytic adrenal tumor', 'Disease', 'MESH:C535584', (17, 40))	('BHD', 'Disease', 'MESH:D058249', (78, 81))	('FLCN', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('FLCN', 'Gene', '201163', (96, 100))	('patient', 'Species', '9606', (65, 72))	('renal tumor', 'Phenotype', 'HP:0009726', (29, 40))	('adrenal tumor', 'Phenotype', 'HP:0100631', (27, 40))	('mutation', 'Var', (101, 109))
60605	22589739	Acquisition Order of Ras and p53 Gene Alterations Defines Distinct Adrenocortical Tumor Phenotypes Sporadic adrenocortical carcinomas (ACC) are rare endocrine neoplasms with a dismal prognosis.	('Alterations', 'Var', (38, 49))	('neoplasms', 'Phenotype', 'HP:0002664', (159, 168))	('ACC', 'Phenotype', 'HP:0006744', (135, 138))	('Sporadic adrenocortical carcinomas', 'Disease', 'MESH:D018268', (99, 133))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (108, 132))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (108, 133))	('Sporadic adrenocortical carcinomas', 'Disease', (99, 133))	('neoplasms', 'Disease', 'MESH:D009369', (159, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('neoplasms', 'Disease', (159, 168))	('p53', 'Gene', (29, 32))	('Tumor', 'Phenotype', 'HP:0002664', (82, 87))	('p53', 'Gene', '7157', (29, 32))	('endocrine neoplasms', 'Phenotype', 'HP:0100568', (149, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('Adrenocortical Tumor', 'Disease', 'MESH:D018268', (67, 87))	('Adrenocortical Tumor', 'Disease', (67, 87))
60609	22589739	The introduction in different orders of the oncogenic allele of Ras (H-RasG12V) and the mutant p53DD that disrupts the p53 pathway yielded tumors displaying major differences in histological features, tumorigenicity, and metastatic behavior.	('p53DD', 'Gene', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('disrupts', 'NegReg', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('metastatic', 'CPA', (221, 231))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mutant', 'Var', (88, 94))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('H-RasG12V', 'Chemical', '-', (69, 78))	('tumor', 'Disease', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('p53 pathway', 'Pathway', (119, 130))
60610	22589739	Whereas the successive expression of RasG12V and p53DD led to highly malignant tumors with metastatic behavior, reminiscent of those formed after the simultaneous introduction of p53DD and RasG12V, the reverse sequence gave rise only to benign tumors.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('benign tumors', 'Disease', (237, 250))	('metastatic behavior', 'CPA', (91, 110))	('RasG12V', 'Var', (37, 44))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('p53DD', 'Var', (49, 54))	('malignant tumors', 'Disease', (69, 85))	('benign tumors', 'Disease', 'MESH:D009369', (237, 250))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('malignant tumors', 'Disease', 'MESH:D018198', (69, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
60613	22589739	A sequential acquisition of genetic events is critical in tumorigenesis, and a dysregulation of a limited set of pathways has been demonstrated as sufficient to progressively transform normal cells into tumor cells in several human tissues.	('rat', 'Species', '10116', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (203, 208))	('human', 'Species', '9606', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('transform', 'Reg', (175, 184))	('dysregulation', 'Var', (79, 92))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (203, 208))
60620	22589739	However, it remains unclear for most cancers which genetic alterations in a cell or group of cells play a causative role in tumor initiation and progression, and which ones represent bystanders with no selective advantage.	('tumor initiation', 'Disease', 'MESH:D009369', (124, 140))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('tumor initiation', 'Disease', (124, 140))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('rat', 'Species', '10116', (63, 66))	('genetic alterations', 'Var', (51, 70))
60621	22589739	Cellular transformation is a process where a normal cell accumulates mutations, as well as epigenetic changes, that activate oncogenes or down-regulate tumor suppressor genes to give rise to a clonal expansion of a subset of transformed cells, independently of both external and internal signals that normally control cell growth.	('give rise to', 'Reg', (178, 190))	('mutations', 'Var', (69, 78))	('activate', 'PosReg', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('oncogenes', 'Protein', (125, 134))	('changes', 'Var', (102, 109))	('tumor', 'Disease', (152, 157))	('down-regulate', 'NegReg', (138, 151))
60622	22589739	This general concept of multistage tumorigenesis has been demonstrated in the case of the colon cancer where distinct histological stages are directly correlated with genetic alterations in key tumor suppressors and oncogenes.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('colon cancer', 'Disease', 'MESH:D015179', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('colon cancer', 'Disease', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (194, 199))	('genetic alterations', 'Var', (167, 186))	('rat', 'Species', '10116', (179, 182))	('colon cancer', 'Phenotype', 'HP:0003003', (90, 102))	('rat', 'Species', '10116', (65, 68))
60628	22589739	Whether ACAs represent a separate entity or are in fact part of a process of tumor progression leading to the emergence of ACC is still an open question, however these numbers are consistent with the hypothesis that only a very small fraction of ACAs may progress to cancer upon the accumulation of additional changes.	('cancer', 'Disease', (267, 273))	('changes', 'Var', (310, 317))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('progress', 'PosReg', (255, 263))	('rat', 'Species', '10116', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('ACC', 'Phenotype', 'HP:0006744', (123, 126))	('ACAs', 'Phenotype', 'HP:0008256', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ACAs', 'Phenotype', 'HP:0008256', (246, 250))	('tumor', 'Disease', (77, 82))
60634	22589739	Our data suggested that a limited number of genetic alterations cooperate to transform long-lived mammalian adrenocortical cells.	('rat', 'Species', '10116', (56, 59))	('transform', 'Reg', (77, 86))	('adrenocortical', 'Disease', (108, 122))	('genetic alterations', 'Var', (44, 63))	('adrenocortical', 'Disease', 'MESH:D018268', (108, 122))	('mammalian', 'Species', '9606', (98, 107))	('rat', 'Species', '10116', (69, 72))
60637	22589739	Strikingly, we show, using our in vivo tissue reconstruction model, that the order of acquisition of genetic mutations is a critical determinant in the outcome of tumor development and aggressiveness.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('aggressiveness', 'Disease', (185, 199))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('aggressiveness', 'Phenotype', 'HP:0000718', (185, 199))	('tumor', 'Disease', (163, 168))	('mutations', 'Var', (109, 118))	('aggressiveness', 'Disease', 'MESH:D001523', (185, 199))
60638	22589739	The primary BAC cells were infected simultaneously with two replication-defective amphotropic retroviruses based on Moloney murine leukemia virus (MoMLV) expressing either p53DD  or H-RasG12V , each encoding a drug selection marker, hygromycin and neomycin, respectively.	('MoMLV', 'Species', '11801', (147, 152))	('H-RasG12V', 'Var', (182, 191))	('hygromycin', 'Chemical', 'MESH:C026273', (233, 243))	('p53DD', 'Var', (172, 177))	('neomycin', 'Chemical', 'MESH:D009355', (248, 256))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('H-RasG12V', 'Chemical', '-', (182, 191))	('Moloney murine leukemia virus', 'Species', '11801', (116, 145))
60642	22589739	Thus, infection of adrenocortical cells with the combination of p53DD and RasG12V dramatically increased the proliferation rate in comparison to infection with either p53DD or RasG12V alone (Figure 1D).	('infection of adrenocortical', 'Disease', (6, 33))	('infection of adrenocortical', 'Disease', 'MESH:D018268', (6, 33))	('p53DD', 'Var', (64, 69))	('RasG12V', 'Var', (74, 81))	('rat', 'Species', '10116', (123, 126))	('proliferation rate', 'CPA', (109, 127))	('rat', 'Species', '10116', (116, 119))	('increased', 'PosReg', (95, 104))
60644	22589739	However, in the absence of serum, only cells transduced with RasG12V and p53DD proliferated independently from extrinsic mitogens.	('proliferated', 'CPA', (79, 91))	('RasG12V', 'Var', (61, 68))	('rat', 'Species', '10116', (86, 89))	('p53DD', 'Var', (73, 78))
60647	22589739	Whereas expression of p53DD was unable to support anchorage-independent growth of adrenocortical cells, cells expressing RasG12V formed small abortive colonies characteristic of transit-amplifying cells (Table 1).	('adrenocortical', 'Disease', (82, 96))	('adrenocortical', 'Disease', 'MESH:D018268', (82, 96))	('RasG12V', 'Var', (121, 128))	('abortive colonies', 'CPA', (142, 159))
60648	22589739	Only the expression of both p53DD and RasG12V led to robust cell growth in soft agar (Table 1).	('agar', 'Chemical', 'MESH:D000362', (80, 84))	('p53DD', 'Var', (28, 33))	('cell growth in soft agar', 'CPA', (60, 84))	('RasG12V', 'Var', (38, 45))
60652	22589739	We then wondered whether these two genetic changes are sufficient to endow BAC cells with the ability to form adrenocortical carcinoma in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (110, 134))	('changes', 'Var', (43, 50))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (110, 134))	('adrenocortical carcinoma', 'Disease', (110, 134))
60673	22589739	In addition to cortisol production, we wanted to ascertain that the tumors and metastases were formed from BAC cells transformed by the transduction of p53DD and RasG12V and not from cells such as fibroblasts or other stromal cells possibly contaminating the primary culture.	('RasG12V', 'Var', (162, 169))	('cortisol', 'Chemical', 'MESH:D006854', (15, 23))	('transduction', 'Var', (136, 148))	('metastases', 'Disease', 'MESH:D009362', (79, 89))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('p53DD', 'Var', (152, 157))	('metastases', 'Disease', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
60676	22589739	To rule out the possibility that mutations other than the introduction of RasG12V and p53DD occurred during the process of engineering the PR cells, we ensured to keep our population polyclonal, to reduce the period in culture for its generation as short as possible and to produce three independent other PR polyclonal populations from primary BAC cells.	('RasG12V', 'Var', (74, 81))	('p53DD', 'Var', (86, 91))	('rat', 'Species', '10116', (239, 242))
60679	22589739	So, the simultaneous alteration of both p53 and Ras pathways is sufficient to fully transform primary BAC cells and form metastatic ACC when transplanted beneath the SRC of mice.	('transform', 'Reg', (84, 93))	('ACC', 'Phenotype', 'HP:0006744', (132, 135))	('p53', 'Pathway', (40, 43))	('alteration', 'Var', (21, 31))	('rat', 'Species', '10116', (25, 28))	('Ras pathways', 'Pathway', (48, 60))	('metastatic ACC', 'CPA', (121, 135))	('mice', 'Species', '10090', (173, 177))
60687	22589739	Simultaneous activation of the Ras oncogene and inactivation of the p53 tumor suppressor deregulate the transcriptional programs and confer PR adrenocortical cells a tumorigenic potential when transplanted into mice.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('deregulate', 'Reg', (89, 99))	('adrenocortical', 'Disease', (143, 157))	('adrenocortical', 'Disease', 'MESH:D018268', (143, 157))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (72, 77))	('transcriptional programs', 'CPA', (104, 128))	('tumor', 'Disease', (166, 171))	('inactivation', 'Var', (48, 60))	('activation', 'PosReg', (13, 23))	('mice', 'Species', '10090', (211, 215))	('p53', 'Gene', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('confer', 'Reg', (133, 139))
60694	22589739	The expression of constitutively active Ras followed by inactivation of wild-type p53 conferred to the cells a proliferation capacity similar to the PR cells (Figure 4D).	('conferred', 'Reg', (86, 95))	('rat', 'Species', '10116', (118, 121))	('inactivation', 'Var', (56, 68))	('proliferation capacity', 'CPA', (111, 133))	('Ras', 'Protein', (40, 43))
60698	22589739	Conversely, the P+R cells exhibited a reduced proliferation index in the absence of mitogens and thus, a stronger dependence to growth factors (Figure 4E).	('stronger', 'PosReg', (105, 113))	('reduced', 'NegReg', (38, 45))	('dependence', 'Interaction', (114, 124))	('rat', 'Species', '10116', (53, 56))	('proliferation index', 'CPA', (46, 65))	('P+R', 'Var', (16, 19))
60700	22589739	The transplantation of R+P cells resulted in highly neoplastic (Figure 5A, 5B), proliferative (Figure 5C) and poorly differentiated tumors that invaded the kidney parenchyma and adjacent organs such as muscle, pancreas and adipose tissue (data not shown).	('proliferative', 'CPA', (80, 93))	('kidney parenchyma', 'Disease', 'MESH:D010195', (156, 173))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('pancreas', 'Disease', (210, 218))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('R+P cells', 'Var', (23, 32))	('tumors', 'Disease', (132, 138))	('pancreas', 'Disease', 'MESH:D010190', (210, 218))	('kidney parenchyma', 'Disease', (156, 173))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('rat', 'Species', '10116', (87, 90))
60703	22589739	In contrast, the tissues formed following the transplantation of P+R cells were benign tumors with no signs of kidney parenchyma invasion (Figure 5A, 5B) or metastases.	('metastases', 'Disease', 'MESH:D009362', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('P+R cells', 'Var', (65, 74))	('kidney parenchyma invasion', 'Disease', 'MESH:D010195', (111, 137))	('benign tumors', 'Disease', (80, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('benign tumors', 'Disease', 'MESH:D009369', (80, 93))	('metastases', 'Disease', (157, 167))	('kidney parenchyma invasion', 'Disease', (111, 137))
60704	22589739	The number of Ki-67+ cells was lower than in the R+P tumors (Figure 5C).	('P tumors', 'Disease', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('lower', 'NegReg', (31, 36))	('Ki-67+', 'Var', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('P tumors', 'Disease', 'MESH:C000656865', (51, 59))
60706	22589739	The malignant tumors generated by the transplantation of R+P cells is always more heterogenous than is benign counterparts, this is partly due to the invasion of the mouse adjacent tissues (kidney, pancreas and muscle) and also by the recruitment of other mouse cells such as stromal cells and fibroblasts.	('heterogenous', 'CPA', (82, 94))	('pancreas', 'Disease', 'MESH:D010190', (198, 206))	('invasion', 'CPA', (150, 158))	('mouse', 'Species', '10090', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('malignant tumors', 'Disease', (4, 20))	('R+P cells', 'Var', (57, 66))	('rat', 'Species', '10116', (25, 28))	('malignant tumors', 'Disease', 'MESH:D018198', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mouse', 'Species', '10090', (256, 261))	('pancreas', 'Disease', (198, 206))
60710	22589739	In particular, p53 transactivates expression of the CDK inhibitor p21WAF1/Cip1.	('p53', 'Var', (15, 18))	('p21', 'Gene', (66, 69))	('expression', 'MPA', (34, 44))	('Cip1', 'Gene', (74, 78))	('transactivates', 'PosReg', (19, 33))	('p21', 'Gene', '644914', (66, 69))	('Cip1', 'Gene', '1026', (74, 78))
60712	22589739	As shown on Figure S2, pL and R cells expressing p53 demonstrated a strong p21 expression in almost all nuclei.	('expression', 'MPA', (79, 89))	('rat', 'Species', '10116', (60, 63))	('p53', 'Var', (49, 52))	('p21', 'Gene', (75, 78))	('p21', 'Gene', '644914', (75, 78))
60713	22589739	In contrast, inactivation of p53 resulted in an absence or a marked decrease of p21 expression in P, P+R, R+P tissues and in an intestinal metastasis (Figure S2).	('inactivation', 'Var', (13, 25))	('intestinal metastasis', 'CPA', (128, 149))	('decrease', 'NegReg', (68, 76))	('p53', 'Gene', (29, 32))	('p21', 'Gene', (80, 83))	('expression', 'MPA', (84, 94))	('p21', 'Gene', '644914', (80, 83))
60716	22589739	Sparc and LRIG1 were under-expressed in R+P cells compared with P+R cells (Figure 6A).	('under-expressed', 'NegReg', (21, 36))	('Sparc', 'Gene', '6678', (0, 5))	('R+P cells', 'Var', (40, 49))	('LRIG1', 'Gene', '26018', (10, 15))	('LRIG1', 'Gene', (10, 15))	('Sparc', 'Gene', (0, 5))
60717	22589739	EglN2, TPD52 and CCND1 were over-expressed (Figure 6A).	('over-expressed', 'PosReg', (28, 42))	('CCND1', 'Gene', '595', (17, 22))	('EglN2', 'Gene', '112398', (0, 5))	('EglN2', 'Gene', (0, 5))	('TPD52', 'Var', (7, 12))	('CCND1', 'Gene', (17, 22))
60721	22589739	Evidence has revealed that expression of both H-RasG12V and LT antigen was sufficient to convert primary BAC cells into fully malignant tumor cells.	('H-RasG12V', 'Chemical', '-', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('H-RasG12V', 'Var', (46, 55))	('tumor', 'Disease', (136, 141))
60723	22589739	However, ablation of both mammalian pRB and p53 tumor suppressor pathways has been recently shown to be sufficient to replace the function of LT oncoprotein in the combination of genes to transform normal human cells.	('tumor', 'Disease', (48, 53))	('ablation', 'Var', (9, 17))	('p53', 'Gene', (44, 47))	('mammalian', 'Species', '9606', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('human', 'Species', '9606', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
60725	22589739	The proto-oncogene N-Ras has been found to be mutated in 12.5% of ACA and ACC.	('N-Ras', 'Gene', '4893', (19, 24))	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('mutated', 'Var', (46, 53))	('ACC', 'Disease', (74, 77))	('N-Ras', 'Gene', (19, 24))	('ACA', 'Disease', (66, 69))
60729	22589739	Somatic mutations in the TP53 tumor suppressor gene occur in 25% to 33% of ACC but not in benign tumors, suggesting that mutations in TP53 participate in tumor progression rather than in initiation.	('TP53', 'Gene', (134, 138))	('mutations', 'Var', (121, 130))	('participate', 'Reg', (139, 150))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('benign tumors', 'Disease', 'MESH:D009369', (90, 103))	('tumor', 'Disease', (154, 159))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('rat', 'Species', '10116', (172, 175))	('TP53', 'Gene', '7157', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('TP53', 'Gene', (25, 29))	('benign tumors', 'Disease', (90, 103))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('ACC', 'Disease', (75, 78))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('TP53', 'Gene', '7157', (25, 29))	('tumor', 'Disease', (30, 35))
60730	22589739	Moreover, TP53 inactivating mutations have been shown to identify a sub-group of ACC patients developing an aggressive tumor associated with a poor outcome.	('tumor', 'Disease', (119, 124))	('TP53', 'Gene', (10, 14))	('inactivating mutations', 'Var', (15, 37))	('ACC', 'Phenotype', 'HP:0006744', (81, 84))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('aggressive', 'Disease', (108, 118))	('TP53', 'Gene', '7157', (10, 14))
60731	22589739	Patients with TP53 mutation also showed a trend towards a shorter survival duration.	('shorter', 'NegReg', (58, 65))	('TP53', 'Gene', '7157', (14, 18))	('mutation', 'Var', (19, 27))	('TP53', 'Gene', (14, 18))	('rat', 'Species', '10116', (77, 80))	('Patients', 'Species', '9606', (0, 8))	('survival duration', 'CPA', (66, 83))
60738	22589739	Therefore, there may exist a selection against cells overexpressing RasG12V, leaving a population with moderate expression of the activated oncogene.	('RasG12V', 'Var', (68, 75))	('rat', 'Species', '10116', (107, 110))	('expression', 'MPA', (112, 122))
60740	22589739	Significantly, these findings show that malignant progression in ACT might be controlled not only by the acquisition of specific genetic changes but also, and more importantly, with their order of acquisition as we found that only BAC cells expressing Ras and p53DD -in that order- could form carcinomas.	('Ras', 'Var', (252, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('carcinomas', 'Phenotype', 'HP:0030731', (293, 303))	('carcinomas', 'Disease', (293, 303))	('carcinomas', 'Disease', 'MESH:D002277', (293, 303))	('p53DD -in', 'Var', (260, 269))	('form', 'Reg', (288, 292))
60741	22589739	This supports the prediction that overexpression or mutation in Ras signaling pathway mediate important early events underlying later tumorigenesis.	('Ras signaling pathway', 'Pathway', (64, 85))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('mutation', 'Var', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
60744	22589739	Currently, we do not know how the order of acquisition of genetic alterations impacts the underlying mechanism of cooperation leading to different tumor phenotypes but this is the focus of our in progress investigations.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('rat', 'Species', '10116', (70, 73))	('rat', 'Species', '10116', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('genetic alterations', 'Var', (58, 77))	('alterations', 'Var', (66, 77))
60745	22589739	Mouse models have been developed to dissect the interplay between mutant p53 and oncogenic Ras in human cancer and have demonstrated that the presence of both genetic alterations give rise to highly invasive and metastatic tumors associated with a decrease in survival.	('presence', 'Var', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('survival', 'CPA', (260, 268))	('mutant', 'Var', (66, 72))	('p53', 'Gene', (73, 76))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rat', 'Species', '10116', (171, 174))	('decrease', 'NegReg', (248, 256))	('rat', 'Species', '10116', (127, 130))	('Mouse', 'Species', '10090', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (104, 110))	('human', 'Species', '9606', (98, 103))
60746	22589739	According to our results, a model of pancreatic tumor progression involving initiation through K-Ras oncogenic mutation and progression through acquisition of p53 point mutation has been suggested, however the reverse combination was not studied.	('K-Ras', 'Gene', '3845', (95, 100))	('p53', 'Gene', (159, 162))	('pancreatic tumor', 'Disease', (37, 53))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (37, 53))	('K-Ras', 'Gene', (95, 100))	('point mutation', 'Var', (163, 177))	('pancreatic tumor', 'Disease', 'MESH:D010190', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
60748	22589739	RhoA, a small GTPase involved in the cell motility process has been found to be negatively regulated by functional p53 and positively regulated by H-RasV12; both signals resulting in a basal level of activated RhoA Upon loss of p53 function, RhoA activation increases, which in turn induces cell motility and disease progression.	('cell motility', 'CPA', (291, 304))	('RhoA', 'Gene', '387', (0, 4))	('disease progression', 'CPA', (309, 328))	('RhoA', 'Gene', (0, 4))	('p53', 'Gene', (228, 231))	('RhoA', 'Gene', (242, 246))	('RhoA', 'Gene', '387', (210, 214))	('activation increases', 'PosReg', (247, 267))	('RhoA', 'Gene', '387', (242, 246))	('function', 'Var', (232, 240))	('RhoA', 'Gene', (210, 214))	('induces', 'Reg', (283, 290))	('activated', 'PosReg', (200, 209))	('loss', 'NegReg', (220, 224))
60749	22589739	Recently, microarray analysis of immortalized human fibroblasts transformed by the expression of H-RasG12V and inactivation of p53 identified a NFkappaB-dependent pro-inflammatory gene signature endowing these cells with an increased tumorigenicity.	('NFkappaB-dependent pro-inflammatory gene signature', 'MPA', (144, 194))	('tumor', 'Disease', (234, 239))	('H-RasG12V', 'Gene', (97, 106))	('human', 'Species', '9606', (46, 51))	('inactivation', 'Var', (111, 123))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('H-RasG12V', 'Chemical', '-', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('p53', 'Gene', (127, 130))	('expression', 'Var', (83, 93))
60760	22589739	Increased TPD52 expression and gene copy number have been reported in breast, prostate and ovarian cancer increasing cell proliferation in vitro and tumorigenicity in mice.	('mice', 'Species', '10090', (167, 171))	('gene copy number', 'Var', (31, 47))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('breast', 'Disease', (70, 76))	('rat', 'Species', '10116', (129, 132))	('cell proliferation', 'CPA', (117, 135))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Increased', 'PosReg', (0, 9))	('increasing', 'PosReg', (106, 116))	('tumor', 'Disease', (149, 154))	('prostate and ovarian cancer', 'Disease', 'MESH:D010051', (78, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TPD52', 'Gene', (10, 15))	('expression', 'MPA', (16, 26))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))
60763	22589739	Moreover, inactivation of EglN2 down-regulated Cyclin D1 and cell proliferation in several cancer cell lines.	('cancer', 'Disease', (91, 97))	('inactivation', 'Var', (10, 22))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cyclin D1', 'Gene', '595', (47, 56))	('EglN2', 'Gene', (26, 31))	('Cyclin D1', 'Gene', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('EglN2', 'Gene', '112398', (26, 31))	('down-regulated', 'NegReg', (32, 46))	('rat', 'Species', '10116', (73, 76))
60769	22589739	We are confident that other gene combinations will lead to ACT development with some specific clinical and histopathological features and it will be then possible to link the genotypes with the tumor phenotype.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('lead to', 'Reg', (51, 58))	('tumor', 'Disease', (194, 199))	('gene combinations', 'Var', (28, 45))	('combinations', 'Var', (33, 45))
60828	22427816	Rearrangements in the benign tumor sometimes take place and turn it into a malignant, invasive cancer.	('Rearrangements', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('benign tumor', 'Disease', (22, 34))	('invasive cancer', 'Disease', (86, 101))	('turn', 'Reg', (60, 64))	('benign tumor', 'Disease', 'MESH:D009369', (22, 34))	('invasive cancer', 'Disease', 'MESH:D009362', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
60833	22427816	SF-1 is also crucial during the embryonic development of the adrenal gland and gonads, a point highlighted by the fact that SF-1 knockout mice lack both adrenals and gonads.	('knockout', 'Var', (129, 137))	('mice', 'Species', '10090', (138, 142))	('SF-1', 'Gene', (124, 128))	('lack', 'NegReg', (143, 147))
60849	22427816	After quality control, samples were analyzed on microarrays to reveal genome-wide effects of SF-1 knockdown (Control vs. siSF-1), effect of cAMP treatment (Control +/-cAMP) and effect of cAMP treatment when SF-1 was knocked down (siSF-1 +/- cAMP).	('cAMP', 'Chemical', 'MESH:D000242', (187, 191))	('cAMP', 'Chemical', 'MESH:D000242', (167, 171))	('knockdown', 'Var', (98, 107))	('cAMP', 'Chemical', 'MESH:D000242', (140, 144))	('cAMP', 'Chemical', 'MESH:D000242', (241, 245))	('SF-1', 'Gene', (93, 97))
60857	22427816	Those appear active in the developing mouse gonad and DAX-1 levels are decreased in SF-1 knockout mice.	('mouse', 'Species', '10090', (38, 43))	('SF-1', 'Gene', (84, 88))	('DAX-1 levels', 'MPA', (54, 66))	('knockout', 'Var', (89, 97))	('decreased', 'NegReg', (71, 80))	('mice', 'Species', '10090', (98, 102))
60869	22427816	The knockdown of RNF31 was less efficient than that of SF-1, about 60% at the mRNA level (Figure 3A) and with some residual protein remaining (Figure 3B).	('RNF31', 'Gene', '55072', (17, 22))	('RNF31', 'Gene', (17, 22))	('knockdown', 'Var', (4, 13))
60870	22427816	However, the protein level of the target gene StAR was notably increased upon knockdown of RNF31, indicating that the achieved level was sufficient to detect putative target genes (Figure 3B).	('RNF31', 'Gene', '55072', (91, 96))	('protein level', 'MPA', (13, 26))	('increased', 'PosReg', (63, 72))	('knockdown', 'Var', (78, 87))	('RNF31', 'Gene', (91, 96))
60871	22427816	Using the same experimental outline as for the SF-1 experiment, we observed that RNF31 knockdown resulted in 355 regulated genes.	('RNF31', 'Gene', (81, 86))	('RNF31', 'Gene', '55072', (81, 86))	('knockdown', 'Var', (87, 96))
60877	22427816	In general, knockdown of SF-1 or RNF31 does not seem to fully inhibit cAMP induced gene regulation, even though it attenuates the response as the basal level changes, and thus the induction starts from a higher (RNF31) or lower (SF-1) level.	('cAMP', 'Chemical', 'MESH:D000242', (70, 74))	('RNF31', 'Gene', '55072', (212, 217))	('knockdown', 'Var', (12, 21))	('attenuates', 'NegReg', (115, 125))	('RNF31', 'Gene', (33, 38))	('SF-1', 'Gene', (25, 29))	('inhibit', 'NegReg', (62, 69))	('response as the basal level changes', 'MPA', (130, 165))	('RNF31', 'Gene', (212, 217))	('RNF31', 'Gene', '55072', (33, 38))
60883	22427816	Additional sub-network enrichment analysis revealed that DAX-1 is statistically linked (p = 0.0015) to the set of differentially regulated genes affected by silencing of RNF31.	('differentially regulated genes', 'MPA', (114, 144))	('RNF31', 'Gene', (170, 175))	('silencing', 'Var', (157, 166))	('RNF31', 'Gene', '55072', (170, 175))
60884	22427816	DAX-1 turns up as a hub among the genes related to steroidogenesis that were upregulated upon RNF31 knockdown (Figure 2C).	('RNF31', 'Gene', '55072', (94, 99))	('knockdown', 'Var', (100, 109))	('RNF31', 'Gene', (94, 99))	('upregulated', 'PosReg', (77, 88))
60895	22427816	Thus it seems that SF-1 can repress Wnt/beta-catenin signaling directly which might explain the increase of Wnt/beta-catenin targets Cyclin D2 and Axin 2 upon SF-1 knock down in NCI-H295R cells.	('SF-1', 'Gene', (159, 163))	('Wnt', 'Gene', '114487', (108, 111))	('Wnt', 'Gene', (36, 39))	('Cyclin D2', 'Gene', (133, 142))	('Axin 2', 'Gene', (147, 153))	('Axin 2', 'Gene', '8313', (147, 153))	('repress', 'NegReg', (28, 35))	('Wnt', 'Gene', '114487', (36, 39))	('NCI-H295R', 'CellLine', 'CVCL:0458', (178, 187))	('Wnt', 'Gene', (108, 111))	('knock down', 'Var', (164, 174))	('increase', 'PosReg', (96, 104))	('Cyclin D2', 'Gene', '894', (133, 142))
60898	22427816	All genes but NLK were downregulated by RNF31 knockdown, indicating that RNF31 is directly or indirectly repressing these genes.	('downregulated', 'NegReg', (23, 36))	('knockdown', 'Var', (46, 55))	('RNF31', 'Gene', (73, 78))	('NLK', 'Gene', '51701', (14, 17))	('NLK', 'Gene', (14, 17))	('RNF31', 'Gene', (40, 45))	('RNF31', 'Gene', '55072', (73, 78))	('RNF31', 'Gene', '55072', (40, 45))
60903	22427816	Aberrant beta-catenin signaling is also a common feature in cancer, including somatic, activating mutations of beta-catenin, which lead to continuous activity of beta-catenin target genes.	('beta-catenin', 'Protein', (111, 123))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', (60, 66))	('activating', 'PosReg', (87, 97))	('beta-catenin signaling', 'MPA', (9, 31))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('activity', 'MPA', (150, 158))
60904	22427816	Such mutations have been identified both directly in adrenal tumors and in the cell line NCI-H295R.	('identified', 'Reg', (25, 35))	('adrenal tumor', 'Phenotype', 'HP:0100631', (53, 66))	('adrenal tumors', 'Disease', (53, 67))	('NCI-H295R', 'CellLine', 'CVCL:0458', (89, 98))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('adrenal tumors', 'Disease', 'MESH:D000310', (53, 67))
60905	22427816	In NCI-H295R the S45P mutation has been shown to cause the beta-catenin pathway to be constitutively active.	('S45P', 'Mutation', 'rs121913407', (17, 21))	('beta-catenin pathway', 'Pathway', (59, 79))	('NCI-H295R', 'CellLine', 'CVCL:0458', (3, 12))	('cause', 'Reg', (49, 54))	('S45P', 'Var', (17, 21))
60908	22427816	Especially encouraging in this aspect is the data showing that repression of either pathway inhibits the growth of adrenocortical cells.	('adrenocortical', 'Disease', 'MESH:D018268', (115, 129))	('inhibits', 'NegReg', (92, 100))	('adrenocortical', 'Disease', (115, 129))	('repression', 'Var', (63, 73))
60911	22427816	Nine genes classified as belonging to the TGFbeta pathway were regulated (TGFB2, BMP4, SMAD9, MAPK1, NOG, LTBP1, FST, TGIF1, RUNX2) by SF-1 knockdown.	('TGFbeta', 'Gene', '7040', (42, 49))	('NOG', 'Gene', '9241', (101, 104))	('knockdown', 'Var', (140, 149))	('TGFB2', 'Gene', (74, 79))	('NOG', 'Gene', (101, 104))	('regulated', 'Reg', (63, 72))	('MAPK1', 'Gene', '5594', (94, 99))	('BMP4', 'Gene', (81, 85))	('LTBP1', 'Gene', '4052', (106, 111))	('RUNX2', 'Gene', (125, 130))	('SMAD9', 'Gene', (87, 92))	('RUNX2', 'Gene', '860', (125, 130))	('LTBP1', 'Gene', (106, 111))	('TGFbeta', 'Gene', (42, 49))	('TGIF1', 'Gene', (118, 123))	('BMP4', 'Gene', '652', (81, 85))	('MAPK1', 'Gene', (94, 99))	('TGIF1', 'Gene', '7050', (118, 123))	('TGFB2', 'Gene', '7042', (74, 79))	('SMAD9', 'Gene', '4093', (87, 92))
60914	22427816	Prominently, all TGFbeta-connected genes but MAPK1 (ERK2) were upregulated upon SF-1 knockdown.	('MAPK1', 'Gene', '5594', (45, 50))	('SF-1', 'Gene', (80, 84))	('ERK2', 'Gene', '5594', (52, 56))	('TGFbeta', 'Gene', (17, 24))	('ERK2', 'Gene', (52, 56))	('upregulated', 'PosReg', (63, 74))	('MAPK1', 'Gene', (45, 50))	('knockdown', 'Var', (85, 94))	('TGFbeta', 'Gene', '7040', (17, 24))
60920	22427816	To investigate the effects of TGFbeta2, which was upregulated by SF-1 knockdown, in adrenocortical NCI-H295R cells, we treated the cells with TGFbeta2 and measured cell proliferation 16 h later using flow cytometry.	('adrenocortical', 'Disease', 'MESH:D018268', (84, 98))	('upregulated', 'PosReg', (50, 61))	('knockdown', 'Var', (70, 79))	('TGFbeta2', 'Gene', (142, 150))	('NCI-H295R', 'CellLine', 'CVCL:0458', (99, 108))	('cell', 'CPA', (164, 168))	('adrenocortical', 'Disease', (84, 98))	('TGFbeta2', 'Gene', '7042', (30, 38))	('TGFbeta2', 'Gene', (30, 38))	('TGFbeta2', 'Gene', '7042', (142, 150))	('SF-1', 'Gene', (65, 69))
60923	22427816	Potentially, the increased TGFbeta2 expression resulting from SF-1 knockdown could pose a problem for such a therapy if childhood tumors have dysregulated TGFbeta signaling like the NCI-H295R cells, and this needs to be explored further.	('tumors', 'Disease', (130, 136))	('increased', 'PosReg', (17, 26))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('increased TGFbeta2', 'Phenotype', 'HP:0030269', (17, 35))	('knockdown', 'Var', (67, 76))	('NCI-H295R', 'CellLine', 'CVCL:0458', (182, 191))	('TGFbeta2', 'Gene', '7042', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('dysregulated TGFbeta', 'Disease', (142, 162))	('dysregulated TGFbeta', 'Disease', 'MESH:D021081', (142, 162))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('SF-1', 'Gene', (62, 66))	('expression', 'MPA', (36, 46))	('TGFbeta2', 'Gene', (27, 35))
60929	22427816	10 of the 12 genes are regulated in the opposite direction in the knockdown compared to the overexpression: FATE1, C21orf25, KIAA1913, APOA1, HSPB7 and SULT2A1 are upregulated by SF-1 overexpression and downregulated by SF-1 knockdown while ANKFN1, ENPP2, FGF13 and ACPL2 are regulated the opposite way.	('HSPB7', 'Gene', (142, 147))	('upregulated', 'PosReg', (164, 175))	('KIAA1913', 'Gene', (125, 133))	('FGF13', 'Gene', '2258', (256, 261))	('FGF13', 'Gene', (256, 261))	('C21orf25', 'Gene', '25966', (115, 123))	('KIAA1913', 'Gene', '114801', (125, 133))	('ENPP2', 'Gene', (249, 254))	('ACPL2', 'Gene', (266, 271))	('knockdown', 'Var', (225, 234))	('APOA1', 'Gene', (135, 140))	('overexpression', 'PosReg', (184, 198))	('APOA1', 'Gene', '335', (135, 140))	('FATE1', 'Gene', '89885', (108, 113))	('HSPB7', 'Gene', '27129', (142, 147))	('ANKFN1', 'Gene', '162282', (241, 247))	('C21orf25', 'Gene', (115, 123))	('FATE1', 'Gene', (108, 113))	('SF-1', 'Gene', (220, 224))	('ANKFN1', 'Gene', (241, 247))	('SULT2A1', 'Gene', (152, 159))	('ACPL2', 'Gene', '92370', (266, 271))	('downregulated', 'NegReg', (203, 216))	('ENPP2', 'Gene', '5168', (249, 254))	('SF-1', 'Gene', (179, 183))
60933	22427816	The Doghman study also showed that RNAi-mediated SF-1 knockdown decreased proliferation in NCI-H295R cells.	('knockdown', 'Var', (54, 63))	('NCI-H295R', 'CellLine', 'CVCL:0458', (91, 100))	('proliferation', 'CPA', (74, 87))	('SF-1', 'Gene', (49, 53))	('decreased', 'NegReg', (64, 73))
60935	22427816	We found that Insulin-like growth factor-II (IGFII) gene IGF2 was downregulated following SF-1 knockdown.	('SF-1', 'Gene', (90, 94))	('IGFII', 'Gene', '3481', (45, 50))	('IGF2', 'Gene', '3481', (57, 61))	('downregulated', 'NegReg', (66, 79))	('knockdown', 'Var', (95, 104))	('IGF2', 'Gene', (57, 61))	('IGFII', 'Gene', (45, 50))	('Insulin-like growth factor-II', 'Gene', (14, 43))	('Insulin-like growth factor-II', 'Gene', '3481', (14, 43))
60941	22427816	IGF2 downregulation upon SF-1 knockdown could be beneficial with respect to decreased tumor growth and of interest therapeutically as different treatments designed to decrease IGF2 levels have been suggested for adrenocortical carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('decreased tumor', 'Disease', (76, 91))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (212, 236))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (212, 236))	('IGF2', 'Gene', (176, 180))	('downregulation', 'NegReg', (5, 19))	('adrenocortical carcinoma', 'Disease', (212, 236))	('IGF2', 'Gene', '3481', (0, 4))	('SF-1', 'Gene', (25, 29))	('knockdown', 'Var', (30, 39))	('decreased tumor', 'Disease', 'MESH:D009369', (76, 91))	('IGF2', 'Gene', '3481', (176, 180))	('IGF2', 'Gene', (0, 4))
60944	22427816	In line with this data is the observation that PBX1 is expressed in the developing adrenal and that PBX1 knockout mice (embryonically lethal at day 15/16) suffer from adrenal agenesis.	('adrenal agenesis', 'CPA', (167, 183))	('knockout', 'Var', (105, 113))	('adrenal agenesis', 'Phenotype', 'HP:0011743', (167, 183))	('PBX1', 'Gene', (100, 104))	('mice', 'Species', '10090', (114, 118))	('suffer', 'Reg', (155, 161))
60950	22427816	To address this limitation, and to assess the clinical relevance of the genes affected by SF-1 knockdown in NCI-H295R, we interrogated their expression in a recent transcriptome-profiling study of 92 adrenocortical tumors.	('SF-1', 'Gene', (90, 94))	('adrenocortical tumors', 'Disease', (200, 221))	('clinical', 'Species', '191496', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('knockdown', 'Var', (95, 104))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (200, 221))	('NCI-H295R', 'CellLine', 'CVCL:0458', (108, 117))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
60962	22427816	In the case of LRH-1, SUMOylation appears to play a pivotal role in the transrepression mechanism by allowing it to tether to target transcription factor-corepressor complexes.	('transrepression', 'MPA', (72, 87))	('SUMOylation', 'Var', (22, 33))	('tether', 'Interaction', (116, 122))	('LRH-1', 'Gene', '2494', (15, 20))	('LRH-1', 'Gene', (15, 20))
60966	22427816	A mixture of four siRNA oligos was used for knockdown of SF-1 (siGENOME SMARTpool M-003429, Dharmacon, Thermo Scientific) and RNF31 (siGENOME SMARTpool D-021419, Dharmacon, Thermo Scientific), respectively.	('SF-1', 'Gene', (57, 61))	('RNF31', 'Gene', (126, 131))	('knockdown', 'Var', (44, 53))	('RNF31', 'Gene', '55072', (126, 131))
60983	21924324	Disruption of adrenal steroid production results in a variety of diseases that can lead to hypertension, metabolic syndrome, infertility and androgen excess.	('hypertension', 'Disease', (91, 103))	('infertility', 'Disease', 'MESH:D007247', (125, 136))	('hypertension', 'Phenotype', 'HP:0000822', (91, 103))	('androgen excess', 'Disease', (141, 156))	('infertility', 'Phenotype', 'HP:0000789', (125, 136))	('infertility', 'Disease', (125, 136))	('lead', 'Reg', (83, 87))	('hypertension', 'Disease', 'MESH:D006973', (91, 103))	('metabolic syndrome', 'Disease', 'MESH:D008659', (105, 123))	('metabolic syndrome', 'Disease', (105, 123))	('diseases', 'Disease', (65, 73))	('steroid', 'Chemical', 'MESH:D013256', (22, 29))	('results in', 'Reg', (41, 51))	('adrenal', 'MPA', (14, 21))	('Disruption', 'Var', (0, 10))
61018	21924324	The PRKAR1A gene that encodes the regulatory subunit type 1A (RIalpha) of cAMP-dependent protein kinase (PKA) was inactivated via gene mutation after the introduction of this cell line.	('cAMP', 'Chemical', '-', (74, 78))	('gene mutation', 'Var', (130, 143))	('inactivated', 'NegReg', (114, 125))	('PRKAR1A', 'Gene', (4, 11))	('PRKAR1A', 'Gene', '5573', (4, 11))
61026	21924324	As with H295R cell lines, the isolated RL-251 cultures exhibited an abnormal karyotypic profile, consisting of numerous deletions and translocations (Table 1).	('translocations', 'MPA', (134, 148))	('deletions', 'Var', (120, 129))	('RL-251', 'CellLine', 'CVCL:S900', (39, 45))
61049	21924324	It is noteworthy that treatment with agonists appears to selectively promote the synthesis of certain zone-specific steroid hormone groups in H295R.	('zone-specific steroid hormone groups', 'MPA', (102, 138))	('steroid hormone', 'Chemical', 'MESH:D013256', (116, 131))	('H295R', 'Var', (142, 147))	('promote', 'PosReg', (69, 76))	('synthesis of', 'MPA', (81, 93))
61088	21924324	Examination in NCI-H295 cells suggested that TZDs might have favorable effects in the treatment of a variety of tumors and appear to act as differentiation-inducing agents.	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TZDs', 'Var', (45, 49))	('TZDs', 'Chemical', 'MESH:D045162', (45, 49))	('NCI-H295', 'CellLine', 'CVCL:0456', (15, 23))	('treatment', 'CPA', (86, 95))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
61091	21924324	T-cell factor/beta-catenin antagonists, PKF115-584 and type I insulin-like growth factor receptor inhibitors have been recently tested in the NCI-H295 cells.	('beta-catenin', 'Gene', '1499', (14, 26))	('PKF115-584', 'Var', (40, 50))	('NCI-H295', 'CellLine', 'CVCL:0456', (142, 150))	('beta-catenin', 'Gene', (14, 26))
61092	21924324	These biochemicals are targeted to a limited number of known genetic mutations in adrenocortical carcinomas which are also present in the NCI-H295 cells.	('mutations', 'Var', (69, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (82, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (82, 107))	('NCI-H295', 'CellLine', 'CVCL:0456', (138, 146))	('adrenocortical carcinomas', 'Disease', (82, 107))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (82, 106))
61123	33677926	Genomic instability such as DNA hypomethylation and chromosomal instability was associated with POU1F1/PIT1 lineage differentiation.	('PIT1', 'Gene', (103, 107))	('DNA hypomethylation', 'Var', (28, 47))	('chromosomal', 'CPA', (52, 63))	('PIT1', 'Gene', '5449', (103, 107))	('chromosomal instability', 'Phenotype', 'HP:0040012', (52, 75))	('POU1F1', 'Gene', '5449', (96, 102))	('associated', 'Reg', (80, 90))	('POU1F1', 'Gene', (96, 102))
61127	33677926	A somatic hotspot mutation in splicing factor 3 subunit B1 (SFB1R625H) was discovered by whole-genome sequencing in 21 patients with prolactinoma and validated by digital polymerase chain reaction in 227 prolactinomas.	('prolactinomas', 'Disease', (204, 217))	('prolactinoma', 'Disease', (204, 216))	('prolactinoma', 'Phenotype', 'HP:0040278', (204, 216))	('prolactinoma', 'Disease', (133, 145))	('patients', 'Species', '9606', (119, 127))	('prolactinoma', 'Disease', 'MESH:D015175', (204, 216))	('prolactinoma', 'Disease', 'MESH:D015175', (133, 145))	('prolactinoma', 'Phenotype', 'HP:0040278', (133, 145))	('prolactinomas', 'Disease', 'MESH:D015175', (204, 217))	('hotspot', 'PosReg', (10, 17))	('mutation', 'Var', (18, 26))	('SFB1R625H', 'Gene', (60, 69))
61181	32156018	High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53 Adrenocortical cancer is a rare malignant neoplasm associated with a dismal prognosis.	('Adrenocortical cancer', 'Disease', 'MESH:D000306', (164, 185))	('malignant neoplasm', 'Disease', 'MESH:D009369', (196, 214))	('neoplasm', 'Phenotype', 'HP:0002664', (206, 214))	('Tumors', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('Patients', 'Species', '9606', (91, 99))	('Adrenocortical Tumors', 'Disease', (105, 126))	('TP53', 'Gene', (159, 163))	('Adrenocortical cancer', 'Disease', (164, 185))	('Adrenocortical Tumors', 'Disease', 'MESH:D018268', (105, 126))	('malignant neoplasm', 'Disease', (196, 214))	('Alterations', 'Var', (19, 30))
61183	32156018	The aim of this study is to define the prevalence of alterations in DNA mismatch repair (MMR) genes in Lynch syndrome among pediatric patients with adrenocortical neoplasia from southern Brazil, where the prevalence of a specific TP53 germline mutation (p.Arg337His) is quite high.	('Lynch syndrome', 'Disease', (103, 117))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (148, 172))	('TP53', 'Gene', (230, 234))	('Lynch syndrome', 'Disease', 'MESH:D003123', (103, 117))	('adrenocortical neoplasia', 'Disease', (148, 172))	('patients', 'Species', '9606', (134, 142))	('neoplasia', 'Phenotype', 'HP:0002664', (163, 172))	('MMR', 'Gene', (89, 92))	('p.Arg337His', 'Var', (254, 265))	('p.Arg337His', 'Mutation', 'rs121912664', (254, 265))	('TP53', 'Gene', '7157', (230, 234))
61189	32156018	The prevalence of altered MMR genes among pediatric patients was elevated (8.57%) and higher than in colorectal and endometrial cancer cohorts.	('colorectal and endometrial cancer', 'Disease', 'MESH:D015179', (101, 134))	('altered', 'Var', (18, 25))	('MMR genes', 'Gene', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('endometrial cancer', 'Phenotype', 'HP:0012114', (116, 134))	('patients', 'Species', '9606', (52, 60))
61195	32156018	This notorious difference is due to the high prevalence of the germline mutation TP53 p.Arg337His in this region of Brazil.	('TP53', 'Gene', '7157', (81, 85))	('p.Arg337His', 'Mutation', 'rs121912664', (86, 97))	('p.Arg337His', 'Var', (86, 97))	('TP53', 'Gene', (81, 85))
61196	32156018	Among pediatric patients, germline mutations are responsible for most cases and TP53 mutations are present in 50-90% of cases; this differs from the adult ACC group, in which sporadic cases are the most common.	('patients', 'Species', '9606', (16, 24))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutations', 'Var', (85, 94))	('responsible', 'Reg', (49, 60))
61197	32156018	Li-Fraumeni syndrome (LFS), first described in 1969, is an autosomal dominant cancer predisposition syndrome in pediatric cases and in young adults, which results from germline mutations in the TP53 tumor suppressor gene.	('tumor', 'Disease', (199, 204))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (59, 84))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('LFS', 'Disease', 'MESH:D016864', (22, 25))	('autosomal dominant cancer', 'Disease', (59, 84))	('results from', 'Reg', (155, 167))	('germline mutations', 'Var', (168, 186))	('TP53', 'Gene', '7157', (194, 198))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('TP53', 'Gene', (194, 198))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('LFS', 'Disease', (22, 25))
61198	32156018	LFS families present ACC in 3-10% of cases, showing that germline mutations in TP53 are linked to adrenal tumorigenesis.	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('LFS', 'Disease', (0, 3))	('germline mutations', 'Var', (57, 75))	('linked', 'Reg', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('LFS', 'Disease', 'MESH:D016864', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
61204	32156018	Germline mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) have been associated with this syndrome since 1993.	('Germline mutations', 'Var', (0, 18))	('MLH1', 'Gene', (33, 37))	('MSH2', 'Gene', (39, 43))	('MSH2', 'Gene', '4436', (39, 43))	('PMS2', 'Gene', (55, 59))	('MSH6', 'Gene', '2956', (45, 49))	('PMS2', 'Gene', '5395', (55, 59))	('MSH6', 'Gene', (45, 49))	('associated', 'Reg', (71, 81))	('MLH1', 'Gene', '4292', (33, 37))
61205	32156018	Germline mutations in MLH1, MSH2, and MSH6 account for more than 90% of cases.	('Germline mutations', 'Var', (0, 18))	('MSH6', 'Gene', (38, 42))	('MLH1', 'Gene', '4292', (22, 26))	('MLH1', 'Gene', (22, 26))	('MSH6', 'Gene', '2956', (38, 42))	('MSH2', 'Gene', (28, 32))	('MSH2', 'Gene', '4436', (28, 32))
61206	32156018	Other genetic alterations can cause LS-like disease with a clinical presentation similar to LS, such as the germline mutation in the EPCAM gene that causes MSH2 silencing and the somatic mutation on BRAF gene that causes MLH1 methylation.	('alterations', 'Var', (14, 25))	('EPCAM', 'Gene', (133, 138))	('cause', 'Reg', (30, 35))	('LS-like disease', 'Disease', (36, 51))	('EPCAM', 'Gene', '4072', (133, 138))	('BRAF', 'Gene', (199, 203))	('silencing', 'NegReg', (161, 170))	('MSH2', 'Gene', (156, 160))	('LS-like disease', 'Disease', 'MESH:D007888', (36, 51))	('mutation', 'Var', (117, 125))	('mutation', 'Var', (187, 195))	('MSH2', 'Gene', '4436', (156, 160))	('BRAF', 'Gene', '673', (199, 203))	('MLH1', 'Gene', '4292', (221, 225))	('MLH1', 'Gene', (221, 225))
61209	32156018	The aim of this study is to define the prevalence of alterations in MMR genes of LS among pediatric patients with adrenocortical tumor.	('adrenocortical tumor', 'Disease', (114, 134))	('MMR genes', 'Gene', (68, 77))	('alterations', 'Var', (53, 64))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('patients', 'Species', '9606', (100, 108))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (114, 134))
61213	32156018	All patients underwent the TP53 genetic test, from which it was found that 33 (91.6%) patients were positive for TP53 germline pathogenic variants.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('positive', 'Reg', (100, 108))	('variants', 'Var', (138, 146))	('TP53', 'Gene', '7157', (113, 117))	('patients', 'Species', '9606', (4, 12))	('TP53', 'Gene', (113, 117))	('patients', 'Species', '9606', (86, 94))
61214	32156018	Thirty-one (31/33, 93.9%) patients exhibited the classical c.1010G > A variant on exon 10 (p.Arg337His), while only two patients presented others described germline pathogenic variants: patient 24, c.818G > A (p.Arg273His); and patient 26, c.733G > A (p.Gly245Ser).	('c.818G > A (p.Arg273His', 'Var', (198, 221))	('c.733G > A', 'Mutation', 'rs28934575', (240, 250))	('p.Arg273His', 'Mutation', 'rs28934576', (210, 221))	('patient', 'Species', '9606', (26, 33))	('p.Arg337His', 'Var', (91, 102))	('c.733G > A', 'Var', (240, 250))	('patient', 'Species', '9606', (120, 127))	('p.Arg337His', 'Mutation', 'rs121912664', (91, 102))	('patients', 'Species', '9606', (26, 34))	('c.1010G > A', 'Var', (59, 70))	('patients', 'Species', '9606', (120, 128))	('c.818G > A', 'Mutation', 'rs28934576', (198, 208))	('p.Gly245Ser', 'Mutation', 'rs28934575', (252, 263))	('patient', 'Species', '9606', (186, 193))	('patient', 'Species', '9606', (228, 235))	('c.1010G > A', 'Mutation', 'rs121912664', (59, 70))
61223	32156018	Three of thirty-five (8.57%) patients presented germline pathogenic and likely pathogenic variants on MMR genes identified on NGS, and all of them presented the TP53 germline mutation (c.1010G > A, p.Arg337His).	('c.1010G > A', 'Mutation', 'rs121912664', (185, 196))	('patients', 'Species', '9606', (29, 37))	('TP53', 'Gene', (161, 165))	('p.Arg337His', 'Mutation', 'rs121912664', (198, 209))	('p.Arg337His', 'Var', (198, 209))	('MMR genes', 'Gene', (102, 111))	('c.1010G > A', 'Var', (185, 196))	('TP53', 'Gene', '7157', (161, 165))
61225	32156018	NGS analyses revealed an in-frame deletion variant in the MLH1 gene [c.1500_1502del, p.Ile501del (rs587778920)].	('c.1500_1502del', 'Mutation', 'c.1500_1502del', (69, 83))	('[c.1500_1502del', 'Var', (68, 83))	('MLH1', 'Gene', '4292', (58, 62))	('MLH1', 'Gene', (58, 62))	('p.Ile501del', 'Var', (85, 96))	('rs587778920', 'Mutation', 'rs587778920', (98, 109))	('p.Ile501del', 'Mutation', 'rs587778920', (85, 96))
61227	32156018	NGS analyses identified a missense variant in the MLH1 gene [c.1808C > T, p.Pro603Leu (rs63750876)].	('MLH1', 'Gene', '4292', (50, 54))	('rs63750876', 'Mutation', 'rs63750876', (87, 97))	('MLH1', 'Gene', (50, 54))	('p.Pro603Leu', 'Mutation', 'rs63750876', (74, 85))	('[c.1808C > T', 'Var', (60, 72))	('c.1808C > T', 'Mutation', 'rs63750876', (61, 72))
61229	32156018	NGS analyses showed a nonsense variant in the MSH6 gene [c.328C > T, p.Arg110* (rs63750019)] (Figure 2).	('rs63750019', 'Mutation', 'rs63750019', (80, 90))	('p.Arg110*', 'Mutation', 'rs63750019', (69, 78))	('MSH6', 'Gene', (46, 50))	('p.Arg110* (rs63750019)]', 'Var', (69, 92))	('rs63750019)]', 'Var', (80, 92))	('MSH6', 'Gene', '2956', (46, 50))	('[c.328C > T', 'Var', (56, 67))	('c.328C > T', 'Mutation', 'rs63750019', (57, 67))
61230	32156018	Nonsense variants in MSH6 are a known mechanism of disease.	('MSH6', 'Gene', (21, 25))	('MSH6', 'Gene', '2956', (21, 25))	('Nonsense variants', 'Var', (0, 17))
61231	32156018	Three out of thirty-five (8.57%) patients presented a variant of uncertain significance (VUS) in NGS, and all of them presented the TP53 germline mutation (c.1010G > A, p.Arg337His) and preserved protein expression of MMR proteins in immunohistochemistry analyses.	('p.Arg337His', 'Mutation', 'rs121912664', (169, 180))	('MMR proteins', 'Protein', (218, 230))	('patients', 'Species', '9606', (33, 41))	('protein expression', 'MPA', (196, 214))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('NGS', 'Disease', (97, 100))	('c.1010G > A', 'Mutation', 'rs121912664', (156, 167))	('p.Arg337His', 'Var', (169, 180))	('c.1010G > A', 'Var', (156, 167))
61237	32156018	NGS data showed a missense variant in MSH6 (c.2420A > G, p.Tyr807Cys) that has not been previously described as being associated with Lynch syndrome.	('MSH6', 'Gene', (38, 42))	('MSH6', 'Gene', '2956', (38, 42))	('c.2420A > G', 'Mutation', 'c.2420A>G', (44, 55))	('p.Tyr807Cys', 'Mutation', 'p.Y807C', (57, 68))	('Lynch syndrome', 'Disease', (134, 148))	('associated', 'Reg', (118, 128))	('c.2420A > G', 'Var', (44, 55))	('Lynch syndrome', 'Disease', 'MESH:D003123', (134, 148))
61239	32156018	NGS analysis found a missense variant in MSH6 [c.359T > C, p.Ile120Thr (rs775971872)].	('p.Ile120Thr (rs775971872)]', 'Var', (59, 85))	('MSH6', 'Gene', '2956', (41, 45))	('p.Ile120Thr', 'Mutation', 'rs775971872', (59, 70))	('rs775971872', 'Mutation', 'rs775971872', (72, 83))	('c.359T > C', 'Mutation', 'rs775971872', (47, 57))	('rs775971872)]', 'Var', (72, 85))	('MSH6', 'Gene', (41, 45))	('[c.359T > C', 'Var', (46, 57))
61242	32156018	NGS showed a missense variant in MSH6 [c.643G > T, p.Val215Leu (rs145959653)].	('[c.643G > T', 'Var', (38, 49))	('MSH6', 'Gene', '2956', (33, 37))	('rs145959653', 'Mutation', 'rs145959653', (64, 75))	('MSH6', 'Gene', (33, 37))	('c.643G > T', 'Mutation', 'rs145959653', (39, 49))	('p.Val215Leu', 'Mutation', 'rs145959653', (51, 62))	('rs145959653)]', 'Var', (64, 77))
61249	32156018	Heterozygous mutations in one of the four genes involved in MMR (MLH1, MSH2, MSH6, and PMS2) are the cause of Lynch syndrome, while biallelic mutations outline a more severe phenotype and are used to identify constitutional mismatch repair deficiency syndrome.	('biallelic mutations', 'Var', (132, 151))	('MSH6', 'Gene', '2956', (77, 81))	('Lynch syndrome', 'Disease', (110, 124))	('MSH2', 'Gene', '4436', (71, 75))	('PMS2', 'Gene', (87, 91))	('deficiency syndrome', 'Disease', (240, 259))	('constitutional mismatch', 'Disease', (209, 232))	('Lynch syndrome', 'Disease', 'MESH:D003123', (110, 124))	('MLH1', 'Gene', '4292', (65, 69))	('PMS2', 'Gene', '5395', (87, 91))	('MLH1', 'Gene', (65, 69))	('MSH6', 'Gene', (77, 81))	('deficiency syndrome', 'Disease', 'MESH:D061325', (240, 259))	('Heterozygous mutations', 'Var', (0, 22))	('cause', 'Reg', (101, 106))	('MSH2', 'Gene', (71, 75))
61255	32156018	This tested cohort was of particular interest, due to the high prevalence of TP53 mutations, mainly the c.1010G > A, p.Arg337His mutation.	('c.1010G > A', 'Mutation', 'rs121912664', (104, 115))	('c.1010G > A', 'Var', (104, 115))	('p.Arg337His', 'Var', (117, 128))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('p.Arg337His', 'Mutation', 'rs121912664', (117, 128))
61256	32156018	Pathogenic variants on the MMR genes were found in 8.57% (3/35) of our pediatric cohort (two were localized in MLH1, and one in MSH6) and VUS were found in 8.57% (3/35).	('MSH6', 'Gene', (128, 132))	('variants', 'Var', (11, 19))	('Pathogenic', 'CPA', (0, 10))	('MSH6', 'Gene', '2956', (128, 132))	('MMR', 'Gene', (27, 30))	('MLH1', 'Gene', '4292', (111, 115))	('MLH1', 'Gene', (111, 115))
61258	32156018	Interestingly, 3464 variants have been described in MSH6, according to UniProt, ClinVar, Varsome, and Pubmed, 1916 of which are missense variants.	('MSH6', 'Gene', '2956', (52, 56))	('variants', 'Var', (20, 28))	('MSH6', 'Gene', (52, 56))
61259	32156018	In these missense variants, 1844 (96.24%) were classified as VUS, the frequency of which is considered high, when compared to other genes such as TP53 and CTNNB1, which showed 66.98% and 22.72% missense variants as VUS, respectively.	('missense variants', 'Var', (194, 211))	('TP53', 'Gene', '7157', (146, 150))	('CTNNB1', 'Gene', '1499', (155, 161))	('TP53', 'Gene', (146, 150))	('CTNNB1', 'Gene', (155, 161))	('missense variants', 'Var', (9, 26))
61260	32156018	The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has suggested a new scheme for the standardized classification of MMR variants, categorizing the variants into five classes of pathogenicity.	('Tumors', 'Phenotype', 'HP:0002664', (58, 64))	('Gastrointestinal Hereditary Tumors', 'Disease', 'MESH:D004067', (30, 64))	('variants', 'Var', (145, 153))	('Gastrointestinal Hereditary Tumors', 'Disease', (30, 64))	('MMR', 'Gene', (141, 144))
61261	32156018	Our six variants were classified with this InSiGHT scheme and only #6 (MLH1, c.1500_1502del, p.Ile501del) was found, which was categorized as Class 3/Uncertain.	('MLH1', 'Gene', '4292', (71, 75))	('c.1500_1502del', 'Mutation', 'c.1500_1502del', (77, 91))	('MLH1', 'Gene', (71, 75))	('p.Ile501del', 'Var', (93, 104))	('p.Ile501del', 'Mutation', 'rs587778920', (93, 104))	('c.1500_1502del', 'Var', (77, 91))
61262	32156018	reported the findings of the Prospective Lynch Syndrome Database, classifying the variants using the InSiGHT scheme, and proposed that LS should be considered as a generic term for a group of four clinically different inherited cancer risk syndromes.	('variants', 'Var', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
61263	32156018	This new suggestion is due to the different results of cancer risk by gene, age, and gender of the class 4 and 5 MMR variants.	('variants', 'Var', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
61264	32156018	When we compared our data with that of a previous study with adult cohorts associated with LS-related cancers, we noticed an important prevalence of MMR variants in our ACT pediatric cohort.	('MMR', 'Gene', (149, 152))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('variants', 'Var', (153, 161))	('cancers', 'Disease', (102, 109))
61266	32156018	We presented three patients with MMR pathogenic variants that probably alter the encoded protein; however, the IHC analyses showed positive immunoexpression of all MMR proteins.	('patients', 'Species', '9606', (19, 27))	('pathogenic', 'Reg', (37, 47))	('variants', 'Var', (48, 56))	('MMR', 'Disease', (33, 36))	('immunoexpression', 'MPA', (140, 156))
61267	32156018	In most cases, MMR pathogenic variants result in loss of protein expression in the tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('variants', 'Var', (30, 38))	('loss', 'NegReg', (49, 53))	('MMR', 'Gene', (15, 18))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('protein expression', 'MPA', (57, 75))
61268	32156018	In our cohort, we demonstrated a high prevalence of MMR pathogenic variants in a cohort of patients who also presented TP53 mutations.	('pathogenic', 'Reg', (56, 66))	('MMR', 'Gene', (52, 55))	('mutations', 'Var', (124, 133))	('patients', 'Species', '9606', (91, 99))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('variants', 'Var', (67, 75))
61269	32156018	Nevertheless, we could not identify any difference in tumor behavior associated with the presence of variants in both genes.	('tumor', 'Disease', (54, 59))	('variants', 'Var', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
61270	32156018	In LS patients with colorectal cancer, it was possible to identify that TP53 variants modulated the age of development of CRC, with the age of tumor development being earlier in patients with TP53 mutations than in LS patients who presented wild-type (WT) TP53.	('variants', 'Var', (77, 85))	('patients', 'Species', '9606', (6, 14))	('TP53', 'Gene', '7157', (256, 260))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('TP53', 'Gene', '7157', (72, 76))	('patients', 'Species', '9606', (178, 186))	('CRC', 'Disease', (122, 125))	('TP53', 'Gene', (192, 196))	('CRC', 'Phenotype', 'HP:0003003', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('patients', 'Species', '9606', (218, 226))	('mutations', 'Var', (197, 206))	('colorectal cancer', 'Disease', 'MESH:D015179', (20, 37))	('TP53', 'Gene', (256, 260))	('modulated', 'Reg', (86, 95))	('tumor', 'Disease', (143, 148))	('CRC', 'Disease', 'MESH:D015179', (122, 125))	('colorectal cancer', 'Disease', (20, 37))	('TP53', 'Gene', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('TP53', 'Gene', '7157', (192, 196))
61271	32156018	In a breast cancer cohort, the association of TP53 variants with MSH variants also impacted the age at diagnosis.	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('MSH', 'Gene', (65, 68))	('variants', 'Var', (69, 77))	('impacted', 'Reg', (83, 91))	('TP53', 'Gene', '7157', (46, 50))	('variants', 'Var', (51, 59))	('association', 'Interaction', (31, 42))	('MSH', 'Gene', '4488', (65, 68))	('TP53', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('breast cancer', 'Disease', 'MESH:D001943', (5, 18))	('breast cancer', 'Disease', (5, 18))
61273	32156018	They demonstrated that TP53 and MSH6 are functionally inter-related and that concomitant variants in both genes lead these tumor suppressors to act together to accelerate tumorigenesis.	('variants', 'Var', (89, 97))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('MSH6', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', (171, 176))	('TP53', 'Gene', '7157', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('TP53', 'Gene', (23, 27))	('MSH6', 'Gene', '2956', (32, 36))	('accelerate', 'PosReg', (160, 170))
61275	32156018	Further follow-up studies are necessary to prove whether MMR variant carriers who have already presented ACT are more likely to develop other cancers at an early age.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('variant', 'Var', (61, 68))	('develop', 'PosReg', (128, 135))	('MMR', 'Gene', (57, 60))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
61276	32156018	Whether the association of MMR variants with TP53 variants could affect tumor behavior, in turn impacting clinical outcomes and the survival rate, also needs to be addressed.	('affect', 'Reg', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('variants', 'Var', (31, 39))	('TP53', 'Gene', (45, 49))	('tumor', 'Disease', (72, 77))	('clinical outcomes', 'CPA', (106, 123))	('impacting', 'Reg', (96, 105))	('variants', 'Var', (50, 58))	('MMR', 'Gene', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('TP53', 'Gene', '7157', (45, 49))
61285	32156018	One set of three slides was selected (one slide from each of the three TMA paraffin blocks of the triplicate) for staining with anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6 ready-to-use Leica Biosystems antibodies (PA0610, PMS2-L-CE, PA0048, and PA0804, respectively).	('PMS2', 'Gene', (144, 148))	('MLH1', 'Gene', '4292', (133, 137))	('PA0048', 'Var', (236, 242))	('MLH1', 'Gene', (133, 137))	('MSH6', 'Gene', (170, 174))	('TMA paraffin', 'Chemical', '-', (71, 83))	('PMS2', 'Gene', '5395', (144, 148))	('MSH2', 'Gene', (155, 159))	('PA0804', 'Var', (248, 254))	('PMS2', 'Gene', (225, 229))	('MSH2', 'Gene', '4436', (155, 159))	('MSH6', 'Gene', '2956', (170, 174))	('PMS2', 'Gene', '5395', (225, 229))
61286	32156018	Formalin-fixed and paraffin-embedded tumor sections were cut at 4 mum thickness and stained on a Ventana Bench Mark Ultra Autostainer (Ventana Medical System, Tucson, Arizona) with the following antibodies: MLH-1 (clone M1, Ventana), MSH2 (clone G219-1129, Ventana), MSH6 (clone SP93, Ventana), and PMS2 (A16-4, Ventana).	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('MLH-1', 'Gene', '4292', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('MSH2', 'Gene', (234, 238))	('PMS2', 'Gene', (299, 303))	('MLH-1', 'Gene', (207, 212))	('clone G219-1129', 'Var', (240, 255))	('clone SP93', 'Var', (273, 283))	('PMS2', 'Gene', '5395', (299, 303))	('tumor', 'Disease', (37, 42))	('MSH2', 'Gene', '4436', (234, 238))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('MSH6', 'Gene', (267, 271))	('paraffin', 'Chemical', 'MESH:D010232', (19, 27))	('MSH6', 'Gene', '2956', (267, 271))
61289	32156018	The genomic DNA was analyzed by the research assay HNPCC MASTR Plus (Agilent Technologies, Santa Clara, CA) to identify single-nucleotide variants in four genes associated with Lynch syndrome (MLH1, MSH2, MSH6, and PMS2) and the 3' UTR of EPCAM, according to the manufacturer's instructions.	('EPCAM', 'Gene', (239, 244))	('MSH6', 'Gene', (205, 209))	('associated', 'Reg', (161, 171))	('HNPCC', 'Disease', 'None', (51, 56))	('MSH2', 'Gene', (199, 203))	('HNPCC', 'Disease', (51, 56))	('EPCAM', 'Gene', '4072', (239, 244))	('single-nucleotide variants', 'Var', (120, 146))	('MSH2', 'Gene', '4436', (199, 203))	('Lynch syndrome', 'Disease', (177, 191))	('Lynch syndrome', 'Disease', 'MESH:D003123', (177, 191))	('MSH6', 'Gene', '2956', (205, 209))	('PMS2', 'Gene', (215, 219))	('MLH1', 'Gene', '4292', (193, 197))	('PMS2', 'Gene', '5395', (215, 219))	('MLH1', 'Gene', (193, 197))
61291	32156018	Additionally, the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) variant database was also used, in order to characterize variants according to MMR classification (Classes 1-5).	('variants', 'Var', (147, 155))	('Tumours', 'Phenotype', 'HP:0002664', (72, 79))	('Gastrointestinal Hereditary Tumours', 'Disease', 'MESH:D004067', (44, 79))	('Gastrointestinal Hereditary Tumours', 'Disease', (44, 79))
61292	32156018	The region corresponding to the allelic variants in the PMS2, MLH1, and MSH6 genes (GenBank accession numbers NM_000535.7, NM_001354630, and NM_000179, respectively) was amplified by polymerase chain reaction (PCR), followed by automatic sequencing of the products using the Sanger method.	('MSH6', 'Gene', (72, 76))	('MSH6', 'Gene', '2956', (72, 76))	('PMS2', 'Gene', (56, 60))	('MLH1', 'Gene', '4292', (62, 66))	('PMS2', 'Gene', '5395', (56, 60))	('MLH1', 'Gene', (62, 66))	('variants', 'Var', (40, 48))
61294	32156018	MLPA analysis was carried out using the commercial kits P008-C1 PMS2 and P003-D1 MLH1/MSH2 (MRC Holland), which are designed to detect exonic deletions/duplications across the coding regions of PMS2, MLH1, and MSH2.	('PMS2', 'Gene', '5395', (194, 198))	('PMS2', 'Gene', '5395', (64, 68))	('MLH1', 'Gene', '4292', (81, 85))	('MLH1', 'Gene', (81, 85))	('MSH2', 'Gene', (210, 214))	('MSH2', 'Gene', '4436', (210, 214))	('detect', 'Reg', (128, 134))	('MSH2', 'Gene', (86, 90))	('PMS2', 'Gene', (194, 198))	('exonic deletions/duplications', 'Var', (135, 164))	('MSH2', 'Gene', '4436', (86, 90))	('MLH1', 'Gene', '4292', (200, 204))	('MLH1', 'Gene', (200, 204))	('PMS2', 'Gene', (64, 68))
61296	32156018	Whether the association with TP53 variants can influence tumor behavior and promote early clinical presentation remains unclear.	('promote', 'PosReg', (76, 83))	('variants', 'Var', (34, 42))	('influence', 'Reg', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('TP53', 'Gene', '7157', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('TP53', 'Gene', (29, 33))	('association', 'Interaction', (12, 23))	('tumor', 'Disease', (57, 62))
61299	32033200	Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers.	('CYP2B6', 'Gene', (80, 86))	('CYP2B6', 'Gene', '1555', (80, 86))	('single nucleotide polymorphisms', 'Var', (87, 118))	('cytochrome P450(CYP)2W1', 'Gene', '54905', (52, 75))	('cytochrome P450(CYP)2W1', 'Gene', (52, 75))
61315	32033200	However, mitotane is often associated with several adverse events, including adrenal insufficiency, gastrointestinal-, central nervous system (CNS)- and other endocrine-related effects.	('gastrointestinal', 'Disease', 'MESH:D005767', (100, 116))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (77, 98))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (77, 98))	('associated', 'Reg', (27, 37))	('central nervous system', 'Disease', (119, 141))	('mitotane', 'Var', (9, 17))	('adrenal insufficiency', 'Disease', (77, 98))	('gastrointestinal', 'Disease', (100, 116))	('mitotane', 'Chemical', 'MESH:D008939', (9, 17))
61317	32033200	Moreover, single nucleotide polymorphism (SNP) of another member of the CYP superfamily, CYP2B6*6, has been proposed to correlate with mitotane plasma levels.	('correlate with', 'Reg', (120, 134))	('mitotane plasma levels', 'MPA', (135, 157))	('single nucleotide polymorphism', 'Var', (10, 40))	('CYP2B6', 'Gene', '1555', (89, 95))	('mitotane', 'Chemical', 'MESH:D008939', (135, 143))	('CYP2B6', 'Gene', (89, 95))
61319	32033200	SNPs in genes coding for members of the CYP superfamily are common and usually affect the enzyme catalytic activity, thereby modifying the drug metabolism, which might result in therapeutic failure or increased adverse reactions.	('affect', 'Reg', (79, 85))	('modifying', 'Reg', (125, 134))	('drug metabolism', 'MPA', (139, 154))	('failure', 'Disease', 'MESH:D017093', (190, 197))	('result', 'Reg', (168, 174))	('SNPs', 'Var', (0, 4))	('failure', 'Disease', (190, 197))	('enzyme catalytic activity', 'MPA', (90, 115))
61323	32033200	Currently, it is unclear whether SNPs of CYP2W1 might affect the metabolic function of the enzyme.	('SNPs', 'Var', (33, 37))	('CYP2W1', 'Gene', '54905', (41, 47))	('CYP2W1', 'Gene', (41, 47))	('metabolic function', 'MPA', (65, 83))	('affect', 'Reg', (54, 60))
61443	32033200	Specifically, we investigated for CYP2W1 (ENSG00000073067: ENST00000308919, transcript position in coding sequence (CDS)): CYP2W1*2 (rs3735684, c.541G > A, p.A181T) and CYP2W1*6 (rs3808348, c.1463C > T, p.P488L).	('c.1463C > T', 'Mutation', 'rs3808348', (190, 201))	('CYP2W1', 'Gene', (123, 129))	('CYP2W1', 'Gene', '54905', (123, 129))	('c.541G > A', 'Var', (144, 154))	('rs3735684', 'Mutation', 'rs3735684', (133, 142))	('c.1463C > T', 'Var', (190, 201))	('rs3735684', 'Var', (133, 142))	('p.A181T', 'Mutation', 'rs3735684', (156, 163))	('p.P488L', 'Mutation', 'rs3808348', (203, 210))	('CYP2W1', 'Gene', '54905', (169, 175))	('rs3808348', 'Var', (179, 188))	('CYP2W1', 'Gene', (169, 175))	('rs3808348', 'Mutation', 'rs3808348', (179, 188))	('CYP2W1', 'Gene', '54905', (34, 40))	('CYP2W1', 'Gene', (34, 40))	('c.541G > A', 'Mutation', 'rs3735684', (144, 154))
61444	32033200	The polymorphisms investigated for CYP2B6 (ENSG00000197408: ENST00000643956, position in CDS) were: CYP2B6*6 (rs3745274, c.516G > T, p.Q172H) and CYP2B6 intronic variant (rs4803419, c.485-18C > T).	('CYP2B6', 'Gene', (35, 41))	('p.Q172H', 'Mutation', 'rs3745274', (133, 140))	('CYP2B6', 'Gene', (100, 106))	('CYP2B6', 'Gene', '1555', (35, 41))	('rs3745274', 'Var', (110, 119))	('CYP2B6', 'Gene', (146, 152))	('CYP2B6', 'Gene', '1555', (146, 152))	('c.485-18C > T', 'Mutation', 'rs4803419', (182, 195))	('rs3745274', 'Mutation', 'rs3745274', (110, 119))	('c.516G > T', 'Mutation', 'rs3745274', (121, 131))	('c.485-18C > T', 'Var', (182, 195))	('rs4803419', 'Mutation', 'rs4803419', (171, 180))	('rs4803419', 'Var', (171, 180))	('c.516G > T', 'Var', (121, 131))	('CYP2B6', 'Gene', '1555', (100, 106))
61463	32033200	The following are available online at , Figure S1: Combination of CYP2W1*6 and CYP2B6*6 SNP and response to mitotane therapy in group B (n = 79), Figure S2: Correlation between mitotane metabolites measured by HPLC-UV and presence of CYP2W1*6 and CYP2B6*6 SNPs, Table S1: Multivariate logistic regression analyses predicting plasma mitotane therapeutic levels, Table S2: PCR Primers sequences used for detecting CYP2W1 and CYP2B6 investigated single nucleotide polymorphisms.	('single nucleotide polymorphisms', 'Var', (443, 474))	('CYP2W1', 'Gene', '54905', (412, 418))	('CYP2B6', 'Gene', '1555', (79, 85))	('CYP2B6', 'Gene', (423, 429))	('CYP2W1', 'Gene', (412, 418))	('mitotane', 'Chemical', 'MESH:D008939', (332, 340))	('CYP2W1', 'Gene', '54905', (66, 72))	('CYP2B6', 'Gene', '1555', (423, 429))	('CYP2W1', 'Gene', (66, 72))	('mitotane', 'Chemical', 'MESH:D008939', (177, 185))	('CYP2W1', 'Gene', (234, 240))	('CYP2W1', 'Gene', '54905', (234, 240))	('CYP2B6', 'Gene', (247, 253))	('CYP2B6', 'Gene', '1555', (247, 253))	('mitotane', 'Chemical', 'MESH:D008939', (108, 116))	('CYP2B6', 'Gene', (79, 85))
61480	31786909	A systematic review showed that only 2% of all adrenal masses <=4 cm turned out to be adrenal carcinoma, whereas the prevalence of adrenocortical carcinoma in adrenal masses measuring 4-6 cm was 6%, and in tumors >6 cm it significantly increased to 25%.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('adrenocortical carcinoma', 'Disease', (131, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('adrenal carcinoma', 'Disease', (86, 103))	('adrenal masses', 'Disease', (47, 61))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('<=4', 'Var', (62, 65))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (131, 155))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (131, 155))	('adrenal carcinoma', 'Disease', 'MESH:D000310', (86, 103))	('adrenal carcinoma', 'Phenotype', 'HP:0006744', (86, 103))
61510	31786909	Unilateral adenoma with or without somatic mutations in the cAMP-dependent protein kinase A or bilateral macronodular adrenal hyperplasia (BMAH) are found.	('cAMP', 'Chemical', '-', (60, 64))	('adenoma', 'Disease', 'MESH:D000236', (11, 18))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (105, 137))	('bilateral macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (95, 137))	('mutations', 'Var', (43, 52))	('adenoma', 'Disease', (11, 18))	('Unilateral', 'Disease', (0, 10))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (118, 137))	('bilateral macronodular adrenal hyperplasia', 'Disease', (95, 137))
61540	31786909	All patients with an AI >10 mm should be evaluated at initial presentation to exclude malignancy and hormonal hyperfunction according to recent guideline recommendations.	('malignancy', 'Disease', 'MESH:D009369', (86, 96))	('patients', 'Species', '9606', (4, 12))	('AI >10 mm', 'Var', (21, 30))	('malignancy', 'Disease', (86, 96))
61550	30042151	Mouse homolog of the human TP53 R337H mutation reveals its role in tumorigenesis Inheritance of germline mutations in the tumor suppressor gene TP53 causes Li-Fraumeni syndrome (LFS), a cancer predisposition disorder.	('mutations', 'Var', (105, 114))	('R337H', 'Mutation', 'rs121912664', (32, 37))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (122, 127))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Li-Fraumeni syndrome', 'Disease', (156, 176))	('causes', 'Reg', (149, 155))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (156, 176))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Disease', (186, 192))	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('human', 'Species', '9606', (21, 26))	('Mouse', 'Species', '10090', (0, 5))
61551	30042151	The arginine to histidine substitution at amino acid position 337 of p53 (R337H) is a founder mutation highly prevalent in southern and southeastern Brazil and is considered an LFS mutation.	('p53', 'Gene', (69, 72))	('arginine to histidine', 'Var', (4, 25))	('R337H', 'Mutation', 'rs121912664', (74, 79))	('R337H', 'Var', (74, 79))	('arginine to histidine substitution at amino acid position 337', 'Mutation', 'rs121912664', (4, 65))
61554	30042151	De novo tumorigenesis was not significantly increased in either heterozygous (p53334R/H) or homozygous (p53334H/H) p53 R334H knockin mice compared with wild-type mice.	('mice', 'Species', '10090', (133, 137))	('p53334H/H', 'Var', (104, 113))	('R334H', 'Mutation', 'p.R334H', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('p53334R/H', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mice', 'Species', '10090', (162, 166))	('tumor', 'Disease', (8, 13))	('p53 R334H', 'Var', (115, 124))
61555	30042151	However, susceptibility to diethylnitrosamine (DEN)-induced liver carcinogenesis was increased in a mutant allele dose-dependent manner.	('liver carcinogenesis', 'Disease', 'MESH:D063646', (60, 80))	('mutant', 'Var', (100, 106))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (27, 45))	('liver carcinogenesis', 'Disease', (60, 80))	('increased', 'PosReg', (85, 94))	('DEN', 'Chemical', 'MESH:D004052', (47, 50))
61556	30042151	In parallel, p53334H/H mice exposed to DEN exhibited increased DNA damage but decreased cell cycle regulation in the liver.	('DNA damage', 'MPA', (63, 73))	('increased', 'PosReg', (53, 62))	('cell cycle', 'CPA', (88, 98))	('p53334H/H', 'Var', (13, 22))	('decreased', 'NegReg', (78, 87))	('mice', 'Species', '10090', (23, 27))	('DEN', 'Chemical', 'MESH:D004052', (39, 42))
61557	30042151	Oligomerization of p53, which is required for transactivation of target genes, was reduced in R334H liver, consistent with its decreased nuclear activity compared to wild-type.	('decreased', 'NegReg', (127, 136))	('reduced', 'NegReg', (83, 90))	('Oligomerization', 'MPA', (0, 15))	('nuclear activity', 'MPA', (137, 153))	('R334H', 'Var', (94, 99))	('p53', 'Gene', (19, 22))	('R334H', 'Mutation', 'p.R334H', (94, 99))
61558	30042151	By modeling a TP53 mutation in mice that has relatively weak cancer penetrance, this study provides in vivo evidence that the human R337H mutation can compromise p53 activity and promote tumorigenesis.	('p53', 'Protein', (162, 165))	('human', 'Species', '9606', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('activity', 'MPA', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Disease', (61, 67))	('promote', 'PosReg', (179, 186))	('tumor', 'Disease', (187, 192))	('mice', 'Species', '10090', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('compromise', 'NegReg', (151, 161))	('R337H', 'Mutation', 'rs121912664', (132, 137))	('R337H', 'Var', (132, 137))
61560	30042151	Somatic mutations of p53, encoded by the human gene TP53, are highly prevalent in human cancers and commonly alter specific "hotspot" amino acid residues located in its DNA-binding core domain.	('alter', 'Reg', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('human', 'Species', '9606', (41, 46))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('mutations', 'Var', (8, 17))	('TP53', 'Gene', (52, 56))	('cancers', 'Disease', (88, 95))	('specific "hotspot" amino acid residues', 'MPA', (115, 153))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('p53', 'Gene', (21, 24))	('human', 'Species', '9606', (82, 87))	('prevalent', 'Reg', (69, 78))
61561	30042151	Because the tetramerization of p53 protein permits its cooperative and efficient binding to DNA, core domain mutants can demonstrate dominant negative activity by hetero-oligomerizing with wild-type protein and suppress the transactivation of its target genes.	('p53', 'Gene', (31, 34))	('transactivation', 'MPA', (224, 239))	('hetero-oligomerizing', 'MPA', (163, 183))	('suppress', 'NegReg', (211, 219))	('rat', 'Species', '10116', (60, 63))	('negative', 'NegReg', (142, 150))	('binding', 'Interaction', (81, 88))	('mutants', 'Var', (109, 116))	('activity', 'MPA', (151, 159))	('rat', 'Species', '10116', (128, 131))
61563	30042151	In contrast to the DNA-binding domain, LFS mutations in the CTD had not been frequently observed until the association of germline TP53 R337H mutation with adrenocortical carcinoma.	('R337H', 'Var', (136, 141))	('adrenocortical carcinoma', 'Disease', (156, 180))	('TP53', 'Gene', (131, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('association', 'Interaction', (107, 118))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (156, 180))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (156, 180))	('R337H', 'Mutation', 'rs121912664', (136, 141))
61565	30042151	Unlike the high penetrance of cancer observed in hotspot DNA-binding domain mutation carriers, the R337H mutation is considered an atypical variant of incomplete penetrance as only a small fraction of carriers develop cancer by age 30 although much higher than the general population.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('R337H', 'Mutation', 'rs121912664', (99, 104))	('develop', 'PosReg', (210, 217))	('cancer', 'Disease', (218, 224))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('R337H', 'Var', (99, 104))
61566	30042151	In vitro work overexpressing p53 R337H has not revealed significant differences in activity compared with wild-type protein despite overwhelming clinical evidence of increased cancer risk associated with this mutation, suggesting that these types of studies may not be sufficient and more physiologic approaches are needed.	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('p53 R337H', 'Var', (29, 38))	('R337H', 'Var', (33, 38))	('R337H', 'Mutation', 'rs121912664', (33, 38))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
61568	30042151	Here, we report generating a mouse model of the human TP53 R337H mutation to study its role in tumorigenesis which reveals low cancer penetrance in mice with the mutation but provides mechanistic insights into its in vivo biology.	('R337H', 'Var', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('R337H', 'Mutation', 'rs121912664', (59, 64))	('human', 'Species', '9606', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mice', 'Species', '10090', (148, 152))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mouse', 'Species', '10090', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', (127, 133))	('rat', 'Species', '10116', (20, 23))	('TP53', 'Gene', (54, 58))	('tumor', 'Disease', (95, 100))
61570	30042151	Briefly, a gene-targeting construct containing the CGC (Arg) to CAC (His) missense mutation and neomycin-resistant gene flanked by loxP sites was electroporated into Prx mES cells derived from C57BL/6N strain (Jackson Laboratories).	('CGC', 'Gene', (51, 54))	('CAC', 'Gene', (64, 67))	('Arg', 'Chemical', 'MESH:D001120', (56, 59))	('neomycin', 'Chemical', 'MESH:D009355', (96, 104))	('His', 'Chemical', 'MESH:D006639', (69, 72))	('rat', 'Species', '10116', (222, 225))	('mES', 'Chemical', 'MESH:C004550', (170, 173))	('missense mutation', 'Var', (74, 91))	('rat', 'Species', '10116', (155, 158))
61574	30042151	p53-/- and p53 hotspot mutant p53+/R172H (strain 01XL9) mice were obtained from the Jackson Laboratories and NCI Frederick Mouse Repository, respectively, and were of the C57BL/6 strain or backcrossed at least 5 generations into the C57BL/6 background.	('p53', 'Gene', (11, 14))	('R172H', 'Mutation', 'p.R172H', (35, 40))	('mice', 'Species', '10090', (56, 60))	('Mouse', 'Species', '10090', (123, 128))	('rat', 'Species', '10116', (96, 99))	('rat', 'Species', '10116', (216, 219))	('p53+/R172H', 'Var', (30, 40))
61582	30042151	or 5 Gy total body gamma-irradiation (TBI) from a Gammacell 40 (K2K 1 X 8; MDS Nordion, Ontario, Canada) 6 h prior to harvesting tissues which were snap frozen in liquid nitrogen and stored at -80  C. Antibodies were obtained from the following sources: p53 mouse mAb (1C12, #2524) for oligomerization assay, phospho-S15 p53 mouse mAb (#9284), BAX rabbit pAb (#2772) (Cell Signaling Technology); p53 rabbit pAb (FL393, #sc-6243) for chromatin immunoprecipitation (Santa Cruz Biotechnology); GAPDH mouse mAb (6C5, #AM4300) (Thermo Fisher Scientific); phospho-S139 histone H2AX mouse mAb (#05-636), p21 mouse mAb (#OP76) (Millipore Sigma).	('p21', 'Gene', (597, 600))	('MDS Nordion', 'Disease', 'MESH:D009190', (75, 86))	('p21', 'Gene', '12575', (597, 600))	('mouse', 'Species', '10090', (258, 263))	('mouse', 'Species', '10090', (601, 606))	('GAPDH', 'Gene', '100009074', (491, 496))	('rabbit', 'Species', '9986', (348, 354))	('MDS Nordion', 'Disease', (75, 86))	('rabbit', 'Species', '9986', (400, 406))	('GAPDH', 'Gene', (491, 496))	('BAX', 'Gene', (344, 347))	('BAX', 'Gene', '12028', (344, 347))	('phospho-S139', 'Var', (550, 562))	('mouse', 'Species', '10090', (497, 502))	('mouse', 'Species', '10090', (325, 330))	('mouse', 'Species', '10090', (576, 581))	('nitrogen', 'Chemical', 'MESH:D009584', (170, 178))
61599	30042151	The p53 R334H amino acid mutation, homologous to the human R337H mutation, was knocked into the p53 gene locus of C57BL/6 mice using a homologous recombination strategy (Fig.	('R334H', 'Mutation', 'p.R334H', (8, 13))	('mice', 'Species', '10090', (122, 126))	('R337H', 'Var', (59, 64))	('rat', 'Species', '10116', (162, 165))	('R337H', 'Mutation', 'rs121912664', (59, 64))	('human', 'Species', '9606', (53, 58))	('R334H', 'Var', (8, 13))	('p53', 'Gene', (4, 7))
61600	30042151	Mice with the p53 R334H mutation were generally born at the expected Mendelian frequency although there was a trend of lower than expected number of female homozygous mutant mice (Supplementary Table 2).	('mice', 'Species', '10090', (174, 178))	('lower', 'NegReg', (119, 124))	('R334H', 'Mutation', 'p.R334H', (18, 23))	('p53 R334H', 'Var', (14, 23))	('Mice', 'Species', '10090', (0, 4))
61602	30042151	Nonetheless, compared with wild-type both the heterozygous and homozygous mutant mice developed normally, exhibiting similar body weight, body mass composition, and aerobic metabolic capacity as assessed by blood lactate levels and running endurance (Supplementary Figs.	('mice', 'Species', '10090', (81, 85))	('running', 'MPA', (232, 239))	('aerobic metabolic capacity', 'MPA', (165, 191))	('blood lactate', 'Phenotype', 'HP:0002151', (207, 220))	('lactate', 'Chemical', 'MESH:D019344', (213, 220))	('mutant', 'Var', (74, 80))
61603	30042151	We next compared the survival time of heterozygous (p53334R/H) and homozygous (p53334H/H) mutant mice with wild-type mice (p53334R/R) and performed necropsies at the end of their survival time for cancer diagnosis.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('mice', 'Species', '10090', (97, 101))	('mice', 'Species', '10090', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('p53334R/H', 'Var', (52, 61))	('p53334H/H', 'Var', (79, 88))
61604	30042151	Although the R334H mutant mice showed a trend of decreased median lifespan and increased cancer incidence, they were not statistically different for either gender (Fig.	('R334H', 'Var', (13, 18))	('increased', 'PosReg', (79, 88))	('R334H', 'Mutation', 'p.R334H', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('decreased', 'NegReg', (49, 58))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('mice', 'Species', '10090', (26, 30))
61606	30042151	Given the previous reports of increased incidence of pediatric adrenocortical carcinoma in TP53 R337H mutation carriers, we specifically examined the adrenal glands of the knockin mice for abnormalities at the endpoint of the survival study.	('TP53', 'Gene', (91, 95))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (63, 87))	('R337H', 'Mutation', 'rs121912664', (96, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('R337H mutation', 'Var', (96, 110))	('pediatric adrenocortical carcinoma', 'Disease', 'MESH:C565973', (53, 87))	('mice', 'Species', '10090', (180, 184))	('pediatric adrenocortical carcinoma', 'Disease', (53, 87))
61609	30042151	In both mouse and rat models of hepatocarcinogenesis, p53 deficiency appears to promote tumorigenesis induced by diethylnitrosamine (DEN), a genotoxic chemical present in tobacco smoke and dietary meat.	('rat', 'Species', '10116', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (113, 131))	('tobacco', 'Species', '4097', (171, 178))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (32, 52))	('deficiency', 'Var', (58, 68))	('p53', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('DEN', 'Chemical', 'MESH:D004052', (133, 136))	('hepatocarcinogenesis', 'Disease', (32, 52))	('mouse', 'Species', '10090', (8, 13))	('promote', 'PosReg', (80, 87))
61610	30042151	We reasoned that this carcinogenesis model may provide a sensitive readout of whether the R334H mutation compromises wild-type p53 activity in vivo and can promote de novo tumor formation.	('carcinogenesis', 'Disease', 'MESH:D063646', (22, 36))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('compromises', 'NegReg', (105, 116))	('carcinogenesis', 'Disease', (22, 36))	('R334H', 'Var', (90, 95))	('R334H', 'Mutation', 'p.R334H', (90, 95))	('wild-type p53 activity', 'MPA', (117, 139))	('promote', 'PosReg', (156, 163))
61612	30042151	Wild-type and mutant mice (14 d old) were injected intraperitoneally with DEN and examined for tumor formation in the liver after 42 wk.	('mice', 'Species', '10090', (21, 25))	('mutant', 'Var', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('DEN', 'Chemical', 'MESH:D004052', (74, 77))	('tumor', 'Disease', (95, 100))
61613	30042151	Indeed, there was a mutant allele dose-dependent increase in the number and size of tumors studding the surface of the liver (total tumors per liver: 2.8 +- 2.2, 4.4 +- 3.9, and 7.6 +- 6.5 for the p53334R/R, p53334R/H, and p53334H/H genotypes, respectively) (Fig.	('increase', 'PosReg', (49, 57))	('p53334R/H', 'Var', (208, 217))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('p53334H/H', 'Var', (223, 232))	('p53334R/R', 'Var', (197, 206))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
61614	30042151	Accordingly, the livers of homozygous R334H mutant mice were significantly heavier than that of wild-type mice (7.5 +- 3.2% versus 5.3 +- 2.2% of body weight, respectively) (Fig.	('mice', 'Species', '10090', (106, 110))	('mice', 'Species', '10090', (51, 55))	('R334H', 'Var', (38, 43))	('R334H', 'Mutation', 'p.R334H', (38, 43))	('heavier', 'PosReg', (75, 82))
61615	30042151	Histopathologic analysis of the liver tumors also showed significantly increased incidence of carcinomas in homozygous mutant p53334H/H livers (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('His', 'Chemical', 'MESH:D006639', (0, 3))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('carcinomas', 'Disease', (94, 104))	('carcinomas', 'Disease', 'MESH:D002277', (94, 104))	('liver tumor', 'Phenotype', 'HP:0002896', (32, 43))	('liver tumors', 'Disease', 'MESH:D008113', (32, 44))	('p53334H/H', 'Var', (126, 135))	('increased', 'PosReg', (71, 80))	('liver tumors', 'Phenotype', 'HP:0002896', (32, 44))	('liver tumors', 'Disease', (32, 44))
61617	30042151	These in vivo observations indicated that the R334H mutation can compromise the tumor suppressive activity of p53 in a mutant allele dose-dependent manner.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('p53', 'Gene', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('R334H', 'Var', (46, 51))	('compromise', 'NegReg', (65, 75))	('R334H', 'Mutation', 'p.R334H', (46, 51))
61618	30042151	To further characterize the effect of the R334H mutation on the in vivo activity of p53, liver samples were harvested from p53334R/R, p53334R/H, p53334H/H and p53-/- mice 24 h after DEN treatment and analyzed for p53 target gene expression using a RT-PCR screening array.	('DEN', 'Chemical', 'MESH:D004052', (182, 185))	('R334H', 'Var', (42, 47))	('p53334R/R', 'Var', (123, 132))	('p53334H/H', 'Var', (145, 154))	('p53334R/H', 'Var', (134, 143))	('R334H', 'Mutation', 'p.R334H', (42, 47))	('mice', 'Species', '10090', (166, 170))
61620	30042151	Out of the 11 genes that were significantly induced in the liver of DEN-treated versus control wild-type mice (>= 2-fold and P < 0.05), the expression levels of 10 genes were mildly reduced with statistical significance in homozygous p53334H/H mice indicating a partial decrease in p53 transcriptional activity (Fig.	('mice', 'Species', '10090', (105, 109))	('DEN', 'Chemical', 'MESH:D004052', (68, 71))	('mice', 'Species', '10090', (244, 248))	('p53', 'Gene', (282, 285))	('transcriptional activity', 'MPA', (286, 310))	('decrease', 'NegReg', (270, 278))	('p53334H/H', 'Var', (234, 243))	('reduced', 'NegReg', (182, 189))	('expression levels', 'MPA', (140, 157))
61621	30042151	The decreased transcriptional activity of the p53 R334H mutant was further demonstrated in the DEN-treated liver samples by performing independent RT-PCR of 4 prototypical p53 target genes p21, BAX, MDM2 and PUMA (Fig.	('MDM2', 'Gene', '17246', (199, 203))	('R334H', 'Mutation', 'p.R334H', (50, 55))	('decreased', 'NegReg', (4, 13))	('p21', 'Gene', (189, 192))	('DEN', 'Chemical', 'MESH:D004052', (95, 98))	('p53', 'Gene', (46, 49))	('transcriptional activity', 'MPA', (14, 38))	('p21', 'Gene', '12575', (189, 192))	('MDM2', 'Gene', (199, 203))	('rat', 'Species', '10116', (82, 85))	('BAX', 'Gene', (194, 197))	('R334H', 'Var', (50, 55))	('BAX', 'Gene', '12028', (194, 197))
61622	30042151	The pattern of decreased expression of the queried p53 target genes in a mutant allele dose-dependent manner in vivo revealed its compromised transcriptional activity and suggested that loss of heterozygosity may promote tumorigenesis.	('expression', 'MPA', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('promote', 'PosReg', (213, 220))	('transcriptional activity', 'MPA', (142, 166))	('mutant', 'Var', (73, 79))	('loss of heterozygosity', 'Var', (186, 208))	('decreased', 'NegReg', (15, 24))	('compromised', 'NegReg', (130, 141))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
61624	30042151	Both the DNA damage marker gamma-H2AX and p53 were consistently higher in the homozygous mutant state, suggesting increased DNA damage as in the p53 null state although the relative contribution of this finding versus other mechanisms to DEN-induced tumorigenesis is unclear (Fig.	('gamma-H2AX', 'Gene', '15270', (27, 37))	('higher', 'PosReg', (64, 70))	('tumor', 'Disease', (250, 255))	('DEN', 'Chemical', 'MESH:D004052', (238, 241))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('gamma-H2AX', 'Gene', (27, 37))	('mutant', 'Var', (89, 95))
61625	30042151	Furthermore, although the basal levels of p21 and BAX proteins in homozygous mutant liver samples were similar to that of wild-type, they were induced to a lower level after DEN treatment in parallel with attenuated cell cycle arrest and apoptosis in vivo (Fig.	('apoptosis', 'CPA', (238, 247))	('BAX', 'Gene', '12028', (50, 53))	('DEN', 'Chemical', 'MESH:D004052', (174, 177))	('arrest', 'Disease', 'MESH:D006323', (227, 233))	('arrest', 'Disease', (227, 233))	('p21', 'Gene', (42, 45))	('p21', 'Gene', '12575', (42, 45))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (216, 233))	('attenuated', 'NegReg', (205, 215))	('mutant', 'Var', (77, 83))	('BAX', 'Gene', (50, 53))
61626	30042151	Impaired senescence response to oncogenic stress has been suggested to promote liver tumorigenesis, but we did not observe significant senescence changes associated with the p53 R334H mutation (Supplementary Fig.	('liver tumor', 'Disease', (79, 90))	('promote', 'PosReg', (71, 78))	('R334H', 'Var', (178, 183))	('R334H', 'Mutation', 'p.R334H', (178, 183))	('p53', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('liver tumor', 'Disease', 'MESH:D008113', (79, 90))	('liver tumor', 'Phenotype', 'HP:0002896', (79, 90))
61627	30042151	Nonetheless, these modest changes in cellular response to genotoxic stress were consistent with the mildly lower levels of BAX, PUMA and p21 mRNA induced in p53334H/H liver compared with wild-type after DEN treatment (Fig.	('BAX', 'Gene', (123, 126))	('p21', 'Gene', '12575', (137, 140))	('BAX', 'Gene', '12028', (123, 126))	('PUMA', 'MPA', (128, 132))	('lower', 'NegReg', (107, 112))	('DEN', 'Chemical', 'MESH:D004052', (203, 206))	('p53334H/H', 'Var', (157, 166))	('levels', 'MPA', (113, 119))	('p21', 'Gene', (137, 140))
61628	30042151	Taken together, the deregulation of some tumor suppressor functions of p53 in the mutant R334H state could contribute to enhanced liver carcinogenesis after DEN exposure.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('DEN', 'Chemical', 'MESH:D004052', (157, 160))	('R334H', 'Var', (89, 94))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (130, 150))	('tumor', 'Disease', (41, 46))	('R334H', 'Mutation', 'p.R334H', (89, 94))	('enhanced', 'PosReg', (121, 129))	('p53', 'Gene', (71, 74))	('liver carcinogenesis', 'Disease', (130, 150))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
61629	30042151	We further investigated the mechanism underlying the decreased transcriptional activity of the R334H mutation which did not appear to be due to decreased mutant p53 levels.	('decreased', 'NegReg', (53, 62))	('R334H', 'Mutation', 'p.R334H', (95, 100))	('R334H', 'Var', (95, 100))	('transcriptional activity', 'MPA', (63, 87))
61630	30042151	The basal and DEN-induced levels of p53 were both higher in the heterozygous and homozygous mutant states (Fig.	('DEN-induced levels', 'MPA', (14, 32))	('higher', 'PosReg', (50, 56))	('p53', 'Protein', (36, 39))	('DEN', 'Chemical', 'MESH:D004052', (14, 17))	('mutant', 'Var', (92, 98))
61631	30042151	The higher basal levels of p53 protein associated with the R334H mutation, also seen in tumor, could be contributed by lower expression of MDM2 which has recently been shown to preferentially degrade oligomerized p53 (Fig.	('MDM2', 'Gene', (139, 143))	('R334H', 'Var', (59, 64))	('basal levels of p53 protein', 'MPA', (11, 38))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('lower', 'NegReg', (119, 124))	('R334H', 'Mutation', 'p.R334H', (59, 64))	('degrade', 'NegReg', (192, 199))	('expression', 'MPA', (125, 135))	('MDM2', 'Gene', '17246', (139, 143))	('higher', 'PosReg', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('oligomerized p53', 'MPA', (200, 216))	('tumor', 'Disease', (88, 93))
61632	30042151	Additionally, the subcellular fractionation of liver tissue after DEN treatment showed proportionally higher levels of p53 in the nucleus of homozygous mutant liver compared with wild-type, indicating that the R334H mutation did not affect its nuclear localization (Supplementary Fig.	('nuclear localization', 'MPA', (244, 264))	('DEN', 'Chemical', 'MESH:D004052', (66, 69))	('R334H', 'Var', (210, 215))	('higher', 'PosReg', (102, 108))	('mutant', 'Var', (152, 158))	('levels', 'MPA', (109, 115))	('R334H', 'Mutation', 'p.R334H', (210, 215))
61633	30042151	Although in vitro studies have shown that the human R337H mutation can disrupt p53 oligomerization in a pH-dependent manner, the lack of a mouse model has precluded testing its properties in vivo.	('R337H', 'Mutation', 'rs121912664', (52, 57))	('R337H', 'Var', (52, 57))	('mouse', 'Species', '10090', (139, 144))	('human', 'Species', '9606', (46, 51))	('disrupt', 'NegReg', (71, 78))	('p53', 'Protein', (79, 82))
61634	30042151	To assess the oligomerization state of mutant p53, liver samples were harvested from mice 24 h after DEN treatment and cross-linked with glutaraldehyde to capture in vivo protein-protein interactions.	('mice', 'Species', '10090', (85, 89))	('p53', 'Gene', (46, 49))	('DEN', 'Chemical', 'MESH:D004052', (101, 104))	('mutant', 'Var', (39, 45))
61635	30042151	Compared with wild-type samples, immunoblotting of the homozygous mutant cross-linked lysates revealed a striking decrease in both the tetramer and dimer forms of p53 R334H with a concomitant increase in the monomer form (Fig.	('mutant', 'Var', (66, 72))	('tetramer', 'MPA', (135, 143))	('R334H', 'Mutation', 'p.R334H', (167, 172))	('increase', 'PosReg', (192, 200))	('decrease', 'NegReg', (114, 122))	('dimer', 'MPA', (148, 153))	('p53 R334H', 'Var', (163, 172))	('monomer form', 'MPA', (208, 220))
61636	30042151	Treatment with a different DNA damaging agent doxorubicin to induce p53 in liver also showed reduced levels of tetramers in the homozygous R334H mutant state (Fig.	('reduced', 'NegReg', (93, 100))	('R334H', 'Var', (139, 144))	('p53', 'Gene', (68, 71))	('doxorubicin', 'Chemical', 'MESH:D004317', (46, 57))	('levels of tetramers', 'MPA', (101, 120))	('R334H', 'Mutation', 'p.R334H', (139, 144))
61637	30042151	To confirm these results, non-denaturing protein gel electrophoresis was used to show decreased high molecular weight p53 complex in the R334H mutant liver sample (Supplementary Fig.	('R334H', 'Mutation', 'p.R334H', (137, 142))	('decreased', 'NegReg', (86, 95))	('R334H', 'Var', (137, 142))	('high molecular weight', 'MPA', (96, 117))
61638	30042151	To further investigate the functional properties of p53 R334H protein in vivo, we employed whole body gamma-irradiation, another widely used stimulus for stabilizing p53 protein, to examine whether this mutation affects its ability to interact with the prototypical p53 target gene p21.	('R334H', 'Var', (56, 61))	('p21', 'Gene', (282, 285))	('ability', 'MPA', (224, 231))	('p21', 'Gene', '12575', (282, 285))	('R334H', 'Mutation', 'p.R334H', (56, 61))	('interact', 'Interaction', (235, 243))
61639	30042151	Chromatin immunoprecipitation of irradiated liver tissue showed significantly reduced interaction of the mutant protein with the p53 response element (p53RE) of p21 gene in a mutant allele dose-dependent manner (Fig.	('p21', 'Gene', (161, 164))	('p21', 'Gene', '12575', (161, 164))	('interaction', 'Interaction', (86, 97))	('reduced', 'NegReg', (78, 85))	('mutant', 'Var', (105, 111))	('protein', 'Protein', (112, 119))
61640	30042151	A tissue survey of p21 expression after whole body gamma-irradiation also revealed a pattern of mutant allele dose-dependent decrease in p21 mRNA levels with some degree of tissue variability (Fig.	('p21', 'Gene', '12575', (137, 140))	('p21', 'Gene', (137, 140))	('decrease', 'NegReg', (125, 133))	('p21', 'Gene', (19, 22))	('mutant allele', 'Var', (96, 109))	('p21', 'Gene', '12575', (19, 22))
61641	30042151	These in vivo data obtained from freshly isolated tissues exposed to a different modality of DNA damage further supported the tumorigenic potential of the mutation and was consistent with the observation of higher frequency of diverse cancers in TP53 R337H carriers.	('R337H', 'Mutation', 'rs121912664', (251, 256))	('R337H', 'Var', (251, 256))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancers', 'Disease', (235, 242))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('supported', 'PosReg', (112, 121))	('mutation', 'Var', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('TP53', 'Gene', (246, 250))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('tumor', 'Disease', (126, 131))
61642	30042151	There are limited data on the human TP53 R337H mutation in de novo tumorigenesis or its biological properties in vivo.	('human', 'Species', '9606', (30, 35))	('TP53', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('R337H', 'Mutation', 'rs121912664', (41, 46))	('R337H', 'Var', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
61643	30042151	Here, we have demonstrated the pro-tumorigenic nature of the mouse homolog by creating a mouse model with knockin of the p53 R334H mutation that corresponds to the human TP53 R337H mutation.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('R337H', 'Mutation', 'rs121912664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('human', 'Species', '9606', (164, 169))	('p53', 'Gene', (121, 124))	('tumor', 'Disease', (35, 40))	('R334H', 'Var', (125, 130))	('rat', 'Species', '10116', (21, 24))	('R334H', 'Mutation', 'p.R334H', (125, 130))	('mouse', 'Species', '10090', (61, 66))	('mouse', 'Species', '10090', (89, 94))
61644	30042151	Using an established liver carcinogenesis model, the knockin mice showed increased susceptibility to tumor development, including higher grade carcinomas, in a mutant allele dose-dependent manner.	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('mice', 'Species', '10090', (61, 65))	('carcinomas', 'Disease', (143, 153))	('carcinomas', 'Disease', 'MESH:D002277', (143, 153))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (21, 41))	('susceptibility', 'Reg', (83, 97))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutant', 'Var', (160, 166))	('liver carcinogenesis', 'Disease', (21, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
61645	30042151	Mechanistically, the increase in liver tumorigenesis was associated with decreased oligomerization, interaction with p53RE and transcriptional activity of the mutant p53 protein after DEN-induced DNA damage.	('transcriptional activity', 'MPA', (127, 151))	('decreased', 'NegReg', (73, 82))	('interaction', 'Interaction', (100, 111))	('mutant', 'Var', (159, 165))	('liver tumor', 'Disease', (33, 44))	('p53', 'Gene', (166, 169))	('liver tumor', 'Disease', 'MESH:D008113', (33, 44))	('liver tumor', 'Phenotype', 'HP:0002896', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('p53RE', 'Protein', (117, 122))	('protein', 'Protein', (170, 177))	('DEN', 'Chemical', 'MESH:D004052', (184, 187))	('oligomerization', 'MPA', (83, 98))	('increase', 'PosReg', (21, 29))
61646	30042151	These results provide new demonstration of the in vivo properties of a mouse homolog of the human TP53 R337H, a prevalent germline mutation in southern and southeastern Brazil that is estimated to affect hundreds of thousands of individuals.	('R337H', 'Var', (103, 108))	('R337H', 'Mutation', 'rs121912664', (103, 108))	('rat', 'Species', '10116', (33, 36))	('mouse', 'Species', '10090', (71, 76))	('human', 'Species', '9606', (92, 97))	('TP53', 'Gene', (98, 102))
61647	30042151	TP53 R337H carriers have higher frequency of diverse cancers, and current data show a clear association with increased risk of childhood adrenocortical carcinoma and many typical LFS-associated cancers occurring in adulthood, albeit at later ages than in classic LFS.	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (137, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('TP53', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('adrenocortical carcinoma', 'Disease', (137, 161))	('cancers', 'Disease', (194, 201))	('LFS-associated', 'Disease', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('R337H', 'Mutation', 'rs121912664', (5, 10))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (137, 161))	('R337H carriers', 'Var', (5, 19))
61649	30042151	Because p53 R334H mice displayed no overt phenotype, we explored whether this unique mutation would promote cancer under conditions of genotoxic stress.	('p53 R334H', 'Var', (8, 17))	('mice', 'Species', '10090', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('promote', 'PosReg', (100, 107))	('R334H', 'Mutation', 'p.R334H', (12, 17))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
61650	30042151	After exposure to the DNA alkylating agent DEN, there was evidence of increased DNA damage and mildly decreased apoptosis and cell cycle arrest in the liver tissue of p53334H/H mice compared with wild-type mice.	('arrest', 'Disease', (137, 143))	('DNA', 'MPA', (80, 83))	('apoptosis', 'CPA', (112, 121))	('increased', 'PosReg', (70, 79))	('mice', 'Species', '10090', (206, 210))	('p53334H/H', 'Var', (167, 176))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (126, 143))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('mice', 'Species', '10090', (177, 181))	('DEN', 'Chemical', 'MESH:D004052', (43, 46))	('decreased', 'NegReg', (102, 111))
61652	30042151	Furthermore, the incidence of liver carcinomas was more significantly increased in the homozygous mutant state, paralleling observations from a large meta-analysis in which patients homozygous for the TP53 R337H allele had more cancer recurrences and shorter survival times.	('shorter', 'NegReg', (251, 258))	('cancer', 'Disease', (228, 234))	('increased', 'PosReg', (70, 79))	('patients', 'Species', '9606', (173, 181))	('liver carcinomas', 'Disease', 'MESH:D006528', (30, 46))	('R337H', 'Mutation', 'rs121912664', (206, 211))	('survival times', 'CPA', (259, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('more', 'PosReg', (223, 227))	('TP53 R337H', 'Var', (201, 211))	('liver carcinomas', 'Disease', (30, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('mutant', 'Var', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
61653	30042151	Because individuals carrying the TP53 R337H mutation have a markedly higher incidence of pediatric adrenocortical carcinoma, we examined the adrenal glands of p53334H/H mice but did not observe significant neoplastic differences compared with that of wild-type mice.	('R337H', 'Mutation', 'rs121912664', (38, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('pediatric adrenocortical carcinoma', 'Disease', (89, 123))	('mice', 'Species', '10090', (261, 265))	('higher', 'PosReg', (69, 75))	('TP53 R337H', 'Var', (33, 43))	('mice', 'Species', '10090', (169, 173))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (99, 123))	('pediatric adrenocortical carcinoma', 'Disease', 'MESH:C565973', (89, 123))
61654	30042151	Structural studies of p53 have revealed that the Arg 337 and Asp 352 residues form an inter-molecular salt-bridge and that the R337H mutation can destabilize this interaction by deprotonating His 337 under physiologic pH.	('R337H', 'Mutation', 'rs121912664', (127, 132))	('Asp', 'Chemical', 'MESH:D001224', (61, 64))	('Arg', 'Chemical', 'MESH:D001120', (49, 52))	('R337H', 'Var', (127, 132))	('deprotonating', 'NegReg', (178, 191))	('His', 'Chemical', 'MESH:D006639', (192, 195))	('interaction', 'Interaction', (163, 174))	('inter-molecular salt-bridge', 'MPA', (86, 113))	('destabilize', 'NegReg', (146, 157))
61655	30042151	In this regard, the liver has one of the lowest concentrations of ascorbic acid amongst the various organs of the body which may facilitate the deprotonation and destabilization of mutant p53 tetramers and contribute to increased carcinogenesis as observed in our study.	('increased', 'PosReg', (220, 229))	('mutant', 'Var', (181, 187))	('carcinogenesis', 'Disease', 'MESH:D063646', (230, 244))	('deprotonation', 'MPA', (144, 157))	('destabilization', 'MPA', (162, 177))	('carcinogenesis', 'Disease', (230, 244))	('ascorbic acid', 'Chemical', 'MESH:D001205', (66, 79))	('p53', 'Gene', (188, 191))	('rat', 'Species', '10116', (55, 58))	('tetramers', 'Protein', (192, 201))	('facilitate', 'PosReg', (129, 139))
61656	30042151	It is also noteworthy that, unlike mice, humans cannot synthesize vitamin C so that deficiency states are prevalent even in socioeconomically developed countries and that the plasma levels of ascorbic acid have been reported to be significantly reduced in TP53 R337H mutation carriers compared to non-carriers.	('R337H', 'Mutation', 'rs121912664', (261, 266))	('vitamin C', 'Chemical', 'MESH:D001205', (66, 75))	('R337H mutation', 'Var', (261, 275))	('ascorbic acid', 'Chemical', 'MESH:D001205', (192, 205))	('plasma levels of ascorbic acid', 'MPA', (175, 205))	('mice', 'Species', '10090', (35, 39))	('reduced', 'NegReg', (245, 252))	('humans', 'Species', '9606', (41, 47))	('TP53', 'Gene', (256, 260))
61657	30042151	Our p53 R334H mouse model reported here should facilitate future investigations designed to examine the biological and tumorigenic characteristics of this mutation under in vivo conditions similar to that observed in humans.	('R334H', 'Mutation', 'p.R334H', (8, 13))	('tumor', 'Disease', (119, 124))	('mouse', 'Species', '10090', (14, 19))	('p53 R334H', 'Var', (4, 13))	('humans', 'Species', '9606', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
61736	29318061	The presence of one major criterion indicates malignancy, 1 to 4 minor criteria indicate uncertain malignant potential (borderline), and the absence of all major and minor criteria suggests a benign clinical behavior.	('presence', 'Var', (4, 12))	('malignancy', 'Disease', (46, 56))	('uncertain malignant potential', 'CPA', (89, 118))	('malignancy', 'Disease', 'MESH:D009369', (46, 56))
61762	29318061	While our findings could indicate that loss of TSPO expression could play a role in the tumorigenesis of this case of adrenocortical oncocytic neoplasm potentially related to defective steroid biosynthesis, additional studies including a larger number of cases of AON are necessary to validate these findings and to determine the role of TSPO in the pathogenesis of adrenocortical neoplasms including AON.	('AON', 'Disease', (401, 404))	('neoplasm', 'Phenotype', 'HP:0002664', (143, 151))	('neoplasm', 'Phenotype', 'HP:0002664', (381, 389))	('adrenocortical oncocytic neoplasm', 'Phenotype', 'HP:0006744', (118, 151))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('steroid', 'Chemical', 'MESH:D013256', (185, 192))	('TSPO', 'Gene', (47, 51))	('adrenocortical oncocytic neoplasm', 'Disease', 'MESH:C535584', (118, 151))	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (366, 390))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('loss', 'Var', (39, 43))	('neoplasms', 'Phenotype', 'HP:0002664', (381, 390))	('tumor', 'Disease', (88, 93))	('adrenocortical neoplasms', 'Disease', (366, 390))	('adrenocortical oncocytic neoplasm', 'Disease', (118, 151))
61789	27144940	Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation.	('MSH2', 'Gene', (123, 127))	('MSH2', 'Gene', '4436', (123, 127))	('Lynch syndrome', 'Disease', 'MESH:D003123', (71, 85))	('Lynch syndrome', 'Disease', (71, 85))	('resulting from', 'Reg', (86, 100))	('familial ACC', 'Disease', (40, 52))	('mutation', 'Var', (128, 136))	('ACC', 'Phenotype', 'HP:0006744', (49, 52))
61795	27144940	We also suggest that screening for ACC should be considered in cancer surveillance strategies directed at individuals with germline mutations in DNA mismatch repair genes.	('ACC', 'Disease', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (132, 141))	('DNA mismatch', 'Gene', (145, 157))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))
61796	27144940	This study provides the first description of an intergenerational occurrence of ACC in a family with Lynch Syndrome resulting from a germline MSH2 mutation.	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('ACC', 'Disease', (80, 83))	('mutation', 'Var', (147, 155))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (101, 115))	('MSH2', 'Gene', (142, 146))	('MSH2', 'Gene', '4436', (142, 146))	('Lynch Syndrome', 'Disease', (101, 115))	('resulting from', 'Reg', (116, 130))
61802	27144940	LS is an autosomal-dominant familial cancer syndrome caused by pathogenic germline mutations in one of several DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2), and associated with an estimated lifetime colorectal cancer risk of 80%.	('mutations', 'Var', (83, 92))	('PMS2', 'Gene', (165, 169))	('MSH2', 'Gene', (150, 154))	('MSH6', 'Gene', (156, 160))	('PMS2', 'Gene', '5395', (165, 169))	('MSH2', 'Gene', '4436', (150, 154))	('MLH1', 'Gene', '4292', (144, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('MLH1', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('caused', 'Reg', (53, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('MSH6', 'Gene', '2956', (156, 160))	('autosomal-dominant familial cancer syndrome', 'Disease', 'MESH:D009386', (9, 52))	('autosomal-dominant familial cancer syndrome', 'Disease', (9, 52))	('colorectal cancer', 'Disease', (214, 231))
61806	27144940	Here, we provide additional evidence to implicate ACC as an LS-associated cancer with the first description of an intergenerational (mother-to-daughter) occurrence of ACC in a family with LS resulting from a germline MSH2 mutation.	('mutation', 'Var', (222, 230))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('MSH2', 'Gene', (217, 221))	('ACC', 'Phenotype', 'HP:0006744', (50, 53))	('cancer', 'Disease', (74, 80))	('ACC', 'Disease', (50, 53))	('MSH2', 'Gene', '4436', (217, 221))	('ACC', 'Phenotype', 'HP:0006744', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
61828	27144940	Further germline genetic testing was undertaken by multiplex ligation dependent probe amplification analysis in the proband and her sister and revealed a heterozygous deletion of exons 1, 2, and 3 of the MSH2 gene.	('MSH2', 'Gene', '4436', (204, 208))	('deletion', 'Var', (167, 175))	('MSH2', 'Gene', (204, 208))
61832	27144940	However, our description of familial ACC arising in the context of a germline MSH2 mutation supports the recent proposal that ACC should be considered an LS-associated tumor.	('MSH2', 'Gene', (78, 82))	('MSH2', 'Gene', '4436', (78, 82))	('tumor', 'Disease', (168, 173))	('familial ACC', 'Disease', (28, 40))	('mutation', 'Var', (83, 91))	('ACC', 'Phenotype', 'HP:0006744', (37, 40))	('ACC', 'Phenotype', 'HP:0006744', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
61833	27144940	Currently, the diagnosis of LS requires patients/kindreds to fulfill the Amsterdam or revised Bethesda criteria, with demonstration of absent MMR protein expression on tumor immunohistochemistry and/or microsatellite instability (MSI) genotyping supporting the diagnosis.	('MSI', 'Disease', 'None', (230, 233))	('tumor', 'Disease', (168, 173))	('MMR protein', 'Protein', (142, 153))	('absent', 'NegReg', (135, 141))	('patients', 'Species', '9606', (40, 48))	('MSI', 'Disease', (230, 233))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('microsatellite', 'Var', (202, 216))	('expression', 'MPA', (154, 164))
61835	27144940	Isolated cases of ACC arising in single patients of families with LS and germline mutations in DNA MMR genes (MLH1, MSH2, MSH6) have been previously reported, but given their rarity, determining whether these tumors were coincidental or part of the LS tumor profile has remained controversial.	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('MLH1', 'Gene', '4292', (110, 114))	('ACC', 'Phenotype', 'HP:0006744', (18, 21))	('ACC', 'Disease', (18, 21))	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('MSH2', 'Gene', (116, 120))	('MSH6', 'Gene', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (209, 215))	('MSH6', 'Gene', '2956', (122, 126))	('MSH2', 'Gene', '4436', (116, 120))	('patients', 'Species', '9606', (40, 48))	('mutations', 'Var', (82, 91))	('MLH1', 'Gene', (110, 114))	('tumor', 'Disease', (252, 257))
61846	27144940	In summary, we report the first description of familial ACC in conjunction with a germline MSH2 mutation and provide support for MMR genes as candidates in hereditary ACC.	('ACC', 'Phenotype', 'HP:0006744', (56, 59))	('MSH2', 'Gene', (91, 95))	('MSH2', 'Gene', '4436', (91, 95))	('mutation', 'Var', (96, 104))	('ACC', 'Phenotype', 'HP:0006744', (167, 170))	('familial ACC', 'Disease', (47, 59))
61868	24859649	Novel PKCs activate mouse PKD by phosphorylating serines 744 and 748 in the activation loop (serines 738 and 742 in human), with inhibition of PKC activity abrogating PKD transphosphorylation and thus its activation.	('mouse', 'Species', '10090', (20, 25))	('abrogating', 'NegReg', (156, 166))	('PKD', 'Disease', 'MESH:C537180', (26, 29))	('PKD', 'Disease', 'MESH:C537180', (167, 170))	('inhibition', 'Var', (129, 139))	('PKD', 'Disease', (167, 170))	('PKC', 'Enzyme', (143, 146))	('human', 'Species', '9606', (116, 121))	('serines', 'Chemical', 'MESH:D012694', (49, 56))	('serines', 'Chemical', 'MESH:D012694', (93, 100))	('activity', 'MPA', (147, 155))	('PKD', 'Disease', (26, 29))
61874	24859649	Freshly isolated cells were cultured overnight in Falcon Primaria dishes in a Dulbecco's modified Eagles's medium-Ham's F-12 medium (1:1) containing 10% horse serum (v/v), 2% fetal bovine serum (v/v), ascorbate (100 muM), alpha-tocopherol (1.2 muM), Na2SeO3 (0.05 muM), butylated hydroxyanisole (50 muM), metyrapone (5 muM), penicillin (100 U/ml), streptomycin (100 mug/ml), and amphotericin-B (0.25 mug/ml).	('muM', 'Gene', (319, 322))	('Falcon Primaria dishes', 'Disease', (50, 72))	('muM', 'Gene', '56925', (216, 219))	('100', 'Var', (362, 365))	('muM', 'Gene', '56925', (299, 302))	('bovine', 'Species', '9913', (181, 187))	('muM', 'Gene', '56925', (244, 247))	('muM', 'Gene', '56925', (264, 267))	('Falcon Primaria dishes', 'Disease', 'None', (50, 72))	('muM', 'Gene', (216, 219))	('muM', 'Gene', (264, 267))	('muM', 'Gene', (299, 302))	('horse', 'Species', '9796', (153, 158))	('muM', 'Gene', (244, 247))	('muM', 'Gene', '56925', (319, 322))
61889	24859649	Antibodies used were anti-PKD and anti-phosphoserine 916 (serine 910 in human) PKD antibodies from Cell Signaling (Danvers, MA), anti-phosphotyrosine from Millipore (Billerica, MA), anti-GFP from Epitomics (Burlingame, CA), and anti-actin antibody from Sigma (St. Louis, MO).	('phosphoserine', 'Chemical', 'MESH:D010768', (39, 52))	('PKD', 'Disease', 'MESH:C537180', (26, 29))	('anti-phosphotyrosine', 'Var', (129, 149))	('PKD', 'Disease', (79, 82))	('serine', 'Chemical', 'MESH:D012694', (58, 64))	('human', 'Species', '9606', (72, 77))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (134, 149))	('PKD', 'Disease', 'MESH:C537180', (79, 82))	('serine', 'Chemical', 'MESH:D012694', (46, 52))	('PKD', 'Disease', (26, 29))
61893	24859649	The cells were incubated with either anti-PKCmu/PKD (Santa Cruz) or anti-phosphotyrosine antibody (Millipore) for 2 hours at 4 C, after which the samples were incubated with Tru-blot anti-rabbit IgG beads (eBioscience) for 1 hour.	('phosphotyrosine', 'Chemical', 'MESH:D019000', (73, 88))	('anti-phosphotyrosine', 'Var', (68, 88))	('PKD', 'Disease', (48, 51))	('rabbit', 'Species', '9986', (188, 194))	('PKD', 'Disease', 'MESH:C537180', (48, 51))
61918	24859649	Ro 31-8220 also inhibited AngII-stimulated aldosterone production (Figure 2C).	('inhibited', 'NegReg', (16, 25))	('Ro 31-8220', 'Var', (0, 10))	('aldosterone', 'Chemical', 'MESH:D000450', (43, 54))	('AngII', 'Gene', (26, 31))	('AngII', 'Gene', '183', (26, 31))	('Ro 31-8220', 'Chemical', 'MESH:C064758', (0, 10))	('stimulated aldosterone', 'Phenotype', 'HP:0000859', (32, 54))	('aldosterone production', 'Phenotype', 'HP:0000859', (43, 65))
61921	24859649	Thus, these results indicated that Ro 31-8220 exhibited neither cytotoxicity to the cells nor non-specific effects on steroidogenic enzyme activities.	('cytotoxicity', 'Disease', (64, 76))	('Ro 31-8220', 'Var', (35, 45))	('cytotoxicity', 'Disease', 'MESH:D064420', (64, 76))	('activities', 'MPA', (139, 149))	('steroid', 'Chemical', 'MESH:D013256', (118, 125))	('steroidogenic', 'MPA', (118, 131))	('Ro 31-8220', 'Chemical', 'MESH:C064758', (35, 45))
61938	24859649	Since tyrosine 463 is critical for Src family kinase-mediated PKD activation in other cell types, we anticipated that mutation of this residue would inhibit the activation of PKD by AngII and decrease AngII-induced aldosterone production.	('tyrosine', 'Chemical', 'MESH:D014443', (6, 14))	('inhibit', 'NegReg', (149, 156))	('activation', 'MPA', (161, 171))	('decrease', 'NegReg', (192, 200))	('aldosterone', 'Chemical', 'MESH:D000450', (215, 226))	('AngII', 'Gene', (201, 206))	('PKD', 'Disease', (175, 178))	('PKD', 'Disease', 'MESH:C537180', (62, 65))	('PKD', 'Disease', (62, 65))	('PKD', 'Disease', 'MESH:C537180', (175, 178))	('AngII', 'Gene', '183', (201, 206))	('mutation', 'Var', (118, 126))	('aldosterone production', 'Phenotype', 'HP:0000859', (215, 237))	('AngII', 'Gene', (182, 187))	('AngII', 'Gene', '183', (182, 187))
61939	24859649	Primary bovine adrenal glomerulosa cells were mock-infected, or infected with empty vector (pAdtrackCMV) or the tyrosine-463-tophenylalanine PKD mutant for 4 hours, after which time the media was replaced with serum-free media for an additional 16-20 hours and the cells stimulated with or without AngII.	('tyrosine-463-tophenylalanine', 'Var', (112, 140))	('AngII', 'Gene', (298, 303))	('PKD', 'Disease', (141, 144))	('PKD', 'Disease', 'MESH:C537180', (141, 144))	('tyrosine', 'Chemical', 'MESH:D014443', (112, 120))	('bovine', 'Species', '9913', (8, 14))	('tophenylalanine', 'Chemical', '-', (125, 140))	('AngII', 'Gene', '183', (298, 303))
61942	24859649	Overexpression of the tyrosine-463-to-phenlyalanine PKD mutant decreased AngII-stimulated aldosterone production (Figure 6B).	('phenlyalanine', 'Chemical', '-', (38, 51))	('AngII', 'Gene', (73, 78))	('stimulated aldosterone', 'Phenotype', 'HP:0000859', (79, 101))	('AngII', 'Gene', '183', (73, 78))	('aldosterone production', 'Phenotype', 'HP:0000859', (90, 112))	('PKD', 'Disease', 'MESH:C537180', (52, 55))	('decreased', 'NegReg', (63, 72))	('tyrosine', 'Chemical', 'MESH:D014443', (22, 30))	('aldosterone', 'Chemical', 'MESH:D000450', (90, 101))	('PKD', 'Disease', (52, 55))	('tyrosine-463-to-phenlyalanine', 'Var', (22, 51))
61944	24859649	To determine if the concentration of the tyrosine-463-to-phenylalanine PKD adenovirus used exerted non-specific cytotoxic effects on the cells, mutant PKD-infected primary bovine adrenal glomerulosa cells were incubated with 22(R)-hydroxycholesterol.	('bovine', 'Species', '9913', (172, 178))	('PKD', 'Disease', 'MESH:C537180', (151, 154))	('PKD', 'Disease', (151, 154))	('22(R)-hydroxycholesterol', 'Chemical', 'MESH:C003585', (225, 249))	('rat', 'Species', '10116', (27, 30))	('PKD-infected', 'Disease', 'MESH:C537180', (151, 163))	('tyrosine-463-to-phenylalanine', 'Mutation', 'p.Y463F', (41, 70))	('PKD', 'Disease', (71, 74))	('mutant', 'Var', (144, 150))	('PKD-infected', 'Disease', (151, 163))	('PKD', 'Disease', 'MESH:C537180', (71, 74))
61946	24859649	To further understand the regulation of AngII-induced PKD activation and aldosterone secretion by PKC and Src family kinase pathways, we sought to determine if the combination of both the PKC inhibitor, Ro 31-8220 (3 muM), and the Src family kinase inhibitor, PP2 (10 muM), would enhance the inhibitory response observed with either inhibitor alone.	('Ro 31-8220', 'Var', (203, 213))	('muM', 'Gene', '56925', (217, 220))	('inhibitory response', 'MPA', (292, 311))	('AngII', 'Gene', (40, 45))	('aldosterone', 'MPA', (73, 84))	('AngII', 'Gene', '183', (40, 45))	('muM', 'Gene', '56925', (268, 271))	('muM', 'Gene', (217, 220))	('aldosterone', 'Chemical', 'MESH:D000450', (73, 84))	('Ro 31-8220', 'Chemical', 'MESH:C064758', (203, 213))	('enhance', 'PosReg', (280, 287))	('muM', 'Gene', (268, 271))	('PP2', 'Gene', (260, 263))	('PKD', 'Disease', 'MESH:C537180', (54, 57))	('PP2', 'Gene', '4888', (260, 263))	('PKD', 'Disease', (54, 57))
61947	24859649	Indeed, Ro 31-8220 and PP2 had an additive inhibitory effect on AngII-induced PKD activation and aldosterone production (Figure 8A-C), and did not elicit any cytotoxicity (Figure 8D), suggesting the importance of both PKC and Src family kinases to AngII-induced PKD activation and aldosterone production.	('aldosterone production', 'Phenotype', 'HP:0000859', (97, 119))	('AngII', 'Gene', '183', (64, 69))	('AngII', 'Gene', (64, 69))	('PKD', 'Disease', (262, 265))	('activation', 'PosReg', (82, 92))	('PKD', 'Disease', 'MESH:C537180', (262, 265))	('Ro 31-8220', 'Chemical', 'MESH:C064758', (8, 18))	('aldosterone production', 'MPA', (97, 119))	('PKD', 'Disease', (78, 81))	('PKD', 'Disease', 'MESH:C537180', (78, 81))	('Ro 31-8220', 'Var', (8, 18))	('cytotoxicity', 'Disease', (158, 170))	('AngII', 'Gene', '183', (248, 253))	('inhibitory', 'NegReg', (43, 53))	('cytotoxicity', 'Disease', 'MESH:D064420', (158, 170))	('PP2', 'Gene', '4888', (23, 26))	('aldosterone', 'Chemical', 'MESH:D000450', (281, 292))	('AngII', 'Gene', (248, 253))	('aldosterone production', 'Phenotype', 'HP:0000859', (281, 303))	('PP2', 'Gene', (23, 26))	('aldosterone', 'Chemical', 'MESH:D000450', (97, 108))
61952	24859649	Overexpression of the constitutively active serine 738/742-to-glutamate PKD mutant increased acute AngII-elicited aldosterone production, whereas the effect of AngII on aldosterone production was inhibited by overexpression of a dominant-negative serine-toalanine PKD mutant in which serines 738 and 742 were mutated to alanines, and thus could not be phosphorylated by PKC.	('serine', 'Chemical', 'MESH:D012694', (284, 290))	('alanines', 'Chemical', 'MESH:D000409', (320, 328))	('aldosterone production', 'Phenotype', 'HP:0000859', (114, 136))	('PKD', 'Disease', (264, 267))	('AngII', 'Gene', '183', (160, 165))	('aldosterone production', 'Phenotype', 'HP:0000859', (169, 191))	('PKD', 'Disease', 'MESH:C537180', (264, 267))	('serine', 'Chemical', 'MESH:D012694', (44, 50))	('increased', 'PosReg', (83, 92))	('AngII', 'Gene', (160, 165))	('glutamate', 'Chemical', 'MESH:D018698', (62, 71))	('PKD', 'Disease', (72, 75))	('PKD', 'Disease', 'MESH:C537180', (72, 75))	('toalanine', 'Chemical', '-', (254, 263))	('serine', 'Chemical', 'MESH:D012694', (247, 253))	('serines', 'Chemical', 'MESH:D012694', (284, 291))	('aldosterone production', 'MPA', (114, 136))	('AngII', 'Gene', '183', (99, 104))	('aldosterone', 'Chemical', 'MESH:D000450', (169, 180))	('aldosterone', 'Chemical', 'MESH:D000450', (114, 125))	('AngII', 'Gene', (99, 104))	('mutant', 'Var', (76, 82))
61980	24859649	This involvement was demonstrated using the Src family kinase inhibitors, PP2 and Src-1 to inhibit AngII-induced PKD activation (Figures 4 and 5), as well as the tyrosine-463-to-phenylalanine PKD mutant that cannot be phosphorylated by the Src family kinase cascade (Figure 7).	('PKD', 'Disease', (113, 116))	('PKD', 'Disease', 'MESH:C537180', (113, 116))	('PKD', 'Disease', 'MESH:C537180', (192, 195))	('inhibit', 'NegReg', (91, 98))	('PKD', 'Disease', (192, 195))	('AngII', 'Gene', (99, 104))	('rat', 'Species', '10116', (28, 31))	('tyrosine-463-to-phenylalanine', 'Mutation', 'p.Y463F', (162, 191))	('Src-1', 'Gene', '6714', (82, 87))	('AngII', 'Gene', '183', (99, 104))	('Src-1', 'Gene', (82, 87))	('PP2', 'Gene', (74, 77))	('tyrosine-463-to-phenylalanine', 'Var', (162, 191))	('PP2', 'Gene', '4888', (74, 77))
61981	24859649	Importantly, all of these manipulations inhibited AngII-stimulated acute aldosterone secretion in bovine adrenal glomerulosa cells (Figures 4-7).	('bovine', 'Species', '9913', (98, 104))	('AngII', 'Gene', (50, 55))	('inhibited', 'NegReg', (40, 49))	('acute aldosterone secretion', 'MPA', (67, 94))	('manipulations', 'Var', (26, 39))	('AngII', 'Gene', '183', (50, 55))	('aldosterone', 'Chemical', 'MESH:D000450', (73, 84))
62034	21859927	cDNA was synthesized from 25 ng total RNA using TaqMan mRNA RT Kit (Applied Biosystems) and used for quantification of miR-483-3p (ID 002339), miR-483-5p (ID 002338), miR-497 (ID 001043), miR-195 (ID 000494), miR-1974 (ID 121209_mat), miR-210 (ID 000512), miR-21 (ID 000397), miR-503 (ID 001048), miR-1202 (ID 002858), miR-1275 (ID 002840), miR-638 (ID 001582), miR-1915 (ID 121111_mat), and miR-572 (ID 001614) with normalization against RNU6B (ID 001093).	('miR-195', 'Gene', (188, 195))	('miR-572', 'Gene', (392, 399))	('miR', 'Gene', '220972', (235, 238))	('miR', 'Gene', (188, 191))	('miR-497', 'Gene', (167, 174))	('miR-497', 'Gene', '574456', (167, 174))	('miR-21', 'Gene', '406991', (235, 241))	('miR', 'Gene', '220972', (209, 212))	('miR-638', 'Gene', (341, 348))	('miR-210', 'Gene', '406992', (235, 242))	('miR', 'Gene', '220972', (392, 395))	('miR', 'Gene', (297, 300))	('miR-572', 'Gene', '693157', (392, 399))	('miR', 'Gene', (362, 365))	('miR', 'Gene', '220972', (256, 259))	('ID 000512', 'Var', (244, 253))	('miR-503', 'Gene', (276, 283))	('miR-638', 'Gene', '693223', (341, 348))	('miR', 'Gene', '220972', (319, 322))	('miR', 'Gene', (235, 238))	('miR-1202', 'Gene', (297, 305))	('miR', 'Gene', (209, 212))	('miR-210', 'Gene', (235, 242))	('miR-503', 'Gene', '574506', (276, 283))	('ID 121111_mat', 'Var', (372, 385))	('miR-21', 'Gene', '406991', (256, 262))	('miR-483', 'Gene', (119, 126))	('miR-483', 'Gene', (143, 150))	('miR-21', 'Gene', (235, 241))	('miR', 'Gene', (392, 395))	('miR-1915', 'Gene', (362, 370))	('ID 002858', 'Var', (307, 316))	('miR', 'Gene', (256, 259))	('ID 002840', 'Var', (329, 338))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', (319, 322))	('miR', 'Gene', '220972', (167, 170))	('miR-1275', 'Gene', '100302123', (319, 327))	('miR', 'Gene', '220972', (143, 146))	('RNU6B', 'Gene', (439, 444))	('miR-483', 'Gene', '619552', (119, 126))	('ID 121209_mat', 'Var', (219, 232))	('miR-483', 'Gene', '619552', (143, 150))	('ID 000397', 'Var', (264, 273))	('ID 001614', 'Var', (401, 410))	('miR-21', 'Gene', (256, 262))	('miR', 'Gene', '220972', (276, 279))	('miR', 'Gene', '220972', (341, 344))	('miR-195', 'Gene', '406971', (188, 195))	('miR', 'Gene', (119, 122))	('miR', 'Gene', (167, 170))	('RNU6B', 'Gene', '26826', (439, 444))	('miR', 'Gene', (143, 146))	('miR', 'Gene', '220972', (188, 191))	('miR-1275', 'Gene', (319, 327))	('miR-1915', 'Gene', '100302129', (362, 370))	('ID 001582', 'Var', (350, 359))	('miR-1202', 'Gene', '100302259', (297, 305))	('miR', 'Gene', '220972', (297, 300))	('miR', 'Gene', (341, 344))	('miR', 'Gene', '220972', (362, 365))	('miR', 'Gene', (276, 279))
62042	21859927	The effect of transfections had a similar magnitude of miRNA expression levels as for the comparison between carcinomas and normal adrenal cortices.	('transfections', 'Var', (14, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('carcinomas', 'Disease', (109, 119))	('carcinomas', 'Disease', 'MESH:D002277', (109, 119))
62077	21859927	We further evaluated the functional consequences from dysregulation of four miRNAs in human NCI-H295R ACC cells.	('NCI-H295R', 'CellLine', 'CVCL:0458', (92, 101))	('human', 'Species', '9606', (86, 91))	('ACC', 'Phenotype', 'HP:0006744', (102, 105))	('miR', 'Gene', '220972', (76, 79))	('miR', 'Gene', (76, 79))	('dysregulation', 'Var', (54, 67))
62110	21859927	Although the factor(s) regulating the transcription of this miRNA cluster are yet unknown, a common deletion within this chromosomal region (17p13) has been reported in ACC, but not in benign adrenocortical conditions.	('miR', 'Gene', '220972', (60, 63))	('ACC', 'Phenotype', 'HP:0006744', (169, 172))	('miR', 'Gene', (60, 63))	('ACC', 'Disease', (169, 172))	('benign adrenocortical conditions', 'Disease', 'MESH:D018268', (185, 217))	('benign adrenocortical conditions', 'Disease', (185, 217))	('deletion', 'Var', (100, 108))
62113	21859927	In this study, we demonstrate the functional role of deregulated miRNAs in ACC cells using experimental cell culture systems.	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('deregulated', 'Var', (53, 64))
62125	21859927	Importantly, recently demonstrated that silencing of miR-483-3p could suppress cell proliferation and induce apoptosis in the hepatocarcinoma cell line HepG2, as well as inhibit tumorigenicity in vivo.	('HepG2', 'CellLine', 'CVCL:0027', (152, 157))	('tumor', 'Disease', (178, 183))	('inhibit', 'NegReg', (170, 177))	('miR-483', 'Gene', '619552', (53, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('suppress', 'NegReg', (70, 78))	('cell proliferation', 'CPA', (79, 97))	('induce', 'PosReg', (102, 108))	('miR-483', 'Gene', (53, 60))	('apoptosis', 'CPA', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('silencing', 'Var', (40, 49))	('hepatocarcinoma', 'Disease', 'None', (126, 141))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('hepatocarcinoma', 'Disease', (126, 141))
62138	21859927	Several studies also showed that miR-21 knockdown could impair cell growth, induce apoptosis and interfere with cell migration and invasion of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('miR-21', 'Gene', '406991', (33, 39))	('impair', 'NegReg', (56, 62))	('knockdown', 'Var', (40, 49))	('induce', 'PosReg', (76, 82))	('cancer', 'Disease', (143, 149))	('apoptosis', 'CPA', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('miR-21', 'Gene', (33, 39))	('interfere', 'NegReg', (97, 106))	('cell growth', 'CPA', (63, 74))
62161	19261630	Although there are unanswered questions about the origin and evolution of adrenocortical neoplasms, analysis of human tumor specimens and animal models indicates that adrenocortical tumorigenesis involves both genetic and epigenetic alterations.	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (74, 98))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', (182, 187))	('neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('epigenetic alterations', 'Var', (222, 244))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (167, 187))	('adrenocortical neoplasms', 'Disease', (74, 98))	('neoplasms', 'Phenotype', 'HP:0002664', (89, 98))	('tumor', 'Disease', (118, 123))	('adrenocortical tumor', 'Disease', (167, 187))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('human', 'Species', '9606', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
62162	19261630	Chromosomal changes accumulate during tumor progression, and aberrant telomere function is one of the key mechanisms underlying chromosome instability during this process.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('aberrant', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('telomere function', 'CPA', (70, 87))	('chromosome instability', 'Phenotype', 'HP:0040012', (128, 150))
62164	19261630	Many of the mutations associated with benign human adrenocortical tumors result in dysregulated cyclic AMP signaling, whereas key factors/signaling pathways associated with adrenocortical carcinomas include dysregulated expression of the IGF2 gene cluster, activation of the Wnt/beta-catenin pathway, and inactivation of the p53 tumor suppressor.	('Wnt', 'Gene', (275, 278))	('result', 'Reg', (73, 79))	('activation', 'PosReg', (257, 267))	('tumor', 'Disease', (329, 334))	('Wnt', 'Gene', '114487', (275, 278))	('tumor', 'Disease', (66, 71))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (51, 72))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('p53', 'Gene', (325, 328))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inactivation', 'Var', (305, 317))	('cyclic AMP', 'Chemical', 'MESH:D000242', (96, 106))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (173, 198))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('dysregulated', 'Var', (207, 219))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (173, 197))	('adrenocortical carcinomas', 'Disease', (173, 198))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('adrenocortical tumors', 'Disease', (51, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('dysregulated cyclic AMP signaling', 'MPA', (83, 116))	('mutations', 'Var', (12, 21))	('human', 'Species', '9606', (45, 50))	('IGF2', 'Gene', (238, 242))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (173, 198))
62178	19261630	Mutations in steroidogenic factor-1 (Sf1) and Wilms tumor-1 (Wt1), two transcription factor genes expressed in the urogenital ridge, disrupt development of both adrenal and gonadal steroidogenic cells, underscoring the close relationship between these lineages.	('Wilms tumor', 'Phenotype', 'HP:0002667', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('steroid', 'Chemical', 'MESH:D013256', (13, 20))	('Wt1', 'Gene', (61, 64))	('Wilms tumor-1', 'Gene', (46, 59))	('steroid', 'Chemical', 'MESH:D013256', (181, 188))	('steroidogenic factor-1 (Sf1', 'Gene', '7536', (13, 40))	('Mutations', 'Var', (0, 9))	('Wt1', 'Gene', '7490', (61, 64))	('Wilms tumor-1', 'Gene', '7490', (46, 59))	('development of', 'CPA', (141, 155))	('disrupt', 'NegReg', (133, 140))
62202	19261630	In humans, heterozygous SF1 mutations cause adrenal insufficiency and male-to-female sex reversal.	('male-to-female sex reversal', 'CPA', (70, 97))	('SF1', 'Gene', (24, 27))	('cause', 'Reg', (38, 43))	('sex reversal', 'Phenotype', 'HP:0012245', (85, 97))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (44, 65))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (44, 65))	('humans', 'Species', '9606', (3, 9))	('adrenal insufficiency', 'Disease', (44, 65))	('mutations', 'Var', (28, 37))
62203	19261630	Subcapsular progenitors expressing Sf1 have limited steroidogenic capacity due to the SF1-dependent expression of Dax1, an X-linked gene that encodes a repressor of steroidogenic gene expression.	('Dax1', 'Gene', (114, 118))	('steroid', 'Chemical', 'MESH:D013256', (165, 172))	('steroidogenic capacity', 'MPA', (52, 74))	('Dax1', 'Gene', '190', (114, 118))	('steroid', 'Chemical', 'MESH:D013256', (52, 59))	('Sf1', 'Var', (35, 38))	('limited', 'NegReg', (44, 51))
51549	19261630	DAX1 deficiency in humans and mice leads to excessive differentiation of subcapsular progenitors and eventual depletion of the stem/progenitor cell compartment.	('depletion of', 'MPA', (110, 122))	('DAX1', 'Gene', '190', (0, 4))	('mice', 'Species', '10090', (30, 34))	('deficiency', 'Var', (5, 15))	('subcapsular progenitors', 'CPA', (73, 96))	('humans', 'Species', '9606', (19, 25))	('DAX1', 'Gene', (0, 4))	('excessive', 'PosReg', (44, 53))
62205	19261630	Consequently, DAX1 deficient males may exhibit transient hypercorticism when young followed by progressive and irreversible hypocorticism.	('DAX1', 'Gene', (14, 18))	('DAX1', 'Gene', '190', (14, 18))	('exhibit', 'Reg', (39, 46))	('deficient', 'Var', (19, 28))
62206	19261630	Histologically, the adrenals of older DAX1 deficient individuals are characterized by a disorganized steroidogenic cortex that contain cytomegalic cells.	('deficient', 'Var', (43, 52))	('DAX1', 'Gene', '190', (38, 42))	('steroid', 'Chemical', 'MESH:D013256', (101, 108))	('DAX1', 'Gene', (38, 42))
62213	19261630	As discussed below and summarized in Table 2, most cases of adrenocortical tumorigenesis reflect a combination of clonal genetic changes and epigenetic alterations.	('adrenocortical tumor', 'Disease', 'MESH:D018268', (60, 80))	('adrenocortical tumor', 'Disease', (60, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('reflect', 'Reg', (89, 96))	('epigenetic alterations', 'Var', (141, 163))
62216	19261630	Increased cell proliferation enhances the susceptibility of cells to oncogene or tumor suppressor gene mutations, leading to the accumulation of specific genetic changes characteristic of these tumors.	('mutations', 'Var', (103, 112))	('susceptibility', 'MPA', (42, 56))	('tumors', 'Disease', (194, 200))	('enhances', 'PosReg', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('cell proliferation', 'CPA', (10, 28))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumor', 'Disease', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('accumulation', 'PosReg', (129, 141))	('tumor', 'Disease', (81, 86))	('specific genetic changes', 'MPA', (145, 169))
62219	19261630	Chromosomal amplifications and/or deletions are present in 28-61% of benign human adrenocortical neoplasias, including cortisol-producing nodular hyperplasias.	('Chromosomal amplifications', 'Var', (0, 26))	('adrenocortical neoplasias', 'Disease', 'MESH:D018268', (82, 107))	('cortisol', 'Chemical', 'MESH:D006854', (119, 127))	('nodular hyperplasias', 'Disease', 'MESH:D020518', (138, 158))	('neoplasia', 'Phenotype', 'HP:0002664', (97, 106))	('deletions', 'Var', (34, 43))	('human', 'Species', '9606', (76, 81))	('nodular hyperplasias', 'Disease', (138, 158))	('neoplasias', 'Phenotype', 'HP:0002664', (97, 107))	('adrenocortical neoplasias', 'Disease', (82, 107))
62226	19261630	Epigenetic alterations occur in cancer cells as commonly as genetic mutations and can mimic the effects of the latter.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('genetic mutations', 'Var', (60, 77))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('Epigenetic', 'MPA', (0, 10))
62228	19261630	Other epigenetic alterations associated with tumorigenesis include hyper- or hypo-methylation of specific genes, chromatin modification, and loss of imprinting (LOI).	('hyper-', 'Var', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('chromatin', 'MPA', (113, 122))	('loss', 'Var', (141, 145))	('hypo-methylation', 'Var', (77, 93))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
62229	19261630	Epigenetic alterations are thought to be central to tumorigenesis in many tissues.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Epigenetic alterations', 'Var', (0, 22))
62231	19261630	Epigenetic alterations could be the consequence of tumor progression, but recent data suggests an alternative explanation; namely, that epigenetic alterations precede tumor formation and increase the probability of cancer when genetic changes arise.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('increase', 'PosReg', (187, 195))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('epigenetic alterations', 'Var', (136, 158))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
62232	19261630	According to the epigenetic progenitor model, the first step in tumorigenesis is epigenetic disruption of stem/progenitor cells in a tissue, which alters the normal balance between undifferentiated stem/progenitor cells and their progeny, leading to polyclonal proliferation of "neoplasia-ready" progenitor cells.	('epigenetic disruption', 'Var', (81, 102))	('neoplasia', 'Disease', (279, 288))	('tumor', 'Disease', (64, 69))	('polyclonal proliferation', 'CPA', (250, 274))	('alters', 'Reg', (147, 153))	('leading to', 'Reg', (239, 249))	('neoplasia', 'Disease', 'MESH:D009369', (279, 288))	('neoplasia', 'Phenotype', 'HP:0002664', (279, 288))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
62236	19261630	In intestinal epithelium, LOI at the IGF2 locus leads to increased IGF-II expression, which in turn promotes expansion the stem/progenitor cell compartment and increases the probability of neoplasia.	('expression', 'MPA', (74, 84))	('neoplasia', 'Disease', 'MESH:D009369', (189, 198))	('neoplasia', 'Phenotype', 'HP:0002664', (189, 198))	('increased IGF-II', 'Phenotype', 'HP:0030269', (57, 73))	('increases', 'PosReg', (160, 169))	('promotes', 'PosReg', (100, 108))	('IGF2', 'Gene', (37, 41))	('LOI', 'Var', (26, 29))	('IGF-II', 'Gene', (67, 73))	('expansion', 'CPA', (109, 118))	('increased', 'PosReg', (57, 66))	('neoplasia', 'Disease', (189, 198))
62238	19261630	This suggests that in adrenocortical progenitors, as in intestinal epithelial progenitors, dysregulated expression of IGF2 may increase tumor risk by expanding the target cell population and/or modulating the effect of subsequent genetic alterations on these cells.	('expanding', 'PosReg', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('genetic alterations', 'CPA', (230, 249))	('dysregulated', 'Var', (91, 103))	('IGF2', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('increase', 'PosReg', (127, 135))	('adrenocortical', 'Disease', (22, 36))	('modulating', 'Reg', (194, 204))	('tumor', 'Disease', (136, 141))	('adrenocortical', 'Disease', 'MESH:D018268', (22, 36))
62239	19261630	Epigenetic alteration of adrenal progenitor cells is followed by mutation of tumor suppressor genes (e.g., p53), which enhances genetic instability and increases the likelihood of additional mutations.	('mutations', 'MPA', (191, 200))	('increases', 'PosReg', (152, 161))	('p53', 'Gene', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('enhances', 'PosReg', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutation', 'Var', (65, 73))	('genetic instability', 'MPA', (128, 147))	('tumor', 'Disease', (77, 82))	('Epigenetic alteration', 'Var', (0, 21))
62240	19261630	In summary, this model proposes that epigenetic changes may contribute to adrenocortical tumorigenesis by modulating size of the stem/progenitor population, altering phenotypic plasticity, and enhancing sensitivity to subsequent mutations.	('epigenetic changes', 'Var', (37, 55))	('altering', 'Reg', (157, 165))	('modulating', 'Reg', (106, 116))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (74, 94))	('contribute', 'Reg', (60, 70))	('adrenocortical tumor', 'Disease', (74, 94))	('sensitivity', 'MPA', (203, 214))	('phenotypic plasticity', 'MPA', (166, 187))	('enhancing', 'PosReg', (193, 202))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
62244	19261630	Other strains including C57BL/6J and FVB/N are resistant to gonadectomy-induced adrenocortical neoplasia.	('neoplasia', 'Phenotype', 'HP:0002664', (95, 104))	('adrenocortical neoplasia', 'Disease', (80, 104))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (80, 104))	('C57BL/6J', 'Var', (24, 32))
62250	19261630	Stem/progenitor cells in the adrenal cortex are subject to epigenetic alteration even in the absence of tumor formation, as illustrated by studies of mice harboring a beta-galactosidase transgene driven either by a P450c21 promoter or a P450scc promoter.	('mice', 'Species', '10090', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('subject', 'Reg', (48, 55))	('beta-galactosidase', 'Gene', '12091', (167, 185))	('tumor', 'Disease', (104, 109))	('beta-galactosidase', 'Gene', (167, 185))	('transgene', 'Var', (186, 195))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
62251	19261630	X-gal staining of the adrenal glands from these mice demonstrates radial columns of cells in the cortex that either express or do not express beta-galactosidase, reflecting random epigenetic activation (or silencing) of the transgene in subcapsular stem/progenitor cells.	('epigenetic', 'Var', (180, 190))	('silencing', 'NegReg', (206, 215))	('beta-galactosidase', 'Gene', (142, 160))	('beta-galactosidase', 'Gene', '12091', (142, 160))	('mice', 'Species', '10090', (48, 52))	('X-gal', 'Chemical', 'MESH:C044888', (0, 5))
62252	19261630	In cases of gonadectomy-induced adrenocortical neoplasia, preexisting epigenetic alterations might impact the phenotypic plasticity of stem/progenitor cells, allowing them to respond to the hormonal changes associated with gonadectomy.	('impact', 'NegReg', (99, 105))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (32, 56))	('respond to', 'MPA', (175, 185))	('epigenetic alterations', 'Var', (70, 92))	('adrenocortical neoplasia', 'Disease', (32, 56))	('neoplasia', 'Phenotype', 'HP:0002664', (47, 56))	('phenotypic plasticity of stem/progenitor cells', 'CPA', (110, 156))	('allowing', 'Reg', (158, 166))
62253	19261630	The rapidly expanding database of genomic DNA sequences and single nucleotide polymorphisms in various strains of mice afford a means to characterize the alleles and genetic modifiers influencing gonadectomy-induced adrenocortical neoplasia (i.e., the "tumor-progenitor" genes is that promote epigenetic disruption of stem/progenitor cells) Linkage analysis of crosses between a susceptible (DBA/2J) and a non-susceptible (C57BL/6J) strain of mice has shown that post-gonadectomy tumorigenesis in DBA/2J mice is a dominant trait and that a major locus for tumorigenesis resides on chromosome 8.	('adrenocortical neoplasia', 'Disease', (216, 240))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('mice', 'Species', '10090', (443, 447))	('tumor', 'Disease', 'MESH:D009369', (480, 485))	('DBA/2J', 'Var', (497, 503))	('tumor', 'Disease', 'MESH:D009369', (556, 561))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (480, 485))	('neoplasia', 'Phenotype', 'HP:0002664', (231, 240))	('tumor', 'Phenotype', 'HP:0002664', (556, 561))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (216, 240))	('tumor', 'Disease', (253, 258))	('mice', 'Species', '10090', (114, 118))	('tumor', 'Disease', (480, 485))	('tumor', 'Disease', (556, 561))	('mice', 'Species', '10090', (504, 508))
62264	19261630	In addition to triggering senescence, telomere dysfunction leads to end-to-end chromosome fusions followed by DNA breakage/fusion/bridge cycles, resulting in chromosomal duplications and deletions that are characteristic of cancers.	('deletions', 'Var', (187, 196))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('end-to-end chromosome fusions', 'CPA', (68, 97))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('cancers', 'Disease', (224, 231))	('chromosomal duplications', 'CPA', (158, 182))
62266	19261630	Telomere-based crisis provides a mechanism of chromosomal instability, leading to regional amplifications and deletions that drive tumorigenesis.	('amplifications', 'Var', (91, 105))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('deletions', 'Var', (110, 119))	('chromosomal instability', 'Phenotype', 'HP:0040012', (46, 69))
62269	19261630	The importance of telomere maintenance of the malignant phenotype is underscored by a series of xeno-transplantation studies with telomerase-negative bovine adrenocortical cells rendered tumorigenic by transfection with Ha-Ras (G12V) and SV40 large T antigen.	('bovine', 'Species', '9913', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('adrenocortical', 'Disease', 'MESH:D018268', (157, 171))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('SV40', 'Var', (238, 242))	('tumor', 'Disease', (187, 192))	('G12V', 'Mutation', 'rs751442241', (228, 232))	('adrenocortical', 'Disease', (157, 171))
62274	19261630	These modifications render p53 resistant to inactivation by MDM2 (mouse double minute 2), an E3-ubiquitin ligase that binds p53 and targets it for degradation in the proteosome.	('modifications', 'Var', (6, 19))	('mouse', 'Species', '10090', (66, 71))	('binds', 'Interaction', (118, 123))	('p53', 'Protein', (124, 127))	('p53', 'Gene', (27, 30))	('degradation', 'MPA', (147, 158))
62275	19261630	There is strong selective pressure for emerging tumors to disrupt the p53 signaling pathway, either through mutation of the p53 gene or overexpression of MDM2 or other negative regulators of p53 function.	('p53', 'Gene', (124, 127))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('overexpression', 'PosReg', (136, 150))	('p53 signaling pathway', 'Pathway', (70, 91))	('mutation', 'Var', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('disrupt', 'NegReg', (58, 65))
62279	19261630	Individuals with Li-Fraumeni Syndrome (LFS), an autosomal dominant tumor predisposition syndrome generally caused by germline mutations in TP53, develop ACC, albeit rarely.	('caused by', 'Reg', (107, 116))	('LFS', 'Disease', (39, 42))	('Li-Fraumeni Syndrome', 'Disease', (17, 37))	('LFS', 'Disease', 'MESH:D016864', (39, 42))	('TP53', 'Gene', '7157', (139, 143))	('ACC', 'Phenotype', 'HP:0006744', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ACC', 'Disease', (153, 156))	('autosomal dominant tumor', 'Disease', (48, 72))	('autosomal dominant tumor', 'Disease', 'MESH:D030342', (48, 72))	('germline mutations', 'Var', (117, 135))	('TP53', 'Gene', (139, 143))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (17, 37))
62281	19261630	Of interest, a specific germline missense mutation in TP53 (R337H) has been observed in a group of children with adrenocortical tumors in southern Brazil.	('adrenocortical tumors', 'Disease', (113, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TP53', 'Gene', '7157', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (113, 134))	('TP53', 'Gene', (54, 58))	('R337H', 'Mutation', 'rs121912664', (60, 65))	('children', 'Species', '9606', (99, 107))	('R337H', 'Var', (60, 65))
62282	19261630	In contrast to most somatic mutations that affect the DNA binding region of P53, the TP53 R337H mutation affects the oligmerization motif in P53, leading to pH-dependent instability.	('oligmerization motif', 'MPA', (117, 137))	('TP53', 'Gene', (85, 89))	('pH-dependent instability', 'MPA', (157, 181))	('affects', 'Reg', (105, 112))	('R337H', 'Mutation', 'rs121912664', (90, 95))	('R337H', 'Var', (90, 95))	('P53', 'Gene', (86, 89))	('P53', 'Gene', '7157', (141, 144))	('P53', 'Gene', (141, 144))	('TP53', 'Gene', '7157', (85, 89))	('P53', 'Gene', (76, 79))	('P53', 'Gene', '7157', (86, 89))	('P53', 'Gene', '7157', (76, 79))
62283	19261630	Carriers of the TP53 R337H mutation have a 20,000-fold increased risk of ACC, but they are not predisposed to other tumor types typical of LFS.	('ACC', 'Phenotype', 'HP:0006744', (73, 76))	('R337H', 'Var', (21, 26))	('ACC', 'Disease', (73, 76))	('R337H', 'Mutation', 'rs121912664', (21, 26))	('LFS', 'Disease', 'MESH:D016864', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('TP53', 'Gene', '7157', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('LFS', 'Disease', (139, 142))	('tumor', 'Disease', (116, 121))	('TP53', 'Gene', (16, 20))
62284	19261630	The loss of chromosome 17 harboring the normal TP53 allele is crucial for ACC development in patients with the R337H mutation.	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('R337H', 'Var', (111, 116))	('R337H', 'Mutation', 'rs121912664', (111, 116))	('TP53', 'Gene', '7157', (47, 51))	('patients', 'Species', '9606', (93, 101))	('TP53', 'Gene', (47, 51))
62285	19261630	Other low penetrance constitutional TP53 mutations associated with childhood ACC have also been identified.	('mutations', 'Var', (41, 50))	('childhood ACC', 'Disease', (67, 80))	('ACC', 'Phenotype', 'HP:0006744', (77, 80))	('TP53', 'Gene', '7157', (36, 40))	('associated', 'Reg', (51, 61))	('TP53', 'Gene', (36, 40))
62288	19261630	Mice with a germline mutation in the Men1 gene are predisposed to benign tumors in the adrenal cortex and other tissues.	('germline mutation', 'Var', (12, 29))	('Men1', 'Gene', (37, 41))	('predisposed', 'Reg', (51, 62))	('benign tumors', 'Disease', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Mice', 'Species', '10090', (0, 4))	('benign tumors', 'Disease', 'MESH:D009369', (66, 79))	('Men1', 'Gene', '4221', (37, 41))
62290	19261630	Menin, the protein encoded by the MEN1 gene, interacts with Smad3 and other binding partners, and menin deficiency elicits widespread effects on transcription, chromatin remodeling, and cell cycle progression.	('MEN1', 'Gene', (34, 38))	('MEN1', 'Gene', '4221', (34, 38))	('Menin', 'Gene', '4221', (0, 5))	('cell cycle progression', 'CPA', (186, 208))	('Smad3', 'Gene', (60, 65))	('Menin', 'Gene', (0, 5))	('menin', 'Gene', '4221', (98, 103))	('elicits', 'Reg', (115, 122))	('transcription', 'MPA', (145, 158))	('effects', 'Reg', (134, 141))	('chromatin remodeling', 'MPA', (160, 180))	('deficiency', 'Var', (104, 114))	('menin', 'Gene', (98, 103))	('interacts', 'Interaction', (45, 54))	('Smad3', 'Gene', '4088', (60, 65))
62291	19261630	Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by mutations in the Fumarate Hydratase (FH) gene on chromosome 1q42.3-43.	('mutations', 'Var', (100, 109))	('autosomal dominant disorder', 'Disease', (62, 89))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('renal cell cancer', 'Phenotype', 'HP:0005584', (30, 47))	('Hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (0, 47))	('HLRCC', 'Disease', 'MESH:C535516', (49, 54))	('Fumarate Hydratase', 'Gene', (117, 135))	('HLRCC', 'Disease', (49, 54))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (62, 89))	('Fumarate Hydratase', 'Gene', '2271', (117, 135))	('FH', 'Gene', '2271', (137, 139))	('caused by', 'Reg', (90, 99))
62294	19261630	Tumor tissue from these patients harbors both a germline FH mutation and allelic loss at the 1q42.3-43 FH locus.	('FH', 'Gene', '2271', (103, 105))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('FH', 'Gene', '2271', (57, 59))	('allelic loss', 'Var', (73, 85))	('germline', 'Var', (48, 56))	('patients', 'Species', '9606', (24, 32))
62297	19261630	Mice homozygous for a hypomorphic allele of Tpp1 exhibit a complex phenotype that includes adrenocortical dysplasia and hypofunction.	('adrenocortical dysplasia and hypofunction', 'Disease', 'MESH:C562711', (91, 132))	('hypomorphic', 'Var', (22, 33))	('Tpp1', 'Gene', (44, 48))	('Mice', 'Species', '10090', (0, 4))
62299	19261630	When telomere dysfunction-associated senescence is prevented by introducing mutant p53 alleles into Tpp1acd/adc mice, there is a partial normalization of adrenal weight and morphology.	('mutant', 'Var', (76, 82))	('p53', 'Gene', (83, 86))	('mice', 'Species', '10090', (112, 116))
62300	19261630	However, p53 deficiency rescues the adverse effects of telomere dysfunction at the cost of accelerating carcinogenesis.	('telomere dysfunction', 'MPA', (55, 75))	('deficiency', 'Var', (13, 23))	('adverse effects', 'MPA', (36, 51))	('rescues', 'PosReg', (24, 31))	('p53', 'Gene', (9, 12))	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('carcinogenesis', 'Disease', (104, 118))
62301	19261630	Recently it has been shown that p53-deficient mice harboring Tpp1acd mutations are predisposed to a spectrum of tumors, including ACC.	('mutations', 'Var', (69, 78))	('Tpp1acd', 'Gene', (61, 68))	('predisposed', 'Reg', (83, 94))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ACC', 'Phenotype', 'HP:0006744', (130, 133))	('mice', 'Species', '10090', (46, 50))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
62311	19261630	Humans homozygous for WNT4 loss-of-function mutations exhibit adrenal dysgenesis and female-to-male sex reversal.	('Humans', 'Species', '9606', (0, 6))	('adrenal dysgenesis', 'Disease', 'MESH:D000312', (62, 80))	('loss-of-function', 'NegReg', (27, 43))	('adrenal dysgenesis', 'Disease', (62, 80))	('female-to-male sex reversal', 'CPA', (85, 112))	('WNT4', 'Gene', (22, 26))	('WNT4', 'Gene', '54361', (22, 26))	('sex reversal', 'Phenotype', 'HP:0012245', (100, 112))	('mutations', 'Var', (44, 53))	('adrenal dysgenesis', 'Phenotype', 'HP:0008216', (62, 80))
62312	19261630	Tissue-specific knockout of beta-catenin in adrenocortical progenitors (using an Sf1 promoter-Cre transgene) produces mice with adrenal glands that function normally at birth but fail by 30 weeks of age.	('mice', 'Species', '10090', (118, 122))	('adrenocortical', 'Disease', (44, 58))	('knockout', 'Var', (16, 24))	('adrenocortical', 'Disease', 'MESH:D018268', (44, 58))
62313	19261630	Like in Dax mice, it is theorized that impairment of the Wnt/beta-catenin signaling pathway leads to depletion of adrenocortical stem/progenitor cells.	('mice', 'Species', '10090', (12, 16))	('Wnt', 'Gene', (57, 60))	('adrenocortical', 'Disease', (114, 128))	('impairment', 'Var', (39, 49))	('adrenocortical', 'Disease', 'MESH:D018268', (114, 128))	('Wnt', 'Gene', '114487', (57, 60))
62319	19261630	The TCF/beta-catenin antagonist PKF115-584 inhibits proliferation of adrenocortical carcinoma cells in vitro, suggesting that inhibitors of the Wnt signaling pathway might be useful in the treatment of adrenocortical tumors.	('Wnt', 'Gene', '114487', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('PKF115-584', 'Var', (32, 42))	('proliferation', 'CPA', (52, 65))	('TCF', 'Gene', (4, 7))	('TCF', 'Gene', '3172', (4, 7))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (202, 223))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (69, 93))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (69, 93))	('adrenocortical tumors', 'Disease', (202, 223))	('Wnt', 'Gene', (144, 147))	('adrenocortical carcinoma', 'Disease', (69, 93))	('inhibits', 'NegReg', (43, 51))
62320	19261630	Individuals with familial adenomatous polyposis (FAP) have constitutive activation of the Wnt/beta-catenin signaling pathway due to germline loss-of-function mutations of the APC gene.	('activation', 'PosReg', (72, 82))	('Wnt', 'Gene', (90, 93))	('Wnt', 'Gene', '114487', (90, 93))	('familial adenomatous polyposis', 'Disease', (17, 47))	('APC', 'Phenotype', 'HP:0005227', (175, 178))	('APC', 'Disease', 'MESH:D011125', (175, 178))	('APC', 'Disease', (175, 178))	('FAP', 'Disease', 'MESH:C567782', (49, 52))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (17, 47))	('loss-of-function', 'NegReg', (141, 157))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (26, 47))	('mutations', 'Var', (158, 167))	('FAP', 'Disease', (49, 52))
62327	19261630	GSK3beta phosphorylation leads to activation of the Wnt/beta-catenin pathway.	('phosphorylation', 'Var', (9, 24))	('Wnt', 'Gene', '114487', (52, 55))	('activation', 'PosReg', (34, 44))	('GSK3beta', 'Gene', (0, 8))	('Wnt', 'Gene', (52, 55))	('GSK3beta', 'Gene', '2932', (0, 8))
62328	19261630	Mice with null mutations in Igf1 or Igf2 appear to have normal adrenocortical function, but mice over-expressing IGF-II develop early adrenal hyperplasia, suggesting that that this growth factor can drive adrenocortical cell growth in vivo.	('adrenal hyperplasia', 'Disease', (134, 153))	('adrenocortical function', 'Disease', 'MESH:D018268', (63, 86))	('Mice', 'Species', '10090', (0, 4))	('Igf1', 'Gene', '16000', (28, 32))	('adrenocortical function', 'Disease', (63, 86))	('mice', 'Species', '10090', (92, 96))	('over-expressing', 'PosReg', (97, 112))	('mutations', 'Var', (15, 24))	('early adrenal hyperplasia', 'Phenotype', 'HP:0008258', (128, 153))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (134, 153))	('IGF-II', 'Gene', (113, 119))	('adrenocortical', 'Disease', 'MESH:D018268', (63, 77))	('adrenocortical', 'Disease', 'MESH:D018268', (205, 219))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (134, 153))	('Igf2', 'Gene', (36, 40))	('Igf1', 'Gene', (28, 32))	('Igf2', 'Gene', '16002', (36, 40))	('adrenocortical', 'Disease', (63, 77))	('adrenocortical', 'Disease', (205, 219))
62332	19261630	Mutation and/or aberrant expression of imprinted genes in the IGF2 locus cause Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome associated with adrenal hyperplasia and ACC.	('IGF2', 'Gene', (62, 66))	('adrenal hyperplasia', 'Disease', (153, 172))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (79, 106))	('ACC', 'Phenotype', 'HP:0006744', (177, 180))	('BWS', 'Disease', 'MESH:D001506', (108, 111))	('Mutation', 'Var', (0, 8))	('overgrowth syndrome', 'Disease', (117, 136))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (153, 172))	('overgrowth', 'Phenotype', 'HP:0001548', (117, 127))	('overgrowth syndrome', 'Disease', 'MESH:C537340', (117, 136))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (153, 172))	('Beckwith-Wiedemann syndrome', 'Disease', (79, 106))	('cause', 'Reg', (73, 78))	('BWS', 'Disease', (108, 111))	('aberrant expression', 'Var', (16, 35))
62336	19261630	Overexpression of IGF2, caused by genetic or epigenetic alterations at chromosome 11p15, is evident approximately 90% of cases of human ACC.	('IGF2', 'Gene', (18, 22))	('genetic', 'Var', (34, 41))	('ACC', 'Phenotype', 'HP:0006744', (136, 139))	('epigenetic alterations', 'Var', (45, 67))	('human', 'Species', '9606', (130, 135))
62338	19261630	The clonal genetic model of tumorigenesis argues that genetic changes at the IGF2 locus are a late event in the evolution of ACAs into carcinomas, whereas the epigenetic progenitor model discussed below posits that LOI at the IGF2 locus is an early event in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Disease', (28, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('tumor', 'Disease', (258, 263))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ACAs', 'Phenotype', 'HP:0008256', (125, 129))	('LOI', 'Var', (215, 218))	('carcinomas', 'Disease', 'MESH:D002277', (135, 145))	('IGF2', 'Gene', (77, 81))	('carcinomas', 'Disease', (135, 145))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('IGF2', 'Gene', (226, 230))
62345	19261630	Recent studies suggest that LOI of at the IGF2 locus increases cancer risk in another way: by increasing the sensitivity of IGF-II signaling pathways.	('IGF2', 'Gene', (42, 46))	('IGF-II signaling pathways', 'Pathway', (124, 149))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('LOI of', 'Var', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('increases', 'PosReg', (53, 62))	('sensitivity', 'MPA', (109, 120))	('cancer', 'Disease', (63, 69))	('increasing', 'PosReg', (94, 104))
62346	19261630	IGF1R antagonists cause growth inhibition in vitro in human ACC xenografts in nude mice, and early clinical testing in humans is underway.	('antagonists', 'Var', (6, 17))	('nude mice', 'Species', '10090', (78, 87))	('ACC', 'Phenotype', 'HP:0006744', (60, 63))	('ACC', 'Disease', (60, 63))	('IGF1R', 'Gene', (0, 5))	('humans', 'Species', '9606', (119, 125))	('growth inhibition', 'CPA', (24, 41))	('IGF1R', 'Gene', '3480', (0, 5))	('human', 'Species', '9606', (54, 59))	('human', 'Species', '9606', (119, 124))
62350	19261630	Disruption of MC2R leads to adrenocortical atrophy and reduced production of glucocorticoids and aldosterone.	('MC2R', 'Gene', (14, 18))	('adrenocortical atrophy', 'Disease', (28, 50))	('MC2R', 'Gene', '4158', (14, 18))	('reduced', 'NegReg', (55, 62))	('adrenocortical atrophy', 'Phenotype', 'HP:0008207', (28, 50))	('adrenocortical atrophy', 'Disease', 'MESH:D018268', (28, 50))	('reduced production of glucocorticoids', 'Phenotype', 'HP:0008163', (55, 92))	('aldosterone', 'Chemical', 'MESH:D000450', (97, 108))	('Disruption', 'Var', (0, 10))
62351	19261630	A constitutively-active, germline mutation of the MC2R gene has been observed in an individual with bilateral adrenal hyperplasia and Cushing's syndrome.	('bilateral adrenal hyperplasia', 'Disease', (100, 129))	("Cushing's syndrome", 'Disease', (134, 152))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (134, 152))	('MC2R', 'Gene', (50, 54))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (110, 129))	('germline mutation', 'Var', (25, 42))	('MC2R', 'Gene', '4158', (50, 54))	('observed', 'Reg', (69, 77))	('bilateral adrenal hyperplasia', 'Disease', 'MESH:D000312', (100, 129))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (134, 152))
62355	19261630	Many of the mutations associated with human adrenocortical hyperplasias and adenomas result in dysregulation of the cAMP-dependent protein kinase signaling pathway.	('adenomas', 'Disease', (76, 84))	('human', 'Species', '9606', (38, 43))	('mutations', 'Var', (12, 21))	('cAMP-dependent protein kinase signaling pathway', 'Pathway', (116, 163))	('adrenocortical hyperplasias', 'Disease', 'MESH:D018268', (44, 71))	('cAMP', 'Chemical', 'MESH:D000242', (116, 120))	('dysregulation', 'MPA', (95, 108))	('adrenocortical hyperplasias', 'Disease', (44, 71))	('adenomas', 'Disease', 'MESH:D000236', (76, 84))
62358	19261630	Certain benign multinodular adrenocortical hyperplasias have been linked to activating mutations in the gene for Gsalpha or inactivating mutations in gene for Gi2alpha, both of which cause excess cAMP signaling.	('Gsalpha', 'Gene', (113, 120))	('Gi2alpha', 'Gene', (159, 167))	('linked', 'Reg', (66, 72))	('inactivating mutations', 'Var', (124, 146))	('cAMP signaling', 'MPA', (196, 210))	('cAMP', 'Chemical', 'MESH:D000242', (196, 200))	('multinodular adrenocortical hyperplasias', 'Disease', (15, 55))	('multinodular adrenocortical hyperplasias', 'Disease', 'MESH:D018268', (15, 55))	('Gsalpha', 'Gene', '2778', (113, 120))	('multinodular adrenocortical hyperplasias', 'Phenotype', 'HP:0008231', (15, 55))	('cause', 'Reg', (183, 188))	('mutations', 'Var', (87, 96))	('excess', 'PosReg', (189, 195))
62359	19261630	Loss-of-function germline mutations in the genes encoding PDE8 and PDE11, two phosphodiesterases that degrade cAMP, have been linked to bilateral adrenocortical hyperplasia and sporadic ACA.	('Loss-of-function', 'NegReg', (0, 16))	('bilateral adrenocortical hyperplasia', 'Disease', (136, 172))	('bilateral adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (136, 172))	('germline', 'Var', (17, 25))	('cAMP', 'MPA', (110, 114))	('PDE11', 'Gene', (67, 72))	('sporadic ACA', 'Disease', (177, 189))	('cAMP', 'Chemical', 'MESH:D000242', (110, 114))	('PDE8', 'Gene', (58, 62))
62360	19261630	Inactivating mutations in the protein kinase A regulatory subunit (PRKAR1A) cause Carney Complex, a multiple endocrine neoplasia syndrome associated with Primary Pigmented Adrenocortical disease (PPNAD), abnormal pigmentation of the skin, myxomas, and other neoplasms.	('PRKAR1A', 'Gene', '5573', (67, 74))	('myxomas', 'Disease', (239, 246))	('neoplasms', 'Phenotype', 'HP:0002664', (258, 267))	('myxomas', 'Disease', 'MESH:D009232', (239, 246))	('neoplasm', 'Phenotype', 'HP:0002664', (258, 266))	('Inactivating mutations', 'Var', (0, 22))	('Primary Pigmented Adrenocortical disease', 'Disease', 'MESH:C566469', (154, 194))	('multiple endocrine neoplasia syndrome', 'Disease', 'MESH:D009377', (100, 137))	('Primary Pigmented Adrenocortical disease', 'Disease', (154, 194))	('multiple endocrine neoplasia syndrome', 'Disease', (100, 137))	('neoplasms', 'Disease', 'MESH:D009369', (258, 267))	('pigmentation of the skin', 'Phenotype', 'HP:0000953', (213, 237))	('abnormal pigmentation', 'Phenotype', 'HP:0001000', (204, 225))	('cause', 'Reg', (76, 81))	('Carney Complex', 'Disease', (82, 96))	('PRKAR1A', 'Gene', (67, 74))	('neoplasia', 'Phenotype', 'HP:0002664', (119, 128))	('neoplasms', 'Disease', (258, 267))	('associated', 'Reg', (138, 148))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (109, 128))	('Pigmented Adrenocortical disease', 'Phenotype', 'HP:0001580', (162, 194))
62361	19261630	Somatic inactivating mutations or allelic losses of the PRKAR1A locus at 17q22-24 are also seen in sporadic cases of ACAs and ACCs.	('ACCs', 'Gene', (126, 130))	('PRKAR1A', 'Gene', '5573', (56, 63))	('ACAs', 'Phenotype', 'HP:0008256', (117, 121))	('allelic losses', 'Var', (34, 48))	('ACCs', 'Gene', '84680', (126, 130))	('ACAs', 'Disease', (117, 121))	('ACC', 'Phenotype', 'HP:0006744', (126, 129))	('PRKAR1A', 'Gene', (56, 63))	('seen', 'Reg', (91, 95))
62379	19261630	Inhibition of the EGFR signaling pathway inhibits proliferation in the ACC cell line NCI-H295.	('inhibits', 'NegReg', (41, 49))	('EGFR', 'Gene', '1956', (18, 22))	('NCI-H295', 'CellLine', 'CVCL:0456', (85, 93))	('ACC', 'Phenotype', 'HP:0006744', (71, 74))	('proliferation', 'CPA', (50, 63))	('EGFR', 'Gene', (18, 22))	('Inhibition', 'Var', (0, 10))
62515	33187258	In preclinical models, inhibition of steroidogenesis enzymes or manipulation of steroidogenic factor-1 expression levels affects cell proliferation and invasion, as well as tumor volume.	('a', 'Gene', '8803', (12, 13))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('a', 'Gene', '8803', (121, 122))	('steroidogenic factor-1', 'Gene', '2516', (80, 102))	('steroidogenic factor-1', 'Gene', (80, 102))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('a', 'Gene', '8803', (142, 143))	('a', 'Gene', '8803', (65, 66))	('steroid', 'Chemical', 'MESH:D013256', (80, 87))	('steroidogenesis', 'Enzyme', (37, 52))	('a', 'Gene', '8803', (71, 72))	('a', 'Gene', '8803', (95, 96))	('steroid', 'Chemical', 'MESH:D013256', (37, 44))	('inhibition', 'Var', (23, 33))	('tumor', 'Disease', (173, 178))	('a', 'Gene', '8803', (162, 163))	('a', 'Gene', '8803', (155, 156))	('a', 'Gene', '8803', (170, 171))	('a', 'Gene', '8803', (148, 149))
62564	33187258	Tumors from ACC patients displayed no mutations or deep deletions in the ABAT gene.	('deep deletions', 'Var', (51, 65))	('a', 'Gene', '8803', (30, 31))	('patients', 'Species', '9606', (16, 24))	('a', 'Gene', '8803', (17, 18))	('A', 'Gene', '8803', (73, 74))	('a', 'Gene', '8803', (41, 42))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('A', 'Gene', '8803', (12, 13))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('A', 'Gene', '8803', (75, 76))
62637	33187258	A search of the NCBI's Gene Expression Omnibus (GEO) identified two microarray datasets in which transcript data for NCI-H295R are available: GDS3537 and GDS3556.	('a', 'Gene', '8803', (82, 83))	('a', 'Gene', '8803', (150, 151))	('a', 'Gene', '8803', (109, 110))	('a', 'Gene', '8803', (4, 5))	('a', 'Gene', '8803', (99, 100))	('a', 'Gene', '8803', (133, 134))	('a', 'Gene', '8803', (136, 137))	('a', 'Gene', '8803', (127, 128))	('a', 'Gene', '8803', (111, 112))	('a', 'Gene', '8803', (73, 74))	('a', 'Gene', '8803', (76, 77))	('a', 'Gene', '8803', (80, 81))	('NCI-H295R', 'CellLine', 'CVCL:0458', (117, 126))	('a', 'Gene', '8803', (131, 132))	('GDS3537', 'Var', (142, 149))	('GDS3556', 'Var', (154, 161))	('A', 'Gene', '8803', (0, 1))
62659	33187258	In primary tumors of other cancers, high ABAT transcript expression is associated with favorable patient outcomes.	('ABAT', 'Gene', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('patient', 'Species', '9606', (97, 104))	('a', 'Gene', '8803', (88, 89))	('a', 'Gene', '8803', (48, 49))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('high', 'Var', (36, 40))	('a', 'Gene', '8803', (71, 72))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('a', 'Gene', '8803', (7, 8))	('a', 'Gene', '8803', (92, 93))	('a', 'Gene', '8803', (77, 78))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('a', 'Gene', '8803', (28, 29))	('tumors', 'Disease', (11, 17))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancers', 'Disease', (27, 34))	('a', 'Gene', '8803', (98, 99))
62663	33187258	Additionally, low levels of ABAT transcripts are associated with poor patient survival in mesenchymal glioblastoma as well as progression, recurrence, and reduced patient survival time in hepatocellular carcinoma (HCC).	('a', 'Gene', '8803', (211, 212))	('a', 'Gene', '8803', (99, 100))	('a', 'Gene', '8803', (123, 124))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('a', 'Gene', '8803', (35, 36))	('a', 'Gene', '8803', (200, 201))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (188, 212))	('a', 'Gene', '8803', (177, 178))	('a', 'Gene', '8803', (113, 114))	('patient', 'Species', '9606', (70, 77))	('a', 'Gene', '8803', (49, 50))	('a', 'Gene', '8803', (115, 116))	('a', 'Gene', '8803', (191, 192))	('poor', 'NegReg', (65, 69))	('a', 'Gene', '8803', (8, 9))	('hepatocellular carcinoma', 'Disease', (188, 212))	('A', 'Gene', '8803', (30, 31))	('a', 'Gene', '8803', (71, 72))	('A', 'Gene', '8803', (28, 29))	('mesenchymal glioblastoma', 'Disease', (90, 114))	('a', 'Gene', '8803', (151, 152))	('low levels', 'Var', (14, 24))	('patient', 'Species', '9606', (163, 170))	('a', 'Gene', '8803', (55, 56))	('a', 'Gene', '8803', (204, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('a', 'Gene', '8803', (84, 85))	('reduced', 'NegReg', (155, 162))	('a', 'Gene', '8803', (164, 165))	('a', 'Gene', '8803', (45, 46))	('a', 'Gene', '8803', (108, 109))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (188, 212))	('mesenchymal glioblastoma', 'Disease', 'MESH:D005909', (90, 114))	('A', 'Gene', '8803', (0, 1))
62665	33187258	Recently, high ABAT transcript levels were found to correlate with positive patient outcome in clear cell renal carcinoma, and to decrease cell proliferation and migration while increasing cell death in a kidney cancer cell line model.	('clear cell renal carcinoma', 'Disease', (95, 121))	('a', 'Gene', '8803', (123, 124))	('ABAT', 'Protein', (15, 19))	('a', 'Gene', '8803', (58, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (95, 121))	('a', 'Gene', '8803', (120, 121))	('a', 'Gene', '8803', (113, 114))	('kidney cancer', 'Disease', 'MESH:D007680', (205, 218))	('a', 'Gene', '8803', (166, 167))	('a', 'Gene', '8803', (152, 153))	('a', 'Gene', '8803', (135, 136))	('a', 'Gene', '8803', (183, 184))	('a', 'Gene', '8803', (213, 214))	('a', 'Gene', '8803', (158, 159))	('kidney cancer', 'Phenotype', 'HP:0009726', (205, 218))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (95, 121))	('renal carcinoma', 'Phenotype', 'HP:0005584', (106, 121))	('kidney cancer', 'Disease', (205, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('a', 'Gene', '8803', (77, 78))	('a', 'Gene', '8803', (22, 23))	('a', 'Gene', '8803', (109, 110))	('a', 'Gene', '8803', (203, 204))	('a', 'Gene', '8803', (196, 197))	('high', 'Var', (10, 14))	('patient', 'Species', '9606', (76, 83))	('a', 'Gene', '8803', (98, 99))
62731	33187258	In particular, flux of carbons through the GABA shunt may affect ROS production, as supported by the demonstration that altered ABAT expression and ABAT activity affects mitochondrial oxygen consumption in non-cancerous cells, and that the deletion of ABAT orthologs in fungi causes increased sensitivity to oxidative stress.	('a', 'Gene', '8803', (211, 212))	('a', 'Gene', '8803', (312, 313))	('a', 'Gene', '8803', (233, 234))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancerous', 'Disease', 'MESH:D009369', (210, 219))	('a', 'Gene', '8803', (58, 59))	('a', 'Gene', '8803', (11, 12))	('a', 'Gene', '8803', (153, 154))	('oxidative stress', 'Phenotype', 'HP:0025464', (308, 324))	('GABA', 'Chemical', 'MESH:D005680', (43, 47))	('a', 'Gene', '8803', (81, 82))	('a', 'Gene', '8803', (120, 121))	('a', 'Gene', '8803', (288, 289))	('a', 'Gene', '8803', (24, 25))	('a', 'Gene', '8803', (144, 145))	('carbons', 'Chemical', 'MESH:D002244', (23, 30))	('cancerous', 'Disease', (210, 219))	('a', 'Gene', '8803', (277, 278))	('a', 'Gene', '8803', (181, 182))	('a', 'Gene', '8803', (117, 118))	('oxygen', 'Chemical', 'MESH:D010100', (184, 190))	('a', 'Gene', '8803', (55, 56))	('ABAT', 'Gene', (252, 256))	('a', 'Gene', '8803', (109, 110))	('ROS', 'Chemical', '-', (65, 68))	('a', 'Gene', '8803', (4, 5))	('a', 'Gene', '8803', (227, 228))	('ROS production', 'MPA', (65, 79))	('deletion', 'Var', (240, 248))	('a', 'Gene', '8803', (162, 163))
62789	33187258	Secondly, GAD1, which encodes the GABA-synthetic enzyme glutamic acid decarboxylase 67 (GAD67), begins the reaction pathway in the production of GABA, and therefore its expression would be expected to affect GABA-dependent processes.	('glutamic acid decarboxylase 67', 'Gene', '2571', (56, 86))	('GABA-dependent processes', 'MPA', (208, 232))	('GAD', 'Gene', '2571', (10, 13))	('a', 'Gene', '8803', (60, 61))	('a', 'Gene', '8803', (121, 122))	('GAD', 'Gene', '2571', (88, 91))	('a', 'Gene', '8803', (201, 202))	('GABA', 'Chemical', 'MESH:D005680', (34, 38))	('begins', 'PosReg', (96, 102))	('a', 'Gene', '8803', (65, 66))	('a', 'Gene', '8803', (80, 81))	('a', 'Gene', '8803', (73, 74))	('GABA', 'Chemical', 'MESH:D005680', (145, 149))	('GABA', 'Chemical', 'MESH:D005680', (208, 212))	('GAD67', 'Gene', '2571', (88, 93))	('expression', 'Var', (169, 179))	('a', 'Gene', '8803', (151, 152))	('a', 'Gene', '8803', (117, 118))	('production', 'MPA', (131, 141))	('GAD', 'Gene', (10, 13))	('a', 'Gene', '8803', (109, 110))	('GAD67', 'Gene', (88, 93))	('glutamic acid decarboxylase 67', 'Gene', (56, 86))	('GAD', 'Gene', (88, 91))
62817	33187258	This search yielded results from two microarray (Affymetrix Human Genome U133 Plus 2.0 Array) studies: dataset GDS3537 (series GSE8588) and dataset GDS3556 (series GSE15918).	('a', 'Gene', '8803', (106, 107))	('A', 'Gene', '8803', (87, 88))	('A', 'Gene', '8803', (49, 50))	('GDS3556', 'Var', (148, 155))	('a', 'Gene', '8803', (136, 137))	('a', 'Gene', '8803', (42, 43))	('a', 'Gene', '8803', (143, 144))	('a', 'Gene', '8803', (7, 8))	('a', 'Gene', '8803', (63, 64))	('a', 'Gene', '8803', (45, 46))	('a', 'Gene', '8803', (90, 91))	('a', 'Gene', '8803', (141, 142))	('GDS3537', 'Var', (111, 118))	('a', 'Gene', '8803', (104, 105))	('Human', 'Species', '9606', (60, 65))
62861	32971946	A Ki67 index over 5% is suggestive of malignancy.	('Ki67', 'Chemical', '-', (2, 6))	('malignancy', 'Disease', 'MESH:D009369', (38, 48))	('Ki67', 'Var', (2, 6))	('malignancy', 'Disease', (38, 48))
62883	32971946	The c-index, which was computed to quantify the ability of the model to separate events of ACC-specific mortality from patients who did not experience the event, was 0.77 (95% CI: 0.73, 0.81) and 0.77 (95% CI: 0.72, 0.81) for the models including and excluding Ki67 in the selection process, respectively.	('mortality', 'Disease', (104, 113))	('patients', 'Species', '9606', (119, 127))	('ACC', 'Phenotype', 'HP:0006744', (91, 94))	('Ki67', 'Var', (261, 265))	('Ki67', 'Chemical', '-', (261, 265))	('mortality', 'Disease', 'MESH:D003643', (104, 113))
62884	32971946	The internal validation yielded a shrinkage factor of 0.91 for the model with Ki67, and 0.95 for the model without Ki67 (Table 2).	('Ki67', 'Chemical', '-', (78, 82))	('shrinkage', 'NegReg', (34, 43))	('Ki67', 'Chemical', '-', (115, 119))	('Ki67', 'Var', (78, 82))
62901	32971946	The model with Ki67 also relied on hormonal status and the pathology criteria capsular and/or vascular invasion.	('capsular and/or', 'CPA', (78, 93))	('Ki67', 'Var', (15, 19))	('Ki67', 'Chemical', '-', (15, 19))
62920	32971946	For example, hypermethylation of CpG islands, or as a pattern called CpG island methylator phenotype (CIMP), is associated with a poor prognosis in ACC.	('ACC', 'Phenotype', 'HP:0006744', (148, 151))	('ACC', 'Disease', (148, 151))	('CIMP', 'Chemical', '-', (102, 106))	('hypermethylation', 'Var', (13, 29))	('associated', 'Reg', (112, 122))
62923	32971946	recently presented a COMBI score, integrating clinical predictors with number of somatic mutations, alterations in the Wnt/beta-catenin and p53/Rb pathways, and promoter region methylation pattern.	('alterations', 'Reg', (100, 111))	('beta-catenin', 'Gene', '1499', (123, 135))	('mutations', 'Var', (89, 98))	('beta-catenin', 'Gene', (123, 135))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))
62931	32971946	The mENSAT classification defines T3-4N0M0 as stage III (invasion of surrounding tissues/organs, or invasion of the renal vein or inferior vena cava), and both T3-4N1M0-1 and T3-4N0M1 as stage IV.	('renal vein', 'Disease', (116, 126))	('T3-4N1M0-1', 'Var', (160, 170))	('T3-4N0M0', 'Var', (34, 42))	('renal vein', 'Disease', 'MESH:D007674', (116, 126))
62954	31694270	The germline TP53 R337H mutation is associated with a cluster of pediatric adrenocortical carcinoma (ACC) that is reported in Southern and Southeastern Brazil, and accounts for the highest global incidence of childhood ACC.	('TP53', 'Gene', (13, 17))	('R337H', 'Var', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('adrenocortical carcinoma', 'Disease', (75, 99))	('R337H', 'Mutation', 'rs121912664', (18, 23))	('TP53', 'Gene', '7157', (13, 17))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (75, 99))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (75, 99))	('associated with', 'Reg', (36, 51))
62974	31694270	Mature CTLs (activated CD8+ T cells) are required to eliminate tumor cells, but impairment in cancer immunity may inhibit receptor signaling and lead to tumors that can evade the immune system.	('tumor', 'Disease', (63, 68))	('lead to', 'Reg', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('inhibit', 'NegReg', (114, 121))	('CD8', 'Gene', (23, 26))	('CD8', 'Gene', '925', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('impairment', 'Var', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('receptor signaling', 'MPA', (122, 140))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
63015	31694270	Children from the International Registry (IPACTR) who were over 13 y had a significantly lower survival rate than children under 3 y. Interestingly, a pediatric ACC series from IPACTR with important differences in relation to our study (e.g., higher mean age, higher frequency of Cushing signs, lower frequency of virilization, absence of TP53 germline mutations, inclusion of adenomas, and differences in disease-free survival) reported a significant association between high Ki-67 expression and worse prognosis.	('expression', 'MPA', (483, 493))	('TP53', 'Gene', '7157', (339, 343))	('Children', 'Species', '9606', (0, 8))	('high', 'Var', (472, 476))	('children', 'Species', '9606', (114, 122))	('TP53', 'Gene', (339, 343))	('Ki-67', 'Gene', (477, 482))	('adenomas', 'Disease', 'MESH:D000236', (377, 385))	('adenomas', 'Disease', (377, 385))
63030	31694270	All ACC patients, three control children without cancer, and half of the parents were carriers of the germline TP53 R337H mutation.	('R337H', 'Var', (116, 121))	('cancer', 'Disease', (49, 55))	('TP53', 'Gene', '7157', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('children', 'Species', '9606', (32, 40))	('TP53', 'Gene', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('R337H', 'Mutation', 'rs121912664', (116, 121))	('patients', 'Species', '9606', (8, 16))
63038	31694270	IHC for PD-L1 was performed in 18 ACC samples with the TP53 R337H mutation according to a previous study.	('TP53', 'Gene', (55, 59))	('R337H', 'Mutation', 'rs121912664', (60, 65))	('TP53', 'Gene', '7157', (55, 59))	('R337H', 'Var', (60, 65))
63044	31694270	Relative risk prediction for childhood ACC beyond the classical clinical and histopathological parameters clearly depends on a number of parameters, including the status of the immune system, age at diagnosis, presence or absence of corticoid-mediated inhibition of the immune system, non-MHC genetic or epigenetic variants, and chromosome instability associated with p53 dysfunction, among others.	('p53', 'Gene', '7157', (368, 371))	('p53', 'Gene', (368, 371))	('epigenetic variants', 'Var', (304, 323))	('chromosome instability', 'Phenotype', 'HP:0040012', (329, 351))	('childhood ACC beyond', 'Disease', (29, 49))	('chromosome instability', 'CPA', (329, 351))
63045	31694270	The emerging evidence suggests that a better understanding of the CD8+ cytotoxic T lymphocytes could reveal variants in antigen presenting cells.	('CD8', 'Gene', '925', (66, 69))	('CD8', 'Gene', (66, 69))	('variants', 'Var', (108, 116))
63047	31694270	Further studies and functional analyses are necessary to estimate HLA variants, the genotype versus phenotype of malignancy to identify the mechanisms of immune response in ACC.	('malignancy', 'Disease', (113, 123))	('variants', 'Var', (70, 78))	('malignancy', 'Disease', 'MESH:D009369', (113, 123))
63065	30413177	Nonfunctioning ACC is correlated with a poor prognosis due to the late diagnosis, local invasion, or recurrence and distant metastases.	('metastases', 'Disease', (124, 134))	('recurrence', 'CPA', (101, 111))	('metastases', 'Disease', 'MESH:D009362', (124, 134))	('local invasion', 'CPA', (82, 96))	('Nonfunctioning', 'Var', (0, 14))	('ACC', 'Disease', (15, 18))	('ACC', 'Phenotype', 'HP:0006744', (15, 18))
63110	28800627	We demonstrated that PA024 significantly suppressed angiotensin II (Ang II)-induced CYP11B2 mRNA expression, promoter activity and aldosterone secretion in human adrenocortical H295R cells.	('PA024', 'Var', (21, 26))	('CYP11B2', 'Gene', '1585', (84, 91))	('H295R', 'CellLine', 'CVCL:0458', (177, 182))	('angiotensin II (Ang II', 'Gene', '183', (52, 74))	('promoter activity', 'MPA', (109, 126))	('adrenocortical', 'Disease', (162, 176))	('adrenocortical', 'Disease', 'MESH:D018268', (162, 176))	('suppressed', 'NegReg', (41, 51))	('human', 'Species', '9606', (156, 161))	('CYP11B2', 'Gene', (84, 91))	('PA024', 'Chemical', '-', (21, 26))	('aldosterone', 'Chemical', 'MESH:D000450', (131, 142))	('aldosterone secretion', 'MPA', (131, 152))
63111	28800627	Human CYP11B2 promoter functional analyses using its deletion and point mutants indicated that the suppression of CYP11B2 promoter activity by PA024 was in the region from -1521 (full length) to -106 including the NBRE-1 and the Ad5 elements, and the Ad5 element may be mainly involved in the PA024-mediated suppression.	('Human', 'Species', '9606', (0, 5))	('PA024', 'Var', (143, 148))	('Ad5', 'Gene', '8081', (251, 254))	('Ad5', 'Gene', (229, 232))	('CYP11B2', 'Gene', (6, 13))	('PA024', 'Chemical', '-', (293, 298))	('CYP11B2', 'Gene', '1585', (6, 13))	('promoter activity', 'MPA', (122, 139))	('Ad5', 'Gene', (251, 254))	('CYP11B2', 'Gene', (114, 121))	('suppression', 'NegReg', (99, 110))	('Ad5', 'Gene', '8081', (229, 232))	('PA024', 'Chemical', '-', (143, 148))	('CYP11B2', 'Gene', '1585', (114, 121))
63112	28800627	PA024 also significantly suppressed the Ang II-induced mRNA expression of transcription factors NURR1 and NGFIB that bind to and activate the Ad5 element.	('Ad5', 'Gene', (142, 145))	('activate', 'PosReg', (129, 137))	('bind', 'Interaction', (117, 121))	('NURR1', 'Gene', (96, 101))	('suppressed', 'NegReg', (25, 35))	('NGFIB', 'Gene', (106, 111))	('Ad5', 'Gene', '8081', (142, 145))	('mRNA expression', 'MPA', (55, 70))	('PA024', 'Var', (0, 5))	('PA024', 'Chemical', '-', (0, 5))	('Ang II', 'Gene', '183', (40, 46))	('Ang II', 'Gene', (40, 46))
63114	28800627	PA024 also suppressed the Ang II-induced mRNA expression of StAR, HSD3beta2 and CYP21A2, a steroidogenic enzyme group involved in aldosterone biosynthesis.	('aldosterone', 'Chemical', 'MESH:D000450', (130, 141))	('StAR', 'Gene', '6770', (60, 64))	('HSD3beta2', 'Gene', (66, 75))	('suppressed', 'NegReg', (11, 21))	('CYP21A2', 'Gene', (80, 87))	('CYP21A2', 'Gene', '1589', (80, 87))	('mRNA expression', 'MPA', (41, 56))	('PA024', 'Var', (0, 5))	('PA024', 'Chemical', '-', (0, 5))	('Ang II', 'Gene', '183', (26, 32))	('StAR', 'Gene', (60, 64))	('Ang II', 'Gene', (26, 32))
63115	28800627	Additionally, the PA024-mediated CYP11B2 transcription suppression was shown to be exerted via RXRalpha.	('CYP11B2', 'Gene', (33, 40))	('transcription', 'MPA', (41, 54))	('CYP11B2', 'Gene', '1585', (33, 40))	('PA024-mediated', 'Var', (18, 32))	('PA024', 'Chemical', '-', (18, 23))
63117	28800627	Finally, PA024 treatment significantly lowered both the systolic and diastolic blood pressure in Tsukuba hypertensive mice (hRN8-12 x hAG2-5).	('lowered', 'NegReg', (39, 46))	('Tsukuba hypertensive', 'Disease', 'MESH:D006973', (97, 117))	('hAG2-5', 'Gene', (134, 140))	('Tsukuba hypertensive', 'Disease', (97, 117))	('PA024', 'Chemical', '-', (9, 14))	('PA024', 'Var', (9, 14))	('mice', 'Species', '10090', (118, 122))	('hAG2-5', 'Gene', '10551;155465', (134, 140))
63118	28800627	Thus, RXR pan-agonist PA024 may be a candidate anti-hypertensive drugs that acts via the suppression of aldosterone synthesis and secretion.	('RXR', 'Gene', (6, 9))	('suppression of aldosterone synthesis', 'Phenotype', 'HP:0004319', (89, 125))	('hypertensive', 'Disease', 'MESH:D006973', (52, 64))	('secretion', 'MPA', (130, 139))	('aldosterone synthesis', 'MPA', (104, 125))	('PA024', 'Chemical', '-', (22, 27))	('hypertensive', 'Disease', (52, 64))	('PA024', 'Var', (22, 27))	('aldosterone', 'Chemical', 'MESH:D000450', (104, 115))	('RXR', 'Gene', '6256', (6, 9))	('suppression', 'NegReg', (89, 100))
63130	28800627	We also demonstrated that HX630 inhibited tumor growth in vivo and decreased pro-opiomelanocortin gene (Pomc) mRNA expression and in vitro.	('tumor', 'Disease', (42, 47))	('inhibited', 'NegReg', (32, 41))	('pro-opiomelanocortin', 'Gene', (77, 97))	('Pomc', 'Gene', (104, 108))	('pro-opiomelanocortin', 'Gene', '5443', (77, 97))	('HX630', 'Var', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('Pomc', 'Gene', '5443', (104, 108))	('decreased', 'NegReg', (67, 76))	('mRNA expression', 'MPA', (110, 125))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
63131	28800627	Thus, we provide new evidence that RXR agonists, especially HX630 could be new therapeutic candidates for Cushing's disease.	('RXR', 'Gene', (35, 38))	("Cushing's disease", 'Disease', 'MESH:D003480', (106, 123))	("Cushing's disease", 'Disease', (106, 123))	('HX630', 'Var', (60, 65))	('RXR', 'Gene', '6256', (35, 38))
63157	28800627	Thereafter, Reverse transcription mixtures were subjected to quantitative real-time PCR (95 C, 3 min for 1 cycle; 95 C, 15 s; 60 C, 10 s; 72 C, 20 s for 40 cycles for HSD3beta1 and 95 C, 3 min for 1 cycle; 95 C, 15 s; 60 C, 10 s; 72 C, 20 s for 40 cycles for the others) with iQ Supermix (for CYP11B1, CYP11B2, CYP17A1, HSD3beta1 and HSD3beta2) or iQ SYBR green Supermix (for others) (Bio-Rad, Hercules, CA) using a DNA Engine thermal cycler attached to a Chromo4 detector (Bio-Rad).	('CYP11B1', 'Gene', (293, 300))	('Rad', 'Gene', (478, 481))	('HSD3beta1', 'Var', (320, 329))	('Rad', 'Gene', (389, 392))	('SYBR green', 'Chemical', '-', (351, 361))	('Rad', 'Gene', '6236', (478, 481))	('CYP11B1', 'Gene', '1584', (293, 300))	('CYP11B2', 'Gene', (302, 309))	('CYP11B2', 'Gene', '1585', (302, 309))	('CYP17A1', 'Gene', (311, 318))	('CYP17A1', 'Gene', '1586', (311, 318))	('Rad', 'Gene', '6236', (389, 392))
63162	28800627	In the overexpression experiments, 100-300 ng of each expression vector including NGFIB-pcDNA3, NURR1-pcDNA3, RXRalpha-pcDNA1/Amp or RXRbeta-pcDNA1/Amp were also transfected.	('RXRalpha-pcDNA1/Amp', 'Gene', '353', (110, 129))	('RXRalpha-pcDNA1/Amp', 'Gene', (110, 129))	('NGFIB-pcDNA3', 'Var', (82, 94))
63171	28800627	For the detection of NURR1, the membrane was blocked with 1% BSA for overnight at 4 C and probed with the primary antibody for NURR1 (sc-991, Santa Cruz Biotechnology, Dallas, TX) (diluted at 1:500) for 3 h at room temperature, and was thereafter incubated with anti-rabbit IgG, horseradish peroxidase (HRP) linked whole antibody from donkey (NA934V, GE Healthcare Life Sciences, Pittsburgh, PA) (1:5000) for 1 h at room temperature.	('rabbit', 'Species', '9986', (267, 273))	('NA934V', 'Var', (343, 349))	('HRP', 'Protein', (303, 306))	('donkey', 'Species', '9793', (335, 341))	('horseradish', 'Species', '3704', (279, 290))
63185	28800627	We examined the effects of RXR pan-agonist PA024 on H295R cells proliferation using a WST-8 assay after incubation with various concentrations of PA024 for 48 h. As shown in Fig 1A, PA024 did not affect the proliferation of H295R cells.	('PA024', 'Var', (182, 187))	('PA024', 'Chemical', '-', (146, 151))	('RXR', 'Gene', (27, 30))	('PA024', 'Chemical', '-', (43, 48))	('RXR', 'Gene', '6256', (27, 30))	('H295R', 'CellLine', 'CVCL:0458', (224, 229))	('H295R', 'CellLine', 'CVCL:0458', (52, 57))	('PA024', 'Chemical', '-', (182, 187))
63190	28800627	On the other hand, co-treatment with PA024 significantly suppressed Ang II-induced CYP11B2 mRNA expression and promoter activity in a dose-dependent manner (Fig 1C and 1D), respectively.	('promoter activity', 'MPA', (111, 128))	('Ang II', 'Gene', '183', (68, 74))	('Ang II', 'Gene', (68, 74))	('PA024', 'Var', (37, 42))	('PA024', 'Chemical', '-', (37, 42))	('CYP11B2', 'Gene', (83, 90))	('CYP11B2', 'Gene', '1585', (83, 90))	('suppressed', 'NegReg', (57, 67))
63192	28800627	Ang II treatment induced aldosterone secretion as well as mRNA expression and transcriptional activity in H295R cells, but 10 mumol/L PA024 significantly suppressed Ang II-induced aldosterone secretion (Fig 1E).	('aldosterone', 'Chemical', 'MESH:D000450', (180, 191))	('suppressed', 'NegReg', (154, 164))	('Ang II', 'Gene', '183', (0, 6))	('Ang II', 'Gene', '183', (165, 171))	('Ang II', 'Gene', (0, 6))	('Ang II', 'Gene', (165, 171))	('H295R', 'CellLine', 'CVCL:0458', (106, 111))	('mRNA expression', 'MPA', (58, 73))	('aldosterone', 'Chemical', 'MESH:D000450', (25, 36))	('PA024', 'Chemical', '-', (134, 139))	('aldosterone secretion', 'MPA', (25, 46))	('PA024', 'Var', (134, 139))	('transcriptional activity', 'MPA', (78, 102))
63194	28800627	To identify the elements in the CYP11B2 promoter involved in the suppression of transcriptional activity by PA024, we first examined the promoter activity of the CYP11B2 5'-flanking region deletion mutants.	('CYP11B2', 'Gene', '1585', (32, 39))	('PA024', 'Chemical', '-', (108, 113))	('transcriptional activity', 'MPA', (80, 104))	('CYP11B2', 'Gene', (162, 169))	('deletion mutants', 'Var', (189, 205))	('CYP11B2', 'Gene', (32, 39))	('CYP11B2', 'Gene', '1585', (162, 169))
63195	28800627	The PA024-mediated suppression of the CYP11B2 promoter activity observed in the 5'-flanking region from -1521/+2 relative to the transcription start site gradually diminished in parallel with gradual deletions from -1521 to -106 including NBRE-1 (-766/-759), Ad4 (-344/-336) and Ad5 (-129/-114) elements (Fig 2A).	('Ad4', 'Gene', '5664', (259, 262))	('CYP11B2', 'Gene', (38, 45))	('Ad5', 'Gene', '8081', (279, 282))	('diminished', 'NegReg', (164, 174))	('Ad4', 'Gene', (259, 262))	('suppression', 'NegReg', (19, 30))	('PA024-mediated', 'Var', (4, 18))	('CYP11B2', 'Gene', '1585', (38, 45))	('deletions', 'Var', (200, 209))	('-766/-759', 'Var', (247, 256))	('PA024', 'Chemical', '-', (4, 9))	('Ad5', 'Gene', (279, 282))	('NBRE-1', 'Gene', (239, 245))
63198	28800627	Although Ad5 mutation affected the suppression by PA024, NBRE-1 and Ad1 mutations did not affect the suppression (Fig 2B).	('Ad5', 'Gene', (9, 12))	('mutation', 'Var', (13, 21))	('suppression', 'MPA', (35, 46))	('PA024', 'Chemical', '-', (50, 55))	('NBRE-1', 'Gene', (57, 63))	('Ad1', 'Gene', '351', (68, 71))	('Ad5', 'Gene', '8081', (9, 12))	('Ad1', 'Gene', (68, 71))
63201	28800627	Therefore, we first examined the effects of PA024 on the NURR1 and NGFIB mRNA expression levels in H295R cells.	('NURR1', 'Gene', (57, 62))	('H295R', 'CellLine', 'CVCL:0458', (99, 104))	('NGFIB', 'Gene', (67, 72))	('PA024', 'Chemical', '-', (44, 49))	('PA024', 'Var', (44, 49))	('mRNA expression levels', 'MPA', (73, 95))
63202	28800627	PA024 significantly suppressed the Ang II-induced mRNA expression of NURR1 and NGFIB in a dose-dependent manner (Fig 3A and 3B).	('mRNA expression', 'MPA', (50, 65))	('Ang II', 'Gene', '183', (35, 41))	('suppressed', 'NegReg', (20, 30))	('Ang II', 'Gene', (35, 41))	('NURR1', 'Gene', (69, 74))	('NGFIB', 'Gene', (79, 84))	('PA024', 'Var', (0, 5))	('PA024', 'Chemical', '-', (0, 5))
63205	28800627	As shown in Fig 3E, PA024 treatment also significantly decreased Ang II-induced NURR1 protein expression approximately to 0.4-fold by Western blot analyses.	('protein', 'Protein', (86, 93))	('Ang II', 'Gene', '183', (65, 71))	('decreased', 'NegReg', (55, 64))	('Ang II', 'Gene', (65, 71))	('PA024', 'Chemical', '-', (20, 25))	('NURR1', 'Gene', (80, 85))	('PA024', 'Var', (20, 25))
63210	28800627	These data suggest that these enzymes may also be involved in the PA024-mediated suppression of aldosterone synthesis.	('suppression of aldosterone synthesis', 'Phenotype', 'HP:0004319', (81, 117))	('PA024-mediated', 'Var', (66, 80))	('aldosterone', 'Chemical', 'MESH:D000450', (96, 107))	('suppression', 'NegReg', (81, 92))	('involved', 'Reg', (50, 58))	('aldosterone synthesis', 'MPA', (96, 117))	('PA024', 'Chemical', '-', (66, 71))
63214	28800627	Co-treatment with 10 mumol/L PA024 significantly suppressed Ang II-induced CYP11B1 mRNA expression (Fig 4G), wheareas 10 mumol/L PA024 did not suppress Ang II-induced cortisol secretion (Fig 1F).	('Ang II', 'Gene', (60, 66))	('PA024', 'Chemical', '-', (29, 34))	('CYP11B1', 'Gene', (75, 82))	('cortisol', 'Chemical', 'MESH:D006854', (167, 175))	('CYP11B1', 'Gene', '1584', (75, 82))	('PA024', 'Var', (29, 34))	('PA024', 'Chemical', '-', (129, 134))	('suppressed', 'NegReg', (49, 59))	('Ang II', 'Gene', '183', (152, 158))	('Ang II', 'Gene', (152, 158))	('Ang II', 'Gene', '183', (60, 66))
63215	28800627	These data suggest that PA024 suppresses Ang II-induced CYP11B1 mRNA expression, but did not affect the cortisol secretion in H295R cells.	('Ang II', 'Gene', '183', (41, 47))	('CYP11B1', 'Gene', '1584', (56, 63))	('suppresses', 'NegReg', (30, 40))	('Ang II', 'Gene', (41, 47))	('H295R', 'CellLine', 'CVCL:0458', (126, 131))	('cortisol', 'Chemical', 'MESH:D006854', (104, 112))	('PA024', 'Var', (24, 29))	('PA024', 'Chemical', '-', (24, 29))	('CYP11B1', 'Gene', (56, 63))
63217	28800627	Endogenous RXRalpha knockdown by its siRNA significantly restored the inhibitory effects of PA024 on CYP11B2 and NURR1 mRNA expression (Fig 5A and 5B).	('NURR1', 'Gene', (113, 118))	('PA024', 'Chemical', '-', (92, 97))	('CYP11B2', 'Gene', (101, 108))	('knockdown', 'Var', (20, 29))	('CYP11B2', 'Gene', '1585', (101, 108))	('inhibitory effects', 'MPA', (70, 88))	('restored', 'PosReg', (57, 65))
63218	28800627	On the other hand, RXRbeta knockdown by its siRNA did not affect inhibitory effects of PA024 on CYP11B2 or NURR1 mRNA expression (data not shown).	('knockdown', 'Var', (27, 36))	('PA024', 'Chemical', '-', (87, 92))	('CYP11B2', 'Gene', (96, 103))	('NURR1', 'Gene', (107, 112))	('CYP11B2', 'Gene', '1585', (96, 103))
63223	28800627	Moreover, co-treatment with 10 mumol/L PA024 and 10 mumol/L pioglitazone further suppressed the Ang II-induced CYP11B2 mRNA expression to approximately 0.25-fold (Fig 6).	('suppressed', 'NegReg', (81, 91))	('Ang II', 'Gene', '183', (96, 102))	('pioglitazone', 'Chemical', 'MESH:D000077205', (60, 72))	('Ang II', 'Gene', (96, 102))	('PA024', 'Chemical', '-', (39, 44))	('PA024', 'Var', (39, 44))	('CYP11B2', 'Gene', (111, 118))	('CYP11B2', 'Gene', '1585', (111, 118))
63224	28800627	These data suggest that the combination of PA024 and pioglitazone causes synergistic suppressive effects on CYP11B2 mRNA expression.	('pioglitazone', 'Chemical', 'MESH:D000077205', (53, 65))	('suppressive', 'NegReg', (85, 96))	('PA024', 'Chemical', '-', (43, 48))	('CYP11B2', 'Gene', (108, 115))	('CYP11B2', 'Gene', '1585', (108, 115))	('PA024', 'Var', (43, 48))
63228	28800627	There was also no significant difference in the HR between the two groups after treatment for 7 weeks (control group: 699+-8 /min versus PA024 treated group: 656+-13 /min, P = 0.13), although PA024 transiently decreased HR after treatment for 6 weeks (control group: 704+-17 /min versus PA024 treated group: 597+-15 /min, P = 0.0012) (Fig 7B).	('decreased', 'NegReg', (210, 219))	('PA024', 'Chemical', '-', (287, 292))	('PA024', 'Chemical', '-', (192, 197))	('PA024', 'Chemical', '-', (137, 142))	('PA024', 'Var', (192, 197))
63229	28800627	On the other hand, PA024 significantly decreased both SBP and DBP after a few weeks of treatment (Fig 7C and 7D).	('SBP', 'MPA', (54, 57))	('PA024', 'Chemical', '-', (19, 24))	('DBP', 'MPA', (62, 65))	('PA024', 'Var', (19, 24))	('decreased', 'NegReg', (39, 48))
63238	28800627	LG100268, AGN194204, 9-cis UAB30) were found to be effective in suppressing tumor development in multiple carcinogenesis models, including those of breast, skin, pancreas, and prostate.	('9-cis UAB30', 'Var', (21, 32))	('LG100268', 'Var', (0, 8))	('suppressing', 'NegReg', (64, 75))	('AGN194204', 'Var', (10, 19))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('breast', 'Disease', (148, 154))	('multiple carcinogenesis', 'Disease', 'MESH:D063646', (97, 120))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('multiple carcinogenesis', 'Disease', (97, 120))
63239	28800627	We also demonstrated that RXR-selective pan-agonists HX630 and PA024 exerted anti-proliferative and pro-apoptotic effects in murine pituitary corticotroph tumor AtT20 cells.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('HX630', 'Var', (53, 58))	('RXR', 'Gene', '6256', (26, 29))	('anti-proliferative', 'CPA', (77, 95))	('pituitary corticotroph tumor', 'Phenotype', 'HP:0008291', (132, 160))	('tumor', 'Disease', (155, 160))	('pro-apoptotic effects', 'CPA', (100, 121))	('RXR', 'Gene', (26, 29))	('murine', 'Species', '10090', (125, 131))	('PA024', 'Gene', (63, 68))	('PA024', 'Chemical', '-', (63, 68))
63240	28800627	Furthermore, we confirmed that HX630 inhibited tumor growth in vivo.	('HX630', 'Var', (31, 36))	('inhibited', 'NegReg', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
63243	28800627	Furthermore, we confirmed the hypotensive effect of PA024 in vivo.	('hypotensive', 'Disease', (30, 41))	('PA024', 'Var', (52, 57))	('hypotensive', 'Disease', 'MESH:D007022', (30, 41))	('hypotensive effect', 'Phenotype', 'HP:0002615', (30, 48))	('PA024', 'Chemical', '-', (52, 57))
63250	28800627	A previous study reported that mutation of the Ad5 site further reduced both NGFIB- and NURR1-stimulated CYP11B2 promoter activities compared to the mutation of the NBRE-1 element, indicating that the Ad5 element is more important than the NBRE-1 element for CYP11B2 transcription.	('CYP11B2', 'Gene', (105, 112))	('Ad5', 'Gene', (201, 204))	('CYP11B2', 'Gene', '1585', (259, 266))	('NGFIB-', 'Gene', (77, 83))	('Ad5', 'Gene', '8081', (47, 50))	('CYP11B2', 'Gene', '1585', (105, 112))	('mutation', 'Var', (31, 39))	('Ad5', 'Gene', '8081', (201, 204))	('Ad5', 'Gene', (47, 50))	('NURR1-stimulated', 'Gene', (88, 104))	('reduced', 'NegReg', (64, 71))	('CYP11B2', 'Gene', (259, 266))
63254	28800627	As shown in Fig 8, PA024 increased the Ang II-mediated intracellular Ca2+ concentration.	('increased', 'PosReg', (25, 34))	('Ca2+', 'Chemical', 'MESH:D000069285', (69, 73))	('PA024', 'Chemical', '-', (19, 24))	('PA024', 'Var', (19, 24))	('Ang II', 'Gene', '183', (39, 45))	('Ang II', 'Gene', (39, 45))
63255	28800627	From this result, we speculated that the PA024-mediated suppression of CYP11B2 transcription is not through Ca2+-CaM-CaMK pathway and that PA024 may directly suppress NURR1 expression or NURR1 binding to the Ad5 element, resulting in the suppression of CYP11B2 transcription.	('suppression', 'NegReg', (238, 249))	('CYP11B2', 'Gene', '1585', (253, 260))	('Ad5', 'Gene', (208, 211))	('transcription', 'MPA', (79, 92))	('CaMK', 'Gene', (117, 121))	('CaMK', 'Gene', '818', (117, 121))	('CYP11B2', 'Gene', (71, 78))	('PA024', 'Chemical', '-', (41, 46))	('suppression', 'NegReg', (56, 67))	('transcription', 'MPA', (261, 274))	('binding', 'Interaction', (193, 200))	('NURR1', 'Gene', (187, 192))	('CYP11B2', 'Gene', (253, 260))	('PA024', 'Var', (139, 144))	('PA024-mediated', 'Var', (41, 55))	('expression', 'MPA', (173, 183))	('Ad5', 'Gene', '8081', (208, 211))	('suppress', 'NegReg', (158, 166))	('CYP11B2', 'Gene', '1585', (71, 78))	('NURR1', 'Gene', (167, 172))	('Ca2+', 'Chemical', 'MESH:D000069285', (108, 112))	('PA024', 'Chemical', '-', (139, 144))
63257	28800627	Since a half-site of RXRE (AGGTCA) exists on the NURR1 promoter region, PA024 may suppress NURR1 transcription through this region via RXRalpha, although further studies are needed to confirm it.	('NURR1', 'Gene', (91, 96))	('RXR', 'Gene', (21, 24))	('RXR', 'Gene', '6256', (135, 138))	('PA024', 'Var', (72, 77))	('RXR', 'Gene', (135, 138))	('transcription', 'MPA', (97, 110))	('RXR', 'Gene', '6256', (21, 24))	('suppress', 'NegReg', (82, 90))	('PA024', 'Chemical', '-', (72, 77))
63259	28800627	We also demonstrated that PA024 significantly suppressed Ang II-induced mRNA expressions of StAR, HSD3beta2 and CYP21A2, which are a steroidogenic enzyme group involved in aldosterone biosynthesis in H295R cells (Fig 4A, 4D and 4E).	('StAR', 'Gene', (92, 96))	('StAR', 'Gene', '6770', (92, 96))	('H295R', 'CellLine', 'CVCL:0458', (200, 205))	('mRNA expressions', 'MPA', (72, 88))	('aldosterone', 'Chemical', 'MESH:D000450', (172, 183))	('PA024', 'Var', (26, 31))	('Ang II', 'Gene', '183', (57, 63))	('CYP21A2', 'Gene', '1589', (112, 119))	('PA024', 'Chemical', '-', (26, 31))	('Ang II', 'Gene', (57, 63))	('CYP21A2', 'Gene', (112, 119))	('HSD3beta2', 'Gene', (98, 107))	('suppressed', 'NegReg', (46, 56))
63260	28800627	Thus, decrease expressions of these enzymes may also contribute to the PA024-mediated suppression of aldosterone synthesis.	('expressions', 'MPA', (15, 26))	('PA024-mediated', 'Var', (71, 85))	('aldosterone', 'Chemical', 'MESH:D000450', (101, 112))	('suppression', 'NegReg', (86, 97))	('suppression of aldosterone synthesis', 'Phenotype', 'HP:0004319', (86, 122))	('aldosterone synthesis', 'MPA', (101, 122))	('decrease', 'NegReg', (6, 14))	('PA024', 'Chemical', '-', (71, 76))
63268	28800627	We here demonstrated that PA024 suppressed the Ang II-induced CYP11B1 mRNA expression (Fig 4G).	('PA024', 'Var', (26, 31))	('PA024', 'Chemical', '-', (26, 31))	('Ang II', 'Gene', '183', (47, 53))	('CYP11B1', 'Gene', (62, 69))	('CYP11B1', 'Gene', '1584', (62, 69))	('Ang II', 'Gene', (47, 53))	('suppressed', 'NegReg', (32, 42))
63269	28800627	In addition, PA024 suppressed the Ang II-induced mRNA expressions of StAR, HSD3beta2 and CYP21A2, which are also involved in cortisol biosynthesis in H295R cells (Fig 4A, 4D and 4E).	('Ang II', 'Gene', '183', (34, 40))	('HSD3beta2', 'Gene', (75, 84))	('Ang II', 'Gene', (34, 40))	('mRNA expressions', 'MPA', (49, 65))	('suppressed', 'NegReg', (19, 29))	('StAR', 'Gene', (69, 73))	('H295R', 'CellLine', 'CVCL:0458', (150, 155))	('StAR', 'Gene', '6770', (69, 73))	('PA024', 'Chemical', '-', (13, 18))	('cortisol', 'Chemical', 'MESH:D006854', (125, 133))	('CYP21A2', 'Gene', (89, 96))	('CYP21A2', 'Gene', '1589', (89, 96))	('PA024', 'Var', (13, 18))
63270	28800627	However, PA024 did not affect the Ang II-induced cortisol secretion in H295R cells (Fig 1F).	('Ang II', 'Gene', '183', (34, 40))	('H295R', 'CellLine', 'CVCL:0458', (71, 76))	('Ang II', 'Gene', (34, 40))	('PA024', 'Chemical', '-', (9, 14))	('PA024', 'Var', (9, 14))	('cortisol', 'Chemical', 'MESH:D006854', (49, 57))	('cortisol secretion', 'MPA', (49, 67))
63271	28800627	Therefore, the use of PA024 may not induce glucocorticoid deficiency, and the clinical value of PA024 might not be limited.	('PA024', 'Chemical', '-', (96, 101))	('PA024', 'Chemical', '-', (22, 27))	('PA024', 'Var', (22, 27))	('glucocorticoid deficiency', 'MPA', (43, 68))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (43, 68))
63273	28800627	In this study, we showed that PA024 inhibited the expression of CYP11B2 through different mechanisms.	('CYP11B2', 'Gene', (64, 71))	('inhibited', 'NegReg', (36, 45))	('CYP11B2', 'Gene', '1585', (64, 71))	('PA024', 'Chemical', '-', (30, 35))	('PA024', 'Var', (30, 35))	('expression', 'MPA', (50, 60))
63276	28800627	Thus, the combination of PA024 and pioglitazone may cause synergistic suppressive effects on CYP11B2 mRNA expression via different mechanisms.	('PA024', 'Chemical', '-', (25, 30))	('PA024', 'Var', (25, 30))	('CYP11B2', 'Gene', (93, 100))	('pioglitazone', 'Chemical', 'MESH:D000077205', (35, 47))	('CYP11B2', 'Gene', '1585', (93, 100))	('suppressive', 'NegReg', (70, 81))
63277	28800627	We confirmed that PA024 suppressed both SBP and DBP in vivo (Fig 7C and 7D).	('PA024', 'Var', (18, 23))	('SBP', 'Disease', (40, 43))	('suppressed', 'NegReg', (24, 34))	('DBP', 'Disease', (48, 51))	('PA024', 'Chemical', '-', (18, 23))
63279	28800627	On the other hand, PA024 transiently decreased the HR after treatment for 6 weeks (Fig 7B).	('PA024', 'Var', (19, 24))	('decreased', 'NegReg', (37, 46))	('PA024', 'Chemical', '-', (19, 24))
63281	28800627	These data indicate that PA024 may affect not only the BP but also the HR transiently.	('PA024', 'Chemical', '-', (25, 30))	('affect', 'Reg', (35, 41))	('PA024', 'Var', (25, 30))
63283	28800627	Loss-of-function mutation of the RXRalpha gene in the mouse germ line resulted in the hypoplastic development of the ventricular chambers of the heart.	('hypoplastic', 'Disease', (86, 97))	('Loss-of-function', 'NegReg', (0, 16))	('hypoplastic development', 'Phenotype', 'HP:0001263', (86, 109))	('mutation', 'Var', (17, 25))	('RXRalpha', 'Gene', (33, 41))	('mouse', 'Species', '10090', (54, 59))	('hypoplastic', 'Disease', 'MESH:D000741', (86, 97))
63285	28800627	Although the mechanism(s) involved in the changes of lowering heart rate by PA024 are unclear, it is at least certain that RXR has an important role in heart development and may possibly be involved.	('lowering', 'NegReg', (53, 61))	('PA024', 'Var', (76, 81))	('RXR', 'Gene', '6256', (123, 126))	('PA024', 'Chemical', '-', (76, 81))	('heart rate', 'MPA', (62, 72))	('RXR', 'Gene', (123, 126))
63289	28800627	In conclusion, we demonstrated that PA024 suppressed Ang II-induced CYP11B2 mRNA expression and promoter activity in a dose-dependent manner, and aldosterone secretion at its high concentrations in H295R cells.	('H295R', 'CellLine', 'CVCL:0458', (198, 203))	('PA024', 'Var', (36, 41))	('CYP11B2', 'Gene', (68, 75))	('CYP11B2', 'Gene', '1585', (68, 75))	('suppressed', 'NegReg', (42, 52))	('Ang II', 'Gene', '183', (53, 59))	('PA024', 'Chemical', '-', (36, 41))	('Ang II', 'Gene', (53, 59))	('mRNA expression', 'MPA', (76, 91))	('aldosterone', 'Chemical', 'MESH:D000450', (146, 157))	('aldosterone secretion', 'MPA', (146, 167))	('promoter activity', 'MPA', (96, 113))
63292	28800627	Furthermore, we confirmed that PA024 treatment lowered both the SBP and the DBP in male THM presenting chronic hypertension in vivo.	('hypertension', 'Disease', (111, 123))	('PA024', 'Chemical', '-', (31, 36))	('hypertension', 'Phenotype', 'HP:0000822', (111, 123))	('DBP', 'MPA', (76, 79))	('lowered', 'NegReg', (47, 54))	('PA024', 'Var', (31, 36))	('hypertension', 'Disease', 'MESH:D006973', (111, 123))	('THM', 'Chemical', '-', (88, 91))	('SBP', 'MPA', (64, 67))
63293	28800627	Thus, these results suggest that the RXR pan-agonist PA024 might be a candidate anti-hypertensive drug that acts via the suppression of aldosterone synthesis and secretion.	('hypertensive', 'Disease', 'MESH:D006973', (85, 97))	('suppression', 'NegReg', (121, 132))	('aldosterone', 'Chemical', 'MESH:D000450', (136, 147))	('suppression of aldosterone synthesis', 'Phenotype', 'HP:0004319', (121, 157))	('hypertensive', 'Disease', (85, 97))	('RXR', 'Gene', '6256', (37, 40))	('PA024', 'Chemical', '-', (53, 58))	('PA024', 'Var', (53, 58))	('RXR', 'Gene', (37, 40))	('secretion', 'MPA', (162, 171))	('aldosterone synthesis', 'MPA', (136, 157))
63334	27706226	A number of side-effects have however been reported with their clinical use and include weight gain, acne, increased risk of invasive breast cancer, cardiovascular disease (CVD) and modulation of immunity in the female genital tract (reviewed in).	('invasive breast cancer', 'Disease', 'MESH:D001943', (125, 147))	('weight gain', 'Disease', 'MESH:D015430', (88, 99))	('CVD', 'Phenotype', 'HP:0001626', (173, 176))	('cardiovascular disease', 'Disease', (149, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('invasive breast cancer', 'Disease', (125, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('acne', 'Phenotype', 'HP:0001061', (101, 105))	('weight gain', 'Phenotype', 'HP:0004324', (88, 99))	('weight gain', 'Disease', (88, 99))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (149, 171))	('cardiovascular disease', 'Disease', 'MESH:D002318', (149, 171))	('acne', 'Disease', (101, 105))	('modulation', 'Var', (182, 192))
63343	27706226	The limited number of studies that have in fact investigated the effects of progestins on adrenal steroid biosynthesis in humans have primarily focussed on the first-generation progestin, medroxyprogesterone acetate (MPA), and showed a reduction in the serum levels of the endogenous glucocorticoid cortisol, the endogenous androgen precursors androstenedione (A4) and dehydroepiandrosterone sulphate (DHEA-S), and the endogenous androgen testosterone.	('DHEA-S', 'Chemical', 'MESH:D019314', (402, 408))	('steroid', 'Chemical', 'MESH:D013256', (98, 105))	('medroxyprogesterone acetate', 'Chemical', 'MESH:D017258', (188, 215))	('glucocorticoid cortisol', 'Chemical', '-', (284, 307))	('serum levels of', 'MPA', (253, 268))	('dehydroepiandrosterone sulphate', 'MPA', (369, 400))	('rat', 'Species', '10116', (170, 173))	('androstenedione', 'Chemical', 'MESH:D000735', (344, 359))	('reduction', 'NegReg', (236, 245))	('A4', 'Chemical', '-', (361, 363))	('humans', 'Species', '9606', (122, 128))	('testosterone', 'Chemical', 'MESH:D013739', (439, 451))	('medroxyprogesterone', 'Var', (188, 207))	('MPA', 'Chemical', 'MESH:D017258', (217, 220))	('adrenal steroid biosynthesis', 'MPA', (90, 118))	('dehydroepiandrosterone sulphate', 'Chemical', 'MESH:D019314', (369, 400))
63347	27706226	For example, MPA has been shown to inhibit the activity of both human and rat 3beta-hydroxysteroid dehydrogenase (3betaHSD), while suppressing the activity of rat, but not human, cytochrome P450 17alpha-hydroxylase/17,20 lyase (CYP17A1).	('human', 'Species', '9606', (64, 69))	('3beta-hydroxysteroid dehydrogenase', 'Gene', (78, 112))	('MPA', 'Chemical', 'MESH:D017258', (13, 16))	('rat', 'Species', '10116', (74, 77))	('human', 'Species', '9606', (172, 177))	('rat', 'Species', '10116', (159, 162))	('MPA', 'Var', (13, 16))	('cytochrome P450 17alpha-hydroxylase/17,20 lyase', 'Gene', '1586', (179, 226))	('activity', 'MPA', (47, 55))	('inhibit', 'NegReg', (35, 42))	('suppressing', 'NegReg', (131, 142))	('3beta-hydroxysteroid dehydrogenase', 'Gene', '360348', (78, 112))	('activity', 'MPA', (147, 155))
63359	27706226	The deuterated internal standards, d2-testosterone, d9-Prog, d9-17OH-Prog and d4-cortisol were purchased from Cambridge Isotope Laboratories (Maryland, USA).	('d9-17OH-Prog', 'Chemical', '-', (61, 73))	('rat', 'Species', '10116', (9, 12))	('rat', 'Species', '10116', (132, 135))	('d4-cortisol', 'Chemical', '-', (78, 89))	('Isotope Laboratories', 'Disease', 'MESH:D007757', (120, 140))	('Isotope Laboratories', 'Disease', (120, 140))	('d2-testosterone', 'Chemical', '-', (35, 50))	('d9-Prog', 'Chemical', '-', (52, 59))	('d9-17OH-Prog', 'Var', (61, 73))
63360	27706226	The plasmids expressing human 3betaHSD2 (pCDNA6-hHSD3beta2-V5), CYP17A1 (pIRES-hCYP17A1-V5-X-hCYPB5-6HIS), and CYP21A2 (pCDNA6-hCYP21A2-V5) were generous gifts from Prof Wiebke Arlt (Institute of Metabolism and Systems Research, University of Birmingham, UK).	('human', 'Species', '9606', (24, 29))	('CYP21A2', 'Gene', (111, 118))	('CYP21A2', 'Gene', (128, 135))	('CYP21A2', 'Gene', '1589', (111, 118))	('pCDNA6-hHSD3beta2-V5', 'Var', (41, 61))	('CYP21A2', 'Gene', '1589', (128, 135))	('CYP17A1', 'Var', (64, 71))
63378	27706226	To assay for the inhibition of substrate conversion by the progestins, the cells were treated with the appropriate steroid substrate, 1 muM Preg (for 3betaHSD2) or Prog (for CYP17A1 and CYP21A2) or 17OH-Prog (CYP21A2), in the absence or presence of 1 muM MPA, LNG, GES, NES, NoMAC or DRSP.	('17OH-Prog', 'Chemical', 'MESH:D019326', (198, 207))	('CYP21A2', 'Gene', '1589', (186, 193))	('Prog', 'Chemical', 'MESH:D011374', (164, 168))	('CYP17A1', 'Var', (174, 181))	('Prog', 'Chemical', 'MESH:D011374', (203, 207))	('muM', 'Gene', '56925', (136, 139))	('muM', 'Gene', (136, 139))	('rat', 'Species', '10116', (36, 39))	('DRSP', 'Chemical', 'MESH:C035144', (284, 288))	('CYP21A2', 'Gene', (209, 216))	('muM', 'Gene', '56925', (251, 254))	('NES', 'Chemical', 'MESH:C029167', (270, 273))	('muM', 'Gene', (251, 254))	('rat', 'Species', '10116', (128, 131))	('NoMAC', 'Chemical', 'MESH:C038501', (275, 280))	('LNG', 'Chemical', 'MESH:D016912', (260, 263))	('CYP21A2', 'Gene', (186, 193))	('MPA', 'Chemical', 'MESH:D017258', (255, 258))	('steroid', 'Chemical', 'MESH:D013256', (115, 122))	('CYP21A2', 'Gene', '1589', (209, 216))
63405	27706226	DRSP increased the basal production of DOC, but had no effect on the production of steroids from the mineralocorticoid pathway in the presence of FSK.	('FSK', 'Chemical', 'MESH:D005576', (146, 149))	('steroids', 'Chemical', 'MESH:D013256', (83, 91))	('DOC', 'Chemical', 'MESH:D003900', (39, 42))	('increased', 'PosReg', (5, 14))	('DRSP', 'Var', (0, 4))	('basal production', 'MPA', (19, 35))	('DRSP', 'Chemical', 'MESH:C035144', (0, 4))
63406	27706226	However, similarly to NES and NoMAC, DRSP inhibited the basal and FSK-stimulated production of deoxycortisol.	('NoMAC', 'Chemical', 'MESH:C038501', (30, 35))	('deoxycortisol', 'Chemical', 'MESH:D003350', (95, 108))	('DRSP', 'Var', (37, 41))	('inhibited', 'NegReg', (42, 51))	('DRSP', 'Chemical', 'MESH:C035144', (37, 41))	('FSK', 'Chemical', 'MESH:D005576', (66, 69))	('NES', 'Chemical', 'MESH:C029167', (22, 25))
63412	27706226	For example, MPA increased the synthesis of the androgen precursors, A4 and 11OH-A4, while GES and LNG inhibited A4 and 11-DHC, respectively.	('increased', 'PosReg', (17, 26))	('11-DHC', 'Chemical', 'MESH:C003552', (120, 126))	('synthesis', 'MPA', (31, 40))	('11-DHC', 'MPA', (120, 126))	('MPA', 'Chemical', 'MESH:D017258', (13, 16))	('A4', 'Chemical', '-', (69, 71))	('inhibited', 'NegReg', (103, 112))	('LNG', 'Chemical', 'MESH:D016912', (99, 102))	('A4', 'Chemical', '-', (81, 83))	('11OH-A4', 'Chemical', '-', (76, 83))	('A4', 'Chemical', '-', (113, 115))	('11OH-A4', 'Var', (76, 83))
63415	27706226	This result suggests that the observed effects in the presence of NoMAC and DRSP on steroid biosynthesis are due to the progestins themselves, while the effects observed for NES may be attibuted to NES itself and/or its metabolites.	('DRSP', 'Chemical', 'MESH:C035144', (76, 80))	('NES', 'Chemical', 'MESH:C029167', (198, 201))	('NES', 'Chemical', 'MESH:C029167', (174, 177))	('DRSP', 'Var', (76, 80))	('NoMAC', 'Chemical', 'MESH:C038501', (66, 71))	('effects', 'Reg', (39, 46))	('steroid biosynthesis', 'MPA', (84, 104))	('steroid', 'Chemical', 'MESH:D013256', (84, 91))
63433	27706226	Despite our observation that NES, NoMAC and DRSP inhibit the activity of 3betaHSD2, and that DRSP also inhibits the activity of CYP17A1, it is possible that the modulation of steroidogenesis seen in H295R cells could also be due to the progestins altering the expression levels of these enzymes.	('expression', 'MPA', (260, 270))	('NES', 'Chemical', 'MESH:C029167', (29, 32))	('DRSP', 'Var', (93, 97))	('DRSP', 'Chemical', 'MESH:C035144', (93, 97))	('NoMAC', 'Chemical', 'MESH:C038501', (34, 39))	('3betaHSD2', 'Enzyme', (73, 82))	('inhibits', 'NegReg', (103, 111))	('steroid', 'Chemical', 'MESH:D013256', (175, 182))	('DRSP', 'Chemical', 'MESH:C035144', (44, 48))	('CYP17A1', 'Enzyme', (128, 135))	('H295R', 'CellLine', 'CVCL:0458', (199, 204))	('activity', 'MPA', (116, 124))	('steroidogenesis', 'MPA', (175, 190))	('activity', 'MPA', (61, 69))	('expression', 'Species', '29278', (260, 270))	('inhibit', 'NegReg', (49, 56))
63447	27706226	To understand the mechanism whereby the fourth-generation progestins modulate adrenal steroid biosynthesis, we investigated the effects of the progestins on the activity and/or expression of 3betaHSD2, CYP17A1 and CYP21A2.	('CYP17A1', 'Var', (202, 209))	('rat', 'Species', '10116', (51, 54))	('steroid', 'Chemical', 'MESH:D013256', (86, 93))	('adrenal steroid biosynthesis', 'MPA', (78, 106))	('CYP21A2', 'Gene', '1589', (214, 221))	('expression', 'Species', '29278', (177, 187))	('modulate', 'Reg', (69, 77))	('CYP21A2', 'Gene', (214, 221))
63448	27706226	3betaHSD2 was investigated as NES and NoMAC tended to increase the concentrations of the Delta5 C21 steroid Preg (Tables 1 and 2) and the Delta5 C19 steroid DHEA (Table 1), while the production of several Delta4 C21 (Prog, 17OH-Prog, 16OH-Prog, DOC, CORT, deoxycortisol and cortisol) and Delta4 C19 (A4, 11OH-A4 and testosterone) steroids were decreased.	('NES', 'Chemical', 'MESH:C029167', (30, 33))	('Prog', 'Chemical', 'MESH:D011374', (228, 232))	('DOC', 'Chemical', 'MESH:D003900', (245, 248))	('increase', 'PosReg', (54, 62))	('CORT', 'Gene', (250, 254))	('16OH', 'Chemical', '-', (234, 238))	('DHEA', 'Chemical', 'MESH:D003687', (157, 161))	('decreased', 'NegReg', (344, 353))	('CORT', 'Gene', '1325', (250, 254))	('production', 'MPA', (183, 193))	('Delta4 C21', 'MPA', (205, 215))	('deoxycortisol', 'Chemical', 'MESH:D003350', (256, 269))	('A4', 'Chemical', '-', (300, 302))	('A4', 'Chemical', '-', (309, 311))	('steroid', 'Chemical', 'MESH:D013256', (149, 156))	('cortisol', 'Chemical', 'MESH:D006854', (261, 269))	('Prog', 'Chemical', 'MESH:D011374', (217, 221))	('NoMAC', 'Chemical', 'MESH:C038501', (38, 43))	('11OH-A4', 'Chemical', '-', (304, 311))	('steroids', 'Chemical', 'MESH:D013256', (330, 338))	('steroid', 'Chemical', 'MESH:D013256', (100, 107))	('Prog', 'Chemical', 'MESH:D011374', (239, 243))	('steroid', 'Chemical', 'MESH:D013256', (330, 337))	('cortisol', 'Chemical', 'MESH:D006854', (274, 282))	('rat', 'Species', '10116', (74, 77))	('concentrations', 'MPA', (67, 81))	('3betaHSD2', 'Var', (0, 9))	('testosterone', 'Chemical', 'MESH:D013739', (316, 328))	('17OH-Prog', 'Chemical', 'MESH:D019326', (223, 232))
63449	27706226	DRSP also increased the production of Preg and decreased the production of A4, 11OH-A4 and testosterone (Delta4 C19 steroids), while differentially affecting the production of Delta4 C21 steroids, suggesting inhibition of additional steroidogenic enzymes.	('Delta4 C21 steroids', 'MPA', (176, 195))	('production', 'MPA', (24, 34))	('affecting', 'Reg', (148, 157))	('A4', 'Chemical', '-', (84, 86))	('DRSP', 'Chemical', 'MESH:C035144', (0, 4))	('increased', 'PosReg', (10, 19))	('DRSP', 'Var', (0, 4))	('decreased', 'NegReg', (47, 56))	('production', 'MPA', (61, 71))	('steroids', 'Chemical', 'MESH:D013256', (187, 195))	('production', 'MPA', (162, 172))	('steroid', 'Chemical', 'MESH:D013256', (187, 194))	('A4', 'Chemical', '-', (75, 77))	('testosterone', 'MPA', (91, 103))	('Preg', 'MPA', (38, 42))	('steroids', 'Chemical', 'MESH:D013256', (116, 124))	('steroid', 'Chemical', 'MESH:D013256', (116, 123))	('steroid', 'Chemical', 'MESH:D013256', (233, 240))	('11OH-A4', 'Chemical', '-', (79, 86))	('11OH-A4', 'MPA', (79, 86))	('testosterone', 'Chemical', 'MESH:D013739', (91, 103))
63450	27706226	Moreover, as progestins were designed to mimic Prog, and considering that Prog is a substrate for both CYP17A1 and CYP21A2, the possibility that progestins modulate the activities and/or expression of these enzymes could not be excluded.	('CYP17A1', 'Var', (103, 110))	('Prog', 'Chemical', 'MESH:D011374', (74, 78))	('CYP21A2', 'Gene', (115, 122))	('Prog', 'Chemical', 'MESH:D011374', (47, 51))	('CYP21A2', 'Gene', '1589', (115, 122))	('expression', 'Species', '29278', (187, 197))	('rat', 'Species', '10116', (89, 92))
63451	27706226	In COS-1 cells transfected to constitutively express human 3betaHSD2 (Fig 5A), CYP17A1 (Fig 5B) and CYP21A2 (Fig 5C and 5D), respectively, we show that NES and NoMAC had no effect on the activity of CYP17A1 or CYP21A2, but that these progestins significantly inhibited the activity of 3betaHSD2.	('CYP21A2', 'Gene', '1589', (210, 217))	('CYP21A2', 'Gene', (100, 107))	('CYP17A1', 'Var', (79, 86))	('CYP21A2', 'Gene', '1589', (100, 107))	('CYP21A2', 'Gene', (210, 217))	('activity', 'MPA', (187, 195))	('COS-1', 'CellLine', 'CVCL:0223', (3, 8))	('activity', 'MPA', (273, 281))	('human', 'Species', '9606', (53, 58))	('NES', 'Chemical', 'MESH:C029167', (152, 155))	('inhibited', 'NegReg', (259, 268))	('NoMAC', 'Chemical', 'MESH:C038501', (160, 165))
63452	27706226	DRSP also had no effect on the activity of CYP21A2 (Fig 5C and 5D), but inhibited the activities of both 3betaHSD2 (Fig 5A) and CYP17A1 (Fig 5B).	('activity', 'MPA', (31, 39))	('3betaHSD2', 'Enzyme', (105, 114))	('activities', 'MPA', (86, 96))	('CYP17A1', 'Enzyme', (128, 135))	('DRSP', 'Var', (0, 4))	('CYP21A2', 'Gene', '1589', (43, 50))	('inhibited', 'NegReg', (72, 81))	('DRSP', 'Chemical', 'MESH:C035144', (0, 4))	('CYP21A2', 'Gene', (43, 50))
63453	27706226	The inhibition of 3betaHSD2 in COS-1 cells by DRSP correlates with the observed increase in the concentration of Preg and decrease in the concentrations of the Delta4 C19 steroids observed in the H295R cells, while the accumulation of Prog, 16OH-Prog and 17OH-Prog in the H295R cells is likely due to a bottleneck caused by the simultaneous inhibition of 3betaHSD2 and CYP17A1.	('concentrations', 'MPA', (138, 152))	('Prog', 'Chemical', 'MESH:D011374', (235, 239))	('increase', 'PosReg', (80, 88))	('H295R', 'CellLine', 'CVCL:0458', (272, 277))	('Prog', 'Chemical', 'MESH:D011374', (260, 264))	('rat', 'Species', '10116', (103, 106))	('COS-1', 'CellLine', 'CVCL:0223', (31, 36))	('16OH', 'Chemical', '-', (241, 245))	('16OH-Prog', 'Var', (241, 250))	('concentration', 'MPA', (96, 109))	('decrease', 'NegReg', (122, 130))	('DRSP', 'Gene', (46, 50))	('DRSP', 'Chemical', 'MESH:C035144', (46, 50))	('inhibition', 'NegReg', (4, 14))	('rat', 'Species', '10116', (145, 148))	('steroids', 'Chemical', 'MESH:D013256', (171, 179))	('Prog', 'Chemical', 'MESH:D011374', (246, 250))	('17OH-Prog', 'Var', (255, 264))	('H295R', 'CellLine', 'CVCL:0458', (196, 201))	('17OH-Prog', 'Chemical', 'MESH:D019326', (255, 264))
63475	27706226	Our study in the COS-1 cells directly investigating the inhibition of CYP17A1, showed that DRSP does indeed inhibit the activty of this enzyme, and also the activity of 3betaHSD2.	('activty', 'MPA', (120, 127))	('activity', 'MPA', (157, 165))	('COS-1', 'CellLine', 'CVCL:0223', (17, 22))	('DRSP', 'Chemical', 'MESH:C035144', (91, 95))	('3betaHSD2', 'Enzyme', (169, 178))	('DRSP', 'Var', (91, 95))	('inhibit', 'NegReg', (108, 115))
63534	24803525	The activating TERT promoter mutation C228T is recurrent in subsets of adrenal tumors The telomerase reverse transcriptase gene (TERT) encodes the reverse transcriptase component of the telomerase complex, which is essential for telomere stabilization and cell immortalization.	('TERT', 'Gene', '7015', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('TERT', 'Gene', '7015', (129, 133))	('adrenal tumors', 'Disease', 'MESH:D000310', (71, 85))	('adrenal tumors', 'Disease', (71, 85))	('activating', 'PosReg', (4, 14))	('C228T', 'Mutation', 'rs764229038', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('C228T', 'Var', (38, 43))	('TERT', 'Gene', (129, 133))	('TERT', 'Gene', (15, 19))
63535	24803525	Recent studies have demonstrated a transcriptional activation role for the TERT promoter mutations C228T and C250T in many human cancers, as well as a role in aggressive disease with potential clinical applications.	('aggressive disease', 'Disease', (159, 177))	('C250T', 'Var', (109, 114))	('transcriptional', 'MPA', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('C250T', 'Mutation', 'c.250C>T', (109, 114))	('TERT', 'Gene', (75, 79))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('human', 'Species', '9606', (123, 128))	('TERT', 'Gene', '7015', (75, 79))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('activation', 'PosReg', (51, 61))	('cancers', 'Disease', (129, 136))	('aggressive disease', 'Disease', 'MESH:D001523', (159, 177))	('C228T', 'Var', (99, 104))	('C228T', 'Mutation', 'rs764229038', (99, 104))
63537	24803525	We assessed C228T and C250T TERT mutations by direct Sanger sequencing in tumors of the adrenal gland, and further evaluated potential associations with clinical parameters and telomerase activation.	('C250T', 'Var', (22, 27))	('tumors of the adrenal gland', 'Disease', 'MESH:D000310', (74, 101))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TERT', 'Gene', (28, 32))	('tumors of the adrenal gland', 'Phenotype', 'HP:0100631', (74, 101))	('C250T', 'SUBSTITUTION', 'None', (22, 27))	('C228T', 'Var', (12, 17))	('C228T', 'Mutation', 'rs764229038', (12, 17))	('tumors of the adrenal gland', 'Disease', (74, 101))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
63540	24803525	The C228T mutation was detected in 4/34 ACCs (12%), but not in any ACA (P=0.028).	('ACC', 'Phenotype', 'HP:0006744', (40, 43))	('ACCs', 'Gene', '84680', (40, 44))	('ACCs', 'Gene', (40, 44))	('ACA', 'Phenotype', 'HP:0008256', (67, 70))	('C228T', 'Var', (4, 9))	('C228T', 'Mutation', 'rs764229038', (4, 9))
63541	24803525	C228T was also observed in one benign PCC and in one metastatic PGL.	('observed', 'Reg', (15, 23))	('PGL', 'Phenotype', 'HP:0002668', (64, 67))	('C228T', 'Var', (0, 5))	('PCC', 'Phenotype', 'HP:0002666', (38, 41))	('C228T', 'Mutation', 'rs764229038', (0, 5))
63544	24803525	To conclude, the TERT promoter mutation C228T is a recurrent event associated with TERT expression in ACCs, but rarely occurs in PGL and PCC.	('ACCs', 'Gene', '84680', (102, 106))	('PGL', 'Phenotype', 'HP:0002668', (129, 132))	('TERT', 'Gene', (17, 21))	('TERT', 'Gene', '7015', (17, 21))	('ACC', 'Phenotype', 'HP:0006744', (102, 105))	('C228T', 'Var', (40, 45))	('TERT', 'Gene', (83, 87))	('C228T', 'Mutation', 'rs764229038', (40, 45))	('TERT', 'Gene', '7015', (83, 87))	('PCC', 'Phenotype', 'HP:0002666', (137, 140))	('ACCs', 'Gene', (102, 106))
63551	24803525	Recently, TERT promoter mutations have been reported in human malignancies, which create de novo ETS1-binding motifs stimulating the TERT transcription.	('TERT', 'Gene', (133, 137))	('TERT', 'Gene', '7015', (133, 137))	('TERT', 'Gene', (10, 14))	('human', 'Species', '9606', (56, 61))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('stimulating', 'PosReg', (117, 128))	('TERT', 'Gene', '7015', (10, 14))	('mutations', 'Var', (24, 33))	('malignancies', 'Disease', (62, 74))
63552	24803525	The two recurrent mutations C228T and C250T (Fig.	('C228T', 'Mutation', 'rs764229038', (28, 33))	('C250T', 'Var', (38, 43))	('C250T', 'Mutation', 'c.250C>T', (38, 43))	('C228T', 'Var', (28, 33))
63559	24803525	However, it is currently unclear whether this upregulation is coupled to TERT promoter mutations.	('TERT', 'Gene', (73, 77))	('TERT', 'Gene', '7015', (73, 77))	('mutations', 'Var', (87, 96))
63575	24803525	The TERT promoter region was sequenced for detection of the two mutations C228T and C250T using previously applied methodology.	('TERT', 'Gene', (4, 8))	('C228T', 'Var', (74, 79))	('C228T', 'Mutation', 'rs764229038', (74, 79))	('TERT', 'Gene', '7015', (4, 8))	('C250T', 'Var', (84, 89))	('C250T', 'Mutation', 'c.250C>T', (84, 89))
63585	24803525	We screened a total of 199 tumors for the activating TERT promoter mutations C228T and C250T by Sanger-based technology (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('activating', 'PosReg', (42, 52))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('C250T', 'Var', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('C250T', 'Mutation', 'c.250C>T', (87, 92))	('C228T', 'Var', (77, 82))	('C228T', 'Mutation', 'rs764229038', (77, 82))
63586	24803525	There were a total of six TERT promoter mutations identified in our cohort (Supplementary Tables S1 and S2).	('mutations', 'Var', (40, 49))	('TERT', 'Gene', (26, 30))	('TERT', 'Gene', '7015', (26, 30))
63590	24803525	Given that the TERT promoter mutation stimulates TERT transcription, we quantified TERT mRNA expression in a total of 27 ACCs, 63 PCCs, and 12 PGLs from Series A.	('TERT', 'Gene', '7015', (15, 19))	('mutation', 'Var', (29, 37))	('ACC', 'Phenotype', 'HP:0006744', (121, 124))	('PGL', 'Phenotype', 'HP:0002668', (143, 146))	('ACCs', 'Gene', (121, 125))	('stimulates', 'PosReg', (38, 48))	('ACCs', 'Gene', '84680', (121, 125))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', (83, 87))	('TERT', 'Gene', '7015', (49, 53))	('TERT', 'Gene', '7015', (83, 87))	('PCC', 'Phenotype', 'HP:0002666', (130, 133))	('TERT', 'Gene', (15, 19))
63596	24803525	Mutation of the succinate dehydrogenase B gene (SDHB) is a frequent genetic event in PGL, especially in malignant PGL.	('malignant PGL', 'Disease', (104, 117))	('PGL', 'Phenotype', 'HP:0002668', (85, 88))	('Mutation', 'Var', (0, 8))	('PGL', 'Disease', (85, 88))	('PGL', 'Phenotype', 'HP:0002668', (114, 117))	('SDHB', 'Gene', '6390', (48, 52))	('SDHB', 'Gene', (48, 52))
63597	24803525	We therefore compared the C228T mutation status with the occurrence of SDHB mutations in the PGL group.	('mutations', 'Var', (76, 85))	('SDHB', 'Gene', '6390', (71, 75))	('SDHB', 'Gene', (71, 75))	('C228T', 'Var', (26, 31))	('PGL', 'Phenotype', 'HP:0002668', (93, 96))	('C228T', 'Mutation', 'rs764229038', (26, 31))
63598	24803525	The C228T-positive tumor and three additional PGLs carried a SDHB mutation, while nine cases were WT for both gene mutations; however, the limited number of cases does not allow for associations between gene mutations in the PGL entity.	('C228T-positive', 'Var', (4, 18))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('SDHB', 'Gene', '6390', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('SDHB', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))	('tumor', 'Disease', (19, 24))	('PGL', 'Phenotype', 'HP:0002668', (46, 49))	('C228T', 'Mutation', 'rs764229038', (4, 9))	('PGL', 'Phenotype', 'HP:0002668', (225, 228))
63600	24803525	However, no significant difference was observed between C228T mutated and WT ACCs, concerning gender, age at diagnosis, overall histology, tumor size, presence of metastasis, or hormonal function.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('C228T', 'Mutation', 'rs764229038', (56, 61))	('ACC', 'Phenotype', 'HP:0006744', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('ACCs', 'Gene', (77, 81))	('ACCs', 'Gene', '84680', (77, 81))	('C228T mutated', 'Var', (56, 69))
63602	24803525	Survival analysis did not reveal a statistically significant difference between the four C228T mutated ACCs and the 30 WT cases (Log Rank=0.191).	('ACC', 'Phenotype', 'HP:0006744', (103, 106))	('ACCs', 'Gene', (103, 107))	('ACCs', 'Gene', '84680', (103, 107))	('C228T mutated', 'Var', (89, 102))	('C228T', 'Mutation', 'rs764229038', (89, 94))
63603	24803525	The PGL patient with a C228T mutated tumor died of the disease after 24 months, while the mutated PCC case was diagnosed as benign but lost to follow-up.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('C228T mutated', 'Var', (23, 36))	('PGL', 'Phenotype', 'HP:0002668', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('PCC', 'Phenotype', 'HP:0002666', (98, 101))	('C228T', 'Mutation', 'rs764229038', (23, 28))	('patient', 'Species', '9606', (8, 15))
63605	24803525	In this study, we show for the first time that subsets of adrenocortical and chromaffin cell tumors carry TERT promoter mutations, thereby proving a genetic event possibly associated with the upregulation of TERT gene expression in these tumor entities.	('TERT', 'Gene', (208, 212))	('adrenocortical', 'Disease', (58, 72))	('TERT', 'Gene', '7015', (208, 212))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('TERT', 'Gene', (106, 110))	('adrenocortical', 'Disease', 'MESH:D018268', (58, 72))	('TERT', 'Gene', '7015', (106, 110))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (238, 243))	('mutations', 'Var', (120, 129))	('tumors', 'Disease', (93, 99))	('chromaffin cell tumors', 'Phenotype', 'HP:0002666', (77, 99))	('chromaffin', 'Chemical', '-', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
63606	24803525	ACC is a highly heterogeneous tumor type, strongly coupled to dysregulation of the IGF2 locus, as well as Wnt- and p53-related pathways.	('IGF2', 'Gene', (83, 87))	('coupled', 'Reg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('dysregulation', 'Var', (62, 75))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('IGF2', 'Gene', '3481', (83, 87))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('tumor', 'Disease', (30, 35))	('ACC', 'Disease', (0, 3))
63608	24803525	In addition, TP53 and CTNNB1 mutations are often seen in this tumor type and are functionally linked to tumor progression.	('CTNNB1', 'Gene', (22, 28))	('TP53', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('linked to', 'Reg', (94, 103))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (62, 67))	('CTNNB1', 'Gene', '1499', (22, 28))	('TP53', 'Gene', '7157', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
63610	24803525	In this study, we establish that the TERT promoter mutation C228T is a recurrent event for this tumor entity, with a frequency of 12% in this cohort.	('TERT', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TERT', 'Gene', '7015', (37, 41))	('tumor', 'Disease', (96, 101))	('C228T', 'Var', (60, 65))	('C228T', 'Mutation', 'rs764229038', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
63611	24803525	Moreover, we observed a statistically significant difference between ACCs and ACAs with regards to the C228T mutation (P=0.028).	('ACC', 'Phenotype', 'HP:0006744', (69, 72))	('C228T', 'Var', (103, 108))	('ACCs', 'Gene', (69, 73))	('C228T', 'Mutation', 'rs764229038', (103, 108))	('ACA', 'Phenotype', 'HP:0008256', (78, 81))	('ACCs', 'Gene', '84680', (69, 73))
63612	24803525	ACCs with the C228T mutation showed TERT mRNA expression, demonstrating that the TERT mutation leads to telomerase activation in ACC.	('ACCs', 'Gene', (0, 4))	('C228T', 'Mutation', 'rs764229038', (14, 19))	('activation', 'PosReg', (115, 125))	('ACCs', 'Gene', '84680', (0, 4))	('TERT', 'Gene', '7015', (36, 40))	('telomerase', 'MPA', (104, 114))	('TERT', 'Gene', (81, 85))	('TERT', 'Gene', '7015', (81, 85))	('ACC', 'Phenotype', 'HP:0006744', (129, 132))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('TERT', 'Gene', (36, 40))	('C228T', 'Var', (14, 19))
63615	24803525	This would in theory make clinical screening for the TERT promoter mutation C228T a promising tool to point out malignant cases, even though the sensitivity is poor.	('C228T', 'Mutation', 'rs764229038', (76, 81))	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('C228T', 'Var', (76, 81))
63616	24803525	However, in our cohort, three out of four ACCs with the C228T mutation were endowed with distant metastases or recurrent disease either at diagnosis or at post-surgical follow-up.	('recurrent disease', 'CPA', (111, 128))	('C228T', 'Var', (56, 61))	('metastases', 'Disease', (97, 107))	('ACCs', 'Gene', (42, 46))	('C228T', 'Mutation', 'rs764229038', (56, 61))	('ACCs', 'Gene', '84680', (42, 46))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('ACC', 'Phenotype', 'HP:0006744', (42, 45))
63619	24803525	The TERT promoter mutation was found to be a rare event in PCC observed in only 1/105 cases analyzed, which is in agreement with who reported lack of TERT promoter mutations in 17 cases analyzed.	('TERT', 'Gene', (150, 154))	('TERT', 'Gene', (4, 8))	('TERT', 'Gene', '7015', (150, 154))	('TERT', 'Gene', '7015', (4, 8))	('mutation', 'Var', (18, 26))	('PCC', 'Disease', (59, 62))	('PCC', 'Phenotype', 'HP:0002666', (59, 62))
63621	24803525	TERT gene expression was evident in 25% of adrenomedullary tumors assayed (15 PCCs and three PGLs), including the single PGL with a C228T mutation.	('evident', 'Reg', (25, 32))	('adrenomedullary tumors', 'Disease', (43, 65))	('C228T', 'Var', (132, 137))	('TERT', 'Gene', (0, 4))	('C228T', 'Mutation', 'rs764229038', (132, 137))	('TERT', 'Gene', '7015', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('PCC', 'Phenotype', 'HP:0002666', (78, 81))	('PGL', 'Phenotype', 'HP:0002668', (93, 96))	('PGL', 'Phenotype', 'HP:0002668', (121, 124))	('adrenomedullary tumors', 'Phenotype', 'HP:0100642', (43, 65))	('adrenomedullary tumors', 'Disease', 'MESH:D009369', (43, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
63622	24803525	Given the low burden of TERT promoter mutations in adrenomedullary tumors, the detected expression in subsets of PCCs/PGLs with WT sequences suggests that alternate genetic mechanisms are responsible for the observed upregulation of TERT mRNA in these cases.	('adrenomedullary tumors', 'Phenotype', 'HP:0100642', (51, 73))	('TERT', 'Gene', (24, 28))	('TERT', 'Gene', (233, 237))	('PCC', 'Phenotype', 'HP:0002666', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('TERT', 'Gene', '7015', (233, 237))	('adrenomedullary tumors', 'Disease', 'MESH:D009369', (51, 73))	('TERT', 'Gene', '7015', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (38, 47))	('PGL', 'Phenotype', 'HP:0002668', (118, 121))	('upregulation', 'PosReg', (217, 229))	('adrenomedullary tumors', 'Disease', (51, 73))
63623	24803525	It is particularly interesting to note that TERT promoter mutations occur in different types of malignant endocrine tumors, and seem to aggregate in aggressive forms.	('TERT', 'Gene', (44, 48))	('mutations', 'Var', (58, 67))	('TERT', 'Gene', '7015', (44, 48))	('occur', 'Reg', (68, 73))	('malignant endocrine tumors', 'Disease', 'MESH:D018198', (96, 122))	('malignant endocrine tumors', 'Disease', (96, 122))	('aggregate', 'Reg', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
63625	24803525	The finding of specific TERT promoter mutations in subsets of endocrine cancers could suggest that these tumors share a common molecular denominator regarding the acquisition of cellular immortality.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('endocrine cancers', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('TERT', 'Gene', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('TERT', 'Gene', '7015', (24, 28))	('mutations', 'Var', (38, 47))	('endocrine cancers', 'Disease', 'MESH:D004701', (62, 79))
63628	24803525	To conclude, TERT promoter mutations are predominantly found in the subgroups of malignant endocrine tumors, such as malignant PGL and adrenocortical cancer, and the observation of C228T mutations in 12% of ACCs adds a new cornerstone to the mutational panorama of these tumors.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('tumors', 'Disease', (271, 277))	('PGL', 'Phenotype', 'HP:0002668', (127, 130))	('ACCs', 'Gene', (207, 211))	('ACCs', 'Gene', '84680', (207, 211))	('adrenocortical cancer', 'Disease', (135, 156))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('ACC', 'Phenotype', 'HP:0006744', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('C228T', 'Mutation', 'rs764229038', (181, 186))	('malignant endocrine tumors', 'Disease', (81, 107))	('malignant endocrine tumors', 'Disease', 'MESH:D018198', (81, 107))	('tumors', 'Disease', (101, 107))	('found', 'Reg', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (135, 156))	('malignant PGL', 'Disease', (117, 130))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('C228T', 'Var', (181, 186))
63629	24803525	The C228T mutations seem to exhibit low sensitivity in conjunction with high specificity toward biologically aggressive disease; the latter providing a promising platform for further studies assessing TERT promoter mutations as a potential malignancy marker in equivocal cases with unknown malignant potential.	('aggressive disease', 'Disease', 'MESH:D001523', (109, 127))	('malignancy', 'Disease', 'MESH:D009369', (240, 250))	('aggressive disease', 'Disease', (109, 127))	('malignancy', 'Disease', (240, 250))	('TERT', 'Gene', (201, 205))	('C228T', 'Var', (4, 9))	('C228T', 'Mutation', 'rs764229038', (4, 9))	('TERT', 'Gene', '7015', (201, 205))
63633	24803525	Future studies of patients in which long-term data is available will possibly reveal if TERT promoter mutations influence survival and if histologically benign PCC with mutation demand more extensive follow-up.	('survival', 'CPA', (122, 130))	('PCC', 'Disease', (160, 163))	('TERT', 'Gene', '7015', (88, 92))	('influence', 'Reg', (112, 121))	('PCC', 'Phenotype', 'HP:0002666', (160, 163))	('mutations', 'Var', (102, 111))	('patients', 'Species', '9606', (18, 26))	('TERT', 'Gene', (88, 92))
63775	22355500	Genetic testing was pursued to rule out known hereditary conditions that could potentially cause the combination of ACC and PTC, specifically LFS and MEN I. Gene mutation analysis revealed a wild-type p53 gene.	('PTC', 'Gene', '5979', (124, 127))	('MEN', 'Gene', '4221', (150, 153))	('PTC', 'Phenotype', 'HP:0002895', (124, 127))	('p53', 'Gene', (201, 204))	('MEN', 'Gene', (150, 153))	('p53', 'Gene', '7157', (201, 204))	('ACC', 'Phenotype', 'HP:0006744', (116, 119))	('LFS', 'Disease', (142, 145))	('PTC', 'Gene', (124, 127))	('mutation analysis', 'Var', (162, 179))	('LFS', 'Disease', 'MESH:D016864', (142, 145))
63951	30693607	The imaging term "macroscopic fat" should be applied when a tumor shows one or more of the following: 1) intratumoral signal intensity loss before and after application of FS, or 2) linear or curvilinear chemical shift artifact of the second kind causing India-ink (etching) artifact within or at the periphery of the mass at macroscopic fat-water interfaces while the central area remains hyperintense (ie, following the signal intensity of subcutaneous and intraabdominal fat).	('causing', 'Reg', (247, 254))	('fat', 'Gene', (30, 33))	('fat', 'Gene', '2195', (30, 33))	('loss', 'NegReg', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('intraabdominal fat', 'Phenotype', 'HP:0008993', (459, 477))	('artifact', 'Var', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('fat', 'Gene', (474, 477))	('fat', 'Gene', (338, 341))	('tumor', 'Disease', (60, 65))	('fat', 'Gene', '2195', (474, 477))	('fat', 'Gene', '2195', (338, 341))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
63957	30693607	Notably, the central area of macroscopic fat surrounded by the chemical shift artifact should remain hyperintense on both IP and OP images, matching the signal of macroscopic fat elsewhere in the abdomen.	('chemical shift', 'Gene', (63, 77))	('artifact', 'Var', (78, 86))	('fat', 'Gene', (41, 44))	('fat', 'Gene', (175, 178))	('fat', 'Gene', '2195', (41, 44))	('fat', 'Gene', '2195', (175, 178))
63960	30693607	To our knowledge, the sensitivity of detecting macroscopic fat has not been formally compared between FS techniques and chemical shift MRI; however, when areas of intratumoral fat are small (<1 cm), chemical shift MRI may outperform unenhanced computed tomography (CT) for the detection of macroscopic fat in small AMLs.	('outperform', 'PosReg', (222, 232))	('fat', 'Gene', '2195', (176, 179))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('fat', 'Gene', (59, 62))	('AML', 'Disease', (315, 318))	('chemical shift MRI', 'Var', (199, 217))	('fat', 'Gene', '2195', (59, 62))	('fat', 'Gene', '2195', (302, 305))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('fat', 'Gene', (302, 305))	('AML', 'Disease', 'MESH:D018207', (315, 318))	('fat', 'Gene', (176, 179))
64002	30693607	Detection of microscopic fat within an adrenal mass is typical for adenoma.	('adenoma', 'Disease', (67, 74))	('microscopic', 'Var', (13, 24))	('fat', 'Gene', (25, 28))	('Detection', 'Reg', (0, 9))	('adenoma', 'Disease', 'MESH:D000236', (67, 74))	('fat', 'Gene', '2195', (25, 28))
64036	30693607	Macroscopic fat is one or more of the following: 1) intratumoral signal loss using fat-suppression techniques, or 2) chemical shift artifact of the second kind causing linear or curvilinear India-ink (etching) artifact within or at the periphery of the mass at macroscopic fat-water interfaces.	('fat', 'Gene', (273, 276))	('loss', 'NegReg', (72, 76))	('fat', 'Gene', '2195', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('fat', 'Gene', '2195', (83, 86))	('fat', 'Gene', '2195', (273, 276))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('causing', 'Reg', (160, 167))	('fat', 'Gene', (83, 86))	('curvilinear India', 'Phenotype', 'HP:0003205', (178, 195))	('tumor', 'Disease', (57, 62))	('artifact', 'Var', (132, 140))	('chemical shift artifact', 'Var', (117, 140))	('fat', 'Gene', (12, 15))
64135	31500637	had actually identified Drosophila melted three years previously, in 1997, in a genetic screen of P-element insertions within chromosome 3 that affected peripheral nervous system (PNS) development.	('thr', 'Chemical', 'MESH:D013912', (42, 45))	('Drosophila', 'Species', '7227', (24, 34))	('affected', 'Reg', (144, 152))	('insertions', 'Var', (108, 118))	('ser', 'Chemical', 'MESH:D012694', (110, 113))
64137	31500637	Deletion of melted resulted in a 30% reduction in flies reaching maturity, an approximate 10% lower body weight, and a 25 and 40% reduction in fat body and total body triglycerides, respectively.	('melted', 'Gene', (12, 18))	('reduction', 'NegReg', (37, 46))	('fat body', 'Phenotype', 'HP:0001513', (143, 151))	('body weight', 'CPA', (100, 111))	('reduction', 'NegReg', (130, 139))	('total body triglycerides', 'MPA', (156, 180))	('lower', 'NegReg', (94, 99))	('triglycerides', 'Chemical', 'MESH:D014280', (167, 180))	('lower body weight', 'Phenotype', 'HP:0004325', (94, 111))	('fat body', 'MPA', (143, 151))	('Deletion', 'Var', (0, 8))
64139	31500637	Knockdown of Veph1 protein expression in zebrafish embryos using targeting morpholino antisense RNA resulted in impaired midbrain and hindbrain development, as well as a curved spine, impaired ear development, pericardial edema, and disordered lateral strip pigmentation, indicating that Veph1 is required for the normal development of multiple tissues.	('antisense', 'Var', (86, 95))	('curved spine', 'Phenotype', 'HP:0002650', (170, 182))	('impaired', 'NegReg', (184, 192))	('impaired midbrain', 'Phenotype', 'HP:0002418', (112, 129))	('zebrafish', 'Species', '7955', (41, 50))	('disordered lateral strip pigmentation', 'Disease', (233, 270))	('pericardial edema', 'Disease', (210, 227))	('impaired midbrain', 'Disease', (112, 129))	('ear development', 'CPA', (193, 208))	('edema', 'Phenotype', 'HP:0000969', (222, 227))	('disordered lateral strip pigmentation', 'Disease', 'MESH:D010859', (233, 270))	('Veph1', 'Gene', (13, 18))	('pericardial edema', 'Disease', 'MESH:D004487', (210, 227))	('protein', 'Protein', (19, 26))	('pericardial edema', 'Phenotype', 'HP:0001698', (210, 227))	('impaired midbrain', 'Disease', 'MESH:D020295', (112, 129))
64142	31500637	Despite this, and the pronounced phenotypes in model organisms, targeted disruption of Veph1 in mice was not associated with an overt phenotype; however, an extensive investigation has not been reported.	('mice', 'Species', '10090', (96, 100))	('targeted disruption', 'Var', (64, 83))	('Veph1', 'Gene', (87, 92))
64145	31500637	Consistent with the complexity of the locus, several transcript variants resulting from alternate RNA splicing have been reported for human VEPH1 (Fig.	('VEPH1', 'Gene', (140, 145))	('human', 'Species', '9606', (134, 139))	('alternate RNA splicing', 'Var', (88, 110))
64163	31500637	Examples of interacting kinases identified by the eukaryotic linear motif prediction tool with high conservation score include GSK3, casein kinase 1 (CK1), LATS, Nim-A related kinase 2 (NEK1), polo-like kinases (PLK), protein kinase A (PKA), and p38 MAPK (Fig.	('ser', 'Chemical', 'MESH:D012694', (103, 106))	('p38', 'Var', (246, 249))	('LATS', 'Gene', '43651', (156, 160))	('PLK', 'Gene', (212, 215))	('LATS', 'Gene', (156, 160))	('casein kinase', 'Gene', (133, 146))	('GSK3', 'Gene', (127, 131))	('NEK1', 'Gene', '4750', (186, 190))	('PLK', 'Gene', '5347', (212, 215))	('CK1', 'Species', '2498238', (150, 153))	('casein kinase', 'Gene', '149420', (133, 146))	('NEK1', 'Gene', (186, 190))
64177	31500637	Consistent with this prediction, expression of VEPH1 in SKOV3 ovarian cancer cells is associated with decreased levels of AKT.	('expression', 'Var', (33, 43))	('VEPH1', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SKOV3 ovarian cancer', 'Disease', (56, 76))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('AKT', 'Gene', '207', (122, 125))	('SKOV3 ovarian cancer', 'Disease', 'MESH:D010051', (56, 76))	('decreased', 'NegReg', (102, 111))	('AKT', 'Gene', (122, 125))
64193	31500637	Consistent with the impact of Drosophila melted on signaling pathways, expression of VEPH1 cDNA in ovarian cancer SKOV3 cells was shown to affect FoxO, mTOR, and YAP/TAZ signaling networks by pathway analysis of differentially expressed genes identified by microarray-based gene expression profiling.	('YAP', 'Gene', '10413', (162, 165))	('ovarian cancer', 'Phenotype', 'HP:0100615', (99, 113))	('ovarian cancer', 'Disease', 'MESH:D010051', (99, 113))	('affect', 'Reg', (139, 145))	('VEPH1 cDNA', 'Gene', (85, 95))	('cDNA', 'Gene', (91, 95))	('FoxO', 'Gene', (146, 150))	('expression', 'Var', (71, 81))	('mTOR', 'Gene', (152, 156))	('mTOR', 'Gene', '2475', (152, 156))	('Drosophila', 'Species', '7227', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('YAP', 'Gene', (162, 165))	('ovarian cancer', 'Disease', (99, 113))	('FoxO', 'Gene', '41709', (146, 150))	('SKOV3', 'CellLine', 'CVCL:0532', (114, 119))
64201	31500637	While VEPH1 expression did not affect SMAD2 phosphorylation levels, it resulted in decreased TGFbeta-induced phosphorylation of SMAD3 and total SMAD3 levels.	('SMAD3', 'Gene', '4088', (144, 149))	('SMAD2', 'Gene', (38, 43))	('SMAD2', 'Gene', '4087', (38, 43))	('expression', 'Var', (12, 22))	('decreased', 'NegReg', (83, 92))	('SMAD3', 'Gene', (144, 149))	('TGFbeta-induced phosphorylation', 'MPA', (93, 124))	('VEPH1', 'Gene', (6, 11))	('SMAD3', 'Gene', '4088', (128, 133))	('SMAD3', 'Gene', (128, 133))
64205	31500637	Interestingly, a splice variant of Veph1 (isoform-B) expressed in mouse (but not reported for humans) is predicted to encode a truncated protein consisting of the C-terminal domain of Veph1 analogous to the TIR2 sequence (Fig.	('splice variant', 'Var', (17, 31))	('Veph1', 'Gene', (184, 189))	('humans', 'Species', '9606', (94, 100))	('TIR2', 'Gene', '110256', (207, 211))	('mouse', 'Species', '10090', (66, 71))	('TIR2', 'Gene', (207, 211))	('Veph1', 'Gene', (35, 40))
64226	31500637	In addition, mutations and loss of heterozygosity in VEPH1 have been associated with invasive breast cancer and genome-wide association studies have produced a growing list of single nucleotide polymorphisms within the VEPH1 locus in a variety of malignant tumors (https://hive.biochemistry.gwu.edu/biomuta/proteinview/Q14D04).	('VEPH1', 'Gene', (53, 58))	('invasive breast cancer', 'Disease', (85, 107))	('single nucleotide', 'Var', (176, 193))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('loss of heterozygosity', 'Var', (27, 49))	('associated', 'Reg', (69, 79))	('malignant tumors', 'Disease', (247, 263))	('invasive breast cancer', 'Disease', 'MESH:D001943', (85, 107))	('malignant tumors', 'Disease', 'MESH:D018198', (247, 263))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (13, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))
64230	31500637	There are two genetic syndromes associated with ACC: Beckwith-Wiedemann syndrome, due to IGF2 overexpression, and Li-Fraumeni Syndrome, due to inactivating p53 mutations.	('overexpression', 'PosReg', (94, 108))	('mutations', 'Var', (160, 169))	('Beckwith-Wiedemann syndrome', 'Disease', (53, 80))	('inactivating', 'Var', (143, 155))	('edema', 'Phenotype', 'HP:0000969', (64, 69))	('p53', 'Gene', (156, 159))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (114, 134))	('p53', 'Gene', '7157', (156, 159))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (53, 80))	('IGF2', 'Gene', '3481', (89, 93))	('Li-Fraumeni Syndrome', 'Disease', (114, 134))	('IGF2', 'Gene', (89, 93))	('ACC', 'Phenotype', 'HP:0006744', (48, 51))
64235	31500637	Consistent with these studies suggesting increased VEPH1 expression associates with better outcome, we found that expression of ectopic VEPH1 in human ovarian cancer SKOV3 cells resulted in decreased tumor progression.	('decreased tumor', 'Disease', 'MESH:D009369', (190, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('VEPH1', 'Gene', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('human', 'Species', '9606', (145, 150))	('ovarian cancer', 'Disease', 'MESH:D010051', (151, 165))	('SKOV3', 'CellLine', 'CVCL:0532', (166, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('decreased tumor', 'Disease', (190, 205))	('ectopic', 'Var', (128, 135))	('ovarian cancer', 'Disease', (151, 165))
64236	31500637	Somewhat surprisingly, VEPH1 expression did not appear to alter tumor cell proliferation but rather increased necrotic regions within the tumor.	('necrotic regions within the tumor', 'Disease', (110, 143))	('VEPH1', 'Gene', (23, 28))	('expression', 'Var', (29, 39))	('tumor', 'Disease', (64, 69))	('increased', 'PosReg', (100, 109))	('necrotic regions within the tumor', 'Disease', 'MESH:D001929', (110, 143))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('rat', 'Species', '10116', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('rat', 'Species', '10116', (93, 96))
64240	31500637	Amplification of the VEPH1 gene locus associated with increased transcript levels has been reported in ovarian cancers, and query of the TCGA database indicates potential amplification in multiple other cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ovarian cancers', 'Phenotype', 'HP:0100615', (103, 118))	('Amplification', 'Var', (0, 13))	('ovarian cancers', 'Disease', 'MESH:D010051', (103, 118))	('cancers', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('increased', 'PosReg', (54, 63))	('VEPH1', 'Gene', (21, 26))	('transcript levels', 'MPA', (64, 81))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('ovarian cancers', 'Disease', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
64241	31500637	However, in gastric cancer, VEPH1 expression is decreased by > 50% in early stage disease, suggesting loss of VEPH1 expression may enable malignant transformation or survival of these cells.	('early stage disease', 'Disease', (70, 89))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('expression', 'MPA', (116, 126))	('malignant transformation', 'CPA', (138, 162))	('expression', 'MPA', (34, 44))	('enable', 'PosReg', (131, 137))	('gastric cancer', 'Disease', (12, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (12, 26))	('decreased', 'NegReg', (48, 57))	('gastric cancer', 'Phenotype', 'HP:0012126', (12, 26))	('VEPH1', 'Gene', (28, 33))	('survival', 'CPA', (166, 174))	('VEPH1', 'Gene', (110, 115))	('loss', 'Var', (102, 106))
64246	31500637	In contrast, VEPH1 expression is decreased by STK4/MST1 overexpression in prostate cancer cell lines.	('expression', 'MPA', (19, 29))	('MST1', 'Gene', (51, 55))	('prostate cancer', 'Disease', (74, 89))	('overexpression', 'Var', (56, 70))	('VEPH1', 'Gene', (13, 18))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('STK4', 'Gene', '6789', (46, 50))	('MST1', 'Gene', '4485', (51, 55))	('decreased', 'NegReg', (33, 42))	('STK4', 'Gene', (46, 50))
64250	31500637	VEPH1 was found to be among the genes with the most strongly up-regulated expression in Huh7 hepatocellular carcinoma cells upon disruption of OSBPL2/ORP2 (Oxysterol Binding Protein-Like 2) by CRISPR-Cas9.	('expression', 'MPA', (74, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('Oxysterol Binding Protein-Like 2', 'Gene', (156, 188))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (93, 117))	('OSBPL2', 'Gene', '9885', (143, 149))	('disruption', 'Var', (129, 139))	('hepatocellular carcinoma', 'Disease', (93, 117))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (93, 117))	('VEPH1', 'Gene', (0, 5))	('Oxysterol Binding Protein-Like 2', 'Gene', '9885', (156, 188))	('ORP2', 'Gene', (150, 154))	('ORP2', 'Gene', '9885', (150, 154))	('OSBPL2', 'Gene', (143, 149))	('up-regulated', 'PosReg', (61, 73))	('Huh7', 'CellLine', 'CVCL:0336', (88, 92))
64252	31500637	Disruption of OSBPL2 in Huh7 cells resulted in abnormal F-actin formation, leading to impaired lamellipodia formation and cell migration.	('impaired lamellipodia', 'Disease', 'MESH:D009422', (86, 107))	('OSBPL2', 'Gene', '9885', (14, 20))	('Huh7', 'CellLine', 'CVCL:0336', (24, 28))	('Disruption', 'Var', (0, 10))	('F-actin', 'MPA', (56, 63))	('rat', 'Species', '10116', (130, 133))	('cell migration', 'CPA', (122, 136))	('OSBPL2', 'Gene', (14, 20))	('impaired lamellipodia', 'Disease', (86, 107))
64266	31500637	Changes to the microenvironment within tissue stem cell niches can have determining effects on renewal vs. progenitor fate decisions and can lead to both cancer initiation and progression.	('renewal vs.', 'CPA', (95, 106))	('cancer initiation', 'Disease', 'MESH:D009369', (154, 171))	('Changes', 'Var', (0, 7))	('effects', 'Reg', (84, 91))	('lead to', 'Reg', (141, 148))	('cancer initiation', 'Disease', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('progression', 'CPA', (176, 187))
64272	31500637	Studies in non-mammalian model organisms show a pronounced developmental phenotype resulting from decreased or lack of expression; however, VEPH1 disruption in mice did not result in an overt phenotype.	('expression', 'MPA', (119, 129))	('VEPH1', 'Gene', (140, 145))	('mammalian', 'Species', '9606', (15, 24))	('lack', 'NegReg', (111, 115))	('mice', 'Species', '10090', (160, 164))	('disruption', 'Var', (146, 156))
64277	31500637	In contrast, the PH domain of VEPH1 amplified TGFbeta-induced signaling through an undefined mechanism.	('VEPH1', 'Gene', (30, 35))	('thr', 'Chemical', 'MESH:D013912', (72, 75))	('TGFbeta-induced signaling', 'MPA', (46, 71))	('PH domain', 'Var', (17, 26))	('amplified', 'PosReg', (36, 45))
64279	31500637	The currently available murine model for Veph1 disruption would not have likely impacted expression of this variant.	('Veph1', 'Gene', (41, 46))	('murine', 'Species', '10090', (24, 30))	('disruption', 'Var', (47, 57))
64282	31500637	Identification of interacting partners of VEPH1 responsible for neural dysplasia in model organisms: In contrast to the mouse model, disruption of VEPH1 in non-mammalian model organisms compromised neural development.	('neural dysplasia', 'Disease', 'MESH:D054220', (64, 80))	('mammalian', 'Species', '9606', (160, 169))	('neural development', 'CPA', (198, 216))	('disruption', 'Var', (133, 143))	('VEPH1', 'Gene', (147, 152))	('neural dysplasia', 'Disease', (64, 80))	('compromised', 'NegReg', (186, 197))	('mouse', 'Species', '10090', (120, 125))
64288	31500637	In an initial test of this, we found that VEPH1 expression in an ovarian cancer cell line did not impact the ability of these cells to form tumors but slowed tumor progression relative to those formed by mock-transfected cells.	('tumor', 'Disease', (158, 163))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('slowed', 'NegReg', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (65, 79))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('VEPH1', 'Gene', (42, 47))	('expression', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('ovarian cancer', 'Disease', 'MESH:D010051', (65, 79))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('ovarian cancer', 'Disease', (65, 79))	('tumor', 'Disease', (140, 145))
64293	27869826	Pan-cancer analysis of somatic copy number alterations implicates IRS4 and IGF2 in enhancer hijacking Extensive prior research has focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearranging cis-regulatory elements remains unclear.	('Pan-cancer', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('IGF2', 'Gene', '3481', (75, 79))	('IRS4', 'Gene', '8471', (66, 70))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('IRS4', 'Gene', (66, 70))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('alterations', 'Var', (43, 54))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('recurrent SCNAs', 'Phenotype', 'HP:0100776', (230, 245))	('IGF2', 'Gene', (75, 79))	('cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
64296	27869826	We demonstrate that IRS4 overexpression in lung cancer associates with recurrent deletions in cis, and present evidence supporting a tumor-promoting role.	('lung cancer', 'Disease', (43, 54))	('cis', 'Gene', (94, 97))	('deletions', 'Var', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('IRS4', 'Gene', (20, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('overexpression', 'PosReg', (25, 39))
64298	27869826	IGF2-containing tandem duplications result in the de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, which mediates high-level gene activation.	('tandem duplications', 'Var', (16, 35))	('IGF2', 'Gene', '3481', (102, 106))	('result in', 'Reg', (36, 45))	('IGF2', 'Gene', '3481', (0, 4))	('IGF2', 'Gene', (102, 106))	('IGF2', 'Gene', (0, 4))
64300	27869826	Several recent studies have uncovered somatic point mutations modulating gene regulation in cancer cells, including those affecting CREs near TERT, PAX5 and TAL1.	('TAL1', 'Gene', (157, 161))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('TAL1', 'Gene', '6886', (157, 161))	('modulating', 'Reg', (62, 72))	('gene regulation', 'MPA', (73, 88))	('TERT', 'Gene', (142, 146))	('PAX5', 'Gene', (148, 152))	('TERT', 'Gene', '7015', (142, 146))	('PAX5', 'Gene', '5079', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('point mutations', 'Var', (46, 61))
64317	27869826	A relatively high expression fold change when measured at the pan-cancer level (>25-fold) was observed for clustered deletions associated with upregulation of the insulin receptor substrate 4 (IRS4) gene.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('upregulation', 'PosReg', (143, 155))	('expression', 'MPA', (18, 28))	('insulin receptor substrate 4', 'Gene', '8471', (163, 191))	('IRS4', 'Gene', (193, 197))	('deletions', 'Var', (117, 126))	('cancer', 'Disease', (66, 72))	('insulin receptor substrate 4', 'Gene', (163, 191))
64325	27869826	Both losses and gains contributed to overexpression, with deletions in cis occasionally resulting in even higher fold-changes than high-level (copy-number >=4) TERT amplicons (Fig.	('fold-changes', 'MPA', (113, 125))	('TERT', 'Gene', '7015', (160, 164))	('resulting', 'Reg', (88, 97))	('overexpression', 'MPA', (37, 51))	('gains', 'PosReg', (16, 21))	('deletions', 'Var', (58, 67))	('higher', 'PosReg', (106, 112))	('cis', 'Gene', (71, 74))	('TERT', 'Gene', (160, 164))
64331	27869826	IRS4 overexpression has been shown to enhance insulin-like growth factor-1 (IGF1) induced cell proliferation in the 3T3 cell line48 and to mediate proliferation and cell migration in hepatoblastoma cells.	('cell migration', 'CPA', (165, 179))	('hepatoblastoma', 'Disease', 'MESH:D018197', (183, 197))	('IRS4', 'Gene', (0, 4))	('3T3', 'CellLine', 'CVCL:0594', (116, 119))	('insulin-like growth factor-1', 'Gene', (46, 74))	('enhance', 'PosReg', (38, 45))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (183, 197))	('cell proliferation', 'CPA', (90, 108))	('mediate', 'Reg', (139, 146))	('hepatoblastoma', 'Disease', (183, 197))	('insulin-like growth factor-1', 'Gene', '16000', (46, 74))	('IGF1', 'Gene', '16000', (76, 80))	('IGF1', 'Gene', (76, 80))	('overexpression', 'Var', (5, 19))	('proliferation', 'CPA', (147, 160))
64334	27869826	We focused our analysis on LUSC, where CESAM identified a set of recurrent deletions (N=20) clustering 103kb downstream of IRS4 within a region demarcated by chrX: 107,549,609-107,872,288 (hg19) (Fig.	('IRS4', 'Gene', (123, 127))	('deletions', 'Var', (75, 84))	('CESAM', 'Chemical', '-', (39, 44))
64335	27869826	IRS4 expression was increased by on average 400-fold when comparing LUSC deletion carriers to non-carrier control LUSC samples, and 25-fold when specifically comparing pan-cancer deletion carriers to pan-cancer non-carrier controls, whereas other genes in cis, by comparison, exhibited only modest expression alteration (Fig.	('increased', 'PosReg', (20, 29))	('cancer', 'Disease', (204, 210))	('expression', 'MPA', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('IRS4', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('deletion', 'Var', (179, 187))	('cancer', 'Disease', (172, 178))	('deletion', 'Var', (73, 81))
64338	27869826	In sarcomas, and to a lesser extent cervical squamous carcinoma, CESAM identified recurrent deletions at the exact same genomic interval in association with IRS4 overexpression (Supplementary Figs.	('sarcomas', 'Disease', 'MESH:D012509', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('sarcomas', 'Phenotype', 'HP:0100242', (3, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('cervical squamous carcinoma', 'Disease', (36, 63))	('sarcomas', 'Disease', (3, 11))	('association', 'Reg', (140, 151))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (45, 63))	('cervical squamous carcinoma', 'Disease', 'MESH:D002294', (36, 63))	('overexpression', 'PosReg', (162, 176))	('CESAM', 'Chemical', '-', (65, 70))	('deletions', 'Var', (92, 101))
64344	27869826	Additionally, we observed a significant co-occurrence of deletions in cis of IRS4 and amplifications of the FGFR1 cancer census gene on chromosome 8 (Pearson's chi-square test, X2=7.6; P=0.006, Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('deletions', 'Var', (57, 66))	('FGFR1', 'Gene', '2260', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('FGFR1', 'Gene', (108, 113))	('IRS4', 'Gene', (77, 81))	('cancer', 'Disease', (114, 120))
64347	27869826	This was achieved by introducing a transgenic IRS4 and an empty control lentivirus vector into HCC-15 cells.	('transgenic', 'Var', (35, 45))	('HCC-15', 'CellLine', 'CVCL:2057', (95, 101))	('IRS4', 'Gene', (46, 50))
64348	27869826	We observed palpable tumor formation in mice receiving transgenic IRS4 overexpression plasmids as well as the empty control, albeit with a significantly increased tumor growth in tumors harboring the IRS4 overexpression plasmids in both experimental replicates (P=0.046 and P=0.03, respectively; two-tailed t-test; Supplementary Fig.	('transgenic', 'Var', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('increased', 'PosReg', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('IRS4', 'Gene', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mice', 'Species', '10090', (40, 44))	('plasmids', 'Var', (86, 94))	('tumor', 'Disease', (179, 184))
64351	27869826	In addition, an H3K27ac peak at the bidirectional promoter of two nearby genes, COL4A5 and COL4A6 encoding collagen type IV subunits, showed significant loss of signal consistent with deletion of these genes' promoter.	('deletion', 'Var', (184, 192))	('loss', 'NegReg', (153, 157))	('COL4A5', 'Gene', '1287', (80, 86))	('signal', 'MPA', (161, 167))	('COL4A6', 'Gene', '1288', (91, 97))	('H3K27ac', 'Var', (16, 23))	('COL4A6', 'Gene', (91, 97))	('COL4A5', 'Gene', (80, 86))
64363	27869826	Amongst the CRC samples exhibiting IGF2 dysregulation, 20 harbored gains and two harbored focal deletions in cis (Fig.	('dysregulation', 'Var', (40, 53))	('IGF2', 'Gene', (35, 39))	('gains', 'PosReg', (67, 72))	('deletions', 'Var', (96, 105))	('IGF2', 'Gene', '3481', (35, 39))
64367	27869826	These data indicate that the recurrent gain at the IGF2 locus results from single-copy tandem duplications.	('gain', 'PosReg', (39, 43))	('single-copy tandem duplications', 'Var', (75, 106))	('IGF2', 'Gene', '3481', (51, 55))	('IGF2', 'Gene', (51, 55))
64371	27869826	Interestingly, the IGF2 locus tandem duplications extend over the intervening TAD boundary and also encompass this super-enhancer (Fig.	('IGF2', 'Gene', '3481', (19, 23))	('tandem duplications', 'Var', (30, 49))	('IGF2', 'Gene', (19, 23))
64372	27869826	We hence used 4C-Seq to investigate whether IGF2 dysregulation could be driven by topological or contact domain reorganization.	('dysregulation', 'Var', (49, 62))	('IGF2', 'Gene', (44, 48))	('IGF2', 'Gene', '3481', (44, 48))
64376	27869826	Indeed, the tandem duplications are inferred to result in copies of IGF2 and the super-enhancer being positioned in a head-to-tail orientation, with both now being able to contact each other via chromatin looping (see our model in Fig.	('tandem duplications', 'Var', (12, 31))	('IGF2', 'Gene', '3481', (68, 72))	('contact', 'Interaction', (172, 179))	('result', 'Reg', (48, 54))	('IGF2', 'Gene', (68, 72))
64378	27869826	Lastly, we also identified three larger somatic duplications of IGF2 in the TCGA data, which based on their size and location with respect to TAD boundaries are inferred to not lead to the formation of a 3D contact domain comprising IGF2 and this super-enhancer (Supplementary Fig.	('lead to', 'Reg', (177, 184))	('3D contact domain', 'MPA', (204, 221))	('IGF2', 'Gene', '3481', (64, 68))	('IGF2', 'Gene', (64, 68))	('IGF2', 'Gene', '3481', (233, 237))	('duplications', 'Var', (48, 60))	('IGF2', 'Gene', (233, 237))
64379	27869826	Notably, none of these three IGF2 duplication carriers exhibited appreciable levels of IGF2 overexpression (exhibiting significantly lower IGF2 expression compared to tandem duplications with the potential to lead to 3D contact domain formation; P=0.01; Wilcoxon rank-sum test), lending additional support to our new model.	('IGF2', 'Gene', '3481', (29, 33))	('IGF2', 'Gene', (87, 91))	('3D contact domain formation', 'MPA', (217, 244))	('expression', 'MPA', (144, 154))	('duplication', 'Var', (34, 45))	('IGF2', 'Gene', (139, 143))	('IGF2', 'Gene', (29, 33))	('IGF2', 'Gene', '3481', (87, 91))	('lower', 'NegReg', (133, 138))	('IGF2', 'Gene', '3481', (139, 143))
64384	27869826	Our data collectively suggest that activation of cancer genes by juxtaposition of CREs is a fairly common process, which may be comparable to the number of recurrent in-frame gene fusions leading to 3' target overexpression in cancer (e.g.	('juxtaposition', 'Var', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('overexpression', 'PosReg', (209, 223))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('activation', 'PosReg', (35, 45))
64388	27869826	Our data are compatible with disruptions of CTCF insulators at TAD boundaries through recurring deletions, the consequence of which appears to be the spreading of active chromatin marks in the context of IRS4 (see our model depicted in Supplementary Fig.	('CTCF', 'Gene', '10664', (44, 48))	('active', 'MPA', (163, 169))	('deletions', 'Var', (96, 105))	('CTCF', 'Gene', (44, 48))
64389	27869826	Consistent with our findings, CRISPR-mediated deletion of a CTCF insulator region at the Hox gene cluster has recently been shown to lead to spreading of active chromatin to neighbouring gene regions in embryonic stem cells.	('deletion', 'Var', (46, 54))	('CTCF', 'Gene', '10664', (60, 64))	('lead to', 'Reg', (133, 140))	('CTCF', 'Gene', (60, 64))	('spreading of active chromatin', 'MPA', (141, 170))
64391	27869826	This involves a previously undescribed mechanism, whereby tandem duplication-mediated de novo formation of a contact domain accompanying a super-enhancer normally inaccessible to IGF2 results in >250-fold gene upregulation.	('gene', 'MPA', (205, 209))	('IGF2', 'Gene', '3481', (179, 183))	('tandem duplication-mediated', 'Var', (58, 85))	('upregulation', 'PosReg', (210, 222))	('IGF2', 'Gene', (179, 183))
64454	27869826	The third most significant differential peak, which again exhibited more H3K27ac in SCNA carriers, localized ~20kb upstream of VSIG1.	('more', 'PosReg', (68, 72))	('VSIG1', 'Gene', (127, 132))	('VSIG1', 'Gene', '340547', (127, 132))	('H3K27ac', 'Var', (73, 80))
64455	27869826	However, as opposed to IRS4, VSIG1 is barely expressed and its expression showed only slight increases in deletion-carriers (2.7-fold for VSIG1, vs. 400-fold for IRS4; see Fig.	('VSIG1', 'Gene', '340547', (138, 143))	('VSIG1', 'Gene', (138, 143))	('expression', 'MPA', (63, 73))	('increases', 'PosReg', (93, 102))	('VSIG1', 'Gene', '340547', (29, 34))	('VSIG1', 'Gene', (29, 34))	('deletion-carriers', 'Var', (106, 123))
64457	27869826	The fourth peak localizing at the bidirectional promoter of the COL4A5/COL4A6 showed significantly less H3K27ac signal in deletion-carriers in line with promoter deletion in SCNA carriers and with the lower expression of COL4A5 and COL4A6 in LUSC deletion-carriers (Fig.	('COL4A5', 'Gene', (221, 227))	('COL4A6', 'Gene', '1288', (232, 238))	('COL4A6', 'Gene', '1288', (71, 77))	('COL4A6', 'Gene', (232, 238))	('COL4A6', 'Gene', (71, 77))	('COL4A5', 'Gene', '1287', (221, 227))	('COL4A5', 'Gene', (64, 70))	('less', 'NegReg', (99, 103))	('deletion-carriers', 'Var', (122, 139))	('H3K27ac', 'Protein', (104, 111))	('COL4A5', 'Gene', '1287', (64, 70))
64458	27869826	Differential H3K27ac occupancy analysis for CRC samples showing IGF2 tandem duplication versus non-carrier controls did not reveal a single peak with differential H3K27ac signal on chromosome 11 when controlling the FDR at 5%.	('tandem duplication', 'Var', (69, 87))	('H3K27ac', 'Var', (163, 170))	('IGF2', 'Gene', (64, 68))	('IGF2', 'Gene', '3481', (64, 68))
64460	27869826	5a) as differentially marked with H3K27ac on chromosome 11 (which is consistent with the massive activation of IGF2 as a consequence of recurrent locus rearrangements).	('H3K27ac', 'Var', (34, 41))	('IGF2', 'Gene', '3481', (111, 115))	('IGF2', 'Gene', (111, 115))
64624	27869719	In a series of in vitro, animal, and human studies, these workers demonstrated 123I-iodometomidate's high binding specificity in tissues of adrenocortical origin, similar pharmacodynamic properties to etomidate/metomidate, lack of toxicity or mutagenicity, and excellent imaging properties in both mice and patients.	('etomidate', 'Chemical', 'MESH:D005045', (201, 210))	('metomidate', 'Chemical', 'MESH:C084586', (88, 98))	('mice', 'Species', '10090', (298, 302))	('binding', 'Interaction', (106, 113))	('adrenocortical', 'Disease', 'MESH:D018268', (140, 154))	('metomidate', 'Chemical', 'MESH:C084586', (211, 221))	('123I-iodometomidate', 'Var', (79, 98))	('etomidate', 'Chemical', 'MESH:D005045', (212, 221))	('etomidate', 'Chemical', 'MESH:D005045', (89, 98))	('human', 'Species', '9606', (37, 42))	('patients', 'Species', '9606', (307, 315))	('toxicity', 'Disease', 'MESH:D064420', (231, 239))	('123I-iodometomidate', 'Chemical', 'MESH:C529450', (79, 98))	('toxicity', 'Disease', (231, 239))	('adrenocortical', 'Disease', (140, 154))
64781	27313728	A subsequent retrospective study demonstrated that mitotane can improve recurrence-free survival but not overall survival in patients with ACC.	('improve', 'PosReg', (64, 71))	('mitotane', 'Var', (51, 59))	('ACC', 'Phenotype', 'HP:0006744', (139, 142))	('mitotane', 'Chemical', 'MESH:D008939', (51, 59))	('recurrence-free survival', 'CPA', (72, 96))	('patients', 'Species', '9606', (125, 133))
64782	27313728	In 2010, a panel of international experts proposed adjuvant mitotane treatment for ACC patients with potential residual disease or >10% Ki67 positivity detected upon immunohistochemical examination.	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('ACC', 'Disease', (83, 86))	('positivity', 'Var', (141, 151))	('Ki67', 'Gene', (136, 140))	('men', 'Species', '9606', (74, 77))	('patients', 'Species', '9606', (87, 95))	('mitotane', 'Chemical', 'MESH:D008939', (60, 68))
64787	24777068	Analogues of Etomidate: Modifications Around Etomidate's Chiral Carbon and the Impact on In Vitro and In Vivo Pharmacology R-etomidate possesses unique desirable properties, but potently suppresses adrenocortical function.	('adrenocortical function', 'Disease', 'MESH:D018268', (198, 221))	('Etomidate', 'Chemical', 'MESH:D005045', (45, 54))	('suppresses', 'NegReg', (187, 197))	('R-etomidate', 'Chemical', '-', (123, 134))	('adrenocortical function', 'Disease', (198, 221))	('Carbon', 'Chemical', 'MESH:D002244', (64, 70))	('R-etomidate', 'Var', (123, 134))	('suppresses adrenocortical function', 'Phenotype', 'HP:0008207', (187, 221))	('Etomidate', 'Chemical', 'MESH:D005045', (13, 22))
64790	24777068	The gamma-aminobutyric acid type A (GABAA) receptor modulatory potencies of drugs were assessed in oocyte-expressed alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L GABAA receptors (for each drug, n=6 oocytes per subtype).	('gamma2', 'Gene', '7453', (164, 170))	('gamma2', 'Gene', '7453', (134, 140))	('alpha1', 'Gene', '146', (116, 122))	('L264T', 'SUBSTITUTION', 'None', (153, 158))	('L264T', 'Var', (153, 158))	('gamma2', 'Gene', (134, 140))	('GABAA', 'Gene', (36, 41))	('GABAA', 'Gene', '414477', (36, 41))	('alpha1', 'Gene', (146, 152))	('alpha1', 'Gene', (116, 122))	('L264T', 'Var', (123, 128))	('gamma2', 'Gene', (164, 170))	('L264T', 'SUBSTITUTION', 'None', (123, 128))	('alpha1', 'Gene', '146', (146, 152))	('GABAA', 'Gene', (172, 177))	('GABAA', 'Gene', '414477', (172, 177))
64814	24777068	We defined their potencies for enhancing GABAA receptor function using two receptor subtypes known to have differing etomidate sensitivities and contains a gating mutation that facilitates quantitation of hypnotic sensitivity.	('enhancing', 'PosReg', (31, 40))	('etomidate', 'Chemical', 'MESH:D005045', (117, 126))	('mutation', 'Var', (163, 171))	('GABAA', 'Gene', (41, 46))	('GABAA', 'Gene', '414477', (41, 46))
64853	24777068	The solvent was removed by rotary evaporation to yield a viscous oily product that was shown to be a mixture of two major components, Rf 0.41 and 0.21 on a silica gel thin layer chromatography plate with ethyl acetate/ether (9:1 V/V) solvent.	('ether', 'Chemical', 'MESH:D004986', (218, 223))	('Rf 0.41', 'Var', (134, 141))	('ethyl acetate', 'Chemical', 'MESH:C007650', (204, 217))	('viscous', 'MPA', (57, 64))	('rat', 'Species', '10116', (39, 42))	('silica', 'Chemical', 'MESH:D012822', (156, 162))
64866	24777068	Oocytes were harvested from frogs as previously described and injected with messenger RNA encoding the alpha1(L264T), gamma2, and either the beta1 or beta3 subunits of the human GABAA receptor (5 ng of messenger RNA total at a subunit ratio of 1:3:1).	('L264T', 'SUBSTITUTION', 'None', (110, 115))	('alpha1', 'Gene', (103, 109))	('L264T', 'Var', (110, 115))	('gamma2', 'Gene', '7453', (118, 124))	('rat', 'Species', '10116', (235, 238))	('human', 'Species', '9606', (172, 177))	('N', 'Chemical', 'MESH:D009584', (213, 214))	('alpha1', 'Gene', '146', (103, 109))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('GABAA', 'Gene', (178, 183))	('GABAA', 'Gene', '414477', (178, 183))	('gamma2', 'Gene', (118, 124))
64867	24777068	As in previous studies, we chose to study GABAA receptors harboring a mutation that significantly enhances channel-gating efficacy because it increases anesthetic sensitivity.	('increases anesthetic sensitivity', 'Phenotype', 'HP:0100963', (142, 174))	('increases', 'PosReg', (142, 151))	('enhances', 'PosReg', (98, 106))	('anesthetic sensitivity', 'MPA', (152, 174))	('channel-gating efficacy', 'MPA', (107, 130))	('GABAA', 'Gene', '414477', (42, 47))	('GABAA', 'Gene', (42, 47))	('mutation', 'Var', (70, 78))
64899	24777068	direct activation EC50s or surge current amplitudes mediated by alpha1(L264T)beta3gamma2L versus alpha1(L264T)beta1gamma2L GABAA receptors) were made using an extra-sum-of-squares F test or t-test with Walsh's correction, respectively, in Prism v6 for the Macintosh.	('L264T', 'SUBSTITUTION', 'None', (104, 109))	('50s', 'Species', '1214577', (20, 23))	('L264T', 'Var', (104, 109))	('alpha1', 'Gene', '146', (97, 103))	('alpha1', 'Gene', '146', (64, 70))	('gamma2', 'Gene', '7453', (115, 121))	('L264T', 'Var', (71, 76))	('L264T', 'SUBSTITUTION', 'None', (71, 76))	('alpha1', 'Gene', (97, 103))	('gamma2', 'Gene', (82, 88))	('alpha1', 'Gene', (64, 70))	('GABAA', 'Gene', (123, 128))	('GABAA', 'Gene', '414477', (123, 128))	('gamma2', 'Gene', '7453', (82, 88))	('gamma2', 'Gene', (115, 121))
64902	24777068	As expected for enantiomeric pairs, R- and S-etomidate had partition coefficients that were not significantly different from one another.	('partition coefficients', 'MPA', (59, 81))	('S-etomidate', 'Var', (43, 54))	('R- and S-etomidate', 'Chemical', '-', (36, 54))
64904	24777068	We quantified the GABAA receptor modulatory potencies and beta subunit selectivities of the four drugs by assessing their abilities to directly activate alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L GABAA receptors expressed in Xenopus oocytes.	('alpha1', 'Gene', '146', (153, 159))	('L264T', 'Var', (190, 195))	('gamma2', 'Gene', (201, 207))	('Xenopus', 'Species', '8355', (238, 245))	('L264T', 'SUBSTITUTION', 'None', (190, 195))	('activate', 'PosReg', (144, 152))	('L264T', 'Var', (160, 165))	('gamma2', 'Gene', (171, 177))	('alpha1', 'Gene', (183, 189))	('L264T', 'SUBSTITUTION', 'None', (160, 165))	('alpha1', 'Gene', (153, 159))	('GABAA', 'Gene', (209, 214))	('GABAA', 'Gene', '414477', (209, 214))	('gamma2', 'Gene', '7453', (201, 207))	('gamma2', 'Gene', '7453', (171, 177))	('GABAA', 'Gene', (18, 23))	('GABAA', 'Gene', '414477', (18, 23))	('alpha1', 'Gene', '146', (183, 189))
64905	24777068	Figure 3 shows representative electrophysiological traces recorded upon 30-sec drug application and demonstrates that all four drugs directly activated alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L GABAA receptors in a concentration-dependent manner.	('alpha1', 'Gene', (182, 188))	('L264T', 'Var', (159, 164))	('gamma2', 'Gene', (170, 176))	('gamma2', 'Gene', '7453', (200, 206))	('L264T', 'SUBSTITUTION', 'None', (159, 164))	('rat', 'Species', '10116', (236, 239))	('GABAA', 'Gene', (208, 213))	('GABAA', 'Gene', '414477', (208, 213))	('gamma2', 'Gene', '7453', (170, 176))	('alpha1', 'Gene', '146', (182, 188))	('L264T', 'Var', (189, 194))	('alpha1', 'Gene', (152, 158))	('L264T', 'SUBSTITUTION', 'None', (189, 194))	('activated', 'PosReg', (142, 151))	('gamma2', 'Gene', (200, 206))	('alpha1', 'Gene', '146', (152, 158))	('rat', 'Species', '10116', (107, 110))
64908	24777068	In both receptor subtypes, the amplitude of the surge currents were significantly larger for cyclopropyl etomidate than for any other drug, with values (at 1000 muM) in alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L GABAA receptors that were 61.5 +- 6.9% and 73.0 +- 38.5%, respectively, of the directly activated peak current (figure 4).	('cyclopropyl etomidate', 'Var', (93, 114))	('GABAA', 'Gene', (225, 230))	('gamma2', 'Gene', '7453', (187, 193))	('L264T', 'Var', (206, 211))	('L264T', 'SUBSTITUTION', 'None', (206, 211))	('gamma2', 'Gene', '7453', (217, 223))	('gamma2', 'Gene', (187, 193))	('alpha1', 'Gene', (169, 175))	('gamma2', 'Gene', (217, 223))	('cyclopropyl etomidate', 'Chemical', '-', (93, 114))	('alpha1', 'Gene', (199, 205))	('L264T', 'Var', (176, 181))	('alpha1', 'Gene', '146', (169, 175))	('L264T', 'SUBSTITUTION', 'None', (176, 181))	('GABAA', 'Gene', '414477', (225, 230))	('alpha1', 'Gene', '146', (199, 205))	('amplitude', 'MPA', (31, 40))	('surge currents', 'MPA', (48, 62))	('larger', 'PosReg', (82, 88))
64911	24777068	Figure 5 shows the concentration-response relationships for peak current activation of alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L GABAA receptors by R-etomidate (panel A), S-etomidate (panel B), cyclopropyl etomidate (panel C), and dihydrogen etomidate (panel D).	('cyclopropyl etomidate', 'Chemical', '-', (208, 229))	('S-etomidate', 'Chemical', 'MESH:D005045', (185, 196))	('alpha1', 'Gene', '146', (117, 123))	('alpha1', 'Gene', '146', (87, 93))	('dihydrogen etomidate', 'Chemical', '-', (245, 265))	('L264T', 'Var', (94, 99))	('L264T', 'SUBSTITUTION', 'None', (94, 99))	('gamma2', 'Gene', '7453', (105, 111))	('R-etomidate', 'Chemical', '-', (162, 173))	('GABAA', 'Gene', '414477', (143, 148))	('activation', 'PosReg', (73, 83))	('L264T', 'SUBSTITUTION', 'None', (124, 129))	('L264T', 'Var', (124, 129))	('gamma2', 'Gene', (105, 111))	('gamma2', 'Gene', '7453', (135, 141))	('GABAA', 'Gene', (143, 148))	('gamma2', 'Gene', (135, 141))	('alpha1', 'Gene', (117, 123))	('alpha1', 'Gene', (87, 93))	('rat', 'Species', '10116', (26, 29))
64912	24777068	In both receptor subtypes, R-etomidate was the most potent of the four drugs with EC50s for direct activation of 1.83 +- 0.28 muM and 50.17 +- 0.83 muM in alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L GABAA receptors, respectively (figure 5A and table 1).	('L264T', 'SUBSTITUTION', 'None', (162, 167))	('gamma2', 'Gene', '7453', (203, 209))	('alpha1', 'Gene', '146', (155, 161))	('L264T', 'Var', (162, 167))	('gamma2', 'Gene', (173, 179))	('alpha1', 'Gene', (185, 191))	('alpha1', 'Gene', (155, 161))	('GABAA', 'Gene', (211, 216))	('GABAA', 'Gene', '414477', (211, 216))	('gamma2', 'Gene', '7453', (173, 179))	('activation', 'PosReg', (99, 109))	('R-etomidate', 'Chemical', '-', (27, 38))	('L264T', 'Var', (192, 197))	('gamma2', 'Gene', (203, 209))	('50s', 'Species', '1214577', (84, 87))	('L264T', 'SUBSTITUTION', 'None', (192, 197))	('alpha1', 'Gene', '146', (185, 191))
64915	24777068	With respective EC50s of 57.0 +- 5.1 muM and 1080 +- 230 muM in alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L GABAA receptors, S-etomidate was 1/20th - 1/30th as potent as R-etomidate as a direct activator of both GABAA receptor subtypes (figure 5B and table 1) but had a subunit selectivity ratio (18.9 +- 4.4) that was similar to that of R-etomidate.	('alpha1', 'Gene', '146', (64, 70))	('S-etomidate', 'Chemical', 'MESH:D005045', (137, 148))	('L264T', 'Var', (71, 76))	('L264T', 'SUBSTITUTION', 'None', (71, 76))	('GABAA', 'Gene', '414477', (120, 125))	('alpha1', 'Gene', '146', (94, 100))	('rat', 'Species', '10116', (302, 305))	('L264T', 'SUBSTITUTION', 'None', (101, 106))	('GABAA', 'Gene', '414477', (224, 229))	('L264T', 'Var', (101, 106))	('50s', 'Species', '1214577', (18, 21))	('GABAA', 'Gene', (120, 125))	('gamma2', 'Gene', '7453', (112, 118))	('gamma2', 'Gene', '7453', (82, 88))	('GABAA', 'Gene', (224, 229))	('gamma2', 'Gene', (112, 118))	('gamma2', 'Gene', (82, 88))	('alpha1', 'Gene', (64, 70))	('R-etomidate', 'Chemical', '-', (182, 193))	('alpha1', 'Gene', (94, 100))	('R-etomidate', 'Chemical', '-', (350, 361))
64916	24777068	The achiral etomidate analogues cyclopropyl etomidate and dihydrogen etomidate were also significantly less potent than R-etomidate as direct activators of both GABAA receptor subtypes (figures 5C and 5D and table 1).	('activators', 'PosReg', (142, 152))	('etomidate', 'Chemical', 'MESH:D005045', (12, 21))	('cyclopropyl', 'Var', (32, 43))	('etomidate', 'Chemical', 'MESH:D005045', (122, 131))	('R-etomidate', 'Chemical', '-', (120, 131))	('dihydrogen etomidate', 'Chemical', '-', (58, 78))	('GABAA', 'Gene', (161, 166))	('GABAA', 'Gene', '414477', (161, 166))	('etomidate', 'Chemical', 'MESH:D005045', (44, 53))	('less', 'NegReg', (103, 107))	('etomidate', 'Chemical', 'MESH:D005045', (69, 78))	('cyclopropyl etomidate', 'Chemical', '-', (32, 53))
64919	24777068	Figure 6 shows the concentration-response relationships for activation of alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L GABAA receptors by propofol (A) and GABA (B).	('L264T', 'Var', (111, 116))	('L264T', 'SUBSTITUTION', 'None', (111, 116))	('gamma2', 'Gene', (92, 98))	('GABAA', 'Gene', (130, 135))	('activation', 'PosReg', (60, 70))	('gamma2', 'Gene', '7453', (122, 128))	('GABA', 'Chemical', 'MESH:D005680', (130, 134))	('gamma2', 'Gene', (122, 128))	('alpha1', 'Gene', (74, 80))	('alpha1', 'Gene', (104, 110))	('GABA', 'Chemical', 'MESH:D005680', (166, 170))	('alpha1', 'Gene', '146', (74, 80))	('rat', 'Species', '10116', (26, 29))	('L264T', 'Var', (81, 86))	('GABAA', 'Gene', '414477', (130, 135))	('L264T', 'SUBSTITUTION', 'None', (81, 86))	('alpha1', 'Gene', '146', (104, 110))	('propofol', 'Chemical', 'MESH:D015742', (149, 157))	('gamma2', 'Gene', '7453', (92, 98))
64920	24777068	Propofol's EC50 for activation was 7.58 +- 0.83 muM and 15.8 +- 1.0 in alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L GABAA receptors, respectively.	('L264T', 'Var', (108, 113))	('alpha1', 'Gene', '146', (101, 107))	('alpha1', 'Gene', '146', (71, 77))	('L264T', 'SUBSTITUTION', 'None', (108, 113))	('Propofol', 'Chemical', 'MESH:D015742', (0, 8))	('L264T', 'SUBSTITUTION', 'None', (78, 83))	('gamma2', 'Gene', (119, 125))	('L264T', 'Var', (78, 83))	('gamma2', 'Gene', (89, 95))	('alpha1', 'Gene', (101, 107))	('alpha1', 'Gene', (71, 77))	('GABAA', 'Gene', (127, 132))	('GABAA', 'Gene', '414477', (127, 132))	('gamma2', 'Gene', '7453', (119, 125))	('gamma2', 'Gene', '7453', (89, 95))
64922	24777068	GABA's EC50 for activation was 1.85 +- 0.17 muM and 1.13 +- 0.16 muM in alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L GABAA receptors, respectively.	('alpha1', 'Gene', (102, 108))	('GABAA', 'Gene', (128, 133))	('activation', 'PosReg', (16, 26))	('GABAA', 'Gene', '414477', (128, 133))	('alpha1', 'Gene', (72, 78))	('alpha1', 'Gene', '146', (102, 108))	('GABA', 'Chemical', 'MESH:D005680', (0, 4))	('gamma2', 'Gene', '7453', (90, 96))	('L264T', 'Var', (109, 114))	('gamma2', 'Gene', (120, 126))	('alpha1', 'Gene', '146', (72, 78))	('L264T', 'SUBSTITUTION', 'None', (109, 114))	('GABA', 'Chemical', 'MESH:D005680', (128, 132))	('L264T', 'Var', (79, 84))	('L264T', 'SUBSTITUTION', 'None', (79, 84))	('gamma2', 'Gene', '7453', (120, 126))	('gamma2', 'Gene', (90, 96))
64926	24777068	Paralleling our potency studies with GABAA receptors, R-etomidate was the most potent drug with a hypnotic ED50 of 0.47 +- 0.17 mg/kg (table 2).	('R-etomidate', 'Chemical', '-', (54, 65))	('GABAA', 'Gene', (37, 42))	('GABAA', 'Gene', '414477', (37, 42))	('hypnotic', 'MPA', (98, 106))	('R-etomidate', 'Var', (54, 65))
64947	24777068	Although the site of anesthetic action of many anesthetics (particularly volatile inhaled agents) remains a debated question, there is overwhelming evidence that R-etomidate produces hypnosis by enhancing the function of GABAA receptors.	('GABAA', 'Gene', (221, 226))	('GABAA', 'Gene', '414477', (221, 226))	('R-etomidate', 'Var', (162, 173))	('hypnosis', 'Disease', 'None', (183, 191))	('enhancing', 'PosReg', (195, 204))	('hypnosis', 'Disease', (183, 191))	('function', 'MPA', (209, 217))	('R-etomidate', 'Chemical', '-', (162, 173))
64960	24777068	In addition to having the highest potency for activating GABAA receptors, R-etomidate also had the highest hypnotic potency in rats.	('R-etomidate', 'Chemical', '-', (74, 85))	('rats', 'Species', '10116', (127, 131))	('hypnotic potency', 'MPA', (107, 123))	('GABAA', 'Gene', (57, 62))	('GABAA', 'Gene', '414477', (57, 62))	('R-etomidate', 'Var', (74, 85))	('activating', 'MPA', (46, 56))
64962	24777068	Our finding that S-etomidate both enhances GABAA receptor function and produces hypnosis in rats (albeit with potencies that are 1-2 orders of magnitude lower than R-etomidate) contrasts with a previous study that reported that S-etomidate is "pharmacologically inactive".	('rats', 'Species', '10116', (92, 96))	('S-etomidate', 'Chemical', 'MESH:D005045', (17, 28))	('hypnosis', 'Disease', 'None', (80, 88))	('R-etomidate', 'Chemical', '-', (164, 175))	('hypnosis', 'Disease', (80, 88))	('GABAA', 'Gene', (43, 48))	('GABAA', 'Gene', '414477', (43, 48))	('enhances', 'PosReg', (34, 42))	('S-etomidate', 'Var', (17, 28))	('S-etomidate', 'Chemical', 'MESH:D005045', (228, 239))
64978	24777068	We found that modifying R-etomidate's chiral center significantly altered its in vitro GABAA receptor modulatory potency and subunit selectivity, and in vivo hypnotic and adrenocortical inhibitory potencies.	('subunit selectivity', 'MPA', (125, 144))	('altered', 'Reg', (66, 73))	('hypnotic and adrenocortical', 'Disease', 'MESH:D018268', (158, 185))	('modifying', 'Var', (14, 23))	('R-etomidate', 'Chemical', '-', (24, 35))	('GABAA', 'Gene', (87, 92))	('GABAA', 'Gene', '414477', (87, 92))
64979	24777068	Such tight linkage between the structure of the chiral center and the pharmacological activity of etomidate analogues suggests the possibility of modifying etomidate's chiral center as part of a strategy to produce analogues with more desirable adrenocortical activities and/or subunit selectivities.	('etomidate', 'Chemical', 'MESH:D005045', (156, 165))	('rat', 'Species', '10116', (197, 200))	('etomidate', 'Chemical', 'MESH:D005045', (98, 107))	('modifying', 'Var', (146, 155))	('adrenocortical', 'Disease', (245, 259))	('adrenocortical', 'Disease', 'MESH:D018268', (245, 259))	('S', 'Chemical', 'MESH:D013455', (0, 1))
64984	24777068	Modification of the chiral center of etomidate may be part of a strategy to produce analogs that cause less adrenocortical suppression.	('etomidate', 'Chemical', 'MESH:D005045', (37, 46))	('Modification', 'Var', (0, 12))	('adrenocortical suppression', 'Disease', 'MESH:D018268', (108, 134))	('adrenocortical suppression', 'Phenotype', 'HP:0008207', (108, 134))	('rat', 'Species', '10116', (66, 69))	('adrenocortical suppression', 'Disease', (108, 134))
64994	23248518	With similar sensitivities (90-100%) and specificities (70-80%) MRI and CT are equally efficacious in diagnosing adrenal lesions.	('adrenal lesion', 'Disease', 'MESH:D000307', (113, 127))	('adrenal lesion', 'Disease', (113, 127))	('MRI', 'Var', (64, 67))
65039	23248518	On chemical shift MRI, pheochromocytomas do not show significant signal loss.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (23, 40))	('chemical shift MRI', 'Var', (3, 21))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (23, 39))	('MRI', 'Var', (18, 21))	('pheochromocytomas', 'Disease', 'MESH:D010673', (23, 40))	('pheochromocytomas', 'Disease', (23, 40))
65042	23248518	Adrenal medullary scintigraphy employs the use of radioiodinated guanethidine derivatives such as 131I-MIBG and 123I-MIBG.	('guanethidine', 'Chemical', 'MESH:D006145', (65, 77))	('123I-MIBG', 'Chemical', 'MESH:D019797', (112, 121))	('123I-MIBG', 'Var', (112, 121))	('131I-MIBG', 'Var', (98, 107))	('131I-MIBG', 'Chemical', '-', (98, 107))
65214	20017945	Identification of a novel germ-line mutation in the TP53 gene in a Mexican family with Li-Fraumeni syndrome Germ-line mutations of the TP53 gene are known to cause Li-Fraumeni syndrome, an autosomal, dominantly inherited, high-penetrance cancer-predisposition syndrome characterized by the occurrence of a variety of cancers, mainly soft tissue sarcomas, adrenocortical carcinoma, leukemia, breast cancer, and brain tumors.	('cancers', 'Disease', 'MESH:D009369', (317, 324))	('leukemia', 'Phenotype', 'HP:0001909', (381, 389))	('brain tumors', 'Disease', (410, 422))	('Li-Fraumeni syndrome', 'Disease', (87, 107))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (355, 379))	('cancer', 'Disease', (398, 404))	('adrenocortical carcinoma', 'Disease', (355, 379))	('cancer', 'Disease', (238, 244))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (87, 107))	('leukemia', 'Disease', (381, 389))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('leukemia', 'Disease', 'MESH:D007938', (381, 389))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (333, 352))	('TP53', 'Gene', '7157', (135, 139))	('cause', 'Reg', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('TP53', 'Gene', (52, 56))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (333, 352))	('soft tissue sarcoma', 'Disease', (333, 352))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (333, 353))	('cancers', 'Phenotype', 'HP:0002664', (317, 324))	('cancer', 'Disease', (317, 323))	('cancers', 'Disease', (317, 324))	('Li-Fraumeni syndrome', 'Disease', (164, 184))	('mutations', 'Var', (118, 127))	('sarcomas', 'Disease', 'MESH:D012509', (345, 353))	('breast cancer', 'Phenotype', 'HP:0003002', (391, 404))	('tumors', 'Phenotype', 'HP:0002664', (416, 422))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('sarcomas', 'Phenotype', 'HP:0100242', (345, 353))	('cancer', 'Disease', 'MESH:D009369', (398, 404))	('sarcomas', 'Disease', (345, 353))	('carcinoma', 'Phenotype', 'HP:0030731', (370, 379))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (164, 184))	('tumor', 'Phenotype', 'HP:0002664', (416, 421))	('breast cancer', 'Disease', 'MESH:D001943', (391, 404))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('brain tumors', 'Disease', 'MESH:D001932', (410, 422))	('brain tumors', 'Phenotype', 'HP:0030692', (410, 422))	('TP53', 'Gene', '7157', (52, 56))	('breast cancer', 'Disease', (391, 404))	('brain tumor', 'Phenotype', 'HP:0030692', (410, 421))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (355, 379))	('sarcoma', 'Phenotype', 'HP:0100242', (345, 352))	('TP53', 'Gene', (135, 139))	('mutation', 'Var', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
65216	20017945	We report herein on Li Fraumeni syndrome in a family whose members are carriers of a novel TP53 gene mutation at exon 4.	('TP53', 'Gene', (91, 95))	('Fraumeni syndrome', 'Disease', (23, 40))	('Fraumeni syndrome', 'Disease', 'MESH:D016864', (23, 40))	('TP53', 'Gene', '7157', (91, 95))	('mutation', 'Var', (101, 109))
65217	20017945	With this mutation, the p53 protein that should be translated lacks the majority of the DNA binding domain.	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('protein', 'Protein', (28, 35))	('lacks', 'NegReg', (62, 67))	('mutation', 'Var', (10, 18))	('majority', 'MPA', (72, 80))
65220	20017945	While the majority of cancer-predisposition syndromes are tissue-specific, such as those associated with breast cancer, colon cancer, and melanoma, LFS is associated with several different cancer types, mainly bone and soft tissue sarcoma, breast cancer, brain tumors, adrenocortical carcinoma, and leukemia.	('LFS', 'Var', (148, 151))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', (247, 253))	('brain tumors', 'Disease', 'MESH:D001932', (255, 267))	('brain tumors', 'Phenotype', 'HP:0030692', (255, 267))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('brain tumor', 'Phenotype', 'HP:0030692', (255, 266))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (231, 238))	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('leukemia', 'Phenotype', 'HP:0001909', (299, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('colon cancer', 'Phenotype', 'HP:0003003', (120, 132))	('cancer', 'Disease', (126, 132))	('brain tumors', 'Disease', (255, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('leukemia', 'Disease', 'MESH:D007938', (299, 307))	('associated', 'Reg', (155, 165))	('cancer', 'Disease', (22, 28))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (269, 293))	('colon cancer', 'Disease', 'MESH:D015179', (120, 132))	('leukemia', 'Disease', (299, 307))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (219, 238))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (219, 238))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (105, 118))	('soft tissue sarcoma', 'Disease', (219, 238))	('cancer', 'Disease', (189, 195))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('breast cancer', 'Disease', (240, 253))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (269, 293))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('adrenocortical carcinoma', 'Disease', (269, 293))	('colon cancer', 'Disease', (120, 132))
65222	20017945	Approximately 70% of LFS families and 8-22% of families with LF like (LFL) carry germ-line mutations at the tumor suppressor gene TP53 .	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('mutations', 'Var', (91, 100))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))
65223	20017945	The majority of missense alterations occur at evolutionarily conserved amino acid residues in the DNA binding domain; outside of this core region, deleterious TP53 changes tend to be nonsense or frameshift mutations that cause premature protein-translation termination.	('changes', 'Var', (164, 171))	('missense alterations', 'Var', (16, 36))	('TP53', 'Gene', (159, 163))	('TP53', 'Gene', '7157', (159, 163))	('premature protein-translation termination', 'MPA', (227, 268))	('frameshift', 'Var', (195, 205))
65224	20017945	At present, 399 pathogenic germ-line mutations have been reported for TP53, 78% of which are missense mutations principally located at the sequence coding for the DNA binding domain.	('TP53', 'Gene', '7157', (70, 74))	('pathogenic', 'Reg', (16, 26))	('mutations', 'Var', (37, 46))	('TP53', 'Gene', (70, 74))	('missense mutations', 'Var', (93, 111))
65225	20017945	Epidemiological studies estimate that approximately 70% of males and 100% of females who inherit a TP53 mutation are at increased risk for developing cancer of the breast, brain, soft tissue, bone, blood, and adrenal cortex.	('TP53', 'Gene', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer of the breast', 'Phenotype', 'HP:0100013', (150, 170))	('cancer', 'Disease', (150, 156))	('mutation', 'Var', (104, 112))	('TP53', 'Gene', '7157', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
65229	20017945	Loss of p53 function is thought to suppress a mechanism of protection against the accumulation of genetic alterations, as the mutant p53 protein is unable to carry out, i.e., transcriptional transactivation of downstream target genes that regulate the cell cycle and apoptosis.	('p53', 'Gene', (8, 11))	('p53', 'Gene', '7157', (133, 136))	('protein', 'Protein', (137, 144))	('p53', 'Gene', '7157', (8, 11))	('Loss', 'NegReg', (0, 4))	('p53', 'Gene', (133, 136))	('transcriptional', 'MPA', (175, 190))	('suppress', 'NegReg', (35, 43))	('mutant', 'Var', (126, 132))
65230	20017945	Somatic TP53 genetic alterations are found frequently in a variety of human sporadic cancers, with frequencies varying from 10-60%, depending on tumor type or population group.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('sporadic cancers', 'Disease', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('human', 'Species', '9606', (70, 75))	('tumor', 'Disease', (145, 150))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('genetic alterations', 'Var', (13, 32))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('sporadic cancers', 'Disease', 'MESH:D009369', (76, 92))
65231	20017945	In this work, we describe a family with LFS syndrome with one novel TP53 germ-line mutation that corresponds to a 7 nucleotide insertion at exon 4, which generates a frameshift and a premature stop codon at position 150.	('frameshift', 'Var', (166, 176))	('mutation', 'Var', (83, 91))	('LFS syndrome', 'Disease', 'MESH:D016864', (40, 52))	('LFS syndrome', 'Disease', (40, 52))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))
65247	20017945	The pedigree (Figure 1) suggested that individual II-5 might be the carrier of the de novo TP53 mutation because none of his ancestors had had cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('TP53', 'Gene', (91, 95))	('mutation', 'Var', (96, 104))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('TP53', 'Gene', '7157', (91, 95))
65256	20017945	Identification of a germ-line TP53 mutation in a patient allows for the following a) to confirm the diagnosis of LFS on a molecular basis; b) to ensure regular clinical surveillance by an informed clinician in order to avoid a delay in diagnosis of a second tumor; c) to avoid radiation whenever possible, and d) to offer genetic counseling and prenatal diagnosis to the families.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', '7157', (30, 34))	('tumor', 'Disease', (258, 263))	('patient', 'Species', '9606', (49, 56))	('mutation', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (258, 263))
65258	20017945	This alteration should induce the generation of a shorter p53 protein with a different amino acid sequence in its carboxy terminal portion.	('p53', 'Gene', (58, 61))	('alteration', 'Var', (5, 15))	('p53', 'Gene', '7157', (58, 61))
65259	20017945	Acquisition of TP53 mutations can have two consequences: 1) a dominant negative effect by hetero-oligomerization of the more stable mutant p53 with wild-type p53 molecules expressed from the normal remaining allele, and 2) a gain of function of the mutant p53 protein.	('negative effect', 'NegReg', (71, 86))	('p53', 'Gene', '7157', (158, 161))	('mutant', 'Var', (132, 138))	('hetero-oligomerization', 'MPA', (90, 112))	('TP53', 'Gene', '7157', (15, 19))	('p53', 'Gene', (139, 142))	('p53', 'Gene', (256, 259))	('TP53', 'Gene', (15, 19))	('p53', 'Gene', '7157', (256, 259))	('protein', 'Protein', (260, 267))	('p53', 'Gene', (158, 161))	('mutant', 'Var', (249, 255))	('p53', 'Gene', '7157', (139, 142))	('mutations', 'Var', (20, 29))	('gain of function', 'PosReg', (225, 241))
65260	20017945	Thus, mutation of TP53 may provide a selective advantage for clonal expansion of pre-neoplastic or neoplastic cells.	('TP53', 'Gene', '7157', (18, 22))	('mutation', 'Var', (6, 14))	('clonal expansion', 'CPA', (61, 77))	('TP53', 'Gene', (18, 22))
65261	20017945	Mutant proteins differ in terms of the extent of their loss of suppressor function and by their capacity to inhibit wild-type p53 in a dominant-negative manner.	('suppressor', 'MPA', (63, 73))	('p53', 'Gene', '7157', (126, 129))	('loss', 'NegReg', (55, 59))	('proteins', 'Protein', (7, 15))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (126, 129))	('inhibit', 'NegReg', (108, 115))
65262	20017945	In addition, some p53 mutants apparently exert an oncogenic activity of their own.	('p53', 'Gene', '7157', (18, 21))	('p53', 'Gene', (18, 21))	('oncogenic activity', 'CPA', (50, 68))	('exert', 'Reg', (41, 46))	('mutants', 'Var', (22, 29))
65263	20017945	The TP53 region that most frequently contains deletions or insertions is that of codons 151-159: CGC CCG CGC CGC ACC CGC GTC CGC GCC.	('TP53', 'Gene', (4, 8))	('GCC', 'Gene', '2984', (129, 132))	('insertions', 'Var', (59, 69))	('GCC', 'Gene', (129, 132))	('deletions', 'Var', (46, 55))	('TP53', 'Gene', '7157', (4, 8))
65264	20017945	In fact, approximately 9% of all deletions and insertions and 1% of all TP53 mutations have been reported at this G:C-rich sequence with multiple runs and direct repeats.	('TP53', 'Gene', '7157', (72, 76))	('TP53', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('deletions', 'Var', (33, 42))	('insertions', 'Var', (47, 57))
65272	20017945	It is necessary to carry out analysis of p53 mRNA and protein in this family in order to further elucidate the consequences of the mutation in the expression of p53 and the possible mechanism of carcinogenesis in carriers of the mutation.	('p53', 'Gene', '7157', (41, 44))	('mutation', 'Var', (131, 139))	('carcinogenesis', 'Disease', 'MESH:D063646', (195, 209))	('carcinogenesis', 'Disease', (195, 209))	('p53', 'Gene', (161, 164))	('p53', 'Gene', (41, 44))	('p53', 'Gene', '7157', (161, 164))
65283	33889305	In conclusion, the P142 panel of metrics successfully predicted cancer progression status in patients with some, but not all cancer types analyzed.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (64, 70))	('P142', 'Var', (19, 23))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('predicted', 'Reg', (54, 63))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
65290	33889305	However, many of the mechanisms driving cancer progression are still not fully understood, such as the causes, effects, and patterns of DNA mutation in oncogenesis.	('DNA', 'Gene', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('mutation', 'Var', (140, 148))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
65291	33889305	As cancer develops, many mechanisms and endogenous cellular processes cause mutations in DNA.	('DNA', 'Gene', (89, 92))	('mutations', 'Var', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('cause', 'Reg', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
65293	33889305	For example, the binding motif for APOBEC3G is two consecutive cytosines ("CC") and deamination of the second cytosine results in another nucleotide being incorporated e.g., "CT".	('cytosines', 'Chemical', 'MESH:D003596', (63, 72))	('APOBEC3G', 'Gene', '60489', (35, 43))	('nucleotide', 'MPA', (138, 148))	('results in', 'Reg', (119, 129))	('cytosine', 'Chemical', 'MESH:D003596', (63, 71))	('cytosine', 'Chemical', 'MESH:D003596', (110, 118))	('APOBEC3G', 'Gene', (35, 43))	('deamination', 'Var', (84, 95))
65295	33889305	Furthermore, the accumulation of specific deaminase-associated mutations in a patient can provide valuable information on how the cancer has developed, and in specific cases provide information on the rate of progression of the disease and likely response to specific treatments.	('mutations', 'Var', (63, 72))	('deaminase-associated', 'Enzyme', (42, 62))	('patient', 'Species', '9606', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
65296	33889305	Despite clinical utility in a handful of examples, quantification of deaminase-associated DNA mutations currently does not provide actionable information for the majority of cancer types.	('mutations', 'Var', (94, 103))	('cancer', 'Disease', (174, 180))	('DNA', 'Gene', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('deaminase-associated', 'Var', (69, 89))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
65298	33889305	In this study, the proposed molecular model of AID/APOBEC and ADAR mutagenesis advances existing models by implicating the open transcription bubble and transcription elongation complex as illustrated by Lindley (Figure 1A).	('ADAR', 'Gene', '103', (62, 66))	('ADAR', 'Gene', (62, 66))	('mutagenesis', 'Var', (67, 78))	('implicating', 'Reg', (107, 118))	('AID', 'Gene', (47, 50))	('AID', 'Gene', '57379', (47, 50))
65304	33889305	The P142 panel is fundamentally different to these existing methods and may provide a new source of cancer progression biomarkers.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('P142', 'Var', (4, 8))
65307	33889305	We hypothesize that the P142 markers associated with AID/APOBEC and ADAR deamination and codon reading frame context can be used to predict cancer progression for patients with a range of different cancer types.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('patients', 'Species', '9606', (163, 171))	('cancer', 'Disease', (198, 204))	('predict', 'Reg', (132, 139))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('AID', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('ADAR', 'Gene', '103', (68, 72))	('AID', 'Gene', '57379', (53, 56))	('P142', 'Var', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ADAR', 'Gene', (68, 72))
65318	33889305	However lower grade glioma (BLGG, Figure 2B), mesothelioma (MESO, Figure 2C) and adrenocortical carcinoma (ADCC, Figure 2D) had significantly more mutations in patients with "Low PFS" vs those with "High PFS" (p < 0.05).	('mesothelioma', 'Disease', 'MESH:D008654', (46, 58))	('mutations', 'Var', (147, 156))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('patients', 'Species', '9606', (160, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('adrenocortical carcinoma', 'Disease', (81, 105))	('mesothelioma', 'Disease', (46, 58))	('ADCC', 'Phenotype', 'HP:0006744', (107, 111))	('glioma', 'Disease', (20, 26))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (81, 105))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (81, 105))
65344	33889305	As this metric denotes a mutation of "G" within an APOBEC3B motif, the mutation occurred at C>T on the opposite strand, which is a measure of strand bias.	('mutation', 'Var', (25, 33))	('APOBEC3B', 'Gene', '9582', (51, 59))	('APOBEC3B', 'Gene', (51, 59))
65345	33889305	This mechanism is associated with many of the P142 metrics, for example #7: "cds:A3G_C-C- MC3%" (Supplementary Table 1), which calculates the proportion of mutations that occur within the APOBEC3G motif ("CC") at the 3rd position of a codon ("MC3").	('mutations', 'Var', (156, 165))	('cds', 'Chemical', 'MESH:D002104', (77, 80))	('APOBEC3G', 'Gene', '60489', (188, 196))	('APOBEC3G', 'Gene', (188, 196))
65347	33889305	Despite a clear correlation between the P142 metrics and patient outcome in the majority of cases, predictive accuracy was low for 8 of the 28 cancer types investigated.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('patient', 'Species', '9606', (57, 64))	('P142', 'Var', (40, 44))	('low', 'NegReg', (123, 126))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
65350	33889305	Yet, in cells that are p53-compromised a significantly higher number of mutations with the expected APOBEC motif were observed when APOBEC3B was overexpressed.	('mutations', 'Var', (72, 81))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('APOBEC3B', 'Gene', (132, 140))	('APOBEC3B', 'Gene', '9582', (132, 140))
65351	33889305	This is another potential explanation for the low level of deaminase-associated mutations seen in some cancer types, such as TGCT and UVME, which do not typically have compromised DNA repair machinery.	('UVME', 'Chemical', '-', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (80, 89))	('UVME', 'Disease', (134, 138))	('TGCT', 'Disease', (125, 129))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
65354	33889305	High TMB is typically associated with positive response to immunotherapy (and subsequently higher PFS), yet in cancer types such as adrenocortical carcinoma and lower grade glioma (ADCC, BLGG) a lower mutation burden was associated with longer PFS (see Figures 3 and 4).	('ADCC', 'Phenotype', 'HP:0006744', (181, 185))	('High', 'Var', (0, 4))	('glioma', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (132, 156))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('TMB', 'MPA', (5, 8))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (132, 156))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('cancer', 'Disease', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('TMB', 'Chemical', '-', (5, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('adrenocortical carcinoma', 'Disease', (132, 156))
65362	33889305	We have previously speculated that the combinatorial association of different deaminase isoforms, homodimers and heterodimers may moderate deaminase targeting specificity and contribute to this accumulation of mutations as cancer progresses.	('mutations', 'Var', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('moderate', 'NegReg', (130, 138))	('deaminase targeting specificity', 'MPA', (139, 170))	('contribute', 'Reg', (175, 185))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))
65368	33889305	This study provides a basis for further development of biomarker panels based on metrics associated with deaminase mutagenesis for predicting cancer progression and patient outcome.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patient', 'Species', '9606', (165, 172))	('mutagenesis', 'Var', (115, 126))	('cancer', 'Disease', (142, 148))
65378	33889305	Genomic metrics included in the P142 panel relate to mutational burden, deaminase binding motifs, incidence of tumor/normal single nucleotide mutations, and reading-frame context of the codon triplet (i.e., if a codon contains a mutation, what is the position of the mutated codon (MC): 1, 2 or 3 as read 5' to 3').	('mutation', 'Var', (229, 237))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', (111, 116))
65498	31522749	The gene expression assays used were: HOTTIP (Hs03649396_m1), CHL1 (Hs04332026_m1), HOXA11-AS1 (Hs_03454334_g1), CRNDE (HS04404483_m1), LINC00271 (Hs03657384_m1), FAM211A-AS1 (Hs03678558_g1), TBXAS1 (Hs01096058_s1) and GAPDH (Hs99999905_m1).	('Hs03649396_m1', 'Var', (46, 59))	('Hs03678558_g1', 'Var', (176, 189))	('CHL1', 'Gene', (62, 66))	('TBXAS1', 'Gene', '6916', (192, 198))	('HOTTIP', 'Gene', (38, 44))	('CRNDE', 'Gene', (113, 118))	('Hs99999905_m1', 'Var', (226, 239))	('AS1', 'Gene', (91, 94))	('LINC00271', 'Gene', '100131814', (136, 145))	('HOXA11', 'Gene', (84, 90))	('TBXAS1', 'Gene', (192, 198))	('CRNDE', 'Gene', '643911', (113, 118))	('AS1', 'Gene', (171, 174))	('AS1', 'Gene', (195, 198))	('HOTTIP', 'Gene', '100316868', (38, 44))	('CHL1', 'Gene', '10752', (62, 66))	('HOXA11', 'Gene', '3207', (84, 90))	('FAM211A-AS1', 'Gene', (163, 174))	('Hs04332026_m1', 'Var', (68, 81))	('LINC00271', 'Gene', (136, 145))	('Hs01096058_s1', 'Var', (200, 213))	('FAM211A-AS1', 'Gene', '125144', (163, 174))	('AS1', 'Gene', '5729', (91, 94))	('Hs_03454334_g1', 'Var', (96, 110))	('HS04404483_m1', 'Var', (120, 133))	('AS1', 'Gene', '5729', (171, 174))	('Hs03657384_m1', 'Var', (147, 160))	('AS1', 'Gene', '5729', (195, 198))
65521	31522749	Only10n lncRNAs were differentially expressed in ACA compared with NAC.	('NAC', 'Chemical', '-', (67, 70))	('ACA', 'Disease', (49, 52))	('Only10n', 'Var', (0, 7))
65536	31522749	One of 11 NAC samples demonstrated a deletion at 6q23.3, whereas 2 of 18 ACA samples demonstrated deletions at 6q23.3, and two other ACA samples demonstrated amplifications at 6q23.3.	('NAC', 'Chemical', '-', (10, 13))	('deletion', 'Var', (37, 45))	('deletions', 'Var', (98, 107))
65537	31522749	The LINC00271 locus appeared to be the most unstable in ACCs, with 4 of 19 ACC samples demonstrating deletions, and 4 of 19 ACC samples demonstrating amplifications of 6q23.3.	('LINC00271', 'Gene', (4, 13))	('ACCs', 'Gene', (56, 60))	('LINC00271', 'Gene', '100131814', (4, 13))	('ACCs', 'Gene', '84680', (56, 60))	('deletions', 'Var', (101, 110))
65552	31522749	Studies have suggested that genes with causal roles in tumorigenesis are often located in chromosomal areas with alterations in copy number.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('alterations', 'Var', (113, 124))	('copy number', 'Var', (128, 139))
65585	29794126	PCC resection led to improvement of cardiomyopathy in 96% of patients, while lack of resection was associated with death or cardiac transplantation in 44% patients.	('improvement', 'PosReg', (21, 32))	('PCC', 'Gene', '1421', (0, 3))	('patients', 'Species', '9606', (61, 69))	('PCC', 'Gene', (0, 3))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (36, 50))	('patients', 'Species', '9606', (155, 163))	('cardiomyopathy', 'Disease', 'MESH:D009202', (36, 50))	('death', 'Disease', 'MESH:D003643', (115, 120))	('death', 'Disease', (115, 120))	('resection', 'Var', (4, 13))	('cardiomyopathy', 'Disease', (36, 50))
65602	29794126	Mutations in succinate dehydrogenase subunits A-D (SDHx) were thought to have almost complete penetrance for PPGL.	('Mutations', 'Var', (0, 9))	('SDHx', 'Chemical', '-', (51, 55))	('SDHx', 'Gene', (51, 55))
65605	29794126	The second study reported outcomes of annual surveillance imaging in SDHB mutation carriers: in 27 index patients, 51 PPGLs (five metachronous) were detected.	('SDHB', 'Gene', (69, 73))	('patients', 'Species', '9606', (105, 113))	('mutation', 'Var', (74, 82))
65612	29794126	Those with RET, VHL or NF1 germline mutations more often had minimally invasive surgery with cortical-sparing adrenalectomy, whereas seven out of eight (87.5%) patients with SDHB mutation had an open approach.	('RET', 'Gene', '5979', (11, 14))	('patients', 'Species', '9606', (160, 168))	('minimally', 'Disease', (61, 70))	('NF1', 'Gene', (23, 26))	('RET', 'Gene', (11, 14))	('NF1', 'Gene', '4763', (23, 26))	('VHL', 'Disease', (16, 19))	('VHL', 'Disease', 'MESH:D006623', (16, 19))	('germline mutations', 'Var', (27, 45))
65620	29794126	Data from The Cancer Genome Atlas (TCGA) have already allowed PPGL to be included into several pan-cancer analyses; the first underscore that PPGL genomes exhibit relatively low number of somatic mutations as well as copy number segmentations compared to other tumors.	('PPGL', 'Gene', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('copy number segmentations', 'Var', (217, 242))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Disease', (261, 267))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', (99, 105))	('Cancer Genome Atlas', 'Disease', (14, 33))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (14, 33))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
65622	29794126	Smaller studies complement the TCGA effort by demonstrating activating FGFR1 mutations as well as different landscapes of aneuploidy in SDHB versus SDHAF2, SDHD and VHL-related cases.	('activating', 'PosReg', (60, 70))	('FGFR1', 'Gene', (71, 76))	('SDHD', 'Gene', (156, 160))	('aneuploidy', 'Disease', 'MESH:D000782', (122, 132))	('VHL', 'Disease', 'MESH:D006623', (165, 168))	('FGFR1', 'Gene', '2260', (71, 76))	('SDHAF2', 'Gene', '54949', (148, 154))	('VHL', 'Disease', (165, 168))	('SDHAF2', 'Gene', (148, 154))	('mutations', 'Var', (77, 86))	('SDHB', 'Gene', (136, 140))	('aneuploidy', 'Disease', (122, 132))	('SDHD', 'Gene', '6392', (156, 160))
65626	29794126	Two mechanisms underlying increased TERT expression were identified: TERT structural rearrangements and TERT promoter hypermethylation.	('TERT', 'Gene', '7015', (36, 40))	('hypermethylation', 'Var', (118, 134))	('TERT', 'Gene', (104, 108))	('TERT', 'Gene', '7015', (104, 108))	('TERT', 'Gene', (69, 73))	('increased', 'PosReg', (26, 35))	('TERT', 'Gene', '7015', (69, 73))	('TERT', 'Gene', (36, 40))
65629	29794126	Effect of the following agents was suggested: HSP90 inhibitor (NVP-AUY922) in PC12 cells, anthracyclines through inhibition of the hypoxia signaling pathway in mouse PCC cell lines and proteasome inhibitor (Bortezomib) in mouse PCC cell lines.	('PCC', 'Gene', (228, 231))	('hypoxia', 'Disease', (131, 138))	('Bortezomib', 'Chemical', 'MESH:D000069286', (207, 217))	('HSP90', 'Gene', '299331', (46, 51))	('PC12', 'CellLine', 'CVCL:0481', (78, 82))	('anthracyclines', 'Chemical', 'MESH:D018943', (90, 104))	('PCC', 'Gene', '1421', (166, 169))	('PCC', 'Gene', '1421', (228, 231))	('inhibition', 'NegReg', (113, 123))	('anthracyclines', 'Var', (90, 104))	('HSP90', 'Gene', (46, 51))	('mouse', 'Species', '10090', (222, 227))	('hypoxia', 'Disease', 'MESH:D000860', (131, 138))	('mouse', 'Species', '10090', (160, 165))	('PCC', 'Gene', (166, 169))
65631	29794126	This may have to be re-challenged as the mTORC1 complex was found to be overactivated in PPGL both of the head and neck and those harboring SDHx mutations.	('mTORC1', 'Gene', '382056', (41, 47))	('mutations', 'Var', (145, 154))	('SDHx', 'Gene', (140, 144))	('PPGL', 'Gene', (89, 93))	('SDHx', 'Chemical', '-', (140, 144))	('mTORC1', 'Gene', (41, 47))	('overactivated', 'PosReg', (72, 85))
65648	29794126	correlated outcome to somatic mutation status among 142 patients with APA; KCNJ5 mutations in young patients with APA emerged as a prognostic biomarker indicating resolution of hypertension.	('patients', 'Species', '9606', (56, 64))	('PA', 'Phenotype', 'HP:0011736', (115, 117))	('hypertension', 'Disease', (177, 189))	('PA', 'Phenotype', 'HP:0011736', (71, 73))	('hypertension', 'Phenotype', 'HP:0000822', (177, 189))	('patients', 'Species', '9606', (100, 108))	('KCNJ5', 'Gene', (75, 80))	('mutations', 'Var', (81, 90))	('hypertension', 'Disease', 'MESH:D006973', (177, 189))	('KCNJ5', 'Gene', '3762', (75, 80))
65650	29794126	Following the discovery of somatic mutations in KCNJ5 (potassium channel) as a driver of APA, macrolides were shown to selectively inhibit mutant KCNJ5 opening, which might provide the option for improved diagnosis and treatment.	('KCNJ5', 'Gene', (48, 53))	('inhibit', 'NegReg', (131, 138))	('KCNJ5', 'Gene', (146, 151))	('macrolides', 'Chemical', 'MESH:D018942', (94, 104))	('KCNJ5', 'Gene', '3762', (48, 53))	('KCNJ5', 'Gene', '3762', (146, 151))	('mutant', 'Var', (139, 145))	('PA', 'Phenotype', 'HP:0011736', (90, 92))	('opening', 'MPA', (152, 159))	('mutations', 'Var', (35, 44))
65656	29794126	Aldosterone-driver gene somatic mutations were detected in 21 of 26 (81%) of CYP11B2-positive cortical micronodules.	('CYP11B2', 'Gene', (77, 84))	('CYP11B2', 'Gene', '1585', (77, 84))	('Aldosterone-driver gene', 'Gene', (0, 23))	('mutations', 'Var', (32, 41))
65660	29794126	The molecular etiology behind a rare subtype of Cushing syndrome caused by ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) was unveiled; microduplications at chromosome 19q13 that contain the GIPR locus.	('GIPR', 'Gene', (152, 156))	('GIPR', 'Gene', '2696', (152, 156))	('microduplications at', 'Var', (172, 192))	('Cushing syndrome', 'Disease', 'MESH:D003480', (48, 64))	('glucose-dependent insulinotropic polypeptide receptor', 'Gene', '2696', (97, 150))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (48, 64))	('caused', 'Reg', (65, 71))	('GIPR', 'Gene', '2696', (227, 231))	('GIPR', 'Gene', (227, 231))	('Cushing syndrome', 'Disease', (48, 64))
65677	29794126	A study of 60 pediatric ACCs investigated the impact of germline TP53 mutations and showed similar prognosis and outcome regardless of mutation status.	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('ACCs', 'Gene', (24, 28))	('TP53', 'Gene', (65, 69))	('ACCs', 'Gene', '84680', (24, 28))	('germline', 'Var', (56, 64))	('ACC', 'Phenotype', 'HP:0006744', (24, 27))
65682	29794126	Traces of MUTYH deficiency can be found in tumor mutatomes through a unique signature of DNA mutations.	('DNA', 'Gene', (89, 92))	('mutations', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('MUTYH', 'Gene', (10, 15))	('MUTYH', 'Gene', '4595', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
65689	29794126	VAV2 was mentioned earlier as a prognostic factor, this study revealed molecular mechanisms involved and suggest that blocking VAV2 may be a new therapeutic approach to inhibit metastatic progression.	('VAV2', 'Gene', '7410', (0, 4))	('inhibit', 'NegReg', (169, 176))	('VAV2', 'Gene', (127, 131))	('VAV2', 'Gene', (0, 4))	('blocking', 'Var', (118, 126))	('metastatic progression', 'CPA', (177, 199))	('VAV2', 'Gene', '7410', (127, 131))
65714	28770300	dFdCDP inhibits ribonucleotide reductase, which is responsible for catalyzing the generation of deoxynucleoside triphosphates (dNTPs) for DNA synthesis.	('dNTPs', 'Chemical', '-', (127, 132))	('inhibits', 'NegReg', (7, 15))	('ribonucleotide reductase', 'Enzyme', (16, 40))	('dFdCDP', 'Chemical', '-', (0, 6))	('deoxynucleoside triphosphates', 'Chemical', '-', (96, 125))	('dFdCDP', 'Var', (0, 6))
65715	28770300	Inhibition of this enzyme by dFdCDP reduces intracellular deoxynucleotide concentrations, including dCTP.	('dFdCDP', 'Var', (29, 35))	('dCTP', 'MPA', (100, 104))	('Inhibition', 'NegReg', (0, 10))	('dCTP', 'Chemical', 'MESH:C024107', (100, 104))	('reduces', 'NegReg', (36, 43))	('dFdCDP', 'Chemical', '-', (29, 35))	('deoxynucleotide', 'Chemical', '-', (58, 73))	('intracellular deoxynucleotide concentrations', 'MPA', (44, 88))
65744	28770300	After achieving the first 2 DLTs at one DL, all subsequent patients without a known BRCA mutation were to be screened with the BRCAPRO computer program to assess the likelihood of having a BRCA mutation.	('mutation', 'Var', (194, 202))	('BRCA', 'Gene', '672', (189, 193))	('BRCA', 'Gene', '672', (127, 131))	('BRCA', 'Gene', (189, 193))	('BRCA', 'Gene', '672', (84, 88))	('patients', 'Species', '9606', (59, 67))	('BRCA', 'Gene', (84, 88))	('BRCA', 'Gene', (127, 131))
65745	28770300	Patients with a BRCAPRO likelihood >20% of having a BRCA mutation were counseled and referred for BRCA testing.	('mutation', 'Var', (57, 65))	('BRCA', 'Gene', (98, 102))	('BRCA', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (52, 56))	('Patients', 'Species', '9606', (0, 8))	('BRCA', 'Gene', '672', (16, 20))	('BRCA', 'Gene', '672', (98, 102))	('BRCA', 'Gene', (16, 20))
65746	28770300	Dose escalation on the 28-day schedule was to be split into two cohorts (BRCA mutant vs BRCA wild-type), with each cohort having a separate dose modification schema, in order to determine whether or not BRCA status influenced toxicity.	('toxicity', 'Disease', 'MESH:D064420', (226, 234))	('BRCA', 'Gene', '672', (203, 207))	('BRCA', 'Gene', '672', (73, 77))	('influenced', 'Reg', (215, 225))	('toxicity', 'Disease', (226, 234))	('BRCA', 'Gene', (203, 207))	('BRCA', 'Gene', (73, 77))	('BRCA', 'Gene', '672', (88, 92))	('mutant', 'Var', (78, 84))	('BRCA', 'Gene', (88, 92))
65747	28770300	This was done to address the concern that BRCA mutated patients might be at increased risk of toxicity with the combination of a PARP inhibitor and a chemotherapeutic agent.	('PARP', 'Protein', (129, 133))	('BRCA', 'Gene', '672', (42, 46))	('BRCA', 'Gene', (42, 46))	('combination', 'Interaction', (112, 123))	('toxicity', 'Disease', 'MESH:D064420', (94, 102))	('mutated', 'Var', (47, 54))	('patients', 'Species', '9606', (55, 63))	('toxicity', 'Disease', (94, 102))
65792	28770300	At DL1 and DL2, the BRCA mutated patients (fallopian tube cancer and breast cancer, respectively) did not experience a DLT.	('BRCA', 'Gene', '672', (20, 24))	('DL2', 'Var', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('patients', 'Species', '9606', (33, 41))	('BRCA', 'Gene', (20, 24))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('fallopian tube cancer', 'Disease', (43, 64))	('DL1', 'Gene', '28514', (3, 6))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('fallopian tube cancer', 'Phenotype', 'HP:0030394', (43, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('DL1', 'Gene', (3, 6))	('fallopian tube cancer', 'Disease', 'MESH:D005185', (43, 64))
65793	28770300	At DL3, the BRCA mutated patient did experience a DLT, as did a BRCAPRO negative patient.	('patient', 'Species', '9606', (81, 88))	('BRCA', 'Gene', '672', (64, 68))	('patient', 'Species', '9606', (25, 32))	('BRCA', 'Gene', '672', (12, 16))	('BRCA', 'Gene', (64, 68))	('BRCA', 'Gene', (12, 16))	('DLT', 'MPA', (50, 53))	('mutated', 'Var', (17, 24))
65795	28770300	In the 28-day patient cohort (11 patients), gemcitabine (500 mg/m2 days 1, 8, and 15) in combination with veliparib (10 mg BID days 1-21) was not clinically tolerable with DLTs noted in 2 of 7 BRCA non-mutated and 1 of 1 BRCA mutated patients.	('patient', 'Species', '9606', (33, 40))	('patients', 'Species', '9606', (33, 41))	('veliparib', 'Chemical', 'MESH:C521013', (106, 115))	('BID', 'Gene', '637', (123, 126))	('BRCA', 'Gene', '672', (221, 225))	('BRCA', 'Gene', '672', (193, 197))	('patient', 'Species', '9606', (234, 241))	('patient', 'Species', '9606', (14, 21))	('patients', 'Species', '9606', (234, 242))	('BRCA', 'Gene', (193, 197))	('BRCA', 'Gene', (221, 225))	('BID', 'Gene', (123, 126))	('gemcitabine', 'Chemical', 'MESH:C056507', (44, 55))	('500 mg/m2', 'Var', (57, 66))
65866	28770300	Lastly, a recent report describes the combination of CEP-9722, a prodrug of the PARP-1/2 inhibitor CEP-8983, combined with cisplatin and gemcitabine.	('PARP-1/2', 'Gene', (80, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('gemcitabine', 'Chemical', 'MESH:C056507', (137, 148))	('CEP-9722', 'Var', (53, 61))	('PARP-1/2', 'Gene', '64761;142;10038', (80, 88))
65901	28770300	A randomized phase II study of gemcitabine, cisplatin, with or without veliparib in patients with advanced pancreatic cancer and a known BRCA/PALB2 mutation is currently ongoing (ClinicalTrials.gov Identifier: NCT01585805).	('BRCA', 'Gene', (137, 141))	('pancreatic cancer', 'Disease', (107, 124))	('patients', 'Species', '9606', (84, 92))	('veliparib', 'Chemical', 'MESH:C521013', (71, 80))	('gemcitabine', 'Chemical', 'MESH:C056507', (31, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('PALB2', 'Gene', '79728', (142, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('mutation', 'Var', (148, 156))	('BRCA', 'Gene', '672', (137, 141))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))	('PALB2', 'Gene', (142, 147))
65902	27105537	Co-inhibition of EGFR and IGF1R synergistically impacts therapeutically on adrenocortical carcinoma Adrenocortical carcinoma (ACC) is a rare tumor with very poor prognosis and no effective treatment.	('impacts', 'Reg', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('adrenocortical carcinoma', 'Disease', (75, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (100, 124))	('IGF1R', 'Gene', (26, 31))	('tumor', 'Disease', (141, 146))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (100, 124))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (75, 99))	('EGFR', 'Gene', '1956', (17, 21))	('IGF1R', 'Gene', '3480', (26, 31))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (75, 99))	('Adrenocortical carcinoma', 'Disease', (100, 124))	('Co-inhibition', 'Var', (0, 13))	('EGFR', 'Gene', (17, 21))
65909	27105537	Erlotinib and NVP-AEW541 significantly inhibited cell viability and induced apoptosis by blocking phosphorylation of MEK/ERK and AKT, respectively.	('ERK', 'Gene', '5594', (121, 124))	('ERK', 'Gene', (121, 124))	('AEW541', 'Chemical', '-', (18, 24))	('phosphorylation', 'MPA', (98, 113))	('inhibited', 'NegReg', (39, 48))	('cell viability', 'CPA', (49, 63))	('AKT', 'Gene', '207', (129, 132))	('MEK', 'Gene', (117, 120))	('MEK', 'Gene', '5609', (117, 120))	('NVP-AEW541', 'Var', (14, 24))	('apoptosis', 'CPA', (76, 85))	('AKT', 'Gene', (129, 132))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))	('blocking', 'NegReg', (89, 97))
65911	27105537	More importantly, the combination of Erlotinib and NVP-AEW541 enhances anti-tumour efficacy compared to treatment with either agent alone or to untreated control in vitro and vivo.	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('NVP-AEW541', 'Var', (51, 61))	('combination', 'Interaction', (22, 33))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('Erlotinib', 'Gene', (37, 46))	('AEW541', 'Chemical', '-', (55, 61))	('enhances', 'PosReg', (62, 70))	('Erlotinib', 'Chemical', 'MESH:D000069347', (37, 46))	('tumour', 'Disease', (76, 82))
65919	27105537	It has been demonstrated that IGF1R inhibitors could inhibit proliferation and promote apoptosis, even with alleviation of mitotane-associated cytotoxicity in ACC cell lines.	('mitotane', 'Chemical', 'MESH:D008939', (123, 131))	('inhibit', 'NegReg', (53, 60))	('inhibitors', 'Var', (36, 46))	('cytotoxicity', 'Disease', (143, 155))	('IGF1R', 'Gene', (30, 35))	('apoptosis', 'CPA', (87, 96))	('IGF1R', 'Gene', '3480', (30, 35))	('promote', 'PosReg', (79, 86))	('cytotoxicity', 'Disease', 'MESH:D064420', (143, 155))	('proliferation', 'CPA', (61, 74))
65921	27105537	Therefore, all these results demonstrated that single inhibition of IGF1R is not sufficient to improve overall survival, owning to heterogeneity of ACC, and led our insight into alternative combination therapy.	('IGF1R', 'Gene', '3480', (68, 73))	('IGF1R', 'Gene', (68, 73))	('improve', 'PosReg', (95, 102))	('single inhibition', 'Var', (47, 64))
65926	27105537	In this study, we firstly evaluated the expression of IGF1R, EGFR and its signaling protein expression in human adrenocortical tumors, then investigated the crosstalk between EGFR and IGF1R pathway, and confirmed the therapeutic effect of co-inhibition of EGFR and IGF1R in ACC.	('IGF1R', 'Gene', '3480', (265, 270))	('human', 'Species', '9606', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('IGF1R', 'Gene', '3480', (184, 189))	('co-inhibition', 'Var', (239, 252))	('adrenocortical tumors', 'Disease', (112, 133))	('IGF1R', 'Gene', (184, 189))	('IGF1R', 'Gene', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (256, 260))	('EGFR', 'Gene', (175, 179))	('IGF1R', 'Gene', '3480', (54, 59))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (112, 133))	('IGF1R', 'Gene', (54, 59))	('ACC', 'Disease', (274, 277))	('EGFR', 'Gene', '1956', (256, 260))	('EGFR', 'Gene', '1956', (175, 179))	('EGFR', 'Gene', (61, 65))
65928	27105537	As shown in Figure 1, the frequency of positivity of EGFR in two groups was 10/15 (66.67%) and 6/20 (30.0%, P=0.044, Figure 1a-1b).	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', '1956', (53, 57))	('positivity', 'Var', (39, 49))
65932	27105537	Furthermore, the frequency of positivity of p-ERK was 11/15 (73.3%) in ACCs, and 7/20 (35.0%) in ACAs (P=0.041, Figure 1e-1f).	('p-ERK', 'Gene', (44, 49))	('positivity', 'Var', (30, 40))	('p-ERK', 'Gene', '9451', (44, 49))
65937	27105537	NVP-AEW541 could suppress IGF-1 stimulated phosphorylation of IGF1R and downstream AKT, but the levels of p-mTOR was unchanged (Figure 2b and Figure 2c).	('AKT', 'Gene', '207', (83, 86))	('IGF1R', 'Gene', '3480', (62, 67))	('mTOR', 'Gene', (108, 112))	('mTOR', 'Gene', '2475', (108, 112))	('phosphorylation', 'MPA', (43, 58))	('IGF-1', 'Gene', '3479', (26, 31))	('IGF-1', 'Gene', (26, 31))	('AKT', 'Gene', (83, 86))	('NVP-AEW541', 'Var', (0, 10))	('IGF1R', 'Gene', (62, 67))	('suppress', 'NegReg', (17, 25))	('AEW541', 'Chemical', '-', (4, 10))
65940	27105537	However, single inhibition of IGF1R by NVP-AEW541 could induce compensatory activation of ERK (Figure 3b).	('ERK', 'Gene', (90, 93))	('NVP-AEW541', 'Var', (39, 49))	('AEW541', 'Chemical', '-', (43, 49))	('IGF1R', 'Gene', (30, 35))	('IGF1R', 'Gene', '3480', (30, 35))	('ERK', 'Gene', '5594', (90, 93))	('activation', 'PosReg', (76, 86))
65941	27105537	To further assess the association of ERK and mTOR signaling, we used PD184352 and NVP-AEW541 in order to dual inhibition of ERK and IGF1R, and the results showed that co-inhibition of ERK and IGF1R could downregulated the level of p-mTOR (Figure 3c).	('mTOR', 'Gene', (233, 237))	('ERK', 'Gene', (124, 127))	('ERK', 'Gene', '5594', (184, 187))	('IGF1R', 'Gene', (132, 137))	('ERK', 'Gene', '5594', (124, 127))	('co-inhibition', 'Var', (167, 180))	('mTOR', 'Gene', '2475', (45, 49))	('IGF1R', 'Gene', '3480', (132, 137))	('ERK', 'Gene', '5594', (37, 40))	('ERK', 'Gene', (184, 187))	('IGF1R', 'Gene', (192, 197))	('ERK', 'Gene', (37, 40))	('PD184352', 'Chemical', 'MESH:C120227', (69, 77))	('IGF1R', 'Gene', '3480', (192, 197))	('downregulated', 'NegReg', (204, 217))	('mTOR', 'Gene', '2475', (233, 237))	('AEW541', 'Chemical', '-', (86, 92))	('mTOR', 'Gene', (45, 49))
65944	27105537	Our results showed that coinhibition therapy could simultaneously block downstream signaling components of EGFR and IGF1R pathways, including p-mTOR (Figure 4).	('EGFR', 'Gene', '1956', (107, 111))	('block', 'NegReg', (66, 71))	('IGF1R', 'Gene', (116, 121))	('EGFR', 'Gene', (107, 111))	('downstream signaling', 'MPA', (72, 92))	('IGF1R', 'Gene', '3480', (116, 121))	('coinhibition', 'Var', (24, 36))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))
65946	27105537	The results of MTT assay showed that NVP-AEW541 induced a dose and time-dependent decrease of cell viability in SW13 and H295R cells, with IC50 values of 1.06 muM and 0.26 muM at 72 h of treatment, respectively (Figure 5b and 5e).	('SW13', 'CellLine', 'CVCL:0542', (112, 116))	('muM', 'Gene', '56925', (172, 175))	('muM', 'Gene', '56925', (159, 162))	('decrease', 'NegReg', (82, 90))	('muM', 'Gene', (172, 175))	('muM', 'Gene', (159, 162))	('cell viability', 'CPA', (94, 108))	('AEW541', 'Chemical', '-', (41, 47))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('NVP-AEW541', 'Var', (37, 47))
65948	27105537	The combination of Erlotinib and NVP-AEW541 showed a significant synergistic anti-proliferative effect on SW13 cells (CI = 0.58+-0.23, range: 0.24-0.85) and H295R cells (CI =0.20+-0.05, range: 0.12-0.26; Figure 5c and 5f), in which a CI <0.9 indicate synergism.	('SW13', 'CellLine', 'CVCL:0542', (106, 110))	('NVP-AEW541', 'Var', (33, 43))	('AEW541', 'Chemical', '-', (37, 43))	('anti-proliferative effect', 'CPA', (77, 102))	('Erlotinib', 'Chemical', 'MESH:D000069347', (19, 28))
65949	27105537	Additionally, Annexin V-FITC/PI double staining results showed that increasing concentration of Erlotinib or NVP-AEW541 could induce early apoptosis and lead to cell death in both cell lines.	('Erlotinib', 'Gene', (96, 105))	('Annexin V', 'Gene', '308', (14, 23))	('induce', 'PosReg', (126, 132))	('NVP-AEW541', 'Var', (109, 119))	('Annexin V', 'Gene', (14, 23))	('Erlotinib', 'Chemical', 'MESH:D000069347', (96, 105))	('AEW541', 'Chemical', '-', (113, 119))	('death', 'Disease', 'MESH:D003643', (166, 171))	('death', 'Disease', (166, 171))	('lead to', 'Reg', (153, 160))
65951	27105537	Furthermore, the combination of Erlotinib and NVP-AEW541 showed a significant synergistic induction of early apoptosis, which was 32.62+-1.05 and 28.05+-2.61 % for SW13 and H295R (P<0.01; Figure 5h and 5j).	('SW13', 'CellLine', 'CVCL:0542', (164, 168))	('AEW541', 'Chemical', '-', (50, 56))	('Erlotinib', 'Gene', (32, 41))	('combination', 'Interaction', (17, 28))	('SW13', 'Var', (164, 168))	('early apoptosis', 'CPA', (103, 118))	('Erlotinib', 'Chemical', 'MESH:D000069347', (32, 41))	('H295R', 'Var', (173, 178))	('NVP-AEW541', 'Var', (46, 56))
65956	27105537	Furthermore, the combination of Erlotinib and NVP-AEW541 showed a significant synergistic inhibition of xenograft tumor growth since day 5 (P<0.01), with average volume at 1.06+-0.29 cm3.	('inhibition', 'NegReg', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('AEW541', 'Chemical', '-', (50, 56))	('tumor', 'Disease', (114, 119))	('combination', 'Interaction', (17, 28))	('Erlotinib', 'Chemical', 'MESH:D000069347', (32, 41))	('NVP-AEW541', 'Var', (46, 56))
65966	27105537	Consistent with previous reports, blockage of IGF1R by NVP-AEW541 could inhibit cell viability by suppression of AKT protein, and induce moderate apoptosis.	('induce', 'Reg', (130, 136))	('IGF1R', 'Gene', '3480', (46, 51))	('blockage', 'NegReg', (34, 42))	('AKT', 'Gene', '207', (113, 116))	('NVP-AEW541', 'Var', (55, 65))	('cell viability', 'CPA', (80, 94))	('inhibit', 'NegReg', (72, 79))	('AKT', 'Gene', (113, 116))	('AEW541', 'Chemical', '-', (59, 65))	('apoptosis', 'CPA', (146, 155))	('suppression', 'NegReg', (98, 109))	('IGF1R', 'Gene', (46, 51))
65967	27105537	Meanwhile, we found that NVP-AEW541 delayed slightly tumor growth in SW13 cell xenograft, which was in line with previous reports of H295R and RL251 cells.	('AEW541', 'Chemical', '-', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('SW13', 'CellLine', 'CVCL:0542', (69, 73))	('NVP-AEW541', 'Var', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('delayed', 'NegReg', (36, 43))
65971	27105537	The therapy by IGF1R inhibitor IMC-A12 and mitotane was then reported to present with limited efficacy, with only one partial response.	('IGF1R', 'Gene', (15, 20))	('mitotane', 'Chemical', 'MESH:D008939', (43, 51))	('IGF1R', 'Gene', '3480', (15, 20))	('inhibitor', 'Var', (21, 30))	('IMC-A12', 'Gene', (31, 38))
65973	27105537	Recently, another IGF1R inhibitor OSI-906 was investigated in patients with advanced ACC, eventually the results also revealed little therapeutic effects, in which OSI-906 could not increase overall survival of ACC as compared with placebo group.	('OSI-906', 'Chemical', 'MESH:C551528', (164, 171))	('OSI-906', 'Var', (164, 171))	('OSI-906', 'Chemical', 'MESH:C551528', (34, 41))	('IGF1R', 'Gene', (18, 23))	('patients', 'Species', '9606', (62, 70))	('IGF1R', 'Gene', '3480', (18, 23))
65980	27105537	Moreover, another study revealed that activation of IGF1R could lead to recruitment and activation of c-Src, which induced the phosphorylation of EGFR.	('recruitment', 'MPA', (72, 83))	('activation', 'Var', (38, 48))	('IGF1R', 'Gene', '3480', (52, 57))	('phosphorylation', 'MPA', (127, 142))	('EGFR', 'Gene', '1956', (146, 150))	('lead to', 'Reg', (64, 71))	('EGFR', 'Gene', (146, 150))	('c-Src', 'Gene', (102, 107))	('c-Src', 'Gene', '6714', (102, 107))	('activation', 'MPA', (88, 98))	('IGF1R', 'Gene', (52, 57))	('induced', 'Reg', (115, 122))
65981	27105537	In this study, we found that single inhibition of IGF1R signaling pathway by NVP-AEW541 could lead to compensatory activation upregulation of p-ERK in ACC.	('p-ERK', 'Gene', '9451', (142, 147))	('p-ERK', 'Gene', (142, 147))	('IGF1R', 'Gene', (50, 55))	('NVP-AEW541', 'Var', (77, 87))	('inhibition', 'NegReg', (36, 46))	('activation upregulation', 'PosReg', (115, 138))	('AEW541', 'Chemical', '-', (81, 87))	('IGF1R', 'Gene', '3480', (50, 55))
65989	27105537	Additionally, it has been reported that this combinational regimen would be well tolerated owning to lack of duplicate toxicities between inhibitors of IGF1R and EGFR.	('toxicities', 'Disease', 'MESH:D064420', (119, 129))	('IGF1R', 'Gene', '3480', (152, 157))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('toxicities', 'Disease', (119, 129))	('IGF1R', 'Gene', (152, 157))	('inhibitors', 'Var', (138, 148))
65992	27105537	We found that co-inhibition of EGFR and IGF1R could synergistically inhibit cell viability and induce apoptosis potently in two ACC cell lines.	('EGFR', 'Gene', '1956', (31, 35))	('apoptosis', 'CPA', (102, 111))	('IGF1R', 'Gene', (40, 45))	('EGFR', 'Gene', (31, 35))	('cell viability', 'CPA', (76, 90))	('inhibit', 'NegReg', (68, 75))	('IGF1R', 'Gene', '3480', (40, 45))	('co-inhibition', 'Var', (14, 27))	('induce', 'Reg', (95, 101))
65993	27105537	Moreover, the combination of Erlotinib and NVP-AEW541 showed greater inhibition of tumour growth than either agent alone in xenograft tumor growth.	('tumour', 'Disease', (83, 89))	('Erlotinib', 'Gene', (29, 38))	('AEW541', 'Chemical', '-', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('Erlotinib', 'Chemical', 'MESH:D000069347', (29, 38))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('combination', 'Interaction', (14, 25))	('inhibition', 'NegReg', (69, 79))	('tumor', 'Disease', (134, 139))	('NVP-AEW541', 'Var', (43, 53))
65994	27105537	Therefore, it could be presumed that coinhibition of EGFR and IGF1R would be promising therapy for patients with ACC.	('IGF1R', 'Gene', '3480', (62, 67))	('coinhibition', 'Var', (37, 49))	('patients', 'Species', '9606', (99, 107))	('ACC', 'Disease', (113, 116))	('EGFR', 'Gene', '1956', (53, 57))	('IGF1R', 'Gene', (62, 67))	('EGFR', 'Gene', (53, 57))
65995	27105537	In this study, we found the cross talk between EGFR and IGF1R downstream signaling pathways in ACC, in which inhibition of IGF1R could induce compensatory activation of ERK pathway.	('IGF1R', 'Gene', '3480', (56, 61))	('ERK', 'Gene', '5594', (169, 172))	('ERK', 'Gene', (169, 172))	('inhibition', 'Var', (109, 119))	('cross talk', 'Reg', (28, 38))	('EGFR', 'Gene', (47, 51))	('IGF1R', 'Gene', (123, 128))	('ACC', 'Disease', (95, 98))	('EGFR', 'Gene', '1956', (47, 51))	('IGF1R', 'Gene', (56, 61))	('IGF1R', 'Gene', '3480', (123, 128))	('activation', 'PosReg', (155, 165))
66035	24382691	RMS tumors diagnosed in 11 TP53 germline mutation carriers all exhibited nonalveolar, anaplastic histology as evidenced by the presence of enlarged hyperchromatic nuclei with or without atypical mitotic figures.	('exhibited', 'Reg', (63, 72))	('TP53', 'Gene', (27, 31))	('germline mutation', 'Var', (32, 49))	('RMS tumors', 'Disease', 'MESH:D009369', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('enlarged hyperchromatic', 'Disease', (139, 162))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('enlarged hyperchromatic', 'Disease', 'MESH:D006529', (139, 162))	('RMS tumors', 'Disease', (0, 10))
66037	24382691	The overall frequency of TP53 germline mutations was 73% (11 of 15 children) in pediatric patients with anRMS.	('patients', 'Species', '9606', (90, 98))	('TP53', 'Gene', (25, 29))	('children', 'Species', '9606', (67, 75))	('germline mutations', 'Var', (30, 48))
66038	24382691	The frequency of TP53 germline mutations in children with anRMS was 100% (5 of 5 children) for those with a family cancer history consistent with Li-Fraumeni syndrome (LFS), and 80% (4 of 5 children) for those without an LFS cancer phenotype.	('cancer', 'Disease', (115, 121))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (146, 166))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('germline mutations', 'Var', (22, 40))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('children', 'Species', '9606', (190, 198))	('children', 'Species', '9606', (44, 52))	('Li-Fraumeni syndrome', 'Disease', (146, 166))	('LFS cancer', 'Disease', (221, 231))	('children', 'Species', '9606', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('LFS cancer', 'Disease', 'MESH:D016864', (221, 231))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('TP53', 'Gene', (17, 21))
66043	24382691	It is clear that, in mouse models, aberrations in distinct oncogenic pathways correlate with the induction of RMS tumors that share uniform histological appearance, such as pleomorphic RMS due to inactivation of TP53 with or without introduction of oncogenic Kras and highly differentiated RMS due to activation of Sonic Hedgehog signaling.	('inactivation', 'Var', (196, 208))	('Kras', 'Gene', (259, 263))	('RMS tumors', 'Disease', (110, 120))	('Kras', 'Gene', '16653', (259, 263))	('mouse', 'Species', '10090', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('RMS tumors', 'Disease', 'MESH:D009369', (110, 120))	('pleomorphic RMS', 'Disease', (173, 188))	('oncogenic pathways', 'Pathway', (59, 77))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('highly differentiated RMS', 'CPA', (268, 293))	('TP53', 'Gene', (212, 216))
66045	24382691	In humans, genetic susceptibility to develop RMS has been linked to germline mutations in PTCH1, HRAS, NF1, DICER1, and TP53.	('NF1', 'Gene', '4763', (103, 106))	('linked', 'Reg', (58, 64))	('PTCH1', 'Gene', '5727', (90, 95))	('HRAS', 'Gene', '3265', (97, 101))	('DICER1', 'Gene', (108, 114))	('RMS', 'Disease', (45, 48))	('HRAS', 'Gene', (97, 101))	('DICER1', 'Gene', '23405', (108, 114))	('mutations', 'Var', (77, 86))	('humans', 'Species', '9606', (3, 9))	('TP53', 'Gene', (120, 124))	('PTCH1', 'Gene', (90, 95))	('NF1', 'Gene', (103, 106))	('develop', 'PosReg', (37, 44))
66046	24382691	In a previous study, 3 of 13 children with RMS diagnosed under 3 years of age, including 1 child with alveolar RMS and 2 children with nonalveolar RMS, were found to have TP53 germline mutations.	('alveolar RMS', 'Disease', (138, 150))	('children', 'Species', '9606', (121, 129))	('child', 'Species', '9606', (29, 34))	('TP53 germline mutations', 'Var', (171, 194))	('children', 'Species', '9606', (29, 37))	('child', 'Species', '9606', (91, 96))	('alveolar RMS', 'Disease', 'MESH:D002282', (138, 150))	('alveolar RMS', 'Disease', 'MESH:D002282', (102, 114))	('alveolar RMS', 'Disease', (102, 114))	('child', 'Species', '9606', (121, 126))
66049	24382691	Our review of 8 RMS tumors arising in children with TP53 germline mutations revealed that these tumors uniformly exhibited anaplasia, a distinctive histological subtype characterized by enlarged, hyperchromatic nuclei.	('mutations', 'Var', (66, 75))	('tumors', 'Disease', (20, 26))	('anaplasia', 'Disease', (123, 132))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('anaplasia', 'Disease', 'MESH:D000708', (123, 132))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('RMS tumors', 'Disease', (16, 26))	('TP53', 'Gene', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('RMS tumors', 'Disease', 'MESH:D009369', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('exhibited', 'Reg', (113, 122))	('children', 'Species', '9606', (38, 46))
66057	24382691	All mutations were previously reported in the germline (IARC database, R16, November 2012; Petitjean et al), or predicted aberrant function based on introduction of a termination codon or disruption of a splice site.	('mutations', 'Var', (4, 13))	('disruption', 'Var', (188, 198))	('R16', 'Gene', '6510', (71, 74))	('R16', 'Gene', (71, 74))
66072	24382691	TP53 mutations in 6 children with anRMS included in this study comprised single-nucleotide variants (SNVs) in the coding sequence of exons 4, 5, 8, and 10 of human TP53 resulting in nonsense mutations (Table 1, cases 3, 5, 7, 8) or altered splicing (Table 1, cases 2 and 10).	('single-nucleotide variants', 'Var', (73, 99))	('TP53', 'Gene', (164, 168))	('TP53', 'Gene', (0, 4))	('human', 'Species', '9606', (158, 163))	('mutations', 'Var', (5, 14))	('altered', 'Reg', (232, 239))	('splicing', 'MPA', (240, 248))	('children', 'Species', '9606', (20, 28))	('nonsense mutations', 'Var', (182, 200))
66074	24382691	Frameshift mutations in exons 4 and 8 of TP53 were found in 2 patients (Table 1, cases 6 and 9).	('TP53', 'Gene', (41, 45))	('patients', 'Species', '9606', (62, 70))	('found', 'Reg', (51, 56))	('Frameshift mutations in', 'Var', (0, 23))
66075	24382691	Four mutations were previously reported in the Catalogue of Somatic Mutations in Cancer (Table 1, case 3/COSM46163, case 5/COSM306146, case 7/COSM10663, case 8/COSM10727).	('Cancer', 'Disease', 'MESH:D009369', (81, 87))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Cancer', 'Disease', (81, 87))	('5/COSM306146', 'Var', (121, 133))
66077	24382691	Thus, all 5 children (100%) diagnosed with anRMS under 3 years, and 6 of 8 children (75%) diagnosed with anRMS between 3 and 7 years of age were TP53 mutation carriers.	('TP53', 'Gene', (145, 149))	('mutation', 'Var', (150, 158))	('children', 'Species', '9606', (12, 20))	('children', 'Species', '9606', (75, 83))
66082	24382691	The frequency of germline TP53 mutations in children with anRMS was 100% (5 of 5 children) for those with a family cancer history consistent with Li-Fraumeni syndrome (LFS), and 80% (4 of 5 children) for those without an LFS cancer phenotype.	('TP53', 'Gene', (26, 30))	('cancer', 'Disease', (115, 121))	('mutations', 'Var', (31, 40))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (146, 166))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('children', 'Species', '9606', (190, 198))	('children', 'Species', '9606', (44, 52))	('Li-Fraumeni syndrome', 'Disease', (146, 166))	('LFS cancer', 'Disease', (221, 231))	('children', 'Species', '9606', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('LFS cancer', 'Disease', 'MESH:D016864', (221, 231))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
66086	24382691	International RMS Study Group (IRSG) grouping/staging information was available on 9 (stage)/10 (group) germline TP53 mutation carriers in this cohort, and primary tumor site was available on all 11 children (Table 3 and Supporting Table 3).	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('IRS', 'Gene', '3376', (31, 34))	('IRS', 'Gene', (31, 34))	('mutation', 'Var', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('TP53', 'Gene', (113, 117))	('children', 'Species', '9606', (199, 207))
66087	24382691	The majority of patients with mutated germline TP53 had IRSG group III tumors (gross residual disease after initial surgical intervention).	('mutated germline', 'Var', (30, 46))	('patients', 'Species', '9606', (16, 24))	('III tumors', 'Disease', 'MESH:D009369', (67, 77))	('IRS', 'Gene', '3376', (56, 59))	('germline', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('IRS', 'Gene', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('TP53', 'Gene', (47, 51))	('III tumors', 'Disease', (67, 77))
66088	24382691	Distant metastases at diagnosis were only present in one child who carried a TP53 splice site mutation (Table 3, case 1).	('TP53 splice site mutation', 'Var', (77, 102))	('child', 'Species', '9606', (57, 62))	('metastases', 'Disease', 'MESH:D009362', (8, 18))	('metastases', 'Disease', (8, 18))
66089	24382691	Seven of 11 anRMS tumors in TP53 germline mutation carriers arose at unfavorable disease sites in the extremities, trunk or parameningeal space (Supporting Table 3).	('RMS tumors', 'Disease', (14, 24))	('TP53', 'Gene', (28, 32))	('arose', 'Reg', (60, 65))	('RMS tumors', 'Disease', 'MESH:D009369', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('germline mutation carriers', 'Var', (33, 59))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
66095	24382691	Several classification schemes were developed to identify individuals at risk for germline TP53 mutations based on family history of cancer in first- and second-degree relatives.	('TP53', 'Gene', (91, 95))	('germline', 'Var', (82, 90))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mutations', 'Var', (96, 105))
66099	24382691	Although adrenocortical carcinomas appeared to be more common in female TP53 germline mutation carriers, 7 of 11 children with anRMS and germline TP53 mutations in this cohort were males (Table 1).	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (9, 34))	('common', 'Reg', (55, 61))	('TP53', 'Gene', (72, 76))	('children', 'Species', '9606', (113, 121))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (9, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))	('adrenocortical carcinomas', 'Disease', (9, 34))	('mutation', 'Var', (86, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (9, 34))
66111	24382691	TP53 mutations were reported in 2 PAX3:-FOXO1a-positive human alveolar RMS cell lines (Rh41 and Rh30), but it is not known if the TP53 mutations in these cell lines originated in the patients' germlines, tumors, or during ex vivo culture.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('TP53', 'Gene', (0, 4))	('alveolar RMS', 'Disease', 'MESH:D002282', (62, 74))	('alveolar RMS', 'Disease', (62, 74))	('Rh30', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('FOXO1a', 'Gene', '2308', (40, 46))	('mutations', 'Var', (5, 14))	('PAX3', 'Gene', '5077', (34, 38))	('human', 'Species', '9606', (56, 61))	('PAX3', 'Gene', (34, 38))	('tumors', 'Disease', (204, 210))	('Rh30', 'Gene', '6007', (96, 100))	('FOXO1a', 'Gene', (40, 46))	('TP53', 'Gene', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('patients', 'Species', '9606', (183, 191))
66112	24382691	Moreover, Takahashi et al reported TP53 mutations of unknown germline status in 4 alveolar tumors, and Diller et al described a TP53 germline mutation in one child with alveolar RMS.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('alveolar tumors', 'Disease', (82, 97))	('alveolar tumors', 'Disease', 'MESH:D002282', (82, 97))	('alveolar RMS', 'Disease', 'MESH:D002282', (169, 181))	('TP53', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('alveolar RMS', 'Disease', (169, 181))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('child', 'Species', '9606', (158, 163))
66114	24382691	Future studies are needed to evaluate germline TP53 mutations in children with fusion-positive alveolar RMS and to determine if TP53 germline mutations confer susceptibility to develop human fusion-positive alveolar RMS with or without anaplasia.	('mutations', 'Var', (52, 61))	('children', 'Species', '9606', (65, 73))	('human', 'Species', '9606', (185, 190))	('TP53', 'Gene', (128, 132))	('alveolar RMS', 'Disease', 'MESH:D002282', (207, 219))	('alveolar RMS', 'Disease', (207, 219))	('alveolar RMS', 'Disease', 'MESH:D002282', (95, 107))	('anaplasia', 'Disease', 'MESH:D000708', (236, 245))	('alveolar RMS', 'Disease', (95, 107))	('susceptibility', 'Reg', (159, 173))	('anaplasia', 'Disease', (236, 245))	('TP53', 'Gene', (47, 51))
66116	24382691	Two lines of evidence in the published literature support the hypothesis that TP53 pathway activation contributes to the biology of anRMS: 1) inactivation of TP53 with or without introduction of oncogenic Kras in skeletal muscle cells results in formation of high-grade pleomorphic RMS in mice; and 2) anaplastic variants of other embryonal tumors (ie, Wilms tumor and medulloblastoma) were previously linked to germline and somatic mutations disrupting the p53 pathway.	('TP53', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('p53 pathway', 'Pathway', (458, 469))	('Wilms tumor', 'Phenotype', 'HP:0002667', (353, 364))	('disrupting', 'NegReg', (443, 453))	('Wilms tumor', 'Disease', (353, 364))	('mice', 'Species', '10090', (289, 293))	('Kras', 'Gene', (205, 209))	('Kras', 'Gene', '16653', (205, 209))	('medulloblastoma', 'Disease', 'MESH:D008527', (369, 384))	('mutations', 'Var', (433, 442))	('medulloblastoma', 'Phenotype', 'HP:0002885', (369, 384))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('embryonal tumors', 'Phenotype', 'HP:0002898', (331, 347))	('medulloblastoma', 'Disease', (369, 384))	('Wilms tumor', 'Disease', 'MESH:D009396', (353, 364))	('embryonal tumors', 'Disease', (331, 347))	('inactivation', 'Var', (142, 154))	('embryonal tumors', 'Disease', 'MESH:D009373', (331, 347))
66117	24382691	It is conceivable that early (germline), inactivating TP53 mutations preferentially drive target cells for sarcomatous transformation to assume an anaplastic phenotype, perhaps due to early catastrophic DNA rearrangements as previously reported in medulloblastomas arising in the context of TP53 germline mutations.	('preferentially', 'PosReg', (69, 83))	('sarcomatous', 'Disease', (107, 118))	('medulloblastomas', 'Disease', 'MESH:D008527', (248, 264))	('sarcomatous transformation', 'Phenotype', 'HP:0100242', (107, 133))	('medulloblastoma', 'Phenotype', 'HP:0002885', (248, 263))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('mutations', 'Var', (59, 68))	('medulloblastomas', 'Disease', (248, 264))	('inactivating', 'Var', (41, 53))	('TP53', 'Gene', (54, 58))	('sarcomatous', 'Disease', 'MESH:D018316', (107, 118))	('drive', 'PosReg', (84, 89))
66119	24382691	In our cohort, TP53 expression was evaluated by IHC in 8 anRMS tumors arising in TP53 germline mutation carriers (Table 1, cases 1-8).	('germline mutation', 'Var', (86, 103))	('RMS tumors', 'Disease', 'MESH:D009369', (59, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('RMS tumors', 'Disease', (59, 69))	('TP53', 'Gene', (81, 85))
66120	24382691	Nuclear TP53 staining was positive in >= 50% of tumor cells in 4 tumors arising in children with mutations predicted to stabilize the protein.	('mutations', 'Var', (97, 106))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (65, 70))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('children', 'Species', '9606', (83, 91))
66121	24382691	Absence of TP53 in the remaining 4 tumors correlated with the presence of germline TP53 mutations that predicted a truncated or deleted product.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('TP53', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('deleted product', 'MPA', (128, 143))	('truncated', 'MPA', (115, 124))
66126	24382691	In our cohort, 9 of 11 children with TP53 germline mutations and anRMS presented as group III tumors (incomplete resection with gross residual disease) and 7 of 11 arose at unfavorable sites.	('III tumors', 'Disease', 'MESH:D009369', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('children', 'Species', '9606', (23, 31))	('III tumors', 'Disease', (90, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('germline mutations', 'Var', (42, 60))	('TP53', 'Gene', (37, 41))
66128	24382691	Extended studies in larger cohorts of patients are needed to define the prevalence, clinical behavior, and specific therapeutic requirements (especially with regards to the use of radiation therapy for local control) of anRMS in TP53 germline mutation carriers.	('TP53', 'Gene', (229, 233))	('germline mutation carriers', 'Var', (234, 260))	('patients', 'Species', '9606', (38, 46))
66130	24382691	Here, we report a strong association between germline TP53 mutations and anRMS diagnosed at a young age, and propose considering TP53 mutation screening for children diagnosed with anRMS irrespective of family history.	('anRMS diagnosed', 'Disease', (73, 88))	('germline', 'Var', (45, 53))	('children', 'Species', '9606', (157, 165))	('mutations', 'Var', (59, 68))	('TP53', 'Gene', (54, 58))
66133	22876234	The starting point of these alterations is the massive entry of glucose in polyol pathway where it is converted into sorbitol by this enzyme.	('sorbitol', 'Chemical', 'MESH:D013012', (117, 125))	('rat', 'Species', '10116', (32, 35))	('alterations', 'Var', (28, 39))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('entry', 'PosReg', (55, 60))	('polyol', 'Enzyme', (75, 81))
66144	22876234	To date, the AKR1 family is the major group encompassing 50 variants of the referring founder protein AKR1A1.	('AKR1A1', 'Gene', (102, 108))	('variants', 'Var', (60, 68))	('AKR1A1', 'Gene', '58810', (102, 108))
66145	22876234	Among the AKR1 family, the AR subgroup (AKR1B) is one of the most characterized because of its involvement in human diseases such as diabetic complications resulting from the ability of AKR1B1 to reduce glucose into sorbitol in a NADPH + H+dependent manner.	('AKR1B1', 'Var', (186, 192))	('diabetic complications', 'Disease', (133, 155))	('NADPH', 'Chemical', 'MESH:D009249', (230, 235))	('glucose', 'Chemical', 'MESH:D005947', (203, 210))	('diabetic complications', 'Disease', 'MESH:D003925', (133, 155))	('involvement', 'Reg', (95, 106))	('reduce', 'NegReg', (196, 202))	('human', 'Species', '9606', (110, 115))	('sorbitol', 'Chemical', 'MESH:D013012', (216, 224))	('glucose into sorbitol', 'MPA', (203, 224))
66146	22876234	In addition to glucose conversion, AKR1B proteins display multiple other activities including reduction of aldehydes generated by lipid peroxidation, steroids and their derivatives or by-products, retinoids, xenobiotics, and prostaglandins.	('retinoids', 'Chemical', 'MESH:D012176', (197, 206))	('aldehydes generated by lipid peroxidation', 'MPA', (107, 148))	('lipid', 'Chemical', 'MESH:D008055', (130, 135))	('reduction', 'NegReg', (94, 103))	('steroids', 'Chemical', 'MESH:D013256', (150, 158))	('steroids', 'MPA', (150, 158))	('glucose', 'Chemical', 'MESH:D005947', (15, 22))	('activities', 'MPA', (73, 83))	('aldehydes', 'Chemical', 'MESH:D000447', (107, 116))	('prostaglandins', 'Chemical', 'MESH:D011453', (225, 239))	('AKR1B', 'Var', (35, 40))	('rat', 'Species', '10116', (121, 124))
66153	22876234	Four murine Akr1b have been described: Akr1b3 (murine AR; Gui et al.,), Akr1b7 [previously named Mouse vas deferens protein (MVDP); Pailhoux et al., ], Akr1b8 [previously named fibroblast growth factor-related protein (FR-1); Donohue et al., ], and Akr1b16 (Salabei et al.,).	('FR-1', 'Gene', (219, 223))	('Akr1b3', 'Gene', (39, 45))	('Mouse vas deferens protein', 'Gene', '11997', (97, 123))	('Akr1b8', 'Gene', '14187', (152, 158))	('Akr1b7', 'Var', (72, 78))	('murine', 'Species', '10090', (5, 11))	('Akr1b16', 'Gene', (249, 256))	('murine', 'Species', '10090', (47, 53))	('FR-1', 'Gene', '14187', (219, 223))	('MVDP', 'Gene', '11997', (125, 129))	('Akr1b8', 'Gene', (152, 158))	('Akr1b16', 'Gene', '67861', (249, 256))	('Akr1b3', 'Gene', '11677', (39, 45))	('MVDP', 'Gene', (125, 129))	('Mouse vas deferens protein', 'Gene', (97, 123))
66155	22876234	Like AKR1B1, Akr1b3 and Akr1b16 seem to be ubiquitously expressed (Joshi et al.,; Salabei et al.,) whereas Akr1b7 and Akr1b8 display more restricted tissue distribution: Akr1b7 is expressed in vas deferens, adrenal glands, gonads, intestine, white adipose tissue, eye, liver, and kidney (Pailhoux et al.,; Lau et al.,; Tirard et al.,; Brunskill et al.,; Schmidt et al.,).	('Akr1b16', 'Gene', '67861', (24, 31))	('Akr1b3', 'Gene', '11677', (13, 19))	('Akr1b8', 'Gene', '14187', (118, 124))	('vas', 'Gene', '24221', (193, 196))	('adipose', 'Gene', '230796', (248, 255))	('Akr1b3', 'Gene', (13, 19))	('Akr1b7', 'Var', (170, 176))	('Akr1b8', 'Gene', (118, 124))	('adipose', 'Gene', (248, 255))	('vas', 'Gene', (193, 196))	('Akr1b16', 'Gene', (24, 31))
66162	22876234	This phylogenetic analysis between rat and mouse AR has some limits: Akr1b14 and Akr1b7 do not exactly display the same expression pattern.	('Akr1b14', 'Gene', (69, 76))	('Akr1b14', 'Gene', '116463', (69, 76))	('Akr1b7', 'Var', (81, 87))	('rat', 'Species', '10116', (35, 38))	('mouse', 'Species', '10090', (43, 48))
66165	22876234	Indeed, using this C-terminal region critical to substrate specificity (Bohren et al.,), we developed immunological tools discriminating Akr1b7, Akr1b3, and Akr1b8 isoforms (Lefrancois-Martinez et al.,).	('Lefrancois-Martinez', 'Disease', (174, 193))	('Akr1b8', 'Gene', (157, 163))	('rat', 'Species', '10116', (54, 57))	('Lefrancois-Martinez', 'Disease', 'MESH:C563346', (174, 193))	('Akr1b3', 'Gene', '11677', (145, 151))	('Akr1b3', 'Gene', (145, 151))	('Akr1b8', 'Gene', '14187', (157, 163))	('Akr1b7', 'Var', (137, 143))
66167	22876234	This review will focus on the most characterized AKR1B proteins: AKR1B1, Akr1b3, Akr1b7, Akr1b8, and AKR1B10.	('Akr1b3', 'Gene', (73, 79))	('Akr1b8', 'Gene', (89, 95))	('Akr1b8', 'Gene', '14187', (89, 95))	('Akr1b3', 'Gene', '11677', (73, 79))	('Akr1b7', 'Var', (81, 87))
66188	22876234	Although both AKR1B1 and AKR1B10 human AR display 4-HNE reductase activity, AKR1B10 exhibits a higher activity and product turn over than AKR1B1 (Shen et al.,).	('AKR1B10', 'Var', (25, 32))	('AKR1B1', 'Var', (14, 20))	('AKR1B10', 'Var', (76, 83))	('4-HNE', 'Chemical', 'MESH:C027576', (50, 55))	('higher', 'PosReg', (95, 101))	('product turn over', 'MPA', (115, 132))	('human', 'Species', '9606', (33, 38))	('4-HNE reductase', 'Enzyme', (50, 65))	('activity', 'MPA', (102, 110))
66190	22876234	Nevertheless, in a comparative enzymatic study, Hara and colleagues showed that AKR1B1 had a more effective isocaproaldehyde reductase activity than AKR1B10, suggesting that the latter was unlikely to play a major role in the detoxification of steroidogenic by-products (Endo et al.,).	('AKR1B1', 'Var', (80, 86))	('aldehyde reductase', 'Gene', (116, 134))	('isocaproaldehyde', 'Chemical', 'MESH:C018575', (108, 124))	('steroid', 'Chemical', 'MESH:D013256', (244, 251))	('aldehyde reductase', 'Gene', '11997', (116, 134))	('rat', 'Species', '10116', (24, 27))
66207	22876234	In vitro studies revealed that Akr1b3, Akr1b7, and Akr1b8 all had the ability to reduce isocaproaldehyde.	('Akr1b8', 'Gene', '14187', (51, 57))	('Akr1b8', 'Gene', (51, 57))	('Akr1b3', 'Gene', '11677', (31, 37))	('Akr1b3', 'Gene', (31, 37))	('isocaproaldehyde', 'Chemical', 'MESH:C018575', (88, 104))	('Akr1b7', 'Var', (39, 45))	('reduce isocaproaldehyde', 'MPA', (81, 104))
66208	22876234	Their kinetic constants suggested that isocaproaldehyde was a major substrate for Akr1b3 and Akr1b7, and a poor substrate for Akr1b8 (Martinez et al.,; Table 3).	('rat', 'Species', '10116', (117, 120))	('Akr1b3', 'Gene', '11677', (82, 88))	('Akr1b7', 'Var', (93, 99))	('Akr1b3', 'Gene', (82, 88))	('Akr1b8', 'Gene', '14187', (126, 132))	('isocaproaldehyde', 'MPA', (39, 55))	('isocaproaldehyde', 'Chemical', 'MESH:C018575', (39, 55))	('rat', 'Species', '10116', (73, 76))	('Akr1b8', 'Gene', (126, 132))
66209	22876234	Akr1b7 silencing in Y1 adrenocortical cells disrupted cAMP-induced isocaproaldehyde reductase activity.	('Akr1b7', 'Gene', (0, 6))	('aldehyde reductase', 'Gene', (75, 93))	('cAMP', 'Chemical', 'MESH:D000242', (54, 58))	('disrupted', 'NegReg', (44, 53))	('isocaproaldehyde', 'Chemical', 'MESH:C018575', (67, 83))	('adrenocortical', 'Disease', (23, 37))	('aldehyde reductase', 'Gene', '11997', (75, 93))	('adrenocortical', 'Disease', 'MESH:D018268', (23, 37))	('silencing', 'Var', (7, 16))
66210	22876234	This strongly suggested that Akr1b7, rather than Akr1b3, was the main isocaproaldehyde reductase in the adrenal gland (Lefrancois-Martinez et al.,).	('Lefrancois-Martinez', 'Disease', (119, 138))	('aldehyde reductase', 'Gene', (78, 96))	('isocaproaldehyde', 'Chemical', 'MESH:C018575', (70, 86))	('rat', 'Species', '10116', (37, 40))	('Akr1b7', 'Var', (29, 35))	('Lefrancois-Martinez', 'Disease', 'MESH:C563346', (119, 138))	('Akr1b3', 'Gene', '11677', (49, 55))	('Akr1b3', 'Gene', (49, 55))	('aldehyde reductase', 'Gene', '11997', (78, 96))
66212	22876234	In a previous study, Madore and colleagues proposed that AKR1B5, initially characterized as the bovine 20alpha-hydroxysteroid dehydrogenase, ensured prostaglandin F2alpha synthase (PGFS) activity in the endometrium (Madore et al.,).	('20alpha-hydroxysteroid dehydrogenase', 'Gene', (103, 139))	('AKR1B5', 'Var', (57, 63))	('20alpha-hydroxysteroid dehydrogenase', 'Gene', '317748', (103, 139))	('bovine', 'Species', '9913', (96, 102))	('activity', 'MPA', (187, 195))	('PGFS', 'Gene', (181, 185))	('PGFS', 'Gene', '8644', (181, 185))	('prostaglandin', 'Chemical', 'MESH:D011453', (149, 162))
66213	22876234	Indeed, AKR1B1, Akr1b3, and Akr1b7 were shown to catalyze the reduction of prostaglandin H2 (PGH2) into PGF2alpha (Table 3).	('Akr1b3', 'Gene', (16, 22))	('Akr1b7', 'Var', (28, 34))	('AKR1B1', 'Var', (8, 14))	('reduction', 'NegReg', (62, 71))	('prostaglandin H2', 'Chemical', 'MESH:D044262', (75, 91))	('PGF2alpha', 'Chemical', 'MESH:D015237', (104, 113))	('Akr1b3', 'Gene', '11677', (16, 22))	('PGH2', 'Chemical', 'MESH:D044262', (93, 97))
66214	22876234	In contrast, Akr1b8 and AKR1B10 recombinant proteins were devoid of this PGH2 9-,11-endoperoxide reductase activity.	('Akr1b8', 'Gene', (13, 19))	('activity', 'MPA', (107, 115))	('PGH2', 'Chemical', 'MESH:D044262', (73, 77))	('Akr1b8', 'Gene', '14187', (13, 19))	('devoid', 'NegReg', (58, 64))	('AKR1B10', 'Var', (24, 31))
66216	22876234	Importantly, based on their kinetic parameters, recombinant AKR1B1, Akr1b3, and Akr1b7 displayed better PGF synthase activities than the previously characterized PGF synthases in mammals (Kabututu et al.,).	('PGF', 'Gene', (104, 107))	('Akr1b3', 'Gene', '11677', (68, 74))	('PGF', 'Gene', (162, 165))	('activities', 'MPA', (117, 127))	('PGF', 'Gene', '18654', (104, 107))	('Akr1b3', 'Gene', (68, 74))	('AKR1B1', 'Var', (60, 66))	('PGF', 'Gene', '18654', (162, 165))	('better', 'PosReg', (97, 103))
66235	22876234	Even if Akr1b7 is the main isocaproaldehyde reductase and Akr1b8 the principal 4-HNE reductase, Akr1b3 is also able to reduce these toxic compounds.	('isocaproaldehyde', 'Chemical', 'MESH:C018575', (27, 43))	('aldehyde reductase', 'Gene', '11997', (35, 53))	('Akr1b8', 'Gene', (58, 64))	('reduce', 'NegReg', (119, 125))	('Akr1b7', 'Var', (8, 14))	('Akr1b3', 'Gene', '11677', (96, 102))	('4-HNE', 'Chemical', 'MESH:C027576', (79, 84))	('Akr1b3', 'Gene', (96, 102))	('aldehyde reductase', 'Gene', (35, 53))	('Akr1b8', 'Gene', '14187', (58, 64))
66239	22876234	This absence of adrenal phenotype may result from functional redundancy between the different family members present in the gland (Akr1b7 and Akr1b8).	('Akr1b8', 'Gene', (142, 148))	('adrenal', 'MPA', (16, 23))	('Akr1b7', 'Var', (131, 137))	('Akr1b8', 'Gene', '14187', (142, 148))
66276	22876234	In order to associate gene signature with metabolic network, a genetic study integrating quantitative trait locus (QTL) mapping and network modeling led to knock-out (KO) the three corresponding identified genes, among which Akr1b8 (Derry et al.,).	('Akr1b8', 'Gene', '14187', (225, 231))	('rat', 'Species', '10116', (82, 85))	('Akr1b8', 'Gene', (225, 231))	('knock-out', 'Var', (156, 165))
66285	22876234	AKR1B10 was the first AKR1B protein which was demonstrated to enhance cell proliferation and promote cell survival through its ability to interact with and stabilize ACCA in breast cancer cells (Ma et al.,) and in colon cancer cells (Wang et al.,).	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('interact', 'Interaction', (138, 146))	('colon cancer', 'Disease', 'MESH:D015179', (214, 226))	('breast cancer', 'Disease', (174, 187))	('colon cancer', 'Phenotype', 'HP:0003003', (214, 226))	('ACCA', 'Gene', '31', (166, 170))	('enhance', 'PosReg', (62, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cell proliferation', 'CPA', (70, 88))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cell survival', 'CPA', (101, 114))	('colon cancer', 'Disease', (214, 226))	('rat', 'Species', '10116', (53, 56))	('rat', 'Species', '10116', (82, 85))	('ACCA', 'Gene', (166, 170))	('AKR1B10', 'Var', (0, 7))	('promote', 'PosReg', (93, 100))
66298	22876234	Wild-type mice treated with PCN (pregnenolone-16alpha-carbonitrile; a PXR agonist) exhibited a decrease in malondialdehyde (MDA) levels (another by-product of polyunsaturated fatty acid peroxidation) compared with their vehicle-treated counterparts.	('decrease', 'NegReg', (95, 103))	('polyunsaturated fatty acid', 'Chemical', 'MESH:D005231', (159, 185))	('mice', 'Species', '10090', (10, 14))	('MDA', 'Chemical', 'MESH:D008315', (124, 127))	('PCN', 'Chemical', 'MESH:D011285', (28, 31))	('malondialdehyde', 'Chemical', 'MESH:D008315', (107, 122))	('PCN', 'Var', (28, 31))	('PXR', 'Gene', (70, 73))	('pregnenolone-16alpha-carbonitrile', 'Chemical', 'MESH:D011285', (33, 66))	('PXR', 'Gene', '18171', (70, 73))
66304	22876234	In the duodenum, a significant decrease in MDA concentrations was seen when wild-type mice were treated with T091317 (a synthetic agonist of LXR).	('LXR', 'Gene', (141, 144))	('MDA concentrations', 'MPA', (43, 61))	('decrease', 'NegReg', (31, 39))	('rat', 'Species', '10116', (54, 57))	('mice', 'Species', '10090', (86, 90))	('MDA', 'Chemical', 'MESH:D008315', (43, 46))	('T091317', 'Chemical', '-', (109, 116))	('T091317', 'Var', (109, 116))	('LXR', 'Gene', '22259', (141, 144))
66309	22876234	Recently three independent studies proposed that Akr1b7 or its rat ortholog Akr1b14 could be involved in bile acid metabolism and/or signaling (Endo et al.,; Ge et al.,; Schmidt et al.,).	('signaling', 'MPA', (133, 142))	('Akr1b14', 'Gene', (76, 83))	('Akr1b7', 'Var', (49, 55))	('involved', 'Reg', (93, 101))	('Akr1b14', 'Gene', '116463', (76, 83))	('bile acid metabolism', 'MPA', (105, 125))	('bile acid', 'Chemical', 'MESH:D001647', (105, 114))	('rat', 'Species', '10116', (63, 66))
66355	22876234	In db/db mice, inhibition and knock-down of Akr1b3 induced the decrease of both plasma and liver triglycerides levels.	('Akr1b3', 'Gene', '11677', (44, 50))	('triglycerides', 'Chemical', 'MESH:D014280', (97, 110))	('Akr1b3', 'Gene', (44, 50))	('decrease', 'NegReg', (63, 71))	('mice', 'Species', '10090', (9, 13))	('knock-down', 'Var', (30, 40))
66356	22876234	Inhibition of Akr1b3 in db/db mice led to an improvement of hepatosteatosis due to the up-regulation of acetyl-coA oxidase and apolipoprotein A-V, two PPARalpha target genes involved in lipid catabolism (Qiu et al.,).	('lipid', 'Chemical', 'MESH:D008055', (186, 191))	('mice', 'Species', '10090', (30, 34))	('up-regulation', 'PosReg', (87, 100))	('acetyl-coA', 'Chemical', 'MESH:D000105', (104, 114))	('acetyl-coA', 'MPA', (104, 114))	('hepatosteatosis', 'Disease', 'None', (60, 75))	('apolipoprotein A-V', 'Gene', '66113', (127, 145))	('Inhibition', 'Var', (0, 10))	('apolipoprotein A-V', 'Gene', (127, 145))	('hepatosteatosis', 'Disease', (60, 75))	('Akr1b3', 'Gene', (14, 20))	('Akr1b3', 'Gene', '11677', (14, 20))	('improvement', 'PosReg', (45, 56))
66359	22876234	However, studies using Akr1b3-/- mice or transgenic mice overexpressing AKR1B1 revealed no abnormalities in either the liver or small intestine (Yamaoka et al.,; Aida et al.,).	('AKR1B1', 'Var', (72, 78))	('Akr1b3', 'Gene', '11677', (23, 29))	('Akr1b3', 'Gene', (23, 29))	('mice', 'Species', '10090', (52, 56))	('mice', 'Species', '10090', (33, 37))	('transgenic mice', 'Species', '10090', (41, 56))
66361	22876234	Characterization of Akr1b3 promoter has shown that Nrf2 could regulate its activity through an antioxidant response element 1 (-953 to -945) and an AP1 site (Nishinaka and Yabe-Nishimura,).	('-953 to -945', 'Var', (127, 139))	('Akr1b3', 'Gene', '11677', (20, 26))	('Akr1b3', 'Gene', (20, 26))	('antioxidant response', 'MPA', (95, 115))	('Nrf2', 'Gene', (51, 55))	('activity', 'MPA', (75, 83))
66376	22876234	Disruption of the mechanisms that control adipose tissue homeostasis can result in massive expansion of the tissue as exemplified during development of obesity (Henry et al.,).	('adipose', 'Gene', '230796', (42, 49))	('obesity', 'Disease', (152, 159))	('adipose', 'Gene', (42, 49))	('expansion', 'PosReg', (91, 100))	('obesity', 'Phenotype', 'HP:0001513', (152, 159))	('obesity', 'Disease', 'MESH:D009765', (152, 159))	('result in', 'Reg', (73, 82))	('Disruption', 'Var', (0, 10))
66391	22876234	In contrast, knock-down of Akr1b7 accelerated differentiation and lipid accumulation in 3T3-L1 cells.	('lipid accumulation', 'MPA', (66, 84))	('Akr1b7', 'Gene', (27, 33))	('knock-down', 'Var', (13, 23))	('accelerated', 'PosReg', (34, 45))	('rat', 'Species', '10116', (40, 43))	('differentiation', 'CPA', (46, 61))	('lipid', 'Chemical', 'MESH:D008055', (66, 71))
66392	22876234	These results allowed us to demonstrate that Akr1b7 is a negative regulator of adipogenesis in vitro, which prevents differentiation by reducing lipid storage (Tirard et al.,).	('differentiation', 'MPA', (117, 132))	('Akr1b7', 'Var', (45, 51))	('reducing', 'NegReg', (136, 144))	('lipid', 'Chemical', 'MESH:D008055', (145, 150))	('prevents', 'NegReg', (108, 116))	('rat', 'Species', '10116', (35, 38))	('lipid storage', 'MPA', (145, 158))
66393	22876234	The mechanisms through which Akr1b7 inhibits adipocyte differentiation in vivo were recently unraveled by our group using Akr1b7-/- mice.	('inhibits', 'NegReg', (36, 44))	('mice', 'Species', '10090', (132, 136))	('adipocyte differentiation', 'CPA', (45, 70))	('Akr1b7', 'Var', (29, 35))
66395	22876234	First, just like Akr1b3, Akr1b7 is endowed with PGFS activity allowing synthesis of PGF2alpha, a potent inhibitor of adipogenesis (Serrero et al.,; Kabututu et al.,).	('PGFS', 'Gene', '8644', (48, 52))	('adipogenesis', 'MPA', (117, 129))	('Akr1b7', 'Var', (25, 31))	('PGF2alpha', 'Gene', (84, 93))	('PGF2alpha', 'Chemical', 'MESH:D015237', (84, 93))	('Akr1b3', 'Gene', '11677', (17, 23))	('Akr1b3', 'Gene', (17, 23))	('Ser', 'Chemical', 'MESH:D012694', (131, 134))	('inhibitor', 'MPA', (104, 113))	('PGFS', 'Gene', (48, 52))
66399	22876234	Second, Akr1b7 reduces 4-HNE, the accumulation of which is known to induce an excessive development of adipose tissue through adipocytes hypertrophy.	('hypertrophy', 'Disease', (137, 148))	('hypertrophy', 'Disease', 'MESH:D006984', (137, 148))	('4-HNE', 'Chemical', 'MESH:C027576', (23, 28))	('adipose', 'Gene', '230796', (103, 110))	('Akr1b7', 'Var', (8, 14))	('adipose', 'Gene', (103, 110))	('adipocytes hypertrophy', 'Phenotype', 'HP:0030759', (126, 148))	('4-HNE', 'MPA', (23, 28))	('reduces', 'NegReg', (15, 22))
66400	22876234	Detailed analysis of Akr1b7-/- mice allowed us to show that Akr1b7 behaved as an anti-adipogenic factor limiting white adipose tissue expansion, essentially through the regulation of PGF2alpha levels in vivo (Volat et al.,; Figure 7).	('regulation', 'Reg', (169, 179))	('mice', 'Species', '10090', (31, 35))	('adipose', 'Gene', '230796', (119, 126))	('PGF2alpha', 'MPA', (183, 192))	('anti-adipogenic', 'MPA', (81, 96))	('PGF2alpha', 'Chemical', 'MESH:D015237', (183, 192))	('Akr1b7', 'Var', (60, 66))	('adipose', 'Gene', (119, 126))
66413	22876234	Although we cannot exclude that Akr1b8 could be expressed in variable amounts depending on the mouse genetic background and the location of fat pads, it should be considered that the effect of Akr1b8 ablation could be indirect.	('ablation', 'Var', (200, 208))	('Akr1b8', 'Gene', '14187', (193, 199))	('Akr1b8', 'Gene', '14187', (32, 38))	('Akr1b8', 'Gene', (193, 199))	('Akr1b8', 'Gene', (32, 38))	('mouse', 'Species', '10090', (95, 100))
66416	22876234	Because AKR1B10 and Akr1b8 are not only detoxifying enzymes but also affect de novo fatty acids synthesis in cancer cells, it would be interesting to determine if and which of the enzymatic activities of AKR1B10 could be involved in adipose tissue homeostasis (Ma et al.,; Wang et al.,; Joshi et al.,).	('adipose', 'Gene', '230796', (233, 240))	('adipose', 'Gene', (233, 240))	('affect', 'Reg', (69, 75))	('AKR1B10', 'Var', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('Akr1b8', 'Gene', '14187', (20, 26))	('fatty acids', 'Chemical', 'MESH:D005227', (84, 95))	('AKR1B10', 'Gene', (204, 211))	('involved', 'Reg', (221, 229))	('de novo fatty acids synthesis', 'MPA', (76, 105))	('Akr1b8', 'Gene', (20, 26))
66419	22876234	In addition to their PGF2alpha synthase activity, Akr1b3 and AKR1B1 also catalyze the isomerization of PGH2 to PGD2 (Nagata et al.,).	('Akr1b3', 'Gene', (50, 56))	('Akr1b3', 'Gene', '11677', (50, 56))	('PGF2alpha synthase', 'Enzyme', (21, 39))	('AKR1B1', 'Var', (61, 67))	('PGF2alpha', 'Chemical', 'MESH:D015237', (21, 30))	('activity', 'MPA', (40, 48))	('PGH2', 'Chemical', 'MESH:D044262', (103, 107))	('isomerization', 'MPA', (86, 99))
66422	22876234	In contrast, the knock-down of L-PGDS decreases lipid accumulation in 3T3-L1 cells (Fujimori et al.,).	('decreases', 'NegReg', (38, 47))	('lipid accumulation', 'MPA', (48, 66))	('lipid', 'Chemical', 'MESH:D008055', (48, 53))	('L-PGDS', 'Gene', '19215', (31, 37))	('knock-down', 'Var', (17, 27))	('L-PGDS', 'Gene', (31, 37))
66550	32457520	Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes Fifty years after the recognition of the Li-Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed: (i) germline TP53 alterations are often identified among children with cancers, in particular soft-tissue sarcomas, adrenocortical carcinomas, central nervous system tumours, or among adult females with early breast cancers, without familial history.	('LFS', 'Disease', 'MESH:D016864', (138, 141))	('cancers', 'Phenotype', 'HP:0002664', (306, 313))	('TP53', 'Gene', '7157', (248, 252))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (351, 376))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('TP53', 'Gene', (45, 49))	('cancers', 'Disease', (306, 313))	('cancers', 'Disease', (162, 169))	('cancers', 'Disease', 'MESH:D009369', (451, 458))	('sarcomas', 'Disease', 'MESH:D012509', (341, 349))	('tumours', 'Phenotype', 'HP:0002664', (401, 408))	('adrenocortical carcinomas', 'Disease', (351, 376))	('cancer syndromes', 'Disease', (58, 74))	('sarcomas', 'Phenotype', 'HP:0100242', (341, 349))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (366, 375))	('carcinomas', 'Phenotype', 'HP:0030731', (366, 376))	('sarcomas', 'Disease', (341, 349))	('cancer syndromes', 'Disease', 'MESH:D009369', (58, 74))	('TP53', 'Gene', '7157', (205, 209))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (351, 376))	('TP53', 'Gene', '7157', (45, 49))	('central nervous system tumours', 'Phenotype', 'HP:0100006', (378, 408))	('cancers', 'Phenotype', 'HP:0002664', (451, 458))	('central nervous system tumours', 'Disease', (378, 408))	('Li-Fraumeni syndrome', 'Disease', (116, 136))	('Li-Fraumeni', 'Disease', (116, 127))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancers', 'Disease', (451, 458))	('cancers', 'Disease', 'MESH:D009369', (306, 313))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (329, 349))	('TP53', 'Gene', (248, 252))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (116, 136))	('cancer', 'Phenotype', 'HP:0002664', (451, 457))	('breast cancers', 'Disease', 'MESH:D001943', (444, 458))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (116, 127))	('breast cancers', 'Disease', (444, 458))	('Li-Fraumeni', 'Disease', (19, 30))	('children', 'Species', '9606', (292, 300))	('identified', 'Reg', (275, 285))	('central nervous system tumours', 'Disease', 'MESH:D016543', (378, 408))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('TP53', 'Gene', (205, 209))	('LFS', 'Disease', (138, 141))	('alterations', 'Var', (253, 264))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (19, 30))	('breast cancers', 'Phenotype', 'HP:0003002', (444, 458))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (444, 457))	('tumour', 'Phenotype', 'HP:0002664', (401, 407))
66551	32457520	This justifies the expansion of the LFS concept to a wider cancer predisposition syndrome designated heritable TP53-related cancer (hTP53rc) syndrome; (ii) the interpretation of germline TP53 variants remains challenging and should integrate epidemiological, phenotypical, bioinformatics prediction, and functional data; (iii) the penetrance of germline disease-causing TP53 variants is variable, depending both on the type of variant (dominant-negative variants being associated with a higher cancer risk) and on modifying factors; (iv) whole-body MRI (WBMRI) allows early detection of tumours in variant carriers and (v) in cancer patients with germline disease-causing TP53 variants, radiotherapy, and conventional genotoxic chemotherapy contribute to the development of subsequent primary tumours.	('cancer', 'Disease', 'MESH:D009369', (626, 632))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (494, 500))	('TP53', 'Gene', (672, 676))	('cancer', 'Phenotype', 'HP:0002664', (494, 500))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('hTP53', 'Gene', (132, 137))	('patients', 'Species', '9606', (633, 641))	('variants', 'Var', (677, 685))	('tumours', 'Disease', (793, 800))	('tumours', 'Disease', (587, 594))	('hTP53', 'Gene', '7157', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (626, 632))	('tumours', 'Phenotype', 'HP:0002664', (793, 800))	('tumours', 'Phenotype', 'HP:0002664', (587, 594))	('cancer', 'Disease', 'MESH:D009369', (494, 500))	('cancer', 'Phenotype', 'HP:0002664', (626, 632))	('tumours', 'Disease', 'MESH:D009369', (793, 800))	('tumours', 'Disease', 'MESH:D009369', (587, 594))	('LFS', 'Disease', (36, 39))	('cancer', 'Disease', (124, 130))	('tumour', 'Phenotype', 'HP:0002664', (793, 799))	('tumour', 'Phenotype', 'HP:0002664', (587, 593))	('LFS', 'Disease', 'MESH:D016864', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (59, 65))
66552	32457520	In children, the recommendations are to perform clinical examination and abdominal ultrasound every 6 months, annual WBMRI and brain MRI from the first year of life, if the TP53 variant is known to be associated with childhood cancers.	('children', 'Species', '9606', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('variant', 'Var', (178, 185))	('associated with', 'Reg', (201, 216))	('child', 'Species', '9606', (217, 222))	('child', 'Species', '9606', (3, 8))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('TP53', 'Gene', (173, 177))	('cancers', 'Disease', (227, 234))	('cancers', 'Disease', 'MESH:D009369', (227, 234))
66553	32457520	Heterozygous germline TP53 alterations were identified in 1990 in the Li-Fraumeni syndrome (LFS), described in 1969 by Frederick Li and Joseph Fraumeni.	('LFS', 'Disease', (92, 95))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (70, 90))	('Joseph Fraumeni', 'Disease', 'MESH:D017827', (136, 151))	('LFS', 'Disease', 'MESH:D016864', (92, 95))	('Li-Fraumeni syndrome', 'Disease', (70, 90))	('Joseph Fraumeni', 'Disease', (136, 151))	('TP53', 'Gene', (22, 26))	('alterations', 'Var', (27, 38))
66556	32457520	Fifty years after the initial clinical recognition of the syndrome, germline alterations of TP53 are mainly identified among children with cancers or among adult females with breast cancers, in both cases often without familial history of cancer.	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancers', 'Disease', (139, 146))	('TP53', 'Gene', (92, 96))	('germline alterations', 'Var', (68, 88))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancer', 'Disease', (239, 245))	('cancers', 'Disease', (182, 189))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancers', 'Disease', 'MESH:D001943', (175, 189))	('breast cancers', 'Disease', (175, 189))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('breast cancers', 'Phenotype', 'HP:0003002', (175, 189))	('cancer', 'Disease', (139, 145))	('children', 'Species', '9606', (125, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('identified', 'Reg', (108, 118))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancers', 'Disease', 'MESH:D009369', (182, 189))
66557	32457520	For this reason, our perception of cancers related to germline alterations of TP53 has drastically changed through time.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('germline alterations', 'Var', (54, 74))	('TP53', 'Gene', (78, 82))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
66558	32457520	The diversity of clinical presentations associated with germline TP53 alterations justifies the expansion of the LFS concept to a wider cancer predisposition syndrome designated heritable TP53-related cancer (hTP53rc) syndrome.	('alterations', 'Var', (70, 81))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('hTP53', 'Gene', '7157', (209, 214))	('TP53', 'Gene', (65, 69))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('LFS', 'Disease', 'MESH:D016864', (113, 116))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('hTP53', 'Gene', (209, 214))	('LFS', 'Disease', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
66559	32457520	Regardless of familial history, the detection rate of disease causing germline TP53 variants has been estimated to be: 50-80% in children presenting with ACC or choroid plexus carcinomas; up to 73% in children with rhabdomyosarcoma of embryonal anaplastic subtype and between 3.8 and 7.7% in females with breast carcinoma before 31 years of age.	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('children', 'Species', '9606', (201, 209))	('breast carcinoma', 'Disease', 'MESH:D001943', (305, 321))	('children', 'Species', '9606', (129, 137))	('rhabdomyosarcoma of embryonal', 'Disease', 'MESH:D018233', (215, 244))	('choroid plexus carcinomas', 'Phenotype', 'HP:0030392', (161, 186))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (161, 185))	('breast carcinoma', 'Phenotype', 'HP:0003002', (305, 321))	('breast carcinoma', 'Disease', (305, 321))	('disease causing', 'Reg', (54, 69))	('choroid plexus carcinomas', 'Disease', 'MESH:D020288', (161, 186))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (215, 231))	('TP53', 'Gene', (79, 83))	('ACC', 'Phenotype', 'HP:0006744', (154, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('choroid plexus carcinomas', 'Disease', (161, 186))	('variants', 'Var', (84, 92))	('rhabdomyosarcoma of embryonal', 'Disease', (215, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
66561	32457520	The frequency of presentations without familial cancer history is explained both by the contribution of de novo variants to hTP53rc syndrome, which has been estimated to be between 7 and 20%, and the incomplete penetrance of germline TP53 variants.	('hTP53', 'Gene', (124, 129))	('TP53', 'Gene', (234, 238))	('familial cancer', 'Disease', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('familial cancer', 'Disease', 'MESH:D009369', (39, 54))	('hTP53', 'Gene', '7157', (124, 129))	('variants', 'Var', (112, 120))
66565	32457520	Classification of TP53 missense variants, in agreement with the ACMG/AMP guidelines, is based on several considerations including phenotypical data (identified in patients fulfilling the Chompret criteria); frequency of the variant in the general population, as reported by the Genome Aggregation Database (https://gnomad.broadinstitute.org/), bioinformatics predictions of the variant impact on protein or RNA splicing using different algorithms, and functional analyses of the variants performed using different in vitro assays performed either in yeast or cultured cells (http://p53.iarc.fr/).	('AMP', 'Chemical', 'MESH:D000249', (69, 72))	('patients', 'Species', '9606', (163, 171))	('impact', 'Reg', (386, 392))	('protein', 'MPA', (396, 403))	('p53', 'Gene', (582, 585))	('p53', 'Gene', '7157', (582, 585))	('variant', 'Var', (378, 385))	('based', 'Chemical', '-', (88, 93))	('yeast', 'Species', '4932', (550, 555))
66566	32457520	Optimised and stringent ACMG/AMP criteria for a specific classification of germline TP53 variants, integrating the above considerations, are being developed by a TP53 variant curation expert panel, under the umbrella of ClinGen.	('TP53', 'Gene', (84, 88))	('variants', 'Var', (89, 97))	('AMP', 'Chemical', 'MESH:D000249', (29, 32))
66567	32457520	This will allow a progressive allocation or re-classification of TP53 variants into the different ACMG/AMP classes.	('variants', 'Var', (70, 78))	('AMP', 'Chemical', 'MESH:D000249', (103, 106))	('TP53', 'Gene', (65, 69))
66568	32457520	The presence of mosaic TP53 alterations should be considered in patients with sporadic cancers strongly suggestive of a disease-causing TP53 variant, such as childhood ACC, choroid plexus carcinoma, and breast cancer before 31 years of age and in patients with multiple primary tumours belonging to the TP53 core tumour spectrum.	('sporadic cancers', 'Disease', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('disease-causing', 'Reg', (120, 135))	('ACC', 'Phenotype', 'HP:0006744', (168, 171))	('choroid plexus carcinoma', 'Disease', (173, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('tumour', 'Phenotype', 'HP:0002664', (313, 319))	('child', 'Species', '9606', (158, 163))	('tumour', 'Disease', 'MESH:D009369', (313, 319))	('variant', 'Var', (141, 148))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('tumour', 'Disease', (313, 319))	('tumours', 'Disease', (278, 285))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('breast cancer', 'Disease', (203, 216))	('tumour', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (278, 284))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (173, 197))	('patients', 'Species', '9606', (247, 255))	('tumours', 'Phenotype', 'HP:0002664', (278, 285))	('tumour', 'Disease', (278, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('TP53', 'Gene', (136, 140))	('tumours', 'Disease', 'MESH:D009369', (278, 285))	('sporadic cancers', 'Disease', 'MESH:D009369', (78, 94))	('patients', 'Species', '9606', (64, 72))	('childhood ACC', 'Disease', (158, 171))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (173, 197))
66569	32457520	Therefore, a complete screening for TP53 disease causing variants in highly suggestive situations should include analysis of tumour tissue, which is so far not systematically performed.	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('disease causing', 'Reg', (41, 56))	('TP53', 'Gene', (36, 40))	('variants', 'Var', (57, 65))	('tumour', 'Disease', (125, 131))
66570	32457520	In contrast, the detection of a TP53 variant in a small fraction of NGS reads from blood DNA does not always correspond to a mosaic alteration and molecular geneticists should be aware of two pitfalls: the first corresponds to circulating tumour DNA, commonly observed in patients with metastatic cancers.	('cancers', 'Disease', 'MESH:D009369', (297, 304))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('tumour', 'Disease', 'MESH:D009369', (239, 245))	('cancers', 'Disease', (297, 304))	('tumour', 'Disease', (239, 245))	('variant', 'Var', (37, 44))	('TP53', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('patients', 'Species', '9606', (272, 280))	('corresponds', 'Reg', (212, 223))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))
66571	32457520	For instance, the detection of a TP53 variant in the blood from a patient with metastatic high grade serous ovary carcinoma is likely to correspond to circulating tumour DNA, considering the very high frequency of somatic TP53 alterations in these malignancies (>95%); the second is due to clonal haematopoiesis, corresponding to the occurrence, in hematopoietic stem cells of somatic TP53 alterations conferring a growth advantage.	('ovary carcinoma', 'Phenotype', 'HP:0025318', (108, 123))	('TP53', 'Gene', (385, 389))	('haematopoiesis', 'Disease', (297, 311))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('alterations', 'Var', (390, 401))	('malignancies', 'Disease', 'MESH:D009369', (248, 260))	('patient', 'Species', '9606', (66, 73))	('serous ovary carcinoma', 'Disease', 'MESH:D010051', (101, 123))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('malignancies', 'Disease', (248, 260))	('TP53', 'Gene', (33, 37))	('growth', 'MPA', (415, 421))	('variant', 'Var', (38, 45))	('haematopoiesis', 'Disease', 'None', (297, 311))	('tumour', 'Disease', (163, 169))	('serous ovary carcinoma', 'Disease', (101, 123))
66576	32457520	A challenge when dealing with TP53 variant carriers is to estimate the cancer risk or penetrance associated with each specific TP53 variant, and this cancer risk has recently been revisited.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('variant', 'Var', (132, 139))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('variant', 'Var', (35, 42))	('TP53', 'Gene', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
66577	32457520	Indeed, the cumulative cancer incidence of germline disease-causing TP53 variants was initially calculated using information mainly from familial cases and was estimated to 73-100% by age 70, with risks close to 100% in women.	('variants', 'Var', (73, 81))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('TP53', 'Gene', (68, 72))	('women', 'Species', '9606', (220, 225))
66578	32457520	This should be regarded in perspective with the prevalence in the general population of germline disease-causing TP53 variants, which was recently estimated, based on a conservative approach, to be in the magnitude of 1 among 4500 individuals.	('TP53', 'Gene', (113, 117))	('variants', 'Var', (118, 126))	('based', 'Chemical', '-', (158, 163))
66579	32457520	In childhood, the main tumour risks are ACC, STS, osteosarcomas and CNS tumours whereas the main tumour risk in adults corresponds to female breast cancers, female TP53 variant carriers have an excessively high risk of developing breast cancer before 31.	('variant', 'Var', (169, 176))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('male breast cancer', 'Disease', (136, 154))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (55, 63))	('breast cancer', 'Disease', (230, 243))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('tumour', 'Disease', (23, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('STS', 'Phenotype', 'HP:0030448', (45, 48))	('osteosarcomas and CNS tumours', 'Disease', 'MESH:D012516', (50, 79))	('TP53', 'Gene', (164, 168))	('ACC', 'Phenotype', 'HP:0006744', (40, 43))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('osteosarcomas', 'Phenotype', 'HP:0002669', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('male breast cancer', 'Disease', 'MESH:D018567', (136, 154))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumour', 'Disease', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('tumour', 'Disease', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancers', 'Disease', (141, 155))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('child', 'Species', '9606', (3, 8))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))
66581	32457520	There is a perception that colorectal cancer is associated with germline pathogenic TP53 variants.	('variants', 'Var', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('associated', 'Reg', (48, 58))	('colorectal cancer', 'Disease', (27, 44))	('TP53', 'Gene', (84, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
66582	32457520	Families with a germline TP53 variant and an additional history of colorectal cancer in the pedigree may have increased risk of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (128, 145))	('germline', 'Var', (16, 24))	('TP53', 'Gene', (25, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('variant', 'Var', (30, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('colorectal cancer', 'Disease', (128, 145))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', (67, 84))
66583	32457520	This increased risk is, however, not associated with the TP53 variant itself and, on the basis of the published studies, a high risk of colorectal cancer can be confidently excluded in carriers of disease-causing TP53 variants.	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('TP53', 'Gene', (213, 217))	('colorectal cancer', 'Disease', (136, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('variants', 'Var', (218, 226))
66584	32457520	One factor explaining the variability of this penetrance is the type of the variant itself: some of the p53 proteins bearing missense mutations are classified as dominant-negative due to their ability to complex and reduce the transcriptional activity of wild-type p53 protein, producing malfunctioning or non-functioning p53 tetramers.	('p53', 'Gene', (265, 268))	('p53', 'Gene', (104, 107))	('p53', 'Gene', '7157', (265, 268))	('p53', 'Gene', '7157', (104, 107))	('malfunctioning', 'MPA', (288, 302))	('proteins', 'Protein', (108, 116))	('transcriptional activity', 'MPA', (227, 251))	('reduce', 'NegReg', (216, 222))	('missense mutations', 'Var', (125, 143))	('p53', 'Gene', '7157', (322, 325))	('p53', 'Gene', (322, 325))	('non-functioning', 'MPA', (306, 321))	('complex', 'Interaction', (204, 211))
66585	32457520	These dominant-negative missense TP53 variants are usually detected in families with childhood cancers and are generally highly penetrant.	('detected', 'Reg', (59, 67))	('missense', 'Var', (24, 32))	('variants', 'Var', (38, 46))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('child', 'Species', '9606', (85, 90))	('TP53', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
66586	32457520	In contrast, null variants (frameshift or nonsense variants, splicing variants, large genomic rearrangements, and non-dominant-negative missense variants), are predominantly identified in families with mostly adult cancers and have a lower disease penetrance.	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('cancers', 'Disease', (215, 222))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('identified', 'Reg', (174, 184))	('splicing variants', 'Var', (61, 78))	('nonsense variants', 'Var', (42, 59))
66587	32457520	A remarkable example of a low penetrant, but still disease-causing variant, is the non-dominant-negative missense p.Arg337His variant, present in 0.3% of the population from Southern Brazil and associated with a founder effect.	('disease-causing', 'Reg', (51, 66))	('p.Arg337His', 'Var', (114, 125))	('p.Arg337His', 'SUBSTITUTION', 'None', (114, 125))
66588	32457520	The difference in the clinical severity between dominant-negative missense variants and the remaining ones is explained by a difference in their biological impact on the p53 transcriptional activity.	('missense variants', 'Var', (66, 83))	('p53', 'Gene', '7157', (170, 173))	('p53', 'Gene', (170, 173))	('transcriptional activity', 'MPA', (174, 198))
66589	32457520	Indeed, measurement of the transcriptional response to DNA damage in cells harbouring heterozygous TP53 variants, has shown that dominant-negative missense variants have a more drastic impact on p53 DNA binding and transcriptional response to DNA damage, than the other types of heterozygous alterations.	('p53', 'Gene', (195, 198))	('TP53', 'Gene', (99, 103))	('p53', 'Gene', '7157', (195, 198))	('transcriptional response to DNA damage', 'MPA', (215, 253))	('variants', 'Var', (104, 112))	('missense variants', 'Var', (147, 164))	('impact', 'Reg', (185, 191))
66590	32457520	The clinical annotation of the variants and updated functional data should allow progressively, dichotomising disease-causing TP53 variants in 'high cancer risk' and 'low cancer risk' alleles.	('cancer', 'Disease', (149, 155))	('TP53', 'Gene', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('variants', 'Var', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
66592	32457520	It is more and more evident that phenotypic expression in carriers of TP53 disease-causing variants is also dependent on environmental factors, as germline TP53 variants may turn p53 into a protein permissive to oncogenic stress.	('turn', 'Reg', (174, 178))	('variants', 'Var', (161, 169))	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('TP53', 'Gene', (156, 160))	('TP53', 'Gene', (70, 74))	('stress', 'Disease', 'MESH:D000079225', (222, 228))	('variants', 'Var', (91, 99))	('stress', 'Disease', (222, 228))
66593	32457520	Germline TP53 variant carriers have a remarkably high incidence of subsequent primary tumours, which may occur in more than 40% of TP53 variant carriers.	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('variant', 'Var', (136, 143))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('TP53', 'Gene', (131, 135))	('TP53', 'Gene', (9, 13))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))	('variant', 'Var', (14, 21))
66594	32457520	Subsequent primary tumours often develop after the exposure of TP53 variant carriers to radio and/or chemotherapy treatments.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('TP53', 'Gene', (63, 67))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('variant', 'Var', (68, 75))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('develop', 'Reg', (33, 40))
66596	32457520	A cause-effect was strongly supported by studies of the impact of chemo- and radiotherapy in lymphocytes with wild-type or mutant TP53 genotype and LFS mouse models.	('LFS', 'Disease', 'MESH:D016864', (148, 151))	('mouse', 'Species', '10090', (152, 157))	('LFS', 'Disease', (148, 151))	('TP53', 'Gene', (130, 134))	('mutant', 'Var', (123, 129))
66597	32457520	Therefore, in cancer patients, testing for disease-causing TP53 variants must absolutely take place before starting treatment and if a disease-causing TP53 variant is found, priority should be given to surgical or ablative treatments, avoiding radiotherapy when possible and using preferably non-genotoxic chemotherapies.	('cancer', 'Disease', (14, 20))	('TP53', 'Gene', (59, 63))	('TP53', 'Gene', (151, 155))	('variant', 'Var', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('patients', 'Species', '9606', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('variants', 'Var', (64, 72))
66600	32457520	Given that GBCAs may be retained for months or years in several organs, multiple GBCAs administrations should probably be avoided in germline TP53 variant carriers and only macrocyclic GBCAs, which are apparently less retained in the body, should be used.	('TP53', 'Gene', (142, 146))	('GBCAs', 'Chemical', '-', (81, 86))	('GBCAs', 'Chemical', '-', (185, 190))	('variant', 'Var', (147, 154))	('GBCAs', 'Chemical', '-', (11, 16))
66601	32457520	These guidelines have been elaborated by members of the European Reference Network (ERN) on the Genetic Tumour Risk Syndromes (GENTURIS) in order to integrate the available information with clinical utility and to assist health care professionals in the identification and management of patients with germline disease-causing TP53 variants, causing heritable TP53-related cancer (hTP53rc) syndrome.	('cancer', 'Disease', (372, 378))	('cancer', 'Disease', 'MESH:D009369', (372, 378))	('causing', 'Reg', (341, 348))	('patients', 'Species', '9606', (287, 295))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('hTP53', 'Gene', (380, 385))	('variants', 'Var', (331, 339))	('Tumour', 'Phenotype', 'HP:0002664', (104, 110))	('hTP53', 'Gene', '7157', (380, 385))	('TP53', 'Gene', (326, 330))
66602	32457520	In particular, these guidelines take into account the diversity of clinical presentations associated with germline TP53 variants, the variability of the TP53 variant penetrance, the role of radiotherapy and chemotherapy in the development of subsequent primary tumour and the medical benefit of surveillance protocols.	('variants', 'Var', (120, 128))	('tumour', 'Phenotype', 'HP:0002664', (261, 267))	('TP53', 'Gene', (115, 119))	('tumour', 'Disease', 'MESH:D009369', (261, 267))	('tumour', 'Disease', (261, 267))
66603	32457520	This is particularly critical for hTP53rc syndrome, considering the diversity of clinical expression related to germline TP53 variants.	('hTP53', 'Gene', (34, 39))	('variants', 'Var', (126, 134))	('hTP53', 'Gene', '7157', (34, 39))	('TP53', 'Gene', (121, 125))
66844	31963898	Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC.	('ACC', 'Phenotype', 'HP:0006744', (108, 111))	('ACC', 'Disease', (108, 111))	('SOAT1', 'Gene', (35, 40))	('cell viability', 'CPA', (90, 104))	('steroid', 'Chemical', 'MESH:D013256', (70, 77))	('SOAT1', 'Gene', '6646', (35, 40))	('impaired', 'NegReg', (61, 69))	('inhibition', 'Var', (41, 51))	('ACC', 'Disease', 'MESH:D018268', (108, 111))	('steroidogenesis', 'MPA', (70, 85))
66860	31963898	In hepatocellular carcinoma, a subgroup of patients characterized by disrupted cholesterol homeostasis present the lowest overall rate of survival and the greatest risk for a poor prognosis; interestingly, the signature of this subgroup is also high SOAT1 expression.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('high', 'Var', (245, 249))	('patients', 'Species', '9606', (43, 51))	('disrupted cholesterol homeostasis', 'Phenotype', 'HP:0003107', (69, 102))	('SOAT1', 'Gene', (250, 255))	('cholesterol', 'Chemical', 'MESH:D002784', (79, 90))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('lowest', 'NegReg', (115, 121))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('expression', 'MPA', (256, 266))	('SOAT1', 'Gene', '6646', (250, 255))
66862	31963898	Consistently, high levels of SOAT1 expression have also previously been reported to be associated with a poor prognosis in prostate and pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('SOAT1', 'Gene', '6646', (29, 34))	('high levels', 'Var', (14, 25))	('prostate', 'Disease', (123, 131))	('expression', 'MPA', (35, 45))	('associated', 'Reg', (87, 97))	('SOAT1', 'Gene', (29, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('pancreatic cancer', 'Disease', (136, 153))	('prostate', 'Disease', 'MESH:D011472', (123, 131))
66864	31963898	demonstrated that in vitro SOAT1 inhibition led to impaired steroidogenesis and cell viability in ACC, mostly due to ER stress triggered by a reduction in cholesterol esters and an increase in free cholesterol and fatty acids in the intracellular environment.	('inhibition', 'Var', (33, 43))	('reduction', 'NegReg', (142, 151))	('ACC', 'Disease', 'MESH:D018268', (98, 101))	('cholesterol esters', 'MPA', (155, 173))	('cholesterol', 'Chemical', 'MESH:D002784', (198, 209))	('SOAT1', 'Gene', '6646', (27, 32))	('steroidogenesis', 'MPA', (60, 75))	('cholesterol esters', 'Chemical', 'MESH:D002788', (155, 173))	('cell viability', 'CPA', (80, 94))	('ACC', 'Phenotype', 'HP:0006744', (98, 101))	('cholesterol', 'Chemical', 'MESH:D002784', (155, 166))	('free cholesterol', 'MPA', (193, 209))	('fatty acids', 'Chemical', 'MESH:D005227', (214, 225))	('ACC', 'Disease', (98, 101))	('impaired', 'NegReg', (51, 59))	('steroid', 'Chemical', 'MESH:D013256', (60, 67))	('increase', 'PosReg', (181, 189))	('SOAT1', 'Gene', (27, 32))
66881	31963898	The combination of a Ki67 index > 10% with strong expression of the SOAT1 protein (score > 2) significantly indicated worse outcomes compared to the presence of a Ki67 index > 10% associated with weak or absent SOAT1 expression (score <= 2) (HR 2.65, 95% CI 1.43-4.9; p = 0.002 for OS; HR 2.24, 95% CI 1.02-4.95; p = 0.044 for RFS), suggesting that these two prognostic markers may be complementary and may define a subgroup of patients with an even more unfavorable prognosis (Figure 4).	('Ki67', 'Var', (21, 25))	('SOAT1', 'Gene', '6646', (68, 73))	('patients', 'Species', '9606', (428, 436))	('Ki67', 'Chemical', '-', (21, 25))	('> 10%', 'Var', (32, 37))	('SOAT1', 'Gene', (211, 216))	('SOAT1', 'Gene', '6646', (211, 216))	('Ki67', 'Chemical', '-', (163, 167))	('SOAT1', 'Gene', (68, 73))
66883	31963898	Similarly, high SOAT1 gene expression was more frequent in patients with a more advanced disease stage at diagnosis (ENSAT 3 and 4, 62% (13 out of 21) versus ENSAT 1 and 2, 24%, (5 out of 21); p = 0.006), and in carcinomas exhibiting a higher Ki67 index (Ki67 > 10%, 76% (16 out of 21) versus Ki67 <= 10%, 29% (6 out of 21); p = 0.005).	('carcinomas', 'Phenotype', 'HP:0030731', (212, 222))	('carcinomas', 'Disease', 'MESH:D002277', (212, 222))	('Ki67', 'Chemical', '-', (243, 247))	('carcinomas', 'Disease', (212, 222))	('Ki67', 'Chemical', '-', (255, 259))	('expression', 'MPA', (27, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('SOAT1', 'Gene', (16, 21))	('patients', 'Species', '9606', (59, 67))	('Ki67', 'Chemical', '-', (293, 297))	('high', 'Var', (11, 15))	('SOAT1', 'Gene', '6646', (16, 21))
66896	31963898	This association is confirmed by our finding of shorter OS and RFS in patients with both Ki67 > 10% and strong expression of SOAT1.	('patients', 'Species', '9606', (70, 78))	('RFS', 'MPA', (63, 66))	('SOAT1', 'Gene', (125, 130))	('Ki67', 'Chemical', '-', (89, 93))	('shorter', 'NegReg', (48, 55))	('Ki67 > 10%', 'Var', (89, 99))	('SOAT1', 'Gene', '6646', (125, 130))
66929	31963898	The assay for the target gene was SOAT1 (Hs00922322_m1).	('Hs00922322_m1', 'Var', (41, 54))	('SOAT1', 'Gene', (34, 39))	('SOAT1', 'Gene', '6646', (34, 39))
66981	31778357	Mitotic count was low, Ki67 was 3% (low) and IGF2 was negative.	('Ki67', 'Var', (23, 27))	('IGF2', 'Gene', '3481', (45, 49))	('low', 'NegReg', (18, 21))	('IGF2', 'Gene', (45, 49))	('Mitotic count', 'CPA', (0, 13))
67037	29784459	While there have been many studies on genetic alterations resulting in the activation of oncogenes and/or the inactivation of tumor suppressor genes leading to the development of cancer, the critical role of epigenetic mechanisms of gene expression is increasingly recognized as an important component in carcinogenesis.	('inactivation', 'MPA', (110, 122))	('carcinogenesis', 'Disease', 'MESH:D063646', (305, 319))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('carcinogenesis', 'Disease', (305, 319))	('activation', 'PosReg', (75, 85))	('alterations', 'Var', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('oncogenes', 'Gene', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancer', 'Disease', (179, 185))	('tumor', 'Disease', (126, 131))
67038	29784459	This role has been supported by the observation that epigenetic modifications can act as a direct driver of tumor formation.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('epigenetic modifications', 'Var', (53, 77))	('tumor', 'Disease', (108, 113))
67040	29784459	The role of epigenetic regulation is also important in endocrine tumors.	('endocrine tumors', 'Disease', (55, 71))	('epigenetic regulation', 'Var', (12, 33))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('endocrine tumors', 'Disease', 'MESH:D004701', (55, 71))
67048	29784459	The third review by Sasanakietkul et al focuses on epigenetic alterations in poorly differentiated thyroid cancer (PDTC) and ATC.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ATC', 'Disease', (125, 128))	('thyroid cancer', 'Phenotype', 'HP:0002890', (99, 113))	('thyroid cancer', 'Disease', (99, 113))	('epigenetic alterations', 'Var', (51, 73))	('thyroid cancer', 'Disease', 'MESH:D013964', (99, 113))
67057	29784459	The first review by Silva-Figueroa and Perrier focuses on three epigenetic mechanisms; DNA methylation, regulation of gene expression by noncoding RNAs, particularly of miRNAs, and posttranslational histone methylation found in parathyroid tumors.	('parathyroid tumors', 'Disease', 'MESH:D010282', (228, 246))	('posttranslational histone methylation', 'Var', (181, 218))	('regulation', 'MPA', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('parathyroid tumors', 'Disease', (228, 246))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
67061	29784459	In pituitary tumors, epigenetic mutations are more frequent than genetic mutations, illustrating the importance of epigenetics in pituitary carcinogenesis.	('pituitary carcinogenesis', 'Disease', (130, 154))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('pituitary carcinogenesis', 'Disease', 'MESH:D063646', (130, 154))	('pituitary tumors', 'Disease', (3, 19))	('epigenetic mutations', 'Var', (21, 41))	('frequent', 'Reg', (51, 59))	('pituitary tumors', 'Disease', 'MESH:D010911', (3, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
67067	29784459	The review provides general background of PPGLs and describes the mutations of genes involved in their development, including the Krebs cycle enzymes, succinate dehydrogenase (SDH) subunits.	('mutations', 'Var', (66, 75))	('Krebs', 'Chemical', '-', (130, 135))	('succinate dehydrogenase', 'Gene', (151, 174))	('succinate dehydrogenase', 'Gene', '6390', (151, 174))	('PGL', 'Disease', (43, 46))	('SDH', 'Gene', '6390', (176, 179))	('PGL', 'Disease', 'MESH:D010235', (43, 46))	('SDH', 'Gene', (176, 179))
67068	29784459	Mutations in SDH genes, their roles in epigenetic regulations in PPGLs and studies on miRNAs are discussed.	('PGL', 'Disease', 'MESH:D010235', (66, 69))	('SDH', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', '6390', (13, 16))	('PGL', 'Disease', (66, 69))
67070	29784459	This review covers the background of gene MEN1 and MENIN, the protein encoded by MEN1, MEN1 mutation, mouse models for Men1 loss, MENIN function, and its epigenetic regulation.	('MENIN', 'Gene', (130, 135))	('MENIN', 'Gene', '17283', (130, 135))	('mutation', 'Var', (92, 100))	('MEN1', 'Gene', (42, 46))	('MEN1', 'Gene', (87, 91))	('MEN1', 'Gene', '17283', (81, 85))	('Men1 loss', 'Disease', (119, 128))	('MENIN', 'Gene', (51, 56))	('MENIN', 'Gene', '17283', (51, 56))	('MEN1', 'Gene', '17283', (42, 46))	('MEN1', 'Gene', '17283', (87, 91))	('MEN1', 'Gene', (81, 85))	('Men1 loss', 'Disease', 'MESH:D018761', (119, 128))	('mouse', 'Species', '10090', (102, 107))
67075	29784459	While more research is required to reach to the point where a combinatory signature of genetic and epigenetic biomarkers can be routinely used for patient care, the recent advance in knowledge of the role of epigenetic modifications in endocrine tumors has already yielded a much deeper understanding of their tumor biology, demonstrating the potential for future improved outcomes in the clinic.	('epigenetic modifications', 'Var', (208, 232))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('patient', 'Species', '9606', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('endocrine tumors', 'Disease', 'MESH:D004701', (236, 252))	('tumor', 'Disease', (310, 315))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('tumor', 'Disease', (246, 251))	('endocrine tumors', 'Disease', (236, 252))
67124	26989553	The existence of at least one major criterion defines a malignant oncocytoma, the presence of at least one minor criterion defines a borderline oncocytoma, and the absence of all criteria indicates benignancy.	('malignant oncocytoma', 'Disease', (56, 76))	('malignant oncocytoma', 'Disease', 'MESH:D018249', (56, 76))	('oncocytoma', 'Disease', (144, 154))	('presence', 'Var', (82, 90))	('oncocytoma', 'Disease', 'MESH:D018249', (144, 154))	('oncocytoma', 'Disease', (66, 76))	('oncocytoma', 'Disease', 'MESH:D018249', (66, 76))
67146	26027919	Additionally, GATA factors have been shown to be mutated, overexpressed, or underexpressed in a variety of endocrine tumors (e.g., adrenocortical neoplasms, parathyroid tumors, pituitary adenomas, and sex cord stromal tumors).	('endocrine tumors', 'Disease', 'MESH:D004701', (107, 123))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('endocrine tumors', 'Disease', (107, 123))	('neoplasms', 'Phenotype', 'HP:0002664', (146, 155))	('GATA factors', 'Gene', (14, 26))	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (131, 155))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('overexpressed', 'PosReg', (58, 71))	('sex cord stromal tumors', 'Disease', 'MESH:D018312', (201, 224))	('adrenocortical neoplasms', 'Disease', (131, 155))	('endocrine tumor', 'Phenotype', 'HP:0100568', (107, 122))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('pituitary adenomas', 'Disease', 'MESH:D010911', (177, 195))	('sex cord stromal tumors', 'Phenotype', 'HP:0031918', (201, 224))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (177, 195))	('pituitary adenomas', 'Disease', (177, 195))	('mutated', 'Var', (49, 56))	('underexpressed', 'NegReg', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('sex cord stromal tumors', 'Disease', (201, 224))	('parathyroid tumors', 'Disease', 'MESH:D010282', (157, 175))	('parathyroid tumors', 'Disease', (157, 175))
67148	26027919	Altered expression or function of GATA factors can also affect the metabolism, ploidy, and invasiveness of tumor cells.	('affect', 'Reg', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('invasiveness of tumor', 'Disease', 'MESH:D009369', (91, 112))	('invasiveness of tumor', 'Disease', (91, 112))	('Altered', 'Var', (0, 7))	('metabolism', 'CPA', (67, 77))	('expression', 'MPA', (8, 18))	('GATA factors', 'Gene', (34, 46))	('function', 'MPA', (22, 30))	('ploidy', 'CPA', (79, 85))
67153	26027919	With the exception of Gata5, homozygous null mutations in genes encoding GATA family members result in embryonic lethality in mice, underscoring the vital roles that these transcription factors play in development [reviewed in ].	('homozygous null mutations', 'Var', (29, 54))	('mice', 'Species', '10090', (126, 130))	('Gata5', 'Gene', (22, 27))	('Gata5', 'Gene', '14464', (22, 27))	('embryonic lethality', 'Disease', 'MESH:D020964', (103, 122))	('men', 'Species', '9606', (209, 212))	('embryonic lethality', 'Disease', (103, 122))	('GATA', 'Gene', (73, 77))	('result in', 'Reg', (93, 102))
67154	26027919	Human diseases associated with germline loss-of-function mutations in GATA factors are summarized in Table 1.	('Human', 'Species', '9606', (0, 5))	('mutations', 'Var', (57, 66))	('loss-of-function', 'NegReg', (40, 56))	('GATA factors', 'Gene', (70, 82))
67162	26027919	Conditional deletion studies in the mouse have shown that Gata3 is required for branching morphogenesis and terminal differentiation of luminal epithelial cells [reviewed in ].	('Gata3', 'Gene', '14462', (58, 63))	('deletion', 'Var', (12, 20))	('Gata3', 'Gene', (58, 63))	('mouse', 'Species', '10090', (36, 41))
67163	26027919	Interestingly, loss of Gata3 in adult mammary epithelium triggers de-differentiation of luminal cells, increased cell proliferation, and disorganization of ducts, features reminiscent of neoplastic transformation.	('cell proliferation', 'CPA', (113, 131))	('increased', 'PosReg', (103, 112))	('Gata3', 'Gene', (23, 28))	('disorganization', 'CPA', (137, 152))	('Gata3', 'Gene', '14462', (23, 28))	('loss', 'Var', (15, 19))	('de-differentiation', 'CPA', (66, 84))
67173	26027919	GATA factor dysregulation can impact tumor cell biology in other ways.	('dysregulation', 'Var', (12, 25))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('impact', 'Reg', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
67184	26027919	At embryonic day (E) 10.5 in the mouse, Gata4 expression is evident in the genital ridge, and by E13.5 GATA4 is found in most ovarian somatic cells.	('Gata4', 'Gene', (40, 45))	('E13.5', 'Var', (97, 102))	('Gata4', 'Gene', '14463', (40, 45))	('mouse', 'Species', '10090', (33, 38))
67192	26027919	GCTs are steroidogenically active and can cause precocious puberty, disturbances in the menstrual cycle, and endometrial hyperplasia.	('endometrial hyperplasia', 'Disease', (109, 132))	('steroid', 'Chemical', 'MESH:D013256', (9, 16))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (109, 132))	('dog', 'Species', '9615', (15, 18))	('cause', 'Reg', (42, 47))	('precocious puberty', 'Disease', (48, 66))	('disturbances in the menstrual cycle', 'Phenotype', 'HP:0000140', (68, 103))	('GCTs', 'Var', (0, 4))	('men', 'Species', '9606', (88, 91))	('precocious puberty', 'Phenotype', 'HP:0000826', (48, 66))	('disturbances', 'Disease', (68, 80))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (109, 132))
67193	26027919	A somatic missense mutation (p.C134W) in FOXL2, a transcription factor required for normal murine granulosa cell differentiation and ovarian maintenance, is present in ~95% of AGCTs, suggesting that it is pathognomonic for this tumor.	('FOXL2', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('murine', 'Species', '10090', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('p.C134W', 'SUBSTITUTION', 'None', (29, 36))	('p.C134W', 'Var', (29, 36))	('FOXL2', 'Gene', '26927', (41, 46))
67195	26027919	Current evidence suggests that a key event in AGCT pathogenesis is a failure of the mutant FOXL2 to form specific protein-protein interactions, leading to subtle changes in the transcription of target genes.	('failure', 'NegReg', (69, 76))	('FOXL2', 'Gene', (91, 96))	('mutant', 'Var', (84, 90))	('transcription of', 'MPA', (177, 193))	('AGCT', 'Disease', (46, 50))	('protein-protein', 'Protein', (114, 129))	('FOXL2', 'Gene', '26927', (91, 96))	('changes', 'Reg', (162, 169))
67197	26027919	The majority of AGCTs express GATA4 at levels comparable to normal preovulatory granulosa cells, and high GATA4 expression in these tumors predicts both increased risk of recurrence and shorter disease specific survival.	('AGCTs', 'Gene', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('shorter', 'NegReg', (186, 193))	('GATA4', 'Gene', (106, 111))	('tumors', 'Disease', (132, 138))	('high', 'Var', (101, 105))	('GATA4', 'Gene', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('expression', 'MPA', (112, 122))
67200	26027919	In contrast to GATA4, GATA6 expression in AGCTs is inversely correlated with tumor size, suggesting that GATA6 may suppress proliferation in this cell type.	('suppress', 'NegReg', (115, 123))	('proliferation', 'CPA', (124, 137))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('GATA6', 'Var', (105, 110))
67202	26027919	Aberrant expression of GATA factors accompanies tumorigenesis in several of these mouse models.	('Aberrant expression', 'Var', (0, 19))	('tumor', 'Disease', (48, 53))	('GATA factors', 'Gene', (23, 35))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mouse', 'Species', '10090', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
67207	26027919	SLCTs are one of the characteristic tumors in the pleuropulmonary blastoma familial tumor predisposition syndrome, which is caused by heterozygous germline mutations in the microRNA maturation gene DICER1.	('caused by', 'Reg', (124, 133))	('pleuropulmonary blastoma familial tumor', 'Disease', (50, 89))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('SLCTs', 'Disease', (0, 5))	('mutations', 'Var', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('DICER1', 'Gene', (198, 204))	('DICER1', 'Gene', '192119', (198, 204))	('pleuropulmonary blastoma familial tumor', 'Disease', 'MESH:C537516', (50, 89))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (50, 74))
67208	26027919	More than half of SLCTs harbor mutations in DICER1.	('SLCTs', 'Disease', (18, 23))	('mutations', 'Var', (31, 40))	('DICER1', 'Gene', (44, 50))	('DICER1', 'Gene', '192119', (44, 50))
67230	26027919	Fog2-/- mice and Gata4ki/ki mice, which bear a knock-in mutation that abrogates the interaction of GATA4 with FOG cofactors, exhibit similar testicular phenotypes including decreased testicular Sry expression, aberrant differentiation of Sertoli cells, and sex reversal.	('abrogates', 'NegReg', (70, 79))	('Fog2', 'Gene', (0, 4))	('FOG', 'Gene', (110, 113))	('FOG', 'Gene', '22761', (110, 113))	('Gata4', 'Gene', (17, 22))	('Sry', 'Gene', '21674', (194, 197))	('mice', 'Species', '10090', (28, 32))	('Sertoli cell', 'Phenotype', 'HP:0100619', (238, 250))	('decreased testicular', 'Phenotype', 'HP:0008734', (173, 193))	('interaction', 'Interaction', (84, 95))	('Sry', 'Gene', (194, 197))	('Fog2', 'Gene', '22762', (0, 4))	('sex reversal', 'Phenotype', 'HP:0012245', (257, 269))	('mutation', 'Var', (56, 64))	('decreased', 'NegReg', (173, 182))	('sex reversal', 'CPA', (257, 269))	('Gata4', 'Gene', '14463', (17, 22))	('mice', 'Species', '10090', (8, 12))	('Sertoli cells', 'Phenotype', 'HP:0100619', (238, 251))
67234	26027919	In contrast, conditional ablation of Gata4 in Leydig cells as early as E12.5 does not cause an overt impairment in the expression of Leydig cell differentiation markers in the fetal or adult testis.	('expression', 'MPA', (119, 129))	('men', 'Species', '9606', (107, 110))	('Leydig cell differentiation', 'CPA', (133, 160))	('Gata4', 'Gene', (37, 42))	('Gata4', 'Gene', '14463', (37, 42))	('E12.5', 'Var', (71, 76))
67236	26027919	To circumvent these limitations, the impact of Gata4 deficiency on Leydig cell function has been analyzed in less complicated experimental models: two immortalized mouse Leydig tumor cell lines (MA-10, mLTC-1) and primary cultures of adult mouse Leydig cells.	('Gata4', 'Gene', '14463', (47, 52))	('Leydig tumor', 'Phenotype', 'HP:0100618', (170, 182))	('mouse', 'Species', '10090', (164, 169))	('mouse', 'Species', '10090', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('men', 'Species', '9606', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('deficiency', 'Var', (53, 63))	('tumor', 'Disease', (177, 182))	('Gata4', 'Gene', (47, 52))
67237	26027919	Using siRNA and related knockdown approaches, Gata4 deficiency has been shown to have profound effects on specific metabolic pathways, notably steroidogenesis and glycolysis.	('dog', 'Species', '9615', (149, 152))	('steroid', 'Chemical', 'MESH:D013256', (143, 150))	('glycolysis', 'MPA', (163, 173))	('Gata4', 'Gene', (46, 51))	('deficiency', 'Var', (52, 62))	('Gata4', 'Gene', '14463', (46, 51))	('effects', 'Reg', (95, 102))	('steroidogenesis', 'MPA', (143, 158))
67238	26027919	A missense mutation in the human GATA4 gene has been linked to abnormal testicular development in one kindred, although the precise impact of this mutation on somatic cell function is unclear.	('men', 'Species', '9606', (90, 93))	('abnormal testicular', 'Phenotype', 'HP:0000035', (63, 82))	('human', 'Species', '9606', (27, 32))	('GATA4', 'Gene', (33, 38))	('linked', 'Reg', (53, 59))	('missense mutation', 'Var', (2, 19))	('abnormal testicular development', 'CPA', (63, 94))
67239	26027919	More recently, mutations in FOG2 have been demonstrated in unrelated individuals with 46,XY gonadal dysgenesis.	('mutations', 'Var', (15, 24))	('46,XY gonadal dysgenesis', 'Phenotype', 'HP:0008668', (86, 110))	('gonadal dysgenesis', 'Disease', (92, 110))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (92, 110))	('FOG2', 'Gene', '22762', (28, 32))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (92, 110))	('FOG2', 'Gene', (28, 32))
67244	26027919	PJS is caused by loss-of-function mutations in the STK11 gene, which inhibit AMP-activated protein kinase, resulting in increased activity of the mammalian target of rapamycin (mTOR).	('STK11', 'Gene', '6794', (51, 56))	('loss-of-function', 'NegReg', (17, 33))	('PJS', 'Disease', 'MESH:D010580', (0, 3))	('AMP-activated protein kinase', 'MPA', (77, 105))	('PJS', 'Disease', (0, 3))	('STK11', 'Gene', (51, 56))	('mammalian target of rapamycin', 'Gene', '2475', (146, 175))	('mutations', 'Var', (34, 43))	('increased', 'PosReg', (120, 129))	('inhibit', 'NegReg', (69, 76))	('activity', 'MPA', (130, 138))	('mammalian target of rapamycin', 'Gene', (146, 175))
67245	26027919	Dysregulation of the mTOR pathway has been linked to tumorigenesis in various tissues, including endocrine tissues.	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mTOR pathway', 'Pathway', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('linked', 'Reg', (43, 49))	('tumor', 'Disease', (53, 58))
67246	26027919	CNC is caused by PRKAR1A mutations, the gene encoding regulatory subunit type 1 of protein kinase A.	('mutations', 'Var', (25, 34))	('PRKAR1A', 'Gene', '19084', (17, 24))	('caused', 'Reg', (7, 13))	('CNC', 'Disease', (0, 3))	('PRKAR1A', 'Gene', (17, 24))
67252	26027919	Heterozygous loss-of-function mutations in Men1, encoding a chromatin remodeling gene, predispose mice to the development of multiple endocrine tumors, recapitulating the human MEN1 cancer predisposition syndrome.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('loss-of-function', 'NegReg', (13, 29))	('human', 'Species', '9606', (171, 176))	('Men1', 'Gene', (43, 47))	('men', 'Species', '9606', (117, 120))	('multiple endocrine tumors', 'Disease', 'MESH:D009377', (125, 150))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('mutations', 'Var', (30, 39))	('cancer', 'Disease', (182, 188))	('MEN1', 'Gene', (177, 181))	('mice', 'Species', '10090', (98, 102))	('MEN1', 'Gene', '4221', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('endocrine tumor', 'Phenotype', 'HP:0100568', (134, 149))	('Men1', 'Gene', '4221', (43, 47))	('multiple endocrine tumors', 'Disease', (125, 150))
67256	26027919	Decreased expression of Gata6 represents an attractive candidate for mediating gonadal somatic cells tumorigenesis in this model because: 1) GATA6 affects TGFbeta signaling in other tumors such as colorectal neoplasms (see Section 1.4), 2) dysregulated TGFbeta superfamily signaling accompanies Leydig cell tumorigenesis in the Men1+/- mice, and 3) targeted mutagenesis of genes involved in TGFbeta signaling (e.g., Inha, Amh, Amhr2) have been linked to testicular and ovarian somatic cell tumors in mice (Table 3).	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('Amhr2', 'Gene', '110542', (427, 432))	('tumor', 'Disease', 'MESH:D009369', (490, 495))	('tumor', 'Disease', (307, 312))	('Amh', 'Gene', '11705', (422, 425))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('Amhr2', 'Gene', (427, 432))	('tumors', 'Phenotype', 'HP:0002664', (490, 496))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('Men1', 'Gene', (328, 332))	('Amh', 'Gene', (422, 425))	('tumors', 'Disease', (182, 188))	('colorectal neoplasms', 'Disease', 'MESH:D015179', (197, 217))	('linked', 'Reg', (444, 450))	('Inha', 'Gene', '16322', (416, 420))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (490, 495))	('Inha', 'Gene', (416, 420))	('colorectal neoplasms', 'Disease', (197, 217))	('mice', 'Species', '10090', (336, 340))	('tumors', 'Disease', (490, 496))	('neoplasms', 'Phenotype', 'HP:0002664', (208, 217))	('targeted mutagenesis', 'Var', (349, 369))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('Amh', 'Gene', '11705', (427, 430))	('ovarian somatic cell tumors', 'Disease', (469, 496))	('ovarian somatic cell tumors', 'Disease', 'MESH:D010051', (469, 496))	('mice', 'Species', '10090', (500, 504))	('Amh', 'Gene', (427, 430))	('tumors', 'Disease', 'MESH:D009369', (490, 496))	('tumor', 'Disease', (182, 187))	('Men1', 'Gene', '4221', (328, 332))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (490, 495))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
67257	26027919	Men with disrupted adrenocortical function due to CYP21 or CYP11B1 deficiency develop neoplastic nodules of hormonally-active adrenocortical tissue in the testis (testicular adrenal rest tumors, TARTs), thought to arise from one of these reservoirs of pluripotential stem/progenitor cells.	('CYP21', 'Gene', '1589', (50, 55))	('testicular adrenal rest tumors', 'Disease', (163, 193))	('adrenocortical', 'Disease', (19, 33))	('disrupted adrenocortical function', 'Disease', 'MESH:D018268', (9, 42))	('AR', 'Gene', '11835', (196, 198))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('deficiency', 'Var', (67, 77))	('adrenocortical', 'Disease', 'MESH:D018268', (126, 140))	('CYP21', 'Gene', (50, 55))	('disrupted adrenocortical function', 'Disease', (9, 42))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('testicular adrenal rest tumors', 'Disease', 'MESH:D000314', (163, 193))	('neoplastic nodules', 'Phenotype', 'HP:0002664', (86, 104))	('CYP11B1', 'Gene', (59, 66))	('disrupted adrenocortical function', 'Phenotype', 'HP:0008207', (9, 42))	('adrenocortical', 'Disease', (126, 140))	('testicular adrenal rest tumors', 'Phenotype', 'HP:0025451', (163, 193))	('adrenocortical', 'Disease', 'MESH:D018268', (19, 33))	('Men', 'Species', '9606', (0, 3))
67258	26027919	TARTs express adrenocortical-specific genes (CYP11B1, CYP11B2, and MC2R) at much higher levels than adjacent testicular tissue.	('AR', 'Gene', '11835', (1, 3))	('CYP11B2', 'Gene', '13072', (54, 61))	('adrenocortical', 'Disease', (14, 28))	('CYP11B1', 'Var', (45, 52))	('adrenocortical', 'Disease', 'MESH:D018268', (14, 28))	('MC2R', 'Gene', (67, 71))	('MC2R', 'Gene', '17200', (67, 71))	('CYP11B2', 'Gene', (54, 61))
67271	26027919	GATA4 can substitute for GATA6 in trans-activation studies of the CYP17A1 promoter, suggesting that GATA4 may serve to augment CYP17A1 expression during fetal development.	('CYP17A1', 'Gene', (66, 73))	('GATA4', 'Var', (100, 105))	('men', 'Species', '9606', (166, 169))	('expression', 'MPA', (135, 145))	('CYP17A1', 'Gene', '13074', (127, 134))	('CYP17A1', 'Gene', (127, 134))	('CYP17A1', 'Gene', '13074', (66, 73))	('men', 'Species', '9606', (122, 125))	('augment', 'PosReg', (119, 126))
67272	26027919	The impact of GATA6 on adrenocortical development and physiology has been assessed through conditional gene deletion using Sf1-cre.	('Sf1', 'Gene', (123, 126))	('men', 'Species', '9606', (45, 48))	('conditional gene deletion', 'Var', (91, 116))	('adrenocortical', 'Disease', (23, 37))	('adrenocortical', 'Disease', 'MESH:D018268', (23, 37))	('Sf1', 'Gene', '26423', (123, 126))
67274	26027919	Based on analogous conditional deletion studies of Gata6 in pulmonary and intestinal epithelia, GATA6 is hypothesized to regulate the balance between stem/progenitor cell expansion and differentiation in the adrenal cortex.	('differentiation', 'CPA', (185, 200))	('stem/progenitor cell expansion', 'CPA', (150, 180))	('deletion', 'Var', (31, 39))	('regulate', 'Reg', (121, 129))	('GATA6', 'Gene', (96, 101))	('pulmonary and intestinal epithelia', 'Disease', 'MESH:D008171', (60, 94))	('Gata6', 'Gene', (51, 56))
67283	26027919	Constitutive and conditional mutations in Gata4 mitigate the accumulation of gonadal-like neoplastic cells and the expression of sex steroidogenic markers in the adrenal cortex of gonadectomized female mice.	('mitigate', 'NegReg', (48, 56))	('Gata4', 'Gene', (42, 47))	('steroid', 'Chemical', 'MESH:D013256', (133, 140))	('mice', 'Species', '10090', (202, 206))	('gonadal-like neoplastic', 'Phenotype', 'HP:0010785', (77, 100))	('accumulation of gonadal-like neoplastic cells', 'CPA', (61, 106))	('Gata4', 'Gene', '14463', (42, 47))	('mutations', 'Var', (29, 38))	('dog', 'Species', '9615', (139, 142))	('expression', 'MPA', (115, 125))
67305	26027919	Collectively, these results suggest that deregulation of GATA factors is probably a general feature of adrenal tumorigenesis (at least in rodents), irrespective of whether it is triggered by GDX or genetic alterations also found in patients.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('deregulation', 'Var', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patients', 'Species', '9606', (232, 240))	('tumor', 'Disease', (111, 116))
67309	26027919	Although global DNA methylation surveys of human adrenocortical neoplasms have yielded inconsistent results, hypermethylation and downregulation of both GATA6 and GATA4 have been reported.	('GATA6', 'Gene', (153, 158))	('downregulation', 'NegReg', (130, 144))	('GATA4', 'Gene', (163, 168))	('neoplasms', 'Phenotype', 'HP:0002664', (64, 73))	('hypermethylation', 'Var', (109, 125))	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (49, 73))	('adrenocortical neoplasms', 'Disease', (49, 73))	('human', 'Species', '9606', (43, 48))
67312	26027919	The importance of GATA3 in parathyroid function has emerged from characterization of patients with hypoparathyroidism, sensorineural deafness, and renal anomaly (HDR) syndrome, a condition caused by heterozygous loss-of-function mutations in GATA3.	('hypoparathyroidism', 'Disease', (99, 117))	('loss-of-function', 'NegReg', (212, 228))	('GATA3', 'Gene', (242, 247))	('hypoparathyroidism', 'Disease', 'MESH:D007011', (99, 117))	('mutations', 'Var', (229, 238))	('renal anomaly (HDR) syndrome', 'Disease', 'MESH:C537907', (147, 175))	('hypoparathyroidism', 'Phenotype', 'HP:0000829', (99, 117))	('sensorineural deafness', 'Disease', (119, 141))	('sensorineural deafness', 'Phenotype', 'HP:0000407', (119, 141))	('patients', 'Species', '9606', (85, 93))	('renal anomaly', 'Phenotype', 'HP:0000077', (147, 160))	('deafness', 'Phenotype', 'HP:0000365', (133, 141))	('sensorineural deafness', 'Disease', 'MESH:D006313', (119, 141))
67322	26027919	The same study demonstrated that mutation of the GATA motif in the Gcg promoter reduces its basal promoter activity in glucagon producing cells.	('Gcg', 'Gene', (67, 70))	('mutation', 'Var', (33, 41))	('Gcg', 'Gene', '14526', (67, 70))	('glucagon', 'Gene', (119, 127))	('reduces', 'NegReg', (80, 87))	('glucagon', 'Gene', '14526', (119, 127))
67325	26027919	Subsequently deletions or mutations of GATA4 were shown to be a monogenic cause of neonatal and childhood-onset diabetes with variable exocrine phenotypes.	('diabetes', 'Disease', 'MESH:D003920', (112, 120))	('GATA4', 'Gene', (39, 44))	('deletions', 'Var', (13, 22))	('mutations', 'Var', (26, 35))	('diabetes', 'Disease', (112, 120))	('cause', 'Reg', (74, 79))
67329	26027919	Conditional mutagenesis of either Gata4 or Gata6 in multipotent pancreatic progenitors (using Pdx1-cre) has minimal impact on pancreatic development or function, whereas mutagenesis of both genes results in pancreatic agenesis and diabetes.	('Gata4', 'Gene', (34, 39))	('Gata6', 'Gene', (43, 48))	('diabetes', 'Disease', (231, 239))	('multipotent pancreatic', 'Disease', 'MESH:D010195', (52, 74))	('pancreatic agenesis', 'Disease', 'MESH:C564908', (207, 226))	('pancreatic', 'Disease', (126, 136))	('pancreatic agenesis', 'Disease', (207, 226))	('pancreatic agenesis', 'Phenotype', 'HP:0100801', (207, 226))	('men', 'Species', '9606', (144, 147))	('pancreatic', 'Disease', 'MESH:D010195', (207, 217))	('Gata4', 'Gene', '14463', (34, 39))	('mutagenesis', 'Var', (170, 181))	('pancreatic', 'Disease', 'MESH:D010195', (64, 74))	('pancreatic', 'Disease', 'MESH:D010195', (126, 136))	('Pdx1', 'Gene', '18609', (94, 98))	('diabetes', 'Disease', 'MESH:D003920', (231, 239))	('Pdx1', 'Gene', (94, 98))	('pancreatic', 'Disease', (207, 217))	('pancreatic', 'Disease', (64, 74))	('multipotent pancreatic', 'Disease', (52, 74))	('results in', 'Reg', (196, 206))
67332	26027919	More recently, investigators have generated beta-cell specific knockouts of Gata4 or Gata6 and concluded that these factors have important but nonessential roles in promoting endoplasmic reticulum integrity and beta-cell survival, which may contribute to the pathogenesis of type 1 diabetes.	('diabetes', 'Disease', (282, 290))	('endoplasmic reticulum integrity', 'CPA', (175, 206))	('Gata6', 'Gene', (85, 90))	('Gata4', 'Gene', (76, 81))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (275, 290))	('Gata4', 'Gene', '14463', (76, 81))	('beta-cell survival', 'CPA', (211, 229))	('diabetes', 'Disease', 'MESH:D003920', (282, 290))	('contribute', 'Reg', (241, 251))	('knockouts', 'Var', (63, 72))	('promoting', 'PosReg', (165, 174))
67334	26027919	Mice harboring loss-of-function mutations in Men1 develop multiple endocrine neoplasias (see Section 3.4) including insulinomas.	('endocrine neoplasias', 'Phenotype', 'HP:0100568', (67, 87))	('Men1', 'Gene', '4221', (45, 49))	('loss-of-function', 'NegReg', (15, 31))	('insulinomas', 'Disease', 'MESH:D007340', (116, 127))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (67, 86))	('Men1', 'Gene', (45, 49))	('mutations', 'Var', (32, 41))	('neoplasia', 'Phenotype', 'HP:0002664', (77, 86))	('Mice', 'Species', '10090', (0, 4))	('insulinomas', 'Disease', (116, 127))	('endocrine neoplasias', 'Disease', (67, 87))	('endocrine neoplasias', 'Disease', 'MESH:D009377', (67, 87))	('neoplasias', 'Phenotype', 'HP:0002664', (77, 87))
67336	26027919	It has been proposed that Gata6 dysregulation plays a fundamental role in tumor formation and progression in this model by modulating TGFbeta superfamily or WNT/beta-catenin signaling, as in other systems (see Section 1.3).	('modulating', 'Reg', (123, 133))	('TGFbeta', 'Protein', (134, 141))	('dysregulation', 'Var', (32, 45))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Gata6', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('WNT/beta-catenin signaling', 'Pathway', (157, 183))	('tumor', 'Disease', (74, 79))	('men', 'Species', '9606', (59, 62))
67338	26027919	PDA has a complex genomic landscape characterized by frequent point mutations and copy number changes.	('PDA', 'Chemical', '-', (0, 3))	('point mutations', 'Var', (62, 77))	('copy number changes', 'Var', (82, 101))
67339	26027919	Common genetic changes include activating mutations of KRAS2 and inactivating mutations in the cell cycle regulator CDKN2A, the tumor suppressor TP53, and SMAD4.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CDKN2A', 'Gene', '12578', (116, 122))	('KRAS2', 'Gene', '16653', (55, 60))	('CDKN2A', 'Gene', (116, 122))	('SMAD4', 'Gene', '17128', (155, 160))	('inactivating mutations', 'Var', (65, 87))	('TP53', 'Gene', '22059', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TP53', 'Gene', (145, 149))	('activating', 'PosReg', (31, 41))	('KRAS2', 'Gene', (55, 60))	('tumor', 'Disease', (128, 133))	('SMAD4', 'Gene', (155, 160))
67340	26027919	GATA6 amplification and overexpression are hallmarks of PDA.	('PDA', 'Chemical', '-', (56, 59))	('GATA6', 'Gene', (0, 5))	('overexpression', 'PosReg', (24, 38))	('amplification', 'Var', (6, 19))	('PDA', 'Disease', (56, 59))
67359	26027919	Altered GATA factor expression or function owing to acquired genetic (mutations, deletions, amplifications) or epigenetic changes (e.g., DNA methylation) has been linked to tumor formation.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('deletions', 'Var', (81, 90))	('expression', 'MPA', (20, 30))	('function', 'MPA', (34, 42))	('linked', 'Reg', (163, 169))	('GATA factor', 'Gene', (8, 19))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('epigenetic changes', 'Var', (111, 129))	('amplifications', 'Var', (92, 106))
67361	26027919	In addition to affecting signaling pathways, GATA factor dysregulation can have effects on tumor cell metabolism, ploidy, and invasiveness.	('affecting', 'Reg', (15, 24))	('ploidy', 'CPA', (114, 120))	('dysregulation', 'Var', (57, 70))	('signaling pathways', 'Pathway', (25, 43))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('effects', 'Reg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('invasiveness', 'CPA', (126, 138))
67363	26027919	A small molecule inhibitor of GATA2 has been shown to suppress AR expression and exert anticancer activity against prostate cancer cell lines.	('prostate cancer', 'Disease', (115, 130))	('cancer', 'Disease', (124, 130))	('inhibitor', 'Var', (17, 26))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('suppress', 'NegReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('AR', 'Gene', '11835', (63, 65))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('GATA2', 'Gene', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
67366	26027919	Dysregulation of GATA factors can alter tumor cell metabolism, ploidy, and invasiveness.	('ploidy', 'CPA', (63, 69))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('alter', 'Reg', (34, 39))	('invasiveness', 'CPA', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
67367	25504670	Variable Transcriptional Regulation of the Human Aldosterone Synthase Gene Causes Salt-Dependent High Blood Pressure in Transgenic Mice Aldosterone, synthesized in the adrenal cortex by the enzyme CYP11B2, induces positive sodium balance and predisposes to hypertension.	('induces', 'PosReg', (206, 213))	('Human', 'Species', '9606', (43, 48))	('Salt', 'Chemical', 'MESH:D012492', (82, 86))	('Salt-Dependent High Blood Pressure', 'Disease', (82, 116))	('Causes', 'Reg', (75, 81))	('predisposes', 'Reg', (242, 253))	('positive sodium balance', 'MPA', (214, 237))	('hypertension', 'Disease', 'MESH:D006973', (257, 269))	('Aldosterone', 'Chemical', 'MESH:D000450', (49, 60))	('positive sodium balance', 'Phenotype', 'HP:0003228', (214, 237))	('Aldosterone Synthase', 'Gene', '1585', (49, 69))	('hypertension', 'Disease', (257, 269))	('hypertension', 'Phenotype', 'HP:0000822', (257, 269))	('Variable', 'Var', (0, 8))	('sodium', 'Chemical', 'MESH:D012964', (223, 229))	('Aldosterone', 'Chemical', 'MESH:D000450', (136, 147))	('High Blood Pressure', 'Phenotype', 'HP:0000822', (97, 116))	('Aldosterone Synthase', 'Gene', (49, 69))
67369	25504670	Human CYP11B2 gene promoter has three SNPs in linkage disequilibrium: T/A at -663, T/C at -470 and C/T at -344.	('Human', 'Species', '9606', (0, 5))	('CYP11B2', 'Gene', (6, 13))	('C/T at -344', 'Var', (99, 110))	('T/C at -470', 'Var', (83, 94))	('T/A at -663', 'Var', (70, 81))
67372	25504670	Our results show increased adrenal and renal expression of hCYP11B2 in TG mice with haplotype-I, as compared to mice with haplotype-II.	('increased', 'PosReg', (17, 26))	('mice', 'Species', '10090', (74, 78))	('increased adrenal', 'Phenotype', 'HP:0008221', (17, 34))	('haplotype-I', 'Var', (84, 95))	('mice', 'Species', '10090', (112, 116))	('hCYP11B2', 'Gene', (59, 67))	('hCYP11B2', 'Gene', '1585', (59, 67))
67373	25504670	Importantly, we observed increased baseline blood pressure in haplotype-I TG mice, an effect accentuated by a high-salt diet.	('mice', 'Species', '10090', (77, 81))	('salt', 'Chemical', 'MESH:D012492', (115, 119))	('increased', 'PosReg', (25, 34))	('haplotype-I TG', 'Var', (62, 76))
67374	25504670	Pathophysiological impact of elevated aldosterone was corroborated by our results showing up-regulation of proinflammatory markers in renal tissues from the TG mice with haplotype-I.	('proinflammatory markers', 'MPA', (107, 130))	('up-regulation', 'PosReg', (90, 103))	('haplotype-I', 'Var', (170, 181))	('aldosterone', 'Chemical', 'MESH:D000450', (38, 49))	('mice', 'Species', '10090', (160, 164))	('aldosterone', 'MPA', (38, 49))	('elevated aldosterone', 'Phenotype', 'HP:0000859', (29, 49))
67375	25504670	These findings characterize haplotype-dependent regulation of the hCYP11B2 gene where -344T serves as a reporter polymorphism and show that haplotype-I leads to increased expression of hCYP11B2, with permissive effects on blood pressure and inflammatory milieu.	('expression', 'MPA', (171, 181))	('hCYP11B2', 'Gene', '1585', (185, 193))	('hCYP11B2', 'Gene', (66, 74))	('hCYP11B2', 'Gene', '1585', (66, 74))	('hCYP11B2', 'Gene', (185, 193))	('increased', 'PosReg', (161, 170))	('haplotype-I', 'Var', (140, 151))
67378	25504670	Additionally, via activation of the classical mineralocorticoid receptor (MR), and a GPCR, aldosterone brings about oxidative stress and tissue remodeling.	('tissue remodeling', 'CPA', (137, 154))	('aldosterone', 'Chemical', 'MESH:D000450', (91, 102))	('mineralocorticoid receptor', 'Gene', (46, 72))	('MR', 'Gene', '110784', (74, 76))	('oxidative stress', 'Phenotype', 'HP:0025464', (116, 132))	('mineralocorticoid receptor', 'Gene', '110784', (46, 72))	('aldosterone', 'Var', (91, 102))	('oxidative stress', 'MPA', (116, 132))	('activation', 'PosReg', (18, 28))
67381	25504670	The human CYP11B2 (hCYP11B2) gene has T/C polymorphism at the -344 site in its promoter region.	('human', 'Species', '9606', (4, 9))	('hCYP11B2', 'Gene', (19, 27))	('CYP11B2', 'Gene', (10, 17))	('hCYP11B2', 'Gene', '1585', (19, 27))	('T/C polymorphism', 'Var', (38, 54))
67384	25504670	Importantly, Iwai et al have analyzed the role of 13 polymorphisms at CYP11B2 locus in 1443 Japanese subjects and concluded that only -344T allele was associated with increased aldosterone levels.	('aldosterone', 'Chemical', 'MESH:D000450', (177, 188))	('increased aldosterone', 'Phenotype', 'HP:0000859', (167, 188))	('only -344T', 'Var', (129, 139))	('aldosterone levels', 'MPA', (177, 195))	('CYP11B2', 'Gene', (70, 77))	('increased', 'PosReg', (167, 176))
67390	25504670	In this regard, we have identified two additional SNPs in the promoter of the hCYP11B2 gene that are in complete linkage disequilibrium with the -344 site.	('SNPs', 'Var', (50, 54))	('hCYP11B2', 'Gene', (78, 86))	('hCYP11B2', 'Gene', '1585', (78, 86))
67392	25504670	Thus, for the first time, we have identified SNP blocks in the hCYP11B2 promoter that form two distinct haplotypes.	('hCYP11B2', 'Gene', '1585', (63, 71))	('SNP blocks', 'Var', (45, 55))	('hCYP11B2', 'Gene', (63, 71))
67393	25504670	These haplotypes were discovered by in silico analysis of the of the promoter variants of the hCYP11B2 gene using the Hap Map data.	('hCYP11B2', 'Gene', '1585', (94, 102))	('hCYP11B2', 'Gene', (94, 102))	('variants', 'Var', (78, 86))
67396	25504670	To this end, we have generated transgenic (TG) mice with "knocked in" hCYP11B2 gene, containing either haplotype-I or haplotype-II, at the mouse HPRT locus.	('transgenic', 'Species', '10090', (31, 41))	('hCYP11B2', 'Gene', '1585', (70, 78))	('hCYP11B2', 'Gene', (70, 78))	('haplotype-I', 'Var', (103, 114))	('mouse', 'Species', '10090', (139, 144))	('haplotype-II', 'Var', (118, 130))	('mice', 'Species', '10090', (47, 51))
67398	25504670	We show here, in our novel TG mice with hCYP11B2 transgene, increased CYP11B2 gene expression in renal and adrenal tissues of mice with haplotype-I (-344T), as compared to mice with haplotype-II (-344C).	('mice', 'Species', '10090', (30, 34))	('mice', 'Species', '10090', (126, 130))	('haplotype-I (-344T', 'Var', (136, 154))	('hCYP11B2', 'Gene', '1585', (40, 48))	('hCYP11B2', 'Gene', (40, 48))	('mice', 'Species', '10090', (172, 176))	('expression', 'MPA', (83, 93))	('increased', 'PosReg', (60, 69))	('CYP11B2 gene', 'Gene', (70, 82))
67399	25504670	Importantly, the haplotype-I TG male mice have significantly increased baseline blood pressure, an effect accentuated by high salt diet, as opposed to mice with haplotype-I.	('salt', 'Chemical', 'MESH:D012492', (126, 130))	('mice', 'Species', '10090', (151, 155))	('baseline blood pressure', 'MPA', (71, 94))	('increased', 'PosReg', (61, 70))	('haplotype-I TG', 'Var', (17, 31))	('mice', 'Species', '10090', (37, 41))
67423	25504670	Then, an 1100 bp fragment was amplified from the genomic DNA of a human subject containing haplotype-II (-344C, -470T, -663T) of the hCYP11B2 gene.	('hCYP11B2', 'Gene', (133, 141))	('-344C', 'Var', (105, 110))	('human', 'Species', '9606', (66, 71))	('hCYP11B2', 'Gene', '1585', (133, 141))
67432	25504670	ES cells (containing either haplotype-I or -II of the hCYP11B2 gene) were used to generate TG mice, on the C57/BL6 background, at the Dartmouth Medical Center.	('mice', 'Species', '10090', (94, 98))	('hCYP11B2', 'Gene', '1585', (54, 62))	('hCYP11B2', 'Gene', (54, 62))	('haplotype-I', 'Var', (28, 39))
67434	25504670	Finally, we confirmed TG animals containing haplotype-I and haplotype-II of hCYP11B2 gene by sequence determination of the promoter region.	('hCYP11B2', 'Gene', (76, 84))	('haplotype-I', 'Var', (44, 55))	('haplotype-II', 'Var', (60, 72))	('hCYP11B2', 'Gene', '1585', (76, 84))
67435	25504670	These TG mice have single copy of the hCYP11B2 gene, as determined by Q-PCR.	('mice', 'Species', '10090', (9, 13))	('hCYP11B2', 'Gene', '1585', (38, 46))	('hCYP11B2', 'Gene', (38, 46))	('single copy', 'Var', (19, 30))
67444	25504670	Adrenal and kidney from 8-week-old male TG mice containing either cyp11B2 haplotype-I or haplotype-II were harvested following CO2 asphyxiation and stored in All-protect tissue reagent (Qiagen).	('mice', 'Species', '10090', (43, 47))	('haplotype-II', 'Var', (89, 101))	('CO2', 'Chemical', '-', (127, 130))	('cyp11B2', 'Gene', '13072', (66, 73))	('cyp11B2', 'Gene', (66, 73))
67445	25504670	Human (PPH01239F) and mouse (PPM57638A) CYP11B2 specific primers, and mouse GAPDH (PPM02946E) primers were purchased from SuperArray Bioscience Corporation (MD).	('Human', 'Species', '9606', (0, 5))	('GAPDH', 'Gene', '14433', (76, 81))	('PPM02946E', 'Var', (83, 92))	('mouse', 'Species', '10090', (70, 75))	('GAPDH', 'Gene', (76, 81))	('PPM57638A', 'Var', (29, 38))	('CYP11B2 specific', 'Gene', (40, 56))	('mouse', 'Species', '10090', (22, 27))	('PPH01239F', 'Var', (7, 16))
67455	25504670	Membranes were blocked in odyssey blocking buffer (Cat# 927-40000, LI-COR Biosciences - U.S.) and immunoblotted with commercially available monoclonal antibodies for hCYP11B2 (Cat#EPR-10494, Abcam, MA, USA) and beta-actin (Cat# A2228-200Ul, Sigma-Aldrich, St. Louis, MO, USA).	('hCYP11B2', 'Gene', (166, 174))	('Cat#EPR-10494', 'Var', (176, 189))	('hCYP11B2', 'Gene', '1585', (166, 174))	('beta-actin', 'Gene', (211, 221))	('COR', 'Gene', (70, 73))	('COR', 'Gene', '108031', (70, 73))	('Cat# A2228-200Ul', 'Var', (223, 239))	('beta-actin', 'Gene', '11461', (211, 221))
67456	25504670	The immune complexes were detected by using secondary antibody conjugated with IRDye800 or IRDye700 (Cat# 926-32222 and Cat#926-32213) and images were captured using an Odyssey Imaging System (LI-COR).	('COR', 'Gene', (196, 199))	('COR', 'Gene', '108031', (196, 199))	('Cat# 926-32222', 'Var', (101, 115))	('Cat#926-32213', 'Var', (120, 133))
67466	25504670	We then collected patient samples and confirmed the haplotype association with human hypertension.	('human', 'Species', '9606', (79, 84))	('hypertension', 'Disease', 'MESH:D006973', (85, 97))	('hypertension', 'Disease', (85, 97))	('haplotype association', 'Var', (52, 73))	('patient', 'Species', '9606', (18, 25))	('hypertension', 'Phenotype', 'HP:0000822', (85, 97))
67470	25504670	The frequency of the -344T allele was 0.56 (95%CI 0.52-0.60) in hypertensive subjects and 0.495 (95%CI 0.45-0.53) in normotensive subjects.	('hypertensive', 'Disease', 'MESH:D006973', (64, 76))	('hypertensive', 'Disease', (64, 76))	('0.495', 'Var', (90, 95))
67471	25504670	The frequency of the -344C allele was 0.44 (95%CI 0.40-0.48) in hypertensive subjects and 0.505 (95%CI 0.47-0.55) in normotensive subjects.	('0.505', 'Var', (90, 95))	('hypertensive', 'Disease', (64, 76))	('hypertensive', 'Disease', 'MESH:D006973', (64, 76))
67474	25504670	We have used a haplotype association test using a chi square test comparing the TCA haplotype (Hap-I) with CTT haplotype (Hap-II) and found that TCA haplotype is significantly associated with hypertension (OR =1.49, 95%CI 1.21-1.82).	('TCA', 'Gene', (145, 148))	('hypertension', 'Disease', 'MESH:D006973', (192, 204))	('hypertension', 'Disease', (192, 204))	('associated', 'Reg', (176, 186))	('hypertension', 'Phenotype', 'HP:0000822', (192, 204))	('TCA', 'Chemical', 'MESH:D014238', (145, 148))	('TCA', 'Chemical', 'MESH:D014238', (80, 83))	('haplotype', 'Var', (149, 158))
67477	25504670	1B, hCYP11B2 is expressed in transfected A295R cells and haplotype-I transfected cells show significantly greater (p<0.05) expression when compared to cells transfected with haplotype-II (1C).	('greater', 'PosReg', (106, 113))	('A295R', 'Var', (41, 46))	('expression', 'MPA', (123, 133))	('haplotype-I', 'Var', (57, 68))	('hCYP11B2', 'Gene', '1585', (4, 12))	('hCYP11B2', 'Gene', (4, 12))	('A295R', 'SUBSTITUTION', 'None', (41, 46))
67478	25504670	We selectively targeted the human CYP11B2 gene to the mouse HPRT locus by employing ES cells harboring a deletion in the endogenous HPRT gene.	('deletion', 'Var', (105, 113))	('HPRT', 'Gene', (132, 136))	('human', 'Species', '9606', (28, 33))	('CYP11B2', 'Gene', (34, 41))	('mouse', 'Species', '10090', (54, 59))
67479	25504670	The use of gene targeting is essential in developing a model for studying effects of allelic gene variants in vivo because it nullifies the copy number and positional effects associated with transgene expression in TG mouse models generated by pronuclear injection.	('mouse', 'Species', '10090', (218, 223))	('nullifies', 'NegReg', (126, 135))	('variants', 'Var', (98, 106))
67482	25504670	2, Pol II enrichment to the chromatin isolated from these tissues are significantly greater in mice with Haplotype-I of the hCYP11B2 gene, as compared to mice with Haplotype-II.	('hCYP11B2', 'Gene', '1585', (124, 132))	('hCYP11B2', 'Gene', (124, 132))	('mice', 'Species', '10090', (95, 99))	('mice', 'Species', '10090', (154, 158))	('Haplotype-I', 'Var', (105, 116))	('Pol II', 'Enzyme', (3, 9))	('enrichment', 'MPA', (10, 20))	('greater', 'PosReg', (84, 91))
67483	25504670	These results show increased Pol II binding to the hCYP11B2 gene in TG mice with the haplotype-I of the hCYP11B2 gene as compared to the gene in mice with haplotype-II.	('mice', 'Species', '10090', (71, 75))	('hCYP11B2', 'Gene', (104, 112))	('hCYP11B2', 'Gene', '1585', (104, 112))	('Pol II', 'Protein', (29, 35))	('mice', 'Species', '10090', (145, 149))	('increased', 'PosReg', (19, 28))	('haplotype-I', 'Var', (85, 96))	('binding', 'Interaction', (36, 43))	('hCYP11B2', 'Gene', (51, 59))	('hCYP11B2', 'Gene', '1585', (51, 59))
67491	25504670	3, renal and adrenal tissues from the TG mice with haplotype-I have significantly (p<0.05) elevated levels of the human CYP11B2 transgene as compared to mice with haplotype-II.	('elevated', 'PosReg', (91, 99))	('levels', 'MPA', (100, 106))	('mice', 'Species', '10090', (41, 45))	('haplotype-I', 'Var', (51, 62))	('CYP11B2', 'Gene', (120, 127))	('human', 'Species', '9606', (114, 119))	('mice', 'Species', '10090', (153, 157))
67493	25504670	Presence of the transgene did not affect endogenous mCYP11B2 expression as no significant difference in gene expression was observed in the two haplotypes, when compared to C57 mice (normalized CT values for mCYP11B2 in the adrenals: haplotype-I- 1.76+-0.26, haplotype-II- 1.54+-0.24, C57- 1.63+-0.1).	('mCYP11B2', 'Gene', (208, 216))	('mCYP11B2', 'Gene', '13072', (52, 60))	('haplotype-I-', 'Var', (234, 246))	('mCYP11B2', 'Gene', '13072', (208, 216))	('mice', 'Species', '10090', (177, 181))	('mCYP11B2', 'Gene', (52, 60))
67494	25504670	These results indicate that the polymorphisms in the human CYP11B2 gene predisposed it to varied transcriptional regulation in the two haplotypes.	('polymorphisms', 'Var', (32, 45))	('predisposed', 'Reg', (72, 83))	('varied transcriptional regulation', 'MPA', (90, 123))	('CYP11B2', 'Gene', (59, 66))	('human', 'Species', '9606', (53, 58))
67496	25504670	Plasma aldosterone levels were also significantly (p=0.002) elevated in the haplotype-I TG mice when compared to both, plasma aldosterone levels in haplotype-II TG and C57 mice (Fig.	('mice', 'Species', '10090', (91, 95))	('haplotype-I TG', 'Var', (76, 90))	('plasma aldosterone levels', 'Phenotype', 'HP:0000859', (119, 144))	('elevated', 'PosReg', (60, 68))	('mice', 'Species', '10090', (172, 176))	('aldosterone', 'Chemical', 'MESH:D000450', (126, 137))	('aldosterone', 'Chemical', 'MESH:D000450', (7, 18))	('Plasma aldosterone levels', 'Phenotype', 'HP:0000859', (0, 25))	('Plasma aldosterone levels', 'MPA', (0, 25))
67499	25504670	The color intensity is appreciably higher in cross-sections from mice with haplotype-I, as compared to sections from mice with haplotype-II.	('mice', 'Species', '10090', (65, 69))	('mice', 'Species', '10090', (117, 121))	('haplotype-I', 'Var', (75, 86))	('color intensity', 'MPA', (4, 19))	('higher', 'PosReg', (35, 41))
67504	25504670	Mean arterial pressure of male TG animals containing haplotype-I and haplotype-II of hCYP11B2 gene is shown in Fig.	('hCYP11B2', 'Gene', '1585', (85, 93))	('haplotype-I', 'Var', (53, 64))	('haplotype-II', 'Var', (69, 81))	('hCYP11B2', 'Gene', (85, 93))
67507	25504670	RAAS overcativity is associated with salt-dependent hypertension.	('overcativity', 'Var', (5, 17))	('associated', 'Reg', (21, 31))	('hypertension', 'Disease', 'MESH:D006973', (52, 64))	('hypertension', 'Disease', (52, 64))	('salt', 'Chemical', 'MESH:D012492', (37, 41))	('hypertension', 'Phenotype', 'HP:0000822', (52, 64))
67509	25504670	There was no difference in BP of TG mice containing either Hap-I or Hap-II of hCYP11B2 gene on a low salt diet (Fig.	('Hap-II', 'Var', (68, 74))	('Hap-I', 'Var', (59, 64))	('salt', 'Chemical', 'MESH:D012492', (101, 105))	('hCYP11B2', 'Gene', (78, 86))	('mice', 'Species', '10090', (36, 40))	('hCYP11B2', 'Gene', '1585', (78, 86))
67510	25504670	High-salt treatment increased the MAP both haplotypes however, this increase was significantly higher in TG mice haplotype-I as compared to mice with haplotype-II (Fig.	('increased', 'PosReg', (20, 29))	('mice', 'Species', '10090', (140, 144))	('higher', 'PosReg', (95, 101))	('mice', 'Species', '10090', (108, 112))	('salt', 'Chemical', 'MESH:D012492', (5, 9))	('haplotype-I', 'Var', (113, 124))
67514	25504670	It is important to note, however, that the aldosterone suppression was attenuated in TG mice with haplotype-I of the hCYP11B2 gene (Fig.	('hCYP11B2', 'Gene', '1585', (117, 125))	('aldosterone suppression', 'MPA', (43, 66))	('aldosterone', 'Chemical', 'MESH:D000450', (43, 54))	('aldosterone suppression', 'Phenotype', 'HP:0004319', (43, 66))	('attenuated', 'NegReg', (71, 81))	('mice', 'Species', '10090', (88, 92))	('haplotype-I', 'Var', (98, 109))	('hCYP11B2', 'Gene', (117, 125))
67517	25504670	8, renal expression of IL1beta, MCP1, iCAM, and VCAM is significantly increased (p<0.05) in mice with haplotype-I of the hCYP11B2 gene when compared to mice with haplotype-II.	('hCYP11B2', 'Gene', (121, 129))	('MCP1', 'Gene', (32, 36))	('MCP1', 'Gene', '17224', (32, 36))	('increased', 'PosReg', (70, 79))	('IL1beta', 'Gene', '16176', (23, 30))	('hCYP11B2', 'Gene', '1585', (121, 129))	('renal expression', 'MPA', (3, 19))	('mice', 'Species', '10090', (152, 156))	('IL1beta', 'Gene', (23, 30))	('iCAM', 'Gene', (38, 42))	('VCAM', 'Gene', (48, 52))	('mice', 'Species', '10090', (92, 96))	('haplotype-I', 'Var', (102, 113))
67520	25504670	In this regard, association studies have linked CYP11B2 polymorphism to human hypertension and cardiovascular diseases.	('cardiovascular diseases', 'Disease', (95, 118))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (95, 118))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (95, 117))	('hypertension', 'Disease', (78, 90))	('polymorphism', 'Var', (56, 68))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (95, 118))	('hypertension', 'Phenotype', 'HP:0000822', (78, 90))	('human', 'Species', '9606', (72, 77))	('CYP11B2', 'Gene', (48, 55))	('hypertension', 'Disease', 'MESH:D006973', (78, 90))
67521	25504670	The first key finding of the study identifies two polymorphic sites (-470 & -663) on the hCYP11B2 promoter that almost always occur in linkage disequilibrium with the -344 site.	('hCYP11B2', 'Gene', (89, 97))	('hCYP11B2', 'Gene', '1585', (89, 97))	('the', 'Gene', (85, 88))	('-470 & -663', 'Var', (69, 80))
67522	25504670	This is the first report identifying these linked polymorphisms in the hCYP11B2 gene.	('hCYP11B2', 'Gene', '1585', (71, 79))	('polymorphisms', 'Var', (50, 63))	('hCYP11B2', 'Gene', (71, 79))
67523	25504670	Importantly, Haplotype-I of the hCYP11B2 gene is associated with human hypertension and shows increased transcriptional activity, in vitro.	('hypertension', 'Disease', 'MESH:D006973', (71, 83))	('human', 'Species', '9606', (65, 70))	('hCYP11B2', 'Gene', (32, 40))	('hypertension', 'Disease', (71, 83))	('increased', 'PosReg', (94, 103))	('associated', 'Reg', (49, 59))	('transcriptional activity', 'MPA', (104, 128))	('hCYP11B2', 'Gene', '1585', (32, 40))	('hypertension', 'Phenotype', 'HP:0000822', (71, 83))	('Haplotype-I', 'Var', (13, 24))
67527	25504670	Results of these experiments showed that insertion of the single copy transgene upstream of HPRT locus does not affect the overall tissue and cell-specific expression or hormonal regulation of human AGT gene.	('AGT', 'Gene', (199, 202))	('human', 'Species', '9606', (193, 198))	('insertion', 'Var', (41, 50))
67529	25504670	We show here that both haplotypes have a single copy of the transgene with observation of increased CYP11B2 expression in TG mice with haplotype-I, as compared to mice with haplotype-II.	('increased', 'PosReg', (90, 99))	('CYP11B2', 'Gene', (100, 107))	('mice', 'Species', '10090', (125, 129))	('haplotype-I', 'Var', (135, 146))	('mice', 'Species', '10090', (163, 167))	('expression', 'MPA', (108, 118))
67530	25504670	Where classical view of the mineralocorticoids places aldosterone synthase primarily in the adrenal cortex, recently emerging evidence highlights CYP11B2 expression in extra adrenal tissues, especially kidneys.	('aldosterone synthase', 'Gene', (54, 74))	('CYP11B2', 'Var', (146, 153))	('aldosterone synthase', 'Gene', '13072', (54, 74))
67555	25504670	These findings further support our hypothesis that haplotype-dependent differential regulation of the CYP11B2 gene predisposes to pathophysiological effects observed with inappropriate kevels of aldosterone.	('CYP11B2', 'Gene', (102, 109))	('regulation', 'MPA', (84, 94))	('predisposes', 'Reg', (115, 126))	('aldosterone', 'Chemical', 'MESH:D000450', (195, 206))	('haplotype-dependent', 'Var', (51, 70))
67556	25504670	In conclusion, we have identified novel polymorphisms in the hCYP11B2 gene that are in linkage disequilibrium and divide the population in two haplotypes, termed I and II.	('hCYP11B2', 'Gene', (61, 69))	('hCYP11B2', 'Gene', '1585', (61, 69))	('polymorphisms', 'Var', (40, 53))
67557	25504670	Consequential increase in tissue and plasma aldosterone bioavailability contributes to salt-sensitive hypertension and a pathophysiological setting of prooxidant and proinflammatory milieu in tissues in mice with the haplotype-I transgene.	('haplotype-I', 'Var', (217, 228))	('hypertension', 'Disease', 'MESH:D006973', (102, 114))	('salt', 'Chemical', 'MESH:D012492', (87, 91))	('mice', 'Species', '10090', (203, 207))	('aldosterone', 'Chemical', 'MESH:D000450', (44, 55))	('hypertension', 'Disease', (102, 114))	('hypertension', 'Phenotype', 'HP:0000822', (102, 114))	('increase', 'PosReg', (14, 22))
67558	25504670	Patients with the haplotype-I of this gene are at an increased risk of inappropriately high aldosterone levels, predisposing these patients to aldosterone-dependent long-term morbidity; especially in cohort with fluctuations in dietary Na.	('patients', 'Species', '9606', (131, 139))	('aldosterone', 'Chemical', 'MESH:D000450', (92, 103))	('haplotype-I', 'Var', (18, 29))	('aldosterone', 'Chemical', 'MESH:D000450', (143, 154))	('Patients', 'Species', '9606', (0, 8))	('high aldosterone', 'Phenotype', 'HP:0000859', (87, 103))	('inappropriately high aldosterone levels', 'MPA', (71, 110))
67569	25078331	The most common inherited predisposition is associated with the Li-Fraumeni Syndrome (LFS) and germline TP53 mutations, but the disease has also been consistently linked to the Lynch Syndrome and germline alterations in DNA repair genes.	('Li-Fraumeni Syndrome', 'Disease', (64, 84))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('linked', 'Reg', (163, 169))	('DNA repair', 'Gene', (220, 230))	('LFS', 'Disease', (86, 89))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (177, 191))	('mutations', 'Var', (109, 118))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (64, 84))	('LFS', 'Disease', 'MESH:D016864', (86, 89))	('Lynch Syndrome', 'Disease', (177, 191))
67570	25078331	In children, TP53 germline mutations may be present in 50-80% of ACC cases, whereas in adults, at least 95% of the tumours arise in the absence of germline TP53 alterations.	('germline mutations', 'Var', (18, 36))	('ACC', 'Disease', (65, 68))	('TP53', 'Gene', (13, 17))	('children', 'Species', '9606', (3, 11))	('tumours', 'Disease', (115, 122))	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('TP53', 'Gene', '7157', (13, 17))	('ACC', 'Phenotype', 'HP:0006744', (65, 68))
67589	25078331	The most common biologically relevant alterations that cannot currently be linked to a targeted treatment option were found in TP53 (34%), MEN1 (14%) CTNNB1 (10%), APC (7%), DAXX (7%), KDM5C (7%), LRP1B (7%), MSH2 (7%) and RB1 (7%).	('RB1', 'Gene', (223, 226))	('DAXX', 'Gene', (174, 178))	('MSH2', 'Gene', '4436', (209, 213))	('TP53', 'Gene', '7157', (127, 131))	('KDM5C', 'Gene', '8242', (185, 190))	('DAXX', 'Gene', '1616', (174, 178))	('LRP1B', 'Gene', (197, 202))	('APC', 'Disease', 'MESH:D011125', (164, 167))	('APC', 'Disease', (164, 167))	('RB1', 'Gene', '5925', (223, 226))	('CTNNB1', 'Gene', '1499', (150, 156))	('LRP1B', 'Gene', '53353', (197, 202))	('KDM5C', 'Gene', (185, 190))	('MEN1', 'Gene', '4221', (139, 143))	('alterations', 'Var', (38, 49))	('TP53', 'Gene', (127, 131))	('CTNNB1', 'Gene', (150, 156))	('MSH2', 'Gene', (209, 213))	('men', 'Species', '9606', (101, 104))	('MEN1', 'Gene', (139, 143))
67591	25078331	The most common potentially actionable alterations involved NF1 (14%), CDKN2A (14%), ATM (10%), CCND2 (7%), CDK4 (7%), DNMT3A (7%) with EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN, PTCH1 and STK11, each altered in a single case.	('KRAS', 'Gene', (149, 153))	('PIK3CA', 'Gene', '5290', (175, 181))	('ERBB4', 'Gene', '2066', (142, 147))	('NRAS', 'Gene', (161, 165))	('ATM', 'Gene', '472', (85, 88))	('MDM2', 'Gene', (155, 159))	('ERBB4', 'Gene', (142, 147))	('CDK4', 'Gene', '1019', (108, 112))	('NF1', 'Gene', '4763', (60, 63))	('PTCH1', 'Gene', (189, 194))	('DNMT3A', 'Gene', '1788', (119, 125))	('MDM2', 'Gene', '4193', (155, 159))	('CCND2', 'Gene', (96, 101))	('EGFR', 'Gene', (136, 140))	('PIK3CA', 'Gene', (175, 181))	('CCND2', 'Gene', '894', (96, 101))	('PTEN', 'Gene', (183, 187))	('STK11', 'Gene', (199, 204))	('ATM', 'Gene', (85, 88))	('CDKN2A', 'Gene', (71, 77))	('NF1', 'Gene', (60, 63))	('PDGFRB', 'Gene', '5159', (167, 173))	('PDGFRB', 'Gene', (167, 173))	('NRAS', 'Gene', '4893', (161, 165))	('PTEN', 'Gene', '5728', (183, 187))	('DNMT3A', 'Gene', (119, 125))	('CDKN2A', 'Gene', '1029', (71, 77))	('KRAS', 'Gene', '3845', (149, 153))	('STK11', 'Gene', '6794', (199, 204))	('alterations', 'Var', (39, 50))	('CDK4', 'Gene', (108, 112))	('EGFR', 'Gene', '1956', (136, 140))	('PTCH1', 'Gene', '5727', (189, 194))
67593	25078331	TP53 mutations have been reported in ACC at frequencies ranging from 10% to 70% and have been associated with decreased disease-free survival and poor outcomes.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('disease-free survival', 'CPA', (120, 141))	('mutations', 'Var', (5, 14))	('decreased', 'NegReg', (110, 119))	('ACC', 'Phenotype', 'HP:0006744', (37, 40))	('ACC', 'Disease', (37, 40))
67594	25078331	Germline TP53 mutations have also been linked with the development of ACC, particularly in paediatric patients with a family history of LFS and Li-Fraumeni-like Syndrome.	('men', 'Species', '9606', (151, 154))	('men', 'Species', '9606', (62, 65))	('ACC', 'Phenotype', 'HP:0006744', (70, 73))	('ACC', 'Disease', (70, 73))	('LFS', 'Disease', (136, 139))	('Li-Fraumeni-like Syndrome', 'Disease', (144, 169))	('linked with', 'Reg', (39, 50))	('patients', 'Species', '9606', (102, 110))	('Li-Fraumeni-like Syndrome', 'Disease', 'MESH:C567189', (144, 169))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('LFS', 'Disease', 'MESH:D016864', (136, 139))	('mutations', 'Var', (14, 23))
67595	25078331	In this study, the mean age of the patients with ACC with and without TP53 mutation was 59.4 years versus 50.2 years, respectively, and no TP53-mutated ACC was identified in a patient younger than 46 years.	('ACC', 'Disease', (49, 52))	('ACC', 'Phenotype', 'HP:0006744', (152, 155))	('TP53', 'Gene', '7157', (70, 74))	('mutation', 'Var', (75, 83))	('patient', 'Species', '9606', (35, 42))	('TP53', 'Gene', '7157', (139, 143))	('TP53', 'Gene', (70, 74))	('TP53', 'Gene', (139, 143))	('patient', 'Species', '9606', (176, 183))	('patients', 'Species', '9606', (35, 43))	('ACC', 'Phenotype', 'HP:0006744', (49, 52))
67596	25078331	Patient-matched normal specimens required to definitively determine the germline status of TP53 mutation were not available for this study.	('TP53', 'Gene', (91, 95))	('men', 'Species', '9606', (28, 31))	('mutation', 'Var', (96, 104))	('TP53', 'Gene', '7157', (91, 95))	('Patient', 'Species', '9606', (0, 7))
67601	25078331	Amplification of CDK4 has been identified in multiple cancer types and in a small number of adrenal carcinomas.	('Amplification', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('adrenal carcinomas', 'Disease', (92, 110))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('identified', 'Reg', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('CDK4', 'Gene', (17, 21))	('cancer', 'Disease', (54, 60))	('adrenal carcinomas', 'Disease', 'MESH:D000310', (92, 110))	('adrenal carcinomas', 'Phenotype', 'HP:0006744', (92, 110))	('CDK4', 'Gene', '1019', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
67604	25078331	In another case (Case 7), a locally advanced oncocytic ACC derived from a 60-year-old man, a single alteration was identified, amplification of PDGFRB (figure 3).	('ACC', 'Phenotype', 'HP:0006744', (55, 58))	('PDGFRB', 'Gene', (144, 150))	('man', 'Species', '9606', (86, 89))	('amplification', 'Var', (127, 140))	('PDGFRB', 'Gene', '5159', (144, 150))
67606	25078331	PDGFRB amplification has been associated with PDGFRB protein overexpression and increased kinase activity in a variety of other tumours.	('associated', 'Reg', (30, 40))	('kinase activity', 'MPA', (90, 105))	('tumours', 'Disease', (128, 135))	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('PDGFRB', 'Gene', '5159', (0, 6))	('PDGFRB', 'Gene', (46, 52))	('overexpression', 'PosReg', (61, 75))	('PDGFRB', 'Gene', (0, 6))	('increased', 'PosReg', (80, 89))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('PDGFRB', 'Gene', '5159', (46, 52))	('protein', 'Protein', (53, 60))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('amplification', 'Var', (7, 20))
67686	32038720	Although these articles established the critical role of lncRNA SOX2-OT expression in some cancers, the prognostic value of SOX2-OT expression in numerous other cancers remained uncharacterized.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('lncRNA', 'Var', (57, 63))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Disease', (161, 168))
67713	32038720	Regarding the clinicopathological characteristics of patients with cancers, our research suggested that high SOX2-OT expression was significantly associated with the invasion of cancers, as reveal by the tumor stage (RR = 1.468, 95% CI: 1.106-1.949), lymphatic metastasis (RR = 1.554, 95% CI: 1.211-1.994), distant metastasis (RR = 3.054, 95% CI: 1.866-4.999), tumor size (RR = 1.264, 95% CI: 1.019-1.566), and depth of tumor invasion (RR = 1.552, 95% CI: 1.274-1.890), but couldn't predict histological differentiation, age, or gender.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (420, 425))	('tumor invasion', 'Disease', (420, 434))	('tumor', 'Disease', (361, 366))	('tumor invasion', 'Disease', 'MESH:D009361', (420, 434))	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('depth of tumor', 'Disease', 'MESH:D007222', (411, 425))	('depth of tumor', 'Disease', (411, 425))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('tumor', 'Disease', (420, 425))	('lymphatic metastasis', 'CPA', (251, 271))	('tumor', 'Disease', 'MESH:D009369', (420, 425))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('distant metastasis', 'CPA', (307, 325))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('tumor', 'Disease', (204, 209))	('high', 'Var', (104, 108))	('cancers', 'Disease', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('associated', 'Reg', (146, 156))
67717	32038720	Kaplan-Meier analysis initially suggested that SOX2-OT overexpression was associated with a bad OS in adrenocortical cancer (ACC), cervical cancer (CESC), mesothelioma (MESO), and glioma (LGG), and associated with a worse OS in breast cancer (BRCA), kidney renal clear cell carcinoma (KIRC), thymoma (THYM), thyroid cancer (THCA), uterine carcinosarcoma (UCS), and endometrioid cancer (UCEC) according to the TCGA datasets ( Table 7  and  Supplementary Figures 3  and  4 ).	('THCA', 'Disease', (324, 328))	('MESO', 'Disease', (169, 173))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (365, 384))	('carcinosarcoma', 'Disease', (339, 353))	('THYM', 'Disease', (301, 305))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('THCA', 'Phenotype', 'HP:0002890', (324, 328))	('kidney renal clear cell carcinoma', 'Disease', (250, 283))	('thyroid cancer', 'Disease', 'MESH:D013964', (308, 322))	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('carcinosarcoma', 'Disease', 'MESH:D002296', (339, 353))	('BRCA', 'Disease', (243, 247))	('thymoma', 'Disease', 'MESH:D013945', (292, 299))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('UCS', 'Phenotype', 'HP:0002891', (355, 358))	('adrenocortical cancer', 'Disease', (102, 123))	('BRCA', 'Disease', 'MESH:D001943', (243, 247))	('THYM', 'Disease', 'MESH:D013945', (301, 305))	('thyroid cancer', 'Phenotype', 'HP:0002890', (308, 322))	('breast cancer', 'Disease', 'MESH:D001943', (228, 241))	('cancer', 'Disease', (117, 123))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (331, 353))	('cancer', 'Disease', (316, 322))	('breast cancer', 'Disease', (228, 241))	('endometrioid cancer', 'Disease', 'MESH:D009369', (365, 384))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', (378, 384))	('thymoma', 'Disease', (292, 299))	('thymoma', 'Phenotype', 'HP:0100522', (292, 299))	('KIRC', 'Disease', (285, 289))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('glioma', 'Disease', (180, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (346, 353))	('THYM', 'Phenotype', 'HP:0100522', (301, 305))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (250, 283))	('mesothelioma', 'Disease', (155, 167))	('cancer', 'Disease', (235, 241))	('ACC', 'Disease', (125, 128))	('SOX2-OT', 'Var', (47, 54))	('ACC', 'Disease', 'MESH:D000306', (125, 128))	('MESO', 'Disease', 'MESH:D008654', (169, 173))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('endometrioid cancer', 'Disease', (365, 384))	('BRCA', 'Phenotype', 'HP:0003002', (243, 247))	('KIRC', 'Disease', 'MESH:D002292', (285, 289))	('thyroid cancer', 'Disease', (308, 322))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('mesothelioma', 'Disease', 'MESH:D008654', (155, 167))	('THCA', 'Disease', 'MESH:D013964', (324, 328))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (102, 123))
67721	32038720	proposed that SOX2-OT was highly expressed in gastric cancer cells, which promoted the expression of AKT2 by targeting miR-194-5p, thus elevating cell proliferation and metastasis.	('promoted', 'PosReg', (74, 82))	('AKT2', 'Gene', (101, 105))	('gastric cancer', 'Disease', (46, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('expression', 'MPA', (87, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('elevating', 'PosReg', (136, 145))	('miR-194-5p', 'Var', (119, 129))	('targeting miR-194-5p', 'Var', (109, 129))	('cell proliferation', 'CPA', (146, 164))
67726	32038720	showed that high SOX2-OT expression predicted poor OS and more advanced tumor progression, but failed to predict distant metastasis and lymph node metastasis in Chinese cancer patients.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Disease', (169, 175))	('high', 'Var', (12, 16))	('tumor', 'Disease', (72, 77))	('expression', 'MPA', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('SOX2-OT', 'Protein', (17, 24))	('poor OS', 'CPA', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
67737	32038720	This research was supported by the National Natural Science Foundation of China (81902498), Natural Science Foundation of Hubei Province of China (2019CFB177), Natural Science Foundation of Hubei Provincial Department of Education (Q20182105), Chen Xiao-ping Foundation for the development of science and technology of Hubei Provincial (CXPJJH11800001-2018333), Natural Science Foundation of Hubei Province of China (2016CFB530) and Faculty Development Foundation of Hubei University of Medicine (2014QDJZR01), and National Students' platform for innovation and entrepreneurship training program (201810929005, 201810929009, 201810929068, and 201813249010).	('201810929068', 'Var', (625, 637))	('201810929009', 'Var', (611, 623))	('201810929005', 'Var', (597, 609))	('201813249010', 'Var', (643, 655))	('2019CFB177', 'Chemical', 'MESH:C045346', (147, 157))
67746	31378849	mTOR inhibition reverted IGF2 triggered cell proliferation and viability while MEK/MAPK/ERK inhibition only reverted IGF2 effects on cell proliferation.	('inhibition', 'Var', (5, 15))	('ERK', 'Gene', '5594', (88, 91))	('IGF2', 'Gene', (117, 121))	('viability', 'CPA', (63, 72))	('MEK', 'Gene', (79, 82))	('MEK', 'Gene', '5609', (79, 82))	('ERK', 'Gene', (88, 91))	('IGF2', 'Gene', '3481', (25, 29))	('IGF2', 'Gene', '3481', (117, 121))	('cell proliferation', 'CPA', (40, 58))	('IGF2', 'Gene', (25, 29))
67761	31378849	IGF2 overexpression was previously described as responsible for increased proliferation of ACC cells.	('ACC', 'Phenotype', 'HP:0006744', (91, 94))	('ACC', 'Disease', (91, 94))	('IGF2', 'Gene', '3481', (0, 4))	('proliferation', 'CPA', (74, 87))	('increased', 'PosReg', (64, 73))	('overexpression', 'Var', (5, 19))	('IGF2', 'Gene', (0, 4))	('ACC', 'Disease', 'MESH:D018268', (91, 94))
67786	31378849	The MEK inhibitor (PD184352, Sigma-Aldrich) concentration used (10 microM) was previously reported to significantly decrease the phospho-ERK in H295R cells.	('PD184352', 'Var', (19, 27))	('decrease', 'NegReg', (116, 124))	('MEK', 'Gene', (4, 7))	('PD184352', 'Chemical', 'MESH:C120227', (19, 27))	('MEK', 'Gene', '5609', (4, 7))	('H295R', 'CellLine', 'CVCL:0458', (144, 149))	('ERK', 'Gene', '5594', (137, 140))	('ERK', 'Gene', (137, 140))
67796	31378849	H295R cells were then exposed to IGF2 with and without the pathway's inhibitors (Rapamycin for mTOR pathway inhibition and PD184352 for MAPK pathway inhibition).	('mTOR pathway', 'Pathway', (95, 107))	('inhibition', 'NegReg', (108, 118))	('IGF2', 'Gene', '3481', (33, 37))	('Rapamycin', 'Chemical', 'MESH:D020123', (81, 90))	('PD184352', 'Chemical', 'MESH:C120227', (123, 131))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('IGF2', 'Gene', (33, 37))	('PD184352', 'Var', (123, 131))	('MAPK pathway', 'Pathway', (136, 148))
67822	31378849	IGF2 (100 ng/mL) also significantly increased cell viability (150.8 +- 15.40 %) when compared to the control (100.0 +- 6.11 %; p < 0.05) (Fig.	('cell viability', 'CPA', (46, 60))	('increased', 'PosReg', (36, 45))	('IGF2', 'Gene', '3481', (0, 4))	('IGF2', 'Gene', (0, 4))	('100 ng/mL', 'Var', (6, 15))
67867	31378849	When inside the cell, glutamine by itself can contribute to nucleotide biosynthesis or it can suffer glutaminolysis, a metabolic pathway in which glutamine is catabolized to generate ATP and lactate.	('lactate', 'Chemical', 'MESH:D019344', (191, 198))	('glutamine', 'Chemical', 'MESH:C578860', (146, 155))	('contribute', 'Reg', (46, 56))	('nucleotide biosynthesis', 'MPA', (60, 83))	('glutaminolysis', 'MPA', (101, 115))	('glutamine', 'Chemical', 'MESH:C578860', (22, 31))	('glutamine', 'Var', (22, 31))	('ATP', 'Chemical', 'MESH:D000255', (183, 186))	('suffer', 'Reg', (94, 100))
67874	31378849	Besides that, H295R cells have a specific genetic profile that includes the presence of beta-catenin protein accumulation associated with a point mutation of Ser45 in exon 3 and so it must be stressed that these results may only be applied to tumors with this characteristic.	('Ser', 'Chemical', 'MESH:C530429', (158, 161))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('point mutation', 'Var', (140, 154))	('tumors', 'Disease', (243, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('Ser45', 'Gene', (158, 163))	('beta-catenin', 'Gene', (88, 100))	('H295R', 'CellLine', 'CVCL:0458', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('beta-catenin', 'Gene', '1499', (88, 100))
67879	30623166	Case Report of an Adrenocortical Carcinoma Associated With Germline CHEK2 Mutation Adrenocortical carcinoma (ACC) is an aggressive form of cancer that originates in the cortex of the adrenal gland; the incidence of ACC is 1.5 to 2 cases per million people per year.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('CHEK2', 'Gene', (68, 73))	('Mutation', 'Var', (74, 82))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (18, 42))	('Carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('ACC', 'Phenotype', 'HP:0006744', (215, 218))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('Adrenocortical Carcinoma', 'Disease', (18, 42))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (83, 107))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('Associated', 'Reg', (43, 53))	('cancer', 'Disease', (139, 145))	('people', 'Species', '9606', (249, 255))	('CHEK2', 'Gene', '11200', (68, 73))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (18, 42))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (83, 107))	('Adrenocortical carcinoma', 'Disease', (83, 107))
67881	30623166	Here, we present a case of ACC with a pathogenic heterozygous germline deletion in CHEK2 (c.1100delC).	('c.1100delC', 'Mutation', 'rs555607708', (90, 100))	('CHEK2', 'Gene', '11200', (83, 88))	('CHEK2', 'Gene', (83, 88))	('c.1100delC', 'Var', (90, 100))	('ACC', 'Phenotype', 'HP:0006744', (27, 30))
67889	30623166	In addition, ACC has been reported in patients with neurofibromatosis type 1, hereditary nonpolyposis colorectal cancer, and succinate dehydrogenase pathogenic mutations.	('reported', 'Reg', (26, 34))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (52, 69))	('mutations', 'Var', (160, 169))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (78, 119))	('ACC', 'Phenotype', 'HP:0006744', (13, 16))	('patients', 'Species', '9606', (38, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('neurofibromatosis type 1, hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:C535972', (52, 119))
67894	30623166	It is hypothesized that the clinical spectrum of cancers associated with CHEK2 mutations may reflect their relative contribution toward the function of TP53 and/or BRCA1.	('BRCA1', 'Gene', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('TP53', 'Gene', '7157', (152, 156))	('CHEK2', 'Gene', '11200', (73, 78))	('TP53', 'Gene', (152, 156))	('CHEK2', 'Gene', (73, 78))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('mutations', 'Var', (79, 88))	('BRCA1', 'Gene', '672', (164, 169))
67895	30623166	There are multiple CHEK2 variants that have been associated with various sporadic cancers or familial hereditary syndromes, including large deletion of exon 9 and 10, 1100delC, missense mutations affecting the forkhead and kinase domains, G190A, A751T, IVS2+1G-A, and I157T.	('missense mutations', 'Var', (177, 195))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('familial hereditary syndromes', 'Disease', (93, 122))	('associated', 'Reg', (49, 59))	('I157T', 'Var', (268, 273))	('G190A', 'Var', (239, 244))	('CHEK2', 'Gene', (19, 24))	('A751T', 'Var', (246, 251))	('I157T', 'Mutation', 'rs17879961', (268, 273))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('variants', 'Var', (25, 33))	('affecting', 'Reg', (196, 205))	('IVS2+1G-A', 'Mutation', 'c.IVS2+1G>A', (253, 262))	('CHEK2', 'Gene', '11200', (19, 24))	('sporadic cancers', 'Disease', 'MESH:D009369', (73, 89))	('1100delC', 'Mutation', 'rs555607708', (167, 175))	('A751T', 'Mutation', 'rs587780189', (246, 251))	('familial hereditary syndromes', 'Disease', 'MESH:D009386', (93, 122))	('sporadic cancers', 'Disease', (73, 89))	('IVS2+1G-A', 'Var', (253, 262))	('G190A', 'Mutation', 'rs141568342', (239, 244))
67897	30623166	Here, we report a case of a 48-year-old woman diagnosed initially with Cushing syndrome and later with ACC, and whom was found to be a carrier of a pathogenic heterozygous deletion in CHEK2 (namely, c.1100delC).	('ACC', 'Phenotype', 'HP:0006744', (103, 106))	('ACC', 'Disease', (103, 106))	('c.1100delC', 'Var', (199, 209))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (71, 87))	('woman', 'Species', '9606', (40, 45))	('CHEK2', 'Gene', '11200', (184, 189))	('Cushing syndrome', 'Disease', 'MESH:D003480', (71, 87))	('Cushing syndrome', 'Disease', (71, 87))	('CHEK2', 'Gene', (184, 189))	('c.1100delC', 'Mutation', 'rs555607708', (199, 209))
67915	30623166	The results revealed a heterozygous deletion (c.1100delC) of the CHEK2 gene as the only positive finding.	('CHEK2', 'Gene', (65, 70))	('CHEK2', 'Gene', '11200', (65, 70))	('c.1100delC', 'Mutation', 'rs555607708', (46, 56))	('c.1100delC', 'Var', (46, 56))
67920	30623166	One daughter was tested for the CHEK2 mutation and was negative.	('CHEK2', 'Gene', '11200', (32, 37))	('mutation', 'Var', (38, 46))	('CHEK2', 'Gene', (32, 37))	('tested', 'Reg', (17, 23))
67921	30623166	Here, we report an ACC case with a heterozygous deletion of the CHEK2 gene (c.1100delC).	('CHEK2', 'Gene', (64, 69))	('CHEK2', 'Gene', '11200', (64, 69))	('c.1100delC', 'Mutation', 'rs555607708', (76, 86))	('c.1100delC', 'Var', (76, 86))	('ACC', 'Phenotype', 'HP:0006744', (19, 22))
67922	30623166	The c.1100delC at exon 11 of the CHEK2 mRNA leads to a frameshift of codon 367 and subsequently creates a premature translational stop signal as p.Thr367Metfs*15 that is expected to result in an absent or disrupted CHK2 protein.	('frameshift', 'Var', (55, 65))	('absent', 'NegReg', (195, 201))	('p.Thr367Metfs*15', 'FRAMESHIFT', 'None', (145, 161))	('disrupted', 'NegReg', (205, 214))	('c.1100delC', 'Var', (4, 14))	('p.Thr367Metfs*15', 'Var', (145, 161))	('CHK2', 'Gene', '11200', (215, 219))	('CHEK2', 'Gene', '11200', (33, 38))	('c.1100delC', 'Mutation', 'rs555607708', (4, 14))	('CHEK2', 'Gene', (33, 38))	('leads to', 'Reg', (44, 52))	('CHK2', 'Gene', (215, 219))
67924	30623166	However, variants with loss of function in CHEK2 are known to be pathogenic for other cancer types.	('loss of function', 'NegReg', (23, 39))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CHEK2', 'Gene', '11200', (43, 48))	('variants', 'Var', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('CHEK2', 'Gene', (43, 48))	('cancer', 'Disease', (86, 92))
67925	30623166	In a large meta-analysis of 16 studies, including 26,488 patients and 27,402 control subjects, women with heterozygosity of this variant had a relative risk for familial breast cancer of 4.8 (95% CI, 3.3 to 7.2).	('patients', 'Species', '9606', (57, 65))	('variant', 'Var', (129, 136))	('women', 'Species', '9606', (95, 100))	('familial breast cancer', 'Disease', 'MESH:D001943', (161, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('familial breast cancer', 'Disease', (161, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('to 7', 'Species', '1214577', (204, 208))
67927	30623166	Although a study reports that the c.1100delC variant contributes an ~10-fold increased risk of breast cancer in males, the results have yet to be validated in others.	('c.1100delC', 'Var', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('c.1100delC', 'Mutation', 'rs555607708', (34, 44))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
67928	30623166	Patients with a history of familial breast cancer who carry the c.1100delC variant and wild-type BRCA1/2 have a considerably higher incidence of the 1-bp deletion.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('c.1100delC', 'Var', (64, 74))	('familial breast cancer', 'Disease', (27, 49))	('BRCA1/2', 'Gene', (97, 104))	('Patients', 'Species', '9606', (0, 8))	('c.1100delC', 'Mutation', 'rs555607708', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('BRCA1/2', 'Gene', '672;675', (97, 104))	('familial breast cancer', 'Disease', 'MESH:D001943', (27, 49))
67929	30623166	Moreover, more patients with hereditary breast cancer with colorectal cancer carry the c.1100delC variant than do patients with breast cancer but without colorectal cancer (18% vs 4%, respectively).	('patients', 'Species', '9606', (15, 23))	('colorectal cancer', 'Disease', (154, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (29, 53))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('patients', 'Species', '9606', (114, 122))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))	('c.1100delC', 'Mutation', 'rs555607708', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('hereditary breast cancer', 'Disease', (29, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('colorectal cancer', 'Disease', (59, 76))	('c.1100delC', 'Var', (87, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
67930	30623166	Nevertheless, the c.1100delC appeared to synergistically act with at least an unknown vulnerability gene and was not the major predisposing factor for the HBCC presentation.	('c.1100delC', 'Var', (18, 28))	('act', 'Reg', (57, 60))	('c.1100delC', 'Mutation', 'rs555607708', (18, 28))
67931	30623166	Interestingly, c.1100delC carriers not only had more frequent female breast cancer in their first- or second-degree relatives, they had a higher occurrence of contralateral breast cancer and poorer distant metastasis-free survival.	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('distant metastasis-free survival', 'CPA', (198, 230))	('c.1100delC', 'Mutation', 'rs555607708', (15, 25))	('c.1100delC carriers', 'Var', (15, 34))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('contralateral breast cancer', 'Disease', (159, 186))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('more', 'PosReg', (48, 52))	('poorer', 'NegReg', (191, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (159, 186))
67933	30623166	Nevertheless, c.1100delC mutation was found in 14 (0.8%) of 1864 Polish men with prostate cancer, in 3 of 249 Polish men (1.2%) with familial prostate cancer, and in 12 (0.2%) of 5496 healthy control subjects (OR, 5.6).	('familial prostate cancer', 'Disease', (133, 157))	('c.1100delC', 'Mutation', 'rs555607708', (14, 24))	('prostate cancer', 'Disease', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (142, 157))	('men', 'Species', '9606', (117, 120))	('men', 'Species', '9606', (72, 75))	('familial prostate cancer', 'Disease', 'MESH:C537243', (133, 157))	('c.1100delC', 'Var', (14, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (142, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))
67934	30623166	In a study in which effort was made to confine the incidence of cancer to those other than breast cancer from 11,116 families with a history of non-BRCA1/2 breast cancer, c.1100delC mutation primarily was associated with breast cancer but also slightly with increased overall risk of other cancers.	('BRCA1/2', 'Gene', '672;675', (148, 155))	('cancer', 'Disease', (98, 104))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('breast cancer', 'Disease', (221, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('cancer', 'Disease', (64, 70))	('cancers', 'Disease', 'MESH:D009369', (290, 297))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('associated', 'Reg', (205, 215))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (228, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('c.1100delC', 'Mutation', 'rs555607708', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('cancers', 'Phenotype', 'HP:0002664', (290, 297))	('BRCA1/2', 'Gene', (148, 155))	('cancer', 'Disease', (290, 296))	('cancers', 'Disease', (290, 297))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('c.1100delC', 'Var', (171, 181))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
67935	30623166	Findings indicate c.1100delC is a founder mutation for the aforementioned cancers.	('c.1100delC', 'Mutation', 'rs555607708', (18, 28))	('c.1100delC', 'Var', (18, 28))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('men', 'Species', '9606', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
67937	30623166	Inactivation of the TP53 pathway is an established feature of human cancers, with nearly all cancers evolving a system to evade this essential tumor-suppressive mechanism.	('cancers', 'Disease', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', (20, 24))	('tumor', 'Disease', (143, 148))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('TP53', 'Gene', '7157', (20, 24))	('Inactivation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
67938	30623166	Although inactivation of TP53 through mutations or deletions of the TP53 locus directly leads to development of various human cancers, there are many other molecular alterations that can functionally attenuate the pathway.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (120, 125))	('TP53', 'Gene', (25, 29))	('men', 'Species', '9606', (104, 107))	('TP53', 'Gene', '7157', (68, 72))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('inactivation', 'NegReg', (9, 21))	('deletions', 'Var', (51, 60))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('leads to', 'Reg', (88, 96))	('mutations', 'Var', (38, 47))	('TP53', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (25, 29))
67941	30623166	Therefore, CHEK2 is crucial for cell-cycle regulation, and its abnormal expression could lead to cancer independent of TP53 mutation status.	('cancer', 'Disease', (97, 103))	('CHEK2', 'Gene', '11200', (11, 16))	('abnormal', 'Var', (63, 71))	('lead to', 'Reg', (89, 96))	('CHEK2', 'Gene', (11, 16))	('expression', 'MPA', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
67943	30623166	This ACC case shows that c.1100delC of CHEK2 may be linked to ACC tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('linked', 'Reg', (52, 58))	('c.1100delC', 'Var', (25, 35))	('tumor', 'Disease', (66, 71))	('ACC', 'Phenotype', 'HP:0006744', (5, 8))	('CHEK2', 'Gene', '11200', (39, 44))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('ACC', 'Disease', (62, 65))	('CHEK2', 'Gene', (39, 44))	('c.1100delC', 'Mutation', 'rs555607708', (25, 35))
67947	30623166	The finding of a germline CHEK2 mutation may entail a clinical surveillance for patients with asymptomatic nonadrenal neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (118, 127))	('patients', 'Species', '9606', (80, 88))	('neoplasms', 'Disease', 'MESH:D009369', (118, 127))	('CHEK2', 'Gene', '11200', (26, 31))	('neoplasms', 'Disease', (118, 127))	('mutation', 'Var', (32, 40))	('CHEK2', 'Gene', (26, 31))
67948	30623166	In conclusion, we report a case showing ACC tumorigenesis is associated with a germline CHEK2 mutation.	('ACC', 'Phenotype', 'HP:0006744', (40, 43))	('ACC', 'Disease', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CHEK2', 'Gene', (88, 93))	('associated', 'Reg', (61, 71))	('tumor', 'Disease', (44, 49))	('mutation', 'Var', (94, 102))	('CHEK2', 'Gene', '11200', (88, 93))
67959	30558313	Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (43, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('neuroblastoma', 'Phenotype', 'HP:0003006', (68, 81))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (32, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mixed', 'Reg', (21, 26))	('neuroblastomas', 'Phenotype', 'HP:0003006', (68, 82))	('neuroblastomas', 'Disease', 'MESH:D009447', (68, 82))	('pancreatic neuroendocrine tumors', 'Disease', (32, 64))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (32, 64))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (43, 63))	('neuroblastomas', 'Disease', (68, 82))	('PPGLs', 'Var', (15, 20))
67966	30558313	Similarly, PPGLs are separated into 4 groups named after their molecular characteristics: pseudohypoxia related to succinate dehydrogenase or VHL/EPAS1 disturbances, wnt-altered and kinase-signaling pathways.	('pseudohypoxia', 'Disease', 'None', (90, 103))	('VHL', 'Disease', 'MESH:D006623', (142, 145))	('EPAS1', 'Gene', '2034', (146, 151))	('VHL', 'Disease', (142, 145))	('EPAS1', 'Gene', (146, 151))	('disturbances', 'Var', (152, 164))	('pseudohypoxia', 'Disease', (90, 103))
68006	30558313	Results showed a separation into two clusters, one consisting of low and high grade gliomas and a second including NBL, PNET, and PPGL (Figure 4, Supplementary Figures S10A-C and S11A-C).	('NBL', 'Phenotype', 'HP:0003006', (115, 118))	('S11A', 'Var', (179, 183))	('S10A', 'Var', (168, 172))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('S11A', 'SUBSTITUTION', 'None', (179, 183))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('S10A', 'SUBSTITUTION', 'None', (168, 172))
68024	30558313	This includes presence of both telomerase activation and alternative lengthening of telomeres due to ATRX or DAXX truncation as well as somatic or germline driver mutations in MEN1.	('telomerase', 'Enzyme', (31, 41))	('mutations', 'Var', (163, 172))	('DAXX', 'Gene', '1616', (109, 113))	('MEN1', 'Gene', (176, 180))	('MEN1', 'Gene', '4221', (176, 180))	('activation', 'PosReg', (42, 52))	('ATRX', 'Gene', (101, 105))	('DAXX', 'Gene', (109, 113))	('ATRX', 'Gene', '546', (101, 105))
68062	30262398	A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes.	('MMR', 'Gene', (124, 127))	('mutations', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ACC', 'Disease', (12, 15))	('resulting from', 'Reg', (70, 84))	('tumor syndrome', 'Disease', (55, 69))	('Lynch syndrome', 'Disease', (26, 40))	('Lynch syndrome', 'Disease', 'MESH:D003123', (26, 40))	('tumor syndrome', 'Disease', 'MESH:D009369', (55, 69))
68072	30262398	In adults, the majority of ACC are sporadic; however, it is recognized that a subset of ACC is associated with Lynch syndrome, an autosomal dominant tumor syndrome caused by pathogenic mutations of DNA mismatch repair (MMR) genes (MSH2, MSH6, PMS2, and MLH1).	('MSH6', 'Gene', (237, 241))	('PMS2', 'Gene', '5395', (243, 247))	('autosomal dominant tumor syndrome', 'Disease', 'MESH:D030342', (130, 163))	('MLH1', 'Gene', '4292', (253, 257))	('Lynch syndrome', 'Disease', (111, 125))	('associated', 'Reg', (95, 105))	('MLH1', 'Gene', (253, 257))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('ACC', 'Disease', (88, 91))	('autosomal dominant tumor syndrome', 'Disease', (130, 163))	('Lynch syndrome', 'Disease', 'MESH:D003123', (111, 125))	('MSH6', 'Gene', '2956', (237, 241))	('caused by', 'Reg', (164, 173))	('mutations', 'Var', (185, 194))	('MSH2', 'Gene', (231, 235))	('MMR', 'Gene', (219, 222))	('MSH2', 'Gene', '4436', (231, 235))	('PMS2', 'Gene', (243, 247))
68079	30262398	Based on these data, pembrolizumab was granted Food and Drug Administration approval for the treatment of unresectable or metastatic, microsatellite instability-high (MSI-H) or MMR-deficient solid tumors regardless of tumor site or histology.	('pembrolizumab', 'Chemical', 'MESH:C582435', (21, 34))	('MSI-H', 'Disease', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('MMR-deficient solid tumors regardless of tumor', 'Disease', 'MESH:D009369', (177, 223))	('MMR-deficient solid tumors regardless of tumor', 'Disease', (177, 223))	('MSI-H', 'Disease', 'MESH:D000848', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('metastatic', 'CPA', (122, 132))	('microsatellite instability-high', 'Var', (134, 165))
68083	30262398	MMR immunohistochemistry was performed using the Ventana Benchmark MMR panel: MLH-1 (M1), PMS2 (EPR3947), MSH2 (G219-1129), and CONFIRM anti-MSH6.	('MLH-1', 'Gene', '4292', (78, 83))	('G219-1129', 'Var', (112, 121))	('MSH2', 'Gene', (106, 110))	('MSH6', 'Gene', (141, 145))	('MLH-1', 'Gene', (78, 83))	('MSH2', 'Gene', '4436', (106, 110))	('PMS2', 'Gene', (90, 94))	('EPR3947', 'Var', (96, 103))	('MSH6', 'Gene', '2956', (141, 145))	('PMS2', 'Gene', '5395', (90, 94))
68087	30262398	Her medical history was significant for Lynch syndrome due to a pathogenic mutation in MSH2 (p.Asn263fs).	('p.Asn263fs', 'Mutation', 'rs63751614', (93, 103))	('MSH2', 'Gene', (87, 91))	('Lynch syndrome', 'Disease', (40, 54))	('pathogenic', 'Reg', (64, 74))	('MSH2', 'Gene', '4436', (87, 91))	('Lynch syndrome', 'Disease', 'MESH:D003123', (40, 54))	('p.Asn263fs', 'Var', (93, 103))
68147	30053901	Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Disease', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('protein/phosphoprotein', 'MPA', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mRNA expression', 'MPA', (142, 157))
68151	30053901	Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively.	('alterations', 'Var', (76, 87))	('tumors', 'Disease', (98, 104))	('ESR1', 'Gene', '2099', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('mTOR', 'Gene', (191, 195))	('AKT', 'Gene', '207', (229, 232))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('mTOR', 'Gene', '2475', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ESR1', 'Gene', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('BRAF', 'Gene', (224, 228))	('AKT', 'Gene', (229, 232))	('BRAF', 'Gene', '673', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
68152	30053901	We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool.	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (59, 68))
68154	30053901	Our results suggest that an integrated analysis platform can nominate multi-omics alterations as biomarkers of druggability and aid ongoing efforts to bring precision oncology to patients.	('oncology', 'Phenotype', 'HP:0002664', (167, 175))	('alterations', 'Var', (82, 93))	('patients', 'Species', '9606', (179, 187))	('multi-omics', 'Var', (70, 81))
68161	30053901	The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and other large-scale sequencing data sets represent an opportunity to identify "druggable" variants, i.e., variants that render a cancer type susceptible to a drug.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('render', 'Reg', (212, 218))	('variants', 'Var', (182, 190))	('Tumor', 'Phenotype', 'HP:0002664', (55, 60))	('variants', 'Var', (198, 206))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))
68164	30053901	We identified tumors with drug-associated mutations and found considerable opportunity for repurposing of drugs across cancer types.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (119, 125))	('drug-associated', 'Reg', (26, 41))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
68165	30053901	We used a structure-based computational tool to identify putative druggable mutations based on proximity to known druggable mutations and experimentally validated a subset of putative druggable mutations in BRAF.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('mutations', 'Var', (76, 85))	('mutations', 'Var', (194, 203))
68173	30053901	Tumor type is included for each variant/drug entry because, with infrequent exception, a variant's effect on a tumor's response to a given drug has only been rigorously studied in one or only a few cancer type(s).	('response to a given drug', 'MPA', (119, 143))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('variant', 'Var', (89, 96))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
68174	30053901	For a variant/drug entry based on preclinical data, tumor type was either inferred from the xenograft or cell line, or left unspecified.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('variant/drug', 'Var', (6, 18))	('tumor', 'Disease', (52, 57))	('unspecified', 'Species', '32644', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
68175	30053901	Copy number amplifications (CNA) and losses (CNL), high expression outliers in oncogenes, low expression outliers in tumor suppressors, and fusions that may lead to druggability are also included.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('druggability', 'MPA', (165, 177))	('losses', 'NegReg', (37, 43))	('tumor', 'Disease', (117, 122))	('lead to', 'Reg', (157, 164))	('Copy number amplifications', 'Var', (0, 26))	('oncogenes', 'Gene', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
68176	30053901	Effect describes whether a variant correlates with increased sensitivity of a tumor to a drug or increased resistance of a tumor to a drug.	('increased', 'PosReg', (97, 106))	('tumor', 'Disease', (123, 128))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('variant', 'Var', (27, 34))	('tumor', 'Disease', (78, 83))	('sensitivity', 'MPA', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('resistance', 'MPA', (107, 117))
68177	30053901	A given drug entry in DEPO could be associated with multiple drug families to allow for the possibility of combining therapies (e.g., dabrafenib [B-Raf inhibitor] and trametinib [MEK inhibitor] for BRAF V600E/K-mutant melanoma) and multi-targeted tyrosine kinase inhibitors (e.g., afatinib as a dual HER2 and EGFR inhibitor).	('EGFR', 'Gene', '1956', (309, 313))	('BRAF', 'Gene', '673', (198, 202))	('BRAF', 'Gene', (198, 202))	('MEK', 'Gene', '5609', (179, 182))	('dabrafenib', 'Chemical', 'MESH:C561627', (134, 144))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('B-Raf', 'Gene', '673', (146, 151))	('V600E', 'Var', (203, 208))	('HER2', 'Gene', '2064', (300, 304))	('MEK', 'Gene', (179, 182))	('EGFR', 'Gene', (309, 313))	('tyrosine kinase', 'Gene', (247, 262))	('tyrosine kinase', 'Gene', '7294', (247, 262))	('afatinib', 'Chemical', 'MESH:D000077716', (281, 289))	('trametinib', 'Chemical', 'MESH:C560077', (167, 177))	('V600E', 'SUBSTITUTION', 'None', (203, 208))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('B-Raf', 'Gene', (146, 151))	('HER2', 'Gene', (300, 304))
68181	30053901	Variant calls were obtained from the TCGA Genome Data Analysis Centers (GDAC), Data Coordinating Center (DCC), and previously published TCGA marker papers until the end of 2014 (https://cancergenome.nih.gov/publications).	('GDAC', 'Chemical', '-', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DCC', 'Chemical', '-', (105, 108))	('cancer', 'Disease', (186, 192))	('Variant', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
68182	30053901	Variant calls were excluded if metastases or recurrent samples were present for samples that already had a primary tumor in the mutation annotation file (MAF).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('metastases', 'Disease', 'MESH:D009362', (31, 41))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('metastases', 'Disease', (31, 41))	('Variant', 'Var', (0, 7))
68185	30053901	We identified tumors in our pan-cancer cohort that harbored one or more drug-associated SNP or indel.	('indel', 'Var', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('SNP', 'Var', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
68186	30053901	Iterating through a mutation annotation format (MAF) file containing all variants in our pan-cancer cohort, we performed two actions for each entry in the MAF.	('cancer', 'Disease', (93, 99))	('variants', 'Var', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
68187	30053901	First, we queried a hash table containing all druggable, unambiguous mutations in DEPO (e.g., BRAF V600E) and a separate hash table containing all druggable, ambiguous, single-residue mutations in DEPO (e.g., BRAF V600).	('single-residue', 'Var', (169, 183))	('mutations', 'Var', (69, 78))	('BRAF', 'Gene', (94, 98))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('DEPO', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (94, 98))	('DEPO', 'Gene', (82, 86))
68188	30053901	Second, we queried several classes of mutations that occur in a specific exon or segment of a gene (EGFR exon 19 in-frame deletion).	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', (100, 104))
68190	30053901	In some cases, DEPO contains multiple entries per gene/mutation pair to reflect possible druggability of a gene/mutation pair in more than one tumor type, or that it may confer an effect (e.g., sensitivity or resistance) that depends on tumor type or other therapeutic context.	('tumor', 'Disease', (237, 242))	('resistance', 'CPA', (209, 219))	('tumor', 'Disease', (143, 148))	('druggability', 'MPA', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('gene/mutation', 'Var', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('sensitivity', 'MPA', (194, 205))
68191	30053901	For example, when visualizing "drug repurposing" across tumor types, a given mutation could be associated with > 1 "cancer-type-specific" tumor type, if a given gene/mutation pair had druggability information in DEPO in multiple tumor types at the same level of evidence.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (138, 143))	('mutation', 'Var', (77, 85))	('cancer', 'Disease', (116, 122))	('tumor', 'Disease', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('associated', 'Reg', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
68195	30053901	When considering potential druggable events in the cancer-type-non-specific setting, the drug with the highest level of evidence found across all tumor types was used for a specific variant (Additional file 2: Table S3).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('variant', 'Var', (182, 189))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
68197	30053901	If any sensitive interaction for a variant was found regardless of the tumor type and level, it was considered a "druggable" event for these analyses.	('variant', 'Var', (35, 42))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
68198	30053901	HotSpot3D was used to spatially cluster "known" drug-associated mutations in DEPO with putative druggable mutations in our pan-cancer cohort.	('DEPO', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', (127, 133))
68212	30053901	The distribution of LN(IC50) values of cell lines with DEPO mutations (both sensitive and resistant) for both the cancer-type-specific and non-specific settings were compared to a background distribution using the Mann-Whitney U test.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('DEPO', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (114, 120))
68219	30053901	Constructions expressing BRAF variants were generated from a plasmid expressing a wild-type BRAF (Addgene, #40775) with an N-terminal Flag tag using Q5 site-directed mutagenesis (New England BioLabs).	('variants', 'Var', (30, 38))	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))
68220	30053901	Cells were transiently transfected with wild-type or mutant BRAF constructs using Lipofectamine 2000 reagent (Life Technologies) in six-well plates.	('BRAF', 'Gene', (60, 64))	('Lipofectamine 2000 reagent', 'Chemical', '-', (82, 108))	('BRAF', 'Gene', '673', (60, 64))	('mutant', 'Var', (53, 59))
68227	30053901	For each tumor, we mapped its "druggable" variants against one or more drugs, which were then mapped to one or more drug classes (Additional file 2: Table S8).	('tumor', 'Disease', (9, 14))	('variants', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))
68228	30053901	For each variant, we used the drug that had the highest level of evidence in DEPO regardless of cancer type (Additional file 2: Table S3).	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('variant', 'Var', (9, 16))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
68229	30053901	For the purposes of visualization, we only considered ten FDA-approved drug classes (Additional file 2: Table S9) mapping to the largest number of variants across our pan-cancer cohort (Additional file 2: Table S10).	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('variants', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (171, 177))
68235	30053901	Further, a substantial number (~ 25%) of sensitive variant/drug interactions are approved by the FDA for a particular cancer type or are based on late-stage clinical studies.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('particular cancer type', 'Disease', (107, 129))	('particular cancer type', 'Disease', 'MESH:D009369', (107, 129))	('variant/drug', 'Var', (51, 63))
68236	30053901	Several genes account for a large proportion of variant/drug interactions (e.g., EGFR, KIT, ERBB2, BRCA1, PDGFRA), reflecting interest in therapeutically exploiting a relatively limited number of cancer driver genes (Fig.	('ERBB2', 'Gene', '2064', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('KIT', 'Gene', (87, 90))	('PDGFRA', 'Gene', '5156', (106, 112))	('ERBB2', 'Gene', (92, 97))	('BRCA1', 'Gene', (99, 104))	('variant/drug', 'Var', (48, 60))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('BRCA', 'Phenotype', 'HP:0003002', (99, 103))	('BRCA1', 'Gene', '672', (99, 104))	('EGFR', 'Gene', '1956', (81, 85))	('PDGFRA', 'Gene', (106, 112))	('EGFR', 'Gene', (81, 85))
68238	30053901	Our analysis reveals 2364 mutations across 2114 tumors that are associated with sensitivity to one or more drugs (mean = 1.12/tumor) (Additional file 2: Table S2).	('associated', 'Reg', (64, 74))	('tumor', 'Disease', (48, 53))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('sensitivity', 'MPA', (80, 91))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (126, 131))
68239	30053901	The low fraction of drug-associated mutations likely reflects the large number of passengers in cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (36, 45))
68240	30053901	Thirty-two percent of tumors had at least one drug-associated mutation, a percentage that is consistent with the 28% of screened patients that could be matched with a targeted therapy or trial.	('patients', 'Species', '9606', (129, 137))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutation', 'Var', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
68242	30053901	2), that is, tumors with mutations associated with a known drug response in the cancer type with the highest level of evidence.	('mutations', 'Var', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Disease', (80, 86))
68243	30053901	Only 3.3% of the samples contain a druggable mutation known to be FDA approved; however, if we consider less mature evidence: clinical trials, preclinical, and case reports, we could potentially increase the percentage of tumors with drug-associated mutations to 8.2, 8.5, and 10.5%, respectively.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('drug-associated', 'Reg', (234, 249))	('mutations', 'Var', (250, 259))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('increase', 'PosReg', (195, 203))
68244	30053901	Here, skin cutaneous melanoma (SKCM) is the cancer type with the largest fraction of drug-associated mutations (78%).	('mutations', 'Var', (101, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (11, 29))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (6, 29))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('skin cutaneous melanoma', 'Disease', (6, 29))	('CM', 'Disease', 'MESH:D009202', (33, 35))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
68245	30053901	SKCM with a BRAF V600E/K mutation (40% of patients) can be treated with BRAF and MEK inhibitors based on FDA approval.	('BRAF', 'Gene', (72, 76))	('V600E', 'Var', (17, 22))	('V600E', 'SUBSTITUTION', 'None', (17, 22))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('CM', 'Disease', 'MESH:D009202', (2, 4))	('patients', 'Species', '9606', (42, 50))	('MEK', 'Gene', (81, 84))	('BRAF', 'Gene', '673', (72, 76))	('MEK', 'Gene', '5609', (81, 84))
68246	30053901	The NRAS Q61 mutations found in 12% of SKCM patients are more challenging to treat, as is any RAS-mutant cancer due to activation of multiple signaling pathways.	('patients', 'Species', '9606', (44, 52))	('CM', 'Disease', 'MESH:D009202', (41, 43))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('activation', 'PosReg', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NRAS', 'Gene', (4, 8))	('mutations', 'Var', (13, 22))	('NRAS', 'Gene', '4893', (4, 8))
68248	30053901	In colon and rectal carcinoma (COADREAD), glioblastoma multiforme (GBM), and lung adenocarcinoma (LUAD), 21, 14, and 40% of their respective tumors contain a drug-associated mutation in a cancer-type-specific setting.	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('colon and rectal carcinoma', 'Disease', 'MESH:D012004', (3, 29))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (13, 29))	('mutation', 'Var', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('glioblastoma multiforme', 'Disease', (42, 65))	('cancer', 'Disease', (188, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('lung adenocarcinoma', 'Disease', (77, 96))	('contain', 'Reg', (148, 155))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('drug-associated', 'Reg', (158, 173))
68249	30053901	In COADREAD, drug-associated variants PIK3CA E542K, E545K, and H1047R are present in 2.1, 5.2, and 1.8% of tumors, respectively, and are associated with sensitivity to PI3K/AKT/mTOR pathway inhibitors in early-stage trials and aspirin in observational studies.	('H1047R', 'Mutation', 'rs121913279', (63, 69))	('AKT', 'Gene', (173, 176))	('sensitivity', 'MPA', (153, 164))	('associated with', 'Reg', (137, 152))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mTOR', 'Gene', (177, 181))	('E545K', 'Mutation', 'rs104886003', (52, 57))	('PIK3CA', 'Gene', '5290', (38, 44))	('aspirin', 'Chemical', 'MESH:D001241', (227, 234))	('E542K', 'Mutation', 'rs121913273', (45, 50))	('E542K', 'Var', (45, 50))	('AKT', 'Gene', '207', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('mTOR', 'Gene', '2475', (177, 181))	('E545K', 'Var', (52, 57))	('PIK3CA', 'Gene', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('H1047R', 'Var', (63, 69))
68251	30053901	In GBM, the EGFR extracellular mutations (A289V, G598V, and R108K) and IDH1 mutation R132H are present in 10 and 4.5% of tumors, respectively, and are associated with drug response based on preclinical data.	('R132H', 'Mutation', 'rs121913500', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('A289V', 'Mutation', 'rs149840192', (42, 47))	('associated', 'Reg', (151, 161))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('IDH1', 'Gene', (71, 75))	('G598V', 'Var', (49, 54))	('R108K', 'Mutation', 'rs1057519828', (60, 65))	('EGFR', 'Gene', '1956', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('IDH1', 'Gene', '3417', (71, 75))	('G598V', 'Mutation', 'rs139236063', (49, 54))	('R132H', 'Var', (85, 90))	('EGFR', 'Gene', (12, 16))	('A289V', 'Var', (42, 47))	('R108K', 'Var', (60, 65))
68252	30053901	In non-small cell lung cancer, EGFR inhibitors (e.g., erlotinib) are FDA approved for tumors with activating EGFR mutations, which are present at 10 and 1% in our LUAD and lung squamous cell carcinoma (LUSC) cohorts, respectively.	('mutations', 'Var', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('EGFR', 'Gene', '1956', (109, 113))	('non-small cell lung cancer', 'Disease', (3, 29))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EGFR', 'Gene', '1956', (31, 35))	('tumors', 'Disease', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (172, 200))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('erlotinib', 'Chemical', 'MESH:D000069347', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('EGFR', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('LUSC', 'Phenotype', 'HP:0030359', (202, 206))	('activating', 'PosReg', (98, 108))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('EGFR', 'Gene', (31, 35))	('lung squamous cell carcinoma', 'Disease', (172, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 200))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))
68253	30053901	Despite the promise of targeted therapy, only 10.5% of this pan-cancer cohort contains potential drug-associated mutations in a cancer-type-specific setting.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('drug-associated', 'Reg', (97, 112))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (128, 134))
68254	30053901	With drug repurposing across cancer types, in which a drug used primarily in cancer type A with mutation X is repurposed for cancer type B with mutation X, we find that an additional 5.4% of patients may be treated with a FDA-approved drug-variant interaction (Figs.	('cancer', 'Disease', (29, 35))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
68256	30053901	In this cancer-type-non-specific setting, cancer types in which at least 40% of tumors have drug-associated mutations include low-grade glioma (LGG, 76%), thyroid carcinoma (THCA, 70%), and colorectal adenocarcinoma (COADREAD, 42%).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('THCA', 'Phenotype', 'HP:0002890', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (80, 86))	('colorectal adenocarcinoma', 'Disease', (190, 215))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (155, 172))	('cancer', 'Disease', (8, 14))	('thyroid carcinoma', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('glioma', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (190, 215))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (155, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('mutations', 'Var', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (42, 48))
68257	30053901	A small number of drug-associated mutations occur at high frequency in these cancer types.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
68260	30053901	However, BRAF V600E also occurs at a lower frequency in HNSC, KIRP, LGG, and GBM, indicating significant repurposing potential for BRAF inhibitors (Fig.	('HNSC', 'Phenotype', 'HP:0012288', (56, 60))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', (131, 135))	('BRAF', 'Gene', (9, 13))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', '673', (9, 13))
68261	30053901	However, COADREAD has been difficult to treat due to a large presence of KRAS and BRAF mutations; EGFR inhibition as monotherapy is used for COADREAD, but only in tumors with wild-type KRAS.	('EGFR', 'Gene', (98, 102))	('KRAS', 'Gene', '3845', (185, 189))	('KRAS', 'Gene', (73, 77))	('KRAS', 'Gene', '3845', (73, 77))	('BRAF', 'Gene', '673', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BRAF', 'Gene', (82, 86))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('EGFR', 'Gene', '1956', (98, 102))	('mutations', 'Var', (87, 96))	('KRAS', 'Gene', (185, 189))
68265	30053901	COADREAD or other cancer types having RAS mutations, such as cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (AML), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC), could benefit from further exploration of combinatorial therapies targeting downstream targets of KRAS (Fig.	('corpus endometrial carcinoma', 'Disease', (207, 235))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (207, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('acute myeloid leukemia', 'Disease', (134, 156))	('cancer', 'Disease', (18, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (61, 125))	('RAS', 'Gene', (38, 41))	('AML', 'Disease', 'MESH:D015470', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('AML', 'Disease', (158, 161))	('stomach adenocarcinoma', 'Disease', (164, 186))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (134, 156))	('AML', 'Phenotype', 'HP:0004808', (158, 161))	('KRAS', 'Gene', '3845', (342, 346))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (134, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('KRAS', 'Gene', (342, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (164, 186))	('mutations', 'Var', (42, 51))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (214, 235))
68268	30053901	Together, cancer-type-specific and non-specific mutational analyses identified potential therapeutic targets in 2114 tumors (32%), some of which will be considered druggable only with further clinical development and FDA approval.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('mutational', 'Var', (48, 58))	('cancer', 'Disease', (10, 16))
68269	30053901	We applied a structure-based clustering tool, HotSpot3D, to the pan-cancer dataset to reveal putative functional mutations (Additional file 2: Table S13).	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))
68270	30053901	HotSpot3D's utility in predicting functional mutations is supported by experimental evidence using cell lines expressing one of several EGFR-mutant proteins.	('EGFR', 'Gene', '1956', (136, 140))	('mutations', 'Var', (45, 54))	('proteins', 'Protein', (148, 156))	('EGFR', 'Gene', (136, 140))
68271	30053901	Among all genes in our analysis, EGFR contains the highest number of putative sensitive mutations, with 36 mutations that clustered with 19 mutations in DEPO from seven different clusters (Fig.	('DEPO', 'Gene', (153, 157))	('mutations', 'Var', (107, 116))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (33, 37))
68273	30053901	This procedure yielded four different clusters with a "resistant" mutation in AKT1, MAP2K1, and RAC1; these four clusters contained 14 putative resistant mutations clustering with four known resistant mutations (Additional file 2: Table S13).	('AKT1', 'Gene', (78, 82))	('contained', 'Reg', (122, 131))	('MAP2K1', 'Gene', (84, 90))	('RAC1', 'Gene', '5879', (96, 100))	('AKT1', 'Gene', '207', (78, 82))	('mutation', 'Var', (66, 74))	('RAC1', 'Gene', (96, 100))	('MAP2K1', 'Gene', '5604', (84, 90))
68274	30053901	RAC1 yielded the largest cluster, with RAC1 P29S mediating resistance to BRAF inhibitors in BRAF-mutant SKCM.	('BRAF', 'Gene', '673', (73, 77))	('P29S', 'Mutation', 'rs1057519874', (44, 48))	('resistance to', 'MPA', (59, 72))	('BRAF', 'Gene', '673', (92, 96))	('CM', 'Disease', 'MESH:D009202', (106, 108))	('RAC1', 'Gene', '5879', (39, 43))	('BRAF', 'Gene', (92, 96))	('RAC1', 'Gene', (39, 43))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (44, 48))	('BRAF', 'Gene', (73, 77))	('RAC1', 'Gene', (0, 4))	('mediating', 'Reg', (49, 58))
68275	30053901	Other mutations in this cluster that may affect binding affinity of BRAF inhibitors (or that may mediate resistance to BRAF inhibitors) are C18Y, E31D, A159V, P29L/T, and P34S.	('P29L', 'SUBSTITUTION', 'None', (159, 163))	('C18Y', 'SUBSTITUTION', 'None', (140, 144))	('BRAF', 'Gene', '673', (68, 72))	('E31D', 'Var', (146, 150))	('A159V', 'Mutation', 'p.A159V', (152, 157))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (68, 72))	('binding', 'Interaction', (48, 55))	('BRAF', 'Gene', (119, 123))	('P34S', 'Var', (171, 175))	('C18Y', 'Var', (140, 144))	('P34S', 'Mutation', 'p.P34S', (171, 175))	('E31D', 'Mutation', 'p.E31D', (146, 150))	('P29L', 'Var', (159, 163))	('affect', 'Reg', (41, 47))	('A159V', 'Var', (152, 157))
68276	30053901	For example, KIT has multiple clusters with known mutations; one of which has three known mutations (E490D, Y494C, S476G) in the same cluster, which are FDA approved as sensitive to combined therapy of imatinib, sunitinib, and regorafenib (KIT and angiogenesis inhibitor).	('E490D', 'Mutation', 'p.E490D', (101, 106))	('regorafenib', 'Chemical', 'MESH:C559147', (227, 238))	('S476G', 'Var', (115, 120))	('Y494C', 'Var', (108, 113))	('sunitinib', 'Chemical', 'MESH:D000077210', (212, 221))	('Y494C', 'Mutation', 'p.Y494C', (108, 113))	('S476G', 'Mutation', 'p.S476G', (115, 120))	('imatinib', 'Chemical', 'MESH:D000068877', (202, 210))	('E490D', 'Var', (101, 106))
68277	30053901	In addition, this cluster contains two other unique mutations (D439H, I438L) not in DEPO that, based on our analysis using HotSpot3D, could also affect binding affinity and potentially tumor sensitivity to KIT combined with angiogenesis inhibitors (Additional file 2: Table S13).	('tumor', 'Disease', (185, 190))	('I438L', 'Var', (70, 75))	('I438L', 'Mutation', 'p.I438L', (70, 75))	('affect', 'Reg', (145, 151))	('binding affinity', 'Interaction', (152, 168))	('D439H', 'Mutation', 'p.D439H', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('D439H', 'Var', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
68278	30053901	To do this, we assessed the activity and drug sensitivity of a set of six BRAF mutations (F635I, G596D, K601E, W604L, L613F, G596R) in close spatial proximity to the well-studied V600E pathogenic mutation (Fig.	('L613F', 'Mutation', 'p.L613F', (118, 123))	('G596D', 'Mutation', 'rs397507483', (97, 102))	('W604L', 'Mutation', 'p.W604L', (111, 116))	('K601E', 'Mutation', 'rs121913364', (104, 109))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('F635I', 'Mutation', 'p.F635I', (90, 95))	('L613F', 'Var', (118, 123))	('K601E', 'Var', (104, 109))	('G596R', 'Mutation', 'rs121913361', (125, 130))	('G596D', 'Var', (97, 102))	('G596R', 'Var', (125, 130))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('F635I', 'Var', (90, 95))	('drug sensitivity', 'Phenotype', 'HP:0020174', (41, 57))	('W604L', 'Var', (111, 116))
68280	30053901	Therefore, we transfected BRAF mutations, along with wild-type BRAF and BRAF V600E, into HEK293T cells in the presence or absence of BRAF inhibitor dabrafenib, and used phosphorylation changes in MEK1/2 as an indicator of BRAF activity.	('MEK1/2', 'Gene', '5604;5605', (196, 202))	('mutations', 'Var', (31, 40))	('BRAF', 'Gene', (72, 76))	('MEK1/2', 'Gene', (196, 202))	('BRAF', 'Gene', '673', (26, 30))	('dabrafenib', 'Chemical', 'MESH:C561627', (148, 158))	('BRAF', 'Gene', '673', (133, 137))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('BRAF', 'Gene', '673', (222, 226))	('BRAF', 'Gene', (26, 30))	('HEK293T', 'CellLine', 'CVCL:0063', (89, 96))	('BRAF', 'Gene', (133, 137))	('BRAF', 'Gene', (222, 226))	('BRAF', 'Gene', '673', (63, 67))	('phosphorylation', 'MPA', (169, 184))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (72, 76))
68281	30053901	The undetectable level of endogenous BRAF in HEK293T cells eliminates potential ambiguity in interpreting the effects of transfected BRAF mutations.	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (37, 41))	('BRAF', 'Gene', (133, 137))	('HEK293T', 'CellLine', 'CVCL:0063', (45, 52))	('mutations', 'Var', (138, 147))
68282	30053901	As expected, BRAF V600E caused drastically increased phosphorylation in MEK1/2 that is reduced by dabrafenib (Fig.	('V600E', 'Var', (18, 23))	('MEK1/2', 'Gene', '5604;5605', (72, 78))	('MEK1/2', 'Gene', (72, 78))	('BRAF', 'Gene', '673', (13, 17))	('dabrafenib', 'Chemical', 'MESH:C561627', (98, 108))	('BRAF', 'Gene', (13, 17))	('increased', 'PosReg', (43, 52))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('phosphorylation', 'MPA', (53, 68))
68283	30053901	Three (G596D, K601E, and W604L) out of six other transfected BRAF mutations also showed higher levels of MEK1/2 phosphorylation and sensitivity to dabrafenib than wild-type BRAF, suggesting that a high percentage of mutations identified by Hotspot3D in close spatial proximity to V600E are activated and similarly sensitive to dabrafenib.	('mutations', 'Var', (66, 75))	('K601E', 'Var', (14, 19))	('dabrafenib', 'Chemical', 'MESH:C561627', (327, 337))	('W604L', 'Var', (25, 30))	('G596D', 'Mutation', 'rs397507483', (7, 12))	('BRAF', 'Gene', '673', (173, 177))	('V600E', 'Mutation', 'rs113488022', (280, 285))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (173, 177))	('BRAF', 'Gene', (61, 65))	('MEK1/2', 'Gene', '5604;5605', (105, 111))	('MEK1/2', 'Gene', (105, 111))	('higher', 'PosReg', (88, 94))	('W604L', 'Mutation', 'p.W604L', (25, 30))	('G596D', 'Var', (7, 12))	('sensitivity', 'MPA', (132, 143))	('dabrafenib', 'Chemical', 'MESH:C561627', (147, 157))	('V600E', 'Var', (280, 285))	('K601E', 'Mutation', 'rs121913364', (14, 19))
68284	30053901	Notably, BRAF G596R-transfected cells appeared to have a much lower level of MEK1/2 phosphorylation when compared to those transfected with wild-type BRAF, supporting prior findings that G596R results in BRAF loss of function.	('loss of function', 'NegReg', (209, 225))	('BRAF', 'Gene', (204, 208))	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (9, 13))	('G596R', 'Mutation', 'rs121913361', (14, 19))	('BRAF', 'Gene', (150, 154))	('lower', 'NegReg', (62, 67))	('BRAF', 'Gene', '673', (150, 154))	('MEK1/2', 'Gene', '5604;5605', (77, 83))	('G596R', 'Var', (187, 192))	('G596R', 'Mutation', 'rs121913361', (187, 192))	('MEK1/2', 'Gene', (77, 83))	('G596R-transfected', 'Var', (14, 31))	('BRAF', 'Gene', '673', (204, 208))
68286	30053901	For example, in the case of breast cancer, elevated mRNA expression and copy number amplification of ESR1 correlate with elevated protein expression of ER, as well as with sensitivity to hormonal therapy with tamoxifen.	('ESR1', 'Gene', '2099', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('elevated', 'PosReg', (43, 51))	('copy number amplification', 'Var', (72, 97))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('tamoxifen', 'Chemical', 'MESH:D013629', (209, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('ESR1', 'Gene', (101, 105))	('protein expression', 'MPA', (130, 148))	('mRNA expression', 'MPA', (52, 67))	('elevated', 'PosReg', (121, 129))
68292	30053901	Interestingly, tumors with "druggable" gene fusions tend to express elevated levels of the corresponding druggable gene (Additional file 2: Table S15, Additional file 3: Figure S1), suggesting that fusions may be one of several drivers of gene and protein expression.	('levels of', 'MPA', (77, 86))	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('fusions', 'Var', (44, 51))	('elevated', 'PosReg', (68, 76))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
68304	30053901	Similarly, 26 and 52% of BRCA and UCEC, respectively, show elevated activity at ESR1's p.S118 phosphosite.	('BRCA', 'Gene', (25, 29))	('ESR1', 'Gene', '2099', (80, 84))	('p.S118', 'Var', (87, 93))	('S118 phosphosite', 'Chemical', '-', (89, 105))	('ESR1', 'Gene', (80, 84))	('activity', 'MPA', (68, 76))	('elevated', 'PosReg', (59, 67))	('BRCA', 'Phenotype', 'HP:0003002', (25, 29))	('BRCA', 'Gene', '672', (25, 29))
68307	30053901	EGFR phosphosites p.Y1068 and p.Y1173 are active in GBM, head and neck squamous cell carcinoma (HNSC), KIRC, LUAD, and LUSC.	('p.Y1068', 'Var', (18, 25))	('EGFR', 'Gene', (0, 4))	('neck squamous cell carcinoma', 'Disease', (66, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('GBM', 'Disease', (52, 55))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (66, 94))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (57, 94))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HNSC', 'Phenotype', 'HP:0012288', (96, 100))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('phosphosite', 'Chemical', '-', (5, 16))	('p.Y1173', 'Var', (30, 37))	('EGFR', 'Gene', '1956', (0, 4))
68317	30053901	RAC1 P29S co-occurs with mutations in BRAF and MEK1 in four SKCM tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('mutations', 'Var', (25, 34))	('MEK1', 'Gene', '5604', (47, 51))	('BRAF', 'Gene', '673', (38, 42))	('MEK1', 'Gene', (47, 51))	('SKCM tumors', 'Disease', 'MESH:D009369', (60, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('SKCM tumors', 'Disease', (60, 71))	('BRAF', 'Gene', (38, 42))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (5, 9))	('RAC1', 'Gene', (0, 4))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
68318	30053901	RAC1 P29S renders SKCM resistant to BRAF/MEK inhibition; testing for RAC1 P29S may identify patients with BRAF V600E SKCM unlikely to benefit from BRAF/MEK inhibitor.	('CM', 'Disease', 'MESH:D009202', (20, 22))	('V600E', 'Var', (111, 116))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('patients', 'Species', '9606', (92, 100))	('RAC1', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (36, 40))	('P29S', 'Mutation', 'rs1057519874', (74, 78))	('BRAF', 'Gene', (36, 40))	('MEK', 'Gene', '5609', (41, 44))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('RAC1', 'Gene', '5879', (0, 4))	('MEK', 'Gene', '5609', (152, 155))	('V600E', 'Mutation', 'rs113488022', (111, 116))	('RAC1', 'Gene', (69, 73))	('CM', 'Disease', 'MESH:D009202', (119, 121))	('MEK', 'Gene', (41, 44))	('BRAF', 'Gene', '673', (106, 110))	('MEK', 'Gene', (152, 155))	('BRAF', 'Gene', (106, 110))	('RAC1', 'Gene', '5879', (69, 73))
68320	30053901	AKT1 E17K co-occurs with BRAF V600E in five tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('AKT1', 'Gene', '207', (0, 4))	('E17K', 'SUBSTITUTION', 'None', (5, 9))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('AKT1', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('BRAF', 'Gene', '673', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BRAF', 'Gene', (25, 29))	('E17K', 'Var', (5, 9))
68322	30053901	Transcriptomic and proteomic expression profiling reveals 48 additional tumors with BRAF V600E/K and elevated AKT (AKT1/2/3) expression at the mRNA or protein/phosphoprotein levels; these may also benefit from BRAF/AKT inhibition (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('elevated', 'PosReg', (101, 109))	('AKT', 'Gene', '207', (115, 118))	('AKT', 'Gene', (110, 113))	('AKT1/2/3', 'Gene', (115, 123))	('tumors', 'Disease', (72, 78))	('V600E', 'SUBSTITUTION', 'None', (89, 94))	('AKT', 'Gene', '207', (215, 218))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('AKT', 'Gene', '207', (110, 113))	('AKT1/2/3', 'Gene', '207;208;10000', (115, 123))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('AKT', 'Gene', (115, 118))	('BRAF', 'Gene', (210, 214))	('BRAF', 'Gene', '673', (210, 214))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('AKT', 'Gene', (215, 218))	('V600E', 'Var', (89, 94))
68325	30053901	Additionally, 105 tumors contain activating PIK3CA mutations co-occurring with elevated mRNA or protein expression of ESR1 or PGR.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (51, 60))	('PGR', 'Gene', '5241', (126, 129))	('ESR1', 'Gene', '2099', (118, 122))	('PIK3CA', 'Gene', '5290', (44, 50))	('mRNA or protein expression', 'MPA', (88, 114))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('elevated', 'PosReg', (79, 87))	('activating', 'PosReg', (33, 43))	('ESR1', 'Gene', (118, 122))	('PGR', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
68331	30053901	Overall, the mean LN(IC50) for cell lines that contain a sensitive mutation from DEPO was significantly lower than background LN(IC50) in both the cancer-type-specific and non-specific setting (Mann-Whitney U test, P = 1.1e-96 and P = 1.3e-109, respectively) (Fig.	('DEPO', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutation', 'Var', (67, 75))	('lower', 'NegReg', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
68333	30053901	In both the cancer-type-specific and non-specific settings, 19 variant/drug combinations had significantly lower mean LN(IC50) than background LN(IC50) for the corresponding drug.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('variant/drug', 'Var', (63, 75))	('cancer', 'Disease', (12, 18))	('lower', 'NegReg', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('combinations', 'Var', (76, 88))
68335	30053901	For example, cell lines with BRAF V600E were associated with sensitivity to BRAF inhibitors PLX4720 (1), PLX4720 (2), and dabrafenib in both the cancer-type-specific (SKCM) and non-specific settings (BRCA, COADREAD, GBM, LGG, LIHC, and THCA) (Fig.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('LIHC', 'Disease', 'None', (226, 230))	('THCA', 'Phenotype', 'HP:0002890', (236, 240))	('BRCA', 'Phenotype', 'HP:0003002', (200, 204))	('PLX4720', 'Var', (105, 112))	('CM', 'Disease', 'MESH:D009202', (169, 171))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('BRCA', 'Gene', '672', (200, 204))	('sensitivity', 'MPA', (61, 72))	('V600E', 'Var', (34, 39))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('dabrafenib', 'Chemical', 'MESH:C561627', (122, 132))	('LIHC', 'Disease', (226, 230))	('BRCA', 'Gene', (200, 204))	('PLX4720', 'Gene', (92, 99))
68336	30053901	Two out of six mutations (PIK3CA H1047R and KRAS G12C) was associated with sensitivity in either the cancer-type-specific or the non-specific setting.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('H1047R', 'Var', (33, 39))	('G12C', 'Mutation', 'rs121913530', (49, 53))	('cancer', 'Disease', (101, 107))	('PIK3CA', 'Gene', '5290', (26, 32))	('sensitivity', 'Disease', (75, 86))	('associated', 'Reg', (59, 69))	('H1047R', 'Mutation', 'rs121913279', (33, 39))	('KRAS', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('KRAS', 'Gene', '3845', (44, 48))	('PIK3CA', 'Gene', (26, 32))
68351	30053901	First, with DEPO, our analysis of druggability in a given tumor is exclusively based on mutation/drug interactions rather than gene/drug interactions, with variants including both predefined mutations (e.g., BRAF V600E) and categories of mutations (e.g., EGFR exon 19 deletions).	('EGFR', 'Gene', '1956', (255, 259))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('EGFR', 'Gene', (255, 259))	('BRAF', 'Gene', '673', (208, 212))	('BRAF', 'Gene', (208, 212))	('deletions', 'Var', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('V600E', 'Mutation', 'rs113488022', (213, 218))
68354	30053901	Third, it uses an analytic tool to create a set of putative druggable mutations, of which a subset occurring in BRAF were tested and validated in vitro.	('mutations', 'Var', (70, 79))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))
68358	30053901	Realistically, only a fraction of the 48% of tumors with potential drug-associated omics alterations will be clinically druggable because the mere presence of a shared genetic biomarker (mutation, mRNA/protein expression outlier) does not guarantee clinical efficacy across cancer types, nor does it guarantee acceptable clinical toxicity.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('toxicity', 'Disease', 'MESH:D064420', (330, 338))	('toxicity', 'Disease', (330, 338))	('cancer', 'Disease', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('alterations', 'Var', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
68359	30053901	Further, we recognize that our computational survey of the landscape of potential drug-associated omics alterations may include some controversial drug/biomarker relationships (e.g., PI3K inhibitors in PIK3CA-mutant cancers), some of which have either failed clinical trials and/or are still being actively developed in clinical trials.	('alterations', 'Var', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('PIK3CA', 'Gene', (202, 208))	('PIK3CA', 'Gene', '5290', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
68362	30053901	Second, our analysis does not account for clonal heterogeneity, which is not unreasonable given that therapies targeting genomic alterations with high variant allele frequencies can induce substantial tumor regression.	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('variant', 'Var', (151, 158))
68372	30053901	ACC Adrenocortical carcinoma AML/LAML Acute myeloid leukemia BLCA Bladder urothelial carcinoma BRCA Breast adenocarcinoma CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma CNA Copy number amplification CNL Copy number loss CNV Copy number variation COADREAD Colon and rectal carcinoma CPTAC Clinical Proteomic Tumor Analysis Consortium DCC Data Coordinating Center DEPO Database of Evidence for Precision Oncology FBS Fetal bovine serum FDA Food and Drug Administration FFPE Formalin-fixed, paraffin-embedded GBM Glioblastoma multiforme GDAC Genome Data Analysis Centers GDSC Genomics of Drug Sensitivity in Cancer HNSC Head and neck squamous cell carcinoma IQR Interquartile range KICH Kidney chromophobe KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LGG Low-grade glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma MAF Mutation annotation file NGS Next-generation sequencing NSCLC Non-small cell lung cancer OV Ovarian serous carcinoma PNNL Pacific Northwest National Laboratory PRAD Prostate adenocarcinoma RBN Replicates-based normalization RPPA Reverse phase protein array SKCM Skin cutaneous melanoma SNP Single nucleotide polymorphism STAD Stomach adenocarcinoma STR Short tandem repeat TCGA The Cancer Genome Atlas TCPA The Cancer Protein Atlas THCA Thyroid carcinoma TKI Tyrosine kinase inhibitor UCEC Uterine corpus endometrial carcinoma UCS Uterine carcinosarcoma VCF Variant call format LD designed and supervised the research.	('adenocarcinoma', 'Disease', (1262, 1276))	('Kidney renal clear cell carcinoma', 'Disease', (731, 764))	('carcinosarcoma', 'Disease', (1467, 1481))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (1310, 1329))	('adenocarcinoma', 'Disease', (1102, 1116))	('RBN', 'Chemical', '-', (1117, 1120))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (777, 807))	('cancer', 'Phenotype', 'HP:0002664', (1010, 1016))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('DCC', 'Chemical', '-', (356, 359))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('carcinoma', 'Disease', (1445, 1454))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (38, 60))	('squamous cell carcinoma', 'Disease', (900, 923))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1262, 1276))	('CM', 'Disease', 'MESH:D009202', (1187, 1189))	('carcinoma', 'Disease', 'MESH:D002277', (798, 807))	('Cancer', 'Disease', 'MESH:D009369', (1339, 1345))	('glioma', 'Phenotype', 'HP:0009733', (822, 828))	('bovine', 'Species', '9913', (444, 450))	('Cancer', 'Phenotype', 'HP:0002664', (1310, 1316))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (44, 60))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (1426, 1454))	('VCF', 'Gene', '6899', (1482, 1485))	('PNNL', 'Chemical', '-', (1045, 1049))	('Breast adenocarcinoma', 'Disease', 'MESH:D000230', (100, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1195, 1213))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (1365, 1382))	('adenocarcinoma', 'Disease', (177, 191))	('Kidney renal papillary cell carcinoma', 'Disease', (770, 807))	('Non-small cell lung cancer', 'Disease', (990, 1016))	('carcinoma', 'Disease', (85, 94))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (288, 304))	('Skin cutaneous melanoma', 'Disease', (1190, 1213))	('Ovarian serous carcinoma', 'Disease', (1020, 1044))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (770, 807))	('urothelial carcinoma', 'Disease', (74, 94))	('FBS', 'Disease', (434, 437))	('AML', 'Phenotype', 'HP:0004808', (29, 32))	('VCF', 'Gene', (1482, 1485))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (990, 1016))	('Uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (1459, 1481))	('NSCLC', 'Disease', 'MESH:D002289', (984, 989))	('Cancer Protein Atlas', 'Disease', 'MESH:D009369', (1339, 1359))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (1433, 1454))	('Cancer', 'Disease', (1339, 1345))	('AML', 'Disease', 'MESH:D015470', (34, 37))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (74, 94))	('AML', 'Phenotype', 'HP:0004808', (34, 37))	('Cancer Genome Atlas', 'Disease', (1310, 1329))	('Ovarian serous carcinoma', 'Disease', 'MESH:D010051', (1020, 1044))	('THCA', 'Phenotype', 'HP:0002890', (1360, 1364))	('UCEC Uterine corpus', 'Phenotype', 'HP:0000139', (1413, 1432))	('adenocarcinoma', 'Disease', (107, 121))	('squamous cell carcinoma', 'Disease', (136, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1102, 1116))	('paraffin', 'Chemical', 'MESH:D010232', (511, 519))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (990, 1016))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (608, 624))	('corpus endometrial carcinoma', 'Disease', (1426, 1454))	('KICH', 'Chemical', '-', (702, 706))	('Tumor', 'Phenotype', 'HP:0002664', (330, 335))	('Kidney chromophobe', 'Disease', 'MESH:D000238', (707, 725))	('Cancer', 'Disease', (628, 634))	('adenocarcinoma', 'Disease', (875, 889))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (649, 677))	('carcinoma', 'Disease', 'MESH:D002277', (755, 764))	('Kidney chromophobe', 'Disease', (707, 725))	('BRCA', 'Phenotype', 'HP:0003002', (95, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (1093, 1116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (900, 923))	('Liver hepatocellular carcinoma', 'Disease', (834, 864))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (834, 864))	('carcinoma', 'Disease', 'MESH:D002277', (150, 159))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('adenocarcinoma', 'Disease', 'MESH:D000230', (875, 889))	('Cancer', 'Disease', 'MESH:D009369', (628, 634))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (654, 677))	('Cancer', 'Phenotype', 'HP:0002664', (1339, 1345))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (164, 191))	('LUSC', 'Phenotype', 'HP:0030359', (890, 894))	('LIHC', 'Disease', (829, 833))	('Formalin', 'Chemical', 'MESH:D005557', (495, 503))	('adenocarcinoma', 'Disease', 'MESH:D000230', (177, 191))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (900, 923))	('carcinosarcoma', 'Disease', 'MESH:D002296', (1467, 1481))	('glioma', 'Disease', 'MESH:D005910', (822, 828))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (654, 677))	('carcinoma', 'Disease', 'MESH:D002277', (1267, 1276))	('NSCLC', 'Disease', (984, 989))	('carcinoma', 'Disease', (755, 764))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (994, 1016))	('Cancer', 'Phenotype', 'HP:0002664', (628, 634))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('Tyrosine kinase', 'Gene', '7294', (1387, 1402))	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (1254, 1276))	('NSCLC', 'Phenotype', 'HP:0030358', (984, 989))	('melanoma', 'Phenotype', 'HP:0002861', (1205, 1213))	('Breast adenocarcinoma', 'Phenotype', 'HP:0003002', (100, 121))	('carcinoma', 'Disease', 'MESH:D002277', (914, 923))	('carcinoma', 'Disease', (150, 159))	('carcinoma', 'Disease', (1373, 1382))	('carcinoma', 'Disease', 'MESH:D002277', (668, 677))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (731, 764))	('carcinoma', 'Disease', 'MESH:D002277', (295, 304))	('HNSC', 'Phenotype', 'HP:0012288', (635, 639))	('Glioblastoma multiforme', 'Disease', (533, 556))	('Variant', 'Var', (1486, 1493))	('Cancer', 'Disease', (1310, 1316))	('Stomach adenocarcinoma', 'Disease', (1254, 1276))	('GDAC', 'Chemical', '-', (557, 561))	('lung cancer', 'Phenotype', 'HP:0100526', (1005, 1016))	('carcinoma', 'Disease', (1267, 1276))	('carcinoma', 'Disease', (1035, 1044))	('LGG Low', 'Phenotype', 'HP:0004315', (808, 815))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('AML', 'Disease', (29, 32))	('carcinoma', 'Disease', (1107, 1116))	('Breast adenocarcinoma', 'Disease', (100, 121))	('carcinoma', 'Disease', 'MESH:D002277', (1373, 1382))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (1190, 1213))	('carcinoma', 'Disease', 'MESH:D002277', (182, 191))	('FBS', 'Disease', 'MESH:D005198', (434, 437))	('Cancer', 'Disease', 'MESH:D009369', (1310, 1316))	('carcinoma', 'Disease', (914, 923))	('glioma', 'Disease', (822, 828))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (533, 556))	('carcinoma', 'Disease', (668, 677))	('carcinoma', 'Disease', (112, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('LUAD', 'Phenotype', 'HP:0030078', (865, 869))	('Acute myeloid leukemia', 'Disease', (38, 60))	('carcinoma', 'Disease', (295, 304))	('BRCA', 'Gene', (95, 99))	('AML', 'Disease', (34, 37))	('LIHC', 'Disease', 'None', (829, 833))	('carcinoma', 'Disease', 'MESH:D002277', (1035, 1044))	('carcinoma', 'Disease', 'MESH:D002277', (19, 28))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (38, 60))	('carcinoma', 'Disease', 'MESH:D002277', (1107, 1116))	('carcinoma', 'Disease', (880, 889))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('carcinoma', 'Disease', (855, 864))	('endocervical adenocarcinoma', 'Disease', (164, 191))	('carcinoma', 'Disease', (182, 191))	('Tyrosine kinase', 'Gene', (1387, 1402))	('neck squamous cell carcinoma', 'Disease', (649, 677))	('Cancer Protein Atlas', 'Disease', (1339, 1359))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (870, 889))	('carcinoma', 'Disease', 'MESH:D002277', (1445, 1454))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Disease', 'MESH:D002277', (112, 121))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('Oncology', 'Phenotype', 'HP:0002664', (425, 433))	('UCS', 'Phenotype', 'HP:0002891', (1455, 1458))	('BLCA', 'Chemical', '-', (61, 65))	('AML', 'Disease', 'MESH:D015470', (29, 32))	('Glioblastoma', 'Phenotype', 'HP:0012174', (533, 545))	('Prostate adenocarcinoma', 'Disease', (1093, 1116))	('carcinoma', 'Disease', 'MESH:D002277', (880, 889))	('TCPA', 'Chemical', '-', (1330, 1334))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (840, 864))	('carcinoma', 'Disease', (798, 807))	('carcinoma', 'Disease', 'MESH:D002277', (855, 864))	('carcinoma', 'Disease', (19, 28))	('BRCA', 'Gene', '672', (95, 99))
68408	28710381	By using Fisher's exact test, we evaluated miRNAs which were not expressed in all samples of a group and we found 2 miRNAs showing a tendency being different between ACA and ACC samples: hsa-miR-101 and hsa-miR-483-5p.	('hsa-miR-483', 'Gene', '619552', (203, 214))	('hsa-miR-101', 'Var', (187, 198))	('miR-101', 'Chemical', '-', (191, 198))	('hsa-miR-483', 'Gene', (203, 214))
68422	28710381	In our previous study on unfractionated plasma samples, we have found significant overexpression of 5 circulating miRNAs (hsa-miR-483-5p, hsa-miR-100, hsa-miR-181b, hsa-miR-184, hsa-miR-210) in ACC relative to ACA.	('hsa-miR-483', 'Gene', (122, 133))	('hsa-miR-483', 'Gene', '619552', (122, 133))	('miR-100', 'Gene', (142, 149))	('hsa-miR-184', 'Gene', (165, 176))	('overexpression', 'PosReg', (82, 96))	('hsa-miR-181b', 'Var', (151, 163))	('miR-210', 'Gene', (182, 189))	('hsa-miR-184', 'Gene', '406960', (165, 176))	('miR-210', 'Gene', '406992', (182, 189))	('miR-100', 'Gene', '406892', (142, 149))
68485	28710381	Among these, hsa-miR-101 (002253) and hsa-miR-483-5p (002338) were selected for validation by real-time RT-qPCR on altogether 34 samples (18 ACA and 16 ACC patients).	('patients', 'Species', '9606', (156, 164))	('ACA', 'Disease', (141, 144))	('hsa-miR-483', 'Gene', (38, 49))	('hsa-miR-483', 'Gene', '619552', (38, 49))	('ACC', 'Disease', (152, 155))	('002253', 'Var', (26, 32))	('002338', 'Var', (54, 60))	('miR-101', 'Chemical', '-', (17, 24))
68486	28710381	Quantitative RT-PCR was performed by TaqMan Fast Universal PCR Master Mix (2x) (PN: 4352042, Thermo Fisher Scientific) on a 7500 Fast Real-Time PCR system (Thermo Fisher Scientific) according to the protocol of manufacturer for TaqMan Small RNA Assays (PN 4364031E, Thermo Fisher Scientific) with minor modifications.	('PN: 4352042', 'Var', (80, 91))	('Mix', 'Gene', '83881', (70, 73))	('PN 4364031E', 'Var', (253, 264))	('Mix', 'Gene', (70, 73))
68508	26843528	ATR-101 caused mitochondrial hyperpolarization, reactive oxygen release and ATP depletion within hours after exposure, followed by cytochrome c release, caspase-3 activation, and membrane permeabilization.	('reactive oxygen', 'Chemical', '-', (48, 63))	('activation', 'PosReg', (163, 173))	('cytochrome c', 'Gene', (131, 143))	('mitochondrial', 'MPA', (15, 28))	('ATR-101', 'Var', (0, 7))	('caspase-3', 'Gene', (153, 162))	('reactive oxygen release', 'MPA', (48, 71))	('hyperpolarization', 'PosReg', (29, 46))	('cytochrome c', 'Gene', '54205', (131, 143))	('caspase-3', 'Gene', '836', (153, 162))	('depletion', 'NegReg', (80, 89))	('ATP', 'Chemical', 'MESH:D000255', (76, 79))	('ATP', 'MPA', (76, 79))
68511	26843528	ATR-101 directly inhibited F1F0-ATPase activity and suppressed ATP synthesis in mitochondrial fractions.	('ATR-101', 'Var', (0, 7))	('F1F0-ATPase', 'Protein', (27, 38))	('ATP', 'Chemical', 'MESH:D000255', (63, 66))	('inhibited', 'NegReg', (17, 26))	('activity', 'MPA', (39, 47))	('suppressed', 'NegReg', (52, 62))	('ATP', 'Chemical', 'MESH:D000255', (32, 35))	('ATP synthesis in mitochondrial fractions', 'MPA', (63, 103))
68523	26843528	ATR-101 reduces the ATP level in the adrenal cortex of guinea pigs and in cultured adrenocortical cells.	('ATR-101', 'Var', (0, 7))	('adrenocortical', 'Disease', (83, 97))	('guinea pigs', 'Species', '10141', (55, 66))	('adrenocortical', 'Disease', 'MESH:D018268', (83, 97))	('ATP', 'Chemical', 'MESH:D000255', (20, 23))	('reduces', 'NegReg', (8, 15))	('ATP level', 'MPA', (20, 29))
68533	26843528	The NCI H295R cell line is the most extensively characterized ACC-derived cell line and carries a mutation in the CTNNB1 gene, which is the most frequently observed mutation in ACC tumors.	('ACC', 'Phenotype', 'HP:0006744', (177, 180))	('mutation', 'Var', (98, 106))	('CTNNB1', 'Gene', '1499', (114, 120))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('CTNNB1', 'Gene', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('NCI H295R', 'CellLine', 'CVCL:0458', (4, 13))
68559	26843528	The growth of the xenografts was slower in the mice that were administered ATR-101 than in the mice that were administered vehicle (Fig.	('mice', 'Species', '10090', (95, 99))	('mice', 'Species', '10090', (47, 51))	('growth of the xenografts', 'CPA', (4, 28))	('ATR-101', 'Var', (75, 82))	('slower', 'NegReg', (33, 39))
68560	26843528	The weight of the xenografts excised from mice that were administered ATR-101 was lower than that of xenografts from control mice.	('ATR-101', 'Var', (70, 77))	('mice', 'Species', '10090', (42, 46))	('mice', 'Species', '10090', (125, 129))	('weight of', 'CPA', (4, 13))	('lower', 'NegReg', (82, 87))
68565	26843528	The proportion of the mice that developed xenografts and the rates of xenograft growth were lower for the mice that were administered ATR-101 than for the control mice (Fig.	('mice', 'Species', '10090', (106, 110))	('mice', 'Species', '10090', (22, 26))	('rat', 'Species', '10116', (61, 64))	('mice', 'Species', '10090', (163, 167))	('lower', 'NegReg', (92, 97))	('ATR-101', 'Var', (134, 141))
68567	26843528	Nevertheless, the cortisol levels of mice that were administered ATR-101 were lower on average than the cortisol levels of control mice with H295R cell implants (Fig.	('ATR-101', 'Var', (65, 72))	('mice', 'Species', '10090', (131, 135))	('cortisol levels', 'MPA', (18, 33))	('cortisol', 'Chemical', 'MESH:D006854', (104, 112))	('H295R', 'CellLine', 'CVCL:0458', (141, 146))	('cortisol', 'Chemical', 'MESH:D006854', (18, 26))	('lower', 'NegReg', (78, 83))	('mice', 'Species', '10090', (37, 41))
68578	26843528	In contrast, the proportion of cells that produced TUNEL signal was higher in the xenografts from mice that were administered ATR-101 than in xenografts from control mice.	('ATR-101', 'Var', (126, 133))	('higher', 'PosReg', (68, 74))	('mice', 'Species', '10090', (166, 170))	('TUNEL signal', 'MPA', (51, 63))	('mice', 'Species', '10090', (98, 102))
68581	26843528	ATR-101 caused rapid and opposite changes in the rates of formazan (MTS) versus resorufin (Prestoblue) reduction in H295R cells (Fig.	('rat', 'Species', '10116', (49, 52))	('ATR-101', 'Var', (0, 7))	('H295R', 'CellLine', 'CVCL:0458', (116, 121))	('formazan', 'MPA', (58, 66))	('resorufin', 'MPA', (80, 89))	('formazan', 'Chemical', 'MESH:D005562', (58, 66))	('resorufin', 'Chemical', 'MESH:C014180', (80, 89))	('reduction', 'NegReg', (103, 112))
68585	26843528	We compared the cytotoxicity of ATR-101 with that of another ACAT inhibitor (Sandoz 58-035) as well as a compound that is structurally related to ATR-101 (S484709).	('ACAT', 'Gene', (61, 65))	('ACAT', 'Gene', '6646', (61, 65))	('S484709', 'Var', (155, 162))	('cytotoxicity', 'Disease', 'MESH:D064420', (16, 28))	('Sandoz 58-035', 'Chemical', 'MESH:C040256', (77, 90))	('cytotoxicity', 'Disease', (16, 28))
68591	26843528	Annexin V labeled a majority of the cells that were cultured with ATR-101, and all of the cells that were labeled by propidium iodide (Fig.	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('ATR-101', 'Var', (66, 73))	('propidium iodide', 'Chemical', 'MESH:D011419', (117, 133))
68592	26843528	Cytochrome c was released into the cytoplasm and the caspase-3 activity increased in cells cultured with ATR-101 (Fig.	('ATR-101', 'Var', (105, 112))	('released into the cytoplasm', 'MPA', (17, 44))	('activity', 'MPA', (63, 71))	('increased', 'PosReg', (72, 81))	('Cytochrome c', 'Gene', (0, 12))	('caspase-3', 'Gene', (53, 62))	('Cytochrome c', 'Gene', '54205', (0, 12))	('caspase-3', 'Gene', '836', (53, 62))
68594	26843528	ATR-101 therefore caused H295R cell apoptosis both in culture and in xenografts.	('ATR-101', 'Var', (0, 7))	('H295R', 'CellLine', 'CVCL:0458', (25, 30))	('H295R cell apoptosis', 'CPA', (25, 45))
68597	26843528	Mitochondria that were visualized by MitoTracker fluorescence and anti-cytochrome c immunofluorescence appeared as small round puncta in cells cultured with ATR-101, whereas mitochondria in cells cultured with vehicle appeared as long reticular strands (Fig.	('ATR-101', 'Var', (157, 164))	('cytochrome c', 'Gene', '54205', (71, 83))	('cytochrome c', 'Gene', (71, 83))
68598	26843528	ATR-101 therefore caused mitochondrial fragmentation in parallel with its effects on mitochondrial membrane potential and ATP depletion.	('ATR-101', 'Var', (0, 7))	('ATP', 'Chemical', 'MESH:D000255', (122, 125))	('mitochondrial fragmentation', 'CPA', (25, 52))	('caused', 'Reg', (18, 24))	('ATP depletion', 'MPA', (122, 135))	('mitochondrial membrane potential', 'MPA', (85, 117))
68600	26843528	Cells that were cultured with ATR-101 had elevated levels of reactive oxygen species detected by 2',7'-dichlorodihydrofluorescin diacetate (DCFH), dihydroethidium (DHE) and MitoSOX (hydroxyethidine) fluorescence (Fig.	("2',7'-dichlorodihydrofluorescin diacetate", 'Chemical', '-', (97, 138))	('ATR-101', 'Var', (30, 37))	('DHE', 'Chemical', 'MESH:C067883', (164, 167))	('hydroxyethidine', 'Chemical', '-', (182, 197))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (61, 84))	('levels of reactive oxygen species', 'MPA', (51, 84))	('dihydroethidium', 'Chemical', 'MESH:C067883', (147, 162))	('dihydroethidium', 'MPA', (147, 162))	('MitoSOX', 'Chemical', 'MESH:C521281', (173, 180))	('elevated', 'PosReg', (42, 50))	('DCFH', 'Chemical', '-', (140, 144))
68617	26843528	None of the many hydrophilic antioxidants tested prevented ATP depletion by ATR-101, indicating that protection from ATR-101 cytotoxicity required antioxidant activity in a lipophilic environment (Fig.	('cytotoxicity', 'Disease', (125, 137))	('ATP', 'Chemical', 'MESH:D000255', (59, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('ATR-101', 'Var', (117, 124))
68619	26843528	Conversely, culture of H295R cells with 2-deoxy-D-glucose aggravated the ATP depletion and membrane permeabilization caused by ATR-101 (Fig.	('H295R', 'CellLine', 'CVCL:0458', (23, 28))	('2-deoxy-D-glucose', 'Chemical', 'MESH:D003847', (40, 57))	('ATR-101', 'Var', (127, 134))	('ATP', 'Chemical', 'MESH:D000255', (73, 76))	('membrane permeabilization', 'MPA', (91, 116))	('aggravated', 'PosReg', (58, 68))	('ATP depletion', 'MPA', (73, 86))
68621	26843528	Glycolytic substrates did not eliminate the rapid increase in mitochondrial membrane potential and DCFH reactive oxygen caused by ATR-101, but they suppressed the slow increase in MitoSOX fluorescence (Fig.	('ATR-101', 'Var', (130, 137))	('reactive oxygen', 'Chemical', '-', (104, 119))	('rat', 'Species', '10116', (16, 19))	('DCFH', 'MPA', (99, 103))	('MitoSOX fluorescence', 'MPA', (180, 200))	('MitoSOX', 'Chemical', 'MESH:C521281', (180, 187))	('suppressed', 'NegReg', (148, 158))	('DCFH', 'Chemical', '-', (99, 103))	('mitochondrial membrane potential', 'MPA', (62, 94))
68631	26843528	Taken together, these results are consistent with the interpretation that ATR-101 blocks ATP synthase activity, and does not inhibit electron transport directly.	('ATR-101', 'Var', (74, 81))	('inhibit', 'NegReg', (125, 132))	('ATP', 'Chemical', 'MESH:D000255', (89, 92))	('blocks', 'NegReg', (82, 88))	('electron transport', 'MPA', (133, 151))	('ATP synthase', 'Enzyme', (89, 101))	('activity', 'MPA', (102, 110))
68632	26843528	ATR-101 therefore had a direct effect on the membrane potential generated by mitochondrial respiration.	('ATR-101', 'Var', (0, 7))	('rat', 'Species', '10116', (68, 71))	('rat', 'Species', '10116', (96, 99))	('mitochondrial respiration', 'MPA', (77, 102))
68634	26843528	ATR-101 reduced the amount of ATP that was produced by respiring mitochondria (Fig.	('ATP', 'Chemical', 'MESH:D000255', (30, 33))	('ATR-101', 'Var', (0, 7))	('reduced', 'NegReg', (8, 15))	('respiring mitochondria', 'MPA', (55, 77))	('amount of ATP', 'MPA', (20, 33))
68667	26843528	Many inhibitors of electron transport as well as of F1F0-ATPase cause cell death under conditions that require respiration, but not under glycolytic conditions.	('cause', 'Reg', (64, 69))	('ATP', 'Chemical', 'MESH:D000255', (57, 60))	('inhibitors', 'Var', (5, 15))	('cell death', 'CPA', (70, 80))	('rat', 'Species', '10116', (116, 119))	('F1F0-ATPase', 'Gene', (52, 63))	('electron transport', 'MPA', (19, 37))
68672	26843528	The mitochondria of the adrenal cortex have unique functions, including corticosteroid biosynthesis, making it plausible that the inhibition of mitochondrial functions can selectively kill cells of adrenocortical origin.	('adrenocortical', 'Disease', (198, 212))	('inhibition', 'Var', (130, 140))	('adrenocortical', 'Disease', 'MESH:D018268', (198, 212))
68679	26843528	Chemical depletion of tocopherols from microsomes isolated from the human adrenal cortex also increases lipid peroxidation.	('tocopherols', 'Chemical', 'MESH:D024505', (22, 33))	('human', 'Species', '9606', (68, 73))	('tocopherols', 'Protein', (22, 33))	('increases', 'PosReg', (94, 103))	('lipid', 'Chemical', 'MESH:D008055', (104, 109))	('depletion of tocopherols', 'Phenotype', 'HP:0100513', (9, 33))	('lipid peroxidation', 'MPA', (104, 122))	('depletion', 'Var', (9, 18))
68692	24086089	In the past few decades, better characterization of the molecular alterations that may occur in these tumors (TP53 mutation found in Li-Fraumeni syndrome, the APC and CTNNB1 genes in familial adenomatous polyposis coli, and the CDKN1Cand IGF-2genes associated with Beckwith-Wiedemann syndrome) have led to the proposal of therapeutic interventions and prognostic markers in ACC.	('CTNNB1', 'Gene', '1499', (167, 173))	('APC', 'Gene', (159, 162))	('IGF-2', 'Gene', (238, 243))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (192, 213))	('IGF-2', 'Gene', '3481', (238, 243))	('mutation', 'Var', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Li-Fraumeni syndrome', 'Disease', (133, 153))	('TP53', 'Gene', '7157', (110, 114))	('CDKN1', 'Gene', (228, 233))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (265, 292))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('CDKN1', 'Gene', '1026', (228, 233))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (133, 153))	('familial adenomatous polyposis coli', 'Disease', 'MESH:D011125', (183, 218))	('CTNNB1', 'Gene', (167, 173))	('tumors', 'Disease', (102, 108))	('familial adenomatous polyposis coli', 'Disease', (183, 218))	('APC', 'Gene', '324', (159, 162))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('TP53', 'Gene', (110, 114))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (192, 218))	('Beckwith-Wiedemann syndrome', 'Disease', (265, 292))
68737	24086089	In univariable analysis, factors associated with poor survival were functioning tumors, R1/R2 surgical resections, stage III or IV at diagnosis, and venous thromboembolism (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('venous thromboembolism', 'Disease', 'MESH:D054556', (149, 171))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('thromboembolism', 'Phenotype', 'HP:0001907', (156, 171))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('venous thromboembolism', 'Disease', (149, 171))	('R1/R2', 'Var', (88, 93))
68751	24086089	In our study, almost 83% of the patients had their initial surgery outside our institution and this referral pattern resulted in lack of consistency in reporting proliferation markers (including Ki67%) and Weiss score.	('proliferation markers', 'CPA', (162, 183))	('patients', 'Species', '9606', (32, 40))	('Ki67', 'Var', (195, 199))
68769	24086089	Carriers of TP53 mutations and some genetic syndromes are conditions that have been associated with ACC in children.	('children', 'Species', '9606', (107, 115))	('Carriers', 'Reg', (0, 8))	('TP53', 'Gene', '7157', (12, 16))	('associated', 'Reg', (84, 94))	('TP53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('ACC', 'Disease', (100, 103))
68770	24086089	In fact, it is estimated that about 50-80% of children with ACC carry a germline TP53 mutation, making Li-Fraumeni syndrome the most common inherited condition in young patients with ACC.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (103, 123))	('patients', 'Species', '9606', (169, 177))	('children', 'Species', '9606', (46, 54))	('ACC', 'Disease', (60, 63))	('Li-Fraumeni syndrome', 'Disease', (103, 123))	('mutation', 'Var', (86, 94))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
68802	22020162	Cyp11b2 (aldosterone synthase), which labels cells with terminal steroidogenic capacity in the ZG, is not expressed until within one day or so of birth.	('steroid', 'Chemical', 'MESH:D013256', (65, 72))	('aldosterone synthase', 'Gene', (9, 29))	('aldosterone synthase', 'Gene', '13072', (9, 29))	('Cyp11b2', 'Var', (0, 7))
68809	22020162	Inhibition of Ptch1 activity upon Hh binding leads to the derepression of Smo and its accumulation in the cilium.	('activity', 'MPA', (20, 28))	('binding', 'Interaction', (37, 44))	('derepression', 'MPA', (58, 70))	('Smo', 'Gene', (74, 77))	('accumulation', 'PosReg', (86, 98))	('Inhibition', 'Var', (0, 10))	('Ptch1', 'Gene', '19206', (14, 19))	('Ptch1', 'Gene', (14, 19))	('Smo', 'Gene', '319757', (74, 77))
68820	22020162	Shh mRNA or transgenic reporter expression were compared to expression on adjacent sections or by multichannel coimmunofluorescence with either pan-adrenocortical markers such as Sf-1 or endogenous biotin, or zonal markers such as Cyp11b2 (ZG) or Cyp11b1 (ZF) to define the population of cells expressing Shh.	('Cyp11b2', 'Var', (231, 238))	('Sf-1', 'Gene', '22668', (179, 183))	('adrenocortical', 'Disease', (148, 162))	('Cyp11b1', 'Gene', '110115', (247, 254))	('biotin', 'Chemical', 'MESH:D001710', (198, 204))	('adrenocortical', 'Disease', 'MESH:D018268', (148, 162))	('Cyp11b1', 'Gene', (247, 254))	('Sf-1', 'Gene', (179, 183))
68823	22020162	The few Shh cells that do overlap with Cyp11b2 or Cyp11b1 cells were marked by weak LacZ expression, and it is likely that this represents perdurance of the LacZ protein rather than bona fide Shh expression, as GFP protein expressed from the Shh-GFP:Cre allele does not extend into the ZF.	('Cyp11b2', 'Var', (39, 46))	('weak', 'NegReg', (79, 83))	('Cyp11b1', 'Gene', '110115', (50, 57))	('rat', 'Species', '10116', (170, 173))	('Cyp11b1', 'Gene', (50, 57))	('LacZ expression', 'MPA', (84, 99))
68826	22020162	However unlike in the mouse, the rat adrenocortical cells that express Shh are not found in clusters immediately underneath the capsule, but rather are present in a continuous layer immediately underneath the ZG cells that express Cyp11b2.	('Cyp11b2', 'Var', (231, 238))	('rat', 'Species', '10116', (141, 144))	('rat', 'Species', '10116', (33, 36))	('mouse', 'Species', '10090', (22, 27))	('adrenocortical', 'Disease', (37, 51))	('adrenocortical', 'Disease', 'MESH:D018268', (37, 51))
68849	22020162	Mice homozygous for a Gli3 mutation (Gli3Delta699/Delta699) that encodes a protein truncated in a similar fashion to PHS mutations are not viable, but were reported to have embryonic adrenal aplasia.	('Gli3', 'Gene', '14634', (22, 26))	('mutations', 'Var', (121, 130))	('PHS', 'Gene', (117, 120))	('Gli3', 'Gene', '14634', (37, 41))	('adrenal aplasia', 'Phenotype', 'HP:0011743', (183, 198))	('Delta699', 'Mutation', 'c.del699', (50, 58))	('Mice', 'Species', '10090', (0, 4))	('Gli3', 'Gene', (37, 41))	('Delta699', 'Mutation', 'c.del699', (41, 49))	('embryonic adrenal aplasia', 'Disease', 'MESH:D000310', (173, 198))	('embryonic adrenal aplasia', 'Disease', (173, 198))	('Gli3', 'Gene', (22, 26))
68856	22020162	It might be due to differences in the genetic backgrounds between the two colonies, or perhaps because the adrenals are displaced relative to the aplastic or hypoplastic kidneys found in the mutant animals.	('aplastic or hypoplastic kidneys', 'Phenotype', 'HP:0008678', (146, 177))	('hypoplastic kidneys', 'Disease', (158, 177))	('mutant', 'Var', (191, 197))	('aplastic', 'Disease', 'MESH:D000741', (146, 154))	('hypoplastic kidneys', 'Phenotype', 'HP:0000089', (158, 177))	('aplastic', 'Disease', (146, 154))	('hypoplastic kidneys', 'Disease', 'MESH:D007674', (158, 177))
68857	22020162	Nonetheless homozygous truncating mutations in Gli3 are clearly compatible with substantially normal adrenal development.	('truncating mutations', 'Var', (23, 43))	('Gli3', 'Gene', '14634', (47, 51))	('adrenal development', 'CPA', (101, 120))	('Gli3', 'Gene', (47, 51))
68858	22020162	This also provides support for the idea that the severe adrenal defects in some PHS patients, who are heterozygotes for GLI3 mutations, are secondary to pituitary dysfunction.	('mutations', 'Var', (125, 134))	('secondary', 'Reg', (140, 149))	('pituitary dysfunction', 'Disease', (153, 174))	('patients', 'Species', '9606', (84, 92))	('adrenal defects', 'Phenotype', 'HP:0000834', (56, 71))	('adrenal defects', 'Disease', 'MESH:D000310', (56, 71))	('pituitary dysfunction', 'Disease', 'MESH:D010900', (153, 174))	('adrenal defects', 'Disease', (56, 71))	('GLI3', 'Gene', (120, 124))
68859	22020162	Three recent studies have examined the phenotypic consequences resulting from conditional deletion of a floxed Shh allele using the Sf-1-cre driver.	('Sf-1', 'Gene', (132, 136))	('conditional deletion', 'Var', (78, 98))	('Shh', 'Gene', (111, 114))	('Sf-1', 'Gene', '22668', (132, 136))
68860	22020162	All three reported that the mutant mice were viable, and that the mutant adrenals were significantly smaller than in controls.	('smaller', 'NegReg', (101, 108))	('mice', 'Species', '10090', (35, 39))	('mutant', 'Var', (66, 72))
68863	22020162	When a Gli1-LacZ reporter allele was crossed onto the conditional Shh mutant background, some LacZ expression was still present in the mutant adrenal capsule.	('mutant', 'Var', (70, 76))	('mutant', 'Var', (135, 141))	('Gli1', 'Gene', '14632', (7, 11))	('Gli1', 'Gene', (7, 11))
68865	22020162	Furthermore the total loss of Gli1-LacZ expression in the Shh null mutants suggests that Shh is the only source of Hh activity associated with the adrenal, at least during embryogenesis.	('expression', 'MPA', (40, 50))	('Gli1', 'Gene', '14632', (30, 34))	('mutants', 'Var', (67, 74))	('loss', 'NegReg', (22, 26))	('Shh', 'Gene', (58, 61))	('Gli1', 'Gene', (30, 34))
68867	22020162	Examination of cell cycle and apoptotic markers revealed that mutant capsule cells proliferate less than in controls, but do not undergo excess programmed cell death.	('rat', 'Species', '10116', (90, 93))	('less', 'NegReg', (95, 99))	('mutant', 'Var', (62, 68))	('proliferate', 'CPA', (83, 94))
68869	22020162	Thus the cortex is disproportionately reduced in Shh mutants, and the growth defects are visible during embryogenesis, as early as 13.5 dpc.	('growth defects', 'Disease', (70, 84))	('dpc', 'Chemical', '-', (136, 139))	('reduced', 'NegReg', (38, 45))	('mutants', 'Var', (53, 60))	('growth defects', 'Disease', 'MESH:D006130', (70, 84))	('Shh', 'Gene', (49, 52))
68870	22020162	Despite the reduction in cortical size, zonation appears normal, with an outer ZG and inner ZF, displaying appropriate expression of Sf-1, Cyp11a1, 3betaHSD, Cyp21, Cyp11b2 and Cyp11b1.	('cortical size', 'CPA', (25, 38))	('Cyp11b1', 'Gene', '110115', (177, 184))	('3betaHSD', 'Var', (148, 156))	('Cyp11b2', 'Var', (165, 172))	('reduction', 'NegReg', (12, 21))	('Cyp21', 'Gene', (158, 163))	('Cyp11b1', 'Gene', (177, 184))	('Cyp11a1', 'Gene', '13070', (139, 146))	('Sf-1', 'Gene', '22668', (133, 137))	('Sf-1', 'Gene', (133, 137))	('Cyp21', 'Gene', '13079', (158, 163))	('Cyp11a1', 'Gene', (139, 146))
68871	22020162	However the individual cells in both the ZG and ZF of mutants are hypertrophic in adults.	('hypertrophic', 'Disease', 'MESH:D006984', (66, 78))	('mutants', 'Var', (54, 61))	('hypertrophic', 'Disease', (66, 78))
68873	22020162	In mutant animals circulating corticosterone levels are approximately normal perinatally, but are several fold reduced compared to controls at one year, when plasma ACTH levels are elevated.	('mutant', 'Var', (3, 9))	('ACTH', 'Gene', '18976', (165, 169))	('circulating corticosterone levels', 'Phenotype', 'HP:0032362', (18, 51))	('circulating corticosterone levels', 'MPA', (18, 51))	('corticosterone', 'Chemical', 'MESH:D003345', (30, 44))	('reduced', 'NegReg', (111, 118))	('ACTH', 'Gene', (165, 169))
68874	22020162	This suggests that the ZF cells in mutant adrenals have sufficient steroidogenic capacity when body mass is small, but fail to compensate fully for the adrenal hypoplasia as the animals grow.	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (152, 170))	('mutant', 'Var', (35, 41))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (152, 170))	('steroid', 'Chemical', 'MESH:D013256', (67, 74))	('steroidogenic capacity', 'MPA', (67, 89))	('adrenal hypoplasia', 'Disease', (152, 170))
68875	22020162	The morphological defects in the Shh mutants present a conundrum: if the Shh signal is received only by cells that are predominantly located in the capsule and are outside the steroidogenic lineages, why is the mutant cortex so severely affected?	('Shh', 'Gene', (33, 36))	('steroid', 'Chemical', 'MESH:D013256', (176, 183))	('mutants', 'Var', (37, 44))
68896	22020162	Could depletion of the Gli1 lineage account for the Shh mutant phenotype?	('mutant', 'Var', (56, 62))	('Gli1', 'Gene', (23, 27))	('Gli1', 'Gene', '14632', (23, 27))	('Shh', 'Disease', (52, 55))
68910	22020162	Shh function might modulate reciprocal signaling back to the cortex, or influence the behavior of the mesenchymal cell population that undergoes a transformation into steroidogenic cortical lineages, or it might function through a combination of both modalities.	('steroid', 'Chemical', 'MESH:D013256', (167, 174))	('modulate', 'Reg', (19, 27))	('behavior of the mesenchymal cell population', 'CPA', (86, 129))	('influence', 'Reg', (72, 81))	('Shh', 'Gene', (0, 3))	('reciprocal signaling back', 'MPA', (28, 53))	('function', 'Var', (4, 12))
68911	22020162	Indeed the correlation between capsule and cortical defects in Shh mutants indicates that mutant analyses of genes that are expressed solely in cortical cell populations should also include an examination of capsule morphology and gene expression patterns.	('mutants', 'Var', (67, 74))	('Shh', 'Gene', (63, 66))	('cortical defects', 'Disease', 'MESH:D001927', (43, 59))	('cortical defects', 'Disease', (43, 59))
68912	22020162	In this context, it is also noteworthy that while the conditional Shh mutant mice had normal glucocorticoid levels when the animals were young and small, they became deficient as the animals aged and grew.	('mice', 'Species', '10090', (77, 81))	('mutant', 'Var', (70, 76))	('glucocorticoid levels', 'MPA', (93, 114))	('Shh', 'Gene', (66, 69))	('deficient', 'NegReg', (166, 175))
68913	22020162	This also raises the possibility that human patients with defects in Shh signaling might suffer from previously undetected adrenal dysfunction, either under normal conditions, or perhaps when elevated adrenal steroid production is required.	('steroid', 'Chemical', 'MESH:D013256', (209, 216))	('adrenal dysfunction', 'Disease', 'MESH:D000312', (123, 142))	('human', 'Species', '9606', (38, 43))	('patients', 'Species', '9606', (44, 52))	('elevated adrenal', 'Phenotype', 'HP:0008221', (192, 208))	('suffer', 'Reg', (89, 95))	('Shh signaling', 'Gene', (69, 82))	('defects', 'Var', (58, 65))	('adrenal dysfunction', 'Phenotype', 'HP:0000846', (123, 142))	('adrenal dysfunction', 'Disease', (123, 142))
69017	20049152	Our patient's tumor was negative for p53 mutation which is estimated to occur in 80-90% of all pediatric adrenocortical tumors.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', (14, 19))	('pediatric adrenocortical tumors', 'Disease', (95, 126))	('patient', 'Species', '9606', (4, 11))	('pediatric adrenocortical tumors', 'Disease', 'MESH:C565973', (95, 126))	('mutation', 'Var', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', (120, 125))
69019	20049152	This mutation leads to an abnormal folding of the TP53 protein and accumulation in the nucleus; loss of heterozygosity at this locus is though to be involved in tumorigenesis.	('folding', 'MPA', (35, 42))	('abnormal', 'Reg', (26, 34))	('TP53', 'Gene', '7157', (50, 54))	('leads to', 'Reg', (14, 22))	('loss of heterozygosity', 'Var', (96, 118))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('TP53', 'Gene', (50, 54))	('involved', 'Reg', (149, 157))	('tumor', 'Disease', (161, 166))	('accumulation', 'PosReg', (67, 79))
69020	20049152	In a study evaluating penetrance of this mutation, 10% of 240 carriers of this mutation developed adrenocortical tumors.	('adrenocortical tumors', 'Disease', (98, 119))	('mutation', 'Var', (79, 87))	('developed', 'PosReg', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (98, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
69049	33842328	APOBEC3B, a member of APOBEC (apolipoprotein B mRNA editing enzyme, catalytic-polypeptide-like) enzymes with cytidine deaminase activity, can induce prevalent mutagen of genomic DNA in multiple cancers.	('cytidine deaminase', 'Gene', (109, 127))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('APOBEC3B', 'Gene', (0, 8))	('mutagen', 'Var', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', (194, 201))	('induce', 'Reg', (142, 148))	('cytidine deaminase', 'Gene', '978', (109, 127))
69051	33842328	High expression of APOBEC3B is associated with immune evasion of cancer.	('High', 'Var', (0, 4))	('APOBEC3B', 'Gene', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('associated', 'Reg', (31, 41))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
69052	33842328	Notably, high expression of APOBEC3B also enhances the sensitivity to immune checkpoint blockade in melanoma.	('APOBEC3B', 'Gene', (28, 36))	('sensitivity to immune checkpoint blockade', 'MPA', (55, 96))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('enhances', 'PosReg', (42, 50))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('high', 'Var', (9, 13))
69073	33842328	To figure out the relationship between APOBEC3B and molecular subtypes, we further investigated the expression level of APOBEC3B among subtypes: increased expression level of APBOEC3B was found in CL and ME compared to PN and NE (P <.05, respectively;  Figure 1C ).	('APBOEC3B', 'Var', (175, 183))	('ME', 'Chemical', '-', (204, 206))	('CL', 'Disease', 'None', (197, 199))	('increased', 'PosReg', (145, 154))	('expression', 'MPA', (155, 165))
69076	33842328	Glioma patients with codeletion of 1p and 19q derived more benefits in several clinical trials.	('codeletion', 'Var', (21, 31))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('benefits', 'PosReg', (59, 67))	('patients', 'Species', '9606', (7, 15))
69077	33842328	We observed that the expression of APOBEC3B was decreased in the 1p19q codeletion cluster in pan-glioma analysis (P <.05, respectively;  Figure 1D ).	('glioma', 'Disease', (97, 103))	('1p19q', 'Var', (65, 70))	('expression', 'MPA', (21, 31))	('decreased', 'NegReg', (48, 57))	('APOBEC3B', 'Gene', (35, 43))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
69092	33842328	We revealed that APOBEC3Bhigh patients showed shorter overall survival (OS) than APOBEC3Blow patients in pan-glioma, LGG, and GBM (P <.05, respectively;  Figures 3A, B ).	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('APOBEC3Bhigh', 'Var', (17, 29))	('overall survival', 'MPA', (54, 70))	('glioma', 'Disease', (109, 115))	('patients', 'Species', '9606', (30, 38))	('shorter', 'NegReg', (46, 53))	('patients', 'Species', '9606', (93, 101))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
69095	33842328	High APOBEC3B expression was significantly correlated to worse prognosis in nine cancer types, including ACC, CHOL, ESCA, LIHC, LUAD, PAAD, UCEC, UCS, and KICH (P <.0001, respectively;  Figure 3C ).	('CHOL', 'Disease', 'None', (110, 114))	('LUAD', 'Phenotype', 'HP:0030078', (128, 132))	('cancer', 'Disease', (81, 87))	('ACC', 'Phenotype', 'HP:0006744', (105, 108))	('ACC', 'Disease', (105, 108))	('LIHC', 'Disease', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ESCA', 'Phenotype', 'HP:0011459', (116, 120))	('KICH', 'Disease', 'None', (155, 159))	('High', 'Var', (0, 4))	('LUAD', 'Disease', (128, 132))	('CHOL', 'Disease', (110, 114))	('UCEC', 'Disease', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('CHOL', 'Phenotype', 'HP:0030153', (110, 114))	('PAAD', 'Phenotype', 'HP:0006725', (134, 138))	('KICH', 'Disease', (155, 159))	('APOBEC3B', 'Gene', (5, 13))	('ESCA', 'Disease', (116, 120))	('PAAD', 'Disease', (134, 138))	('expression', 'MPA', (14, 24))	('UCS', 'Disease', (146, 149))
69098	33842328	Besides the variation of chr1 and chr19, amplification of chr7 and deletion of chr10 most frequently occurred in glioma patients ( Figure 4A ).	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('occurred', 'Reg', (101, 109))	('deletion', 'Var', (67, 75))	('chr7', 'Gene', (58, 62))	('glioma', 'Disease', (113, 119))	('patients', 'Species', '9606', (120, 128))	('amplification', 'Var', (41, 54))	('chr10', 'Gene', (79, 84))
69099	33842328	As a genomic symbol of oligodendroglioma, deletion of 1p and 19q tended to appear in APOBEC3Blow cluster ( Figure 4B ).	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('APOBEC3Blow', 'Gene', (85, 96))	('oligodendroglioma', 'Disease', (23, 40))	('oligodendroglioma', 'Disease', 'MESH:D009837', (23, 40))	('deletion', 'Var', (42, 50))	('appear', 'Reg', (75, 81))
69105	33842328	Common carcinogenic pathways were found to be more active in APOBEC3Bhigh group ( Figures 5E, G ).	('carcinogenic', 'Disease', 'MESH:D063646', (7, 19))	('more active', 'PosReg', (46, 57))	('APOBEC3Bhigh', 'Var', (61, 73))	('carcinogenic', 'Disease', (7, 19))
69106	33842328	The strongest co-occurrent pairs of gene alteration in the APOBEC3Bhigh group were ATRX-TP53, and in the APOBEC3Blow groups were ATRX-TP53 as well as ATRX-IDH1, which was in line with previous studies> Meanwhile, the most mutually exclusive pairs in APOBEC3Bhigh and APOBEC3Blow groups were CIC-TP53 and EGFR-IDH1, respectively ( Figures 5F, H ).	('TP53', 'Gene', (134, 138))	('ATRX', 'Gene', (150, 154))	('IDH1', 'Gene', '3417', (155, 159))	('TP53', 'Gene', '7157', (88, 92))	('ATRX', 'Gene', '546', (150, 154))	('IDH1', 'Gene', (309, 313))	('EGFR', 'Gene', (304, 308))	('TP53', 'Gene', '7157', (295, 299))	('ATRX', 'Gene', (83, 87))	('ATRX', 'Gene', '546', (83, 87))	('ATRX', 'Gene', (129, 133))	('TP53', 'Gene', '7157', (134, 138))	('rat', 'Species', '10116', (45, 48))	('IDH1', 'Gene', '3417', (309, 313))	('ATRX', 'Gene', '546', (129, 133))	('EGFR', 'Gene', '1956', (304, 308))	('alteration', 'Var', (41, 51))	('TP53', 'Gene', (88, 92))	('TP53', 'Gene', (295, 299))	('IDH1', 'Gene', (155, 159))
69131	33842328	Generally, somatic mutation has been considered as a therapy evasion promoter of cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('somatic mutation', 'Var', (11, 27))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
69132	33842328	Correspondingly, mutation can also promote antitumor T-cell response.	('mutation', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('promote', 'PosReg', (35, 42))	('tumor', 'Disease', (47, 52))
69135	33842328	For example, highly expressed APOBEC3B is regarded as an unfavorable prognostic factors in myeloma, ovarian cancer, and clear cell renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (131, 151))	('APOBEC3B', 'Gene', (30, 38))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 151))	('clear cell renal cell carcinoma', 'Disease', (120, 151))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (120, 151))	('myeloma, ovarian cancer', 'Disease', 'MESH:D009101', (91, 114))	('highly expressed', 'Var', (13, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
69138	33842328	Most recently, the duality of APOBEC3B in immunotherapy has been demonstrated, in which APOBEC3B not only acts as the general driving force of therapy escape but also significantly activates the immune system in melanoma.	('rat', 'Species', '10116', (72, 75))	('APOBEC3B', 'Var', (88, 96))	('immune system', 'CPA', (195, 208))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('activates', 'PosReg', (181, 190))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))
69142	33842328	But the activation of tumor-infiltrating immune cells also mediates APOBEC3B deletion in breast cancer in Asian patients.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('APOBEC3B', 'Gene', (68, 76))	('breast cancer', 'Disease', (89, 102))	('patients', 'Species', '9606', (112, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('deletion', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('rat', 'Species', '10116', (34, 37))
69150	33842328	Several immune infiltrating cell types possess the features of immunosuppression: It is well documented that MDSC is able to inhibit innate and adaptive immunity, and macrophages have been indicated to promote cancer cell proliferation, immunosuppression, and angiogenesis in cancers.	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('inhibit', 'NegReg', (125, 132))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('rat', 'Species', '10116', (229, 232))	('cancers', 'Disease', (276, 283))	('promote', 'PosReg', (202, 209))	('immunosuppression', 'CPA', (237, 254))	('angiogenesis', 'CPA', (260, 272))	('rat', 'Species', '10116', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('MDSC', 'Var', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
69153	33842328	Cell type enrichment analysis further revealed that APOBEC3B was significantly correlated with MDSC, macrophage, regulatory T cells, and Th2 cells in glioma, KICH, PAAD, and UCS, providing evidence to the statement that APOBEC3B was an immunotherapy escape driver in LGG.	('KICH', 'Disease', (158, 162))	('PAAD', 'Phenotype', 'HP:0006725', (164, 168))	('APOBEC3B', 'Var', (220, 228))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Disease', (150, 156))	('KICH', 'Disease', 'None', (158, 162))	('UCS', 'Phenotype', 'HP:0002891', (174, 177))	('APOBEC3B', 'Gene', (52, 60))	('correlated', 'Reg', (79, 89))	('Th2', 'Chemical', '-', (137, 140))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
69161	33842328	CD276 has become a novel Cart-T target for GBM while inhibition of PD-1/PD-L1 pathway can be a latent treatment strategy for glioma.	('glioma', 'Disease', (125, 131))	('inhibition', 'Var', (53, 63))	('PD-1', 'Gene', (67, 71))	('PD-1', 'Gene', '5133', (67, 71))	('rat', 'Species', '10116', (114, 117))	('PD-L1', 'Gene', '29126', (72, 77))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('CD276', 'Gene', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('CD276', 'Gene', '80381', (0, 5))	('PD-L1', 'Gene', (72, 77))
69177	31156552	Cancers are often associated with aberrant transcriptomes.	('Cancers', 'Disease', (0, 7))	('aberrant', 'Var', (34, 42))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('associated', 'Reg', (18, 28))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))
69179	31156552	In theory, ceRNAs refer to all transcripts that may become the targets of miRNA such as long non-coding RNA (lncRNA), pseudogene RNA, and circular RNA.	('ncRNA', 'Gene', (110, 115))	('pseudogene', 'Var', (118, 128))	('ncRNA', 'Gene', '54719', (110, 115))
69194	31156552	Therefore, in this paper lncRNA and pseudogenes were both identified as potential cancer specific ceRNAs.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ncRNA', 'Gene', (26, 31))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('pseudogenes', 'Var', (36, 47))	('ncRNA', 'Gene', '54719', (26, 31))
69242	30721134	Both patients carried novel germline heterozygous mutation (c.400_401insC) of MEN1.	('patients', 'Species', '9606', (5, 13))	('c.400_401insC', 'Mutation', 'c.400_401insC', (60, 73))	('c.400_401insC', 'Var', (60, 73))	('MEN1', 'Gene', '4221', (78, 82))	('MEN1', 'Gene', (78, 82))
69244	30721134	The ACC tissue had nuclear beta-catenin staining, with heterozygous CTNNB1 mutation of 357del24 and P53 staining in only 20% cells.	('CTNNB1', 'Gene', (68, 74))	('nuclear beta-catenin staining', 'MPA', (19, 48))	('mutation', 'Var', (75, 83))	('ACC', 'Phenotype', 'HP:0006744', (4, 7))	('P53', 'Gene', (100, 103))	('P53', 'Gene', '7157', (100, 103))	('CTNNB1', 'Gene', '1499', (68, 74))	('357del24', 'Mutation', 'c.357del24', (87, 95))
69254	30721134	In addition, ACC occurred in 3-7% of adults and 50-80% of children patients of Li-Fraumeni syndrome, which was caused by germline TP53 mutation.	('caused by', 'Reg', (111, 120))	('TP53', 'Gene', (130, 134))	('patients', 'Species', '9606', (67, 75))	('Li-Fraumeni syndrome', 'Disease', (79, 99))	('ACC', 'Phenotype', 'HP:0006744', (13, 16))	('TP53', 'Gene', '7157', (130, 134))	('mutation', 'Var', (135, 143))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (79, 99))	('children', 'Species', '9606', (58, 66))
69256	30721134	Activating point mutations of CTNNB1 have been identified in over 25% ACCs.	('Activating', 'PosReg', (0, 10))	('ACC', 'Phenotype', 'HP:0006744', (70, 73))	('CTNNB1', 'Gene', (30, 36))	('point mutations', 'Var', (11, 26))	('ACCs', 'Gene', (70, 74))	('ACCs', 'Gene', '84680', (70, 74))	('CTNNB1', 'Gene', '1499', (30, 36))
69258	30721134	Coincident beta-catenin activation and TP53 inactivation predicted poor outcome.	('TP53', 'Gene', '7157', (39, 43))	('activation', 'PosReg', (24, 34))	('inactivation', 'Var', (44, 56))	('beta-catenin', 'Protein', (11, 23))	('TP53', 'Gene', (39, 43))
69259	30721134	In the recently published TCGA, profiles of ACC, TP53 and CTNNB1 mutations were the most common mutations in ACC, and MEN1 was one of the five significantly mutated genes in ACC.	('mutations', 'Var', (96, 105))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('CTNNB1', 'Gene', (58, 64))	('ACC', 'Phenotype', 'HP:0006744', (44, 47))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('MEN1', 'Gene', '4221', (118, 122))	('ACC', 'Disease', (109, 112))	('ACC', 'Phenotype', 'HP:0006744', (174, 177))	('MEN1', 'Gene', (118, 122))	('common', 'Reg', (89, 95))	('ACC', 'Gene', (44, 47))	('mutations', 'Var', (65, 74))	('CTNNB1', 'Gene', '1499', (58, 64))
69260	30721134	Seven percent of tumors harbored inactivating MEN1 mutations, consistent with a prior study identifying recurrent somatic MEN1 mutation in ACC.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutations', 'Var', (51, 60))	('mutation', 'Var', (127, 135))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('inactivating', 'Var', (33, 45))	('ACC', 'Phenotype', 'HP:0006744', (139, 142))	('MEN1', 'Gene', (46, 50))	('MEN1', 'Gene', '4221', (46, 50))	('MEN1', 'Gene', '4221', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('MEN1', 'Gene', (122, 126))
69272	30721134	MEN1 gene is located between D11S4946 (intragenic in 5' untranslated region, about 500 bp from MEN1 transcription start site) and D11S1983, transcribing from telomere to centromere.	('D11S4946', 'Var', (29, 37))	('MEN1', 'Gene', '4221', (0, 4))	('D11S1983', 'Var', (130, 138))	('MEN1', 'Gene', (95, 99))	('MEN1', 'Gene', '4221', (95, 99))	('MEN1', 'Gene', (0, 4))
69273	30721134	D11S4940 is located approximately 93 kb 5' of MEN1 gene.	('MEN1', 'Gene', '4221', (46, 50))	('D11S4940', 'Var', (0, 8))	('MEN1', 'Gene', (46, 50))
69277	30721134	Normal parathyroid tissue was employed as positive control, while negative controls were performed by pancreatic neuroendocrine tumors (PNETs) of patient IV:5 (self-control) with known loss expression of menin (somatic sequencing revealed homozygous MEN1 mutation and IHC staining showed absence of menin).	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (113, 134))	('pancreatic neuroendocrine tumors', 'Disease', (102, 134))	('menin', 'Gene', (299, 304))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (102, 134))	('menin', 'Gene', (204, 209))	('mutation', 'Var', (255, 263))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('patient', 'Species', '9606', (146, 153))	('MEN1', 'Gene', (250, 254))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (113, 133))	('MEN1', 'Gene', '4221', (250, 254))	('loss', 'NegReg', (185, 189))	('menin', 'Gene', '4221', (299, 304))	('menin', 'Gene', '4221', (204, 209))
69302	30721134	Genetic testing found a hitherto undescribed heterozygous mutation at codon 97 of MEN1 gene, c.400_401insC (Fig.	('c.400_401insC', 'Mutation', 'c.400_401insC', (93, 106))	('MEN1', 'Gene', (82, 86))	('c.400_401insC', 'Var', (93, 106))	('MEN1', 'Gene', '4221', (82, 86))
69306	30721134	We screened MEN1 c.400_401insC mutation in his kindred and found eight carriers (Fig.	('c.400_401insC', 'Var', (17, 30))	('MEN1', 'Gene', (12, 16))	('MEN1', 'Gene', '4221', (12, 16))	('c.400_401insC', 'Mutation', 'c.400_401insC', (17, 30))
69308	30721134	Four of the eight mutation carriers were evaluated for MEN1-related tumors and three members were affected by adrenal tumors.	('MEN1', 'Gene', (55, 59))	('tumors', 'Disease', (68, 74))	('affected', 'Reg', (98, 106))	('MEN1', 'Gene', '4221', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('adrenal tumors', 'Disease', 'MESH:D000310', (110, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('mutation', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', (118, 124))	('adrenal tumors', 'Disease', (110, 124))
69321	30721134	The tumor was defined as an adrenocortical carcinoma according to Weiss's criteria with the Weiss score of 7 (on a scale from 0 to 9): high nuclear grade, mitotic rate greater than 5 per 50 high-power fields, atypical mitoses, clear cells comprising 25% or less of the tumor, diffuse architecture (greater than one-third of the tumor), necrosis and invasion of capsule of tumor.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (28, 52))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', (328, 333))	('high', 'Var', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('diffuse architecture', 'CPA', (276, 296))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (28, 52))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('adrenocortical carcinoma', 'Disease', (28, 52))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('to 9', 'Species', '1214577', (128, 132))	('tumor', 'Disease', (372, 377))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('atypical mitoses', 'CPA', (209, 225))	('tumor', 'Disease', 'MESH:D009369', (372, 377))	('necrosis', 'Disease', 'MESH:D009336', (336, 344))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('tumor', 'Disease', (269, 274))	('mitotic rate', 'CPA', (155, 167))	('necrosis', 'Disease', (336, 344))
69332	30721134	The resected ACC tissue harbored homogenous frame-shift mutation of c.400_401insC in MEN1 gene (Fig.	('ACC', 'Phenotype', 'HP:0006744', (13, 16))	('c.400_401insC', 'Mutation', 'c.400_401insC', (68, 81))	('c.400_401insC', 'Var', (68, 81))	('MEN1', 'Gene', (85, 89))	('MEN1', 'Gene', '4221', (85, 89))
69333	30721134	The resected ACC also showed LOH of chromosome 11q13, where MEN1 gene was located (Fig.	('MEN1', 'Gene', '4221', (60, 64))	('ACC', 'Phenotype', 'HP:0006744', (13, 16))	('LOH', 'Var', (29, 32))	('MEN1', 'Gene', (60, 64))
69337	30721134	DNA sequencing revealed a somatic 357del24 mutation of CTNNB1 and no mutation in TP53.	('revealed', 'Reg', (15, 23))	('CTNNB1', 'Gene', '1499', (55, 61))	('357del24', 'Var', (34, 42))	('357del24', 'Mutation', 'c.357del24', (34, 42))	('CTNNB1', 'Gene', (55, 61))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
69338	30721134	In this study, we found ACC can exhibit familial aggregation in MEN1 kindred with novel MEN1 germline mutation.	('MEN1', 'Gene', '4221', (88, 92))	('germline', 'Var', (93, 101))	('MEN1', 'Gene', (88, 92))	('familial aggregation', 'Disease', 'MESH:D020914', (40, 60))	('familial aggregation', 'Disease', (40, 60))	('MEN1', 'Gene', (64, 68))	('MEN1', 'Gene', '4221', (64, 68))	('ACC', 'Phenotype', 'HP:0006744', (24, 27))
69343	30721134	Functional ACCs can cause feminization (2/11), virilization (4/11), hypercortisolism (4/11) or both virilization and hypercortisolism (1/11).	('Functional', 'Var', (0, 10))	('feminization', 'Disease', (26, 38))	('cause', 'Reg', (20, 25))	('hypercortisolism', 'Disease', (68, 84))	('ACCs', 'Gene', '84680', (11, 15))	('hypercortisolism', 'Phenotype', 'HP:0003118', (117, 133))	('ACCs', 'Gene', (11, 15))	('hypercortisolism', 'Disease', 'MESH:D003480', (117, 133))	('hypercortisolism', 'Disease', (117, 133))	('hypercortisolism', 'Phenotype', 'HP:0003118', (68, 84))	('ACC', 'Phenotype', 'HP:0006744', (11, 14))	('virilization', 'Disease', (47, 59))	('hypercortisolism', 'Disease', 'MESH:D003480', (68, 84))
69352	30721134	The novel germline frame-shift mutation (c.400_401insC) of MEN1 gene was pathogenic because it segregated with MEN1 phenotype: 8/12 mutation carriers were affected by MEN1-related lesions (primary hyperparathyroidism, PNET or pituitary adenoma), the other four mutation carriers refused evaluation due to young age (IV:7, IV:8, V:3, V:4 were 21, 20, 7, 4 years old, respectively) or lack of symptoms; those without MEN1 mutation were free of MEN1 tumor.	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (197, 216))	('MEN1', 'Gene', (415, 419))	('MEN1', 'Gene', '4221', (111, 115))	('c.400_401insC', 'Var', (41, 54))	('MEN1', 'Gene', (167, 171))	('primary hyperparathyroidism', 'Phenotype', 'HP:0008200', (189, 216))	('tumor', 'Disease', (447, 452))	('MEN1', 'Gene', (111, 115))	('MEN1', 'Gene', '4221', (442, 446))	('affected', 'Reg', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (447, 452))	('pituitary adenoma', 'Disease', 'MESH:D010911', (226, 243))	('MEN1', 'Gene', '4221', (59, 63))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (226, 243))	('MEN1', 'Gene', (442, 446))	('PNET', 'Disease', (218, 222))	('pituitary adenoma', 'Disease', (226, 243))	('tumor', 'Phenotype', 'HP:0002664', (447, 452))	('MEN1', 'Gene', (59, 63))	('primary hyperparathyroidism', 'Disease', (189, 216))	('MEN1', 'Gene', '4221', (415, 419))	('c.400_401insC', 'Mutation', 'c.400_401insC', (41, 54))	('primary hyperparathyroidism', 'Disease', 'MESH:D049950', (189, 216))	('MEN1', 'Gene', '4221', (167, 171))
69354	30721134	Mutations located in NTD would decrease LEDGF-Menin interaction, therefore diminishing Hoxc8 expression and leading to tumor formation.	('tumor', 'Disease', (119, 124))	('Hoxc8', 'Gene', (87, 92))	('LEDGF', 'Gene', '11168', (40, 45))	('Menin', 'Gene', '4221', (46, 51))	('Hoxc8', 'Gene', '3224', (87, 92))	('decrease', 'NegReg', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('diminishing', 'NegReg', (75, 86))	('Menin', 'Gene', (46, 51))	('LEDGF', 'Gene', (40, 45))	('leading to', 'Reg', (108, 118))
69356	30721134	CTNNB1 (16%) and TP53 (16%) were the most common mutant genes.	('CTNNB1', 'Gene', '1499', (0, 6))	('mutant', 'Var', (49, 55))	('CTNNB1', 'Gene', (0, 6))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
69358	30721134	ACCs were absent from the tumor profile of p53-deficient or mutant mice, possibly due to the different physiology between humans and mice.	('ACCs', 'Gene', (0, 4))	('mice', 'Species', '10090', (133, 137))	('ACCs', 'Gene', '84680', (0, 4))	('humans', 'Species', '9606', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('mutant', 'Var', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('mice', 'Species', '10090', (67, 71))
69359	30721134	Deletion of exons 8 and 9 of TP53 and a Ser45 of CTNNB1 mutation in H295R cells and H193Y mutation of TP53 in SW13 cells has previously been described.	('TP53', 'Gene', (102, 106))	('CTNNB1', 'Gene', '1499', (49, 55))	('SW13', 'CellLine', 'CVCL:0542', (110, 114))	('H295R', 'CellLine', 'CVCL:0458', (68, 73))	('TP53', 'Gene', '7157', (29, 33))	('CTNNB1', 'Gene', (49, 55))	('H193Y', 'Var', (84, 89))	('TP53', 'Gene', (29, 33))	('H193Y', 'Mutation', 'rs876658468', (84, 89))	('Ser45', 'Chemical', '-', (40, 45))	('TP53', 'Gene', '7157', (102, 106))	('mutation', 'Var', (56, 64))	('Deletion', 'Var', (0, 8))
69360	30721134	Consistently, we found the MEN1-associated ACC tissue had nuclear beta-catenin staining, with heterozygosis CTNNB1 mutation of 357del24 and P53 staining in 20% cells.	('MEN1', 'Gene', '4221', (27, 31))	('mutation', 'Var', (115, 123))	('MEN1', 'Gene', (27, 31))	('CTNNB1', 'Gene', '1499', (108, 114))	('357del24', 'Mutation', 'c.357del24', (127, 135))	('P53', 'Gene', (140, 143))	('P53', 'Gene', '7157', (140, 143))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('ACC', 'Disease', (43, 46))	('CTNNB1', 'Gene', (108, 114))	('nuclear beta-catenin staining', 'MPA', (58, 87))
69371	29371329	CU-ACC1 cells had a mutation in CTNNB1 and secreted cortisol but not aldosterone.	('ACC1', 'Gene', '597', (3, 7))	('secreted cortisol', 'MPA', (43, 60))	('mutation', 'Var', (20, 28))	('CTNNB1', 'Gene', '1499', (32, 38))	('ACC1', 'Gene', (3, 7))	('aldosterone', 'Chemical', 'MESH:D000450', (69, 80))	('cortisol', 'Chemical', 'MESH:D006854', (52, 60))	('CU', 'Chemical', 'MESH:D003300', (0, 2))	('CTNNB1', 'Gene', (32, 38))
69383	29371329	Approximately 40% of ACC tumors show activation of the beta-catenin and canonical WNT pathways and 20% of tumors have a mutation in TP53.	('beta-catenin', 'Gene', (55, 67))	('canonical WNT pathways', 'Pathway', (72, 94))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Disease', (106, 112))	('activation', 'PosReg', (37, 47))	('TP53', 'Gene', '7157', (132, 136))	('mutation', 'Var', (120, 128))	('TP53', 'Gene', (132, 136))	('beta-catenin', 'Gene', '1499', (55, 67))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
69386	29371329	Specific molecular subtypes of ACC tumors exist with high mutational rates, chromosomal duplications and mutations in TP53 or in genes in the Wnt/beta-catenin pathways that portend poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('beta-catenin', 'Gene', (146, 158))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('chromosomal duplications', 'Var', (76, 100))	('beta-catenin', 'Gene', '1499', (146, 158))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('tumors', 'Disease', (35, 41))	('mutations', 'Var', (105, 114))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
69398	29371329	Five micron thick paraffin sections of human tumors and PDX samples were prepared for immunodetection of alpha-Inhibin (Ventana/Roche; Tuscon, AZ; #760-2834, predilute) and MSH2 (Ventana; #760-4265, predilute) on the Ventana Ultra autostainer under standard antigen retrieval (AR) conditions with CC1 using UltraView DAB polymer detection.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MSH2', 'Gene', '4436', (173, 177))	('paraffin', 'Chemical', 'MESH:D010232', (18, 26))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('DAB polymer', 'Chemical', '-', (317, 328))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('human', 'Species', '9606', (39, 44))	('MSH2', 'Gene', (173, 177))	('Ventana; #760-4265', 'Var', (179, 197))
69423	29371329	Mutations were considered deleterious if predicted damaging in at least three different in silico programs, including SIFT, Polyphen 2, MutationTaster and MutationAssessor.	('Mutations', 'Var', (0, 9))	('SIFT', 'Disease', (118, 122))	('SIFT', 'Disease', 'None', (118, 122))
69435	29371329	The patient had prior clinical genetic testing which showed a germline deletion of exons 1-6 in MSH2.	('germline deletion of exons', 'Var', (62, 88))	('MSH2', 'Gene', (96, 100))	('patient', 'Species', '9606', (4, 11))	('MSH2', 'Gene', '4436', (96, 100))
69466	29371329	Analysis of the exome sequencing data for genes frequently mutated in ACC, identified a CTNNB1 mutation in CU-ACC1 and TP53 mutation in CU-ACC2, with the frequency of mutated alleles being higher in the cell lines and PDXs compared to human tumor samples (Fig 4A), suggesting enrichment of the mutated clones, and the frequency of the mutated CTNNB1 allele in CU-ACC1 most likely suggests some early passage polyclonality of the novel cell line.	('CTNNB1', 'Gene', '1499', (88, 94))	('CTNNB1', 'Gene', '1499', (343, 349))	('TP53', 'Gene', '7157', (119, 123))	('CU', 'Chemical', 'MESH:D003300', (107, 109))	('tumor', 'Disease', (241, 246))	('CU', 'Chemical', 'MESH:D003300', (360, 362))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('CTNNB1', 'Gene', (88, 94))	('mutation', 'Var', (95, 103))	('CTNNB1', 'Gene', (343, 349))	('CU', 'Chemical', 'MESH:D003300', (136, 138))	('human', 'Species', '9606', (235, 240))	('ACC1', 'Gene', (110, 114))	('TP53', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('ACC1', 'Gene', '597', (110, 114))	('ACC1', 'Gene', (363, 367))	('mutation', 'Var', (124, 132))	('ACC1', 'Gene', '597', (363, 367))
69467	29371329	The CTNNB1 mutation detected in CU-ACC1 was predicted as damaging using at least three in silico callers and has been previously reported in ACC.	('CU', 'Chemical', 'MESH:D003300', (32, 34))	('ACC1', 'Gene', '597', (35, 39))	('CTNNB1', 'Gene', (4, 10))	('damaging', 'MPA', (57, 65))	('mutation', 'Var', (11, 19))	('CTNNB1', 'Gene', '1499', (4, 10))	('ACC1', 'Gene', (35, 39))
69468	29371329	The TP53 mutation in the CU-ACC2 tissue was predicted as damaging using three in silico callers and has also been described in ACC.	('mutation', 'Var', (9, 17))	('TP53', 'Gene', (4, 8))	('damaging', 'MPA', (57, 65))	('CU', 'Chemical', 'MESH:D003300', (25, 27))	('TP53', 'Gene', '7157', (4, 8))
69470	29371329	A heterozygous deletion of exons 1-6 in MSH2 was seen in 50% of the reads in the human blood.	('deletion', 'Var', (15, 23))	('MSH2', 'Gene', '4436', (40, 44))	('human', 'Species', '9606', (81, 86))	('MSH2', 'Gene', (40, 44))
69471	29371329	By comparison, there was a complete loss of heterozygosity in the human tumor, PDX and cell line confirming the validity of these new models for the Lynch Syndrome mutation.	('heterozygosity', 'MPA', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (149, 163))	('human', 'Species', '9606', (66, 71))	('mutation', 'Var', (164, 172))	('Lynch Syndrome', 'Disease', (149, 163))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
69472	29371329	The mutation status of CU-ACC1 and CU-ACC2 replicates that of known subsets of human ACC tumors reflecting the relevance of these new model for future investigation.	('tumors', 'Disease', (89, 95))	('human', 'Species', '9606', (79, 84))	('CU-ACC2', 'Gene', (35, 42))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('ACC1', 'Gene', (26, 30))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('mutation', 'Var', (4, 12))	('CU', 'Chemical', 'MESH:D003300', (23, 25))	('ACC1', 'Gene', '597', (26, 30))	('CU', 'Chemical', 'MESH:D003300', (35, 37))
69474	29371329	The PCA plot demonstrated separation of gene expression between H295R, normal adrenal samples (obtained from GTeX project), CU-ACC1 cells and PDX and CU-ACC2 cells and PDX.	('CU', 'Chemical', 'MESH:D003300', (124, 126))	('CU', 'Chemical', 'MESH:D003300', (150, 152))	('ACC1', 'Gene', (127, 131))	('H295R', 'CellLine', 'CVCL:0458', (64, 69))	('H295R', 'Var', (64, 69))	('ACC1', 'Gene', '597', (127, 131))
69477	29371329	To further characterize the two new ACC tumor cell lines, a steroid secretome profile was measured using LC-MS/MS compared to H295R cells (Fig 6).	('measured', 'Reg', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('H295R', 'CellLine', 'CVCL:0458', (126, 131))	('steroid secretome profile', 'MPA', (60, 85))	('LC-MS/MS', 'Var', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('steroid', 'Chemical', 'MESH:D013256', (60, 67))
69492	29371329	At the genetic level, these new ACC cell lines and PDX models represent examples of known molecular defects detected in human ACC with mutations in CTNNB1, TP53 and MSH2.	('human', 'Species', '9606', (120, 125))	('CTNNB1', 'Gene', '1499', (148, 154))	('MSH2', 'Gene', (165, 169))	('mutations', 'Var', (135, 144))	('MSH2', 'Gene', '4436', (165, 169))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('ACC', 'Disease', (126, 129))	('CTNNB1', 'Gene', (148, 154))
69493	29371329	H295R cells have a known activating mutation in CTNNB1, and whole exome sequencing identified a mutation in CTNNB1 (p.G34R) in the CU-ACC1 models that has been previously reported in ACC tumor samples.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('CTNNB1', 'Gene', '1499', (108, 114))	('p.G34R', 'Var', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('ACC1', 'Gene', (134, 138))	('CTNNB1', 'Gene', (48, 54))	('tumor', 'Disease', (187, 192))	('p.G34R', 'Mutation', 'rs121913399', (116, 122))	('CTNNB1', 'Gene', (108, 114))	('CTNNB1', 'Gene', '1499', (48, 54))	('ACC1', 'Gene', '597', (134, 138))	('CU', 'Chemical', 'MESH:D003300', (131, 133))
69494	29371329	The precise functional significance of this mutation has not yet been reported, but the G34R location within the ubiquitination recognition motif of the protein predicts a gain-of-function mutation.	('gain-of-function', 'PosReg', (172, 188))	('G34R', 'Var', (88, 92))	('G34R', 'SUBSTITUTION', 'None', (88, 92))
69495	29371329	In addition, the pan-cancer MSK-IMPACT study has identified this mutation in multiple malignancies including lung, liver, uterine and bladder cancer.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('bladder cancer', 'Disease', 'MESH:D001749', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('malignancies', 'Disease', 'MESH:D009369', (86, 98))	('bladder cancer', 'Disease', (134, 148))	('mutation', 'Var', (65, 73))	('uterine', 'Disease', (122, 129))	('cancer', 'Disease', (21, 27))	('lung', 'Disease', (109, 113))	('malignancies', 'Disease', (86, 98))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))	('liver', 'Disease', (115, 120))	('cancer', 'Disease', (142, 148))
69496	29371329	Consistent with these data, a recent study exploring mutation hotspots in CTNNB1 identified G34R as a recurrent mutation across various cancer types.	('CTNNB1', 'Gene', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('CTNNB1', 'Gene', '1499', (74, 80))	('cancer', 'Disease', (136, 142))	('G34R', 'SUBSTITUTION', 'None', (92, 96))	('G34R', 'Var', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
69497	29371329	The TP53 mutation (G245S) identified in the CU-ACC2 models has also been previously reported in adrenocortical carcinoma samples.	('G245S', 'Mutation', 'rs28934575', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (96, 120))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (96, 120))	('TP53', 'Gene', (4, 8))	('adrenocortical carcinoma', 'Disease', (96, 120))	('CU', 'Chemical', 'MESH:D003300', (44, 46))	('G245S', 'Var', (19, 24))	('reported', 'Reg', (84, 92))	('TP53', 'Gene', '7157', (4, 8))
69498	29371329	Although the functional significance has not been yet elucidated, crystallographic studies have identified G245S as a cancer hotspot mutation in TP53 in abrogating DNA binding, where it induces conformational change in structure.	('cancer', 'Disease', (118, 124))	('G245S', 'Var', (107, 112))	('abrogating', 'NegReg', (153, 163))	('structure', 'MPA', (219, 228))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('G245S', 'Mutation', 'rs28934575', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('DNA binding', 'Interaction', (164, 175))	('conformational change', 'MPA', (194, 215))
69499	29371329	MSH2 mutations have been well described as critical components of the Lynch syndrome phenotype which has been reported in subpopulation of patients with adrenocortical carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('Lynch syndrome', 'Disease', (70, 84))	('patients', 'Species', '9606', (139, 147))	('MSH2', 'Gene', (0, 4))	('adrenocortical carcinoma', 'Disease', (153, 177))	('Lynch syndrome', 'Disease', 'MESH:D003123', (70, 84))	('mutations', 'Var', (5, 14))	('MSH2', 'Gene', '4436', (0, 4))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (153, 177))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (153, 177))
69500	29371329	Interestingly, the allele frequency for both the CTNNB1 and TP53 mutation was higher in the pre-clinical models when compared to the human tumor, suggesting that models, and especially cell lines, are enriched for the mutated allele.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CTNNB1', 'Gene', '1499', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('CTNNB1', 'Gene', (49, 55))	('TP53', 'Gene', '7157', (60, 64))	('mutation', 'Var', (65, 73))	('higher', 'Reg', (78, 84))	('human', 'Species', '9606', (133, 138))	('TP53', 'Gene', (60, 64))
69543	29330226	Mitotane also diminishes androgen action by inhibiting 5alpha-reductase and hence activation of testosterone to 5alpha-dihydrotestosterone.	('inhibiting', 'NegReg', (44, 54))	('Mitotane', 'Var', (0, 8))	('5alpha-reductase', 'Enzyme', (55, 71))	('testosterone', 'Chemical', 'MESH:D013739', (126, 138))	('testosterone', 'Chemical', 'MESH:D013739', (96, 108))	('diminishes', 'NegReg', (14, 24))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('activation', 'PosReg', (82, 92))	('testosterone to 5alpha-dihydrotestosterone', 'MPA', (96, 138))	('5alpha-dihydrotestosterone', 'Chemical', 'MESH:D013196', (112, 138))	('androgen action', 'MPA', (25, 40))
69577	29330226	Both patients experienced significant improvement in signs and symptoms with mitotane therapy, swift normalization of steroid excess and some stabilization of radiologically quantified tumor load.	('tumor', 'Disease', (185, 190))	('mitotane', 'Var', (77, 85))	('mitotane', 'Chemical', 'MESH:D008939', (77, 85))	('patients', 'Species', '9606', (5, 13))	('men', 'Species', '9606', (45, 48))	('steroid excess', 'MPA', (118, 132))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('signs', 'MPA', (53, 58))	('steroid', 'Chemical', 'MESH:D013256', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('improvement', 'PosReg', (38, 49))
69597	29330226	A recent study has provided evidence of inhibition of SOAT1 by mitotane in an adrenocortical cell model, by demonstrating an increase in free cholesterol, oxysterols and fatty acids after treatment with mitotane.	('fatty acids', 'MPA', (170, 181))	('SOAT1', 'Gene', '6646', (54, 59))	('free cholesterol', 'MPA', (137, 153))	('adrenocortical', 'Disease', 'MESH:D018268', (78, 92))	('oxysterols', 'Chemical', 'MESH:D000072376', (155, 165))	('increase', 'PosReg', (125, 133))	('fatty acids', 'Chemical', 'MESH:D005227', (170, 181))	('mitotane', 'Var', (203, 211))	('men', 'Species', '9606', (193, 196))	('mitotane', 'Chemical', 'MESH:D008939', (203, 211))	('mitotane', 'Chemical', 'MESH:D008939', (63, 71))	('SOAT1', 'Gene', (54, 59))	('mitotane', 'Gene', (63, 71))	('oxysterols', 'MPA', (155, 165))	('cholesterol', 'Chemical', 'MESH:D002784', (142, 153))	('adrenocortical', 'Disease', (78, 92))
69604	23313103	Disruption of Sf-1 can lead to disorders of adrenal development, while increased dosage of SF-1 has been related to increased adrenal cell proliferation and tumorigenesis.	('Sf-1', 'Gene', (14, 18))	('tumor', 'Disease', (157, 162))	('lead to', 'Reg', (23, 30))	('increased adrenal', 'Phenotype', 'HP:0008221', (116, 133))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('adrenal cell proliferation', 'CPA', (126, 152))	('Disruption', 'Var', (0, 10))	('SF-1', 'Gene', (91, 95))	('increased', 'PosReg', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('disorders', 'CPA', (31, 40))	('adrenal development', 'CPA', (44, 63))
69611	23313103	Loss of Pod-1 leads to lung, kidney, and spleen abnormalities and neonatal lethality ( and).	('lung', 'CPA', (23, 27))	('spleen abnormalities', 'Phenotype', 'HP:0001743', (41, 61))	('Pod-1', 'Gene', (8, 13))	('Loss', 'Var', (0, 4))	('spleen abnormalities and neonatal lethality', 'Disease', 'OMIM:202370', (41, 84))
69615	23313103	Increased SF-1 dosage can augment human adrenal cell proliferation, playing a critical role in adrenocortical tumorigenesis.	('augment', 'NegReg', (26, 33))	('human', 'Species', '9606', (34, 39))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (95, 115))	('human adrenal cell proliferation', 'CPA', (34, 66))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('adrenocortical tumor', 'Disease', (95, 115))	('SF-1', 'Gene', (10, 14))	('dosage', 'Var', (15, 21))
69640	23313103	The 5.0-kb upstream sequences of human steroidogenic factor-1 (NR5A1, transcript ENST00000373588, Ensembl release 64, GRCh37) and androgen receptor (AR, transcript ENST00000374690) were analyzed for putative E-box binding sites using MatInspector.	('steroidogenic factor-1', 'Gene', (39, 61))	('ENST00000374690', 'Var', (164, 179))	('NR5A1', 'Gene', '2516', (63, 68))	('androgen receptor', 'Gene', '367', (130, 147))	('AR', 'Gene', '367', (149, 151))	('ENST00000373588', 'Var', (81, 96))	('NR5A1', 'Gene', (63, 68))	('human', 'Species', '9606', (33, 38))	('androgen receptor', 'Gene', (130, 147))	('steroidogenic factor-1', 'Gene', '2516', (39, 61))
69661	23313103	To investigate whether induced expression of POD-1 affects the endogenous expression of SF-1, we performed a RT-qPCR for the analysis of SF-1 expression in cells transiently transfected with expression vectors pcDNA3Pod1 or pCMVMycPod1.	('expression vectors', 'Species', '29278', (191, 209))	('expression', 'Species', '29278', (31, 41))	('pcDNA3Pod1', 'Var', (210, 220))	('SF-1', 'Gene', (137, 141))	('expression', 'Species', '29278', (142, 152))	('Myc', 'Gene', '4609', (228, 231))	('expression', 'Species', '29278', (191, 201))	('expression', 'Species', '29278', (74, 84))	('Myc', 'Gene', (228, 231))
69672	23313103	7) was downregulated following the transfection of POD-1, consistent with a decrease in SF-1-mediated StAR transcription.	('POD-1', 'Gene', (51, 56))	('transfection', 'Var', (35, 47))	('downregulated', 'NegReg', (7, 20))	('decrease', 'NegReg', (76, 84))	('AR', 'Gene', '367', (104, 106))
69683	23313103	Indeed, induced expression of Pod-1 has been shown to inhibit the expression of Sf-1 in the Leydig cell-derived I-10 cells.	('Pod-1', 'Gene', (30, 35))	('expression', 'Var', (16, 26))	('inhibit', 'NegReg', (54, 61))	('expression', 'Species', '29278', (66, 76))	('Sf-1', 'Gene', (80, 84))	('expression', 'MPA', (66, 76))	('I-10', 'CellLine', 'CVCL:3527', (112, 116))	('expression', 'Species', '29278', (16, 26))
69693	23313103	Moreover, POD-1 over-expression decreases StAR expression, consistent with a down-regulation of SF-1 mediated steroidogenesis.	('POD-1', 'Gene', (10, 15))	('over-expression', 'Var', (16, 31))	('expression', 'Species', '29278', (21, 31))	('AR', 'Gene', '367', (44, 46))	('expression', 'Species', '29278', (47, 57))	('decreases', 'NegReg', (32, 41))
69695	28753846	Little is known, however, about how the level of genetic alteration across an entire cancer genome affects tumor grade or stage or survival.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('affects', 'Reg', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('genetic alteration', 'Var', (49, 67))	('stage', 'CPA', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('survival', 'CPA', (131, 139))
69705	28753846	Cancers with higher levels of genomic alterations are associated with worse pathologic features and survival.	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('genomic alterations', 'Var', (30, 49))
69709	28753846	Much less is known about how the level of genetic alteration across an entire cancer genome affects the natural history of an individual malignancy.	('malignancy', 'Disease', (137, 147))	('affects', 'Reg', (92, 99))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('genetic alteration', 'Var', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
69711	28753846	While some studies have shown clustering of mutations that are associated with grade and stage, the effect that genomic alterations have on tumor grade and stage on histopathologic analysis has not been fully elucidated.	('associated', 'Reg', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
69712	28753846	With the publication of whole cancer genomes as part of The Cancer Genome Atlas (TCGA) and International Cancer Genome consortium, the association of whole-genome alterations such as mutation count (MC) and copy number variation (CNV) can now be correlated with clinicopathologic characteristics, survival outcomes, and therapeutic response.	('Cancer', 'Disease', (105, 111))	('Cancer Genome Atlas', 'Disease', (60, 79))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (60, 79))	('Cancer', 'Disease', 'MESH:D009369', (105, 111))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (30, 36))	('correlated', 'Reg', (246, 256))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('MC', 'Chemical', '-', (199, 201))	('copy number variation', 'Var', (207, 228))	('mutation count', 'Disease', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
69722	28753846	For tumors types with substaging (eg, T2a and T2b in BLCA), substages were combined for analysis.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('T2b', 'Var', (46, 49))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
69743	28753846	There was no association with Fuhrman grade and MC for a four-tier (p = 0.27) or a two-tier system; however, CNV was associated with higher Fuhrman grade in both four-tier (p = 0.0006) and two-tier (p = 0.0001) systems.	('Fuhrman grade', 'CPA', (140, 153))	('CNV', 'Var', (109, 112))	('MC', 'Chemical', '-', (48, 50))	('higher', 'PosReg', (133, 139))
69751	28753846	PRAD had the third lowest MC and the lowest CNV.	('lowest', 'NegReg', (37, 43))	('lowest', 'NegReg', (19, 25))	('MC', 'Chemical', '-', (26, 28))	('CNV', 'MPA', (44, 47))	('PRAD', 'Var', (0, 4))
69764	28753846	Genetic instability has largely been studied in terms of microsatellite instability and chromosomal instability, and has been linked to adverse pathology and survival in colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (170, 182))	('colon cancer', 'Disease', 'MESH:D015179', (170, 182))	('colon cancer', 'Disease', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('microsatellite', 'Var', (57, 71))	('linked', 'Reg', (126, 132))	('chromosomal instability', 'Phenotype', 'HP:0040012', (88, 111))
69765	28753846	One theory, described by Kinzler and Vogelstein, is that mutations in "caretaker" genes that maintain the integrity of the genome is an early event in cancer development that accelerates the accumulation of additional mutations that eventually lead to neoplasia.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (218, 227))	('accelerates', 'PosReg', (175, 186))	('neoplasia', 'Phenotype', 'HP:0002664', (252, 261))	('neoplasia', 'Disease', (252, 261))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', (151, 157))	('lead to', 'Reg', (244, 251))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('neoplasia', 'Disease', 'MESH:D009369', (252, 261))
69766	28753846	Our data support the role of genetic instability in the progression to higher grade and/or higher stage cancer for some genitourinary malignancies.	('cancer for some genitourinary malignancies', 'Phenotype', 'HP:0007379', (104, 146))	('genetic instability', 'Var', (29, 48))	('higher grade', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('genitourinary malignancies', 'Disease', 'MESH:D014564', (120, 146))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('genitourinary malignancies', 'Disease', (120, 146))
69767	28753846	High MC has previously been associated with greater response to checkpoint inhibitors in melanoma, non-small cell lung cancer, and renal cell carcinoma.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (99, 125))	('renal cell carcinoma', 'Disease', (131, 151))	('MC', 'Chemical', '-', (5, 7))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (99, 125))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (131, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('non-small cell lung cancer', 'Disease', (99, 125))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (131, 151))	('High MC', 'Var', (0, 7))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (103, 125))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('response', 'MPA', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
69814	27307598	Primary tumor samples were obtained in all cases, with the exception of three biopsy samples (ACT080, ACT084 and ACT086) from COG patients who had stage IV disease, as the tumors were considered inoperable.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('Primary tumor', 'Disease', (0, 13))	('COG', 'Chemical', '-', (126, 129))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ACT086', 'Var', (113, 119))	('patients', 'Species', '9606', (130, 138))	('Primary tumor', 'Disease', 'MESH:D009369', (0, 13))
69828	27307598	Eight ACTs (ACT005, ACT008, ACT012, ACT030, ACT031, ACT032, ACT033 and ACT034) were stained with antibodies specific to HLA-DPA1 and HLA-DRA and markers of mononuclear hematopoietic cells (CD3, CD4, CD8, CD68 and CD163) (Supplementary Table 3).	('HLA-DRA', 'Gene', '3122', (133, 140))	('CD163', 'Gene', '9332', (213, 218))	('CD4', 'Gene', '920', (194, 197))	('HLA-DRA', 'Gene', (133, 140))	('ACT033', 'Var', (60, 66))	('HLA-DPA1', 'Gene', '3113', (120, 128))	('CD8', 'Gene', (199, 202))	('ACT034', 'Var', (71, 77))	('CD68', 'Gene', (204, 208))	('CD163', 'Gene', (213, 218))	('CD68', 'Gene', '968', (204, 208))	('CD8', 'Gene', '925', (199, 202))	('CD4', 'Gene', (194, 197))	('HLA-DPA1', 'Gene', (120, 128))
69838	27307598	However, three cases (ACT040, ACT047 and ACT048) (17%) showed focal HLA-DPA1 immunostaining within the adrenocortical tumor cells (Fig 5B and Supplementary Table 6).	('ACT047', 'Var', (30, 36))	('adrenocortical tumor', 'Disease', (103, 123))	('HLA-DPA1', 'Gene', '3113', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('immunostaining', 'MPA', (77, 91))	('HLA-DPA1', 'Gene', (68, 76))	('ACT048', 'Var', (41, 47))	('ACT040', 'Var', (22, 28))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (103, 123))
69844	27307598	Three of these cases expressed high levels of MHC class II based on microarray (ACT005 and ACT006) and IHC (ACT047), which is characteristic of pediatric adrenocortical adenomas.	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (154, 177))	('pediatric adrenocortical adenomas', 'Disease', (144, 177))	('ACT006', 'Var', (91, 97))	('pediatric adrenocortical adenomas', 'Disease', 'MESH:D018246', (144, 177))	('ACT047', 'Var', (108, 114))	('ACT005', 'Var', (80, 86))	('high levels of MHC class II', 'Phenotype', 'HP:0031391', (31, 58))
69846	27307598	Three of the remaining four ACTs of undetermined histology (ACT034, ACT039 and ACT046) expressed high levels of HLA-DPA1 and are free of disease for more than 2 years.	('HLA-DPA1', 'Gene', (112, 120))	('ACT046', 'Var', (79, 85))	('ACT034', 'Var', (60, 66))	('HLA-DPA1', 'Gene', '3113', (112, 120))
69853	27307598	Overexpression of IGF2 and BUB1B is associated with poor prognosis in adult ACT.	('BUB1B', 'Gene', '701', (27, 32))	('IGF2', 'Gene', (18, 22))	('BUB1B', 'Gene', (27, 32))	('Overexpression', 'Var', (0, 14))	('IGF2', 'Gene', '3481', (18, 22))	('adult ACT', 'Disease', (70, 79))
69856	27307598	Similar to adult ACT and other adult cancers overexpression of BUB1B inversely correlated with progression-free survival in pediatric ACT from both cohorts (P = 0.003) (Supplementary Table 5).	('progression-free survival', 'CPA', (95, 120))	('BUB1B', 'Gene', '701', (63, 68))	('BUB1B', 'Gene', (63, 68))	('overexpression', 'Var', (45, 59))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('inversely', 'NegReg', (69, 78))	('adult cancers', 'Disease', (31, 44))	('adult cancers', 'Disease', 'MESH:C535836', (31, 44))
69862	27307598	In contrast, three ACTs (ACT40, ACT047 and ACT048) displayed focal tumor-cell expression of HLA-DPA1 in addition to the infiltrating hematopoietic cells.	('ACT40', 'Var', (25, 30))	('ACT048', 'Var', (43, 49))	('HLA-DPA1', 'Gene', '3113', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('ACT047', 'Var', (32, 38))	('HLA-DPA1', 'Gene', (92, 100))
69865	27307598	Whether tumor cells expressing MHC class II are capable of participating in regulatory immune mechanisms and have prognostic implications remains to be determined.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MHC class', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('participating', 'Reg', (59, 72))	('tumor', 'Disease', (8, 13))	('regulatory immune', 'MPA', (76, 93))
69881	27957352	reported the first description of NICTH due to aberrant expression of an immature form of IGF-II in a patient with leiomyosarcoma.	('aberrant', 'Var', (47, 55))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (115, 129))	('patient', 'Species', '9606', (102, 109))	('IGF-II', 'Gene', (90, 96))	('IGF-II', 'Gene', '3481', (90, 96))	('leiomyosarcoma', 'Disease', (115, 129))	('NICTH', 'Disease', (34, 39))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (115, 129))
69919	27957352	When we consider that many ACCs are associated with IGF-II overexpression, ACC might be a potential candidate causing NICTH through incomplete processing of pro-IGF-II.	('IGF-II', 'Gene', (52, 58))	('IGF-II', 'Gene', (161, 167))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('IGF-II', 'Gene', '3481', (52, 58))	('overexpression', 'Var', (59, 73))	('IGF-II', 'Gene', '3481', (161, 167))	('ACC', 'Phenotype', 'HP:0006744', (27, 30))	('associated', 'Reg', (36, 46))
69953	27617213	Adrenal metabolic work-up at the time of referral was significant for inappropriate suppression of serum cortisol on low-dose dexamethasone suppression test (8.74 mcg/dL, normal < 5 mcg/dL).	('serum cortisol', 'MPA', (99, 113))	('dexamethasone', 'Chemical', 'MESH:D003907', (126, 139))	('suppression', 'NegReg', (84, 95))	('8.74', 'Var', (158, 162))
69979	26775162	After excluding all patients who received chemotherapy, adjuvant mitotane remained associated with decreased RFS and similar OS; multivariable analyses again showed no association with recurrence or survival.	('decreased', 'NegReg', (99, 108))	('mitotane', 'Var', (65, 73))	('RFS', 'Disease', 'MESH:D005198', (109, 112))	('OS', 'Chemical', '-', (125, 127))	('adjuvant', 'Var', (56, 64))	('mitotane', 'Chemical', 'MESH:D008939', (65, 73))	('patients', 'Species', '9606', (20, 28))	('RFS', 'Disease', (109, 112))
69980	26775162	Stage-specific analyses in both cohorts revealed no association between adjuvant mitotane and improved RFS or OS.	('OS', 'Chemical', '-', (110, 112))	('mitotane', 'Chemical', 'MESH:D008939', (81, 89))	('adjuvant', 'Var', (72, 80))	('RFS', 'Disease', (103, 106))	('RFS', 'Disease', 'MESH:D005198', (103, 106))
69995	26775162	Additionally, mitotane affects hepatic metabolism of other drugs.	('hepatic metabolism of other drugs', 'MPA', (31, 64))	('affects', 'Reg', (23, 30))	('mitotane', 'Var', (14, 22))	('mitotane', 'Chemical', 'MESH:D008939', (14, 22))
70021	26775162	Similarly, on univariate analysis, adjuvant mitotane was associated with decreased OS (31.7 vs 58.9 months; p = 0.01; Fig.	('mitotane', 'Chemical', 'MESH:D008939', (44, 52))	('mitotane', 'Gene', (44, 52))	('adjuvant', 'Var', (35, 43))	('OS', 'Chemical', '-', (83, 85))	('decreased', 'NegReg', (73, 82))
70024	26775162	When the 38 patients who received adjuvant systemic therapy instead of or in addition to mitotane were excluded, adjuvant mitotane remained associated with decreased RFS (9.8 vs 29.4 months; p = 0.01; Fig.	('RFS', 'Disease', 'MESH:D005198', (166, 169))	('patients', 'Species', '9606', (12, 20))	('mitotane', 'Var', (122, 130))	('mitotane', 'Chemical', 'MESH:D008939', (122, 130))	('mitotane', 'Chemical', 'MESH:D008939', (89, 97))	('decreased', 'NegReg', (156, 165))	('RFS', 'Disease', (166, 169))	('adjuvant', 'Var', (113, 121))
70026	26775162	Similarly, after also excluding patients who received radiation therapy from this subgroup (n = 15), such that mitotane was the only adjuvant therapy given, mitotane again was associated with decreased RFS (9.8 vs 31.5 months; p = 0.002) and was not associated with OS (33.2 vs 58.9 months; p = 0.06).	('mitotane', 'Var', (157, 165))	('patients', 'Species', '9606', (32, 40))	('decreased', 'NegReg', (192, 201))	('RFS', 'Disease', (202, 205))	('mitotane', 'Chemical', 'MESH:D008939', (157, 165))	('RFS', 'Disease', 'MESH:D005198', (202, 205))	('mitotane', 'Chemical', 'MESH:D008939', (111, 119))	('OS', 'Chemical', '-', (266, 268))
70040	26775162	Another nonrandomized prospective study of 19 patients who were all offered mitotane treatment revealed that patients who received adjuvant mitotane did not have improved disease-free survival or OS compared with those who did not receive adjuvant mitotane.	('disease-free survival', 'CPA', (171, 192))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (109, 117))	('mitotane', 'Var', (140, 148))	('mitotane', 'Chemical', 'MESH:D008939', (140, 148))	('mitotane', 'Chemical', 'MESH:D008939', (248, 256))	('mitotane', 'Chemical', 'MESH:D008939', (76, 84))	('OS', 'Chemical', '-', (196, 198))
70048	26775162	Patients who received adjuvant mitotane had improved RFS compared with both control groups (mitotane: 42 months vs Italian control: 10 months; p < 0.001; mitotane: 42 months vs German control: 25 months, p = 0.005), and the OS was only improved when compared with the Italian cohort, but not the German control group (mitotane: 110 months vs Italian control: 52 months; p = 0.01; mitotane: 110 months vs German control: 67 months; p = 0.10).	('mitotane', 'Chemical', 'MESH:D008939', (92, 100))	('mitotane', 'Chemical', 'MESH:D008939', (318, 326))	('OS', 'Chemical', '-', (224, 226))	('mitotane', 'Var', (31, 39))	('RFS', 'Disease', 'MESH:D005198', (53, 56))	('mitotane', 'Chemical', 'MESH:D008939', (154, 162))	('mitotane', 'Chemical', 'MESH:D008939', (380, 388))	('mitotane', 'Chemical', 'MESH:D008939', (31, 39))	('Patients', 'Species', '9606', (0, 8))	('improved', 'PosReg', (44, 52))	('RFS', 'Disease', (53, 56))
70055	26775162	Mitotane can be associated with severe toxicity and side effects including lethargy, somnolence, vertigo, nausea, vomiting, diarrhea, anorexia, hematologic changes, and endocrine abnormalities.	('endocrine abnormalities', 'Disease', (169, 192))	('nausea', 'Phenotype', 'HP:0002018', (106, 112))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('diarrhea', 'Disease', (124, 132))	('vertigo', 'Phenotype', 'HP:0002321', (97, 104))	('endocrine abnormalities', 'Disease', 'MESH:D004700', (169, 192))	('toxicity', 'Disease', 'MESH:D064420', (39, 47))	('anorexia', 'Disease', (134, 142))	('lethargy', 'Disease', (75, 83))	('hematologic changes', 'Phenotype', 'HP:0001871', (144, 163))	('lethargy', 'Phenotype', 'HP:0001254', (75, 83))	('nausea', 'Disease', (106, 112))	('diarrhea', 'Disease', 'MESH:D003967', (124, 132))	('vomiting', 'Disease', 'MESH:D014839', (114, 122))	('toxicity', 'Disease', (39, 47))	('Mitotane', 'Var', (0, 8))	('lethargy', 'Disease', 'MESH:D053609', (75, 83))	('nausea', 'Disease', 'MESH:D009325', (106, 112))	('vertigo', 'Disease', (97, 104))	('vertigo', 'Disease', 'MESH:D014717', (97, 104))	('somnolence', 'Disease', 'MESH:D006970', (85, 95))	('vomiting', 'Phenotype', 'HP:0002013', (114, 122))	('anorexia', 'Disease', 'MESH:D000855', (134, 142))	('vomiting', 'Disease', (114, 122))	('hematologic changes', 'Disease', (144, 163))	('somnolence', 'Disease', (85, 95))	('diarrhea', 'Phenotype', 'HP:0002014', (124, 132))	('endocrine abnormalities', 'Phenotype', 'HP:0000818', (169, 192))	('anorexia', 'Phenotype', 'HP:0002039', (134, 142))
70057	26775162	In a subgroup analysis of these high-risk patients for whom mitotane is recommended, however, mitotane still was not associated with improved RFS or OS in the current study.	('OS', 'Chemical', '-', (149, 151))	('RFS', 'Disease', (142, 145))	('mitotane', 'Var', (94, 102))	('mitotane', 'Chemical', 'MESH:D008939', (94, 102))	('patients', 'Species', '9606', (42, 50))	('RFS', 'Disease', 'MESH:D005198', (142, 145))	('mitotane', 'Chemical', 'MESH:D008939', (60, 68))
70101	24616598	Nuclear cellular atypia with enlarged nuclei were identified (x200, x400 High Power Field [HPF], hematoxylin and eosin [H&E], Fig.	('H&E', 'Chemical', '-', (120, 123))	('hematoxylin', 'Chemical', 'MESH:D006416', (97, 108))	('x200', 'Var', (62, 66))	('x400', 'Var', (68, 72))	('eosin', 'Chemical', 'MESH:D004801', (113, 118))
70154	24066089	Single Nucleotide Polymorphism Array Profiling of Adrenocortical Tumors - Evidence for an Adenoma Carcinoma Sequence?	('Carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('Single Nucleotide Polymorphism', 'Var', (0, 30))	('Tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Adrenocortical Tumors', 'Disease', (50, 71))	('Adrenocortical Tumors', 'Disease', 'MESH:D018268', (50, 71))	('Tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Adenoma Carcinoma', 'Disease', (90, 107))	('Adenoma Carcinoma', 'Disease', 'MESH:D000236', (90, 107))
70158	24066089	The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%).	('benign tumors', 'Disease', 'MESH:D009369', (64, 77))	('malignant tumors', 'Disease', 'MESH:D018198', (4, 20))	('CNAs >100 Kb', 'Var', (141, 153))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('malignant tumors', 'Disease', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('benign tumors', 'Disease', (64, 77))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
70175	24066089	For instance, microsatellite markers revealed common inactivating mutations or loss of heterozygosity (LOH) at 17p13, a region that includes the TP53 tumor suppressor gene, LOH at 11q13 (MEN1 locus), and alterations of the imprinted 11p15 locus (paternal isodisomy) leading to IGF2 overexpression.	('loss of heterozygosity', 'NegReg', (79, 101))	('alterations', 'Var', (204, 215))	('MEN1', 'Gene', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('TP53', 'Gene', '7157', (145, 149))	('MEN1', 'Gene', '4221', (187, 191))	('TP53', 'Gene', (145, 149))	('LOH at', 'Var', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('overexpression', 'PosReg', (282, 296))	('IGF2', 'Gene', (277, 281))	('tumor', 'Disease', (150, 155))
70177	24066089	Copy number alterations (CNAs) have also been described in adrenal hyperplasia, ACA and ACC using fluorescence in situ hybridization (FISH), karyotyping, and either conventional comparative genomic hybridization (CGH) or array-based CGH.	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (59, 78))	('ACA', 'Disease', (80, 83))	('ACC', 'Disease', (88, 91))	('Copy number alterations', 'Var', (0, 23))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (59, 78))	('adrenal hyperplasia', 'Disease', (59, 78))
70182	24066089	By merging these two analyses, it is possible to identify copy neutral LOH (cnLOH, or uniparental disomy, UPD), a chromosomal defect which comprises 50-70% of all LOH events detected in human tumors.	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('chromosomal defect', 'Phenotype', 'HP:0040012', (114, 132))	('uniparental disomy', 'Disease', (86, 104))	('human', 'Species', '9606', (186, 191))	('uniparental disomy', 'Disease', 'MESH:D024182', (86, 104))	('UPD', 'Gene', '7389', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('UPD', 'Gene', (106, 109))	('copy neutral', 'Var', (58, 70))
70183	24066089	Furthermore, recent high resolution SNP array platforms can identify amplifications/deletions at a single gene level, offering a powerful method for oncogene and tumor suppressor gene discovery.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('amplifications/deletions', 'Var', (69, 93))
70184	24066089	Recently, we applied this method to investigate the genetic events in a group of 15 benign cortisol-secreting tumors, detecting several recurrent CN gains and losses, mostly microalterations, in both already known and newly identified chromosomal regions.	('losses', 'NegReg', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('CN gains', 'Var', (146, 154))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('cortisol', 'Chemical', 'MESH:D006854', (91, 99))
70209	24066089	The probes chosen for the region 5q-5p, largely amplified in ACC according to the SNP array results, were CSF1R/D5S23 and D5S721.	('CSF1R', 'Gene', '1436', (106, 111))	('D5S721', 'Var', (122, 128))	('CSF1R', 'Gene', (106, 111))
70211	24066089	Endogenously expressed beta-actin (Hs9999903_m1) was used for normalization.	('beta-actin', 'Gene', (23, 33))	('Hs9999903_m1', 'Var', (35, 47))	('beta-actin', 'Gene', '728378', (23, 33))
70219	24066089	The genetic alterations at the chr 5 were further validated by FISH analysis (Figure 1B ), which confirmed the presence of 5p/5q amplifications in 10/10 ACCs (>50% of evaluated cells in 8/10 ACCs).	('5p/5q amplifications', 'Var', (123, 143))	('ACCs', 'Gene', '84680', (191, 195))	('ACCs', 'Gene', (191, 195))	('ACCs', 'Gene', (153, 157))	('ACCs', 'Gene', '84680', (153, 157))
70220	24066089	In addition, 5p/5q amplifications were also observed by FISH in 3/12 ACAs (P<0.05 vs ACC), but only one benign tumor showed this alteration in >50% of evaluated cells.	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('5p/5q amplifications', 'Var', (13, 33))
70222	24066089	These results imply a role for the amplification of almost the entire chr 5 in adrenocortical tumorigenesis and suggest it as a new potential diagnostic marker.	('amplification', 'Var', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (79, 107))	('adrenocortical tumorigenesis', 'Disease', (79, 107))	('chr 5', 'Gene', (70, 75))
70228	24066089	Only few recurrent CN gains, involving 13 chromosomal regions, were detected only in benign tumors, but not in ACC.	('CN gains', 'Var', (19, 27))	('benign tumors', 'Disease', 'MESH:D009369', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('benign tumors', 'Disease', (85, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
70230	24066089	Interestingly, most of these regions were also altered among ACCs, but they were affected by losses instead of gains (excluding chr 2q24.2, 3p24.1, 8q24.3, 10q24.32).	('ACCs', 'Gene', (61, 65))	('gains', 'PosReg', (111, 116))	('losses', 'NegReg', (93, 99))	('10q24.32', 'Var', (156, 164))	('3p24.1', 'Var', (140, 146))	('chr', 'Var', (128, 131))	('ACCs', 'Gene', '84680', (61, 65))
70241	24066089	A number of these genes (n=18) have been previously associated with resistance to chemotherapy in other cancer types (i.e.	('resistance to chemotherapy', 'MPA', (68, 94))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('genes', 'Var', (18, 23))	('associated with', 'Reg', (52, 67))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
70251	24066089	Finally, the pathway analysis showed as most affected by cnLOH the cytoskeleton remodeling (TGF, WNT, and cytoskeleton remodeling, P<0.0001), immune response (HSP60 and 70/TLR, P<0.0001, and HMGB1/TLR signaling, P<0.001), and cell adhesion (chemokines and adhesion, P<0.001).	('HSP60', 'Gene', (159, 164))	('HSP60', 'Gene', '3329', (159, 164))	('HMGB1', 'Gene', (191, 196))	('cnLOH', 'Var', (57, 62))	('cell adhesion', 'CPA', (226, 239))	('HMGB1', 'Gene', '3146', (191, 196))
70254	24066089	In particular, the tumors included in the clusters 1a (n=8) and 1b (n=5) behaved quite similar presenting several large amplification at chr 5, 7, 12, and 19, and large deletions at chr 1, 2, 13, 17, and 22, while the 9 other tumors showed an extremely variable pattern of genetic alterations.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('large deletions', 'Var', (163, 178))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
70261	24066089	Moreover, we recognize some genetic aberrations specific for ACC, such as the amplification of the chr 5, recurrent large CNA (mostly losses), and frequent LOH and cnLOH events distributed all over the genome, that could be used as markers of malignancy.	('amplification', 'Var', (78, 91))	('losses', 'NegReg', (134, 140))	('chr 5', 'Gene', (99, 104))	('ACC', 'Disease', (61, 64))	('malignancy', 'Disease', 'MESH:D009369', (243, 253))	('malignancy', 'Disease', (243, 253))
70269	24066089	Finally, recurrent gains at 8q24, 9q33-34 and 19p13-q13 have been also similarly reported in childhood adrenocortical tumors.	('gains', 'PosReg', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (103, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('adrenocortical tumors', 'Disease', (103, 124))	('19p13-q13', 'Gene', (46, 55))	('9q33-34', 'Var', (34, 41))
70274	24066089	Specifically, we observed in this region (including the genes IGF2, IGF2AS, INS, INS-IGF2, and MIR483) frequent cnLOH or LOH associated with CN loss in ACC (54% and 23% of cases, respectively) and CN gains in 25% of ACA.	('IGF2', 'Gene', (62, 66))	('INS-IGF2', 'Gene', (81, 89))	('IGF2AS', 'Gene', (68, 74))	('gains', 'PosReg', (200, 205))	('INS-IGF2', 'Gene', '723961;3481', (81, 89))	('LOH', 'Var', (121, 124))	('INS', 'Gene', (76, 79))	('MIR483', 'Gene', (95, 101))	('IGF2AS', 'Gene', '51214', (68, 74))	('MIR483', 'Gene', '619552', (95, 101))	('INS', 'Gene', '723961', (76, 79))	('INS', 'Gene', (81, 84))	('cnLOH', 'Var', (112, 117))	('INS', 'Gene', '723961', (81, 84))	('loss', 'NegReg', (144, 148))	('ACA', 'Disease', (216, 219))
70277	24066089	Aberrations of the 11p15 region were found in both Beckwith-Wiedemann and Silver-Russell syndromes, and were also reported by SNP array profiling in childhood adrenocortical tumors.	('Silver-Russell syndromes', 'Disease', (74, 98))	('adrenocortical tumors', 'Disease', (159, 180))	('found', 'Reg', (37, 42))	('11p15', 'Gene', (19, 24))	('Beckwith-Wiedemann', 'Disease', (51, 69))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (159, 180))	('Beckwith-Wiedemann', 'Disease', 'MESH:D001506', (51, 69))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Aberrations', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
70284	24066089	A series of genetic alterations detected with the SNP array analysis were found to be unique in malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('malignant tumors', 'Disease', (96, 112))	('genetic alterations', 'Var', (12, 31))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('malignant tumors', 'Disease', 'MESH:D018198', (96, 112))
70286	24066089	CN gain of chr 5p) have been already reported in other cancer types, such as the cervical cancer, and also in adrenocortical cancer, but only together with other chromosomes (i.e.	('adrenocortical cancer', 'Disease', (110, 131))	('chr 5p', 'Gene', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('CN gain', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (110, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (55, 61))
70294	24066089	Our findings suggest a potential major role for these alterations in early tumorigenesis and provide new insight on a postulated adenoma-carcinoma sequence in adrenocortical tumors.	('tumor', 'Disease', (174, 179))	('adenoma-carcinoma', 'Disease', (129, 146))	('adrenocortical tumors', 'Disease', (159, 180))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('alterations', 'Var', (54, 65))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (159, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (129, 146))	('tumor', 'Disease', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
70306	23333623	In the former, membrane-bound PI-bisphosphate (PIP2) is cleaved by PLC to yield inositol trisphosphate (IP3) and DAG; IP3 is released into the cytoplasm and triggers the release of Ca2+ from the endoplasmic reticulum, while DAG remains in the plasma membrane and activates PKC.	('Ca2+', 'Chemical', 'MESH:D000069285', (181, 185))	('DAG', 'Chemical', 'MESH:D004075', (113, 116))	('PKC', 'Enzyme', (273, 276))	('inositol trisphosphate', 'Chemical', '-', (80, 102))	('release', 'MPA', (170, 177))	('IP3', 'Var', (118, 121))	('IP3', 'Chemical', 'MESH:D015544', (104, 107))	('activates', 'PosReg', (263, 272))	('DAG', 'Chemical', 'MESH:D004075', (224, 227))	('IP3', 'Chemical', 'MESH:D015544', (118, 121))	('PI-bisphosphate', 'Chemical', '-', (30, 45))	('orm', 'Gene', (8, 11))	('Ca2+', 'MPA', (181, 185))	('PL', 'Chemical', 'MESH:D010743', (67, 69))	('orm', 'Gene', '5004', (8, 11))	('PIP2', 'Chemical', 'MESH:D019269', (47, 51))
70333	23333623	Disruption of the LRH-1 gene in mice leads to the loss of Oct4 expression in the epiblast, causing lethality at embryonic day 6.5.	('loss', 'NegReg', (50, 54))	('lethality at embryonic', 'CPA', (99, 121))	('expression', 'MPA', (63, 73))	('LRH-1', 'Gene', '2494', (18, 23))	('LRH-1', 'Gene', (18, 23))	('Oct4', 'Protein', (58, 62))	('1 ', 'Gene', '2516', (22, 24))	('mice', 'Species', '10090', (32, 36))	('Disruption', 'Var', (0, 10))
70341	23333623	Disruption of the LRH-1 gene in healthy livers not only disrupted lipogenesis but resulted in reduced glycogen synthesis and glycolysis in response to acute and prolonged glucose exposure.	('glycolysis', 'MPA', (125, 135))	('reduced', 'NegReg', (94, 101))	('reduced glycogen synthesis', 'Phenotype', 'HP:0012270', (94, 120))	('glycogen synthesis', 'MPA', (102, 120))	('LRH-1', 'Gene', '2494', (18, 23))	('LRH-1', 'Gene', (18, 23))	('lipogenesis', 'MPA', (66, 77))	('1 ', 'Gene', '2516', (22, 24))	('response to acute', 'MPA', (139, 156))	('disrupted', 'NegReg', (56, 65))	('glucose', 'Chemical', 'MESH:D005947', (171, 178))	('glycogen', 'Chemical', 'MESH:D006003', (102, 110))	('Disruption', 'Var', (0, 10))
70352	23333623	Mutations designed to reduce PL binding showed decreased transcriptional activity in reporter gene assays and a decrease in the ability to recruit coregulators and coregulator fragments both in vitro and in cells.	('recruit', 'Interaction', (139, 146))	('reduce', 'NegReg', (22, 28))	('decrease', 'NegReg', (112, 120))	('PL', 'Chemical', 'MESH:D010743', (29, 31))	('transcriptional activity', 'MPA', (57, 81))	('Mutations', 'Var', (0, 9))	('binding', 'Interaction', (32, 39))	('ability', 'MPA', (128, 135))	('reporter gene assays', 'MPA', (85, 105))	('decreased', 'NegReg', (47, 56))
70357	23333623	LBP mutations designed to prevent lipid binding decreased the ability of LRH-1 to bind these immobilized lipids.	('lipid', 'Chemical', 'MESH:D008055', (34, 39))	('1 ', 'Gene', '2516', (77, 79))	('decreased', 'NegReg', (48, 57))	('ability', 'MPA', (62, 69))	('bind', 'Interaction', (82, 86))	('lipids', 'Chemical', 'MESH:D008055', (105, 111))	('mutations', 'Var', (4, 13))	('LRH-1', 'Gene', '2494', (73, 78))	('LRH-1', 'Gene', (73, 78))	('lipid', 'Chemical', 'MESH:D008055', (105, 110))
70359	23333623	showed that both human and mouse LRH-1 are specifically activated by the exogenous medium chain phosphatidylcholine isoforms - diundecanoyl (DUPC, PC 11:0/11:0) and dilauroyl (DLPC, PC 12:0/12:0) phosphatidylcholine.	('orm', 'Gene', '5004', (120, 123))	('dilauroyl', 'Chemical', '-', (165, 174))	('human', 'Species', '9606', (17, 22))	('orm', 'Gene', (120, 123))	('mouse', 'Species', '10090', (27, 32))	('PC', 'Chemical', '-', (182, 184))	('LRH-1', 'Gene', '2494', (33, 38))	('diundecanoyl', 'Chemical', '-', (127, 139))	('dilauroyl', 'Var', (165, 174))	('DUPC', 'Chemical', '-', (141, 145))	('phosphatidylcholine', 'Chemical', 'MESH:D010713', (196, 215))	('PC', 'Chemical', '-', (143, 145))	('phosphatidylcholine', 'Chemical', 'MESH:D010713', (96, 115))	('PC', 'Chemical', '-', (178, 180))	('1 ', 'Gene', '2516', (37, 39))	('activated', 'PosReg', (56, 65))	('PC', 'Chemical', '-', (147, 149))	('LRH-1', 'Gene', (33, 38))
70361	23333623	Moreover, DLPC lowers serum lipid levels and reduces blood glucose levels in diabetic mice in a LRH-1 dependent manner.	('diabetic', 'Disease', 'MESH:D003920', (77, 85))	('serum lipid levels', 'MPA', (22, 40))	('PC', 'Chemical', '-', (12, 14))	('1 ', 'Gene', '2516', (100, 102))	('blood glucose levels', 'MPA', (53, 73))	('reduces', 'NegReg', (45, 52))	('diabetic', 'Disease', (77, 85))	('lipid', 'Chemical', 'MESH:D008055', (28, 33))	('LRH-1', 'Gene', '2494', (96, 101))	('reduces blood glucose', 'Phenotype', 'HP:0001943', (45, 66))	('mice', 'Species', '10090', (86, 90))	('glucose', 'Chemical', 'MESH:D005947', (59, 66))	('LRH-1', 'Gene', (96, 101))	('lowers', 'NegReg', (15, 21))	('DLPC', 'Var', (10, 14))
70364	23333623	DLPC simultaneously enhanced co-activator peptide recruitment while disfavoring repressor peptide interaction.	('DLPC', 'Var', (0, 4))	('repressor peptide interaction', 'MPA', (80, 109))	('enhanced', 'PosReg', (20, 28))	('PC', 'Chemical', '-', (2, 4))	('co-activator peptide recruitment', 'MPA', (29, 61))
70369	23333623	Dysfunction of SF-1 has been linked to a number of human disorders.	('human', 'Species', '9606', (51, 56))	('1 ', 'Gene', '2516', (18, 20))	('linked', 'Reg', (29, 35))	('Dysfunction', 'Var', (0, 11))
70370	23333623	Mutations in SF-1 have been detected in patients with disorders in sexual development, ovarian insufficiency, and adrenal failure, while SF-1 dysregulation has been linked to endometriosis and adrenocortical carcinoma.	('endometriosis and adrenocortical carcinoma', 'Disease', 'MESH:D018268', (175, 217))	('detected', 'Reg', (28, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('patients', 'Species', '9606', (40, 48))	('ovarian insufficiency', 'Disease', (87, 108))	('endometriosis', 'Phenotype', 'HP:0030127', (175, 188))	('ovarian insufficiency', 'Phenotype', 'HP:0008209', (87, 108))	('adrenal failure', 'Phenotype', 'HP:0000846', (114, 129))	('adrenal failure', 'Disease', 'MESH:D000312', (114, 129))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (193, 217))	('Mutations', 'Var', (0, 9))	('adrenal failure', 'Disease', (114, 129))	('1 ', 'Gene', '2516', (16, 18))	('sexual development', 'CPA', (67, 85))	('ovarian insufficiency', 'Disease', 'MESH:D016649', (87, 108))	('1 ', 'Gene', '2516', (140, 142))	('linked', 'Reg', (165, 171))
70375	23333623	These results indicate that pharmacological modulation of SF-1 may be a viable strategy in treating adrenocortical carcinomas, and possibly other human diseases.	('adrenocortical carcinomas', 'Disease', (100, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (100, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (100, 125))	('pharmacological modulation', 'Var', (28, 54))	('human', 'Species', '9606', (146, 151))	('1 ', 'Gene', '2516', (61, 63))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (100, 125))
70382	23333623	Further analysis showed that sphingosine acts as a SF-1 antagonist, blocking cAMP-stimulated CYP17 reporter gene activity and coactivator recruitment, which could be negated by inhibiting the acid ceramidases that produce sphingosine from ceramide, or by introducing mutations into the LBP that abrogated sphingosine binding.	('inhibiting', 'NegReg', (177, 187))	('coactivator recruitment', 'MPA', (126, 149))	('sphingosine', 'Chemical', 'MESH:D013110', (222, 233))	('ceramide', 'Chemical', 'MESH:D002518', (239, 247))	('cAMP', 'Chemical', 'MESH:D000242', (77, 81))	('CYP17', 'Gene', (93, 98))	('sphingosine', 'Chemical', 'MESH:D013110', (29, 40))	('mutations', 'Var', (267, 276))	('binding', 'Interaction', (317, 324))	('sphingosine', 'Chemical', 'MESH:D013110', (305, 316))	('abrogated', 'NegReg', (295, 304))	('activity', 'MPA', (113, 121))	('CYP17', 'Gene', '1586', (93, 98))	('LBP', 'Gene', (286, 289))	('1 ', 'Gene', '2516', (54, 56))	('acid ceramidases', 'Enzyme', (192, 208))	('blocking', 'NegReg', (68, 76))
70388	23333623	Mutations to these residues greatly impaired exchange of bacterial PG with PIP2 and PIP3 and diminished SF-1 transcriptional activity, suggesting that the binding of PIPs to SF- 1 is a biologically relevant interaction.	('1 ', 'Gene', '2516', (178, 180))	('impaired', 'NegReg', (36, 44))	('PIPs', 'Chemical', 'MESH:C032727', (166, 170))	('exchange', 'MPA', (45, 53))	('PIP3', 'Chemical', '-', (84, 88))	('PG', 'Chemical', '-', (67, 69))	('1 ', 'Gene', '2516', (107, 109))	('bacterial', 'Protein', (57, 66))	('Mutations', 'Var', (0, 9))	('PIP2', 'Chemical', 'MESH:D019269', (75, 79))	('diminished', 'NegReg', (93, 103))
70389	23333623	Indeed, IPMK phosphorylates PIP2 only when bound to SF-1, increasing downstream gene transcription; likewise, PTEN cleaves PIP3 only when complexed with SF-1, attenuating downstream activity.	('attenuating', 'NegReg', (159, 170))	('PIP2', 'Chemical', 'MESH:D019269', (28, 32))	('PIP3', 'Chemical', '-', (123, 127))	('increasing', 'PosReg', (58, 68))	('downstream activity', 'MPA', (171, 190))	('cleaves', 'Var', (115, 122))	('PIP3', 'Protein', (123, 127))	('downstream gene transcription', 'MPA', (69, 98))
70422	23333623	In addition to direct NR-mediated gene expression, PLs have been shown to indirectly affect gene regulation through lipid shuttling proteins such as phosphatidylcholine transfer protein (PC-TP).	('phosphatidylcholine', 'Chemical', 'MESH:D010713', (149, 168))	('lipid', 'Chemical', 'MESH:D008055', (116, 121))	('PC', 'Chemical', '-', (187, 189))	('PLs', 'Var', (51, 54))	('phosphatidylcholine transfer protein', 'MPA', (149, 185))	('affect', 'Reg', (85, 91))	('lipid shuttling proteins', 'MPA', (116, 140))	('PLs', 'Chemical', 'MESH:D010743', (51, 54))	('gene regulation', 'MPA', (92, 107))
70428	23333623	In addition to PPAR-alpha regulating the expression of PC-TP, PC-TP was shown to upregulate the transcriptional activity of both PPAR-alpha and HNF-4alpha.	('PC-TP', 'Var', (62, 67))	('PC', 'Chemical', '-', (55, 57))	('transcriptional activity', 'MPA', (96, 120))	('PPAR-alpha', 'Gene', (129, 139))	('upregulate', 'PosReg', (81, 91))	('PA', 'Chemical', 'MESH:D011478', (130, 132))	('HNF-4alpha', 'Protein', (144, 154))	('PA', 'Chemical', 'MESH:D011478', (16, 18))	('PC', 'Chemical', '-', (62, 64))
70443	23333623	The binding and presentation of both PC and PI by CD1b and CD1d, respectively, is remarkably similar to the presentation of PLs by NRs (Fig.	('CD1b', 'Var', (50, 54))	('PLs', 'Chemical', 'MESH:D010743', (124, 127))	('PC', 'Chemical', '-', (37, 39))	('CD1d', 'Var', (59, 63))
70458	23333623	NR mediated gene program alteration, whether by responding to cellular PL content, PL delivery by transporters, or in place PL modification, connects PL levels not only to glucose and lipid homeostasis but to steroid synthesis, reproduction, inflammation, development and cell differentiation (Fig.	('steroid', 'Chemical', 'MESH:D013256', (209, 216))	('development', 'CPA', (256, 267))	('inflammation', 'Disease', 'MESH:D007249', (242, 254))	('inflammation', 'Disease', (242, 254))	('cell differentiation', 'CPA', (272, 292))	('PL', 'Chemical', 'MESH:D010743', (83, 85))	('PL', 'Chemical', 'MESH:D010743', (124, 126))	('PL', 'Chemical', 'MESH:D010743', (71, 73))	('PL', 'Chemical', 'MESH:D010743', (150, 152))	('gene program', 'Gene', (12, 24))	('alteration', 'Var', (25, 35))	('lipid', 'Chemical', 'MESH:D008055', (184, 189))	('glucose', 'Chemical', 'MESH:D005947', (172, 179))
70460	23333623	Clearly, modulating PL-driven transcriptional pathways remains an untapped therapeutic opportunity and advances in this area of research are desperately needed.	('PL', 'Chemical', 'MESH:D010743', (20, 22))	('modulating', 'Var', (9, 19))	('PL-driven transcriptional pathways', 'Pathway', (20, 54))
70461	18762572	Identification of a Novel TP53 Germline Mutation E285V in a Rare Case of Pediatric Adrenocortical Carcinoma and Choroid Plexus Carcinoma Pediatric choroid plexus carcinomas (CPC) and adrenocortical carcinomas (ACC) are exceedingly rare tumors, each occurring at an annual rate of 0.3 cases per million children or less.	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (183, 208))	('CPC', 'Phenotype', 'HP:0030392', (174, 177))	('adrenocortical carcinomas', 'Disease', (183, 208))	('Pediatric Adrenocortical Carcinoma and Choroid Plexus Carcinoma', 'Disease', 'MESH:C565972', (73, 136))	('Carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('TP53', 'Gene', '7157', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('Pediatric choroid plexus carcinomas', 'Disease', (137, 172))	('Choroid Plexus Carcinoma', 'Phenotype', 'HP:0030392', (112, 136))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (183, 208))	('Pediatric choroid plexus carcinomas', 'Disease', 'MESH:D020288', (137, 172))	('E285V', 'SUBSTITUTION', 'None', (49, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (236, 242))	('Carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('children', 'Species', '9606', (302, 310))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('TP53', 'Gene', (26, 30))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (83, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('E285V', 'Var', (49, 54))	('ACC', 'Phenotype', 'HP:0006744', (210, 213))	('choroid plexus carcinomas', 'Phenotype', 'HP:0030392', (147, 172))
70462	18762572	Although both tumor types are associated with Li-Fraumeni Syndrome (LFS), the penetrance of germline TP53 mutations in CPC remains to be established.	('associated', 'Reg', (30, 40))	('CPC', 'Phenotype', 'HP:0030392', (119, 122))	('LFS', 'Disease', (68, 71))	('tumor', 'Disease', (14, 19))	('TP53', 'Gene', '7157', (101, 105))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (46, 66))	('TP53', 'Gene', (101, 105))	('LFS', 'Disease', 'MESH:D016864', (68, 71))	('mutations', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('Li-Fraumeni Syndrome', 'Disease', (46, 66))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
70464	18762572	Genetic testing revealed a novel de novo germline TP53 mutation (E285V).	('TP53', 'Gene', '7157', (50, 54))	('E285V', 'Var', (65, 70))	('E285V', 'SUBSTITUTION', 'None', (65, 70))	('TP53', 'Gene', (50, 54))
70466	18762572	Consistent with this observation, functional analyses demonstrated that E285V acts as a dominant-negative mutant that is defective in regulating target gene expression, growth suppression and apoptosis.	('expression', 'Species', '29278', (157, 167))	('E285V', 'Var', (72, 77))	('apoptosis', 'CPA', (192, 201))	('growth suppression', 'CPA', (169, 187))	('E285V', 'SUBSTITUTION', 'None', (72, 77))
70467	18762572	These results further strengthen the association between germline TP53 mutations and childhood CPC, even when occurring in the absence of familial tumor susceptibility.	('childhood CPC', 'Disease', (85, 98))	('germline', 'Var', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('familial tumor', 'Disease', 'MESH:D009386', (138, 152))	('familial tumor', 'Disease', (138, 152))	('mutations', 'Var', (71, 80))	('child', 'Species', '9606', (85, 90))	('CPC', 'Phenotype', 'HP:0030392', (95, 98))
70471	18762572	LFS is usually associated with germline TP53 mutations that predispose carriers to diverse tumor types at a young age.	('mutations', 'Var', (45, 54))	('LFS', 'Disease', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('predispose', 'Reg', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('LFS', 'Disease', 'MESH:D016864', (0, 3))	('tumor', 'Disease', (91, 96))
70472	18762572	However, pediatric ACC can also occur in association with a germline TP53 mutation without a family history of cancer, suggesting the existence of de novo and/or low penetrance TP53 mutations.	('mutation', 'Var', (74, 82))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('ACC', 'Phenotype', 'HP:0006744', (19, 22))	('TP53', 'Gene', '7157', (177, 181))	('pediatric ACC', 'Disease', (9, 22))	('occur', 'Reg', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('TP53', 'Gene', (177, 181))	('germline', 'Var', (60, 68))
70473	18762572	To our knowledge only two pediatric cases of combined CPC and ACC have been previously reported, one of which is believed to be related to a germline TP53 mutation based on strong nuclear staining of p53 in the tumors and surrounding normal tissue.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('TP53', 'Gene', (150, 154))	('p53', 'Gene', (200, 203))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('p53', 'Gene', '7157', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('mutation', 'Var', (155, 163))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('CPC', 'Phenotype', 'HP:0030392', (54, 57))	('tumors', 'Disease', (211, 217))	('TP53', 'Gene', '7157', (150, 154))
70475	18762572	We report here a young boy with no family history of cancer who was diagnosed with CPC and ACC, and harbored a novel de novo germline TP53 mutation (E285V).	('boy', 'Species', '9606', (23, 26))	('CPC', 'Disease', (83, 86))	('TP53', 'Gene', (134, 138))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('ACC', 'Phenotype', 'HP:0006744', (91, 94))	('ACC', 'Disease', (91, 94))	('CPC', 'Phenotype', 'HP:0030392', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('E285V', 'Var', (149, 154))	('E285V', 'SUBSTITUTION', 'None', (149, 154))	('TP53', 'Gene', '7157', (134, 138))
70476	18762572	Detailed molecular and biochemical analyses demonstrated that TP53-E285V has lost tumor suppressor activity, and functions as a dominant-negative mutant.	('lost', 'NegReg', (77, 81))	('TP53', 'Gene', '7157', (62, 66))	('E285V', 'SUBSTITUTION', 'None', (67, 72))	('TP53', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('E285V', 'Var', (67, 72))
70477	18762572	These results further implicate constitutional TP53 mutations in the genesis of CPC, as well as childhood ACC, and support the genetic testing of individuals for TP53 alterations in these settings regardless of family cancer history.	('mutations', 'Var', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('implicate', 'Reg', (22, 31))	('cancer', 'Disease', (218, 224))	('CPC', 'Disease', (80, 83))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('TP53', 'Gene', '7157', (47, 51))	('ACC', 'Phenotype', 'HP:0006744', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('childhood ACC', 'Disease', (96, 109))	('CPC', 'Phenotype', 'HP:0030392', (80, 83))	('TP53', 'Gene', (47, 51))	('child', 'Species', '9606', (96, 101))
70478	18762572	T.D was the second child born at term to parents without a medical history suggestive of familial cancer predisposition.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('familial cancer', 'Disease', (89, 104))	('child', 'Species', '9606', (19, 24))	('familial cancer', 'Disease', 'MESH:D009369', (89, 104))	('T.D', 'Var', (0, 3))
70492	18762572	SaOS2 cells were transfected in duplicate with 1 microg CMV-Neo-Bam (CMV; empty vector) or CMV-expressing wild-type p53 (WT), E285V or R175H and selected in medium containing 800 ng/ml G418 antibiotic (Invitrogen, Carlsbad, CA) for up to 21 days as previously described.	('SaOS2', 'CellLine', 'CVCL:0548', (0, 5))	('p53', 'Gene', (116, 119))	('R175H', 'Mutation', 'rs28934578', (135, 140))	('E285V', 'Var', (126, 131))	('G418', 'Chemical', 'MESH:C010680', (185, 189))	('R175H', 'Var', (135, 140))	('E285V', 'SUBSTITUTION', 'None', (126, 131))	('p53', 'Gene', '7157', (116, 119))
70494	18762572	SaOS2 cells were transfected in duplicate with 150 ng wild-type p53-responsive p50-2Luc promoter-reporter and 1 microg CMV or WT, E285V, R175H, R273H or R248W as previously described.	('SaOS2', 'CellLine', 'CVCL:0548', (0, 5))	('E285V', 'Var', (130, 135))	('R175H', 'Var', (137, 142))	('R175H', 'Mutation', 'rs28934578', (137, 142))	('E285V', 'SUBSTITUTION', 'None', (130, 135))	('R248W', 'Mutation', 'rs121912651', (153, 158))	('R248W', 'Var', (153, 158))	('p53', 'Gene', (64, 67))	('R273H', 'Var', (144, 149))	('R273H', 'Mutation', 'rs28934576', (144, 149))	('p53', 'Gene', '7157', (64, 67))
70498	18762572	The ACC and CPC samples remained heterozygous for the TP53-E285V mutation, indicating that there was no selection against the wild-type allele (Fig.	('E285V', 'Var', (59, 64))	('E285V', 'SUBSTITUTION', 'None', (59, 64))	('TP53', 'Gene', '7157', (54, 58))	('ACC', 'Phenotype', 'HP:0006744', (4, 7))	('CPC', 'Phenotype', 'HP:0030392', (12, 15))	('TP53', 'Gene', (54, 58))
70500	18762572	Immunohistochemical analysis showed strong positive staining for p53 in the nuclei of both the ACC and CPC cells, which is consistent with these tumors expressing mutant TP53-E285V (Fig.	('p53', 'Gene', (65, 68))	('E285V', 'Var', (175, 180))	('p53', 'Gene', '7157', (65, 68))	('ACC', 'Phenotype', 'HP:0006744', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('E285V', 'SUBSTITUTION', 'None', (175, 180))	('tumors', 'Disease', (145, 151))	('TP53', 'Gene', '7157', (170, 174))	('TP53', 'Gene', (170, 174))	('CPC', 'Phenotype', 'HP:0030392', (103, 106))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))
70501	18762572	The capacity of the E285V mutant to regulate gene expression was tested in a standard promoter-reporter assay.	('E285V', 'SUBSTITUTION', 'None', (20, 25))	('regulate gene expression', 'MPA', (36, 60))	('E285V', 'Var', (20, 25))	('expression', 'Species', '29278', (50, 60))
70502	18762572	3, wild-type p53 (WT) efficiently induced promoter activity, whereas each of the established mutants R175H, R273H and R248W, as well as the novel mutant E285V, was inactive (upper panel).	('R273H', 'Var', (108, 113))	('induced', 'PosReg', (34, 41))	('R273H', 'Mutation', 'rs28934576', (108, 113))	('R175H', 'Var', (101, 106))	('R175H', 'Mutation', 'rs28934578', (101, 106))	('R248W', 'Mutation', 'rs121912651', (118, 123))	('promoter activity', 'MPA', (42, 59))	('R248W', 'Var', (118, 123))	('p53', 'Gene', (13, 16))	('E285V', 'Var', (153, 158))	('p53', 'Gene', '7157', (13, 16))	('E285V', 'SUBSTITUTION', 'None', (153, 158))
70503	18762572	In addition, colony growth was significantly inhibited by wild-type p53, but not the R175H and E285V mutants (Fig.	('colony growth', 'CPA', (13, 26))	('E285V', 'Var', (95, 100))	('E285V', 'SUBSTITUTION', 'None', (95, 100))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('R175H', 'Mutation', 'rs28934578', (85, 90))	('inhibited', 'NegReg', (45, 54))
70504	18762572	Therefore, the E285V mutant is defective in regulating promoter activity and in repressing tumor cell growth.	('E285V', 'SUBSTITUTION', 'None', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('regulating promoter activity', 'MPA', (44, 72))	('defective', 'NegReg', (31, 40))	('tumor', 'Disease', (91, 96))	('E285V', 'Var', (15, 20))
70507	18762572	Indeed, DNA sequencing analysis revealed a germline TP53 mutation corresponding to a single amino acid substitution (E285V).	('E285V', 'SUBSTITUTION', 'None', (117, 122))	('E285V', 'Var', (117, 122))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))
70508	18762572	Although the TP53-E285V mutant has not been previously reported as a germline mutation (www-p53.iarc.fr), it has been infrequently observed in sporadic tumors of the liver, bladder, lung, ovary, brain, colon, blood and skin.	('TP53', 'Gene', (13, 17))	('observed', 'Reg', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors of the liver', 'Disease', (152, 171))	('ovary', 'Disease', (188, 193))	('ovary', 'Disease', 'MESH:D010051', (188, 193))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('E285V', 'Var', (18, 23))	('p53', 'Gene', (92, 95))	('E285V', 'SUBSTITUTION', 'None', (18, 23))	('TP53', 'Gene', '7157', (13, 17))	('p53', 'Gene', '7157', (92, 95))	('tumors of the liver', 'Disease', 'MESH:D008113', (152, 171))
70510	18762572	Functional analyses of E285V revealed significant defects in its ability to regulate promoter activity (Fig.	('E285V', 'Var', (23, 28))	('regulate promoter activity', 'MPA', (76, 102))	('ability', 'MPA', (65, 72))	('E285V', 'SUBSTITUTION', 'None', (23, 28))
70512	18762572	Although some mutant p53 proteins exhibit a gain-of-function that induces oncogenic target genes to promote malignancy, the E285V mutant is inactive in this assay (Supplemental Fig.	('induces', 'PosReg', (66, 73))	('gain-of-function', 'PosReg', (44, 60))	('mutant', 'Var', (14, 20))	('malignancy', 'Disease', 'MESH:D009369', (108, 118))	('p53', 'Gene', '7157', (21, 24))	('E285V', 'Var', (124, 129))	('malignancy', 'Disease', (108, 118))	('oncogenic target genes', 'Gene', (74, 96))	('promote', 'PosReg', (100, 107))	('E285V', 'SUBSTITUTION', 'None', (124, 129))	('p53', 'Gene', (21, 24))	('proteins', 'Protein', (25, 33))
70513	18762572	We also determined that E285V efficiently functions as a dominant negative regulator that neutralizes wild-type p53 activity (Supplemental Fig.	('E285V', 'Var', (24, 29))	('E285V', 'SUBSTITUTION', 'None', (24, 29))	('neutralizes', 'NegReg', (90, 101))	('p53', 'Gene', (112, 115))	('activity', 'MPA', (116, 124))	('p53', 'Gene', '7157', (112, 115))
70515	18762572	2) while maintaining both wild-type and mutant TP53 alleles (Fig.	('mutant', 'Var', (40, 46))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))
70516	18762572	Therefore, E285V is severely compromised as a tumor suppressor in terms of failing to induce wild-type p53 responsive genes, blocking tumor cell growth and activating tumor cell death.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('E285V', 'Var', (11, 16))	('blocking', 'NegReg', (125, 133))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('E285V', 'SUBSTITUTION', 'None', (11, 16))	('activating', 'Reg', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
70517	18762572	The proband carries a germline TP53 mutation, but does not have a strong family history of cancer.	('germline', 'Var', (22, 30))	('TP53', 'Gene', '7157', (31, 35))	('cancer', 'Disease', (91, 97))	('TP53', 'Gene', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutation', 'Var', (36, 44))
70518	18762572	Genetic testing of both parents failed to detect any TP53 alterations, indicating that the E285V mutation arose de novo.	('E285V', 'Var', (91, 96))	('E285V', 'SUBSTITUTION', 'None', (91, 96))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))
70519	18762572	This finding is in keeping with other studies of childhood ACC where de novo and low penetrant germline TP53 mutations have been reported.	('child', 'Species', '9606', (49, 54))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('mutations', 'Var', (109, 118))	('ACC', 'Phenotype', 'HP:0006744', (59, 62))
70520	18762572	It also highlights the need to consider constitutional TP53 mutations in children who present with CPC and/or ACC, even outside the context of tumor prone families.	('ACC', 'Disease', (110, 113))	('children', 'Species', '9606', (73, 81))	('CPC', 'Phenotype', 'HP:0030392', (99, 102))	('tumor', 'Disease', (143, 148))	('TP53', 'Gene', '7157', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('TP53', 'Gene', (55, 59))	('CPC', 'Disease', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (60, 69))	('ACC', 'Phenotype', 'HP:0006744', (110, 113))
70522	18762572	It also becomes important to establish structure-function relationships between TP53 mutations and tumor suppressor activity, as it is becoming increasingly clear that different p53 mutants retain different degrees of function.	('tumor', 'Disease', (99, 104))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (178, 181))	('mutants', 'Var', (182, 189))
70523	18762572	Studying rare tumors, such as ACC and CPC, provides a powerful, natural approach to identify clinically relevant mutants and to study their consequence on tumor susceptibility.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ACC', 'Phenotype', 'HP:0006744', (30, 33))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', (14, 20))	('ACC', 'Disease', (30, 33))	('CPC', 'Phenotype', 'HP:0030392', (38, 41))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('mutants', 'Var', (113, 120))	('CPC', 'Disease', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
70568	20484036	In these cells, the active Ser2448-phosphorylated form of mTOR is present only in mitotic cells in association with the mitotic spindle and midbody in the G2/M phases of the cell cycle.	('Ser2448', 'Chemical', '-', (27, 34))	('mTOR', 'Gene', (58, 62))	('Ser2448-phosphorylated', 'Var', (27, 49))
70571	20484036	Adrenocortical tumors (ACT) in children may occur sporadically or in association with other types of neoplasms in the context of multiple neoplasia syndromes linked to germline tumor suppressor gene mutations.	('multiple neoplasia syndromes', 'Disease', (129, 157))	('neoplasms', 'Phenotype', 'HP:0002664', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('Adrenocortical tumors', 'Disease', (0, 21))	('children', 'Species', '9606', (31, 39))	('neoplasia', 'Phenotype', 'HP:0002664', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('neoplasms', 'Disease', 'MESH:D009369', (101, 110))	('multiple neoplasia syndromes', 'Disease', 'MESH:D009369', (129, 157))	('neoplasms', 'Disease', (101, 110))	('tumor', 'Disease', (15, 20))	('neoplasm', 'Phenotype', 'HP:0002664', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mutations', 'Var', (199, 208))	('Adrenocortical tumors', 'Disease', 'MESH:D018268', (0, 21))	('tumor', 'Disease', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
70573	20484036	In that geographical region, childhood ACT are almost invariably associated with the germline R337H tumor protein p53 (TP53) mutation.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('tumor', 'Disease', (100, 105))	('TP53', 'Gene', (119, 123))	('associated', 'Reg', (65, 75))	('R337H', 'Mutation', 'rs121912664', (94, 99))	('TP53', 'Gene', '7157', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('childhood ACT', 'Disease', (29, 42))	('mutation', 'Var', (125, 133))
70575	20484036	While the most common genetic basis of childhood ACT are germline TP53 mutations with loss of heterozygosity (LOH) in the tumor, our knowledge of the molecular pathogenesis of these neoplasms is still limited.	('germline', 'Var', (57, 65))	('neoplasms', 'Disease', (182, 191))	('loss of', 'NegReg', (86, 93))	('TP53', 'Gene', '7157', (66, 70))	('neoplasm', 'Phenotype', 'HP:0002664', (182, 190))	('TP53', 'Gene', (66, 70))	('neoplasms', 'Disease', 'MESH:D009369', (182, 191))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mutations', 'Var', (71, 80))	('neoplasms', 'Phenotype', 'HP:0002664', (182, 191))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
70576	20484036	A very frequent feature is represented by LOH of the distal region of the short arm of chromosome 11, with preferential expression of the imprinted paternal allele and overexpression of the IGF2 growth factor.	('IGF2', 'Gene', '3481', (190, 194))	('expression', 'MPA', (120, 130))	('short arm', 'Phenotype', 'HP:0009824', (74, 83))	('IGF2', 'Gene', (190, 194))	('preferential', 'PosReg', (107, 119))	('LOH', 'Var', (42, 45))	('overexpression', 'PosReg', (168, 182))
70578	20484036	In addition, amplification and overexpression of the nuclear receptor Steroidogenic Factor-1 (SF-1; NR5A1) is thought to play an important role in ACT pathogenesis.	('NR5A1', 'Gene', '2516', (100, 105))	('nuclear receptor Steroidogenic Factor-1 (SF-1', 'Gene', '7536', (53, 98))	('amplification', 'Var', (13, 26))	('NR5A1', 'Gene', (100, 105))	('overexpression', 'PosReg', (31, 45))
70580	20484036	In their mature form, miRNAs recognize by base-pairing sequences in the 3'UTR of protein-coding transcripts, leading to translational repression or mRNA degradation.	('miR', 'Gene', '220972', (22, 25))	('mRNA degradation', 'MPA', (148, 164))	('translational repression', 'MPA', (120, 144))	('miR', 'Gene', (22, 25))	('base-pairing sequences', 'Var', (42, 64))
70601	20484036	Primary antibodies used were anti mTOR (#2833 from Abcam, Paris, France), anti phospho-mTOR (Ser 2448) (#2971 from Cell Signaling Technology, Danvers, MA), anti raptor (#2280 from Cell Signaling Technology), anti rictor (#2114 from Cell Signaling Technology), anti IGF-1Rbeta (#3027 from Cell Signaling Technology) and anti p42/p44 MAP kinases (#9102 from Cell Signaling Technology).	('#3027', 'Var', (277, 282))	('raptor', 'Gene', (161, 167))	('IGF-1R', 'Gene', (265, 271))	('Ser', 'Chemical', 'MESH:D012694', (93, 96))	('IGF-1R', 'Gene', '3480', (265, 271))	('p44', 'Gene', (328, 331))	('#2833', 'Var', (40, 45))	('#2280', 'Var', (169, 174))	('p42', 'Gene', '5706', (324, 327))	('p44', 'Gene', '10561', (328, 331))	('p42', 'Gene', (324, 327))	('#9102', 'Var', (345, 350))	('raptor', 'Gene', '57521', (161, 167))
70603	20484036	It was performed on tumor paraffin sections after antigen retrieval using antibodies directed against phospho-mTOR (Ser 2448) (#2976 from Cell Signaling Technology) and phospho-RPS6 (Ser240/244) (#2215 from Cell Signaling Technology).	('RPS6', 'Gene', '6194', (177, 181))	('Ser', 'Chemical', 'MESH:D012694', (183, 186))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('Ser', 'Chemical', 'MESH:D012694', (116, 119))	('Ser240', 'Chemical', '-', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Ser 2448) (#2976', 'Var', (116, 132))	('RPS6', 'Gene', (177, 181))	('Ser240/244', 'Var', (183, 193))	('#2976', 'Var', (127, 132))	('tumor', 'Disease', (20, 25))	('paraffin', 'Chemical', 'MESH:D010232', (26, 34))
70605	20484036	Deletions in the 3' UTR predicted miR99a/miR-100 binding sites were made by QuickChange mutagenesis (Stratagene, La Jolla, CA).	('miR-100', 'Gene', (41, 48))	('binding', 'Interaction', (49, 56))	('miR99a', 'Gene', (34, 40))	('miR99a', 'Gene', '407055', (34, 40))	('miR-100', 'Gene', '406892', (41, 48))	('Deletions', 'Var', (0, 9))
70626	20484036	Probability of relapse was significantly associated with localization in the T1 subcluster (p=0.002, Fisher's exact test), while histological type (adenoma or carcinoma) was not significantly associated with any group of samples (p=0.35, Fisher's exact test).	('adenoma or carcinoma', 'Disease', 'MESH:D000236', (148, 168))	('localization', 'Var', (57, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('adenoma or carcinoma', 'Disease', (148, 168))
70633	20484036	Finally, phosphorylation of mTOR at Ser2448 and of ribosomal protein S6 as markers of active mTOR signalling were detected in ACT by immunohistochemistry (Figure 2C).	('Ser2448', 'Chemical', '-', (36, 43))	('Ser2448', 'Var', (36, 43))	('phosphorylation', 'MPA', (9, 24))
70634	20484036	To investigate whether downregulation of endogenous miR-100 can modulate the levels of mTOR, raptor and IGF-1R proteins, we transfected a specific miR-100 knockdown probe or a control probe into two different human adrenocortical cell lines (H295R and SW-13) and detected a dose-dependent increase in mTOR, raptor and IGF-1R proteins expression only after miR-100 specific knockdown (Figure 2D).	('downregulation', 'NegReg', (23, 37))	('human', 'Species', '9606', (209, 214))	('IGF-1R', 'Gene', '3480', (318, 324))	('miR-100', 'Gene', (52, 59))	('IGF-1R', 'Gene', (318, 324))	('raptor', 'Gene', '57521', (307, 313))	('raptor', 'Gene', '57521', (93, 99))	('miR-100', 'Gene', '406892', (356, 363))	('IGF-1R', 'Gene', '3480', (104, 110))	('IGF-1R', 'Gene', (104, 110))	('expression', 'MPA', (334, 344))	('miR-100', 'Gene', '406892', (147, 154))	('mTOR', 'MPA', (301, 305))	('miR-100', 'Gene', '406892', (52, 59))	('adrenocortical', 'Disease', 'MESH:D018268', (215, 229))	('raptor', 'Gene', (307, 313))	('raptor', 'Gene', (93, 99))	('increase', 'PosReg', (289, 297))	('SW-13', 'CellLine', 'CVCL:0542', (252, 257))	('adrenocortical', 'Disease', (215, 229))	('miR-100', 'Gene', (356, 363))	('knockdown', 'Var', (373, 382))	('miR-100', 'Gene', (147, 154))	('H295R', 'CellLine', 'CVCL:0458', (242, 247))
70643	20484036	While mTOR is distributed in the cytoplasm of adrenocortical tumor H295R cells, phospho-mTOR is strikingly enriched in mitotic cells (Supplementary Figure 4).	('adrenocortical tumor', 'Disease', (46, 66))	('H295R', 'CellLine', 'CVCL:0458', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('phospho-mTOR', 'Var', (80, 92))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (46, 66))
70647	20484036	RAD001 also inhibited the proliferation of primary childhood ACT cells, with an IC50 of 10-9.2 M, and of the HAC15 cell line, derived from a pediatric adrenocortical carcinoma, with an of IC50 10-8.6 M (Figure 5A).	('inhibited', 'NegReg', (12, 21))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (151, 175))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (151, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('HAC15', 'CellLine', 'CVCL:S898', (109, 114))	('RAD001', 'Var', (0, 6))	('adrenocortical carcinoma', 'Disease', (151, 175))	('proliferation', 'CPA', (26, 39))
70676	20484036	In any case, mTOR inhibition appears particularly promising as a therapeutic tool for cancers characterized by an activated Akt pathway and a relevant angiogenic component, like adrenocortical tumors.	('Akt', 'Gene', (124, 127))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (178, 199))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('mTOR', 'Protein', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('inhibition', 'Var', (18, 28))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('Akt', 'Gene', '207', (124, 127))	('adrenocortical tumors', 'Disease', (178, 199))
70682	20484036	Recently, a similar pattern of subcellular localization of phospho-mTOR has been described in ovarian granulosa and breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('phospho-mTOR', 'Var', (59, 71))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('ovarian granulosa', 'Disease', (94, 111))	('ovarian granulosa', 'Disease', 'MESH:D010051', (94, 111))
70698	32304391	Although appropriate to dissect the signaling pathways and molecular mechanisms of particular driver mutations or gene targets, in vitro cell line models often fail to fully recapitulate patient tumor characteristics and tumor microenvironment, which can lead to discordance between laboratory results and clinical outcomes.	('tumor', 'Disease', (195, 200))	('mutations', 'Var', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('lead to', 'Reg', (255, 262))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('patient', 'Species', '9606', (187, 194))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
70707	32304391	The most common somatic variants reported in ACCs involved gene alterations in CTNNB1, TP53, and CDKN2A, followed by RB1, MEN1, ZNRF3, and TERT.	('ACCs', 'Gene', (45, 49))	('CDKN2A', 'Gene', (97, 103))	('ZNRF3', 'Gene', (128, 133))	('RB1', 'Gene', (117, 120))	('TERT', 'Gene', '21752', (139, 143))	('TP53', 'Gene', (87, 91))	('ACCs', 'Gene', '329470', (45, 49))	('ZNRF3', 'Gene', '407821', (128, 133))	('MEN1', 'Gene', '17283', (122, 126))	('gene alterations', 'Var', (59, 75))	('CTNNB1', 'Gene', (79, 85))	('RB1', 'Gene', '19645', (117, 120))	('TERT', 'Gene', (139, 143))	('ACC', 'Phenotype', 'HP:0006744', (45, 48))	('MEN1', 'Gene', (122, 126))	('CDKN2A', 'Gene', '12578', (97, 103))
70715	32304391	To model initiation events of ACC, mouse models were generated with either alteration in the beta-catenin gene itself or one of its negative regulators, such as APC.	('beta-catenin', 'Gene', (93, 105))	('alteration', 'Var', (75, 85))	('APC', 'Disease', 'MESH:D011125', (161, 164))	('ACC', 'Phenotype', 'HP:0006744', (30, 33))	('mouse', 'Species', '10090', (35, 40))	('APC', 'Disease', (161, 164))	('beta-catenin', 'Gene', '12387', (93, 105))
70717	32304391	Excising the third exon prevented beta-catenin degradation and led to constitutive activation of beta-catenin target genes mimicking Wnt signaling.	('beta-catenin', 'Gene', (97, 109))	('prevented', 'NegReg', (24, 33))	('constitutive', 'MPA', (70, 82))	('Excising', 'Var', (0, 8))	('beta-catenin', 'Gene', '12387', (34, 46))	('beta-catenin', 'Gene', '12387', (97, 109))	('beta-catenin', 'Gene', (34, 46))	('activation', 'PosReg', (83, 93))
70718	32304391	Most of DeltaCat mice developed adrenal hyperplasia and dysplasia with older mice developing benign aldosterone secreting tumors with certain malignant characteristics such as neovascularization and regional invasion.	('tumors', 'Disease', (122, 128))	('regional invasion', 'CPA', (199, 216))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('mice', 'Species', '10090', (17, 21))	('mice', 'Species', '10090', (77, 81))	('adrenal hyperplasia and dysplasia', 'Phenotype', 'HP:0008216', (32, 65))	('neovascularization', 'CPA', (176, 194))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('aldosterone', 'Chemical', 'MESH:D000450', (100, 111))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (32, 51))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('adrenal hyperplasia and dysplasia', 'Disease', 'MESH:D000312', (32, 65))	('DeltaCat', 'Var', (8, 16))
70719	32304391	Another approach to target Wnt activation utilized APC knockout mouse models, where exon 14 of APC was deleted and targeted with the steroidogenic specific Sf-1 Cre recombinase resulting in beta-catenin stabilization in the adrenal cortex.	('beta-catenin', 'Gene', '12387', (190, 202))	('Sf-1', 'Gene', '22668', (156, 160))	('APC', 'Disease', 'MESH:D011125', (95, 98))	('APC', 'Disease', (95, 98))	('Sf-1', 'Gene', (156, 160))	('beta-catenin', 'Gene', (190, 202))	('deleted', 'Var', (103, 110))	('APC', 'Disease', 'MESH:D011125', (51, 54))	('APC', 'Disease', (51, 54))	('mouse', 'Species', '10090', (64, 69))
70724	32304391	The first PDX of pediatric ACC (SJACC3) was developed by implantation of an adrenal mass collected from a 11-year-old patient bearing a germline TP53 mutation (G245C).	('TP53', 'Gene', (145, 149))	('ACC', 'Phenotype', 'HP:0006744', (34, 37))	('G245C', 'Mutation', 'rs28934573', (160, 165))	('ACC', 'Phenotype', 'HP:0006744', (27, 30))	('G245C', 'Var', (160, 165))	('patient', 'Species', '9606', (118, 125))
70737	32304391	Large-scale ACC genomic studies have identified as much as 20% genetic alterations in ZNRF3.	('genetic alterations', 'Var', (63, 82))	('ACC', 'Phenotype', 'HP:0006744', (12, 15))	('ZNRF3', 'Gene', '407821', (86, 91))	('ZNRF3', 'Gene', (86, 91))
70742	32304391	Although these mice did not demonstrate progression from hyperplasia to adrenocortical carcinoma, this is clinically relevant model recapitulating loss of ZNNRF3 as one of the most common genetic alterations in ACC.	('ZNNRF3', 'Gene', (155, 161))	('hyperplasia to adrenocortical carcinoma', 'Disease', 'MESH:D018268', (57, 96))	('ACC', 'Phenotype', 'HP:0006744', (211, 214))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (72, 96))	('mice', 'Species', '10090', (15, 19))	('hyperplasia to adrenocortical carcinoma', 'Disease', (57, 96))	('loss', 'Var', (147, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
70746	32304391	CU-ACC1 was derived from a sporadic ACC metastasis to the perinephric region and CU-ACC2 was derived from an ACC liver metastasis in a patient with Lynch syndrome characterized by the germline deletion of exons 1-6 in the mismatch repair gene MSH2.	('patient', 'Species', '9606', (135, 142))	('MSH2', 'Gene', (243, 247))	('MSH2', 'Gene', '4436', (243, 247))	('Lynch syndrome', 'Disease', (148, 162))	('ACC', 'Phenotype', 'HP:0006744', (36, 39))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('CU', 'Chemical', 'MESH:D003300', (81, 83))	('Lynch syndrome', 'Disease', 'MESH:D003123', (148, 162))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('ACC', 'Phenotype', 'HP:0006744', (3, 6))	('CU', 'Chemical', 'MESH:D003300', (0, 2))	('germline', 'Var', (184, 192))
70750	32304391	Whole exomic sequencing of the patient tumors and the PDX models identified a known ACC-associated mutation in CTNNB1 (p.G34R) in CU-ACC1 and a TP53 (G245S) mutation in CU-ACC2.	('CU', 'Chemical', 'MESH:D003300', (169, 171))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('ACC-associated', 'Disease', (84, 98))	('TP53 (G245S', 'Var', (144, 155))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('G245S', 'Mutation', 'rs28934575', (150, 155))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('p.G34R', 'Var', (119, 125))	('CU', 'Chemical', 'MESH:D003300', (130, 132))	('patient', 'Species', '9606', (31, 38))	('ACC', 'Phenotype', 'HP:0006744', (133, 136))	('CTNNB1', 'Gene', (111, 117))	('p.G34R', 'Mutation', 'rs121913399', (119, 125))	('ACC', 'Phenotype', 'HP:0006744', (172, 175))	('tumors', 'Disease', (39, 45))
70751	32304391	In-silico predictions for both mutations were damaging and have been reported in other human cancers.	('cancers', 'Disease', (93, 100))	('mutations', 'Var', (31, 40))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('human', 'Species', '9606', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
70755	32304391	Although most ACCs are sporadic, a subset of ACC tumors harbor either germline or somatic mutations in DNA mismatch repair genes, or mismatch repair components.	('mutations', 'Var', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('ACCs', 'Gene', (14, 18))	('ACCs', 'Gene', '329470', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('DNA mismatch repair genes', 'Gene', (103, 128))	('ACC', 'Phenotype', 'HP:0006744', (14, 17))	('ACC', 'Phenotype', 'HP:0006744', (45, 48))	('ACC', 'Disease', (45, 48))
70768	32304391	Targeting the mitotic kinase PBK in in vitro and in vivo models of ACC inhibited many of the malignant properties, induced apoptosis and colony formation, and significantly reduced ACC tumorigenic growth.	('tumor', 'Disease', (185, 190))	('PBK', 'Gene', (29, 32))	('inhibited', 'NegReg', (71, 80))	('ACC', 'Phenotype', 'HP:0006744', (67, 70))	('reduced', 'NegReg', (173, 180))	('ACC', 'Disease', (67, 70))	('PBK', 'Gene', '52033', (29, 32))	('apoptosis', 'CPA', (123, 132))	('colony formation', 'CPA', (137, 153))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('ACC', 'Phenotype', 'HP:0006744', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('ACC', 'Disease', (181, 184))	('Targeting', 'Var', (0, 9))	('induced', 'Reg', (115, 122))
70769	32304391	Similarly, targeting MELK, another mitotic kinase, caused apoptosis and inhibited proliferation and clonogenicity in in vitro assays using multiple ACC cell lines, and in newly established PDX models.	('ACC', 'Phenotype', 'HP:0006744', (148, 151))	('caused', 'Reg', (51, 57))	('MELK', 'Gene', '17279', (21, 25))	('clonogenicity', 'CPA', (100, 113))	('MELK', 'Gene', (21, 25))	('apoptosis', 'CPA', (58, 67))	('proliferation', 'CPA', (82, 95))	('targeting', 'Var', (11, 20))	('inhibited', 'NegReg', (72, 81))
70808	33578890	Monoclonality indicates that tumor progression is the end result of an intrinsic genetic tumor driver mutation.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutation', 'Var', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
70809	33578890	Most common mutations implicated in sporadic ACC are insulin-like growth factor 2 (IGF2), beta-catenin (CTNNB1 or ZNRF3) and TP53 mutations.	('IGF2', 'Gene', (83, 87))	('insulin-like growth factor 2', 'Gene', (53, 81))	('CTNNB1', 'Gene', '1499', (104, 110))	('TP53', 'Gene', '7157', (125, 129))	('beta-catenin', 'Gene', (90, 102))	('TP53', 'Gene', (125, 129))	('CTNNB1', 'Gene', (104, 110))	('mutations', 'Var', (130, 139))	('beta-catenin', 'Gene', '1499', (90, 102))	('IGF2', 'Gene', '3481', (83, 87))	('ZNRF3', 'Gene', '84133', (114, 119))	('insulin-like growth factor 2', 'Gene', '3481', (53, 81))	('ZNRF3', 'Gene', (114, 119))
70820	33578890	The Wnt/beta-catenin pathway in ACC can be activated by CTNNB1 mutations and by ZNRF3 (zinc and ring finger protein 3) inactivation.	('mutations', 'Var', (63, 72))	('CTNNB1', 'Gene', '1499', (56, 62))	('zinc and ring finger protein 3', 'Gene', '84133', (87, 117))	('beta-catenin', 'Gene', (8, 20))	('activated', 'PosReg', (43, 52))	('ACC', 'Disease', (32, 35))	('beta-catenin', 'Gene', '1499', (8, 20))	('CTNNB1', 'Gene', (56, 62))	('ZNRF3', 'Gene', '84133', (80, 85))	('inactivation', 'NegReg', (119, 131))	('ZNRF3', 'Gene', (80, 85))
70825	33578890	According to genomic analyses, germline mutations in TP53 were observed in 50-80% of children with sporadic ACC, while somatic TP53 mutation was observed in 20% to 30% of sporadic ACC patients where it correlates with poor outcome.	('TP53', 'Gene', (53, 57))	('patients', 'Species', '9606', (184, 192))	('TP53', 'Gene', '7157', (53, 57))	('germline mutations', 'Var', (31, 49))	('TP53', 'Gene', '7157', (127, 131))	('observed', 'Reg', (63, 71))	('TP53', 'Gene', (127, 131))	('children', 'Species', '9606', (85, 93))
70826	33578890	In immunohistochemical studies diffuse p53 staining correlates positively with increased Ki-67 expression.	('increased', 'PosReg', (79, 88))	('Ki-67', 'Chemical', '-', (89, 94))	('diffuse', 'Var', (31, 38))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('Ki-67', 'Protein', (89, 94))	('expression', 'MPA', (95, 105))
70853	33578890	ARR > 20-30 is indicative of hyperaldosteronism.	('hyperaldosteronism', 'Disease', 'MESH:D003480', (29, 47))	('hyperaldosteronism', 'Disease', (29, 47))	('ARR > 20-30', 'Var', (0, 11))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (29, 47))
70855	33578890	However, it is important to keep in mind that regardless of ACC size, due to insufficient or aberrant steroid hormone synthesis, symptoms of hormonal hyper production or blood hormone levels can be absent or just moderately elevated.	('steroid', 'Chemical', 'MESH:D013256', (102, 109))	('absent', 'NegReg', (198, 204))	('aberrant', 'Var', (93, 101))	('steroid hormone synthesis', 'MPA', (102, 127))	('elevated', 'PosReg', (224, 232))	('blood hormone levels', 'MPA', (170, 190))	('insufficient', 'NegReg', (77, 89))	('hormonal hyper', 'Disease', (141, 155))	('hormonal hyper', 'Disease', 'MESH:C565870', (141, 155))
70896	33578890	Ki67 index >10% correlates with higher risk of recurrence in ACCs and it is associated with worse overall survival in patients with advanced disease or rapid disease recurrence.	('ACCs', 'Gene', (61, 65))	('Ki67', 'Var', (0, 4))	('>10%', 'Var', (11, 15))	('patients', 'Species', '9606', (118, 126))	('ACCs', 'Gene', '84680', (61, 65))
70934	33578890	Finally, a novel germ line variant of the 177 mutant (Pro to Arg; P177R) of p53 by genomic sequencing was then identified.	('Pro', 'Chemical', 'MESH:D011392', (54, 57))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('Pro to Arg; P177R', 'Var', (54, 71))	('P177R', 'Mutation', 'rs751477326', (66, 71))	('Arg', 'Chemical', 'MESH:D001120', (61, 64))
70939	33578890	DNA hypermethylation of promoters correlates with poor survival and can distinguish carcinomas from adenomas with a sensitivity of 96% and specificity of 100%, highlighting a possible role of methylation in the 11p15 locus containing IGF2 and H19 as a valuable biomarker.	('poor', 'NegReg', (50, 54))	('carcinomas', 'Disease', 'MESH:D009369', (84, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('IGF2', 'Gene', '3481', (234, 238))	('adenomas', 'Disease', 'MESH:D000236', (100, 108))	('survival', 'MPA', (55, 63))	('carcinomas', 'Disease', (84, 94))	('H19', 'Gene', '283120', (243, 246))	('adenomas', 'Disease', (100, 108))	('IGF2', 'Gene', (234, 238))	('H19', 'Gene', (243, 246))	('hypermethylation', 'Var', (4, 20))
70946	33578890	Interestingly, dysregulation of iron metabolism-related genes has been characterized as a promising prognostic biomarker in cancers, including ACC.	('iron metabolism-related genes', 'Gene', (32, 61))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('iron', 'Chemical', 'MESH:D007501', (32, 36))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('ACC', 'Disease', (143, 146))	('cancers', 'Disease', (124, 131))	('dysregulation', 'Var', (15, 28))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
70964	33578890	MiR-483-5p is one of the most investigated miRNAs in ACCs, both as a diagnostic and prognostic biomarker and has been proven as the best single-gene malignancy marker.	('malignancy', 'Disease', 'MESH:D009369', (149, 159))	('malignancy', 'Disease', (149, 159))	('ACCs', 'Gene', '84680', (53, 57))	('ACCs', 'Gene', (53, 57))	('MiR-483-5p', 'Var', (0, 10))	('MiR-483-5p', 'Chemical', '-', (0, 10))
70965	33578890	Since miR-483-5p is located at 11p15.5 within the second intron of IGF2, the high expression of miR-483-5p observed in ACC may be an indirect consequence of IGF2 over-expression.	('miR-483-5p', 'Chemical', '-', (6, 16))	('IGF2', 'Gene', '3481', (67, 71))	('miR-483-5p', 'Chemical', '-', (96, 106))	('miR-483-5p', 'Var', (96, 106))	('over-expression', 'PosReg', (162, 177))	('IGF2', 'Gene', '3481', (157, 161))	('IGF2', 'Gene', (67, 71))	('IGF2', 'Gene', (157, 161))
70966	33578890	Expression levels of six microRNAs including miR-503-5p, miR-483-3p, miR-450a-5p, miR-210, miR-483-5p and miR-421 can predict malignant potential with at least 95% accuracy.	('malignant potential', 'CPA', (126, 145))	('miR-450a-5p', 'Var', (69, 80))	('miR-483', 'Gene', '619552', (91, 98))	('predict', 'Reg', (118, 125))	('miR-483', 'Gene', '619552', (57, 64))	('miR-483', 'Gene', (91, 98))	('miR-421', 'Gene', (106, 113))	('miR-503', 'Gene', (45, 52))	('miR-210', 'Gene', (82, 89))	('miR-483', 'Gene', (57, 64))	('miR-210', 'Gene', '406992', (82, 89))	('miR-483-5p', 'Chemical', '-', (91, 101))	('miR-421', 'Gene', '693122', (106, 113))	('miR-503', 'Gene', '574506', (45, 52))
70967	33578890	High circulating levels of miR-483-5p or low circulating levels of miR-195 are associated with both shorter recurrence-free survival and shorter overall survival in ACC.	('miR-483-5p', 'Chemical', '-', (27, 37))	('shorter', 'NegReg', (137, 144))	('overall', 'MPA', (145, 152))	('miR-483-5p', 'Var', (27, 37))	('shorter', 'NegReg', (100, 107))	('recurrence-free survival', 'CPA', (108, 132))	('miR-195', 'Gene', (67, 74))	('miR-195', 'Gene', '406971', (67, 74))
70979	33578890	Tumor-specific mutations were found in the cfDNA of one of the three patients who had metastatic ACC at diagnosis.	('cfDNA', 'Disease', (43, 48))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (15, 24))	('found', 'Reg', (30, 35))	('patients', 'Species', '9606', (69, 77))
70999	33578890	In this study, co-treatment with mitotane negatively impacted on the anti-tumoral effect and level of the drug due to mitotane-induced CYP3A4.	('mitotane', 'Chemical', 'MESH:D008939', (33, 41))	('tumoral', 'Disease', (74, 81))	('level of the drug', 'MPA', (93, 110))	('tumoral', 'Disease', 'MESH:D009369', (74, 81))	('mitotane-induced', 'Var', (118, 134))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CYP3A4', 'Gene', '1576', (135, 141))	('CYP3A4', 'Gene', (135, 141))	('mitotane', 'Chemical', 'MESH:D008939', (118, 126))	('impacted', 'Reg', (53, 61))	('negatively', 'NegReg', (42, 52))
71005	33578890	Microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized, according to Raj et al..	('Microsatellite-high', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('pembrolizumab', 'Chemical', 'MESH:C582435', (85, 98))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mismatch repair', 'Var', (27, 42))
71011	33578890	In experimental models of ACC, metformin was proven to reduce cell viability and proliferation in a dose- and time-dependent manner, trigger apoptosis and inhibit tumor growth.	('apoptosis', 'CPA', (141, 150))	('cell viability', 'CPA', (62, 76))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('trigger', 'Reg', (133, 140))	('metformin', 'Var', (31, 40))	('tumor', 'Disease', (163, 168))	('reduce', 'NegReg', (55, 61))	('inhibit', 'NegReg', (155, 162))	('metformin', 'Chemical', 'MESH:D008687', (31, 40))
71015	33578890	Furthermore, mitotane use can cause hypercholesterolemia in patients with adrenocortical carcinoma and it is possible that cholesterol increases intratumor activity.	('cholesterol increases', 'Phenotype', 'HP:0003124', (123, 144))	('adrenocortical carcinoma', 'Disease', (74, 98))	('cause', 'Reg', (30, 35))	('mitotane', 'Chemical', 'MESH:D008939', (13, 21))	('cholesterol', 'Chemical', 'MESH:D002784', (123, 134))	('patients', 'Species', '9606', (60, 68))	('hypercholesterolemia', 'Disease', (36, 56))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (36, 56))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (36, 56))	('cholesterol', 'Chemical', 'MESH:D002784', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (74, 98))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (74, 98))	('tumor', 'Disease', (150, 155))	('mitotane', 'Var', (13, 21))
71017	33578890	In experimental studies on cell lines, C-terminal Hsp90 (heat shock protein 90) inhibitor KU758 has proven effectiveness as treatment for adrenocortical carcinoma cells upregulating long noncoding RNA expression for tumor suppression, including tumor suppressor GAS5, which is implicated in the beta-catenin and mammalian target of rapamycin pathways.	('GAS5', 'Gene', '60674', (262, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (138, 162))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor suppression', 'Disease', 'MESH:D009369', (216, 233))	('Hsp90', 'Gene', (50, 55))	('beta-catenin', 'Gene', (295, 307))	('tumor', 'Disease', (216, 221))	('beta-catenin', 'Gene', '1499', (295, 307))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (138, 162))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('GAS5', 'Gene', (262, 266))	('adrenocortical carcinoma', 'Disease', (138, 162))	('heat shock protein 90', 'Gene', (57, 78))	('KU758', 'Var', (90, 95))	('upregulating', 'PosReg', (169, 181))	('long', 'Protein', (182, 186))	('shock', 'Phenotype', 'HP:0031273', (62, 67))	('mammalian target of rapamycin', 'Gene', '2475', (312, 341))	('tumor', 'Disease', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor suppression', 'Disease', (216, 233))	('KU758', 'Chemical', '-', (90, 95))	('mammalian target of rapamycin', 'Gene', (312, 341))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('heat shock protein 90', 'Gene', '3320', (57, 78))	('Hsp90', 'Gene', '3320', (50, 55))
71028	33578890	In an experimental study on ACC cell lines, withanolides reduce ACC cell viability, induce cell cycle arrest and apoptosis as well as modulate expression of several key oncogenic pathway proteins.	('withanolides', 'Var', (44, 56))	('reduce', 'NegReg', (57, 63))	('arrest', 'Disease', (102, 108))	('expression', 'MPA', (143, 153))	('apoptosis', 'CPA', (113, 122))	('withanolides', 'Chemical', 'MESH:D054358', (44, 56))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('modulate', 'Reg', (134, 142))	('induce', 'PosReg', (84, 90))	('ACC', 'Disease', (64, 67))	('arrest', 'Disease', 'MESH:D006323', (102, 108))
71106	30860644	No intra-observer agreement scores could be calculated for the Ki67 PI (Figure 2F) because both observers assessed all ACTs once, but the inter-observer agreement score was excellent (0.96, P < 0.001).	('Ki67', 'Var', (63, 67))	('ACT', 'Disease', 'MESH:D000306', (119, 122))	('ACT', 'Disease', (119, 122))
71107	30860644	In assessing the potential of the histopathological parameters as prognostic indicators, three parameters were significantly associated with survival according to univariate analyses (Table 2): the percentage of clear/vacuolated cytoplasm, the presence of necrosis, and the Ki67 PI.	('necrosis', 'Disease', (256, 264))	('Ki67', 'Var', (274, 278))	('associated', 'Reg', (125, 135))	('necrosis', 'Disease', 'MESH:D009336', (256, 264))
71109	30860644	This indicated that the Ki67 PI, clear/vacuolated cytoplasm in at least 33% of the tumour cells, and the presence of necrosis were all independent predictors of survival.	('tumour', 'Disease', (83, 89))	('necrosis', 'Disease', (117, 125))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('Ki67 PI', 'Var', (24, 31))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('necrosis', 'Disease', 'MESH:D009336', (117, 125))
71110	30860644	Based on their hazard ratios in the multivariate analysis (Table 3), this led to the scoring system: 1.12 x Ki67 PI, + 4.35 if clear/vacuolated cytoplasm was present in at least 33% of the tumour cells, + 3.18 if necrosis was present.	('necrosis', 'Disease', (213, 221))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('necrosis', 'Disease', 'MESH:D009336', (213, 221))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('Ki67 PI', 'Var', (108, 115))	('tumour', 'Disease', (189, 195))
71115	30860644	We propose to classify ACTs with a score of <6 as having low risk of recurrence, with a score of >=6 to <11 as having moderate risk of recurrence, and with a score of >=11 as having high risk of recurrence.	('score', 'Var', (35, 40))	('ACT', 'Disease', (23, 26))	('ACT', 'Disease', 'MESH:D000306', (23, 26))
71236	29596439	Many of these, including agonists of growth-hormone-releasing hormone (GHRH) (MR409, MR403, JI36 etc.)	('growth-hormone-releasing hormone', 'Gene', (37, 69))	('GHRH', 'Gene', (71, 75))	('growth-hormone-releasing hormone', 'Gene', '2691', (37, 69))	('MR409', 'Var', (78, 83))	('MR403', 'Var', (85, 90))	('GHRH', 'Gene', '2691', (71, 75))
71288	29264446	Functional Implications of LH/hCG Receptors in Pregnancy-Induced Cushing Syndrome Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS).	('hCG', 'Gene', '93659', (182, 185))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (263, 295))	('Cushing Syndrome', 'Phenotype', 'HP:0003118', (65, 81))	('bilateral macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (253, 295))	('LH', 'Chemical', 'MESH:D007986', (178, 180))	('LH', 'Chemical', 'MESH:D007986', (27, 29))	('Cushing Syndrome', 'Disease', 'MESH:D003480', (65, 81))	('hCG', 'Gene', '93659', (30, 33))	('Cushing Syndrome', 'Disease', (65, 81))	('stimulate', 'PosReg', (126, 135))	('bilateral macronodular adrenal hyperplasia', 'Disease', (253, 295))	('LHCGR', 'Gene', (196, 201))	('hCG', 'Gene', '93659', (117, 120))	('hCG', 'Gene', (182, 185))	('Cushing syndrome', 'Disease', 'MESH:D003480', (310, 326))	('hCG', 'Gene', (30, 33))	('aberrantly', 'Var', (136, 146))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (310, 326))	('Cushing syndrome', 'Disease', (310, 326))	('hCG', 'Gene', (117, 120))	('Elevated human choriogonadotropin', 'Phenotype', 'HP:0000837', (82, 115))	('LH', 'Gene', (178, 180))	('LH', 'Chemical', 'MESH:D007986', (196, 198))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (276, 295))	('human', 'Species', '9606', (91, 96))
71290	29264446	Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)-increased cortisol secretion.	('-increased', 'PosReg', (95, 105))	('arginine', 'Var', (69, 77))	('cortisol secretion', 'MPA', (106, 124))	('AVP', 'Gene', '551', (91, 94))	('-increased cortisol', 'Phenotype', 'HP:0003118', (95, 114))	('cortisol', 'Chemical', 'MESH:D006854', (106, 114))	('vasopressin', 'Gene', '551', (78, 89))	('vasopressin', 'Gene', (78, 89))	('AVP', 'Gene', (91, 94))	('increased cortisol', 'Phenotype', 'HP:0003118', (96, 114))
71306	29264446	In pregnancy-induced CS, ectopic adrenal LH/hCG receptor (LHCGR) expression has been related to hypercortisolism, hyperandrogenism, and hyperaldosteronism.	('hypercortisolism', 'Phenotype', 'HP:0003118', (96, 112))	('ectopic adrenal', 'Phenotype', 'HP:0011742', (25, 40))	('hypercortisolism', 'Disease', 'MESH:D003480', (96, 112))	('hCG', 'Gene', '93659', (44, 47))	('related', 'Reg', (85, 92))	('hyperaldosteronism', 'Disease', (136, 154))	('LHCGR', 'Gene', (58, 63))	('hCG', 'Gene', (44, 47))	('hypercortisolism', 'Disease', (96, 112))	('hyperandrogenism', 'Disease', (114, 130))	('ectopic', 'Var', (25, 32))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (136, 154))	('LH', 'Chemical', 'MESH:D007986', (41, 43))	('LH', 'Chemical', 'MESH:D007986', (58, 60))	('hyperandrogenism', 'Disease', 'MESH:D017588', (114, 130))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (136, 154))
71310	29264446	Somatic mutations in the CTNNB1, PRKAR1A, ARMC5, and PRKACA genes have been found in pregnancy/menopause-induced aldosterone-producing adenomas (APAs), primary pigmented nodular adrenocortical disease, familial BMAH, and cortisol-producing adrenocortical adenomas, respectively.	('found', 'Reg', (76, 81))	('adenomas', 'Disease', 'MESH:D000236', (135, 143))	('adenomas', 'Disease', (135, 143))	('APA', 'Gene', '2028', (145, 148))	('pregnancy/menopause-induced', 'Disease', (85, 112))	('PRKACA', 'Gene', (53, 59))	('CTNNB1', 'Gene', '1499', (25, 31))	('PRKAR1A', 'Gene', (33, 40))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (160, 200))	('mutations', 'Var', (8, 17))	('ARMC5', 'Gene', (42, 47))	('cortisol', 'Chemical', 'MESH:D006854', (221, 229))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (160, 200))	('pigmented nodular adrenocortical disease', 'Disease', (160, 200))	('CTNNB1', 'Gene', (25, 31))	('PRKAR1A', 'Gene', '5573', (33, 40))	('APA', 'Gene', (145, 148))	('adenomas', 'Disease', 'MESH:D000236', (255, 263))	('adenomas', 'Disease', (255, 263))	('menopause-', 'Phenotype', 'HP:0008209', (95, 105))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (240, 263))	('familial BMAH', 'Disease', (202, 215))	('PRKACA', 'Gene', '5566', (53, 59))	('aldosterone', 'Chemical', 'MESH:D000450', (113, 124))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (240, 263))	('adrenocortical adenomas', 'Disease', (240, 263))	('ARMC5', 'Gene', '79798', (42, 47))
71340	29264446	The steroidogenic profiles of the hyperplastic cortical cells and the ectopic cortical cells in the medulla were defined by immunofluorescence localization of CYP11A1, 3beta-HSD, CYP21A1, CYP17, CYP11B1, and CYP11B2 (Fig.	('CYP11B2', 'Gene', (208, 215))	('CYP17', 'Gene', (188, 193))	('CYP21A1', 'Var', (179, 186))	('steroidogenic', 'MPA', (4, 17))	('CYP11B2', 'Gene', '1585', (208, 215))	('steroid', 'Chemical', 'MESH:D013256', (4, 11))	('3beta-HSD', 'Gene', (168, 177))	('CYP17', 'Gene', '1586', (188, 193))	('3beta-HSD', 'Gene', '3283', (168, 177))	('CYP11B1', 'Gene', (195, 202))	('CYP11B1', 'Gene', '1584', (195, 202))	('CYP11A1', 'Gene', '1583', (159, 166))	('CYP11A1', 'Gene', (159, 166))
71372	29264446	Negative results of familial and somatic CTNNB1, PRKACA, ARMC5, and PRKACA gene mutation analyses excluded a genetic background of CS in our patient.	('PRKACA', 'Gene', (68, 74))	('PRKACA', 'Gene', '5566', (68, 74))	('ARMC5', 'Gene', (57, 62))	('CTNNB1', 'Gene', (41, 47))	('PRKACA', 'Gene', (49, 55))	('patient', 'Species', '9606', (141, 148))	('ARMC5', 'Gene', '79798', (57, 62))	('PRKACA', 'Gene', '5566', (49, 55))	('mutation', 'Var', (80, 88))	('CTNNB1', 'Gene', '1499', (41, 47))
71373	29264446	Nevertheless, our patient displayed some similarities with patients who presented with pregnancy/menopause-induced primary hyperaldosteronism due to a somatic mutation in CTNNB1 and beta-catenin activation.	('CTNNB1', 'Gene', (171, 177))	('beta-catenin', 'Gene', '1499', (182, 194))	('primary hyperaldosteronism', 'Phenotype', 'HP:0011736', (115, 141))	('patient', 'Species', '9606', (59, 66))	('mutation', 'Var', (159, 167))	('primary hyperaldosteronism', 'Disease', (115, 141))	('due to', 'Reg', (142, 148))	('patient', 'Species', '9606', (18, 25))	('patients', 'Species', '9606', (59, 67))	('primary hyperaldosteronism', 'Disease', 'MESH:D003480', (115, 141))	('CTNNB1', 'Gene', '1499', (171, 177))	('menopause-', 'Phenotype', 'HP:0008209', (97, 107))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (123, 141))	('beta-catenin', 'Gene', (182, 194))
71375	29264446	In the CTNNB1 mutation case, the authors postulated hyperaldosteronism as a consequence of aberrant gonadal differentiation caused by beta-catenin activation through a mutation in CTNNB1.	('aberrant gonadal differentiation', 'Phenotype', 'HP:0000133', (91, 123))	('beta-catenin', 'Gene', '1499', (134, 146))	('CTNNB1', 'Gene', '1499', (180, 186))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (52, 70))	('gonadal differentiation', 'CPA', (100, 123))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (52, 70))	('CTNNB1', 'Gene', (7, 13))	('CTNNB1', 'Gene', (180, 186))	('mutation', 'Var', (168, 176))	('mutation', 'Var', (14, 22))	('CTNNB1', 'Gene', '1499', (7, 13))	('hyperaldosteronism', 'Disease', (52, 70))	('postulated hyperaldosteronism', 'Phenotype', 'HP:0011741', (41, 70))	('activation', 'PosReg', (147, 157))	('beta-catenin', 'Gene', (134, 146))
71556	26834703	A link between miRNAs and cancer was brought by the seminal observation of Croce's group who reported that miR-15 and miR-16, two miRNAs located in chromosome 13 (13q14) are frequently deleted in chronic lymphocytic leukemia (CLL) and function as tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('cancer', 'Disease', (26, 32))	('miR-16', 'Gene', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('miR', 'Gene', '220972', (107, 110))	('CLL', 'Phenotype', 'HP:0005550', (226, 229))	('deleted', 'Var', (185, 192))	('miR', 'Gene', '220972', (130, 133))	('miR', 'Gene', (107, 110))	('miR-16', 'Gene', '51573', (118, 124))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (196, 224))	('tumor', 'Disease', (247, 252))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('miR', 'Gene', (130, 133))	('chronic lymphocytic leukemia', 'Disease', (196, 224))	('miR', 'Gene', '220972', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('miR', 'Gene', '220972', (15, 18))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (196, 224))	('leukemia', 'Phenotype', 'HP:0001909', (216, 224))	('miR', 'Gene', (118, 121))	('miR', 'Gene', (15, 18))
71557	26834703	Since then, miRNAs have been studied most intensively in the field of cancer research and growing evidence suggests that altered miRNA expression is involved in the pathogenesis of cancers.	('miR', 'Gene', '220972', (129, 132))	('cancers', 'Disease', (181, 188))	('miR', 'Gene', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('altered', 'Var', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('involved', 'Reg', (149, 157))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
71560	26834703	The second mechanism involves epigenetic regulation of miRNA expression.	('miR', 'Gene', '220972', (55, 58))	('epigenetic regulation', 'Var', (30, 51))	('miR', 'Gene', (55, 58))
71561	26834703	DNA hypomethylation, CpG island hypermethylation and histone-modification losses have been shown to also affect miRNA expression.	('hypomethylation', 'Var', (4, 19))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('affect', 'Reg', (105, 111))	('histone-modification', 'MPA', (53, 73))	('losses', 'NegReg', (74, 80))	('CpG island hypermethylation', 'Var', (21, 48))
71563	26834703	The third mechanism is abnormalities in miRNA-processing genes and proteins.	('proteins', 'Protein', (67, 75))	('abnormalities', 'Var', (23, 36))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))
71564	26834703	As the machinery involved in the biogenesis and maturation of miRNAs involve multiple protein complexes, one can anticipate that alterations of these proteins should have dramatic effects on miRNA expression.	('miR', 'Gene', (191, 194))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('effects', 'Reg', (180, 187))	('alterations', 'Var', (129, 140))	('miR', 'Gene', '220972', (191, 194))
71567	26834703	Consequently, p53 gene mutations may lead to decreased processing of pri-miRNAs by Drosha and decreased levels of mature miRNAs in cancer cells.	('cancer', 'Disease', (131, 137))	('Drosha', 'Gene', '29102', (83, 89))	('p53', 'Gene', (14, 17))	('miR', 'Gene', (73, 76))	('p53', 'Gene', '7157', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('decreased', 'NegReg', (45, 54))	('mutations', 'Var', (23, 32))	('decreased', 'NegReg', (94, 103))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', '220972', (121, 124))	('Drosha', 'Gene', (83, 89))	('miR', 'Gene', (121, 124))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
71600	26834703	Besides chromosomal alterations, major dysfunctional pathways in ACC, such as somatic mutations of the tumor suppressor gene TP53, overexpression of IGF2, and activation of the Wnt/beta catenin signaling pathway, are likely to impact miRNA expression.	('activation', 'PosReg', (159, 169))	('mutations', 'Var', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('TP53', 'Gene', '7157', (125, 129))	('tumor', 'Disease', (103, 108))	('IGF2', 'Gene', (149, 153))	('miR', 'Gene', '220972', (234, 237))	('beta catenin', 'Gene', (181, 193))	('TP53', 'Gene', (125, 129))	('miR', 'Gene', (234, 237))	('beta catenin', 'Gene', '1499', (181, 193))	('impact', 'Reg', (227, 233))	('overexpression', 'PosReg', (131, 145))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('ACC', 'Phenotype', 'HP:0006744', (65, 68))
71609	26834703	In this context, the use of RNA sequencing would enable to address different questions that remain unanswered by RT-qPCR or microarray approaches, such as the detection of single nucleotide variants and copy number as well as the discovery of novel miRNAs.	('single nucleotide variants', 'Var', (172, 198))	('miR', 'Gene', '220972', (249, 252))	('miR', 'Gene', (249, 252))	('copy number', 'Var', (203, 214))
71662	26834703	In breast cancer, the methylation state of CpG islands upstream of the miR-195/497 gene was found to be responsible for the downregulation of both miRNAs.	('miR', 'Gene', (71, 74))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('miR', 'Gene', '220972', (71, 74))	('miR', 'Gene', '220972', (147, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('miR', 'Gene', (147, 150))	('miR-195', 'Gene', (71, 78))	('miR-195', 'Gene', '406971', (71, 78))	('downregulation', 'NegReg', (124, 138))	('methylation', 'Var', (22, 33))
71671	26834703	The genetic deletion and epigenetic promoter hypermethylation occurring at miR-335 locus has been correlated with breast cancer metastases and ovarian cancer recurrence.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('genetic deletion', 'Var', (4, 20))	('ovarian cancer', 'Phenotype', 'HP:0100615', (143, 157))	('miR-335', 'Gene', (75, 82))	('correlated', 'Reg', (98, 108))	('epigenetic promoter hypermethylation', 'Var', (25, 61))	('breast cancer metastases and ovarian cancer', 'Disease', 'MESH:D001943', (114, 157))	('miR-335', 'Gene', '442904', (75, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))
71676	26834703	identified three ACC clusters characterized by three distinct miRNA profiles Mi1, Mi2, and Mi3.	('Mi1', 'Var', (77, 80))	('Mi1', 'Chemical', '-', (77, 80))	('Mi2', 'Chemical', '-', (82, 85))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('Mi3', 'Var', (91, 94))	('ACC', 'Phenotype', 'HP:0006744', (17, 20))
71688	26834703	In humans, the DLK1-DIO3 genomic region, located on human chromosome 14 (14q32) contains the paternally expressed imprinted genes DLK1, RTL1, and DIO3 and the maternally expressed imprinted genes MEG3 and MEG8, and antisense RTL1.	('human', 'Species', '9606', (3, 8))	('RTL1', 'Gene', (225, 229))	('MEG8', 'Gene', (205, 209))	('DLK1', 'Gene', '8788', (130, 134))	('DLK1', 'Gene', (130, 134))	('MEG3', 'Gene', (196, 200))	('RTL1', 'Gene', '388015', (225, 229))	('RTL1', 'Gene', (136, 140))	('MEG8', 'Gene', '79104', (205, 209))	('humans', 'Species', '9606', (3, 9))	('DLK1', 'Gene', '8788', (15, 19))	('RTL1', 'Gene', '388015', (136, 140))	('MEG3', 'Gene', '55384', (196, 200))	('DLK1', 'Gene', (15, 19))	('DIO3', 'Gene', '1735', (20, 24))	('DIO3', 'Gene', '1735', (146, 150))	('human', 'Species', '9606', (52, 57))	('DIO3', 'Gene', (20, 24))	('antisense', 'Var', (215, 224))	('DIO3', 'Gene', (146, 150))
71711	26834703	Copy number gain of the Tarbp2 gene was observed in 57% of the ACCs analyzed in this study.	('Tarbp2', 'Gene', (24, 30))	('Tarbp2', 'Gene', '6895', (24, 30))	('gain', 'PosReg', (12, 16))	('Copy number', 'Var', (0, 11))	('ACC', 'Phenotype', 'HP:0006744', (63, 66))
71712	26834703	Inhibition of Tarbp2 expression in NCI-H295R cells resulted in a decreased cell proliferation and induction of apoptosis.	('decreased', 'NegReg', (65, 74))	('Tarbp2', 'Gene', '6895', (14, 20))	('Inhibition', 'Var', (0, 10))	('Tarbp2', 'Gene', (14, 20))	('NCI-H295R', 'CellLine', 'CVCL:0458', (35, 44))	('apoptosis', 'CPA', (111, 120))	('cell proliferation', 'CPA', (75, 93))
71772	26834703	The exchange of exosomal miR-21 and miR-155 between neuroblastoma cells and human monocytes has been implicated in the development of resistance to chemotherapy.	('neuroblastoma', 'Disease', (52, 65))	('neuroblastoma', 'Phenotype', 'HP:0003006', (52, 65))	('miR-21', 'Gene', (25, 31))	('implicated', 'Reg', (101, 111))	('exosomal', 'Protein', (16, 24))	('human', 'Species', '9606', (76, 81))	('exchange', 'Var', (4, 12))	('miR-155', 'Gene', '406947', (36, 43))	('miR-21', 'Gene', '406991', (25, 31))	('neuroblastoma', 'Disease', 'MESH:D009447', (52, 65))	('miR-155', 'Gene', (36, 43))
71790	26834703	Deregulations of miRNAs expression and activity are important steps in the development of many cancers, including adrenocortical cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('adrenocortical cancer', 'Disease', (114, 135))	('Deregulations', 'Var', (0, 13))	('expression', 'MPA', (24, 34))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('activity', 'MPA', (39, 47))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (114, 135))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
71890	22415797	The other issue to be addressed is how to best combine IGF-1R inhibitors with other therapeutic approaches.	('IGF-1R', 'Gene', (55, 61))	('IGF-1R', 'Gene', '3480', (55, 61))	('inhibitors', 'Var', (62, 72))
71896	22415797	Similarly, mammalian target of rapamycin (m-TOR) inhibitors can activate PI3K-Akt pathway via loss of negative feedback on IRS-1 (insulin receptor substrate:1), an effect that can be suppressed by IGF-1R blockade.	('IRS-1', 'Gene', (123, 128))	('insulin receptor substrate:1', 'Gene', '3667', (130, 158))	('IGF-1R', 'Gene', '3480', (197, 203))	('insulin receptor substrate:1', 'Gene', (130, 158))	('loss', 'NegReg', (94, 98))	('Akt', 'Gene', '207', (78, 81))	('IGF-1R', 'Gene', (197, 203))	('negative feedback', 'MPA', (102, 119))	('TOR', 'Gene', (44, 47))	('TOR', 'Gene', '6097', (44, 47))	('mammalian target of rapamycin', 'Gene', '2475', (11, 40))	('mammalian target of rapamycin', 'Gene', (11, 40))	('Akt', 'Gene', (78, 81))	('inhibitors', 'Var', (49, 59))	('IRS-1', 'Gene', '3667', (123, 128))	('activate', 'PosReg', (64, 72))
71905	22415797	The main event following IGF-1R phosphorylation is the stimulation of phophoinositol 3-kinase (PI3K)-Akt signaling pathway, leading to cell survival.	('Akt', 'Gene', '207', (101, 104))	('phosphorylation', 'Var', (32, 47))	('Akt', 'Gene', (101, 104))	('cell survival', 'CPA', (135, 148))	('stimulation', 'PosReg', (55, 66))	('IGF-1R', 'Gene', '3480', (25, 31))	('IGF-1R', 'Gene', (25, 31))
71909	22415797	Low levels of IGF-1R copy number gain were also shown in lung cancer, pancreatic adenocarcinoma and colon cancer.	('IGF-1R', 'Gene', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Low levels of IGF', 'Phenotype', 'HP:0002850', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('pancreatic adenocarcinoma and colon cancer', 'Disease', 'MESH:D010190', (70, 112))	('colon cancer', 'Phenotype', 'HP:0003003', (100, 112))	('copy number', 'Var', (21, 32))	('gain', 'PosReg', (33, 37))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (70, 95))	('IGF-1R', 'Gene', '3480', (14, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
71919	22415797	Hyperglycemia was more frequently observed with tyrosine kinase inhibitors.	('Hyperglycemia', 'Disease', 'MESH:D006943', (0, 13))	('observed', 'Reg', (34, 42))	('Hyperglycemia', 'Disease', (0, 13))	('tyrosine', 'Var', (48, 56))	('Hyperglycemia', 'Phenotype', 'HP:0003074', (0, 13))
71923	22415797	Grade 3 thrombocytopenia was considered a DLT with 20 mg/kg of AMG-479 and lymphocyte count decrease occurred in 7 % of the patients treated with CP-751, 871.	('lymphocyte', 'MPA', (75, 85))	('AMG', 'Gene', '265', (63, 66))	('thrombocytopenia', 'Disease', 'MESH:D013921', (8, 24))	('decrease', 'NegReg', (92, 100))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (8, 24))	('CP-751', 'Chemical', '-', (146, 152))	('CP-751', 'Var', (146, 152))	('thrombocytopenia', 'Disease', (8, 24))	('patients', 'Species', '9606', (124, 132))	('lymphocyte count decrease', 'Phenotype', 'HP:0001888', (75, 100))	('AMG', 'Gene', (63, 66))
71929	22415797	As an example IGF-1R gene copy number gain (3 % amplification and 24 % high polysomy) had surprisingly positive prognostic value.	('IGF-1R', 'Gene', (14, 20))	('IGF-1R', 'Gene', '3480', (14, 20))	('gain', 'PosReg', (38, 42))	('copy number', 'Var', (26, 37))
71931	22415797	The predictive value of IGF-1R copy number gain needs further investigation.	('copy number', 'Var', (31, 42))	('gain', 'PosReg', (43, 47))	('IGF-1R', 'Gene', '3480', (24, 30))	('IGF-1R', 'Gene', (24, 30))
71949	22415797	In desmoplastic small round cell tumors (DSRCT) EWS-WT1 translocation induces a threefold over-expression of IGF-1R.	('CT', 'Chemical', 'MESH:D002251', (44, 46))	('EWS-WT1', 'Gene', '7490', (48, 55))	('desmoplastic small round cell tumors', 'Disease', (3, 39))	('over-expression', 'PosReg', (90, 105))	('IGF-1R', 'Gene', '3480', (109, 115))	('translocation', 'Var', (56, 69))	('IGF-1R', 'Gene', (109, 115))	('EWS-WT1', 'Gene', (48, 55))	('desmoplastic small round cell tumors', 'Disease', 'MESH:D058405', (3, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))
71950	22415797	Gastrointestinal stromal tumors (GISTs) lacking of KIT and PDGFRalpha mutations presented significantly higher prevalence of IGF-1R amplification compared to mutated ones.	('lacking', 'NegReg', (40, 47))	('IGF-1R', 'Gene', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutations', 'Var', (70, 79))	('KIT', 'Gene', (51, 54))	('PDGFRalpha', 'Gene', '5156', (59, 69))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('Gastrointestinal stromal tumors', 'Disease', (0, 31))	('PDGFRalpha', 'Gene', (59, 69))	('Gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (0, 31))	('Gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (0, 31))	('GISTs', 'Phenotype', 'HP:0100723', (33, 38))	('higher', 'PosReg', (104, 110))	('IGF-1R', 'Gene', '3480', (125, 131))	('amplification', 'MPA', (132, 145))
71951	22415797	High IGF-1 and IGF-2 expression levels were associated to a highly malignant phenotype and negative prognostic value in wild type and mutant GISTs.	('High IGF-1', 'Phenotype', 'HP:0030269', (0, 10))	('expression levels', 'MPA', (21, 38))	('IGF-1', 'Gene', '3479', (5, 10))	('IGF-1', 'Gene', (5, 10))	('GISTs', 'Phenotype', 'HP:0100723', (141, 146))	('IGF-2', 'Gene', (15, 20))	('IGF-2', 'Gene', '3481', (15, 20))	('mutant', 'Var', (134, 140))
71955	22415797	The results of two phase II trials were recently published, evaluating the efficacy and safety of R1507 (robatumumab, a fully human IgG1 mAb to IGF-1R) in recurrent and refractory Ewing's sarcomas and AMG 479 (fully human mAb to IGF-1R) in recurrent refractory Ewing's family of tumors and desmoplastic small round cell tumors (DSRT).	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('human', 'Species', '9606', (216, 221))	('desmoplastic small round cell tumors', 'Disease', 'MESH:D058405', (290, 326))	('AMG', 'Gene', '265', (201, 204))	('IGF-1R', 'Gene', '3480', (144, 150))	("Ewing's sarcomas", 'Disease', 'MESH:C563168', (180, 196))	('IGF-1R', 'Gene', (144, 150))	("Ewing's family of tumors", 'Disease', (261, 285))	('R1507', 'Var', (98, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (188, 196))	('desmoplastic small round cell tumors', 'Disease', (290, 326))	("Ewing's sarcomas", 'Disease', (180, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('human', 'Species', '9606', (126, 131))	('robatumumab', 'Chemical', 'MESH:C573312', (105, 116))	('IGF-1R', 'Gene', '3480', (229, 235))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('IGF-1R', 'Gene', (229, 235))	("Ewing's family of tumors", 'Disease', 'MESH:C563168', (261, 285))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('AMG', 'Gene', (201, 204))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (180, 195))	("Ewing's sarcomas", 'Phenotype', 'HP:0012254', (180, 196))
71956	22415797	In the SARC 001 study 111 Ewing's sarcoma patients were treated with R1507, administered intravenously at 9 mg/kg weekly.	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('R1507', 'Var', (69, 74))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (26, 41))	("Ewing's sarcoma", 'Disease', (26, 41))	('patients', 'Species', '9606', (42, 50))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (26, 41))
71980	22415797	Reciprocal inhibition of ERS1 or IGF-1R transcript levels was produced by siRNA knockdown of one or the other of these targets.	('IGF-1R', 'Gene', '3480', (33, 39))	('knockdown', 'Var', (80, 89))	('IGF-1R', 'Gene', (33, 39))	('transcript levels', 'MPA', (40, 57))	('ERS1', 'Gene', (25, 29))
71981	22415797	Furthermore it was shown in vitro and in vivo synergism of dual targeting of these pathways by fulvestrant or tamoxifen combined with h10H5, an IGF-1R monoclonal antibody.	('IGF-1R', 'Gene', '3480', (144, 150))	('h10H5', 'Var', (134, 139))	('IGF-1R', 'Gene', (144, 150))	('fulvestrant', 'Chemical', 'MESH:D000077267', (95, 106))	('tamoxifen', 'Chemical', 'MESH:D013629', (110, 119))	('h10H5', 'Chemical', '-', (134, 139))
71985	22415797	HER2 heterodimerisation with other members of HER family is a well-known phenomenon.	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('heterodimerisation', 'Var', (5, 23))
71987	22415797	Another mechanism contributing to trastuzumab resistance is p27kip down-regulation and this was stimulated by IGF-1 in some preclinical models.	('IGF-1', 'Gene', (110, 115))	('trastuzumab', 'Chemical', 'MESH:D000068878', (34, 45))	('p27kip', 'Var', (60, 66))	('down-regulation', 'NegReg', (67, 82))	('IGF-1', 'Gene', '3479', (110, 115))
71991	22415797	Additional phase II trials are evaluating the IGF-1R inhibitors associated to endocrine treatment or HER2 inhibitors in advanced breast cancer tumors (Table 2).	('inhibitors', 'Var', (53, 63))	('breast cancer tumors', 'Disease', 'MESH:D001943', (129, 149))	('HER2', 'Gene', (101, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('IGF-1R', 'Gene', '3480', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HER2', 'Gene', '2064', (101, 105))	('IGF-1R', 'Gene', (46, 52))	('breast cancer tumors', 'Disease', (129, 149))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
72004	22415797	This was related to several genetic alterations such as loss of imprinting or loss of heterozygosity of the 11p15 gene locus.	('p15', 'Gene', '1030', (110, 113))	('p15', 'Gene', (110, 113))	('loss', 'NegReg', (56, 60))	('loss', 'Var', (78, 82))
72015	22415797	(Table 3) Aberrant expression of IGF-1R is detected in many cancers.	('IGF-1R', 'Gene', '3480', (33, 39))	('expression', 'MPA', (19, 29))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('IGF-1R', 'Gene', (33, 39))	('cancers', 'Disease', (60, 67))	('Aberrant', 'Var', (10, 18))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('detected', 'Reg', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
72021	22415797	(Figure 2) To give an example: sarcoma cell lines resistant to BMS 536924 (small molecule IGF-1R tyrosine kinase inhibitor) expressed high levels of IGFBP-3 and IGFBP-6 whereas the sensitive ones showed high expression level of IGF-1 and IGF-2.	('IGF-1', 'Gene', '3479', (90, 95))	('sarcoma', 'Disease', (31, 38))	('IGFBP-6', 'Gene', '3489', (161, 168))	('IGFBP-3', 'Gene', '3486', (149, 156))	('IGF-1', 'Gene', '3479', (228, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('IGF-1', 'Gene', (228, 233))	('IGFBP-3', 'Gene', (149, 156))	('IGF-2', 'Gene', (238, 243))	('IGFBP-6', 'Gene', (161, 168))	('sarcoma', 'Disease', 'MESH:D012509', (31, 38))	('IGF-2', 'Gene', '3481', (238, 243))	('IGF-1R', 'Gene', '3480', (90, 96))	('IGF-1R', 'Gene', (90, 96))	('BMS 536924', 'Var', (63, 73))	('IGF-1', 'Gene', (90, 95))
72028	22415797	On the other hand IGF-1R gene copy number gain was identified in some tumor types, such as wild-type GIST, breast cancer and NSCLC.	('IGF-1R', 'Gene', '3480', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('gene copy number', 'Var', (25, 41))	('IGF-1R', 'Gene', (18, 24))	('gain', 'PosReg', (42, 46))	('NSCLC', 'Disease', (125, 130))	('tumor', 'Disease', (70, 75))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
72030	22415797	IGF-1R phosphorylation leads to the activation of multiple signaling pathways.	('activation', 'PosReg', (36, 46))	('multiple signaling pathways', 'Pathway', (50, 77))	('IGF-1R', 'Gene', '3480', (0, 6))	('phosphorylation', 'Var', (7, 22))	('IGF-1R', 'Gene', (0, 6))
72036	22415797	Parallel inhibition of a second growth factor receptor such as EGFR or HER2 or a concomitant downstream signaling blockade such as m-TOR or PI3K could considerably enhance antitumor activity.	('inhibition', 'NegReg', (9, 19))	('enhance', 'PosReg', (164, 171))	('EGFR', 'Gene', '1956', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('PI3K', 'Var', (140, 144))	('EGFR', 'Gene', (63, 67))	('HER2', 'Gene', (71, 75))	('tumor', 'Disease', (176, 181))	('HER2', 'Gene', '2064', (71, 75))	('TOR', 'Gene', '6097', (133, 136))	('TOR', 'Gene', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
72037	22415797	Combination of two HER-2 targeting antibodies directed against different epitopes of Cerb-B2 receptor showed improvement of clinical activity in the treatment of HER-2 amplified metastatic breast cancer.	('HER-2', 'Gene', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('HER-2', 'Gene', '2064', (19, 24))	('HER-2', 'Gene', (19, 24))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('improvement', 'PosReg', (109, 120))	('breast cancer', 'Disease', (189, 202))	('clinical activity', 'MPA', (124, 141))	('HER-2', 'Gene', '2064', (162, 167))	('amplified', 'Var', (168, 177))
72106	33340399	Paired t tests (2-tailed) were used to compare Log Kd/Ki values of E2 and 11OHE2 for ERalpha and ERbeta.	('11OHE2', 'Chemical', '-', (74, 80))	('E2', 'Chemical', 'MESH:D004958', (67, 69))	('ERbeta', 'Gene', (97, 103))	('E2', 'Chemical', 'MESH:D004958', (78, 80))	('11OHE2', 'Var', (74, 80))	('ERbeta', 'Gene', '26284', (97, 103))	('ERalpha', 'Gene', '26284', (85, 92))	('ERalpha', 'Gene', (85, 92))
72111	33340399	In all 3 aromatase-expression systems, 11-oxygenated estrogens were detected after incubations with 11OHA4, 11KA4, and 11KT (Fig.	('11KT', 'Var', (119, 123))	('11-oxygenated estrogens', 'Chemical', '-', (39, 62))	('aromatase', 'Gene', (9, 18))	('A4', 'Chemical', '-', (104, 106))	('11OHA4', 'Var', (100, 106))	('11-oxygenated estrogens', 'MPA', (39, 62))	('11KA4', 'Var', (108, 113))	('aromatase', 'Gene', '1588', (9, 18))	('11OHA4', 'Chemical', '-', (100, 106))	('A4', 'Chemical', '-', (111, 113))
72125	33340399	Contamination with an 11beta-hydroxylase can be eliminated as neither A4 nor T was converted to 11OHA4 or 11OHT, as would have been expected in the presence of CYP11B1 or CYP11B2.	('11OHT', 'Chemical', '-', (106, 111))	('A4', 'Chemical', '-', (100, 102))	('A4', 'Chemical', '-', (70, 72))	('11OHA4', 'Chemical', '-', (96, 102))	('CYP11B1', 'Var', (160, 167))	('CYP11B2', 'Var', (171, 178))
72126	33340399	Moreover, incubations of the human 11beta-hydroxylase enzymes CYP11B1 or CYP11B2 with E2 or E1 failed to yield 11-oxygenated estrogens (data not shown).	('11-oxygenated estrogens', 'Chemical', '-', (111, 134))	('E1', 'Chemical', '-', (92, 94))	('11-oxygenated estrogens', 'MPA', (111, 134))	('CYP11B2', 'Var', (73, 80))	('E2', 'Chemical', 'MESH:D004958', (86, 88))	('human', 'Species', '9606', (29, 34))
72129	33340399	First, we confirmed that 11OHE2, the only commercially available 11-oxygenated estrogen, binds to both subtypes of the nuclear human ER, ERalpha and ERbeta.	('ER', 'Gene', '2099', (133, 135))	('ERalpha', 'Gene', '26284', (137, 144))	('ERalpha', 'Gene', (137, 144))	('ERbeta', 'Gene', (149, 155))	('human', 'Species', '9606', (127, 132))	('11OHE2', 'Chemical', '-', (25, 31))	('ER', 'Gene', '2099', (149, 151))	('ERbeta', 'Gene', '26284', (149, 155))	('binds', 'Interaction', (89, 94))	('ER', 'Gene', '2099', (137, 139))	('11OHE2', 'Var', (25, 31))
72131	33340399	Next, using a promoter-reporter system, we showed that 11OHE2 could transactivate via both ERalpha and ERbeta to a similar degree (not significantly different) to E2 (Fig.	('ERbeta', 'Gene', (103, 109))	('11OHE2', 'Var', (55, 61))	('11OHE2', 'Chemical', '-', (55, 61))	('E2', 'Chemical', 'MESH:D004958', (59, 61))	('transactivate', 'MPA', (68, 81))	('E2', 'Chemical', 'MESH:D004958', (163, 165))	('ERalpha', 'Gene', (91, 98))	('ERalpha', 'Gene', '26284', (91, 98))	('ERbeta', 'Gene', '26284', (103, 109))
72134	33340399	The estrogenic properties of 11OHE2 were further confirmed by demonstrating that 11OHE2, like E2, induced significant cell growth (P = .003) in the estrogen-responsive MCF7-BUS breast cancer cell line (Fig.	('cell growth', 'CPA', (118, 129))	('E2', 'Chemical', 'MESH:D004958', (85, 87))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('11OHE2', 'Var', (81, 87))	('MCF7-BUS breast cancer', 'Disease', (168, 190))	('E2', 'Chemical', 'MESH:D004958', (94, 96))	('11OHE2', 'Chemical', '-', (29, 35))	('MCF7-BUS breast cancer', 'Disease', 'MESH:D001943', (168, 190))	('E2', 'Chemical', 'MESH:D004958', (33, 35))	('11OHE2', 'Chemical', '-', (81, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))
72135	33340399	Our findings are in agreement with a previous study that showed that 11OHE2 can bind to the ER and induce proliferation in estrogen-responsive MCF-7 breast cancer cells.	('induce', 'PosReg', (99, 105))	('11OHE2', 'Var', (69, 75))	('bind', 'Interaction', (80, 84))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (143, 162))	('11OHE2', 'Chemical', '-', (69, 75))	('MCF-7 breast cancer', 'Disease', (143, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('proliferation', 'CPA', (106, 119))	('ER', 'Gene', '2099', (92, 94))	('men', 'Species', '9606', (25, 28))
72136	33340399	Next, we determined whether the aromatization of the potent androgen 11KT could result in ER-mediated effects.	('result in', 'Reg', (80, 89))	('ER', 'Gene', '2099', (90, 92))	('aromatization', 'Var', (32, 45))	('11KT', 'Gene', (69, 73))
72145	33340399	We also analyzed serum samples from 7 patients with steroidogenically active adrenocortical carcinoma and increased 11-oxygenated adrenal androgen excretion, that is, increased substrate availability and potentially dysregulated steroidogenesis due to ectopic adrenal aromatase expression.	('aromatase', 'Gene', (268, 277))	('steroid', 'Chemical', 'MESH:D013256', (229, 236))	('ectopic', 'Var', (252, 259))	('adrenocortical carcinoma', 'Disease', (77, 101))	('aromatase', 'Gene', '1588', (268, 277))	('substrate availability', 'MPA', (177, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('steroidogenesis', 'MPA', (229, 244))	('dysregulated', 'Reg', (216, 228))	('steroid', 'Chemical', 'MESH:D013256', (52, 59))	('increased', 'PosReg', (167, 176))	('ectopic adrenal', 'Phenotype', 'HP:0011742', (252, 267))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (77, 101))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (77, 101))	('patients', 'Species', '9606', (38, 46))	('increased', 'PosReg', (106, 115))	('11-oxygenated adrenal androgen excretion', 'MPA', (116, 156))
72152	33340399	We show that 11KA4, 11OHA4, and 11KT are all aromatizable, albeit to a lower degree than the classic aromatase substrates.	('aromatase', 'Gene', (101, 110))	('aromatase', 'Gene', '1588', (101, 110))	('A4', 'Chemical', '-', (24, 26))	('11OHA4', 'Chemical', '-', (20, 26))	('aromatizable', 'MPA', (45, 57))	('A4', 'Chemical', '-', (16, 18))	('11KA4', 'Var', (13, 18))	('11OHA4', 'Var', (20, 26))
72160	33340399	Incubations of the human 11beta-hydroxylase enzymes CYP11B1 or CYP11B2 with E2 or E1 failed to yield 11-oxygenated estrogens (data not shown), demonstrating that although these enzymes are essential for the biosynthesis of 11-oxygenated androgens, they play no direct role in the production of 11-oxygenated estrogens.	('11-oxygenated estrogens', 'Chemical', '-', (101, 124))	('CYP11B2', 'Var', (63, 70))	('11-oxygenated estrogens', 'Chemical', '-', (294, 317))	('11-oxygenated androgens', 'Chemical', '-', (223, 246))	('CYP11B1', 'Var', (52, 59))	('E2', 'Chemical', 'MESH:D004958', (76, 78))	('human', 'Species', '9606', (19, 24))	('E1', 'Chemical', '-', (82, 84))
72161	33340399	In agreement with our findings, a previous study had shown that incubations of human adrenal slices, the exclusive site of CYP11B1 and CYP11B2 expression, failed to yield 11beta-hydroxylated products when using E1 as a substrate.	('human', 'Species', '9606', (79, 84))	('CYP11B1', 'Var', (123, 130))	('men', 'Species', '9606', (8, 11))	('CYP11B2', 'Var', (135, 142))	('E1', 'Chemical', '-', (211, 213))	('11beta-hydroxylated products', 'MPA', (171, 199))
72162	33340399	In terms of activity, we show that 11OHE2, the only commercially available 11-oxygenated estrogen, binds and activates ERalpha and ERbeta in a similar manner to E2.	('binds', 'Interaction', (99, 104))	('11OHE2', 'Var', (35, 41))	('ERbeta', 'Gene', (131, 137))	('E2', 'Chemical', 'MESH:D004958', (161, 163))	('11OHE2', 'Chemical', '-', (35, 41))	('ERalpha', 'Gene', '26284', (119, 126))	('activates', 'PosReg', (109, 118))	('E2', 'Chemical', 'MESH:D004958', (39, 41))	('ERbeta', 'Gene', '26284', (131, 137))	('ERalpha', 'Gene', (119, 126))
72163	33340399	11OHE2 also stimulated proliferation and expression of estrogen-responsive genes in an estrogen-responsive breast cancer cell line, thereby confirming its estrogenic activity.	('stimulated', 'PosReg', (12, 22))	('estrogen-responsive genes', 'Gene', (55, 80))	('expression', 'MPA', (41, 51))	('11OHE2', 'Chemical', '-', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('proliferation', 'CPA', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('11OHE2', 'Var', (0, 6))
72171	33340399	Indeed, the degree of aromatization observed was dependent on the level of aromatase expression and activity in our in vitro test systems, with only 11KA4 being significantly aromatized in JEG3 cells, which had the lowest aromatase activity (Fig.	('lowest', 'NegReg', (215, 221))	('end', 'Disease', (52, 55))	('A4', 'Chemical', '-', (152, 154))	('aromatase', 'Gene', (222, 231))	('11KA4', 'Var', (149, 154))	('aromatase', 'Gene', (75, 84))	('end', 'Disease', 'MESH:D007676', (52, 55))	('activity', 'MPA', (232, 240))	('aromatase', 'Gene', '1588', (222, 231))	('aromatase', 'Gene', '1588', (75, 84))
72208	32512410	Another implication should be considered in cases where the ectopic gland is the only adrenal tissue in the patient, or when it's hyperfunctioning, causing regression of the normal adrenals.	('regression', 'MPA', (156, 166))	('ectopic gland', 'Var', (60, 73))	('patient', 'Species', '9606', (108, 115))
72234	32050622	cccDNA integrates its DNA into the host genome resulting in both genomic instability and mutagenesis of diverse cancer-related genes.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('genomic', 'MPA', (65, 72))	('mutagenesis', 'Var', (89, 100))
72245	32050622	Missing proteins may be involved in various cellular activities in both normal and tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('proteins', 'Protein', (8, 16))	('involved', 'Reg', (24, 32))	('Missing', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
72246	32050622	Thus, missing proteins in tumor-developing tissue could be potential biomarkers associated with carcinogenesis.	('proteins', 'Protein', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('missing', 'Var', (6, 13))	('carcinogenesis', 'Disease', 'MESH:D063646', (96, 110))	('associated', 'Reg', (80, 90))	('carcinogenesis', 'Disease', (96, 110))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
72337	32050622	Half of the cold tumors belong to the "immune exclusion class", which is characterized by Wnt/CTNNB1 mutations and might have innate resistance to anti-PD-1/PD-L1 inhibitors.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutations', 'Var', (101, 110))	('CTNNB1', 'Gene', '1499', (94, 100))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('PD-L1', 'Gene', (157, 162))	('PD-L1', 'Gene', '29126', (157, 162))	('CTNNB1', 'Gene', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
72387	32050622	The loss of BMP-5 expression takes place as an early event in CRC where BMP-5 may dysregulate E-cadherin and then trigger tumor initiation and development.	('E-cadherin', 'Gene', (94, 104))	('E-cadherin', 'Gene', '999', (94, 104))	('tumor initiation', 'Disease', (122, 138))	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('CRC', 'Disease', 'MESH:D015179', (62, 65))	('BMP-5', 'Gene', (12, 17))	('CRC', 'Disease', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor initiation', 'Disease', 'MESH:D009369', (122, 138))	('dysregulate', 'Var', (82, 93))	('loss', 'NegReg', (4, 8))	('trigger', 'Reg', (114, 121))	('BMP-5', 'Gene', (72, 77))
72396	32050622	Moreover, Chen and coworkers reported that gene amplification and increased gene expression of BMP-5 were significant in HCC samples.	('HCC', 'Phenotype', 'HP:0001402', (121, 124))	('increased', 'PosReg', (66, 75))	('gene expression', 'MPA', (76, 91))	('BMP-5', 'Gene', (95, 100))	('HCC', 'Disease', 'MESH:D006528', (121, 124))	('gene amplification', 'Var', (43, 61))	('HCC', 'Disease', (121, 124))
72410	32050622	The tissue sections were stained with antibodies against Hepatitis B Virus X antigen (ab39716), FSTL1 (20182-1-AP), Cathepsin B (PA5-47975) or TGF-beta (GTX 108510).	('PA5-47975', 'Var', (129, 138))	('Hepatitis B Virus X', 'Protein', (57, 76))	('TGF-beta', 'Gene', '7039', (143, 151))	('20182-1-AP', 'Var', (103, 113))	('FSTL1', 'Gene', (96, 101))	('Hepatitis B Virus', 'Species', '10407', (57, 74))	('TGF-beta', 'Gene', (143, 151))	('Hepatitis', 'Phenotype', 'HP:0012115', (57, 66))
72419	32050622	The membranes were then separately incubated overnight with primary antibodies (1 ug/ mL) of anti- FSTL1, anti- Cathepsin B, anti- TGF-beta, anti-PREX2 and anti-beta-actin.	('anti-PREX2', 'Var', (141, 151))	('anti- FSTL1', 'Gene', (93, 104))	('anti-', 'Var', (106, 111))	('TGF-beta', 'Gene', (131, 139))	('beta-actin', 'Gene', '728378', (161, 171))	('beta-actin', 'Gene', (161, 171))	('anti-', 'Var', (125, 130))	('TGF-beta', 'Gene', '7039', (131, 139))
72431	32050622	The following are available online at , Figure S1: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level measurements showed that the averages of AST and ALT in the HBx transgenic mice were significantly higher than that in the wild-type mice.	('HBx', 'Gene', (191, 194))	('ALT', 'Gene', '76282', (180, 183))	('ALT', 'Gene', '76282', (83, 86))	('mice', 'Species', '10090', (206, 210))	('aspartate aminotransferase', 'MPA', (92, 118))	('mice', 'Species', '10090', (264, 268))	('higher', 'PosReg', (230, 236))	('ALT', 'Gene', (83, 86))	('transgenic', 'Var', (195, 205))	('HBx', 'Gene', '944566', (191, 194))	('AST', 'MPA', (172, 175))	('ALT', 'Gene', (180, 183))	('transgenic mice', 'Species', '10090', (195, 210))	('Serum alanine aminotransferase', 'MPA', (51, 81))
72440	31057613	Genetic alterations of different pathways involved in ACC carcinogenesis are also known substrates of resistance to immunotherapy.	('Genetic alterations', 'Var', (0, 19))	('ACC', 'Phenotype', 'HP:0006744', (54, 57))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('ACC', 'Disease', (54, 57))	('carcinogenesis', 'Disease', (58, 72))
72456	31057613	In particular, several comprehensive analyses of the genomic profile of ACC have been performed, showing a complex genomic landscape with the identification of recurring mutations in different genes such as ZNFR (20%), CTNNB1 (14%), TP53 (14%), and RB1 (11%).	('ACC', 'Phenotype', 'HP:0006744', (72, 75))	('TP53', 'Gene', (233, 237))	('mutations', 'Var', (170, 179))	('CTNNB1', 'Gene', (219, 225))	('ZNFR', 'Gene', (207, 211))	('RB1', 'Gene', (249, 252))	('CTNNB1', 'Gene', '1499', (219, 225))	('RB1', 'Gene', '5925', (249, 252))	('TP53', 'Gene', '7157', (233, 237))
72457	31057613	As previously mentioned, various genetic alterations are present in subgroups of tumors with different clinical characteristics and outcomes; of relevance, mutations in the CTNNB1 gene encoding for beta-catenin and in the TP53 gene encoding for the tumor suppressor p53 proteins have been defined as poor prognostic factors for ACC.	('tumors', 'Disease', (81, 87))	('tumor', 'Disease', (249, 254))	('ACC', 'Phenotype', 'HP:0006744', (328, 331))	('ACC', 'Disease', (328, 331))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('beta-catenin', 'Gene', (198, 210))	('TP53', 'Gene', '7157', (222, 226))	('beta-catenin', 'Gene', '1499', (198, 210))	('tumor', 'Disease', (81, 86))	('mutations', 'Var', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('CTNNB1', 'Gene', '1499', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('p53', 'Gene', '7157', (266, 269))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('p53', 'Gene', (266, 269))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('TP53', 'Gene', (222, 226))	('CTNNB1', 'Gene', (173, 179))
72458	31057613	Moreover, both mutations in CTNNB1 and TP53 genes have been shown to play a role in ACC carcinogenesis, as early and late events, respectively.	('carcinogenesis', 'Disease', (88, 102))	('role', 'Reg', (76, 80))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('mutations', 'Var', (15, 24))	('CTNNB1', 'Gene', (28, 34))	('TP53', 'Gene', '7157', (39, 43))	('play', 'Reg', (69, 73))	('CTNNB1', 'Gene', '1499', (28, 34))	('carcinogenesis', 'Disease', 'MESH:D063646', (88, 102))	('TP53', 'Gene', (39, 43))
72459	31057613	The Cancer Genome Atlas - Adrenal Cortex, that analyzed 91 cases for alterations in the ACC genome, reveals that, beside the cited molecular alterations, mutations in the PRKAR1A gene (8%) and the overexpression of IGF2 (90%) can be observed as well.	('IGF2', 'Gene', '3481', (215, 219))	('PRKAR1A', 'Gene', (171, 178))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('IGF2', 'Gene', (215, 219))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('mutations', 'Var', (154, 163))	('PRKAR1A', 'Gene', '5573', (171, 178))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
72490	31057613	The rationale to explain why ACC displays resistance to immunotherapy could be linked to the above-mentioned molecular alterations highly prevalent in ACC, namely, mutations in TP53 and CTNNB genes.	('linked', 'Reg', (79, 85))	('CTNNB', 'Gene', (186, 191))	('ACC', 'Phenotype', 'HP:0006744', (29, 32))	('CTNNB', 'Gene', '1499', (186, 191))	('TP53', 'Gene', '7157', (177, 181))	('mutations', 'Var', (164, 173))	('ACC', 'Phenotype', 'HP:0006744', (151, 154))	('ACC', 'Disease', (151, 154))	('TP53', 'Gene', (177, 181))
72496	31057613	In addition to the Wnt/ beta-catenin pathway, the inactivating mutations TP53 have been associated with defects in the ability of tumor cells to produce key chemokines required for BAFT3 DC recruitment; p53 loss of function and lack of T-cell infiltration have been found in basal-like ER-negative breast cancers, but not in ER-positive breast cancer.	('TP53', 'Gene', '7157', (73, 77))	('inactivating', 'Var', (50, 62))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('tumor', 'Disease', (130, 135))	('beta-catenin', 'Gene', (24, 36))	('breast cancers', 'Disease', 'MESH:D001943', (298, 312))	('breast cancers', 'Disease', (298, 312))	('beta-catenin', 'Gene', '1499', (24, 36))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('loss of function', 'NegReg', (207, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (337, 350))	('breast cancers', 'Phenotype', 'HP:0003002', (298, 312))	('breast cancer', 'Disease', 'MESH:D001943', (337, 350))	('TP53', 'Gene', (73, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (298, 311))	('breast cancer', 'Disease', (337, 350))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('p53', 'Gene', '7157', (203, 206))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('breast cancer', 'Disease', 'MESH:D001943', (298, 311))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('p53', 'Gene', (203, 206))
72497	31057613	Therefore, either overactivation of the Wnt/beta-catenin pathway or loss of p53 is potential tumor-intrinsic factors that, altering on the ability of ACC cells to recruit BAFT3 DC cell and leading to T-cell exclusion, likely indicate that this type of tumor is potentially resistant to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('T-cell exclusion', 'CPA', (200, 216))	('tumor', 'Disease', (93, 98))	('beta-catenin', 'Gene', (44, 56))	('beta-catenin', 'Gene', '1499', (44, 56))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('ACC', 'Phenotype', 'HP:0006744', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('overactivation', 'PosReg', (18, 32))	('loss', 'Var', (68, 72))	('tumor', 'Disease', (252, 257))	('altering', 'Reg', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
72499	31057613	Interestingly, high levels of CTNNB1 expression have been associated as well with increased cortisol levels that likely contribute to the clinical resistance of ACC to immunotherapy.	('cortisol', 'Chemical', 'MESH:D006854', (92, 100))	('CTNNB1', 'Gene', (30, 36))	('cortisol levels', 'MPA', (92, 107))	('CTNNB1', 'Gene', '1499', (30, 36))	('ACC', 'Phenotype', 'HP:0006744', (161, 164))	('increased', 'PosReg', (82, 91))	('increased cortisol', 'Phenotype', 'HP:0003118', (82, 100))	('high levels', 'Var', (15, 26))
72500	31057613	Dysfunction of p53 due to mutations may contribute not only to carcinogenesis, but evidence indicates that it may also contribute immunologically to tumorigenesis and tumor progression, altering as well the immune-mediated response in the microenvironment.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('contribute', 'Reg', (40, 50))	('contribute', 'Reg', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('p53', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('mutations', 'Var', (26, 35))	('p53', 'Gene', '7157', (15, 18))	('tumor', 'Disease', (149, 154))	('altering', 'Reg', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('carcinogenesis', 'Disease', 'MESH:D063646', (63, 77))	('tumor', 'Disease', (167, 172))	('carcinogenesis', 'Disease', (63, 77))
72501	31057613	Indeed, in cancer cells with p53 dysfunction, restoring wild-type p53 drives immunological activity towards antitumor response.	('p53', 'Gene', '7157', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('p53', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('immunological activity', 'CPA', (77, 99))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('p53', 'Gene', '7157', (29, 32))	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', (11, 17))	('dysfunction', 'Var', (33, 44))	('p53', 'Gene', (66, 69))
72502	31057613	Accordingly, in acute myeloid leukemia, there was also a significant increase in PD-L1 expression in patients with TP53 mutations when compared to wild-type TP53 patients.	('TP53', 'Gene', (157, 161))	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (101, 109))	('increase', 'PosReg', (69, 77))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (16, 38))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('acute myeloid leukemia', 'Disease', (16, 38))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (22, 38))	('PD-L1', 'Gene', (81, 86))	('TP53', 'Gene', '7157', (115, 119))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (16, 38))	('expression', 'MPA', (87, 97))	('TP53', 'Gene', (115, 119))	('PD-L1', 'Gene', '29126', (81, 86))	('mutations', 'Var', (120, 129))	('TP53', 'Gene', '7157', (157, 161))
72511	31057613	Therefore, targeting functional variant mutant p53 requires a mutation-specific approach, ranging from the restoring of wild-type activity of the mutant p53 to the degradation of mutant protein.	('mutant', 'Var', (179, 185))	('wild-type', 'MPA', (120, 129))	('degradation', 'MPA', (164, 175))	('p53', 'Gene', (153, 156))	('mutant', 'Var', (146, 152))	('protein', 'Protein', (186, 193))	('p53', 'Gene', '7157', (153, 156))	('mutant', 'Var', (40, 46))	('p53', 'Gene', (47, 50))	('variant mutant', 'Var', (32, 46))	('p53', 'Gene', '7157', (47, 50))
72512	31057613	In ACC, TP53 mutations lead to the production of p53 protein that lacks its physiological function, appearing mostly in the late phase of tumor progression and associated with a poor outcome.	('p53', 'Gene', (49, 52))	('lead to', 'Reg', (23, 30))	('p53', 'Gene', '7157', (49, 52))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('TP53', 'Gene', '7157', (8, 12))	('protein', 'Protein', (53, 60))	('TP53', 'Gene', (8, 12))	('ACC', 'Phenotype', 'HP:0006744', (3, 6))	('mutations', 'Var', (13, 22))	('associated with', 'Reg', (160, 175))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
72513	31057613	Efforts in designing short synthetic peptides able to stabilize p53 or small molecules targeting key signaling interactions involving mutant p53 have been described, including gene therapy that uses viruses to deliver p53 to cancer cells.	('p53', 'Gene', (141, 144))	('p53', 'Gene', '7157', (141, 144))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (225, 231))	('p53', 'Gene', (218, 221))	('p53', 'Gene', '7157', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('p53', 'Gene', (64, 67))	('mutant', 'Var', (134, 140))	('p53', 'Gene', '7157', (64, 67))
72515	31057613	For example, the analysis of nonsynonymous mutations likely represents a useful predictive marker in selecting tumor types that are mostly likely to respond to the immune checkpoint therapy.	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('nonsynonymous mutations', 'Var', (29, 52))
72516	31057613	The mutational load, in fact, is defined as the total number of somatic nonsynonymous point mutations that, by generating novel gene products detected by the immune subsystem as foreign, may trigger an anticancer response.	('trigger', 'Reg', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('nonsynonymous point mutations', 'Var', (72, 101))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
72517	31057613	On this line, analyses of the mutational load in ACC tumors resulted in an intermediate mutational load value, thus suggesting that ACC could respond to immunotherapy.	('ACC', 'Disease', (49, 52))	('mutational load', 'MPA', (88, 103))	('ACC', 'Phenotype', 'HP:0006744', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutational', 'Var', (30, 40))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))	('ACC', 'Phenotype', 'HP:0006744', (49, 52))
72518	31057613	According to previous conclusions, recent evidences underlined the potential value of microsatellite instability as determinant of immune responsiveness in ACC patients.	('ACC', 'Phenotype', 'HP:0006744', (156, 159))	('patients', 'Species', '9606', (160, 168))	('ACC', 'Disease', (156, 159))	('microsatellite', 'Var', (86, 100))
72519	31057613	While in a normal cell, the length of microsatellites is maintained stable during multiple cell divisions by the mismatch repair (MMR) system, in cancer cells, the length of microsatellites can vary due to defects in the MMR system leading to the so-called "microsatellite instability" (MSI).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('length', 'MPA', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('defects', 'Var', (206, 213))	('MMR', 'Enzyme', (221, 224))
72520	31057613	Tumors with abnormal MMR processes and high MSI lead to additive mutations throughout the genome (e.g., "hypermutator" phenotype), a condition that is associated with response to immunotherapy.	('additive mutations', 'Var', (56, 74))	('MMR processes', 'CPA', (21, 34))	('MSI', 'Gene', (44, 47))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
72522	31057613	Furthermore, high MSI is a constitutional characteristic of the Lynch syndrome, an autosomal dominant genetic condition associated with high risk of colon cancer as well as other cancers including ACC.	('colon cancer', 'Disease', 'MESH:D015179', (149, 161))	('Lynch syndrome', 'Disease', 'MESH:D003123', (64, 78))	('ACC', 'Phenotype', 'HP:0006744', (197, 200))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colon cancer', 'Disease', (149, 161))	('high MSI', 'Var', (13, 21))	('Lynch syndrome', 'Disease', (64, 78))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))	('colon cancer', 'Phenotype', 'HP:0003003', (149, 161))
72523	31057613	Recently, mutations in the MUTYH gene encoding for a DNA glycosylase involved in base excision repair (BER) of DNA damage have been described in two series of ACC patients.	('patients', 'Species', '9606', (163, 171))	('ACC', 'Disease', (159, 162))	('described', 'Reg', (132, 141))	('MUTYH', 'Gene', (27, 32))	('MUTYH', 'Gene', '4595', (27, 32))	('mutations', 'Var', (10, 19))	('ACC', 'Phenotype', 'HP:0006744', (159, 162))
72529	31057613	Several lines of evidence indicate in fact that the cytotoxic effects of chemo- and radiotherapy may function as immunogenic treatments by inducing expression or reexpression of tumor-associated antigens (TAAs) or by inducing additional new mutations and, therefore, inducing T-cell-specific immune responses.	('tumor', 'Disease', (178, 183))	('inducing', 'Reg', (217, 225))	('T-cell-specific immune responses', 'CPA', (276, 308))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('inducing', 'Reg', (139, 147))	('expression', 'MPA', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('inducing', 'Reg', (267, 275))	('mutations', 'Var', (241, 250))
72603	30777494	However, the efficiency of the steroid modulator 4 for NCI-H295R cells became lower than that of cyclosporin A, in contrast to the order observed for K562/R7 cells.	('NCI-H295R', 'Var', (55, 64))	('cyclosporin A', 'Chemical', 'MESH:D016572', (97, 110))	('K562/R7', 'CellLine', 'CVCL:D573', (150, 157))	('steroid', 'Chemical', 'MESH:D013256', (31, 38))	('NCI-H295R', 'CellLine', 'CVCL:0458', (55, 64))	('lower', 'NegReg', (78, 83))	('efficiency', 'MPA', (13, 23))
72611	30777494	In MCF7-MTX cells, the effects on mitoxantrone accumulation produced by the same steroids were much lower (2-fold increase) than that produced by elacridar, a reference modulator of BCRP (11-fold increase).	('mitoxantrone', 'Chemical', 'MESH:D008942', (34, 46))	('steroids', 'Chemical', 'MESH:D013256', (81, 89))	('increase', 'PosReg', (114, 122))	('MCF7-MTX', 'CellLine', 'CVCL:0031', (3, 11))	('mitoxantrone accumulation', 'MPA', (34, 59))	('lower', 'NegReg', (100, 105))	('BCRP', 'Gene', (182, 186))	('BCRP', 'Gene', '9429', (182, 186))	('MCF7-MTX', 'Var', (3, 11))
72617	30777494	For K562/R7 cells, development of tumours in mice after sc injection was much slower (40 days) and therefore, treatments began 20 days after this injection.	('K562/R7', 'Var', (4, 11))	('mice', 'Species', '10090', (45, 49))	('slower', 'NegReg', (78, 84))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('K562/R7', 'CellLine', 'CVCL:D573', (4, 11))	('tumours', 'Disease', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
72642	30777494	None of the tested derivatives could strongly reverse the resistance mediated by the two other ABC transport proteins MRP1 or BCRP, measured in HL60-MRP1 cells and in MCF7-MTX cells, respectively and present only in low amounts in the two studied K562/R7 or NCI-H295R cell lines.	('MRP1', 'Gene', (118, 122))	('derivatives', 'Var', (19, 30))	('reverse', 'Reg', (46, 53))	('ABC', 'Gene', '10058', (95, 98))	('MRP1', 'Gene', '4363', (118, 122))	('MRP1', 'Gene', '4363', (149, 153))	('BCRP', 'Gene', (126, 130))	('ABC', 'Gene', (95, 98))	('BCRP', 'Gene', '9429', (126, 130))	('HL60-MRP1', 'CellLine', 'CVCL:0002', (144, 153))	('K562/R7', 'CellLine', 'CVCL:D573', (247, 254))	('NCI-H295R', 'CellLine', 'CVCL:0458', (258, 267))	('resistance', 'MPA', (58, 68))	('MRP1', 'Gene', (149, 153))	('MCF7-MTX', 'CellLine', 'CVCL:0031', (167, 175))
72669	30347759	Of note, ZFPM1/FOG1 mutations occurred in 50% of adrenocortical carcinoma patients and were localized in a hotspot region.	('ZFPM1/FOG1', 'Gene', (9, 19))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (49, 73))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (49, 73))	('patients', 'Species', '9606', (74, 82))	('adrenocortical carcinoma', 'Disease', (49, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('occurred', 'Reg', (30, 38))	('mutations', 'Var', (20, 29))
72679	30347759	The imbalance in favor of the PR-minus is found in many human malignancies and it can be due to inactivating mutations or silencing of the complete form and/or to increased expression of the PR-minus form.	('inactivating mutations', 'Var', (96, 118))	('increased', 'PosReg', (163, 172))	('human', 'Species', '9606', (56, 61))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('silencing', 'NegReg', (122, 131))	('expression', 'MPA', (173, 183))	('malignancies', 'Disease', (62, 74))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
72684	30347759	For instance, frameshift mutations of microsatellite repeats within the PRDM2 coding region are frequent events in various cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('frameshift mutations', 'Var', (14, 34))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('PRDM2', 'Gene', (72, 77))	('cancers', 'Disease', (123, 130))	('PRDM2', 'Gene', '7799', (72, 77))	('microsatellite repeats', 'Var', (38, 60))
72685	30347759	A recent study has described a frameshift mutation in the C-terminal region of PRDM2, affecting the (A)9 repeat within exon 8, as a microsatellite indel driver hotspot and as a driver mutation in microsatellite instability (MSI) colorectal cancer.	('colorectal cancer', 'Disease', (229, 246))	('frameshift mutation', 'Var', (31, 50))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('colorectal cancer', 'Disease', 'MESH:D015179', (229, 246))	('MSI', 'Disease', 'None', (224, 227))	('colorectal cancer', 'Phenotype', 'HP:0003003', (229, 246))	('PRDM2', 'Gene', (79, 84))	('PRDM2', 'Gene', '7799', (79, 84))	('MSI', 'Disease', (224, 227))	('affecting', 'Reg', (86, 95))	('microsatellite instability', 'Disease', (196, 222))
72686	30347759	Notably, a similar frameshift mutation was found to occur in a mononucleotide repeat (A7) of PRDM3/MECOM gene in this cancer type.	('cancer', 'Disease', (118, 124))	('PRDM3', 'Gene', (93, 98))	('occur', 'Reg', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MECOM', 'Gene', (99, 104))	('PRDM3', 'Gene', '2122', (93, 98))	('frameshift', 'Var', (19, 29))	('mononucleotide', 'Chemical', '-', (63, 77))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('MECOM', 'Gene', '2122', (99, 104))
72692	30347759	This evidence suggests that PRDMs are involved in human cancer through modulation of several processes, such as epigenetic modifications, genetic reprogramming, inflammation, and metabolic homeostasis.	('epigenetic modifications', 'Var', (112, 136))	('modulation', 'Reg', (71, 81))	('involved', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('metabolic homeostasis', 'CPA', (179, 200))	('genetic reprogramming', 'CPA', (138, 159))	('human', 'Species', '9606', (50, 55))	('inflammation', 'Disease', 'MESH:D007249', (161, 173))	('inflammation', 'Disease', (161, 173))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
72693	30347759	To date, both mutations and altered expression have been reported for some PRDMs in specific cancer entities.	('PRDMs', 'Disease', (75, 80))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('reported', 'Reg', (57, 65))	('mutations', 'Var', (14, 23))	('expression', 'MPA', (36, 46))
72699	30347759	Silent or synonymous mutations were 1531 (26.7% of total mutations) and ranged between 11% (PRDM6) and 41% (PRDM8) of the total mutations for each gene (Figure 1).	('PRDM6', 'Gene', '93166', (92, 97))	('PRDM6', 'Gene', (92, 97))	('mutations', 'Var', (57, 66))	('PRDM8', 'Gene', '56978', (108, 113))	('Silent', 'Var', (0, 6))	('PRDM8', 'Gene', (108, 113))
72701	30347759	Non-sense mutations were more recurrent in PRDM5 (23), PRDM9 (60), and ZFPM2/FOG2 (34), whereas splice sites disrupting mutations were more frequently detected in PRDM3/MECOM (13), PRDM9 (19), PRDM10 (14) and PRDM12 (13) (Figure 1).	('MECOM', 'Gene', (169, 174))	('PRDM9', 'Gene', (55, 60))	('PRDM9', 'Gene', '56979', (55, 60))	('PRDM5', 'Gene', '11107', (43, 48))	('PRDM10', 'Gene', '56980', (193, 199))	('MECOM', 'Gene', '2122', (169, 174))	('ZFPM2', 'Gene', '23414', (71, 76))	('ZFPM2', 'Gene', (71, 76))	('PRDM12', 'Gene', '59335', (209, 215))	('FOG2', 'Gene', '23414', (77, 81))	('FOG2', 'Gene', (77, 81))	('PRDM5', 'Gene', (43, 48))	('PRDM3', 'Gene', (163, 168))	('PRDM3', 'Gene', '2122', (163, 168))	('PRDM12', 'Gene', (209, 215))	('Non-sense mutations', 'Var', (0, 19))	('PRDM10', 'Gene', (193, 199))	('PRDM9', 'Gene', (181, 186))	('PRDM9', 'Gene', '56979', (181, 186))
72705	30347759	In detail, PRDM8 and PRDM15 were mutated at low rates in most of the analyzed cancer types except PAAD where they were both frequently mutated (16.0% and 11.2%, respectively).	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutated', 'Var', (33, 40))	('PRDM8', 'Gene', (11, 16))	('PRDM8', 'Gene', '56978', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PRDM15', 'Gene', '63977', (21, 27))	('PRDM15', 'Gene', (21, 27))
72711	30347759	Through this approach, we evaluated the percentage of samples with at least one mutated PRDM gene in each tumor type ranging from 1.02% (2/196) in LAML samples to 55.43% (51/92) in ACC samples.	('PRDM', 'Gene', (88, 92))	('mutated', 'Var', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
72713	30347759	Specifically, we found 11/18 (61%) multi-hit mutations in COAD, 10/11 (90%) in READ, and 23/47 (48%) in ACC (see Supplementary file S1).	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('mutations', 'Var', (45, 54))	('COAD', 'Disease', (58, 62))
72714	30347759	Missense mutations with a SIFT score ranging in the interval 0.0-0.05 and/or with a PolyPhen score in the interval 0.5-1 were considered as deleterious or probably damaging, respectively.	('SIFT', 'Disease', (26, 30))	('SIFT', 'Disease', 'None', (26, 30))	('Missense mutations', 'Var', (0, 18))
72717	30347759	Interestingly, a random sampling weighted on the size of the annotated protein domains demonstrated that somatic deleterious mutations were significantly enriched in the PR domain of PRDM1, PRDM5, PRDM6, PRDM8, PRDM9, PRDM12 and PRDM13 (p < 0.005).	('PRDM13', 'Gene', '59336', (229, 235))	('PRDM12', 'Gene', '59335', (218, 224))	('PRDM8', 'Gene', (204, 209))	('PRDM13', 'Gene', (229, 235))	('PRDM1', 'Gene', '639', (229, 234))	('PRDM1', 'Gene', '639', (183, 188))	('PRDM9', 'Gene', (211, 216))	('PRDM6', 'Gene', '93166', (197, 202))	('PRDM9', 'Gene', '56979', (211, 216))	('PRDM1', 'Gene', (229, 234))	('PRDM1', 'Gene', (183, 188))	('mutations', 'Var', (125, 134))	('PRDM5', 'Gene', '11107', (190, 195))	('PRDM6', 'Gene', (197, 202))	('PRDM12', 'Gene', (218, 224))	('PRDM5', 'Gene', (190, 195))	('PRDM1', 'Gene', '639', (218, 223))	('PRDM8', 'Gene', '56978', (204, 209))	('PRDM1', 'Gene', (218, 223))
72718	30347759	Another important aspect of cancer genetic studies is the presence of possible recurrent and hotspot mutations.	('cancer', 'Disease', (28, 34))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))
72719	30347759	Figure 3 illustrates mutations in PRDM genes recurring in more than three tumor types.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PRDM genes', 'Gene', (34, 44))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (21, 30))
72720	30347759	Interestingly, the frameshift mutation T/- K678X, despite affecting PRDM3/MECOM in a region not containing known domains, was recurrent in different tumor types; similarly, also the missense mutation G/A S237L occurred in a region without known domains but in many tumors.	('MECOM', 'Gene', (74, 79))	('G/A S237L', 'Var', (200, 209))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (265, 270))	('PRDM3', 'Gene', '2122', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('affecting', 'Reg', (58, 67))	('tumors', 'Disease', (265, 271))	('S237L', 'Mutation', 'rs748747672', (204, 209))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('K678X', 'Mutation', 'p.K678X', (43, 48))	('tumor', 'Disease', (149, 154))	('MECOM', 'Gene', '2122', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('T/- K678X', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('PRDM3', 'Gene', (68, 73))
72721	30347759	Otherwise, missense mutations affecting a Zn-finger domain and occurring in different tumors were observed for PRDM9, PRDM14, and PRDM16.	('PRDM16', 'Gene', '63976', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Zn-finger domain', 'MPA', (42, 58))	('PRDM9', 'Gene', (111, 116))	('affecting', 'Reg', (30, 39))	('PRDM9', 'Gene', '56979', (111, 116))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('missense mutations', 'Var', (11, 29))	('PRDM16', 'Gene', (130, 136))	('PRDM14', 'Gene', (118, 124))	('PRDM14', 'Gene', '63978', (118, 124))
72722	30347759	Likewise, PRDM12 was frequently mutated in a splice donor site in a region coding for the PR domain whereas in different tumor types, ZFPM2/FOG2 was affected by the missense mutation C/T R734C in a region without known domains.	('donor', 'Species', '9606', (52, 57))	('ZFPM2', 'Gene', '23414', (134, 139))	('R734C', 'Mutation', 'rs781567366', (187, 192))	('ZFPM2', 'Gene', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('PRDM12', 'Gene', '59335', (10, 16))	('PRDM12', 'Gene', (10, 16))	('FOG2', 'Gene', '23414', (140, 144))	('FOG2', 'Gene', (140, 144))	('C/T R734C', 'Var', (183, 192))	('affected', 'Reg', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
72723	30347759	In addition, PRDM2 and PRDM15 revealed an in-frame deletion in various cancers and PRDM11 a frameshift mutation.	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('in-frame deletion', 'Var', (42, 59))	('cancers', 'Disease', (71, 78))	('PRDM11', 'Gene', '56981', (83, 89))	('PRDM2', 'Gene', (13, 18))	('PRDM2', 'Gene', '7799', (13, 18))	('frameshift mutation', 'Var', (92, 111))	('PRDM15', 'Gene', '63977', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('PRDM11', 'Gene', (83, 89))	('PRDM15', 'Gene', (23, 29))
72724	30347759	Interestingly, all these mutations were particularly recurrent in ACC patients.	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (25, 34))	('ACC', 'Disease', (66, 69))
72725	30347759	Otherwise, the frameshift mutations E444X and P445X led to premature stop codons at the residues 669 and 796, respectively; both of the mutated proteins shared only the first 443 residues with the canonical protein whereas they changed in the 444-669 and 444-796 regions and missed respectively 337 and 210 residues at the C-terminal, which contains the last five zinc fingers of ZFPM1/FOG1.	('P445X', 'Var', (46, 51))	('E444X', 'Mutation', 'p.E444X', (36, 41))	('ZFPM1/FOG1', 'Gene', (380, 390))	('P445X', 'Mutation', 'p.P445X', (46, 51))	('E444X', 'Var', (36, 41))
72727	30347759	This method is based on the feature that cancer gene mutations frequently cluster in particular positions of the protein.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (53, 62))	('cluster', 'Reg', (74, 81))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
72728	30347759	Based on the scores of this analysis, ZFPM1/FOG1 can be considered as a cancer driver for ACC (Figure 4f) and PRDM8 for PAAD (Figure S2).	('ACC', 'Disease', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ZFPM1/FOG1', 'Var', (38, 48))	('PAAD', 'Disease', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('PRDM8', 'Gene', (110, 115))	('PRDM8', 'Gene', '56978', (110, 115))	('cancer', 'Disease', (72, 78))
72753	30347759	Remarkably, VEP analysis indicated that the percentage of total deleterious mutations across the tumor samples was high for most genes.	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mutations', 'Var', (76, 85))
72754	30347759	More interestingly, a random sampling weighted on the size of the annotated protein domains demonstrated that deleterious mutations were significantly enriched in the PR domain of PRDM1, PRDM5, PRDM6, PRDM8, PRDM9, PRDM12 and PRDM13.	('PRDM5', 'Gene', '11107', (187, 192))	('PRDM12', 'Gene', (215, 221))	('PRDM5', 'Gene', (187, 192))	('PRDM1', 'Gene', '639', (215, 220))	('PRDM1', 'Gene', (215, 220))	('PRDM8', 'Gene', '56978', (201, 206))	('PRDM13', 'Gene', '59336', (226, 232))	('PRDM1', 'Gene', '639', (180, 185))	('PRDM9', 'Gene', (208, 213))	('PRDM6', 'Gene', '93166', (194, 199))	('PRDM13', 'Gene', (226, 232))	('PRDM1', 'Gene', (180, 185))	('PRDM9', 'Gene', '56979', (208, 213))	('PRDM1', 'Gene', '639', (226, 231))	('PRDM8', 'Gene', (201, 206))	('PRDM12', 'Gene', '59335', (215, 221))	('PRDM1', 'Gene', (226, 231))	('PRDM6', 'Gene', (194, 199))	('mutations', 'Var', (122, 131))
72755	30347759	Frequent mutations disrupting the PR domain in tumor samples would be a mechanism for removing the tumor suppressor function of the PR-plus isoform in favor of the oncogenic PR-minus form.	('tumor', 'Disease', (99, 104))	('removing', 'NegReg', (86, 94))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (47, 52))
72756	30347759	A big challenge in cancer biology studies is distinguishing between mutations conferring a selective growth advantage to cancer cells (drivers) and those randomly accumulating and without significant effects on the oncogenic process (passengers).	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('growth advantage', 'CPA', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (68, 77))	('cancer', 'Disease', (121, 127))
72757	30347759	Moreover, recent studies have highlighted the existence of "mini-driver" genes with weaker tumor-promoting effects, thus expanding the previous driver-passenger dichotomy to a continuous model.	('genes', 'Var', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
72760	30347759	Notably, these hotspot mutations recurred also in other malignancies, such as COAD, KIRP, READ, STAD, and UCS, supporting an important role of this gene in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (156, 170))	('STAD', 'Disease', (96, 100))	('READ', 'Disease', (90, 94))	('carcinogenesis', 'Disease', (156, 170))	('KIRP', 'Disease', (84, 88))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('UCS', 'Disease', (106, 109))	('COAD', 'Disease', 'MESH:D029424', (78, 82))	('mutations', 'Var', (23, 32))	('malignancies', 'Disease', (56, 68))	('COAD', 'Disease', (78, 82))
72768	30347759	Additionally, a recent study identified a driver PRDM2 mutation in MSI colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MSI colorectal cancer', 'Disease', 'MESH:D015179', (67, 88))	('MSI colorectal cancer', 'Disease', (67, 88))	('PRDM2', 'Gene', '7799', (49, 54))	('mutation', 'Var', (55, 63))	('PRDM2', 'Gene', (49, 54))
72775	30347759	Moreover, it would be interesting to investigate whether these mutations contribute to cancer progression and metastasis, as well as whether they correlate with prognosis and/or with drug response and resistance.	('mutations', 'Var', (63, 72))	('contribute', 'Reg', (73, 83))	('cancer', 'Disease', (87, 93))	('metastasis', 'CPA', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
72778	30347759	To assess whether one or more PRDM proteins could be considered as cancer driver genes based on the positional clustering of the variants in the selected human cancers, we used a re-implementation of the software OncodriveCLUST within the maftools package.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('human', 'Species', '9606', (154, 159))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancer', 'Disease', (160, 166))	('cancers', 'Disease', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('variants', 'Var', (129, 137))
72779	30347759	Three-dimensional (3D) modeling of the human canonical and mutant ZFPM1/FOG1 proteins was carried out using I-TASSER.	('ZFPM1/FOG1', 'Gene', (66, 76))	('mutant', 'Var', (59, 65))	('human', 'Species', '9606', (39, 44))
72798	30159433	Dysregulation of miRNA expression in cancers is now being exploited for potential therapeutic applications.	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
72885	30159433	In CLL, low IgVh (immunoglobulin variable region heavy chain) gene mutation status and high ZAP-70 (70-kD zeta-associated protein) protein expression correlated with aggressive disease.	('CLL', 'Phenotype', 'HP:0005550', (3, 6))	('ZAP-70', 'Gene', '7535', (92, 98))	('correlated with', 'Reg', (150, 165))	('CLL', 'Disease', (3, 6))	('ZAP-70', 'Gene', (92, 98))	('aggressive disease', 'Disease', (166, 184))	('immunoglobulin variable region heavy chain', 'Gene', '28402', (18, 60))	('high', 'Var', (87, 91))	('IgVh', 'Gene', (12, 16))	('IgVh', 'Gene', '28402', (12, 16))	('aggressive disease', 'Disease', 'MESH:D001523', (166, 184))	('immunoglobulin variable region heavy chain', 'Gene', (18, 60))
72894	30159433	In the patients demonstrating no disease recurrence in the three-year follow up period, serum levels of miR-125b and miR-130a decreased at 2 months following treatment and normalised at one year.	('decreased', 'NegReg', (126, 135))	('miR-130a', 'Gene', (117, 125))	('miR-125b', 'Var', (104, 112))	('miR-130a', 'Gene', '406919', (117, 125))	('normalised', 'MPA', (172, 182))	('serum levels', 'MPA', (88, 100))	('patients', 'Species', '9606', (7, 15))
72910	30159433	Further to this, inhibition of miR-95 expression in the radioresistant cell line improved apoptosis efficiency following repeat radiotherapy.	('improved', 'PosReg', (81, 89))	('expression', 'MPA', (38, 48))	('inhibition', 'Var', (17, 27))	('miR-95', 'Gene', (31, 37))	('apoptosis efficiency', 'CPA', (90, 110))	('miR-95', 'Gene', '407052', (31, 37))
72911	30159433	In a mouse model with miR-95 knockout cell xenografts, the miR-95 knockout xenografts exhibited decreased tumour volume compared to the control cell xenografts following irradiation.	('knockout', 'Var', (66, 74))	('miR-95', 'Gene', (22, 28))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('miR-95', 'Gene', '407052', (22, 28))	('decreased', 'NegReg', (96, 105))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('tumour', 'Disease', (106, 112))	('mouse', 'Species', '10090', (5, 10))	('miR-95', 'Gene', (59, 65))	('miR-95', 'Gene', '407052', (59, 65))
72920	30159433	Furthermore, there was a median 20-month difference in disease specific survival between patients with a high miR-155 expression level compared to those with a low miR-155 level, as well as longer overall survival.	('high', 'Var', (105, 109))	('miR-155', 'Gene', '406947', (110, 117))	('miR-155', 'Gene', (164, 171))	('overall survival', 'CPA', (197, 213))	('miR-155', 'Gene', '406947', (164, 171))	('patients', 'Species', '9606', (89, 97))	('miR-155', 'Gene', (110, 117))	('longer', 'PosReg', (190, 196))	('expression', 'MPA', (118, 128))	('disease specific survival', 'CPA', (55, 80))
72922	30159433	GBC cell lines were transfected with miR-155 inhibitors, mimics, or negative controls.	('miR-155', 'Gene', (37, 44))	('inhibitors', 'Var', (45, 55))	('miR-155', 'Gene', '406947', (37, 44))
72923	30159433	Cells treated with miR-155 inhibitors showed significantly decreased proliferation and invasiveness compared to negative controls, and cells treated with miR-155 mimics displayed increased proliferation and invasiveness compared to negative controls.	('invasiveness', 'CPA', (87, 99))	('miR-155', 'Gene', (19, 26))	('proliferation', 'CPA', (189, 202))	('decreased', 'NegReg', (59, 68))	('miR-155', 'Gene', (154, 161))	('proliferation', 'CPA', (69, 82))	('invasiveness', 'CPA', (207, 219))	('inhibitors', 'Var', (27, 37))	('miR-155', 'Gene', '406947', (19, 26))	('miR-155', 'Gene', '406947', (154, 161))	('increased', 'PosReg', (179, 188))
72932	30159433	It has been found that naturally occurring non-coding RNAs can function as miRNA sponges in plants, animals and humans.	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (75, 78))	('humans', 'Species', '9606', (112, 118))	('non-coding', 'Var', (43, 53))	('RNAs', 'Protein', (54, 58))
72970	30159433	In malignant mesothelioma, it was shown that by replacing underexpressed miR-16 in preclinical models of mesothelioma, xenograft growth was inhibited.	('mesothelioma', 'Disease', 'MESH:D008654', (105, 117))	('mesothelioma', 'Disease', (13, 25))	('malignant mesothelioma', 'Disease', (3, 25))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (3, 25))	('clinical', 'Species', '191496', (86, 94))	('inhibited', 'NegReg', (140, 149))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (3, 25))	('miR-16', 'Gene', (73, 79))	('mesothelioma', 'Disease', (105, 117))	('replacing', 'Var', (48, 57))	('miR-16', 'Gene', '51573', (73, 79))	('xenograft growth', 'CPA', (119, 135))
72983	30159433	Prostate cancer, amongst other cancers, exhibit loss of heterozygosity (LOH) at the 13q genetic locus and studies have examined the frequency of 13q LOH in prostate cancer, with increased LOH at 13q correlated with higher stage and grade prostate cancers.	('prostate cancer', 'Disease', (156, 171))	('prostate cancers', 'Disease', 'MESH:D011471', (238, 254))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', (247, 254))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('prostate cancer', 'Disease', 'MESH:D011471', (238, 253))	('correlated with', 'Reg', (199, 214))	('prostate cancer', 'Phenotype', 'HP:0012125', (238, 253))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancers', 'Disease', (31, 38))	('higher', 'Disease', (215, 221))	('prostate cancers', 'Phenotype', 'HP:0012125', (238, 254))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))	('prostate cancers', 'Disease', (238, 254))	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('LOH', 'Var', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Prostate cancer', 'Disease', (0, 15))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
73045	29768344	In the English literature, 3 patients showed a germline mutation of the p53 gene.	('patients', 'Species', '9606', (29, 37))	('germline mutation', 'Var', (47, 64))	('p53', 'Gene', (72, 75))
73046	29768344	One with simultaneous ACC and ganglioneuroblastoma possessed a single base substitution in codon 248, the other one with synchronous rhabdomyosarcoma, osteosarcoma, and ACC showed a mutation at codon 273.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (133, 149))	('osteosarcoma', 'Disease', (151, 163))	('ACC', 'Phenotype', 'HP:0006744', (169, 172))	('ACC', 'Phenotype', 'HP:0006744', (22, 25))	('ganglioneuroblastoma', 'Phenotype', 'HP:0006747', (30, 50))	('osteosarcoma', 'Phenotype', 'HP:0002669', (151, 163))	('ACC', 'Disease', (22, 25))	('osteosarcoma', 'Disease', 'MESH:D012516', (151, 163))	('ganglioneuroblastoma', 'Disease', (30, 50))	('synchronous rhabdomyosarcoma', 'Disease', (121, 149))	('synchronous rhabdomyosarcoma', 'Disease', 'MESH:D009378', (121, 149))	('neuroblastoma', 'Phenotype', 'HP:0003006', (37, 50))	('ganglioneuroblastoma', 'Disease', 'MESH:D018305', (30, 50))	('single base substitution in', 'Var', (63, 90))
73047	29768344	Another one with synchronous neuroblastoma and ACC had I162F germline p53 mutation.	('I162F', 'Mutation', 'p.I162F', (55, 60))	('p53', 'Gene', (70, 73))	('neuroblastoma', 'Phenotype', 'HP:0003006', (29, 42))	('synchronous neuroblastoma', 'Disease', (17, 42))	('ACC', 'Phenotype', 'HP:0006744', (47, 50))	('I162F', 'Var', (55, 60))	('synchronous neuroblastoma', 'Disease', 'MESH:D009378', (17, 42))
73048	29768344	Our case was also found to have diffuse nuclear positive staining for p53 at ACC and ovarian tumor, suggesting that p53 mutation may be one of the molecular events of the tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ovarian tumor', 'Disease', (85, 98))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mutation', 'Var', (120, 128))	('tumor', 'Disease', (93, 98))	('ACC', 'Phenotype', 'HP:0006744', (77, 80))	('ovarian tumor', 'Phenotype', 'HP:0100615', (85, 98))	('ovarian tumor', 'Disease', 'MESH:D010051', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('p53', 'Gene', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
73049	29768344	Patient from a Lynch syndrome (LS) family with a germline mutation c.2063T>G (p.M688R) in the MSH2 gene can develop an ACC with the same MSH2 mutation, which indicated that ACC is probably due to the mismatch repair defect.	('c.2063T>G', 'Var', (67, 76))	('ACC', 'Phenotype', 'HP:0006744', (173, 176))	('MSH2', 'Gene', (137, 141))	('p.M688R', 'Mutation', 'rs63749993', (78, 85))	('develop', 'PosReg', (108, 115))	('Lynch syndrome', 'Disease', (15, 29))	('Lynch syndrome', 'Disease', 'MESH:D003123', (15, 29))	('ACC', 'Phenotype', 'HP:0006744', (119, 122))	('ACC', 'Disease', (119, 122))	('MSH2', 'Gene', (94, 98))	('Patient', 'Species', '9606', (0, 7))	('c.2063T>G', 'Mutation', 'rs63749993', (67, 76))
73064	27698791	Mutations of miRNA processing genes have been observed in human cancers, e.g., TARBP2 and exportin-5 in microsatellite unstable colon tumors, Dicer1 in pleuropulmonary blastomas and Drosha in Wilms' tumors.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('human', 'Species', '9606', (58, 63))	("Wilms' tumors", 'Disease', 'MESH:D009396', (192, 205))	('TARBP2', 'Gene', '6895', (79, 85))	('colon tumors', 'Disease', 'MESH:D015179', (128, 140))	('TARBP2', 'Gene', (79, 85))	('pleuropulmonary blastomas', 'Phenotype', 'HP:0100528', (152, 177))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('colon tumors', 'Phenotype', 'HP:0100273', (128, 140))	('observed', 'Reg', (46, 54))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', (64, 71))	('colon tumors', 'Disease', (128, 140))	("Wilms' tumors", 'Disease', (192, 205))	("Wilms' tumors", 'Phenotype', 'HP:0002667', (192, 205))	('miRNA processing genes', 'Gene', (13, 35))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('microsatellite', 'Var', (104, 118))	('Dicer1', 'Gene', (142, 148))	('pleuropulmonary blastomas', 'Disease', (152, 177))	('Drosha', 'Gene', (182, 188))	('pleuropulmonary blastomas', 'Disease', 'MESH:C537516', (152, 177))	('Drosha', 'Gene', '29102', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('exportin-5', 'Gene', (90, 100))	('exportin-5', 'Gene', '57510', (90, 100))
73068	27698791	Epigenetic changes, such as DNA methylation and histone modifications, potentially affect the transcription of miRNA genes in cancer, e.g., hypermethylation of miR-337, miR-432, and miR-371 have been often observed in ovarian cancer.	('miR-371', 'Gene', (182, 189))	('observed', 'Reg', (206, 214))	('miRNA genes', 'Gene', (111, 122))	('miR-432', 'Gene', (169, 176))	('ovarian cancer', 'Disease', (218, 232))	('cancer', 'Disease', (126, 132))	('miR-432', 'Gene', '574451', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('transcription', 'MPA', (94, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (218, 232))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('affect', 'Reg', (83, 89))	('miR-337', 'Gene', '442905', (160, 167))	('hypermethylation', 'Var', (140, 156))	('miR-337', 'Gene', (160, 167))	('miR-371', 'Gene', '442916', (182, 189))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', (226, 232))	('ovarian cancer', 'Disease', 'MESH:D010051', (218, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
73069	27698791	The epigenetic silencing of miR-15a, miR-16 and miR-29b by histone deacetylases was reported recently in chronic lymphocytic leukemia (CLL).	('miR-15a', 'Gene', '406948', (28, 35))	('chronic lymphocytic leukemia', 'Disease', (105, 133))	('epigenetic silencing', 'Var', (4, 24))	('miR-15a', 'Gene', (28, 35))	('miR-29b', 'Gene', '407024', (48, 55))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (105, 133))	('CLL', 'Phenotype', 'HP:0005550', (135, 138))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('miR-16', 'Gene', (37, 43))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (105, 133))	('reported', 'Reg', (84, 92))	('miR-16', 'Gene', '51573', (37, 43))	('miR-29b', 'Gene', (48, 55))
73070	27698791	Another main contributor of miRNA deregulation in cancer is the copy number abnormalities of miRNA genes.	('miRNA genes', 'Gene', (93, 104))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('copy number abnormalities', 'Var', (64, 89))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
73071	27698791	One classical example is the deletion of miR-16 and miR-15a at 13q14 in CLL patients, in which approximately 60% of the patients had deletions of these miRNA genes.	('deletion', 'Var', (29, 37))	('patients', 'Species', '9606', (76, 84))	('deletions', 'Var', (133, 142))	('miR-15a', 'Gene', '406948', (52, 59))	('miR-16', 'Gene', (41, 47))	('miRNA', 'Gene', (152, 157))	('miR-15a', 'Gene', (52, 59))	('CLL', 'Phenotype', 'HP:0005550', (72, 75))	('miR-16', 'Gene', '51573', (41, 47))	('patients', 'Species', '9606', (120, 128))
73073	27698791	These characteristics include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling the stimulation of angiogenesis, invasion of tissue, metastasis, replicative immortality, deregulation of cellular metabolism, elevation in inflammation, instability in genome and immune compromises.	('inflammation', 'Disease', (265, 277))	('stimulation', 'PosReg', (129, 140))	('elevation', 'PosReg', (252, 261))	('replicative immortality', 'CPA', (190, 213))	('sustaining', 'MPA', (30, 40))	('invasion of tissue', 'CPA', (158, 176))	('deregulation', 'Var', (215, 227))	('angiogenesis', 'CPA', (144, 156))	('metastasis', 'CPA', (178, 188))	('cellular metabolism', 'MPA', (231, 250))	('inflammation', 'Disease', 'MESH:D007249', (265, 277))	('instability', 'Var', (279, 290))	('enabling', 'PosReg', (116, 124))	('immune compromises', 'CPA', (305, 323))
73076	27698791	miRNAs may therefore function as oncogenic or tumor suppressive miRNAs depending on cellular context.	('miRNAs', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
73078	27698791	Previous findings have shown the contribution of the deregulation of miR-17-92 in cancer through multiple pathways, such as metastasis and senescence.	('miR-17-92', 'Gene', '407975', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('senescence', 'CPA', (139, 149))	('miR-17-92', 'Gene', (69, 78))	('metastasis', 'CPA', (124, 134))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('deregulation', 'Var', (53, 65))
73079	27698791	Notably, inhibition of this cluster in cervical cancer led to elevated oncogenic activity of E2F1, suggesting its tumor suppressive activity is dependent on cellular context.	('E2F1', 'Gene', '1869', (93, 97))	('E2F1', 'Gene', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cervical cancer', 'Disease', (39, 54))	('cervical cancer', 'Disease', 'MESH:D002583', (39, 54))	('elevated', 'PosReg', (62, 70))	('tumor', 'Disease', (114, 119))	('oncogenic activity', 'CPA', (71, 89))	('inhibition', 'Var', (9, 19))
73088	27698791	These miRNAs were significantly downregulated in approximately 60% of CLL patients due to the deletion of the 13q14 region where these miRNAs reside.	('13q14', 'Gene', (110, 115))	('downregulated', 'NegReg', (32, 45))	('deletion', 'Var', (94, 102))	('patients', 'Species', '9606', (74, 82))	('CLL', 'Phenotype', 'HP:0005550', (70, 73))
73089	27698791	Deletion of this locus and a decreased expression of these miRNAs have been reported in other cancer types, such as lung and prostate cancers.	('lung and prostate cancers', 'Disease', 'MESH:D011471', (116, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('prostate cancers', 'Phenotype', 'HP:0012125', (125, 141))	('decreased', 'NegReg', (29, 38))	('expression', 'MPA', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (94, 100))	('Deletion', 'Var', (0, 8))
73119	27043680	A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found.	('c.215C>G', 'Var', (49, 57))	('TP53', 'Gene', (24, 28))	('c.215C>G', 'Mutation', 'rs1042522', (49, 57))	('Pro72Arg', 'Var', (62, 70))	('Pro72Arg', 'SUBSTITUTION', 'None', (62, 70))	('TP53', 'Gene', '7157', (24, 28))
73122	27043680	These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients.	('metastatic ACC', 'Disease', (75, 89))	('men', 'Species', '9606', (67, 70))	('mitotane', 'Var', (28, 36))	('mitotane', 'Chemical', 'MESH:D008939', (28, 36))	('patients', 'Species', '9606', (147, 155))
73123	27043680	The annual incidence of adrenocortical carcinoma (ACC) is 0.7 to 2.0 cases per million population with a higher incidence in southern Brazil due to the high prevalence (0.27%) of a specific TP53 germline mutation (R337H).	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (24, 48))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (24, 48))	('TP53', 'Gene', '7157', (190, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('TP53', 'Gene', (190, 194))	('R337H', 'Mutation', 'rs121912664', (214, 219))	('adrenocortical carcinoma', 'Disease', (24, 48))	('R337H', 'Var', (214, 219))
73149	27043680	Only a heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found.	('c.215C>G', 'Var', (45, 53))	('TP53', 'Gene', (20, 24))	('c.215C>G', 'Mutation', 'rs1042522', (45, 53))	('Pro72Arg', 'Var', (58, 66))	('Pro72Arg', 'SUBSTITUTION', 'None', (58, 66))	('TP53', 'Gene', '7157', (20, 24))
73183	27043680	D'Avolio et al showed that the single-nucleotide polymorphism (SNP) CYP2B6 rs3745274GT/TT was a predictor of mitotane concentrations of at least 14 mg/L after 3 months of treatment.	('men', 'Species', '9606', (176, 179))	('mitotane concentrations', 'MPA', (109, 132))	('rs3745274GT/TT', 'Var', (75, 89))	('CYP2B6', 'Gene', '1555', (68, 74))	('single-nucleotide', 'Var', (31, 48))	('CYP2B6', 'Gene', (68, 74))	('mitotane', 'Chemical', 'MESH:D008939', (109, 117))
73186	27043680	Finally, Volante et al evaluated the gene expression of ribonucleotide reductase large subunit 1 (RRM1) in ACC and showed that high RRM1 gene expression was associated to shorter disease-free survival (DFS); in patients with low RRM1 gene expression, adjuvant mitotane was associated with improved DFS, whereas this effect was lost in cases with high RRM1 expression.	('RRM1', 'Gene', (98, 102))	('shorter', 'NegReg', (171, 178))	('low', 'Var', (225, 228))	('disease-free survival', 'CPA', (179, 200))	('DFS', 'MPA', (298, 301))	('patients', 'Species', '9606', (211, 219))	('RRM1', 'Gene', '6240', (132, 136))	('improved', 'PosReg', (289, 297))	('mitotane', 'Chemical', 'MESH:D008939', (260, 268))	('RRM1', 'Gene', (132, 136))	('RRM1', 'Gene', '6240', (351, 355))	('RRM1', 'Gene', (351, 355))	('RRM1', 'Gene', '6240', (229, 233))	('RRM1', 'Gene', (229, 233))	('RRM1', 'Gene', '6240', (98, 102))
73196	26690546	Pharmacological inactivation of Chk2, CDK2 or ERK1/2 or depletion of CDK2 or Chk2 inhibited the centrosome amplification in ETO-treated ACT cells.	('ETO-', 'Chemical', 'MESH:D005047', (124, 128))	('Chk2', 'Gene', (32, 36))	('Chk2', 'Gene', '11200', (77, 81))	('CDK2', 'Gene', (38, 42))	('inhibited', 'NegReg', (82, 91))	('Chk2', 'Gene', (77, 81))	('CDK2', 'Gene', (69, 73))	('ERK1/2', 'Gene', (46, 52))	('inactivation', 'Var', (16, 28))	('CDK2', 'Gene', '1017', (38, 42))	('CDK2', 'Gene', '1017', (69, 73))	('depletion', 'Var', (56, 65))	('centrosome amplification', 'MPA', (96, 120))	('ERK1/2', 'Gene', '5595;5594', (46, 52))	('Chk2', 'Gene', '11200', (32, 36))
73217	26690546	When cells harbor supernumerary centrosomes and there is deficiency in DNA repair machinery, these cells are more susceptible to malignancy.	('malignancy', 'Disease', (129, 139))	('deficiency', 'NegReg', (57, 67))	('supernumerary', 'Var', (18, 31))	('malignancy', 'Disease', 'MESH:D009369', (129, 139))	('susceptible', 'Reg', (114, 125))
73220	26690546	In addition, overexpression of Cyclin A and aberrant activation of CDK2 induces centrosome amplification due to centrosome over-duplication.	('CDK2', 'Gene', '1017', (67, 71))	('activation', 'PosReg', (53, 63))	('centrosome amplification', 'MPA', (80, 104))	('Cyclin A', 'Gene', '890', (31, 39))	('overexpression', 'PosReg', (13, 27))	('over-duplication', 'PosReg', (123, 139))	('Cyclin A', 'Gene', (31, 39))	('aberrant', 'Var', (44, 52))	('CDK2', 'Gene', (67, 71))	('centrosome', 'MPA', (112, 122))
73232	26690546	It has been shown that autophagy protects cancer cells from apoptosis when cells treated with anticancer drugs and thus co-treatment of chloroquine with anticancer drugs accelerates cell death in several cancers such as brain tumor and leukemia.	('accelerates', 'PosReg', (170, 181))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (98, 104))	('autophagy', 'CPA', (23, 32))	('chloroquine', 'Chemical', 'MESH:D002738', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('chloroquine', 'Var', (136, 147))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('leukemia', 'Phenotype', 'HP:0001909', (236, 244))	('cancer', 'Disease', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cell death', 'CPA', (182, 192))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (157, 163))	('brain tumor', 'Phenotype', 'HP:0030692', (220, 231))	('leukemia', 'Disease', (236, 244))	('leukemia', 'Disease', 'MESH:D007938', (236, 244))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('brain tumor', 'Disease', 'MESH:D001932', (220, 231))	('brain tumor', 'Disease', (220, 231))	('cancer', 'Disease', (42, 48))	('co-treatment', 'Var', (120, 132))
73238	26690546	ETO affects cell cycle progression by inducing DNA damage responses.	('DNA damage responses', 'MPA', (47, 67))	('inducing', 'Reg', (38, 46))	('ETO', 'Chemical', 'MESH:D005047', (0, 3))	('affects', 'Reg', (4, 11))	('cell cycle progression', 'CPA', (12, 34))	('ETO', 'Var', (0, 3))
73252	26690546	Although G2/M population was increased in ETO-treated cells, the population of mitotic cells was reduced (Figure 2c).	('G2/M population', 'CPA', (9, 24))	('ETO-treated', 'Var', (42, 53))	('increased', 'PosReg', (29, 38))	('reduced', 'NegReg', (97, 104))	('population of mitotic cells', 'CPA', (65, 92))	('ETO-', 'Chemical', 'MESH:D005047', (42, 46))
73254	26690546	We found that, during prolonged treatment of sublethal dose of ETO, the population of cells with larger nucleus was increased (Figures 3a and b).	('increased', 'PosReg', (116, 125))	('ETO', 'Chemical', 'MESH:D005047', (63, 66))	('ETO', 'Gene', (63, 66))	('sublethal dose', 'Var', (45, 59))
73268	26690546	Inactivation of CDK2 alleviated the centrosome amplification in ETO-treated ACT cells in a dose-dependent manner (Figure 4f).	('CDK2', 'Gene', '1017', (16, 20))	('centrosome amplification', 'MPA', (36, 60))	('ETO-', 'Chemical', 'MESH:D005047', (64, 68))	('alleviated', 'NegReg', (21, 31))	('CDK2', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
73281	26690546	Centrosome amplification induced cellular senescence in ETO-treated ACT cells (Figures 3c and d), and thus, we checked whether chloroquine alleviated cellular senescence.	('chloroquine', 'Chemical', 'MESH:D002738', (127, 138))	('cellular senescence', 'MPA', (33, 52))	('ETO-', 'Chemical', 'MESH:D005047', (56, 60))	('Centrosome', 'Var', (0, 10))	('induced', 'Reg', (25, 32))
73286	26690546	In addition to ETO, it is known that treatment of hydroxyurea results in prolonged replication stress and induces centrosome amplification.	('hydroxyurea', 'Var', (50, 61))	('centrosome amplification', 'MPA', (114, 138))	('hydroxyurea', 'Chemical', 'MESH:D006918', (50, 61))	('induces', 'Reg', (106, 113))	('replication stress', 'CPA', (83, 101))	('ETO', 'Chemical', 'MESH:D005047', (15, 18))
73291	26690546	In ACT cells, chloroquine did not inhibit Chk2 activation (Supplementary Figure S2E) although inactivation of Chk2 reduced centrosome amplification indicating that the distinct role of DNA damage response in controlling centrosome homeostasis.	('Chk2', 'Gene', '11200', (110, 114))	('reduced', 'NegReg', (115, 122))	('chloroquine', 'Chemical', 'MESH:D002738', (14, 25))	('Chk2', 'Gene', '11200', (42, 46))	('centrosome amplification', 'MPA', (123, 147))	('inactivation', 'Var', (94, 106))	('Chk2', 'Gene', (42, 46))	('Chk2', 'Gene', (110, 114))
73298	26690546	These data were consistent with our previous results that inactivation of CDK2 and ERK1/2 alleviated ETO-induced centrosome amplification.	('ETO-induced centrosome amplification', 'MPA', (101, 137))	('alleviated', 'NegReg', (90, 100))	('ETO-', 'Chemical', 'MESH:D005047', (101, 105))	('CDK2', 'Gene', '1017', (74, 78))	('ERK1/2', 'Gene', (83, 89))	('inactivation', 'Var', (58, 70))	('ERK1/2', 'Gene', '5595;5594', (83, 89))	('CDK2', 'Gene', (74, 78))
73309	26690546	In our current study, we found that treatment of ACT cells with chloroquine also inhibited cell growth.	('cell growth', 'CPA', (91, 102))	('inhibited', 'NegReg', (81, 90))	('chloroquine', 'Chemical', 'MESH:D002738', (64, 75))	('chloroquine', 'Var', (64, 75))
73315	26690546	It is known that supernumerary centrosomes contribute to chemoresistance and poor outcome in tumor cells.	('contribute', 'Reg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('chemoresistance', 'CPA', (57, 72))	('supernumerary', 'Var', (17, 30))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
73317	26690546	This ETO-induced ERK activation was facilitated by autophagy as inhibition of autophagy alleviated ERK activation and centrosome amplification.	('centrosome amplification', 'CPA', (118, 142))	('alleviated', 'NegReg', (88, 98))	('inhibition', 'Var', (64, 74))	('ERK', 'Gene', '5594', (99, 102))	('ERK', 'Gene', (99, 102))	('ERK', 'Gene', '5594', (17, 20))	('ETO-', 'Chemical', 'MESH:D005047', (5, 9))	('ERK', 'Gene', (17, 20))
73320	26690546	On the contrary, inactivation of MEK/ERK signaling inhibits autophagy in response to chemotherapy drugs.	('inactivation', 'Var', (17, 29))	('inhibits', 'NegReg', (51, 59))	('ERK', 'Gene', '5594', (37, 40))	('ERK', 'Gene', (37, 40))	('MEK', 'Gene', (33, 36))	('MEK', 'Gene', '5609', (33, 36))	('autophagy', 'CPA', (60, 69))
73373	22019902	Interestingly, StAR, which is responsible for the limiting step of cholesterol transport into the mitochondria, is also directly activated by PKA phosphorylation.	('PKA phosphorylation', 'Var', (142, 161))	('cholesterol', 'Chemical', 'MESH:D002784', (67, 78))	('StAR', 'Gene', '20845', (15, 19))	('StAR', 'Gene', (15, 19))
73378	22019902	Autonomous activation of ZF has been linked to induction of the cAMP/PKA pathway resulting from alterations occurring at different levels of signal transduction: ectopic expression of illegitimate G protein coupled receptors, activating mutations of the GNAS gene (encoding Gsalpha subunit), inactivating mutations of genes encoding RIalpha (PRKAR1A) or encoding phosphodiesterases (PDE11A4 and PDE8B).	('Gsalpha', 'Gene', (274, 281))	('phosphodiesterases', 'Gene', (363, 381))	('cAMP/PKA pathway', 'Pathway', (64, 80))	('Gsalpha', 'Gene', '14683', (274, 281))	('inactivating mutations', 'Var', (292, 314))	('activating', 'PosReg', (226, 236))	('cAMP', 'Chemical', 'MESH:D000242', (64, 68))	('GNAS', 'Gene', (254, 258))	('RIalpha', 'Gene', (333, 340))	('PDE11A', 'Gene', '50940', (383, 389))	('illegitimate G protein coupled receptors', 'Protein', (184, 224))	('expression', 'Species', '29278', (170, 180))	('GNAS', 'Gene', '14683', (254, 258))	('PDE11A', 'Gene', (383, 389))	('mutations', 'Var', (237, 246))	('RIalpha', 'Gene', '19084', (333, 340))	('phosphodiesterases', 'Gene', '50940;241489', (363, 381))
73380	22019902	Indeed, presence of ectopically expressed G-protein coupled receptors or GNAS mutations were found in ACTH-independent macronodular adrenal hyperplasia (AIMAH).	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (119, 151))	('mutations', 'Var', (78, 87))	('macronodular adrenal hyperplasia', 'Disease', (119, 151))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (119, 151))	('G-protein coupled receptors', 'Protein', (42, 69))	('GNAS', 'Gene', (73, 77))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (132, 151))	('GNAS', 'Gene', '14683', (73, 77))	('found', 'Reg', (93, 98))
73381	22019902	Both PRKAR1A mutations and PDE mutations have been associated with isolated micronodular adrenocortical disease, notably with PPNAD.	('mutations', 'Var', (31, 40))	('PRKAR1A', 'Gene', (5, 12))	('PDE', 'Gene', (27, 30))	('associated', 'Reg', (51, 61))	('PDE', 'Gene', '50940;241489', (27, 30))	('PPNAD', 'Disease', (126, 131))	('adrenocortical disease', 'Disease', (89, 111))	('mutations', 'Var', (13, 22))	('adrenocortical disease', 'Disease', 'MESH:D018268', (89, 111))
73382	22019902	Loss of heterozygosity on the wild-type allele was associated with PRKAR1A and PDE11A4 inactivating mutations.	('PRKAR1A', 'Gene', (67, 74))	('inactivating mutations', 'Var', (87, 109))	('Loss', 'NegReg', (0, 4))	('PDE11A', 'Gene', (79, 85))	('PDE11A', 'Gene', '50940', (79, 85))
73384	22019902	Strikingly, in many of the patients displaying PRKAR1A mutations, PPNAD was detected as part of Carney complex.	('PPNAD', 'Disease', (66, 71))	('Carney complex', 'Disease', (96, 110))	('PRKAR1A', 'Gene', (47, 54))	('mutations', 'Var', (55, 64))	('detected', 'Reg', (76, 84))	('patients', 'Species', '9606', (27, 35))
73386	22019902	Moreover, altered cAMP signalling, somatic PRKAR1A mutations and somatic losses in PRKAR1A locus have all been reported in sporadic adrenocortical adenomas and carcinomas.	('losses', 'NegReg', (73, 79))	('altered', 'Reg', (10, 17))	('mutations', 'Var', (51, 60))	('PRKAR1A', 'Gene', (43, 50))	('reported', 'Reg', (111, 119))	('cAMP signalling', 'MPA', (18, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (132, 155))	('PRKAR1A', 'Gene', (83, 90))	('cAMP', 'Chemical', 'MESH:D000242', (18, 22))	('adrenocortical adenomas and carcinomas', 'Disease', 'MESH:D018246', (132, 170))
73390	22019902	Both gene inactivation strategies failed to induce adrenal defects during foetal development or the neonatal period but later induced a progressive atrophy of the ZF.	('atrophy', 'Disease', (148, 155))	('inactivation', 'Var', (10, 22))	('adrenal defects', 'Phenotype', 'HP:0000834', (51, 66))	('adrenal defects', 'Disease', 'MESH:D000310', (51, 66))	('induced', 'Reg', (126, 133))	('adrenal defects', 'Disease', (51, 66))	('atrophy', 'Disease', 'MESH:D001284', (148, 155))
73398	22019902	These mouse phenotypes reflect what is seen in human with Familial Glucocorticoid deficiency type 1, a disease mostly resulting from mutations in MC2R that impair its trafficking to the membrane.	('MC2R', 'Gene', (146, 150))	('Familial Glucocorticoid deficiency type 1', 'Disease', (58, 99))	('Familial Glucocorticoid deficiency type 1', 'Disease', 'MESH:C565974', (58, 99))	('mutations', 'Var', (133, 142))	('resulting from', 'Reg', (118, 132))	('trafficking to the membrane', 'MPA', (167, 194))	('human', 'Species', '9606', (47, 52))	('Glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (67, 92))	('mouse', 'Species', '10090', (6, 11))
73405	22019902	Both PDE8B and PDE11A4 have been found mutated in some patients developing adrenal hyperplasia, in association with loss of heterozygosity at the chromosomal region containing the PDE11A4 gene.	('PDE11A', 'Gene', (15, 21))	('PDE11A', 'Gene', '50940', (15, 21))	('adrenal hyperplasia', 'Disease', (75, 94))	('mutated', 'Var', (39, 46))	('patients', 'Species', '9606', (55, 63))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (75, 94))	('PDE11A', 'Gene', (180, 186))	('PDE11A', 'Gene', '50940', (180, 186))	('PDE8B', 'Gene', (5, 10))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (75, 94))
73408	22019902	It is consistent with the human data where PDE11A mutations were considered as phenotype modifiers of already pre-existing conditions resulting from PRKAR1A mutations (especially as an enhancer of phenotype in males).	('PDE11A', 'Gene', (43, 49))	('enhancer', 'PosReg', (185, 193))	('mutations', 'Var', (50, 59))	('mutations', 'Var', (157, 166))	('PRKAR1A', 'Gene', (149, 156))	('PDE11A', 'Gene', '50940', (43, 49))	('human', 'Species', '9606', (26, 31))
73409	22019902	Similarly, PDE8B variants seemed to predispose to adrenal defects, but were not clearly shown to promote adrenal tumour formation.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('adrenal defects', 'Disease', (50, 65))	('variants', 'Var', (17, 25))	('adrenal tumour', 'Disease', (105, 119))	('PDE8B', 'Gene', (11, 16))	('adrenal tumour', 'Disease', 'MESH:D000310', (105, 119))	('predispose', 'Reg', (36, 46))	('adrenal defects', 'Phenotype', 'HP:0000834', (50, 65))	('promote', 'PosReg', (97, 104))	('adrenal defects', 'Disease', 'MESH:D000310', (50, 65))
73414	22019902	A more severe loss of RIalpha protein was achieved by an antisense strategy, which resulted in decreases up to 70% in some tissues.	('antisense', 'Var', (57, 66))	('RIalpha', 'Gene', (22, 29))	('RIalpha', 'Gene', '19084', (22, 29))	('decreases', 'NegReg', (95, 104))	('loss', 'NegReg', (14, 18))
73417	22019902	In our system, genetic ablation occurs in adrenocortical cells at E14.5 and targets all cortical subtypes in adults.	('E14', 'Gene', '114729', (66, 69))	('adrenocortical', 'Disease', 'MESH:D018268', (42, 56))	('adrenocortical', 'Disease', (42, 56))	('E14', 'Gene', (66, 69))	('genetic', 'Var', (15, 22))
73456	22019902	The Wnt/beta-catenin signalling pathway is widely implicated in the control of cell proliferation and differentiation, deregulation of this pathway being found in many cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('beta-catenin', 'Gene', (8, 20))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('beta-catenin', 'Gene', '12387', (8, 20))	('deregulation', 'Var', (119, 131))
73459	22019902	Activating mutations of the CTNNB1 gene were frequently detected in both adrenocortical adenomas and carcinomas.	('detected', 'Reg', (56, 64))	('Activating mutations', 'Var', (0, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('CTNNB1', 'Gene', (28, 34))	('adrenocortical adenomas and carcinomas', 'Disease', 'MESH:D018246', (73, 111))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (73, 96))
73461	22019902	This was definitively proven by the DeltaCat mouse model, where adrenocortical specific expression of a constitutively active beta-catenin induced hyperplasia and carcinogenesis in late stages.	('induced', 'Reg', (139, 146))	('expression', 'Var', (88, 98))	('carcinogenesis', 'Disease', (163, 177))	('adrenocortical', 'Disease', 'MESH:D018268', (64, 78))	('hyperplasia', 'Disease', 'MESH:D006965', (147, 158))	('mouse', 'Species', '10090', (45, 50))	('beta-catenin', 'Gene', '12387', (126, 138))	('expression', 'Species', '29278', (88, 98))	('carcinogenesis', 'Disease', 'MESH:D063646', (163, 177))	('hyperplasia', 'Disease', (147, 158))	('adrenocortical', 'Disease', (64, 78))	('beta-catenin', 'Gene', (126, 138))
73462	22019902	Interestingly, CTNNB1 gene somatic mutations have been found in adrenal tumours developing secondarily in patients with PPNAD, as well as in patients suffering from Carney complex.	('found', 'Reg', (55, 60))	('adrenal tumours', 'Disease', (64, 79))	('CTNNB1', 'Gene', (15, 21))	('adrenal tumours', 'Disease', 'MESH:D000310', (64, 79))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('mutations', 'Var', (35, 44))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (141, 149))	('Carney complex', 'Disease', (165, 179))
73469	22019902	Deregulation of mTOR pathway is found in many tumours.	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('Deregulation', 'Var', (0, 12))	('tumours', 'Disease', (46, 53))	('mTOR', 'Gene', (16, 20))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('mTOR', 'Gene', '56717', (16, 20))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
73473	22019902	This could account for the more penetrant tumour promoting activity of PRKAR1A mutations compared with PDE mutations that would preferentially impact PKA catalytic activity (Section 2.2.).	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('PKA catalytic activity', 'MPA', (150, 172))	('impact', 'Reg', (143, 149))	('more', 'PosReg', (27, 31))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('PDE', 'Gene', (103, 106))	('tumour', 'Disease', (42, 48))	('PDE', 'Gene', '50940;241489', (103, 106))	('PRKAR1A', 'Gene', (71, 78))	('mutations', 'Var', (79, 88))
73476	22019902	What was suspected in human, where up to 80% of the PPNAD cases were related to PRKAR1A inactivating mutations, has been confirmed in mice.	('PPNAD', 'Disease', (52, 57))	('mice', 'Species', '10090', (134, 138))	('inactivating mutations', 'Var', (88, 110))	('human', 'Species', '9606', (22, 27))	('related', 'Reg', (69, 76))	('PRKAR1A', 'Gene', (80, 87))
73477	22019902	Mice heterozygous for Prkar1a developed a Carney-like complex, and ablation of RIalpha in adrenocortical cells induced tumourigenesis.	('induced', 'Reg', (111, 118))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('RIalpha', 'Gene', (79, 86))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('RIalpha', 'Gene', '19084', (79, 86))	('ablation', 'Var', (67, 75))	('adrenocortical', 'Disease', (90, 104))	('tumour', 'Disease', (119, 125))	('adrenocortical', 'Disease', 'MESH:D018268', (90, 104))	('Mice', 'Species', '10090', (0, 4))
73489	22019902	Moreover, both low 3betaHSD and high Cytb5 levels were expressed in AdKO mice when compared to WT (Fig.	('high Cytb5 levels', 'MPA', (32, 49))	('3betaHSD', 'MPA', (19, 27))	('mice', 'Species', '10090', (73, 77))	('AdKO', 'Var', (68, 72))	('low', 'NegReg', (15, 18))
73497	22019902	The antisense strategy resulting in a loss of 50% of RIalpha protein in adrenal cells was able to promote defects in the inner cortex of the adrenal (Section 2.2.).	('promote', 'PosReg', (98, 105))	('RIalpha', 'Gene', (53, 60))	('RIalpha', 'Gene', '19084', (53, 60))	('antisense', 'Var', (4, 13))	('loss', 'NegReg', (38, 42))
73498	22019902	Total Prkar1a knockout in the population of adrenocortical steroidogenic cells (AdKO) induced clear hyperplasia, foetal characters resurgence, gender predilection and adult cortex atrophy.	('hyperplasia', 'Disease', (100, 111))	('cortex atrophy', 'Phenotype', 'HP:0002120', (173, 187))	('foetal characters resurgence', 'CPA', (113, 141))	('adrenocortical', 'Disease', 'MESH:D018268', (44, 58))	('gender predilection', 'CPA', (143, 162))	('atrophy', 'Disease', (180, 187))	('hyperplasia', 'Disease', 'MESH:D006965', (100, 111))	('steroid', 'Chemical', 'MESH:D013256', (59, 66))	('knockout', 'Var', (14, 22))	('Prkar1a', 'Gene', (6, 13))	('adrenocortical', 'Disease', (44, 58))	('atrophy', 'Disease', 'MESH:D001284', (180, 187))
73509	22019902	One hypothesis that could account for these observations is that the loss of Prkar1a in steroidogenic cells is directly responsible for all the phenotypes that were described in the AdKO model.	('loss', 'Var', (69, 73))	('responsible', 'Reg', (120, 131))	('Prkar1a', 'Gene', (77, 84))	('steroid', 'Chemical', 'MESH:D013256', (88, 95))
73511	22019902	To address this question, we are currently analysing mice in which genetic ablation of RIalpha in steroidogenic cells is combined with haploinsufficiency in all other cell types within the adrenal.	('steroid', 'Chemical', 'MESH:D013256', (98, 105))	('RIalpha', 'Gene', (87, 94))	('RIalpha', 'Gene', '19084', (87, 94))	('haploinsufficiency', 'Disease', (135, 153))	('haploinsufficiency', 'Disease', 'MESH:D058495', (135, 153))	('genetic ablation', 'Var', (67, 83))	('mice', 'Species', '10090', (53, 57))
73530	23509640	Acute adrenal hematomas appear isointense to hypointense relative to liver on T1-weighted images and hypointense on T2-weighted images due to deoxyhemoglobin.	('deoxyhemoglobin', 'MPA', (142, 157))	('adrenal hematomas', 'Disease', 'MESH:D006406', (6, 23))	('hypointense', 'Var', (101, 112))	('adrenal hematomas', 'Disease', (6, 23))
73573	22100615	A polymorphism which results in a substitution from alanine to serine at residue 172 of the protein appears to influence steroidogenic capacity of adrenocortical cells.	('adrenocortical', 'Disease', (147, 161))	('alanine to serine at residue 172', 'Mutation', 'p.A172S', (52, 84))	('adrenocortical', 'Disease', 'MESH:D018268', (147, 161))	('dog', 'Species', '9615', (127, 130))	('steroid', 'Chemical', 'MESH:D013256', (121, 128))	('substitution', 'Var', (34, 46))	('influence', 'Reg', (111, 120))
73574	22100615	Since Sf1 dosage has been described as a relevant trigger of tumor growth in human ACC and in a transgenic mouse model, it is possible that the polymorphism could be associated with higher baseline Sf1 expression levels, thus, predisposing the development of ACT growth.	('polymorphism', 'Var', (144, 156))	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('ACT growth', 'Disease', (259, 269))	('Sf1', 'Gene', (198, 201))	('predisposing', 'Reg', (227, 239))	('expression levels', 'MPA', (202, 219))	('mouse', 'Species', '10090', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('men', 'Species', '9606', (251, 254))	('higher', 'PosReg', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('transgenic', 'Species', '10090', (96, 106))	('tumor', 'Disease', (61, 66))	('human', 'Species', '9606', (77, 82))
73577	22100615	Bovine adrenal cells transduced with either the gastric inhibitory polypeptide receptor (GIPR) or the LH receptor (LHR) developed into hyper-proliferative adenomatous, but not overtly malignant, tissue when transplanted under the kidney capsule and resulted in a mild ACTH-independent hypercortisolism in the host animal.	('LH', 'Chemical', 'MESH:D007986', (115, 117))	('hyper-proliferative adenomatous', 'Disease', (135, 166))	('Bovine', 'Species', '9913', (0, 6))	('hypercortisolism', 'Phenotype', 'HP:0003118', (285, 301))	('transduced', 'Var', (21, 31))	('ACTH-independent hypercortisolism', 'Phenotype', 'HP:0001579', (268, 301))	('LH', 'Chemical', 'MESH:D007986', (102, 104))	('hypercortisolism', 'Disease', 'MESH:D003480', (285, 301))	('hyper-proliferative adenomatous', 'Disease', 'MESH:D011125', (135, 166))	('hypercortisolism', 'Disease', (285, 301))	('ACTH', 'Gene', '403659', (268, 272))	('ACTH', 'Gene', (268, 272))
73578	22100615	Thus, these experiments show that expression of either GIPR or LHR is sufficient to induce a phenotype similar to those defining the clinical entity, although these genetic changes are unlikely to be the sole reason for malignant ACT growth.	('men', 'Species', '9606', (18, 21))	('LHR', 'Gene', (63, 66))	('expression', 'Var', (34, 44))	('induce', 'Reg', (84, 90))	('GIPR', 'Gene', (55, 59))
73600	22100615	The gain in Sf1 copy number which resulted in an increase in adrenal SF1 protein levels was associated with the development of macronodular adrenocortical disease that further progressed into adrenal tumors in an age dependent manner.	('gain', 'PosReg', (4, 8))	('increase', 'PosReg', (49, 57))	('copy number', 'Var', (16, 27))	('macronodular adrenocortical disease', 'Disease', 'MESH:C565662', (127, 162))	('macronodular adrenocortical disease', 'Phenotype', 'HP:0008231', (127, 162))	('adrenal tumors', 'Disease', 'MESH:D000310', (192, 206))	('adrenal SF1 protein levels', 'MPA', (61, 87))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('adrenal tumor', 'Phenotype', 'HP:0100631', (192, 205))	('Sf1', 'Gene', (12, 15))	('macronodular adrenocortical disease', 'Disease', (127, 162))	('men', 'Species', '9606', (119, 122))	('adrenal tumors', 'Disease', (192, 206))
73601	22100615	Together with clinical findings from childhood ACC in which the Sf1 is amplified and overexpressed and from adult patients where Sf1 expression has been associated with a poor prognosis this model presents further evidence that gene dosage of Sf1 can contribute to the phenotype of adrenocortical tumors.	('Sf1', 'Gene', (243, 246))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (282, 303))	('contribute', 'Reg', (251, 261))	('ACC', 'Phenotype', 'HP:0006744', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('gene dosage', 'Var', (228, 239))	('patients', 'Species', '9606', (114, 122))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('adrenocortical tumors', 'Disease', (282, 303))
73603	22100615	Like susceptible inbred mouse strains and the inhalpha/Tag transgenic model, mice with a targeted deletion of the inhibin alpha subunit (Inha-/-) develop adrenocortical tumors in response to gonadectomy.	('mice', 'Species', '10090', (77, 81))	('mouse', 'Species', '10090', (24, 29))	('transgenic', 'Species', '10090', (59, 69))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (154, 175))	('deletion', 'Var', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Inha', 'Gene', (137, 141))	('develop', 'PosReg', (146, 153))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('adrenocortical tumors', 'Disease', (154, 175))	('Inha', 'Gene', '16322', (137, 141))
73607	22100615	Despite the clear-cut evidence for TP53 mutations as the underlying cause of childhood ACC, only recently has its role as a tumor suppressor gene in murine ACC development has been highlighted in a mouse model of telomere dysfunction in which animals with p53 haploinsufficiency developed ACC in 5% of cases.	('ACC', 'Phenotype', 'HP:0006744', (289, 292))	('ACC', 'Disease', (289, 292))	('childhood ACC', 'Disease', (77, 90))	('tumor', 'Disease', (124, 129))	('developed', 'PosReg', (279, 288))	('p53', 'Gene', (256, 259))	('mouse', 'Species', '10090', (198, 203))	('murine', 'Species', '10090', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('mutations', 'Var', (40, 49))	('men', 'Species', '9606', (167, 170))	('ACC', 'Phenotype', 'HP:0006744', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('TP53', 'Gene', (35, 39))	('p53', 'Gene', '22059', (256, 259))	('telomere dysfunction', 'Disease', (213, 233))	('ACC', 'Phenotype', 'HP:0006744', (156, 159))	('haploinsufficiency', 'Disease', 'MESH:D058495', (260, 278))	('cause', 'Reg', (68, 73))	('TP53', 'Gene', '22059', (35, 39))	('telomere dysfunction', 'Disease', 'MESH:C536801', (213, 233))	('haploinsufficiency', 'Disease', (260, 278))
73611	22100615	Interestingly and in contrast to other mutations that were either present in benign or in malignant adrenocortical neoplasia, beta-catenin mutations were found with similar frequency in adrenocortical adenoma and carcinoma and represented the most frequent genetic event in adrenal tumors in humans.	('adrenocortical adenoma and carcinoma', 'Disease', 'MESH:D018246', (186, 222))	('adrenal tumors', 'Disease', 'MESH:D000310', (274, 288))	('malignant adrenocortical neoplasia', 'Disease', 'MESH:D018268', (90, 124))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('mutations', 'Var', (139, 148))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('humans', 'Species', '9606', (292, 298))	('neoplasia', 'Phenotype', 'HP:0002664', (115, 124))	('malignant adrenocortical neoplasia', 'Disease', (90, 124))	('adrenal tumor', 'Phenotype', 'HP:0100631', (274, 287))	('adrenal tumors', 'Disease', (274, 288))	('beta-catenin', 'Protein', (126, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (186, 208))
73645	22100615	Whether such genetic changes contribute to adrenocortical neoplasia in gonadectomized ferrets awaits further study.	('contribute', 'Reg', (29, 39))	('neoplasia', 'Phenotype', 'HP:0002664', (58, 67))	('ferrets', 'Species', '9669', (86, 93))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (43, 67))	('adrenocortical neoplasia', 'Disease', (43, 67))	('genetic changes', 'Var', (13, 28))
73646	22100615	In addition to genetic changes, preexisting epigenetic alterations may impact the phenotypic plasticity of tumor progenitor cells in the adrenal cortex, allowing cells to respond to the hormonal changes associated with gonadectomy or increasing the likelihood of subsequent genetic alterations.	('impact', 'Reg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('genetic alterations', 'CPA', (274, 293))	('allowing', 'Reg', (153, 161))	('epigenetic alterations', 'Var', (44, 66))	('increasing', 'PosReg', (234, 244))	('phenotypic plasticity', 'CPA', (82, 103))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('respond', 'MPA', (171, 178))
73693	22100615	Whether these changes in hormone receptor expression are sufficient to induce tumorigenesis, as demonstrated by in vitro studies with bovine adrenocortical cells, still needs to be answered.	('bovine', 'Species', '9913', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('adrenocortical', 'Disease', (141, 155))	('adrenocortical', 'Disease', 'MESH:D018268', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('changes', 'Var', (14, 21))	('tumor', 'Disease', (78, 83))	('induce', 'Reg', (71, 77))
73752	20668603	Genetic changes are more common in malignant than benign adenomas.	('common', 'Reg', (25, 31))	('Genetic changes', 'Var', (0, 15))	('benign adenomas', 'Disease', (50, 65))	('benign adenomas', 'Disease', 'MESH:D000236', (50, 65))	('malignant', 'Disease', (35, 44))
73753	20668603	Mutations in p53 gene are common and may be used as an optional diagnostic test.	('Mutations', 'Var', (0, 9))	('p53', 'Gene', '7157', (13, 16))	('p53', 'Gene', (13, 16))
73762	20668603	Both adrenocortical cancers and ectopic secretion of ACTH cause no suppression of cortisol secretion after both low dose and high dose of overnight dexamethasone.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('adrenocortical cancers', 'Disease', (5, 27))	('adrenocortical cancers', 'Disease', 'MESH:D000306', (5, 27))	('ectopic secretion', 'Var', (32, 49))	('cortisol secretion', 'MPA', (82, 100))	('dexamethasone', 'Chemical', 'MESH:D003907', (148, 161))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))
73774	20668603	Patients having less than two tumoral organs with metastases and less than 20 mitoses per high-power field in the primary tumor can be predicted to have a relatively better 5-year survival compared to patients having metastatic diseases with increased tumor burden.	('patients', 'Species', '9606', (201, 209))	('better', 'PosReg', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('metastases', 'Disease', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('less', 'Var', (65, 69))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('metastases', 'Disease', 'MESH:D009362', (50, 60))	('tumor', 'Disease', (252, 257))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', (122, 127))
73811	20465827	Seladin-1 mRNA expression in ACC (1452 +- 196) was significantly lower than in normal adrenal glands (3614 +- 949; p = 0.01).	('Seladin-1', 'Gene', '1718', (0, 9))	('ACC', 'Phenotype', 'HP:0006744', (29, 32))	('lower', 'NegReg', (65, 70))	('1452 +- 196', 'Var', (34, 45))	('mRNA expression', 'MPA', (10, 25))	('Seladin-1', 'Gene', (0, 9))
73826	20465827	In the hypothesis that epigenetic modifications may influence differential expression of seladin-1 in adrenal cancer we analyzed whether methylation could be regarded as a mechanism of seladin-1 regulation in human adrenal cancer cell lines and tissues.	('human', 'Species', '9606', (209, 214))	('differential expression', 'MPA', (62, 85))	('seladin-1', 'Gene', '1718', (185, 194))	('seladin-1', 'Gene', '1718', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('renal cancer', 'Phenotype', 'HP:0009726', (217, 229))	('seladin-1', 'Gene', (89, 98))	('adrenal cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('seladin-1', 'Gene', (185, 194))	('adrenal cancer', 'Disease', (215, 229))	('influence', 'Reg', (52, 61))	('renal cancer', 'Phenotype', 'HP:0009726', (104, 116))	('adrenal cancer', 'Disease', 'MESH:D000310', (215, 229))	('adrenal cancer', 'Disease', 'MESH:D000310', (102, 116))	('epigenetic modifications', 'Var', (23, 47))
73829	20465827	For H295R, medium was enriched with a mixture of insulin/transferrin/selenium.	('insulin', 'Gene', (49, 56))	('H295R', 'Var', (4, 9))	('transferrin', 'Gene', '7018', (57, 68))	('transferrin', 'Gene', (57, 68))	('selenium', 'Chemical', 'MESH:D012643', (69, 77))	('insulin', 'Gene', '3630', (49, 56))
73837	20465827	Methyl Primer Express  Software v1.0 (Applied Biosystems, Foster City, CA, USA) was used to evaluate methylation-sensitive sites in seladin-1 sequence from -4384 bp and +1826 bp.	('+1826 bp', 'Var', (169, 177))	('seladin-1', 'Gene', '1718', (132, 141))	('seladin-1', 'Gene', (132, 141))
73839	20465827	The unmethylated form of the same sequence was amplified using the primers: F2unmeth 5'-TTGTGGGTTATAGGTGTAGAGT-3' at -93 nucleotide from translation start site and R2unmeth 5'-CCAAACACACACATAATAATAAA-3' at +141 (amplicon length of 258 bp).	('F2unmeth', 'Var', (76, 84))	('GTG', 'Gene', '2678', (90, 93))	('R2unmeth', 'Var', (164, 172))	('GTG', 'Gene', '2678', (101, 104))	('GTG', 'Gene', (90, 93))	('GTG', 'Gene', (101, 104))
73850	20465827	As reported in Figure 1, in both cases amplification generated amplicons with the expected size, suggesting that methylation of seladin-1 promoter is in hemi-methylated status in both cell lines.	('methylation', 'Var', (113, 124))	('seladin-1', 'Gene', (128, 137))	('seladin-1', 'Gene', '1718', (128, 137))
73851	20465827	When cell lines were submitted to 5-Aza treatment, MSP revealed a reduction of the intensity of the band corresponding to methylated DNA in comparison to untreated cell lines, which was paralleled by an increase of amplification products when primers for unmethylated DNA were used (Figure 1, Panel B).	('5-Aza', 'Chemical', 'MESH:D001374', (34, 39))	('intensity', 'MPA', (83, 92))	('methylated DNA', 'Var', (122, 136))	('increase', 'PosReg', (203, 211))	('reduction', 'NegReg', (66, 75))
73859	20465827	Conversely, DNA methylation evidenced a statistically significant (p = 0.02) increase in carcinoma samples (2633 +- 707) compared to normal tissues (362 +- 97).	('carcinoma', 'Disease', (89, 98))	('2633 +- 707', 'Var', (108, 119))	('increase', 'PosReg', (77, 85))	('carcinoma', 'Disease', 'MESH:D002277', (89, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('DNA methylation', 'MPA', (12, 27))
73861	20465827	Disruption of this program leads to an aberrant mRNA transcription and potential loss of anti-cancer checkpoints.	('Disruption', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mRNA transcription', 'MPA', (48, 66))	('loss', 'NegReg', (81, 85))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
73871	20465827	In the same experiments we demonstrated that the expression of seladin-1 mRNA could be directly related to the altered pattern of promoter methylation since exposure of adrenal cell lines to 5-Aza was associated to a significant induction of Seladin-1 mRNA expression in SW13 and H295R lines, even if the effects of 5-AZA on H295R methylation is apparently less evident than in SW13.	('mRNA expression', 'MPA', (252, 267))	('SW13', 'CellLine', 'CVCL:0542', (271, 275))	('seladin-1', 'Gene', '1718', (63, 72))	('SW13', 'CellLine', 'CVCL:0542', (378, 382))	('5-AZA', 'Chemical', 'MESH:D001374', (316, 321))	('Seladin-1', 'Gene', (242, 251))	('Seladin-1', 'Gene', '1718', (242, 251))	('seladin-1', 'Gene', (63, 72))	('5-Aza', 'Chemical', 'MESH:D001374', (191, 196))	('5-Aza', 'Var', (191, 196))	('induction', 'PosReg', (229, 238))
73874	20465827	Conversely, H295R tend to proliferate more slowly and after 6 days 30% of their DNA is still methylated and the gain of mRNA expression, even if significantly increased, is less intense than in SW13.	('methylated', 'MPA', (93, 103))	('H295R', 'Var', (12, 17))	('SW13', 'CellLine', 'CVCL:0542', (194, 198))	('mRNA expression', 'MPA', (120, 135))	('proliferate', 'CPA', (26, 37))	('gain', 'PosReg', (112, 116))
73877	20465827	After these preliminary indications obtained 'in vitro', we tried to confirm the presence of an epigenetic control of seladin-1 expression also in 'ex vivo' samples.	('epigenetic', 'Var', (96, 106))	('seladin-1', 'Gene', '1718', (118, 127))	('seladin-1', 'Gene', (118, 127))	('expression', 'MPA', (128, 138))
73878	20465827	Real time analysis performed on the same promoter region in DNA of adrenal carcinomas, adenomas and normal glands showed an inverse relationship between methylation of seladin-1 and its expression.	('adenomas', 'Disease', (87, 95))	('adrenal carcinomas', 'Disease', (67, 85))	('seladin-1', 'Gene', '1718', (168, 177))	('adrenal carcinomas', 'Disease', 'MESH:D000310', (67, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('seladin-1', 'Gene', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('adrenal carcinomas', 'Phenotype', 'HP:0006744', (67, 85))	('inverse', 'NegReg', (124, 131))	('expression', 'MPA', (186, 196))	('methylation', 'Var', (153, 164))	('adenomas', 'Disease', 'MESH:D000236', (87, 95))
73879	20465827	In particular hypermethylation was associated to reduced seladin-1 expression levels in adrenal cancer compared to normal adrenal gland and adenomas.	('renal cancer', 'Phenotype', 'HP:0009726', (90, 102))	('hypermethylation', 'Var', (14, 30))	('seladin-1', 'Gene', (57, 66))	('reduced', 'NegReg', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('adrenal cancer', 'Disease', (88, 102))	('adenomas', 'Disease', 'MESH:D000236', (140, 148))	('adrenal cancer', 'Disease', 'MESH:D000310', (88, 102))	('adenomas', 'Disease', (140, 148))	('expression levels', 'MPA', (67, 84))	('seladin-1', 'Gene', '1718', (57, 66))
73881	20465827	Thus, at least in adrenal carcinomas, hypermethylation could account for the reduction of mRNA expression.	('hypermethylation', 'Var', (38, 54))	('adrenal carcinomas', 'Disease', (18, 36))	('adrenal carcinomas', 'Phenotype', 'HP:0006744', (18, 36))	('reduction', 'NegReg', (77, 86))	('adrenal carcinomas', 'Disease', 'MESH:D000310', (18, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))	('mRNA expression', 'MPA', (90, 105))
73883	20465827	In fact an indirect effect resulting from the demethylation of other genes regulating seladin-1 expression cannot be excluded.	('seladin-1', 'Gene', '1718', (86, 95))	('seladin-1', 'Gene', (86, 95))	('demethylation', 'Var', (46, 59))
73884	20465827	Additional studies should be performed in order to determine whether the degree of methylation may account for the different levels of expression between normal and pathologic tissues detected in other human organs According to our results, methylation could be involved in the altered pattern of seladin-1 gene expression in ACC.	('expression', 'MPA', (312, 322))	('seladin-1', 'Gene', (297, 306))	('human', 'Species', '9606', (202, 207))	('ACC', 'Phenotype', 'HP:0006744', (326, 329))	('methylation', 'Var', (241, 252))	('involved', 'Reg', (262, 270))	('ACC', 'Disease', (326, 329))	('seladin-1', 'Gene', '1718', (297, 306))
73956	33260476	The Li-Fraumeni syndrome (LFS), a severe tumor-predisposition disease, is related to the germline inactivating mutations of TP53, and it is characterized by a high-risk and early-onset cancer development.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TP53', 'Gene', '7157', (124, 128))	('Li-Fraumeni syndrome', 'Disease', (4, 24))	('related', 'Reg', (74, 81))	('tumor', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('germline', 'Var', (89, 97))	('LFS', 'Disease', 'MESH:D016864', (26, 29))	('TP53', 'Gene', (124, 128))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (4, 24))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('LFS', 'Disease', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('cancer', 'Disease', (185, 191))
73958	33260476	The Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth and tumor predisposition syndrome caused by genetic or epigenetic changes on chromosome 11p15, involving the IGF2 gene.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (4, 31))	('genetic overgrowth and tumor', 'Disease', 'MESH:D030342', (43, 71))	('IGF2', 'Gene', '3481', (171, 175))	('epigenetic changes', 'Var', (117, 135))	('overgrowth', 'Phenotype', 'HP:0001548', (51, 61))	('Beckwith-Wiedemann syndrome', 'Disease', (4, 31))	('IGF2', 'Gene', (171, 175))	('caused by', 'Reg', (96, 105))
73961	33260476	The Carney complex (CNC), due to the germline inactivating mutation of PRKAR1A, is a familial tumor predisposition syndrome associated with growth-hormone (GH)-secreting pituitary adenoma, testicular Sertoli cell tumors, thyroid tumors and extra-endocrine manifestation such as myxomas, pigmented skin lesions, schwannomas, breast and bone tumors.	('GH', 'Gene', '2688', (156, 158))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (200, 219))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('thyroid tumors', 'Disease', 'MESH:D013964', (221, 235))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('thyroid tumors', 'Disease', (221, 235))	('PRKAR1A', 'Gene', (71, 78))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('familial tumor', 'Disease', (85, 99))	('myxomas', 'Disease', (278, 285))	('tumors', 'Disease', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('schwannomas', 'Phenotype', 'HP:0100008', (311, 322))	('pigmented skin lesions', 'Disease', (287, 309))	('pigmented skin lesions', 'Disease', 'MESH:D010859', (287, 309))	('myxomas', 'Disease', 'MESH:D009232', (278, 285))	('tumors', 'Disease', (229, 235))	('Carney complex', 'Disease', (4, 18))	('bone tumors', 'Disease', (335, 346))	('familial tumor', 'Disease', 'MESH:D009386', (85, 99))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('bone tumors', 'Phenotype', 'HP:0010622', (335, 346))	('tumors', 'Disease', (340, 346))	('growth-hormone', 'Gene', (140, 154))	('PRKAR1A', 'Gene', '5573', (71, 78))	('germline inactivating mutation', 'Var', (37, 67))	('associated', 'Reg', (124, 134))	('pituitary adenoma', 'Disease', 'MESH:D010911', (170, 187))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (170, 187))	('bone tumors', 'Disease', 'MESH:D001859', (335, 346))	('schwannomas', 'Disease', 'MESH:D009442', (311, 322))	('tumors', 'Disease', 'MESH:D009369', (340, 346))	('schwannomas', 'Disease', (311, 322))	('pituitary adenoma', 'Disease', (170, 187))	('growth-hormone', 'Gene', '2688', (140, 154))
73965	33260476	Seven percent of ACCs show somatic inactivating MEN1 mutations, confirming the findings of other studies, which identified recurrent somatic MEN1 mutation in ACC.	('mutation', 'Var', (146, 154))	('MEN1', 'Gene', (48, 52))	('MEN1', 'Gene', (141, 145))	('MEN1', 'Gene', '4221', (48, 52))	('MEN1', 'Gene', '4221', (141, 145))	('mutations', 'Var', (53, 62))	('ACC', 'Phenotype', 'HP:0006744', (158, 161))	('ACC', 'Phenotype', 'HP:0006744', (17, 20))	('ACCs', 'Gene', (17, 21))	('ACCs', 'Gene', '84680', (17, 21))
73968	33260476	A possible causative link between ACC and FAP is related to the role of activating mutations of Wnt/beta-catenin pathway.	('mutations', 'Var', (83, 92))	('FAP', 'Disease', (42, 45))	('beta-catenin', 'Gene', (100, 112))	('beta-catenin', 'Gene', '1499', (100, 112))	('FAP', 'Disease', 'MESH:C567782', (42, 45))	('ACC', 'Phenotype', 'HP:0006744', (34, 37))	('ACC', 'Disease', (34, 37))
73973	33260476	ACC associated with pathogenic germline MSH2 mutation has been reported for the first time in 2012.	('MSH2', 'Gene', '4436', (40, 44))	('germline', 'Var', (31, 39))	('MSH2', 'Gene', (40, 44))	('mutation', 'Var', (45, 53))	('pathogenic', 'Reg', (20, 30))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('ACC', 'Disease', (0, 3))
73975	33260476	At the somatic level, the most frequent mutations found involve TP53 inactivating mutations and proto-oncogene beta-catenin (CTNNB1) activating mutations.	('activating', 'PosReg', (133, 143))	('beta-catenin', 'Gene', (111, 123))	('mutations', 'Var', (40, 49))	('CTNNB1', 'Gene', (125, 131))	('beta-catenin', 'Gene', '1499', (111, 123))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('inactivating', 'NegReg', (69, 81))	('CTNNB1', 'Gene', '1499', (125, 131))
73988	33260476	DNA methylation is a mechanism for silencing tumor-suppressor genes expression in cancer, that has been also studied in ACC.	('silencing', 'NegReg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('expression', 'MPA', (68, 78))	('tumor', 'Disease', (45, 50))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ACC', 'Phenotype', 'HP:0006744', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
73991	33260476	Furthermore, in the group of hypermethylated carcinomas, which can be further classified into two subgroups with different levels of methylation, hypermethylation was found to be associated with poorer prognosis.	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('hypermethylated carcinomas', 'Disease', 'MESH:D009369', (29, 55))	('hypermethylation', 'Var', (146, 162))	('hypermethylated carcinomas', 'Disease', (29, 55))	('poorer', 'NegReg', (195, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
73992	33260476	The abnormal methylation at the IGF2/H19 locus is common in adrenocortical carcinomas and methylation patterns of IGF2 regulatory regions has been proposed to discriminate ACC from adrenal adenomas with high diagnostic accuracy.	('IGF2', 'Gene', '3481', (32, 36))	('adrenal adenomas', 'Disease', 'MESH:D000236', (181, 197))	('discriminate', 'Reg', (159, 171))	('abnormal', 'Var', (4, 12))	('IGF2', 'Gene', (32, 36))	('common', 'Reg', (50, 56))	('IGF2', 'Gene', (114, 118))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (60, 85))	('methylation', 'Var', (90, 101))	('H19', 'Gene', (37, 40))	('adrenocortical carcinomas', 'Disease', (60, 85))	('ACC', 'Phenotype', 'HP:0006744', (172, 175))	('ACC', 'Disease', (172, 175))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (181, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('H19', 'Gene', '283120', (37, 40))	('adrenal adenomas', 'Disease', (181, 197))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (60, 85))	('IGF2', 'Gene', '3481', (114, 118))
73993	33260476	Genes involved in important mechanisms for the development of adrenal tumors (cell cycle regulation, apoptosis, transcriptional regulation such as CDKN2A, GATA4, BCL2, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1), showed significant and frequent hypermethylation.	('GATA4', 'Gene', (155, 160))	('DLEC1', 'Gene', (168, 173))	('BCL2', 'Gene', '596', (162, 166))	('adrenal tumors', 'Disease', 'MESH:D000310', (62, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('HDAC10', 'Gene', '83933', (175, 181))	('CDKN2A', 'Gene', (147, 153))	('SCGB3A1', 'Gene', (195, 202))	('PYCARD', 'Gene', (183, 189))	('apoptosis', 'CPA', (101, 110))	('HIN1', 'Gene', '92304', (203, 207))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('HIN1', 'Gene', (203, 207))	('BCL2', 'Gene', (162, 166))	('CDKN2A', 'Gene', '1029', (147, 153))	('adrenal tumors', 'Disease', (62, 76))	('GATA4', 'Gene', '2626', (155, 160))	('DLEC1', 'Gene', '9940', (168, 173))	('PYCARD', 'Gene', '29108', (183, 189))	('HDAC10', 'Gene', (175, 181))	('hypermethylation', 'Var', (242, 258))	('SCGB3A1', 'Gene', '92304', (195, 202))
73996	33260476	Furthermore, miR-139-5p and miR-376a levels have been found to be significantly increased in aggressive ACC patients compared with non-aggressive ACC patients in tumor samples, while serum miR-483-5p was detected only in aggressive ACC patients.	('miR-376a', 'Var', (28, 36))	('miR-483', 'Gene', (189, 196))	('ACC', 'Phenotype', 'HP:0006744', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ACC', 'Phenotype', 'HP:0006744', (232, 235))	('tumor', 'Disease', (162, 167))	('miR-139-5p', 'MPA', (13, 23))	('increased', 'PosReg', (80, 89))	('patients', 'Species', '9606', (236, 244))	('miR-139-5p', 'Chemical', '-', (13, 23))	('patients', 'Species', '9606', (150, 158))	('aggressive ACC', 'Disease', (93, 107))	('miR-376a', 'Chemical', '-', (28, 36))	('patients', 'Species', '9606', (108, 116))	('ACC', 'Phenotype', 'HP:0006744', (104, 107))	('miR-483', 'Gene', '619552', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
74011	33260476	The sensitivity of adrenal tissue to mitotane activity is different between species: in humans, mitotane causes adrenal atrophy, leading to the destruction of both the zona fasciculata and reticularis which are under the control of adrenocorticotropic hormone (ACTH) secretion.	('zona fasciculata', 'Disease', 'MESH:D006562', (168, 184))	('humans', 'Species', '9606', (88, 94))	('mitotane', 'Chemical', 'MESH:D008939', (37, 45))	('adrenocorticotropic hormone', 'Gene', (232, 259))	('adrenocorticotropic hormone', 'Gene', '5443', (232, 259))	('mitotane', 'Var', (96, 104))	('mitotane', 'Chemical', 'MESH:D008939', (96, 104))	('adrenal atrophy', 'Disease', (112, 127))	('adrenal atrophy', 'Disease', 'MESH:D000310', (112, 127))	('ACTH', 'Gene', (261, 265))	('zona fasciculata', 'Disease', (168, 184))	('ACTH', 'Gene', '5443', (261, 265))
74015	33260476	Mitotane has been shown to inhibit sterol-O-acyltransferase-1 (SOAT1), leading to endoplasmic reticulum stress and cell death in ACC cells.	('Mitotane', 'Var', (0, 8))	('inhibit', 'NegReg', (27, 34))	('stress', 'Disease', (104, 110))	('stress', 'Disease', 'MESH:D000079225', (104, 110))	('leading to', 'Reg', (71, 81))	('SOAT1', 'Gene', '6646', (63, 68))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('sterol-O-acyltransferase-1', 'Gene', '6646', (35, 61))	('ACC', 'Phenotype', 'HP:0006744', (129, 132))	('cell death', 'CPA', (115, 125))	('sterol-O-acyltransferase-1', 'Gene', (35, 61))	('SOAT1', 'Gene', (63, 68))
74017	33260476	Metabolomic and lipidomic studies demonstrate that mitotane significantly decreases aspartate and increases glutamate content, inducing a respiratory chain defect.	('inducing', 'Reg', (127, 135))	('increases glutamate content', 'Phenotype', 'HP:0500149', (98, 125))	('aspartate', 'Chemical', 'MESH:D001224', (84, 93))	('respiratory chain defect', 'Phenotype', 'HP:0200125', (138, 162))	('respiratory chain defect', 'MPA', (138, 162))	('mitotane', 'Var', (51, 59))	('aspartate', 'MPA', (84, 93))	('glutamate', 'Chemical', 'MESH:D018698', (108, 117))	('mitotane', 'Chemical', 'MESH:D008939', (51, 59))	('decreases', 'NegReg', (74, 83))	('increases', 'PosReg', (98, 107))	('glutamate content', 'MPA', (108, 125))	('lipid', 'Chemical', 'MESH:D008055', (16, 21))
74018	33260476	Furthermore, mitotane reduces the phosphatidylserine/phosphatidylethanolamine ratio, leading to a dysfunction of phosphatidylserine decarboxylase located in mitochondria-associated membranes.	('dysfunction', 'MPA', (98, 109))	('mitotane', 'Chemical', 'MESH:D008939', (13, 21))	('phosphatidylserine', 'Chemical', 'MESH:D010718', (113, 131))	('reduces', 'NegReg', (22, 29))	('phosphatidylethanolamine', 'Chemical', 'MESH:C483858', (53, 77))	('phosphatidylserine decarboxylase', 'Enzyme', (113, 145))	('phosphatidylserine', 'Chemical', 'MESH:D010718', (34, 52))	('mitotane', 'Var', (13, 21))	('phosphatidylserine/phosphatidylethanolamine ratio', 'MPA', (34, 83))
74021	33260476	However, gene expression analyses showed conflicting results, with some authors suggesting that the suppression of the steroidogenic mitochondrial enzymes (HSD3B1, HSD3B2, CYP21A2, CYP11A1, CYP17A, STAR, CYP11A1, HSD3B2 and CYP11B2) is not associated with a decreased gene expression, while other authors affirm that genes are suppressed.	('CYP11A1', 'Gene', (204, 211))	('CYP11B2', 'Gene', (224, 231))	('HSD3B2', 'Gene', '3284', (164, 170))	('steroid', 'Chemical', 'MESH:D013256', (119, 126))	('HSD3B1', 'Gene', (156, 162))	('steroidogenic mitochondrial enzymes', 'Enzyme', (119, 154))	('CYP17A', 'Var', (190, 196))	('HSD3B2', 'Gene', (213, 219))	('HSD3B1', 'Gene', '3283', (156, 162))	('suppression', 'NegReg', (100, 111))	('CYP21A2', 'Gene', (172, 179))	('CYP11A1', 'Gene', '1583', (181, 188))	('CYP11B2', 'Gene', '1585', (224, 231))	('HSD3B2', 'Gene', (164, 170))	('STAR', 'Gene', '6770', (198, 202))	('CYP11A1', 'Gene', '1583', (204, 211))	('CYP21A2', 'Gene', '1589', (172, 179))	('CYP11A1', 'Gene', (181, 188))	('HSD3B2', 'Gene', '3284', (213, 219))	('STAR', 'Gene', (198, 202))
74027	33260476	A retrospective analysis involving 177 patients from Italy and Germany treated with mitotane after radical surgery, showed that RFS was significantly prolonged in the mitotane group (42 months) compared with the two non-treated control groups (10 months and 25 months).	('mitotane', 'Var', (167, 175))	('prolonged', 'PosReg', (150, 159))	('patients', 'Species', '9606', (39, 47))	('RFS', 'MPA', (128, 131))	('mitotane', 'Chemical', 'MESH:D008939', (167, 175))	('mitotane', 'Chemical', 'MESH:D008939', (84, 92))
74052	33260476	Neurological disturbances (ataxia, paresthesia, vertigo, dizziness, headache, polyneuropathy) have also been reported, especially for plasma mitotane levels > 20 ng/mL.	('headache', 'Disease', (68, 76))	('vertigo', 'Phenotype', 'HP:0002321', (48, 55))	('ataxia', 'Phenotype', 'HP:0001251', (27, 33))	('headache', 'Disease', 'MESH:D006261', (68, 76))	('paresthesia', 'Disease', (35, 46))	('> 20', 'Var', (157, 161))	('polyneuropathy', 'Disease', 'MESH:D011115', (78, 92))	('dizziness', 'Disease', 'MESH:D004244', (57, 66))	('polyneuropathy', 'Phenotype', 'HP:0001271', (78, 92))	('ataxia', 'Disease', (27, 33))	('ataxia', 'Disease', 'MESH:D001259', (27, 33))	('plasma mitotane levels', 'MPA', (134, 156))	('dizziness', 'Phenotype', 'HP:0002321', (57, 66))	('mitotane', 'Chemical', 'MESH:D008939', (141, 149))	('Neurological disturbances', 'Phenotype', 'HP:0000707', (0, 25))	('Neurological disturbances', 'Disease', (0, 25))	('vertigo', 'Disease', (48, 55))	('polyneuropathy', 'Disease', (78, 92))	('vertigo', 'Disease', 'MESH:D014717', (48, 55))	('headache', 'Phenotype', 'HP:0002315', (68, 76))	('paresthesia', 'Phenotype', 'HP:0003401', (35, 46))	('dizziness', 'Disease', (57, 66))	('Neurological disturbances', 'Disease', 'MESH:D009422', (0, 25))
74054	33260476	Mitotane also has antihormonal effects, due to its ability to inhibit a number of adrenal enzymes involved in steroid synthesis.	('adrenal enzymes', 'Enzyme', (82, 97))	('Mitotane', 'Var', (0, 8))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('steroid', 'Chemical', 'MESH:D013256', (110, 117))	('inhibit', 'NegReg', (62, 69))	('antihormonal effects', 'MPA', (18, 38))
74055	33260476	Mitotane treatment results in adrenal insufficiency and it is often preferred to start glucocorticoid replacement therapy concomitantly with mitotane.	('Mitotane', 'Var', (0, 8))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (30, 51))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (30, 51))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('results in', 'Reg', (19, 29))	('mitotane', 'Chemical', 'MESH:D008939', (141, 149))	('adrenal insufficiency', 'Disease', (30, 51))
74059	33260476	Mitotane can potentially interfere with pituitary function, causing a reduction in ACTH levels despite the primary impairment of adrenal steroidogenesis.	('ACTH', 'Gene', '5443', (83, 87))	('reduction', 'NegReg', (70, 79))	('Mitotane', 'Var', (0, 8))	('impairment of adrenal steroidogenesis', 'Disease', 'MESH:D054882', (115, 152))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('impairment of adrenal steroidogenesis', 'Disease', (115, 152))	('pituitary function', 'MPA', (40, 58))	('interfere', 'NegReg', (25, 34))	('ACTH', 'Gene', (83, 87))
74074	33260476	Data demonstrated a modest improvement in PFS in the EDP-M arm (5.0 vs. 2.1 months), but no benefit in the OS although the crossover design and the presence of mitotane in both arms should be considered.	('improvement', 'PosReg', (27, 38))	('EDP-M', 'Var', (53, 58))	('PFS', 'MPA', (42, 45))	('EDP-M', 'Chemical', '-', (53, 58))	('2.1', 'Gene', (72, 75))	('2.1', 'Gene', '6700', (72, 75))	('mitotane', 'Chemical', 'MESH:D008939', (160, 168))
74102	33260476	Cixutumumab has been demonstrated to inhibit the tumor growth of several cancers, both in experimental models and clinical trials.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancers', 'Disease', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Cixutumumab', 'Var', (0, 11))	('Cixutumumab', 'Chemical', 'MESH:C557414', (0, 11))	('inhibit', 'NegReg', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (49, 54))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
74117	33260476	Two of twelve patients (17%) treated with PD-1 inhibitors (either alone or in combination with cytotoxic chemotherapy) obtained a stable disease with one patient achieving a partial response.	('inhibitors', 'Var', (47, 57))	('patient', 'Species', '9606', (154, 161))	('PD-1', 'Gene', '6139', (42, 46))	('PD-1', 'Gene', (42, 46))	('patient', 'Species', '9606', (14, 21))	('patients', 'Species', '9606', (14, 22))
74128	32781574	High throughput analyses focused on characterizing the molecular signature of ACC have revealed specific micro-RNAs (miRNAs) that are associated with aggressive tumor phenotypes.	('associated with', 'Reg', (134, 149))	('aggressive tumor', 'Disease', (150, 166))	('micro-RNAs', 'Var', (105, 115))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('aggressive tumor', 'Disease', 'MESH:D001523', (150, 166))
74130	32781574	This review summarizes the current insights into dysregulated miRNAs in ACC tumorigenesis, their known functions, and specific targetomes.	('ACC', 'Phenotype', 'HP:0006744', (72, 75))	('dysregulated', 'Var', (49, 61))	('ACC', 'Disease', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('miRNAs', 'Protein', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
74138	32781574	This study compared mitotane administered in combination with either streptozocin or etoposide, doxorubicin, and cisplatin (EDPM) and demonstrated a modest improvement in progression-free survival in the EDPM arm, but no benefit in the overall survival.	('streptozocin', 'Chemical', 'MESH:D013311', (69, 81))	('mitotane', 'Chemical', 'MESH:D008939', (20, 28))	('improvement', 'PosReg', (156, 167))	('doxorubicin', 'Chemical', 'MESH:D004317', (96, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('etoposide', 'Chemical', 'MESH:D005047', (85, 94))	('EDPM', 'Var', (204, 208))
74144	32781574	In contrast, most cases of adult ACC are sporadic, with germline TP53 mutations being present in around three percent of patients.	('adult ACC', 'Disease', (27, 36))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', (65, 69))	('ACC', 'Phenotype', 'HP:0006744', (33, 36))	('patients', 'Species', '9606', (121, 129))
74145	32781574	In rare cases, ACC can be associated with specific germline mutations that cause hereditary cancer syndromes.	('cause', 'Reg', (75, 80))	('hereditary cancer syndromes', 'Disease', (81, 108))	('ACC', 'Phenotype', 'HP:0006744', (15, 18))	('ACC', 'Disease', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('hereditary cancer syndromes', 'Disease', 'MESH:D061325', (81, 108))	('germline mutations', 'Var', (51, 69))
74146	32781574	ACC is a core malignancy in Li Fraumeni Syndrome (LFS) caused by the germline TP53 mutation and affects ten percent of cases.	('caused by', 'Reg', (55, 64))	('malignancy in Li Fraumeni Syndrome', 'Disease', (14, 48))	('malignancy in Li Fraumeni Syndrome', 'Disease', 'MESH:D016864', (14, 48))	('LFS', 'Disease', 'MESH:D016864', (50, 53))	('mutation', 'Var', (83, 91))	('TP53', 'Gene', (78, 82))	('LFS', 'Disease', (50, 53))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('ACC', 'Disease', (0, 3))
74148	32781574	ACC affects approximately seven percent of children with Beckwith-Weidemann Syndrome (BWS), which is caused by mutations or epigenetic modifications at the genetic locus 11p15 containing the Insulin-Like Growth Factor 2 (IGF2) gene.	('Beckwith-Weidemann Syndrome', 'Disease', 'MESH:C565755', (57, 84))	('IGF2', 'Gene', (221, 225))	('Beckwith-Weidemann Syndrome', 'Disease', (57, 84))	('Insulin-Like Growth Factor 2', 'Gene', '3481', (191, 219))	('children', 'Species', '9606', (43, 51))	('epigenetic modifications', 'Var', (124, 148))	('Insulin-Like Growth Factor 2', 'Gene', (191, 219))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('caused by', 'Reg', (101, 110))
74150	32781574	Approximately three percent of patients with Familial Adenomatous Polyposis (FAP), caused by mutations in the Adenomatous Polyposis Coli (APC) gene, develop adrenocortical cancer as adults.	('FAP', 'Disease', 'MESH:C567782', (77, 80))	('Adenomatous Polyposis Coli', 'Phenotype', 'HP:0005227', (110, 136))	('Familial Adenomatous Polyposis', 'Disease', 'MESH:D011125', (45, 75))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mutations', 'Var', (93, 102))	('develop', 'Reg', (149, 156))	('Adenomatous Polyposis', 'Phenotype', 'HP:0005227', (110, 131))	('APC', 'Phenotype', 'HP:0005227', (138, 141))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('FAP', 'Disease', (77, 80))	('patients', 'Species', '9606', (31, 39))	('Familial Adenomatous Polyposis', 'Disease', (45, 75))	('Adenomatous Polyposis Coli', 'Gene', (110, 136))	('cancer', 'Disease', (172, 178))	('Adenomatous Polyposis Coli', 'Gene', '324', (110, 136))	('Adenomatous Polyposis', 'Phenotype', 'HP:0005227', (54, 75))	('caused by', 'Reg', (83, 92))
74153	32781574	Although mutations in TP53, IGF-2, and beta-catenin genes have been established as drivers of sporadic ACC, the low penetrance of ACC in these genetic cancer syndromes indicates that mutations or the epigenetic regulation of the expression of nearby genes may play an important role in its etiology.	('IGF-2', 'Gene', (28, 33))	('ACC', 'Phenotype', 'HP:0006744', (103, 106))	('epigenetic regulation', 'Var', (200, 221))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (9, 18))	('IGF-2', 'Gene', '3481', (28, 33))	('ACC', 'Phenotype', 'HP:0006744', (130, 133))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('TP53', 'Gene', (22, 26))
74154	32781574	It is now known that mutations in gene drivers alone do not completely explain the pathogenesis of ACC, and therefore non-coding gene mutations that lead to aberrant regulation of driver genes through their pathways can also contribute to tumor biogenesis.	('contribute', 'Reg', (225, 235))	('aberrant', 'Var', (157, 165))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('regulation', 'MPA', (166, 176))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('ACC', 'Phenotype', 'HP:0006744', (99, 102))	('ACC', 'Disease', (99, 102))	('mutations', 'Var', (134, 143))	('tumor', 'Disease', (239, 244))
74159	32781574	TP53 mutations in cancer are common and are present in more than half of human tumors.	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('human', 'Species', '9606', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
74160	32781574	ACC, despite its rarity, accounts for 11.9% of all human tumors harboring germline TP53 mutations, after breast, soft-tissue, and brain tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('TP53', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('brain tumors', 'Disease', 'MESH:D001932', (130, 142))	('brain tumors', 'Phenotype', 'HP:0030692', (130, 142))	('human', 'Species', '9606', (51, 56))	('brain tumors', 'Disease', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
74161	32781574	The majority of TP53 mutations associated with ACC are loss-of-function mutations; however, many of these are predicted to result only in partial loss of p53 function.	('function', 'MPA', (158, 166))	('loss-of-function', 'NegReg', (55, 71))	('ACC', 'Phenotype', 'HP:0006744', (47, 50))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
74162	32781574	Curiously, transgenic TP53 knockout and mutant mouse models do not develop ACC despite developing multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('mutant', 'Var', (40, 46))	('transgenic', 'Species', '10090', (11, 21))	('TP53', 'Gene', (22, 26))	('mouse', 'Species', '10090', (47, 52))
74163	32781574	Else and colleagues showed that transgenic mice carrying an inactivation mutation in the tripeptidyl peptidase 1/ACD sheltering complex subunit and telomerase recruitment factor (Tpp/Acd) in addition to a single wild type TP53 allele do develop ACCs at low frequencies.	('develop', 'PosReg', (237, 244))	('transgenic mice', 'Species', '10090', (32, 47))	('ACC', 'Phenotype', 'HP:0006744', (245, 248))	('ACCs', 'CPA', (245, 249))	('tripeptidyl peptidase 1', 'Gene', (89, 112))	('tripeptidyl peptidase 1', 'Gene', '12751', (89, 112))	('inactivation mutation', 'Var', (60, 81))
74168	32781574	Tyrosine phosphorylation of IRS-1 activates the phosphatidylinositol-3-kinase(PI3K)/serine/threonine protein kinase B (Akt) and mammalian target of rapamycin(mTOR) pathway as well as the Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-related kinase (ERK) pathways, potentiating cellular proliferation and viability in ACC cell models.	('Akt', 'Gene', '207', (119, 122))	('ERK', 'Gene', '5594', (271, 274))	('MEK', 'Gene', (229, 232))	('viability', 'CPA', (326, 335))	('IRS-1', 'Gene', (28, 33))	('ERK', 'Gene', (271, 274))	('cellular proliferation', 'CPA', (299, 321))	('mammalian target of rapamycin', 'Gene', '2475', (128, 157))	('ACC', 'Phenotype', 'HP:0006744', (339, 342))	('IRS-1', 'Gene', '3667', (28, 33))	('activates', 'PosReg', (34, 43))	('potentiating', 'PosReg', (286, 298))	('mTOR', 'Gene', (158, 162))	('Tyrosine phosphorylation', 'Var', (0, 24))	('Akt', 'Gene', (119, 122))	('mammalian target of rapamycin', 'Gene', (128, 157))	('Tyrosine', 'Chemical', 'MESH:D014443', (0, 8))	('MEK', 'Gene', '5609', (229, 232))	('serine', 'Chemical', 'MESH:D012694', (84, 90))	('mTOR', 'Gene', '2475', (158, 162))
74172	32781574	Assie and colleagues performed exome sequencing and single nucleotide polymorphism (SNP) analysis of 77 ACC tissues and showed alterations in the beta-catenin pathway associated genes zinc and ring finger 3 (ZNRF3) (21%), cadherin-associated protein beta1 (CTNNB1) (16%) and APC (2%).	('ZNRF3', 'Gene', (208, 213))	('zinc and ring finger 3', 'Gene', '84133', (184, 206))	('single', 'Var', (52, 58))	('APC', 'Gene', (275, 278))	('APC', 'Phenotype', 'HP:0005227', (275, 278))	('CTNNB1', 'Gene', (257, 263))	('beta-catenin pathway', 'Pathway', (146, 166))	('alterations', 'Reg', (127, 138))	('CTNNB1', 'Gene', '1499', (257, 263))	('ACC', 'Phenotype', 'HP:0006744', (104, 107))	('ZNRF3', 'Gene', '84133', (208, 213))
74178	32781574	In addition, in vitro inhibition of TARBP2 expression in the ACC cell line H295R resulted in decreased cellular proliferation and increased apoptosis.	('inhibition', 'Var', (22, 32))	('apoptosis', 'CPA', (140, 149))	('decreased', 'NegReg', (93, 102))	('TARBP2', 'Gene', '6895', (36, 42))	('ACC', 'Phenotype', 'HP:0006744', (61, 64))	('TARBP2', 'Gene', (36, 42))	('cellular proliferation', 'CPA', (103, 125))	('increased', 'PosReg', (130, 139))
74179	32781574	This evidence suggests that dysregulation of the miRNA biogenesis pathway may potentiate tumorigenesis in ACC.	('potentiate', 'PosReg', (78, 88))	('miRNA biogenesis pathway', 'Pathway', (49, 73))	('dysregulation', 'Var', (28, 41))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('ACC', 'Phenotype', 'HP:0006744', (106, 109))	('ACC', 'Disease', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
74181	32781574	In cancer, the dysregulation of miRNA expression results from various mechanisms, including amplification or deletion of miRNA genes, dysregulation of transcriptional machinery, changes in methylation and histone modifications, as well as mutations and changes in expression of miRNA biogenesis-related proteins.	('deletion', 'Var', (109, 117))	('results', 'Reg', (49, 56))	('dysregulation', 'Var', (134, 147))	('expression', 'MPA', (264, 274))	('changes', 'Reg', (253, 260))	('histone modifications', 'MPA', (205, 226))	('changes', 'Reg', (178, 185))	('methylation', 'MPA', (189, 200))	('mutations', 'Var', (239, 248))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('miRNA', 'Gene', (32, 37))	('cancer', 'Disease', (3, 9))	('miRNA genes', 'Gene', (121, 132))	('amplification', 'PosReg', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
74183	32781574	Inaccurate cleavage by either DICER or DROSHA, nucleotide additions at the 3  end, and nucleotide modifications could result in the production of miRNA isoforms (isomiRs).	('result in', 'Reg', (118, 127))	('nucleotide modifications', 'Var', (87, 111))	('nucleotide', 'Var', (47, 57))	('production', 'Reg', (132, 142))	('cleavage', 'MPA', (11, 19))	('DICER', 'Gene', '23405', (30, 35))	('miRNA isoforms', 'MPA', (146, 160))	('DICER', 'Gene', (30, 35))	('DROSHA', 'Gene', '29102', (39, 45))	('Inaccurate', 'Var', (0, 10))	('DROSHA', 'Gene', (39, 45))
74195	32781574	Across these studies, miR-483-5p, miR-503-5p, miR-210, and miR-483-3p were overexpressed in ACC compared with ACA or NAC in multiple datasets, and miR-195, miR-497, and miR-335 were underexpressed.	('miR-497', 'Gene', (156, 163))	('miR-195', 'Gene', (147, 154))	('miR-195', 'Gene', '406971', (147, 154))	('miR-210', 'Gene', (46, 53))	('ACA', 'Phenotype', 'HP:0008256', (110, 113))	('miR-335', 'Gene', (169, 176))	('NAC', 'Chemical', '-', (117, 120))	('ACC', 'Phenotype', 'HP:0006744', (92, 95))	('miR-210', 'Gene', '406992', (46, 53))	('miR-503', 'Gene', (34, 41))	('miR-483-3p', 'Chemical', '-', (59, 69))	('miR-483-3p', 'Var', (59, 69))	('miR-483-5p', 'Chemical', '-', (22, 32))	('miR-335', 'Gene', '442904', (169, 176))	('miR-483-5p', 'Var', (22, 32))	('miR-497', 'Gene', '574456', (156, 163))	('overexpressed', 'PosReg', (75, 88))	('miR-503', 'Gene', '574506', (34, 41))
74200	32781574	Circulating miR-483-5p is also overexpressed in hepatocellular as well as head and neck cancers, and has been proposed as a diagnostic marker in these diseases as in ACC.	('head and neck cancers', 'Phenotype', 'HP:0012288', (74, 95))	('ACC', 'Phenotype', 'HP:0006744', (166, 169))	('hepatocellular', 'Disease', (48, 62))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('neck cancers', 'Disease', (83, 95))	('overexpressed', 'PosReg', (31, 44))	('neck cancers', 'Disease', 'MESH:D006258', (83, 95))	('miR-483-5p', 'Chemical', '-', (12, 22))	('miR-483-5p', 'Var', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
74207	32781574	Various RT-q-PCR studies have shown that tissue relative expression levels of miR-210, miR-483-5p, miR-195, miR-503, miR-1202, and miR-1275 are associated with overall survival in ACC.	('miR-503', 'Gene', '574506', (108, 115))	('associated with', 'Reg', (144, 159))	('ACC', 'Phenotype', 'HP:0006744', (180, 183))	('miR-1202', 'Gene', '100302259', (117, 125))	('miR-483-5p', 'Chemical', '-', (87, 97))	('miR-210', 'Gene', (78, 85))	('overall', 'MPA', (160, 167))	('miR-210', 'Gene', '406992', (78, 85))	('miR-503', 'Gene', (108, 115))	('miR-483-5p', 'Var', (87, 97))	('miR-1275', 'Gene', '100302123', (131, 139))	('miR-195', 'Gene', (99, 106))	('miR-195', 'Gene', '406971', (99, 106))	('miR-1275', 'Gene', (131, 139))	('miR-1202', 'Gene', (117, 125))
74208	32781574	In addition, ACC tissue miR-9 relative expression has been shown to correlate with recurrence-free survival as well as overall survival, as has the serum relative expression of miR-483-5p and miR-195.	('ACC', 'Phenotype', 'HP:0006744', (13, 16))	('recurrence-free survival', 'CPA', (83, 107))	('miR-483-5p', 'Chemical', '-', (177, 187))	('miR-483-5p', 'Var', (177, 187))	('miR-9', 'Gene', (24, 29))	('miR-195', 'Gene', (192, 199))	('miR-195', 'Gene', '406971', (192, 199))
74210	32781574	The cluster most distinct from NAC, Mi1, was also characterized by consistent 14q32 LOH and maternally expressed 3 (MEG3) long non-coding RNA promotor methylation.	('MEG3', 'Gene', (116, 120))	('MEG3', 'Gene', '55384', (116, 120))	('14q32', 'Var', (78, 83))	('NAC', 'Chemical', '-', (31, 34))
74212	32781574	The Mi2 group was characterized by weak overexpression of the miR-506-514 cluster, known to have an oncogenic role in melanoma, while the Mi3 group was strongly correlated with the poor prognosis transcriptome cluster C1A.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('Mi3', 'Chemical', '-', (138, 141))	('overexpression', 'PosReg', (40, 54))	('Mi2', 'Chemical', '-', (4, 7))	('Mi2', 'Var', (4, 7))	('miR-506', 'Gene', '574511', (62, 69))	('miR-506', 'Gene', (62, 69))	('correlated', 'Reg', (161, 171))
74213	32781574	Interestingly, while miRNA expression was maximally deregulated in Mi1 and Mi2 cluster tumors, ACC driver pathway alterations were more consistently associated with Mi3 cluster tumors.	('Mi3', 'Chemical', '-', (165, 168))	('ACC driver pathway', 'Pathway', (95, 113))	('cluster tumors', 'Disease', 'MESH:D003027', (169, 183))	('cluster tumors', 'Disease', (79, 93))	('alterations', 'Var', (114, 125))	('deregulated', 'Reg', (52, 63))	('ACC', 'Phenotype', 'HP:0006744', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Mi2', 'Gene', (75, 78))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('associated', 'Reg', (149, 159))	('miRNA expression', 'MPA', (21, 37))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cluster tumors', 'Disease', (169, 183))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('cluster tumors', 'Disease', 'MESH:D003027', (79, 93))	('Mi1', 'Disease', (67, 70))	('Mi2', 'Chemical', '-', (75, 78))
74215	32781574	miR-9, miR-21, miR-483-3p, and miR-483-5p have been well described in the literature as 'oncomiRs' across multiple mammalian cell types, which is consistent with their role in ACC.	('ACC', 'Phenotype', 'HP:0006744', (176, 179))	('miR-483-5p', 'Chemical', '-', (31, 41))	('mammalian', 'Species', '9606', (115, 124))	('miR-21', 'Gene', (7, 13))	('miR-9', 'Var', (0, 5))	('miR-483-5p', 'Var', (31, 41))	('miR-21', 'Gene', '406991', (7, 13))	('miR-483-3p', 'Chemical', '-', (15, 25))	('miR-483-3p', 'Var', (15, 25))
74216	32781574	In contrast, miR-139-5p is an established tumor suppressor in head and neck/oral, breast, and gastric cancers, but is overexpressed in aggressive ACCs compared with non-aggressive ACCs.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (42, 47))	('ACC', 'Phenotype', 'HP:0006744', (146, 149))	('ACC', 'Phenotype', 'HP:0006744', (180, 183))	('aggressive ACCs', 'Disease', (135, 150))	('miR-139-5p', 'Var', (13, 23))	('miR-139-5p', 'Chemical', '-', (13, 23))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('gastric cancers', 'Disease', 'MESH:D013274', (94, 109))	('overexpressed', 'PosReg', (118, 131))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('gastric cancers', 'Disease', (94, 109))	('gastric cancers', 'Phenotype', 'HP:0012126', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('breast', 'Disease', (82, 88))
74225	32781574	miR-483-3p is an oncomiR in ACC, promoting cellular proliferation and inhibiting apoptosis in in vitro cell models.	('miR-483-3p', 'Var', (0, 10))	('cellular proliferation', 'CPA', (43, 65))	('apoptosis', 'CPA', (81, 90))	('miR-483-3p', 'Chemical', '-', (0, 10))	('promoting', 'PosReg', (33, 42))	('inhibiting', 'NegReg', (70, 80))	('ACC', 'Phenotype', 'HP:0006744', (28, 31))
74226	32781574	Reporter assays in three different cell lines, including human embryonic kidney (HEK293), liver cancer (HepG2), and colon cancer (HCT116), demonstrated that miR-483-3p directly inhibits PUMA expression.	('HCT116', 'CellLine', 'CVCL:0291', (130, 136))	('PUMA', 'Gene', (186, 190))	('HEK293', 'CellLine', 'CVCL:0045', (81, 87))	('colon cancer', 'Disease', 'MESH:D015179', (116, 128))	('miR-483-3p', 'Chemical', '-', (157, 167))	('miR-483-3p', 'Var', (157, 167))	('human', 'Species', '9606', (57, 62))	('HepG2', 'CellLine', 'CVCL:0027', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('liver cancer', 'Disease', 'MESH:D006528', (90, 102))	('colon cancer', 'Disease', (116, 128))	('embryonic kidney', 'Disease', (63, 79))	('liver cancer', 'Phenotype', 'HP:0002896', (90, 102))	('PUMA', 'Gene', '27113', (186, 190))	('liver cancer', 'Disease', (90, 102))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('embryonic kidney', 'Disease', 'MESH:D007674', (63, 79))	('inhibits', 'NegReg', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
74228	32781574	PUMA expression was found to be inversely correlated with miR-483-3p expression in ACC, but not in ACA or NAC tissue.	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('ACC', 'Disease', (83, 86))	('PUMA', 'Gene', '27113', (0, 4))	('ACA', 'Phenotype', 'HP:0008256', (99, 102))	('NAC', 'Chemical', '-', (106, 109))	('miR-483-3p', 'Var', (58, 68))	('miR-483-3p', 'Chemical', '-', (58, 68))	('PUMA', 'Gene', (0, 4))
74231	32781574	These miRNAs include miR-7 and miR-205 which have demonstrated tumor suppressor activity in in vivo xenograft ACC models.	('tumor', 'Disease', (63, 68))	('miR-205', 'Var', (31, 38))	('miR-7', 'Gene', '10859', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('ACC', 'Phenotype', 'HP:0006744', (110, 113))	('miR-7', 'Gene', (21, 26))
74241	32781574	miR-100 specific knockdown in in vitro ACC cell models was associated with increased mTOR and IGFR1 protein expression, and furthermore, luciferase reporter assays in HEK293 cells showed that both miRNAs could regulate mTOR and IGFR1.	('mTOR', 'Gene', (219, 223))	('IGFR1', 'Gene', (94, 99))	('protein', 'Protein', (100, 107))	('IGFR1', 'Gene', (228, 233))	('ACC', 'Phenotype', 'HP:0006744', (39, 42))	('miR-100', 'Gene', '406892', (0, 7))	('regulate', 'Reg', (210, 218))	('IGFR1', 'Gene', '3480', (94, 99))	('expression', 'MPA', (108, 118))	('knockdown', 'Var', (17, 26))	('mTOR', 'Gene', '2475', (219, 223))	('increased', 'PosReg', (75, 84))	('IGFR1', 'Gene', '3480', (228, 233))	('mTOR', 'Gene', (85, 89))	('mTOR', 'Gene', '2475', (85, 89))	('miR-100', 'Gene', (0, 7))	('HEK293', 'CellLine', 'CVCL:0045', (167, 173))
74243	32781574	In cancer, miR-99 regulation of mTOR has been demonstrated to enhance radiation sensitivity in urothelial carcinoma as well as non-small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (127, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('urothelial carcinoma', 'Disease', (95, 115))	('enhance', 'PosReg', (62, 69))	('miR-99 regulation', 'Var', (11, 28))	('lung cancer', 'Disease', (142, 153))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mTOR', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('mTOR', 'Gene', '2475', (32, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (95, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cancer', 'Disease', (3, 9))	('cancer', 'Disease', (147, 153))	('radiation sensitivity', 'CPA', (70, 91))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
74244	32781574	The subsequent gain of function studies carried out using SW13 cells (a cell line derived from adrenocortical metastasis of unknown origin) showed that miR-205 promoted apoptosis and impaired cellular proliferation in vitro, and in vivo mouse SW13 xenograft studies showed that it could inhibit tumor growth.	('promoted', 'PosReg', (160, 168))	('apoptosis', 'CPA', (169, 178))	('impaired', 'NegReg', (183, 191))	('mouse', 'Species', '10090', (237, 242))	('SW13', 'CellLine', 'CVCL:0542', (243, 247))	('SW13', 'CellLine', 'CVCL:0542', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('inhibit', 'NegReg', (287, 294))	('miR-205', 'Var', (152, 159))	('cellular proliferation', 'CPA', (192, 214))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', (295, 300))
74262	32781574	In H295R, miR-497 overexpression and MALAT1 knockdown inhibit the expression of eukaryotic translation initiation factor 4E (eIF4E), which directs ribosomes to the cap structure of mRNAs and is, therefore, essential for protein synthesis.	('eukaryotic translation initiation factor 4E', 'Gene', (80, 123))	('eukaryotic translation initiation factor 4E', 'Gene', '1977', (80, 123))	('inhibit', 'NegReg', (54, 61))	('eIF4E', 'Gene', (125, 130))	('MALAT1', 'Gene', '378938', (37, 43))	('expression', 'MPA', (66, 76))	('miR-497', 'Gene', (10, 17))	('miR-497', 'Gene', '574456', (10, 17))	('knockdown', 'Var', (44, 53))	('eIF4E', 'Gene', '1977', (125, 130))	('MALAT1', 'Gene', (37, 43))
74264	32781574	This supports the notion that miRNA modulation of protein expression, which in healthy cells helps to finetune and maintain the homeostatic balance, can potentiate oncogenesis when dysregulated.	('oncogenesis', 'CPA', (164, 175))	('finetune', 'MPA', (102, 110))	('finetune', 'Chemical', '-', (102, 110))	('protein', 'Protein', (50, 57))	('homeostatic balance', 'MPA', (128, 147))	('potentiate', 'PosReg', (153, 163))	('miRNA modulation', 'Var', (30, 46))
74266	32781574	miR-483-3p suppression of PUMA expression and the alleviation of miR-205 modulated Bcl-2 inhibition of Bax, act synergistically to inhibit p53-mediated apoptosis.	('suppression', 'NegReg', (11, 22))	('Bcl-2', 'Gene', '596', (83, 88))	('PUMA', 'Gene', '27113', (26, 30))	('inhibit', 'NegReg', (131, 138))	('Bcl-2', 'Gene', (83, 88))	('miR-483-3p', 'Var', (0, 10))	('Bax', 'Gene', '581', (103, 106))	('PUMA', 'Gene', (26, 30))	('miR-483-3p', 'Chemical', '-', (0, 10))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('miR-205', 'Gene', (65, 72))	('Bax', 'Gene', (103, 106))
74280	32207273	In multivariate models, high expression of cyclin B1 and TfR1 was significantly associated with mortality (hazard ratio [HR], 6.13; 95% confidence interval [CI], 1.02 to 36.7; and HR, 6.59; 95% CI, 1.14 to 38.2; respectively), whereas high fibronectin expression was not (HR, 3.92; 95% CI, 0.75 to 20.4).	('TfR1', 'Gene', (57, 61))	('fibronectin', 'Gene', (240, 251))	('mortality', 'Disease', 'MESH:D003643', (96, 105))	('associated with', 'Reg', (80, 95))	('high expression', 'Var', (24, 39))	('cyclin B1', 'Gene', '891', (43, 52))	('cyclin B1', 'Gene', (43, 52))	('fibronectin', 'Gene', '2335', (240, 251))	('mortality', 'Disease', (96, 105))	('TfR1', 'Gene', '7037', (57, 61))
74304	32207273	The survival rate was significantly lower in patients with high expression levels of each of these three proteins than in those with low expression levels (overall log-rank P value <0.001 for all).	('lower', 'NegReg', (36, 41))	('survival rate', 'CPA', (4, 17))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (45, 53))	('expression levels', 'MPA', (64, 81))
74309	32207273	All combinations of each protein expression signature (high cyclin B1/high TfR1, high cyclin B1/high fibronectin, high TfR1/high fibronectin, and high cyclin B1/high TfR1/high fibronectin) significantly predicted mortality.	('TfR1', 'Gene', '7037', (75, 79))	('high', 'Var', (114, 118))	('cyclin B1', 'Gene', '891', (151, 160))	('cyclin B1', 'Gene', (151, 160))	('predicted', 'Reg', (203, 212))	('cyclin B1', 'Gene', '891', (86, 95))	('cyclin B1', 'Gene', (86, 95))	('high', 'Var', (81, 85))	('fibronectin', 'Gene', (176, 187))	('high', 'Var', (55, 59))	('TfR1', 'Gene', '7037', (119, 123))	('fibronectin', 'Gene', '2335', (129, 140))	('mortality', 'Disease', 'MESH:D003643', (213, 222))	('TfR1', 'Gene', '7037', (166, 170))	('fibronectin', 'Gene', '2335', (101, 112))	('cyclin B1', 'Gene', '891', (60, 69))	('cyclin B1', 'Gene', (60, 69))	('fibronectin', 'Gene', '2335', (176, 187))	('TfR1', 'Gene', (75, 79))	('fibronectin', 'Gene', (101, 112))	('TfR1', 'Gene', (119, 123))	('TfR1', 'Gene', (166, 170))	('fibronectin', 'Gene', (129, 140))	('mortality', 'Disease', (213, 222))
74310	32207273	The HRs for mortality of combinations involving each DEP were higher than those of each protein individually.	('combinations', 'Var', (25, 37))	('mortality', 'Disease', 'MESH:D003643', (12, 21))	('higher', 'PosReg', (62, 68))	('mortality', 'Disease', (12, 21))
74311	32207273	The C-index of the reference model (age and staging) was 0.78, and it increased when each protein (high cyclin B1, high TfR1, and high fibronectin) was added, to 0.82, 0.83, and 0.82, respectively.	('TfR1', 'Gene', '7037', (120, 124))	('fibronectin', 'Gene', '2335', (135, 146))	('increased', 'PosReg', (70, 79))	('TfR1', 'Gene', (120, 124))	('cyclin B1', 'Gene', '891', (104, 113))	('C-index', 'MPA', (4, 11))	('fibronectin', 'Gene', (135, 146))	('cyclin B1', 'Gene', (104, 113))	('high', 'Var', (99, 103))
74314	32207273	Some combinations of DEPs (high cyclin B/high TfR1 and high TfR1/high fibronectin) showed significant associations with mortality, while other combinations (high cyclin B1/high fibronectin and high cyclin B1/high TfR1/high fibronectin) showed near-significant associations with mortality.	('fibronectin', 'Gene', (223, 234))	('TfR1', 'Gene', (46, 50))	('mortality', 'Disease', 'MESH:D003643', (120, 129))	('mortality', 'Disease', 'MESH:D003643', (278, 287))	('TfR1', 'Gene', (213, 217))	('fibronectin', 'Gene', '2335', (177, 188))	('high cyclin', 'Var', (27, 38))	('cyclin B1', 'Gene', '891', (162, 171))	('cyclin B1', 'Gene', (162, 171))	('TfR1', 'Gene', (60, 64))	('fibronectin', 'Gene', (70, 81))	('fibronectin', 'Gene', '2335', (223, 234))	('TfR1', 'Gene', '7037', (46, 50))	('TfR1', 'Gene', '7037', (213, 217))	('mortality', 'Disease', (120, 129))	('fibronectin', 'Gene', '2335', (70, 81))	('mortality', 'Disease', (278, 287))	('TfR1', 'Gene', '7037', (60, 64))	('associations', 'Interaction', (102, 114))	('fibronectin', 'Gene', (177, 188))	('cyclin B1', 'Gene', '891', (198, 207))	('cyclin B1', 'Gene', (198, 207))
74322	32207273	Molecular studies revealed that mutations in several potential driver genes such as CTNNB1 and TP53 may serve as prognostic markers.	('CTNNB1', 'Gene', '1499', (84, 90))	('mutations', 'Var', (32, 41))	('CTNNB1', 'Gene', (84, 90))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
74333	32207273	In addition, as potential TfR1 inhibitors, curcumin, antibody A24 or JST-TFR09, and miR-320 have been studied in several cancers.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('A24', 'Gene', '28924', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('miR-320', 'Var', (84, 91))	('JST', 'Gene', (69, 72))	('curcumin', 'Chemical', 'MESH:D003474', (43, 51))	('TfR1', 'Gene', (26, 30))	('JST', 'Gene', '449523', (69, 72))	('TfR1', 'Gene', '7037', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('A24', 'Gene', (62, 65))
74335	32207273	It has also been reported that abnormal expression of fibronectin promotes invasion and migration of cancers, including breast, ovarian, prostate, lung, and colon cancers.	('abnormal expression', 'Var', (31, 50))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('invasion', 'CPA', (75, 83))	('fibronectin', 'Gene', (54, 65))	('colon cancers', 'Phenotype', 'HP:0003003', (157, 170))	('ovarian', 'Disease', (128, 135))	('promotes', 'PosReg', (66, 74))	('breast', 'Disease', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('colon cancers', 'Disease', 'MESH:D015179', (157, 170))	('lung', 'Disease', (147, 151))	('cancers', 'Disease', (163, 170))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('fibronectin', 'Gene', '2335', (54, 65))	('prostate', 'Disease', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('colon cancers', 'Disease', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
74337	32207273	In vitro studies of lung, pancreatic neuroendocrine, and breast cancers have shown that several molecules (e.g., PP2, PF-04554878, pUR4B, and AdF512v1) that inhibit fibronectin and its upstream or downstream pathways reduced its effects on tumor cell proliferation, migration, and angiogenesis.	('breast cancers', 'Disease', 'MESH:D001943', (57, 71))	('fibronectin', 'Gene', (165, 176))	('breast cancers', 'Disease', (57, 71))	('tumor', 'Disease', (240, 245))	('PF-04554878', 'Var', (118, 129))	('fibronectin', 'Gene', '2335', (165, 176))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('angiogenesis', 'CPA', (281, 293))	('pancreatic neuroendocrine', 'Disease', 'MESH:D018358', (26, 51))	('inhibit', 'NegReg', (157, 164))	('pancreatic neuroendocrine', 'Disease', (26, 51))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('migration', 'CPA', (266, 275))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('breast cancers', 'Phenotype', 'HP:0003002', (57, 71))	('reduced', 'NegReg', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('AdF512v1', 'Var', (142, 150))
74379	28450405	The following metabolites were quantified by monitoring characteristic fragmentation reactions (in bracket); alpha-aminopimelic acid (176  112, ESI+), 3-methylhistidine (170  96, ESI+), Nepsilon,Nepsilon,Nepsilon-trimethyllysine (189  84, ESI+), L-tryptophan (205  118, ESI-), creatine (132  90, ESI+), and creatine riboside (264  132, ESI+).	('creatine', 'MPA', (277, 285))	('189  84', 'Var', (230, 237))	('Nepsilon', 'Chemical', 'MESH:C005205', (186, 194))	('176  112', 'Var', (134, 142))	('Nepsilon-trimethyllysine', 'Chemical', 'MESH:C003712', (204, 228))	('Nepsilon', 'Chemical', 'MESH:C005205', (204, 212))	('alpha-aminopimelic acid', 'Chemical', 'MESH:C009845', (109, 132))	('creatine', 'Chemical', 'MESH:D003401', (307, 315))	('Nepsilon', 'Chemical', 'MESH:C005205', (195, 203))	('creatine riboside', 'MPA', (307, 324))	('L-tryptophan', 'Chemical', 'MESH:D014364', (246, 258))	('205  118', 'Var', (260, 268))	('creatine', 'Chemical', 'MESH:D003401', (277, 285))	('creatine riboside', 'Chemical', 'MESH:C000590396', (307, 324))	('170  96', 'Var', (170, 177))	('3-methylhistidine', 'Chemical', 'MESH:C028118', (151, 168))	('264', 'Var', (326, 329))	('Nepsilon', 'MPA', (186, 194))
74385	28450405	The following metabolites were quantified by monitoring characteristic fragmentation reactions (in bracket); alpha-aminopimelic acid (176  112, ESI+), 3-methylhistidine (170  96, ESI+), Nepsilon,Nepsilon,Nepsilon-trimethyllysine (189  84, ESI+), L-tryptophan (205  118, ESI-), creatine (132  90, ESI+), creatine riboside (264  132, ESI+), Var_0001 (334  85), and Var_0012 (306  85).	('Nepsilon', 'Chemical', 'MESH:C005205', (186, 194))	('3-methylhistidine', 'Chemical', 'MESH:C028118', (151, 168))	('creatine', 'MPA', (277, 285))	('189  84', 'Var', (230, 237))	('176  112', 'Var', (134, 142))	('Var_0001', 'Var', (339, 347))	('creatine', 'Chemical', 'MESH:D003401', (303, 311))	('Var_0012', 'Var', (363, 371))	('creatine riboside', 'MPA', (303, 320))	('264  132', 'Var', (322, 330))	('creatine riboside', 'Chemical', 'MESH:C000590396', (303, 320))	('alpha-aminopimelic acid', 'Chemical', 'MESH:C009845', (109, 132))	('Nepsilon-trimethyllysine', 'Chemical', 'MESH:C003712', (204, 228))	('205  118', 'Var', (260, 268))	('creatine', 'Chemical', 'MESH:D003401', (277, 285))	('170  96', 'Var', (170, 177))	('Nepsilon', 'Chemical', 'MESH:C005205', (204, 212))	('Nepsilon', 'Chemical', 'MESH:C005205', (195, 203))	('L-tryptophan', 'Chemical', 'MESH:D014364', (246, 258))
74410	28450405	The four metabolites identified through fragmentation patterns and database searches were creatine riboside, Nepsilon,Nepsilon,Nepsilon-trimethyllysine, 3-methylhistidine, and L-tryptophan (Supplementary Data, Figure 4A, 4B, 4C, and 4D).	('Nepsilon', 'Chemical', 'MESH:C005205', (109, 117))	('3-methylhistidine', 'Chemical', 'MESH:C028118', (153, 170))	('Nepsilon', 'Chemical', 'MESH:C005205', (127, 135))	('Nepsilon-trimethyllysine', 'Chemical', 'MESH:C003712', (127, 151))	('L-tryptophan', 'Chemical', 'MESH:D014364', (176, 188))	('creatine riboside', 'MPA', (90, 107))	('Nepsilon', 'Chemical', 'MESH:C005205', (118, 126))	('creatine riboside', 'Chemical', 'MESH:C000590396', (90, 107))	('Nepsilon-trimethyllysine', 'Var', (127, 151))
74446	28450405	Nepsilon,Nepsilon,Nepsilon-trimethyllysine, is associated with trimethylation of lysine residues on histone complexes.	('Nepsilon', 'Var', (0, 8))	('Nepsilon', 'Chemical', 'MESH:C005205', (0, 8))	('lysine', 'Chemical', 'MESH:D008239', (36, 42))	('lysine', 'Chemical', 'MESH:D008239', (81, 87))	('Nepsilon', 'Chemical', 'MESH:C005205', (18, 26))	('trimethylation', 'MPA', (63, 77))	('associated', 'Reg', (47, 57))	('Nepsilon', 'Chemical', 'MESH:C005205', (9, 17))	('Nepsilon-trimethyllysine', 'Chemical', 'MESH:C003712', (18, 42))
74450	28450405	However, in the subset of tissue samples Nepsilon,Nepsilon,Nepsilon-trimethyllysine showed an elevated level in patients with ACC compared to benign adrenocortical neoplasms.	('Nepsilon-trimethyllysine', 'Var', (59, 83))	('Nepsilon', 'Chemical', 'MESH:C005205', (50, 58))	('elevated', 'PosReg', (94, 102))	('Nepsilon', 'Var', (41, 49))	('level', 'MPA', (103, 108))	('neoplasm', 'Phenotype', 'HP:0002664', (164, 172))	('Nepsilon', 'Chemical', 'MESH:C005205', (41, 49))	('patients', 'Species', '9606', (112, 120))	('Nepsilon', 'Chemical', 'MESH:C005205', (59, 67))	('Nepsilon-trimethyllysine', 'Chemical', 'MESH:C003712', (59, 83))	('benign adrenocortical neoplasms', 'Disease', 'MESH:D018268', (142, 173))	('neoplasms', 'Phenotype', 'HP:0002664', (164, 173))	('benign adrenocortical neoplasms', 'Disease', (142, 173))	('ACC', 'Disease', (126, 129))	('Nepsilon', 'Var', (50, 58))
74452	28450405	In vitro studies showed knockdown of EZH2 to lead to decreased cellular growth, inhibition of migration and clonogenic growth, and apoptosis.	('inhibition', 'NegReg', (80, 90))	('cellular growth', 'CPA', (63, 78))	('EZH2', 'Gene', '2146', (37, 41))	('apoptosis', 'CPA', (131, 140))	('decreased', 'NegReg', (53, 62))	('knockdown', 'Var', (24, 33))	('EZH2', 'Gene', (37, 41))
74547	23652308	Other inclusion criteria included Cr-EDTA clearance >60 ml min-1, neutrophil count >1.5 x 109 per l, platelet count >100 x 109 per l, bilirubin <1.5 ULN and aspartate aminotransferase or alanine aminotransferase <3 ULN.	('aspartate aminotransferase', 'Enzyme', (157, 183))	('>100 x', 'Var', (116, 122))	('alanine aminotransferase', 'Enzyme', (187, 211))	('neutrophil count', 'CPA', (66, 82))	('min-1', 'Gene', '966', (59, 64))	('min-1', 'Gene', (59, 64))	('bilirubin', 'MPA', (134, 143))	('Cr-EDTA clearance', 'MPA', (34, 51))	('Cr-EDTA', 'Chemical', '-', (34, 41))	('bilirubin', 'Chemical', 'MESH:D001663', (134, 143))
74607	22752623	Nuclear pleomorphism and necrosis were found (Fig.	('Nuclear', 'Var', (0, 7))	('necrosis', 'Disease', (25, 33))	('necrosis', 'Disease', 'MESH:D009336', (25, 33))
74640	22752623	reported a young boy with no family history of cancer who was diagnosed with CPC and adrenocortical carcinoma, and harbored a novel de novo germline TP53 mutation.	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (85, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('CPC', 'Disease', 'MESH:D020288', (77, 80))	('CPC', 'Disease', (77, 80))	('TP53', 'Gene', '7157', (149, 153))	('cancer', 'Disease', (47, 53))	('mutation', 'Var', (154, 162))	('boy', 'Species', '9606', (17, 20))	('adrenocortical carcinoma', 'Disease', (85, 109))	('TP53', 'Gene', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('CPC', 'Phenotype', 'HP:0030392', (77, 80))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (85, 109))
74646	33810347	Transcriptional and epigenetic dysregulation is significantly associated with cancer stemness.	('cancer stemness', 'Disease', 'MESH:D009369', (78, 93))	('associated', 'Reg', (62, 72))	('epigenetic dysregulation', 'Var', (20, 44))	('cancer stemness', 'Disease', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
74649	33810347	Our results indicate that only TIF1beta (also known as Tripartite Motif protein 28, TRIM28) high expression is consequently associated with a "stemness high" phenotype, regardless of the tumor type, resulting in a worse prognosis for cancer patients.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('TIF1beta', 'Gene', (31, 39))	('high expression', 'Var', (92, 107))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('TIF1beta', 'Gene', '8805', (31, 39))	('associated with', 'Reg', (124, 139))	('TRIM28', 'Gene', (84, 90))	('tumor', 'Disease', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('TRIM28', 'Gene', '10155', (84, 90))	('patients', 'Species', '9606', (241, 249))
74652	33810347	Our results demonstrate that the association between high TRIM28 expression and an enriched cancer stem cell-like phenotype is a common phenomenon across solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('TRIM28', 'Gene', (58, 64))	('high', 'Var', (53, 57))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('solid tumors', 'Disease', (154, 166))	('TRIM28', 'Gene', '10155', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('expression', 'MPA', (65, 75))	('solid tumors', 'Disease', 'MESH:D009369', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
74654	33810347	Cancer de-differentiation and the acquisition of stemness features are mediated by the transcriptional and epigenetic dysregulation of cancer cells.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('epigenetic dysregulation', 'Var', (107, 131))	('stemness features', 'CPA', (49, 66))
74670	33810347	Reactivation of the ESC-like program in cancer strongly predicts metastatic potential and patient death.	('death', 'Disease', 'MESH:D003643', (98, 103))	('metastatic potential', 'CPA', (65, 85))	('death', 'Disease', (98, 103))	('predicts', 'Reg', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('Reactivation', 'Var', (0, 12))	('patient', 'Species', '9606', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ESC-like program', 'Gene', (20, 36))
74671	33810347	Cell de-differentiation and the acquisition of stemness features is mediated by the transcriptional and epigenetic dysregulation of cancer cells.	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('epigenetic dysregulation', 'Var', (104, 128))	('stemness features', 'CPA', (47, 64))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('Cell de-differentiation', 'CPA', (0, 23))
74678	33810347	TIF1 members are aberrantly expressed or mutated in multiple cancer types; however, their role in cancer stem cells is still not fully understood.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutated', 'Var', (41, 48))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('TIF1', 'Gene', '8805', (0, 4))	('TIF1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
74694	33810347	Among other TIF1 family members, only high TRIM28 expression might serve as a marker for stemness-associated traits of solid tumors.	('TIF1', 'Gene', '8805', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('TIF1', 'Gene', (12, 16))	('high', 'Var', (38, 42))	('solid tumors', 'Disease', 'MESH:D009369', (119, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('TRIM28', 'Gene', (43, 49))	('TRIM28', 'Gene', '10155', (43, 49))	('solid tumors', 'Disease', (119, 131))
74700	33810347	The representative results of immunohistochemistry staining of Prostate Adenocarcinoma (PRAD) samples with anti-TRIM24 (antibody name: HPA043495), anti-TRIM28 (HPA064033), anti-TRIM33 (HPA004345), and anti-TRIM66 (HPA027420) antibodies were downloaded from the Human Protein Atlas database (, accessed on 10 October 2020).	('anti-TRIM24', 'Var', (107, 118))	('TRIM66', 'Gene', (206, 212))	('HPA004345', 'Var', (185, 194))	('TRIM28', 'Gene', (152, 158))	('Human', 'Species', '9606', (261, 266))	('Prostate Adenocarcinoma', 'Disease', (63, 86))	('TRIM33', 'Gene', (177, 183))	('TRIM33', 'Gene', '51592', (177, 183))	('TRIM66', 'Gene', '9866', (206, 212))	('TRIM28', 'Gene', '10155', (152, 158))	('Prostate Adenocarcinoma', 'Disease', 'MESH:D011471', (63, 86))
74706	33810347	All datasets were analyzed online using the R2 Platform (, accessed on 10 October 2020) to find genes that correlate with TRIM24, TRIM28, TRIM33, or TRIM66 expression.	('TRIM24', 'Var', (122, 128))	('TRIM33', 'Gene', '51592', (138, 144))	('TRIM28', 'Gene', (130, 136))	('TRIM33', 'Gene', (138, 144))	('TRIM66', 'Gene', (149, 155))	('TRIM66', 'Gene', '9866', (149, 155))	('TRIM28', 'Gene', '10155', (130, 136))
74713	33810347	Higher TRIM28 expression is significantly associated with worse survival for Kidney Renal Clear Cell Carcinoma (KIRC), Kidney Renal Papillary Cell Carcinoma (KIRP), LIHC, Lung Adenocarcinoma (LUAD), MESO, Adrenocortical Carcinoma (ACC), Skin Cutaneous Melanoma (SKCM), and Bladder Urothelial Carcinoma (BLCA), and with better survival for THYM, Uveal Melanoma (UVM), and Testicular Germ Cell Tumor (TGCT) patients (Figure 1B).	('UVM', 'Phenotype', 'HP:0007716', (361, 364))	('Bladder Urothelial Carcinoma', 'Disease', 'MESH:D001749', (273, 301))	('Carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('THYM', 'Phenotype', 'HP:0100522', (339, 343))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (171, 190))	('Melanoma', 'Disease', (351, 359))	('Carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('Carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('Kidney Renal Papillary Cell Carcinoma', 'Disease', 'MESH:C538614', (119, 156))	('MESO', 'Disease', (199, 203))	('TRIM28', 'Gene', (7, 13))	('expression', 'Var', (14, 24))	('Kidney Renal Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (77, 110))	('ACC', 'Phenotype', 'HP:0006744', (231, 234))	('Melanoma', 'Phenotype', 'HP:0002861', (351, 359))	('Germ Cell Tumor', 'Phenotype', 'HP:0100728', (382, 397))	('Skin Cutaneous Melanoma', 'Disease', (237, 260))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (205, 229))	('Kidney Renal Clear Cell Carcinoma', 'Disease', (77, 110))	('Lung Adenocarcinoma', 'Disease', (171, 190))	('Melanoma', 'Disease', 'MESH:D008545', (252, 260))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (242, 260))	('Tumor', 'Phenotype', 'HP:0002664', (392, 397))	('Bladder Urothelial Carcinoma', 'Disease', (273, 301))	('TRIM28', 'Gene', '10155', (7, 13))	('Carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (345, 359))	('Renal Papillary Cell Carcinoma', 'Phenotype', 'HP:0006766', (126, 156))	('LIHC', 'Disease', (165, 169))	('Melanoma', 'Disease', (252, 260))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (205, 229))	('Kidney Renal Papillary Cell Carcinoma', 'Disease', (119, 156))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (171, 190))	('patients', 'Species', '9606', (405, 413))	('Melanoma', 'Disease', 'MESH:D008545', (351, 359))	('Melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (237, 260))	('Adrenocortical Carcinoma', 'Disease', (205, 229))	('LUAD', 'Phenotype', 'HP:0030078', (192, 196))
74717	33810347	Using the cBioportal data, we observed that across all tested tumor types (10,506 profiled samples in 27 solid TCGA tumor types), the frequencies of alterations (missense mutations, amplifications, deletions) in TIF1 member-encoding genes were relatively low (Figure S1A), with 2.6%, 2.2%, 1.8%, and 0.9% genetic alterations in profiled samples for TRIM24, TRIM28, TRIM33, and TRIM66, respectively.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('TRIM28', 'Gene', '10155', (357, 363))	('TRIM66', 'Gene', (377, 383))	('TRIM24', 'Var', (349, 355))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('TIF1', 'Gene', '8805', (212, 216))	('TRIM33', 'Gene', '51592', (365, 371))	('TRIM33', 'Gene', (365, 371))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('TRIM66', 'Gene', '9866', (377, 383))	('TIF1', 'Gene', (212, 216))	('tumor', 'Disease', (116, 121))	('TRIM28', 'Gene', (357, 363))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
74718	33810347	In most cancer types, the frequency of alterations did not exceed 5% for each of the tested genes (Figure S1B-E), except for TRIM24 in Ovarian Serous Cystadenocarcinoma (OV) (10.98%) and SKCM (8.05%), and TRIM28 and TRIM33 in Esophageal Carcinoma (ESCA) (5.41% and 5.41% of altered samples, respectively), suggesting that genetic alterations in TIF1 members are not of great importance in cancer development.	('TIF1', 'Gene', (345, 349))	('Carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('Ovarian Serous Cystadenocarcinoma', 'Phenotype', 'HP:0012887', (135, 168))	('cancer', 'Disease', (389, 395))	('TIF1', 'Gene', '8805', (345, 349))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('Ovarian Serous Cystadenocarcinoma', 'Disease', (135, 168))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('TRIM28', 'Gene', (205, 211))	('TRIM24', 'Var', (125, 131))	('Carcinoma', 'Disease', (237, 246))	('Esophageal Carcinoma', 'Phenotype', 'HP:0011459', (226, 246))	('Carcinoma', 'Disease', 'MESH:D009369', (237, 246))	('ESCA', 'Phenotype', 'HP:0011459', (248, 252))	('TRIM33', 'Gene', (216, 222))	('Ovarian Serous Cystadenocarcinoma', 'Disease', 'MESH:D018284', (135, 168))	('TRIM28', 'Gene', '10155', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('TRIM33', 'Gene', '51592', (216, 222))	('OV', 'Phenotype', 'HP:0012887', (170, 172))
74735	33810347	The number of genes that are significantly correlated with the expression of TRIM24, TRIM28, TRIM33, or TRIM66 are presented in Figure S2.	('TRIM28', 'Gene', '10155', (85, 91))	('TRIM24', 'Var', (77, 83))	('TRIM66', 'Gene', (104, 110))	('TRIM33', 'Gene', '51592', (93, 99))	('TRIM33', 'Gene', (93, 99))	('TRIM28', 'Gene', (85, 91))	('TRIM66', 'Gene', '9866', (104, 110))
74774	33810347	We have previously shown that high TRIM28 expression is strictly related to the stem cell-like phenotype of breast cancer and melanomas.	('melanomas', 'Disease', 'MESH:D008545', (126, 135))	('TRIM28', 'Gene', (35, 41))	('melanomas', 'Disease', (126, 135))	('expression', 'MPA', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('high', 'Var', (30, 34))	('TRIM28', 'Gene', '10155', (35, 41))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('related', 'Reg', (65, 72))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
74777	33810347	Here, we reported for the first time that the association between high TRIM28 expression and an enriched stem cell-like phenotype is a common phenomenon across solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('TRIM28', 'Gene', (71, 77))	('association', 'Interaction', (46, 57))	('high', 'Var', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('TRIM28', 'Gene', '10155', (71, 77))	('solid tumors', 'Disease', (160, 172))
74800	33810347	As presented by Massague et al., the loss of TRIM33 expression does not affect stem cell self-renewal, but it impairs the differentiation process.	('differentiation process', 'CPA', (122, 145))	('TRIM33', 'Gene', '51592', (45, 51))	('TRIM33', 'Gene', (45, 51))	('impairs', 'NegReg', (110, 117))	('loss', 'Var', (37, 41))
74811	33810347	TRIM24 and TRIM28 are generally positively associated, while TRIM33 and TRIM66 are mostly negatively associated with cancer stemness in solid tumors.	('cancer stemness', 'Disease', (117, 132))	('associated', 'Interaction', (43, 53))	('TRIM28', 'Gene', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('solid tumors', 'Disease', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('negatively', 'NegReg', (90, 100))	('TRIM66', 'Gene', '9866', (72, 78))	('TRIM28', 'Gene', '10155', (11, 17))	('cancer stemness', 'Disease', 'MESH:D009369', (117, 132))	('TRIM24', 'Var', (0, 6))	('TRIM66', 'Gene', (72, 78))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('associated', 'Reg', (101, 111))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('TRIM33', 'Gene', '51592', (61, 67))	('TRIM33', 'Gene', (61, 67))
74852	31804360	Genetic investigation was negative for RET, VHL, SDHB, SDHC, SDHD mutations.	('mutations', 'Var', (66, 75))	('SDHB', 'Gene', (49, 53))	('RET', 'Gene', (39, 42))	('VHL', 'Disease', 'MESH:D006623', (44, 47))	('SDHD', 'Gene', '6392', (61, 65))	('SDHC', 'Gene', (55, 59))	('SDHD', 'Gene', (61, 65))	('SDHC', 'Gene', '6391', (55, 59))	('RET', 'Gene', '5979', (39, 42))	('SDHB', 'Gene', '6390', (49, 53))	('VHL', 'Disease', (44, 47))
74895	31804360	The improved survival benefited from reducing the tumor burden, decompressing the spinal stenosis to alleviate radiculopathy or myelopathy, and facilitating subsequent adjuvant therapies.	('radiculopathy or myelopathy', 'Disease', (111, 138))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('spinal stenosis', 'Disease', (82, 97))	('spinal stenosis', 'Disease', 'MESH:D013130', (82, 97))	('myelopathy', 'Phenotype', 'HP:0002196', (128, 138))	('radiculopathy or myelopathy', 'Disease', 'MESH:D011843', (111, 138))	('spinal stenosis', 'Phenotype', 'HP:0003416', (82, 97))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('decompressing', 'Var', (64, 77))	('tumor', 'Disease', (50, 55))
74915	30738017	Cushing's syndrome (CS) exacerbation during pregnancy can be associated with aberrant expression of LHCG receptor on primary adrenocortical tumour or hyperplasia in some cases, but not in this patient.	('adrenocortical tumour', 'Disease', 'MESH:D000306', (125, 146))	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('hyperplasia', 'Disease', 'MESH:D006965', (150, 161))	('LHCG receptor', 'Gene', (100, 113))	('adrenocortical tumour', 'Disease', (125, 146))	('LH', 'Chemical', 'MESH:D007986', (100, 102))	("Cushing's syndrome", 'Disease', (0, 18))	('CS', 'Phenotype', 'HP:0003118', (20, 22))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (0, 18))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (0, 18))	('hyperplasia', 'Disease', (150, 161))	('patient', 'Species', '9606', (193, 200))	('exacerbation', 'PosReg', (24, 36))	('aberrant expression', 'Var', (77, 96))
74940	30738017	The patient was evaluated with in vivo sequential tests to identify the presence of aberrant adrenal hormone receptors as previously described including an i.v.	('aberrant', 'Var', (84, 92))	('patient', 'Species', '9606', (4, 11))	('adrenal hormone receptors', 'Protein', (93, 118))
74997	30593126	A small subset of patients with adrenocortical carcinoma may have high mutational burden and harbor mutations in mismatch-repair genes.	('mutations', 'Var', (100, 109))	('adrenocortical carcinoma', 'Disease', (32, 56))	('mutational burden', 'MPA', (71, 88))	('mismatch-repair genes', 'Gene', (113, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (32, 56))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (32, 56))	('patients', 'Species', '9606', (18, 26))
74999	30593126	Next-generation sequencing detected high mutational burden (>10 mutations/megabase) in both patients, one of them with MSH2 mutation.	('MSH2', 'Gene', (119, 123))	('MSH2', 'Gene', '4436', (119, 123))	('mutation', 'Var', (124, 132))	('patients', 'Species', '9606', (92, 100))
75001	30593126	The patient harboring a MSH2 mutation experienced a long-term complete response after pembrolizumab, while the patient with high mutational burden and absence of mismatch repair deficiency did not have any response.	('mutation', 'Var', (29, 37))	('pembrolizumab', 'Chemical', 'MESH:C582435', (86, 99))	('MSH2', 'Gene', (24, 28))	('patient', 'Species', '9606', (4, 11))	('MSH2', 'Gene', '4436', (24, 28))	('patient', 'Species', '9606', (111, 118))
75005	30593126	Although controversies for adjuvant therapy still exists, surgery may be followed by adjuvant mitotane in those patients considered to be at high-risk (eg, tumor rupture, Ki67 immunoexpression in greater than 10% of tumor cells, positive lymph nodes or positive margins).	('tumor', 'Disease', (216, 221))	('Ki67', 'Var', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor rupture', 'Disease', (156, 169))	('tumor rupture', 'Disease', 'MESH:D012421', (156, 169))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('mitotane', 'Chemical', 'MESH:D008939', (94, 102))
75009	30593126	Molecularly, adrenocortical carcinomas are characterized by a high heterogeneity and low mutational burden, in which driver implicated mutations may include CTNNB1, TP53, ZNFR3, CCNE1, and PRKRAR1A.	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('TP53', 'Gene', (165, 169))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (13, 38))	('CTNNB1', 'Gene', (157, 163))	('ZNFR3', 'Gene', (171, 176))	('mutations', 'Var', (135, 144))	('CCNE1', 'Gene', (178, 183))	('CCNE1', 'Gene', '898', (178, 183))	('TP53', 'Gene', '7157', (165, 169))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (13, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (13, 37))	('CTNNB1', 'Gene', '1499', (157, 163))	('adrenocortical carcinomas', 'Disease', (13, 38))
75010	30593126	Whole genome doubling is a typical event in a subset of adrenocortical carcinomas, and is associated with aggressiveness.	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (56, 81))	('aggressiveness', 'Disease', (106, 120))	('aggressiveness', 'Disease', 'MESH:D001523', (106, 120))	('adrenocortical carcinomas', 'Disease', (56, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('aggressiveness', 'Phenotype', 'HP:0000718', (106, 120))	('associated', 'Reg', (90, 100))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (56, 80))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (56, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('Whole genome doubling', 'Var', (0, 21))
75011	30593126	Interestingly, a hypermutator phenotype is detected in a small subset of patients, which is associated with mutations in DNA mismatch repair genes.	('associated', 'Reg', (92, 102))	('patients', 'Species', '9606', (73, 81))	('mutations', 'Var', (108, 117))
75012	30593126	Associations with Lynch syndrome and mutations in MHS2, MSH6, MLH1, and POLE have been identified in approximately 3% of cases.	('Associations', 'Interaction', (0, 12))	('MHS2', 'Gene', (50, 54))	('MSH6', 'Gene', (56, 60))	('Lynch syndrome', 'Disease', (18, 32))	('mutations', 'Var', (37, 46))	('MHS2', 'Gene', '4264', (50, 54))	('MSH6', 'Gene', '2956', (56, 60))	('Lynch syndrome', 'Disease', 'MESH:D003123', (18, 32))	('MLH1', 'Gene', '4292', (62, 66))	('MLH1', 'Gene', (62, 66))
75015	30593126	Although the perfect predictive biomarker has not been identified, mutations in genes of DNA mismatch repair enzymes (or the lack of immunoexpression of these enzymes), high tumor mutational burden, increased ratios of tumor-infiltrating lymphocytes, or increased PD-L1 expression have been implicated in better outcomes after treatment with anti-PD-1/anti-PD-L1 agents in different clinical settings.	('PD-L1', 'Gene', '29126', (264, 269))	('tumor', 'Disease', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('better', 'PosReg', (305, 311))	('DNA', 'Gene', (89, 92))	('increased PD', 'Phenotype', 'HP:0008151', (254, 266))	('PD-L1', 'Gene', (357, 362))	('PD-L1', 'Gene', '29126', (357, 362))	('expression', 'MPA', (270, 280))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('high tumor', 'Disease', (169, 179))	('high tumor', 'Disease', 'MESH:D009369', (169, 179))	('increased', 'PosReg', (199, 208))	('tumor', 'Disease', (174, 179))	('increased', 'PosReg', (254, 263))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('PD-L1', 'Gene', (264, 269))
75017	30593126	One of them, in which a splice mutation in MSH2 and high tumor mutational burden were detected, achieved a long-lasting complete response following pembrolizumab monotherapy, after the disease had progressed on multiple treatments, including radiotherapy and different chemotherapy regimens.	('pembrolizumab', 'Chemical', 'MESH:C582435', (148, 161))	('MSH2', 'Gene', '4436', (43, 47))	('high tumor', 'Disease', (52, 62))	('high tumor', 'Disease', 'MESH:D009369', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('MSH2', 'Gene', (43, 47))	('splice mutation', 'Var', (24, 39))
75019	30593126	Insights on the predictive effect of mutational status of DNA repair-related genes, high tumor mutational burden, and possible abscopal effect after multiple radiotherapy treatments are discussed.	('high tumor', 'Disease', (84, 94))	('mutational', 'Var', (37, 47))	('high tumor', 'Disease', 'MESH:D009369', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('DNA repair-related genes', 'Gene', (58, 82))
75021	30593126	This is a retrospective series of 2 patients with metastatic adrenocortical carcinoma harboring high mutational burden treated with pembrolizumab.	('patients', 'Species', '9606', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('pembrolizumab', 'Chemical', 'MESH:C582435', (132, 145))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (61, 85))	('adrenocortical carcinoma', 'Disease', (61, 85))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (61, 85))	('mutational burden', 'Var', (101, 118))
75031	30593126	A Next-Generation Sequencing analysis (NGS, Foundation One, Roche) of this lesion identified mutations on the following genes: MSH2, ATM, APC, DAXX, KDM5LC, as shown in Table 2.	('DAXX', 'Gene', (143, 147))	('mutations', 'Var', (93, 102))	('MSH2', 'Gene', (127, 131))	('ATM', 'Gene', (133, 136))	('MSH2', 'Gene', '4436', (127, 131))	('DAXX', 'Gene', '1616', (143, 147))	('APC', 'Disease', 'MESH:D011125', (138, 141))	('APC', 'Disease', (138, 141))	('ATM', 'Gene', '472', (133, 136))
75073	30593126	The recent introduction of anti-PD1/anti-PD-L1 agents changed the landscape of the treatment for many tumors, particularly those with known mutations in genes related to DNA repair.	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('PD-L1', 'Gene', '29126', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('PD1', 'Gene', '5133', (32, 35))	('PD1', 'Gene', (32, 35))	('changed', 'Reg', (54, 61))	('mutations', 'Var', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('PD-L1', 'Gene', (41, 46))
75076	30593126	Immune-related response rate was 71% in the mismatch-repair-deficient-noncolorectal cancer cohort, 40% in the mismatch-repair-deficient colorectal cancer cohort, and no responses were observed in the cohort of mismatch-repair-proficient colorectal cancer.	('deficient-noncolorectal cancer', 'Disease', 'MESH:D009369', (60, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (237, 254))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('colorectal cancer', 'Disease', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('deficient-noncolorectal cancer', 'Disease', (60, 90))	('colorectal cancer', 'Disease', (237, 254))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', 'MESH:D015179', (237, 254))	('mismatch-repair-deficient', 'Var', (110, 135))
75077	30593126	These compelling findings led to the approval of anti-PD1 agents by the Food and Drug Administration in the setting of tumors harboring mutations in genes related to mismatch-repair enzymes.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('PD1', 'Gene', '5133', (54, 57))	('mutations', 'Var', (136, 145))	('PD1', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
75078	30593126	Other predictive findings, such as high mutational burden, increased PD-L1 expression, and high presence of tumor infiltrating lymphocytes may be directly linked to response and better outcomes, although the ideal predictive biomarker remains elusive.	('PD-L1', 'Gene', '29126', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('linked', 'Reg', (155, 161))	('increased PD', 'Phenotype', 'HP:0008151', (59, 71))	('tumor', 'Disease', (108, 113))	('mutational', 'Var', (40, 50))	('increased', 'PosReg', (59, 68))	('PD-L1', 'Gene', (69, 74))	('expression', 'MPA', (75, 85))
75079	30593126	Case #1 had no familial history of Lynch, but NGS analysis showed a splice mutation in MSH2, along with a high mutational burden.	('MSH2', 'Gene', (87, 91))	('splice mutation', 'Var', (68, 83))	('MSH2', 'Gene', '4436', (87, 91))	('showed', 'Reg', (59, 65))
75091	30593126	This patient had a splice mutation in MSH2 gene and a high mutational burden.	('patient', 'Species', '9606', (5, 12))	('splice mutation', 'Var', (19, 34))	('MSH2', 'Gene', (38, 42))	('MSH2', 'Gene', '4436', (38, 42))
75093	30593126	These findings may help to support the role of immune checkpoint inhibitors in patients with adrenocortical carcinomas harboring mutations in mismatch-repair genes.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('mismatch-repair genes', 'Gene', (142, 163))	('mutations', 'Var', (129, 138))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (93, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('adrenocortical carcinomas', 'Disease', (93, 118))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (93, 118))	('patients', 'Species', '9606', (79, 87))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (93, 118))
75112	29941883	We found that steroidogenesis was promoted in cells stained with gammaH2AX, a marker of DNA damaged cells.	('steroidogenesis', 'CPA', (14, 29))	('steroid', 'Chemical', 'MESH:D013256', (14, 21))	('promoted', 'PosReg', (34, 42))	('gammaH2AX', 'Chemical', '-', (65, 74))	('gammaH2AX', 'Var', (65, 74))
75116	29941883	Knockdown of GADD45A using small interfering RNA markedly inhibited the EP-induced upregulation of steroidogenesis-related gene expression, and glucocorticoid production.	('GADD45A', 'Gene', '1647', (13, 20))	('EP-induced', 'Disease', (72, 82))	('upregulation', 'PosReg', (83, 95))	('EP', 'Chemical', 'MESH:D005047', (72, 74))	('small interfering RNA', 'Var', (27, 48))	('GADD45A', 'Gene', (13, 20))	('glucocorticoid production', 'MPA', (144, 169))	('steroidogenesis-related gene expression', 'MPA', (99, 138))	('inhibited', 'NegReg', (58, 67))	('steroid', 'Chemical', 'MESH:D013256', (99, 106))
75126	29941883	In particular, their anti-inflammatory properties underpin the concept that glucocorticoid synthesis must be readily turned on and off because the production of too little glucocorticoid may result in the overactivation of immune cells, chronic inflammation, and immunopathology, whereas too much glucocorticoid synthesis may render the host immunosuppressed and thus incapable of responding to pathogens.	('immunopathology', 'CPA', (263, 278))	('result in', 'Reg', (191, 200))	('glucocorticoid', 'MPA', (172, 186))	('too much glucocorticoid', 'Phenotype', 'HP:0008163', (288, 311))	('immune cells', 'CPA', (223, 235))	('inflammation', 'Disease', 'MESH:D007249', (245, 257))	('inflammation', 'Disease', (245, 257))	('too little glucocorticoid', 'Phenotype', 'HP:0008163', (161, 186))	('too', 'Var', (288, 291))	('too little', 'Var', (161, 171))	('overactivation', 'PosReg', (205, 219))
75129	29941883	Then, subsequent phosphorylation of specific transcription factors activates steroidogenic enzyme expression through an increase in the availability of free cholesterol, steroidogenic acute regulatory protein (StAR), cytochrome P450c11 (encoded by CYP11A1), cytochrome P450c21A2 (encoded by CYP21A2), cytochrome P450c17 (encoded by CYP17A1), and 3beta-hydroxysteroid dehydrogenase II (encoded by HSD3B2).	('steroidogenic enzyme', 'Enzyme', (77, 97))	('HSD3B2', 'Gene', '3284', (396, 402))	('P450c17', 'Gene', (312, 319))	('steroid', 'Chemical', 'MESH:D013256', (359, 366))	('CYP11A1', 'Gene', '1583', (248, 255))	('StAR', 'Gene', '6770', (210, 214))	('cytochrome P450c21A2', 'Enzyme', (258, 278))	('steroidogenic acute regulatory protein', 'Gene', '6770', (170, 208))	('steroidogenic acute regulatory protein', 'Gene', (170, 208))	('CYP21A2', 'Gene', '1589', (291, 298))	('3beta-hydroxysteroid dehydrogenase II', 'Disease', (346, 383))	('phosphorylation', 'Var', (17, 32))	('CYP17A1', 'Gene', (332, 339))	('CYP17A1', 'Gene', '1586', (332, 339))	('P450c17', 'Gene', '1586', (312, 319))	('steroid', 'Chemical', 'MESH:D013256', (77, 84))	('CYP11A1', 'Gene', (248, 255))	('availability', 'MPA', (136, 148))	('HSD3B2', 'Gene', (396, 402))	('cytochrome P450c11', 'Gene', '1584', (217, 235))	('activates', 'PosReg', (67, 76))	('cholesterol', 'Chemical', 'MESH:D002784', (157, 168))	('3beta-hydroxysteroid dehydrogenase II', 'Disease', 'MESH:C579862', (346, 383))	('cytochrome P450c11', 'Gene', (217, 235))	('CYP21A2', 'Gene', (291, 298))	('StAR', 'Gene', (210, 214))	('increase', 'PosReg', (120, 128))	('steroid', 'Chemical', 'MESH:D013256', (170, 177))	('expression', 'MPA', (98, 108))
75134	29941883	One central signaling pathway triggered by the DDR is the activation of the p53 tumor suppressor, leading to cell cycle arrest and apoptosis.	('arrest', 'Disease', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (109, 126))	('tumor', 'Disease', (80, 85))	('arrest', 'Disease', 'MESH:D006323', (120, 126))	('apoptosis', 'CPA', (131, 140))	('activation', 'PosReg', (58, 68))	('DDR', 'Var', (47, 50))	('DDR', 'Chemical', '-', (47, 50))
75143	29941883	p38MAPK is activated following phosphorylation at Thr180 and Tyr182 in a Thr-Gly-Tyr motif.	('Gly', 'Chemical', 'MESH:D005998', (77, 80))	('Tyr182', 'Var', (61, 67))	('Thr180', 'Chemical', '-', (50, 56))	('p38', 'Gene', '1432', (0, 3))	('Tyr', 'Chemical', 'MESH:D014443', (61, 64))	('Tyr', 'Chemical', 'MESH:D014443', (81, 84))	('activated', 'PosReg', (11, 20))	('p38', 'Gene', (0, 3))	('Tyr182 in a Thr', 'Mutation', 'p.Y182T', (61, 76))
75150	29941883	To determine whether the DDR induces steroidogenesis, we treated H295R cells with different concentrations of etoposide (EP) for 3 days (72 h), followed by culturing with normal growth medium.	('induces', 'Reg', (29, 36))	('steroid', 'Chemical', 'MESH:D013256', (37, 44))	('DDR', 'Chemical', '-', (25, 28))	('etoposide', 'Chemical', 'MESH:D005047', (110, 119))	('EP', 'Chemical', 'MESH:D005047', (121, 123))	('H295R', 'CellLine', 'CVCL:0458', (65, 70))	('steroidogenesis', 'MPA', (37, 52))	('DDR', 'Var', (25, 28))
75151	29941883	By treatment of 0.75 and 1.0 muM EP, the number of gammaH2AX-positive cells was significantly increased 4 days after treatment (Fig.	('muM', 'Gene', (29, 32))	('gammaH2AX-positive', 'Protein', (51, 69))	('0.75', 'Var', (16, 20))	('increased', 'PosReg', (94, 103))	('EP', 'Chemical', 'MESH:D005047', (33, 35))	('muM', 'Gene', '56925', (29, 32))	('gammaH2AX', 'Chemical', '-', (51, 60))
75156	29941883	As shown in quantitative analyses of double staining of gammaH2AX and CYP21A2, a remarkable increase in the number of CYP21A2-positive cells by EP treatment was observed in gammaH2AX-positive cells, but not in gammaH2AX-negative cells (Fig.	('EP', 'Chemical', 'MESH:D005047', (144, 146))	('CYP21A2', 'Gene', '1589', (70, 77))	('CYP21A2', 'Gene', (70, 77))	('gammaH2AX', 'Chemical', '-', (173, 182))	('CYP21A2', 'Gene', '1589', (118, 125))	('CYP21A2', 'Gene', (118, 125))	('increase', 'PosReg', (92, 100))	('gammaH2AX-positive', 'Var', (173, 191))	('gammaH2AX', 'Chemical', '-', (56, 65))	('gammaH2AX', 'Chemical', '-', (210, 219))
75180	29941883	RT-qPCR revealed that SB203580, an inhibitor of p38MAPK, significantly reduced the levels of HSD3B2, CYP21A2, CYP17A1, CYP11A1, CYP11B1, CYP11B2, Nurr1, and Nur77 mRNA levels (Fig.	('Nur77', 'Gene', (157, 162))	('CYP11B2', 'Gene', (137, 144))	('CYP11B1', 'Gene', (128, 135))	('SB203580', 'Chemical', 'MESH:C093642', (22, 30))	('Nur77', 'Gene', '3164', (157, 162))	('Nurr1', 'Gene', '4929', (146, 151))	('p38', 'Gene', '1432', (48, 51))	('SB203580', 'Var', (22, 30))	('CYP11A1', 'Gene', '1583', (119, 126))	('HSD3B2', 'Gene', '3284', (93, 99))	('CYP17A1', 'Gene', (110, 117))	('CYP17A1', 'Gene', '1586', (110, 117))	('reduced', 'NegReg', (71, 78))	('CYP11B2', 'Gene', '1585', (137, 144))	('CYP21A2', 'Gene', (101, 108))	('CYP11A1', 'Gene', (119, 126))	('Nurr1', 'Gene', (146, 151))	('p38', 'Gene', (48, 51))	('levels', 'MPA', (83, 89))	('HSD3B2', 'Gene', (93, 99))	('CYP11B1', 'Gene', '1584', (128, 135))	('CYP21A2', 'Gene', '1589', (101, 108))
75184	29941883	EP-induced cortisol synthesis was decreased to 40% or 20% by H89 or SB203580, respectively (Fig.	('EP-induced cortisol synthesis', 'MPA', (0, 29))	('SB203580', 'Chemical', 'MESH:C093642', (68, 76))	('EP', 'Chemical', 'MESH:D005047', (0, 2))	('SB203580', 'Var', (68, 76))	('decreased', 'NegReg', (34, 43))	('H89', 'Chemical', 'MESH:C063509', (61, 64))	('cortisol', 'Chemical', 'MESH:D006854', (11, 19))	('H89', 'Var', (61, 64))
75185	29941883	SB203580 was significantly more effective than H89 at suppressing EP-induced cortisol synthesis.	('suppressing', 'NegReg', (54, 65))	('EP', 'Chemical', 'MESH:D005047', (66, 68))	('H89', 'Chemical', 'MESH:C063509', (47, 50))	('SB203580', 'Var', (0, 8))	('cortisol', 'Chemical', 'MESH:D006854', (77, 85))	('SB203580', 'Chemical', 'MESH:C093642', (0, 8))	('EP-induced cortisol synthesis', 'MPA', (66, 95))
75187	29941883	Furthermore, H89 significantly decreased HSD3B2, CYP17A1, CYP11B1, CYP11B2, and Nurr1 expression (Supplementary Fig.	('CYP17A1', 'Gene', (49, 56))	('HSD3B2', 'Gene', '3284', (41, 47))	('CYP17A1', 'Gene', '1586', (49, 56))	('CYP11B2', 'Gene', '1585', (67, 74))	('H89', 'Chemical', 'MESH:C063509', (13, 16))	('decreased', 'NegReg', (31, 40))	('CYP11B1', 'Gene', (58, 65))	('expression', 'MPA', (86, 96))	('Nurr1', 'Gene', (80, 85))	('H89', 'Var', (13, 16))	('Nurr1', 'Gene', '4929', (80, 85))	('CYP11B1', 'Gene', '1584', (58, 65))	('HSD3B2', 'Gene', (41, 47))	('CYP11B2', 'Gene', (67, 74))
75209	29941883	In this study, we found that GADD45A expression was upregulated, and knockdown of GADD45A using siRNA inhibited EP-induced steroidogenesis, which was accompanied by blocking the expression of steroidogenesis-related genes, such as HSD3B2 (Figs 2 and S3).	('blocking', 'NegReg', (165, 173))	('GADD45A', 'Gene', '1647', (82, 89))	('GADD45A', 'Gene', '1647', (29, 36))	('steroid', 'Chemical', 'MESH:D013256', (192, 199))	('GADD45A', 'Gene', (29, 36))	('inhibited', 'NegReg', (102, 111))	('expression', 'MPA', (178, 188))	('steroid', 'Chemical', 'MESH:D013256', (123, 130))	('GADD45A', 'Gene', (82, 89))	('HSD3B2', 'Gene', (231, 237))	('HSD3B2', 'Gene', '3284', (231, 237))	('EP-induced steroidogenesis', 'MPA', (112, 138))	('EP', 'Chemical', 'MESH:D005047', (112, 114))	('expression', 'MPA', (37, 47))	('upregulated', 'PosReg', (52, 63))	('knockdown', 'Var', (69, 78))	('steroidogenesis-related genes', 'Gene', (192, 221))
75236	29941883	These data strongly indicate that the DDR may surely promote steroidogenesis via a pathway other than the HPA axis.	('DDR', 'Var', (38, 41))	('steroid', 'Chemical', 'MESH:D013256', (61, 68))	('DDR', 'Chemical', '-', (38, 41))	('steroidogenesis', 'MPA', (61, 76))	('promote', 'PosReg', (53, 60))
75248	29941883	The cell cycle analysis by flow cytometry revealed that the population of cells in the G2/M phase was significantly increased following EP treatement, and was decreased to the control level at 20 days after EP treatment (Supplementary Fig.	('EP', 'Chemical', 'MESH:D005047', (207, 209))	('EP treatement', 'Var', (136, 149))	('decreased', 'NegReg', (159, 168))	('increased', 'PosReg', (116, 125))	('EP', 'Chemical', 'MESH:D005047', (136, 138))
75253	29941883	reported that H295R cells have p53 mutation, the lack of exons 8 and 9, including the part of the DNA binding domain and the entire C-terminal domain, suggesting that p53 activity is completely lost.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('p53', 'Gene', '7157', (167, 170))	('H295R', 'CellLine', 'CVCL:0458', (14, 19))	('mutation', 'Var', (35, 43))	('p53', 'Gene', (167, 170))	('lost', 'NegReg', (194, 198))	('activity', 'MPA', (171, 179))
75285	29941883	The primary anti-flag, anti-gammaH2AX, anti-GADD45A, and anti-CYP21A2 antibodies were used at concentrations of 1:1000, 1:50, 1:250, and 1:50, respectively, and the secondary antibodies were used at a concentration of 1:500.	('CYP21A2', 'Gene', (62, 69))	('GADD45A', 'Gene', (44, 51))	('CYP21A2', 'Gene', '1589', (62, 69))	('gammaH2AX', 'Chemical', '-', (28, 37))	('anti-gammaH2AX', 'Var', (23, 37))	('GADD45A', 'Gene', '1647', (44, 51))
75292	28302174	Treatment of Y1 cells with H2O2 greatly enhanced the phosphorylation of both p38 MAPK and CREB protein.	('p38 MAPK', 'Gene', '26416', (77, 85))	('CREB', 'Gene', '12912', (90, 94))	('p38 MAPK', 'Gene', (77, 85))	('CREB', 'Gene', (90, 94))	('H2O2', 'Chemical', 'MESH:D006861', (27, 31))	('H2O2', 'Var', (27, 31))	('enhanced', 'PosReg', (40, 48))	('phosphorylation', 'MPA', (53, 68))
75312	28302174	Indeed, there is evidence that ROS such as H2O2 interferes with the normal transport of mobilized cytoplasmic cholesterol to and within the mitochondria for side chain cleavage in steroidogenic cells.	('interferes', 'NegReg', (48, 58))	('ROS', 'Chemical', 'MESH:D017382', (31, 34))	('H2O2', 'Chemical', 'MESH:D006861', (43, 47))	('H2O2', 'Var', (43, 47))	('steroid', 'Chemical', 'MESH:D013256', (180, 187))	('cholesterol', 'Chemical', 'MESH:D002784', (110, 121))
75337	28302174	Y1-BS1 has been proven to be robust in steroidogenesis and retains responsiveness to hormone.	('steroid', 'Chemical', 'MESH:D013256', (39, 46))	('steroidogenesis', 'MPA', (39, 54))	('responsiveness to hormone', 'MPA', (67, 92))	('Y1-BS1', 'Var', (0, 6))
75359	28302174	Increasing evidence suggests that ROS such as  O2 -,  OH and H2O2, promote the phosphorylation and activation of MAPK, among which p38 MAPK is highly responsive to oxidant stress which has important roles in cell signaling and homeostasis.	('activation', 'MPA', (99, 109))	('ROS', 'Chemical', 'MESH:D017382', (34, 37))	('p38 MAPK', 'Gene', (131, 139))	('O2 -', 'Var', (47, 51))	('O2', 'Chemical', '-', (47, 49))	('phosphorylation', 'MPA', (79, 94))	('H2O2', 'Chemical', 'MESH:D006861', (61, 65))	('H2O2', 'Var', (61, 65))	('MAPK', 'Gene', (113, 117))	('oxidant stress', 'Phenotype', 'HP:0025464', (164, 178))	('O2', 'Chemical', '-', (63, 65))	('p38 MAPK', 'Gene', '26416', (131, 139))	('promote', 'PosReg', (67, 74))
75363	28302174	1a and b demonstrate that treatment of Y1-BS1 cells with 100 nM H2O2 for 5 min caused a robust phosphorylation of p38 MAPK and a modest but significant stimulation of phosphorylated form of CREB for 20 min, thereafter the phosphorylation of p38 and CREB decreased.	('p38 MAPK', 'Gene', (114, 122))	('phosphorylated form', 'MPA', (167, 186))	('phosphorylation', 'MPA', (222, 237))	('rat', 'Species', '10116', (16, 19))	('H2O2', 'Var', (64, 68))	('CREB', 'Gene', '12912', (190, 194))	('CREB', 'Gene', '12912', (249, 253))	('H2O2', 'Chemical', 'MESH:D006861', (64, 68))	('p38 MAPK', 'Gene', '26416', (114, 122))	('CREB', 'Gene', (190, 194))	('CREB', 'Gene', (249, 253))	('stimulation', 'PosReg', (152, 163))	('phosphorylation', 'MPA', (95, 110))
75366	28302174	Meanwhile, we detected that Bt2cAMP could stimulated both the phosphorylation of p38 MAPK and CREB (Fig.	('phosphorylation', 'MPA', (62, 77))	('p38 MAPK', 'Gene', '26416', (81, 89))	('Bt2cAMP', 'Var', (28, 35))	('CREB', 'Gene', '12912', (94, 98))	('CREB', 'Gene', (94, 98))	('p38 MAPK', 'Gene', (81, 89))	('stimulated', 'PosReg', (42, 52))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (28, 35))
75367	28302174	While SB203580 abolished the stimulatory phosphorylation of p38 MAPK by Bt2cAMP, phosphorylation of CREB was not diminished (Fig.1d).	('p38 MAPK', 'Gene', '26416', (60, 68))	('CREB', 'Gene', '12912', (100, 104))	('Bt2cAMP', 'Var', (72, 79))	('SB203580', 'Chemical', 'MESH:C093642', (6, 14))	('CREB', 'Gene', (100, 104))	('p38 MAPK', 'Gene', (60, 68))	('stimulatory phosphorylation', 'MPA', (29, 56))	('abolished', 'NegReg', (15, 24))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (72, 79))
75370	28302174	This possibility is in line with the earlier evidence showing that the steroid intermediates, testosterone, testosterone precursors or analogs e.g., epitestosterone and 17a-methyltestosterone, can cause oxygen tension sensitive decrement in P450 hydroxylase activity.	('activity', 'MPA', (258, 266))	('epitestosterone', 'Var', (149, 164))	('oxygen', 'Chemical', 'MESH:D010100', (203, 209))	('17a-methyltestosterone', 'Chemical', '-', (169, 191))	('testosterone', 'Chemical', 'MESH:D013739', (179, 191))	('epitestosterone', 'Chemical', 'MESH:D004845', (149, 164))	('oxygen tension sensitive', 'MPA', (203, 227))	('testosterone', 'Chemical', 'MESH:D013739', (108, 120))	('P450 hydroxylase', 'Enzyme', (241, 257))	('testosterone', 'Chemical', 'MESH:D013739', (152, 164))	('testosterone', 'Chemical', 'MESH:D013739', (94, 106))	('steroid', 'Chemical', 'MESH:D013256', (71, 78))
75389	28302174	5, CREB activity was slightly but significantly decreased in response to treatment with these three agents for 3 to 5 h. These data open up the possibility that overproduction/increased accumulation of steroid intermediates or sustained activation of cells to HDL leads to enhanced ROS production and consequently loss of CREB activity.	('CREB', 'Gene', (322, 326))	('overproduction/increased', 'PosReg', (161, 185))	('CREB', 'Gene', '12912', (3, 7))	('activity', 'MPA', (327, 335))	('CREB', 'Gene', (3, 7))	('loss', 'NegReg', (314, 318))	('ROS production', 'MPA', (282, 296))	('steroid', 'Chemical', 'MESH:D013256', (202, 209))	('ROS', 'Chemical', 'MESH:D017382', (282, 285))	('steroid', 'MPA', (202, 209))	('activation', 'PosReg', (237, 247))	('CREB', 'Gene', '12912', (322, 326))	('HDL', 'Gene', (260, 263))	('accumulation', 'MPA', (186, 198))	('overproduction/increased', 'Var', (161, 185))	('enhanced', 'PosReg', (273, 281))
75395	28302174	We have demonstrated that inhibition of p38 MAPK activity with SB203580 potentiated the Bt2cAMP and Bt2cAMP + hHDL3-stimulated steroid production in Y1-BS1 adrenal cells.	('p38 MAPK', 'Gene', '26416', (40, 48))	('hHDL3', 'Gene', '53369', (110, 115))	('activity', 'MPA', (49, 57))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (100, 107))	('hHDL3', 'Gene', (110, 115))	('rat', 'Species', '10116', (15, 18))	('steroid', 'Chemical', 'MESH:D013256', (127, 134))	('SB203580', 'Var', (63, 71))	('inhibition', 'NegReg', (26, 36))	('p38 MAPK', 'Gene', (40, 48))	('SB203580', 'Chemical', 'MESH:C093642', (63, 71))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (88, 95))	('steroid production', 'MPA', (127, 145))	('potentiated', 'PosReg', (72, 83))
75398	28302174	7, although additional substrates (HDL3, 22(R)-diol or pregnenolone) loading increased the steroid production, inclusion of SB203580 to inhibit the p38 activity could increase the steroid production in HDL3, 22(R)-diol or pregnenolone treated cells.	('22(R)-diol', 'Chemical', '-', (208, 218))	('HDL3', 'Gene', '114576', (35, 39))	('activity', 'MPA', (152, 160))	('steroid production', 'MPA', (91, 109))	('HDL3', 'Gene', (202, 206))	('SB203580', 'Var', (124, 132))	('22(R)-diol', 'Chemical', '-', (41, 51))	('HDL3', 'Gene', (35, 39))	('p38', 'Protein', (148, 151))	('pregnenolone', 'Chemical', 'MESH:D011284', (55, 67))	('steroid', 'Chemical', 'MESH:D013256', (180, 187))	('HDL3', 'Gene', '114576', (202, 206))	('rat', 'Species', '10116', (28, 31))	('steroid', 'Chemical', 'MESH:D013256', (91, 98))	('steroid production', 'MPA', (180, 198))	('pregnenolone', 'Chemical', 'MESH:D011284', (222, 234))	('inhibit', 'NegReg', (136, 143))	('SB203580', 'Chemical', 'MESH:C093642', (124, 132))	('increase', 'PosReg', (167, 175))
75412	28302174	In contrast, overproduction or high levels of ROS results in oxidative stress, a deleterious process that can be an important mediator of damage to cellular macromolecular structures including lipids and membranes, proteins and DNA.	('overproduction', 'PosReg', (13, 27))	('high levels', 'Var', (31, 42))	('oxidative stress', 'Phenotype', 'HP:0025464', (61, 77))	('results in', 'Reg', (50, 60))	('lipids', 'Chemical', 'MESH:D008055', (193, 199))	('oxidative stress', 'MPA', (61, 77))	('proteins', 'Protein', (215, 223))	('ROS', 'Chemical', 'MESH:D017382', (46, 49))	('ROS', 'Gene', (46, 49))
75418	28302174	Our results suggest that it is not only the H2O2 produced during Mn-SOD catalyzed dismutation of superoxide anions and ensuing inactivation of peroxiredoxin 3 that inhibits steroidogenesis, but also steroid metabolites such as 22(R)-diol and pregnenolone possess similar capabilities in promoting ROS production and interfering with normal steroidogenesis.	('pregnenolone', 'Chemical', 'MESH:D011284', (242, 254))	('superoxide anions', 'Chemical', 'MESH:D013481', (97, 114))	('interfering', 'NegReg', (316, 327))	('normal steroidogenesis', 'MPA', (333, 355))	('Mn-SOD', 'Gene', (65, 71))	('H2O2', 'Chemical', 'MESH:D006861', (44, 48))	('cat', 'Gene', (72, 75))	('steroid', 'Chemical', 'MESH:D013256', (199, 206))	('steroidogenesis', 'MPA', (173, 188))	('peroxiredoxin 3', 'Gene', (143, 158))	('steroid', 'Chemical', 'MESH:D013256', (173, 180))	('H2O2', 'Var', (44, 48))	('ROS production', 'MPA', (297, 311))	('cat', 'Gene', '12359', (72, 75))	('inhibits', 'NegReg', (164, 172))	('steroid', 'Chemical', 'MESH:D013256', (340, 347))	('promoting', 'PosReg', (287, 296))	('ROS', 'Chemical', 'MESH:D017382', (297, 300))	('22(R)-diol', 'Chemical', '-', (227, 237))	('Mn-SOD', 'Gene', '20656', (65, 71))	('inactivation', 'Var', (127, 139))	('peroxiredoxin 3', 'Gene', '11757', (143, 158))
75439	28302174	Other investigators reported that HDL2, very-low-density lipoprotein (VLDL) and glyco-oxidized VLDL can induce Cyp11B2 expression and stimulate steroid production in a human adrenocortical carcinoma cell line, NCI H295R.	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (174, 198))	('expression', 'MPA', (119, 129))	('human', 'Species', '9606', (168, 173))	('NCI H295', 'CellLine', 'CVCL:0456', (210, 218))	('stimulate', 'PosReg', (134, 143))	('adrenocortical carcinoma', 'Disease', (174, 198))	('VLDL', 'Gene', (70, 74))	('Cyp11B2', 'Gene', (111, 118))	('very-low-density', 'Var', (40, 56))	('steroid', 'Chemical', 'MESH:D013256', (144, 151))	('VLDL', 'Gene', '54219', (70, 74))	('steroid production', 'MPA', (144, 162))	('induce', 'PosReg', (104, 110))	('Cyp11B2', 'Gene', '1585', (111, 118))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (174, 198))	('VLDL', 'Gene', '54219', (95, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('VLDL', 'Gene', (95, 99))
75443	28302174	Our steroid hormone production data provide additional support to the notion that SB203580 inhibition of p38 MAPK augments the steroids production in Y1-BS1 cells treated with steroid metabolites/intermediates.	('p38 MAPK', 'Gene', '26416', (105, 113))	('SB203580', 'Chemical', 'MESH:C093642', (82, 90))	('steroid', 'Chemical', 'MESH:D013256', (127, 134))	('steroids', 'Chemical', 'MESH:D013256', (127, 135))	('SB203580', 'Var', (82, 90))	('steroid', 'Chemical', 'MESH:D013256', (4, 11))	('p38 MAPK', 'Gene', (105, 113))	('steroid hormone', 'Chemical', 'MESH:D013256', (4, 19))	('inhibition', 'NegReg', (91, 101))	('steroids production', 'MPA', (127, 146))	('augments', 'NegReg', (114, 122))	('steroid', 'Chemical', 'MESH:D013256', (176, 183))
75445	28302174	For example, inhibition of p38 MAPK activity by SB203580 in IL-1alpha-stimulated immature rat Leydig cells leads to downregulation of StAR gene expression and attenuation of steroid production.. Other studies have shown that inhibition of p38 MAPK activity by SB203580 in ovarian granulosa cells is accompanied by increased inhibition of LH/hCG/FSH mediated StAR expression and progesterone synthesis.	('LH', 'Chemical', 'MESH:D007986', (338, 340))	('ovarian granulosa', 'Disease', (272, 289))	('progesterone', 'Chemical', 'MESH:D011374', (378, 390))	('activity', 'MPA', (248, 256))	('SB203580', 'Chemical', 'MESH:C093642', (260, 268))	('FSH', 'Gene', (345, 348))	('progesterone synthesis', 'MPA', (378, 400))	('inhibition', 'NegReg', (324, 334))	('steroid', 'Chemical', 'MESH:D013256', (174, 181))	('FSH', 'Gene', '14308', (345, 348))	('SB203580', 'Var', (260, 268))	('increased', 'PosReg', (314, 323))	('p38 MAPK', 'Gene', '26416', (27, 35))	('p38 MAPK', 'Gene', (27, 35))	('SB203580', 'Chemical', 'MESH:C093642', (48, 56))	('ovarian granulosa', 'Disease', 'MESH:D010051', (272, 289))	('IL-1alpha', 'Gene', '24493', (60, 69))	('IL-1alpha', 'Gene', (60, 69))	('rat', 'Species', '10116', (90, 93))	('p38 MAPK', 'Gene', '26416', (239, 247))	('inhibition', 'NegReg', (225, 235))	('p38 MAPK', 'Gene', (239, 247))
75447	28302174	Interestingly, our previous studies have shown that inhibition of p38 MAPK by either SB203580 or SB202190 in adrenocortical from old rats restores corticosterone synthesis to the levels seen in cells from young animals.	('corticosterone synthesis', 'MPA', (147, 171))	('p38 MAPK', 'Gene', (66, 74))	('SB203580', 'Chemical', 'MESH:C093642', (85, 93))	('SB203580', 'Var', (85, 93))	('SB202190', 'Chemical', 'MESH:C090942', (97, 105))	('corticosterone', 'Chemical', 'MESH:D003345', (147, 161))	('SB202190', 'Var', (97, 105))	('p38 MAPK', 'Gene', '26416', (66, 74))	('rats', 'Species', '10116', (133, 137))	('restores', 'PosReg', (138, 146))	('inhibition', 'NegReg', (52, 62))	('adrenocortical', 'Disease', (109, 123))	('adrenocortical', 'Disease', 'MESH:D018268', (109, 123))
75471	26286367	Readmission can lead to adverse medical outcomes, lower patient satisfaction, as well as increased health care costs.	('lower', 'NegReg', (50, 55))	('Readmission', 'Var', (0, 11))	('patient satisfaction', 'CPA', (56, 76))	('patient', 'Species', '9606', (56, 63))	('increased', 'PosReg', (89, 98))
75607	25240470	Inappropriate aldosterone production is caused by a hybrid gene, resulting from unequal crossing over between CYP11B1 and CYP11B2, which encode 11beta-hydroxylase and aldosterone synthase, respectively.	('aldosterone production', 'Phenotype', 'HP:0000859', (14, 36))	('CYP11B2', 'Var', (122, 129))	('CYP11B1', 'Gene', '1584', (110, 117))	('aldosterone', 'Chemical', 'MESH:D000450', (167, 178))	('aldosterone synthase', 'Gene', (167, 187))	('caused by', 'Reg', (40, 49))	('aldosterone synthase', 'Gene', '1585', (167, 187))	('aldosterone', 'Chemical', 'MESH:D000450', (14, 25))	('CYP11B1', 'Gene', (110, 117))	('aldosterone production', 'MPA', (14, 36))
75614	25240470	FH-III is a severe form of hyperaldosteronism due to mutations in KCNJ5, which will be discussed in more detail below in this manuscript.	('FH-II', 'Gene', (0, 5))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (27, 45))	('due', 'Reg', (46, 49))	('KCNJ5', 'Gene', (66, 71))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (27, 45))	('man', 'Species', '9606', (126, 129))	('form of hyperaldosteronism', 'Phenotype', 'HP:0011741', (19, 45))	('mutations', 'Var', (53, 62))	('KCNJ5', 'Gene', '3762', (66, 71))	('FH-II', 'Gene', '79179', (0, 5))	('hyperaldosteronism', 'Disease', (27, 45))
75615	25240470	Three main polymorphisms of CYP11B2 have been identified: (i) a c.-344C>T substitution in the promoter region; (ii) an intron 2 gene conversion in which part of intron 2 of CYP11B2 is substituted with the corresponding region of CYP11B1 and (iii) a single nucleotide substitution in codon 173 (c.518A>G) leading to a substitution of the arginine with a lysine.	('c.-344C>T', 'Var', (64, 73))	('c.-344C>T', 'Mutation', 'rs1799998', (64, 73))	('lysine', 'MPA', (353, 359))	('CYP11B1', 'Gene', (229, 236))	('CYP11B1', 'Gene', '1584', (229, 236))	('CYP11B2', 'Gene', (28, 35))	('c.518A>G', 'Mutation', 'rs142163070', (294, 302))	('CYP11B2', 'Gene', (173, 180))	('arginine', 'Chemical', 'MESH:D001120', (337, 345))	('lysine', 'Chemical', 'MESH:D008239', (353, 359))	('substitution', 'Var', (317, 329))	('arginine', 'MPA', (337, 345))
75616	25240470	The c.-344C>T polymorphism is located in the putative binding site for the steroidogenic factor 1 (SF1, NR5A1).	('SF1', 'Gene', '2516', (99, 102))	('c.-344C>T', 'Var', (4, 13))	('NR5A1', 'Gene', '2516', (104, 109))	('steroidogenic factor 1', 'Gene', '2516', (75, 97))	('steroidogenic factor 1', 'Gene', (75, 97))	('SF1', 'Gene', (99, 102))	('c.-344C>T', 'Mutation', 'rs1799998', (4, 13))	('NR5A1', 'Gene', (104, 109))
75617	25240470	The biological effect of this variant is unclear: despite SF1 binding being increased in the presence of the c.-344C allele, no effect on CYP11B2 transcription has been shown by in vitro studies.	('SF1', 'Gene', '2516', (58, 61))	('increased', 'PosReg', (76, 85))	('binding', 'Interaction', (62, 69))	('c.-344C', 'Var', (109, 116))	('CYP11B2', 'Gene', (138, 145))	('transcription', 'MPA', (146, 159))	('SF1', 'Gene', (58, 61))
75618	25240470	Interestingly, the c.-344C>T polymorphism has been shown recently to be in tight linkage disequilibrium with another T/C polymorphism at position -1651 (c.-1651T>C) at the binding site of the multifunctional protein DNA (apurinic/apyrimidinic site) lyase called APEX1.	('APEX1', 'Gene', (262, 267))	('c.-1651T>C', 'Var', (153, 163))	('c.-1651T>C', 'Mutation', 'c.-1651T>C', (153, 163))	('c.-344C>T', 'Mutation', 'rs1799998', (19, 28))	('c.-344C>T', 'Var', (19, 28))	('linkage', 'Interaction', (81, 88))	('APEX1', 'Gene', '328', (262, 267))
75619	25240470	The substitution affects APEX1 binding and results in different repressor effects on CYP11B2 transcription; intriguingly, this polymorphism associates also with lower excretion rates of aldosterone metabolites in human subjects.	('lower', 'NegReg', (161, 166))	('excretion rates of aldosterone metabolites', 'MPA', (167, 209))	('APEX1', 'Gene', (25, 30))	('aldosterone', 'Chemical', 'MESH:D000450', (186, 197))	('human', 'Species', '9606', (213, 218))	('binding', 'Interaction', (31, 38))	('rat', 'Species', '10116', (177, 180))	('lower excretion rates of aldosterone', 'Phenotype', 'HP:0004319', (161, 197))	('affects', 'Reg', (17, 24))	('substitution', 'Var', (4, 16))	('APEX1', 'Gene', '328', (25, 30))	('repressor effects', 'MPA', (64, 81))	('CYP11B2', 'Gene', (85, 92))
75620	25240470	The gene conversion in intron 2 and the p.Arg173Lys substitution have both been shown to have a strong linkage disequilibrium with the c.-344C>T polymorphism.	('p.Arg173Lys', 'Mutation', 'rs4539', (40, 51))	('c.-344C>T', 'Mutation', 'rs1799998', (135, 144))	('linkage', 'Interaction', (103, 110))	('p.Arg173Lys', 'Var', (40, 51))	('c.-344C>T', 'Var', (135, 144))
75621	25240470	However, the p.Arg173Lys does not affect aldosterone synthase activity in vitro.	('activity', 'MPA', (62, 70))	('p.Arg173Lys', 'Mutation', 'rs4539', (13, 24))	('aldosterone synthase', 'Gene', (41, 61))	('aldosterone synthase', 'Gene', '1585', (41, 61))	('p.Arg173Lys', 'Var', (13, 24))
75623	25240470	Recently, polymorphisms in other genes were found to associate with PA. Polymorphisms in KCNJ5 and HSD3beta associate with PA in the Chinese populations.	('HSD3beta', 'Gene', (99, 107))	('KCNJ5', 'Gene', '3762', (89, 94))	('associate with', 'Reg', (108, 122))	('HSD3beta', 'Gene', '3284', (99, 107))	('Polymorphisms', 'Var', (72, 85))	('KCNJ5', 'Gene', (89, 94))
75624	25240470	Finally, polymorphisms in alpha-adducin (p.Gly460Trp) and bradykinin B2 receptor (p.Cys58Thr) affect blood pressure in PA patients presumably by effects on renal sodium handling.	('sodium', 'Chemical', 'MESH:D012964', (162, 168))	('blood pressure', 'MPA', (101, 115))	('p.Cys58Thr', 'Mutation', 'p.C58T', (82, 92))	('alpha-adducin', 'Gene', (26, 39))	('effects', 'Reg', (145, 152))	('p.Cys58Thr', 'Var', (82, 92))	('affect', 'Reg', (94, 100))	('p.Gly460Trp', 'Mutation', 'p.G460W', (41, 52))	('alpha-adducin', 'Gene', '118', (26, 39))	('patients', 'Species', '9606', (122, 130))	('p.Gly460Trp', 'Var', (41, 52))	('polymorphisms', 'Var', (9, 22))
75633	25240470	Results regarding CYP11B2 expression in APAs have been conflicting with most studies reporting a significant up-regulation of CYP11B2 in comparison to non-adenomatous adrenal tissue.	('up-regulation', 'PosReg', (109, 122))	('CYP11B2', 'Gene', (18, 25))	('adenomatous adrenal', 'Disease', 'MESH:D011125', (155, 174))	('adenomatous adrenal', 'Disease', (155, 174))	('CYP11B2', 'Var', (126, 133))
75635	25240470	normal adrenals removed from nephroadrenalectomized patients vs. adjacent adrenal cortex), iv) heterogeneity of CYP11B2 within APA or v) the potential for misdiagnosis of benign tumors as APA.	('benign tumors', 'Disease', (171, 184))	('heterogeneity', 'Var', (95, 108))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('nephroadrenalectomized', 'Disease', (29, 51))	('benign tumors', 'Disease', 'MESH:D009369', (171, 184))	('nephroadrenalectomized', 'Disease', 'None', (29, 51))	('CYP11B2', 'Var', (112, 119))	('patients', 'Species', '9606', (52, 60))
75637	25240470	CYP11A1, CYP17A and HSD3B2 expression levels showed a relative heterogeneity amongst studies, being either increased, unchanged or decreased.	('CYP11A1', 'Gene', '1583', (0, 7))	('decreased', 'NegReg', (131, 140))	('CYP17A', 'Var', (9, 15))	('HSD3B2', 'Gene', (20, 26))	('HSD3B2', 'Gene', '3284', (20, 26))	('CYP11A1', 'Gene', (0, 7))
75639	25240470	Aberrant or ectopic hormone receptor expression has been reported to play a central role in ACTH-independent macronodular adrenal hyperplasia and in some unilateral cortisol producing adenomas leading to cortisol hypersecretion regulated by hormones other than ACTH.	('adenomas', 'Disease', 'MESH:D000236', (184, 192))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (109, 141))	('Aberrant', 'Var', (0, 8))	('adenomas', 'Disease', (184, 192))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (122, 141))	('macronodular adrenal hyperplasia', 'Disease', (109, 141))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (109, 141))	('ectopic', 'Var', (12, 19))	('cortisol hypersecretion regulated', 'MPA', (204, 237))
75643	25240470	Interestingly, the aberrant expression of LHR and/or gonadotropin-releasing hormone receptors (GnRHRs) in aldosterone-producing adenomas is associated with stimulation of aldosterone secretion during pregnancy.	('adenomas', 'Disease', (128, 136))	('adenomas', 'Disease', 'MESH:D000236', (128, 136))	('GnRHR', 'Gene', (95, 100))	('LHR', 'Gene', '3973', (42, 45))	('GnRHR', 'Gene', '2798', (95, 100))	('aldosterone', 'Chemical', 'MESH:D000450', (106, 117))	('aldosterone', 'Chemical', 'MESH:D000450', (171, 182))	('aldosterone secretion', 'MPA', (171, 192))	('LHR', 'Gene', (42, 45))	('aberrant', 'Var', (19, 27))	('stimulation', 'PosReg', (156, 167))
75645	25240470	In H295R cells with doxycicline inducible GnRHR, chronic stimulation with the agonist (GnRH) resulted in a significant increase in both CYP11B2 mRNA (over 100-fold) and aldosterone production (50-fold).	('doxycicline', 'Chemical', '-', (20, 31))	('GnRHR', 'Gene', (42, 47))	('aldosterone production', 'MPA', (169, 191))	('doxycicline', 'Var', (20, 31))	('GnRH', 'Gene', (87, 91))	('aldosterone production', 'Phenotype', 'HP:0000859', (169, 191))	('H295R', 'CellLine', 'CVCL:0458', (3, 8))	('increase', 'PosReg', (119, 127))	('GnRHR', 'Gene', '2798', (42, 47))	('aldosterone', 'Chemical', 'MESH:D000450', (169, 180))
75659	25240470	Inhibition of these channels by AngII results in cell membrane depolarization and activates the intracellular cascade that finally leads to aldosterone production.	('depolarization', 'NegReg', (63, 77))	('cell membrane', 'MPA', (49, 62))	('aldosterone', 'Chemical', 'MESH:D000450', (140, 151))	('leads to', 'Reg', (131, 139))	('activates', 'Reg', (82, 91))	('aldosterone production', 'MPA', (140, 162))	('Inhibition', 'Var', (0, 10))	('intracellular cascade', 'Pathway', (96, 117))	('aldosterone production', 'Phenotype', 'HP:0000859', (140, 162))
75664	25240470	Inactivation of the Dkk3 gene in Task1-/- mice resulted in the extension of the PA phenotype to male animals, without inducing abnormal zonation of the adrenal cortex.	('mice', 'Species', '10090', (42, 46))	('Inactivation', 'Var', (0, 12))	('Dkk3', 'Gene', '50781', (20, 24))	('Dkk3', 'Gene', (20, 24))
75665	25240470	This has led several authors to hypothesize that alterations in the KCNK family genes might be causative of PA also in man.	('causative', 'Reg', (95, 104))	('alterations', 'Var', (49, 60))	('man', 'Species', '9606', (119, 122))	('rat', 'Species', '10116', (53, 56))	('KCNK family', 'Gene', (68, 79))
75668	25240470	To explore the effect of KCNK5 inactivation on aldosterone secretion H295R cell were transfected with a dominant negative mutant with subsequent increase in CYP11B2 gene expression and aldosterone production.	('KCNK5', 'Gene', (25, 30))	('aldosterone', 'Chemical', 'MESH:D000450', (47, 58))	('increase', 'PosReg', (145, 153))	('CYP11B2 gene', 'Gene', (157, 169))	('H295R', 'CellLine', 'CVCL:0458', (69, 74))	('aldosterone', 'Chemical', 'MESH:D000450', (185, 196))	('KCNK5', 'Gene', '8645', (25, 30))	('aldosterone production', 'MPA', (185, 207))	('mutant', 'Var', (122, 128))	('aldosterone production', 'Phenotype', 'HP:0000859', (185, 207))	('expression', 'MPA', (170, 180))
75683	25240470	identified two KCNJ5 somatic point mutations (p.Leu168Arg and p.Gly151Arg) in 8/22 sporadic APAs.	('p.Leu168Arg', 'Var', (46, 57))	('p.Leu168Arg', 'Mutation', 'rs386352318', (46, 57))	('KCNJ5', 'Gene', (15, 20))	('p.Gly151Arg', 'Mutation', 'rs386352319', (62, 73))	('KCNJ5', 'Gene', '3762', (15, 20))	('p.Gly151Arg', 'Var', (62, 73))
75684	25240470	The mutations, located near or within the selectivity filter of the channel, are responsible for loss of ion selectivity, facilitating Na+ entry, chronic cell membrane depolarization, opening of the voltage-gated calcium channels, increase in intracellular calcium and constitutive aldosterone production (Figure 2, panel A).	('constitutive aldosterone production', 'MPA', (269, 304))	('loss', 'NegReg', (97, 101))	('aldosterone production', 'Phenotype', 'HP:0000859', (282, 304))	('increase', 'PosReg', (231, 239))	('ion selectivity', 'MPA', (105, 120))	('facilitating', 'PosReg', (122, 134))	('aldosterone', 'Chemical', 'MESH:D000450', (282, 293))	('Na+ entry', 'MPA', (135, 144))	('calcium', 'Chemical', 'MESH:D002118', (213, 220))	('mutations', 'Var', (4, 13))	('intracellular calcium', 'MPA', (243, 264))	('opening', 'PosReg', (184, 191))	('calcium', 'Chemical', 'MESH:D002118', (257, 264))	('facilitating', 'Reg', (122, 134))
75685	25240470	Interestingly, the same authors, identified an inherited KCNJ5 mutation (p.Thr158Ala) with similar electrophysiological effects in a family affected by FH-III.	('KCNJ5', 'Gene', '3762', (57, 62))	('p.Thr158Ala', 'Mutation', 'rs387906778', (73, 84))	('FH-II', 'Gene', (152, 157))	('KCNJ5', 'Gene', (57, 62))	('p.Thr158Ala', 'Var', (73, 84))	('FH-II', 'Gene', '79179', (152, 157))
75689	25240470	Over the last two years, an additional seven families and four different germline KCNJ5 mutations have been reported (Table 1).	('KCNJ5', 'Gene', (82, 87))	('KCNJ5', 'Gene', '3762', (82, 87))	('mutations', 'Var', (88, 97))
75690	25240470	In most cases, with the exception of the three families with the p.Gly151Glu mutation and the index case carrying the p.Tyr152Cys substitution, affected members displayed marked bilateral adrenal hyperplasia and a severe clinical and biochemical phenotype requiring bilateral adrenalectomy.	('bilateral adrenal hyperplasia', 'Disease', (178, 207))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (188, 207))	('p.Gly151Glu', 'Var', (65, 76))	('p.Tyr152Cys', 'Mutation', 'rs780531503', (118, 129))	('p.Gly151Glu', 'Mutation', 'rs587777437', (65, 76))	('bilateral adrenal hyperplasia', 'Disease', 'MESH:D000312', (178, 207))
75691	25240470	Interestingly, the two mutations (p.Gly151Glu and p.Tyr152Cys) responsible for a mild clinical and biochemical phenotype, displayed different electrophysiological effects in human embryonic kidney HEK293T cells with the p.Gly151Glu mutation having a severe impact on the channel function and the p.Tyr152Cys substitution showing a small effect on Na+ conductance.	('p.Gly151Glu', 'Var', (220, 231))	('human', 'Species', '9606', (174, 179))	('HEK293T', 'CellLine', 'CVCL:0063', (197, 204))	('p.Gly151Glu', 'Mutation', 'rs587777437', (220, 231))	('Na+ conductance', 'MPA', (347, 362))	('p.Gly151Glu', 'Mutation', 'rs587777437', (34, 45))	('p.Tyr152Cys', 'Mutation', 'rs780531503', (296, 307))	('p.Tyr152Cys', 'Var', (296, 307))	('embryonic kidney', 'Disease', (180, 196))	('impact', 'Reg', (257, 263))	('p.Tyr152Cys', 'Mutation', 'rs780531503', (50, 61))	('p.Tyr152Cys', 'Var', (50, 61))	('embryonic kidney', 'Disease', 'MESH:D007674', (180, 196))	('channel function', 'MPA', (271, 287))	('p.Gly151Glu', 'Var', (34, 45))
75692	25240470	Following the original finding of two recurrent KCNJ5 mutations in sporadic APAs, several centers have investigated the prevalence of KCNJ5 mutations in adrenal tumors.	('adrenal tumors', 'Disease', (153, 167))	('KCNJ5', 'Gene', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('mutations', 'Var', (54, 63))	('KCNJ5', 'Gene', '3762', (48, 53))	('APAs', 'Disease', (76, 80))	('adrenal tumors', 'Disease', 'MESH:D000310', (153, 167))	('KCNJ5', 'Gene', (134, 139))	('KCNJ5', 'Gene', '3762', (134, 139))
75693	25240470	In addition to the originally identified p.Gly151Arg and p.Leu168Arg substitutions, three additional somatic KCNJ5 mutations have been reported, resulting in p.Glu145Gln (Akerstrom et al., 2012), p.Glu145Lys (that was found concurrent with p.Leu168Arg KCNJ5 mutation in a Czech patient) and p.Trp126Arg amino acid change, one deletion of isoleucine at residue 157 and one threonine insertion at position 149 (Table 1).	('p.Gly151Arg', 'Var', (41, 52))	('KCNJ5', 'Gene', '3762', (252, 257))	('p.Trp126Arg', 'Mutation', 'rs749227488', (291, 302))	('p.Glu145Gln', 'Mutation', 'p.E145Q', (158, 169))	('threonine', 'Chemical', 'MESH:D013912', (372, 381))	('KCNJ5', 'Gene', '3762', (109, 114))	('isoleucine', 'Chemical', 'MESH:D007532', (338, 348))	('p.Leu168Arg', 'Mutation', 'rs386352318', (240, 251))	('p.Leu168Arg', 'Mutation', 'rs386352318', (57, 68))	('p.Trp126Arg amino acid change', 'Var', (291, 320))	('p.Leu168Arg', 'Var', (240, 251))	('p.Glu145Lys', 'Var', (196, 207))	('patient', 'Species', '9606', (278, 285))	('KCNJ5', 'Gene', (252, 257))	('p.Glu145Gln', 'Var', (158, 169))	('p.Gly151Arg', 'Mutation', 'rs386352319', (41, 52))	('KCNJ5', 'Gene', (109, 114))	('p.Glu145Lys', 'Mutation', 'p.E145K', (196, 207))
75695	25240470	So far no APAs carrying mutations in more than one gene among KCNJ5, ATP1A1, ATP2B3 or CACNA1D have been identified.	('CACNA1D', 'Gene', '776', (87, 94))	('KCNJ5', 'Gene', (62, 67))	('CACNA1D', 'Gene', (87, 94))	('KCNJ5', 'Gene', '3762', (62, 67))	('ATP2B3', 'Gene', '492', (77, 83))	('mutations', 'Var', (24, 33))	('ATP2B3', 'Gene', (77, 83))
75696	25240470	Recently, sequencing of the flanking and coding region of KCNJ5 in peripheral blood DNA from 251 PA patients led to the identification of three heterozygous missense mutation (p.Arg52His, p.Glu246Lys and p.Gly247Arg); in addition, 12 patients resulted to be carriers of the rare SNP rs7102584, resulting in the p.Glu282Gln substitution.	('p.Glu282Gln', 'Var', (311, 322))	('KCNJ5', 'Gene', (58, 63))	('p.Arg52His', 'Var', (176, 186))	('KCNJ5', 'Gene', '3762', (58, 63))	('p.Glu246Lys', 'Mutation', 'rs587777439', (188, 199))	('p.Glu282Gln', 'Mutation', 'rs7102584', (311, 322))	('p.Arg52His', 'Mutation', 'rs144062083', (176, 186))	('patients', 'Species', '9606', (100, 108))	('rs7102584', 'Var', (283, 292))	('patients', 'Species', '9606', (234, 242))	('rs7102584', 'Mutation', 'rs7102584', (283, 292))	('p.Gly247Arg)', 'Var', (204, 216))	('p.Gly247Arg', 'Mutation', 'rs200170681', (204, 215))	('p.Glu246Lys', 'Var', (188, 199))
75697	25240470	Functional in vitro studies demonstrated that the p.Arg52His, p.Glu246Lys and p.Glu282Gln mutations can induce cell membrane depolarization, while the p.Gly247Arg mutant was undistinguishable from the wild-type channel.	('p.Glu282Gln', 'Var', (78, 89))	('p.Glu246Lys', 'Var', (62, 73))	('p.Arg52His', 'Mutation', 'rs144062083', (50, 60))	('p.Gly247Arg', 'Mutation', 'rs200170681', (151, 162))	('cell membrane depolarization', 'CPA', (111, 139))	('p.Glu282Gln', 'Mutation', 'rs7102584', (78, 89))	('p.Arg52His', 'Var', (50, 60))	('p.Glu246Lys', 'Mutation', 'rs587777439', (62, 73))	('rat', 'Species', '10116', (35, 38))
75698	25240470	Taken together this data indicate that also germline mutations in KCNJ5 might also play a role in the pathogenesis of sporadic PA.	('role', 'Reg', (90, 94))	('KCNJ5', 'Gene', (66, 71))	('germline mutations', 'Var', (44, 62))	('KCNJ5', 'Gene', '3762', (66, 71))	('sporadic PA', 'Disease', (118, 129))	('play', 'Reg', (83, 87))
75702	25240470	observed a lower prevalence of KCNJ5 mutations in centers adopting more permissive adrenal vein sampling criteria compared to those centers using strict criteria to define successful cannulation and lateralization of aldosterone production.	('KCNJ5', 'Gene', (31, 36))	('aldosterone', 'Chemical', 'MESH:D000450', (217, 228))	('mutations', 'Var', (37, 46))	('KCNJ5', 'Gene', '3762', (31, 36))	('aldosterone production', 'Phenotype', 'HP:0000859', (217, 239))
75703	25240470	Of note, the comparison of clinical and biochemical parameters between APA carrying mutations in KCNJ5 and noncarriers, revealed that KCNJ5 mutations were more prevalent in female than in male patients.	('patients', 'Species', '9606', (193, 201))	('prevalent', 'Reg', (160, 169))	('KCNJ5', 'Gene', (97, 102))	('mutations', 'Var', (84, 93))	('KCNJ5', 'Gene', '3762', (97, 102))	('mutations', 'Var', (140, 149))	('KCNJ5', 'Gene', (134, 139))	('KCNJ5', 'Gene', '3762', (134, 139))
75705	25240470	KCNJ5 mutations have been associated with a young age at diagnosis, increased preoperative aldosterone levels and reduced potassium levels) nonetheless, this apparently more severe form of hyperaldosteronism was not associated with higher systolic and diastolic blood pressure levels.	('hyperaldosteronism', 'Disease', 'MESH:D003480', (189, 207))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (189, 207))	('aldosterone', 'Chemical', 'MESH:D000450', (91, 102))	('KCNJ5', 'Gene', '3762', (0, 5))	('form of hyperaldosteronism', 'Phenotype', 'HP:0011741', (181, 207))	('rat', 'Species', '10116', (84, 87))	('potassium', 'Chemical', 'MESH:D011188', (122, 131))	('hyperaldosteronism', 'Disease', (189, 207))	('increased preoperative aldosterone', 'Phenotype', 'HP:0000859', (68, 102))	('aldosterone levels', 'MPA', (91, 109))	('reduced potassium levels', 'Phenotype', 'HP:0002900', (114, 138))	('KCNJ5', 'Gene', (0, 5))	('increased', 'PosReg', (68, 77))	('mutations', 'Var', (6, 15))
75707	25240470	In order to better define the molecular mechanism responsible for inappropriate aldosterone production and adrenal cell proliferation, several groups compared the transcriptome profile of APAs with and without KCNJ5 mutations.	('KCNJ5', 'Gene', (210, 215))	('aldosterone production', 'Phenotype', 'HP:0000859', (80, 102))	('rat', 'Species', '10116', (127, 130))	('KCNJ5', 'Gene', '3762', (210, 215))	('aldosterone', 'Chemical', 'MESH:D000450', (80, 91))	('mutations', 'Var', (216, 225))	('compared', 'Reg', (150, 158))
75708	25240470	In the largest of these studies, including 100 APAs from a cohort of French patients, hierarchical clustering showed that APAs carrying p.Gly151Arg and p.Leu168Arg substitutions were not associated with a unique molecular phenotype in comparison to tumors without KCNJ5 mutations.	('KCNJ5', 'Gene', (264, 269))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('patients', 'Species', '9606', (76, 84))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('KCNJ5', 'Gene', '3762', (264, 269))	('p.Gly151Arg', 'Mutation', 'rs386352319', (136, 147))	('p.Leu168Arg', 'Mutation', 'rs386352318', (152, 163))	('p.Gly151Arg', 'Var', (136, 147))	('p.Leu168Arg', 'Var', (152, 163))	('tumors', 'Disease', (249, 255))
75709	25240470	Recently, reported that VSNL1 was highly overexpressed in APAs with KCNJ5 mutations compared to APAs without KCNJ5 mutations.	('overexpressed', 'PosReg', (41, 54))	('KCNJ5', 'Gene', '3762', (109, 114))	('KCNJ5', 'Gene', '3762', (68, 73))	('mutations', 'Var', (74, 83))	('KCNJ5', 'Gene', (109, 114))	('VSNL1', 'Gene', (24, 29))	('VSNL1', 'Gene', '7447', (24, 29))	('KCNJ5', 'Gene', (68, 73))
75711	25240470	In H295R cells VSNL1 overexpression increases basal and AngII-stimulated CYP11B2 gene expression, whereas silencing VSNL1 negatively modulates CYP11B2 transcription and reduces aldosterone secretion.	('VSNL1', 'Gene', '7447', (116, 121))	('aldosterone', 'Chemical', 'MESH:D000450', (177, 188))	('CYP11B2', 'Gene', (143, 150))	('VSNL1', 'Gene', (15, 20))	('aldosterone secretion', 'MPA', (177, 198))	('reduces aldosterone', 'Phenotype', 'HP:0004319', (169, 188))	('transcription', 'MPA', (151, 164))	('reduces', 'NegReg', (169, 176))	('increases', 'PosReg', (36, 45))	('VSNL1', 'Gene', (116, 121))	('expression', 'MPA', (86, 96))	('VSNL1', 'Gene', '7447', (15, 20))	('H295R', 'CellLine', 'CVCL:0458', (3, 8))	('silencing', 'Var', (106, 115))	('negatively', 'NegReg', (122, 132))	('CYP11B2 gene', 'Gene', (73, 85))	('modulates', 'Reg', (133, 142))
75712	25240470	Moreover, VSNL1 had been shown to promote cell survival from the calcium toxicity induced by KCNJ5 mutations.	('KCNJ5', 'Gene', (93, 98))	('cell survival', 'CPA', (42, 55))	('calcium', 'CPA', (65, 72))	('KCNJ5', 'Gene', '3762', (93, 98))	('toxicity', 'Disease', 'MESH:D064420', (73, 81))	('mutations', 'Var', (99, 108))	('promote', 'PosReg', (34, 41))	('toxicity', 'Disease', (73, 81))	('VSNL1', 'Gene', (10, 15))	('VSNL1', 'Gene', '7447', (10, 15))	('calcium', 'Chemical', 'MESH:D002118', (65, 72))
75713	25240470	To better define the influence of KCNJ5 mutations on CYP11B2 expression, we overexpressed wild type or mutant KCNJ5 in the HAC15 adrenal cell culture model.	('KCNJ5', 'Gene', (34, 39))	('KCNJ5', 'Gene', '3762', (34, 39))	('mutant', 'Var', (103, 109))	('KCNJ5', 'Gene', (110, 115))	('KCNJ5', 'Gene', '3762', (110, 115))
75714	25240470	Both p.Gly151Arg and p.Leu168Arg mutations increased CYP11B2 transcript levels compared to wild type KCNJ5, supporting a mechanistic role for these mutations in the activation of aldosterone production through increased CYP11B2 expression.	('p.Leu168Arg', 'Mutation', 'rs386352318', (21, 32))	('increased', 'PosReg', (210, 219))	('KCNJ5', 'Gene', (101, 106))	('CYP11B2 transcript levels', 'MPA', (53, 78))	('p.Leu168Arg', 'Var', (21, 32))	('p.Gly151Arg', 'Mutation', 'rs386352319', (5, 16))	('aldosterone', 'Chemical', 'MESH:D000450', (179, 190))	('p.Gly151Arg', 'Var', (5, 16))	('KCNJ5', 'Gene', '3762', (101, 106))	('increased', 'PosReg', (43, 52))	('aldosterone production', 'MPA', (179, 201))	('aldosterone production', 'Phenotype', 'HP:0000859', (179, 201))	('activation', 'PosReg', (165, 175))	('expression', 'MPA', (228, 238))
75715	25240470	Importantly, we also observed a large increase in two of the transcriptional regulators of CYP11B2, NURR1 (encoded by NR4A2) and NOR-1 (encoded by NR4A3).	('NR4A2', 'Gene', '4929', (118, 123))	('increase', 'PosReg', (38, 46))	('NOR-1', 'Gene', (129, 134))	('NR4A3', 'Gene', '8013', (147, 152))	('NR4A3', 'Gene', (147, 152))	('NURR1', 'Gene', '4929', (100, 105))	('NURR1', 'Gene', (100, 105))	('CYP11B2', 'Var', (91, 98))	('NR4A2', 'Gene', (118, 123))	('NOR-1', 'Gene', '8013', (129, 134))
75717	25240470	demonstrated that the expression of the p.Thr158Ala mutation in HAC15 cells was responsible for a significant increase in aldosterone production and this effect was dependent on calcium influx, as it was specifically inhibited by the calcium channel blocker nifedipine and the calmodulin antagonist W-7.	('increase', 'PosReg', (110, 118))	('calmodulin', 'Gene', (277, 287))	('p.Thr158Ala', 'Var', (40, 51))	('calmodulin', 'Gene', '801', (277, 287))	('nifedipine', 'Chemical', 'MESH:D009543', (258, 268))	('aldosterone', 'Chemical', 'MESH:D000450', (122, 133))	('p.Thr158Ala', 'Mutation', 'rs387906778', (40, 51))	('rat', 'Species', '10116', (7, 10))	('calcium', 'Chemical', 'MESH:D002118', (178, 185))	('aldosterone production', 'Phenotype', 'HP:0000859', (122, 144))	('calcium', 'Chemical', 'MESH:D002118', (234, 241))	('aldosterone production', 'MPA', (122, 144))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (110, 133))
75718	25240470	While the causal relationship between KCNJ5 mutations and autonomous aldosterone secretion is now well established, it is still unknown whether KCNJ5 mutations stimulate cell proliferation or promote APA formation.	('KCNJ5', 'Gene', (144, 149))	('autonomous aldosterone secretion', 'MPA', (58, 90))	('KCNJ5', 'Gene', '3762', (38, 43))	('KCNJ5', 'Gene', '3762', (144, 149))	('promote', 'PosReg', (192, 199))	('rat', 'Species', '10116', (182, 185))	('cell proliferation', 'CPA', (170, 188))	('mutations', 'Var', (44, 53))	('mutations', 'Var', (150, 159))	('aldosterone', 'Chemical', 'MESH:D000450', (69, 80))	('APA formation', 'MPA', (200, 213))	('stimulate', 'PosReg', (160, 169))	('KCNJ5', 'Gene', (38, 43))
75719	25240470	KCNJ5 mutations have in fact been associated with a slight inhibitory effect on cell proliferation and to some degree of cell lethality induced by osmotic shock.	('shock', 'Phenotype', 'HP:0031273', (155, 160))	('KCNJ5', 'Gene', '3762', (0, 5))	('osmotic shock', 'Disease', 'MESH:D012769', (147, 160))	('osmotic shock', 'Disease', (147, 160))	('cell lethality', 'CPA', (121, 135))	('inhibitory effect', 'NegReg', (59, 76))	('rat', 'Species', '10116', (92, 95))	('cell proliferation', 'CPA', (80, 98))	('KCNJ5', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
75720	25240470	have recently explored the relationship between adrenal cortex remodeling and KCNJ5 mutations without finding any correlation between the nodulation score in the peritumoral tissue, vascularization and zona glomerulosa hyperplasia in the peritumoral cortex and KCNJ5 status, indicating that KCNJ5 mutations are not likely to be responsible for a proliferative microenvironment leading to APA formation.	('KCNJ5', 'Gene', '3762', (291, 296))	('KCNJ5', 'Gene', (261, 266))	('zona glomerulosa hyperplasia', 'Disease', (202, 230))	('mutations', 'Var', (297, 306))	('mutations', 'Var', (84, 93))	('KCNJ5', 'Gene', '3762', (261, 266))	('KCNJ5', 'Gene', (78, 83))	('rat', 'Species', '10116', (353, 356))	('KCNJ5', 'Gene', (291, 296))	('zona glomerulosa hyperplasia', 'Disease', 'MESH:D006562', (202, 230))	('KCNJ5', 'Gene', '3762', (78, 83))
75722	25240470	Although unilateral adrenalectomy is the preferred treatment for APA patients, the development of highly selective inhibitors of mutant KCNJ5, able to suppress autonomous aldosterone overproduction and perhaps stop adrenal cell proliferation would be highly attractive since more than one third of patients with APA carry mutations in KCNJ5.	('KCNJ5', 'Gene', '3762', (136, 141))	('KCNJ5', 'Gene', '3762', (335, 340))	('adrenal cell proliferation', 'CPA', (215, 241))	('mutations', 'Var', (322, 331))	('patients', 'Species', '9606', (298, 306))	('rat', 'Species', '10116', (235, 238))	('aldosterone', 'Chemical', 'MESH:D000450', (171, 182))	('stop', 'NegReg', (210, 214))	('autonomous aldosterone overproduction', 'MPA', (160, 197))	('patients', 'Species', '9606', (69, 77))	('KCNJ5', 'Gene', (136, 141))	('suppress', 'NegReg', (151, 159))	('KCNJ5', 'Gene', (335, 340))	('mutant', 'Var', (129, 135))
75723	25240470	To summarize, KCNJ5 mutations have been implicated in the pathogenesis of both a consistent proportion of sporadic APAs and familial hyperaldosteronism type III.	('familial hyperaldosteronism type III', 'Disease', 'MESH:D003480', (124, 160))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (133, 151))	('KCNJ5', 'Gene', (14, 19))	('familial hyperaldosteronism type I', 'Phenotype', 'HP:0011739', (124, 158))	('KCNJ5', 'Gene', '3762', (14, 19))	('implicated', 'Reg', (40, 50))	('familial hyperaldosteronism type III', 'Disease', (124, 160))	('familial hyperaldosteronism type', 'Phenotype', 'HP:0011739', (124, 156))	('sporadic APAs', 'Disease', (106, 119))	('mutations', 'Var', (20, 29))
75724	25240470	The mutations, located near or within the selectivity filter of the channel result in cell membrane depolarization and autonomous aldosterone production via a pathological Na+ permeability through the mutated channel.	('cell membrane', 'MPA', (86, 99))	('aldosterone', 'Chemical', 'MESH:D000450', (130, 141))	('depolarization', 'NegReg', (100, 114))	('mutated', 'Var', (201, 208))	('autonomous aldosterone production', 'MPA', (119, 152))	('Na+ permeability', 'MPA', (172, 188))	('aldosterone production', 'Phenotype', 'HP:0000859', (130, 152))	('mutations', 'Var', (4, 13))
75725	25240470	The mutations are significantly more prevalent in female patients than in males, an observation that is still to be accounted for.	('mutations', 'Var', (4, 13))	('patients', 'Species', '9606', (57, 65))	('prevalent', 'Reg', (37, 46))
75727	25240470	performed exome sequencing of nine KCNJ5 mutation negative APAs from male PA patients (Beuscphlein et al., 2013).	('KCNJ5', 'Gene', (35, 40))	('KCNJ5', 'Gene', '3762', (35, 40))	('mutation', 'Var', (41, 49))	('patients', 'Species', '9606', (77, 85))	('negative', 'NegReg', (50, 58))
75732	25240470	Moreover, ATP1A1 haploinsufficient mice displayed 2-fold higher aldosterone levels compared to wild-type animals.	('higher aldosterone', 'Phenotype', 'HP:0000859', (57, 75))	('higher', 'PosReg', (57, 63))	('aldosterone', 'Chemical', 'MESH:D000450', (64, 75))	('haploinsufficient', 'Var', (17, 34))	('mice', 'Species', '10090', (35, 39))	('aldosterone levels', 'MPA', (64, 82))	('ATP1A1', 'Gene', (10, 16))
75735	25240470	In vitro studies demonstrated that the two point ATP1A1 mutations, leading to the p.Leu104Arg and p.Val332Gly substitutions, resulted in a disturbed gating mechanism, reduced affinity for potassium compared to wild-type Na+/K+ -ATPase and induced cell membrane depolarization (Figure 2, panel B).	('p.Leu104Arg', 'Mutation', 'rs11540945', (82, 93))	('gating mechanism', 'MPA', (149, 165))	('p.Val332Gly', 'Var', (98, 109))	('rat', 'Species', '10116', (24, 27))	('p.Leu104Arg', 'Var', (82, 93))	('cell membrane', 'CPA', (247, 260))	('disturbed', 'Reg', (139, 148))	('ATPase', 'Gene', '1769', (228, 234))	('p.Val332Gly', 'Mutation', 'rs724160010', (98, 109))	('potassium', 'Chemical', 'MESH:D011188', (188, 197))	('ATP1A1', 'Gene', (49, 55))	('ATPase', 'Gene', (228, 234))	('reduced', 'NegReg', (167, 174))	('affinity for potassium', 'MPA', (175, 197))
75736	25240470	In fact, both leucine 104 and valine 322 have been shown to interact with glutamic acid 334, which is crucial for gating of the binding pocket and potassium ion binding.	('leucine 104', 'Var', (14, 25))	('valine 322', 'Var', (30, 40))	('leucine', 'Chemical', 'MESH:D007930', (14, 21))	('glutamic acid', 'Chemical', 'MESH:D018698', (74, 87))	('glutamic', 'Protein', (74, 82))	('interact', 'Interaction', (60, 68))	('potassium', 'Chemical', 'MESH:D011188', (147, 156))	('valine', 'Chemical', 'MESH:D014633', (30, 36))
75737	25240470	Similarly, the two ATP2AB3 deletions (c.1272_1277delGCTGGT and c.1273_1278delCTGGTC, both resulting in p.Leu425_Val426del) (Table 1), affect the same region in which lies the glutamate homologous to gluatmic acid 334 in Na+/K+-ATPase and are predicted to affect the calcium binding ion site (Figure 2, panel C).	('c.1273_1278delCTGGTC', 'Var', (63, 83))	('ATPase', 'Gene', '1769', (227, 233))	('p.Leu425_Val426del', 'Mutation', 'p.425_,426delV', (103, 121))	('c.1273_1278delCTGGTC', 'Mutation', 'rs724160011', (63, 83))	('ATPase', 'Gene', (227, 233))	('calcium', 'Chemical', 'MESH:D002118', (266, 273))	('ATP2AB3', 'Gene', (19, 26))	('affect', 'Reg', (134, 140))	('c.1272_1277delGCTGGT', 'Mutation', 'rs724160009', (38, 58))	('calcium binding ion site', 'MPA', (266, 290))	('c.1272_1277delGCTGGT', 'Var', (38, 58))	('affect', 'Reg', (255, 261))	('p.Leu425_Val426del', 'Var', (103, 121))	('glutamate', 'Protein', (175, 184))
75738	25240470	The additional sequencing of 299 APAs led to the identification of a novel ATP1A1 in-frame deletion of five amino acids (c.299_313delTCTCAATGTTACTGT; p.Phe100_Leu104del) and a novel ATP2B3 in-frame deletion of two amino acids (c.1277_1282delTCGTGG; p.Val426_Val427del), with an overall prevalence of ATP1A1 and ATP2B3 mutations of 5.2% and 1.6% respectively.	('ATP2B3', 'Gene', '492', (182, 188))	('p.Val426_Val427del', 'Mutation', 'rs724160012', (249, 267))	('c.299_313delTCTCAATGTTACTGT', 'Var', (121, 148))	('c.1277_1282delTCGTGG', 'Mutation', 'rs724160012', (227, 247))	('p.Val426_Val427del', 'Var', (249, 267))	('ATP1A1', 'Gene', (75, 81))	('ATP2B3', 'Gene', (182, 188))	('p.Phe100_Leu104del', 'Var', (150, 168))	('c.299_313delTCTCAATGTTACTGT', 'Mutation', 'c.299_313del', (121, 148))	('p.Phe100_Leu104del', 'Mutation', 'p.100,104del', (150, 168))	('ATP2B3', 'Gene', '492', (311, 317))	('c.1277_1282delTCGTGG; p.Val426_Val427del', 'Var', (227, 267))	('ATP1A1', 'Gene', (300, 306))	('ATP2B3', 'Gene', (311, 317))
75740	25240470	Four out of ten adenomas harbored somatic mutations in the gene ATP1A1 (including a newly described substitution of residues 960-963 by a serine residue; p.GluGluThrAla963Ser).	('ATP1A1', 'Gene', (64, 70))	('adenomas', 'Disease', 'MESH:D000236', (16, 24))	('serine', 'Chemical', 'MESH:D012694', (138, 144))	('p.GluGluThrAla963Ser', 'Var', (154, 174))	('adenomas', 'Disease', (16, 24))	('GluGluThrAla963Ser', 'Chemical', '-', (156, 174))
75741	25240470	Compared to KCNJ5 mutant APAs, tumors carrying mutations in ATP1A1 in this report, seemed to be associated with older age at diagnosis, male sex and zona glomerulusa-like phenotype.	('tumors', 'Disease', (31, 37))	('associated', 'Reg', (96, 106))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('ATP1A1', 'Gene', (60, 66))	('mutations', 'Var', (47, 56))	('KCNJ5', 'Gene', (12, 17))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('KCNJ5', 'Gene', '3762', (12, 17))
75743	25240470	Sequencing analysis revealed a prevalence of ATP1A1 and ATP2B3 mutations of 6.3% and 0.9% by Williams et al.	('mutations', 'Var', (63, 72))	('ATP1A1', 'Gene', (45, 51))	('ATP2B3', 'Gene', '492', (56, 62))	('ATP2B3', 'Gene', (56, 62))
75744	25240470	A novel ATP1A1 somatic (c.295G>A) mutation (p.Gly99Arg) was identified; in vitro studies revealed that the p.Gly99Arg mutant displayed severely impaired ATPase and decreased cation binding, resulting in cell membrane depolarization.	('c.295G>A', 'Mutation', 'c.295G>A', (24, 32))	('p.Gly99Arg', 'Mutation', 'p.G99R', (44, 54))	('decreased', 'NegReg', (164, 173))	('ATPase', 'Gene', '1769', (153, 159))	('p.Gly99Arg', 'Var', (107, 117))	('p.Gly99Arg', 'Mutation', 'p.G99R', (107, 117))	('cell', 'MPA', (203, 207))	('impaired', 'NegReg', (144, 152))	('cation binding', 'MPA', (174, 188))	('ATPase', 'Gene', (153, 159))
75748	25240470	identified 7 different somatic mutations (p.Val259Asp, p.Gly403Arg, p.Phe747Leu, p.Ile750Met, p.Arg990His, p.Pro1336Arg, p.Met1354Ile), while Scholl et al.	('p.Phe747Leu', 'Var', (68, 79))	('p.Phe747Leu', 'Mutation', 'p.F747L', (68, 79))	('p.Val259Asp', 'Var', (42, 53))	('p.Pro1336Arg', 'Mutation', 'p.P1336R', (107, 119))	('p.Gly403Arg', 'Mutation', 'p.G403R', (55, 66))	('p.Val259Asp', 'Mutation', 'p.V259D', (42, 53))	('p.Met1354Ile', 'Var', (121, 133))	('p.Arg990His', 'Mutation', 'p.R990H', (94, 105))	('p.Arg990His', 'Var', (94, 105))	('p.Gly403Arg', 'Var', (55, 66))	('p.Ile750Met', 'Var', (81, 92))	('p.Pro1336Arg', 'Var', (107, 119))	('p.Met1354Ile', 'Mutation', 'p.M1354I', (121, 133))	('p.Ile750Met', 'Mutation', 'rs41276445', (81, 92))
75749	25240470	identified 4 mutations (p.Gly403Arg, p.Phe767Val, p.Ile770Met, and p.Val1373Met) in sporadic APAs without KCNJ5 mutations (Table 1).	('p.Val1373Met', 'Var', (67, 79))	('p.Phe767Val', 'Mutation', 'p.F767V', (37, 48))	('KCNJ5', 'Gene', '3762', (106, 111))	('p.Gly403Arg', 'Mutation', 'p.G403R', (24, 35))	('p.Ile770Met', 'Var', (50, 61))	('p.Ile770Met', 'Mutation', 'rs41276445', (50, 61))	('p.Gly403Arg', 'Var', (24, 35))	('p.Phe767Val', 'Var', (37, 48))	('p.Val1373Met', 'Mutation', 'p.V1373M', (67, 79))	('KCNJ5', 'Gene', (106, 111))
75750	25240470	Expression of CACNA1D mutations in the human embryonic kidney cell line resulted in a shift of the voltage-dependent activation to more negative potentials, suppression of the inactivation or increase in the currents, suggestive of increased Ca2+ entry in APAs harboring mutations in CACNA1D (Figure 2, panel D).	('CACNA1D', 'Gene', (14, 21))	('embryonic kidney', 'Disease', (45, 61))	('inactivation', 'MPA', (176, 188))	('CACNA1D', 'Gene', '776', (284, 291))	('CACNA1D', 'Gene', (284, 291))	('embryonic kidney', 'Disease', 'MESH:D007674', (45, 61))	('voltage-dependent', 'MPA', (99, 116))	('mutations', 'Var', (22, 31))	('increased', 'PosReg', (232, 241))	('increase', 'PosReg', (192, 200))	('Ca2+ entry', 'MPA', (242, 252))	('activation', 'PosReg', (117, 127))	('human', 'Species', '9606', (39, 44))	('suppression', 'NegReg', (157, 168))	('mutations', 'Var', (271, 280))	('currents', 'MPA', (208, 216))	('CACNA1D', 'Gene', '776', (14, 21))
75751	25240470	Interestingly, two de-novo CACNA1D germline mutations (p.Gly403Asp and p.Ile770Met) (Table 1) were detected in two subjects with early onset PA associated with seizure and neuromuscular disease.	('CACNA1D', 'Gene', (27, 34))	('associated', 'Reg', (144, 154))	('neuromuscular disease', 'Disease', 'MESH:D009468', (172, 193))	('p.Gly403Asp', 'Mutation', 'rs386834264', (55, 66))	('seizure', 'Phenotype', 'HP:0001250', (160, 167))	('p.Ile770Met', 'Var', (71, 82))	('p.Gly403Asp', 'Var', (55, 66))	('p.Ile770Met', 'Mutation', 'rs41276445', (71, 82))	('neuromuscular disease', 'Disease', (172, 193))	('CACNA1D', 'Gene', '776', (27, 34))	('seizure', 'Disease', (160, 167))	('early onset PA', 'Disease', (129, 143))	('seizure', 'Disease', 'MESH:D012640', (160, 167))
75752	25240470	Notably, treatment with the calcium channel blocker amlodipine normalized blood pressure in one of the two affected subjects, raising the possibility of specific treatment for PA patients affected by APAs carrying mutations in CACNA1D.	('CACNA1D', 'Gene', '776', (227, 234))	('CACNA1D', 'Gene', (227, 234))	('mutations', 'Var', (214, 223))	('patients', 'Species', '9606', (179, 187))	('normalized blood pressure', 'MPA', (63, 88))	('amlodipine', 'Chemical', 'MESH:D017311', (52, 62))	('calcium', 'Chemical', 'MESH:D002118', (28, 35))
75753	25240470	Overall, CACNA1D mutations have been identified in 7/64 (11%) APAs and in 12/152 (7.9%) in these two sample sets.	('CACNA1D', 'Gene', '776', (9, 16))	('CACNA1D', 'Gene', (9, 16))	('APAs', 'Protein', (62, 66))	('identified', 'Reg', (37, 47))	('mutations', 'Var', (17, 26))
75754	25240470	In a large series of 474 APA samples collected through the ENS@T, CACNA1D mutations were identified in 44 tumors (9.3%); in addition to previously reported somatic mutations, 10 novel substitutions were identified (Table 1).	('CACNA1D', 'Gene', (66, 73))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Disease', (106, 112))	('mutations', 'Var', (74, 83))	('CACNA1D', 'Gene', '776', (66, 73))
75755	25240470	Interestingly, patients with CACNA1D mutations had smaller adenomas compared to those with KCNJ5 mutations or no mutations, as previously reported, while the association with other clinical and biochemical parameters was mainly dependent on the population structures of different centers.	('patients', 'Species', '9606', (15, 23))	('smaller', 'NegReg', (51, 58))	('CACNA1D', 'Gene', '776', (29, 36))	('mutations', 'Var', (37, 46))	('CACNA1D', 'Gene', (29, 36))	('adenomas', 'Disease', 'MESH:D000236', (59, 67))	('KCNJ5', 'Gene', (91, 96))	('adenomas', 'Disease', (59, 67))	('KCNJ5', 'Gene', '3762', (91, 96))
75756	25240470	In conclusion CACNA1D mutation are un infrequent cause of APA and are responsible for a novel genetic form of primary aldosteronism associated with neurological developmental disorders.	('neurological developmental disorders', 'Disease', (148, 184))	('CACNA1D', 'Gene', (14, 21))	('mutation', 'Var', (22, 30))	('neurological developmental disorders', 'Disease', 'MESH:D009422', (148, 184))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (110, 131))	('primary aldosteronism', 'Disease', (110, 131))	('cause', 'Reg', (49, 54))	('form of primary aldosteronism', 'Phenotype', 'HP:0011739', (102, 131))	('APA', 'Disease', (58, 61))	('CACNA1D', 'Gene', '776', (14, 21))
75757	25240470	Most strikingly, all to date identified disease causing genes fall in well-defined pathways involved in regulation of aldosterone production, such as potassium sensing, membrane potential regulation and steroidogenesis.	('aldosterone', 'Chemical', 'MESH:D000450', (118, 129))	('potassium sensing', 'MPA', (150, 167))	('fall', 'NegReg', (62, 66))	('potassium', 'Chemical', 'MESH:D011188', (150, 159))	('steroid', 'Chemical', 'MESH:D013256', (203, 210))	('aldosterone production', 'Phenotype', 'HP:0000859', (118, 140))	('fall', 'Phenotype', 'HP:0002527', (62, 66))	('membrane potential regulation', 'MPA', (169, 198))	('genes', 'Var', (56, 61))
75759	25240470	NGS-based methods increased our knowledge of genetics and pathophysiology of PA. Somatic mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D are present in 50% of APAs.	('KCNJ5', 'Gene', '3762', (102, 107))	('ATP2B3', 'Gene', '492', (117, 123))	('CACNA1D', 'Gene', '776', (128, 135))	('CACNA1D', 'Gene', (128, 135))	('ATP1A1', 'Gene', (109, 115))	('ATP2B3', 'Gene', (117, 123))	('mutations', 'Var', (89, 98))	('KCNJ5', 'Gene', (102, 107))
75760	25240470	Germline mutations in KCNJ5 are causative of familial hyperaldosteronism type III.	('Germline mutations', 'Var', (0, 18))	('familial hyperaldosteronism type I', 'Phenotype', 'HP:0011739', (45, 79))	('familial hyperaldosteronism type III', 'Disease', (45, 81))	('familial hyperaldosteronism type', 'Phenotype', 'HP:0011739', (45, 77))	('KCNJ5', 'Gene', (22, 27))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (54, 72))	('KCNJ5', 'Gene', '3762', (22, 27))	('causative', 'Reg', (32, 41))	('familial hyperaldosteronism type III', 'Disease', 'MESH:D003480', (45, 81))
75762	25520849	There has not been any clear evidence of a causal association between NF1 gene mutations and adrenocortical malignancy development.	('NF1', 'Gene', '4763', (70, 73))	('adrenocortical malignancy', 'Disease', 'MESH:D018268', (93, 118))	('adrenocortical malignancy', 'Disease', (93, 118))	('NF1', 'Gene', (70, 73))	('mutations', 'Var', (79, 88))
75763	25520849	We report the case of a 49-year-old female, with no family history of endocrinopathy, who was diagnosed with ACC on the background of NF1, due to a novel germline frame shift mutation (c.5452_5453delAT) in exon 37 of the NF1 gene.	('endocrinopathy', 'Disease', 'MESH:C567425', (70, 84))	('endocrinopathy', 'Disease', (70, 84))	('NF1', 'Gene', (221, 224))	('NF1', 'Gene', '4763', (221, 224))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('NF1', 'Gene', (134, 137))	('c.5452_5453delAT', 'Mutation', 'c.5452_5453delAT', (185, 201))	('c.5452_5453delAT', 'Var', (185, 201))	('due to', 'Reg', (139, 145))	('NF1', 'Gene', '4763', (134, 137))
75770	25520849	The LOH at the NF1 region of the adrenal tumour supports the role of loss of neurofibromin in the development of ACC.	('neurofibromin', 'Gene', (77, 90))	('NF1', 'Gene', (15, 18))	('adrenal tumour', 'Disease', 'MESH:D000310', (33, 47))	('loss', 'Var', (69, 73))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('NF1', 'Gene', '4763', (15, 18))	('neurofibromin', 'Gene', '4763', (77, 90))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('ACC', 'Disease', (113, 116))	('adrenal tumour', 'Disease', (33, 47))
75783	25520849	Genetic analysis in 2011 demonstrated that she had a novel heterozygous mutation c.5452_5453delAT in exon 37 of NF1 (RefSeq NM_000267.3).	('NF1', 'Gene', (112, 115))	('c.5452_5453delAT', 'Mutation', 'c.5452_5453delAT', (81, 97))	('c.5452_5453delAT', 'Var', (81, 97))	('NF1', 'Gene', '4763', (112, 115))
75801	25520849	The DNA from blood and adrenal tissue were analysed for sequence alterations in the region in which a germline heterozygous AT deletion, c.5452_5453delAT; p.Ile1818Profs*22 in exon 37 of NF1 (RefSeq NM_000267.3), had been previously found by the Cardiff genetics laboratory.	('NF1', 'Gene', '4763', (187, 190))	('NF1', 'Gene', (187, 190))	('c.5452_5453delAT', 'Mutation', 'c.5452_5453delAT', (137, 153))	('p.Ile1818Profs*22', 'FRAMESHIFT', 'None', (155, 172))	('p.Ile1818Profs*22', 'Var', (155, 172))
75814	25520849	NF1 results from a loss-of-function mutation or deletion in the NF1 gene located on chromosome 17.	('NF1', 'Gene', '4763', (0, 3))	('NF1', 'Gene', (64, 67))	('NF1', 'Gene', '4763', (64, 67))	('NF1', 'Gene', (0, 3))	('deletion', 'Var', (48, 56))	('loss-of-function', 'NegReg', (19, 35))	('mutation', 'Var', (36, 44))
75820	25520849	In patients with a heterozygous germline NF1 mutation, the loss of the other (WT) allele will lead to the complete loss of neurofibromin function and the development of tumours, according to the Knudson two-hit hypothesis.	('tumours', 'Disease', (169, 176))	('loss', 'NegReg', (115, 119))	('neurofibromin', 'Gene', '4763', (123, 136))	('neurofibromin', 'Gene', (123, 136))	('mutation', 'Var', (45, 53))	('NF1', 'Gene', (41, 44))	('patients', 'Species', '9606', (3, 11))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('NF1', 'Gene', '4763', (41, 44))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('germline', 'Var', (32, 40))	('tumours', 'Disease', 'MESH:D009369', (169, 176))	('function', 'MPA', (137, 145))
75821	25520849	This LOH at the NF1 locus has been found in both benign and malignant tumours associated with germline NF1 mutations.	('NF1', 'Gene', (16, 19))	('NF1', 'Gene', '4763', (103, 106))	('mutations', 'Var', (107, 116))	('NF1', 'Gene', '4763', (16, 19))	('malignant tumours', 'Disease', 'MESH:D009369', (60, 77))	('malignant tumours', 'Disease', (60, 77))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('NF1', 'Gene', (103, 106))
75822	25520849	Interestingly, somatic NF1 mutations are common in sporadic phaeochromocytomas.	('mutations', 'Var', (27, 36))	('NF1', 'Gene', (23, 26))	('sporadic phaeochromocytomas', 'Disease', 'MESH:D004421', (51, 78))	('NF1', 'Gene', '4763', (23, 26))	('sporadic phaeochromocytomas', 'Disease', (51, 78))	('common', 'Reg', (41, 47))
75835	25520849	Our analysis suggests that the LOH in the tumour may have a direct link with the development of her ACC.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('LOH', 'Var', (31, 34))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', (42, 48))	('ACC', 'Phenotype', 'HP:0006744', (100, 103))
75836	25520849	In conclusion, we report herein an NF1 patient with a novel NF1 gene mutation and an ACC.	('patient', 'Species', '9606', (39, 46))	('NF1', 'Gene', '4763', (60, 63))	('NF1', 'Gene', (60, 63))	('mutation', 'Var', (69, 77))	('ACC', 'Phenotype', 'HP:0006744', (85, 88))	('NF1', 'Gene', (35, 38))	('NF1', 'Gene', '4763', (35, 38))
75908	24932598	Findings suggestive of Cushing's syndrome were rapid increase in weight associated with growth deceleration, presence of moon face, buffalo hump, purple or bright red striae and/or hypertension.	('buffalo hump', 'Phenotype', 'HP:0025383', (132, 144))	("Cushing's syndrome", 'Disease', (23, 41))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (23, 41))	('hypertension', 'Disease', 'MESH:D006973', (181, 193))	('moon face', 'Phenotype', 'HP:0500011', (121, 130))	('growth deceleration', 'CPA', (88, 107))	('increase', 'PosReg', (53, 61))	('presence', 'Var', (109, 117))	('red striae', 'Phenotype', 'HP:0001065', (163, 173))	('hypertension', 'Disease', (181, 193))	('increase in weight', 'Phenotype', 'HP:0004324', (53, 71))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (23, 41))	('hypertension', 'Phenotype', 'HP:0000822', (181, 193))	('weight', 'MPA', (65, 71))
75947	24932598	Analysis of the STK11 gene showed a missense mutation leading to the amino acid change E199D in the kinase domain, confirming the diagnosis of Peutz-Jeghers syndrome (7).	('STK11', 'Gene', '6794', (16, 21))	('gene', 'Gene', (22, 26))	('E199D', 'Var', (87, 92))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (143, 165))	('E199D', 'Mutation', 'p.E199D', (87, 92))	('Peutz-Jeghers syndrome', 'Disease', (143, 165))	('STK11', 'Gene', (16, 21))
75987	24932598	In such cases, excision of the tumor may lead to signs of adrenal insufficiency or crisis during surgery or after surgery during stress since adrenal glucocorticoid production may not recover quickly after tumor removal.	('adrenal insufficiency', 'Disease', (58, 79))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (31, 36))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (58, 79))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (58, 79))	('lead to', 'Reg', (41, 48))	('adrenal glucocorticoid production', 'MPA', (142, 175))	('excision', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
76022	32516327	The function of a heterozygous p53 mutation in a Li-Fraumeni syndrome patient p53 is one of the most extensively studied proteins in cancer research.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (49, 69))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('in a', 'Gene', (44, 48))	('Li-Fraumeni syndrome', 'Disease', (49, 69))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('p53', 'Gene', (78, 81))	('in a', 'Gene', '9118', (44, 48))	('mutation', 'Var', (35, 43))	('p53', 'Gene', '7157', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
76023	32516327	However, the mechanisms underlying p53 mutation-driven cancer remains to be elucidated.	('p53', 'Gene', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutation-driven', 'Var', (39, 54))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
76024	32516327	Our study investigated the function of a heterozygous p53 mutation (p.Asn268Glufs*4) in a Li-Fraumeni syndrome (LFS) patient.	('LFS', 'Disease', (112, 115))	('Li-Fraumeni syndrome', 'Disease', (90, 110))	('p53', 'Gene', (54, 57))	('LFS', 'Disease', 'MESH:D016864', (112, 115))	('p.Asn268Glufs*4', 'Var', (68, 83))	('patient', 'Species', '9606', (117, 124))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (68, 83))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (90, 110))
76027	32516327	p53 mutation facilitates the proliferation of tumor cells by inhibiting apoptosis and promoting cell division.	('p53', 'Gene', (0, 3))	('facilitates', 'PosReg', (13, 24))	('is a', 'Gene', '312', (79, 83))	('inhibiting', 'NegReg', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('promoting', 'PosReg', (86, 95))	('tumor', 'Disease', (46, 51))	('mutation', 'Var', (4, 12))	('is a', 'Gene', (79, 83))	('cell division', 'CPA', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
76028	32516327	Moreover, not all p53 mutant iPS cell lines have mutant p53 RNA sequences.	('p53', 'Gene', (18, 21))	('mutant', 'Var', (49, 55))	('p53', 'Gene', (56, 59))	('iPS', 'Disease', 'OMIM:613661', (29, 32))	('mutant', 'Var', (22, 28))	('iPS', 'Disease', (29, 32))
76029	32516327	A small percentage of mutant p53 mRNA is present in the somatic cells from the patient and his mother.	('mRNA', 'MPA', (33, 37))	('patient', 'Species', '9606', (79, 86))	('mutant', 'Var', (22, 28))	('p53', 'Gene', (29, 32))
76030	32516327	In summary, this p53 mutation can promote tumor cell proliferation, inhibit somatic reprogramming, and exhibit random p53 allelic expression of heterozygous mutations in the patient and iPS cells which may be one of the reasons why the people with p53 mutations develop cancer at random.	('iPS', 'Disease', 'OMIM:613661', (186, 189))	('tumor', 'Disease', (42, 47))	('patient', 'Species', '9606', (174, 181))	('cancer', 'Disease', (270, 276))	('inhibit', 'NegReg', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('mutation', 'Var', (21, 29))	('iPS', 'Disease', (186, 189))	('mutations', 'Var', (252, 261))	('somatic reprogramming', 'CPA', (76, 97))	('promote', 'PosReg', (34, 41))	('people', 'Species', '9606', (236, 242))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('p53', 'Gene', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
76031	32516327	This finding suggested that mutant p53 allelic expression should be added to the risk forecasting of cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mutant', 'Var', (28, 34))	('p53', 'Gene', (35, 38))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
76035	32516327	Missense mutations of p53 can be a key factor of cell carcinogenesis and reduce the induction efficiency of induced pluripotent stem cells (iPS).	('is a', 'Gene', '312', (66, 70))	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('carcinogenesis', 'Disease', (54, 68))	('iPS', 'Disease', (140, 143))	('p53', 'Gene', (22, 25))	('is a', 'Gene', (66, 70))	('induced pluripotent', 'MPA', (108, 127))	('iPS', 'Disease', 'OMIM:613661', (140, 143))	('reduce', 'NegReg', (73, 79))	('induction', 'MPA', (84, 93))	('Missense mutations', 'Var', (0, 18))
76036	32516327	Moreover, the p53 mutation might not only loss its anti-cancer functions, but also obtain oncogenic traits called gain of function (GOF), including malignant progression and invasion, metastasis and even chemotherapy resistance.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('p53', 'Gene', (14, 17))	('cancer', 'Disease', (56, 62))	('invasion', 'CPA', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('is a', 'Gene', (192, 196))	('chemotherapy resistance', 'CPA', (204, 227))	('mutation', 'Var', (18, 26))	('is a', 'Gene', '312', (192, 196))	('malignant progression', 'CPA', (148, 169))	('gain of function', 'PosReg', (114, 130))	('loss', 'NegReg', (42, 46))
76038	32516327	Additionally, p53 does not fully follow the classic Knudson's two-hit theory during carcinogenesis or cancer progression.Therefore, so many healthy people with the same p53 mutation can go their entire lives without developing cancer.	('carcinogenesis', 'Disease', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('p53', 'Gene', (169, 172))	('people', 'Species', '9606', (148, 154))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('carcinogenesis', 'Disease', 'MESH:D063646', (84, 98))	('mutation', 'Var', (173, 181))
76040	32516327	The p53 mutation facilitates the proliferation of tumor cells by inhibiting apoptosis and promoting cell division.	('cell division', 'CPA', (100, 113))	('is a', 'Gene', '312', (83, 87))	('facilitates', 'PosReg', (17, 28))	('promoting', 'PosReg', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('is a', 'Gene', (83, 87))	('inhibiting', 'NegReg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutation', 'Var', (8, 16))	('p53', 'Gene', (4, 7))	('tumor', 'Disease', (50, 55))
76041	32516327	In three mutant p53 iPS cell lines, we found that the expression levels of WT p53 protein in one iPS line was different from that in the other two iPS cell lines.	('iPS', 'Disease', (147, 150))	('mutant', 'Var', (9, 15))	('iPS', 'Disease', (20, 23))	('iPS', 'Disease', 'OMIM:613661', (147, 150))	('iPS', 'Disease', 'OMIM:613661', (20, 23))	('expression levels', 'MPA', (54, 71))	('iPS', 'Disease', (97, 100))	('iPS', 'Disease', 'OMIM:613661', (97, 100))
76053	32516327	Retroviral constructs pMXs-Klf4 (#13370), pMXs-Sox2 (#13367), pMXs-Oct4 (#13366), pMXs-c-Myc (#13375), were obtained from Addgene.	('#13370', 'Var', (33, 39))	('Sox2', 'Gene', '6657', (47, 51))	('#13375', 'Var', (94, 100))	('#13366', 'Var', (73, 79))	('Sox2', 'Gene', (47, 51))	('#13367', 'Var', (53, 59))
76063	32516327	WT p53, mutant p53 p.Asn268Glufs*4 and p53 R175H coding DNA sequences (CDS) were cloned into a pLL CMV puro mammalian lentiviral expression vector.	('mammalian', 'Species', '9606', (108, 117))	('p53', 'Gene', (15, 18))	('p.Asn268Glufs*4', 'Var', (19, 34))	('R175H', 'Mutation', 'rs28934578', (43, 48))	('p53', 'Gene', (39, 42))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (19, 34))
76080	32516327	To detect the expression of pluripotent genes in MEF cells at different time points of reprogramming, we collected SSEA1-positive cells and extracted total RNA from the groups of p53 mutant, WT, or an empty vector control for 2, 4, 8 and 12 days using a RNeasy plus kit (Qiagen).	('p53', 'Gene', (179, 182))	('mutant', 'Var', (183, 189))	('MEF', 'CellLine', 'CVCL:9115', (49, 52))
76092	32516327	We found a heterozygous insertion of c.801dupG that caused a p.Asn268Glufs*4 in the p53 gene in this patient and his mother, suggesting that this patient inherited the mutation from his healthy mother (Fig 1D).	('c.801dupG', 'Mutation', 'c.801dupG', (37, 46))	('caused', 'Reg', (52, 58))	('p.Asn268Glufs*4', 'Var', (61, 76))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (61, 76))	('c.801dupG', 'Var', (37, 46))	('p53', 'Gene', (84, 87))	('patient', 'Species', '9606', (101, 108))	('patient', 'Species', '9606', (146, 153))
76094	32516327	Asn268Glufs*4 mutation is a nonsense mutation which is located in specific DNA binding domain, which caused early termination of this specific protein synthesis and may affect the function of p53.	('Asn268Glufs*4 mutation', 'Var', (0, 22))	('affect', 'Reg', (169, 175))	('is a', 'Gene', (23, 27))	('p53', 'Protein', (192, 195))	('is a', 'Gene', '312', (23, 27))	('is a', 'Gene', (158, 162))	('function', 'MPA', (180, 188))	('Asn268Glufs', 'Chemical', '-', (0, 11))	('is a', 'Gene', '312', (158, 162))
76095	32516327	To explore the function of the mutant p53, we separately infected lentivirus-mediated p53 mutant, wild type (WT), or an empty vector (EV) control into p53-/- MEF.	('MEF', 'CellLine', 'CVCL:9115', (158, 161))	('infected', 'Disease', (57, 65))	('mutant', 'Var', (90, 96))	('infected', 'Disease', 'MESH:D007239', (57, 65))	('p53', 'Gene', (86, 89))
76096	32516327	As p53 known functional mutant R175H, the expression of BCL-2 in mutant cells was similar to that in control cells, and higher than that in p53 WT cells.	('R175H', 'Mutation', 'rs28934578', (31, 36))	('R175H', 'Var', (31, 36))	('expression', 'MPA', (42, 52))	('mutant', 'Var', (65, 71))	('higher', 'PosReg', (120, 126))	('BCL-2', 'Gene', (56, 61))
76098	32516327	Unlike p53 R175H, p53 p.Asn268Glufs*4 mutant as well as its WT dramatically inhibited cell proliferation (Fig 2C, S1D Fig).	('R175H', 'Mutation', 'rs28934578', (11, 16))	('p.Asn268Glufs*4', 'Var', (22, 37))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (22, 37))	('cell proliferation', 'CPA', (86, 104))	('inhibited', 'NegReg', (76, 85))
76099	32516327	These data suggest that p53 mutant lost WT p53 ability to induce apoptosis and DNA damage and thereby reduced the inhibition of cell division.	('inhibition', 'CPA', (114, 124))	('mutant', 'Var', (28, 34))	('is a', 'Gene', (72, 76))	('p53', 'Gene', (24, 27))	('ability', 'MPA', (47, 54))	('induce', 'PosReg', (58, 64))	('is a', 'Gene', '312', (72, 76))	('DNA', 'CPA', (79, 82))	('lost', 'NegReg', (35, 39))	('reduced', 'NegReg', (102, 109))
76102	32516327	As shown in Fig 3A, the patient showed lower p53 WT protein levels compared with his mother and the healthy control and a truncated p53 protein was found only in the patient's MNC, suggesting that the p53 mutant protein does not express in all cells with this gene mutation.	('protein', 'Protein', (212, 219))	('p53', 'Gene', (201, 204))	('patient', 'Species', '9606', (24, 31))	('mutant', 'Var', (205, 211))	('p53 WT protein levels', 'MPA', (45, 66))	('patient', 'Species', '9606', (166, 173))	('lower', 'NegReg', (39, 44))
76109	32516327	To confirm that p53 mutant inhibited somatic reprogramming, we separately introduced p53 mutant, WT, or an EV control into p53-/- and p53+/+ mouse embryonic fibroblast (MEF) cells and then MEFs were reprogrammed to iPS cells.	('somatic reprogramming', 'CPA', (37, 58))	('iPS', 'Disease', (215, 218))	('MEF', 'CellLine', 'CVCL:9115', (189, 192))	('mouse', 'Species', '10090', (141, 146))	('MEFs', 'CellLine', 'CVCL:9115', (189, 193))	('MEF', 'CellLine', 'CVCL:9115', (169, 172))	('inhibited', 'NegReg', (27, 36))	('p53', 'Gene', (85, 88))	('mutant', 'Var', (89, 95))	('mutant', 'Var', (20, 26))	('iPS', 'Disease', 'OMIM:613661', (215, 218))
76110	32516327	The numbers of iPS colonies in the mutant and WT groups on the 14th day of reprogramming were significantly lower than that in the control group (Fig 3E).	('iPS colonies', 'Disease', (15, 27))	('lower', 'NegReg', (108, 113))	('mutant', 'Var', (35, 41))	('iPS colonies', 'Disease', 'OMIM:613661', (15, 27))
76111	32516327	However, p53 R175H did not affect the reprogramming rate (S1F Fig).	('R175H', 'Mutation', 'rs28934578', (13, 18))	('p53 R175H', 'Var', (9, 18))	('reprogramming rate', 'CPA', (38, 56))
76112	32516327	Compared the expression of pluripotent genes on Day 2nd, 4th, 8th, and 12th during reprogramming, Oct4 expression in p53 WT and mutant cells had been significantly less than that in the control (Fig 3F), whereas the expression of SOX2 and NANOG had no difference (S1A and S1B Fig).	('SOX2', 'Gene', (230, 234))	('p53', 'Gene', (117, 120))	('expression', 'MPA', (103, 113))	('mutant', 'Var', (128, 134))	('less', 'NegReg', (164, 168))	('SOX2', 'Gene', '6657', (230, 234))	('Oct4', 'Gene', (98, 102))
76113	32516327	To investigate whether p53 p.Asn268Glufs*4 mutation influenced cell pluripotency, three p53 p.Asn268Glufs*4 iPS cell lines were picked up.	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (27, 42))	('cell pluripotency', 'MPA', (63, 80))	('p.Asn268Glufs*4', 'Var', (92, 107))	('iPS', 'Disease', (108, 111))	('p53', 'Gene', (23, 26))	('p.Asn268Glufs*4', 'Var', (27, 42))	('iPS', 'Disease', 'OMIM:613661', (108, 111))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (92, 107))	('influenced', 'Reg', (52, 62))
76114	32516327	Using RT-PCR, we found that the expression of pluripotency genes, including OCT4, SOX-2, NANOG, and Rex-1 in these three p53 mutant iPS cell lines was coincident with the H1 ESC at RNA level (S2A Fig).	('iPS', 'Disease', 'OMIM:613661', (132, 135))	('mutant', 'Var', (125, 131))	('Rex-1', 'Gene', (100, 105))	('p53', 'Gene', (121, 124))	('ES', 'Chemical', 'MESH:D004540', (174, 176))	('OCT4', 'Gene', (76, 80))	(', NANOG,', 'Gene', '79923', (87, 95))	('iPS', 'Disease', (132, 135))
76116	32516327	What's more, the iPSCs with the p53 p.Asn268Glufs*4 mutation as normal iPS could differentiate into three primary germ layers and form teratomas in immunodeficient mice (S2C Fig).	('iPS', 'Disease', 'OMIM:613661', (71, 74))	('teratomas in immunodeficient', 'Disease', (135, 163))	('iPS', 'Disease', (17, 20))	('p.Asn268Glufs*4', 'Var', (36, 51))	('mice', 'Species', '10090', (164, 168))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (36, 51))	('iPS', 'Disease', 'OMIM:613661', (17, 20))	('teratomas', 'Phenotype', 'HP:0009792', (135, 144))	('teratomas in immunodeficient', 'Disease', 'MESH:D013724', (135, 163))	('form', 'Reg', (130, 134))	('iPS', 'Disease', (71, 74))
76117	32516327	All of these data indicate that iPSCs with the p53 p.Asn268Glufs*4 mutation can maintain pluripotency.	('p.Asn268Glufs*4', 'Var', (51, 66))	('iPS', 'Disease', 'OMIM:613661', (32, 35))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (51, 66))	('pluripotency', 'MPA', (89, 101))	('iPS', 'Disease', (32, 35))	('p53', 'Gene', (47, 50))
76120	32516327	The results showed that all iPS cell lines contained the same p53 mutation with patient's somatic cells.	('contained', 'Reg', (43, 52))	('iPS', 'Disease', (28, 31))	('mutation', 'Var', (66, 74))	('iPS', 'Disease', 'OMIM:613661', (28, 31))	('p53', 'Gene', (62, 65))	('patient', 'Species', '9606', (80, 87))
76121	32516327	(Fig 4A), which confirmed that the p53 p.Asn268Glufs*4 mutant is a germline mutation.	('p.Asn268Glufs*4', 'Var', (39, 54))	('is a', 'Gene', '312', (62, 66))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (39, 54))	('is a', 'Gene', (62, 66))
76123	32516327	However, not all p53 mutations carriers will develop into LFS patients p53 does not fully follow the classic Knudson's two-hit theory during carcinogenesis or cancer progression.	('cancer', 'Disease', (159, 165))	('LFS', 'Disease', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('carcinogenesis', 'Disease', 'MESH:D063646', (141, 155))	('LFS', 'Disease', 'MESH:D016864', (58, 61))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('p53', 'Gene', (17, 20))	('patients', 'Species', '9606', (62, 70))	('carcinogenesis', 'Disease', (141, 155))	('mutations', 'Var', (21, 30))
76126	32516327	p53 protein levels in one of the iPS cell lines were same as in H1 ESCs, whereas the other two iPS cell lines expressed lower levels of p53 WT and mutant proteins (Fig 4C).	('iPS', 'Disease', (33, 36))	('mutant', 'Var', (147, 153))	('lower', 'NegReg', (120, 125))	('iPS', 'Disease', 'OMIM:613661', (33, 36))	('iPS', 'Disease', 'OMIM:613661', (95, 98))	('H1 ESCs', 'CellLine', 'CVCL:9108', (64, 71))	('p53 protein levels', 'MPA', (0, 18))	('iPS', 'Disease', (95, 98))
76128	32516327	What's more, all of the three iPS cell lines contained p53 WT RNA sequence (S3C Fig).	('p53 WT', 'Var', (55, 61))	('iPS', 'Disease', (30, 33))	('iPS', 'Disease', 'OMIM:613661', (30, 33))
76131	32516327	This finding indicates that checking the protein level of mutant p53 may be more important than sequencing p53 DNA and mutant p53 allelic expression is a potential predictor of cancer risk.	('mutant', 'Var', (58, 64))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('is a', 'Gene', (149, 153))	('is a', 'Gene', '312', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('mutant', 'Var', (119, 125))	('p53', 'Gene', (126, 129))
76132	32516327	In summary, the goal of the present study was to gain a better understanding of the specific roles of p53 mutations during iPSC reprogramming and p53 related tumorigenesis.	('tumor', 'Disease', (158, 163))	('iPS', 'Disease', (123, 126))	('iPS', 'Disease', 'OMIM:613661', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mutations', 'Var', (106, 115))	('p53', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
76133	32516327	In a word, this specific p53 mutation loses the ability to induce apoptosis and inhibit proliferation, which facilitates tumorigenesis.	('p53', 'Gene', (25, 28))	('loses', 'NegReg', (38, 43))	('mutation', 'Var', (29, 37))	('is a', 'Gene', '312', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('inhibit', 'NegReg', (80, 87))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('proliferation', 'CPA', (88, 101))	('In a', 'Gene', '9118', (0, 4))	('In a', 'Gene', (0, 4))	('facilitates', 'PosReg', (109, 120))	('is a', 'Gene', (73, 77))
76134	32516327	Random allelic expression of p53 in heterozygous p53 mutations caused variable WT p53 protein expression, which might be one of the reasons why people with the same p53 mutation had different states of health.	('people', 'Species', '9606', (144, 150))	('p53', 'Gene', (49, 52))	('WT p53 protein expression', 'MPA', (79, 104))	('mutations', 'Var', (53, 62))
76135	32516327	In the present study, we found that losing part of p53 function caused by a heterozygous mutation did not promote cell reprogramming, instead, it did significantly decrease induction frequency of iPS generation by inhibiting OCT4 expression during reprogramming.	('p53', 'Gene', (51, 54))	('induction', 'MPA', (173, 182))	('OCT4', 'Protein', (225, 229))	('iPS', 'Disease', (196, 199))	('mutation', 'Var', (89, 97))	('iPS', 'Disease', 'OMIM:613661', (196, 199))	('expression', 'MPA', (230, 240))	('function', 'MPA', (55, 63))	('decrease', 'NegReg', (164, 172))	('inhibiting', 'NegReg', (214, 224))
76136	32516327	For example, the high expression of the p53 isoform Delta133 improved the induction efficiency of iPSCs and ensured genomic integrity during reprogramming.	('improved', 'PosReg', (61, 69))	('iPS', 'Disease', (98, 101))	('iPS', 'Disease', 'OMIM:613661', (98, 101))	('induction efficiency', 'CPA', (74, 94))	('genomic integrity', 'CPA', (116, 133))	('ensured', 'PosReg', (108, 115))	('Delta133', 'Var', (52, 60))
76137	32516327	Consistent with our results, the OCT4 expression dramatically increased in p53 knockout MEF cells compared with WT p53 MEF cells.	('increased', 'PosReg', (62, 71))	('MEF', 'CellLine', 'CVCL:9115', (119, 122))	('expression', 'MPA', (38, 48))	('OCT4', 'Protein', (33, 37))	('p53', 'Gene', (75, 78))	('knockout', 'Var', (79, 87))	('MEF', 'CellLine', 'CVCL:9115', (88, 91))
76140	32516327	Biallelic inactivation of p53 has a significant impact on clinical outcome in multiple myeloma.	('p53', 'Gene', (26, 29))	('Biallelic inactivation', 'Var', (0, 22))	('impact', 'Reg', (48, 54))	('multiple myeloma', 'Phenotype', 'HP:0006775', (78, 94))	('multiple myeloma', 'Disease', 'MESH:D009101', (78, 94))	('multiple myeloma', 'Disease', (78, 94))
76141	32516327	In our paper, we found that the patient and his mother had the same p53 mutation, but his mother was a healthy carrier without any clinical symptoms.	('patient', 'Species', '9606', (32, 39))	('p53', 'Gene', (68, 71))	('mutation', 'Var', (72, 80))
76142	32516327	Using Sanger sequencing to analyze the p53 cDNA of the six patient-derived iPS cell lines, we found that four iPS cell lines only contained the p53 WT cDNA sequence, while the other two with low p53 expression contained both WT and mutant p53 cDNA sequences, indicating that p53 random allelic expression occurred in heterozygous mutations.	('iPS', 'Disease', 'OMIM:613661', (110, 113))	('iPS', 'Disease', 'OMIM:613661', (75, 78))	('patient', 'Species', '9606', (59, 66))	('iPS', 'Disease', (110, 113))	('mutant', 'Var', (232, 238))	('iPS', 'Disease', (75, 78))
76143	32516327	When testing the cDNA sequence of the patient and his mother's somatic cells, we also found very little mutant p53 RNA.	('mutant', 'Var', (104, 110))	('p53', 'Gene', (111, 114))	('patient', 'Species', '9606', (38, 45))
76144	32516327	Random allelic expression of heterozygous p53 mutations may be a reason why the people with p53 mutations develop cancer at random.	('p53', 'Gene', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutations', 'Var', (46, 55))	('people', 'Species', '9606', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('p53', 'Gene', (92, 95))	('mutations', 'Var', (96, 105))	('cancer', 'Disease', (114, 120))
76145	32516327	This finding suggested that mutated p53 allelic expression should be added to the risk forecasting of cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutated', 'Var', (28, 35))	('p53', 'Gene', (36, 39))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
76146	32516327	Our data demonstrate that the mutation of p53 p.Asn268Glufs*4 maintains partial p53 function, which decreases the efficiency of somatic reprogramming by inhibiting OCT4 expression during the reprogramming stage and exhibites random p53 allelic expression in heterozygous p53 mutant cells.	('p53', 'Gene', (42, 45))	('p53', 'Protein', (80, 83))	('p.Asn268Glufs*4', 'Var', (46, 61))	('mutation', 'Var', (30, 38))	('exhibites', 'Reg', (215, 224))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (46, 61))	('decreases', 'NegReg', (100, 109))	('OCT4 expression', 'MPA', (164, 179))	('reprogramming', 'CPA', (191, 204))	('somatic reprogramming', 'CPA', (128, 149))	('p53', 'Gene', (271, 274))	('inhibiting', 'NegReg', (153, 163))	('function', 'MPA', (84, 92))
76147	32516327	Random allelic expression of p53 in heterozygous mutation scenarios may be a reason why the people who carry p53 mutations develop cancer at random.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (113, 122))	('p53', 'Gene', (109, 112))	('people', 'Species', '9606', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
76148	32516327	Our finding also suggests that the mutant p53 allelic expression may be a risk forecasting of cancers.	('p53', 'Gene', (42, 45))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('mutant', 'Var', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
76150	32516327	6 Mar 2020  PONE-D-20-04840 The function of a heterozygous p53 mutation (p.Asn268Glufs*4) in a Li-Fraumeni syndrome (LFS) patient PLOS ONE Dear Dr Li, Thank you for submitting your manuscript to PLOS ONE.	('p53', 'Gene', (59, 62))	('ipt', 'Gene', '54802', (188, 191))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (73, 88))	('ipt', 'Gene', (188, 191))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (95, 115))	('patient', 'Species', '9606', (122, 129))	('PONE-D-20-04840', 'Chemical', '-', (12, 27))	('LFS', 'Disease', (117, 120))	('Li-Fraumeni syndrome', 'Disease', (95, 115))	('LFS', 'Disease', 'MESH:D016864', (117, 120))	('p.Asn268Glufs*4', 'Var', (73, 88))
76167	32516327	(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: In this manuscript the authors have described a heterozygous p53 mutation in a LFS patient.	('LFS', 'Disease', 'MESH:D016864', (169, 172))	('LFS', 'Disease', (169, 172))	('mutation', 'Var', (155, 163))	('patient', 'Species', '9606', (173, 180))	('ipt', 'Gene', (105, 108))	('p53', 'Gene', (151, 154))	('ipt', 'Gene', '54802', (105, 108))
76168	32516327	The authors claim that p.Asn268Glufs*4 mutation promotes tumorigenecity and inhibit the efficiency of somatic reprogramming by inhibiting OCT4 expression.	('OCT4', 'Protein', (138, 142))	('somatic reprogramming', 'CPA', (102, 123))	('inhibit', 'NegReg', (76, 83))	('p.Asn268Glufs*4', 'Var', (23, 38))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('inhibiting', 'NegReg', (127, 137))	('promotes', 'PosReg', (48, 56))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (23, 38))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
76173	32516327	What did the authors mean by "Asn268Glufs*4 mutation was located in specific DNA binding domain to stop this specific protein synthesis".	('specific protein synthesis', 'MPA', (109, 135))	('Asn268Glufs*4', 'Var', (30, 43))	('Asn268Glufs', 'Chemical', '-', (30, 41))	('stop', 'NegReg', (99, 103))
76176	32516327	The result "TP53 p.Asn268Glufs*4 mutation promotes the tumorigenesis" cannot be concluded using just apoptosis and DNA damage experiments.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('is a', 'Gene', '312', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('P53', 'Gene', (13, 16))	('P53', 'Gene', '7157', (13, 16))	('tumor', 'Disease', (55, 60))	('promotes', 'PosReg', (42, 50))	('p.Asn268Glufs*4', 'Var', (17, 32))	('is a', 'Gene', (108, 112))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (17, 32))
76177	32516327	How are the authors concluding that mutant p53 protein is present in the patient's MNC?	('protein', 'Protein', (47, 54))	('patient', 'Species', '9606', (73, 80))	('mutant', 'Var', (36, 42))	('p53', 'Gene', (43, 46))
76181	32516327	Reviewer #2: The manuscript titled "The function of a heterozygous p53 mutation (p.Asn268Glufs*4) in a Li-Fraumeni syndrome (LFS) patient" by Li, et al.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (103, 123))	('patient', 'Species', '9606', (130, 137))	('LFS', 'Disease', 'MESH:D016864', (125, 128))	('ipt', 'Gene', '54802', (24, 27))	('p.Asn268Glufs*4', 'Var', (81, 96))	('ipt', 'Gene', (24, 27))	('p53', 'Gene', (67, 70))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (81, 96))	('Li-Fraumeni syndrome', 'Disease', (103, 123))	('LFS', 'Disease', (125, 128))
76182	32516327	presents a follow-up analysis of a TP53 mutation they found in a Li Fraumeni Syndrome patient.	('mutation', 'Var', (40, 48))	('P53', 'Gene', '7157', (36, 39))	('Li Fraumeni Syndrome', 'Disease', (65, 85))	('Li Fraumeni Syndrome', 'Disease', 'MESH:D016864', (65, 85))	('patient', 'Species', '9606', (86, 93))	('P53', 'Gene', (36, 39))
76186	32516327	The entirety of Figure 2 uses the 293T cell line, which has endogenous wildtype p53, to show the consequence of overexpressing the Asn268Glufs*4 mutant as well as wildtype p53 on wildtype p53 target proteins, apoptosis, cell proliferation, and DNA damage.	('Asn268Glufs*4', 'Var', (131, 144))	('Asn268Glufs', 'Chemical', '-', (131, 142))	('293T', 'CellLine', 'CVCL:0063', (34, 38))	('apoptosis', 'CPA', (209, 218))	('cell proliferation', 'CPA', (220, 238))	('overexpressing', 'PosReg', (112, 126))
76188	32516327	Figure 2C-the authors state that "this TP53 mutation can promote tumor cell proliferation".	('P53', 'Gene', (40, 43))	('mutation', 'Var', (44, 52))	('tumor', 'Disease', (65, 70))	('promote', 'PosReg', (57, 64))	('P53', 'Gene', '7157', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
76194	32516327	If the MEFs contain wildtype p53, then the same problem exists as in the 293T system for Figure 2.	('p53', 'Var', (29, 32))	('293T', 'CellLine', 'CVCL:0063', (73, 77))	('wildtype p53', 'Var', (20, 32))	('MEFs', 'CellLine', 'CVCL:9115', (7, 11))
76198	32516327	Another point-since the authors state that the mutation being studied here may have lost its function, it would be helpful to show a known functional mutant found in LFS patients as a positive control.	('patients', 'Species', '9606', (170, 178))	('LFS', 'Disease', 'MESH:D016864', (166, 169))	('mutation', 'Var', (47, 55))	('function', 'MPA', (93, 101))	('LFS', 'Disease', (166, 169))
76205	32516327	Unlike p53 R175H, p53 p.Asn268Glufs*4 mutant as well as its WT dramatically inhibited cell proliferation (Fig.	('R175H', 'Mutation', 'rs28934578', (11, 16))	('p.Asn268Glufs*4', 'Var', (22, 37))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (22, 37))	('cell proliferation', 'CPA', (86, 104))	('inhibited', 'NegReg', (76, 85))
76206	32516327	We have corrected as: "p.Asn268Glufs*4 mutation of p53 loses some functions of wild type p53" Q10.	('p53', 'Gene', (51, 54))	('functions', 'MPA', (66, 75))	('Q10', 'Chemical', 'MESH:C024989', (94, 97))	('p.Asn268Glufs*4', 'Var', (23, 38))	('loses', 'NegReg', (55, 60))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (23, 38))
76208	32516327	We have corrected as: "p.Asn268Glufs*4 mutation of p53 loses some functions of wild type p53" Q8.	('p53', 'Gene', (51, 54))	('functions', 'MPA', (66, 75))	('p.Asn268Glufs*4', 'Var', (23, 38))	('loses', 'NegReg', (55, 60))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (23, 38))
76210	32516327	We have repeated this and showed p53 WT and mutant bands in the same film in new Fig.3a.	('is a', 'Gene', '312', (19, 23))	('is a', 'Gene', (19, 23))	('mutant bands', 'Var', (44, 56))	('p53', 'Var', (33, 36))
76215	32516327	So we modified to: "the iPSCs with the p53 p.Asn268Glufs*4 mutation as normal iPSCs could differentiate into three primary germ layers and form teratomas in immunodeficient mice (Fig.	('teratomas', 'Phenotype', 'HP:0009792', (144, 153))	('iPS', 'Disease', (78, 81))	('teratomas in immunodeficient', 'Disease', 'MESH:D013724', (144, 172))	('iPS', 'Disease', 'OMIM:613661', (78, 81))	('p.Asn268Glufs*4', 'Var', (43, 58))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (43, 58))	('iPS', 'Disease', (24, 27))	('p53', 'Gene', (39, 42))	('teratomas in immunodeficient', 'Disease', (144, 172))	('iPS', 'Disease', 'OMIM:613661', (24, 27))	('form', 'Reg', (139, 143))	('mice', 'Species', '10090', (173, 177))
76216	32516327	All of these data indicate that iPSCs with the p53 p.Asn268Glufs*4 mutation can maintain pluripotency" Q14.	('p.Asn268Glufs*4', 'Var', (51, 66))	('iPS', 'Disease', 'OMIM:613661', (32, 35))	('p.Asn268Glufs*4', 'FRAMESHIFT', 'None', (51, 66))	('iPS', 'Disease', (32, 35))	('p53', 'Gene', (47, 50))	('pluripotency" Q14', 'MPA', (89, 106))	('maintain', 'PosReg', (80, 88))
76219	32516327	22 May 2020  The function of a heterozygous p53 mutation in a Li-Fraumeni syndrome patient PONE-D-20-04840R1 Dear Dr. Li, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.	('ipt', 'Gene', '54802', (168, 171))	('ipt', 'Gene', (168, 171))	('function', 'MPA', (17, 25))	('Li-Fraumeni syndrome', 'Disease', (62, 82))	('p53', 'Gene', (44, 47))	('mutation', 'Var', (48, 56))	('PONE-D-20-04840', 'Chemical', '-', (91, 106))	('patient', 'Species', '9606', (83, 90))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (62, 82))
76224	32516327	27 May 2020  PONE-D-20-04840R1  The function of a heterozygous p53 mutation in a Li-Fraumeni syndrome patient  Dear Dr. Li: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE.	('ipt', 'Gene', '54802', (168, 171))	('ipt', 'Gene', (168, 171))	('p53', 'Gene', (63, 66))	('mutation', 'Var', (67, 75))	('patient', 'Species', '9606', (102, 109))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (81, 101))	('PONE-D-20-04840', 'Chemical', '-', (13, 28))	('Li-Fraumeni syndrome', 'Disease', (81, 101))
76226	30890735	Burden of unique and low prevalence somatic mutations correlates with cancer survival Tumor mutational burden correlates with improved survival and immunotherapy response in some malignancies, and with tumor aggressiveness in others.	('improved', 'PosReg', (126, 134))	('tumor aggressiveness', 'Disease', (202, 222))	('aggressiveness', 'Phenotype', 'HP:0000718', (208, 222))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('malignancies', 'Disease', (179, 191))	('Tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (202, 222))	('mutations', 'Var', (44, 53))	('survival', 'CPA', (135, 143))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
76229	30890735	High TEMMB was associated with improved survival in cutaneous melanoma: hazard ratio (HR) = 0.71 [0.60-0.85], p = 0.0002, urothelial bladder carcinoma: HR = 0.74 [0.59-0.93], p = 0.01, and ovarian carcinoma: HR = 0.80 [0.70-0.93], p = 0.003.	('improved', 'PosReg', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('TEMMB', 'Chemical', '-', (5, 10))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (122, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('urothelial bladder carcinoma', 'Disease', (122, 150))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (189, 206))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (133, 150))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (189, 206))	('High TEMMB', 'Var', (0, 10))	('ovarian carcinoma', 'Disease', (189, 206))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
76230	30890735	High TEMMB was associated with decreased survival in colorectal adenocarcinoma: HR = 1.32 [1.00-1.74], p < 0.05.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (53, 78))	('TEMMB', 'Chemical', '-', (5, 10))	('decreased', 'NegReg', (31, 40))	('colorectal adenocarcinoma', 'Disease', (53, 78))	('High TEMMB', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
76232	30890735	In cancers with a low RS, high TEMMB was correlated with better survival outcomes (r = 0.49, p = 0.02).	('high TEMMB', 'Var', (26, 36))	('survival outcomes', 'CPA', (64, 81))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('better', 'PosReg', (57, 63))	('TEMMB', 'Chemical', '-', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
76233	30890735	In conclusion, TEMMB effects on survival depend on recurrent mutation enrichment; tumor types that are highly enriched in passenger mutations show a survival benefit in the setting of high tumor mutational burden.	('tumor', 'Disease', (189, 194))	('TEMMB', 'Chemical', '-', (15, 20))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('survival', 'CPA', (149, 157))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('benefit', 'PosReg', (158, 165))
76236	30890735	Alternatively, highly mutated tumors may develop many novel peptides and thus display more neoantigens, rendering them more susceptible T-cell targets.	('tumors', 'Disease', (30, 36))	('peptides', 'MPA', (60, 68))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('develop', 'PosReg', (41, 48))	('neoantigens', 'MPA', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('more', 'PosReg', (86, 90))	('highly mutated', 'Var', (15, 29))
76237	30890735	For example, patients with melanomas with a high mutational load showed improved survival with ipilimumab and improved overall survival; patients with highly mutated ovarian cancer had improved postoperative chemotherapy response and higher overall survival.	('melanomas', 'Disease', 'MESH:D008545', (27, 36))	('improved', 'PosReg', (185, 193))	('overall', 'MPA', (241, 248))	('improved', 'PosReg', (110, 118))	('highly mutated', 'Var', (151, 165))	('improved', 'PosReg', (72, 80))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (137, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (166, 180))	('melanomas', 'Disease', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('ipilimumab', 'Chemical', 'MESH:D000074324', (95, 105))	('higher', 'PosReg', (234, 240))	('ovarian cancer', 'Disease', 'MESH:D010051', (166, 180))	('overall', 'MPA', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('ovarian cancer', 'Disease', (166, 180))
76242	30890735	Furthermore, missense variants specifically have been suggested to be the most frequent class of alterations to carry the potential for neoepitope generation in chronic lymphocytic leukemia malignancy (as compared to frameshift or splice-site variants).	('neoepitope generation', 'MPA', (136, 157))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (161, 189))	('leukemia', 'Phenotype', 'HP:0001909', (181, 189))	('chronic lymphocytic leukemia malignancy', 'Disease', (161, 200))	('chronic lymphocytic leukemia malignancy', 'Disease', 'MESH:D015451', (161, 200))	('missense variants', 'Var', (13, 30))	('lymphocytic leukemia malignancy', 'Phenotype', 'HP:0005526', (169, 200))
76243	30890735	In multiple myeloma, missense mutational load was found to be highly correlated with predicted neoantigen loads.	('multiple myeloma', 'Disease', (3, 19))	('correlated', 'Reg', (69, 79))	('neoantigen loads', 'MPA', (95, 111))	('missense mutational load', 'Var', (21, 45))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
76244	30890735	Total missense mutational burden across all cohorts ranged from a low of 8 (median) missense mutations among acute myeloid leukemia (LAML) and thymoma (THYM), to 256 median mutations among the skin cutaneous melanoma (SKCM) cohort (Fig.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (109, 131))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('thymoma', 'Disease', 'MESH:D013945', (143, 150))	('THYM', 'Phenotype', 'HP:0100522', (152, 156))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('thymoma', 'Disease', (143, 150))	('acute myeloid leukemia', 'Disease', (109, 131))	('mutations', 'Var', (173, 182))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (193, 216))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (115, 131))	('thymoma', 'Phenotype', 'HP:0100522', (143, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (109, 131))	('skin cutaneous melanoma', 'Disease', (193, 216))	('missense mutations', 'Var', (84, 102))
76246	30890735	Total (TEMB) and missense (TEMMB) tumor exonic mutational burden were found to be closely correlated among all cohorts: Pearson's r ranged from 0.95-1.00 for all cohorts other than uveal melanoma (UVM) which also revealed a strong positive correlation with r = 0.88 likely due to a small (N = 79) sample size (p < 2.2 x 10-16 for all cohorts) (Fig.	('missense', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('UVM', 'Phenotype', 'HP:0007716', (197, 200))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('TEMMB', 'Chemical', '-', (27, 32))	('uveal melanoma', 'Disease', (181, 195))
76248	30890735	Male sex was significantly associated with high TEMMB in renal papillary cell carcinoma (KIRP), sarcoma (SARC), and cutaneous melanoma (SKCM).	('high TEMMB', 'Var', (43, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('SARC', 'Phenotype', 'HP:0100242', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('associated', 'Reg', (27, 37))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (57, 87))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('cutaneous melanoma', 'Disease', (116, 134))	('TEMMB', 'Chemical', '-', (48, 53))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (116, 134))	('renal papillary cell carcinoma', 'Disease', (57, 87))	('sarcoma', 'Disease', (96, 103))
76249	30890735	Female sex was significantly associated with high TEMMB in colorectal adenocarcinoma (COAD) and glioblastoma multiforme (GBM).	('COAD', 'Disease', 'MESH:D029424', (86, 90))	('colorectal adenocarcinoma', 'Disease', (59, 84))	('TEMMB', 'Chemical', '-', (50, 55))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (59, 84))	('COAD', 'Disease', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('glioblastoma multiforme', 'Disease', (96, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('high TEMMB', 'Var', (45, 55))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (96, 119))
76252	30890735	High TEMMB correlated with improved survival in skin cutaneous melanoma (SKCM): HR = 0.71 [0.60-0.85], p = 0.0002, bladder urothelial carcinoma (BLCA): HR = 0.74 [0.59-0.93], p = 0.01, and ovarian carcinoma (OV): HR = 0.80 [0.70-0.93], p = 0.003.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 71))	('improved', 'PosReg', (27, 35))	('OV', 'Phenotype', 'HP:0025318', (208, 210))	('TEMMB', 'Chemical', '-', (5, 10))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (115, 143))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('survival', 'MPA', (36, 44))	('skin cutaneous melanoma', 'Disease', (48, 71))	('bladder urothelial carcinoma', 'Disease', (115, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (189, 206))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (53, 71))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (189, 206))	('High TEMMB', 'Var', (0, 10))	('ovarian carcinoma', 'Disease', (189, 206))
76253	30890735	High TEMMB was associated with decreased survival in colorectal adenocarcinoma (COAD): HR = 1.32 [1.00-1.74], p < 0.05 (p = 0.0497).	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (53, 78))	('TEMMB', 'Chemical', '-', (5, 10))	('decreased', 'NegReg', (31, 40))	('COAD', 'Disease', (80, 84))	('colorectal adenocarcinoma', 'Disease', (53, 78))	('High TEMMB', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('COAD', 'Disease', 'MESH:D029424', (80, 84))
76255	30890735	To characterize the somatic mutational profile of each cancer, we determined the relative burden of recurrent mutations to total mutations within each cohort, expressed as a recurrence score (RS).	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (110, 119))	('cancer', 'Disease', (55, 61))
76257	30890735	Several cohorts, notably adrenocortical carcinoma (ACC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), thyroid carcinoma (THCA), thymoma (THYM), and uveal melanoma (UVM), revealed mutations occurring at high prevalence among the sequenced population.	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('UVM', 'Phenotype', 'HP:0007716', (225, 228))	('glioma', 'Disease', (148, 154))	('THCA', 'Phenotype', 'HP:0002890', (182, 186))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (63, 79))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (57, 79))	('uveal melanoma', 'Disease', 'MESH:C536494', (209, 223))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (57, 79))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (163, 180))	('uveal melanoma', 'Disease', (209, 223))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (25, 49))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('mutations', 'Var', (240, 249))	('thyroid carcinoma', 'Disease', (163, 180))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (120, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('glioma', 'Disease', (106, 112))	('paraganglioma', 'Phenotype', 'HP:0002668', (141, 154))	('uveal melanoma', 'Phenotype', 'HP:0007716', (209, 223))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (25, 49))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (163, 180))	('thymoma', 'Disease', 'MESH:D013945', (189, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('adrenocortical carcinoma', 'Disease', (25, 49))	('THYM', 'Phenotype', 'HP:0100522', (198, 202))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('acute myeloid leukemia', 'Disease', (57, 79))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (120, 136))	('thymoma', 'Disease', (189, 196))	('ACC', 'Phenotype', 'HP:0006744', (51, 54))	('thymoma', 'Phenotype', 'HP:0100522', (189, 196))
76258	30890735	The recurrent mutations can be readily visualized as sharp peaks in the cancers' mutational profiles.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('mutations', 'Var', (14, 23))
76261	30890735	In the adrenocortical carcinoma (ACC) cohort, 0.29% of all pooled missense mutations were in the ZNF517 gene (p.V349A), and 0.29% of missense mutations were recurrent GARS (p.P42A) mutations.	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (7, 31))	('ZNF517', 'Gene', '340385', (97, 103))	('ZNF517', 'Gene', (97, 103))	('missense mutations', 'Var', (133, 151))	('ACC', 'Phenotype', 'HP:0006744', (33, 36))	('missense mutations', 'Var', (66, 84))	('p.V349A', 'Mutation', 'rs2976653', (110, 117))	('p.P42A', 'Mutation', 'rs1049402', (173, 179))	('adrenocortical carcinoma', 'Disease', (7, 31))	('GARS', 'Gene', '2617', (167, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('GARS', 'Gene', (167, 171))	('p.P42A', 'Var', (173, 179))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (7, 31))
76262	30890735	In uveal melanoma (UVM) cohort, 2.54% were recurrent GNA11 (p.Q209P) mutations, 2.01% were recurrent GNAQ p.Q209P, and 0.75% GNAQ p.Q1209L.	('p.Q1209L', 'Var', (130, 138))	('uveal melanoma', 'Disease', (3, 17))	('GNA11', 'Gene', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('GNA11', 'Gene', '2767', (53, 58))	('p.Q209P', 'Mutation', 'rs1057519742', (106, 113))	('p.Q209P', 'Mutation', 'rs1057519742', (60, 67))	('UVM', 'Phenotype', 'HP:0007716', (19, 22))	('p.Q1209L', 'Mutation', 'p.Q1209L', (130, 138))	('p.Q209P', 'Var', (106, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))
76263	30890735	In thyroid carcinoma (THCA), 5.23% were BRAF p.V600E, 0.65% were NRAS p.Q61R, and 0.25% HRAS p.Q61R.	('p.Q61R', 'Mutation', 'rs755829919', (70, 76))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (3, 20))	('thyroid carcinoma', 'Disease', (3, 20))	('THCA', 'Phenotype', 'HP:0002890', (22, 26))	('p.Q61R', 'Mutation', 'rs755829919', (93, 99))	('p.V600E', 'Mutation', 'p.V600E', (45, 52))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (3, 20))	('p.V600E', 'Var', (45, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
76264	30890735	In the acute myeloid leukemia (LAML) cohort, 1.38% of missense mutations were in DNMT3A gene (p.R882H), 1.05% were IDH2 p.R140Q, and 0.79% were IDH1 p.R132C.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (7, 29))	('p.R882H', 'Mutation', 'rs147001633', (94, 101))	('leukemia', 'Phenotype', 'HP:0001909', (21, 29))	('missense mutations', 'Var', (54, 72))	('DNMT3A', 'Gene', (81, 87))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (7, 29))	('DNMT3A', 'Gene', '1788', (81, 87))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (13, 29))	('p.R140Q', 'Var', (120, 127))	('p.R132C', 'Mutation', 'rs121913499', (149, 156))	('p.R140Q', 'Mutation', 'rs121913502', (120, 127))	('acute myeloid leukemia', 'Disease', (7, 29))
76265	30890735	In pheochromocytoma and paraganglioma (PCPG), 0.64% of mutations were recurrent HRAS p.Q61R, and 0.36% were CHEK2 p.K152E.	('p.Q61R', 'Var', (85, 91))	('mutations', 'Var', (55, 64))	('paraganglioma', 'Phenotype', 'HP:0002668', (24, 37))	('CHEK2', 'Gene', '11200', (108, 113))	('p.K152E', 'Mutation', 'rs74751600', (114, 121))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('p.Q61R', 'Mutation', 'rs755829919', (85, 91))	('CHEK2', 'Gene', (108, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (3, 19))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (3, 37))
76267	30890735	Cancers with low RS tended to exhibit survival benefit (HR < 1) with increased adjusted-TEMMB.	('adjusted-TEMMB', 'Var', (79, 93))	('increased', 'PosReg', (69, 78))	('TEMMB', 'Chemical', '-', (88, 93))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('survival benefit', 'CPA', (38, 54))
76268	30890735	Conversely, cancers with high RS were observed to have a decrease in survival (HR > 1) with increased adjusted-TEMMB.	('decrease', 'NegReg', (57, 65))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('high RS', 'Var', (25, 32))	('cancers', 'Disease', (12, 19))	('increased', 'PosReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('adjusted-TEMMB', 'Var', (102, 116))	('TEMMB', 'Chemical', '-', (111, 116))	('survival', 'MPA', (69, 77))
76269	30890735	Exonic missense mutation distribution displays considerable variability among cancers studied in TCGA.	('Exonic missense mutation', 'Var', (0, 24))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
76271	30890735	Somatic missense mutations strongly contribute to the generation of novel tumor epitopes.	('tumor epitopes', 'Disease', (74, 88))	('tumor epitopes', 'Disease', 'MESH:D009369', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('missense mutations', 'Var', (8, 26))
76276	30890735	Interestingly, low tumor stage was correlated (after Bonferroni adjustment) with high TEMMB in breast carcinoma, colon and rectal adenocarcinoma, and uveal melanoma.	('breast carcinoma', 'Disease', 'MESH:D001943', (95, 111))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('high TEMMB', 'Var', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('low tumor', 'Disease', 'MESH:D009800', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('low tumor', 'Disease', (15, 24))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (150, 164))	('uveal melanoma', 'Disease', (150, 164))	('uveal melanoma', 'Disease', 'MESH:C536494', (150, 164))	('colon and rectal adenocarcinoma', 'Disease', 'MESH:D012004', (113, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('TEMMB', 'Chemical', '-', (86, 91))	('breast carcinoma', 'Disease', (95, 111))
76283	30890735	Given the high propensity for rapid metastasis in uveal melanoma, it is possible that intercepting such tumors at an early stage may partially be explained by a higher mutational load and thus more favorable immune response.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutational load', 'Var', (168, 183))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('uveal melanoma', 'Disease', (50, 64))	('higher', 'PosReg', (161, 167))
76284	30890735	Driver mutations impart tumor growth advantage and are positively selected in cancer evolution, while biologically inert passengers accumulate without directional selection over the tumor growth timespan.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('mutations', 'Var', (7, 16))
76285	30890735	Many established bioinformatics methods to study drivers rely on techniques that identify recurrent mutations, and thus we quantified recurrent and non-recurrent mutations to serve as proxy for relative amounts of drivers and passengers within a cancer type.	('cancer', 'Disease', (246, 252))	('mutations', 'Var', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))
76286	30890735	Our results suggest high TEMMB tends to confer survival benefit in cancers with more non-recurrent (likely passenger) mutations, and decreased survival in cancers with high recurrent (likely driver) fractions.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (118, 127))	('benefit', 'PosReg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('survival', 'MPA', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('TEMMB', 'Chemical', '-', (25, 30))	('cancers', 'Disease', (155, 162))	('decreased', 'NegReg', (133, 142))
76287	30890735	We propose that in malignancies with large enrichments of non-recurrent mutations, high TEMMB marks a high passenger count, and increasing passenger mutation load increases neoantigen presentation without imparting additional growth advantage or aggressiveness.	('aggressiveness', 'Disease', (246, 260))	('malignancies', 'Disease', (19, 31))	('TEMMB', 'Chemical', '-', (88, 93))	('passenger mutation load', 'Var', (139, 162))	('aggressiveness', 'Phenotype', 'HP:0000718', (246, 260))	('increases', 'PosReg', (163, 172))	('aggressiveness', 'Disease', 'MESH:D001523', (246, 260))	('increasing', 'PosReg', (128, 138))	('malignancies', 'Disease', 'MESH:D009369', (19, 31))	('neoantigen presentation', 'MPA', (173, 196))
76288	30890735	Our observed benefit with high TEMMB supports literature findings for melanoma and ovarian carcinoma.	('melanoma', 'Disease', (70, 78))	('ovarian carcinoma', 'Disease', (83, 100))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('high TEMMB', 'Var', (26, 36))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (83, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (83, 100))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('TEMMB', 'Chemical', '-', (31, 36))	('benefit', 'PosReg', (13, 20))
76291	30890735	Recent work has suggested a "double-edged" effect of increased DNA variants, noting that on the one hand, high DNA variation increases accumulation of drivers which are beneficial to tumor adaptation; conversely, high concurrent passenger loads may outweigh the driver effects.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('high', 'Var', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('accumulation', 'MPA', (135, 147))
76304	30890735	Cancers with higher proportions of non-recurrent and thus likely passenger mutations showed survival benefit with high TEMMB, while cancers with higher recurrent mutation fractions (likely drivers) revealed a decrease in survival.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('decrease', 'NegReg', (209, 217))	('TEMMB', 'Chemical', '-', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('benefit', 'PosReg', (101, 108))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('survival', 'MPA', (92, 100))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('high TEMMB', 'Var', (114, 124))
76305	30890735	Mutational signatures for some cancers might contribute significantly to overall TEMMB (e.g.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('TEMMB', 'Disease', (81, 86))	('TEMMB', 'Chemical', '-', (81, 86))	('cancers', 'Disease', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('Mutational signatures', 'Var', (0, 21))	('contribute', 'Reg', (45, 55))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
76324	30890735	We aggregated all nonsynonymous missense mutations among all individuals in each cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('nonsynonymous missense mutations', 'Var', (18, 50))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
76325	30890735	A somatic recurrence score (RS) was calculated as the fraction of total mutations in the cohort's pool comprised by recurrent mutations as defined above: A RS was assigned to each cancer type, and the correlation between log10-adjusted survival HR and log10-adjusted RS was computed with Pearson's correlation.	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (180, 186))	('mutations', 'Var', (126, 135))
76367	30356827	In the second part of this work, we performed two exploratory genome-wide analyses: mRNA expression profiling and a Genome-Wide Association Study (GWAS) of Single Nucleotide Polymorphisms (SNPs) of ST with elevated serum ALP activity in an attempt to better understand its pathogenesis.	('ALP', 'Gene', (221, 224))	('elevated serum ALP', 'Phenotype', 'HP:0003155', (206, 224))	('elevated', 'PosReg', (206, 214))	('Single Nucleotide Polymorphisms', 'Var', (156, 187))	('ALP', 'Gene', '403548', (221, 224))
76368	30356827	The goal of a GWAS is to identify genes that affect the risk of developing a disorder (in this case increased ALP and HAC).	('increased', 'PosReg', (100, 109))	('increased ALP', 'Phenotype', 'HP:0003155', (100, 113))	('genes', 'Var', (34, 39))	('ALP', 'Gene', '403548', (110, 113))	('ALP', 'Gene', (110, 113))
76419	30356827	The mean/median serum cortisol concentration 8 h after administration of dexamethasone was higher in the HAC group as compared to the ST and control dogs (HAC 58/43 ng/mL, ST 5.4/5.2 ng/mL, Normal 5.7/3.5 ng/mL, reference interval < 10 ng/mL).	('HAC', 'Var', (105, 108))	('cortisol', 'Chemical', 'MESH:D006854', (22, 30))	('higher', 'PosReg', (91, 97))	('serum cortisol concentration', 'MPA', (16, 44))	('serum cortisol concentration', 'Phenotype', 'HP:0003118', (16, 44))	('dexamethasone', 'Chemical', 'MESH:D003907', (73, 86))	('dogs', 'Species', '9615', (149, 153))
76423	30356827	Post-ACTH concentrations of one or more of the sex steroids was elevated in all ST and HAC dogs, while they were elevated in only 2 of the 7 Normal dogs.	('Post-ACTH', 'MPA', (0, 9))	('concentrations', 'MPA', (10, 24))	('dogs', 'Species', '9615', (91, 95))	('elevated', 'PosReg', (64, 72))	('steroids', 'Chemical', 'MESH:D013256', (51, 59))	('dogs', 'Species', '9615', (148, 152))	('HAC', 'Var', (87, 90))
76424	30356827	Urine cortisol/creatinine ratio was higher in the ST and HAC groups than in the Normal group, but there was no difference between the ST and HAC groups.	('Urine cortisol/creatinine ratio', 'MPA', (0, 31))	('higher', 'PosReg', (36, 42))	('HAC', 'Var', (57, 60))	('cortisol', 'Chemical', 'MESH:D006854', (6, 14))	('creatinine', 'Chemical', 'MESH:D003404', (15, 25))	('Urine cortisol', 'Phenotype', 'HP:0012030', (0, 14))
76426	30356827	Basal and 8 h post-dexamethasone serum concentrations of cortisol, progesterone, 17-OH progesterone, and androstenedione were higher in the HAC group compared with the ST and Normal groups, but no difference was found between the ST and Normal groups.	('dexamethasone', 'Chemical', 'MESH:D003907', (19, 32))	('cortisol', 'Chemical', 'MESH:D006854', (57, 65))	('progesterone', 'Chemical', 'MESH:D011374', (87, 99))	('HAC', 'Var', (140, 143))	('higher', 'PosReg', (126, 132))	('androstenedione', 'Chemical', 'MESH:D000735', (105, 120))	('17-OH progesterone', 'MPA', (81, 99))	('progesterone', 'Chemical', 'MESH:D011374', (67, 79))	('serum concentrations', 'MPA', (33, 53))	('17-OH progesterone', 'Chemical', 'MESH:D019326', (81, 99))
76458	30356827	Until that time, it does not appear that a corticotroph abnormality is responsible for the excess steroid hormone secretion in the ST. Because of the apparent normal pituitary-adrenal axis in ST, it is possible that the pathogenesis of excess adrenocortical hormone secretion could be the result of aberrant receptors on adrenocortical cells.	('adrenocortical', 'Disease', 'MESH:D018268', (321, 335))	('steroid hormone', 'Chemical', 'MESH:D013256', (98, 113))	('adrenocortical', 'Disease', 'MESH:D018268', (243, 257))	('aberrant', 'Var', (299, 307))	('pituitary-adrenal axis', 'Disease', (166, 188))	('excess adrenocortical hormone secretion', 'Disease', 'MESH:C531600', (236, 275))	('pituitary-adrenal axis', 'Disease', 'MESH:C566610', (166, 188))	('adrenocortical', 'Disease', (321, 335))	('excess adrenocortical hormone secretion', 'Disease', (236, 275))	('adrenocortical', 'Disease', (243, 257))
76484	30356827	We speculate that this polymorphism could be linked with HSD17B2 gene silencing by some undetermined mechanism, e.g., microRNA, small interfering RNA, or long non-coding RNA.	('HSD17B2', 'Gene', (57, 64))	('long non-coding RNA', 'Var', (154, 173))	('HSD17B2', 'Gene', '489690', (57, 64))	('small interfering', 'Var', (128, 145))
76485	30356827	Since none of these genomic possibilities were directly assessed in this study, the nature of the potential association between the SNP polymorphism on chromosome 5 and increased ALP activity remains untested.	('polymorphism', 'Var', (136, 148))	('increased', 'PosReg', (169, 178))	('SNP', 'Gene', (132, 135))	('ALP', 'Gene', '403548', (179, 182))	('increased ALP', 'Phenotype', 'HP:0003155', (169, 182))	('ALP', 'Gene', (179, 182))
76486	30356827	However, if silencing or suppression of HSD17B2 gene is occurring in these ST, prolonged intracellular concentrations of sex steroids could be a contributing factor for hepatic glycogen accumulation and ALP changes as reported in this breed.	('suppression', 'NegReg', (25, 36))	('hepatic glycogen accumulation', 'Phenotype', 'HP:0006568', (169, 198))	('hepatic glycogen accumulation', 'MPA', (169, 198))	('HSD17B2', 'Gene', (40, 47))	('silencing', 'Var', (12, 21))	('intracellular concentrations of', 'MPA', (89, 120))	('steroids', 'Chemical', 'MESH:D013256', (125, 133))	('glycogen', 'Chemical', 'MESH:D006003', (177, 185))	('ALP', 'Gene', '403548', (203, 206))	('ALP', 'Gene', (203, 206))	('HSD17B2', 'Gene', '489690', (40, 47))
76512	28983351	The final pathology report showed adrenocortical carcinoma, reaching surgical margins; vascular invasion; histological changes consistent with minor changes to neoadjuvant therapy; round stent without significant histological alterations; and YpT3NxM1 pathological staging.	('YpT3NxM1', 'Var', (243, 251))	('vascular invasion', 'CPA', (87, 104))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (34, 58))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (34, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('adrenocortical carcinoma', 'Disease', (34, 58))
76520	28983351	The importance of proliferative rate in prognostication was shown in an analysis of 124 patients with ACC, in whom the 5-year disease-specific survival rates for individuals with tumor mitotic rates of <= 5, 6 - 10, 21 - 50, and > 50 per 50 high-power fields were 63%, 50%, 25%, and 0%, respectively.	('patients', 'Species', '9606', (88, 96))	('<= 5', 'Var', (202, 206))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('ACC', 'Phenotype', 'HP:0006744', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
76636	28911133	Treatment of H295R adrenocortical cells with kisspeptin resulted in a significant (60%) decrease in Kiss1R mRNA expression [Fig.	('decrease', 'NegReg', (88, 96))	('Kiss1R', 'Gene', '84634', (100, 106))	('H295R', 'Var', (13, 18))	('Kiss1R', 'Gene', (100, 106))	('adrenocortical', 'Disease', (19, 33))	('adrenocortical', 'Disease', 'MESH:D018268', (19, 33))
76642	28911133	Kisspeptin significantly increased DHEAS secretion from H295R, 8- to 10-wpc and 15- to 20-wpc HFA cells 3.7-fold [P < 0.05; Fig.	('DHEAS', 'Gene', (35, 40))	('increased', 'PosReg', (25, 34))	('DHEAS', 'Gene', '6822', (35, 40))	('Kisspeptin', 'Gene', (0, 10))	('H295R', 'Var', (56, 61))	('HFA', 'Chemical', '-', (94, 97))
76681	28911133	Our ELISA data confirm that kisspeptin can significantly increase DHEAS production from H295R and 8- to 10-wpc and 15- to 20-wpc (10- to 22-weeks' gestation) HFA cells.	('H295R', 'Var', (88, 93))	('DHEAS', 'Gene', '6822', (66, 71))	('HFA', 'Chemical', '-', (158, 161))	('increase', 'PosReg', (57, 65))	('DHEAS', 'Gene', (66, 71))	('kisspeptin', 'Protein', (28, 38))
76701	26515592	Inhibition of the Tcf/beta-catenin complex increases apoptosis and impairs adrenocortical tumor cell proliferation and adrenal steroidogenesis To date, there is no effective therapy for patients with advanced/metastatic adrenocortical cancer (ACC).	('beta-catenin', 'Gene', '1499', (22, 34))	('apoptosis', 'CPA', (53, 62))	('adrenal steroidogenesis', 'MPA', (119, 142))	('metastatic adrenocortical cancer', 'Disease', (209, 241))	('impairs adrenocortical tumor', 'Disease', (67, 95))	('metastatic adrenocortical cancer', 'Disease', 'MESH:D000306', (209, 241))	('impairs adrenocortical tumor', 'Disease', 'MESH:C565972', (67, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Tcf', 'Gene', '3172', (18, 21))	('increases', 'PosReg', (43, 52))	('beta-catenin', 'Gene', (22, 34))	('Inhibition', 'Var', (0, 10))	('Tcf', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('patients', 'Species', '9606', (186, 194))
76702	26515592	Adrenal (NCI-H295 and Y1) and non-adrenal (HeLa) cell lines were treated with PNU-74654 (5-200 muM) for 24-96 h to assess cell viability (MTS-based assay), apoptosis (Annexin V), expression/localization of beta-catenin (qPCR, immunofluorescence, immunocytochemistry and western blot), expression of beta-catenin target genes (qPCR and western blot), and adrenal steroidogenesis (radioimmunoassay, qPCR and western blot).	('PNU-74654', 'Var', (78, 87))	('adrenal steroidogenesis', 'CPA', (354, 377))	('PNU-74654', 'Chemical', '-', (78, 87))	('apoptosis', 'CPA', (156, 165))	('HeLa', 'CellLine', 'CVCL:0030', (43, 47))	('expression', 'MPA', (285, 295))	('muM', 'Gene', '56925', (95, 98))	('steroid', 'Chemical', 'MESH:D013256', (362, 369))	('NCI-H295', 'CellLine', 'CVCL:0456', (9, 17))	('Annexin V', 'Gene', '308', (167, 176))	('Annexin V', 'Gene', (167, 176))	('muM', 'Gene', (95, 98))
76703	26515592	In NCI-H295 cells, PNU-74654 significantly decreased cell proliferation 96 h after treatment, increased early and late apoptosis, decreased nuclear beta-catenin accumulation, impaired CTNNB1/beta-catenin expression and increased beta-catenin target genes 48 h after treatment.	('PNU-74654', 'Var', (19, 28))	('CTNNB1', 'Gene', '1499', (184, 190))	('increased', 'PosReg', (94, 103))	('expression', 'MPA', (204, 214))	('NCI-H295', 'CellLine', 'CVCL:0456', (3, 11))	('PNU-74654', 'Chemical', '-', (19, 28))	('beta-catenin', 'Gene', (229, 241))	('CTNNB1', 'Gene', (184, 190))	('impaired', 'NegReg', (175, 183))	('cell proliferation', 'CPA', (53, 71))	('nuclear beta-catenin accumulation', 'MPA', (140, 173))	('decreased', 'NegReg', (43, 52))	('decreased', 'NegReg', (130, 139))	('increased', 'PosReg', (219, 228))
76705	26515592	In NCI-H295 cells, PNU-74654 decreased cortisol, testosterone and androstenedione secretion 24 and 48 h after treatment.	('PNU-74654', 'Var', (19, 28))	('cortisol', 'Chemical', 'MESH:D006854', (39, 47))	('androstenedione secretion', 'MPA', (66, 91))	('testosterone', 'Chemical', 'MESH:D013739', (49, 61))	('PNU-74654', 'Chemical', '-', (19, 28))	('NCI-H295', 'CellLine', 'CVCL:0456', (3, 11))	('decreased', 'NegReg', (29, 38))	('decreased cortisol', 'Phenotype', 'HP:0008163', (29, 47))	('cortisol', 'MPA', (39, 47))	('androstenedione', 'Chemical', 'MESH:D000735', (66, 81))
76706	26515592	Additionally, in NCI-H295 cells, PNU-74654 decreased SF1 and CYP21A2 mRNA expression as well as the protein levels of STAR and aldosterone synthase 48 h after treatment.	('STAR', 'Gene', (118, 122))	('SF1', 'Gene', '7536', (53, 56))	('PNU-74654', 'Chemical', '-', (33, 42))	('NCI-H295', 'CellLine', 'CVCL:0456', (17, 25))	('PNU-74654', 'Var', (33, 42))	('aldosterone synthase', 'Gene', (127, 147))	('aldosterone synthase', 'Gene', '1585', (127, 147))	('SF1', 'Gene', (53, 56))	('CYP21A2', 'Gene', (61, 68))	('STAR', 'Gene', '6770', (118, 122))	('CYP21A2', 'Gene', '1589', (61, 68))	('decreased', 'NegReg', (43, 52))	('protein levels', 'MPA', (100, 114))
76707	26515592	In Y1 cells, PNU-74654 impaired corticosterone secretion 24 h after treatment but did not decrease cell viability.	('corticosterone', 'Chemical', 'MESH:D003345', (32, 46))	('PNU-74654', 'Var', (13, 22))	('impaired', 'NegReg', (23, 31))	('corticosterone secretion', 'MPA', (32, 56))	('PNU-74654', 'Chemical', '-', (13, 22))	('impaired corticosterone', 'Phenotype', 'HP:0032363', (23, 46))
76709	26515592	The inhibition of this pathway may become a promising adjuvant therapy for patients with ACC.	('ACC', 'Disease', (89, 92))	('patients', 'Species', '9606', (75, 83))	('inhibition', 'Var', (4, 14))
76714	26515592	Several genetic abnormalities have been found in these tumors, the most prominent being IGF2 overexpression and mutations in TP53 and CTNNB1 (the beta-catenin gene) in both adult and pediatric adrenocortical tumors (ACTs).	('IGF2', 'Gene', '3481', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (112, 121))	('TP53', 'Gene', (125, 129))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('overexpression', 'PosReg', (93, 107))	('genetic abnormalities', 'Disease', 'MESH:D030342', (8, 29))	('genetic abnormalities', 'Disease', (8, 29))	('pediatric adrenocortical tumors', 'Disease', 'MESH:C565973', (183, 214))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', (55, 61))	('CTNNB1', 'Gene', '1499', (134, 140))	('TP53', 'Gene', '7157', (125, 129))	('IGF2', 'Gene', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('pediatric adrenocortical tumors', 'Disease', (183, 214))	('CTNNB1', 'Gene', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))
76715	26515592	Transcriptome studies have shown that ACCs are clustered within different sets of poor prognosis for adult ACC patients according to TP53 or CTNNB1 abnormalities.	('ACCs', 'Phenotype', 'HP:0006744', (38, 42))	('abnormalities', 'Var', (148, 161))	('CTNNB1', 'Gene', '1499', (141, 147))	('CTNNB1', 'Gene', (141, 147))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))	('patients', 'Species', '9606', (111, 119))
76716	26515592	Exon 3 CTNNB1 mutations have been found in 15-36% and 6% of adult and pediatric ACTs, respectively.	('CTNNB1', 'Gene', (7, 13))	('mutations', 'Var', (14, 23))	('CTNNB1', 'Gene', '1499', (7, 13))	('found', 'Reg', (34, 39))
76717	26515592	We previously showed that activation of both canonical and non-canonical Wnt signaling pathways are common in ACTs with or without CTNNB1 mutations.	('activation', 'PosReg', (26, 36))	('CTNNB1', 'Gene', '1499', (131, 137))	('CTNNB1', 'Gene', (131, 137))	('mutations', 'Var', (138, 147))
76718	26515592	The hypothesis that the Wnt pathway can be activated through other mechanisms than CTNNB1 mutations has been recently reinforced.	('CTNNB1', 'Gene', (83, 89))	('mutations', 'Var', (90, 99))	('CTNNB1', 'Gene', '1499', (83, 89))	('Wnt pathway', 'Pathway', (24, 35))
76719	26515592	A large-scale high-resolution analysis study showed that variations in ZNRF3, which is a Wnt/beta-catenin pathway inhibitor, were the most common genetic defect found in a large number of ACC samples.	('genetic defect', 'Disease', 'MESH:D030342', (146, 160))	('genetic defect', 'Disease', (146, 160))	('ZNRF3', 'Gene', '84133', (71, 76))	('common', 'Reg', (139, 145))	('ZNRF3', 'Gene', (71, 76))	('found', 'Reg', (161, 166))	('ACC', 'Disease', (188, 191))	('variations', 'Var', (57, 67))
76720	26515592	ACCs presenting ZNRF3 variants showed transcriptional activation of beta-catenin target genes.	('ZNRF3', 'Gene', (16, 21))	('ACCs', 'Phenotype', 'HP:0006744', (0, 4))	('activation', 'PosReg', (54, 64))	('transcriptional', 'MPA', (38, 53))	('variants', 'Var', (22, 30))	('ZNRF3', 'Gene', '84133', (16, 21))
76721	26515592	Thus, activation of the Wnt/beta-catenin pathway triggered by CTNNB1 and ZNRF3 mutations or down regulation of Wnt/beta-catenin inhibitors are important for ACC pathogenesis.	('ZNRF3', 'Gene', (73, 78))	('CTNNB1', 'Gene', '1499', (62, 68))	('CTNNB1', 'Gene', (62, 68))	('Wnt/beta-catenin pathway', 'Pathway', (24, 48))	('down regulation', 'NegReg', (92, 107))	('activation', 'PosReg', (6, 16))	('ZNRF3', 'Gene', '84133', (73, 78))	('mutations', 'Var', (79, 88))
76722	26515592	CTNNB1 mutations found in ACCs are located at residues involved in phosphorylation, which are essential sites for beta-catenin degradation by ubiquitin/proteasome signaling.	('CTNNB1', 'Gene', '1499', (0, 6))	('ACCs', 'Phenotype', 'HP:0006744', (26, 30))	('CTNNB1', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
76723	26515592	Therefore, mutations in these sites lead to beta-catenin accumulation in the nucleus, where it binds with the T cell factor (Tcf) and enhances its transcriptional activity.	('transcriptional activity', 'MPA', (147, 171))	('mutations', 'Var', (11, 20))	('lead to', 'Reg', (36, 43))	('accumulation', 'PosReg', (57, 69))	('T cell factor', 'Gene', (110, 123))	('beta-catenin', 'Protein', (44, 56))	('T cell factor', 'Gene', '3172', (110, 123))	('enhances', 'PosReg', (134, 142))	('Tcf', 'Gene', (125, 128))	('Tcf', 'Gene', '3172', (125, 128))	('binds', 'Interaction', (95, 100))
76725	26515592	Remarkably, this cell line harbors the CTNNB1 p.S45P mutation, thus representing a good in vitro model of ACC showing Wnt/beta-catenin pathway activation.	('p.S45P', 'Var', (46, 52))	('CTNNB1', 'Gene', (39, 45))	('CTNNB1', 'Gene', '1499', (39, 45))	('p.S45P', 'Mutation', 'rs121913407', (46, 52))
76727	26515592	Among Tcf/beta-catenin antagonists, PKF115-584 has been reported to inhibit proliferation of the NCI-H295R cell line and the expression of the beta-catenin target genes cyclin D1 and c-Myc.	('cyclin D1', 'Gene', '595', (169, 178))	('PKF115-584', 'Var', (36, 46))	('Tcf', 'Gene', '3172', (6, 9))	('cyclin D1', 'Gene', (169, 178))	('c-Myc', 'Gene', '4609', (183, 188))	('Tcf', 'Gene', (6, 9))	('inhibit', 'NegReg', (68, 75))	('proliferation', 'CPA', (76, 89))	('expression', 'MPA', (125, 135))	('c-Myc', 'Gene', (183, 188))	('NCI-H295R', 'CellLine', 'CVCL:0458', (97, 106))
76728	26515592	The PNU-74654 (PNU) compound is a non-FDA-approved drug which prevents that Tcf from binding to beta-catenin, acting as a Wnt/beta-catenin antagonist (Figure 1).	('PNU', 'Chemical', '-', (15, 18))	('PNU-74654', 'Var', (4, 13))	('PNU-74654', 'Chemical', '-', (4, 13))	('Tcf', 'Gene', '3172', (76, 79))	('PNU', 'Chemical', '-', (4, 7))	('beta-catenin', 'Protein', (96, 108))	('Tcf', 'Gene', (76, 79))	('binding', 'Interaction', (85, 92))
76737	26515592	In our own stock of NCI-H295 cells, we confirmed the presence of the pathogenic p.S45P CTNNB1 variation.	('CTNNB1', 'Gene', '1499', (87, 93))	('NCI-H295', 'CellLine', 'CVCL:0456', (20, 28))	('p.S45P', 'Mutation', 'rs121913407', (80, 86))	('CTNNB1', 'Gene', (87, 93))	('p.S45P', 'Var', (80, 86))	('pathogenic', 'Reg', (69, 79))
76740	26515592	In addition, we also detected the presence of the p.P278L TP53 variation in this cell line.	('TP53', 'Gene', (58, 62))	('p.P278L', 'Mutation', 'rs876659802', (50, 57))	('p.P278L', 'Var', (50, 57))	('TP53', 'Gene', '7157', (58, 62))
76741	26515592	HeLa, a cervix carcinoma cell lineage, was employed as a non-adrenal cell line that did not carry the exon 3 CTNNB1 mutation but which also showed the p.P72R TP53 variation as well as a second intronic TP53 variation (c.97-30C > A/g.11298).	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (202, 206))	('CTNNB1', 'Gene', (109, 115))	('TP53', 'Gene', (158, 162))	('carcinoma', 'Disease', 'MESH:D002277', (15, 24))	('c.97-30C > A/g.11298', 'Var', (218, 238))	('c.97-30C > A', 'Mutation', 'c.97-30C>A', (218, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('p.P72R', 'Var', (151, 157))	('p.P72R', 'Mutation', 'rs1042522', (151, 157))	('CTNNB1', 'Gene', '1499', (109, 115))	('carcinoma', 'Disease', (15, 24))	('cervix carcinoma', 'Phenotype', 'HP:0030079', (8, 24))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	('TP53', 'Gene', '7157', (202, 206))
76742	26515592	Additionally, we identified an intronic TP53 variation at position c.74 + 38 (C > G rs1642785) in HeLa cells.	('rs1642785', 'DBSNP_MENTION', 'None', (84, 93))	('HeLa', 'CellLine', 'CVCL:0030', (98, 102))	('rs1642785', 'Var', (84, 93))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))
76746	26515592	PNU did not decrease HeLa cell viability 96 h after treatment compared to vehicle (p = 0.05; Figure 3e).	('PNU', 'Var', (0, 3))	('HeLa cell viability', 'CPA', (21, 40))	('PNU', 'Chemical', '-', (0, 3))	('HeLa', 'CellLine', 'CVCL:0030', (21, 25))
76763	26515592	PNU decreased cortisol production by 72 and 78% (50 and 100 muM, respectively; ANOVA: p = 0.0002; Figure 8a) 24 h after treatment and by 60 and 78% (50 and 100 muM, respectively; ANOVA: p = 0.0001; Figure 8b) 48 h after treatment.	('muM', 'Gene', (160, 163))	('decreased', 'NegReg', (4, 13))	('muM', 'Gene', (60, 63))	('decreased cortisol', 'Phenotype', 'HP:0008163', (4, 22))	('PNU', 'Var', (0, 3))	('cortisol production', 'MPA', (14, 33))	('cortisol', 'Chemical', 'MESH:D006854', (14, 22))	('muM', 'Gene', '56925', (160, 163))	('muM', 'Gene', '56925', (60, 63))	('PNU decreased cortisol', 'Phenotype', 'HP:0008163', (0, 22))	('PNU', 'Chemical', '-', (0, 3))
76764	26515592	PNU decreased testosterone production by 50 and 73% (50 and 100 muM, respectively; ANOVA: p = 0.0012; Figure 8c) 24 h after treatment and by 37 and 69% (50 and 100 muM, respectively; ANOVA: p < 0.0001; Figure 8d) 48 h after treatment.	('decreased', 'NegReg', (4, 13))	('muM', 'Gene', (64, 67))	('PNU', 'Var', (0, 3))	('muM', 'Gene', (164, 167))	('testosterone', 'Chemical', 'MESH:D013739', (14, 26))	('testosterone production', 'MPA', (14, 37))	('decreased testosterone', 'Phenotype', 'HP:0040171', (4, 26))	('muM', 'Gene', '56925', (64, 67))	('PNU', 'Chemical', '-', (0, 3))	('muM', 'Gene', '56925', (164, 167))
76765	26515592	PNU decreased androstenedione production by 97.5% at 200 muM (ANOVA: p = 0.02; Figure 8e and 8f) 48 h after treatment.	('decreased', 'NegReg', (4, 13))	('androstenedione', 'Chemical', 'MESH:D000735', (14, 29))	('muM', 'Gene', (57, 60))	('PNU', 'Var', (0, 3))	('decreased androstenedione production', 'Phenotype', 'HP:0025380', (4, 40))	('androstenedione production', 'MPA', (14, 40))	('PNU', 'Chemical', '-', (0, 3))	('muM', 'Gene', '56925', (57, 60))
76770	26515592	Additionally, PNU markedly decreased the relative protein expression of aldosterone synthase 48 h after treatment with 10, 50 and 100 muM PNU (23%, 62% and 70%, respectively; Figure 9d).	('muM', 'Gene', '56925', (134, 137))	('PNU', 'Chemical', '-', (14, 17))	('aldosterone synthase', 'Gene', '1585', (72, 92))	('decreased', 'NegReg', (27, 36))	('muM', 'Gene', (134, 137))	('PNU', 'Var', (14, 17))	('PNU', 'Var', (138, 141))	('PNU', 'Chemical', '-', (138, 141))	('aldosterone synthase', 'Gene', (72, 92))
76772	26515592	In addition, we provided evidence that PNU may directly impair adrenal steroid secretion.	('adrenal steroid secretion', 'MPA', (63, 88))	('impair', 'NegReg', (56, 62))	('PNU', 'Chemical', '-', (39, 42))	('PNU', 'Var', (39, 42))	('steroid', 'Chemical', 'MESH:D013256', (71, 78))
76778	26515592	In agreement, a previous study confirmed overexpression of Wnt target genes in ACTs harboring beta-catenin mutations as well as in the adrenal cell lineage NCI-H295.	('beta-catenin', 'Protein', (94, 106))	('overexpression', 'PosReg', (41, 55))	('NCI-H295', 'CellLine', 'CVCL:0456', (156, 164))	('mutations', 'Var', (107, 116))
76779	26515592	In that study, 24 h treatment with Wnt inhibitors, 10 muM PKF115-584 and 100 muM PNU, resulted in decreased beta-catenin target gene transcription.	('muM', 'Gene', (54, 57))	('muM', 'Gene', (77, 80))	('PNU', 'Chemical', '-', (81, 84))	('PKF115-584', 'Var', (58, 68))	('beta-catenin target gene transcription', 'MPA', (108, 146))	('muM', 'Gene', '56925', (54, 57))	('muM', 'Gene', '56925', (77, 80))	('decreased', 'NegReg', (98, 107))	('decreased beta-catenin target', 'Phenotype', 'HP:0040209', (98, 127))
76783	26515592	On the other hand, the topological surface of PNU-74654 is 63.8 A2 causing this compound to be very well absorbed by cells for a better effect on Wnt signaling inhibition (National Center for Biotechnology Information.	('PNU-74654', 'Chemical', '-', (46, 55))	('Wnt signaling', 'Pathway', (146, 159))	('PNU-74654', 'Var', (46, 55))
76785	26515592	In our study, PNU was able to decrease cell viability since 24 h after treatment at higher but apparently non-cytotoxic concentrations (100 muM).	('muM', 'Gene', '56925', (140, 143))	('PNU', 'Chemical', '-', (14, 17))	('decrease', 'NegReg', (30, 38))	('muM', 'Gene', (140, 143))	('PNU', 'Var', (14, 17))	('cell viability', 'CPA', (39, 53))
76789	26515592	In contrast, PNU prevented the cell proliferation stimulated by Forskolin.	('PNU', 'Var', (13, 16))	('Forskolin', 'Chemical', 'MESH:D005576', (64, 73))	('cell proliferation', 'CPA', (31, 49))	('prevented', 'NegReg', (17, 26))	('PNU', 'Chemical', '-', (13, 16))
76791	26515592	Our results showed that PNU does not decrease cell proliferation in cells that do not carry exon 3 beta-catenin mutations, such as HeLa, a non-adrenal cell line, as previously reported, and Y1, a mouse adrenal tumor cell line.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('HeLa', 'CellLine', 'CVCL:0030', (131, 135))	('mouse', 'Species', '10090', (196, 201))	('adrenal tumor', 'Disease', (202, 215))	('adrenal tumor', 'Disease', 'MESH:D000310', (202, 215))	('beta-catenin', 'Protein', (99, 111))	('mutations', 'Var', (112, 121))	('adrenal tumor', 'Phenotype', 'HP:0100631', (202, 215))	('cell proliferation', 'CPA', (46, 64))	('PNU', 'Chemical', '-', (24, 27))
76793	26515592	In addition, an increase of TUNEL-positive cells, which indicates the presence of apoptotic cells, was described in Sf1/Crelowbeta-catenin knockout mice, supporting the idea that the loss of beta-catenin in the adrenal cortex progressively contributes to the loss of adrenocortical tissue via apoptosis.	('Sf1', 'Gene', '22668', (116, 119))	('Sf1', 'Gene', (116, 119))	('beta-catenin', 'Protein', (191, 203))	('loss', 'Var', (183, 187))	('loss', 'NegReg', (259, 263))	('mice', 'Species', '10090', (148, 152))	('adrenocortical', 'Disease', (267, 281))	('adrenocortical', 'Disease', 'MESH:D018268', (267, 281))	('apoptosis', 'CPA', (293, 302))
76795	26515592	In addition, we also found a reduction of nuclear beta-catenin accumulation in PNU-treated cells, as shown by immunofluorescence.	('nuclear beta-catenin accumulation', 'MPA', (42, 75))	('PNU-treated', 'Var', (79, 90))	('reduction', 'NegReg', (29, 38))	('PNU', 'Chemical', '-', (79, 82))
76797	26515592	In agreement with our results, it has been reported that PNU was able to decrease beta-catenin protein expression in juvenile zebrafish after 10 days of exposure.	('zebrafish', 'Species', '7955', (126, 135))	('PNU', 'Var', (57, 60))	('PNU', 'Chemical', '-', (57, 60))	('beta-catenin protein', 'Protein', (82, 102))	('decrease', 'NegReg', (73, 81))
76799	26515592	Thus, PNU may directly decrease beta-catenin expression as well as its nuclear localization by directly binding to beta-catenin.	('decrease', 'NegReg', (23, 31))	('beta-catenin', 'Protein', (115, 127))	('beta-catenin', 'Protein', (32, 44))	('PNU', 'Var', (6, 9))	('nuclear localization', 'MPA', (71, 91))	('binding', 'Interaction', (104, 111))	('expression', 'MPA', (45, 55))	('PNU', 'Chemical', '-', (6, 9))
76802	26515592	In addition, silencing beta-catenin reduced cell proliferation in H295R in vitro and in a xenograft mouse model.	('cell proliferation', 'CPA', (44, 62))	('mouse', 'Species', '10090', (100, 105))	('beta-catenin', 'Protein', (23, 35))	('H295R', 'Var', (66, 71))	('reduced', 'NegReg', (36, 43))	('silencing', 'Var', (13, 22))
76814	26515592	This hypothesis is supported by the fact that PNU elicited reduction of corticosterone secretion but not of cell viability in Y1 cells.	('PNU', 'Chemical', '-', (46, 49))	('corticosterone', 'Chemical', 'MESH:D003345', (72, 86))	('corticosterone secretion', 'MPA', (72, 96))	('reduction', 'NegReg', (59, 68))	('PNU', 'Var', (46, 49))
76815	26515592	At higher doses it is also likely that the effect of PNU on cell decrease may contribute in part to decreased hormone production.	('cell', 'MPA', (60, 64))	('PNU', 'Chemical', '-', (53, 56))	('decreased', 'NegReg', (100, 109))	('decrease', 'NegReg', (65, 73))	('hormone production', 'MPA', (110, 128))	('PNU', 'Var', (53, 56))
76816	26515592	On the other hand, we found that PNU treatment impaired the mRNA expression of SF1 and CYP21A2, both important genes required for steroidogenesis, suggesting that PNU directly impairs adrenal steroid secretion by inhibiting the initial steps of steroidogenesis.	('steroid', 'Chemical', 'MESH:D013256', (245, 252))	('SF1', 'Gene', (79, 82))	('PNU', 'Chemical', '-', (163, 166))	('inhibiting', 'NegReg', (213, 223))	('mRNA expression', 'MPA', (60, 75))	('CYP21A2', 'Gene', (87, 94))	('steroid', 'Chemical', 'MESH:D013256', (192, 199))	('CYP21A2', 'Gene', '1589', (87, 94))	('PNU', 'Chemical', '-', (33, 36))	('initial steps of steroidogenesis', 'MPA', (228, 260))	('adrenal steroid secretion', 'MPA', (184, 209))	('impaired', 'NegReg', (47, 55))	('SF1', 'Gene', '7536', (79, 82))	('PNU', 'Var', (163, 166))	('impairs', 'NegReg', (176, 183))	('steroid', 'Chemical', 'MESH:D013256', (130, 137))
76820	26515592	This result agrees with data reported by Berthon et al (2014), who showed that the inhibition of the Wnt pathway decreased hormone secretion, CYP11B2 and CYP21 expression after angiotensin stimulation.	('CYP21', 'Gene', (154, 159))	('hormone secretion', 'MPA', (123, 140))	('CYP21', 'Gene', '1589', (154, 159))	('CYP11B2', 'Gene', (142, 149))	('inhibition', 'Var', (83, 93))	('decreased', 'NegReg', (113, 122))	('CYP11B2', 'Gene', '1585', (142, 149))	('Wnt pathway', 'Pathway', (101, 112))
76823	26515592	Partial knockout of beta-catenin in the adrenal cortex resulted in depletion of adrenocortical cells upon aging.	('adrenocortical', 'Disease', 'MESH:D018268', (80, 94))	('beta-catenin', 'Protein', (20, 32))	('adrenocortical', 'Disease', (80, 94))	('Partial knockout', 'Var', (0, 16))
76832	26515592	In conclusion, the results of this in vitro study demonstrated that blocking the Tcf/beta-catenin complex inhibited the Wnt/beta-catenin signaling as shown by decreased beta-catenin expression and nuclear accumulation, and impaired expression of beta-catenin target genes.	('beta-catenin expression', 'MPA', (169, 192))	('Tcf', 'Gene', (81, 84))	('blocking', 'Var', (68, 76))	('nuclear accumulation', 'CPA', (197, 217))	('inhibited', 'NegReg', (106, 115))	('decreased', 'NegReg', (159, 168))	('expression', 'MPA', (232, 242))	('Tcf', 'Gene', '3172', (81, 84))	('Wnt/beta-catenin signaling', 'MPA', (120, 146))	('impaired', 'NegReg', (223, 231))
76840	26515592	NCI-H295 and HeLa cell lines were authenticated by analyzing the following STR markers: CSF1PO, D13S317, D16S539, D5S818, D7S820, THO1, TPOX and vWA (Supplementary Table 1).	('SF1', 'Gene', '7536', (89, 92))	('D7S820', 'Var', (122, 128))	('D16S539', 'Var', (105, 112))	('NCI-H295', 'CellLine', 'CVCL:0456', (0, 8))	('THO1', 'Gene', '9984', (130, 134))	('HeLa', 'CellLine', 'CVCL:0030', (13, 17))	('D13S317', 'Var', (96, 103))	('THO1', 'Gene', (130, 134))	('SF1', 'Gene', (89, 92))	('D5S818', 'Var', (114, 120))
76841	26515592	The analysis of exon 3 CTNNB1 and TP53 coding gene was performed to confirm the presence of previously described TP53 and CTNNB1 genetic variations in our own stock of NCI-H295 and HeLa cells.	('CTNNB1', 'Gene', (122, 128))	('variations', 'Var', (137, 147))	('CTNNB1', 'Gene', (23, 29))	('TP53', 'Gene', (34, 38))	('NCI-H295', 'CellLine', 'CVCL:0456', (168, 176))	('CTNNB1', 'Gene', '1499', (122, 128))	('HeLa', 'CellLine', 'CVCL:0030', (181, 185))	('TP53', 'Gene', '7157', (113, 117))	('CTNNB1', 'Gene', '1499', (23, 29))	('TP53', 'Gene', (113, 117))	('TP53', 'Gene', '7157', (34, 38))
76847	26515592	After 48 h, cells were treated with vehicle (0.1%-0.4% DMSO) or 10, 50, 100 and 200 muM PNU-74654.	('PNU-74654', 'Var', (88, 97))	('PNU-74654', 'Chemical', '-', (88, 97))	('muM', 'Gene', '56925', (84, 87))	('DMSO', 'Chemical', 'MESH:D004121', (55, 59))	('muM', 'Gene', (84, 87))
76850	26515592	After 24 h, cells were treated with vehicle or 10, 50, 100 and 200 muM PNU-74654.	('muM', 'Gene', '56925', (67, 70))	('PNU-74654', 'Chemical', '-', (71, 80))	('PNU-74654', 'Var', (71, 80))	('muM', 'Gene', (67, 70))
76867	26515592	TaqMan  assays for NCI-H295 and HeLa cells: CTNNB1 (Hs00170025_m1), CCND1 (Hs00765553_m1), AXIN2 (Hs00610344_m1), MYC (Hs00153408_m1), TCF7 (Hs00175273_m1), NR5A1/SF1 (Hs00610436_m1) and CYP21A2 (Custom: AIVI3LV).	('CCND1', 'Gene', '595', (68, 73))	('TCF7', 'Gene', '6932', (135, 139))	('Hs00765553_m1', 'Var', (75, 88))	('MYC', 'Gene', (114, 117))	('CCND1', 'Gene', (68, 73))	('AXIN2', 'Gene', '8313', (91, 96))	('CTNNB1', 'Gene', (44, 50))	('HeLa', 'CellLine', 'CVCL:0030', (32, 36))	('Hs00153408_m1', 'Var', (119, 132))	('MYC', 'Gene', '4609', (114, 117))	('Hs00610436_m1', 'Var', (168, 181))	('Hs00610344_m1', 'Var', (98, 111))	('NCI-H295', 'CellLine', 'CVCL:0456', (19, 27))	('CYP21A2', 'Gene', (187, 194))	('NR5A1', 'Gene', (157, 162))	('AXIN2', 'Gene', (91, 96))	('TCF7', 'Gene', (135, 139))	('Hs00170025_m1', 'Var', (52, 65))	('SF1', 'Gene', (163, 166))	('SF1', 'Gene', '7536', (163, 166))	('CYP21A2', 'Gene', '1589', (187, 194))	('CTNNB1', 'Gene', '1499', (44, 50))	('NR5A1', 'Gene', '2516', (157, 162))	('Hs00175273_m1', 'Var', (141, 154))
76868	26515592	TaqMan  assay for Y1 cells: Ctnnb1 (Mm01350391_m1).	('Mm01350391_m1', 'Var', (36, 49))	('Ctnnb1', 'Gene', '1499', (28, 34))	('Ctnnb1', 'Gene', (28, 34))
76915	22025964	In particular, the Weiss system is widely used, which assesses a total of nine histologic features; Fuhrman nuclear grade, mitotic rate >5 per 50 high power field, atypical mitoses, clear cell composition less than 25% of the entire tumor mass, diffuse architecture, necrosis, venous invasion, sinusoidal invasion, and capsular invasion.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('necrosis', 'Disease', 'MESH:D009336', (267, 275))	('less', 'NegReg', (205, 209))	('tumor', 'Disease', (233, 238))	('diffuse architecture', 'CPA', (245, 265))	('mitotic rate', 'CPA', (123, 135))	('necrosis', 'Disease', (267, 275))	('capsular invasion', 'CPA', (319, 336))	('Fuhrman', 'Var', (100, 107))	('venous invasion', 'CPA', (277, 292))	('sinusoidal invasion', 'CPA', (294, 313))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
76927	20029641	Surgical Approach to a Large Left Adrenocortical Mass with Associated Tumour Thrombosis of the Left Renal Vein: Preservation of the Ipsilateral Kidney A sixty-years-old male with diagnosis of a left adrenal mass (146 x 99 x 126 mm) with associated tumour thrombosis of the  left renal vein with no clear signs of thrombosis of the inferior  vena cava was admitted for elective surgery Finally an adrenalectomy and excision of tumour  thrombus preserving the ipsilateral kidney was made.	('Tumour', 'Phenotype', 'HP:0002664', (70, 76))	('Tumour Thrombosis of the Left Renal Vein', 'Disease', (70, 110))	('thrombosis', 'Disease', (255, 265))	('tumour', 'Phenotype', 'HP:0002664', (426, 432))	('Left Adrenocortical', 'Disease', 'MESH:D018268', (29, 48))	('thrombosis', 'Disease', (313, 323))	('tumour  thrombus', 'Disease', (426, 442))	('thrombosis', 'Disease', 'MESH:D013927', (255, 265))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('Tumour Thrombosis of the Left Renal Vein', 'Disease', 'MESH:D007680', (70, 110))	('146 x 99 x 126 mm', 'Var', (213, 230))	('tumour  thrombus', 'Disease', 'MESH:D013927', (426, 442))	('tumour thrombosis of the  left renal vein', 'Disease', 'MESH:D007680', (248, 289))	('thrombosis', 'Disease', 'MESH:D013927', (313, 323))	('Left Adrenocortical', 'Disease', (29, 48))	('tumour thrombosis of the  left renal vein', 'Disease', (248, 289))
77010	33626208	To explore the underlying biological mechanism, we performed a GSEA of high-risk and low-risk groups and the results indicated that the most significant pathways associated with candidate proteins included chromosome separation, metaphase-anaphase transition of cell cycle and protein modification by small protein removal.	('GSEA', 'Chemical', '-', (63, 67))	('chromosome separation', 'CPA', (206, 227))	('small', 'Var', (301, 306))	('metaphase-anaphase transition of cell cycle', 'CPA', (229, 272))
77026	33626208	44  We found mutual inhibition between TFRC and SMAC, and that the abundances of X1433ZETA, ERK2 and CYCLINB1 were positively correlated with TFRC abundance.	('X1433ZETA', 'Var', (81, 90))	('ERK2', 'Gene', (92, 96))	('TFRC', 'Gene', '7037', (142, 146))	('CYCLINB1', 'Gene', (101, 109))	('CYCLINB1', 'Gene', '891', (101, 109))	('TFRC', 'Gene', (142, 146))	('TFRC', 'Gene', '7037', (39, 43))	('correlated', 'Reg', (126, 136))	('ERK2', 'Gene', '5594', (92, 96))	('TFRC', 'Gene', (39, 43))	('abundance', 'MPA', (147, 156))
77031	33626208	49  Maintaining the integrity of the genome is the basis of cell survival, and PARP inhibitors kill tumours mainly by inhibiting DNA repair and destroying the genomes of tumour cells.	('inhibitors', 'Var', (84, 94))	('tumours', 'Disease', (100, 107))	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('tumour', 'Disease', (170, 176))	('DNA repair', 'MPA', (129, 139))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('PARP', 'Gene', '142', (79, 83))	('PARP', 'Gene', (79, 83))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('destroying', 'NegReg', (144, 154))	('inhibiting', 'NegReg', (118, 128))	('tumour', 'Disease', (100, 106))	('tumour', 'Disease', 'MESH:D009369', (170, 176))	('genomes', 'MPA', (159, 166))
77050	32607875	Lean body weight (LBW) and genotypes of CYP2C19*2 (rs4244285), SLCO1B3 699A>G (rs7311358) and SLCO1B1 571T>C (rs4149057) were found to significantly affect mitotane clearance (CL/F), which decreased the coefficient of variation (CV%) of the random inter-individual variability of CL/F from 67.0 to 43.0%.	('CL/F', 'Gene', (280, 284))	('affect', 'Reg', (149, 155))	('CL/F', 'Gene', (176, 180))	('CYP2C19', 'Gene', (40, 47))	('SLCO1B3', 'Gene', '28234', (63, 70))	('random inter-individual variability', 'MPA', (241, 276))	('571T>C', 'Mutation', 'rs4149057', (102, 108))	('coefficient', 'MPA', (203, 214))	('CYP2C19', 'Gene', '1557', (40, 47))	('rs4244285', 'Mutation', 'rs4244285', (51, 60))	('rs4149057', 'Mutation', 'rs4149057', (110, 119))	('SLCO1B1', 'Gene', (94, 101))	('decreased', 'NegReg', (189, 198))	('rs4149057', 'Var', (110, 119))	('699A>G', 'Mutation', 'rs7311358', (71, 77))	('rs7311358', 'Var', (79, 88))	('rs7311358', 'Mutation', 'rs7311358', (79, 88))	('SLCO1B1', 'Gene', '10599', (94, 101))	('mitotane', 'Chemical', 'MESH:D008939', (156, 164))	('CL/F', 'Gene', '51340', (280, 284))	('rs4244285', 'Var', (51, 60))	('mitotane clearance', 'MPA', (156, 174))	('SLCO1B3', 'Gene', (63, 70))	('CL/F', 'Gene', '51340', (176, 180))
77074	32607875	One study demonstrated that the genotype of CYP2B6*6 (rs3745274) was significantly correlated with mitotane plasma concentrations at 3 and 6 months after the initiation of treatment.	('correlated', 'Reg', (83, 93))	('rs3745274', 'Var', (54, 63))	('mitotane', 'Chemical', 'MESH:D008939', (99, 107))	('CYP2B6', 'Gene', (44, 50))	('CYP2B6', 'Gene', '1555', (44, 50))	('rs3745274', 'Mutation', 'rs3745274', (54, 63))	('mitotane plasma concentrations', 'MPA', (99, 129))
77136	32607875	Among these 11 SNPs, the genotyping results of CYP2C18 1154C > T (rs2281891) and CYP2C19*2 (rs4244285) were shown to be 100% in linkage disequilibrium in our dataset, which was the same as the genotyping results of SLCO1B3 334G>T (rs4149117), 699A>G (rs7311358), and 1557G>A (rs2053098) and that of the three SNPs located on VKORC1 (283 + 124G>C, 174-136C>T, and -1639G>A).	('rs4244285', 'Mutation', 'rs4244285', (92, 101))	('CYP2C19', 'Gene', (81, 88))	('rs7311358', 'Var', (251, 260))	('283 + 124G>C', 'Var', (333, 345))	('SLCO1B3', 'Gene', '28234', (215, 222))	('rs7311358', 'Mutation', 'rs7311358', (251, 260))	('699A>G', 'Mutation', 'rs7311358', (243, 249))	('CYP2C19', 'Gene', '1557', (81, 88))	('1154C > T', 'Mutation', 'rs2281891', (55, 64))	('rs4149117', 'Mutation', 'rs4149117', (231, 240))	('rs2053098', 'Mutation', 'rs2053098', (276, 285))	('1557G>A (rs2053098', 'Var', (267, 285))	('-1639G>A', 'Mutation', 'rs9923231', (363, 371))	('CYP2C18', 'Gene', (47, 54))	('rs2281891', 'Mutation', 'rs2281891', (66, 75))	('CYP2C18', 'Gene', '1562', (47, 54))	('1557G>A', 'Mutation', 'rs2053098', (267, 274))	('VKORC1', 'Gene', (325, 331))	('rs4149117', 'Var', (231, 240))	('VKORC1', 'Gene', '79001', (325, 331))	('334G>T', 'Mutation', 'rs4149117', (223, 229))	('rs2053098', 'Var', (276, 285))	('283 + 124G>C', 'Mutation', 'rs8050894', (333, 345))	('SLCO1B3', 'Gene', (215, 222))	('174-136C>T', 'Mutation', 'rs9934438', (347, 357))
77137	32607875	The CYP2C19*2 (rs4244285), SLCO1B3 699A>G (rs7311358) and SLCO1B1 571T>C (rs4149057) genotypes, and LBW at the start of treatment, with power relation, were found to have a significant effect on the CL/F of mitotane (Table 2).	('rs7311358', 'Var', (43, 52))	('effect', 'Reg', (185, 191))	('rs4244285', 'Mutation', 'rs4244285', (15, 24))	('SLCO1B3', 'Gene', '28234', (27, 34))	('rs7311358', 'Mutation', 'rs7311358', (43, 52))	('SLCO1B1', 'Gene', '10599', (58, 65))	('rs4149057', 'Mutation', 'rs4149057', (74, 83))	('rs4244285', 'Var', (15, 24))	('rs4149057', 'Var', (74, 83))	('571T>C', 'Mutation', 'rs4149057', (66, 72))	('CYP2C19', 'Gene', (4, 11))	('CL/F', 'Gene', (199, 203))	('CL/F', 'Gene', '51340', (199, 203))	('mitotane', 'Chemical', 'MESH:D008939', (207, 215))	('SLCO1B3', 'Gene', (27, 34))	('SLCO1B1', 'Gene', (58, 65))	('CYP2C19', 'Gene', '1557', (4, 11))	('699A>G', 'Mutation', 'rs7311358', (35, 41))
77138	32607875	Carrying the 'A' variant in CYP2C19*2 reduced the CL/F by 44.9%, and carrying 'G' variant in SLCO1B3 699A>G resulted in a 39.9% reduction in CL/F (Table 2).	('CYP2C19', 'Gene', '1557', (28, 35))	('SLCO1B3', 'Gene', (93, 100))	('CL/F', 'Gene', '51340', (50, 54))	('reduction', 'NegReg', (128, 137))	('reduced', 'NegReg', (38, 45))	('SLCO1B3', 'Gene', '28234', (93, 100))	('699A>G', 'Mutation', 'rs7311358', (101, 107))	('CYP2C19', 'Gene', (28, 35))	('variant', 'Var', (17, 24))	('CL/F', 'Gene', '51340', (141, 145))	('CL/F', 'Gene', (141, 145))	('CL/F', 'Gene', (50, 54))
77139	32607875	As for SLCO1B1 571T>C, the CL/F of patients carrying one 'C' variant decreased to 40.2% that of wild-type patients, while the CL/F of patients carrying two 'C' variants decreased to 30.2%.	('SLCO1B1', 'Gene', '10599', (7, 14))	('decreased', 'NegReg', (69, 78))	('patients', 'Species', '9606', (134, 142))	('variant', 'Var', (61, 68))	('CL/F', 'Gene', (27, 31))	('CL/F', 'Gene', (126, 130))	('patients', 'Species', '9606', (106, 114))	('CL/F', 'Gene', '51340', (126, 130))	('CL/F', 'Gene', '51340', (27, 31))	('patients', 'Species', '9606', (35, 43))	('SLCO1B1', 'Gene', (7, 14))	('571T>C', 'Mutation', 'rs4149057', (15, 21))
77164	32607875	CYP2C19*2 (rs4244285), SLCO1B3 699A>G (rs7311358) and SLCO1B1 571T>C (rs4149057), were included in the final model and were considered as the pharmacogenetic polymorphisms that should be considered for mitotane dose selection.	('rs7311358', 'Mutation', 'rs7311358', (39, 48))	('rs4244285', 'Var', (11, 20))	('rs4149057', 'Var', (70, 79))	('mitotane', 'Chemical', 'MESH:D008939', (202, 210))	('rs4149057', 'Mutation', 'rs4149057', (70, 79))	('SLCO1B3', 'Gene', (23, 30))	('571T>C', 'Mutation', 'rs4149057', (62, 68))	('CYP2C19', 'Gene', (0, 7))	('SLCO1B1', 'Gene', (54, 61))	('SLCO1B3', 'Gene', '28234', (23, 30))	('rs4244285', 'Mutation', 'rs4244285', (11, 20))	('CYP2C19', 'Gene', '1557', (0, 7))	('SLCO1B1', 'Gene', '10599', (54, 61))	('rs7311358', 'Var', (39, 48))	('699A>G', 'Mutation', 'rs7311358', (31, 37))
77166	32607875	In fact, in our dataset, CYP2C19*2 was in 100% linkage disequilibrium with CYP2C18 1154C>T (rs2281891), which was the same as SLCO1B3 699A>G with SLCO1B3 334G>T (rs4149117) and SLCO1B3 1557G>A (rs2053098).	('CYP2C19', 'Gene', '1557', (25, 32))	('SLCO1B3', 'Gene', (146, 153))	('SLCO1B3', 'Gene', (177, 184))	('334G>T', 'Mutation', 'rs4149117', (154, 160))	('SLCO1B3', 'Gene', '28234', (146, 153))	('CYP2C18', 'Gene', (75, 82))	('1557G>A', 'Mutation', 'rs2053098', (185, 192))	('rs2053098', 'Mutation', 'rs2053098', (194, 203))	('SLCO1B3', 'Gene', '28234', (177, 184))	('CYP2C19', 'Gene', (25, 32))	('CYP2C18', 'Gene', '1562', (75, 82))	('rs4149117', 'Mutation', 'rs4149117', (162, 171))	('1154C>T', 'Mutation', 'rs2281891', (83, 90))	('SLCO1B3', 'Gene', (126, 133))	('699A>G', 'Mutation', 'rs7311358', (134, 140))	('rs4149117', 'Var', (162, 171))	('SLCO1B3', 'Gene', '28234', (126, 133))	('rs2281891', 'Mutation', 'rs2281891', (92, 101))
77167	32607875	Compared with CYP2C18 1154C>T, for which no sufficient evidence has been found regarding the effect on the drug PK, the 'A' variant of CYP2C19*2 is known to be a nonfunctioning variant and has been demonstrated to decrease the activity of CYP2C19.	('CYP2C19', 'Gene', (135, 142))	('1154C>T', 'Mutation', 'rs2281891', (22, 29))	('CYP2C19', 'Gene', (239, 246))	('CYP2C18', 'Gene', '1562', (14, 21))	('activity', 'MPA', (227, 235))	("'A' variant", 'Var', (120, 131))	('CYP2C19', 'Gene', '1557', (135, 142))	('CYP2C19', 'Gene', '1557', (239, 246))	('CYP2C18', 'Gene', (14, 21))	('decrease', 'NegReg', (214, 222))	('variant', 'Var', (124, 131))
77168	32607875	Similarly, the variants of SLCO1B3 699A>G with SLCO1B3 334G>T have been reported to be associated with a decrease in drug clearance, and SLCO1B3 699A>G has a stronger level of clinical annotations.	('699A>G', 'Mutation', 'rs7311358', (145, 151))	('SLCO1B3', 'Gene', '28234', (27, 34))	('SLCO1B3', 'Gene', '28234', (137, 144))	('SLCO1B3', 'Gene', (47, 54))	('SLCO1B3', 'Gene', (137, 144))	('334G>T', 'Mutation', 'rs4149117', (55, 61))	('SLCO1B3', 'Gene', '28234', (47, 54))	('SLCO1B3', 'Gene', (27, 34))	('variants', 'Var', (15, 23))	('drug clearance', 'MPA', (117, 131))	('decrease', 'NegReg', (105, 113))	('699A>G', 'Mutation', 'rs7311358', (35, 41))
77192	32607875	The polymorphisms of CYP2C19*2 (rs4244285), SLCO1B3 699G>A (rs7311358) and SLCO1B1 571T>C (rs4149057) were found to be correlated to mitotane PK.	('mitotane PK', 'Disease', (133, 144))	('rs7311358', 'Var', (60, 69))	('rs4244285', 'Mutation', 'rs4244285', (32, 41))	('699G>A', 'Mutation', 'rs7311358', (52, 58))	('mitotane', 'Chemical', 'MESH:D008939', (133, 141))	('rs7311358', 'Mutation', 'rs7311358', (60, 69))	('SLCO1B3', 'Gene', (44, 51))	('CYP2C19', 'Gene', (21, 28))	('rs4149057', 'Mutation', 'rs4149057', (91, 100))	('SLCO1B1', 'Gene', (75, 82))	('SLCO1B3', 'Gene', '28234', (44, 51))	('rs4244285', 'Var', (32, 41))	('571T>C', 'Mutation', 'rs4149057', (83, 89))	('correlated', 'Reg', (119, 129))	('rs4149057', 'Var', (91, 100))	('SLCO1B1', 'Gene', '10599', (75, 82))	('CYP2C19', 'Gene', '1557', (21, 28))
77209	33178583	Genetic analyses showed TP53 germline mutations in six of eight patients analyzed (five inherited, one de novo).	('TP53', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (24, 28))	('patients', 'Species', '9606', (64, 72))	('germline mutations', 'Var', (29, 47))
77215	33178583	ACC incidence rises of 10-15 times the worldwide rate in Southern Brazil, which is likely associated with high prevalence of the founder p.R337H TP53 mutation.	('TP53', 'Gene', (145, 149))	('p.R337H', 'Var', (137, 144))	('p.R337H', 'Mutation', 'rs121912664', (137, 144))	('TP53', 'Gene', '7157', (145, 149))
77224	33178583	However, because many children with ACT carry germline TP53 mutations, radiation therapy in pediatric ACTs has not been studied and should be avoided.	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('ACT', 'Disease', (36, 39))	('children', 'Species', '9606', (22, 30))	('mutations', 'Var', (60, 69))	('germline', 'Var', (46, 54))
77243	33178583	Genetic analyses were conducted for eight patients showing TP53 germline mutations in six (five inherited and one de novo) (Table 4).	('germline mutations', 'Var', (64, 82))	('patients', 'Species', '9606', (42, 50))	('TP53', 'Gene', '7157', (59, 63))	('TP53', 'Gene', (59, 63))
77268	33178583	In pediatric population, radiation therapy has not been investigated for the high probability for patients of carrying germline TP53 mutations and thus should be avoided.	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('mutations', 'Var', (133, 142))	('patients', 'Species', '9606', (98, 106))
77272	33178583	Rates of response and progression-free survival were significantly better with EDP plus mitotane as first-line therapy, with similar rates of toxic events [58%), but no significant differences in OS were observed ].	('response', 'CPA', (9, 17))	('EDP', 'Var', (79, 82))	('EDP', 'Chemical', '-', (79, 82))	('progression-free survival', 'CPA', (22, 47))	('better', 'PosReg', (67, 73))	('mitotane', 'Chemical', 'MESH:D008939', (88, 96))
77281	33178583	CNC, mostly due to germline inactivating mutations of PRKAR1A, is rarely associated with ACC but is the main cause of primary pigmented nodular adrenal diseases and usually linked to other tumors (somatotroph pituitary adenomas, thyroid, breast, and bone tumors, Sertoli tumors, melanocytic schwannoma, and cardiac and cutaneous myxomas).	('pigmented nodular adrenal diseases', 'Disease', (126, 160))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('melanocytic schwannoma', 'Disease', 'MESH:D009464', (279, 301))	('tumors', 'Disease', (271, 277))	('tumors', 'Disease', (255, 261))	('somatotroph pituitary adenomas', 'Disease', (197, 227))	('bone tumors', 'Disease', (250, 261))	('cutaneous myxomas', 'Disease', (319, 336))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('melanocytic schwannoma', 'Disease', (279, 301))	('bone tumors', 'Phenotype', 'HP:0010622', (250, 261))	('germline inactivating mutations', 'Var', (19, 50))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('cutaneous myxomas', 'Phenotype', 'HP:0030428', (319, 336))	('bone tumors', 'Disease', 'MESH:D001859', (250, 261))	('cutaneous myxomas', 'Disease', 'MESH:D009232', (319, 336))	('thyroid', 'Disease', (229, 236))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (209, 227))	('PRKAR1A', 'Gene', (54, 61))	('cause', 'Reg', (109, 114))	('CNC', 'Disease', (0, 3))	('Sertoli tumors', 'Phenotype', 'HP:0100619', (263, 277))	('pigmented nodular adrenal diseases', 'Disease', 'MESH:C566469', (126, 160))	('tumors', 'Disease', (189, 195))	('linked', 'Reg', (173, 179))	('somatotroph pituitary adenomas', 'Disease', 'MESH:D049912', (197, 227))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('PRKAR1A', 'Gene', '5573', (54, 61))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('schwannoma', 'Phenotype', 'HP:0100008', (291, 301))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('breast', 'Disease', (238, 244))
77282	33178583	BWS is an overgrowth and tumor predisposition syndrome caused by genetic or epigenetic changes at the 11p15 locus.	('caused by', 'Reg', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('BWS', 'Gene', (0, 3))	('genetic', 'Var', (65, 72))	('overgrowth and tumor', 'Disease', 'MESH:D019214', (10, 30))	('BWS', 'Gene', '1028', (0, 3))	('11p15', 'Gene', (102, 107))	('epigenetic changes', 'Var', (76, 94))	('overgrowth', 'Phenotype', 'HP:0001548', (10, 20))
77285	33178583	Then, the diagnosis of mosaic BWS was genetically confirmed by the evidence of chromosome 11 trisomy on healthy and neoplastic adrenal tissue but not on peripheral lymphocytes.	('BWS', 'Gene', (30, 33))	('BWS', 'Gene', '1028', (30, 33))	('trisomy', 'Var', (93, 100))	('neoplastic adrenal', 'Phenotype', 'HP:0100631', (116, 134))	('neoplastic adrenal tissue', 'Phenotype', 'HP:0100631', (116, 141))
77287	33178583	LFS is a dramatic cancer predisposition syndrome, caused by germline inactivating mutations of TP53 that highly expose to various and precocious cancer risk.	('cancer', 'Disease', (145, 151))	('caused by', 'Reg', (50, 59))	('germline inactivating mutations', 'Var', (60, 91))	('LFS', 'Disease', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('TP53', 'Gene', '7157', (95, 99))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('TP53', 'Gene', (95, 99))
77289	33178583	We found TP53 mutation in 75% of tested patients (6/8) underlining the need to predict carrier and familial disease penetrance with potentially broad implications for clinical surveillance and counseling.	('familial disease', 'Disease', 'MESH:D003141', (99, 115))	('patients', 'Species', '9606', (40, 48))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutation', 'Var', (14, 22))	('familial disease', 'Disease', (99, 115))
77290	33178583	Of note, the familial history was positive for cancer in four patients with TP53 mutation and highly suggestive of LFS in two cases for the tumor histotypes and the very young age of the affected individuals.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('positive', 'Reg', (34, 42))	('TP53', 'Gene', '7157', (76, 80))	('mutation', 'Var', (81, 89))	('cancer', 'Disease', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('TP53', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('patients', 'Species', '9606', (62, 70))	('tumor', 'Disease', (140, 145))
77291	33178583	In particular, the R248W missense TP53 mutant that we found in patient 8 has been described to gain novel oncogenic activities.	('TP53', 'Gene', (34, 38))	('R248W missense', 'Var', (19, 33))	('R248W', 'Mutation', 'rs121912651', (19, 24))	('patient', 'Species', '9606', (63, 70))	('oncogenic activities', 'CPA', (106, 126))	('TP53', 'Gene', '7157', (34, 38))	('gain', 'PosReg', (95, 99))
77292	33178583	have investigated the clinicopathologic characteristics and outcomes of children with ACT without germline TP53 mutations.	('mutations', 'Var', (112, 121))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('children', 'Species', '9606', (72, 80))
77293	33178583	They found overlapping features with those reported for children with germline TP53 mutations, highlighting the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACT.	('epigenetic alterations', 'Var', (139, 161))	('children', 'Species', '9606', (56, 64))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))
77310	32973129	Knockdown of BMP7 or its neutralization via follistatin in combination with anti-PD1 re-sensitizes resistant tumors to immunotherapies.	('PD', 'Disease', 'MESH:D010300', (81, 83))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('BMP7', 'Gene', (13, 17))	('neutralization', 'Var', (25, 39))
77313	32973129	Although antibodies blocking PD1/PDL1 have led to impressive clinical responses in some patients with melanoma, lung cancer, or renal cell carcinoma, the objective response rates to single-agent anti-PD1 or -PDL1 therapies are only 15-25% in chemotherapy-refractory non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', 'MESH:D002289', (294, 299))	('lung cancer', 'Disease', (112, 123))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (128, 148))	('lung cancer', 'Disease', 'MESH:D008175', (281, 292))	('antibodies', 'Var', (9, 19))	('NSCLC', 'Disease', (294, 299))	('lung cancer', 'Phenotype', 'HP:0100526', (281, 292))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('PD', 'Disease', 'MESH:D010300', (29, 31))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (266, 292))	('renal cell carcinoma', 'Disease', (128, 148))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (128, 148))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (270, 292))	('PD', 'Disease', 'MESH:D010300', (200, 202))	('lung cancer', 'Disease', (281, 292))	('patients', 'Species', '9606', (88, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('PD', 'Disease', 'MESH:D010300', (208, 210))	('PD', 'Disease', 'MESH:D010300', (33, 35))
77316	32973129	To answer these questions, we previously generated an anti-PD1-resistant preclinical tumor model involving an anti-PD1-resistant variant of the murine lung cancer cell line 344SQ in syngeneic mice.	('tumor', 'Disease', (85, 90))	('mice', 'Species', '10090', (192, 196))	('344SQ', 'Chemical', '-', (173, 178))	('variant', 'Var', (129, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('PD', 'Disease', 'MESH:D010300', (59, 61))	('lung cancer', 'Disease', (151, 162))	('murine', 'Species', '10090', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('PD', 'Disease', 'MESH:D010300', (115, 117))
77317	32973129	On that study, we found that 344SQR-resistant tumors are enriched in myeloid-derived suppressor cells (MDSCs) with decreased infiltration of CD4+ and CD8+ T cells, and reduced interferon-gamma (IFNG) production.	('interferon-gamma', 'Gene', (176, 192))	('infiltration', 'CPA', (125, 137))	('344SQ', 'Chemical', '-', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CD4', 'Gene', (141, 144))	('344SQR-resistant', 'Var', (29, 45))	('CD4', 'Gene', '12504', (141, 144))	('decreased', 'NegReg', (115, 124))	('interferon-gamma', 'Gene', '15978', (176, 192))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('reduced', 'NegReg', (168, 175))
77329	32973129	Furthermore, BMP7 inhibition in combination with anti-PD1 therapy activates CD4+ and CD8+ T cells in tumors, decreases M2 macrophages, and re-sensitizes resistant tumors to immunotherapies.	('M2 macrophages', 'CPA', (119, 133))	('PD', 'Disease', 'MESH:D010300', (54, 56))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CD4', 'Gene', (76, 79))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('inhibition', 'Var', (18, 28))	('CD4', 'Gene', '12504', (76, 79))	('re-sensitizes', 'CPA', (139, 152))	('BMP7', 'Gene', (13, 17))	('decreases', 'NegReg', (109, 118))	('tumors', 'Disease', (101, 107))	('activates', 'PosReg', (66, 75))
77330	32973129	We previously generated a syngeneic preclinical model of NSCLC (p53R172HDeltag/+KrasLA1/+) with acquired resistance to anti-PD1.	('PD', 'Disease', 'MESH:D010300', (124, 126))	('p53R172HDeltag/+KrasLA1/+', 'Var', (64, 89))	('NSCLC', 'Disease', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
77331	32973129	In the current study, we investigated methylation differences in specific genomic regions comparing anti-PD1-resistant tumors (344SQR) with their parental-tumor counterparts (344SQP).	('parental-tumor', 'Disease', 'MESH:D063129', (146, 160))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('344SQR', 'Var', (127, 133))	('PD', 'Disease', 'MESH:D010300', (105, 107))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('344SQ', 'Chemical', '-', (127, 132))	('344SQ', 'Chemical', '-', (175, 180))	('parental-tumor', 'Disease', (146, 160))
77332	32973129	Overall, genes were hypomethylated in anti-PD1-resistant tumors compared with parental tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('parental tumors', 'Disease', 'MESH:D063129', (78, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('parental tumors', 'Disease', (78, 93))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('hypomethylated', 'Var', (20, 34))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', (57, 63))	('PD', 'Disease', 'MESH:D010300', (43, 45))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
77333	32973129	Although some genes such as KCNK4, RAVER2, and NAV1 were hypermethylated, others including BMP7, SNORD37, and SLC2a13 were hypomethylated in 344SQR tumors compared with parental tumors (Fig.	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('SLC2a13', 'Gene', '239606', (110, 117))	('NAV1', 'Gene', (47, 51))	('RAVER2', 'Gene', (35, 41))	('KCNK4', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('344SQR', 'Var', (141, 147))	('NAV1', 'Gene', '215690', (47, 51))	('RAVER2', 'Gene', '242570', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('344SQ', 'Chemical', '-', (141, 146))	('parental tumors', 'Disease', (169, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('SLC2a13', 'Gene', (110, 117))	('KCNK4', 'Gene', '16528', (28, 33))	('hypomethylated', 'Var', (123, 137))	('tumors', 'Disease', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('BMP7', 'Gene', (91, 95))	('parental tumors', 'Disease', 'MESH:D063129', (169, 184))	('tumors', 'Disease', (178, 184))	('SNORD37', 'Gene', '100217454', (97, 104))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('SNORD37', 'Gene', (97, 104))
77336	32973129	We next validated BMP7 upregulation at the mRNA level in 344SQR and 344SQP tumors using quantitative polymerase chain reaction (PCR) (Fig.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('344SQP', 'Var', (68, 74))	('344SQR', 'Disease', (57, 63))	('BMP7', 'Gene', (18, 22))	('upregulation', 'PosReg', (23, 35))	('344SQ', 'Chemical', '-', (57, 62))	('344SQ', 'Chemical', '-', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
77339	32973129	We then analyzed BMP7 levels in pretreatment plasma samples from patients with subsequent progressive disease (PD) on pembrolizumab versus patients with progressive response (PR) or stable disease (SD) (NCT02444741; NCT02402920).	('NCT02444741; NCT02402920', 'Var', (203, 227))	('patients', 'Species', '9606', (139, 147))	('progressive disease', 'Disease', 'MESH:D018450', (90, 109))	('progressive disease', 'Disease', (90, 109))	('pembrolizumab', 'Chemical', 'MESH:C582435', (118, 131))	('BMP7 levels', 'MPA', (17, 28))	('patients', 'Species', '9606', (65, 73))	('PD', 'Disease', 'MESH:D010300', (111, 113))	('SD', 'Disease', 'MESH:D029461', (198, 200))
77341	32973129	We validated BMP7 upregulation at the protein level in 344SQR and 344SQP tumors (Fig.	('upregulation', 'PosReg', (18, 30))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('344SQ', 'Chemical', '-', (55, 60))	('344SQR', 'Var', (55, 61))	('344SQP', 'Var', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('344SQ', 'Chemical', '-', (66, 71))	('BMP7', 'Gene', (13, 17))
77342	32973129	1g) and in samples from patients with NSCLC, mixed Mullerian carcinoma, and adrenocortical carcinoma that initially responded to and later progressed on pembrolizumab (NCT02444741) or ipilimumab (NCT02239900) using immunohistochemical staining.	('NSCLC', 'Disease', (38, 43))	('carcinoma', 'Disease', 'MESH:D009369', (61, 70))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('NCT02444741', 'Var', (168, 179))	('ipilimumab', 'Chemical', 'MESH:D000074324', (184, 194))	('NCT02239900', 'Var', (196, 207))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (76, 100))	('carcinoma', 'Disease', 'MESH:D009369', (91, 100))	('pembrolizumab', 'Chemical', 'MESH:C582435', (153, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (76, 100))	('carcinoma', 'Disease', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('patients', 'Species', '9606', (24, 32))	('carcinoma', 'Disease', (61, 70))	('progressed', 'PosReg', (139, 149))	('adrenocortical carcinoma', 'Disease', (76, 100))
77347	32973129	For example, MAPK14 was downregulated and CTNNB1 (beta-catenin) was upregulated in 344SQR versus 344SQP.	('344SQ', 'Chemical', '-', (97, 102))	('CTNNB1', 'Gene', '12387', (42, 48))	('upregulated', 'PosReg', (68, 79))	('downregulated', 'NegReg', (24, 37))	('344SQR', 'Var', (83, 89))	('MAPK14', 'Gene', (13, 19))	('beta-catenin', 'Gene', (50, 62))	('CTNNB1', 'Gene', (42, 48))	('344SQP', 'Var', (97, 103))	('344SQ', 'Chemical', '-', (83, 88))	('beta-catenin', 'Gene', '12387', (50, 62))
77350	32973129	Because MAPK14 is inhibited by BMP7 via SMAD1 at high BMP7 concentrations, we analyzed MAPK14, SMAD1, and p-SMAD1/5/9 expression in 344SQP versus 344SQR tumors treated with IgG or anti-PD1.	('344SQ', 'Chemical', '-', (146, 151))	('344SQ', 'Chemical', '-', (132, 137))	('344SQP', 'Var', (132, 138))	('PD', 'Disease', 'MESH:D010300', (185, 187))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('inhibited', 'NegReg', (18, 27))	('tumors', 'Disease', (153, 159))	('MAPK14', 'Gene', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
77362	32973129	To validate these findings, we analyzed serum levels of MAPK14-regulated cytokines and chemokines from mice bearing 344SQR or 344SQP tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('mice', 'Species', '10090', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('344SQ', 'Chemical', '-', (116, 121))	('344SQ', 'Chemical', '-', (126, 131))	('344SQR', 'Var', (116, 122))
77365	32973129	As BMP7 was shown to be correlated with TGFB, we analyzed serum levels of TGFG1, TGFG2, and TGFB3 from mice bearing 344SQR or 344SQP tumors treated with IgG control or anti-PD1 antibodies by enzyme-linked immunosorbent assay (ELISA).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('TGFG1', 'Gene', (74, 79))	('TGFB3', 'Gene', (92, 97))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('mice', 'Species', '10090', (103, 107))	('TGFB3', 'Gene', '21809', (92, 97))	('TGFG2', 'Gene', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('344SQ', 'Chemical', '-', (116, 121))	('344SQ', 'Chemical', '-', (126, 131))	('344SQP', 'Var', (126, 132))	('PD', 'Disease', 'MESH:D010300', (173, 175))
77366	32973129	We did not find differences in TGFB levels in 344SQP vs. 344SQR treated with IgG control or 344SQP vs. 344SQR treated with anti-PD1 antibodies.	('344SQ', 'Chemical', '-', (46, 51))	('344SQ', 'Chemical', '-', (92, 97))	('TGFB levels', 'MPA', (31, 42))	('PD', 'Disease', 'MESH:D010300', (128, 130))	('344SQ', 'Chemical', '-', (57, 62))	('344SQP', 'Var', (92, 98))	('344SQ', 'Chemical', '-', (103, 108))
77373	32973129	We then treated RAW 264.7 cells and peritoneal macrophages with BMP7 and found that these cells had lower expression of MAPK14 and MAPK14-regulated cytokines and chemokines when treated with BM7 versus untreated control (Fig.	('RAW 264.7', 'CellLine', 'CVCL:0493', (16, 25))	('MAPK14', 'Gene', (120, 126))	('expression', 'MPA', (106, 116))	('lower', 'NegReg', (100, 105))	('MAPK14-regulated', 'Gene', (131, 147))	('BM7', 'Var', (191, 194))
77374	32973129	We next treated RAW 264.7 cells with BMP7 with or without follistatin and found that RAW 264.7 cells had lower expression of MAPK14 and MAPK14-regulated cytokines and chemokines when treated with BM7 versus untreated control and BM7 plus follistatin (Fig.	('lower', 'NegReg', (105, 110))	('RAW 264.7', 'CellLine', 'CVCL:0493', (16, 25))	('RAW 264.7', 'CellLine', 'CVCL:0493', (85, 94))	('BM7', 'Var', (196, 199))	('expression', 'MPA', (111, 121))	('MAPK14', 'Gene', (125, 131))	('MAPK14-regulated', 'Gene', (136, 152))
77376	32973129	We first measured BMP7 levels in media from 344SQP vs. 344SQR, and 344SQR ctrl vs. 344SQR shBMP7.	('vs. 344SQR', 'Var', (79, 89))	('344SQ', 'Chemical', '-', (55, 60))	('measured', 'Reg', (9, 17))	('344SQ', 'Chemical', '-', (67, 72))	('344SQ', 'Chemical', '-', (44, 49))	('344SQR', 'Var', (67, 73))	('BMP7 levels', 'MPA', (18, 29))	('344SQ', 'Chemical', '-', (83, 88))
77377	32973129	As expected, 344SQR cells secreted higher levels of BMP7 than 344SQP cells, and BMP7-knockdown cells secreted lower BMP7 levels than 344SQR ctrl (Fig.	('secreted', 'MPA', (26, 34))	('344SQ', 'Chemical', '-', (133, 138))	('levels of BMP7', 'MPA', (42, 56))	('BMP7 levels', 'MPA', (116, 127))	('lower', 'NegReg', (110, 115))	('344SQ', 'Chemical', '-', (13, 18))	('higher', 'PosReg', (35, 41))	('BMP7-knockdown', 'Var', (80, 94))	('344SQ', 'Chemical', '-', (62, 67))
77378	32973129	We then co-cultured RAW 264.7 cells with 344SQP or 344SQR and found that macrophages cultured with 344SQR cells had lower expression of MAPK14 and MAPK14-regulated cytokines and chemokines compared with cells co-cultured with 344SQP cells.	('lower', 'NegReg', (116, 121))	('expression', 'MPA', (122, 132))	('MAPK14', 'Gene', (136, 142))	('RAW 264.7', 'CellLine', 'CVCL:0493', (20, 29))	('344SQ', 'Chemical', '-', (226, 231))	('344SQ', 'Chemical', '-', (99, 104))	('344SQR', 'Var', (99, 105))	('MAPK14-regulated cytokines', 'MPA', (147, 173))	('344SQ', 'Chemical', '-', (41, 46))	('344SQ', 'Chemical', '-', (51, 56))
77379	32973129	To confirm that these findings depended on BMP7 rather than some other secreted molecule, we co-cultured macrophages with 344SQR ctrl or 344SQR shBMP7 cells.	('344SQR', 'Var', (137, 143))	('344SQ', 'Chemical', '-', (137, 142))	('344SQ', 'Chemical', '-', (122, 127))	('344SQR', 'Var', (122, 128))
77380	32973129	Macrophages co-cultured with 344SQR shBMP7 cells had higher expression of MAPK14 and MAPK14-regulated cytokines and chemokines compared with 344SQR ctrl (Fig.	('expression', 'MPA', (60, 70))	('MAPK14', 'Gene', (74, 80))	('344SQ', 'Chemical', '-', (141, 146))	('higher', 'PosReg', (53, 59))	('344SQ', 'Chemical', '-', (29, 34))	('shBMP7', 'Gene', (36, 42))	('344SQR', 'Var', (29, 35))	('MAPK14-regulated', 'Gene', (85, 101))
77382	32973129	We found that macrophages co-cultured with 344SQR and treated with follistatin or the BMP receptor inhibitor K02288 had higher expression of MAPK14 and MAPK14-regulated cytokines and chemokines versus 344SQR co-culture only (Fig.	('K02288', 'Chemical', 'MESH:C584410', (109, 115))	('BMP', 'Gene', (86, 89))	('MAPK14-regulated cytokines', 'MPA', (152, 178))	('expression', 'MPA', (127, 137))	('higher', 'PosReg', (120, 126))	('344SQ', 'Chemical', '-', (201, 206))	('344SQ', 'Chemical', '-', (43, 48))	('MAPK14', 'Gene', (141, 147))	('344SQR', 'Var', (43, 49))	('BMP', 'Gene', '649', (86, 89))
77391	32973129	We next co-cultured CD4+ T cells with 344SQP or 344SQR cells, and 344SQR ctrl or 344SQR shBMP7 cells, and analyzed the expression of MAPK14, IFNG, and IL2.	('CD4', 'Gene', (20, 23))	('IFNG', 'Gene', (141, 145))	('MAPK14', 'Gene', (133, 139))	('344SQR', 'Var', (66, 72))	('CD4', 'Gene', '12504', (20, 23))	('344SQ', 'Chemical', '-', (81, 86))	('344SQ', 'Chemical', '-', (38, 43))	('IL2', 'Gene', (151, 154))	('344SQ', 'Chemical', '-', (48, 53))	('344SQ', 'Chemical', '-', (66, 71))
77393	32973129	We found that co-culture of activated CD4+ T cells with 344SQR cells led to decreased MAPK14, IFNG, and IL2 expression compared with 344SQP cells (Fig.	('IFNG', 'Gene', (94, 98))	('CD4', 'Gene', (38, 41))	('344SQR', 'Var', (56, 62))	('344SQ', 'Chemical', '-', (133, 138))	('CD4', 'Gene', '12504', (38, 41))	('decreased', 'NegReg', (76, 85))	('MAPK14', 'Gene', (86, 92))	('expression', 'MPA', (108, 118))	('IL2', 'Gene', (104, 107))	('344SQ', 'Chemical', '-', (56, 61))
77394	32973129	To confirm that these findings depended on BMP7 and not on some other secreted molecule, we co-cultured CD4+ T cells with 344SQR ctrl or 344SQR shBMP7 cells.	('344SQR', 'Var', (137, 143))	('CD4', 'Gene', (104, 107))	('344SQ', 'Chemical', '-', (122, 127))	('CD4', 'Gene', '12504', (104, 107))	('344SQR', 'Var', (122, 128))	('344SQ', 'Chemical', '-', (137, 142))
77395	32973129	Co-culture of CD4+ T cells with 344SQR shBMP7 upregulated MAPK14, IFNG, and IL2 expression compared with 344SQR ctrl (Fig.	('shBMP7', 'Gene', (39, 45))	('IFNG', 'Gene', (66, 70))	('IL2', 'Gene', (76, 79))	('CD4', 'Gene', (14, 17))	('MAPK14', 'Gene', (58, 64))	('344SQ', 'Chemical', '-', (32, 37))	('344SQ', 'Chemical', '-', (105, 110))	('CD4', 'Gene', '12504', (14, 17))	('344SQR', 'Var', (32, 38))	('expression', 'MPA', (80, 90))	('upregulated', 'PosReg', (46, 57))
77400	32973129	Next, we tested if BMP7 knockdown could sensitize anti-PD1-resistant tumors to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('sensitize', 'Reg', (40, 49))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('PD', 'Disease', 'MESH:D010300', (55, 57))	('knockdown', 'Var', (24, 33))	('tested', 'Reg', (9, 15))
77402	32973129	BMP7 knockdown was found to re-sensitize tumors to anti-PD1 and extended mouse survival relative to the control group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('BMP7', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('re-sensitize', 'PosReg', (28, 40))	('knockdown', 'Var', (5, 14))	('extended', 'PosReg', (64, 72))	('tumors', 'Disease', (41, 47))	('PD', 'Disease', 'MESH:D010300', (56, 58))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('mouse survival', 'CPA', (73, 87))	('mouse', 'Species', '10090', (73, 78))
77405	32973129	In order to confirm these effects are not specific to 344SQR cell line, we tested if BMP7 knockdown in 4T1 mouse mammary carcinoma model promote sensitivity to anti-PD1 therapy.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('BMP7', 'Gene', (85, 89))	('knockdown', 'Var', (90, 99))	('tested', 'Reg', (75, 81))	('mouse', 'Species', '10090', (107, 112))	('344SQ', 'Chemical', '-', (54, 59))	('promote', 'PosReg', (137, 144))	('sensitivity', 'MPA', (145, 156))	('carcinoma', 'Disease', (121, 130))	('PD', 'Disease', 'MESH:D010300', (165, 167))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (113, 130))	('carcinoma', 'Disease', 'MESH:D009369', (121, 130))
77418	32973129	We also tested the combination of BMP7 knockdown and anti-CTLA4 or anti-PDL1.	('tested', 'Reg', (8, 14))	('BMP7', 'Gene', (34, 38))	('knockdown', 'Var', (39, 48))	('CTLA4', 'Gene', (58, 63))	('anti-PDL1', 'Var', (67, 76))	('CTLA4', 'Gene', '12477', (58, 63))
77419	32973129	We found that antibodies to both PDL1 and CTLA4 increased survival in combination with BMP7-knockdown compared with control (Fig.	('increased', 'PosReg', (48, 57))	('PDL1', 'Gene', (33, 37))	('survival', 'CPA', (58, 66))	('CTLA4', 'Gene', (42, 47))	('BMP7-knockdown', 'Gene', (87, 101))	('antibodies', 'Var', (14, 24))	('CTLA4', 'Gene', '12477', (42, 47))
77426	32973129	We found GSE50081 with 181 Stage I and II NSCLC cases from Der SD et al.	('GSE50081', 'Var', (9, 17))	('SD', 'Disease', 'MESH:D029461', (63, 65))	('NSCLC', 'Disease', (42, 47))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))
77437	32973129	For example, epigenetic drugs enhance the efficacy of immune checkpoint inhibitor therapy by increasing the expression of immune checkpoint ligands and tumor-associated antigens on tumor cells.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('immune checkpoint', 'Gene', (122, 139))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('increasing', 'PosReg', (93, 103))	('tumor', 'Disease', (152, 157))	('epigenetic drugs', 'Var', (13, 29))	('expression', 'MPA', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('efficacy', 'MPA', (42, 50))	('enhance', 'PosReg', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
77440	32973129	Along with BMP7, we found other genes to be epigenetically modulated in the anti-PD1-resistant tumors compared with parental tumors.	('PD', 'Disease', 'MESH:D010300', (81, 83))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('parental tumors', 'Disease', 'MESH:D063129', (116, 131))	('epigenetically modulated', 'Var', (44, 68))	('parental tumors', 'Disease', (116, 131))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
77444	32973129	We then validated MAPK14 downregulation in 344SQP versus 344SQR tumors, and in cancer patients with progression on immunotherapies.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('344SQ', 'Chemical', '-', (43, 48))	('344SQ', 'Chemical', '-', (57, 62))	('344SQR', 'Var', (57, 63))	('MAPK14', 'Gene', (18, 24))	('344SQP', 'Var', (43, 49))	('downregulation', 'NegReg', (25, 39))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('patients', 'Species', '9606', (86, 94))
77454	32973129	Others have also found that BMP7 treatment led to significant reductions in proinflammatory cytokines, including TNF, in macrophages in vivo and that BMP7 represses TNF and IL1B in models of chronic and acute renal failure and in chondrocytes from patients with osteoarthritis.	('proinflammatory cytokines', 'MPA', (76, 101))	('renal failure', 'Phenotype', 'HP:0000083', (209, 222))	('osteoarthritis', 'Disease', 'MESH:D010003', (262, 276))	('acute renal failure', 'Disease', (203, 222))	('BMP7', 'Gene', (28, 32))	('represses', 'NegReg', (155, 164))	('IL1B', 'Gene', (173, 177))	('acute renal failure', 'Disease', 'MESH:D058186', (203, 222))	('acute renal failure', 'Phenotype', 'HP:0001919', (203, 222))	('BMP7', 'Var', (150, 154))	('reductions', 'NegReg', (62, 72))	('patients', 'Species', '9606', (248, 256))	('osteoarthritis', 'Phenotype', 'HP:0002758', (262, 276))	('osteoarthritis', 'Disease', (262, 276))	('TNF', 'MPA', (113, 116))	('TNF', 'Gene', (165, 168))
77462	32973129	We found that murine macrophages co-cultured with 344SQR cells had lower expression of MAPK14, IL1A, IL1B, TNF, and CCL5 compared with cells co-cultured with 344SQP cells.	('murine', 'Species', '10090', (14, 20))	('IL1A', 'Gene', (95, 99))	('TNF', 'Gene', (107, 110))	('IL1B', 'Gene', (101, 105))	('344SQ', 'Chemical', '-', (50, 55))	('344SQR', 'Var', (50, 56))	('expression', 'MPA', (73, 83))	('MAPK14', 'Gene', (87, 93))	('344SQ', 'Chemical', '-', (158, 163))	('CCL5', 'Gene', (116, 120))	('lower', 'NegReg', (67, 72))
77464	32973129	We found that murine macrophages co-cultured with BMP7-knockdown 344SQR cells expressed higher levels of MAPK14, IL1A, IL1B, TNF, and CCL5 compared with 344SQR ctrl cells.	('higher', 'PosReg', (88, 94))	('murine', 'Species', '10090', (14, 20))	('344SQ', 'Chemical', '-', (153, 158))	('MAPK14', 'MPA', (105, 111))	('344SQR', 'Var', (65, 71))	('IL1B', 'MPA', (119, 123))	('CCL5', 'MPA', (134, 138))	('344SQ', 'Chemical', '-', (65, 70))	('TNF', 'MPA', (125, 128))	('IL1A', 'Gene', (113, 117))
77469	32973129	Previous studies showed that treating cells with SB203580, a specific inhibitor of MAPK14, suppressed the transcriptional activation of the IL2 promoter in T lymphocytes.	('suppressed', 'NegReg', (91, 101))	('IL2 promoter', 'Gene', (140, 152))	('SB203580', 'Var', (49, 57))	('SB203580', 'Chemical', 'MESH:C093642', (49, 57))	('transcriptional activation', 'MPA', (106, 132))
77477	32973129	We then tested whether BMP7 knockdown could re-sensitize anti-PD1-resistant tumors to immunotherapy.	('tested', 'Reg', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('PD', 'Disease', 'MESH:D010300', (62, 64))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('knockdown', 'Var', (28, 37))
77478	32973129	We found that BMP7 knockdown in anti-PD1-resistant 344SQR model and in 4T1 mouse mammary carcinoma model sensitized tumors to anti-PD1 and extended survival relative to the control.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('extended', 'PosReg', (139, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('knockdown', 'Var', (19, 28))	('carcinoma', 'Disease', 'MESH:D009369', (89, 98))	('344SQ', 'Chemical', '-', (51, 56))	('mouse', 'Species', '10090', (75, 80))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (81, 98))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('PD', 'Disease', 'MESH:D010300', (131, 133))	('survival', 'CPA', (148, 156))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('sensitized', 'Reg', (105, 115))	('PD', 'Disease', 'MESH:D010300', (37, 39))	('carcinoma', 'Disease', (89, 98))
77480	32973129	As follistatin not only neutralizes BMP7 but other members of the TGFB superfamily such as activins, it might represent a broader approach to overcome resistance to anti-PD1.	('BMP7', 'Gene', (36, 40))	('PD', 'Disease', 'MESH:D010300', (170, 172))	('neutralizes', 'Var', (24, 35))
77481	32973129	Interestingly, the combination of BMP7 knockdown and anti-CTLA4 or anti-PDL1 also extended survival compared with control, which suggests that mechanisms of resistance to anti-PD1 might overlap with resistance to anti-CTLA4 or anti-PDL1.	('survival', 'CPA', (91, 99))	('BMP7', 'Gene', (34, 38))	('knockdown', 'Var', (39, 48))	('CTLA4', 'Gene', '12477', (218, 223))	('CTLA4', 'Gene', (58, 63))	('extended', 'PosReg', (82, 90))	('PD', 'Disease', 'MESH:D010300', (176, 178))	('PD', 'Disease', 'MESH:D010300', (72, 74))	('CTLA4', 'Gene', '12477', (58, 63))	('PD', 'Disease', 'MESH:D010300', (232, 234))	('CTLA4', 'Gene', (218, 223))
77492	32973129	At the same time, BMP7 decreased CD4+ T-cell activation by downregulating IFNG and IL2 expression via SMAD1/ MAPK14 signaling (Fig.	('IL2', 'Gene', (83, 86))	('BMP7', 'Var', (18, 22))	('downregulating', 'NegReg', (59, 73))	('CD4', 'Gene', '12504', (33, 36))	('IFNG', 'Gene', (74, 78))	('expression', 'MPA', (87, 97))	('CD4', 'Gene', (33, 36))	('decreased', 'NegReg', (23, 32))
77494	32973129	Tumor biopsies from a NSCLC patient with disease progression after pembrolizumab (NCT02444741), a patient with adrenocortical carcinoma and a patient with Mixed Mullerian carcinoma with disease progression after ipilimumab (NCT02239900) were examined.	('adrenocortical carcinoma', 'Disease', (111, 135))	('carcinoma', 'Disease', (126, 135))	('carcinoma', 'Disease', (171, 180))	('ipilimumab', 'Chemical', 'MESH:D000074324', (212, 222))	('patient', 'Species', '9606', (98, 105))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('NCT02444741', 'Var', (82, 93))	('carcinoma', 'Disease', 'MESH:D009369', (171, 180))	('pembrolizumab', 'Chemical', 'MESH:C582435', (67, 80))	('carcinoma', 'Disease', 'MESH:D009369', (126, 135))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (111, 135))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (111, 135))	('patient', 'Species', '9606', (28, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('NSCLC', 'Disease', (22, 27))	('patient', 'Species', '9606', (142, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))
77514	32973129	Culture supernatants were freshly collected from 344SQP, 344SQP, 344SQR ctrl, and shBMP7 tumors and directly submitted for analysis.	('344SQ', 'Chemical', '-', (49, 54))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('344SQR', 'Var', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('344SQ', 'Chemical', '-', (57, 62))	('shBMP7', 'Gene', (82, 88))	('344SQP', 'Var', (57, 63))	('344SQ', 'Chemical', '-', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
77515	32973129	Plasma samples from patients with PD on pembrolizumab (NCT02444741; NCT02402920) and radiotherapy versus patients with PR or SD were collected as previously described.	('patients', 'Species', '9606', (105, 113))	('SD', 'Disease', 'MESH:D029461', (125, 127))	('NCT02444741; NCT02402920', 'Var', (55, 79))	('PD', 'Disease', 'MESH:D010300', (34, 36))	('patients', 'Species', '9606', (20, 28))	('pembrolizumab', 'Chemical', 'MESH:C582435', (40, 53))	('NCT02402920', 'Var', (68, 79))
77535	32973129	Cells were then treated with 0.1% NP40 in PBS for 20 min, washed in PBS four times, and then blocked with 5% bovine serum albumin in PBS for 30 min.	('PBS', 'Chemical', '-', (68, 71))	('PBS', 'Chemical', '-', (133, 136))	('serum albumin', 'Gene', '11657', (116, 129))	('serum albumin', 'Gene', (116, 129))	('NP40', 'Var', (34, 38))	('PBS', 'Chemical', '-', (42, 45))
77536	32973129	Cells were then incubated with MAPK14 (L53F8) (Cell Signaling, Catalog #9228) and Phospho-Smad1 (Ser463/465), Smad5 (Ser463/465), and Smad9 (Ser465/467) (D5B10) (Cell Signaling, Catalog #13820) in 5% bovine serum albumin in PBS overnight according to the manufacturer's protocol (dilution 1:25).	('PBS', 'Chemical', '-', (224, 227))	('serum albumin', 'Gene', '11657', (207, 220))	('Smad5', 'Gene', '17129', (110, 115))	('Ser465/467', 'Var', (141, 151))	('Smad9', 'Gene', (134, 139))	('Cat', 'Gene', (178, 181))	('Ser463', 'Chemical', '-', (117, 123))	('serum albumin', 'Gene', (207, 220))	('Smad9', 'Gene', '55994', (134, 139))	('Cat', 'Gene', (63, 66))	('L53F8', 'Var', (39, 44))	('Ser463', 'Chemical', '-', (97, 103))	('Ser465', 'Chemical', '-', (141, 147))	('Smad1', 'Gene', (90, 95))	('Cat', 'Gene', '12359', (178, 181))	('Smad5', 'Gene', (110, 115))	('Smad1', 'Gene', '17125', (90, 95))	('Cat', 'Gene', '12359', (63, 66))
77540	32973129	344SQP, 344SQR, 344SQ ctrl, or 344SQ-shBMP7 cells were seeded at the top inserts (24-mm Transwell with 0.4-microm pore polycarbonate membrane insert, Sigma-Aldrich), and RAW 264.7, peritoneal macrophages or CD4+ T cells were seeded at the bottom of the transwell system.	('pore', 'Chemical', '-', (114, 118))	('344SQ', 'Chemical', '-', (16, 21))	('344SQ', 'Chemical', '-', (8, 13))	('CD4', 'Gene', '12504', (207, 210))	('344SQ', 'Chemical', '-', (0, 5))	('344SQ-shBMP7', 'Var', (31, 43))	('CD4', 'Gene', (207, 210))	('344SQ', 'Var', (16, 21))	('RAW 264.7', 'CellLine', 'CVCL:0493', (170, 179))	('344SQ', 'Chemical', '-', (31, 36))
77545	32973129	For RRBS, RPPA, and TILs studies, primary tumors were established by subcutaneous injection of 344SQP or 344SQR cells (0.5 x 106 in 100 muL of sterile PBS) into the leg of syngeneic 129 Sv/Ev mice (female, 12-16 weeks old).	('primary tumors', 'Disease', (34, 48))	('mice', 'Species', '10090', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('primary tumors', 'Disease', 'MESH:D001932', (34, 48))	('344SQ', 'Chemical', '-', (105, 110))	('344SQ', 'Chemical', '-', (95, 100))	('PBS', 'Chemical', '-', (151, 154))	('344SQR', 'Var', (105, 111))	('344SQP', 'Var', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('129 Sv', 'Species', '10090', (182, 188))
77573	32251318	However, the functions of the many variants of these proteins in cancer remain incompletely understood.	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('variants', 'Var', (35, 43))
77575	32251318	Although the mutation rate of the netrin family is low in pan-cancer, among the tumor patients with netrin mutations, the highest number are Uterine Corpus Endometrial Carcinoma patients, accounting for 13.6% of cases (54 of 397).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('netrin', 'Gene', (100, 106))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (178, 186))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (149, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('tumor', 'Disease', (80, 85))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('Corpus Endometrial Carcinoma', 'Disease', (149, 177))	('patients', 'Species', '9606', (86, 94))
77583	32251318	HGF inhibits the treatment of RAF inhibitors of BRAF mutant melanoma.	('inhibits', 'NegReg', (4, 12))	('RAF', 'Gene', '22882', (49, 52))	('HGF', 'Gene', (0, 3))	('RAF', 'Gene', (49, 52))	('treatment of', 'MPA', (17, 29))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('HGF', 'Gene', '3082', (0, 3))	('melanoma', 'Disease', (60, 68))	('RAF', 'Gene', '22882', (30, 33))	('mutant', 'Var', (53, 59))	('RAF', 'Gene', (30, 33))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
77602	32251318	Mutations in the netrins were identified in the 33 cancers included in TCGA (Fig.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('netrins', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('identified', 'Reg', (30, 40))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
77603	32251318	At the cancer level, netrins associated with uterine corpus endometrial carcinoma (UCEC) exhibited the highest number of mutations (54), followed by colon adenocarcinoma (COAD) (49), skin cutaneous melanoma (SKCM) (47), stomach adenocarcinoma (STAD) (42), lung adenocarcinoma (LUAD) (38), and lung squamous cell carcinoma (LUSC)(36).	('mutations', 'Var', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (60, 81))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('lung adenocarcinoma', 'Disease', (256, 275))	('cancer', 'Disease', (7, 13))	('associated', 'Reg', (29, 39))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (188, 206))	('stomach adenocarcinoma', 'Disease', (220, 242))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (220, 242))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (256, 275))	('corpus endometrial carcinoma', 'Disease', (53, 81))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (53, 81))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (293, 321))	('colon adenocarcinoma (COAD) (49), skin cutaneous melanoma', 'Disease', 'MESH:D029424', (149, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (298, 321))	('lung squamous cell carcinoma', 'Disease', (293, 321))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (256, 275))	('netrins', 'Gene', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
77604	32251318	The total mutation rates of Netrin family members in the above six cancers were 10.19%, 12.28%, 10.06%, 9.61%, 6.70% and 7.32%, respectively.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('Netrin family', 'Gene', (28, 41))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('mutation', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
77606	32251318	However, the hot spot mutation P201Qfs*15 of NTN3 was identified in three patients, each with a different cancer (ESCA, STAD, UCEC), and encodes a truncated protein.	('STAD', 'Disease', (120, 124))	('P201Qfs*15', 'Var', (31, 41))	('NTN3', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('ESCA', 'Phenotype', 'HP:0011459', (114, 118))	('cancer', 'Disease', (106, 112))	('NTN3', 'Gene', '4917', (45, 49))
77607	32251318	E59K, one of the hotspot mutations of NTN4, was detected in four patients with three cancers (READ, COAD, and UCEC) and both VEST3 and REVEL algorithms indicated this change was dual-damaging.	('READ', 'Disease', (94, 98))	('detected', 'Reg', (48, 56))	('COAD', 'Disease', (100, 104))	('NTN4', 'Gene', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('E59K', 'Var', (0, 4))	('cancers', 'Disease', (85, 92))	('NTN4', 'Gene', '59277', (38, 42))	('E59K', 'Mutation', 'rs762617558', (0, 4))	('patients', 'Species', '9606', (65, 73))	('READ', 'Disease', '-', (94, 98))	('COAD', 'Disease', 'MESH:D029424', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
77608	32251318	The hot spot mutation X342_splice of NTN5 occurred in two cancers (SKCM and UCEC) in two patients, and also encodes a truncated protein.	('occurred', 'Reg', (42, 50))	('NTN5', 'Gene', '126147', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('NTN5', 'Gene', (37, 41))	('patients', 'Species', '9606', (89, 97))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('X342_splice', 'Var', (22, 33))
77609	32251318	The hot spot mutation R238C/H of NTNG1 was detected in three patients with three cancers (COAD, STAD, and UCEC), and R238C was predicted as damaging in VEST3 and REVEL algorithms.	('STAD', 'Disease', (96, 100))	('NTNG1', 'Gene', '22854', (33, 38))	('R238C', 'Var', (117, 122))	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('R238C', 'SUBSTITUTION', 'None', (117, 122))	('NTNG1', 'Gene', (33, 38))	('R238C', 'Mutation', 'p.R238C', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('patients', 'Species', '9606', (61, 69))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('R238C', 'Var', (22, 27))	('COAD', 'Disease', (90, 94))	('R238C', 'Mutation', 'p.R238C', (22, 27))	('R238C', 'SUBSTITUTION', 'None', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
77610	32251318	The NTNG2 hotspot mutation D226N/Rfs*141 occurred in three patients with three cancers (LAML, GBM, and COAD), and NTN1 hotspot mutation P459T was detected in three patients with two cancers (STAD, READ).The mutations in NTN1, NTN3, NTN4, NTNG1, and NTNG2 were mainly in the laminin-N domain, and most mutations of NTN5 were concentrated in the laminin_EGF2 domain.	('NTNG1', 'Gene', '22854', (238, 243))	('NTNG2', 'Gene', (249, 254))	('NTN1', 'Gene', '9423', (114, 118))	('P459T', 'Mutation', 'rs376278603', (136, 141))	('NTN4', 'Gene', (232, 236))	('NTN1', 'Gene', (220, 224))	('COAD', 'Disease', (103, 107))	('NTN5', 'Gene', (314, 318))	('D226N', 'SUBSTITUTION', 'None', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('mutations', 'Var', (207, 216))	('patients', 'Species', '9606', (59, 67))	('cancers', 'Disease', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('NTN5', 'Gene', '126147', (314, 318))	('patients', 'Species', '9606', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (79, 86))	('NTN1', 'Gene', '9423', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NTN4', 'Gene', '59277', (232, 236))	('NTNG2', 'Gene', '84628', (4, 9))	('D226N', 'Var', (27, 32))	('NTN3', 'Gene', '4917', (226, 230))	('NTNG2', 'Gene', '84628', (249, 254))	('NTNG1', 'Gene', (238, 243))	('NTN1', 'Gene', (114, 118))	('READ', 'Disease', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('COAD', 'Disease', 'MESH:D029424', (103, 107))	('READ', 'Disease', '-', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('NTN3', 'Gene', (226, 230))	('NTNG2', 'Gene', (4, 9))
77611	32251318	After screening by genetic ancestry groups and non-synonymous mutations, 62 patients had complete mutation information (64 mutations) for NTN1, 34 patients were included with complete mutation information (37 mutations) for NTN3, and 107 patients had complete mutation information (120 mutations) for NTN4.	('NTN4', 'Gene', (301, 305))	('patients', 'Species', '9606', (76, 84))	('NTN3', 'Gene', '4917', (224, 228))	('NTN1', 'Gene', (138, 142))	('NTN3', 'Gene', (224, 228))	('NTN4', 'Gene', '59277', (301, 305))	('NTN1', 'Gene', '9423', (138, 142))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (238, 246))	('mutations', 'Var', (123, 132))
77612	32251318	Additionally, the data included 33 patients with 33 mutations in NTN5, 152 patient and 161 mutations in NTNG1, and 91 patients with 98 mutations in (Fig.	('mutations', 'Var', (52, 61))	('NTNG1', 'Gene', '22854', (104, 109))	('patient', 'Species', '9606', (75, 82))	('patient', 'Species', '9606', (35, 42))	('NTN5', 'Gene', '126147', (65, 69))	('patients', 'Species', '9606', (35, 43))	('patient', 'Species', '9606', (118, 125))	('patients', 'Species', '9606', (118, 126))	('NTN5', 'Gene', (65, 69))	('NTNG1', 'Gene', (104, 109))
77613	32251318	By comparing the data, we found that up to four netrin family members in individual patients contained mutations in four patients, three UCEC patients and one STAD patient with mutations in both NTN1 and NTNG2.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (84, 92))	('NTNG2', 'Gene', (204, 209))	('patient', 'Species', '9606', (164, 171))	('patient', 'Species', '9606', (121, 128))	('patient', 'Species', '9606', (84, 91))	('patient', 'Species', '9606', (142, 149))	('contained', 'Reg', (93, 102))	('NTN1', 'Gene', (195, 199))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (121, 129))	('NTNG2', 'Gene', '84628', (204, 209))	('NTN1', 'Gene', '9423', (195, 199))
77614	32251318	In cancer studies with at least five mutations in members of netrin genes (Fig.	('netrin genes', 'Gene', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
77615	32251318	2b), UCEC patients were one of the two highest among the cancers associated with the netrin family mutations, with most mutations in NTNG1.	('NTNG1', 'Gene', '22854', (133, 138))	('UCEC', 'Disease', (5, 9))	('NTNG1', 'Gene', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (10, 18))
77616	32251318	SKCM has the most mutations in NTN4.	('NTN4', 'Gene', '59277', (31, 35))	('NTN4', 'Gene', (31, 35))	('mutations', 'Var', (18, 27))
77617	32251318	2c), the highest number of cancer mutations among the four genetic ancestry groups was UCEC, and the netrin family mutations in STAD were mainly distributed in EAA and NA.	('netrin family', 'Gene', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (34, 43))
77618	32251318	Most netrin mutations in COAD occur in EA and AA.	('mutations', 'Var', (12, 21))	('COAD', 'Disease', (25, 29))	('COAD', 'Disease', 'MESH:D029424', (25, 29))	('netrin', 'Gene', (5, 11))
77619	32251318	2d,e) revealed that most mutations in netrins were in the laminin N-terminal domain, except for NTN5.	('NTN5', 'Gene', '126147', (96, 100))	('mutations', 'Var', (25, 34))	('netrins', 'Gene', (38, 45))	('NTN5', 'Gene', (96, 100))
77620	32251318	In the laminin EGF domains of NTN1, NTN3, NTN4, and NTN5, most mutations were in the laminin EGF-like 2 domain.	('mutations', 'Var', (63, 72))	('NTN4', 'Gene', (42, 46))	('NTN5', 'Gene', '126147', (52, 56))	('NTN3', 'Gene', '4917', (36, 40))	('NTN4', 'Gene', '59277', (42, 46))	('NTN3', 'Gene', (36, 40))	('NTN1', 'Gene', (30, 34))	('NTN1', 'Gene', '9423', (30, 34))	('NTN5', 'Gene', (52, 56))
77621	32251318	In the NTNG1 laminin EGF domains, the mutation of laminin EGF-like 3 was the most frequent, and in the NTNG2 laminin EGF domains, the mutation of laminin EGF-like 1 was the most frequent.	('NTNG2', 'Gene', (103, 108))	('mutation', 'Var', (134, 142))	('frequent', 'Reg', (82, 90))	('frequent', 'Reg', (178, 186))	('laminin EGF-like 3', 'Gene', (50, 68))	('NTNG1', 'Gene', '22854', (7, 12))	('mutation', 'Var', (38, 46))	('NTNG2', 'Gene', '84628', (103, 108))	('NTNG1', 'Gene', (7, 12))
77622	32251318	The mutations in the NTR domain were mainly concentrated in NTN1 and 4.	('NTR', 'Gene', (21, 24))	('NTN1', 'Gene', (60, 64))	('NTN1', 'Gene', '9423', (60, 64))	('NTR', 'Gene', '4923', (21, 24))	('mutations', 'Var', (4, 13))
77632	32251318	Additionally, MLK1 enhanced cancer cell migration and invasion by epigenetic activation of MMP9 transcription in lung cancer.	('cancer', 'Disease', (118, 124))	('lung cancer', 'Disease', (113, 124))	('invasion', 'CPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MLK1', 'Gene', (14, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('epigenetic activation', 'Var', (66, 87))	('transcription', 'MPA', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MLK1', 'Gene', '4293', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('MMP9', 'Gene', (91, 95))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('MMP9', 'Gene', '4318', (91, 95))	('enhanced', 'PosReg', (19, 27))
77667	32251318	5c) showed the survival was worse for hypomethylation of NTN1 in kidney renal papillary cell carcinoma (KIRP) and worse for NTNG1 in kidney renal clear cell carcinoma (KIRC), which is consistent with the correlation of high expression of NTN1 in KIRP and NTNG1 in KIRC with worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('kidney renal papillary cell carcinoma', 'Disease', (65, 102))	('hypomethylation', 'Var', (38, 53))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (65, 102))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (133, 166))	('NTN1', 'Gene', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('NTN1', 'Gene', '9423', (238, 242))	('NTN1', 'Gene', '9423', (57, 61))	('NTN1', 'Gene', (57, 61))	('NTNG1', 'Gene', '22854', (255, 260))	('NTNG1', 'Gene', (255, 260))	('NTNG1', 'Gene', '22854', (124, 129))	('kidney renal clear cell carcinoma', 'Disease', (133, 166))	('NTNG1', 'Gene', (124, 129))
77670	32251318	Methylation of NTN1, NTN3, NTN4, NTN5, and NTNG1 was associated with radiation therapy and overall survival of LGG.	('NTN3', 'Gene', (21, 25))	('NTN4', 'Gene', (27, 31))	('NTNG1', 'Gene', '22854', (43, 48))	('Methylation', 'Var', (0, 11))	('NTNG1', 'Gene', (43, 48))	('NTN5', 'Gene', (33, 37))	('NTN1', 'Gene', (15, 19))	('NTN4', 'Gene', '59277', (27, 31))	('radiation therapy', 'CPA', (69, 86))	('NTN1', 'Gene', '9423', (15, 19))	('associated with', 'Reg', (53, 68))	('NTN3', 'Gene', '4917', (21, 25))	('NTN5', 'Gene', '126147', (33, 37))
77672	32251318	In pan-kidney (KIRP and KIRC), methylation of NTN4 was associated with pathology T stage and overall survival of KIRP and KIRC.	('methylation', 'Var', (31, 42))	('associated', 'Reg', (55, 65))	('NTN4', 'Gene', '59277', (46, 50))	('NTN4', 'Gene', (46, 50))
77673	32251318	Methylation of NTN1 and NTNG1 was associated with pathology T stage and pathology N stage of KIRP.	('associated', 'Reg', (34, 44))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('NTNG1', 'Gene', (24, 29))	('NTN1', 'Gene', '9423', (15, 19))	('NTNG1', 'Gene', '22854', (24, 29))
77675	32251318	Methylation of NTN1 and NTN3 was associated with radiation therapy and pathology T stage of ESCA.	('radiation', 'CPA', (49, 58))	('NTN3', 'Gene', '4917', (24, 28))	('NTN3', 'Gene', (24, 28))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('associated', 'Reg', (33, 43))	('NTN1', 'Gene', '9423', (15, 19))	('ESCA', 'Phenotype', 'HP:0011459', (92, 96))
77676	32251318	Methylation of NTN3 was associated with pathology T stage, pathology N stage and number of lymph nodes of PRAD.	('Methylation', 'Var', (0, 11))	('NTN3', 'Gene', (15, 19))	('associated', 'Reg', (24, 34))	('NTN3', 'Gene', '4917', (15, 19))
77677	32251318	Methylation of NTN1, NTN3, NTN4, and NTNG1 was associated with PAM50 typing of BRCA, and NTNG1 was also associated with ER.Status and PR.Status.	('NTNG1', 'Gene', (37, 42))	('ER.Status', 'Disease', (120, 129))	('BRCA', 'Gene', (79, 83))	('associated', 'Reg', (104, 114))	('NTN1', 'Gene', (15, 19))	('NTN4', 'Gene', '59277', (27, 31))	('associated', 'Reg', (47, 57))	('NTNG1', 'Gene', '22854', (37, 42))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', '9423', (15, 19))	('NTN3', 'Gene', '4917', (21, 25))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))	('NTNG1', 'Gene', (89, 94))	('PAM50 typing', 'Var', (63, 75))	('NTN3', 'Gene', (21, 25))	('BRCA', 'Gene', '672', (79, 83))	('NTN4', 'Gene', (27, 31))	('PR.Status', 'Disease', (134, 143))	('NTNG1', 'Gene', '22854', (89, 94))
77678	32251318	In UCEC, methylation of NTN3, NTN4, NTNG1, and NTNG2 was associated with MSI phenotype.	('methylation', 'Var', (9, 20))	('NTN3', 'Gene', '4917', (24, 28))	('NTN4', 'Gene', (30, 34))	('MSI', 'Disease', '-', (73, 76))	('NTN3', 'Gene', (24, 28))	('NTNG2', 'Gene', '84628', (47, 52))	('NTNG1', 'Gene', '22854', (36, 41))	('NTN4', 'Gene', '59277', (30, 34))	('NTNG1', 'Gene', (36, 41))	('NTNG2', 'Gene', (47, 52))	('MSI', 'Disease', (73, 76))	('associated', 'Reg', (57, 67))
77682	32251318	Overexpression of EZH2 is also associated with the development of prostate cancer, and phosphorylated EZH2 can act as a co-activator of transcription factors, such as promoting the expression of AR.	('EZH2', 'Gene', (102, 106))	('EZH2', 'Gene', '2146', (102, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('expression', 'MPA', (181, 191))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('EZH2', 'Gene', '2146', (18, 22))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('phosphorylated', 'Var', (87, 101))	('EZH2', 'Gene', (18, 22))	('AR', 'Gene', '367', (195, 197))	('prostate cancer', 'Disease', (66, 81))	('promoting', 'PosReg', (167, 176))
77697	32251318	Among the many statistically significant results, hsa-miR-361-3p had the strongest inhibitory effect on NTN1 in TCGT (r = 0.612), hsa-miR-33a-5p had the strongest inhibitory effect on NTN4 in TCGT and ESCA (r = -0.494), and hsa-miR-20b-5p had the strongest inhibitory effect on NTNG1 in DLBC (r = -0.528).	('inhibitory effect', 'MPA', (83, 100))	('NTN4', 'Gene', '59277', (184, 188))	('NTN1', 'Gene', (104, 108))	('hsa-miR-361-3p', 'Gene', '100500908', (50, 64))	('NTN1', 'Gene', '9423', (104, 108))	('inhibitory effect', 'MPA', (163, 180))	('hsa-miR-33a-5p', 'Var', (130, 144))	('ESCA', 'Phenotype', 'HP:0011459', (201, 205))	('NTN4', 'Gene', (184, 188))	('NTNG1', 'Gene', '22854', (278, 283))	('hsa-miR-361-3p', 'Gene', (50, 64))	('NTNG1', 'Gene', (278, 283))	('BC', 'Phenotype', 'HP:0003002', (289, 291))
77703	32251318	The expression of NTN5 was affected by eQTL in BRCA, COAD, KIRC, KIRP, LGG, PRAD, and THCA.	('expression', 'MPA', (4, 14))	('COAD', 'Disease', 'MESH:D029424', (53, 57))	('affected', 'Reg', (27, 35))	('eQTL', 'Var', (39, 43))	('NTN5', 'Gene', '126147', (18, 22))	('BRCA', 'Phenotype', 'HP:0003002', (47, 51))	('THCA', 'Phenotype', 'HP:0002890', (86, 90))	('BRCA', 'Gene', '672', (47, 51))	('COAD', 'Disease', (53, 57))	('NTN5', 'Gene', (18, 22))	('BRCA', 'Gene', (47, 51))
77706	32251318	Of these, 186 (74.4%) NTNG1 eQTLs were associated with AIDS and 57 (22.9%) were associated with non-obstructive azoospermia.	('NTNG1', 'Gene', '22854', (22, 27))	('non-obstructive azoospermia', 'Disease', 'MESH:D053713', (96, 123))	('NTNG1', 'Gene', (22, 27))	('obstructive azoospermia', 'Phenotype', 'HP:0011962', (100, 123))	('azoospermia', 'Phenotype', 'HP:0000027', (112, 123))	('non-obstructive azoospermia', 'Disease', (96, 123))	('AIDS', 'Disease', (55, 59))	('associated', 'Reg', (80, 90))	('associated', 'Reg', (39, 49))	('AIDS', 'Disease', 'MESH:D000163', (55, 59))	('eQTLs', 'Var', (28, 33))	('non-obstructive azoospermia', 'Phenotype', 'HP:0011961', (96, 123))
77709	32251318	Further, three eQTLs (rs9894790, rs9901637, and rs11650713) were found to affect the binding of MYC, TCF12, EBF1, EGR1, and NR2F2.	('rs11650713', 'Var', (48, 58))	('binding', 'Interaction', (85, 92))	('rs11650713', 'Mutation', 'rs11650713', (48, 58))	('MYC', 'Gene', (96, 99))	('EBF1', 'Gene', '1879', (108, 112))	('TCF12', 'Gene', '6938', (101, 106))	('rs9894790', 'Var', (22, 31))	('EGR1', 'Gene', (114, 118))	('MYC', 'Gene', '4609', (96, 99))	('NR2F2', 'Gene', '7026', (124, 129))	('affect', 'Reg', (74, 80))	('EGR1', 'Gene', '1958', (114, 118))	('rs9894790', 'Mutation', 'rs9894790', (22, 31))	('NR2F2', 'Gene', (124, 129))	('rs9901637', 'Mutation', 'rs9901637', (33, 42))	('rs9901637', 'Var', (33, 42))	('EBF1', 'Gene', (108, 112))	('TCF12', 'Gene', (101, 106))
77710	32251318	Additionally, high expression of NTN1 in thyroid carcinoma was correlated with a worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (41, 58))	('NTN1', 'Gene', '9423', (33, 37))	('high', 'Var', (14, 18))	('NTN1', 'Gene', (33, 37))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (41, 58))	('thyroid carcinoma', 'Disease', (41, 58))
77718	32251318	Highly expressed NTN4 is more sensitive to SRC inhibitors such as Dasatinib, WH-4-023, and AZD0530.	('NTN4', 'Gene', (17, 21))	('SRC', 'Gene', '6714', (43, 46))	('SRC', 'Gene', (43, 46))	('more', 'PosReg', (25, 29))	('NTN4', 'Gene', '59277', (17, 21))	('WH-4-023', 'Chemical', '-', (77, 85))	('AZD0530', 'Var', (91, 98))	('AZD0530', 'Chemical', 'MESH:C515233', (91, 98))	('Dasatinib', 'Chemical', 'MESH:D000069439', (66, 75))
77730	32251318	In particular, ML162 and ML210 are compounds that target and change the mesenchymal state, inhibit GPX4 activity, and promote apoptosis.	('change', 'Reg', (61, 67))	('GPX4', 'Gene', (99, 103))	('GPX4', 'Gene', '2879', (99, 103))	('inhibit', 'NegReg', (91, 98))	('activity', 'MPA', (104, 112))	('apoptosis', 'CPA', (126, 135))	('ML162', 'Var', (15, 20))	('mesenchymal state', 'CPA', (72, 89))	('promote', 'PosReg', (118, 125))	('ML210', 'Var', (25, 30))
77739	32251318	Our findings are as follows: (1) members of the Netrin family are tightly regulated by multiple mechanisms at the genetic, transcriptional, and post-transcriptional levels; (2) mutations of members of the Netrin family correlate with tumor genetic characteristics; (3) Netrins may play important roles in the occurrence and development of endocrine system-related tumors and sex hormone targeting tumors; (4) Netrin family members may be promising prognostic indicators and potential therapeutic targets for lung and kidney cancer; (5) NTNG1 and NTNG2 are potential diagnostic markers and therapeutic targets that should be further studied systematically.	('tumor', 'Disease', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (364, 370))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumors', 'Disease', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('kidney cancer', 'Disease', 'MESH:D007680', (517, 530))	('NTNG1', 'Gene', (536, 541))	('tumors', 'Disease', (364, 370))	('lung', 'Disease', (508, 512))	('NTNG2', 'Gene', '84628', (546, 551))	('tumors', 'Disease', 'MESH:D009369', (397, 403))	('cancer', 'Phenotype', 'HP:0002664', (524, 530))	('NTNG1', 'Gene', '22854', (536, 541))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('kidney cancer', 'Phenotype', 'HP:0009726', (517, 530))	('kidney cancer', 'Disease', (517, 530))	('tumors', 'Disease', 'MESH:D009369', (364, 370))	('tumor', 'Disease', (397, 402))	('tumor', 'Disease', (364, 369))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('NTNG2', 'Gene', (546, 551))	('tumors', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (364, 369))
77742	32251318	This study was the first comprehensive analysis of tumor genetic characteristics of mutations in members of the Netrin family.	('mutations', 'Var', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
77743	32251318	We found that tumor mutations of members of the Netrin family showed a unique distribution pattern for cancer type, protein structure, and ethnic group.	('tumor', 'Disease', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (20, 29))
77744	32251318	It is worth noting that a significant number of missense or truncating mutations have been found in the Laminin N-terminal and EGF domains that interact with related receptors and the regulatory localization of the NTR domain.	('interact', 'Interaction', (144, 152))	('truncating mutations', 'Var', (60, 80))	('NTR', 'Gene', '4923', (215, 218))	('missense', 'Var', (48, 56))	('NTR', 'Gene', (215, 218))
77747	32251318	Our mutation analysis found highly enriched mutation of netrin family genes in uterine corpus endometrial carcinoma.	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (87, 115))	('corpus endometrial carcinoma', 'Disease', (87, 115))	('mutation', 'Var', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (94, 115))	('netrin family genes', 'Gene', (56, 75))
77755	32251318	This study found that the NTN family not only has a high overall mutation rate in lung cancer, but that netrin activity is also closely related to the survival and clinical parameters of kidney cancer and non-small cell lung cancer.	('kidney cancer', 'Disease', (187, 200))	('clinical', 'Species', '191496', (164, 172))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (205, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('related', 'Reg', (136, 143))	('lung cancer', 'Disease', (82, 93))	('non-small cell lung cancer', 'Disease', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('kidney cancer', 'Disease', 'MESH:D007680', (187, 200))	('mutation', 'Var', (65, 73))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('kidney cancer', 'Phenotype', 'HP:0009726', (187, 200))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
77763	32251318	Here we find that the expression or methylation of NTNG1 and NTNG2 is associated with survival and other clinical parameters of more than 10 types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('NTNG2', 'Gene', '84628', (61, 66))	('methylation', 'Var', (36, 47))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('clinical', 'Species', '191496', (105, 113))	('associated', 'Reg', (70, 80))	('cancer', 'Disease', (150, 156))	('NTNG2', 'Gene', (61, 66))	('survival', 'CPA', (86, 94))	('NTNG1', 'Gene', '22854', (51, 56))	('expression', 'MPA', (22, 32))	('NTNG1', 'Gene', (51, 56))
77764	32251318	There are also important epigenetic and transcriptional modifications of netrins that occur in pan-cancer that are related to the activation of the EMT pathway.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('activation', 'PosReg', (130, 140))	('EMT', 'Gene', (148, 151))	('cancer', 'Disease', (99, 105))	('EMT', 'Gene', '3702', (148, 151))	('netrins', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('epigenetic', 'Var', (25, 35))
77766	32251318	It is worth noting that the mutations and potential mirRNA targeting of NTNG1 and NTNG2 in cancer exhibit rates that are much higher than those predicted for NTN1 and NTN4.	('NTN4', 'Gene', (167, 171))	('NTN1', 'Gene', '9423', (158, 162))	('NTNG2', 'Gene', '84628', (82, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('higher', 'PosReg', (126, 132))	('NTN4', 'Gene', '59277', (167, 171))	('NTNG2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NTNG1', 'Gene', '22854', (72, 77))	('NTNG1', 'Gene', (72, 77))	('mutations', 'Var', (28, 37))	('NTN1', 'Gene', (158, 162))
77767	32251318	TCGA fusion transcripts analysis suggests the presence of fusion transcripts composed of NTNG1 or NTNG2 in multiple cancers.	('multiple cancers', 'Disease', (107, 123))	('NTNG2', 'Gene', '84628', (98, 103))	('NTNG1', 'Gene', '22854', (89, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (107, 123))	('NTNG1', 'Gene', (89, 94))	('fusion transcripts', 'Var', (58, 76))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NTNG2', 'Gene', (98, 103))
77771	32251318	However, in some cancers, the selective inhibition of this receptor-dependent apoptosis pathway depends on the silencing of pro-apoptotic proteins.	('silencing', 'Var', (111, 120))	('receptor-dependent apoptosis pathway', 'Pathway', (59, 95))	('inhibition', 'NegReg', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
77798	31744167	Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT).	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (185, 189))	('R337H', 'Var', (190, 195))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (52, 76))	('TP53', 'Gene', (18, 22))	('R337H', 'SUBSTITUTION', 'None', (23, 28))	('R337H', 'Var', (23, 28))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (257, 277))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (52, 76))	('adrenocortical tumor', 'Disease', (257, 277))	('Adrenocortical Carcinoma', 'Disease', (52, 76))	('R337H', 'SUBSTITUTION', 'None', (190, 195))	('TP53', 'Gene', '7157', (185, 189))	('Carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
77800	31744167	Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 cohort with 4165 R337H carriers living in Parana state (PR) subregions.	('R337H', 'Var', (122, 127))	('R337H', 'Var', (10, 15))	('R337H', 'SUBSTITUTION', 'None', (122, 127))	('R337H', 'Var', (49, 54))	('R337H', 'SUBSTITUTION', 'None', (10, 15))	('R337H', 'SUBSTITUTION', 'None', (49, 54))	('PR', 'Chemical', '-', (161, 163))
77801	31744167	The effectiveness of a second surveillance for R337H probands selected from 42,438 tested newborns in PR (2016 cohort) was tested to detect early stage I tumor among educated families without periodical exams.	('R337H', 'SUBSTITUTION', 'None', (47, 52))	('PR', 'Chemical', '-', (102, 104))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('R337H', 'Var', (47, 52))	('tumor', 'Disease', (154, 159))
77802	31744167	Estimation of R337H frequencies and ACT incidence in Santa Catarina state (SC) used data from 50,115 tested newborns without surveillance, ACT cases from a SC hospital, and a public cancer registry.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('R337H', 'Var', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('R337H', 'SUBSTITUTION', 'None', (14, 19))	('cancer', 'Disease', (182, 188))	('SC', 'Chemical', '-', (75, 77))	('SC', 'Chemical', '-', (156, 158))
77806	31744167	R337H carriers living in an agricultural subregion (C1) had a lower risk of developing pediatric ACT than those living in industrial and large urban subregion (relative risk = 2.4).	('R337H', 'SUBSTITUTION', 'None', (0, 5))	('lower', 'NegReg', (62, 67))	('R337H', 'Var', (0, 5))	('developing pediatric ACT', 'Disease', (76, 100))
77810	31744167	Germline mutations in the TP53 gene are associated with Li-Fraumeni syndrome (LFS) and are responsible for the majority of ACT cases in young children worldwide, which merits genotyping and counseling, including for low-penetrance TP53 mutation carriers.	('Germline mutations', 'Var', (0, 18))	('TP53', 'Gene', (26, 30))	('children', 'Species', '9606', (142, 150))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (56, 76))	('TP53', 'Gene', '7157', (26, 30))	('TP53', 'Gene', '7157', (231, 235))	('Li-Fraumeni syndrome', 'Disease', (56, 76))	('TP53', 'Gene', (231, 235))	('associated', 'Reg', (40, 50))
77811	31744167	Although approximately 80% of pathogenic TP53 mutations occur within the DNA binding domain (DBD), TP53 R337H, which is the single most commonly found germline mutation, is located in the tetramerization domain in exon 10 (p.Arg337His, c.1010G > A).	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (99, 103))	('TP53', 'Gene', (41, 45))	('c.1010G > A', 'Var', (236, 247))	('mutations', 'Var', (46, 55))	('R337H', 'SUBSTITUTION', 'None', (104, 109))	('c.1010G > A', 'Mutation', 'rs121912664', (236, 247))	('p.Arg337His', 'Var', (223, 234))	('R337H', 'Var', (104, 109))	('pathogenic', 'Reg', (30, 40))	('p.Arg337His', 'Mutation', 'rs121912664', (223, 234))	('TP53', 'Gene', '7157', (99, 103))
77812	31744167	TP53 R337H is a founder mutation, and its increasing frequency in the population is facilitated by its low penetrance, with a relatively low cancer risk during the reproductive years.	('R337H', 'SUBSTITUTION', 'None', (5, 10))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('R337H', 'Var', (5, 10))	('cancer', 'Disease', (141, 147))
77813	31744167	While R337H occurs in 1:370 births in Parana state, other TP53 germline mutations are thought to occur at a frequency of between 1:5000 and 1:20,000 births in other countries.	('TP53', 'Gene', (58, 62))	('R337H', 'Var', (6, 11))	('TP53', 'Gene', '7157', (58, 62))	('R337H', 'SUBSTITUTION', 'None', (6, 11))
77814	31744167	These conclusions were based on mutations found in patients with early onset breast cancer unselected for family history (2-3%) or any type of cancer family history (17.3%).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('breast cancer', 'Disease', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('cancer', 'Disease', (84, 90))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('patients', 'Species', '9606', (51, 59))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
77815	31744167	Predisposition of R337H carriers and non-carriers to ACT has an early peak in the first three years after birth (virilization syndrome more common than Cushing syndrome), decreases with age toward a second phenotype (Cushing syndrome > single virilizing syndrome) in the second decade, and is associated with a poorer ACT prognosis in adulthood.	('Cushing syndrome', 'Disease', 'MESH:D003480', (217, 233))	('Cushing syndrome', 'Disease', (152, 168))	('R337H', 'Var', (18, 23))	('Cushing syndrome', 'Disease', 'MESH:D003480', (152, 168))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (217, 233))	('R337H', 'SUBSTITUTION', 'None', (18, 23))	('Cushing syndrome', 'Disease', (217, 233))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (152, 168))
77816	31744167	The elevated susceptibility of the adrenal cortex to ACT during the first postnatal years may be related to fetal zone instability around birth, and the expected incidence of ACT is proportional to the number of children born with the germline TP53 R337H mutation.	('susceptibility', 'MPA', (13, 27))	('ACT', 'MPA', (53, 56))	('TP53', 'Gene', (244, 248))	('children', 'Species', '9606', (212, 220))	('R337H', 'Var', (249, 254))	('R337H', 'SUBSTITUTION', 'None', (249, 254))	('TP53', 'Gene', '7157', (244, 248))
77817	31744167	In addition, a minor contribution to tumorigenesis is attributed to genetic and epigenetic alterations affecting chromosome 11p15, as well as other unknown constitutional predispositions or environmental factors.	('genetic', 'Var', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('epigenetic alterations', 'Var', (80, 102))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))
77822	31744167	Testing newborns for R337H, combined with specific surveillance for ACT, has improved the early preclinical diagnosis of ACT and raised the cure rate.	('R337H', 'Var', (21, 26))	('ACT', 'Disease', (121, 124))	('R337H', 'SUBSTITUTION', 'None', (21, 26))	('raised', 'PosReg', (129, 135))	('cure', 'MPA', (140, 144))	('improved', 'PosReg', (77, 85))
77823	31744167	However, higher-penetrance TP53 mutations merit extended surveillance for children and adults with diagnoses of early onset tumors.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('higher-penetrance', 'Reg', (9, 26))	('children', 'Species', '9606', (74, 82))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))
77826	31744167	The aims of this study were (1) to determine the frequency of the R337H carrier in newborns and the overall ACT incidence among children of Parana (PR) and Santa Catarina (SC) states; (2) to compare the ACT incidence and estimate relative risk (RR) among three PR subregions with distinct environmental conditions (C1 with very strong agriculture production; C2 with moderate agriculture and mild industry; and C3 with strong industry activity and mild agriculture production); and (3) to test a cost-effective surveillance method to detect early stage ACT among R337H-carrier children from PR.	('children', 'Species', '9606', (577, 585))	('R337H', 'Var', (563, 568))	('SC', 'Chemical', '-', (172, 174))	('children', 'Species', '9606', (128, 136))	('R337H', 'SUBSTITUTION', 'None', (563, 568))	('R337H', 'Var', (66, 71))	('PR', 'Chemical', '-', (261, 263))	('R337H', 'SUBSTITUTION', 'None', (66, 71))	('PR', 'Chemical', '-', (148, 150))	('PR', 'Chemical', '-', (591, 593))
77827	31744167	To test the hypothesis that R337H frequency and different environmental factors influence the incidence of pediatric ACT, we evaluated differences in the cumulative ACT incidence according to the total number of R337H carriers in our cohort (2006-C) living in C1, C2, and C3.	('R337H', 'Var', (212, 217))	('R337H', 'Var', (28, 33))	('R337H', 'SUBSTITUTION', 'None', (212, 217))	('R337H', 'SUBSTITUTION', 'None', (28, 33))	('influence', 'Reg', (80, 89))	('C1, C2, and C3', 'Gene', '6966;717;6358', (260, 274))
77828	31744167	The second neonatal R337H screening in PR empowered estimates of R337H frequencies and established a second cohort of R337H-carrier newborns efficiently monitored without periodical exams.	('PR', 'Chemical', '-', (39, 41))	('R337H', 'Var', (20, 25))	('R337H', 'Var', (65, 70))	('R337H', 'SUBSTITUTION', 'None', (20, 25))	('R337H', 'SUBSTITUTION', 'None', (65, 70))	('R337H', 'Var', (118, 123))	('R337H', 'SUBSTITUTION', 'None', (118, 123))
77829	31744167	We performed the first R337H neonatal screening in SC without any surveillance (as approved by the Ethics Committee just to confirm the epidemiological problem), and the obtained frequency of R337H in pediatric ACT from SC to compare with PR's status.	('PR', 'Chemical', '-', (239, 241))	('SC', 'Chemical', '-', (51, 53))	('R337H', 'Var', (192, 197))	('SC', 'Chemical', '-', (220, 222))	('R337H', 'SUBSTITUTION', 'None', (192, 197))	('R337H', 'Var', (23, 28))	('R337H', 'SUBSTITUTION', 'None', (23, 28))
77844	31744167	The cumulative incidence for childhood ACT among all 4162 carriers was 0.95% in C1, 1.83% in C2, and 2.47% in C3.	('carriers', 'Var', (58, 66))	('childhood ACT', 'Disease', (29, 42))	('child', 'Species', '9606', (29, 34))
77845	31744167	The number of ACT cases divided by the number of carriers in each subregion for the 2006 cohort identified one ACT for each 105 R337H carriers in C1, in contrast to the 1:44 proportion in C3, suggesting that it is easier to develop ACT in C3 and/or the risk is lowered in C1.	('lowered', 'NegReg', (261, 268))	('R337H', 'SUBSTITUTION', 'None', (128, 133))	('R337H', 'Var', (128, 133))
77851	31744167	Dividing the number of ACT cases by the number of estimated R337H carriers in each subregion demonstrated that there is one ACT for every 93 R337H carriers in C1 and one ACT for every 26 carriers in C3 for children less than 10 years of age.	('R337H', 'SUBSTITUTION', 'None', (60, 65))	('R337H', 'Var', (141, 146))	('R337H', 'SUBSTITUTION', 'None', (141, 146))	('children', 'Species', '9606', (206, 214))	('R337H', 'Var', (60, 65))
77852	31744167	These proportions are slightly different to the calculated proportions using the 2006-C cohort (1:44 and 1:103), because the database from the Brazilian Single Health System (DATASUS) registry (1) included a low percentage of ACT cases from other small public hospitals, (2) may have included non-R337H ACTs, and (3) may have excluded patients with private medical health insurance.	('R337H', 'Var', (297, 302))	('patients', 'Species', '9606', (335, 343))	('included', 'Reg', (284, 292))	('R337H', 'SUBSTITUTION', 'None', (297, 302))
77855	31744167	In addition to the neonatal screening in SC, we tested 35 pediatric ACT patients admitted to the main SC pediatric hospital (Joana Gusmao Pediatric Hospital at Florianopolis) from 2000 to 2018 and found 30 R337H positive and five R337H negative tumors.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('SC', 'Chemical', '-', (102, 104))	('R337H', 'SUBSTITUTION', 'None', (230, 235))	('R337H', 'Var', (206, 211))	('SC', 'Chemical', '-', (41, 43))	('patients', 'Species', '9606', (72, 80))	('R337H', 'SUBSTITUTION', 'None', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumors', 'Disease', (245, 251))	('R337H', 'Var', (230, 235))
77857	31744167	The mean R337H carrier frequencies in the general population (Y) were 0.210% (SP) according to data by Caminha et al., 0.245% (SC), and 0.306% (PR) (calculated in the present study) associated with 87%, 87%, and 95% R337H frequencies in pediatric ACTs, respectively.	('0.306%', 'Var', (136, 142))	('SC', 'Chemical', '-', (127, 129))	('R337H', 'SUBSTITUTION', 'None', (216, 221))	('PR', 'Chemical', '-', (144, 146))	('R337H', 'Var', (9, 14))	('R337H', 'SUBSTITUTION', 'None', (9, 14))	('SP', 'Chemical', 'MESH:C000604007', (78, 80))	('pediatric ACTs', 'Disease', (237, 251))	('0.245%', 'Var', (119, 125))	('R337H', 'Var', (216, 221))
77858	31744167	Paired coordinates of the average frequencies of R337H-positive ACT (X) and of R337H carriers in the general population (Y) from SP, PR, and SC states were used to detect the approximate LR (Y = -0.6788 + 0.0104X) (Figure 2).	('R337H', 'Var', (79, 84))	('SC', 'Chemical', '-', (141, 143))	('R337H', 'SUBSTITUTION', 'None', (79, 84))	('PR', 'Chemical', '-', (133, 135))	('R337H', 'Var', (49, 54))	('R337H', 'SUBSTITUTION', 'None', (49, 54))	('SP', 'Chemical', 'MESH:C000604007', (129, 131))
77874	31744167	Data from the 2006 and 2016 cohorts revealed that TP53 R337H is a low-penetrance mutation based on the observed average lifetime cancer risks, estimated as less than 40% in our 2006 cohort.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('R337H', 'Var', (55, 60))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('TP53', 'Gene', '7157', (50, 54))	('R337H', 'SUBSTITUTION', 'None', (55, 60))	('TP53', 'Gene', (50, 54))
77875	31744167	We further confirmed the 2006 cohort findings that TP53 R337H is a low-penetrance mutation with a low lifetime cancer risk.	('TP53', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('R337H', 'Var', (56, 61))	('R337H', 'SUBSTITUTION', 'None', (56, 61))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('TP53', 'Gene', '7157', (51, 55))
77877	31744167	On average, only 3.9 more cancer cases of all types occur in the carrier side of the family than in the non-R337H segregating side of the family, in contrast to the high penetrance and high lifetime cancer risk reported in classical LFS.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('R337H', 'Var', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', (199, 205))	('R337H', 'SUBSTITUTION', 'None', (108, 113))
77878	31744167	Despite the fact that the R337H mutation lies within the p53 dimerization domain which may affect tetrameric stability, R337H had wild-type p53 activity in in vitro assays, in contrast to the profound defects in DNA binding domain mutant reported in LFS.	('p53', 'Gene', '7157', (57, 60))	('R337H', 'Var', (120, 125))	('R337H', 'SUBSTITUTION', 'None', (26, 31))	('R337H', 'SUBSTITUTION', 'None', (120, 125))	('affect', 'Reg', (91, 97))	('p53', 'Gene', (57, 60))	('tetrameric stability', 'MPA', (98, 118))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('activity', 'MPA', (144, 152))	('R337H', 'Var', (26, 31))
77879	31744167	The pH-dependent destabilization of p.R337H tetramer demonstrated in vitro has not yet been validated in human cells.	('tetramer', 'Protein', (44, 52))	('human', 'Species', '9606', (105, 110))	('p.R337H', 'SUBSTITUTION', 'None', (36, 43))	('destabilization', 'MPA', (17, 32))	('p.R337H', 'Var', (36, 43))
77880	31744167	One interesting aspect of R337H carriers in our two cohorts is the variable frequency of pediatric ACT among different PR subregions.	('pediatric ACT', 'Disease', (89, 102))	('PR', 'Chemical', '-', (119, 121))	('R337H', 'SUBSTITUTION', 'None', (26, 31))	('R337H', 'Var', (26, 31))
77884	31744167	The updated average frequency of R337H carriers in PR (0.306%) is the highest, followed by that in SC (0.245%), and SP (0.21%), which was partially consistent with the highest R337H frequencies estimated in ACTs for PR (95%), SP (87%), and SC (87%).	('SC', 'Chemical', '-', (240, 242))	('R337H', 'Var', (176, 181))	('PR', 'Chemical', '-', (216, 218))	('SP', 'Chemical', 'MESH:C000604007', (116, 118))	('R337H', 'Var', (33, 38))	('R337H', 'SUBSTITUTION', 'None', (176, 181))	('PR', 'Chemical', '-', (51, 53))	('R337H', 'SUBSTITUTION', 'None', (33, 38))	('SC', 'Chemical', '-', (99, 101))	('SP', 'Chemical', 'MESH:C000604007', (226, 228))
77891	31744167	It is clear that the adrenocortical tissue is highly susceptible to most TP53 mutations, and one of the reasons for this may be the adrenal cortex physiological transition across birth (reviewed by).	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))	('susceptible', 'Reg', (53, 64))	('mutations', 'Var', (78, 87))
77900	31744167	PR is a territory with the highest worldwide frequency of R337H carriers, the highest pediatric ACT incidence, and very diverse environment conditions, ranging from a highly agricultural region to industrial areas and large urban regions.	('R337H', 'SUBSTITUTION', 'None', (58, 63))	('PR', 'Chemical', '-', (0, 2))	('pediatric ACT', 'Disease', (86, 99))	('R337H', 'Var', (58, 63))
77901	31744167	Remarkably, C3 is a subregion where industries converge with large urban areas, and this region demonstrated a higher RR of developing pediatric ACT (adjusted for the number of R337H carriers) than C1 with the highest agriculture productivity.	('R337H', 'Var', (177, 182))	('R337H', 'SUBSTITUTION', 'None', (177, 182))	('developing pediatric', 'MPA', (124, 144))
77903	31744167	However, the p.R337H in the adrenal cortex could unfold and lose function in carriers living in any subregion.	('p.R337H', 'SUBSTITUTION', 'None', (13, 20))	('function', 'MPA', (65, 73))	('p.R337H', 'Var', (13, 20))	('lose', 'NegReg', (60, 64))
77904	31744167	We speculate that low-penetrance mutations in tumor suppressor genes may be altered by specific environmental modifiers for each type of cancer (e.g., smoking for lung cancer or hepatitis B/C virus for liver cancer).	('cancer', 'Disease', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('liver cancer', 'Disease', 'MESH:D006528', (202, 214))	('mutations', 'Var', (33, 42))	('hepatitis B', 'Disease', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('liver cancer', 'Phenotype', 'HP:0002896', (202, 214))	('liver cancer', 'Disease', (202, 214))	('lung cancer', 'Disease', (163, 174))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Disease', (46, 51))	('hepatitis B', 'Disease', 'MESH:D006509', (178, 189))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('altered', 'Reg', (76, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('hepatitis', 'Phenotype', 'HP:0012115', (178, 187))
77905	31744167	The R337H frequencies across subregions of SC would predict an ACT incidence rate very similar to that in PR.	('R337H', 'Var', (4, 9))	('predict', 'Reg', (52, 59))	('R337H', 'SUBSTITUTION', 'None', (4, 9))	('ACT', 'MPA', (63, 66))	('PR', 'Chemical', '-', (106, 108))	('SC', 'Chemical', '-', (43, 45))
77907	31744167	Given the frequency of other TP53 germline mutations in other countries of between 1:5000 and 1:20,000 births and 80% frequency of low-penetrance germline TP53 mutations identified in pediatric ACT as reported by the Manchester Children's Tumor Registry, it is important to consider the influence of environmental factors on the development of ACT in R337H carriers.	('mutations', 'Var', (160, 169))	('TP53', 'Gene', '7157', (155, 159))	('TP53', 'Gene', (155, 159))	('R337H', 'Var', (351, 356))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('Children', 'Species', '9606', (228, 236))	('ACT', 'Disease', (194, 197))	('R337H', 'SUBSTITUTION', 'None', (351, 356))	('Tumor', 'Phenotype', 'HP:0002664', (239, 244))
77908	31744167	However, it is not yet possible to rule out anticipation in R337H carriers, nor can we rule out a stronger burden of environmental pollutants in the last several decades leading to an increased number of somatic variants causing different cancer types.	('R337H', 'SUBSTITUTION', 'None', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (239, 245))	('causing', 'Reg', (221, 228))	('variants', 'Var', (212, 220))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('R337H', 'Var', (60, 65))
77911	31744167	R337H carrier frequencies obtained from these newly tested newborns as well as more accurate R337H frequencies obtained from 22 Administrative Health Regions (AHRs) gave rise to a second PR cohort (2016-C) under a surveillance protocol without PE to be compared with the cohort with PE (2006-C) established in 2006.	('PR', 'Chemical', '-', (187, 189))	('R337H', 'Var', (0, 5))	('R337H', 'SUBSTITUTION', 'None', (0, 5))	('R337H', 'Var', (93, 98))	('R337H', 'SUBSTITUTION', 'None', (93, 98))
77917	31744167	Neonatal screening in SC was performed to compare the R337H frequency in 16 SC AHRs.	('R337H', 'SUBSTITUTION', 'None', (54, 59))	('SC AHRs', 'Disease', (76, 83))	('SC', 'Chemical', '-', (76, 78))	('SC', 'Chemical', '-', (22, 24))	('SC AHRs', 'Disease', 'MESH:D000755', (76, 83))	('R337H', 'Var', (54, 59))
77921	31744167	A PCR-restriction fragment length polymorphism (PCR-RFLP) assay was used to detect the TP53 R337H mutation as described previously.	('R337H', 'SUBSTITUTION', 'None', (92, 97))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('R337H', 'Var', (92, 97))
77923	31744167	Blood and ACT samples from patients admitted to Joana de Gusmao Children's Hospital (HIJG) from 2000 to 2018 (N = 35) were approved to be tested for the TP53 R337H mutation by the hospital Ethics Committee (HIJG-2014).	('R337H', 'Var', (158, 163))	('R337H', 'SUBSTITUTION', 'None', (158, 163))	('TP53', 'Gene', '7157', (153, 157))	('patients', 'Species', '9606', (27, 35))	('Children', 'Species', '9606', (64, 72))	('TP53', 'Gene', (153, 157))
77931	31744167	LR was calculated by the method of weighted least squares using two datasets: the R337H frequencies in the populations of PR, SC, and SP and the respective averages for R337H frequencies in ACT cases in each state.	('PR', 'Chemical', '-', (122, 124))	('R337H', 'SUBSTITUTION', 'None', (82, 87))	('R337H', 'Var', (169, 174))	('SP', 'Chemical', 'MESH:C000604007', (134, 136))	('R337H', 'Var', (82, 87))	('R337H', 'SUBSTITUTION', 'None', (169, 174))	('SC', 'Chemical', '-', (126, 128))
77935	31744167	The linear regression (LR) was estimated for the R337H frequency in the populations of three states with the respective R337H frequencies in their ACT cases.	('R337H', 'SUBSTITUTION', 'None', (120, 125))	('R337H', 'SUBSTITUTION', 'None', (49, 54))	('R337H', 'Var', (120, 125))	('R337H', 'Var', (49, 54))
77936	31744167	Collectively, the results from these two states have created an opportunity for classifying pediatric ACT incidence on the basis of R337H frequencies and geographical differences.	('R337H', 'Var', (132, 137))	('pediatric ACT', 'Disease', (92, 105))	('R337H', 'SUBSTITUTION', 'None', (132, 137))
77937	31744167	Importantly, environmental influences should be considered in cancer risk, especially for carriers of germline TP53 mutations.	('germline', 'Var', (102, 110))	('TP53', 'Gene', '7157', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TP53', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
77938	31744167	A complete understanding of the variability among environmental conditions to which R337H and non-R337H carriers are exposed is hindered by the lack of measurement of exact components needed to characterize the factor(s) associated with the observed high ACT incidence in C3 and lower incidence in C1 subregions.	('R337H', 'SUBSTITUTION', 'None', (98, 103))	('R337H', 'SUBSTITUTION', 'None', (84, 89))	('R337H', 'Var', (98, 103))	('R337H', 'Var', (84, 89))
77952	31745526	The therapy appeared to be effective in both microsatellite instability-high and microsatellite stable tumors, suggesting some synergistic effect with mitotane.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('mitotane', 'Chemical', 'MESH:D008939', (151, 159))	('microsatellite instability-high', 'Var', (45, 76))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('microsatellite', 'Var', (81, 95))
78033	31745526	Patient 1 had a germline mutation in MSH2 with loss of the MSH2 protein in the tumor, whereas patient 3 had a germline mutation in MSH2 with loss of the MSH2 and MutS protein homolog 6 proteins.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('MSH2', 'Gene', (153, 157))	('MSH2', 'Gene', '4436', (37, 41))	('germline mutation', 'Var', (16, 33))	('loss', 'NegReg', (141, 145))	('MSH2', 'Gene', (59, 63))	('MSH2', 'Gene', '4436', (59, 63))	('loss', 'NegReg', (47, 51))	('patient', 'Species', '9606', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('Patient', 'Species', '9606', (0, 7))	('protein', 'Protein', (64, 71))	('MSH2', 'Gene', (131, 135))	('MSH2', 'Gene', (37, 41))	('MSH2', 'Gene', '4436', (153, 157))	('MSH2', 'Gene', '4436', (131, 135))
78049	31745526	There may have been a slightly better response rate to immunotherapy in the patients receiving mitotane, although mitotane levels were not reported.	('patients', 'Species', '9606', (76, 84))	('better', 'PosReg', (31, 37))	('mitotane', 'Chemical', 'MESH:D008939', (114, 122))	('mitotane', 'Var', (95, 103))	('mitotane', 'Chemical', 'MESH:D008939', (95, 103))
78054	31745526	A recent case report of a patient with a cortisol-secreting ACC and a mutation in MSH2 reported progression after two cycles of pembrolizumab.	('patient', 'Species', '9606', (26, 33))	('MSH2', 'Gene', (82, 86))	('MSH2', 'Gene', '4436', (82, 86))	('cortisol', 'Chemical', 'MESH:D006854', (41, 49))	('ACC', 'Phenotype', 'HP:0006744', (60, 63))	('ACC', 'Disease', (60, 63))	('cortisol-secreting', 'MPA', (41, 59))	('mutation', 'Var', (70, 78))	('ACC', 'Disease', 'MESH:D018268', (60, 63))
78056	31745526	In our case series, patient 3 had a cortisol-secreting tumor and MSH2 mutation, and she has had SD.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('MSH2', 'Gene', (65, 69))	('patient', 'Species', '9606', (20, 27))	('MSH2', 'Gene', '4436', (65, 69))	('SD', 'Disease', 'MESH:D060050', (96, 98))	('mutation', 'Var', (70, 78))	('cortisol', 'Chemical', 'MESH:D006854', (36, 44))
78073	31065237	We report that NaAsO2 alters the cell proliferation of prostate cells, in a hormetic manner, by increasing cell proliferation at low concentrations and decreasing the cell proliferation at high concentrations.	('alters', 'Reg', (22, 28))	('decreasing', 'NegReg', (152, 162))	('cell proliferation', 'CPA', (107, 125))	('NaAsO2', 'Var', (15, 21))	('increasing', 'PosReg', (96, 106))	('cell proliferation', 'CPA', (33, 51))	('NaAsO2', 'Chemical', 'MESH:C017947', (15, 21))	('cell proliferation', 'CPA', (167, 185))
78075	31065237	We conclude that NaAsO2 is able to increase cell proliferation of prostate cells in vitro at low concentrations, while it decreases cell viability at high concentrations.	('increase', 'PosReg', (35, 43))	('cell proliferation', 'CPA', (44, 62))	('NaAsO2', 'Chemical', 'MESH:C017947', (17, 23))	('NaAsO2', 'Var', (17, 23))	('cell viability', 'CPA', (132, 146))	('decreases', 'NegReg', (122, 131))
78089	31065237	Kim et al reported that NaAsO2 reduced cell viability of both androgen-sensitive and androgen-insensitive prostate cancer cells in vitro.	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('reduced', 'NegReg', (31, 38))	('NaAsO2', 'Chemical', 'MESH:C017947', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('prostate cancer', 'Disease', (106, 121))	('NaAsO2', 'Var', (24, 30))	('cell viability', 'CPA', (39, 53))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))
78112	31065237	The proliferation of breast cancer MCF-7 cells was increased by treatment with NaAsO2 in the concentration 3 and 10 microM, although the stimulatory effect was only 5% to 7% (Figure 2A).	('proliferation', 'CPA', (4, 17))	('NaAsO2', 'Var', (79, 85))	('men', 'Species', '9606', (69, 72))	('F', 'Chemical', 'MESH:D005461', (175, 176))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('increased', 'PosReg', (51, 60))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('to 7', 'Species', '1214577', (168, 172))	('breast cancer', 'Disease', (21, 34))	('MCF-7', 'CellLine', 'CVCL:0031', (35, 40))	('NaAsO2', 'Chemical', 'MESH:C017947', (79, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('F', 'Chemical', 'MESH:D005461', (37, 38))
78113	31065237	At the concentration 30 microM and above, NaAsO2 was found to significantly decrease the cell viability.	('NaAsO2', 'Chemical', 'MESH:C017947', (42, 48))	('decrease', 'NegReg', (76, 84))	('NaAsO2', 'Var', (42, 48))	('cell viability', 'CPA', (89, 103))
78114	31065237	The proliferation of adrenocortical carcinoma NCI-H295R cells was found to be altered by NaAsO2 treatment in a monotonic manner, where increased levels of NaAsO2 resulted in decreased cell proliferation (Figure 2B).	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (21, 45))	('NCI-H295R', 'CellLine', 'CVCL:0458', (46, 55))	('decreased', 'NegReg', (174, 183))	('proliferation', 'CPA', (4, 17))	('NaAsO2', 'Chemical', 'MESH:C017947', (89, 95))	('men', 'Species', '9606', (101, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('adrenocortical carcinoma', 'Disease', (21, 45))	('cell proliferation', 'CPA', (184, 202))	('NaAsO2', 'Var', (89, 95))	('NaAsO2', 'Chemical', 'MESH:C017947', (155, 161))	('altered', 'Reg', (78, 85))	('F', 'Chemical', 'MESH:D005461', (204, 205))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (21, 45))
78122	31065237	NaAsO2, a water soluble and orally bioavailable arsenic compound, has been reported to significantly decrease the proliferation of prostate cancer cells  with suggested mechanisms at multiple levels, including that NaAsO2 could act as a telomere-targeting agent, that it could induce apoptosis and necrosis via a ROS-dependent mechanism, or that it could reduce androgen receptor levels, stability, and translocation into the nucleus.	('apoptosis', 'CPA', (284, 293))	('reduce androgen receptor levels', 'Phenotype', 'HP:0030349', (355, 386))	('water', 'Chemical', 'MESH:D014867', (10, 15))	('reduce', 'NegReg', (355, 361))	('decrease', 'NegReg', (101, 109))	('androgen receptor', 'Gene', (362, 379))	('androgen receptor', 'Gene', '367', (362, 379))	('NaAsO2', 'Chemical', 'MESH:C017947', (215, 221))	('induce', 'PosReg', (277, 283))	('necrosis', 'Disease', 'MESH:D009336', (298, 306))	('translocation into the nucleus', 'MPA', (403, 433))	('NaAsO2', 'Chemical', 'MESH:C017947', (0, 6))	('NaAsO2', 'Var', (215, 221))	('arsenic', 'Chemical', 'MESH:D001151', (48, 55))	('NaAsO2', 'Var', (0, 6))	('necrosis', 'Disease', (298, 306))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('stability', 'MPA', (388, 397))	('prostate cancer', 'Disease', 'MESH:D011471', (131, 146))	('ROS', 'Chemical', 'MESH:D017382', (313, 316))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('proliferation', 'CPA', (114, 127))	('prostate cancer', 'Disease', (131, 146))
78142	25449630	Germline PRKACA Amplification Leads To Cushing Syndrome Caused By 3 Adrenocortical Pathologic Phenotypes We describe the pathology of 5 patients with germline PRKACA copy number gain and Cushing syndrome: 4 males and 1 female, aged 2 through 43 years, including a mother and son.	('Cushing syndrome', 'Phenotype', 'HP:0003118', (187, 203))	('Cushing Syndrome', 'Phenotype', 'HP:0003118', (39, 55))	('Leads To', 'Reg', (30, 38))	('Adrenocortical', 'Disease', (68, 82))	('Cushing syndrome', 'Disease', (187, 203))	('gain', 'PosReg', (178, 182))	('copy number', 'Var', (166, 177))	('Cushing syndrome', 'Disease', 'MESH:D003480', (187, 203))	('PRKACA', 'Gene', (159, 165))	('PRKACA', 'Gene', (9, 15))	('patients', 'Species', '9606', (136, 144))	('Cushing Syndrome', 'Disease', 'MESH:D003480', (39, 55))	('Adrenocortical', 'Disease', 'MESH:D018268', (68, 82))	('PRKACA', 'Gene', '5566', (159, 165))	('PRKACA', 'Gene', '5566', (9, 15))	('Cushing Syndrome', 'Disease', (39, 55))	('Amplification', 'Var', (16, 29))
78153	25449630	The other, corticotropin-independent disease, is primary in an adrenal gland and is caused by a cortisol-secreting adenoma or carcinoma; exceptionally, the disorder is due to ectopic corticotropin secretion (Cushing syndrome).	('Cushing syndrome', 'Phenotype', 'HP:0003118', (208, 224))	('adenoma or carcinoma', 'Disease', (115, 135))	('due to', 'Reg', (168, 174))	('caused by', 'Reg', (84, 93))	('Cushing syndrome', 'Disease', (208, 224))	('Cushing syndrome', 'Disease', 'MESH:D003480', (208, 224))	('ectopic', 'Var', (175, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('adenoma or carcinoma', 'Disease', 'MESH:D000236', (115, 135))	('corticotropin-independent disease', 'Disease', (11, 44))
78157	25449630	Recently, we described patients with Cushing syndrome who had 1) adrenal adenomas caused by PRKACA somatic amplification or 2) PPNAD or isolated micronodular adrenocortical disease or adrenal independent macronodular adrenocortical disease resulting from germline PRKACA copy number gain.	('adrenocortical disease', 'Disease', 'MESH:D018268', (158, 180))	('adrenocortical disease', 'Disease', 'MESH:D018268', (217, 239))	('adrenal adenomas', 'Disease', (65, 81))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (37, 53))	('patients', 'Species', '9606', (23, 31))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (65, 81))	('caused by', 'Reg', (82, 91))	('PRKACA', 'Gene', (264, 270))	('PRKACA', 'Gene', (92, 98))	('Cushing syndrome', 'Disease', (37, 53))	('Cushing syndrome', 'Disease', 'MESH:D003480', (37, 53))	('macronodular adrenocortical disease', 'Phenotype', 'HP:0008231', (204, 239))	('adrenocortical disease', 'Disease', (158, 180))	('adrenal adenomas', 'Disease', 'MESH:D018246', (65, 81))	('PRKACA', 'Gene', '5566', (264, 270))	('PRKACA', 'Gene', '5566', (92, 98))	('copy number gain', 'Var', (271, 287))	('adrenocortical disease', 'Disease', (217, 239))
78167	25449630	With the use of standard methods, DNA was extracted from peripheral blood lymphocytes of the 5 patients and tested for genetic mutations, deletions, and genomic alterations (copy number gain) associated with Cushing syndrome, including those affecting PRKACA, PRKAR1A, PDE11A, and PDE8B.	('PRKACA', 'Gene', '5566', (252, 258))	('PRKAR1A', 'Gene', (260, 267))	('PDE8B', 'Gene', '8622', (281, 286))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (208, 224))	('associated', 'Reg', (192, 202))	('patients', 'Species', '9606', (95, 103))	('Cushing syndrome', 'Disease', (208, 224))	('Cushing syndrome', 'Disease', 'MESH:D003480', (208, 224))	('PRKAR1A', 'Gene', '5573', (260, 267))	('deletions', 'Var', (138, 147))	('PDE11A', 'Gene', (269, 275))	('PDE11A', 'Gene', '50940', (269, 275))	('mutations', 'Var', (127, 136))	('PRKACA', 'Gene', (252, 258))	('PDE8B', 'Gene', (281, 286))
78174	25449630	There were no PRKAR1A, PDE11A, or PDE8B mutations.	('PRKAR1A', 'Gene', '5573', (14, 21))	('PDE11A', 'Gene', (23, 29))	('PDE8B', 'Gene', (34, 39))	('PDE11A', 'Gene', '50940', (23, 29))	('PDE8B', 'Gene', '8622', (34, 39))	('mutations', 'Var', (40, 49))	('PRKAR1A', 'Gene', (14, 21))
78200	25449630	For patients 4 and 5, the intracapsular and extracapsular micronodules stained with all the antisera: vimentin, synaptophysin, inhibinA, melan A, CD56, beta-catenin, and Ki-67 (scattered nuclei).	('CD56', 'Gene', '4684', (146, 150))	('melan A', 'Gene', '2315', (137, 144))	('synaptophysin', 'Gene', (112, 125))	('beta-catenin', 'Gene', (152, 164))	('Ki-67', 'Var', (170, 175))	('synaptophysin', 'Gene', '6855', (112, 125))	('CD56', 'Gene', (146, 150))	('stained', 'Reg', (71, 78))	('beta-catenin', 'Gene', '1499', (152, 164))	('melan A', 'Gene', (137, 144))	('patients', 'Species', '9606', (4, 12))	('vimentin', 'Gene', (102, 110))	('vimentin', 'Gene', '7431', (102, 110))	('scattered nuclei', 'Phenotype', 'HP:0003687', (177, 193))
78209	25449630	Interestingly, copy number gain of the second subunit of the gene, PRKACB, was recently found in a patient with Carney complex but without Cushing syndrome.	('patient', 'Species', '9606', (99, 106))	('Cushing syndrome', 'Disease', (139, 155))	('copy number gain', 'Var', (15, 31))	('Carney complex', 'Disease', (112, 126))	('Cushing syndrome', 'Disease', 'MESH:D003480', (139, 155))	('PRKACB', 'Gene', '5567', (67, 73))	('PRKACB', 'Gene', (67, 73))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (139, 155))
78210	25449630	Because the PRKACA copy number gain was in the germline in our patients, familial involvement was a likely possibility; in fact, patients 2 and 3 were mother and son.	('PRKACA', 'Gene', '5566', (12, 18))	('copy number', 'Var', (19, 30))	('familial involvement', 'Disease', 'MESH:C566895', (73, 93))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (63, 71))	('familial involvement', 'Disease', (73, 93))	('PRKACA', 'Gene', (12, 18))
78212	25449630	It is likely that PRKACA copy number gain may provide an explanation for other patients with PPNAD with an as yet unidentified genetic aberration.	('copy number', 'Var', (25, 36))	('PRKACA', 'Gene', (18, 24))	('patients', 'Species', '9606', (79, 87))	('PRKACA', 'Gene', '5566', (18, 24))	('gain', 'PosReg', (37, 41))
78222	25449630	The multiple micronodules in the cortex proper in patients 1, 2, and 3 suggest that the genetic copy number gain affected scattered cells or small groups of cortical cells in the cortex and that their hypertrophy and proliferation resulted in micronodules.	('affected', 'Reg', (113, 121))	('resulted in', 'Reg', (231, 242))	('patients', 'Species', '9606', (50, 58))	('gain', 'PosReg', (108, 112))	('genetic copy number', 'Var', (88, 107))	('hypertrophy', 'Disease', (201, 212))	('hypertrophy', 'Disease', 'MESH:D006984', (201, 212))	('micronodules', 'CPA', (243, 255))	('proliferation', 'CPA', (217, 230))
78225	25449630	The findings for the latter patients were similar to those described for some patients with PRKAR1A, PDE11A, and PDE8B mutations.	('PDE11A', 'Gene', (101, 107))	('PDE11A', 'Gene', '50940', (101, 107))	('PDE8B', 'Gene', (113, 118))	('PRKAR1A', 'Gene', (92, 99))	('PDE8B', 'Gene', '8622', (113, 118))	('patients', 'Species', '9606', (78, 86))	('PRKAR1A', 'Gene', '5573', (92, 99))	('mutations', 'Var', (119, 128))	('patients', 'Species', '9606', (28, 36))
78228	25449630	A cortical adenoma was described in 1 of the 4 patients in the original report on PPNAD (they had a germline PRKAR1A mutation), and the tumor has been found bilaterally in McCune-Albright syndrome (somatic GNAS mutation).	('McCune-Albright syndrome', 'Disease', (172, 196))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (172, 196))	('cortical adenoma', 'Disease', (2, 18))	('PRKAR1A', 'Gene', (109, 116))	('cortical adenoma', 'Disease', 'MESH:D000236', (2, 18))	('patients', 'Species', '9606', (47, 55))	('GNAS', 'Gene', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('PRKAR1A', 'Gene', '5573', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mutation', 'Var', (117, 125))	('tumor', 'Disease', (136, 141))	('GNAS', 'Gene', '2778', (206, 210))
78229	25449630	Thus, germline and somatic adrenal mutation may cause adrenal cortical hyperplastic or neoplastic lesions (benign), or both.	('adrenal', 'Gene', (27, 34))	('hyperplastic or neoplastic lesions', 'Phenotype', 'HP:0002664', (71, 105))	('cause', 'Reg', (48, 53))	('adrenal cortical hyperplastic or neoplastic lesions', 'Disease', 'MESH:D000310', (54, 105))	('mutation', 'Var', (35, 43))
78235	25449630	There was strong staining for vimentin in the atrophic cortex in patients 1, 2, and 3 (similar to that in familial micronodular adrenocortical disease associated with PDE11A mutation and in bimorphic adrenocortical disease due to activation of the stimulatory G protein (GNAS), and lack of staining in the hyperplastic cortex in patients 4 and 5.	('GNAS', 'Gene', '2778', (271, 275))	('adrenocortical disease', 'Disease', (128, 150))	('adrenocortical disease due', 'Phenotype', 'HP:0008207', (200, 226))	('PDE11A', 'Gene', '50940', (167, 173))	('atrophic cortex', 'Disease', (46, 61))	('PDE11A', 'Gene', (167, 173))	('mutation', 'Var', (174, 182))	('adrenocortical disease', 'Disease', 'MESH:D018268', (200, 222))	('patients', 'Species', '9606', (329, 337))	('patients', 'Species', '9606', (65, 73))	('activation', 'PosReg', (230, 240))	('adrenocortical disease', 'Disease', (200, 222))	('atrophic cortex', 'Phenotype', 'HP:0002120', (46, 61))	('adrenocortical disease', 'Disease', 'MESH:D018268', (128, 150))	('atrophic cortex', 'Disease', 'MESH:D000303', (46, 61))	('GNAS', 'Gene', (271, 275))	('staining', 'MPA', (17, 25))	('vimentin', 'Gene', '7431', (30, 38))	('vimentin', 'Gene', (30, 38))
78239	25449630	From past experience with genetic bilateral adrenal disorders, it was not surprising to find several types of adrenocortical pathology associated with copy number gain of PRKACA.	('PRKACA', 'Gene', (171, 177))	('adrenal disorders', 'Phenotype', 'HP:0000834', (44, 61))	('genetic bilateral adrenal disorders', 'Disease', 'MESH:D030342', (26, 61))	('PRKACA', 'Gene', '5566', (171, 177))	('adrenocortical', 'Disease', (110, 124))	('copy number gain', 'Var', (151, 167))	('adrenocortical', 'Disease', 'MESH:D018268', (110, 124))	('genetic bilateral adrenal disorders', 'Disease', (26, 61))
78240	25449630	The current findings:and those reported in other recently recognized Cushing syndrome-associated primary, bilateral, genetically mediated adrenal disorders :have revealed a surprising spectrum and flexibility of the adrenal cortical morphologic response to genetic mutation and copy number gain.	('Cushing syndrome', 'Disease', (69, 85))	('Cushing syndrome', 'Disease', 'MESH:D003480', (69, 85))	('adrenal disorders', 'Disease', 'MESH:D000312', (138, 155))	('adrenal disorders', 'Phenotype', 'HP:0000834', (138, 155))	('adrenal disorders', 'Disease', (138, 155))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (69, 85))	('genetic mutation', 'Var', (257, 273))	('copy number gain', 'Var', (278, 294))
78276	23406775	The patient harbored a germline TP53 G245C mutation, and the primary tumor showed loss of heterozygosity with retention of the mutated TP53 allele.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('TP53', 'Gene', '7157', (135, 139))	('TP53', 'Gene', '7157', (32, 36))	('patient', 'Species', '9606', (4, 11))	('G245C', 'Var', (37, 42))	('TP53', 'Gene', (32, 36))	('TP53', 'Gene', (135, 139))	('G245C', 'Mutation', 'rs28934573', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
78280	23406775	Screening the xenograft for drug responsiveness showed cisplatin had a potent antitumor effect.	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('cisplatin', 'Var', (55, 64))
78285	23406775	ACT is more common among children who harbor germline TP53 mutations (e.g., Li-Fraumeni syndrome) or who have other tumor-prone constitutional syndromes.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (76, 96))	('germline', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('children', 'Species', '9606', (25, 33))	('TP53', 'Gene', '7157', (54, 58))	('Li-Fraumeni syndrome', 'Disease', (76, 96))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (59, 68))	('TP53', 'Gene', (54, 58))	('tumor', 'Disease', (116, 121))	('ACT', 'Disease', (0, 3))
78294	23406775	In particular, with the use of topoisomerase inhibitors such as doxorubicin and etoposide may result in leukemogenesis.	('result in', 'Reg', (94, 103))	('etoposide', 'Chemical', 'MESH:D005047', (80, 89))	('doxorubicin', 'Chemical', 'MESH:D004317', (64, 75))	('leukemogenesis', 'Disease', (104, 118))	('doxorubicin', 'Var', (64, 75))	('etoposide', 'Gene', (80, 89))	('topoisomerase', 'Protein', (31, 44))
78366	23406775	Elevated levels of IGF-2 are usually caused by genetic or epigenetic alterations at chromosome 11p15 and occur in approximately 90% of pediatric ACT.	('genetic', 'Var', (47, 54))	('caused by', 'Reg', (37, 46))	('Elevated levels of IGF-2', 'Phenotype', 'HP:0030269', (0, 24))	('IGF-2', 'Gene', (19, 24))	('IGF-2', 'Gene', '3481', (19, 24))	('epigenetic alterations', 'Var', (58, 80))
78367	23406775	Overexpression of IGF-2 presumably drives ACC proliferation and survival, and therefore this signaling pathway may be a rational target for developing new drug therapies.	('survival', 'CPA', (64, 72))	('IGF-2', 'Gene', (18, 23))	('IGF-2', 'Gene', '3481', (18, 23))	('ACC proliferation', 'CPA', (42, 59))	('drives', 'PosReg', (35, 41))	('Overexpression', 'Var', (0, 14))
78403	23412108	Furthermore, in vitro, in vivo, and tumour biopsy studies demonstrate that mTOR inhibitors activate a feedback loop, which results in upregulated AKT phosphorylation in tumour tissue via an IGF-1R-dependent mechanism.	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('IGF-1R', 'Gene', (190, 196))	('AKT', 'Gene', '207', (146, 149))	('IGF-1R', 'Gene', '3480', (190, 196))	('tumour', 'Disease', (169, 175))	('tumour', 'Disease', (36, 42))	('upregulated', 'PosReg', (134, 145))	('AKT', 'Gene', (146, 149))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('inhibitors', 'Var', (80, 90))
78438	23412108	Preclinical in vitro and animal studies showed reduced ACC cell proliferation induced by cixutumumab that was augmented in combination with the antineoplastic agent mitotane.	('ACC', 'Phenotype', 'HP:0006744', (55, 58))	('cixutumumab', 'Var', (89, 100))	('mitotane', 'Chemical', 'MESH:D008939', (165, 173))	('cixutumumab', 'Chemical', 'MESH:C557414', (89, 100))	('men', 'Species', '9606', (113, 116))	('ACC cell proliferation', 'CPA', (55, 77))	('reduced', 'NegReg', (47, 54))
78444	23412108	Recent preclinical study showed that sirolimus inhibits cortisol secretion in ACC.	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('sirolimus', 'Var', (37, 46))	('sirolimus', 'Chemical', 'MESH:D020123', (37, 46))	('cortisol secretion', 'MPA', (56, 74))	('inhibits', 'NegReg', (47, 55))
78449	23412108	Mitotane is the most commonly used drug for the treatment of ACC and can induce this enzyme, and it may cause sub-therapeutic levels of temsirolimus.	('sub-therapeutic levels of temsirolimus', 'MPA', (110, 148))	('Mitotane', 'Var', (0, 8))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('men', 'Species', '9606', (53, 56))	('ACC', 'Phenotype', 'HP:0006744', (61, 64))	('cause', 'Reg', (104, 109))	('ACC', 'Disease', (61, 64))	('induce', 'PosReg', (73, 79))	('temsirolimus', 'Chemical', 'MESH:C401859', (136, 148))
78456	23412108	One patient was a 34-year-old woman who was treated with a single-agent IGF-1R inhibitor for nearly 10 months.	('IGF-1R', 'Gene', (72, 78))	('woman', 'Species', '9606', (30, 35))	('inhibitor', 'Var', (79, 88))	('patient', 'Species', '9606', (4, 11))	('IGF-1R', 'Gene', '3480', (72, 78))
78463	23412108	This was not unexpected since a concern for this class of drugs, especially the IGF-1R inhibitors, is that they induce hyperglycaemia.	('IGF-1R', 'Gene', (80, 86))	('induce', 'Reg', (112, 118))	('hyperglycaemia', 'Disease', (119, 133))	('hyperglycaemia', 'Disease', 'None', (119, 133))	('IGF-1R', 'Gene', '3480', (80, 86))	('inhibitors', 'Var', (87, 97))
78475	23412108	Other pathways such as those involving fibroblast growth factor receptor (FGFR) and Wnt-beta-catenin signalling cascades and loss of p53 function have been implicated in ACC tumorigenesis.	('implicated', 'Reg', (156, 166))	('loss', 'Var', (125, 129))	('ACC', 'Phenotype', 'HP:0006744', (170, 173))	('p53', 'Gene', '7157', (133, 136))	('beta-catenin', 'Gene', (88, 100))	('p53', 'Gene', (133, 136))	('beta-catenin', 'Gene', '1499', (88, 100))	('ACC tumorigenesis', 'Disease', (170, 187))
78524	23152728	Norepinephrine-secreting tumours cause sustained hypertension, while tumours that secrete large amounts of both epinephrine and norepinephrine are associated with episodic hypertension.	('associated with', 'Reg', (147, 162))	('hypertension', 'Disease', 'MESH:D006973', (172, 184))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('Norepinephrine-secreting', 'Var', (0, 24))	('hypertension', 'Disease', (172, 184))	('tumours', 'Disease', (25, 32))	('episodic hypertension', 'Disease', 'MESH:D006973', (163, 184))	('hypertension', 'Disease', 'MESH:D006973', (49, 61))	('epinephrine', 'Chemical', 'MESH:D004837', (112, 123))	('episodic hypertension', 'Phenotype', 'HP:0000875', (163, 184))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('hypertension', 'Disease', (49, 61))	('hypertension', 'Phenotype', 'HP:0000822', (172, 184))	('norepinephrine', 'Chemical', 'MESH:D009638', (128, 142))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('hypertension', 'Phenotype', 'HP:0000822', (49, 61))	('Norepinephrine', 'Chemical', 'MESH:D009638', (0, 14))	('tumours', 'Disease', (69, 76))	('epinephrine', 'Chemical', 'MESH:D004837', (3, 14))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('episodic hypertension', 'Disease', (163, 184))	('epinephrine', 'Chemical', 'MESH:D004837', (131, 142))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
78571	20223012	However, some children who develop ACTs in the absence of familial cancer syndromes harbour germline mutations in other regions of TP53 .	('children', 'Species', '9606', (14, 22))	('germline mutations', 'Var', (92, 110))	('familial cancer syndromes', 'Disease', (58, 83))	('harbour', 'Reg', (84, 91))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (58, 83))
78572	20223012	Due to ACTs having a higher incidence in our state and the absence of mutations in exons 5-9 of TP53, all coding regions of the gene have been examined.	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (96, 100))	('TP53', 'Gene', (96, 100))
78573	20223012	A germline mutation, R337H in exon 10 of TP53, was identified in 35 of 36 patients studied.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('R337H', 'Var', (21, 26))	('R337H', 'Mutation', 'rs121912664', (21, 26))	('patients', 'Species', '9606', (74, 82))
78574	20223012	Because Parana and Sao Paulo have extensive agricultural activities, it is tempting to speculate that environmental pollutants, such as pesticides, may pose a substantial health hazard and possibly contribute to adrenal tumorigenesis in individuals with the TP53 R337H mutations.	('TP53', 'Gene', '7157', (258, 262))	('contribute', 'Reg', (198, 208))	('TP53', 'Gene', (258, 262))	('adrenal', 'Disease', (212, 219))	('Sao', 'Gene', (19, 22))	('Sao', 'Gene', '6521', (19, 22))	('R337H', 'Mutation', 'rs121912664', (263, 268))	('R337H', 'Var', (263, 268))
78584	20223012	In order to further understand adrenocortical tumorigenesis several mechanisms were identified from studies on rare genetic syndromes (reviewed in), such as multiple endocrine neoplasia type 1 (Menin gene and locus 11q13), Carney complex (regulatory R1A subunit of protein kinase A - PRKAR1A gene), Beckwith-Wiedemann (IGF- II and 11p15 changes) and McCune-Albright (GNAS1 gene) syndromes, hemihypertrophy, congenital adrenal hyperplasia (CYP21 gene), glucocorticoid-remediable aldosteronism (hybrid gene formed by CYP11B1 and CYP11B2 genes), hereditary isolated glucocorticoid deficiency (MC2-R gene) and alterations of the TP53 gene.	('TP53', 'Gene', (625, 629))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (407, 437))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (418, 437))	('congenital adrenal hyperplasia', 'Disease', (407, 437))	('CYP11B1', 'Gene', '1584', (515, 522))	('CYP11B2', 'Gene', (527, 534))	('glucocorticoid-remediable', 'Disease', (452, 477))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (407, 437))	('Menin', 'Gene', (194, 199))	('hemihypertrophy', 'Disease', (390, 405))	('CYP11B1', 'Gene', (515, 522))	('multiple endocrine neoplasia type', 'Disease', (157, 190))	('hemihypertrophy', 'Disease', 'MESH:C563014', (390, 405))	('neoplasia', 'Phenotype', 'HP:0002664', (176, 185))	('hereditary isolated glucocorticoid deficiency', 'Disease', 'MESH:C565974', (543, 588))	('alterations', 'Var', (606, 617))	('CYP21', 'Gene', (439, 444))	('Beckwith-Wiedemann', 'Disease', 'MESH:D001506', (299, 317))	('MC2-R', 'Gene', (590, 595))	('IGF- II', 'Gene', '3481', (319, 326))	('TP53', 'Gene', '7157', (625, 629))	('PRKAR1A', 'Gene', (284, 291))	('hereditary isolated glucocorticoid deficiency', 'Disease', (543, 588))	('GNAS1', 'Gene', '2778', (367, 372))	('MC2-R', 'Gene', '4158', (590, 595))	('McCune-Albright', 'Disease', (350, 365))	('adrenocortical', 'Disease', 'MESH:D018268', (31, 45))	('CYP11B2', 'Gene', '1585', (527, 534))	('Carney complex', 'Disease', (223, 237))	('GNAS1', 'Gene', (367, 372))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (166, 185))	('Menin', 'Gene', '4221', (194, 199))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (563, 588))	('IGF- II', 'Gene', (319, 326))	('adrenocortical', 'Disease', (31, 45))	('PRKAR1A', 'Gene', '5573', (284, 291))	('hemihypertrophy', 'Phenotype', 'HP:0001528', (390, 405))	('Beckwith-Wiedemann', 'Disease', (299, 317))	('CYP21', 'Gene', '1589', (439, 444))	('multiple endocrine neoplasia type', 'Disease', 'MESH:D018761', (157, 190))
78589	20223012	Moreover, LOH at the 17p13 loci is highly specific to malignant tumours.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('malignant tumours', 'Disease', 'MESH:D009369', (54, 71))	('malignant tumours', 'Disease', (54, 71))	('LOH', 'Var', (10, 13))	('17p13', 'Gene', (21, 26))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
78595	20223012	IGF type-2 receptor (IGF2R) loss of function by inactivating mutations located in the DNA coding region and LOH at the IGF2R loci were reported in ACTs.	('inactivating mutations', 'Var', (48, 70))	('IGF2R', 'Gene', '3482', (119, 124))	('loss of function', 'NegReg', (28, 44))	('IGF2R', 'Gene', '3482', (21, 26))	('LOH', 'Var', (108, 111))	('IGF type-2 receptor', 'Gene', '3482', (0, 19))	('IGF type-2 receptor', 'Gene', (0, 19))	('IGF2R', 'Gene', (119, 124))	('IGF2R', 'Gene', (21, 26))
78598	20223012	More generally, lesions either in the machinery that senses DNA damage or in the machinery that implements a response to DNA damage greatly alters the likelihood of cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('alters', 'Reg', (140, 146))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('lesions', 'Var', (16, 23))
78599	20223012	Mutation in the tumour suppressor gene TP53 is a key mutational event in over half of all human cancers, and mutations in TP53 are the most frequently observed genetic change in cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('human', 'Species', '9606', (90, 95))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))	('cancer', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (122, 126))	('mutations', 'Var', (109, 118))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Disease', (16, 22))	('Mutation', 'Var', (0, 8))	('cancer', 'Disease', (178, 184))	('TP53', 'Gene', '7157', (122, 126))	('TP53', 'Gene', (39, 43))
78601	20223012	In many cases, TP53 itself is mutated or deleted.	('deleted', 'Var', (41, 48))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))
78603	20223012	Stress signals are transmitted to p53 proteins by post-translational modification.	('p53', 'Gene', (34, 37))	('post-translational modification', 'Var', (50, 81))	('p53', 'Gene', '7157', (34, 37))
78608	20223012	The majority of TP53 germline mutations in cancer are localized between exons 5 and 8, the highly conserved DNA-binding-domain of the gene, although mutations located in other regions have also been described.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('germline mutations', 'Var', (21, 39))	('TP53', 'Gene', '7157', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('TP53', 'Gene', (16, 20))
78611	20223012	Thus, TP53 mutations appear to increase ACTs predisposition in children.	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('ACTs', 'Disease', (40, 44))	('children', 'Species', '9606', (63, 71))	('increase', 'PosReg', (31, 39))
78612	20223012	In North America and Europe, 50-80% of children with apparently sporadic ACTs carried TP53 germline mutations.	('TP53', 'Gene', (86, 90))	('TP53', 'Gene', '7157', (86, 90))	('children', 'Species', '9606', (39, 47))	('germline mutations', 'Var', (91, 109))
78613	20223012	Functional analysis of the TP53 germline mutation described in patients from Parana showed that in contrast to TP53 R248W, the TP53 R337H mutant and wild type TP53 were able to suppress colony growth of SaOs-2 cells lacking endogenous p53.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('TP53', 'Gene', '7157', (111, 115))	('colony growth of SaOs-2 cells', 'CPA', (186, 215))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', (111, 115))	('TP53', 'Gene', (159, 163))	('suppress', 'NegReg', (177, 185))	('R248W', 'Mutation', 'rs121912651', (116, 121))	('p53', 'Gene', (235, 238))	('patients', 'Species', '9606', (63, 71))	('R337H', 'Var', (132, 137))	('p53', 'Gene', '7157', (235, 238))	('R337H', 'Mutation', 'rs121912664', (132, 137))	('TP53', 'Gene', (127, 131))	('TP53', 'Gene', '7157', (127, 131))
78615	20223012	Taken together these data indicate that the R337H mutant retains p53 activity at physiological conditions.	('R337H', 'Var', (44, 49))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('activity', 'MPA', (69, 77))	('R337H', 'Mutation', 'rs121912664', (44, 49))
78621	20223012	TP53 germline mutations were identified in over 80% and in one case the TP53 R337H mutation was present in a tumour, with the complete loss of the wild type allele; however, they were unable to determine whether this mutation was inherited or acquired.	('R337H', 'Var', (77, 82))	('TP53', 'Gene', '7157', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (72, 76))	('tumour', 'Disease', (109, 115))	('TP53', 'Gene', (72, 76))	('R337H', 'Mutation', 'rs121912664', (77, 82))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
78622	20223012	From their study, it was shown that tetramer formation of the R337H p53 mutant becomes significantly less stable as pH increases toward the physiological range between 7 and 8.	('less', 'NegReg', (101, 105))	('R337H', 'Var', (62, 67))	('R337H', 'Mutation', 'rs121912664', (62, 67))	('tetramer formation', 'MPA', (36, 54))	('p53', 'Gene', '7157', (68, 71))	('p53', 'Gene', (68, 71))
78623	20223012	A substantial fraction of mutant p53 R337H variants remain unfolded at pH 8 and at 37 C (>70% unfolded), whereas wildtype p53 is fully folded under the same conditions.	('p53', 'Gene', '7157', (122, 125))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('R337H', 'Mutation', 'rs121912664', (37, 42))	('R337H', 'Var', (37, 42))	('mutant', 'Var', (26, 32))	('p53', 'Gene', (122, 125))
78624	20223012	using circular dichroism spectroscopy were also able to show the effects of temperature on the stability of the p53 mutant protein in families with LFS and Li-Fraumeni like syndrome with TP53 L344P and TP53 R337C mutations, respectively, located in the tetradimerization zone of TP53 .	('TP53', 'Gene', '7157', (279, 283))	('R337C', 'Mutation', 'rs587782529', (207, 212))	('L344P', 'Var', (192, 197))	('TP53', 'Gene', (187, 191))	('p53', 'Gene', '7157', (112, 115))	('TP53', 'Gene', (202, 206))	('p53', 'Gene', (112, 115))	('circular dichroism', 'Disease', (6, 24))	('TP53', 'Gene', '7157', (187, 191))	('TP53', 'Gene', (279, 283))	('LFS', 'Disease', (148, 151))	('mutant', 'Var', (116, 122))	('protein', 'Protein', (123, 130))	('stability', 'MPA', (95, 104))	('TP53', 'Gene', '7157', (202, 206))	('R337C', 'Var', (207, 212))	('LFS', 'Disease', 'MESH:D016864', (148, 151))	('L344P', 'Mutation', 'rs121912662', (192, 197))	('circular dichroism', 'Disease', 'None', (6, 24))	('Li-Fraumeni like syndrome', 'Disease', 'MESH:C567189', (156, 181))	('Li-Fraumeni like syndrome', 'Disease', (156, 181))
78625	20223012	The cause of the TP53 R337H mutation is presently unknown.	('R337H', 'Mutation', 'rs121912664', (22, 27))	('R337H', 'Var', (22, 27))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
78627	20223012	studied 22 patients (16 children and 6 adults) from the State of Sao Paulo and concluded that the TP53 R337H germline mutation arose from a single common ancestor.	('R337H', 'Var', (103, 108))	('R337H', 'Mutation', 'rs121912664', (103, 108))	('TP53', 'Gene', '7157', (98, 102))	('patients', 'Species', '9606', (11, 19))	('Sao', 'Gene', (65, 68))	('Sao', 'Gene', '6521', (65, 68))	('children', 'Species', '9606', (24, 32))	('TP53', 'Gene', (98, 102))
78628	20223012	Several lines of evidence show that the TP53 R337H mutation is strongly related to ACT in children in southern Brazil: a) the families do not have a common ancestry; b) TP53 R337H is not a common polymorphism among southern Brazilians; c) the loss of heterozygosity with retention of the mutant allele in the tumour cells, and d) the mutant p53 protein is highly expressed in the ACTs.	('R337H', 'Mutation', 'rs121912664', (174, 179))	('mutant', 'Var', (334, 340))	('p53', 'Gene', (341, 344))	('children', 'Species', '9606', (90, 98))	('tumour', 'Phenotype', 'HP:0002664', (309, 315))	('expressed', 'MPA', (363, 372))	('R337H', 'Mutation', 'rs121912664', (45, 50))	('TP53', 'Gene', '7157', (169, 173))	('p53', 'Gene', '7157', (341, 344))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('protein', 'Protein', (345, 352))	('TP53', 'Gene', (169, 173))	('tumour', 'Disease', 'MESH:D009369', (309, 315))	('tumour', 'Disease', (309, 315))
78629	20223012	Over 927 individuals were tested for the TP53 R337H mutation, 232 from the non-carrier and 695 (including 40 probands) from the carrier parental line.	('TP53', 'Gene', '7157', (41, 45))	('R337H', 'Var', (46, 51))	('TP53', 'Gene', (41, 45))	('R337H', 'Mutation', 'rs121912664', (46, 51))
78634	20223012	had already described TP53 mutations in 14 cases of childhood ACT with equally low cancer penetrance.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('childhood ACT', 'Disease', (52, 65))	('TP53', 'Gene', '7157', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('TP53', 'Gene', (22, 26))	('cancer', 'Disease', (83, 89))
78636	20223012	Relevant in this regard are the data of Pereira et al., where 65 children (siblings and first-degree relatives), 0.25 to 14.6 years of age and all carriers of the TP53 R337H mutation, have been followed for three consecutive years, on a clinical, laboratory and imaging basis.	('children', 'Species', '9606', (65, 73))	('R337H', 'Var', (168, 173))	('R337H', 'Mutation', 'rs121912664', (168, 173))	('TP53', 'Gene', '7157', (163, 167))	('TP53', 'Gene', (163, 167))
78689	20223012	Several characterized TP53 polymorphisms showed altered regulation of p53 protein post-translational modifications, protein stability, nuclear localization and downstream signalling.	('TP53', 'Gene', (22, 26))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('altered regulation', 'Reg', (48, 66))	('nuclear localization', 'MPA', (135, 155))	('downstream signalling', 'MPA', (160, 181))	('TP53', 'Gene', '7157', (22, 26))	('polymorphisms', 'Var', (27, 40))	('protein', 'Protein', (74, 81))	('protein stability', 'MPA', (116, 133))
78697	20223012	More importantly, future studies should delineate more complex genotypes associated with p53 mutations, novel elements in p53 cellular response and deregulated cellular processes in ACT.	('mutations', 'Var', (93, 102))	('p53', 'Gene', (89, 92))	('p53', 'Gene', (122, 125))	('p53', 'Gene', '7157', (89, 92))	('p53', 'Gene', '7157', (122, 125))
78721	33907586	Moreover, mitotane cannot improve long-term survival rates for patients with metastatic ACC or inoperable ACC, although it may delay tumour progression.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('mitotane', 'Var', (10, 18))	('metastatic ACC', 'Disease', (77, 91))	('delay', 'NegReg', (127, 132))	('mitotane', 'Chemical', 'MESH:D008939', (10, 18))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('tumour', 'Disease', (133, 139))	('ACC', 'Phenotype', 'HP:0006744', (106, 109))	('patients', 'Species', '9606', (63, 71))
78724	33907586	Curcumin induces the apoptosis of colon cancer cells with wild-type p53 and mutant p53 in a dose- and time-dependent manner.	('colon cancer', 'Disease', (34, 46))	('Curcumin', 'Chemical', 'MESH:D003474', (0, 8))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('mutant', 'Var', (76, 82))	('apoptosis', 'CPA', (21, 30))	('colon cancer', 'Disease', 'MESH:D015179', (34, 46))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('colon cancer', 'Phenotype', 'HP:0003003', (34, 46))	('induces', 'Reg', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
78794	33907586	To further determine whether CHOP plays a notable role in curcumin-induced apoptosis, a shRNA was used to knock down CHOP expression.	('CHOP', 'Gene', (117, 121))	('CHOP', 'Gene', (29, 33))	('knock', 'Var', (106, 111))	('CHOP', 'Gene', '1649', (117, 121))	('curcumin', 'Chemical', 'MESH:D003474', (58, 66))	('CHOP', 'Gene', '1649', (29, 33))
78825	33907586	The overall survival rates of patients with nasopharyngeal carcinoma with positive expression of HSP70 were significantly lower than those with negative expression.	('carcinoma', 'Disease', (59, 68))	('lower', 'NegReg', (122, 127))	('HSP70', 'Gene', (97, 102))	('positive expression', 'Var', (74, 93))	('carcinoma', 'Disease', 'MESH:D009369', (59, 68))	('patients', 'Species', '9606', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (44, 68))	('HSP70', 'Gene', '3308', (97, 102))
78826	33907586	Sheng et al showed that inhibition of HSP70 expression enhances the sensitivity of gastric cancer cells to cisplatin via the MAPK signalling pathway and that HSP70 may be a therapeutic target in gastric cancer.	('HSP70', 'Gene', (38, 43))	('HSP70', 'Gene', (158, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('gastric cancer', 'Disease', (195, 209))	('inhibition', 'Var', (24, 34))	('HSP70', 'Gene', '3308', (38, 43))	('HSP70', 'Gene', '3308', (158, 163))	('gastric cancer', 'Disease', (83, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (195, 209))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('MAPK signalling pathway', 'Pathway', (125, 148))	('enhances', 'PosReg', (55, 63))	('sensitivity', 'MPA', (68, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (195, 209))
78838	33907586	The shRNA-mediated knockdown of CHOP expression inhibited curcumin-induced apoptosis in ACC SW-13 cells.	('SW-13', 'CellLine', 'CVCL:0542', (92, 97))	('CHOP', 'Gene', (32, 36))	('knockdown', 'Var', (19, 28))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('inhibited', 'NegReg', (48, 57))	('CHOP', 'Gene', '1649', (32, 36))	('curcumin', 'Chemical', 'MESH:D003474', (58, 66))	('curcumin-induced', 'MPA', (58, 74))
78869	32429325	Class II is commonly subdivided into two sub-classes (Table 1) based on sequence analysis: IIa (HDAC4, HDAC5, HDAC7, and HDAC9) and IIb (HDAC6 and HDAC10).	('HDAC10', 'Gene', '83933', (147, 153))	('HDAC5', 'Gene', '10014', (103, 108))	('IIb', 'Gene', (132, 135))	('HDAC5', 'Gene', (103, 108))	('HDAC6', 'Gene', '10013', (137, 142))	('HDAC7', 'Gene', '51564', (110, 115))	('HDAC6', 'Gene', (137, 142))	('IIb', 'Gene', '5658173', (132, 135))	('HDAC7', 'Gene', (110, 115))	('HDAC4', 'Var', (96, 101))	('HDAC10', 'Gene', (147, 153))	('HDAC9', 'Gene', '9734', (121, 126))	('HDAC9', 'Gene', (121, 126))
78887	32429325	Drosophila melanogaster (fruit fly) carries a total of 5 HDAC genes, translated in the following protein products: NP_001259507.1 located in Class IIa, NP_001259569.1 in Class IIb, NP_733048.1 in Class IV and two Class I HDACs: NP_647918.2 and NP_651978.2.	('NP_651978.2', 'Var', (244, 255))	('IIb', 'Gene', (176, 179))	('NP_733048.1', 'Var', (181, 192))	('IIb', 'Gene', '5658173', (176, 179))	('Drosophila melanogaster', 'Species', '7227', (0, 23))	('fruit fly', 'Species', '7227', (25, 34))	('HDAC genes', 'Gene', (57, 67))	('NP_001259569.1', 'Var', (152, 166))	('NP_001259507.1', 'Var', (115, 129))
78892	32429325	Arabidopsis in particular carries the largest number of HDAC genes in all species investigated (14, Table 2); this is the result of recent HDAC expansion, as this plant carries a cluster of three recently duplicated Class I HDAC loci, which are located in succession on its genome: NP_190052.1 (encoded by gene At3g44660), NP_190054.2 (At3g44680), and NP_190035.1 (At3g44490).	('At3', 'Species', '1239833', (311, 314))	('At3g44660', 'Var', (311, 320))	('At3', 'Species', '1239833', (336, 339))	('Arabidopsis', 'Species', '3702', (0, 11))	('At3g44680', 'Var', (336, 345))	('At3g44490', 'Var', (365, 374))	('At3', 'Species', '1239833', (365, 368))
78893	32429325	Two more highly homologous Arabidopsis Class I HDAC loci, represented by protein NP_198410.1 (gene At5g35600) and NP_201116.1 (gene At5g63110) are separated instead by more than 10 million nucleotides on the plant chromosome 5.	('At5', 'Species', '1239833', (99, 102))	('Arabidopsis', 'Species', '3702', (27, 38))	('gene At5g35600', 'Var', (94, 108))	('At5', 'Species', '1239833', (132, 135))	('gene At5g63110', 'Var', (127, 141))
78895	32429325	Sequences NP_563817.1 (Arabidopsis) and XP_015638622.1 (rice), dubbed HDAC8 by the NCBI annotation and in our tree (Figure 1, between Class IV and Class IIb) are even more separated from the rest of the organisms, and appear as a completely unique class of plant-specific HDACs.	('NP_563817.1', 'Var', (10, 21))	('HDAC8', 'Gene', (70, 75))	('Arabidopsis', 'Species', '3702', (23, 34))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('IIb', 'Gene', (153, 156))	('IIb', 'Gene', '5658173', (153, 156))	('HDAC8', 'Gene', '55869', (70, 75))	('XP_015638622.1', 'Var', (40, 54))	('rice', 'Species', '4530', (56, 60))
78897	32429325	Schizosaccharomyces pombe (fission yeast) HDACs appear very similar to S.cerevisiae, with clear orthologs of Rpd3 (NP_595333.1), Hos2 (NP_594079.1) and Hda1 (NP_595104.1).	('Hda1', 'Gene', (152, 156))	('fission yeast', 'Species', '4896', (27, 40))	('Hos2', 'Gene', (129, 133))	('NP_595333.1', 'Var', (115, 126))	('NP_594079.1', 'Var', (135, 146))	('Schizosaccharomyces pombe', 'Species', '4896', (0, 25))	('Hda1', 'Gene', '855710', (152, 156))	('Hos2', 'Gene', '852681', (129, 133))	('S.cerevisiae', 'Species', '4932', (71, 83))
78931	32429325	These methodologies were applied for the identification of HDAC8 candidate substrates using, respectively, the specific HDAC8 inhibitor PCI-34051 and a recombinant HDAC8 protein in which tyrosine 100 is replaced with a p-benzoyl-L-phenylalanine (Bpa).	('tyrosine', 'Chemical', 'MESH:D014443', (187, 195))	('HDAC8', 'Gene', '55869', (120, 125))	('HDAC8', 'Gene', '55869', (59, 64))	('Bpa', 'Chemical', 'MESH:C488060', (246, 249))	('HDAC8', 'Gene', '55869', (164, 169))	('HDAC8', 'Gene', (120, 125))	('tyrosine 100', 'Var', (187, 199))	('HDAC8', 'Gene', (164, 169))	('HDAC8', 'Gene', (59, 64))	('p-benzoyl-L-phenylalanine', 'Chemical', 'MESH:C488060', (219, 244))
78939	32429325	HDAC8 has been shown to deacetylate ERRalpha, which results in an enhancement of the transcription factor function, and SMC3, one of the components of the cohesin complex, the deacetylation of which facilitates renewal of cohesin following its removal from chromatin during prophase or anaphase.	('acetyl', 'Chemical', '-', (26, 32))	('HDAC8', 'Gene', '55869', (0, 5))	('ERRalpha', 'Gene', '2101', (36, 44))	('deacetylate', 'Var', (24, 35))	('transcription factor function', 'MPA', (85, 114))	('facilitates', 'PosReg', (199, 210))	('acetyl', 'Chemical', '-', (178, 184))	('SMC3', 'Gene', '9126', (120, 124))	('deacetylation', 'Var', (176, 189))	('renewal', 'MPA', (211, 218))	('SMC3', 'Gene', (120, 124))	('cohesin', 'Protein', (222, 229))	('HDAC8', 'Gene', (0, 5))	('ERRalpha', 'Gene', (36, 44))	('enhancement', 'PosReg', (66, 77))
78943	32429325	For example, HDAC1 decrotonylates H3K4cr, H3K9cr, H3K23cr, H4K8cr, and H4K12cr in vitro; H3K8cr can be also decrotonylated by HDAC2 and HDAC8.	('HDAC2', 'Gene', (126, 131))	('HDAC2', 'Gene', '3066', (126, 131))	('HDAC8', 'Gene', '55869', (136, 141))	('H3K23cr', 'Var', (50, 57))	('H3K9cr', 'Var', (42, 48))	('H4K8cr', 'Var', (59, 65))	('HDAC8', 'Gene', (136, 141))	('H3K8cr', 'Var', (89, 95))	('H4K12cr', 'Var', (71, 78))	('H3K4cr', 'Var', (34, 40))
78946	32429325	About the catalytic activity, for vertebrate Class IIa HDACs, the catalytic Tyrosine 345 residue is replaced by a histidine side chain, which is too short to reach into the active site (Figure 3A).	('histidine', 'Chemical', 'MESH:D006639', (114, 123))	('Tyrosine', 'Chemical', 'MESH:D014443', (76, 84))	('catalytic', 'MPA', (66, 75))	('Tyrosine 345', 'Var', (76, 88))
78947	32429325	Due to the Y-H substitution, the catalytic activity of those enzymes on acetylated lysines of histone tail peptides is very low when compared to that of Class I HDACs.	('lysines', 'Chemical', 'MESH:D008239', (83, 90))	('catalytic activity', 'MPA', (33, 51))	('peptides', 'Chemical', 'MESH:D010455', (107, 115))	('Y-H substitution', 'Var', (11, 27))	('low', 'NegReg', (124, 127))	('acetyl', 'Chemical', '-', (72, 78))
78948	32429325	This property is independent from the Y-H catalytic residue as replacement of H with a Y in Class IIa HDACs promotes deacetylation of acetylated histone tail peptides, but it does not impact on transcriptional repression.	('peptides', 'Chemical', 'MESH:D010455', (158, 166))	('acetyl', 'Chemical', '-', (134, 140))	('acetyl', 'Chemical', '-', (119, 125))	('replacement', 'Var', (63, 74))	('promotes', 'PosReg', (108, 116))	('deacetylation of acetylated histone tail peptides', 'MPA', (117, 166))
78977	32429325	Since simultaneous deletion of HDAC1 and 2 genes results in early embryonic lethality conditional mutants were produced to investigate their role during development.	('results in', 'Reg', (49, 59))	('deletion', 'Var', (19, 27))	('embryonic lethality', 'Disease', 'MESH:D020964', (66, 85))	('embryonic lethality', 'Disease', (66, 85))	('HDAC1', 'Gene', (31, 36))	('S', 'Chemical', 'MESH:D012694', (0, 1))
78983	32429325	In adult individuals, deletion of HDAC3 in hepatocytes causes an increase of adipogenesis leading to hepatosteatosis whereas its loss in the heart cause interstitial fibrosis.	('increase', 'PosReg', (65, 73))	('HDAC3', 'Gene', '8841', (34, 39))	('hepatosteatosis', 'Disease', 'None', (101, 116))	('leading to', 'Reg', (90, 100))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (153, 174))	('HDAC3', 'Gene', (34, 39))	('deletion', 'Var', (22, 30))	('loss', 'NegReg', (129, 133))	('fibrosis', 'Disease', (166, 174))	('hepatosteatosis', 'Disease', (101, 116))	('fibrosis', 'Disease', 'MESH:D005355', (166, 174))	('adipogenesis', 'MPA', (77, 89))
78993	32429325	Its deletions in mouse knockout models has been linked to cardiac defects, mainly depending on deregulation of one of its targets, transcription factor MEF2.	('cardiac defects', 'Disease', 'MESH:D006331', (58, 73))	('mouse', 'Species', '10090', (17, 22))	('deletions', 'Var', (4, 13))	('cardiac defects', 'Disease', (58, 73))	('deregulation', 'MPA', (95, 107))	('MEF2', 'Gene', (152, 156))	('linked', 'Reg', (48, 54))
78999	32429325	However, deletion of HDAC6 led to no evident defects in animal models, possibly due to redundancy of functions shared with HDAC10.	('deletion', 'Var', (9, 17))	('HDAC6', 'Gene', '10013', (21, 26))	('HDAC10', 'Gene', (123, 129))	('HDAC6', 'Gene', (21, 26))	('HDAC10', 'Gene', '83933', (123, 129))
79003	32429325	It is thought to have a role in immune cells development, and it has been recently shown that HDAC10 deletion improves Foxp3+ Treg cells suppressive function in vivo.	('deletion', 'Var', (101, 109))	('Foxp3', 'Gene', (119, 124))	('HDAC10', 'Gene', '83933', (94, 100))	('improves', 'PosReg', (110, 118))	('Foxp3', 'Gene', '50943', (119, 124))	('HDAC10', 'Gene', (94, 100))
79015	32429325	The interaction of SIN3A/HDAC1 complex with cell cycle regulators such as Rb and the Mxd1 family suggests that loss of SIN3A would cause an uncontrollably cell cycle progression.	('interaction', 'Interaction', (4, 15))	('SIN3A', 'Gene', (119, 124))	('loss', 'Var', (111, 115))	('Mxd1', 'Gene', (85, 89))	('cause', 'Reg', (131, 136))	('uncontrollably', 'MPA', (140, 154))	('Mxd1', 'Gene', '4084', (85, 89))
79052	32429325	After that, LSD1 demethylates H3-K4Me1-2 causing the reversibly transcriptional repression of the gene locus.	('H3-K4Me1-2', 'Var', (30, 40))	('demethylates H3-K4Me1-2', 'Var', (17, 40))	('LSD1', 'Gene', (12, 16))	('LSD1', 'Gene', '23028', (12, 16))	('reversibly transcriptional repression', 'MPA', (53, 90))
79053	32429325	Finally, the recruitment of histone methyltransferase such as G9a or SUV39H1 and methylation of "repressive" sites like H3-K9 induces a stable long-term silencing of targets through the binding to K9-methyl residues of the heterochromatin protein 1 (HP1) that generate the heterochromatinization of the locus.	('SUV39H1', 'Gene', (69, 76))	('methylation', 'Var', (81, 92))	('H3-K9', 'Gene', (120, 125))	('SUV39H1', 'Gene', '6839', (69, 76))	('silencing', 'NegReg', (153, 162))	('HP1', 'Gene', (250, 253))	('HP1', 'Gene', '23468', (250, 253))	('G9a', 'Gene', '10919', (62, 65))	('heterochromatin protein 1', 'Gene', '23468', (223, 248))	('G9a', 'Gene', (62, 65))	('binding', 'Interaction', (186, 193))	('heterochromatin protein 1', 'Gene', (223, 248))
79060	32429325	An aberrant protein levels of ZNF217 has been reported in many cancer cell lines and may cause unregulated targeting by the CoREST-LSD1 complex, with a profound effect on cancer progression.	('unregulated targeting', 'MPA', (95, 116))	('cause', 'Reg', (89, 94))	('aberrant', 'Var', (3, 11))	('protein levels', 'MPA', (12, 26))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('LSD1', 'Gene', '23028', (131, 135))	('CoREST', 'Gene', '23186', (124, 130))	('cancer', 'Disease', (171, 177))	('LSD1', 'Gene', (131, 135))	('CoREST', 'Gene', (124, 130))	('reported', 'Reg', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('ZNF217', 'Gene', (30, 36))	('ZNF217', 'Gene', '7764', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (63, 69))	('effect', 'Reg', (161, 167))
79069	32429325	In particular, it has been demonstrated that NuRD complex binds methylated DNA in correspondence to the pericentric heterochromatin containing MBD2 proteins.	('methylated', 'Var', (64, 74))	('MBD2', 'Gene', (143, 147))	('MBD2', 'Gene', '8932', (143, 147))	('rice', 'Species', '4530', (106, 110))
79072	32429325	PWWP2A was correlated to H3K36me3 marked genes and PWWP2B to active promoters and enhancers.	('H3K36me3 marked', 'Var', (25, 40))	('PWWP2A', 'Gene', '70802', (0, 6))	('PWWP2B', 'Gene', (51, 57))	('PWWP2B', 'Gene', '101631', (51, 57))	('PWWP2A', 'Gene', (0, 6))
79074	32429325	Specifically, MBD2 and MBD3 mediates NuRD recruitment to methylated or hemi-methylated DNA, respectively.	('MBD3', 'Gene', (23, 27))	('mediates', 'Reg', (28, 36))	('MBD3', 'Gene', '53615', (23, 27))	('MBD2', 'Gene', '8932', (14, 18))	('hemi-methylated', 'Var', (71, 86))	('MBD2', 'Gene', (14, 18))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('methylated', 'Var', (57, 67))
79076	32429325	Furthermore, WDR529 and UpSET30 recruits the complex to promoter regions.	('S', 'Chemical', 'MESH:D012694', (26, 27))	('UpSET30', 'Var', (24, 31))	('complex', 'MPA', (45, 52))	('WDR529', 'Var', (13, 19))
79078	32429325	For instance, in mESCs, it has been reported that after H3K36me3 deposition by SET2 on specific promoters of active genes, NuRD/HDAC complex are recruited to the action of PWWP2A/B and the deacetylation of H3K9ac by HDAC2 facilitates RNA Pol II transcriptional elongation.	('recruited', 'PosReg', (145, 154))	('facilitates', 'PosReg', (222, 233))	('SET2', 'Gene', (79, 83))	('deacetylation', 'Var', (189, 202))	('PWWP2A', 'Gene', '70802', (172, 178))	('HDAC2', 'Gene', (216, 221))	('HDAC2', 'Gene', '3066', (216, 221))	('S', 'Chemical', 'MESH:D012694', (79, 80))	('S', 'Chemical', 'MESH:D012694', (19, 20))	('H3K36me3', 'Var', (56, 64))	('RNA Pol II transcriptional', 'Enzyme', (234, 260))	('SET2', 'Gene', '29072', (79, 83))	('PWWP2A', 'Gene', (172, 178))	('acetyl', 'Chemical', '-', (191, 197))
79086	32429325	Specifically, the knockdown of CHD4, an ATPase subunit of NuRD complex (Figure 5), dramatically upregulates C4B expression, a critical component of the complement system, and this can trigger proliferation and tumor progression.	('C4B', 'Gene', '721', (108, 111))	('knockdown', 'Var', (18, 27))	('CHD4', 'Gene', (31, 35))	('trigger', 'Reg', (184, 191))	('expression', 'MPA', (112, 122))	('proliferation', 'CPA', (192, 205))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('CHD4', 'Gene', '1108', (31, 35))	('upregulates', 'PosReg', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('C4B', 'Gene', (108, 111))
79116	32429325	Although, the production of the aberrant PML-RARalpha protein causes an increase in the binding affinity between RARalpha and NCoR/SMRT complex.	('SMRT', 'Gene', (131, 135))	('PML-RAR', 'Gene', (41, 48))	('increase', 'PosReg', (72, 80))	('RARalpha', 'Gene', '5914', (45, 53))	('NCoR', 'Gene', (126, 130))	('binding affinity', 'Interaction', (88, 104))	('RARalpha', 'Gene', (45, 53))	('PML-RAR', 'Gene', '84106', (41, 48))	('RARalpha', 'Gene', '5914', (113, 121))	('aberrant', 'Var', (32, 40))	('SMRT', 'Gene', '9612', (131, 135))	('RARalpha', 'Gene', (113, 121))	('NCoR', 'Gene', '9611', (126, 130))
79125	32429325	In the bone morphogenetic protein pathway, the level of Runx2 protein is controlled by the action of HDAC4 and HDAC5.	('bone morphogenetic protein pathway', 'Pathway', (7, 41))	('Runx2', 'Gene', '860', (56, 61))	('Runx2', 'Gene', (56, 61))	('HDAC5', 'Gene', '10014', (111, 116))	('HDAC5', 'Gene', (111, 116))	('controlled', 'Reg', (73, 83))	('HDAC4', 'Var', (101, 106))	('level', 'MPA', (47, 52))
79129	32429325	In mice, deletion of HDAC4 in the forebrain resulted in the impairment of memory, behavioral learning, and long-term synaptic plasticity.	('impairment of memory', 'Disease', 'MESH:D008569', (60, 80))	('impairment of memory', 'Disease', (60, 80))	('long-term synaptic plasticity', 'CPA', (107, 136))	('deletion', 'Var', (9, 17))	('mice', 'Species', '10090', (3, 7))	('HDAC4', 'Gene', (21, 26))	('impairment of memory', 'Phenotype', 'HP:0002354', (60, 80))	('behavioral learning', 'CPA', (82, 101))
79130	32429325	In human, the HDAC4 locus is deleted or mutated in patients with brachydactyly mental retardation (BDMR) syndrome, which is characterized by intellectual disabilities, developmental delays, behavioral abnormalities, and skeletal abnormalities.	('developmental delays', 'Disease', 'MESH:D002658', (168, 188))	('behavioral abnormalities', 'Disease', 'MESH:D001523', (190, 214))	('behavioral abnormalities', 'Phenotype', 'HP:0000708', (190, 214))	('human', 'Species', '9606', (3, 8))	('skeletal abnormalities', 'Disease', (220, 242))	('developmental delays', 'Disease', (168, 188))	('developmental delays', 'Phenotype', 'HP:0001263', (168, 188))	('brachydactyly', 'Phenotype', 'HP:0001156', (65, 78))	('behavioral abnormalities', 'Disease', (190, 214))	('brachydactyly mental retardation (BDMR) syndrome', 'Disease', 'MESH:C538317', (65, 113))	('intellectual disabilities', 'Phenotype', 'HP:0001249', (141, 166))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (220, 242))	('mutated', 'Var', (40, 47))	('patients', 'Species', '9606', (51, 59))	('mental retardation', 'Phenotype', 'HP:0001249', (79, 97))	('HDAC4', 'Gene', (14, 19))	('skeletal abnormalities', 'Disease', 'MESH:C538496', (220, 242))
79146	32429325	HDAC11 was shown to de-acetylate Lys24 and Lys49 at the N-terminus of the chromatin licensing and DNA replication factor 1 (Cdt1) and affect its proteasomal degradation.	('de-acetylate', 'NegReg', (20, 32))	('Lys49', 'Chemical', '-', (43, 48))	('Cdt1', 'Gene', '81620', (124, 128))	('acetyl', 'Chemical', '-', (23, 29))	('proteasomal degradation', 'MPA', (145, 168))	('Cdt1', 'Gene', (124, 128))	('affect', 'Reg', (134, 140))	('Lys24', 'Var', (33, 38))	('Lys49', 'Var', (43, 48))	('HDAC11', 'Gene', (0, 6))	('Lys24', 'Chemical', '-', (33, 38))
79150	32429325	However, deregulation of HDACs has been reported a role in the development and progression of several cancer types.	('role', 'Reg', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('deregulation', 'Var', (9, 21))	('HDACs', 'Protein', (25, 30))
79157	32429325	Silencing or inhibition of HDAC1 was proven to be effective in reducing acquired chemoresistance and aggressiveness in cellular models of ovarian and lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('aggressiveness', 'Phenotype', 'HP:0000718', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('inhibition', 'Var', (13, 23))	('reducing', 'NegReg', (63, 71))	('ovarian and lung cancers', 'Disease', 'MESH:D055370', (138, 162))	('lung cancers', 'Phenotype', 'HP:0100526', (150, 162))	('acquired chemoresistance', 'CPA', (72, 96))	('HDAC1', 'Gene', (27, 32))	('aggressiveness', 'Disease', 'MESH:D001523', (101, 115))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('Silencing', 'Var', (0, 9))	('aggressiveness', 'Disease', (101, 115))	('S', 'Chemical', 'MESH:D012694', (0, 1))
79178	32429325	Overexpression of HDAC8 and 3 was associated with an improved survival in stage IV metastatic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('HDAC8', 'Gene', '55869', (18, 23))	('Overexpression', 'Var', (0, 14))	('improved', 'PosReg', (53, 61))	('HDAC8', 'Gene', (18, 23))
79194	32429325	Survival analysis reported several significant associations in different tumor subtypes: high transcript levels are associated with a reduced OS in CESC, GBM, LGG, and KIRP, while it is a good prognostic factor in BLCA, DLBC, KICH, NBL, and THYM (Figure 6B).	('KICH', 'Disease', (226, 230))	('CESC', 'Disease', (148, 152))	('KIRP', 'Disease', (168, 172))	('DLBC', 'Disease', (220, 224))	('NBL', 'Gene', (232, 235))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('NBL', 'Gene', '9253', (232, 235))	('BLCA', 'Disease', (214, 218))	('LGG', 'Disease', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('KICH', 'Disease', 'None', (226, 230))	('high', 'Var', (89, 93))	('tumor', 'Disease', (73, 78))	('GBM', 'Disease', (154, 157))	('reduced', 'NegReg', (134, 141))	('S', 'Chemical', 'MESH:D012694', (150, 151))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('S', 'Chemical', 'MESH:D012694', (143, 144))
79197	32429325	Overexpression of HDAC7 is frequently reported in several hematologic malignancies like ALL and CLL, often correlated with poor outcomes.	('CLL', 'Phenotype', 'HP:0005550', (96, 99))	('CLL', 'Disease', (96, 99))	('ALL', 'Phenotype', 'HP:0006721', (88, 91))	('reported', 'Reg', (38, 46))	('HDAC7', 'Gene', (18, 23))	('hematologic malignancies', 'Disease', 'MESH:D019337', (58, 82))	('Overexpression', 'Var', (0, 14))	('hematologic malignancies', 'Disease', (58, 82))	('ALL', 'Disease', (88, 91))	('HDAC7', 'Gene', '51564', (18, 23))
79200	32429325	Low expression is associated with a significantly poorer OS in ACC and CHOL.	('ACC', 'Disease', (63, 66))	('S', 'Chemical', 'MESH:D012694', (58, 59))	('CHOL', 'Disease', (71, 75))	('Low expression', 'Var', (0, 14))	('CHOL', 'Disease', 'None', (71, 75))	('poorer', 'NegReg', (50, 56))	('ACC', 'Phenotype', 'HP:0006744', (63, 66))
79214	32429325	It has been found in cervical cancers as metastasis suppressor, and low expression is associated to a bad prognosis in lung and gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('expression', 'MPA', (72, 82))	('low', 'Var', (68, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('gastric cancers', 'Disease', 'MESH:D013274', (128, 143))	('gastric cancers', 'Phenotype', 'HP:0012126', (128, 143))	('gastric cancers', 'Disease', (128, 143))	('lung', 'Disease', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
79215	32429325	In the TCGA cohort, low expression is associated with a bad OS in BLCA and PCPG, while better outcomes are expected in HDAC10 low-expressing KIRC and THCA patients (Figure 6B).	('PCPG', 'Disease', (75, 79))	('THCA', 'Chemical', '-', (150, 154))	('low expression', 'Var', (20, 34))	('HDAC10', 'Gene', '83933', (119, 125))	('HDAC10', 'Gene', (119, 125))	('S', 'Chemical', 'MESH:D012694', (61, 62))	('patients', 'Species', '9606', (155, 163))	('BLCA', 'Disease', (66, 70))
79220	32429325	Low-expressing LUAD, NBL, and UVM patients experience worse OS (Figure 6B).	('Low-expressing', 'Var', (0, 14))	('LUAD', 'Disease', (15, 19))	('patients', 'Species', '9606', (34, 42))	('NBL', 'Gene', '9253', (21, 24))	('S', 'Chemical', 'MESH:D012694', (61, 62))	('NBL', 'Gene', (21, 24))
79233	32429325	Cell cycle blocks is mainly caused by the mis-regulation of key genes such as CDKN1A and AKT and by the hyperacetylation/activation of the tumor suppressor p53.	('caused', 'Reg', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mis-regulation', 'Var', (42, 56))	('acetyl', 'Chemical', '-', (109, 115))	('hyperacetylation/activation', 'PosReg', (104, 131))	('CDKN1A', 'Gene', (78, 84))	('p53', 'Gene', (156, 159))	('AKT', 'Gene', '207', (89, 92))	('p53', 'Gene', '7157', (156, 159))	('tumor', 'Disease', (139, 144))	('CDKN1A', 'Gene', '1026', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('AKT', 'Gene', (89, 92))	('Cell cycle blocks', 'CPA', (0, 17))
79239	32429325	In vitro and in vivo studies have revealed an important link between ARID1A mutation status and SAHA sensitivity in ovarian cancer.	('SAHA sensitivity in ovarian cancer', 'Disease', 'MESH:D003807', (96, 130))	('ARID1A', 'Gene', '8289', (69, 75))	('SAHA sensitivity in ovarian cancer', 'Disease', (96, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ARID1A', 'Gene', (69, 75))	('mutation', 'Var', (76, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))
79244	32429325	The loss of Crebbp leads to reduced H3K27Ac and transcriptional downregulation of CDH1 which, in turn, promotes cell transformation.	('reduced', 'NegReg', (28, 35))	('downregulation', 'NegReg', (64, 78))	('Crebbp', 'Gene', (12, 18))	('CDH1', 'Gene', '999', (82, 86))	('cell transformation', 'CPA', (112, 131))	('promotes', 'PosReg', (103, 111))	('CDH1', 'Gene', (82, 86))	('H3K27Ac', 'Protein', (36, 43))	('loss', 'Var', (4, 8))
79245	32429325	Pracinostat treatment of DMS53 (human SCLC cells with CRISPR-generated CREBBP deletion) resulted in a widely increase in H3K27Ac, H3K18Ac, and increased CDH1 RNA and protein expression.	('Pracinostat', 'Chemical', 'MESH:C557525', (0, 11))	('CREBBP', 'Gene', (71, 77))	('increased', 'PosReg', (143, 152))	('DMS53', 'Chemical', '-', (25, 30))	('S', 'Chemical', 'MESH:D012694', (38, 39))	('S', 'Chemical', 'MESH:D012694', (27, 28))	('increase', 'PosReg', (109, 117))	('CREBBP', 'Gene', '1387', (71, 77))	('CDH1', 'Gene', (153, 157))	('S', 'Chemical', 'MESH:D012694', (57, 58))	('CDH1', 'Gene', '999', (153, 157))	('human', 'Species', '9606', (32, 37))	('DMS53', 'Var', (25, 30))	('H3K27Ac', 'Protein', (121, 128))	('H3K18Ac', 'Protein', (130, 137))
79249	32429325	Specifically, LBH589 treatment seems to induce a depletion of histone H2B ubiquitination via misregulation of the RNF20/RNF40/WAC E3 ligase complex axis.	('RNF40', 'Gene', (120, 125))	('ubiquitination', 'MPA', (74, 88))	('depletion', 'MPA', (49, 58))	('RNF40', 'Gene', '9810', (120, 125))	('RNF20', 'Gene', (114, 119))	('LBH589', 'Chemical', 'MESH:D000077767', (14, 20))	('histone H2B', 'Protein', (62, 73))	('misregulation', 'Var', (93, 106))	('LBH589', 'Var', (14, 20))	('RNF20', 'Gene', '56254', (114, 119))	('S', 'Chemical', 'MESH:D012694', (0, 1))
79271	32429325	Mocetinostat (MGCD0103), Entinostat (MS275), Chidamide (HBI-8000), K560, and K560(1a) are the best characterized HDACi benzamide compounds able to interfere in tumor cell growth of many types of tumor.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('K560', 'Chemical', '-', (67, 71))	('Mocetinostat', 'Chemical', 'MESH:C523184', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('benzamide', 'Chemical', 'MESH:C037689', (119, 128))	('K560', 'Chemical', '-', (77, 81))	('Entinostat', 'Chemical', 'MESH:C118739', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Chidamide', 'Chemical', 'MESH:C547816', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('HBI-8000', 'Chemical', 'MESH:C000613826', (56, 64))	('K560', 'Var', (77, 81))	('tumor', 'Disease', (160, 165))	('MGCD0103', 'Chemical', 'MESH:C523184', (14, 22))	('interfere', 'NegReg', (147, 156))	('MS275', 'Chemical', 'MESH:C118739', (37, 42))
79278	32429325	Interestingly, Entinostat stimulate MHCII pathway only in the immunocompetent C57BL/6 mouse model, suggesting a strong coordination between the epigenetic modulation exerted by MS275 treatment and the consequent stimulation of adaptive immunity.	('Entinostat', 'Chemical', 'MESH:C118739', (15, 25))	('MHCII', 'Gene', '111364', (36, 41))	('adaptive immunity', 'CPA', (227, 244))	('stimulation', 'PosReg', (212, 223))	('mouse', 'Species', '10090', (86, 91))	('MS275', 'Var', (177, 182))	('epigenetic modulation', 'MPA', (144, 165))	('MHCII', 'Gene', (36, 41))	('MS275', 'Chemical', 'MESH:C118739', (177, 182))
79281	32429325	Specifically, cytofluorimetric and biochemical assays have revealed that MS275 and 5-fluorouracil co-treatment exert a synergistic effect triggering apoptosis via deregulation of key cell cycle related genes such as p53, CDKN1A, and cyclin A.	('CDKN1A', 'Gene', (221, 227))	('apoptosis', 'CPA', (149, 158))	('MS275', 'Var', (73, 78))	('CDKN1A', 'Gene', '1026', (221, 227))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('cyclin A', 'Gene', (233, 241))	('deregulation', 'PosReg', (163, 175))	('S', 'Chemical', 'MESH:D012694', (74, 75))	('p53', 'Gene', '7157', (216, 219))	('triggering', 'Reg', (138, 148))	('MS275', 'Chemical', 'MESH:C118739', (73, 78))	('cyclin A', 'Gene', '890', (233, 241))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (83, 97))	('p53', 'Gene', (216, 219))
79285	32429325	In two recent studies, two putative HDAC1,2 benzamide specific inhibitors, K560 and K560(1a), were developed and tested for their neuroprotective abilities.	('neuroprotective abilities', 'CPA', (130, 155))	('K560', 'Chemical', '-', (84, 88))	('benzamide', 'Chemical', 'MESH:C037689', (44, 53))	('K560', 'Var', (84, 88))	('K560', 'Chemical', '-', (75, 79))	('K560', 'Var', (75, 79))
79286	32429325	Authors have shown how K560 benzamide drugs can exert neuroprotective abilities in MPP+ induced toxicity on in vitro SH-SY5Y retinoic acid differentiated cells.	('neuroprotective abilities', 'CPA', (54, 79))	('toxicity', 'Disease', 'MESH:D064420', (96, 104))	('K560', 'Chemical', '-', (23, 27))	('toxicity', 'Disease', (96, 104))	('benzamide', 'Chemical', 'MESH:C037689', (28, 37))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (117, 124))	('K560', 'Var', (23, 27))	('retinoic acid', 'Chemical', 'MESH:D014212', (125, 138))	('MPP+', 'Chemical', 'MESH:C044202', (83, 87))
79287	32429325	Specifically, K560 treatment stimulates HDAC1,2 protein expression and abrogates the cell death effect of MPP+ by modulating key apoptosis-related factors such as claspin, XIAP, and livin, and observed an increased p53 activation through phosphorylation.	('claspin', 'Gene', (163, 170))	('cell death effect', 'CPA', (85, 102))	('K560', 'Var', (14, 18))	('livin', 'Gene', (182, 187))	('XIAP', 'Gene', (172, 176))	('XIAP', 'Gene', '331', (172, 176))	('abrogates', 'NegReg', (71, 80))	('MPP+', 'Chemical', 'MESH:C044202', (106, 110))	('p53', 'Gene', (215, 218))	('livin', 'Gene', '79444', (182, 187))	('p53', 'Gene', '7157', (215, 218))	('activation', 'PosReg', (219, 229))	('modulating', 'Reg', (114, 124))	('K560', 'Chemical', '-', (14, 18))	('phosphorylation', 'MPA', (238, 253))	('claspin', 'Gene', '63967', (163, 170))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('stimulates', 'PosReg', (29, 39))
79305	32429325	Among these, FR901375 chromopeptide A, FR901375, largazole, spiruchostatin A, HC-toxin, trapoxin, and azumamide are currently investigated for their anti-tumorigenic potential.	('FR901375', 'Chemical', 'MESH:C482963', (39, 47))	('azumamide', 'Chemical', '-', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('FR901375', 'Chemical', 'MESH:C482963', (13, 21))	('HC-toxin', 'Disease', (78, 86))	('largazole', 'Chemical', 'MESH:C527895', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('trapoxin', 'Chemical', 'MESH:C067070', (88, 96))	('HC-toxin', 'Disease', 'MESH:D065766', (78, 86))	('FR901375', 'Var', (39, 47))	('FR901375 chromopeptide A', 'Chemical', '-', (13, 37))	('FR901375', 'Var', (13, 21))	('tumor', 'Disease', (154, 159))
79315	32429325	For example, inhibition of HDACs could modulate their action in genomic instability, often observed in cancer in the form of amplifications/deletions, chromosomic rearrangements, and chromothripsis.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('genomic instability', 'MPA', (64, 83))	('inhibition', 'Var', (13, 23))	('chromothripsis', 'Disease', (183, 197))	('modulate', 'Reg', (39, 47))	('chromothripsis', 'Disease', 'MESH:D000072837', (183, 197))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('HDACs', 'Protein', (27, 32))
79357	31572440	identified an SNP (rs769236) at the CCNA2 promoter that may be significantly associated with an increased risk of colon, liver and lung cancers.	('lung cancers', 'Phenotype', 'HP:0100526', (131, 143))	('liver and lung cancers', 'Disease', 'MESH:D008175', (121, 143))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('rs769236', 'Mutation', 'rs769236', (19, 27))	('colon', 'Disease', (114, 119))	('CCNA2', 'Gene', (36, 41))	('rs769236', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('associated', 'Reg', (77, 87))
79460	30886771	These processes and pathways all play critical roles in cancer progression, implying that genes in this module may be involved in ACC progression.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('involved', 'Reg', (118, 126))	('ACC', 'Phenotype', 'HP:0006744', (130, 133))	('ACC progression', 'Disease', (130, 145))	('cancer', 'Disease', (56, 62))	('genes', 'Var', (90, 95))
79483	30886771	In addition, inhibition of CENPA expression in cancer cells can reduce sphere forming ability, proliferation, and cell viability.	('CENPA', 'Gene', (27, 32))	('sphere forming ability', 'CPA', (71, 93))	('reduce', 'NegReg', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('CENPA', 'Gene', '1058', (27, 32))	('inhibition', 'Var', (13, 23))	('cancer', 'Disease', (47, 53))	('cell viability', 'CPA', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('proliferation', 'CPA', (95, 108))
79488	30886771	Furthermore, inhibitors of TOP2A, TTK, and CHEK1, which are already used for treating certain cancers, could potentially be used in ACC treatment.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('CHEK1', 'Gene', (43, 48))	('TOP2A', 'Gene', '7153', (27, 32))	('ACC', 'Phenotype', 'HP:0006744', (132, 135))	('TOP2A', 'Gene', (27, 32))	('TTK', 'Gene', '7272', (34, 37))	('inhibitors', 'Var', (13, 23))	('cancers', 'Disease', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('CHEK1', 'Gene', '1111', (43, 48))	('TTK', 'Gene', (34, 37))
79527	30536676	Displacement, distortion, or disappearance of the pituitary flush in nonenlarged pituitary glands was interpreted as consistent with the presence of a pituitary microadenoma.	('pituitary flush', 'Disease', 'MESH:D005483', (50, 65))	('disappearance', 'NegReg', (29, 42))	('distortion', 'Var', (14, 24))	('enlarged pituitary gland', 'Phenotype', 'HP:0012505', (72, 96))	('flush', 'Phenotype', 'HP:0031284', (60, 65))	('pituitary flush', 'Disease', (50, 65))	('pituitary microadenoma', 'Disease', (151, 173))	('pituitary microadenoma', 'Disease', 'MESH:D010900', (151, 173))
79597	30634925	Although many explorations have revealed that high TMB may yield many neoantigens to incite antitumor immune response, a systematic exploration of the correlation between TMB and immune signatures in different cancer types is lacking.	('neoantigens', 'MPA', (70, 81))	('high', 'Var', (46, 50))	('incite', 'PosReg', (85, 91))	('TMB', 'Chemical', '-', (171, 174))	('TMB', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TMB', 'Chemical', '-', (51, 54))	('tumor', 'Disease', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', (210, 216))
79601	30634925	Importantly, high TMB was associated with elevated expression of PD-L1 in diverse prevailing cancers.	('cancers', 'Disease', (93, 100))	('high', 'Var', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('TMB', 'Chemical', '-', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PD-L1', 'Gene', (65, 70))	('expression', 'MPA', (51, 61))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('elevated', 'PosReg', (42, 50))	('PD-L1', 'Gene', '29126', (65, 70))
79603	30634925	High TMB may inhibit immune cell infiltrations while promote CTAs expression and inflammatory response in cancer.	('CTAs expression', 'CPA', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('High TMB', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('immune cell infiltrations', 'CPA', (21, 46))	('cancer', 'Disease', (106, 112))	('inhibit', 'NegReg', (13, 20))	('inflammatory response', 'CPA', (81, 102))	('TMB', 'Chemical', '-', (5, 8))	('promote', 'PosReg', (53, 60))
79605	30634925	Our data implicate that higher-TMB patients could gain a more favorable prognosis in diverse cancer types if treated with immunotherapy, otherwise would have a poorer prognosis compared to lower-TMB patients.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TMB', 'Chemical', '-', (195, 198))	('TMB', 'Chemical', '-', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gain', 'PosReg', (50, 54))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (35, 43))	('higher-TMB', 'Var', (24, 34))
79609	30634925	Some well-recognized molecular determinants include PD-L1 expression on tumor, DNA mismatch-repair deficiency, neoantigen load, and tumor-infiltrating lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('deficiency', 'Var', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PD-L1', 'Gene', '29126', (52, 57))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (132, 137))	('PD-L1', 'Gene', (52, 57))
79612	30634925	These studies demonstrated that higher nonsynonymous mutation burden in tumors is inclined to form more neoantigens that make tumors to have higher immunogenicity, and thus result to improved clinical response to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('improved', 'PosReg', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('higher', 'PosReg', (141, 147))	('make tumors', 'Disease', (121, 132))	('clinical response', 'CPA', (192, 209))	('nonsynonymous mutation burden', 'Var', (39, 68))	('make tumors', 'Disease', 'MESH:C537705', (121, 132))	('immunogenicity', 'MPA', (148, 162))
79625	30634925	These results suggest that the relatedness between TMB and Treg cells infiltration degree depends on cancer types, whereas the lower-TMB subtype is likely to have stronger Treg cells infiltration than the higher-TMB subtype in diverse cancers.	('TMB', 'Chemical', '-', (133, 136))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('TMB', 'Chemical', '-', (212, 215))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('TMB', 'Chemical', '-', (51, 54))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancers', 'Disease', (235, 242))	('Treg cells infiltration', 'CPA', (172, 195))	('lower-TMB', 'Var', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('stronger', 'PosReg', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
79645	30634925	Again, this suggests that high TMB tends to inhibit immune cell infiltration in cancer.	('high', 'Var', (26, 30))	('inhibit', 'NegReg', (44, 51))	('TMB', 'Chemical', '-', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('immune cell infiltration', 'CPA', (52, 76))	('cancer', 'Disease', (80, 86))
79653	30634925	These results indicated that although the association between TMB and TILs infiltration was cancer type dependent, high TMB tended to inhibit TILs infiltration in various cancer types.	('high', 'Var', (115, 119))	('TILs infiltration', 'MPA', (142, 159))	('TMB', 'Chemical', '-', (120, 123))	('TMB', 'Chemical', '-', (62, 65))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('inhibit', 'NegReg', (134, 141))	('association', 'Interaction', (42, 53))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('TMB', 'Gene', (120, 123))
79664	30634925	These results suggest that high TMB is associated with elevated expression of many CTAs in cancer.	('expression', 'MPA', (64, 74))	('CTAs', 'Disease', (83, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('high', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TMB', 'Chemical', '-', (32, 35))	('elevated', 'PosReg', (55, 63))
79677	30634925	It suggests that high TMB may lead to depressed cytokine activity in diverse cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('depressed cytokine activity', 'Phenotype', 'HP:0031407', (38, 65))	('cancers', 'Disease', (77, 84))	('high', 'Var', (17, 21))	('TMB', 'Chemical', '-', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cytokine', 'Gene', '943', (48, 56))	('cytokine', 'Gene', (48, 56))	('depressed', 'NegReg', (38, 47))
79696	30634925	However, the Treg cells, immune cell infiltrate, TILs, and CCR signatures were inclined to be upregulated in the lower-TMB subtype of various cancer types, suggesting that high TMB may inhibit immune cell infiltration in the TIM.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('immune cell infiltration in the', 'CPA', (193, 224))	('lower-TMB', 'Disease', (113, 122))	('TMB', 'Chemical', '-', (119, 122))	('high TMB', 'Var', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('TMB', 'Chemical', '-', (177, 180))	('upregulated', 'PosReg', (94, 105))	('inhibit', 'NegReg', (185, 192))	('cancer', 'Disease', (142, 148))
79697	30634925	In contrast, the CTA and pro-inflammatory signatures tended to be upregulated in the higher-TMB subtype of various cancer types, suggesting that high TMB may promote CTA expression and tumor inflammatory response.	('tumor', 'Disease', (185, 190))	('cancer', 'Disease', (115, 121))	('CTA', 'MPA', (17, 20))	('promote', 'PosReg', (158, 165))	('upregulated', 'PosReg', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('expression', 'MPA', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('CTA', 'Protein', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('TMB', 'Chemical', '-', (150, 153))	('TMB', 'Chemical', '-', (92, 95))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('high', 'Var', (145, 149))
79700	30634925	In fact, when we compared survival prognosis between the lower-TMB subtype and the higher-TMB subtype of cancers, we found that the lower-TMB subtype had better OS and/or DFS prognosis than the higher-TMB subtype in three of the four cancer types including HNSC, ACC, and LIHC (Fig.	('HNSC', 'Disease', (257, 261))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', (105, 111))	('cancers', 'Disease', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('LIHC', 'Disease', (272, 276))	('OS', 'Chemical', '-', (161, 163))	('better', 'PosReg', (154, 160))	('TMB', 'Chemical', '-', (90, 93))	('TMB', 'Chemical', '-', (138, 141))	('TMB', 'Chemical', '-', (201, 204))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('lower-TMB', 'Var', (132, 141))	('DFS', 'MPA', (171, 174))	('ACC', 'Gene', '31', (263, 266))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('ACC', 'Gene', (263, 266))	('TMB', 'Chemical', '-', (63, 66))	('cancer', 'Disease', (234, 240))
79702	30634925	Interestingly, we found that high TMB was associated with elevated pro-inflammatory immune activity while depressed immune cell infiltration in diverse cancers.	('high', 'Var', (29, 33))	('pro-inflammatory immune activity', 'MPA', (67, 99))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('TMB', 'Chemical', '-', (34, 37))	('depressed immune cell', 'Phenotype', 'HP:0002721', (106, 127))	('immune cell infiltration', 'CPA', (116, 140))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('depressed', 'NegReg', (106, 115))	('elevated', 'PosReg', (58, 66))	('TMB', 'Gene', (34, 37))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
79703	30634925	These findings appear to be contradictory and disagree with the established notion that high TMB may yield numerous neoantigens that incite anti-tumor immune response.	('high', 'Var', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('incite', 'PosReg', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('TMB', 'Chemical', '-', (93, 96))	('neoantigens', 'MPA', (116, 127))
79704	30634925	The possible explanations are that high TMB is often associated with genome instability that may inhibit anti-tumor immune response, and that the increased pro-inflammatory immune activity could be attributed to the higher percent of tumor necrosis component elicited by gene mutations in the higher-TMB cancer.	('pro-inflammatory immune activity', 'MPA', (156, 188))	('inhibit', 'NegReg', (97, 104))	('tumor', 'Disease', (234, 239))	('cancer', 'Disease', (304, 310))	('TMB', 'Chemical', '-', (300, 303))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('gene mutations', 'Var', (271, 285))	('increased', 'PosReg', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor necrosis', 'Disease', 'MESH:D009336', (234, 248))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('tumor necrosis', 'Disease', (234, 248))	('high', 'Disease', (35, 39))	('TMB', 'Chemical', '-', (40, 43))	('tumor', 'Disease', (110, 115))	('higher', 'PosReg', (216, 222))	('higher-TMB', 'Disease', (293, 303))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
79725	30634925	High TMB was associated with elevated expression of PD-L1 in diverse prevailing cancers.	('elevated', 'PosReg', (29, 37))	('High', 'Var', (0, 4))	('PD-L1', 'Gene', '29126', (52, 57))	('expression', 'MPA', (38, 48))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('TMB', 'Chemical', '-', (5, 8))	('PD-L1', 'Gene', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
79728	30634925	Consistent with a method we proposed previously, the TMB score of a tumor sample was calculated as follows:  total number of truncating mutations * 2.0 + total number of non-truncating mutations * 1.0  Nonsense, frame-shift deletion or insertion, and splice-site mutations were included in the truncating mutation category, and missense, in-frame deletion or insertion, and nonstop mutations were included in the non-truncating mutation category.	('tumor', 'Disease', (68, 73))	('missense', 'Var', (328, 336))	('frame-shift deletion', 'Var', (212, 232))	('insertion', 'Var', (236, 245))	('splice-site mutations', 'Var', (251, 272))	('Nonsense', 'Var', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('in-frame deletion', 'Var', (338, 355))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('TMB', 'Chemical', '-', (53, 56))
79734	25999916	New Directions for the Treatment of Adrenal Insufficiency Adrenal disease, whether primary, caused by defects in the hypothalamic-pituitary-adrenal (HPA) axis, or secondary, caused by defects outside the HPA axis, usually results in adrenal insufficiency, which requires lifelong daily replacement of corticosteroids.	('Adrenal disease', 'Disease', (58, 73))	('adrenal insufficiency', 'Disease', (233, 254))	('Adrenal disease', 'Phenotype', 'HP:0000834', (58, 73))	('Adrenal Insufficiency', 'Disease', (36, 57))	('results in', 'Reg', (222, 232))	('Adrenal disease', 'Disease', 'MESH:D000309', (58, 73))	('caused by', 'Reg', (92, 101))	('hypothalamic-pituitary-adrenal (HPA) axis', 'Disease', 'MESH:D007029', (117, 158))	('Adrenal Insufficiency', 'Phenotype', 'HP:0000846', (36, 57))	('Adrenal Insufficiency', 'Disease', 'MESH:D000309', (36, 57))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (233, 254))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (233, 254))	('defects', 'Var', (102, 109))	('steroids', 'Chemical', 'MESH:D013256', (308, 316))
79742	25999916	Other than SF1, at least four additional transcription factors have been shown to be key determinants of adrenal cortex development: Wilms tumor 1 (WT1), a zinc finger protein, and CBP/p300-interacting transactivator 2 (CITED2), which are both expressed at early stages in the urogenital ridge and synergistically promote adrenal development through induction of SF1 transcription; pre-B-cell leukemia transcription factor 1 (PBX1), a homeodomain protein, which has been proposed to facilitate the access of important developmental factors (such as SF1) to chromatin to induce differentiation; dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1), whose mutations are associated with a variety of developmentally relevant conditions in the adrenal and gonads, such as adrenal hypoplasia congenita.	('sex reversal', 'Phenotype', 'HP:0012245', (611, 623))	('mutations', 'Var', (699, 708))	('adrenal hypoplasia', 'Disease', (625, 643))	('Wilms tumor', 'Disease', (133, 144))	('WT1', 'Gene', '7490', (148, 151))	('DAX1', 'Gene', '190', (686, 690))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (625, 643))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (625, 643))	('adrenal hypoplasia congenita', 'Disease', 'MESH:D000312', (813, 841))	('adrenal hypoplasia congenita', 'Disease', (813, 841))	('CBP/p300-interacting transactivator 2', 'Gene', '10370', (181, 218))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (813, 831))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (813, 831))	('DAX1', 'Gene', (686, 690))	('PBX1', 'Gene', (426, 430))	('CITED2', 'Gene', (220, 226))	('Wilms tumor', 'Disease', 'MESH:D009396', (133, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('CITED2', 'Gene', '10370', (220, 226))	('PBX1', 'Gene', '5087', (426, 430))	('leukemia', 'Phenotype', 'HP:0001909', (393, 401))	('associated with', 'Reg', (713, 728))	('adrenal hypoplasia congenita', 'Phenotype', 'HP:0008244', (813, 841))	('CBP/p300-interacting transactivator 2', 'Gene', (181, 218))	('Wilms tumor', 'Phenotype', 'HP:0002667', (133, 144))	('leukemia', 'Disease', (393, 401))	('leukemia', 'Disease', 'MESH:D007938', (393, 401))	('WT1', 'Gene', (148, 151))
79743	25999916	Not surprisingly, the alteration of some of these pathways, such as the WNT pathway, results in adrenal cancer [reviewed in Ref.	('alteration', 'Var', (22, 32))	('adrenal cancer', 'Disease', (96, 110))	('adrenal cancer', 'Disease', 'MESH:D000310', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('WNT pathway', 'Pathway', (72, 83))	('rat', 'Species', '10116', (26, 29))	('results in', 'Reg', (85, 95))
79802	25999916	Human steroidogenic-like cells were also successfully reprogramed from umbilical cord blood mesenchymal stem cells (UCB-MSCs) and umbilical cord Wharton's jelly-derived MSC (UC-MSCs) through retroviral or adenoviral overexpression of SF1.	('SF1', 'Gene', (234, 237))	('Human', 'Species', '9606', (0, 5))	('steroid', 'Chemical', 'MESH:D013256', (6, 13))	('retroviral', 'Var', (191, 201))	('adenoviral', 'Var', (205, 215))	('overexpression', 'PosReg', (216, 230))
79807	25999916	Alternatively, Jadhav and Jameson provided evidence that steroidogenic cells can be produced from mESCs using different protocols, the most efficient involving the withdrawal of leukemia inhibitory factor from the ESC medium followed by treatment with cAMP.	('steroid', 'Chemical', 'MESH:D013256', (57, 64))	('leukemia inhibitory factor', 'Gene', (178, 204))	('withdrawal', 'Var', (164, 174))	('leukemia inhibitory factor', 'Gene', '3976', (178, 204))	('cAMP', 'Chemical', '-', (252, 256))	('leukemia', 'Phenotype', 'HP:0001909', (178, 186))
79836	24238056	Analysis of a previously published data set confirmed the association of high PTTG1 expression with a poor prognosis.	('expression', 'MPA', (84, 94))	('high', 'Var', (73, 77))	('PTTG1', 'Gene', (78, 83))	('PTTG1', 'Gene', '9232', (78, 83))
79867	24238056	Expression values for probes corresponding to PTTG1 and beta-actin (203554_x_at, AFFX-HSAC07/X00351_5_at, and AFFX-HSAC07/X00351_M_at) were extracted and compared to survival as above.	('203554_x_at', 'Var', (68, 79))	('PTTG1', 'Gene', (46, 51))	('beta-actin', 'Gene', '728378', (56, 66))	('PTTG1', 'Gene', '9232', (46, 51))	('beta-actin', 'Gene', (56, 66))
79876	24238056	The primary antibodies used were securin (ab3305, Abcam, Cambridge MA) and anti-beta-actin (#4967, Cell Signaling Technology, Danvers MA).	('beta-actin', 'Gene', (80, 90))	('securin', 'Gene', '9232', (33, 40))	('ab3305', 'Var', (42, 48))	('securin', 'Gene', (33, 40))	('beta-actin', 'Gene', '728378', (80, 90))
79887	24238056	Pathway enrichment analysis demonstrated that there dysregulation in G2/M transition was enriched in ACC (Figure 1).	('G2/M transition', 'Gene', (69, 84))	('dysregulation', 'Var', (52, 65))	('ACC', 'Disease', (101, 104))	('men', 'Species', '9606', (14, 17))
79902	24238056	Vorinostat inhibited cell growth with IC50 values of 1.69 M and 0.891 M, for SW-13 and H295R, respectively.	('SW-13', 'CellLine', 'CVCL:0542', (77, 82))	('cell growth', 'CPA', (21, 32))	('Vorinostat', 'Chemical', 'MESH:D000077337', (0, 10))	('H295R', 'Var', (87, 92))	('inhibited', 'NegReg', (11, 20))
79904	24238056	In this study of 44 ACC tumors, we implicate aberrations in the p53 pathway and dysregulation of cell cycle progression though G2/M to be involved in the pathogenesis of ACC.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('aberrations', 'Var', (45, 56))	('dysregulation of cell cycle', 'Phenotype', 'HP:0011018', (80, 107))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('ACC', 'Disease', (170, 173))	('cell cycle progression', 'CPA', (97, 119))	('involved', 'Reg', (138, 146))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
79923	24238056	Taken together, these results suggest ACC pathogenesis is driven in part by deficiencies in p53 pathway function, with vulnerabilities in the G2/M transition that may expose viable therapeutic targets, including potentially PTTG1.	('function', 'MPA', (104, 112))	('deficiencies', 'Var', (76, 88))	('p53', 'Gene', (92, 95))	('PTTG1', 'Gene', '9232', (224, 229))	('p53', 'Gene', '7157', (92, 95))	('PTTG1', 'Gene', (224, 229))
80062	22567117	Identity by Descent Mapping of Founder Mutations in Cancer Using High-Resolution Tumor SNP Data Dense genotype data can be used to detect chromosome fragments inherited from a common ancestor in apparently unrelated individuals.	('Mutations', 'Var', (39, 48))	('Cancer', 'Disease', (52, 58))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Tumor', 'Phenotype', 'HP:0002664', (81, 86))
80063	22567117	A disease-causing mutation inherited from a common founder may thus be detected by searching for a common haplotype signature in a sample population of patients.	('disease-causing', 'Reg', (2, 17))	('patients', 'Species', '9606', (152, 160))	('mutation', 'Var', (18, 26))
80065	22567117	First, the wild-type allele frequently undergoes loss of heterozygosity (LOH) in the tumors of germline mutation carriers.	('loss', 'NegReg', (49, 53))	('tumors', 'Disease', (85, 91))	('germline mutation', 'Var', (95, 112))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
80068	22567117	FounderTracker is thus a powerful tool for discovering unknown founder mutations that may explain part of the "missing" heritability in cancer.	('mutations', 'Var', (71, 80))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
80070	22567117	One key feature of cancers is that tumor cells accumulate chromosome aberrations providing a growth advantage during cancer progression, such that the tumor genome eventually becomes a highly rearranged version of the constitutive genome of the patient.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('growth', 'MPA', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('tumor', 'Disease', (151, 156))	('cancer', 'Disease', (19, 25))	('tumor', 'Disease', (35, 40))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', (117, 123))	('chromosome aberrations', 'Var', (58, 80))	('patient', 'Species', '9606', (245, 252))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
80071	22567117	In particular, patients inheriting a germline mutation in a tumor suppressor gene frequently lose its normal counterpart in cancer cells, revealing the mutant phenotype, as in Knudson's two-hit model.	('lose', 'NegReg', (93, 97))	('patients', 'Species', '9606', (15, 23))	('cancer', 'Disease', (124, 130))	('germline mutation', 'Var', (37, 54))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
80075	22567117	Our method is designed for detecting cancer-associated mutations inherited from a common founder, using recurrent IBD in minimal regions of LOH (Figure 1).	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (55, 64))
80078	22567117	In the first dataset, comprising 13 childhood adrenocortical tumors from southern Brazil, we delineate a conserved haplotype spanning 520 kb around the previously reported p.R337H TP53 founder mutation.	('p.R337H', 'Var', (172, 179))	('TP53', 'Gene', '7157', (180, 184))	('p.R337H', 'Mutation', 'rs121912664', (172, 179))	('TP53', 'Gene', (180, 184))	('childhood adrenocortical tumors', 'Disease', (36, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('childhood adrenocortical tumors', 'Disease', 'MESH:D018268', (36, 67))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
80081	22567117	In addition, the wild-type counterpart of the mutant gene is frequently lost by LOH in tumors occurring in germline mutation carriers.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('lost', 'NegReg', (72, 76))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('LOH', 'Var', (80, 83))
80082	22567117	Our approach to the mapping of founder mutations using SNP array data thus involves (i) identifying recurrent regions of LOH, (ii) reconstructing tumor haplotypes in these regions, and (iii) searching for recurrent IBD in tumor haplotypes.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', (146, 151))	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
80091	22567117	These rare cancers (0.3-0.4 cases per year per million children under the age of 15 years) are exceptionally prevalent in southern Brazil (3.4-4.2 cases per million), where they are almost invariably linked to a specific germline mutation of TP53 (c.1010G>A, p.R337H), identified as a founder mutation.	('p.R337H', 'Mutation', 'rs121912664', (259, 266))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('linked', 'Reg', (200, 206))	('c.1010G>A', 'Var', (248, 257))	('TP53', 'Gene', '7157', (242, 246))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('TP53', 'Gene', (242, 246))	('cancers', 'Disease', (11, 18))	('p.R337H', 'Var', (259, 266))	('c.1010G>A', 'Mutation', 'rs121912664', (248, 257))	('children', 'Species', '9606', (55, 63))
80092	22567117	All tumors were found to carry the p.R337H TP53 mutation.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('p.R337H', 'Var', (35, 42))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('p.R337H', 'Mutation', 'rs121912664', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
80094	22567117	Detailed haplotype analysis revealed that the mutated copies retained in the 13 tumors displayed an identical haplotype for this region, whereas the wild-type copies reconstructed for the six patients with matched blood samples displayed different haplotypes (Figure 4b).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (192, 200))	('mutated', 'Var', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))
80095	22567117	This recurrent IBD segment thus corresponds to the chromosome fragment carrying the p.R337H TP53 mutation inherited by all the patients from the common founder, which has not been disrupted by crossover in the lineage.	('p.R337H', 'Mutation', 'rs121912664', (84, 91))	('patients', 'Species', '9606', (127, 135))	('p.R337H', 'Var', (84, 91))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))
80097	22567117	As pairwise IBD segments are estimated to have a length of 1/(2n) Morgans after n generations (hence 2n meiosis), this suggests that the p.R337H TP53 mutation occurred around nine generations ago.	('TP53', 'Gene', (145, 149))	('p.R337H', 'Var', (137, 144))	('p.R337H', 'Mutation', 'rs121912664', (137, 144))	('TP53', 'Gene', '7157', (145, 149))
80100	22567117	Germline mutations associated with familial pheochromocytoma include mutations of RET, NF1, VHL, TMEM127, MAX, and genes encoding proteins from the succinate dehydrogenase complex (SDHA, SDHB, SDHC, SDHD and SDHAF2).	('associated', 'Reg', (19, 29))	('NF1', 'Gene', '4763', (87, 90))	('TMEM127', 'Gene', (97, 104))	('SDHAF2', 'Gene', '54949', (208, 214))	('SDHAF2', 'Gene', (208, 214))	('SDHD', 'Gene', '6392', (199, 203))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (35, 60))	('NF1', 'Gene', (87, 90))	('SDHB', 'Gene', '6390', (187, 191))	('MAX', 'Gene', (106, 109))	('RET', 'Gene', (82, 85))	('TMEM127', 'Gene', '55654', (97, 104))	('VHL', 'Gene', (92, 95))	('SDHC', 'Gene', (193, 197))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (44, 60))	('SDHD', 'Gene', (199, 203))	('RET', 'Gene', '5979', (82, 85))	('mutations', 'Var', (69, 78))	('SDHB', 'Gene', (187, 191))	('familial pheochromocytoma', 'Disease', (35, 60))	('VHL', 'Gene', '7428', (92, 95))	('SDHC', 'Gene', '6391', (193, 197))
80103	22567117	Interestingly, this chromosome segment contains 32 genes including SDHD, and is identical by descent in two samples (HS_048 and HS_158, Figure 5B), which are precisely the two samples in our cohort for which a c.64C>T (p.Arg22X) germline SDHD mutation was identified (Table S1).	('SDHD', 'Gene', (238, 242))	('SDHD', 'Gene', '6392', (238, 242))	('SDHD', 'Gene', '6392', (67, 71))	('SDHD', 'Gene', (67, 71))	('c.64C>T (p.Arg22X', 'Var', (210, 227))	('p.Arg22X', 'Mutation', 'rs104894306', (219, 227))	('c.64C>T', 'Mutation', 'rs104894306', (210, 217))
80104	22567117	This finding demonstrates that the p.Arg22X SDHD mutations in these two seemingly unrelated patients originate from a single founder, and further validate the relevance of our method for detecting founder mutations in cancer.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('SDHD', 'Gene', (44, 48))	('SDHD', 'Gene', '6392', (44, 48))	('patients', 'Species', '9606', (92, 100))	('p.Arg22X', 'Mutation', 'rs104894306', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('p.Arg22X', 'Var', (35, 43))
80105	22567117	As this disease is extremely rare in absence of the p.R337H TP53 founder mutation, all of the samples selected through a random sampling of tumors bear this mutation.	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('p.R337H', 'Var', (52, 59))	('TP53', 'Gene', '7157', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('p.R337H', 'Mutation', 'rs121912664', (52, 59))	('TP53', 'Gene', (60, 64))
80106	22567117	In most contexts, tumors attributable to a given founder mutation account for only a subset of cancers in a population.	('mutation', 'Var', (57, 65))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
80112	22567117	SNP arrays are widely used in cancer research for two main purposes: the discovery of germline risk variants in linkage or association studies, and the identification of recurrent chromosome rearrangements.	('variants', 'Var', (100, 108))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
80115	22567117	Finally, LOH at a cancer gene locus is likely to be more frequent in mutation carriers than in non-carriers, as already shown for the BRCA genes.	('LOH', 'Disease', (9, 12))	('BRCA', 'Gene', '672', (134, 138))	('BRCA', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('mutation carriers', 'Var', (69, 86))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
80119	22567117	For instance, a founder mutation present in only 5% of tumors, lying within a conserved haplotype of mean length 5 cM, (like the p.R337H TP53 mutation in Brazilian ACT) will be detected with a power of 0.92 with FounderTracker versus 0 with DASH (Table 1).	('p.R337H', 'Mutation', 'rs121912664', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('TP53', 'Gene', '7157', (137, 141))	('p.R337H', 'Var', (129, 136))	('TP53', 'Gene', (137, 141))
80122	22567117	Our method is therefore suitable for the detection of cancer-related mutations that appeared less than 100 generations ago.	('mutations', 'Var', (69, 78))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (54, 60))
80125	22567117	The proportion of tumors harboring a founder mutation in a random population sample depends principally on the genetic diversity of the population and the prevalence of the disease.	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('mutation', 'Var', (45, 53))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
80161	22567117	In a real data set of tumors harboring a founder mutation, all patients have inherited a different chromosome segment from the founder.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutation', 'Var', (49, 57))	('patients', 'Species', '9606', (63, 71))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
80195	18765068	The extra-adrenal causes are polycystic ovary, adrenal rests, ovarian tumors, testicular tumors, adrenal hyperplasia secondary to a pituitary adenoma or ectopic secretion of ACTH or CRH, hyperprolactinemia, and acromegaly.	('acromegaly', 'Disease', 'MESH:D000172', (211, 221))	('adrenal hyperplasia', 'Disease', (97, 116))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('acromegaly', 'Disease', (211, 221))	('CRH', 'Gene', (182, 185))	('ACTH', 'Gene', '5443', (174, 178))	('acromegaly', 'Phenotype', 'HP:0000845', (211, 221))	('polycystic ovary', 'Disease', (29, 45))	('ovarian tumors', 'Phenotype', 'HP:0100615', (62, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('hyperprolactinemia', 'Disease', (187, 205))	('testicular tumors', 'Disease', 'MESH:D013736', (78, 95))	('pituitary adenoma', 'Disease', 'MESH:D010911', (132, 149))	('testicular tumors', 'Phenotype', 'HP:0010788', (78, 95))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (97, 116))	('hyperprolactinemia', 'Disease', 'MESH:D002640', (187, 205))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (132, 149))	('pituitary adenoma', 'Disease', (132, 149))	('ACTH', 'Gene', (174, 178))	('adrenal rests', 'Disease', (47, 60))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (97, 116))	('ovarian tumors', 'Disease', (62, 76))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('CRH', 'Gene', '1392', (182, 185))	('ovarian tumors', 'Disease', 'MESH:D010051', (62, 76))	('hyperprolactinemia', 'Phenotype', 'HP:0000870', (187, 205))	('polycystic ovary', 'Disease', 'MESH:D011085', (29, 45))	('ectopic', 'Var', (153, 160))	('testicular tumors', 'Disease', (78, 95))	('polycystic ovary', 'Phenotype', 'HP:0000147', (29, 45))
80237	33952721	Even some classic molecular targeted drugs, such as IGF1R (insulin-like growth factor 1 receptor) inhibitors, VEGF (vascular endothelial growth factor) inhibitors and EGFR (epidermal growth factor receptor) inhibitors, have been proven to fail to effectively prolong the OS time of ACC patients.	('vascular endothelial growth factor', 'Gene', (116, 150))	('epidermal growth factor receptor', 'Gene', '1956', (173, 205))	('S', 'Chemical', 'MESH:D013455', (272, 273))	('ACC', 'Phenotype', 'HP:0006744', (282, 285))	('IGF1R', 'Gene', '3480', (52, 57))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (59, 96))	('inhibitors', 'Var', (98, 108))	('vascular endothelial growth factor', 'Gene', '7422', (116, 150))	('VEGF', 'Gene', '7422', (110, 114))	('patients', 'Species', '9606', (286, 294))	('insulin-like growth factor 1 receptor', 'Gene', (59, 96))	('epidermal growth factor receptor', 'Gene', (173, 205))	('prolong', 'PosReg', (259, 266))	('EGFR', 'Gene', '1956', (167, 171))	('IGF1R', 'Gene', (52, 57))	('EGFR', 'Gene', (167, 171))	('VEGF', 'Gene', (110, 114))
80239	33952721	Among kinds of epigenetic modifications, N6-methyladenosine (M6A) is the most common form of RNA modification, accounting for approximately 60% of all RNA modifications, and it can edit all types of RNA.	('M6A', 'Gene', '56339', (61, 64))	('M6A', 'Gene', (61, 64))	('modifications', 'Var', (155, 168))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (41, 59))	('N6-methyladenosine', 'Var', (41, 59))
80248	33952721	The aberrant expression of FTO and ALKBH5 promotes the proliferation of glioblastoma by increasing the expression level of FOXM1.	('expression level', 'MPA', (103, 119))	('ALKBH5', 'Gene', (35, 41))	('FTO', 'Gene', '79068', (27, 30))	('proliferation', 'CPA', (55, 68))	('promotes', 'PosReg', (42, 50))	('aberrant expression', 'Var', (4, 23))	('FTO', 'Gene', (27, 30))	('glioblastoma', 'Disease', (72, 84))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('FOXM1', 'Gene', (123, 128))	('FOXM1', 'Gene', '2305', (123, 128))	('increasing', 'PosReg', (88, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))	('ALKBH5', 'Gene', '54890', (35, 41))
80249	33952721	In breast cancer (BRC), elevated METTL3 can promote tumor progression by inhibiting the tumor suppressor let-7g.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('elevated', 'Var', (24, 32))	('promote', 'PosReg', (44, 51))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('let-7g', 'Gene', '406890', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('METTL3', 'Gene', '56339', (33, 39))	('BRC', 'Phenotype', 'HP:0003002', (18, 21))	('inhibiting', 'NegReg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (88, 93))	('METTL3', 'Gene', (33, 39))	('let-7g', 'Gene', (105, 111))
80258	33952721	Among remaining 20 ACC datasets, only four datasets (GSE19775, GSE19750, GSE19776 and GSE33371) contain clinical information.	('GSE19775', 'Var', (53, 61))	('GSE19750', 'Var', (63, 71))	('S', 'Chemical', 'MESH:D013455', (87, 88))	('GSE19776', 'Var', (73, 81))	('GSE33371', 'Var', (86, 94))	('ACC', 'Phenotype', 'HP:0006744', (19, 22))	('S', 'Chemical', 'MESH:D013455', (74, 75))	('S', 'Chemical', 'MESH:D013455', (54, 55))	('S', 'Chemical', 'MESH:D013455', (64, 65))
80347	33952721	Using the cBioPortal database, only four out of 89 ACC samples (4.49%) were found to have HNRNPC and RBM15 mutations (Figure 4H).	('RBM15', 'Gene', (101, 106))	('mutations', 'Var', (107, 116))	('P', 'Chemical', 'MESH:D010758', (14, 15))	('HNRNPC', 'Gene', (90, 96))	('P', 'Chemical', 'MESH:D010758', (94, 95))	('HNRNPC', 'Gene', '3183', (90, 96))	('RBM15', 'Gene', '64783', (101, 106))	('ACC', 'Phenotype', 'HP:0006744', (51, 54))
80349	33952721	Overall, HNRNPC and RBM15 infrequently mutated in ACC, suggesting that their aberrant expressions may result from epigenetic modification.	('result from', 'Reg', (102, 113))	('RBM15', 'Gene', '64783', (20, 25))	('ACC', 'Phenotype', 'HP:0006744', (50, 53))	('RBM15', 'Gene', (20, 25))	('epigenetic modification', 'Var', (114, 137))	('HNRNPC', 'Gene', '3183', (9, 15))	('HNRNPC', 'Gene', (9, 15))
80368	33952721	Similar results were observed in this study, ACC patients with high PD-L1 expression (training cohort) had better prognosis than that with low expression (Figure 7G).	('PD-L1', 'Gene', '29126', (68, 73))	('PD-L1', 'Gene', (68, 73))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (49, 57))	('ACC', 'Phenotype', 'HP:0006744', (45, 48))	('S', 'Chemical', 'MESH:D013455', (0, 1))
80380	33952721	Further, silencing HNRNPC can retard the proliferative, migrative and invasive abilities of adrenal cancer cells (Figure 8F, 8G, 8H).	('retard', 'NegReg', (30, 36))	('HNRNPC', 'Gene', '3183', (19, 25))	('HNRNPC', 'Gene', (19, 25))	('silencing', 'Var', (9, 18))	('adrenal cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('adrenal cancer', 'Disease', 'MESH:D000310', (92, 106))	('proliferative', 'CPA', (41, 54))	('renal cancer', 'Phenotype', 'HP:0009726', (94, 106))	('invasive abilities', 'CPA', (70, 88))
80412	33952721	The dysfunction of antigen presenting process (Figure 5B) and the ectopic expression of APCs (Figure 5A) both retard the anti-cancer immunity.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('APC', 'Gene', '324', (88, 91))	('dysfunction', 'Var', (4, 15))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('retard', 'NegReg', (110, 116))	('APC', 'Gene', (88, 91))
80423	33952721	Despite the optimum prediction marker of ICIs therapeutic effect remains controversial, the patients with PD-L1 overexpression or positive commonly have a better objective response rate (ORS) and longer progression-free survival (PFS).	('P', 'Chemical', 'MESH:D010758', (230, 231))	('progression-free survival', 'CPA', (203, 228))	('P', 'Chemical', 'MESH:D010758', (106, 107))	('overexpression', 'PosReg', (112, 126))	('objective', 'MPA', (162, 171))	('positive', 'Var', (130, 138))	('longer', 'PosReg', (196, 202))	('patients', 'Species', '9606', (92, 100))	('PD-L1', 'Gene', (106, 111))	('S', 'Chemical', 'MESH:D013455', (232, 233))	('better', 'PosReg', (155, 161))	('PD-L1', 'Gene', '29126', (106, 111))	('S', 'Chemical', 'MESH:D013455', (189, 190))
80429	33952721	In the present study, HNRNPC knockdown inhibited the proliferation, migration and invasion of ACC cells, which was the first verification of its biofunction in ACC.	('ACC', 'Phenotype', 'HP:0006744', (94, 97))	('invasion of ACC cells', 'CPA', (82, 103))	('HNRNPC', 'Gene', '3183', (22, 28))	('inhibited', 'NegReg', (39, 48))	('knockdown', 'Var', (29, 38))	('HNRNPC', 'Gene', (22, 28))	('ACC', 'Phenotype', 'HP:0006744', (160, 163))
80431	33952721	ascertained that the repression of HNRNPC inhibited cell proliferation and tumor growth through the accumulation of endogenous dsRNA (double-stranded RNA) and the activation of down-stream interferon (IFN) response.	('activation', 'PosReg', (163, 173))	('cell proliferation', 'CPA', (52, 70))	('accumulation', 'PosReg', (100, 112))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('inhibited', 'NegReg', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('repression', 'Var', (21, 31))	('HNRNPC', 'Gene', (35, 41))	('HNRNPC', 'Gene', '3183', (35, 41))	('tumor', 'Disease', (75, 80))
80620	30081524	Mutational studies of Giot1 proximal promoter in ovarian granulosa cells identified importance of cAMP response element (CRE) in Giot1 regulation.	('ovarian granulosa', 'Disease', (49, 66))	('Mutational', 'Var', (0, 10))	('cAMP', 'Chemical', 'MESH:D000242', (98, 102))	('Giot1', 'Gene', (129, 134))	('ovarian granulosa', 'Disease', 'MESH:D010051', (49, 66))
80681	30081524	None of the other transcriptional variants had the potential of CREB1 binding sequences.	('CREB1', 'Gene', '81646', (64, 69))	('variants', 'Var', (34, 42))	('CREB1', 'Gene', (64, 69))	('binding', 'Interaction', (70, 77))
80692	30081524	The (Cys)2-(His)2-type zinc finger motif is responsible for DNA-binding properties of transcription factors, whereas the KRAB-A domain has been shown to possess transcriptional repressor activity.	('responsible', 'Reg', (44, 55))	('transcriptional repressor activity', 'MPA', (161, 195))	('Cys', 'Chemical', 'MESH:D003545', (5, 8))	('DNA-binding', 'Interaction', (60, 71))	('Cys', 'Var', (5, 8))
80695	30081524	Moreover, it has been shown that in vitro levels of mRNA Giot1 in Leydig cells increase significantly after addition to the medium of pMSG/hCG.	('levels', 'MPA', (42, 48))	('addition', 'Interaction', (108, 116))	('increase', 'PosReg', (79, 87))	('hCG', 'Gene', '93659', (139, 142))	('Leydig cells increase', 'Phenotype', 'HP:0010791', (66, 87))	('hCG', 'Gene', (139, 142))	('mRNA', 'Var', (52, 56))
80747	30081524	Furthermore, it has been demonstrated that Giot1 represses the steroidogenic factor-1 (SF-1; NR5A1) transactivation.	('transactivation', 'MPA', (100, 115))	('steroidogenic factor-1 (SF-1', 'Gene', '117855', (63, 91))	('rat', 'Species', '10116', (32, 35))	('represses', 'NegReg', (49, 58))	('Giot1', 'Var', (43, 48))	('NR5A1', 'Gene', '83826', (93, 98))	('NR5A1', 'Gene', (93, 98))
80837	29109191	The silencing of CALN1 decreased Ca2+ in ER, and abrogated A-II or KCNJ5 T158A mediated aldosterone production in HAC15 cells.	('decreased', 'NegReg', (23, 32))	('HAC15', 'CellLine', 'CVCL:S898', (114, 119))	('T158A', 'Mutation', 'rs387906778', (73, 78))	('abrogated', 'NegReg', (49, 58))	('Ca2+', 'MPA', (33, 37))	('aldosterone', 'Chemical', 'MESH:D000450', (88, 99))	('CALN1', 'Gene', (17, 22))	('aldosterone production', 'MPA', (88, 110))	('aldosterone production', 'Phenotype', 'HP:0000859', (88, 110))	('KCNJ5', 'Gene', (67, 72))	('A-II', 'Gene', '183', (59, 63))	('Ca2+', 'Chemical', 'MESH:D000069285', (33, 37))	('A-II', 'Gene', (59, 63))	('silencing', 'Var', (4, 13))	('KCNJ5', 'Gene', '3762', (67, 72))
80839	29109191	Suppression of CALN1 expression prevented A-II or KCNJ5 T158A mediated aldosterone production in HAC15 cells, suggesting that CALN1 is a potential therapeutic target for excess aldosterone production.	('A-II', 'Gene', (42, 46))	('aldosterone', 'Chemical', 'MESH:D000450', (71, 82))	('aldosterone', 'Chemical', 'MESH:D000450', (177, 188))	('HAC15', 'CellLine', 'CVCL:S898', (97, 102))	('excess aldosterone', 'Phenotype', 'HP:0000859', (170, 188))	('T158A', 'Var', (56, 61))	('aldosterone production', 'Phenotype', 'HP:0000859', (177, 199))	('aldosterone production', 'MPA', (71, 93))	('KCNJ5', 'Gene', (50, 55))	('aldosterone production', 'Phenotype', 'HP:0000859', (71, 93))	('Suppression', 'NegReg', (0, 11))	('CALN1', 'Gene', (15, 20))	('T158A', 'Mutation', 'rs387906778', (56, 61))	('prevented', 'NegReg', (32, 41))	('A-II', 'Gene', '183', (42, 46))	('KCNJ5', 'Gene', '3762', (50, 55))
80848	29109191	Recently, exome-sequencing analyses demonstrated that 50 to 80% of APA harbored somatic mutations in KCNJ5, ATP1A1, ATP2B3, or CACNA1D .	('KCNJ5', 'Gene', (101, 106))	('mutations', 'Var', (88, 97))	('rat', 'Species', '10116', (43, 46))	('ATP1A1', 'Gene', '476', (108, 114))	('PA', 'Phenotype', 'HP:0011736', (68, 70))	('KCNJ5', 'Gene', '3762', (101, 106))	('ATP2B3', 'Gene', '492', (116, 122))	('CACNA1D', 'Gene', '776', (127, 134))	('ATP1A1', 'Gene', (108, 114))	('ATP2B3', 'Gene', (116, 122))	('CACNA1D', 'Gene', (127, 134))
80849	29109191	All of these mutations directly or indirectly activate intracellular Ca2+ signaling and CYP11B2 transcription .	('Ca2+', 'Chemical', 'MESH:D000069285', (69, 73))	('transcription', 'MPA', (96, 109))	('activate', 'PosReg', (46, 54))	('intracellular Ca2+ signaling', 'MPA', (55, 83))	('mutations', 'Var', (13, 22))	('CYP11B2', 'Gene', (88, 95))
80859	29109191	Our results showed that the CALN1 gene encoding calneuron 1 was one of the most highly expressed genes and had the strongest correlation with CYP11B2 in APA.	('calneuron 1', 'Gene', '83698', (48, 59))	('calneuron 1', 'Gene', (48, 59))	('CYP11B2', 'Var', (142, 149))	('CALN1', 'Gene', (28, 33))	('correlation', 'Interaction', (125, 136))	('PA', 'Phenotype', 'HP:0011736', (154, 156))
80863	29109191	CALN1 was located in ER, its increased expression resulted in increased stored Ca2+ in ER, and it potentiated aldosterone production in human adrenocortical carcinoma (HAC15) cells.	('human', 'Species', '9606', (136, 141))	('increased', 'PosReg', (62, 71))	('CALN1', 'Var', (0, 5))	('Ca2+', 'Chemical', 'MESH:D000069285', (79, 83))	('aldosterone production', 'Phenotype', 'HP:0000859', (110, 132))	('stored Ca2+', 'MPA', (72, 83))	('aldosterone production', 'MPA', (110, 132))	('increased', 'PosReg', (29, 38))	('HAC15', 'CellLine', 'CVCL:S898', (168, 173))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (142, 166))	('potentiated', 'PosReg', (98, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('aldosterone', 'Chemical', 'MESH:D000450', (110, 121))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (142, 166))	('expression', 'MPA', (39, 49))	('adrenocortical carcinoma', 'Disease', (142, 166))
80885	29109191	After CALN1 transduction in HAC15 cells, the cells were incubated with Fluo4-AM for the detection of Ca2+ concentration in cytosol as previously described .	('CALN1', 'Gene', (6, 11))	('rat', 'Species', '10116', (113, 116))	('Ca2+', 'Chemical', 'MESH:D000069285', (101, 105))	('transduction', 'Var', (12, 24))	('HAC15', 'CellLine', 'CVCL:S898', (28, 33))	('Fluo4-AM', 'Chemical', '-', (71, 79))
80899	29109191	CYP11B2 expression was 535.1-fold higher in APAs than in NFAs (P<0.001, Figure 2A), and CALN1 expression was in 4.4-fold greater in APAs than in NFAs (P<0.001, Figure 2B).	('CYP11B2', 'Var', (0, 7))	('NFAs', 'Chemical', 'MESH:D009544', (57, 61))	('higher', 'PosReg', (34, 40))	('APAs', 'Disease', (132, 136))	('greater', 'PosReg', (121, 128))	('PA', 'Phenotype', 'HP:0011736', (133, 135))	('expression', 'MPA', (94, 104))	('expression', 'MPA', (8, 18))	('APAs', 'Disease', (44, 48))	('CALN1', 'Gene', (88, 93))	('PA', 'Phenotype', 'HP:0011736', (45, 47))	('NFAs', 'Chemical', 'MESH:D009544', (145, 149))
80900	29109191	CALN1 mRNA expression levels was not different among APA genotypes such as no mutation (n=16), KCNJ5 mutation (n=27), and ATP1A1 mutation (n=5) (Figure 2C).	('CALN1 mRNA expression levels', 'MPA', (0, 28))	('KCNJ5', 'Gene', '3762', (95, 100))	('ATP1A1', 'Gene', (122, 128))	('PA', 'Phenotype', 'HP:0011736', (54, 56))	('mutation', 'Var', (101, 109))	('KCNJ5', 'Gene', (95, 100))	('ATP1A1', 'Gene', '476', (122, 128))
80901	29109191	CALN1 expression was detected in APAs, but not in NFAs, and the expression appeared to be colocalized with CYP11B2 expression in APAs (Figure 3A).	('CALN1', 'Gene', (0, 5))	('CYP11B2', 'Var', (107, 114))	('PA', 'Phenotype', 'HP:0011736', (130, 132))	('PA', 'Phenotype', 'HP:0011736', (34, 36))	('NFAs', 'Chemical', 'MESH:D009544', (50, 54))
80909	29109191	CALN1 immunoreactivity faded in the inner ZG next to the transition zone comprising smaller and more densely packed cells between the ZG and ZF, and is coexpressed in cells expressing CYP11B2, also consistent with its expression the human adrenal.	('faded', 'NegReg', (23, 28))	('CALN1', 'Gene', (0, 5))	('human', 'Species', '9606', (233, 238))	('CYP11B2', 'Var', (184, 191))	('immunoreactivity', 'MPA', (6, 22))
80911	29109191	HAC15 cells expressing the KCNJ5 mutation had 1.4-fold higher CALN1 mRNA levels than control HAC15 cells (P<0.05, Figure 3E).	('mutation', 'Var', (33, 41))	('KCNJ5', 'Gene', (27, 32))	('KCNJ5', 'Gene', '3762', (27, 32))	('HAC15', 'CellLine', 'CVCL:S898', (0, 5))	('CALN1 mRNA levels', 'MPA', (62, 79))	('HAC15', 'CellLine', 'CVCL:S898', (93, 98))	('higher', 'PosReg', (55, 61))
80914	29109191	The CALN1 protein levels were detected by western blotting in HAC15 cells harboring the KCNJ5 mutation.	('CALN1 protein levels', 'MPA', (4, 24))	('KCNJ5', 'Gene', (88, 93))	('HAC15', 'CellLine', 'CVCL:S898', (62, 67))	('detected', 'Reg', (30, 38))	('KCNJ5', 'Gene', '3762', (88, 93))	('mutation', 'Var', (94, 102))
80915	29109191	Interestingly, CALN1 tv1 expression was significantly increased, whereas CALN1 tv2 was attenuated by this KCNJ5 mutation (Figure 3F).	('CALN1', 'MPA', (15, 20))	('mutation', 'Var', (112, 120))	('KCNJ5', 'Gene', '3762', (106, 111))	('expression', 'MPA', (25, 35))	('attenuated', 'NegReg', (87, 97))	('increased', 'PosReg', (54, 63))	('KCNJ5', 'Gene', (106, 111))
80916	29109191	In addition, CALN1 tv1 transduction in HAC15 cells resulted in higher CYP11B2 expression and aldosterone levels than CALN1 tv2 transduction (Figure S1AB).	('expression', 'MPA', (78, 88))	('CYP11B2', 'Enzyme', (70, 77))	('aldosterone levels', 'MPA', (93, 111))	('HAC15', 'CellLine', 'CVCL:S898', (39, 44))	('CALN1 tv1 transduction', 'Var', (13, 35))	('aldosterone', 'Chemical', 'MESH:D000450', (93, 104))	('higher', 'PosReg', (63, 69))
80921	29109191	Additionally, Ca2+ in ER was significantly increased by the KCNJ5 mutation in HAC15 cells (Figure S2).	('KCNJ5', 'Gene', '3762', (60, 65))	('Ca2+ in ER', 'MPA', (14, 24))	('Ca2+', 'Chemical', 'MESH:D000069285', (14, 18))	('HAC15', 'CellLine', 'CVCL:S898', (78, 83))	('increased', 'PosReg', (43, 52))	('mutation', 'Var', (66, 74))	('KCNJ5', 'Gene', (60, 65))
80924	29109191	TMB-8 showed a dose-responsive inhibition of aldosterone production mediated by A-II and CALN1 in HAC15 cells (Figure 5E).	('A-II', 'Gene', '183', (80, 84))	('aldosterone production', 'MPA', (45, 67))	('TMB-8', 'Chemical', 'MESH:C006014', (0, 5))	('CALN1', 'Var', (89, 94))	('aldosterone production', 'Phenotype', 'HP:0000859', (45, 67))	('HAC15', 'CellLine', 'CVCL:S898', (98, 103))	('A-II', 'Gene', (80, 84))	('aldosterone', 'Chemical', 'MESH:D000450', (45, 56))	('TMB-8', 'Gene', (0, 5))
80926	29109191	CALN1 was silenced using a lentivirus delivering shRNA-CALN1 in HAC15 cells (shCALN1 cells) and resulted in a decreased CALN1 tv1 and tv2 protein expression by 32% and 47%, respectively (Figure 6AB).	('HAC15', 'CellLine', 'CVCL:S898', (64, 69))	('tv2 protein', 'Protein', (134, 145))	('decreased', 'NegReg', (110, 119))	('shRNA-CALN1', 'Var', (49, 60))	('CALN1', 'Gene', (120, 125))
80927	29109191	shCALN1 cells had significantly less Ca2+ in ER compared with control cells (P<0.05, Figure 6C).	('less', 'NegReg', (32, 36))	('shCALN1', 'Var', (0, 7))	('Ca2+ in', 'MPA', (37, 44))	('Ca2+', 'Chemical', 'MESH:D000069285', (37, 41))
80929	29109191	We demonstrated that expression of CALN1 correlated strongly with that of CYP11B2 and was limited to the normal ZG of human and rat adrenal, and that CALN1 co-localized with CYP11B2 in APA.	('PA', 'Phenotype', 'HP:0011736', (186, 188))	('CALN1', 'Gene', (150, 155))	('CALN1', 'Gene', (35, 40))	('human', 'Species', '9606', (118, 123))	('CYP11B2', 'Var', (174, 181))	('rat', 'Species', '10116', (10, 13))	('rat', 'Species', '10116', (128, 131))
80930	29109191	CALN1 is located in ER and increases Ca2+ in ER and cytosol in HAC15 cells.	('CALN1', 'Var', (0, 5))	('increases', 'PosReg', (27, 36))	('Ca2+', 'MPA', (37, 41))	('HAC15', 'CellLine', 'CVCL:S898', (63, 68))	('Ca2+', 'Chemical', 'MESH:D000069285', (37, 41))
80931	29109191	Both A-II and the KCNJ5 mutation potentiated CALN1 expression, and increased CALN1 expression led to increased aldosterone production in HAC15 cells.	('KCNJ5', 'Gene', (18, 23))	('aldosterone production', 'MPA', (111, 133))	('increased', 'PosReg', (101, 110))	('potentiated', 'PosReg', (33, 44))	('A-II', 'Gene', '183', (5, 9))	('A-II', 'Gene', (5, 9))	('KCNJ5', 'Gene', '3762', (18, 23))	('aldosterone production', 'Phenotype', 'HP:0000859', (111, 133))	('HAC15', 'CellLine', 'CVCL:S898', (137, 142))	('CALN1 expression', 'MPA', (45, 61))	('increased', 'PosReg', (67, 76))	('expression', 'MPA', (83, 93))	('mutation', 'Var', (24, 32))	('increased aldosterone', 'Phenotype', 'HP:0000859', (101, 122))	('CALN1', 'Gene', (77, 82))	('aldosterone', 'Chemical', 'MESH:D000450', (111, 122))
80932	29109191	In contrast, CALN1 suppression significantly decreased A-II or KCNJ5 mutation mediated aldosterone production in HAC15 cells.	('aldosterone production', 'MPA', (87, 109))	('KCNJ5', 'Gene', (63, 68))	('CALN1', 'Gene', (13, 18))	('KCNJ5', 'Gene', '3762', (63, 68))	('aldosterone production', 'Phenotype', 'HP:0000859', (87, 109))	('HAC15', 'CellLine', 'CVCL:S898', (113, 118))	('decreased', 'NegReg', (45, 54))	('mutation', 'Var', (69, 77))	('suppression', 'NegReg', (19, 30))	('aldosterone', 'Chemical', 'MESH:D000450', (87, 98))	('A-II', 'Gene', '183', (55, 59))	('A-II', 'Gene', (55, 59))
80936	29109191	Our results regarding SERCA function in ER suggest that CALN1 collaborates with SERCA to transfer Ca2+ from the cytosol to the ER in aldosterone-producing adrenal cells.	('aldosterone', 'Chemical', 'MESH:D000450', (133, 144))	('transfer Ca2+', 'MPA', (89, 102))	('CALN1', 'Var', (56, 61))	('Ca2+', 'Chemical', 'MESH:D000069285', (98, 102))	('rat', 'Species', '10116', (69, 72))
80939	29109191	According to a previous study, excess Ca2+ in ER leads to Ca2+ efflux through IP3R without IP3 stimulation .	('Ca2+', 'Var', (38, 42))	('IP3R', 'Gene', '3710', (78, 82))	('Ca2+', 'Chemical', 'MESH:D000069285', (38, 42))	('IP3R', 'Gene', (78, 82))	('Ca2+', 'Chemical', 'MESH:D000069285', (58, 62))	('IP3', 'Chemical', 'MESH:D015544', (91, 94))	('IP3', 'Chemical', 'MESH:D015544', (78, 81))
80942	29109191	CALN1 is a potential therapeutic target to mitigate excess of aldosterone production, because KCNJ5 T158A mediated aldosterone production was found to be inhibited by silencing CALN1 mRNA.	('aldosterone', 'Chemical', 'MESH:D000450', (115, 126))	('aldosterone production', 'Phenotype', 'HP:0000859', (62, 84))	('aldosterone production', 'MPA', (115, 137))	('aldosterone production', 'Phenotype', 'HP:0000859', (115, 137))	('inhibited', 'NegReg', (154, 163))	('KCNJ5', 'Gene', (94, 99))	('silencing', 'Var', (167, 176))	('aldosterone', 'Chemical', 'MESH:D000450', (62, 73))	('KCNJ5', 'Gene', '3762', (94, 99))	('T158A', 'Mutation', 'rs387906778', (100, 105))	('CALN1', 'Gene', (177, 182))
80943	29109191	Likewise, this study was performed to identify a key molecule for Ca2+ signaling in APA and lead to our finding that CALN1 had the strongest correlation with CYP11B2 among CaBPs and was co-localized with CYP11B2 in APAs.	('CaBP', 'Gene', '795', (172, 176))	('correlation', 'Interaction', (141, 152))	('CALN1', 'Var', (117, 122))	('Ca2+', 'Chemical', 'MESH:D000069285', (66, 70))	('PA', 'Phenotype', 'HP:0011736', (216, 218))	('CaBP', 'Gene', (172, 176))	('PA', 'Phenotype', 'HP:0011736', (85, 87))	('CYP11B2', 'Var', (158, 165))
80947	29109191	The aldosterone production mediated by A-II was also abrogated by the silencing of CALN1 in this study.	('silencing', 'Var', (70, 79))	('CALN1', 'Gene', (83, 88))	('abrogated', 'NegReg', (53, 62))	('A-II', 'Gene', '183', (39, 43))	('A-II', 'Gene', (39, 43))	('aldosterone', 'Chemical', 'MESH:D000450', (4, 15))	('aldosterone production', 'MPA', (4, 26))	('aldosterone production', 'Phenotype', 'HP:0000859', (4, 26))
80951	29109191	Ca2+ storage in ER was decreased in adrenal cells in which CALN1 was silenced, reducing aldosterone production by A-II stimulation.	('CALN1', 'Gene', (59, 64))	('Ca2+', 'Chemical', 'MESH:D000069285', (0, 4))	('aldosterone', 'Chemical', 'MESH:D000450', (88, 99))	('reducing', 'NegReg', (79, 87))	('silenced', 'Var', (69, 77))	('A-II', 'Gene', '183', (114, 118))	('aldosterone production', 'MPA', (88, 110))	('A-II', 'Gene', (114, 118))	('aldosterone production', 'Phenotype', 'HP:0000859', (88, 110))	('Ca2+ storage', 'MPA', (0, 12))
80954	29109191	Additionally, the adrenal ZG of rats consuming a high-salt diet which had low plasma renin and aldosterone concentrations as expected, also had some expression of CALN1.	('rat', 'Species', '10116', (114, 117))	('aldosterone', 'Chemical', 'MESH:D000450', (95, 106))	('rat', 'Species', '10116', (32, 35))	('low', 'NegReg', (74, 77))	('CALN1', 'Var', (163, 168))	('rats', 'Species', '10116', (32, 36))	('salt', 'Chemical', 'MESH:D012492', (54, 58))
80956	29109191	It appears that CYP11B2 expression is regulated by CALN1 expression and Ca2+ signaling induced by A-II or a mutation driving aldosterone production, all of which, to date, cause an increase in intracellular Ca2+ mobilization.	('expression', 'MPA', (24, 34))	('aldosterone production', 'Phenotype', 'HP:0000859', (125, 147))	('Ca2+', 'Chemical', 'MESH:D000069285', (207, 211))	('intracellular Ca2+ mobilization', 'MPA', (193, 224))	('A-II', 'Gene', '183', (98, 102))	('CALN1', 'Gene', (51, 56))	('Ca2+', 'Chemical', 'MESH:D000069285', (72, 76))	('A-II', 'Gene', (98, 102))	('mutation', 'Var', (108, 116))	('Ca2+ signaling', 'MPA', (72, 86))	('CYP11B2', 'Gene', (16, 23))	('aldosterone', 'Chemical', 'MESH:D000450', (125, 136))	('increase', 'PosReg', (181, 189))
80961	29109191	Since patients with PA have an increased risk of cardiovascular and cerebrovascular complications compared with those with essential hypertension , all of somatic mutations which drive aldosterone production directly or indirectly activate intracellular Ca2+ signaling and CYP11B2 transcription .	('cardiovascular and cerebrovascular complications', 'Disease', 'MESH:D002318', (49, 97))	('CYP11B2', 'Gene', (273, 280))	('transcription', 'MPA', (281, 294))	('hypertension', 'Disease', (133, 145))	('mutations', 'Var', (163, 172))	('Ca2+', 'Chemical', 'MESH:D000069285', (254, 258))	('hypertension', 'Phenotype', 'HP:0000822', (133, 145))	('aldosterone production', 'Phenotype', 'HP:0000859', (185, 207))	('intracellular Ca2+ signaling', 'MPA', (240, 268))	('patients', 'Species', '9606', (6, 14))	('aldosterone', 'Chemical', 'MESH:D000450', (185, 196))	('activate', 'PosReg', (231, 239))	('PA', 'Phenotype', 'HP:0011736', (20, 22))	('hypertension', 'Disease', 'MESH:D006973', (133, 145))
80964	29109191	Suppression of CALN1 expression abrogated A-II or KCNJ5 T158A-mediated aldosterone production in HAC15 cells.	('A-II', 'Gene', (42, 46))	('aldosterone', 'Chemical', 'MESH:D000450', (71, 82))	('T158A-mediated', 'Var', (56, 70))	('HAC15', 'CellLine', 'CVCL:S898', (97, 102))	('abrogated', 'NegReg', (32, 41))	('aldosterone production', 'MPA', (71, 93))	('KCNJ5', 'Gene', (50, 55))	('aldosterone production', 'Phenotype', 'HP:0000859', (71, 93))	('Suppression', 'NegReg', (0, 11))	('CALN1', 'Gene', (15, 20))	('T158A', 'Mutation', 'rs387906778', (56, 61))	('A-II', 'Gene', '183', (42, 46))	('KCNJ5', 'Gene', '3762', (50, 55))
80967	29109191	CALN1, calneuron 1, expression strongly correlated with CYP11B2 expression and was limited to the normal zona glomerulosa (ZG) of human and rat adrenal, and that CALN1 co-localized with CYP11B2 in APA.	('PA', 'Phenotype', 'HP:0011736', (198, 200))	('correlated', 'Reg', (40, 50))	('CALN1', 'Var', (162, 167))	('CYP11B2', 'Gene', (56, 63))	('calneuron 1', 'Gene', '83698', (7, 18))	('rat', 'Species', '10116', (140, 143))	('calneuron 1', 'Gene', (7, 18))	('human', 'Species', '9606', (130, 135))
80968	29109191	CALN1 located in endoplasmic reticulum (ER) and increases Ca2+ in ER and cytosol in HAC15 cells.	('HAC15', 'CellLine', 'CVCL:S898', (84, 89))	('CALN1', 'Var', (0, 5))	('increases', 'PosReg', (48, 57))	('Ca2+', 'Chemical', 'MESH:D000069285', (58, 62))	('Ca2+', 'MPA', (58, 62))
80969	29109191	Both Angiotensin II (A-II) and the KCNJ5 mutation potentiated CALN1 expression, and increased CALN1 expression led to increased aldosterone production in HAC15 cells.	('CALN1 expression', 'MPA', (94, 110))	('expression', 'MPA', (68, 78))	('aldosterone production', 'MPA', (128, 150))	('potentiated', 'PosReg', (50, 61))	('aldosterone', 'Chemical', 'MESH:D000450', (128, 139))	('CALN1', 'Gene', (62, 67))	('KCNJ5', 'Gene', (35, 40))	('aldosterone production', 'Phenotype', 'HP:0000859', (128, 150))	('increased', 'PosReg', (118, 127))	('mutation', 'Var', (41, 49))	('HAC15', 'CellLine', 'CVCL:S898', (154, 159))	('Angiotensin II', 'Gene', '183', (5, 19))	('KCNJ5', 'Gene', '3762', (35, 40))	('increased', 'PosReg', (84, 93))	('A-II', 'Gene', '183', (21, 25))	('Angiotensin II', 'Gene', (5, 19))	('increased aldosterone', 'Phenotype', 'HP:0000859', (118, 139))	('A-II', 'Gene', (21, 25))
80970	29109191	CALN1 suppression significantly decreased A-II or KCNJ5 mutation mediated aldosterone production in HAC15 cells.	('suppression', 'NegReg', (6, 17))	('A-II', 'Gene', (42, 46))	('CALN1', 'Gene', (0, 5))	('aldosterone', 'Chemical', 'MESH:D000450', (74, 85))	('aldosterone production', 'MPA', (74, 96))	('aldosterone production', 'Phenotype', 'HP:0000859', (74, 96))	('KCNJ5', 'Gene', (50, 55))	('mutation', 'Var', (56, 64))	('HAC15', 'CellLine', 'CVCL:S898', (100, 105))	('decreased', 'NegReg', (32, 41))	('A-II', 'Gene', '183', (42, 46))	('KCNJ5', 'Gene', '3762', (50, 55))
80974	29109191	Suppression of CALN1 expression prevented A-II or KCNJ5 T158A mediated aldosterone production in HAC15 cells.	('A-II', 'Gene', (42, 46))	('aldosterone', 'Chemical', 'MESH:D000450', (71, 82))	('HAC15', 'CellLine', 'CVCL:S898', (97, 102))	('T158A', 'Var', (56, 61))	('aldosterone production', 'MPA', (71, 93))	('KCNJ5', 'Gene', (50, 55))	('aldosterone production', 'Phenotype', 'HP:0000859', (71, 93))	('Suppression', 'NegReg', (0, 11))	('CALN1', 'Gene', (15, 20))	('T158A', 'Mutation', 'rs387906778', (56, 61))	('prevented', 'NegReg', (32, 41))	('A-II', 'Gene', '183', (42, 46))	('KCNJ5', 'Gene', '3762', (50, 55))
80995	27333825	Herein, we report that YPEL4 potentiates aldosterone production by increasing cell proliferation.	('aldosterone production', 'MPA', (41, 63))	('cell proliferation', 'CPA', (78, 96))	('rat', 'Species', '10116', (90, 93))	('aldosterone production', 'Phenotype', 'HP:0000859', (41, 63))	('YPEL4', 'Var', (23, 28))	('potentiates', 'PosReg', (29, 40))	('aldosterone', 'Chemical', 'MESH:D000450', (41, 52))	('potentiates aldosterone production', 'Phenotype', 'HP:0000859', (29, 63))	('increasing', 'PosReg', (67, 77))
81000	27333825	The full length cDNA of YPEL4 was ligated downstream of the cytomegalovirus promoter of a feline immunodeficiency virus based lentivector (System Biosciences, Mountain View, CA), resulting in pCDF-YPEL4.	('pCDF', 'Chemical', '-', (192, 196))	('immunodeficiency', 'Phenotype', 'HP:0002721', (97, 113))	('pCDF-YPEL4', 'Var', (192, 202))	('YPEL4', 'Gene', (24, 29))	('feline immunodeficiency virus', 'Species', '11673', (90, 119))
81023	27333825	YPEL2 mRNA levels were also decreased by A-II (0.57-fold, P < 0.05).	('A-II', 'Var', (41, 45))	('YPEL2', 'Gene', (0, 5))	('decreased', 'NegReg', (28, 37))	('YPEL2', 'Gene', '388403', (0, 5))
81025	27333825	To assess the effect of YPEL4 on aldosterone production, we measured aldosterone concentration in the medium of HAC15 cells with YPEL4 or control, with and without stimulation by several concentrations of A-II or K+.	('aldosterone', 'Chemical', 'MESH:D000450', (33, 44))	('YPEL4', 'Var', (129, 134))	('rat', 'Species', '10116', (194, 197))	('HAC15', 'CellLine', 'CVCL:S898', (112, 117))	('measured', 'Reg', (60, 68))	('rat', 'Species', '10116', (88, 91))	('aldosterone production', 'Phenotype', 'HP:0000859', (33, 55))	('aldosterone', 'Chemical', 'MESH:D000450', (69, 80))	('aldosterone concentration', 'MPA', (69, 94))	('aldosterone concentration', 'Phenotype', 'HP:0000859', (69, 94))
81034	27333825	There were no differences in staining between YPEL4 and control 24 h, after plating, but by 48 h the rate of increase in staining of YPEL4 cells was significant greater than that of controls (YPEL4, 4.07 +- 0.12; control, 3.23 +- 0.08; P < 0.01) and 72 h (YPEL4, 5.30 +- 0.15; control, 4.23 +- 0.13; P < 0.01).	('rat', 'Species', '10116', (101, 104))	('greater', 'PosReg', (161, 168))	('YPEL4', 'Var', (133, 138))	('increase', 'PosReg', (109, 117))	('staining', 'MPA', (121, 129))
81048	27333825	Additionally, some single nucleotide polymorphisms of YPEL family were reported to be a risk factor for the development of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('breast cancer', 'Disease', (123, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('YPEL family', 'Gene', (54, 65))	('risk factor', 'Reg', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('single nucleotide polymorphisms', 'Var', (19, 50))
81063	27333825	Orexin is a hypothalamic hormone that also modulates the growth of rat adrenocortical cells through MAPK.	('MAPK', 'Var', (100, 104))	('Orexin', 'Gene', (0, 6))	('rat', 'Species', '10116', (67, 70))	('modulates', 'Reg', (43, 52))	('growth', 'CPA', (57, 63))	('Orexin', 'Gene', '25723', (0, 6))	('adrenocortical', 'Disease', (71, 85))	('adrenocortical', 'Disease', 'MESH:D018268', (71, 85))
81064	27333825	However, this is the first study demonstrating that YPEL4 expression in a human adrenocortical cell line is increased by A-II or K+ stimulation and that YPEL4 has a potentially relevant role in stimulating the proliferation and perhaps growth of adrenal cells.	('YPEL4', 'Var', (153, 158))	('stimulating', 'PosReg', (194, 205))	('expression', 'MPA', (58, 68))	('proliferation', 'CPA', (210, 223))	('increased', 'PosReg', (108, 117))	('rat', 'Species', '10116', (40, 43))	('adrenocortical', 'Disease', (80, 94))	('adrenocortical', 'Disease', 'MESH:D018268', (80, 94))	('growth', 'CPA', (236, 242))	('human', 'Species', '9606', (74, 79))	('YPEL4', 'Gene', (52, 57))	('rat', 'Species', '10116', (217, 220))
81075	27751767	Immunohistochemistry of aldosterone synthase leads the way to the pathogenesis of primary aldosteronism Our group previously purified human and rat aldosterone synthase (CYP11B2 and Cyp11b2, respectively) from their adrenals and verified that it is distinct from steroid 11beta-hydroxylase (CYP11B1 or Cyp11b1), the cortisol- or corticosterone-synthesizing enzyme.	('aldosterone synthase', 'Gene', '1585', (148, 168))	('human', 'Species', '9606', (134, 139))	('Cyp11b2', 'Var', (182, 189))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (82, 103))	('aldosterone synthase', 'Gene', (24, 44))	('corticosterone', 'Chemical', 'MESH:D003345', (329, 343))	('cortisol', 'Chemical', 'MESH:D006854', (316, 324))	('aldosterone synthase', 'Gene', '1585', (24, 44))	('aldosterone synthase', 'Gene', (148, 168))	('rat', 'Species', '10116', (144, 147))
81076	27751767	In rats, there is layered functional zonation with the Cyp11b2-positive zona glomerulosa (ZG), Cyp11b1-positive zona fasciculata (ZF), and Cyp11b2/Cyp11b1-negative undifferentiated zone between the ZG and ZF.	('Cyp11b1-positive', 'Var', (95, 111))	('rats', 'Species', '10116', (3, 7))	('Cyp11b2-positive', 'Var', (55, 71))	('zona fasciculata', 'Disease', (112, 128))	('zona fasciculata', 'Disease', 'MESH:D006562', (112, 128))
81081	27751767	Immunohistochemistry for CYP11B2 and CYP11B1 has become an important tool for the diagnosis of and research on adrenocortical pathological conditions and suggests that APCCs may be the origin of aldosterone-producing adenoma.	('CYP11B2', 'Var', (25, 32))	('CYP11B1', 'Var', (37, 44))	('adenoma', 'Disease', 'MESH:D000236', (217, 224))	('adrenocortical', 'Disease', (111, 125))	('adenoma', 'Disease', (217, 224))	('adrenocortical', 'Disease', 'MESH:D018268', (111, 125))	('aldosterone', 'Chemical', 'MESH:D000450', (195, 206))
81086	27751767	Dysregulation of aldosterone synthesis resulting in excessive aldosterone production despite suppressed renin and angiotensin is known as primary aldosteronism (PA).	('aldosterone synthesis', 'MPA', (17, 38))	('aldosterone production', 'Phenotype', 'HP:0000859', (62, 84))	('excessive', 'PosReg', (52, 61))	('suppressed renin', 'Phenotype', 'HP:0003351', (93, 109))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (138, 159))	('Dysregulation', 'Var', (0, 13))	('known as primary aldosteronism', 'Phenotype', 'HP:0011739', (129, 159))	('aldosterone', 'Chemical', 'MESH:D000450', (17, 28))	('primary aldosteronism', 'Disease', (138, 159))	('renin', 'Gene', (104, 109))	('aldosterone', 'Chemical', 'MESH:D000450', (62, 73))	('excessive aldosterone', 'Phenotype', 'HP:0000859', (52, 73))	('suppressed', 'NegReg', (93, 103))	('renin', 'Gene', '5972', (104, 109))	('aldosterone production', 'MPA', (62, 84))
81089	27751767	In the past several years, somatic mutations in a subset of ion channel and pump genes have been reported in APAs (APA-associated mutations) and the prevalence of each mutation in APAs has been reported in a large scale cohort study.	('pump genes', 'Gene', (76, 86))	('APA', 'Gene', '13809', (180, 183))	('APA', 'Gene', (109, 112))	('APA', 'Gene', '13809', (115, 118))	('APA', 'Gene', '13809', (109, 112))	('reported', 'Reg', (97, 105))	('ion channel', 'Gene', (60, 71))	('APA', 'Gene', (115, 118))	('APA', 'Gene', (180, 183))	('mutations', 'Var', (35, 44))
81090	27751767	These diverse mutations directly or indirectly increase intracellular calcium concentrations leading to increased expression and activity of the CYP11B2 enzyme and excessive aldosterone production, however their effect on cell proliferation in in vitro systems has been variable, calling into question the role of these mutations in adenoma formation.	('mutations', 'Var', (14, 23))	('aldosterone production', 'Phenotype', 'HP:0000859', (174, 196))	('adenoma', 'Disease', 'MESH:D000236', (333, 340))	('aldosterone', 'Chemical', 'MESH:D000450', (174, 185))	('increased', 'PosReg', (104, 113))	('adenoma', 'Disease', (333, 340))	('intracellular calcium concentrations', 'MPA', (56, 92))	('rat', 'Species', '10116', (85, 88))	('CYP11B2', 'Gene', (145, 152))	('excessive aldosterone', 'Phenotype', 'HP:0000859', (164, 185))	('activity', 'MPA', (129, 137))	('rat', 'Species', '10116', (234, 237))	('increase', 'PosReg', (47, 55))	('increase intracellular calcium', 'Phenotype', 'HP:0003575', (47, 77))	('calcium', 'Chemical', 'MESH:D002118', (70, 77))	('expression', 'MPA', (114, 124))	('aldosterone production', 'MPA', (174, 196))
81091	27751767	Until several years ago, functional zonation in humans, including aldosterone production, had not been visualized due to the absence of effective methods for immunohistochemistry that distinguished between CYP11B1 and CYP11B2.	('aldosterone production', 'Phenotype', 'HP:0000859', (66, 88))	('CYP11B1', 'Var', (206, 213))	('aldosterone', 'Chemical', 'MESH:D000450', (66, 77))	('CYP11B2', 'Var', (218, 225))	('humans', 'Species', '9606', (48, 54))
81104	27751767	Other research groups confirmed our results by producing recombinant CYP11B1 and CYP11B2 in cultured mammalian cells, and by demonstrating their enzymatic activities of 11beta-hydroxylase and aldosterone synthase, respectively.	('rat', 'Species', '10116', (132, 135))	('mammalian', 'Species', '9606', (101, 110))	('aldosterone synthase', 'Enzyme', (192, 212))	('11beta-hydroxylase', 'Enzyme', (169, 187))	('11beta', 'Chemical', '-', (169, 175))	('CYP11B2', 'Var', (81, 88))	('CYP11B1', 'Var', (69, 76))
81105	27751767	In 1992, our group also generated a pair of antibodies with the ability to distinguish between rat Cyp11b2 and Cyp11b1 and revealed the distribution of the rat Cyp11b2 and Cyp11b1 in the ZG and ZF-ZR of rat adrenal glands, respectively, by immunohistochemistry.	('Cyp11b1', 'Var', (111, 118))	('rat', 'Species', '10116', (156, 159))	('rat', 'Species', '10116', (95, 98))	('Cyp11b1', 'Var', (172, 179))	('rat', 'Species', '10116', (203, 206))	('rat', 'Species', '10116', (28, 31))	('Cyp11b2', 'Var', (160, 167))
81108	27751767	Thus, the Cyp11b1 and Cyp11b2 are localized in a mutually exclusive manner in rats and mice consistent with the classical view of the layered functional zonation of adrenocortical hormonal production.	('rats', 'Species', '10116', (78, 82))	('Cyp11b2', 'Var', (22, 29))	('adrenocortical', 'Disease', (165, 179))	('mice', 'Species', '10090', (87, 91))	('adrenocortical', 'Disease', 'MESH:D018268', (165, 179))	('Cyp11b1', 'Var', (10, 17))
81115	27751767	Our group recently double-immunostained adrenal tissues prepared from autopsied patients aged between 0 and 50 years old for CYP11B2 and CYP11B1.	('CYP11B2', 'Var', (125, 132))	('patients', 'Species', '9606', (80, 88))	('CYP11B1', 'Var', (137, 144))
81121	27751767	An immunohistochemical examination of adrenal tumors for CYP11B2 and CYP11B1 was shown to be useful for reaching confirmatory diagnoses of apparent APAs, aldosterone-producing micronodules, cortisol-producing adenomas (CPAs), and unclassified pathological conditions such as PA due to multiple APCCs.	('cortisol', 'Chemical', 'MESH:D006854', (190, 198))	('adenomas', 'Disease', (209, 217))	('aldosterone', 'Chemical', 'MESH:D000450', (154, 165))	('CPA', 'Chemical', '-', (219, 222))	('APA', 'Gene', '13809', (148, 151))	('adrenal tumors', 'Disease', 'MESH:D000310', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('aldosterone-producing', 'MPA', (154, 175))	('APA', 'Gene', (148, 151))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('adenomas', 'Disease', 'MESH:D000236', (209, 217))	('CYP11B1', 'Var', (69, 76))	('CYP11B2', 'Var', (57, 64))	('adrenal tumors', 'Disease', (38, 52))
81122	27751767	Immunohistochemistry for CYP11B2 and CYP11B1 is more reliable than that of 3beta-hydroxysteroid dehydrogenase (3betaHSD, an upstream enzyme for both CYP11B2 and CYP11B1) and 17alpha-hydroxylase/17, 20 lyase (CYP17, an upstream enzyme for CYP11B1, but not CYP11B2).	('CYP11B2', 'Var', (25, 32))	('3beta-hydroxysteroid dehydrogenase', 'Gene', (75, 109))	('CYP17', 'Gene', '1586', (208, 213))	('CYP11B1', 'Var', (37, 44))	('3beta-hydroxysteroid dehydrogenase', 'Gene', '3283', (75, 109))	('3betaHSD', 'Gene', '3283', (111, 119))	('3betaHSD', 'Gene', (111, 119))	('CYP17', 'Gene', (208, 213))
81123	27751767	Recently-developed monoclonal antibodies for CYP11B2 and CYP11B1 may play an important role in the development of adrenal pathological diagnostic and aldosterone-research fields.	('CYP11B1', 'Var', (57, 64))	('aldosterone', 'Chemical', 'MESH:D000450', (150, 161))	('CYP11B2', 'Var', (45, 52))
81125	27751767	Double-immunostaining revealed that APAs include CYP11B2- and CYP11B1-positive cells, while CPAs consist of CYP11B1-positive cells only.	('APA', 'Gene', '13809', (36, 39))	('CYP11B1-positive', 'Var', (62, 78))	('CYP11B2-', 'Var', (49, 57))	('APA', 'Gene', (36, 39))	('CPA', 'Chemical', '-', (92, 95))
81126	27751767	The expression of 3betaHSD and CYP17 is coordinated for the intended hormone synthesis in APAs and CPAs; CYP11B2-positive cells are positive for 3betaHSD, but not for CYP17, while CYP11B1-positive cells are positive for 3betaHSD and CYP17.	('CYP17', 'Gene', '1586', (31, 36))	('APA', 'Gene', '13809', (90, 93))	('CYP17', 'Gene', (233, 238))	('3betaHSD', 'Gene', (220, 228))	('3betaHSD', 'Gene', '3283', (220, 228))	('CYP17', 'Gene', (31, 36))	('CYP17', 'Gene', '1586', (167, 172))	('3betaHSD', 'Gene', '3283', (18, 26))	('3betaHSD', 'Gene', (18, 26))	('APA', 'Gene', (90, 93))	('CYP11B2-positive', 'Var', (105, 121))	('3betaHSD', 'Gene', (145, 153))	('CYP17', 'Gene', '1586', (233, 238))	('3betaHSD', 'Gene', '3283', (145, 153))	('CPA', 'Chemical', '-', (99, 102))	('CYP17', 'Gene', (167, 172))
81128	27751767	In ACC, a large number of CYP11B2-positive cells are negative for 3betaHSD, but enough are positive for 3betaHSD to support high autonomous synthesis of aldosterone.	('3betaHSD', 'Gene', '3283', (104, 112))	('3betaHSD', 'Gene', (104, 112))	('CYP11B2-positive', 'Var', (26, 42))	('3betaHSD', 'Gene', (66, 74))	('3betaHSD', 'Gene', '3283', (66, 74))	('aldosterone', 'Chemical', 'MESH:D000450', (153, 164))	('high autonomous synthesis of aldosterone', 'MPA', (124, 164))
81130	27751767	recently showed that APCCs have higher CYP11B2 mRNA expression levels than the ZG, ZF, and ZR and that some APCCs carry APA-associated somatic mutations.	('higher', 'PosReg', (32, 38))	('APA', 'Gene', (120, 123))	('APA', 'Gene', '13809', (120, 123))	('CYP11B2 mRNA expression levels', 'MPA', (39, 69))	('mutations', 'Var', (143, 152))
81134	27751767	The mAPA-like portion consists of a heterogeneous mixture of CYP11B1-positive cells and CYP11B2-positive cells.	('CYP11B1-positive', 'Var', (61, 77))	('mAPA', 'Gene', (4, 8))	('mAPA', 'Gene', '13809', (4, 8))	('CYP11B2-positive', 'Var', (88, 104))	('heterogeneous mixture', 'MPA', (36, 57))
81135	27751767	We performed next generation sequencing (NGS) analyses using isolated DNA from pAATLs, detected APA-associated mutations in both portions, and concluded that the introduction of APA-associated mutations in the ion channel/pump genes may be involved in the development of mAPA from existing APCCs.	('mutations', 'Var', (111, 120))	('mAPA', 'Gene', (271, 275))	('APA', 'Gene', (178, 181))	('involved', 'Reg', (240, 248))	('rat', 'Species', '10116', (22, 25))	('APA', 'Gene', (96, 99))	('APA', 'Gene', (272, 275))	('mAPA', 'Gene', '13809', (271, 275))	('mutations', 'Var', (193, 202))	('APA', 'Gene', '13809', (178, 181))	('APA', 'Gene', '13809', (96, 99))	('APA', 'Gene', '13809', (272, 275))
81158	27751767	The expression patterns of these enzymes were consistent with normal steroidogenic pathways: i.e., CYP11B2-positive cells expressed 3betaHSD, but not CYP17, while CYP11B1-positive cells expressed 3betaHSD and CYP17 (Fig.	('CYP17', 'Gene', (209, 214))	('3betaHSD', 'Gene', (196, 204))	('3betaHSD', 'Gene', '3283', (196, 204))	('CYP17', 'Gene', '1586', (150, 155))	('CYP17', 'Gene', '1586', (209, 214))	('CYP11B2-positive', 'Var', (99, 115))	('3betaHSD', 'Gene', '3283', (132, 140))	('3betaHSD', 'Gene', (132, 140))	('CYP17', 'Gene', (150, 155))
81169	27751767	Immunohistochemistry revealed that the APAs strongly expressed CYP11B2 (#14 in Fig.	('APA', 'Gene', (39, 42))	('APA', 'Gene', '13809', (39, 42))	('CYP11B2', 'Var', (63, 70))
81170	27751767	This pAATL was distinct from those in Cases 1-2, because it consisted of a mixture of CYP11B2-positive cells and CYP11B1-positive cells similar to APAs, had a columnar arrangement similar to APCCs, but was not subcapsular as expected for APCCs.	('CYP11B2-positive', 'Var', (86, 102))	('columnar arrangement', 'Disease', (159, 179))	('APA', 'Gene', (147, 150))	('columnar arrangement', 'Disease', 'None', (159, 179))	('APA', 'Gene', '13809', (147, 150))	('CYP11B1-positive', 'Var', (113, 129))
81180	27751767	These lesions possessed the characteristics of APCCs in the following two points (see Section 3.2): (i) they were comprised of cells express strong, uniform immunoreactivity for CYP11B2 but not for CYP11B1/CYP17 (Fig.	('CYP17', 'Gene', (206, 211))	('CYP17', 'Gene', '1586', (206, 211))	('CYP11B2', 'Var', (178, 185))
81185	27751767	DNA and RNA were isolated from these tissues, and were used in quantitative real-time PCR analyses for CYP11B2 (CYP11B2-qPCR) and NGS for reported APA-associated mutations, as previously described (Table 2, detailed sequence data are shown in Supplemental Tables 1 and 2).	('APA', 'Gene', (147, 150))	('CYP11B2', 'Var', (103, 110))	('CYP11B2-qPCR', 'Gene', '1585', (112, 124))	('CYP11B2-qPCR', 'Gene', (112, 124))	('APA', 'Gene', '13809', (147, 150))
81188	27751767	Well documented KCNJ5 mutations were detected in the largest pAATL in Case 1 (pAATL #9, Fig.	('KCNJ5', 'Gene', (16, 21))	('detected', 'Reg', (37, 45))	('mutations', 'Var', (22, 31))	('KCNJ5', 'Gene', '3762', (16, 21))
81189	27751767	1B; DNA #82; p. Gly151Arg, Table 2) and in APAs in Case 3 (APA #1, DNA #14, Fig.	('APA #1', 'Gene', '57862', (59, 65))	('APA', 'Gene', '13809', (43, 46))	('APA', 'Gene', (59, 62))	('APA #1', 'Gene', (59, 65))	('Gly151Arg', 'SUBSTITUTION', 'None', (16, 25))	('APA', 'Gene', '13809', (59, 62))	('Gly151Arg', 'Var', (16, 25))	('APA', 'Gene', (43, 46))
81190	27751767	1A and B; APA #2, DNA #13, image is not shown; p.Leu168Arg, Table 2), suggesting that KCNJ5 mutations frequently occur in larger aldosterone-producing lesions.	('p.Leu168Arg', 'Mutation', 'rs386352318', (47, 58))	('larger aldosterone', 'Phenotype', 'HP:0000859', (122, 140))	('KCNJ5', 'Gene', (86, 91))	('APA', 'Gene', (10, 13))	('aldosterone', 'Chemical', 'MESH:D000450', (129, 140))	('mutations', 'Var', (92, 101))	('KCNJ5', 'Gene', '3762', (86, 91))	('APA', 'Gene', '13809', (10, 13))	('occur', 'Reg', (113, 118))
81191	27751767	The pAATL #13 in Case 3 also harbored mutations, although they were different from the KCNJ5 mutations detected in both APA #1 and #2.	('APA #1 and #2', 'Gene', '57862', (120, 133))	('mutations', 'Var', (38, 47))	('KCNJ5', 'Gene', (87, 92))	('KCNJ5', 'Gene', '3762', (87, 92))
81192	27751767	Immunohistochemistry for CYP11B2 and CYP11B1 is a powerful tool for identifying aldosterone-producing lesions.	('aldosterone', 'Chemical', 'MESH:D000450', (80, 91))	('CYP11B2', 'Var', (25, 32))	('aldosterone-producing lesions', 'Disease', (80, 109))	('CYP11B1', 'Var', (37, 44))
81194	27751767	It appears that, when pAATL-type 1 nodules grow larger than 3 mm, they often harbor a KCNJ5 mutation, which suggests that the KCNJ5 mutations might be a second hit mutation, rather than a causal mutation of pAATL.	('mutation', 'Var', (92, 100))	('KCNJ5', 'Gene', (86, 91))	('KCNJ5', 'Gene', '3762', (126, 131))	('mutations', 'Var', (132, 141))	('harbor', 'Reg', (77, 83))	('KCNJ5', 'Gene', '3762', (86, 91))	('rat', 'Species', '10116', (174, 177))	('KCNJ5', 'Gene', (126, 131))
81195	27751767	This is consistent with two important findings: 1) In depth re-sequencing of the adrenals found that adrenal hyperplasia causing unilateral aldosterone hypersecretion did not harbor the KCNJ5 mutations.	('unilateral aldosterone hypersecretion', 'MPA', (129, 166))	('aldosterone hypersecretion', 'Phenotype', 'HP:0000859', (140, 166))	('adrenal hyperplasia', 'Disease', (101, 120))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (101, 120))	('aldosterone', 'Chemical', 'MESH:D000450', (140, 151))	('KCNJ5', 'Gene', (186, 191))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (101, 120))	('KCNJ5', 'Gene', '3762', (186, 191))	('mutations', 'Var', (192, 201))
81196	27751767	2) KCNJ5 mutations did not increase cell proliferation in vitro.	('KCNJ5', 'Gene', (3, 8))	('mutations', 'Var', (9, 18))	('KCNJ5', 'Gene', '3762', (3, 8))	('rat', 'Species', '10116', (48, 51))
81221	28423559	Indeed, abnormal functioning of the Wnt/beta-catenin signal pathway may lead to adrenal tumourigenesis.	('Wnt', 'Chemical', '-', (36, 39))	('Wnt/beta-catenin signal pathway', 'Pathway', (36, 67))	('abnormal', 'Var', (8, 16))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('lead to', 'Reg', (72, 79))	('adrenal', 'Disease', (80, 87))
81226	28423559	To investigate the effects of rottlerin on ACC, we first evaluated whether or not rottlerin decreases viability in ACC cell lines.	('ACC', 'Phenotype', 'HP:0006744', (115, 118))	('rottlerin', 'Var', (82, 91))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('viability', 'MPA', (102, 111))	('rottlerin', 'Chemical', 'MESH:C085746', (82, 91))	('decreases', 'NegReg', (92, 101))	('rottlerin', 'Chemical', 'MESH:C085746', (30, 39))
81244	28423559	The percentage of cells in the G1 phase was 85.14% in NCI-H295R cells and 81.88% in SW-13 cells, which was significantly increased compared with the control group (Figure 1D, *p < 0.05).	('NCI-H295R', 'CellLine', 'CVCL:0458', (54, 63))	('increased', 'PosReg', (121, 130))	('NCI-H295R', 'Var', (54, 63))	('cells in the G1 phase', 'CPA', (18, 39))	('SW-13', 'CellLine', 'CVCL:0542', (84, 89))
81255	28423559	As shown in Figure 5, tumors were smaller in the experimental groups than the control and DSMO groups, and tumors were smaller in the rottlerin 4 mg/kg group than the rottlerin 2 mg/kg group.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('smaller', 'NegReg', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (107, 113))	('4 mg/kg', 'Var', (144, 151))	('smaller', 'NegReg', (34, 41))	('rottlerin', 'Gene', (134, 143))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('rottlerin', 'Chemical', 'MESH:C085746', (167, 176))	('rottlerin', 'Chemical', 'MESH:C085746', (134, 143))	('tumors', 'Disease', (22, 28))
81261	28423559	Furthermore, we performed H&E (Figure 4D) and immunohistochemistry staining in xenograft tissues, and the results showed that rottlerin also down-regulated the expression of beta-catenin, LRP6, and p-LRP compared with the control and DMSO-treated groups in vivo (Figure 5, *p < 0.05).	('LRP', 'Gene', (188, 191))	('rottlerin', 'Chemical', 'MESH:C085746', (126, 135))	('also', 'NegReg', (136, 140))	('that', 'Var', (121, 125))	('and', 'Protein', (194, 197))	('LRP', 'Gene', '4035', (200, 203))	('DMSO', 'Chemical', 'MESH:D004121', (234, 238))	('LRP', 'Gene', '4035', (188, 191))	('LRP6', 'Gene', (188, 192))	('LRP6', 'Gene', '4040', (188, 192))	('the', 'MPA', (156, 159))	('LRP', 'Gene', (200, 203))
81262	28423559	Moreover, in the higher dose-treated group (rottlerin 4 mg/kg), the expression of beta-catenin, LRP6, and p-LRP was lower than the lower dose-treated group (rottlerin 2 mg/kg).	('lower', 'NegReg', (116, 121))	('LRP6', 'Gene', '4040', (96, 100))	('LRP', 'Gene', '4035', (108, 111))	('LRP6', 'Gene', (96, 100))	('expression', 'MPA', (68, 78))	('LRP', 'Gene', (96, 99))	('LRP', 'Gene', (108, 111))	('beta-catenin', 'Protein', (82, 94))	('rottlerin 4 mg/kg', 'Var', (44, 61))	('LRP', 'Gene', '4035', (96, 99))	('rottlerin', 'Chemical', 'MESH:C085746', (157, 166))	('rottlerin', 'Chemical', 'MESH:C085746', (44, 53))
81270	28423559	Activation of the Wnt/beta-catenin pathway occurs in ACC and is frequently caused by activating mutations of the gene encoding Wnt/beta-catenin.	('Wnt/beta-catenin', 'Gene', (127, 143))	('ACC', 'Phenotype', 'HP:0006744', (53, 56))	('ACC', 'Disease', (53, 56))	('Wnt', 'Chemical', '-', (127, 130))	('Activation', 'PosReg', (0, 10))	('caused', 'Reg', (75, 81))	('Wnt', 'Chemical', '-', (18, 21))	('Wnt/beta-catenin pathway', 'Pathway', (18, 42))	('mutations', 'Var', (96, 105))
81283	28423559	Mutations in beta-catenin have been associated with a poor prognosis in patients with ACC, and higher-grade ACC is associated with higher beta-catenin expression.	('ACC', 'Phenotype', 'HP:0006744', (108, 111))	('patients', 'Species', '9606', (72, 80))	('Mutations', 'Var', (0, 9))	('beta-catenin', 'Protein', (13, 25))	('ACC', 'Phenotype', 'HP:0006744', (86, 89))	('associated', 'Reg', (36, 46))	('ACC', 'Disease', (86, 89))	('higher', 'PosReg', (131, 137))	('beta-catenin expression', 'MPA', (138, 161))
81286	28423559	LRP6 is expressed in human cancer cell lines and up-regulated in human malignant tissues, and LRP6 silencing weakens Wnt/beta-catenin signaling and inhibits cell proliferation and tumor growth in breast and prostate cancers.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('human', 'Species', '9606', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('weakens', 'NegReg', (109, 116))	('cancer', 'Disease', (216, 222))	('LRP6', 'Gene', (0, 4))	('LRP6', 'Gene', '4040', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('inhibits', 'NegReg', (148, 156))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('prostate cancers', 'Phenotype', 'HP:0012125', (207, 223))	('Wnt', 'Chemical', '-', (117, 120))	('LRP6', 'Gene', '4040', (94, 98))	('breast and prostate cancers', 'Disease', 'MESH:D011471', (196, 223))	('LRP6', 'Gene', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('silencing', 'Var', (99, 108))	('Wnt/beta-catenin signaling', 'MPA', (117, 143))	('human', 'Species', '9606', (21, 26))	('tumor', 'Disease', (180, 185))	('cancer', 'Disease', (27, 33))
81363	27391065	The drug's therapeutic range is reached in less than 50% of treated patients; moreover, specific polymorphisms of the CYP2B6 gene have been associated with reduced circulating levels of mitotane, further decreasing its efficacy.	('CYP2B6', 'Gene', (118, 124))	('CYP2B6', 'Gene', '1555', (118, 124))	('reduced', 'NegReg', (156, 163))	('patients', 'Species', '9606', (68, 76))	('decreasing', 'NegReg', (204, 214))	('efficacy', 'MPA', (219, 227))	('polymorphisms', 'Var', (97, 110))	('mitotane', 'Chemical', 'MESH:D008939', (186, 194))	('circulating levels of mitotane', 'MPA', (164, 194))
81368	27391065	Epidemiological studies and meta-analyses on large cohorts of diabetic patients have demonstrated a significant association between metformin and a reduced incidence of various types of solid tumors, supporting the potential use of metformin as an anti-cancer drug.	('metformin', 'Chemical', 'MESH:D008687', (132, 141))	('solid tumors', 'Disease', 'MESH:D009369', (186, 198))	('patients', 'Species', '9606', (71, 79))	('reduced', 'NegReg', (148, 155))	('metformin', 'Chemical', 'MESH:D008687', (232, 241))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('diabetic', 'Disease', 'MESH:D003920', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', (253, 259))	('diabetic', 'Disease', (62, 70))	('solid tumors', 'Disease', (186, 198))	('metformin', 'Var', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
81379	27391065	Since in non-tumor cells metformin acts as a hypoglycemic drug by facilitating glucose uptake and its utilization, we next evaluated these properties in the H295R cell line and found that metformin dose-dependently stimulated a significant increase in cell basal glucose uptake (Table 1).	('tumor', 'Disease', (13, 18))	('utilization', 'MPA', (102, 113))	('glucose uptake', 'CPA', (79, 93))	('metformin', 'Var', (188, 197))	('glucose', 'Chemical', 'MESH:D005947', (79, 86))	('glucose', 'Chemical', 'MESH:D005947', (263, 270))	('metformin', 'Chemical', 'MESH:D008687', (188, 197))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('facilitating', 'PosReg', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))	('cell basal glucose uptake', 'CPA', (252, 277))	('increase', 'PosReg', (240, 248))
81382	27391065	Western blot analysis of cell lysates showed a significant dose-related AMPK phosphorylation stimulation, confirming that this intracellular pathway downstream from metformin action is also activated in H295R (Figure 3A, 3B).	('activated', 'PosReg', (190, 199))	('AMPK', 'Gene', (72, 76))	('AMPK', 'Gene', '5563', (72, 76))	('metformin', 'Chemical', 'MESH:D008687', (165, 174))	('H295R', 'Var', (203, 208))
81385	27391065	Signaling pathways downstream from IGF-1R have been shown to converge in mTOR activation to sustain cell proliferation in both H295R and ACC.	('mTOR', 'MPA', (73, 77))	('cell proliferation', 'CPA', (100, 118))	('H295R', 'Var', (127, 132))	('IGF-1R', 'Gene', '3480', (35, 41))	('IGF-1R', 'Gene', (35, 41))
81386	27391065	A 24 hour metformin treatment induced a dose-dependent inhibition of mTOR activating phosphorylation in the Ser2448 residues (Figure 3E, 3F), as well as a significantly lower IGF-1R net expression (Figure 3G, 3H).	('mTOR activating phosphorylation', 'MPA', (69, 100))	('IGF-1R', 'Gene', '3480', (175, 181))	('Ser2448', 'Chemical', '-', (108, 115))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))	('Ser2448', 'Var', (108, 115))	('IGF-1R', 'Gene', (175, 181))	('lower IGF', 'Phenotype', 'HP:0002850', (169, 178))	('lower', 'NegReg', (169, 174))	('inhibition', 'NegReg', (55, 65))	('3H', 'Chemical', 'MESH:D014316', (209, 211))
81393	27391065	Metformin administration was associated with a statistically significant reduced increase in tumor volume after 27 days compared with controls, (Figure 5A).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('reduced', 'NegReg', (73, 80))	('tumor', 'Disease', (93, 98))	('Metformin', 'Var', (0, 9))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('increase', 'PosReg', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
81405	27391065	Our findings demonstrate that metformin inhibits proliferation in the adrenocortical cancer cell model H295R in association with a decreased expression of the IGF2/IGF-1R system.	('adrenocortical cancer', 'Disease', (70, 91))	('IGF2', 'Gene', '3481', (159, 163))	('metformin', 'Var', (30, 39))	('IGF2', 'Gene', (159, 163))	('proliferation', 'CPA', (49, 62))	('decreased', 'NegReg', (131, 140))	('metformin', 'Chemical', 'MESH:D008687', (30, 39))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (70, 91))	('inhibits', 'NegReg', (40, 48))	('expression', 'MPA', (141, 151))	('IGF-1R', 'Gene', '3480', (164, 170))	('IGF-1R', 'Gene', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
81407	27391065	In H295R, metformin induces a decrease in IGF2 and IGF-1R expression.	('IGF2', 'Gene', (42, 46))	('IGF-1R', 'Gene', (51, 57))	('expression', 'MPA', (58, 68))	('decrease', 'NegReg', (30, 38))	('H295R', 'Var', (3, 8))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))	('IGF2', 'Gene', '3481', (42, 46))	('IGF-1R', 'Gene', '3480', (51, 57))
81421	27391065	Inhibition of OXOPHOS leads to a reduction in the ATP/ADP ratio, thus activating the intracellular key energy sensor AMPK.	('OXOPHOS', 'Chemical', '-', (14, 21))	('reduction', 'NegReg', (33, 42))	('OXOPHOS', 'Enzyme', (14, 21))	('activating', 'PosReg', (70, 80))	('ATP/ADP ratio', 'MPA', (50, 63))	('ADP', 'Chemical', 'MESH:D000244', (54, 57))	('AMPK', 'Gene', '5563', (117, 121))	('Inhibition', 'Var', (0, 10))	('AMPK', 'Gene', (117, 121))	('ATP', 'Chemical', 'MESH:D000255', (50, 53))
81425	27391065	Similarly, in H295R metformin-induced ERK inhibition and AMPK activation may converge in mTOR blockage.	('AMPK', 'Gene', '5563', (57, 61))	('AMPK', 'Gene', (57, 61))	('H295R', 'Var', (14, 19))	('metformin', 'Chemical', 'MESH:D008687', (20, 29))	('mTOR blockage', 'Disease', (89, 102))	('ERK', 'Gene', '5594', (38, 41))	('ERK', 'Gene', (38, 41))
81428	27391065	Metformin also induces a significant reduction in the expression of heat shock proteins (HSPs) involved in tumorigenesis.	('expression', 'MPA', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('shock', 'Phenotype', 'HP:0031273', (73, 78))	('reduction', 'NegReg', (37, 46))	('heat shock proteins', 'Disease', 'MESH:D012769', (68, 87))	('Metformin', 'Var', (0, 9))	('heat shock proteins', 'Disease', (68, 87))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('HSPs', 'Gene', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
81446	27391065	Primary antibodies directed against phospho-Thr172-AMPKalpha1/2 (sc-33524), Actin (sc-1615), IGF-1Rbeta (sc-713) were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA); anti-AMPK-alpha, anti-phospho-p44/42 ERK1/2 (Thr202/Tyr204), anti-p44/42 ERK1/2, anti-Bcl-xl and anti-mTOR antibodies were from Cell Signaling Technology, Inc. (Danvers, Mass, USA); anti-phospho-Ser2448-mTOR (09-213), and anti-Caspase 3 (AB1899) antibodies were from Merck-Millipore (Darmstadt, Germany).	('p44', 'Gene', (243, 246))	('Thr172', 'Chemical', '-', (44, 50))	('AMPK', 'Gene', (51, 55))	('Ser2448', 'Chemical', '-', (372, 379))	('p44', 'Gene', '2966', (243, 246))	('AMPKalpha1/2', 'Gene', '5562;5563', (51, 63))	('p44', 'Gene', (207, 210))	('Caspase 3', 'Gene', '836', (404, 413))	('AMPK', 'Gene', '5563', (182, 186))	('anti-phospho-Ser2448-mTOR', 'Var', (359, 384))	('Bcl-xl', 'Gene', '598', (263, 269))	('IGF-1R', 'Gene', '3480', (93, 99))	('AMPKalpha1/2', 'Gene', (51, 63))	('IGF-1R', 'Gene', (93, 99))	('Bcl-xl', 'Gene', (263, 269))	('p44', 'Gene', '2966', (207, 210))	('AMPK', 'Gene', '5563', (51, 55))	('AMPK', 'Gene', (182, 186))	('Caspase 3', 'Gene', (404, 413))
81464	27391065	Almost all H295R injected mice developed a detectable tumor except one (84% overall tumor take rate), confirming the aggressiveness of ACC derived cells.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('aggressiveness', 'Disease', 'MESH:D001523', (117, 131))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('aggressiveness', 'Disease', (117, 131))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('H295R', 'Var', (11, 16))	('tumor', 'Disease', (54, 59))	('aggressiveness', 'Phenotype', 'HP:0000718', (117, 131))	('mice', 'Species', '10090', (26, 30))
81492	27150059	High levels of NUCB-2 mRNA and protein is associated with shorter biochemical recurrence-free survival time in prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('shorter', 'NegReg', (58, 65))	('prostate cancer', 'Disease', (111, 126))	('mRNA and', 'MPA', (22, 30))	('High levels', 'Var', (0, 11))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('NUCB-2', 'Gene', (15, 21))	('biochemical recurrence-free survival time', 'CPA', (66, 107))
81495	27150059	Furthermore, high NUCB-2 expression is associated with metastasis and shorter overall survival in clear cell renal cell carcinoma tissue.	('metastasis', 'CPA', (55, 65))	('high', 'Var', (13, 17))	('shorter', 'NegReg', (70, 77))	('expression', 'MPA', (25, 35))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (109, 129))	('NUCB-2', 'Gene', (18, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (98, 129))	('clear cell renal cell carcinoma', 'Disease', (98, 129))	('overall', 'MPA', (78, 85))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (98, 129))
81509	27150059	SW480 and SW620 are colon cancer cell lines which are derived from the primary colon cancer (SW480) and lymph node metastasis (SW620) of the same patient.	('colon cancer', 'Disease', (79, 91))	('SW480', 'Var', (93, 98))	('SW480', 'CellLine', 'CVCL:0546', (0, 5))	('colon cancer', 'Phenotype', 'HP:0003003', (20, 32))	('colon cancer', 'Disease', 'MESH:D015179', (20, 32))	('SW480', 'CellLine', 'CVCL:0546', (93, 98))	('SW620', 'CellLine', 'CVCL:0547', (10, 15))	('SW620', 'CellLine', 'CVCL:0547', (127, 132))	('lymph node metastasis', 'Disease', 'MESH:D009362', (104, 125))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('lymph node metastasis', 'Disease', (104, 125))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('colon cancer', 'Disease', (20, 32))	('patient', 'Species', '9606', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
81510	27150059	SW620 showed higher NUCB-2 expression than SW480 (Figure 2A).	('SW480', 'CellLine', 'CVCL:0546', (43, 48))	('SW620', 'Var', (0, 5))	('SW620', 'CellLine', 'CVCL:0547', (0, 5))	('higher', 'PosReg', (13, 19))	('expression', 'MPA', (27, 37))	('NUCB-2', 'Gene', (20, 26))
81513	27150059	The proliferation assay indicated NUCB-2 knockdown did not suppress or enhance proliferation rate in SW620 after 24 hours of incubation (Figure 3B).	('proliferation rate', 'CPA', (79, 97))	('SW620', 'CellLine', 'CVCL:0547', (101, 106))	('rat', 'Species', '10116', (93, 96))	('rat', 'Species', '10116', (11, 14))	('enhance', 'PosReg', (71, 78))	('knockdown', 'Var', (41, 50))	('rat', 'Species', '10116', (86, 89))	('NUCB-2', 'Gene', (34, 40))
81517	27150059	To further determine the regulatory mechanism, we performed microarray assay for analyzing gene expression pattern of nesfatin-1/NUCB-2 knockdowned SW620 and control SW620.	('SW620', 'CellLine', 'CVCL:0547', (148, 153))	('knockdowned', 'Var', (136, 147))	('SW620', 'CellLine', 'CVCL:0547', (166, 171))	('nesfatin-1/NUCB-2', 'Gene', (118, 135))
81523	27150059	The level of both molecules in NUCB-2 knockdowned SW620 was significantly lower than that in SW620, which was transfected with control vector (Figure 4D).	('NUCB-2', 'Gene', (31, 37))	('SW620', 'CellLine', 'CVCL:0547', (50, 55))	('level', 'MPA', (4, 9))	('SW620', 'Var', (50, 55))	('SW620', 'CellLine', 'CVCL:0547', (93, 98))	('lower', 'NegReg', (74, 79))	('knockdowned SW620', 'Var', (38, 55))
81524	27150059	The level of epithelial phenotype-related markers, including E-cadherin, beta-catenin and Claudin-3, increased in NUCB-2 knockdowned stable clones (Figure 4E).	('beta-catenin', 'Gene', (73, 85))	('level', 'MPA', (4, 9))	('increased', 'PosReg', (101, 110))	('E-cadherin', 'Gene', (61, 71))	('knockdowned', 'Var', (121, 132))	('E-cadherin', 'Gene', '999', (61, 71))	('beta-catenin', 'Gene', '1499', (73, 85))	('NUCB-2', 'Gene', (114, 120))	('Claudin-3', 'Gene', '1365', (90, 99))	('Claudin-3', 'Gene', (90, 99))
81536	27150059	The migration and invasion ability of NUCB-2 knockdowned clones was significantly enhanced after treatment of AMPK inhibitor (Figure 6C and 6D).	('enhanced', 'PosReg', (82, 90))	('NUCB-2', 'Gene', (38, 44))	('knockdowned', 'Var', (45, 56))	('invasion ability', 'CPA', (18, 34))	('rat', 'Species', '10116', (7, 10))
81541	27150059	To determine the role of NUCB-2 in vivo, CT-26, which is a murine colon cancer cell line, was transfected with NUCB-2 targeting shRNA or control shRNA.	('colon cancer', 'Disease', (66, 78))	('NUCB-2', 'Gene', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CT-26', 'CellLine', 'CVCL:7254', (41, 46))	('colon cancer', 'Phenotype', 'HP:0003003', (66, 78))	('colon cancer', 'Disease', 'MESH:D015179', (66, 78))	('murine', 'Species', '10090', (59, 65))	('targeting', 'Var', (118, 127))
81558	27150059	In addition, ZEB1 overexpression enhanced the migration and invasion ability in NUCB-2 knockdowned stable clones.	('invasion ability', 'CPA', (60, 76))	('migration', 'CPA', (46, 55))	('NUCB-2', 'Gene', (80, 86))	('ZEB1', 'Gene', '6935', (13, 17))	('overexpression', 'Var', (18, 32))	('ZEB1', 'Gene', (13, 17))	('rat', 'Species', '10116', (49, 52))	('enhanced', 'PosReg', (33, 41))
81602	27150059	The RNA from NUCB-2 knockdowned SW620 cells and vector control SW620 were collected and performed microarray assay.	('SW620', 'CellLine', 'CVCL:0547', (63, 68))	('SW620', 'CellLine', 'CVCL:0547', (32, 37))	('knockdowned', 'Var', (20, 31))	('NUCB-2', 'Gene', (13, 19))
81607	27150059	For scratch wound-healing assay, 5 x 104 SW620 and NUCB-2 knockdowned SW620 cells were seeded into 96 well plate.	('rat', 'Species', '10116', (6, 9))	('knockdowned', 'Var', (58, 69))	('NUCB-2', 'Gene', (51, 57))	('SW620', 'CellLine', 'CVCL:0547', (70, 75))	('SW620', 'CellLine', 'CVCL:0547', (41, 46))
81622	26400872	Copy number variations alter methylation and parallel IGF2 overexpression in adrenal tumors Overexpression of insulin growth factor 2 (IGF2) is a hallmark of adrenocortical carcinomas and pheochromocytomas.	('adrenal tumor', 'Phenotype', 'HP:0100631', (77, 90))	('methylation', 'MPA', (29, 40))	('pheochromocytomas', 'Disease', (188, 205))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('pheochromocytomas', 'Disease', 'MESH:D010673', (188, 205))	('adrenal tumors', 'Disease', 'MESH:D000310', (77, 91))	('IGF2', 'Gene', '3481', (54, 58))	('IGF2', 'Gene', '3481', (135, 139))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (158, 183))	('overexpression', 'PosReg', (59, 73))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('alter', 'Reg', (23, 28))	('Copy number variations', 'Var', (0, 22))	('adrenal tumors', 'Disease', (77, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('hallmark of adrenocortical carcinomas', 'Disease', 'MESH:D018268', (146, 183))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (188, 205))	('Overexpression', 'PosReg', (92, 106))	('hallmark of adrenocortical carcinomas', 'Disease', (146, 183))	('IGF2', 'Gene', (135, 139))	('IGF2', 'Gene', (54, 58))
81628	26400872	These copy number changes correlated with hypermethylation of the H19 ICR suggesting that the lost alleles were the unmethylated maternal alleles.	('changes', 'Var', (18, 25))	('hypermethylation', 'Var', (42, 58))	('H19 ICR', 'Gene', '105259599', (66, 73))	('correlated', 'Reg', (26, 36))	('H19 ICR', 'Gene', (66, 73))
81636	26400872	Recently, integrated large-scale analyses have identified alterations in driver genes including CTNNB1, TP53, CDKN2A, RB1, ZNRF3, and MEN1.	('MEN1', 'Gene', (134, 138))	('CDKN2A', 'Gene', (110, 116))	('CTNNB1', 'Gene', '1499', (96, 102))	('TP53', 'Gene', '7157', (104, 108))	('MEN1', 'Gene', '4221', (134, 138))	('TP53', 'Gene', (104, 108))	('CDKN2A', 'Gene', '1029', (110, 116))	('RB1', 'Gene', (118, 121))	('ZNRF3', 'Gene', '84133', (123, 128))	('CTNNB1', 'Gene', (96, 102))	('ZNRF3', 'Gene', (123, 128))	('RB1', 'Gene', '5925', (118, 121))	('alterations', 'Var', (58, 69))
81645	26400872	IGF2 DMR0 and IGF2 DMR2 are located between exons 2 and 3 and exons 8 and 9 respectively, while the H19 DMR is located 4 kb upstream of the H19 transcription start site.	('H19', 'Gene', '283120', (100, 103))	('H19', 'Gene', (140, 143))	('H19', 'Gene', (100, 103))	('DMR0', 'Var', (5, 9))	('DMR2', 'Var', (19, 23))	('H19', 'Gene', '283120', (140, 143))
81646	26400872	The H19 DMR represents the imprinting control region (ICR) of the IGF2/H19 locus and harbors seven binding sites for the methylation-sensitive insulator CTCF, a multifunctional protein involved in nuclear organization, which brings downstream enhancers into physical proximity to either the IGF2 or the H19 promoter through parent-of-origin dependent methylation patterns of the H19 ICR.	('enhancers', 'PosReg', (243, 252))	('H19', 'Gene', (4, 7))	('H19', 'Gene', '283120', (303, 306))	('H19', 'Gene', '283120', (379, 382))	('H19', 'Gene', (303, 306))	('H19', 'Gene', (379, 382))	('CTCF', 'Gene', (153, 157))	('methylation', 'Var', (351, 362))	('H19', 'Gene', '283120', (71, 74))	('H19', 'Gene', (71, 74))	('CTCF', 'Gene', '10664', (153, 157))	('H19', 'Gene', '283120', (4, 7))	('H19 ICR', 'Gene', '105259599', (379, 386))	('H19 ICR', 'Gene', (379, 386))
81648	26400872	DNA hypermethylation of the H19 promoter region has previously been associated with IGF2 overexpression in ACCs as well as somatic copy number changes, where loss of the maternal allele was accompanied by a duplication of the paternal allele.	('H19', 'Gene', '283120', (28, 31))	('associated', 'Reg', (68, 78))	('H19', 'Gene', (28, 31))	('overexpression', 'PosReg', (89, 103))	('IGF2', 'Gene', (84, 88))	('changes', 'Var', (143, 150))
81673	26400872	Copy number changes were verified by genotyping rs680, which is located in IGF2 (chr11:2,153,634) for paired tumor and blood samples heterozygous for rs680.	('rs680', 'Mutation', 'rs680', (150, 155))	('rs680', 'Var', (150, 155))	('rs680', 'Mutation', 'rs680', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('rs680', 'Var', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('IGF2', 'Gene', (75, 79))	('tumor', 'Disease', (109, 114))
81695	26400872	Genome-wide SNP analysis was used to establish the chromosomal status of chr11:1 986 296-2 223 233 harboring the IGF2/H19 locus as this technology allows the detection of copy number changes as well as copy number neutral events.	('H19', 'Gene', (118, 121))	('copy number changes', 'Var', (171, 190))	('H19', 'Gene', '283120', (118, 121))
81696	26400872	The chromosomal and allelic status was established using the BAF and Log R ratios, estimated by ASCAT, allowing discrimination between different forms of events: polyploidy, allelic loss and gain, and uniparental disomy (UPD).	('BAF', 'Gene', (61, 64))	('polyploidy', 'Var', (162, 172))	('BAF', 'Gene', '8815', (61, 64))	('allelic loss and gain', 'Disease', 'MESH:D015430', (174, 195))	('uniparental disomy', 'Disease', (201, 219))	('uniparental disomy', 'Disease', 'MESH:D024182', (201, 219))
81718	26400872	28/38 adrenal tumors with LOH of the IGF2/H19 locus had lost the maternal allele and gained an extra copy of the paternal allele.	('H19', 'Gene', '283120', (42, 45))	('H19', 'Gene', (42, 45))	('adrenal tumors', 'Disease', 'MESH:D000310', (6, 20))	('adrenal tumors', 'Disease', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('adrenal tumor', 'Phenotype', 'HP:0100631', (6, 19))	('lost', 'NegReg', (56, 60))	('gained', 'PosReg', (85, 91))	('maternal allele', 'MPA', (65, 80))	('LOH', 'Var', (26, 29))
81719	26400872	In our cohort 15 out of 19 ACC samples analyzed had somatic copy number alterations at the IGF2/H19 locus, with 6/15 samples having an extra copy of a single allele (Fig.	('copy number alterations', 'Var', (60, 83))	('H19', 'Gene', (96, 99))	('H19', 'Gene', '283120', (96, 99))
81720	26400872	As all six samples with UPD or an UPD-like genotype displayed hypermethylation of the H19 ICR, we can assume that the unmethylated maternal allele is lost and accompanied by a duplication of the normally methylated paternal allele.	('H19 ICR', 'Gene', '105259599', (86, 93))	('hypermethylation', 'MPA', (62, 78))	('duplication', 'Var', (176, 187))	('H19 ICR', 'Gene', (86, 93))
81730	26400872	In conclusion, our data suggest that IGF2 overexpression in adrenal tumors correlates mainly with allelic loss leading to an imbalance of the ratio between paternal and maternal alleles and that the aberrant DNA methylation levels observed for the H19 ICR are a consequence thereof.	('imbalance of the ratio between paternal and', 'MPA', (125, 168))	('adrenal tumor', 'Phenotype', 'HP:0100631', (60, 73))	('adrenal tumors', 'Disease', 'MESH:D000310', (60, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('imbalance', 'Phenotype', 'HP:0002172', (125, 134))	('allelic', 'Var', (98, 105))	('DNA methylation levels', 'MPA', (208, 230))	('IGF2', 'Gene', (37, 41))	('adrenal tumors', 'Disease', (60, 74))	('overexpression', 'PosReg', (42, 56))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('loss', 'NegReg', (106, 110))	('H19 ICR', 'Gene', '105259599', (248, 255))	('H19 ICR', 'Gene', (248, 255))
81776	26421305	The 5.0-kb upstream sequences of human Liver Receptor Homolog-1 (NR5A2, transcript ENST00000367362, Ensembl release 64, GRCh37), human Small Heterodimer Partner (NR0B2-001 ENST00000254227, Ensembl release 64, GRCh37), and androgen receptor (AR, transcript ENST00000374690, Ensembl release 64, GRCh37) were analyzed for putative E-box binding sites using MatInspector.	('ENST00000367362', 'Var', (83, 98))	('Small Heterodimer Partner', 'Gene', '8431', (135, 160))	('NR5A2', 'Gene', '2494', (65, 70))	('androgen receptor', 'Gene', (222, 239))	('human', 'Species', '9606', (33, 38))	('NR0B2', 'Gene', (162, 167))	('Small Heterodimer Partner', 'Gene', (135, 160))	('human', 'Species', '9606', (129, 134))	('NR5A2', 'Gene', (65, 70))	('ENST00000374690', 'Var', (256, 271))	('androgen receptor', 'Gene', '367', (222, 239))	('NR0B2', 'Gene', '8431', (162, 167))	('AR', 'Gene', '367', (241, 243))
81787	26421305	SHP mRNA levels of H295R and HepG2 cell lines were reduced by 3.7 +- 0.08-fold (p = 0.0013; Figure 2(b)) and 2.3 +- 0.04 (p = 0.0002; Figure 2(c)), respectively, compared to cells transfected with the empty vector.	('H295R', 'Var', (19, 24))	('SHP mRNA levels', 'MPA', (0, 15))	('HepG2', 'CellLine', 'CVCL:0027', (29, 34))	('reduced', 'NegReg', (51, 58))
81794	26421305	ChIP-PCR assays using specifically designed primers showed that Myc immunoprecipitated DNA from HepG2-pCMVMycPod-1 cells amplified both "E-box-177" and "E-box-3702" sequences.	('E-box-3702', 'Var', (153, 163))	('Myc', 'Gene', '4609', (64, 67))	('Myc', 'Gene', (64, 67))	('Myc', 'Gene', '4609', (106, 109))	('Myc', 'Gene', (106, 109))	('HepG2', 'CellLine', 'CVCL:0027', (96, 101))
81795	26421305	Nevertheless, as shown in Figure 3, MYC-IP DNA from HepG2 transfected cells did not amplify "E-box-53" and "E-box-1300" LRH-1 sequences, as well as the ChIP negative control sequence (intron 2-3).	('E-box-1300', 'Var', (108, 118))	('MYC', 'Gene', '4609', (36, 39))	('LRH-1', 'Gene', '2494', (120, 125))	('LRH-1', 'Gene', (120, 125))	('amplify', 'MPA', (84, 91))	('MYC', 'Gene', (36, 39))	('HepG2', 'CellLine', 'CVCL:0027', (52, 57))
81800	26421305	POD-1 overexpression also significantly increased Cyclin E1 protein levels in the HepG2 cell line relative to controls transfected with pCMVMyc (1.94 +- 0.09 fold, p = 0.0016).	('Myc', 'Gene', '4609', (140, 143))	('Cyclin E1', 'Gene', (50, 59))	('overexpression', 'Var', (6, 20))	('Myc', 'Gene', (140, 143))	('HepG2', 'CellLine', 'CVCL:0027', (82, 87))	('increased', 'PosReg', (40, 49))	('Cyclin E1', 'Gene', '898', (50, 59))	('POD-1', 'Gene', (0, 5))
81814	26421305	In vivo and in vitro approaches have shown that LRH-1 overexpression promoted pancreatic cancer cell growth, proliferation, and angiogenesis by regulating Cyclins E1 and D1.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('pancreatic cancer', 'Disease', (78, 95))	('regulating', 'Reg', (144, 154))	('LRH-1', 'Gene', (48, 53))	('Cyclin', 'Gene', '5111', (155, 161))	('LRH-1', 'Gene', '2494', (48, 53))	('promoted', 'PosReg', (69, 77))	('overexpression', 'Var', (54, 68))	('proliferation', 'CPA', (109, 122))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('angiogenesis', 'CPA', (128, 140))	('Cyclin', 'Gene', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
81860	25144458	Two predesigned Taqman Gene Expression assays for CYP2W1 (Hs00908623_m1, Exon boundary 7-9, and Hs00214994_m1, Exon boundary 2-3) were purchased from Applied Biosystems (Darmstadt, Germany).	('Hs00214994_m1', 'Var', (96, 109))	('CYP2W1', 'Gene', '54905', (50, 56))	('Hs00908623_m1', 'Var', (58, 71))	('CYP2W1', 'Gene', (50, 56))
70211	25144458	Endogenously expressed beta-actin (Hs9999903_m1) was used for normalization.	('beta-actin', 'Gene', (23, 33))	('Hs9999903_m1', 'Var', (35, 47))	('beta-actin', 'Gene', '728378', (23, 33))
81899	25144458	Considering only ACC samples obtained from primary surgery (n = 196), CYP2W1 immunoreactivity was significantly lower in tumors with a high Ki67 proliferation index (Ki67>10%, n = 59) than in those with low Ki67 (n = 56, P<0.005) and in those with a high Weiss score (Weiss score >6, n = 113) compared to those with low Weiss score (n = 58, P<0.005,   Figure 3C and 3D  and  Table 1 ).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('high Ki67', 'Var', (135, 144))	('Ki67', 'Var', (140, 144))	('CYP2W1', 'Gene', '54905', (70, 76))	('CYP2W1', 'Gene', (70, 76))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('lower', 'NegReg', (112, 117))
81930	25144458	This approach has recently been studied both in vitro and in vivo demonstrating that the duocarmycin analog ICT2706 is converted by tumor cells into a potent cytotoxin inhibiting the growth of human colon cancer xenografts.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('inhibiting', 'NegReg', (168, 178))	('ICT2706', 'Var', (108, 115))	('colon cancer', 'Phenotype', 'HP:0003003', (199, 211))	('colon cancer', 'Disease', 'MESH:D015179', (199, 211))	('duocarmycin', 'Chemical', '-', (89, 100))	('tumor', 'Disease', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('colon cancer', 'Disease', (199, 211))	('human', 'Species', '9606', (193, 198))
82033	19026713	In the current study using H295 cells after stimulation of the cAMP/PKA pathway with VIP we found that the principal aromatase promoters utilized were promoters PII and I.3.	('VIP', 'Gene', (85, 88))	('H295', 'CellLine', 'CVCL:0456', (27, 31))	('PII', 'Var', (161, 164))	('cAMP', 'Chemical', '-', (63, 67))	('VIP', 'Gene', '7432', (85, 88))
82057	33498467	The anti-neoplastic activity of immune checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated-antigen 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-ligand-1 (PD-L1) antibodies in different solid tumors has aroused interest to explore the potential therapeutic effect in ACC as well.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('CTLA-4', 'Gene', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('anti-PD-ligand-1', 'Var', (174, 190))	('ACC', 'Phenotype', 'HP:0006744', (304, 307))	('PD-L1', 'Gene', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('CTLA-4', 'Gene', '1493', (124, 130))	('tumors', 'Disease', (229, 235))	('anti-neoplastic activity', 'CPA', (4, 28))
82060	33498467	Therefore, attempts are made to combine therapy: anti-PD-1 antibody and anti-CTLA-4 antibody, anti-PD-1 antibody and antagonist of the glucocorticoid receptor.	('glucocorticoid receptor', 'Gene', (135, 158))	('CTLA-4', 'Gene', '1493', (77, 83))	('anti-PD-1', 'Var', (49, 58))	('CTLA-4', 'Gene', (77, 83))	('glucocorticoid receptor', 'Gene', '2908', (135, 158))
82090	33498467	Excess estrogen can cause gynecomastia and other feminization symptoms in men, such as a change in the distribution of body fat, and heavy menstrual bleeding in women.	('estrogen', 'Protein', (7, 15))	('gynecomastia', 'Phenotype', 'HP:0000771', (26, 38))	('menstrual bleeding', 'Phenotype', 'HP:0100608', (139, 157))	('change', 'Reg', (89, 95))	('gynecomastia', 'Disease', (26, 38))	('cause', 'Reg', (20, 25))	('men', 'Species', '9606', (163, 166))	('menstrual bleeding', 'Disease', 'MESH:D008595', (139, 157))	('women', 'Species', '9606', (161, 166))	('men', 'Species', '9606', (139, 142))	('menstrual bleeding', 'Disease', (139, 157))	('distribution of body fat', 'MPA', (103, 127))	('men', 'Species', '9606', (74, 77))	('Excess', 'Var', (0, 6))	('gynecomastia', 'Disease', 'MESH:D006177', (26, 38))
82116	33498467	The dysregulation of mammalian targets of the rapamycin kinase (mTOR) pathway and activation of the Wingless and Int-1 (WNT)/beta-catenin pathway plays an important role in sporadic adrenocortical tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('beta-catenin', 'Gene', (125, 137))	('Int-1', 'Gene', '7471', (113, 118))	('dysregulation', 'Var', (4, 17))	('mTOR', 'Gene', (64, 68))	('mTOR', 'Gene', '2475', (64, 68))	('beta-catenin', 'Gene', '1499', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('mammalian', 'Species', '9606', (21, 30))	('tumor', 'Disease', (197, 202))	('Int-1', 'Gene', (113, 118))
82138	33498467	Pembrolizumab is a humanized recombinant monoclonal IgG class 4 kappa-isotype antibody to PD-1, and it results in an increased immune reactivity that can overcome immune tolerance, thus enabling its use in immunotherapy.	('immune tolerance', 'CPA', (163, 179))	('increased', 'PosReg', (117, 126))	('Pembrolizumab', 'Var', (0, 13))	('enabling', 'PosReg', (186, 194))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('human', 'Species', '9606', (19, 24))	('immune reactivity', 'MPA', (127, 144))
82156	33498467	Due to the mechanism of action of the aforementioned anti-PD-1 and anti-PD-L1 antibodies, the predictor of cancer immunotherapy, determining the effectiveness of treatment, should be PD-L1 expression on the surface of cancer cells and antigen presenting cells.	('PD-L1', 'Var', (183, 188))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('men', 'Species', '9606', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('men', 'Species', '9606', (167, 170))
82161	33498467	In cancer patients with tumors characterized by a high number of mutations and neoantigens, as well as high immunogenicity, the response rate is higher, and the response time is longer.	('response', 'MPA', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('higher', 'PosReg', (145, 151))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('neoantigens', 'Var', (79, 90))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('patients', 'Species', '9606', (10, 18))	('mutations', 'Var', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
82164	33498467	Other potential mechanisms of immunoresistance that have been identified are the activation of the WNT-beta-catenin pathway or TP53 mutations.	('beta-catenin', 'Gene', (103, 115))	('mutations', 'Var', (132, 141))	('beta-catenin', 'Gene', '1499', (103, 115))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
82173	33498467	LAG-3 blockade resulted in superior T cell activation compared to the inhibition of other pathways, including PD-1/PD-L1.	('T cell', 'CPA', (36, 42))	('activation', 'PosReg', (43, 53))	('blockade', 'Var', (6, 14))	('LAG-3', 'Gene', '3902', (0, 5))	('LAG-3', 'Gene', (0, 5))
82183	33498467	Therefore, attempts are made to combine therapy: anti-PD-1 antibody and anti-CTLA-4 antibody; anti-PD-1 antibody and an antagonist of the glucocorticoid receptor (Table 1).	('glucocorticoid receptor', 'Gene', (138, 161))	('CTLA-4', 'Gene', '1493', (77, 83))	('anti-PD-1', 'Var', (94, 103))	('CTLA-4', 'Gene', (77, 83))	('glucocorticoid receptor', 'Gene', '2908', (138, 161))
82213	33498467	Thyroid disorders are more frequently associated with anti-PD-1-antibodies and combination anti-PD-1 and anti-CTLA-4 therapy.	('Thyroid disorders', 'Phenotype', 'HP:0000820', (0, 17))	('associated', 'Reg', (38, 48))	('CTLA-4', 'Gene', (110, 116))	('Thyroid disorders', 'Disease', 'MESH:D013959', (0, 17))	('anti-PD-1-antibodies', 'Var', (54, 74))	('Thyroid disorders', 'Disease', (0, 17))	('CTLA-4', 'Gene', '1493', (110, 116))
82214	33498467	Immune checkpoint blockers are associated with a high risk of thyroid autoimmunity; this risk is highest for anti-PD-1 and increases further when a combination of checkpoint inhibitors is used.	('thyroid autoimmunity', 'Disease', (62, 82))	('anti-PD-1', 'Var', (109, 118))	('thyroid autoimmunity', 'Disease', 'MESH:D013967', (62, 82))	('autoimmunity', 'Phenotype', 'HP:0002960', (70, 82))
82227	33498467	Clinical trials of metastatic melanoma showed that the combination of ipilimumab and nivolumab compared with respective monotherapies was associated with higher frequencies of arthralgia and myalgia.	('ipilimumab', 'Var', (70, 80))	('nivolumab', 'Gene', (85, 94))	('ipilimumab', 'Chemical', 'MESH:D000074324', (70, 80))	('nivolumab', 'Chemical', 'MESH:D000077594', (85, 94))	('arthralgia', 'Disease', (176, 186))	('arthralgia', 'Disease', 'MESH:D018771', (176, 186))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('myalgia', 'Disease', 'MESH:D063806', (191, 198))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('myalgia', 'Disease', (191, 198))	('arthralgia', 'Phenotype', 'HP:0002829', (176, 186))	('melanoma', 'Disease', (30, 38))	('combination', 'Interaction', (55, 66))	('myalgia', 'Phenotype', 'HP:0003326', (191, 198))
82256	32290298	In this trial, patients receiving EDP-M obtained a significantly better response rate and PFS than those submitted to SZ-M.	('patients', 'Species', '9606', (15, 23))	('response rate', 'CPA', (72, 85))	('better', 'PosReg', (65, 71))	('PFS', 'CPA', (90, 93))	('EDP-M', 'Var', (34, 39))	('EDP-M', 'Chemical', '-', (34, 39))
82301	32290298	Patients with Ki67 expression below the median obtained a longer PFS (15.3 months, CI 95%: 13.3-17.3) than those with residual Ki67 above or equal to the median value (11.3 months, CI 95%: 8.9-13.6; p = 0.025) (Figure 6).	('Ki67', 'Chemical', '-', (127, 131))	('Ki67 expression', 'Var', (14, 29))	('PFS', 'MPA', (65, 68))	('Ki67', 'Chemical', '-', (14, 18))	('Patients', 'Species', '9606', (0, 8))
82304	32290298	In this responding patient subset, baseline Ki67 above the median was associated with a longer PFS than Ki67 expression below or equal the median value (15.1 months [95% CI: 14.5-15.7] versus 12.3 months [95% CI: 1.1-23.5], respectively, p = 0.034), while no difference in OS was observed (p = 0.788).	('Ki67', 'Chemical', '-', (44, 48))	('patient', 'Species', '9606', (19, 26))	('Ki67', 'Chemical', '-', (104, 108))	('longer', 'PosReg', (88, 94))	('PFS', 'MPA', (95, 98))	('Ki67', 'Var', (44, 48))
82328	32290298	In early breast cancer patients, Ki67 immunostaining after neoadjuvant chemotherapy was found to have a stronger prognostic significance than its expression at baseline conditions.	('immunostaining', 'Var', (38, 52))	('patients', 'Species', '9606', (23, 31))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancer', 'Disease', (9, 22))	('Ki67 immunostaining', 'Var', (33, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('Ki67', 'Chemical', '-', (33, 37))
82330	32290298	Therefore, Ki67 at residual histology after EDP in ACC patients could have the same significance as in breast cancer and this issue deserves to be further explored.	('EDP', 'Chemical', '-', (44, 47))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('Ki67', 'Var', (11, 15))	('Ki67', 'Chemical', '-', (11, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('patients', 'Species', '9606', (55, 63))	('ACC', 'Phenotype', 'HP:0006744', (51, 54))
82331	32290298	Noteworthily, in the patient subset who had surgery after EDP-M, who were carefully selected, we also evaluated the prognostic role of Ki67 assessed at baseline and an opposite result was observed, i.e., patients with higher Ki67 had a better prognosis.	('patients', 'Species', '9606', (204, 212))	('EDP-M', 'Chemical', '-', (58, 63))	('patient', 'Species', '9606', (204, 211))	('higher', 'PosReg', (218, 224))	('patient', 'Species', '9606', (21, 28))	('Ki67', 'Chemical', '-', (135, 139))	('Ki67', 'Chemical', '-', (225, 229))	('Ki67', 'Var', (225, 229))
82429	32332902	Diets with oleic, linolenic, linoleic and linoleic conjugates have been shown to reduce plasma cholesterol levels, in addition to affecting some physiological reactions, such as immune response and inhibition of tumor growth, decreased risk of coronary heart disease, and protective action against stroke, age-related cognitive decline and Alzheimer disease.	('stroke', 'Phenotype', 'HP:0001297', (298, 304))	('inhibition', 'NegReg', (198, 208))	('age-related', 'Disease', (306, 317))	('immune response', 'CPA', (178, 193))	('linoleic conjugates', 'Var', (42, 61))	('cognitive decline', 'Disease', 'MESH:D003072', (318, 335))	('stroke', 'Disease', 'MESH:D020521', (298, 304))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('plasma cholesterol levels', 'MPA', (88, 113))	('coronary heart disease', 'Disease', 'MESH:D003324', (244, 266))	('oleic', 'Chemical', '-', (32, 37))	('di', 'Disease', 'MESH:D003643', (120, 122))	('stroke', 'Disease', (298, 304))	('cholesterol', 'Chemical', 'MESH:D002784', (95, 106))	('di', 'Disease', 'MESH:D003643', (350, 352))	('linoleic', 'Var', (29, 37))	('physiological reactions', 'MPA', (145, 168))	('linoleic', 'Chemical', '-', (29, 37))	('affecting', 'Reg', (130, 139))	('Alzheimer disease', 'Phenotype', 'HP:0002511', (340, 357))	('cognitive decline', 'Disease', (318, 335))	('oleic', 'Chemical', '-', (45, 50))	('tumor', 'Disease', (212, 217))	('di', 'Disease', 'MESH:D003643', (259, 261))	('decreased', 'NegReg', (226, 235))	('Alzheimer disease', 'Disease', (340, 357))	('reduce', 'NegReg', (81, 87))	('Alzheimer disease', 'Disease', 'MESH:D000544', (340, 357))	('linolenic', 'Chemical', '-', (18, 27))	('linoleic', 'Chemical', '-', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('coronary heart disease', 'Disease', (244, 266))	('oleic', 'Chemical', '-', (11, 16))	('linolenic', 'Var', (18, 27))	('cognitive decline', 'Phenotype', 'HP:0001268', (318, 335))
82430	32332902	Moreover, Omega-6 fatty acids has gained attention in medicine studies for showing potential in preventing sarcopenia, modulate cancer, atherosclerosis, obesity, immune function and diabetes.	('sarcopenia', 'Disease', (107, 117))	('diabetes', 'Disease', 'MESH:D003920', (182, 190))	('di', 'Disease', 'MESH:D003643', (66, 68))	('obesity', 'Disease', (153, 160))	('cancer', 'Disease', (128, 134))	('atherosclerosis', 'Disease', 'MESH:D050197', (136, 151))	('atherosclerosis', 'Disease', (136, 151))	('di', 'Disease', 'MESH:D003643', (56, 58))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('obesity', 'Disease', 'MESH:D009765', (153, 160))	('diabetes', 'Disease', (182, 190))	('atherosclerosis', 'Phenotype', 'HP:0002621', (136, 151))	('di', 'Disease', 'MESH:D003643', (182, 184))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('Omega-6 fatty acids', 'Chemical', 'MESH:D043371', (10, 29))	('Omega-6', 'Var', (10, 17))	('obesity', 'Phenotype', 'HP:0001513', (153, 160))	('immune function', 'Disease', (162, 177))	('sarcopenia', 'Disease', 'MESH:D055948', (107, 117))
82437	32332902	Furthermore, recent works showed that chlorophyll derivatives, such as chlorophyllide, are also closely correlated to enhanced selectivity and improved cytotoxic activity against a range of carcinoma cells.	('improved', 'PosReg', (143, 151))	('selectivity', 'MPA', (127, 138))	('chlorophyll', 'Chemical', 'MESH:D002734', (38, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('chlorophyll', 'Chemical', 'MESH:D002734', (71, 82))	('enhanced', 'PosReg', (118, 126))	('carcinoma', 'Disease', (190, 199))	('chlorophyll', 'Var', (38, 49))	('chlorophyllide', 'Chemical', 'MESH:D002735', (71, 85))	('carcinoma', 'Disease', 'MESH:D009369', (190, 199))
82456	32332902	In comparison to other phenolic acids, trihydroxilated derivatives displays grater biological activities than phenolic acids with fewer hydroxyl radicals in their molecular structure, such as p-coumaric, trans-ferulic and trans-caffeic acids.	('di', 'Disease', 'MESH:D003643', (67, 69))	('p-coumaric', 'Var', (192, 202))	('hydroxyl radicals', 'Chemical', 'MESH:D017665', (136, 153))	('biological activities', 'CPA', (83, 104))	('phenolic acids', 'Chemical', 'MESH:C017616', (110, 124))	('-caffeic acids', 'Chemical', 'MESH:D002109', (227, 241))	('phenolic acids', 'Chemical', 'MESH:C017616', (23, 37))	('di', 'Disease', 'MESH:D003643', (147, 149))
82466	32332902	Furthermore, unsaturated fatty acids have previously shown to improve phagocytosis ability, and according to Table 3, HA presented higher content of unsaturated fatty acids (73%) than CA (60%).	('di', 'Disease', 'MESH:D003643', (101, 103))	('unsaturated fatty acids', 'MPA', (149, 172))	('unsaturated fatty acids', 'Chemical', 'MESH:D005231', (149, 172))	('improve', 'PosReg', (62, 69))	('HA', 'Chemical', '-', (118, 120))	('content', 'MPA', (138, 145))	('unsaturated fatty acids', 'Chemical', 'MESH:D005231', (13, 36))	('unsaturated', 'Var', (13, 24))	('phagocytosis ability', 'CPA', (70, 90))	('higher', 'PosReg', (131, 137))
82476	32332902	Furthermore, the higher concentration of H2O2 in relation to superoxide anion radical could be involved through the formation of enzyme-flavonoids hydrogen bonds, inhibiting the antioxidant activity of some peroxidase enzymes, such as catalase.	('antioxidant activity', 'MPA', (178, 198))	('catalase', 'Enzyme', (235, 243))	('flavonoids', 'Chemical', 'MESH:D005419', (136, 146))	('hydrogen', 'Chemical', 'MESH:D006859', (147, 155))	('superoxide anion radical', 'Chemical', '-', (61, 85))	('H2O2', 'Chemical', 'MESH:D006861', (41, 45))	('H2O2', 'Var', (41, 45))	('inhibiting', 'NegReg', (163, 173))	('peroxidase enzymes', 'Enzyme', (207, 225))
82509	32332902	The phytochemical tests were carried out in four different extracts from N. procerum: hexane (Analytical standard-VETEC), ethanolic (Analytical standard-VETEC), hot aqueous (100  C) and cold aqueous (25  C).	('100  C', 'Var', (174, 180))	('hexane', 'Chemical', 'MESH:D006586', (86, 92))	('cold aqueous', 'Disease', (186, 198))	('cold aqueous', 'Disease', 'MESH:D000067390', (186, 198))	('N. procerum', 'Species', '326797', (73, 84))	('di', 'Disease', 'MESH:D003643', (49, 51))	('ethanol', 'Chemical', 'MESH:D000431', (122, 129))
82540	32332902	(2):Where lambda734-Sample is the absorbance of control without radical scavenger and lambda734-Control the remaining ABTS in the presence of scavenger.	('ABTS', 'Chemical', '-', (118, 122))	('lambda734-Sample', 'Var', (10, 26))	('di', 'Disease', 'MESH:D003643', (66, 68))	('lambda734-Control', 'Var', (86, 103))
82564	30915114	After referencing the literature, several comorbidities of CS patients were identified and retrieved by ICD-10 codes assigned to the twenty diagnoses for each patient in the hospital DAD, including hypertension (I10-I15, H35.0, and I67.4), diabetes mellitus (E10-E14), impaired glucose intolerance (IGT) (R73.0 and R73.9), osteoporosis without fractures (M81, M82.1*), osteoporotic fractures (M80.0, M84.4), cerebrovascular disease (I60-I69), ischemic heart disease (I20-I25), dyslipidemia (E78), fatty liver (K76.0), hypokalemia (E87), and psychiatric disorders (F00-F99).	('impaired glucose intolerance', 'Disease', (269, 297))	('diabetes mellitus', 'Disease', (240, 257))	('glucose', 'Chemical', 'MESH:D005947', (278, 285))	('hypokalemia', 'Disease', (518, 529))	('hypertension', 'Phenotype', 'HP:0000822', (198, 210))	('fatty liver', 'Phenotype', 'HP:0001397', (497, 508))	('cerebrovascular disease', 'Disease', (408, 431))	('osteoporosis', 'Disease', (323, 335))	('I20-I25', 'Var', (467, 474))	('osteoporosis', 'Phenotype', 'HP:0000939', (323, 335))	('dyslipidemia', 'Phenotype', 'HP:0003119', (477, 489))	('dyslipidemia', 'Disease', (477, 489))	('ischemic heart disease', 'Disease', (443, 465))	('IGT', 'Disease', 'None', (299, 302))	('I60-I69', 'Var', (433, 440))	('hypokalemia', 'Phenotype', 'HP:0002900', (518, 529))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (240, 257))	('psychiatric disorders', 'Disease', 'MESH:D001523', (541, 562))	('ischemic heart disease', 'Disease', 'MESH:D003324', (443, 465))	('osteoporotic', 'Disease', (369, 381))	('IGT', 'Disease', (299, 302))	('psychiatric disorders', 'Phenotype', 'HP:0000708', (541, 562))	('glucose intolerance', 'Phenotype', 'HP:0001952', (278, 297))	('fatty liver', 'Disease', (497, 508))	('CS', 'Phenotype', 'HP:0003118', (59, 61))	('cerebrovascular disease', 'Disease', 'MESH:D002561', (408, 431))	('hypertension', 'Disease', (198, 210))	('psychiatric disorders', 'Disease', (541, 562))	('impaired glucose intolerance', 'Disease', 'MESH:D018149', (269, 297))
82581	30915114	Furthermore, a defect in the PRKAR1A gene is the most frequent cause of PPNAD and Carney complex.	('PPNAD', 'Disease', (72, 77))	('PRKAR1A', 'Gene', (29, 36))	('cause', 'Reg', (63, 68))	('defect', 'Var', (15, 21))	('PRKAR1A', 'Gene', '5573', (29, 36))	('Carney complex', 'Disease', (82, 96))
82606	26742968	Patients >=18 years of age with ACC were identified in the SEER database utilizing the primary site codes C74.0 and C74.9, and International Classification of Diseases for Oncology, 9th edition (ICD-9) code 1940 for a study cohort of 1271 patients.	('ACC', 'Phenotype', 'HP:0006744', (32, 35))	('C74.0', 'Var', (106, 111))	('patients', 'Species', '9606', (239, 247))	('C74.9', 'Var', (116, 121))	('Patients', 'Species', '9606', (0, 8))	('Oncology', 'Phenotype', 'HP:0002664', (172, 180))
82620	26742968	This population-based study analyzing factors associated with mortality in patients with ACC demonstrates that SDW patients have significantly worse all cause and cancer specific mortality compared to married patients.	('patients', 'Species', '9606', (115, 123))	('worse', 'NegReg', (143, 148))	('patients', 'Species', '9606', (75, 83))	('SDW', 'Chemical', '-', (111, 114))	('all cause', 'CPA', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ACC', 'Phenotype', 'HP:0006744', (89, 92))	('patients', 'Species', '9606', (209, 217))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('SDW', 'Var', (111, 114))
82624	26742968	The survival benefit associated with marital status has been described in other urologic malignancies, including bladder, prostate, penile and testis cancer.	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('testis cancer', 'Phenotype', 'HP:0010788', (143, 156))	('penile', 'Disease', (132, 138))	('testis cancer', 'Disease', 'MESH:D013736', (143, 156))	('bladder', 'Disease', (113, 120))	('prostate', 'Disease', (122, 130))	('malignancies', 'Disease', (89, 101))	('marital status', 'Var', (37, 51))	('testis cancer', 'Disease', (143, 156))	('penile', 'Disease', 'MESH:D004414', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
82650	26742968	SDW status is associated with poorer survival in patients with ACC, suggesting that the decreased survival seen among SDW individuals in other urologic malignancies may also be relevant for patients with ACC.	('SDW', 'Chemical', '-', (0, 3))	('SDW', 'Var', (118, 121))	('ACC', 'Disease', (63, 66))	('patients', 'Species', '9606', (190, 198))	('ACC', 'Phenotype', 'HP:0006744', (204, 207))	('SDW', 'Chemical', '-', (118, 121))	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('decreased', 'NegReg', (88, 97))	('patients', 'Species', '9606', (49, 57))	('malignancies', 'Disease', (152, 164))	('ACC', 'Phenotype', 'HP:0006744', (63, 66))
82766	25722719	18F-FDG PET/CT allowed a correct diagnosis in 13 of 15 adenomas which remained undetermined at CT. 18F-FDG PET/CT has a high sensitivity and specificity to characterize undetermined adrenal masses and the value of SUVmax may be correlated to the Weiss score.	('adenomas', 'Disease', 'MESH:D000236', (55, 63))	('18F-FDG', 'Var', (99, 106))	('adrenal masses', 'Disease', (182, 196))	('adenomas', 'Disease', (55, 63))
82773	25722719	In conclusion, this large series of all pathologically confirmed adrenal masses including adrenocortical atypical adenomas, adrenal metastases, and adrenocortical carcinomas showed that the presence of macroscopic fat on CT is an important indicator of benignity for adrenal tumors that remain indeterminate.	('adrenal metastases', 'Disease', (124, 142))	('adrenal tumor', 'Phenotype', 'HP:0100631', (267, 280))	('adrenal metastases', 'Disease', 'MESH:D009362', (124, 142))	('adrenal tumors', 'Disease', (267, 281))	('macroscopic', 'Var', (202, 213))	('adrenocortical atypical adenomas', 'Disease', (90, 122))	('presence', 'Var', (190, 198))	('adrenocortical atypical adenomas', 'Disease', 'MESH:D018246', (90, 122))	('adrenocortical carcinomas', 'Disease', (148, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (148, 173))	('adrenal tumors', 'Disease', 'MESH:D000310', (267, 281))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (148, 173))
82813	21916912	Germline MEN1 mutational testing results were available on 11 of 19 patients and showed a distribution of truncation and missense mutations across the MEN1 gene similar to those previously reported in MEN1 patients (Table 1, Supplementary Figure 1) .	('MEN1', 'Gene', (151, 155))	('MEN1', 'Gene', '4221', (151, 155))	('MEN1', 'Gene', (201, 205))	('MEN1', 'Gene', '4221', (201, 205))	('MEN1', 'Gene', '4221', (9, 13))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (206, 214))	('missense mutations', 'Var', (121, 139))	('MEN1', 'Gene', (9, 13))	('truncation', 'Var', (106, 116))
82915	30087832	In addition, miR-99a-5p was expressed at higher levels in G1-G2 than in G3-G4 neoplasms (8.140 +- 1.239 vs 7.968 +- 1.525, respectively, P = 0.001).	('neoplasms', 'Phenotype', 'HP:0002664', (78, 87))	('miR-99a', 'Gene', '407055', (13, 20))	('G1-G2', 'Var', (58, 63))	('miR-99a', 'Gene', (13, 20))	('neoplasms', 'Disease', (78, 87))	('neoplasms', 'Disease', 'MESH:D009369', (78, 87))	('neoplasm', 'Phenotype', 'HP:0002664', (78, 86))
82945	30087832	also reported that IGFR1 and MTOR were repressed by ectopic transfection of miR-99-5p 51.	('MTOR', 'Gene', (29, 33))	('IGFR1', 'Gene', (19, 24))	('miR-99-5p 51', 'Var', (76, 88))	('MTOR', 'Gene', '2475', (29, 33))	('IGFR1', 'Gene', '3480', (19, 24))
82954	30087832	Thus, together with the findings of previous researches and our results, we speculated that the dysfunctional PI3K-Akt signaling pathway was implicated in the development of HNSCC.	('Akt', 'Gene', '207', (115, 118))	('Akt', 'Gene', (115, 118))	('men', 'Species', '9606', (166, 169))	('SCC', 'Gene', (176, 179))	('dysfunctional', 'Var', (96, 109))	('HNSCC', 'Phenotype', 'HP:0012288', (174, 179))	('SCC', 'Gene', '6317', (176, 179))	('implicated', 'Reg', (141, 151))
83057	25332762	His family history revealed the presence of a 37-year-old sister with an established diagnosis of MEN1 (primary hyperparathyroidism, pancreatic gastrinoma, and prolactinoma) with germline mutation 894-9 G A, and a 50-year-old brother affected by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma causing Cushing's disease.	('ACTH', 'Gene', '5443', (278, 282))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (294, 311))	('adrenocorticotropic hormone', 'Gene', '5443', (249, 276))	('pituitary adenoma', 'Disease', (294, 311))	('894-9 G A', 'Var', (197, 206))	('primary hyperparathyroidism', 'Disease', (104, 131))	('prolactinoma', 'Phenotype', 'HP:0040278', (160, 172))	('pancreatic gastrinoma', 'Disease', (133, 154))	('primary hyperparathyroidism', 'Disease', 'MESH:D049950', (104, 131))	('ACTH', 'Gene', (278, 282))	('prolactinoma', 'Disease', (160, 172))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (112, 131))	('adrenocorticotropic hormone', 'Gene', (249, 276))	('primary hyperparathyroidism', 'Phenotype', 'HP:0008200', (104, 131))	('MEN1', 'Gene', '4221', (98, 102))	("Cushing's disease", 'Disease', (320, 337))	('prolactinoma', 'Disease', 'MESH:D015175', (160, 172))	("Cushing's disease", 'Disease', 'MESH:D003480', (320, 337))	('pituitary adenoma', 'Disease', 'MESH:D010911', (294, 311))	('MEN1', 'Gene', (98, 102))	('pancreatic gastrinoma', 'Disease', 'MESH:D015408', (133, 154))
83104	25332762	The phase III FIRM-ACT trial comparing two different regimens in metastatic ACCs (etoposide, doxorubicin, cisplatin, and mitotane versus streptozotocin and mitotane) showed no difference between the two regimens in terms of overall survival (14.8 vs 12.0 months; P=0.07).	('streptozotocin', 'Chemical', 'MESH:D013311', (137, 151))	('mitotane', 'Var', (121, 129))	('etoposide', 'Chemical', 'MESH:D005047', (82, 91))	('mitotane', 'Chemical', 'MESH:D008939', (121, 129))	('metastatic', 'Disease', (65, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('mitotane', 'Chemical', 'MESH:D008939', (156, 164))	('doxorubicin', 'Chemical', 'MESH:D004317', (93, 104))
83108	23599797	Suppression of NF-kappaB activity by mutant IkappaBalpha: A molecular target for radiosensitization of adenoid cystic carcinoma The constitutive activation of the nuclear factor kappaB (NF-kappaB) signaling pathway is involved in oncogenesis, invasive growth, metastasis and induced resistance to radiation and chemotherapy.	('kappaB', 'Gene', (189, 195))	('kappaB', 'Gene', (45, 51))	('NF-kappaB', 'Gene', (15, 24))	('activation', 'PosReg', (145, 155))	('kappaB', 'Gene', (178, 184))	('kappaB', 'Gene', '4790', (189, 195))	('IkappaBalpha', 'Gene', (44, 56))	('kappaB', 'Gene', '4790', (45, 51))	('NF-kappaB', 'Gene', '4790', (15, 24))	('kappaB', 'Gene', '4790', (178, 184))	('IkappaBalpha', 'Gene', '4792', (44, 56))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (103, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('mutant', 'Var', (37, 43))	('kappaB', 'Gene', (18, 24))	('NF-kappaB', 'Gene', (186, 195))	('kappaB', 'Gene', '4790', (18, 24))	('NF-kappaB', 'Gene', '4790', (186, 195))	('adenoid cystic carcinoma', 'Disease', (103, 127))	('activity', 'MPA', (25, 33))
83109	23599797	Selective inhibition of the NF-kappaB signaling pathway, either by a mutant inhibitor or pharmacological agents, improves the therapeutic efficiency of irradiation.	('inhibition', 'NegReg', (10, 20))	('improves', 'PosReg', (113, 121))	('mutant', 'Var', (69, 75))	('NF-kappaB', 'Gene', '4790', (28, 37))	('therapeutic efficiency of irradiation', 'CPA', (126, 163))	('NF-kappaB', 'Gene', (28, 37))
83110	23599797	In the present study, the changes in NF-kappaB expression and the rate of apoptosis were investigated following irradiation of cells of an adenoid cystic carcinoma cell line (ACC-M) in which NF-kappaB expression had been inhibited by transient transfection with a mutant IkappaBalpha plasmid.	('IkappaBalpha', 'Gene', (271, 283))	('adenoid cystic carcinoma', 'Disease', (139, 163))	('NF-kappaB', 'Gene', (37, 46))	('NF-kappaB', 'Gene', (191, 200))	('mutant', 'Var', (264, 270))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (139, 163))	('IkappaBalpha', 'Gene', '4792', (271, 283))	('expression', 'MPA', (201, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('inhibited', 'NegReg', (221, 230))	('NF-kappaB', 'Gene', '4790', (37, 46))	('NF-kappaB', 'Gene', '4790', (191, 200))
83112	23599797	The presence of the mutant IkappaBalpha gene alone did not result in a reduction in cell proliferation.	('IkappaBalpha', 'Gene', '4792', (27, 39))	('cell proliferation', 'CPA', (84, 102))	('mutant', 'Var', (20, 26))	('IkappaBalpha', 'Gene', (27, 39))
83115	23599797	We conclude that the mutant IkappaBalpha gene selectively inhibited the NF-kappaB pathway, which may be a promising method to improve the radiosensitivity of adenoid cystic carcinomas.	('mutant', 'Var', (21, 27))	('IkappaBalpha', 'Gene', (28, 40))	('adenoid cystic carcinomas', 'Disease', (158, 183))	('improve', 'PosReg', (126, 133))	('adenoid cystic carcinomas', 'Disease', 'MESH:D003528', (158, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('NF-kappaB', 'Gene', '4790', (72, 81))	('inhibited', 'NegReg', (58, 67))	('NF-kappaB', 'Gene', (72, 81))	('IkappaBalpha', 'Gene', '4792', (28, 40))
83129	23599797	By transfecting a gene encoding mutated IkappaBalpha that is not able to be phosphorylated and thereby inhibits the activation of the NF-kappaB pathway, similar findings have been demonstrated in that suppressive NF-kappaB radiosensitizes prostate cancer cells.	('NF-kappaB', 'Gene', '4790', (134, 143))	('radiosensitizes', 'CPA', (223, 238))	('prostate cancer', 'Phenotype', 'HP:0012125', (239, 254))	('IkappaBalpha', 'Gene', '4792', (40, 52))	('prostate cancer', 'Disease', (239, 254))	('NF-kappaB', 'Gene', '4790', (213, 222))	('inhibits', 'NegReg', (103, 111))	('mutated', 'Var', (32, 39))	('NF-kappaB', 'Gene', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('NF-kappaB', 'Gene', (213, 222))	('IkappaBalpha', 'Gene', (40, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (239, 254))	('suppressive', 'Var', (201, 212))
83131	23599797	Jung et al demonstrated that by transfecting a phosphorylation-defective IkappaBalpha gene into cells derived from a patient with ataxia telangiectasia (AT) group D, the constitutive activation of NF-kappaB was suppressed and the previous radiation hypersensitivity in AT was restored to the normal level.	('suppressed', 'NegReg', (211, 221))	('AT', 'Disease', 'None', (269, 271))	('AT', 'Disease', 'None', (153, 155))	('IkappaBalpha', 'Gene', (73, 85))	('NF-kappaB', 'Gene', (197, 206))	('ataxia telangiectasia', 'Disease', (130, 151))	('ataxia', 'Phenotype', 'HP:0001251', (130, 136))	('transfecting', 'Var', (32, 44))	('hypersensitivity in AT', 'Disease', (249, 271))	('previous radiation hypersensitivity', 'Phenotype', 'HP:0011133', (230, 265))	('telangiectasia', 'Phenotype', 'HP:0001009', (137, 151))	('patient', 'Species', '9606', (117, 124))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (130, 151))	('constitutive activation', 'MPA', (170, 193))	('IkappaBalpha', 'Gene', '4792', (73, 85))	('hypersensitivity in AT', 'Disease', 'MESH:D004342', (249, 271))	('NF-kappaB', 'Gene', '4790', (197, 206))
83132	23599797	Additionally, to the best of our knowledge, the impact of this mutant IkappaBalpha gene on the expression of NF-kappaB and subsequent changes in radiosensitivity in ACC cells had not yet been studied.	('NF-kappaB', 'Gene', '4790', (109, 118))	('IkappaBalpha', 'Gene', '4792', (70, 82))	('mutant', 'Var', (63, 69))	('IkappaBalpha', 'Gene', (70, 82))	('NF-kappaB', 'Gene', (109, 118))
83135	23599797	While analyzing the results, we observed that suppressing the NF-kappaB pathway by transfecting ACC-M cells with mutant IkappaBalpha, as compared with cells with a control pBalphabe plasmid transfection, leads to increased radiosensitivity.	('radiosensitivity', 'CPA', (223, 239))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (213, 239))	('IkappaBalpha', 'Gene', (120, 132))	('NF-kappaB', 'Gene', '4790', (62, 71))	('IkappaBalpha', 'Gene', '4792', (120, 132))	('mutant', 'Var', (113, 119))	('NF-kappaB', 'Gene', (62, 71))	('increased', 'PosReg', (213, 222))	('suppressing', 'NegReg', (46, 57))
83163	23599797	The changes in the expression of NF-kappaB and mutant IkappaBalpha following transfection and irradiation treatment were evaluated by western blot analysis.	('NF-kappaB', 'Gene', (33, 42))	('IkappaBalpha', 'Gene', '4792', (54, 66))	('IkappaBalpha', 'Gene', (54, 66))	('NF-kappaB', 'Gene', '4790', (33, 42))	('mutant', 'Var', (47, 53))
83173	23599797	However, the ACC-M cells that had been transfected with the pBalphabe-SR-IkappaBalpha plasmid expressed endogenous IkappaBalpha protein, as well as the mutant IkappaBalpha protein with a higher molecular weight.	('IkappaBalpha', 'Gene', '4792', (115, 127))	('IkappaBalpha', 'Gene', (159, 171))	('IkappaBalpha', 'Gene', (73, 85))	('IkappaBalpha', 'Gene', (115, 127))	('mutant', 'Var', (152, 158))	('IkappaBalpha', 'Gene', '4792', (159, 171))	('IkappaBalpha', 'Gene', '4792', (73, 85))
83174	23599797	To determine whether the mutant IkappaBalpha gene exerted its antiproliferative activity on the transfected cells, cells were subjected to an MTT analysis.	('antiproliferative activity', 'MPA', (62, 88))	('mutant', 'Var', (25, 31))	('IkappaBalpha', 'Gene', '4792', (32, 44))	('IkappaBalpha', 'Gene', (32, 44))	('MTT', 'Chemical', 'MESH:C070243', (142, 145))
83177	23599797	Accordingly, it is likely that the expression of mutant IkappaBalpha protein does not necessarily lead to the in vitro growth inhibition of non-stimulated ACC-M cells.	('IkappaBalpha', 'Gene', '4792', (56, 68))	('mutant', 'Var', (49, 55))	('IkappaBalpha', 'Gene', (56, 68))
83179	23599797	Following exposure to different doses of irradiation, the previously suppressed NF-kappaB pathway (achieved by transfecting the ACC-M cells with mutant IkappaBalpha) was activated and thereafter liberated NF-kappaB translocated to the nucleus.	('activated', 'PosReg', (170, 179))	('NF-kappaB', 'Gene', (205, 214))	('IkappaBalpha', 'Gene', '4792', (152, 164))	('mutant', 'Var', (145, 151))	('IkappaBalpha', 'Gene', (152, 164))	('translocated to the', 'MPA', (215, 234))	('NF-kappaB', 'Gene', '4790', (80, 89))	('suppressed', 'NegReg', (69, 79))	('NF-kappaB', 'Gene', '4790', (205, 214))	('NF-kappaB', 'Gene', (80, 89))
83188	23599797	Cells in the pBalphabe-SR-IkappaBalpha plasmid group demonstrated downregulated levels of NF-kappaB protein (P<0.05), which suggested transfection of mutant IkappaBalpha simultaneously blocked the synthesis and translocation of NF-kappaB protein (data not shown).	('NF-kappaB', 'Gene', (228, 237))	('IkappaBalpha', 'Gene', (26, 38))	('translocation', 'MPA', (211, 224))	('IkappaBalpha', 'Gene', '4792', (157, 169))	('downregulated', 'NegReg', (66, 79))	('IkappaBalpha', 'Gene', '4792', (26, 38))	('NF-kappaB', 'Gene', '4790', (90, 99))	('NF-kappaB', 'Gene', '4790', (228, 237))	('blocked', 'NegReg', (185, 192))	('NF-kappaB', 'Gene', (90, 99))	('synthesis', 'MPA', (197, 206))	('IkappaBalpha', 'Gene', (157, 169))	('mutant', 'Var', (150, 156))
83194	23599797	5, treatment with mutant IkappaBalpha transfection significantly enhanced the radiosensitivity of ACC-M cells, as assessed by flow cytometric analysis (P<0.05).	('IkappaBalpha', 'Gene', (25, 37))	('mutant', 'Var', (18, 24))	('enhanced', 'PosReg', (65, 73))	('radiosensitivity', 'CPA', (78, 94))	('IkappaBalpha', 'Gene', '4792', (25, 37))
83196	23599797	Furthermore, cells with equal irradiation exposure exhibited a similar survival tendency in that the apoptotic rate reached the minimal value at 6-10 h, and the maximal value at 24 h. The apoptotic rates of cells with mutant IkappaBalpha transfection, 3 h following irradiation treatment, were 50.83, 48.61, 44.32, 42.53 and 40.42%, between the different dosage groups (2, 4, 6, 8 and 10 Gy, respectively).	('mutant', 'Var', (218, 224))	('IkappaBalpha', 'Gene', (225, 237))	('IkappaBalpha', 'Gene', '4792', (225, 237))
83202	23599797	The primary aim of our study was to determine whether the transfected mutant IkappaBalpha gene was able to inhibit the activity of the NF-kappaB pathway, and to investigate the negative contribution of the radio-activated NF-kappaB pathway on radio-sensitivity.	('inhibit', 'NegReg', (107, 114))	('NF-kappaB', 'Gene', (135, 144))	('IkappaBalpha', 'Gene', (77, 89))	('mutant', 'Var', (70, 76))	('NF-kappaB', 'Gene', (222, 231))	('IkappaBalpha', 'Gene', '4792', (77, 89))	('NF-kappaB', 'Gene', '4790', (135, 144))	('activity', 'MPA', (119, 127))	('NF-kappaB', 'Gene', '4790', (222, 231))
83203	23599797	We transiently transfected a mutant IkappaBalpha gene into ACC-M cells, obtaining simultaneous blockage of the synthesis and translocation of the NF-kappaB protein.	('IkappaBalpha', 'Gene', '4792', (36, 48))	('blockage', 'NegReg', (95, 103))	('mutant', 'Var', (29, 35))	('NF-kappaB', 'Gene', '4790', (146, 155))	('IkappaBalpha', 'Gene', (36, 48))	('translocation', 'MPA', (125, 138))	('NF-kappaB', 'Gene', (146, 155))
83204	23599797	The mutant IkappaBalpha gene promoted radiosensitivity via suppression of the NF-kappaB pathway.	('promoted', 'PosReg', (29, 37))	('suppression', 'NegReg', (59, 70))	('radiosensitivity', 'CPA', (38, 54))	('NF-kappaB', 'Gene', '4790', (78, 87))	('mutant', 'Var', (4, 10))	('NF-kappaB', 'Gene', (78, 87))	('IkappaBalpha', 'Gene', (11, 23))	('IkappaBalpha', 'Gene', '4792', (11, 23))
83210	23599797	When cells were stimulated by different exogenous stimuli, the Ser 32 and 36 residues of IkappaBalpha were phosphorylated by IKK and IkappaBalpha underwent subsequent ubiquitylation and degradation, thus releasing the NF-kappaB protein for nuclear translocation.	('IkappaBalpha', 'Gene', (89, 101))	('Ser', 'Chemical', 'MESH:D012694', (63, 66))	('ubiquitylation', 'MPA', (167, 181))	('nuclear translocation', 'MPA', (240, 261))	('NF-kappaB', 'Gene', (218, 227))	('degradation', 'MPA', (186, 197))	('IkappaBalpha', 'Gene', '4792', (133, 145))	('releasing', 'PosReg', (204, 213))	('IkappaBalpha', 'Gene', '4792', (89, 101))	('IKK', 'Var', (125, 128))	('IkappaBalpha', 'Gene', (133, 145))	('NF-kappaB', 'Gene', '4790', (218, 227))
83211	23599797	Fujioka et al transfected a retroviral vector encoding phosphorylation-defective IkappaBalpha by inducing point mutations at the potential phosphoacceptor sites of Ser 32 and 36, and observed decreased NF-kappaB DNA binding activity in the non-metastatic human pancreatic tumor cell line.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('Ser', 'Chemical', 'MESH:D012694', (164, 167))	('pancreatic tumor', 'Disease', 'MESH:D010190', (261, 277))	('decreased', 'NegReg', (192, 201))	('human', 'Species', '9606', (255, 260))	('IkappaBalpha', 'Gene', '4792', (81, 93))	('inducing', 'Reg', (97, 105))	('point mutations', 'Var', (106, 121))	('NF-kappaB', 'Gene', '4790', (202, 211))	('pancreatic tumor', 'Disease', (261, 277))	('NF-kappaB', 'Gene', (202, 211))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (261, 277))	('IkappaBalpha', 'Gene', (81, 93))
83212	23599797	However, to the best of our knowledge, applying a mutant form of IkappaBalpha to specifically inhibit the NF-kappaB pathway in ACC-M cells has not been previously studied.	('NF-kappaB', 'Gene', '4790', (106, 115))	('IkappaBalpha', 'Gene', (65, 77))	('NF-kappaB', 'Gene', (106, 115))	('inhibit', 'NegReg', (94, 101))	('mutant', 'Var', (50, 56))	('IkappaBalpha', 'Gene', '4792', (65, 77))
83213	23599797	As we have demonstrated in ACC-M cells, the synthesis and translocation of the NF-kappaB protein were highly specifically suppressed by transfecting the cells with the use of a pBalphabe-SR-IkappaBalpha plasmid, and this blocking effect persisted following irradiation and hence when the NF-kappaB pathway was activated.	('transfecting', 'Var', (136, 148))	('synthesis', 'MPA', (44, 53))	('NF-kappaB', 'Gene', '4790', (288, 297))	('suppressed', 'NegReg', (122, 132))	('IkappaBalpha', 'Gene', '4792', (190, 202))	('NF-kappaB', 'Gene', (288, 297))	('translocation', 'MPA', (58, 71))	('IkappaBalpha', 'Gene', (190, 202))	('NF-kappaB', 'Gene', '4790', (79, 88))	('NF-kappaB', 'Gene', (79, 88))
83214	23599797	Given the involvement of the NF-kappaB pathway in oncogenesis and induction of resistance to conventional therapy, such as chemotherapy and irradiation, blockage of the pathway by specific inhibitors is beneficial and may be a promising antitumor therapy.	('oncogenesis', 'CPA', (50, 61))	('NF-kappaB', 'Gene', (29, 38))	('tumor', 'Disease', (241, 246))	('blockage', 'Var', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('NF-kappaB', 'Gene', '4790', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
83216	23599797	van Hogerlinden et al applied a super-repressor form of IkappaBalpha with mutant phosphorylation sites that selectively inhibited the NF-kappaB pathway, yielding elevated apoptosis in the basal and suprabasal keratinocytes in vivo.	('NF-kappaB', 'Gene', '4790', (134, 143))	('IkappaBalpha', 'Gene', '4792', (56, 68))	('elevated', 'PosReg', (162, 170))	('IkappaBalpha', 'Gene', (56, 68))	('inhibited', 'NegReg', (120, 129))	('apoptosis', 'CPA', (171, 180))	('NF-kappaB', 'Gene', (134, 143))	('mutant', 'Var', (74, 80))
83217	23599797	Duffey et al also demonstrated that stable expression of a mutant form of IkappaBalpha in squamous carcinoma cells resulted in an augmented apoptotic rate, and this blocking effect was not relieved by TNF-alpha induced activation.	('TNF-alpha', 'Gene', '7124', (201, 210))	('mutant', 'Var', (59, 65))	('IkappaBalpha', 'Gene', '4792', (74, 86))	('TNF-alpha', 'Gene', (201, 210))	('squamous carcinoma', 'Disease', 'MESH:D002294', (90, 108))	('squamous carcinoma', 'Disease', (90, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('IkappaBalpha', 'Gene', (74, 86))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (90, 108))	('augmented', 'PosReg', (130, 139))	('apoptotic rate', 'CPA', (140, 154))
83219	23599797	By contrast, cells with prior mutant IkappaBalpha plasmid transfection were susceptible to radio-induced apoptosis.	('IkappaBalpha', 'Gene', '4792', (37, 49))	('susceptible', 'Reg', (76, 87))	('mutant', 'Var', (30, 36))	('IkappaBalpha', 'Gene', (37, 49))
83220	23599797	Accordingly, we estimate that inhibition of the NF-kappaB pathway in non-stimulated ACC-M cells does not necessarily result in increased apoptosis, whereas inhibition of the NF-kappaB pathway combined with irradiation yielded a significant radiosensitizing outcome.	('inhibition', 'Var', (156, 166))	('NF-kappaB', 'Gene', '4790', (174, 183))	('NF-kappaB', 'Gene', '4790', (48, 57))	('NF-kappaB', 'Gene', (174, 183))	('NF-kappaB', 'Gene', (48, 57))
83228	23599797	Aberrant activation of the NF-kappaB pathway has been identified in various types of cancer, including both solid and hematopoietic malignancies.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('hematopoietic malignancies', 'Disease', (118, 144))	('solid', 'Disease', (108, 113))	('NF-kappaB', 'Gene', '4790', (27, 36))	('NF-kappaB', 'Gene', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (118, 144))
83234	23599797	In the present study, we demonstrated that ACC-M cells exhibited markedly increased radiosensitivity following selective inhibition of the NF-kappaB pathway by transfection with a mutant IkappaBalpha plasmid.	('IkappaBalpha', 'Gene', '4792', (187, 199))	('NF-kappaB', 'Gene', (139, 148))	('NF-kappaB', 'Gene', '4790', (139, 148))	('mutant', 'Var', (180, 186))	('IkappaBalpha', 'Gene', (187, 199))	('increased', 'PosReg', (74, 83))	('radiosensitivity', 'CPA', (84, 100))	('inhibition', 'NegReg', (121, 131))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (74, 100))
83242	23599797	In conclusion, the results of our study demonstrated that by transfecting a mutant form of the IkappaBalpha gene, the synthesis and translocation of the NF-kappaB protein were specifically inhibited, and a concomitant decrease in survival rate following irradiation was observed in ACC-M cells.	('survival rate', 'CPA', (230, 243))	('decrease', 'NegReg', (218, 226))	('protein', 'Protein', (163, 170))	('mutant', 'Var', (76, 82))	('IkappaBalpha', 'Gene', '4792', (95, 107))	('inhibited', 'NegReg', (189, 198))	('synthesis', 'MPA', (118, 127))	('IkappaBalpha', 'Gene', (95, 107))	('translocation', 'MPA', (132, 145))	('NF-kappaB', 'Gene', '4790', (153, 162))	('NF-kappaB', 'Gene', (153, 162))
83246	33937245	Moreover, the mutation in CTC1 caused cancer-prone diseases including Coats plus (CP) or dyskeratosis congenita (DC).	('caused', 'Reg', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('CTC1', 'Gene', (26, 30))	('Coats plus (CP) or dyskeratosis congenita', 'Disease', 'MESH:C567401', (70, 111))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('mutation', 'Var', (14, 22))	('cancer', 'Disease', (38, 44))
83253	33937245	Telomere length could be maintained by the telomerase via adding TTAGGG repeats to the chromosome ends, and the activity of telomerase, which is a ribonucleoprotein reverse transcriptase, could be detected in a variety of cells, such as cancer cells, stem cells, and reproductive cells.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('TTAGGG repeats', 'Var', (65, 79))	('activity', 'MPA', (112, 120))
83261	33937245	Moreover, a naturally occurring mutation of CTC1 was observed in rare genetic telomere biology disorders (TBD) such as Coats plus (CP) or dyskeratosis congenita (DC), of which patients always show shortened telomeres.	('patients', 'Species', '9606', (176, 184))	('CTC1', 'Gene', (44, 48))	('observed', 'Reg', (53, 61))	('shortened telomeres', 'Phenotype', 'HP:0031413', (197, 216))	('Coats plus (CP) or dyskeratosis congenita', 'Disease', 'MESH:C567401', (119, 160))	('telomere biology disorders', 'Disease', (78, 104))	('mutation', 'Var', (32, 40))	('shortened', 'NegReg', (197, 206))
83283	33937245	We found that treatment with either of the two miRNAs or by shCTC1 knockdown could finally lead to the repression of cell growth (Figure 2C).	('lead to', 'Reg', (91, 98))	('repression', 'MPA', (103, 113))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('knockdown', 'Var', (67, 76))	('shCTC1', 'Gene', (60, 66))
83287	33937245	In contrast to the MTS result, no significant increase of SFEs was observed (Supplementary Figure 1), suggesting that depletion of CTC1 by miRNA promoted telomere replication stress and telomere dysfunction, but not telomere loss.	('depletion', 'Var', (118, 127))	('telomere dysfunction', 'CPA', (186, 206))	('miR', 'Gene', '220972', (139, 142))	('miR', 'Gene', (139, 142))	('s an', 'Gene', '80218', (180, 184))	('stress', 'Disease', 'MESH:D000079225', (175, 181))	('s an', 'Gene', (180, 184))	('CTC1', 'Gene', (131, 135))	('promoted', 'PosReg', (145, 153))	('stress', 'Disease', (175, 181))
83297	33937245	It has been reported that the depletion of CST leads to telomere signal loss and the deregulation of telomere length.	('s an', 'Gene', '80218', (75, 79))	('depletion', 'Var', (30, 39))	('telomere signal', 'MPA', (56, 71))	('deregulation', 'MPA', (85, 97))	('telomere length', 'MPA', (101, 116))	('CST', 'Gene', (43, 46))	('s an', 'Gene', (75, 79))
83308	33937245	As anticipated, the recovery of the fork restart was observed with CTC1 re-expression and upon ATRi treatment.	('fork restart', 'MPA', (36, 48))	('ATRi', 'Chemical', '-', (95, 99))	('CTC1', 'Gene', (67, 71))	('s an', 'Gene', '80218', (1, 5))	('s an', 'Gene', (1, 5))	('re-expression', 'Var', (72, 85))
83326	33937245	The depletion of CST led to telomere replication stress, including increased fragility and gradual telomere shortening.	('CST', 'Gene', (17, 20))	('stress', 'Disease', (49, 55))	('telomere shortening', 'CPA', (99, 118))	('stress', 'Disease', 'MESH:D000079225', (49, 55))	('depletion', 'Var', (4, 13))	('telomere shortening', 'Phenotype', 'HP:0031413', (99, 118))	('fragility', 'CPA', (77, 86))	('increased', 'PosReg', (67, 76))
83337	33937245	Germline CTC1 mutation has also been observed in DC and acquired bone marrow failure patients.	('bone marrow failure', 'Disease', (65, 84))	('observed', 'Reg', (37, 45))	('bone marrow failure', 'Disease', 'MESH:D000080983', (65, 84))	('patients', 'Species', '9606', (85, 93))	('mutation', 'Var', (14, 22))	('bone marrow failure', 'Phenotype', 'HP:0005528', (65, 84))	('CTC1', 'Gene', (9, 13))
83338	33937245	DC is a rare inherited bone marrow failure disorder caused by aberrant telomere shortening.	('bone marrow failure disorder', 'Disease', (23, 51))	('telomere shortening', 'Phenotype', 'HP:0031413', (71, 90))	('aberrant telomere shortening', 'Var', (62, 90))	('bone marrow failure', 'Phenotype', 'HP:0005528', (23, 42))	('caused by', 'Reg', (52, 61))	('bone marrow failure disorder', 'Disease', 'MESH:D000080983', (23, 51))
83339	33937245	It has been reviewed that the incidence of cancer in DC patients with abnormal telomere is dramatically high compared to the control group, including head and neck squamous cell carcinoma (HNSCC), skin SCC, anogenital cancer, stomach cancer, esophagus cancer, and lymphomas, as well as acute myeloid leukemia (AML).	('lymphomas', 'Disease', (264, 273))	('patients', 'Species', '9606', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('neck squamous cell carcinoma', 'Disease', (159, 187))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (159, 187))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (286, 308))	('leukemia', 'Phenotype', 'HP:0001909', (300, 308))	('stomach cancer', 'Disease', 'MESH:D013274', (226, 240))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (286, 308))	('acute myeloid leukemia', 'Disease', (286, 308))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (292, 308))	('stomach cancer', 'Phenotype', 'HP:0012126', (226, 240))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('abnormal telomere', 'Var', (70, 87))	('lymphomas', 'Disease', 'MESH:D008223', (264, 273))	('AML', 'Disease', 'MESH:D015470', (310, 313))	('cancer', 'Disease', (252, 258))	('AML', 'Phenotype', 'HP:0004808', (310, 313))	('AML', 'Disease', (310, 313))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('anogenital cancer', 'Disease', (207, 224))	('HNSCC', 'Phenotype', 'HP:0012288', (189, 194))	('skin SCC', 'Disease', (197, 205))	('cancer', 'Disease', (218, 224))	('cancer', 'Disease', (43, 49))	('anogenital cancer', 'Disease', 'MESH:D009369', (207, 224))	('skin SCC', 'Disease', 'MESH:D012871', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (150, 187))	('cancer', 'Disease', (234, 240))	('stomach cancer', 'Disease', (226, 240))
83340	33937245	TCGA expression analysis reveals that CTC1 mutation or CTC1 downregulation is highly associated with adrenocortical carcinoma, kidney chromophobe, rectum adenocarcinoma, uterine carcinosarcoma, and some other types of cancer formation.	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (101, 125))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('adrenocortical carcinoma', 'Disease', (101, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('mutation', 'Var', (43, 51))	('carcinosarcoma', 'Disease', (178, 192))	('CTC1', 'Gene', (55, 59))	('carcinosarcoma', 'Disease', 'MESH:D002296', (178, 192))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (147, 168))	('downregulation', 'NegReg', (60, 74))	('CTC1', 'Gene', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (170, 192))	('kidney chromophobe', 'Disease', 'MESH:D000238', (127, 145))	('cancer', 'Disease', (218, 224))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (101, 125))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('kidney chromophobe', 'Disease', (127, 145))	('rectum adenocarcinoma', 'Disease', (147, 168))
83356	33937245	Quick-change PCR was conducted to mutate the seed region of miR-367a in the CTC1 3'-UTR.	('mutate', 'Var', (34, 40))	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))
83391	32872281	Germline mutations of p53 are present in about 4% of patients with ACC and in 70% of patients with LFS.	('Germline mutations', 'Var', (0, 18))	('patients', 'Species', '9606', (53, 61))	('ACC', 'Phenotype', 'HP:0006744', (67, 70))	('ACC', 'Disease', (67, 70))	('p53', 'Gene', (22, 25))	('LFS', 'Disease', 'MESH:D016864', (99, 102))	('patients', 'Species', '9606', (85, 93))	('p53', 'Gene', '7157', (22, 25))	('LFS', 'Disease', (99, 102))
83464	32872281	Mitotane blocks steroidogenesis is at the level of 20, 22-desmolase, and 11beta-hydroxylase, therefore inducing adrenal insufficiency and thus requiring hydrocortisone replacement therapy.	('Mitotane', 'Var', (0, 8))	('inducing', 'PosReg', (103, 111))	('steroid', 'Chemical', 'MESH:D013256', (16, 23))	('hydrocortisone', 'Chemical', 'MESH:D006854', (153, 167))	('steroidogenesis', 'MPA', (16, 31))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (112, 133))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (112, 133))	('adrenal insufficiency', 'Disease', (112, 133))	('hydroxyl', 'Chemical', 'MESH:D017665', (80, 88))	('men', 'Species', '9606', (175, 178))
83465	32872281	Assessment of the adequacy of replacement therapy is hardly feasible on the basis of symptoms and quality of life in oncologic patients; plasma cortisol cannot be reliable since mitotane increases cortisol binding globulin levels and also urinary free cortisol may be falsely elevated due to the drug induced corticosteroid catabolism.	('mitotane', 'Var', (178, 186))	('elevated', 'PosReg', (276, 284))	('urinary free cortisol', 'MPA', (239, 260))	('mitotane', 'Chemical', 'MESH:D008939', (178, 186))	('cortisol', 'Chemical', 'MESH:D006854', (252, 260))	('cortisol', 'Chemical', 'MESH:D006854', (144, 152))	('increases cortisol', 'Phenotype', 'HP:0003118', (187, 205))	('corticosteroid catabolism', 'Disease', 'MESH:C565152', (309, 334))	('patients', 'Species', '9606', (127, 135))	('increases', 'PosReg', (187, 196))	('men', 'Species', '9606', (37, 40))	('cortisol binding globulin levels', 'MPA', (197, 229))	('corticosteroid catabolism', 'Disease', (309, 334))	('cortisol', 'Chemical', 'MESH:D006854', (197, 205))	('men', 'Species', '9606', (6, 9))
83565	32872281	Imbalances in production or metabolism of steroids lead to a wide range of steroid related disorders, sometimes complex adrenal diseases, including congenital adrenal hyperplasia (CAH), adrenal cancer, hyperaldosteronism, Cushing's syndrome, disorder of sexual development (DSD), and polycystic ovary syndrome (PCOS).	('ovary syndrome', 'Phenotype', 'HP:0000137', (295, 309))	("Cushing's syndrome", 'Disease', (222, 240))	('renal cancer', 'Phenotype', 'HP:0009726', (188, 200))	('disorder of sexual development', 'Disease', (242, 272))	('steroids', 'Chemical', 'MESH:D013256', (42, 50))	('adrenal diseases', 'Disease', 'MESH:C537027', (120, 136))	('adrenal diseases', 'Disease', (120, 136))	('steroid', 'Chemical', 'MESH:D013256', (42, 49))	('adrenal cancer', 'Disease', 'MESH:D000310', (186, 200))	('hyperaldosteronism', 'Disease', (202, 220))	('PCOS', 'Disease', (311, 315))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (202, 220))	('PCOS', 'Disease', 'MESH:D011085', (311, 315))	('lead to', 'Reg', (51, 58))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (148, 178))	('polycystic ovary syndrome', 'Disease', (284, 309))	('congenital adrenal hyperplasia', 'Disease', (148, 178))	('polycystic ovary syndrome', 'Disease', 'MESH:D011085', (284, 309))	('adrenal cancer', 'Disease', (186, 200))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (148, 178))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (159, 178))	('steroid', 'Chemical', 'MESH:D013256', (75, 82))	('polycystic ovary', 'Phenotype', 'HP:0000147', (284, 300))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (202, 220))	('complex', 'Disease', (112, 119))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (222, 240))	('Imbalances', 'Phenotype', 'HP:0002172', (0, 10))	('Imbalances', 'Var', (0, 10))	('men', 'Species', '9606', (268, 271))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('CAH', 'Phenotype', 'HP:0008258', (180, 183))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (222, 240))
83569	32872281	Indeed, as already described, alterations in the expression of steroidogenic enzymes in adrenal tumors often lead to the accumulation of steroid precursors and other steroid products that may immediately suggest at which level of steroidogenesis the defect lies.	('steroid', 'Chemical', 'MESH:D013256', (137, 144))	('lead to', 'Reg', (109, 116))	('adrenal tumor', 'Phenotype', 'HP:0100631', (88, 101))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('steroidogenic', 'Enzyme', (63, 76))	('steroid', 'Chemical', 'MESH:D013256', (230, 237))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('adrenal tumors', 'Disease', (88, 102))	('expression', 'MPA', (49, 59))	('steroid', 'Chemical', 'MESH:D013256', (63, 70))	('alterations', 'Var', (30, 41))	('accumulation of steroid precursors', 'MPA', (121, 155))	('steroid', 'Chemical', 'MESH:D013256', (166, 173))	('adrenal tumors', 'Disease', 'MESH:D000310', (88, 102))
83573	32872281	In conclusion, LC-MS/MS serum steroid paneling offers a potentially important advancement in the clinical workup of patients with adrenal diseases by combining the measurement of both common and rarely measured steroids in a single analysis.	('adrenal diseases', 'Disease', 'MESH:C537027', (130, 146))	('adrenal diseases', 'Disease', (130, 146))	('patients', 'Species', '9606', (116, 124))	('men', 'Species', '9606', (85, 88))	('LC-MS/MS', 'Var', (15, 23))	('steroid', 'Chemical', 'MESH:D013256', (211, 218))	('steroids', 'Chemical', 'MESH:D013256', (211, 219))	('men', 'Species', '9606', (171, 174))	('steroid', 'Chemical', 'MESH:D013256', (30, 37))
83646	31586196	In human primary ACC cultures, mitotane suppressed cell amount and cortisol production in a dose-dependent fashion.	('suppressed', 'NegReg', (40, 50))	('cortisol', 'Chemical', 'MESH:D006854', (67, 75))	('ACC', 'Disease', 'MESH:D018268', (17, 20))	('mitotane', 'Var', (31, 39))	('human', 'Species', '9606', (3, 8))	('mitotane', 'Chemical', 'MESH:D008939', (31, 39))	('cell amount', 'MPA', (51, 62))	('cortisol production', 'MPA', (67, 86))	('ACC', 'Disease', (17, 20))
83688	31586196	Mitotane decreased cortisol production in all cortisol-producing ACCs, and in general at concentrations much lower than required for inhibition of cell growth.	('Mitotane', 'Var', (0, 8))	('cortisol', 'Chemical', 'MESH:D006854', (19, 27))	('ACCs', 'Gene', '84680', (65, 69))	('ACCs', 'Gene', (65, 69))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('decreased', 'NegReg', (9, 18))	('cortisol production', 'MPA', (19, 38))	('decreased cortisol', 'Phenotype', 'HP:0008163', (9, 27))	('cortisol', 'Chemical', 'MESH:D006854', (46, 54))
83716	31586196	Research is now focusing on the predictive value of CYP2W1 polymorphisms in ACC.	('ACC', 'Disease', (76, 79))	('CYP2W1', 'Gene', '54905', (52, 58))	('CYP2W1', 'Gene', (52, 58))	('polymorphisms', 'Var', (59, 72))	('ACC', 'Disease', 'MESH:D018268', (76, 79))
83724	31586196	The trend towards higher SOAT1 protein expression (with mAb) in patients with a stronger response to mitotane in primary cultures on cortisol production is in concordance with previously published in vivo data showing a prolonged progression-free survival in patients with high SOAT1 protein expression, although they used the PoAb.	('high', 'Var', (273, 277))	('cortisol', 'Chemical', 'MESH:D006854', (133, 141))	('patients', 'Species', '9606', (259, 267))	('SOAT1', 'Gene', (278, 283))	('SOAT1', 'Gene', (25, 30))	('protein', 'Protein', (31, 38))	('patients', 'Species', '9606', (64, 72))	('expression', 'MPA', (39, 49))	('higher', 'PosReg', (18, 24))	('mitotane', 'Chemical', 'MESH:D008939', (101, 109))
83727	31586196	The increased mitotane response in patients with high SOAT1 expression might be explained by the fact that SOAT1 expression is a prerequisite for mitotane efficacy.	('expression', 'Var', (60, 70))	('mitotane response', 'MPA', (14, 31))	('mitotane', 'Chemical', 'MESH:D008939', (14, 22))	('high', 'Var', (49, 53))	('SOAT1', 'Gene', (54, 59))	('mitotane', 'Chemical', 'MESH:D008939', (146, 154))	('patients', 'Species', '9606', (35, 43))	('increased', 'PosReg', (4, 13))
83731	31586196	Furthermore, future studies could investigate whether factors that have currently been associated with prognosis in ACC, like CTNNB1 and TP53 mutations, Ki67, SF-1, Fascin-1, also correlate with mitotane sensitivity in vivo and in vitro.	('SF-1', 'Gene', (159, 163))	('mutations', 'Var', (142, 151))	('SF-1', 'Gene', '7536', (159, 163))	('mitotane sensitivity', 'MPA', (195, 215))	('CTNNB1', 'Gene', (126, 132))	('ACC', 'Disease', 'MESH:D018268', (116, 119))	('mitotane', 'Chemical', 'MESH:D008939', (195, 203))	('CTNNB1', 'Gene', '1499', (126, 132))	('TP53', 'Gene', '7157', (137, 141))	('correlate', 'Reg', (180, 189))	('ACC', 'Disease', (116, 119))	('TP53', 'Gene', (137, 141))
83765	29534182	When adjusted for age, sex, and urinary sodium excretion, the bimodally distributed aldosterone concentrations in the cohort with low renin hypertension were observed within normal range, suggesting a possibility that some proportion of patients with low renin hypertension might be likely to manifest autonomous secretion of aldosterone in the evolving process into clinically established state of PA. Another issue of clinical relevance to ARR screening is a shift of assays to active (or direct) renin concentrations.	('PA', 'Phenotype', 'HP:0011736', (399, 401))	('hypertension', 'Disease', 'MESH:D006973', (140, 152))	('aldosterone', 'Chemical', 'MESH:D000450', (326, 337))	('hypertension', 'Disease', (140, 152))	('patients', 'Species', '9606', (237, 245))	('rat', 'Species', '10116', (103, 106))	('urinary sodium', 'Phenotype', 'HP:0012605', (32, 46))	('renin', 'Gene', (255, 260))	('hypertension', 'Phenotype', 'HP:0000822', (140, 152))	('renin', 'Gene', '5972', (255, 260))	('renin', 'Gene', (134, 139))	('aldosterone', 'Chemical', 'MESH:D000450', (84, 95))	('hypertension', 'Disease', 'MESH:D006973', (261, 273))	('renin', 'Gene', (499, 504))	('renin', 'Gene', '5972', (134, 139))	('hypertension', 'Disease', (261, 273))	('low renin hypertension', 'Phenotype', 'HP:0003351', (251, 273))	('renin', 'Gene', '5972', (499, 504))	('rat', 'Species', '10116', (512, 515))	('sodium', 'Chemical', 'MESH:D012964', (40, 46))	('low renin hypertension', 'Phenotype', 'HP:0003351', (130, 152))	('low', 'Var', (251, 254))	('hypertension', 'Phenotype', 'HP:0000822', (261, 273))
83783	29534182	documented that rapid, automated CLEIA of cortisol significantly improved their success rates from 55% to 85%.	('improved', 'PosReg', (65, 73))	('rat', 'Species', '10116', (88, 91))	('cortisol', 'Chemical', 'MESH:D006854', (42, 50))	('CLEIA', 'Var', (33, 38))	('success', 'MPA', (80, 87))
83809	29534182	Extensive search was performed to discover compounds with higher potency and selectivity and clinically manageable property, and the following 3 agents have been evaluated in preclinical and clinical trials; apararenone (MT-3995), esaxerenone (CS-3150), and finerenone (BAY 94-8862).	('MT-3995', 'Chemical', '-', (221, 228))	('CS-3150', 'Var', (244, 251))	('esaxerenone', 'Chemical', '-', (231, 242))	('potency', 'MPA', (65, 72))	('BAY 94-8862', 'Chemical', 'MESH:C576501', (270, 281))	('finerenone', 'Chemical', 'MESH:C576501', (258, 268))	('CS-3150', 'Chemical', 'MESH:C000607547', (244, 251))	('apararenone', 'Chemical', '-', (208, 219))	('MT-3995', 'Var', (221, 228))
83811	29534182	Esaxerenone was reported to have improved potency and selectivity in vitro and more potent antihypertensive effects in rat models, when compared to spironolactone and eplerenone.	('Esaxerenone', 'Var', (0, 11))	('hypertensive', 'Disease', 'MESH:D006973', (95, 107))	('eplerenone', 'Chemical', 'MESH:D000077545', (167, 177))	('rat', 'Species', '10116', (119, 122))	('spironolactone', 'Chemical', 'MESH:D013148', (148, 162))	('potency', 'MPA', (42, 49))	('improved', 'PosReg', (33, 41))	('Esaxerenone', 'Chemical', '-', (0, 11))	('selectivity', 'MPA', (54, 65))	('hypertensive', 'Disease', (95, 107))
83816	29534182	documented that finerenone decreased hospitalization for cardiovascular causes and mortality in those with heart failure with reduced ejection fraction complicated with diabetes and/or renal insufficiency in a randomized controlled study when compared to eplerenone (ARTS-HF).	('decreased', 'NegReg', (27, 36))	('renal insufficiency', 'Disease', (185, 204))	('diabetes', 'Disease', (169, 177))	('hospitalization', 'MPA', (37, 52))	('heart failure', 'Phenotype', 'HP:0001635', (107, 120))	('heart failure', 'Disease', 'MESH:D006333', (107, 120))	('eplerenone', 'Chemical', 'MESH:D000077545', (255, 265))	('renal insufficiency', 'Disease', 'MESH:D051437', (185, 204))	('ejection fraction', 'MPA', (134, 151))	('ARTS-HF', 'Disease', 'MESH:C535388', (267, 274))	('renal insufficiency', 'Phenotype', 'HP:0000083', (185, 204))	('heart failure', 'Disease', (107, 120))	('mortality', 'CPA', (83, 92))	('diabetes', 'Disease', 'MESH:D003920', (169, 177))	('reduced', 'NegReg', (126, 133))	('finerenone', 'Var', (16, 26))	('ARTS-HF', 'Disease', (267, 274))	('finerenone', 'Chemical', 'MESH:C576501', (16, 26))	('reduced ejection fraction', 'Phenotype', 'HP:0012664', (126, 151))
83820	29534182	In its early phase, LCI699 showed significant reduction in blood pressure in those with essential hypertension (dosage: 0.25-1.0 mg/day) and reduction in both plasma aldosterone level and blood pressure in patients with PA (dosage: 1-2 mg/day) with accepted clinical tolerability.	('plasma aldosterone level', 'MPA', (159, 183))	('aldosterone', 'Chemical', 'MESH:D000450', (166, 177))	('reduction', 'NegReg', (46, 55))	('LCI699', 'Chemical', 'MESH:C553306', (20, 26))	('reduction in blood pressure', 'Phenotype', 'HP:0002615', (46, 73))	('hypertension', 'Disease', (98, 110))	('hypertension', 'Phenotype', 'HP:0000822', (98, 110))	('blood pressure', 'MPA', (188, 202))	('blood pressure', 'MPA', (59, 73))	('LCI699', 'Var', (20, 26))	('patients', 'Species', '9606', (206, 214))	('plasma aldosterone level', 'Phenotype', 'HP:0000859', (159, 183))	('PA', 'Phenotype', 'HP:0011736', (220, 222))	('reduction', 'NegReg', (141, 150))	('hypertension', 'Disease', 'MESH:D006973', (98, 110))
83821	29534182	LCI699, on the other hand, was reported to show attenuated secretion of cortisol in cosyntropin stimulation in dose- and time-dependent manner in following studies.	('attenuated', 'NegReg', (48, 58))	('LCI699', 'Chemical', 'MESH:C553306', (0, 6))	('secretion of cortisol in cosyntropin stimulation', 'MPA', (59, 107))	('LCI699', 'Var', (0, 6))	('cortisol', 'Chemical', 'MESH:D006854', (72, 80))
83823	29534182	reported that high dosage of eplerenone (100-200 mg/day) showed better clinical profiles of blood pressure and potassium metabolism, when compared to relatively low dosage of LCI699 (1-2 mg/day) by sequential administration of these 2 agents.	('better', 'PosReg', (64, 70))	('blood pressure', 'MPA', (92, 106))	('LCI699', 'Chemical', 'MESH:C553306', (175, 181))	('eplerenone', 'Gene', (29, 39))	('potassium metabolism', 'MPA', (111, 131))	('100-200 mg/day', 'Var', (41, 55))	('potassium', 'Chemical', 'MESH:D011188', (111, 120))	('rat', 'Species', '10116', (217, 220))	('eplerenone', 'Chemical', 'MESH:D000077545', (29, 39))
83824	29534182	According to the latest information on the trial registration, LCI699 has been clinically evaluated as an inhibitor of cortisol synthesis in those with excess secretion of cortisol.	('cortisol', 'Chemical', 'MESH:D006854', (119, 127))	('LCI699', 'Chemical', 'MESH:C553306', (63, 69))	('cortisol', 'Chemical', 'MESH:D006854', (172, 180))	('cortisol synthesis', 'MPA', (119, 137))	('secretion', 'MPA', (159, 168))	('rat', 'Species', '10116', (55, 58))	('LCI699', 'Var', (63, 69))	('excess secretion of cortisol', 'Phenotype', 'HP:0003118', (152, 180))
83829	29534182	first reported somatic mutations in KCNJ5, potassium voltage-gated channel subfamily J member 5, and other genes, including CACNA1D, ATP1A1, and ATP2B3 (calcium voltage-gated channel subunit alpha1 D, ATPase Na+/K+ transporting subunit alpha 1, ATPase plasma membrane Ca2+ transporting 3, respectively), were also identified as somatically mutated in APA.	('calcium', 'Chemical', 'MESH:D002118', (153, 160))	('CACNA1D', 'Gene', '776', (124, 131))	('ATP1A1', 'Gene', '476', (133, 139))	('CACNA1D', 'Gene', (124, 131))	('potassium', 'Chemical', 'MESH:D011188', (43, 52))	('PA', 'Phenotype', 'HP:0011736', (352, 354))	('ATP2B3', 'Gene', '492', (145, 151))	('ATP1A1', 'Gene', (133, 139))	('mutations', 'Var', (23, 32))	('ATP2B3', 'Gene', (145, 151))	('KCNJ5', 'Gene', (36, 41))	('KCNJ5', 'Gene', '3762', (36, 41))
83830	29534182	Through in vitro studies in adrenal cell lines, mutations in these genes have been demonstrated to increase intracellular calcium levels, resulting in CYP11B2 (aldosterone synthase) overexpression and aldosterone overproduction.	('overproduction', 'PosReg', (213, 227))	('aldosterone', 'Chemical', 'MESH:D000450', (160, 171))	('rat', 'Species', '10116', (90, 93))	('aldosterone synthase', 'Gene', (160, 180))	('CYP11B2', 'Gene', (151, 158))	('aldosterone synthase', 'Gene', '1585', (160, 180))	('intracellular calcium levels', 'MPA', (108, 136))	('aldosterone', 'MPA', (201, 212))	('CYP11B2', 'Gene', '1585', (151, 158))	('overexpression', 'PosReg', (182, 196))	('calcium', 'Chemical', 'MESH:D002118', (122, 129))	('increase', 'PosReg', (99, 107))	('increase intracellular calcium', 'Phenotype', 'HP:0003575', (99, 129))	('mutations', 'Var', (48, 57))	('aldosterone', 'Chemical', 'MESH:D000450', (201, 212))
83831	29534182	To date, approximately 40% and 70% of sporadic APA in Caucasian and Eastern Asian patients harbor somatic mutations in KCNJ5, respectively, while each of the other genes accounts for up to 10% of APA in these populations.	('KCNJ5', 'Gene', '3762', (119, 124))	('PA', 'Phenotype', 'HP:0011736', (197, 199))	('patients', 'Species', '9606', (82, 90))	('mutations', 'Var', (106, 115))	('KCNJ5', 'Gene', (119, 124))	('APA', 'Disease', (47, 50))	('PA', 'Phenotype', 'HP:0011736', (48, 50))
83832	29534182	Whether the rest of APA, currently regarded as "wild-type", harbor abnormalities in other gene(s) and/or epigenetic modifications needs further experiments.	('harbor abnormalities', 'Disease', (60, 80))	('PA', 'Phenotype', 'HP:0011736', (21, 23))	('epigenetic modifications', 'Var', (105, 129))	('harbor abnormalities', 'Disease', 'MESH:C537062', (60, 80))
83833	29534182	In addition to these aldosterone-driver gene mutations, somatic mutations in CTNNB1 (catenin beta 1) are also reported in up to 5% of APA, but its involvement in tumorigenesis warrants further investigation.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('CTNNB1', 'Gene', (77, 83))	('PA', 'Phenotype', 'HP:0011736', (135, 137))	('catenin beta 1', 'Gene', '1499', (85, 99))	('reported', 'Reg', (110, 118))	('aldosterone', 'Chemical', 'MESH:D000450', (21, 32))	('CTNNB1', 'Gene', '1499', (77, 83))	('mutations', 'Var', (64, 73))	('APA', 'Disease', (134, 137))	('catenin beta 1', 'Gene', (85, 99))
83839	29534182	Furthermore, hypothesizing these APCC harbor somatic mutations similar to APA, we performed targeted next-generation sequencing on APCC from the unilateral non-APA cohort and the normotensive cohort, and showed that these APCC harbor somatic mutations in genes previously described as mutated in APA.	('rat', 'Species', '10116', (110, 113))	('PA', 'Phenotype', 'HP:0011736', (297, 299))	('PA', 'Phenotype', 'HP:0011736', (75, 77))	('mutations', 'Var', (242, 251))	('mutations', 'Var', (53, 62))	('PA', 'Phenotype', 'HP:0011736', (161, 163))
83858	27293433	In addition, by inducing expression of the regulatory protein SOCS 3, Ang II may inhibit insulin-induced tyrosine phosphorylation of IRS1 and IRS2 and [Ser473] phosphorylation of AKT, as a consequence, impairing the transduction of insulin signals in the JAK2/STAT-5b pathway.	('SOCS 3', 'Gene', '9021', (62, 68))	('SOCS 3', 'Gene', (62, 68))	('insulin', 'Gene', '3630', (232, 239))	('insulin', 'Gene', '3630', (89, 96))	('AKT', 'Pathway', (179, 182))	('JAK2', 'Gene', (255, 259))	('STAT-5b', 'Gene', '6777', (260, 267))	('IRS2', 'Gene', '8660', (142, 146))	('Ang', 'Var', (70, 73))	('inducing', 'Reg', (16, 24))	('STAT-5b', 'Gene', (260, 267))	('insulin', 'Gene', (232, 239))	('insulin', 'Gene', (89, 96))	('IRS2', 'Gene', (142, 146))	('Ser473', 'Chemical', '-', (152, 158))	('tyrosine', 'Chemical', 'MESH:D014443', (105, 113))	('transduction', 'MPA', (216, 228))	('JAK2', 'Gene', '3717', (255, 259))	('inhibit', 'NegReg', (81, 88))	('IRS1', 'Gene', '3667', (133, 137))	('IRS1', 'Gene', (133, 137))	('impairing', 'NegReg', (202, 211))
83861	27293433	Mayer and colleagues found that, after treatment with Ang II, the phospho-ERK1/2 activity at the hypothalamic level was significantly higher in rats pretreated with insulin than in those treated with insulin or Ang II alone.	('insulin', 'Gene', '3630', (200, 207))	('insulin', 'Gene', (200, 207))	('higher', 'PosReg', (134, 140))	('rats', 'Species', '10116', (144, 148))	('phospho-ERK1/2 activity', 'MPA', (66, 89))	('insulin', 'Gene', (165, 172))	('insulin', 'Gene', '3630', (165, 172))	('Ang', 'Var', (54, 57))
83870	27293433	PKC inhibitor Go6983, PI3K inhibitor LY294202, and MEK1/2 inhibitor U0126 were purchased from Calbiochem (San Diego, CA, USA).	('Go6983', 'Chemical', 'MESH:C465664', (14, 20))	('LY294202', 'Var', (37, 45))	('MEK1/2', 'Gene', '5604;5605', (51, 57))	('MEK1/2', 'Gene', (51, 57))	('LY294202', 'Chemical', '-', (37, 45))	('U0126', 'Chemical', 'MESH:C113580', (68, 73))
83874	27293433	Anti-phospho-ERK1/2 (Thr202/Tyr204), anti-phospho-AKT (Ser473), anti-ERK1/2, and anti-AKT antibodies were from Cell Signaling Technology (Danvers, MA, USA).	('Thr202/Tyr204', 'Var', (21, 34))	('Ser473', 'Chemical', '-', (55, 61))	('Thr202', 'Chemical', '-', (21, 27))	('Tyr204', 'Chemical', '-', (28, 34))	('Ser473', 'Var', (55, 61))
83891	27293433	Phospho-ERK1/2 was increased much more by Ang II in combination with insulin/IGF-1 than by Ang II or insulin/IGF-1 alone, indicating that the elevation was caused by more than an additive effect.	('insulin', 'Gene', (101, 108))	('insulin', 'Gene', '3630', (101, 108))	('Phospho-ERK1/2', 'MPA', (0, 14))	('IGF-1', 'Gene', '3479', (77, 82))	('IGF-1', 'Gene', (77, 82))	('IGF-1', 'Gene', '3479', (109, 114))	('Ang', 'Var', (42, 45))	('IGF-1', 'Gene', (109, 114))	('increased', 'PosReg', (19, 28))	('insulin', 'Gene', (69, 76))	('combination', 'Interaction', (52, 63))	('insulin', 'Gene', '3630', (69, 76))
83897	27293433	Both ERK1/2 inhibitor U0126 and PKC inhibitor Go6983 showed a marginal stimulatory effect on phospho-AKT, under basal condition or after treatment with agonists (Figures 4 and 5).	('phospho-AKT', 'Pathway', (93, 104))	('inhibitor U0126', 'Var', (12, 27))	('U0126', 'Var', (22, 27))	('Go6983', 'Chemical', 'MESH:C465664', (46, 52))	('U0126', 'Chemical', 'MESH:C113580', (22, 27))	('ERK1/2', 'Gene', (5, 11))	('stimulatory', 'Reg', (71, 82))
83904	27293433	Monoclonal antibodies against IGF-1R were found to decrease the cell surface expression of IGF-1R homodimers and IR-IGF-1R heterodimers by causing receptor internalization.	('IGF-1R', 'Gene', '3480', (116, 122))	('IGF-1R', 'Gene', (116, 122))	('IGF-1R', 'Gene', (91, 97))	('IGF-1R', 'Gene', '3480', (91, 97))	('IGF-1R', 'Gene', '3480', (30, 36))	('cell surface expression', 'MPA', (64, 87))	('antibodies', 'Var', (11, 21))	('IGF-1R', 'Gene', (30, 36))	('decrease', 'NegReg', (51, 59))	('causing', 'Reg', (139, 146))	('receptor internalization', 'MPA', (147, 171))	('homodimers', 'MPA', (98, 108))	('heterodimers', 'Interaction', (123, 135))
83914	27293433	In vascular smooth muscle cells (VSMC), Ang II-elicited ERK1/2 activation leads to phosphorylation of IRS1 at Ser307 and Ser616, thereby inhibiting AKT activation and ultimately suppressing the insulin-induced glucose uptake.	('Ser616', 'Var', (121, 127))	('glucose', 'Chemical', 'MESH:D005947', (210, 217))	('Ser307', 'Chemical', '-', (110, 116))	('insulin', 'Gene', (194, 201))	('ERK1/2', 'Gene', (56, 62))	('insulin', 'Gene', '3630', (194, 201))	('inhibiting', 'NegReg', (137, 147))	('phosphorylation', 'MPA', (83, 98))	('suppressing', 'NegReg', (178, 189))	('IRS1', 'Gene', '3667', (102, 106))	('activation', 'MPA', (152, 162))	('Ser307', 'Var', (110, 116))	('IRS1', 'Gene', (102, 106))	('Ser616', 'Chemical', '-', (121, 127))	('AKT', 'Pathway', (148, 151))
83915	27293433	reported that Ang II inhibited insulin-mediated GLUT4 translocation in rat skeletal muscle cells through at least two pathways: (1) the transient activation of ERK1/2 which inhibits IRS1/2 and (2) direct inhibitory nitration of AKT.	('insulin', 'Gene', '3630', (31, 38))	('activation', 'PosReg', (146, 156))	('AKT', 'Pathway', (228, 231))	('rat', 'Species', '10116', (71, 74))	('ERK1/2', 'Protein', (160, 166))	('Ang', 'Var', (14, 17))	('IRS1/2', 'Gene', (182, 188))	('IRS1/2', 'Gene', '25467;29376', (182, 188))	('rat', 'Species', '10116', (218, 221))	('insulin', 'Gene', (31, 38))	('inhibited', 'NegReg', (21, 30))	('inhibits', 'NegReg', (173, 181))	('GLUT4', 'Gene', (48, 53))	('GLUT4', 'Gene', '25139', (48, 53))
83965	25767039	Blood samples from patients were collected at 30 min before infusion, and at 0, 5, 15, 30, 60, 90, 120, 180, 240 min, and 24 h after infusion completion on C1D1, C1D3, and C2D1 if treatment was continued.	('C1D3', 'Var', (162, 166))	('C2D1', 'Var', (172, 176))	('patients', 'Species', '9606', (19, 27))	('C1D1', 'Var', (156, 160))
84022	25767039	This would be consistent with the finding that on C2D1, the anti-IL-13-PE antibody titer was much higher in Pt.5 (104) than in Pt.1 (50) (Fig.3A).	('IL-13', 'Gene', (65, 70))	('Pt.5 (104', 'Var', (108, 117))	('IL-13', 'Gene', '3596', (65, 70))	('higher', 'PosReg', (98, 104))	('titer', 'MPA', (83, 88))	('C2D1', 'Var', (50, 54))	('PE', 'Chemical', '-', (71, 73))
84034	25925845	Germline TP53 mutational spectrum in French Canadians with breast cancer Specific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors.	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('hereditary breast-ovarian cancer', 'Disease', (108, 140))	('PALB2', 'Gene', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('TP53', 'Gene', '7157', (9, 13))	('PALB2', 'Gene', '79728', (191, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('BRCA2', 'Gene', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('hereditary breast-ovarian cancer', 'Disease', 'MESH:D061325', (108, 140))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('breast cancer', 'Disease', (59, 72))	('TP53', 'Gene', (9, 13))	('BRCA1', 'Gene', '672', (174, 179))	('BRCA2', 'Gene', '675', (181, 186))	('BRCA1', 'Gene', (174, 179))	('Canada', 'Disease', (254, 260))	('French Canadians', 'Disease', (226, 242))	('mutations', 'Var', (91, 100))
84035	25925845	Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (58, 78))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('Li-Fraumeni syndrome', 'Disease', (58, 78))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutation', 'Var', (14, 22))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
84036	25925845	We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutation', 'Var', (27, 35))	('cancer', 'Disease', (137, 143))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
84037	25925845	Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer.	('hereditary cancer', 'Disease', 'MESH:D009369', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (342, 348))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('TP53', 'Gene', (202, 206))	('breast cancer', 'Disease', (287, 300))	('BRCA2', 'Gene', '675', (152, 157))	('cancer', 'Disease', (294, 300))	('mutations', 'Var', (207, 216))	('TP53', 'Gene', '7157', (246, 250))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('TP53', 'Gene', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('BRCA1', 'Gene', '672', (142, 147))	('BRCA1', 'Gene', (142, 147))	('cancer', 'Disease', (107, 113))	('TP53', 'Gene', '7157', (202, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (287, 300))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('hereditary cancer', 'Disease', (96, 113))	('breast cancer', 'Disease', 'MESH:D001943', (287, 300))	('TP53', 'Gene', (246, 250))	('TP53', 'Gene', '7157', (17, 21))	('cancer', 'Disease', (66, 72))	('BRCA2', 'Gene', (152, 157))
84040	25925845	Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('TP53', 'Gene', '7157', (84, 88))	('cancer', 'Disease', (144, 150))	('mutations', 'Var', (89, 98))	('TP53', 'Gene', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (189, 195))
84041	25925845	Five new TP53 mutations were identified in six pedigrees from hereditary cancer clinics.	('hereditary cancer', 'Disease', 'MESH:D009369', (62, 79))	('hereditary cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
84043	25925845	A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier.	('c.844C>T [p.Arg282Trp]', 'Var', (72, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('p.Arg282Trp', 'Mutation', 'rs28934574', (82, 93))	('c.844C>T', 'Mutation', 'rs28934574', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('breast cancer', 'Disease', (39, 52))
84045	25925845	The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('c.685T>C', 'Mutation', 'rs1064794312', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('c.685T>C [p.Cys229Arg]', 'Var', (56, 78))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('p.Cys229Arg', 'Mutation', 'rs1064794312', (66, 77))
84046	25925845	All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age.	('mutation', 'Var', (9, 17))	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('TP53', 'Gene', (4, 8))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('TP53', 'Gene', '7157', (4, 8))	('women', 'Species', '9606', (46, 51))
84047	25925845	In all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families.	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
84048	25925845	Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutation', 'Var', (44, 52))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('cancer', 'Disease', (37, 43))	('breast cancer', 'Disease', (30, 43))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (137, 157))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Li-Fraumeni syndrome', 'Disease', (137, 157))
84049	25925845	Germline TP53 mutations have been reported in rare instances of hereditary breast cancer (HBC) and hereditary breast and ovarian cancer (HBOC) syndrome families found negative for mutations in the BRCA1 and BRCA2 breast and ovarian cancer susceptibility genes.	('BRCA1', 'Gene', (197, 202))	('TP53', 'Gene', '7157', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('hereditary breast cancer', 'Disease', (64, 88))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('BRCA2', 'Gene', (207, 212))	('mutations', 'Var', (14, 23))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (213, 238))	('mutations', 'Var', (180, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (110, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('TP53', 'Gene', (9, 13))	('BRCA2', 'Gene', '675', (207, 212))	('hereditary breast and ovarian cancer (HBOC) syndrome', 'Disease', 'MESH:D061325', (99, 151))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (64, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (224, 238))	('BRCA1', 'Gene', '672', (197, 202))
84050	25925845	TP53, BRCA1 and BRCA2 mutation carriers share in common a significant risk for premenopausal breast cancer with estimated lifetime risks of 80-90%, 60-85% and 40-85%, respectively.	('TP53', 'Gene', '7157', (0, 4))	('mutation', 'Var', (22, 30))	('BRCA1', 'Gene', (6, 11))	('TP53', 'Gene', (0, 4))	('BRCA2', 'Gene', '675', (16, 21))	('premenopausal breast cancer', 'Disease', 'MESH:D001943', (79, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BRCA2', 'Gene', (16, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('premenopausal breast cancer', 'Disease', (79, 106))	('BRCA1', 'Gene', '672', (6, 11))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (79, 106))
84051	25925845	The rarity of TP53 mutation carrier HBC/HBOC families reflects the estimated 0.025% frequency of mutation carriers in the population.	('TP53', 'Gene', (14, 18))	('TP53', 'Gene', '7157', (14, 18))	('mutation', 'Var', (19, 27))
84058	25925845	Identifying TP53 mutation carriers is important as evidence suggests that mutation carrier LFS patients have an abnormal response to low dose radiation and should avoid radiation therapy whenever possible in order to limit the risk of secondary radiation-induced malignancies.	('malignancies', 'Disease', (263, 275))	('mutation', 'Var', (74, 82))	('patients', 'Species', '9606', (95, 103))	('radiation-induced malignancies', 'Phenotype', 'HP:0010997', (245, 275))	('response to low dose radiation', 'MPA', (121, 151))	('TP53', 'Gene', '7157', (12, 16))	('malignancies', 'Disease', 'MESH:D009369', (263, 275))	('TP53', 'Gene', (12, 16))
84061	25925845	Routine screening for germline TP53 mutations in breast cancer cases has not been advocated due to the low estimated frequency of carriers.	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (36, 45))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
84063	25925845	In a recent study of 28 women with diagnoses of breast cancer before age 30 years, TP53 mutation carriers were found in 33.3% of the cases where 7.7% did not meet criteria for LSF.	('TP53', 'Gene', '7157', (83, 87))	('found', 'Reg', (111, 116))	('mutation', 'Var', (88, 96))	('TP53', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('women', 'Species', '9606', (24, 29))	('LSF', 'Gene', (176, 179))	('LSF', 'Gene', '7024', (176, 179))
84064	25925845	In the United Kingdom, it is estimated that 6% of women with breast cancer under age 31 years carry TP53 mutations, and based on this evidence, a prevalence of 1/10,000 to 1/25,000 live births harboring pathogenic mutations was estimated.	('TP53', 'Gene', '7157', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('TP53', 'Gene', (100, 104))	('women', 'Species', '9606', (50, 55))	('mutations', 'Var', (105, 114))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
84065	25925845	The significance of mutation carriers the young age of onset breast cancer has resulted in recommendations from the National Comprehensive Cancer Network  for clinical practice of genetic/familial high risk cases of breast and ovarian cancers to test (concurrent with or following genetic testing of BRCA1 and BRCA2) women with breast cancer diagnoses less than age 35 years of age.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutation', 'Var', (20, 28))	('Cancer', 'Disease', (139, 145))	('women', 'Species', '9606', (317, 322))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('BRCA2', 'Gene', (310, 315))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (216, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (227, 241))	('Cancer', 'Disease', 'MESH:D009369', (139, 145))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (328, 341))	('BRCA2', 'Gene', '675', (310, 315))	('breast cancer', 'Disease', 'MESH:D001943', (328, 341))	('breast cancer', 'Disease', (328, 341))	('BRCA1', 'Gene', '672', (300, 305))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('BRCA1', 'Gene', (300, 305))	('ovarian cancers', 'Phenotype', 'HP:0100615', (227, 242))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))
84066	25925845	We have reported germline TP53 mutations in 3.8% of 52 HBC/HBOC families of French Canadian descent found negative for BRCA1 and BRCA2 mutations.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('BRCA1', 'Gene', (119, 124))	('BRCA2', 'Gene', (129, 134))	('negative', 'NegReg', (106, 114))	('mutations', 'Var', (135, 144))	('BRCA2', 'Gene', '675', (129, 134))	('TP53', 'Gene', '7157', (26, 30))	('BRCA1', 'Gene', '672', (119, 124))
84067	25925845	Our initial study was prompted by the observation of a TP53 mutation-positive HBC French Canadian family that also exhibited LFS features.	('mutation-positive', 'Var', (60, 77))	('TP53', 'Gene', (55, 59))	('positive HBC', 'Phenotype', 'HP:0032146', (69, 81))	('TP53', 'Gene', '7157', (55, 59))
84069	25925845	The carrier frequency of TP53 mutations in the French Canadian population of Quebec is unknown.	('TP53', 'Gene', (25, 29))	('mutations', 'Var', (30, 39))	('TP53', 'Gene', '7157', (25, 29))
84070	25925845	A targeted analysis of c.638G>A [p.Arg213Gln] and c.869G>A [p.Arg290His], mutations initially found in a TP53 mutation screen of HBC families, did not identify any additional carriers among the 381 French Canadian women with breast cancer before age 50 years that were not selected for a family history of cancer.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('c.638G>A', 'Mutation', 'rs587778720', (23, 31))	('cancer', 'Disease', (232, 238))	('women', 'Species', '9606', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('c.869G>A', 'Mutation', 'rs55819519', (50, 58))	('c.869G>A [', 'Var', (50, 60))	('TP53', 'Gene', '7157', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('TP53', 'Gene', (105, 109))	('p.Arg213Gln', 'Mutation', 'rs587778720', (33, 44))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('p.Arg290His', 'Mutation', 'rs55819519', (60, 71))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('c.638G>A [p.Arg213Gln]', 'Var', (23, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancer', 'Disease', (225, 238))	('cancer', 'Disease', (306, 312))
84072	25925845	Since our report of TP53 mutations, a specific mutation in a moderately penetrant breast cancer susceptibility gene, PALB2 (c.2323C>T [p.Gln775Ter]), has been found to recur in French Canadian HBC families and breast cancer cases.	('breast cancer', 'Disease', (82, 95))	('mutations', 'Var', (25, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('TP53', 'Gene', (20, 24))	('PALB2', 'Gene', '79728', (117, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('p.Gln775Ter', 'Mutation', 'rs180177111', (135, 146))	('breast cancer', 'Disease', 'MESH:D001943', (210, 223))	('breast cancer', 'Disease', (210, 223))	('c.2323C>T', 'Mutation', 'rs180177111', (124, 133))	('PALB2', 'Gene', (117, 122))	('c.2323C>T', 'Var', (124, 133))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('TP53', 'Gene', '7157', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
84074	25925845	To further characterized the spectrum of TP53 germline mutations in French Canadians, we describe the mutations found in hereditary cancer clinics, investigate breast/ovarian cancer probands from 37 new HBC/HBOC families found negative for BRCA1 and BRCA2 germline mutations, and report on the frequency of mutations found in a targeted screen of 1235 French Canadian breast cancer cases for TP53 mutations found in hereditary cancer families.	('TP53', 'Gene', '7157', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('BRCA2', 'Gene', '675', (250, 255))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('BRCA1', 'Gene', '672', (240, 245))	('BRCA1', 'Gene', (240, 245))	('TP53', 'Gene', (392, 396))	('mutations', 'Var', (102, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (368, 381))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (55, 64))	('breast cancer', 'Disease', 'MESH:D001943', (368, 381))	('hereditary cancer', 'Disease', (121, 138))	('hereditary cancer', 'Disease', (416, 433))	('breast cancer', 'Disease', (368, 381))	('breast/ovarian cancer', 'Disease', 'MESH:D010051', (160, 181))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('ovarian cancer', 'Phenotype', 'HP:0100615', (167, 181))	('breast/ovarian cancer', 'Disease', (160, 181))	('hereditary cancer', 'Disease', 'MESH:D009369', (416, 433))	('hereditary cancer', 'Disease', 'MESH:D009369', (121, 138))	('TP53', 'Gene', '7157', (392, 396))	('BRCA2', 'Gene', (250, 255))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
84075	25925845	Five new TP53 mutations in French Canadian cancer families were identified among the six pedigrees provided by local hereditary cancer clinics.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('hereditary cancer', 'Disease', 'MESH:D009369', (117, 134))	('cancer', 'Disease', (43, 49))	('hereditary cancer', 'Disease', (117, 134))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutations', 'Var', (14, 23))	('cancer', 'Disease', (128, 134))
84077	25925845	However, a screen of genomic regions found mutated in French Canadian cancer families identified a breast cancer case harboring the c.844C>T [p.Arg282Trp] mutation.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', (99, 112))	('c.844C>T [p.Arg282Trp]', 'Var', (132, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('p.Arg282Trp', 'Mutation', 'rs28934574', (142, 153))	('c.844C>T', 'Mutation', 'rs28934574', (132, 140))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
84079	25925845	Two breast cancer cases each carrying a c.685T>C [p.Cys229Arg] mutation were also found.	('c.685T>C [p.Cys229Arg]', 'Var', (40, 62))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('p.Cys229Arg', 'Mutation', 'rs1064794312', (50, 61))	('breast cancer', 'Disease', (4, 17))	('c.685T>C', 'Mutation', 'rs1064794312', (40, 48))
84083	25925845	From this request, six TP53 mutation carrier pedigrees (F171, F187, F1580, F1581, F1582 and F1583) were provided to the study by the hereditary cancer clinics affiliated with the McGill University Health Centre (MUHC), Jewish General Hospital and Centre hospitalier de l'Universite de Montreal (CHUM) (Figures 1,2,3,4 and 5).	('F1582', 'Var', (82, 87))	('F1581', 'Var', (75, 80))	('hereditary cancer', 'Disease', 'MESH:D009369', (133, 150))	('F171', 'Var', (56, 60))	('F1580', 'Var', (68, 73))	('TP53', 'Gene', '7157', (23, 27))	('F187', 'Var', (62, 66))	('F1583', 'Var', (92, 97))	('TP53', 'Gene', (23, 27))	('hereditary cancer', 'Disease', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
84084	25925845	All index cases carrying a TP53 mutation in the pedigrees self reported French Canadian (Quebec) ancestry.	('TP53', 'Gene', '7157', (27, 31))	('French Canadian', 'Disease', (72, 87))	('TP53', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))
84085	25925845	The pedigrees were provided along with the TP53 mutation results as indicated on the pedigrees, and not all cancer phenotypes indicated on the pedigrees (to our knowledge) were confirmed.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutation', 'Var', (48, 56))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
84086	25925845	The adrenocortical carcinomas (ACC) cases in pedigrees F171 (Figure 1) and F187 (Figure 2) were described in an earlier study of the role of germline TP53 mutations in childhood ACC but the pedigrees had not been previously reported.	('adrenocortical carcinomas', 'Disease', (4, 29))	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (155, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (4, 29))	('childhood ACC', 'Disease', (168, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (4, 29))	('TP53', 'Gene', '7157', (150, 154))
84087	25925845	The proband in Family F1581 had been tested due to prior knowledge of a TP53 mutation carrier in a family with childhood ACC (Figure 2).	('TP53', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('TP53', 'Gene', '7157', (72, 76))
84088	25925845	The remaining three families (F1580, F1582, and F1583) that were provided to the study were tested for TP53 because they each had at least one LFS spectrum cancer.	('F1582', 'Var', (37, 42))	('TP53', 'Gene', '7157', (103, 107))	('F1583', 'Var', (48, 53))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('TP53', 'Gene', (103, 107))	('had', 'Reg', (126, 129))	('F1580', 'Var', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
84089	25925845	Table 1 includes information for all TP53 mutation positive pedigrees that were provided by the hereditary cancer clinics as described above.	('hereditary cancer', 'Disease', 'MESH:D009369', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('hereditary cancer', 'Disease', (96, 113))	('mutation', 'Var', (42, 50))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))
84090	25925845	Table 1 also includes information for three other pedigrees (F875, F1039 and F1444) that have been described previously in the context of the TP53 mutation screening study of HBC families from our group.	('TP53', 'Gene', '7157', (142, 146))	('F875', 'Var', (61, 65))	('TP53', 'Gene', (142, 146))	('F1444', 'Var', (77, 82))	('F1039', 'Var', (67, 72))
84092	25925845	The index cases were recruited through the hereditary cancer clinics affiliated with the MUHC and CHUM as part of research studies of BRCA1/BRCA2 mutations in families of French Canadian (Quebec) origin as described previously.	('BRCA1', 'Gene', (134, 139))	('mutations', 'Var', (146, 155))	('BRCA2', 'Gene', (140, 145))	('BRCA1', 'Gene', '672', (134, 139))	('hereditary cancer', 'Disease', 'MESH:D009369', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('hereditary cancer', 'Disease', (43, 60))	('BRCA2', 'Gene', '675', (140, 145))
84094	25925845	An index case from each family had been evaluated for BRCA1 and BRCA2 mutations by commercial DNA sequencing (Myriad Genetics, Myriad Genetics Laboratories, Salt Lake City, UT, USA) and was found negative or found to harbor a variant of unknown clinical significance.	('BRCA2', 'Gene', '675', (64, 69))	('mutations', 'Var', (70, 79))	('BRCA1', 'Gene', '672', (54, 59))	('BRCA2', 'Gene', (64, 69))	('BRCA1', 'Gene', (54, 59))
84099	25925845	Among these 1235 patients, there were 62 known carriers of BRCA1, BRCA2, PALB2 or CHEK2 mutations.	('BRCA2', 'Gene', (66, 71))	('PALB2', 'Gene', '79728', (73, 78))	('BRCA1', 'Gene', '672', (59, 64))	('BRCA1', 'Gene', (59, 64))	('mutations', 'Var', (88, 97))	('BRCA2', 'Gene', '675', (66, 71))	('patients', 'Species', '9606', (17, 25))	('CHEK2', 'Gene', '11200', (82, 87))	('CHEK2', 'Gene', (82, 87))	('PALB2', 'Gene', (73, 78))
84101	25925845	The mutation analysis of the index cases from 36 HBC/HBOC cancer families was designed to detect variants in the protein coding exons 2 to 11, and adjacent splice sites of TP53 as described previously.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('HBC/HBOC cancer', 'Disease', 'MESH:D061325', (49, 64))	('variants', 'Var', (97, 105))	('HBC/HBOC cancer', 'Disease', (49, 64))
84107	25925845	In a genetic analysis of TP53 we initially reported three mutation carrier HBC families of French Canadian descent (F875, F1039 and F1444), where F1039 and F1444 harbored the same c.638G>A [p.Arg213Gln] mutation and were found to be closely related following a case review (Table 1).	('TP53', 'Gene', (25, 29))	('F1039', 'Var', (146, 151))	('c.638G>A [p.Arg213Gln]', 'Var', (180, 202))	('F1444', 'Var', (156, 161))	('p.Arg213Gln', 'Mutation', 'rs587778720', (190, 201))	('c.638G>A', 'Mutation', 'rs587778720', (180, 188))	('TP53', 'Gene', '7157', (25, 29))
84108	25925845	To further characterize the spectrum of TP53 mutations in the French Canadian population of Quebec, we requested mutation positive pedigrees from hereditary cancer clinics based in Montreal, Quebec.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mutations', 'Var', (45, 54))	('hereditary cancer', 'Disease', 'MESH:D009369', (146, 163))	('hereditary cancer', 'Disease', (146, 163))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))
84109	25925845	Six TP53 mutation positive pedigrees (F171, F187, F1580, F1581, F1582 and F1583) where provided to the study along with carrier status and familial cancer phenotypes (Figures 1,2,3,4 and 5).	('F1580', 'Var', (50, 55))	('TP53', 'Gene', (4, 8))	('F171', 'Var', (38, 42))	('F187', 'Var', (44, 48))	('F1582', 'Var', (64, 69))	('familial cancer', 'Disease', 'MESH:D009369', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('F1581', 'Var', (57, 62))	('F1583', 'Var', (74, 79))	('familial cancer', 'Disease', (139, 154))	('TP53', 'Gene', '7157', (4, 8))
84110	25925845	All mutations are missense and predicted to affect the DNA binding domain of p53 based on the IARC TP53 Database.	('TP53', 'Gene', (99, 103))	('missense', 'Var', (18, 26))	('DNA binding domain', 'MPA', (55, 73))	('TP53', 'Gene', '7157', (99, 103))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('mutations', 'Var', (4, 13))	('affect', 'Reg', (44, 50))
84111	25925845	Three of pedigrees provided by the hereditary cancer clinics had at least one pediatric ACC case (F171, F187 and F1581) (Figures 1 and 2).	('F171', 'Var', (98, 102))	('hereditary cancer', 'Disease', 'MESH:D009369', (35, 52))	('hereditary cancer', 'Disease', (35, 52))	('F1581', 'Var', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('F187', 'Var', (104, 108))	('pediatric ACC', 'Disease', (78, 91))
84112	25925845	As mentioned above (see Methods), the ACC cases in families F171 and F187 were tested for TP53 in the context of a study evaluating germline TP53 mutation in this disease.	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('TP53', 'Gene', (90, 94))	('mutation', 'Var', (146, 154))
84113	25925845	Interestingly, families F187 and F1581 both harbored the same mutation, c.655C>T [p.Pro219Ser] (Figure 2).	('p.Pro219Ser', 'Mutation', 'rs879253894', (82, 93))	('c.655C>T', 'Mutation', 'rs879253894', (72, 80))	('harbored', 'Reg', (44, 52))	('c.655C>T [', 'Var', (72, 82))
84117	25925845	Additional cancer cases have since been reported for the ACC case linked to family F187 (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('linked', 'Reg', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('family F187', 'Var', (76, 87))	('cancer', 'Disease', (11, 17))
84119	25925845	The remaining families that were provided from the hereditary cancer clinics (F1580, F1582 and F1583 (Figures 3,4 and 5)) had cancer cases consistent with LFS syndrome, such as pediatric or young age of onset brain tumors and sarcomas, and each family harbored a unique TP53 mutation (Table 1).	('F1582', 'Var', (85, 90))	('TP53', 'Gene', '7157', (270, 274))	('brain tumors', 'Disease', 'MESH:D001932', (209, 221))	('brain tumors', 'Phenotype', 'HP:0030692', (209, 221))	('LFS syndrome', 'Disease', (155, 167))	('F1580', 'Var', (78, 83))	('pediatric', 'Disease', (177, 186))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', (62, 68))	('sarcomas', 'Disease', 'MESH:D012509', (226, 234))	('brain tumors', 'Disease', (209, 221))	('F1583', 'Var', (95, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('LFS syndrome', 'Disease', 'MESH:D016864', (155, 167))	('sarcomas', 'Disease', (226, 234))	('hereditary cancer', 'Disease', (51, 68))	('TP53', 'Gene', (270, 274))	('hereditary cancer', 'Disease', 'MESH:D009369', (51, 68))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
84121	25925845	Five of the six families, the exception being F1580 (Figure 3) provided by the hereditary cancer clinics, each had reported a case of breast and/or ovarian cancer (Table 1).	('hereditary cancer', 'Disease', 'MESH:D009369', (79, 96))	('hereditary cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('ovarian cancer', 'Phenotype', 'HP:0100615', (148, 162))	('breast and/or ovarian cancer', 'Disease', (134, 162))	('breast and/or ovarian cancer', 'Disease', 'MESH:D010051', (134, 162))	('F1580', 'Var', (46, 51))
84123	25925845	Gender bias in TP53 mutation carriers has been reported in independent studies, where penetrance appears to be higher in females than males perhaps due to the high penetrance for female breast cancer.	('mutation', 'Var', (20, 28))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (186, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))
84125	25925845	In all there were seven different TP53 mutations associated with French Canadian (Quebec) cancer families at the initiation of the present study.	('TP53', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('associated', 'Reg', (49, 59))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('TP53', 'Gene', '7157', (34, 38))
84126	25925845	Eleven of these variants occurred within intronic sequences and two resulted in synonymous amino acid substitutions that are all classified as polymorphisms based on information from the IARC TP53, dbSNP and EVS Databases.	('TP53', 'Gene', '7157', (192, 196))	('resulted in', 'Reg', (68, 79))	('EVS', 'Chemical', '-', (208, 211))	('substitutions', 'Var', (102, 115))	('occurred', 'Reg', (25, 33))	('variants', 'Var', (16, 24))	('TP53', 'Gene', (192, 196))
84129	25925845	Although the allele frequencies of these variants in the French Canadian population are not known, our results are comparable to a previous analysis of 52 probands from HBC/HBOC families analyzed for TP53 mutations from our group and to those reported for European (Caucasian) populations as reported in the dbSNP and/or EVS Databases (Table 2).	('variants', 'Var', (41, 49))	('mutations', 'Var', (205, 214))	('TP53', 'Gene', '7157', (200, 204))	('EVS', 'Chemical', '-', (321, 324))	('TP53', 'Gene', (200, 204))
84130	25925845	Thus no new deleterious mutations were identified in cancer cases representative of 37 French Canadian HBC/HBOC families found negative for deleterious BRCA1/ BRCA2 mutations.	('BRCA2', 'Gene', (159, 164))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('BRCA1', 'Gene', '672', (152, 157))	('BRCA2', 'Gene', '675', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BRCA1', 'Gene', (152, 157))	('mutations', 'Var', (165, 174))
84131	25925845	Three mutation carriers among the 1235 women with breast cancer not selected for family history of cancer were identified in a targeted TP53 mutation screen for regions containing mutations found in French Canadians (Table 1).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('mutations', 'Var', (180, 189))	('cancer', 'Disease', (57, 63))	('women', 'Species', '9606', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('cancer', 'Disease', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('TP53', 'Gene', '7157', (136, 140))	('mutation', 'Var', (141, 149))	('TP53', 'Gene', (136, 140))
84134	25925845	The c.844C>T [p.Arg282Trp] mutation is predicted to affect the DNA binding domain of p53 based on the IARC TP53 database (Table 1).	('c.844C>T', 'Mutation', 'rs28934574', (4, 12))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('DNA binding domain', 'MPA', (63, 81))	('p.Arg282Trp', 'Mutation', 'rs28934574', (14, 25))	('p53', 'Gene', (85, 88))	('c.844C>T [p.Arg282Trp]', 'Var', (4, 26))	('p53', 'Gene', '7157', (85, 88))	('affect', 'Reg', (52, 58))
84135	25925845	The carrier of this mutation had breast cancer at ages 30 and 38, and reported an unremarkable family history of cancer: a paternal uncle with stomach cancer in his 40's and a maternal grandmother with liver cancer at age 80 (Figure 6).	('cancer', 'Disease', (208, 214))	('liver cancer', 'Disease', 'MESH:D006528', (202, 214))	('mutation', 'Var', (20, 28))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('stomach cancer', 'Disease', 'MESH:D013274', (143, 157))	('stomach cancer', 'Phenotype', 'HP:0012126', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('liver cancer', 'Phenotype', 'HP:0002896', (202, 214))	('liver cancer', 'Disease', (202, 214))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('stomach cancer', 'Disease', (143, 157))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('breast cancer', 'Disease', (33, 46))
84138	25925845	The same c.685T>C [p.Cys229Arg] mutation was found in two women with breast cancer not selected for cancer family history (Table 1).	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('p.Cys229Arg', 'Mutation', 'rs1064794312', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('c.685T>C [p.Cys229Arg]', 'Var', (9, 31))	('women', 'Species', '9606', (58, 63))	('c.685T>C', 'Mutation', 'rs1064794312', (9, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('found', 'Reg', (45, 50))
84139	25925845	This mutation is predicted to affect the DNA binding domain of p53 based on the IARC TP53 database.	('TP53', 'Gene', (85, 89))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('DNA binding domain', 'MPA', (41, 59))	('TP53', 'Gene', '7157', (85, 89))	('affect', 'Reg', (30, 36))	('mutation', 'Var', (5, 13))
84140	25925845	The familial relationship of these carriers is unknown and their reported family histories of cancer are shown in pedigrees F1602 and F1603 (Figure 6).	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('F1603', 'Var', (134, 139))
84145	25925845	Thus both of these independently ascertained mutation carriers had a family history of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('mutation', 'Var', (45, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
84146	25925845	Although the carrier frequency of TP53 mutations in the French Canadian population of Quebec is currently unknown, a picture is emerging of the contribution of this gene to hereditary breast cancer.	('hereditary breast cancer', 'Disease', 'MESH:D001943', (173, 197))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))	('hereditary breast cancer', 'Disease', (173, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('TP53', 'Gene', '7157', (34, 38))
84147	25925845	In previous studies we reported that 3.8% (2/52) of HBC/HBOC families negative for BRCA1 and BRCA2 mutations harbored TP53 mutations.	('BRCA1', 'Gene', '672', (83, 88))	('BRCA2', 'Gene', '675', (93, 98))	('BRCA1', 'Gene', (83, 88))	('TP53', 'Gene', '7157', (118, 122))	('mutations', 'Var', (99, 108))	('TP53', 'Gene', (118, 122))	('mutations', 'Var', (123, 132))	('BRCA2', 'Gene', (93, 98))	('harbored', 'Reg', (109, 117))
84148	25925845	None of the 37 families evaluated in the present study were found to carry variants predicted to have deleterious effect on p53 function.	('function', 'MPA', (128, 136))	('p53', 'Gene', '7157', (124, 127))	('p53', 'Gene', (124, 127))	('variants', 'Var', (75, 83))
84150	25925845	Although our ascertainment criteria differ from independent reports, this frequency is consistent with the low carrier frequency in HBC/HBOC families found negative for germline BRCA1 and BRCA2 mutations.	('BRCA2', 'Gene', '675', (188, 193))	('BRCA1', 'Gene', (178, 183))	('mutations', 'Var', (194, 203))	('BRCA2', 'Gene', (188, 193))	('BRCA1', 'Gene', '672', (178, 183))
84151	25925845	The TP53 mutations c.685T>C [p.Cys229Arg] and c.844C>T [p.Arg282Trp] identified in a screen of women with breast cancer not selected for family history of cancer are both predicted to effect the DNA binding domain of p53.	('p53', 'Gene', '7157', (217, 220))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('p53', 'Gene', (217, 220))	('TP53', 'Gene', (4, 8))	('women', 'Species', '9606', (95, 100))	('p.Cys229Arg', 'Mutation', 'rs1064794312', (29, 40))	('c.685T>C [p.Cys229Arg]', 'Var', (19, 41))	('effect', 'Reg', (184, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (155, 161))	('TP53', 'Gene', '7157', (4, 8))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('c.844C>T [p.Arg282Trp', 'Var', (46, 67))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('c.844C>T', 'Mutation', 'rs28934574', (46, 54))	('c.685T>C', 'Mutation', 'rs1064794312', (19, 27))	('p.Arg282Trp', 'Mutation', 'rs28934574', (56, 67))	('DNA binding domain', 'MPA', (195, 213))
84152	25925845	The clinical significance c.685T>C [p.Cys229Arg] mutation is unknown as various bioinformatic tools render neutral to partial functionality of the encoded protein as reported in the IARC TP53 mutation database.	('c.685T>C', 'Mutation', 'rs1064794312', (26, 34))	('c.685T', 'Var', (26, 32))	('TP53', 'Gene', '7157', (187, 191))	('p.Cys229Arg', 'Mutation', 'rs1064794312', (36, 47))	('TP53', 'Gene', (187, 191))
84154	25925845	In contrast, c.844C>T [p.Arg282Trp] is predicted to have a deleterious effect on protein function and has been reported as a common somatic and germline mutation in the IARC TP53 mutation database.	('c.844C>T', 'Mutation', 'rs28934574', (13, 21))	('TP53', 'Gene', (174, 178))	('p.Arg282Trp', 'Mutation', 'rs28934574', (23, 34))	('protein function', 'MPA', (81, 97))	('effect', 'Reg', (71, 77))	('c.844C>T [p.Arg282Trp]', 'Var', (13, 35))	('TP53', 'Gene', '7157', (174, 178))
84156	25925845	The mutation carrier in F1583 had a liposarcoma at age 21 and her mother had breast cancer in her 30's and pancreatic carcinoma at age 36 (Figure 5).	('liposarcoma', 'Disease', (36, 47))	('breast cancer', 'Disease', (77, 90))	('pancreatic carcinoma', 'Disease', (107, 127))	('F1583', 'Var', (24, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (107, 127))	('liposarcoma', 'Disease', 'MESH:D008080', (36, 47))	('liposarcoma', 'Phenotype', 'HP:0012034', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
84158	25925845	It is tempting to speculate that when taken together the mutations identified in breast cancer cases not selected for family history of cancer are likely pathogenic.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
84159	25925845	Our findings suggest that less than 0.5% of French Canadian (Quebec) women with breast cancer carry a germline TP53 mutation.	('germline', 'Var', (102, 110))	('TP53', 'Gene', '7157', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('TP53', 'Gene', (111, 115))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('women', 'Species', '9606', (69, 74))
84160	25925845	However a mutation screen of these exons covers the regions that encode the DNA binding domain of p53, which we estimate accounts for 74% of germline TP53 mutations according to IARC TP53 Mutation Database.	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (155, 164))	('TP53', 'Gene', '7157', (183, 187))	('TP53', 'Gene', (183, 187))	('p53', 'Gene', (98, 101))	('TP53', 'Gene', '7157', (150, 154))	('p53', 'Gene', '7157', (98, 101))
84162	25925845	However, its role as a modifier of cancer risk is controversial, as large case control studies by the Breast Cancer Association Consortium found no significant association with breast cancer risk or breast cancer risk in BRCA1/BRCA2 mutation carriers.	('cancer', 'Disease', (184, 190))	('breast cancer', 'Disease', (177, 190))	('breast cancer', 'Disease', 'MESH:D001943', (199, 212))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BRCA2', 'Gene', '675', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancer', 'Disease', (199, 212))	('mutation', 'Var', (233, 241))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('Breast Cancer', 'Phenotype', 'HP:0003002', (102, 115))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('BRCA1', 'Gene', '672', (221, 226))	('Breast Cancer', 'Disease', 'MESH:D001943', (102, 115))	('BRCA1', 'Gene', (221, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('BRCA2', 'Gene', (227, 232))	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Breast Cancer', 'Disease', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('cancer', 'Disease', (35, 41))
84164	25925845	The observation that all mutation carriers were among the women diagnosed under age 50 years is also in keeping with independent reports and is a reflection of the high penetrance of mutated TP53 alleles, which is estimated to confer an 18-60 fold increased risk of breast cancer.	('breast cancer', 'Disease', (266, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (266, 279))	('mutated', 'Var', (183, 190))	('mutation', 'Var', (25, 33))	('TP53', 'Gene', '7157', (191, 195))	('TP53', 'Gene', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('women', 'Species', '9606', (58, 63))	('breast cancer', 'Disease', 'MESH:D001943', (266, 279))
84166	25925845	A study of 564 French Canadian women with breast cancer under 50 years of age reported a 4.8% carrier frequency in a mutation screen for eight BRCA1/BRCA2 mutations found to recur in French Canadian HBC/HBOC cancer families.	('BRCA1', 'Gene', '672', (143, 148))	('BRCA2', 'Gene', (149, 154))	('mutations', 'Var', (155, 164))	('HBC/HBOC cancer', 'Disease', 'MESH:D061325', (199, 214))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('BRCA1', 'Gene', (143, 148))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('BRCA2', 'Gene', '675', (149, 154))	('HBC/HBOC cancer', 'Disease', (199, 214))	('breast cancer', 'Disease', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('women', 'Species', '9606', (31, 36))
84167	25925845	Within this cohort 0.7% and 1.1% were found to harbor either the PALB2:p.Gln775Ter or CHEK2:c.1100delC recurrent French Canadian mutations, respectively.	('PALB2:p.Gln775Ter', 'Var', (65, 82))	('PALB2:p.Gln775Ter', 'SUBSTITUTION', 'None', (65, 82))	('CHEK2:c.1100delC', 'DELETION', 'None', (86, 102))	('CHEK2:c.1100delC', 'Var', (86, 102))
84168	25925845	A more recent study from the same group, found that 5.3% of French Canadian women with invasive breast cancer had one of six recurrent BRCA1/BRCA2 mutations.	('mutations', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('invasive breast cancer', 'Disease', (87, 109))	('BRCA1', 'Gene', '672', (135, 140))	('BRCA2', 'Gene', '675', (141, 146))	('BRCA1', 'Gene', (135, 140))	('invasive breast cancer', 'Disease', 'MESH:D001943', (87, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('women', 'Species', '9606', (76, 81))	('BRCA2', 'Gene', (141, 146))
84170	25925845	Thus relative to BRCA1/BRCA2, germline TP53 mutations are infrequent in French Canadian women with breast cancer, and may be similar (if not lower than) the mutation frequencies observed for specific PALB2 and CHEK2 mutations observed for this population.	('BRCA1', 'Gene', '672', (17, 22))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('PALB2', 'Gene', (200, 205))	('PALB2', 'Gene', '79728', (200, 205))	('women', 'Species', '9606', (88, 93))	('breast cancer', 'Disease', (99, 112))	('CHEK2', 'Gene', '11200', (210, 215))	('BRCA1', 'Gene', (17, 22))	('BRCA2', 'Gene', (23, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('CHEK2', 'Gene', (210, 215))	('mutations', 'Var', (44, 53))	('BRCA2', 'Gene', '675', (23, 28))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
84171	25925845	The identification of carriers with the same c.685T>C [p.Cys229Arg] or c.844C>T [p.Arg282Trp] mutation in TP53 is not surprising given the founder effects observed in the French Canadian population.	('c.844C>T', 'Mutation', 'rs28934574', (71, 79))	('p.Cys229Arg', 'Mutation', 'rs1064794312', (55, 66))	('c.685T>C', 'Mutation', 'rs1064794312', (45, 53))	('p.Arg282Trp', 'Mutation', 'rs28934574', (81, 92))	('c.844C>T [p.Arg282Trp]', 'Var', (71, 93))	('c.685T>C [p.Cys229Arg]', 'Var', (45, 67))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
84172	25925845	Reports of recurrent TP53 mutations due to common founders have been rare.	('mutations', 'Var', (26, 35))	('TP53', 'Gene', (21, 25))	('TP53', 'Gene', '7157', (21, 25))
84173	25925845	For example, the recurrence of p.Arg337His variant appears to be the cause of the high incidence of childhood ACC in Southeastern Brazil.	('p.Arg337His', 'Var', (31, 42))	('childhood ACC', 'Disease', (100, 113))	('p.Arg337His', 'Mutation', 'rs121912664', (31, 42))
84174	25925845	However, the familial relationship of the carriers of identical TP53 mutations in our study is not known.	('mutations', 'Var', (69, 78))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))
84175	25925845	The low frequency of carriers and broad spectrum of mutations identified does not warrant a targeted screen for these mutations at the present time, as has been recommended for recurrent mutations in BRCA1 and BRCA2.	('BRCA2', 'Gene', '675', (210, 215))	('BRCA1', 'Gene', '672', (200, 205))	('mutations', 'Var', (187, 196))	('BRCA1', 'Gene', (200, 205))	('BRCA2', 'Gene', (210, 215))
84178	25925845	The identification of TP53 mutation carriers would identify those women who are predicted to have an abnormal response to low dose radiation.	('mutation', 'Var', (27, 35))	('women', 'Species', '9606', (66, 71))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
84180	25925845	Counseling issues are complex with TP53 mutation carriers due to the spectrum of cancer type involved, particularly where there are few options for cancer surveillance or prevention.	('cancer', 'Disease', (148, 154))	('mutation', 'Var', (40, 48))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('TP53', 'Gene', '7157', (35, 39))	('cancer', 'Disease', (81, 87))	('TP53', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
84185	25925845	However, the risk for female breast cancer risk is high in mutation carriers and nonionizing cancer surveillance methods are available for carriers.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutation', 'Var', (59, 67))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
84186	25925845	Recently recommendations by the National Comprehensive Cancer Network  have been made to revise practice guidelines, which recommend TP53 mutation testing for women with breast cancer diagnoses under of the age of 35 years.	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('Cancer', 'Disease', (55, 61))	('mutation', 'Var', (138, 146))	('women', 'Species', '9606', (159, 164))	('breast cancer', 'Disease', (170, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('TP53', 'Gene', '7157', (133, 137))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))	('TP53', 'Gene', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
84189	25925845	New germline TP53 mutations were identified in French Canadians with cancer, a population that exhibits a unique genetic demography due to common founders.	('TP53', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('TP53', 'Gene', '7157', (13, 17))	('cancer', 'Disease', (69, 75))	('mutations', 'Var', (18, 27))
84192	25925845	Our findings further define the spectrum and frequency of germline TP53 mutations in women with breast cancer not selected for family history of cancer and could further inform the development of mutation screening policies for French Canadians in Quebec.	('cancer', 'Disease', (145, 151))	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('women', 'Species', '9606', (85, 90))	('breast cancer', 'Disease', (96, 109))	('TP53', 'Gene', '7157', (67, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('TP53', 'Gene', (67, 71))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
84227	25050346	Patients diagnosed with chronic lymphocytic leukemia and deletion of locus 13q14 presented low expression of two miRNAs, miR-15 and miR-16.	('low', 'NegReg', (91, 94))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (24, 52))	('miR', 'Gene', '220972', (113, 116))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (24, 52))	('miR', 'Gene', (113, 116))	('deletion', 'Var', (57, 65))	('chronic lymphocytic leukemia', 'Disease', (24, 52))	('Patients', 'Species', '9606', (0, 8))	('miR', 'Gene', '220972', (132, 135))	('miR-16', 'Gene', (132, 138))	('miR-16', 'Gene', '51573', (132, 138))	('miR', 'Gene', (132, 135))	('miR', 'Gene', '220972', (121, 124))	('leukemia', 'Phenotype', 'HP:0001909', (44, 52))	('miR', 'Gene', (121, 124))	('expression', 'MPA', (95, 105))
84228	25050346	Furthermore, two patients also presented germline mutation of one locus of miR-16-1 gene and loss-of-heterozygosity in the chronic lymphocytic leukemia cells, fulfilling the Knudson model of inactivation of a tumor-suppressor gene.	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('tumor', 'Disease', (209, 214))	('loss-of-heterozygosity', 'NegReg', (93, 115))	('chronic lymphocytic leukemia', 'Disease', (123, 151))	('germline mutation', 'Var', (41, 58))	('miR-16-1', 'Gene', (75, 83))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (123, 151))	('miR-16-1', 'Gene', '406950', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (123, 151))
84272	25050346	The authors also evaluated the functional consequences from the dysregulation of four miRNAs in a human ACC cell line.	('dysregulation', 'Var', (64, 77))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('human', 'Species', '9606', (98, 103))	('ACC', 'Phenotype', 'HP:0006744', (104, 107))
84307	25050346	The correlation between miRNA profiles and the type of the genetic pathways differently activated in adrenocortical tumors, like mutant p53 or abnormal expression of beta-catenin, would possibly explain some of these divergent findings as it could only reflect the selection of mutually exclusive drivers of tumorigenesis.	('tumor', 'Disease', (308, 313))	('adrenocortical tumors', 'Disease', (101, 122))	('beta-catenin', 'Gene', (166, 178))	('p53', 'Gene', '7157', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (101, 122))	('beta-catenin', 'Gene', '1499', (166, 178))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('activated', 'Reg', (88, 97))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))	('mutant', 'Var', (129, 135))	('p53', 'Gene', (136, 139))
84344	24238045	Five miRNAs previously shown to be dysregulated in cancer were selected from miRNA profiling studies in ACC (miR-let-7d, -34a, -195, -214, and 483-5p).	('miR', 'Gene', (77, 80))	('miR', 'Gene', (5, 8))	('miR', 'Gene', (109, 112))	('let-7d', 'Gene', '406886', (113, 119))	('miR', 'Gene', '22877', (77, 80))	('miR', 'Gene', '22877', (5, 8))	('let-7d', 'Gene', (113, 119))	('miR', 'Gene', '22877', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('483-5p', 'Var', (143, 149))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
84347	24238045	The following TaqMan MicroRNA Assays used in this study were obtained from Applied Biosystems: miR-483-5p (002338), miR-214 (002306), miR-195 (000494), miR-34a (000426), and miR-let-7d (002283).	('miR-214', 'Gene', '406996', (116, 123))	('miR', 'Gene', '22877', (152, 155))	('miR', 'Gene', (134, 137))	('miR', 'Gene', '22877', (95, 98))	('miR', 'Gene', '22877', (174, 177))	('002283', 'Var', (186, 192))	('miR', 'Gene', (116, 119))	('miR-483', 'Gene', (95, 102))	('miR', 'Gene', '22877', (134, 137))	('miR-214', 'Gene', (116, 123))	('miR-195', 'Gene', '406971', (134, 141))	('miR-483', 'Gene', '619552', (95, 102))	('miR-34a', 'Gene', (152, 159))	('miR', 'Gene', '22877', (116, 119))	('let-7d', 'Gene', '406886', (178, 184))	('000426', 'Var', (161, 167))	('miR-195', 'Gene', (134, 141))	('miR', 'Gene', (152, 155))	('miR-34a', 'Gene', '407040', (152, 159))	('miR', 'Gene', (95, 98))	('miR', 'Gene', (174, 177))	('let-7d', 'Gene', (178, 184))
84375	24238045	But we were interested in evaluating miR-34a levels in serum because it targets p53 and ectopic expression of miR-34a has been shown to induce apoptosis.	('induce', 'PosReg', (136, 142))	('ectopic expression', 'Var', (88, 106))	('miR-34a', 'Gene', (110, 117))	('p53', 'Gene', (80, 83))	('miR-34a', 'Gene', '407040', (37, 44))	('p53', 'Gene', '7157', (80, 83))	('apoptosis', 'CPA', (143, 152))	('miR-34a', 'Gene', (37, 44))	('miR-34a', 'Gene', '407040', (110, 117))
84376	24238045	Inactivating mutations of the tumor suppressor gene TP53 have been shown to be present in 25% to 70% of sporadic ACCs.	('sporadic ACCs', 'Disease', (104, 117))	('TP53', 'Gene', '7157', (52, 56))	('Inactivating mutations', 'Var', (0, 22))	('TP53', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
84455	23125857	all patients with incomplete (R1 or R2) or uncertain (Rx) resections, all patients with stage III disease regardless of resection adequacy, strong consideration in cases of >8 cm tumor size, Ki-67 index > 10%, and invasion of adjacent vasculature, even in cases of complete resection.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('> 10', 'Var', (203, 207))	('II disease', 'Disease', (95, 105))	('patients', 'Species', '9606', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('patients', 'Species', '9606', (4, 12))	('II disease', 'Disease', 'MESH:D005776', (95, 105))	('tumor', 'Disease', (179, 184))
84458	23125857	Mitotane is a derivate of the insecticide DDT and is directly toxic to the adrenocortical parenchyma.	('Mitotane', 'Var', (0, 8))	('DDT', 'Chemical', 'MESH:D003634', (42, 45))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('adrenocortical parenchyma', 'Disease', (75, 100))	('adrenocortical parenchyma', 'Disease', 'MESH:D010195', (75, 100))
84468	23125857	A panel of international experts in 2008 unanimously recommended adjuvant mitotane in patients with potential residual disease (R1 or Rx resection) or greater than 10% Ki67 positivity on pathologic examination.	('patients', 'Species', '9606', (86, 94))	('Ki67', 'Gene', (168, 172))	('mitotane', 'Chemical', 'MESH:D008939', (74, 82))	('positivity', 'Var', (173, 183))
84482	23125857	As second-line therapies, the efficacy of both regimens was similar to their efficacy as first-line therapy, with M-EDP showing superior antitumor efficacy and progression-free survival.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('M-EDP', 'Chemical', '-', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('M-EDP', 'Var', (114, 119))	('progression-free survival', 'CPA', (160, 185))
84487	23125857	Alterations in expression of the insulin-growth factor genes (IGF-1 and -2) are one of the most common mutations in ACC and one of the earliest recognized.	('IGF-1 and -2', 'Gene', '3479;3481', (62, 74))	('insulin', 'Gene', (33, 40))	('Alterations', 'Var', (0, 11))	('insulin', 'Gene', '3630', (33, 40))	('ACC', 'Phenotype', 'HP:0006744', (116, 119))	('expression', 'MPA', (15, 25))	('ACC', 'Disease', (116, 119))
84498	23125857	demonstrated that inhibition of mTOR signaling reduced adrenocortical tumor growth in vitro and in an in vivo mouse model in 2010.	('adrenocortical tumor', 'Disease', (55, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mTOR', 'Protein', (32, 36))	('mouse', 'Species', '10090', (110, 115))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (55, 75))	('inhibition', 'Var', (18, 28))	('reduced', 'NegReg', (47, 54))
84501	23125857	Microarray analysis has demonstrated upregulation of this pathway in ACC, and CTNNB1, the gene encoding beta-catenin, is frequently mutated in adrenocortical neoplasia.	('ACC', 'Phenotype', 'HP:0006744', (69, 72))	('ACC', 'Disease', (69, 72))	('CTNNB1', 'Gene', (78, 84))	('upregulation', 'PosReg', (37, 49))	('mutated', 'Var', (132, 139))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (143, 167))	('CTNNB1', 'Gene', '1499', (78, 84))	('adrenocortical neoplasia', 'Disease', (143, 167))	('neoplasia', 'Phenotype', 'HP:0002664', (158, 167))
84502	23125857	Furthermore, CTNNB1, the gene encoding beta-catenin, has been found to be frequently mutated in both ACC and adrenocortical adenomas.	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (109, 132))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (109, 132))	('adrenocortical adenomas', 'Disease', (109, 132))	('ACC', 'Phenotype', 'HP:0006744', (101, 104))	('CTNNB1', 'Gene', (13, 19))	('ACC', 'Disease', (101, 104))	('mutated', 'Var', (85, 92))	('CTNNB1', 'Gene', '1499', (13, 19))
84514	23125857	Additionally, a phase II trial is underway for ACC utilizing a regimen including XR9576, an inhibitor of MDR1, expression of which has been implicated in other multidrug-resistant tumors.	('MDR1', 'Gene', (105, 109))	('XR9576', 'Chemical', 'MESH:C402343', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('MDR1', 'Gene', '5243', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('implicated', 'Reg', (140, 150))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('XR9576', 'Var', (81, 87))	('tumors', 'Disease', (180, 186))	('ACC', 'Phenotype', 'HP:0006744', (47, 50))
84546	21094677	Using mice in which Shh is ablated specifically in Sf1-expressing cells, experiments revealed marked adrenal hypoplasia, decreased proliferation, and a depleted capsule.	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (101, 119))	('ablated', 'Var', (27, 34))	('Shh', 'Gene', '20423', (20, 23))	('proliferation', 'CPA', (131, 144))	('mice', 'Species', '10090', (6, 10))	('decreased', 'NegReg', (121, 130))	('Shh', 'Gene', (20, 23))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (101, 119))	('adrenal hypoplasia', 'Disease', (101, 119))
84559	21094677	It is reasonable to consider a model that unifies the two experimental observations that cells of the Sf1-positive fetal zone and cells of the Sf1-negative capsule both give rise to Sf1-positive adult adrenocortical cells (Figure 2B,C).	('give rise to', 'Reg', (169, 181))	('Sf1-positive', 'Var', (182, 194))	('adrenocortical', 'Disease', 'MESH:D018268', (201, 215))	('adrenocortical', 'Disease', (201, 215))
84567	21094677	In humans, beta-catenin dysregulation has been observed in a subset of sporadic adrenocortical adenomas and carcinomas.	('sporadic adrenocortical adenomas and carcinomas', 'Disease', 'MESH:D018246', (71, 118))	('dysregulation', 'Var', (24, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('observed', 'Reg', (47, 55))	('humans', 'Species', '9606', (3, 9))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (80, 103))	('beta-catenin', 'Protein', (11, 23))
84587	21094677	In support of the role of Dax1 in adrenocortical progenitor cells, studies in mouse embryonic stem cells suggest that Dax1 helps maintain pluripotency and knockdown of Dax1 in mouse embryonic stem cells induces differentiation.	('pluripotency', 'Disease', (138, 150))	('knockdown', 'Var', (155, 164))	('adrenocortical', 'Disease', 'MESH:D018268', (34, 48))	('pluripotency', 'Disease', 'None', (138, 150))	('mouse', 'Species', '10090', (176, 181))	('induces', 'Reg', (203, 210))	('differentiation', 'CPA', (211, 226))	('Dax1', 'Gene', (168, 172))	('mouse', 'Species', '10090', (78, 83))	('adrenocortical', 'Disease', (34, 48))
84801	33363514	Among these compounds, roscovitine has shown promising experimental results, being able to inhibit many CDK/cyclin complexes, including CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, CDK5/p35, CDK7/cyclin H, and CDK9/cyclin H. Further experimental evidences on neoplastic cell lines, including L1210 mouse leukemia, A549 and MR65 human lung cancer, and CHP212 human neuroblastoma cell lines, demonstrated that roscovitine inhibited cell proliferation and promoted cell apoptosis.	('rat', 'Species', '10116', (397, 400))	('cyclin A', 'Gene', '890', (156, 164))	('CDK7', 'Gene', (191, 195))	('roscovitine', 'Chemical', 'MESH:D000077546', (23, 34))	('CD', 'Gene', '13033', (181, 183))	('men', 'Species', '9606', (61, 64))	('CDK9', 'Gene', (210, 214))	('CDK7', 'Gene', '1022', (191, 195))	('promoted', 'PosReg', (453, 461))	('cyclin A', 'Gene', (156, 164))	('lung cancer', 'Disease', 'MESH:D008175', (334, 345))	('roscovitine', 'Chemical', 'MESH:D000077546', (408, 419))	('cell apoptosis', 'CPA', (462, 476))	('cyclin H', 'Gene', '902', (196, 204))	('CD', 'Gene', '13033', (210, 212))	('CHP212', 'CellLine', 'CVCL:1125', (351, 357))	('p35', 'Gene', '8851', (186, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (334, 345))	('cell proliferation', 'CPA', (430, 448))	('p35', 'Gene', (186, 189))	('CDK2', 'Gene', '1017', (151, 155))	('CD', 'Gene', '13033', (136, 138))	('human', 'Species', '9606', (358, 363))	('men', 'Species', '9606', (239, 242))	('roscovitine', 'Var', (408, 419))	('neuroblastoma', 'Disease', (364, 377))	('CDK2', 'Gene', '1017', (166, 170))	('CDK9', 'Gene', '1025', (210, 214))	('CDK2', 'Gene', (151, 155))	('neuroblastoma', 'Phenotype', 'HP:0003006', (364, 377))	('CD', 'Gene', '13033', (104, 106))	('CDK1', 'Gene', '983', (136, 140))	('rat', 'Species', '10116', (442, 445))	('CDK1', 'Gene', (136, 140))	('cyclin H', 'Gene', (215, 223))	('CDK5', 'Gene', (181, 185))	('CD', 'Gene', '13033', (191, 193))	('CDK2', 'Gene', (166, 170))	('neuroblastoma', 'Disease', 'MESH:D009447', (364, 377))	('leukemia', 'Phenotype', 'HP:0001909', (304, 312))	('inhibited', 'NegReg', (420, 429))	('mouse', 'Species', '10090', (298, 303))	('CDK5', 'Gene', '1020', (181, 185))	('CD', 'Gene', '13033', (151, 153))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('CD', 'Gene', '13033', (166, 168))	('lung cancer', 'Disease', (334, 345))	('cyclin H', 'Gene', '902', (215, 223))	('A549', 'CellLine', 'CVCL:0023', (314, 318))	('human', 'Species', '9606', (328, 333))	('leukemia', 'Disease', (304, 312))	('leukemia', 'Disease', 'MESH:D007938', (304, 312))	('cyclin H', 'Gene', (196, 204))
84807	33363514	Indeed, in vitro and in vivo studies have shown cyclin E overexpression in corticotroph pituitary tumors, mainly associated with dysregulation in pituitary tumor transforming gene (PTTG) and in Brahma-related gene-1 (Brg1) genes, both involved in the regulation of corticotroph cells cycle.	('cyclin E', 'Gene', (48, 56))	('corticotroph pituitary tumor', 'Phenotype', 'HP:0008291', (75, 103))	('Brg1', 'Gene', (217, 221))	('dysregulation', 'Var', (129, 142))	('pituitary tumor', 'Disease', 'MESH:D010911', (146, 161))	('corticotroph pituitary tumors', 'Disease', (75, 104))	('Brg1', 'Gene', '6597', (217, 221))	('pituitary tumor', 'Disease', (146, 161))	('Brahma-related gene-1', 'Gene', '6597', (194, 215))	('PTTG', 'Gene', '9232', (181, 185))	('overexpression', 'PosReg', (57, 71))	('pituitary tumor', 'Disease', 'MESH:D010911', (88, 103))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Brahma-related gene-1', 'Gene', (194, 215))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('corticotroph pituitary tumors', 'Phenotype', 'HP:0008291', (75, 104))	('PTTG', 'Gene', (181, 185))	('corticotroph pituitary tumors', 'Disease', 'MESH:D049913', (75, 104))	('associated', 'Reg', (113, 123))
84813	33363514	Interestingly, the mutant zebrafish embryos were exposed to different CDK inhibitors, including roscovitine, which reduced POMC expression of about 40% compared with controls.	('CD', 'Gene', '13033', (70, 72))	('roscovitine', 'Chemical', 'MESH:D000077546', (96, 107))	('reduced', 'NegReg', (115, 122))	('mutant', 'Var', (19, 25))	('zebrafish', 'Species', '7955', (26, 35))	('POMC expression', 'MPA', (123, 138))
84814	33363514	Moreover, in vitro evaluation on AtT20 mouse corticotroph tumor cell line demonstrated that roscovitine decreased ACTH secretion and cell proliferation, inhibiting cyclin E and inducing cell cycle inhibitors (p27Kip1, p57Kip2, and p21Cip1) expression, as well as inhibiting phosphorylation of retinoblastoma protein.	('p57Kip2', 'Gene', '12577', (218, 225))	('p27Kip1', 'Gene', '12576', (209, 216))	('cyclin E', 'MPA', (164, 172))	('p21Cip1', 'Gene', (231, 238))	('p21Cip1', 'Gene', '12575', (231, 238))	('ACTH secretion', 'MPA', (114, 128))	('mouse', 'Species', '10090', (39, 44))	('retinoblastoma', 'Phenotype', 'HP:0009919', (293, 307))	('roscovitine', 'Chemical', 'MESH:D000077546', (92, 103))	('retinoblastoma', 'Disease', (293, 307))	('corticotroph tumor', 'Disease', 'MESH:D049913', (45, 63))	('decreased', 'NegReg', (104, 113))	('inducing', 'PosReg', (177, 185))	('roscovitine', 'Var', (92, 103))	('decreased ACTH', 'Phenotype', 'HP:0002920', (104, 118))	('expression', 'MPA', (240, 250))	('inhibiting', 'NegReg', (263, 273))	('inhibiting', 'NegReg', (153, 163))	('p57Kip2', 'Gene', (218, 225))	('p27Kip1', 'Gene', (209, 216))	('cell cycle inhibitors', 'CPA', (186, 207))	('rat', 'Species', '10116', (145, 148))	('phosphorylation', 'MPA', (274, 289))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cell proliferation', 'CPA', (133, 151))	('retinoblastoma', 'Disease', 'MESH:D012175', (293, 307))	('rat', 'Species', '10116', (81, 84))	('corticotroph tumor', 'Phenotype', 'HP:0008291', (45, 63))	('corticotroph tumor', 'Disease', (45, 63))
84815	33363514	In the in vivo evaluation in athymic nude mice injected with AtT20 corticotroph tumor cell line, with consequent development of local subcutaneous corticotroph tumors, representing a model of CD, roscovitine induced a reduction of tumor mass of about 50% compared with controls after 3 weeks of treatment, together with a decrease in plasma ACTH and serum corticosterone levels, which were significantly lower in mice treated with roscovitine than in controls.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('corticotroph tumor', 'Disease', (67, 85))	('roscovitine', 'Chemical', 'MESH:D000077546', (196, 207))	('decrease in plasma ACTH', 'Phenotype', 'HP:0002920', (322, 345))	('corticotroph tumor', 'Phenotype', 'HP:0008291', (147, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('roscovitine', 'Var', (196, 207))	('decrease', 'NegReg', (322, 330))	('reduction', 'NegReg', (218, 227))	('tumor', 'Disease', (231, 236))	('corticotroph tumor', 'Disease', 'MESH:D049913', (67, 85))	('plasma ACTH', 'MPA', (334, 345))	('CD', 'Gene', '13033', (192, 194))	('roscovitine', 'Chemical', 'MESH:D000077546', (431, 442))	('men', 'Species', '9606', (120, 123))	('corticotroph tumors', 'Phenotype', 'HP:0008291', (147, 166))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('corticotroph tumor', 'Disease', 'MESH:D049913', (147, 165))	('mice', 'Species', '10090', (42, 46))	('nude mice', 'Species', '10090', (37, 46))	('corticosterone', 'Chemical', 'MESH:D003345', (356, 370))	('tumor', 'Disease', (80, 85))	('mice', 'Species', '10090', (413, 417))	('lower', 'NegReg', (404, 409))	('corticotroph tumors', 'Disease', (147, 166))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('men', 'Species', '9606', (300, 303))	('corticotroph tumors', 'Disease', 'MESH:D049913', (147, 166))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('serum corticosterone levels', 'MPA', (350, 377))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('corticotroph tumor', 'Phenotype', 'HP:0008291', (67, 85))
84909	33363514	Noteworthy, ketoconazole impairs not only adrenal, but also gonadal steroidogenesis, in particular with a negative effect on testicular androgen production, thus potentially leading to male hypogonadism.	('hypogonadism', 'Phenotype', 'HP:0000135', (190, 202))	('male hypogonadism', 'Disease', 'MESH:D005058', (185, 202))	('ketoconazole', 'Chemical', 'MESH:D007654', (12, 24))	('steroid', 'Chemical', 'MESH:D013256', (68, 75))	('gonadal steroidogenesis', 'MPA', (60, 83))	('negative', 'NegReg', (106, 114))	('male hypogonadism', 'Disease', (185, 202))	('male hypogonadism', 'Phenotype', 'HP:0000026', (185, 202))	('impairs', 'NegReg', (25, 32))	('testicular androgen production', 'MPA', (125, 155))	('leading to', 'Reg', (174, 184))	('ketoconazole', 'Var', (12, 24))	('adrenal', 'MPA', (42, 49))
84910	33363514	Moreover, ketoconazole inhibits liver enzymes involved in metabolism of chemical substances not normally found or expected to be present in human organism, therefore favoring the occurrence of liver damage.	('human', 'Species', '9606', (140, 145))	('liver damage', 'Disease', 'MESH:D056486', (193, 205))	('metabolism of chemical substances', 'MPA', (58, 91))	('liver enzymes', 'Enzyme', (32, 45))	('favoring', 'PosReg', (166, 174))	('ketoconazole', 'Var', (10, 22))	('ketoconazole', 'Chemical', 'MESH:D007654', (10, 22))	('inhibits', 'NegReg', (23, 31))	('liver damage', 'Disease', (193, 205))
84918	33363514	In both CD and CS patients, ketoconazole treatment is associated with a general improvement in clinical features, mainly overweight or obesity, hypertension, impairment of glucose metabolism, muscle weakness, and hypokalemia.	('impairment of glucose metabolism', 'Disease', (158, 190))	('obesity', 'Disease', 'MESH:D009765', (135, 142))	('impairment of glucose metabolism', 'Disease', 'MESH:D044882', (158, 190))	('CS', 'Phenotype', 'HP:0003118', (15, 17))	('muscle weakness', 'Disease', (192, 207))	('hypokalemia', 'Disease', (213, 224))	('obesity', 'Phenotype', 'HP:0001513', (135, 142))	('muscle weakness', 'Disease', 'MESH:D018908', (192, 207))	('ketoconazole', 'Chemical', 'MESH:D007654', (28, 40))	('men', 'Species', '9606', (87, 90))	('hypertension', 'Disease', 'MESH:D006973', (144, 156))	('men', 'Species', '9606', (46, 49))	('ketoconazole', 'Var', (28, 40))	('hypertension', 'Disease', (144, 156))	('CD', 'Gene', '13033', (8, 10))	('patients', 'Species', '9606', (18, 26))	('hypokalemia', 'Phenotype', 'HP:0002900', (213, 224))	('men', 'Species', '9606', (164, 167))	('overweight', 'Disease', (121, 131))	('improvement', 'PosReg', (80, 91))	('obesity', 'Disease', (135, 142))	('overweight', 'Phenotype', 'HP:0025502', (121, 131))	('hypokalemia', 'Disease', 'MESH:D007008', (213, 224))	('hypertension', 'Phenotype', 'HP:0000822', (144, 156))	('muscle weakness', 'Phenotype', 'HP:0001324', (192, 207))
84946	33363514	The primary endpoint of this study was the proportion of patients with mUC <= ULN or who had a >=50% mUC decrease from baseline at week 10.	('patients', 'Species', '9606', (57, 65))	('mUC <= ULN', 'Var', (71, 81))	('mUC', 'MPA', (101, 104))	('decrease', 'NegReg', (105, 113))
84984	33363514	In this study, 137 patients with mUC >=1.5-fold the ULN entered a 12-week, open-label period, during which, starting at an initial dose of 4 mg/day, a dose up-titration was performed every 2 weeks until mUC normalization (mUC <= ULN) or a maximum dose of 60 mg/day was reached, followed by a 12-week, maintenance period.	('mUC >=1.5-fold', 'Var', (33, 47))	('mUC', 'MPA', (203, 206))	('rat', 'Species', '10116', (162, 165))	('patients', 'Species', '9606', (19, 27))
85028	33363514	Therefore, new preclinical studies were started, showing in animal models that levoketoconazole reduced by 50% serum corticosterone levels at a dose of 100 mg/kg, significantly lower than those required by racemic ketoconazole, with a maximum corticosterone suppression within 4 h, maintained over 24 h with a 200 mg/kg dose.	('lower', 'NegReg', (177, 182))	('serum corticosterone levels', 'MPA', (111, 138))	('ketoconazole', 'Chemical', 'MESH:D007654', (214, 226))	('corticosterone', 'Chemical', 'MESH:D003345', (243, 257))	('levoketoconazole', 'Chemical', '-', (79, 95))	('ketoconazole', 'Chemical', 'MESH:D007654', (83, 95))	('corticosterone', 'Chemical', 'MESH:D003345', (117, 131))	('levoketoconazole', 'Var', (79, 95))	('reduced', 'NegReg', (96, 103))
85032	33363514	In this study, 94 patients with mUC >=1.5-fold the ULN, including 80 CD patients, entered an up-titration period of 2-21 weeks, during which, starting at an initial dose of 300 mg/day, a dose up-titration was performed every 2 weeks until mUC normalization (mUC <= ULN) or a maximum dose of 1,200 mg/day was reached, followed by a 6-month, open-label, stable-dose, maintenance period, during which they were treated with stable doses, unless a dose change was needed to maintain disease control or in response to safety and tolerability issues.	('mUC', 'MPA', (239, 242))	('CD', 'Gene', '13033', (69, 71))	('rat', 'Species', '10116', (99, 102))	('rat', 'Species', '10116', (198, 201))	('patients', 'Species', '9606', (18, 26))	('mUC', 'Var', (32, 35))	('patients', 'Species', '9606', (72, 80))
85061	33363514	The loss of therapeutic response was considered as the mUC rebound after normalization during randomization period, defined as mUC >=1.5-fold the ULN or an increase >40% in mUC compared to the start of randomization period, or as the occurrence of rescue criteria, requiring open-label treatment, during randomization period.	('mUC', 'MPA', (173, 176))	('increase', 'PosReg', (156, 164))	('mUC', 'Var', (127, 130))	('mUC', 'Disease', (55, 58))	('ULN', 'MPA', (146, 149))	('men', 'Species', '9606', (291, 294))	('>=1.5-fold', 'PosReg', (131, 141))
85085	33363514	Moreover, experimental studies on adrenocortical cell cultures derived from guinea pigs and clinical studies on guinea pigs showed that ATR-101 induced an impairment of mitochondrial respiration.	('guinea pigs', 'Species', '10141', (112, 123))	('ATR-101', 'Var', (136, 143))	('ATR-101', 'Chemical', 'MESH:C079534', (136, 143))	('impairment', 'NegReg', (155, 165))	('guinea pigs', 'Species', '10141', (76, 87))	('men', 'Species', '9606', (16, 19))	('mitochondrial respiration', 'MPA', (169, 194))	('rat', 'Species', '10116', (188, 191))	('men', 'Species', '9606', (161, 164))
85104	33363514	Mitotane induces a cytotoxic effect on the mitochondrial system of adrenocortical cells, resulting in mitochondrial disruption, swelling, and lysis, followed by cell death.	('Mitotane', 'Var', (0, 8))	('lysis', 'CPA', (142, 147))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('swelling', 'Disease', (128, 136))	('cell death', 'CPA', (161, 171))	('swelling', 'Disease', 'MESH:D004487', (128, 136))	('mitochondrial disruption', 'CPA', (102, 126))
85105	33363514	Moreover, mitotane inhibits several adrenal enzymes involved in adrenal steroidogenesis, including cholesterol side-chain cleavage complex, 11beta-hydroxylase, 18-hydroxylase, and 3beta-hydroxysteroid-dehydrogenase.	('11beta-hydroxylase', 'Enzyme', (140, 158))	('cholesterol', 'Chemical', 'MESH:D002784', (99, 110))	('cholesterol side-chain', 'Enzyme', (99, 121))	('mitotane', 'Var', (10, 18))	('mitotane', 'Chemical', 'MESH:D008939', (10, 18))	('steroid', 'Chemical', 'MESH:D013256', (72, 79))	('adrenal enzymes', 'Enzyme', (36, 51))	('inhibits', 'NegReg', (19, 27))	('18-hydroxylase', 'Enzyme', (160, 174))	('3beta-hydroxysteroid-dehydrogenase', 'Enzyme', (180, 214))	('steroid', 'Chemical', 'MESH:D013256', (193, 200))
85106	33363514	Therefore, mitotane reduces cortisol production and secretion in two different combined mechanisms.	('reduces', 'NegReg', (20, 27))	('cortisol production', 'MPA', (28, 47))	('mitotane', 'Var', (11, 19))	('cortisol', 'Chemical', 'MESH:D006854', (28, 36))	('secretion', 'MPA', (52, 61))	('mitotane', 'Chemical', 'MESH:D008939', (11, 19))	('reduces cortisol', 'Phenotype', 'HP:0008163', (20, 36))
85112	33363514	In both CD and CS patients mitotane treatment is associated with a general improvement in clinical features, mainly overweight or obesity and impairment of glucose metabolism.	('CS', 'Phenotype', 'HP:0003118', (15, 17))	('obesity', 'Phenotype', 'HP:0001513', (130, 137))	('obesity', 'Disease', 'MESH:D009765', (130, 137))	('mitotane', 'Var', (27, 35))	('impairment of glucose metabolism', 'Disease', 'MESH:D044882', (142, 174))	('overweight', 'Phenotype', 'HP:0025502', (116, 126))	('obesity', 'Disease', (130, 137))	('men', 'Species', '9606', (148, 151))	('mitotane', 'Chemical', 'MESH:D008939', (27, 35))	('improvement', 'PosReg', (75, 86))	('impairment of glucose metabolism', 'Disease', (142, 174))	('CD', 'Gene', '13033', (8, 10))	('overweight', 'Disease', (116, 126))	('patients', 'Species', '9606', (18, 26))	('men', 'Species', '9606', (82, 85))	('men', 'Species', '9606', (41, 44))
85179	33363514	The primary endpoints of this study were the response in glucose tolerance, defined as a decrease in HbA1c >=0.5%, normalization or a >=50 mg/dl decrease in 2-h glucose levels after OGTT, or a decrease in total daily insulin dose of >=25% or in daily sulphonylureas dose of >=50%, compared to baseline, and in blood pressure, defined as a decrease of >=5 mmHg in either mean systolic or diastolic blood pressure levels compared to baseline, at study completion.	('sulphonylureas', 'Chemical', 'MESH:D013453', (251, 265))	('glucose', 'MPA', (57, 64))	('normalization', 'Var', (115, 128))	('mean systolic', 'MPA', (370, 383))	('decrease', 'NegReg', (89, 97))	('insulin', 'Gene', (217, 224))	('diastolic blood pressure levels', 'MPA', (387, 418))	('insulin', 'Gene', '3630', (217, 224))	('glucose', 'Chemical', 'MESH:D005947', (57, 64))	('HbA1c', 'Gene', (101, 106))	('blood', 'MPA', (310, 315))	('decrease', 'NegReg', (145, 153))	('decrease', 'NegReg', (193, 201))	('glucose', 'Chemical', 'MESH:D005947', (161, 168))	('2-h glucose levels', 'MPA', (157, 175))
85190	33363514	In detail, the endpoint in patients with diabetes mellitus/IGT with an initial response, including normalization or >=50 mg/dL decrease of 2-h glucose levels after OGTT, decrease of >=0.5% of HbA1c and/or decrease >=25% of total daily insulin dose or >=50% daily sulfonylurea dose, was the mean change in glucose AUC during OGTT, whereas the endpoint in patients with hypertension was the proportion of patients with loss of response with respect to hypertension, defined as an increase in systolic and/or diastolic blood pressure of >=5 mmHg at ambulatory blood pressure monitoring or any increase or modification in antihypertensive medication.	('hypertension', 'Disease', 'MESH:D006973', (368, 380))	('diabetes mellitus', 'Disease', (41, 58))	('hypertension', 'Disease', (368, 380))	('hypertension', 'Phenotype', 'HP:0000822', (450, 462))	('patients', 'Species', '9606', (354, 362))	('IGT', 'Phenotype', 'HP:0040270', (59, 62))	('patients', 'Species', '9606', (403, 411))	('hypertensive', 'Disease', (622, 634))	('diabetes mellitus', 'Disease', 'MESH:D003920', (41, 58))	('insulin', 'Gene', (235, 242))	('glucose', 'Chemical', 'MESH:D005947', (305, 312))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (41, 58))	('patients', 'Species', '9606', (27, 35))	('hypertension', 'Phenotype', 'HP:0000822', (368, 380))	('decrease', 'NegReg', (170, 178))	('systolic and/or', 'MPA', (490, 505))	('2-h glucose levels', 'MPA', (139, 157))	('decrease', 'Var', (205, 213))	('IGT', 'Disease', 'None', (59, 62))	('antihypertensive medication', 'Phenotype', 'HP:0000822', (618, 645))	('hypertensive', 'Disease', 'MESH:D006973', (622, 634))	('IGT', 'Disease', (59, 62))	('increase', 'PosReg', (478, 486))	('hypertension', 'Disease', 'MESH:D006973', (450, 462))	('decrease', 'NegReg', (127, 135))	('insulin', 'Gene', '3630', (235, 242))	('glucose AUC', 'MPA', (305, 316))	('hypertension', 'Disease', (450, 462))	('glucose', 'Chemical', 'MESH:D005947', (143, 150))
85195	33363514	In a study on adrenal-directed agents on 11 severe CS patients, including four CD, combination of ketoconazole (400-1,200 mg/day), metyrapone (3-4.5 g/day), and mitotane (3-5 g/day) induced UC normalization (UC <= ULN) in seven (63.6%) patients after 24-48 h, with UC remaining low to normal throughout the period of combination therapy, with improvement of clinical status.	('UC normalization', 'MPA', (190, 206))	('CD', 'Gene', '13033', (79, 81))	('mitotane', 'Chemical', 'MESH:D008939', (161, 169))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (236, 244))	('400-1,200', 'Var', (112, 121))	('combination', 'Var', (83, 94))	('ketoconazole', 'Chemical', 'MESH:D007654', (98, 110))	('CS', 'Phenotype', 'HP:0003118', (51, 53))	('men', 'Species', '9606', (350, 353))	('metyrapone', 'Chemical', 'MESH:D008797', (131, 141))
85212	33363514	At week 9, 18, and 27, patients with mUC > ULN underwent pasireotide up-titration to a total dose of 1,800 mug/day, addition of cabergoline at 0.5 mg/day, and cabergoline up-titration to 1 mg/day, respectively, whereas patients with mUC <= ULN continued the previously assigned treatment throughout the study.	('mUC > ULN', 'Var', (37, 46))	('rat', 'Species', '10116', (177, 180))	('patients', 'Species', '9606', (23, 31))	('rat', 'Species', '10116', (75, 78))	('cabergoline', 'Chemical', 'MESH:D000077465', (128, 139))	('cabergoline', 'Chemical', 'MESH:D000077465', (159, 170))	('men', 'Species', '9606', (283, 286))	('pasireotide', 'Disease', 'None', (57, 68))	('patients', 'Species', '9606', (219, 227))	('up-titration', 'PosReg', (69, 81))	('pasireotide', 'Disease', (57, 68))
85305	32474412	For both CD3+- and CD3+CD4+ T cells, a clear decline of immune cells was detectable in 12 of 14 patients and for CD3+CD8+ T cells, the same trend was seen in all but one single patient (figure 2, D-F).	('decline', 'NegReg', (45, 52))	('CD3+-', 'Var', (9, 14))	('patient', 'Species', '9606', (177, 184))	('patient', 'Species', '9606', (96, 103))	('immune cells', 'CPA', (56, 68))	('decline of immune cells', 'Phenotype', 'HP:0002721', (45, 68))	('CD8', 'Gene', (117, 120))	('patients', 'Species', '9606', (96, 104))	('CD8', 'Gene', '925', (117, 120))	('CD4', 'Gene', (23, 26))	('CD4', 'Gene', '920', (23, 26))
85306	32474412	Accordingly, the median number of CD3+-, CD3+CD4+-, and CD3+CD8+ T cells were higher in primary tumors (4.5, 4.7 and 4.4 cells per HPF, respectively) than in metastases (2.15, 1.15 and 2.0 cells per HPF, respectively).	('metastases', 'Disease', 'MESH:D009362', (158, 168))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('CD4', 'Gene', (45, 48))	('CD4', 'Gene', '920', (45, 48))	('higher', 'PosReg', (78, 84))	('tumors', 'Disease', (96, 102))	('CD8', 'Gene', '925', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('metastases', 'Disease', (158, 168))	('CD3+-', 'Var', (34, 39))	('CD8', 'Gene', (60, 63))
85308	32474412	More precisely, ACC patients with a primary tumor with CD3+ T cell infiltration showed a median survival of 81.8 months, whereas in the absence of CD3+ TILs the median survival was only 29.7 months (figure 3, table 2A).	('CD3+ T cell infiltration', 'Var', (55, 79))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Disease', (44, 49))
85314	32474412	Similarly to the results on overall survival, CD3+-, CD3+CD4+- and CD3+CD8+ TILs were associated with a significantly longer median recurrence-free survival (24.2 vs. 10.7 months, 25.5 vs. 10.7 months and 24.2 vs 10.7 months, respectively; figure 3D-F, table 2B).	('CD8', 'Gene', '925', (71, 74))	('CD4', 'Gene', '920', (57, 60))	('CD3+-', 'Var', (46, 51))	('recurrence-free survival', 'CPA', (132, 156))	('longer', 'PosReg', (118, 124))	('CD4', 'Gene', (57, 60))	('CD8', 'Gene', (71, 74))
85331	32474412	Here, we quantified CD3+-, CD3+CD4+-, CD3+CD8+- and CD3+CD4+FoxP3+ TILs in a cohort of 146 ACC patients and studied the influence of their presence on patients' survival.	('FoxP3', 'Gene', (60, 65))	('CD4', 'Gene', (31, 34))	('patients', 'Species', '9606', (95, 103))	('CD4', 'Gene', '920', (31, 34))	('CD4', 'Gene', (56, 59))	('patients', 'Species', '9606', (151, 159))	('CD8', 'Gene', (42, 45))	('ACC', 'Disease', (91, 94))	('CD8', 'Gene', '925', (42, 45))	('CD4', 'Gene', '920', (56, 59))	('CD3+-', 'Var', (20, 25))	('FoxP3', 'Gene', '50943', (60, 65))
85339	32474412	Accordingly, CD3+-, CD3+CD4+- and CD3+CD8+ TIL number was associated with a risk reduction of 53% to 61% for death and 57% to 69% for recurrence.	('death', 'Disease', 'MESH:D003643', (109, 114))	('death', 'Disease', (109, 114))	('CD4', 'Gene', (24, 27))	('CD4', 'Gene', '920', (24, 27))	('CD8', 'Gene', (38, 41))	('reduction', 'NegReg', (81, 90))	('CD8', 'Gene', '925', (38, 41))	('CD3+-', 'Var', (13, 18))
85340	32474412	In particular, TILs in localized, non-metastatic ACC may serve as a prognostic marker independently of clinically established factors, like ENSAT stage, resection status, and Ki67 index leading to a risk reduction for death of 70% to 81%.	('TILs', 'Var', (15, 19))	('death', 'Disease', 'MESH:D003643', (218, 223))	('death', 'Disease', (218, 223))	('localized', 'Disease', (23, 32))
85365	32474412	In addition to parameters like PD-1/PD-L1 (programmed cell death-ligand-1) expression or tumor mutational burden, the presence of TILs could be a promising predictive marker that should be explored.	('PD-L1', 'Gene', '574058', (36, 41))	('TILs', 'Gene', (130, 134))	('presence', 'Var', (118, 126))	('PD-L1', 'Gene', (36, 41))	('death', 'Disease', 'MESH:D003643', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('death', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
85405	28658440	The aim of this study was to investigate whether silencing or overexpression of the gene Transcription Factor 21 could modulate the gene and protein expression of steroidogenic factor 1 in adrenocortical tumors.	('silencing', 'Var', (49, 58))	('steroidogenic factor 1', 'Gene', '2516', (163, 185))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (189, 210))	('steroidogenic factor 1', 'Gene', (163, 185))	('Transcription Factor 21', 'Gene', '6943', (89, 112))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('modulate', 'Reg', (119, 127))	('gene and', 'MPA', (132, 140))	('overexpression', 'PosReg', (62, 76))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('Transcription Factor 21', 'Gene', (89, 112))	('adrenocortical tumors', 'Disease', (189, 210))
85406	28658440	We analyzed the gene expression of steroidogenic factor 1 using qPCR after silencing endogenous Transcription Factor 21 in pediatric adrenal adenoma-T7 cells through small interfering RNA.	('steroidogenic factor 1', 'Gene', '2516', (35, 57))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (133, 148))	('steroidogenic factor 1', 'Gene', (35, 57))	('endogenous', 'Gene', (85, 95))	('Transcription Factor 21', 'Gene', '6943', (96, 119))	('adenoma', 'Disease', 'MESH:D000236', (141, 148))	('silencing', 'NegReg', (75, 84))	('small interfering', 'Var', (166, 183))	('adenoma', 'Disease', (141, 148))	('Transcription Factor 21', 'Gene', (96, 119))
85408	28658440	Transcription Factor 21 knockdown increased the mRNA expression of steroidogenic factor 1 by 5.97-fold in pediatric adrenal adenoma-T7 cells.	('adrenal adenoma', 'Phenotype', 'HP:0008256', (116, 131))	('steroidogenic factor 1', 'Gene', '2516', (67, 89))	('steroidogenic factor 1', 'Gene', (67, 89))	('Transcription Factor 21', 'Gene', '6943', (0, 23))	('Transcription Factor 21', 'Gene', (0, 23))	('adenoma', 'Disease', 'MESH:D000236', (124, 131))	('adenoma', 'Disease', (124, 131))	('mRNA expression', 'MPA', (48, 63))	('increased', 'PosReg', (34, 43))	('knockdown', 'Var', (24, 33))
85415	28658440	Alterations of SF-1 dosage regulate compensatory adrenal growth after unilateral adrenalectomy, proliferation and tumorigenesis in mice.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('rat', 'Species', '10116', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('proliferation', 'CPA', (96, 109))	('SF-1', 'Gene', (15, 19))	('Alterations', 'Var', (0, 11))	('compensatory adrenal growth', 'Phenotype', 'HP:0011734', (36, 63))	('tumor', 'Disease', (114, 119))	('compensatory adrenal growth', 'CPA', (36, 63))	('mice', 'Species', '10090', (131, 135))	('rat', 'Species', '10116', (4, 7))
85434	28658440	POD1 mRNA expression was significantly lower in T7-siPOD1 transfected cells (0.35+-0.22-fold), with a 65% decrease compared to that in transfected controls (ANOVA, p=0.001; Figure 1C), whereas the mRNA levels of SF1 increased 5.97+-0.22-fold in T7-siPOD-1 cells compared to those in transfected controls (ANOVA, p=0.05; Figure 1D).	('SF1', 'Gene', (212, 215))	('transfected', 'Var', (58, 69))	('mRNA expression', 'MPA', (5, 20))	('mRNA levels', 'MPA', (197, 208))	('SF1', 'Gene', '7536', (212, 215))	('decrease', 'NegReg', (106, 114))	('POD1', 'Gene', (0, 4))	('T7-siPOD1', 'Var', (48, 57))	('lower', 'NegReg', (39, 44))
85437	28658440	Taken together, the findings of this study and the POD1 inactivation observed in several types of tumors suggest that POD1 may act as a tumor suppressor in pediatric and adult adrenocortical tumors.	('tumors', 'Disease', (98, 104))	('adrenocortical tumors', 'Disease', (176, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (98, 103))	('tumors', 'Disease', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (176, 197))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (191, 196))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('POD1', 'Gene', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('inactivation', 'Var', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('POD1', 'Gene', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))
85482	27278528	In this study, for a tumour size >4 cm or <=4 cm, the proportion of having a malignant tumour was 56/229 and 1/249, respectively (P < 0.001).	('tumour', 'Disease', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('malignant tumour', 'Disease', 'MESH:D009369', (77, 93))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('tumour', 'Disease', (21, 27))	('malignant tumour', 'Disease', (77, 93))	('<=4 cm', 'Var', (42, 48))
85485	27278528	For tumour size >5.4 cm or <=5.4 cm, the proportion of having a malignant tumour was 53/302 and 4/176, respectively (P < 0.001).	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Disease', (74, 80))	('malignant tumour', 'Disease', 'MESH:D009369', (64, 80))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('malignant tumour', 'Disease', (64, 80))	('tumour', 'Disease', (4, 10))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('<=5.4 cm', 'Var', (27, 35))
85528	26464434	Genome-wide CpG island methylation and intergenic demethylation propensities vary among different tumor sites The epigenetic landscape of cancer includes both focal hypermethylation and broader hypomethylation in a genome-wide manner.	('focal hypermethylation', 'Var', (159, 181))	('cancer', 'Disease', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
85529	26464434	By means of a comprehensive genomic analysis on 6637 tissues of 21 tumor types, we here show that the degrees of overall methylation in CpG island (CGI) and demethylation in intergenic regions, defined as 'backbone', largely vary among different tumors.	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('methylation', 'MPA', (121, 132))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('demethylation', 'Var', (157, 170))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (67, 72))	('vary', 'Reg', (225, 229))	('tumor', 'Disease', (246, 251))	('tumors', 'Disease', (246, 252))
85531	26464434	We found connections between CGI methylation and hypermutability, microsatellite instability, IDH1 mutation, 19p gain and polycomb features, and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains.	('IDH1', 'Gene', (94, 98))	('microsatellite instability', 'MPA', (66, 92))	('NSD1', 'Gene', '64324', (198, 202))	('IDH1', 'Gene', '3417', (94, 98))	('backbone', 'MPA', (145, 153))	('TP53', 'Gene', '7157', (207, 211))	('mutation', 'Var', (99, 107))	('TP53', 'Gene', (207, 211))	('gain', 'PosReg', (113, 117))	('mutations', 'Var', (212, 221))	('NSD1', 'Gene', (198, 202))	('chromosomal instability', 'Phenotype', 'HP:0040012', (173, 196))	('loss', 'NegReg', (234, 238))
85532	26464434	These broad epigenetic patterns add a new dimension to our understanding of tumor biology and its clinical implications.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('epigenetic patterns', 'Var', (12, 31))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
85533	26464434	Epigenetic alterations have pivotal roles in development and cancer biology.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
85534	26464434	A canonical observation in many cancers is the de novo methylation of CpG islands (CGIs) in the promoters of tumor-related genes, which is significantly associated with clinical behavior in many tumors.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', (195, 200))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('cancers', 'Disease', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('associated', 'Reg', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('methylation', 'Var', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (109, 114))
85541	26464434	TF-binding sites behaved differently according to TF contents; the binding sites of embryonic stem cell (ESC)-related TFs including polycomb proteins and CTBP2 were frequently de novo methylated while the binding sites of other differentiation-associated TFs were rather demethylated or unchanged.	('CTBP2', 'Gene', '1488', (154, 159))	('polycomb proteins', 'Protein', (132, 149))	('methylated', 'Var', (184, 194))	('binding', 'Interaction', (67, 74))	('CTBP2', 'Gene', (154, 159))
85561	26464434	Likewise, we selected 49 277 CpGs in backbone, as defined above, and averaged their methylation levels for each tumor.	('CpGs', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('methylation levels', 'MPA', (84, 102))
85566	26464434	Nonetheless, most tumors showed both CGI methylation and backbone demethylation with variable degrees (HC-LB; Figure 1F; Supplementary Figure S2).	('backbone demethylation', 'MPA', (57, 79))	('methylation', 'Var', (41, 52))	('HC-LB; Figure 1F; Supplementary Figure S2', 'Disease', 'MESH:D017034', (103, 144))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('HC-LB; Figure 1F; Supplementary Figure S2', 'Disease', (103, 144))	('CGI', 'MPA', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
85568	26464434	And in most tumors, DNA methylation correlated with mRNA expression, miRNA expression, copy number and pathway clusters suggesting an underlying biological background.	('copy number', 'Var', (87, 98))	('DNA', 'Gene', (20, 23))	('pathway clusters', 'Pathway', (103, 119))	('methylation', 'Var', (24, 35))	('correlated', 'Reg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('miRNA expression', 'MPA', (69, 85))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('mRNA expression', 'MPA', (52, 67))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
85572	26464434	In THCA, histories of lymphocytic thyroiditis significantly correlated with high CGI methylation (P = 6.3 x 10-4).	('CGI', 'Protein', (81, 84))	('thyroiditis', 'Phenotype', 'HP:0100646', (34, 45))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('lymphocytic thyroiditis', 'Disease', (22, 45))	('lymphocytic thyroiditis', 'Phenotype', 'HP:0000872', (22, 45))	('correlated', 'Reg', (60, 70))	('lymphocytic thyroiditis', 'Disease', 'MESH:D013967', (22, 45))	('high', 'Var', (76, 80))
85574	26464434	In COADREAD, CGI methylation was highest in cecum tumors and became modest when moving towards the rectum (P = 1.3 x 10-16; Supplementary Figure S25A).	('highest', 'Reg', (33, 40))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('S25A', 'SUBSTITUTION', 'None', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('S25A', 'Var', (145, 149))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
85575	26464434	In HNSC, CGI methylation was highest in the oral cavity and lower in the caudal direction in the oropharangeal tract (P = 8.9 x 10-5; Supplementary Figure S25B).	('methylation', 'MPA', (13, 24))	('S25B', 'SUBSTITUTION', 'None', (155, 159))	('highest', 'Reg', (29, 36))	('S25B', 'Var', (155, 159))	('CGI', 'MPA', (9, 12))	('HNSC', 'Phenotype', 'HP:0012288', (3, 7))	('lower', 'NegReg', (60, 65))
85579	26464434	Type 2 KIRP, an eosinophilic tumor with worse prognosis, was associated with both CGI methylation and backbone demethylation (P = 4.4 x 10-5 and 1.9 x 10-3, respectively).	('backbone demethylation', 'MPA', (102, 124))	('Type 2 KIRP', 'Disease', (0, 11))	('eosinophilic tumor', 'Disease', (16, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('methylation', 'Var', (86, 97))	('eosinophilic tumor', 'Disease', 'MESH:D004802', (16, 34))	('CGI', 'MPA', (82, 85))
85581	26464434	In PRAD, Gleason scores tended to be high both in CGI-methylated and backbone-demethylated tumors (P = 6.1 x 10-3 and 3.9 x 10-4, respectively).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('high', 'PosReg', (37, 41))	('CGI-methylated', 'Var', (50, 64))	('PRAD', 'Disease', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Gleason', 'MPA', (9, 16))	('backbone-demethylated', 'Var', (69, 90))
85582	26464434	An association of CGI methylation with high mitosis was observed in ACC (P = 4.5 x 10-4).	('association', 'Interaction', (3, 14))	('high mitosis', 'Disease', (39, 51))	('ACC', 'Phenotype', 'HP:0006744', (68, 71))	('high mitosis', 'Disease', 'MESH:D008228', (39, 51))	('ACC', 'Disease', (68, 71))	('CGI', 'Protein', (18, 21))	('methylation', 'Var', (22, 33))
85585	26464434	MSI-H tumors were very significantly associated with CGI methylation in COADREAD, STAD and UCEC (P = 3.2 x 10-12, 2.4 x 10-7 and 2.0 x 10-22, respectively) (Figure 2B).	('methylation', 'Var', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('associated', 'Reg', (37, 47))	('MSI-H tumors', 'Disease', 'MESH:D009369', (0, 12))	('CGI', 'MPA', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('MSI-H tumors', 'Disease', (0, 12))
85586	26464434	In COADREAD, CGI methylation was associated with negative expression of MSH6 and PMS2 proteins (P = 9.3 x 10-3).	('MSH6', 'Gene', (72, 76))	('expression', 'MPA', (58, 68))	('proteins', 'Protein', (86, 94))	('PMS2', 'Gene', '5395', (81, 85))	('methylation', 'Var', (17, 28))	('negative', 'NegReg', (49, 57))	('MSH6', 'Gene', '2956', (72, 76))	('PMS2', 'Gene', (81, 85))
85587	26464434	In BRCA, CGI methylation was significantly associated with positive expression of estrogen and HER2/neu receptors (P = 1.5 x 10-5 and 8.3 x 10-8, respectively) and thus with luminal B subtype (P = 1.3 x 10-9).	('BRCA', 'Gene', (3, 7))	('expression', 'MPA', (68, 78))	('CGI methylation', 'Var', (9, 24))	('methylation', 'Var', (13, 24))	('BRCA', 'Gene', '672', (3, 7))	('positive', 'PosReg', (59, 67))	('estrogen', 'Protein', (82, 90))	('HER2/neu receptors', 'Protein', (95, 113))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
85588	26464434	The number of gene mutations correlated positively with CGI methylation in THCA, KIRC, LAML, LGG, GBM, PRAD, STAD, BRCA, ACC and UCEC (Figure 2A and B).	('ACC', 'Phenotype', 'HP:0006744', (121, 124))	('CGI methylation', 'MPA', (56, 71))	('THCA', 'Phenotype', 'HP:0002890', (75, 79))	('BRCA', 'Phenotype', 'HP:0003002', (115, 119))	('BRCA', 'Gene', '672', (115, 119))	('mutations', 'Var', (19, 28))	('BRCA', 'Gene', (115, 119))
85589	26464434	In line with the previous knowledge, IDH1 mutation was associated with high CGI methylation in LGG (P = 2.1 x 10-20), GBM, PRAD and CESC, and IDH2 was so in LAML.	('IDH2', 'Gene', '3418', (142, 146))	('IDH1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))	('CGI methylation', 'MPA', (76, 91))	('IDH2', 'Gene', (142, 146))
85590	26464434	Mutations in CIC, NOTCH1 and FUBP1 were very significantly associated with high CGI methylation in LGG (P = 5.7 x 10-11, 5.2 x 10-7 and 9.9 x 10-5, respectively), mutation in PIK3CA was so in STAD (P = 7.4 x 10-9), and mutations in PTEN and PIK3R1 were so in UCEC (P = 5.9 x 10-7 and 1.6 x 10-4, respectively).	('NOTCH1', 'Gene', (18, 24))	('PIK3CA', 'Gene', (175, 181))	('UCEC', 'Disease', (259, 263))	('PIK3R1', 'Gene', '5295', (241, 247))	('PIK3R1', 'Gene', (241, 247))	('PIK3CA', 'Gene', '5290', (175, 181))	('associated', 'Reg', (59, 69))	('high CGI methylation', 'MPA', (75, 95))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', '5728', (232, 236))	('FUBP1', 'Gene', '8880', (29, 34))	('PTEN', 'Gene', (232, 236))	('mutations', 'Var', (219, 228))	('CIC', 'Gene', (13, 16))	('mutation', 'Var', (163, 171))	('FUBP1', 'Gene', (29, 34))	('NOTCH1', 'Gene', '4851', (18, 24))
85591	26464434	NRAS mutation was frequent in THCA with higher CGI methylation and BRAF was so in THCA with lower backbone methylation (P = 5.9 x 10-3 and 9.9 x 10-7, respectively) but this may be confounded by the difference in methylation according to histological type, as described above, and high frequency of NRAS mutation in follicular and BRAF mutation in papillary types.	('THCA', 'Phenotype', 'HP:0002890', (82, 86))	('BRAF', 'Gene', (331, 335))	('BRAF', 'Gene', '673', (331, 335))	('NRAS', 'Gene', '4893', (299, 303))	('higher', 'PosReg', (40, 46))	('BRAF', 'Gene', '673', (67, 71))	('backbone methylation', 'MPA', (98, 118))	('THCA', 'Phenotype', 'HP:0002890', (30, 34))	('BRAF', 'Gene', (67, 71))	('CGI methylation', 'MPA', (47, 62))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))	('mutation', 'Var', (5, 13))	('NRAS', 'Gene', (299, 303))
85592	26464434	TP53 mutation was associated with backbone demethylation in STAD and PRAD (P = 5.1 x 10-5 and 4.9 x 10-3, respectively) (Figure 2C), and NSD1 mutation was so in HNSC (P = 3.2 x 10-9) (Supplementary Figure S17B).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('backbone demethylation', 'MPA', (34, 56))	('S17B', 'Var', (205, 209))	('S17B', 'SUBSTITUTION', 'None', (205, 209))	('mutation', 'Var', (5, 13))	('NSD1', 'Gene', '64324', (137, 141))	('HNSC', 'Phenotype', 'HP:0012288', (161, 165))	('NSD1', 'Gene', (137, 141))
85597	26464434	The most remarkable P value peak was in chromosome 5q showing recurrent correlations between deletion and backbone demethylation in many tumors (Figure 3A and B).	('tumors', 'Disease', (137, 143))	('backbone demethylation', 'MPA', (106, 128))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('correlations', 'Reg', (72, 84))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('deletion', 'Var', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
85598	26464434	Candidate genes in this region include CHD1, LMNB1, KDM3B, HDAC3 and NSD1, and among them, NSD1 was of particular interest in that mutation in this gene also showed the most significant association with backbone demethylation in HNSC and other tumors (Figure 3C).	('NSD1', 'Gene', (69, 73))	('backbone demethylation', 'MPA', (203, 225))	('mutation', 'Var', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('HDAC3', 'Gene', (59, 64))	('CHD1', 'Gene', '1105', (39, 43))	('LMNB1', 'Gene', '4001', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('NSD1', 'Gene', '64324', (69, 73))	('NSD1', 'Gene', (91, 95))	('CHD1', 'Gene', (39, 43))	('HNSC', 'Disease', (229, 233))	('tumors', 'Disease', (244, 250))	('KDM3B', 'Gene', '51780', (52, 57))	('LMNB1', 'Gene', (45, 50))	('HDAC3', 'Gene', '8841', (59, 64))	('HNSC', 'Phenotype', 'HP:0012288', (229, 233))	('association', 'Reg', (186, 197))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('NSD1', 'Gene', '64324', (91, 95))	('KDM3B', 'Gene', (52, 57))
85599	26464434	Bi-allelic aberration of NSD1 either by mutation or copy loss showed more demethylation (Figure 3D).	('mutation', 'Var', (40, 48))	('NSD1', 'Gene', (25, 29))	('demethylation', 'MPA', (74, 87))	('copy loss', 'Var', (52, 61))	('NSD1', 'Gene', '64324', (25, 29))
85602	26464434	Among the pathways recurrently associated in several tumors, the bone morphogenic protein (BMP) receptor pathway was significantly suppressed among backbone-demethylated tumors in LGG, PRAD and LIHC and CGI-methylated tumors in LUAD.	('backbone-demethylated', 'Var', (148, 169))	('BMP', 'Gene', '649', (91, 94))	('LIHC', 'Disease', (194, 198))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('CGI-methylated', 'Var', (203, 217))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('LIHC', 'Disease', 'None', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PRAD', 'Disease', (185, 189))	('BMP', 'Gene', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('LGG', 'Disease', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('suppressed', 'NegReg', (131, 141))	('LUAD', 'Phenotype', 'HP:0030078', (228, 232))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
85609	26464434	In all tumor types, differentially methylated CpGs were highly enriched in binding sites of polycomb-related SUZ12, EZH2 and CTBP2, and the enrichment rate strongly correlated with the degree of CGI methylation (Supplementary Figure S30).	('EZH2', 'Gene', (116, 120))	('EZH2', 'Gene', '2146', (116, 120))	('tumor', 'Disease', (7, 12))	('differentially', 'Var', (20, 34))	('correlated', 'Reg', (165, 175))	('CTBP2', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('CGI methylation', 'MPA', (195, 210))	('CTBP2', 'Gene', '1488', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('binding sites', 'Interaction', (75, 88))	('SUZ12', 'Gene', '23512', (109, 114))	('SUZ12', 'Gene', (109, 114))
85610	26464434	Demethylated CpGs were often enriched in IKZF1, BATF and ZNF217 binding sites but the enrichment rate usually did not correlate with the degree of backbone demethylation, suggesting a minor role of transcription factors in the genome-wide demethylation (Supplementary Figure S31).	('BATF', 'Gene', (48, 52))	('BATF', 'Gene', '10538', (48, 52))	('IKZF1', 'Gene', '10320', (41, 46))	('ZNF217', 'Gene', (57, 63))	('ZNF217', 'Gene', '7764', (57, 63))	('IKZF1', 'Gene', (41, 46))	('Demethylated', 'Var', (0, 12))
85614	26464434	Intriguingly, CGI-methylated tumors showed better primary responses in STAD and LUAD (P = 7.5 x 10-3 and 1.8 x 10-2, respectively).	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('primary responses', 'CPA', (50, 67))	('LUAD', 'Disease', (80, 84))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('better', 'PosReg', (43, 49))	('STAD', 'Disease', (71, 75))	('CGI-methylated', 'Var', (14, 28))
85621	26464434	As supporting evidence, we could observe correlation of HC-tumors with many CIMP-associated features such as MSI-H and IDH1 mutation.	('HC-tumors', 'Disease', (56, 65))	('CIMP', 'Chemical', '-', (76, 80))	('MSI-H', 'Disease', (109, 114))	('correlation', 'Interaction', (41, 52))	('IDH1', 'Gene', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('MSI-H', 'Disease', 'MESH:D000848', (109, 114))	('mutation', 'Var', (124, 132))	('HC-tumors', 'Disease', 'MESH:D009369', (56, 65))	('IDH1', 'Gene', '3417', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
85626	26464434	Polycomb site methylation has now been accepted as a hallmark of cancers, and so the enrichment of polycomb proteins, SUZ12 and EZH2, should be an innate quality.	('hallmark of cancers', 'Disease', (53, 72))	('hallmark of cancers', 'Disease', 'MESH:D009369', (53, 72))	('Polycomb', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('EZH2', 'Gene', (128, 132))	('SUZ12', 'Gene', '23512', (118, 123))	('EZH2', 'Gene', '2146', (128, 132))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('SUZ12', 'Gene', (118, 123))
85628	26464434	Global demethylation in repetitive elements has been suggested in many cancers and yet a systematical analysis is lacking.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Global demethylation', 'Var', (0, 20))
85629	26464434	Associations of demethylation with histological grade and stage have been suggested in several tumors, and we could find such an association in an expanded set of tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('Associations', 'Interaction', (0, 12))	('demethylation', 'Var', (16, 29))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
85631	26464434	Although it has been experimentally shown that demethylation is linked to mitotic dysfunction and genomic rearrangement and anticipated to cause chromosome instability, it remained uninvestigated in clinical series.	('mitotic dysfunction', 'Disease', (74, 93))	('chromosome instability', 'MPA', (145, 167))	('demethylation', 'Var', (47, 60))	('mitotic dysfunction', 'Disease', 'MESH:C536987', (74, 93))	('linked', 'Reg', (64, 70))	('chromosome instability', 'Phenotype', 'HP:0040012', (145, 167))	('genomic rearrangement', 'CPA', (98, 119))	('cause', 'Reg', (139, 144))
85635	26464434	NSD1 is a SET domain histone methyltransferase that primarily dimethylates histone H3K36, implicated in Sotos and Weaver overgrowth syndromes.	('NSD1', 'Gene', (0, 4))	('dimethylates', 'Var', (62, 74))	('overgrowth', 'Phenotype', 'HP:0001548', (121, 131))	('Weaver overgrowth syndromes', 'Disease', 'MESH:C536687', (114, 141))	('histone H3K36', 'Protein', (75, 88))	('Weaver overgrowth syndromes', 'Disease', (114, 141))	('NSD1', 'Gene', '64324', (0, 4))
85640	26464434	TP53 was also among the most significant genes, and this can be understood on the basis that TP53 mutations can directly cause DNA demethylation.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('mutations', 'Var', (98, 107))	('cause', 'Reg', (121, 126))	('DNA demethylation', 'MPA', (127, 144))
85641	26464434	Moreover, TP53 plays critical roles DNA repair and maintaining genomic stability and its mutation may exhibit communal pathways with DNA demethylation leading to chromosome instability.	('chromosome instability', 'MPA', (162, 184))	('TP53', 'Gene', (10, 14))	('mutation', 'Var', (89, 97))	('TP53', 'Gene', '7157', (10, 14))	('genomic', 'MPA', (63, 70))	('chromosome instability', 'Phenotype', 'HP:0040012', (162, 184))	('leading to', 'Reg', (151, 161))	('exhibit', 'Reg', (102, 109))
85642	26464434	It is often hypothesized that demethylation in cancer cells can activate proto-oncogenes and thus contribute to tumorigenesis.	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('contribute to', 'Reg', (98, 111))	('cancer', 'Disease', (47, 53))	('demethylation', 'Var', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('proto-oncogenes', 'Gene', (73, 88))	('activate', 'PosReg', (64, 72))
85643	26464434	As more supporting evidence, we found that many pathways such as BMP receptor, LPA receptor, Ephrin B, PLK1, Aurora A and B, FoxM1, neurotrophic factor and p75NTR pathways tended to be suppressed rather than activated in demethylated tumors.	('Ephrin B', 'Gene', (93, 101))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('LPA', 'Protein', (79, 82))	('neurotrophic factor', 'Gene', '4908', (132, 151))	('demethylated', 'Var', (221, 233))	('BMP', 'Gene', '649', (65, 68))	('Aurora A and B', 'Gene', '6790;9212', (109, 123))	('PLK1', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('activated', 'PosReg', (208, 217))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('neurotrophic factor', 'Gene', (132, 151))	('p75NTR', 'Gene', (156, 162))	('FoxM1', 'Gene', '2305', (125, 130))	('LPA', 'Chemical', 'MESH:C032881', (79, 82))	('BMP', 'Gene', (65, 68))	('PLK1', 'Gene', '5347', (103, 107))	('suppressed', 'NegReg', (185, 195))	('tumors', 'Disease', (234, 240))	('p75NTR', 'Gene', '4804', (156, 162))	('FoxM1', 'Gene', (125, 130))
85645	26464434	We observed that low BMP, especially BMP-7, activity is associated with backbone demethylation and such demethylated tumors show aggressive features like high Gleason score and prostate specific antigen level (Supplementary Figure S10B).	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('S10B', 'Var', (231, 235))	('BMP', 'Gene', '649', (37, 40))	('associated', 'Reg', (56, 66))	('prostate specific antigen', 'Gene', (177, 202))	('low', 'NegReg', (17, 20))	('demethylated', 'Var', (104, 116))	('prostate specific antigen', 'Gene', '354', (177, 202))	('BMP', 'Gene', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BMP-7', 'Gene', '655', (37, 42))	('tumors', 'Disease', (117, 123))	('BMP', 'Gene', (37, 40))	('BMP-7', 'Gene', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('activity', 'MPA', (44, 52))	('backbone demethylation', 'MPA', (72, 94))	('S10B', 'SUBSTITUTION', 'None', (231, 235))	('BMP', 'Gene', '649', (21, 24))
85647	26464434	We also noticed that the demethylated tumors also tended to have worse outcome although the significance varied according to the cutoffs for average backbone methylation (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('demethylated', 'Var', (25, 37))	('tumors', 'Disease', 'MESH:D009369', (38, 44))
85649	26464434	We observed low BMP activity in demethylated LGGs which showed higher histological grade and worse treatment response and survival (Supplementary Figure S9B).	('histological', 'CPA', (70, 82))	('BMP', 'Gene', '649', (16, 19))	('survival', 'CPA', (122, 130))	('treatment response', 'CPA', (99, 117))	('BMP', 'Gene', (16, 19))	('demethylated', 'Var', (32, 44))	('higher', 'PosReg', (63, 69))	('low', 'NegReg', (12, 15))
85656	26464434	We observed that Ephrin pathways are epigenetically suppressed in a set of tumors preferentially by backbone demethylation.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('suppressed', 'NegReg', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Ephrin pathways', 'Pathway', (17, 32))	('tumors', 'Disease', (75, 81))	('backbone demethylation', 'Var', (100, 122))
85658	26464434	We found that PLK1 and Aurora pathways are often suppressed and sometimes activated in backbone-demethylated or CGI-methylated tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('CGI-methylated', 'Var', (112, 126))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('activated', 'PosReg', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('suppressed', 'NegReg', (49, 59))	('backbone-demethylated', 'Var', (87, 108))	('PLK1', 'Gene', (14, 18))	('Aurora pathways', 'Pathway', (23, 38))	('PLK1', 'Gene', '5347', (14, 18))
85660	26464434	Either loss or gain of FoxM function can alter cell fate and promote tumorigenesis, and we observed epigenetic suppression of FoxM1 pathway in a set of tumors.	('cell fate', 'CPA', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('loss', 'NegReg', (7, 11))	('FoxM', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', (69, 74))	('FoxM1', 'Gene', '2305', (126, 131))	('promote', 'PosReg', (61, 68))	('FoxM1', 'Gene', (126, 131))	('tumor', 'Disease', (152, 157))	('gain', 'PosReg', (15, 19))	('alter', 'Reg', (41, 46))	('epigenetic suppression', 'Var', (100, 122))	('tumors', 'Disease', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
85670	26464434	The slightly-high tumors showed poor survival compared to slightly-low tumors.	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('slightly-high', 'Var', (4, 17))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
85675	26464434	Collectively, we present a pan-cancer model connecting CGI methylation with hypermutability, MSI-H, IDH1 mutation, 19p gain and polycomb proteins and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains (Figure 5).	('MSI-H', 'Disease', 'MESH:D000848', (93, 98))	('mutation', 'Var', (105, 113))	('IDH1', 'Gene', '3417', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('chromosomal instability', 'Phenotype', 'HP:0040012', (178, 201))	('NSD1', 'Gene', (203, 207))	('MSI-H', 'Disease', (93, 98))	('loss', 'NegReg', (239, 243))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('TP53', 'Gene', '7157', (212, 216))	('IDH1', 'Gene', (100, 104))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (217, 226))	('NSD1', 'Gene', '64324', (203, 207))	('gain', 'PosReg', (119, 123))	('TP53', 'Gene', (212, 216))
85677	26464434	Since many pathways are suppressed in methylated and demethylated tumors, thoughtful usage of new targeted drugs inhibiting such pathways is warranted.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('methylated', 'Var', (38, 48))	('tumors', 'Disease', (66, 72))	('suppressed', 'NegReg', (24, 34))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('pathways', 'Pathway', (11, 19))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('demethylated', 'Var', (53, 65))
85699	25978633	Among these is the C1858T allele in the lymphoid tyrosine phosphatase nonreceptor type 22 (PTPN22) gene, a susceptibility allele for numerous autoimmune diseases (Skinningsrud and others; Roycroft and others).	('PTPN22', 'Gene', '26191', (91, 97))	('C1858T', 'Mutation', 'rs2476601', (19, 25))	('autoimmune disease', 'Phenotype', 'HP:0002960', (142, 160))	('Roycroft', 'Disease', (188, 196))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (142, 161))	('C1858T', 'Var', (19, 25))	('PTPN22', 'Gene', (91, 97))	('numerous autoimmune diseases', 'Disease', (133, 161))	('numerous autoimmune diseases', 'Disease', 'MESH:D001327', (133, 161))
85700	25978633	This single nucleotide polymorphism (SNP) causes an amino acid shift from arginine to tryptophan at position 620, affecting the functional properties of PTPN22, including its recently described role as a regulator of IFN production in myeloid cells (Bottini and others; Wang and others).	('amino acid shift from', 'MPA', (52, 73))	('arginine to tryptophan at position 620', 'Mutation', 'rs2476601', (74, 112))	('causes', 'Reg', (42, 48))	('IFN', 'Gene', '3439', (217, 220))	('acid shift', 'Phenotype', 'HP:0032239', (58, 68))	('PTPN22', 'Gene', (153, 159))	('functional properties', 'MPA', (128, 149))	('poly', 'Chemical', '-', (23, 27))	('PTPN22', 'Gene', '26191', (153, 159))	('IFN', 'Gene', (217, 220))	('single nucleotide polymorphism', 'Var', (5, 35))	('affecting', 'Reg', (114, 123))
85764	25978633	As for IFN-alpha, patient cells that were stimulated with poly (I:C) after 24 h of resting did not show consistently increased CXCL10 production compared to cells stimulated directly at the start of culture (data not shown).	('poly (I:C)', 'Chemical', '-', (58, 68))	('CXCL10', 'Gene', '3627', (127, 133))	('patient', 'Species', '9606', (18, 25))	('poly (I:C', 'Var', (58, 67))	('CXCL10', 'Gene', (127, 133))	('IFN-alpha', 'Gene', '3439', (7, 16))	('IFN-alpha', 'Gene', (7, 16))
85774	25978633	No other significant correlations were found between age and IFN- or poly (I:C)-induced CXCL10 or CXCL9 (Supplementary Fig.	('IFN', 'Gene', '3439', (61, 64))	('CXCL10', 'Gene', (88, 94))	('poly', 'Var', (69, 73))	('CXCL9', 'Gene', '4283', (98, 103))	('IFN', 'Gene', (61, 64))	('poly (I:C)', 'Chemical', '-', (69, 79))	('CXCL9', 'Gene', (98, 103))	('CXCL10', 'Gene', '3627', (88, 94))
85780	25978633	To find any characteristics among the AAD patients that could help to explain their poor response to IFNs, we looked in the literature and noted that a SNP of the PTPN22 gene (rs2476601) (which is associated with increased risk for developing AAD) was also associated with impaired IFN response after TLR stimulation in healthy individuals (Wang and others).	('IFN', 'Gene', (101, 104))	('IFN', 'Gene', (282, 285))	('rs2476601', 'Mutation', 'rs2476601', (176, 185))	('AAD', 'Disease', (243, 246))	('associated', 'Reg', (257, 267))	('impaired', 'NegReg', (273, 281))	('rs2476601', 'Var', (176, 185))	('PTPN22', 'Gene', (163, 169))	('AAD', 'Disease', 'None', (38, 41))	('TLR', 'Gene', (301, 304))	('IFN', 'Gene', '3439', (282, 285))	('TLR', 'Gene', '7098', (301, 304))	('PTPN22', 'Gene', '26191', (163, 169))	('AAD', 'Disease', (38, 41))	('IFN', 'Gene', '3439', (101, 104))	('patients', 'Species', '9606', (42, 50))	('AAD', 'Disease', 'None', (243, 246))
85783	25978633	When stimulated with poly (I:C), there was a significant difference in the production of CXCL10 between carriers of the 1858T allele and the 1858C homozygotes (P<0.05, Fig.	('CXCL10', 'Gene', (89, 95))	('poly (I:C)', 'Chemical', '-', (21, 31))	('1858T', 'Var', (120, 125))	('CXCL10', 'Gene', '3627', (89, 95))
85785	25978633	Although no other statistically significant associations were found, mean CXCL10 levels were lower in T carriers also after IFN stimulation (as shown for IFN-alpha, Fig.	('CXCL10', 'Gene', '3627', (74, 80))	('IFN', 'Gene', (154, 157))	('T carriers', 'Var', (102, 112))	('CXCL10', 'Gene', (74, 80))	('IFN-alpha', 'Gene', '3439', (154, 163))	('IFN-alpha', 'Gene', (154, 163))	('lower', 'NegReg', (93, 98))	('IFN', 'Gene', '3439', (124, 127))	('IFN', 'Gene', (124, 127))	('IFN', 'Gene', '3439', (154, 157))
85789	25978633	The involvement of IFNs, either type I or II or both, in the immunopathogenesis of AAD is strongly suggested by several observations in both clinical and experimental settings: Individuals treated with IFN-alpha for viral infections or cancer have developed autoantibodies against 21OH, with or without concomitant clinical adrenocortical insufficiency (Wesche and others; Tran and others; Krysiak and others).	('Tran', 'Gene', (373, 377))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('adrenocortical insufficiency', 'Disease', (324, 352))	('viral infections', 'Disease', 'MESH:D001102', (216, 232))	('AAD', 'Disease', (83, 86))	('IFN', 'Gene', (202, 205))	('IFN-alpha', 'Gene', (202, 211))	('Tran', 'Gene', '7154', (373, 377))	('viral infections', 'Disease', (216, 232))	('IFN', 'Gene', (19, 22))	('adrenocortical insufficiency', 'Disease', 'MESH:D000224', (324, 352))	('cancer', 'Disease', (236, 242))	('21OH', 'Protein', (281, 285))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('IFN-alpha', 'Gene', '3439', (202, 211))	('adrenocortical insufficiency', 'Phenotype', 'HP:0008207', (324, 352))	('autoantibodies', 'Var', (258, 272))	('developed', 'PosReg', (248, 257))	('21OH', 'Chemical', '-', (281, 285))	('IFN', 'Gene', '3439', (202, 205))	('AAD', 'Disease', 'None', (83, 86))	('IFN', 'Gene', '3439', (19, 22))
85815	25978633	To investigate chemokine production elicited by endogenous IFNs, we stimulated patient and control PBMCs with the TLR3 agonist poly (I:C), a well-characterized inducer of IFNs (Alexopoulou and others).	('poly', 'Var', (127, 131))	('IFN', 'Gene', '3439', (171, 174))	('IFN', 'Gene', '3439', (59, 62))	('poly (I:C)', 'Chemical', '-', (127, 137))	('IFN', 'Gene', (171, 174))	('patient', 'Species', '9606', (79, 86))	('TLR3', 'Gene', (114, 118))	('TLR3', 'Gene', '7098', (114, 118))	('IFN', 'Gene', (59, 62))
85819	25978633	We also estimated the relative levels of IFN-beta induced by poly (I:C), but these levels were not significantly different between patients and controls.	('patients', 'Species', '9606', (131, 139))	('poly (I:C)', 'Chemical', '-', (61, 71))	('poly (I:C', 'Var', (61, 70))	('IFN-beta', 'Gene', '3456', (41, 49))	('IFN-beta', 'Gene', (41, 49))
85832	25978633	We also compared phosphorylated STAT1/STAT2 levels after stimulation with IFNs-alpha, -beta, -gamma, or poly (I:C).	('STAT2', 'Gene', '6773', (38, 43))	('STAT2', 'Gene', (38, 43))	('STAT1', 'Gene', (32, 37))	('poly (I:C)', 'Chemical', '-', (104, 114))	('STAT1', 'Gene', '6772', (32, 37))	('poly (I:C', 'Var', (104, 113))
85839	25978633	Strikingly, the patients carrying the 1858T allele appeared to produce less CXCL10 in response to poly (I:C) than patients homozygous for the 1858C allele.	('CXCL10', 'Gene', (76, 82))	('1858T', 'Var', (38, 43))	('patients', 'Species', '9606', (16, 24))	('less', 'NegReg', (71, 75))	('CXCL10', 'Gene', '3627', (76, 82))	('patients', 'Species', '9606', (114, 122))	('poly (I:C)', 'Chemical', '-', (98, 108))
85871	26038200	However, mutant mice lacking the glucocorticoid receptor exhibit normal embryonic neural crest cell migration to the adrenal and normal early fetal chromaffin cell development .	('rat', 'Species', '10116', (103, 106))	('early fetal chromaffin cell development', 'CPA', (136, 175))	('glucocorticoid receptor', 'Gene', '14815', (33, 56))	('lacking', 'NegReg', (21, 28))	('glucocorticoid receptor', 'Gene', (33, 56))	('mutant', 'Var', (9, 15))	('chromaffin', 'Chemical', '-', (148, 158))	('mice', 'Species', '10090', (16, 20))
85894	26038200	Consistent with this role and the enriched expression of Dax1 in the outer cortex, knockdown of Dax1 results in premature differentiation of mouse adrenocortical progenitor cells.	('adrenocortical', 'Disease', (147, 161))	('adrenocortical', 'Disease', 'MESH:D018268', (147, 161))	('mouse', 'Species', '10090', (141, 146))	('Dax1', 'Gene', (96, 100))	('premature differentiation', 'CPA', (112, 137))	('knockdown', 'Var', (83, 92))
85926	26038200	A more recent study found the IGF pathway essential in adrenogonadal development and primary sex determination, since knocking down the receptors causes adrenal agenesis, possibly by decreased expression of Sf1 in AGP and subsequent failure of adrenal primordia specification.	('adrenal agenesis', 'Disease', (153, 169))	('knocking down', 'Var', (118, 131))	('decreased', 'NegReg', (183, 192))	('failure of adrenal primordia', 'Disease', (233, 261))	('failure of adrenal primordia', 'Disease', 'MESH:D000312', (233, 261))	('adrenal agenesis', 'Phenotype', 'HP:0011743', (153, 169))	('expression', 'MPA', (193, 203))	('causes', 'Reg', (146, 152))	('Sf1', 'Gene', (207, 210))
85992	26038200	In adult adrenal glands, Shh colocalizes with Sf1 in non-steroidogenic cortical cells of the zG region but not in differentiated zG or zF cells, which express both Sf1 and markers of fully differentiated steroidogenic cells (Cyp11b2 and Cyp11b1, respectively).	('steroid', 'Chemical', 'MESH:D013256', (57, 64))	('Shh', 'Gene', (25, 28))	('Sf1', 'Gene', (46, 49))	('Cyp11b2', 'Var', (225, 232))	('steroid', 'Chemical', 'MESH:D013256', (204, 211))	('Cyp11b1', 'Gene', (237, 244))	('Cyp11b1', 'Gene', '1584', (237, 244))
85994	26038200	Mice in which Shh is ablated specifically in Sf1-expressing cells reveal marked adrenal hypoplasia, decreased proliferation, and a thin capsule.	('rat', 'Species', '10116', (117, 120))	('thin capsule', 'CPA', (131, 143))	('ablated', 'Var', (21, 28))	('Sf1-expressing', 'Gene', (45, 59))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (80, 98))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (80, 98))	('proliferation', 'CPA', (110, 123))	('decreased', 'NegReg', (100, 109))	('Mice', 'Species', '10090', (0, 4))	('adrenal hypoplasia', 'Disease', (80, 98))
85998	26038200	Employing a cre-lox technology to ablate beta-catenin specifically in Sf1-expressing cells of the adrenal cortex, Kim et al observed adrenal aplasia at birth in mice expressing a highly penetrant Sf1-cre transgene.	('observed', 'Reg', (124, 132))	('mice', 'Species', '10090', (161, 165))	('lox', 'Gene', '16948', (16, 19))	('adrenal aplasia', 'Phenotype', 'HP:0011743', (133, 148))	('adrenal aplasia', 'Disease', 'MESH:D000310', (133, 148))	('adrenal aplasia', 'Disease', (133, 148))	('ablate', 'Var', (34, 40))	('lox', 'Gene', (16, 19))	('beta-catenin', 'Protein', (41, 53))
86013	26038200	Surprisingly, when Sf1is ablated in zG cells, the mice are able to maintain a normal functional zF zone, despite the complete absence of zG-derived GPF cells within the zF, suggesting perhaps that progenitor cells can (although they usually do not) directly adopt a zF phenotype without first becoming a Cyp11b2-expressing zG cell.	('Sf1is', 'Gene', (19, 24))	('ablated', 'Var', (25, 32))	('mice', 'Species', '10090', (50, 54))
86021	26038200	The most common form of AHC is the X-linked congenital adrenal hypoplasia due to disruption of the nuclear receptor DAX1 (OMIM 300200).	('nuclear receptor DAX1', 'Gene', (99, 120))	('AHC', 'Disease', (24, 27))	('congenital adrenal hypoplasia', 'Phenotype', 'HP:0008244', (44, 73))	('nuclear receptor DAX1', 'Gene', '190', (99, 120))	('disruption', 'Var', (81, 91))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (55, 73))	('X-linked congenital adrenal hypoplasia', 'Disease', 'MESH:D000075262', (35, 73))	('X-linked congenital adrenal hypoplasia', 'Disease', (35, 73))	('AHC', 'Disease', 'MESH:D000312', (24, 27))
86022	26038200	Mutations of SF1 are one contributing cause of the autosomal form of AHC.	('AHC', 'Disease', (69, 72))	('cause', 'Reg', (38, 43))	('Mutations', 'Var', (0, 9))	('SF1', 'Gene', (13, 16))	('AHC', 'Disease', 'MESH:D000312', (69, 72))
86023	26038200	Rare autosomal forms of AHC include the IMAGE syndrome (OMIM 600856) and the SERKAL syndrome (OMIM 603490), caused by mutations of CDKN1C and WNT4, respectively.	('caused by', 'Reg', (108, 117))	('AHC', 'Disease', (24, 27))	('CDKN1C', 'Gene', (131, 137))	('WNT4', 'Gene', '54361', (142, 146))	('IMAGE syndrome', 'Disease', (40, 54))	('mutations', 'Var', (118, 127))	('CDKN1C', 'Gene', '1028', (131, 137))	('SERKAL syndrome', 'Disease', 'OMIM:611812', (77, 92))	('SERKAL syndrome', 'Disease', (77, 92))	('AHC', 'Disease', 'MESH:D000312', (24, 27))	('WNT4', 'Gene', (142, 146))
86024	26038200	Familial isolated glucocorticoid deficiency syndromes (broadly known as "ACTH resistance" syndromes) are autosomal recessive diseases caused by mutations in genes that participate in the ACTH signaling.	('autosomal recessive diseases', 'Disease', 'MESH:D030342', (105, 133))	('ACTH', 'Gene', '5443', (73, 77))	('ACTH', 'Gene', '5443', (187, 191))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (18, 43))	('caused by', 'Reg', (134, 143))	('Familial isolated glucocorticoid deficiency syndromes', 'Disease', 'MESH:C565974', (0, 53))	('autosomal recessive diseases', 'Disease', (105, 133))	('ACTH', 'Gene', (73, 77))	('mutations', 'Var', (144, 153))	('ACTH', 'Gene', (187, 191))
86025	26038200	These include mutations in MC2R and MRAP (a gene that codes for an accessory protein of the ACTH receptor, essential for its targeting and function).	('mutations', 'Var', (14, 23))	('MC2R', 'Gene', '4158', (27, 31))	('MRAP', 'Gene', '56246', (36, 40))	('ACTH receptor', 'Gene', (92, 105))	('MRAP', 'Gene', (36, 40))	('MC2R', 'Gene', (27, 31))	('ACTH receptor', 'Gene', '4158', (92, 105))
86026	26038200	More recently, mutations in the NNT and MCM4 genes were also associated with familial glucocorticoid deficiency .	('familial glucocorticoid deficiency', 'Disease', 'MESH:C564577', (77, 111))	('MCM4', 'Gene', '4173', (40, 44))	('NNT', 'Gene', (32, 35))	('mutations', 'Var', (15, 24))	('MCM4', 'Gene', (40, 44))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (86, 111))	('associated', 'Reg', (61, 71))	('familial glucocorticoid deficiency', 'Disease', (77, 111))
86027	26038200	Patients with ACTH resistance usually do not present with the salt-wasting phenotype because aldosterone-producing cells are not affected by these mutations.	('mutations', 'Var', (147, 156))	('salt-wasting', 'Phenotype', 'HP:0000127', (62, 74))	('salt', 'Chemical', 'MESH:D012492', (62, 66))	('Patients', 'Species', '9606', (0, 8))	('ACTH', 'Gene', (14, 18))	('aldosterone', 'Chemical', 'MESH:D000450', (93, 104))	('ACTH', 'Gene', '5443', (14, 18))
86030	26038200	Causes of secondary adrenal hypoplasia include 1) developmental abnormalities of the CNS such as anencephaly, septo-optic dysplasia (OMIM 182230) and holoprosencephaly/Pallister-Hall syndrome 2 spectrum (OMIM 615849), the last two caused by mutations in HESX1 and GLI2; 2) diseases of pituitary development such as pituitary combined hormone deficiency syndromes (caused by mutations in PROP1, POU1F1, OTX2, LHX3 and LHX4); 3) isolated ACTH deficiency (OMIM 201400) (caused by TBX19 mutations)); 4) defects in POMC and neuroendocrine convertase 1 (PCSK1), which leads to deficiencies in all POMC-related peptides; and 5) miscellaneous non-genetic causes that lead to hypothalamic or pituitary dysfunction such as idiopathic, intracranial tumors, infections or birth-related traumatic injuries.	('hypothalamic or pituitary dysfunction', 'Disease', (667, 704))	('GLI2', 'Gene', (264, 268))	('GLI2', 'Gene', '2736', (264, 268))	('developmental abnormalities', 'Disease', (50, 77))	('tumors', 'Phenotype', 'HP:0002664', (738, 744))	('anencephaly', 'Disease', 'MESH:D000757', (97, 108))	('adrenal hypoplasia', 'Disease', (20, 38))	('neuroendocrine convertase 1', 'Gene', (519, 546))	('pituitary combined hormone deficiency syndromes', 'Disease', (315, 362))	('traumatic injuries', 'Disease', 'MESH:D000070642', (774, 792))	('developmental abnormalities', 'Disease', 'MESH:D006130', (50, 77))	('TBX19', 'Gene', '9095', (477, 482))	('septo-optic dysplasia', 'Disease', (110, 131))	('POU1F1', 'Gene', (394, 400))	('mutations', 'Var', (374, 383))	('infections', 'Disease', 'MESH:D007239', (746, 756))	('hypothalamic or pituitary dysfunction', 'Disease', 'MESH:D007029', (667, 704))	('PROP1', 'Gene', (387, 392))	('tumor', 'Phenotype', 'HP:0002664', (738, 743))	('intracranial tumors', 'Disease', (725, 744))	('septo-optic dysplasia', 'Phenotype', 'HP:0100842', (110, 131))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (20, 38))	('traumatic injuries', 'Disease', (774, 792))	('infections', 'Disease', (746, 756))	('POU1F1', 'Gene', '5449', (394, 400))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (20, 38))	('holoprosencephaly/Pallister-Hall syndrome', 'Disease', 'MESH:D054975', (150, 191))	('POMC', 'Gene', '5443', (510, 514))	('POMC', 'Gene', '5443', (591, 595))	('LHX3', 'Gene', '8022', (408, 412))	('intracranial tumors', 'Disease', 'MESH:D001932', (725, 744))	('LHX3', 'Gene', (408, 412))	('ACTH', 'Gene', (436, 440))	('neuroendocrine convertase 1', 'Gene', '5122', (519, 546))	('secondary adrenal hypoplasia', 'Phenotype', 'HP:0011734', (10, 38))	('TBX19', 'Gene', (477, 482))	('defects', 'Var', (499, 506))	('POMC', 'Gene', (591, 595))	('ACTH deficiency', 'Phenotype', 'HP:0011748', (436, 451))	('POMC', 'Gene', (510, 514))	('PCSK1', 'Gene', '5122', (548, 553))	('holoprosencephaly/Pallister-Hall syndrome', 'Disease', (150, 191))	('HESX1', 'Gene', (254, 259))	('LHX4', 'Gene', (417, 421))	('septo-optic dysplasia', 'Disease', 'MESH:D025962', (110, 131))	('OTX2', 'Gene', '5015', (402, 406))	('hormone deficiency', 'Phenotype', 'HP:0000824', (334, 352))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (50, 77))	('PROP1', 'Gene', '5626', (387, 392))	('OTX2', 'Gene', (402, 406))	('abnormalities of the CNS', 'Phenotype', 'HP:0002011', (64, 88))	('idiopathic', 'Disease', (713, 723))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (150, 167))	('HESX1', 'Gene', '8820', (254, 259))	('anencephaly', 'Disease', (97, 108))	('LHX4', 'Gene', '89884', (417, 421))	('pituitary combined hormone deficiency syndromes', 'Disease', 'MESH:C580003', (315, 362))	('anencephaly', 'Phenotype', 'HP:0002323', (97, 108))	('ACTH', 'Gene', '5443', (436, 440))	('PCSK1', 'Gene', (548, 553))
86044	26038200	Other types of CAH (each of these with distinct clinical manifestations) may result from mutations in other genes that code for enzymes of the steroidogenesis cascade, including STAR, CYP11A1, HSD3B2, CYP17A1, CYP11B1 and POR.	('steroid', 'Chemical', 'MESH:D013256', (143, 150))	('result from', 'Reg', (77, 88))	('HSD3B2', 'Gene', (193, 199))	('CYP11A1', 'Gene', (184, 191))	('POR', 'Gene', '5447', (222, 225))	('CYP11B1', 'Gene', '1584', (210, 217))	('CAH', 'Disease', (15, 18))	('CYP17A1', 'Gene', (201, 208))	('CAH', 'Disease', 'None', (15, 18))	('CYP17A1', 'Gene', '1586', (201, 208))	('HSD3B2', 'Gene', '3284', (193, 199))	('STAR', 'Gene', '6770', (178, 182))	('STAR', 'Gene', (178, 182))	('mutations', 'Var', (89, 98))	('POR', 'Gene', (222, 225))	('CYP11B1', 'Gene', (210, 217))	('CYP11A1', 'Gene', '1583', (184, 191))
86050	26038200	Recently, germline mutations in ARMC5 have been described in about half of the PMAH cases, being the most frequent genetic alteration associated with this disease.	('PMAH', 'Disease', (79, 83))	('described', 'Reg', (48, 57))	('ARMC5', 'Gene', '79798', (32, 37))	('ARMC5', 'Gene', (32, 37))	('germline mutations', 'Var', (10, 28))	('rat', 'Species', '10116', (127, 130))
86051	26038200	Remarkably, the prevalence of germline ARMC5 mutations is high even among patients with apparent sporadic disease, suggesting that familial forms are actually much more prevalent than previously appreciated.	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (45, 54))	('ARMC5', 'Gene', '79798', (39, 44))	('ARMC5', 'Gene', (39, 44))
86054	26038200	Abnormal activation of the protein kinase A (PKA) pathway by different molecular mechanisms, such as ectopic expression of G-protein-coupled receptors by adrenal cells, activating somatic mutations in GNAS, inactivating mutations of PRKAR1A (the gene that codes for one of the regulatory subunits of the PKA complex), inactivating mutations of PDE11A and PDE8B and gene amplification of a catalytic subunit of the PKA complex (PRKACA), is usually present in the hormonally-active group.	('PKA', 'Gene', '5566', (45, 48))	('PRKACA', 'Gene', (427, 433))	('PRKAR1A', 'Gene', '5573', (233, 240))	('PKA', 'Gene', (304, 307))	('activation', 'PosReg', (9, 19))	('PDE8B', 'Gene', (355, 360))	('PDE11A', 'Gene', '50940', (344, 350))	('inactivating mutations', 'Var', (318, 340))	('PDE11A', 'Gene', (344, 350))	('PKA', 'Gene', (414, 417))	('PKA', 'Gene', '5566', (304, 307))	('inactivating mutations', 'Var', (207, 229))	('mutations', 'Var', (188, 197))	('GNAS', 'Gene', (201, 205))	('PKA', 'Gene', '5566', (414, 417))	('PRKACA', 'Gene', '5566', (427, 433))	('PRKAR1A', 'Gene', (233, 240))	('GNAS', 'Gene', '2778', (201, 205))	('PKA', 'Gene', (45, 48))	('PDE8B', 'Gene', '8622', (355, 360))
86061	26038200	Molecularly, APAs are characterized by somatic mutations in several genes involved in the regulation of the intracellular calcium concentration, leading to abnormal activation of the calcium-calmodulin-dependent protein kinase 1/II (CAMK1/2), the main regulators of angiotensin-II and potassium-stimulated CYP11B2 transcription.	('angiotensin-II', 'Gene', '183', (266, 280))	('CAMK1/2', 'Gene', (233, 240))	('CYP11B2', 'Gene', '1585', (306, 313))	('calcium', 'Chemical', 'MESH:D002118', (183, 190))	('CAMK1/2', 'Gene', '8536;816', (233, 240))	('mutations', 'Var', (47, 56))	('rat', 'Species', '10116', (137, 140))	('angiotensin-II', 'Gene', (266, 280))	('calcium', 'Chemical', 'MESH:D002118', (122, 129))	('CYP11B2', 'Gene', (306, 313))	('activation', 'PosReg', (165, 175))	('potassium', 'Chemical', 'MESH:D011188', (285, 294))	('APAs', 'Disease', (13, 17))
86063	26038200	Interestingly, heterozygous germline KCNJ5 mutations have also been described as the cause of familial primary aldosteronism type III.	('primary aldosteronism', 'Phenotype', 'HP:0011736', (103, 124))	('cause', 'Reg', (85, 90))	('familial primary aldosteronism type', 'Phenotype', 'HP:0011739', (94, 129))	('familial primary aldosteronism type III', 'Disease', (94, 133))	('KCNJ5', 'Gene', (37, 42))	('mutations', 'Var', (43, 52))	('KCNJ5', 'Gene', '3762', (37, 42))
86066	26038200	Mutations in KCNJ5 increase its permeability to potassium, favoring membrane depolarization (which in turn lead to the opening of membrane voltage-gated calcium channels, increasing the intracellular calcium concentrations resulting in activation of the CAMK1/2).	('lead to', 'Reg', (107, 114))	('calcium', 'Chemical', 'MESH:D002118', (153, 160))	('calcium', 'Chemical', 'MESH:D002118', (200, 207))	('CAMK1/2', 'Gene', (254, 261))	('increasing', 'PosReg', (171, 181))	('membrane depolarization', 'MPA', (68, 91))	('opening', 'MPA', (119, 126))	('rat', 'Species', '10116', (215, 218))	('activation', 'PosReg', (236, 246))	('KCNJ5', 'Gene', '3762', (13, 18))	('CAMK1/2', 'Gene', '8536;816', (254, 261))	('intracellular calcium concentrations', 'MPA', (186, 222))	('increase', 'PosReg', (19, 27))	('Mutations', 'Var', (0, 9))	('membrane voltage-gated calcium channels', 'MPA', (130, 169))	('potassium', 'Chemical', 'MESH:D011188', (48, 57))	('permeability to potassium', 'MPA', (32, 57))	('KCNJ5', 'Gene', (13, 18))
86067	26038200	Subsequently, mutations in other genes that regulate intracellular calcium concentrations have been described in APAs, including mutations of the sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1), the plasma membrane calcium-transporting ATPase 3 (ATP2B3) and the voltage-dependent L-type calcium channel subunit alpha-1D (CACNA1D).	('ATP2B3', 'Gene', '492', (260, 266))	('sodium', 'Chemical', 'MESH:D012964', (146, 152))	('ATP2B3', 'Gene', (260, 266))	('potassium', 'Chemical', 'MESH:D011188', (153, 162))	('calcium', 'Chemical', 'MESH:D002118', (301, 308))	('calcium', 'Chemical', 'MESH:D002118', (67, 74))	('mutations', 'Var', (129, 138))	('alpha-1', 'Gene', '146', (191, 198))	('calcium', 'Chemical', 'MESH:D002118', (229, 236))	('ATP1A1', 'Gene', '476', (200, 206))	('rat', 'Species', '10116', (82, 85))	('CACNA1D', 'Gene', '776', (335, 342))	('alpha-1', 'Gene', (191, 198))	('alpha-1', 'Gene', '146', (325, 332))	('CACNA1D', 'Gene', (335, 342))	('ATP1A1', 'Gene', (200, 206))	('alpha-1', 'Gene', (325, 332))	('voltage-dependent L-type calcium channel subunit alpha-1D', 'Gene', '776', (276, 333))
86080	26038200	In fact, abnormalities of the IGF system and of the Wnt pathway are present in a large subset of ACCs, as will be discussed below.	('abnormalities', 'Var', (9, 22))	('IGF system', 'Pathway', (30, 40))	('ACCs', 'Gene', (97, 101))	('ACCs', 'Gene', '84680', (97, 101))	('Wnt pathway', 'Pathway', (52, 63))
86082	26038200	This syndrome is caused by germline mutations of the APC gene, which is part of a multiprotein complex (destruction complex) that ubiquitinates cytoplasmatic beta-catenin, targeting it to proteosomal degradation.	('APC', 'Disease', 'MESH:D011125', (53, 56))	('targeting', 'MPA', (172, 181))	('APC', 'Disease', (53, 56))	('proteosomal degradation', 'MPA', (188, 211))	('caused by', 'Reg', (17, 26))	('germline mutations', 'Var', (27, 45))	('ubiquitinates', 'MPA', (130, 143))
86084	26038200	Accordingly, somatic activating CTNNB1 mutations are also observed in both ACAs and ACCs, suggesting that some ACAs may be precursor lesions of ACCs .	('ACCs', 'Gene', '84680', (144, 148))	('ACCs', 'Gene', (144, 148))	('activating', 'PosReg', (21, 31))	('mutations', 'Var', (39, 48))	('CTNNB1', 'Gene', '1499', (32, 38))	('ACCs', 'Gene', (84, 88))	('ACCs', 'Gene', '84680', (84, 88))	('CTNNB1', 'Gene', (32, 38))
86089	26038200	Ultimately, imbalances in proliferation, differentiation and apoptosis of these cells favor tumor formation.	('apoptosis', 'CPA', (61, 70))	('favor', 'PosReg', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('imbalances', 'Var', (12, 22))	('rat', 'Species', '10116', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('imbalances', 'Phenotype', 'HP:0002172', (12, 22))	('differentiation', 'CPA', (41, 56))
86090	26038200	Further extending the importance of the Wnt pathway in adrenocortical tumorigenesis, biallelic inactivation of ZNRF3 (an ubiquitin ligase that is a negative regulator of the Frizzled receptor), have been described as the most common changes in a large cohort of adrenocortical carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('adrenocortical', 'Disease', (262, 276))	('adrenocortical carcinomas', 'Disease', (262, 287))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (262, 287))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (262, 286))	('tumor', 'Disease', (70, 75))	('adrenocortical', 'Disease', 'MESH:D018268', (262, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('adrenocortical', 'Disease', (55, 69))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (262, 287))	('adrenocortical', 'Disease', 'MESH:D018268', (55, 69))	('ZNRF3', 'Gene', '84133', (111, 116))	('biallelic inactivation', 'Var', (85, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (277, 287))	('common', 'Reg', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('ZNRF3', 'Gene', (111, 116))
86091	26038200	Interestingly, these mutations are mutually exclusive with those of the CTNNB1 gene, further suggesting that either mutation resulting in elevated Wnt signaling can have a causative role in adrenocortical tumorigenesis.	('Wnt signaling', 'MPA', (147, 160))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mutation', 'Var', (116, 124))	('adrenocortical', 'Disease', (190, 204))	('adrenocortical', 'Disease', 'MESH:D018268', (190, 204))	('CTNNB1', 'Gene', (72, 78))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('elevated', 'PosReg', (138, 146))	('CTNNB1', 'Gene', '1499', (72, 78))
86097	26038200	Mutant mice overexpressing Igf2 exhibit a BWS-like phenotype, including adrenal hyperplasia and cytomegaly.	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (72, 91))	('mice', 'Species', '10090', (7, 11))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (72, 91))	('Igf2', 'Gene', (27, 31))	('cytomegaly', 'CPA', (96, 106))	('Igf2', 'Gene', '16002', (27, 31))	('Mutant', 'Var', (0, 6))	('BWS-like', 'Disease', (42, 50))	('adrenal hyperplasia', 'Disease', (72, 91))
86099	26038200	In a recent study, Igf2 overexpressing mice are crossed with mutant mice that have stabilized beta-catenin (Apc mutant).	('mice', 'Species', '10090', (68, 72))	('Apc', 'Gene', '11789', (108, 111))	('Igf2', 'Gene', (19, 23))	('beta-catenin', 'Protein', (94, 106))	('Igf2', 'Gene', '16002', (19, 23))	('mutant', 'Var', (61, 67))	('Apc', 'Gene', (108, 111))	('mice', 'Species', '10090', (39, 43))
86103	26038200	Unfortunately, although preclinical studies indicate that blocking the IGF1R, (one of the most important mediators of the IGF2 mitogenic effects) had anti-growth effects in-vitro and in-vivo, phase I and phase II clinical studies combining different agents displayed low therapeutic efficacy.	('IGF1R', 'Gene', (71, 76))	('IGF2', 'Gene', '3481', (122, 126))	('anti-growth effects', 'CPA', (150, 169))	('IGF1R', 'Gene', '3480', (71, 76))	('blocking', 'Var', (58, 66))	('low therapeutic efficacy', 'Phenotype', 'HP:0020173', (267, 291))	('IGF2', 'Gene', (122, 126))
86108	26038200	This syndrome is caused by germline inactivating mutations of the TP53 and is characterized by various types of early-onset malignant tumors, such as breast cancer, brain tumors and sarcomas.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('TP53', 'Gene', '7157', (66, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('germline inactivating mutations', 'Var', (27, 58))	('malignant tumors', 'Disease', (124, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('breast cancer', 'Disease', (150, 163))	('sarcomas', 'Disease', (182, 190))	('caused by', 'Reg', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('TP53', 'Gene', (66, 70))	('brain tumors', 'Disease', 'MESH:D001932', (165, 177))	('brain tumors', 'Phenotype', 'HP:0030692', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('brain tumors', 'Disease', (165, 177))	('malignant tumors', 'Disease', 'MESH:D018198', (124, 140))
86111	26038200	Among sporadic ACC patients, germline TP53 mutations are estimated to account for ~5%.	('patients', 'Species', '9606', (19, 27))	('TP53', 'Gene', (38, 42))	('ACC', 'Disease', (15, 18))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', '7157', (38, 42))
86112	26038200	However, unlike in adults, the prevalence of germline TP53 mutations in the pediatric population is high, ranging from 50 to 90%.	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', (54, 58))	('mutations', 'Var', (59, 68))	('to 9', 'Species', '1214577', (122, 126))
86117	26038200	The adrenocortical dysplasia mouse (acd) bears mutations in the ACD/TPP1 gene, which codes for one component of the shelterin complex.	('adrenocortical dysplasia', 'Disease', 'MESH:D018268', (4, 28))	('adrenocortical dysplasia', 'Disease', (4, 28))	('TPP1', 'Gene', '12751', (68, 72))	('TPP1', 'Gene', (68, 72))	('mutations', 'Var', (47, 56))	('mouse', 'Species', '10090', (29, 34))
86118	26038200	Since the shelterin complex is critical for protecting the ends of chromosomes and ensuing complete replication of coding sequences, loss of function promotes non-proliferative states and may explain some of the phenotypes seen in the acd mouse.	('promotes', 'PosReg', (150, 158))	('rat', 'Species', '10116', (170, 173))	('loss of', 'Var', (133, 140))	('mouse', 'Species', '10090', (239, 244))	('non-proliferative states', 'CPA', (159, 183))
86120	26038200	Interestingly, crossing the acd mutant mice with Tp53 null mice results in rescue of adrenal senescence and overall dysplasia, highlighting the role of the DNA repair mechanisms in removing cells with dysfunctional telomeres from the pool.	('mice', 'Species', '10090', (59, 63))	('Tp53', 'Gene', (49, 53))	('dysfunctional', 'Disease', (201, 214))	('adrenal senescence', 'MPA', (85, 103))	('Tp53', 'Gene', '22059', (49, 53))	('dysfunctional', 'Disease', 'MESH:D006331', (201, 214))	('mutant', 'Var', (32, 38))	('dysplasia', 'Disease', (116, 125))	('rescue', 'PosReg', (75, 81))	('dysplasia', 'Disease', 'MESH:D004476', (116, 125))	('mice', 'Species', '10090', (39, 43))
86122	26038200	Interestingly, the cross between the two strains results in offsprings with earlier onset of a larger spectrum of tumors including adrenocortical carcinoma, suggesting that mutations that affect genes involved in telomere maintenance together with cell cycle checkpoint genes may act by synergistic mechanisms.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('adrenocortical carcinoma', 'Disease', (131, 155))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (131, 155))	('mutations', 'Var', (173, 182))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (131, 155))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
86140	26038200	As detailed in this review, the most common mutated genes in both adrenocortical hypoplasia and adrenocortical tumors are also stem/ progenitor cell factors critical for proper adrenal development and homeostasis.	('adrenocortical hypoplasia', 'Disease', (66, 91))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (96, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('adrenocortical tumors', 'Disease', (96, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('adrenocortical hypoplasia', 'Phenotype', 'HP:0008182', (66, 91))	('adrenocortical hypoplasia', 'Disease', 'MESH:D018268', (66, 91))	('mutated genes', 'Var', (44, 57))
86163	21836496	In 1991, Weinstein et al discovered a constitutive activating mutation of the GNAS1 gene in adrenal nodules.	('GNAS1', 'Gene', (78, 83))	('mutation', 'Var', (62, 70))	('GNAS1', 'Gene', '2778', (78, 83))	('activating', 'PosReg', (51, 61))
86236	21836496	In this connection, it will be recalled that mutations of different genes may result in the same pathologic phenotype, as with primary pigmented nodular adrenocortical disease.	('result in', 'Reg', (78, 87))	('pigmented nodular adrenocortical disease', 'Disease', (135, 175))	('mutations', 'Var', (45, 54))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (135, 175))
86284	23889916	reported sensitivity of 97% and specificity of 100% for a score of 4 or 5 as being predictive of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (97, 107))	('score', 'Var', (58, 63))	('malignancy', 'Disease', (97, 107))
86307	22096502	SiRNA knockdown was used to determine the functional role of KIAA0101 on cell proliferation, cell cycle, apoptosis, soft agar anchorage independent growth and invasion in the ACC cell line, NCI-H295R.	('KIAA0101', 'Var', (61, 69))	('apoptosis', 'CPA', (105, 114))	('soft agar anchorage independent growth', 'CPA', (116, 154))	('agar', 'Chemical', 'MESH:D000362', (121, 125))	('cell proliferation', 'CPA', (73, 91))	('cell cycle', 'CPA', (93, 103))	('invasion', 'CPA', (159, 167))	('NCI-H295R', 'CellLine', 'CVCL:0458', (190, 199))
86308	22096502	KIAA0101 had sparse protein expression in only a few normal adrenal cortex samples, which was confined to adrenocortical progenitor cells.	('KIAA0101', 'Var', (0, 8))	('adrenocortical', 'Disease', (106, 120))	('adrenocortical', 'Disease', 'MESH:D018268', (106, 120))
86310	22096502	Our data supports that KIAA0101 is a marker of cellular proliferation, promotes growth and invasion, and is a good diagnostic marker for distinguishing benign from malignant adrenocortical neoplasm.	('promotes', 'PosReg', (71, 79))	('invasion', 'CPA', (91, 99))	('neoplasm', 'Phenotype', 'HP:0002664', (189, 197))	('growth', 'CPA', (80, 86))	('malignant adrenocortical neoplasm', 'Disease', 'MESH:D009369', (164, 197))	('malignant adrenocortical neoplasm', 'Disease', (164, 197))	('KIAA0101', 'Var', (23, 31))
86316	22096502	ACC may be associated with hereditary cancer syndromes such as Beckwith-Wiedemann syndrome (associated with germline 11p15 chromosomal alterations leading to IGF2 overexpression, OMIM #130650), Li-Fraumeni syndrome (TP53 mutation, OMIM #151623), multiple endocrine neoplasia type 1 (mutations in the menin tumor suppressor gene, OMIM #131100), and Gardner's syndrome (APC mutation, OMIM #175100).	('IGF2', 'Gene', (158, 162))	('tumor', 'Disease', (306, 311))	('overexpression', 'PosReg', (163, 177))	('p15', 'Gene', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('neoplasia', 'Phenotype', 'HP:0002664', (265, 274))	('OMIM #131100', 'Var', (329, 341))	('IGF2', 'Gene', '3481', (158, 162))	('Beckwith-Wiedemann syndrome', 'Disease', (63, 90))	('TP53', 'Gene', (216, 220))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (255, 274))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('p15', 'Gene', '1030', (119, 122))	('hereditary cancer', 'Disease', (27, 44))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('mutations', 'Var', (283, 292))	('APC', 'Disease', 'MESH:D011125', (368, 371))	('multiple endocrine neoplasia type', 'Disease', 'MESH:D018761', (246, 279))	('Li-Fraumeni syndrome', 'Disease', (194, 214))	('APC', 'Disease', (368, 371))	("Gardner's syndrome", 'Disease', 'MESH:D005736', (348, 366))	('hereditary cancer', 'Disease', 'MESH:D009369', (27, 44))	('associated', 'Reg', (11, 21))	("Gardner's syndrome", 'Disease', (348, 366))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (63, 90))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (194, 214))	('alterations', 'Var', (135, 146))	('TP53', 'Gene', '7157', (216, 220))	('multiple endocrine neoplasia type', 'Disease', (246, 279))
86317	22096502	The genetic changes associated with hereditary cancer syndromes have provided important information about the possible molecular mechanisms involved in ACC.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('genetic changes', 'Var', (4, 19))	('hereditary cancer', 'Disease', (36, 53))	('hereditary cancer', 'Disease', 'MESH:D009369', (36, 53))
86320	22096502	Since the molecular mechanism of adrenocortical carcinogenesis is poorly understood, cDNA microarray analysis of adrenocortical tumors has been used to reveal genes whose misexpression is associated with ACC.	('associated', 'Reg', (188, 198))	('adrenocortical carcinogenesis', 'Disease', (33, 62))	('ACC', 'Disease', (204, 207))	('adrenocortical tumors', 'Disease', (113, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('misexpression', 'Var', (171, 184))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (113, 134))	('adrenocortical carcinogenesis', 'Disease', 'MESH:D063646', (33, 62))
86335	22096502	The PCR primers and probes for KIAA0101 (Hs00207134_m1) and GAPDH (Hs99999905_m1) were obtained from Applied Biosystems (Assay-on-Demand kit , Foster City, CA).	('GAPDH', 'Gene', '2597', (60, 65))	('GAPDH', 'Gene', (60, 65))	('Hs99999905_m1', 'Var', (67, 80))	('Hs00207134_m1', 'Var', (41, 54))
86337	22096502	Western blotting was performed following standard procedures using primary mouse monoclonal antibodies, anti-KIAA0101 (Abcam; ab56773) at 1:100 dilution and anti-beta-actin (sc-81178, Santa Cruz Biotechnology Inc, Santa Cruz, CA) at 1:2,000 dilution.	('anti-KIAA0101', 'Var', (104, 117))	('beta-actin', 'Gene', '728378', (162, 172))	('mouse', 'Species', '10090', (75, 80))	('beta-actin', 'Gene', (162, 172))
86367	22096502	To address this, we used siRNA to knockdown KIAA0101 expression in the ACC cell line, NCI-H295R.	('knockdown', 'Var', (34, 43))	('NCI-H295R', 'CellLine', 'CVCL:0458', (86, 95))	('KIAA0101', 'Gene', (44, 52))
86370	22096502	KIAA0101 knockdown in NCI-H295R cells reduced the number of colonies that were able to grow in soft agar by almost 80% (p = 0.001) at 16 days of culture ( Figures 5A and 5B ) with a 60% reduction in cell invasion in the NCI-H295R cell line (p = 0.006) ( Figures 5C and 5D ).	('knockdown', 'Var', (9, 18))	('KIAA0101', 'Gene', (0, 8))	('reduction', 'NegReg', (186, 195))	('reduced', 'NegReg', (38, 45))	('NCI-H295R', 'CellLine', 'CVCL:0458', (22, 31))	('agar', 'Chemical', 'MESH:D000362', (100, 104))	('cell invasion in the NCI-H295R cell line', 'CPA', (199, 239))	('NCI-H295R', 'CellLine', 'CVCL:0458', (220, 229))
86380	22096502	KIAA0101 and SF-1 co-expression in the progenitor region of normal adrenal cortex suggests that KIAA0101 may be a marker of proliferation in adrenocortical cells.	('KIAA0101', 'Var', (96, 104))	('SF-1', 'Gene', '7536', (13, 17))	('adrenocortical', 'Disease', (141, 155))	('adrenocortical', 'Disease', 'MESH:D018268', (141, 155))	('SF-1', 'Gene', (13, 17))
86383	22096502	Indeed, KIAA0101 encodes a 15-kDa protein, which contains a conserved proliferating cell nuclear antigen (PCNA) binding motif, and was initially discovered in a study screening for binding partners for the PCNA in yeast.	('yeast', 'Species', '4932', (214, 219))	('PCNA', 'Gene', (106, 110))	('proliferating cell nuclear antigen', 'Gene', (70, 104))	('PCNA', 'Gene', (206, 210))	('KIAA0101', 'Var', (8, 16))	('proliferating cell nuclear antigen', 'Gene', '5111', (70, 104))	('PCNA', 'Gene', '5111', (106, 110))	('PCNA', 'Gene', '5111', (206, 210))
86384	22096502	KIAA0101 shares the PCNA binding motif with many important cell cycle regulatory PCNA binding proteins such as p21, p57 and p33ING1b.	('p57', 'Gene', '1028', (116, 119))	('KIAA0101', 'Var', (0, 8))	('p57', 'Gene', (116, 119))	('PCNA', 'Gene', (81, 85))	('p21', 'Gene', (111, 114))	('PCNA', 'Gene', (20, 24))	('p33ING1b', 'Gene', (124, 132))	('p21', 'Gene', '644914', (111, 114))	('p33ING1b', 'Gene', '3621', (124, 132))	('PCNA', 'Gene', '5111', (81, 85))	('PCNA', 'Gene', '5111', (20, 24))
86385	22096502	KIAA0101 also competes with p21 for binding to PCNA and regulate cell cycle progression.	('PCNA', 'Gene', (47, 51))	('KIAA0101', 'Var', (0, 8))	('cell cycle progression', 'CPA', (65, 87))	('p21', 'Gene', (28, 31))	('PCNA', 'Gene', '5111', (47, 51))	('p21', 'Gene', '644914', (28, 31))	('regulate', 'Reg', (56, 64))	('binding', 'Interaction', (36, 43))
86386	22096502	In our study, it is possible that after knockdown of KIAA0101, p21 may bind to PCNA and leads to G1/S arrest.	('KIAA0101', 'Var', (53, 61))	('p21', 'Gene', (63, 66))	('S arrest', 'Disease', (100, 108))	('p21', 'Gene', '644914', (63, 66))	('bind', 'Interaction', (71, 75))	('PCNA', 'Gene', (79, 83))	('S arrest', 'Disease', 'MESH:D006323', (100, 108))	('leads to', 'Reg', (88, 96))	('PCNA', 'Gene', '5111', (79, 83))
86391	22096502	Specifically, depending on the tumor type and cell line studied, KIAA0101 has been found to have both growth inhibitory and stimulatory effects.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('stimulatory', 'MPA', (124, 135))	('tumor', 'Disease', (31, 36))	('growth inhibitory', 'CPA', (102, 119))	('KIAA0101', 'Var', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
86393	22096502	While most genes upregulated in malignancy have a growth promoting function, one of the most common tumor suppressor genes in human malignancy, p53, is overexpressed and has a tumor suppressor function because of inactivating dominant negative mutations.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('human', 'Species', '9606', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('p53', 'Gene', '7157', (144, 147))	('upregulated', 'PosReg', (17, 28))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (176, 181))	('malignancy', 'Disease', 'MESH:D009369', (132, 142))	('overexpressed', 'PosReg', (152, 165))	('inactivating dominant', 'Var', (213, 234))	('malignancy', 'Disease', 'MESH:D009369', (32, 42))	('malignancy', 'Disease', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('malignancy', 'Disease', (132, 142))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('p53', 'Gene', (144, 147))	('growth promoting', 'CPA', (50, 66))
86401	33565732	COSMIC, cBioPortal, and CCLE were used to examine FZD2 mutations in human cancers.	('human', 'Species', '9606', (68, 73))	('mutations', 'Var', (55, 64))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('CCLE', 'Chemical', '-', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('FZD2', 'Gene', '2535', (50, 54))	('FZD2', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
86431	33565732	The catalog of somatic mutations in cancer (COSMIC) database (https://cancer.sanger.ac.uk/cosmic/) collects millions of coding mutations, noncoding mutations, genome rearrangements, fusion genes, copy number abnormalities, and gene expression variations in the human genome [12].	('fusion genes', 'Var', (182, 194))	('number abnormalities', 'Disease', 'MESH:D007674', (201, 221))	('variations', 'Var', (243, 253))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (36, 42))	('human', 'Species', '9606', (261, 266))	('number abnormalities', 'Disease', (201, 221))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
86432	33565732	In this study, COSMIC was used to examine FZD2 mutations in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('FZD2', 'Gene', '2535', (42, 46))	('FZD2', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('human', 'Species', '9606', (60, 65))
86435	33565732	The Cancer Cell Line Encyclopedia (CCLE) project dataset is a compilation of gene expression data from human cancer cell lines and was used to analyze FZD2 mutations in various cancer cell lines [14].	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('FZD2', 'Gene', '2535', (151, 155))	('FZD2', 'Gene', (151, 155))	('human', 'Species', '9606', (103, 108))	('mutations', 'Var', (156, 165))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('CCLE', 'Chemical', '-', (35, 39))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
86436	33565732	Tumor mutation burden (TMB) is defined as the total number of somatic gene coding errors, base substitutions, insertions, or deletions detected per million bases.	('Tumor mutation burden', 'Disease', (0, 21))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('insertions', 'Var', (110, 120))	('deletions', 'Var', (125, 134))	('TMB', 'Chemical', '-', (23, 26))	('base substitutions', 'Var', (90, 108))
86460	33565732	According to the median expression of FZD2 across the different cancer types, patients were divided into either a high or low expression group; when analyzed, it was found that the survival difference between the high and low expression groups was significant and that patients with high FZD2 expression had earlier recurrence after tumor resection (Fig.	('earlier', 'PosReg', (308, 315))	('tumor', 'Disease', (333, 338))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('high', 'Var', (283, 287))	('FZD2', 'Gene', (38, 42))	('FZD2', 'Gene', '2535', (38, 42))	('cancer', 'Disease', (64, 70))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('recurrence', 'CPA', (316, 326))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('expression', 'MPA', (293, 303))	('FZD2', 'Gene', '2535', (288, 292))	('FZD2', 'Gene', (288, 292))	('patients', 'Species', '9606', (269, 277))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
86461	33565732	COSMIC provides information about FZD2 mutations in different cancers, including missense mutations, nonsense mutations, and synonymous mutations (Figs 3A and Fig.	('missense mutations', 'Var', (81, 99))	('FZD2', 'Gene', (34, 38))	('FZD2', 'Gene', '2535', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (39, 48))	('nonsense mutations', 'Var', (101, 119))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('synonymous mutations', 'Var', (125, 145))	('cancers', 'Disease', (62, 69))
86464	33565732	C>T and G>A mutations were found to be the most common in the FZD2 coding chain, while A>T and T>A mutations were rare.	('G>A mutations', 'Var', (8, 21))	('C>T', 'Var', (0, 3))	('FZD2', 'Gene', '2535', (62, 66))	('FZD2', 'Gene', (62, 66))	('common', 'Reg', (48, 54))
86467	33565732	Among these, the mutation rate was higher in esophagogastric adenocarcinoma and endometrial carcinoma (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutation', 'Var', (17, 25))	('esophagogastric adenocarcinoma', 'Phenotype', 'HP:0011459', (45, 75))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (61, 101))	('higher', 'Reg', (35, 41))
86468	33565732	Missense mutations and silent mutations were also found in cancer cell lines (Fig.	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Missense mutations', 'Var', (0, 18))
86503	33565732	In addition, the latest research has found that FZD2 is more highly expressed in hepatocellular carcinoma tissues than in adjacent tissues, and the recurrence-free survival rate of patients with high FZD2 expression is significantly lower than that of patients with low expression.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('recurrence-free survival rate', 'CPA', (148, 177))	('patients', 'Species', '9606', (252, 260))	('FZD2', 'Gene', '2535', (48, 52))	('FZD2', 'Gene', (48, 52))	('highly', 'PosReg', (61, 67))	('lower', 'NegReg', (233, 238))	('FZD2', 'Gene', '2535', (200, 204))	('high', 'Var', (195, 199))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (81, 105))	('patients', 'Species', '9606', (181, 189))	('hepatocellular carcinoma', 'Disease', (81, 105))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (81, 105))	('FZD2', 'Gene', (200, 204))	('expression', 'MPA', (205, 215))
86504	33565732	Furthermore, FZD2 expression is significantly correlated with the mesenchymal phenotype in HCC cell lines, and knocking out FZD2 can inhibit the migration and invasiveness of liver cancer cells [23].	('liver cancer', 'Phenotype', 'HP:0002896', (175, 187))	('FZD2', 'Gene', '2535', (13, 17))	('FZD2', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('knocking out', 'Var', (111, 123))	('invasiveness of liver cancer', 'Disease', (159, 187))	('migration', 'CPA', (145, 154))	('FZD2', 'Gene', '2535', (124, 128))	('FZD2', 'Gene', (124, 128))	('inhibit', 'NegReg', (133, 140))	('invasiveness of liver cancer', 'Disease', 'MESH:D006528', (159, 187))
86512	33565732	Knockout of FZD7 or use of Wnt/beta-catenin inhibitors has been shown to reduce the stemness and chemoresistance of GC cells [33].	('chemoresistance', 'CPA', (97, 112))	('beta-catenin', 'Gene', (31, 43))	('GC', 'Phenotype', 'HP:0012126', (116, 118))	('beta-catenin', 'Gene', '1499', (31, 43))	('Knockout', 'Var', (0, 8))	('FZD7', 'Gene', '8324', (12, 16))	('FZD7', 'Gene', (12, 16))	('reduce', 'NegReg', (73, 79))
86513	33565732	FZD8 is highly expressed in human lung cancer tissue samples and cell lines, and knockout of FZD8 can increase the sensitivity of lung cancer cells to paclitaxel [34].	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('FZD8', 'Gene', '8325', (93, 97))	('paclitaxel', 'Chemical', 'MESH:D017239', (151, 161))	('FZD8', 'Gene', (93, 97))	('lung cancer', 'Disease', (34, 45))	('human', 'Species', '9606', (28, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('knockout', 'Var', (81, 89))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('increase', 'PosReg', (102, 110))	('sensitivity', 'MPA', (115, 126))	('FZD8', 'Gene', '8325', (0, 4))	('lung cancer', 'Disease', (130, 141))	('FZD8', 'Gene', (0, 4))
86529	33565732	Those with high TMB expression have been shown to benefit more from immune checkpoint inhibitor therapy [44].	('TMB', 'Chemical', '-', (16, 19))	('TMB', 'Protein', (16, 19))	('benefit', 'PosReg', (50, 57))	('high', 'Var', (11, 15))
86530	33565732	TMB reflects the total number of replacement and insertion/deletion mutations per megabase in the exon coding region of the evaluated gene in the tumor cell genome.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('TMB', 'Chemical', '-', (0, 3))	('insertion/deletion mutations', 'Var', (49, 77))	('tumor', 'Disease', (146, 151))	('replacement', 'Var', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
86531	33565732	Driving gene mutations can lead to tumors, and a large number of somatic mutations can produce new antigens, which can activate T cells and cause immune responses [45].	('T cells', 'CPA', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cause', 'Reg', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('immune responses', 'CPA', (146, 162))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('lead to', 'Reg', (27, 34))	('mutations', 'Var', (13, 22))	('activate', 'PosReg', (119, 127))	('mutations', 'Var', (73, 82))	('produce', 'Reg', (87, 94))
86534	33565732	Studies have shown that frameshift mutations of AXIN2 and TCF7L2 are common in GC with high MSI, and these mutations may promote the development of GC through the control of Wnt signaling [46].	('mutations', 'Var', (107, 116))	('AXIN2', 'Gene', (48, 53))	('development', 'CPA', (133, 144))	('AXIN2', 'Gene', '8313', (48, 53))	('GC', 'Phenotype', 'HP:0012126', (79, 81))	('TCF7L2', 'Gene', (58, 64))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('TCF7L2', 'Gene', '6934', (58, 64))	('promote', 'PosReg', (121, 128))	('frameshift mutations', 'Var', (24, 44))
86536	33565732	It was also found that FZD2 was mutated in breast, endometrial, large intestine, liver, lung, skin, and stomach cancer.	('endometrial', 'Disease', (51, 62))	('skin', 'Disease', (94, 98))	('stomach cancer', 'Disease', 'MESH:D013274', (104, 118))	('stomach cancer', 'Phenotype', 'HP:0012126', (104, 118))	('liver', 'Disease', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('large intestine', 'Disease', (64, 79))	('mutated', 'Var', (32, 39))	('stomach cancer', 'Disease', (104, 118))	('breast', 'Disease', (43, 49))	('lung', 'Disease', (88, 92))	('FZD2', 'Gene', '2535', (23, 27))	('FZD2', 'Gene', (23, 27))
86550	32130788	The target relationships among UCA1, miR-143-3p, and MYO6 were verified by dual-luciferase assay.	('miR-143-3p', 'Var', (37, 47))	('MYO6', 'Gene', '4646', (53, 57))	('MYO6', 'Gene', (53, 57))	('UCA1', 'Gene', '652995', (31, 35))	('miR-143-3p', 'Chemical', '-', (37, 47))	('UCA1', 'Gene', (31, 35))
86554	32130788	MYO6 was validated as a target for miR-143-3p, and MYO6 overexpression reversed the effects of miR-143-3p mimic on OSCC cells.	('MYO6', 'Gene', (0, 4))	('MYO6', 'Gene', (51, 55))	('miR-143-3p', 'Chemical', '-', (95, 105))	('OSCC', 'Disease', (115, 119))	('miR-143-3p mimic', 'Var', (95, 111))	('si', 'Chemical', '-', (66, 68))	('miR-143-3p', 'Chemical', '-', (35, 45))	('overexpression', 'PosReg', (56, 70))	('MYO6', 'Gene', '4646', (0, 4))	('MYO6', 'Gene', '4646', (51, 55))
86555	32130788	LncRNA UCA1 contributes to the proliferation and metastasis of OSCC cells by targeting miR-143-3p and upregulating its downstream gene MYO6.	('upregulating', 'PosReg', (102, 114))	('metastasis', 'CPA', (49, 59))	('targeting', 'Var', (77, 86))	('proliferation', 'CPA', (31, 44))	('MYO6', 'Gene', '4646', (135, 139))	('MYO6', 'Gene', (135, 139))	('miR-143-3p', 'Gene', (87, 97))	('si', 'Chemical', '-', (56, 58))	('UCA1', 'Gene', '652995', (7, 11))	('UCA1', 'Gene', (7, 11))	('miR-143-3p', 'Chemical', '-', (87, 97))
86574	32130788	The levels of UCA1/mRNA and miR-143-3p were normalized to GAPDH and U6, respectively.	('miR-143-3p', 'Var', (28, 38))	('GAPDH', 'Gene', '2597', (58, 63))	('GAPDH', 'Gene', (58, 63))	('miR-143-3p', 'Chemical', '-', (28, 38))	('UCA1', 'Gene', '652995', (14, 18))	('UCA1', 'Gene', (14, 18))
86588	32130788	The membranes were subsequently incubated at 4 C overnight with primary antibodies including anti-MYO6 (1:1000, ab230478, Abcam), anti-MMP-2 (1:1000, ab37150, Abcam), anti-MMP-9 (1:1000, ab38898, Abcam), anti-GAPDH (1:1000, ab8245, Abcam), anti-E-cadherin (1:1000, #3195, Cell Signaling Technology), and anti-N-cadherin (1:1000, #13116, Cell Signaling Technology).	('1:1000', 'Var', (104, 110))	('1:1000', 'Var', (142, 148))	('ab230478', 'Var', (112, 120))	('anti-MMP-9', 'Var', (167, 177))	('MYO6', 'Gene', '4646', (98, 102))	('MYO6', 'Gene', (98, 102))	('GAPDH', 'Gene', '2597', (209, 214))	('GAPDH', 'Gene', (209, 214))
86603	32130788	Similarly, the UCA1 showed a higher level in the two OSCC cell lines than that in human normal oral cells, while miR-143-3p had an opposite expression (P < .01, Figure 1D,E).	('higher', 'PosReg', (29, 35))	('miR-143-3p', 'Chemical', '-', (113, 123))	('UCA1', 'Gene', '652995', (15, 19))	('UCA1', 'Gene', (15, 19))	('miR-143-3p', 'Var', (113, 123))	('si', 'Chemical', '-', (135, 137))	('si', 'Chemical', '-', (146, 148))	('level', 'MPA', (36, 41))	('human', 'Species', '9606', (82, 87))
86605	32130788	As shown in Table 2, high UCA1 expression was remarkably correlated with lymphatic metastasis and recurrence.	('si', 'Chemical', '-', (37, 39))	('recurrence', 'CPA', (98, 108))	('lymphatic metastasis', 'CPA', (73, 93))	('correlated', 'Reg', (57, 67))	('high', 'Var', (21, 25))	('UCA1', 'Gene', '652995', (26, 30))	('expression', 'MPA', (31, 41))	('UCA1', 'Gene', (26, 30))	('si', 'Chemical', '-', (90, 92))
86606	32130788	We also evaluated the clinical significance of miR-143-3p in OSCC.	('miR-143-3p', 'Var', (47, 57))	('OSCC', 'Disease', (61, 65))	('si', 'Chemical', '-', (31, 33))	('miR-143-3p', 'Chemical', '-', (47, 57))
86607	32130788	We found that low level of miR-143-3p was significantly related to lymphatic metastasis and recurrence (Table 3).	('si', 'Chemical', '-', (84, 86))	('miR-143-3p', 'Var', (27, 37))	('recurrence', 'CPA', (92, 102))	('si', 'Chemical', '-', (42, 44))	('lymphatic metastasis', 'CPA', (67, 87))	('miR-143-3p', 'Chemical', '-', (27, 37))
86610	32130788	Furthermore, the miR-143-3p mimics obviously suppressed the luciferase activity of the vector containing UCA1-WT (P < .01); however, it had no effect on that of the vector with UCA1-Mut in YD-38 and MK-1 cells (Figure 1G,H).	('miR-143-3p', 'Var', (17, 27))	('MK-1', 'Gene', '4072', (199, 203))	('UCA1', 'Gene', '652995', (105, 109))	('UCA1', 'Gene', (105, 109))	('MK-1', 'Gene', (199, 203))	('UCA1', 'Gene', '652995', (177, 181))	('luciferase', 'Enzyme', (60, 70))	('suppressed', 'NegReg', (45, 55))	('UCA1', 'Gene', (177, 181))	('miR-143-3p', 'Chemical', '-', (17, 27))	('YD-38', 'Chemical', '-', (189, 194))	('activity', 'MPA', (71, 79))
86614	32130788	The CCK8 assay results showed that compared with the controls, knocking down UCA1 in YD-38 cells significantly suppressed the cell viability, which, however, was rescued by the miR-143-3p inhibitors (P < .05, Figure 2E).	('cell viability', 'CPA', (126, 140))	('knocking down', 'Var', (63, 76))	('UCA1', 'Gene', '652995', (77, 81))	('miR-143-3p', 'Chemical', '-', (177, 187))	('UCA1', 'Gene', (77, 81))	('YD-38', 'Chemical', '-', (85, 90))	('suppressed', 'NegReg', (111, 121))	('si', 'Chemical', '-', (97, 99))
86620	32130788	The targeted binding site between miR-143-3p and MYO6 was predicted by TargetScan7.2 (Figure 3B), and luciferase reporter assays verified that miR-143-3p mimics markedly reduced the luciferase activity in the MYO6-wt group but it had no effect on the MYO6-mut group in YD-38 and MK-1 cells (Figure 3C,D).	('MYO6', 'Gene', (209, 213))	('MYO6', 'Gene', (251, 255))	('miR-143-3p', 'Var', (143, 153))	('YD-38', 'Chemical', '-', (269, 274))	('miR-143-3p', 'Chemical', '-', (34, 44))	('MYO6', 'Gene', (49, 53))	('MK-1', 'Gene', '4072', (279, 283))	('activity', 'MPA', (193, 201))	('MK-1', 'Gene', (279, 283))	('reduced', 'NegReg', (170, 177))	('miR-143-3p', 'Chemical', '-', (143, 153))	('si', 'Chemical', '-', (21, 23))	('luciferase', 'Enzyme', (182, 192))	('MYO6', 'Gene', '4646', (209, 213))	('MYO6', 'Gene', '4646', (251, 255))	('MYO6', 'Gene', '4646', (49, 53))
86625	32130788	We found that MYO6 was negatively correlated with miR-143-3p but positively correlated with UCA1 in 56 pairs of OSCC tissues by qRT-PCR (P < .001, Figure 4J,K).	('si', 'Chemical', '-', (67, 69))	('MYO6', 'Gene', '4646', (14, 18))	('miR-143-3p', 'Chemical', '-', (50, 60))	('MYO6', 'Gene', (14, 18))	('correlated', 'Interaction', (76, 86))	('UCA1', 'Gene', '652995', (92, 96))	('UCA1', 'Gene', (92, 96))	('miR-143-3p', 'Var', (50, 60))
86627	32130788	The knockdown of MYO6 in YD-38 cells and overexpression of MYO6 in MK-1 cells were effective, and miR-143-3p reversed the expression tendency of MYO6 (P < .01, Figure 5A-F).	('MK-1', 'Gene', (67, 71))	('MYO6', 'Gene', (59, 63))	('MYO6', 'Gene', (17, 21))	('miR-143-3p', 'Chemical', '-', (98, 108))	('MYO6', 'Gene', '4646', (145, 149))	('YD-38', 'Chemical', '-', (25, 30))	('miR-143-3p', 'Var', (98, 108))	('MYO6', 'Gene', (145, 149))	('si', 'Chemical', '-', (51, 53))	('MYO6', 'Gene', '4646', (17, 21))	('si', 'Chemical', '-', (128, 130))	('MYO6', 'Gene', '4646', (59, 63))	('MK-1', 'Gene', '4072', (67, 71))
86628	32130788	The CCK-8 results showed that proliferation of YD-38 cells was sharply inhibited by the knockdown of MYO6 but significantly increased by miR-143-3p inhibitors (P < .01, Figure 6A).	('inhibited', 'NegReg', (71, 80))	('increased', 'PosReg', (124, 133))	('CCK-8', 'Chemical', '-', (4, 9))	('MYO6', 'Gene', '4646', (101, 105))	('knockdown', 'Var', (88, 97))	('MYO6', 'Gene', (101, 105))	('miR-143-3p', 'Chemical', '-', (137, 147))	('YD-38', 'Chemical', '-', (47, 52))	('si', 'Chemical', '-', (110, 112))	('proliferation', 'CPA', (30, 43))
86630	32130788	Similarly, the inhibitory effect of miR-143-3p on cell migration and invasion was also rescued by MYO6 (P < .01, Figure 6C-J).	('miR-143-3p', 'Chemical', '-', (36, 46))	('invasion', 'CPA', (69, 77))	('MYO6', 'Gene', '4646', (98, 102))	('cell migration', 'CPA', (50, 64))	('miR-143-3p', 'Var', (36, 46))	('MYO6', 'Gene', (98, 102))	('si', 'Chemical', '-', (73, 75))
86631	32130788	To further determine the role of UCA1 in OSCC tumorigenesis in vivo, transfected cells were injected into the nude mice, and we found that UCA1 silencing significantly suppressed tumor weight and size in xenograft mice; however, overexpressing UCA1 noticeably accelerated tumor growth, and the effect of UCA1 was attenuated by miR-143-3p (P < .01, Figure 7A-D).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('si', 'Chemical', '-', (154, 156))	('suppressed', 'NegReg', (168, 178))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('UCA1', 'Gene', '652995', (244, 248))	('UCA1', 'Gene', (244, 248))	('miR-143-3p', 'Chemical', '-', (327, 337))	('tumor', 'Disease', (272, 277))	('si', 'Chemical', '-', (144, 146))	('accelerated', 'PosReg', (260, 271))	('overexpressing', 'PosReg', (229, 243))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('si', 'Chemical', '-', (56, 58))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mice', 'Species', '10090', (115, 119))	('nude mice', 'Species', '10090', (110, 119))	('si', 'Chemical', '-', (239, 241))	('UCA1', 'Gene', '652995', (139, 143))	('UCA1', 'Gene', '652995', (304, 308))	('UCA1', 'Gene', (139, 143))	('UCA1', 'Gene', (304, 308))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('UCA1', 'Gene', '652995', (33, 37))	('UCA1', 'Gene', (33, 37))	('si', 'Chemical', '-', (196, 198))	('silencing', 'Var', (144, 153))	('mice', 'Species', '10090', (214, 218))	('tumor', 'Disease', (179, 184))
86632	32130788	Additionally, the protein and mRNA expressions of MYO6 were significantly reduced in the si-UCA1 group but elevated in the pc-UCA1 group, and miR-143-3p overturned these functions of UCA1 (P < .01, Figure 7E-J).	('UCA1', 'Gene', '652995', (183, 187))	('mRNA expressions', 'MPA', (30, 46))	('UCA1', 'Gene', (183, 187))	('si', 'Chemical', '-', (89, 91))	('si', 'Chemical', '-', (60, 62))	('miR-143-3p', 'Var', (142, 152))	('MYO6', 'Gene', '4646', (50, 54))	('UCA1', 'Gene', (126, 130))	('UCA1', 'Gene', '652995', (92, 96))	('si', 'Chemical', '-', (41, 43))	('UCA1', 'Gene', (92, 96))	('MYO6', 'Gene', (50, 54))	('miR-143-3p', 'Chemical', '-', (142, 152))	('UCA1', 'Gene', '652995', (126, 130))	('reduced', 'NegReg', (74, 81))	('protein', 'MPA', (18, 25))	('elevated', 'PosReg', (107, 115))
86642	32130788	Moreover, high expression of UCA1 was associated with lymphatic metastasis and recurrence of OSCC patients.	('OSCC', 'Disease', (93, 97))	('si', 'Chemical', '-', (71, 73))	('associated', 'Reg', (38, 48))	('UCA1', 'Gene', '652995', (29, 33))	('UCA1', 'Gene', (29, 33))	('patients', 'Species', '9606', (98, 106))	('si', 'Chemical', '-', (21, 23))	('recurrence', 'CPA', (79, 89))	('high', 'Var', (10, 14))	('lymphatic metastasis', 'CPA', (54, 74))
86648	32130788	Herein, we found that miR-143-3p mimics exerted an inhibitory effect on the OSCC cell growth and metastasis and was related to lymphatic metastasis and recurrence of patients with OSCC.	('lymphatic metastasis', 'CPA', (127, 147))	('miR-143-3p', 'Chemical', '-', (22, 32))	('OSCC', 'Disease', (76, 80))	('OSCC', 'Disease', (180, 184))	('si', 'Chemical', '-', (144, 146))	('related to', 'Reg', (116, 126))	('inhibitory effect', 'NegReg', (51, 68))	('si', 'Chemical', '-', (104, 106))	('miR-143-3p mimics', 'Var', (22, 39))	('patients', 'Species', '9606', (166, 174))
86649	32130788	We discovered that miR-143-3p suppressed OSCC progression via targeting MYO6.	('si', 'Chemical', '-', (53, 55))	('MYO6', 'Gene', '4646', (72, 76))	('miR-143-3p', 'Chemical', '-', (19, 29))	('suppressed', 'NegReg', (30, 40))	('MYO6', 'Gene', (72, 76))	('OSCC progression', 'Disease', (41, 57))	('miR-143-3p', 'Var', (19, 29))
86650	32130788	The data revealed that MYO6 exhibited a tumor-promoting property in various cancers, including prostate,19 gastric,21 breast,49 and lung cancer.50 Moreover, consistent with previous studies, we observed that MYO6 is a downstream target for miR-143-3p,51 and that MYO6 can also be regulated by lncRNA such as SOX21-AS1.52 We also found that MYO6 was elevated in OSCC tissues and cells, and increased MYO6 reversed the inhibitory effects of miR-143-3p on OSCC cells, suggesting that miR-143-3p attenuated OSCC cell proliferation, migration, and invasion by suppressing MYO6.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('AS1', 'Gene', '5729', (314, 317))	('MYO6', 'Gene', '4646', (23, 27))	('MYO6', 'Gene', (399, 403))	('MYO6', 'Gene', (263, 267))	('miR-143-3p', 'Chemical', '-', (240, 250))	('MYO6', 'Gene', (208, 212))	('SOX21', 'Gene', '11166', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('MYO6', 'Gene', '4646', (340, 344))	('invasion', 'CPA', (543, 551))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('attenuated', 'NegReg', (492, 502))	('MYO6', 'Gene', (23, 27))	('MYO6', 'Gene', (340, 344))	('si', 'Chemical', '-', (160, 162))	('MYO6', 'Gene', '4646', (567, 571))	('AS1', 'Gene', (314, 317))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('SOX21', 'Gene', (308, 313))	('miR-143-3p', 'Var', (481, 491))	('gastric,21 breast,49 and lung cancer', 'Disease', 'MESH:D001943', (107, 143))	('miR-143-3p', 'Chemical', '-', (481, 491))	('tumor', 'Disease', (40, 45))	('si', 'Chemical', '-', (547, 549))	('migration', 'CPA', (528, 537))	('suppressing', 'NegReg', (555, 566))	('MYO6', 'Gene', '4646', (399, 403))	('MYO6', 'Gene', (567, 571))	('MYO6', 'Gene', '4646', (208, 212))	('miR-143-3p', 'Chemical', '-', (439, 449))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('si', 'Chemical', '-', (562, 564))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MYO6', 'Gene', '4646', (263, 267))	('OSCC cell proliferation', 'CPA', (503, 526))
86724	30651927	Bioenergetic modulation with the mitochondria uncouplers SR4 and niclosamide prevents proliferation and growth of treatment-naive and vemurafenib-resistant melanomas BRAF mutations are detected in >50% of all melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanomas', 'Phenotype', 'HP:0002861', (156, 165))	('melanomas', 'Disease', (209, 218))	('niclosamide', 'Chemical', 'MESH:D009534', (65, 76))	('growth', 'CPA', (104, 110))	('melanomas', 'Disease', 'MESH:D008545', (156, 165))	('proliferation', 'CPA', (86, 99))	('melanomas', 'Disease', 'MESH:D008545', (209, 218))	('prevents', 'NegReg', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanomas', 'Phenotype', 'HP:0002861', (209, 218))	('SR4', 'Gene', '408116', (57, 60))	('mutations', 'Var', (171, 180))	('melanomas', 'Disease', (156, 165))	('SR4', 'Gene', (57, 60))	('vemurafenib', 'Chemical', 'MESH:D000077484', (134, 145))
86725	30651927	These mutations impair the LKB1-AMPK signaling, an important metabolic pathway associated with cell growth, proliferation and survival.	('AMPK', 'Gene', (32, 36))	('LKB1', 'Gene', (27, 31))	('impair', 'NegReg', (16, 22))	('LKB1', 'Gene', '6794', (27, 31))	('AMPK', 'Gene', '5563', (32, 36))	('mutations', 'Var', (6, 15))
86726	30651927	Melanoma patients with BRAF mutations are usually treated with BRAF inhibitors such as vemurafenib, but responses are short-lived as drug resistant tumors metabolically switch to mitochondrial oxidative phosphorylation (OXPHOS) to escape metabolic stress-induced BRAF inhibition.	('patients', 'Species', '9606', (9, 17))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('Melanoma', 'Disease', (0, 8))	('BRAF', 'Gene', (23, 27))	('switch', 'Reg', (169, 175))	('vemurafenib', 'Chemical', 'MESH:D000077484', (87, 98))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (28, 37))	('mitochondrial oxidative phosphorylation', 'MPA', (179, 218))
86728	30651927	Therefore, uncoupling of OXPHOS to perturb energy homeostasis and to indirectly stimulate AMPK could be a novel treatment for melanoma and to overcome intrinsic and acquired resistance to BRAF inhibitors.	('perturb energy homeostasis', 'Disease', 'MESH:C536875', (35, 61))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('perturb energy homeostasis', 'Disease', (35, 61))	('AMPK', 'Gene', '5563', (90, 94))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('stimulate', 'PosReg', (80, 89))	('uncoupling', 'Var', (11, 21))	('melanoma', 'Disease', (126, 134))	('AMPK', 'Gene', (90, 94))
86731	30651927	Melanomas with greater OXPHOS phenotype (higher OCR/ECAR), with LKB1 mutation, or with acquired resistance to vemurafenib displayed greater sensitivity to both uncouplers.	('LKB1', 'Gene', '6794', (64, 68))	('sensitivity', 'MPA', (140, 151))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('OCR/ECAR', 'MPA', (48, 56))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('vemurafenib', 'Chemical', 'MESH:D000077484', (110, 121))	('mutation', 'Var', (69, 77))	('OCR', 'Chemical', '-', (48, 51))	('higher', 'PosReg', (41, 47))	('OXPHOS phenotype', 'MPA', (23, 39))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('LKB1', 'Gene', (64, 68))
86737	30651927	Approximately 50-60% of melanomas have a mutation in the BRAF (v-Raf murine sarcoma viral oncogene homolog B protein) kinase.	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (63, 108))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (63, 108))	('melanomas', 'Disease', (24, 33))	('BRAF', 'Gene', (57, 61))	('mutation', 'Var', (41, 49))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('melanomas', 'Disease', 'MESH:D008545', (24, 33))
86738	30651927	All the mutations occur within the kinase domain, and the specific V600E missense valine to glutamic acid mutation accounts for approximately 80-90% of BRAF mutations.	('BRAF', 'Gene', (152, 156))	('V600E', 'Mutation', 'rs113488022', (67, 72))	('glutamic acid', 'Chemical', 'MESH:D018698', (92, 105))	('mutations', 'Var', (157, 166))	('valine', 'Chemical', 'MESH:D014633', (82, 88))	('V600E missense valine to', 'Var', (67, 91))
86739	30651927	This mutation leads to a conformational change resulting in constitutive activation of BRAF, and consequently of the MEK/ERK MAPK pathway, promoting survival and proliferation of melanoma cells.	('activation', 'PosReg', (73, 83))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('conformational change', 'MPA', (25, 46))	('MEK/ERK MAPK pathway', 'Pathway', (117, 137))	('proliferation', 'CPA', (162, 175))	('promoting', 'PosReg', (139, 148))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('survival', 'CPA', (149, 157))	('melanoma', 'Disease', (179, 187))	('mutation', 'Var', (5, 13))	('BRAF', 'Gene', (87, 91))
86740	30651927	Currently, there are two BRAF mutation inhibitors (vemurafenib and dabrafenib) that are approved by the U.S. FDA to treat stage 3 or 4 melanoma with positive BRAFV600E or BRAFV600K mutation.	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('BRAFV600K', 'Var', (171, 180))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('dabrafenib', 'Chemical', 'MESH:C561627', (67, 77))	('vemurafenib', 'Chemical', 'MESH:D000077484', (51, 62))	('BRAFV600K', 'Mutation', 'rs121913227', (171, 180))	('BRAF', 'Gene', (25, 29))	('BRAFV600E', 'Var', (158, 167))	('BRAFV600E', 'Mutation', 'rs113488022', (158, 167))
86742	30651927	The former is primarily due to MEK/ERK reactivation resulting from amplification of BRAF, BRAF splicing, NRAS mutation, MEK mutation and loss of NF1, while the latter resistance mechanisms include up-regulated receptor tyrosine kinases (RTKS), activating mutations in AKT and loss of function mutations in PTEN and overexpression of COT.	('BRAF', 'Gene', (90, 94))	('MEK', 'Gene', (120, 123))	('NRAS', 'Gene', (105, 109))	('up-regulated', 'PosReg', (197, 209))	('mutations', 'Var', (255, 264))	('PTEN', 'Gene', (306, 310))	('amplification', 'Var', (67, 80))	('AKT', 'Gene', (268, 271))	('reactivation', 'PosReg', (39, 51))	('MEK/ERK', 'Gene', (31, 38))	('NF1', 'Gene', '4763', (145, 148))	('PTEN', 'Gene', '5728', (306, 310))	('mutations', 'Var', (293, 302))	('BRAF', 'Gene', (84, 88))	('activating', 'PosReg', (244, 254))	('mutation', 'Var', (110, 118))	('loss', 'Var', (137, 141))	('loss of function', 'NegReg', (276, 292))	('NF1', 'Gene', (145, 148))	('AKT', 'Gene', '207', (268, 271))	('mutation', 'Var', (124, 132))
86747	30651927	Studies suggested that many melanomas have low AMPK and high mTOR activity due to mutations that enable them to escape energetic stress and continue proliferation.	('mTOR activity', 'MPA', (61, 74))	('AMPK', 'Gene', (47, 51))	('melanomas', 'Disease', (28, 37))	('escape energetic stress', 'MPA', (112, 135))	('mutations', 'Var', (82, 91))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('AMPK', 'Gene', '5563', (47, 51))	('melanomas', 'Disease', 'MESH:D008545', (28, 37))
86749	30651927	BRAFV600E mutation has been shown to turn off the LKB1-AMPK pathway by phosphorylating LKB1, preventing its ability to bind and activate AMPK.	('preventing', 'NegReg', (93, 103))	('AMPK', 'Gene', '5563', (55, 59))	('LKB1', 'Gene', (87, 91))	('AMPK', 'Gene', (137, 141))	('LKB1', 'Gene', '6794', (87, 91))	('activate', 'PosReg', (128, 136))	('phosphorylating', 'MPA', (71, 86))	('bind', 'Interaction', (119, 123))	('LKB1', 'Gene', (50, 54))	('turn off', 'NegReg', (37, 45))	('ability', 'MPA', (108, 115))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('BRAFV600E mutation', 'Var', (0, 18))	('LKB1', 'Gene', '6794', (50, 54))	('AMPK', 'Gene', (55, 59))	('AMPK', 'Gene', '5563', (137, 141))
86755	30651927	In this study, we investigated the metabolic effects of SR4 and niclosamide (Figure 1A), two small molecules that were recently identified as mitochondria uncouplers, against treatment naive wild type, BRAFV600E and NRAS mutant, and BRAF inhibitor (vemurafenib)-resistant melanomas.	('BRAFV600E', 'Var', (202, 211))	('melanomas', 'Disease', 'MESH:D008545', (272, 281))	('BRAFV600E', 'Mutation', 'rs113488022', (202, 211))	('investigated', 'Reg', (18, 30))	('SR4', 'Gene', '408116', (56, 59))	('SR4', 'Gene', (56, 59))	('melanomas', 'Disease', (272, 281))	('NRAS', 'Gene', (216, 220))	('niclosamide', 'Chemical', 'MESH:D009534', (64, 75))	('vemurafenib', 'Chemical', 'MESH:D000077484', (249, 260))	('melanoma', 'Phenotype', 'HP:0002861', (272, 280))	('melanomas', 'Phenotype', 'HP:0002861', (272, 281))
86759	30651927	However, the effects of both compounds in melanoma with various oncogenic driver mutations and with drug-resistant melanoma have not been investigated, as well as the metabolic signaling mechanisms of both uncouplers in melanoma.	('melanoma', 'Disease', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (220, 228))	('mutations', 'Var', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('melanoma', 'Disease', (220, 228))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
86760	30651927	Our current data showed that the anti-proliferative and anti-tumor effects of both SR4 and niclosamide in vitro and in mice xenograft studies result from uncoupling of mitochondrial OXPHOS that induces energetic stress on cells, consequently leading to AMPK activation and mTOR inhibition without any effects on ERK/MEK MAPK signaling.	('mitochondrial OXPHOS', 'Enzyme', (168, 188))	('mice', 'Species', '10090', (119, 123))	('induces', 'Reg', (194, 201))	('SR4', 'Gene', '408116', (83, 86))	('AMPK', 'Gene', (253, 257))	('SR4', 'Gene', (83, 86))	('AMPK', 'Gene', '5563', (253, 257))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('uncoupling', 'Var', (154, 164))	('niclosamide', 'Chemical', 'MESH:D009534', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('activation', 'PosReg', (258, 268))	('mTOR', 'MPA', (273, 277))	('tumor', 'Disease', (61, 66))	('anti-proliferative', 'CPA', (33, 51))
86762	30651927	The anti-proliferative effects of both SR4 and niclosamide were evaluated in melanoma cells with wild type BRAF (Mewo, SK-MEL-2), BRAFV600E (A101D, A375, A2058, SK-MEL5, SK-MEL-28) and NRAS (SK-MEL-2) mutations using the Cell Titer Glo cell viability assay.	('SK-MEL-2', 'CellLine', 'CVCL:0069', (170, 178))	('A101D', 'Var', (141, 146))	('SR4', 'Gene', '408116', (39, 42))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('NRAS', 'Gene', (185, 189))	('SR4', 'Gene', (39, 42))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (191, 199))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (119, 127))	('SK-MEL', 'Chemical', '-', (170, 176))	('A2058', 'Var', (154, 159))	('SK-MEL', 'Chemical', '-', (161, 167))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('anti-proliferative', 'MPA', (4, 22))	('A101D', 'SUBSTITUTION', 'None', (141, 146))	('SK-MEL', 'Chemical', '-', (191, 197))	('BRAFV600E', 'Mutation', 'rs113488022', (130, 139))	('SK-MEL', 'Chemical', '-', (119, 125))	('A375', 'CellLine', 'CVCL:0132', (148, 152))	('niclosamide', 'Chemical', 'MESH:D009534', (47, 58))
86764	30651927	There was no correlation between the responses to SR4 or niclosamide and the BRAF/NRAS mutation status of each cell line, but both A2058 and SK-MEL-5, known LKB1 mutant and LKB1 null cells, respectively, were the most sensitive to both uncouplers.	('LKB1', 'Gene', '6794', (173, 177))	('LKB1', 'Gene', (157, 161))	('SK-MEL', 'Chemical', '-', (141, 147))	('LKB1', 'Gene', '6794', (157, 161))	('niclosamide', 'Chemical', 'MESH:D009534', (57, 68))	('SR4', 'Gene', '408116', (50, 53))	('A2058', 'Var', (131, 136))	('SR4', 'Gene', (50, 53))	('LKB1', 'Gene', (173, 177))
86768	30651927	Even at 1 muM concentration, both SR4 and niclosamide almost completely inhibited colony formation of all seven melanoma cells after 10 days incubation with the compounds, whereas vemurafenib displayed variable effects on BRAFV600E mutants and failed to inhibit colony growth of wild type BRAF cells (Figure 1C).	('muM', 'Gene', '56925', (10, 13))	('niclosamide', 'Chemical', 'MESH:D009534', (42, 53))	('SR4', 'Gene', (34, 37))	('BRAFV600E', 'Mutation', 'rs113488022', (222, 231))	('muM', 'Gene', (10, 13))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('vemurafenib', 'Chemical', 'MESH:D000077484', (180, 191))	('BRAFV600E', 'Var', (222, 231))	('inhibited', 'NegReg', (72, 81))	('colony formation of', 'CPA', (82, 101))	('SR4', 'Gene', '408116', (34, 37))
86772	30651927	These data suggest that cells that are LKB1 deficient are most susceptible to SR4 and niclosamide.	('SR4', 'Gene', (78, 81))	('LKB1', 'Gene', '6794', (39, 43))	('niclosamide', 'Chemical', 'MESH:D009534', (86, 97))	('deficient', 'Var', (44, 53))	('SR4', 'Gene', '408116', (78, 81))	('LKB1', 'Gene', (39, 43))
86788	30651927	Acute exposure to either compound, even in the presence of ATP synthase inhibitor oligomycin (to inhibit stage 3 respiration), significantly shifted the baseline phenotype to the energetic phenotype characterized by increase in both OCR and ECAR metabolic potential in both BRAFV600E mutant (A2058, A375, SK-MEL-28) and BRAF wild type (MeWo) cells (Figure 3C and 3D).	('baseline phenotype', 'MPA', (153, 171))	('A375', 'CellLine', 'CVCL:0132', (299, 303))	('shifted', 'Reg', (141, 148))	('ECAR metabolic potential', 'MPA', (241, 265))	('OCR', 'Chemical', '-', (233, 236))	('ATP', 'Chemical', 'MESH:D000255', (59, 62))	('oligomycin', 'Chemical', 'MESH:D009840', (82, 92))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (305, 313))	('BRAFV600E', 'Var', (274, 283))	('increase', 'PosReg', (216, 224))	('BRAFV600E', 'Mutation', 'rs113488022', (274, 283))
86791	30651927	Taken together, these data suggest that uncoupling induces an acute energetic stress in melanoma cells to utilize both OXPHOS and glycolysis in response to increased energy demand.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('glycolysis', 'MPA', (130, 140))	('induces', 'Reg', (51, 58))	('utilize', 'MPA', (106, 113))	('uncoupling', 'Var', (40, 50))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))
86799	30651927	Among the BRAFV600E mutants, A2058 and SK-MEL-5, two of the most sensitive cells to both uncouplers, and expressing either low or lacking the LKB1 protein, respectively, displayed the lowest AMPK phosphorylation (Figure 4B).	('AMPK', 'Gene', (191, 195))	('BRAFV600E', 'Var', (10, 19))	('BRAFV600E', 'Mutation', 'rs113488022', (10, 19))	('LKB1', 'Gene', (142, 146))	('SK-MEL', 'Chemical', '-', (39, 45))	('LKB1', 'Gene', '6794', (142, 146))	('AMPK', 'Gene', '5563', (191, 195))	('A2058', 'Var', (29, 34))	('lowest', 'NegReg', (184, 190))	('lacking', 'NegReg', (130, 137))
86802	30651927	Treatment of cells with either SR4 or niclosamide also inhibited mTOR signaling, as shown by increased phosphorylation of Raptor, a well-defined downstream target of AMPK, and decreased phosphorylation of the mTOR downstream effector p70S6 kinase (S6K).	('AMPK', 'Gene', (166, 170))	('niclosamide', 'Chemical', 'MESH:D009534', (38, 49))	('SR4', 'Gene', '408116', (31, 34))	('Raptor', 'Gene', (122, 128))	('Raptor', 'Gene', '57521', (122, 128))	('SR4', 'Gene', (31, 34))	('increased', 'PosReg', (93, 102))	('mTOR', 'MPA', (65, 69))	('S6K', 'Gene', (248, 251))	('decreased', 'NegReg', (176, 185))	('niclosamide', 'Var', (38, 49))	('S6K', 'Gene', '6198', (248, 251))	('AMPK', 'Gene', '5563', (166, 170))	('phosphorylation', 'MPA', (103, 118))	('phosphorylation', 'MPA', (186, 201))	('inhibited', 'NegReg', (55, 64))
86804	30651927	We used the human A375 BRAFV600E mutant melanoma xenograft model to assess the in vivo efficacy of the two uncouplers in comparison with the BRAF inhibitor vemurafenib.	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('A375', 'CellLine', 'CVCL:0132', (18, 22))	('melanoma', 'Disease', (40, 48))	('BRAFV600E', 'Var', (23, 32))	('BRAFV600E', 'Mutation', 'rs113488022', (23, 32))	('human', 'Species', '9606', (12, 17))	('vemurafenib', 'Chemical', 'MESH:D000077484', (156, 167))
86815	30651927	Cells were considered resistant when they can be continuously cultured at 10 muM concentration of vemurafenib (it took approximately 1 and 2 months for SK-MEL-28VR and A375VR, respectively, to become resistant).	('muM', 'Gene', (77, 80))	('A375VR', 'Var', (168, 174))	('A375VR', 'CellLine', 'CVCL:AP96', (168, 174))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (152, 160))	('28VR', 'Chemical', '-', (159, 163))	('muM', 'Gene', '56925', (77, 80))	('SK-MEL-28VR', 'Var', (152, 163))	('vemurafenib', 'Chemical', 'MESH:D000077484', (98, 109))
86822	30651927	In A375VR cells, treatment with SR4 or niclosamide significantly shifted the cells' metabolism to an energetic phenotype with increased OCR and ECAR (Supplementary Figure 2A), resulting to a significantly higher metabolic stress potential as seen earlier with the A375 parental line treated at the same duration (Supplementary Figure 2B).	('A375', 'CellLine', 'CVCL:0132', (3, 7))	('metabolic stress potential', 'MPA', (212, 238))	('shifted', 'Reg', (65, 72))	('higher', 'PosReg', (205, 211))	('niclosamide', 'Var', (39, 50))	('A375', 'CellLine', 'CVCL:0132', (264, 268))	('OCR', 'Chemical', '-', (136, 139))	('A375VR', 'CellLine', 'CVCL:AP96', (3, 9))	('OCR', 'MPA', (136, 139))	('SR4', 'Gene', '408116', (32, 35))	('SR4', 'Gene', (32, 35))	('niclosamide', 'Chemical', 'MESH:D009534', (39, 50))	('increased', 'PosReg', (126, 135))
86837	30651927	In this study, we demonstrated that both small molecule SR4 and niclosamide create energetic stress in melanoma irrespective of BRAF/NRAS status by uncoupling mitochondrial OXPHOS, decreasing intracellular ATP production, activating the energy sensor and metabolic tumor suppressor AMPK, and downregulating the mTOR pathway, leading to inhibition of tumor proliferation in vitro and in xenograft mice models.	('downregulating', 'NegReg', (292, 306))	('niclosamide', 'Var', (64, 75))	('SR4', 'Gene', '408116', (56, 59))	('SR4', 'Gene', (56, 59))	('energy', 'CPA', (237, 243))	('AMPK', 'Gene', (282, 286))	('uncoupling mitochondrial OXPHOS', 'MPA', (148, 179))	('activating', 'PosReg', (222, 232))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('metabolic tumor', 'Disease', 'MESH:D008659', (255, 270))	('melanoma', 'Disease', (103, 111))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', (350, 355))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('energetic', 'MPA', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('metabolic tumor', 'Disease', (255, 270))	('niclosamide', 'Chemical', 'MESH:D009534', (64, 75))	('intracellular ATP production', 'MPA', (192, 220))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('ATP', 'Chemical', 'MESH:D000255', (206, 209))	('mTOR pathway', 'Pathway', (311, 323))	('AMPK', 'Gene', '5563', (282, 286))	('decreasing', 'NegReg', (181, 191))	('mice', 'Species', '10090', (396, 400))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('inhibition', 'NegReg', (336, 346))
86840	30651927	This treatment strategy offers a distinct advantage over MAPK inhibitors that can only be used for melanomas harboring the BRAF mutations, consequently limiting the population of patients that is eligible for their use.	('melanomas', 'Disease', (99, 108))	('mutations', 'Var', (128, 137))	('limiting', 'NegReg', (152, 160))	('BRAF', 'Gene', (123, 127))	('melanomas', 'Disease', 'MESH:D008545', (99, 108))	('patients', 'Species', '9606', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))
86849	30651927	These high OXPHOS melanomas exhibit aggressive clinical behavior and confer de novo resistance to both MAPK inhibition and oxidative stress.	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (36, 64))	('melanomas', 'Disease', 'MESH:D008545', (18, 27))	('oxidative stress', 'Phenotype', 'HP:0025464', (123, 139))	('melanomas', 'Disease', (18, 27))	('high OXPHOS', 'Var', (6, 17))	('MAPK', 'Protein', (103, 107))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))
86850	30651927	In the current study, we screened seven human melanoma cells lines representing distinct oncogenic drivers (two BRAF wild type, five BRAF600E and one NRAS mutant) for their basal metabolic phenotype and observed that all of them displayed OCR/ECAR ratio indicative of OXPHOS activity.	('OCR', 'Chemical', '-', (239, 242))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('basal metabolic phenotype', 'MPA', (173, 198))	('BRAF600E', 'Var', (133, 141))	('OCR/ECAR ratio', 'MPA', (239, 253))	('human', 'Species', '9606', (40, 45))
86858	30651927	BRAFV600E oncogenic mutation has been shown to impair AMPK activation in melanoma by promoting inhibitory phosphorylation on LKB1 by ERK 1/2 and that this AMPK inhibition is critical for melanoma cell proliferation.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('LKB1', 'Gene', (125, 129))	('promoting', 'PosReg', (85, 94))	('AMPK', 'Gene', (155, 159))	('ERK 1/2', 'Gene', '5595;5594', (133, 140))	('AMPK', 'Gene', '5563', (54, 58))	('BRAFV600E', 'Var', (0, 9))	('inhibitory phosphorylation', 'MPA', (95, 121))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('LKB1', 'Gene', '6794', (125, 129))	('AMPK', 'Gene', (54, 58))	('AMPK', 'Gene', '5563', (155, 159))	('ERK 1/2', 'Gene', (133, 140))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('impair', 'NegReg', (47, 53))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
86859	30651927	In this study, we observed that AMPK activation by both uncouplers was significantly less in BRAFV600E melanoma compared with BRAF wild type as seen in the Western blot analyses.	('AMPK', 'Gene', (32, 36))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('BRAFV600E', 'Var', (93, 102))	('BRAFV600E', 'Mutation', 'rs113488022', (93, 102))	('less', 'NegReg', (85, 89))	('AMPK', 'Gene', '5563', (32, 36))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
86860	30651927	Among the five BRAFV600E mutants screened in our studies, A2058 and SK-MEL-5 were the most sensitive to both uncouplers, despite the fact their AMPK phosphorylation levels were the lowest.	('SK-MEL', 'Chemical', '-', (68, 74))	('sensitive', 'Reg', (91, 100))	('A2058', 'Var', (58, 63))	('AMPK', 'Gene', '5563', (144, 148))	('BRAFV600E', 'Mutation', 'rs113488022', (15, 24))	('lowest', 'NegReg', (181, 187))	('AMPK', 'Gene', (144, 148))	('BRAFV600E', 'Gene', (15, 24))
86861	30651927	As noted previously, these two melanoma cells are LKB1 mutant and LKB1 null, respectively.	('LKB1', 'Gene', (66, 70))	('mutant', 'Var', (55, 61))	('LKB1', 'Gene', '6794', (66, 70))	('LKB1', 'Gene', (50, 54))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('LKB1', 'Gene', '6794', (50, 54))
86862	30651927	Cancer cells with a defective LKB1/AMPK pathway are less able to restore ATP levels in response to energetic stress, and thus, are more susceptible to cell death than cells with a functional LKB1/AMPK.	('AMPK', 'Gene', '5563', (196, 200))	('LKB1', 'Gene', (30, 34))	('AMPK', 'Gene', (35, 39))	('LKB1', 'Gene', '6794', (30, 34))	('defective', 'Var', (20, 29))	('restore ATP levels in response to energetic stress', 'MPA', (65, 115))	('susceptible', 'Reg', (136, 147))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('LKB1', 'Gene', (191, 195))	('AMPK', 'Gene', (196, 200))	('cell death', 'CPA', (151, 161))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('ATP', 'Chemical', 'MESH:D000255', (73, 76))	('AMPK', 'Gene', '5563', (35, 39))	('LKB1', 'Gene', '6794', (191, 195))	('less', 'NegReg', (52, 56))
86864	30651927	Although LKB1 mutant melanomas appear to be excellent therapeutic targets for uncouplers and other energy stressors, less than 10% of melanomas have this mutation.	('melanomas', 'Disease', (134, 143))	('mutant', 'Var', (14, 20))	('melanomas', 'Disease', (21, 30))	('melanomas', 'Disease', 'MESH:D008545', (134, 143))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('LKB1', 'Gene', (9, 13))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('LKB1', 'Gene', '6794', (9, 13))
86866	30651927	Previous research showed that wild type BRAF is phosphorylated at Ser729 by AMPK, and this phosphorylation promotes the association of BRAF with 14-3-3 proteins and disrupts its interaction with the KSR1 scaffolding protein, leading to attenuation of the MEK-ERK signaling.	('interaction', 'Interaction', (178, 189))	('attenuation', 'NegReg', (236, 247))	('association', 'Interaction', (120, 131))	('BRAF', 'Gene', (135, 139))	('disrupts', 'NegReg', (165, 173))	('KSR1', 'Gene', '8844', (199, 203))	('AMPK', 'Gene', (76, 80))	('KSR1', 'Gene', (199, 203))	('promotes', 'PosReg', (107, 115))	('AMPK', 'Gene', '5563', (76, 80))	('Ser729', 'Chemical', '-', (66, 72))	('MEK-ERK signaling', 'Pathway', (255, 272))	('Ser729', 'Var', (66, 72))	('14-3-3 proteins', 'Protein', (145, 160))
86867	30651927	Furthermore, it is thought that oncogenic BRAF is resistant to AMPK-mediated inhibition, so ERK signaling cannot be attenuated by AMPK in BRAF mutant melanoma.	('AMPK', 'Gene', '5563', (130, 134))	('mutant', 'Var', (143, 149))	('AMPK', 'Gene', '5563', (63, 67))	('AMPK', 'Gene', (130, 134))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('BRAF', 'Gene', (138, 142))	('AMPK', 'Gene', (63, 67))
86868	30651927	Studies using the biguanides metformin and phenformin, both indirect AMPK activators, showed minimal effects on ERK dephosphorylation in both BRAF wild type and BRAFV600E mutant, as well as NRAS mutant melanomas.	('melanomas', 'Disease', 'MESH:D008545', (202, 211))	('ERK dephosphorylation', 'MPA', (112, 133))	('metformin', 'Chemical', 'MESH:D008687', (29, 38))	('AMPK', 'Gene', '5563', (69, 73))	('melanomas', 'Disease', (202, 211))	('biguanides', 'Chemical', 'MESH:D001645', (18, 28))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('phenformin', 'Chemical', 'MESH:D010629', (43, 53))	('melanomas', 'Phenotype', 'HP:0002861', (202, 211))	('AMPK', 'Gene', (69, 73))	('BRAFV600E', 'Var', (161, 170))	('BRAFV600E', 'Mutation', 'rs113488022', (161, 170))
86869	30651927	In contrast, several studies using other indirect AMPK agonists demonstrated that activation of AMPK was associated with reduced ERK signaling even in BRAFV600E mutant cells.	('AMPK', 'Gene', (50, 54))	('BRAFV600E', 'Var', (151, 160))	('AMPK', 'Gene', '5563', (96, 100))	('BRAFV600E', 'Mutation', 'rs113488022', (151, 160))	('reduced', 'NegReg', (121, 128))	('activation', 'PosReg', (82, 92))	('AMPK', 'Gene', (96, 100))	('reduced ERK', 'Phenotype', 'HP:0000654', (121, 132))	('AMPK', 'Gene', '5563', (50, 54))	('ERK signaling', 'MPA', (129, 142))
86871	30651927	Nonetheless, the strategy of simultaneously targeting both the MAPK pathway and OXPHOS using a combination of MAPK inhibitors and OXPHOS inhibitors/AMPK agonists has been highly effective in several preclinical studies, and are currently being investigated in phase I/II metastatic melanoma clinical trials (NCT01638676, NCT02143050 NCT03026517).	('melanoma', 'Disease', (282, 290))	('melanoma', 'Disease', 'MESH:D008545', (282, 290))	('MAPK', 'Gene', (110, 114))	('AMPK', 'Gene', '5563', (148, 152))	('inhibitors', 'Var', (115, 125))	('AMPK', 'Gene', (148, 152))	('melanoma', 'Phenotype', 'HP:0002861', (282, 290))
86873	30651927	Inhibition of BRAF mutations using MAPK inhibitors suppresses glycolysis leading to temporarily suppression of melanoma growth, but also promotes metabolic switch to OXPHOS phenotype via induction of MITF and PGC1alpha expression.	('metabolic switch to OXPHOS phenotype', 'MPA', (146, 182))	('MITF', 'Gene', (200, 204))	('suppression', 'NegReg', (96, 107))	('promotes', 'PosReg', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('mutations', 'Var', (19, 28))	('induction', 'Reg', (187, 196))	('melanoma growth', 'Disease', (111, 126))	('BRAF', 'Gene', (14, 18))	('suppresses', 'NegReg', (51, 61))	('PGC1alpha', 'Gene', (209, 218))	('melanoma growth', 'Disease', 'MESH:D008545', (111, 126))	('glycolysis', 'MPA', (62, 72))
86874	30651927	Indeed, we observed increased mRNA expression of both MITF and PGC1alpha in the two BRAFV600E mutant cell lines chronically treated with vemurafenib, concomitant with increased mitochondria density.	('vemurafenib', 'Chemical', 'MESH:D000077484', (137, 148))	('mitochondria density', 'MPA', (177, 197))	('increased', 'PosReg', (20, 29))	('MITF', 'Gene', (54, 58))	('mRNA expression', 'MPA', (30, 45))	('mutant', 'Var', (94, 100))	('increased', 'PosReg', (167, 176))	('BRAFV600E', 'Mutation', 'rs113488022', (84, 93))	('PGC1alpha', 'Gene', (63, 72))	('increased mitochondria', 'Phenotype', 'HP:0041045', (167, 189))	('BRAFV600E', 'Gene', (84, 93))
86892	30651927	Like most drug targets, uncoupling OXPHOS and activating AMPK might cause some undesirable side effects.	('cause', 'Reg', (68, 73))	('AMPK', 'Gene', (57, 61))	('activating', 'Var', (46, 56))	('uncoupling', 'Var', (24, 34))	('AMPK', 'Gene', '5563', (57, 61))
86897	30651927	In previous animal studies, oral administration of SR4 in C57B mice showed no overt toxic effects in most of the blood and metabolic parameters.	('SR4', 'Gene', '408116', (51, 54))	('SR4', 'Gene', (51, 54))	('mice', 'Species', '10090', (63, 67))	('C57B', 'SUBSTITUTION', 'None', (58, 62))	('C57B', 'Var', (58, 62))
86904	30651927	We found that melanomas with higher OCR/ECAR, with LKB1 mutation, or with acquired resistance from MAPK inhibitors displayed greater sensitivity to both uncouplers.	('higher', 'PosReg', (29, 35))	('LKB1', 'Gene', (51, 55))	('melanomas', 'Disease', (14, 23))	('OCR/ECAR', 'MPA', (36, 44))	('LKB1', 'Gene', '6794', (51, 55))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('greater', 'PosReg', (125, 132))	('melanomas', 'Phenotype', 'HP:0002861', (14, 23))	('mutation', 'Var', (56, 64))	('OCR', 'Chemical', '-', (36, 39))	('melanomas', 'Disease', 'MESH:D008545', (14, 23))	('sensitivity to both uncouplers', 'MPA', (133, 163))
86909	30651927	Antibodies against AMPKalpha, phospho-AMPKalpha (Thr172), ACC, phospho-ACC (Ser79), p70S6 kinase (S6K), phospho-S6K (Thr389), ERK 1/2 (p44/42 MAPK), phospho-ERK (Thr202/Tyr204), Raptor, phospho-Raptor (Ser792), MEK, phospho-MEK (Ser217/Ser221), p38, phospho-p38 (Thr180/Tyr182), LKB1 and beta-actin were obtained from Cell Signaling Technology (Danvers, MA, USA).	('S6K', 'Gene', (98, 101))	('beta-actin', 'Gene', '728378', (288, 298))	('LKB1', 'Gene', '6794', (279, 283))	('S6K', 'Gene', (112, 115))	('Raptor', 'Gene', (194, 200))	('p38', 'Gene', '5594', (245, 248))	('p38', 'Gene', (258, 261))	('AMPK', 'Gene', (19, 23))	('Raptor', 'Gene', (178, 184))	('ERK 1/2', 'Gene', '5595;5594', (126, 133))	('S6K', 'Gene', '6198', (98, 101))	('AMPK', 'Gene', '5563', (38, 42))	('LKB1', 'Gene', (279, 283))	('beta-actin', 'Gene', (288, 298))	('Thr180/Tyr182', 'Var', (263, 276))	('p38', 'Gene', '5594', (258, 261))	('Raptor', 'Gene', '57521', (194, 200))	('p44', 'Gene', (135, 138))	('S6K', 'Gene', '6198', (112, 115))	('p38', 'Gene', (245, 248))	('Raptor', 'Gene', '57521', (178, 184))	('p44', 'Gene', '10561', (135, 138))	('ERK 1/2', 'Gene', (126, 133))	('AMPK', 'Gene', (38, 42))	('AMPK', 'Gene', '5563', (19, 23))
86911	30651927	The human melanoma cell lines A101D, A375, A2058, MeWo, SK-MEL-2, SK-MEL-5, SK-MEL-28 were obtained from ATCC and were cultured in RPMI-1640 containing 10% fetal bovine serum and 1% penicillin/streptomycin antibiotics (ATCC, Manassas, VA, USA) at 37 C in a humidified atmosphere of 5% CO2.	('A101D', 'SUBSTITUTION', 'None', (30, 35))	('human', 'Species', '9606', (4, 9))	('streptomycin', 'Chemical', 'MESH:D013307', (193, 205))	('SK-MEL', 'Chemical', '-', (66, 72))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (56, 64))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (76, 84))	('SK-MEL', 'Chemical', '-', (56, 62))	('SK-MEL', 'Chemical', '-', (76, 82))	('penicillin', 'Chemical', 'MESH:D010406', (182, 192))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('bovine', 'Species', '9913', (162, 168))	('A375', 'CellLine', 'CVCL:0132', (37, 41))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('RPMI-1640', 'Chemical', '-', (131, 140))	('CO2', 'Chemical', '-', (285, 288))	('melanoma', 'Disease', (10, 18))	('A101D', 'Var', (30, 35))
86952	29946497	Surveillance Screening in Li-Fraumeni Syndrome: Raising Awareness of False Positives Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome inherited in an autosomal dominant fashion that involves a germline mutation of tumor protein 53 (TP53).	('Li-Fraumeni Syndrome', 'Disease', (26, 46))	('Li-Fraumeni syndrome', 'Disease', (85, 105))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor protein 53', 'Gene', '7157', (233, 249))	('TP53', 'Gene', (251, 255))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('LFS', 'Disease', (107, 110))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (26, 46))	('germline mutation', 'Var', (212, 229))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (85, 105))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor protein 53', 'Gene', (233, 249))	('TP53', 'Gene', '7157', (251, 255))	('LFS', 'Disease', 'MESH:D016864', (107, 110))
86962	29946497	This incidence represents the risk of malignancy for families with strong cancer predisposition syndromes and likely tumor protein 53 (TP53) null mutations; it is possible, however, that as more mutations involving slightly more functional TP53 alleles are identified, the incidence of malignancy in certain subsets of the Li-Fraumeni population may be different.	('malignancy', 'Disease', 'MESH:D009369', (38, 48))	('TP53', 'Gene', '7157', (240, 244))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('TP53', 'Gene', (240, 244))	('tumor protein 53', 'Gene', (117, 133))	('malignancy', 'Disease', (38, 48))	('malignancy', 'Disease', 'MESH:D009369', (286, 296))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('TP53', 'Gene', '7157', (135, 139))	('malignancy', 'Disease', (286, 296))	('cancer', 'Disease', (74, 80))	('tumor protein 53', 'Gene', '7157', (117, 133))	('TP53', 'Gene', (135, 139))	('mutations', 'Var', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
86965	29946497	However, since a germline pathogenic TP53 mutation is the only gene known to be implicated in LFS, targeted gene sequencing can now quickly identify both affected and unaffected carriers.	('LFS', 'Disease', (94, 97))	('mutation', 'Var', (42, 50))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('LFS', 'Disease', 'MESH:D016864', (94, 97))
86966	29946497	reported that 95% of pathogenic germline TP53 variants can be detected via sequencing the entire coding region (exons two through eleven) and that 80% of patients with LFS should have a detectable variant by sequencing.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('LFS', 'Disease', (168, 171))	('patients', 'Species', '9606', (154, 162))	('LFS', 'Disease', 'MESH:D016864', (168, 171))	('variants', 'Var', (46, 54))	('pathogenic', 'Reg', (21, 31))
86969	29946497	Based on the literature, it has been demonstrated that choroid plexus carcinoma (CPC) may be an indicator of an existing TP53 mutation irrespective of family history.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (55, 79))	('choroid plexus carcinoma', 'Disease', (55, 79))	('TP53', 'Gene', '7157', (121, 125))	('mutation', 'Var', (126, 134))	('TP53', 'Gene', (121, 125))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (55, 79))	('CPC', 'Phenotype', 'HP:0030392', (81, 84))
86977	29946497	demonstrated the feasibility of a surveillance protocol in asymptomatic germline TP53 mutation carriers and showed that in a small group of eight families, comprehensive screening resulted in early detection of tumors and improved overall survival.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('overall survival', 'CPA', (231, 247))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('mutation', 'Var', (86, 94))	('improved', 'PosReg', (222, 230))	('tumors', 'Disease', (211, 217))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
86978	29946497	In their prospective observational study, they identified 33 TP53 mutation carriers, 18 of whom chose to undergo surveillance.	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))
86982	29946497	demonstrated again, that with a comprehensive clinical screening protocol including physical exams, labs, and frequent imaging with a combination of whole body MRI, brain MRI, breast MRI, mammography, abdominal and pelvic ultrasound (U/S), and colonoscopy, individuals with TP53 mutations had earlier detection of asymptomatic tumors and improved long-term survival compared to their unscreened counterparts (five year overall survival 88.8% versus 59.6%).	('tumors', 'Disease', 'MESH:D009369', (327, 333))	('mutations', 'Var', (279, 288))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('improved', 'PosReg', (338, 346))	('earlier', 'PosReg', (293, 300))	('TP53', 'Gene', '7157', (274, 278))	('tumors', 'Disease', (327, 333))	('TP53', 'Gene', (274, 278))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))
86984	29946497	Based on the above experience of the Hospital for Sick Children in Toronto, Canada, the "Sick Kids Protocol" or the "Toronto Protocol" is widely accepted as a surveillance strategy for children with TP53 mutations, grouped by cancer type, as listed below.	('Children', 'Species', '9606', (55, 63))	('TP53', 'Gene', (199, 203))	('mutations', 'Var', (204, 213))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('children', 'Species', '9606', (185, 193))	('TP53', 'Gene', '7157', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
86992	29946497	A very strong and concerning maternal family history of cancer prompted genetic testing for the patient and his mother and revealed a TP53 mutation (TP53p.E286K).	('TP53', 'Gene', (134, 138))	('TP53', 'Gene', '7157', (149, 153))	('patient', 'Species', '9606', (96, 103))	('p.E286K', 'Var', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('TP53', 'Gene', (149, 153))	('p.E286K', 'SUBSTITUTION', 'None', (153, 160))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('TP53', 'Gene', '7157', (134, 138))
86997	29946497	The patient and her mother have an exon five tandem duplication of the TP53 gene, which, of note, was not identified by targeted sequencing and required special testing.	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('exon five tandem duplication', 'Var', (35, 63))	('patient', 'Species', '9606', (4, 11))
87002	29946497	A concerning family history on both maternal and paternal sides prompted genetic testing, which demonstrated a TP53 mutation (TP53p.C141W) that was found in the patient and his father.	('TP53', 'Gene', (126, 130))	('TP53', 'Gene', '7157', (111, 115))	('patient', 'Species', '9606', (161, 168))	('p.C141W', 'Var', (130, 137))	('TP53', 'Gene', (111, 115))	('p.C141W', 'SUBSTITUTION', 'None', (130, 137))	('TP53', 'Gene', '7157', (126, 130))
87008	29946497	He was found to have a de novo germline TP53 mutation (TP53p.M246V), as his parents and sibling were all negative.	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (40, 44))	('p.M246V', 'Var', (59, 66))	('TP53', 'Gene', (40, 44))	('p.M246V', 'SUBSTITUTION', 'None', (59, 66))
87011	29946497	The patient also has a diagnosis of Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), due to the presence of one mutated allele of MutS Homolog 6 (MSH6) (MSH6p.T716fs) on his genetic testing results.	('HNPCC', 'Phenotype', 'HP:0006716', (104, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MSH6', 'Gene', (180, 184))	('MSH6', 'Gene', (173, 177))	('Lynch syndrome', 'Disease', (36, 50))	('MSH6', 'Gene', '2956', (180, 184))	('hereditary nonpolyposis colorectal cancer', 'Disease', (61, 102))	('MSH6', 'Gene', '2956', (173, 177))	('HNPCC', 'Disease', 'None', (104, 109))	('HNPCC', 'Disease', (104, 109))	('p.T716fs', 'Var', (184, 192))	('p.T716fs', 'FRAMESHIFT', 'None', (184, 192))	('Lynch syndrome', 'Disease', 'MESH:D003123', (36, 50))	('patient', 'Species', '9606', (4, 11))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (61, 102))	('MutS Homolog 6', 'Gene', (157, 171))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (61, 102))	('MutS Homolog 6', 'Gene', '2956', (157, 171))
87025	29946497	She was found to have a germline TP53 mutation (TP53p.A248G).	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (33, 37))	('p.A248G', 'SUBSTITUTION', 'None', (52, 59))	('p.A248G', 'Var', (52, 59))
87040	29946497	Unfortunately, her sibling, (who did not undergo genetic testing and has not been undergoing surveillance screening) was recently diagnosed with osteosarcoma and thus is most likely a carrier of the same TP53 mutation.	('TP53', 'Gene', '7157', (204, 208))	('mutation', 'Var', (209, 217))	('osteosarcoma', 'Phenotype', 'HP:0002669', (145, 157))	('osteosarcoma', 'Disease', (145, 157))	('osteosarcoma', 'Disease', 'MESH:D012516', (145, 157))	('TP53', 'Gene', (204, 208))
87056	29946497	However, it has been shown that there is an increased incidence of hospitalization for children with false positives as compared to those with normal results and that mothers of these children have higher levels of stress as quantified on a parental stress index test.	('children', 'Species', '9606', (87, 95))	('children', 'Species', '9606', (184, 192))	('hospitalization', 'MPA', (67, 82))	('false positives', 'Var', (101, 116))	('stress', 'MPA', (215, 221))	('higher', 'PosReg', (198, 204))
87069	29642543	Aldosterone-producing adenomas frequently carry a causative somatic mutation in either of a number of genes with the KCNJ5 gene, encoding an inwardly rectifying potassium channel, a recurrent target harboring mutations at a prevalence of more than 40% worldwide.	('KCNJ5', 'Gene', (117, 122))	('mutation', 'Var', (68, 76))	('KCNJ5', 'Gene', '3762', (117, 122))	('adenomas', 'Disease', 'MESH:D000236', (22, 30))	('adenomas', 'Disease', (22, 30))
87076	29642543	A landmark in PA research was the discovery of germline and somatic mutations that drive the aldosterone overproduction in patients with PA, discoveries that were made possible by the application of next-generation sequencing.	('PA', 'Phenotype', 'HP:0011736', (137, 139))	('patients', 'Species', '9606', (123, 131))	('aldosterone overproduction', 'MPA', (93, 119))	('mutations', 'Var', (68, 77))	('aldosterone', 'Chemical', 'MESH:D000450', (93, 104))	('PA', 'Phenotype', 'HP:0011736', (14, 16))
87077	29642543	We describe the genetic basis of familial forms of hyperaldosteronism and the identification of somatic mutations that lead to excess aldosterone production.	('mutations', 'Var', (104, 113))	('aldosterone', 'Chemical', 'MESH:D000450', (134, 145))	('excess aldosterone', 'Phenotype', 'HP:0000859', (127, 145))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (51, 69))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (51, 69))	('forms of hyperaldosteronism', 'Phenotype', 'HP:0011741', (42, 69))	('familial forms', 'Disease', (33, 47))	('excess', 'PosReg', (127, 133))	('aldosterone production', 'MPA', (134, 156))	('aldosterone production', 'Phenotype', 'HP:0000859', (134, 156))	('hyperaldosteronism', 'Disease', (51, 69))
87083	29642543	Angiotensin II and potassium regulate aldosterone production via Ca2+ signalling which also plays a key role in the aldosterone excess in PA due to the somatic and germline mutations in ion channels and transporters.	('aldosterone production', 'MPA', (38, 60))	('Ca2+ signalling', 'MPA', (65, 80))	('PA', 'Phenotype', 'HP:0011736', (138, 140))	('aldosterone excess', 'Phenotype', 'HP:0000859', (116, 134))	('Ca2+', 'Chemical', 'MESH:D000069285', (65, 69))	('aldosterone', 'Chemical', 'MESH:D000450', (116, 127))	('mutations', 'Var', (173, 182))	('aldosterone', 'Chemical', 'MESH:D000450', (38, 49))	('Angiotensin II', 'Gene', (0, 14))	('Angiotensin II', 'Gene', '183', (0, 14))	('aldosterone production', 'Phenotype', 'HP:0000859', (38, 60))	('aldosterone excess', 'MPA', (116, 134))
87085	29642543	Familial hyperaldosteronism type I (FH type I or GRA, glucocorticoid remediable aldosteronism) is caused by a hybrid CYP11B1/CYP11B2 gene inherited as an autosomal dominant trait.	('CYP11B1', 'Gene', '1584', (117, 124))	('caused by', 'Reg', (98, 107))	('hybrid', 'Var', (110, 116))	('Familial hyperaldosteronism type', 'Phenotype', 'HP:0011739', (0, 32))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (9, 27))	('Familial hyperaldosteronism type I', 'Disease', 'MESH:C563177', (0, 34))	('Familial hyperaldosteronism type I', 'Disease', (0, 34))	('FH type I', 'Disease', 'MESH:C563177', (36, 45))	('Familial hyperaldosteronism type I', 'Phenotype', 'HP:0011739', (0, 34))	('FH type I', 'Disease', (36, 45))	('CYP11B1', 'Gene', (117, 124))
87089	29642543	identified the genetic variant responsible in the original kindred with FH type II described by Michael Stowasser as a heterozygous variant of the CLCN2 gene that caused early-onset primary aldosteronism and hypertension often with hypokalaemia.	('FH type II', 'Disease', (72, 82))	('variant', 'Var', (132, 139))	('hypertension', 'Disease', (208, 220))	('CLCN2', 'Gene', '1181', (147, 152))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (182, 203))	('hypertension', 'Phenotype', 'HP:0000822', (208, 220))	('caused', 'Reg', (163, 169))	('hypokalaemia', 'Disease', (232, 244))	('-onset primary aldosteronism', 'Phenotype', 'HP:0011739', (175, 203))	('early-onset primary aldosteronism', 'Disease', (170, 203))	('CLCN2', 'Gene', (147, 152))	('hypokalaemia', 'Disease', 'MESH:D007008', (232, 244))	('FH type II', 'Disease', 'MESH:C565312', (72, 82))	('hypertension', 'Disease', 'MESH:D006973', (208, 220))
87091	29642543	In the original family with FH type II, eight individuals were carriers of the CLCN2 mutation (resulting in the CIC-2 p.Arg172Gln substitution) and of these, seven tested positive with a screening test for primary aldosteronism (elevated aldosterone-to-renin ratio).	('positive', 'Reg', (171, 179))	('elevated', 'PosReg', (229, 237))	('CIC-2', 'Gene', (112, 117))	('renin', 'Gene', '5972', (253, 258))	('CLCN2', 'Gene', '1181', (79, 84))	('primary aldosteronism', 'Disease', (206, 227))	('CIC-2', 'Gene', '1181', (112, 117))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (206, 227))	('p.Arg172Gln', 'Var', (118, 129))	('mutation', 'Var', (85, 93))	('CLCN2', 'Gene', (79, 84))	('p.Arg172Gln', 'Mutation', 'rs1293789661', (118, 129))	('FH type II', 'Disease', 'MESH:C565312', (28, 38))	('renin', 'Gene', (253, 258))	('aldosterone', 'Chemical', 'MESH:D000450', (238, 249))	('carriers', 'Reg', (63, 71))	('FH type II', 'Disease', (28, 38))	('elevated aldosterone', 'Phenotype', 'HP:0000859', (229, 249))
87092	29642543	One carrier for the CIC-2 p.Arg172Gln variant had a normal aldosterone-to-renin ratio, and therefore did not have primary aldosteronism, indicating an incomplete penetrance of the allele.	('renin', 'Gene', '5972', (74, 79))	('CIC-2', 'Gene', (20, 25))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (114, 135))	('aldosterone', 'Chemical', 'MESH:D000450', (59, 70))	('renin', 'Gene', (74, 79))	('p.Arg172Gln', 'Mutation', 'rs1293789661', (26, 37))	('p.Arg172Gln', 'Var', (26, 37))	('CIC-2', 'Gene', '1181', (20, 25))
87093	29642543	found the p.Arg172Gln substitution in an additional kindred and two further cases of p.Arg172Gln mutations (1 occurring de novo) in 2 unrelated patients with early-onset PA as well as other CLCN2 variants encoding 4 different mutations in CIC-2 (a de novo p.Met22Lys mutation, p.Tyr26Asn, p.Ser865Arg and p.Lys362del).	('CIC-2', 'Gene', '1181', (239, 244))	('p.Ser865Arg', 'Mutation', 'p.S865R', (289, 300))	('PA', 'Phenotype', 'HP:0011736', (170, 172))	('p.Arg172Gln', 'Mutation', 'rs1293789661', (10, 21))	('p.Met22Lys', 'Var', (256, 266))	('p.Lys362del', 'Var', (305, 316))	('p.Ser865Arg', 'Var', (289, 300))	('patients', 'Species', '9606', (144, 152))	('CLCN2', 'Gene', '1181', (190, 195))	('p.Tyr26Asn', 'Mutation', 'p.Y26N', (277, 287))	('p.Tyr26Asn', 'Var', (277, 287))	('p.Lys362del', 'Mutation', 'p.362del', (305, 316))	('CIC-2', 'Gene', (239, 244))	('p.Met22Lys', 'Mutation', 'rs758379595', (256, 266))	('CLCN2', 'Gene', (190, 195))	('p.Arg172Gln', 'Mutation', 'rs1293789661', (85, 96))
87094	29642543	At the same time, Fernandes-Rosa et al., reported a de novo heterozygous p.Gly24Asp mutation in the CIC-2 chloride channel associated with PA. Electrophysiological recordings showed that the mutated CIC-2 channels display modified gating resulting in increased chloride efflux compared with wild-type CIC-2 channels.	('increased', 'PosReg', (251, 260))	('CIC-2', 'Gene', (301, 306))	('CIC-2', 'Gene', '1181', (100, 105))	('chloride', 'Chemical', 'MESH:D002712', (261, 269))	('p.Gly24Asp', 'Mutation', 'rs1085307938', (73, 83))	('PA', 'Phenotype', 'HP:0011736', (139, 141))	('CIC-2', 'Gene', (199, 204))	('p.Gly24Asp', 'Var', (73, 83))	('mutated', 'Var', (191, 198))	('CIC-2', 'Gene', '1181', (301, 306))	('modified', 'Reg', (222, 230))	('CIC-2', 'Gene', (100, 105))	('chloride efflux', 'MPA', (261, 276))	('chloride', 'Chemical', 'MESH:D002712', (106, 114))	('CIC-2', 'Gene', '1181', (199, 204))
87097	29642543	A gain-of-function mutation in the KCNJ5 gene (encoding the G-protein-coupled inwardly rectifying potassium channel GIRK4) was identified in the male index case and his two daughters.	('mutation', 'Var', (19, 27))	('gain-of-function', 'PosReg', (2, 18))	('KCNJ5', 'Gene', (35, 40))	('KCNJ5', 'Gene', '3762', (35, 40))	('GIRK4', 'Gene', '3762', (116, 121))	('GIRK4', 'Gene', (116, 121))
87098	29642543	The mutation results in the substitution of a threonine residue (p.Thr158Ala) located just above the selectivity filter of the channel pore which interferes with the Thr158-Pro128 hydrogen bonding.	('Thr158-Pro128 hydrogen bonding', 'MPA', (166, 196))	('Pro128', 'Chemical', '-', (173, 179))	('Thr158', 'Chemical', '-', (166, 172))	('Thr158', 'Chemical', '-', (67, 73))	('p.Thr158Ala', 'Mutation', 'rs387906778', (65, 76))	('threonine', 'Chemical', 'MESH:D013912', (46, 55))	('interferes', 'NegReg', (146, 156))	('results in', 'Reg', (13, 23))	('p.Thr158Ala', 'Var', (65, 76))	('hydrogen', 'Chemical', 'MESH:D006859', (180, 188))
87099	29642543	Patch clamp recordings of human embryonic kidney cells expressing the mutated GIRK4 p.Thr158Ala channel showed that the mutation results in a loss of selectivity for K+ and permissively allows the passage of Na+ resulting in membrane depolarization.	('embryonic kidney', 'Disease', 'MESH:D007674', (32, 48))	('loss', 'NegReg', (142, 146))	('passage of Na+', 'MPA', (197, 211))	('membrane depolarization', 'MPA', (225, 248))	('GIRK4', 'Gene', '3762', (78, 83))	('p.Thr158Ala', 'Var', (84, 95))	('GIRK4', 'Gene', (78, 83))	('p.Thr158Ala', 'Mutation', 'rs387906778', (84, 95))	('embryonic kidney', 'Disease', (32, 48))	('allows', 'Reg', (186, 192))	('selectivity for K+', 'MPA', (150, 168))	('permissively', 'MPA', (173, 185))	('human', 'Species', '9606', (26, 31))	('mutated', 'Var', (70, 77))
87101	29642543	Expression of GIRK4 p.Thr158Ala in the human adrenocortical carcinoma cell line (HAC15) caused a marked increase in aldosterone secretion that was dependent on membrane depolarization and Na+ and Ca2+ influx.	('increase', 'PosReg', (104, 112))	('GIRK4', 'Gene', (14, 19))	('Ca2+', 'Chemical', 'MESH:D000069285', (196, 200))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (45, 69))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (45, 69))	('HAC15', 'CellLine', 'CVCL:S898', (81, 86))	('aldosterone secretion', 'MPA', (116, 137))	('aldosterone', 'Chemical', 'MESH:D000450', (116, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('adrenocortical carcinoma', 'Disease', (45, 69))	('GIRK4', 'Gene', '3762', (14, 19))	('p.Thr158Ala', 'Var', (20, 31))	('human', 'Species', '9606', (39, 44))	('p.Thr158Ala', 'Mutation', 'rs387906778', (20, 31))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (104, 127))
87103	29642543	Notable is that over half of the patients described with FH type III (14 of 22 cases occurring in 7 of 12 families) carried mutations of the Gly151 residue (p.Gly151Glu or p.Gly151Arg) in the GlyTyrGly motif implicated in K+ selectivity.	('GlyTyrGly', 'Chemical', 'MESH:C078834', (192, 201))	('patients', 'Species', '9606', (33, 41))	('Gly151', 'Chemical', '-', (141, 147))	('FH type III', 'Disease', (57, 68))	('Gly151', 'Chemical', '-', (159, 165))	('p.Gly151Glu', 'Mutation', 'rs587777437', (157, 168))	('p.Gly151Arg', 'Mutation', 'rs386352319', (172, 183))	('p.Gly151Arg', 'Var', (172, 183))	('FH type III', 'Disease', 'MESH:D003480', (57, 68))	('Gly151', 'Chemical', '-', (174, 180))	('p.Gly151Glu', 'Var', (157, 168))
87104	29642543	Familial hyperaldosteronism type IV (FH type IV) is caused by gain-of-function mutations in Cav3.2, a T type Ca2+ channel encoded by CACNA1H.	('Familial hyperaldosteronism type IV', 'Disease', (0, 35))	('CACNA1H', 'Gene', '8912', (133, 140))	('Cav3.2', 'Gene', (92, 98))	('Cav3.2', 'Gene', '8912', (92, 98))	('FH type IV', 'Disease', 'OMIM:617027', (37, 47))	('Familial hyperaldosteronism type I', 'Phenotype', 'HP:0011739', (0, 34))	('Familial hyperaldosteronism type', 'Phenotype', 'HP:0011739', (0, 32))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (9, 27))	('FH type IV', 'Disease', (37, 47))	('Ca2+', 'Chemical', 'MESH:D000069285', (109, 113))	('gain-of-function', 'PosReg', (62, 78))	('CACNA1H', 'Gene', (133, 140))	('Familial hyperaldosteronism type IV', 'Disease', 'OMIM:617027', (0, 35))	('mutations', 'Var', (79, 88))
87106	29642543	identified five subjects with the same heterozygous mutation in CACNA1H encoding the Ca2+ voltage gated channel (Cav3.2) resulting in a Cav3.2 p.Met1549Val substitution.	('Ca2+', 'Chemical', 'MESH:D000069285', (85, 89))	('CACNA1H', 'Gene', '8912', (64, 71))	('Cav3.2', 'Gene', (113, 119))	('Cav3.2', 'Gene', (136, 142))	('p.Met1549Val', 'Var', (143, 155))	('Cav3.2', 'Gene', '8912', (113, 119))	('Cav3.2', 'Gene', '8912', (136, 142))	('p.Met1549Val', 'Mutation', 'rs786205050', (143, 155))	('CACNA1H', 'Gene', (64, 71))
87107	29642543	Comparisons of whole cell patch clamp recordings of Cav3.2 p.Met1549Val and wild-type Cav3.2 expressed in human embryonic kidney cells showed that the p.Met1549Val mutation causes an impairment of channel activation and inactivation.	('human', 'Species', '9606', (106, 111))	('p.Met1549Val', 'Mutation', 'rs786205050', (59, 71))	('Cav3.2', 'Gene', '8912', (86, 92))	('activation', 'PosReg', (205, 215))	('embryonic kidney', 'Disease', 'MESH:D007674', (112, 128))	('p.Met1549Val', 'Mutation', 'rs786205050', (151, 163))	('Cav3.2', 'Gene', (52, 58))	('p.Met1549Val', 'Var', (151, 163))	('Cav3.2', 'Gene', '8912', (52, 58))	('Cav3.2', 'Gene', (86, 92))	('channel', 'MPA', (197, 204))	('embryonic kidney', 'Disease', (112, 128))	('inactivation', 'MPA', (220, 232))
87109	29642543	Validation of this concept was subsequently demonstrated by the same group by expression of the Cav3.2 p.Met1549Val mutation in human adrenocortical (HAC15) cells which resulted in an increase in CYP11B2 gene transcription and aldosterone secretion relative to cells expressing the wild-type channel.	('transcription', 'MPA', (209, 222))	('p.Met1549Val', 'Mutation', 'rs786205050', (103, 115))	('increase', 'PosReg', (184, 192))	('HAC15', 'CellLine', 'CVCL:S898', (150, 155))	('Cav3.2', 'Gene', '8912', (96, 102))	('CYP11B2 gene', 'Gene', (196, 208))	('p.Met1549Val', 'Var', (103, 115))	('Cav3.2', 'Gene', (96, 102))	('human', 'Species', '9606', (128, 133))	('aldosterone', 'Chemical', 'MESH:D000450', (227, 238))	('aldosterone secretion', 'MPA', (227, 248))	('adrenocortical', 'Disease', (134, 148))	('adrenocortical', 'Disease', 'MESH:D018268', (134, 148))
87110	29642543	Following the discovery by Scholl, additional mutations in CACNA1H were described involving a substitution of the same Met1549 residue (Met1549Ile) or other amino acid residues (Ser196Leu, Val1951Glu and Pro2083Leu).	('Pro2083Leu', 'Var', (204, 214))	('Pro2083Leu', 'SUBSTITUTION', 'None', (204, 214))	('CACNA1H', 'Gene', (59, 66))	('Val1951Glu', 'SUBSTITUTION', 'None', (189, 199))	('Ser196Leu', 'Var', (178, 187))	('CACNA1H', 'Gene', '8912', (59, 66))	('Ser196Leu', 'SUBSTITUTION', 'None', (178, 187))	('Val1951Glu', 'Var', (189, 199))	('Met1549Ile', 'Var', (136, 146))	('Met1549Ile', 'Mutation', 'p.M1549I', (136, 146))
87112	29642543	in 2011 by exome sequencing, mutations in KCNJ5 were identified in 8 of 22 APA resulting in GIRK p.Gly151Arg or p.Leu168Arg mutations.	('KCNJ5', 'Gene', (42, 47))	('p.Leu168Arg', 'Mutation', 'rs386352318', (112, 123))	('p.Gly151Arg', 'Var', (97, 108))	('p.Gly151Arg', 'Mutation', 'rs386352319', (97, 108))	('p.Leu168Arg', 'Var', (112, 123))	('KCNJ5', 'Gene', '3762', (42, 47))	('PA', 'Phenotype', 'HP:0011736', (76, 78))
87113	29642543	Both mutations were demonstrated to interfere with the selectivity filter of the channel pore and result in membrane depolarization causing the opening of voltage gated Ca2+ channels in adrenal glomerulosa cells and Ca2+ influx.	('depolarization', 'NegReg', (117, 131))	('Ca2+', 'Chemical', 'MESH:D000069285', (216, 220))	('interfere', 'NegReg', (36, 45))	('mutations', 'Var', (5, 14))	('voltage gated Ca2+ channels', 'MPA', (155, 182))	('Ca2+', 'Chemical', 'MESH:D000069285', (169, 173))	('Ca2+ influx', 'MPA', (216, 227))	('opening', 'MPA', (144, 151))	('membrane', 'MPA', (108, 116))	('selectivity filter', 'MPA', (55, 73))
87114	29642543	Somatic KCNJ5 mutations are found at a prevalence of 40-50% although a higher prevalence has been reported in populations from Japan and China.	('mutations', 'Var', (14, 23))	('KCNJ5', 'Gene', (8, 13))	('KCNJ5', 'Gene', '3762', (8, 13))
87115	29642543	Following the description of the KCNJ5 mutations, the application of next generation sequencing rapidly identified additional somatic mutations associated with aldosterone overproduction in sporadic PA.	('aldosterone overproduction', 'MPA', (160, 186))	('aldosterone', 'Chemical', 'MESH:D000450', (160, 171))	('associated', 'Reg', (144, 154))	('mutations', 'Var', (39, 48))	('KCNJ5', 'Gene', (33, 38))	('mutations', 'Var', (134, 143))	('KCNJ5', 'Gene', '3762', (33, 38))	('PA', 'Phenotype', 'HP:0011736', (199, 201))
87116	29642543	These include heterozygous gain-of-function mutations in Cav1.3 (the alpha1D subunit of the L-type voltage-dependent calcium channel) encoded by CACNA1D and the ion transporters, Na+/K+-ATPase (encoded by ATP1A1) and Ca2+-ATPase (encoded by ATP2B3).	('ATPase', 'Gene', (222, 228))	('calcium', 'Chemical', 'MESH:D002118', (117, 124))	('ATP2B3', 'Gene', '492', (241, 247))	('CACNA1D', 'Gene', (145, 152))	('ATP1A1', 'Gene', (205, 211))	('Ca2+', 'Chemical', 'MESH:D000069285', (217, 221))	('ATPase', 'Gene', '1769', (186, 192))	('ATP2B3', 'Gene', (241, 247))	('Cav1.3', 'Gene', (57, 63))	('Cav1.3', 'Gene', '776', (57, 63))	('ATPase', 'Gene', '1769', (222, 228))	('gain-of-function', 'PosReg', (27, 43))	('ATPase', 'Gene', (186, 192))	('mutations', 'Var', (44, 53))	('ATP1A1', 'Gene', '476', (205, 211))	('CACNA1D', 'Gene', '776', (145, 152))
87117	29642543	These mutations result in an increase in intracellular Ca2+ concentration thereby causing an increase in transcription of the CYP11B2 gene that encodes aldosterone synthase.	('aldosterone synthase', 'Gene', (152, 172))	('aldosterone synthase', 'Gene', '1585', (152, 172))	('increase', 'PosReg', (93, 101))	('CYP11B2', 'Gene', (126, 133))	('Ca2+', 'Chemical', 'MESH:D000069285', (55, 59))	('increase', 'PosReg', (29, 37))	('transcription', 'MPA', (105, 118))	('mutations', 'Var', (6, 15))	('intracellular Ca2+ concentration', 'MPA', (41, 73))
87119	29642543	Despite these major advances, the mechanisms underlying the deregulated cell growth of APAs are probably not explained by somatic mutations and the GIRK4 Thr158Ala mutation does not enhance proliferation of adrenal cells in vitro.	('GIRK4', 'Gene', '3762', (148, 153))	('GIRK4', 'Gene', (148, 153))	('enhance', 'PosReg', (182, 189))	('APAs', 'Disease', (87, 91))	('Thr158Ala', 'Var', (154, 163))	('PA', 'Phenotype', 'HP:0011736', (88, 90))	('Thr158Ala', 'SUBSTITUTION', 'None', (154, 163))
87121	29642543	However, another study of APA transcriptomes reported two distinct and opposing expression profiles for genes encoding steroidogenic enzymes with CYP11B2 displaying increased or decreased expression levels with respect to normal adrenal tissue.	('decreased', 'NegReg', (178, 187))	('CYP11B2', 'Var', (146, 153))	('expression levels', 'MPA', (188, 205))	('PA', 'Phenotype', 'HP:0011736', (27, 29))	('steroid', 'Chemical', 'MESH:D013256', (119, 126))
87123	29642543	In fact, these may contain aldosterone-producing cell clusters (APCC) that express high levels of CYP11B2 with somatic CACNA1D, ATP1A1 or ATP2B3 mutations.	('ATP2B3', 'Gene', '492', (138, 144))	('aldosterone', 'Chemical', 'MESH:D000450', (27, 38))	('ATP2B3', 'Gene', (138, 144))	('CACNA1D', 'Gene', '776', (119, 126))	('ATP1A1', 'Gene', '476', (128, 134))	('CACNA1D', 'Gene', (119, 126))	('CYP11B2', 'Var', (98, 105))	('ATP1A1', 'Gene', (128, 134))
87124	29642543	Conversely large APA with low expression of CYP11B2 that give rise to inappropriate aldosterone production might occur.	('aldosterone', 'Chemical', 'MESH:D000450', (84, 95))	('PA', 'Phenotype', 'HP:0011736', (18, 20))	('inappropriate aldosterone production', 'MPA', (70, 106))	('aldosterone production', 'Phenotype', 'HP:0000859', (84, 106))	('CYP11B2', 'Var', (44, 51))	('APA', 'Disease', (17, 20))
87125	29642543	APAs carrying KCNJ5 mutations have been widely reported to comprise predominantly large lipid-rich ZF-like cells (Figure 2).	('KCNJ5', 'Gene', (14, 19))	('KCNJ5', 'Gene', '3762', (14, 19))	('PA', 'Phenotype', 'HP:0011736', (1, 3))	('lipid', 'Chemical', 'MESH:D008055', (88, 93))	('mutations', 'Var', (20, 29))
87126	29642543	Some studies have also described a predominance of small compact ZG-like cells in APA harbouring CACNA1D, ATP1A1 or ATP2B3 mutations and somatic APA genotype is associated with plasma steroid profiles.	('small compact ZG-like cells', 'CPA', (51, 78))	('PA', 'Phenotype', 'HP:0011736', (83, 85))	('associated', 'Reg', (161, 171))	('ATP1A1', 'Gene', '476', (106, 112))	('CACNA1D', 'Gene', (97, 104))	('PA', 'Phenotype', 'HP:0011736', (146, 148))	('CACNA1D', 'Gene', '776', (97, 104))	('ATP1A1', 'Gene', (106, 112))	('plasma steroid profiles', 'MPA', (177, 200))	('ATP2B3', 'Gene', '492', (116, 122))	('steroid', 'Chemical', 'MESH:D013256', (184, 191))	('mutations', 'Var', (123, 132))	('ATP2B3', 'Gene', (116, 122))
87128	29642543	No differences in the transcriptome profiles of APA with and without KCNJ5 mutations were initially described.	('PA', 'Phenotype', 'HP:0011736', (49, 51))	('KCNJ5', 'Gene', '3762', (69, 74))	('mutations', 'Var', (75, 84))	('KCNJ5', 'Gene', (69, 74))
87129	29642543	However, later studies reported distinct expression profiles of APA with KCNJ5 mutations compared with APA without KCNJ5 mutations (with higher CYP11B2 expression in the tumours with KCNJ5 mutations).	('tumours', 'Disease', 'MESH:D009369', (170, 177))	('tumours', 'Disease', (170, 177))	('KCNJ5', 'Gene', (115, 120))	('higher', 'PosReg', (137, 143))	('KCNJ5', 'Gene', (183, 188))	('CYP11B2', 'Gene', (144, 151))	('KCNJ5', 'Gene', (73, 78))	('KCNJ5', 'Gene', '3762', (73, 78))	('KCNJ5', 'Gene', '3762', (115, 120))	('PA', 'Phenotype', 'HP:0011736', (65, 67))	('KCNJ5', 'Gene', '3762', (183, 188))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('expression', 'MPA', (152, 162))	('tumours', 'Phenotype', 'HP:0002664', (170, 177))	('mutations', 'Var', (79, 88))	('PA', 'Phenotype', 'HP:0011736', (104, 106))
87130	29642543	Different expression profiles were reported in APA with ATP1A1 and ATP2B3 mutations relative to APA with KCNJ5 mutations (with higher CYP11B2 expression in the tumors with ATP1A1 and ATP2B3 mutations).	('ATP1A1', 'Gene', '476', (172, 178))	('ATP2B3', 'Gene', '492', (183, 189))	('higher', 'PosReg', (127, 133))	('ATP2B3', 'Gene', (183, 189))	('tumors', 'Disease', (160, 166))	('KCNJ5', 'Gene', '3762', (105, 110))	('PA', 'Phenotype', 'HP:0011736', (48, 50))	('CYP11B2', 'Gene', (134, 141))	('PA', 'Phenotype', 'HP:0011736', (97, 99))	('ATP1A1', 'Gene', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('ATP1A1', 'Gene', '476', (56, 62))	('ATP2B3', 'Gene', '492', (67, 73))	('expression', 'MPA', (142, 152))	('ATP2B3', 'Gene', (67, 73))	('mutations', 'Var', (74, 83))	('ATP1A1', 'Gene', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('KCNJ5', 'Gene', (105, 110))
87132	29642543	If CYP17A1 and CYP11B2 are expressed in the same cell then cortisol can be metabolized further to produce the hybrid steroids 18-hydroxycortisol and 18-oxocortisol.	('18-oxocortisol', 'Chemical', 'MESH:C038135', (149, 163))	('cortisol', 'Chemical', 'MESH:D006854', (136, 144))	('steroids', 'Chemical', 'MESH:D013256', (117, 125))	('cortisol', 'Chemical', 'MESH:D006854', (155, 163))	('CYP11B2', 'Var', (15, 22))	('18-hydroxycortisol', 'Chemical', 'MESH:C033689', (126, 144))	('cortisol', 'Chemical', 'MESH:D006854', (59, 67))	('18-hydroxycortisol', 'MPA', (126, 144))	('CYP17A1', 'Gene', (3, 10))	('CYP17A1', 'Gene', '1586', (3, 10))
87133	29642543	Higher levels of these hybrid steroids are associated with FH type I and FH type III (although not in all cases) and in patients with an APA with a KCNJ5 mutation.	('FH type I', 'Disease', 'MESH:C563177', (59, 68))	('FH type III', 'Disease', (73, 84))	('FH type I', 'Disease', (59, 68))	('PA', 'Phenotype', 'HP:0011736', (138, 140))	('KCNJ5', 'Gene', (148, 153))	('FH type I', 'Disease', 'MESH:C563177', (73, 82))	('mutation', 'Var', (154, 162))	('FH type III', 'Disease', 'MESH:D003480', (73, 84))	('KCNJ5', 'Gene', '3762', (148, 153))	('Higher', 'PosReg', (0, 6))	('patients', 'Species', '9606', (120, 128))	('levels', 'MPA', (7, 13))	('steroids', 'Chemical', 'MESH:D013256', (30, 38))
87142	29642543	Therefore, the presence of activating APA CTNNB1 mutations might contribute to an abnormal receptor activation.	('mutations', 'Var', (49, 58))	('activating', 'PosReg', (27, 37))	('PA', 'Phenotype', 'HP:0011736', (39, 41))	('CTNNB1', 'Gene', (42, 48))	('receptor activation', 'MPA', (91, 110))	('CTNNB1', 'Gene', '1499', (42, 48))
87143	29642543	NEFM, encoding the medium neurofilament protein, is highly upregulated only in APAs without KCNJ5 mutations and is selectively expressed in the ZG and in APA comprised of predominantly ZG cells.	('PA', 'Phenotype', 'HP:0011736', (155, 157))	('PA', 'Phenotype', 'HP:0011736', (80, 82))	('mutations', 'Var', (98, 107))	('upregulated', 'PosReg', (59, 70))	('NEFM', 'Gene', (0, 4))	('KCNJ5', 'Gene', (92, 97))	('NEFM', 'Gene', '4741', (0, 4))	('KCNJ5', 'Gene', '3762', (92, 97))
87144	29642543	Dopamine regulates aldosterone production via activation of its G-protein-coupled receptor (GPCR) subtypes and silencing of NEFM amplified aldosterone stimulation by a DR1 (dopamine receptor subunit 1) agonist and aldosterone secretion in response to the DR1 agonist was greater in primary cultures of APAs composed of primarily ZF cells compared with cultures of APAs with ZG cells.	('DR1', 'Gene', (255, 258))	('silencing', 'Var', (111, 120))	('NEFM', 'Gene', (124, 128))	('amplified aldosterone stimulation', 'Phenotype', 'HP:0000859', (129, 162))	('PA', 'Phenotype', 'HP:0011736', (303, 305))	('aldosterone', 'Chemical', 'MESH:D000450', (214, 225))	('PA', 'Phenotype', 'HP:0011736', (365, 367))	('aldosterone production', 'MPA', (19, 41))	('Dopamine', 'Chemical', 'MESH:D004298', (0, 8))	('amplified', 'PosReg', (129, 138))	('NEFM', 'Gene', '4741', (124, 128))	('DR1', 'Gene', (168, 171))	('dopamine receptor subunit 1', 'Gene', (173, 200))	('dopamine receptor subunit 1', 'Gene', '1810', (173, 200))	('aldosterone', 'Chemical', 'MESH:D000450', (19, 30))	('aldosterone', 'Chemical', 'MESH:D000450', (139, 150))	('aldosterone production', 'Phenotype', 'HP:0000859', (19, 41))	('aldosterone stimulation', 'MPA', (139, 162))	('DR1', 'Gene', '1810', (168, 171))	('DR1', 'Gene', '1810', (255, 258))
87146	29642543	Analysis of the methylome of APAs demonstrated hypomethylation of GPCR genes and a strong association of promoter hypomethylation of the HTR4 and PTGER1 genes with the upregulation of mRNA levels, validated by real-time PCR, was demonstrated in APAs compared with non-functioning adrenocortical adenomas.	('PTGER1', 'Gene', '5731', (146, 152))	('hypomethylation', 'Var', (47, 62))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (280, 303))	('adrenocortical adenomas', 'Disease', (280, 303))	('mRNA levels', 'MPA', (184, 195))	('PA', 'Phenotype', 'HP:0011736', (246, 248))	('PA', 'Phenotype', 'HP:0011736', (30, 32))	('promoter', 'MPA', (105, 113))	('PTGER1', 'Gene', (146, 152))	('APAs', 'Disease', (245, 249))	('HTR4', 'Gene', '3360', (137, 141))	('upregulation', 'PosReg', (168, 180))	('HTR4', 'Gene', (137, 141))	('GPCR', 'Gene', (66, 70))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (280, 303))
87148	29642543	The most hypomethylated promoter in APA is the PCP4 (encoding purkinje cell protein 4) promoter with demethylation associated with enhanced gene transcription.	('purkinje cell protein 4', 'Gene', (62, 85))	('PA', 'Phenotype', 'HP:0011736', (37, 39))	('PCP4', 'Gene', '5121', (47, 51))	('PCP4', 'Gene', (47, 51))	('purkinje cell protein 4', 'Gene', '5121', (62, 85))	('enhanced', 'PosReg', (131, 139))	('demethylation', 'Var', (101, 114))	('gene transcription', 'MPA', (140, 158))
87153	29642543	Analysis of a larger sample set of tumours showed that VSNL1 was overexpressed in APAs carrying a KCNJ5 mutation compared with those APA without a KCNJ5 mutation.	('tumours', 'Disease', (35, 42))	('KCNJ5', 'Gene', (147, 152))	('KCNJ5', 'Gene', '3762', (98, 103))	('VSNL1', 'Gene', (55, 60))	('VSNL1', 'Gene', '7447', (55, 60))	('PA', 'Phenotype', 'HP:0011736', (83, 85))	('overexpressed', 'PosReg', (65, 78))	('KCNJ5', 'Gene', '3762', (147, 152))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('PA', 'Phenotype', 'HP:0011736', (134, 136))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('mutation', 'Var', (104, 112))	('KCNJ5', 'Gene', (98, 103))	('tumours', 'Disease', 'MESH:D009369', (35, 42))
87155	29642543	The expression of the VSNL1 protein in an APA (carrying a KCNJ5 mutation) that displays strong CYP11B2 immunostaining is shown in Figure 3.	('KCNJ5', 'Gene', (58, 63))	('mutation', 'Var', (64, 72))	('VSNL1', 'Gene', (22, 27))	('KCNJ5', 'Gene', '3762', (58, 63))	('PA', 'Phenotype', 'HP:0011736', (43, 45))	('VSNL1', 'Gene', '7447', (22, 27))
87157	29642543	CALN1 was shown to potentiate aldosterone production and silencing CALN1 led to a decrease in Ca2+ storage in the endoplasmic reticulum and abrogated angiotensin II-mediated aldosterone secretion in an adrenocortical carcinoma cell line.	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (202, 226))	('aldosterone', 'Chemical', 'MESH:D000450', (174, 185))	('CALN1', 'Gene', '83698', (67, 72))	('aldosterone production', 'MPA', (30, 52))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (202, 226))	('potentiate', 'PosReg', (19, 29))	('Ca2+ storage in the endoplasmic reticulum', 'MPA', (94, 135))	('aldosterone', 'Chemical', 'MESH:D000450', (30, 41))	('angiotensin II', 'Gene', (150, 164))	('adrenocortical carcinoma', 'Disease', (202, 226))	('CALN1', 'Gene', '83698', (0, 5))	('abrogated', 'NegReg', (140, 149))	('CALN1', 'Gene', (67, 72))	('decrease', 'NegReg', (82, 90))	('aldosterone production', 'Phenotype', 'HP:0000859', (30, 52))	('CALN1', 'Gene', (0, 5))	('angiotensin II', 'Gene', '183', (150, 164))	('silencing', 'Var', (57, 66))	('Ca2+', 'Chemical', 'MESH:D000069285', (94, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('potentiate aldosterone production', 'Phenotype', 'HP:0000859', (19, 52))
87161	29642543	GSTA1 (encoding glutathione-S-transferase, an enzyme that protects cells from reactive oxygen species, ROS) gene expression is inversely correlated with the level of aldosterone production in APAs with a KCNJ5 mutation and appears to regulate aldosterone secretion via ROS and Ca2+ signalling.	('PA', 'Phenotype', 'HP:0011736', (193, 195))	('mutation', 'Var', (210, 218))	('GSTA1', 'Gene', '2938', (0, 5))	('aldosterone', 'Chemical', 'MESH:D000450', (166, 177))	('ROS', 'Chemical', 'MESH:D017382', (269, 272))	('aldosterone production', 'Phenotype', 'HP:0000859', (166, 188))	('ROS', 'Chemical', 'MESH:D017382', (103, 106))	('KCNJ5', 'Gene', (204, 209))	('regulate', 'Reg', (234, 242))	('glutathione-S-transferase', 'Gene', (16, 41))	('correlated', 'Reg', (137, 147))	('aldosterone', 'MPA', (243, 254))	('aldosterone', 'Chemical', 'MESH:D000450', (243, 254))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (78, 101))	('KCNJ5', 'Gene', '3762', (204, 209))	('Ca2+', 'Chemical', 'MESH:D000069285', (277, 281))	('level', 'MPA', (157, 162))	('glutathione-S-transferase', 'Gene', '373156', (16, 41))	('GSTA1', 'Gene', (0, 5))
87162	29642543	GSTA1 overexpression suppressed aldosterone biosynthesis, while silencing of GSTA1 increased aldosterone production through increasing ROS, superoxide, H2O2 levels, Ca2+ influx and the expression of CAMK1 (encoding Ca2+/calmodulin dependent protein kinase 1) and the transcription factors NR4A1 (also called NGFIB) and NR4A2 that regulate CYP11B2 gene expression.	('aldosterone', 'Chemical', 'MESH:D000450', (32, 43))	('H2O2 levels', 'MPA', (152, 163))	('aldosterone production', 'MPA', (93, 115))	('increased aldosterone', 'Phenotype', 'HP:0000859', (83, 104))	('calmodulin', 'Gene', '801', (220, 230))	('silencing', 'Var', (64, 73))	('suppressed aldosterone', 'Phenotype', 'HP:0004319', (21, 43))	('GSTA1', 'Gene', '2938', (0, 5))	('increased', 'PosReg', (83, 92))	('ROS', 'MPA', (135, 138))	('CAMK1', 'Gene', '8536', (199, 204))	('superoxide', 'Chemical', 'MESH:D013481', (140, 150))	('GSTA1', 'Gene', (77, 82))	('calmodulin', 'Gene', (220, 230))	('Ca2+', 'Chemical', 'MESH:D000069285', (215, 219))	('ROS', 'Chemical', 'MESH:D017382', (135, 138))	('aldosterone', 'Chemical', 'MESH:D000450', (93, 104))	('increasing', 'PosReg', (124, 134))	('CAMK1', 'Gene', (199, 204))	('NGFIB', 'Gene', '3164', (308, 313))	('CYP11B2', 'Gene', (339, 346))	('aldosterone production', 'Phenotype', 'HP:0000859', (93, 115))	('suppressed', 'NegReg', (21, 31))	('H2O2', 'Chemical', 'MESH:D006861', (152, 156))	('GSTA1', 'Gene', '2938', (77, 82))	('Ca2+', 'Chemical', 'MESH:D000069285', (165, 169))	('NR4A2', 'Gene', (319, 324))	('NGFIB', 'Gene', (308, 313))	('aldosterone biosynthesis', 'MPA', (32, 56))	('GSTA1', 'Gene', (0, 5))	('Ca2+ influx', 'MPA', (165, 176))	('superoxide', 'MPA', (140, 150))
87165	29642543	Overexpression of TDGF1 in NCI H295R adrenal cells activated the PI3K-Akt signalling pathway and led to an increase in aldosterone production, indicating a potential role in APA pathophysiology.	('aldosterone production', 'Phenotype', 'HP:0000859', (119, 141))	('TDGF1', 'Gene', '6997', (18, 23))	('TDGF1', 'Gene', (18, 23))	('NCI H295R', 'CellLine', 'CVCL:0458', (27, 36))	('increase', 'PosReg', (107, 115))	('Akt', 'Gene', (70, 73))	('aldosterone', 'Chemical', 'MESH:D000450', (119, 130))	('Overexpression', 'Var', (0, 14))	('Akt', 'Gene', '207', (70, 73))	('aldosterone production', 'MPA', (119, 141))	('activated', 'PosReg', (51, 60))	('PA', 'Phenotype', 'HP:0011736', (175, 177))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (107, 130))
87166	29642543	The activation of PI3K/Akt mTOR signalling, a pathway with a known role in cell proliferation, was also reported in patients with PA. Wnt plays a key role in the development of the adrenal cortex and the dysregulation of this signalling pathway is associated with tumorigenesis.	('tumorigenesis', 'Disease', (264, 277))	('Akt', 'Gene', '207', (23, 26))	('patients', 'Species', '9606', (116, 124))	('mTOR', 'Gene', (27, 31))	('associated', 'Reg', (248, 258))	('PA', 'Phenotype', 'HP:0011736', (130, 132))	('Akt', 'Gene', (23, 26))	('dysregulation', 'Var', (204, 217))	('activation', 'PosReg', (4, 14))	('mTOR', 'Gene', '2475', (27, 31))
87169	29642543	Mice with an ablation of Sfrp2 display enhanced aldosterone production.	('aldosterone production', 'Phenotype', 'HP:0000859', (48, 70))	('Sfrp2', 'Gene', (25, 30))	('ablation', 'Var', (13, 21))	('Sfrp2', 'Gene', '20319', (25, 30))	('Mice', 'Species', '10090', (0, 4))	('aldosterone', 'Chemical', 'MESH:D000450', (48, 59))	('enhanced aldosterone', 'Phenotype', 'HP:0000859', (39, 59))	('aldosterone production', 'MPA', (48, 70))	('enhanced', 'PosReg', (39, 47))
87170	29642543	beta-catenin appears to mediate aldosterone production by increasing the transcription of several genes including AT1R, CYP21 and CYP11B2 as well as upregulating expression of transcription factors NURR1 (NR4A2) and NUR77 (NR4A1).	('aldosterone', 'Chemical', 'MESH:D000450', (32, 43))	('transcription', 'MPA', (73, 86))	('CYP21', 'Gene', (120, 125))	('NUR77', 'Gene', (216, 221))	('increasing', 'PosReg', (58, 68))	('expression', 'MPA', (162, 172))	('aldosterone production', 'MPA', (32, 54))	('AT1R', 'Gene', (114, 118))	('CYP11B2', 'Var', (130, 137))	('beta-catenin', 'Protein', (0, 12))	('AT1R', 'Gene', '11610', (114, 118))	('NUR77', 'Gene', '15370', (216, 221))	('CYP21', 'Gene', '13079', (120, 125))	('aldosterone production', 'Phenotype', 'HP:0000859', (32, 54))	('upregulating', 'PosReg', (149, 161))	('NURR1', 'Gene', (198, 203))
87171	29642543	NPNT (nephronectin), a secreted matrix protein, was most highly expressed in APAs with a ZG phenotype with CTNNB1 mutations.	('CTNNB1', 'Gene', '1499', (107, 113))	('mutations', 'Var', (114, 123))	('highly', 'PosReg', (57, 63))	('NPNT', 'Gene', (0, 4))	('PA', 'Phenotype', 'HP:0011736', (78, 80))	('CTNNB1', 'Gene', (107, 113))	('nephronectin', 'Gene', (6, 18))	('NPNT', 'Gene', '255743', (0, 4))	('nephronectin', 'Gene', '255743', (6, 18))
87173	29642543	These studies show that aberrant Wnt/beta-catenin pathway activation is associated with APA development and suggests that the Wnt/beta-catenin signalling mediates aldosterone production at multiple levels.	('Wnt/beta-catenin pathway', 'Pathway', (33, 57))	('aberrant', 'Var', (24, 32))	('associated', 'Reg', (72, 82))	('PA', 'Phenotype', 'HP:0011736', (89, 91))	('aldosterone production', 'Phenotype', 'HP:0000859', (163, 185))	('activation', 'PosReg', (58, 68))	('aldosterone', 'Chemical', 'MESH:D000450', (163, 174))	('APA development', 'CPA', (88, 103))
87176	29642543	Five common SNPs of the KCNJ5 gene (rs6590357, rs4937391, rs3740835, rs2604204, and rs11221497) were found in patients with sporadic PA and essential hypertension and a significant association of the rs2604204 variant with sporadic PA in Chinese males was found indicating a potential role for this polymorphism in the pathogenesis of sporadic PA in this specific subgroup of patients.	('rs2604204', 'Mutation', 'rs2604204', (200, 209))	('sporadic PA', 'Disease', (335, 346))	('rs6590357', 'Var', (36, 45))	('PA', 'Phenotype', 'HP:0011736', (344, 346))	('sporadic PA', 'Disease', (223, 234))	('PA', 'Phenotype', 'HP:0011736', (232, 234))	('hypertension', 'Phenotype', 'HP:0000822', (150, 162))	('rs2604204', 'Var', (200, 209))	('rs11221497', 'Var', (84, 94))	('rs4937391', 'Mutation', 'rs4937391', (47, 56))	('rs3740835', 'Var', (58, 67))	('rs11221497', 'Mutation', 'rs11221497', (84, 94))	('KCNJ5', 'Gene', '3762', (24, 29))	('rs4937391', 'Var', (47, 56))	('rs2604204', 'Var', (69, 78))	('rs2604204', 'Mutation', 'rs2604204', (69, 78))	('patients', 'Species', '9606', (376, 384))	('sporadic PA', 'Disease', (124, 135))	('PA', 'Phenotype', 'HP:0011736', (133, 135))	('rs3740835', 'Mutation', 'rs3740835', (58, 67))	('hypertension', 'Disease', 'MESH:D006973', (150, 162))	('hypertension', 'Disease', (150, 162))	('rs6590357', 'Mutation', 'rs6590357', (36, 45))	('patients', 'Species', '9606', (110, 118))	('KCNJ5', 'Gene', (24, 29))
87179	29642543	APAs with a low level of CYP11B2 gene transcription are associated with a longer known duration of hypertension and a lower rate of long-term cure.	('CYP11B2', 'Var', (25, 32))	('hypertension', 'Disease', (99, 111))	('PA', 'Phenotype', 'HP:0011736', (1, 3))	('hypertension', 'Phenotype', 'HP:0000822', (99, 111))	('hypertension', 'Disease', 'MESH:D006973', (99, 111))
87183	29642543	In a prospective study by the TAIPAI (Taiwan Primary Aldosteronsim Investigation study group) of 108 patients that were divided into KCNJ5 mutated and non-mutated groups, patients with an APA carrying a KCNJ5 mutation aged between 37 and 60 years may have an advantage in blood pressure response to surgery but mutation status is not associated with an improvement in arterial stiffness.	('KCNJ5', 'Gene', (203, 208))	('patients', 'Species', '9606', (101, 109))	('KCNJ5', 'Gene', '3762', (133, 138))	('blood pressure response to surgery', 'MPA', (272, 306))	('PA', 'Phenotype', 'HP:0011736', (189, 191))	('PA', 'Phenotype', 'HP:0011736', (33, 35))	('KCNJ5', 'Gene', '3762', (203, 208))	('stiffness', 'Disease', 'MESH:D016750', (377, 386))	('patients', 'Species', '9606', (171, 179))	('mutation', 'Var', (209, 217))	('KCNJ5', 'Gene', (133, 138))	('stiffness', 'Disease', (377, 386))	('advantage', 'PosReg', (259, 268))	('Taiwan Primary Aldosteronsim', 'Phenotype', 'HP:0011739', (38, 66))
87184	29642543	Cardiovascular complications before and after unilateral adrenalectomy in patients harboring APAs with and without KCNJ5 gene mutations were evaluated in a Japanese population.	('PA', 'Phenotype', 'HP:0011736', (94, 96))	('KCNJ5', 'Gene', (115, 120))	('Cardiovascular complications', 'Disease', (0, 28))	('Cardiovascular complications', 'Disease', 'MESH:D002318', (0, 28))	('patients', 'Species', '9606', (74, 82))	('KCNJ5', 'Gene', '3762', (115, 120))	('Cardiovascular complications', 'Phenotype', 'HP:0001626', (0, 28))	('mutations', 'Var', (126, 135))
87185	29642543	The KCNJ5-mutated group displayed a significant improvement in left ventricular mass index which was independently associated with the presence of APA KCNJ5 mutations whereas the group without KCNJ5 mutations had no such improvement.	('KCNJ5', 'Gene', (151, 156))	('improvement', 'PosReg', (48, 59))	('PA', 'Phenotype', 'HP:0011736', (148, 150))	('KCNJ5', 'Gene', '3762', (4, 9))	('left ventricular mass index', 'MPA', (63, 90))	('KCNJ5', 'Gene', '3762', (151, 156))	('mutations', 'Var', (157, 166))	('KCNJ5', 'Gene', (193, 198))	('KCNJ5', 'Gene', '3762', (193, 198))	('KCNJ5', 'Gene', (4, 9))
87186	29642543	A higher left ventricular mass index and plasma aldosterone concentration in patients with APA KCNJ5 mutations relative to those without KCNJ5 mutations has also been reported.	('higher', 'PosReg', (2, 8))	('KCNJ5', 'Gene', (137, 142))	('mutations', 'Var', (101, 110))	('KCNJ5', 'Gene', '3762', (137, 142))	('KCNJ5', 'Gene', '3762', (95, 100))	('plasma aldosterone concentration', 'Phenotype', 'HP:0000859', (41, 73))	('PA', 'Phenotype', 'HP:0011736', (92, 94))	('patients', 'Species', '9606', (77, 85))	('left ventricular mass index', 'MPA', (9, 36))	('plasma aldosterone concentration', 'MPA', (41, 73))	('aldosterone', 'Chemical', 'MESH:D000450', (48, 59))	('KCNJ5', 'Gene', (95, 100))
87187	29642543	Despite the increased cardiac damage, patients with KCNJ5 mutations exhibited a decrease of blood pressure and plasma aldosterone concentrations and a regression of left ventricular mass index similar to the KCNJ5 wild type group after adrenalectomy.	('mutations', 'Var', (58, 67))	('cardiac damage', 'Disease', (22, 36))	('plasma aldosterone concentration', 'Phenotype', 'HP:0000859', (111, 143))	('KCNJ5', 'Gene', (52, 57))	('blood pressure', 'MPA', (92, 106))	('left ventricular mass index', 'MPA', (165, 192))	('plasma aldosterone concentrations', 'MPA', (111, 144))	('plasma aldosterone concentrations', 'Phenotype', 'HP:0000859', (111, 144))	('increased', 'PosReg', (12, 21))	('KCNJ5', 'Gene', '3762', (52, 57))	('cardiac damage', 'Disease', 'MESH:D006331', (22, 36))	('KCNJ5', 'Gene', (208, 213))	('decrease of blood pressure', 'Phenotype', 'HP:0002615', (80, 106))	('patients', 'Species', '9606', (38, 46))	('regression', 'NegReg', (151, 161))	('aldosterone', 'Chemical', 'MESH:D000450', (118, 129))	('KCNJ5', 'Gene', '3762', (208, 213))	('decrease', 'NegReg', (80, 88))
87188	29642543	Another study reported an association of APA KCNJ5 mutations with lower blood pressure and the higher likelihood of cure of PA by adrenalectomy relative to patients with APA without KCNJ5 mutations.	('patients', 'Species', '9606', (156, 164))	('PA', 'Phenotype', 'HP:0011736', (124, 126))	('mutations', 'Var', (51, 60))	('KCNJ5', 'Gene', (182, 187))	('lower blood pressure', 'Phenotype', 'HP:0002615', (66, 86))	('KCNJ5', 'Gene', (45, 50))	('lower', 'NegReg', (66, 71))	('KCNJ5', 'Gene', '3762', (182, 187))	('KCNJ5', 'Gene', '3762', (45, 50))	('PA', 'Phenotype', 'HP:0011736', (42, 44))	('blood pressure', 'MPA', (72, 86))	('PA', 'Phenotype', 'HP:0011736', (171, 173))
87190	29642543	Somatic mutations have been identified in ion channels and transporters that alter intracellular ion homeostasis and drive the constitutive aldosterone production in over half of aldosterone-producing adenomas.	('alter', 'Reg', (77, 82))	('adenomas', 'Disease', (201, 209))	('intracellular ion homeostasis', 'MPA', (83, 112))	('aldosterone', 'Chemical', 'MESH:D000450', (140, 151))	('drive', 'Reg', (117, 122))	('mutations', 'Var', (8, 17))	('aldosterone', 'Chemical', 'MESH:D000450', (179, 190))	('aldosterone production', 'Phenotype', 'HP:0000859', (140, 162))	('adenomas', 'Disease', 'MESH:D000236', (201, 209))	('constitutive', 'MPA', (127, 139))
87237	29147395	Even though there is no adequate data on the role of adjuvant radiotherapy, to reduce the risk of local recurrence which is highest in the first 2 years, German ACC registry recommends adjuvant radiotherapy be started no later than 3 months after surgery for all patients with microscopically incomplete (R1 or R2) or uncertain (Rx) margin status, and for those with stage III disease (ENSAT criteria).	('ACC', 'Gene', (161, 164))	('patients', 'Species', '9606', (263, 271))	('R1', 'Var', (305, 307))	('man', 'Species', '9606', (157, 160))	('ACC', 'Gene', '31', (161, 164))
87240	29147395	EDP plus mitotane is shown to have higher rates of tumor response and longer median progression-free survival than steptozotocin plus mitotane in the first international randomized trial in locally advanced and metastatic adrenocortical carcinoma treatment (FIRM-ACT) trial.	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mitotane', 'Chemical', 'MESH:D008939', (134, 142))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (222, 246))	('tumor', 'Disease', (51, 56))	('adrenocortical carcinoma', 'Disease', (222, 246))	('EDP', 'Var', (0, 3))	('steptozotocin', 'Chemical', '-', (115, 128))	('mitotane', 'Var', (9, 17))	('EDP', 'Chemical', '-', (0, 3))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (222, 246))	('higher', 'PosReg', (35, 41))	('mitotane', 'Chemical', 'MESH:D008939', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
87313	27504106	In the 26 R0 patients, the univariate analysis indicated that ACC recurrence was positively associated with tumor size (HR 1.32, 95% CI 1.12-1.64; p = 0.007), ki-67 (HR 1.06, 95% CI 1.02-1.11; p = 0.009), and advanced stage at diagnosis (III-IV vs. I-II: HR 6.51, 95% CI 1.65-24.68; p = 0.006) (Table 4).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Disease', (108, 113))	('ki-67', 'Var', (159, 164))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('ACC', 'Disease', (62, 65))
87322	27504106	In the complete series of 32 patients, the univariate analysis indicated that poor survival was associated with positive margins of resection (HR 10.61, 95% CI 3.02-38.31; p < 0.001), ki-67 (HR 1.04 95% CI 1.01-1.07; p = 0.01), and advanced stage (III-IV) at diagnosis (HR 11.31, 95% CI 1.45-87.76; p = 0.02).	('positive', 'Var', (112, 120))	('patients', 'Species', '9606', (29, 37))	('poor', 'NegReg', (78, 82))	('ki-67', 'Var', (184, 189))	('survival', 'MPA', (83, 91))
87352	27504106	Recently, genomic studies led to the identification of genetic and epigenetic alterations characterizing subgroups of tumors with activation of specific molecular pathway patterns and with different clinical outcome.	('epigenetic alterations', 'Var', (67, 89))	('activation', 'PosReg', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('genetic', 'Var', (55, 62))	('tumors', 'Disease', (118, 124))	('molecular pathway', 'Pathway', (153, 170))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
87361	26848413	An Unusual Recurrence of Signet Ring Cell Gastric Adenocarcinoma Treated by Right Hemicolectomy, Pancreaticoduodenectomy, and IVC Resection: Controversies and Dilemmas of Following Standard Treatment Pathways We present the case of a 67-year-old male patient with a past history of previously resected T3 right adrenocortical carcinoma and T3N1 signet ring cell adenocarcinoma of the stomach who presented with recurrence of gastric cancer in the form of a large solitary mass in the right abdomen.	('cancer', 'Phenotype', 'HP:0002664', (433, 439))	('adenocarcinoma', 'Disease', 'MESH:D000230', (362, 376))	('T3N1', 'Var', (340, 344))	('right adrenocortical carcinoma', 'Disease', 'MESH:D018268', (305, 335))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('patient', 'Species', '9606', (251, 258))	('gastric cancer', 'Disease', (425, 439))	('adenocarcinoma of the stomach', 'Phenotype', 'HP:0006753', (362, 391))	('carcinoma', 'Phenotype', 'HP:0030731', (367, 376))	('gastric cancer', 'Disease', 'MESH:D013274', (425, 439))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('N1', 'CellLine', 'CVCL:D425', (342, 344))	('Adenocarcinoma', 'Disease', (50, 64))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (311, 335))	('adenocarcinoma', 'Disease', (362, 376))	('gastric cancer', 'Phenotype', 'HP:0012126', (425, 439))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (50, 64))	('right adrenocortical carcinoma', 'Disease', (305, 335))
87511	25097323	In patients with co-secretion, the level of hybrid steroids like 18-hydroxy-cortisol (18-OH-F) is much higher than in pure aldosterone secreting tumors.	('18-OH-F', 'Chemical', '-', (86, 93))	('steroids', 'Chemical', 'MESH:D013256', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('aldosterone', 'Chemical', 'MESH:D000450', (123, 134))	('level', 'MPA', (35, 40))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('18-hydroxy-cortisol', 'Chemical', 'MESH:C033689', (65, 84))	('patients', 'Species', '9606', (3, 11))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('higher', 'PosReg', (103, 109))	('co-secretion', 'Var', (17, 29))
87512	25097323	This phenomenon of co-secretion may be explained by the unequal crossover between the genes for 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) resulting in a chimerical CYP11B1/CYP11B2 gene.	('CYP11B2', 'Gene', (194, 201))	('aldosterone synthase', 'Gene', (129, 149))	('CYP11B2', 'Gene', '1585', (194, 201))	('CYP11B1', 'Gene', (186, 193))	('CYP11B2', 'Gene', (151, 158))	('CYP11B1', 'Gene', '1584', (186, 193))	('aldosterone synthase', 'Gene', '1585', (129, 149))	('CYP11B2', 'Gene', '1585', (151, 158))	('CYP11B1', 'Gene', (116, 123))	('CYP11B1', 'Gene', '1584', (116, 123))	('chimerical', 'Var', (175, 185))
87522	25097323	In addition to the Weiss scoring used for describing adreno-cortical carcinomas, various Immuno-histochemical studies with antibodies against CYP17A, CYP11B1 and CYP11B2 etc., have been described.	('adreno-cortical carcinomas', 'Disease', (53, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('adreno-cortical carcinomas', 'Phenotype', 'HP:0006744', (53, 79))	('CYP11B1', 'Gene', (150, 157))	('adreno-cortical carcinomas', 'Disease', 'MESH:D018268', (53, 79))	('CYP17A', 'Var', (142, 148))	('CYP11B1', 'Gene', '1584', (150, 157))	('CYP11B2', 'Gene', (162, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('CYP11B2', 'Gene', '1585', (162, 169))
87541	24790366	Although his familial history reminded us of p53 gene mutation, genetic analysis was not performed because informed consent was not obtained.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('mutation', 'Var', (54, 62))
87551	24790366	Hydrocortisone replacement was also initiated for treatment of adrenal insufficiency caused by mitotane.	('adrenal insufficiency', 'Disease', (63, 84))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (63, 84))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (63, 84))	('Hydrocortisone', 'Chemical', 'MESH:D006854', (0, 14))	('mitotane', 'Var', (95, 103))	('mitotane', 'Chemical', 'MESH:D008939', (95, 103))
87566	24790366	Although he required adjuvant chemotherapy, anti-cancer drugs and genetic factors, such as p53 gene mutation, are presumed to be related to the occurrence of the second cancer.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('mutation', 'Var', (100, 108))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
87837	31496655	The SW-13 and NCI-H295R cells were cultured with different concentrations of TG or JNK inhibitor SP600125 (AbMole, USA) for 48 h, followed by harvesting and suspending in 1x Binding Buffer; the cells were incubated with 5 microL Annexin V-FITC and 5 microL PI (BD Biosciences, USA).	('SP600125', 'Var', (97, 105))	('SP600125', 'Chemical', 'MESH:C432165', (97, 105))	('SW-13', 'CellLine', 'CVCL:0542', (4, 9))	('TG', 'Chemical', 'MESH:D019284', (77, 79))	('NCI-H295R', 'CellLine', 'CVCL:0458', (14, 23))	('Annexin V', 'Gene', '308', (229, 238))	('Annexin V', 'Gene', (229, 238))
87845	31496655	The membranes were probed with primary antibodies (anti-JNK, anti-p-JNK, anti-ERK, anti-p-ERK, anti-AMPK, anti-p-AMPK, anti-PERK, anti-p-PERK, IRE1 and anti-GRP78, Cell Signaling Technology, USA).	('PERK', 'Gene', (124, 128))	('ERK', 'Gene', (125, 128))	('p-ERK', 'Gene', '9451', (88, 93))	('p-ERK', 'Gene', (88, 93))	('IRE1', 'Gene', (143, 147))	('ERK', 'Gene', (90, 93))	('ERK', 'Gene', (138, 141))	('PERK', 'Gene', '9451', (124, 128))	('PERK', 'Gene', (137, 141))	('anti-p-AMPK', 'Var', (106, 117))	('ERK', 'Gene', '5594', (78, 81))	('anti-JNK', 'Var', (51, 59))	('anti-p-JNK', 'Var', (61, 71))	('PERK', 'Gene', '9451', (137, 141))	('ERK', 'Gene', '5594', (125, 128))	('anti-AMPK', 'Var', (95, 104))	('ERK', 'Gene', (78, 81))	('IRE1', 'Gene', '2081', (143, 147))	('GRP78', 'Gene', (157, 162))	('ERK', 'Gene', '5594', (90, 93))	('ERK', 'Gene', '5594', (138, 141))	('GRP78', 'Gene', '3309', (157, 162))
87873	31496655	Bcl-2 was increased in the TG8 groups compared with that in the TG0 group (P<0.05) (Figure 4C and D).	('TG', 'Chemical', 'MESH:D019284', (64, 66))	('TG8', 'Var', (27, 30))	('TG', 'Chemical', 'MESH:D019284', (27, 29))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))	('increased', 'PosReg', (10, 19))
87877	31496655	As shown in Figure 6A-E, the apoptosis rate of the cells and the expression of JNK had not significant difference in the treatment of SP600125.	('SP600125', 'Chemical', 'MESH:C432165', (134, 142))	('JNK', 'Gene', (79, 82))	('SP600125', 'Var', (134, 142))
87900	31496655	Mutations occurring in the JNK signaling pathway (eg, MAP3K1, MAP2K4, and MAP2K7) are implicated in the pathology of breast cancer.	('MAP2K4', 'Gene', (62, 68))	('MAP3K1', 'Gene', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('MAP3K1', 'Gene', '4214', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('Mutations', 'Var', (0, 9))	('MAP2K7', 'Gene', (74, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('MAP2K7', 'Gene', '5609', (74, 80))	('JNK signaling pathway', 'Pathway', (27, 48))	('MAP2K4', 'Gene', '6416', (62, 68))	('implicated', 'Reg', (86, 96))
87926	29850653	Mismatch repair deficiency that leads to MSI has been well described in several types of human cancer, most frequently in colorectal, endometrial, and gastric adenocarcinomas.	('human', 'Species', '9606', (89, 94))	('MSI', 'MPA', (41, 44))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (151, 174))	('colorectal', 'Disease', (122, 132))	('endometrial', 'Disease', (134, 145))	('gastric adenocarcinomas', 'Disease', (151, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Mismatch', 'Var', (0, 8))	('deficiency', 'Var', (16, 26))
87932	29850653	In addition, MSI-high ACC and CESC tumors were observed to have a higher average mutational burden than microsatellite-stable ACC and CESC tumors.	('CESC tumors', 'Disease', 'MESH:D009369', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CESC tumors', 'Disease', 'MESH:D009369', (30, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('mutational burden', 'MPA', (81, 98))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('CESC tumors', 'Disease', (30, 41))	('higher', 'PosReg', (66, 72))	('CESC tumors', 'Disease', (134, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('MSI-high', 'Var', (13, 21))
87966	29850653	Somatic mutations in the repair genes MSH2, MSH6, MLH1, PMS2, EXO1, POLD1, and POLE were determined by filtering variants with a DANN pathogenicity score greater than 0.96 (included in ANNOVAR).	('MLH1', 'Gene', '4292', (50, 54))	('MLH1', 'Gene', (50, 54))	('EXO1', 'Gene', '9156', (62, 66))	('MSH2', 'Gene', (38, 42))	('MSH2', 'Gene', '4436', (38, 42))	('PMS2', 'Gene', (56, 60))	('EXO1', 'Gene', (62, 66))	('POLD1', 'Gene', (68, 73))	('POLD1', 'Gene', '5424', (68, 73))	('MSH6', 'Gene', (44, 48))	('PMS2', 'Gene', '5395', (56, 60))	('variants', 'Var', (113, 121))	('MSH6', 'Gene', '2956', (44, 48))
87983	29850653	In particular, an average of 1,157 somatic mutations were detected within MSI-H ACC samples versus 216 within MSS ACC (P = .01).	('MSI-H', 'Disease', 'MESH:D000848', (74, 79))	('somatic mutations', 'Var', (35, 52))	('detected', 'Reg', (58, 66))	('MSI-H', 'Disease', (74, 79))
87984	29850653	An average of 5,675 somatic mutations were detected within MSI-H CESC samples versus 639 within MSS CESC (P = .003).	('MSI-H', 'Disease', 'MESH:D000848', (59, 64))	('somatic mutations', 'Var', (20, 37))	('detected', 'Reg', (43, 51))	('MSI-H', 'Disease', (59, 64))
87988	29850653	This analysis was first performed on pooled mutations among MSI-H or MSS samples within each of these three cancer cohorts (Appendix Fig A2).	('MSI-H', 'Disease', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (44, 53))	('MSI-H', 'Disease', 'MESH:D000848', (60, 65))	('MSS', 'Gene', (69, 72))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
87989	29850653	MSI-H Lynch syndrome-associated tumors are known to lack the expression or function of at least one MMR protein; therefore, we analyzed somatic mutations that were predicted to be deleterious (by DANN) in the MMR genes MSH2, MSH6, MLH1, PMS2, and EXO1, and the proofreading DNA polymerases POLD1 and POLE, among MSI-H and MSS samples within ACC, CESC, and MESO (Appendix Table A3; Data Supplement).	('MLH1', 'Gene', '4292', (231, 235))	('PMS2', 'Gene', (237, 241))	('POLD1', 'Gene', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('MSI-H', 'Disease', 'MESH:D000848', (0, 5))	('mutations', 'Var', (144, 153))	('EXO1', 'Gene', (247, 251))	('MMR', 'Gene', (209, 212))	('EXO1', 'Gene', '9156', (247, 251))	('MSI-H', 'Disease', (312, 317))	('MSH2', 'Gene', (219, 223))	('MSH6', 'Gene', (225, 229))	('PMS2', 'Gene', '5395', (237, 241))	('POLD1', 'Gene', '5424', (290, 295))	('MSH6', 'Gene', '2956', (225, 229))	('MLH1', 'Gene', (231, 235))	('MSI-H Lynch syndrome-associated tumors', 'Disease', (0, 38))	('MSI-H', 'Disease', (0, 5))	('MSH2', 'Gene', '4436', (219, 223))	('MSI-H', 'Disease', 'MESH:D000848', (312, 317))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('MSI-H Lynch syndrome-associated tumors', 'Disease', 'MESH:D003123', (0, 38))
87992	29850653	Compared with a study by Hause et al, we observed similar rates of MSI in 18 types of cancer, and we also analyzed another 5,209 whole-exome tumor-normal pairs from 21 additional types of cancer.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('MSI', 'Var', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (141, 146))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
87998	29850653	Clinical trials of immune checkpoint inhibitors are beginning or are underway in ACC (ClinicalTrials.gov identifier: NCT02673333), CESC (ClinicalTrials.gov identifier: NCT02635360), and MESO (ClinicalTrials.gov identifiers: NCT02784171, NCT02991482, NCT02707666, and NCT02399371), and a previous study of dendritic cell immunotherapy in ACC demonstrated tumor marker but not clinical response.	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('NCT02784171', 'Var', (224, 235))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('NCT02707666', 'Var', (250, 261))	('NCT02991482', 'Var', (237, 248))	('tumor', 'Disease', (354, 359))	('NCT02399371', 'Var', (267, 278))
88004	29850653	Compared with germline alterations in MMR genes, somatic events are most often a result of hypermethylation of CpG islands in the promoter region of MLH1.	('MLH1', 'Gene', (149, 153))	('result', 'Reg', (81, 87))	('somatic events', 'Disease', (49, 63))	('hypermethylation', 'Var', (91, 107))	('MLH1', 'Gene', '4292', (149, 153))
88008	29850653	In summary, we have detected MSI in multiple cancer types, including ACC, CESC, and MESO, which indicates that MSI may affect non-Lynch syndrome tumor types.	('detected', 'Reg', (20, 28))	('ACC', 'Disease', (69, 72))	('non-Lynch syndrome tumor', 'Disease', (126, 150))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CESC', 'Disease', (74, 78))	('MSI', 'Var', (29, 32))	('MESO', 'Disease', (84, 88))	('non-Lynch syndrome tumor', 'Disease', 'MESH:D003123', (126, 150))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('affect', 'Reg', (119, 125))	('cancer', 'Disease', (45, 51))
88024	29713282	In 2013, the Centers for Disease Control and Prevention (CDC) classified A. baumannii as a "Serious threat" as approximately 63% of healthcare-associated Acinetobacter infections occurring in the United States were MDR (i.e., non-susceptible to >=1 treating agent in >=3 antimicrobial categories).	('MDR', 'Var', (215, 218))	('A. baumannii', 'Species', '470', (73, 85))	('Acinetobacter infections', 'Disease', 'MESH:D000151', (154, 178))	('Acinetobacter infections', 'Disease', (154, 178))	('Acinetobacter infections', 'Phenotype', 'HP:0032250', (154, 178))
88027	29713282	Although polymyxins are believed to cause cell death primarily by disorganizing the Gram-negative outer membrane via binding to lipopolysaccharide (LPS), the precise antibacterial killing mechanism is not completely understood.	('disorganizing', 'NegReg', (66, 79))	('Gram-negative outer membrane', 'MPA', (84, 112))	('binding', 'Interaction', (117, 124))	('polymyxins', 'Var', (9, 19))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (128, 146))
88028	29713282	Worryingly, we and others have demonstrated that polymyxin resistance rapidly emerges in polymyxin-susceptible A. baumannii following polymyxin monotherapy.	('polymyxin', 'Var', (49, 58))	('A. baumannii', 'Species', '470', (111, 123))	('emerges', 'Reg', (78, 85))
88032	29713282	Unlike other anticancer drugs that damage DNA and inhibit DNA replication, mitotane inhibits steroidogenesis in adrenocortical carcinoma cells.	('mitotane', 'Var', (75, 83))	('steroidogenesis', 'MPA', (93, 108))	('mitotane', 'Chemical', 'MESH:D008939', (75, 83))	('adrenocortical carcinoma', 'Disease', (112, 136))	('inhibits', 'NegReg', (84, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (112, 136))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (112, 136))
88034	29713282	Given the potential repositioning of mitotane to treat MDR A. baumannii, it is essential to understand the mechanisms by which the polymyxin/mitotane combination achieves this enhanced bacterial killing and suppression of bacterial regrowth.	('A. baumannii', 'Species', '470', (59, 71))	('mitotane', 'Chemical', 'MESH:D008939', (37, 45))	('bacterial regrowth', 'CPA', (222, 240))	('suppression', 'NegReg', (207, 218))	('polymyxin/mitotane', 'Var', (131, 149))	('enhanced', 'PosReg', (176, 184))	('mitotane', 'Chemical', 'MESH:D008939', (141, 149))	('bacterial killing', 'CPA', (185, 202))
88039	29713282	A. baumannii FADDI-AB225 (formally designated ATCC 17978-R2) is polymyxin-resistant (polymyxin B MIC = 16 mg/L) with phosphoethanolamine-modified lipid A and pmrB mutation derived from A. baumannii ATCC 17978.	('A. baumannii', 'Species', '470', (0, 12))	('phosphoethanolamine', 'Chemical', 'MESH:C005448', (117, 136))	('A. baumannii ATCC 17978', 'Species', '400667', (185, 208))	('A. baumannii', 'Species', '470', (185, 197))	('ATCC 17978', 'Chemical', '-', (198, 208))	('ATCC 17978', 'Chemical', '-', (46, 56))	('lipid A', 'Chemical', 'MESH:D008050', (146, 153))	('pmrB', 'Gene', (158, 162))	('FADDI-AB225', 'Chemical', '-', (13, 24))	('mutation', 'Var', (163, 171))
88061	29713282	Polymyxin B monotherapy caused significant perturbations in a total of 142 metabolites in ATCC 17978, 51 in ATCC 19606, 13 in FADDI-AB225, and 13 in FADDI-AB065 (Figure 1B).	('metabolites', 'MPA', (75, 86))	('Polymyxin', 'Var', (0, 9))	('perturbations', 'Reg', (43, 56))	('ATCC 17978', 'Chemical', '-', (90, 100))	('ATCC 19606', 'Species', '470', (108, 118))	('FADDI-AB065', 'Chemical', '-', (149, 160))	('FADDI-AB225', 'Chemical', '-', (126, 137))
88066	29713282	The common perturbed metabolites between combination therapy and polymyxin B monotherapy were much higher than the common perturbed metabolites between the combination therapy and mitotane monotherapy (Figure 1B).	('mitotane', 'Chemical', 'MESH:D008939', (180, 188))	('metabolites', 'MPA', (21, 32))	('higher', 'PosReg', (99, 105))	('polymyxin B', 'Var', (65, 76))
88068	29713282	Most of the perturbed metabolites caused by the combination in this strain, consequently, were in common with those perturbed by mitotane monotherapy (Figure 1B).	('combination', 'Var', (48, 59))	('metabolites', 'MPA', (22, 33))	('mitotane', 'Chemical', 'MESH:D008939', (129, 137))	('perturbed', 'Reg', (12, 21))
88071	29713282	In the polymyxin-susceptible strains, polymyxin B monotherapy induced significant changes in a wide range of GPL while mitotane monotherapy induced minimal changes.	('GPL', 'Chemical', 'MESH:D020404', (109, 112))	('polymyxin B monotherapy', 'Var', (38, 61))	('changes', 'Reg', (82, 89))	('mitotane', 'Chemical', 'MESH:D008939', (119, 127))
88072	29713282	Overall, polymyxin B monotherapy caused a higher level of GPL perturbation in ATCC 17978 than ATCC 19606.	('polymyxin', 'Var', (9, 18))	('GPL', 'Chemical', 'MESH:D020404', (58, 61))	('ATCC 19606', 'Species', '470', (94, 104))	('GPL perturbation', 'MPA', (58, 74))	('ATCC 17978', 'Chemical', '-', (78, 88))
88074	29713282	Against ATCC 19606, where the perturbation caused by polymyxin B monotherapy was lower than two-fold change in most cases, the combination did not significantly affect the GPL.	('perturbation', 'MPA', (30, 42))	('polymyxin', 'Var', (53, 62))	('ATCC 19606', 'Species', '470', (8, 18))	('GPL', 'Chemical', 'MESH:D020404', (172, 175))
88079	29713282	In ATCC 19606, polymyxin B monotherapy and combination therapy caused statistically significant perturbation in total putative PEs (the sum of all detected putative PE species), although the changes in relative abundance were less than two-fold.	('putative PEs', 'Enzyme', (118, 130))	('ATCC 19606', 'Species', '470', (3, 13))	('polymyxin B', 'Var', (15, 26))	('combination', 'Interaction', (43, 54))	('perturbation', 'NegReg', (96, 108))	('PEs', 'Chemical', '-', (127, 130))
88081	29713282	For ATCC 17978, in addition to total putative PEs, polymyxin B monotherapy and combination therapy also substantially reduced putative sn-glycero-3-phosphoethanolamine (Log2FC = -2.42 and -2.83, respectively).	('sn-glycero-3-phosphoethanolamine', 'Chemical', '-', (135, 167))	('ATCC 17978', 'Chemical', '-', (4, 14))	('PEs', 'Chemical', '-', (46, 49))	('reduced', 'NegReg', (118, 125))	('putative sn-glycero-3-phosphoethanolamine', 'MPA', (126, 167))	('polymyxin B', 'Var', (51, 62))
88089	29713282	Compared to polymyxin B monotherapy, the combination caused a greater reduction of oleoyl-CoA in polymyxin-resistant FADDI-AB225.	('FADDI-AB225', 'Chemical', '-', (117, 128))	('reduction', 'NegReg', (70, 79))	('polymyxin-resistant', 'Var', (97, 116))	('oleoyl-CoA', 'MPA', (83, 93))	('oleoyl-CoA', 'Chemical', 'MESH:C017585', (83, 93))
88091	29713282	Metabolites involved in pentose phosphate pathway of A. baumannii were perturbed by polymyxin B and mitotane (Figure 6).	('Metabolites involved', 'MPA', (0, 20))	('pentose', 'Enzyme', (24, 31))	('pentose phosphate', 'Chemical', 'MESH:D010428', (24, 41))	('perturbed', 'Reg', (71, 80))	('mitotane', 'Var', (100, 108))	('mitotane', 'Chemical', 'MESH:D008939', (100, 108))	('polymyxin B', 'Var', (84, 95))	('A. baumannii', 'Species', '470', (53, 65))
88095	29713282	In ATCC 17978, succinate was significantly reduced by both polymyxin B and mitotane monotherapies; however, the highest level of reduction was observed with combination treatment (Log2FC = -2.49).	('ATCC 17978', 'Chemical', '-', (3, 13))	('succinate', 'MPA', (15, 24))	('mitotane', 'Chemical', 'MESH:D008939', (75, 83))	('succinate', 'Chemical', 'MESH:D019802', (15, 24))	('polymyxin', 'Var', (59, 68))	('reduced', 'NegReg', (43, 50))
88098	29713282	A high number of metabolites involved in nucleotide metabolism in A. baumannii were significantly impacted by polymyxin B and mitotane alone and in combination (Supplementary Tables S1-S4).	('polymyxin', 'Var', (110, 119))	('A. baumannii', 'Species', '470', (66, 78))	('mitotane', 'Chemical', 'MESH:D008939', (126, 134))	('impacted', 'Reg', (98, 106))
88100	29713282	In ATCC 17978, UMP was significantly reduced by both polymyxin B monotherapy and the combination (Log2FC = -1.19 and -2.07, respectively); and the combination also reduced UDP and putative CDP (Log2FC = -1.47 and -1.57, respectively).	('UMP', 'MPA', (15, 18))	('ATCC 17978', 'Chemical', '-', (3, 13))	('combination', 'Var', (147, 158))	('polymyxin B', 'Var', (53, 64))	('UDP', 'Chemical', 'MESH:D014530', (172, 175))	('reduced', 'NegReg', (37, 44))	('UDP', 'MPA', (172, 175))	('reduced', 'NegReg', (164, 171))
88103	29713282	In this pathway, GMP abundance was significantly reduced by polymyxin B monotherapy and the combination (Log2FC = -1.28 and -3.22, respectively) in ATCC 17978, with greater perturbation caused by the combination.	('reduced', 'NegReg', (49, 56))	('GMP abundance', 'MPA', (17, 30))	('ATCC 17978', 'Chemical', '-', (148, 158))	('polymyxin B', 'Var', (60, 71))	('GMP', 'Chemical', 'MESH:C066524', (17, 20))	('combination', 'Var', (92, 103))
88104	29713282	Additionally, only the combination impacted putative xanthosine 5'-phosphate (XMP) and GDP (Log2FC = -1.40 and -0.05, respectively), with greater perturbation occurring for putative XMP.	('impacted', 'Reg', (35, 43))	('XMP', 'Chemical', 'MESH:C011141', (78, 81))	('GDP', 'MPA', (87, 90))	('XMP', 'Chemical', 'MESH:C011141', (182, 185))	("xanthosine 5'-phosphate", 'Chemical', 'MESH:C011141', (53, 76))	('GDP', 'Chemical', 'MESH:D006153', (87, 90))	('combination', 'Var', (23, 34))
88106	29713282	Across ATCC 17978, ATCC 19606 and FADDI-AB065, histidine degradation was over-represented (>=2 metabolites in the module affected) (Figure 9).	('FADDI-AB065', 'Chemical', '-', (34, 45))	('over-represented', 'PosReg', (73, 89))	('histidine degradation', 'MPA', (47, 68))	('ATCC 17978', 'Chemical', '-', (7, 17))	('FADDI-AB065', 'Var', (34, 45))	('histidine', 'Chemical', 'MESH:D006639', (47, 56))	('ATCC 19606', 'Species', '470', (19, 29))
88107	29713282	In ATCC 17978, polymyxin B monotherapy and the combination treatment caused significant perturbations in putative urocanate (Log2FC = 1.46 and 2.49, respectively), putative N-formimino-L-glutamate (Log2FC = 1.27 and 2.29, respectively) and L-glutamate (Log2FC = -1.25 and -4.44, respectively).	('ATCC 17978', 'Chemical', '-', (3, 13))	('polymyxin B', 'Var', (15, 26))	('L-glutamate', 'MPA', (240, 251))	('N-formimino-L-glutamate', 'Chemical', '-', (173, 196))	('urocanate', 'Chemical', '-', (114, 123))	('L-glutamate', 'Chemical', 'MESH:D018698', (240, 251))	('putative urocanate', 'MPA', (105, 123))	('L-glutamate', 'Chemical', 'MESH:D018698', (185, 196))	('putative N-formimino-L-glutamate', 'MPA', (164, 196))
88108	29713282	In ATCC 19606, the intracellular concentration of putative urocanate was significantly increased by polymyxin B, mitotane, and combination treatment (Log2FC = 0.11, 0.30, and 0.71, respectively), with the highest level of perturbation observed with the combination.	('increased', 'PosReg', (87, 96))	('mitotane', 'Chemical', 'MESH:D008939', (113, 121))	('urocanate', 'Chemical', '-', (59, 68))	('ATCC 19606', 'Species', '470', (3, 13))	('combination', 'Interaction', (127, 138))	('intracellular concentration of putative urocanate', 'MPA', (19, 68))	('polymyxin B', 'Var', (100, 111))	('mitotane', 'Var', (113, 121))
88112	29713282	The combination of polymyxin B and the antineoplastic drug mitotane has been shown to produce synergistic bacterial killing and prevent regrowth in MDR A. baumannii.	('A. baumannii', 'Species', '470', (152, 164))	('polymyxin B', 'Var', (19, 30))	('mitotane', 'Chemical', 'MESH:D008939', (59, 67))	('prevent', 'NegReg', (128, 135))	('regrowth', 'CPA', (136, 144))	('combination', 'Interaction', (4, 15))
88118	29713282	Similar to a previous metabolomics study, pathway analysis revealed the majority of the significantly perturbed metabolites caused by polymyxin B monotherapy were in fatty acid and GPL metabolism (Figures 4, 5).	('GPL metabolism', 'MPA', (181, 195))	('metabolites', 'MPA', (112, 123))	('fatty acid', 'Chemical', 'MESH:D005227', (166, 176))	('perturbed', 'Reg', (102, 111))	('GPL', 'Chemical', 'MESH:D020404', (181, 184))	('polymyxin B monotherapy', 'Var', (134, 157))	('monotherapy', 'Var', (146, 157))
88122	29713282	In addition to the effect on the membrane lipids, pathway analysis also suggested that polymyxin B might affect the bacterial stress response through the degradation of L-histidine to L-glutamate.	('degradation of L-histidine to L-glutamate', 'MPA', (154, 195))	('lipids', 'Chemical', 'MESH:D008055', (42, 48))	('polymyxin B', 'Var', (87, 98))	('L-histidine', 'Chemical', 'MESH:D006639', (169, 180))	('affect', 'Reg', (105, 111))	('bacterial stress response', 'CPA', (116, 141))	('L-glutamate', 'Chemical', 'MESH:D018698', (184, 195))
88123	29713282	Since L-glutamate is an important metabolite involved in a wide range of bacterial metabolic processes including responses to acids and other stresses, a reduced level of L-glutamate can stifle the stress response and result in cell death.	('stress response', 'CPA', (198, 213))	('result in', 'Reg', (218, 227))	('L-glutamate', 'Var', (171, 182))	('L-glutamate', 'Chemical', 'MESH:D018698', (171, 182))	('reduced level of L-glutamate', 'Phenotype', 'HP:0500150', (154, 182))	('L-glutamate', 'Chemical', 'MESH:D018698', (6, 17))	('stifle', 'Reg', (187, 193))	('reduced', 'NegReg', (154, 161))	('cell death', 'CPA', (228, 238))
88125	29713282	LPS is a key component of the outer membrane, a permeability barrier in Gram-negative bacteria; hence, the loss of LPS likely enables hydrophobic mitotane to cross the outer membrane and access its intracellular target(s).	('enables', 'Reg', (126, 133))	('hydrophobic mitotane', 'MPA', (134, 154))	('loss', 'Var', (107, 111))	('LPS', 'Gene', (115, 118))	('mitotane', 'Chemical', 'MESH:D008939', (146, 154))
88134	29713282	In combination, our findings showed polymyxin B and mitotane additionally affected citric acid cycle and nucleotide metabolism.	('nucleotide metabolism', 'MPA', (105, 126))	('affected', 'Reg', (74, 82))	('polymyxin B', 'Var', (36, 47))	('mitotane', 'Chemical', 'MESH:D008939', (52, 60))	('citric acid cycle', 'MPA', (83, 100))	('citric acid', 'Chemical', 'MESH:D019343', (83, 94))
88144	29713282	In addition to effects on lipid metabolism pathways identified in our previous metabolomic studies with colistin, the histidine degradation pathway has been shown to be impacted by polymyxin B monotherapy.	('lipid', 'Chemical', 'MESH:D008055', (26, 31))	('histidine', 'Chemical', 'MESH:D006639', (118, 127))	('monotherapy', 'Var', (193, 204))	('polymyxin', 'Var', (181, 190))	('lipid metabolism pathways', 'Pathway', (26, 51))	('histidine degradation pathway', 'Pathway', (118, 147))	('impacted', 'Reg', (169, 177))
88147	29713282	The novel finding from this study is that polymyxin B treatment per se causes significant perturbations in cellular lipids and amino acid metabolism, specifically histidine degradation, all of which were further enhanced by mitotane leading ultimately to the depletion of nucleotides.	('polymyxin B', 'Var', (42, 53))	('histidine', 'Chemical', 'MESH:D006639', (163, 172))	('enhanced', 'PosReg', (212, 220))	('perturbations', 'MPA', (90, 103))	('mitotane', 'Chemical', 'MESH:D008939', (224, 232))	('lipids', 'Chemical', 'MESH:D008055', (116, 122))	('histidine degradation', 'MPA', (163, 184))	('depletion of nucleotides', 'MPA', (259, 283))
88148	29713282	This study provides valuable mechanistic insights into the synergistic antibacterial killing of polymyxin and mitotane combinations against MDR A. baumannii, and is important for the potential repositioning of mitotane for an antimicrobial indication in combination with polymyxins.	('combinations', 'Var', (119, 131))	('synergistic', 'MPA', (59, 70))	('mitotane', 'Chemical', 'MESH:D008939', (210, 218))	('MDR', 'Gene', (140, 143))	('mitotane', 'Chemical', 'MESH:D008939', (110, 118))	('A. baumannii', 'Species', '470', (144, 156))
88188	25287283	Establishment of the AGP is followed by its separation into adrenal and gonadal primordia, with subsequent mesenchymal cell encapsulation of the adrenal primordium (the 'fetal adrenal gland') by 9 weeks postconception in humans or E12.5 in mice.	('gonadal primordia', 'Disease', 'MESH:D006058', (72, 89))	('gonadal primordia', 'Disease', (72, 89))	('humans', 'Species', '9606', (221, 227))	('mice', 'Species', '10090', (240, 244))	('mesenchymal cell encapsulation', 'CPA', (107, 137))	('E12.5', 'Var', (231, 236))
88192	25287283	Definitive adrenocortical cells emerge during late embryogenesis and zonation of the adrenal cortex into distinct steroidogenic layers is completed in the perinatal period with the onset of specific expression of Cyp11b2 in the zona glomerulosa.	('cortex', 'Gene', '33937', (93, 99))	('cortex', 'Gene', (93, 99))	('adrenocortical', 'Disease', (11, 25))	('Cyp11b2', 'Var', (213, 220))	('adrenocortical', 'Disease', 'MESH:D018268', (11, 25))	('steroid', 'Chemical', 'MESH:D013256', (114, 121))
88235	25287283	These data collectively demonstrate that SF-1 expression is extinguished in the capsular descendants of fetal adrenal cells, which contribute to the population of SF-1-;Gli1+ capsular cells (Figure 1).	('Gli1', 'Gene', (169, 173))	('SF-1', 'Gene', (41, 45))	('SF-1-', 'Var', (163, 168))	('Gli1', 'Gene', '14632', (169, 173))
88242	25287283	Genetic evidence for this conversion was provided in 2013 by cell-lineage-tracing experiments in mice harbouring a Cre recombinase gene inserted at the Cyp11b2 locus, in which Cre was expressed only in terminally differentiated zona glomerulosa cells (ASCre mice).	('Cre', 'Gene', (254, 257))	('Cre', 'Gene', (176, 179))	('Cre', 'Gene', (115, 118))	('Cre', 'Gene', '39441', (254, 257))	('mice', 'Species', '10090', (258, 262))	('mice', 'Species', '10090', (97, 101))	('Cre', 'Gene', '39441', (176, 179))	('Cre', 'Gene', '39441', (115, 118))	('inserted', 'Var', (136, 144))
88244	25287283	Of note, Cyp11b1-expressing cells in the zona fasciculata (which do not express Cyp11b2) also became GFP+ over time, indicating that these cells underwent lineage conversion from zona glomerulosa cells.	('underwent', 'Reg', (145, 154))	('Cyp11b1', 'Gene', '110115', (9, 16))	('Cyp11b1', 'Gene', (9, 16))	('lineage conversion', 'CPA', (155, 173))	('Cyp11b2', 'Var', (80, 87))	('zona fasciculata', 'Disease', (41, 57))	('zona fasciculata', 'Disease', 'MESH:D006562', (41, 57))
88245	25287283	In 12-week-old mice, nearly the entire cortex was GFP+.	('mice', 'Species', '10090', (15, 19))	('cortex', 'Gene', '33937', (39, 45))	('GFP+', 'Var', (50, 54))	('cortex', 'Gene', (39, 45))
88249	25287283	Shortly thereafter, the importance of SF-1 in specification of adrenal cell identity and in adrenal growth became evident from studies of mice in which the Nr5a1 gene was knocked out.	('Nr5a1', 'Gene', (156, 161))	('knocked out', 'Var', (171, 182))	('mice', 'Species', '10090', (138, 142))	('Nr5a1', 'Gene', '26423', (156, 161))
88251	25287283	Mice globally deficient for SF-1 exhibit degeneration of the AGP due to apoptosis between E11.5 and E12.0, which results in agenesis of the adrenal glands and gonads.	('agenesis of the adrenal glands', 'Phenotype', 'HP:0011743', (124, 154))	('E11.5', 'Var', (90, 95))	('results in', 'Reg', (113, 123))	('agenesis', 'CPA', (124, 132))	('apoptosis', 'CPA', (72, 81))	('Mice', 'Species', '10090', (0, 4))	('E12.0', 'Var', (100, 105))	('SF-1', 'Gene', (28, 32))	('degeneration', 'NegReg', (41, 53))
88254	25287283	Although the incidence of NR5A1 mutations in humans is low, patients with mutations in the DNA-binding domain of SF-1 exhibit primary adrenal failure and gonadal dysgenesis (Table 1).	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (154, 172))	('patients', 'Species', '9606', (60, 68))	('mutations in', 'Var', (74, 86))	('SF-1', 'Gene', (113, 117))	('primary adrenal failure', 'Disease', 'MESH:D000310', (126, 149))	('humans', 'Species', '9606', (45, 51))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (154, 172))	('NR5A1', 'Gene', (26, 31))	('primary adrenal failure', 'Disease', (126, 149))	('adrenal failure', 'Phenotype', 'HP:0000846', (134, 149))	('NR5A1', 'Gene', '2516', (26, 31))	('gonadal dysgenesis', 'Disease', (154, 172))	('primary adrenal failure', 'Phenotype', 'HP:0008207', (126, 149))
88258	25287283	Amplification and overexpression of SF-1 are associated with paediatric adrenocortical adenomas and carcinomas, and are correlated with poor clinical outcomes in patients with adrenocortical carcinomas (Table 1).	('patients', 'Species', '9606', (162, 170))	('Amplification', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (176, 201))	('SF-1', 'Gene', (36, 40))	('adrenocortical carcinomas', 'Disease', (176, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('associated', 'Reg', (45, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (176, 200))	('adrenocortical adenomas and carcinomas', 'Disease', 'MESH:D018246', (72, 110))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (176, 201))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (72, 95))	('overexpression', 'PosReg', (18, 32))
88267	25287283	When compared with wild-type littermates, DAX-1 knockout mice exhibit enhanced steroidogenesis and proliferation at early ages but display progressive loss of proliferating cells, which is associated with adrenal gland dysplasia and hypofunction, as they age.	('steroidogenesis', 'MPA', (79, 94))	('mice', 'Species', '10090', (57, 61))	('adrenal gland dysplasia and hypofunction', 'Disease', 'MESH:D000309', (205, 245))	('steroid', 'Chemical', 'MESH:D013256', (79, 86))	('enhanced', 'PosReg', (70, 78))	('knockout', 'Var', (48, 56))	('DAX-1', 'Gene', (42, 47))	('loss', 'NegReg', (151, 155))	('adrenal gland dysplasia', 'Phenotype', 'HP:0008216', (205, 228))	('proliferation', 'CPA', (99, 112))	('proliferating', 'MPA', (159, 172))
88268	25287283	Mutations or deletion of NR0B1 in humans are the underlying basis of X-linked adrenal hypoplasia congenita (AHC; Table 1).	('adrenal hypoplasia congenita', 'Phenotype', 'HP:0008244', (78, 106))	('NR0B1', 'Gene', (25, 30))	('AHC', 'Disease', (108, 111))	('X-linked adrenal hypoplasia congenita', 'Disease', (69, 106))	('AHC', 'Phenotype', 'HP:0008244', (108, 111))	('NR0B1', 'Gene', '190', (25, 30))	('deletion', 'Var', (13, 21))	('Mutations', 'Var', (0, 9))	('X-linked adrenal hypoplasia congenita', 'Disease', 'MESH:D000075262', (69, 106))	('humans', 'Species', '9606', (34, 40))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (78, 96))	('AHC', 'Disease', 'MESH:D000312', (108, 111))
88270	25287283	These human data together with the DAX-1 knockout mouse study indicate that DAX-1 deficiency leads to precocious differentiation of adrenocortical progenitor cells, which ultimately leads to progenitor depletion and adrenal insufficiency.	('human', 'Species', '9606', (6, 11))	('DAX-1', 'Gene', (76, 81))	('deficiency', 'Var', (82, 92))	('leads to', 'Reg', (182, 190))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (216, 237))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (216, 237))	('leads to', 'Reg', (93, 101))	('adrenocortical', 'Disease', (132, 146))	('adrenocortical', 'Disease', 'MESH:D018268', (132, 146))	('mouse', 'Species', '10090', (50, 55))	('progenitor depletion', 'MPA', (191, 211))	('adrenal insufficiency', 'Disease', (216, 237))
88277	25287283	By E18.5, Wnt-beta-catenin signalling is restricted to the outer subcapsular region of the adrenal cortex.	('beta-catenin', 'Gene', (14, 26))	('cortex', 'Gene', (99, 105))	('cortex', 'Gene', '33937', (99, 105))	('beta-catenin', 'Gene', '12387', (14, 26))	('E18.5', 'Var', (3, 8))
88280	25287283	Adrenal gland development is initiated in the absence of beta-catenin; however, the proliferation of adrenocortical cells is dramatically decreased between E12.5 and E14.5, and the entire gland disappears by E18.5.	('E14.5', 'Var', (166, 171))	('E12.5', 'Var', (156, 161))	('beta-catenin', 'Gene', '12387', (57, 69))	('decreased', 'NegReg', (138, 147))	('adrenocortical', 'Disease', (101, 115))	('beta-catenin', 'Gene', (57, 69))	('adrenocortical', 'Disease', 'MESH:D018268', (101, 115))
88287	25287283	Alterations resulting in Wnt pathway activation, such as genetic loss of APC or gain-of-function mutations in CTNNB1, are frequent perturbations in human adrenocortical carcinomas and are correlated with poor prognosis (Table 1).	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (154, 179))	('adrenocortical carcinomas', 'Disease', (154, 179))	('mutations', 'Var', (97, 106))	('genetic loss', 'Disease', 'MESH:D030342', (57, 69))	('genetic loss', 'Disease', (57, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('activation', 'PosReg', (37, 47))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (154, 179))	('CTNNB1', 'Gene', '1499', (110, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('Wnt pathway', 'Pathway', (25, 36))	('human', 'Species', '9606', (148, 153))	('APC', 'Disease', 'MESH:D011125', (73, 76))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (154, 178))	('CTNNB1', 'Gene', (110, 116))	('APC', 'Disease', (73, 76))	('gain-of-function', 'PosReg', (80, 96))
88293	25287283	In humans, WNT4 loss-of-function mutations result in SERKAL syndrome, an autosomal-recessive disorder whose manifestations include female sex reversal and dysgenesis of the kidneys, lungs and adrenal glands (Table 1).	('autosomal-recessive disorder', 'Disease', (73, 101))	('mutations', 'Var', (33, 42))	('SERKAL', 'Gene', '54361', (53, 59))	('autosomal-recessive disorder', 'Disease', 'MESH:D030342', (73, 101))	('female sex reversal', 'Disease', (131, 150))	('dysgenesis of the kidneys', 'Disease', (155, 180))	('humans', 'Species', '9606', (3, 9))	('sex reversal', 'Phenotype', 'HP:0012245', (138, 150))	('loss-of-function', 'NegReg', (16, 32))	('dysgenesis of the kidneys', 'Phenotype', 'HP:0000110', (155, 180))	('dysgenesis of the kidneys', 'Disease', 'MESH:D007674', (155, 180))	('SERKAL', 'Gene', (53, 59))	('WNT4', 'Gene', (11, 15))
88296	25287283	Evidence for the importance of SHH signalling in adrenal gland development arose from the discovery that frameshift mutations that result in truncation of GLI3 into a constitutive repressor are the underlying cause of Pallister-Hall syndrome (PHS).	('Pallister-Hall syndrome', 'Disease', (218, 241))	('cause', 'Reg', (209, 214))	('GLI3', 'Gene', '14634', (155, 159))	('GLI3', 'Gene', (155, 159))	('frameshift mutations', 'Var', (105, 125))	('PHS', 'Disease', 'MESH:D054975', (243, 246))	('truncation', 'MPA', (141, 151))	('Pallister-Hall syndrome', 'Disease', 'MESH:D054975', (218, 241))	('PHS', 'Disease', (243, 246))
88300	25287283	Mice with global Shh ablation (Shh-/- mice), as well as mice with conditional ablation of Shh in steroidogenic cells (Sf1/Cre:Shhfl/fl and Sf1/Cre:Shhfl/- mice), exhibit hypoplastic adrenal glands during embryonic development, owing to reduced cortical and capsular cell proliferation (Table 1).	('Sf1', 'Gene', (139, 142))	('Cre', 'Gene', '39441', (122, 125))	('hypoplastic adrenal', 'Phenotype', 'HP:0000835', (170, 189))	('hypoplastic adrenal glands', 'Disease', (170, 196))	('mice', 'Species', '10090', (38, 42))	('ablation', 'Var', (78, 86))	('mice', 'Species', '10090', (56, 60))	('Sf1', 'Gene', '22668', (118, 121))	('mice', 'Species', '10090', (155, 159))	('Cre', 'Gene', (143, 146))	('reduced', 'NegReg', (236, 243))	('Sf1', 'Gene', (118, 121))	('Cre', 'Gene', (122, 125))	('steroid', 'Chemical', 'MESH:D013256', (97, 104))	('Mice', 'Species', '10090', (0, 4))	('hypoplastic adrenal glands', 'Disease', 'MESH:D000307', (170, 196))	('Sf1', 'Gene', '22668', (139, 142))	('Cre', 'Gene', '39441', (143, 146))
88311	25287283	Ablation of Fgfr2 in steroidogenic cells results in adrenal hypoplasia observable by E15.5.	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (52, 70))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (52, 70))	('steroid', 'Chemical', 'MESH:D013256', (21, 28))	('Ablation', 'Var', (0, 8))	('Fgfr2', 'Gene', (12, 17))	('adrenal hypoplasia', 'Disease', (52, 70))	('results in', 'Reg', (41, 51))
88327	25287283	The loss of Inha results in constitutive TGF-beta2 and SMAD3 activation in adrenocortical progenitor cells, with subsequent expansion of GATA4-expressing cells.	('TGF-beta2', 'Gene', (41, 50))	('Inha', 'Gene', (12, 16))	('activation', 'PosReg', (61, 71))	('SMAD3', 'Gene', (55, 60))	('adrenocortical', 'Disease', (75, 89))	('SMAD3', 'Gene', '17127', (55, 60))	('Inha', 'Gene', '16322', (12, 16))	('GATA4', 'Gene', '14463', (137, 142))	('GATA4', 'Gene', (137, 142))	('adrenocortical', 'Disease', 'MESH:D018268', (75, 89))	('loss', 'Var', (4, 8))
88339	25287283	Mice deficient in both the insulin receptor gene (Insr) and Igf1r exhibit gonadal dysgenesis, male-to-female sex reversal and adrenal aplasia.	('insulin receptor', 'Gene', (27, 43))	('Igf1r', 'Gene', (60, 65))	('male-to-female sex reversal', 'CPA', (94, 121))	('sex reversal', 'Phenotype', 'HP:0012245', (109, 121))	('Insr', 'Gene', '16337', (50, 54))	('adrenal aplasia', 'Phenotype', 'HP:0011743', (126, 141))	('Insr', 'Gene', (50, 54))	('Igf1r', 'Gene', '16001', (60, 65))	('deficient', 'Var', (5, 14))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (74, 92))	('Mice', 'Species', '10090', (0, 4))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (74, 92))	('adrenal aplasia', 'Disease', 'MESH:D000310', (126, 141))	('gonadal dysgenesis', 'Disease', (74, 92))	('gonadal dysgenesis, male', 'Phenotype', 'HP:0008668', (74, 98))	('insulin receptor', 'Gene', '16337', (27, 43))	('adrenal aplasia', 'Disease', (126, 141))
88343	25287283	Genetic and epigenetic aberrations in this locus result in diseases with clinically important adrenal gland abnormalities, such as Beckwith-Wiedemann syndrome (BWS) and IMAGe (intrauterine growth retardation, metaphyseal dysplasia, AHC and genital anomalies) (Table 1).	('intrauterine growth retardation', 'Disease', (176, 207))	('AHC', 'Disease', 'MESH:D000312', (232, 235))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (131, 158))	('epigenetic aberrations', 'Var', (12, 34))	('AHC', 'Phenotype', 'HP:0008244', (232, 235))	('adrenal gland abnormalities', 'Disease', 'MESH:D000307', (94, 121))	('growth retardation', 'Phenotype', 'HP:0001510', (189, 207))	('BWS', 'Gene', '1028', (160, 163))	('adrenal gland abnormalities', 'Phenotype', 'HP:0000834', (94, 121))	('BWS', 'Gene', (160, 163))	('intrauterine growth retardation', 'Phenotype', 'HP:0001511', (176, 207))	('dysplasia', 'Disease', (221, 230))	('intrauterine growth retardation', 'Disease', 'MESH:D005317', (176, 207))	('dysplasia', 'Disease', 'MESH:D004476', (221, 230))	('AHC', 'Disease', (232, 235))	('adrenal gland abnormalities', 'Disease', (94, 121))	('genital anomalies', 'Phenotype', 'HP:0000078', (240, 257))	('Beckwith-Wiedemann syndrome', 'Disease', (131, 158))	('genital anomalies', 'Disease', 'MESH:D014564', (240, 257))	('result in', 'Reg', (49, 58))	('genital anomalies', 'Disease', (240, 257))	('metaphyseal dysplasia', 'Phenotype', 'HP:0100255', (209, 230))	('diseases', 'Disease', (59, 67))
88344	25287283	BWS, a heterogeneous paediatric overgrowth syndrome characterized by embryonic tumours, macrosomia, macroglossia and other developmental defects, results from loss of imprinting of 11p15.5 leading to upregulation of IGF2 and down-regulation of CKDN1C and H19.	('overgrowth', 'Phenotype', 'HP:0001548', (32, 42))	('H19', 'Gene', (255, 258))	('overgrowth syndrome', 'Disease', 'MESH:C537340', (32, 51))	('upregulation', 'PosReg', (200, 212))	('loss', 'Var', (159, 163))	('overgrowth syndrome', 'Disease', (32, 51))	('CKDN1C', 'Gene', (244, 250))	('IGF2', 'Gene', (216, 220))	('embryonic tumours', 'Disease', (69, 86))	('BWS', 'Gene', (0, 3))	('embryonic tumours', 'Disease', 'MESH:D009373', (69, 86))	('macrosomia', 'Phenotype', 'HP:0001520', (88, 98))	('BWS', 'Gene', '1028', (0, 3))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('macrosomia', 'Disease', (88, 98))	('down-regulation', 'NegReg', (225, 240))	('macrosomia', 'Disease', 'MESH:D005320', (88, 98))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('macroglossia', 'Phenotype', 'HP:0000158', (100, 112))	('macroglossia', 'Disease', (100, 112))	('macroglossia', 'Disease', 'MESH:D008260', (100, 112))
88347	25287283	Interestingly, loss of the major imprinting control region of the Igf2 locus in the mouse adrenal gland increases Igf2 expression but does not by itself increase the incidence of adrenal tumours.	('expression', 'MPA', (119, 129))	('Igf2', 'Gene', '16002', (114, 118))	('adrenal gland increases', 'Phenotype', 'HP:0008221', (90, 113))	('adrenal tumours', 'Disease', 'MESH:D000310', (179, 194))	('increases', 'PosReg', (104, 113))	('adrenal tumours', 'Disease', (179, 194))	('loss', 'Var', (15, 19))	('mouse', 'Species', '10090', (84, 89))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('increases Igf2', 'Phenotype', 'HP:0030269', (104, 118))	('Igf2', 'Gene', (66, 70))	('Igf2', 'Gene', '16002', (66, 70))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))	('Igf2', 'Gene', (114, 118))
88350	25287283	The constellation of congenital anomalies that characterize IMAGe result from gain-of-function mutations in CDKN1C that increase the stability of the p57Kip2 protein.	('p57Kip2', 'Gene', '12577', (150, 157))	('CDKN1C', 'Gene', (108, 114))	('gain-of-function', 'PosReg', (78, 94))	('genital anomalies', 'Phenotype', 'HP:0000078', (24, 41))	('CDKN1C', 'Gene', '12577', (108, 114))	('mutations', 'Var', (95, 104))	('increase', 'PosReg', (120, 128))	('constellation of congenital anomalies', 'Disease', (4, 41))	('constellation of congenital anomalies', 'Disease', 'MESH:D000013', (4, 41))	('stability', 'MPA', (133, 142))	('p57Kip2', 'Gene', (150, 157))
88370	25287283	Genetic mutations of the cAMP-PKA pathway are associated with an array of hyperproliferative adrenocortical diseases in humans and in mouse models (Table 1).	('cAMP-PKA', 'Gene', (25, 33))	('adrenocortical diseases', 'Phenotype', 'HP:0008207', (93, 116))	('humans', 'Species', '9606', (120, 126))	('hyperproliferative adrenocortical diseases', 'Disease', (74, 116))	('cAMP', 'Chemical', 'MESH:D000242', (25, 29))	('associated', 'Reg', (46, 56))	('Genetic mutations', 'Var', (0, 17))	('hyperproliferative adrenocortical diseases', 'Disease', 'MESH:D018268', (74, 116))	('mouse', 'Species', '10090', (134, 139))
88371	25287283	Activating mutations in the GNAS gene, which encodes adenylate cyclase-stimulating Galpha protein (also known as Gs protein), have been identified in patients with cortisol-producing adrenal adenomas and ACTH-independent macronodular adrenal hyperplasia (AIMAH), and are the genetic basis of McCune-Albright syndrome.	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (11, 20))	('ACTH', 'Gene', (204, 208))	('adrenal adenomas', 'Disease', (183, 199))	('macronodular adrenal hyperplasia', 'Disease', (221, 253))	('GNAS', 'Gene', '2778', (28, 32))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (221, 253))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (183, 199))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (234, 253))	('patients', 'Species', '9606', (150, 158))	('cortisol', 'Chemical', 'MESH:D006854', (164, 172))	('GNAS', 'Gene', (28, 32))	('ACTH', 'Gene', '18976', (204, 208))	('identified', 'Reg', (136, 146))	('adrenal adenomas', 'Disease', 'MESH:D018246', (183, 199))	('McCune-Albright syndrome', 'Disease', (292, 316))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (221, 253))
88372	25287283	Gain-of-function mutations in PRKACA, one of the three genes encoding the catalytic subunits of PKA, are the genetic basis of many cortisol-producing adrenal adenomas.	('Gain-of-function', 'PosReg', (0, 16))	('adrenal adenomas', 'Disease', (150, 166))	('PRKACA', 'Gene', '18747', (30, 36))	('mutations', 'Var', (17, 26))	('cortisol', 'Chemical', 'MESH:D006854', (131, 139))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (150, 166))	('PRKACA', 'Gene', (30, 36))	('adrenal adenomas', 'Disease', 'MESH:D018246', (150, 166))
88373	25287283	Loss-of-function mutations in PRKAR1A, which codes for one of the regulatory subunits of PKA, are responsible for primary pigmented nodular adrenal dysplasia and Carney complex.	('Loss-of-function', 'NegReg', (0, 16))	('PRKAR1A', 'Gene', (30, 37))	('primary pigmented nodular adrenal dysplasia', 'Disease', (114, 157))	('adrenal dysplasia', 'Phenotype', 'HP:0008216', (140, 157))	('PRKAR1A', 'Gene', '19084', (30, 37))	('primary pigmented nodular adrenal dysplasia', 'Disease', 'MESH:D020518', (114, 157))	('mutations', 'Var', (17, 26))	('Carney complex', 'Disease', (162, 176))
88374	25287283	In different mouse models, genetic ablation or reduction of expression of Prkar1a variably recapitulates aspects of Carney complex.	('expression', 'MPA', (60, 70))	('mouse', 'Species', '10090', (13, 18))	('genetic ablation', 'Var', (27, 43))	('Prkar1a', 'Gene', '19084', (74, 81))	('Prkar1a', 'Gene', (74, 81))	('reduction of', 'NegReg', (47, 59))	('Carney complex', 'Disease', (116, 130))
88375	25287283	Adrenal-specific knockout of Prkar1a in mice results in autonomous adrenal hyperplasia and glucocorticoid production reminiscent of Cushing syndrome.	('Cushing syndrome', 'Disease', (132, 148))	('Cushing syndrome', 'Disease', 'MESH:D003480', (132, 148))	('Prkar1a', 'Gene', '19084', (29, 36))	('autonomous adrenal hyperplasia', 'Disease', 'MESH:D000312', (56, 86))	('knockout', 'Var', (17, 25))	('glucocorticoid production', 'MPA', (91, 116))	('autonomous adrenal hyperplasia', 'Disease', (56, 86))	('Prkar1a', 'Gene', (29, 36))	('mice', 'Species', '10090', (40, 44))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (132, 148))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (67, 86))
88378	25287283	Finally, inactivating mutations in PDE11A and PDE8B, which encode phosphodiesterases that dampen cAMP signalling, have been associated with adrenal hyperplasia, AIMAH and adrenocortical adenomas.	('dampen', 'NegReg', (90, 96))	('phosphodiesterases', 'Gene', '50940;241489', (66, 84))	('PDE8B', 'Gene', '218461', (46, 51))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (140, 159))	('inactivating mutations', 'Var', (9, 31))	('phosphodiesterases', 'Gene', (66, 84))	('adrenal hyperplasia', 'Disease', (140, 159))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (171, 194))	('associated', 'Reg', (124, 134))	('adrenocortical adenomas', 'Disease', (171, 194))	('PDE11A', 'Gene', (35, 41))	('PDE8B', 'Gene', (46, 51))	('AIMAH', 'Disease', (161, 166))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (171, 194))	('PDE11A', 'Gene', '241489', (35, 41))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (140, 159))	('cAMP', 'Chemical', 'MESH:D000242', (97, 101))	('cAMP signalling', 'MPA', (97, 112))
88394	25287283	Diseases resulting in adrenal insufficiency (AHC, SERKAL, PHS and IMAGe) are consequences of loss-of-function mutations in the specific transcription factors (SF-1, DAX-1) and paracrine signalling pathways (Wnt, Hedgehog, IGF) that are critical for adrenocortical stem and progenitor cells.	('SF-1', 'Gene', (159, 163))	('AHC', 'Disease', (45, 48))	('AHC', 'Phenotype', 'HP:0008244', (45, 48))	('mutations', 'Var', (110, 119))	('PHS', 'Disease', (58, 61))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (22, 43))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (22, 43))	('SERKAL', 'Gene', '54361', (50, 56))	('paracrine signalling pathways', 'Pathway', (176, 205))	('adrenocortical', 'Disease', (249, 263))	('loss-of-function', 'NegReg', (93, 109))	('adrenal insufficiency', 'Disease', (22, 43))	('PHS', 'Disease', 'MESH:D054975', (58, 61))	('AHC', 'Disease', 'MESH:D000312', (45, 48))	('SERKAL', 'Gene', (50, 56))	('adrenocortical', 'Disease', 'MESH:D018268', (249, 263))
88395	25287283	Conversely, activating mutations in these pathways result in adrenal tissue 'overgrowth' that contributes to the formation of adrenocortical hyperplasias, adenomas and carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('adenomas and carcinomas', 'Disease', 'MESH:D000236', (155, 178))	('overgrowth', 'Phenotype', 'HP:0001548', (77, 87))	("'overgrowth'", 'PosReg', (76, 88))	('mutations', 'Var', (23, 32))	('adrenocortical hyperplasias', 'Disease', 'MESH:D018268', (126, 153))	('activating', 'PosReg', (12, 22))	('adrenal tissue', 'CPA', (61, 75))	('adrenocortical hyperplasias', 'Disease', (126, 153))
88397	25287283	We present a comprehensive list of genetic mutations underlying a spectrum of adrenocortical diseases in Table 1 (primary disorders of steroidogenesis due to loss-of-function mutations in MC2R, MRAP and in genes encoding steroidogenic enzymes that result in primary hypoplasias or compensatory hyperplasias [congenital adrenal hyperplasias and familial glucocorticoid deficiency] are not included but have been discussed extensively elsewhere).	('MRAP', 'Gene', '77037', (194, 198))	('primary hypoplasias', 'Disease', (258, 277))	('mutations', 'Var', (175, 184))	('hyperplasias', 'Disease', (327, 339))	('hyperplasias', 'Disease', (294, 306))	('adrenocortical diseases', 'Disease', 'MESH:D018268', (78, 101))	('hyperplasias', 'Disease', 'MESH:D006965', (327, 339))	('steroid', 'Chemical', 'MESH:D013256', (221, 228))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (353, 378))	('hyperplasias', 'Disease', 'MESH:D006965', (294, 306))	('steroid', 'Chemical', 'MESH:D013256', (135, 142))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (319, 338))	('MC2R', 'Gene', (188, 192))	('adrenocortical diseases', 'Disease', (78, 101))	('adrenal hyperplasias', 'Phenotype', 'HP:0008221', (319, 339))	('primary hypoplasias', 'Disease', 'MESH:C562992', (258, 277))	('congenital adrenal hyperplasias and familial glucocorticoid deficiency', 'Disease', 'MESH:D000312', (308, 378))	('loss-of-function', 'NegReg', (158, 174))	('adrenocortical diseases', 'Phenotype', 'HP:0008207', (78, 101))	('congenital adrenal hyperplasias', 'Phenotype', 'HP:0008258', (308, 339))	('MRAP', 'Gene', (194, 198))	('MC2R', 'Gene', '17200', (188, 192))
88401	25287283	Fetal adrenal cells are critical for the establishment of the capsular-cortical unit of the adrenal gland; these cells populate the mesenchymal capsule to become stem cells for the underlying adult (definitive) cortex The adrenal capsular and subcapsular cell populations have a crucial role in gland maintenance; paracrine signals between the capsule and the cortex coordinate normal homeostasis by regulating capsular and subcapsular cellular lineages Genetic defects in signalling pathways that regulate adrenocortical stem and progenitor cells contribute to diseases across the spectrum of adrenal failure and neoplasia PubMed and Google Scholar were used to find original full-length research articles and reviews published between 1866 and 2014.	('neoplasia', 'Disease', 'MESH:D009369', (614, 623))	('neoplasia', 'Phenotype', 'HP:0002664', (614, 623))	('adrenal failure', 'Phenotype', 'HP:0000846', (594, 609))	('cortex', 'Gene', '33937', (211, 217))	('cortex', 'Gene', (211, 217))	('adrenal failure', 'Disease', 'MESH:D000312', (594, 609))	('cortex', 'Gene', (360, 366))	('defects', 'Var', (462, 469))	('adrenal failure', 'Disease', (594, 609))	('cortex', 'Gene', '33937', (360, 366))	('neoplasia', 'Disease', (614, 623))	('adrenocortical', 'Disease', (507, 521))	('adrenocortical', 'Disease', 'MESH:D018268', (507, 521))
88448	25741090	A 10-15-fold higher annual incidence of ACC has been reported in children in southern Brazil when compared to children <= 15 years old in the United States due to a point mutation in the p53 tumor suppressor gene.	('p53', 'Gene', (187, 190))	('ACC', 'Phenotype', 'HP:0006744', (40, 43))	('point mutation', 'Var', (165, 179))	('ACC', 'Disease', (40, 43))	('p53', 'Gene', '7157', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))
88466	25741090	The presence of these findings dramatically increases the likelihood of adrenal metastasis in patients with known extra-adrenal malignancy.	('extra-adrenal malignancy', 'Disease', (114, 138))	('extra-adrenal malignancy', 'Disease', 'MESH:D010236', (114, 138))	('adrenal malignancy', 'Disease', 'MESH:D009369', (120, 138))	('presence', 'Var', (4, 12))	('adrenal metastasis', 'CPA', (72, 90))	('increases', 'PosReg', (44, 53))	('adrenal malignancy', 'Phenotype', 'HP:0100631', (120, 138))
88525	25112588	PPH02516A-200) UTS2-sense, and UTS2-antisense primers and SYBR Green PCR Master Mix were used.	('SYBR Green', 'Chemical', '-', (58, 68))	('PPH02516A-200', 'Var', (0, 13))	('UTS2', 'Gene', (31, 35))	('UTS2', 'Gene', '10911', (31, 35))	('UTS2', 'Gene', (15, 19))	('UTS2', 'Gene', '10911', (15, 19))
88527	25112588	PPH14061A-200) UTS2 R-sense and antisense primers were tested.	('UTS2', 'Gene', '10911', (15, 19))	('PPH14061A-200', 'Var', (0, 13))	('UTS2', 'Gene', (15, 19))
88601	21839803	Secretion of aldosterone is regulated tightly by the adrenocortical glomerulosa cells due to the selective expression of CYP11B2 in the outermost zone, the zona glomerulosa.	('CYP11B2', 'Var', (121, 128))	('Secretion of aldosterone', 'MPA', (0, 24))	('adrenocortical glomerulosa', 'Disease', 'MESH:D018268', (53, 79))	('aldosterone', 'Chemical', 'MESH:D000450', (13, 24))	('adrenocortical glomerulosa', 'Disease', (53, 79))
88605	21839803	Imbalance in any of these processes may lead to several aldosterone excess disorders.	('Imbalance', 'Var', (0, 9))	('lead to', 'Reg', (40, 47))	('aldosterone excess', 'Phenotype', 'HP:0000859', (56, 74))	('excess disorders', 'Disease', (68, 84))	('Imbalance', 'Phenotype', 'HP:0002172', (0, 9))	('excess disorders', 'Disease', 'MESH:D006970', (68, 84))	('aldosterone', 'Chemical', 'MESH:D000450', (56, 67))
88614	21839803	CYP11A1 and CYP11B2 are localized to the inner mitochondrial membrane, while CYP21 is found in the endoplasmic reticulum.	('CYP11A1', 'Gene', '1583', (0, 7))	('CYP21', 'Gene', (77, 82))	('CYP11B2', 'Var', (12, 19))	('CYP21', 'Gene', '1589', (77, 82))	('CYP11A1', 'Gene', (0, 7))
88615	21839803	Cytochrome P450 enzymes are heme-containing proteins that accept electrons from NADPH via accessory proteins and utilize molecular oxygen to perform hydroxylations (CYP21 and CYP11B2) or other oxidative conversions (CYP11A1).	('accept electrons', 'MPA', (58, 74))	('CYP11B2', 'Var', (175, 182))	('P450', 'Gene', '1555', (11, 15))	('hydroxylations', 'Enzyme', (149, 163))	('CYP11A1', 'Gene', '1583', (216, 223))	('CYP21', 'Gene', (165, 170))	('NADPH', 'Chemical', 'MESH:D009249', (80, 85))	('P450', 'Gene', (11, 15))	('CYP11A1', 'Gene', (216, 223))	('CYP21', 'Gene', '1589', (165, 170))	('oxygen', 'Chemical', 'MESH:D010100', (131, 137))	('heme', 'Chemical', 'MESH:D006418', (28, 32))
88617	21839803	Aldosterone and cortisol share the first few enzymatic reactions in their biosynthetic pathways (cholesterol to progesterone); however, adrenal zone-specific expression of CYP11B2 (aldosterone synthase) in the glomerulosa and that of CYP11B1 (11beta-hydoxylase) in the fasciculata leads to the functional zonation observed in the adrenal cortex.	('CYP11B2', 'Var', (172, 179))	('leads to', 'Reg', (281, 289))	('cortisol', 'Chemical', 'MESH:D006854', (16, 24))	('Aldosterone', 'Chemical', 'MESH:D000450', (0, 11))	('fasciculata', 'Disease', 'None', (269, 280))	('functional zonation', 'MPA', (294, 313))	('11beta', 'Chemical', '-', (243, 249))	('progesterone', 'Chemical', 'MESH:D011374', (112, 124))	('cholesterol', 'Chemical', 'MESH:D002784', (97, 108))	('fasciculata', 'Disease', (269, 280))
88628	21839803	First, the selective expression of CYP11B2 in the glomerulosa creates a tightly controlled zone-specific ability to make aldosterone and limits production of the steroid outside of this relatively small adrenal zone.	('production of the steroid', 'MPA', (144, 169))	('ability', 'MPA', (105, 112))	('CYP11B2', 'Var', (35, 42))	('make aldosterone', 'MPA', (116, 132))	('aldosterone', 'Chemical', 'MESH:D000450', (121, 132))	('limits', 'NegReg', (137, 143))	('steroid', 'Chemical', 'MESH:D013256', (162, 169))	('small adrenal', 'Phenotype', 'HP:0000835', (197, 210))
88630	21839803	A recent study revealed a variation in human adrenal glomerulosa zonation characterized by the presence of relatively few subcapsular cell clusters expressing CYP11B2.	('CYP11B2', 'Var', (159, 166))	('adrenal glomerulosa zonation', 'Disease', 'MESH:D000312', (45, 73))	('adrenal glomerulosa zonation', 'Disease', (45, 73))	('subcapsular cell clusters', 'Phenotype', 'HP:0000523', (122, 147))	('human', 'Species', '9606', (39, 44))
88632	21839803	It is hypothesized that these CYP11B2-expressing cortical cell clusters may be the precursors to aldosterone-producing adenomas (APA).	('CYP11B2-expressing', 'Var', (30, 48))	('adenomas', 'Disease', 'MESH:D000236', (119, 127))	('PA', 'Phenotype', 'HP:0011736', (130, 132))	('adenomas', 'Disease', (119, 127))	('PA', 'Chemical', 'MESH:D010712', (130, 132))	('aldosterone', 'Chemical', 'MESH:D000450', (97, 108))
88633	21839803	The absence of CYP17 in glomerulosa cells is a second mechanism resulting in diversion of the steroidogenic pathway toward aldosterone.	('CYP17', 'Gene', '1586', (15, 20))	('aldosterone', 'Chemical', 'MESH:D000450', (123, 134))	('steroidogenic pathway', 'Pathway', (94, 115))	('CYP17', 'Gene', (15, 20))	('steroid', 'Chemical', 'MESH:D013256', (94, 101))	('diversion', 'MPA', (77, 86))	('absence', 'Var', (4, 11))
88643	21839803	IP3 is thought to initiate aldosterone secretion by eliciting a transient increase in the cytosolic calcium concentration and activating calcium/calmodulin-dependent protein kinases (CaMK).	('calcium', 'Chemical', 'MESH:D002118', (100, 107))	('aldosterone', 'MPA', (27, 38))	('rat', 'Species', '10116', (115, 118))	('cytosolic calcium concentration', 'MPA', (90, 121))	('IP3', 'Var', (0, 3))	('increase', 'PosReg', (74, 82))	('aldosterone', 'Chemical', 'MESH:D000450', (27, 38))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))	('CaMK', 'Gene', (183, 187))	('calcium', 'Chemical', 'MESH:D002118', (137, 144))	('calmodulin', 'Gene', (145, 155))	('CaMK', 'Gene', '818', (183, 187))	('calmodulin', 'Gene', '801', (145, 155))	('activating', 'PosReg', (126, 136))
88644	21839803	CaMK activity is clearly important in mediating aldosterone secretion, as inhibition of this enzyme decreases AngII-induced aldosterone secretion.	('inhibition', 'Var', (74, 84))	('AngII-induced aldosterone secretion', 'MPA', (110, 145))	('CaMK', 'Gene', (0, 4))	('decreases', 'NegReg', (100, 109))	('CaMK', 'Gene', '818', (0, 4))	('aldosterone', 'Chemical', 'MESH:D000450', (48, 59))	('aldosterone', 'Chemical', 'MESH:D000450', (124, 135))
88649	21839803	Indeed, this calcium influx is essential for a continued aldosterone secretory response, as well as for regulating PKC activity, since inhibition of calcium influx with calcium channel antagonists decreases AngII-induced aldosterone secretion.	('aldosterone', 'Chemical', 'MESH:D000450', (221, 232))	('aldosterone', 'Chemical', 'MESH:D000450', (57, 68))	('calcium', 'Chemical', 'MESH:D002118', (149, 156))	('calcium', 'Chemical', 'MESH:D002118', (169, 176))	('AngII-induced aldosterone secretion', 'MPA', (207, 242))	('decreases', 'NegReg', (197, 206))	('inhibition', 'Var', (135, 145))	('calcium', 'Chemical', 'MESH:D002118', (13, 20))
88652	21839803	Emptying of the endoplasmic reticulum store by IP3 also results in capacitative calcium influx, as discussed above.	('capacitative calcium influx', 'MPA', (67, 94))	('calcium', 'Chemical', 'MESH:D002118', (80, 87))	('IP3', 'Chemical', 'MESH:D015544', (47, 50))	('IP3', 'Var', (47, 50))	('results in', 'Reg', (56, 66))
88673	21839803	Thus, as discussed above, DAG can be produced by both AngII-activated phospholipase C and PLD and, in turn, can activate DAG effector enzymes, which include PKC isoenzymes and protein kinase D (PKD), as well as Ras guanine nucleotide exchange factors (Ras-GRP1 through 3), which are upstream of the mitogen-activated protein kinase pathway involving Ras, Raf, MEK and ERK-1/2, and chimaerins (GTPase-activating proteins for Rac).	('DAG', 'Chemical', 'MESH:D004075', (26, 29))	('ERK-1/2', 'Gene', (368, 375))	('DAG', 'Gene', (121, 124))	('DAG', 'Chemical', 'MESH:D004075', (121, 124))	('Raf', 'Gene', '22882', (355, 358))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (215, 233))	('protein kinase D', 'Gene', '5587', (176, 192))	('ERK-1/2', 'Gene', '5595;5594', (368, 375))	('MEK', 'Gene', '5609', (360, 363))	('AngII-activated', 'Var', (54, 69))	('protein kinase D', 'Gene', (176, 192))	('activate', 'PosReg', (112, 120))	('Raf', 'Gene', (355, 358))	('PLD', 'Gene', '2822', (90, 93))	('MEK', 'Gene', (360, 363))	('PKC', 'Enzyme', (157, 160))	('PLD', 'Gene', (90, 93))	('mitogen-activated', 'Pathway', (299, 316))	('GTP', 'Chemical', 'MESH:D006160', (393, 396))
88682	21839803	Bollag and colleagues have also demonstrated that treatment of H295R cells with the DAG-mimicking phorbol ester, phorbol 12-myristate 13-acetate (PMA) increases mitochondrial cholesterol levels and aldosterone secretion, providing evidence for a possible role of PKC (and/or other DAG effector enzymes) in cholesterol transport and aldosterone production.	('PMA', 'Chemical', 'MESH:D013755', (146, 149))	('DAG', 'Chemical', 'MESH:D004075', (281, 284))	('aldosterone', 'Chemical', 'MESH:D000450', (198, 209))	('aldosterone secretion', 'MPA', (198, 219))	('increases', 'PosReg', (151, 160))	('aldosterone', 'Chemical', 'MESH:D000450', (332, 343))	('cholesterol', 'Chemical', 'MESH:D002784', (175, 186))	('mitochondrial cholesterol levels', 'MPA', (161, 193))	('phorbol 12-myristate 13-acetate', 'Chemical', 'MESH:D013755', (113, 144))	('rat', 'Species', '10116', (39, 42))	('H295R', 'CellLine', 'CVCL:0458', (63, 68))	('phorbol', 'Var', (113, 120))	('cholesterol', 'Chemical', 'MESH:D002784', (306, 317))	('aldosterone production', 'Phenotype', 'HP:0000859', (332, 354))	('phorbol ester', 'Chemical', 'MESH:D010703', (98, 111))	('DAG', 'Chemical', 'MESH:D004075', (84, 87))
88686	21839803	Introduction of a null mutation of the PBR gene into R2C rat Leydig tumor cells inhibited pregnenolone production in response to 22R-hydroxycholesterol, a precursor that bypasses the need for StAR supporting an important role for this protein in steroidogenesis.	('null mutation', 'Var', (18, 31))	('Leydig tumor', 'Disease', (61, 73))	('22R-hydroxycholesterol', 'Chemical', 'MESH:C003585', (129, 151))	('steroid', 'Chemical', 'MESH:D013256', (246, 253))	('Leydig tumor', 'Phenotype', 'HP:0100618', (61, 73))	('pregnenolone production', 'MPA', (90, 113))	('response to 22R-hydroxycholesterol', 'MPA', (117, 151))	('rat', 'Species', '10116', (57, 60))	('PBR', 'Gene', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Leydig tumor', 'Disease', 'MESH:D007984', (61, 73))	('pregnenolone', 'Chemical', 'MESH:D011284', (90, 102))	('inhibited', 'NegReg', (80, 89))
88691	21839803	Moreover, adenovirus-mediated overexpression of a constitutively active PKD1 mutant enhances, and a dominant-negative PKD1 mutant inhibits acute AngII-induced aldosterone secretion in these cells.	('PKD1', 'Gene', '5310', (72, 76))	('enhances', 'PosReg', (84, 92))	('PKD1', 'Gene', '5310', (118, 122))	('PKD1', 'Gene', (72, 76))	('acute AngII-induced aldosterone secretion', 'MPA', (139, 180))	('aldosterone', 'Chemical', 'MESH:D000450', (159, 170))	('mutant', 'Var', (77, 83))	('PKD1', 'Gene', (118, 122))	('inhibits', 'NegReg', (130, 138))
88692	21839803	PKD performs a similar role to enhance chronic AngII-induced aldosterone secretion and aldosterone synthase expression in the H295R cell model, a result which was corroborated by a study showing that knocking down PKD levels with RNA interference decreased AngII-stimulated aldosterone secretion from these cells.	('decreased', 'NegReg', (247, 256))	('aldosterone', 'Chemical', 'MESH:D000450', (61, 72))	('PKD', 'Var', (0, 3))	('aldosterone', 'Chemical', 'MESH:D000450', (274, 285))	('knocking down', 'Var', (200, 213))	('enhance', 'PosReg', (31, 38))	('rat', 'Species', '10116', (170, 173))	('H295R', 'CellLine', 'CVCL:0458', (126, 131))	('stimulated aldosterone', 'Phenotype', 'HP:0000859', (263, 285))	('chronic AngII-induced aldosterone secretion', 'MPA', (39, 82))	('RNA interference', 'MPA', (230, 246))	('aldosterone synthase expression', 'MPA', (87, 118))	('aldosterone', 'Chemical', 'MESH:D000450', (87, 98))
88695	21839803	While the mechanism by which PKD enhances aldosterone secretion is unclear, it is known that StAR gene transcription is influenced by several transcription factors that are targets for PKD, including cAMP response-element (CRE)-binding protein (CREB)/CRE modulator (CREM)/activating transcription factor (ATF) family members and activator protein-1 (AP-1, Fos/Jun).	('Fos', 'Gene', (356, 359))	('enhances', 'PosReg', (33, 41))	('activator protein-1', 'Gene', '2353', (329, 348))	('activator protein-1', 'Gene', (329, 348))	('influenced', 'Reg', (120, 130))	('transcription', 'MPA', (103, 116))	('PKD', 'Var', (29, 32))	('StAR gene', 'Gene', (93, 102))	('aldosterone', 'Chemical', 'MESH:D000450', (42, 53))	('aldosterone secretion', 'MPA', (42, 63))	('Fos', 'Gene', '2353', (356, 359))
88697	21839803	Also as with AngII, this influx is required for the response to potassium, since inhibition of calcium influx abolishes potassium-stimulated aldosterone secretion.	('inhibition', 'Var', (81, 91))	('potassium', 'Chemical', 'MESH:D011188', (120, 129))	('potassium-stimulated aldosterone secretion', 'MPA', (120, 162))	('calcium', 'Chemical', 'MESH:D002118', (95, 102))	('potassium', 'Chemical', 'MESH:D011188', (64, 73))	('aldosterone', 'Chemical', 'MESH:D000450', (141, 152))	('stimulated aldosterone', 'Phenotype', 'HP:0000859', (130, 152))	('abolishes', 'NegReg', (110, 119))
88713	21839803	AngII increases the expression of enzymes required for aldosterone synthesis, particularly CYP11B2.	('CYP11B2', 'Var', (91, 98))	('expression', 'MPA', (20, 30))	('aldosterone', 'Chemical', 'MESH:D000450', (55, 66))	('increases', 'PosReg', (6, 15))
88714	21839803	Sodium restriction experiments in rats indicate that activation of the renin-AngII system (most often by low sodium diets) induces the expression of CYP11B2 in glomerulosa cells without affecting that of CYP11B1.	('sodium', 'Chemical', 'MESH:D012964', (109, 115))	('rats', 'Species', '10116', (34, 38))	('renin', 'Gene', '5972', (71, 76))	('low sodium', 'Phenotype', 'HP:0002902', (105, 115))	('CYP11B2', 'Var', (149, 156))	('Sodium', 'Chemical', 'MESH:D012964', (0, 6))	('expression', 'MPA', (135, 145))	('renin', 'Gene', (71, 76))
88728	21839803	However, it appears that the relative level of SF1 may decide its ability to repress CYP11B2 expression, since complete knock down of SF1 impairs the entire steroidogenic synthetic pathway.	('steroid', 'Chemical', 'MESH:D013256', (157, 164))	('SF1', 'Gene', '2516', (47, 50))	('SF1', 'Gene', '2516', (134, 137))	('steroidogenic', 'Pathway', (157, 170))	('expression', 'MPA', (93, 103))	('knock down', 'Var', (120, 130))	('impairs', 'NegReg', (138, 145))	('SF1', 'Gene', (47, 50))	('SF1', 'Gene', (134, 137))	('CYP11B2', 'Gene', (85, 92))
88738	21839803	Worth noting is the fact that in mice with targeted deletion of the renin/AngII system, potassium can substitute for the effects of AngII to increase adrenal expression of CYP11B2 and synthesis of aldosterone.	('adrenal expression', 'MPA', (150, 168))	('renin', 'Gene', (68, 73))	('aldosterone', 'Chemical', 'MESH:D000450', (197, 208))	('potassium', 'Chemical', 'MESH:D011188', (88, 97))	('increase', 'PosReg', (141, 149))	('renin', 'Gene', '5972', (68, 73))	('mice', 'Species', '10090', (33, 37))	('synthesis of aldosterone', 'MPA', (184, 208))	('increase adrenal', 'Phenotype', 'HP:0008221', (141, 157))	('deletion', 'Var', (52, 60))
88747	21839803	These results may help to explain the finding that in transgenic mice with targeted deletion in the renin-angiotensin system, potassium can induce CYP11B2 expression in the adrenal as well as the synthesis of aldosterone.	('synthesis of aldosterone', 'MPA', (196, 220))	('induce', 'PosReg', (140, 146))	('targeted deletion', 'Var', (75, 92))	('CYP11B2', 'Gene', (147, 154))	('renin', 'Gene', (100, 105))	('aldosterone', 'Chemical', 'MESH:D000450', (209, 220))	('transgenic mice', 'Species', '10090', (54, 69))	('expression', 'MPA', (155, 165))	('potassium', 'Chemical', 'MESH:D011188', (126, 135))	('renin', 'Gene', '5972', (100, 105))
88757	21839803	Another similarity that potassium shares with AngII is the ability to activate several transcription factors, such as of NURR1, ATF1, ATF2 and CREB, which bind the proximal promoter of CYP11B2 at key cis-elements to enhance transcription.	('CYP11B2', 'Var', (185, 192))	('enhance', 'PosReg', (216, 223))	('transcription', 'MPA', (224, 237))	('ATF2', 'Gene', '1386', (134, 138))	('ATF1', 'Gene', (128, 132))	('ATF1', 'Gene', '466', (128, 132))	('NURR1', 'Gene', '4929', (121, 126))	('potassium', 'Chemical', 'MESH:D011188', (24, 33))	('NURR1', 'Gene', (121, 126))	('ATF2', 'Gene', (134, 138))
88759	21839803	Supporting these data is a recent study in which knock down of these transcription factors by siRNA technology reduced potassium-induced CYP11B2 promoter activity and mRNA levels.	('knock down', 'Var', (49, 59))	('potassium-induced CYP11B2 promoter activity', 'MPA', (119, 162))	('reduced', 'NegReg', (111, 118))	('potassium', 'Chemical', 'MESH:D011188', (119, 128))	('mRNA levels', 'MPA', (167, 178))
88771	21839803	demonstrated that ablation of the pituitary pre-proopiomelanocortin-secreting cells that produce ACTH, and the resultant low ACTH level, was accompanied by a steep decrease in the transcript levels of CYP11B1, but not of CYP11B2.	('ACTH', 'Gene', (97, 101))	('transcript levels', 'MPA', (180, 197))	('ACTH', 'Gene', '5443', (97, 101))	('ACTH', 'Gene', '5443', (125, 129))	('decrease', 'NegReg', (164, 172))	('rat', 'Species', '10116', (7, 10))	('low ACTH level', 'Phenotype', 'HP:0002920', (121, 135))	('low', 'NegReg', (121, 124))	('ablation', 'Var', (18, 26))	('ACTH', 'Gene', (125, 129))	('CYP11B1', 'MPA', (201, 208))
88774	21839803	While the H295R adrenocortical cell lines express low levels of ACTH receptors, treatment of these cells with cAMP analogs preferentially increases the expression of CYP11B1 over that of CYP11B2.	('increases', 'PosReg', (138, 147))	('ACTH receptor', 'Gene', (64, 77))	('H295R', 'CellLine', 'CVCL:0458', (10, 15))	('ACTH receptor', 'Gene', '4158', (64, 77))	('adrenocortical', 'Disease', (16, 30))	('CYP11B1', 'Var', (166, 173))	('adrenocortical', 'Disease', 'MESH:D018268', (16, 30))	('expression', 'MPA', (152, 162))
88778	21839803	Since CYP11B2 has a cAMP-regulatory element (CRE) in its 5' promoter region, the mechanism preventing glomerulosa cells from responding to ACTH with increased CYP11B2 and excessive aldosterone production is not clear, but two possible mechanisms have been suggested thus far.	('aldosterone production', 'Phenotype', 'HP:0000859', (181, 203))	('ACTH', 'Gene', (139, 143))	('CYP11B2', 'Var', (6, 13))	('ACTH', 'Gene', '5443', (139, 143))	('excessive aldosterone', 'Phenotype', 'HP:0000859', (171, 192))	('CYP11B2', 'Var', (159, 166))	('increased', 'PosReg', (149, 158))	('aldosterone', 'Chemical', 'MESH:D000450', (181, 192))
88787	21839803	Recently, several mouse models have been developed in an attempt to study PA. Two recent studies using different mouse models, both with a deletion of genes encoding TWIK-related acid-sensitive K (TASK) channels, have provided interestingly different and complex primary aldosteronism phenotypes.	('PA', 'Chemical', 'MESH:D010712', (74, 76))	('deletion', 'Var', (139, 147))	('mouse', 'Species', '10090', (18, 23))	('complex primary aldosteronism', 'Phenotype', 'HP:0011739', (255, 284))	('primary aldosteronism', 'Disease', (263, 284))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (263, 284))	('PA', 'Phenotype', 'HP:0011736', (74, 76))	('mouse', 'Species', '10090', (113, 118))
88789	21839803	In the study by Heitzmann et al., deletion of the TASK-1 channel resulted in a phenotype similar to the pathology of GRA, with characteristics such as salt-insensitive hyperaldosteronism, hypokalemia and dexamethasone-suppressible aldosterone secretion.	('salt', 'Chemical', 'MESH:D012492', (151, 155))	('aldosterone', 'Chemical', 'MESH:D000450', (231, 242))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (168, 186))	('dexamethasone-suppressible aldosterone', 'Phenotype', 'HP:0011739', (204, 242))	('dexamethasone-suppressible aldosterone secretion', 'MPA', (204, 252))	('hypokalemia', 'Disease', (188, 199))	('salt-insensitive', 'Phenotype', 'HP:0000127', (151, 167))	('hypokalemia', 'Disease', 'MESH:D007008', (188, 199))	('deletion', 'Var', (34, 42))	('resulted in', 'Reg', (65, 76))	('hyperaldosteronism', 'Disease', (168, 186))	('hypokalemia', 'Phenotype', 'HP:0002900', (188, 199))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (168, 186))	('dexamethasone', 'Chemical', 'MESH:D003907', (204, 217))
88790	21839803	The deletion of TASK-1 also seemed to change adrenal zonation and expression of CYP11B2, which was absent in the outermost zona glomerulosa but was expressed to a large extent in the zona fasciculata.	('CYP11B2', 'Gene', (80, 87))	('zona fasciculata', 'Disease', (183, 199))	('zona fasciculata', 'Disease', 'MESH:D006562', (183, 199))	('change', 'Reg', (38, 44))	('expression', 'MPA', (66, 76))	('deletion', 'Var', (4, 12))	('adrenal zonation', 'MPA', (45, 61))	('TASK-1', 'Gene', (16, 22))
88792	21839803	have also identified both germ-line and somatic mutations that occur near the selectivity filter of the inward rectifying potassium channel KCNJ5 (Kir3.4) to result in PA.	('Kir3.4', 'Gene', (147, 153))	('PA', 'Chemical', 'MESH:D010712', (168, 170))	('potassium', 'Chemical', 'MESH:D011188', (122, 131))	('KCNJ5', 'Gene', (140, 145))	('Kir3.4', 'Gene', '3762', (147, 153))	('result in', 'Reg', (158, 167))	('PA', 'Phenotype', 'HP:0011736', (168, 170))	('mutations', 'Var', (48, 57))
88793	21839803	The amino acid substitutions resulting from these mutations modified channel ion selectivity, such that the channel became permeable to both sodium and potassium, which led to increased depolarization of adrenocortical cells.	('channel ion selectivity', 'MPA', (69, 92))	('became', 'Reg', (116, 122))	('increased', 'PosReg', (176, 185))	('mutations', 'Var', (50, 59))	('modified', 'Reg', (60, 68))	('adrenocortical', 'Disease', (204, 218))	('depolarization', 'MPA', (186, 200))	('adrenocortical', 'Disease', 'MESH:D018268', (204, 218))	('sodium', 'Chemical', 'MESH:D012964', (141, 147))	('potassium', 'Chemical', 'MESH:D011188', (152, 161))
88794	21839803	This depolarization is believed to cause elevated intracellular calcium and thereby the production of aldosterone and cell proliferation.	('depolarization', 'Var', (5, 19))	('calcium', 'Chemical', 'MESH:D002118', (64, 71))	('aldosterone', 'Chemical', 'MESH:D000450', (102, 113))	('elevated', 'PosReg', (41, 49))	('rat', 'Species', '10116', (130, 133))	('production of aldosterone', 'MPA', (88, 113))	('cell proliferation', 'CPA', (118, 136))	('intracellular calcium', 'MPA', (50, 71))	('elevated intracellular calcium', 'Phenotype', 'HP:0003575', (41, 71))
88795	21839803	These findings are particularly relevant in that almost 40% of aldosterone-producing adenomas appeared to have such a mutation in KCNJ5.	('adenomas', 'Disease', 'MESH:D000236', (85, 93))	('mutation', 'Var', (118, 126))	('aldosterone', 'Chemical', 'MESH:D000450', (63, 74))	('adenomas', 'Disease', (85, 93))	('KCNJ5', 'Gene', (130, 135))
88796	21839803	Additional studies will be needed to determine the exact mechanisms through which these mutations cause expansion of aldosterone-producing cells and formation of adenomas.	('adenomas', 'Disease', 'MESH:D000236', (162, 170))	('adenomas', 'Disease', (162, 170))	('expansion of aldosterone', 'Phenotype', 'HP:0000859', (104, 128))	('mutations', 'Var', (88, 97))	('aldosterone', 'Chemical', 'MESH:D000450', (117, 128))	('aldosterone-producing cells', 'MPA', (117, 144))
88799	21839803	Dysregulation in aldosterone secretion, as is seen in primary aldosteronism, leads to pathologies such as hypertension and cardiovascular disease.	('hypertension', 'Disease', 'MESH:D006973', (106, 118))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (123, 145))	('Dysregulation', 'Var', (0, 13))	('aldosterone', 'Chemical', 'MESH:D000450', (17, 28))	('hypertension', 'Disease', (106, 118))	('cardiovascular disease', 'Disease', 'MESH:D002318', (123, 145))	('hypertension', 'Phenotype', 'HP:0000822', (106, 118))	('primary aldosteronism', 'Disease', (54, 75))	('aldosterone secretion', 'MPA', (17, 38))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (54, 75))	('cardiovascular disease', 'Disease', (123, 145))	('leads to', 'Reg', (77, 85))
88801	21839803	The recent development of unique mouse models of primary aldosteronism and the discovery of the KCNJ5 mutations as a cause of human PA have been particularly helpful in providing new clues to the mechanisms controlling aldosterone production and the adrenal glomerulosa cell phenotype.	('primary aldosteronism', 'Phenotype', 'HP:0011736', (49, 70))	('human', 'Species', '9606', (126, 131))	('KCNJ5', 'Gene', (96, 101))	('PA', 'Phenotype', 'HP:0011736', (132, 134))	('aldosterone', 'Chemical', 'MESH:D000450', (219, 230))	('mutations', 'Var', (102, 111))	('cause', 'Reg', (117, 122))	('PA', 'Chemical', 'MESH:D010712', (132, 134))	('mouse', 'Species', '10090', (33, 38))	('aldosterone production', 'Phenotype', 'HP:0000859', (219, 241))
88821	21693041	Inhibition of aromatase enzyme activity has been shown to reduce estrogen production throughout the body and aromatase inhibitors (AIs) are being used clinically to retard the development and progression of hormone-responsive breast cancer.	('activity', 'MPA', (31, 39))	('aromatase', 'Gene', '1588', (109, 118))	('estrogen production', 'MPA', (65, 84))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('breast cancer', 'Disease', (226, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('retard', 'NegReg', (165, 171))	('reduce', 'NegReg', (58, 64))	('aromatase', 'Gene', (109, 118))	('Inhibition', 'Var', (0, 10))	('aromatase', 'Gene', (14, 23))	('aromatase', 'Gene', '1588', (14, 23))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))
88838	21693041	Estrogens are suggested to cause breast cancer by stimulating cell growth and proliferation through receptor-mediated processes and via their genotoxic metabolites; therefore, inhibition of estrogen production/effect is nowadays a common practice for breast cancer treatment.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('breast cancer', 'Disease', 'MESH:D001943', (251, 264))	('rat', 'Species', '10116', (85, 88))	('breast cancer', 'Disease', (251, 264))	('inhibition', 'Var', (176, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cell growth', 'CPA', (62, 73))	('breast cancer', 'Disease', (33, 46))	('stimulating', 'PosReg', (50, 61))
88852	21693041	Moreover, due to indiscriminate reduction of aromatase activity in all expression sites of the body, AIs can induce many side effects such as bone loss, hepatic steatosis and abnormal lipid metabolism.	('abnormal lipid metabolism', 'MPA', (175, 200))	('activity', 'MPA', (55, 63))	('aromatase', 'Gene', '1588', (45, 54))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (153, 170))	('bone loss', 'Phenotype', 'HP:0002797', (142, 151))	('hepatic steatosis', 'Disease', (153, 170))	('bone loss', 'Disease', (142, 151))	('hepatic steatosis', 'Disease', 'MESH:D005234', (153, 170))	('reduction', 'NegReg', (32, 41))	('lipid', 'Chemical', 'MESH:D008055', (184, 189))	('bone loss', 'Disease', 'MESH:D016301', (142, 151))	('abnormal lipid metabolism', 'Phenotype', 'HP:0003119', (175, 200))	('induce', 'Reg', (109, 115))	('AIs', 'Var', (101, 104))	('aromatase', 'Gene', (45, 54))
88859	21693041	The RXR agonist LG101305 (the FDA approved drug is bexarotene) induced hypertriglyceridemia, hypercholesterolemia, hypothyroidism and leucopenia.	('bexarotene', 'Chemical', 'MESH:D000077610', (51, 61))	('hypothyroidism', 'Phenotype', 'HP:0000821', (115, 129))	('RXR', 'Gene', (4, 7))	('hypercholesterolemia', 'Disease', (93, 113))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (93, 113))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (93, 113))	('RXR', 'Gene', '6256', (4, 7))	('hypothyroidism and leucopenia', 'Disease', 'MESH:C536227', (115, 144))	('hypertriglyceridemia', 'Phenotype', 'HP:0002155', (71, 91))	('hypertriglyceridemia', 'Disease', 'MESH:D015228', (71, 91))	('LG101305', 'Chemical', 'MESH:C424882', (16, 24))	('hypertriglyceridemia', 'Disease', (71, 91))	('LG101305', 'Var', (16, 24))
88860	21693041	Sodium butyrate induced bradycardia while p38 inhibitor SB202190 is toxic to liver and the JNK inhibitor AS601245 have no reported side effects compared to others.	('p38', 'Gene', (42, 45))	('bradycardia', 'Disease', (24, 35))	('SB202190', 'Chemical', 'MESH:C090942', (56, 64))	('JNK', 'Gene', (91, 94))	('Sodium butyrate', 'Chemical', 'MESH:D020148', (0, 15))	('JNK', 'Gene', '5599', (91, 94))	('bradycardia', 'Disease', 'MESH:D001919', (24, 35))	('SB202190', 'Var', (56, 64))	('p38', 'Gene', '5594', (42, 45))	('bradycardia', 'Phenotype', 'HP:0001662', (24, 35))	('AS601245', 'Chemical', 'MESH:C489138', (105, 113))
88890	21693041	Dietary genistein, which produced circulating concentrations consistent with human exposures, did not act as an aromatase inhibitor; rather, dietary intake of genistein negated the inhibitory effect of an aromatase inhibitor letrozole (a 3rd generation aromatase inhibitor), by stimulating the growth of aromatase-expressing estrogen-dependent breast tumors.	('breast tumors', 'Disease', 'MESH:D001943', (344, 357))	('rat', 'Species', '10116', (246, 249))	('breast tumors', 'Disease', (344, 357))	('genistein', 'Var', (159, 168))	('aromatase', 'Gene', (304, 313))	('aromatase', 'Gene', '1588', (253, 262))	('letrozole', 'Chemical', 'MESH:D000077289', (225, 234))	('stimulating', 'PosReg', (278, 289))	('breast tumors', 'Phenotype', 'HP:0100013', (344, 357))	('negated', 'NegReg', (169, 176))	('aromatase', 'Gene', (112, 121))	('rat', 'Species', '10116', (133, 136))	('aromatase', 'Gene', '1588', (205, 214))	('tumors', 'Phenotype', 'HP:0002664', (351, 357))	('aromatase', 'Gene', (253, 262))	('rat', 'Species', '10116', (53, 56))	('aromatase', 'Gene', '1588', (304, 313))	('genistein', 'Chemical', 'MESH:D019833', (159, 168))	('genistein', 'Chemical', 'MESH:D019833', (8, 17))	('inhibitory effect', 'MPA', (181, 198))	('human', 'Species', '9606', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('aromatase', 'Gene', (205, 214))	('growth', 'MPA', (294, 300))	('aromatase', 'Gene', '1588', (112, 121))	('breast tumor', 'Phenotype', 'HP:0100013', (344, 356))
88921	21693041	However, in human skin fibroblasts hypermethylation of almost all six CpG sites resulted in markedly reduced aromatase promoter I.3/II activity, whereas hypomethylation of only two of the six sites led to increased promoter activity associated with an increase in cAMP.	('hypermethylation', 'Var', (35, 51))	('CpG', 'Gene', (70, 73))	('promoter activity', 'MPA', (215, 232))	('cAMP', 'MPA', (264, 268))	('increased', 'PosReg', (205, 214))	('reduced', 'NegReg', (101, 108))	('aromatase', 'Gene', (109, 118))	('human', 'Species', '9606', (12, 17))	('aromatase', 'Gene', '1588', (109, 118))	('cAMP', 'Chemical', '-', (264, 268))
88925	21693041	These studies indicate that disruption in epigenetic regulation may give rise to increase in aromatase levels in the breast.	('aromatase', 'Gene', (93, 102))	('aromatase', 'Gene', '1588', (93, 102))	('disruption', 'Var', (28, 38))	('increase', 'PosReg', (81, 89))	('epigenetic regulation', 'Var', (42, 63))
88943	17520059	Exogenous SF-1 conveyed atrazine-responsiveness to otherwise nonresponsive KGN and NIH/3T3 cells.	('Exogenous', 'Var', (0, 9))	('atrazine', 'Chemical', 'MESH:D001280', (24, 32))	('SF-1', 'Gene', (10, 14))	('KGN', 'Chemical', '-', (75, 78))	('atrazine-responsiveness', 'MPA', (24, 47))	('NIH/3T3', 'CellLine', 'CVCL:0594', (83, 90))
88944	17520059	Atrazine induced binding of SF-1 to chromatin and mutation of the SF-1 binding site in ArPII eliminated SF-1 binding and atrazine-responsiveness in H295R cells.	('atrazine-responsiveness', 'MPA', (121, 144))	('binding', 'Interaction', (17, 24))	('SF-1', 'MPA', (104, 108))	('atrazine', 'Chemical', 'MESH:D001280', (121, 129))	('Atrazine', 'Chemical', 'MESH:D001280', (0, 8))	('binding', 'Interaction', (109, 116))	('eliminated', 'NegReg', (93, 103))	('mutation', 'Var', (50, 58))	('SF-1', 'Gene', (66, 70))
88952	17520059	Among other endocrine-disrupting effects, atrazine disrupts androgen- and estrogen-mediated processes.	('disrupts', 'NegReg', (51, 59))	('atrazine', 'Var', (42, 50))	('atrazine', 'Chemical', 'MESH:D001280', (42, 50))	('androgen-', 'CPA', (60, 69))
88954	17520059	Atrazine reduces androgen synthesis and action via several mechanisms and it increases estrogen production.	('androgen synthesis', 'MPA', (17, 35))	('estrogen production', 'MPA', (87, 106))	('Atrazine', 'Var', (0, 8))	('increases', 'PosReg', (77, 86))	('increases estrogen production', 'Phenotype', 'HP:0025134', (77, 106))	('reduces androgen synthesis', 'Phenotype', 'HP:0008226', (9, 35))	('action', 'MPA', (40, 46))	('Atrazine', 'Chemical', 'MESH:D001280', (0, 8))
88968	17520059	We used surface plasmon resonance (SPR) to examine the ability of atrazine to bind directly to SF-1 as a second mechanism by which atrazine could induce gene expression via ArPII.	('atrazine', 'Var', (131, 139))	('atrazine', 'Chemical', 'MESH:D001280', (66, 74))	('ArPII', 'Protein', (173, 178))	('induce', 'PosReg', (146, 152))	('atrazine', 'Chemical', 'MESH:D001280', (131, 139))	('gene expression', 'MPA', (153, 168))
89004	17520059	We also performed deletion-mutation assays on the 4.0 kb ArPII to identify the responsible site for atrazine and simazine stimulation.	('deletion-mutation', 'Var', (18, 35))	('ArPII', 'Gene', (57, 62))	('atrazine', 'Chemical', 'MESH:D001280', (100, 108))	('simazine', 'Chemical', 'MESH:D012839', (113, 121))
89006	17520059	The 516 bp ArPII luciferase reporter (PGL3-PII-516) and the PGL3-PII-516-SF1-M (of which the SF-1 site was mutated from AGGTCA to ATTTCA) were provided courtesy of E.R.	('PGL3', 'Gene', '6391', (60, 64))	('PGL3', 'Gene', (60, 64))	('SF1', 'Gene', (73, 76))	('mutated', 'Var', (107, 114))	('PGL3', 'Gene', '6391', (38, 42))	('PGL3', 'Gene', (38, 42))	('SF1', 'Gene', '7536', (73, 76))
89031	17520059	Thus, exogenous SF-1 conferred aromatase responsiveness to atrazine and simazine in otherwise atrazine-nonresponsive KGN granulosa cells.	('aromatase', 'Gene', '1588', (31, 40))	('SF-1', 'Gene', (16, 20))	('atrazine', 'Chemical', 'MESH:D001280', (59, 67))	('KGN', 'Chemical', '-', (117, 120))	('atrazine', 'Chemical', 'MESH:D001280', (94, 102))	('exogenous', 'Var', (6, 15))	('simazine', 'Chemical', 'MESH:D012839', (72, 80))	('aromatase', 'Gene', (31, 40))
89035	17520059	The responsiveness to atrazine and simazine was well-preserved when ArPII was reduced to 516 bp; however, when the SF-1 binding site (AGGTCA) was mutated to ATTTCA (a treatment that impairs SF-1 binding to ArPII), the responsiveness to atrazine and simazine was eliminated (ANOVA, p < 0.05; Figure 5C).	('binding', 'Interaction', (195, 202))	('mutated', 'Var', (146, 153))	('simazine', 'Chemical', 'MESH:D012839', (249, 257))	('simazine', 'Chemical', 'MESH:D012839', (35, 43))	('AGGTCA', 'Gene', (134, 140))	('men', 'Species', '9606', (172, 175))	('atrazine', 'Chemical', 'MESH:D001280', (236, 244))	('atrazine', 'Chemical', 'MESH:D001280', (22, 30))
89065	17520059	Atrazine increases the incidence of mammary cancer in rodents, and at least one cohort study in humans showed that atrazine is associated with breast cancer in women whose well water is contaminated with atrazine.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('associated', 'Reg', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('breast cancer', 'Disease', (143, 156))	('water', 'Chemical', 'MESH:D014867', (177, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('cancer', 'Disease', (44, 50))	('women', 'Species', '9606', (160, 165))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('Atrazine', 'Var', (0, 8))	('atrazine', 'Chemical', 'MESH:D001280', (115, 123))	('atrazine', 'Chemical', 'MESH:D001280', (204, 212))	('humans', 'Species', '9606', (96, 102))	('atrazine', 'Var', (115, 123))	('Atrazine', 'Chemical', 'MESH:D001280', (0, 8))
89066	17520059	Atrazine induces prostatitis and prostate cancer in rats and was also associated with an 8.4-fold increase in prostate cancer in men working in an atrazine production facility in San Gabriel, Louisiana.	('prostatitis and prostate cancer', 'Disease', 'MESH:D011471', (17, 48))	('prostatitis', 'Phenotype', 'HP:0000024', (17, 28))	('atrazine', 'Chemical', 'MESH:D001280', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('prostate cancer', 'Disease', (33, 48))	('rats', 'Species', '10116', (52, 56))	('increase', 'PosReg', (98, 106))	('men', 'Species', '9606', (129, 132))	('Atrazine', 'Var', (0, 8))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('prostate cancer', 'Disease', 'MESH:D011471', (33, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('prostate cancer', 'Disease', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('Atrazine', 'Chemical', 'MESH:D001280', (0, 8))
89109	31437624	TARGET datasets include large-scale genomic data including gene-expression, copy number variation, epigenetics, along with annotated clinical information for a selected set of pediatric cancers (https://ocg.cancer.gov/programs/target/data-matrix).	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('copy number variation', 'Var', (76, 97))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
89140	31437624	Using 39 pedigrees, researchers were able to determine that the most common cause of LFS is inherited mutations in the tumor suppressor gene TP53.	('tumor', 'Disease', (119, 124))	('TP53', 'Gene', '7157', (141, 145))	('LFS', 'Disease', 'MESH:D016864', (85, 88))	('TP53', 'Gene', (141, 145))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cause', 'Reg', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('LFS', 'Disease', (85, 88))
89160	31437624	analyzed the mutation landscape of 12 major cancer types and found that TP53 and PIK3CA were the most commonly mutated genes, ARID1A were frequently mutated in bladder urothelial carcinoma (BLCA), uterine corpus endometrial carcinoma (UCEC), lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and EGFR were frequently mutated in GBM and LUAD.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (278, 301))	('mutated', 'Var', (149, 156))	('PIK3CA', 'Gene', '5290', (81, 87))	('lung adenocarcinoma', 'Disease', (242, 261))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (212, 233))	('bladder urothelial carcinoma', 'Disease', (160, 188))	('LUAD', 'Phenotype', 'HP:0030078', (263, 267))	('EGFR', 'Gene', (314, 318))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (212, 233))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (273, 301))	('TP53', 'Gene', '7157', (72, 76))	('lung squamous cell carcinoma', 'Disease', (273, 301))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (160, 188))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('GBM', 'Phenotype', 'HP:0012174', (346, 349))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (242, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (242, 261))	('PIK3CA', 'Gene', (81, 87))	('LUAD', 'Phenotype', 'HP:0030078', (354, 358))	('ARID1A', 'Gene', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('EGFR', 'Gene', '1956', (314, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('ARID1A', 'Gene', '8289', (126, 132))	('endometrial carcinoma', 'Disease', (212, 233))	('cancer', 'Disease', (44, 50))	('USC', 'Phenotype', 'HP:0002891', (304, 307))	('TP53', 'Gene', (72, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
89161	31437624	In contrast, VHL and PBRM1 mutations were exclusive to kidney renal clear cell carcinoma (KIRC), and NPM1 and FLT3 mutations were exclusive to AML.	('mutations', 'Var', (27, 36))	('FLT3', 'Gene', (110, 114))	('NPM1', 'Gene', '4869', (101, 105))	('kidney renal clear cell carcinoma', 'Disease', (55, 88))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (55, 88))	('FLT3', 'Gene', '2322', (110, 114))	('PBRM1', 'Gene', (21, 26))	('VHL', 'Gene', (13, 16))	('PBRM1', 'Gene', '55193', (21, 26))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('VHL', 'Gene', '7428', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('AML', 'Disease', (143, 146))	('NPM1', 'Gene', (101, 105))	('AML', 'Phenotype', 'HP:0004808', (143, 146))
89162	31437624	Numerous pan-cancer analyses have been performed, including pan-cancer analyses of copy number alteration, enhancer expression, oncogenic signaling pathways, and transcriptional metabolic dysregulation.	('copy number alteration', 'Var', (83, 105))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('enhancer', 'PosReg', (107, 115))	('oncogenic', 'CPA', (128, 137))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
89172	31437624	To illustrate the integrative clustering analysis, we analyzed 241 sarcoma tumor samples from the TCGA SARC study that had somatic mutation, copy number, methylation and mRNA expression data using the recently developed iClusterBayes software.	('sarcoma tumor', 'Disease', 'MESH:D012509', (67, 80))	('sarcoma tumor', 'Disease', (67, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('copy', 'Var', (141, 145))	('SARC', 'Phenotype', 'HP:0100242', (103, 107))	('mRNA expression', 'MPA', (170, 185))
89184	31949236	A reporter assay using the upstream region of rDhh and a GATA binding motif revealed that rDhh promoters were significantly upregulated by co-transfection with Gata4 or Gata6 or both.	('rDhh', 'Gene', (90, 94))	('rDhh', 'Gene', (46, 50))	('promoters', 'MPA', (95, 104))	('Gata6', 'Var', (169, 174))	('upregulated', 'PosReg', (124, 135))	('rDhh', 'Gene', '84380', (90, 94))	('rDhh', 'Gene', '84380', (46, 50))
89206	31949236	Dhh expression was 5-fold higher in the autografts than in the sham (Fig.	('autografts', 'Var', (40, 50))	('expression', 'Species', '29278', (4, 14))	('higher', 'PosReg', (26, 32))	('expression', 'MPA', (4, 14))	('Dhh', 'Gene', (0, 3))
89221	31949236	The rDhh promoter was significantly upregulated by co-transfection with Gata4 and/or Gata6 in H295R cells (Fig.	('upregulated', 'PosReg', (36, 47))	('Gata6', 'Var', (85, 90))	('Gata4', 'Var', (72, 77))	('rDhh', 'Gene', '84380', (4, 8))	('co-transfection', 'Var', (51, 66))	('rDhh', 'Gene', (4, 8))	('H295R', 'CellLine', 'CVCL:0458', (94, 99))
89222	31949236	GATA binding motifs are conserved in the upstream region of mouse Dhh (-230/-224) and human DHH (-1024/-1027, -1031/-1034, -1075/-1081).	('-230/-224', 'Var', (71, 80))	('mouse', 'Species', '10090', (60, 65))	('human', 'Species', '9606', (86, 91))	('-1024/-1027', 'Var', (97, 108))
89231	31949236	After E11.5-E12, the bipotent gonad differentiates into the testis or ovary with or without Sry and by Sox9 upregulation or downregulation.	('ovary', 'Disease', (70, 75))	('Sry', 'Gene', '25221', (92, 95))	('Sox9', 'Gene', (103, 107))	('E11.5-E12', 'Var', (6, 15))	('ovary', 'Disease', 'MESH:D010051', (70, 75))	('Sox9', 'Gene', '140586', (103, 107))	('downregulation', 'NegReg', (124, 138))	('upregulation', 'PosReg', (108, 120))	('Sry', 'Gene', (92, 95))
89283	31949236	; critical manuscript revision for important intellectual content: T.Y., N.T., T.M., S.T., H.Y.	('N.T.', 'Var', (73, 77))	('T.M.', 'Var', (79, 83))	('S.T', 'Disease', (85, 88))	('S.T', 'Disease', 'MESH:D018455', (85, 88))
89390	31516579	Furthermore, the yellow module negatively correlated with these two indexes, indicating that genes in this module may be associated with the prognosis of patients (Fig.	('associated with', 'Reg', (121, 136))	('patients', 'Species', '9606', (154, 162))	('genes', 'Var', (93, 98))	('negatively', 'NegReg', (31, 41))
89407	31516579	Mohan et al demonstrated that evaluation of G0S2 hypermethylation identified a subgroup of patients with ACC with a rapidly progressive disease course which is feasible for clinical treatment options.	('patients', 'Species', '9606', (91, 99))	('G0S2', 'Gene', (44, 48))	('hypermethylation', 'Var', (49, 65))	('ACC', 'Phenotype', 'HP:0006744', (105, 108))	('ACC', 'Disease', (105, 108))	('clinical', 'Species', '191496', (173, 181))	('G0S2', 'Gene', '50486', (44, 48))
89412	31516579	Uncontrolled self-renewal capacity and aberrant regulation of genetic material may promote tumor cell progression and recurrence.	('recurrence', 'CPA', (118, 128))	('genetic material', 'Protein', (62, 78))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('aberrant regulation', 'Var', (39, 58))	('promote', 'PosReg', (83, 90))	('tumor', 'Disease', (91, 96))
89413	31516579	Tripartite motif-containing protein 3 (TRIM3) has been used as a tumor suppressor due to its ability to regulate asymmetric cell division in glioblastoma and expression of TRIM3 additionally attenuates the stem-like quality of primary glioblastoma cultures.	('TRIM3', 'Gene', '10612', (172, 177))	('glioblastoma', 'Disease', 'MESH:D005909', (235, 247))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('tumor', 'Disease', (65, 70))	('TRIM3', 'Gene', (39, 44))	('glioblastoma', 'Phenotype', 'HP:0012174', (235, 247))	('TRIM3', 'Gene', '10612', (39, 44))	('expression', 'Var', (158, 168))	('attenuates', 'NegReg', (191, 201))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TRIM3', 'Gene', (172, 177))	('glioblastoma', 'Disease', (141, 153))	('Tripartite motif-containing protein 3', 'Gene', '10612', (0, 37))	('glioblastoma', 'Disease', 'MESH:D005909', (141, 153))	('Tripartite motif-containing protein 3', 'Gene', (0, 37))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('glioblastoma', 'Disease', (235, 247))
89415	31516579	These results indicate that cell division is associated with tumor progression and genes in the brown module may serve an important role in the regulation of cell division in patients with ACC.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('patients', 'Species', '9606', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('genes', 'Var', (83, 88))	('ACC', 'Phenotype', 'HP:0006744', (189, 192))	('ACC', 'Disease', (189, 192))	('tumor', 'Disease', (61, 66))
89423	31516579	Furthermore, knockdown of UBC and UBB with mixed small hairpin RNAs suppressed the growth and radio sensitivity of H1299 lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('H1299 lung cancer', 'Disease', (115, 132))	('suppressed', 'NegReg', (68, 78))	('UBC', 'Gene', '7316', (26, 29))	('UBB', 'Gene', (34, 37))	('H1299 lung cancer', 'Disease', 'MESH:D008175', (115, 132))	('UBC', 'Gene', (26, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('radio sensitivity', 'CPA', (94, 111))	('UBB', 'Gene', '7314', (34, 37))	('knockdown', 'Var', (13, 22))
89432	30442178	The rationale behind such molecular reclassifications is that genetic alterations underlying cancer pathology predict response to therapy and may therefore offer a more precise view on cancer than histology.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('predict', 'Reg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('genetic alterations', 'Var', (62, 81))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('response to therapy', 'MPA', (118, 137))
89433	30442178	The use of individual actionable mutations to select cancers for treatment across histotypes is already being tested in the so-called basket trials with variable success rates.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
89435	30442178	To determine effects of oncogenic mutations on protein profiles, we used the energy distance, which compares the Euclidean distances of protein profiles in tumors with an oncogenic mutation (inner distance) to that in tumors without the mutation (outer distance) and performed Monte Carlo simulations for the significance analysis.	('tumors', 'Disease', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('mutation', 'Var', (181, 189))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
89441	30442178	Next-generation sequencing has facilitated comprehensive mutational profiling of all major cancers and has led to the discovery of oncogenic driver mutations, many of which can be targeted therapeutically.	('mutations', 'Var', (148, 157))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
89443	30442178	However, sequencing data has shown that actionable mutations, albeit with different frequencies, occur across cancers, which has raised the question about histotype-independent therapies and novel ways of tumor classifications no longer relying on histology but on genetic profiles.	('cancers', 'Disease', (110, 117))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
89446	30442178	That targeted therapies against the same single molecular alteration can be effective across cancers, as shown, for instance, by the efficacy of anti-Her2 therapy in both gastric and breast cancers or the clinical benefit from inhibition of mutated cKIT in gastrointestinal stromal tumors (GIST) and melanoma or mastocytosis.	('gastric and breast cancers', 'Disease', 'MESH:D013274', (171, 197))	('melanoma or mastocytosis', 'Disease', (300, 324))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('Her2', 'Gene', '2064', (150, 154))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('gastrointestinal stromal tumors', 'Disease', (257, 288))	('GIST', 'Phenotype', 'HP:0100723', (290, 294))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('Her2', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('mutated', 'Var', (241, 248))	('melanoma', 'Phenotype', 'HP:0002861', (300, 308))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cKIT', 'Gene', '3815', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('cancers', 'Disease', (190, 197))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancers', 'Disease', (93, 100))	('melanoma or mastocytosis', 'Disease', 'MESH:D008415', (300, 324))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (257, 288))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (257, 288))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancers', 'Phenotype', 'HP:0003002', (183, 197))	('inhibition', 'Var', (227, 237))	('mastocytosis', 'Phenotype', 'HP:0100495', (312, 324))	('cKIT', 'Gene', (249, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
89447	30442178	However, the fact that inhibition of BRAF mutated at V600 is effective in melanoma but not in colorectal cancer is a prominent example against the general transferability of knowledge on a single actionable mutation from one histological tumor type to another.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('BRAF', 'Gene', '673', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('rectal cancer', 'Phenotype', 'HP:0100743', (98, 111))	('BRAF', 'Gene', (37, 41))	('mutated at V600', 'Var', (42, 57))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('ran', 'Gene', (156, 159))	('ran', 'Gene', '5901', (156, 159))
89449	30442178	Using mutational profiles or just single genetic aberrations, as is the case in the current basket trials, is unlikely to cover the full scope of (tissue-specific) molecular effects including epigenetic mechanisms and downstream regulation such as post-translational modifications.	('mutational', 'Var', (6, 16))	('ran', 'Gene', (254, 257))	('ran', 'Gene', '5901', (254, 257))
89464	30442178	To address the question of how mutational differences between two classes affect protein expressions in more than one histotype in the same way, we performed a cross-cancer effect analysis.	('mutational', 'Var', (31, 41))	('affect', 'Reg', (74, 80))	('protein expressions', 'MPA', (81, 100))	('cross-cancer', 'Disease', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cross-cancer', 'Disease', 'MESH:C537866', (160, 172))
89479	30442178	At this point, it is unclear whether the reason for this inconsistency between genetic and protein profiles is the differential translation of genetic profiles into protein levels in different cancer types, or organ- and tissue-specific protein base levels that are modulated by mutations:or a combination of both.	('ran', 'Gene', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('mutations', 'Var', (279, 288))	('ran', 'Gene', '5901', (129, 132))	('cancer', 'Disease', (193, 199))	('modulated', 'Reg', (266, 275))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
89493	30442178	In the proposal by Ciriello et al., tumors are classified by the presence of somatic mutations and copy number alterations in cancer-related pathways.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('copy number alterations', 'Var', (99, 122))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
89505	30442178	The least pronounced but still significant class discriminability is achieved for classes C12 and C5 in breast cancer (sdis = - 0.31, p = 4.4e-3; srand = - 8.0e-5).	('sdis', 'Chemical', '-', (119, 123))	('ran', 'Gene', (147, 150))	('ran', 'Gene', '5901', (147, 150))	('C12', 'Var', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
89524	30442178	With CES = 2%, the overall classification effectivity score of this classification is the lowest among all tested classifications indicating that global comparisons based on somatic mutations only are not effective in classifying tumors in a meaningful way if the available protein profiles are considered relevant.	('CES', 'Chemical', '-', (5, 8))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Disease', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('CES', 'Var', (5, 8))	('lowest', 'NegReg', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
89527	30442178	For this classification, class discriminability sdis is highest between class toLGG (cases that are most similar to low-grade glioma cases by their mutation profile) and class toPRAD for low-grade glioma (LGG) (sdis = - 3.26; p = 0.0; srand = - 6.1e-5; characteristic protein profiles increased in toLGG: p70S6K_pT389; increased in ToPRAD: YAP_pS127, HER2_pY1248, HER2, EGFR_pY1068, EGFR_pY1173, Src_pY416, and Cyclin_D1).	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('EGFR', 'Gene', (370, 374))	('HER2', 'Gene', '2064', (351, 355))	('increased', 'PosReg', (285, 294))	('sdis', 'Chemical', '-', (48, 52))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('p70S6K', 'Gene', '6198', (305, 311))	('Cyclin_D1', 'Gene', (411, 420))	('EGFR', 'Gene', (383, 387))	('sdis', 'Chemical', '-', (211, 215))	('EGFR', 'Gene', '1956', (370, 374))	('HER2', 'Gene', '2064', (364, 368))	('HER2', 'Gene', (351, 355))	('glioma', 'Disease', (126, 132))	('ran', 'Gene', (236, 239))	('ran', 'Gene', '5901', (236, 239))	('increased', 'PosReg', (319, 328))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('p70S6K', 'Gene', (305, 311))	('EGFR', 'Gene', '1956', (383, 387))	('glioma', 'Disease', (197, 203))	('Src_pY416', 'Var', (396, 405))	('HER2', 'Gene', (364, 368))	('Cyclin_D1', 'Gene', '595', (411, 420))	('glioma', 'Disease', 'MESH:D005910', (197, 203))
89550	30442178	Using the same approach as above, we are systematically evaluating all major actionable somatic mutations and copy number alterations against which drugs are approved for clinical use or which are currently tested in clinical trials with respect to their effects on proteins across cancers.	('cancers', 'Disease', (282, 289))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('cancers', 'Disease', 'MESH:D009369', (282, 289))	('copy number alterations', 'Var', (110, 133))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))	('mutations', 'Var', (96, 105))
89555	30442178	Overall, our analysis showed for all analyzed 12 actionable genes (OncoKB evidence levels 1-3) that the mutational status is associated with significant differences in protein profiles in histotypes for which the respective targeted drugs are approved or currently being clinically tested and showed additional mutation-associated protein profiles in 9 histological tumor types.	('tumor', 'Disease', (366, 371))	('mutational', 'Var', (104, 114))	('associated', 'Reg', (125, 135))	('protein profiles', 'MPA', (168, 184))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('differences', 'Reg', (153, 164))
89557	30442178	Only KRAS/NRAS mutations in colorectal cancer do not result in discriminable protein profiles comparing wild-type and mutated cases, whereas an effect can be observed for thyroid cancer and melanoma.	('result', 'Reg', (53, 59))	('NRAS', 'Gene', '4893', (10, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('rectal cancer', 'Phenotype', 'HP:0100743', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutations', 'Var', (15, 24))	('colorectal cancer', 'Disease', (28, 45))	('KRAS', 'Gene', (5, 9))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('KRAS', 'Gene', '3845', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('thyroid cancer', 'Disease', (171, 185))	('thyroid cancer', 'Phenotype', 'HP:0002890', (171, 185))	('NRAS', 'Gene', (10, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('thyroid cancer', 'Disease', 'MESH:D013964', (171, 185))
89560	30442178	Our results demonstrate that in addition to confirming known druggable genes in the available cell line data, protein profile discriminability in between presence or absence of oncogenic mutations is predictive of drug response in cell line data across cancers (p = 0.048, Table 2).	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('cancers', 'Disease', (253, 260))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('mutations', 'Var', (187, 196))	('protein', 'MPA', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
89561	30442178	BRAF mutations are actionable in melanomas (OncoKB level 1).	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Disease', (33, 42))
89562	30442178	Mutations of BRAF are frequent enough in our data for melanoma (46% cases with mutation) and thyroid carcinoma (not yet reported by OncoKB, 56% cases with mutation) for further analysis.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (93, 110))	('thyroid carcinoma', 'Disease', (93, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('BRAF', 'Gene', '673', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('mutation', 'Var', (79, 87))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (93, 110))
89563	30442178	The actionable mutations create discriminable groups of cases for thyroid carcinoma (sdis = - 2.07; p = 0.0; srand = - 1.0e-4) and melanoma (sdis = - 0.10; p = 4.7e-3; srand = - 1.1e-4).	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (66, 83))	('melanoma', 'Disease', (131, 139))	('thyroid carcinoma', 'Disease', (66, 83))	('sdis', 'Chemical', '-', (85, 89))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('mutations', 'Var', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ran', 'Gene', (110, 113))	('ran', 'Gene', '5901', (110, 113))	('sdis', 'Chemical', '-', (141, 145))	('ran', 'Gene', (169, 172))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (66, 83))	('ran', 'Gene', '5901', (169, 172))
89567	30442178	CDK4 amplification is actionable for differentiated sarcomas (OncoKB level 2).	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('amplification', 'Var', (5, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('sarcomas', 'Disease', (52, 60))	('CDK4', 'Gene', (0, 4))	('CDK4', 'Gene', '1019', (0, 4))
89569	30442178	For sarcoma, 36% of the cases show CDK4 amplification and protein profiles are discriminable (sdis = - 0.34; p = 0.0; srand = - 6.0e-5) with E-Cadherin, Caveolin-1, Akt_pS473, Cyclin_B1, ER-alpha, Akt_pT308, YAP_pS127, S6_pS240_S244, and Cyclin_E1 decreased and HSP70, Syk, Lck, Src_pY416, and Src_pY527 increased in CDK4 amplified cases.	('CDK4', 'Gene', '1019', (317, 321))	('Cyclin_B1', 'Gene', (176, 185))	('decreased', 'NegReg', (248, 257))	('Lck', 'Gene', (274, 277))	('ER-alpha', 'Gene', (187, 195))	('E-Cadherin', 'Gene', '999', (141, 151))	('ER-alpha', 'Gene', '2099', (187, 195))	('increased', 'PosReg', (304, 313))	('sdis', 'Chemical', '-', (94, 98))	('Syk', 'Gene', '6850', (269, 272))	('Cyclin_B1', 'Gene', '891', (176, 185))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('CDK4', 'Gene', (35, 39))	('HSP70', 'Gene', (262, 267))	('ran', 'Gene', (119, 122))	('sarcoma', 'Disease', (4, 11))	('ran', 'Gene', '5901', (119, 122))	('Syk', 'Gene', (269, 272))	('Cyclin_E1', 'Gene', '898', (238, 247))	('E-Cadherin', 'Gene', (141, 151))	('Caveolin-1', 'Gene', (153, 163))	('CDK4', 'Gene', (317, 321))	('CDK4', 'Gene', '1019', (35, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('Src_pY416', 'Var', (279, 288))	('Caveolin-1', 'Gene', '857', (153, 163))	('Src_pY527', 'Var', (294, 303))	('Cyclin_E1', 'Gene', (238, 247))	('HSP70', 'Gene', '3308', (262, 267))	('Lck', 'Gene', '3932', (274, 277))
89571	30442178	EGFR mutations are actionable in non-small cell lung cancer (OncoKB level 1).	('EGFR', 'Gene', (0, 4))	('non-small cell lung cancer', 'Disease', (33, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (37, 59))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (33, 59))	('EGFR', 'Gene', '1956', (0, 4))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (33, 59))
89573	30442178	Lung adenocarcinoma (LUAD) cases with actionable mutation of EGFR are discriminable from those without by protein profile (sdis = - 0.44; p = 5.9e-4; srand = 3.1e-5).	('sdis', 'Chemical', '-', (123, 127))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('ran', 'Gene', (151, 154))	('ran', 'Gene', '5901', (151, 154))	('mutation', 'Var', (49, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
89574	30442178	EGFR_pY1068 levels are increased for cases with the respective mutations, and Claudin-7 levels are decreased among those cases.	('mutations', 'Var', (63, 72))	('decreased', 'NegReg', (99, 108))	('EGFR', 'Gene', (0, 4))	('Claudin-7', 'Gene', '1366', (78, 87))	('increased', 'PosReg', (23, 32))	('EGFR', 'Gene', '1956', (0, 4))	('Claudin-7', 'Gene', (78, 87))
89575	30442178	ERBB2/HER2 amplification is actionable in breast cancer and gastric cancer (level 1 evidence, FDA-approved).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ERBB2', 'Gene', '2064', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ERBB2', 'Gene', (0, 5))	('gastric cancer', 'Disease', (60, 74))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('breast cancer', 'Disease', (42, 55))	('HER2', 'Gene', (6, 10))	('HER2', 'Gene', '2064', (6, 10))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('amplification', 'Var', (11, 24))
89585	30442178	Two histological tumor types in which ERBB2 amplification has a similar impact on proteins are breast (BRCA) and gastric (STAD) cancers (p = 2.3e-3).	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('tumor', 'Disease', (17, 22))	('BRCA', 'Gene', '672', (103, 107))	('BRCA', 'Gene', (103, 107))	('gastric (STAD) cancers', 'Disease', 'MESH:D013274', (113, 135))	('amplification', 'Var', (44, 57))	('ERBB2', 'Gene', (38, 43))	('proteins', 'MPA', (82, 90))	('ERBB2', 'Gene', '2064', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('impact', 'Reg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
89590	30442178	For FGFR1 amplification, clinical evidence (OncoKB level 3) exists on its actionability in lung squamous cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('FGFR1', 'Gene', (4, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('lung squamous cell carcinomas', 'Disease', (91, 120))	('FGFR1', 'Gene', '2260', (4, 9))	('amplification', 'Var', (10, 23))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (96, 120))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (91, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))
89591	30442178	Our analysis shows that besides lung squamous cell carcinoma, protein expression of amplified cases is discriminable from non-amplified cases in renal clear cell carcinoma, testicular germ cell tumors, lung adenocarcinoma, endometrial carcinoma, breast cancer, and thymoma (all currently not reported by OncoKB).	('endometrial carcinoma', 'Disease', 'MESH:D016889', (223, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (145, 171))	('renal clear cell carcinoma', 'Disease', (145, 171))	('thymoma', 'Disease', (265, 272))	('thymoma', 'Phenotype', 'HP:0100522', (265, 272))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('breast cancer', 'Disease', (246, 259))	('lung adenocarcinoma', 'Disease', (202, 221))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 60))	('lung squamous cell carcinoma', 'Disease', (32, 60))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('endometrial carcinoma', 'Disease', (223, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('tumors', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('protein expression', 'MPA', (62, 80))	('thymoma', 'Disease', 'MESH:D013945', (265, 272))	('testicular', 'Disease', (173, 183))	('amplified', 'Var', (84, 93))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (223, 244))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
89594	30442178	A cross-cancer effect is found between breast cancer and lung adenocarcinoma with HER2, HER2_pY1248, and EGFR_pY1068 levels decrease and 4E-BP1 levels increase associated with FGFR1 amplification for both histological tumor types.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('A cross-cancer', 'Disease', 'MESH:C537866', (0, 14))	('increase', 'PosReg', (151, 159))	('HER2', 'Gene', '2064', (88, 92))	('4E-BP1', 'Gene', (137, 143))	('decrease', 'NegReg', (124, 132))	('EGFR', 'Gene', (105, 109))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('tumor', 'Disease', (218, 223))	('breast cancer', 'Disease', (39, 52))	('A cross-cancer', 'Disease', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('lung adenocarcinoma', 'Disease', (57, 76))	('HER2', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGFR1', 'Gene', '2260', (176, 181))	('HER2', 'Gene', (88, 92))	('EGFR', 'Gene', '1956', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))	('4E-BP1', 'Gene', '1978', (137, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('FGFR1', 'Gene', (176, 181))	('HER2', 'Gene', '2064', (82, 86))	('levels', 'MPA', (144, 150))	('amplification', 'Var', (182, 195))
89595	30442178	Certain FGFR3 mutations are actionable in bladder cancer (OncoKB level 3).	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('FGFR3', 'Gene', '2261', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('actionable', 'Reg', (28, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))	('mutations', 'Var', (14, 23))	('FGFR3', 'Gene', (8, 13))
89596	30442178	Targetable FGFR3 mutations are only frequent enough in urothelial and bladder carcinoma for our analysis.	('frequent', 'Reg', (36, 44))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (70, 87))	('FGFR3', 'Gene', '2261', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('bladder carcinoma', 'Disease', 'MESH:D001749', (70, 87))	('FGFR3', 'Gene', (11, 16))	('bladder carcinoma', 'Disease', (70, 87))	('urothelial', 'Disease', (55, 65))	('mutations', 'Var', (17, 26))
89597	30442178	The protein profiles of cases with at least one of these mutations are discriminable from the profiles of those without (sdis = - 0.76; p = 2.7e-3; srand = - 1.3e-5).	('ran', 'Gene', '5901', (149, 152))	('mutations', 'Var', (57, 66))	('sdis', 'Chemical', '-', (121, 125))	('ran', 'Gene', (149, 152))
89598	30442178	E-Cadherin, beta-Catenin, HER2, Ku80, PTEN, IRS1, and 53BP1 are increased among cases having one or more specific FGF3 mutation.	('PTEN', 'Gene', '5728', (38, 42))	('FGF3', 'Gene', (114, 118))	('mutation', 'Var', (119, 127))	('Ku80', 'Gene', '7520', (32, 36))	('53BP1', 'Gene', '7158', (54, 59))	('beta-Catenin', 'Gene', (12, 24))	('beta-Catenin', 'Gene', '1499', (12, 24))	('Ku80', 'Gene', (32, 36))	('HER2', 'Gene', (26, 30))	('E-Cadherin', 'Gene', (0, 10))	('HER2', 'Gene', '2064', (26, 30))	('IRS1', 'Gene', '3667', (44, 48))	('IRS1', 'Gene', (44, 48))	('FGF3', 'Gene', '2248', (114, 118))	('increased', 'PosReg', (64, 73))	('E-Cadherin', 'Gene', '999', (0, 10))	('PTEN', 'Gene', (38, 42))	('53BP1', 'Gene', (54, 59))
89599	30442178	IDH1 mutations are actionable in acute myeloid leukemia, cholangiocarcinoma, and glioma (OncoKB level 3).	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (57, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('IDH1', 'Gene', '3417', (0, 4))	('acute myeloid leukemia', 'Disease', (33, 55))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (39, 55))	('mutations', 'Var', (5, 14))	('glioma', 'Disease', (81, 87))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (33, 55))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (33, 55))	('IDH1', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', (57, 75))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
89600	30442178	Specific IDH1 mutations lead to discriminable protein profiles for low-grade glioma (sdis = - 0.47; p = 0.0; srand = - 3.1e-6) and glioblastoma (sdis = - 1.59; p = 5.0e-4; srand = - 1.0e-5).	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('IDH1', 'Gene', (9, 13))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('sdis', 'Chemical', '-', (85, 89))	('IDH1', 'Gene', '3417', (9, 13))	('ran', 'Gene', (110, 113))	('ran', 'Gene', '5901', (110, 113))	('ran', 'Gene', (173, 176))	('glioma', 'Disease', (77, 83))	('protein profiles', 'MPA', (46, 62))	('ran', 'Gene', '5901', (173, 176))	('sdis', 'Chemical', '-', (145, 149))	('mutations', 'Var', (14, 23))	('glioblastoma', 'Disease', (131, 143))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
89602	30442178	For glioblastoma IGFBP2, EGFR_pY1068, HER2_pY1248, Caveolin-1, Akt_pT308, Fibronectin, Collagen_VI, and EGFR_pY1173 are decreased in the group of mutated cases.	('decreased', 'NegReg', (120, 129))	('Fibronectin', 'Gene', (74, 85))	('HER2', 'Gene', (38, 42))	('EGFR', 'Gene', (25, 29))	('mutated', 'Var', (146, 153))	('EGFR', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (104, 108))	('Caveolin-1', 'Gene', '857', (51, 61))	('glioblastoma', 'Disease', (4, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (4, 16))	('Caveolin-1', 'Gene', (51, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (4, 16))	('IGFBP2', 'Gene', '3485', (17, 23))	('IGFBP2', 'Gene', (17, 23))	('EGFR', 'Gene', '1956', (25, 29))	('HER2', 'Gene', '2064', (38, 42))	('Fibronectin', 'Gene', '2335', (74, 85))
89603	30442178	Therefore, IGFBP2, EGFR_pY1068, HER2_pY1248, and EGFR_pY1173 are affected in the same way by IDH1 mutations in low-grade glioma and glioblastoma, and we report a cross-cancer effect for those groups.	('HER2', 'Gene', '2064', (32, 36))	('EGFR', 'Gene', (19, 23))	('glioblastoma', 'Disease', (132, 144))	('glioma', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('EGFR', 'Gene', (49, 53))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('cross-cancer', 'Disease', 'MESH:C537866', (162, 174))	('IDH1', 'Gene', (93, 97))	('HER2', 'Gene', (32, 36))	('EGFR', 'Gene', '1956', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('cross-cancer', 'Disease', (162, 174))	('IGFBP2', 'Gene', '3485', (11, 17))	('EGFR', 'Gene', '1956', (49, 53))	('IDH1', 'Gene', '3417', (93, 97))	('mutations', 'Var', (98, 107))	('affected', 'Reg', (65, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('IGFBP2', 'Gene', (11, 17))
89604	30442178	KIT mutations are actionable in gastrointestinal stromal tumors (OncoKB level 1).	('gastrointestinal stromal tumors', 'Disease', (32, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (4, 13))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (32, 63))	('KIT', 'Gene', (0, 3))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (32, 63))
89605	30442178	For the tested KIT mutations, only testicular germ cell tumors (TGCT) had enough mutated cases sufficient for our analysis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('KIT', 'Gene', (15, 18))	('mutations', 'Var', (19, 28))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
89606	30442178	The protein profiles of the mutated and wild-type cases are discriminable (sdis = - 0.90; p = 4.5e-3; srand = - 2.6e-4) with decreased E-Cadherin and Fibronectin expression in wildtype cases and increased c-Kit, STAT5-alpha, and Syk expression levels.	('Fibronectin', 'Gene', '2335', (150, 161))	('mutated', 'Var', (28, 35))	('c-Kit', 'Gene', (205, 210))	('Fibronectin', 'Gene', (150, 161))	('sdis', 'Chemical', '-', (75, 79))	('expression levels', 'MPA', (233, 250))	('E-Cadherin', 'Gene', '999', (135, 145))	('Syk', 'Gene', '6850', (229, 232))	('decreased', 'NegReg', (125, 134))	('c-Kit', 'Gene', '3815', (205, 210))	('STAT5-alpha', 'Gene', '6776', (212, 223))	('expression', 'MPA', (162, 172))	('ran', 'Gene', (103, 106))	('ran', 'Gene', '5901', (103, 106))	('STAT5-alpha', 'Gene', (212, 223))	('Syk', 'Gene', (229, 232))	('increased', 'PosReg', (195, 204))	('E-Cadherin', 'Gene', (135, 145))
89608	30442178	KRAS/NRAS mutations are therapeutically relevant for melanomas, colorectal cancer, and thyroid cancer (OncoKB level 3).	('melanomas', 'Disease', (53, 62))	('KRAS', 'Gene', '3845', (0, 4))	('colorectal cancer', 'Disease', (64, 81))	('NRAS', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('thyroid cancer', 'Disease', 'MESH:D013964', (87, 101))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('NRAS', 'Gene', '4893', (5, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('rectal cancer', 'Phenotype', 'HP:0100743', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('thyroid cancer', 'Phenotype', 'HP:0002890', (87, 101))	('thyroid cancer', 'Disease', (87, 101))
89609	30442178	Specific KRAS/NRAS mutations are correlated with differences in protein profiles for melanomas and thyroid cancer and also for testicular germ cell tumors, endometrial carcinoma, and lung adenocarcinoma (in conformity with OncoKB level 4 data).	('melanomas', 'Disease', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('thyroid cancer', 'Disease', (99, 113))	('differences', 'Reg', (49, 60))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('NRAS', 'Gene', '4893', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (156, 177))	('KRAS', 'Gene', '3845', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('thyroid cancer', 'Disease', 'MESH:D013964', (99, 113))	('protein profiles', 'MPA', (64, 80))	('lung adenocarcinoma', 'Disease', (183, 202))	('KRAS', 'Gene', (9, 13))	('thyroid cancer', 'Phenotype', 'HP:0002890', (99, 113))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('tumors', 'Disease', (148, 154))	('NRAS', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (183, 202))	('mutations', 'Var', (19, 28))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('endometrial carcinoma', 'Disease', (156, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (183, 202))
89612	30442178	For melanoma (sdis = - 0.16; p = 1.0e-3; and = 5.2e-6) E-Cadherin, Caveolin-1, and c-Kit expression levels are decreased for mutated cases, and MAPK_pT202_Y204 is increased.	('E-Cadherin', 'Gene', '999', (55, 65))	('mutated', 'Var', (125, 132))	('MAPK_pT202_Y204', 'Var', (144, 159))	('decreased', 'NegReg', (111, 120))	('E-Cadherin', 'Gene', (55, 65))	('sdis', 'Chemical', '-', (14, 18))	('Caveolin-1', 'Gene', '857', (67, 77))	('c-Kit', 'Gene', (83, 88))	('c-Kit', 'Gene', '3815', (83, 88))	('expression levels', 'MPA', (89, 106))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))	('Caveolin-1', 'Gene', (67, 77))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))
89613	30442178	For thyroid carcinoma (sdis = - 1.53; p = 0.0; srand = - 3.0e-4), the level of Fibronectin is decreased in mutated cases.	('sdis', 'Chemical', '-', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('mutated', 'Var', (107, 114))	('ran', 'Gene', (48, 51))	('ran', 'Gene', '5901', (48, 51))	('Fibronectin', 'Gene', '2335', (79, 90))	('decreased', 'NegReg', (94, 103))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (4, 21))	('Fibronectin', 'Gene', (79, 90))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (4, 21))	('thyroid carcinoma', 'Disease', (4, 21))
89614	30442178	For lung adenocarcinoma and endometrial carcinoma, we observed a cross-cancer effect for KRAS/NRAS-mutated cases as ATM levels are decreased, and MAPK_pT202_Y204, Claudin-7, S6_pS235_S236, and MEK1_pS217_S221 are increased in both histological tumor types consistently.	('S6_pS235_S236', 'Var', (174, 187))	('endometrial carcinoma', 'Disease', (28, 49))	('Claudin-7', 'Gene', '1366', (163, 172))	('lung adenocarcinoma', 'Disease', (4, 23))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (28, 49))	('NRAS', 'Gene', '4893', (94, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MEK', 'Gene', '5609', (193, 196))	('ATM', 'Gene', '472', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('KRAS', 'Gene', '3845', (89, 93))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (28, 49))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 23))	('cross-cancer', 'Disease', 'MESH:C537866', (65, 77))	('MEK', 'Gene', (193, 196))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('MAPK_pT202_Y204', 'Var', (146, 161))	('KRAS', 'Gene', (89, 93))	('NRAS', 'Gene', (94, 98))	('tumor', 'Disease', (244, 249))	('cross-cancer', 'Disease', (65, 77))	('decreased', 'NegReg', (131, 140))	('ATM', 'Gene', (116, 119))	('Claudin-7', 'Gene', (163, 172))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('increased', 'PosReg', (213, 222))
89615	30442178	MDM2 amplification is actionable in liposarcoma (OncoKB level 3).	('liposarcoma', 'Disease', (36, 47))	('amplification', 'Var', (5, 18))	('liposarcoma', 'Phenotype', 'HP:0012034', (36, 47))	('liposarcoma', 'Disease', 'MESH:D008080', (36, 47))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))
89616	30442178	Besides sarcoma, the protein profiles of cases with MDM2 amplification are discriminable from those with normal copy numbers for renal clear cell carcinoma, lung adenocarcinoma, thyroid carcinoma, breast cancer, ovarian carcinoma, and low-grade glioma (all currently not reported by OncoKB).	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('MDM2', 'Gene', (52, 56))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (129, 155))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('renal clear cell carcinoma', 'Disease', (129, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (178, 195))	('MDM2', 'Gene', '4193', (52, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('thyroid carcinoma', 'Disease', (178, 195))	('breast cancer', 'Disease', (197, 210))	('amplification', 'Var', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (212, 229))	('ovarian carcinoma', 'Disease', (212, 229))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (178, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('sarcoma', 'Disease', (8, 15))	('glioma', 'Disease', (245, 251))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (212, 229))	('lung adenocarcinoma', 'Disease', (157, 176))	('glioma', 'Disease', 'MESH:D005910', (245, 251))
89617	30442178	Protein levels of sarcoma cases with MDM2 amplifications are discriminable from those without, with a dissimilarity score of sdis = - 0.41 (p = 0.0; srand = - 8.9e-5).	('ran', 'Gene', '5901', (150, 153))	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('sarcoma', 'Disease', (18, 25))	('Protein levels', 'MPA', (0, 14))	('MDM2', 'Gene', '4193', (37, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('amplifications', 'Var', (42, 56))	('MDM2', 'Gene', (37, 41))	('sdis', 'Chemical', '-', (125, 129))	('ran', 'Gene', (150, 153))
89618	30442178	Amplified cases show decreased levels of E-Cadherin, Akt_pS473, Akt_pT308, ER-alpha, Caveolin-1, S6_pS240_S244, S6_pS235_S236, and Cyclin_B1 and increased levels of HSP70, Syk, and Lck.	('Lck', 'Gene', (181, 184))	('Akt_pT308', 'Gene', (64, 73))	('HSP70', 'Gene', '3308', (165, 170))	('Cyclin_B1', 'Gene', '891', (131, 140))	('Caveolin-1', 'Gene', (85, 95))	('E-Cadherin', 'Gene', (41, 51))	('Caveolin-1', 'Gene', '857', (85, 95))	('S6_pS240_S244', 'Var', (97, 110))	('levels', 'MPA', (155, 161))	('ER-alpha', 'Gene', (75, 83))	('increased', 'PosReg', (145, 154))	('ER-alpha', 'Gene', '2099', (75, 83))	('Syk', 'Gene', '6850', (172, 175))	('HSP70', 'Gene', (165, 170))	('S6_pS235_S236', 'Var', (112, 125))	('Syk', 'Gene', (172, 175))	('decreased', 'NegReg', (21, 30))	('Cyclin_B1', 'Gene', (131, 140))	('Lck', 'Gene', '3932', (181, 184))	('Akt_pS473', 'Protein', (53, 62))	('E-Cadherin', 'Gene', '999', (41, 51))
89621	30442178	In addition to these histotypes, we found 11 other histological tumor types (renal clear cell carcinoma, low-grade glioma, renal papillary cell carcinoma, colon carcinoma, thyroid carcinoma, thymoma, sarcoma, lung adenocarcinoma, testicular germ cell tumors, prostate adenocarcinoma, glioblastoma, breast and ovarian carcinoma) where MET amplification is associated with a significant change in protein expression.	('tumor', 'Disease', (251, 256))	('glioma', 'Disease', (115, 121))	('breast and ovarian carcinoma', 'Disease', 'MESH:D001943', (298, 326))	('glioblastoma', 'Phenotype', 'HP:0012174', (284, 296))	('protein expression', 'MPA', (395, 413))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('MET amplification', 'Var', (334, 351))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('lung adenocarcinoma', 'Disease', (209, 228))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (172, 189))	('thymoma', 'Disease', 'MESH:D013945', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('thyroid carcinoma', 'Disease', (172, 189))	('renal papillary cell carcinoma', 'Disease', (123, 153))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (209, 228))	('thymoma', 'Disease', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (172, 189))	('thymoma', 'Phenotype', 'HP:0100522', (191, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (209, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('tumors', 'Disease', (251, 257))	('prostate adenocarcinoma', 'Disease', (259, 282))	('colon carcinoma', 'Disease', (155, 170))	('change', 'Reg', (385, 391))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (77, 103))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (309, 326))	('renal clear cell carcinoma', 'Disease', (77, 103))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (123, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('tumor', 'Disease', (64, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (284, 296))	('sarcoma', 'Disease', 'MESH:D012509', (200, 207))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('colon carcinoma', 'Disease', 'MESH:D015179', (155, 170))	('sarcoma', 'Disease', (200, 207))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (259, 282))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('glioblastoma', 'Disease', (284, 296))
89624	30442178	MET amplification is present in renal clear cell carcinoma cases, and protein profiles of amplified and non-amplified cases can be discriminated (sdis = - 0.18; p = 0.0; srand = - 2.0e-5; Src_pY527, Bcl-2, beta-Catenin, PTEN, MAPK_pT202_Y204 are decreased in amplified cases and ACC1, Cyclin_B1, ASNS, ACC_pS79, and Transglutaminase are increased).	('Cyclin_B1', 'Gene', '891', (285, 294))	('ran', 'Gene', (171, 174))	('ran', 'Gene', '5901', (171, 174))	('beta-Catenin', 'Gene', '1499', (206, 218))	('ASNS', 'Gene', (296, 300))	('Src_pY527', 'Var', (188, 197))	('PTEN', 'Gene', '5728', (220, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('increased', 'PosReg', (337, 346))	('ACC_pS79', 'MPA', (302, 310))	('ACC1', 'Gene', (279, 283))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (32, 58))	('beta-Catenin', 'Gene', (206, 218))	('MAPK_pT202_Y204', 'Gene', (226, 241))	('renal clear cell carcinoma', 'Disease', (32, 58))	('decreased', 'NegReg', (246, 255))	('ACC1', 'Gene', '597', (279, 283))	('Cyclin_B1', 'Gene', (285, 294))	('ran', 'Gene', (317, 320))	('ran', 'Gene', '5901', (317, 320))	('sdis', 'Chemical', '-', (146, 150))	('Bcl-2', 'Gene', (199, 204))	('ASNS', 'Gene', '440', (296, 300))	('PTEN', 'Gene', (220, 224))	('Bcl-2', 'Gene', '596', (199, 204))
89626	30442178	PIK3CA activating mutations are actionable for breast cancer (OncoKB evidence level 3).	('breast cancer', 'Disease', (47, 60))	('activating', 'PosReg', (7, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('mutations', 'Var', (18, 27))
89628	30442178	OncoKB level 4 data lists all available histological tumor types as possibly actionable for PIK3CA activating mutations.	('mutations', 'Var', (110, 119))	('PIK3CA', 'Gene', '5290', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('PIK3CA', 'Gene', (92, 98))
89630	30442178	Breast cancer cases with PIK3CA-activating mutations are discriminable from those without (sdis = - 0.52; p = 0.0; srand = 6.2e-6) with specific proteins (increased levels) PR, ER-alpha, MAPK_pT202_Y204, Fibronectin, AR, and GATA3 in mutated cases and Cyclin_B1, Cyclin_E1, ASNS, and HER2 being decreased.	('ran', 'Gene', (116, 119))	('ran', 'Gene', '5901', (116, 119))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Cyclin_B1', 'Gene', '891', (252, 261))	('PIK3CA', 'Gene', '5290', (25, 31))	('increased', 'PosReg', (155, 164))	('HER2', 'Gene', '2064', (284, 288))	('Cyclin_E1', 'Gene', '898', (263, 272))	('ASNS', 'Gene', '440', (274, 278))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('mutated', 'Var', (234, 241))	('GATA3', 'Gene', '2625', (225, 230))	('PIK3CA', 'Gene', (25, 31))	('Cyclin_E1', 'Gene', (263, 272))	('Fibronectin', 'Gene', '2335', (204, 215))	('Cyclin_B1', 'Gene', (252, 261))	('sdis', 'Chemical', '-', (91, 95))	('ASNS', 'Gene', (274, 278))	('HER2', 'Gene', (284, 288))	('GATA3', 'Gene', (225, 230))	('ER-alpha', 'Gene', (177, 185))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('mutations', 'Var', (43, 52))	('ER-alpha', 'Gene', '2099', (177, 185))	('Breast cancer', 'Disease', (0, 13))	('Fibronectin', 'Gene', (204, 215))
89634	30442178	However, many open questions remain because apart from mutations with unknown functional effects, it is often not possible even for oncogenic mutations with established clinical relevance in one cancer type to transfer knowledge of actionability to another cancer type.	('mutations', 'Var', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('ran', 'Gene', (211, 214))	('ran', 'Gene', '5901', (211, 214))	('cancer', 'Disease', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
89640	30442178	This indicates that identical genetic alterations are not translated into protein profiles in the same way in different histotypes.	('ran', 'Gene', '5901', (59, 62))	('ran', 'Gene', (59, 62))	('genetic alterations', 'Var', (30, 49))
89644	30442178	In addition to showing that our analysis identifies protein-level effects for known actionable genes and corresponding cancer types, our approach also identified protein-level alterations indicative of potential novel actionable gene:cancer combinations that are so far unknown according to OncoKB including level 4 evidence (biological information).	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('combinations', 'Var', (241, 253))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
89645	30442178	This includes ERBB2/HER2 amplification in endometrial carcinoma, renal papillary carcinoma, testicular germ cell tumors, urothelial carcinoma, renal clear cell carcinoma, colon carcinoma, ovarian carcinoma, thymoma, thyroid carcinoma, cervical carcinoma, and head and neck squamous cell carcinoma.	('colon carcinoma', 'Disease', 'MESH:D015179', (171, 186))	('tumors', 'Disease', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('HER2', 'Gene', (20, 24))	('thymoma', 'Disease', 'MESH:D013945', (207, 214))	('renal papillary carcinoma', 'Disease', (65, 90))	('cervical carcinoma', 'Disease', (235, 253))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('endometrial carcinoma', 'Disease', (42, 63))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (216, 233))	('ERBB2', 'Gene', (14, 19))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (121, 141))	('thyroid carcinoma', 'Disease', (216, 233))	('thymoma', 'Disease', (207, 214))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (143, 169))	('cervical carcinoma', 'Disease', 'MESH:D002575', (235, 253))	('renal clear cell carcinoma', 'Disease', (143, 169))	('thymoma', 'Phenotype', 'HP:0100522', (207, 214))	('neck squamous cell carcinoma', 'Disease', (268, 296))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (188, 205))	('ERBB2', 'Gene', '2064', (14, 19))	('ovarian carcinoma', 'Disease', (188, 205))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (42, 63))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (268, 296))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (216, 233))	('HER2', 'Gene', '2064', (20, 24))	('amplification', 'Var', (25, 38))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('renal papillary carcinoma', 'Disease', 'MESH:D007681', (65, 90))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (42, 63))	('colon carcinoma', 'Disease', (171, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (188, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (273, 296))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('urothelial carcinoma', 'Disease', (121, 141))
89649	30442178	Interestingly, actionable genes with copy number alterations showed effects on protein expression for more histotypes than those with simple somatic mutations (10.2 affected tumor types on average for amplifications vs. 2.14 for simple somatic mutations).	('tumor', 'Disease', (174, 179))	('protein expression', 'MPA', (79, 97))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('effects', 'Reg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('copy number alterations', 'Var', (37, 60))
89653	30442178	With respect to the actionable gene analysis, our approach may underestimate the number of potentially druggable genes, but the fact that it readily identifies many well-established actionable gene, cancer combinations, such as, for instance, HER2 amplification in breast and gastric cancer, indicates its validity.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', (284, 290))	('HER2', 'Gene', (243, 247))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('HER2', 'Gene', '2064', (243, 247))	('cancer', 'Disease', (199, 205))	('gastric cancer', 'Phenotype', 'HP:0012126', (276, 290))	('breast and gastric cancer', 'Disease', 'MESH:D013274', (265, 290))	('amplification', 'Var', (248, 261))
89660	30442178	By evaluating protein-level effects of genetic aberrations, our approach facilitates the identification of functionally relevant mutations and may therefore contribute to predicting actionable mutations across cancers and to guide basket trial design.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mutations', 'Var', (129, 138))	('facilitates', 'PosReg', (73, 84))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancers', 'Disease', (210, 217))
89688	30505399	Studies have suggested that among men, low DHEA-S levels have been consistently associated with an increased risk of all-cause mortality and cardiovascular disease but there are no studies correlating high levels of DHEA-S and cardiac disease.	('cardiac disease', 'Disease', (227, 242))	('DHEA-S', 'Gene', '6822', (216, 222))	('cardiovascular disease', 'Disease', (141, 163))	('DHEA-S', 'Gene', (216, 222))	('cardiac disease', 'Disease', 'MESH:D006331', (227, 242))	('low', 'Var', (39, 42))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (141, 163))	('DHEA-S', 'Gene', (43, 49))	('cardiovascular disease', 'Disease', 'MESH:D002318', (141, 163))	('DHEA-S', 'Gene', '6822', (43, 49))	('all-cause', 'Disease', (117, 126))	('men', 'Species', '9606', (34, 37))
89705	30094411	Three early developments ~50 years ago made current metabolic profiling possible: First, the development of GC in 1960; second, the combination of GC with mass spectrometry (MS) through Ryhage's molecular separator invention; and, finally, derivatization methodologies that increased the volatility and stability of steroids.	('volatility', 'MPA', (288, 298))	('men', 'Species', '9606', (100, 103))	('derivatization', 'Var', (240, 254))	('stability', 'MPA', (303, 312))	('steroids', 'Chemical', 'MESH:D013256', (316, 324))	('men', 'Species', '9606', (19, 22))	('increased', 'PosReg', (274, 283))
89783	30094411	For silylated steroids, the presence of water in the source as a modifier promoted the formation of principally [M+H]+, [M+H-TMSOH]+, and [M+H-2 TMSOH]+ ions.	('promoted', 'PosReg', (74, 82))	('[M+H-TMSOH]', 'Var', (120, 131))	('water', 'Chemical', 'MESH:D014867', (40, 45))	('formation', 'MPA', (87, 96))	('[M+H-2 TMSOH]+', 'Var', (138, 152))	('steroids', 'Chemical', 'MESH:D013256', (14, 22))	('TMSOH', 'Chemical', '-', (125, 130))	('TMSOH', 'Chemical', '-', (145, 150))
89841	30094411	showed that mutations in the enzyme H6PDH (hexose-6-phosphate dehydrogenase; encoded by H6PD) caused the disorder.	('hydrogen', 'Chemical', 'MESH:D006859', (64, 72))	('mutations', 'Var', (12, 21))	('caused', 'Reg', (94, 100))	('H6PD', 'Gene', (36, 40))	('H6PD', 'Gene', (88, 92))	('H6PD', 'Gene', '9563', (36, 40))	('H6PD', 'Gene', '9563', (88, 92))
89885	30094411	The addition of a further hydroxyl tends to shift the molecular ions to other precursor ions such as [M+H-H2O]+ or [M+H-2H2O]+.	('H-2H2O', 'Chemical', '-', (118, 124))	('shift', 'Reg', (44, 49))	('hydroxyl', 'Chemical', 'MESH:D017665', (26, 34))	('H2O', 'Chemical', 'MESH:D014867', (106, 109))	('molecular ions', 'MPA', (54, 68))	('H2O', 'Chemical', 'MESH:D014867', (121, 124))	('[M+H-2H2O]+', 'Var', (115, 126))
89937	27743992	Corticosteroid production is also highly dependent on variation of cytosolic calcium induced by these regulatory factors.	('steroid', 'Chemical', 'MESH:D013256', (7, 14))	('Corticosteroid production', 'MPA', (0, 25))	('calcium', 'Chemical', 'MESH:D002118', (77, 84))	('dependent', 'Reg', (41, 50))	('cytosolic calcium', 'MPA', (67, 84))	('variation', 'Var', (54, 63))
89938	27743992	Ca2+ signaling results from IP3-induced Ca2+ release from intracellular pools and/or calcium influx through voltage-sensitive membrane channels.	('results from', 'Reg', (15, 27))	('IP3-induced', 'Var', (28, 39))	('IP3', 'Chemical', 'MESH:D015544', (28, 31))	('Ca2+ signaling', 'MPA', (0, 14))	('calcium', 'Chemical', 'MESH:D002118', (85, 92))	('Ca2+ release from intracellular pools', 'MPA', (40, 77))	('calcium', 'CPA', (85, 92))
89990	27743992	The cortisol response to 5-HT (10-6 M) was inhibited by the protein kinase A (PKA) inhibitor H-89 in a dose-dependent manner, but was not affected by the protein kinase C inhibitor chelerythrine (10-5 M; Fig.	('H-89', 'Var', (93, 97))	('inhibited', 'NegReg', (43, 52))	('cortisol response', 'MPA', (4, 21))	('5-HT', 'Chemical', 'MESH:D012701', (25, 29))	('cortisol', 'Chemical', 'MESH:D006854', (4, 12))	('chelerythrine', 'Chemical', 'MESH:C016299', (181, 194))	('H-89', 'Chemical', 'MESH:C063509', (93, 97))
90003	27743992	Diminution of extracellular Ca2+ concentration decreased the amplitude of maximum response, indicating that efficacy of signal transduction was reduced (Emax = 243+- 4% at 1 mM Ca2+ to 170+- 5% at 0.01 mM Ca2+).	('reduced', 'NegReg', (144, 151))	('Diminution', 'Var', (0, 10))	('rat', 'Species', '10116', (40, 43))	('mum', 'Gene', '56925', (78, 81))	('mum', 'Gene', (78, 81))	('amplitude', 'MPA', (61, 70))	('efficacy', 'MPA', (108, 116))	('decreased', 'NegReg', (47, 56))
90005	27743992	In addition, perifusion experiments revealed that chelation of extracellular Ca2+ markedly attenuated the cortisol response of adrenocortical explants to zacopride (Fig.	('adrenocortical', 'Disease', (127, 141))	('cortisol response', 'MPA', (106, 123))	('adrenocortical', 'Disease', 'MESH:D018268', (127, 141))	('cortisol', 'Chemical', 'MESH:D006854', (106, 114))	('chelation', 'Var', (50, 59))	('zacopride', 'Chemical', 'MESH:C055971', (154, 163))	('attenuated', 'NegReg', (91, 101))
90014	27743992	Both in vivo and in vitro experiments have formerly shown that, in human, 5-HT stimulates corticosteroid production through 5-HT4 receptors.	('5-HT', 'Chemical', 'MESH:D012701', (74, 78))	('5-HT4 receptors', 'Protein', (124, 139))	('5-HT', 'Var', (74, 78))	('stimulates', 'PosReg', (79, 89))	('corticosteroid production', 'MPA', (90, 115))	('5-HT', 'Chemical', 'MESH:D012701', (124, 128))	('steroid', 'Chemical', 'MESH:D013256', (97, 104))	('human', 'Species', '9606', (67, 72))
90015	27743992	The present study demonstrates that activation of 5-HT4 receptors stimulates adenylyl cyclase activity and Ca2+ influx through T-type Ca2+ currents that provoke an increase in cortisol secretion.	('5-HT', 'Chemical', 'MESH:D012701', (50, 54))	('Ca2+ influx', 'MPA', (107, 118))	('T-type Ca2+ currents', 'MPA', (127, 147))	('cortisol', 'Chemical', 'MESH:D006854', (176, 184))	('5-HT4 receptors', 'Protein', (50, 65))	('activity', 'MPA', (94, 102))	('stimulates', 'PosReg', (66, 76))	('cortisol secretion', 'MPA', (176, 194))	('rat', 'Species', '10116', (25, 28))	('adenylyl cyclase', 'Enzyme', (77, 93))	('activation', 'Var', (36, 46))	('increase', 'PosReg', (164, 172))
90042	27743992	By using the patch-clamp technique, we found that 5-HT weakly enhanced the T-type Ca2+ currents.	('5-HT', 'Var', (50, 54))	('T-type Ca2+ currents', 'MPA', (75, 95))	('5-HT', 'Chemical', 'MESH:D012701', (50, 54))	('enhanced', 'PosReg', (62, 70))
90068	25086465	Multiple endocrine neoplasia type 2 is an autosomal dominant syndrome caused by germline activating mutations of the RET proto-oncogene which encodes for RET, a receptor tyrosine kinase that modulates C cell proliferation and apoptosis.	('mutations', 'Var', (100, 109))	('RET', 'Gene', (154, 157))	('RET', 'Gene', '5979', (117, 120))	('caused', 'Reg', (70, 76))	('Multiple endocrine neoplasia type', 'Disease', (0, 33))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (9, 28))	('neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('Multiple endocrine neoplasia type', 'Disease', 'MESH:D018761', (0, 33))	('RET', 'Gene', (117, 120))	('RET', 'Gene', '5979', (154, 157))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (42, 69))	('autosomal dominant syndrome', 'Disease', (42, 69))
90070	25086465	In vitro and in vivo studies of the most common germline and somatic RET mutations have established their role in oncogenesis.	('oncogenesis', 'CPA', (114, 125))	('RET', 'Gene', (69, 72))	('mutations', 'Var', (73, 82))	('RET', 'Gene', '5979', (69, 72))
90169	23326744	Although SPECT-CT is not commonly performed for adrenocortical scintigraphy, in our patient, SPECT-CT increased the confidence that the high uptake in the pelvis was in the osteolytic lesion in the sacrum.	('osteolytic lesion', 'Disease', (173, 190))	('adrenocortical', 'Disease', (48, 62))	('adrenocortical', 'Disease', 'MESH:D018268', (48, 62))	('osteolytic lesion', 'Phenotype', 'HP:0002797', (173, 190))	('osteolytic lesion', 'Disease', 'MESH:D030981', (173, 190))	('increased', 'PosReg', (102, 111))	('SPECT-CT', 'Var', (93, 101))	('patient', 'Species', '9606', (84, 91))
90189	19018264	Germline mutations of the tumour supressor p53 and overexpression of insulin-like growth factor 1 are well known to promote the development of ACC (Edgren et al, 1997; Ignaszak-Szczepaniak et al, 2006; Slater et al, 2006).	('Germline mutations', 'Var', (0, 18))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumour', 'Disease', (26, 32))	('promote', 'PosReg', (116, 123))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('insulin-like growth factor 1', 'Gene', (69, 97))	('insulin-like growth factor 1', 'Gene', '3479', (69, 97))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('ACC', 'Disease', (143, 146))	('overexpression', 'PosReg', (51, 65))
90194	19018264	Downregulation of E-cadherin can arise - among other mechanisms - through transcriptional repression.	('transcriptional repression', 'Var', (74, 100))	('Downregulation', 'NegReg', (0, 14))	('E-cadherin', 'Gene', (18, 28))	('E-cadherin', 'Gene', '999', (18, 28))
90199	19018264	In a transgenic mouse model of breast cancer, Snail expression was associated with a more aggressive phenotype, higher risk of tumour recurrence, and with poor survival rates (Moody et al, 2005).	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('mouse', 'Species', '10090', (16, 21))	('expression', 'Var', (52, 62))	('tumour', 'Disease', (127, 133))	('Moody', 'Phenotype', 'HP:0001575', (176, 181))
90282	19018264	In ovarian cancer, a high Snail mRNA expression predicted a shorter effusion-free survival in ovarian cancer (Elloul et al, 2005).	('ovarian cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('effusion-free survival', 'CPA', (68, 90))	('high', 'Var', (21, 25))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('ovarian cancer', 'Disease', (3, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (94, 108))	('shorter', 'NegReg', (60, 67))
90376	32371905	Performing variant-prioritization analysis on germline DNA of 1,507 C-AYA patients with solid tumors, we show 12% of these patients carrying germline pathogenic and/or likely pathogenic variants (P/LP) in known cancer-predisposing genes (KCPG).	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('KCPG', 'Gene', (238, 242))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', (211, 217))	('solid tumors', 'Disease', 'MESH:D009369', (88, 100))	('patients', 'Species', '9606', (123, 131))	('pathogenic', 'Reg', (175, 185))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('variants', 'Var', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('C-AYA', 'Chemical', '-', (68, 73))	('solid tumors', 'Disease', (88, 100))
90377	32371905	An additional 61% have germline pathogenic variants in non-KCPG genes, including PRKN, SMARCAL1, SMAD7, which we refer to as candidate genes.	('SMAD7', 'Gene', '4092', (97, 102))	('SMARCAL1', 'Gene', '50485', (87, 95))	('PRKN', 'Gene', '5071', (81, 85))	('PRKN', 'Gene', (81, 85))	('SMAD7', 'Gene', (97, 102))	('non-KCPG genes', 'Gene', (55, 69))	('SMARCAL1', 'Gene', (87, 95))	('variants', 'Var', (43, 51))
90378	32371905	Despite germline variants in a broad gene spectrum, pathway analysis leads to top networks centering around p53.	('germline', 'Var', (8, 16))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))
90379	32371905	Our drug-target analysis shows 1/3 of patients with germline P/LP variants have at least one druggable alteration, while more than half of them are from our candidate gene group, which would otherwise go unidentified in routine clinical care.	('P/LP', 'Gene', (61, 65))	('druggable alteration', 'MPA', (93, 113))	('variants', 'Var', (66, 74))	('patients', 'Species', '9606', (38, 46))
90381	32371905	Here, the authors study the germline genomic signatures of 1,507 C-AYA patients with solid tumors and find pathogenic/likely pathogenic germline variants in diverse genes of which 1/3 of these alterations are druggable.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('C-AYA', 'Chemical', '-', (65, 70))	('patients', 'Species', '9606', (71, 79))	('solid tumors', 'Disease', (85, 97))	('variants', 'Var', (145, 153))	('solid tumors', 'Disease', 'MESH:D009369', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
90383	32371905	Although there has been substantial advancement in understanding somatic variants in cancers, our knowledge regarding the spectrum, frequency, and implications of germline variants in C-AYA with solid tumors is limited.	('variants', 'Var', (73, 81))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('solid tumors', 'Disease', (195, 207))	('C-AYA', 'Chemical', '-', (184, 189))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('solid tumors', 'Disease', 'MESH:D009369', (195, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
90384	32371905	Recent pan-cancer studies showed that 7-8% of patients with these malignancies diagnosed <20 years of age have pathogenic or likely pathogenic (P/LP) germline variants in known cancer-predisposing genes, with adrenocortical carcinoma (50%) and high-grade glioma (25%) having the highest percentage of variants among all solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (320, 332))	('cancer', 'Disease', (177, 183))	('patients', 'Species', '9606', (46, 54))	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('malignancies', 'Disease', (66, 78))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (209, 233))	('variants', 'Var', (159, 167))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('glioma', 'Disease', (255, 261))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (209, 233))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('glioma', 'Disease', 'MESH:D005910', (255, 261))	('adrenocortical carcinoma', 'Disease', (209, 233))	('solid tumors', 'Disease', (320, 332))	('pathogenic', 'Reg', (111, 121))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('cancer', 'Disease', (11, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
90387	32371905	In general, pathogenic loss-of-function variants in oncogenes can disrupt normal cellular processes, and predispose to cancer development; moreover, multiple genes can have both types of variants with different functional and phenotypic effects.	('loss-of-function', 'NegReg', (23, 39))	('disrupt', 'NegReg', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('normal cellular processes', 'CPA', (74, 99))	('variants', 'Var', (40, 48))	('oncogenes', 'Gene', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
90390	32371905	This is despite prior studies showing that a family history of cancer could only be obtained in about 40% of patients with P/LP mutations due to multiple limitations.	('patients', 'Species', '9606', (109, 117))	('mutations', 'Var', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('P/LP', 'Gene', (123, 127))	('cancer', 'Disease', (63, 69))
90391	32371905	It is now confirmed, as well, that there is a remarkably elevated risk of secondary primary neoplasms in C-AYA cancer survivors who carry a germline P/LP mutation in cancer-predisposing genes compared to those who do not.	('cancer', 'Disease', (166, 172))	('neoplasms', 'Disease', 'MESH:D009369', (92, 101))	('P/LP', 'Var', (149, 153))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('neoplasms', 'Phenotype', 'HP:0002664', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('neoplasms', 'Disease', (92, 101))	('C-AYA', 'Chemical', '-', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('neoplasm', 'Phenotype', 'HP:0002664', (92, 100))
90392	32371905	In addition to implications for heritability and second primary neoplasms, germline (in every single cell of the body) variants can also provide novel therapeutic targets.	('neoplasms', 'Disease', (64, 73))	('neoplasms', 'Phenotype', 'HP:0002664', (64, 73))	('neoplasm', 'Phenotype', 'HP:0002664', (64, 72))	('variants', 'Var', (119, 127))	('neoplasms', 'Disease', 'MESH:D009369', (64, 73))
90399	32371905	We found three pathogenic germline variants (Methods), one nonsense mutation in TP53, and two frameshift indels in BRCA2 and GJB2 genes in two patients with osteosarcoma, which were further confirmed by Sanger sequencing (Table 1; Fig.	('GJB2', 'Gene', '2706', (125, 129))	('osteosarcoma', 'Phenotype', 'HP:0002669', (157, 169))	('osteosarcoma', 'Disease', (157, 169))	('BRCA2', 'Gene', (115, 120))	('osteosarcoma', 'Disease', 'MESH:D012516', (157, 169))	('pathogenic', 'Reg', (15, 25))	('TP53', 'Gene', '7157', (80, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('TP53', 'Gene', (80, 84))	('patients', 'Species', '9606', (143, 151))	('BRCA2', 'Gene', '675', (115, 120))	('GJB2', 'Gene', (125, 129))	('frameshift indels', 'Var', (94, 111))
90400	32371905	The average mean depth was 258x (range 45x-444x) for the CCF P/LP KCPG variants.	('KCPG', 'Disease', (66, 70))	('45x-44', 'STRUCTURAL_ABNORMALITY', 'None', (39, 45))	('variants', 'Var', (71, 79))	('CCF', 'Disease', (57, 60))
90402	32371905	In a rare circumstance, a 27-year-old male with multiple primary sarcomas was found to have two pathogenic KCPG variants, one in BRCA2 (paternally inherited) and the other in TP53 (maternally inherited), the latter confirming a Li-Fraumeni syndrome diagnosis (Table 1).	('KCPG', 'Gene', (107, 111))	('sarcomas', 'Disease', 'MESH:D012509', (65, 73))	('TP53', 'Gene', (175, 179))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (65, 72))	('BRCA2', 'Gene', (129, 134))	('sarcomas', 'Disease', (65, 73))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (228, 248))	('BRCA2', 'Gene', '675', (129, 134))	('TP53', 'Gene', '7157', (175, 179))	('pathogenic', 'Reg', (96, 106))	('Li-Fraumeni syndrome', 'Disease', (228, 248))	('variants', 'Var', (112, 120))
90404	32371905	Our second representative case was a female patient with osteosarcoma, diagnosed at 10, who carried a pathogenic variant in GJB2 in addition to a germline duplication of DDX10, the latter, a known marker somatically associated with poor prognosis for osteosarcoma (Table 1; Fig.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('osteosarcoma', 'Disease', (251, 263))	('patient', 'Species', '9606', (44, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (57, 69))	('osteosarcoma', 'Disease', 'MESH:D012516', (251, 263))	('GJB2', 'Gene', '2706', (124, 128))	('DDX10', 'Gene', (170, 175))	('variant', 'Var', (113, 120))	('GJB2', 'Gene', (124, 128))	('DDX10', 'Gene', '1662', (170, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (256, 263))	('osteosarcoma', 'Phenotype', 'HP:0002669', (57, 69))	('osteosarcoma', 'Disease', (57, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (251, 263))
90405	32371905	Overall, 2 out of 50 C-AYA CCF patients with solid tumors carried a germline pathogenic KCPG variant, and 3 other C-AYA CCF patients harbored a germline CNV.	('C-AYA', 'Chemical', '-', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('KCPG', 'Gene', (88, 92))	('C-AYA', 'Chemical', '-', (114, 119))	('solid tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('patients', 'Species', '9606', (31, 39))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('patients', 'Species', '9606', (124, 132))	('variant', 'Var', (93, 100))
90415	32371905	RB1 (32 patients, 53% with nonsense mutations), NF1 (22 patients, 41% with nonsense mutations), CHEK2 (19 patients, 58% with frameshift deletions), and TP53 (10 patients, 50% with missense mutations) were the genes with the most frequent P/LP mutations among the 54 mutated genes in our dataset (Fig.	('patients', 'Species', '9606', (56, 64))	('NF1', 'Gene', '4763', (48, 51))	('RB1', 'Gene', '5925', (0, 3))	('CHEK2', 'Gene', (96, 101))	('CHEK2', 'Gene', '11200', (96, 101))	('TP53', 'Gene', '7157', (152, 156))	('mutations', 'Var', (243, 252))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (106, 114))	('TP53', 'Gene', (152, 156))	('P/LP mutations', 'Var', (238, 252))	('RB1', 'Gene', (0, 3))	('NF1', 'Gene', (48, 51))	('patients', 'Species', '9606', (8, 16))
90416	32371905	All of these 198 P/LP variants belong to KCPG genes with autosomal-dominant (AD), autosomal-recessive/autosomal-dominant (AR/AD), or X-linked-dominant (XLD) pattern of inheritance.	('AD', 'Disease', 'MESH:D000544', (125, 127))	('AD', 'Disease', 'MESH:D000544', (77, 79))	('AD', 'Disease', (77, 79))	('P/LP variants', 'Var', (17, 30))	('KCPG genes', 'Gene', (41, 51))	('autosomal-dominant', 'Disease', (57, 75))	('belong', 'Reg', (31, 37))	('variants', 'Var', (22, 30))	('AD', 'Disease', (125, 127))
90417	32371905	From 182 patients with P/LP KCPG mutations, 168 (92.3%) individuals had only one P/LP KCPG variant each.	('KCPG', 'Gene', (28, 32))	('patients', 'Species', '9606', (9, 17))	('mutations', 'Var', (33, 42))
90418	32371905	Twelve patients carried two P/LP KCPG variants, with 6 of those diagnosed with retinoblastoma.	('patients', 'Species', '9606', (7, 15))	('variants', 'Var', (38, 46))	('KCPG', 'Gene', (33, 37))	('retinoblastoma', 'Phenotype', 'HP:0009919', (79, 93))	('P/LP', 'Var', (28, 32))	('retinoblastoma', 'Disease', (79, 93))	('retinoblastoma', 'Disease', 'MESH:D012175', (79, 93))
90419	32371905	We had a 2-year-old male patient with adrenocortical carcinoma who had three P/LP KCPG variants in NTRK1, EP300, and HMBS genes.	('EP300', 'Gene', '2033', (106, 111))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (38, 62))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (38, 62))	('EP300', 'Gene', (106, 111))	('variants', 'Var', (87, 95))	('patient', 'Species', '9606', (25, 32))	('HMBS', 'Gene', (117, 121))	('NTRK1', 'Gene', '4914', (99, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('adrenocortical carcinoma', 'Disease', (38, 62))	('HMBS', 'Gene', '3145', (117, 121))	('NTRK1', 'Gene', (99, 104))
90420	32371905	Our second case with three P/LP KCPG variants was a female diagnosed with CNS tumor at 6 years of age and carrying variants in NF1, LZTR1, and RECQL genes; she is a cancer survivor with no SMN after 20 years of clinical follow-up (Supplementary Data 8).	('RECQL', 'Gene', (143, 148))	('CNS tumor', 'Disease', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('LZTR1', 'Gene', '8216', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('variants', 'Var', (115, 123))	('NF1', 'Gene', (127, 130))	('LZTR1', 'Gene', (132, 137))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('variants', 'Var', (37, 45))	('CNS tumor', 'Disease', 'MESH:D016543', (74, 83))	('NF1', 'Gene', '4763', (127, 130))	('CNS tumor', 'Phenotype', 'HP:0100006', (74, 83))
90422	32371905	Among 1173 mutated candidate genes in our dataset, PRKN (23 patients), PAH and TYR (each found in 17 patients), and EYS and TMPRSS3 (each found in 16 patients) had the highest number of P/LP variants (Fig.	('PAH', 'Chemical', '-', (71, 74))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (60, 68))	('PRKN', 'Gene', '5071', (51, 55))	('EYS', 'Gene', '346007', (116, 119))	('patients', 'Species', '9606', (150, 158))	('PRKN', 'Gene', (51, 55))	('P/LP variants', 'Var', (186, 199))	('TMPRSS3', 'Gene', (124, 131))	('variants', 'Var', (191, 199))	('TMPRSS3', 'Gene', '64699', (124, 131))	('TYR', 'Chemical', 'MESH:D014443', (79, 82))	('EYS', 'Gene', (116, 119))
90424	32371905	Overall, 28% of the candidate genes with four and more P/LP variants had statistically significant P/LP variant allele frequencies (OR = 4.3-247 and infinity, Bonferroni-corrected P values = 0.049 to 2.44 x 10-17) in our C-AYA dataset compared to that in the non-TCGA ExAC dataset (Supplementary Data 12-13).	('P/LP', 'Gene', (55, 59))	('P/LP', 'Disease', (99, 103))	('C-AYA', 'Chemical', '-', (221, 226))	('variants', 'Var', (60, 68))	('variant', 'Var', (104, 111))
90426	32371905	Individuals with adrenocortical carcinoma and high-grade glioma tumors had the highest number of germline P/LP variants (combined KCPG and candidate genes) per sample, 3.6 and 2.8, respectively, compared to the overall 1.9 P/LP variants per sample.	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (17, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('adrenocortical carcinoma', 'Disease', (17, 41))	('variants', 'Var', (111, 119))	('glioma tumors', 'Disease', (57, 70))	('glioma tumors', 'Disease', 'MESH:D005910', (57, 70))	('P/LP', 'Gene', (106, 110))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (17, 41))
90429	32371905	For example, while TP53, PMS2, and RET are already reported as genes with germline alterations in individuals with Ewing sarcoma, we identified germline P/LP variants in ATM (1 patient), BRCA1 (1), CHEK2 (3), GJB2 (1), LZTR1 (1), and POLE (1) genes in cases with Ewing sarcoma (Supplementary Fig.	('LZTR1', 'Gene', '8216', (219, 224))	('ATM', 'Gene', (170, 173))	('GJB2', 'Gene', (209, 213))	('PMS2', 'Gene', '5395', (25, 29))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (263, 276))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (263, 276))	('BRCA1', 'Gene', '672', (187, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('RET', 'Gene', (35, 38))	('BRCA1', 'Gene', (187, 192))	('Ewing sarcoma', 'Disease', (115, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (269, 276))	('TP53', 'Gene', (19, 23))	('Ewing sarcoma', 'Disease', (263, 276))	('PMS2', 'Gene', (25, 29))	('ATM', 'Gene', '472', (170, 173))	('GJB2', 'Gene', '2706', (209, 213))	('CHEK2', 'Gene', (198, 203))	('LZTR1', 'Gene', (219, 224))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (115, 128))	('RET', 'Gene', '5979', (35, 38))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (115, 128))	('variants', 'Var', (158, 166))	('TP53', 'Gene', '7157', (19, 23))	('CHEK2', 'Gene', '11200', (198, 203))	('patient', 'Species', '9606', (177, 184))
90430	32371905	Other examples include germline P/LP variants in MEN1 (1), BRCA2 (1), PALB2 (1), KIT (1), MPL (1), CDC73 (1), and COL7A1 (4) in patients with Wilms tumor.	('BRCA2', 'Gene', '675', (59, 64))	('MEN1', 'Gene', (49, 53))	('MPL', 'Gene', (90, 93))	('PALB2', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('KIT', 'Gene', (81, 84))	('COL7A1', 'Gene', (114, 120))	('PALB2', 'Gene', '79728', (70, 75))	('COL7A1', 'Gene', '1294', (114, 120))	('Wilms tumor', 'Disease', 'MESH:D009396', (142, 153))	('P/LP variants', 'Var', (32, 45))	('BRCA2', 'Gene', (59, 64))	('CDC73', 'Gene', '79577', (99, 104))	('CDC73', 'Gene', (99, 104))	('patients', 'Species', '9606', (128, 136))	('Wilms tumor', 'Phenotype', 'HP:0002667', (142, 153))	('MEN1', 'Gene', '4221', (49, 53))	('KIT', 'Gene', '3815', (81, 84))	('MPL', 'Gene', '4352', (90, 93))	('variants', 'Var', (37, 45))	('Wilms tumor', 'Disease', (142, 153))
90431	32371905	Although RB1 was mutated in about one-third of our retinoblastoma cases, RB1 mutation-negative retinoblastoma patients had germline P/LP variants in other known cancer predisposition genes like BRCA1 (2), EGFR (1), and MSH6 (1) (Fig.	('retinoblastoma', 'Phenotype', 'HP:0009919', (95, 109))	('EGFR', 'Gene', '1956', (205, 209))	('RB1', 'Gene', '5925', (73, 76))	('BRCA1', 'Gene', '672', (194, 199))	('retinoblastoma', 'Disease', (95, 109))	('cancer', 'Disease', (161, 167))	('RB1', 'Gene', '5925', (9, 12))	('BRCA1', 'Gene', (194, 199))	('variants', 'Var', (137, 145))	('retinoblastoma', 'Disease', 'MESH:D012175', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('MSH6', 'Gene', (219, 223))	('EGFR', 'Gene', (205, 209))	('MSH6', 'Gene', '2956', (219, 223))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('retinoblastoma', 'Phenotype', 'HP:0009919', (51, 65))	('retinoblastoma', 'Disease', 'MESH:D012175', (95, 109))	('retinoblastoma', 'Disease', (51, 65))	('RB1', 'Gene', (73, 76))	('RB1', 'Gene', (9, 12))	('patients', 'Species', '9606', (110, 118))
90432	32371905	For example, we found germline P/LP variants in TMPRSS3, a member of the serine protease family, in patients with CNS tumors (5), retinoblastoma (3), and soft tissue sarcoma (3) (Fig.	('sarcoma', 'Disease', 'MESH:D012509', (166, 173))	('retinoblastoma', 'Phenotype', 'HP:0009919', (130, 144))	('TMPRSS3', 'Gene', '64699', (48, 55))	('CNS tumors', 'Disease', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('sarcoma', 'Disease', (166, 173))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (154, 173))	('P/LP variants', 'Var', (31, 44))	('retinoblastoma', 'Disease', 'MESH:D012175', (130, 144))	('retinoblastoma', 'Disease', (130, 144))	('patients', 'Species', '9606', (100, 108))	('CNS tumor', 'Phenotype', 'HP:0100006', (114, 123))	('serine', 'Chemical', 'MESH:D012694', (73, 79))	('variants', 'Var', (36, 44))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('TMPRSS3', 'Gene', (48, 55))	('CNS tumors', 'Disease', 'MESH:D016543', (114, 124))
90433	32371905	Another example is the detection of germline P/LP variants in MCPH1, which encodes a DNA damage response protein in three of our Ewing sarcoma patients.	('Ewing sarcoma', 'Disease', (129, 142))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (129, 142))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (129, 142))	('MCPH1', 'Gene', '79648', (62, 67))	('patients', 'Species', '9606', (143, 151))	('P/LP variants', 'Var', (45, 58))	('MCPH1', 'Gene', (62, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))
90434	32371905	Germline P/LP variants in SMARCAL1, another gene related to the DNA damage pathway, was detected in three patients with osteosarcoma.	('osteosarcoma', 'Disease', (120, 132))	('variants', 'Var', (14, 22))	('osteosarcoma', 'Disease', 'MESH:D012516', (120, 132))	('SMARCAL1', 'Gene', (26, 34))	('detected', 'Reg', (88, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('patients', 'Species', '9606', (106, 114))	('P/LP variants', 'Var', (9, 22))	('SMARCAL1', 'Gene', '50485', (26, 34))	('osteosarcoma', 'Phenotype', 'HP:0002669', (120, 132))
90435	32371905	Germline P/LP variants in SMAD7, a gene associated with colorectal and breast cancers, were found in six of our high-grade glioma patients.	('SMAD7', 'Gene', (26, 31))	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('found', 'Reg', (92, 97))	('variants', 'Var', (14, 22))	('SMAD7', 'Gene', '4092', (26, 31))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('patients', 'Species', '9606', (130, 138))	('colorectal and breast cancers', 'Disease', 'MESH:D001943', (56, 85))	('breast cancers', 'Phenotype', 'HP:0003002', (71, 85))	('glioma', 'Disease', (123, 129))	('P/LP variants', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
90438	32371905	Finally, in order to investigate if C-AYA patients with solid tumors have any germline alteration enrichment in genes related to other common non-cancerous congenital syndromes, we cross-matched our data with 185 congenital heart defect (CHD)-related genes and found 67 (4.4%) of our patients carried at least one P/LP variant in one autosomal-dominant CHD-related gene (7 KCPG and 19 candidate genes).	('congenital heart defect', 'Phenotype', 'HP:0001627', (213, 236))	('CHD', 'Disease', 'None', (353, 356))	('P/LP', 'Var', (314, 318))	('patients', 'Species', '9606', (284, 292))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('CHD', 'Phenotype', 'HP:0001627', (238, 241))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('C-AYA', 'Chemical', '-', (36, 41))	('congenital heart defect', 'Disease', 'MESH:D006330', (213, 236))	('cancerous congenital syndromes', 'Disease', (146, 176))	('heart defect', 'Phenotype', 'HP:0030680', (224, 236))	('solid tumors', 'Disease', 'MESH:D009369', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancerous congenital syndromes', 'Disease', 'MESH:D009369', (146, 176))	('CHD', 'Disease', 'None', (238, 241))	('CHD', 'Disease', (353, 356))	('patients', 'Species', '9606', (42, 50))	('congenital heart defect', 'Disease', (213, 236))	('CHD', 'Phenotype', 'HP:0001627', (353, 356))	('CHD', 'Disease', (238, 241))	('solid tumors', 'Disease', (56, 68))
90440	32371905	C-AYA patients with CNS (32 variants), neuroblastoma (21), rhabdomyosarcoma (15), and Wilms (15) tumors had the highest number of CHD-related gene variants, and patients with retinoblastoma (2) and osteosarcoma (2) tumors had the least number of those variants (Supplementary Fig.	('variants', 'Var', (147, 155))	('CHD', 'Phenotype', 'HP:0001627', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('patients', 'Species', '9606', (6, 14))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (59, 75))	('CNS', 'Disease', (20, 23))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (59, 75))	('CHD', 'Disease', 'None', (130, 133))	('neuroblastoma', 'Disease', (39, 52))	('neuroblastoma', 'Phenotype', 'HP:0003006', (39, 52))	('Wilms (15) tumors', 'Disease', 'MESH:D009396', (86, 103))	('retinoblastoma', 'Disease', 'MESH:D012175', (175, 189))	('osteosarcoma', 'Phenotype', 'HP:0002669', (198, 210))	('C-AYA', 'Chemical', '-', (0, 5))	('neuroblastoma', 'Disease', 'MESH:D009447', (39, 52))	('osteosarcoma (2) tumors', 'Disease', 'MESH:D012516', (198, 221))	('patients', 'Species', '9606', (161, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (203, 210))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CHD', 'Disease', (130, 133))	('retinoblastoma', 'Phenotype', 'HP:0009919', (175, 189))	('rhabdomyosarcoma', 'Disease', (59, 75))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('retinoblastoma', 'Disease', (175, 189))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
90452	32371905	One hundred twenty-seven (8.4%) patients had KCPG P/LP variants, and an additional 384 (25.5%) individuals had P/LP variants in druggable candidate genes.	('KCPG', 'Gene', (45, 49))	('variants', 'Var', (55, 63))	('P/LP variants', 'Var', (50, 63))	('patients', 'Species', '9606', (32, 40))
90453	32371905	About one-third of these patients (161 individuals), 72 individuals with KCPG P/LP variants, and 89 with candidate genes P/LP variants had existing FDA-approved antineoplastic and immunomodulating-related compounds.	('KCPG', 'Gene', (73, 77))	('patients', 'Species', '9606', (25, 33))	('variants', 'Var', (83, 91))
90463	32371905	To our knowledge, this study provides the largest evaluation of germline mutations in C-AYA patients with solid tumors.	('C-AYA', 'Chemical', '-', (86, 91))	('solid tumors', 'Disease', (106, 118))	('patients', 'Species', '9606', (92, 100))	('germline mutations', 'Var', (64, 82))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
90464	32371905	Here, we performed variant-prioritization analysis on germline exome data of 1507 C-AYA patients with solid tumors, while focusing not only on the well-known germline mutations in KCPGs but also any P/LP germline alterations in genes previously unknown to be associated with cancer predisposition.	('solid tumors', 'Disease', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('mutations', 'Var', (167, 176))	('solid tumors', 'Disease', 'MESH:D009369', (102, 114))	('C-AYA', 'Chemical', '-', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('KCPGs', 'Gene', (180, 185))	('cancer', 'Disease', (275, 281))	('P/LP', 'Var', (199, 203))
90465	32371905	Starting with our prospectively-recruited CCF series, we showed that 10% of our cases harbored P/LP germline alterations, either a truncating mutation in a KCPG and/or a larger CNV in cancer-related genes, consistent with the previous studies.	('cancer', 'Disease', (184, 190))	('KCPG', 'Gene', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('truncating mutation', 'Var', (131, 150))	('CNV', 'MPA', (177, 180))
90466	32371905	One of our CCF osteosarcoma cases presented with a germline truncating mutation in GJB2 and duplication of DDX10.	('GJB2', 'Gene', '2706', (83, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('DDX10', 'Gene', (107, 112))	('DDX10', 'Gene', '1662', (107, 112))	('duplication', 'Var', (92, 103))	('CCF osteosarcoma', 'Disease', (11, 27))	('presented', 'Reg', (34, 43))	('GJB2', 'Gene', (83, 87))	('CCF osteosarcoma', 'Disease', 'MESH:D003025', (11, 27))	('osteosarcoma', 'Phenotype', 'HP:0002669', (15, 27))
90468	32371905	It has been reported that these KID patients with germline GJB2 mutation have increased risks of developing epithelial malignancies, for example, 19% occurrence of squamous cell carcinoma of the skin and oral mucosa compared to the normal population.	('mutation', 'Var', (64, 72))	('patients', 'Species', '9606', (36, 44))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (108, 131))	('malignancies', 'Disease', 'MESH:D009369', (119, 131))	('GJB2', 'Gene', (59, 63))	('malignancies', 'Disease', (119, 131))	('KID', 'Disease', (32, 35))	('squamous cell carcinoma of the skin', 'Disease', (164, 199))	('KID', 'Disease', 'MESH:C536168', (32, 35))	('GJB2', 'Gene', '2706', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('squamous cell carcinoma of the skin', 'Phenotype', 'HP:0006739', (164, 199))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('squamous cell carcinoma of the skin', 'Disease', 'MESH:D002294', (164, 199))	('germline', 'Var', (50, 58))
90469	32371905	In total, combined with StJ cases, we detected seven GJB2 germline P/LP variants in C-AYA patients with CNS tumors (3 patients), osteosarcoma (2), Ewing sarcoma (1), and rhabdomyosarcoma (1).	('Ewing sarcoma', 'Disease', (147, 160))	('rhabdomyosarcoma', 'Disease', (170, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('CNS tumors', 'Disease', (104, 114))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (170, 186))	('GJB2', 'Gene', '2706', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (170, 186))	('osteosarcoma', 'Disease', (129, 141))	('osteosarcoma', 'Disease', 'MESH:D012516', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('variants', 'Var', (72, 80))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (147, 160))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (147, 160))	('CNS tumors', 'Disease', 'MESH:D016543', (104, 114))	('patients', 'Species', '9606', (90, 98))	('GJB2', 'Gene', (53, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('C-AYA', 'Chemical', '-', (84, 89))	('CNS tumor', 'Phenotype', 'HP:0100006', (104, 113))	('osteosarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('patients', 'Species', '9606', (118, 126))
90471	32371905	Shi and Hao showed that silencing of DDX10 could potentially be therapeutic, and inhibit proliferation, invasion, and migration of the tumor cells, by inhibiting MAPK pathway.	('proliferation', 'CPA', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('MAPK pathway', 'Pathway', (162, 174))	('inhibit', 'NegReg', (81, 88))	('tumor', 'Disease', (135, 140))	('inhibiting', 'NegReg', (151, 161))	('DDX10', 'Gene', (37, 42))	('DDX10', 'Gene', '1662', (37, 42))	('invasion', 'CPA', (104, 112))	('silencing', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
90472	32371905	Validating our findings with a larger dataset, focusing on single-nucleotide variations (SNVs) and small indels, we confirmed that 12% of C-AYA patients with solid tumors harbored at least one germline P/LP variant in the KCPGs, with an additional 61% of our cases carrying pathogenic variants in other candidate genes.	('C-AYA', 'Disease', (138, 143))	('C-AYA', 'Chemical', '-', (138, 143))	('solid tumors harbored', 'Disease', 'MESH:C537062', (158, 179))	('KCPGs', 'Gene', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('patients', 'Species', '9606', (144, 152))	('P/LP', 'Var', (202, 206))	('solid tumors harbored', 'Disease', (158, 179))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
90473	32371905	As expected, about one-third of these KCPGs and candidate genes, each with four and more P/LP variants, were enriched and had statistically significant higher P/LP variant allele frequencies in our C-AYA patients with solid tumor dataset compared to the control group from non-TCGA ExAC dataset.	('higher', 'PosReg', (152, 158))	('patients', 'Species', '9606', (204, 212))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (224, 229))	('C-AYA', 'Chemical', '-', (198, 203))	('KCPGs', 'Gene', (38, 43))	('variant', 'Var', (164, 171))	('variants', 'Var', (94, 102))	('P/LP', 'MPA', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
90474	32371905	Recently, Wang et al., with the same approach, proposed that having a germline heterozygous BRCA2 mutation predisposes to pediatric or adolescent non-Hodgkin lymphoma, by showing an overrepresentation of the BRCA2 mutations in the target group compared to a control population without cancer (odds ratio, 3.3; 95% CI, 1.7-5.8).	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (150, 166))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (150, 166))	('mutation', 'Var', (98, 106))	('BRCA2', 'Gene', (208, 213))	('mutations', 'Var', (214, 223))	('BRCA2', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (146, 166))	('overrepresentation', 'PosReg', (182, 200))	('lymphoma', 'Phenotype', 'HP:0002665', (158, 166))	('BRCA2', 'Gene', '675', (208, 213))	('cancer', 'Disease', (285, 291))	('BRCA2', 'Gene', '675', (92, 97))	('Hodgkin lymphoma', 'Disease', (150, 166))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
90478	32371905	In another example, somatic depletion of PRKN, a component of a multiprotein E3 ubiquitin ligase complex, and a known gene associated with Parkinson's disease, was also reported in ovarian and lung cancers.	('lung cancers', 'Phenotype', 'HP:0100526', (193, 205))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	("Parkinson's disease", 'Disease', 'MESH:D010300', (139, 158))	('ovarian and lung cancers', 'Disease', 'MESH:D055370', (181, 205))	('PRKN', 'Gene', '5071', (41, 45))	('PRKN', 'Gene', (41, 45))	('depletion', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('reported', 'Reg', (169, 177))	("Parkinson's disease", 'Disease', (139, 158))
90486	32371905	Here, we also showed that 67 (4.4%) of our C-AYA patients with solid tumors carried at least one germline P/LP variant in a CHD-related gene (7 KCPG and 19 candidate genes) (Supplementary Fig.	('variant', 'Var', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('solid tumors', 'Disease', (63, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('CHD', 'Disease', (124, 127))	('CHD', 'Phenotype', 'HP:0001627', (124, 127))	('CHD', 'Disease', 'None', (124, 127))	('C-AYA', 'Chemical', '-', (43, 48))	('patients', 'Species', '9606', (49, 57))	('solid tumors', 'Disease', 'MESH:D009369', (63, 75))
90487	32371905	As examples, germline NF1 and PTPN11 P/LP variants were found in 24 of our C-AYA patients with solid tumors (Supplementary Data 5): both of these KCPGs predispose to CNS-related tumors, are also strongly correlated with CHDs, via up-regulation of the RAS pathway.	('NF1', 'Gene', '4763', (22, 25))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('solid tumors', 'Disease', 'MESH:D009369', (95, 107))	('CHDs', 'Disease', (220, 224))	('C-AYA', 'Chemical', '-', (75, 80))	('up-regulation', 'PosReg', (230, 243))	('NF1', 'Gene', (22, 25))	('CHDs', 'Disease', 'None', (220, 224))	('PTPN11', 'Gene', (30, 36))	('variants', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('PTPN11', 'Gene', '5781', (30, 36))	('CHD', 'Phenotype', 'HP:0001627', (220, 223))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('predispose', 'Reg', (152, 162))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumors', 'Disease', (101, 107))	('solid tumors', 'Disease', (95, 107))	('tumors', 'Disease', (178, 184))	('patients', 'Species', '9606', (81, 89))	('RAS pathway', 'Pathway', (251, 262))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
90488	32371905	NOTCH1 germline P/LP variants in two of our cases (Supplementary Data 16) is another example of a candidate gene associated with both CHD and cancer via varied mechanisms, including downregulation of the TGF-beta signaling pathway affecting epithelial-to-mesenchymal transformation (EMT).	('variants', 'Var', (21, 29))	('epithelial-to-mesenchymal transformation', 'CPA', (241, 281))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('CHD', 'Disease', (134, 137))	('CHD', 'Disease', 'None', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('downregulation', 'NegReg', (182, 196))	('TGF-beta', 'Gene', (204, 212))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('CHD', 'Phenotype', 'HP:0001627', (134, 137))	('TGF-beta', 'Gene', '7039', (204, 212))	('associated', 'Reg', (113, 123))	('cancer', 'Disease', (142, 148))
90491	32371905	Our pathway analysis showed that not only point mutations, and deletion of TP53 itself are important in cancer predisposition in C-AYA patients, but also that P/LP germline mutations of other, seemingly disparate, genes point to a final common disruption of the p53 pathway.	('patients', 'Species', '9606', (135, 143))	('TP53', 'Gene', '7157', (75, 79))	('p53', 'Gene', (262, 265))	('disruption', 'Reg', (244, 254))	('point mutations', 'Var', (42, 57))	('P/LP', 'Var', (159, 163))	('p53', 'Gene', '7157', (262, 265))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('C-AYA', 'Chemical', '-', (129, 134))	('deletion', 'Var', (63, 71))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('TP53', 'Gene', (75, 79))
90494	32371905	The prime example is using poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of adults with advanced breast, ovarian, and prostate cancers in the context of germline mutations in DDR genes, such as BRCA1, BRCA2, ATM, or PALB2.	('BRCA2', 'Gene', '675', (220, 225))	('ovarian', 'Disease', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast', 'Disease', (116, 122))	('prostate cancers', 'Phenotype', 'HP:0012125', (137, 153))	('PALB2', 'Gene', (235, 240))	('prostate cancers', 'Disease', (137, 153))	('germline mutations', 'Var', (172, 190))	('poly (ADP-ribose) polymerase', 'Gene', '142', (27, 55))	('poly (ADP-ribose) polymerase', 'Gene', (27, 55))	('PALB2', 'Gene', '79728', (235, 240))	('ATM', 'Gene', '472', (227, 230))	('PARP', 'Gene', '142', (57, 61))	('BRCA2', 'Gene', (220, 225))	('BRCA1', 'Gene', '672', (213, 218))	('DDR genes', 'Gene', (194, 203))	('PARP', 'Gene', (57, 61))	('BRCA1', 'Gene', (213, 218))	('ATM', 'Gene', (227, 230))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('prostate cancers', 'Disease', 'MESH:D011471', (137, 153))
90501	32371905	Therefore, the prioritized variants here for cancer risk may be challenged by survivor bias.	('variants', 'Var', (27, 35))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))
90514	32371905	Variants were excluded if the allele frequency was greater than or equal to 1.0% in any of the following population databases: 1000 Genomes Project (phase3v5b), NHLBI ESP exomes (ESP6500SI-V2), ExAC Frequency (0.3.1), and the gnomAD Maximum Frequency (2.0.1).	('AD', 'Disease', 'MESH:D000544', (230, 232))	('AD', 'Disease', (230, 232))	('ESP6500SI-V2', 'Var', (179, 191))
90519	32371905	Also, we extracted germline exome data, for all the KCPG and candidate genes found in our study, and independently performed another IVA analysis, with the same parameters, on 53,105 individuals from non-TCGA ExAC database to compare the frequency of P/LP allele variants between C-AYA patients with solid tumors and this non-cancer control population.	('solid tumors', 'Disease', 'MESH:D009369', (300, 312))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('solid tumors', 'Disease', (300, 312))	('cancer', 'Disease', (326, 332))	('C-AYA', 'Chemical', '-', (280, 285))	('variants', 'Var', (263, 271))	('patients', 'Species', '9606', (286, 294))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
90522	32371905	After extracting the bioactivity data related to the drugs from the prepared bioactivity databases, only those items meeting the following four criteria were retained: (i) binding affinities, including Ki, Kd, IC50, or EC50, <=10 muM; (ii) proteins represented by unique UniProt accession number; (iii) proteins marked as "reviewed" in the UniProt database, and (iv) proteins of human origin.	('IC50', 'Var', (210, 214))	('binding', 'Interaction', (172, 179))	('EC50', 'Var', (219, 223))	('human', 'Species', '9606', (379, 384))	('<=10 muM', 'Var', (225, 233))
90523	32371905	P values were adjusted, when we compared the frequency of P/LP variants in C-AYA with solid tumors versus non-TCGA ExAC control population, for multiple testing with Bonferroni correction considering 593 tests.	('solid tumors', 'Disease', 'MESH:D009369', (86, 98))	('C-AYA', 'Chemical', '-', (75, 80))	('P/LP variants', 'Var', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('solid tumors', 'Disease', (86, 98))	('C-AYA', 'Disease', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
90534	32093223	Mounting evidence has demonstrated that NR5A1 can be SUMOylated on lysine 194 (K194, the major site) and lysine 119 (K119, the minor site), and SUMO modification of NR5A1 regulates its transcriptional activities.	('SUMO', 'Var', (144, 148))	('K119', 'Chemical', 'MESH:C118156', (117, 121))	('transcriptional activities', 'MPA', (185, 211))	('regulates', 'Reg', (171, 180))	('NR5A1', 'Gene', (40, 45))	('lysine', 'Chemical', 'MESH:D008239', (67, 73))	('K194', 'Chemical', '-', (79, 83))	('lysine', 'Chemical', 'MESH:D008239', (105, 111))	('NR5A1', 'Gene', (165, 170))	('lysine', 'Var', (105, 111))
90535	32093223	In addition to the SUMOylation, phosphorylation at serine 203 (S203) plays a key in the transcriptional capacity of NR5A1.	('S203', 'Var', (63, 67))	('NR5A1', 'Gene', (116, 121))	('serine', 'Chemical', 'MESH:D012694', (51, 57))	('transcriptional capacity', 'MPA', (88, 112))	('phosphorylation', 'MPA', (32, 47))
90548	32093223	H1299 and Saos2 cells were co-transfected the ATF3 promoter-LUC reporter plasmid with either wild-type (WT), K119R (mimicking de-SUMOylated at K119), K194R (mimicking de-SUMOylated at K194), 2KR (mimicking de-SUMOylated at both K119 and K194), S203A (mimicking de-phosphorylated at S203), or SUMO-WT (mimicking SUMOylated) NR5A1 expression plasmid.	('K194', 'Chemical', '-', (150, 154))	('S203A', 'Mutation', 'p.S203A', (244, 249))	('K119', 'Chemical', 'MESH:C118156', (228, 232))	('S203A', 'Var', (244, 249))	('K119R', 'Mutation', 'rs1175310478', (109, 114))	('K194', 'Var', (237, 241))	('K119', 'Chemical', 'MESH:C118156', (143, 147))	('K194R', 'Mutation', 'p.K194R', (150, 155))	('K194', 'Chemical', '-', (237, 241))	('K119', 'Chemical', 'MESH:C118156', (109, 113))	('K194', 'Chemical', '-', (184, 188))	('K119', 'Var', (228, 232))
90549	32093223	As shown in Figure 5A and 5B, in both H1299 and Saos2 cell lines, while the WT and SUMO-WT NR5A1 enhanced ATF3 promoter activity, K119R, K194R, 2KR, and S203A NR5A1 reduced this effect.	('2KR', 'Var', (144, 147))	('K194R', 'Var', (137, 142))	('K119R', 'Mutation', 'rs1175310478', (130, 135))	('K119R', 'Var', (130, 135))	('enhanced', 'PosReg', (97, 105))	('S203A', 'Var', (153, 158))	('K194R', 'Mutation', 'p.K194R', (137, 142))	('S203A', 'Mutation', 'p.S203A', (153, 158))	('ATF3', 'Protein', (106, 110))
90551	32093223	Mutations of NR5A1 lead to many disorders and phenotypes, including premature ovarian failure, adrenocortical insufficiency, sex reversal, and spermatogenesis failure.	('lead to', 'Reg', (19, 26))	('adrenocortical insufficiency', 'Phenotype', 'HP:0008207', (95, 123))	('premature ovarian failure', 'Disease', (68, 93))	('premature ovarian failure', 'Disease', 'MESH:D016649', (68, 93))	('spermatogenesis failure', 'Disease', 'MESH:C536875', (143, 166))	('premature ovarian failure', 'Phenotype', 'HP:0008209', (68, 93))	('adrenocortical insufficiency', 'Disease', 'MESH:D000224', (95, 123))	('Mutations', 'Var', (0, 9))	('spermatogenesis failure', 'Disease', (143, 166))	('adrenocortical insufficiency', 'Disease', (95, 123))	('NR5A1', 'Gene', (13, 18))	('sex reversal', 'Phenotype', 'HP:0012245', (125, 137))	('sex reversal', 'Disease', (125, 137))
90561	32093223	It has been determined that NR5A1 can be SUMOylated on K194 and K119, which are major and minor sites, respectively, and the SUMOylation of NR5A1 influences its transcriptional activities.	('transcriptional activities', 'MPA', (161, 187))	('NR5A1', 'Gene', (140, 145))	('K194', 'Chemical', '-', (55, 59))	('K119', 'Chemical', 'MESH:C118156', (64, 68))	('influences', 'Reg', (146, 156))	('K119', 'Var', (64, 68))
90562	32093223	In the present work, we demonstrated that replacement of K194 and/or K119 by an arginine residue in NR5A1 leads to reduce ATF3's transcriptional activity, suggesting that SUMOylation of NR5A1 plays an important role for ATF3 expression.	('K194', 'Var', (57, 61))	('K194', 'Chemical', '-', (57, 61))	('K119', 'Chemical', 'MESH:C118156', (69, 73))	('arginine', 'Chemical', 'MESH:D001120', (80, 88))	('K119', 'Var', (69, 73))	('ATF3', 'Gene', (122, 126))	('NR5A1', 'Gene', (100, 105))	('reduce', 'NegReg', (115, 121))	('transcriptional activity', 'MPA', (129, 153))
90563	32093223	Importantly, loss of phosphorylation on NR5A1 S203 (S203A) significantly decreases its activity in regulating the ATF3 promoter more than SUMOylation mutants.	('S203 (S203A', 'Var', (46, 57))	('decreases', 'NegReg', (73, 82))	('activity', 'MPA', (87, 95))	('NR5A1', 'Gene', (40, 45))	('phosphorylation', 'MPA', (21, 36))	('S203A', 'Mutation', 'p.S203A', (52, 57))	('loss', 'NegReg', (13, 17))	('regulating the ATF3 promoter', 'MPA', (99, 127))
90567	32093223	S203A, K119R, K194R, and 2KR NR5A1 expression plasmids were created by PCR-based mutagenesis (QuikChange Lightning site-directed mutagenesis kit, Agilent/Strategene, La Jolla, CA, USA).	('NR5A1', 'Gene', (29, 34))	('S203A', 'Mutation', 'p.S203A', (0, 5))	('K194R', 'Var', (14, 19))	('K119R', 'Mutation', 'rs1175310478', (7, 12))	('K194R', 'Mutation', 'p.K194R', (14, 19))	('K119R', 'Var', (7, 12))
90593	31307011	Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('metformin', 'Chemical', 'MESH:D008687', (26, 35))	('repositioning', 'Var', (9, 22))	('endocrine tumors', 'Disease', 'MESH:D009377', (96, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('endocrine tumors', 'Disease', (96, 112))	('rat', 'Species', '10116', (65, 68))
90599	31307011	These patients treated with metformin were characterized by a lower cancer incidence in comparison to patients who were on other anti-diabetic medications.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('diabetic', 'Disease', 'MESH:D003920', (134, 142))	('metformin', 'Var', (28, 37))	('patients', 'Species', '9606', (102, 110))	('diabetic', 'Disease', (134, 142))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('lower', 'NegReg', (62, 67))	('patients', 'Species', '9606', (6, 14))	('metformin', 'Chemical', 'MESH:D008687', (28, 37))	('cancer', 'Disease', (68, 74))
90600	31307011	Subsequently, several epidemiological data documented the association between metformin therapy and a lower risk of developing breast, colon, pancreatic and liver cancers in diabetic patients.	('liver cancers', 'Phenotype', 'HP:0002896', (157, 170))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('breast', 'Disease', (127, 133))	('metformin', 'Chemical', 'MESH:D008687', (78, 87))	('diabetic', 'Disease', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('colon', 'Disease', (135, 140))	('pancreatic and liver cancers', 'Disease', 'MESH:D006528', (142, 170))	('metformin', 'Var', (78, 87))	('patients', 'Species', '9606', (183, 191))	('diabetic', 'Disease', 'MESH:D003920', (174, 182))
90631	31307011	In a recent retrospective study based on the Korean population, metformin intake was associated with lower thyroid cancer incidence risk.	('thyroid cancer', 'Disease', (107, 121))	('metformin', 'Var', (64, 73))	('thyroid cancer', 'Phenotype', 'HP:0002890', (107, 121))	('thyroid cancer', 'Disease', 'MESH:D013964', (107, 121))	('metformin', 'Chemical', 'MESH:D008687', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lower thyroid', 'Phenotype', 'HP:0000821', (101, 114))	('lower', 'NegReg', (101, 106))
90638	31307011	In a retrospective study involving 240 DTC individuals, diabetic patients who were treated with metformin had smaller thyroid cancer size, higher complete response rate and longer progression-free survival in comparison to non-metformin treated diabetic patients and non-diabetic thyroid cancer patients matched by age, gender and BMI.	('diabetic', 'Disease', 'MESH:D003920', (271, 279))	('non-diabetic thyroid cancer', 'Disease', 'MESH:D003920', (267, 294))	('diabetic', 'Disease', (271, 279))	('smaller', 'NegReg', (110, 117))	('progression-free survival', 'CPA', (180, 205))	('thyroid cancer', 'Disease', 'MESH:D013964', (118, 132))	('non-diabetic thyroid cancer', 'Disease', (267, 294))	('metformin', 'Chemical', 'MESH:D008687', (227, 236))	('smaller thyroid', 'Phenotype', 'HP:0005990', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('thyroid cancer', 'Phenotype', 'HP:0002890', (118, 132))	('diabetic', 'Disease', 'MESH:D003920', (56, 64))	('diabetic', 'Disease', 'MESH:D003920', (245, 253))	('rat', 'Species', '10116', (164, 167))	('diabetic', 'Disease', (56, 64))	('higher', 'PosReg', (139, 145))	('diabetic', 'Disease', (245, 253))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('non-diabetic thyroid cancer', 'Phenotype', 'HP:0040198', (267, 294))	('metformin', 'Var', (96, 105))	('patients', 'Species', '9606', (65, 73))	('metformin', 'Chemical', 'MESH:D008687', (96, 105))	('thyroid cancer', 'Disease', 'MESH:D013964', (280, 294))	('thyroid cancer', 'Disease', (118, 132))	('DTC', 'Chemical', '-', (39, 42))	('patients', 'Species', '9606', (295, 303))	('thyroid cancer', 'Phenotype', 'HP:0002890', (280, 294))	('complete response', 'CPA', (146, 163))	('patients', 'Species', '9606', (254, 262))	('longer', 'PosReg', (173, 179))
90648	31307011	Since p70S6K/pS6 is downstream of mTOR, inhibition of mTOR hampers their activation leading to reduced protein synthesis, which is necessary for cancer cell growth.	('cancer', 'Disease', (145, 151))	('protein synthesis', 'MPA', (103, 120))	('inhibition', 'Var', (40, 50))	('pS6', 'Gene', '338413', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('p70S6K', 'Gene', (6, 12))	('mTOR', 'Gene', (54, 58))	('activation', 'MPA', (73, 83))	('p70S6K', 'Gene', '6198', (6, 12))	('reduced', 'NegReg', (95, 102))	('hampers', 'NegReg', (59, 66))	('pS6', 'Gene', (13, 16))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
90656	31307011	IRS-1 is also a substrate for insulin signaling and metformin mediated inhibition of IRS-1 blocks insulin/IGF1/AKT/mTOR signaling pathway and protects against insulin-associated cancer progression.	('insulin', 'Gene', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('IGF1', 'Gene', (106, 110))	('insulin', 'Gene', '3630', (98, 105))	('IRS-1', 'Gene', '3667', (0, 5))	('metformin', 'Chemical', 'MESH:D008687', (52, 61))	('IRS-1', 'Gene', (85, 90))	('insulin', 'Gene', '3630', (159, 166))	('protects', 'NegReg', (142, 150))	('blocks insulin', 'Disease', 'MESH:D006327', (91, 105))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('rat', 'Species', '10116', (21, 24))	('inhibition', 'Var', (71, 81))	('insulin', 'Gene', (98, 105))	('insulin', 'Gene', '3630', (30, 37))	('IRS-1', 'Gene', '3667', (85, 90))	('IGF1', 'Gene', '3479', (106, 110))	('insulin', 'Gene', (159, 166))	('IRS-1', 'Gene', (0, 5))	('blocks insulin', 'Disease', (91, 105))	('cancer', 'Disease', (178, 184))
90680	31307011	The presence of growth factors, such as insulin or insulin-like growth factor (IGF) along with TSH, has been shown to augment the growth of thyroid cancer cells to a much greater extent.	('insulin or insulin', 'Disease', 'MESH:D007333', (40, 58))	('insulin or insulin', 'Disease', (40, 58))	('thyroid cancer', 'Disease', 'MESH:D013964', (140, 154))	('thyroid cancer', 'Phenotype', 'HP:0002890', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('TSH', 'Chemical', 'MESH:D013972', (95, 98))	('presence', 'Var', (4, 12))	('augment', 'PosReg', (118, 125))	('growth', 'CPA', (130, 136))	('thyroid cancer', 'Disease', (140, 154))
90721	31307011	The combination of metformin with sorafenib resulted in increased apoptosis and cell cycle arrest in ATC cells in comparison to treatment with either metformin or sorafenib alone.	('sorafenib', 'Chemical', 'MESH:D000077157', (34, 43))	('metformin', 'Chemical', 'MESH:D008687', (19, 28))	('increased', 'PosReg', (56, 65))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('sorafenib', 'Gene', (34, 43))	('metformin', 'Chemical', 'MESH:D008687', (150, 159))	('sorafenib', 'Chemical', 'MESH:D000077157', (163, 172))	('arrest', 'Disease', 'MESH:D006323', (91, 97))	('apoptosis', 'CPA', (66, 75))	('combination', 'Interaction', (4, 15))	('metformin', 'Var', (19, 28))	('arrest', 'Disease', (91, 97))	('ATC', 'Phenotype', 'HP:0011779', (101, 104))
90738	31307011	Metformin treatment was also associated with lower thyroid gland volume compared with the placebo group.	('lower thyroid', 'Phenotype', 'HP:0000821', (45, 58))	('lower', 'NegReg', (45, 50))	('Metformin', 'Var', (0, 9))	('thyroid gland volume', 'CPA', (51, 71))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))
90753	31307011	In a recent retrospective study conducted in Italy, metformin treatment was associated with longer progression-free survival (PFS) in diabetic patients with pNETs in comparison to diabetic patients or non-diabetic patients who were not receiving metformin.	('progression-free survival', 'CPA', (99, 124))	('diabetic', 'Disease', (205, 213))	('diabetic', 'Disease', 'MESH:D003920', (134, 142))	('patients', 'Species', '9606', (214, 222))	('metformin', 'Chemical', 'MESH:D008687', (246, 255))	('NET', 'Phenotype', 'HP:0100634', (158, 161))	('diabetic', 'Disease', (134, 142))	('metformin', 'Var', (52, 61))	('patients', 'Species', '9606', (143, 151))	('metformin', 'Chemical', 'MESH:D008687', (52, 61))	('NETs', 'Phenotype', 'HP:0100634', (158, 162))	('diabetic', 'Disease', 'MESH:D003920', (205, 213))	('diabetic', 'Disease', 'MESH:D003920', (180, 188))	('patients', 'Species', '9606', (189, 197))	('diabetic', 'Disease', (180, 188))	('longer', 'PosReg', (92, 98))
90770	31307011	Diminished oncogenic growth in these cell lines upon GSK-3 inhibition was associated with the inhibition of mTOR and EGFR signaling pathways.	('inhibition', 'NegReg', (94, 104))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('Diminished', 'NegReg', (0, 10))	('GSK-3', 'Gene', '2931', (53, 58))	('inhibition', 'Var', (59, 69))	('GSK-3', 'Gene', (53, 58))	('oncogenic growth', 'CPA', (11, 27))
90779	31307011	As is reported in thyroid cancer and NET cell lines, metformin exposure inhibited cell proliferation, promoted cell cycle arrest and apoptosis of pheochromocytoma rat-derived cells (PC12 cell line).	('thyroid cancer', 'Phenotype', 'HP:0002890', (18, 32))	('metformin', 'Chemical', 'MESH:D008687', (53, 62))	('apoptosis', 'CPA', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('rat', 'Species', '10116', (94, 97))	('pheochromocytoma', 'Disease', 'MESH:D010673', (146, 162))	('promoted', 'PosReg', (102, 110))	('cell proliferation', 'CPA', (82, 100))	('NET', 'Phenotype', 'HP:0100634', (37, 40))	('arrest', 'Disease', (122, 128))	('rat', 'Species', '10116', (163, 166))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (111, 128))	('pheochromocytoma', 'Disease', (146, 162))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (146, 162))	('thyroid cancer', 'Disease', (18, 32))	('inhibited', 'NegReg', (72, 81))	('arrest', 'Disease', 'MESH:D006323', (122, 128))	('thyroid cancer', 'Disease', 'MESH:D013964', (18, 32))	('PC12', 'CellLine', 'CVCL:0481', (182, 186))	('metformin', 'Var', (53, 62))
90786	31307011	Cell lines derived from head and neck PGLs (PTJ64i and PTJ86i) are also sensitive to metformin-mediated growth suppression.	('metformin-mediated growth suppression', 'MPA', (85, 122))	('PTJ64i', 'Var', (44, 50))	('metformin', 'Chemical', 'MESH:D008687', (85, 94))	('PTJ86i', 'Var', (55, 61))	('sensitive', 'Reg', (72, 81))
90819	31307011	In ACTH-secreting AtT20 cells, metformin inhibited cell proliferation by activating the AMPK signaling pathway and inhibiting the IGF-1R/AKT/mTOR pathway.	('IGF-1R/AKT/mTOR pathway', 'Pathway', (130, 153))	('AMPK', 'Gene', (88, 92))	('metformin', 'Var', (31, 40))	('inhibiting', 'NegReg', (115, 125))	('activating', 'PosReg', (73, 83))	('cell proliferation', 'CPA', (51, 69))	('inhibited', 'NegReg', (41, 50))	('rat', 'Species', '10116', (63, 66))	('AMPK', 'Gene', '5563', (88, 92))	('metformin', 'Chemical', 'MESH:D008687', (31, 40))
90826	31307011	In GH3 cells, inhibition of ATF3 activity prevented metformin-induced apoptosis, which suggests its tumor suppressor role in PitNET cells.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('metformin-induced', 'MPA', (52, 69))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('prevented', 'NegReg', (42, 51))	('activity', 'MPA', (33, 41))	('apoptosis', 'CPA', (70, 79))	('metformin', 'Chemical', 'MESH:D008687', (52, 61))	('NET', 'Phenotype', 'HP:0100634', (128, 131))	('inhibition', 'Var', (14, 24))
90827	31307011	Similar to ATF3, STAT3 can also promote or inhibit cancer cell growth.	('inhibit', 'NegReg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('STAT3', 'Var', (17, 22))	('promote', 'PosReg', (32, 39))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
90855	31307011	Moreover, metformin can also decrease the production of certain growth-promoting hormones, such as TSH and GH, which could further contribute to the reduction of TSH- and GH-dependent tumors.	('GH-dependent tumors', 'Disease', 'MESH:D004393', (171, 190))	('TSH', 'Chemical', 'MESH:D013972', (162, 165))	('reduction', 'NegReg', (149, 158))	('metformin', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('production', 'MPA', (42, 52))	('TSH', 'Gene', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('TSH', 'Chemical', 'MESH:D013972', (99, 102))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))	('GH-dependent tumors', 'Disease', (171, 190))	('reduction of TSH', 'Phenotype', 'HP:0031098', (149, 165))	('decrease', 'NegReg', (29, 37))
90874	31307011	Overall, although there are several limitations in studies investigating the role of metformin in endocrine cancers, metformin appears to be a promising adjuvant agent in the treatment of endocrine malignancies.	('endocrine cancer', 'Phenotype', 'HP:0100568', (98, 114))	('endocrine cancers', 'Disease', 'MESH:D004701', (98, 115))	('endocrine malignancies', 'Disease', (188, 210))	('metformin', 'Chemical', 'MESH:D008687', (85, 94))	('metformin', 'Var', (117, 126))	('endocrine cancers', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('endocrine malignancies', 'Disease', 'MESH:D004701', (188, 210))	('endocrine malignancies', 'Phenotype', 'HP:0100568', (188, 210))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('metformin', 'Chemical', 'MESH:D008687', (117, 126))
90882	29112114	Moreover, treatment of H295R with E2 or IGF-II induced a multiprotein complex formation consisting of PELP1, IGF1R, ERalpha, and Src that is involved in ERK1/2 rapid activation.	('PELP1', 'Gene', '27043', (102, 107))	('IGF-II', 'Gene', '3481', (40, 46))	('multiprotein complex formation', 'MPA', (57, 87))	('H295R', 'Var', (23, 28))	('Src', 'Gene', (129, 132))	('ERalpha', 'Gene', (116, 123))	('H295R', 'CellLine', 'CVCL:0458', (23, 28))	('Src', 'Gene', '6714', (129, 132))	('IGF1R', 'Gene', (109, 114))	('ERalpha', 'Gene', '2099', (116, 123))	('ERK1/2', 'Gene', (153, 159))	('induced', 'Reg', (47, 54))	('ERK1/2', 'Gene', '5595;5594', (153, 159))	('IGF1R', 'Gene', '3480', (109, 114))	('PELP1', 'Gene', (102, 107))	('IGF-II', 'Gene', (40, 46))
90886	29112114	The cause of adrenal cancer remains elusive, but studies in the past 10 years suggest genetic mutations in the adrenal gland lead to the initiation of a malignant tumor.	('adrenal cancer', 'Disease', 'MESH:D000310', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('malignant tumor', 'Disease', (153, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('adrenal', 'Gene', (111, 118))	('malignant tumor', 'Disease', 'MESH:D018198', (153, 168))	('lead to', 'Reg', (125, 132))	('genetic mutations', 'Var', (86, 103))	('adrenal cancer', 'Disease', (13, 27))
90893	29112114	Furthermore, the growth inhibitory effect was also achieved using XCT790, the estrogen related receptor alpha (ERRalpha) inverse agonist.	('ERRalpha', 'Gene', '2101', (111, 119))	('estrogen related receptor alpha', 'Gene', '2101', (78, 109))	('growth', 'MPA', (17, 23))	('estrogen related receptor alpha', 'Gene', (78, 109))	('ERRalpha', 'Gene', (111, 119))	('XCT790', 'Var', (66, 72))	('XCT790', 'Chemical', 'MESH:C488234', (66, 72))
90897	29112114	Accordingly, ERalpha knock-down was more effective than an IGF1R antibody in controlling H295R cell proliferation.	('H295R cell proliferation', 'CPA', (89, 113))	('ERalpha', 'Gene', (13, 20))	('knock-down', 'Var', (21, 31))	('ERalpha', 'Gene', '2099', (13, 20))	('H295R', 'CellLine', 'CVCL:0458', (89, 94))	('IGF1R', 'Gene', (59, 64))	('IGF1R', 'Gene', '3480', (59, 64))
90944	29112114	Importantly, PELP1 silencing reduced IGF1R expression, even in basal conditions (Figure 4).	('PELP1', 'Gene', (13, 18))	('IGF1R', 'Gene', (37, 42))	('PELP1', 'Gene', '27043', (13, 18))	('silencing', 'Var', (19, 28))	('IGF1R', 'Gene', '3480', (37, 42))	('reduced', 'NegReg', (29, 36))	('reduced IGF1R', 'Phenotype', 'HP:0030269', (29, 42))	('expression', 'MPA', (43, 53))
90946	29112114	For this reason, we evaluated Cyclin D1 expression in H295R cells after PELP1gene silencing.	('expression', 'MPA', (40, 50))	('evaluated', 'Reg', (20, 29))	('H295R', 'CellLine', 'CVCL:0458', (54, 59))	('PELP1', 'Gene', (72, 77))	('PELP1', 'Gene', '27043', (72, 77))	('silencing', 'Var', (82, 91))	('Cyclin D1', 'Gene', '595', (30, 39))	('Cyclin D1', 'Gene', (30, 39))
90948	29112114	It is worth noting that, in basal condition also, the Cyclin D1 expression is lowered in the presence of silenced PELP-1 expression (Figure 5).	('Cyclin D1', 'Gene', '595', (54, 63))	('expression', 'MPA', (64, 74))	('lowered', 'NegReg', (78, 85))	('Cyclin D1', 'Gene', (54, 63))	('PELP-1', 'Gene', '27043', (114, 120))	('silenced', 'Var', (105, 113))	('PELP-1', 'Gene', (114, 120))
90949	29112114	Considering that PELP1 silencing was able to reduce the expression of genes involved in E2- and IGF-II-dependent H295R cell growth, we investigated the effects of PELP1 silencing on H295R cell proliferation.	('PELP1', 'Gene', (17, 22))	('E2- and IGF-II', 'Gene', '106478911;3481', (88, 102))	('PELP1', 'Gene', '27043', (17, 22))	('H295R', 'CellLine', 'CVCL:0458', (113, 118))	('silencing', 'Var', (23, 32))	('PELP1', 'Gene', (163, 168))	('expression of genes', 'MPA', (56, 75))	('reduce', 'NegReg', (45, 51))	('H295R', 'CellLine', 'CVCL:0458', (182, 187))	('PELP1', 'Gene', '27043', (163, 168))
90950	29112114	As shown in Figure 6A,B, PELP1 silencing in H295R cells significantly reduced the ability of both E2 and IGF-II to induce cell proliferation as assessed by both MTT assay and [3H] thymidine incorporation.	('silencing', 'Var', (31, 40))	('reduced', 'NegReg', (70, 77))	('3H', 'Chemical', 'MESH:D014316', (176, 178))	('PELP1', 'Gene', (25, 30))	('H295R', 'CellLine', 'CVCL:0458', (44, 49))	('MTT', 'Chemical', 'MESH:C070243', (161, 164))	('thymidine', 'Chemical', 'MESH:D013936', (180, 189))	('PELP1', 'Gene', '27043', (25, 30))	('induce', 'PosReg', (115, 121))	('IGF-II', 'Gene', (105, 111))	('IGF-II', 'Gene', '3481', (105, 111))	('cell proliferation', 'CPA', (122, 140))
90966	29112114	Mutation of the PELP1 PXXP c-Src interaction site abolished estrogen-induced MAPK activation and ER transcriptional activity.	('Mutation', 'Var', (0, 8))	('estrogen-induced', 'MPA', (60, 76))	('activation', 'PosReg', (82, 92))	('abolished', 'NegReg', (50, 59))	('ER', 'Gene', '2099', (97, 99))	('PELP1', 'Gene', (16, 21))	('PELP1', 'Gene', '27043', (16, 21))	('c-Src', 'Gene', (27, 32))	('c-Src', 'Gene', '6714', (27, 32))
90970	29112114	Mechanistic studies demonstrated that overexpression of a mutated form of PELP1 that lacks the nuclear localization signal was able to drive MAPK signaling and constitutive AKT activation in unstimulated breast cancer cells, resulting in increased phosphorylation of ERalpha at Serine 118 and Serine 167.	('Serine', 'Chemical', 'MESH:D012694', (293, 299))	('ERalpha', 'Gene', '2099', (267, 274))	('AKT', 'Gene', (173, 176))	('phosphorylation', 'MPA', (248, 263))	('PELP1', 'Gene', (74, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))	('activation', 'PosReg', (177, 187))	('breast cancer', 'Disease', 'MESH:D001943', (204, 217))	('drive', 'Reg', (135, 140))	('breast cancer', 'Disease', (204, 217))	('mutated', 'Var', (58, 65))	('MAPK signaling', 'MPA', (141, 155))	('AKT', 'Gene', '207', (173, 176))	('Serine 167', 'MPA', (293, 303))	('Serine', 'Chemical', 'MESH:D012694', (278, 284))	('PELP1', 'Gene', '27043', (74, 79))	('ERalpha', 'Gene', (267, 274))	('increased', 'PosReg', (238, 247))	('overexpression', 'PosReg', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
90973	29112114	Here, we demonstrated that PELP1 silencing is able to inhibit both basal and E2-induced IGF1R protein expression.	('IGF1R', 'Gene', (88, 93))	('inhibit', 'NegReg', (54, 61))	('PELP1', 'Gene', (27, 32))	('silencing', 'Var', (33, 42))	('protein', 'Protein', (94, 101))	('PELP1', 'Gene', '27043', (27, 32))	('IGF1R', 'Gene', '3480', (88, 93))
90974	29112114	A further demonstration of PELP1 involvement in pathways regulating ACC cell growth came from the observation that PELP1 gene silencing was able to decrease basal and abrogate E2- and IGF-II-dependent expression of Cyclin D1.	('PELP1', 'Gene', (27, 32))	('PELP1', 'Gene', (115, 120))	('Cyclin D1', 'Gene', '595', (215, 224))	('PELP1', 'Gene', '27043', (27, 32))	('PELP1', 'Gene', '27043', (115, 120))	('ACC', 'Phenotype', 'HP:0006744', (68, 71))	('Cyclin D1', 'Gene', (215, 224))	('abrogate', 'NegReg', (167, 175))	('gene silencing', 'Var', (121, 135))	('decrease', 'NegReg', (148, 156))	('E2- and IGF-II', 'Gene', '106478911;3481', (176, 190))
90975	29112114	Accordingly, reduced H295R cell growth was also detected after PELP1 gene silencing.	('PELP1', 'Gene', (63, 68))	('PELP1', 'Gene', '27043', (63, 68))	('H295R cell growth', 'CPA', (21, 38))	('H295R', 'CellLine', 'CVCL:0458', (21, 26))	('reduced', 'NegReg', (13, 20))	('gene silencing', 'Var', (69, 83))
90976	29112114	Importantly, silencing of PELP1 using a liposomal formulation to vehicle PELP1 siRNA in vivo was shown to be significantly effective in reducing the growth of an orthotopic model of ER positive breast cancer, suggesting that targeting this protein is feasible in vivo and could have promising therapeutic effects.	('PELP1', 'Gene', '27043', (26, 31))	('ER', 'Gene', '2099', (182, 184))	('reducing', 'NegReg', (136, 144))	('growth', 'CPA', (149, 155))	('PELP1', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('PELP1', 'Gene', '27043', (73, 78))	('PELP1', 'Gene', (26, 31))	('breast cancer', 'Disease', (194, 207))	('silencing', 'Var', (13, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
91070	26029016	Here, we describe a case of a young woman with a de novo mutation in TP53 and multiple malignancies, with her most recent cancers found at early, curable stages due to aggressive cancer screening.	('mutation', 'Var', (57, 65))	('aggressive cancer', 'Disease', (168, 185))	('TP53', 'Gene', '7157', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('TP53', 'Gene', (69, 73))	('multiple malignancies', 'Disease', 'MESH:D009369', (78, 99))	('woman', 'Species', '9606', (36, 41))	('multiple malignancies', 'Disease', (78, 99))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('aggressive cancer', 'Disease', 'MESH:D009369', (168, 185))
91076	26029016	When individuals harbor a defective copy of the TP53 gene, they become prone to cancer development if the cell can no longer utilize a functional p53 protein to repair DNA or initiate normal apoptosis.	('defective', 'Var', (26, 35))	('TP53', 'Gene', '7157', (48, 52))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('TP53', 'Gene', (48, 52))	('prone', 'Reg', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
91077	26029016	While mutations in TP53 are typically inherited in an autosomal dominant manner, some families with Li-Fraumeni cancer phenotypes do not harbor an identifiable mutation or, on other occasions, TP53 mutations can arise de novo in an individual without a remarkable family history.	('Li-Fraumeni cancer', 'Disease', 'MESH:D016864', (100, 118))	('Li-Fraumeni cancer', 'Disease', (100, 118))	('TP53', 'Gene', '7157', (193, 197))	('mutations', 'Var', (198, 207))	('TP53', 'Gene', (193, 197))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (6, 15))
91079	26029016	In 2009, DNA sequencing of 525 patients with clinical suspicion of Li-Fraumeni syndrome found mutations in 91 patients.	('mutations', 'Var', (94, 103))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (67, 87))	('Li-Fraumeni syndrome', 'Disease', (67, 87))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (110, 118))
91080	26029016	All families with a TP53 mutation had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma, and these were identified as "core cancers" in this syndrome.	('sarcoma', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('TP53', 'Gene', (20, 24))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('cancers', 'Disease', (160, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('mutation', 'Var', (25, 33))	('adrenocortical carcinoma', 'Disease', (99, 123))	('brain', 'Disease', (89, 94))	('sarcoma', 'Disease', 'MESH:D012509', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (99, 123))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (99, 123))	('TP53', 'Gene', '7157', (20, 24))	('breast', 'Disease', (81, 87))
91083	26029016	For female carriers of a TP53 mutation, lifetime risk of cancer by age 60 approaches 90 percent, with average age of first cancer diagnosis reported to be 28.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('TP53', 'Gene', (25, 29))	('cancer', 'Disease', (57, 63))	('mutation', 'Var', (30, 38))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('TP53', 'Gene', '7157', (25, 29))
91104	26029016	The patient has no children of her own at this time, but she was counseled that as a confirmed TP53 germline mutation carrier, she has a 50 percent chance of passing the mutation on to her future children.	('patient', 'Species', '9606', (4, 11))	('children', 'Species', '9606', (19, 27))	('children', 'Species', '9606', (196, 204))	('passing', 'Reg', (158, 165))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))	('mutation', 'Var', (170, 178))
91114	26029016	While the lack of a strong family history in this case is unusual for Li-Fraumeni syndrome, de novo TP53 mutations are felt to arise in 7 to 20 percent of all cases.	('TP53', 'Gene', '7157', (100, 104))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (70, 90))	('TP53', 'Gene', (100, 104))	('Li-Fraumeni syndrome', 'Disease', (70, 90))	('mutations', 'Var', (105, 114))
91118	26029016	Her specific germline TP53 mutation, namely IVS6-2A>G, might be predicted to yield a mild phenotype.	('IVS6-2A>G', 'Var', (44, 53))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))	('IVS6-2A>G', 'Mutation', 'c.IVS6-2A>G', (44, 53))
91126	26029016	The differential diagnosis of Li-Fraumeni syndrome includes other inherited cancer syndromes, including hereditary breast and ovarian cancer syndrome, typically characterized by mutations in BRCA 1 and 2, and hereditary non-polyposis colorectal carcinoma (Lynch) syndrome.	('hereditary non-polyposis colorectal carcinoma', 'Phenotype', 'HP:0006716', (209, 254))	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('hereditary non-polyposis colorectal carcinoma (Lynch) syndrome', 'Disease', 'MESH:D003123', (209, 271))	('polyposis colorectal carcinoma', 'Phenotype', 'HP:0200063', (224, 254))	('characterized by', 'Reg', (161, 177))	('BRCA 1 and 2', 'Gene', '672;675', (191, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (30, 50))	('cancer syndromes', 'Disease', 'MESH:D009369', (76, 92))	('hereditary breast and ovarian cancer syndrome', 'Disease', 'MESH:D061325', (104, 149))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer syndromes', 'Disease', (76, 92))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutations', 'Var', (178, 187))	('Li-Fraumeni syndrome', 'Disease', (30, 50))
91130	26029016	If mutations in BRCA 1/2 and/or Lynch syndrome-associated genes have been considered and not found, screening for Li-Fraumeni syndrome may be appropriate.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (114, 134))	('BRCA 1/2', 'Gene', (16, 24))	('Li-Fraumeni syndrome', 'Disease', (114, 134))	('Lynch syndrome', 'Disease', (32, 46))	('Lynch syndrome', 'Disease', 'MESH:D003123', (32, 46))	('mutations', 'Var', (3, 12))	('BRCA 1/2', 'Gene', '672;675', (16, 24))
91132	26029016	In general, the Classic and Chompret criteria can help identify families at risk for germline p53 mutation, though it is important to remember that negative results do not rule out a diagnosis of Li-Fraumeni syndrome if the personal or family history is suggestive of the syndrome.	('Li-Fraumeni syndrome', 'Disease', (196, 216))	('p53', 'Gene', '7157', (94, 97))	('p53', 'Gene', (94, 97))	('mutation', 'Var', (98, 106))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (196, 216))
91133	26029016	While most guidelines generally suggest testing for TP53 mutations in families with classic tumor types (sarcoma, breast, adrenocortical carcinoma, and brain tumors) and with cancer onset < age 45, an important independent testing criteria for clinicians to recognize is that all women with early-onset breast cancer (age of diagnosis < 35), regardless of family history, should also be considered for TP53 mutation testing, particularly if the breast tumor is Her2-positive.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('Her2', 'Gene', '2064', (461, 465))	('breast tumor', 'Disease', 'MESH:D001943', (445, 457))	('cancer', 'Disease', (175, 181))	('women', 'Species', '9606', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (452, 457))	('mutations', 'Var', (57, 66))	('brain tumors', 'Phenotype', 'HP:0030692', (152, 164))	('Her2', 'Gene', (461, 465))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('breast tumor', 'Phenotype', 'HP:0100013', (445, 457))	('brain tumors', 'Disease', 'MESH:D001932', (152, 164))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (122, 146))	('cancer', 'Disease', (310, 316))	('TP53', 'Gene', (402, 406))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('TP53', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('breast tumor', 'Disease', (445, 457))	('mutation', 'Var', (407, 415))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (122, 146))	('brain tumors', 'Disease', (152, 164))	('sarcoma', 'Disease', 'MESH:D012509', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('sarcoma', 'Disease', (105, 112))	('adrenocortical carcinoma', 'Disease', (122, 146))	('classic tumor', 'Disease', 'MESH:D005693', (84, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('TP53', 'Gene', '7157', (402, 406))	('classic tumor', 'Disease', (84, 97))	('TP53', 'Gene', '7157', (52, 56))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))
91141	26029016	Knowing she carried a TP53 mutation, she then opted to pursue bilateral mastectomies, not only to avoid radiation treatment but primarily to prevent future breast cancers from developing.	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutation', 'Var', (27, 35))	('breast cancers', 'Phenotype', 'HP:0003002', (156, 170))	('TP53', 'Gene', '7157', (22, 26))	('breast cancers', 'Disease', 'MESH:D001943', (156, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('TP53', 'Gene', (22, 26))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('breast cancers', 'Disease', (156, 170))
91145	26029016	In 33 asymptomatic TP53 mutation carriers, Villani et al.	('mutation', 'Var', (24, 32))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))
91151	26029016	At the time of the discovery of her deleterious TP53 mutation, this patient expressed a sense of "exhaustion" about her clinical course thus far and indicated her worry about how many times she would have to go through cancer diagnosis and treatment before "enough was enough."	('TP53', 'Gene', '7157', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('mutation', 'Var', (53, 61))	('patient', 'Species', '9606', (68, 75))	('TP53', 'Gene', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))
91153	26029016	Very little exists in the literature specifically addressing psychosocial distress in Li-Fraumeni syndrome, though one small study reported that 36 percent of TP53 carriers report unnecessary worry as a barrier to screening adherence.	('psychosocial distress', 'Disease', (61, 82))	('psychosocial distress', 'Disease', 'MESH:C535569', (61, 82))	('Li-Fraumeni syndrome', 'Disease', (86, 106))	('TP53', 'Gene', '7157', (159, 163))	('unnecessary worry', 'Phenotype', 'HP:0000739', (180, 197))	('TP53', 'Gene', (159, 163))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (86, 106))	('carriers', 'Var', (164, 172))
91163	25071437	The noteworthy events are that augmented by GCAPs, ROS-GC proves to be a transducer of the free Ca2+ signals generated within neurons; ROS-GC becomes a two-component transduction system and establishes itself as a source of cyclic GMP, the second messenger of phototransduction.	('ROS-GC', 'Var', (135, 141))	('GCAP', 'Gene', '2978', (44, 48))	('rat', 'Species', '10116', (113, 116))	('GCAP', 'Gene', (44, 48))	('free', 'Chemical', '-', (91, 95))	('GMP', 'Gene', (231, 234))	('GMP', 'Gene', '22978', (231, 234))
91216	25071437	The tailoring created a heightened membrane response to ACTH and it was direct, reflective of membrane-specific guanylate cyclase activity.	('ACTH', 'Gene', '5443', (56, 60))	('ACTH', 'Gene', (56, 60))	('tailoring', 'Var', (4, 13))	('heightened', 'PosReg', (24, 34))
91228	25071437	This feature established its unique functional identity because the dibutyryl cyclic AMP was more potent than cyclic AMP in stimulating cyclic AMP-dependent protein kinase.	('cyclic AMP', 'Chemical', 'MESH:D000242', (78, 88))	('stimulating cyclic AMP-dependent protein kinase', 'MPA', (124, 171))	('cyclic AMP', 'Chemical', 'MESH:D000242', (110, 120))	('cyclic AMP', 'Chemical', 'MESH:D000242', (136, 146))	('dibutyryl cyclic AMP', 'Var', (68, 88))
91252	25071437	With the model system of the variant form of ANF-RGC, GCalpha, cloned from the adrenal cortex, the original study of Duda et al.	('GCalpha', 'Gene', '25801', (54, 61))	('variant', 'Var', (29, 36))	('GCalpha', 'Gene', (54, 61))
91254	25071437	Compared to ANF-GC, GCalpha in its structure had only two amino acid substitutions, Gln338His and Leu364Pro, but it did not bind ANF.	('GCalpha', 'Gene', (20, 27))	('Gln338His', 'Var', (84, 93))	('Leu364Pro', 'Var', (98, 107))	('Leu364Pro', 'SUBSTITUTION', 'None', (98, 107))	('Gln338His', 'SUBSTITUTION', 'None', (84, 93))	('GCalpha', 'Gene', '25801', (20, 27))
91255	25071437	Thus, the ANF ligand-binding domain resided in the extracellular domain of ANF-RGC; and one, or both of the residues:Gln338, Leu364:controlled its ANF-binding and ANF-dependent catalytic activities.	('ANF-binding', 'Interaction', (147, 158))	('ANF-dependent catalytic activities', 'MPA', (163, 197))	('Gln338', 'Var', (117, 123))	('Gln338', 'Chemical', '-', (117, 123))	('ANF-RGC', 'Gene', (75, 82))	('Leu364', 'Var', (125, 131))	('Leu364', 'Chemical', '-', (125, 131))	('controlled', 'Reg', (132, 142))
91256	25071437	Refined point mutation analysis demonstrated that both of these controls resided in Leu364 (Duda et al.,).	('rat', 'Species', '10116', (39, 42))	('Leu364', 'Var', (84, 90))	('Leu364', 'Chemical', '-', (84, 90))	('resided', 'Reg', (73, 80))
91260	25071437	It was found that Glu332 residue of CNP-RGC was critical for the CNP binding and the CNP-dependent catalytic activity of CNP-RGC (Duda et al.,).	('CNP', 'Gene', '4880', (121, 124))	('CNP', 'Gene', (65, 68))	('CNP', 'Gene', '4880', (36, 39))	('CNP', 'Gene', (121, 124))	('CNP', 'Gene', (36, 39))	('CNP', 'Gene', '4880', (85, 88))	('Glu332', 'Chemical', '-', (18, 24))	('CNP', 'Gene', (85, 88))	('Glu332', 'Var', (18, 24))	('CNP', 'Gene', '4880', (65, 68))
91261	25071437	The counterpart of CNP-RGC-Glu332 residue is the Gln338 residue of ANF-RGC, and that of ANF-RGC-Leu364 residue is Val358 of CNP-RGC.	('Leu364', 'Chemical', '-', (96, 102))	('CNP', 'Gene', '4880', (124, 127))	('GC-G', 'Gene', '2641', (24, 28))	('CNP', 'Gene', (124, 127))	('Val358', 'Chemical', '-', (114, 120))	('CNP', 'Gene', '4880', (19, 22))	('GC-G', 'Gene', (24, 28))	('Gln338', 'Var', (49, 55))	('Gln338', 'Chemical', '-', (49, 55))	('Glu332', 'Chemical', '-', (27, 33))	('CNP', 'Gene', (19, 22))	('Val358', 'Var', (114, 120))
91262	25071437	Conversion of the ANF-RGC residue Gln338 to Glu resulted in a change from none to significant CNP signal transduction activity.	('CNP', 'Gene', '4880', (94, 97))	('CNP', 'Gene', (94, 97))	('Gln338', 'Var', (34, 40))	('Gln338 to Glu', 'Mutation', 'p.Q338E', (34, 47))
91263	25071437	And, the conversion of Val358 to Leu generated significant ANF signal transduction activity in CNP-RGC (Duda et al.,).	('Val358', 'Var', (23, 29))	('Leu', 'Var', (33, 36))	('ANF signal transduction activity', 'MPA', (59, 91))	('conversion', 'Var', (9, 19))	('CNP', 'Gene', '4880', (95, 98))	('rat', 'Species', '10116', (41, 44))	('CNP', 'Gene', (95, 98))	('Val358 to Leu', 'Mutation', 'p.V358L', (23, 36))
91265	25071437	The subsequent crystallization studies on the isolated extracellular domains of ANF-RGC and CNP-RGC validated the conclusions that the hormone-binding site, indeed, resides in the external domain of the guanylate cyclase and Leu364 of ANF-RGC and Val358 of CNP-RGC constitute critical hydrophobic sites essential for the ANF or CNP signaling but the sites are not the direct hormone-binding sites (Ogawa et al.,; He et al.,).	('CNP', 'Gene', (257, 260))	('Leu364', 'Var', (225, 231))	('Leu364', 'Chemical', '-', (225, 231))	('CNP', 'Gene', '4880', (328, 331))	('CNP', 'Gene', '4880', (92, 95))	('CNP', 'Gene', (92, 95))	('Val358', 'Chemical', '-', (247, 253))	('CNP', 'Gene', (328, 331))	('CNP', 'Gene', '4880', (257, 260))
91274	25071437	Sharma's group challenged this model on the grounds of their findings that partial or complete deletion of the KHD did not cause any significant elevation in the basal activity of the guanylate cyclase; therefore, ANF signaling did not involve overcoming the KHD suppression of the guanylate cyclase activity, contradicting the central theme of MODEL 1.	('heme', 'Chemical', 'MESH:D006418', (337, 341))	('deletion', 'Var', (95, 103))	('KHD', 'Gene', (111, 114))
91295	25071437	And the ROS-GC protein beyond the catalytic domain contained a C-terminal extension tail of 90 amino acids, Y965-K1054, this tail was absent in ANF-RGC and CNP-RGC.	('CNP', 'Gene', '4880', (156, 159))	('CNP', 'Gene', (156, 159))	('ROS-GC protein', 'Protein', (8, 22))	('Y965-K1054', 'Var', (108, 118))
91307	25071437	(3) The multiple cone rod dystrophies in humans have only been linked with the ROS-GC1 mutations, none so far with ROS-GC2 (reviewed in Hunt et al.,).	('ROS-GC1', 'Gene', (79, 86))	('linked', 'Reg', (63, 69))	('dystrophies', 'Disease', 'MESH:D009136', (26, 37))	('cone rod dystrophies', 'Phenotype', 'HP:0000548', (17, 37))	('humans', 'Species', '9606', (41, 47))	('dystrophies', 'Disease', (26, 37))	('mutations', 'Var', (87, 96))
91308	25071437	Finally, (4) it has been demonstrated that the ROS-GC1 gene deletion results sequentially in the cone and then the rod degenerations, indicating that the guanylate cyclase is directly linked with the vitality and the function of photoreceptors (Yang et al.,).	('rat', 'Species', '10116', (125, 128))	('rat', 'Species', '10116', (32, 35))	('results', 'Reg', (69, 76))	('deletion', 'Var', (60, 68))	('cone', 'CPA', (97, 101))	('degenerations', 'NegReg', (119, 132))	('rod', 'CPA', (115, 118))	('ROS-GC1', 'Gene', (47, 54))
91316	25071437	In a recent proposal, the transition from the DARK State to the illuminated state of the photoreceptors occurs by the substitution of bound Ca2+ with the bound Mg2+ to ROS-GC1 (Peshenko and Dizhoor,).	('substitution', 'Var', (118, 130))	('Mg2', 'Gene', (160, 163))	('ROS-GC1', 'Gene', (168, 175))	('Mg2', 'Gene', '4589', (160, 163))
91319	25071437	Thus, these nanomolar affinities result in fast dissociation rates (for example, koff = kon x KD = 2 x 108 M-1 s-1 x 0.2 x 10-6 M = 40 s-1; 1/koff = 25 ms), consistent with the kinetics of the photoresponse.	('KD = 2', 'Species', '752784', (94, 100))	('dissociation', 'MPA', (48, 60))	('rat', 'Species', '10116', (61, 64))	('koff', 'Var', (81, 85))
91320	25071437	Cysteine accessibility study with GCAP2 mutants shows its restricted reactivity toward Cys111 at sub-micromolar Ca2+-concentrations, indicating that within the Ca2+ concentration range where ROS-GCs are regulated, Ca2+-induces conformational changes in GCAP2 (Helten and Koch,).	('GCAP2', 'Gene', (253, 258))	('rat', 'Species', '10116', (124, 127))	('conformational changes', 'MPA', (227, 249))	('GCAP2', 'Gene', (34, 39))	('Cysteine', 'Chemical', 'MESH:D003545', (0, 8))	('Koch', 'Disease', (271, 275))	('mutants', 'Var', (40, 47))	('Cys111', 'Chemical', '-', (87, 93))	('rat', 'Species', '10116', (172, 175))
91334	25071437	These results prove that the two GCAPs signal ROS-GC1 activation through different modes and the differences reside in the spatial characteristics of ROS-GC1; and because orientations of the two domains of their signal origins are different, their migration pathways are different: GCAP1 downstream from M445-L456 and L503-I522 to the P808-K1054.	('GCAP', 'Gene', (282, 286))	('GCAP', 'Gene', (33, 37))	('M445-L456', 'Var', (304, 313))	('P808-K1054', 'Var', (335, 345))	('activation', 'PosReg', (54, 64))	('L503-I522', 'Var', (318, 327))	('ROS-GC1', 'Gene', (46, 53))	('GCAP', 'Gene', '2978', (282, 286))	('rat', 'Species', '10116', (251, 254))	('GCAP', 'Gene', '2978', (33, 37))
91335	25071437	This pathway is unique to GCAP2 and runs opposite to that of GCAP1, upstream from the Y965-N981 site in CTE to the CCD for translation of the signal into the production of cyclic GMP (Figure 4).	('GMP', 'Gene', (179, 182))	('GMP', 'Gene', '22978', (179, 182))	('Y965-N981', 'Var', (86, 95))
91339	25071437	demonstrated that there is a point mutation in the human ROS-GC1 gene, F565S.	('F565S', 'Var', (71, 76))	('human', 'Species', '9606', (51, 56))	('rat', 'Species', '10116', (7, 10))	('ROS-GC1', 'Gene', (57, 64))	('F565S', 'Mutation', 'rs61749755', (71, 76))
91340	25071437	Patients inheriting this mutation are inflicted with Leber's congetinal amauresis type 1 (LCA1); they are born blind or become blind soon after birth.	('born blind', 'Disease', (106, 116))	("Leber's congetinal amauresis type 1", 'Disease', (53, 88))	('mutation', 'Var', (25, 33))	('Patients', 'Species', '9606', (0, 8))	('born blind', 'Disease', 'MESH:D001766', (106, 116))	("Leber's congetinal amauresis type 1", 'Disease', 'MESH:D029242', (53, 88))
91343	25071437	Biochemical analysis on the heterologusly expressed LCA1-linked ROS-GC1 mutant in COS cells demonstrated that the point mutation causes almost complete loss (84%) of the basal catalytic activity of ROS-GC1 and also of its Ca2+ sensitivity to modulation by GCAP1 (Duda et al.,).	('basal catalytic activity', 'MPA', (170, 194))	('mutant', 'Var', (72, 78))	('loss', 'NegReg', (152, 156))	('rat', 'Species', '10116', (99, 102))	('Ca2+ sensitivity to modulation', 'MPA', (222, 252))	('ROS-GC1', 'Gene', (64, 71))	('point mutation', 'Var', (114, 128))	('ROS-GC1', 'Gene', (198, 205))	('COS', 'Chemical', '-', (82, 85))
91344	25071437	Following this lead, similar approach has been used to investigate the second type of retinal disease that correlates with mutations of the ROS-GC1 gene.	('retinal disease', 'Disease', 'MESH:D012164', (86, 101))	('retinal disease', 'Disease', (86, 101))	('retinal disease', 'Phenotype', 'HP:0000479', (86, 101))	('ROS-GC1', 'Gene', (140, 147))	('mutations', 'Var', (123, 132))
91346	25071437	One example is ROS-GC1-E786D, R787C, T788M mutation.	('R787C', 'Var', (30, 35))	('T788M', 'Mutation', 'p.T788M', (37, 42))	('R787C', 'Mutation', 'p.R787C', (30, 35))	('T788M', 'Var', (37, 42))	('E786D', 'Mutation', 'p.E786D', (23, 28))
91350	25071437	S100B possesses a striking property toward ROS-GC1 stimulation that is opposite to that of GCAPs.	('GCAP', 'Gene', '2978', (91, 95))	('S100B', 'Var', (0, 5))	('ROS-GC1', 'Protein', (43, 50))	('GCAP', 'Gene', (91, 95))
91360	25071437	ERG recordings on the retinas of the mouse S100B-/- model suggest that S100B up-regulates ROS-GC1 Ca2+-dependent catalytic activity and modulates the transmission of neural signals to cone ON-bipolar cells (Wen et al.,).	('ROS-GC1 Ca2+-dependent catalytic activity', 'MPA', (90, 131))	('S100B', 'Var', (71, 76))	('mouse', 'Species', '10090', (37, 42))	('up-regulates', 'PosReg', (77, 89))	('modulates', 'Reg', (136, 145))
91378	25071437	With a K1/2 of 0.3-0.8 muM, Ca2+ binds NCdelta facilitating its interaction with the ONE-GC's segment M880-L921 (Duda and Sharma,; Duda et al.,); Ca2+-bound NCdelta than signals full activation of ONE-GC and maximal synthesis of cyclic GMP (reviewed in Sharma and Duda,; Zufall and Munger,).	('Ca2+-bound', 'Var', (146, 156))	('GMP', 'Gene', (236, 239))	('muM', 'Gene', '56925', (23, 26))	('GMP', 'Gene', '22978', (236, 239))	('muM', 'Gene', (23, 26))
91384	25071437	Yet in a general scheme Ca2+ is pivotal for the process; it depolarizes plasma membrane of the given taste cell, releases the transmitter release and functions through the CNG-gated channels, cyclic AMP and cyclic GMP (Kolesnikov and Margolskee,).	('Ca2+', 'Var', (24, 28))	('cyclic AMP', 'Chemical', 'MESH:D000242', (192, 202))	('cyclic AMP', 'MPA', (192, 202))	('heme', 'Chemical', 'MESH:D006418', (19, 23))	('GMP', 'Gene', '22978', (214, 217))	('plasma membrane', 'MPA', (72, 87))	('transmitter release', 'MPA', (126, 145))	('functions', 'MPA', (150, 159))	('GMP', 'Gene', (214, 217))	('CNG-gated channels', 'Pathway', (172, 190))	('releases', 'PosReg', (113, 121))	('depolarizes', 'NegReg', (60, 71))
91499	23565434	Nuclear pleomorphism is comparatively higher in pheochromocytoma.	('pheochromocytoma', 'Disease', 'MESH:D010673', (48, 64))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (48, 64))	('Nuclear pleomorphism', 'Var', (0, 20))	('higher', 'Reg', (38, 44))	('pheochromocytoma', 'Disease', (48, 64))
91521	22086150	Allelotyping with microsatellites and a few reported cases provide support for an adrenal adenoma-carcinoma sequence.	('adrenal adenoma', 'Phenotype', 'HP:0008256', (82, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('microsatellites', 'Var', (18, 33))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (90, 107))	('adenoma-carcinoma', 'Disease', (90, 107))
91526	22086150	The malignant component exhibited diffuse cytoplasmic and focal nuclear beta-catenin accumulation and harbored a beta-catenin gene (CTNNB1) mutation, whereas the benign component showed only focal cytoplasmic staining and no such mutation.	('CTNNB1', 'Gene', '1499', (132, 138))	('mutation', 'Var', (140, 148))	('CTNNB1', 'Gene', (132, 138))
91533	22086150	identified three subgroups by using unsupervised clustering analysis: (1) p53 group, encompassing all tumors with a TP53 mutation, (2) beta-catenin group, containing all tumors with beta-catenin nuclear staining, and (3) x group, with neither p53 nor beta-catenin altered pathways, but enriched in cell cycle and metabolism genes.	('TP53', 'Gene', (116, 120))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('p53', 'Gene', (74, 77))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('mutation', 'Var', (121, 129))	('p53', 'Gene', (243, 246))	('p53', 'Gene', '7157', (243, 246))	('p53', 'Gene', '7157', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('TP53', 'Gene', '7157', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Disease', (170, 176))
91538	22086150	In fact, it has been demonstrated that this activation, as assessed by abnormal nuclear and/or cytoplasmic beta-catenin accumulation with or without somatic activating CTNNB1 mutations, is involved both in benign and malignant adrenocortical tumors.	('benign', 'Disease', (206, 212))	('CTNNB1', 'Gene', (168, 174))	('involved', 'Reg', (189, 197))	('malignant adrenocortical tumors', 'Disease', 'MESH:D018268', (217, 248))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('mutations', 'Var', (175, 184))	('malignant adrenocortical tumors', 'Disease', (217, 248))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('CTNNB1', 'Gene', '1499', (168, 174))
91539	22086150	It is of particular interest to note that CTNNB1 mutations (1) were detected only in macronodules of primary pigmented nodular adrenocortical disease cases, suggesting that these are secondary genetic events contributing to the nodular development of the disease and potentially implying a more aggressive phenotype, (2) were related to a specific phenotype of larger and non-secreting ACAs, indicating a less differentiated state, and (3) were associated with decreased overall and disease-free survival in ACCs, suggesting a specific effect on tumor biology in terms of progression towards a more aggressive phenotype within the group of ACCs.	('tumor', 'Phenotype', 'HP:0002664', (546, 551))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', (546, 551))	('ACCs', 'Gene', (508, 512))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (109, 149))	('ACCs', 'Gene', '84680', (508, 512))	('pigmented nodular adrenocortical disease', 'Disease', (109, 149))	('CTNNB1', 'Gene', (42, 48))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (109, 149))	('ACC', 'Phenotype', 'HP:0006744', (640, 643))	('ACCs', 'Gene', (640, 644))	('ACCs', 'Gene', '84680', (640, 644))	('contributing', 'Reg', (208, 220))	('CTNNB1', 'Gene', '1499', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (546, 551))	('ACC', 'Phenotype', 'HP:0006744', (508, 511))
91606	21445348	Increased Incidence of Choroid Plexus Carcinoma Due to the Germline TP53 R337H Mutation in Southern Brazil Choroid plexus carcinomas (CPC) are rare tumors predominantly found in children.	('rare tumors', 'Disease', 'MESH:D035583', (143, 154))	('Choroid plexus carcinomas', 'Disease', (107, 132))	('Increased Incidence of Choroid Plexus', 'Phenotype', 'HP:0012422', (0, 37))	('Choroid Plexus Carcinoma', 'Phenotype', 'HP:0030392', (23, 47))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('Choroid plexus carcinomas', 'Phenotype', 'HP:0030392', (107, 132))	('Carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('children', 'Species', '9606', (178, 186))	('Choroid Plexus Carcinoma', 'Disease', 'MESH:D020288', (23, 47))	('Choroid plexus carcinomas', 'Disease', 'MESH:D020288', (107, 132))	('R337H', 'Var', (73, 78))	('R337H', 'Mutation', 'rs121912664', (73, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('rare tumors', 'Disease', (143, 154))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('Choroid Plexus Carcinoma', 'Disease', (23, 47))
91613	21445348	We found 63.3% (14/22) of the CPC patients positive for the germline R337H mutation; CPC samples were either heterozygous (n = 7), lost only the wild-type (n = 4), or only the R337H copy (n = 2).	('R337H', 'Var', (69, 74))	('R337H', 'Mutation', 'rs121912664', (69, 74))	('R337H', 'Mutation', 'rs121912664', (176, 181))	('R337H', 'Var', (176, 181))	('patients', 'Species', '9606', (34, 42))	('lost', 'NegReg', (131, 135))	('positive', 'Reg', (43, 51))
91615	21445348	Cure (>5 years survival free of disease) was observed in 18.1% of the CPC cases with the R337H mutation (2/11), 71.4% of the Pp (5/7), and 25% of CPC cases negative for the R337H mutation (2/8).	('R337H', 'Var', (89, 94))	('R337H', 'Mutation', 'rs121912664', (173, 178))	('CPC', 'Disease', (70, 73))	('R337H', 'Mutation', 'rs121912664', (89, 94))
91616	21445348	Family history of cancer (with 2 or more cancer cases) was exclusively identified on the parental side segregating the R337H mutation, and 50% (7/14) of them were compatible with Li-Fraumeni-like syndrome.	('R337H', 'Var', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('R337H', 'Mutation', 'rs121912664', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (179, 204))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', (18, 24))	('Li-Fraumeni-like syndrome', 'Disease', (179, 204))
91617	21445348	Our results show for the first time that the R337H TP53 mutation is responsible for 63% of the CPC cases in children, suggesting a higher incidence of CPC in southern Brazil.	('children', 'Species', '9606', (108, 116))	('TP53', 'Gene', (51, 55))	('CPC', 'Disease', (95, 98))	('R337H', 'Mutation', 'rs121912664', (45, 50))	('R337H', 'Var', (45, 50))	('TP53', 'Gene', '7157', (51, 55))
91622	21445348	The most common mechanism involved in CPC formation is related to dysfunction in the tumor suppressor p53, more frequently found in families with Li-Fraumeni syndrome (LFS).	('tumor', 'Disease', (85, 90))	('LFS', 'Disease', (168, 171))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (146, 166))	('dysfunction', 'Var', (66, 77))	('p53', 'Gene', '7157', (102, 105))	('LFS', 'Disease', 'MESH:D016864', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Li-Fraumeni syndrome', 'Disease', (146, 166))	('found', 'Reg', (123, 128))	('p53', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
91623	21445348	It was recently reported that 50% of the patients with CPC were positive for germline TP53 mutation.	('positive', 'Reg', (64, 72))	('mutation', 'Var', (91, 99))	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', (86, 90))	('patients', 'Species', '9606', (41, 49))
91625	21445348	The present study was designed to address the question whether the increased number of CPC cases proposed in this previous study was related to the high frequency of the R337H germline mutation in southern Brazil.	('R337H', 'Mutation', 'rs121912664', (170, 175))	('R337H', 'Var', (170, 175))	('CPC', 'Disease', (87, 90))
91626	21445348	This mutation produces a 10-15 times higher adrenocortical tumor (ACT) incidence in southern Brazil than in the United States.	('higher', 'PosReg', (37, 43))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (44, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('adrenocortical tumor', 'Disease', (44, 64))	('mutation', 'Var', (5, 13))
91629	21445348	A total of 22 cases of CPC from 15 boys and 7 girls, and 7 Pp from 4 girls and 3 boys were screened for the R337H mutation in the TP53 gene.	('boys', 'Species', '9606', (35, 39))	('CPC', 'Disease', (23, 26))	('girls', 'Species', '9606', (69, 74))	('girls', 'Species', '9606', (46, 51))	('R337H', 'Mutation', 'rs121912664', (108, 113))	('R337H', 'Var', (108, 113))	('boys', 'Species', '9606', (81, 85))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))
91647	21445348	Progression-free survival rate for tumors positive for the germline mutation was compared with those negative for the mutation by using the Kaplan-Meier method.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('germline mutation', 'Var', (59, 76))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
91648	21445348	Fourteen children with CPC (14/22, 63.6%) were identified with the germline R337H TP53 mutation (Table 1).	('TP53', 'Gene', (82, 86))	('children', 'Species', '9606', (9, 17))	('CPC', 'Disease', (23, 26))	('R337H', 'Mutation', 'rs121912664', (76, 81))	('R337H', 'Var', (76, 81))	('TP53', 'Gene', '7157', (82, 86))
91649	21445348	Only 9 relatives of these children who had other types of cancer were tested and were found to be carriers of the R337H mutation (9/9).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('R337H', 'Mutation', 'rs121912664', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('R337H', 'Var', (114, 119))	('children', 'Species', '9606', (26, 34))	('cancer', 'Disease', (58, 64))
91650	21445348	Loss of heterozygosity (LOH) was found in 46.1% (6/13) of the CPC cases, including 4 CPC with loss of the wild-type TP53 and 2 with loss of the R337H haplotype, while the remaining available CPC (n = 7) were heterozygous (Table 1).	('TP53', 'Gene', (116, 120))	('R337H', 'Mutation', 'rs121912664', (144, 149))	('R337H', 'Var', (144, 149))	('loss', 'NegReg', (132, 136))	('loss', 'NegReg', (94, 98))	('CPC', 'Disease', (85, 88))	('Loss', 'NegReg', (0, 4))	('heterozygosity', 'MPA', (8, 22))	('TP53', 'Gene', '7157', (116, 120))	('CPC', 'Disease', (62, 65))
91655	21445348	Age, gender, outcome, and family history of cancer are shown for CPC with the mutation (Table 1) and for CPC and Pp without the R337H mutation in the TP53 gene (Table 2).	('TP53', 'Gene', (150, 154))	('mutation', 'Var', (78, 86))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('R337H', 'Mutation', 'rs121912664', (128, 133))	('CPC', 'Disease', (65, 68))	('TP53', 'Gene', '7157', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
91656	21445348	Survival rate (>5 years free of disease) was not significantly different among patients with CPC and the mutation (2/11, 18.1%), CPC patients without the mutation (2/8, 25%) and patients with Pp without the mutation (5/7, 71.4%) probably due to the small number of cases.	('CPC', 'Disease', (93, 96))	('mutation', 'Var', (105, 113))	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (178, 186))	('patients', 'Species', '9606', (79, 87))
91658	21445348	The pedigrees of the 14 families with the germline mutation were obtained together with the history of cancer reported by both sides of the families; ipsilateral and contralateral to the parental side segregating the R337H mutation (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('R337H', 'Mutation', 'rs121912664', (217, 222))	('R337H', 'Var', (217, 222))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
91660	21445348	The tumor types reported by all families revealed that the most common tumor types were: breast (n = 8, 12.1%), stomach (n = 6, 9.0%), prostate (n = 6, 9.0%) and ACT (n = 6, 9.0%) in families with CPC and the R337H mutation.	('tumor', 'Disease', (4, 9))	('prostate', 'Disease', (135, 143))	('R337H', 'Var', (209, 214))	('CPC', 'Disease', (197, 200))	('ACT', 'Disease', (162, 165))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('stomach', 'Disease', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (71, 76))	('breast', 'Disease', (89, 95))	('R337H', 'Mutation', 'rs121912664', (209, 214))
91662	21445348	However, LFS-like syndrome (LFL) as defined by Birch et al., was identified in 7 of the 14 families with the R337H mutation (50%), and in 6 of the 14 families with the R337H mutation (42.8%) according to Tinat et al.. None of the families contralateral to the parental side segregating the R337H mutation presented LFL.	('R337H', 'Mutation', 'rs121912664', (290, 295))	('R337H', 'Mutation', 'rs121912664', (109, 114))	('R337H mutation', 'Var', (290, 304))	('R337H', 'Mutation', 'rs121912664', (168, 173))	('LFL', 'Disease', (315, 318))	('LFS-like syndrome', 'Disease', 'MESH:D016864', (9, 26))	('LFS-like syndrome', 'Disease', (9, 26))
91663	21445348	History of cancer in the families negative for the R337H mutation, presented LFL only in one family with CPC without the R337H mutation and none in families with Pp.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('R337H', 'Mutation', 'rs121912664', (51, 56))	('R337H', 'Mutation', 'rs121912664', (121, 126))	('R337H', 'Var', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
91664	21445348	Although none of the families can be classified as LFS, LFL was clearly associated with the parental side segregating the R337H mutation.	('R337H', 'Var', (122, 127))	('associated', 'Reg', (72, 82))	('LFS', 'Disease', (51, 54))	('LFS', 'Disease', 'MESH:D016864', (51, 54))	('R337H', 'Mutation', 'rs121912664', (122, 127))
91669	21445348	The hemizygous pattern with the R337H haplotype, after loss of the wild type TP53 found in 4/14 CPC cases, reinforces the idea that the R337H protein is defective and may under certain metabolic conditions lose its protective role against cancer formation.	('R337H', 'Var', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('protein', 'Protein', (142, 149))	('cancer', 'Disease', (239, 245))	('R337H', 'Mutation', 'rs121912664', (32, 37))	('lose', 'NegReg', (206, 210))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('R337H', 'Var', (32, 37))	('R337H', 'Mutation', 'rs121912664', (136, 141))
91670	21445348	Remarkably, permanence of the wild-type allele in most CPC (9/13), including loss of the R337H copy (n = 2), challenge the general assumption that the tumor suppressor activity for TP53 must be inactivated in the tumor.	('tumor', 'Disease', (213, 218))	('R337H', 'Var', (89, 94))	('TP53', 'Gene', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('loss', 'NegReg', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('TP53', 'Gene', '7157', (181, 185))	('CPC', 'Disease', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('R337H', 'Mutation', 'rs121912664', (89, 94))
91672	21445348	It was previously found 100% of LOH (loss of the wild-type allele) in childhood adrenocortical cancer with the R337H germ-line mutation, which is consistent with the classical two-hit mechanism of cancer proposed by Knudson.	('adrenocortical cancer', 'Disease', (80, 101))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (197, 203))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (80, 101))	('cancer', 'Disease', (95, 101))	('R337H', 'Var', (111, 116))	('childhood adrenocortical cancer', 'Phenotype', 'HP:0008207', (70, 101))	('R337H', 'Mutation', 'rs121912664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
91673	21445348	In contrast, other studies have shown lower frequency of LOH (60-78%) in the same type of tumor with R337H.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('R337H', 'Mutation', 'rs121912664', (101, 106))	('R337H', 'Var', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
91674	21445348	Furthermore, LOH was described in 3 cases of breast cancer, including loss of the mutant R337H and permanence of the wild-type TP53 allele.	('R337H', 'Var', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('loss', 'NegReg', (70, 74))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('R337H', 'Mutation', 'rs121912664', (89, 94))
91675	21445348	Conversely, in all families described in the present study the pedigrees show that the cancer cases are clearly associated with the R337H allele in one parental side, which reduces the remote possibility of a second mutation in the second copy of the TP53 gene in the contralateral side of the families (negative for R337H), because none of them presented either LFS or LFL cancer history.	('cancer', 'Disease', (87, 93))	('LFS', 'Disease', (363, 366))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('TP53', 'Gene', (251, 255))	('LFL cancer', 'Disease', 'MESH:D016864', (370, 380))	('LFL cancer', 'Disease', (370, 380))	('LFS', 'Disease', 'MESH:D016864', (363, 366))	('R337H', 'Mutation', 'rs121912664', (317, 322))	('cancer', 'Disease', (374, 380))	('cancer', 'Disease', 'MESH:D009369', (374, 380))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('R337H', 'Mutation', 'rs121912664', (132, 137))	('TP53', 'Gene', '7157', (251, 255))	('R337H', 'Var', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('associated', 'Reg', (112, 122))
91676	21445348	Functional analysis of the R337H p53 protein was previously performed using two cell types devoid of endogenous p53.	('R337H', 'Var', (27, 32))	('R337H', 'Mutation', 'rs121912664', (27, 32))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('p53', 'Gene', (112, 115))	('p53', 'Gene', '7157', (112, 115))
91678	21445348	The R337H mutant activated the reporter as efficiently as wild-type p53 did.	('R337H', 'Mutation', 'rs121912664', (4, 9))	('R337H', 'Var', (4, 9))	('activated', 'PosReg', (17, 26))	('p53', 'Gene', '7157', (68, 71))	('p53', 'Gene', (68, 71))
91679	21445348	Similarly, wild-type p53 and the R337H mutant were able to suppress colony growth of SaOS-2 cells.	('p53', 'Gene', '7157', (21, 24))	('R337H', 'Var', (33, 38))	('colony growth of SaOS-2 cells', 'CPA', (68, 97))	('SaOS-2', 'CellLine', 'CVCL:0548', (85, 91))	('R337H', 'Mutation', 'rs121912664', (33, 38))	('suppress', 'NegReg', (59, 67))	('p53', 'Gene', (21, 24))
91680	21445348	One year later, DiGiammarino et al., demonstrated that a pH-sensitive molecular defect of p53 (R337H) leading to diminished p53 tetramerization is the molecular basis for these cases of ACC in Brazilian children.	('R337H', 'Mutation', 'rs121912664', (95, 100))	('children', 'Species', '9606', (203, 211))	('p53', 'Gene', (90, 93))	('R337H', 'Var', (95, 100))	('p53', 'Gene', (124, 127))	('p53', 'Gene', '7157', (90, 93))	('p53', 'Gene', '7157', (124, 127))	('diminished', 'NegReg', (113, 123))	('ACC', 'Disease', (186, 189))
91681	21445348	They have also shown that supraphysiologic temperature contributes to loss of R337H function.	('R337H', 'Mutation', 'rs121912664', (78, 83))	('R337H', 'Var', (78, 83))	('loss', 'NegReg', (70, 74))
91682	21445348	Considering that this peculiar TP53 mutation is present in similar frequency in other states of southern Brazil, it is likely that the actual number of CPC in children caused by R337H per year is higher than the previously reported 0.3 per million incidence.	('children', 'Species', '9606', (159, 167))	('caused', 'Reg', (168, 174))	('R337H', 'Mutation', 'rs121912664', (178, 183))	('CPC', 'Disease', (152, 155))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('R337H per', 'Var', (178, 187))
91687	21445348	These observations are consistent with a lower R337H penetrance for CPC than for ACT in Brazilian children in these areas.	('lower', 'NegReg', (41, 46))	('CPC', 'Disease', (68, 71))	('children', 'Species', '9606', (98, 106))	('R337H', 'Var', (47, 52))	('R337H', 'Mutation', 'rs121912664', (47, 52))
91689	21445348	In addition, in that previous study we described that the maximal number of cancer cases per family (excluding ACT) were 4 cases in two families and 2 cases in six families in the parental side segregating the R337H mutation.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('R337H', 'Mutation', 'rs121912664', (210, 215))	('R337H', 'Var', (210, 215))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
91690	21445348	In contrast, in the present study the families carrying the R337H mutation are more frequently associated with a larger number of other tumor types, where 71.4% of the families with R337H (10/14) present 4 or more cancer cases and 50% (7/14) are LFL according to Birch et al..	('cancer', 'Disease', (214, 220))	('R337H', 'Mutation', 'rs121912664', (182, 187))	('R337H', 'Var', (182, 187))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('R337H', 'Mutation', 'rs121912664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('associated', 'Reg', (95, 105))	('tumor', 'Disease', (136, 141))	('R337H', 'Var', (60, 65))
91692	21445348	Interestingly, almost all patients (Table 2) without cases of cancer in their families are alive (P<0.05, Fisher's Exact Test), which is consistent with a lower malignancy of these tumors without the germline TP53 R337H mutation (CPC and Pp).	('malignancy', 'Disease', 'MESH:D009369', (161, 171))	('TP53', 'Gene', (209, 213))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('malignancy', 'Disease', (161, 171))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('patients', 'Species', '9606', (26, 34))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('TP53', 'Gene', '7157', (209, 213))	('R337H', 'Mutation', 'rs121912664', (214, 219))	('R337H', 'Var', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
91696	21445348	All histopathologic criteria proposed for malignancy were found in all CPC of the present series: a) obvious invasion of adjacent neural tissue, b) loss of regular papillary architecture, c) marked nuclear pleomorphism, d) frequent mitoses increased with cell density, and e) presence of focal necrosis.	('necrosis', 'Disease', 'MESH:D009336', (294, 302))	('increased', 'PosReg', (240, 249))	('invasion', 'CPA', (109, 117))	('regular papillary architecture', 'Phenotype', 'HP:0007482', (156, 186))	('loss', 'NegReg', (148, 152))	('CPC', 'Disease', (71, 74))	('malignancy', 'Disease', (42, 52))	('necrosis', 'Disease', (294, 302))	('marked nuclear pleomorphism', 'Var', (191, 218))	('malignancy', 'Disease', 'MESH:D009369', (42, 52))	('regular papillary architecture', 'CPA', (156, 186))
91700	21445348	Previous reports suggested that inactivation of hSNF5/INI-1 might play a special role in CPC development.	('INI-1', 'Gene', (54, 59))	('hSNF5', 'Gene', (48, 53))	('CPC', 'Disease', (89, 92))	('hSNF5', 'Gene', '6598', (48, 53))	('inactivation', 'Var', (32, 44))	('INI-1', 'Gene', '6598', (54, 59))	('play', 'Reg', (66, 70))
91701	21445348	Furthermore, it was recently reported that loss of p53 function seems to be the most prevalent cause.	('loss', 'Var', (43, 47))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))
91702	21445348	These authors have found germline TP53 mutation in 50% of the cases (32/64).	('mutation', 'Var', (39, 47))	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', (34, 38))
91713	21445348	In contrast, these authors have shown that high TSV was associated with significant risk of progression and that five-year survival rates for patients with TP53-immunopositive and immunonegative CPCs were 0% and 82%, respectively.	('high TSV', 'Var', (43, 51))	('progression', 'MPA', (92, 103))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('patients', 'Species', '9606', (142, 150))
91715	21445348	Survival rate (>5 years free of disease) in our present series was 18.1% (2/11) for R337H positive CPC (Table 1) and 22% for R337H-negative CPC (Table 2).	('R337H positive', 'Var', (84, 98))	('R337H', 'Mutation', 'rs121912664', (125, 130))	('R337H', 'Mutation', 'rs121912664', (84, 89))	('CPC', 'Disease', (99, 102))
91716	21445348	This lower survival rate in R337H-negative CPC, in contrast to the Canadian series (82%), may be due to differences in treatment protocols, or delay in tumor diagnosis.	('survival', 'MPA', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('R337H-negative', 'Var', (28, 42))	('R337H', 'Mutation', 'rs121912664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('CPC', 'Disease', (43, 46))	('tumor', 'Disease', (152, 157))	('lower', 'NegReg', (5, 10))
91717	21445348	Patients with germline TP53 mutations seem to be at a higher risk of secondary radio-induced malignancies due to the risk of inducing new mutations in the wild-copy of the gene.	('inducing', 'Reg', (125, 133))	('malignancies', 'Disease', 'MESH:D009369', (93, 105))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('malignancies', 'Disease', (93, 105))	('mutations', 'Var', (28, 37))
91719	21445348	In conclusion, the R337H TP53 mutation may be responsible for an increased CPC incidence in Curitiba and probably in other regions of southern Brazil, where the mutation was already documented to be very frequent in ACT (around 85-95% in the states of Sao Paulo and Parana).	('TP53', 'Gene', (25, 29))	('increased CPC', 'Phenotype', 'HP:0003236', (65, 78))	('CPC', 'Disease', (75, 78))	('R337H', 'Var', (19, 24))	('R337H', 'Mutation', 'rs121912664', (19, 24))	('TP53', 'Gene', '7157', (25, 29))
91720	21445348	Further studies of TP53 mutations are necessary to understand their contribution to CPC formation and their participation in CPC prognosis.	('mutations', 'Var', (24, 33))	('CPC', 'Disease', (84, 87))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))
91721	21445348	It will be necessary to continue identifying relatives positive for the R337H mutation in order to provide genetic counseling and orientation for precocious cancer diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('R337H', 'Mutation', 'rs121912664', (72, 77))	('R337H', 'Var', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))
91745	31910152	ACCs can be part of rare hereditary cancer syndromes including Beckwith-Wiedemann syndrome (with alterations of imprinted genes on chromosome 11p15.5) and Li-Fraumeni syndrome (with mutations in TP53), but most cases are sporadic.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (155, 175))	('ACCs', 'Gene', (0, 4))	('TP53', 'Gene', (195, 199))	('ACCs', 'Gene', '84680', (0, 4))	('Li-Fraumeni syndrome', 'Disease', (155, 175))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (63, 90))	('alterations', 'Var', (97, 108))	('hereditary cancer syndromes', 'Disease', (25, 52))	('hereditary cancer syndromes', 'Disease', 'MESH:D009386', (25, 52))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('Beckwith-Wiedemann syndrome', 'Disease', (63, 90))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('TP53', 'Gene', '7157', (195, 199))	('mutations', 'Var', (182, 191))
91751	31910152	A retrospective study demonstrated an association of adjuvant mitotane with prolonged recurrence-free survival after radical resection; however, results of a randomized controlled trial (ADIUVO) remain to be published.	('association', 'Interaction', (38, 49))	('mitotane', 'Var', (62, 70))	('mitotane', 'Chemical', 'MESH:D008939', (62, 70))	('prolonged', 'PosReg', (76, 85))	('recurrence-free survival', 'CPA', (86, 110))	('adjuvant', 'Var', (53, 61))
91757	31910152	Cytotoxic effects are visible at therapeutic mitotane concentrations (30-50 microM), and mitochondrial disruption appears to activate apoptosis through caspase 3/7, accounting for cytotoxicity.	('mitochondrial', 'Var', (89, 102))	('caspase 3', 'Gene', (152, 161))	('cytotoxicity', 'Disease', 'MESH:D064420', (180, 192))	('apoptosis', 'CPA', (134, 143))	('caspase 3', 'Gene', '836', (152, 161))	('mitotane', 'Chemical', 'MESH:D008939', (45, 53))	('activate', 'PosReg', (125, 133))	('cytotoxicity', 'Disease', (180, 192))
91760	31910152	Because SOAT catalyzes the generation of cholesterol esters from free sterol and acyl CoA, inhibition of its activity has been proposed to result in elevated levels of free cholesterol, ER stress and apoptosis.	('ER stress', 'MPA', (186, 195))	('SOAT', 'Gene', '6646', (8, 12))	('elevated', 'PosReg', (149, 157))	('inhibition', 'Var', (91, 101))	('sterol', 'Chemical', 'MESH:D013261', (46, 52))	('elevated levels of free cholesterol', 'Phenotype', 'HP:0003124', (149, 184))	('cholesterol esters', 'Chemical', 'MESH:D002788', (41, 59))	('sterol', 'Chemical', 'MESH:D013261', (70, 76))	('free cholesterol', 'MPA', (168, 184))	('activity', 'MPA', (109, 117))	('cholesterol', 'Chemical', 'MESH:D002784', (41, 52))	('sterol', 'Chemical', 'MESH:D013261', (178, 184))	('cholesterol', 'Chemical', 'MESH:D002784', (173, 184))	('levels', 'MPA', (158, 164))	('SOAT', 'Gene', (8, 12))	('apoptosis', 'CPA', (200, 209))	('acyl CoA', 'Chemical', 'MESH:D000214', (81, 89))
91849	31910152	Unlike in nonresistant controls, intracellular free cholesterol - a major mediator of mitotane-associated apoptosis - remained unchanged in resistant cells upon mitotane treatment.	('mitotane', 'Var', (161, 169))	('mitotane', 'Chemical', 'MESH:D008939', (161, 169))	('mitotane', 'Chemical', 'MESH:D008939', (86, 94))	('intracellular free cholesterol', 'MPA', (33, 63))	('cholesterol', 'Chemical', 'MESH:D002784', (52, 63))
91855	31910152	Potential strategies to overcome mitotane resistance include SOAT inhibitors such as ATR-101, inhibition of ER chaperones or proteasome inhibitors.	('mitotane', 'Chemical', 'MESH:D008939', (33, 41))	('ATR-101', 'Gene', (85, 92))	('SOAT', 'Gene', '6646', (61, 65))	('ER chaperones', 'Protein', (108, 121))	('inhibition', 'Var', (94, 104))	('SOAT', 'Gene', (61, 65))
91859	31910152	This effect is of particular importance because mitotane therapy can cause an increase in lipoprotein levels, potentially promoting resistance.	('resistance', 'Disease', (132, 142))	('mitotane', 'Var', (48, 56))	('mitotane', 'Chemical', 'MESH:D008939', (48, 56))	('increase', 'PosReg', (78, 86))	('lipoprotein levels', 'MPA', (90, 108))	('promoting', 'PosReg', (122, 131))
91861	31910152	Novel PCSK9 inhibitors could be more promising given their ability to lower LDL levels beyond statin therapy.	('inhibitors', 'Var', (12, 22))	('PCSK9', 'Gene', (6, 11))	('LDL levels', 'MPA', (76, 86))	('lower', 'NegReg', (70, 75))	('PCSK9', 'Gene', '255738', (6, 11))	('lower LDL levels', 'Phenotype', 'HP:0003563', (70, 86))
91941	30139816	In case of breast cancers, BRCA1 or BRCA2 mutations are the main causes of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('breast cancer', 'Disease', (75, 88))	('BRCA1', 'Gene', '672', (27, 32))	('breast cancers', 'Phenotype', 'HP:0003002', (11, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('BRCA1', 'Gene', (27, 32))	('BRCA2', 'Gene', (36, 41))	('breast cancers', 'Disease', 'MESH:D001943', (11, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancers', 'Disease', (11, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('causes', 'Reg', (65, 71))	('BRCA2', 'Gene', '675', (36, 41))	('mutations', 'Var', (42, 51))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
91942	30139816	Although there are 28 breast cancer patients (23.7%) in our cohort that develop adrenal gland tumor as a second malignancy, there are only 3 case reports in literature that showed association between adrenal gland tumors and BRCA1 or BRCA2 mutations.	('BRCA2', 'Gene', '675', (234, 239))	('adrenal gland tumor', 'Disease', 'MESH:D000310', (80, 99))	('BRCA1', 'Gene', '672', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('adrenal gland tumor', 'Disease', (80, 99))	('BRCA1', 'Gene', (225, 230))	('adrenal gland tumor', 'Phenotype', 'HP:0100631', (200, 219))	('patients', 'Species', '9606', (36, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutations', 'Var', (240, 249))	('adrenal gland tumors', 'Phenotype', 'HP:0100631', (200, 220))	('association', 'Interaction', (180, 191))	('adrenal gland tumor', 'Phenotype', 'HP:0100631', (80, 99))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('breast cancer', 'Disease', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('BRCA2', 'Gene', (234, 239))	('adrenal gland tumors', 'Disease', (200, 220))	('adrenal gland tumor', 'Disease', 'MESH:D000310', (200, 219))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('adrenal gland tumors', 'Disease', 'MESH:D000310', (200, 220))	('malignancy', 'Disease', (112, 122))
91947	30139816	Also, TP53 genetic mutation contributes to 40-50% of all human tumors.	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('human', 'Species', '9606', (57, 62))	('human', 'Disease', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('contributes', 'Reg', (28, 39))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('genetic mutation', 'Var', (11, 27))
91993	28416583	NPNT was identified by immunohistochemistry as a secreted matrix protein expressed exclusively around aldosterone-producing glomeruli in normal adrenal ZG and in aldosterone-dense ZG-like APAs; the highest expression was in ZG-like APAs with gain-of-function CTNNB1 mutations, whose removal cured hypertension in our patients.	('aldosterone-dense', 'Phenotype', 'HP:0000859', (162, 179))	('CTNNB1', 'Gene', '1499', (259, 265))	('aldosterone', 'Chemical', 'MESH:D000450', (162, 173))	('hypertension', 'Disease', (297, 309))	('hypertension', 'Phenotype', 'HP:0000822', (297, 309))	('aldosterone', 'Chemical', 'MESH:D000450', (102, 113))	('mutations', 'Var', (266, 275))	('CTNNB1', 'Gene', (259, 265))	('patients', 'Species', '9606', (317, 325))	('gain-of-function', 'PosReg', (242, 258))	('hypertension', 'Disease', 'MESH:D006973', (297, 309))
91995	28416583	NPNT production was regulated by canonical Wnt pathway, and NPNT overexpression or silencing increased or reduced aldosterone, respectively.	('canonical Wnt pathway', 'Pathway', (33, 54))	('NPNT', 'Gene', (60, 64))	('aldosterone', 'MPA', (114, 125))	('overexpression', 'PosReg', (65, 79))	('reduced aldosterone', 'Phenotype', 'HP:0004319', (106, 125))	('reduced', 'NegReg', (106, 113))	('aldosterone', 'Chemical', 'MESH:D000450', (114, 125))	('silencing', 'Var', (83, 92))
92002	28416583	Compared with the classical large lipid-laden zona fasciculata (ZF)-like APA with mutations in inward rectifier potassium channel 4 (KCNJ5), not only is this ZG-like subtype of APA histologically and biochemically different, it also harbors hallmark somatic mutations in genes encoding a subunit of the voltage-gated calcium channel (CACNA1D), Na+/K+-ATPase (ATP1A1), Ca2+-ATPase (ATP2B3), or the Wnt pathway mediator beta-catenin (CTNNB1).	('CTNNB1', 'Gene', '1499', (432, 438))	('CACNA1D', 'Gene', (334, 341))	('zona fasciculata', 'Disease', (46, 62))	('Ca2+-ATPase', 'Protein', (368, 379))	('Ca2+', 'Chemical', 'MESH:D000069285', (368, 372))	('KCNJ5', 'Gene', (133, 138))	('ATP1A1', 'Gene', (359, 365))	('Na+/K+-ATPase', 'Protein', (344, 357))	('ATP2B3', 'Gene', '492', (381, 387))	('lipid', 'Chemical', 'MESH:D008055', (34, 39))	('ATP2B3', 'Gene', (381, 387))	('CTNNB1', 'Gene', (432, 438))	('ATP1A1', 'Gene', '476', (359, 365))	('beta-catenin', 'Gene', (418, 430))	('KCNJ5', 'Gene', '3762', (133, 138))	('beta-catenin', 'Gene', '1499', (418, 430))	('zona fasciculata', 'Disease', 'MESH:D006562', (46, 62))	('calcium', 'Chemical', 'MESH:D002118', (317, 324))	('mutations', 'Var', (258, 267))	('mutations', 'Var', (82, 91))	('CACNA1D', 'Gene', '776', (334, 341))
92018	28416583	Quantitative real-time polymerase chain reaction was performed using TaqMan ABI probes (Applied Biosystems) for NPNT (Hs01568126), ITGB1 (Hs00559595), and BCL2 (Hs00608023).	('Hs00608023', 'Var', (161, 171))	('BCL2', 'Gene', '596', (155, 159))	('ITGB1', 'Gene', (131, 136))	('BCL2', 'Gene', (155, 159))	('Hs00559595', 'Var', (138, 148))	('Hs01568126', 'Var', (118, 128))	('ITGB1', 'Gene', '3688', (131, 136))
92031	28416583	After silencing, adherent cells were trypsinized, added to any detached cells in the supernatant as previously described, stained with annexin V-propidium iodide, and analyzed with the FACSCanto II flow cytometer (Becton-Dickinson).	('silencing', 'Var', (6, 15))	('annexin V', 'Gene', (135, 144))	('annexin V', 'Gene', '308', (135, 144))	('propidium iodide', 'Chemical', 'MESH:D011419', (145, 161))
92037	28416583	The 2 APAs with the highest levels of NPNT harbored gain-of-function mutations in the Wnt gene CTNNB1.	('gain-of-function', 'PosReg', (52, 68))	('mutations', 'Var', (69, 78))	('CTNNB1', 'Gene', (95, 101))	('CTNNB1', 'Gene', '1499', (95, 101))
92047	28416583	In our study, silencing of ITGB1, encoding integrin subunit beta1, by  80%, caused a similar reduction in aldosterone production comparable to silencing of NPNT (Figure 3C).	('silencing', 'Var', (14, 23))	('reduction', 'NegReg', (93, 102))	('integrin subunit beta1', 'Gene', '3688', (43, 65))	('aldosterone', 'Chemical', 'MESH:D000450', (106, 117))	('ITGB1', 'Gene', (27, 32))	('integrin subunit beta1', 'Gene', (43, 65))	('aldosterone production', 'MPA', (106, 128))	('reduction in aldosterone production', 'Phenotype', 'HP:0004319', (93, 128))	('aldosterone production', 'Phenotype', 'HP:0000859', (106, 128))	('ITGB1', 'Gene', '3688', (27, 32))
92050	28416583	To activate the Wnt canonical pathway, DeltaN47 beta-catenin, a strong constitutive inducer encoding an N-terminally truncated form of beta-catenin resistant to proteolysis, was expressed.	('beta-catenin', 'Gene', (48, 60))	('Wnt canonical pathway', 'Pathway', (16, 37))	('DeltaN47', 'Var', (39, 47))	('activate', 'PosReg', (3, 11))	('beta-catenin', 'Gene', (135, 147))	('beta-catenin', 'Gene', '1499', (48, 60))	('beta-catenin', 'Gene', '1499', (135, 147))	('DeltaN47', 'DELETION', 'None', (39, 47))
92061	28416583	Kinetic measurement of cytotoxicity via the YOYO-1-iodide reagent revealed >3-fold increase in fluorescent (dead) cells when NPNT was silenced (Figure 6B).	('cytotoxicity', 'Disease', (23, 35))	('increase', 'PosReg', (83, 91))	('silenced', 'Var', (134, 142))	('cytotoxicity', 'Disease', 'MESH:D064420', (23, 35))	('YOYO-1-iodide', 'Chemical', '-', (44, 57))	('NPNT', 'Gene', (125, 129))
92067	28416583	We first discovered NPNT in the adrenal as the most upregulated gene in the smaller ZG-like APAs with higher aldosterone synthetic capacity, harboring mutations of CACNA1D or ATP1A1, when compared with those with a ZF-like phenotype and mutations of KCNJ5.	('aldosterone synthetic capacity', 'MPA', (109, 139))	('aldosterone', 'Chemical', 'MESH:D000450', (109, 120))	('higher aldosterone', 'Phenotype', 'HP:0000859', (102, 120))	('ATP1A1', 'Gene', (175, 181))	('KCNJ5', 'Gene', '3762', (250, 255))	('higher', 'PosReg', (102, 108))	('KCNJ5', 'Gene', (250, 255))	('CACNA1D', 'Gene', '776', (164, 171))	('upregulated', 'PosReg', (52, 63))	('CACNA1D', 'Gene', (164, 171))	('mutations', 'Var', (151, 160))	('ATP1A1', 'Gene', '476', (175, 181))
92074	28416583	Together with the consistent correlation between NPNT and CYP11B2 staining, and evidence showing NPNT increases aldosterone production, we propose that the role of this matrix protein is to cluster ZG cells together to form a functional unit as indicated by its periglomerular staining.	('increases aldosterone', 'Phenotype', 'HP:0000859', (102, 123))	('CYP11B2', 'Gene', (58, 65))	('aldosterone', 'Chemical', 'MESH:D000450', (112, 123))	('NPNT', 'Var', (97, 101))	('CYP11B2', 'Gene', '1585', (58, 65))	('aldosterone production', 'MPA', (112, 134))	('aldosterone production', 'Phenotype', 'HP:0000859', (112, 134))	('increases', 'PosReg', (102, 111))
92083	28416583	It has been shown that an aberrant planar cell polarity pathway leads to disruption of integrin beta1-mediated interactions and, in turn, disorganization of the ECM.	('aberrant', 'Var', (26, 34))	('disruption', 'NegReg', (73, 83))	('planar cell', 'Pathway', (35, 46))	('disorganization of the ECM', 'CPA', (138, 164))	('integrin beta1', 'Gene', (87, 101))	('integrin beta1', 'Gene', '3688', (87, 101))
92092	28416583	In addition, the H295R cell line is already known to harbor a CTNNB1 mutation with high levels of NPNT; so, whenever applicable, silencing NPNT was prioritized.	('CTNNB1', 'Gene', (62, 68))	('H295R', 'CellLine', 'CVCL:0458', (17, 22))	('CTNNB1', 'Gene', '1499', (62, 68))	('mutation', 'Var', (69, 77))
92099	28416583	Recently, the discovery of somatic mutations in CACNA1D/ATP1A1/ATP2B3/CTNNB1 characterize a subtype of small ZG-like APAs that are also histologically and biochemically distinct from the classical large KCNJ5-mutant ZF-like APAs.	('KCNJ5', 'Gene', (203, 208))	('CTNNB1', 'Gene', '1499', (70, 76))	('CACNA1D', 'Gene', (48, 55))	('CACNA1D', 'Gene', '776', (48, 55))	('ATP2B3', 'Gene', '492', (63, 69))	('KCNJ5', 'Gene', '3762', (203, 208))	('ATP1A1', 'Gene', '476', (56, 62))	('ATP2B3', 'Gene', (63, 69))	('CTNNB1', 'Gene', (70, 76))	('ATP1A1', 'Gene', (56, 62))	('mutations', 'Var', (35, 44))
92151	28097033	Positivity with calretinin and/or alpha-inhibin is known to be of highly diagnostic value for adrenocortical carcinoma, although all of these immunohistochemical markers were negative in the present case.	('calretinin', 'Gene', '794', (16, 26))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (94, 118))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (94, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('calretinin', 'Gene', (16, 26))	('Positivity', 'Var', (0, 10))	('adrenocortical carcinoma', 'Disease', (94, 118))	('alpha-inhibin', 'Protein', (34, 47))
92166	26582501	Combination-Index (CI) for sHDL and either etoposide(E), cisplatin(P) or mitotane(M) demonstrated synergy (CI<1) for anti-proliferation.	('sHDL', 'Var', (27, 31))	('etoposide', 'Chemical', 'MESH:D005047', (43, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('mitotane', 'Chemical', 'MESH:D008939', (73, 81))	('anti-proliferation', 'CPA', (117, 135))
92167	26582501	sHDL alone or in combination with chemo drugs was able to reduce cortisol production by 70-90% compared to cisplatin alone or controls (p<0.01).	('sHDL', 'Var', (0, 4))	('reduce cortisol', 'Phenotype', 'HP:0008163', (58, 73))	('cortisol production', 'MPA', (65, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('reduce', 'NegReg', (58, 64))	('cortisol', 'Chemical', 'MESH:D006854', (65, 73))
92221	26582501	To verify how changes in the steroidogenic pathway are influenced by combination therapy, we measured the concentration of Cortisol in the culture supernatant of hormone-producing NCI-H295R cells after E, P or M treatment alone or in combination with sHDL for 24 h. Treatment of cells with drug alone decreased Cortisol production levels by 89.6% for sHDL, 84.7% for M, and 82.1% for E (p<0.01 each vs. controls while P decreased it only by 8.39% (p=NS) (Fig.	('Cortisol production levels', 'MPA', (311, 337))	('sHDL', 'Var', (351, 355))	('decreased Cortisol', 'Phenotype', 'HP:0008163', (301, 319))	('Cortisol', 'Chemical', 'MESH:D006854', (123, 131))	('decreased', 'NegReg', (301, 310))	('NCI-H295R', 'CellLine', 'CVCL:0458', (180, 189))	('steroid', 'Chemical', 'MESH:D013256', (29, 36))	('Cortisol', 'Chemical', 'MESH:D006854', (311, 319))
92222	26582501	Next, since Cortisol levels were significantly decreased with sHDL, we wanted to look more at its mechanistic effect on steroidogenesis in these ACC cells.	('steroid', 'Chemical', 'MESH:D013256', (120, 127))	('sHDL', 'Var', (62, 66))	('Cortisol', 'Chemical', 'MESH:D006854', (12, 20))	('Cortisol levels', 'MPA', (12, 27))	('ACC', 'Phenotype', 'HP:0006744', (145, 148))	('decreased', 'NegReg', (47, 56))
92225	26582501	During combination of sHDL with either cisplatin, etoposide, or mitotane, the levels of StAR (0.18-1.88), CYP21A2 (0.05-2.6) and CYP19A1 (0.22-4.9) increased (in terms of fold changes); whereas the levels of CYP11A1 (0.1-0.5), CYP11B1 (0.1-0.64), CYP11B2 (0.04-0.52), CYP17A1 (0.1-0.58) and HSD3B2 (0.1-0.2 for P and M respectively; but increased by 2.1 for E) decreased as fold change.	('CYP21A2', 'Gene', (106, 113))	('CYP11B2', 'Gene', (247, 254))	('HSD3B2', 'Gene', '3284', (291, 297))	('CYP21A2', 'Gene', '1589', (106, 113))	('StAR', 'Gene', (88, 92))	('mitotane', 'Chemical', 'MESH:D008939', (64, 72))	('CYP11A1', 'Gene', '1583', (208, 215))	('cisplatin', 'Var', (39, 48))	('CYP19A1', 'Gene', '1588', (129, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('CYP11B1', 'Gene', '1584', (227, 234))	('CYP17A1', 'Gene', (268, 275))	('CYP17A1', 'Gene', '1586', (268, 275))	('StAR', 'Gene', '6770', (88, 92))	('HSD3B2', 'Gene', (291, 297))	('etoposide', 'Chemical', 'MESH:D005047', (50, 59))	('CYP11B2', 'Gene', '1585', (247, 254))	('CYP11A1', 'Gene', (208, 215))	('CYP19A1', 'Gene', (129, 136))	('CYP11B1', 'Gene', (227, 234))
92233	26582501	Despite the antagonistic effect of doxorubicin, we observed an enhanced dose dependent decrease in viability for both NCI-H295R (Fig.8A) and SW13 (Fig.8B) for sHDL combinations compared to EDPM alone.	('NCI-H295R', 'CellLine', 'CVCL:0458', (118, 127))	('EDPM', 'Chemical', '-', (189, 193))	('combinations', 'Var', (164, 176))	('sHDL', 'Var', (159, 163))	('SW13', 'CellLine', 'CVCL:0542', (141, 145))	('viability', 'MPA', (99, 108))	('decrease', 'NegReg', (87, 95))	('doxorubicin', 'Chemical', 'MESH:D004317', (35, 46))
92238	26582501	Recently, it was noted that mitotane induces CYP3A4.	('CYP3A4', 'Gene', (45, 51))	('CYP3A4', 'Gene', '1576', (45, 51))	('mitotane', 'Var', (28, 36))	('mitotane', 'Chemical', 'MESH:D008939', (28, 36))
92250	26582501	Our results indicated that compared to monotherapy, combination therapy with sHDL increased expression levels of StAR, the intra mitochondrial transporter; CYP21A2, the enzyme metabolizing17-hydroxyprogesterone into 11-deoxycortisol, and CYP19A1 whereas the levels of CYP11B1, CYP11B2, CYP11A1 and CYP21A2 decreased.	('11-deoxycortisol', 'Chemical', 'MESH:D003350', (216, 232))	('CYP11B2', 'Gene', '1585', (277, 284))	('StAR', 'Gene', '6770', (113, 117))	('CYP11B1', 'Gene', '1584', (268, 275))	('combination', 'Var', (52, 63))	('increased', 'PosReg', (82, 91))	('expression levels', 'MPA', (92, 109))	('CYP11A1', 'Gene', '1583', (286, 293))	('intra', 'MPA', (123, 128))	('CYP11B1', 'Gene', (268, 275))	('CYP11B2', 'Gene', (277, 284))	('CYP19A1', 'Gene', '1588', (238, 245))	('CYP21A2', 'Gene', (156, 163))	('CYP21A2', 'Gene', (298, 305))	('CYP11A1', 'Gene', (286, 293))	('CYP19A1', 'Gene', (238, 245))	('CYP21A2', 'Gene', '1589', (156, 163))	('CYP21A2', 'Gene', '1589', (298, 305))	('-hydroxyprogesterone', 'Chemical', 'MESH:D006908', (190, 210))	('StAR', 'Gene', (113, 117))
92251	26582501	These results suggest that our combination has multiple effects and blocks both the upstream and the downstream regulators of cortisol.	('blocks', 'NegReg', (68, 74))	('combination', 'Var', (31, 42))	('upstream', 'MPA', (84, 92))	('cortisol', 'Chemical', 'MESH:D006854', (126, 134))
92320	23956055	Preclinical data suggest that inhibition of the IGF-IR may constitute an important therapeutic target in a variety of pediatric solid tumors, including rhabdomyosarcoma, neuroblastoma and Wilms tumor.	('rhabdomyosarcoma', 'Disease', (152, 168))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('neuroblastoma', 'Disease', (170, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('inhibition', 'Var', (30, 40))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (152, 168))	('Wilms tumor', 'Disease', (188, 199))	('Wilms tumor', 'Disease', 'MESH:D009396', (188, 199))	('Wilms tumor', 'Phenotype', 'HP:0002667', (188, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('IGF-IR', 'Gene', (48, 54))	('pediatric solid tumors', 'Disease', (118, 140))	('neuroblastoma', 'Phenotype', 'HP:0003006', (170, 183))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (152, 168))	('IGF-IR', 'Gene', '3480', (48, 54))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (118, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('neuroblastoma', 'Disease', 'MESH:D009447', (170, 183))
92322	23956055	In preclinical cancer models, cixutumumab has single-agent activity and potentiates the effect of cytotoxic therapy in vitro and in vivo.	('potentiates', 'PosReg', (72, 83))	('cixutumumab', 'Var', (30, 41))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cixutumumab', 'Chemical', 'MESH:C557414', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
92323	23956055	When evaluated by the Pediatric Preclinical Testing Program, cixutumumab demonstrated single-agent activity in osteosarcoma, Ewing sarcoma (ES), neuroblastoma, glioblastoma, and rhabdomyosarcoma models.	('neuroblastoma', 'Disease', (145, 158))	('neuroblastoma', 'Phenotype', 'HP:0003006', (145, 158))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (178, 194))	('neuroblastoma', 'Disease', 'MESH:D009447', (145, 158))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (178, 194))	('cixutumumab', 'Var', (61, 72))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (125, 138))	('glioblastoma', 'Disease', 'MESH:D005909', (160, 172))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (125, 138))	('cixutumumab', 'Chemical', 'MESH:C557414', (61, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('ES', 'Phenotype', 'HP:0012254', (140, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('glioblastoma', 'Disease', (160, 172))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('rhabdomyosarcoma', 'Disease', (178, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('osteosarcoma', 'Disease', (111, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (111, 123))	('Ewing sarcoma', 'Disease', (125, 138))
92400	23956055	In addition, there are several ongoing phase 1 and 2 combination studies of IGFR inhibitors in adults with a variety of solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('solid tumors', 'Disease', (120, 132))	('IGFR', 'Gene', (76, 80))	('inhibitors', 'Var', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))	('IGFR', 'Gene', '3480', (76, 80))
92477	26558005	For Cushing's syndrome, LA has been used for unilateral and bilateral adenomas and hyperplasia, pituitary-dependent disease and ectopic adrenocorticotropic hormone (ACTH) secretion.	('adenomas', 'Disease', (70, 78))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (4, 22))	("Cushing's syndrome", 'Disease', (4, 22))	('pituitary-dependent disease', 'Disease', 'MESH:D047748', (96, 123))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (4, 22))	('adrenocorticotropic hormone', 'Gene', '5443', (136, 163))	('hyperplasia', 'Disease', 'MESH:D006965', (83, 94))	('adrenocorticotropic hormone', 'Gene', (136, 163))	('ACTH', 'Gene', (165, 169))	('ACTH', 'Gene', '5443', (165, 169))	('ectopic', 'Var', (128, 135))	('adenomas', 'Disease', 'MESH:D000236', (70, 78))	('pituitary-dependent disease', 'Disease', (96, 123))	('hyperplasia', 'Disease', (83, 94))
92609	18684447	In NCI-H295R cells dihydrotestosterone resulted in a significant reduction in cellular proliferation; however, these investigators did not evaluate the change in AA production in response to testosterone itself.	('testosterone', 'Chemical', 'MESH:D013739', (26, 38))	('cellular proliferation', 'CPA', (78, 100))	('NCI-H295R', 'CellLine', 'CVCL:0458', (3, 12))	('testosterone', 'Chemical', 'MESH:D013739', (191, 203))	('dihydrotestosterone', 'Chemical', 'MESH:D013196', (19, 38))	('reduction', 'NegReg', (65, 74))	('dihydrotestosterone', 'Var', (19, 38))
92623	18684447	While this observation remains to be confirmed, other mechanisms may be responsible for this discrepancy including increase degradation of DHEAS and post-translational modification (e.g.	('degradation', 'MPA', (124, 135))	('DHEAS', 'Gene', (139, 144))	('increase', 'PosReg', (115, 123))	('post-translational modification', 'Var', (149, 180))	('DHEAS', 'Gene', '6822', (139, 144))
92630	33592039	In this study, using data from The Cancer Genome Atlas (TCGA) project and the Gene Expression Omnibus (GEO) database, a secondary analysis was performed to explore the expression profile of CYP4B1, as well as its prognostic value in patients with lung adenocarcinoma (LUAD).	('LUAD', 'Phenotype', 'HP:0030078', (268, 272))	('CYP4B1', 'Var', (190, 196))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (247, 266))	('Cancer', 'Disease', (35, 41))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('patients', 'Species', '9606', (233, 241))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('lung adenocarcinoma', 'Disease', (247, 266))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (247, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
92631	33592039	Based on the obtained results, a significantly decreased CYP4B1 expression was discovered in patients with LUAD when compared with their normal counterparts (p<0.05), and was linked to age younger than 65 years (p = 0.0041), history of pharmaceutical (p = 0.0127) and radiation (p = 0.0340) therapy, mutations in KRAS/EGFR/ALK (p = 0.0239), and living status of dead (p = 0.0026).	('expression', 'MPA', (64, 74))	('ALK', 'Gene', '238', (323, 326))	('mutations', 'Var', (300, 309))	('KRAS', 'Gene', '3845', (313, 317))	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('LUAD', 'Disease', (107, 111))	('CYP4B1', 'Gene', (57, 63))	('EGFR', 'Gene', '1956', (318, 322))	('age', 'Gene', (185, 188))	('age', 'Gene', '5973', (185, 188))	('ALK', 'Gene', (323, 326))	('EGFR', 'Gene', (318, 322))	('patients', 'Species', '9606', (93, 101))	('KRAS', 'Gene', (313, 317))	('decreased', 'NegReg', (47, 56))
92632	33592039	Survival analysis indicated that the low CYP4B1 expression was an independent prognostic indicator of shorter survival in terms of overall survival (OS) and recurrence-free survival (RFS) in patients with LUAD.	('shorter', 'NegReg', (102, 109))	('patients', 'Species', '9606', (191, 199))	('low', 'NegReg', (37, 40))	('CYP4B1', 'Var', (41, 47))	('overall survival', 'CPA', (131, 147))	('expression', 'MPA', (48, 58))	('LUAD', 'Disease', (205, 209))	('recurrence-free survival', 'CPA', (157, 181))	('LUAD', 'Phenotype', 'HP:0030078', (205, 209))	('RFS', 'Disease', (183, 186))	('RFS', 'Disease', 'MESH:D005198', (183, 186))
92633	33592039	The copy number alterations (CNAs) and sites of cg23440155 and cg23414387 hypermethylation might contribute to the decreased CYP4B1 expression.	('CYP4B1', 'Gene', (125, 131))	('cg23440155', 'Chemical', '-', (48, 58))	('cg23440155', 'Var', (48, 58))	('decreased', 'NegReg', (115, 124))	('cg23414387', 'Var', (63, 73))	('expression', 'MPA', (132, 142))	('cg23414387', 'Chemical', '-', (63, 73))
92634	33592039	Gene set enrichment analysis (GSEA) suggested that CYP4B1 might act as an oncogene in LUAD by preventing biological metabolism pathways of exogenous and endogenous compounds and enhancing DNA replication and cell cycle activities.	('cell cycle activities', 'CPA', (208, 229))	('preventing', 'NegReg', (94, 104))	('DNA replication', 'CPA', (188, 203))	('biological', 'Pathway', (105, 115))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('enhancing', 'PosReg', (178, 187))	('CYP4B1', 'Var', (51, 57))	('LUAD', 'Disease', (86, 90))	('GSEA', 'Chemical', '-', (30, 34))
92647	33592039	As the primary site of exposure to inhaled toxicants and carcinogens, the metabolic balance of the protective detoxification system of the lung organ is essential to maintain its normal physiological function; thus, it is reasonable to speculate that the dysregulation of CYP4B1 is presumably associated with carcinogenesis in the lung owing to its catalytic activity in the first step of xenobiotic processing.	('CYP4B1', 'Gene', (272, 278))	('carcinogenesis', 'Disease', 'MESH:D063646', (309, 323))	('dysregulation', 'Var', (255, 268))	('carcinogenesis', 'Disease', (309, 323))	('associated', 'Reg', (293, 303))
92648	33592039	Accordingly, in the present study, using data from The Cancer Genome Atlas (TCGA) project and the Gene Expression Omnibus (GEO) database, we performed a secondary analysis to thoroughly analyze the CYP4B1 expression level, determine its prognostic role, explore the underlying mechanisms of its dysregulation, as well as to probe its potential functions in LUAD.	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Cancer', 'Disease', (55, 61))	('CYP4B1', 'Var', (198, 204))	('LUAD', 'Phenotype', 'HP:0030078', (357, 361))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))	('LUAD', 'Disease', (357, 361))
92658	33592039	Three gene microarray datasets of lung cancer (GSE30219, GSE31210 and GSE32863) were retrieved from the GEO database (http://www.ncbi.nlm.nih.gov/geo/) for validation.	('GSE31210', 'Var', (57, 65))	('GSE30219', 'Var', (47, 55))	('lung cancer', 'Disease', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('GSE32863', 'Var', (70, 78))
92662	33592039	Kaplan-Meier curves of OS and RFS were generated using GraphPad Prism by setting the median CYP4B1 expression as the cut-off.	('RFS', 'Disease', 'MESH:D005198', (30, 33))	('RFS', 'Disease', (30, 33))	('CYP4B1', 'Var', (92, 98))
92663	33592039	To examine the mRNA expression level of CYP4B1 in patients with LUAD, we extracted RNA-seq data from the TCGA project and microarray data of GSE30219, GSE31210, and GSE32863 from the GEO database for validation.	('patients', 'Species', '9606', (50, 58))	('GSE31210', 'Var', (151, 159))	('GSE32863', 'Var', (165, 173))	('LUAD', 'Disease', (64, 68))	('LUAD', 'Phenotype', 'HP:0030078', (64, 68))	('GSE30219', 'Var', (141, 149))
92665	33592039	The results revealed that the significantly decreased CYP4B1 expression was more frequently observed in patients with age younger than 65 years (p = 0.0041), in those with a history of pharmaceutical therapy (p = 0.0127) and radiation therapy (p = 0.0340), mutations in KRAS/EGFR/ALK (p = 0.0239), and deaths (i.e., living status; p = 0.0026) (Table 1).	('deaths', 'Disease', (302, 308))	('ALK', 'Gene', (280, 283))	('EGFR', 'Gene', (275, 279))	('mutations', 'Var', (257, 266))	('EGFR', 'Gene', '1956', (275, 279))	('deaths', 'Disease', 'MESH:D003643', (302, 308))	('age', 'Gene', '5973', (118, 121))	('KRAS', 'Gene', (270, 274))	('ALK', 'Gene', '238', (280, 283))	('KRAS', 'Gene', '3845', (270, 274))	('age', 'Gene', (118, 121))	('patients', 'Species', '9606', (104, 112))	('expression', 'MPA', (61, 71))	('decreased', 'NegReg', (44, 53))	('CYP4B1', 'Gene', (54, 60))
92667	33592039	As shown in Fig 2A and 2D, low CYP4B1 expression was more strongly associated with shorter OS and RFS in patients with primary LUAD (p = 0.0018 and p = 0.0103, respectively).	('shorter OS', 'Disease', (83, 93))	('patients', 'Species', '9606', (105, 113))	('RFS', 'Disease', (98, 101))	('RFS', 'Disease', 'MESH:D005198', (98, 101))	('CYP4B1', 'Var', (31, 37))	('low', 'NegReg', (27, 30))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))
92668	33592039	On using GEO datasets for validation, the decreased CYP4B1 expression group was found to possess remarkably inferior OS and RFS when compared with the high CYP4B1 expression group in both GSE30219 (p = 0.0111 and p = 0.0118, respectively; Fig 2B and 2E) and GSE31210 (p = 0.0003 and p<0.0001, respectively; Fig 2C & 2F) datasets.	('CYP4B1 expression', 'Var', (52, 69))	('decreased', 'NegReg', (42, 51))	('RFS', 'Disease', (124, 127))	('inferior', 'NegReg', (108, 116))	('RFS', 'Disease', 'MESH:D005198', (124, 127))
92669	33592039	Moreover, to verify the robust prognostic value of CYP4B1 in terms of OS and RFS, univariate and multivariate analyses based on the Cox regression model were performed.	('RFS', 'Disease', 'MESH:D005198', (77, 80))	('RFS', 'Disease', (77, 80))	('CYP4B1', 'Var', (51, 57))
92671	33592039	In terms of RFS, the independent prognostic value of CYP4B1 in patients with LUAD was observed in the TCGA-LUAD cohort (p = 0.046) and was validated in the two independent GEO datasets (pGSE30219 = 0.031 and pGSE31210<0.0001, respectively; Fig 3B).	('pGSE31210', 'Var', (208, 217))	('RFS', 'Disease', (12, 15))	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('CYP4B1', 'Var', (53, 59))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))	('patients', 'Species', '9606', (63, 71))	('LUAD', 'Disease', (77, 81))	('RFS', 'Disease', 'MESH:D005198', (12, 15))
92672	33592039	First, genetic alterations in CYP4B1 were detected in TCGA-LUAD using the cBio-Portal for the Cancer Genomics platform (http://www.cbioportal.org/).	('LUAD', 'Phenotype', 'HP:0030078', (59, 63))	('Cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TCGA-LUAD', 'Disease', (54, 63))	('Cancer', 'Disease', 'MESH:D009369', (94, 100))	('Cancer', 'Disease', (94, 100))	('genetic alterations', 'Var', (7, 26))	('CYP4B1', 'Gene', (30, 36))	('detected', 'Reg', (42, 50))
92673	33592039	By comparing the methylation level between tumor (n = 457) and normal tissues (n = 32), we observed that two CpG sites, cg23440155 and cg23414387, were remarkably hypermethylated in the tumor group (Fig 4D and S1 Table).	('cg23440155', 'Chemical', '-', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cg23440155', 'Var', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cg23414387', 'Chemical', '-', (135, 145))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (186, 191))	('hypermethylated', 'PosReg', (163, 178))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('cg23414387', 'Var', (135, 145))
92674	33592039	In Pearson's regression analysis, CYP4B1 expression was found to be strongly and negatively correlated with DNA methylation in the two selected CpG sites (cg23440155: Pearson's r = -0.5198, p<0.0001; cg23414387: Pearson's r = -0.4568, p<0.0001) (Fig 4E).	('cg23414387', 'Var', (200, 210))	('cg23414387', 'Chemical', '-', (200, 210))	('CYP4B1', 'Gene', (34, 40))	('expression', 'MPA', (41, 51))	('cg23440155', 'Chemical', '-', (155, 165))	('correlated', 'Interaction', (92, 102))	('DNA methylation', 'MPA', (108, 123))	('negatively', 'NegReg', (81, 91))	('cg23440155:', 'Var', (155, 166))
92679	33592039	To further investigate the possible gene ontology terms and signaling pathways in which CYP4B1 might be involved, GO and GSEA analyses were performed using the LinkInterpreter module of LinkedOmics.	('involved', 'Reg', (104, 112))	('CYP4B1', 'Var', (88, 94))	('GSEA', 'Chemical', '-', (121, 125))
92683	33592039	Studies have revealed that the human forms of CYP4B1 possess limited activity in vivo when compared with animals, rendering rabbit CYP4B1 a feasible gene therapy in humans to treat cancers in humans.	('human', 'Species', '9606', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('human', 'Species', '9606', (192, 197))	('human', 'Species', '9606', (31, 36))	('CYP4B1', 'Var', (131, 137))	('humans', 'Species', '9606', (192, 198))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancers', 'Disease', (181, 188))	('humans', 'Species', '9606', (165, 171))
92686	33592039	The CYP4B1 catalytic metabolites or reactive intermediates of these xenobiotics reportedly exert toxicological effects by forming adducts with DNA or proteins, eliciting organ-specific toxicities, which might contribute to the formation and progression of carcinogenesis.	('organ-specific', 'MPA', (170, 184))	('toxicities', 'Disease', 'MESH:D064420', (185, 195))	('carcinogenesis', 'Disease', 'MESH:D063646', (256, 270))	('contribute', 'Reg', (209, 219))	('carcinogenesis', 'Disease', (256, 270))	('CYP4B1', 'Var', (4, 10))	('toxicological', 'MPA', (97, 110))	('eliciting', 'Reg', (160, 169))	('proteins', 'Protein', (150, 158))	('toxicities', 'Disease', (185, 195))	('DNA', 'Protein', (143, 146))	('adducts', 'Interaction', (130, 137))
92687	33592039	One example is that a high expression of CYP4B1 increases the risk of bladder tumor by activation of 2-AF.	('activation', 'PosReg', (87, 97))	('bladder tumor', 'Disease', 'MESH:D001749', (70, 83))	('AF', 'Disease', 'MESH:D001281', (103, 105))	('increases', 'PosReg', (48, 57))	('bladder tumor', 'Phenotype', 'HP:0009725', (70, 83))	('CYP4B1', 'Var', (41, 47))	('bladder tumor', 'Disease', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
92689	33592039	In this study, we confirmed the carcinogenic role of CYP4B1 in LUAD for the first time.	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('LUAD', 'Disease', (63, 67))	('CYP4B1', 'Var', (53, 59))	('carcinogenic', 'Disease', 'MESH:D063646', (32, 44))	('carcinogenic', 'Disease', (32, 44))
92690	33592039	By analyzing RNA-seq and microarray data of LUAD, CYP4B1 was found to demonstrate a remarkably lower expression in tumor specimens than in noncancerous lung tissues.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('lower', 'NegReg', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', (115, 120))	('LUAD', 'Phenotype', 'HP:0030078', (44, 48))	('expression', 'MPA', (101, 111))	('CYP4B1', 'Var', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('cancer', 'Disease', (142, 148))
92691	33592039	Several studies have explored the role and significance of dysregulated CYP4B1 in human cancers.	('dysregulated', 'Var', (59, 71))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('CYP4B1', 'Gene', (72, 78))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('human', 'Species', '9606', (82, 87))
92692	33592039	In adrenocortical carcinoma (ACC), CYP4B1 expression was nearly absent when compared with that in the normal adrenal cortex.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (3, 27))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (3, 27))	('ACC', 'Phenotype', 'HP:0006744', (29, 32))	('expression', 'MPA', (42, 52))	('CYP4B1', 'Var', (35, 41))	('adrenocortical carcinoma', 'Disease', (3, 27))	('absent', 'NegReg', (64, 70))
92693	33592039	Ectopic expression of CYP4B1 reportedly promotes cytotoxicity and increases chemosensitivity in ACC cell lines, implicating the role of CYP4B1 in tumorigenesis and chemoresistance in ACC.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ACC', 'Phenotype', 'HP:0006744', (183, 186))	('increases', 'PosReg', (66, 75))	('Ectopic expression', 'Var', (0, 18))	('tumor', 'Disease', (146, 151))	('cytotoxicity', 'Disease', (49, 61))	('chemosensitivity', 'CPA', (76, 92))	('ACC', 'Phenotype', 'HP:0006744', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('CYP4B1', 'Gene', (22, 28))	('cytotoxicity', 'Disease', 'MESH:D064420', (49, 61))	('promotes', 'PosReg', (40, 48))
92695	33592039	By applying siRNA duplexes targeting CYP4B1 in vitro, the neovascular response and expression of corneal VEGF were notably reduced.	('neovascular response', 'CPA', (58, 78))	('corneal VEGF', 'Disease', (97, 109))	('corneal VEGF', 'Disease', 'MESH:D003316', (97, 109))	('expression', 'MPA', (83, 93))	('CYP4B1', 'Var', (37, 43))	('reduced', 'NegReg', (123, 130))
92696	33592039	These results strongly suggest that corneal CYP4B1 is a component of the inflammatory and neovascular cascade initiated by injury to the corneal epithelium.	('corneal', 'Disease', (137, 144))	('corneal', 'Disease', 'MESH:D003316', (137, 144))	('corneal', 'Disease', 'MESH:D003316', (36, 43))	('corneal', 'Disease', (36, 43))	('CYP4B1', 'Var', (44, 50))
92698	33592039	Our findings revealed that low CYP4B1 mRNA expression was linked to factors such as age less than 65 years, history of pharmaceutical therapy and radiation therapy, mutations in KRAS/EGFR/ALK, and death (living status).	('KRAS', 'Gene', (178, 182))	('KRAS', 'Gene', '3845', (178, 182))	('EGFR', 'Gene', '1956', (183, 187))	('ALK', 'Gene', (188, 191))	('EGFR', 'Gene', (183, 187))	('CYP4B1', 'Gene', (31, 37))	('age', 'Gene', '5973', (84, 87))	('low', 'NegReg', (27, 30))	('ALK', 'Gene', '238', (188, 191))	('mutations', 'Var', (165, 174))	('age', 'Gene', (84, 87))
92699	33592039	have observed that the exogenous expression of CYP4B1 accentuates the apparent cytotoxicity in ACC cell lines that were treated with mitotane or cisplatin.	('cytotoxicity', 'Disease', 'MESH:D064420', (79, 91))	('mitotane', 'Chemical', 'MESH:D008939', (133, 141))	('ACC', 'Phenotype', 'HP:0006744', (95, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('cytotoxicity', 'Disease', (79, 91))	('accentuates', 'PosReg', (54, 65))	('CYP4B1', 'Var', (47, 53))
92701	33592039	Kaplan-Meier survival analyses indicated that patients with low CYP4B1 expression had remarkably shorter OS and RFS.	('patients', 'Species', '9606', (46, 54))	('RFS', 'Disease', (112, 115))	('low', 'NegReg', (60, 63))	('RFS', 'Disease', 'MESH:D005198', (112, 115))	('shorter', 'NegReg', (97, 104))	('CYP4B1', 'Var', (64, 70))
92703	33592039	Therefore, we infer that reduced CYP4B1 expression could serve as an independent predictor of unfavorable OS and RFS.	('expression', 'MPA', (40, 50))	('RFS', 'Disease', (113, 116))	('reduced', 'NegReg', (25, 32))	('unfavorable OS', 'Disease', (94, 108))	('RFS', 'Disease', 'MESH:D005198', (113, 116))	('CYP4B1', 'Var', (33, 39))
92708	33592039	In addition to regulation at the transcriptional level, genetic and epigenetic alterations affect gene expression during carcinogenesis.	('gene expression', 'MPA', (98, 113))	('affect', 'Reg', (91, 97))	('genetic', 'Var', (56, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (121, 135))	('epigenetic alterations', 'Var', (68, 90))	('carcinogenesis', 'Disease', (121, 135))
92709	33592039	In a Japanese population, subjects carrying the CYP4B1*1/*2 or CYP4B1*2/*2 genotypes exhibited a 1.75-fold increased risk of bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('CYP4B1*1/*2', 'Var', (48, 59))	('CYP4B1*2/*2', 'Var', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))
92710	33592039	Moreover, CYP4B1 dysregulation was found to be regulated by copy number variation, as well as the hypermethylation of cg23440155 and cg23414387 sites.	('copy number variation', 'Var', (60, 81))	('regulated', 'Reg', (47, 56))	('cg23414387 sites', 'Var', (133, 149))	('cg23414387', 'Chemical', '-', (133, 143))	('CYP4B1 dysregulation', 'Gene', (10, 30))	('cg23440155', 'Chemical', '-', (118, 128))	('cg23440155', 'Var', (118, 128))	('hypermethylation', 'Var', (98, 114))
92711	33592039	Additionally, the prognostic role of CYP4B1 indicated that it might act as a tumor-driven gene in LUAD.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CYP4B1', 'Var', (37, 43))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('tumor', 'Disease', (77, 82))	('LUAD', 'Disease', (98, 102))
92712	33592039	We then identified its co-expressed genes and performed the GO and GSEA enrichment analyses to explore the underlying oncogenic properties of CYP4B1 in LUAD.	('CYP4B1', 'Var', (142, 148))	('LUAD', 'Phenotype', 'HP:0030078', (152, 156))	('LUAD', 'Disease', (152, 156))	('GSEA', 'Chemical', '-', (67, 71))
92719	33592039	These results suggest that inhibition of CYP4B1 in LUAD promotes tumorigenesis by preventing metabolism and enhancing DNA replication and cell cycle activities.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('CYP4B1', 'Gene', (41, 47))	('metabolism', 'CPA', (93, 103))	('DNA replication', 'CPA', (118, 133))	('inhibition', 'Var', (27, 37))	('cell cycle activities', 'CPA', (138, 159))	('preventing', 'NegReg', (82, 92))	('promotes', 'PosReg', (56, 64))	('enhancing', 'PosReg', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
92720	33592039	CYP4B1 expression may serve as a valuable independent prognostic biomarker and a potential therapeutic target in patients with LUAD.	('patients', 'Species', '9606', (113, 121))	('LUAD', 'Disease', (127, 131))	('CYP4B1', 'Var', (0, 6))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))
92734	31777292	Studies with anti-PD-1, anti-PD-L1, or anti-CTLA-4 monotherapy or a combination of any two of these therapies that enrolled at least ten patients who had no PD-L1 tumor expression were included in our analysis.	('PD-L1 tumor', 'Disease', 'MESH:D010300', (157, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('patients', 'Species', '9606', (137, 145))	('PD-L1 tumor', 'Disease', (157, 168))	('anti-PD-L1', 'Var', (24, 34))
92736	31777292	Databases including MEDLINE and Google Scholar, as well as abstracts presented at the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and the American Association for Cancer Research (AACR) were also used to identify clinical data for anti-PD1 or anti-PD-L1 therapy in each of these cancer types or subtypes.	('anti-PD1', 'Var', (283, 291))	('Cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('Cancer', 'Phenotype', 'HP:0002664', (215, 221))	('Oncology', 'Phenotype', 'HP:0002664', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('Oncology', 'Phenotype', 'HP:0002664', (115, 123))	('Cancer', 'Disease', (215, 221))
92737	31777292	We searched for clinical trials using the following specific search terms: nivolumab, BMS-936558, pembrolizumab, MK-3475, atezolizumab, MPDL3280A, durvalumab, MEDI4736, avelumab, MSB0010718C, BMS-936559, cemiplimab, and REGN2810.	('MPDL3280A', 'Var', (136, 145))	('atezolizumab', 'Chemical', 'MESH:C000594389', (122, 134))	('nivolumab', 'Chemical', 'MESH:D000077594', (75, 84))	('cemiplimab', 'Chemical', 'MESH:C000627974', (204, 214))	('BMS-936558', 'Gene', (86, 96))	('durvalumab', 'Chemical', 'MESH:C000613593', (147, 157))	('pembrolizumab', 'Chemical', 'MESH:C582435', (98, 111))	('REGN2810', 'Chemical', 'MESH:C000627974', (220, 228))	('MK-3475', 'Var', (113, 120))
92740	31777292	We plotted the ORR for anti-PD-1, anti-PD-L1, anti-CTLA-4, or combination therapy against the corresponding all-grade and G3/4 TRAEs across a variety of cancer types.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('anti-PD-L1', 'Var', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (153, 159))
92750	31777292	The precise mechanism of ICI-induced AEs remains unclear and current understanding includes increasing T-cell activity against antigens that are present in tumors and healthy tissue, increasing levels of preexisting autoantibodies, increasing level of inflammatory cytokines, and enhanced complement-mediated inflammation resulting from direct binding of an antibody against CTLA-4, which is expressed on normal tissue.	('inflammation', 'Disease', (309, 321))	('increasing', 'PosReg', (232, 242))	('antibody', 'Var', (358, 366))	('enhanced', 'PosReg', (280, 288))	('increasing', 'PosReg', (92, 102))	('level', 'MPA', (243, 248))	('CTLA-4', 'Gene', (375, 381))	('levels', 'MPA', (194, 200))	('T-cell activity', 'CPA', (103, 118))	('inflammatory cytokines', 'MPA', (252, 274))	('increasing level of inflammatory cytokines', 'Phenotype', 'HP:0012649', (232, 274))	('binding', 'Interaction', (344, 351))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('inflammation', 'Disease', 'MESH:D007249', (309, 321))	('tumors', 'Disease', (156, 162))	('increasing', 'PosReg', (183, 193))
92753	31777292	However, CTLA-4 blockade entails a more global immune modulation than PD-1/PD-L1 blockade.	('blockade', 'Var', (16, 24))	('PD-1/PD-L1 blockade', 'Disease', (70, 89))	('CTLA-4', 'Gene', (9, 15))	('PD-1/PD-L1 blockade', 'Disease', 'MESH:D010300', (70, 89))
92764	31777292	There is agreement with the predictive effect between all-grade and G3/4 TREAs in most cancer types.	('cancer', 'Disease', (87, 93))	('G3/4', 'Var', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
92797	33299884	Another study revealed that high body mass index (BMI) was positively associated with the incidence of several types of cancer, while patients with high BMI at the time of initial diagnosis had higher two/five-year survival rates than those with low BMI.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('higher', 'PosReg', (194, 200))	('high BMI', 'Var', (148, 156))	('low BMI', 'Phenotype', 'HP:0045082', (246, 253))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('associated', 'Reg', (70, 80))	('patients', 'Species', '9606', (134, 142))	('high body mass index', 'Phenotype', 'HP:0031418', (28, 48))	('two/five-year survival rates', 'CPA', (201, 229))
92811	33299884	The patients were divided into four groups based on BMI: normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI<40 kg/m2), and extremely obese (BMI >= 40 kg/m2).	('obese', 'Disease', 'MESH:D009765', (191, 196))	('25 kg/m2 <=', 'Var', (114, 125))	('obese', 'Disease', 'MESH:D009765', (143, 148))	('obese', 'Disease', (191, 196))	('patients', 'Species', '9606', (4, 12))	('30 kg/m2 <=', 'Var', (150, 161))	('obese', 'Disease', (143, 148))
92821	33299884	Mutations, copy number variations (CNVs), and controlling expression levels of obesity-related genes were downloaded from TCGA.	('obesity', 'Phenotype', 'HP:0001513', (79, 86))	('Mutations', 'Var', (0, 9))	('obesity', 'Disease', 'MESH:D009765', (79, 86))	('obesity', 'Disease', (79, 86))	('copy number variations', 'Var', (11, 33))
92848	33299884	As displayed in Figure 2(c), for each of the five obesity-related genes (LEPR, MTCH2, MC4R, LEP, and KCTD15), the patients in a high-expression group had a greater cancer survival rate than those in the low/medium-expression groups (P < 0.05).	('KCTD15', 'Gene', '79047', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('LEP', 'Gene', '3952', (92, 95))	('KCTD15', 'Gene', (101, 107))	('obesity', 'Disease', (50, 57))	('greater', 'PosReg', (156, 163))	('patients', 'Species', '9606', (114, 122))	('LEP', 'Gene', (92, 95))	('obesity', 'Disease', 'MESH:D009765', (50, 57))	('LEPR', 'Gene', '3953', (73, 77))	('cancer', 'Disease', (164, 170))	('LEP', 'Gene', '3952', (73, 76))	('LEPR', 'Gene', (73, 77))	('MC4R', 'Gene', (86, 90))	('high-expression', 'Var', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('MTCH2', 'Gene', '23788', (79, 84))	('LEP', 'Gene', (73, 76))	('obesity', 'Phenotype', 'HP:0001513', (50, 57))	('MC4R', 'Gene', '4160', (86, 90))	('MTCH2', 'Gene', (79, 84))
92851	33299884	For patients with six types of cancer (KIRC, LUAD, LGG, GBM, UCEC, and BLCA), those in the PCSK1 low/medium-expression group had higher survival probability than those in the high-expression group.	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('LUAD', 'Disease', (45, 49))	('LGG', 'Disease', (51, 54))	('PCSK1', 'Gene', '5122', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('survival', 'CPA', (136, 144))	('higher', 'PosReg', (129, 135))	('GBM', 'Disease', (56, 59))	('UCEC', 'Disease', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (4, 12))	('PCSK1', 'Gene', (91, 96))	('cancer', 'Disease', (31, 37))	('low/medium-expression', 'Var', (97, 118))
92852	33299884	However, for patients with SKCM, patients with high expression level of PCSK1 may benefit from a superior survival probability than those with low/medium expression level.	('patients', 'Species', '9606', (33, 41))	('PCSK1', 'Gene', (72, 77))	('survival', 'CPA', (106, 114))	('patients', 'Species', '9606', (13, 21))	('high expression level', 'Var', (47, 68))	('PCSK1', 'Gene', '5122', (72, 77))	('benefit', 'PosReg', (82, 89))
92862	33299884	However, the mutation rates of five obesity-related genes in few cancer tissues were >0.05 (i.e., LEPR in SKCM (0.11), UCEC (0.07), and LUSC (0.07) and PCSK1 in SKCM (0.09) and UCEC (0.06)).	('obesity', 'Disease', 'MESH:D009765', (36, 43))	('obesity', 'Phenotype', 'HP:0001513', (36, 43))	('mutation', 'Var', (13, 21))	('LEPR', 'Gene', (98, 102))	('PCSK1', 'Gene', (152, 157))	('obesity', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PCSK1', 'Gene', '5122', (152, 157))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('LEPR', 'Gene', '3953', (98, 102))
92867	33299884	Then, for each of the 33 types of cancer, the expression levels of the 13 obesity-related genes were divided into different groups based on the seven factors as follows: (1) patients' gender (male or female), (2) patients' race (African-American, Caucasian, and Asian), (3) menopausal status (premenopause, perimenopause, and postmenopause), (4) history of smoking (smoker, nonsmoker, reformed smoker #1 (<=15 years), and reformed smoker #2 (>15 years)), (5) tumor grade (grade 1, grade 2, grade 3, and grade 4), (6) BMI (normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI < 40 kg/m2), and extremely obese (BMI >= 40 kg/m2)), and (7) history of drinking (occasional drinker, social drinker, daily drinker, weekly drinker, and nondrinker).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('menopausal status', 'Phenotype', 'HP:0008209', (274, 291))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('patients', 'Species', '9606', (213, 221))	('obese', 'Disease', (658, 663))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('obesity', 'Disease', (74, 81))	('obese', 'Disease', 'MESH:D009765', (658, 663))	('30 kg/m2 <= BMI < 40 kg/m2', 'Var', (615, 641))	('obesity', 'Disease', 'MESH:D009765', (74, 81))	('tumor', 'Disease', (459, 464))	('obese', 'Disease', (608, 613))	('25 kg/m2 <= BMI < 30 kg/m2', 'Var', (579, 605))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('3 obesity', 'Phenotype', 'HP:0025501', (72, 81))	('obese', 'Disease', 'MESH:D009765', (608, 613))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Disease', (34, 40))	('obesity', 'Phenotype', 'HP:0001513', (74, 81))
92914	33299884	For the majority of obesity-related genes, cancer patients who were in low/medium-expression level group had a superior prognosis than those in the high-expression level group.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Disease', (43, 49))	('obesity', 'Phenotype', 'HP:0001513', (20, 27))	('low/medium-expression level', 'Var', (71, 98))	('obesity', 'Disease', 'MESH:D009765', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('obesity', 'Disease', (20, 27))
92917	33299884	However, for three types of cancer (SKCM, ACC, and LUAD), patients in the high-expression group for GPR120 gene could benefit from a greater prognosis as compared to those in the low/medium-expression level group.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('high-expression', 'Var', (74, 89))	('benefit', 'PosReg', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('GPR120', 'Gene', '338557', (100, 106))	('GPR120', 'Gene', (100, 106))	('cancer', 'Disease', (28, 34))
92918	33299884	Moreover, for four types of cancer (KIRP, UVM, CESC, and LUSC), patients in the high-expression level group for SH2B1 gene experienced a better prognosis than those in the low/medium-expression level group.	('SH2B1', 'Gene', (112, 117))	('better', 'PosReg', (137, 143))	('high-expression level', 'Var', (80, 101))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('UVM', 'Disease', (42, 45))	('CESC', 'Disease', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('SH2B1', 'Gene', '25970', (112, 117))
92923	33299884	According to the Kaplan-Meier survival curves, patients with kidney cancer in the low/medium-expression level group for each of LEPR and NEGR1 genes had a long-time life expectancy in comparison to those in the high-expression level group.	('NEGR1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('kidney cancer', 'Disease', (61, 74))	('LEPR', 'Gene', '3953', (128, 132))	('patients', 'Species', '9606', (47, 55))	('low/medium-expression level', 'Var', (82, 109))	('kidney cancer', 'Disease', 'MESH:D007680', (61, 74))	('kidney cancer', 'Phenotype', 'HP:0009726', (61, 74))	('LEPR', 'Gene', (128, 132))	('NEGR1', 'Gene', '257194', (137, 142))
92924	33299884	However, patients with kidney cancer in the high-expression level group for each of TMEM18 and SH2B1 genes had a long life expectancy than those who in the low/medium-expression level group.	('TMEM18', 'Gene', '129787', (84, 90))	('kidney cancer', 'Disease', (23, 36))	('SH2B1', 'Gene', '25970', (95, 100))	('patients', 'Species', '9606', (9, 17))	('SH2B1', 'Gene', (95, 100))	('TMEM18', 'Gene', (84, 90))	('high-expression level', 'Var', (44, 65))	('kidney cancer', 'Disease', 'MESH:D007680', (23, 36))	('kidney cancer', 'Phenotype', 'HP:0009726', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
92931	33299884	Once mutations or modify alterations occur for obesity gene, microenvironment probably impacts behavior and adaptive evolution of cancer cells.	('behavior', 'CPA', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('obesity', 'Disease', 'MESH:D009765', (47, 54))	('mutations', 'Var', (5, 14))	('obesity', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('impacts', 'Reg', (87, 94))	('obesity', 'Phenotype', 'HP:0001513', (47, 54))
92958	31115496	We hypothesized that mitotane targets mitochondria and induces apoptosis in TC cells.	('mitotane', 'Var', (21, 29))	('TC', 'Phenotype', 'HP:0002890', (76, 78))	('mitotane', 'Chemical', 'MESH:D008939', (21, 29))	('induces', 'Reg', (55, 62))	('apoptosis', 'CPA', (63, 72))	('mitochondria', 'MPA', (38, 50))
92959	31115496	Cell lines representative of the major histological variants of TC were chosen: Follicular (FTC-133), poorly differentiated (BCPAP), anaplastic (SW1736 and C643) and medullary (TT) TC cells, and were treated with mitotane (0-100 muM).	('TC', 'Phenotype', 'HP:0002890', (64, 66))	('TC', 'Phenotype', 'HP:0002890', (181, 183))	('mitotane', 'Chemical', 'MESH:D008939', (213, 221))	('SW1736', 'CellLine', 'CVCL:3883', (145, 151))	('poorly differentiated', 'CPA', (102, 123))	('TC', 'Phenotype', 'HP:0002890', (93, 95))	('muM', 'Gene', '56925', (229, 232))	('C643', 'Var', (156, 160))	('muM', 'Gene', (229, 232))
92965	31115496	Consistent with the results of the cell viability assays, the overexpression of pro-apoptotic genes following treatment with mitotane was more prominent in TC cells harboring mutations in the serine/threonine-protein kinase B-raf gene and proto-oncogene tyrosine-protein kinase receptor Ret.	('protein kinase B', 'Gene', '2185', (209, 225))	('proto-oncogene tyrosine-protein kinase receptor Ret', 'Gene', '5979', (239, 290))	('B-raf', 'Gene', (224, 229))	('mutations', 'Var', (175, 184))	('overexpression', 'PosReg', (62, 76))	('B-raf', 'Gene', '673', (224, 229))	('TC', 'Phenotype', 'HP:0002890', (156, 158))	('protein kinase B', 'Gene', (209, 225))	('mitotane', 'Chemical', 'MESH:D008939', (125, 133))
92993	31115496	These cell lines harbor thyroid oncogene mutations, including serine/threonine-protein kinase B-raf V600E (BCPAP and SW1736), phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (FTC-133), cellular tumor antigen p53 (D259Y mutation; BCPAP), p53 (R248Q mutation; C643), GTPase HRas (C643), and Ret (C634W mutation; TT).	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('SW1736', 'CellLine', 'CVCL:3883', (117, 123))	('R248Q mutation;', 'Var', (295, 310))	('B-raf', 'Gene', (94, 99))	('V600E', 'Mutation', 'rs113488022', (100, 105))	('mutations', 'Var', (41, 50))	('Ret', 'Gene', (342, 345))	('p53', 'Gene', '7157', (261, 264))	('cellular tumor antigen p53', 'Gene', (238, 264))	('R248Q', 'Mutation', 'rs11540652', (295, 300))	('B-raf', 'Gene', '673', (94, 99))	('C634W', 'Var', (347, 352))	('thyroid', 'Gene', (24, 31))	('TC', 'Phenotype', 'HP:0002890', (229, 231))	('protein kinase B', 'Gene', (79, 95))	('p53', 'Gene', (261, 264))	('Ret', 'Gene', '5979', (342, 345))	('cellular tumor antigen p53', 'Gene', '7157', (238, 264))	('p53', 'Gene', '7157', (290, 293))	('protein kinase B', 'Gene', '2185', (79, 95))	('D259Y', 'Mutation', 'p.D259Y', (266, 271))	('p53', 'Gene', (290, 293))	('C634W', 'SUBSTITUTION', 'None', (347, 352))
93031	31115496	MTC-derived TT cells expressing GFP (TT-GFP cells) were co-cultured with human fibroblasts in the same plate, and subsequently treated with 50 muM mitotane for 24 h. The TT-GFP cells formed cellular clusters that were barely distinguishable from the fibroblasts by bright-field microscopy, but easily identifiable by fluorescence microscopy (Fig.	('muM', 'Gene', '56925', (143, 146))	('muM', 'Gene', (143, 146))	('mitotane', 'Chemical', 'MESH:D008939', (147, 155))	('TT-GFP', 'Var', (170, 176))	('MTC', 'Phenotype', 'HP:0008659', (0, 3))	('human', 'Species', '9606', (73, 78))	('TC', 'Phenotype', 'HP:0002890', (1, 3))
93048	31115496	2A, the cell cycle was arrested at the G1 phase for mitotane-treated BCPAP, C643, SW1736 and TT cells compared with untreated cells.	('arrest', 'Disease', (23, 29))	('SW1736', 'CellLine', 'CVCL:3883', (82, 88))	('C643', 'Var', (76, 80))	('cell cycle', 'CPA', (8, 18))	('mitotane', 'Chemical', 'MESH:D008939', (52, 60))	('arrest', 'Disease', 'MESH:D006323', (23, 29))
93065	31115496	To confirm that mitotane-induced toxicity in TC cells is associated with the induction of DNA damage and apoptosis, western blot analysis was performed using antibodies against gammaH2AX and cleaved caspase-3 (Fig.	('gammaH2AX', 'Protein', (177, 186))	('mitotane', 'Chemical', 'MESH:D008939', (16, 24))	('DNA', 'MPA', (90, 93))	('caspase-3', 'Gene', '836', (199, 208))	('TC', 'Phenotype', 'HP:0002890', (45, 47))	('cleaved', 'Var', (191, 198))	('caspase-3', 'Gene', (199, 208))	('toxicity', 'Disease', 'MESH:D064420', (33, 41))	('toxicity', 'Disease', (33, 41))
93070	31115496	Combined, these data suggest that treatment with mitotane leads to the induction of DNA damage and apoptosis in TC cells, particularly in cells harboring BRAF and RET mutations.	('DNA damage', 'MPA', (84, 94))	('RET', 'Gene', '5979', (163, 166))	('BRAF', 'Gene', '673', (154, 158))	('apoptosis', 'CPA', (99, 108))	('mutations', 'Var', (167, 176))	('BRAF', 'Gene', (154, 158))	('mitotane', 'Chemical', 'MESH:D008939', (49, 57))	('RET', 'Gene', (163, 166))	('TC', 'Phenotype', 'HP:0002890', (112, 114))
93114	31115496	It has been reported that mitotane induces a mitochondrial respiratory chain defect by inhibiting COX2 and COX4I1.	('mitotane', 'Var', (26, 34))	('COX4I1', 'Gene', (107, 113))	('mitotane', 'Chemical', 'MESH:D008939', (26, 34))	('mitochondrial respiratory', 'MPA', (45, 70))	('COX2', 'Gene', (98, 102))	('COX4I1', 'Gene', '1327', (107, 113))	('COX2', 'Gene', '4513', (98, 102))	('inhibiting', 'NegReg', (87, 97))	('mitochondrial respiratory chain defect', 'Phenotype', 'HP:0200125', (45, 83))
93124	31115496	These TC cell lines are characterized by constitutive activation of the MAPK/ERK signaling pathway as result of BRAF (BCPAP and SW1736 cells) or RET (TT cells) mutations.	('mutations', 'Var', (160, 169))	('ERK', 'Gene', '5594', (77, 80))	('RET', 'Gene', '5979', (145, 148))	('TC', 'Phenotype', 'HP:0002890', (6, 8))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('activation', 'PosReg', (54, 64))	('ERK', 'Gene', (77, 80))	('MAPK', 'Gene', '5595;5594;5595', (72, 76))	('SW1736', 'CellLine', 'CVCL:3883', (128, 134))	('MAPK', 'Gene', (72, 76))	('RET', 'Gene', (145, 148))
93125	31115496	One of the main questions that should be addressed by future studies is whether the mutational status in TC serves a significant role in the response to mitotane.	('response to mitotane', 'MPA', (141, 161))	('mitotane', 'Chemical', 'MESH:D008939', (153, 161))	('TC', 'Phenotype', 'HP:0002890', (105, 107))	('mutational', 'Var', (84, 94))
93135	31115496	Limited studies have also been performed on thyroid function, revealing that mitotane can cause central hypothyroidism by inhibiting thyrotrophic cell viability, and thyroid-stimulating hormone expression and secretion.	('hypothyroidism', 'Disease', 'MESH:D007037', (104, 118))	('inhibiting', 'NegReg', (122, 132))	('thyroid-stimulating hormone expression', 'MPA', (166, 204))	('hypothyroidism', 'Phenotype', 'HP:0000821', (104, 118))	('mitotane', 'Var', (77, 85))	('mitotane', 'Chemical', 'MESH:D008939', (77, 85))	('secretion', 'MPA', (209, 218))	('hypothyroidism', 'Disease', (104, 118))	('central hypothyroidism', 'Phenotype', 'HP:0011787', (96, 118))	('thyrotrophic cell', 'MPA', (133, 150))	('cause', 'Reg', (90, 95))
93149	31115496	In summary, the present findings provide evidence that mitotane inhibits proliferation, promotes apoptosis and induces DNA damage in TC cells.	('promotes', 'PosReg', (88, 96))	('TC', 'Phenotype', 'HP:0002890', (133, 135))	('proliferation', 'CPA', (73, 86))	('mitotane', 'Var', (55, 63))	('mitotane', 'Chemical', 'MESH:D008939', (55, 63))	('DNA damage', 'MPA', (119, 129))	('induces', 'Reg', (111, 118))	('inhibits', 'NegReg', (64, 72))	('apoptosis', 'CPA', (97, 106))
93206	30566905	All 14 CAH patients had a genetically confirmed diagnosis of 21-hydroxylase (CYP21A2) deficiency; 12 had the classic salt-wasting form and two subjects had non-classic CAH.	('salt-wasting', 'Phenotype', 'HP:0000127', (117, 129))	('CAH', 'Phenotype', 'HP:0008258', (168, 171))	('CAH', 'Phenotype', 'HP:0008258', (7, 10))	('salt', 'Chemical', 'MESH:D012492', (117, 121))	('deficiency', 'Var', (86, 96))	('CYP21A2', 'Gene', '1589', (77, 84))	('CAH', 'Disease', (7, 10))	('CYP21A2', 'Gene', (77, 84))	('patients', 'Species', '9606', (11, 19))
93268	30566905	ACC is an extremely rare entity in children, apart from certain geographical areas like Brazil where ACC is more prevalent due to a distinct founder mutation (p.R337H) of the TP53 gene.	('TP53', 'Gene', (175, 179))	('children', 'Species', '9606', (35, 43))	('ACC', 'Phenotype', 'HP:0006744', (101, 104))	('ACC', 'Disease', (101, 104))	('p.R337H', 'Var', (159, 166))	('p.R337H', 'Mutation', 'rs121912664', (159, 166))	('TP53', 'Gene', '7157', (175, 179))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('ACC', 'Disease', (0, 3))
93349	28423361	This discrepancy results most probably from the methods used in the studies, such as microarrays or real-time PCR quantification that do not allow for thorough analysis of all the miRNAs expressed in adrenal cortex and aberrant in adrenocortical tumors.	('adrenocortical tumors', 'Disease', (231, 252))	('aberrant', 'Var', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('miR', 'Gene', '220972', (180, 183))	('miR', 'Gene', (180, 183))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (231, 252))
93352	28423361	An average of 452 thousand (k) reads were aligned to the sequences of mature microRNAs from miRBase with a mean number of 465k, 658k and 234k reads in the ACC, AA and NA groups, respectively.	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('658k', 'Var', (128, 132))
93355	28423361	Individual miRNA genes produced several mature miRNA molecules that differed in length, called isomiRs.	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('genes', 'Var', (17, 22))
93378	28423361	Diagnostic imaging plays an essential role, as the sensitivity and specificity in predicting malignancy were 96% and 52%, respectively, for tumors >= 4cm, while for tumors >= 6cm the parameters reached 90% and 80%.	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Disease', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('malignancy', 'Disease', 'MESH:D009369', (93, 103))	('malignancy', 'Disease', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('>= 4cm', 'Var', (147, 153))
93395	28423361	Sequence variations of many of the isomiRs are based on addition or deletion of nucleotides at their 5'end when compared to the reference miRNA, resulting in a change of the "seed region" and leading to recognition and regulation of distinct sets of target genes.	('the "seed region', 'MPA', (170, 186))	('recognition', 'MPA', (203, 214))	('deletion', 'Var', (68, 76))	('variations', 'Var', (9, 19))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', '220972', (38, 41))	('leading to', 'Reg', (192, 202))	('miR', 'Gene', (38, 41))	('miR', 'Gene', (138, 141))	('regulation', 'MPA', (219, 229))	('change', 'Reg', (160, 166))
93563	24127413	These preliminary results suggest the importance of dysregulated circulating miR-483-5p as a potential HCC biomarker.	('dysregulated', 'Var', (52, 64))	('miR-483', 'Gene', '619552', (77, 84))	('HCC', 'Phenotype', 'HP:0001402', (103, 106))	('miR-483', 'Gene', (77, 84))
93564	24127413	Confirmation of aberrant expression of miR-483-5p in a large prospective HCC study will provide support for its application to HCC detection.	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('miR-483', 'Gene', '619552', (39, 46))	('miR-483', 'Gene', (39, 46))	('HCC', 'Phenotype', 'HP:0001402', (127, 130))	('aberrant expression', 'Var', (16, 35))
93570	24127413	Aberrant miRNA expression has been associated with a variety of cancers, including HCC by examining tumor and non-tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('HCC', 'Phenotype', 'HP:0001402', (83, 86))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (100, 105))	('associated', 'Reg', (35, 45))	('non-tumor', 'Disease', (110, 119))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('tumor', 'Disease', (114, 119))	('cancers', 'Disease', (64, 71))	('non-tumor', 'Disease', 'MESH:D009369', (110, 119))	('HCC', 'Disease', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
93617	24127413	A two-sample t-test assuming equal variance was carried out to compare log2 miRNA levels by categorical covariates of HCC risk factors and clinic-pathological characteristics, including gender (male vs. female), HBsAg (negative vs. positive), anti-HCV (negative vs. positive), cigarette smoking (no vs. yes), alcohol drinking (no vs. yes), AFP (<400ng/mL vs. >=400ng/mL), cirrhosis (no vs. yes), within Milan criteria (yes vs. no), Child-Pugh score (A vs. B), tumor size (<5cm vs. >=5cm), tumor stage (I-II vs. III-IV) and survival (yes vs. no).	('tumor', 'Disease', 'MESH:D009369', (489, 494))	('cirrhosis', 'Phenotype', 'HP:0001394', (372, 381))	('alcohol drinking', 'Phenotype', 'HP:0030955', (309, 325))	('<400ng/mL', 'Var', (345, 354))	('miR', 'Gene', '220972', (76, 79))	('alcohol', 'Chemical', 'MESH:D000438', (309, 316))	('<5cm', 'Var', (472, 476))	('cirrhosis', 'Disease', (372, 381))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (489, 494))	('Child', 'Species', '9606', (432, 437))	('miR', 'Gene', (76, 79))	('tumor', 'Disease', (460, 465))	('tumor', 'Disease', 'MESH:D009369', (460, 465))	('HCV', 'Species', '11103', (248, 251))	('Child-Pugh score', 'Disease', (432, 448))	('AFP', 'Gene', (340, 343))	('tumor', 'Disease', (489, 494))	('tumor', 'Phenotype', 'HP:0002664', (460, 465))	('AFP', 'Gene', '174', (340, 343))	('cirrhosis', 'Disease', 'MESH:D005355', (372, 381))
93639	24127413	Enriched genes were significantly associated with more than 20 biological pathways, including pathways of Hedgehog, interleukin, TGF-beta, EGF receptor/Wnt signaling, p38 MAPK, Ras, p53, PI3 kinase etc.	('Ras', 'Pathway', (177, 180))	('associated', 'Reg', (34, 44))	('PI3', 'Gene', (187, 190))	('Hedgehog', 'Gene', (106, 114))	('p53', 'Gene', '7157', (182, 185))	('p38', 'Var', (167, 170))	('biological pathways', 'Pathway', (63, 82))	('TGF-beta', 'Gene', '7040', (129, 137))	('TGF-beta', 'Gene', (129, 137))	('EGF', 'MPA', (139, 142))	('PI3', 'Gene', '5266', (187, 190))	('p53', 'Gene', (182, 185))
93646	24127413	To increase the specificity of dysregulated miRNA in detecting HCC, we used the 75th percentile among controls as a cutoff point for over-expression.	('dysregulated', 'Var', (31, 43))	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('HCC', 'Disease', (63, 66))	('HCC', 'Phenotype', 'HP:0001402', (63, 66))	('increase', 'PosReg', (3, 11))
93684	23563208	Surgery for Li Fraumeni Syndrome: Pushing the Limits of Surgical Oncology Li Fraumeni syndrome is an autosomal dominant cancer syndrome due to a germline mutation in the p53 tumor suppressor gene.	('tumor', 'Disease', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('due to', 'Reg', (136, 142))	('autosomal dominant cancer syndrome', 'Disease', 'MESH:D009386', (101, 135))	('p53', 'Gene', (170, 173))	('Li Fraumeni syndrome', 'Disease', 'MESH:D016864', (74, 94))	('Li Fraumeni syndrome', 'Disease', (74, 94))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('Oncology', 'Phenotype', 'HP:0002664', (65, 73))	('p53', 'Gene', '7157', (170, 173))	('Li Fraumeni Syndrome', 'Disease', (12, 32))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Li Fraumeni Syndrome', 'Disease', 'MESH:D016864', (12, 32))	('autosomal dominant cancer syndrome', 'Disease', (101, 135))	('germline mutation', 'Var', (145, 162))
93706	23563208	Tumor markers were: CEA 4.7 (range 0.8-3.4), AFP 7.0 (range 0.6-6.6), CA19-9 8 (range 0-55), CA15.3 27 (range 0-30) and CA 27.9 25 (range 0-38).	('CEA', 'Gene', '1084', (20, 23))	('AFP', 'Gene', (45, 48))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CA15.3', 'Var', (93, 99))	('AFP', 'Gene', '174', (45, 48))	('CEA', 'Gene', (20, 23))
93724	23563208	This syndrome has now been linked to germline mutations of p53, a tumor suppressor gene on the short arm of chromosome 17.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('p53', 'Gene', (59, 62))	('linked', 'Reg', (27, 33))	('p53', 'Gene', '7157', (59, 62))	('germline mutations', 'Var', (37, 55))	('tumor', 'Disease', (66, 71))	('short arm', 'Phenotype', 'HP:0009824', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
93725	23563208	These mutations allow for the accumulation of genetic damage, in effect leading to genomic instability and neoplastic formation.	('leading to', 'Reg', (72, 82))	('genetic damage', 'Disease', (46, 60))	('genetic damage', 'Disease', 'MESH:D030342', (46, 60))	('genomic instability', 'CPA', (83, 102))	('neoplastic formation', 'CPA', (107, 127))	('mutations', 'Var', (6, 15))
93764	23563208	The role of radiation stress in human cells containing heterozygous germ-line p53 mutations leads to a defective cell cycle arrest in G1/S and a lesser apoptotic response of lymphocytes.	('cell cycle arrest in G1/S', 'CPA', (113, 138))	('apoptotic response of lymphocytes', 'CPA', (152, 185))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (113, 130))	('mutations', 'Var', (82, 91))	('p53', 'Gene', (78, 81))	('human', 'Species', '9606', (32, 37))	('defective', 'NegReg', (103, 112))	('p53', 'Gene', '7157', (78, 81))
93791	23255991	The chemical shift MRI was suggestive of adrenocortical carcinoma as it demonstrated insufficient intracytoplasmic lipid for a diagnosis of an adrenal adenoma.	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (41, 65))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (41, 65))	('insufficient', 'Disease', (85, 97))	('insufficient', 'Disease', 'MESH:D000309', (85, 97))	('intracytoplasmic lipid', 'MPA', (98, 120))	('chemical', 'Var', (4, 12))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (143, 158))	('adrenal adenoma', 'Disease', 'MESH:D018246', (143, 158))	('adrenocortical carcinoma', 'Disease', (41, 65))	('adrenal adenoma', 'Disease', (143, 158))	('lipid', 'Chemical', 'MESH:D008055', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
93804	23255991	Additionally, pregnancy is associated with weight gain, and often glucose intolerance and hypertension.	('pregnancy', 'Var', (14, 23))	('hypertension', 'Disease', (90, 102))	('weight gain', 'Disease', 'MESH:D015430', (43, 54))	('glucose intolerance', 'Phenotype', 'HP:0001952', (66, 85))	('weight gain', 'Phenotype', 'HP:0004324', (43, 54))	('glucose intolerance', 'Disease', (66, 85))	('hypertension', 'Disease', 'MESH:D006973', (90, 102))	('weight gain', 'Disease', (43, 54))	('glucose', 'Chemical', 'MESH:D005947', (66, 73))	('hypertension', 'Phenotype', 'HP:0000822', (90, 102))
93826	22999104	Pyrimethamine caused growth inhibition in both cell lines at 10 fold of IC50 concentration.	('Pyrimethamine', 'Chemical', 'MESH:D011739', (0, 13))	('Pyrimethamine', 'Var', (0, 13))	('growth inhibition', 'CPA', (21, 38))
93917	22999104	At 0.08 muM, 0.16 muM and 0.8 muM (1 fold, 2 fold and 10 fold of IC50, respectively), ouabain inhibited growth and MCA in both cell lines were significantly smaller.	('0.16 muM', 'Var', (13, 21))	('smaller', 'NegReg', (157, 164))	('growth', 'CPA', (104, 110))	('MCA', 'CPA', (115, 118))	('ouabain', 'Chemical', 'MESH:D010042', (86, 93))	('inhibited', 'NegReg', (94, 103))
93927	22999104	The antiproliferative effect of pyrimethamine in monolayer cultures of NCI-H295R cells was observed only when cells were treated with a concentration of 7.5 muM (10 fold of IC50) (Figure 3D).	('pyrimethamine', 'Chemical', 'MESH:D011739', (32, 45))	('antiproliferative effect', 'CPA', (4, 28))	('NCI-H295R', 'CellLine', 'CVCL:0458', (71, 80))	('pyrimethamine', 'Var', (32, 45))
93928	22999104	At 7.5 muM (10 fold of IC50), pyrimethamine demonstrated antiproliferative effect in SW-13 cells (Figure 3E).	('pyrimethamine', 'Chemical', 'MESH:D011739', (30, 43))	('pyrimethamine', 'Var', (30, 43))	('SW-13', 'CellLine', 'CVCL:0542', (85, 90))	('antiproliferative effect', 'CPA', (57, 81))
93930	22999104	Pyrimethamine caused growth inhibition, and resulted in significantly smaller and fewer MCA of NCI-H295R and SW-13 cells at 7.5 muM concentration (10 fold of IC50) but had no significant difference in size of MCA when either cell line was treated with 3.7 muM pyrimethamine (5 fold of IC50) (Figure 4D and Table 3).	('Pyrimethamine', 'Chemical', 'MESH:D011739', (0, 13))	('Pyrimethamine', 'Var', (0, 13))	('SW-13', 'CellLine', 'CVCL:0542', (109, 114))	('NCI-H295R', 'CellLine', 'CVCL:0458', (95, 104))	('pyrimethamine', 'Chemical', 'MESH:D011739', (260, 273))	('smaller', 'NegReg', (70, 77))	('fewer', 'NegReg', (82, 87))	('MCA', 'CPA', (88, 91))	('growth inhibition', 'CPA', (21, 38))
93931	22999104	Caspase-3 and -7 activities were significantly higher in NCI-H295R cells treated with 0.34 muM Bortezomib (p <0.01) and 0.08 muM ouabain (p < 0.01), compared to vehicle control groups, at 48 hours and 72 hours (p = 0.02 and p = 0.01, respectively) (Figure 5).	('Bortezomib', 'Chemical', 'MESH:D000069286', (95, 105))	('activities', 'MPA', (17, 27))	('Caspase-3 and -7', 'Gene', '836;840', (0, 16))	('ouabain', 'Chemical', 'MESH:D010042', (129, 136))	('NCI-H295R', 'CellLine', 'CVCL:0458', (57, 66))	('higher', 'PosReg', (47, 53))	('0.08 muM', 'Var', (120, 128))	('0.34 muM', 'Var', (86, 94))
93935	22999104	However, we found that 7.5 muM pyrimethamine caused an increase in number of SW-13 cells in S-phase, from 32.7% to 52.7% (Figure 6C).	('pyrimethamine', 'Var', (31, 44))	('increase', 'PosReg', (55, 63))	('SW-13', 'CellLine', 'CVCL:0542', (77, 82))	('pyrimethamine', 'Chemical', 'MESH:D011739', (31, 44))
93958	22999104	The antineoplastic effect of pyrimethamine has been recently demonstrated in melanoma by inducing apoptosis .	('apoptosis', 'CPA', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('pyrimethamine', 'Var', (29, 42))	('antineoplastic effect', 'CPA', (4, 25))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('pyrimethamine', 'Chemical', 'MESH:D011739', (29, 42))	('inducing', 'PosReg', (89, 97))
93959	22999104	On the other hand, pyrimethamine was reported to stimulate the growth of breast cancer cells (MCF-7) .	('pyrimethamine', 'Chemical', 'MESH:D011739', (19, 32))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('growth', 'CPA', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('MCF-7', 'CellLine', 'CVCL:0031', (94, 99))	('breast cancer', 'Disease', (73, 86))	('pyrimethamine', 'Var', (19, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('stimulate', 'PosReg', (49, 58))
93963	22999104	Similarly, we observed an increase of pyrimethamine treated SW-13 cells in S-phase, consistent with a disruption of DNA synthesis caused by DHFR inhibitor .	('SW-13', 'CellLine', 'CVCL:0542', (60, 65))	('pyrimethamine', 'Var', (38, 51))	('DHFR', 'Gene', (140, 144))	('pyrimethamine', 'Chemical', 'MESH:D011739', (38, 51))	('S-phase', 'Disease', (75, 82))	('increase', 'PosReg', (26, 34))	('DHFR', 'Gene', '1719', (140, 144))
93975	22999104	Even drugs that have IC50 above maximal serum level could possibly be administered locally or regionally, such as catheter-based treatment of metastasis confined to the liver, to reduce systemic toxicity.	('toxicity', 'Disease', 'MESH:D064420', (195, 203))	('toxicity', 'Disease', (195, 203))	('IC50', 'Var', (21, 25))
94068	18941403	This report demonstrates that ectopic adrenocortical tumors in the nervous system may exhibit clinicopathologic and cytogenetic features suggestive of adrenocortical carcinoma.	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (151, 175))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (151, 175))	('ectopic', 'Var', (30, 37))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (38, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('tumors in the nervous system', 'Phenotype', 'HP:0004375', (53, 81))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('adrenocortical carcinoma', 'Disease', (151, 175))	('adrenocortical tumors', 'Disease', (38, 59))
94115	18941403	Comparative genomic hybridization has shown aberrations in chromosomes and chromosomal arms 1p, 4q, 5, 11, 12, and 17 to be common in these neoplasms.	('neoplasms', 'Disease', 'MESH:D009369', (140, 149))	('neoplasms', 'Disease', (140, 149))	('common', 'Reg', (124, 130))	('neoplasms', 'Phenotype', 'HP:0002664', (140, 149))	('aberrations', 'Var', (44, 55))	('neoplasm', 'Phenotype', 'HP:0002664', (140, 148))
94117	18941403	We found immunohistochemical overexpression of p53, which suggests the possibility of a TP53 point mutation, a more common mechanism of inactivation in some tumors than large deletions identifiable by FISH.	('overexpression', 'PosReg', (29, 43))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('p53', 'Gene', '7157', (47, 50))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('point mutation', 'Var', (93, 107))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('p53', 'Gene', (47, 50))	('TP53', 'Gene', (88, 92))
94144	22457682	The following were regarded as indications for surgery: tumour size >= 4 cm (until 2004, >= 3 cm), increasing tumour size during follow-up and/or abnormalities of adrenal hormonal function, or findings on imaging studies suggestive of malignancy.	('abnormalities of adrenal', 'Phenotype', 'HP:0000834', (146, 170))	('abnormalities', 'Var', (146, 159))	('increasing', 'PosReg', (99, 109))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('malignancy', 'Disease', 'MESH:D009369', (235, 245))	('tumour', 'Disease', (56, 62))	('tumour', 'Disease', (110, 116))	('malignancy', 'Disease', (235, 245))
94167	22457682	In PHEO patients, increased 24-h urinary excretion of VMA was significantly more frequent than in patients with other adrenal tumours (p = 0.012).	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('PHEO', 'Phenotype', 'HP:0002666', (3, 7))	('increased', 'PosReg', (18, 27))	('PHEO', 'Var', (3, 7))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('24-h urinary excretion of VMA', 'MPA', (28, 57))	('patients', 'Species', '9606', (98, 106))	('adrenal tumours', 'Disease', 'MESH:D000310', (118, 133))	('adrenal tumours', 'Disease', (118, 133))	('VMA', 'Chemical', 'MESH:D014642', (54, 57))	('patients', 'Species', '9606', (8, 16))
94263	22457682	Others believe that the presence of hormonal activity improves survival in this type of cancer.	('presence', 'Var', (24, 32))	('cancer', 'Disease', (88, 94))	('improves', 'PosReg', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('survival', 'CPA', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
94288	20211726	It is not surprising, therefore, that defects in any mechanisms that alter renal Na+ transport may contribute to the net gain or loss of salt (and water).	('loss', 'NegReg', (129, 133))	('gain', 'PosReg', (121, 125))	('loss of salt', 'Phenotype', 'HP:0000127', (129, 141))	('water', 'Chemical', 'MESH:D014867', (147, 152))	('salt', 'Chemical', 'MESH:D012492', (137, 141))	('renal Na+ transport', 'MPA', (75, 94))	('defects', 'Var', (38, 45))
94294	20211726	Importantly, any of several genetic variants (single nucleotide polymorphisms, SNPs), such as those in G-protein coupled receptor kinase type 4, alpha-adducin, or serine/threonine kinase (STK39) genes may favor salt retention by the kidneys and, therefore, predispose the bearers of these genes to salt-dependent hypertension.	('salt', 'MPA', (211, 215))	('salt', 'Chemical', 'MESH:D012492', (298, 302))	('STK39', 'Gene', '54348', (188, 193))	('hypertension', 'Disease', 'MESH:D006973', (313, 325))	('salt', 'Chemical', 'MESH:D012492', (211, 215))	('STK39', 'Gene', (188, 193))	('favor', 'PosReg', (205, 210))	('variants', 'Var', (36, 44))	('hypertension', 'Disease', (313, 325))	('hypertension', 'Phenotype', 'HP:0000822', (313, 325))	('salt retention', 'Phenotype', 'HP:0000127', (211, 225))	('predispose', 'Reg', (257, 267))
94295	20211726	A related, unresolved issue in hypertension, and our main focus, is the specific mechanism(s) or "signaling pathway" by which salt retention actually elevates BP.	('salt', 'Chemical', 'MESH:D012492', (126, 130))	('elevates', 'PosReg', (150, 158))	('hypertension', 'Disease', 'MESH:D006973', (31, 43))	('elevates BP', 'Phenotype', 'HP:0032263', (150, 161))	('hypertension', 'Disease', (31, 43))	('hypertension', 'Phenotype', 'HP:0000822', (31, 43))	('salt retention', 'Phenotype', 'HP:0000127', (126, 140))	('salt', 'Var', (126, 130))
94372	20211726	For example, one striking observation is that mortality from breast cancer was markedly reduced in patients on digitalis therapy; this has prompted greatly renewed interest in CTS and their possible role in cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('cancer', 'Disease', (207, 213))	('CTS', 'Chemical', 'MESH:D002301', (176, 179))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (68, 74))	('digitalis', 'Var', (111, 120))	('reduced', 'NegReg', (88, 95))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
94388	20211726	Certain steroids with trans-trans-cis ring fusions are cardiotonic, while those with cis-trans-trans ring fusions (e.g., common bile salts, 14alpha-digitoxigenin and 14alpha-artebufogenin) are either inactive or very weak.	('cardiotonic', 'Disease', (55, 66))	('bile salts', 'Chemical', 'MESH:D001647', (128, 138))	('steroids', 'Chemical', 'MESH:D013256', (8, 16))	('14alpha-artebufogenin', 'Chemical', '-', (166, 187))	('14alpha-digitoxigenin', 'Chemical', '-', (140, 161))	('trans-trans-cis', 'Var', (22, 37))	('cardiotonic', 'Disease', 'None', (55, 66))
94389	20211726	Addition of one or more sugars to the cardenolide steroid nucleus increases the potency, while inversion of the lactone configuration at C17 from beta to alpha, or saturation (e.g., dihydroouabain and dihydrodigoxin) of the lactone ring, reduces the cardiotonic activity 10-30 fold.	('lactone', 'Chemical', 'MESH:D007783', (112, 119))	('potency', 'MPA', (80, 87))	('inversion', 'Var', (95, 104))	('cardiotonic', 'Disease', 'None', (250, 261))	('increases', 'PosReg', (66, 75))	('lactone', 'Chemical', 'MESH:D007783', (224, 231))	('sugars', 'Chemical', 'MESH:D000073893', (24, 30))	('cardenolide', 'Chemical', 'MESH:D002298', (38, 49))	('reduces', 'NegReg', (238, 245))	('rat', 'Species', '10116', (168, 171))	('rat', 'Species', '10116', (127, 130))	('cardiotonic', 'Disease', (250, 261))	('dihydroouabain', 'Chemical', 'MESH:C000977', (182, 196))	('steroid', 'Chemical', 'MESH:D013256', (50, 57))	('dihydrodigoxin', 'Chemical', 'MESH:C000967', (201, 215))
94392	20211726	Nanomolar ouabain, however, augments myogenic constriction in rodent isolated arteries.	('ouabain', 'Chemical', 'MESH:D010042', (10, 17))	('Nanomolar', 'Var', (0, 9))	('myogenic constriction', 'MPA', (37, 58))	('augments', 'PosReg', (28, 36))
94404	20211726	The depressor activity of the cardenolides appears to be linked with the cis-trans-cis steroid configuration, deoxygenation of the AB ring at C5 and substituents at C17 that augment potency as Na+ pump inhibitors including unsaturated 5- and 6-member lactone rings.	('cardenolides', 'Chemical', 'MESH:D002298', (30, 42))	('augment', 'PosReg', (174, 181))	('cis-trans-cis steroid', 'Chemical', '-', (73, 94))	('lactone', 'Chemical', 'MESH:D007783', (251, 258))	('Na+ pump inhibitors', 'MPA', (193, 212))	('potency', 'MPA', (182, 189))	('rat', 'Species', '10116', (229, 232))	('substituents', 'Var', (149, 161))	('depressor activity', 'MPA', (4, 22))	('linked', 'Reg', (57, 63))	('rat', 'Species', '10116', (102, 105))	('unsaturated 5- and', 'MPA', (223, 241))	('deoxygenation', 'MPA', (110, 123))	('oxygen', 'Chemical', 'MESH:D010100', (112, 118))
94414	20211726	Even in humans, however, where alpha1 Na+ pumps have high affinity for ouabain, partial inhibition of Na+ pumps by nanomolar ouabain will elevate [Na+] in the junctional space much more than in bulk cytosol.	('nanomolar', 'Var', (115, 124))	('ouabain', 'Chemical', 'MESH:D010042', (71, 78))	('alpha1', 'Gene', (31, 37))	('humans', 'Species', '9606', (8, 14))	('inhibition', 'NegReg', (88, 98))	('elevate', 'PosReg', (138, 145))	('ouabain', 'Gene', (125, 132))	('alpha1', 'Gene', '146', (31, 37))	('Na+ pumps', 'MPA', (102, 111))	('ouabain', 'Chemical', 'MESH:D010042', (125, 132))	('[Na+] in the junctional space', 'MPA', (146, 175))
94423	20211726	The fact that chronic administration of exogenous ouabain induces hypertension in rodents has already been mentioned.	('ouabain', 'Chemical', 'MESH:D010042', (50, 57))	('rat', 'Species', '10116', (30, 33))	('hypertension', 'Disease', 'MESH:D006973', (66, 78))	('exogenous', 'Var', (40, 49))	('hypertension', 'Disease', (66, 78))	('hypertension', 'Phenotype', 'HP:0000822', (66, 78))
94424	20211726	The questions we now address are: How does ouabain (or EO) elevate BP?	('elevate', 'PosReg', (59, 66))	('elevate BP', 'Phenotype', 'HP:0032263', (59, 69))	('ouabain', 'Var', (43, 50))	('ouabain', 'Chemical', 'MESH:D010042', (43, 50))
94425	20211726	We have reported that acute application of nanomolar ouabain to isolated, pressurized rodent arteries with myogenic tone augments the tone.	('augments', 'PosReg', (121, 129))	('tone', 'MPA', (134, 138))	('ouabain', 'Chemical', 'MESH:D010042', (53, 60))	('nanomolar', 'Var', (43, 52))
94430	20211726	Moreover, mesenteric small arteries from the alpha2+/-, but not alpha1+/- mice, exhibit augmented myogenic reactivity and myogenic tone (MT).	('myogenic reactivity', 'CPA', (98, 117))	('alpha1', 'Gene', '146', (64, 70))	('myogenic tone', 'CPA', (122, 135))	('mesenteric small arteries', 'Phenotype', 'HP:0011934', (10, 35))	('augmented', 'PosReg', (88, 97))	('alpha1', 'Gene', (64, 70))	('mice', 'Species', '10090', (74, 78))	('alpha2+/-', 'Var', (45, 54))
94432	20211726	The alpha2+/- mice are "global" single allele null mutants, but it is important to determine if the effects are the result of reduced alpha2 Na+ pump activity/expression in ASM.	('alpha2+/-', 'Var', (4, 13))	('alpha2 Na+ pump activity/expression', 'MPA', (134, 169))	('mice', 'Species', '10090', (14, 18))	('reduced', 'NegReg', (126, 133))
94435	20211726	Conversely, mice that overexpress alpha2, but not those overexpress alpha1, Na+ pumps in smooth muscle, have, on average, significantly reduced BP compared to wild type (WT) mice (Fig.	('alpha1', 'Gene', (68, 74))	('Na+ pumps in', 'MPA', (76, 88))	('mice', 'Species', '10090', (174, 178))	('alpha1', 'Gene', '146', (68, 74))	('reduced', 'NegReg', (136, 143))	('mice', 'Species', '10090', (12, 16))	('alpha2', 'Var', (34, 40))	('overexpress', 'Var', (22, 33))
94438	20211726	In isolated arteries, Rostafuroxin counteracts the augmentation of MT by nanomolar ouabain, but not the (ouabain-independent) augmenting effect of reduced alpha2 expression on MT.	('ouabain', 'Chemical', 'MESH:D010042', (105, 112))	('augmentation', 'PosReg', (51, 63))	('nanomolar', 'Var', (73, 82))	('ouabain', 'Chemical', 'MESH:D010042', (83, 90))	('Rostafuroxin', 'Chemical', 'MESH:C106263', (22, 34))
94440	20211726	Alternatively, mice that expressed mutant, ouabain-resistant alpha2 pumps (alpha2R/R) are resistant to ACTH-induced hypertension as well as to ouabain-induced hypertension.	('hypertension', 'Disease', 'MESH:D006973', (116, 128))	('resistant', 'MPA', (90, 99))	('hypertension', 'Disease', (116, 128))	('ouabain', 'Chemical', 'MESH:D010042', (143, 150))	('mutant', 'Var', (35, 41))	('ouabain', 'Chemical', 'MESH:D010042', (43, 50))	('hypertension', 'Disease', 'MESH:D006973', (159, 171))	('hypertension', 'Phenotype', 'HP:0000822', (116, 128))	('hypertension', 'Disease', (159, 171))	('ACTH-induced', 'MPA', (103, 115))	('hypertension', 'Phenotype', 'HP:0000822', (159, 171))	('mice', 'Species', '10090', (15, 19))
94450	20211726	Studies on primary cultured rat arterial myocytes indicated that inhibition of Na+ pumps by nanomolar ouabain augments Ca2+ signaling without elevating bulk cytosolic Na+.	('inhibition', 'NegReg', (65, 75))	('Na+ pumps', 'MPA', (79, 88))	('nanomolar', 'Var', (92, 101))	('Ca2', 'Gene', '54231', (119, 122))	('ouabain', 'Chemical', 'MESH:D010042', (102, 109))	('Ca2', 'Gene', (119, 122))	('augments', 'PosReg', (110, 118))	('rat', 'Species', '10116', (28, 31))
94451	20211726	Even knockout of alpha2 Na+ pumps in cultured cells (astrocytes) had only minimal effect of bulk cytosolic Na+, but a large effect on Ca2+ signaling.	('Ca2', 'Gene', (134, 137))	('knockout', 'Var', (5, 13))	('effect', 'Reg', (124, 130))	('Ca2', 'Gene', '54231', (134, 137))	('bulk cytosolic Na+', 'MPA', (92, 110))
94455	20211726	The elevated BP in the NCX1 overexpressors on high dietary salt is abolished by SEA0400, a selective NCX1 inhibitor, but not if the overexpressed NCX1 contains a G833C mutation, which specifically antagonizes the action of SEA0400.	('SEA0400', 'Chemical', 'MESH:C430918', (223, 230))	('salt', 'Chemical', 'MESH:D012492', (59, 63))	('G833C', 'Var', (162, 167))	('SEA0400', 'Chemical', 'MESH:C430918', (80, 87))	('NCX1', 'Gene', (23, 27))	('elevated BP', 'Phenotype', 'HP:0032263', (4, 15))	('SEA0400', 'Var', (80, 87))	('elevated', 'PosReg', (4, 12))	('abolished', 'NegReg', (67, 76))	('G833C', 'Mutation', 'c.833G>C', (162, 167))
94459	20211726	Indeed, SEA0400 also lowers BP by about 5-10 mm Hg in WT mice and reduces MT by about 10% in isolated arteries from these mice.	('mice', 'Species', '10090', (57, 61))	('mice', 'Species', '10090', (122, 126))	('lowers', 'NegReg', (21, 27))	('SEA0400', 'Chemical', 'MESH:C430918', (8, 15))	('reduces', 'NegReg', (66, 73))	('SEA0400', 'Var', (8, 15))
94460	20211726	SEA0400 also attenuated the increased MT in arteries from alpha2+/- mice, indicating that NCX1 mediates effects that are distal to those of the alpha2 Na+ pumps.	('SEA0400', 'Var', (0, 7))	('mice', 'Species', '10090', (68, 72))	('attenuated', 'NegReg', (13, 23))	('NCX1', 'Gene', (90, 94))	('SEA0400', 'Chemical', 'MESH:C430918', (0, 7))
94462	20211726	The mice with genetically engineered NCX1 demonstrate that this exchanger contributes to long-term BP regulation: increased NCX1 expression increases BP, while knockout of NCX1 reduces BP.	('NCX1', 'Gene', (172, 176))	('increases', 'PosReg', (140, 149))	('knockout', 'Var', (160, 168))	('expression', 'MPA', (129, 139))	('mice', 'Species', '10090', (4, 8))	('increases BP', 'Phenotype', 'HP:0032263', (140, 152))	('increased', 'PosReg', (114, 123))	('rat', 'Species', '10116', (49, 52))	('NCX1', 'Gene', (124, 128))
94464	20211726	In DOCA+salt hypertensive rats, spontaneously hypertensive rats (SHR) on a high salt diet, and Dahl salt-sensitive rats on high salt, SEA0400 markedly reduced BP.	('DOCA+salt', 'Chemical', '-', (3, 12))	('hypertensive', 'Disease', (13, 25))	('rats', 'Species', '10116', (26, 30))	('Dahl salt', 'Chemical', '-', (95, 104))	('reduced', 'NegReg', (151, 158))	('salt', 'Chemical', 'MESH:D012492', (100, 104))	('rats', 'Species', '10116', (59, 63))	('salt', 'Chemical', 'MESH:D012492', (128, 132))	('hypertensive', 'Disease', 'MESH:D006973', (46, 58))	('SEA0400', 'Chemical', 'MESH:C430918', (134, 141))	('salt', 'Chemical', 'MESH:D012492', (80, 84))	('hypertensive', 'Disease', (46, 58))	('rats', 'Species', '10116', (115, 119))	('salt', 'Chemical', 'MESH:D012492', (8, 12))	('hypertensive', 'Disease', 'MESH:D006973', (13, 25))	('SEA0400', 'Var', (134, 141))
94465	20211726	Also, KB-R7943, a less potent blocker, prevents ACTH from elevating BP in mice.	('elevating BP', 'MPA', (58, 70))	('elevating BP', 'Phenotype', 'HP:0032263', (58, 70))	('prevents', 'NegReg', (39, 47))	('ACTH', 'MPA', (48, 52))	('KB-R7943', 'Var', (6, 14))	('mice', 'Species', '10090', (74, 78))
94468	20211726	Importantly, SEA0400 does not lower BP in several salt-independent rat hypertension models: SHR on a normal salt diet, stroke prone-SHR, and the renin-dependent two-kidney/one-clip rat.	('stroke', 'Phenotype', 'HP:0001297', (119, 125))	('hypertension', 'Disease', 'MESH:D006973', (71, 83))	('rat', 'Species', '10116', (67, 70))	('stroke', 'Disease', (119, 125))	('hypertension', 'Disease', (71, 83))	('salt', 'Chemical', 'MESH:D012492', (108, 112))	('renin', 'Gene', (145, 150))	('hypertension', 'Phenotype', 'HP:0000822', (71, 83))	('salt', 'Chemical', 'MESH:D012492', (50, 54))	('stroke', 'Disease', 'MESH:D020521', (119, 125))	('renin', 'Gene', '24715', (145, 150))	('rat', 'Species', '10116', (181, 184))	('SEA0400', 'Chemical', 'MESH:C430918', (13, 20))	('SEA0400', 'Var', (13, 20))
94473	20211726	For example, nanomolar ouabain-induced increases in MT are associated with increases in myocyte [Ca2+]; conversely, reduction of MT by SEA0400 is associated with reduced myocyte [Ca2+].	('Ca2', 'Gene', (179, 182))	('ouabain', 'Chemical', 'MESH:D010042', (23, 30))	('reduced', 'NegReg', (162, 169))	('Ca2', 'Gene', (97, 100))	('SEA0400', 'Chemical', 'MESH:C430918', (135, 142))	('Ca2', 'Gene', '54231', (179, 182))	('reduction', 'NegReg', (116, 125))	('nanomolar', 'Var', (13, 22))	('SEA0400', 'Var', (135, 142))	('increases', 'PosReg', (39, 48))	('Ca2', 'Gene', '54231', (97, 100))	('increases', 'PosReg', (75, 84))
94480	20211726	Nanomolar ouabain increases the myogenic reactivity of normal rodent arteries with a time course of seconds to minutes, and with an apparent EC50 (concentration for half-maximal effect) of 0.6-1.3 nM.	('increases', 'PosReg', (18, 27))	('rat', 'Species', '10116', (154, 157))	('Nanomolar', 'Var', (0, 9))	('ouabain', 'Chemical', 'MESH:D010042', (10, 17))	('myogenic reactivity', 'MPA', (32, 51))
94534	33639858	Except cg23646375 and cg07434244, nine CpG sites (cg02638691, cg06616057, cg08158408, cg08185241, cg09666230, cg14824901, cg17710021, cg26050864 and cg27176828) are among the top 5% important features of DNA methylation.	('cg26050864', 'Var', (134, 144))	('cg23646375', 'Chemical', '-', (7, 17))	('cg02638691', 'Var', (50, 60))	('cg27176828', 'Var', (149, 159))	('cg14824901', 'Var', (110, 120))	('cg09666230', 'Var', (98, 108))	('cg08185241', 'Var', (86, 96))	('cg17710021', 'Var', (122, 132))	('cg06616057', 'Var', (62, 72))	('cg08158408', 'Var', (74, 84))
94535	33639858	This suggests that G0S2 methylation may be one of the biological characteristics of the subtype 1.	('G0S2', 'Gene', (19, 23))	('G0S2', 'Gene', '50486', (19, 23))	('methylation', 'Var', (24, 35))
94536	33639858	Indeed, a recent study confirmed that hypermethylation of the G0S2 locus and decreased G0S2 expression are hallmarks of rapidly recurrent or fatal ACC.	('hypermethylation', 'Var', (38, 54))	('G0S2', 'Gene', '50486', (62, 66))	('G0S2', 'Gene', '50486', (87, 91))	('ACC', 'Phenotype', 'HP:0006744', (147, 150))	('G0S2', 'Gene', (62, 66))	('G0S2', 'Gene', (87, 91))	('decreased', 'NegReg', (77, 86))	('expression', 'MPA', (92, 102))
94537	33639858	Moreover, G0S2 hypermethylation and silencing is exclusive to ACC.	('G0S2', 'Gene', '50486', (10, 14))	('G0S2', 'Gene', (10, 14))	('hypermethylation', 'Var', (15, 31))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('silencing', 'MPA', (36, 45))
94539	33639858	Among the top important features of miRNA expression in this study, four miRNAs (miR-125b-5p, miR-139-3p, miR-139-5p and miR-335-5p) are shown as potential biomarkers in ACC according to previous researches.	('miR-139-3p', 'Gene', (94, 104))	('miR-335', 'Gene', (121, 128))	('ACC', 'Phenotype', 'HP:0006744', (170, 173))	('ACC', 'Disease', (170, 173))	('miR-139-5p', 'Var', (106, 116))	('miR-335', 'Gene', '442904', (121, 128))	('miR-125b-5p', 'Var', (81, 92))	('miR-139-3p', 'Gene', '406931', (94, 104))
94540	33639858	Overexpressed miR-139-5p, and underexpressed miR-125b-5p, miR-139-3p and miR-335-5p were found associated with ACC aggressiveness and poor prognosis.	('miR-139-3p', 'Gene', (58, 68))	('miR-125b-5p', 'Var', (45, 56))	('ACC', 'Phenotype', 'HP:0006744', (111, 114))	('miR-335', 'Gene', (73, 80))	('aggressiveness', 'Disease', 'MESH:D001523', (115, 129))	('miR-139-3p', 'Gene', '406931', (58, 68))	('miR-335', 'Gene', '442904', (73, 80))	('aggressiveness', 'Disease', (115, 129))	('miR-139-5p', 'Var', (14, 24))	('associated', 'Reg', (95, 105))	('aggressiveness', 'Phenotype', 'HP:0000718', (115, 129))
94544	33639858	A recent study has shown that the genomes of rapidly recurrent carcinomas are characterized by aberrant methylation directed to promoter CpG islands.	('carcinomas', 'Disease', 'MESH:D009369', (63, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('methylation', 'MPA', (104, 115))	('carcinomas', 'Disease', (63, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('aberrant', 'Var', (95, 103))
94601	30110910	Cancer is a complex disease and it represents the result of the progressive accumulation of genetic aberrations and epigenetic changes that escaped from the regular cellular and environmental controls.	('epigenetic changes', 'Var', (116, 134))	('genetic aberrations', 'Disease', (92, 111))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('genetic aberrations', 'Disease', 'MESH:D030342', (92, 111))
94602	30110910	Cancer cells usually acquire genetic aberration including aneuploidy, chromosomal rearrangement, loss or gain of function mutations, deletions, gene rearrangements and amplifications.	('deletions', 'Var', (133, 142))	('gain', 'Disease', (105, 109))	('loss', 'NegReg', (97, 101))	('gene rearrangements', 'Var', (144, 163))	('gain', 'Disease', 'MESH:D015430', (105, 109))	('amplifications', 'Var', (168, 182))	('aneuploidy', 'Disease', 'MESH:D000782', (58, 68))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('chromosomal', 'Disease', (70, 81))	('mutations', 'Var', (122, 131))	('aneuploidy', 'Disease', (58, 68))
94614	30110910	Moreover, the antidiarrheal loperamide has been shown to enter into the central nervous system (CNS) (from which it is normally excluded) by the simultaneous administration of the P-gp modulator quinidine, and genetic disruption of P-gp in mice enhances levels of substrate drugs accumulated in the brain, with markedly slower elimination from the circulation, resulting in dramatically increased toxicity to normal tissue.	('genetic disruption', 'Var', (210, 228))	('enhances', 'PosReg', (245, 253))	('quinidine', 'Chemical', 'MESH:D011802', (195, 204))	('P-gp', 'Gene', (232, 236))	('toxicity', 'Disease', 'MESH:D064420', (397, 405))	('mice', 'Species', '10090', (240, 244))	('loperamide', 'Chemical', 'MESH:D008139', (28, 38))	('increased', 'PosReg', (387, 396))	('toxicity', 'Disease', (397, 405))	('levels of substrate drugs', 'MPA', (254, 279))
94625	30110910	Aberrant activation of Hh signaling has been shown to be involved in the initiation, promotion, metastasis, and chemotherapy resistance of a growing number of solid and hematologic tumors.	('metastasis', 'CPA', (96, 106))	('activation', 'PosReg', (9, 19))	('hematologic tumors', 'Disease', (169, 187))	('Aberrant', 'Var', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('promotion', 'CPA', (85, 94))	('chemotherapy resistance', 'CPA', (112, 135))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('hematologic tumors', 'Disease', 'MESH:D006402', (169, 187))	('involved', 'Reg', (57, 65))
94627	30110910	The major mechanisms by which the Hh pathway is aberrantly activated in cancer can be attributed to mutations of Hh pathway constituents (Type I: ligand-independent), excessive expression of Hh pathway ligands (Type II-IIIb: ligand-dependent), and the generation of a cancer stem cell (CSC) phenotype (Type IV) (Table 2).	('mutations', 'Var', (100, 109))	('cancer', 'Disease', (268, 274))	('Hh pathway', 'Pathway', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('activated', 'PosReg', (59, 68))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Hh pathway', 'Pathway', (191, 201))	('cancer', 'Disease', (72, 78))
94645	30110910	The molecules/signaling pathways that can bypass the ligand-receptor signaling axis to activate Hh signaling, including Kras signaling, TGFbeta, PI3K, PKC, and epigenetic regulators.	('PKC', 'Disease', (151, 154))	('epigenetic regulators', 'Var', (160, 181))	('activate', 'PosReg', (87, 95))	('PKC', 'Disease', 'MESH:C537180', (151, 154))
94655	30110910	Interestingly, significant associations were observed between high Ptch1 and Gli1 expression with large tumor size, locoregional progression, and an incomplete response to chemotherapy.	('Gli1', 'Gene', '2735', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Ptch1', 'Gene', '5727', (67, 72))	('Ptch1', 'Gene', (67, 72))	('tumor', 'Disease', (104, 109))	('locoregional progression', 'CPA', (116, 140))	('Gli1', 'Gene', (77, 81))	('high', 'Var', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
94658	30110910	Hence, there are multiple lines of evidence that suggest that Ptch1 expression may contribute to cancer resistance to chemotherapy.	('cancer', 'Disease', (97, 103))	('expression', 'Var', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Ptch1', 'Gene', '5727', (62, 67))	('Ptch1', 'Gene', (62, 67))	('contribute', 'Reg', (83, 93))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
94669	30110910	Indeed, blocking Ptch1 SSD activity in Drosophila causes not only endosomal lipid accumulation, but also alters the trafficking of Smo from endosomes.	('trafficking of Smo from endosomes', 'MPA', (116, 149))	('Drosophila', 'Species', '7227', (39, 49))	('alters', 'Reg', (105, 111))	('blocking', 'Var', (8, 16))	('Ptch1', 'Gene', '5727', (17, 22))	('lipid', 'Chemical', 'MESH:D008055', (76, 81))	('endosomal lipid accumulation', 'MPA', (66, 94))	('Ptch1', 'Gene', (17, 22))	('activity', 'MPA', (27, 35))
94677	30110910	Defective regulation of cholesterol biosynthesis could further aggravate impaired Hh signaling in holoprosencephaly which is the most severe form of SLOS.	('aggravate', 'PosReg', (63, 72))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (98, 115))	('SLOS', 'Disease', (149, 153))	('impaired Hh signaling', 'MPA', (73, 94))	('holoprosencephaly', 'Disease', 'MESH:D016142', (98, 115))	('SLOS', 'Disease', 'MESH:D019082', (149, 153))	('cholesterol biosynthesis', 'MPA', (24, 48))	('cholesterol', 'Chemical', 'MESH:D002784', (24, 35))	('Defective', 'Var', (0, 9))	('holoprosencephaly', 'Disease', (98, 115))
94680	30110910	Notably, of the many mutations in Ptch1 that are known to be associated with Gorlin's syndrome, three affect these two conserved residues, strongly suggesting the existence of a function that is conserved between the RND family and Ptch1.	('Ptch1', 'Gene', (232, 237))	("Gorlin's syndrome", 'Disease', 'MESH:D001478', (77, 94))	('Ptch1', 'Gene', '5727', (232, 237))	("Gorlin's syndrome", 'Disease', (77, 94))	('Ptch1', 'Gene', (34, 39))	('Ptch1', 'Gene', '5727', (34, 39))	('associated', 'Reg', (61, 71))	('affect', 'Reg', (102, 108))	('mutations', 'Var', (21, 30))
94681	30110910	These mutations were shown to inhibit Ptch1 suppression activity on the Hh pathway.	('activity', 'MPA', (56, 64))	('inhibit', 'NegReg', (30, 37))	('Hh pathway', 'Pathway', (72, 82))	('Ptch1', 'Gene', '5727', (38, 43))	('Ptch1', 'Gene', (38, 43))	('mutations', 'Var', (6, 15))
94686	30110910	They reported that the expression of Ptch1 in S. cerevisiae increased the efflux of doxorubicin, and conferred resistance on yeast to this chemotherapeutic agent, which is used to treat recurrent cases of cancers.	('resistance', 'MPA', (111, 121))	('Ptch1', 'Gene', '5727', (37, 42))	('doxorubicin', 'Chemical', 'MESH:D004317', (84, 95))	('efflux of doxorubicin', 'MPA', (74, 95))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('Ptch1', 'Gene', (37, 42))	('conferred', 'Reg', (101, 110))	('cancers', 'Disease', (205, 212))	('expression', 'Var', (23, 33))	('S. cerevisiae', 'Species', '4932', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('yeast', 'Species', '4932', (125, 130))	('increased', 'PosReg', (60, 69))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
94687	30110910	They showed that this doxorubicin efflux was dependent on the proton motive force, and that yeast expressing Ptch1 protein carrying the double mutation G509VD513Y in the transport GXXXD motif were significantly less resistant to doxorubicin, and transported significantly less doxorubicin than yeast expressing wild-type Ptch1.	('yeast', 'Species', '4932', (92, 97))	('doxorubicin', 'Chemical', 'MESH:D004317', (22, 33))	('doxorubicin efflux', 'MPA', (22, 40))	('less', 'NegReg', (211, 215))	('doxorubicin', 'Chemical', 'MESH:D004317', (229, 240))	('Ptch1', 'Gene', '5727', (321, 326))	('yeast', 'Species', '4932', (294, 299))	('Ptch1', 'Gene', (321, 326))	('doxorubicin', 'Chemical', 'MESH:D004317', (277, 288))	('Ptch1', 'Gene', '5727', (109, 114))	('resistant to doxorubicin', 'MPA', (216, 240))	('Ptch1', 'Gene', (109, 114))	('transported', 'MPA', (246, 257))	('G509VD513Y', 'Var', (152, 162))	('less', 'NegReg', (272, 276))
94689	30110910	They also showed that Ptch1 expression allows yeast to efflux the antiseptic acriflavine as efficiently as doxorubicin.	('acriflavine', 'Chemical', 'MESH:D000167', (77, 88))	('efflux the antiseptic acriflavine', 'MPA', (55, 88))	('Ptch1', 'Gene', '5727', (22, 27))	('Ptch1', 'Gene', (22, 27))	('expression', 'Var', (28, 38))	('yeast', 'Species', '4932', (46, 51))	('doxorubicin', 'Chemical', 'MESH:D004317', (107, 118))
94693	30110910	Furthermore, they showed that the presence of Shh increased the cytotoxicity of doxorubicin on melanoma cells.	('cytotoxicity', 'Disease', (64, 76))	('Shh', 'Gene', (46, 49))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('increased', 'PosReg', (50, 59))	('melanoma', 'Disease', (95, 103))	('cytotoxicity', 'Disease', 'MESH:D064420', (64, 76))	('doxorubicin', 'Chemical', 'MESH:D004317', (80, 91))	('presence', 'Var', (34, 42))
94718	30110910	In a recent study, Hasanovic and co-workers showed that methiothepin, a serotonin transporter antagonist, significantly enhances the cytotoxic, pro-apoptotic, anti-proliferative, and anti-clonogenic effects of doxorubicin on ACC cells by inhibiting the doxorubicin efflux activity of Ptch1.	('anti-clonogenic effects', 'CPA', (183, 206))	('ACC', 'Phenotype', 'HP:0006744', (225, 228))	('methiothepin', 'Chemical', 'MESH:D008719', (56, 68))	('doxorubicin', 'Chemical', 'MESH:D004317', (253, 264))	('Ptch1', 'Gene', (284, 289))	('Ptch1', 'Gene', '5727', (284, 289))	('enhances', 'PosReg', (120, 128))	('cytotoxic', 'CPA', (133, 142))	('doxorubicin', 'Chemical', 'MESH:D004317', (210, 221))	('doxorubicin efflux activity', 'MPA', (253, 280))	('inhibiting', 'NegReg', (238, 248))	('anti-proliferative', 'CPA', (159, 177))	('pro-apoptotic', 'CPA', (144, 157))	('methiothepin', 'Var', (56, 68))
94733	30110910	Since methiothepin strongly increases doxorubicin efficacy and specifically inhibits Ptch1 doxorubicin efflux in cancer cells, the effective dose of doxorubicin received by patients could be reduced, thereby inducing less impairment in cardiac function.	('impairment in cardiac function', 'Phenotype', 'HP:0001635', (222, 252))	('increases', 'PosReg', (28, 37))	('doxorubicin efficacy', 'MPA', (38, 58))	('doxorubicin', 'Chemical', 'MESH:D004317', (91, 102))	('patients', 'Species', '9606', (173, 181))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('doxorubicin', 'Chemical', 'MESH:D004317', (149, 160))	('cardiac function', 'MPA', (236, 252))	('reduced', 'NegReg', (191, 198))	('inhibits', 'NegReg', (76, 84))	('Ptch1', 'Gene', (85, 90))	('cancer', 'Disease', (113, 119))	('doxorubicin', 'Chemical', 'MESH:D004317', (38, 49))	('Ptch1', 'Gene', '5727', (85, 90))	('inducing', 'Reg', (208, 216))	('methiothepin', 'Var', (6, 18))	('methiothepin', 'Chemical', 'MESH:D008719', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
94749	26831715	Erlotinib is a potent first-generation inhibitor of EGFR, and is an established first-line therapy for patients with NSCLC positive for exon 19 deletions or exon 21 mutations.	('exon 21 mutations', 'Var', (157, 174))	('NSCLC', 'Disease', (117, 122))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('exon 19 deletions', 'Var', (136, 153))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('patients', 'Species', '9606', (103, 111))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))
94756	26831715	INSR-A signaling can compensate for IGF1R inhibition, and coinhibition of IGF1R and INSR may provide enhanced antitumor activity.	('INSR', 'Gene', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('INSR', 'Gene', '3643', (0, 4))	('IGF1R', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('IGF1R', 'Gene', '3480', (74, 79))	('INSR', 'Gene', (0, 4))	('tumor', 'Disease', (114, 119))	('IGF1R', 'Gene', '3480', (36, 41))	('enhanced', 'PosReg', (101, 109))	('INSR', 'Gene', '3643', (84, 88))	('coinhibition', 'Var', (58, 70))	('IGF1R', 'Gene', (74, 79))
94759	26831715	Combined IGF1R/INSR and EGFR blockade may enhance inhibition of common downstream signaling pathways, and suppress resistance to single receptor blockade.	('blockade', 'Var', (29, 37))	('EGFR', 'Gene', '1956', (24, 28))	('INSR', 'Gene', (15, 19))	('resistance to single receptor blockade', 'MPA', (115, 153))	('common downstream signaling pathways', 'Pathway', (64, 100))	('enhance', 'PosReg', (42, 49))	('EGFR', 'Gene', (24, 28))	('IGF1R', 'Gene', '3480', (9, 14))	('INSR', 'Gene', '3643', (15, 19))	('inhibition', 'MPA', (50, 60))	('suppress', 'NegReg', (106, 114))	('IGF1R', 'Gene', (9, 14))
94760	26831715	Preclinical data indicate that IGF1R mediates acquired resistance to erlotinib in lung cancers with wild-type EGFR, and combined inhibition of IGF1R/INSR and EGFR results in supra-additive inhibition of tumor growth in vitro and in vivo in NSCLC, breast, pancreatic, and colorectal cancer (CRC; refs.).	('tumor', 'Disease', (203, 208))	('EGFR', 'Gene', '1956', (110, 114))	('lung cancers', 'Disease', 'MESH:D008175', (82, 94))	('colorectal cancer', 'Disease', (271, 288))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('CRC', 'Phenotype', 'HP:0003003', (290, 293))	('lung cancers', 'Disease', (82, 94))	('EGFR', 'Gene', '1956', (158, 162))	('INSR', 'Gene', (149, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('inhibition', 'Var', (129, 139))	('lung cancers', 'Phenotype', 'HP:0100526', (82, 94))	('pancreatic', 'Disease', 'MESH:D010195', (255, 265))	('IGF1R', 'Gene', '3480', (143, 148))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('inhibition', 'NegReg', (189, 199))	('IGF1R', 'Gene', '3480', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('as', 'Chemical', 'MESH:D001151', (250, 252))	('colorectal cancer', 'Phenotype', 'HP:0003003', (271, 288))	('EGFR', 'Gene', (110, 114))	('NSCLC', 'Disease', 'MESH:D002289', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('IGF1R', 'Gene', (143, 148))	('mediates', 'Reg', (37, 45))	('rectal cancer', 'Phenotype', 'HP:0100743', (275, 288))	('IGF1R', 'Gene', (31, 36))	('erlotinib', 'Chemical', 'MESH:D000069347', (69, 78))	('breast', 'Disease', (247, 253))	('pancreatic', 'Disease', (255, 265))	('EGFR', 'Gene', (158, 162))	('NSCLC', 'Disease', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('INSR', 'Gene', '3643', (149, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (271, 288))	('NSCLC', 'Phenotype', 'HP:0030358', (240, 245))
94766	26831715	Patients were required to be nonsmokers for >=3 months prior to study entry, have a negative urine cotinine test, and have adequate cardiac, hematopoietic, hepatic, and renal function, including corrected QT interval (QTc) <=450 ms with no concurrent use of drugs that may prolong QTc, fasting glucose <=125 mg/dL (7.0 mmol/L), and blood ketones equal to or below the upper limit of normal.	('QTc', 'Chemical', '-', (281, 284))	('ketones', 'Chemical', 'MESH:D007659', (338, 345))	('glucose', 'MPA', (294, 301))	('QTc', 'MPA', (281, 284))	('cotinine', 'Chemical', 'MESH:D003367', (99, 107))	('blood ketones', 'MPA', (332, 345))	('<=125', 'NegReg', (302, 307))	('Patients', 'Species', '9606', (0, 8))	('negative urine', 'Phenotype', 'HP:0100519', (84, 98))	('<=450', 'Var', (223, 228))	('prolong', 'PosReg', (273, 280))	('glucose', 'Chemical', 'MESH:D005947', (294, 301))	('blood ketones', 'Phenotype', 'HP:0410175', (332, 345))	('QTc', 'Chemical', '-', (218, 221))	('as', 'Chemical', 'MESH:D001151', (287, 289))
94842	26831715	Prolonged QTc occurred in 9 patients (10%; see Table 2B): grade 1 in 2 patients (S1: 450/100 mg and S2: 300/150 mg), grade 2 in 5 patients (S1: 400/150 mg, 1 case, and 450/150 mg, 2 cases; S2: 1 case at 400/150 mg; NSCLC expansion cohort: 1 case at 150/150 mg), and grade 3 in 2 patients (S1: 450/150 mg and S2: 400/150 mg); 7 of these were attributed to linsitinib.	('as', 'Chemical', 'MESH:D001151', (183, 185))	('Prolonged QTc', 'Phenotype', 'HP:0005184', (0, 13))	('patients', 'Species', '9606', (71, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (215, 220))	('S1: 400/150 mg', 'Var', (140, 154))	('QTc', 'Chemical', '-', (10, 13))	('as', 'Chemical', 'MESH:D001151', (196, 198))	('patients', 'Species', '9606', (130, 138))	('linsitinib', 'Chemical', 'MESH:C551528', (355, 365))	('as', 'Chemical', 'MESH:D001151', (159, 161))	('patients', 'Species', '9606', (279, 287))	('NSCLC', 'Disease', (215, 220))	('S2: 300/150 mg', 'Var', (100, 114))	('NSCLC', 'Disease', 'MESH:D002289', (215, 220))	('patients', 'Species', '9606', (28, 36))	('S1: 450/100 mg', 'Var', (81, 95))	('as', 'Chemical', 'MESH:D001151', (242, 244))
94874	26831715	Of the 5 PR patients, analysis of ctDNA detected an EGFR exon 19 deletion in 1 patient with NSCLC, and PIK3CA exon 9 mutation in the spinal chordoma, although the latter was not detected in tumor DNA.	('patients', 'Species', '9606', (12, 20))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('EGFR', 'Gene', '1956', (52, 56))	('spinal chordoma', 'Disease', 'MESH:D002817', (133, 148))	('EGFR', 'Gene', (52, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('chordoma', 'Phenotype', 'HP:0010762', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('as', 'Chemical', 'MESH:D001151', (171, 173))	('PIK3CA', 'Gene', (103, 109))	('spinal chordoma', 'Disease', (133, 148))	('tumor', 'Disease', (190, 195))	('patient', 'Species', '9606', (79, 86))	('NSCLC', 'Disease', (92, 97))	('patient', 'Species', '9606', (12, 19))	('PIK3CA', 'Gene', '5290', (103, 109))	('deletion', 'Var', (65, 73))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))
94875	26831715	Mutations in EGFR, KRAS, PIK3CA, and BRAF were not detected in plasma or tumor DNA of the other 3 patients achieving PR: 2 with NSCLC, including the patient shown in Fig.	('patient', 'Species', '9606', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('NSCLC', 'Disease', (128, 133))	('KRAS', 'Gene', '3845', (19, 23))	('PIK3CA', 'Gene', '5290', (25, 31))	('EGFR', 'Gene', '1956', (13, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('KRAS', 'Gene', (19, 23))	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (149, 156))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('patients', 'Species', '9606', (98, 106))	('PIK3CA', 'Gene', (25, 31))	('tumor', 'Disease', (73, 78))	('EGFR', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('as', 'Chemical', 'MESH:D001151', (65, 67))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))
94877	26831715	EGFR exon 19 mutations were detected in ctDNA of 2 further NSCLC patients, both treated at the RP2D in the NSCLC expansion cohort.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('NSCLC', 'Disease', (107, 112))	('detected', 'Reg', (28, 36))	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('ctDNA', 'Disease', (40, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('patients', 'Species', '9606', (65, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('mutations', 'Var', (13, 22))	('EGFR', 'Gene', '1956', (0, 4))	('NSCLC', 'Disease', (59, 64))
94878	26831715	Neither responded to trial therapy; both cases had received prior erlotinib and also harbored the exon 20 T790M mutation associated with erlotinib resistance.	('associated', 'Reg', (121, 131))	('T790M', 'Mutation', 'rs121434569', (106, 111))	('as', 'Chemical', 'MESH:D001151', (42, 44))	('T790M', 'Var', (106, 111))	('as', 'Chemical', 'MESH:D001151', (121, 123))	('erlotinib', 'Chemical', 'MESH:D000069347', (137, 146))	('erlotinib', 'Chemical', 'MESH:D000069347', (66, 75))
94879	26831715	A CRC patient with brief SD as best response had ctDNA mutations in both PIK3CA (E542K) and KRAS (G12V).	('PIK3CA', 'Gene', '5290', (73, 79))	('as', 'Chemical', 'MESH:D001151', (28, 30))	('patient', 'Species', '9606', (6, 13))	('KRAS', 'Gene', (92, 96))	('E542K', 'Var', (81, 86))	('G12V', 'Mutation', 'rs121913529', (98, 102))	('CRC', 'Phenotype', 'HP:0003003', (2, 5))	('PIK3CA', 'Gene', (73, 79))	('KRAS', 'Gene', '3845', (92, 96))	('E542K', 'Mutation', 'rs121913273', (81, 86))
94880	26831715	KRAS codon 12 mutations were also detected in the plasma and tumor DNA of 2 NSCLC patients, both with SD as best response (duration 6 weeks, 30 weeks).	('as', 'Chemical', 'MESH:D001151', (105, 107))	('patients', 'Species', '9606', (82, 90))	('NSCLC', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('as', 'Chemical', 'MESH:D001151', (52, 54))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (61, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('KRAS', 'Gene', '3845', (0, 4))
94889	26831715	In contrast thrombocytopenia and neutropenia were reported in studies of IGF-1R antibodies but were not observed with linsitinib.	('IGF-1R', 'Gene', (73, 79))	('neutropenia', 'Phenotype', 'HP:0001875', (33, 44))	('as', 'Chemical', 'MESH:D001151', (8, 10))	('thrombocytopenia', 'Disease', 'MESH:D013921', (12, 28))	('linsitinib', 'Chemical', 'MESH:C551528', (118, 128))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (12, 28))	('IGF-1R', 'Gene', '3480', (73, 79))	('neutropenia', 'Disease', (33, 44))	('thrombocytopenia', 'Disease', (12, 28))	('antibodies', 'Var', (80, 90))	('neutropenia', 'Disease', 'MESH:D009503', (33, 44))
94899	26831715	IGF1R inhibition induces an increase in circulating IGF-1, attributed to hypothalamic-pituitary axis activation in response to pituitary IGF1R blockade.	('IGF1R', 'Gene', '3480', (137, 142))	('hypothalamic-pituitary axis', 'Disease', 'MESH:D007029', (73, 100))	('as', 'Chemical', 'MESH:D001151', (33, 35))	('IGF1R', 'Gene', (0, 5))	('IGF1R', 'Gene', (137, 142))	('hypothalamic-pituitary axis', 'Disease', (73, 100))	('inhibition', 'Var', (6, 16))	('circulating', 'MPA', (40, 51))	('IGF-1', 'Gene', '3479', (52, 57))	('IGF1R', 'Gene', '3480', (0, 5))	('IGF-1', 'Gene', (52, 57))	('increase', 'PosReg', (28, 36))
94907	26831715	Also in NSCLC, R1507 was tolerable with erlotinib; there was no progression-free survival or overall survival advantage over erlotinib alone in unselected patients, but the 12-week progression-free survival rate in patients with KRAS-mutant tumors was 36% for R1507 versus 0% on the placebo arm.	('patients', 'Species', '9606', (215, 223))	('NSCLC', 'Phenotype', 'HP:0030358', (8, 13))	('NSCLC', 'Disease', 'MESH:D002289', (8, 13))	('erlotinib', 'Chemical', 'MESH:D000069347', (125, 134))	('as', 'Chemical', 'MESH:D001151', (22, 24))	('as', 'Chemical', 'MESH:D001151', (249, 251))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('erlotinib', 'Chemical', 'MESH:D000069347', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('KRAS', 'Gene', (229, 233))	('as', 'Chemical', 'MESH:D001151', (58, 60))	('KRAS', 'Gene', '3845', (229, 233))	('NSCLC', 'Disease', (8, 13))	('patients', 'Species', '9606', (155, 163))	('R1507', 'Var', (260, 265))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
94911	26831715	Functionally significant KRAS mutations were detected in 2 NSCLC patients, both of whom had SD, one durable.	('detected', 'Reg', (45, 53))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('mutations', 'Var', (30, 39))	('patients', 'Species', '9606', (65, 73))	('KRAS', 'Gene', (25, 29))	('NSCLC', 'Disease', (59, 64))	('KRAS', 'Gene', '3845', (25, 29))
94912	26831715	There are conflicting reports of the association of RAS mutation and/or RAS-MEK-ERK pathway activation with response to IGF1R inhibition, some (including the clinical R1507 study highlighted above) supporting association with sensitivity to IGF1R inhibition, and others with resistance.	('as', 'Chemical', 'MESH:D001151', (37, 39))	('activation', 'PosReg', (92, 102))	('IGF1R', 'Gene', (120, 125))	('ERK', 'Gene', (80, 83))	('ERK', 'Gene', '2048', (80, 83))	('as', 'Chemical', 'MESH:D001151', (209, 211))	('RAS', 'Gene', (52, 55))	('IGF1R', 'Gene', (241, 246))	('IGF1R', 'Gene', '3480', (120, 125))	('mutation', 'Var', (56, 64))	('IGF1R', 'Gene', '3480', (241, 246))
94913	26831715	EGFR mutations were detected in ctDNA of 3 of 30 NSCLC cases, consistent with the published incidence (10%-13%) of NSCLC EGFR mutations.	('detected', 'Reg', (20, 28))	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (49, 54))	('EGFR', 'Gene', '1956', (121, 125))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('EGFR', 'Gene', (121, 125))	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('as', 'Chemical', 'MESH:D001151', (56, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('EGFR', 'Gene', '1956', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
94914	26831715	The clinical response in a patient with EGFR exon 19-deleted NSCLC (Table 4B) is consistent with the association between this mutation and erlotinib sensitivity, and the additional "gatekeeper" EGFR T790M mutation, detected in 2 nonresponders here, with erlotinib resistance.	('as', 'Chemical', 'MESH:D001151', (101, 103))	('erlotinib', 'Chemical', 'MESH:D000069347', (139, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('erlotinib sensitivity', 'MPA', (139, 160))	('patient', 'Species', '9606', (27, 34))	('T790M', 'Mutation', 'rs121434569', (199, 204))	('EGFR', 'Gene', '1956', (40, 44))	('gatekeeper', 'Species', '111938', (182, 192))	('EGFR', 'Gene', (40, 44))	('NSCLC', 'Disease', (61, 66))	('T790M', 'Var', (199, 204))	('EGFR', 'Gene', (194, 198))	('association', 'Interaction', (101, 112))	('EGFR', 'Gene', '1956', (194, 198))	('erlotinib', 'Chemical', 'MESH:D000069347', (254, 263))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
94915	26831715	The presence of only 2 informative cases harboring EGFR T790M is insufficient to assess activity of the linsitinib/erlotinib combination in this setting.	('erlotinib', 'Chemical', 'MESH:D000069347', (115, 124))	('T790M', 'Var', (56, 61))	('linsitinib', 'Chemical', 'MESH:C551528', (104, 114))	('as', 'Chemical', 'MESH:D001151', (36, 38))	('as', 'Chemical', 'MESH:D001151', (81, 83))	('EGFR', 'Gene', (51, 55))	('insufficient', 'Disease', (65, 77))	('insufficient', 'Disease', 'MESH:D000309', (65, 77))	('T790M', 'Mutation', 'rs121434569', (56, 61))	('EGFR', 'Gene', '1956', (51, 55))
94921	26831715	Mutation analysis identified EGFR mutations in 3 non-small cell lung cancer patients, correlating with response (exon 19 del, 1 case) or resistance (exon 19 del, T790M, 2 cases) to trial therapy.	('response', 'MPA', (103, 111))	('T790M', 'Var', (162, 167))	('patients', 'Species', '9606', (76, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('as', 'Chemical', 'MESH:D001151', (129, 131))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('exon 19 del', 'Var', (149, 160))	('as', 'Chemical', 'MESH:D001151', (172, 174))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('resistance', 'MPA', (137, 147))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (49, 75))	('exon 19 del', 'Var', (113, 124))	('T790M', 'Mutation', 'rs121434569', (162, 167))	('mutations', 'Var', (34, 43))	('non-small cell lung cancer', 'Disease', (49, 75))
94922	26831715	There was also evidence of clinical activity in tumors lacking detectable EGFR mutation, unlikely to respond to single-agent erlotinib.	('erlotinib', 'Chemical', 'MESH:D000069347', (125, 134))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('as', 'Chemical', 'MESH:D001151', (7, 9))	('EGFR', 'Gene', '1956', (74, 78))	('mutation', 'Var', (79, 87))	('EGFR', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
94951	28030838	Such Smac mimetics, like the monovalent compounds GDC-0152 and GDC-0917 (CUDC-427) and the bivalent compound TL32711 (Birinapant) are being investigated in more than twenty phase I and II clinical trials in solid cancers and hematologic tumors (ClinicalTrials.gov).	('CUDC-427', 'Chemical', '-', (73, 81))	('GDC-0917', 'Var', (63, 71))	('hematologic tumors', 'Disease', 'MESH:D006402', (225, 243))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('hematologic tumors', 'Disease', (225, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('Smac', 'Gene', (5, 9))	('TL32711', 'Chemical', 'MESH:C582429', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('GDC-0152', 'Chemical', 'MESH:C579046', (50, 58))	('GDC-0917', 'Chemical', '-', (63, 71))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('cancers', 'Disease', (213, 220))	('Smac', 'Gene', '56616', (5, 9))
94958	28030838	In a previous study on genomic alterations in adrenocortical tumors, we identified recurrent copy number gains at the region 20q13.3 (including the gene BIRC7) in 6/24 ACA (25%) and in 14/22 ACC (68%).	('ACC', 'Phenotype', 'HP:0006744', (191, 194))	('adrenocortical tumors', 'Disease', (46, 67))	('copy number gains', 'Var', (93, 110))	('BIRC7', 'Gene', '79444', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (46, 67))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('ACA', 'Disease', (168, 171))	('BIRC7', 'Gene', (153, 158))
94959	28030838	Looking at other genes involved in the pathway of BIRC7, we found frequent copy number gains also in chromosomal region 12q (including DIABLO) in 11/22 ACC (50%).	('BIRC7', 'Gene', (50, 55))	('ACC', 'Phenotype', 'HP:0006744', (152, 155))	('DIABLO', 'Gene', (135, 141))	('DIABLO', 'Gene', '56616', (135, 141))	('BIRC7', 'Gene', '79444', (50, 55))	('copy number gains', 'Var', (75, 92))
94967	28030838	Accordingly, when we analyzed the paired tumor/adjacent normal adrenal samples, livin was consistently higher in tumors (in both ACC and ACA) than in adjacent adrenal tissues (0.101 +- 0.131 vs 0.008 +- 0.016 and 0.001 +- 0.002 vs 0.0003 +- 0.0018 in ACC and ACA vs adjacent NAG, respectively; Figure 1B and 1C).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (113, 118))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', (41, 46))	('0.101 +- 0.131', 'Var', (176, 190))	('livin', 'Gene', (80, 85))	('ACC', 'Phenotype', 'HP:0006744', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('NAG', 'Chemical', '-', (275, 278))	('ACC', 'Phenotype', 'HP:0006744', (251, 254))	('higher', 'PosReg', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('0.001 +- 0.002 vs 0.0003 +- 0.0018', 'Var', (213, 247))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('livin', 'Gene', '79444', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
94971	28030838	DIABLO mRNA levels were similar between NAG (0.245 +- 0.179) and adrenocortical tumors (0.241 +- 0.204 and 0.232 +- 0.189, respectively in ACC and ACA).	('DIABLO', 'Gene', (0, 6))	('DIABLO', 'Gene', '56616', (0, 6))	('NAG', 'Chemical', '-', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('0.241 +- 0.204', 'Var', (88, 102))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (65, 86))	('adrenocortical tumors', 'Disease', (65, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('ACC', 'Phenotype', 'HP:0006744', (139, 142))	('ACC', 'Disease', (139, 142))	('ACA', 'Disease', (147, 150))	('0.232 +- 0.189', 'Var', (107, 121))
94996	28030838	In particular, cytoplasmic livin protein staining was higher in ACT showing high livin mRNA levels (n = 16, of which 14 with H-score 2-3) as compared with ACT with low mRNA levels (n = 15, of which 9 with H-score 2-3, p < 0.0001 by Chi-squared test).	('H-score 2-3', 'Var', (125, 136))	('higher', 'PosReg', (54, 60))	('livin', 'Gene', (27, 32))	('livin', 'Gene', '79444', (27, 32))	('livin', 'Gene', (81, 86))	('livin', 'Gene', '79444', (81, 86))
94998	28030838	In this group, we observed a recurrent copy number (CN) gain at the region 20q13.3 including the gene BIRC7 in 6 ACA and 8 ACC.	('BIRC7', 'Gene', (102, 107))	('copy number', 'Var', (39, 50))	('gain', 'PosReg', (56, 60))	('ACC', 'Phenotype', 'HP:0006744', (123, 126))	('BIRC7', 'Gene', '79444', (102, 107))
95048	28030838	Nachmias and colleagues demonstrated that the full-length livin protein, which is associated with anti-apoptotic activity, is detected exclusively in the cytoplasm, whereas the accumulation of truncated livin in the nucleus is correlated with an increase in apoptosis.	('livin', 'Gene', (58, 63))	('livin', 'Gene', (203, 208))	('livin', 'Gene', '79444', (58, 63))	('livin', 'Gene', '79444', (203, 208))	('Nachmias', 'Disease', (0, 8))	('apoptosis', 'CPA', (258, 267))	('truncated', 'Var', (193, 202))	('Nachmias', 'Disease', 'None', (0, 8))	('accumulation', 'PosReg', (177, 189))
95054	28030838	In terms of pathogenetic mechanisms, we observed a trend to a positive correlation between the livin protein levels and the BIRC7 copy number status.	('copy number status', 'Var', (130, 148))	('BIRC7', 'Gene', '79444', (124, 129))	('positive', 'PosReg', (62, 70))	('BIRC7', 'Gene', (124, 129))	('livin', 'Gene', (95, 100))	('livin', 'Gene', '79444', (95, 100))
95055	28030838	Specifically, the adrenocortical tumors with copy number gains in the chromosomal region including the BIRC7 gene showed a higher livin expression, thus suggesting a potential causative genomic alteration in this segment.	('adrenocortical tumors', 'Disease', (18, 39))	('livin', 'Gene', (130, 135))	('expression', 'MPA', (136, 146))	('copy number gains', 'Var', (45, 62))	('BIRC7', 'Gene', '79444', (103, 108))	('livin', 'Gene', '79444', (130, 135))	('higher', 'PosReg', (123, 129))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (18, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('BIRC7', 'Gene', (103, 108))
95092	28030838	Predesigned Taqman  gene expression assays for livin (Hs01086675_m1), CASP3 (Hs00234387_m1), XIAP (Hs00745222_s1) and DIABLO (Hs00219876_m1) (Applied Biosystems, Darmstadt, Germany) were used.	('Hs00745222_s1', 'Var', (99, 112))	('Hs00234387_m1', 'Var', (77, 90))	('DIABLO', 'Gene', (118, 124))	('CASP3', 'Gene', '836', (70, 75))	('XIAP', 'Gene', (93, 97))	('XIAP', 'Gene', '331', (93, 97))	('DIABLO', 'Gene', '56616', (118, 124))	('CASP3', 'Gene', (70, 75))	('Hs00219876_m1', 'Var', (126, 139))	('Hs01086675_m1', 'Var', (54, 67))	('livin', 'Gene', (47, 52))	('livin', 'Gene', '79444', (47, 52))
95124	28030838	Transient livin overexpression was induced in the ACC cell line NCI-H295R by using a TrueORF Gold Myc-DDK-tagged livin cDNA clone (RC204906, OriGene, Herford, Germany).	('livin', 'Gene', (113, 118))	('livin', 'Gene', '79444', (113, 118))	('RC204906', 'Var', (131, 139))	('overexpression', 'PosReg', (16, 30))	('livin', 'Gene', (10, 15))	('livin', 'Gene', '79444', (10, 15))	('NCI-H295R', 'CellLine', 'CVCL:0458', (64, 73))	('ACC', 'Phenotype', 'HP:0006744', (50, 53))
95204	24505527	Histopathological examination revealed adrenal tissue with a cortical adenoma with areas of hemorrhage and necrosis, composed of cells with granular cytoplasm, mild and focal nuclear pleomorphism and occasional mitosis.	('mitosis', 'Disease', (211, 218))	('necrosis', 'Disease', (107, 115))	('cortical adenoma', 'Disease', 'MESH:D000236', (61, 77))	('cortical adenoma', 'Disease', (61, 77))	('mitosis', 'Disease', 'None', (211, 218))	('necrosis', 'Disease', 'MESH:D009336', (107, 115))	('hemorrhage', 'Disease', (92, 102))	('hemorrhage', 'Disease', 'MESH:D006470', (92, 102))	('mild', 'Var', (160, 164))
95265	24034279	This implies that the aberrant expression of these GPCRs may play a role in adrenal cell hyperplasia apart from modulating cortisol production.	('aberrant', 'Var', (22, 30))	('adrenal cell hyperplasia', 'Disease', 'MESH:D000312', (76, 100))	('cortisol', 'Chemical', 'MESH:D006854', (123, 131))	('adrenal cell hyperplasia', 'Phenotype', 'HP:0008221', (76, 100))	('adrenal cell hyperplasia', 'Disease', (76, 100))	('play', 'Reg', (61, 65))	('role', 'Reg', (68, 72))	('modulating', 'Reg', (112, 122))	('cortisol production', 'MPA', (123, 142))
95320	24034279	Only the mean cortisol responses to epinephrine and norepinephrine were significantly higher in AIMAH cultures than in the non-AIMAH cultures (P<0.05, Figure 1B).	('AIMAH cultures', 'Var', (96, 110))	('cortisol', 'Chemical', 'MESH:D006854', (14, 22))	('higher', 'PosReg', (86, 92))	('norepinephrine', 'Chemical', 'MESH:D009638', (52, 66))	('epinephrine', 'Chemical', 'MESH:D004837', (55, 66))	('epinephrine', 'Chemical', 'MESH:D004837', (36, 47))
95322	24034279	Again AVP (86%) and metoclopramide (50%) were the non-ACTH stimuli that most often led to >50% increases in cortisol levels.	('metoclopramide', 'Chemical', 'MESH:D008787', (20, 34))	('AVP', 'Gene', (6, 9))	('ACTH', 'Gene', (54, 58))	('metoclopramide', 'Var', (20, 34))	('ACTH', 'Gene', '5443', (54, 58))	('cortisol levels', 'MPA', (108, 123))	('AVP', 'Gene', '551', (6, 9))	('increases in cortisol levels', 'Phenotype', 'HP:0003118', (95, 123))	('cortisol', 'Chemical', 'MESH:D006854', (108, 116))	('increases', 'PosReg', (95, 104))
95340	24034279	AIMAH is a rare disease associated with the presence of aberrantly expressed eutopic and ectopic receptors on adrenocortical cells.	('aberrantly expressed', 'Var', (56, 76))	('adrenocortical', 'Disease', (110, 124))	('ectopic receptors', 'Protein', (89, 106))	('eutopic', 'Protein', (77, 84))	('adrenocortical', 'Disease', 'MESH:D018268', (110, 124))	('AIMAH', 'Disease', (0, 5))
95435	22937299	Feminizing ACC in males leads to gynecomastia, diminished libido and sexual potency, feminizing hair change, and testicular atrophy.	('libido', 'CPA', (58, 64))	('testicular atrophy', 'Disease', (113, 131))	('gynecomastia', 'Disease', 'MESH:D006177', (33, 45))	('hair change', 'Phenotype', 'HP:0001596', (96, 107))	('diminished', 'NegReg', (47, 57))	('ACC', 'Phenotype', 'HP:0006744', (11, 14))	('testicular atrophy', 'Disease', 'MESH:C567108', (113, 131))	('testicular atrophy', 'Phenotype', 'HP:0000029', (113, 131))	('gynecomastia', 'Phenotype', 'HP:0000771', (33, 45))	('feminizing', 'Var', (85, 95))	('gynecomastia', 'Disease', (33, 45))
95443	22937299	It has been noted in the literature that males with CHF with low or high levels of estradiol demonstrate increased mortality when compared to the mean.	('estradiol', 'Chemical', 'MESH:D004958', (83, 92))	('CHF', 'Disease', (52, 55))	('CHF', 'Disease', 'MESH:D006333', (52, 55))	('high levels of estradiol', 'Phenotype', 'HP:0025134', (68, 92))	('high levels', 'Var', (68, 79))	('CHF', 'Phenotype', 'HP:0001635', (52, 55))
95462	22937299	found a higher incidence of torsades in dogs receiving cisapride (a drug known to increase QT interval) and estradiol than in those receiving cisapride alone.	('cisapride', 'Var', (55, 64))	('torsades', 'Disease', (28, 36))	('cisapride', 'Chemical', 'MESH:D020117', (142, 151))	('estradiol', 'Chemical', 'MESH:D004958', (108, 117))	('torsades', 'Chemical', '-', (28, 36))	('cisapride', 'Chemical', 'MESH:D020117', (55, 64))	('dogs', 'Species', '9615', (40, 44))	('increase QT interval', 'Phenotype', 'HP:0001657', (82, 102))
95473	22937299	Studies have suggested that among men, low DHEA-S levels have been consistently associated with an increased risk of all-cause mortality and cardiovascular disease.	('men', 'Species', '9606', (34, 37))	('DHEA-S', 'Chemical', 'MESH:D003687', (43, 49))	('cardiovascular disease', 'Disease', (141, 163))	('low', 'Var', (39, 42))	('DHEA-S', 'MPA', (43, 49))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (141, 163))	('associated', 'Reg', (80, 90))	('cardiovascular disease', 'Disease', 'MESH:D002318', (141, 163))	('all-cause', 'Disease', (117, 126))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('S', 'Chemical', 'MESH:D013455', (48, 49))
95532	33687146	EDP plus mitotane had a significantly better response rate (23.2% vs. 9.2%) and progression-free survival (5.0 months vs. 2.1 months) than streptozocin plus mitotane.	('mitotane', 'Chemical', 'MESH:D008939', (157, 165))	('streptozocin', 'Chemical', 'MESH:D013311', (139, 151))	('mitotane', 'Var', (9, 17))	('EDP', 'Chemical', '-', (0, 3))	('response', 'CPA', (45, 53))	('mitotane', 'Chemical', 'MESH:D008939', (9, 17))
95731	32067422	Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan-cancer analysis Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.	('mutations', 'Var', (248, 257))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('lung cancer', 'Disease', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epidermal growth factor receptor', 'Gene', '1956', (118, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('cancer', 'Disease', (231, 237))	('Human', 'Species', '9606', (112, 117))	('epidermal growth factor receptor', 'Gene', (118, 150))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('EGFR', 'Gene', (243, 247))	('cancer', 'Disease', (96, 102))
95732	32067422	Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', (206, 213))	('EGFR', 'Gene', (88, 92))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
95734	32067422	The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene.	('mutations', 'Var', (117, 126))	('rat', 'Species', '10116', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('EGFR', 'Gene', (199, 203))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('DNA methylation', 'Var', (180, 195))	('cancer', 'Disease', (47, 53))	('expression', 'MPA', (165, 175))	('amplification/deletion', 'Var', (131, 153))	('patients', 'Species', '9606', (77, 85))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('abnormal', 'Reg', (156, 164))
95736	32067422	EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('rat', 'Species', '10116', (9, 12))	('EGFR', 'Gene', (0, 4))	('alteration', 'Var', (5, 15))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
95738	32067422	Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain.	('mutations', 'Var', (11, 20))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
95739	32067422	Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.	('rat', 'Species', '10116', (52, 55))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('rat', 'Species', '10116', (40, 43))	('Glioblastoma multiforme', 'Disease', (0, 23))	('mutations', 'Var', (113, 122))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('Furin', 'Gene', '5045', (135, 140))	('Furin', 'Gene', (135, 140))
95740	32067422	Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.	('gene amplification', 'Var', (27, 45))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('increased', 'PosReg', (50, 59))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('expression', 'MPA', (65, 75))	('EGFR', 'Gene', (60, 64))	('glioma', 'Disease', (10, 16))
95741	32067422	Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (135, 142))	('Colon and pancreatic adenocarcinoma', 'Disease', 'MESH:D003110', (0, 35))	('associated', 'Reg', (113, 123))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (10, 35))	('expression', 'MPA', (84, 94))	('short', 'NegReg', (129, 134))
95743	32067422	DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('expression', 'MPA', (48, 58))	('associated', 'Reg', (27, 37))	('methylation', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('EGFR', 'Gene', (43, 47))
95745	32067422	While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR-driven tumors.	('rat', 'Species', '10116', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('leads to', 'Reg', (171, 179))	('increased', 'PosReg', (86, 95))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('deregulation', 'MPA', (129, 141))	('expression', 'MPA', (96, 106))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('affects', 'Reg', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('mutations', 'Var', (6, 15))
95747	32067422	Five functional domains are characterized for EGFR according to the database of protein families (Pfam, http://pfam.xfam.org/protein/P00533): Recep_L (57-168aa), Furin-like (177-338aa), Recep_L (361-481aa), GF_recep_IV (505-637aa), and Pkinase_Tyr domains (712-968aa).	('177-338aa', 'Var', (174, 183))	('712-968aa', 'Var', (257, 266))	('Furin', 'Gene', (162, 167))	('Furin', 'Gene', '5045', (162, 167))	('505-637aa', 'Var', (220, 229))
95749	32067422	Upon stimulation by its ligands, dimerization (both homodimerization and heterodimerization) of EGFR results in its intracellular tyrosine kinase activation and autophosphorylation at multiple tyrosine residues, which activates a number of downstream signaling cascades that not only promote proliferation, growth, and survival of normal cells but also contribute to processes that are crucial to cancer progression, including angiogenesis, metastasis, and apoptosis [4, 5].	('activation', 'PosReg', (146, 156))	('cancer', 'Disease', (397, 403))	('promote', 'PosReg', (284, 291))	('proliferation', 'CPA', (292, 305))	('tyrosine', 'Chemical', 'MESH:D014443', (193, 201))	('EGFR', 'Gene', (96, 100))	('dimerization', 'Var', (33, 45))	('survival', 'CPA', (319, 327))	('metastasis', 'CPA', (441, 451))	('growth', 'CPA', (307, 313))	('activates', 'PosReg', (218, 227))	('contribute', 'Reg', (353, 363))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('autophosphorylation', 'MPA', (161, 180))	('tyrosine', 'Chemical', 'MESH:D014443', (130, 138))	('intracellular tyrosine kinase', 'MPA', (116, 145))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('rat', 'Species', '10116', (299, 302))
95751	32067422	It is frequently activated by gene mutation, amplification, or overexpression through abnormal regulation in human cancers.	('human', 'Species', '9606', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gene mutation', 'Var', (30, 43))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (45, 58))	('overexpression', 'PosReg', (63, 77))
95753	32067422	In cancers like non-small-cell lung cancer (NSCLC) [13] and colon adenocarcinoma (COAD) [14], EGFR mutation status is considered as a poor prognostic factor, which is often associated with a more aggressive behavior and decreased patient survival.	('COAD', 'Disease', (82, 86))	('lung cancer', 'Disease', (31, 42))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (60, 80))	('aggressive behavior', 'Phenotype', 'HP:0000718', (196, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('patient', 'Species', '9606', (230, 237))	('mutation', 'Var', (99, 107))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('colon adenocarcinoma', 'Disease', (60, 80))	('NSCLC', 'Disease', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('EGFR', 'Gene', (94, 98))	('cancers', 'Disease', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
95756	32067422	Such treatments are very effective and provide significantly improved patient outcomes, particularly for lung adenocarcinoma (LUAD) patients with EGFR mutations [20, 21].	('improved', 'PosReg', (61, 69))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('patient', 'Species', '9606', (70, 77))	('lung adenocarcinoma', 'Disease', (105, 124))	('EGFR', 'Gene', (146, 150))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))	('mutations', 'Var', (151, 160))
95758	32067422	Although many literature reports are available on EGFR mutation, overexpression, or amplification for particular cancer types [12, 13, 14, 23, 24], a simultaneous comprehensive profiling over multiple cancer types to explore their similarity and difference is not available.	('rat', 'Species', '10116', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (55, 63))	('EGFR', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
95761	32067422	We first examined the patterns of EGFR mutations, including single nucleotide variant (SNV) and short insertion/deletion (indel), across tumors and their implications for targeted therapies.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('single nucleotide variant', 'Var', (60, 85))	('EGFR', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('short insertion/deletion', 'Var', (96, 120))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
95765	32067422	The mutation data included SNVs, indels, and CNVs (defined by GISTIC 2.0 as following for log ratio value: -2/-1 = deletion; 0 = diploid; 1 = gain; 2 = amplification).	('deletion', 'Var', (115, 123))	('rat', 'Species', '10116', (94, 97))	('gain', 'PosReg', (142, 146))
95775	32067422	The prognostic values of EGFR alterations and its CpG methylation were analyzed with Cox proportional hazard model.	('alterations', 'Var', (30, 41))	('EGFR', 'Gene', (25, 29))	('rat', 'Species', '10116', (34, 37))
95776	32067422	The overall EGFR mutation frequency was 2.8% (320/11,410) for all tumor samples and 2.4% (268/11,314) for all patients across the 32 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (66, 71))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('EGFR', 'Gene', (12, 16))	('patients', 'Species', '9606', (110, 118))
95777	32067422	The most common tumors with EGFR mutations were glioblastoma multiforme (GBM, 26.8%), LUAD (14.4%), diffuse large B-cell lymphoma (DLBC, 8.3%), and skin cutaneous melanoma (SKCM, 6.5%).	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('EGFR', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', (16, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (114, 129))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (148, 171))	('skin cutaneous melanoma', 'Disease', (148, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('B-cell lymphoma', 'Disease', (114, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('LUAD', 'Disease', (86, 90))	('glioblastoma multiforme', 'Disease', (48, 71))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (48, 71))
95778	32067422	On the contrary, kidney chromophobe cell carcinoma (KICH), mesothelioma (MESO), pheochromocytoma and paraganglioma (PCPG), thymoma (THYM), thyroid carcinoma (THCA), uterine carcinosarcoma (UCS), and uveal melanoma (UVM) showed almost no EGFR mutations (Figure 1A).	('mesothelioma', 'Disease', (59, 71))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('THCA', 'Phenotype', 'HP:0002890', (158, 162))	('thymoma', 'Disease', (123, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('carcinosarcoma', 'Disease', 'MESH:D002296', (173, 187))	('thymoma', 'Phenotype', 'HP:0100522', (123, 130))	('UCS', 'Phenotype', 'HP:0002891', (189, 192))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (139, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('UVM', 'Phenotype', 'HP:0007716', (215, 218))	('melanoma', 'Disease', (205, 213))	('thyroid carcinoma', 'Disease', (139, 156))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('kidney chromophobe cell carcinoma', 'Disease', (17, 50))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (80, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (139, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('kidney chromophobe cell carcinoma', 'Disease', 'MESH:C538614', (17, 50))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (165, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('thymoma', 'Disease', 'MESH:D013945', (123, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('mutations', 'Var', (242, 251))	('THYM', 'Phenotype', 'HP:0100522', (132, 136))	('carcinosarcoma', 'Disease', (173, 187))
95780	32067422	The 320 EGFR somatic mutations (from 268 tumor samples) were observed across all cancer types and were widely distributed along different functional domains of EGFR gene.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', (41, 46))	('cancer', 'Disease', (81, 87))	('observed', 'Reg', (61, 69))	('EGFR', 'Gene', (160, 164))	('EGFR', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutations', 'Var', (21, 30))
95782	32067422	The location distribution of these EGFR mutations was dramatically different among different cancers (Figure 1B, Supplementary Table S2).	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('EGFR', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('different', 'Reg', (67, 76))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
95783	32067422	Mutations in GBM and brain lower-grade glioma (LGG) were most commonly located in the Furin-like domain, about 5 times more than the mutations located in the Pkinase_Tyr domain.	('glioma', 'Disease', (39, 45))	('GBM', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('located', 'Reg', (71, 78))	('Furin', 'Gene', (86, 91))	('Furin', 'Gene', '5045', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
95784	32067422	On the contrary, mutations in NSCLC were primarily in the Pkinase_Tyr domain, especially for LUAD, which amounted to four fifths of all mutations.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('NSCLC', 'Disease', (30, 35))	('mutations', 'Var', (17, 26))
95785	32067422	Mutations in stomach adenocarcinoma (STAD), head and neck squamous cell carcinoma (HNSC), and SKCM were mostly in other domains whose functions were less known.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (53, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', (21, 35))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (44, 81))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('adenocarcinoma', 'Disease', 'MESH:D000230', (21, 35))	('HNSC', 'Phenotype', 'HP:0012288', (83, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('neck squamous cell carcinoma', 'Disease', (53, 81))
95786	32067422	The 289aa in the Furin-like domain was the most frequently mutated position, which was observed in 27 samples (3 samples with A289D, 1 with A289I, 1 with A289N, 6 with A289T, 15 with A289V, and 1 with A289Rfs*9).	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (201, 210))	('A289V', 'Var', (183, 188))	('A289D', 'Mutation', 'p.A289D', (126, 131))	('A289T', 'Mutation', 'rs769696078', (168, 173))	('A289I', 'Mutation', 'p.A289I', (140, 145))	('Furin', 'Gene', (17, 22))	('A289I', 'Var', (140, 145))	('Furin', 'Gene', '5045', (17, 22))	('A289N', 'Var', (154, 159))	('A289N', 'Mutation', 'p.A289N', (154, 159))	('A289V', 'Mutation', 'p.A289V', (183, 188))	('A289D', 'Var', (126, 131))	('A289T', 'Var', (168, 173))
95787	32067422	A289V is known to be oncogenic, while other mutation types (A289D/T/N/I) are likely oncogenic.	('A289V', 'Mutation', 'p.A289V', (0, 5))	('A289V', 'Var', (0, 5))	('A289D/T/N/I', 'Var', (60, 71))	('A289D', 'Mutation', 'p.A289D', (60, 65))
95788	32067422	The only other tumor with mutations at this position was HNSC (1 sample with A289T and 1 with A289Rfs*9), and their importance was little known to this cancer.	('A289Rfs*', 'Var', (94, 102))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('HNSC', 'Phenotype', 'HP:0012288', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('A289T', 'Mutation', 'rs769696078', (77, 82))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('A289T', 'Var', (77, 82))	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (94, 103))
95789	32067422	The second most mutated position was 598aa in the GF_recep_IV domain: 16 GBMs had G598V, 2 GBMs had G598A, and 1 esophageal squamous cell carcinoma (ESCC) had G598E.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('G598V', 'Mutation', 'rs139236063', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('G598A', 'Mutation', 'rs139236063', (100, 105))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('G598E', 'Mutation', 'p.G598E', (159, 164))	('G598E', 'Var', (159, 164))	('G598A', 'Var', (100, 105))	('G598V', 'Var', (82, 87))
95790	32067422	Most mutations in LUAD (35 of 45 mutations) were located in the Pkinase_Tyr domain, especially at the positions of 858aa (8 samples with L858R) and 746-750aa (6 with E746_A750del, 2 with L747_E749del, and 1 with L747_T751del) (Figure 1E).	('E746_A750del', 'Var', (166, 178))	('L747_T751del', 'Var', (212, 224))	('L747_T751del', 'Mutation', 'p.747,751delT', (212, 224))	('L747_E749del', 'Var', (187, 199))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('L858R', 'Mutation', 'rs121434568', (137, 142))	('LUAD', 'Gene', (18, 22))	('E746_A750del', 'Mutation', 'p.746,750delA', (166, 178))	('L747_E749del', 'Mutation', 'p.747,749delE', (187, 199))
95792	32067422	All Level 1 mutations were found in NSCLC (28 in LUAD and 2 in lung squamous cell carcinoma [LUSC]), and these mutations were concentrated in exons 19-21, which included L858R, L861Q, G719A, S768I, L833F, E796_A750del, L747_E749del, E709_T710delinsD, L747_T751del, and T751_E758del (Figure 3).	('S768I', 'Var', (191, 196))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('L747_T751del', 'Var', (251, 263))	('E709_T710delinsD', 'Mutation', 'p.709,710delinsT,D', (233, 249))	('L833F', 'Mutation', 'p.L833F', (198, 203))	('T751_E758del', 'Mutation', 'p.751,758delE', (269, 281))	('L858R', 'Mutation', 'rs121434568', (170, 175))	('E709_T710delinsD', 'Var', (233, 249))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (63, 91))	('S768I', 'Mutation', 'rs121913465', (191, 196))	('rat', 'Species', '10116', (133, 136))	('L833F', 'Var', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('L747_T751del', 'Mutation', 'p.747,751delT', (251, 263))	('G719A', 'Mutation', 'rs121913428', (184, 189))	('L747_E749del', 'Mutation', 'p.747,749delE', (219, 231))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 91))	('lung squamous cell carcinoma', 'Disease', (63, 91))	('L858R', 'Var', (170, 175))	('NSCLC', 'Disease', (36, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('L747_E749del', 'Var', (219, 231))	('E796_A750del', 'Var', (205, 217))	('L861Q', 'Mutation', 'rs121913444', (177, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('G719A', 'Var', (184, 189))	('E796_A750del', 'Mutation', 'p.796,750delA', (205, 217))	('L861Q', 'Var', (177, 182))	('T751_E758del', 'Var', (269, 281))
95796	32067422	The combined EGFR mutation and CNV frequency in all tumors was about 7.0% (746 of 11,314 patients, 748 of 11,410 samples).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('patients', 'Species', '9606', (89, 97))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', (13, 17))
95798	32067422	Other cancers with dominantEGFR amplification but at much lower amplification rate included ESCA (13.0%), HNSC (9.4%), STAD (5.2%), LGG (5.4%), LUSC (6.4%), and BLCA (4.4%).	('LUSC', 'Disease', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('dominantEGFR', 'Var', (19, 31))	('amplification', 'Var', (32, 45))	('BLCA', 'Disease', (161, 165))	('HNSC', 'Disease', (106, 110))	('rat', 'Species', '10116', (78, 81))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('LGG', 'Disease', (132, 135))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('ESCA', 'Disease', (92, 96))	('STAD', 'Disease', (119, 123))
95800	32067422	Over half of the mutations (47 of 82 mutations) in the Furin-like domain were accompanied by EGFR amplification, while nearly half of mutations (40 of 85 mutations) in the Pkinase_Tyr domain had copy gain.	('copy', 'MPA', (195, 199))	('EGFR amplification', 'MPA', (93, 111))	('mutations', 'Var', (37, 46))	('Furin', 'Gene', (55, 60))	('mutations', 'Var', (17, 26))	('Furin', 'Gene', '5045', (55, 60))
95801	32067422	In order to evaluate the clinical significance of EGFR alterations, we analyzed patient survival for pan-cancer and for each cancer type separately by alteration status (mutations and CNVs alone or in combination).	('rat', 'Species', '10116', (141, 144))	('alterations', 'Var', (55, 66))	('mutations', 'Var', (170, 179))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rat', 'Species', '10116', (59, 62))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rat', 'Species', '10116', (155, 158))	('patient', 'Species', '9606', (80, 87))
95802	32067422	When all tumors were analyzed together, patients with any EGFR alteration had significantly shorter median OS and DFS than those without EGFR alteration (both P < 0.001, Supplementary Figure S1).	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (146, 149))	('DFS', 'CPA', (114, 117))	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('alteration', 'Var', (63, 73))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('shorter', 'NegReg', (92, 99))	('median OS', 'MPA', (100, 109))
95803	32067422	When analysis was performed for CNV and mutation separately, the presence of either aberration was associated with shortened patients' OS and DFS (all P < 0.001, Supplementary Figure S2 and S3).	('DFS', 'CPA', (142, 145))	('presence', 'Var', (65, 73))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (53, 56))	('patients', 'Species', '9606', (125, 133))
95804	32067422	For survival association in individual cancer types, only those cancer types with at least 10 tumor samples containing either EGFR mutations or CNVs were included in the analysis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (39, 45))	('EGFR', 'Gene', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
95805	32067422	Among patients with HNSC, LGG, or LUAD, EGFR amplification was associated with short survival (Figure 6A).	('LUAD', 'Phenotype', 'HP:0030078', (34, 38))	('HNSC', 'Disease', (20, 24))	('short survival', 'MPA', (79, 93))	('EGFR', 'Gene', (40, 44))	('patients', 'Species', '9606', (6, 14))	('HNSC', 'Phenotype', 'HP:0012288', (20, 24))	('LGG', 'Disease', (26, 29))	('amplification', 'Var', (45, 58))
95807	32067422	Not surprisingly, EGFR-amplified tumors had significantly higher EGFR expression than those without EGFR amplification in all 9 cancers types (all P < 0.001, Figure 6C); however, there was no much EGFR expression difference between tumors with or without EGFR mutations except that EGFR mutation status was associated with significantly increased EGFR expression in GBM (P = 0.024) and LUAD (P = 0.001, Figure 6D).	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('mutation', 'Var', (287, 295))	('increased', 'PosReg', (337, 346))	('cancers', 'Disease', (128, 135))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('EGFR', 'Gene', (282, 286))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('LUAD', 'Phenotype', 'HP:0030078', (386, 390))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', (33, 39))	('EGFR expression', 'MPA', (347, 362))	('tumors', 'Disease', (232, 238))
95827	32067422	In individual cancer type analysis, most tumor types had the similar patterns of methylation association with gene expression in promoter and gene body, but a few others had predominant hypomethylation in both regions, such as GBM, LUSC, PRAD, THYM, KIRC, and KICH (Supplementary Figure S5).	('cancer', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('methylation', 'Var', (81, 92))	('tumor', 'Disease', (41, 46))	('THYM', 'Phenotype', 'HP:0100522', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('hypomethylation', 'Var', (186, 201))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('gene expression', 'MPA', (110, 125))
95828	32067422	Survival analysis for all tumors with tumor type as a covariate only found 2 CpG sites (cg07311521 and cg16751451) significantly associated with OS, and both were in the promoter region (TSS1500).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('associated with', 'Reg', (129, 144))	('cg16751451', 'Var', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('cg07311521', 'Var', (88, 98))	('tumor', 'Disease', (26, 31))	('tumors', 'Disease', (26, 32))
95831	32067422	For both cancer types, the CpGs with significant associations were mostly located in the gene body, where higher CpG methylation was associated with a better outcome.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('higher', 'PosReg', (106, 112))	('methylation', 'Var', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('CpG', 'MPA', (113, 116))
95833	32067422	GBM had the highest rate of EGFR alterations, and amplification was the primary alteration.	('rat', 'Species', '10116', (84, 87))	('rat', 'Species', '10116', (37, 40))	('alterations', 'Var', (33, 44))	('EGFR', 'MPA', (28, 32))	('rat', 'Species', '10116', (20, 23))
95836	32067422	Other common tumor types with EGFR alterations include ESCA, HNSC, LGG, LUSC, and BLCA, all with similar characteristics: alteration frequency of about 5.0% and amplification as a dominant type.	('tumor', 'Disease', (13, 18))	('alterations', 'Var', (35, 46))	('EGFR', 'Gene', (30, 34))	('alteration', 'Var', (122, 132))	('LUSC', 'Disease', (72, 76))	('BLCA', 'Disease', (82, 86))	('HNSC', 'Phenotype', 'HP:0012288', (61, 65))	('ESCA', 'Disease', (55, 59))	('LGG', 'Disease', (67, 70))	('rat', 'Species', '10116', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('rat', 'Species', '10116', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HNSC', 'Disease', (61, 65))
95838	32067422	On the other side of the spectrum, tumors such as DLBC and SKCM mainly had SNV mutations but rarely CNV; tumors including KIRC, MESO, THCA, THYM, UCS and UVM almost had no EGFR alterations.	('tumors', 'Disease', (105, 111))	('THCA', 'Phenotype', 'HP:0002890', (134, 138))	('THYM', 'Phenotype', 'HP:0100522', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('THYM', 'Disease', (140, 144))	('rat', 'Species', '10116', (181, 184))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('THCA', 'Disease', (134, 138))	('UVM', 'Phenotype', 'HP:0007716', (154, 157))	('tumors', 'Disease', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('UCS', 'Disease', (146, 149))	('SNV', 'Gene', (75, 78))	('MESO', 'Disease', (128, 132))
95839	32067422	Mutations in the Furin-like and Pkinase_Tyr domains accounted for most of EGFR single nucleotide or indel mutations.	('single nucleotide', 'Var', (79, 96))	('Furin', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('Furin', 'Gene', '5045', (17, 22))	('EGFR', 'Gene', (74, 78))
95840	32067422	However, the Pkinase_Tyr domain was far more important in terms of targeted therapy with TKIs as 90% EGFR mutations in LUAD occurred in this region, particularly the exon 19 deletion and the L858R point mutation in exon 21.	('L858R', 'Mutation', 'rs121434568', (191, 196))	('L858R point', 'Var', (191, 202))	('LUAD', 'Gene', (119, 123))	('mutations', 'Var', (106, 115))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('exon 19 deletion', 'Var', (166, 182))
95841	32067422	Mutations in these regions are proven predictive markers for effective TKI therapy for NSCLC in clinical practice [7, 33, 34, 35], with significantly prolonged survival as compared with traditional combination chemotherapy [21, 36, 37].	('NSCLC', 'Disease', (87, 92))	('prolonged', 'PosReg', (150, 159))	('survival', 'MPA', (160, 168))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
95843	32067422	For other uncommon EGFR mutations in NSCLC, targeted therapy generated inconsistent results [34, 40, 41, 42].	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('NSCLC', 'Disease', (37, 42))	('EGFR', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))	('rat', 'Species', '10116', (65, 68))
95844	32067422	In this large TCGA dataset, the combined alteration rate (amplification, deletion, or mutation) reached 67.3% in GBM.	('rat', 'Species', '10116', (52, 55))	('deletion', 'Var', (73, 81))	('rat', 'Species', '10116', (45, 48))	('mutation', 'Var', (86, 94))
95846	32067422	Compared with LUAD, most EGFR mutations in GBM were located in extracellular domain or single-span transmembrane segment, which was known to be associated with tumorigenesis but not responsiveness to TKIs.	('associated with', 'Reg', (144, 159))	('EGFR', 'Gene', (25, 29))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('GBM', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (160, 165))
95847	32067422	Although EGFR amplification was a predictor of poor prognosis for several cancer types, it was not significantly associated with GBM, consistent with the paradox phenomenon reported in the literature [46].	('rat', 'Species', '10116', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('EGFR', 'Gene', (9, 13))	('GBM', 'Disease', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplification', 'Var', (14, 27))
95848	32067422	Both amplification and high expression of EGFR were correlated with short patient survival in this dataset as reported previously [49, 50].	('amplification', 'Var', (5, 18))	('patient', 'Species', '9606', (74, 81))	('EGFR', 'Gene', (42, 46))	('short patient survival', 'CPA', (68, 90))
95849	32067422	More interestingly, we found that LGG had the highest number of CpGs whose methylation level was associated with patient survival (i.e., hypermethylation of CpGs in the gene body with better survival), which has not been reported before.	('patient', 'Species', '9606', (113, 120))	('methylation', 'MPA', (75, 86))	('hypermethylation', 'Var', (137, 153))	('patient survival', 'CPA', (113, 129))	('associated', 'Reg', (97, 107))
95850	32067422	COAD and PAAD had very few EGFR mutations in this TCGA dataset.	('PAAD', 'Phenotype', 'HP:0006725', (9, 13))	('COAD', 'Disease', (0, 4))	('EGFR', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('COAD', 'Disease', 'MESH:D029424', (0, 4))
95851	32067422	However, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (70, 77))	('expression', 'MPA', (19, 29))	('EGFR', 'Gene', (14, 18))	('high', 'Var', (9, 13))
95853	32067422	Squamous cell carcinomas in the head and neck (HNSC), lung (LUSC), and esophagus (ESCA) have some commonalities: significantly increased EGFR expression, high frequency of EGFR amplification, and low rate of SNV/indel mutations.	('EGFR', 'Gene', (137, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('amplification', 'Var', (177, 190))	('rat', 'Species', '10116', (200, 203))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('EGFR', 'Gene', (172, 176))	('Squamous cell carcinomas', 'Phenotype', 'HP:0002860', (0, 24))	('HNSC', 'Phenotype', 'HP:0012288', (47, 51))	('Squamous cell carcinomas', 'Disease', 'MESH:D002294', (0, 24))	('Squamous cell carcinomas', 'Disease', (0, 24))	('esophagus', 'Disease', (71, 80))	('expression', 'MPA', (142, 152))	('lung', 'Disease', (54, 58))	('increased', 'PosReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
95858	32067422	Our analysis provides a comprehensive view of EGFR mutation, abnormal expression, DNA methylation, and their interplay and clinical implications for 32 cancer types covering over ten thousand tumor samples.	('cancer', 'Disease', (152, 158))	('tumor', 'Disease', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('mutation', 'Var', (51, 59))	('EGFR', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
95859	32067422	While some alternations are involved more in tumorigenesis, others are more therapeutic.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('involved', 'Reg', (28, 36))	('alternations', 'Var', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
95860	32067422	Some cancer types have a higher frequency of EGFR alternations where mutation, amplification, or abnormal expression is associated with outcome or indicated for clinical action.	('associated', 'Reg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('EGFR', 'Gene', (45, 49))	('alternations', 'Var', (50, 62))	('cancer', 'Disease', (5, 11))	('abnormal expression', 'MPA', (97, 116))	('mutation', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('amplification', 'Var', (79, 92))
95914	32116670	After 48  h, the active nauplii were transferred to a 96-well plate and used for the study with ME at 0.0625, 0.125, 0.25, 0.5, 1, 2, 10 mug/mul.	('0.0625', 'Var', (102, 108))	('ME', 'Chemical', '-', (96, 98))	('0.125', 'Var', (110, 115))
95923	32116670	Trypan blue dye exclusion method was used to assess cell viability after treatment with ME at 0.0625, 0.125, 0.25, 0.5, 1, 2, 10 mug/mul.	('0.125', 'Var', (102, 107))	('0.25', 'Var', (109, 113))	('Trypan blue', 'Chemical', 'MESH:D014343', (0, 11))	('ME', 'Chemical', '-', (88, 90))
95926	32116670	Cells were cultured on coverslips and then processed with ME at 0.0625, 0.125, 0.25, 0.5, 1, 2 mug/mul.	('0.25', 'Var', (79, 83))	('0.125', 'Var', (72, 77))	('ME', 'Chemical', '-', (58, 60))
95939	32116670	The primary antibodies were: anti-Erk1/2, anti-phospho-Erk1/2 (Thr202/Tyr204), anti-Akt, anti-phospho-Akt (Ser473), all diluted 1:1,000 (Cell Signaling, Danvers, MA, USA), and anti-beta-actin diluted 1:5,000 (Sigma-Aldrich).	('Akt', 'Gene', '207', (84, 87))	('Akt', 'Gene', (102, 105))	('anti-phospho-Erk1/2 (Thr202/Tyr204', 'Var', (42, 76))	('Akt', 'Gene', '207', (102, 105))	('Tyr204', 'Chemical', '-', (70, 76))	('Akt', 'Gene', (84, 87))	('Thr202', 'Chemical', '-', (63, 69))	('anti-Erk1/2', 'Var', (29, 40))	('Thr202/Tyr204', 'Var', (63, 76))	('Ser473', 'Chemical', '-', (107, 113))
96010	31964418	Dysregulated IAPs have been reported to contribute to tumor progression and chemoresistance in various cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('IAP', 'Gene', '84061', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('contribute', 'Reg', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('IAP', 'Gene', (13, 16))	('Dysregulated', 'Var', (0, 12))	('cancers', 'Disease', (103, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('chemoresistance', 'CPA', (76, 91))
96075	31964418	We also found that BIRC5, BIRC6 and XIAP were heavily involved in cell cycle related pathways such as M/G1 transition, G1/S transition, G2/M checkpoints, and DNA replication.	('DNA replication', 'CPA', (158, 173))	('BIRC6', 'Gene', (26, 31))	('G2/M checkpoints', 'CPA', (136, 152))	('BIRC5', 'Gene', '332', (19, 24))	('BIRC5', 'Gene', (19, 24))	('XIAP', 'Gene', (36, 40))	('G1/S transition', 'CPA', (119, 134))	('cell', 'Pathway', (66, 70))	('M/G1', 'SUBSTITUTION', 'None', (102, 106))	('BIRC6', 'Gene', '57448', (26, 31))	('XIAP', 'Gene', '331', (36, 40))	('M/G1', 'Var', (102, 106))	('involved', 'Reg', (54, 62))
96090	31964418	For example, BIRC5 was significantly anti-correlated with miR-101, miR-664a, miR-29c, miR-30a, miR-125 and miR-139 expression in over 40% of the cancers.	('cancers', 'Disease', (145, 152))	('miR-664a', 'Gene', '100302234', (67, 75))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('miR-664a', 'Gene', (67, 75))	('miR-29c', 'Gene', (77, 84))	('miR-29c', 'Gene', '407026', (77, 84))	('miR-125', 'Gene', (95, 102))	('miR-30a', 'Gene', (86, 93))	('anti-correlated', 'NegReg', (37, 52))	('miR-139', 'Gene', '406931', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('expression', 'MPA', (115, 125))	('miR-139', 'Gene', (107, 114))	('BIRC5', 'Gene', '332', (13, 18))	('BIRC5', 'Gene', (13, 18))	('miR-30a', 'Gene', '407029', (86, 93))	('miR-101', 'Var', (58, 65))
96095	31964418	Evasion of apoptosis through dysregulated IAPs might led to uncontrolled cell growth and poor prognosis.	('IAP', 'Gene', (42, 45))	('uncontrolled cell growth', 'CPA', (60, 84))	('led', 'Reg', (53, 56))	('Evasion', 'MPA', (0, 7))	('dysregulated', 'Var', (29, 41))	('IAP', 'Gene', '84061', (42, 45))	('apoptosis', 'CPA', (11, 20))
96144	31964418	The demonstrated complexities of IAPs expression provided vast possibilities for apoptosis regulation and potential mechanisms of oncogenesis resulting from aberrant expression of IAPs.	('IAP', 'Gene', '84061', (33, 36))	('IAP', 'Gene', (180, 183))	('aberrant expression', 'Var', (157, 176))	('apoptosis', 'CPA', (81, 90))	('IAP', 'Gene', (33, 36))	('IAP', 'Gene', '84061', (180, 183))
96185	31964418	This study is supported by The National Natural Science Foundation of China 31501054, 81301092, 31301118, 81900431, Peking Unicersity International Hospital Research Grant No.	('31301118', 'Var', (96, 104))	('81900431', 'Var', (106, 114))	('C', 'Chemical', 'MESH:D002244', (70, 71))
96200	29192018	Furthermore, a query in the French national pharmacovigilance database from 2004:the date of mitotane commercialization in France:to 2016 found only 14 cases of neurological adverse effects probably related to mitotane, including drowsiness, asthenia, memory disorders, confusion, concentration troubles, headaches, and space-time disorientations, but no case of encephalopathy [10].	('concentration troubles', 'Phenotype', 'HP:0031987', (281, 303))	('asthenia', 'Disease', (242, 250))	('concentration troubles', 'Disease', (281, 303))	('disorientations', 'Phenotype', 'HP:0001289', (331, 346))	('confusion', 'Disease', (270, 279))	('encephalopathy', 'Disease', 'MESH:D001927', (363, 377))	('space-time disorientations', 'Disease', (320, 346))	('memory disorders', 'Disease', (252, 268))	('headaches', 'Disease', 'MESH:D006261', (305, 314))	('encephalopathy', 'Phenotype', 'HP:0001298', (363, 377))	('memory disorders', 'Disease', 'MESH:D008569', (252, 268))	('asthenia', 'Disease', 'MESH:D001247', (242, 250))	('drowsiness', 'Disease', (230, 240))	('asthenia', 'Phenotype', 'HP:0025406', (242, 250))	('mitotane', 'Var', (210, 218))	('memory disorders', 'Phenotype', 'HP:0002354', (252, 268))	('mitotane', 'Chemical', 'MESH:D008939', (93, 101))	('headaches', 'Phenotype', 'HP:0002315', (305, 314))	('encephalopathy', 'Disease', (363, 377))	('confusion', 'Phenotype', 'HP:0001289', (270, 279))	('mitotane', 'Chemical', 'MESH:D008939', (210, 218))	('headaches', 'Disease', (305, 314))	('drowsiness', 'Phenotype', 'HP:0002329', (230, 240))
96265	29310349	Therefore, Bisceglia et al modified the Weiss system according to the pathological features of adrenal cortex eosinophils tumor as follows: mitosis count> 5/50 HPF, atypical mitosis and venous invasion as the main criteria, and tumor diameter> 10 cm and (or) weight> 200 g, necrosis, capsular invasion, and sinusoids infiltration as the secondary criteria.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('adrenal cortex eosinophils tumor', 'Disease', 'MESH:D004802', (95, 127))	('venous invasion', 'CPA', (186, 201))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mitosis', 'Disease', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('atypical', 'Var', (165, 173))	('mitosis', 'Disease', 'None', (140, 147))	('mitosis', 'Disease', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('necrosis', 'Disease', (274, 282))	('tumor', 'Disease', (228, 233))	('mitosis', 'Disease', 'None', (174, 181))	('adrenal cortex eosinophils tumor', 'Disease', (95, 127))	('tumor', 'Disease', (122, 127))	('necrosis', 'Disease', 'MESH:D009336', (274, 282))
96276	29179432	Increased SF-1 dosage is associated with enhanced adrenocortical tumor cell proliferation, development of adrenocortical tumors in mice and confers a more severe prognosis to adult adrenocortical cancers.	('development', 'CPA', (91, 102))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (50, 70))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (106, 127))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('adrenocortical tumor', 'Disease', (50, 70))	('enhanced', 'PosReg', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('adult adrenocortical cancers', 'Disease', 'MESH:D000306', (175, 203))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (106, 126))	('mice', 'Species', '10090', (131, 135))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('adrenocortical tumors', 'Disease', (106, 127))	('SF-1', 'Gene', (10, 14))	('dosage', 'Var', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('adult adrenocortical cancers', 'Disease', (175, 203))
96299	29179432	A remarkable clinically relevant outcome of our study consists in the highly significant correlation between high VAV2 abundance and reduced ACC patient survival.	('high', 'Var', (109, 113))	('VAV2', 'Gene', (114, 118))	('patient', 'Species', '9606', (145, 152))	('VAV2', 'Gene', '7410', (114, 118))	('reduced', 'NegReg', (133, 140))	('ACC patient survival', 'CPA', (141, 161))
96304	29179432	The combined assessment of VAV2 expression and Ki67 LI improves prognostic prediction in ACC.	('VAV2', 'Gene', '7410', (27, 31))	('prognostic', 'MPA', (64, 74))	('Ki67 LI', 'Var', (47, 54))	('ACC', 'Disease', (89, 92))	('VAV2', 'Gene', (27, 31))	('improves', 'PosReg', (55, 63))
96351	23869313	It is caused by mutations of MENIN gene located on Chromosome 11q13.3.	('caused by', 'Reg', (6, 15))	('MENIN', 'Gene', '4221', (29, 34))	('MENIN', 'Gene', (29, 34))	('mutations', 'Var', (16, 25))
96352	23869313	Germline mutations in this gene lead to development of one or more components of the classic triad of parathyroid hyperplasia (90%), pancreatic neuroendocrine tumors (PET) (60%), and pituitary adenomas (40%).	('Germline mutations', 'Var', (0, 18))	('lead to', 'Reg', (32, 39))	('parathyroid hyperplasia', 'Disease', 'MESH:D006965', (102, 125))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (133, 165))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (144, 164))	('parathyroid hyperplasia', 'Disease', (102, 125))	('pituitary adenomas', 'Disease', 'MESH:D010911', (183, 201))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (144, 165))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('endocrine tumor', 'Phenotype', 'HP:0100568', (149, 164))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (133, 164))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('parathyroid hyperplasia', 'Phenotype', 'HP:0008208', (102, 125))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (183, 201))	('pancreatic neuroendocrine tumors', 'Disease', (133, 165))	('pituitary adenomas', 'Disease', (183, 201))
96392	23869313	She was vaccinated with pneumococcal, meningococcal and H. Influenza vaccine in view of lesion in tail of pancreas which were to be excised, which are associated with risk of splenic injury and subsequent splenectomy.	('meningococcal', 'Disease', (38, 51))	('meningococcal', 'Disease', 'MESH:D008589', (38, 51))	('pneumococcal', 'Disease', 'MESH:D011008', (24, 36))	('pneumococcal', 'Disease', (24, 36))	('splenic injury', 'Disease', 'MESH:D006971', (175, 189))	('lesion', 'Var', (88, 94))	('splenic injury', 'Disease', (175, 189))
96406	23869313	MEN1 is caused by mutations in a tumor suppressor gene, MENIN, located at chromosome 11q13.3.	('MEN1', 'Gene', '4221', (0, 4))	('mutations', 'Var', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('caused by', 'Reg', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('MENIN', 'Gene', (56, 61))	('tumor', 'Disease', (33, 38))	('MENIN', 'Gene', '4221', (56, 61))	('MEN1', 'Gene', (0, 4))
96428	23869313	From the molecular biologic point of view, it remains unclear whether the development of MEN1-related adrenal tumors is directly caused by inactivation of the MENIN gene.	('MEN1', 'Gene', '4221', (89, 93))	('caused by', 'Reg', (129, 138))	('adrenal tumors', 'Disease', (102, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('MENIN', 'Gene', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('adrenal tumors', 'Disease', 'MESH:D000310', (102, 116))	('MENIN', 'Gene', '4221', (159, 164))	('inactivation', 'Var', (139, 151))	('MEN1', 'Gene', (89, 93))
96498	19958922	Perhaps someday, genetic surgeons will repair a mutated gene and restore normality in order to prevent the development of a cancer not only in patients but also in their potential offspring.	('cancer', 'Disease', (124, 130))	('prevent', 'NegReg', (95, 102))	('mutated gene', 'Var', (48, 60))	('repair', 'Var', (39, 45))	('patients', 'Species', '9606', (143, 151))	('restore', 'PosReg', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('normality', 'MPA', (73, 82))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
96500	19958922	Sam Wells, in his Grey-Turner address presented at the International Surgical Week in 2007, detailed the criteria for an optimal prophylactic surgical procedure based on genomics: (1) for given hereditary cancer, the causative genetic mutation must have a very high likelihood of causing the cancer regardless of environmental factors; (2) One must be able to reliably test for the genomic aberration and identify patients who have inherited the mutated gene; (3) the operation to remove the target organ must be associated with minimal morbidity and virtually no mortality; (4) there must be a feasible replacement for the function of the removed organ; and (5) there must be a reliable method of ascertaining over time that the patient has been cured by prophylactic operation.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('patients', 'Species', '9606', (414, 422))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('cancer', 'Disease', (205, 211))	('hereditary cancer', 'Disease', 'MESH:D009369', (194, 211))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('hereditary cancer', 'Disease', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Disease', (292, 298))	('patient', 'Species', '9606', (414, 421))	('mutated', 'Var', (446, 453))	('patient', 'Species', '9606', (730, 737))
96502	19958922	FAP is characterized by a germ line mutations in APC, a tumor suppressor gene, resulting in the formation of adenomatous polyps in the colon.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('adenomatous polyps in the colon', 'Disease', 'MESH:D018256', (109, 140))	('FAP', 'Disease', 'MESH:C567782', (0, 3))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (109, 127))	('tumor', 'Disease', (56, 61))	('mutations', 'Var', (36, 45))	('APC', 'Disease', 'MESH:D011125', (49, 52))	('adenomatous polyps in the colon', 'Disease', (109, 140))	('APC', 'Disease', (49, 52))	('FAP', 'Disease', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
96506	19958922	Lynch Syndrome is due to mutations in at least one of four DNA mismatch repair genes, MLH1, MSH2, MSH6 and PMS2.	('mutations', 'Var', (25, 34))	('MSH2', 'Gene', (92, 96))	('MSH2', 'Gene', '4436', (92, 96))	('Lynch Syndrome', 'Disease', (0, 14))	('MSH6', 'Gene', '2956', (98, 102))	('PMS2', 'Gene', (107, 111))	('due to', 'Reg', (18, 24))	('MSH6', 'Gene', (98, 102))	('PMS2', 'Gene', '5395', (107, 111))	('MLH1', 'Gene', '4292', (86, 90))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (0, 14))	('MLH1', 'Gene', (86, 90))
96508	19958922	The most well studied hereditary breast cancers are the result of germ-line BRCA1 and BRCA2 mutations.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('BRCA2', 'Gene', (86, 91))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('BRCA2', 'Gene', '675', (86, 91))	('mutations', 'Var', (92, 101))	('BRCA1', 'Gene', '672', (76, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (33, 47))	('result', 'Reg', (56, 62))	('breast cancers', 'Disease', 'MESH:D001943', (33, 47))	('breast cancers', 'Disease', (33, 47))	('BRCA1', 'Gene', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
96511	19958922	In contrast for a woman harboring the BRCA1 mutation, the lifetime risks of breast cancer and ovarian cancer are 85% and 54-63%, respectively; for BRCA2 carriers the same risks are 86% and 23-27%.	('ovarian cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutation', 'Var', (44, 52))	('BRCA2', 'Gene', '675', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('BRCA1', 'Gene', (38, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('woman', 'Species', '9606', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('ovarian cancer', 'Disease', 'MESH:D010051', (94, 108))	('BRCA2', 'Gene', (147, 152))	('BRCA1', 'Gene', '672', (38, 43))
96521	19958922	Approximately 5-10% of thyroid cancers arise from the parafollicular cells and of these medullary thyroid cancers, about 25% arise due to an inherited genetic mutation in the RET proto-oncogene as part of multiple endocrine neoplasia type 2A (MEN2A)(60%), MEN2B (5%), or familial medullary thyroid cancer (FMTC)(35%).	('thyroid cancers', 'Disease', 'MESH:D013964', (23, 38))	('MTC', 'Gene', (307, 310))	('thyroid cancer', 'Phenotype', 'HP:0002890', (23, 37))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('thyroid cancer', 'Disease', (290, 304))	('RET', 'Gene', '5979', (175, 178))	('medullary thyroid cancers', 'Phenotype', 'HP:0002865', (88, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('neoplasia', 'Phenotype', 'HP:0002664', (224, 233))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('thyroid cancer', 'Disease', 'MESH:D013964', (98, 112))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (280, 304))	('MEN2B', 'Gene', (256, 261))	('thyroid cancers', 'Disease', (23, 38))	('MEN2B', 'Gene', '5979', (256, 261))	('thyroid cancer', 'Disease', 'MESH:D013964', (290, 304))	('thyroid cancers', 'Disease', 'MESH:D013964', (98, 113))	('MEN2A', 'Gene', '5979', (243, 248))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('MEN2A', 'Gene', (243, 248))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (214, 233))	('RET', 'Gene', (175, 178))	('MTC', 'Gene', '4489', (307, 310))	('thyroid cancer', 'Phenotype', 'HP:0002890', (98, 112))	('thyroid cancer', 'Phenotype', 'HP:0002890', (290, 304))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (88, 112))	('arise due to', 'Reg', (125, 137))	('multiple endocrine neoplasia type 2A', 'Gene', (205, 241))	('multiple endocrine neoplasia type 2A', 'Gene', '5979', (205, 241))	('thyroid cancer', 'Disease', 'MESH:D013964', (23, 37))	('genetic mutation', 'Var', (151, 167))	('thyroid cancers', 'Disease', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
96522	19958922	The penetrance of MTC associated with the known mutations in RET is virtually 100%.	('RET', 'Gene', (61, 64))	('MTC', 'Gene', '4489', (18, 21))	('MTC', 'Gene', (18, 21))	('RET', 'Gene', '5979', (61, 64))	('mutations', 'Var', (48, 57))
96523	19958922	Since the identification of RET as the susceptibility gene for MTC, the phenotypic expression associated with mutations in the various "hot spots' has been better defined.	('MTC', 'Gene', '4489', (63, 66))	('mutations', 'Var', (110, 119))	('MTC', 'Gene', (63, 66))	('RET', 'Gene', '5979', (28, 31))	('RET', 'Gene', (28, 31))
96524	19958922	Over 80% of patients with MEN2A have RET mutations in codon 634 of exon 11 but mutations have also been reported in exon 10 (codons 609, 611, 618, 620).	('MEN2A', 'Gene', (26, 31))	('patients', 'Species', '9606', (12, 20))	('RET', 'Gene', (37, 40))	('RET', 'Gene', '5979', (37, 40))	('mutations in codon 634', 'Var', (41, 63))	('MEN2A', 'Gene', '5979', (26, 31))
96525	19958922	Several studies have shown correlation of specific mutations with aggressive tumor behavior.	('aggressive tumor behavior', 'Disease', (66, 91))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (51, 60))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (66, 91))
96527	19958922	The spectrum of mutations associated with familial MTC overlaps with that of MEN2A in about 50% of cases in that RET mutations occur in codon 634.	('RET', 'Gene', '5979', (113, 116))	('mutations', 'Var', (117, 126))	('occur', 'Reg', (127, 132))	('RET', 'Gene', (113, 116))	('familial MTC overlaps', 'Disease', (42, 63))	('familial MTC overlaps', 'Disease', 'MESH:C536911', (42, 63))	('MEN2A', 'Gene', (77, 82))	('MEN2A', 'Gene', '5979', (77, 82))
96530	19958922	For patients with an apparent sporadic medullary thyroid cancer the risk of a germ-line RET mutation ranges between 1.5% and 22.7% depending on the series.	('thyroid cancer', 'Phenotype', 'HP:0002890', (49, 63))	('thyroid cancer', 'Disease', (49, 63))	('mutation', 'Var', (92, 100))	('RET', 'Gene', (88, 91))	('thyroid cancer', 'Disease', 'MESH:D013964', (49, 63))	('RET', 'Gene', '5979', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('patients', 'Species', '9606', (4, 12))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (39, 63))
96531	19958922	The risk of a pheochromocytoma occurring the background of a RET mutation is about 2.5% but these tumors are the first manifestation of MEN2A in only 9 to 27% of cases.	('MEN2A', 'Gene', '5979', (136, 141))	('pheochromocytoma', 'Disease', 'MESH:D010673', (14, 30))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (14, 30))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('MEN2A', 'Gene', (136, 141))	('RET', 'Gene', (61, 64))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutation', 'Var', (65, 73))	('pheochromocytoma', 'Disease', (14, 30))	('RET', 'Gene', '5979', (61, 64))
96532	19958922	Recently, investigators including members of this organization have begun to link the penetrance of pheochromocytoma to specific mutations in RET.	('pheochromocytoma', 'Disease', 'MESH:D010673', (100, 116))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (100, 116))	('RET', 'Gene', '5979', (142, 145))	('mutations', 'Var', (129, 138))	('RET', 'Gene', (142, 145))	('pheochromocytoma', 'Disease', (100, 116))
96533	19958922	Undoubtedly, these observations will continue be refined but at present no RET mutation fully distinguishes the risk of this tumor, as all have been reported in associated with syndromic pheochromocytomas.	('RET', 'Gene', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('syndromic pheochromocytomas', 'Disease', (177, 204))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (187, 203))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (187, 204))	('syndromic pheochromocytomas', 'Disease', 'MESH:D010673', (177, 204))	('tumor', 'Disease', (125, 130))	('mutation', 'Var', (79, 87))	('RET', 'Gene', '5979', (75, 78))
96534	19958922	Any patient with a malignant pheochromocytoma or a paraganglionoma, should be evaluated for a germ-line mutation in RET, the Von Hippel-Lindau gene, neurofibromatosis or the succinate dehydrogenase subunit B or D genes.	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (19, 45))	('malignant pheochromocytoma', 'Disease', (19, 45))	('Von Hippel-Lindau', 'Disease', (125, 142))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (29, 45))	('paraganglionoma', 'Disease', (51, 66))	('RET', 'Gene', (116, 119))	('patient', 'Species', '9606', (4, 11))	('paraganglionoma', 'Disease', 'None', (51, 66))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (149, 166))	('mutation', 'Var', (104, 112))	('neurofibromatosis or the succinate dehydrogenase subunit B or D', 'Gene', '4763', (149, 212))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (125, 142))	('RET', 'Gene', '5979', (116, 119))
96535	19958922	A mutation in the VHL, SDHB or SDHD genes could have therapeutic importance in the treatment of a malignant pheochromocytoma because these patients' tumors have increased levels of hypoxia inducible factor 1alpha and its downstream effector TrkA.	('SDHB', 'Gene', '6390', (23, 27))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (98, 124))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (108, 124))	('hypoxia inducible factor 1alpha', 'Gene', (181, 212))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('VHL', 'Disease', (18, 21))	('tumors', 'Disease', (149, 155))	('SDHB', 'Gene', (23, 27))	('levels', 'MPA', (171, 177))	('TrkA', 'Gene', (241, 245))	('increased', 'PosReg', (161, 170))	('mutation', 'Var', (2, 10))	('malignant pheochromocytoma', 'Disease', (98, 124))	('patients', 'Species', '9606', (139, 147))	('SDHD', 'Disease', (31, 35))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('hypoxia inducible factor 1alpha', 'Gene', '3091', (181, 212))	('VHL', 'Disease', 'MESH:D006623', (18, 21))	('SDHD', 'Disease', 'None', (31, 35))	('TrkA', 'Gene', '4914', (241, 245))
96537	19958922	In papillary thyroid cancer (PTC), emerging data regarding the role of BRAF mutation may alter the way we approach patients with this disease.	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('PTC', 'Gene', (29, 32))	('BRAF', 'Gene', '673', (71, 75))	('papillary thyroid cancer', 'Disease', (3, 27))	('PTC', 'Gene', '5979', (29, 32))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (3, 27))	('BRAF', 'Gene', (71, 75))	('alter', 'Reg', (89, 94))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (3, 27))	('PTC', 'Phenotype', 'HP:0002895', (29, 32))	('thyroid cancer', 'Phenotype', 'HP:0002890', (13, 27))	('mutation', 'Var', (76, 84))
96538	19958922	Mutation in this gene occurs in about 44% of these tumors.	('occurs', 'Reg', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Mutation', 'Var', (0, 8))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))
96544	19958922	While the role of activating mutations of ras in carcinogenesis is well established, only recently have investigators shown mutations in BRAF in many human cancers resulting in activation of the MAPK pathway.	('MAPK pathway', 'Pathway', (195, 207))	('human', 'Species', '9606', (150, 155))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('mutations', 'Var', (124, 133))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('activation', 'PosReg', (177, 187))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('carcinogenesis', 'Disease', 'MESH:D063646', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('activating', 'PosReg', (18, 28))	('carcinogenesis', 'Disease', (49, 63))
96545	19958922	The most common such mutation in BRAF is the T1799A point mutation resulting in a substitution of glutamic acid for valine at position 600 and it is this mutation that is described in thyroid cancer.	('BRAF', 'Gene', '673', (33, 37))	('thyroid cancer', 'Disease', (184, 198))	('thyroid cancer', 'Phenotype', 'HP:0002890', (184, 198))	('T1799A', 'Mutation', 'rs113488022', (45, 51))	('BRAF', 'Gene', (33, 37))	('valine', 'MPA', (116, 122))	('substitution', 'Var', (82, 94))	('glutamic acid for valine at position 600', 'Mutation', 'rs113488022', (98, 138))	('thyroid cancer', 'Disease', 'MESH:D013964', (184, 198))	('T1799A', 'Var', (45, 51))	('glutamic acid', 'MPA', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
96546	19958922	Many studies have now shown an association between BRAF mutation and extra-thyroidal extension, lymph node metastases and advanced stage.	('metastases', 'Disease', 'MESH:D009362', (107, 117))	('extra-thyroidal extension', 'CPA', (69, 94))	('BRAF', 'Gene', '673', (51, 55))	('advanced stage', 'CPA', (122, 136))	('mutation', 'Var', (56, 64))	('BRAF', 'Gene', (51, 55))	('metastases', 'Disease', (107, 117))
96547	19958922	Furthermore, there is some evidence to suggest that for patients with low risk tumors by clinical criteria, a mutation in BRAF portends an increased risk of recurrence of PTC.	('patients', 'Species', '9606', (56, 64))	('BRAF', 'Gene', '673', (122, 126))	('PTC', 'Gene', (171, 174))	('BRAF', 'Gene', (122, 126))	('tumors', 'Disease', (79, 85))	('PTC', 'Gene', '5979', (171, 174))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mutation', 'Var', (110, 118))	('PTC', 'Phenotype', 'HP:0002895', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
96548	19958922	At this point, we are left to evaluate how one might alter treatment decisions based on whether an otherwise low-risk patient's tumor harbors a somatic BRAF mutation, in favor of more aggressive treatment.	('BRAF', 'Gene', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mutation', 'Var', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('patient', 'Species', '9606', (118, 125))	('BRAF', 'Gene', '673', (152, 156))
96557	19958922	For example, such is the case of Gastrointestinal Stromal Tumors (GIST), c-kit mutations and the remarkable response to targeted therapy with imatinib mesylate (Gleevec ).	('Gastrointestinal Stromal Tumors', 'Disease', 'MESH:D046152', (33, 64))	('Gastrointestinal Stromal Tumors', 'Disease', (33, 64))	('Tumors', 'Phenotype', 'HP:0002664', (58, 64))	('Gastrointestinal Stromal Tumors', 'Phenotype', 'HP:0100723', (33, 64))	('GIST', 'Phenotype', 'HP:0100723', (66, 70))	('c-kit', 'Gene', '3815', (73, 78))	('c-kit', 'Gene', (73, 78))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (142, 159))	('mutations', 'Var', (79, 88))
96558	19958922	Many refractory GIST tumors harbor mutations in the platelet derived growth factor receptor alpha gene and these patients often respond to the multiple tyrosine kinase inhibitor sunitinib malate (Sutent ).	('GIST tumors', 'Disease', 'MESH:D046152', (16, 27))	('sunitinib malate', 'Chemical', 'MESH:D000077210', (178, 194))	('Sutent', 'Chemical', 'MESH:D000077210', (196, 202))	('GIST', 'Phenotype', 'HP:0100723', (16, 20))	('patients', 'Species', '9606', (113, 121))	('GIST tumors', 'Disease', (16, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('platelet derived growth factor receptor alpha', 'Gene', '5156', (52, 97))	('platelet derived growth factor receptor alpha', 'Gene', (52, 97))	('respond', 'Reg', (128, 135))	('sunitinib malate', 'MPA', (178, 194))	('mutations', 'Var', (35, 44))
96570	19958922	Virtually all basal cell cancers arise from mutations in PTCH (90%) and SMO (10%), When treated with GDC-0449, an investigational compound that inhibits signaling in the Hedgehog pathway, eight of nine patients with metastatic basal cell carcinoma had durable clinical benefit with minimal toxicity.	('SMO', 'Gene', (72, 75))	('Hedgehog pathway', 'Pathway', (170, 186))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', (25, 32))	('PTCH', 'Gene', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('patients', 'Species', '9606', (202, 210))	('PTC', 'Phenotype', 'HP:0002895', (57, 60))	('carcinoma', 'Disease', (238, 247))	('GDC-0449', 'Chemical', 'MESH:C538724', (101, 109))	('toxicity', 'Disease', 'MESH:D064420', (290, 298))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (227, 247))	('arise from', 'Reg', (33, 43))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('toxicity', 'Disease', (290, 298))	('carcinoma', 'Disease', 'MESH:D002277', (238, 247))	('PTCH', 'Gene', '5727', (57, 61))	('SMO', 'Gene', '6608', (72, 75))	('mutations', 'Var', (44, 53))
96576	19958922	With each patient's time to progression while on his or her previous course of therapy used as a basis for comparison, we found molecularly targeted treatment was associated with a longer progression-free survival.	('longer', 'PosReg', (181, 187))	('progression-free survival', 'CPA', (188, 213))	('patient', 'Species', '9606', (10, 17))	('molecularly targeted treatment', 'Var', (128, 158))
96606	19958922	For example, inhibition of angiogenesis may reduce the delivery of chemotherapeutic agents into tumors.	('delivery of chemotherapeutic agents into', 'MPA', (55, 95))	('reduce', 'NegReg', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('inhibition', 'Var', (13, 23))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('angiogenesis', 'CPA', (27, 39))
96612	19958922	In this way, an abnormality in a pathway or pattern of mutations seen in a small number of tumors when examined in the context of similar abnormalities in other tumors can yield insights regarding the pathogenesis, biologic behavior or vulnerabilities of the rare tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('mutations', 'Var', (55, 64))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', (264, 270))	('rare tumors', 'Disease', (259, 270))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('rare tumors', 'Disease', 'MESH:D035583', (259, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('abnormality', 'Var', (16, 27))	('yield insights', 'Reg', (172, 186))
96632	33178590	A total of 10,967 tumor samples comprising 32 cancer types from The Cancer Genome Atlas (TCGA) datasets were analyzed for MET abnormal expression, mutations, and copy number variants (CNVs).	('MET', 'Gene', '79811', (122, 125))	('mutations', 'Var', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', (18, 23))	('cancer', 'Disease', (46, 52))	('MET', 'Gene', (122, 125))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('Cancer', 'Disease', (68, 74))	('copy number variants', 'Var', (162, 182))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
96634	33178590	Lung adenocarcinoma (LUAD) has most targetable mutations located in the juxtamembrane domain, and both high expression and amplification of MET are significantly associated with poor prognosis.	('MET', 'Gene', '79811', (140, 143))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('MET', 'Gene', (140, 143))	('mutations', 'Var', (47, 56))	('associated', 'Reg', (162, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('amplification', 'Var', (123, 136))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))
96639	33178590	This study provided significant and comprehensive information regarding MET abnormal expression, alterations (mutations and CNVs), and their clinical associations among 32 cancer types and offered insights into the full MET alteration spectrum and its implications for prognosis and treatment.	('MET', 'Gene', '79811', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('abnormal', 'Var', (76, 84))	('MET', 'Gene', (220, 223))	('alterations', 'Var', (97, 108))	('MET', 'Gene', '79811', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('MET', 'Gene', (72, 75))	('cancer', 'Disease', (172, 178))	('associations', 'Interaction', (150, 162))
96642	33178590	It is frequently activated in human tumors by various mechanisms, such as mutations, amplification, and overexpression, thus leading to malignant transformation and metastasis.	('leading to', 'Reg', (125, 135))	('malignant transformation', 'CPA', (136, 160))	('metastasis', 'CPA', (165, 175))	('human', 'Species', '9606', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('overexpression', 'Var', (104, 118))	('mutations', 'Var', (74, 83))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
96645	33178590	Moreover, in esophageal carcinoma (ESCA) and kidney renal papillary cell carcinoma (KIRP), gene amplification with consequent protein overexpression and constitutive kinase activation of MET has been reported.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (13, 33))	('protein', 'Protein', (126, 133))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (13, 33))	('overexpression', 'PosReg', (134, 148))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (52, 82))	('MET', 'Gene', '79811', (187, 190))	('ESCA', 'Phenotype', 'HP:0011459', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('MET', 'Gene', (187, 190))	('kidney renal papillary cell carcinoma', 'Disease', (45, 82))	('gene amplification', 'Var', (91, 109))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (45, 82))	('esophageal carcinoma', 'Disease', (13, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
96648	33178590	Especially in lung cancer, inhibition of MET receptor activity has shown promising results and has become a standard therapy for patients.	('patients', 'Species', '9606', (129, 137))	('MET', 'Gene', (41, 44))	('lung cancer', 'Disease', (14, 25))	('MET', 'Gene', '79811', (41, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('inhibition', 'Var', (27, 37))	('activity', 'MPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
96662	33178590	Especially, in single- and cross-cancer queries, OQL algorithm can be utilized to accurately identify copy number alterations, mutations, mRNA, and protein expression profiles.	('copy number alterations', 'Var', (102, 125))	('mRNA', 'MPA', (138, 142))	('cross-cancer', 'Disease', (27, 39))	('cross-cancer', 'Disease', 'MESH:D009369', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (127, 136))
96680	33178590	MET mutations were observed most commonly in UCEC (12.3%), SKCM (10.5%), KIRP (8.8%), bladder urothelial carcinoma (BLCA, 4.4%), COADREAD (4.4%), and LUAD (4.2%).	('KIRP', 'Disease', (73, 77))	('MET', 'Gene', '79811', (0, 3))	('bladder urothelial carcinoma', 'Disease', (86, 114))	('observed', 'Reg', (19, 27))	('COADREAD', 'Disease', (129, 137))	('MET', 'Gene', (0, 3))	('UCEC', 'Disease', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('mutations', 'Var', (4, 13))	('SKCM', 'Disease', (59, 63))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (86, 114))
96686	33178590	The most common domains were the other domain (91 samples), Sema domain (83 samples), Pkinase-Tyr domain (69 samples), TIG domain (563-654 aa, 18 samples), TIG domain (742-815 aa, 17 samples), TIG domain (657-728 aa, 12 samples), and PSI domain (7 samples).	('Sema', 'Gene', '7869', (60, 64))	('Tyr', 'Chemical', 'MESH:D014443', (94, 97))	('657-728 aa', 'Var', (205, 215))	('Sema', 'Gene', (60, 64))
96688	33178590	Mutations in KIRP were primarily located in the Pkinase-Tyr domain, approximately three times more than the mutations located in the other domain.	('Tyr', 'Chemical', 'MESH:D014443', (56, 59))	('Mutations', 'Var', (0, 9))	('KIRP', 'Gene', (13, 17))
96689	33178590	Mutations in COADREAD and GBM were mainly located in the Sema domain (Figure 2B and Supplementary Table S3).	('located', 'Reg', (42, 49))	('GBM', 'Gene', (26, 29))	('Sema', 'Gene', (57, 61))	('Sema', 'Gene', '7869', (57, 61))	('Mutations', 'Var', (0, 9))	('COADREAD', 'Gene', (13, 21))
96692	33178590	For example, the 1,010-aa mutation was found in seven samples (six samples with X1010 splice, one with D1010fs) and occurred almost exclusively in LUAD (6/7) (Supplementary Figure S2B).	('D1010fs', 'Var', (103, 110))	('D1010fs', 'Mutation', 'p.D1010fsX', (103, 110))	('X1010 splice', 'Var', (80, 92))	('LUAD', 'Phenotype', 'HP:0030078', (147, 151))
96695	33178590	The only other tumor with mutations at this position was LGG (one sample with X1010_splice), but its role was almost unknown to this cancer.	('LGG', 'Disease', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (133, 139))	('tumor', 'Disease', (15, 20))	('X1010_splice', 'Var', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
96696	33178590	The 1,148-aa mutation in the Pkinase-Tyr domain was also observed in seven samples [six samples with R1148Q (three SKCMs, one BLCA, one BRCA, one COADREAD), one sample with R1148* (one UCEC)].	('R1148*', 'Var', (173, 179))	('observed', 'Reg', (57, 65))	('Pkinase-Tyr', 'Enzyme', (29, 40))	('R1148Q', 'Var', (101, 107))	('R1148Q', 'Mutation', 'p.R1148Q', (101, 107))	('Tyr', 'Chemical', 'MESH:D014443', (37, 40))	('R1148*', 'SUBSTITUTION', 'None', (173, 179))
96698	33178590	The most mutated positions in KIRP (17 of 25 mutations) were located at the Pkinase Tyr domain, especially at the 1,250-aa position (four samples with M1250T) and the 1,092- to 1,094-aa position (three with V1092I, three with H1094Y).	('H1094Y', 'Var', (226, 232))	('V1092I', 'Var', (207, 213))	('M1250T', 'Var', (151, 157))	('Tyr', 'Chemical', 'MESH:D014443', (84, 87))	('V1092I', 'Mutation', 'p.V1092I', (207, 213))	('H1094Y', 'Mutation', 'p.H1094Y', (226, 232))	('M1250T', 'Mutation', 'p.M1250T', (151, 157))	('mutated', 'Reg', (9, 16))
96700	33178590	The most mutated positions in UCEC (3 of 78 mutations) were located at the Pkinase-Tyr domain at the 1,186-aa position (one with L1186F, one with L1186I, one with L1186R), but its oncogenic role was considered unknown.	('L1186F', 'Mutation', 'p.L1186F', (129, 135))	('Tyr', 'Chemical', 'MESH:D014443', (83, 86))	('L1186F', 'Var', (129, 135))	('L1186I', 'Mutation', 'p.L1186I', (146, 152))	('L1186R', 'Mutation', 'p.L1186R', (163, 169))	('L1186I', 'Var', (146, 152))	('L1186R', 'Var', (163, 169))	('mutated', 'Reg', (9, 16))
96701	33178590	D1228Y/A and T222K alterations were found in UCEC (one with D1228Y, one with D1228A, one with T222K) and known to be likely oncogenic and predicted oncogenic, respectively (Supplementary Figure S2D).	('D1228Y', 'SUBSTITUTION', 'None', (60, 66))	('T222K', 'Var', (13, 18))	('D1228A', 'Var', (77, 83))	('D1228Y', 'Var', (60, 66))	('T222K', 'Mutation', 'p.T222K', (94, 99))	('D1228Y', 'Mutation', 'p.D1228Y', (0, 6))	('D1228A', 'Mutation', 'p.D1228A', (77, 83))	('D1228Y', 'SUBSTITUTION', 'None', (0, 6))	('D1228Y', 'Var', (0, 6))	('UCEC', 'Disease', (45, 49))	('D1228Y', 'Mutation', 'p.D1228Y', (60, 66))	('T222K', 'Mutation', 'p.T222K', (13, 18))
96703	33178590	Next, we analyzed the clinical targeted therapy implications of MET mutation using cBioPortal, which could provide the annotation of variants from different databases, including COSMIC, Cancer Hotspots method, CIViC, My Cancer Genome, and OncoKB.	('MET', 'Gene', (64, 67))	('MET', 'Gene', '79811', (64, 67))	('CIViC', 'Disease', 'None', (210, 215))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('CIViC', 'Disease', (210, 215))	('Cancer', 'Disease', (220, 226))	('Cancer', 'Disease', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (220, 226))	('Cancer', 'Phenotype', 'HP:0002664', (220, 226))	('variants', 'Var', (133, 141))
96704	33178590	Thus, for the clinical targeted therapy implications, each MET somatic mutation could be classified into four levels as defined by OncoKB: level 2 (seven mutations), level 3B (one mutation), level 4 (13 mutations), and level NA (290 mutations) (Figure 4A and Supplementary Table S2).	('MET', 'Gene', '79811', (59, 62))	('MET', 'Gene', (59, 62))	('mutations', 'Var', (154, 163))
96711	33178590	Among the 311 samples with MET mutations mentioned above, 129 also harbored MET CNVs (108 with gain, nine with amplification, and 12 with shallow deletion).	('mutations', 'Var', (31, 40))	('MET', 'Gene', (27, 30))	('MET', 'Gene', '79811', (76, 79))	('MET', 'Gene', (76, 79))	('gain', 'PosReg', (95, 99))	('MET', 'Gene', '79811', (27, 30))
96713	33178590	As shown in Figure 5A and Figures 1A,B, KIRP harbored a very high proportion of gain and was also the cancer type with higher MET expression.	('MET', 'Gene', '79811', (126, 129))	('KIRP', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MET', 'Gene', (126, 129))	('gain', 'PosReg', (80, 84))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
96718	33178590	MET alterations were observed most commonly in UCEC (10.21%), SKCM (10.14%), and KIRP (9.89%), in which mutations were more common.	('SKCM', 'Disease', (62, 66))	('MET', 'Gene', '79811', (0, 3))	('alterations', 'Var', (4, 15))	('UCEC', 'Disease', (47, 51))	('MET', 'Gene', (0, 3))	('KIRP', 'Disease', (81, 85))	('observed', 'Reg', (21, 29))
96719	33178590	Other cancer types with dominant MET mutations but at much lower mutation rates included LUAD (3.53%), BLCA (3.89%), COADREAD (3.2%), UCS (3.51%), and PAAD (0.54%).	('COADREAD', 'Disease', (117, 125))	('LUAD', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('UCS', 'Disease', (134, 137))	('PAAD', 'Phenotype', 'HP:0006725', (151, 155))	('PAAD', 'Disease', (151, 155))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('BLCA', 'Disease', (103, 107))	('MET', 'Gene', '79811', (33, 36))	('cancer', 'Disease', (6, 12))	('MET', 'Gene', (33, 36))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
96722	33178590	Approximately half of the mutations (29 of 67 mutations) in the Pkinase-Tyr domain also had MET copy gain, while nearly half of the mutations (44 of 90 mutations) in the other function-unknown domain were accompanied by amplification, gain, and shallow deletion.	('Pkinase-Tyr', 'Gene', (64, 75))	('copy', 'MPA', (96, 100))	('mutations', 'Var', (46, 55))	('MET', 'Gene', (92, 95))	('mutations', 'Var', (132, 141))	('gain', 'PosReg', (101, 105))	('amplification', 'MPA', (220, 233))	('Tyr', 'Chemical', 'MESH:D014443', (72, 75))	('mutations', 'Var', (26, 35))	('gain', 'PosReg', (235, 239))	('MET', 'Gene', '79811', (92, 95))
96729	33178590	Moreover, when the survival association analysis was performed only for MET mutation status, MET mutations were associated with poor prognosis in LUAD (Figure 7D).	('mutations', 'Var', (97, 106))	('LUAD', 'Phenotype', 'HP:0030078', (146, 150))	('MET', 'Gene', '79811', (93, 96))	('LUAD', 'Disease', (146, 150))	('MET', 'Gene', '79811', (72, 75))	('MET', 'Gene', (93, 96))	('MET', 'Gene', (72, 75))
96731	33178590	UCEC, SKCM, and KIRP had the highest MET alteration, and mutations accounted for the major proportion.	('MET', 'Gene', (37, 40))	('mutations', 'Var', (57, 66))	('MET', 'Gene', '79811', (37, 40))
96732	33178590	While mutations in UCEC and SKCM were most commonly located in the Sema domain and the other function-unknown domain, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is more important for treatment selection.	('KIRP', 'Gene', (131, 135))	('located', 'Reg', (52, 59))	('Sema', 'Gene', (67, 71))	('mutations', 'Var', (118, 127))	('Sema', 'Gene', '7869', (67, 71))	('Tyr', 'Chemical', 'MESH:D014443', (174, 177))	('mutations', 'Var', (6, 15))	('UCEC', 'Gene', (19, 23))
96734	33178590	Other cancer types, including LUAD, BLCA, COADREAD, and UCS harbored similar characteristics; all their alteration frequency was between 4 and 6%, and mutation was the primary alteration.	('LUAD', 'Disease', (30, 34))	('BLCA', 'Disease', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('COADREAD', 'Disease', (42, 50))	('UCS', 'Disease', (56, 59))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))
96735	33178590	Mutations in LUAD are mainly X1010_splices, which are in exon 14, and mutations in this region are known for targeted therapy in clinical practice in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('LUAD', 'Gene', (13, 17))	('X1010_splices', 'Var', (29, 42))	('NSCLC', 'Disease', (150, 155))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))
96743	33178590	In addition, the prognostic role of MET in LUAD was quite clear, and both high expression and amplification of MET were significantly associated with poor prognosis.	('associated', 'Reg', (134, 144))	('amplification', 'Var', (94, 107))	('high', 'Var', (74, 78))	('MET', 'Gene', '79811', (111, 114))	('MET', 'Gene', (111, 114))	('MET', 'Gene', '79811', (36, 39))	('MET', 'Gene', (36, 39))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))
96746	33178590	Compared with other cancer types, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is known for targeted therapy with TKIs.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Tyr', 'Chemical', 'MESH:D014443', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('mutations', 'Var', (34, 43))
96749	33178590	In addition, high expression of MET was discovered in KIRP, and most mutations in KIRP were oncogenic and likely oncogenic; however, there was no association observed between MET expression and patient prognosis in this dataset, although some reports indicated otherwise.	('MET', 'Gene', '79811', (175, 178))	('mutations', 'Var', (69, 78))	('patient', 'Species', '9606', (194, 201))	('MET', 'Gene', (175, 178))	('KIRP', 'Gene', (82, 86))	('MET', 'Gene', '79811', (32, 35))	('MET', 'Gene', (32, 35))
96750	33178590	This paradox could be due to the absence of well-known responsive mutations and the presence of alternative compensatory pathways interacting with MET pathways, such as the MAPK/ERK and PI3K/AKT pathways, which inspired further research on combinatorial therapy strategies in KIRP.	('mutations', 'Var', (66, 75))	('MET', 'Gene', '79811', (147, 150))	('AKT', 'Gene', '207', (191, 194))	('MET', 'Gene', (147, 150))	('AKT', 'Gene', (191, 194))	('ERK', 'Gene', '2048', (178, 181))	('ERK', 'Gene', (178, 181))
96752	33178590	It is well known that genomic instability and high mutation rates cause cancer to acquire numerous mutations during evolution.	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('genomic instability', 'Var', (22, 41))	('cancer', 'Disease', (72, 78))
96755	33178590	However, several recent reports have showed that passenger mutations may also have critical functional roles in driving cancer, with some authors describing them as mini drivers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (120, 126))	('mutations', 'Var', (59, 68))
96756	33178590	They found that the aggregated impact of putative passenger mutations could provide significant predictive power to distinguish cancer from non-cancer phenotypes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('non-cancer', 'Disease', 'MESH:D009369', (140, 150))	('cancer', 'Disease', (144, 150))	('non-cancer', 'Disease', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (128, 134))
96757	33178590	The above content implied to us that in some types of cancers, such as UCEC, even most of these mutations belonged to the unknown class; more efforts are needed to determine the meanings of these mutations, which might be found to also have important functional roles in driving tumorigenesis.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('cancers', 'Disease', (54, 61))	('UCEC', 'Disease', (71, 75))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Disease', (279, 284))	('mutations', 'Var', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mutations', 'Var', (96, 105))
96758	33178590	In addition, several reports have showed that some gene mutations, like BRAF mutation and ERBB2 mutation, were associated with MSI status in several cancer types.	('cancer', 'Disease', (149, 155))	('BRAF', 'Gene', (72, 76))	('MSI status', 'Disease', (127, 137))	('mutation', 'Var', (77, 85))	('associated', 'Reg', (111, 121))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('BRAF', 'Gene', '673', (72, 76))	('ERBB2', 'Gene', '2064', (90, 95))	('ERBB2', 'Gene', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
96778	33178590	Some alterations are more involved in the development of tumors, while others participate more in targeted therapy.	('involved', 'Reg', (26, 34))	('participate', 'Reg', (78, 89))	('alterations', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
96837	32295220	Cytoreduction was CC0, CC1, and CC2 in 11, 1, and 2 cases, respectively.	('CC2', 'Var', (32, 35))	('CC1', 'Gene', '6358', (23, 26))	('CC0', 'Var', (18, 21))	('CC1', 'Gene', (23, 26))
96845	32295220	Abdominal disease progressed in all patients with CC1-2 resections despite mitotane and multiple chemotherapy schemas.	('CC1-2', 'Gene', (50, 55))	('CC1-2', 'Gene', '6358', (50, 55))	('patients', 'Species', '9606', (36, 44))	('mitotane', 'Chemical', 'MESH:D008939', (75, 83))	('resections', 'Var', (56, 66))	('progressed', 'PosReg', (18, 28))	('Abdominal disease', 'Disease', (0, 17))
96897	30102398	FACER: comprehensive molecular and functional characterization of epigenetic chromatin regulators Epigenetic alterations, a well-recognized cancer hallmark, are driven by chromatin regulators (CRs).	('CRs', 'Chemical', '-', (193, 196))	('cancer hallmark', 'Disease', (140, 155))	('cancer hallmark', 'Disease', 'MESH:D009369', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Epigenetic alterations', 'Var', (98, 120))
96898	30102398	However, little is known about the extent of CR deregulation in cancer, and less is known about their common and specialized roles across various cancers.	('cancer', 'Disease', (146, 152))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('CR', 'Chemical', '-', (45, 47))	('cancer', 'Disease', (64, 70))	('deregulation', 'Var', (48, 60))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
96909	30102398	DNA methylators and histone modifiers can code and decode various modifications on cytosine and histone residues and are usually further divided into readers, writers, and erasers.	('cytosine', 'MPA', (83, 91))	('modifications', 'Var', (66, 79))	('cytosine', 'Chemical', 'MESH:D003596', (83, 91))	('histone', 'Protein', (96, 103))
96912	30102398	Chromatin remodelers are a special type of CRs that can disrupt the contact between nucleosomes and DNA, shuffle nucleosomes around, replace them or remove them from the chromatin, and cause abnormal epigenetic modifications.	('contact', 'Interaction', (68, 75))	('epigenetic modifications', 'MPA', (200, 224))	('cause', 'Reg', (185, 190))	('replace', 'Reg', (133, 140))	('disrupt', 'NegReg', (56, 63))	('CRs', 'Chemical', '-', (43, 46))	('shuffle', 'Var', (105, 112))	('remove', 'NegReg', (149, 155))
96913	30102398	The alteration of epigenetic marks is a prevalent feature in cancer.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('alteration', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('epigenetic marks', 'Var', (18, 34))
96915	30102398	For example, it is widely accepted that mutations can perturb CR functions.	('CR functions', 'CPA', (62, 74))	('mutations', 'Var', (40, 49))	('perturb', 'NegReg', (54, 61))	('CR', 'Chemical', '-', (62, 64))
96916	30102398	have found that genetic alteration of DNMT3A (a DNA methylation transferase) can induce genome-wide alterations of DNA methylation and gene expression.	('gene expression', 'MPA', (135, 150))	('genetic alteration', 'Var', (16, 34))	('alterations', 'Reg', (100, 111))	('DNMT3A', 'Gene', (38, 44))	('DNMT3A', 'Gene', '1788', (38, 44))	('DNA methylation', 'MPA', (115, 130))
96917	30102398	Moreover, patients with DNMT3A mutations have poor prognosis compared with those without such mutations.	('DNMT3A', 'Gene', (24, 30))	('DNMT3A', 'Gene', '1788', (24, 30))	('mutations', 'Var', (31, 40))	('patients', 'Species', '9606', (10, 18))
96920	30102398	They found that dysregulation of these CRs results in structural abnormalities in chromatins and epigenetic alterations of numerous cancer-associated genes, which finally lead to increased tumor volume, extracapsular extension, and metastases in prostate cancer patients.	('numerous cancer', 'Disease', 'MESH:D009369', (123, 138))	('structural abnormalities', 'Disease', (54, 78))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('increased', 'PosReg', (179, 188))	('structural abnormalities', 'Disease', 'MESH:C566527', (54, 78))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('metastases in prostate cancer', 'Disease', 'MESH:D009362', (232, 261))	('chromatins', 'Protein', (82, 92))	('metastases in prostate cancer', 'Disease', (232, 261))	('prostate cancer', 'Phenotype', 'HP:0012125', (246, 261))	('numerous cancer', 'Disease', (123, 138))	('epigenetic alterations', 'Var', (97, 119))	('extracapsular extension', 'CPA', (203, 226))	('dysregulation', 'Var', (16, 29))	('tumor', 'Disease', (189, 194))	('CRs', 'Chemical', '-', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('patients', 'Species', '9606', (262, 270))
96921	30102398	These studies demonstrate that CRs hold crucial roles in epigenetics and that various molecular alterations can cause functional perturbation of CRs.	('cause', 'Reg', (112, 117))	('alterations', 'Var', (96, 107))	('CRs', 'Chemical', '-', (145, 148))	('CRs', 'Chemical', '-', (31, 34))
96951	30102398	To evaluate the global regulatory effect of a given CR on the DNA hypermethylation (or hypomethylation) in a specific cancer type, we computed the significance of Pearson correlation (P value) between CR expression and aberrant hypermethylation (or hypomethylation) of tumor samples.	('CR', 'Chemical', '-', (52, 54))	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('cancer', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('aberrant', 'Var', (219, 227))	('tumor', 'Disease', (269, 274))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CR', 'Chemical', '-', (201, 203))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
97027	30102398	Mutation frequency and centrality in PPIN were found to be the top two recurrent features (Figure 2I), which were involved in 25 and 29 cancer types, respectively.	('Mutation frequency', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('PPIN', 'Gene', (37, 41))	('cancer', 'Disease', (136, 142))	('involved', 'Reg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
97038	30102398	Moreover, we found that DNA methylation readers and histone modification writers were the most common functional CRs across all 33 cancer types (Figure 3A).	('cancer', 'Disease', (131, 137))	('DNA methylation readers', 'Var', (24, 47))	('histone modification writers', 'Var', (52, 80))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CRs', 'Chemical', '-', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
97041	30102398	Moreover, histone modification readers and writers as well as chromatin remodelers played important roles across cancer types compared with DNA methylation erasers and histone modification erasers (Figure 3B, bottom).	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('histone', 'Var', (10, 17))	('cancer', 'Disease', (113, 119))	('played', 'Reg', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
97047	30102398	Functional enrichment analysis showed that DNA methylators, histone modifiers and chromatin remodelers were all enriched in at least one cancer hallmark, especially in the hallmark 'genome instability and mutation', highlighting the extent of genome alternations in cancer (Supplementary Figure S8 and Supplementary Table S5).	("mutation'", 'Var', (205, 214))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('Supplementary Figure S8', 'Disease', (274, 297))	('cancer', 'Disease', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer hallmark', 'Disease', (137, 152))	('cancer', 'Disease', (137, 143))	('cancer hallmark', 'Disease', 'MESH:D009369', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('Supplementary Figure S8', 'Disease', 'MESH:D017034', (274, 297))
97049	30102398	Functional histone modifiers in almost all cancer types were enriched in the functions 'evading apoptosis', 'genome instability and mutation', 'insensitivity to antigrowth signals', and 'self-sufficiency in growth signals'.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	("'evading", 'Disease', (87, 95))	('sufficiency in growth', 'Phenotype', 'HP:0001510', (192, 213))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	("mutation'", 'Var', (132, 141))
97061	30102398	For example, we found that PHF19, a writer for H3K36me3 as a component of polycomb repressive complex 2 (PRC2), was prioritized as a breast invasive carcinoma (BRCA) related CR in our analyses.	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('H3K36me3', 'Var', (47, 55))	('PHF19', 'Gene', '26147', (27, 32))	('BRCA', 'Phenotype', 'HP:0003002', (160, 164))	('PHF19', 'Gene', (27, 32))	('BRCA', 'Gene', '672', (160, 164))	('BRCA', 'Gene', (160, 164))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (133, 158))	('CR', 'Chemical', '-', (174, 176))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (133, 158))	('breast invasive carcinoma', 'Disease', (133, 158))
97064	30102398	Moreover, the genome-wide H3K36me3 marks showed an obvious increase in cancer.	('H3K36me3 marks', 'Var', (26, 40))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('increase', 'PosReg', (59, 67))
97079	30102398	Among these CRs, 14 were up-regulated in cancer, and 1 was down-regulated (Supplementary Figure S11A).	('up-regulated', 'PosReg', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('CRs', 'Chemical', '-', (12, 15))	('S11A', 'Var', (96, 100))	('down-regulated', 'NegReg', (59, 73))	('S11A', 'SUBSTITUTION', 'None', (96, 100))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
97080	30102398	Interestingly, 11 of these 15 CRs showed consistent deregulation across cancer types compared with the corresponding adjacent normal samples (Supplementary Figure S11B).	('deregulation', 'MPA', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CRs', 'Chemical', '-', (30, 33))	('S11B', 'Var', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('S11B', 'SUBSTITUTION', 'None', (163, 167))	('cancer', 'Disease', (72, 78))
97087	30102398	For cancer-specific CRs, we found that these CRs included 36% of the DNA methylation erasers and 35% of the histone modification erasers.	('CRs', 'Chemical', '-', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (4, 10))	('histone modification', 'MPA', (108, 128))	('methylation', 'Var', (73, 84))	('DNA', 'MPA', (69, 72))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('CRs', 'Chemical', '-', (45, 48))
97095	30102398	KMT2C showed a higher mutation frequency in KIRP patients, whereas the aberrant regulation of miRNAs and its regulation of DNA methylation over open sea regions were additional features in KICH patients.	('mutation', 'Var', (22, 30))	('KICH', 'Disease', (189, 193))	('patients', 'Species', '9606', (194, 202))	('DNA methylation', 'MPA', (123, 138))	('KMT2C', 'Gene', '58508', (0, 5))	('KMT2C', 'Gene', (0, 5))	('KICH', 'Disease', 'None', (189, 193))	('patients', 'Species', '9606', (49, 57))
97101	30102398	We found that common CRs in cancer had higher values for all seven features compared with specific CRs, especially in four functional features (all P < 0.05, Wilcoxon rank-sum test), including mutation frequency, differential expression, degree in PPIN, and regulation of genome hypermethylation (Figure 5C, top, and Supplementary Table S8).	('higher', 'PosReg', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutation frequency', 'Var', (193, 211))	('CRs', 'Chemical', '-', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('CRs', 'Chemical', '-', (21, 24))	('PPIN', 'Protein', (248, 252))	('cancer', 'Disease', (28, 34))	('differential expression', 'MPA', (213, 236))
97127	30102398	Patients in subtype 1 of ACC showed the highest mutation frequency of TP53 and CGI methylation, while patients in subtype 3 showed high mutation of KDM6B and the lowest open sea methylation.	('TP53', 'Gene', '7157', (70, 74))	('patients', 'Species', '9606', (102, 110))	('KDM6B', 'Gene', '23135', (148, 153))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', (70, 74))	('mutation', 'Var', (48, 56))	('ACC', 'Phenotype', 'HP:0006744', (25, 28))	('KDM6B', 'Gene', (148, 153))	('methylation', 'Var', (83, 94))	('CGI', 'Protein', (79, 82))
97152	30102398	Analysis of the functional features revealed recurrent multi-omics effects of functional CRs across 33 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('effects', 'Reg', (67, 74))	('CRs', 'Chemical', '-', (89, 92))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('functional', 'Var', (78, 88))
97157	30102398	By comparison between common, specific and mixed CRs as well as DNA methylators, histone modifiers and chromatin remodelers, we found that DNA methylation readers as well as histone modification readers and writers were with more common CRs, suggesting that these three categories of CRs tend to be aberrant across cancer types.	('methylation', 'Var', (143, 154))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('DNA', 'Var', (139, 142))	('cancer', 'Disease', (315, 321))	('CRs', 'Chemical', '-', (284, 287))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('CRs', 'Chemical', '-', (237, 240))	('CRs', 'Chemical', '-', (49, 52))
97158	30102398	We also found that DNA methylation erasers and histone modification erasers tend to be dysregulated in specific cancer type.	('DNA', 'MPA', (19, 22))	('histone modification', 'MPA', (47, 67))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('methylation', 'Var', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
97164	30102398	Moreover, we found that DNA methylators and histone modifiers can induce the development of cancer by regulation of DNA methylation and histone modifications, such as DNMT1, DNMT3A and PHF19.	('PHF19', 'Gene', '26147', (185, 190))	('histone', 'Protein', (136, 143))	('cancer', 'Disease', (92, 98))	('development of', 'CPA', (77, 91))	('PHF19', 'Gene', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('DNMT3A', 'Gene', (174, 180))	('DNMT3A', 'Gene', '1788', (174, 180))	('induce', 'PosReg', (66, 72))	('DNMT1', 'Gene', (167, 172))	('DNA', 'MPA', (116, 119))	('DNMT1', 'Gene', '1786', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('modifications', 'Var', (144, 157))
97200	25587902	In humans, the 915C allele of a single nucleotide polymorphism in the TGFbeta1 gene (TGFB1), which leads to proline at residue 25 within the signal peptide sequence, has been associated in a population with a reduced risk of hypertension.	('TGFB1', 'Gene', (85, 90))	('hypertension', 'Phenotype', 'HP:0000822', (225, 237))	('hypertension', 'Disease', (225, 237))	('proline', 'Chemical', 'MESH:D011392', (108, 115))	('humans', 'Species', '9606', (3, 9))	('hypertension', 'Disease', 'MESH:D006973', (225, 237))	('TGFB1', 'Gene', '7040', (85, 90))	('single nucleotide polymorphism', 'Var', (32, 62))
97211	25587902	have reported that the stimulation of TGFbeta1 mRNA expression by aldosterone is significantly inhibited by an extracellular-signal regulated kinase 1/2 inhibitor PD98059, a c-Jun N-terminal kinase inhibitor SP600125, or an activator protein-1 inhibitor curcumin in rat mesangial cells.	('SP600125', 'Chemical', 'MESH:C432165', (208, 216))	('inhibited', 'NegReg', (95, 104))	('rat', 'Species', '10116', (266, 269))	('aldosterone', 'Chemical', 'MESH:D000450', (66, 77))	('mRNA expression', 'MPA', (47, 62))	('PD98059', 'Var', (163, 170))	('activator protein-1', 'Gene', '16476', (224, 243))	('curcumin', 'Chemical', 'MESH:D003474', (254, 262))	('TGFbeta1', 'Gene', (38, 46))	('stimulation', 'MPA', (23, 34))	('PD98059', 'Chemical', 'MESH:C093973', (163, 170))	('activator protein-1', 'Gene', (224, 243))
97214	25587902	Additionally, urinary TGFbeta1 has been found to be associated with increasing interstitial fibrosis as well as proteinuria and mesangial expansion in patients with certain glomerulonephritides.	('fibrosis', 'Disease', 'MESH:D005355', (92, 100))	('fibrosis', 'Disease', (92, 100))	('urinary', 'Var', (14, 21))	('proteinuria', 'Disease', 'MESH:D011507', (112, 123))	('mesangial expansion', 'CPA', (128, 147))	('TGFbeta1', 'Gene', (22, 30))	('patients', 'Species', '9606', (151, 159))	('increasing', 'PosReg', (68, 78))	('mesangial expansion', 'Phenotype', 'HP:0012574', (128, 147))	('proteinuria', 'Disease', (112, 123))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (79, 100))	('proteinuria', 'Phenotype', 'HP:0000093', (112, 123))
97219	25587902	In contrast to the stimulatory effect of aldosterone on the expression of TGFbeta1, TGFbeta1 has been shown to exert potent inhibitory effects on aldosterone synthesis in cultured adrenocortical cells.	('TGFbeta1', 'Gene', (74, 82))	('aldosterone synthesis', 'MPA', (146, 167))	('adrenocortical', 'Disease', (180, 194))	('aldosterone', 'Chemical', 'MESH:D000450', (41, 52))	('adrenocortical', 'Disease', 'MESH:D018268', (180, 194))	('TGFbeta1', 'Var', (84, 92))	('aldosterone', 'Chemical', 'MESH:D000450', (146, 157))	('inhibitory effects', 'MPA', (124, 142))
97229	25587902	Higher than normal levels of TGFbeta1 lead to reduced plasma aldosterone levels despite the plasma volume being decreased, due to reduced expression of Cyp11b1, Cyp11b2, Hsd3b1, and Star, whereas lower than normal levels of TGFbeta1 lead to increased plasma aldosterone levels despite the plasma volume being expanded, due to increased expression of these genes.	('expression', 'MPA', (138, 148))	('decreased', 'NegReg', (112, 121))	('TGFbeta1', 'Gene', (29, 37))	('aldosterone', 'Chemical', 'MESH:D000450', (61, 72))	('expression', 'MPA', (336, 346))	('Hsd3b1', 'Gene', (170, 176))	('Star', 'Gene', (182, 186))	('plasma aldosterone levels', 'Phenotype', 'HP:0000859', (54, 79))	('Cyp11b1', 'Var', (152, 159))	('increased', 'PosReg', (241, 250))	('plasma aldosterone levels', 'Phenotype', 'HP:0000859', (251, 276))	('reduced plasma aldosterone', 'Phenotype', 'HP:0004319', (46, 72))	('reduced', 'NegReg', (46, 53))	('increased', 'PosReg', (326, 335))	('plasma aldosterone levels', 'MPA', (54, 79))	('aldosterone', 'Chemical', 'MESH:D000450', (258, 269))	('increased plasma aldosterone', 'Phenotype', 'HP:0000859', (241, 269))	('plasma aldosterone levels', 'MPA', (251, 276))	('Star', 'Gene', '20845', (182, 186))	('Cyp11b2', 'Var', (161, 168))	('reduced', 'NegReg', (130, 137))	('plasma volume', 'MPA', (92, 105))
97230	25587902	In addition to the alteration in plasma aldosterone levels, corticosterone levels were also significantly higher than normal in TGFbeta1 hypomorphic mice, whereas in hypermorphic mice plasma aldosterone levels were significantly lower than normal.	('aldosterone', 'Chemical', 'MESH:D000450', (40, 51))	('plasma aldosterone levels', 'Phenotype', 'HP:0000859', (33, 58))	('aldosterone', 'Chemical', 'MESH:D000450', (191, 202))	('mice', 'Species', '10090', (179, 183))	('rat', 'Species', '10116', (23, 26))	('hypomorphic', 'Var', (137, 148))	('corticosterone levels', 'MPA', (60, 81))	('higher', 'PosReg', (106, 112))	('plasma aldosterone levels', 'MPA', (33, 58))	('corticosterone', 'Chemical', 'MESH:D003345', (60, 74))	('mice', 'Species', '10090', (149, 153))	('alteration', 'Reg', (19, 29))	('TGFbeta1', 'Gene', (128, 136))	('plasma aldosterone levels', 'Phenotype', 'HP:0000859', (184, 209))
97232	25587902	Additionally, the hypomorphic mice had a markedly higher systolic blood pressure and less natriuresis than WT mice, which was normalized by administration of spironolactone, a mineralocorticoid receptor antagonist, or amiloride, an epithelial sodium channel (ENaC) blocker.	('mice', 'Species', '10090', (30, 34))	('ENaC', 'Gene', (259, 263))	('higher', 'PosReg', (50, 56))	('rat', 'Species', '10116', (148, 151))	('mineralocorticoid receptor', 'Gene', '110784', (176, 202))	('higher systolic blood pressure', 'Phenotype', 'HP:0004421', (50, 80))	('amiloride', 'Chemical', 'MESH:D000584', (218, 227))	('mice', 'Species', '10090', (110, 114))	('sodium', 'Chemical', 'MESH:D012964', (243, 249))	('less', 'NegReg', (85, 89))	('ENaC', 'Gene', '20276', (259, 263))	('mineralocorticoid receptor', 'Gene', (176, 202))	('systolic blood pressure', 'MPA', (57, 80))	('spironolactone', 'Chemical', 'MESH:D013148', (158, 172))	('natriuresis', 'MPA', (90, 101))	('hypomorphic', 'Var', (18, 29))
97257	25587902	PN-1 inhibited prostasin-induced ENaC activation in Xenopus oocytes, and knock down of PN-1 gene expression increased baseline sodium current in M-1 cells; a mouse cortical collecting duct cell line.	('Xenopus', 'Species', '8355', (52, 59))	('ENaC', 'Gene', (33, 37))	('PN-1', 'Gene', (87, 91))	('inhibited', 'NegReg', (5, 14))	('prostasin', 'Gene', '76560', (15, 24))	('mouse', 'Species', '10090', (158, 163))	('knock down', 'Var', (73, 83))	('baseline sodium current', 'MPA', (118, 141))	('increased', 'PosReg', (108, 117))	('sodium', 'Chemical', 'MESH:D012964', (127, 133))	('M-1', 'CellLine', 'CVCL:J159', (145, 148))	('prostasin', 'Gene', (15, 24))	('ENaC', 'Gene', '20276', (33, 37))
97287	26568275	In 1983, Ledingham and 2 other research groups found that ETO had the effect of inhibiting the synthesis and release of human adrenocortical hormones.	('adrenocortical', 'Disease', 'MESH:D018268', (126, 140))	('human', 'Species', '9606', (120, 125))	('ETO', 'Chemical', 'MESH:D005045', (58, 61))	('release', 'MPA', (109, 116))	('ETO', 'Var', (58, 61))	('inhibiting', 'NegReg', (80, 90))	('synthesis', 'MPA', (95, 104))	('adrenocortical', 'Disease', (126, 140))
97332	26568275	In other words, ETO reduced the basal secretion of CORT in a dose-dependent manner.	('reduced', 'NegReg', (20, 27))	('ETO', 'Var', (16, 19))	('CORT', 'Chemical', 'MESH:D003348', (51, 55))	('basal secretion of CORT', 'MPA', (32, 55))	('ETO', 'Chemical', 'MESH:D005045', (16, 19))
97335	26568275	The inhibitory effect reached the peak at the concentration of EXP (10.5) [36 000]nM.	('rat', 'Species', '10116', (53, 56))	('inhibitory effect', 'MPA', (4, 21))	('EXP (10.5) [36 000]nM', 'Var', (63, 84))
97348	26568275	In addition, with alteration of the ACTH concentration, a biphasic effect of either inhibition or promotion was noticed.	('promotion', 'PosReg', (98, 107))	('rat', 'Species', '10116', (22, 25))	('rat', 'Species', '10116', (48, 51))	('alteration', 'Var', (18, 28))
97356	26568275	It was found that in the dose-effect model parameters, EC50 and gamma represent the effective drug dose and the dose-response curve slope, respectively; when gamma is relatively large, the concentration-effect curve is relatively steep, and even a subtle change in the concentration would induce a relatively large change in the effect.	('gamma', 'Var', (158, 163))	('rat', 'Species', '10116', (276, 279))	('steep', 'MPA', (230, 235))	('concentration-effect curve', 'MPA', (189, 215))	('rat', 'Species', '10116', (196, 199))
97380	25741319	Pediatric Adrenocortical Tumors: What They Can Tell Us on Adrenal Development and Comparison with Adult Adrenal Tumors Adrenocortical tumors (ACT) in children are very rare and are most frequently diagnosed in the context of the Li-Fraumeni syndrome, a multiple cancer syndrome linked to germline mutations of the tumor suppressor gene TP53 with loss of heterozygosity in the tumors.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', (376, 381))	('tumor', 'Disease', (314, 319))	('loss', 'NegReg', (346, 350))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Li-Fraumeni syndrome', 'Disease', (229, 249))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('tumors', 'Disease', 'MESH:D009369', (376, 382))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('tumors', 'Disease', (134, 140))	('linked', 'Reg', (278, 284))	('diagnosed', 'Reg', (197, 206))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (229, 249))	('Adrenocortical tumors', 'Disease', 'MESH:D018268', (119, 140))	('a multiple cancer syndrome', 'Disease', (251, 277))	('Adrenocortical tumors', 'Disease', (119, 140))	('Pediatric Adrenocortical Tumors', 'Disease', (0, 31))	('TP53', 'Gene', (336, 340))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('a multiple cancer syndrome', 'Disease', 'MESH:D009369', (251, 277))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('Adrenal Tumors', 'Disease', 'MESH:D000310', (104, 118))	('tumors', 'Phenotype', 'HP:0002664', (376, 382))	('Pediatric Adrenocortical Tumors', 'Disease', 'MESH:C565973', (0, 31))	('children', 'Species', '9606', (150, 158))	('tumor', 'Disease', (134, 139))	('Tumors', 'Phenotype', 'HP:0002664', (112, 118))	('germline mutations', 'Var', (288, 306))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', (376, 382))	('Adrenal Tumors', 'Disease', (104, 118))	('TP53', 'Gene', '7157', (336, 340))
97381	25741319	A peak of children ACT incidence is present in the states of southern Brazil, where they are linked to the high prevalence in the population of a specific TP53 mutation (R337H).	('TP53', 'Gene', '7157', (155, 159))	('TP53', 'Gene', (155, 159))	('R337H', 'Mutation', 'rs121912664', (170, 175))	('R337H', 'Var', (170, 175))	('children', 'Species', '9606', (10, 18))
97390	25741319	Defects in this process may cause the cytomegalic form of adrenal hypoplasia congenita, a syndrome of adrenal insufficiency due to altered postnatal adrenocortical differentiation due to mutations in the NR0B1 (DAX-1) gene [reviewed in Ref.	('postnatal adrenocortical differentiation', 'Phenotype', 'HP:0008207', (139, 179))	('postnatal adrenocortical', 'Disease', 'MESH:D018268', (139, 163))	('adrenal hypoplasia congenita', 'Disease', 'MESH:D000312', (58, 86))	('adrenal hypoplasia congenita', 'Phenotype', 'HP:0008244', (58, 86))	('DAX-1', 'Gene', '190', (211, 216))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (102, 123))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (58, 76))	('Defects', 'Var', (0, 7))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (102, 123))	('NR0B1', 'Gene', (204, 209))	('cause', 'Reg', (28, 33))	('mutations', 'Var', (187, 196))	('DAX-1', 'Gene', (211, 216))	('cytomegalic form', 'Disease', (38, 54))	('NR0B1', 'Gene', '190', (204, 209))	('adrenal insufficiency', 'Disease', (102, 123))	('adrenal hypoplasia congenita', 'Disease', (58, 86))	('postnatal adrenocortical', 'Disease', (139, 163))
97404	25741319	Favorable prognostic factors are younger age (<4 years), stage I at diagnosis, tumor weight <=200 g, volume <200 cm3, and presence of virilization alone.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('<=200', 'Var', (92, 97))	('tumor', 'Disease', (79, 84))
97411	25741319	Conversely, IGF2 overexpression and abnormalities in the 11p15 region are a marker of malignancy in ACT of adults.	('malignancy', 'Disease', 'MESH:D009369', (86, 96))	('malignancy', 'Disease', (86, 96))	('IGF2', 'Gene', (12, 16))	('abnormalities', 'Var', (36, 49))	('overexpression', 'PosReg', (17, 31))
97412	25741319	In mouse models, Igf2 overexpression in the adrenal induces tissue hyperplasia but is not able to induce malignant tumorigenesis per se.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mouse', 'Species', '10090', (3, 8))	('hyperplasia', 'Disease', (67, 78))	('tumor', 'Disease', (115, 120))	('Igf2', 'Gene', (17, 21))	('Igf2', 'Gene', '16002', (17, 21))	('induces', 'Reg', (52, 59))	('hyperplasia', 'Disease', 'MESH:D006965', (67, 78))	('overexpression', 'Var', (22, 36))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
97415	25741319	It has been shown that in LFS, excessive DNA copy number variation exists in the patients' germline, which may predispose to cancer.	('predispose', 'Reg', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('patients', 'Species', '9606', (81, 89))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('DNA copy number variation', 'Var', (41, 66))
97416	25741319	Due to its rarity and its characteristic association with LFS, discovery of an ACT in a child is an absolute indication for researching TP53 mutations in the proband and in his/her parents as well indicative for genetic counseling.	('LFS', 'Disease', (58, 61))	('mutations', 'Var', (141, 150))	('child', 'Species', '9606', (88, 93))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))
97417	25741319	Conversely, germline TP53 mutations are much less common in adults with ACC (Table 1).	('mutations', 'Var', (26, 35))	('ACC', 'Disease', (72, 75))	('TP53', 'Gene', (21, 25))	('TP53', 'Gene', '7157', (21, 25))
97419	25741319	In the absence of p53, genetic alterations may accumulate in the adrenal driving proliferation [such as NR5A1 overexpression,; see below section on Whole Genome Studies in Children and Adult ACT Reveal Important Drivers for Tumorigenesis and LOH of 11p15 leading to IGF2 overexpression ] of specific cellular clones.	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('Tumorigenesis', 'CPA', (224, 237))	('Children', 'Species', '9606', (172, 180))	('IGF2', 'Gene', (266, 270))	('NR5A1', 'Gene', '2516', (104, 109))	('overexpression ]', 'PosReg', (271, 287))	('adrenal driving proliferation', 'CPA', (65, 94))	('LOH', 'Var', (242, 245))	('NR5A1', 'Gene', (104, 109))
97421	25741319	In classical LFS, due to TP53 mutations that completely abolish protein function, the lifetime incidence of cancer in carriers is close to 100%.	('TP53', 'Gene', (25, 29))	('LFS', 'Disease', (13, 16))	('abolish', 'NegReg', (56, 63))	('TP53', 'Gene', '7157', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (30, 39))	('protein', 'Protein', (64, 71))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
97422	25741319	However, low-penetrance mutated TP53 alleles exist that can increase the risk of developing cancer only in a fraction of carriers.	('mutated', 'Var', (24, 31))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
97424	25741319	This is related to a specific germline TP53 mutation (R337H), whose prevalence is very high (0.3%) in the population but whose penetrance to produce ACT in children has been estimated at only about 2%.	('TP53', 'Gene', (39, 43))	('children', 'Species', '9606', (156, 164))	('TP53', 'Gene', '7157', (39, 43))	('R337H', 'Mutation', 'rs121912664', (54, 59))	('R337H', 'Var', (54, 59))
97426	25741319	R337 is a conserved arginine residue in the C-terminal tetramerization domain of p53 whose mutation to histidine destabilizes p53 tetramer formation in conditions of elevated temperature and pH.	('p53', 'Gene', '7157', (126, 129))	('mutation', 'Var', (91, 99))	('arginine', 'Chemical', 'MESH:D001120', (20, 28))	('tetramer formation', 'MPA', (130, 148))	('destabilizes', 'NegReg', (113, 125))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('histidine', 'Chemical', 'MESH:D006639', (103, 112))	('p53', 'Gene', (126, 129))
97427	25741319	It has been shown that a founder effect is responsible for the spreading of the TP53 R337H mutation in the population of southern Brazil.	('TP53', 'Gene', '7157', (80, 84))	('R337H', 'Mutation', 'rs121912664', (85, 90))	('R337H', 'Var', (85, 90))	('TP53', 'Gene', (80, 84))
97428	25741319	An about 0.5 Mb identical by descent haplotype in 17p13 encompassing the TP53 gene carrying the R337H mutation is conserved in all carriers of the mutation.	('R337H', 'Mutation', 'rs121912664', (96, 101))	('R337H', 'Var', (96, 101))	('TP53', 'Gene', (73, 77))	('TP53', 'Gene', '7157', (73, 77))
97429	25741319	A newborn screening and surveillance program of the TP53 R337H mutation carriers in the state of Parana has proven to be successful to detect ACT in children at an early stage and to treat it with better therapeutic results compared to children who did not undergo surveillance.	('TP53', 'Gene', '7157', (52, 56))	('children', 'Species', '9606', (149, 157))	('TP53', 'Gene', (52, 56))	('children', 'Species', '9606', (236, 244))	('R337H', 'Mutation', 'rs121912664', (57, 62))	('R337H', 'Var', (57, 62))
97430	25741319	Apart from rare cases of germline TP53 mutations, as mentioned before, ACC in adults may also be associated to other hereditary conditions in some uncommon cases [reviewed in Ref.	('TP53', 'Gene', (34, 38))	('ACC', 'Disease', (71, 74))	('mutations', 'Var', (39, 48))	('men', 'Species', '9606', (53, 56))	('associated', 'Reg', (97, 107))	('TP53', 'Gene', '7157', (34, 38))
97447	25741319	Further studies showed that tumors classified in the C1A group could be further divided into two subgroups each one bearing either TP53 or CTNNB1 (beta-catenin) mutations and in a third subgroup with no other known mutation.	('C1A', 'Gene', (53, 56))	('CTNNB1', 'Gene', '1499', (139, 145))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('mutations', 'Var', (161, 170))	('C1A', 'Gene', '100862690', (53, 56))	('CTNNB1', 'Gene', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
97465	25741319	A subsequent SNP array study on both Brazilian and non-Brazilian ACT cases precisely defined recurrent genomic alterations in children ACT, the most frequent being loss of 4q34, gain of 9q33-q34 and 19p, and LOH of the whole chromosome 17 (harboring TP53) and 11p15 (harboring IGF2).	('loss', 'Var', (164, 168))	('gain', 'PosReg', (178, 182))	('4q34', 'Protein', (172, 176))	('children', 'Species', '9606', (126, 134))	('11p15', 'Gene', (260, 265))	('TP53', 'Gene', '7157', (250, 254))	('TP53', 'Gene', (250, 254))	('9q33-q34', 'Var', (186, 194))	('LOH', 'Var', (208, 211))
97467	25741319	It is also noteworthy that the extent of the peak region of gain in 9q33-q34 suggests that other genes lying in a telomeric position with respect to NR5A1 may also be important for ACT pathogenesis.	('9q33-q34', 'Var', (68, 76))	('gain', 'PosReg', (60, 64))	('NR5A1', 'Gene', (149, 154))	('NR5A1', 'Gene', '2516', (149, 154))
97469	25741319	Although genomic profiles in non-Brazilian tumors with a mutated TP53 (other than R337H) were similar to Brazilian tumors, those with a wild-type TP53 displayed distinct genomic alterations, harboring significantly fewer rearrangements.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('men', 'Species', '9606', (230, 233))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', '7157', (146, 150))	('TP53', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('TP53', 'Gene', (146, 150))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('mutated', 'Var', (57, 64))	('R337H', 'Mutation', 'rs121912664', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
97470	25741319	Remarkably, 50% of TP53 wild-type tumors investigated in this study displayed as sole rearrangement a copy-neutral LOH of the imprinted region at 11p15, providing further evidence for a major role of this region in ACT development.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('rearrangement', 'Var', (86, 99))	('men', 'Species', '9606', (95, 98))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('men', 'Species', '9606', (226, 229))
97472	25741319	This work confirmed LOH in the 11p15 region in the large majority of cases and systematic overexpression of IGF2, together with frequent TP53 mutations, widespread 9q copy number gain, and 4q34 loss.	('gain', 'PosReg', (179, 183))	('mutations', 'Var', (142, 151))	('IGF2', 'Gene', (108, 112))	('LOH', 'Var', (20, 23))	('loss', 'NegReg', (194, 198))	('TP53', 'Gene', '7157', (137, 141))	('overexpression', 'PosReg', (90, 104))	('TP53', 'Gene', (137, 141))
97473	25741319	By comparing the mutant allele fraction of SNV in copy-neutral LOH regions to allelic imbalance values, it was possible to establish that in most cases copy-neutral LOH of chromosomes 11p and 17 occurred early during tumorigenesis, suggesting that those events drive tumor formation.	('copy-neutral LOH', 'Var', (152, 168))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('imbalance', 'Phenotype', 'HP:0002172', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', (267, 272))
97475	25741319	Intriguingly, some tumors bore integration of human herpesvirus-6 (HHV6) in the telomeric region of chromosome 11p.	('integration', 'Var', (31, 42))	('tumors', 'Disease', (19, 25))	('HHV6', 'Species', '10368', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('human herpesvirus-6', 'Species', '10368', (46, 65))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('HHV6', 'Gene', (67, 71))
97476	25741319	A poor outcome was predicted by concomitant TP53/ATRX mutations and associated genomic abnormalities, including massive structural variations and a high background mutation rate (Table 1).	('background mutation', 'MPA', (153, 172))	('genomic abnormalities', 'Disease', (79, 100))	('mutations', 'Var', (54, 63))	('ATRX', 'Gene', (49, 53))	('genomic abnormalities', 'Disease', 'MESH:D042822', (79, 100))	('TP53', 'Gene', '7157', (44, 48))	('ATRX', 'Gene', '546', (49, 53))	('structural', 'MPA', (120, 130))	('TP53', 'Gene', (44, 48))
97478	25741319	Carcinomas were confirmed to harbor a higher number of chromosomal alterations than adenomas.	('Carcinomas', 'Disease', (0, 10))	('adenomas', 'Disease', 'MESH:D000236', (84, 92))	('chromosomal alterations', 'Var', (55, 78))	('adenomas', 'Disease', (84, 92))	('Carcinomas', 'Disease', 'MESH:D002277', (0, 10))	('Carcinomas', 'Phenotype', 'HP:0030731', (0, 10))
97479	25741319	Recently, activating mutations of the PKA catalytic subunit were shown to be associated with cortisol-secreting adrenocortical adenomas in adults.	('adrenocortical adenomas', 'Disease', (112, 135))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (112, 135))	('PKA', 'Gene', (38, 41))	('cortisol', 'Chemical', 'MESH:D006854', (93, 101))	('activating mutations', 'Var', (10, 30))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (112, 135))	('associated', 'Reg', (77, 87))
97482	25741319	This hypermethylated tumors group could in turn be subdivided into two subgroups (CIMP-high and CIMP-low), which had prognostic relevance, with the CIMP-high phenotype clearly being associated to worse prognosis.	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('CIMP', 'Chemical', '-', (82, 86))	('CIMP', 'Chemical', '-', (96, 100))	('CIMP-high', 'Var', (148, 157))	('CIMP', 'Chemical', '-', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
97483	25741319	A study integrating transcriptome, miRNome, copy number alterations, methylome, and whole exome sequencing data in adult ACC was recently published, showing that major pathways involved by mutation or homozygous deletion include beta-catenin (CTNNB1 and ZNRF3), p53/Rb signaling (TP53, CDKN2A, and RB1), and chromatin remodeling (MEN1, DAXX, ATRX, MED12, and TERT) (Table 1).	('ZNRF3', 'Gene', '84133', (254, 259))	('ZNRF3', 'Gene', (254, 259))	('MEN1', 'Gene', '4221', (330, 334))	('p53', 'Gene', '7157', (262, 265))	('CTNNB1', 'Gene', (243, 249))	('TP53', 'Gene', (280, 284))	('RB1', 'Gene', (298, 301))	('CDKN2A', 'Gene', (286, 292))	('MEN1', 'Gene', (330, 334))	('DAXX', 'Gene', (336, 340))	('p53', 'Gene', (262, 265))	('MED12', 'Gene', '9968', (348, 353))	('DAXX', 'Gene', '1616', (336, 340))	('TERT', 'Gene', (359, 363))	('TERT', 'Gene', '7015', (359, 363))	('ATRX', 'Gene', (342, 346))	('RB1', 'Gene', '5925', (298, 301))	('CDKN2A', 'Gene', '1029', (286, 292))	('TP53', 'Gene', '7157', (280, 284))	('ATRX', 'Gene', '546', (342, 346))	('mutation', 'Var', (189, 197))	('CTNNB1', 'Gene', '1499', (243, 249))	('MED12', 'Gene', (348, 353))
97487	25741319	Important fields of investigation in the future will be the search for genetic and environmental factors that modulate penetrance of ACT in carriers of germline TP53 mutations in order to orient screening procedures to detect disease at an early stage, the identification of robust biomarkers of malignancy, which are still lacking, and the clinical testing of targeted therapies against the major molecular pathways that are altered in this disease.	('TP53', 'Gene', (161, 165))	('malignancy', 'Disease', 'MESH:D009369', (296, 306))	('mutations', 'Var', (166, 175))	('men', 'Species', '9606', (90, 93))	('malignancy', 'Disease', (296, 306))	('TP53', 'Gene', '7157', (161, 165))
97488	25110710	Amplification of the Insulin-Like Growth Factor 1 Receptor Gene Is a Rare Event in Adrenocortical Adenocarcinomas: Searching for Potential Mechanisms of Overexpression Context.	('Amplification', 'Var', (0, 13))	('Adrenocortical Adenocarcinomas', 'Disease', (83, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('carcinomas', 'Disease', (103, 113))	('carcinomas', 'Disease', 'MESH:D002277', (103, 113))	('carcinoma', 'Disease', (103, 112))	('Insulin-Like Growth Factor 1 Receptor', 'Gene', '3480', (21, 58))	('Insulin-Like Growth Factor 1 Receptor', 'Gene', (21, 58))	('Adrenocortical Adenocarcinomas', 'Disease', 'MESH:D018268', (83, 113))	('carcinoma', 'Disease', 'MESH:D002277', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
97491	25110710	IGF1R copy number variation was determined in all patients using MLPA and confirmed using real time PCR.	('copy number variation', 'Var', (6, 27))	('patient', 'Species', '9606', (50, 57))	('patients', 'Species', '9606', (50, 58))	('IGF1R', 'Gene', (0, 5))
97492	25110710	IGF1R amplification was detected in an adrenocortical carcinoma that was diagnosed in a 46-year-old woman with Cushing's syndrome and virilization.	("Cushing's syndrome", 'Disease', (111, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('adrenocortical carcinoma', 'Disease', (39, 63))	('IGF1R', 'Gene', (0, 5))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (111, 129))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (39, 63))	('woman', 'Species', '9606', (100, 105))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (39, 63))	('amplification', 'Var', (6, 19))
97507	25110710	This molecular assay was designed to detect deletions/duplications of one or more exons of the IGF1R (chromosome 15q26) and IGFBP3 (chromosome 7p13) genes.	('IGF1R', 'Gene', (95, 100))	('IGFBP3', 'Gene', (124, 130))	('IGFBP3', 'Gene', '3486', (124, 130))	('deletions/duplications', 'Var', (44, 66))
97515	25110710	RNU 44 (ID: 001094, Applied Biosystems) and RNU 48 (ID: 001006, Applied Biosystems) were used as house-keeping genes.	('RNU 48', 'Gene', '26801', (44, 50))	('RNU 44', 'Gene', '26806', (0, 6))	('RNU 44', 'Gene', (0, 6))	('ID: 001094', 'Var', (8, 18))	('RNU 48', 'Gene', (44, 50))
97520	25110710	Normal growth and differentiation are result of a fine balance between the process of cell proliferation and death, and the disruption of one or more factors involved in these actions can result in pathologic phenotypes, including malignancy.	('death', 'Disease', 'MESH:D003643', (109, 114))	('death', 'Disease', (109, 114))	('differentiation', 'CPA', (18, 33))	('result in', 'Reg', (188, 197))	('malignancy', 'Disease', (231, 241))	('disruption', 'Var', (124, 134))
97521	25110710	In fact, IGF1R amplification has been reported in malignant melanomas, breast cancers, pancreatic adenocarcinomas, gastric cell lines, rhabdomyosarcomas, Wilms' tumors, and gastrointestinal stromal tumors.	('malignant melanomas', 'Phenotype', 'HP:0002861', (50, 69))	('gastric cell', 'Disease', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	("Wilms' tumors", 'Disease', (154, 167))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (87, 113))	('IGF1R', 'Gene', (9, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('pancreatic adenocarcinomas', 'Disease', (87, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (135, 152))	('rhabdomyosarcomas', 'Disease', (135, 152))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (173, 204))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (173, 204))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (135, 152))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (87, 113))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('malignant melanomas', 'Disease', 'MESH:D008545', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('malignant melanomas', 'Disease', (50, 69))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancers', 'Disease', (71, 85))	('breast cancers', 'Disease', 'MESH:D001943', (71, 85))	("Wilms' tumors", 'Disease', 'MESH:D009396', (154, 167))	('amplification', 'Var', (15, 28))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('reported', 'Reg', (38, 46))	('gastrointestinal stromal tumors', 'Disease', (173, 204))	('breast cancers', 'Phenotype', 'HP:0003002', (71, 85))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
97523	25110710	Amplification of IGF1R was detected in only one adrenocortical carcinoma (Weiss score 7) that was diagnosed in a woman who had an endocrine hyperfunction that was characterized by hypercortisolism and hyperandrogenism.	('Amplification', 'Var', (0, 13))	('hypercortisolism and hyperandrogenism', 'Disease', 'MESH:D017588', (180, 217))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (48, 72))	('hypercortisolism', 'Phenotype', 'HP:0003118', (180, 196))	('adrenocortical carcinoma', 'Disease', (48, 72))	('IGF1R', 'Gene', (17, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
97526	25110710	P53 was able to suppress IGF1R promoter activity by approximately 90%, whereas its mutant forms were associated with IGF1R upregulation.	('mutant', 'Var', (83, 89))	('suppress', 'NegReg', (16, 24))	('P53', 'Gene', (0, 3))	('upregulation', 'PosReg', (123, 135))	('IGF1R', 'Gene', (25, 30))	('P53', 'Gene', '7157', (0, 3))	('promoter activity', 'MPA', (31, 48))
97527	25110710	A specific germinative mutation (p.R337H) that affected the tetramerization domain of p53 has been identified in high frequency in Brazilian children with adrenocortical tumors.	('adrenocortical tumors', 'Disease', (155, 176))	('p.R337H', 'Mutation', 'rs121912664', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('affected', 'Reg', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tetramerization domain', 'MPA', (60, 82))	('p.R337H', 'Var', (33, 40))	('p53', 'Gene', (86, 89))
97528	25110710	In addition, the adrenocortical carcinoma with IGF1R amplification did not harbor the p.R337H mutation in blood or tumor tissue DNA (data not shown).	('p.R337H', 'SUBSTITUTION', 'None', (86, 93))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (17, 41))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('p.R337H', 'Var', (86, 93))	('IGF1R', 'Gene', (47, 52))	('amplification', 'Var', (53, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('adrenocortical carcinoma', 'Disease', (17, 41))
97531	25110710	Previous studies in esophagus carcinoma cells showed that miR-375 has a tumor suppressor effect by inhibiting IGF1R.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('esophagus carcinoma', 'Disease', 'MESH:D004938', (20, 39))	('inhibiting', 'NegReg', (99, 109))	('miR-375', 'Var', (58, 65))	('esophagus carcinoma', 'Disease', (20, 39))	('tumor suppressor effect', 'CPA', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('esophagus carcinoma', 'Phenotype', 'HP:0011459', (20, 39))	('IGF1R', 'Gene', (110, 115))
97539	23907384	Multiple factors regulate SF-1 activity: association with positive and negative cofactors, post-translational modifications, phospholipid ligand availability, epigenetic regulations and gene dosage [reviewed in ].	('activity', 'MPA', (31, 39))	('SF-1', 'Gene', (26, 30))	('gene dosage', 'Var', (186, 197))	('phospholipid', 'Chemical', 'MESH:D010743', (125, 137))	('epigenetic regulations', 'Var', (159, 181))
97540	23907384	In particular, alterations of SF-1 dosage, both in defect and in excess, produce relevant pathological effects.	('rat', 'Species', '10116', (19, 22))	('dosage', 'MPA', (35, 41))	('SF-1', 'Gene', (30, 34))	('alterations', 'Var', (15, 26))
97542	23907384	In humans, heterozygote NR5A1 mutations are mostly associated with disorders of sex development, with only a few cases also displaying adrenal insufficiency.	('NR5A1', 'Gene', '2516', (24, 29))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (135, 156))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (135, 156))	('adrenal insufficiency', 'Disease', (135, 156))	('associated', 'Reg', (51, 61))	('humans', 'Species', '9606', (3, 9))	('mutations', 'Var', (30, 39))	('NR5A1', 'Gene', (24, 29))	('disorders of sex development', 'Disease', (67, 95))
97556	23907384	After centrifugation to pellet debris, the supernatant was incubated overnight at 4 C on a rotating wheel with anti SF-1 (#07-618 from Millipore or PP-N1665-00 from R&D Systems) or anti NRSF/REST (#07-579 from Millipore) antibodies adsorbed to immunomagnetic protein A/protein G beads (Dynabeads, Invitrogen).	('NRSF', 'Gene', (186, 190))	('PP-N1665-00', 'Var', (148, 159))	('NRSF', 'Gene', '5978', (186, 190))
97570	23907384	The supernatant was incubated with 3 mug of preimmune rabbit immunoglobulin G (Abcam) or antibodies directed against SF-1 (#07-618 from Millipore) or NRSF/REST (#07-579 from Millipore) overnight at 4 C on a rotating wheel.	('SF-1', 'Gene', (117, 121))	('NRSF', 'Gene', '5978', (150, 154))	('#07-618', 'Var', (123, 130))	('rabbit', 'Species', '9986', (54, 60))	('NRSF', 'Gene', (150, 154))
97574	23907384	cDNAs encoding wild-type, L451A/L452A (AF-2 mut) and G35E/R92Q (DBD mut) SF1 were cloned in the HindIII-BamHI sites of the pcDNA4/TO vector.	('L452A', 'Var', (32, 37))	('G35E', 'Var', (53, 57))	('SF1', 'Gene', (73, 76))	('L451A', 'Var', (26, 31))	('G35E', 'SUBSTITUTION', 'None', (53, 57))	('L452A', 'SUBSTITUTION', 'None', (32, 37))	('R92Q', 'SUBSTITUTION', 'None', (58, 62))	('SF1', 'Gene', '7536', (73, 76))	('L451A', 'SUBSTITUTION', 'None', (26, 31))	('R92Q', 'Var', (58, 62))
97575	23907384	Wild-type and mutant SF-1 proteins were all expressed at similar levels in transfected HeLa cells (Supplementary Figure S1B).	('SF-1', 'Gene', (21, 25))	('mutant', 'Var', (14, 20))	('proteins', 'Protein', (26, 34))	('HeLa', 'CellLine', 'CVCL:0030', (87, 91))
97577	23907384	Efficient SF-1 knockdown was obtained by synthetic siRNA electroporation (Supplementary Figure S1C).	('SF-1', 'Gene', (10, 14))	('rat', 'Species', '10116', (66, 69))	('knockdown', 'Var', (15, 24))
97579	23907384	Genes negatively regulated by SF-1 knockdown (activated by SF-1) are enriched in genes involved in lipid and steroid metabolism, Ras guanyl-nucleotide exchange factor activity and cytoskeleton function, whereas genes positively regulated by SF-1 knockdown (repressed by SF-1) are enriched in genes involved in angiogenesis, cell proliferation and apoptosis, interaction with the extracellular matrix, Notch and TGFbeta signaling (Table 1; full lists of enriched Gene Ontology categories for genes regulated by SF-1 knockdown are shown in Supplementary Table S2).	('knockdown', 'Var', (35, 44))	('steroid', 'Chemical', 'MESH:D013256', (109, 116))	('lipid', 'Chemical', 'MESH:D008055', (99, 104))	('lipid', 'MPA', (99, 104))	('negatively', 'NegReg', (6, 16))	('involved', 'Reg', (87, 95))	('SF-1', 'Gene', (30, 34))	('rat', 'Species', '10116', (336, 339))
97581	23907384	Altogether, these findings show that distinct categories of genes are regulated according to SF-1 dosage in H295R cells.	('regulated', 'Reg', (70, 79))	('SF-1', 'Gene', (93, 97))	('dosage', 'Var', (98, 104))	('H295R', 'CellLine', 'CVCL:0458', (108, 113))
97583	23907384	No significant overlap existed between genes in whose proximity SF-1 bound only in conditions of basal expression and genes that were upregulated following SF-1 overexpression in H295R cells (P=0.91).	('SF-1', 'Gene', (156, 160))	('upregulated', 'PosReg', (134, 145))	('H295R', 'CellLine', 'CVCL:0458', (179, 184))	('overexpression', 'Var', (161, 175))
97588	23907384	Sequence enrichment analysis of SF-1-binding sites using several algorithms revealed that the consensus SF-1-binding sequence identified in vitro or close variants of it are significantly enriched in SF-1-binding sites in the chromatin of H295R cells both when the factor is expressed at basal levels and in overexpression conditions (Figure 4A).	('SF-1-binding', 'Gene', (104, 116))	('SF-1-binding', 'MPA', (200, 212))	('H295R', 'CellLine', 'CVCL:0458', (239, 244))	('variants', 'Var', (155, 163))
97609	23907384	Wild-type SF-1 could significantly relieve transcriptional repression of NRSF/REST luc, whereas both an AF-2 (L451A/L452A) and a DNA-binding domain (G35E/R92Q) SF-1 mutants were inactive (Figure 6B).	('NRSF', 'Gene', (73, 77))	('G35E', 'Var', (149, 153))	('L452A', 'Var', (116, 121))	('NRSF', 'Gene', '5978', (73, 77))	('transcriptional repression', 'MPA', (43, 69))	('G35E', 'SUBSTITUTION', 'None', (149, 153))	('relieve', 'NegReg', (35, 42))	('R92Q', 'SUBSTITUTION', 'None', (154, 158))	('L451A', 'SUBSTITUTION', 'None', (110, 115))	('R92Q', 'Var', (154, 158))	('L451A', 'Var', (110, 115))	('L452A', 'SUBSTITUTION', 'None', (116, 121))
97617	23907384	Moreover, the NRSF/REST positive regulatory action was completely impaired by overexpressed SF-1 (Figure 6D).	('NRSF', 'Gene', '5978', (14, 18))	('impaired', 'NegReg', (66, 74))	('SF-1', 'Gene', (92, 96))	('overexpressed', 'Var', (78, 91))	('NRSF', 'Gene', (14, 18))
97621	23907384	Although Nr5a1 homozygote inactivation causes complete absence of adrenal glands and gonads and spleen defects, Nr5a1 heterozygote mice have hypoplastic adrenals and gonads, in the presence of decreased corticosterone and increased (especially after stress) ACTH plasma levels, also displaying a deficient compensatory adrenal growth following unilateral adrenalectomy.	('inactivation', 'Var', (26, 38))	('Nr5a1', 'Gene', (9, 14))	('absence of adrenal glands', 'Phenotype', 'HP:0011743', (55, 80))	('corticosterone', 'MPA', (203, 217))	('ACTH plasma levels', 'MPA', (258, 276))	('Nr5a1', 'Gene', (112, 117))	('hypoplastic adrenals', 'Disease', 'MESH:D000312', (141, 161))	('decreased corticosterone', 'Phenotype', 'HP:0032363', (193, 217))	('hypoplastic adrenals', 'Phenotype', 'HP:0000835', (141, 161))	('absence of adrenal glands', 'Disease', (55, 80))	('corticosterone', 'Chemical', 'MESH:D003345', (203, 217))	('mice', 'Species', '10090', (131, 135))	('increased', 'PosReg', (222, 231))	('absence of adrenal glands', 'Disease', 'MESH:D000307', (55, 80))	('decreased', 'NegReg', (193, 202))	('hypoplastic adrenals', 'Disease', (141, 161))	('compensatory adrenal growth', 'Phenotype', 'HP:0011734', (306, 333))
97622	23907384	This different sensitivity to NR5A1 dosage also exists in humans, where heterozygote NR5A1 mutations are most commonly associated with gonadal, but not adrenal, defects.	('gonadal', 'Disease', (135, 142))	('NR5A1', 'Gene', (30, 35))	('NR5A1', 'Gene', (85, 90))	('mutations', 'Var', (91, 100))	('NR5A1', 'Gene', '2516', (30, 35))	('humans', 'Species', '9606', (58, 64))	('NR5A1', 'Gene', '2516', (85, 90))	('associated', 'Reg', (119, 129))
97623	23907384	Conversely, SF-1 overexpression is associated with increased adrenocortical tumor cell proliferation, development of adrenocortical tumors in mice and is a widespread finding in pediatric adrenocortical tumors, whereas it confers a more severe prognosis to adult adrenocortical cancers.	('adult adrenocortical cancers', 'Disease', (257, 285))	('SF-1', 'Gene', (12, 16))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (188, 208))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (117, 138))	('adrenocortical tumor', 'Disease', (61, 81))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (117, 137))	('rat', 'Species', '10116', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (61, 81))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('pediatric adrenocortical tumors', 'Disease', (178, 209))	('adult adrenocortical cancers', 'Disease', 'MESH:D000306', (257, 285))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('adrenocortical tumors', 'Disease', (117, 138))	('overexpression', 'Var', (17, 31))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('increased', 'PosReg', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('development', 'CPA', (102, 113))	('mice', 'Species', '10090', (142, 146))	('pediatric adrenocortical tumors', 'Disease', 'MESH:C565973', (178, 209))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (188, 209))
97649	23907384	Functional experiments are supporting this scenario, as cotransfection of wild-type, but not AF-2 mutant or DBD mutant, SF-1 could relieve repression imparted by the NRSF/REST sequence on a basal promoter.	('NRSF', 'Gene', (166, 170))	('NRSF', 'Gene', '5978', (166, 170))	('SF-1', 'Gene', (120, 124))	('repression', 'MPA', (139, 149))	('AF-2', 'Gene', (93, 97))	('relieve', 'NegReg', (131, 138))	('mutant', 'Var', (112, 118))	('mutant', 'Var', (98, 104))
97679	22654799	We were intrigued by the fact that sunitinib has been shown to induce adrenal hemorrhage in animal experiments (Patyna et al.,).	('adrenal hemorrhage', 'Disease', (70, 88))	('sunitinib', 'Var', (35, 44))	('sunitinib', 'Chemical', 'MESH:D000077210', (35, 44))	('induce', 'Reg', (63, 69))	('adrenal hemorrhage', 'Disease', 'MESH:D006470', (70, 88))
97714	22654799	mRNA of beta-actin was demonstrated to be expressed at similar levels in NCI-H295 and SW13 cells (Ct-values 22.35 +- 0.19 for NCI-H295 vs. 22.14 +- 0.023 in SW13, n = 3, p = 0.12 for difference in unpaired Student's t-test) and hence chosen as reference gene.	('beta-actin', 'Gene', (8, 18))	('SW13', 'CellLine', 'CVCL:0542', (157, 161))	('NCI-H295', 'CellLine', 'CVCL:0456', (126, 134))	('NCI-H295', 'CellLine', 'CVCL:0456', (73, 81))	('NCI-H295', 'Var', (126, 134))	('SW13', 'CellLine', 'CVCL:0542', (86, 90))	('beta-actin', 'Gene', '728378', (8, 18))
97719	22654799	Primary polyclonal rabbit antibody against HSD3B2 (R1484) was a generous gift from Ian Mason, Edinburgh and used in a dilution of 1:2500 (Thomas et al.,).	('R1484', 'Var', (51, 56))	('HSD3B2', 'Gene', '3284', (43, 49))	('HSD3B2', 'Gene', (43, 49))	('rabbit', 'Species', '9986', (19, 25))
97783	22654799	Similarly to our observations, a pharmacologic study demonstrated reduced secretion of cortisol and increased DHEA and DHEA-S production in NCI-H295 cells upon inhibition of Src tyrosine kinase with the specific inhibitor PP2 (Sirianni et al.,).	('PP2', 'Gene', '4888', (222, 225))	('reduced', 'NegReg', (66, 73))	('DHEA-S production', 'MPA', (119, 136))	('inhibition', 'Var', (160, 170))	('increased', 'PosReg', (100, 109))	('DHEA', 'Chemical', 'MESH:D003687', (119, 123))	('reduced secretion of cortisol', 'Phenotype', 'HP:0008163', (66, 95))	('NCI-H295', 'CellLine', 'CVCL:0456', (140, 148))	('DHEA-S', 'Chemical', 'MESH:D003687', (119, 125))	('cortisol', 'Chemical', 'MESH:D006854', (87, 95))	('secretion of cortisol', 'MPA', (74, 95))	('DHEA', 'MPA', (110, 114))	('DHEA', 'Chemical', 'MESH:D003687', (110, 114))	('PP2', 'Gene', (222, 225))	('Src tyrosine kinase', 'Enzyme', (174, 193))
97793	22654799	In humans, sunitinib is metabolized in the intestine and liver by CYP3A4 monooxygenase to first form the active metabolite SU12662 which is then inactivated in a second CYP3A4-mediated step (Faivre et al.,).	('SU12662', 'Chemical', 'MESH:C544393', (123, 130))	('sunitinib', 'Chemical', 'MESH:D000077210', (11, 20))	('CYP3A4', 'Gene', (66, 72))	('humans', 'Species', '9606', (3, 9))	('CYP3A4', 'Gene', (169, 175))	('SU12662', 'Var', (123, 130))	('CYP3A4', 'Gene', '1576', (66, 72))	('CYP3A4', 'Gene', '1576', (169, 175))
97799	22654799	Although clinically evident adrenal insufficiency appears to be a rare event in patients treated with sunitinib (Lodish and Stratakis,), physicians should be aware that sunitinib may unmask clinically inapparent adrenal insufficiency due to concomitant treatment with other drugs influencing steroidogenesis (e.g., ketoconazole, fluconazole) or heterozygous congenital adrenal hyperplasia.	('adrenal insufficiency', 'Disease', (28, 49))	('patients', 'Species', '9606', (80, 88))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (212, 233))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (369, 388))	('clinically', 'Disease', (190, 200))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (358, 388))	('sunitinib', 'Chemical', 'MESH:D000077210', (102, 111))	('congenital adrenal hyperplasia', 'Disease', (358, 388))	('steroid', 'Chemical', 'MESH:D013256', (292, 299))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (212, 233))	('sunitinib', 'Var', (169, 178))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (28, 49))	('ketoconazole', 'Chemical', 'MESH:D007654', (315, 327))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (358, 388))	('heterozygous', 'Disease', (345, 357))	('unmask', 'Reg', (183, 189))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (28, 49))	('adrenal insufficiency', 'Disease', (212, 233))	('fluconazole', 'Chemical', 'MESH:D015725', (329, 340))	('sunitinib', 'Chemical', 'MESH:D000077210', (169, 178))
97807	33300026	It is estimated that ~70 000 lesions occur in genomic DNA in each human cell per day, most of which (75%) originate from oxidation reactions with endogenous byproducts of metabolism and base hydrolysis.	('human', 'Species', '9606', (66, 71))	('lesions', 'Var', (29, 36))	('originate from', 'Reg', (106, 120))
97808	33300026	To counteract the continuous threat these lesions pose to genome stability, cells have evolved a wide-ranging arsenal of repair programs, including DNA base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), translesion synthesis (TLS) and strand break repair (homologous recombination and various non-homologous end joining pathways), which together act upon particular types of lesion or at specific phases of the cell cycle to prevent mutations in DNA and cell death.	('mutations', 'Var', (467, 476))	('death', 'Disease', 'MESH:D003643', (493, 498))	('death', 'Disease', (493, 498))	('DNA', 'Gene', (480, 483))
97812	33300026	Indeed, despite the fact that replication-associated mutations have been linked to high frequencies of single base-pair substitutions (SBSs) in human cancers, mutational landscapes in cancer genomes are highly heterogeneous.	('cancer', 'Disease', (184, 190))	('human', 'Species', '9606', (144, 149))	('single base-pair substitutions', 'Var', (103, 133))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('replication-associated', 'Disease', (30, 52))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
97816	33300026	We showed that NEIL1 becomes stabilized on chromatin after site-specific (Lys296-298) acetylation, and accumulates almost exclusively at highly transcribed genomic regions as well as the transcription start sites (TSS) of weakly expressed genes, some of which are associated with poor prognosis when overexpressed in cancer.	('acetylation', 'Var', (86, 97))	('NEIL1', 'Gene', (15, 20))	('accumulates', 'PosReg', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('Lys296-298) acetylation', 'Var', (74, 97))	('Lys296', 'Chemical', '-', (74, 80))	('acetyl', 'Chemical', '-', (86, 92))	('cancer', 'Disease', (317, 323))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
97817	33300026	Bioinformatic analyses using cancer genome datasets and human germline population mutation datasets provide, with unprecedented resolution, information on the relationship between local variations in single base substitution (SBS) rates and ChIP-seq AcNEIL1 occupancy, both in cancer genomes and the germline.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('human', 'Species', '9606', (56, 61))	('variations', 'Var', (186, 196))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
97881	33300026	For XRCC1, we downloaded the original fastq file from the GEO (https://www.ncbi.nlm.nih.gov/geo/) repository (GSE95302, file SRR5282040) and processed it according to the pipeline we used here.	('GSE95302', 'Var', (110, 118))	('XRCC1', 'Gene', (4, 9))	('XRCC1', 'Gene', '7515', (4, 9))
97883	33300026	The file for OGG1 was GSM2357433_CP-Sample_Flag-OGG1-Con-2.tdf from the GEO record GSM2357433; the file was first converted to a bedGraph format using the 'igvtools tdftobedgraph'and then to bigWig.	('OGG1', 'Gene', '4968', (48, 52))	('GSM2357433', 'Var', (83, 93))	('OGG1', 'Gene', (13, 17))	('OGG1', 'Gene', '4968', (13, 17))	('OGG1', 'Gene', (48, 52))
97890	33300026	To this end we divided patients with each tumor type into two groups: group 1, with expression of gene x above the mean; and group 2, with expression of gene x below or at the mean value.	('tumor', 'Disease', (42, 47))	('above', 'PosReg', (105, 110))	('patients', 'Species', '9606', (23, 31))	('gene x', 'Var', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('expression', 'MPA', (84, 94))	('below', 'NegReg', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
97903	33300026	We recently showed that p300 acetylates NEIL1 (herein referred to as AcNEIL1) at residues Lys296, Lys297 and Lys298, which serves to increase DG activity and stabilize the enzyme on chromatin-bound complexes.	('Lys298', 'Var', (109, 115))	('Lys297', 'Chemical', '-', (98, 104))	('Lys296', 'Var', (90, 96))	('p300', 'Gene', (24, 28))	('Lys296', 'Chemical', '-', (90, 96))	('NEIL1', 'Gene', (40, 45))	('DG activity', 'MPA', (142, 153))	('Lys297', 'Var', (98, 104))	('p300', 'Gene', '2033', (24, 28))	('increase', 'PosReg', (133, 141))	('Lys298', 'Chemical', '-', (109, 115))	('acetyl', 'Chemical', '-', (29, 35))	('stabilize', 'MPA', (158, 167))
97906	33300026	STED of human colorectal adenocarcinoma HCT116 cells labeled with anti-AcNEIL1 or anti-total-NEIL1 antibodies showed strong AcNEIL1 nuclear localization, as opposed to diffuse staining in nuclei and cytoplasm for non-acetylated NEIL1.	('anti-total-NEIL1', 'Var', (82, 98))	('HCT116', 'CellLine', 'CVCL:0291', (40, 46))	('AcNEIL1', 'Gene', (124, 131))	('colorectal adenocarcinoma', 'Disease', (14, 39))	('nuclear localization', 'MPA', (132, 152))	('acetyl', 'Chemical', '-', (217, 223))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (14, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('human', 'Species', '9606', (8, 13))	('TE', 'Chemical', 'MESH:D013691', (1, 3))
97916	33300026	H3K27Ac (Figure 1Dii) colocalized with AcNEIL1 on condensed chromosomes to a greater extent than total histone H3 (Figure 1Diii) and, likewise, AcNEIL1 yielded stronger fluorescent signal than total NEIL1 in nuclei (Supplementary Figure S2A, green trace).	('H3K27Ac', 'Protein', (0, 7))	('H3K27Ac', 'Chemical', '-', (0, 7))	('AcNEIL1', 'Var', (144, 151))	('fluorescent signal', 'MPA', (169, 187))	('stronger', 'PosReg', (160, 168))
97965	33300026	We therefore analyzed ~25.4 million SBSs specific to tumor samples, including 5.6 million coding region mutations and 19.8 million non-coding variants.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
97966	33300026	We conclude that transcription is an intrinsically mutagenic process, and that chromatin-bound AcNEIL1 is the active DG form of NElL1 in the context of BERosomes, which is responsible for the repair of oxidative DNA damage and the prevention of base-pair change accumulations, particularly transversion mutations at A:T base pairs.	('transversion mutations', 'Var', (290, 312))	('NElL1', 'Gene', (128, 133))	('NElL1', 'Gene', '4745', (128, 133))
97967	33300026	After establishing that the local variations in mutation rates observed in cancer genomes coincide with segmental AcNEIL1 occupancy, we next addressed whether similar patterns exist for genetic variations between populations.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutation', 'Var', (48, 56))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
97968	33300026	We selected SweGen, a database of single nucleotide polymorphisms (SNPs) in the Swedish population, which is comparable in size (~23 million SNPs) to the cancer dataset.	('single nucleotide polymorphisms', 'Var', (34, 65))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))
97969	33300026	No qualitative differences were observed in the genome-wide distribution of SNPs as a function of AcNEIL1 ICS compared with those observed for cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('SNPs', 'Disease', (76, 80))	('AcNEIL1 ICS', 'Var', (98, 109))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
97970	33300026	Quantitatively, the frequency of incurring base changes at low AcNEIL1 (<500 000 ICS) was greater in cancer than in the germline, particularly for A>T and A>C transversions (Supplementary Figure S9C).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('A>C transversions', 'Var', (155, 172))	('A>T', 'Var', (147, 150))	('cancer', 'Disease', (101, 107))	('base changes', 'MPA', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
97971	33300026	We surveyed the Human Gene Mutation Database (HGMD) to assess the frequency of variants at G4 DNA motifs in 5'-UTRs known to cause or predispose toward inherited disease.	('Human', 'Species', '9606', (16, 21))	('variants', 'Var', (79, 87))	('inherited disease', 'Disease', (152, 169))	('cause', 'Reg', (125, 130))	('G4 DNA', 'Gene', (91, 97))	('inherited disease', 'Disease', 'MESH:D030342', (152, 169))
97976	33300026	The AcNEIL1 acetyl acceptors, Lys296, Lys297 and Lys298, are embedded within an intrinsically unstructured carboxyl-terminal (C-ter) domain (Supplementary Figure S10B), whose disordered nature has been well-conserved (Supplementary Figure S10B-D) despite the high degree of ordered protein folds expected among thermophilic lifeforms.	('acetyl', 'Chemical', '-', (12, 18))	('Lys297', 'Chemical', '-', (38, 44))	('Lys298', 'Chemical', '-', (49, 55))	('S10B', 'SUBSTITUTION', 'None', (162, 166))	('S10B', 'Var', (239, 243))	('Lys298', 'Var', (49, 55))	('Lys297', 'Var', (38, 44))	('Lys296', 'Var', (30, 36))	('S10B', 'SUBSTITUTION', 'None', (239, 243))	('Lys296', 'Chemical', '-', (30, 36))	('S10B', 'Var', (162, 166))
97982	33300026	The observed loading and stabilization of AcNEIL1 on chromatin is critically dependent upon PTM at three consecutive lysine residues (Lys297-299), an acetylation center that appears to be the result of consolidation among variable amino acids in protostomes, probably occurring during the Cambrian explosion, ~540 million years ago, during a transition from sulfur to oxygen as an energy source.	('AcNEIL1', 'Gene', (42, 49))	('acetyl', 'Chemical', '-', (150, 156))	('oxygen', 'Chemical', 'MESH:D010100', (368, 374))	('Lys297-299', 'Var', (134, 144))	('sulfur', 'Chemical', 'MESH:D013455', (358, 364))	('Lys297', 'Chemical', '-', (134, 140))	('lysine', 'Chemical', 'MESH:D008239', (117, 123))
97984	33300026	C>T (G>A) substitutions occur frequently at methylated CpG dinucleotides, particularly in single-stranded DNA where deamination of 5-methylcytosine to thymine, which produces G:T mismatches resulting in mutations (i.e.	('C>T (G>A', 'Gene', (0, 8))	('G:T mismatches', 'Var', (175, 189))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (131, 147))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (55, 72))	('mismatches', 'Var', (179, 189))	('thymine', 'Chemical', 'MESH:D013941', (151, 158))	('mutations', 'Var', (203, 212))	('substitutions', 'Var', (10, 23))
97986	33300026	C>T transitions also arise from stable cytosine oxidation products, such as 5-hydroxycytosine.	('5-hydroxycytosine', 'Chemical', 'MESH:C017400', (76, 93))	('cytosine oxidation', 'MPA', (39, 57))	('5-hydroxycytosine', 'MPA', (76, 93))	('C>T', 'Var', (0, 3))	('cytosine', 'Chemical', 'MESH:D003596', (39, 47))	('cytosine', 'Chemical', 'MESH:D003596', (85, 93))	('arise', 'Reg', (21, 26))
97992	33300026	Regarding transcription-associated mutagenesis, the tumor suppressor TP53, the most commonly mutated gene associated with cancer, strikingly resides within the most highly transcribed 1-Mb domain in the human genome, raising the intriguing possibility that susceptibility to human cancer may stem, in part, from intrinsic genome architecture.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutagenesis', 'Var', (35, 46))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('human', 'Species', '9606', (203, 208))	('tumor', 'Disease', (52, 57))	('TP53', 'Gene', (69, 73))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', (281, 287))	('human', 'Species', '9606', (275, 280))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
97994	33300026	Studies on the mutagenic potential of formamidopyrimidines have suggested that direct base misincorporation can generate both transition and transversion mutations.	('transversion mutations', 'CPA', (141, 163))	('misincorporation', 'Var', (91, 107))	('formamidopyrimidines', 'Chemical', '-', (38, 58))	('transition', 'MPA', (126, 136))
97995	33300026	TG blocks DNA replication and its bypass, aided by translesion synthesis polymerases, can yield mutations when Poltheta is utilized.	('yield', 'Reg', (90, 95))	('TG', 'Chemical', 'MESH:C029389', (0, 2))	('DNA replication', 'CPA', (10, 25))	('mutations', 'Var', (96, 105))
98000	33300026	Our analysis that Hox overexpression, and especially AcNEIL1-containing Hox gene reactivation in low grade glioma, contributes to poor survival strengthens the growing support for their key role in tumorigenesis.	('Hox', 'Gene', '42536', (72, 75))	('overexpression', 'PosReg', (22, 36))	('Hox', 'Gene', (72, 75))	('survival', 'MPA', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('poor', 'NegReg', (130, 134))	('reactivation', 'Var', (81, 93))	('glioma', 'Disease', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('Hox', 'Gene', (18, 21))	('Hox', 'Gene', '42536', (18, 21))
98001	33300026	Neil1-/- (or Neil2-/-) mouse embryoid bodies display neural defects, the downregulation of key developmental genes, including Hox genes, elevated levels of reactive oxygen species (ROS) and a pro-apoptotic TP53-associated DNA damage response.	('pro-apoptotic', 'PosReg', (192, 205))	('neural defects', 'CPA', (53, 67))	('Neil2', 'Gene', (13, 18))	('Neil1-/-', 'Var', (0, 8))	('ROS', 'Chemical', 'MESH:D017382', (181, 184))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (156, 179))	('elevated', 'PosReg', (137, 145))	('TP53-associated', 'CPA', (206, 221))	('mouse', 'Species', '10090', (23, 28))	('levels of reactive oxygen species', 'MPA', (146, 179))	('elevated levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (137, 179))	('Hox', 'Gene', '42536', (126, 129))	('downregulation', 'NegReg', (73, 87))	('Neil2', 'Gene', '382913', (13, 18))	('Hox', 'Gene', (126, 129))
98004	33300026	The altered expression and mutations associated with polycomb complexes have also been linked to cancer, and it will be of interest to determine the extent to which escape from NEIL1 damage repair beyond the early developmental stages may contribute to tumorigenesis.	('mutations', 'Var', (27, 36))	('NEIL1', 'Gene', (177, 182))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('contribute', 'Reg', (239, 249))	('linked', 'Reg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (253, 258))	('expression', 'MPA', (12, 22))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
98015	33287648	CTNNB1 Knockdown Inhibits Cell Proliferation and Aldosterone Secretion Through Inhibiting Wnt/beta-Catenin Signaling in H295R Cells Aldosterone-producing adenomas (APA) is one of the causative factors of primary aldosteronism.	('CTNNB1', 'Gene', '1499', (0, 6))	('Cell Proliferation', 'CPA', (26, 44))	('beta-Catenin', 'Gene', (94, 106))	('Inhibiting', 'NegReg', (79, 89))	('beta-Catenin', 'Gene', '1499', (94, 106))	('H295R', 'CellLine', 'CVCL:0458', (120, 125))	('aldoster', 'Chemical', '-', (212, 220))	('Knockdown', 'Var', (7, 16))	('Aldosterone', 'Chemical', 'MESH:D000450', (49, 60))	('CTNNB1', 'Gene', (0, 6))	('adenomas', 'Disease', 'MESH:D000236', (154, 162))	('Aldosterone', 'Chemical', 'MESH:D000450', (132, 143))	('primary aldosteronism', 'Phenotype', 'HP:0011736', (204, 225))	('Inhibits', 'NegReg', (17, 25))	('adenomas', 'Disease', (154, 162))	('Aldosterone Secretion', 'MPA', (49, 70))	('PA', 'Phenotype', 'HP:0011736', (165, 167))
98016	33287648	Previous studies have suggested that there are somatic CTNNB1 mutations in APA, but the specific mechanism of CTNNB1 mutation in APA tumorigenesis and aldosterone secretion remains unclear.	('CTNNB1', 'Gene', '1499', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('CTNNB1', 'Gene', '1499', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('PA', 'Phenotype', 'HP:0011736', (130, 132))	('CTNNB1', 'Gene', (55, 61))	('aldosterone', 'Chemical', 'MESH:D000450', (151, 162))	('tumor', 'Disease', (133, 138))	('CTNNB1', 'Gene', (110, 116))	('mutations', 'Var', (62, 71))	('PA', 'Phenotype', 'HP:0011736', (76, 78))
98019	33287648	We found that CTNNB1 knockdown reduced beta-catenin expression and inhibited proliferation of H295 R cells.	('reduced', 'NegReg', (31, 38))	('inhibited', 'NegReg', (67, 76))	('CTNNB1', 'Gene', '1499', (14, 20))	('H295', 'CellLine', 'CVCL:0456', (94, 98))	('beta-catenin', 'Protein', (39, 51))	('CTNNB1', 'Gene', (14, 20))	('knockdown', 'Var', (21, 30))	('proliferation of H295 R cells', 'CPA', (77, 106))
98020	33287648	CTNNB1 knockdown inhibited Wnt/beta-catenin signaling pathway and downregulated expression of downstream genes including axin 2, lymphoid enhancer binding factor 1 (LEF1), and cyclin D1.	('CTNNB1', 'Gene', '1499', (0, 6))	('Wnt/beta-catenin signaling pathway', 'Pathway', (27, 61))	('cyclin D1', 'Gene', (176, 185))	('LEF1', 'Gene', '51176', (165, 169))	('axin 2', 'Gene', '8313', (121, 127))	('CTNNB1', 'Gene', (0, 6))	('lymphoid enhancer binding factor 1', 'Gene', (129, 163))	('downregulated', 'NegReg', (66, 79))	('LEF1', 'Gene', (165, 169))	('inhibited', 'NegReg', (17, 26))	('expression', 'MPA', (80, 90))	('lymphoid enhancer binding factor 1', 'Gene', '51176', (129, 163))	('cyclin D1', 'Gene', '595', (176, 185))	('axin 2', 'Gene', (121, 127))	('knockdown', 'Var', (7, 16))
98021	33287648	In addition, CTNNB1 knockdown decreased responses of H295 R cells to Agn II and decreased aldosterone secretion.	('CTNNB1', 'Gene', '1499', (13, 19))	('decreased aldosterone', 'Phenotype', 'HP:0004319', (80, 101))	('CTNNB1', 'Gene', (13, 19))	('decreased', 'NegReg', (80, 89))	('aldosterone', 'Chemical', 'MESH:D000450', (90, 101))	('responses', 'MPA', (40, 49))	('H295', 'CellLine', 'CVCL:0456', (53, 57))	('knockdown', 'Var', (20, 29))	('aldosterone secretion', 'MPA', (90, 111))	('decreased', 'NegReg', (30, 39))
98022	33287648	Our findings suggest that CTNNB1 knockdown can inhibit H295 R cell proliferation and decrease aldosterone secretion in the responses of H295 R cells to Ang II through inhibiting Wnt/beta-catenin signaling pathway, indicating that targeting Wnt/beta-catenin signaling pathway may be an important approach to decrease aldosterone secretion in the treatment of aldoster-producing adenomas.	('CTNNB1', 'Gene', '1499', (26, 32))	('aldosterone', 'Chemical', 'MESH:D000450', (316, 327))	('aldosterone', 'Chemical', 'MESH:D000450', (94, 105))	('aldoster', 'Chemical', '-', (358, 366))	('Wnt/beta-catenin signaling pathway', 'Pathway', (178, 212))	('H295 R cell proliferation', 'CPA', (55, 80))	('inhibit', 'NegReg', (47, 54))	('decrease', 'NegReg', (85, 93))	('adenomas', 'Disease', 'MESH:D000236', (377, 385))	('adenomas', 'Disease', (377, 385))	('Ang II', 'Gene', '183', (152, 158))	('Ang II', 'Gene', (152, 158))	('H295', 'CellLine', 'CVCL:0456', (136, 140))	('H295', 'CellLine', 'CVCL:0456', (55, 59))	('inhibiting', 'NegReg', (167, 177))	('CTNNB1', 'Gene', (26, 32))	('decrease aldosterone', 'Phenotype', 'HP:0004319', (307, 327))	('knockdown', 'Var', (33, 42))	('aldoster', 'Chemical', '-', (316, 324))	('decrease aldosterone', 'Phenotype', 'HP:0004319', (85, 105))	('aldosterone secretion', 'MPA', (94, 115))	('aldoster', 'Chemical', '-', (94, 102))
98031	33287648	Abnormal Wnt/beta-catenin activation caused by somatic CTNNB1 mutations has been found in APA, and silencing CTNNB1 has been shown to inhibit cell proliferation and stimulates apoptosis in APA cell line H295 R through decreasing Wnt/beta-catenin-LEF/TCF dependent transcription.	('CTNNB1', 'Gene', (109, 115))	('decreasing', 'NegReg', (218, 228))	('H295', 'CellLine', 'CVCL:0456', (203, 207))	('CTNNB1', 'Gene', '1499', (55, 61))	('PA', 'Phenotype', 'HP:0011736', (190, 192))	('LEF/TCF', 'Gene', '3172', (246, 253))	('inhibit', 'NegReg', (134, 141))	('LEF/TCF', 'Gene', (246, 253))	('PA', 'Phenotype', 'HP:0011736', (91, 93))	('stimulates', 'PosReg', (165, 175))	('activation', 'PosReg', (26, 36))	('cell proliferation', 'CPA', (142, 160))	('CTNNB1', 'Gene', (55, 61))	('CTNNB1', 'Gene', '1499', (109, 115))	('silencing', 'Var', (99, 108))	('apoptosis', 'CPA', (176, 185))	('mutations', 'Var', (62, 71))
98034	33287648	APA patients with CTNNB1 mutation are older and have more obvious hypertension symptoms.	('CTNNB1', 'Gene', '1499', (18, 24))	('mutation', 'Var', (25, 33))	('PA', 'Phenotype', 'HP:0011736', (1, 3))	('hypertension', 'Disease', 'MESH:D006973', (66, 78))	('patients', 'Species', '9606', (4, 12))	('CTNNB1', 'Gene', (18, 24))	('hypertension', 'Phenotype', 'HP:0000822', (66, 78))	('hypertension', 'Disease', (66, 78))
98035	33287648	After adrenalectomy, CTNNB1 mutation carriers have a higher likelihood of residual hypertension than other APA patients.	('PA', 'Phenotype', 'HP:0011736', (108, 110))	('hypertension', 'Disease', 'MESH:D006973', (83, 95))	('mutation', 'Var', (28, 36))	('CTNNB1', 'Gene', (21, 27))	('hypertension', 'Disease', (83, 95))	('hypertension', 'Phenotype', 'HP:0000822', (83, 95))	('CTNNB1', 'Gene', '1499', (21, 27))	('patients', 'Species', '9606', (111, 119))
98036	33287648	Akerstrom et al reported that APA tissue containing the CTNNB1 mutant gene has a high expression of CYP11B2.	('CTNNB1', 'Gene', '1499', (56, 62))	('mutant', 'Var', (63, 69))	('CYP11B2', 'Gene', (100, 107))	('expression', 'MPA', (86, 96))	('CTNNB1', 'Gene', (56, 62))	('CYP11B2', 'Gene', '1585', (100, 107))	('PA', 'Phenotype', 'HP:0011736', (31, 33))
98038	33287648	The specific mechanism of CTNNB1 mutation in APA-induced hyperaldosteronism remains unclear.	('CTNNB1', 'Gene', (26, 32))	('mutation', 'Var', (33, 41))	('hyperaldosteronism', 'Disease', (57, 75))	('PA', 'Phenotype', 'HP:0011736', (46, 48))	('CTNNB1', 'Gene', '1499', (26, 32))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (57, 75))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (57, 75))
98043	33287648	The corresponding negative control sequence for the target gene was purchased from RiboBio Co., Ltd. To stably and efficiently knockdown CTNNB1 in H295 R cells, siRNA targeting the si-CTNNB1_003 coding sequence 5'-AGCTGATATTGATGGACAG-3' was designed and inserted into a pGMLV-SC5RNAi lentiviral vector (Genomeditech Co., Ltd, Shanghai, China), and an interference-free siRNA was used as a negative control.	('knockdown', 'Var', (127, 136))	('CTNNB1', 'Gene', '1499', (184, 190))	('CTNNB1', 'Gene', (137, 143))	('CTNNB1', 'Gene', '1499', (137, 143))	('CTNNB1', 'Gene', (184, 190))	('H295', 'CellLine', 'CVCL:0456', (147, 151))
98055	33287648	We utilized this lentivirus-mediated siRNA to induce CTNNB1 knockdown in H295 R cells (Figure 1B).	('H295', 'CellLine', 'CVCL:0456', (73, 77))	('CTNNB1', 'Gene', (53, 59))	('knockdown', 'Var', (60, 69))	('CTNNB1', 'Gene', '1499', (53, 59))
98056	33287648	CCK-8 assays showed that CTNNB1 knockdown markedly reduced cell viability, compared with the control group (Figure 1C).	('CTNNB1', 'Gene', '1499', (25, 31))	('reduced', 'NegReg', (51, 58))	('cell viability', 'CPA', (59, 73))	('knockdown', 'Var', (32, 41))	('CTNNB1', 'Gene', (25, 31))
98057	33287648	Similarly, colony formation assays showed that cell proliferation was significantly decreased with CTNNB1 knockdown in H295 R cells (Figure 1D).	('CTNNB1', 'Gene', (99, 105))	('CTNNB1', 'Gene', '1499', (99, 105))	('knockdown', 'Var', (106, 115))	('H295', 'CellLine', 'CVCL:0456', (119, 123))	('decreased', 'NegReg', (84, 93))	('colony formation', 'CPA', (11, 27))	('cell proliferation', 'CPA', (47, 65))
98059	33287648	Compared with the control group, the mRNA expression levels of AXIN2 (Figure 2A) and LEF1 (Figure 2B) in CTNNB1 knockdown group were significantly decreased.	('mRNA expression levels', 'MPA', (37, 59))	('LEF1', 'Gene', '51176', (85, 89))	('AXIN2', 'Gene', (63, 68))	('decreased', 'NegReg', (147, 156))	('LEF1', 'Gene', (85, 89))	('AXIN2', 'Gene', '8313', (63, 68))	('CTNNB1', 'Gene', '1499', (105, 111))	('knockdown', 'Var', (112, 121))	('CTNNB1', 'Gene', (105, 111))
98060	33287648	Western blot analysis revealed that the protein expression levels of AXIN2 and LEF1 were downregulated in CTNNB1 knockdown group (Figure 2C).	('CTNNB1', 'Gene', (106, 112))	('protein expression levels', 'MPA', (40, 65))	('downregulated', 'NegReg', (89, 102))	('AXIN2', 'Gene', (69, 74))	('LEF1', 'Gene', '51176', (79, 83))	('AXIN2', 'Gene', '8313', (69, 74))	('knockdown', 'Var', (113, 122))	('LEF1', 'Gene', (79, 83))	('CTNNB1', 'Gene', '1499', (106, 112))
98062	33287648	These results suggest that CTNNB1 knockdown inhibited Wnt/beta-catenin signaling pathway.	('inhibited', 'NegReg', (44, 53))	('CTNNB1', 'Gene', (27, 33))	('Wnt/beta-catenin signaling pathway', 'Pathway', (54, 88))	('knockdown', 'Var', (34, 43))	('CTNNB1', 'Gene', '1499', (27, 33))
98064	33287648	In CTNNB1 knockdown group, the mRNA levels of cycling D1 were significantly decreased (Figure 3A) and the protein expression levels of cycling D1 were also downregulated (Figure 3B), compared to the control group.	('mRNA levels', 'MPA', (31, 42))	('CTNNB1', 'Gene', (3, 9))	('decreased', 'NegReg', (76, 85))	('protein expression levels', 'MPA', (106, 131))	('downregulated', 'NegReg', (156, 169))	('CTNNB1', 'Gene', '1499', (3, 9))	('knockdown', 'Var', (10, 19))
98066	33287648	These results suggest that CTNNB1 knockdown inhibits cell proliferation through reducing expression of cycling D1.	('expression', 'MPA', (89, 99))	('reducing', 'NegReg', (80, 88))	('CTNNB1', 'Gene', (27, 33))	('knockdown', 'Var', (34, 43))	('cell proliferation', 'CPA', (53, 71))	('inhibits', 'NegReg', (44, 52))	('CTNNB1', 'Gene', '1499', (27, 33))	('cycling D1', 'Protein', (103, 113))
98069	33287648	CTNNB1 knockdown inhibited the mRNA and protein expression levels of CYP11B2 (Figure 4A and C), but not the expression levels of CYP11B1 (Figure 4B and C).	('CTNNB1', 'Gene', '1499', (0, 6))	('CYP11B1', 'Gene', (129, 136))	('CTNNB1', 'Gene', (0, 6))	('inhibited', 'NegReg', (17, 26))	('CYP11B2', 'Gene', (69, 76))	('CYP11B1', 'Gene', '1584', (129, 136))	('knockdown', 'Var', (7, 16))	('CYP11B2', 'Gene', '1585', (69, 76))
98073	33287648	We found that Ang II-induced upregulation of aldosterone secretion was reversed by CTNNB1 knockdown (Figure 4D).	('CTNNB1', 'Gene', '1499', (83, 89))	('knockdown', 'Var', (90, 99))	('Ang II', 'Gene', '183', (14, 20))	('upregulation', 'PosReg', (29, 41))	('Ang II', 'Gene', (14, 20))	('aldosterone', 'Chemical', 'MESH:D000450', (45, 56))	('CTNNB1', 'Gene', (83, 89))	('aldosterone secretion', 'MPA', (45, 66))	('upregulation of aldosterone', 'Phenotype', 'HP:0000859', (29, 56))
98074	33287648	These results suggest that CTNNB1 knockdown reduces the responses of H295 R cells to Ang II and decreases secretion of aldosterone.	('Ang II', 'Gene', (85, 91))	('H295', 'CellLine', 'CVCL:0456', (69, 73))	('decreases', 'NegReg', (96, 105))	('responses', 'MPA', (56, 65))	('aldosterone', 'Chemical', 'MESH:D000450', (119, 130))	('decreases secretion of aldosterone', 'Phenotype', 'HP:0004319', (96, 130))	('CTNNB1', 'Gene', (27, 33))	('secretion of aldosterone', 'MPA', (106, 130))	('knockdown', 'Var', (34, 43))	('reduces', 'NegReg', (44, 51))	('Ang II', 'Gene', '183', (85, 91))	('CTNNB1', 'Gene', '1499', (27, 33))
98081	33287648	These mutations may increase intracellular calcium concentrations through various ways, opening voltage-dependent calcium channels, thereby activating calcium signaling and aldosterone secretion.	('voltage-dependent', 'MPA', (96, 113))	('increase intracellular calcium', 'Phenotype', 'HP:0003575', (20, 50))	('aldosterone secretion', 'MPA', (173, 194))	('calcium', 'Chemical', 'MESH:D002118', (114, 121))	('increase', 'PosReg', (20, 28))	('calcium', 'Chemical', 'MESH:D002118', (43, 50))	('calcium signaling', 'MPA', (151, 168))	('opening', 'Reg', (88, 95))	('intracellular calcium concentrations', 'MPA', (29, 65))	('aldosterone', 'Chemical', 'MESH:D000450', (173, 184))	('calcium', 'Chemical', 'MESH:D002118', (151, 158))	('mutations', 'Var', (6, 15))	('activating', 'PosReg', (140, 150))
98082	33287648	However, there are no obvious association between these mutations and adrenal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', (78, 83))
98084	33287648	In adrenal tumors, the main cause for activation of Wnt/beta-catenin signal pathway is CTNNB1 mutation.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('adrenal tumors', 'Disease', 'MESH:D000310', (3, 17))	('CTNNB1', 'Gene', '1499', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('adrenal tumors', 'Disease', (3, 17))	('CTNNB1', 'Gene', (87, 93))	('activation', 'PosReg', (38, 48))	('mutation', 'Var', (94, 102))	('Wnt/beta-catenin signal pathway', 'Pathway', (52, 83))
98085	33287648	Patients with CTNNB1 mutation have larger adenomas size, but not higher level of aldosterone, compared to the patients with other mutations.	('larger', 'PosReg', (35, 41))	('adenomas', 'Disease', (42, 50))	('aldosterone', 'Chemical', 'MESH:D000450', (81, 92))	('CTNNB1', 'Gene', '1499', (14, 20))	('mutation', 'Var', (21, 29))	('Patients', 'Species', '9606', (0, 8))	('CTNNB1', 'Gene', (14, 20))	('higher level of aldosterone', 'Phenotype', 'HP:0000859', (65, 92))	('adenomas', 'Disease', 'MESH:D000236', (42, 50))	('patients', 'Species', '9606', (110, 118))
98087	33287648	Gaujoux et al has reported that silencing CTNNB1 can inhibit cell proliferation and stimulate apoptosis of H295 R through decreasing Wnt/beta-catenin-LEF/TCF dependent transcription, but the relationship between Wnt/beta-catenin signaling and Ang II-induced aldosterone secretion is unclear.	('LEF/TCF', 'Gene', '3172', (150, 157))	('stimulate', 'PosReg', (84, 93))	('Ang II', 'Gene', '183', (243, 249))	('inhibit', 'NegReg', (53, 60))	('Ang II', 'Gene', (243, 249))	('H295', 'CellLine', 'CVCL:0456', (107, 111))	('decreasing', 'NegReg', (122, 132))	('CTNNB1', 'Gene', (42, 48))	('LEF/TCF', 'Gene', (150, 157))	('silencing', 'Var', (32, 41))	('aldosterone', 'Chemical', 'MESH:D000450', (258, 269))	('CTNNB1', 'Gene', '1499', (42, 48))	('apoptosis', 'CPA', (94, 103))	('cell proliferation', 'CPA', (61, 79))
98088	33287648	In the present study, the secretion of aldosterone and the expression of rate-limiting enzyme gene CYP11B1 and CYP11B2 were increased by Ang II, and the silencing CTNNB1 inhibited aldosterone secretion and the expression of CYP11B2 but not CYP11B1 in H295 R cells.	('expression', 'MPA', (210, 220))	('CYP11B2', 'Gene', (224, 231))	('expression', 'MPA', (59, 69))	('CTNNB1', 'Gene', (163, 169))	('inhibited', 'NegReg', (170, 179))	('Ang II', 'Gene', '183', (137, 143))	('Ang II', 'Gene', (137, 143))	('inhibited aldosterone secretion', 'Phenotype', 'HP:0004319', (170, 201))	('secretion of aldosterone', 'MPA', (26, 50))	('increased', 'PosReg', (124, 133))	('aldosterone', 'Chemical', 'MESH:D000450', (39, 50))	('CYP11B1', 'Gene', '1584', (99, 106))	('CYP11B2', 'Gene', (111, 118))	('aldosterone', 'Chemical', 'MESH:D000450', (180, 191))	('CYP11B1', 'Gene', (99, 106))	('CYP11B2', 'Gene', '1585', (224, 231))	('aldosterone secretion', 'MPA', (180, 201))	('H295', 'CellLine', 'CVCL:0456', (251, 255))	('CYP11B1', 'Gene', '1584', (240, 247))	('CTNNB1', 'Gene', '1499', (163, 169))	('silencing', 'Var', (153, 162))	('CYP11B1', 'Gene', (240, 247))	('CYP11B2', 'Gene', '1585', (111, 118))
98089	33287648	Furthermore, the expression of CYP11B2 and aldosterone secretion of H295 R cells in response to Ang II were both decreased by CTNNB1 knockdown, but CTNNB1 knockdown had no effect on expression of CYP11B1.	('aldosterone', 'Chemical', 'MESH:D000450', (43, 54))	('aldosterone secretion', 'MPA', (43, 64))	('Ang II', 'Gene', '183', (96, 102))	('CTNNB1', 'Gene', (126, 132))	('expression', 'MPA', (17, 27))	('Ang II', 'Gene', (96, 102))	('CTNNB1', 'Gene', '1499', (148, 154))	('knockdown', 'Var', (133, 142))	('CYP11B2', 'Gene', (31, 38))	('H295', 'CellLine', 'CVCL:0456', (68, 72))	('CYP11B1', 'Gene', (196, 203))	('CTNNB1', 'Gene', '1499', (126, 132))	('CYP11B2', 'Gene', '1585', (31, 38))	('CYP11B1', 'Gene', '1584', (196, 203))	('CTNNB1', 'Gene', (148, 154))	('decreased', 'NegReg', (113, 122))
98090	33287648	These results suggested that silencing CTNNB1 genes reduced aldosterone secretion and responsiveness to Ang II of H295 R cells by inhibiting the expression of CYP11B2.	('inhibiting', 'NegReg', (130, 140))	('CTNNB1', 'Gene', (39, 45))	('reduced', 'NegReg', (52, 59))	('aldosterone', 'Chemical', 'MESH:D000450', (60, 71))	('aldosterone secretion', 'MPA', (60, 81))	('silencing', 'Var', (29, 38))	('Ang II', 'Gene', '183', (104, 110))	('CTNNB1', 'Gene', '1499', (39, 45))	('H295', 'CellLine', 'CVCL:0456', (114, 118))	('expression', 'MPA', (145, 155))	('Ang II', 'Gene', (104, 110))	('CYP11B2', 'Gene', (159, 166))	('CYP11B2', 'Gene', '1585', (159, 166))	('reduced aldosterone', 'Phenotype', 'HP:0004319', (52, 71))
98091	33287648	In addition, the relationship between CTNNB1 knockdown and H295 R cell proliferation in response to Ang II was also investigated.	('H295 R cell proliferation', 'CPA', (59, 84))	('Ang II', 'Gene', '183', (100, 106))	('CTNNB1', 'Gene', (38, 44))	('Ang II', 'Gene', (100, 106))	('CTNNB1', 'Gene', '1499', (38, 44))	('H295', 'CellLine', 'CVCL:0456', (59, 63))	('knockdown', 'Var', (45, 54))
98092	33287648	Our results showed that CTNNB1 knockdown decreased expression of beta-catenin and inhibited proliferation of H295 R cells.	('inhibited', 'NegReg', (82, 91))	('decreased', 'NegReg', (41, 50))	('CTNNB1', 'Gene', (24, 30))	('H295', 'CellLine', 'CVCL:0456', (109, 113))	('expression', 'MPA', (51, 61))	('CTNNB1', 'Gene', '1499', (24, 30))	('beta-catenin', 'Protein', (65, 77))	('proliferation of H295 R cells', 'CPA', (92, 121))	('knockdown', 'Var', (31, 40))
98093	33287648	Moreover, the downstream target genes of Wnt/beta-catenin signaling pathway, AXIN2 and LEF1, were downregulated by CTNNB1 knockdown in H295 R cells, which were consistent with Gaujoux et al.	('downregulated', 'NegReg', (98, 111))	('Wnt/beta-catenin signaling pathway', 'Pathway', (41, 75))	('CTNNB1', 'Gene', '1499', (115, 121))	('AXIN2', 'Gene', '8313', (77, 82))	('H295', 'CellLine', 'CVCL:0456', (135, 139))	('knockdown', 'Var', (122, 131))	('LEF1', 'Gene', '51176', (87, 91))	('CTNNB1', 'Gene', (115, 121))	('LEF1', 'Gene', (87, 91))	('AXIN2', 'Gene', (77, 82))
98099	33287648	The protein and mRNA levels of cyclin D1 were significantly reduced by CTNNB1 knockdown.	('knockdown', 'Var', (78, 87))	('CTNNB1', 'Gene', '1499', (71, 77))	('reduced', 'NegReg', (60, 67))	('protein', 'MPA', (4, 11))	('cyclin D1', 'Gene', '595', (31, 40))	('CTNNB1', 'Gene', (71, 77))	('cyclin D1', 'Gene', (31, 40))
98100	33287648	These results suggest that CTNNB1 knockdown downregulates cyclin D1 expression to inhibit H295 R cell proliferation.	('expression', 'MPA', (68, 78))	('H295', 'CellLine', 'CVCL:0456', (90, 94))	('downregulates', 'NegReg', (44, 57))	('inhibit', 'NegReg', (82, 89))	('H295 R cell proliferation', 'CPA', (90, 115))	('CTNNB1', 'Gene', (27, 33))	('cyclin D1', 'Gene', '595', (58, 67))	('knockdown', 'Var', (34, 43))	('cyclin D1', 'Gene', (58, 67))	('CTNNB1', 'Gene', '1499', (27, 33))
98101	33287648	In conclusion, our findings suggest that CTNNB1 knockdown can inhibit H295 R cell proliferation and decrease aldosterone secretion in the responses of H295 R cells to Ang II through inhibiting Wnt/beta-catenin signaling pathway, indicating that targeting Wnt/beta-catenin signaling pathway may be an important approach to decrease aldosterone secretion in the treatment of aldoster-producing adenomas.	('decrease', 'NegReg', (100, 108))	('Ang II', 'Gene', '183', (167, 173))	('inhibit', 'NegReg', (62, 69))	('Ang II', 'Gene', (167, 173))	('CTNNB1', 'Gene', '1499', (41, 47))	('aldosterone', 'Chemical', 'MESH:D000450', (109, 120))	('aldoster', 'Chemical', '-', (373, 381))	('Wnt/beta-catenin signaling pathway', 'Pathway', (193, 227))	('H295', 'CellLine', 'CVCL:0456', (151, 155))	('adenomas', 'Disease', 'MESH:D000236', (392, 400))	('aldoster', 'Chemical', '-', (109, 117))	('aldosterone', 'Chemical', 'MESH:D000450', (331, 342))	('adenomas', 'Disease', (392, 400))	('aldosterone secretion', 'MPA', (109, 130))	('decrease aldosterone', 'Phenotype', 'HP:0004319', (100, 120))	('CTNNB1', 'Gene', (41, 47))	('H295 R cell proliferation', 'CPA', (70, 95))	('decrease aldosterone', 'Phenotype', 'HP:0004319', (322, 342))	('knockdown', 'Var', (48, 57))	('aldoster', 'Chemical', '-', (331, 339))	('H295', 'CellLine', 'CVCL:0456', (70, 74))	('inhibiting', 'NegReg', (182, 192))
98102	32414074	Past, Present and Future of Epigenetics in Adrenocortical Carcinoma DNA methylation profiling has been suggested a reliable technique to distinguish between benign and malignant adrenocortical tumors, a process which with current diagnostic methods remains challenging and lacks diagnostic accuracy of borderline tumors.	('Adrenocortical Carcinoma', 'Disease', (43, 67))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (43, 67))	('malignant adrenocortical tumors', 'Disease', 'MESH:D009369', (168, 199))	('tumors', 'Disease', (313, 319))	('tumors', 'Disease', 'MESH:D009369', (313, 319))	('Epigenetics', 'Var', (28, 39))	('malignant adrenocortical tumors', 'Disease', (168, 199))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('Carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (43, 67))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))
98108	32414074	Knowledge on epigenetic alterations in the process of adrenal tumorigenesis is rapidly increasing and will add to a better understanding of the pathogenesis of ACC.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('epigenetic alterations', 'Var', (13, 35))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
98126	32414074	In ACC, the Wnt/beta-catenin (CTNNB1) is frequently activated trough CTNNB1 mutations and even associated with a poor outcome.	('mutations', 'Var', (76, 85))	('CTNNB1', 'Gene', '1499', (69, 75))	('CTNNB1', 'Gene', (30, 36))	('beta-catenin', 'Gene', (16, 28))	('CTNNB1', 'Gene', '1499', (30, 36))	('CTNNB1', 'Gene', (69, 75))	('beta-catenin', 'Gene', '1499', (16, 28))	('activated', 'PosReg', (52, 61))	('associated with', 'Reg', (95, 110))
98127	32414074	In approximately 25% of both benign and malignant sporadic adrenocortical neoplasms beta-catenin gain-of-function mutations are evident.	('malignant sporadic adrenocortical neoplasms', 'Disease', 'MESH:D000306', (40, 83))	('mutations', 'Var', (114, 123))	('neoplasms', 'Phenotype', 'HP:0002664', (74, 83))	('benign', 'Disease', (29, 35))	('malignant sporadic adrenocortical neoplasms', 'Disease', (40, 83))	('beta-catenin', 'Gene', (84, 96))	('gain-of-function', 'PosReg', (97, 113))	('neoplasm', 'Phenotype', 'HP:0002664', (74, 82))	('beta-catenin', 'Gene', '1499', (84, 96))
98128	32414074	Zheng et al (2016) found 41% of ACC cases to have alterations of ZNRF3, CTNNB1, APC and MEN1 resulting in modification of the Wnt/beta-catenin pathway.	('APC', 'Disease', 'MESH:D011125', (80, 83))	('APC', 'Disease', (80, 83))	('modification', 'Reg', (106, 118))	('alterations', 'Var', (50, 61))	('ZNRF3', 'Gene', '84133', (65, 70))	('CTNNB1', 'Gene', (72, 78))	('ZNRF3', 'Gene', (65, 70))	('MEN1', 'Gene', (88, 92))	('MEN1', 'Gene', '4221', (88, 92))	('beta-catenin', 'Gene', (130, 142))	('CTNNB1', 'Gene', '1499', (72, 78))	('beta-catenin', 'Gene', '1499', (130, 142))
98137	32414074	It is recommended in the guidelines to use the Ki67 immunohistochemistry for every resection specimen of an adrenocortical tumor, and therapeutic strategies are suggested based on low-risk (Ki67 <=10%) or high-risk (Ki67 >10%) stratification.	('adrenocortical tumor', 'Disease', (108, 128))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (108, 128))	('Ki67 <=10%', 'Var', (190, 200))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
98156	32414074	Epigenetic alterations occur frequently in cancer cells and have the ability to mimic the effects of the latter.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
98162	32414074	Aldosterone-secreting tumor samples compared with nonfunctioning samples showed mostly hypomethylated CpG sites (75,3).	('Aldosterone', 'Chemical', 'MESH:D000450', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('hypomethylated CpG sites', 'Var', (87, 111))
98172	32414074	Genetic mutations of the beta-catenin gene are common in preferentially non-functioning adenomas and in ACC.	('ACC', 'Disease', (104, 107))	('adenomas', 'Disease', 'MESH:D000236', (88, 96))	('preferentially', 'Disease', (57, 71))	('beta-catenin', 'Gene', '1499', (25, 37))	('adenomas', 'Disease', (88, 96))	('common', 'Reg', (47, 53))	('Genetic mutations', 'Var', (0, 17))	('beta-catenin', 'Gene', (25, 37))
98181	32414074	IGF2 DMR0 and DMR2 are located between exons 2 and 3 and exons 8 and 9 respectively (Table 3).	('IGF2', 'Gene', '3481', (0, 4))	('DMR0', 'Var', (5, 9))	('IGF2', 'Gene', (0, 4))	('DMR2', 'Var', (14, 18))
98195	32414074	(2015) found methylation of the promoter of the vitamin D receptor and a reduced expression of the vitamin D receptor in ACC.	('methylation', 'Var', (13, 24))	('vitamin D receptor', 'Gene', '7421', (99, 117))	('reduced', 'NegReg', (73, 80))	('promoter', 'MPA', (32, 40))	('vitamin D receptor', 'Gene', (99, 117))	('vitamin D receptor', 'Gene', '7421', (48, 66))	('vitamin D receptor', 'Gene', (48, 66))	('expression', 'MPA', (81, 91))
98210	32414074	The level of methylation was associated with survival and CIMP carcinomas show a worse prognosis compared to non-CIMP tumors.	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('CIMP carcinomas', 'Disease', (58, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('methylation', 'Var', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('CIMP', 'Chemical', '-', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('associated', 'Reg', (29, 39))	('tumors', 'Disease', (118, 124))	('CIMP', 'Chemical', '-', (58, 62))	('CIMP carcinomas', 'Disease', 'MESH:D009369', (58, 73))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
98219	32414074	(2014) identified three stable tumor clusters, Mi1-Mi3, with Mi1 having a significantly better overall survival rate then Mi2 and Mi3.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Mi1', 'Var', (61, 64))	('tumor', 'Disease', (31, 36))	('overall survival', 'CPA', (95, 111))	('better', 'PosReg', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
98226	32414074	Furthermore, it was shown that collectively the genes altered most frequently by somatic mutations, DNA copy-number alterations and epigenetic silencing were TP53 (21%), ZNRF3 (19%), CDKN2A (15%), CTNNB1 (16%), TERT (14%) and PRKAR1A (11%).	('CTNNB1', 'Gene', (197, 203))	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('CDKN2A', 'Gene', (183, 189))	('TERT', 'Gene', '7015', (211, 215))	('CDKN2A', 'Gene', '1029', (183, 189))	('PRKAR1A', 'Gene', (226, 233))	('copy-number alterations', 'Var', (104, 127))	('epigenetic silencing', 'Var', (132, 152))	('CTNNB1', 'Gene', '1499', (197, 203))	('mutations', 'Var', (89, 98))	('TERT', 'Gene', (211, 215))	('ZNRF3', 'Gene', '84133', (170, 175))	('PRKAR1A', 'Gene', '5573', (226, 233))	('ZNRF3', 'Gene', (170, 175))
98233	32414074	Interestingly, seven percent of ACC cases have mutation in gene MEN1.	('MEN1', 'Gene', (64, 68))	('mutation', 'Var', (47, 55))	('MEN1', 'Gene', '4221', (64, 68))	('ACC', 'Disease', (32, 35))
98235	32414074	Inhibitors of both IG2/IGF1R and the mTOR pathways cause inhibition of cell proliferation of human ACC cell lines in vitro, and of growth of tumor xenografts in vivo.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('IGF1R', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('human', 'Species', '9606', (93, 98))	('Inhibitors', 'Var', (0, 10))	('tumor', 'Disease', (141, 146))	('inhibition', 'NegReg', (57, 67))	('IGF1R', 'Gene', '3480', (23, 28))	('mTOR', 'Gene', (37, 41))	('mTOR', 'Gene', '2475', (37, 41))	('cell proliferation of human ACC cell lines', 'CPA', (71, 113))
98242	32414074	Studies suggest that DNA methylation, in addition to genetic modifications causes altered patterns of gene expression resulting in tumorigenesis and harvest potential therapeutic markers.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patterns of gene expression', 'MPA', (90, 117))	('tumor', 'Disease', (131, 136))	('DNA methylation', 'Var', (21, 36))	('altered', 'Reg', (82, 89))
98243	32414074	A role for temozolomide (TMZ), a cytotoxic and antiproliferative agent, has been proposed in the treatment for ACC, which is thought to act primarily by alkylation of specific sites on especially the O6 position of guanine, which mispairs with thymine during the next DNA replication cycle.	('alkylation', 'Var', (153, 163))	('ACC', 'Disease', (111, 114))	('temozolomide', 'Chemical', 'MESH:D000077204', (11, 23))	('thymine', 'Chemical', 'MESH:D013941', (244, 251))	('guanine', 'Chemical', 'MESH:D006147', (215, 222))	('TMZ', 'Chemical', 'MESH:D000077204', (25, 28))
98245	32414074	Epigenetic marks regulating MGMT expression are used as a predictive marker for response to TMZ in glioblastoma patients, since epigenetic silencing of MGMT sensitizes glioblastoma cells to TMZ.	('glioblastoma', 'Disease', (99, 111))	('MGMT', 'Gene', (28, 32))	('MGMT', 'Gene', '4255', (28, 32))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('MGMT', 'Gene', (152, 156))	('TMZ', 'Chemical', 'MESH:D000077204', (190, 193))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('patients', 'Species', '9606', (112, 120))	('epigenetic silencing', 'Var', (128, 148))	('MGMT', 'Gene', '4255', (152, 156))	('glioblastoma', 'Disease', (168, 180))	('glioblastoma', 'Disease', 'MESH:D005909', (168, 180))	('sensitizes', 'Reg', (157, 167))	('TMZ', 'Chemical', 'MESH:D000077204', (92, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (168, 180))
98249	32414074	was mentioned earlier: they treated H295R with Azad (also known as 5-aza/decitabine), a demethylating agent (5-aza-2'-deoxycytidine), which led to a significant increase in the H19 RNA content.	('H295R', 'Var', (36, 41))	('H19', 'Gene', '283120', (177, 180))	('decitabine', 'Chemical', 'MESH:D000077209', (73, 83))	('Azad', 'Chemical', '-', (47, 51))	('H19', 'Gene', (177, 180))	('5-aza', 'Chemical', 'MESH:D001374', (67, 72))	('increase', 'PosReg', (161, 169))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (109, 131))	('5-aza', 'Chemical', 'MESH:D001374', (109, 114))
98261	32414074	Whereas, patients in the COC3 group characterized by mutations involving the cell cycle and DNA damage repair machinery would probably better respond to chemotherapy.	('patients', 'Species', '9606', (9, 17))	('better', 'PosReg', (135, 141))	('COC3', 'Gene', (25, 29))	('mutations', 'Var', (53, 62))
98263	32414074	found 51 potentially actionable alterations in 22 ACCs, considering existing clinical trials and FDA-approved drugs for cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('alterations', 'Var', (32, 43))	('cancers', 'Disease', (120, 127))	('ACCs', 'Gene', (50, 54))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('ACCs', 'Gene', '84680', (50, 54))
98264	32414074	In cancer in general, there has been growing evidence to suggest that DNA methylation in addition to direct genetic modification causes altered gene expression resulting in tumorigenesis.	('DNA methylation', 'Var', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('gene expression', 'MPA', (144, 159))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('cancer', 'Disease', (3, 9))	('altered', 'Reg', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
98265	32414074	Epigenetic analysis in adrenocortical tumors so far has been a significant addition to the understanding of molecular events involved in adrenocortical carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('adrenocortical carcinogenesis', 'Disease', 'MESH:D063646', (137, 166))	('Epigenetic analysis', 'Var', (0, 19))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('adrenocortical carcinogenesis', 'Disease', (137, 166))	('adrenocortical tumors', 'Disease', (23, 44))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (23, 44))
98270	32414074	IGF2 overexpression and structural abnormalities of 11p15 are present in up to 90% of cases of human ACC.	('human', 'Species', '9606', (95, 100))	('human ACC', 'Disease', (95, 104))	('structural abnormalities', 'Var', (24, 48))	('overexpression', 'PosReg', (5, 19))	('IGF2', 'Gene', '3481', (0, 4))	('IGF2', 'Gene', (0, 4))
98272	32414074	found that 69% of tumours had at least one alteration of potential driver genes when combining somatic mutations, copy-number alterations, and epigenetic modification.	('tumours', 'Disease', (18, 25))	('epigenetic modification', 'Var', (143, 166))	('alteration', 'Reg', (43, 53))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('copy-number alterations', 'Var', (114, 137))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('tumours', 'Disease', 'MESH:D009369', (18, 25))
98273	32414074	Further research is needed to understand the implications of epigenetic changes in adrenal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('epigenetic changes', 'Var', (61, 79))
98279	32414074	G0S2 hypermethylation was shown to be a hallmark of the CIMP-high cluster.	('CIMP', 'Chemical', '-', (56, 60))	('G0S2', 'Gene', '50486', (0, 4))	('G0S2', 'Gene', (0, 4))	('hypermethylation', 'Var', (5, 21))	('CIMP-high cluster', 'Disease', (56, 73))
98280	32414074	When validated G0S2 hypermethylation and the BUB1B-PINK1 score could be potential markers on a molecular panel for ACC.	('G0S2', 'Gene', (15, 19))	('hypermethylation', 'Var', (20, 36))	('BUB1B', 'Gene', '701', (45, 50))	('ACC', 'Disease', (115, 118))	('PINK1', 'Gene', '65018', (51, 56))	('BUB1B', 'Gene', (45, 50))	('PINK1', 'Gene', (51, 56))	('G0S2', 'Gene', '50486', (15, 19))
98282	32414074	already showed that including IGF2 methylation status to the pathology review could be supportive for the decision of adjuvant mitotane treatment.	('IGF2', 'Gene', (30, 34))	('IGF2', 'Gene', '3481', (30, 34))	('methylation status', 'Var', (35, 53))	('mitotane', 'Chemical', 'MESH:D008939', (127, 135))
98283	32414074	Epigenetic changes may contribute to adrenocortical tumorigenesis by modulating size of the stem/progenitor population, altering phenotypic plasticity and enhancing sensitivity to subsequent mutations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('altering', 'Reg', (120, 128))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (37, 57))	('sensitivity', 'MPA', (165, 176))	('mutations', 'Var', (191, 200))	('contribute', 'Reg', (23, 33))	('enhancing', 'PosReg', (155, 164))	('adrenocortical tumor', 'Disease', (37, 57))	('modulating', 'Reg', (69, 79))	('phenotypic', 'MPA', (129, 139))	('Epigenetic changes', 'Var', (0, 18))
98284	32414074	Mutations in the Wnt/beta catenin pathway have been shown to occur during progression.	('Mutations', 'Var', (0, 9))	('beta catenin', 'Gene', (21, 33))	('beta catenin', 'Gene', '1499', (21, 33))
98285	32414074	Epigenetic and genetic mutations reflect alternate ways of inactivation during tumor progressions, i.e.	('genetic mutations', 'Var', (15, 32))	('tumor', 'Disease', (79, 84))	('Epigenetic', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
98286	32414074	a synergy between epigenetic and genetic alterations causing tumorigenesis, suggesting that combined inhibition of multiple affected pathways may hold the key to successful targeted therapy for ACC.	('epigenetic', 'Var', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('causing', 'Reg', (53, 60))	('genetic alterations', 'Var', (33, 52))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
98288	32414074	With epigenetic studies, we are entering a new and complex phase in the understanding of ACC tumorigenesis.	('epigenetic studies', 'Var', (5, 23))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('ACC', 'Disease', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
98296	32204444	Serum miR-483-5p levels were higher in R < 3yrs than in NR3yrs: 1,541,990 +- 428,377 copies/mL vs. 388,457 +- 62,169 copies/mL (p = 0.002).	('higher', 'PosReg', (29, 35))	('NR3', 'Gene', '2904', (56, 59))	('miR-483-5p', 'Chemical', '-', (6, 16))	('R < 3yrs', 'Var', (39, 47))	('NR3', 'Gene', (56, 59))	('Serum miR-483-5p levels', 'MPA', (0, 23))
98297	32204444	Receiver operating characteristic analysis showed that a value of 752,898 copies/mL distinguished R < 3yrs from NR3yrs with 61.5% sensitivity (CI 31.6-86.1) and 100% specificity (CI 71.5-100) with an area under the curve of 0.853.	('NR3', 'Gene', '2904', (112, 115))	('R < 3yrs', 'Var', (98, 106))	('NR3', 'Gene', (112, 115))
98299	32204444	In multivariate analysis, miR-483-5p provided the single best prognostic value for recurrence-free survival (RFS) (hazard ratio (HR) for recurrence 5.98, p < 0.011) but not for overall survival.	('miR-483-5p', 'Chemical', '-', (26, 36))	('miR-483-5p', 'Var', (26, 36))	('recurrence-free', 'Disease', (83, 98))
98322	32204444	Figure 2a shows that the mean of miR-483-5p copy number was significantly higher in the group R < 3yrs as compared to the group NR3yrs: 1,541,990 +- 428,377 copies/mL vs. 388,457 +- 62,169 copies/mL, respectively (p = 0.0025).	('NR3', 'Gene', (128, 131))	('NR3', 'Gene', '2904', (128, 131))	('higher', 'PosReg', (74, 80))	('R < 3yrs', 'Var', (94, 102))	('miR-483-5p', 'Gene', (33, 43))	('miR-483-5p', 'Chemical', '-', (33, 43))
98328	32204444	Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic performance of miR-483-5p in discriminating between the R < 3yrs group and the NR3yrs group (Figure 3).	('NR3', 'Gene', '2904', (176, 179))	('R < 3yrs', 'Var', (153, 161))	('NR3', 'Gene', (176, 179))	('miR-483-5p', 'Chemical', '-', (112, 122))	('miR-483-5p', 'Gene', (112, 122))
98331	32204444	Using this cut-off, no association was found between miR-483-5p levels and ENSAT stage (Fisher's exact test: p = 0.673; low miR-483-5p: <752,898 copies/mL and high miR-483-5p: >752,898 copies/mL).	('ENSAT stage', 'Disease', (75, 86))	('miR-483-5p', 'Chemical', '-', (124, 134))	('miR-483-5p', 'Chemical', '-', (53, 63))	('low', 'Var', (120, 123))	('miR-483-5p', 'Chemical', '-', (164, 174))
98333	32204444	We then used the ROC-derived miR-483-5p cut-off value to perform a Kaplan-Meier analysis of recurrence-free (RFS) and overall survival (OS) in the whole cohort of 26 patients, including not only the 13-patient group R < 3yrs and the 11-patient group NR3yrs but also the two patients with no recurrence but a follow-up < 3yrs.	('patient', 'Species', '9606', (274, 281))	('NR3', 'Gene', '2904', (250, 253))	('patients', 'Species', '9606', (274, 282))	('patient', 'Species', '9606', (202, 209))	('NR3', 'Gene', (250, 253))	('miR-483-5p', 'Chemical', '-', (29, 39))	('R < 3yrs', 'Var', (216, 224))	('patient', 'Species', '9606', (166, 173))	('patient', 'Species', '9606', (236, 243))	('patients', 'Species', '9606', (166, 174))
98335	32204444	Likewise, patients with high levels of miR-483-5p had also a poorer OS (n = 9; median OS 3.5 years) as compared to the low miR-483-5p group (n = 17, median OS >11.8 years) (HR for death: 5.23; 95% CI: 1.36-20; log-rank test p = 0.007) (Figure 5).	('high levels', 'Var', (24, 35))	('miR-483-5p', 'Chemical', '-', (39, 49))	('miR-483-5p', 'Chemical', '-', (123, 133))	('death', 'Disease', 'MESH:D003643', (180, 185))	('death', 'Disease', (180, 185))	('miR-483-5p', 'Var', (39, 49))	('patients', 'Species', '9606', (10, 18))
98341	32204444	Upon multivariate analyses involving tumor size, Ki67, ENSAT stage and miR-483-5p level, miR-483-5p retained a strong prognostic power for RFS with an HR = 5.9 (p = 0.011) (Table 3).	('miR-483-5p', 'Var', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('miR-483-5p', 'Chemical', '-', (71, 81))	('RFS', 'Disease', (139, 142))	('miR-483-5p', 'Chemical', '-', (89, 99))
98344	32204444	Among candidate miRNAs, miR-483-5p was found to be increased in pre-operative serum or plasma samples from ACC patients.	('miR-483-5p', 'Chemical', '-', (24, 34))	('miR-483-5p', 'Var', (24, 34))	('ACC', 'Disease', (107, 110))	('increased', 'PosReg', (51, 60))	('patients', 'Species', '9606', (111, 119))
98351	32204444	In the present work, we measured circulating miR-483-5p absolute levels in ACC patients based on three criteria: (1) tumors with or without recurrence within 3 years post-surgery, (2) serum sampling within 3 months post-surgery and (3) one sample per patient (the first one).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('miR-483-5p', 'Chemical', '-', (45, 55))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('patient', 'Species', '9606', (251, 258))	('miR-483-5p', 'Var', (45, 55))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('patient', 'Species', '9606', (79, 86))	('patients', 'Species', '9606', (79, 87))
98352	32204444	We show that high circulating miR-483-5p within 3 months post-surgery was associated with more than a four-fold increased risk of recurrence and was predictive of poor overall survival for ACC patients.	('patients', 'Species', '9606', (193, 201))	('poor', 'NegReg', (163, 167))	('high', 'Var', (13, 17))	('recurrence', 'CPA', (130, 140))	('miR-483-5p', 'Chemical', '-', (30, 40))	('miR-483-5p', 'Var', (30, 40))
98355	32204444	We derived a cut-off value of miR-483-5p copy numbers from ROC curve, which distinguishes between recurring and non-recurring ACC patients with a high diagnostic accuracy (AUC of 0.853).	('ACC', 'Disease', (126, 129))	('patients', 'Species', '9606', (130, 138))	('miR-483-5p copy numbers', 'Var', (30, 53))	('miR-483-5p', 'Chemical', '-', (30, 40))
98365	32204444	While the prognostic values of the ENSAT stage and Ki67 index have been largely validated for ACC management, we found here in this cohort that ENSAT stage II and III or Ki67 > 10% did not predict recurrence risk or death.	('Ki67', 'Var', (170, 174))	('death', 'Disease', 'MESH:D003643', (216, 221))	('death', 'Disease', (216, 221))	('recurrence', 'Disease', (197, 207))
98367	32204444	However, with the same number of patients, the concentration of circulating miR-483-5p is able to distinguish between patients with different prognoses of recurrence and death.	('patients', 'Species', '9606', (33, 41))	('miR-483-5p', 'Chemical', '-', (76, 86))	('miR-483-5p', 'Var', (76, 86))	('death', 'Disease', (170, 175))	('death', 'Disease', 'MESH:D003643', (170, 175))	('patients', 'Species', '9606', (118, 126))
98368	32204444	We found that miR-483-5p detection in post-operative samples 3 months post-surgery was not significantly different between tumor ENSAT stage II (n = 13) and stage III (n = 11) patients.	('patients', 'Species', '9606', (176, 184))	('tumor', 'Disease', (123, 128))	('miR-483-5p', 'Chemical', '-', (14, 24))	('miR-483-5p', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
98372	32204444	At the cellular level, we have recently shown that miR-483-5p promotes ACC aggressiveness by targeting the N-myc-Downstream Regulated Gene member 2 (NDRG2) in NCI H295R cell line.	('aggressiveness', 'Phenotype', 'HP:0000718', (75, 89))	('miR-483-5p', 'Chemical', '-', (51, 61))	('NDRG2', 'Gene', '57447', (149, 154))	('N-myc-Downstream Regulated Gene member 2', 'Gene', (107, 147))	('miR-483-5p', 'Var', (51, 61))	('NCI H295R', 'CellLine', 'CVCL:0458', (159, 168))	('NDRG2', 'Gene', (149, 154))	('promotes', 'PosReg', (62, 70))	('aggressiveness', 'Disease', 'MESH:D001523', (75, 89))	('targeting', 'Reg', (93, 102))	('N-myc-Downstream Regulated Gene member 2', 'Gene', '57447', (107, 147))	('aggressiveness', 'Disease', (75, 89))
98373	32204444	In another work, inhibition of miR-483-5p in NCI-H295R cells was reported to also reduce their proliferation.	('miR-483-5p', 'Chemical', '-', (31, 41))	('inhibition', 'Var', (17, 27))	('miR-483-5p', 'Protein', (31, 41))	('reduce', 'NegReg', (82, 88))	('NCI-H295R', 'CellLine', 'CVCL:0458', (45, 54))	('proliferation', 'CPA', (95, 108))
98389	32204444	Univariate analyses were performed for quantitative variables (age, tumor size), qualitative variables (sex, ENSAT stage) and according to cut-off values (Ki67 > 10% and miR-483-5p >752,898 copies/mL).	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('miR-483-5p', 'Chemical', '-', (170, 180))	('Ki67', 'Var', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
98390	32204444	Multivariate hazard ratios (HRs) were determined for tumor size, Ki67, ENSAT stage and miR-483-5p.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('miR-483-5p', 'Chemical', '-', (87, 97))	('Ki67', 'Var', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('miR-483-5p', 'Var', (87, 97))	('tumor', 'Disease', (53, 58))
98391	32204444	Nonetheless, miR-483-5p was consistently found to be upregulated in the tumor as well as in the serum/plasma of ACC patients, thus positioning this miRNA among the hallmarks of adrenocortical cancer.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('upregulated', 'PosReg', (53, 64))	('miR-483-5p', 'Var', (13, 23))	('tumor', 'Disease', (72, 77))	('patients', 'Species', '9606', (116, 124))	('hallmarks of adrenocortical cancer', 'Disease', (164, 198))	('hallmarks of adrenocortical cancer', 'Disease', 'MESH:D000306', (164, 198))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('miR-483-5p', 'Chemical', '-', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
98393	32204444	Indeed, high miR-483-5p levels in sera sampled within 3 months post-surgery were significantly associated with reduced overall survival and recurrence-free survival.	('miR-483-5p', 'Var', (13, 23))	('recurrence-free survival', 'CPA', (140, 164))	('reduced', 'NegReg', (111, 118))	('overall survival', 'CPA', (119, 135))	('miR-483-5p', 'Chemical', '-', (13, 23))
98398	32231811	Adrenocorticotropic hormone- (ACTH) independent hypercortisolism is the norm of hormonally active ACCs, but aberrant ACTH production by tumor cells can theoretically cause ACTH-dependent hypercortisolism.	('hypercortisolism', 'Disease', (187, 203))	('Adrenocorticotropic hormone', 'Gene', (0, 27))	('ACTH production', 'MPA', (117, 132))	('dependent hypercortisolism', 'Phenotype', 'HP:0011744', (177, 203))	('independent hypercortisolism', 'Phenotype', 'HP:0001579', (36, 64))	('dependent hypercortisolism', 'Phenotype', 'HP:0011744', (38, 64))	('hypercortisolism', 'Phenotype', 'HP:0003118', (187, 203))	('aberrant', 'Var', (108, 116))	('hypercortisolism', 'Phenotype', 'HP:0003118', (48, 64))	('ACTH-dependent hypercortisolism', 'Phenotype', 'HP:0011744', (172, 203))	('hypercortisolism', 'Disease', 'MESH:D003480', (48, 64))	('ACCs', 'Phenotype', 'HP:0006744', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('hypercortisolism', 'Disease', 'MESH:D003480', (187, 203))	('cause', 'Reg', (166, 171))	('hypercortisolism', 'Disease', (48, 64))	('Adrenocorticotropic hormone', 'Gene', '5443', (0, 27))
98405	32231811	Cushing's syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion was first described by Hurst Brown in 1928 in association with bronchial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('ectopic', 'Var', (26, 33))	("Cushing's syndrome", 'Disease', (0, 18))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (0, 18))	('adrenocorticotropic hormone', 'Gene', '5443', (34, 61))	('adrenocorticotropic hormone', 'Gene', (34, 61))	('bronchial carcinoma', 'Disease', (142, 161))	('bronchial carcinoma', 'Disease', 'MESH:D002283', (142, 161))
98406	32231811	Though non-ACTH-dependent hypercortisolism is the norm of adrenal malignancies, ectopic ACTH secretion by adrenal tumor cells can theoretically result in ACTH-dependent Cushing's syndrome.	("ACTH-dependent Cushing's syndrome", 'Disease', (154, 187))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('ACTH-dependent hypercortisolism', 'Phenotype', 'HP:0011744', (11, 42))	('adrenal malignancies', 'Disease', (58, 78))	('adrenal tumor', 'Phenotype', 'HP:0100631', (106, 119))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (169, 187))	('adrenal malignancies', 'Phenotype', 'HP:0100631', (58, 78))	('result in', 'Reg', (144, 153))	('adrenal malignancies', 'Disease', 'MESH:D009369', (58, 78))	('dependent hypercortisolism', 'Phenotype', 'HP:0011744', (16, 42))	('hypercortisolism', 'Phenotype', 'HP:0003118', (26, 42))	('adrenal tumor', 'Disease', 'MESH:D000310', (106, 119))	('ectopic', 'Var', (80, 87))	('adrenal tumor', 'Disease', (106, 119))
98439	32231811	Tumors with aberrant IGF-II gene transcription and gene expression produce this big IGF-II due to abnormal processing.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('IGF-II', 'Gene', (21, 27))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('aberrant', 'Var', (12, 20))
98465	31419939	For instance, to predict overall survival and cause-specific survival in prostate cancer, E2F3 is considered a relatively independent factor.	('prostate cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('E2F3', 'Var', (90, 94))
98466	31419939	Furthermore, E2F3a stimulates the proliferation of ovarian cancer cells through EGFR-driven mitogenic cell signals.	('proliferation', 'CPA', (34, 47))	('stimulates', 'PosReg', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('EGFR', 'Gene', '1956', (80, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (51, 65))	('EGFR', 'Gene', (80, 84))	('E2F3a', 'Var', (13, 18))	('ovarian cancer', 'Disease', 'MESH:D010051', (51, 65))	('ovarian cancer', 'Disease', (51, 65))
98467	31419939	In lung cancer cells, miR-200b can target E2F3 to lessen cell sensitivity to docetaxel.	('E2F3', 'Gene', (42, 46))	('lung cancer', 'Disease', (3, 14))	('lessen', 'NegReg', (50, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('miR-200b', 'Var', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cell sensitivity to docetaxel', 'MPA', (57, 86))	('docetaxel', 'Chemical', 'MESH:D000077143', (77, 86))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('miR-200b', 'Chemical', '-', (22, 30))
98469	31419939	verified that manipulating K6a phosphorylation or UPS activity may provide opportunities to harness the innate immunity of epithelia against infection.	('epithelia against infection', 'Disease', (123, 150))	('UPS', 'MPA', (50, 53))	('K6a', 'Gene', (27, 30))	('epithelia against infection', 'Disease', 'MESH:D024821', (123, 150))	('manipulating', 'Var', (14, 26))	('K6a', 'Gene', '3853', (27, 30))
98472	31419939	revealed that defects in IPCD and digit separation in Hoxa13 mutant mice may be partly caused by reduced levels of RA signaling stemming from a loss in the direct regulation of Aldh1a2.	('mice', 'Species', '10090', (68, 72))	('Hoxa13', 'Gene', (54, 60))	('levels of RA signaling', 'MPA', (105, 127))	('IPCD', 'Disease', (25, 29))	('Aldh1a2', 'Gene', '19378', (177, 184))	('IPCD', 'Disease', 'None', (25, 29))	('Aldh1a2', 'Gene', (177, 184))	('reduced', 'NegReg', (97, 104))	('mutant', 'Var', (61, 67))	('Hoxa13', 'Gene', '15398', (54, 60))	('loss', 'NegReg', (144, 148))	('defects', 'NegReg', (14, 21))
98499	28114280	We show that RARRES2 expression is downregulated in ACC as compared to normal and benign adrenocortical tissues, which is a result of CpG hypermethylation.	('hypermethylation', 'Var', (138, 154))	('ACC', 'Phenotype', 'HP:0006744', (52, 55))	('RARRES2', 'Gene', (13, 20))	('ACC', 'Disease', (52, 55))	('benign adrenocortical tissues', 'Disease', (82, 111))	('expression', 'MPA', (21, 31))	('downregulated', 'NegReg', (35, 48))	('benign adrenocortical tissues', 'Disease', 'MESH:D018268', (82, 111))
98503	28114280	Cancer initiation and progression are the consequence of cumulative genetic and epigenetic alterations.	('genetic', 'Var', (68, 75))	('epigenetic alterations', 'Var', (80, 102))	('Cancer initiation', 'Disease', 'MESH:D009369', (0, 17))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer initiation', 'Disease', (0, 17))
98504	28114280	Such alterations, especially in proto-oncogenes, will disrupt tissue homeostasis and lead to tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tissue homeostasis', 'MPA', (62, 80))	('lead to', 'Reg', (85, 92))	('tumor', 'Disease', (93, 98))	('alterations', 'Var', (5, 16))	('disrupt', 'NegReg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
98522	28114280	In our previous genome-wide methylation profiling study in adrenocortical tissues, we found that RARRES2 was significantly hypermethylated in ACCs as compared to benign adrenocortical tumors and normal adrenocortical samples.	('benign adrenocortical tumors', 'Disease', 'MESH:D018268', (162, 190))	('ACC', 'Phenotype', 'HP:0006744', (142, 145))	('benign adrenocortical tumors', 'Disease', (162, 190))	('adrenocortical', 'Disease', (202, 216))	('adrenocortical', 'Disease', 'MESH:D018268', (202, 216))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('ACCs', 'Gene', '84680', (142, 146))	('adrenocortical', 'Disease', (59, 73))	('adrenocortical', 'Disease', 'MESH:D018268', (59, 73))	('ACCs', 'Gene', (142, 146))	('adrenocortical', 'Disease', (169, 183))	('hypermethylated', 'Var', (123, 138))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('adrenocortical', 'Disease', 'MESH:D018268', (169, 183))	('RARRES2', 'Gene', (97, 104))
98523	28114280	Significant hypermethylation was detected at five CpG sites (cg11327659, cg 13722127, cg19310340, cg21521758 and cg274550017), three of which were located in the body of the gene, while the other two were located in the 5' UTR region (Figure 1a).	('cg274550017', 'Var', (113, 124))	('hypermethylation', 'MPA', (12, 28))	('cg', 'Chemical', 'MESH:C028505', (86, 88))	('cg', 'Chemical', 'MESH:C028505', (73, 75))	('cg274550017', 'Chemical', '-', (113, 124))	('cg19310340', 'Chemical', '-', (86, 96))	('cg', 'Chemical', 'MESH:C028505', (61, 63))	('cg21521758', 'Chemical', '-', (98, 108))	('cg 13722127', 'Var', (73, 84))	('cg11327659', 'Chemical', '-', (61, 71))	('cg', 'Chemical', 'MESH:C028505', (113, 115))	('cg21521758', 'Var', (98, 108))	('cg11327659', 'Var', (61, 71))	('cg', 'Chemical', 'MESH:C028505', (98, 100))	('cg19310340', 'Var', (86, 96))
98527	28114280	These findings suggest that, in ACC, RARRES2 expression is suppressed by CpG hypermethylation, a common mechanism of gene silencing in cancer.	('cancer', 'Disease', (135, 141))	('ACC', 'Phenotype', 'HP:0006744', (32, 35))	('RARRES2', 'Gene', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('suppressed', 'NegReg', (59, 69))	('expression', 'MPA', (45, 55))	('hypermethylation', 'Var', (77, 93))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('CpG', 'Protein', (73, 76))
98554	28114280	Only H295R cells harbored a heterozygous S45P mutation in CTNNB1 (Supplementary Table 1).	('S45P', 'Mutation', 'rs121913407', (41, 45))	('CTNNB1', 'Gene', (58, 64))	('H295R', 'CellLine', 'CVCL:0458', (5, 10))	('S45P', 'Var', (41, 45))
98575	28114280	CK1alpha phosphorylates beta-catenin at Ser45, which primes it for the subsequent phosphorylation at Thr41, Ser37 and Ser33 by GSK3.	('Ser33', 'Chemical', '-', (118, 123))	('Thr41', 'Chemical', '-', (101, 106))	('phosphorylation', 'MPA', (82, 97))	('Thr41', 'Var', (101, 106))	('Ser37', 'Chemical', '-', (108, 113))	('CK1', 'Species', '2498238', (0, 3))	('Ser45', 'Chemical', '-', (40, 45))	('beta-catenin', 'Protein', (24, 36))	('Ser37', 'Var', (108, 113))	('Ser33', 'Var', (118, 123))
98578	28114280	H295R cells harbor a heterozygous beta-catenin mutation on the CK1alpha phosphorylation site (Ser45Pro), resulting in constitutive TCF-dependent transcription.	('Ser45Pro', 'SUBSTITUTION', 'None', (94, 102))	('mutation', 'Var', (47, 55))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('TCF', 'Gene', (131, 134))	('TCF', 'Gene', '3172', (131, 134))	('CK1', 'Species', '2498238', (63, 66))	('Ser45Pro', 'Var', (94, 102))	('beta-catenin', 'Gene', (34, 46))
98580	28114280	We also showed that RARRES2 overexpression could enhance beta-catenin phosphorylation at Ser33/Ser37/Thr41, thus promoting the degradation of the beta-catenin protein.	('Thr41', 'Chemical', '-', (101, 106))	('Ser33/Ser37/Thr41', 'Var', (89, 106))	('Ser33', 'Chemical', '-', (89, 94))	('RARRES2', 'Gene', (20, 27))	('enhance', 'PosReg', (49, 56))	('beta-catenin', 'Protein', (57, 69))	('beta-catenin protein', 'MPA', (146, 166))	('overexpression', 'PosReg', (28, 42))	('degradation', 'MPA', (127, 138))	('promoting', 'PosReg', (113, 122))	('Ser37', 'Chemical', '-', (95, 100))
98585	28114280	Through pyrosequencing, we also confirmed that epigenetic CpG hypermethylation is a cause of RARRES2 downregulation in ACCs.	('downregulation', 'NegReg', (101, 115))	('hypermethylation', 'Var', (62, 78))	('epigenetic CpG hypermethylation', 'Var', (47, 78))	('ACC', 'Phenotype', 'HP:0006744', (119, 122))	('RARRES2', 'Gene', (93, 100))	('ACCs', 'Gene', (119, 123))	('ACCs', 'Gene', '84680', (119, 123))
98608	28114280	In breast and lung cancers, Wnt signaling is hyperactive despite rare pathway mutations.	('breast and lung cancers', 'Disease', 'MESH:D001943', (3, 26))	('hyperactive', 'PosReg', (45, 56))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('mutations', 'Var', (78, 87))	('Wnt signaling', 'Pathway', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('lung cancers', 'Phenotype', 'HP:0100526', (14, 26))
98615	28114280	Human adrenocortical tissue samples were collected according to an institutional review board-approved clinical protocol after written informed consent was obtained (NCT01005654 and NCT01348698).	('Human', 'Species', '9606', (0, 5))	('adrenocortical', 'Disease', (6, 20))	('NCT01005654', 'Var', (166, 177))	('NCT01348698', 'Var', (182, 193))	('adrenocortical', 'Disease', 'MESH:D018268', (6, 20))
98632	28114280	The gene expression assays used were: RARRES2 (Hs0016120_g1), CMKLR1 (Hs01081979_s1), mouse CMKLR1 (Mm01700212_m1), CTNNB1 (Hs00355049_m1), and GAPDH (Hs99999905_m1).	('mouse', 'Species', '10090', (86, 91))	('Hs0016120_g1', 'Var', (47, 59))	('Hs01081979_s1', 'Var', (70, 83))	('Hs00355049_m1', 'Var', (124, 137))	('Hs99999905_m1', 'Var', (151, 164))	('Mm01700212_m1', 'Var', (100, 113))
98676	27102148	The most widely used diagnostic score are known as Weiss criteria, with several updates, and includes the following parameters: mitosis, atypical mitosis, necrosis, venous invasion, sinusal invasion, capsular invasion, nuclear atypia, diffuse architecture, and clear cell change.	('mitosis', 'Disease', (146, 153))	('nuclear atypia', 'CPA', (219, 233))	('necrosis', 'Disease', (155, 163))	('mitosis', 'Disease', (128, 135))	('mitosis', 'Disease', 'None', (146, 153))	('sinusal invasion', 'CPA', (182, 198))	('capsular invasion', 'CPA', (200, 217))	('mitosis', 'Disease', 'None', (128, 135))	('atypical', 'Var', (137, 145))	('diffuse architecture', 'CPA', (235, 255))	('necrosis', 'Disease', 'MESH:D009336', (155, 163))	('venous invasion', 'CPA', (165, 180))
98677	27102148	Molecular analyses have been recently attempted in helping diagnosis, in particular hypermethylation, miRNA, TP53, ZNRF3, beta-catenin are possible candidates that could help diagnose and establish prognosis, but are not yet used in current pathologic diagnosis.	('ZNRF3', 'Gene', (115, 120))	('beta-catenin', 'Gene', '1499', (122, 134))	('TP53', 'Gene', '7157', (109, 113))	('ZNRF3', 'Gene', '84133', (115, 120))	('hypermethylation', 'Var', (84, 100))	('TP53', 'Gene', (109, 113))	('beta-catenin', 'Gene', (122, 134))
98693	27102148	The patients randomized to receive EDPM had higher tumor response rates when compared to patients treated with streptozocin combined with mitotane (23% vs. 9%).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('higher', 'PosReg', (44, 50))	('tumor', 'Disease', (51, 56))	('streptozocin', 'Chemical', 'MESH:D013311', (111, 123))	('mitotane', 'Chemical', 'MESH:D008939', (138, 146))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (4, 12))	('EDPM', 'Chemical', '-', (35, 39))	('EDPM', 'Var', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
98694	27102148	Prolongation of progression-free survival (PFS) was also observed in the EDPM arm (5 vs. 2 months).	('EDPM', 'Var', (73, 77))	('EDPM', 'Chemical', '-', (73, 77))	('progression-free survival', 'CPA', (16, 41))
98698	27102148	It is important to review that mitotane is a strong cytochrome P450-3A4 (CYP3A4) inducer and this may lead to significant drug interactions and decrease the activity of combination strategies.	('combination', 'Interaction', (169, 180))	('cytochrome P450-3A4', 'Gene', '1576', (52, 71))	('drug', 'MPA', (122, 126))	('mitotane', 'Var', (31, 39))	('mitotane', 'Chemical', 'MESH:D008939', (31, 39))	('decrease', 'NegReg', (144, 152))	('lead to', 'Reg', (102, 109))	('CYP3A4', 'Gene', '1576', (73, 79))	('CYP3A4', 'Gene', (73, 79))	('cytochrome P450-3A4', 'Gene', (52, 71))	('inducer', 'PosReg', (81, 88))	('activity', 'MPA', (157, 165))
98702	27102148	Chromosome 11p15 abnormalities are present in up to 90% of sporadic ACCs and IGF2 is commonly overexpressed in this tumor.	('IGF2', 'Gene', '3481', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('ACC', 'Phenotype', 'HP:0006744', (68, 71))	('IGF2', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('abnormalities', 'Var', (17, 30))	('ACCs', 'Gene', (68, 72))	('ACCs', 'Gene', '84680', (68, 72))	('tumor', 'Disease', (116, 121))
98738	27102148	However sunitinib serum levels might have been reduced by mitotane induced CYP3A4 activity attenuating its antitumor activity and adverse effects.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('serum levels', 'MPA', (18, 30))	('CYP3A4', 'Gene', '1576', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mitotane', 'Var', (58, 66))	('attenuating', 'NegReg', (91, 102))	('tumor', 'Disease', (111, 116))	('sunitinib', 'Chemical', 'MESH:D000077210', (8, 17))	('mitotane', 'Chemical', 'MESH:D008939', (58, 66))	('activity', 'MPA', (82, 90))	('reduced', 'NegReg', (47, 54))	('CYP3A4', 'Gene', (75, 81))
98740	27102148	These results document the limited clinical efficacy of these VEGF and VEGFR inhibitors for the treatment of ACC.	('inhibitors', 'Var', (77, 87))	('VEGFR', 'Gene', (71, 76))	('ACC', 'Phenotype', 'HP:0006744', (109, 112))	('VEGF', 'Gene', '7422', (62, 66))	('ACC', 'Disease', (109, 112))	('VEGF', 'Gene', (71, 75))	('VEGF', 'Gene', (62, 66))	('VEGFR', 'Gene', '3791', (71, 76))	('VEGF', 'Gene', '7422', (71, 75))
98748	27102148	EGFR has been show to be overexpressed in ACC when compared to adrenal adenomas and normal tissue suggesting the potential use of EGFR expression as a marker of malignancy.. EGFR amplification by FISH and polysomy of chromosome 7 are noted to be more frequent in ACC specimens compared to adrenocortical adenomas.	('malignancy', 'Disease', (161, 171))	('amplification', 'Var', (179, 192))	('ACC', 'Phenotype', 'HP:0006744', (42, 45))	('EGFR', 'Gene', (130, 134))	('EGFR', 'Gene', '1956', (174, 178))	('ACC', 'Phenotype', 'HP:0006744', (263, 266))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (63, 78))	('adrenal adenomas', 'Disease', 'MESH:D018246', (63, 79))	('ACC', 'Disease', (263, 266))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (289, 312))	('EGFR', 'Gene', (0, 4))	('polysomy', 'Var', (205, 213))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (63, 79))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (289, 312))	('EGFR', 'Gene', '1956', (130, 134))	('adrenocortical adenomas', 'Disease', (289, 312))	('EGFR', 'Gene', (174, 178))	('malignancy', 'Disease', 'MESH:D009369', (161, 171))	('adrenal adenomas', 'Disease', (63, 79))	('EGFR', 'Gene', '1956', (0, 4))
98750	27102148	Nevertheless, inhibition of EGFR signaling was able to reduce cell viability in ACC lines in vitro.	('EGFR', 'Gene', '1956', (28, 32))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('cell viability in ACC lines in vitro', 'CPA', (62, 98))	('EGFR', 'Gene', (28, 32))	('reduce', 'NegReg', (55, 61))	('inhibition', 'Var', (14, 24))
98752	27102148	Despite the frequent expression of EGFR, the rarity of activating mutations predictive of response to EGFR tyrosine kinase inhibitors (TKIs) makes unlikely that this class of drugs will be clinically effective for ACC.	('mutations', 'Var', (66, 75))	('EGFR', 'Gene', '1956', (35, 39))	('ACC', 'Phenotype', 'HP:0006744', (214, 217))	('EGFR', 'Gene', (35, 39))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
98755	27102148	In adults, FGFR4 overexpression and amplification (identified in 13% of pediatric tumors and 30% of adults) was associated with worse outcomes.	('FGFR4', 'Gene', '2264', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('FGFR4', 'Gene', (11, 16))	('pediatric tumors', 'Disease', (72, 88))	('amplification', 'Var', (36, 49))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('overexpression', 'PosReg', (17, 31))	('pediatric tumors', 'Disease', 'MESH:D063766', (72, 88))
98758	27102148	These preliminary results support the current investigation of the potential role of selective FGFR inhibitors for treatment of ACC, particularly in tumors with FGFR overexpression or carrying other genetic aberrations such as amplifications, activating mutations or gene fusions.	('ACC', 'Phenotype', 'HP:0006744', (128, 131))	('ACC', 'Disease', (128, 131))	('FGFR', 'Gene', (161, 165))	('FGFR', 'Gene', (95, 99))	('activating mutations', 'Var', (243, 263))	('amplifications', 'Var', (227, 241))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('gene fusions', 'Var', (267, 279))	('overexpression', 'PosReg', (166, 180))
98766	27102148	SF-1 inhibitors inhibited the proliferation elicited by SF-1 overexpression in vitro suggesting a possible therapeutic potential.	('SF-1', 'Gene', (56, 60))	('inhibited', 'NegReg', (16, 25))	('SF-1', 'Gene', '2516', (0, 4))	('overexpression', 'PosReg', (61, 75))	('inhibitors', 'Var', (5, 15))	('SF-1', 'Gene', (0, 4))	('SF-1', 'Gene', '2516', (56, 60))	('proliferation', 'CPA', (30, 43))
98771	27102148	The most common genetic alteration identified among 77 ACC tumors by exome sequencing and single nucleotide polymorphism (SNP) array analysis were homozygous deletions in the ZNRF3 gene.	('ACC', 'Phenotype', 'HP:0006744', (55, 58))	('ACC', 'Disease', (55, 58))	('ZNRF3', 'Gene', '84133', (175, 180))	('common', 'Reg', (9, 15))	('deletions', 'Var', (158, 167))	('tumors', 'Disease', (59, 65))	('ZNRF3', 'Gene', (175, 180))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
98774	27102148	In addition, beta-catenin nuclear expression assessed by immunohistochemistry and the presence of mutations in the CTNNB1 and APC genes represented independent prognostic factors in patients with resected ACC.	('CTNNB1', 'Gene', '1499', (115, 121))	('ACC', 'Phenotype', 'HP:0006744', (205, 208))	('beta-catenin', 'Gene', '1499', (13, 25))	('APC', 'Gene', (126, 129))	('mutations', 'Var', (98, 107))	('patients', 'Species', '9606', (182, 190))	('CTNNB1', 'Gene', (115, 121))	('beta-catenin', 'Gene', (13, 25))
98775	27102148	The therapeutic potential of this pathway was suggested by pre-clinical data showing that a small-molecule inhibitor of the Tcf/beta-catenin complex (PKF115-584) induced apoptosis in ACC cell lines carrying mutations in beta-catenin.	('ACC', 'Phenotype', 'HP:0006744', (183, 186))	('beta-catenin', 'Gene', '1499', (220, 232))	('beta-catenin', 'Gene', (128, 140))	('beta-catenin', 'Gene', '1499', (128, 140))	('induced', 'PosReg', (162, 169))	('mutations', 'Var', (207, 216))	('Tcf', 'Gene', '3172', (124, 127))	('Tcf', 'Gene', (124, 127))	('beta-catenin', 'Gene', (220, 232))	('apoptosis', 'CPA', (170, 179))
98778	27102148	For instance, inhibition of gamma-secretase, which is a key component in the Notch extra-cellular signal transduction pathway showed significant anti-tumor activity in patients desmoid tumors (ORR 71.4%) in a phase I trial.	('tumor', 'Disease', (185, 190))	('desmoid tumors', 'Disease', (177, 191))	('gamma-secretase', 'Protein', (28, 43))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('desmoid tumors', 'Phenotype', 'HP:0100245', (177, 191))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('patients', 'Species', '9606', (168, 176))	('desmoid tumors', 'Disease', 'MESH:C535944', (177, 191))	('inhibition', 'Var', (14, 24))	('tumor', 'Disease', (150, 155))
98779	27102148	CTNNB1 mutations are observed is as much as 85% of desmoid tumors, which may indicate potential interactions between the Notch and Wnt/beta-catenin pathways.	('CTNNB1', 'Gene', '1499', (0, 6))	('interactions', 'Interaction', (96, 108))	('desmoid tumors', 'Disease', 'MESH:C535944', (51, 65))	('desmoid tumors', 'Phenotype', 'HP:0100245', (51, 65))	('beta-catenin', 'Gene', (135, 147))	('CTNNB1', 'Gene', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('beta-catenin', 'Gene', '1499', (135, 147))	('observed', 'Reg', (21, 29))	('desmoid tumors', 'Disease', (51, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutations', 'Var', (7, 16))
98790	27102148	Activation of this pathway through mutations or overexpression can lead to cellular proliferation and metastasis in several solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (124, 136))	('lead to', 'Reg', (67, 74))	('cellular proliferation', 'CPA', (75, 97))	('solid tumors', 'Disease', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('overexpression', 'PosReg', (48, 62))	('metastasis', 'CPA', (102, 112))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('mutations', 'Var', (35, 44))
98797	27102148	For example, both miR-483-5p and miR-7, have been shown to regulate the expression of apoptotic pathways, making these molecules attractive for anticancer therapy.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('miR-7', 'Gene', (33, 38))	('expression', 'MPA', (72, 82))	('regulate', 'Reg', (59, 67))	('miR-483-5p', 'Var', (18, 28))	('apoptotic pathways', 'Pathway', (86, 104))	('miR-7', 'Gene', '10859', (33, 38))
98804	27102148	Clinical trials evaluating this strategy will be soon recruiting patients (NCT02673333, NCT02720484 and NCT02720484).	('patients', 'Species', '9606', (65, 73))	('NCT02720484', 'Var', (88, 99))	('NCT02673333', 'Var', (75, 86))	('NCT02720484', 'Var', (104, 115))
98823	27102148	These studies have identified recurring mutations in several genes such as ZNRF3 (20%), CTNNB1 (14%), TP53 (14%), CDKN2A (11%), RB1 (5%), MEN (16%), DAXX (5%), MED12 (3%) and TERT (5%).	('ZNRF3', 'Gene', '84133', (75, 80))	('TP53', 'Gene', (102, 106))	('CDKN2A', 'Gene', '1029', (114, 120))	('TERT', 'Gene', (175, 179))	('RB1', 'Gene', (128, 131))	('MED12', 'Gene', (160, 165))	('DAXX', 'Gene', '1616', (149, 153))	('ZNRF3', 'Gene', (75, 80))	('CTNNB1', 'Gene', '1499', (88, 94))	('MED12', 'Gene', '9968', (160, 165))	('TERT', 'Gene', '7015', (175, 179))	('mutations', 'Var', (40, 49))	('MEN', 'Species', '9606', (138, 141))	('RB1', 'Gene', '5925', (128, 131))	('DAXX', 'Gene', (149, 153))	('TP53', 'Gene', '7157', (102, 106))	('CDKN2A', 'Gene', (114, 120))	('CTNNB1', 'Gene', (88, 94))
98992	24102952	Moreover, it has been reported that approximately 55% of pancreatic adenocarcinomas show inactivation of the Smad4/DPC4 gene by one of two mechanisms: homozygous deletion and loss of heterozygosity.	('inactivation', 'NegReg', (89, 101))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (57, 83))	('homozygous deletion', 'Var', (151, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('Smad4', 'Gene', (109, 114))	('DPC4', 'Gene', (115, 119))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (57, 83))	('DPC4', 'Gene', '4089', (115, 119))	('pancreatic adenocarcinomas', 'Disease', (57, 83))	('Smad4', 'Gene', '4089', (109, 114))	('loss of heterozygosity', 'Var', (175, 197))
99064	24383032	In addition, adrenocortical heterotopia may also be related to genetic or epigenetic alterations.	('adrenocortical heterotopia', 'Disease', (13, 39))	('epigenetic alterations', 'Var', (74, 96))	('heterotopia', 'Phenotype', 'HP:0002282', (28, 39))	('genetic', 'Var', (63, 70))	('related', 'Reg', (52, 59))	('adrenocortical heterotopia', 'Disease', 'MESH:D018268', (13, 39))
99066	24383032	The results suggest that any genetic alteration or epigenetic signals that lead to Ad4BP/SF1 activation could facilitate the formation of adrenocortical heterotopia.	('activation', 'PosReg', (93, 103))	('adrenocortical heterotopia', 'Disease', 'MESH:D018268', (138, 164))	('SF1', 'Gene', '7536', (89, 92))	('adrenocortical heterotopia', 'Disease', (138, 164))	('Ad4BP', 'Gene', '2516', (83, 88))	('heterotopia', 'Phenotype', 'HP:0002282', (153, 164))	('facilitate', 'PosReg', (110, 120))	('epigenetic signals', 'Var', (51, 69))	('Ad4BP', 'Gene', (83, 88))	('SF1', 'Gene', (89, 92))
99088	24086826	For primary ACC, histopathologic findings of tumor necrosis, a mitotic rate of more than 5 of 50 in the high power field, and atypical mitotic figures are associated with reduced disease-free survival.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('primary ACC', 'Disease', (4, 15))	('tumor necrosis', 'Disease', 'MESH:D009336', (45, 59))	('disease-free survival', 'CPA', (179, 200))	('ACC', 'Phenotype', 'HP:0006744', (12, 15))	('atypical', 'Var', (126, 134))	('tumor necrosis', 'Disease', (45, 59))	('mitotic rate', 'CPA', (63, 75))	('reduced', 'NegReg', (171, 178))
99098	33889043	Complete Radiological Response of Recurrent Metastatic Adrenocortical Carcinoma to Pembrolizumab and Mitotane Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (55, 79))	('malignancy', 'Disease', 'MESH:D009369', (151, 161))	('Adrenocortical Carcinoma to Pembrolizumab', 'Disease', 'MESH:D018268', (55, 96))	('malignancy', 'Disease', (151, 161))	('Mitotane', 'Var', (101, 109))	('Adrenocortical Carcinoma to Pembrolizumab', 'Disease', (55, 96))	('Carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('ACC', 'Phenotype', 'HP:0006744', (136, 139))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (110, 134))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (110, 134))	('Mitotane', 'Chemical', 'MESH:D008939', (101, 109))	('Adrenocortical carcinoma', 'Disease', (110, 134))
99109	33889043	We present a case of a 40-year-old woman who was initially diagnosed with ACC in 2012 following left adrenalectomy that revealed a 7 x 6 x 3.5 cm soft tissue mass weighing 91 g. The presence of pleomorphism, <25% clear cells, diffuse pattern of growth, high mitotic index, hemorrhage and necrosis, large tumor weight (91 g), and foci of lymphovascular invasion was consistent with stage-II ACC.	('high mitotic index', 'CPA', (253, 271))	('ACC', 'Phenotype', 'HP:0006744', (390, 393))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('soft tissue mass', 'Phenotype', 'HP:0031459', (146, 162))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('tumor', 'Disease', (304, 309))	('necrosis', 'Disease', (288, 296))	('hemorrhage', 'Disease', (273, 283))	('woman', 'Species', '9606', (35, 40))	('hemorrhage', 'Disease', 'MESH:D006470', (273, 283))	('pleomorphism', 'Var', (194, 206))	('necrosis', 'Disease', 'MESH:D009336', (288, 296))
99119	33889043	Next-generation sequencing showed the tumor to be microsatellite stable (MSS), and the tumor mutational burden to be 6 Muts/Mb (<10 Muts/Mb is considered low).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('microsatellite', 'Var', (50, 64))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
99120	33889043	Next-generation sequencing genomic findings showed CCND2 amplification, ATRX splice site 5698-2A > C, FANCC inversion exons 10-11, FGF23 amplification, FGF6 amplification, KDM5A amplification, AND TP53 Q52* alteration.	('KDM5A', 'Gene', (172, 177))	('ATRX', 'Gene', '546', (72, 76))	('FGF23', 'Gene', (131, 136))	('FGF6', 'Gene', (152, 156))	('CCND2', 'Gene', '894', (51, 56))	('Q52*', 'Var', (202, 206))	('Q52*', 'SUBSTITUTION', 'None', (202, 206))	('KDM5A', 'Gene', '5927', (172, 177))	('FANCC', 'Gene', (102, 107))	('amplification', 'Reg', (157, 170))	('FANCC', 'Gene', '2176', (102, 107))	('5698-2A > C', 'Mutation', 'c.5698-2A>C', (89, 100))	('FGF23', 'Gene', '8074', (131, 136))	('ATRX', 'Gene', (72, 76))	('TP53', 'Gene', '7157', (197, 201))	('FGF6', 'Gene', '2251', (152, 156))	('CCND2', 'Gene', (51, 56))	('TP53', 'Gene', (197, 201))
99124	33889043	The combination therapy was effective in both microsatellite instability-high and MSS adrenocortical tumors.	('adrenocortical tumors', 'Disease', (86, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('microsatellite instability-high', 'Var', (46, 77))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (86, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))
99148	33889043	In addition, of the genomic findings obtained from NGS, CCND2 amplification has been linked to ACC, and has been reported in 1% to 7% of ACC in data sets.	('CCND2', 'Gene', (56, 61))	('CCND2', 'Gene', '894', (56, 61))	('ACC', 'Phenotype', 'HP:0006744', (95, 98))	('ACC', 'Disease', (95, 98))	('ACC', 'Phenotype', 'HP:0006744', (137, 140))	('amplification', 'Var', (62, 75))	('linked', 'Reg', (85, 91))
99149	33889043	TP53 mutations have been reported in 20% to 33% of ACCs118-122, and both mutations and aberrant expression have been associated with poor outcomes and decreased disease-free survival.	('decreased disease-free', 'Disease', (151, 173))	('TP53', 'Gene', '7157', (0, 4))	('ACC', 'Phenotype', 'HP:0006744', (51, 54))	('TP53', 'Gene', (0, 4))	('decreased disease-free', 'Disease', 'MESH:D008569', (151, 173))	('mutations', 'Var', (5, 14))	('aberrant', 'Var', (87, 95))	('mutations', 'Var', (73, 82))
99165	33889043	Microsatellite status, tumor burden, TAM density and type (M1/M2), immunoscore, and regulatory T-cells are all markers that have been explored in other types of cancer, but data regarding their utility in ACC is scarcely available, with immunoscore only calibrated for colorectal cancer.	('Microsatellite', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('colorectal cancer', 'Disease', 'MESH:D015179', (269, 286))	('ACC', 'Phenotype', 'HP:0006744', (205, 208))	('cancer', 'Disease', (280, 286))	('TAM', 'Chemical', '-', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (269, 286))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('colorectal cancer', 'Disease', (269, 286))	('cancer', 'Disease', (161, 167))	('tumor', 'Disease', (23, 28))
99190	33578929	Non-functioning ACCs commonly present with abdominal mass, abdominal pain as well as general symptoms of malignancy.	('abdominal pain', 'Phenotype', 'HP:0002027', (59, 73))	('abdominal pain', 'Disease', (59, 73))	('abdominal pain', 'Disease', 'MESH:D015746', (59, 73))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('Non-functioning', 'Var', (0, 15))	('ACCs', 'Gene', (16, 20))	('malignancy', 'Disease', (105, 115))	('abdominal mass', 'Phenotype', 'HP:0031500', (43, 57))	('ACCs', 'Gene', '84680', (16, 20))	('abdominal mass', 'Disease', (43, 57))	('pain', 'Phenotype', 'HP:0012531', (69, 73))
99207	33578929	Using this system, ACC could be diagnosed on at least three of the 9 histological features:high nuclear grade (Fuhrman III or IV), high mitotic rate (>5 mitoses per 50 high power field, atypical mitotic figures, <=25% clear cells, diffuse architecture, tumour confluent necrosis, venous invasion, sinusoidal invasion, and capsular invasion.	('necrosis', 'Disease', 'MESH:D009336', (270, 278))	('high nuclear grade', 'CPA', (91, 109))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('diffuse architecture', 'CPA', (231, 251))	('tumour', 'Disease', (253, 259))	('capsular invasion', 'CPA', (322, 339))	('venous invasion', 'CPA', (280, 295))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('sinusoidal invasion', 'CPA', (297, 316))	('necrosis', 'Disease', (270, 278))	('<=25', 'Var', (212, 216))	('atypical mitotic figures', 'CPA', (186, 210))
99228	33578929	Preliminary data also shows that for localised ACC, molecular makers (expression, methylation, and chromosome alterations) could predict cancer recurrence.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('methylation', 'Var', (82, 93))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('chromosome alterations', 'CPA', (99, 121))	('expression', 'MPA', (70, 80))	('cancer', 'Disease', (137, 143))	('predict', 'Reg', (129, 136))
99237	33578929	On the other hand, the incidence of paediatric ACC is reported to be high in southern regions of Brazil in which 4 case per million was reported in children of less than 10 years which may be related to high incidence of germline mutation of TP53 (R337H) detected in the region.	('R337H', 'Mutation', 'rs121912664', (248, 253))	('children', 'Species', '9606', (148, 156))	('R337H', 'Var', (248, 253))	('TP53', 'Gene', '7157', (242, 246))	('TP53', 'Gene', (242, 246))
99252	33578929	Wienke criteria comprises 9 parameters which incorporate macroscopic features (tumour weight > 400 g; tumour size > 105 mm) as well as microscopic features (extension into periadrenal soft tissues and/or adjacent organs, invasion into the vena cava, venous invasion (emboli, independent of main tumour), capsular invasion (beyond the capsule), tumour necrosis (confluent), atypical mitotic figures and high mitotic count (defined by more than 15 mitoses/20 high-power fields).	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('capsular invasion', 'CPA', (304, 321))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('atypical', 'Var', (373, 381))	('tumour', 'Phenotype', 'HP:0002664', (344, 350))	('tumour', 'Disease', 'MESH:D009369', (344, 350))	('tumour', 'Phenotype', 'HP:0002664', (295, 301))	('tumour', 'Disease', (344, 350))	('tumour', 'Disease', 'MESH:D009369', (295, 301))	('tumour', 'Disease', (295, 301))	('tumour necrosis', 'Disease', 'MESH:D009336', (344, 359))	('tumour weight', 'Disease', 'MESH:D009369', (79, 92))	('tumour necrosis', 'Disease', (344, 359))	('invasion into the', 'CPA', (221, 238))	('tumour weight', 'Disease', (79, 92))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('high mitotic count', 'CPA', (402, 420))	('venous invasion', 'CPA', (250, 265))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
99369	33578929	Papathomas and colleagues have demonstrated in 6 cases of sarcomatoid ACC, that dysregulation of Wnt/beta-catenin signalling pathway and p53 mutation were common.	('dysregulation', 'MPA', (80, 93))	('beta-catenin', 'Gene', (101, 113))	('p53', 'Gene', '7157', (137, 140))	('sarcomatoid ACC', 'Disease', (58, 73))	('Papathomas', 'Disease', (0, 10))	('sarcomatoid ACC', 'Disease', 'MESH:D004476', (58, 73))	('Papathomas', 'Disease', 'None', (0, 10))	('beta-catenin', 'Gene', '1499', (101, 113))	('p53', 'Gene', (137, 140))	('mutation', 'Var', (141, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))
99389	33578929	The driver genes mutations in paediatric ACC include IGF-2, TP53 as well as mutations in alpha-thalassemia/mental retardation, X-linked (ATRX), CTNNB1 and integration of human herpesvirus-6 in chromosome 11p.	('mental retardation', 'Disease', (107, 125))	('thalassemia', 'Disease', (95, 106))	('ATRX', 'Gene', (137, 141))	('mutations', 'Var', (76, 85))	('mental retardation', 'Disease', 'MESH:D008607', (107, 125))	('CTNNB1', 'Gene', (144, 150))	('ACC', 'Gene', (41, 44))	('thalassemia', 'Disease', 'MESH:D013789', (95, 106))	('ATRX', 'Gene', '546', (137, 141))	('TP53', 'Gene', '7157', (60, 64))	('IGF-2', 'Gene', (53, 58))	('IGF-2', 'Gene', '3481', (53, 58))	('CTNNB1', 'Gene', '1499', (144, 150))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (17, 26))	('human herpesvirus-6', 'Species', '10368', (170, 189))	('mental retardation', 'Phenotype', 'HP:0001249', (107, 125))
99390	33578929	The authors noted that paediatric ACC could be divided into 3 groups based on TP53 and ATRX mutations (group 1:TP53 mutated and ATRX mutated; group 2:TP53 mutated and ATRX wide type; group 3:TP53 wide type and ATRX wide type) which may be associated with disease progression.	('TP53', 'Gene', (150, 154))	('TP53', 'Gene', '7157', (191, 195))	('associated', 'Reg', (239, 249))	('mutated', 'Var', (155, 162))	('TP53', 'Gene', '7157', (111, 115))	('ATRX', 'Gene', (210, 214))	('TP53', 'Gene', '7157', (78, 82))	('ATRX', 'Gene', '546', (210, 214))	('TP53', 'Gene', '7157', (150, 154))	('mutated', 'Var', (116, 123))	('TP53', 'Gene', (191, 195))	('ATRX', 'Gene', (128, 132))	('ATRX', 'Gene', '546', (128, 132))	('ATRX', 'Gene', (167, 171))	('ATRX', 'Gene', '546', (167, 171))	('ATRX', 'Gene', (87, 91))	('TP53', 'Gene', (111, 115))	('TP53', 'Gene', (78, 82))	('ATRX', 'Gene', '546', (87, 91))
99396	33578929	In the 7th Edition of AJCC cancer staging manual, carcinoma of either T4 N0 M0 or T3/T4 N1 which was labelled as Stage IV in 7th Edition now re-classified into stage III.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('T3/T4 N1', 'Var', (82, 90))	('carcinoma', 'Disease', (50, 59))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('carcinoma', 'Disease', 'MESH:D009369', (50, 59))
99406	33578929	These core features include the classification according to WHO classification, integrity of the specimen, greatest dimension, weight, extent of invasion, architecture, percentage of lipid-rich cells, capsular invasion, lymphatic invasion, vascular invasion, atypical mitotic figures, coagulative necrosis, nuclear grade, mitotic count, Ki-67 proliferative index, margin status, lymph node status, and pathological stage.	('margin', 'CPA', (364, 370))	('coagulative necrosis', 'Disease', (285, 305))	('atypical', 'Var', (259, 267))	('capsular invasion', 'CPA', (201, 218))	('nuclear grade', 'CPA', (307, 320))	('vascular invasion', 'CPA', (240, 257))	('coagulative necrosis', 'Disease', 'MESH:D001778', (285, 305))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (285, 305))	('Ki-67 proliferative index', 'CPA', (337, 362))	('mitotic count', 'CPA', (322, 335))	('greatest dimension', 'CPA', (107, 125))	('lymphatic invasion', 'CPA', (220, 238))
99452	33490290	The miRNA-target network was associated with (TCCGTCC) MIR-184, (TGCACGA) MIR-517, (GTGGTGA) MIR-197, (CCAGGGG) MIR-331, and (CAGCAGG) MIR-370.	('MIR-331', 'Gene', '442903', (112, 119))	('associated', 'Interaction', (29, 39))	('MIR-197', 'Gene', '406974', (93, 100))	('MIR-331', 'Gene', (112, 119))	('TGCACGA', 'Gene', (65, 72))	('MIR-184', 'Gene', (55, 62))	('MIR-370', 'Gene', (135, 142))	('MIR-184', 'Gene', '406960', (55, 62))	('MIR-370', 'Gene', '442915', (135, 142))	('MIR-197', 'Gene', (93, 100))	('MIR-517', 'Var', (74, 81))
99510	33388518	It is fair to hypothesize that homeostatic endocrine mechanisms may be disrupted if the tissue is either functional in the absence of normal adrenal glands or hyperfunctional with suppression of the hypothalamic-pituitary-adrenal axis.	('disrupted', 'NegReg', (71, 80))	('hypothalamic-pituitary-adrenal axis', 'Disease', (199, 234))	('suppression', 'NegReg', (180, 191))	('hypothalamic-pituitary-adrenal axis', 'Disease', 'MESH:D007029', (199, 234))	('hyperfunctional', 'Var', (159, 174))	('homeostatic endocrine mechanisms', 'MPA', (31, 63))
99533	31611976	Following developments in microarray technology, several studies have demonstrated that abnormal expressed and mutated genes are involved in the tumorigenesis and progression of ACC.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('involved', 'Reg', (129, 137))	('ACC', 'Disease', 'MESH:D018268', (178, 181))	('genes', 'Gene', (119, 124))	('mutated', 'Var', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('ACC', 'Phenotype', 'HP:0006744', (178, 181))	('ACC', 'Disease', (178, 181))
99538	31611976	In addition, Duregon et al assessed the expression of miRNAs associated with the regulation of the IGF2 gene and hypoxia induced microRNA in histological variants including 35 classical, 6 myxoid and 10 oncocytic cases of ACC and reported that miR-483-3p, miR-483-5p and miR-210, which were identified as candidates for tumor aggressiveness and poor prognosis in ACC, are differentially expressed in ACC variants.	('ACC', 'Disease', 'MESH:D018268', (363, 366))	('ACC', 'Disease', 'MESH:D018268', (222, 225))	('hypoxia', 'Disease', (113, 120))	('ACC', 'Phenotype', 'HP:0006744', (400, 403))	('ACC', 'Disease', (400, 403))	('miR-483-3p', 'Var', (244, 254))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('variants', 'Var', (154, 162))	('tumor aggressiveness', 'Disease', (320, 340))	('aggressiveness', 'Phenotype', 'HP:0000718', (326, 340))	('IGF2', 'Gene', (99, 103))	('ACC', 'Disease', 'MESH:D018268', (400, 403))	('miR-210', 'Gene', '406992', (271, 278))	('ACC', 'Phenotype', 'HP:0006744', (363, 366))	('ACC', 'Disease', (363, 366))	('ACC', 'Phenotype', 'HP:0006744', (222, 225))	('ACC', 'Disease', (222, 225))	('miR-210', 'Gene', (271, 278))	('variants', 'Var', (404, 412))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (320, 340))	('miR-483-5p', 'Var', (256, 266))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('IGF2', 'Gene', '3481', (99, 103))
99566	31611976	Nonetheless, no change was observed in the patients with ACC with SMC4 alterations, according to the cBioPortal data (P=0.527 for overall survival and P=0.429 for disease-free survival; Fig.	('ACC', 'Disease', 'MESH:D018268', (57, 60))	('patients', 'Species', '9606', (43, 51))	('SMC4', 'Gene', '10051', (66, 70))	('SMC4', 'Gene', (66, 70))	('alterations', 'Var', (71, 82))	('ACC', 'Phenotype', 'HP:0006744', (57, 60))	('ACC', 'Disease', (57, 60))
99570	31611976	The pathogenetic mechanisms of ACC includes alterations of the Insulin-like Growth Factor system, Wnt/beta-catenin pathway activation, TP53 mutations and prognostic molecular markers involved in cancer cell invasion properties and angiogenesis, appear to be very promising in elucidating of tumorigenesis and progression of ACC.	('beta-catenin', 'Gene', '1499', (102, 114))	('ACC', 'Disease', (324, 327))	('TP53', 'Gene', '7157', (135, 139))	('cancer', 'Disease', (195, 201))	('beta-catenin', 'Gene', (102, 114))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('ACC', 'Disease', 'MESH:D018268', (31, 34))	('ACC', 'Disease', 'MESH:D018268', (324, 327))	('alterations', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('TP53', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))	('tumor', 'Disease', (291, 296))	('ACC', 'Phenotype', 'HP:0006744', (31, 34))	('ACC', 'Phenotype', 'HP:0006744', (324, 327))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('ACC', 'Disease', (31, 34))
99575	31611976	BP analysis suggested that these hub genes were significantly enriched in cell division and the mitotic cell cycle, which indicated that the deregulation of the cell cycle may serve a key role in the tumorigenesis and development of ACC.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('cell division', 'CPA', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('hub', 'Gene', (33, 36))	('ACC', 'Disease', 'MESH:D018268', (233, 236))	('tumor', 'Disease', (200, 205))	('deregulation', 'Var', (141, 153))	('mitotic cell cycle', 'CPA', (96, 114))	('ACC', 'Phenotype', 'HP:0006744', (233, 236))	('ACC', 'Disease', (233, 236))	('hub', 'Gene', '1993', (33, 36))
99581	31611976	In particular, overexpressed CCNB1 dysregulated the cell cycle in the G2-M phase transition, with poor survival in the majority of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (131, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('CCNB1', 'Gene', (29, 34))	('CCNB1', 'Gene', '891', (29, 34))	('poor', 'NegReg', (98, 102))	('overexpressed', 'Var', (15, 28))	('survival', 'CPA', (103, 111))	('dysregulated', 'Reg', (35, 47))	('solid tumors', 'Disease', (131, 143))	('cell cycle in the G2-M phase transition', 'CPA', (52, 91))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
99603	31611976	In the present study, although SMC4 alteration was not significantly associated with a worse overall and disease-free survival, hierarchical clustering for hub genes and data from Oncomine indicates that it serves a crucial role in ACC tumorigenesis.	('hub', 'Gene', (156, 159))	('alteration', 'Var', (36, 46))	('ACC', 'Disease', 'MESH:D018268', (232, 235))	('ACC', 'Phenotype', 'HP:0006744', (232, 235))	('ACC', 'Disease', (232, 235))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('SMC4', 'Gene', '10051', (31, 35))	('SMC4', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('hub', 'Gene', '1993', (156, 159))	('tumor', 'Disease', (236, 241))
99636	31398711	inhibition of cortisol production) of mTOR inhibitors in ACC cell lines has been reported, although up to date, signs or symptoms of hypoadrenalism with the use of mTOR inhibitors in the clinical setting have not been clearly described.	('inhibitors', 'Var', (43, 53))	('mTOR', 'Gene', '2475', (38, 42))	('hypoadrenalism', 'Phenotype', 'HP:0000846', (133, 147))	('hypoadrenalism', 'Disease', (133, 147))	('hypoadrenalism', 'Disease', 'MESH:D000309', (133, 147))	('inhibition of cortisol production', 'MPA', (0, 33))	('mTOR', 'Gene', (38, 42))	('mTOR', 'Gene', (164, 168))	('mTOR', 'Gene', '2475', (164, 168))
99649	31398711	observed a negative phospho-mTOR staining in tumors with high Weiss score.	('mTOR', 'Gene', '2475', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mTOR', 'Gene', (28, 32))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('negative', 'NegReg', (11, 19))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('high Weiss', 'Var', (57, 67))
99658	31398711	Using different methodologies (Table 2), it was demonstrated that mTOR inhibitors inhibit the proliferation in ACC cell lines (including NCI-H295R).	('mTOR', 'Gene', (66, 70))	('inhibitors', 'Var', (71, 81))	('mTOR', 'Gene', '2475', (66, 70))	('inhibit', 'NegReg', (82, 89))	('proliferation', 'CPA', (94, 107))
99674	31398711	A recent study reported that n-3 polyunsaturated fatty acids prevent ACC growth by inhibiting mTORC1/2 in preclinical models of ACCs, which suggests that both mTORC complexes might play a role in ACC cell proliferation.	('ACC', 'Disease', (69, 72))	('prevent', 'NegReg', (61, 68))	('mTOR', 'Gene', (94, 98))	('mTOR', 'Gene', (159, 163))	('mTORC1/2', 'Gene', '74343;382056', (94, 102))	('mTOR', 'Gene', '2475', (94, 98))	('n-3', 'Var', (29, 32))	('mTOR', 'Gene', '2475', (159, 163))	('ACCs', 'Phenotype', 'HP:0006744', (128, 132))	('n-3 polyunsaturated fatty acids', 'Chemical', 'MESH:D015525', (29, 60))	('inhibiting', 'NegReg', (83, 93))	('mTORC1/2', 'Gene', (94, 102))
99680	31398711	These studies demonstrate that both ACC cell lines have a similar protein expression of IGF1R and the main components of the mTOR pathway, but both mRNA and protein expression of IGF2 were considerably higher in NCI-H295R compared with SW13.	('SW13', 'CellLine', 'CVCL:0542', (236, 240))	('mTOR', 'Gene', '2475', (125, 129))	('IGF1R', 'Gene', (88, 93))	('protein expression', 'MPA', (157, 175))	('mTOR', 'Gene', (125, 129))	('IGF2', 'Gene', '3481', (179, 183))	('IGF1R', 'Gene', '3480', (88, 93))	('higher', 'PosReg', (202, 208))	('NCI-H295R', 'Var', (212, 221))	('IGF2', 'Gene', (179, 183))
99690	31398711	Therefore, it could be speculated that high IGF2 expression could negatively influence the in vitro sensitivity of ACC cell lines to mTOR inhibitors, which supports the rationale to combine mTOR inhibitors and drugs specifically targeting the IGF pathway in ACCs.	('negatively', 'NegReg', (66, 76))	('high', 'Var', (39, 43))	('IGF2', 'Gene', '3481', (44, 48))	('influence', 'Reg', (77, 86))	('mTOR', 'Gene', '2475', (190, 194))	('ACCs', 'Phenotype', 'HP:0006744', (258, 262))	('mTOR', 'Gene', (190, 194))	('mTOR', 'Gene', '2475', (133, 137))	('IGF2', 'Gene', (44, 48))	('mTOR', 'Gene', (133, 137))	('high IGF2', 'Phenotype', 'HP:0030269', (39, 48))	('expression', 'Var', (49, 59))
99738	30455982	Disparity in prevalence of germline mutations across tumour types suggested variable genetic susceptibility and implied potential contribution of novel susceptibility genes.	('tumour', 'Disease', (53, 59))	('germline', 'Var', (27, 35))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))
99739	30455982	Only five (50%) children with pathogenic germline mutations had a family history of cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('children', 'Species', '9606', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('germline mutations', 'Var', (41, 59))
99743	30455982	Joanne Ngeow from the National Cancer Centre Singapore and colleagues reviewed the medical records of 102 paediatric patients diagnosed with cancer and profiled for inherited mutations in 100 cancer-associated genes.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('mutations', 'Var', (175, 184))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('patients', 'Species', '9606', (117, 125))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
99751	30455982	Second, family members identified to harbour the same germline mutation can be informed of their individual cancer risks, whereby appropriate cancer risk management and reproductive counselling can be provided.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', (142, 148))	('germline mutation', 'Var', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
99762	30455982	We screened our prospectively enrolled cohort using two published clinical tools, and concurrently identified germline mutations in cancer predisposition genes using whole-exome sequencing and digital multiplex ligation-dependent probe amplification (MLPA).	('mutations', 'Var', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
99783	30455982	Frequency of mutations was highest in TP53 affecting five patients, followed by DICER1 mutations in three patients (Fig.	('TP53', 'Gene', (38, 42))	('DICER1', 'Gene', (80, 86))	('DICER1', 'Gene', '23405', (80, 86))	('highest', 'Reg', (27, 34))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (58, 66))	('mutations', 'Var', (13, 22))	('TP53', 'Gene', '7157', (38, 42))
99784	30455982	Two patients harboured more than one pathogenic variant: one with diffuse astrocytoma was found to have concurrent TP53 exon 1 deletion and NF1 nonsense mutation, and a Sertoli-Leydig cell tumour (SLCT) patient harboured both DICER1 frameshift and nonsense FH mutations.	('Sertoli-Leydig cell tumour', 'Disease', 'MESH:D018310', (169, 195))	('DICER1', 'Gene', '23405', (226, 232))	('Leydig cell tumour', 'Phenotype', 'HP:0100618', (177, 195))	('TP53', 'Gene', '7157', (115, 119))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('patient', 'Species', '9606', (4, 11))	('deletion', 'Var', (127, 135))	('NF1', 'Gene', (140, 143))	('patient', 'Species', '9606', (203, 210))	('TP53', 'Gene', (115, 119))	('nonsense mutation', 'Var', (144, 161))	('patients', 'Species', '9606', (4, 12))	('astrocytoma', 'Disease', 'MESH:D001254', (74, 85))	('Sertoli-Leydig cell tumour', 'Disease', (169, 195))	('astrocytoma', 'Disease', (74, 85))	('DICER1', 'Gene', (226, 232))	('astrocytoma', 'Phenotype', 'HP:0009592', (74, 85))
99785	30455982	In addition, two patients were found with a deleterious mutation in VHL and SDHD respectively.	('SDHD', 'Gene', (76, 80))	('SDHD', 'Gene', '6392', (76, 80))	('VHL', 'Disease', (68, 71))	('VHL', 'Disease', 'MESH:D006623', (68, 71))	('patients', 'Species', '9606', (17, 25))	('mutation', 'Var', (56, 64))
99786	30455982	All TP53 variants identified were previously seen in LFS families.	('LFS', 'Disease', (53, 56))	('TP53', 'Gene', (4, 8))	('LFS', 'Disease', 'MESH:D016864', (53, 56))	('variants', 'Var', (9, 17))	('TP53', 'Gene', '7157', (4, 8))
99787	30455982	Three (Cys141Tyr, Arg213Gln, Arg273Cys) are known to reduce p53 transactivation activity, whereas Arg110Pro was demonstrated to have a dominant-negative effect on wild-type p53 function.	('reduce', 'NegReg', (53, 59))	('Arg273Cys', 'SUBSTITUTION', 'None', (29, 38))	('Cys141Tyr', 'SUBSTITUTION', 'None', (7, 16))	('Arg110Pro', 'Var', (98, 107))	('Arg213Gln', 'Var', (18, 27))	('p53', 'Protein', (60, 63))	('Arg213Gln', 'SUBSTITUTION', 'None', (18, 27))	('Arg110Pro', 'SUBSTITUTION', 'None', (98, 107))	('Cys141Tyr', 'Var', (7, 16))	('Arg273Cys', 'Var', (29, 38))
99788	30455982	Somatic loss-of-heterozygosity (LOH) was observed in all TP53 mutation carriers, including the hemizygous exon 1 deletion carrier.	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))	('loss-of-heterozygosity', 'NegReg', (8, 30))
99790	30455982	Reported carriers of TP53 promoter or exon 1 deletion mostly presented soft tissue sarcomas and breast cancer.	('TP53', 'Gene', (21, 25))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (71, 90))	('presented', 'Reg', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('sarcomas', 'Phenotype', 'HP:0100242', (83, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (71, 90))	('sarcomas', 'Disease', (83, 91))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (71, 91))	('breast cancer', 'Disease', (96, 109))	('soft tissue sarcoma', 'Disease', (71, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('deletion', 'Var', (45, 53))	('sarcomas', 'Disease', 'MESH:D012509', (83, 91))	('TP53', 'Gene', '7157', (21, 25))
99792	30455982	Interestingly, this child also harboured a truncating germline mutation in NF1 (Arg1513*) previously observed in other NF1 patients.	('NF1', 'Gene', (75, 78))	('truncating', 'MPA', (43, 53))	('Arg1513', 'Chemical', '-', (80, 87))	('patients', 'Species', '9606', (123, 131))	('child', 'Species', '9606', (20, 25))	('Arg1513*', 'Var', (80, 88))
99794	30455982	A second DICER1 somatic mutation was found in all three patients at the RNase IIIb domain hotspot Glu1813 residue known to inactivate DICER1 activity (Fig.	('patients', 'Species', '9606', (56, 64))	('Glu1813', 'Chemical', '-', (98, 105))	('activity', 'MPA', (141, 149))	('DICER1', 'Gene', (9, 15))	('inactivate', 'NegReg', (123, 133))	('DICER1', 'Gene', '23405', (9, 15))	('Glu1813 residue', 'Var', (98, 113))	('DICER1', 'Gene', (134, 140))	('DICER1', 'Gene', '23405', (134, 140))
99795	30455982	A concurrent truncating FH mutation with somatic LOH was seen in one of the DICER1 germline mutation carriers (Table 3).	('mutation', 'Var', (27, 35))	('truncating', 'Var', (13, 23))	('DICER1', 'Gene', '23405', (76, 82))	('DICER1', 'Gene', (76, 82))
99796	30455982	Amongst the tumour types, prevalence of pathogenic germline mutation was highest in endocrine or neuroendocrine tumours (n = 4/6, 67%).	('germline mutation', 'Var', (51, 68))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('endocrine or neuroendocrine tumours', 'Disease', (84, 119))	('tumour', 'Disease', (112, 118))	('tumour', 'Disease', (12, 18))	('pathogenic', 'Reg', (40, 50))	('endocrine or neuroendocrine tumours', 'Disease', 'MESH:D004701', (84, 119))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
99798	30455982	Further breakdown by histological subtypes highlighted that all enrolled patients with adrenocortical carcinoma (ACC), pheochromocytoma and SLCT harboured germline mutations, implying a higher genetic susceptibility in these tumour types (Supplementary Table 2).	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('tumour', 'Disease', (225, 231))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (87, 111))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (87, 111))	('pheochromocytoma', 'Disease', (119, 135))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (119, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('pheochromocytoma', 'Disease', 'MESH:D010673', (119, 135))	('germline mutations', 'Var', (155, 173))	('patients', 'Species', '9606', (73, 81))	('harboured', 'Reg', (145, 154))	('adrenocortical carcinoma', 'Disease', (87, 111))
99800	30455982	Four among five TP53 mutation carriers presented tumours typical of LFS spectrum: ACC (n = 2) and soft tissue sarcoma (n = 2) (Fig.	('tumours', 'Disease', (49, 56))	('LFS', 'Disease', (68, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (98, 117))	('mutation', 'Var', (21, 29))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (98, 117))	('ACC', 'Phenotype', 'HP:0006744', (82, 85))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('TP53', 'Gene', '7157', (16, 20))	('ACC', 'Disease', (82, 85))	('LFS', 'Disease', 'MESH:D016864', (68, 71))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('soft tissue sarcoma', 'Disease', (98, 117))	('TP53', 'Gene', (16, 20))
99801	30455982	Moreover, their mutations were also reported in LFS families and paediatric patients with similar tumour types.	('patients', 'Species', '9606', (76, 84))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('mutations', 'Var', (16, 25))	('LFS', 'Disease', (48, 51))	('tumour', 'Disease', (98, 104))	('reported', 'Reg', (36, 44))	('LFS', 'Disease', 'MESH:D016864', (48, 51))
99802	30455982	Similarly, germline mutations in SDHD and VHL, two genes known to confer susceptibility to pheochromocytoma, were found in both patients with this diagnosis (Fig.	('found', 'Reg', (114, 119))	('SDHD', 'Gene', '6392', (33, 37))	('pheochromocytoma', 'Disease', (91, 107))	('SDHD', 'Gene', (33, 37))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (91, 107))	('VHL', 'Disease', (42, 45))	('VHL', 'Disease', 'MESH:D006623', (42, 45))	('pheochromocytoma', 'Disease', 'MESH:D010673', (91, 107))	('germline mutations', 'Var', (11, 29))	('patients', 'Species', '9606', (128, 136))
99803	30455982	Unsurprisingly, our DICER1 germline mutation carriers presented tumour types most frequently associated with DICER1 syndrome, namely PPB (n = 1) and SLCT with multinodular goitre (MNG) (n = 2).	('goitre', 'Phenotype', 'HP:0000853', (172, 178))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('PPB', 'Disease', (133, 136))	('associated', 'Reg', (93, 103))	('MNG', 'Phenotype', 'HP:0005987', (180, 183))	('multinodular goitre', 'Disease', (159, 178))	('multinodular goitre', 'Disease', 'MESH:C564546', (159, 178))	('DICER1', 'Gene', (109, 115))	('DICER1', 'Gene', '23405', (109, 115))	('germline mutation', 'Var', (27, 44))	('multinodular goitre', 'Phenotype', 'HP:0005987', (159, 178))	('DICER1', 'Gene', (20, 26))	('DICER1', 'Gene', '23405', (20, 26))
99805	30455982	For instance, the 2.6-year-old diffuse astrocytoma patient with concurrent NF1 and TP53 mutations exhibited clinical features mostly characteristic of NF1: multiple cafe-au-lait spots, neurofibroma and global developmental delay.	('global', 'Disease', (202, 208))	('TP53', 'Gene', '7157', (83, 87))	('neurofibroma', 'Phenotype', 'HP:0001067', (185, 197))	('astrocytoma', 'Phenotype', 'HP:0009592', (39, 50))	('neurofibroma', 'Disease', 'MESH:D009455', (185, 197))	('TP53', 'Gene', (83, 87))	('NF1', 'Gene', (75, 78))	('multiple cafe-au-lait spots', 'Phenotype', 'HP:0007565', (156, 183))	('mutations', 'Var', (88, 97))	('global developmental delay', 'Phenotype', 'HP:0001263', (202, 228))	('patient', 'Species', '9606', (51, 58))	('astrocytoma', 'Disease', 'MESH:D001254', (39, 50))	('cafe-au-lait spots', 'Phenotype', 'HP:0000957', (165, 183))	('neurofibroma', 'Disease', (185, 197))	('astrocytoma', 'Disease', (39, 50))
99807	30455982	However, the presence of astrocytoma unrelated to the optic pathway at this age is more consistent with the germline TP53 mutation harboured by this child, which was missed by the treating physicians given his characteristic NF1 clinical features.	('astrocytoma', 'Disease', (25, 36))	('child', 'Species', '9606', (149, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (25, 36))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('mutation', 'Var', (122, 130))	('astrocytoma', 'Disease', 'MESH:D001254', (25, 36))
99808	30455982	Six of the ten germline mutation carriers had at least one relative with cancer (Table 3); however, only five (50%) showed a family history typical of CPS.	('germline mutation', 'Var', (15, 32))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('CPS', 'Disease', (151, 154))	('CPS', 'Disease', 'MESH:D020165', (151, 154))
99810	30455982	The remaining VHL mutation carrier demonstrated a family history of pheochromocytoma and renal cell carcinoma consistent with VHL syndrome.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('VHL syndrome', 'Disease', 'MESH:D006623', (126, 138))	('VHL', 'Disease', (126, 129))	('VHL', 'Disease', 'MESH:D006623', (126, 129))	('pheochromocytoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (68, 109))	('VHL', 'Disease', 'MESH:D006623', (14, 17))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (68, 84))	('VHL', 'Disease', (14, 17))	('VHL syndrome', 'Disease', (126, 138))	('mutation', 'Var', (18, 26))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (89, 109))
99811	30455982	A total of 86 rare variants of uncertain significance (VUS) were detected, predominantly in neuroblastic tumours with an adjusted frequency of four variants, followed by soft tissue sarcoma with three VUS (Supplementary Figure 1).	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (170, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (170, 189))	('VUS', 'Chemical', '-', (55, 58))	('VUS', 'Chemical', '-', (201, 204))	('soft tissue sarcoma', 'Disease', (170, 189))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('neuroblastic tumours', 'Disease', (92, 112))	('variants', 'Var', (19, 27))	('neuroblastic tumours', 'Disease', 'MESH:D009369', (92, 112))
99815	30455982	For example, a variant in MAX, an essential interacting partner of MYC, was identified in a patient with neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (105, 118))	('patient', 'Species', '9606', (92, 99))	('neuroblastoma', 'Disease', (105, 118))	('identified', 'Reg', (76, 86))	('variant', 'Var', (15, 22))	('neuroblastoma', 'Phenotype', 'HP:0003006', (105, 118))	('MAX', 'Gene', (26, 29))
99816	30455982	The mutation Arg100Cys, which occurred within the leucine-zipper domain of MAX important for regulation of MYC, could impair MYC activities.	('Arg100Cys', 'SUBSTITUTION', 'None', (13, 22))	('impair', 'NegReg', (118, 124))	('MYC activities', 'CPA', (125, 139))	('Arg100Cys', 'Var', (13, 22))
99817	30455982	Additionally, we found two variants:CDH1 Pro373Leu and RAF1 Pro332Ala:individually associated with hereditary diffuse gastric cancer (HDGC) and childhood-onset dilated cardiomyopathy in two patients with hepatocellular carcinoma (HCC) and testicular germ cell tumour respectively.	('tumour', 'Phenotype', 'HP:0002664', (260, 266))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (160, 182))	('tumour', 'Disease', 'MESH:D009369', (260, 266))	('patients', 'Species', '9606', (190, 198))	('Pro332Ala', 'Mutation', 'rs1057403865', (60, 69))	('tumour', 'Disease', (260, 266))	('associated with', 'Reg', (83, 98))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (204, 228))	('child', 'Species', '9606', (144, 149))	('CDH1', 'Gene', '999', (36, 40))	('Pro373Leu', 'Mutation', 'rs587782359', (41, 50))	('Pro373Leu', 'Var', (41, 50))	('HDGC', 'Disease', 'MESH:D013274', (134, 138))	('HCC', 'Phenotype', 'HP:0001402', (230, 233))	('hereditary diffuse gastric cancer', 'Disease', (99, 132))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (204, 228))	('CDH1', 'Gene', (36, 40))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (160, 182))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (99, 132))	('hepatocellular carcinoma', 'Disease', (204, 228))	('Pro332Ala', 'Var', (60, 69))	('RAF1', 'Gene', '5894', (55, 59))	('dilated cardiomyopathy', 'Disease', (160, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (168, 182))	('germ cell tumour', 'Phenotype', 'HP:0100728', (250, 266))	('HDGC', 'Disease', (134, 138))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('RAF1', 'Gene', (55, 59))
99826	30455982	Thus, lack of detectable germline mutations in subtypes such as neuroblastic tumours may be attributed to alterations in genes and CPS beyond the currently defined spectrum investigated.	('CPS', 'Disease', (131, 134))	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('CPS', 'Disease', 'MESH:D020165', (131, 134))	('neuroblastic tumours', 'Disease', (64, 84))	('alterations', 'Var', (106, 117))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('neuroblastic tumours', 'Disease', 'MESH:D009369', (64, 84))
99832	30455982	For instance, the germline mutation CDH1 Pro373Leu previously identified in an HDGC family and shown to impair E-cadherin in vitro was detected in our HCC patient.	('E-cadherin', 'Gene', '999', (111, 121))	('HDGC', 'Disease', 'MESH:D013274', (79, 83))	('impair', 'NegReg', (104, 110))	('patient', 'Species', '9606', (155, 162))	('CDH1', 'Gene', (36, 40))	('HDGC', 'Disease', (79, 83))	('CDH1', 'Gene', '999', (36, 40))	('Pro373Leu', 'Mutation', 'rs587782359', (41, 50))	('Pro373Leu', 'Var', (41, 50))	('E-cadherin', 'Gene', (111, 121))	('HCC', 'Phenotype', 'HP:0001402', (151, 154))
99834	30455982	Presentation of unusual neoplasms for a diagnosed CPS may stem from multiple pathogenic germline mutations, as demonstrated in our NF1 patient presenting with diffuse astrocytoma at age 2.6 years who was subsequently found to also harbour a pathogenic germline TP53 mutation.	('astrocytoma', 'Phenotype', 'HP:0009592', (167, 178))	('patient', 'Species', '9606', (135, 142))	('neoplasms', 'Disease', 'MESH:D009369', (24, 33))	('CPS', 'Disease', 'MESH:D020165', (50, 53))	('neoplasms', 'Disease', (24, 33))	('TP53', 'Gene', '7157', (261, 265))	('TP53', 'Gene', (261, 265))	('astrocytoma', 'Disease', (167, 178))	('astrocytoma', 'Disease', 'MESH:D001254', (167, 178))	('neoplasms', 'Phenotype', 'HP:0002664', (24, 33))	('stem', 'Reg', (58, 62))	('mutation', 'Var', (266, 274))	('pathogenic', 'Reg', (241, 251))	('CPS', 'Disease', (50, 53))
99835	30455982	Children with NF1 are predisposed to CNS tumours typically of pilocytic astrocytoma subtype in the optic pathway, often accompanied by complete inactivation of NF1 through somatic events.	('pilocytic astrocytoma subtype', 'Disease', (62, 91))	('inactivation', 'NegReg', (144, 156))	('Children', 'Species', '9606', (0, 8))	('optic pathway', 'Pathway', (99, 112))	('NF1', 'Gene', (160, 163))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('CNS tumours', 'Disease', 'MESH:D016543', (37, 48))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('astrocytoma', 'Phenotype', 'HP:0009592', (72, 83))	('predisposed', 'Reg', (22, 33))	('pilocytic astrocytoma subtype', 'Disease', 'MESH:D001254', (62, 91))	('CNS tumour', 'Phenotype', 'HP:0100006', (37, 47))	('NF1', 'Var', (14, 17))	('CNS tumours', 'Disease', (37, 48))
99838	30455982	Deficiency of p53 prior to NF1 loss has been correlated with complete penetrance of malignant astrocytomas in mice and could explain the histological subtype presented by our patient.	('loss', 'NegReg', (31, 35))	('p53', 'Gene', (14, 17))	('patient', 'Species', '9606', (175, 182))	('astrocytoma', 'Phenotype', 'HP:0009592', (94, 105))	('mice', 'Species', '10090', (110, 114))	('NF1', 'Gene', (27, 30))	('malignant astrocytomas', 'Disease', (84, 106))	('malignant astrocytomas', 'Disease', 'MESH:D020339', (84, 106))	('Deficiency', 'Var', (0, 10))
99839	30455982	Also noteworthy is that deletion of the TP53 exon 1 in this patient was not detected on whole-exome sequencing but identified through MLPA, hence would have been also missed by next-generation sequencing panels currently utilized for clinical genetic testing.	('patient', 'Species', '9606', (60, 67))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('deletion', 'Var', (24, 32))
99842	30455982	Genetically unresolved cases may have pathogenic germline mutations in novel predisposition genes and data on VUS from our study highlights the particular tumour types that could benefit from further research into novel cancer predisposition genes.	('particular tumour', 'Disease', 'MESH:D009369', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('VUS', 'Chemical', '-', (110, 113))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('pathogenic', 'Reg', (38, 48))	('cancer', 'Disease', (220, 226))	('germline mutations', 'Var', (49, 67))	('particular tumour', 'Disease', (144, 161))
99855	30455982	Variants were filtered by read depth (10x) and quality score (Phred score > 30), annotated using ANNOVAR and curated in a stepwise manner into five classifications: pathogenic, likely pathogenic, VUS, likely benign, benign.	('Variants', 'Var', (0, 8))	('VUS', 'Disease', (196, 199))	('pathogenic', 'Reg', (165, 175))	('VUS', 'Chemical', '-', (196, 199))
99856	30455982	To identify candidate variants in autosomal dominant cancer predisposition genes (Supplementary Table 3), we filtered for rare coding and splice-site variants, determined by a minor allele frequency (MAF) of <=0.1% in Exome Aggregation Consortium (ExAC), 1000 Genomes (1000G) databases and our in-house database of local population (n = 1412).	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (34, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('autosomal dominant cancer', 'Disease', (34, 59))	('variants', 'Var', (22, 30))
99860	30455982	Somatic status of variants was similarly validated on tumour DNA.	('tumour', 'Disease', (54, 60))	('variants', 'Var', (18, 26))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumour', 'Disease', 'MESH:D009369', (54, 60))
99888	29998153	In another large retrospective study from Turkey the prevalence of thyroid incidentaloma using F-18 FDG PET/CT was reported 5.6% and malignancy risk of incidental thyroid lesions was calculated as 32.7% with proved biopsy or thyroid surgery.	('thyroid incidentaloma', 'Disease', 'MESH:C538238', (67, 88))	('F-18 FDG', 'Var', (95, 103))	('Turkey', 'Species', '9103', (42, 48))	('thyroid lesions', 'Disease', 'MESH:D013959', (163, 178))	('thyroid lesions', 'Disease', (163, 178))	('thyroid incidentaloma', 'Disease', (67, 88))
99891	29998153	A target group with history of neuroendocrine tumors (NETs) were evaluated for focal and furthermore diffuse thyroid uptake because of difference in biodistribution of Ga-68-Dotate in contrast to F-18 FDG.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (31, 52))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (31, 52))	('Ga-68-Dotate', 'Var', (168, 180))	('biodistribution', 'MPA', (149, 164))	('Ga-68-Dotate', 'Chemical', '-', (168, 180))	('neuroendocrine tumors', 'Disease', (31, 52))
99895	29383116	Overexpression of HSD17B4 exerts tumor suppressive function in adrenocortical carcinoma and is not associated with hormone excess Adrenocortical carcinoma (ACC) is characterized with excessive hormone production.	('hormone excess', 'Phenotype', 'HP:0000845', (115, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (63, 87))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (63, 87))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (130, 154))	('ACC', 'Phenotype', 'HP:0006744', (156, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (130, 154))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Adrenocortical carcinoma', 'Disease', (130, 154))	('HSD17B4', 'Gene', '3295', (18, 25))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (33, 38))	('adrenocortical carcinoma', 'Disease', (63, 87))	('HSD17B4', 'Gene', (18, 25))
99897	29383116	Overexpression of HSD17B4 was significantly associate with a normo-hormonal phenotype.	('HSD17B4', 'Gene', '3295', (18, 25))	('Overexpression', 'Var', (0, 14))	('associate', 'Reg', (44, 53))	('normo-hormonal phenotype', 'MPA', (61, 85))	('HSD17B4', 'Gene', (18, 25))
99901	29383116	Replenish of HSD17B4 in SW13 cells and knockdown of HSD17B4 in H295R cells confirmed alterations in MDM4, ATR, and IE24 with alterations more contrasting in H295R cells.	('MDM4', 'Gene', (100, 104))	('HSD17B4', 'Gene', '3295', (13, 20))	('H295R', 'CellLine', 'CVCL:0458', (157, 162))	('IE24', 'MPA', (115, 119))	('SW13', 'CellLine', 'CVCL:0542', (24, 28))	('HSD17B4', 'Gene', (13, 20))	('ATR', 'Gene', (106, 109))	('ATR', 'Gene', '545', (106, 109))	('H295R', 'CellLine', 'CVCL:0458', (63, 68))	('HSD17B4', 'Gene', '3295', (52, 59))	('alterations', 'Var', (85, 96))	('HSD17B4', 'Gene', (52, 59))	('MDM4', 'Gene', '4194', (100, 104))
99912	29383116	Of note, HSD17B4 was altered in ~39% of cases, ranking top of all genes with overexpression in 29 cases, mutation in 3 cases and gene amplification in 1 case, respectively.	('mutation', 'Var', (105, 113))	('gene amplification', 'Var', (129, 147))	('HSD17B4', 'Gene', '3295', (9, 16))	('altered', 'Reg', (21, 28))	('HSD17B4', 'Gene', (9, 16))
99923	29383116	HSD27B4-KD NCI-H295R cells showed significantly increased proliferation, whilst the effect was not significant in SW13 cells (Figure 2D).	('increased', 'PosReg', (48, 57))	('proliferation', 'CPA', (58, 71))	('HSD27B4-KD', 'Var', (0, 10))	('NCI-H295R', 'CellLine', 'CVCL:0458', (11, 20))	('SW13', 'CellLine', 'CVCL:0542', (114, 118))
99925	29383116	However, only HSD17B4 overexpression induced increased G1 population in SW13 cells and KD did not, indicating an inherent difference between the cancer types (Figure 2E).	('cancer', 'Disease', (145, 151))	('increased', 'PosReg', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('HSD17B4', 'Gene', '3295', (14, 21))	('SW13', 'CellLine', 'CVCL:0542', (72, 76))	('HSD17B4', 'Gene', (14, 21))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('overexpression', 'Var', (22, 36))	('G1 population', 'CPA', (55, 68))
99971	29383116	Alteration of HSD17B4, predominantly overexpression, was analyzed for association with clinicopathological parameters (adjuvant mitotane therapy, tumor stage, metastasis, Weiss score, response to primary therapy, residual tumor status, lymph node involvement, patient gender, and overall survival).	('patient', 'Species', '9606', (260, 267))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('Alteration', 'Var', (0, 10))	('tumor', 'Disease', (146, 151))	('HSD17B4', 'Gene', '3295', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('mitotane', 'Chemical', 'MESH:D008939', (128, 136))	('HSD17B4', 'Gene', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
99974	29383116	Both cell lines were subject to HSD17B4 knockdown (KD) using shRNAs.	('HSD17B4', 'Gene', '3295', (32, 39))	('HSD17B4', 'Gene', (32, 39))	('knockdown', 'Var', (40, 49))
100001	29383116	A total of 1.5 x 107 NCI-H295R cancer cells with or without HAD17B4-KD, resuspended in 100 ml of PBS were injected subcutaneously at the left axilla of each mouse.	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('HAD17B4-KD', 'Var', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('NCI-H295R', 'CellLine', 'CVCL:0458', (21, 30))	('PBS', 'Chemical', 'MESH:D007854', (97, 100))	('mouse', 'Species', '10090', (157, 162))
100016	28972963	ARQ 087 had manageable toxicity at the RP2D of 300 mg QD, showed pharmacodynamics effects, and achieved objective responses, notably in patients with FGFR2 genetic alterations.	('toxicity', 'Disease', (23, 31))	('ARQ 087', 'Chemical', 'MESH:C000621805', (0, 7))	('FGFR2', 'Gene', '2263', (150, 155))	('genetic alterations', 'Var', (156, 175))	('patients', 'Species', '9606', (136, 144))	('FGFR2', 'Gene', (150, 155))	('toxicity', 'Disease', 'MESH:D064420', (23, 31))
100018	28972963	Dysregulation of the fibroblast growth factor (FGF)/FGFR tyrosine kinase family signalling axis has been implicated in a number of developmental syndromes and human malignancies, including gastric, breast, endometrial, bladder, small cell, and squamous non-small cell lung cancer, and intrahepatic cholangiocarcinoma (iCCA).	('Dysregulation', 'Var', (0, 13))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (298, 316))	('bladder', 'Disease', (219, 226))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (257, 279))	('implicated', 'Reg', (105, 115))	('human', 'Species', '9606', (159, 164))	('small cell', 'Disease', (228, 238))	('endometrial', 'Disease', (206, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('malignancies', 'Disease', 'MESH:D009369', (165, 177))	('squamous non-small cell lung cancer', 'Disease', 'MESH:D002289', (244, 279))	('squamous non-small cell lung cancer', 'Disease', (244, 279))	('malignancies', 'Disease', (165, 177))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (285, 316))	('gastric', 'Disease', (189, 196))	('breast', 'Disease', (198, 204))	('intrahepatic cholangiocarcinoma', 'Disease', (285, 316))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('lung cancer', 'Phenotype', 'HP:0100526', (268, 279))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (253, 279))
100019	28972963	In human cancers, FGFRs can be deregulated by multiple mechanisms, including aberrant expression, amplifications, mutations, translocations, and fusions.	('FGFRs', 'Gene', (18, 23))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('translocations', 'Var', (125, 139))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('mutations', 'Var', (114, 123))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('amplifications', 'Var', (98, 112))	('fusions', 'Var', (145, 152))	('deregulated', 'Reg', (31, 42))	('aberrant expression', 'Var', (77, 96))
100020	28972963	These pathogenic alterations have fueled significant interest in the FGFR pathway as a target for therapeutic intervention, with several drugs in development but none yet specifically approved for FGFR-driven tumours.	('tumours', 'Phenotype', 'HP:0002664', (209, 216))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('tumours', 'Disease', 'MESH:D009369', (209, 216))	('tumours', 'Disease', (209, 216))	('alterations', 'Var', (17, 28))
100022	28972963	In biochemical studies, ARQ 087 showed potent activity against both wild-type and variants of the FGFR kinases (FGFR1-3), and to a lesser extent against FGFR4, with inhibitor concentration required for 50% inhibition (IC50) values in the low nM range for FGFR family members.	('variants', 'Var', (82, 90))	('FGFR4', 'Gene', '2264', (153, 158))	('FGFR4', 'Gene', (153, 158))	('ARQ 087', 'Chemical', 'MESH:C000621805', (24, 31))	('FGFR1-3', 'Gene', (112, 119))
100024	28972963	In Ba/F3 cell proliferation assays, except for FGFR1-2, FGFR fusions, KIT, LCK, and ARG, the majority of kinases had growth inhibition of 50% values above 1000 nM.	('LCK', 'Gene', '16818', (75, 78))	('fusions', 'Var', (61, 68))	('Ba/F3', 'CellLine', 'CVCL:0161', (3, 8))	('FGFR', 'Gene', (56, 60))	('LCK', 'Gene', (75, 78))	('growth', 'MPA', (117, 123))
100025	28972963	Further, in an autophosphorylation assay, ARQ 087 inhibited autophosphorylation of FGFR1 and FGFR2 in a dose-dependent manner, suggesting that, in addition to inhibiting the active (phosphorylated) form of the kinase, ARQ 087 binds to the unphosphorylated or inactive form of the kinase and delays its activation.	('FGFR2', 'Gene', (93, 98))	('ARQ 087', 'Chemical', 'MESH:C000621805', (218, 225))	('autophosphorylation', 'MPA', (60, 79))	('FGFR2', 'Gene', '2263', (93, 98))	('activation', 'MPA', (302, 312))	('ARQ 087', 'Chemical', 'MESH:C000621805', (42, 49))	('ARQ 087', 'Var', (218, 225))	('binds', 'Interaction', (226, 231))	('inhibited', 'NegReg', (50, 59))	('delays', 'NegReg', (291, 297))
100026	28972963	Preclinical studies demonstrated potent inhibition of tumour growth in FGFR pathway-activated models, including in FGFR2-driven (amplification/fusion/mutation) tumour xenografts.	('amplification/fusion/mutation', 'Var', (129, 158))	('tumour', 'Disease', (160, 166))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('FGFR2', 'Gene', (115, 120))	('FGFR2', 'Gene', '2263', (115, 120))	('tumour', 'Disease', (54, 60))	('inhibition', 'NegReg', (40, 50))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('FGFR', 'Gene', (71, 75))	('tumour', 'Disease', 'MESH:D009369', (160, 166))
100035	28972963	Once a potential RP2D was defined, only patients with cholangiocarcinoma and adrenocortical carcinoma independent of the molecular characteristics, and other solid tumours harbouring FGFR1-3 genetic alterations or KIT/PDGFR mutations were eligible for enrolment.	('FGFR1-3', 'Gene', (183, 190))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('adrenocortical carcinoma', 'Disease', (77, 101))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (54, 72))	('PDGFR', 'Gene', (218, 223))	('patients', 'Species', '9606', (40, 48))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (54, 72))	('genetic alterations', 'Var', (191, 210))	('solid tumours', 'Disease', 'MESH:D009369', (158, 171))	('PDGFR', 'Gene', '5159', (218, 223))	('cholangiocarcinoma', 'Disease', (54, 72))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (77, 101))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (77, 101))	('mutations', 'Var', (224, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('solid tumours', 'Disease', (158, 171))
100039	28972963	The protocol was subsequently amended to include only selected patients with tumours having confirmed FGFR mutations or translocations, including iCCA with FGFR2 gene fusion; the Phase 2 part of the study is ongoing and will be reported separately.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('mutations', 'Var', (107, 116))	('FGFR', 'Gene', (102, 106))	('tumours', 'Disease', (77, 84))	('gene fusion', 'Var', (162, 173))	('FGFR2', 'Gene', (156, 161))	('FGFR2', 'Gene', '2263', (156, 161))	('patients', 'Species', '9606', (63, 71))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
100055	28972963	FGFR genetic alterations were documented in 22 patients.	('FGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (47, 55))	('genetic alterations', 'Var', (5, 24))
100096	28972963	Sixteen patients, including seven patients whose tumours had FGFR genetic alterations, received therapy for >=16 weeks (Figure 3).	('tumours', 'Disease', (49, 56))	('FGFR', 'Gene', (61, 65))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('patients', 'Species', '9606', (34, 42))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('genetic alterations', 'Var', (66, 85))	('patients', 'Species', '9606', (8, 16))
100097	28972963	No response was observed in two patients with PDGFR/KIT mutations.	('mutations', 'Var', (56, 65))	('PDGFR', 'Gene', (46, 51))	('PDGFR', 'Gene', '5159', (46, 51))	('patients', 'Species', '9606', (32, 40))
100099	28972963	In the five iCCA patients with FGFR2 fusions (BICC1 (n=2), KIAA1217, TACC1, CCDC6), two confirmed PRs and a SD (25% tumour reduction) of 24-41 weeks duration were observed.	('CCDC6', 'Gene', '8030', (76, 81))	('CCDC6', 'Gene', (76, 81))	('SD', 'Disease', 'MESH:D029461', (108, 110))	('KIAA1217', 'Gene', '56243', (59, 67))	('TACC1', 'Gene', '6867', (69, 74))	('FGFR2', 'Gene', (31, 36))	('tumour reduction', 'Disease', (116, 132))	('FGFR2', 'Gene', '2263', (31, 36))	('BICC1', 'Gene', '80114', (46, 51))	('KIAA1217', 'Gene', (59, 67))	('fusions', 'Var', (37, 44))	('patients', 'Species', '9606', (17, 25))	('TACC1', 'Gene', (69, 74))	('tumour reduction', 'Disease', 'MESH:D009369', (116, 132))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('BICC1', 'Gene', (46, 51))
100100	28972963	In the remaining two patients with FGFR2 fusions and five iCCA patients without FGFR aberrations, progressive disease was the best response.	('FGFR2', 'Gene', (35, 40))	('FGFR2', 'Gene', '2263', (35, 40))	('patients', 'Species', '9606', (21, 29))	('patients', 'Species', '9606', (63, 71))	('fusions', 'Var', (41, 48))	('progressive disease', 'Disease', (98, 117))
100101	28972963	Two patients with FGFR amplification had clinical benefit with reduction in tumour burden.	('tumour burden', 'Disease', (76, 89))	('amplification', 'Var', (23, 36))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour burden', 'Disease', 'MESH:D009369', (76, 89))	('FGFR', 'Gene', (18, 22))	('patients', 'Species', '9606', (4, 12))	('reduction', 'NegReg', (63, 72))
100102	28972963	A patient with urothelial cancer with FGFR2 (copy number (CN)=11) and FGF19 (CN=19) amplification had a confirmed PR (35% tumour reduction) and completed 40 weeks of treatment, and another patient with adrenocortical carcinoma with FGFR1 amplification had SD with a maximum tumour reduction of 20% and was on study for 3.5 years.	('FGFR2', 'Gene', '2263', (38, 43))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (202, 226))	('tumour reduction', 'Disease', (122, 138))	('amplification', 'Var', (84, 97))	('tumour reduction', 'Disease', 'MESH:D009369', (274, 290))	('FGF19', 'Gene', (70, 75))	('FGF19', 'Gene', '9965', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (202, 226))	('tumour', 'Phenotype', 'HP:0002664', (274, 280))	('adrenocortical carcinoma', 'Disease', (202, 226))	('tumour reduction', 'Disease', 'MESH:D009369', (122, 138))	('patient', 'Species', '9606', (189, 196))	('SD', 'Disease', 'MESH:D029461', (256, 258))	('FGFR2', 'Gene', (38, 43))	('amplification', 'Var', (238, 251))	('tumour reduction', 'Disease', (274, 290))	('urothelial cancer', 'Disease', 'MESH:D014523', (15, 32))	('urothelial cancer', 'Disease', (15, 32))	('patient', 'Species', '9606', (2, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
100107	28972963	The toxicity profile of ARQ 087 differs from that expected of other potent FGFR inhibitors.	('ARQ 087', 'Var', (24, 31))	('ARQ 087', 'Chemical', 'MESH:C000621805', (24, 31))	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('toxicity', 'Disease', (4, 12))
100119	28972963	We hypothesise that considering the lack of clinically significant hyperphosphataemia, the relative sparing of FGFR1, and the lack of clear dose-related increase in FGF23, ARQ 087 may be in the unique position of potently inhibiting cancers with FGFR2 dysregulation without causing hyperphosphataemia.	('inhibiting', 'NegReg', (222, 232))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('dysregulation', 'Var', (252, 265))	('hyperphosphataemia', 'Disease', (67, 85))	('FGF23', 'Gene', '8074', (165, 170))	('hyperphosphataemia', 'Disease', 'None', (67, 85))	('ARQ 087', 'Chemical', 'MESH:C000621805', (172, 179))	('FGFR2', 'Gene', (246, 251))	('FGF23', 'Gene', (165, 170))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('hyperphosphataemia', 'Disease', (282, 300))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('FGFR2', 'Gene', '2263', (246, 251))	('cancers', 'Disease', (233, 240))	('hyperphosphataemia', 'Disease', 'None', (282, 300))
100123	28972963	A number of selective and non-selective FGFR tyrosine kinase inhibitors have been evaluated in various cancers harbouring FGFR genetic alterations.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('FGFR', 'Gene', (122, 126))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('genetic alterations', 'Var', (127, 146))	('cancers', 'Disease', (103, 110))
100124	28972963	In general, toxicity profiles of selective FGFR inhibitors fare better compared with non-selective multi-kinase inhibitors, with fewer off-target effects attributable to vascular endothelial growth factor receptor and platelet-derived growth factor receptor (PDGFR) inhibition.	('platelet-derived growth factor receptor', 'Gene', (218, 257))	('FGFR', 'Gene', (43, 47))	('PDGFR', 'Gene', (259, 264))	('PDGFR', 'Gene', '5159', (259, 264))	('inhibitors', 'Var', (48, 58))	('toxicity', 'Disease', 'MESH:D064420', (12, 20))	('toxicity', 'Disease', (12, 20))	('platelet-derived growth factor receptor', 'Gene', '5159', (218, 257))
100125	28972963	In the results from the phase I study of the selective FGFR inhibitor JNJ-42756493, the most common AEs were hyperphosphataemia (65%), asthenia (55%), dry mouth (45%), nail toxicity (35%), constipation (34%), and decreased appetite (32%).	('FGFR', 'Gene', (55, 59))	('JNJ-42756493', 'Gene', (70, 82))	('dry mouth', 'Phenotype', 'HP:0000217', (151, 160))	('constipation', 'Disease', 'MESH:D003248', (189, 201))	('asthenia', 'Disease', 'MESH:D001247', (135, 143))	('asthenia', 'Phenotype', 'HP:0025406', (135, 143))	('appetite', 'Disease', (223, 231))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (70, 82))	('toxicity', 'Disease', 'MESH:D064420', (173, 181))	('hyperphosphataemia', 'Disease', (109, 127))	('decreased', 'NegReg', (213, 222))	('constipation', 'Disease', (189, 201))	('hyperphosphataemia', 'Disease', 'None', (109, 127))	('dry mouth', 'Disease', 'MESH:D014987', (151, 160))	('toxicity', 'Disease', (173, 181))	('dry mouth', 'Disease', (151, 160))	('inhibitor', 'Var', (60, 69))	('asthenia', 'Disease', (135, 143))	('constipation', 'Phenotype', 'HP:0002019', (189, 201))	('decreased appetite', 'Phenotype', 'HP:0004396', (213, 231))
100133	28972963	In conclusion, in this Phase 1 study, ARQ 087 was well tolerated with manageable toxicities in a non-selected patient population, and demonstrated single-agent antitumour activity in heavily pretreated patients with specific FGFR genetic alterations.	('toxicities', 'Disease', 'MESH:D064420', (81, 91))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('FGFR', 'Gene', (225, 229))	('patient', 'Species', '9606', (202, 209))	('ARQ 087', 'Gene', (38, 45))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('toxicities', 'Disease', (81, 91))	('patients', 'Species', '9606', (202, 210))	('ARQ 087', 'Chemical', 'MESH:C000621805', (38, 45))	('tumour', 'Disease', (164, 170))	('patient', 'Species', '9606', (110, 117))	('genetic alterations', 'Var', (230, 249))
100140	28427185	The dysregulation of these genes is likely to be associated with poor clinical outcomes in cancer.	('dysregulation', 'Var', (4, 17))	('associated', 'Reg', (49, 59))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
100152	28427185	Lawrence et al analyzed 27 cancer types and found that the median frequency of non-synonymous mutations varied by more than 1,000-fold across different cancer types.	('cancer', 'Disease', (152, 158))	('non-synonymous mutations', 'Var', (79, 103))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
100154	28427185	Zack et al analyzed the copy number profiles of 4,934 primary cancer specimens across 11 cancer types and found that the mean rate of somatic copy number alterations (SCNAs) varied across different cancer types with ovarian, cervix, breast and bladder cancers having a large number of SCNAs while leukemia and kidney cancers very few SCNAs.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', (89, 95))	('breast and bladder cancers', 'Disease', 'MESH:D001749', (233, 259))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', (198, 204))	('kidney cancers', 'Disease', (310, 324))	('cervix', 'Disease', (225, 231))	('kidney cancers', 'Disease', 'MESH:D007680', (310, 324))	('cancer', 'Disease', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (317, 323))	('cancers', 'Phenotype', 'HP:0002664', (317, 324))	('copy number', 'Var', (142, 153))	('cancer', 'Disease', (317, 323))	('ovarian', 'Disease', (216, 223))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('ovarian', 'Disease', 'MESH:D010051', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('kidney cancers', 'Phenotype', 'HP:0009726', (310, 324))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('kidney cancer', 'Phenotype', 'HP:0009726', (310, 323))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('leukemia', 'Phenotype', 'HP:0001909', (297, 305))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('bladder cancers', 'Phenotype', 'HP:0009725', (244, 259))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('leukemia', 'Disease', (297, 305))	('leukemia', 'Disease', 'MESH:D007938', (297, 305))
100273	28427185	Likewise, we found a number of genes whose expression follows this pattern: late-stage cancers < early-stage cancers < normal tissue (Figure 7C), such as ADHFE1, LOC653501, NT5DC1, RSBN1, SOCS2 and TAPT1 in five cancer types.	('RSBN1', 'Gene', '54665', (181, 186))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('LOC653501', 'Var', (162, 171))	('late-stage cancers', 'Disease', 'MESH:D009369', (76, 94))	('ADHFE1', 'Gene', '137872', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('RSBN1', 'Gene', (181, 186))	('NT5DC1', 'Gene', '221294', (173, 179))	('NT5DC1', 'Gene', (173, 179))	('SOCS2', 'Gene', '8835', (188, 193))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('SOCS2', 'Gene', (188, 193))	('cancers', 'Disease', (87, 94))	('cancer', 'Disease', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Disease', (109, 115))	('cancers', 'Disease', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('late-stage cancers', 'Disease', (76, 94))	('cancer', 'Disease', (212, 218))	('TAPT1', 'Gene', '202018', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('TAPT1', 'Gene', (198, 203))	('ADHFE1', 'Gene', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
100295	28427185	These results demonstrate that there exist common genes and pathways whose dysregulations lead to the development of different types of cancer.	('dysregulations', 'Var', (75, 89))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('lead to', 'Reg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
100326	28427185	In addition, many upstream factors may affect expression of mRNAs (genes) in cancers such as gene mutations, DNA copy number alterations, DNA methylation, microRNA expression, and expression change of regulators.	('expression', 'MPA', (46, 56))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('affect', 'Reg', (39, 45))	('expression', 'MPA', (180, 190))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('methylation', 'Var', (142, 153))	('microRNA', 'MPA', (155, 163))
100369	25595907	CYP17 catalyzes key reactions in the testosterone synthesis pathway; inhibition of CYP17 activity by abiraterone thus interferes with the processes in the testes and the adrenals leading to testosterone production.	('CYP17', 'Gene', (0, 5))	('CYP17', 'Gene', (83, 88))	('CYP17', 'Gene', '1586', (0, 5))	('testosterone', 'Chemical', 'MESH:D013739', (37, 49))	('interferes', 'NegReg', (118, 128))	('processes', 'MPA', (138, 147))	('abiraterone', 'Chemical', 'MESH:C089740', (101, 112))	('inhibition', 'Var', (69, 79))	('testosterone', 'Chemical', 'MESH:D013739', (190, 202))	('CYP17', 'Gene', '1586', (83, 88))	('testosterone production', 'MPA', (190, 213))	('activity', 'MPA', (89, 97))
100371	25595907	It is conceivable that interrogation of androgen receptor positivity and treatment with androgen antagonistic agents could therefore be an effective strategy in these cancers.	('androgen receptor', 'Gene', '367', (40, 57))	('positivity', 'Var', (58, 68))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('men', 'Species', '9606', (78, 81))	('cancers', 'Disease', (167, 174))	('androgen receptor', 'Gene', (40, 57))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('rat', 'Species', '10116', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
100424	25595907	AR positivity was associated with a significantly better progression-free survival (PFS) compared to AR negativity in renal cancer [S45].	('better', 'PosReg', (50, 56))	('positivity', 'Var', (3, 13))	('AR', 'Gene', '367', (101, 103))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('renal cancer', 'Disease', (118, 130))	('renal cancer', 'Disease', 'MESH:D007680', (118, 130))	('renal cancer', 'Phenotype', 'HP:0009726', (118, 130))	('AR', 'Gene', '367', (0, 2))	('progression-free survival', 'CPA', (57, 82))
100450	25595907	AR positivity may correlate with poorer survival [S66].	('positivity', 'Var', (3, 13))	('AR', 'Gene', '367', (0, 2))	('poorer', 'NegReg', (33, 39))
100478	25595907	The authors suggested the loss of AR expression is a common occurrence in malignant cervical transformation [S91].	('loss', 'Var', (26, 30))	('malignant cervical transformation', 'Disease', (74, 107))	('trans', 'Chemical', 'MESH:C057348', (93, 98))	('AR', 'Gene', '367', (34, 36))
100506	25595907	Interestingly, AR reactivity was seen in 30% (13/43) of BRCA1 and in 78% (14/18) in BRCA2, suggesting that many ER-/PR- BRCA-mutant tumors are actually AR positive [S112].	('BRCA', 'Gene', (120, 124))	('BRCA', 'Gene', '672', (84, 88))	('BRCA', 'Gene', (56, 60))	('S11', 'Gene', '6267', (165, 168))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('BRCA', 'Gene', (84, 88))	('S11', 'Gene', (165, 168))	('ER-/PR-', 'Var', (112, 119))	('AR', 'Gene', '367', (152, 154))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA2', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('BRCA1', 'Gene', (56, 61))	('tumors', 'Disease', (132, 138))	('BRCA', 'Gene', '672', (120, 124))	('BRCA', 'Gene', '672', (56, 60))	('AR', 'Gene', '367', (15, 17))	('BRCA2', 'Gene', '675', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('man', 'Species', '9606', (107, 110))
100516	25595907	Lessons from prostate cancer: During the last several decades, androgen deprivation (Table 2, Figure 1) has been standard of care for metastatic prostate cancer; however, most patients eventually develop disease progression despite pharmacologic suppression of testosterone levels, denoted as castration-resistant prostate cancer (Figure 2) perhaps mediated by androgen independence (Figure 1).	('prostate cancer', 'Disease', 'MESH:D011471', (145, 160))	('disease', 'Disease', (204, 211))	('suppression', 'NegReg', (246, 257))	('prostate cancer', 'Phenotype', 'HP:0012125', (145, 160))	('testosterone levels', 'MPA', (261, 280))	('prostate cancer', 'Disease', (145, 160))	('pharmacologic', 'Var', (232, 245))	('develop', 'PosReg', (196, 203))	('rat', 'Species', '10116', (297, 300))	('testosterone', 'Chemical', 'MESH:D013739', (261, 273))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (13, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (13, 28))	('patients', 'Species', '9606', (176, 184))	('prostate cancer', 'Disease', 'MESH:D011471', (314, 329))	('prostate cancer', 'Phenotype', 'HP:0012125', (314, 329))	('prostate cancer', 'Disease', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('prostate cancer', 'Disease', (314, 329))
100523	25595907	Long-term administration of supra-physiologic Gn-RH produce the paradoxical effect of pituitary overstimulation including pituitary desensitization to Gn-RH, breakdown of physiological feedback systems, down-regulation of Gn-RH receptors, depletion of releasable LH content, and reduction of testosterone secretion to castrate levels.	('rat', 'Species', '10116', (18, 21))	('breakdown', 'MPA', (158, 167))	('Gn-RH', 'Gene', '2796', (46, 51))	('Gn-RH', 'Gene', '2796', (222, 227))	('LH', 'Chemical', 'MESH:D007986', (263, 265))	('Gn-RH', 'Gene', '2796', (151, 156))	('Gn-RH', 'Gene', (46, 51))	('reduction of testosterone', 'Phenotype', 'HP:0040171', (279, 304))	('Gn-RH', 'Gene', (222, 227))	('pituitary desensitization', 'MPA', (122, 147))	('Gn-RH', 'Gene', (151, 156))	('overstimulation', 'PosReg', (96, 111))	('rat', 'Species', '10116', (322, 325))	('down-regulation', 'NegReg', (203, 218))	('reduction', 'NegReg', (279, 288))	('testosterone secretion', 'MPA', (292, 314))	('depletion of releasable', 'MPA', (239, 262))	('supra-physiologic', 'Var', (28, 45))	('testosterone', 'Chemical', 'MESH:D013739', (292, 304))	('pituitary', 'MPA', (86, 95))
100534	25595907	Indeed, this pathway is deregulated in up to 65% of prostate cancers, most commonly due to PTEN loss, and less commonly related to PIK3CA amplification or mutation.	('PIK3CA', 'Gene', '5290', (131, 137))	('prostate cancers', 'Disease', 'MESH:D011471', (52, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('PTEN', 'Gene', '5728', (91, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutation', 'Var', (155, 163))	('PIK3CA', 'Gene', (131, 137))	('PTEN', 'Gene', (91, 95))	('prostate cancers', 'Phenotype', 'HP:0012125', (52, 68))	('prostate cancers', 'Disease', (52, 68))	('loss', 'NegReg', (96, 100))	('deregulated', 'Reg', (24, 35))
100537	25595907	found significantly higher AR levels in breast cancer patients with kinase domain PIK3CA mutations versus wild-type PIK3CA.	('PIK3CA', 'Gene', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('PIK3CA', 'Gene', (82, 88))	('breast cancer', 'Disease', (40, 53))	('patients', 'Species', '9606', (54, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('higher', 'PosReg', (20, 26))	('PIK3CA', 'Gene', '5290', (116, 122))	('PIK3CA', 'Gene', '5290', (82, 88))	('mutations', 'Var', (89, 98))	('kinase domain', 'Var', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('AR', 'Gene', '367', (27, 29))
100545	25595907	In a preclinical model, DHT enhanced IL-6 and IL-8 expression and flutamide abrogated IL-6 and IL-8 expression.	('flutamide', 'Chemical', 'MESH:D005485', (66, 75))	('abrogated', 'NegReg', (76, 85))	('IL-8', 'Gene', (46, 50))	('DHT', 'Chemical', 'MESH:D013196', (24, 27))	('IL-6', 'Gene', (37, 41))	('IL-8', 'Gene', '3576', (95, 99))	('IL-6', 'Gene', '3569', (86, 90))	('enhanced', 'PosReg', (28, 36))	('IL-8', 'Gene', (95, 99))	('expression', 'MPA', (100, 110))	('IL-6', 'Gene', '3569', (37, 41))	('expression', 'MPA', (51, 61))	('DHT', 'Var', (24, 27))	('IL-8', 'Gene', '3576', (46, 50))	('IL-6', 'Gene', (86, 90))
100549	25595907	The synthesis of constitutively active AR variants lacking the canonical ligand-binding domain may also promote resistance.	('AR', 'Gene', '367', (39, 41))	('variants', 'Var', (42, 50))	('lacking', 'NegReg', (51, 58))	('promote', 'PosReg', (104, 111))	('resistance', 'CPA', (112, 122))
100733	25047265	Identifying genetic changes common to these diversely behaving endocrine tumor types has been shown to play an important role in many types of human cancers.	('cancers', 'Disease', (149, 156))	('human', 'Species', '9606', (143, 148))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('endocrine tumor', 'Disease', 'MESH:D004701', (63, 78))	('endocrine tumor', 'Disease', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('endocrine tumor', 'Phenotype', 'HP:0100568', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('genetic changes', 'Var', (12, 27))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
100734	25047265	For example, BRAF mutations are highly prevalent in thyroid cancer and other cancers, and are associated with more aggressive disease in thyroid cancer.	('aggressive disease', 'Disease', (115, 133))	('thyroid cancer', 'Disease', (52, 66))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('aggressive disease', 'Disease', 'MESH:D001523', (115, 133))	('BRAF', 'Gene', '673', (13, 17))	('prevalent', 'Reg', (39, 48))	('thyroid cancer', 'Disease', 'MESH:D013964', (52, 66))	('BRAF', 'Gene', (13, 17))	('thyroid cancer', 'Disease', (137, 151))	('thyroid cancer', 'Phenotype', 'HP:0002890', (52, 66))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('associated with', 'Reg', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('thyroid cancer', 'Disease', 'MESH:D013964', (137, 151))	('thyroid cancer', 'Phenotype', 'HP:0002890', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('mutations', 'Var', (18, 27))
100735	25047265	SDHB mutations were initially identified in familial paraganglioma, but were later found to be prevalent in kidney cancers and gastrointestinal stromal tumors, and recently pituitary tumors.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('pituitary tumors', 'Disease', 'MESH:D010911', (173, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('kidney cancers', 'Phenotype', 'HP:0009726', (108, 122))	('SDHB', 'Gene', (0, 4))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (127, 158))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (127, 158))	('familial paraganglioma', 'Disease', 'MESH:D010235', (44, 66))	('prevalent', 'Reg', (95, 104))	('pituitary tumors', 'Disease', (173, 189))	('paraganglioma', 'Phenotype', 'HP:0002668', (53, 66))	('mutations', 'Var', (5, 14))	('identified', 'Reg', (30, 40))	('gastrointestinal stromal tumors', 'Disease', (127, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('familial paraganglioma', 'Disease', (44, 66))	('kidney cancers', 'Disease', 'MESH:D007680', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('kidney cancers', 'Disease', (108, 122))	('SDHB', 'Gene', '6390', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
100752	25047265	The human papillary thyroid cancer (TPC-1) cell line was maintained in DMEM supplemented with FBS, penicillin (100 U/ml), streptomycin (100 microg/ml), fungizone (250 ng/ml), TSH (10 I.U/L), and insulin (10 microg/ml).	('250 ng/ml', 'Var', (163, 172))	('human', 'Species', '9606', (4, 9))	('TPC-1', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('FBS', 'Disease', (94, 97))	('penicillin', 'Chemical', 'MESH:D010406', (99, 109))	('papillary thyroid cancer', 'Disease', (10, 34))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (10, 34))	('fungizone', 'Chemical', 'MESH:D000666', (152, 161))	('insulin', 'Gene', (195, 202))	('TPC-1', 'Gene', '53373', (36, 41))	('FBS', 'Disease', 'MESH:D005198', (94, 97))	('streptomycin', 'Chemical', 'MESH:D013307', (122, 134))	('DMEM', 'Chemical', '-', (71, 75))	('thyroid cancer', 'Phenotype', 'HP:0002890', (20, 34))	('insulin', 'Gene', '3630', (195, 202))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (10, 34))	('TSH', 'Chemical', '-', (175, 178))
100763	25047265	The PCR primers and probes for ZNF367 (Hs00400665_m1), ITGA3 (Hs01076873_m1), and GAPDH (Hs_99999905_m1) were obtained from Applied Biosystems.	('ITGA3', 'Gene', (55, 60))	('Hs00400665_m1', 'Var', (39, 52))	('Hs_99999905_m1', 'Var', (89, 103))	('GAPDH', 'Gene', '2597', (82, 87))	('Hs01076873_m1', 'Var', (62, 75))	('ITGA3', 'Gene', '3675', (55, 60))	('ZNF367', 'Gene', (31, 37))	('GAPDH', 'Gene', (82, 87))
100776	25047265	The mutant construct of ZNF367 3'UTR was obtained by introducing the mutation into the first three nucleotides of the seed region (143-150, GCTGCTA -- CGAGCTA) for miR-195.	('mutation', 'Var', (69, 77))	('miR-195', 'Gene', '406971', (164, 171))	('miR-195', 'Gene', (164, 171))
100777	25047265	Wild-type ZNF367 3'UTR or mutant ZNF367 3'UTR and the empty 3'UTR vector with pre-miR-195 or pre-NC were co-transfected into SW13 cells (Switchgear Genomics).	('miR-195', 'Gene', '406971', (82, 89))	('ZNF367', 'Gene', (33, 39))	('SW13', 'CellLine', 'CVCL:0542', (125, 129))	('mutant', 'Var', (26, 32))	('miR-195', 'Gene', (82, 89))
100788	25047265	ZNF367 knockdown in SW13 cells, increased cellular proliferation (30-40%) in vitro and (3.5-fold) in vivo (p<0.05; Figure 2).	('SW13', 'CellLine', 'CVCL:0542', (20, 24))	('cellular proliferation', 'CPA', (42, 64))	('increased', 'PosReg', (32, 41))	('ZNF367', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))
100790	25047265	The knockdown had a similar effect on the cellular invasion and migration of BD140A, TPC-1, and HEK293 cell lines (p<0.05; Figure 3, B-D).	('TPC-1', 'Gene', (85, 90))	('cellular invasion', 'CPA', (42, 59))	('HEK293', 'CellLine', 'CVCL:0045', (96, 102))	('TPC-1', 'Gene', '53373', (85, 90))	('migration', 'CPA', (64, 73))	('knockdown', 'Var', (4, 13))
100792	25047265	We found increased cellular adhesion, with ZNF367 knockdown, to Laminin I (two-three-fold high) and fibrinogen (three-six-fold high) (p<0.05; Figure 3H).	('fibrinogen', 'Gene', '2244', (100, 110))	('fibrinogen', 'Gene', (100, 110))	('ZNF367', 'Gene', (43, 49))	('knockdown', 'Var', (50, 59))	('increased', 'PosReg', (9, 18))	('cellular adhesion', 'CPA', (19, 36))	('Laminin', 'Protein', (64, 71))
100794	25047265	Using genome-wide mRNA expression analysis in cells transfected with ZNF367 and negative control siRNAs, we identified two candidate genes (ITGA3, serpin peptidase inhibitor, clade B (ovalbumin), member 9 [SERPINB9]) possibly regulated by ZNF367 based on applying several filter criteria (FDR<0.25, fold-change>1.5, common to all siRNA knockdown, and strong correlation in expression in human tumor samples) (Figure S3).	('human', 'Species', '9606', (387, 392))	('tumor', 'Disease', 'MESH:D009369', (393, 398))	('ITGA3', 'Gene', '3675', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (393, 398))	('tumor', 'Disease', (393, 398))	('knockdown', 'Var', (336, 345))	('ITGA3', 'Gene', (140, 145))
100795	25047265	ITGA3 was chosen as a promising candidate for further study because it plays a significant role in cellular adhesion and invasion and was validated to be upregulated up to 2.5-fold with ZNF367 knockdown (p<0.05; Figure 4A).	('upregulated', 'PosReg', (154, 165))	('ITGA3', 'Gene', '3675', (0, 5))	('knockdown', 'Var', (193, 202))	('ITGA3', 'Gene', (0, 5))	('invasion', 'CPA', (121, 129))	('cellular adhesion', 'CPA', (99, 116))
100797	25047265	ITGA3 protein expression was also increased with siRNA knockdown of ZNF367 (Figure 4C).	('knockdown', 'Var', (55, 64))	('protein', 'Protein', (6, 13))	('ITGA3', 'Gene', '3675', (0, 5))	('expression', 'MPA', (14, 24))	('ZNF367', 'Gene', (68, 74))	('ITGA3', 'Gene', (0, 5))	('increased', 'PosReg', (34, 43))
100807	25047265	We observed significant reduced luciferase activity with miR-195 overexpression in wild-type 3'UTR compared to negative control and mutated ZNF367 3'UTR-transfected cells (p<0.01; Figure 5E).	('miR-195', 'Gene', (57, 64))	('miR-195', 'Gene', '406971', (57, 64))	('reduced', 'NegReg', (24, 31))	('luciferase', 'Enzyme', (32, 42))	('mutated', 'Var', (132, 139))	('activity', 'MPA', (43, 51))	('overexpression', 'PosReg', (65, 79))
100812	25047265	Lastly, we demonstrate that dysregulated ZNF367 expression was associated with the loss of miR-195 expression in tumor samples and that this microRNA directly targets ZNF367 and regulates cellular invasion, providing an understanding of the mechanism for dysregulated ZNF367 expression.	('tumor', 'Disease', (113, 118))	('expression', 'MPA', (99, 109))	('cellular invasion', 'CPA', (188, 205))	('dysregulated', 'Var', (28, 40))	('expression', 'MPA', (48, 58))	('regulates', 'Reg', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('miR-195', 'Gene', (91, 98))	('miR-195', 'Gene', '406971', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('loss', 'NegReg', (83, 87))	('ZNF367', 'Gene', (41, 47))
100816	25047265	According to the Catalogue of Somatic Mutations in Cancer (COSMIC) database (http://cancer.sanger.ac.uk/cosmic/gene/overview?ln=ZNF367), missense, nonsense, and insertion mutations of ZNF367 have been identified at a low rate (16 of 5,089 samples) in a variety of cancers.	('ZNF367', 'Gene', (184, 190))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancers', 'Disease', (264, 271))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('insertion mutations', 'Var', (161, 180))	('nonsense', 'Var', (147, 155))	('Cancer', 'Disease', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('missense', 'Var', (137, 145))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
100829	25047265	The increased ITGA3 levels from ZNF367 knockdown and increased adhesion of cells to Laminin I and Fibronectin suggest that decreased ITGA3 may mediate the inhibitory effect of ZNF367 on cellular adhesion and invasion.	('invasion', 'CPA', (208, 216))	('Fibronectin', 'Gene', '2335', (98, 109))	('Fibronectin', 'Gene', (98, 109))	('decreased', 'NegReg', (123, 132))	('ZNF367', 'Gene', (32, 38))	('knockdown', 'Var', (39, 48))	('adhesion', 'MPA', (63, 71))	('cellular adhesion', 'CPA', (186, 203))	('ITGA3', 'Gene', '3675', (14, 19))	('ITGA3', 'Gene', (133, 138))	('increased', 'PosReg', (53, 62))	('increased', 'PosReg', (4, 13))	('ITGA3', 'Gene', (14, 19))	('ITGA3', 'Gene', '3675', (133, 138))
100835	23056559	Increased Oxidative Damage in Carriers of the Germline TP53 p.R337H Mutation Germline mutations in TP53 are the underlying defect of Li-Fraumeni Syndrome (LFS) and Li-Fraumeni-like (LFL) Syndrome, autosomal dominant disorders characterized by predisposition to multiple early onset cancers.	('autosomal dominant disorders', 'Disease', (197, 225))	('cancers', 'Disease', (282, 289))	('defect of Li-Fraumeni Syndrome', 'Disease', (123, 153))	('Li-Fraumeni-like (LFL) Syndrome', 'Disease', 'MESH:C567189', (164, 195))	('TP53', 'Gene', '7157', (55, 59))	('autosomal dominant disorders', 'Disease', 'MESH:D030342', (197, 225))	('p.R337H', 'Var', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (282, 289))	('TP53', 'Gene', (99, 103))	('LFS', 'Disease', (155, 158))	('Increased', 'PosReg', (0, 9))	('LFS', 'Disease', 'MESH:D016864', (155, 158))	('p.R337H', 'Mutation', 'rs121912664', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('TP53', 'Gene', (55, 59))	('Oxidative Damage', 'MPA', (10, 26))	('TP53', 'Gene', '7157', (99, 103))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))	('defect of Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (123, 153))
100836	23056559	In Brazil, a variant form of LFS/LFL is commonly detected because of the high prevalence of a founder mutation at codon 337 in TP53 (p.R337H).	('p.R337H', 'Mutation', 'rs121912664', (133, 140))	('LFS', 'Disease', 'MESH:D016864', (29, 32))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('LFS', 'Disease', (29, 32))	('p.R337H', 'Var', (133, 140))
100839	23056559	We identified a significant increase in erythrocyte GPx activity and in plasma carbonyl content,an indicator of protein oxidative damage, in mutation carriers compared to non-carriers (P = 0.048 and P = 0.035, respectively).	('protein oxidative damage', 'Disease', (112, 136))	('GPx', 'Gene', (52, 55))	('plasma carbonyl content', 'MPA', (72, 95))	('increase in erythrocyte', 'Phenotype', 'HP:0001901', (28, 51))	('GPx', 'Gene', '2876', (52, 55))	('erythrocyte', 'MPA', (40, 51))	('mutation', 'Var', (141, 149))	('increase', 'PosReg', (28, 36))	('protein oxidative damage', 'Disease', 'MESH:D004194', (112, 136))
100840	23056559	Mutation carriers also showed a four-fold increase in plasma malondialdehyde levels, indicating increased lipid peroxidation (NC = 40.20+-0.71, C = 160.5+-0.88, P<0.0001).	('lipid', 'Chemical', 'MESH:D008055', (106, 111))	('increased', 'PosReg', (96, 105))	('plasma malondialdehyde levels', 'MPA', (54, 83))	('Mutation', 'Var', (0, 8))	('increased lipid peroxidation', 'Phenotype', 'HP:0025464', (96, 124))	('lipid peroxidation', 'MPA', (106, 124))	('malondialdehyde', 'Chemical', 'MESH:D008315', (61, 76))	('increased lipid', 'Phenotype', 'HP:0003077', (96, 111))	('increase', 'PosReg', (42, 50))
100843	23056559	These findings provide the first evidence that oxidative damage occurs in carriers of a germline TP53 mutation, and these may have important implications regarding our understanding of the mechanisms responsible for germline TP53 p.R337H mutation-associated carcinogenesis.	('p.R337H', 'Var', (230, 237))	('TP53', 'Gene', '7157', (97, 101))	('mutation', 'Var', (102, 110))	('carcinogenesis', 'Disease', 'MESH:D063646', (258, 272))	('p.R337H', 'Mutation', 'rs121912664', (230, 237))	('TP53', 'Gene', '7157', (225, 229))	('TP53', 'Gene', (97, 101))	('carcinogenesis', 'Disease', (258, 272))	('TP53', 'Gene', (225, 229))	('oxidative damage', 'MPA', (47, 63))
100848	23056559	Currently, germline mutations in the TP53 gene are the only known genetic defect underlying LFS/LFL.	('LFS', 'Disease', (92, 95))	('LFS', 'Disease', 'MESH:D016864', (92, 95))	('germline mutations', 'Var', (11, 29))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))
100849	23056559	About 56% of the families that meet the strict "classic" criteria for LFS have germline TP53 mutations.	('LFS', 'Disease', 'MESH:D016864', (70, 73))	('mutations', 'Var', (93, 102))	('TP53', 'Gene', '7157', (88, 92))	('LFS', 'Disease', (70, 73))	('TP53', 'Gene', (88, 92))
100856	23056559	presented convincing evidence supporting that the antioxidant functions of low or basal levels of p53 have a role in the control of genetic stability and prevention of cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('low', 'Var', (75, 78))	('genetic stability', 'CPA', (132, 149))	('antioxidant functions', 'MPA', (50, 71))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('p53', 'Gene', (98, 101))	('cancer', 'Disease', (168, 174))	('p53', 'Gene', '7157', (98, 101))
100857	23056559	However, thus far, there has been no published evidence that carriers of germline TP53 mutations harbor differences in their redox metabolism and anti-oxidant responses compared to non-carriers.	('TP53', 'Gene', (82, 86))	('redox metabolism', 'MPA', (125, 141))	('anti-oxidant responses', 'MPA', (146, 168))	('differences', 'Reg', (104, 115))	('TP53', 'Gene', '7157', (82, 86))	('mutations', 'Var', (87, 96))
100858	23056559	The most common TP53 germline mutations that are associated with LFS and LFL are substitutions clustering in highly conserved regions of the DBD.	('associated', 'Reg', (49, 59))	('LFS', 'Disease', (65, 68))	('TP53', 'Gene', '7157', (16, 20))	('mutations', 'Var', (30, 39))	('LFL', 'Disease', (73, 76))	('LFS', 'Disease', 'MESH:D016864', (65, 68))	('TP53', 'Gene', (16, 20))
100859	23056559	Inheritance of such mutations is generally associated with severe forms of LFS/LFL.	('LFS', 'Disease', (75, 78))	('LFS', 'Disease', 'MESH:D016864', (75, 78))	('mutations', 'Var', (20, 29))	('associated', 'Reg', (43, 53))
100860	23056559	Among these, is the p.R337H (c.1010 G>A, CGC to CAC at codon 337) mutation in exon 10, which was initially reported in Brazilian children diagnosed with ACC but no documented familial history of other cancers.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('ACC', 'Phenotype', 'HP:0006744', (153, 156))	('children', 'Species', '9606', (129, 137))	('p.R337H', 'Mutation', 'rs121912664', (20, 27))	('c.1010 G>A', 'Var', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('CGC to CAC at codon 337', 'Mutation', 'c.337CGC>CAC', (41, 64))	('c.1010 G>A', 'Mutation', 'rs121912664', (29, 39))
100861	23056559	Subsequently, p.R337H has been associated with a broader cancer spectrum, similar to that of LFS/LFL, including premenopausal breast cancer, early sarcoma, and other tumors that occur at an earlier age in carriers when compared to non-carriers.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Disease', (57, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('p.R337H', 'Var', (14, 21))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Disease', (126, 139))	('associated', 'Reg', (31, 41))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('tumors', 'Disease', (166, 172))	('sarcoma', 'Disease', (147, 154))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (112, 139))	('LFS', 'Disease', (93, 96))	('cancer', 'Disease', (133, 139))	('p.R337H', 'Mutation', 'rs121912664', (14, 21))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('LFS', 'Disease', 'MESH:D016864', (93, 96))
100862	23056559	Unlike other common LFS mutants, which dramatically disrupt p53 transcriptional activity, p.R337H is thought to partially retain the ability to suppress cell growth under certain physiological conditions.	('cell growth', 'CPA', (153, 164))	('LFS', 'Disease', (20, 23))	('p.R337H', 'Var', (90, 97))	('LFS', 'Disease', 'MESH:D016864', (20, 23))	('p53', 'Gene', (60, 63))	('p.R337H', 'Mutation', 'rs121912664', (90, 97))	('suppress', 'NegReg', (144, 152))	('transcriptional activity', 'MPA', (64, 88))	('p53', 'Gene', '7157', (60, 63))
100863	23056559	Structural studies have shown that the mutation hampers p53 oligomerization in a pH-dependent manner.	('hampers', 'NegReg', (48, 55))	('mutation', 'Var', (39, 47))	('p53', 'Gene', '7157', (56, 59))	('p53', 'Gene', (56, 59))
100864	23056559	Thus, at pH 7, p.R337H retains its capacity to form oligomers and exhibits a structure and activity that are similar to wild-type p53.	('p.R337H', 'Mutation', 'rs121912664', (15, 22))	('form', 'Interaction', (47, 51))	('activity', 'MPA', (91, 99))	('p.R337H', 'Var', (15, 22))	('p53', 'Gene', (130, 133))	('structure', 'MPA', (77, 86))	('p53', 'Gene', '7157', (130, 133))	('oligomers', 'MPA', (52, 61))
100865	23056559	At slightly elevated pH, however (pH 8.0), p.R337H loses its capacity to form oligomers and thus to bind to p53 DNA response elements despite retaining a structurally intact DBD.	('form oligomers', 'MPA', (73, 87))	('p.R337H', 'Mutation', 'rs121912664', (43, 50))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('loses', 'NegReg', (51, 56))	('elevated pH', 'Phenotype', 'HP:0008151', (12, 23))	('bind', 'Interaction', (100, 104))	('capacity', 'MPA', (61, 69))	('p.R337H', 'Var', (43, 50))
100866	23056559	This biochemical property defines p.R337H as being a dysfunctional pH-dependent p53 mutant.	('p.R337H', 'Var', (34, 41))	('p53', 'Gene', '7157', (80, 83))	('p53', 'Gene', (80, 83))	('p.R337H', 'Mutation', 'rs121912664', (34, 41))
100867	23056559	Given the relatively high population prevalence of this mutant allele in southern Brazil and its association with increased risk of developing several cancers, p.R337H may make an important contribution to the cancer burden in the region.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('p.R337H', 'Var', (160, 167))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', (151, 158))	('cancer', 'Disease', (210, 216))	('p.R337H', 'Mutation', 'rs121912664', (160, 167))
100871	23056559	Group C (p.R337H carriers) comprised subjects who had previously been ascertained as being carriers of the p.R337H mutation in genomic (white blood cells) DNA by standard sequencing protocols (http://www-p53.iarc.fr/Download/TP53_DirectSequencing_IARC.pdf).	('TP53', 'Gene', '7157', (225, 229))	('p53', 'Gene', (204, 207))	('p53', 'Gene', '7157', (204, 207))	('p.R337H', 'Var', (107, 114))	('TP53', 'Gene', (225, 229))	('p.R337H', 'Mutation', 'rs121912664', (107, 114))	('p.R337H', 'Mutation', 'rs121912664', (9, 16))
100872	23056559	Group NC (non-p.R337H carriers) comprised 17 subjects who were ascertained as being non-carriers of the p.R337H or of any other mutation within the TP53 coding sequence (exons 2-11).	('p.R337H', 'Var', (104, 111))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('p.R337H', 'Mutation', 'rs121912664', (14, 21))	('p.R337H', 'Mutation', 'rs121912664', (104, 111))
100876	23056559	The Group NC subjects included 12 relatives of the p.R337H carriers that were included in Group C, all without personal histories of cancer, and 5 subjects who had histories of cancer, including one patient with ACC who had no detectable germline TP53 mutation determined by sequencing of the entire coding region.	('TP53', 'Gene', (247, 251))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('p.R337H', 'Var', (51, 58))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('patient', 'Species', '9606', (199, 206))	('p.R337H', 'Mutation', 'rs121912664', (51, 58))	('cancer', 'Disease', (133, 139))	('ACC', 'Phenotype', 'HP:0006744', (212, 215))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('TP53', 'Gene', '7157', (247, 251))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
100902	23056559	Erythrocyte GPx activity was significantly higher in Group C (mutation carriers) than in NC (non- carriers) (C = 9.23+-0.81, NC = 6.99+-0.58, P = 0.048).	('higher', 'PosReg', (43, 49))	('GPx', 'Gene', (12, 15))	('mutation', 'Var', (62, 70))	('Erythrocyte', 'MPA', (0, 11))	('GPx', 'Gene', '2876', (12, 15))
100903	23056559	The measure of total anti-oxidant status (TAS), which primarily represents non-enzymatic anti-oxidant levels, was significantly higher in carriers when compared to non-carriers (C = 1.47+-0.04, NC = 1.30+-0.04, P = 0.007; Figure 1).	('carriers', 'Var', (138, 146))	('TAS', 'Chemical', '-', (42, 45))	('higher', 'PosReg', (128, 134))	('anti-oxidant status', 'MPA', (21, 40))
100904	23056559	In addition, we observed an association between plasma MDA content and mutation status.	('mutation', 'Var', (71, 79))	('MDA', 'Chemical', 'MESH:D008315', (55, 58))	('association', 'Interaction', (28, 39))	('plasma MDA content', 'MPA', (48, 66))
100906	23056559	Furthermore, the plasma CO content was increased in the carriers (C = 0.46+-0.10, NC = 0.23+-0.05, P = 0.035; Figure 3).	('CO', 'Chemical', '-', (24, 26))	('plasma CO content', 'MPA', (17, 34))	('increased', 'PosReg', (39, 48))	('carriers', 'Var', (56, 64))
100907	23056559	Finally, ascorbic acid (vitamin C) levels were significantly lower in carriers when compared to non-carriers (C = 2.33+-0.15, NC = 3.84+-0.15, P<0.0001; Figure 4).	('lower', 'NegReg', (61, 66))	('vitamin C', 'Chemical', 'MESH:D001205', (24, 33))	('carriers', 'Var', (70, 78))	('ascorbic acid', 'Chemical', 'MESH:D001205', (9, 22))
100916	23056559	This mutation occurs at codon 337 (G>A, CGC to CAC) and induces the substitution of an arginine for histidine in the tetramerization domain of p53 (p.R337H, c.1010).	('histidine', 'Chemical', 'MESH:D006639', (100, 109))	('p53', 'Gene', '7157', (143, 146))	('c.1010', 'Var', (157, 163))	('p.R337H', 'Var', (148, 155))	('induces', 'Reg', (56, 63))	('arginine', 'Chemical', 'MESH:D001120', (87, 95))	('p53', 'Gene', (143, 146))	('p.R337H', 'Mutation', 'rs121912664', (148, 155))
100917	23056559	Since TP53 mutations vary in their position in the coding sequence and their impact on p53 protein structure and function, this design had the advantage of reducing the baseline heterogeneity that could have occurred with the comparison of samples from subjects with different inherited mutations.	('function', 'MPA', (113, 121))	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('impact', 'Reg', (77, 83))	('baseline heterogeneity', 'MPA', (169, 191))	('protein', 'Protein', (91, 98))	('reducing', 'NegReg', (156, 164))
100918	23056559	We have provided evidence suggesting that subjects who carry TP53 p.R337H in their germline have higher levels of several blood indicators of oxidative stress than do subjects (matched by age and clinical history) who do not carry a germline TP53 mutation.	('higher', 'PosReg', (97, 103))	('p.R337H', 'Var', (66, 73))	('p.R337H', 'Mutation', 'rs121912664', (66, 73))	('TP53', 'Gene', '7157', (242, 246))	('oxidative stress', 'Phenotype', 'HP:0025464', (142, 158))	('TP53', 'Gene', (242, 246))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
100919	23056559	An increase in oxidative damage was detected in all p.R337H carriers irrespective of their previous cancer history, while it was not observed in subjects in the reference group.	('p.R337H', 'Var', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('oxidative damage', 'MPA', (15, 31))	('p.R337H', 'Mutation', 'rs121912664', (52, 59))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('increase', 'PosReg', (3, 11))
100920	23056559	This observation suggests that altered levels of molecular damage caused by oxidative stress in blood products of TP53 p.R337H carriers are related to the carcinogenic process and are not a consequence of malignancy.	('p.R337H', 'Mutation', 'rs121912664', (119, 126))	('oxidative stress', 'MPA', (76, 92))	('carcinogenic process', 'Disease', (155, 175))	('oxidative stress', 'Phenotype', 'HP:0025464', (76, 92))	('TP53', 'Gene', '7157', (114, 118))	('carcinogenic process', 'Disease', 'MESH:D009385', (155, 175))	('related', 'Reg', (140, 147))	('malignancy', 'Disease', 'MESH:D009369', (205, 215))	('TP53', 'Gene', (114, 118))	('malignancy', 'Disease', (205, 215))	('levels of molecular damage', 'MPA', (39, 65))	('p.R337H', 'Var', (119, 126))
100921	23056559	Whether the same biochemical phenotype occurs with germline TP53 mutations other than p.R337H and whether it is part of the mechanisms that lead to increased cancer predisposition in this high-risk group remains to be determined.	('p.R337H', 'Var', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('p.R337H', 'Mutation', 'rs121912664', (86, 93))	('cancer', 'Disease', (158, 164))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
100922	23056559	Our results demonstrate an increased CO content and a four-fold increase in MDA, which are markers of protein oxidative damage and lipid peroxidation, respectively, in the plasma of TP53 p.R337H carriers versus non-carriers.	('protein oxidative damage', 'Disease', 'MESH:D004194', (102, 126))	('increased', 'PosReg', (27, 36))	('TP53', 'Gene', '7157', (182, 186))	('TP53', 'Gene', (182, 186))	('protein oxidative damage', 'Disease', (102, 126))	('MDA', 'Chemical', 'MESH:D008315', (76, 79))	('CO', 'Chemical', '-', (37, 39))	('increase', 'PosReg', (64, 72))	('MDA', 'MPA', (76, 79))	('CO content', 'MPA', (37, 47))	('p.R337H', 'Var', (187, 194))	('lipid', 'Chemical', 'MESH:D008055', (131, 136))	('p.R337H', 'Mutation', 'rs121912664', (187, 194))
100923	23056559	Lipid peroxidation may cause significant changes in the permeability, fluidity, integrity, and functional abnormalities of biomembranes, resulting in altered cell signaling and in the release of other potentially toxic cellular products.	('fluidity', 'MPA', (70, 78))	('cell', 'CPA', (158, 162))	('Lipid', 'Var', (0, 5))	('changes', 'Reg', (41, 48))	('permeability', 'MPA', (56, 68))	('integrity', 'MPA', (80, 89))	('Lipid', 'Chemical', 'MESH:D008055', (0, 5))	('altered', 'Reg', (150, 157))	('cause', 'Reg', (23, 28))	('functional', 'MPA', (95, 105))
100925	23056559	Although there is compelling evidence from cohort studies that increased levels in a wide range of markers of oxidative stress and inflammation are associated with an increased risk of cancer, there is only few published data on baseline oxidative stress parameters for individuals with cancer-predisposing germline mutations in tumor suppressor genes.	('oxidative stress', 'MPA', (110, 126))	('increased', 'PosReg', (63, 72))	('cancer', 'Disease', (287, 293))	('inflammation', 'Disease', (131, 143))	('levels', 'MPA', (73, 79))	('inflammation', 'Disease', 'MESH:D007249', (131, 143))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('oxidative stress', 'Phenotype', 'HP:0025464', (110, 126))	('germline', 'Var', (307, 315))	('associated', 'Reg', (148, 158))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('oxidative stress', 'Phenotype', 'HP:0025464', (238, 254))	('cancer', 'Disease', (185, 191))	('tumor', 'Disease', (329, 334))
100926	23056559	To the best of our knowledge, only one study assessed the serum oxidative stress parameters of cancer-unaffected carriers of germline BRCA1 mutations and found that the mutation status did not influence lipid and protein peroxidation content when compared to controls.	('oxidative stress', 'Phenotype', 'HP:0025464', (64, 80))	('BRCA1', 'Gene', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('serum oxidative stress parameters', 'MPA', (58, 91))	('lipid', 'Chemical', 'MESH:D008055', (203, 208))	('cancer', 'Disease', (95, 101))	('mutations', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BRCA1', 'Gene', '672', (134, 139))
100927	23056559	In addition to the evidence regarding oxidative damage, we also found higher erythrocyte GPx activity in TP53 p.R337H carriers.	('GPx', 'Gene', '2876', (89, 92))	('p.R337H', 'Var', (110, 117))	('p.R337H', 'Mutation', 'rs121912664', (110, 117))	('GPx', 'Gene', (89, 92))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('higher', 'PosReg', (70, 76))
100929	23056559	In contrast, we did not detect significant differences in CAT and SOD activities between p.R337H carriers and non-carriers.	('SOD', 'Gene', (66, 69))	('p.R337H', 'Mutation', 'rs121912664', (89, 96))	('p.R337H carriers', 'Var', (89, 105))	('CAT', 'Gene', '847', (58, 61))	('SOD', 'Gene', '6647', (66, 69))	('CAT', 'Gene', (58, 61))
100930	23056559	Since our methodology for assessing SOD activity did not distinguish between different enzyme isoforms, further studies are needed to determine the extent of altered redox enzyme activities in the blood of TP53 mutation carriers.	('SOD', 'Gene', '6647', (36, 39))	('TP53', 'Gene', '7157', (206, 210))	('TP53', 'Gene', (206, 210))	('SOD', 'Gene', (36, 39))	('carriers', 'Reg', (220, 228))	('mutation', 'Var', (211, 219))
100931	23056559	Furthermore, we observed a significant decrease in ascorbic acid content among the carriers, which was associated with an overall increase in TAS.	('carriers', 'Var', (83, 91))	('decrease', 'NegReg', (39, 47))	('TAS', 'Chemical', '-', (142, 145))	('increase', 'PosReg', (130, 138))	('TAS', 'Disease', (142, 145))	('ascorbic acid', 'Chemical', 'MESH:D001205', (51, 64))	('ascorbic acid content', 'MPA', (51, 72))
100937	23056559	In fact, biochemical and structural studies on the p.R337H mutant protein are consistent with the hypothesis that in heterozygotes, the mutant p.R337H protein may have a dominant-negative effect over the wild-type allele, thus exerting essentially the same loss-of-function effects in either a heterozygous or homozygous context.	('p.R337H', 'Var', (143, 150))	('loss-of-function', 'NegReg', (257, 273))	('p.R337H', 'Var', (51, 58))	('p.R337H', 'Mutation', 'rs121912664', (143, 150))	('p.R337H', 'Mutation', 'rs121912664', (51, 58))
100938	23056559	Structural analysis of a peptide that encompasses the oligomerization domain of p53 revealed that the mutant retains the capacity to oligomerize and thus potentially behaves like wild-type p53 at pH 7.0 but looses this property at pH 8.0 due to the incapacity of histidine to donate an intermolecular hydrogen bond, which is required for p53 dimerization.	('mutant', 'Var', (102, 108))	('p53', 'Gene', (338, 341))	('histidine', 'Chemical', 'MESH:D006639', (263, 272))	('p53', 'Gene', '7157', (189, 192))	('hydrogen', 'Chemical', 'MESH:D006859', (301, 309))	('p53', 'Gene', '7157', (338, 341))	('p53', 'Gene', (80, 83))	('oligomerize', 'MPA', (133, 144))	('p53', 'Gene', '7157', (80, 83))	('looses', 'NegReg', (207, 213))	('p53', 'Gene', (189, 192))
100940	23056559	In summary, this pilot study provides the first evidence that oxidative damage to lipids and proteins, and increased erythrocyte GPx activity, as well as increased total antioxidant status TAS, occur in carriers of a germline TP53 mutation.	('lipids', 'Chemical', 'MESH:D008055', (82, 88))	('mutation', 'Var', (231, 239))	('TAS', 'Chemical', '-', (189, 192))	('increased', 'PosReg', (107, 116))	('GPx', 'Gene', (129, 132))	('increased erythrocyte', 'Phenotype', 'HP:0001901', (107, 128))	('increased', 'PosReg', (154, 163))	('TP53', 'Gene', '7157', (226, 230))	('total antioxidant status TAS', 'MPA', (164, 192))	('TP53', 'Gene', (226, 230))	('GPx', 'Gene', '2876', (129, 132))
100942	23056559	Whether this imbalance is specific to the TP53 p.R337H mutation or is a general feature of TP53 mutation carriers, whatever the mutation type, remains to be determined.	('p.R337H', 'Var', (47, 54))	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (91, 95))	('p.R337H', 'Mutation', 'rs121912664', (47, 54))	('TP53', 'Gene', (42, 46))	('TP53', 'Gene', '7157', (91, 95))	('imbalance', 'Phenotype', 'HP:0002172', (13, 22))
100945	23056559	If confirmed in a larger series of patients, and extended to a wider panel of markers of oxidative stress, these findings may have important implications on our understanding of the mechanisms of carcinogenesis associated to the TP53 p.R337H mutation.	('p.R337H', 'Var', (234, 241))	('oxidative stress', 'Phenotype', 'HP:0025464', (89, 105))	('p.R337H', 'Mutation', 'rs121912664', (234, 241))	('carcinogenesis', 'Disease', 'MESH:D063646', (196, 210))	('TP53', 'Gene', '7157', (229, 233))	('carcinogenesis', 'Disease', (196, 210))	('patients', 'Species', '9606', (35, 43))	('TP53', 'Gene', (229, 233))
100966	33714956	Previous studies have suggested that iron metabolism dysfunction caused by FPN1 mutations or polymorphisms is involved in hemochromatosis, inflammation, and cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('FPN1', 'Gene', (75, 79))	('inflammation', 'Disease', 'MESH:D007249', (139, 151))	('mutations', 'Var', (80, 89))	('hemochromatosis', 'Disease', (122, 137))	('inflammation', 'Disease', (139, 151))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('involved', 'Reg', (110, 118))	('polymorphisms', 'Var', (93, 106))	('cancer', 'Disease', (157, 163))	('hemochromatosis', 'Disease', 'MESH:D006432', (122, 137))	('iron metabolism dysfunction', 'Disease', (37, 64))	('iron metabolism dysfunction', 'Disease', 'MESH:D019189', (37, 64))
100969	33714956	Downregulated FPN1 might facilitate cancer cell proliferation by reducing iron efflux.	('Downregulated', 'Var', (0, 13))	('facilitate', 'PosReg', (25, 35))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('reducing', 'NegReg', (65, 73))	('cancer', 'Disease', (36, 42))	('FPN1', 'Gene', (14, 18))	('iron efflux', 'MPA', (74, 85))	('iron', 'Chemical', 'MESH:D007501', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
101022	33714956	However, there was no significant association between low/high FPN1 expression and LUAD patient prognosis in the B cell, type 1 T helper cell, or type 2 T helper cell cohorts (Figure 10A, 10G, 10H).	('FPN1', 'Gene', (63, 67))	('patient', 'Species', '9606', (88, 95))	('LUAD patient', 'Disease', (83, 95))	('low/high', 'Var', (54, 62))
101026	33714956	Excess free radicals will promote gene mutations that may accelerate tumor initiation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('accelerate', 'PosReg', (58, 68))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('free radicals', 'Chemical', 'MESH:D005609', (7, 20))
101029	33714956	Many kinds of iron chelators, including deferasirox (DFX), deferoxamine (DFO) and Dp44mT, have been developed as anticancer drugs that target iron metabolism.	('Dp44mT', 'Var', (82, 88))	('deferoxamine', 'Chemical', 'MESH:D003676', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('iron', 'Chemical', 'MESH:D007501', (14, 18))	('Dp44mT', 'Chemical', 'MESH:C539263', (82, 88))	('iron', 'Chemical', 'MESH:D007501', (142, 146))	('DFX', 'Chemical', 'MESH:D000077588', (53, 56))	('DFO', 'Chemical', 'MESH:D003676', (73, 76))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('deferasirox', 'Chemical', 'MESH:D000077588', (40, 51))	('cancer', 'Disease', (117, 123))
101032	33714956	For example, sulfasalazine can cause ferroptosis in cancer cells by inhibiting xCT.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('inhibiting', 'NegReg', (68, 78))	('sulfasalazine', 'Var', (13, 26))	('ferroptosis', 'Disease', (37, 48))	('xCT', 'Gene', (79, 82))	('sulfasalazine', 'Chemical', 'MESH:D012460', (13, 26))	('xCT', 'Gene', '23657', (79, 82))	('cause', 'Reg', (31, 36))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
101034	33714956	In addition, Dp44mT could significantly reverse drug resistance to etoposide in breast cancer cells and vinblastine in epidermal carcinoma cells.	('vinblastine', 'Chemical', 'MESH:D014747', (104, 115))	('carcinoma', 'Disease', 'MESH:D009369', (129, 138))	('Dp44mT', 'Var', (13, 19))	('drug resistance to etoposide', 'MPA', (48, 76))	('Dp44mT', 'Chemical', 'MESH:C539263', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('etoposide', 'Chemical', 'MESH:D005047', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('drug resistance', 'Phenotype', 'HP:0020174', (48, 63))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('carcinoma', 'Disease', (129, 138))	('breast cancer', 'Disease', (80, 93))	('reverse', 'NegReg', (40, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
101049	33714956	Ferroportin disease, also known as type IV hereditary hemochromatosis (HH), is primarily caused by missense mutations in FPN1.	('missense mutations', 'Var', (99, 117))	('type IV hereditary hemochromatosis', 'Disease', (35, 69))	('HH', 'Disease', 'MESH:D006432', (71, 73))	('caused by', 'Reg', (89, 98))	('FPN1', 'Gene', (121, 125))	('Ferroportin disease', 'Disease', (0, 19))	('type IV hereditary hemochromatosis', 'Disease', 'MESH:D006432', (35, 69))
101051	33714956	Currently, numerous FPN1 heterozygous mutations have been identified to be associated with type IV HH.	('associated', 'Reg', (75, 85))	('HH', 'Disease', 'MESH:D006432', (99, 101))	('FPN1', 'Gene', (20, 24))	('heterozygous mutations', 'Var', (25, 47))
101052	33714956	In addition, due to the increased need for phenotypic and genetic testing, rare SLC40A1 variants have been found by chance in patients with secondary causes of hyperferritinemia.	('hyperferritinemia', 'Phenotype', 'HP:0003281', (160, 177))	('SLC40A1', 'Gene', '30061', (80, 87))	('hyperferritinemia', 'Disease', 'MESH:C538137', (160, 177))	('hyperferritinemia', 'Disease', (160, 177))	('patients', 'Species', '9606', (126, 134))	('variants', 'Var', (88, 96))	('SLC40A1', 'Gene', (80, 87))	('found', 'Reg', (107, 112))
101054	33714956	In addition, FPN1 overexpression reduces the growth of xenografted breast cancer cells in vivo.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('FPN1', 'Gene', (13, 17))	('overexpression', 'Var', (18, 32))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('reduces', 'NegReg', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
101063	33714956	Although FPN1 profoundly influences cellular iron levels and is essential for systemic iron trafficking, the biological effects of abnormal FPN1 expression on lung cancer development and the connection between FPN1 and immune infiltration remain largely unexplored.	('iron', 'Chemical', 'MESH:D007501', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('iron', 'Chemical', 'MESH:D007501', (87, 91))	('influences', 'Reg', (25, 35))	('FPN1', 'Gene', (140, 144))	('abnormal', 'Var', (131, 139))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('cellular iron levels', 'MPA', (36, 56))
101072	33714956	Recent studies have demonstrated that cancer progression and recurrence are promoted not only by genetic alterations but also by the TME.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('genetic alterations', 'Var', (97, 116))	('recurrence', 'CPA', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('promoted', 'PosReg', (76, 84))
101075	33714956	PD-1 and CTLA-4 inhibitors exhibit promising anticancer effects in multiple cancers, including NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('inhibitors', 'Var', (16, 26))	('PD-1', 'Gene', (0, 4))	('multiple cancers', 'Disease', (67, 83))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CTLA-4', 'Gene', (9, 15))	('NSCLC', 'Disease', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PD-1', 'Gene', '9825', (0, 4))	('multiple cancers', 'Disease', 'MESH:D009369', (67, 83))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('CTLA-4', 'Gene', '1493', (9, 15))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (49, 55))
101082	33714956	In addition, the loss of FPN1 obviously increases the secretion of well-known cytokines, including IL-6 and TNF-alpha, in mouse macrophages.	('mouse', 'Species', '10090', (122, 127))	('secretion of', 'MPA', (54, 66))	('FPN1', 'Gene', (25, 29))	('TNF-alpha', 'Gene', (108, 117))	('IL-6', 'Gene', (99, 103))	('IL-6', 'Gene', '16193', (99, 103))	('increases', 'PosReg', (40, 49))	('loss', 'Var', (17, 21))	('TNF-alpha', 'Gene', '21926', (108, 117))
101165	33677483	Although size alone is often used as an indicator of the risk of malignancy (4 cm is generally adopted as first cut-off), overlap between benign and malignant lesions can result in unnecessary surgery for diagnostic purposes.	('malignant lesions', 'Disease', 'MESH:D009369', (149, 166))	('malignancy', 'Disease', 'MESH:D009369', (65, 75))	('overlap', 'Var', (122, 129))	('result in', 'Reg', (171, 180))	('malignancy', 'Disease', (65, 75))	('malignant lesions', 'Disease', (149, 166))
101189	33672007	Auto-antibodies are classically associated with autoimmune diseases, where they are an integral part of diagnostic panels.	('autoimmune diseases', 'Disease', 'MESH:D001327', (48, 67))	('Auto-antibodies', 'Var', (0, 15))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (48, 67))	('autoimmune diseases', 'Disease', (48, 67))	('associated', 'Reg', (32, 42))
101191	33672007	Auto-antibodies might initially represent an epiphenomenon derived from the inflammatory environment induced by the tumor.	('men', 'Species', '9606', (96, 99))	('Auto-antibodies', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('men', 'Species', '9606', (53, 56))	('tumor', 'Disease', (116, 121))
101203	33672007	In these pathological conditions, auto-antibodies cause inflammation in joints, such as in rheumatoid arthritis (RA), or can affect the lungs, blood cells, nerves, and kidneys in systemic lupus erythematosus (SLE), or intestines, such as in inflammatory bowel disease (IBD).	('cause', 'Reg', (50, 55))	('affect', 'Reg', (125, 131))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (179, 207))	('inflammation', 'Disease', (56, 68))	('joints', 'Disease', (72, 78))	('RA', 'Disease', 'MESH:D001172', (113, 115))	('rheumatoid arthritis', 'Disease', (91, 111))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (179, 207))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (91, 111))	('RA', 'Phenotype', 'HP:0001370', (113, 115))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (241, 267))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (241, 267))	('IBD', 'Disease', 'MESH:D015212', (269, 272))	('inflammatory bowel disease', 'Disease', (241, 267))	('auto-antibodies', 'Var', (34, 49))	('systemic lupus erythematosus', 'Disease', (179, 207))	('IBD', 'Phenotype', 'HP:0002037', (269, 272))	('inflammation', 'Disease', 'MESH:D007249', (56, 68))	('joints', 'Disease', 'MESH:D007592', (72, 78))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (91, 111))	('IBD', 'Disease', (269, 272))	('SLE', 'Disease', 'MESH:D008180', (209, 212))	('SLE', 'Disease', (209, 212))	('arthritis', 'Phenotype', 'HP:0001369', (102, 111))	('SLE', 'Phenotype', 'HP:0002725', (209, 212))
101206	33672007	It is possible that pre-existing auto-antibodies could directly contribute to promote or suppress cancer progression, but they could also represent the indirect beacons of underlying immunological phenomena closely conditioning cancer development.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('men', 'Species', '9606', (202, 205))	('promote', 'PosReg', (78, 85))	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('men', 'Species', '9606', (242, 245))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', (98, 104))	('auto-antibodies', 'Var', (33, 48))	('suppress', 'NegReg', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
101212	33672007	The second class of antigens are derived from normal genes by somatic mutation, deletion, or epigenetic modifications and are called tumor-specific antigens (TSAs).	('deletion', 'Var', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('epigenetic modifications', 'Var', (93, 117))	('tumor', 'Disease', (133, 138))
101217	33672007	Polymorphisms in various genes can result in defective regulation or reduced threshold for lymphocyte activation, and environmental factors (e.g., infections, traumas) initiate or augment activation of self-reactive lymphocytes that have escaped control and that can react against auto-antigens.	('traumas', 'Disease', 'MESH:D014947', (159, 166))	('activation', 'MPA', (188, 198))	('initiate', 'Reg', (168, 176))	('reduced threshold for lymphocyte activation', 'Phenotype', 'HP:0005419', (69, 112))	('reduced', 'NegReg', (69, 76))	('men', 'Species', '9606', (183, 186))	('men', 'Species', '9606', (125, 128))	('Polymorphisms', 'Var', (0, 13))	('traumas', 'Disease', (159, 166))	('infections', 'Disease', 'MESH:D007239', (147, 157))	('self-reactive lymphocytes', 'CPA', (202, 227))	('augment', 'PosReg', (180, 187))	('defective', 'NegReg', (45, 54))	('threshold for lymphocyte activation', 'MPA', (77, 112))	('infections', 'Disease', (147, 157))	('regulation', 'MPA', (55, 65))
101223	33672007	However, there is growing evidence suggesting that B cells and antibodies can also be involved in tumor promotion and resistance to cancer therapy, with the observation that B cell depletion can suppress tumor growth in mice.	('cancer', 'Disease', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('mice', 'Species', '10090', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('depletion', 'Var', (181, 190))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', (98, 103))	('suppress', 'NegReg', (195, 203))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
101224	33672007	In ovarian cancer, the presence of CD20+ B cells has been associated with an increased survival, while in contrast, the presence of regulatory B cells (Bregs) induces immunosuppressive effects, supporting tumor growth.	('immunosuppressive effects', 'MPA', (167, 192))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CD20+ B cells', 'Var', (35, 48))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('survival', 'CPA', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('ovarian cancer', 'Disease', (3, 17))	('increased', 'PosReg', (77, 86))	('supporting', 'PosReg', (194, 204))
101244	33672007	A peptide microarray study was conducted to evaluate the production of auto-antibodies against MGMT, and the authors found a good correlation between the presence of the MGMT-2 peptide auto-antibodies and the risk of chemotherapy resistance and disease recurrence.	('chemotherapy resistance', 'CPA', (217, 240))	('MGMT', 'Gene', '4255', (170, 174))	('MGMT', 'Gene', (170, 174))	('MGMT', 'Gene', '4255', (95, 99))	('disease recurrence', 'CPA', (245, 263))	('presence', 'Var', (154, 162))	('MGMT', 'Gene', (95, 99))
101252	33672007	Diffuse gastrointestinal cancers are mainly related to abnormal expression or mutations of E-cadherin, a cell-cell adhesion protein.	('gastrointestinal cancers', 'Disease', (8, 32))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (8, 31))	('abnormal', 'Var', (55, 63))	('related', 'Reg', (44, 51))	('E-cadherin', 'Gene', (91, 101))	('E-cadherin', 'Gene', '999', (91, 101))	('mutations', 'Var', (78, 87))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (8, 32))
101262	33672007	Lymphatic node metastases and distant metastases, but not overall survival, were all significantly associated with the presence of p53 auto-antibodies.	('metastases', 'Disease', (15, 25))	('metastases', 'Disease', 'MESH:D009362', (38, 48))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('metastases', 'Disease', 'MESH:D009362', (15, 25))	('presence', 'Var', (119, 127))	('auto-antibodies', 'Protein', (135, 150))	('metastases', 'Disease', (38, 48))	('associated', 'Reg', (99, 109))
101265	33672007	A different six-antigen panel, including CTAG1B/CTAG2, DDX53, IGF2BP2, P53P53, and MAGEA3, detected 13% of gastric cancer patients.	('P53P53', 'Var', (71, 77))	('DDX53', 'Gene', '168400', (55, 60))	('CTAG1B', 'Gene', '1485', (41, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('CTAG2', 'Gene', (48, 53))	('IGF2BP2', 'Gene', '10644', (62, 69))	('CTAG2', 'Gene', '30848', (48, 53))	('MAGEA3', 'Gene', '4102', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('detected', 'Reg', (91, 99))	('patients', 'Species', '9606', (122, 130))	('IGF2BP2', 'Gene', (62, 69))	('MAGEA3', 'Gene', (83, 89))	('gastric cancer', 'Disease', (107, 121))	('CTAG1B', 'Gene', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))	('DDX53', 'Gene', (55, 60))
101276	33672007	MUC4 is an antigen that is normally not expressed in the pancreas but often appears in tumor cells and can induce the production of auto-antibodies and reactive T cells, especially against MUC4 forms carrying aberrant glycosylation patterns or mutations, or differing for alternative splicing.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (209, 231))	('MUC4', 'Gene', (189, 193))	('aberrant', 'Var', (209, 217))	('induce', 'Reg', (107, 113))	('MUC4', 'Gene', (0, 4))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutations', 'Var', (244, 253))	('MUC4', 'Gene', '4585', (189, 193))	('MUC4', 'Gene', '4585', (0, 4))
101282	33672007	In 2013, the general concept of "driver genes" was introduced to indicate mutations of about 140 genes that can lead or "drive" carcinogenesis following intragenic mutations, acting on 12 pathways and 3 functions: cell fate, cell survival, and genome maintenance.	('carcinogenesis', 'Disease', (128, 142))	('lead', 'Reg', (112, 116))	('mutations', 'Var', (74, 83))	('acting', 'Reg', (175, 181))	('drive', 'PosReg', (121, 126))	('carcinogenesis', 'Disease', 'MESH:D063646', (128, 142))	('mutations', 'Var', (164, 173))
101283	33672007	A typical tumor contains two to eight driver mutations, while all the others do not confer growth advantage.	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
101291	33672007	Importantly, there was a higher cumulative survival rate in patients with serum anti-NY-ESO-1 positivity than in those with serum negativity among the patients with stage III or IV.	('NY-ESO-1', 'Gene', (85, 93))	('cumulative survival rate', 'CPA', (32, 56))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (151, 159))	('NY-ESO-1', 'Gene', '1485', (85, 93))	('positivity', 'Var', (94, 104))	('higher', 'PosReg', (25, 31))
101299	33672007	The current most specific and reliable biomarkers of esophageal cells' malignant transformation are aberrant expression of p53, reported in 50-60% of patients; moreover, early stage dysplasia is often associated with high or low expression of p53.	('dysplasia', 'Disease', (182, 191))	('low', 'NegReg', (225, 228))	('high', 'Var', (217, 221))	('patients', 'Species', '9606', (150, 158))	('p53', 'Gene', (123, 126))	('p53', 'Gene', (243, 246))	('p53', 'Gene', '7157', (243, 246))	('dysplasia', 'Disease', 'MESH:C536170', (182, 191))	('p53', 'Gene', '7157', (123, 126))	('expression', 'MPA', (229, 239))
101302	33672007	Monitoring of auto-antibodies against p53 in post-surgical patients is predictive of residual tumor cells and recurrence.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('auto-antibodies', 'Var', (14, 29))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('patients', 'Species', '9606', (59, 67))
101346	33672007	Early detection (within 30 days) of more than one auto-antibody type among anti-nuclear antigens (ANAs), anti-extractable nuclear antigens (ENAs), and anti-smooth cell antigens (ASMAs), in patients treated with nivolumab-based salvage therapy, associated with prolonged progression-free survival.	('anti-extractable', 'Var', (105, 121))	('prolonged', 'PosReg', (260, 269))	('nivolumab', 'Chemical', 'MESH:D000077594', (211, 220))	('anti-nuclear antigens', 'Protein', (75, 96))	('progression-free survival', 'CPA', (270, 295))	('patients', 'Species', '9606', (189, 197))
101348	33672007	Some of these proteins (CT47A, PAGE3, VCX, MAGEB1, LIN28B, or C12orf54) were proven to induce the production of auto-antibodies, although in a limited number of cases.	('production', 'MPA', (98, 108))	('VCX', 'Gene', '26609', (38, 41))	('PAGE3', 'Gene', (31, 36))	('LIN28B', 'Gene', '389421', (51, 57))	('C12orf54', 'Gene', (62, 70))	('CT47A', 'Var', (24, 29))	('VCX', 'Gene', (38, 41))	('CT47A', 'CellLine', 'CVCL:L675', (24, 29))	('auto-antibodies', 'MPA', (112, 127))	('MAGEB1', 'Gene', '4112', (43, 49))	('MAGEB1', 'Gene', (43, 49))	('PA', 'Phenotype', 'HP:0003765', (31, 33))	('induce', 'PosReg', (87, 93))	('PAGE3', 'Gene', '139793', (31, 36))	('C12orf54', 'Gene', '121273', (62, 70))	('LIN28B', 'Gene', (51, 57))
101356	33672007	Out of the detected proteins, the highest score was for PI3K and p53.	('PI3K', 'Var', (56, 60))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))
101359	33672007	Serum p53 auto-antibodies have also been shown to be associated with aggressiveness of breast cancer.	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('auto-antibodies', 'Var', (10, 25))	('aggressiveness of breast cancer', 'Disease', 'MESH:D001943', (69, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('aggressiveness of breast cancer', 'Disease', (69, 100))	('associated', 'Reg', (53, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('aggressiveness', 'Phenotype', 'HP:0000718', (69, 83))
101367	33672007	Additionally, FATE1 could be relevant also in other tumors as it has been reported that its silencing increased sensitivity of the NCI-H1155 NSLC cell line to paclitaxel and reduced the viability of a variety of other cancer cell lines.	('FATE1', 'Gene', '89885', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('sensitivity', 'MPA', (112, 123))	('FATE1', 'Gene', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('paclitaxel', 'Chemical', 'MESH:D017239', (159, 169))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (218, 224))	('tumors', 'Disease', (52, 58))	('silencing', 'Var', (92, 101))	('NCI-H1155 NSLC', 'CellLine', 'CVCL:1456', (131, 145))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('viability', 'CPA', (186, 195))	('increased', 'PosReg', (102, 111))	('reduced', 'NegReg', (174, 181))	('LC', 'Phenotype', 'HP:0100526', (143, 145))
101411	33672007	A combination of ELISAs for anti-CA15-3, anti-CEA, and anti-CA19-9 reliably discriminated CINs from normal cases, and cancer from normal cases, suggesting that this combination assay could be useful for primary screening of cervical cancer.	('cancer', 'Disease', (118, 124))	('CA15-3', 'Gene', (33, 39))	('discriminated', 'Reg', (76, 89))	('CA15-3', 'Gene', '4582', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('CEA', 'Gene', (46, 49))	('CINs', 'Disease', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('CEA', 'Gene', '1084', (46, 49))	('CA19-9', 'Chemical', 'MESH:C086528', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('anti-CA19-9', 'Var', (55, 66))
101415	33672007	Several cancer progression subclassifications (using three stages and two grades) have been introduced to define the chance of recurrence, which, in more progressive cases, is very high (50-70%) and will eventually lead to a muscle-invasive disease (MIBC) variant that is associated with a very poor prognosis.	('muscle-invasive disease', 'Disease', 'MESH:D009362', (225, 248))	('cancer', 'Disease', (8, 14))	('lead to', 'Reg', (215, 222))	('MIBC', 'Chemical', '-', (250, 254))	('variant', 'Var', (256, 263))	('muscle-invasive disease', 'Disease', (225, 248))	('BC', 'Phenotype', 'HP:0009725', (252, 254))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
101430	33672007	have described the association of detection of Kelch-like protein 11 auto-antibodies to testicular seminoma in patients with paraneoplastic encephalitis.	('auto-antibodies', 'Var', (69, 84))	('paraneoplastic encephalitis', 'Disease', (125, 152))	('Kelch-like protein 11', 'Gene', '55175', (47, 68))	('encephalitis', 'Phenotype', 'HP:0002383', (140, 152))	('testicular seminoma', 'Phenotype', 'HP:0100617', (88, 107))	('paraneoplastic encephalitis', 'Disease', 'MESH:D010257', (125, 152))	('testicular seminoma', 'Disease', (88, 107))	('testicular seminoma', 'Disease', 'MESH:D018239', (88, 107))	('Kelch-like protein 11', 'Gene', (47, 68))	('patients', 'Species', '9606', (111, 119))
101437	33672007	Interestingly, the detected levels of anti-double strand DNA (dsDNA) and anti-ssDNA were relatively low compared to another study by Swissa et al., who showed high levels in 23.8% NHL patients as well as anti-RNP and anti-SM antibodies that were not detected in most of the control group.	('NHL', 'Disease', (180, 183))	('anti-double', 'Var', (38, 49))	('patients', 'Species', '9606', (184, 192))
101444	33672007	Different from lymphomas and many other cancers, melanomas are often characterized by a very high mutational load, which increases the likelihood of this type of tumor generating neoantigens.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('tumor', 'Disease', (162, 167))	('neoantigens', 'MPA', (179, 190))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('increases', 'PosReg', (121, 130))	('lymphomas', 'Disease', (15, 24))	('cancers', 'Disease', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mutational load', 'Var', (98, 113))	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('melanomas', 'Disease', 'MESH:D008545', (49, 58))	('melanomas', 'Disease', (49, 58))	('generating', 'Reg', (168, 178))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('lymphomas', 'Disease', 'MESH:D008223', (15, 24))	('lymphomas', 'Phenotype', 'HP:0002665', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
101445	33672007	In melanomas, the prognostic value of the mutational load has been investigated and was found to be associated with the clinical benefits of immunotherapy such as the adoptive T cell therapy (ACT), which has shown remarkable results in clinical trials in certain patient groups while failing in others.	('patient', 'Species', '9606', (263, 270))	('mutational load', 'Var', (42, 57))	('melanomas', 'Disease', (3, 12))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanomas', 'Phenotype', 'HP:0002861', (3, 12))	('melanomas', 'Disease', 'MESH:D008545', (3, 12))
101447	33672007	This also aligns well with the observation that tumors with a high mutational load respond better to treatment with immune checkpoint inhibitors in melanoma and lung cancer, and is indicative of an increased production of neoantigens.	('better', 'PosReg', (91, 97))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('respond', 'MPA', (83, 90))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('lung cancer', 'Disease', (161, 172))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('high mutational load', 'Var', (62, 82))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))	('men', 'Species', '9606', (106, 109))
101460	33672007	There are several paraneoplastic syndromes associated to auto-antibodies.	('paraneoplastic syndromes', 'Disease', 'MESH:D010257', (18, 42))	('paraneoplastic syndromes', 'Disease', (18, 42))	('associated', 'Reg', (43, 53))	('auto-antibodies', 'Var', (57, 72))
101467	33672007	Thus, while mutations of some common antigens, such as p53, have been well documented, much less is known about the mutational status of the newly identified auto-antigens, leaving open the question of their true nature.	('men', 'Species', '9606', (79, 82))	('mutations', 'Var', (12, 21))	('p53', 'Gene', '7157', (55, 58))	('p53', 'Gene', (55, 58))
101480	33672007	Auto-antibodies might initially represent a simple epiphenomenon or a by-product of the inflammatory microenvironment but could become a main player in the tumor progression, conditioning its evolution and outcome.	('Auto-antibodies', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('men', 'Species', '9606', (113, 116))	('tumor', 'Disease', (156, 161))	('men', 'Species', '9606', (59, 62))
101500	31734779	For example, the implementation of KRAS mutation status as a companion test to exclude patients unlikely to benefit from such therapies has been estimated to a net cost of $7500-12,400 per patient in the United States and $3900-9600 per patient in Germany, with equivalent clinical outcomes.	('mutation', 'Var', (40, 48))	('KRAS', 'Gene', (35, 39))	('patient', 'Species', '9606', (237, 244))	('patient', 'Species', '9606', (189, 196))	('KRAS', 'Gene', '3845', (35, 39))	('patient', 'Species', '9606', (87, 94))	('patients', 'Species', '9606', (87, 95))
101553	31734779	In early prediction of rapidly progressive well differentiated NENs, 18F-FDG PET/CT was found to be more accurate than Ki67.	('18F-FDG', 'Chemical', 'MESH:D019788', (69, 76))	('well differentiated NENs', 'Disease', (43, 67))	('18F-FDG PET/CT', 'Var', (69, 83))
101567	31734779	A patient with significantly positive 18F-FDG PET/CT will comparatively have a shorter PFS after PRRT than a patient with negative 18F-FDG imaging, but this does not necessarily mean that the patient would not derive benefit from PRRT.	('patient', 'Species', '9606', (192, 199))	('patient', 'Species', '9606', (109, 116))	('shorter', 'NegReg', (79, 86))	('18F-FDG', 'Chemical', 'MESH:D019788', (38, 45))	('PFS', 'MPA', (87, 90))	('18F-FDG PET/CT', 'Var', (38, 52))	('18F-FDG', 'Chemical', 'MESH:D019788', (131, 138))	('patient', 'Species', '9606', (2, 9))
101576	31734779	It has been recently reported that diagnostic Iodine-124 PET/CT may be highly accurate in predicting findings on post-therapy RAI scanning and this method was shown to have a high prognostic power in patients with DTC.	('patients', 'Species', '9606', (200, 208))	('Iodine-124 PET/CT', 'Var', (46, 63))	('RAI', 'Chemical', 'MESH:C000614965', (126, 129))	('Iodine', 'Chemical', 'MESH:D007455', (46, 52))	('DTC', 'Disease', (214, 217))	('DTC', 'Chemical', '-', (214, 217))
101581	31734779	Overall, based on the available literature, there exists significant data suggesting the prognostic role of 18F-FDG PET/CT in DTC patients both after primary surgery and at restaging, as 18F-FDG PET result was found to be an independent prognostic factor by several studies.	('DTC', 'Chemical', '-', (126, 129))	('18F-FDG', 'Var', (187, 194))	('18F-FDG', 'Chemical', 'MESH:D019788', (108, 115))	('patients', 'Species', '9606', (130, 138))	('DTC', 'Disease', (126, 129))	('18F-FDG', 'Chemical', 'MESH:D019788', (187, 194))
101591	31734779	BRAFV600E mutation and high 18F-FDG uptake are considered as potential prognostic factors in patients with papillary thyroid cancer (PTC).	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (107, 131))	('thyroid cancer', 'Phenotype', 'HP:0002890', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('18F-FDG', 'Chemical', 'MESH:D019788', (28, 35))	('papillary thyroid cancer', 'Disease', (107, 131))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (107, 131))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('patients', 'Species', '9606', (93, 101))	('BRAFV600E', 'Var', (0, 9))
101592	31734779	Interestingly, the presence of the BRAFV600E mutation has been independently associated with high 18F-FDG uptake on preoperative PET/CT in patients with PTC.	('high 18F-FDG uptake', 'MPA', (93, 112))	('patients', 'Species', '9606', (139, 147))	('18F-FDG', 'Chemical', 'MESH:D019788', (98, 105))	('BRAFV600E', 'Var', (35, 44))	('BRAFV600E', 'Mutation', 'rs113488022', (35, 44))
101593	31734779	In summary, based on current evidences, the role of 18FFDG PET/CT is primarily supported in patients with high-risk DTC with elevated serum thyroglobulin under stimulation (generally > 10 ng/mL) after primary treatment and negative RAI imaging.	('elevated', 'PosReg', (125, 133))	('stimulation', 'PosReg', (160, 171))	('thyroglobulin', 'Gene', '7038', (140, 153))	('thyroglobulin', 'Gene', (140, 153))	('patients', 'Species', '9606', (92, 100))	('elevated serum thyroglobulin', 'Phenotype', 'HP:0025484', (125, 153))	('18FFDG', 'Chemical', 'MESH:D019788', (52, 58))	('DTC', 'Chemical', '-', (116, 119))	('RAI', 'Chemical', 'MESH:C000614965', (232, 235))	('18FFDG', 'Var', (52, 58))
101616	31734779	PHEO/PGLs with an underlying SDHB mutation are associated with a higher risk of aggressive behavior leading to development of the metastatic disease.	('SDHB', 'Gene', '6390', (29, 33))	('metastatic disease', 'CPA', (130, 148))	('mutation', 'Var', (34, 42))	('SDHB', 'Gene', (29, 33))	('aggressive behavior', 'Disease', (80, 99))	('aggressive behavior', 'Phenotype', 'HP:0000718', (80, 99))
101617	31734779	Importantly, mutation of any of the SDH genes leads to the disruption of the TCA cycle with subsequent accumulation of succinate.	('TCA', 'Chemical', 'MESH:D014238', (77, 80))	('TCA cycle', 'MPA', (77, 86))	('mutation', 'Var', (13, 21))	('disruption', 'MPA', (59, 69))	('succinate', 'Chemical', 'MESH:D019802', (119, 128))	('accumulation', 'PosReg', (103, 115))	('leads to', 'Reg', (46, 54))	('SDH', 'Gene', (36, 39))
101628	31734779	In relapsing MTC, 18F-FDOPA PET/CT seems to have a predictive and prognostic value, as well as 18F-FDG PET/CT (in association with calcitonin doubling time) in patients with more aggressive disease.	('18F-FDG', 'Chemical', 'MESH:D019788', (95, 102))	('patients', 'Species', '9606', (160, 168))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (18, 27))	('calcitonin doubling', 'Phenotype', 'HP:0003528', (131, 150))	('18F-FDG PET/CT', 'Var', (95, 109))	('aggressive disease', 'Disease', 'MESH:D001523', (179, 197))	('relapsing MTC', 'Disease', (3, 16))	('aggressive disease', 'Disease', (179, 197))
101734	31683663	investigated the effects of association between mitotane and statins in NCI-H295R human ACC cells and found that rosuvastatin potentiated the effects of mitotane which may provide novel therapeutic strategies for ACC.	('rosuvastatin', 'Var', (113, 125))	('mitotane', 'Chemical', 'MESH:D008939', (153, 161))	('rosuvastatin', 'Chemical', 'MESH:D000068718', (113, 125))	('mitotane', 'Chemical', 'MESH:D008939', (48, 56))	('ACC', 'Disease', (213, 216))	('potentiated', 'PosReg', (126, 137))	('effects', 'MPA', (142, 149))	('NCI-H295R', 'CellLine', 'CVCL:0458', (72, 81))	('mitotane', 'MPA', (153, 161))	('human', 'Species', '9606', (82, 87))
101746	31683663	hypothesized that mitotane metabolism may be affected by autoinduction and modelled this by a linear enzyme autoinduction process.	('autoinduction', 'Var', (57, 70))	('mitotane', 'Chemical', 'MESH:D008939', (18, 26))	('affected', 'Reg', (45, 53))	('mitotane metabolism', 'MPA', (18, 37))
101765	31683663	showed differences on plasma concentrations between GG and GT/TT patients concerning the 516 polymorphism in the CYP2B6 gene (rs3745274 (G516T)) Regarding pharmacokinetics characteristics of mitotane as previously cited, we can hypothesize that subpopulations are to be considered concerning Cl.	('rs3745274', 'Mutation', 'rs3745274', (126, 135))	('differences', 'Reg', (7, 18))	('CYP2B6', 'Gene', (113, 119))	('CYP2B6', 'Gene', '1555', (113, 119))	('patients', 'Species', '9606', (65, 73))	('rs3745274', 'Var', (126, 135))	('G516T', 'Mutation', 'rs3745274', (137, 142))	('mitotane', 'Chemical', 'MESH:D008939', (191, 199))
101962	30555465	In most cancer types [e.g., acute myeloid leukemia (AML), adrenocortical carcinoma (ACC), breast cancer, Ewing sarcoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer (NSCLC), prostate cancer, and squamous cell carcinoma of the skin] chemerin is downregulated, likely via hypermethylation of RARRES2 (Table 1).	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (58, 82))	('RARRES2', 'Gene', (308, 315))	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('AML', 'Phenotype', 'HP:0004808', (52, 55))	('cancer', 'Disease', (201, 207))	('AML', 'Disease', (52, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('non-small cell lung cancer', 'Disease', (156, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('RARRES2', 'Gene', '5919', (308, 315))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('Ewing sarcoma', 'Disease', (105, 118))	('prostate cancer', 'Disease', 'MESH:D011471', (192, 207))	('prostate cancer', 'Phenotype', 'HP:0012125', (192, 207))	('hepatocellular carcinoma', 'Disease', (120, 144))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (58, 82))	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', (97, 103))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('downregulated', 'NegReg', (262, 275))	('adrenocortical carcinoma', 'Disease', (58, 82))	('prostate cancer', 'Disease', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('acute myeloid leukemia', 'Disease', (28, 50))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (156, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('squamous cell carcinoma of the skin', 'Phenotype', 'HP:0006739', (213, 248))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (160, 182))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (120, 144))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (28, 50))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (156, 182))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('squamous cell carcinoma of the skin', 'Disease', (213, 248))	('NSCLC', 'Disease', (184, 189))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (28, 50))	('hypermethylation', 'Var', (288, 304))	('breast cancer', 'Disease', (90, 103))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (34, 50))	('squamous cell carcinoma of the skin', 'Disease', 'MESH:D002294', (213, 248))	('cancer', 'Disease', (176, 182))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (120, 144))	('AML', 'Disease', 'MESH:D015470', (52, 55))
101971	30555465	Moreover, multivariate analysis on parameters such as age, various gene mutations, chemerin expression, karyotypic classifications, and white blood cell count verified that chemerin was independently able to prognosticate AML patients, while univariate analysis of chemerin expression levels showed that high chemerin expression was associated with positive prognosis.	('mutations', 'Var', (72, 81))	('AML', 'Disease', 'MESH:D015470', (222, 225))	('AML', 'Phenotype', 'HP:0004808', (222, 225))	('patients', 'Species', '9606', (226, 234))	('AML', 'Disease', (222, 225))
101978	30555465	Chemerin's role as a chemoattractant, in recruiting immune cells to sites of inflammation, has already been well documented; for instance, chemerin has been shown to suppress neoplasia by eliciting natural killer cells to the tumor site in melanoma.	('eliciting', 'PosReg', (188, 197))	('neoplasia', 'Phenotype', 'HP:0002664', (175, 184))	('chemerin', 'Var', (139, 147))	('suppress', 'NegReg', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (240, 248))	('Chemerin', 'Gene', (0, 8))	('inflammation', 'Disease', 'MESH:D007249', (77, 89))	('neoplasia', 'Disease', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('inflammation', 'Disease', (77, 89))	('melanoma', 'Disease', (240, 248))	('Chemerin', 'Gene', '5919', (0, 8))	('neoplasia', 'Disease', 'MESH:D009369', (175, 184))	('tumor', 'Disease', (226, 231))
101984	30555465	Specifically, the silenced RARRES2 gene in ACC tumors was characterized by hypermethylation at five CpG sites.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('hypermethylation', 'Var', (75, 91))	('RARRES2', 'Gene', (27, 34))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('RARRES2', 'Gene', '5919', (27, 34))
101987	30555465	Thus, hypermethylation of RARRES2 is likely a common method of gene silencing in tumors where chemerin is downregulated].	('RARRES2', 'Gene', (26, 33))	('tumors', 'Disease', (81, 87))	('hypermethylation', 'Var', (6, 22))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('RARRES2', 'Gene', '5919', (26, 33))	('silencing', 'NegReg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
101990	30555465	The phosphorylated sites were identified as Ser33, Ser37, and Thr41.	('Thr41', 'Var', (62, 67))	('Ser33', 'Chemical', '-', (44, 49))	('Ser33', 'Var', (44, 49))	('Ser37', 'Chemical', '-', (51, 56))	('Ser37', 'Var', (51, 56))	('Thr41', 'Chemical', '-', (62, 67))
101997	30555465	beta-catenin (CTNNB1), a proto-oncogene, is frequently mutated in ACC, resulting in constitutive activation of the Wnt/beta-catenin pathway.	('Wnt/beta-catenin pathway', 'Pathway', (115, 139))	('activation', 'PosReg', (97, 107))	('CTNNB1', 'Gene', '1499', (14, 20))	('mutated', 'Var', (55, 62))	('CTNNB1', 'Gene', (14, 20))	('ACC', 'Phenotype', 'HP:0006744', (66, 69))
102000	30555465	Aberrant activation of the Wnt/beta-catenin pathway is common in many other cancer types, such as breast cancer, lung cancer, hepatocellular carcinoma, and squamous cell carcinoma.	('cancer', 'Disease', (105, 111))	('squamous cell carcinoma', 'Disease', (156, 179))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (126, 150))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cancer', 'Disease', (118, 124))	('hepatocellular carcinoma', 'Disease', (126, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (76, 82))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('lung cancer', 'Disease', (113, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('Wnt/beta-catenin pathway', 'Pathway', (27, 51))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (126, 150))
102038	30555465	VEGF, IL-6, and MMP-7 have all been associated with enhanced tumor invasiveness in gastric cancer, while high expression of VEGF and IL-6 have been shown to stimulate metastasis of malignant cells and indicate poor clinical outcomes in gastric cancer patients, suggesting a potential impact of chemerin in this setting.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('IL-6', 'Gene', (133, 137))	('IL-6', 'Gene', (6, 10))	('patients', 'Species', '9606', (251, 259))	('high expression', 'Var', (105, 120))	('tumor invasiveness', 'Disease', 'MESH:D009369', (61, 79))	('metastasis of malignant cells', 'CPA', (167, 196))	('gastric cancer', 'Disease', (236, 250))	('stimulate', 'PosReg', (157, 166))	('gastric cancer', 'Disease', (83, 97))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MMP-7', 'Gene', (16, 21))	('VEGF', 'Gene', '7422', (0, 4))	('gastric cancer', 'Disease', 'MESH:D013274', (236, 250))	('tumor invasiveness', 'Disease', (61, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('VEGF', 'Gene', (0, 4))	('MMP-7', 'Gene', '4316', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('enhanced', 'PosReg', (52, 60))	('VEGF', 'Gene', '7422', (124, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('VEGF', 'Gene', (124, 128))
102049	30555465	First, one study found that chem158 K, a bioactive isoform of chemerin, was elevated in the cerebrospinal fluid of patients with malignant glioblastoma.	('patients', 'Species', '9606', (115, 123))	('elevated', 'PosReg', (76, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('malignant glioblastoma', 'Disease', 'MESH:D005909', (129, 151))	('malignant glioblastoma', 'Disease', (129, 151))	('chem158 K', 'Var', (28, 37))
102052	30555465	Experimental results determined that the addition of chem157S, another bioactive isoform of chemerin, to U-87 MG cells resulted in a transient, dose-dependent increase of intracellular calcium, indicating that chemerin could instigate intracellular signaling in U-87 MG cells.	('intracellular calcium', 'MPA', (171, 192))	('U-87 MG', 'CellLine', 'CVCL:0022', (105, 112))	('instigate', 'Reg', (225, 234))	('chem157S', 'Var', (53, 61))	('increase of intracellular calcium', 'Phenotype', 'HP:0003575', (159, 192))	('U-87 MG', 'CellLine', 'CVCL:0022', (262, 269))	('calcium', 'Chemical', 'MESH:D002118', (185, 192))	('increase', 'PosReg', (159, 167))
102073	30555465	Chemerin knockdown, in turn, resulted in increased migratory ability and invasiveness.	('invasiveness', 'CPA', (73, 85))	('increased', 'PosReg', (41, 50))	('knockdown', 'Var', (9, 18))	('Chemerin', 'Gene', (0, 8))	('migratory ability', 'CPA', (51, 68))	('Chemerin', 'Gene', '5919', (0, 8))
102096	30555465	Additionally, high expression of chemerin was shown to be associated with better outcomes for patients in two clinical studies, demonstrating chemerin's potential for therapeutic intervention in melanoma.	('patients', 'Species', '9606', (94, 102))	('high expression', 'Var', (14, 29))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))
102120	30555465	Thus, the results of both in vitro and in vivo experiments indicated that targeting chemerin/CMKLR1 could potentially elicit antitumor effects in clinical settings.	('chemerin/CMKLR1', 'Gene', (84, 99))	('tumor', 'Disease', (129, 134))	('targeting', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('elicit', 'Reg', (118, 124))
102143	30555465	In syngeneic C57BL6 mice implanted with prochemerin-expressing LLC grafts, tumor formation was impeded by prochemerin expression.	('prochemerin', 'Var', (106, 117))	('impeded', 'NegReg', (95, 102))	('mice', 'Species', '10090', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
102178	30555465	In some cases, cancers may silence RARRES2 via hypermethylation to evade immune surveillance.	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('silence', 'NegReg', (27, 34))	('RARRES2', 'Gene', (35, 42))	('RARRES2', 'Gene', '5919', (35, 42))	('hypermethylation', 'Var', (47, 63))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
102181	30555465	Importantly, for cases in which silencing of RARRES2 has been reported, the restoration and/or forced overexpression of chemerin in the microtumor environment may incite compelling antitumor effects, indicating new avenues of research for chemerin in cancer.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('incite', 'NegReg', (163, 169))	('RARRES2', 'Gene', (45, 52))	('overexpression', 'PosReg', (102, 116))	('tumor', 'Disease', (141, 146))	('silencing', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Disease', (251, 257))	('RARRES2', 'Gene', '5919', (45, 52))
102255	28250426	Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas Somatic mutations in protein kinase A catalytic alpha subunit (PRKACA) were found to be causative for 30-40% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active.	('adenomas', 'Disease', 'MESH:D000236', (101, 109))	('adenomas', 'Disease', (241, 249))	('CPA', 'Chemical', '-', (251, 254))	('cortisol', 'Chemical', 'MESH:D006854', (222, 230))	('adenomas', 'Disease', (101, 109))	('mutations', 'Var', (118, 127))	('PRKACA', 'Gene', '5566', (173, 179))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (86, 109))	('protein kinase A catalytic alpha subunit', 'Gene', '5566', (131, 171))	('adrenocortical adenomas', 'Disease', (86, 109))	('adenomas', 'Disease', 'MESH:D000236', (241, 249))	('PRKACA', 'Gene', (173, 179))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (86, 109))	('causative', 'Reg', (198, 207))	('protein kinase A catalytic alpha subunit', 'Gene', (131, 171))
102258	28250426	In this study, we linked for the first time the loss of RIIbeta protein levels to the PRKACA mutation status and found the down-regulation of RIIbeta to arise post-transcriptionally.	('loss', 'NegReg', (48, 52))	('RIIbeta', 'Gene', '5577', (142, 149))	('RIIbeta', 'Gene', (142, 149))	('RIIbeta', 'Gene', (56, 63))	('RIIbeta', 'Gene', '5577', (56, 63))	('PRKACA', 'Gene', (86, 92))	('down-regulation', 'NegReg', (123, 138))	('PRKACA', 'Gene', '5566', (86, 92))	('mutation', 'Var', (93, 101))
102263	28250426	Also other components of cAMP/PKA signalling were often shown to be either mutated, such as the stimulating G protein (Gas) which is encoded by the GNAS gene or deregulated in different endocrine disorders indicating the major role played by this pathway in hormonal secretion functions.	('endocrine disorders', 'Disease', (186, 205))	('GNAS', 'Gene', '2778', (148, 152))	('Gas', 'Gene', (119, 122))	('mutated', 'Var', (75, 82))	('endocrine disorders', 'Disease', 'MESH:D004700', (186, 205))	('cAMP', 'Chemical', 'MESH:D000242', (25, 29))	('Gas', 'Gene', '79447', (119, 122))	('GNAS', 'Gene', (148, 152))	('endocrine disorders', 'Phenotype', 'HP:0000818', (186, 205))	('deregulated', 'Reg', (161, 172))
102269	28250426	Interestingly, the PRKACA mutations identified in CPA are situated at the interface between the catalytic subunit and the regulatory subunits.	('PRKACA', 'Gene', '5566', (19, 25))	('CPA', 'Gene', (50, 53))	('mutations', 'Var', (26, 35))	('CPA', 'Chemical', '-', (50, 53))	('PRKACA', 'Gene', (19, 25))
102270	28250426	By functional characterization of the initially identified L206R substitution and 199-200 insW insertion, it was shown that the binding of the regulatory subunits to the catalytic subunits is affected by these mutations, rendering PKA constitutively active.	('mutations', 'Var', (210, 219))	('affected', 'Reg', (192, 200))	('L206R', 'Mutation', 'rs386352352', (59, 64))	('L206R', 'Var', (59, 64))	('binding', 'Interaction', (128, 135))	('199-200 insW', 'Mutation', 'p.199_200insW', (82, 94))
102274	28250426	Here we investigate if the PRKACA mutations leading to hyperactivity of PKA signalling in CPA are associated with the loss of RIIbeta protein levels and demonstrate a clear connection between RIIbeta protein levels and the mutation status of PRKACA.	('hyperactivity', 'Disease', (55, 68))	('hyperactivity', 'Phenotype', 'HP:0000752', (55, 68))	('PRKACA', 'Gene', (27, 33))	('CPA', 'Chemical', '-', (90, 93))	('PRKACA', 'Gene', '5566', (242, 248))	('loss', 'NegReg', (118, 122))	('PRKACA', 'Gene', '5566', (27, 33))	('hyperactivity', 'Disease', 'MESH:D006948', (55, 68))	('PRKACA', 'Gene', (242, 248))	('mutations', 'Var', (34, 43))	('RIIbeta', 'Gene', '5577', (192, 199))	('RIIbeta', 'Gene', (192, 199))	('RIIbeta', 'Gene', '5577', (126, 133))	('RIIbeta', 'Gene', (126, 133))	('PKA signalling', 'MPA', (72, 86))
102280	28250426	In addition, GNAS mutation status was determined using exome sequencing (CPAGNASmut n = 7, CPAGNASWT n = 26) or Sanger Sequencing of the hotspot region between amino acids R201 and Q227 (CPAGNASWT n = 5).	('GNAS', 'Gene', (13, 17))	('GNAS', 'Gene', '2778', (94, 98))	('GNAS', 'Gene', '2778', (190, 194))	('GNAS', 'Gene', '2778', (76, 80))	('GNAS', 'Gene', '2778', (13, 17))	('Q227', 'Var', (181, 185))	('GNAS', 'Gene', (94, 98))	('GNAS', 'Gene', (190, 194))	('GNAS', 'Gene', (76, 80))
102295	28250426	qRT-PCR was performed using pre-designed Taqman gene expression probes (Thermo Fischer Scientific) for PRKACA (Hs00427274_m1) and all PKA regulatory subunits (PRRKAR1A: Hs00267597_m1, PRKAR2A: Hs00177760_m1; PRKAR1B: Hs00406762_m1; PRKAR2B: Hs00176966_m1).	('PRKAR2B', 'Gene', '5577', (232, 239))	('Hs00406762_m1', 'Var', (217, 230))	('PRKAR2A', 'Gene', '5576', (184, 191))	('PRKAR2A', 'Gene', (184, 191))	('PRKACA', 'Gene', (103, 109))	('Hs00427274_m1', 'Var', (111, 124))	('PRKACA', 'Gene', '5566', (103, 109))	('PRKAR1B', 'Gene', (208, 215))	('Hs00176966_m1', 'Var', (241, 254))	('PRKAR2B', 'Gene', (232, 239))	('PRKAR1B', 'Gene', '5575', (208, 215))
70211	28250426	Endogenously expressed beta-actin (Hs9999903_m1) was used for normalization.	('beta-actin', 'Gene', (23, 33))	('Hs9999903_m1', 'Var', (35, 47))	('beta-actin', 'Gene', '728378', (23, 33))
102304	28250426	Chromogenic immunohistochemistry staining on FFPE tissue from CPA (with mutated (n = 18) and WT (n = 20) PRKACA), aldosterone producing adenoma = APA (n = 20), EIA (n = 25) and ACC (n = 33) was performed for all PKA regulatory subunits and the catalytic subunit alpha.	('PRKACA', 'Gene', '5566', (105, 111))	('mutated', 'Var', (72, 79))	('adenoma', 'Disease', (136, 143))	('CPA', 'Chemical', '-', (62, 65))	('adenoma', 'Disease', 'MESH:D000236', (136, 143))	('PRKACA', 'Gene', (105, 111))	('aldosterone', 'Chemical', 'MESH:D000450', (114, 125))
102313	28250426	A few PRKACA mutated samples showed a strong or normal expression of RIIbeta, but they did not harbour the most common, L206R mutation, but other mutations in PRKACA (p.E32V: green, p.245_248.del: red, see Fig.	('p.245_248.del', 'Mutation', 'p.245_248del', (182, 195))	('p.E32V: green', 'Var', (167, 180))	('RIIbeta', 'Gene', '5577', (69, 76))	('RIIbeta', 'Gene', (69, 76))	('L206R', 'Mutation', 'rs386352352', (120, 125))	('PRKACA', 'Gene', (6, 12))	('PRKACA', 'Gene', (159, 165))	('PRKACA', 'Gene', '5566', (6, 12))	('p.E32V', 'Mutation', 'p.E32V', (167, 173))	('PRKACA', 'Gene', '5566', (159, 165))	('p.245_248.del', 'Var', (182, 195))
102318	28250426	The only exception was the recently detected p.245_248del mutation, which was found in a patient with autonomous cortisol secretion but no overt Cushing syndrome (upper blot).	('cortisol', 'Chemical', 'MESH:D006854', (113, 121))	('patient', 'Species', '9606', (89, 96))	('p.245_248del', 'Mutation', 'p.245_248del', (45, 57))	('Cushing syndrome', 'Disease', (145, 161))	('Cushing syndrome', 'Disease', 'MESH:D003480', (145, 161))	('p.245_248del', 'Var', (45, 57))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (145, 161))
102319	28250426	Since approximately 10% of CPA harbour activating somatic mutations in the GNAS gene, leading to increased PKA signalling, we investigated if GNAS mutations also affect the stability of PKA regulatory subunits.	('mutations', 'Var', (58, 67))	('CPA', 'Chemical', '-', (27, 30))	('PKA signalling', 'MPA', (107, 121))	('GNAS', 'Gene', '2778', (142, 146))	('increased', 'PosReg', (97, 106))	('GNAS', 'Gene', (75, 79))	('affect', 'Reg', (162, 168))	('GNAS', 'Gene', '2778', (75, 79))	('GNAS', 'Gene', (142, 146))	('activating', 'PosReg', (39, 49))
102321	28250426	However, mutations in the GNAS gene did not point to any degradation of the PKA regulatory subunits in CPA (Supplementary Fig.	('GNAS', 'Gene', (26, 30))	('mutations', 'Var', (9, 18))	('rad', 'Gene', '6236', (60, 63))	('CPA', 'Chemical', '-', (103, 106))	('rad', 'Gene', (60, 63))	('GNAS', 'Gene', '2778', (26, 30))
102328	28250426	In PRKACA L206Rmut CPA, RIIbeta staining was not detectable and there was no indication that it changed location in these cells (Fig.	('PRKACA', 'Gene', (3, 9))	('RIIbeta', 'Gene', '5577', (24, 31))	('L206Rmut', 'Var', (10, 18))	('RIIbeta', 'Gene', (24, 31))	('PRKACA', 'Gene', '5566', (3, 9))	('L206R', 'Mutation', 'rs386352352', (10, 15))	('CPA', 'Chemical', '-', (19, 22))
102339	28250426	One study demonstrated that also mutations in the regulatory subunit RIalpha, leading to its decreased expression, induced the compensatory mechanism leading to an increase of other regulatory subunits.	('RIalpha', 'Gene', (69, 76))	('RIalpha', 'Gene', '19084', (69, 76))	('expression', 'MPA', (103, 113))	('other regulatory subunits', 'MPA', (176, 201))	('mutations', 'Var', (33, 42))	('decreased', 'NegReg', (93, 102))	('increase', 'PosReg', (164, 172))
102341	28250426	Recently, we could prove that mutations in the Calpha subunit decrease the binding potential of regulatory subunits and already many years ago it was demonstrated, that unbound regulatory subunits are normally degraded in the proteasome in a ubiquitin-dependent manner.	('decrease', 'NegReg', (62, 70))	('mutations', 'Var', (30, 39))	('Calpha', 'Gene', (47, 53))	('rad', 'Gene', '6236', (213, 216))	('rad', 'Gene', (213, 216))	('binding', 'Interaction', (75, 82))
102342	28250426	Following the discovery of mutations in the gene encoding for the catalytic subunit alpha of PKA as the underlying cause of CPA tumourigenesis we hypothesized that these mutations might be causative for the decreased RIIbeta protein expression in these tumours.	('mutations', 'Var', (27, 36))	('tumour', 'Disease', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (253, 260))	('RIIbeta', 'Gene', '5577', (217, 224))	('expression', 'MPA', (233, 243))	('decreased', 'NegReg', (207, 216))	('mutations', 'Var', (170, 179))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('tumours', 'Disease', 'MESH:D009369', (253, 260))	('tumour', 'Disease', (253, 259))	('tumours', 'Disease', (253, 260))	('CPA', 'Chemical', '-', (124, 127))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('cause', 'Reg', (115, 120))	('PKA', 'Gene', (93, 96))	('RIIbeta', 'Gene', (217, 224))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))
102343	28250426	Therefore, we assessed the protein levels of PKA subunits by both immunohistochemistry and immunoblotting in a large series of adrenocortical tumours with known PRKACA mutation status, including 10 samples that had already been included in the study by Vincent-Dejean et al..	('PRKACA', 'Gene', (161, 167))	('PRKACA', 'Gene', '5566', (161, 167))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('mutation', 'Var', (168, 176))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('adrenocortical tumours', 'Disease', 'MESH:D000306', (127, 149))	('adrenocortical tumours', 'Disease', (127, 149))
102345	28250426	This hypothesis was confirmed by our immunohistochemistry results where CPA with mutations in the PRKACA gene showed reduced RIIbeta protein levels compared to PRKACA wt CPA.	('PRKACA', 'Gene', '5566', (160, 166))	('PRKACA', 'Gene', (98, 104))	('reduced', 'NegReg', (117, 124))	('PRKACA', 'Gene', '5566', (98, 104))	('RIIbeta', 'Gene', '5577', (125, 132))	('RIIbeta', 'Gene', (125, 132))	('CPA', 'Chemical', '-', (72, 75))	('mutations', 'Var', (81, 90))	('CPA', 'Chemical', '-', (170, 173))	('PRKACA', 'Gene', (160, 166))
102349	28250426	Interestingly, in this sample, by whole exome sequencing, we could identify a germline genomic variant in the GNAS gene (encoding the alpha subunit of the stimulatory G protein (Gs) and involved in cAMP regulation) (p.R600G, SNP: rs74897360), however, the clinical significance of this SNP has never been investigated before.	('GNAS', 'Gene', '2778', (110, 114))	('cAMP', 'Chemical', 'MESH:D000242', (198, 202))	('GNAS', 'Gene', (110, 114))	('p.R600G', 'Mutation', 'rs74897360', (216, 223))	('p.R600G', 'Var', (216, 223))	('rs74897360', 'Mutation', 'rs74897360', (230, 240))
102356	28250426	But also other groups found a reduced expression of the mutant Calpha protein in the tumours.	('Calpha protein', 'Protein', (63, 77))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('expression', 'MPA', (38, 48))	('mutant', 'Var', (56, 62))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('tumours', 'Disease', (85, 92))	('reduced', 'NegReg', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
102358	28250426	Highest RIIbeta expression was observed in the sample carrying the p.E32V mutation, which lies outside the interface of regulatory and catalytic subunits and does maybe not influence the formation of a stable PKA holoenzyme.	('p.E32V', 'Var', (67, 73))	('RIIbeta', 'Gene', '5577', (8, 15))	('RIIbeta', 'Gene', (8, 15))	('p.E32V', 'Mutation', 'p.E32V', (67, 73))
102359	28250426	Unchanged RIIbeta protein expression in western blot analysis was also found in the sample carrying the p.245_248.del mutation, however, this tumour is from a patient without signs of clinical Cushing Syndrome, suggesting that the effects of this mutation are less severe.	('tumour', 'Disease', (142, 148))	('RIIbeta', 'Gene', '5577', (10, 17))	('RIIbeta', 'Gene', (10, 17))	('p.245_248.del', 'Mutation', 'p.245_248del', (104, 117))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('p.245_248.del mutation', 'Var', (104, 126))	('Cushing Syndrome', 'Phenotype', 'HP:0003118', (193, 209))	('patient', 'Species', '9606', (159, 166))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
102365	28250426	As we hypothesized that the PRKACA mutations possibly changes RIIbeta subcellular localization we checked if RIIbeta is also co-localized with the golgi apparatus in tissues derived from PRKACA wt and PRKACA L206Rmut CPA or if this localization changes in the mutated samples.	('RIIbeta', 'Gene', '5577', (62, 69))	('changes', 'Reg', (54, 61))	('PRKACA', 'Gene', (201, 207))	('PRKACA', 'Gene', '5566', (201, 207))	('CPA', 'Chemical', '-', (217, 220))	('PRKACA', 'Gene', (28, 34))	('PRKACA', 'Gene', '5566', (187, 193))	('L206R', 'Mutation', 'rs386352352', (208, 213))	('PRKACA', 'Gene', '5566', (28, 34))	('subcellular localization', 'MPA', (70, 94))	('RIIbeta', 'Gene', '5577', (109, 116))	('RIIbeta', 'Gene', (109, 116))	('PRKACA', 'Gene', (187, 193))	('RIIbeta', 'Gene', (62, 69))	('mutations', 'Var', (35, 44))
102372	28250426	In conclusion, our study shows a direct link between PRKACA mutations and reduced protein levels of two regulatory subunits of PKA in a sub-group of CPA and that specific expression overlapping the different functional zones of the adrenal cortex, could indicate distinct roles of the different PKA regulatory subunits in the secretion of different hormones.	('CPA', 'Chemical', '-', (149, 152))	('protein levels', 'MPA', (82, 96))	('PRKACA', 'Gene', (53, 59))	('mutations', 'Var', (60, 69))	('reduced', 'NegReg', (74, 81))	('PRKACA', 'Gene', '5566', (53, 59))
102380	26873959	Next, we investigated the mechanism by which niclosamide inhibited ACC cell proliferation, and found that it induced caspase-dependent apoptosis and G1 cell cycle arrest.	('ACC cell proliferation', 'CPA', (67, 89))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (152, 169))	('inhibited', 'NegReg', (57, 66))	('ACC', 'Phenotype', 'HP:0006744', (67, 70))	('niclosamide', 'Var', (45, 56))	('caspase-dependent', 'CPA', (117, 134))	('G1 cell cycle arrest', 'CPA', (149, 169))	('niclosamide', 'Chemical', 'MESH:D009534', (45, 56))
102388	26873959	Our knowledge of the molecular pathogenesis of ACC has improved, and alterations in CTNNB1, IGF-2, and TP53 are common in ACC cases and are associated with ACC prognosis.	('TP53', 'Gene', '7157', (103, 107))	('associated with', 'Reg', (140, 155))	('alterations', 'Var', (69, 80))	('CTNNB1', 'Gene', '1499', (84, 90))	('ACC', 'Phenotype', 'HP:0006744', (156, 159))	('TP53', 'Gene', (103, 107))	('ACC', 'Disease', (156, 159))	('common', 'Reg', (112, 118))	('IGF-2', 'Gene', (92, 97))	('ACC', 'Phenotype', 'HP:0006744', (47, 50))	('IGF-2', 'Gene', '3481', (92, 97))	('ACC', 'Phenotype', 'HP:0006744', (122, 125))	('CTNNB1', 'Gene', (84, 90))	('ACC', 'Disease', (122, 125))
102398	26873959	We demonstrated that niclosamide inhibits ACC cellular proliferation, induces caspase-dependent apoptosis and G1 cell cycle arrest, and decreases ACC cellular migration.	('ACC', 'Phenotype', 'HP:0006744', (42, 45))	('niclosamide', 'Chemical', 'MESH:D009534', (21, 32))	('ACC', 'Phenotype', 'HP:0006744', (146, 149))	('ACC cellular proliferation', 'CPA', (42, 68))	('caspase-dependent apoptosis', 'CPA', (78, 105))	('niclosamide', 'Var', (21, 32))	('induces', 'Reg', (70, 77))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (113, 130))	('G1 cell cycle arrest', 'CPA', (110, 130))	('inhibits', 'NegReg', (33, 41))	('ACC cellular migration', 'CPA', (146, 168))	('decreases', 'NegReg', (136, 145))
102432	26873959	qHTS was performed in order to identify compounds with anti-ACC activity in BD140A, SW-13, and NCI-H295R.	('SW-13', 'CellLine', 'CVCL:0542', (84, 89))	('anti-ACC', 'MPA', (55, 63))	('ACC', 'Phenotype', 'HP:0006744', (60, 63))	('BD140A', 'Var', (76, 82))
102440	26873959	After three and four weeks of treatment of SW-13 and NCI-H295R, respectively, we observed growth inhibition and disintegration of the MCAs (Fig.	('growth inhibition', 'CPA', (90, 107))	('NCI-H295R', 'Var', (53, 62))	('SW-13', 'CellLine', 'CVCL:0542', (43, 48))	('disintegration', 'CPA', (112, 126))
102441	26873959	To further elucidate the mechanism by which niclosamide inhibited cellular proliferation and caused cell death, we determined the effect on cell cycle progression and apoptosis.	('cellular proliferation', 'CPA', (66, 88))	('niclosamide', 'Var', (44, 55))	('caused', 'Reg', (93, 99))	('cell death', 'CPA', (100, 110))	('niclosamide', 'Chemical', 'MESH:D009534', (44, 55))	('inhibited', 'NegReg', (56, 65))
102447	26873959	The OCR and ECAR increased with niclosamide treatment in all three cell lines, which is consistent with an uncoupling of the electron transport chain from ATP synthesis and the subsequent metabolic shift to glycolysis for energy production (Fig.	('increased', 'PosReg', (17, 26))	('ECAR', 'MPA', (12, 16))	('niclosamide', 'Chemical', 'MESH:D009534', (32, 43))	('ATP', 'Chemical', 'MESH:D000255', (155, 158))	('OCR', 'Chemical', '-', (4, 7))	('OCR', 'MPA', (4, 7))	('niclosamide', 'Var', (32, 43))
102462	26873959	Mechanistically, we found that niclosamide induces caspase-dependent apoptosis and G1 cell cycle arrest, and decreases cellular migration.	('induces', 'Reg', (43, 50))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (86, 103))	('niclosamide', 'Var', (31, 42))	('caspase-dependent apoptosis', 'CPA', (51, 78))	('G1 cell cycle arrest', 'CPA', (83, 103))	('cellular migration', 'CPA', (119, 137))	('decreases', 'NegReg', (109, 118))	('niclosamide', 'Chemical', 'MESH:D009534', (31, 42))
102468	26873959	In addition, niclosamide has been found to have antineoplastic activity in various cancers by inhibiting multiple cellular pathways known to play important roles in carcinogenesis, including WNT/beta-catenin, notch, mTOR, NF-kB, and STAT3.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('mTOR', 'Gene', (216, 220))	('beta-catenin', 'Gene', '1499', (195, 207))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('niclosamide', 'Var', (13, 24))	('carcinogenesis', 'Disease', 'MESH:D063646', (165, 179))	('carcinogenesis', 'Disease', (165, 179))	('inhibiting', 'NegReg', (94, 104))	('STAT3', 'Gene', '6774', (233, 238))	('mTOR', 'Gene', '2475', (216, 220))	('niclosamide', 'Chemical', 'MESH:D009534', (13, 24))	('cellular pathways', 'Pathway', (114, 131))	('beta-catenin', 'Gene', (195, 207))	('STAT3', 'Gene', (233, 238))	('cancers', 'Disease', (83, 90))	('antineoplastic activity', 'MPA', (48, 71))
102473	26873959	Validation of the screening results confirmed that niclosamide inhibits cellular proliferation in a time- and dose-dependent manner in both monolayer cell culture and MCA, and that it induces cell death at high doses.	('cellular proliferation', 'CPA', (72, 94))	('niclosamide', 'Chemical', 'MESH:D009534', (51, 62))	('inhibits', 'NegReg', (63, 71))	('cell death', 'CPA', (192, 202))	('niclosamide', 'Var', (51, 62))	('induces', 'Reg', (184, 191))
102476	26873959	The WNT/beta-catenin pathway has been shown to play an important role in ACC, with alteration of this pathway found in over 30% of ACC cases.	('ACC', 'Phenotype', 'HP:0006744', (73, 76))	('ACC', 'Disease', (73, 76))	('beta-catenin', 'Gene', (8, 20))	('ACC', 'Phenotype', 'HP:0006744', (131, 134))	('beta-catenin', 'Gene', '1499', (8, 20))	('alteration', 'Var', (83, 93))
102479	26873959	Mutations in beta-catenin have been associated with poor prognosis in patients with ACC, and higher-grade ACC is associated with higher beta-catenin expression.	('beta-catenin', 'Gene', '1499', (136, 148))	('patients', 'Species', '9606', (70, 78))	('beta-catenin', 'Gene', '1499', (13, 25))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('higher', 'PosReg', (129, 135))	('Mutations', 'Var', (0, 9))	('ACC', 'Disease', (84, 87))	('expression', 'MPA', (149, 159))	('ACC', 'Phenotype', 'HP:0006744', (106, 109))	('beta-catenin', 'Gene', (13, 25))	('beta-catenin', 'Gene', (136, 148))
102480	26873959	Silencing of beta-catenin in NCI-H295R has been shown to decrease proliferation, induce cell cycle arrest and apoptosis, reverse the EMT phenotype, and inhibit in vivo tumor development.	('beta-catenin', 'Gene', (13, 25))	('inhibit', 'NegReg', (152, 159))	('decrease', 'NegReg', (57, 65))	('apoptosis', 'CPA', (110, 119))	('induce', 'Reg', (81, 87))	('tumor', 'Disease', (168, 173))	('beta-catenin', 'Gene', '1499', (13, 25))	('proliferation', 'CPA', (66, 79))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (88, 105))	('NCI-H295R', 'Gene', (29, 38))	('EMT phenotype', 'CPA', (133, 146))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('Silencing', 'Var', (0, 9))	('cell cycle arrest', 'CPA', (88, 105))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('reverse', 'Reg', (121, 128))
102492	26873959	Cancer-specific changes in mitochondrial metabolism have been linked to malignant cell transformation, apoptosis evasion, the high proliferative capacity of cancer cells, and driver gene/pathway mutations.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('changes', 'Reg', (16, 23))	('apoptosis evasion', 'CPA', (103, 120))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('malignant cell transformation', 'CPA', (72, 101))	('mutations', 'Var', (195, 204))	('cancer', 'Disease', (157, 163))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mitochondrial metabolism', 'MPA', (27, 51))	('linked', 'Reg', (62, 68))
102500	26873959	We established that niclosamide has antiproliferative and proapoptotic activities, and induces G1 cell cycle arrest.	('G1 cell cycle arrest', 'CPA', (95, 115))	('proapoptotic activities', 'CPA', (58, 81))	('niclosamide', 'Var', (20, 31))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (98, 115))	('induces', 'Reg', (87, 94))	('antiproliferative', 'CPA', (36, 53))	('niclosamide', 'Chemical', 'MESH:D009534', (20, 31))
102556	26973596	The resting membrane potential in bovine fasciculata cells is set by the background K+ channel bTREK-1, whereas the TASK-3 background K+ channel, characteristic for rat glomerulosa cell, is undetectable in bovine fasciculata cells.	('bovine', 'Species', '9913', (34, 40))	('bovine', 'Species', '9913', (206, 212))	('resting membrane potential', 'MPA', (4, 30))	('bTREK-1', 'Var', (95, 102))	('rat', 'Species', '10116', (165, 168))	('TASK', 'Gene', (116, 120))	('TASK', 'Gene', '29553', (116, 120))
102558	26973596	or inositol 1,4,5-trisphosphate receptor (IP3R) mRNA and, accordingly, AII does not stimulate steroid production in these cells.	('steroid production', 'MPA', (94, 112))	('IP3R', 'Gene', '25262', (42, 46))	('inositol 1,4,5-trisphosphate', 'Chemical', 'MESH:D015544', (3, 31))	('steroid', 'Chemical', 'MESH:D013256', (94, 101))	('mRNA', 'Var', (48, 52))	('IP3R', 'Gene', (42, 46))
102582	26973596	], the ensuing Ca2+ current activates phospholipase Cdelta, and the generated IP3 induces Ca2+ release from the endoplasmic reticulum (ER).	('IP3', 'Chemical', 'MESH:D015544', (78, 81))	('induces', 'Reg', (82, 89))	('rat', 'Species', '10116', (72, 75))	('phospholipase Cdelta', 'Enzyme', (38, 58))	('Ca2+ current', 'MPA', (15, 27))	('IP3', 'Var', (78, 81))	('activates', 'PosReg', (28, 37))	('Ca2+ release from', 'MPA', (90, 107))
102585	26973596	By the same token, 8Br-cAMP enhanced AII-induced IP3 formation in bovine cells.	('IP3', 'Chemical', 'MESH:D015544', (49, 52))	('enhanced', 'PosReg', (28, 36))	('bovine', 'Species', '9913', (66, 72))	('8Br-cAMP', 'Var', (19, 27))	('8Br-cAMP', 'Chemical', 'MESH:D015124', (19, 27))
102596	26973596	Li+ inhibits the resynthesis of phosphoinositides and precludes the maintained formation of IP3, and thus attenuates the post-initial phase of AII-induced (but not ACTH-induced) aldosterone output of glomerulosa cells.	('resynthesis of phosphoinositides', 'MPA', (17, 49))	('inhibits', 'NegReg', (4, 12))	('attenuates', 'NegReg', (106, 116))	('precludes', 'NegReg', (54, 63))	('formation of IP3', 'MPA', (79, 95))	('Li+', 'Var', (0, 3))	('post-initial phase of AII-induced', 'MPA', (121, 154))	('phosphoinositides', 'Chemical', 'MESH:D010716', (32, 49))	('aldosterone', 'Chemical', 'MESH:D000450', (178, 189))	('ACTH', 'Gene', (164, 168))	('IP3', 'Chemical', 'MESH:D015544', (92, 95))	('ACTH', 'Gene', '5443', (164, 168))
102616	26973596	The opposite, increased mitochondrial Ca2+ uptake after the knockdown of p38 MAPK or the silencing of mitochondrial protein OPA1 results in increased NAD(P)H formation and enhanced aldosterone production.	('increased', 'PosReg', (14, 23))	('OPA1', 'Gene', '171116', (124, 128))	('aldosterone production', 'Phenotype', 'HP:0000859', (181, 203))	('enhanced aldosterone', 'Phenotype', 'HP:0000859', (172, 192))	('aldosterone production', 'MPA', (181, 203))	('enhanced', 'PosReg', (172, 180))	('aldosterone', 'Chemical', 'MESH:D000450', (181, 192))	('increased NAD(P)H', 'Disease', 'MESH:C000656865', (140, 157))	('p38 MAPK', 'Var', (73, 81))	('silencing', 'Var', (89, 98))	('OPA1', 'Gene', (124, 128))	('mitochondrial Ca2+ uptake', 'MPA', (24, 49))
102624	26973596	Mitochondrial cAMP signaling was attenuated with the sAC inhibitor 2-OH-estradiol, after silencing of the sAC gene and by the buffering of mitochondrial Ca2+ by S100G protein.	('sAC gene', 'Gene', (106, 114))	('2-OH-estradiol', 'Chemical', 'MESH:C001390', (67, 81))	('attenuated', 'NegReg', (33, 43))	('Mitochondrial cAMP signaling', 'MPA', (0, 28))	('S100G', 'Gene', '24249', (161, 166))	('cAMP', 'Chemical', 'MESH:D000242', (14, 18))	('silencing', 'Var', (89, 98))	('S100G', 'Gene', (161, 166))
102625	26973596	All these maneuvers also attenuated aldosterone production, showing the cell-type-specific significance of mt-cAMP for the first time.	('mt-cAMP', 'Chemical', '-', (107, 114))	('aldosterone', 'Chemical', 'MESH:D000450', (36, 47))	('attenuated', 'NegReg', (25, 35))	('attenuated aldosterone', 'Phenotype', 'HP:0004319', (25, 47))	('aldosterone production', 'MPA', (36, 58))	('man', 'Species', '9606', (10, 13))	('aldosterone production', 'Phenotype', 'HP:0000859', (36, 58))	('maneuvers', 'Var', (10, 19))
102682	26413177	On the other hand, the term metastatic calcification is used when the deposition of calcium salts occurs in normal renal parenchyma secondary to derangements in calcium metabolism, caused by hyperparathyroidism, renal tubular acidosis and renal failure.	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (191, 210))	('renal tubular acidosis', 'Phenotype', 'HP:0001947', (212, 234))	('hyperparathyroidism', 'Disease', (191, 210))	('derangements', 'Var', (145, 157))	('renal failure', 'Phenotype', 'HP:0000083', (239, 252))	('caused by hyperparathyroidism', 'Phenotype', 'HP:0000867', (181, 210))	('calcium', 'Chemical', 'MESH:D002118', (84, 91))	('calcification', 'Disease', 'MESH:D002114', (39, 52))	('renal tubular acidosis and renal failure', 'Disease', 'MESH:D051437', (212, 252))	('acidosis', 'Phenotype', 'HP:0001941', (226, 234))	('calcification', 'Disease', (39, 52))	('calcium', 'Chemical', 'MESH:D002118', (161, 168))	('calcium metabolism', 'MPA', (161, 179))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (191, 210))
102889	25498963	Conditional mutagenesis of Shh in steroidogenic cells results in adrenocortical hypoplasia and capsular thinning.	('Conditional mutagenesis', 'Var', (0, 23))	('Shh', 'Gene', '20423', (27, 30))	('results in', 'Reg', (54, 64))	('steroid', 'Chemical', 'MESH:D013256', (34, 41))	('adrenocortical hypoplasia', 'Disease', 'MESH:D018268', (65, 90))	('capsular thinning', 'CPA', (95, 112))	('Shh', 'Gene', (27, 30))	('adrenocortical hypoplasia', 'Phenotype', 'HP:0008182', (65, 90))	('adrenocortical hypoplasia', 'Disease', (65, 90))
102892	25498963	Targeted mutagenesis of beta-catenin in SFI+ cells causes late onset adrenal hypoplasia, which is thought to be the result of stem/progenitor cell pool depletion.	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (69, 87))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (69, 87))	('Targeted mutagenesis', 'Var', (0, 20))	('causes', 'Reg', (51, 57))	('adrenal hypoplasia', 'Disease', (69, 87))	('beta-catenin', 'Protein', (24, 36))
102895	25498963	When zG-to-zF lineage conversion was disrupted through conditional mutagenesis of Sf1 in CYP11B2+ cells, a fully functional zF still formed, implying the existence of alternative routes for differentiation of particular cell types.	('CYP11B2', 'Gene', (89, 96))	('Sf1', 'Gene', (82, 85))	('disrupted', 'NegReg', (37, 46))	('CYP11B2', 'Gene', '13072', (89, 96))	('conditional mutagenesis', 'Var', (55, 78))	('Sf1', 'Gene', '26423', (82, 85))
102906	25498963	C57Bl/6 mice are more susceptible to sex reversal, and transcriptomic analyses have shown that this susceptibility correlates with delayed activation of testis pathway genes and delayed repression of ovarian pathway genes.	('repression', 'NegReg', (186, 196))	('activation', 'PosReg', (139, 149))	('ovarian pathway', 'Pathway', (200, 215))	('testis', 'Gene', (153, 159))	('C57Bl/6', 'Var', (0, 7))	('sex reversal', 'CPA', (37, 49))	('mice', 'Species', '10090', (8, 12))	('sex reversal', 'Phenotype', 'HP:0012245', (37, 49))
102917	25498963	In addition to genetic factors, epigenetic modifications are thought to contribute to the pathogenesis of GDX-induced adrenocortical neoplasia.	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (118, 142))	('adrenocortical neoplasia', 'Disease', (118, 142))	('neoplasia', 'Phenotype', 'HP:0002664', (133, 142))	('contribute', 'Reg', (72, 82))	('epigenetic modifications', 'Var', (32, 56))
102919	25498963	The adrenal glands of these mice contain centripetally-migrating columns of cortical cells that either do or do not express beta-galactosidase, reflecting random epigenetic activation (or silencing) of the transgenes in stem/progenitor cells.	('beta-galactosidase', 'Gene', '12091', (124, 142))	('beta-galactosidase', 'Gene', (124, 142))	('mice', 'Species', '10090', (28, 32))	('silencing', 'NegReg', (188, 197))	('epigenetic', 'Var', (162, 172))
102920	25498963	Preexisting epigenetic alterations are hypothesized to affect the phenotypic plasticity of adrenocortical stem/progenitor cells, allowing some to respond to the hormonal changes associated with GDX.	('respond to', 'MPA', (146, 156))	('affect', 'Reg', (55, 61))	('phenotypic plasticity', 'CPA', (66, 87))	('epigenetic alterations', 'Var', (12, 34))	('allowing', 'Reg', (129, 137))	('adrenocortical', 'Disease', (91, 105))	('adrenocortical', 'Disease', 'MESH:D018268', (91, 105))
102921	25498963	Epigenetic variability among stem/ progenitor cells may explain why GDX of susceptible mouse strains leads to discrete columns or wedges of proliferating neoplastic cells in the adrenal cortex (Fig.	('wedges of proliferating neoplastic cells', 'CPA', (130, 170))	('Epigenetic variability', 'Var', (0, 22))	('mouse', 'Species', '10090', (87, 92))
102923	25498963	One epigenetic modification, methylation of cytosine residues in CpG dinucleotides, has been shown to modulate progenitor cell fate in endocrine tissues.	('methylation', 'Var', (29, 40))	('dinucleotides', 'Chemical', 'MESH:D015226', (69, 82))	('cytosine', 'Chemical', 'MESH:D003596', (44, 52))	('modulate', 'Reg', (102, 110))	('progenitor cell fate in endocrine tissues', 'CPA', (111, 152))
102924	25498963	For instance, conditional mutagenesis of the mouse Dnmt1 gene, which encodes the maintenance DNA methyl-transferase, causes reprogramming of pancreatic beta-cells into alpha-cells.	('pancreatic', 'Disease', (141, 151))	('reprogramming', 'CPA', (124, 137))	('Dnmt1', 'Gene', '13433', (51, 56))	('mouse', 'Species', '10090', (45, 50))	('causes', 'Reg', (117, 123))	('conditional mutagenesis', 'Var', (14, 37))	('Dnmt1', 'Gene', (51, 56))	('pancreatic', 'Disease', 'MESH:D010195', (141, 151))
102932	25498963	GDX-induced perturbations in the hormonal milieu cause gonadal-like cells to accumulate in the adrenal cortex of mice, and this experimental model can be harnessed to study the genetic and epigenetic factors that influence steroidogenic cell fate.	('mice', 'Species', '10090', (113, 117))	('perturbations', 'Var', (12, 25))	('steroid', 'Chemical', 'MESH:D013256', (223, 230))	('accumulate', 'PosReg', (77, 87))	('GDX-induced', 'Gene', (0, 11))	('gonadal-like cells', 'CPA', (55, 73))	('men', 'Species', '9606', (134, 137))
102934	25498963	Neoplastic and normal adrenocortical cells exhibit differences in DNA methylation that may reflect differences in the epigenetic fingerprints of the stem cell pools giving rise to these different cell types.	('Neoplastic', 'Disease', 'MESH:D009369', (0, 10))	('methylation', 'Var', (70, 81))	('differences', 'Reg', (51, 62))	('DNA', 'MPA', (66, 69))	('adrenocortical', 'Disease', (22, 36))	('adrenocortical', 'Disease', 'MESH:D018268', (22, 36))	('Neoplastic', 'Disease', (0, 10))
102943	25498963	In humans, mutations in GATA4 and its cofactor FOG2/ZFPM2 have been linked to defects in testicular development and function.	('linked', 'Reg', (68, 74))	('mutations', 'Var', (11, 20))	('men', 'Species', '9606', (107, 110))	('FOG2', 'Gene', (47, 51))	('ZFPM2', 'Gene', '23414', (52, 57))	('ZFPM2', 'Gene', (52, 57))	('defects', 'NegReg', (78, 85))	('FOG2', 'Gene', '23414', (47, 51))	('humans', 'Species', '9606', (3, 9))	('testicular development', 'CPA', (89, 111))	('GATA4', 'Gene', (24, 29))
102948	25498963	Constitutive and acquired mutations in Gata4 were found to mitigate the accumulation of gonadal-like neoplastic cells and the expression of sex steroidogenic markers in the adrenal cortex of gonadectomized female mice.	('gonadal-like neoplastic cells', 'CPA', (88, 117))	('mitigate', 'NegReg', (59, 67))	('mice', 'Species', '10090', (213, 217))	('expression of', 'MPA', (126, 139))	('steroid', 'Chemical', 'MESH:D013256', (144, 151))	('mutations', 'Var', (26, 35))	('accumulation', 'CPA', (72, 84))	('Gata4', 'Gene', (39, 44))	('Gata4', 'Gene', '14463', (39, 44))
102958	25498963	The impact of GATA6 deficiency on adrenal gland development and physiology has been assessed by conditionally deleting Gata6 in murine adrenocortical cells using Cre-LoxP recombination with Sf1-cre.	('murine', 'Species', '10090', (128, 134))	('men', 'Species', '9606', (55, 58))	('Gata6', 'Gene', (119, 124))	('adrenocortical', 'Disease', (135, 149))	('impact of GATA6 deficiency', 'Disease', 'MESH:D014095', (4, 30))	('impact of GATA6 deficiency', 'Disease', (4, 30))	('deleting', 'Var', (110, 118))	('Sf1', 'Gene', '26423', (190, 193))	('adrenocortical', 'Disease', 'MESH:D018268', (135, 149))	('Sf1', 'Gene', (190, 193))
102965	25498963	Gata6Flox/Flox;Sf1-cre mice, together with the aforementioned Gata4 mouse models (Sections 3.2 and 3.3), offer genetic support of the longstanding hypotheses that GATA6 promotes adrenocortical differentiation and GATA4 enhances gonadal-like differentiation [reviewed in)].	('promotes', 'PosReg', (169, 177))	('mouse', 'Species', '10090', (68, 73))	('adrenocortical', 'Disease', (178, 192))	('adrenocortical', 'Disease', 'MESH:D018268', (178, 192))	('gonadal-like differentiation', 'CPA', (228, 256))	('Gata4', 'Gene', '14463', (62, 67))	('men', 'Species', '9606', (52, 55))	('Gata4', 'Gene', (62, 67))	('mice', 'Species', '10090', (23, 27))	('enhances', 'PosReg', (219, 227))	('GATA6', 'Var', (163, 168))	('Sf1', 'Gene', '26423', (15, 18))	('Sf1', 'Gene', (15, 18))	('GATA4', 'Var', (213, 218))
102967	25498963	Hindlimb buds express Gata6 in an anterior-posterior gradient, and conditional mutagenesis of Gata6 using Prx1-cre leads to ectopic expression of Shh and its target genes, including Gli1, in the anterior mesenchyme of hindlimb buds.	('Gata6', 'Gene', (94, 99))	('Gli1', 'Gene', (182, 186))	('Shh', 'Gene', '20423', (146, 149))	('mutagenesis', 'Var', (79, 90))	('Gli1', 'Gene', '14632', (182, 186))	('ectopic expression', 'MPA', (124, 142))	('leads to', 'Reg', (115, 123))	('Prx1', 'Gene', '18477', (106, 110))	('Prx1', 'Gene', (106, 110))	('Shh', 'Gene', (146, 149))
102979	25498963	Of note, methylation mapping studies have shown that an epigenetic switch from GATA2 to GATA6 expression accompanies endometriosis in women and leads to aberrant expression of genes involved in steroidogenesis.	('GATA2', 'Gene', (79, 84))	('leads to', 'Reg', (144, 152))	('GATA6', 'Gene', (88, 93))	('endometriosis', 'Disease', 'MESH:D004715', (117, 130))	('women', 'Species', '9606', (134, 139))	('expression', 'MPA', (162, 172))	('epigenetic switch', 'Var', (56, 73))	('endometriosis', 'Disease', (117, 130))	('endometriosis', 'Phenotype', 'HP:0030127', (117, 130))	('steroid', 'Chemical', 'MESH:D013256', (194, 201))
102982	25498963	The analogous zone in humans, the fetal zone, expresses CYP17A1 and CYTB5 and produces large amounts of the androgen DHEA and its sulfated form DHEA-S that are converted by the sequential actions of the liver and placenta into estrogens.	('CYTB5', 'Gene', (68, 73))	('DHEA', 'Chemical', '-', (144, 148))	('humans', 'Species', '9606', (22, 28))	('CYP17A1', 'Var', (56, 63))	('CYTB5', 'Gene', '1528', (68, 73))	('DHEA', 'Chemical', '-', (117, 121))	('DHEA-S', 'Chemical', '-', (144, 150))
102984	25498963	Heterozygous loss-of-function mutations in human GATA6 have been linked to pancreatic agenesis, cardiac malformations, and biliary tract abnormalities, but not primary adrenocortical defects.	('pancreatic agenesis', 'Phenotype', 'HP:0100801', (75, 94))	('cardiac malformations', 'Disease', 'MESH:D006331', (96, 117))	('loss-of-function', 'NegReg', (13, 29))	('adrenocortical defects', 'Disease', 'MESH:D018268', (168, 190))	('human', 'Species', '9606', (43, 48))	('adrenocortical defects', 'Disease', (168, 190))	('biliary tract abnormalities', 'Disease', 'MESH:D001660', (123, 150))	('cardiac malformations', 'Disease', (96, 117))	('mutations', 'Var', (30, 39))	('pancreatic agenesis', 'Disease', 'MESH:C564908', (75, 94))	('biliary tract abnormalities', 'Phenotype', 'HP:0001080', (123, 150))	('cardiac malformations', 'Phenotype', 'HP:0001627', (96, 117))	('GATA6', 'Gene', (49, 54))	('primary adrenocortical defects', 'Phenotype', 'HP:0008207', (160, 190))	('pancreatic agenesis', 'Disease', (75, 94))	('biliary tract abnormalities', 'Disease', (123, 150))
102994	25498963	Using ChIP and related experiments, Schedl and colleagues have shown that WT1 directly regulates the expression of Gli1 in adrenal tissue and proposed that ectopic expression of Wt1 prevents differentiation into SF1+ adrenocortical steroidogenic cells by maintaining cells in a GLI1+ progenitor state.	('Gli1', 'Gene', '14632', (115, 119))	('WT1', 'Gene', '22431', (74, 77))	('adrenocortical', 'Disease', 'MESH:D018268', (217, 231))	('prevents', 'NegReg', (182, 190))	('Wt1', 'Gene', '22431', (178, 181))	('WT1', 'Gene', (74, 77))	('adrenocortical', 'Disease', (217, 231))	('ectopic expression', 'Var', (156, 174))	('GLI1', 'Gene', (278, 282))	('Gli1', 'Gene', (115, 119))	('SF1', 'Gene', '22668', (212, 215))	('differentiation', 'CPA', (191, 206))	('regulates', 'Reg', (87, 96))	('SF1', 'Gene', (212, 215))	('GLI1', 'Gene', '14632', (278, 282))	('Wt1', 'Gene', (178, 181))	('men', 'Species', '9606', (29, 32))	('steroid', 'Chemical', 'MESH:D013256', (232, 239))	('expression', 'MPA', (101, 111))
51544	25498963	Intriguingly, genetic ablation of the SF1 target gene Vnn1, encoding the gonadal-like marker Vanin-1, has been shown to reduce the severity of neoplastic lesions in the Sf1 transgenic mice.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (143, 161))	('SF1', 'Gene', (38, 41))	('Vanin-1', 'Gene', (93, 100))	('transgenic mice', 'Species', '10090', (173, 188))	('reduce', 'NegReg', (120, 126))	('Vnn1', 'Gene', (54, 58))	('SF1', 'Gene', '22668', (38, 41))	('Vnn1', 'Gene', '22361', (54, 58))	('genetic ablation', 'Var', (14, 30))	('Vanin-1', 'Gene', '22361', (93, 100))	('Sf1', 'Gene', '26423', (169, 172))	('neoplastic lesions', 'Disease', (143, 161))	('neoplastic lesions', 'Disease', 'MESH:D051437', (143, 161))	('Sf1', 'Gene', (169, 172))
103002	25498963	Inactivating mutations in the protein kinase A regulatory subunit gene (PRKAR1A) lead to excessive cAMP production and cause Carney complex, a syndrome associated with adrenocortical neoplasia and pituitary-independent Cushing syndrome.	('Carney complex', 'Disease', (125, 139))	('pituitary-independent Cushing syndrome', 'Disease', 'MESH:D047748', (197, 235))	('PRKAR1A', 'Gene', '19084', (72, 79))	('lead', 'Reg', (81, 85))	('cAMP production', 'MPA', (99, 114))	('cause', 'Reg', (119, 124))	('pituitary-independent Cushing syndrome', 'Disease', (197, 235))	('Inactivating mutations', 'Var', (0, 22))	('cAMP', 'Chemical', '-', (99, 103))	('neoplasia', 'Phenotype', 'HP:0002664', (183, 192))	('PRKAR1A', 'Gene', (72, 79))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (168, 192))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (219, 235))	('excessive', 'PosReg', (89, 98))	('adrenocortical neoplasia', 'Disease', (168, 192))
103010	25498963	During colorectal tumorigenesis, human GATA6 directly enhances the expression of LGR5, which interacts with R-spondins and thereby activates Wnt/beta-catenin signaling.	('activates', 'PosReg', (131, 140))	('R-spondin', 'Gene', '192199', (108, 117))	('Wnt/beta-catenin signaling', 'MPA', (141, 167))	('enhances', 'PosReg', (54, 62))	('human GATA6', 'Var', (33, 44))	('LGR5', 'Gene', '8549', (81, 85))	('colorectal tumorigenesis', 'Disease', (7, 31))	('LGR5', 'Gene', (81, 85))	('R-spondin', 'Gene', (108, 117))	('human', 'Species', '9606', (33, 38))	('expression', 'MPA', (67, 77))	('interacts', 'Interaction', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
103011	25498963	At the 2014 Adrenal Meeting Andreas Schedl reported that conditional mutagenesis of Rspo3, an R-spondin expressed in adrenal subcapsular cells, causes adrenocortical hypoplasia.	('R-spondin', 'Gene', '192199', (94, 103))	('conditional mutagenesis', 'Var', (57, 80))	('adrenocortical hypoplasia', 'Disease', 'MESH:D018268', (151, 176))	('causes', 'Reg', (144, 150))	('R-spondin', 'Gene', (94, 103))	('adrenocortical hypoplasia', 'Phenotype', 'HP:0008182', (151, 176))	('Rspo3', 'Gene', '72780', (84, 89))	('adrenocortical hypoplasia', 'Disease', (151, 176))	('Rspo3', 'Gene', (84, 89))
103012	25498963	SUMO (small ubiquitin-like modifier) proteins function as post-translational modifiers, and SUMOylation represses the transcriptional activity of Sf1 by affecting its DNA binding.	('DNA', 'MPA', (167, 170))	('represses', 'NegReg', (104, 113))	('Sf1', 'Gene', '26423', (146, 149))	('transcriptional activity', 'MPA', (118, 142))	('SUMOylation', 'Var', (92, 103))	('Sf1', 'Gene', (146, 149))	('affecting', 'Reg', (153, 162))
103015	25498963	In another model, mice with a global increase in SUMOylation due to deficiency of the deSUMOylase Senp2 exhibit impaired cardiogenesis due in part to repression of the Gata6 gene by the Polycomb repressor complex.	('impaired cardiogenesis', 'Disease', (112, 134))	('Senp2', 'Gene', (98, 103))	('deficiency', 'Var', (68, 78))	('mice', 'Species', '10090', (18, 22))	('repression', 'NegReg', (150, 160))	('Gata6', 'Gene', (168, 173))	('increase', 'PosReg', (37, 45))	('impaired cardiogenesis', 'Disease', 'MESH:D009422', (112, 134))	('Senp2', 'Gene', '75826', (98, 103))	('SUMOylation', 'MPA', (49, 60))
103021	25498963	When expressed under the control of the Inha promoter, SV40 large T-antigen elicits gonadal-like tumors in the adrenal glands of gonadectomized transgenic mice.	('Inha', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('SV40 large', 'Var', (55, 65))	('elicits', 'Reg', (76, 83))	('transgenic mice', 'Species', '10090', (144, 159))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Inha', 'Gene', '16322', (40, 44))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
103034	25498963	Ferret adrenocortical tumors express CYTB5, which enhances the 17,20-lyase activity of CYP17A1 and favors the production of androgens over cortisol (Fig.	('enhances', 'PosReg', (50, 58))	('CYTB5', 'Gene', '1528', (37, 42))	('CYP17A1', 'Var', (87, 94))	('Ferret', 'Species', '9669', (0, 6))	('production of androgens', 'MPA', (110, 133))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (7, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('favors', 'PosReg', (99, 105))	('CYTB5', 'Gene', (37, 42))	('adrenocortical tumors', 'Disease', (7, 28))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))
103035	25498963	In ferrets the ectopic production of sex steroids by neoplastic adrenocortical tissue causes a syndrome known as adrenal-associated endocrinopathy (AAE), characterized by alopecia, vulvar enlargement, and stranguria.	('ectopic', 'Var', (15, 22))	('neoplastic adrenocortical tissue', 'Disease', (53, 85))	('endocrinopathy', 'Disease', 'MESH:C567425', (132, 146))	('steroids', 'Chemical', 'MESH:D013256', (41, 49))	('alopecia', 'Phenotype', 'HP:0001596', (171, 179))	('endocrinopathy', 'Disease', (132, 146))	('vulvar enlargement', 'Disease', 'MESH:D014845', (181, 199))	('neoplastic adrenocortical tissue', 'Disease', 'MESH:D018268', (53, 85))	('causes', 'Reg', (86, 92))	('vulvar enlargement', 'Disease', (181, 199))	('ferrets', 'Species', '9669', (3, 10))	('stranguria', 'Disease', (205, 215))	('alopecia', 'Disease', (171, 179))
103045	25498963	Ovarian hyperthecosis occurs in only a minority of postmenopausal women, suggesting that genetic or epigenetic modifiers impact the development of this disease, as is true of GDX-induced adrenocortical neoplasms in the mouse.	('neoplasm', 'Phenotype', 'HP:0002664', (202, 210))	('men', 'Species', '9606', (55, 58))	('adrenocortical neoplasms', 'Disease', (187, 211))	('mouse', 'Species', '10090', (219, 224))	('Ovarian hyperthecosis', 'Disease', (0, 21))	('men', 'Species', '9606', (139, 142))	('Ovarian hyperthecosis', 'Disease', 'MESH:D010051', (0, 21))	('neoplasms', 'Phenotype', 'HP:0002664', (202, 211))	('impact', 'Reg', (121, 127))	('men', 'Species', '9606', (68, 71))	('development', 'CPA', (132, 143))	('women', 'Species', '9606', (66, 71))	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (187, 211))	('epigenetic modifiers', 'Var', (100, 120))
103048	25498963	Men with disrupted adrenocortical function due to CYP21A1 deficiency develop neoplastic nodules of hormonally-active adrenocortical tissue in the testis (testicular adrenal rest tumors, TARTs), thought to arise from one of these reservoirs of pluripotential stem/ progenitor cells.	('adrenocortical', 'Disease', (117, 131))	('CYP21A1', 'Gene', '13079', (50, 57))	('disrupted adrenocortical function', 'Disease', 'MESH:D018268', (9, 42))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('disrupted adrenocortical function', 'Disease', (9, 42))	('neoplastic nodules', 'Phenotype', 'HP:0002664', (77, 95))	('deficiency', 'Var', (58, 68))	('adrenocortical', 'Disease', 'MESH:D018268', (19, 33))	('adrenocortical', 'Disease', 'MESH:D018268', (117, 131))	('testicular adrenal rest tumors', 'Disease', 'MESH:D000314', (154, 184))	('disrupted adrenocortical function', 'Phenotype', 'HP:0008207', (9, 42))	('CYP21A1', 'Gene', (50, 57))	('adrenocortical', 'Disease', (19, 33))	('testicular adrenal rest tumors', 'Disease', (154, 184))	('testicular adrenal rest tumors', 'Phenotype', 'HP:0025451', (154, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('Men', 'Species', '9606', (0, 3))
103052	25498963	Reharmonization with a tritone substitution imparts movement to the bass line, but creates tension.	('movement', 'MPA', (52, 60))	('men', 'Species', '9606', (56, 59))	('tension', 'MPA', (91, 98))	('tritone', 'Chemical', '-', (23, 30))	('creates', 'Reg', (83, 90))	('substitution', 'Var', (31, 43))
103053	25498963	Stem/progenitor cell pluripotency facilitates stress adaptation, but creates ectopic foci of steroidogenesis.	('pluripotency', 'Var', (21, 33))	('steroidogenesis', 'MPA', (93, 108))	('steroid', 'Chemical', 'MESH:D013256', (93, 100))	('stress', 'MPA', (46, 52))	('creates', 'Reg', (69, 76))	('ectopic foci', 'MPA', (77, 89))	('facilitates', 'PosReg', (34, 45))
103074	25289806	Targeted mutagenesis of Gata4, a gene normally expressed in gonadal but not adrenal steroidogenic cells of the adult mouse, attenuates post-GDX adrenocortical tumor formation in susceptible strains, and transgenic expression of Gata4 induces adrenocortical neoplasia in a non-susceptible strain.	('Gata4', 'Gene', (24, 29))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (242, 266))	('GDX', 'Gene', '27643', (140, 143))	('Gata4', 'Gene', '14463', (24, 29))	('transgenic', 'Species', '10090', (203, 213))	('neoplasia', 'Phenotype', 'HP:0002664', (257, 266))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('induces', 'Reg', (234, 241))	('mouse', 'Species', '10090', (117, 122))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (144, 164))	('attenuates', 'NegReg', (124, 134))	('adrenocortical neoplasia', 'Disease', (242, 266))	('mutagenesis', 'Var', (9, 20))	('steroid', 'Chemical', 'MESH:D013256', (84, 91))	('Gata4', 'Gene', (228, 233))	('GDX', 'Gene', (140, 143))	('adrenocortical tumor', 'Disease', (144, 164))	('Gata4', 'Gene', '14463', (228, 233))
103075	25289806	In addition to genetic factors, epigenetic changes such as DNA methylation may contribute to the pathogenesis of GDX-induced adrenocortical neoplasia.	('neoplasia', 'Phenotype', 'HP:0002664', (140, 149))	('DNA methylation', 'Var', (59, 74))	('epigenetic changes', 'Var', (32, 50))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (125, 149))	('adrenocortical neoplasia', 'Disease', (125, 149))	('GDX', 'Gene', (113, 116))	('contribute', 'Reg', (79, 89))	('GDX', 'Gene', '27643', (113, 116))
103076	25289806	Altered methylation of cytosine residues in CpG dinucleotides has been shown to modulate gene expression and progenitor cell fate in various tissues, including endocrine organs.	('cytosine', 'Chemical', 'MESH:D003596', (23, 31))	('modulate', 'Reg', (80, 88))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (44, 61))	('gene expression', 'MPA', (89, 104))	('Altered', 'Var', (0, 7))	('methylation', 'MPA', (8, 19))	('progenitor cell fate', 'CPA', (109, 129))
103077	25289806	For example, conditional mutagenesis of the mouse Dnmt1 gene, which encodes the maintenance DNA methyl-transferase, causes reprogramming of pancreatic beta-cells into alpha-cells.	('causes', 'Reg', (116, 122))	('Dnmt1', 'Gene', (50, 55))	('conditional mutagenesis', 'Var', (13, 36))	('pancreatic', 'Disease', 'MESH:D010195', (140, 150))	('Dnmt1', 'Gene', '13433', (50, 55))	('pancreatic', 'Disease', (140, 150))	('reprogramming', 'CPA', (123, 136))	('mouse', 'Species', '10090', (44, 49))
103079	25289806	According to this hypothesis, epigenetic alterations affect the phenotypic plasticity of adrenocortical stem/progenitor cells, allowing them to respond to the hormonal changes associated with GDX.	('GDX', 'Gene', '27643', (192, 195))	('adrenocortical', 'Disease', 'MESH:D018268', (89, 103))	('affect', 'Reg', (53, 59))	('GDX', 'Gene', (192, 195))	('respond to the hormonal changes', 'MPA', (144, 175))	('epigenetic alterations', 'Var', (30, 52))	('allowing', 'Reg', (127, 135))	('phenotypic plasticity', 'CPA', (64, 85))	('adrenocortical', 'Disease', (89, 103))
103080	25289806	The current study was undertaken to identify novel genetic and epigenetic markers of GDX-induced adrenocortical neoplasia, so as to gain a better foothold for investigations into the mechanistic basis of tumorigenesis.	('epigenetic', 'Var', (63, 73))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (97, 121))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('GDX', 'Gene', (85, 88))	('tumor', 'Disease', (204, 209))	('adrenocortical neoplasia', 'Disease', (97, 121))	('neoplasia', 'Phenotype', 'HP:0002664', (112, 121))	('GDX', 'Gene', '27643', (85, 88))
103081	25289806	Complementary approaches, including genome-wide DNA methylation mapping and microarray expression profiling, were used to screen for genes that are hypomethylated and/or overexpressed in post-GDX adrenocortical neoplasms of the mouse.	('GDX', 'Gene', '27643', (192, 195))	('hypomethylated', 'Var', (148, 162))	('neoplasms', 'Phenotype', 'HP:0002664', (211, 220))	('GDX', 'Gene', (192, 195))	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (196, 220))	('overexpressed', 'PosReg', (170, 183))	('mouse', 'Species', '10090', (228, 233))	('adrenocortical neoplasms', 'Disease', (196, 220))
103125	25289806	Mice harboring null mutations in Foxl2 develop ovaries that express testicular differentiation markers.	('ovaries', 'Disease', (47, 54))	('testicular differentiation', 'CPA', (68, 94))	('Foxl2', 'Gene', '26927', (33, 38))	('Foxl2', 'Gene', (33, 38))	('Mice', 'Species', '10090', (0, 4))	('ovaries', 'Disease', 'MESH:D010051', (47, 54))	('null mutations', 'Var', (15, 29))
103149	25289806	Male and female Foxs1 knockout mice are viable and fertile, but the mutant males accumulate blood in the fetal testis, presumably due to apoptosis of periendothelial cells.	('mice', 'Species', '10090', (31, 35))	('Foxs1', 'Gene', (16, 21))	('Foxs1', 'Gene', '14239', (16, 21))	('accumulate', 'PosReg', (81, 91))	('blood', 'MPA', (92, 97))	('mutant', 'Var', (68, 74))
103154	25289806	Using complementary approaches, including microarray expression profiling, candidate gene analysis, and DNA methylation mapping, we have identified novel genetic (Spinlw1, Insl3, Foxl2) and epigenetic (Igfbp6, Foxs1) markers of GDX-induced adrenocortical neoplasia in the mouse.	('Igfbp6', 'Gene', '16012', (202, 208))	('mouse', 'Species', '10090', (272, 277))	('GDX', 'Gene', (228, 231))	('epigenetic', 'Var', (190, 200))	('adrenocortical neoplasia', 'Disease', (240, 264))	('neoplasia', 'Phenotype', 'HP:0002664', (255, 264))	('Igfbp6', 'Gene', (202, 208))	('Spinlw1', 'Gene', (163, 170))	('Foxs1', 'Gene', (210, 215))	('Foxs1', 'Gene', '14239', (210, 215))	('Insl3', 'Gene', (172, 177))	('Insl3', 'Gene', '16336', (172, 177))	('Spinlw1', 'Gene', '75526', (163, 170))	('GDX', 'Gene', '27643', (228, 231))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (240, 264))	('Foxl2', 'Gene', (179, 184))	('Foxl2', 'Gene', '26927', (179, 184))
103173	22275959	A possible mechanism largely remain unknown although it is known that germline mutations in certain cancer-associated genes, such as the TP53 or BRCA2 gene, predispose to the development of both specific childhood cancers, for example sarcomas or CNS and adult breast cancer.	('BRCA2', 'Gene', (145, 150))	('adult breast cancer', 'Disease', (255, 274))	('breast cancer', 'Phenotype', 'HP:0003002', (261, 274))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('germline mutations', 'Var', (70, 88))	('cancer', 'Disease', (214, 220))	('predispose to', 'Reg', (157, 170))	('BRCA2', 'Gene', '675', (145, 150))	('sarcomas', 'Disease', 'MESH:D012509', (235, 243))	('childhood cancers', 'Disease', 'MESH:C536928', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('childhood cancers', 'Disease', (204, 221))	('sarcomas', 'Phenotype', 'HP:0100242', (235, 243))	('CNS', 'Disease', (247, 250))	('TP53', 'Gene', (137, 141))	('sarcomas', 'Disease', (235, 243))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Disease', (268, 274))	('adult breast cancer', 'Disease', 'MESH:D001943', (255, 274))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('TP53', 'Gene', '7157', (137, 141))
103185	22275959	Germline mutations may lead to earlier ages of cancer onset.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
103216	22275959	We hypothesize that a germline defect in the foetus in a gene involved in cell-cycle control, apoptosis and tissue development, results in abnormal levels of steroid hormones via aberrant functioning of the foetal adrenal cortex, due to failure of the normal process of apoptosis and maturation.	('defect', 'Var', (31, 37))	('aberrant', 'Var', (179, 187))	('functioning', 'MPA', (188, 199))	('results in abnormal', 'Reg', (128, 147))	('steroid hormones', 'Chemical', 'MESH:D013256', (158, 174))	('levels of steroid hormones', 'MPA', (148, 174))
103223	22275959	In these circumstances, carrying a foetus with a cancer predisposing mutation may trigger the process of carcinogenesis, and thus accelerate the development of breast cancer, following the birth of the index child.	('process', 'CPA', (94, 101))	('carcinogenesis', 'Disease', 'MESH:D063646', (105, 119))	('accelerate', 'PosReg', (130, 140))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('child', 'Species', '9606', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('carcinogenesis', 'Disease', (105, 119))	('cancer', 'Disease', (167, 173))	('trigger', 'Reg', (82, 89))	('mutation', 'Var', (69, 77))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('cancer', 'Disease', (49, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
103225	22275959	In this series of eRMS, there was one known case with a germline TP53 mutation, whose mother was also a mutation carrier.	('mutation', 'Var', (70, 78))	('RMS', 'Phenotype', 'HP:0002859', (19, 22))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))
103227	22275959	Four children with other tumours, ACC, astrocytoma and PNET (2 cases) carried germline TP53 mutations.	('astrocytoma', 'Phenotype', 'HP:0009592', (39, 50))	('TP53', 'Gene', '7157', (87, 91))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('TP53', 'Gene', (87, 91))	('children', 'Species', '9606', (5, 13))	('mutations', 'Var', (92, 101))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('ACC', 'Phenotype', 'HP:0006744', (34, 37))	('astrocytoma', 'Disease', 'MESH:D001254', (39, 50))	('tumours', 'Disease', (25, 32))	('astrocytoma', 'Disease', (39, 50))
103229	22275959	The striking excesses of breast cancer in mothers of children with eRMS in the ten years following birth of the index are unlikely to be completely explained by a transient increase in risk of breast cancer following the first pregnancy in mothers.	('breast cancer', 'Disease', (193, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('excesses of breast', 'Phenotype', 'HP:0010313', (13, 31))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('children', 'Species', '9606', (53, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('eRMS', 'Var', (67, 71))	('RMS', 'Phenotype', 'HP:0002859', (68, 71))
103254	22275959	It is known that germline mutations in CDKN2A are the most common cause of inherited susceptibility to melanoma.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('CDKN2A', 'Gene', (39, 45))	('CDKN2A', 'Gene', '1029', (39, 45))	('germline mutations', 'Var', (17, 35))	('cause', 'Reg', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
103257	22275959	In multi-case melanoma families with mutations affecting p14ARF specifically there appears to be increased risk of breast cancer.	('melanoma', 'Disease', (14, 22))	('p14ARF', 'Gene', (57, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('p14ARF', 'Gene', '1029', (57, 63))	('mutations', 'Var', (37, 46))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
103263	22275959	It has been reported that loss of BRCA gene function activates a p53-dependent cellular response, suggesting mutation in p53 may be required before inactivation of BRCA2 may lead to the development of breast cancer.	('BRCA', 'Gene', '672', (34, 38))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('BRCA', 'Gene', (164, 168))	('BRCA2', 'Gene', '675', (164, 169))	('BRCA', 'Gene', (34, 38))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('lead to', 'Reg', (174, 181))	('activates', 'PosReg', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('loss', 'Var', (26, 30))	('breast cancer', 'Disease', (201, 214))	('BRCA2', 'Gene', (164, 169))	('BRCA', 'Gene', '672', (164, 168))	('mutation', 'Var', (109, 117))
103266	22275959	We considered the possibility that there may be an excess risk of breast cancer in mothers in both groups, during early years of follow-up, mediated by mutations in the RB1 gene.	('mutations', 'Var', (152, 161))	('RB1', 'Gene', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('RB1', 'Gene', '5925', (169, 172))	('mediated by', 'Reg', (140, 151))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('RB', 'Phenotype', 'HP:0009919', (169, 171))
103273	22275959	Furthermore, germline mutations in TP53 have been found among the majority of ACC cases in a number of studies.	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('found', 'Reg', (50, 55))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('germline mutations', 'Var', (13, 31))	('ACC', 'Disease', (78, 81))
103287	22275959	Germline mutations to cancer-associated genes, inherited or de novo might play an important role.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (22, 28))
103288	22275959	Germline mutations might commonly target the p53 pathway affecting tissue remodelling in the foetal adrenal cortex, not just a single gene within that pathway.	('affecting', 'Reg', (57, 66))	('p53', 'Gene', (45, 48))	('Germline mutations', 'Var', (0, 18))	('p53', 'Gene', '7157', (45, 48))	('target', 'Reg', (34, 40))
103289	22275959	The pathway may be disrupted by a germline mutation within the TP53 gene itself, as well as p14ARF, BRCA1 and BRCA2, etc.	('BRCA2', 'Gene', (110, 115))	('TP53', 'Gene', '7157', (63, 67))	('BRCA1', 'Gene', '672', (100, 105))	('TP53', 'Gene', (63, 67))	('BRCA1', 'Gene', (100, 105))	('BRCA2', 'Gene', '675', (110, 115))	('p14ARF', 'Gene', '1029', (92, 98))	('germline mutation', 'Var', (34, 51))	('disrupted', 'Reg', (19, 28))	('p14ARF', 'Gene', (92, 98))
103348	32923148	As is depicted in Figure 3, the abundance of TIICs varies from sample to sample and TIMC abundance of normal samples is higher than that of tumor tissues in both GSE90713 and GSE12368.	('GSE90713', 'Var', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('TIMC', 'Chemical', '-', (84, 88))	('GSE12368', 'Var', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
103361	32923148	As shown in Figure 7c, expression of the hub genes was significantly decreased in the high TIMC group compared with low TIMC group (p < .001).	('hub', 'Gene', '1993', (41, 44))	('decreased', 'NegReg', (69, 78))	('expression', 'MPA', (23, 33))	('hub', 'Gene', (41, 44))	('TIMC', 'Chemical', '-', (120, 124))	('TIMC', 'Chemical', '-', (91, 95))	('high TIMC', 'Var', (86, 95))
103366	32923148	FCM validated that both CD8 + T and CD4 + T cells' abundance was significantly higher in high TIMC group (Supplementary figure 3A).	('TIMC', 'Chemical', '-', (94, 98))	('CD4', 'Gene', (36, 39))	('high TIMC', 'Var', (89, 98))	('CD8', 'Gene', (24, 27))	('CD8', 'Gene', '925', (24, 27))	('higher', 'PosReg', (79, 85))	('CD4', 'Gene', '920', (36, 39))
103367	32923148	As is shown in Supplementary figure 3B, IL-4 of CD4 + T cells was significantly higher in high TIMC group.	('high TIMC', 'Var', (90, 99))	('CD4', 'Gene', (48, 51))	('IL-4', 'Gene', '3565', (40, 44))	('IL-4', 'Gene', (40, 44))	('CD4', 'Gene', '920', (48, 51))	('TIMC', 'Chemical', '-', (95, 99))	('higher', 'PosReg', (80, 86))
103368	32923148	PRF1 and Ki-67 of CD8 + T cells also elevated significantly in high TIMC group (Supplementary figure 3 C).	('PRF1', 'Gene', '5551', (0, 4))	('PRF1', 'Gene', (0, 4))	('elevated', 'PosReg', (37, 45))	('CD8', 'Gene', (18, 21))	('TIMC', 'Chemical', '-', (68, 72))	('CD8', 'Gene', '925', (18, 21))	('high TIMC', 'Var', (63, 72))	('Ki-67', 'CPA', (9, 14))
103377	32923148	Many studies have shown that TIMC may be related to tumor microvessels density and promote tumor angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('TIMC', 'Chemical', '-', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('promote', 'PosReg', (83, 90))	('TIMC', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (91, 96))
103444	31701230	However, a number of high-grade complications of adrenalectomy not typically reported in the literature have come to light in the minimally invasive era including injuries to the porta hepatis that have resulted in liver failure and have led to liver transplantation, injuries to the renal vessels or ureter requiring nephrectomy, and inappropriate organ resection, particularly mistaken resection of the tail of the pancreas instead of the adrenal gland.	('liver', 'Disease', (245, 250))	('ureter', 'Disease', (301, 307))	('liver failure', 'Phenotype', 'HP:0001399', (215, 228))	('injuries', 'Var', (268, 276))	('injuries', 'Var', (163, 171))	('led to', 'Reg', (238, 244))	('liver failure', 'Disease', 'MESH:D017093', (215, 228))	('liver failure', 'Disease', (215, 228))	('ureter', 'Disease', 'MESH:D014516', (301, 307))
103494	30140784	Congenital adrenal hyperplasia (CAH) (MIM 201910) is a group of autosomal recessive disorders caused by a deficiency of an enzyme involved in cortisol biosynthesis.	('caused by', 'Reg', (94, 103))	('CAH', 'Disease', (32, 35))	('autosomal recessive disorders', 'Disease', 'MESH:D030342', (64, 93))	('CAH', 'Disease', 'None', (32, 35))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (11, 30))	('deficiency', 'Var', (106, 116))	('Congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (0, 30))	('Congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (0, 30))	('CAH', 'Phenotype', 'HP:0008258', (32, 35))	('autosomal recessive disorders', 'Disease', (64, 93))	('cortisol', 'Chemical', 'MESH:D006854', (142, 150))	('Congenital adrenal hyperplasia', 'Disease', (0, 30))
103496	30140784	Deficiencies of 21OH are caused by mutations in the CYP21A2 gene encoding the adrenal enzyme 21-hydroxylase.	('Deficiencies', 'Var', (0, 12))	('CYP21A2', 'Gene', (52, 59))	('CYP21A2', 'Gene', '1589', (52, 59))	('caused by', 'Reg', (25, 34))	('mutations', 'Var', (35, 44))
103535	30140784	Mutations in CYP21A2 can be classified according to the impact on 21-hydroxylase enzymatic activity.	('CYP21A2', 'Gene', '1589', (13, 20))	('Mutations', 'Var', (0, 9))	('impact', 'Reg', (56, 62))	('21-hydroxylase enzymatic activity', 'MPA', (66, 99))	('CYP21A2', 'Gene', (13, 20))
103536	30140784	The homozygous mutation identified in our patient has been previously associated with a severe form of 21OHD, revealed by SW during the neonatal period.	('21OHD', 'Disease', (103, 108))	('associated with', 'Reg', (70, 85))	('patient', 'Species', '9606', (42, 49))	('21OHD', 'Chemical', '-', (103, 108))	('SW', 'Phenotype', 'HP:0000127', (122, 124))	('homozygous', 'Var', (4, 14))
103540	30140784	Apart from the CYP21A2 mutations, other genes may affect the phenotype by modifying steroid action or salt balance.	('mutations', 'Var', (23, 32))	('affect', 'Reg', (50, 56))	('salt balance', 'MPA', (102, 114))	('modifying', 'Reg', (74, 83))	('steroid action', 'MPA', (84, 98))	('CYP21A2', 'Gene', (15, 22))	('CYP21A2', 'Gene', '1589', (15, 22))	('steroid', 'Chemical', 'MESH:D013256', (84, 91))	('salt balance', 'Phenotype', 'HP:0000127', (102, 114))	('salt', 'Chemical', 'MESH:D012492', (102, 106))
103553	29344287	For example, microRNA-483 (miR-483) aberrant expression plays a pivotal part in tumor biology in a variety of human cancer, including DTCs.	('aberrant expression', 'Var', (36, 55))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('miR-483', 'Gene', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('DTCs', 'Disease', (134, 138))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Disease', (80, 85))	('human', 'Species', '9606', (110, 115))	('microRNA-483', 'Gene', '619552', (13, 25))	('miR-483', 'Gene', '619552', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('microRNA-483', 'Gene', (13, 25))
103557	29344287	Particularly, emerging evidence suggests that abnormalities in the expression of miRNA are associated with a variety of cancers, including DTCs.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('abnormalities', 'Var', (46, 59))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('miRNA', 'Gene', (81, 86))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('expression', 'MPA', (67, 77))	('DTCs', 'Disease', (139, 143))	('associated', 'Reg', (91, 101))
103587	29344287	Furthermore, epigenetic features, including DNA methylation, histone modifications, and miRNAs, have been described as early events in carcinogenesis recently.	('carcinogenesis', 'Disease', (135, 149))	('miRNAs', 'CPA', (88, 94))	('DNA methylation', 'Var', (44, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (135, 149))	('histone', 'MPA', (61, 68))
103596	29344287	It has been reported that miR-483-3p is over-expressed in hepatocellular carcinoma that carry mutations in Wnt/beta-catenin signaling pathway genes and in hepatocellular carcinoma with wild-type TP53 gene.	('hepatocellular carcinoma', 'Disease', (58, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 82))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('TP53', 'Gene', (195, 199))	('hepatocellular carcinoma', 'Disease', (155, 179))	('miR-483', 'Gene', '619552', (26, 33))	('mutations', 'Var', (94, 103))	('beta-catenin', 'Gene', (111, 123))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (58, 82))	('miR-483', 'Gene', (26, 33))	('beta-catenin', 'Gene', '1499', (111, 123))	('over-expressed', 'PosReg', (40, 54))	('TP53', 'Gene', '7157', (195, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
103599	29344287	In another research by this author, researchers found that O-GlcNAc transferase(OGT) is an important factor which meditates numeral cellular processes and repression of its activity brings about low-expression of miR-483-3p.	('low-expression', 'MPA', (195, 209))	('OGT', 'Gene', '8473', (80, 83))	('miR-483', 'Gene', '619552', (213, 220))	('miR-483', 'Gene', (213, 220))	('repression', 'Var', (155, 165))	('OGT', 'Gene', (80, 83))
103610	29344287	Compared with side normal tissue, miR-483-3p is aberrantly over-active in pancreatic cancer tissues as a member of miR-483 family, indicating that aberrant expression of miR-483-3p is an important indicator in pancreatic cancer in the early stage and is related to tumor distinction and prognosis.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('miR-483', 'Gene', (170, 177))	('miR-483', 'Gene', (115, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (210, 227))	('miR-483', 'Gene', '619552', (115, 122))	('miR-483', 'Gene', (34, 41))	('miR-483', 'Gene', '619552', (170, 177))	('tumor', 'Disease', (265, 270))	('miR-483', 'Gene', '619552', (34, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('pancreatic cancer', 'Disease', 'MESH:D010190', (210, 227))	('pancreatic cancer', 'Disease', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('aberrant', 'Var', (147, 155))	('pancreatic cancer', 'Disease', (210, 227))	('related', 'Reg', (254, 261))
103617	29344287	In esophageal cancer, high expression of miR-483 had a poorer overall survival and a less median survival, and it may predict less sensitivity to chemotherapy.	('high expression', 'Var', (22, 37))	('miR-483', 'Gene', (41, 48))	('overall survival', 'CPA', (62, 78))	('median survival', 'CPA', (90, 105))	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('less', 'NegReg', (85, 89))	('poorer', 'NegReg', (55, 61))	('less', 'NegReg', (126, 130))	('miR-483', 'Gene', '619552', (41, 48))
103653	28727379	The mean time to present with local recurrence was significantly longer in the ARDT group compared with the control Group (419+-206 days vs. 181+-86 days, respectively; p=0.03).	('ARDT', 'Chemical', '-', (79, 83))	('longer', 'PosReg', (65, 71))	('ARDT', 'Var', (79, 83))	('local recurrence', 'CPA', (30, 46))
103875	27894345	Adrenal laterality (right or left sides) was not found to be a useful predictor for adrenal gland abnormality, whereas bilateral lesions were significantly associated with cortical hyperplasia.	('cortical hyperplasia', 'Disease', 'MESH:D006965', (172, 192))	('adrenal gland abnormality', 'Disease', (84, 109))	('adrenal gland abnormality', 'Phenotype', 'HP:0000834', (84, 109))	('adrenal gland abnormality', 'Disease', 'MESH:D000307', (84, 109))	('associated', 'Reg', (156, 166))	('cortical hyperplasia', 'Disease', (172, 192))	('bilateral lesions', 'Var', (119, 136))
103953	21167385	Rare and Unusual Endocrine Cancer Syndromes with Mutated Genes The study of a number of rare familial syndromes associated with endocrine tumor development has led to the identification of genes involved in the development of these tumors.	('familial syndrome', 'Disease', (93, 110))	('Mutated Genes', 'Var', (49, 62))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('endocrine tumor', 'Disease', 'MESH:D004701', (128, 143))	('endocrine tumor', 'Disease', (128, 143))	('Endocrine Cancer', 'Phenotype', 'HP:0100568', (17, 33))	('Endocrine Cancer', 'Disease', 'MESH:D004701', (17, 33))	('endocrine tumor', 'Phenotype', 'HP:0100568', (128, 143))	('familial syndrome', 'Disease', 'MESH:D009386', (93, 110))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('Endocrine Cancer', 'Disease', (17, 33))	('tumors', 'Disease', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
103973	21167385	The molecular cause of the disease in most patients with Carney complex and PPNAD has been identified as mutations within the gene PRKAR1A on chromosome 17q22-24.	('patients', 'Species', '9606', (43, 51))	('PRKAR1A', 'Gene', '5573', (131, 138))	('Carney complex', 'Disease', (57, 71))	('cause', 'Reg', (14, 19))	('mutations', 'Var', (105, 114))	('PRKAR1A', 'Gene', (131, 138))	('PPNAD', 'Chemical', '-', (76, 81))
103975	21167385	Inactivating mutations of PRKAR1A have been reported in 45-80% of families with Carney complex.	('Carney complex', 'Disease', (80, 94))	('PRKAR1A', 'Gene', (26, 33))	('Inactivating mutations', 'Var', (0, 22))	('PRKAR1A', 'Gene', '5573', (26, 33))	('reported', 'Reg', (44, 52))
103983	21167385	One classic example is the development of BMAH in children with McCune Albright syndrome, who harbor a somatic activating mutation in GNAS which encodes the stimulatory G-protein alpha subunit.	('GNAS', 'Gene', (134, 138))	('mutation', 'Var', (122, 130))	('children', 'Species', '9606', (50, 58))	('activating', 'PosReg', (111, 121))	('McCune Albright syndrome', 'Disease', (64, 88))	('McCune Albright syndrome', 'Disease', 'MESH:D005357', (64, 88))	('GNAS', 'Gene', '2778', (134, 138))
103990	21167385	Li-Fraumeni syndrome is associated with heterozygous germ line inactivating mutations of the p53 tumor suppressor gene on chromosome 17p.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('inactivating mutations', 'Var', (63, 85))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('tumor', 'Disease', (97, 102))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))
103991	21167385	Loss of heterozygosity by deletion of the wild-type p53 allele has been demonstrated in adrenocortical tumors isolated from patients with Li-Fraumeni syndrome.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('adrenocortical tumors', 'Disease', (88, 109))	('deletion', 'Var', (26, 34))	('Li-Fraumeni syndrome', 'Disease', (138, 158))	('Loss', 'NegReg', (0, 4))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (88, 109))	('patients', 'Species', '9606', (124, 132))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (138, 158))
103992	21167385	Because of the strong link between individuals with adrenocortical cancer and germline p53 mutations, genetic testing of p53 is recommended for individuals with ACC; screening for the spectrum of cancers associated with Li-Fraumeni syndrome should therefore be performed in these patients.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('patients', 'Species', '9606', (280, 288))	('Li-Fraumeni syndrome', 'Disease', (220, 240))	('p53', 'Gene', (87, 90))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (87, 90))	('p53', 'Gene', '7157', (121, 124))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (52, 73))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (91, 100))	('cancers', 'Disease', (196, 203))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (220, 240))	('adrenocortical cancer', 'Disease', (52, 73))
103995	21167385	The molecular basis of Beckwith-Wiedemann syndrome is complex, involving deregulation of imprinted genes found within the 11p15 region, including IGF2, H19, KCNQ1, KCNQ1OT1, and CDKN1C Individuals with Beckwith-Wiedemann syndrome often have uniparental paternal isodisomy for the IGF2 locus, leading to overexpression of IGF2 and subsequent tumor progression; rearrangements at the 11p15 locus and overexpression of IGF2 are also seen in sporadic adrenocortical tumors.	('p15', 'Gene', '1030', (384, 387))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('KCNQ1', 'Gene', (157, 162))	('H19', 'Gene', (152, 155))	('CDKN1C', 'Gene', (178, 184))	('KCNQ1', 'Gene', '3784', (157, 162))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (202, 229))	('uniparental paternal isodisomy', 'Disease', (241, 271))	('IGF2', 'Gene', (146, 150))	('KCNQ1OT1', 'Gene', '10984', (164, 172))	('IGF2', 'Gene', (280, 284))	('H19', 'Gene', '283120', (152, 155))	('sporadic adrenocortical tumors', 'Disease', (438, 468))	('KCNQ1OT1', 'Gene', (164, 172))	('KCNQ1', 'Gene', (164, 169))	('tumor', 'Disease', (462, 467))	('IGF2', 'Gene', (321, 325))	('sporadic adrenocortical tumors', 'Disease', 'MESH:D018268', (438, 468))	('KCNQ1', 'Gene', '3784', (164, 169))	('IGF2', 'Gene', (416, 420))	('tumor', 'Disease', 'MESH:D009369', (462, 467))	('tumor', 'Disease', (341, 346))	('Beckwith-Wiedemann syndrome', 'Disease', (23, 50))	('p15', 'Gene', (124, 127))	('tumors', 'Phenotype', 'HP:0002664', (462, 468))	('IGF2', 'Gene', '3481', (146, 150))	('CDKN1C', 'Gene', '1028', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (341, 346))	('overexpression', 'PosReg', (303, 317))	('rearrangements', 'Var', (360, 374))	('p15', 'Gene', (384, 387))	('IGF2', 'Gene', '3481', (280, 284))	('IGF2', 'Gene', '3481', (321, 325))	('tumor', 'Phenotype', 'HP:0002664', (462, 467))	('IGF2', 'Gene', '3481', (416, 420))	('Beckwith-Wiedemann syndrome', 'Disease', (202, 229))	('p15', 'Gene', '1030', (124, 127))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (23, 50))	('uniparental paternal isodisomy', 'Disease', 'MESH:D024182', (241, 271))
103998	21167385	Hypoglycemia due to hyperplastic islets of Langerhans is a feature leading to hypoglycemia in 54% of patents with Beckwith-Widemann syndrome.	('Hypoglycemia', 'Disease', 'MESH:D007003', (0, 12))	('Hypoglycemia', 'Disease', (0, 12))	('hypoglycemia', 'Disease', (78, 90))	('hyperplastic islets of Langerhans', 'Phenotype', 'HP:0004510', (20, 53))	('hypoglycemia', 'Phenotype', 'HP:0001943', (78, 90))	('Hypoglycemia', 'Phenotype', 'HP:0001943', (0, 12))	('Beckwith-Widemann syndrome', 'Disease', 'MESH:D001506', (114, 140))	('hyperplastic', 'Var', (20, 32))	('hypoglycemia', 'Disease', 'MESH:D007003', (78, 90))	('Beckwith-Widemann syndrome', 'Disease', (114, 140))
103999	21167385	Familial polyposis coli (FPC) is an autosomal dominant disorder due to mutations in the adenomatous polyposis coli gene (APC) located on chromosome 5q21-22.	('due to', 'Reg', (64, 70))	('Familial polyposis coli', 'Disease', 'MESH:D011125', (0, 23))	('FPC', 'Disease', (25, 28))	('FPC', 'Disease', 'MESH:D011125', (25, 28))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (36, 63))	('adenomatous polyposis coli gene', 'Gene', (88, 119))	('mutations', 'Var', (71, 80))	('Familial polyposis coli', 'Disease', (0, 23))	('autosomal dominant disorder', 'Disease', (36, 63))	('APC', 'Disease', 'MESH:D011125', (121, 124))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (88, 114))	('APC', 'Disease', (121, 124))	('adenomatous polyposis coli gene', 'Gene', '324', (88, 119))
104004	21167385	Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by mutations in the fumarate hydratase gene (FH) on chromosome 1q42.3-43.	('mutations', 'Var', (100, 109))	('autosomal dominant disorder', 'Disease', (62, 89))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('renal cell cancer', 'Phenotype', 'HP:0005584', (30, 47))	('fumarate hydratase', 'Gene', '2271', (117, 135))	('Hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (0, 47))	('FH', 'Gene', (142, 144))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (62, 89))	('fumarate hydratase', 'Gene', (117, 135))	('caused by', 'Reg', (90, 99))
104017	21167385	NF-1 is caused by mutations of the gene encoding neurofibromin, located on chromosome 17q11.2.	('NF-1', 'Gene', '4763', (0, 4))	('neurofibromin', 'Gene', '4763', (49, 62))	('NF-1', 'Gene', (0, 4))	('caused by', 'Reg', (8, 17))	('neurofibromin', 'Gene', (49, 62))	('mutations', 'Var', (18, 27))
104019	21167385	Loss-of function mutations in NF-1 lead to dysregulated growth due to increased signaling via downstream pathways, including the mitogen-activated protein kinase (MAPK) pathway and mTOR pathway.	('NF-1', 'Gene', (30, 34))	('dysregulated growth', 'MPA', (43, 62))	('increased', 'PosReg', (70, 79))	('Loss-of function', 'NegReg', (0, 16))	('signaling', 'MPA', (80, 89))	('mTOR', 'Gene', '2475', (181, 185))	('mutations', 'Var', (17, 26))	('mTOR', 'Gene', (181, 185))	('NF-1', 'Gene', '4763', (30, 34))
104026	21167385	If biochemical testing is positive, conventional imaging as well as functional imaging with I123 MIBG may be utilized for additional tumor characterization.	('MIBG', 'Gene', (97, 101))	('I123', 'Var', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('MIBG', 'Chemical', 'MESH:D019797', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))
104030	21167385	TSC is caused by mutations of two tumor suppressor genes, TSC1 and TSC2.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('TSC', 'Gene', (58, 61))	('TSC', 'Gene', (0, 3))	('TSC', 'Gene', '7248', (58, 61))	('TSC', 'Gene', '7248', (0, 3))	('TSC2', 'Gene', '7249', (67, 71))	('TSC1', 'Gene', '7248', (58, 62))	('mutations', 'Var', (17, 26))	('TSC', 'Gene', '7248', (67, 70))	('caused by', 'Reg', (7, 16))	('TSC1', 'Gene', (58, 62))	('TSC2', 'Gene', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('TSC', 'Gene', (67, 70))
104049	21167385	Mutations in the phosphate and tensin gene (PTEN) on chromosome 10q23.31 are found in approximately 80 percent of patients with Cowden disease.	('Cowden disease', 'Disease', (128, 142))	('found', 'Reg', (77, 82))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('Cowden disease', 'Disease', 'MESH:D006223', (128, 142))	('patients', 'Species', '9606', (114, 122))	('phosphate', 'Chemical', 'MESH:D010710', (17, 26))
104050	21167385	Loss-of-function mutations in this regulator of neuroendocrine development lead to constitutive activation of mTOR.	('mTOR', 'Gene', (110, 114))	('Loss-of-function', 'NegReg', (0, 16))	('mTOR', 'Gene', '2475', (110, 114))	('constitutive activation', 'MPA', (83, 106))	('mutations', 'Var', (17, 26))
104056	21167385	In over one half of cases, PJS is due to mutations in the serine-threonine kinase STK11/LKB1 tumor suppressor gene, located on 19p13.	('mutations', 'Var', (41, 50))	('STK11', 'Gene', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('STK11', 'Gene', '6794', (82, 87))	('tumor', 'Disease', (93, 98))	('PJS', 'Disease', (27, 30))	('due', 'Reg', (34, 37))	('LKB1', 'Gene', (88, 92))	('PJS', 'Disease', 'MESH:D010580', (27, 30))	('LKB1', 'Gene', '6794', (88, 92))
104057	21167385	Mutations in STK11/LKB1 lead to deregulated mTOR signaling.	('LKB1', 'Gene', '6794', (19, 23))	('STK11', 'Gene', (13, 18))	('mTOR', 'Gene', (44, 48))	('Mutations', 'Var', (0, 9))	('mTOR', 'Gene', '2475', (44, 48))	('STK11', 'Gene', '6794', (13, 18))	('LKB1', 'Gene', (19, 23))
104063	21167385	Germline loss-of-function mutations of the SDHB, SDHC, and SDHD genes have been found in the majority of patients with the Carney-Stratakis syndrome.	('patients', 'Species', '9606', (105, 113))	('SDHB', 'Gene', '6390', (43, 47))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (123, 148))	('SDHC', 'Gene', (49, 53))	('mutations', 'Var', (26, 35))	('SDHB', 'Gene', (43, 47))	('SDHC', 'Gene', '6391', (49, 53))	('SDHD', 'Gene', '6392', (59, 63))	('SDHD', 'Gene', (59, 63))	('Carney-Stratakis syndrome', 'Disease', (123, 148))	('loss-of-function', 'NegReg', (9, 25))
104064	21167385	SDH is a component of the mitochondrial electron transport chain; mutations cause increased susceptibility to cancer by acting as a tumor suppressor gene, leading to aberrant regulation of tumor growth.	('mutations', 'Var', (66, 75))	('cancer', 'Disease', (110, 116))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('SDH', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('SDH', 'Gene', '6390', (0, 3))
104088	21167385	Results of the phase III trial of sunitinib versus placebo for treatment of advanced pancreatic neuroendocrine tumors show that sunitinib prolonged progression free survival, and increased objective response rate and overall survival in those studied.	('sunitinib', 'Chemical', 'MESH:D000077210', (34, 43))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (96, 116))	('overall survival', 'CPA', (217, 233))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (96, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('objective response rate', 'CPA', (189, 212))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('prolonged', 'PosReg', (138, 147))	('sunitinib', 'Var', (128, 137))	('sunitinib', 'Chemical', 'MESH:D000077210', (128, 137))	('endocrine tumor', 'Phenotype', 'HP:0100568', (101, 116))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (85, 117))	('pancreatic neuroendocrine tumors', 'Disease', (85, 117))	('increased', 'PosReg', (179, 188))	('progression', 'MPA', (148, 159))
104105	31956294	However, due to the lack of MMR genes in tumor cells or defects in the process of replication repair, the possibility of gene mutation is increased.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('defects', 'NegReg', (56, 63))	('tumor', 'Disease', (41, 46))	('gene mutation', 'Var', (121, 134))	('MMR genes', 'Gene', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
104109	31956294	Early findings by researchers showed that most of the MSI cases are sporadic colorectal cancer, which is caused by epigenetic inactivation of gene expression in offspring on account of the methylation of hMLH1 promoter without the gene mutation.	('sporadic colorectal cancer', 'Disease', 'MESH:D015179', (68, 94))	('methylation', 'Var', (189, 200))	('hMLH1', 'Gene', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('hMLH1', 'Gene', '4292', (204, 209))	('MSI', 'Disease', 'MESH:D053842', (54, 57))	('sporadic colorectal cancer', 'Disease', (68, 94))	('MSI', 'Disease', (54, 57))
104110	31956294	Lynch syndrome is an autosomal dominant tumor syndrome caused by mutations in MMR strains, and it can also cause tumors in other parts of the colon and rectum.	('colon', 'Disease', 'MESH:D015179', (142, 147))	('caused by', 'Reg', (55, 64))	('autosomal dominant tumor syndrome', 'Disease', 'None', (21, 54))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('MMR strains', 'Gene', (78, 89))	('autosomal dominant tumor syndrome', 'Disease', (21, 54))	('cause', 'Reg', (107, 112))	('Lynch syndrome', 'Disease', (0, 14))	('colon', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('mutations', 'Var', (65, 74))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
104116	31956294	Owing to errors in the function of MMR during DNA replication, MSI can be liable to emerge.	('function', 'MPA', (23, 31))	('errors', 'Var', (9, 15))	('MSI', 'Disease', 'MESH:D053842', (63, 66))	('MSI', 'Disease', (63, 66))	('MMR', 'Gene', (35, 38))
104120	31956294	In 2017, MSK's IMPACT products were approved to detect microsatellite instability in cancer tissues.	('detect', 'Reg', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('microsatellite', 'Var', (55, 69))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
104122	31956294	The method of Polymerase Chain Reaction (PCR) is to compare the microsatellite loci detected in tumor tissues with normal DNA.	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('microsatellite', 'Var', (64, 78))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))
104123	31956294	And the National Cancer Institute recommended two single nucleotide repeat loci BAT-25 and BAT-26 and three multi-nucleotide repeat loci D2S123, D5S346 and D17S250 as microsatellite markers to determine the status of MSI.	('D17S250', 'Var', (156, 163))	('Cancer', 'Disease', (17, 23))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('MSI', 'Disease', 'MESH:D053842', (217, 220))	('D2S123', 'Var', (137, 143))	('MSI', 'Disease', (217, 220))	('D5S346', 'Var', (145, 151))
104135	31956294	For example, dMMR caused by MSH6 mutation could not meet the criteria of MSI-H diagnosis, and MSI-H positive tumor may come from MMR pathway protein which could not be detected by current technology.	('MMR', 'Pathway', (129, 132))	('MSH6', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('come from', 'Reg', (119, 128))	('dMMR', 'Disease', (13, 17))	('MSI', 'Disease', (94, 97))	('MSI', 'Disease', 'MESH:D053842', (73, 76))	('MSH6', 'Gene', '2956', (28, 32))	('MSI', 'Disease', (73, 76))	('MSI', 'Disease', 'MESH:D053842', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
104138	31956294	This method can accurately diagnose pan cancer microsatellite instability by single molecule reverse probe capture and high-throughput sequencing.	('diagnose', 'Reg', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('microsatellite instability', 'Var', (47, 73))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
104145	31956294	Researchers have found that mutations in MSI-H patients had commonalities.	('patients', 'Species', '9606', (47, 55))	('mutations', 'Var', (28, 37))	('MSI', 'Disease', (41, 44))	('MSI', 'Disease', 'MESH:D053842', (41, 44))
104148	31956294	According to the research results, a class of noncoding RNA molecules similar to cancer cell pathogens can trigger human immune response and accelerate the development of cancer.	('noncoding', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', (171, 177))	('human', 'Species', '9606', (115, 120))	('accelerate', 'PosReg', (141, 151))	('trigger', 'PosReg', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('human immune response', 'CPA', (115, 136))
104160	31956294	Silencing WRN can induce DNA double-strand breakage, activate DNA damage response, induce apoptosis and cell cycle arrest MSI tumors require WRN helicases but do not cause death of their own cells, suggesting that WRN may be a target for lethal synthesis.	('WRN', 'Gene', (141, 144))	('WRN', 'Gene', '7486', (141, 144))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('induce', 'Reg', (83, 89))	('WRN', 'Gene', '7486', (214, 217))	('cell cycle arrest', 'CPA', (104, 121))	('WRN', 'Gene', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Silencing', 'Var', (0, 9))	('activate', 'PosReg', (53, 61))	('tumors', 'Disease', (126, 132))	('DNA double-strand breakage', 'MPA', (25, 51))	('induce', 'Reg', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (104, 121))	('MSI', 'Disease', 'MESH:D053842', (122, 125))	('MSI', 'Disease', (122, 125))	('DNA damage response', 'MPA', (62, 81))	('apoptosis', 'CPA', (90, 99))	('WRN', 'Gene', '7486', (10, 13))	('WRN', 'Gene', (10, 13))
104161	31956294	The above studies indicate that microsatellite mutation is a multi-pathway process, and the continuously updated and developed MSI mechanism will play a more important role in the diagnosis and treatment of future clinical applications.	('MSI', 'Disease', 'MESH:D053842', (127, 130))	('MSI', 'Disease', (127, 130))	('microsatellite mutation', 'Var', (32, 55))
104166	31956294	The IHC test results show that the negative hMLH1 cannot directly indicate that there is no mutation in hMLH1, and the hMLH1 promoter needs to be tested to determine whether there is methylation or BRAF (v-RAF murine sarcoma viral oncogene homologB1) mutation, so as to exclude Lynch syndrome.	('Lynch syndrome', 'Disease', (278, 292))	('hMLH1', 'Gene', (44, 49))	('v-RAF', 'Gene', '110157', (204, 209))	('murine', 'Species', '10090', (210, 216))	('hMLH1', 'Gene', '4292', (44, 49))	('hMLH1', 'Gene', (119, 124))	('Lynch syndrome', 'Disease', 'MESH:D003123', (278, 292))	('hMLH1', 'Gene', '4292', (119, 124))	('mutation', 'Var', (251, 259))	('BRAF', 'Gene', (198, 202))	('hMLH1', 'Gene', '4292', (104, 109))	('hMLH1', 'Gene', (104, 109))	('sarcoma', 'Disease', 'MESH:D012509', (217, 224))	('sarcoma', 'Disease', (217, 224))	('methylation', 'Var', (183, 194))	('v-RAF', 'Gene', (204, 209))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))
104167	31956294	However, EpCAM (Epithelial cell adhesion molecule) gene is still needed to be detected in suspected hMSH2 patients, because LS caused by hypermethylation of hMSH2 which caused by EpCAM body mutation will also lead to the loss of MMR protein expression in IHC detection, but hMSH2 mutation analysis is negative.	('EpCAM', 'Gene', (9, 14))	('hMSH2', 'Gene', (274, 279))	('EpCAM', 'Gene', '4072', (9, 14))	('Epithelial cell adhesion molecule', 'Gene', '4072', (16, 49))	('hMSH2', 'Gene', '4436', (157, 162))	('Epithelial cell adhesion molecule', 'Gene', (16, 49))	('hMSH2', 'Gene', (157, 162))	('MMR protein', 'Protein', (229, 240))	('patients', 'Species', '9606', (106, 114))	('hMSH2', 'Gene', '4436', (100, 105))	('EpCAM', 'Gene', (179, 184))	('IHC', 'Disease', (255, 258))	('mutation', 'Var', (190, 198))	('hMSH2', 'Gene', '4436', (274, 279))	('loss', 'NegReg', (221, 225))	('EpCAM', 'Gene', '4072', (179, 184))	('hypermethylation', 'Var', (137, 153))	('hMSH2', 'Gene', (100, 105))	('LS', 'Disease', 'MESH:D003123', (124, 126))
104168	31956294	Only when EpCAM immunostaining is negative, EpCAM abnormality indicates hMSH2 mutation.	('mutation', 'Var', (78, 86))	('EpCAM', 'Gene', '4072', (10, 15))	('EpCAM', 'Gene', (44, 49))	('hMSH2', 'Gene', '4436', (72, 77))	('hMSH2', 'Gene', (72, 77))	('EpCAM', 'Gene', '4072', (44, 49))	('EpCAM', 'Gene', (10, 15))
104176	31956294	BRAF mutation affects the MMR function of early diseases, and has an important effect on CRC.	('effect', 'Reg', (79, 85))	('MMR function', 'CPA', (26, 38))	('CRC', 'Disease', (89, 92))	('affects', 'Reg', (14, 21))	('BRAF', 'Gene', (0, 4))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))	('early diseases', 'Disease', (42, 56))	('mutation', 'Var', (5, 13))	('CRC', 'Disease', 'MESH:D015179', (89, 92))
104177	31956294	found that the prognosis of MSI-H colorectal cancer was good, which was the important reason of BRAF mutation in early diseases, while the prognosis of MSS and MSI-L CRC was poor.	('MSI', 'Disease', (160, 163))	('MSI-L CRC', 'Disease', 'MESH:D015179', (160, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('colorectal cancer', 'Disease', (34, 51))	('CRC', 'Phenotype', 'HP:0003003', (166, 169))	('colorectal cancer', 'Disease', 'MESH:D015179', (34, 51))	('MSI', 'Disease', 'MESH:D053842', (28, 31))	('MSI', 'Disease', (28, 31))	('mutation', 'Var', (101, 109))	('MSI-L CRC', 'Disease', (160, 169))	('MSI', 'Disease', 'MESH:D053842', (160, 163))
104178	31956294	showed that BRAF mutation is associated with MSI-H in metastatic CRC patients with advanced BRAF mutation,but BRAF mutation is a bad factor.	('mutation', 'Var', (97, 105))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', (92, 96))	('CRC', 'Phenotype', 'HP:0003003', (65, 68))	('CRC', 'Disease', 'MESH:D015179', (65, 68))	('MSI', 'Disease', 'MESH:D053842', (45, 48))	('MSI', 'Disease', (45, 48))	('associated', 'Reg', (29, 39))	('patients', 'Species', '9606', (69, 77))	('CRC', 'Disease', (65, 68))
104184	31956294	suggest that microsatellite instability is also found in gastric cancer.	('gastric cancer', 'Disease', (57, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('found', 'Reg', (48, 53))	('microsatellite instability', 'Var', (13, 39))
104190	31956294	Because the American Society of clinical oncology gastrointestinal cancer symposium found that MSI can be used as a good prognostic indicator for resectable primary gastric cancer, future clinical trials need to consider whether to use immunosuppressive checkpoint inhibitors (ICI) to treat gastric cancer with high microsatellite instability due to MSI as a stratification factor.	('gastrointestinal cancer', 'Disease', (50, 73))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (50, 73))	('gastric cancer', 'Phenotype', 'HP:0012126', (165, 179))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (50, 73))	('gastric cancer', 'Disease', (291, 305))	('oncology', 'Phenotype', 'HP:0002664', (41, 49))	('resectable', 'Disease', (146, 156))	('gastric cancer', 'Disease', (165, 179))	('gastric cancer', 'Disease', 'MESH:D013274', (291, 305))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('gastric cancer', 'Disease', 'MESH:D013274', (165, 179))	('MSI', 'Disease', 'MESH:D053842', (95, 98))	('MSI', 'Disease', (95, 98))	('microsatellite', 'Var', (316, 330))	('MSI', 'Disease', 'MESH:D053842', (350, 353))	('MSI', 'Disease', (350, 353))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gastric cancer', 'Phenotype', 'HP:0012126', (291, 305))
104194	31956294	IHC detection of hMSH2, hMLH1 and MSI related loci D3S1766 and D2S2739 can identify MSI related breast cancer.	('MSI', 'Disease', 'MESH:D053842', (84, 87))	('MSI', 'Disease', (84, 87))	('hMLH1', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('identify', 'Reg', (75, 83))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('D2S2739', 'Var', (63, 70))	('hMLH1', 'Gene', '4292', (24, 29))	('MSI', 'Disease', (34, 37))	('D3S1766', 'Var', (51, 58))	('hMSH2', 'Gene', (17, 22))	('breast cancer', 'Disease', (96, 109))	('hMSH2', 'Gene', '4436', (17, 22))	('MSI', 'Disease', 'MESH:D053842', (34, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
104196	31956294	has shown that BRCA1 expression function can affect the silencing mechanism of satellite DNA in chromatin, which will be damaged by BRCA1 mutation, resulting in failure of normal cell replication process.	('affect', 'Reg', (45, 51))	('silencing mechanism', 'MPA', (56, 75))	('BRCA1', 'Gene', (15, 20))	('cell replication process', 'CPA', (179, 203))	('BRCA1', 'Gene', '672', (15, 20))	('BRCA1', 'Gene', '672', (132, 137))	('mutation', 'Var', (138, 146))	('BRCA1', 'Gene', (132, 137))	('failure', 'NegReg', (161, 168))
104197	31956294	At the same time, the mutation of BRCA1, which can make the repair function of DNA loss, will cause microsatellite instability and abnormal cells.	('BRCA1', 'Gene', '672', (34, 39))	('abnormal cells', 'CPA', (131, 145))	('mutation', 'Var', (22, 30))	('microsatellite instability', 'MPA', (100, 126))	('BRCA1', 'Gene', (34, 39))	('cause', 'Reg', (94, 99))
104206	31956294	clarified that MSI was detected in patients with chronic myeloid leukemia, while there was no MSI in normal people, so it was speculated that there was a certain relationship between chronic myeloid leukemia and microsatellite instability.	('microsatellite', 'Var', (212, 226))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (57, 73))	('leukemia', 'Phenotype', 'HP:0001909', (65, 73))	('leukemia', 'Phenotype', 'HP:0001909', (199, 207))	('people', 'Species', '9606', (108, 114))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (49, 73))	('chronic myeloid leukemia', 'Disease', (49, 73))	('MSI', 'Disease', 'MESH:D053842', (94, 97))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (49, 73))	('MSI', 'Disease', (94, 97))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (183, 207))	('patients', 'Species', '9606', (35, 43))	('chronic myeloid leukemia', 'Disease', (183, 207))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (183, 207))	('MSI', 'Disease', 'MESH:D053842', (15, 18))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (191, 207))	('MSI', 'Disease', (15, 18))
104207	31956294	They found that analysis of MSI related loci D17S261 and D3S643 is helpful to identify MSI related chronic leukemia.	('D3S643', 'Chemical', 'MESH:C040977', (57, 63))	('D3S643', 'Var', (57, 63))	('S261', 'CellLine', 'CVCL:2490', (48, 52))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('leukemia', 'Disease', 'MESH:D007938', (107, 115))	('D17S261', 'Var', (45, 52))	('leukemia', 'Disease', (107, 115))	('MSI', 'Disease', (28, 31))	('MSI', 'Disease', (87, 90))	('MSI', 'Disease', 'MESH:D053842', (28, 31))	('MSI', 'Disease', 'MESH:D053842', (87, 90))	('chronic leukemia', 'Phenotype', 'HP:0005558', (99, 115))
104210	31956294	has indicated that patients with MSI-H Lynch syndrome have a rising risk of bladder cancer because of hMSH2 mutations.	('bladder cancer', 'Disease', (76, 90))	('MSI', 'Disease', 'MESH:D053842', (33, 36))	('MSI', 'Disease', (33, 36))	('patients', 'Species', '9606', (19, 27))	('hMSH2', 'Gene', '4436', (102, 107))	('mutations', 'Var', (108, 117))	('hMSH2', 'Gene', (102, 107))	('Lynch syndrome', 'Disease', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('Lynch syndrome', 'Disease', 'MESH:D003123', (39, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
104213	31956294	suggested that the MSI related loci D16S476, D9S171 of MSI-H patients with bladder cancer are consistent with those in urine, and the MSI of urine sediment can be considered as a clinical assistant diagnosis.	('MSI', 'Disease', 'MESH:D053842', (19, 22))	('MSI', 'Disease', (19, 22))	('MSI', 'Disease', 'MESH:D053842', (134, 137))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('MSI', 'Disease', (134, 137))	('bladder cancer', 'Disease', (75, 89))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('D9S171', 'Var', (45, 51))	('MSI', 'Disease', 'MESH:D053842', (55, 58))	('MSI', 'Disease', (55, 58))	('D16S476', 'Var', (36, 43))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
104214	31956294	stated that MSI related loci D9S63, D9S156, and D9S283 can be used to screen patients with high micro bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('D9S156', 'Var', (36, 42))	('D9S63', 'Var', (29, 34))	('D9S156', 'CellLine', 'CVCL:M260', (36, 42))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('patients', 'Species', '9606', (77, 85))	('D9S283', 'Var', (48, 54))	('MSI', 'Disease', 'MESH:D053842', (12, 15))	('micro bladder', 'Phenotype', 'HP:0005343', (96, 109))	('MSI', 'Disease', (12, 15))
104226	31956294	And hMLH1 and hMSH2 inactivation have been detected in many pancreatic cancer patients.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('hMLH1', 'Gene', (4, 9))	('inactivation', 'Var', (20, 32))	('hMLH1', 'Gene', '4292', (4, 9))	('patients', 'Species', '9606', (78, 86))	('hMSH2', 'Gene', '4436', (14, 19))	('hMSH2', 'Gene', (14, 19))	('pancreatic cancer', 'Disease', (60, 77))	('detected', 'Reg', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))
104233	31956294	showed that the occurrence of MSI in adrenocortical carcinoma is related to the deletion mutations of MSH2.	('MSI', 'Disease', 'MESH:D053842', (30, 33))	('MSI', 'Disease', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('deletion mutations', 'Var', (80, 98))	('MSH2', 'Gene', (102, 106))	('MSH2', 'Gene', '4436', (102, 106))	('adrenocortical carcinoma', 'Disease', (37, 61))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (37, 61))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (37, 61))	('related', 'Reg', (65, 72))
104239	31956294	suggested that aspirin/sulinda may play a preventive role in reducing the risk of Lynch syndrome-related cancer by reducing microsatellite instability in colorectal cancer cells, especially in patients with hMSH2 and hMLH1 gene changes.	('changes', 'Var', (228, 235))	('aspirin', 'Chemical', 'MESH:D001241', (15, 22))	('colorectal cancer', 'Disease', (154, 171))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hMSH2', 'Gene', '4436', (207, 212))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))	('patients', 'Species', '9606', (193, 201))	('hMLH1', 'Gene', (217, 222))	('hMSH2', 'Gene', (207, 212))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('hMLH1', 'Gene', '4292', (217, 222))	('cancer', 'Disease', (165, 171))	('Lynch syndrome', 'Disease', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('microsatellite instability', 'MPA', (124, 150))	('reducing', 'NegReg', (115, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))	('Lynch syndrome', 'Disease', 'MESH:D003123', (82, 96))
104247	31956294	Some studies have shown that due to dMMR cancer cells can produce heterologous antigens that are easily recognized by T cells,the effectiveness of PD-1 inhibitors on solid tumors expressing MSI-H is higher than that of solid tumors expressing MSI-L and MSS.	('MSI-L', 'Disease', 'MESH:D053842', (243, 248))	('PD-1', 'Gene', (147, 151))	('PD-1', 'Gene', '5133', (147, 151))	('cancer', 'Disease', (41, 47))	('solid tumors', 'Disease', 'MESH:D009369', (166, 178))	('MSI', 'Disease', 'MESH:D053842', (243, 246))	('inhibitors', 'Var', (152, 162))	('MSI', 'Disease', (243, 246))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('solid tumors', 'Disease', (219, 231))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('solid tumors', 'Disease', 'MESH:D009369', (219, 231))	('MSI-L', 'Disease', (243, 248))	('effectiveness', 'MPA', (130, 143))	('higher', 'PosReg', (199, 205))	('solid tumors', 'Disease', (166, 178))	('MSI', 'Disease', 'MESH:D053842', (190, 193))	('MSI', 'Disease', (190, 193))
104251	31956294	We can also find this in Mark Yarchoan's article that the high benefit rate of dMMR patients on PD-1/PD-L1 inhibitors may be related to the gradual accumulation of mutations.	('patients', 'Species', '9606', (84, 92))	('PD-1', 'Gene', (96, 100))	('PD-L1', 'Gene', '29126', (101, 106))	('PD-1', 'Gene', '5133', (96, 100))	('mutations', 'Var', (164, 173))	('dMMR', 'Disease', (79, 83))	('PD-L1', 'Gene', (101, 106))
104254	31956294	suggested that Nivolumab is effective not only for patients with dMMR/MSI-H metastatic colorectal cancer, but also for those with poor prognosis of BRAF mutation in CRC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('CRC', 'Phenotype', 'HP:0003003', (165, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('CRC', 'Disease', 'MESH:D015179', (165, 168))	('colorectal cancer', 'Disease', (87, 104))	('MSI', 'Disease', 'MESH:D053842', (70, 73))	('patients', 'Species', '9606', (51, 59))	('MSI', 'Disease', (70, 73))	('CRC', 'Disease', (165, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))	('mutation', 'Var', (153, 161))
104255	31956294	It can be inferred that Nivolumab is also effective for dMMR/MSI-H metastatic colorectal cancer caused by BRAF mutation.	('MSI', 'Disease', 'MESH:D053842', (61, 64))	('MSI', 'Disease', (61, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('BRAF', 'Gene', (106, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('mutation', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('caused by', 'Reg', (96, 105))	('colorectal cancer', 'Disease', (78, 95))
104277	31956294	MSI is due to MMR deletion or gene replication process deletion or error, leading to changes in the length of MS. TMB refers to tumor mutational burden, representing the number of mutations per million bases.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('MSI', 'Disease', 'MESH:D053842', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('MSI', 'Disease', (0, 3))	('tumor', 'Disease', (128, 133))	('deletion', 'Var', (55, 63))
104284	31956294	For example, if the dMMR caused by MSH6 mutation cannot meet the criteria of MSI-H diagnosis, scientists need to increase MS loci other than BAT-25 and BAT-26 and three multi nuclear repeat loca D2S123, D5S346 and D17S250 to improve the accuracy of MSI.	('MSI', 'Disease', (77, 80))	('mutation', 'Var', (40, 48))	('MSI', 'Disease', 'MESH:D053842', (249, 252))	('MSI', 'Disease', (249, 252))	('D17S250', 'Var', (214, 221))	('MSH6', 'Gene', (35, 39))	('D2S123', 'Var', (195, 201))	('D5S346', 'Var', (203, 209))	('MSH6', 'Gene', '2956', (35, 39))	('dMMR', 'Disease', (20, 24))	('MSI', 'Disease', 'MESH:D053842', (77, 80))
104292	31956294	Besides, early diagnosis can help to take preventive measures for its diseases, such as Lynch syndrome, and early use of aspirin in patients with hMSH2 and hMLH1 gene changes is of great significance to reduce the risk of cancer related to Lynch syndrome.	('Lynch syndrome', 'Disease', (240, 254))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('hMLH1', 'Gene', '4292', (156, 161))	('Lynch syndrome', 'Disease', 'MESH:D003123', (240, 254))	('cancer', 'Disease', (222, 228))	('reduce', 'NegReg', (203, 209))	('Lynch syndrome', 'Disease', (88, 102))	('changes', 'Var', (167, 174))	('Lynch syndrome', 'Disease', 'MESH:D003123', (88, 102))	('aspirin', 'Chemical', 'MESH:D001241', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('hMSH2', 'Gene', '4436', (146, 151))	('hMLH1', 'Gene', (156, 161))	('hMSH2', 'Gene', (146, 151))	('patients', 'Species', '9606', (132, 140))
104312	27865598	Recent genetic analyses of ACC have shown recurrent gene copy deletion of CYP4B1, a cytochrome P450 isozyme.	('CYP4B1', 'Gene', (74, 80))	('cytochrome P450', 'Gene', '4051', (84, 99))	('ACC', 'Disease', 'MESH:D018268', (27, 30))	('cytochrome P450', 'Gene', (84, 99))	('gene copy deletion', 'Var', (52, 70))	('ACC', 'Phenotype', 'HP:0006744', (27, 30))	('ACC', 'Disease', (27, 30))
104313	27865598	This study investigates a potential role for CYP4B1 in modulating adrenocortical tumorigenesis and/or conferring chemoresistance to ACCs.	('ACC', 'Phenotype', 'HP:0006744', (132, 135))	('ACCs', 'Gene', (132, 136))	('CYP4B1', 'Var', (45, 51))	('ACCs', 'Gene', '84680', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('modulating', 'Reg', (55, 65))	('chemoresistance', 'CPA', (113, 128))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
104315	27865598	ACC cell lines were enforced to express CYP4B1 and effects on cell death and enhanced mitotane and cisplatin sensitivity were tested.	('CYP4B1', 'Var', (40, 46))	('enhanced', 'PosReg', (77, 85))	('cisplatin sensitivity', 'MPA', (99, 120))	('ACC', 'Disease', 'MESH:D018268', (0, 3))	('mitotane', 'Chemical', 'MESH:D008939', (86, 94))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))	('ACC', 'Disease', (0, 3))
104319	27865598	CYP4B1 is silenced in adrenocortical tumors (ACTs) and may contribute to tumorigenesis and chemoresistance.	('ACTs', 'Disease', (45, 49))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (22, 43))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('ACTs', 'Disease', 'MESH:D018268', (45, 49))	('CYP4B1', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('chemoresistance', 'CPA', (91, 106))	('adrenocortical tumors', 'Disease', (22, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('contribute', 'Reg', (59, 69))	('silenced', 'NegReg', (10, 18))
104320	27865598	Sensitization of ACC cells engineered to overexpress CYP4B1 further supports this notion.	('ACC', 'Disease', 'MESH:D018268', (17, 20))	('overexpress', 'PosReg', (41, 52))	('ACC', 'Phenotype', 'HP:0006744', (17, 20))	('CYP4B1', 'Var', (53, 59))	('ACC', 'Disease', (17, 20))
104336	27865598	Altered CYP expression has been shown to increase rates of anti-cancer drug degradation, decreasing the intended cytotoxic effect.	('CYP', 'Gene', '4051', (8, 11))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('Altered', 'Var', (0, 7))	('decreasing', 'NegReg', (89, 99))	('increase', 'PosReg', (41, 49))	('rates', 'MPA', (50, 55))	('CYP', 'Gene', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
104337	27865598	Additionally, while not considered typical oncogenes or tumor suppressors, differential expression of cytochrome P450 genes has been demonstrated to be associated with pancreatic, breast, bladder, and lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('differential', 'Var', (75, 87))	('cytochrome P450', 'Gene', '4051', (102, 117))	('tumor', 'Disease', (56, 61))	('expression', 'MPA', (88, 98))	('breast', 'Disease', (180, 186))	('pancreatic', 'Disease', 'MESH:D010195', (168, 178))	('bladder', 'Disease', (188, 195))	('cytochrome P450', 'Gene', (102, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('pancreatic', 'Disease', (168, 178))	('associated', 'Reg', (152, 162))	('lung cancer', 'Disease', (201, 212))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
104338	27865598	Recent bioinformatic analysis of copy number variations (CNVs) in ACC displayed widespread genomic instability and multiple arm-level and focal alterations in the cytochrome P450 genes.	('copy number variations', 'Var', (33, 55))	('cytochrome P450', 'Gene', (163, 178))	('ACC', 'Disease', 'MESH:D018268', (66, 69))	('alterations', 'Reg', (144, 155))	('cytochrome P450', 'Gene', '4051', (163, 178))	('ACC', 'Phenotype', 'HP:0006744', (66, 69))	('ACC', 'Disease', (66, 69))
104341	27865598	CYP4B1 is unique among the cytochrome P450 class in that it is involved in both endobiotic and xenobiotic metabolism.	('cytochrome P450', 'Gene', '4051', (27, 42))	('CYP4B1', 'Var', (0, 6))	('involved', 'Reg', (63, 71))	('cytochrome P450', 'Gene', (27, 42))
104343	27865598	Research on bladder cancer has demonstrated that the absence of wild type CYP4B1 is associated with tumor carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('CYP4B1', 'Var', (74, 80))	('absence', 'Var', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('bladder cancer', 'Disease', 'MESH:D001749', (12, 26))	('bladder cancer', 'Disease', (12, 26))	('tumor carcinogenesis', 'Disease', (100, 120))	('tumor carcinogenesis', 'Disease', 'MESH:D063646', (100, 120))	('associated', 'Reg', (84, 94))	('bladder cancer', 'Phenotype', 'HP:0009725', (12, 26))
104344	27865598	Additionally, CYP4B1 has differential expression patterns in lung cancer compared to normal tissue.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('CYP4B1', 'Var', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))
104345	27865598	The association of CYP4B1 with other malignancies and the demonstrated copy number loss in ACC led us to investigate its potential role in adrenocortical tumors.	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('association', 'Interaction', (4, 15))	('adrenocortical tumors', 'Disease', (139, 160))	('malignancies', 'Disease', (37, 49))	('ACC', 'Phenotype', 'HP:0006744', (91, 94))	('copy number loss', 'Var', (71, 87))	('ACC', 'Disease', (91, 94))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (139, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('malignancies', 'Disease', 'MESH:D009369', (37, 49))	('CYP4B1', 'Var', (19, 25))	('ACC', 'Disease', 'MESH:D018268', (91, 94))
104354	27865598	Quantitative RT-PCR was performed on a CFX96 Real-Time System thermocycler (Bio-Rad) using TaqMan PCR master mix with primers and probes specific to CYP4B1 (all from Applied Biosystems, Foster City, CA).	('Rad', 'Gene', (80, 83))	('Rad', 'Gene', '6236', (80, 83))	('CYP4B1', 'Var', (149, 155))
104363	27865598	Cells were treated with either (1) mock, (2) mitotane 5 muM, (3) mitotane 50 muM, (4) mitotane 50 muM plus cisplatin 700 nM, or (5) untreated.	('muM', 'Gene', (77, 80))	('muM', 'Gene', (98, 101))	('mitotane', 'Var', (45, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('muM', 'Gene', '56925', (56, 59))	('mitotane', 'Chemical', 'MESH:D008939', (45, 53))	('mitotane', 'Chemical', 'MESH:D008939', (65, 73))	('mitotane', 'Chemical', 'MESH:D008939', (86, 94))	('muM', 'Gene', '56925', (77, 80))	('muM', 'Gene', (56, 59))	('muM', 'Gene', '56925', (98, 101))
104373	27865598	Average relative expression of CYP4B1 in ACA was 0.19 (0.01 - 0.50) and was significantly reduced when compared to expression levels in the normal adrenal cortex (P < .01; Fig 1, 2).	('CYP4B1', 'Var', (31, 37))	('reduced', 'NegReg', (90, 97))	('ACA', 'Disease', (41, 44))	('ACA', 'Disease', 'MESH:D018246', (41, 44))
104377	27865598	Stable transfection of CYP4B1 in NCI-H295R cells resulted in immediate loss of viability.	('NCI-H295R', 'CellLine', 'CVCL:0458', (33, 42))	('loss', 'NegReg', (71, 75))	('CYP4B1', 'Var', (23, 29))
104379	27865598	Since the enforced stable expression of CYP4B1 appeared to be toxic to both ACC cell lines, we performed transient expression of CYP4B1 in relatively more tolerant SW-13 cells to determine if the presence of the protein was initiating cytotoxicity.	('CYP4B1', 'Var', (40, 46))	('cytotoxicity', 'Disease', (235, 247))	('ACC', 'Phenotype', 'HP:0006744', (76, 79))	('ACC', 'Disease', (76, 79))	('SW-13', 'CellLine', 'CVCL:0542', (164, 169))	('cytotoxicity', 'Disease', 'MESH:D064420', (235, 247))	('ACC', 'Disease', 'MESH:D018268', (76, 79))	('CYP4B1', 'Var', (129, 135))
104380	27865598	Cells were also tested to determine whether standard ACC chemotherapy agents accentuate CYP4B1-promoted cytotoxicity.	('ACC', 'Disease', 'MESH:D018268', (53, 56))	('CYP4B1-promoted', 'Var', (88, 103))	('cytotoxicity', 'Disease', 'MESH:D064420', (104, 116))	('accentuate', 'PosReg', (77, 87))	('ACC', 'Phenotype', 'HP:0006744', (53, 56))	('ACC', 'Disease', (53, 56))	('cytotoxicity', 'Disease', (104, 116))
104381	27865598	As could be predicted from the outcome of stable expression, expression of CYP4B1 alone was found to be sufficient to promote loss of ACC cell viability (Fig 5).	('loss', 'CPA', (126, 130))	('ACC', 'Disease', 'MESH:D018268', (134, 137))	('ACC', 'Phenotype', 'HP:0006744', (134, 137))	('ACC', 'Disease', (134, 137))	('promote', 'PosReg', (118, 125))	('CYP4B1', 'Var', (75, 81))
104382	27865598	This pattern of CYP4B1 promoted cellular toxicity persisted independent of the chemotherapy regimen tested (Fig 5).	('toxicity', 'Disease', (41, 49))	('CYP4B1', 'Var', (16, 22))	('promoted', 'PosReg', (23, 31))	('toxicity', 'Disease', 'MESH:D064420', (41, 49))
104383	27865598	While control cells treated with low-dose mitotane therapy (5 muM) did not result in cytotoxicity, cells transfected to express CYP4B1 had significantly decreased viability and increased cell death (P < .01; Fig 5, 6).	('muM', 'Gene', '56925', (62, 65))	('muM', 'Gene', (62, 65))	('mitotane', 'Chemical', 'MESH:D008939', (42, 50))	('CYP4B1', 'Var', (128, 134))	('increased', 'PosReg', (177, 186))	('decreased', 'NegReg', (153, 162))	('cytotoxicity', 'Disease', (85, 97))	('cell death', 'CPA', (187, 197))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))
104384	27865598	Addition of cisplatin to mitotane resulted in increased loss of viability compared to mitotane (50 uM) alone, and was further accentuated by expression of CYP4B1 (Fig 5).	('cisplatin', 'Var', (12, 21))	('viability', 'CPA', (64, 73))	('loss', 'NegReg', (56, 60))	('mitotane', 'Chemical', 'MESH:D008939', (25, 33))	('CYP4B1', 'Var', (155, 161))	('cisplatin', 'Chemical', 'MESH:D002945', (12, 21))	('mitotane', 'Chemical', 'MESH:D008939', (86, 94))
104388	27865598	In this study, we demonstrate significantly reduced expression of CYP4B1 in 100% of adrenocortical tumors, a previously undescribed event of potential metabolic and carcinogenic significance.	('carcinogenic', 'Disease', 'MESH:D063646', (165, 177))	('adrenocortical tumors', 'Disease', (84, 105))	('carcinogenic', 'Disease', (165, 177))	('CYP4B1', 'Var', (66, 72))	('expression', 'MPA', (52, 62))	('reduced', 'NegReg', (44, 51))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (84, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
104390	27865598	Alternatively, epigenetic alteration may be a more dominant influence as the global silencing observed in all ACTs studied would not be explained by the lesser degree of gene copy loss.	('epigenetic alteration', 'Var', (15, 36))	('global', 'MPA', (77, 83))	('silencing', 'NegReg', (84, 93))	('ACTs', 'Disease', 'MESH:D018268', (110, 114))	('ACTs', 'Disease', (110, 114))
104391	27865598	CYP4B1 dysregulation has been noted in numerous malignancies.	('malignancies', 'Disease', (48, 60))	('malignancies', 'Disease', 'MESH:D009369', (48, 60))	('CYP4B1 dysregulation', 'Var', (0, 20))
104393	27865598	However, in bladder cancer, this shift appears to be associated only with allelic variants and not observed in the wild type protein.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('bladder cancer', 'Disease', 'MESH:D001749', (12, 26))	('bladder cancer', 'Disease', (12, 26))	('allelic variants', 'Var', (74, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (12, 26))
104394	27865598	It is very likely that the metabolically intense endocrine physiology of the adrenal gland requires CYP4B1 for steroid synthesis, which, when perturbed, may lead to metabolic chaos and cell death.	('metabolic chaos', 'CPA', (165, 180))	('cell death', 'CPA', (185, 195))	('lead to', 'Reg', (157, 164))	('perturbed', 'Var', (142, 151))	('CYP4B1', 'Var', (100, 106))	('steroid synthesis', 'MPA', (111, 128))	('steroid', 'Chemical', 'MESH:D013256', (111, 118))
104395	27865598	Since a specific role for CYP4B1 in the normal adrenal cortex is not yet known, it is difficult to speculate on the impact of its dysregulation or the possible effects of its silencing on adrenocortical dedifferentiation or carcinogenesis.	('adrenocortical dedifferentiation', 'CPA', (188, 220))	('carcinogenesis', 'Disease', 'MESH:D063646', (224, 238))	('CYP4B1', 'Var', (26, 32))	('carcinogenesis', 'Disease', (224, 238))	('adrenocortical dedifferentiation', 'Phenotype', 'HP:0008207', (188, 220))
104396	27865598	Of special interest, is the observation that both transient and stable expression of CYP4B1 resulted in toxicity in two well-studied ACC cell lines.	('CYP4B1', 'Var', (85, 91))	('ACC', 'Disease', 'MESH:D018268', (133, 136))	('toxicity', 'Disease', 'MESH:D064420', (104, 112))	('resulted', 'Reg', (92, 100))	('ACC', 'Phenotype', 'HP:0006744', (133, 136))	('toxicity', 'Disease', (104, 112))	('ACC', 'Disease', (133, 136))
104397	27865598	Although the effect needs to be confirmed using inducible promoters, the preliminary results point towards a tumor suppressor role for CYP4B1 in ACC.	('ACC', 'Disease', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('ACC', 'Disease', 'MESH:D018268', (145, 148))	('CYP4B1', 'Var', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ACC', 'Phenotype', 'HP:0006744', (145, 148))	('tumor', 'Disease', (109, 114))
104399	27865598	Results of our experiments assessing the cytotoxic effect of CYP4B1 further support its role as a cell-death promoter in ACTs.	('ACTs', 'Disease', 'MESH:D018268', (121, 125))	('ACTs', 'Disease', (121, 125))	('CYP4B1', 'Var', (61, 67))
104400	27865598	Treatment with both mitotane and cisplatin in CYP4B1-expressing cells decreased viability in the two ACC cell lines studied.	('mitotane', 'Chemical', 'MESH:D008939', (20, 28))	('ACC', 'Phenotype', 'HP:0006744', (101, 104))	('decreased', 'NegReg', (70, 79))	('ACC', 'Disease', (101, 104))	('CYP4B1-expressing', 'Var', (46, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('viability', 'CPA', (80, 89))	('ACC', 'Disease', 'MESH:D018268', (101, 104))
104401	27865598	In the doses and combinations tested, presence of CYP4B1 appears to accentuate toxicity irrespective of the agent used.	('toxicity', 'Disease', 'MESH:D064420', (79, 87))	('accentuate', 'PosReg', (68, 78))	('CYP4B1', 'Var', (50, 56))	('toxicity', 'Disease', (79, 87))
104402	27865598	It is also noteworthy that CYP4B1 promoted significant cytotoxicity in SW-13 cells with low-dose mitotane (5 muM; Fig 5, 6).	('SW-13', 'CellLine', 'CVCL:0542', (71, 76))	('muM', 'Gene', (109, 112))	('CYP4B1', 'Var', (27, 33))	('cytotoxicity', 'Disease', (55, 67))	('promoted', 'PosReg', (34, 42))	('mitotane', 'Chemical', 'MESH:D008939', (97, 105))	('muM', 'Gene', '56925', (109, 112))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))
104407	27865598	In summary, this study offers new insight into the potential roles of CYP4B1 in the overall process of adrenal tumorigenesis and ACC chemoresistance.	('ACC', 'Disease', 'MESH:D018268', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('CYP4B1', 'Var', (70, 76))	('tumor', 'Disease', (111, 116))	('ACC', 'Phenotype', 'HP:0006744', (129, 132))	('ACC', 'Disease', (129, 132))
104462	30936196	Loss-of-function mutations were identified in MSH2, TP53, RB1, and PTEN, resulting in tumors with mismatch repair signatures and microsatellite instability.	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('RB1', 'Gene', '5925', (58, 61))	('TP53', 'Gene', '7157', (52, 56))	('tumors', 'Disease', (86, 92))	('TP53', 'Gene', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('PTEN', 'Gene', (67, 71))	('mutations', 'Var', (17, 26))	('PTEN', 'Gene', '5728', (67, 71))	('MSH2', 'Gene', (46, 50))	('RB1', 'Gene', (58, 61))	('mismatch repair signatures', 'MPA', (98, 124))	('microsatellite instability', 'MPA', (129, 155))	('MSH2', 'Gene', '4436', (46, 50))
104478	30936196	Mitotane is recommended in patients with Ki67 of >10% and tumor size >8 cm, and those with potential residual disease following resection.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('Ki67', 'Chemical', '-', (41, 45))	('Ki67', 'Var', (41, 45))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
104482	30936196	In landmark studies, next-generation sequencing (NGS) identified therapeutically actionable mutations in 76% of 2221 tumor samples of various types studied and has also facilitated successful repurposing of existing therapeutics.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('mutations', 'Var', (92, 101))
104485	30936196	Targetable genetic changes are highly likely to be detected in other less common malignancies also, but like their common-cancer counterparts, the buildup of resistance needs to be countered.	('genetic changes', 'Var', (11, 26))	('malignancies', 'Disease', 'MESH:D009369', (81, 93))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('malignancies', 'Disease', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
104489	30936196	At the germline level, mutations in TP53 are found in 7.5% of ACC cases generally, but much more frequently (50%-97%) in childhood ACC.	('TP53', 'Gene', (36, 40))	('ACC', 'Phenotype', 'HP:0006744', (131, 134))	('TP53', 'Gene', '7157', (36, 40))	('mutations', 'Var', (23, 32))	('ACC', 'Phenotype', 'HP:0006744', (62, 65))	('childhood ACC', 'Disease', (121, 134))	('ACC', 'Disease', (62, 65))	('found', 'Reg', (45, 50))
104491	30936196	Somatically, dysregulation of protein kinase A and mutations in ADIPOR1, ADIPOR2, APC, ARMC5, SDHA, SDHC, SF1, and IGF2, among others, have also been implicated as mediators of ACC tumorigenesis, along with mutations in RB1 and APC.	('mutations', 'Var', (51, 60))	('ACC', 'Phenotype', 'HP:0006744', (177, 180))	('ACC', 'Disease', (177, 180))	('SDHC', 'Gene', (100, 104))	('ARMC5', 'Gene', '79798', (87, 92))	('SF1', 'Gene', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('APC', 'Disease', 'MESH:D011125', (228, 231))	('APC', 'Disease', (228, 231))	('RB1', 'Gene', (220, 223))	('IGF2', 'Gene', (115, 119))	('SF1', 'Gene', '7536', (106, 109))	('protein kinase A', 'Enzyme', (30, 46))	('ADIPOR1', 'Gene', (64, 71))	('ADIPOR2', 'Gene', '79602', (73, 80))	('RB1', 'Gene', '5925', (220, 223))	('SDHC', 'Gene', '6391', (100, 104))	('implicated', 'Reg', (150, 160))	('SDHA', 'Gene', (94, 98))	('ARMC5', 'Gene', (87, 92))	('IGF2', 'Gene', '3481', (115, 119))	('tumor', 'Disease', (181, 186))	('SDHA', 'Gene', '6389', (94, 98))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('APC', 'Disease', (82, 85))	('ADIPOR1', 'Gene', '51094', (64, 71))	('dysregulation', 'MPA', (13, 26))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('ADIPOR2', 'Gene', (73, 80))
104493	30936196	At the miRNA level, miR-483-3p and miR-139-5p promote ACC aggressiveness.	('promote', 'PosReg', (46, 53))	('miR-483-3p', 'Var', (20, 30))	('ACC', 'Phenotype', 'HP:0006744', (54, 57))	('aggressiveness', 'Disease', (58, 72))	('aggressiveness', 'Phenotype', 'HP:0000718', (58, 72))	('miR-139-5p', 'Var', (35, 45))	('aggressiveness', 'Disease', 'MESH:D001523', (58, 72))
104518	30936196	By comparing the mutations observed in both metastases, we identified a total of 50,289 somatic variants, of which 24,735 were shared, and 8237 and 17,317 were private to the LLM and RLM respectively (Fig.	('metastases', 'Disease', 'MESH:D009362', (44, 54))	('metastases', 'Disease', (44, 54))	('variants', 'Var', (96, 104))
104519	30936196	Mutational signature analysis revealed a strong signal for defective DNA mismatch repair (MMR), along with strong signals for deamination of 5-methylcytosine and polymerase eta; all attributable to C>T mutations (Fig.	('deamination of 5-methylcytosine', 'MPA', (126, 157))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (141, 157))	('defective', 'NegReg', (59, 68))	('DNA mismatch repair', 'MPA', (69, 88))	('C>T mutations', 'Var', (198, 211))
104521	30936196	The MSH2 deletion, and RB1 and TP53 mutations were also detected in the primary tumor.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('deletion', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('MSH2', 'Gene', (4, 8))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (80, 85))	('MSH2', 'Gene', '4436', (4, 8))	('RB1', 'Gene', (23, 26))	('RB1', 'Gene', '5925', (23, 26))
104523	30936196	A functionally deleterious missense variant, c.793C>T, p.Arg265Cys was detected in MMR gene MLH1 in the primary, but not in the metastases.	('MLH1', 'Gene', '4292', (92, 96))	('metastases', 'Disease', (128, 138))	('p.Arg265Cys', 'Mutation', 'rs63751194', (55, 66))	('MLH1', 'Gene', (92, 96))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('c.793C>T', 'Var', (45, 53))	('c.793C>T', 'Mutation', 'rs63751194', (45, 53))
104524	30936196	Given the deletion detected in MSH2, we assessed both metastatic tumors for MSI, and confirmed its presence in both cases (Fig.	('MSI', 'Disease', 'None', (76, 79))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('MSH2', 'Gene', (31, 35))	('deletion', 'Var', (10, 18))	('MSI', 'Disease', (76, 79))	('MSH2', 'Gene', '4436', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
104531	30936196	Only one somatic variation, predicted pathogenic in silico by PolyPhen and SIFT, was observed in the mitochondrial genome:namely, MT-ND5:c.400G>A, a component of complex I.	('SIFT', 'Disease', 'None', (75, 79))	('SIFT', 'Disease', (75, 79))	('ND5:c.400G>A', 'Var', (133, 145))	('ND5:c.400G>A', 'SUBSTITUTION', 'None', (133, 145))
104532	30936196	No variants of interest were detected in MMR genes, except apparent polymorphisms recorded in dbSNP and 1000 Genomes, in MSH3 (c.162-179del) and PMS2 (c.706-4del).	('MSH3', 'Gene', '4437', (121, 125))	('MSH3', 'Gene', (121, 125))	('c.162-179del', 'Var', (127, 139))	('PMS2', 'Gene', (145, 149))	('c.162-179del', 'Mutation', 'c.162_179del', (127, 139))	('c.706-4del', 'Mutation', 'c.706-4del', (151, 161))	('PMS2', 'Gene', '5395', (145, 149))	('MMR', 'Gene', (41, 44))	('c.706-4del', 'Var', (151, 161))
104533	30936196	Similarly, a variant of unknown significance (conflicting in silico data but reported in dbSNP), in complex III gene MT-CYB (c.20C>T), was detected.	('MT-CYB', 'Gene', '4519', (117, 123))	('MT-CYB', 'Gene', (117, 123))	('c.20C>T', 'Var', (125, 132))	('c.20C>T', 'Mutation', 'c.20C>T', (125, 132))
104535	30936196	To enable early detection of cancer recurrence, we conducted a serial liquid biopsy of ctDNA, using ddPCR probes against the somatic MSH2 c.1277-9_1292del deletion, and a reference control, targeting Chr 2:47600540.	('MSH2', 'Gene', (133, 137))	('cancer', 'Disease', (29, 35))	('MSH2', 'Gene', '4436', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('c.1277-9_1292del', 'Mutation', 'c.1277-9_1292del', (138, 154))	('c.1277-9_1292del deletion', 'Var', (138, 163))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
104536	30936196	The MSH2 deletion was detected only in the tumor tissue-derived DNA and not in any of the 10 subsequent liquid biopsies collected between June 2015 and November 2017 (Fig.	('deletion', 'Var', (9, 17))	('MSH2', 'Gene', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('MSH2', 'Gene', '4436', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
104537	30936196	The TP53, RB1, and MEN1 mutations were also analyzed in the germline, metastatic tumor DNA, and ctDNA and only detected in the metastases (data not shown).	('metastases', 'Disease', 'MESH:D009362', (127, 137))	('TP53', 'Gene', (4, 8))	('RB1', 'Gene', '5925', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('MEN1', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))	('MEN1', 'Gene', '4221', (19, 23))	('RB1', 'Gene', (10, 13))	('TP53', 'Gene', '7157', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('metastases', 'Disease', (127, 137))	('tumor', 'Disease', (81, 86))
104540	30936196	The primary and metastatic tumors were characterized by a mass hyperhaploidization event in the primary, and mutational signatures were associated with defects in MMR.	('associated', 'Reg', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('MMR', 'Gene', (163, 166))	('mass hyperhaploidization', 'MPA', (58, 82))	('defects', 'Var', (152, 159))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))
104541	30936196	We hypothesize that this was driven by a driver-somatic, loss-of-function (LOF) deletion, detected in MSH2.	('MSH2', 'Gene', '4436', (102, 106))	('loss-of-function', 'NegReg', (57, 73))	('deletion', 'Var', (80, 88))	('MSH2', 'Gene', (102, 106))
104543	30936196	Digenic alterations in both proteins have been previously reported in hereditary nonpolyposis colorectal tumors; however, the MLH1 mutation leads to a functional protein, albeit at reduced capacity compared to wild type.	('hereditary nonpolyposis colorectal tumors', 'Disease', 'MESH:D003123', (70, 111))	('leads to', 'Reg', (140, 148))	('hereditary nonpolyposis colorectal tumors', 'Disease', (70, 111))	('MLH1', 'Gene', '4292', (126, 130))	('MLH1', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('functional protein', 'MPA', (151, 169))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('mutation', 'Var', (131, 139))
104546	30936196	Furthermore, LOF MSH2 deletions, induce a "mutator phenotype," which leads to (i) disrupted methylation of CpG islands, possibly accounting for the deamination of 5-methylcytosine signature, usually observed in aging individuals, and (ii) the elevated accumulation of mutations in oncogenes and tumor suppressor genes, including often in TP53.	('MSH2', 'Gene', (17, 21))	('accumulation', 'PosReg', (252, 264))	('deletions', 'Var', (22, 31))	('mutations', 'Var', (268, 277))	('TP53', 'Gene', '7157', (338, 342))	('disrupted', 'NegReg', (82, 91))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (163, 179))	('MSH2', 'Gene', '4436', (17, 21))	('TP53', 'Gene', (338, 342))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('LOF', 'NegReg', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('methylation', 'MPA', (92, 103))	('tumor', 'Disease', (295, 300))
104548	30936196	Our patient's somatic, mutational-hotspot TP53 (p.Gly245Ser) variant, is known to disrupt DNA binding and, consequently, transcription.	('TP53', 'Gene', '7157', (42, 46))	('p.Gly245Ser', 'Var', (48, 59))	('DNA binding', 'Interaction', (90, 101))	('TP53', 'Gene', (42, 46))	('transcription', 'MPA', (121, 134))	('patient', 'Species', '9606', (4, 11))	('p.Gly245Ser', 'Mutation', 'rs28934575', (48, 59))	('disrupt', 'NegReg', (82, 89))
104549	30936196	Dysfunctional p53 allows the cycle cell to continue unabated, even in the presence of erroneously mutated DNA.	('DNA', 'Gene', (106, 109))	('p53', 'Gene', '7157', (14, 17))	('Dysfunctional', 'Var', (0, 13))	('p53', 'Gene', (14, 17))
104551	30936196	Our patient's LOF mutations in RB1 and TP53 may allow for the uncontrolled proliferation of cancerous lesions.	('uncontrolled proliferation', 'CPA', (62, 88))	('RB1', 'Gene', (31, 34))	('patient', 'Species', '9606', (4, 11))	('RB1', 'Gene', '5925', (31, 34))	('allow', 'Reg', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TP53', 'Gene', '7157', (39, 43))	('cancerous lesions', 'Disease', 'MESH:D009062', (92, 109))	('LOF', 'NegReg', (14, 17))	('cancerous lesions', 'Disease', (92, 109))	('TP53', 'Gene', (39, 43))	('mutations', 'Var', (18, 27))
104563	30936196	Second, our patient exhibits dysfunctional p53 and the somatic p.Arg233Ter mutation in PTEN.	('PTEN', 'Gene', (87, 91))	('PTEN', 'Gene', '5728', (87, 91))	('p.Arg233Ter', 'Mutation', 'rs121909219', (63, 74))	('p.Arg233Ter', 'Var', (63, 74))	('dysfunctional', 'Disease', 'MESH:D006331', (29, 42))	('dysfunctional', 'Disease', (29, 42))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('patient', 'Species', '9606', (12, 19))
104567	30936196	Our patient's mutations in TP53 and PTEN have also been shown to induce activation of oncogene AKT, another factor which stimulates expression of HIF1alpha.	('activation', 'PosReg', (72, 82))	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('HIF1alpha', 'Gene', '3091', (146, 155))	('PTEN', 'Gene', (36, 40))	('patient', 'Species', '9606', (4, 11))	('oncogene AKT', 'Pathway', (86, 98))	('stimulates', 'PosReg', (121, 131))	('HIF1alpha', 'Gene', (146, 155))	('PTEN', 'Gene', '5728', (36, 40))	('expression', 'MPA', (132, 142))	('mutations', 'Var', (14, 23))
104575	30936196	Two other studies have applied liquid biopsy to ACC with very limited success., detected somatic mutations in just one of the three patients with ACC, and observed decreases in mutation load following surgery in that patient.	('mutations', 'Var', (97, 106))	('decreases', 'NegReg', (164, 173))	('mutation load', 'MPA', (177, 190))	('ACC', 'Phenotype', 'HP:0006744', (146, 149))	('patient', 'Species', '9606', (217, 224))	('ACC', 'Phenotype', 'HP:0006744', (48, 51))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))
104576	30936196	similarly was able to track mutations in the ctDNA in just two of the eight patients with ACC.	('ctDNA', 'Gene', (45, 50))	('patients', 'Species', '9606', (76, 84))	('mutations', 'Var', (28, 37))	('ACC', 'Phenotype', 'HP:0006744', (90, 93))
104581	30936196	Given the issues of ctDNA sensitivity outlined above, we chose ddPCR to sensitively monitor for the MSH2 mutation, rather than NGS.	('MSH2', 'Gene', '4436', (100, 104))	('mutation', 'Var', (105, 113))	('MSH2', 'Gene', (100, 104))
104601	30936196	This was performed according to <1% frequency in 1000 Genomes and Exome Aggregation Consortium (ExAC) databases, conservation (assessed by GERP), functional impact (PolyPhen-2 and SIFT), biological likelihood through candidate gene and pathway analysis, and association with known Catalogue of Somatic Mutations in Cancer (COSMIC) variants.	('Cancer', 'Phenotype', 'HP:0002664', (315, 321))	('Cancer', 'Disease', (315, 321))	('SIFT', 'Disease', (180, 184))	('Cancer', 'Disease', 'MESH:D009369', (315, 321))	('GERP', 'Gene', (139, 143))	('GERP', 'Gene', '81603', (139, 143))	('SIFT', 'Disease', 'None', (180, 184))	('variants', 'Var', (331, 339))
104610	30936196	ctDNA was immediately extracted from 4 mL plasma aliquots using the Circulating Nuclei Acid Kit (QIAGEN 55114) according to manufacturer's instructions, and frozen at -80 C. Somatic variants of interest were probed by droplet digital PCR (ddPCR), using the Bio-Rad QX200 Droplet Digital PCR System.	('Rad', 'Gene', (261, 264))	('variants', 'Var', (182, 190))	('Rad', 'Gene', '6236', (261, 264))
104614	30936196	produced this manuscript and led the processing of germline and metastatic tumor samples with C.-L.C., and the design, development, and interpretation of liquid biopsy assay, under the expert direction of Y.Y.C.	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (75, 80))	('C.-L.C.', 'Var', (94, 101))
104633	30514817	A proper balance between the proliferation and differentiation of such stem/progenitor cells is crucial, as a dysregulation of this mechanism might result in organ failure (reviewed in ref.).	('organ failure', 'Disease', (158, 171))	('result in', 'Reg', (148, 157))	('dysregulation', 'Var', (110, 123))	('organ failure', 'Disease', 'MESH:D009102', (158, 171))
104733	30514817	This might be a result of the CO2/O2 anesthesia, which has previously been shown to increase serum corticosterone levels.	('serum corticosterone levels', 'MPA', (93, 120))	('CO2/O2', 'Var', (30, 36))	('increase serum corticosterone', 'Phenotype', 'HP:0032362', (84, 113))	('CO2', 'Chemical', '-', (30, 33))	('corticosterone', 'Chemical', 'MESH:D003345', (99, 113))	('increase', 'PosReg', (84, 92))	('O2', 'Chemical', '-', (34, 36))	('O2', 'Chemical', '-', (31, 33))
104759	30540124	However, a much higher incidence of adrenal tumors (>15 times) has been demonstrated in the pediatric population in south and southeastern Brazil, and these tumors are associated with a specific germline mutation in TP53 .	('TP53', 'Gene', (216, 220))	('tumors', 'Disease', (44, 50))	('associated', 'Reg', (168, 178))	('adrenal tumors', 'Disease', 'MESH:D000310', (36, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('adrenal tumors', 'Disease', (36, 50))	('germline mutation', 'Var', (195, 212))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('TP53', 'Gene', '7157', (216, 220))
104764	30540124	In south and southeastern Brazil, approximately 78% of children and 13% of adults with adrenal tumors harbor a specific germline mutation (p.R337H) of the p53 tumor suppressor.	('p.R337H', 'Mutation', 'rs121912664', (139, 146))	('p53', 'Gene', (155, 158))	('p53', 'Gene', '7157', (155, 158))	('adrenal tumors', 'Disease', 'MESH:D000310', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('adrenal tumors', 'Disease', (87, 101))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p.R337H', 'Var', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (95, 100))	('children', 'Species', '9606', (55, 63))
104765	30540124	A founder effect has been demonstrated in the great majority of pediatric Brazilian patients with adrenocortical tumors caused by this p53 mutation.	('mutation', 'Var', (139, 147))	('patients', 'Species', '9606', (84, 92))	('p53', 'Gene', (135, 138))	('adrenocortical tumors', 'Disease', (98, 119))	('p53', 'Gene', '7157', (135, 138))	('caused by', 'Reg', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (98, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
104771	30540124	LFS is a cancer predisposition syndrome usually caused by an inherited TP53 gene mutation and is characterized by a high occurrence of sarcomas, early onset breast cancer, brain cancer and leukemia.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('sarcomas', 'Disease', 'MESH:D012509', (135, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('brain cancer', 'Phenotype', 'HP:0030692', (172, 184))	('sarcomas', 'Disease', (135, 143))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('LFS', 'Disease', (0, 3))	('breast cancer', 'Disease', (157, 170))	('leukemia', 'Phenotype', 'HP:0001909', (189, 197))	('brain cancer', 'Disease', 'MESH:D001932', (172, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('TP53', 'Gene', '7157', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('caused by', 'Reg', (48, 57))	('mutation', 'Var', (81, 89))	('leukemia', 'Disease', (189, 197))	('leukemia', 'Disease', 'MESH:D007938', (189, 197))	('cancer', 'Disease', (164, 170))	('brain cancer', 'Disease', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (178, 184))	('TP53', 'Gene', (71, 75))
104773	30540124	Somatic TP53 mutations have been identified in 25-35% of sporadic ACCs.	('mutations', 'Var', (13, 22))	('identified', 'Reg', (33, 43))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))
104774	30540124	Nevertheless, these mutations represent a late event during carcinogenesis and have been associated with larger tumors and more advanced disease.	('associated', 'Reg', (89, 99))	('carcinogenesis', 'Disease', 'MESH:D063646', (60, 74))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('carcinogenesis', 'Disease', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (20, 29))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
104775	30540124	Somatic mutations in the TP53 gene are a predictor of poor overall survival in adults with ACC.	('Somatic mutations', 'Var', (0, 17))	('TP53', 'Gene', '7157', (25, 29))	('TP53', 'Gene', (25, 29))
104779	30540124	Genetic or epigenetic alterations in the 11p15 region may alter the expression of the CDKN1C, IGF2 and H19 genes, which are structurally organized in a cluster, increasing IGF2 expression and inactivating the CDKN1C and H19 genes, which are a negative cell cycle regulator and a transcriptional repressor of IGF2, respectively.	('expression', 'MPA', (68, 78))	('IGF2', 'Gene', (94, 98))	('alter', 'Reg', (58, 63))	('CDKN1C', 'Gene', (209, 215))	('expression', 'MPA', (177, 187))	('IGF2', 'Gene', (172, 176))	('IGF2', 'Gene', '3481', (308, 312))	('CDKN1C', 'Gene', '1028', (86, 92))	('H19', 'Gene', (103, 106))	('epigenetic alterations', 'Var', (11, 33))	('IGF2', 'Gene', '3481', (94, 98))	('H19', 'Gene', (220, 223))	('H19', 'Gene', '283120', (103, 106))	('IGF2', 'Gene', '3481', (172, 176))	('CDKN1C', 'Gene', (86, 92))	('CDKN1C', 'Gene', '1028', (209, 215))	('H19', 'Gene', '283120', (220, 223))	('inactivating', 'NegReg', (192, 204))	('increasing', 'PosReg', (161, 171))	('IGF2', 'Gene', (308, 312))
104781	30540124	Children with BWS also have a high risk of developing Wilms' tumors, hepatoblastomas, rhabdomyosarcomas, and ACCs.	('ACCs', 'Disease', (109, 113))	('Children', 'Species', '9606', (0, 8))	("Wilms' tumors", 'Disease', (54, 67))	('BWS', 'Var', (14, 17))	('hepatoblastomas', 'Disease', (69, 84))	("Wilms' tumors", 'Phenotype', 'HP:0002667', (54, 67))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (86, 103))	('rhabdomyosarcomas', 'Disease', (86, 103))	('sarcomas', 'Phenotype', 'HP:0100242', (95, 103))	('hepatoblastomas', 'Disease', 'MESH:D018197', (69, 84))	('developing', 'PosReg', (43, 53))	("Wilms' tumors", 'Disease', 'MESH:D009396', (54, 67))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (86, 103))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
104783	30540124	Furthermore, the difference between BUB1B and PINK1 gene expression was a significant predictor of OS in adults.	('expression', 'MPA', (57, 67))	('PINK1', 'Gene', '65018', (46, 51))	('PINK1', 'Gene', (46, 51))	('predictor', 'Reg', (86, 95))	('BUB1B', 'Gene', '701', (36, 41))	('BUB1B', 'Gene', (36, 41))	('difference', 'Var', (17, 27))
104800	30540124	High levels of Ki67 have also been associated with worse OS in patients with advanced disease and can help in decision-making regarding treatment.	('men', 'Species', '9606', (141, 144))	('worse OS', 'Disease', (51, 59))	('associated', 'Reg', (35, 45))	('help', 'Reg', (102, 106))	('patients', 'Species', '9606', (63, 71))	('Ki67', 'Var', (15, 19))
104832	30540124	In addition to its use in the adjuvant setting, mitotane is associated with a 30% objective response rate among patients with metastatic disease in retrospective studies.	('mitotane', 'Chemical', 'MESH:D008939', (48, 56))	('metastatic disease', 'Disease', (126, 144))	('patients', 'Species', '9606', (112, 120))	('mitotane', 'Var', (48, 56))
104840	30540124	Mitotane also increases the concentrations of cortisol-binding globulin hormone (CBG), steroid-binding globulin (SHBG), and thyroxine-binding globulin (TBG).	('CBG', 'Gene', '866', (81, 84))	('Mitotane', 'Var', (0, 8))	('cortisol-binding globulin hormone', 'MPA', (46, 79))	('increases', 'PosReg', (14, 23))	('SHBG', 'Gene', '6462', (113, 117))	('steroid-binding globulin', 'MPA', (87, 111))	('CBG', 'Gene', (81, 84))	('thyroxine-binding globulin', 'Gene', '6906', (124, 150))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('TBG', 'Gene', (152, 155))	('thyroxine-binding globulin', 'Gene', (124, 150))	('steroid', 'Chemical', 'MESH:D013256', (87, 94))	('SHBG', 'Gene', (113, 117))	('TBG', 'Gene', '6906', (152, 155))	('concentrations', 'MPA', (28, 42))
104841	30540124	Furthermore, mitotane may impair pituitary gland function by reducing TSH secretion with consequent hypothyroidism and gonadal function causing hypergonadotropic hypogonadism.	('reducing', 'NegReg', (61, 69))	('hypogonadism', 'Phenotype', 'HP:0000135', (162, 174))	('reducing TSH secretion with consequent hypothyroidism', 'Phenotype', 'HP:0008245', (61, 114))	('reducing TSH', 'Phenotype', 'HP:0031098', (61, 73))	('hypothyroidism', 'Disease', 'MESH:D007037', (100, 114))	('mitotane', 'Chemical', 'MESH:D008939', (13, 21))	('hypothyroidism', 'Disease', (100, 114))	('gonadal function', 'CPA', (119, 135))	('TSH', 'Chemical', '-', (70, 73))	('hypothyroidism', 'Phenotype', 'HP:0000821', (100, 114))	('TSH secretion', 'MPA', (70, 83))	('hypergonadotropic hypogonadism', 'Phenotype', 'HP:0000815', (144, 174))	('mitotane', 'Var', (13, 21))	('impair', 'NegReg', (26, 32))	('hypogonadism', 'Disease', (162, 174))	('pituitary', 'CPA', (33, 42))	('hypogonadism', 'Disease', 'MESH:D007006', (162, 174))
104845	30540124	Notably, mitotane induces adrenal insufficiency due to the inhibition of steroidogenesis enzymes.	('inhibition', 'NegReg', (59, 69))	('steroidogenesis enzymes', 'Enzyme', (73, 96))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (26, 47))	('steroid', 'Chemical', 'MESH:D013256', (73, 80))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (26, 47))	('mitotane', 'Var', (9, 17))	('induces', 'Reg', (18, 25))	('adrenal insufficiency', 'Disease', (26, 47))	('mitotane', 'Chemical', 'MESH:D008939', (9, 17))
104864	30540124	These susceptibility genes can be divided into two clusters: cluster 1 tumors include those with mutations of genes encoding the von Hippel-Lindau (VHL) suppressor, the four subunits of the succinate dehydrogenase complex (SDHA, SDHB, SDHC, and SDHD), and less commonly, the enzyme responsible for flavination of the SDHA subunit (SDHAF2), fumarate hydratase, malate dehydrogenase 2, and prolyl hydroxylases 1 and 2.	('mutations', 'Var', (97, 106))	('SDHB', 'Gene', '6390', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('SDHC', 'Gene', (235, 239))	('SDHD', 'Gene', '6392', (245, 249))	('fumarate hydratase', 'Gene', '2271', (340, 358))	('SDHB', 'Gene', (229, 233))	('VHL', 'Disease', 'MESH:D006623', (148, 151))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('von Hippel-Lindau', 'Gene', (129, 146))	('malate dehydrogenase 2', 'Gene', (360, 382))	('SDHD', 'Gene', (245, 249))	('SDHC', 'Gene', '6391', (235, 239))	('malate dehydrogenase 2', 'Gene', '4191', (360, 382))	('von Hippel-Lindau', 'Gene', '7428', (129, 146))	('fumarate hydratase', 'Gene', (340, 358))	('SDHAF2', 'Gene', (331, 337))	('SDHAF2', 'Gene', '54949', (331, 337))	('VHL', 'Disease', (148, 151))
104865	30540124	These genetic alterations result in stabilization of hypoxia-inducible factors and activation of the hypoxia signaling pathways.	('hypoxia', 'Disease', (53, 60))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('hypoxia', 'Disease', (101, 108))	('stabilization', 'MPA', (36, 49))	('hypoxia', 'Disease', 'MESH:D000860', (101, 108))	('genetic alterations', 'Var', (6, 25))	('activation', 'PosReg', (83, 93))
104866	30540124	Cluster 2 includes tumors with mutations of the neurofibromatosis type 1 (NF1) tumor suppressor gene, the rearranged during transfection (RET) proto-oncogene, genes encoding transmembrane protein 127 (TMEM127) and MYC-associated factor X (MAX) (Table 3).	('tumors', 'Disease', (19, 25))	('transmembrane protein 127', 'Gene', (174, 199))	('mutations', 'Var', (31, 40))	('neurofibromatosis type 1 (NF1) tumor', 'Disease', 'MESH:C537392', (48, 84))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('RET', 'Gene', '5979', (138, 141))	('transmembrane protein 127', 'Gene', '55654', (174, 199))	('TMEM127', 'Gene', (201, 208))	('TMEM127', 'Gene', '55654', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MYC-associated factor X', 'Gene', '4149', (214, 237))	('MYC-associated factor X', 'Gene', (214, 237))	('RET', 'Gene', (138, 141))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('MAX', 'Gene', '4149', (239, 242))	('MAX', 'Gene', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (48, 65))
104869	30540124	Most PPGLs hypersecrete catecholamines and are associated with increased cardiovascular morbidity and mortality.	('PPGLs', 'Chemical', '-', (5, 10))	('PPGLs', 'Var', (5, 10))	('cardiovascular morbidity', 'Phenotype', 'HP:0001626', (73, 97))	('increased', 'PosReg', (63, 72))	('associated with', 'Reg', (47, 62))	('cardiovascular', 'Disease', (73, 87))	('hypersecrete catecholamines', 'MPA', (11, 38))	('catecholamines', 'Chemical', 'MESH:D002395', (24, 38))
104870	30540124	Additionally, PPGLs may cause mass-effect symptoms and have malignant potential.	('mass-effect', 'Disease', (30, 41))	('cause', 'Reg', (24, 29))	('PPGLs', 'Var', (14, 19))	('PPGLs', 'Chemical', '-', (14, 19))	('malignant potential', 'CPA', (60, 79))
104875	30540124	Patients who are young and those with larger tumors (>6 cm), positive genetic testing (especially SDHB) or paragangliomas have an increased risk of metastasis and require long-term follow-up.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('paragangliomas', 'Disease', (107, 121))	('metastasis', 'CPA', (148, 158))	('paragangliomas', 'Disease', 'MESH:D010235', (107, 121))	('SDHB', 'Gene', '6390', (98, 102))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('SDHB', 'Gene', (98, 102))	('Patients', 'Species', '9606', (0, 8))	('paragangliomas', 'Phenotype', 'HP:0002668', (107, 121))	('paraganglioma', 'Phenotype', 'HP:0002668', (107, 120))	('positive genetic testing', 'Var', (61, 85))
104877	30540124	In a recent study, 76% of patients with malignant PPGLs had germline mutations in susceptibility genes for PPGL (SDHB, 44%; SDHD, 8%; VHL, 12%; NF1, 12%; and RET, 0%).	('mutations', 'Var', (69, 78))	('SDHB', 'Gene', '6390', (113, 117))	('VHL', 'Disease', (134, 137))	('RET', 'Gene', (158, 161))	('VHL', 'Disease', 'MESH:D006623', (134, 137))	('SDHD', 'Gene', '6392', (124, 128))	('PPGLs', 'Chemical', '-', (50, 55))	('SDHB', 'Gene', (113, 117))	('patients', 'Species', '9606', (26, 34))	('RET', 'Gene', '5979', (158, 161))	('SDHD', 'Gene', (124, 128))	('NF1', 'Gene', '4763', (144, 147))	('NF1', 'Gene', (144, 147))	('PPGL', 'Gene', (107, 111))
104878	30540124	TMEM127 and MAX mutations have also been described in patients with malignant PPGLs.	('described', 'Reg', (41, 50))	('PPGLs', 'Chemical', '-', (78, 83))	('patients', 'Species', '9606', (54, 62))	('TMEM127', 'Gene', '55654', (0, 7))	('mutations', 'Var', (16, 25))	('MAX', 'Gene', '4149', (12, 15))	('MAX', 'Gene', (12, 15))	('PPGLs', 'Disease', (78, 83))	('TMEM127', 'Gene', (0, 7))
104887	30540124	123I-MIBG is inferior to 18F-FDG-PET or somatostatin receptor imaging for paragangliomas or metastatic disease associated with SDHx-related tumors.	('paragangliomas', 'Disease', (74, 88))	('paragangliomas', 'Disease', 'MESH:D010235', (74, 88))	('paragangliomas', 'Phenotype', 'HP:0002668', (74, 88))	('123I-MIBG', 'Var', (0, 9))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('SDHx', 'Chemical', '-', (127, 131))	('123I-MIBG', 'Chemical', '-', (0, 9))	('18F-FDG', 'Chemical', '-', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('paraganglioma', 'Phenotype', 'HP:0002668', (74, 87))	('metastatic disease', 'CPA', (92, 110))
104899	30540124	Patients with pheochromocytomas larger than 6 cm or paragangliomas of any size and/or those who are carriers of SDHB mutations need imaging studies to localize metastatic disease.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (14, 30))	('mutations', 'Var', (117, 126))	('paragangliomas', 'Disease', (52, 66))	('pheochromocytomas', 'Disease', (14, 31))	('paragangliomas', 'Disease', 'MESH:D010235', (52, 66))	('pheochromocytomas', 'Disease', 'MESH:D010673', (14, 31))	('SDHB', 'Gene', '6390', (112, 116))	('paraganglioma', 'Phenotype', 'HP:0002668', (52, 65))	('paragangliomas', 'Phenotype', 'HP:0002668', (52, 66))	('SDHB', 'Gene', (112, 116))	('Patients', 'Species', '9606', (0, 8))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (14, 31))	('carriers', 'Reg', (100, 108))
104918	30540124	Two small studies of 90Y-DOTATOC and 177Lu-DOTATOC showed tumor response rates of 8% and 17%, respectively.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('90Y-DOTATOC', 'Var', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('177Lu-DOTATOC', 'Var', (37, 50))
104924	30540124	In this study, most of the patients who exhibited a positive response to sunitinib therapy had SDHB germline mutations.	('sunitinib', 'Chemical', 'MESH:D000077210', (73, 82))	('SDHB', 'Gene', '6390', (95, 99))	('patients', 'Species', '9606', (27, 35))	('SDHB', 'Gene', (95, 99))	('germline mutations', 'Var', (100, 118))
104927	30540124	Among PPGL patients, SDHB and SDHD mutation carriers have a significant risk of recurrence.	('SDHB', 'Gene', '6390', (21, 25))	('SDHD', 'Gene', '6392', (30, 34))	('SDHD', 'Gene', (30, 34))	('PPGL', 'Gene', (6, 10))	('mutation', 'Var', (35, 43))	('patients', 'Species', '9606', (11, 19))	('SDHB', 'Gene', (21, 25))
104930	29532999	Nutlin-3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation Adrenocortical carcinoma (ACC) is a rare malignancy, and CTNNB1 is frequently mutated in ACC.	('ACC', 'Phenotype', 'HP:0006744', (114, 117))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (88, 112))	('malignancy', 'Disease', (129, 139))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (88, 112))	('CTNNB1', 'Gene', '1499', (145, 151))	('ACC', 'Phenotype', 'HP:0006744', (177, 180))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (42, 66))	('Adrenocortical carcinoma', 'Disease', (88, 112))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (42, 66))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('CTNNB1', 'Gene', (72, 78))	('mutation', 'Var', (79, 87))	('adrenocortical carcinoma', 'Disease', (42, 66))	('CTNNB1', 'Gene', (145, 151))	('malignancy', 'Disease', 'MESH:D009369', (129, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('CTNNB1', 'Gene', '1499', (72, 78))
104931	29532999	Our study aims to screen for effective agents with antineoplastic activity against ACC with CTNNB1 mutation.	('ACC', 'Phenotype', 'HP:0006744', (83, 86))	('CTNNB1', 'Gene', (92, 98))	('ACC', 'Disease', (83, 86))	('CTNNB1', 'Gene', '1499', (92, 98))	('mutation', 'Var', (99, 107))
104933	29532999	Drug sensitivity in cells with CTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound.	('Drug sensitivity', 'Phenotype', 'HP:0020174', (0, 16))	('CTNNB1', 'Gene', '1499', (31, 37))	('mutation', 'Var', (38, 46))	('CTNNB1', 'Gene', (31, 37))
104934	29532999	Only one compound, Nutlin-3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells with CTNNB1 mutation.	('MDM2', 'Gene', (33, 37))	('MDM2', 'Gene', '4193', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CTNNB1', 'Gene', '1499', (101, 107))	('mutation', 'Var', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (19, 28))	('CTNNB1', 'Gene', (101, 107))	('cancer', 'Disease', (83, 89))
104935	29532999	Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutations indicating concomitant TP53 mutation did not impact on drug efficacy.	('CTNNB1', 'Gene', '1499', (90, 96))	('TP53', 'Gene', '7157', (101, 105))	('TP53', 'Gene', '7157', (139, 143))	('TP53', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('TP53', 'Gene', (139, 143))	('CTNNB1', 'Gene', (90, 96))
104936	29532999	We verified that Nutlin-3a inhibited cellular proliferation in ACC cell line NCI-H295R which harbored CTNNB1 mutation but not in SW13 cells which did not.	('Nutlin-3a', 'Chemical', 'MESH:C482205', (17, 26))	('NCI-H295R', 'CellLine', 'CVCL:0458', (77, 86))	('cellular proliferation', 'CPA', (37, 59))	('CTNNB1', 'Gene', (102, 108))	('ACC', 'Phenotype', 'HP:0006744', (63, 66))	('inhibited', 'NegReg', (27, 36))	('CTNNB1', 'Gene', '1499', (102, 108))	('SW13', 'CellLine', 'CVCL:0542', (129, 133))	('mutation', 'Var', (109, 117))
104942	29532999	Our study has revealed that Nutlin-3a potently inhibits ACC with CTNNB1 mutation.	('CTNNB1', 'Gene', '1499', (65, 71))	('ACC', 'Phenotype', 'HP:0006744', (56, 59))	('ACC', 'Disease', (56, 59))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (28, 37))	('CTNNB1', 'Gene', (65, 71))	('mutation', 'Var', (72, 80))	('inhibits', 'NegReg', (47, 55))
104952	29532999	Contemporary multilevel next-generation sequencing has not only revealed a series of genetic alterations that consolidate the activated Wnt signaling in ACC, but also strengthened the predominant role of beta-catenin in Wnt activation 9, 10.	('strengthened', 'PosReg', (167, 179))	('alterations', 'Var', (93, 104))	('ACC', 'Phenotype', 'HP:0006744', (153, 156))	('Wnt', 'Gene', (136, 139))	('beta-catenin', 'Gene', (204, 216))	('Wnt', 'Gene', (220, 223))	('activated', 'PosReg', (126, 135))	('beta-catenin', 'Gene', '1499', (204, 216))	('Wnt', 'Gene', '114487', (136, 139))	('Wnt', 'Gene', '114487', (220, 223))
104954	29532999	In our study, we aim to explore the online Genomics of Drug Sensitivity in Cancer (GDSC) database to screen drug sensitivity in cells with CTNNB1 mutation.	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (55, 71))	('Cancer', 'Disease', (75, 81))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CTNNB1', 'Gene', '1499', (139, 145))	('Cancer', 'Disease', 'MESH:D009369', (75, 81))	('drug sensitivity', 'Phenotype', 'HP:0020174', (108, 124))	('mutation', 'Var', (146, 154))	('CTNNB1', 'Gene', (139, 145))
104957	29532999	Cases with TP53 and CTNNB1 alteration, including mutation and CNV, were queried using the OncoPrint function.	('TP53', 'Gene', '7157', (11, 15))	('CTNNB1', 'Gene', (20, 26))	('TP53', 'Gene', (11, 15))	('alteration', 'Var', (27, 37))	('CTNNB1', 'Gene', '1499', (20, 26))
104960	29532999	We started by searching compounds with significant selectivity for CTNNB1 mutations on the online visual platform (http://www.cancerrxgene.org/).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (74, 83))	('CTNNB1', 'Gene', '1499', (67, 73))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('CTNNB1', 'Gene', (67, 73))
104961	29532999	The selected compounds were then tested for TP53 mutations.	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('mutations', 'Var', (49, 58))	('tested', 'Reg', (33, 39))
104964	29532999	Our search thus included all cancer cell lines available with genetic status of CTNNB1 and TP53.	('cancer', 'Disease', (29, 35))	('TP53', 'Gene', (91, 95))	('CTNNB1', 'Gene', '1499', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('CTNNB1', 'Gene', (80, 86))	('TP53', 'Gene', '7157', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('genetic status', 'Var', (62, 76))
104970	29532999	The H295R cell line was subject to CTNNB1 knockdown (KD) using shRNAs.	('CTNNB1', 'Gene', (35, 41))	('CTNNB1', 'Gene', '1499', (35, 41))	('knockdown', 'Var', (42, 51))	('H295R', 'CellLine', 'CVCL:0458', (4, 9))
105006	29532999	As CTNNB1 was the truncal gene in ACC, we explored compounds in GDSC database with significant selectivity to cancer cells harboring CTNNB1 mutation.	('cancer', 'Disease', (110, 116))	('CTNNB1', 'Gene', (133, 139))	('CTNNB1', 'Gene', (3, 9))	('mutation', 'Var', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ACC', 'Phenotype', 'HP:0006744', (34, 37))	('CTNNB1', 'Gene', '1499', (133, 139))	('CTNNB1', 'Gene', '1499', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
105007	29532999	Only one compound, Nutlin-3a, showed significant selectivity for CTNNB1 mutation (Fig.	('CTNNB1', 'Gene', '1499', (65, 71))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (19, 28))	('mutation', 'Var', (72, 80))	('CTNNB1', 'Gene', (65, 71))
105011	29532999	To investigate whether TP53 mutation could interfere with Nutlin-3a's selectivity, we further stratified TP53 mutation among CTNNB1-mutated cell lines and found no statistical power (Fig.	('Nutlin-3a', 'Chemical', 'MESH:C482205', (58, 67))	('mutation', 'Var', (28, 36))	('TP53', 'Gene', '7157', (105, 109))	('CTNNB1', 'Gene', (125, 131))	('mutation', 'Var', (110, 118))	('TP53', 'Gene', (105, 109))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('CTNNB1', 'Gene', '1499', (125, 131))
105012	29532999	Here we showed that MDM2 inhibitor, Nutlin-3a, conferred selective inhibition in cancer cells with CTNNB1 mutations, regardless of TP53 mutation status.	('Nutlin-3a', 'Chemical', 'MESH:C482205', (36, 45))	('inhibition', 'NegReg', (67, 77))	('CTNNB1', 'Gene', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('MDM2', 'Gene', '4193', (20, 24))	('cancer', 'Disease', (81, 87))	('TP53', 'Gene', '7157', (131, 135))	('CTNNB1', 'Gene', '1499', (99, 105))	('TP53', 'Gene', (131, 135))	('MDM2', 'Gene', (20, 24))	('mutations', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
105020	29532999	Silencing of CTNNB1 in H295R cells effaced the inhibitory effect of Nutlin-3a at 10 mumol/L on day 9 (Fig.	('H295R', 'CellLine', 'CVCL:0458', (23, 28))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (68, 77))	('CTNNB1', 'Gene', (13, 19))	('inhibitory effect', 'MPA', (47, 64))	('CTNNB1', 'Gene', '1499', (13, 19))	('Silencing', 'Var', (0, 9))
105023	29532999	Similarly, Nutlin-3a induced G1/S arrest in H259R but not in SW13 cells (Fig.	('SW13', 'CellLine', 'CVCL:0542', (61, 65))	('H259R', 'Mutation', 'rs771782116', (44, 49))	('H259R', 'Var', (44, 49))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (11, 20))	('S arrest', 'Disease', (32, 40))	('S arrest', 'Disease', 'MESH:D006323', (32, 40))
105026	29532999	Nutlin-3a also demonstrated selective inhibition of migration in H295R but not in SW13 cells (Fig.	('Nutlin-3a', 'Chemical', 'MESH:C482205', (0, 9))	('migration', 'CPA', (52, 61))	('SW13', 'CellLine', 'CVCL:0542', (82, 86))	('H295R', 'CellLine', 'CVCL:0458', (65, 70))	('H295R', 'Var', (65, 70))	('inhibition', 'NegReg', (38, 48))
105033	29532999	Together, we use in vivo and in vitro models to confirm that Nutlin-3a selectively inhibits ACC cells with CTNNB1 mutation.	('Nutlin-3a', 'Chemical', 'MESH:C482205', (61, 70))	('CTNNB1', 'Gene', '1499', (107, 113))	('inhibits', 'NegReg', (83, 91))	('ACC', 'Phenotype', 'HP:0006744', (92, 95))	('CTNNB1', 'Gene', (107, 113))	('ACC cells', 'Disease', (92, 101))	('mutation', 'Var', (114, 122))
105037	29532999	Likewise, alteration in Wnt/beta-catenin signaling plays a critical role in tumorigenesis of adrenal gland.	('Wnt', 'Gene', '114487', (24, 27))	('beta-catenin', 'Gene', (28, 40))	('beta-catenin', 'Gene', '1499', (28, 40))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Wnt', 'Gene', (24, 27))	('alteration', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
105038	29532999	CTNNB1 mutation is the predominant alteration within Wnt/beta-catenin axis in ACC with consolidation from other genetic alterations in ZNRF3, APC, and MEN1.	('CTNNB1', 'Gene', '1499', (0, 6))	('MEN1', 'Gene', (151, 155))	('Wnt', 'Gene', (53, 56))	('MEN1', 'Gene', '4221', (151, 155))	('CTNNB1', 'Gene', (0, 6))	('Wnt', 'Gene', '114487', (53, 56))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('mutation', 'Var', (7, 15))	('ZNRF3', 'Gene', '84133', (135, 140))	('beta-catenin', 'Gene', (57, 69))	('ZNRF3', 'Gene', (135, 140))	('beta-catenin', 'Gene', '1499', (57, 69))
105039	29532999	Most mutations in CTNNB1 cluster on the N-terminal segment of beta-catenin, also known as the beta-TrCP binding motif, including S45P, S45F, T41A, S45del, G34E, G34R, G34V, S45_P52del, A39Efs*3, and Y30* 9.	('P52del', 'Mutation', 'p.52delP', (177, 183))	('T41A', 'Mutation', 'rs121913412', (141, 145))	('G34V', 'Mutation', 'rs28931589', (167, 171))	('CTNNB1', 'Gene', '1499', (18, 24))	('S45del', 'Mutation', 'p.45delS', (147, 153))	('G34E', 'Var', (155, 159))	('G34E', 'Mutation', 'rs28931589', (155, 159))	('Y30*', 'SUBSTITUTION', 'None', (199, 203))	('S45F', 'Mutation', 'rs121913409', (135, 139))	('S45del', 'Var', (147, 153))	('beta-catenin', 'Gene', (62, 74))	('S45F', 'Var', (135, 139))	('G34V', 'Var', (167, 171))	('Y30*', 'Var', (199, 203))	('G34R', 'Mutation', 'rs121913399', (161, 165))	('S45_P52del', 'Var', (173, 183))	('beta-catenin', 'Gene', '1499', (62, 74))	('S45P', 'Var', (129, 133))	('CTNNB1', 'Gene', (18, 24))	('G34R', 'Var', (161, 165))	('A39Efs*3', 'Var', (185, 193))	('T41A', 'Var', (141, 145))	('S45P', 'Mutation', 'rs121913407', (129, 133))	('cluster', 'Reg', (25, 32))
105040	29532999	Those activating mutations in this region render degradation and ubiquitinylation of beta-catenin inefficient, and accumulated beta-catenin can translocate into nucleus for continuous transcription of target genes.	('ubiquitinylation', 'MPA', (65, 81))	('inefficient', 'NegReg', (98, 109))	('degradation', 'MPA', (49, 60))	('beta-catenin', 'Gene', '1499', (85, 97))	('activating', 'PosReg', (6, 16))	('beta-catenin', 'Gene', (85, 97))	('beta-catenin', 'Gene', (127, 139))	('mutations', 'Var', (17, 26))	('beta-catenin', 'Gene', '1499', (127, 139))
105041	29532999	In this study, we first explored the association between CTNNB1 mutation and clinical presentations of ACC, namely hormone excess.	('ACC', 'Phenotype', 'HP:0006744', (103, 106))	('hormone excess', 'Phenotype', 'HP:0000845', (115, 129))	('ACC', 'Disease', (103, 106))	('mutation', 'Var', (64, 72))	('CTNNB1', 'Gene', '1499', (57, 63))	('hormone excess', 'Disease', (115, 129))	('CTNNB1', 'Gene', (57, 63))
105042	29532999	We find that CTNNB1 mutation is associated with excessive hormone but not with specific type of hormone.	('CTNNB1', 'Gene', (13, 19))	('mutation', 'Var', (20, 28))	('associated', 'Reg', (32, 42))	('excessive hormone', 'MPA', (48, 65))	('CTNNB1', 'Gene', '1499', (13, 19))
105043	29532999	Specific mutations in adrenal gland, S33C, and G34R, S45P are reported to produce aldosterone in zona glomerulosa type of aldosterone-producing adenoma 20.	('aldosterone', 'MPA', (82, 93))	('G34R', 'Mutation', 'rs121913399', (47, 51))	('mutations', 'Var', (9, 18))	('S33C', 'Var', (37, 41))	('adenoma', 'Disease', 'MESH:D000236', (144, 151))	('aldosterone', 'Chemical', 'MESH:D000450', (82, 93))	('aldosterone', 'Chemical', 'MESH:D000450', (122, 133))	('adenoma', 'Disease', (144, 151))	('produce', 'Reg', (74, 81))	('S33C', 'Mutation', 'rs121913400', (37, 41))	('S45P', 'Mutation', 'rs121913407', (53, 57))	('G34R', 'Var', (47, 51))
105044	29532999	In our study, we find that two of the mutations are associated with a variety of hormone types in ACC patients in the TCGA cohort.	('mutations', 'Var', (38, 47))	('patients', 'Species', '9606', (102, 110))	('associated', 'Reg', (52, 62))	('ACC', 'Phenotype', 'HP:0006744', (98, 101))
105047	29532999	CTNNB1 mutation may need to occur in specific adrenocortical cell types for the full effects to be seen.	('CTNNB1', 'Gene', '1499', (0, 6))	('CTNNB1', 'Gene', (0, 6))	('mutation', 'Var', (7, 15))	('adrenocortical', 'Disease', (46, 60))	('adrenocortical', 'Disease', 'MESH:D018268', (46, 60))
105051	29532999	Intriguingly, theoretical drug resistance to TP53 mutation is also found to be circumvented by concomitant CTNNB1 mutation.	('CTNNB1', 'Gene', '1499', (107, 113))	('TP53', 'Gene', (45, 49))	('CTNNB1', 'Gene', (107, 113))	('mutation', 'Var', (114, 122))	('drug resistance', 'Phenotype', 'HP:0020174', (26, 41))	('TP53', 'Gene', '7157', (45, 49))	('mutation', 'Var', (50, 58))
105058	29532999	Scholars suggest disruption of the RP-MDM2-p53 pathway accelerates APC loss-induced colorectal tumorigenesis, yet how much APC loss can simulate CTNNB1 mutation in the ACC context remains undetermined.	('colorectal tumorigenesis', 'Disease', (84, 108))	('CTNNB1', 'Gene', '1499', (145, 151))	('MDM2', 'Gene', '4193', (38, 42))	('ACC', 'Phenotype', 'HP:0006744', (168, 171))	('MDM2', 'Gene', (38, 42))	('APC loss-induced', 'Gene', (67, 83))	('disruption', 'Var', (17, 27))	('p53', 'Gene', (43, 46))	('CTNNB1', 'Gene', (145, 151))	('p53', 'Gene', '7157', (43, 46))	('accelerates', 'PosReg', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('colorectal tumorigenesis', 'Disease', 'MESH:D015179', (84, 108))
105060	29532999	In ACC, both CTNNB1 and TP53 mutations are considered truncal and irrelevant to whole genome doubling.	('TP53', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('CTNNB1', 'Gene', (13, 19))	('ACC', 'Phenotype', 'HP:0006744', (3, 6))	('CTNNB1', 'Gene', '1499', (13, 19))	('TP53', 'Gene', '7157', (24, 28))
105062	29532999	We suggest that mutated or functionally enhanced CTNNB1 requires MDM2 to exert tumorigenic effect regardless of TP53 status, proposing a novel nexus between Wnt/beta-catenin and p53 signaling.	('enhanced', 'PosReg', (40, 48))	('beta-catenin', 'Gene', '1499', (161, 173))	('CTNNB1', 'Gene', '1499', (49, 55))	('tumor', 'Disease', (79, 84))	('Wnt', 'Gene', (157, 160))	('mutated', 'Var', (16, 23))	('CTNNB1', 'Gene', (49, 55))	('MDM2', 'Gene', '4193', (65, 69))	('Wnt', 'Gene', '114487', (157, 160))	('TP53', 'Gene', '7157', (112, 116))	('MDM2', 'Gene', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('p53', 'Gene', (178, 181))	('beta-catenin', 'Gene', (161, 173))	('p53', 'Gene', '7157', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('TP53', 'Gene', (112, 116))
105065	29532999	However, those reports provided indirect evidence that solely account in part for our observation and can hardly be extrapolated to explain the sensitivity of CTNNB1 mutation to Nutlin-3a.	('Nutlin-3a', 'Chemical', 'MESH:C482205', (178, 187))	('mutation', 'Var', (166, 174))	('CTNNB1', 'Gene', (159, 165))	('CTNNB1', 'Gene', '1499', (159, 165))
105067	29532999	We found that Nutlin-3a selectively inhibited the growth of ACC cell with CTNNB1 mutation in vitro and in vivo.	('inhibited', 'NegReg', (36, 45))	('CTNNB1', 'Gene', (74, 80))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (14, 23))	('ACC', 'Phenotype', 'HP:0006744', (60, 63))	('mutation', 'Var', (81, 89))	('CTNNB1', 'Gene', '1499', (74, 80))	('growth', 'CPA', (50, 56))
105144	26810939	Moreover, mitotane is a well-known inducer of Cytochrome P450 3A4 leading to rapid inactivation of more than 50% of postoperatively administered hydrocortisone that, in turn, increases the need for hydrocortisone replacement in mitotane-treated patients.	('mitotane', 'Chemical', 'MESH:D008939', (228, 236))	('hydrocortisone', 'Chemical', 'MESH:D006854', (145, 159))	('Cytochrome P450 3A4', 'Gene', (46, 65))	('patients', 'Species', '9606', (245, 253))	('inactivation', 'NegReg', (83, 95))	('hydrocortisone', 'Chemical', 'MESH:D006854', (198, 212))	('mitotane', 'Var', (10, 18))	('mitotane', 'Chemical', 'MESH:D008939', (10, 18))	('Cytochrome P450 3A4', 'Gene', '1576', (46, 65))	('increases', 'PosReg', (175, 184))
105178	25915569	Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production.	('human', 'Species', '9606', (54, 59))	('LGR5', 'Gene', '8549', (33, 37))	('suppressed', 'NegReg', (74, 84))	('suppressed aldosterone', 'Phenotype', 'HP:0004319', (74, 96))	('aldosterone', 'Chemical', 'MESH:D000450', (85, 96))	('aldosterone production', 'Phenotype', 'HP:0000859', (85, 107))	('transfection', 'Var', (38, 50))	('R-spondin-3', 'Gene', (5, 16))	('aldosterone production', 'MPA', (85, 107))	('LGR5', 'Gene', (33, 37))	('R-spondin-3', 'Gene', '84870', (5, 16))
105186	25915569	Novel drug targets can be identified by the discovery of either a gene whose gain-of-function mutation increases aldosterone production in APAs or pathways coupled to inhibition of aldosterone in the normal adrenal.	('increases', 'PosReg', (103, 112))	('aldosterone production', 'Phenotype', 'HP:0000859', (113, 135))	('aldosterone', 'Chemical', 'MESH:D000450', (113, 124))	('pathways', 'Pathway', (147, 155))	('inhibition', 'NegReg', (167, 177))	('gain-of-function', 'PosReg', (77, 93))	('increases aldosterone', 'Phenotype', 'HP:0000859', (103, 124))	('aldosterone', 'Chemical', 'MESH:D000450', (181, 192))	('aldosterone production', 'MPA', (113, 135))	('APA', 'Gene', (139, 142))	('mutation', 'Var', (94, 102))	('APA', 'Gene', '2028', (139, 142))
105189	25915569	Exome sequencing of ten such ZG-like APAs led us to identify somatic mutations in three genes, encoding caveolin-1.3, Na+, K+-ATPase, and beta-catenin; no ZG-like APAs have yet been found to have one of the KCNJ5 mutations common in larger, more ZF-like APAs.	('APA', 'Gene', '2028', (37, 40))	('beta-catenin', 'Gene', (138, 150))	('beta-catenin', 'Gene', '1499', (138, 150))	('APA', 'Gene', '2028', (254, 257))	('APA', 'Gene', (254, 257))	('APA', 'Gene', (163, 166))	('APA', 'Gene', '2028', (163, 166))	('KCNJ5', 'Gene', (207, 212))	('mutations', 'Var', (213, 222))	('KCNJ5', 'Gene', '3762', (207, 212))	('APA', 'Gene', (37, 40))
105191	25915569	This observation suggested to us that cells in a ZG-like APA may derive a survival advantage from constitutive aldosterone production, rather than cell division, thus explaining the frequency of somatic mutations, 19 different mutations in caveolin-1.3 alone, which switch on constitutive aldosterone production.	('APA', 'Gene', '2028', (57, 60))	('APA', 'Gene', (57, 60))	('rat', 'Species', '10116', (135, 138))	('aldosterone production', 'Phenotype', 'HP:0000859', (289, 311))	('aldosterone production', 'Phenotype', 'HP:0000859', (111, 133))	('constitutive', 'MPA', (276, 288))	('aldosterone', 'Chemical', 'MESH:D000450', (289, 300))	('switch', 'Reg', (266, 272))	('mutations', 'Var', (203, 212))	('aldosterone', 'Chemical', 'MESH:D000450', (111, 122))	('mutations', 'Var', (227, 236))
105213	25915569	Cells were transfected with vector controls, pCMV6-AC-GFP (Origene) or pcDNA3.1/His A (Invitrogen), and green fluorescent protein (GFP)-tagged LGR5 (Origene; 600 ng/muL).	('LGR5', 'Gene', '8549', (143, 147))	('pCMV6-AC-GFP', 'Var', (45, 57))	('LGR5', 'Gene', (143, 147))
105223	25915569	To activate the pathway, pcDNA3 deltaN47 beta-catenin was used; and to suppress the pathway, pcDNA/Myc deltaN TCF4 (both from Addgene) were used.	('beta-catenin', 'Gene', (41, 53))	('beta-catenin', 'Gene', '1499', (41, 53))	('Myc', 'Gene', (99, 102))	('TCF4', 'Gene', (110, 114))	('TCF4', 'Gene', '6925', (110, 114))	('activate', 'PosReg', (3, 11))	('deltaN47', 'Var', (32, 40))	('suppress', 'NegReg', (71, 79))	('deltaN47', 'DELETION', 'None', (32, 40))	('Myc', 'Gene', '4609', (99, 102))
105237	25915569	Functional studies, overexpression and silencing of LGR5 and treatment with its cognate ligand R-spondin-3, were performed on either the immortalized human adrenocortical H295R cell line or normal primary adrenal cells cultured from adrenalectomized adrenals of patients diagnosed with either primary hyperaldosteronism or pheochromocytoma.	('human', 'Species', '9606', (150, 155))	('R-spondin-3', 'Gene', '84870', (95, 106))	('pheochromocytoma', 'Disease', (323, 339))	('pheochromocytoma', 'Disease', 'MESH:D010673', (323, 339))	('H295R', 'CellLine', 'CVCL:0458', (171, 176))	('primary hyperaldosteronism', 'Disease', 'MESH:D003480', (293, 319))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (323, 339))	('primary hyperaldosteronism', 'Phenotype', 'HP:0011736', (293, 319))	('R-spondin-3', 'Gene', (95, 106))	('silencing', 'Var', (39, 48))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (301, 319))	('LGR5', 'Gene', (52, 56))	('adrenocortical', 'Disease', (156, 170))	('primary hyperaldosteronism', 'Disease', (293, 319))	('LGR5', 'Gene', '8549', (52, 56))	('patients', 'Species', '9606', (262, 270))	('adrenocortical', 'Disease', 'MESH:D018268', (156, 170))
105239	25915569	LGR5 transfection similarly reduced aldosterone production (Figure 2, E and F).	('transfection', 'Var', (5, 17))	('reduced', 'NegReg', (28, 35))	('aldosterone', 'Chemical', 'MESH:D000450', (36, 47))	('LGR5', 'Gene', (0, 4))	('LGR5', 'Gene', '8549', (0, 4))	('aldosterone production', 'MPA', (36, 58))	('aldosterone production', 'Phenotype', 'HP:0000859', (36, 58))	('reduced aldosterone', 'Phenotype', 'HP:0004319', (28, 47))
105240	25915569	Conversely, silencing of LGR5 caused an increase in aldosterone production and CYP11B2 transcription (Figure 2, G and H).	('aldosterone production', 'Phenotype', 'HP:0000859', (52, 74))	('aldosterone production', 'MPA', (52, 74))	('LGR5', 'Gene', (25, 29))	('LGR5', 'Gene', '8549', (25, 29))	('increase', 'PosReg', (40, 48))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (40, 63))	('silencing', 'Var', (12, 21))	('CYP11B2', 'Gene', (79, 86))	('aldosterone', 'Chemical', 'MESH:D000450', (52, 63))
105243	25915569	We consistently noted a qualitative reduction in cell number and adhesion after LGR5 transfection or R-spondin-3 stimulation.	('adhesion', 'CPA', (65, 73))	('R-spondin-3', 'Gene', (101, 112))	('transfection', 'Var', (85, 97))	('reduction', 'NegReg', (36, 45))	('cell number', 'CPA', (49, 60))	('R-spondin-3', 'Gene', '84870', (101, 112))	('LGR5', 'Gene', '8549', (80, 84))	('LGR5', 'Gene', (80, 84))
105247	25915569	In the absence of aldosterone production, eg, in the CYP11B2-/- mouse, the processes of migration and apoptosis are accelerated.	('CYP11B2-/-', 'Var', (53, 63))	('aldosterone production', 'Phenotype', 'HP:0000859', (18, 40))	('rat', 'Species', '10116', (91, 94))	('apoptosis', 'CPA', (102, 111))	('accelerated', 'PosReg', (116, 127))	('rat', 'Species', '10116', (122, 125))	('aldosterone', 'Chemical', 'MESH:D000450', (18, 29))	('mouse', 'Species', '10090', (64, 69))
105253	25915569	In addition, we also investigated the effect on aldosterone production of a constitutively active or dominant-negative canonical Wnt pathway through transfection of a constitutively active beta-catenin (deltaN47 beta-catenin) or dominant-negative TCF (deltaN TCF4); and using small molecule inhibitors, we interrogated nonselective inhibition of Wnt signaling pathways (through inhibition of the Wnt chaperone porcupine) and selective inhibition of the noncanonical Wnt signaling pathway (through inhibition of JNK).	('deltaN47', 'Var', (203, 211))	('Wnt', 'Gene', (466, 469))	('Wnt', 'Gene', '114487', (396, 399))	('deltaN47', 'DELETION', 'None', (203, 211))	('Wnt', 'Gene', '114487', (466, 469))	('aldosterone', 'Chemical', 'MESH:D000450', (48, 59))	('TCF', 'Gene', (247, 250))	('aldosterone production', 'Phenotype', 'HP:0000859', (48, 70))	('TCF', 'Gene', '6925', (259, 262))	('Wnt', 'Gene', (346, 349))	('inhibition', 'NegReg', (435, 445))	('TCF4', 'Gene', '6925', (259, 263))	('inhibition', 'NegReg', (378, 388))	('Wnt', 'Gene', '114487', (346, 349))	('beta-catenin', 'Gene', (212, 224))	('beta-catenin', 'Gene', (189, 201))	('beta-catenin', 'Gene', '1499', (212, 224))	('Wnt', 'Gene', (129, 132))	('TCF', 'Gene', '6925', (247, 250))	('beta-catenin', 'Gene', '1499', (189, 201))	('Wnt', 'Gene', '114487', (129, 132))	('TCF4', 'Gene', (259, 263))	('TCF', 'Gene', (259, 262))	('JNK', 'Gene', (511, 514))	('JNK', 'Gene', '5599', (511, 514))	('Wnt', 'Gene', (396, 399))
105254	25915569	H295R cells, whose S45P mutant beta-catenin is constitutively active, had the expected high basal levels of TCF/LEF activity, with only slight further activation on the addition of the deltaN47 beta-catenin construct (Figure 4B).	('deltaN47', 'Var', (185, 193))	('beta-catenin', 'Gene', (31, 43))	('TCF/LEF', 'Gene', '3172', (108, 115))	('beta-catenin', 'Gene', '1499', (31, 43))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('beta-catenin', 'Gene', (194, 206))	('deltaN47', 'DELETION', 'None', (185, 193))	('S45P', 'Var', (19, 23))	('beta-catenin', 'Gene', '1499', (194, 206))	('S45P', 'Mutation', 'rs121913407', (19, 23))	('TCF/LEF', 'Gene', (108, 115))
105255	25915569	On the other hand, the deltaN TCF4 construct markedly reduced both TCF/LEF activity and aldosterone production (Figure 4, B and C).	('TCF/LEF', 'Gene', '3172', (67, 74))	('TCF/LEF', 'Gene', (67, 74))	('aldosterone', 'Chemical', 'MESH:D000450', (88, 99))	('aldosterone production', 'MPA', (88, 110))	('aldosterone production', 'Phenotype', 'HP:0000859', (88, 110))	('reduced', 'NegReg', (54, 61))	('deltaN', 'Var', (23, 29))	('TCF4', 'Gene', (30, 34))	('TCF4', 'Gene', '6925', (30, 34))
105256	25915569	In contrast, transfection of LGR5 caused a slight increase in TCF/LEF activity while decreasing aldosterone secretion (Figure 4, B and C).	('LGR5', 'Gene', (29, 33))	('activity', 'MPA', (70, 78))	('transfection', 'Var', (13, 25))	('decreasing', 'NegReg', (85, 95))	('aldosterone secretion', 'MPA', (96, 117))	('decreasing aldosterone', 'Phenotype', 'HP:0004319', (85, 107))	('increase', 'PosReg', (50, 58))	('TCF/LEF', 'Gene', '3172', (62, 69))	('TCF/LEF', 'Gene', (62, 69))	('aldosterone', 'Chemical', 'MESH:D000450', (96, 107))	('LGR5', 'Gene', '8549', (29, 33))
105257	25915569	Supporting a predominant action of LGR5 on a noncanonical Wnt pathway (Figure 4D), LGR5 transfection increased AP1/Jun activity by almost 3-fold, and the noncanonical selective JNK inhibitor, JNK-IN-8, ameliorated this increase (Figure 4E).	('transfection', 'Var', (88, 100))	('JNK', 'Gene', (177, 180))	('LGR5', 'Gene', '8549', (35, 39))	('rat', 'Species', '10116', (208, 211))	('increased', 'PosReg', (101, 110))	('JNK', 'Gene', '5599', (192, 195))	('AP1', 'Gene', '3725', (111, 114))	('JNK', 'Gene', '5599', (177, 180))	('Wnt', 'Gene', (58, 61))	('LGR5', 'Gene', (83, 87))	('JNK', 'Gene', (192, 195))	('LGR5', 'Gene', '8549', (83, 87))	('Wnt', 'Gene', '114487', (58, 61))	('AP1', 'Gene', (111, 114))	('LGR5', 'Gene', (35, 39))
105261	25915569	We found the most-up-regulated gene in normal human ZG, compared with its adjacent ZF, to be LGR5 and that its transfection into human adrenocortical cells results in the inhibition of aldosterone production, reduction in cell number, and activation of a noncanonical Wnt signaling pathway postulated as the mediator of the LGR5 response.	('Wnt', 'Gene', (268, 271))	('transfection', 'Var', (111, 123))	('Wnt', 'Gene', '114487', (268, 271))	('cell number', 'CPA', (222, 233))	('inhibition', 'NegReg', (171, 181))	('human', 'Species', '9606', (46, 51))	('reduction', 'NegReg', (209, 218))	('adrenocortical', 'Disease', 'MESH:D018268', (135, 149))	('aldosterone production', 'MPA', (185, 207))	('inhibition of aldosterone production', 'Phenotype', 'HP:0004319', (171, 207))	('adrenocortical', 'Disease', (135, 149))	('activation', 'PosReg', (239, 249))	('LGR5', 'Gene', '8549', (93, 97))	('LGR5', 'Gene', '8549', (324, 328))	('LGR5', 'Gene', (93, 97))	('LGR5', 'Gene', (324, 328))	('aldosterone', 'Chemical', 'MESH:D000450', (185, 196))	('human', 'Species', '9606', (129, 134))	('aldosterone production', 'Phenotype', 'HP:0000859', (185, 207))
105267	25915569	Finally, only one of our 18 Wnt related genes (GPC3) was similarly up-regulated in a microarray comparison of CYP11B2-positive cells in rat ZG with adjacent ZF.	('Wnt', 'Gene', '114487', (28, 31))	('CYP11B2-positive', 'Var', (110, 126))	('GPC3', 'Gene', (47, 51))	('GPC3', 'Gene', '25236', (47, 51))	('up-regulated', 'PosReg', (67, 79))	('rat', 'Species', '10116', (136, 139))	('Wnt', 'Gene', (28, 31))
105270	25915569	The AP1/Jun pathway, which was markedly stimulated by LGR5 transfection of H295R cells, influences cell migration.	('LGR5', 'Gene', (54, 58))	('LGR5', 'Gene', '8549', (54, 58))	('AP1', 'Gene', '3725', (4, 7))	('H295R', 'CellLine', 'CVCL:0458', (75, 80))	('AP1', 'Gene', (4, 7))	('stimulated', 'PosReg', (40, 50))	('transfection', 'Var', (59, 71))	('influences', 'Reg', (88, 98))	('cell migration', 'CPA', (99, 113))	('rat', 'Species', '10116', (107, 110))
105277	25915569	If aldosterone is required for ZG cell survival, as implied by CYP11B2-/- mice, cells that mutate to protect aldosterone production will have a selective advantage.	('mutate', 'Var', (91, 97))	('aldosterone', 'Chemical', 'MESH:D000450', (109, 120))	('aldosterone', 'Chemical', 'MESH:D000450', (3, 14))	('aldosterone production', 'MPA', (109, 131))	('aldosterone production', 'Phenotype', 'HP:0000859', (109, 131))	('mice', 'Species', '10090', (74, 78))
105279	25915569	The sparseness of CYP11B2 in ZG is a general phenomenon whether adjacent to an APA or to a pheochromocytoma.	('pheochromocytoma', 'Disease', (91, 107))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (91, 107))	('CYP11B2', 'Var', (18, 25))	('APA', 'Gene', '2028', (79, 82))	('APA', 'Gene', (79, 82))	('pheochromocytoma', 'Disease', 'MESH:D010673', (91, 107))
105281	25915569	If physiological inhibition of aldosterone production has the same consequences as genetic deletion, as is suggested by our apoptosis data (Figure 3), then constitutive activation of aldosterone production after somatic mutations would confer a local selection advantage to mutated cells.	('deletion', 'Var', (91, 99))	('activation', 'PosReg', (169, 179))	('aldosterone production', 'Phenotype', 'HP:0000859', (31, 53))	('local selection advantage', 'CPA', (245, 270))	('aldosterone', 'Chemical', 'MESH:D000450', (183, 194))	('aldosterone', 'MPA', (183, 194))	('inhibition of aldosterone production', 'Phenotype', 'HP:0004319', (17, 53))	('aldosterone production', 'Phenotype', 'HP:0000859', (183, 205))	('aldosterone', 'Chemical', 'MESH:D000450', (31, 42))	('mutations', 'Var', (220, 229))
105293	25915569	But the discovery of adrenally expressed genes whose mutation activates aldosterone production, and of adrenal pathways linked to reduced aldosterone secretion, provides novel targets, with potential for clinical development.	('aldosterone production', 'MPA', (72, 94))	('mutation', 'Var', (53, 61))	('aldosterone production', 'Phenotype', 'HP:0000859', (72, 94))	('adrenal pathways', 'Pathway', (103, 119))	('reduced aldosterone', 'Phenotype', 'HP:0004319', (130, 149))	('aldosterone', 'Chemical', 'MESH:D000450', (72, 83))	('activates', 'PosReg', (62, 71))	('aldosterone', 'Chemical', 'MESH:D000450', (138, 149))	('aldosterone secretion', 'MPA', (138, 159))
105295	25915569	We speculate that inhibition of aldosterone production by a R-spondin-3-LGR5-noncanonical Wnt signaling pathway creates a mechanism that is an appropriate response to excess salt but could paradoxically create a survival advantage for cells with somatic mutations causing autonomous aldosterone production.	('aldosterone', 'Chemical', 'MESH:D000450', (32, 43))	('inhibition', 'NegReg', (18, 28))	('aldosterone', 'Chemical', 'MESH:D000450', (283, 294))	('survival advantage', 'CPA', (212, 230))	('salt', 'Chemical', 'MESH:D012492', (174, 178))	('Wnt', 'Gene', '114487', (90, 93))	('appropriate response to excess salt', 'Phenotype', 'HP:0000127', (143, 178))	('LGR5', 'Gene', '8549', (72, 76))	('R-spondin-3', 'Gene', (60, 71))	('aldosterone production', 'Phenotype', 'HP:0000859', (283, 305))	('aldosterone production', 'MPA', (32, 54))	('aldosterone production', 'Phenotype', 'HP:0000859', (32, 54))	('LGR5', 'Gene', (72, 76))	('inhibition of aldosterone production', 'Phenotype', 'HP:0004319', (18, 54))	('Wnt', 'Gene', (90, 93))	('R-spondin-3', 'Gene', '84870', (60, 71))	('mutations', 'Var', (254, 263))
105364	25593821	MRI depicts the age of hemorrhage or hematoma which is isointense to slightly hypointense on T1 WI and hypointense on T2 WI in acute stage owing to the presence of intracellular deoxyhemoglobin and is hyperintense on both T1 and T2 WI by virtue of the presence of methemoglobin in the subacute stage.	('hematoma', 'Disease', 'MESH:D006406', (37, 45))	('methemoglobin', 'Gene', (264, 277))	('hemorrhage', 'Disease', 'MESH:D006470', (23, 33))	('hematoma', 'Disease', (37, 45))	('hypointense', 'Var', (103, 114))	('hemorrhage', 'Disease', (23, 33))	('methemoglobin', 'Gene', '3048', (264, 277))
105371	25593821	On chemical shift MRI (CS-MRI), metastases do not produce signal drop on opposed phase images.	('metastases', 'Disease', 'MESH:D009362', (32, 42))	('metastases', 'Disease', (32, 42))	('CS', 'Chemical', '-', (23, 25))	('chemical shift', 'Var', (3, 17))
105373	25593821	Differentiation of metastases from lipid-poor adenomas can be difficult as lipid poor adenomas also have attenuation more than 10 HU and do not demonstrate signal drop on CS-MRI.	('adenomas', 'Disease', 'MESH:D000236', (86, 94))	('adenomas', 'Disease', 'MESH:D000236', (46, 54))	('adenomas', 'Disease', (86, 94))	('adenomas', 'Disease', (46, 54))	('CS', 'Chemical', '-', (171, 173))	('lipid poor', 'Var', (75, 85))	('lipid', 'Chemical', 'MESH:D008055', (35, 40))	('metastases', 'Disease', (19, 29))	('attenuation', 'MPA', (105, 116))	('metastases', 'Disease', 'MESH:D009362', (19, 29))	('lipid', 'Chemical', 'MESH:D008055', (75, 80))
105374	25593821	However, contrast CT can help in such cases as lipid poor adenomas also have APW and RPW of more than 60% and 40% similar to lipid-rich adenomas.	('lipid', 'Chemical', 'MESH:D008055', (47, 52))	('adenomas', 'Disease', 'MESH:D000236', (58, 66))	('lipid poor', 'Var', (47, 57))	('lipid', 'Chemical', 'MESH:D008055', (125, 130))	('adenomas', 'Disease', 'MESH:D000236', (136, 144))	('adenomas', 'Disease', (136, 144))	('adenomas', 'Disease', (58, 66))
105479	22493766	found that patients with tumors <200 cm3 in volume and <100 g in weight that were completely resected had an excellent prognosis, and the long-term survival rate of children with adrenocortical carcinoma has been reported to be between 10% and 46%.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (179, 203))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (179, 203))	('<100 g', 'Var', (55, 61))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('adrenocortical carcinoma', 'Disease', (179, 203))	('patients', 'Species', '9606', (11, 19))	('children', 'Species', '9606', (165, 173))
105482	20407015	Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation Mutations of the sequence-specific master regulator p53 that alter transactivation function from promoter response elements (REs) could result in changes in the strength of gene activation or spectra of genes regulated.	('breast cancers', 'Disease', (54, 68))	('transactivation', 'MPA', (96, 111))	('spectra of genes regulated', 'MPA', (304, 330))	('breast cancers', 'Phenotype', 'HP:0003002', (54, 68))	('p53', 'Gene', (17, 20))	('transactivation function', 'MPA', (179, 203))	('Mutations', 'Var', (112, 121))	('effects', 'Reg', (85, 92))	('p53', 'Gene', '7157', (164, 167))	('strength', 'MPA', (273, 281))	('missense mutations', 'Var', (21, 39))	('gene activation', 'MPA', (285, 300))	('changes', 'Reg', (258, 265))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('p53', 'Gene', (164, 167))	('alter', 'Reg', (173, 178))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('p53', 'Gene', '7157', (17, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('breast cancers', 'Disease', 'MESH:D001943', (54, 68))
105483	20407015	Such mutations in this tumor suppressor might lead to dramatic phenotypic changes and diversification of cell responses to stress.	('lead to', 'Reg', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))
105484	20407015	We have determined "functional fingerprints" of sporadic breast cancer-related p53 mutants many of which are also associated with familial cancer proneness such as the Li-Fraumeni Syndrome and germline BRCA1/2 mutant-associated cancers.	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('p53', 'Gene', (79, 82))	('familial cancer', 'Disease', (130, 145))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (168, 188))	('cancers', 'Disease', (228, 235))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (48, 70))	('familial cancer', 'Disease', 'MESH:D009369', (130, 145))	('mutants', 'Var', (83, 90))	('BRCA1/2', 'Gene', '672;675', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Li-Fraumeni Syndrome', 'Disease', (168, 188))	('associated', 'Reg', (114, 124))	('BRCA1/2', 'Gene', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('sporadic breast cancer', 'Disease', (48, 70))
105487	20407015	When the level of galactose was reduced, transactivation defects could be revealed suggesting that some breast cancer related mutants can have subtle changes in transcription.	('transcription', 'MPA', (161, 174))	('changes', 'Reg', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('galactose', 'Chemical', 'MESH:D005690', (18, 27))	('mutants', 'Var', (126, 133))
105489	20407015	The functional and nonfunctional missense mutations may distinguish tumors in terms of demographics, appearance and relapse, implying that heterogeneity in the functionality of specific p53 mutations could impact clinical behavior and outcome.	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('p53', 'Gene', (186, 189))	('impact', 'Reg', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('missense mutations', 'Var', (33, 51))
105492	20407015	The importance of p53 as a tumor suppressor and sequence-specific transcription factor in human cells is highlighted by the occurrence of p53 mutations in the majority of cancers.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (142, 151))	('p53', 'Gene', (138, 141))	('tumor', 'Disease', (27, 32))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('human', 'Species', '9606', (90, 95))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('occurrence', 'Reg', (124, 134))	('cancers', 'Disease', (171, 178))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
105493	20407015	Interestingly, p53 is unique in comparison to other transcription factors in that over 75% of mutations that occur in this tumor suppressor are single amino acid changes which result in missense mutations.	('tumor', 'Disease', (123, 128))	('mutations', 'Var', (94, 103))	('missense mutations', 'MPA', (186, 204))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
105494	20407015	These missense mutations predominantly occur in the DNA binding domain (DBD) of the protein (>80%).	('occur', 'Reg', (39, 44))	('missense mutations', 'Var', (6, 24))	('DBD', 'Chemical', '-', (72, 75))
105495	20407015	At the molecular level, p53 mutations found in cancers, including breast cancer, are usually associated with loss of the ability to maintain proper cell cycle checkpoints, suppress transformation caused by oncogenes, induce apoptosis and maintain the integrity of the genome.	('induce', 'PosReg', (217, 223))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('transformation', 'CPA', (181, 195))	('oncogenes', 'Protein', (206, 215))	('integrity', 'MPA', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('ability', 'MPA', (121, 128))	('maintain', 'Reg', (238, 246))	('p53', 'Gene', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('apoptosis', 'CPA', (224, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('mutations', 'Var', (28, 37))	('loss', 'NegReg', (109, 113))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('suppress', 'NegReg', (172, 180))
105496	20407015	Such mutations are thought to provide a selective advantage within cancerous cells by forming a hetero-tetramer with WT p53 and functioning in a dominant-negative fashion.	('cancerous', 'Disease', (67, 76))	('forming', 'Reg', (86, 93))	('mutations', 'Var', (5, 14))	('hetero-tetramer', 'Interaction', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancerous', 'Disease', 'MESH:D009369', (67, 76))	('advantage', 'PosReg', (50, 59))
105497	20407015	Alternatively, gain-of-function mutations can potentiate tumorigenesis through oncogenic mechanisms including aberrant transcriptional regulation of either known or novel target genes--presumably through structure-selective DNA binding or protein-protein interactions.	('gain-of-function', 'PosReg', (15, 31))	('transcriptional regulation', 'MPA', (119, 145))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('potentiate', 'PosReg', (46, 56))
105498	20407015	For example, change-in-spectrum mutants may be capable of regulating genes containing a strong RE, such as p21, but unable to regulate those with a weak RE, such as Bax.	('p21', 'Gene', '1026', (107, 110))	('Bax', 'Gene', '581', (165, 168))	('mutants', 'Var', (32, 39))	('p21', 'Gene', (107, 110))	('change-in-spectrum', 'Reg', (13, 31))	('Bax', 'Gene', (165, 168))
105499	20407015	Modifications in the transcriptional network due to altered-function mutations may result in cellular responses that impact genome stability, repair, replication, and programmed cell death.	('death', 'Disease', (183, 188))	('mutations', 'Var', (69, 78))	('result in', 'Reg', (83, 92))	('transcriptional network', 'Pathway', (21, 44))	('replication', 'CPA', (150, 161))	('altered-function', 'Reg', (52, 68))	('Modifications', 'Reg', (0, 13))	('impact', 'Reg', (117, 123))	('repair', 'CPA', (142, 148))	('cellular responses', 'CPA', (93, 111))	('death', 'Disease', 'MESH:D003643', (183, 188))	('genome stability', 'CPA', (124, 140))
105500	20407015	Varying patterns of cellular responses, including apoptosis and survival have been elicited in human cells as a consequence of distinct altered-function p53 mutations.	('human', 'Species', '9606', (95, 100))	('survival', 'CPA', (64, 72))	('altered-function', 'Reg', (136, 152))	('mutations', 'Var', (157, 166))	('p53', 'Gene', (153, 156))	('apoptosis', 'CPA', (50, 59))
105501	20407015	Mutations in p53 are associated with approximately 25% of sporadic cases of breast cancer, a frequency lower than that in other sporadic cancers, such as lung and colorectal carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (163, 184))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('associated', 'Reg', (21, 31))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Disease', (76, 89))	('sporadic cancers', 'Disease', 'MESH:D009369', (128, 144))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('p53', 'Gene', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('sporadic cancers', 'Disease', (128, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))	('colorectal carcinomas', 'Disease', (163, 184))
105502	20407015	However, sporadic p53 mutations occur at much higher frequencies in BRCA1/2 germline-associated breast cancers possibly due to a decreased efficiency to repair damage.	('BRCA1/2', 'Gene', '672;675', (68, 75))	('p53', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancers', 'Phenotype', 'HP:0003002', (96, 110))	('efficiency', 'MPA', (139, 149))	('breast cancers', 'Disease', 'MESH:D001943', (96, 110))	('breast cancers', 'Disease', (96, 110))	('BRCA1/2', 'Gene', (68, 75))	('mutations', 'Var', (22, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('decreased', 'NegReg', (129, 138))
105503	20407015	BRCA1/2 and p53 are involved in maintaining genome stability by controlling aspects of homologous recombination and repair, centrosome regulation, cell cycle checkpoints and transcription, where loss of either increases the likelihood of cancer.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('centrosome regulation', 'MPA', (124, 145))	('increases', 'PosReg', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('p53', 'Gene', (12, 15))	('BRCA1/2', 'Gene', (0, 7))	('loss', 'Var', (195, 199))
105504	20407015	Interestingly, BRCA1-associated cancers have an altered spectrum of p53 mutations which may reflect changes in mutagenesis and/or selection for the acquired mutations.	('mutations', 'Var', (72, 81))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('altered', 'Reg', (48, 55))	('cancers', 'Disease', (32, 39))	('BRCA1', 'Gene', '672', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('p53', 'Gene', (68, 71))	('BRCA1', 'Gene', (15, 20))
105505	20407015	While BRCA1 mutations are largely absent in somatic breast tumors, silencing of the gene through hypermethylation has been reported in sporadic cases.	('BRCA1', 'Gene', (6, 11))	('silencing', 'NegReg', (67, 76))	('mutations', 'Var', (12, 21))	('breast tumors', 'Phenotype', 'HP:0100013', (52, 65))	('hypermethylation', 'Var', (97, 113))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('breast tumor', 'Phenotype', 'HP:0100013', (52, 64))	('breast tumors', 'Disease', 'MESH:D001943', (52, 65))	('BRCA1', 'Gene', '672', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('breast tumors', 'Disease', (52, 65))
105506	20407015	Such epigenetic changes have been reported to associate with estrogen receptor negative (ER-) tumors and occur concomitantly with p53 mutations.	('estrogen receptor', 'Gene', '2099', (61, 78))	('epigenetic changes', 'Var', (5, 23))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('associate', 'Reg', (46, 55))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('mutations', 'Var', (134, 143))	('p53', 'Gene', (130, 133))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('estrogen receptor', 'Gene', (61, 78))
105507	20407015	At the clinical level, p53 mutations in breast cancer have been associated with poor prognosis, earlier on-set, increased aggressiveness of tumors, aneuploidy, and adverse responses to chemotherapeutic treatments.	('mutations', 'Var', (27, 36))	('associated', 'Reg', (64, 74))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('aggressiveness', 'Phenotype', 'HP:0000718', (122, 136))	('aneuploidy', 'Disease', (148, 158))	('increased', 'PosReg', (112, 121))	('p53', 'Gene', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('aggressiveness of tumors', 'Disease', (122, 146))	('aggressiveness of tumors', 'Disease', 'MESH:D001523', (122, 146))	('aneuploidy', 'Disease', 'MESH:D000782', (148, 158))
105508	20407015	Studies that classify breast cancers based on gene expression profiling have shown p53 mutations are more frequent in the hormone receptor-negative subtypes such as the HER2+/ER- [human epidermal growth factor-2 positive/estrogen receptor negative] and the basal-like subtypes [ER-, PR- (progesterone receptor), HER2-, cytokeratin 5/6+, and/or HER1+].	('p53', 'Gene', (83, 86))	('HER2', 'Gene', '2064', (169, 173))	('frequent', 'Reg', (106, 114))	('PR-', 'Disease', (283, 286))	('breast cancers', 'Phenotype', 'HP:0003002', (22, 36))	('mutations', 'Var', (87, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('HER2', 'Gene', (312, 316))	('estrogen receptor', 'Gene', '2099', (221, 238))	('HER2', 'Gene', (169, 173))	('HER1', 'Gene', (344, 348))	('HER2+/ER-', 'Gene', (169, 178))	('human', 'Species', '9606', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('estrogen receptor', 'Gene', (221, 238))	('cytokeratin 5/6+', 'Disease', (319, 335))	('HER1', 'Gene', '1956', (344, 348))	('HER2', 'Gene', '2064', (312, 316))	('HER2+/ER-', 'Gene', '2064', (169, 178))	('breast cancers', 'Disease', 'MESH:D001943', (22, 36))	('breast cancers', 'Disease', (22, 36))
105510	20407015	Regardless of subtype, p53 status (WT or mutant) also displays a signature expression profile in breast tumors which is a prognostic indicator of patient survival, where WT p53 associates with a more favorable outcome.	('breast tumors', 'Disease', 'MESH:D001943', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('WT p53', 'Var', (170, 176))	('breast tumors', 'Phenotype', 'HP:0100013', (97, 110))	('breast tumor', 'Phenotype', 'HP:0100013', (97, 109))	('patient', 'Species', '9606', (146, 153))	('breast tumors', 'Disease', (97, 110))
105511	20407015	We have employed a newly developed model system in diploid yeast to analyze the functional consequences of p53 missense mutations found in breast cancers on gene activation endpoints in the p53 transcriptional network at various levels of p53 expression.	('p53', 'Gene', (107, 110))	('yeast', 'Species', '4932', (59, 64))	('breast cancers', 'Phenotype', 'HP:0003002', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancers', 'Disease', 'MESH:D001943', (139, 153))	('missense mutations', 'Var', (111, 129))	('breast cancers', 'Disease', (139, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
105512	20407015	Transactivation capacities of WT and mutant p53 have been determined using a qualitative and a quantitative reporter, and a "functional fingerprint" was established for each p53 variant towards a subset of human REs that are representative of p53-dependent cellular responses.	('variant', 'Var', (178, 185))	('Transactivation', 'MPA', (0, 15))	('p53', 'Gene', (174, 177))	('human', 'Species', '9606', (206, 211))
105513	20407015	We have determined that p53 missense mutations found in sporadic and familial breast cancers can retain function and the alterations in transactivation are often subtle where differences can be exaggerated by changes in p53 levels.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('familial breast cancers', 'Disease', (69, 92))	('p53', 'Gene', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('function', 'MPA', (104, 112))	('missense mutations', 'Var', (28, 46))	('breast cancers', 'Phenotype', 'HP:0003002', (78, 92))	('transactivation', 'MPA', (136, 151))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('familial breast cancers', 'Disease', 'MESH:D001943', (69, 92))
105514	20407015	While patient numbers are limited, the separation of missense p53-associated breast cancer mutations into functional (which include fully functional and altered function) versus nonfunctional classes appears to associate with prognostic factors and outcome in a largely locally-advanced patient population treated with chemotherapy prior to surgery.	('breast cancer', 'Disease', (77, 90))	('patient', 'Species', '9606', (287, 294))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('patient', 'Species', '9606', (6, 13))	('associate', 'Reg', (211, 220))	('mutations', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('missense', 'Var', (53, 61))
105515	20407015	Functional fingerprinting of cancer-associated p53 mutants may thus be a useful tool for understanding tumor biology and behavior.	('cancer', 'Disease', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutants', 'Var', (51, 58))	('tumor', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('p53', 'Gene', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
105517	20407015	Each "p53-host" strain, yAT-iGAL::p53 (MATa leu2-3,112 trpl-1 his3-11,15 can 1-100 ura3-1, trp5::pGAL1:p53:cyc1-Ter, lys2::HygroR), contains the wild type or mutant p53 cDNA controlled by the inducible, "rheostatable" GAL1 promoter integrated at the TRP5 locus on chromosome VII.	('mutant', 'Var', (158, 164))	('p53', 'Gene', (165, 168))	('TRP5', 'Gene', '7224', (250, 254))	('cyc1', 'Gene', '1537', (107, 111))	('cyc1', 'Gene', (107, 111))	('lys2', 'Gene', (117, 121))	('trp5', 'Gene', (91, 95))	('lys2', 'Gene', '60496', (117, 121))	('TRP5', 'Gene', (250, 254))	('trp5', 'Gene', '7224', (91, 95))
105518	20407015	Modifications of the p53 cDNA were performed using the delitto perfetto approach so that CORE cassettes were replaced with an oligonucleotide containing the mutation of interest to generate a full-length mutant p53 cDNA.	('mutant', 'Var', (204, 210))	('p53', 'Gene', (211, 214))	('oligonucleotide', 'Chemical', 'MESH:D009841', (126, 141))
105521	20407015	The second panel of isogenic strains, constructed previously, contain human target p53 REs upstream of the CYC1 minimal promoter and either the ADE2 or firefly luciferase reporter.	('CYC1', 'Gene', '1537', (107, 111))	('CYC1', 'Gene', (107, 111))	('p53 REs', 'Var', (83, 90))	('human', 'Species', '9606', (70, 75))
105523	20407015	Mating of the reporter and p53-host strains followed by selection for diploid cells on Lys- Hygro+ plates, results in isogenomic yeast that enable the assessment of the transactivation potential for WT or mutant p53 proteins towards individual REs in the p53 transcriptional network.	('proteins', 'Protein', (216, 224))	('yeast', 'Species', '4932', (129, 134))	('transactivation', 'MPA', (169, 184))	('mutant', 'Var', (205, 211))	('p53', 'Gene', (212, 215))
105524	20407015	Single colony isolates of the p53-inducible RE-ADE2 reporter strains were streaked onto an YPDA control plate containing glucose and high levels of adenine and grown to equivalent amounts at 30 C. The plates were then replica plated onto a series of 9 plates containing selective media with low levels of adenine [5 mg/L], 2% raffinose and increasing galactose (0, 0.001, 0.002, 0.004, 0.008, 0.016, 0.032, 0.064 and 0.128%).	('0.002', 'Var', (372, 377))	('raffinose', 'Chemical', 'MESH:D011887', (326, 335))	('YPDA', 'Chemical', '-', (91, 95))	('galactose', 'MPA', (351, 360))	('glucose', 'Chemical', 'MESH:D005947', (121, 128))	('adenine', 'Chemical', 'MESH:D000225', (148, 155))	('adenine', 'Chemical', 'MESH:D000225', (305, 312))	('0.004', 'Var', (379, 384))	('galactose', 'Chemical', 'MESH:D005690', (351, 360))
105525	20407015	Transactivation capacities for the p53 mutants were determined after three days of growth at 30 C by the ability of the mutant to produce a change in colony pigmentation.	('change', 'Reg', (140, 146))	('p53', 'Gene', (35, 38))	('colony pigmentation', 'Disease', 'MESH:D010859', (150, 169))	('colony pigmentation', 'Disease', (150, 169))	('mutants', 'Var', (39, 46))
105526	20407015	Transactivation capacities for the p53 WT and mutants were determined after three days of growth at 30 C by the ability of the mutant to produce a change in colony pigmentation.	('mutant', 'Var', (127, 133))	('colony pigmentation', 'Disease', 'MESH:D010859', (157, 176))	('change', 'Reg', (147, 153))	('colony pigmentation', 'Disease', (157, 176))
105530	20407015	For each measurement, 1 ml of the diluted culture was spun down, washed of residual glucose with H2O and re-suspended in 2mL synthetic complete -LYS media plus 2% raffinose supplemented with increasing amounts of galactose (0, 0.002, 0.004, 0.008, 0.010, 0.012, 0.016, 0.020, 0.024, 0.028 or 0.032%).	('0.032%', 'Var', (292, 298))	('0.020', 'Var', (269, 274))	('0.004', 'Var', (234, 239))	('glucose', 'Chemical', 'MESH:D005947', (84, 91))	('raffinose', 'Chemical', 'MESH:D011887', (163, 172))	('0.008', 'Var', (241, 246))	('galactose', 'Chemical', 'MESH:D005690', (213, 222))	('0.028 or 0.032%', 'Var', (283, 298))	('0.016', 'Var', (262, 267))	('H2O', 'Chemical', 'MESH:D014867', (97, 100))	('0.012', 'Var', (255, 260))	('0.024', 'Var', (276, 281))	('0.010', 'Var', (248, 253))
105533	20407015	Diploid yeast strains containing GAL1::p53 (WT or mutant) crossed with the p21-5' RE-luciferase reporter were grown as described above.	('yeast', 'Species', '4932', (8, 13))	('p21', 'Gene', (75, 78))	('p21', 'Gene', '1026', (75, 78))	(':p53', 'Var', (38, 42))
105544	20407015	We sought to define how specific p53 missense mutations found in breast cancers interfere with p53 function by assessing the ability of mutant p53 to transactivate from a panel of REs associated with p53-dependent downstream target genes (Table 1).	('missense mutations', 'Var', (37, 55))	('breast cancers', 'Phenotype', 'HP:0003002', (65, 79))	('function', 'MPA', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('p53', 'Protein', (95, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('transactivate', 'MPA', (150, 163))	('p53', 'Gene', (33, 36))	('breast cancers', 'Disease', (65, 79))	('breast cancers', 'Disease', 'MESH:D001943', (65, 79))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('mutant', 'Var', (136, 142))	('p53', 'Gene', (143, 146))	('interfere', 'NegReg', (80, 89))
105545	20407015	Fifty missense mutations were chosen for examination if they were identified in cases of sporadic breast cancers.	('sporadic breast cancers', 'Disease', (89, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('missense mutations', 'Var', (6, 24))	('breast cancers', 'Phenotype', 'HP:0003002', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('sporadic breast cancers', 'Disease', 'MESH:D001943', (89, 112))
105548	20407015	Of particular interest were mutations present in the L2 loop, L3 loop or zinc binding regions of the protein which have been correlated with breast cancers that are often nonresponsive to chemotherapeutic treatments including doxorubicin, tamoxifen, and/or combined therapies of 5-flurouracil and mitomycin.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('mitomycin', 'Chemical', 'MESH:D016685', (297, 306))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('zinc binding', 'MPA', (73, 85))	('breast cancers', 'Disease', (141, 155))	('doxorubicin', 'Chemical', 'MESH:D004317', (226, 237))	('correlated with', 'Reg', (125, 140))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('mutations', 'Var', (28, 37))	('5-flurouracil', 'Chemical', '-', (279, 292))	('tamoxifen', 'Chemical', 'MESH:D013629', (239, 248))
105549	20407015	The yeast ADE2 plate color assay was used to determine functional fingerprints for WT and p53 missense mutations based on their ability to transactivate from 11 different human REs at variable levels of protein expression (Figure 2 and Supplemental Figures 1 and 2).	('yeast', 'Species', '4932', (4, 9))	('p53', 'Gene', (90, 93))	('human', 'Species', '9606', (171, 176))	('missense mutations', 'Var', (94, 112))
105550	20407015	Briefly, single colony isolates of yeast strains containing the mutation and RE of interest were replicated onto plates containing increasing concentrations of galactose where the ability of the p53 variant to drive transactivation from a specific sequence could be assessed based on colony pigmentation (see Materials and Methods and Supplemental Figure 2).	('p53', 'Gene', (195, 198))	('galactose', 'Chemical', 'MESH:D005690', (160, 169))	('colony pigmentation', 'Disease', 'MESH:D010859', (284, 303))	('colony pigmentation', 'Disease', (284, 303))	('yeast', 'Species', '4932', (35, 40))	('variant', 'Var', (199, 206))	('transactivation', 'MPA', (216, 231))
105552	20407015	Among the 21 functional mutations, 9 were clearly altered in transactivation capacity at high levels of galactose (0.128% galactose) (Supplemental Figure 1) and displayed a change-in-spectrum for REs transactivated, as exemplified by reduced or complete lack of transactivation from the 14-3-3sigma and PCNA REs by P151A and R283P, respectively, in Figure 2.	('R283P', 'Var', (325, 330))	('14-3-3sigma', 'Gene', '2810', (287, 298))	('R283P', 'Mutation', 'rs371409680', (325, 330))	('lack', 'NegReg', (254, 258))	('transactivation', 'MPA', (262, 277))	('transactivation capacity', 'MPA', (61, 85))	('high levels of galactose', 'Phenotype', 'HP:0012024', (89, 113))	('P151A', 'Mutation', 'rs28934874', (315, 320))	('galactose', 'Chemical', 'MESH:D005690', (122, 131))	('altered', 'Reg', (50, 57))	('mutations', 'Var', (24, 33))	('14-3-3sigma', 'Gene', (287, 298))	('P151A', 'Var', (315, 320))	('galactose', 'Chemical', 'MESH:D005690', (104, 113))
105553	20407015	Of these 9 mutations, 3 (Y220C, M237I and P278A) retained the ability to transactivate from only the strongest REs, p21-5' and P53R2 when p53 expression was induced with high levels of galactose (and, in the case of P278A, MDM2 which contains two full-site REs) (Supplemental Figure 1).	('p21', 'Gene', (116, 119))	('transactivate', 'MPA', (73, 86))	('p53', 'Gene', (138, 141))	('P53R2', 'Gene', '50484', (127, 132))	('M237I', 'Var', (32, 37))	('M237I', 'Mutation', 'rs587782664', (32, 37))	('ability', 'MPA', (62, 69))	('P53R2', 'Gene', (127, 132))	('MDM2', 'Gene', '4193', (223, 227))	('P278A', 'Var', (216, 221))	('P278A', 'Mutation', 'rs17849781', (216, 221))	('MDM2', 'Gene', (223, 227))	('P278A', 'Var', (42, 47))	('P278A', 'Mutation', 'rs17849781', (42, 47))	('galactose', 'Chemical', 'MESH:D005690', (185, 194))	('p21', 'Gene', '1026', (116, 119))	('Y220C', 'Mutation', 'rs121912666', (25, 30))	('high levels of galactose', 'Phenotype', 'HP:0012024', (170, 194))
105554	20407015	At high levels of galactose, the remaining 12 of the 21 mutants (L130V, A138V, C141W, P151H, R174K, R174W, P190L, H214R, R267Q, V272L, E285K, and R337H) looked similar to WT in their transactivation capacity (i.e., L130V in Figure 2, Supplemental Figure 1).	('V272L', 'Mutation', 'rs121912657', (128, 133))	('R267Q', 'Var', (121, 126))	('high levels of galactose', 'Phenotype', 'HP:0012024', (3, 27))	('C141W', 'Var', (79, 84))	('R174K', 'Var', (93, 98))	('R174K', 'Mutation', 'rs753138941', (93, 98))	('E285K', 'Var', (135, 140))	('H214R', 'Var', (114, 119))	('L130V', 'Mutation', 'rs863224683', (215, 220))	('L130V', 'Var', (215, 220))	('R174W', 'Var', (100, 105))	('P151H', 'Var', (86, 91))	('transactivation capacity', 'MPA', (183, 207))	('P151H', 'Mutation', 'rs1057520000', (86, 91))	('E285K', 'Mutation', 'rs112431538', (135, 140))	('H214R', 'Mutation', 'rs1057519992', (114, 119))	('P190L', 'Mutation', 'rs876660825', (107, 112))	('R337H', 'Var', (146, 151))	('A138V', 'Var', (72, 77))	('R337H', 'Mutation', 'rs121912664', (146, 151))	('R267Q', 'Mutation', 'rs587780075', (121, 126))	('galactose', 'Chemical', 'MESH:D005690', (18, 27))	('P190L', 'Var', (107, 112))	('C141W', 'SUBSTITUTION', 'None', (79, 84))	('A138V', 'SUBSTITUTION', 'None', (72, 77))	('R174W', 'Mutation', 'p.R174W', (100, 105))	('L130V', 'Var', (65, 70))	('L130V', 'Mutation', 'rs863224683', (65, 70))	('V272L', 'Var', (128, 133))
105556	20407015	However, when the levels of galactose were reduced, subtle transactivation defects were revealed that further differentiated 6 of the 12 mutants (underlined) from WT p53 at 3 or more REs.	('galactose', 'Chemical', 'MESH:D005690', (28, 37))	('transactivation', 'MPA', (59, 74))	('mutants', 'Var', (137, 144))
105559	20407015	For example, A138V was only observed to be slightly reduced in transactivation compared to WT p53 towards PCNA at 0.008% galactose (Supplemental Figure 1).	('transactivation', 'MPA', (63, 78))	('A138V', 'Var', (13, 18))	('reduced', 'NegReg', (52, 59))	('A138V', 'SUBSTITUTION', 'None', (13, 18))	('galactose', 'Chemical', 'MESH:D005690', (121, 130))
105560	20407015	The transactivation capacities from the p21-5', GADD45 and 14-3-3sigma REs were comparable to those with the color plate assay in terms of classifying functional status; however, the assay provides greater discrimination between mutant and WT p53 transactivation.	('transactivation', 'MPA', (4, 19))	('GADD45 and 14-3-3sigma REs', 'Gene', '1647', (48, 74))	('p21', 'Gene', '1026', (40, 43))	('p53', 'Gene', (243, 246))	('mutant', 'Var', (229, 235))	('p21', 'Gene', (40, 43))	('transactivation', 'MPA', (247, 262))
105562	20407015	Similar to the results with the plate assay, several mutants (i.e., R267Q) differed from WT p53 in their ability to transactivate from the p21-5' RE only at low levels of galactose (low p53 expression), whereas other mutations (i.e., L194P) displayed a decreased ability to transactivate from the p21-5' RE at all levels of induction and corresponding p53 expression.	('expression', 'MPA', (356, 366))	('R267Q', 'Mutation', 'rs587780075', (68, 73))	('L194P', 'SUBSTITUTION', 'None', (234, 239))	('p21', 'Gene', '1026', (297, 300))	('p21', 'Gene', '1026', (139, 142))	('p21', 'Gene', (297, 300))	('galactose', 'Chemical', 'MESH:D005690', (171, 180))	('transactivate', 'MPA', (116, 129))	('p21', 'Gene', (139, 142))	('L194P', 'Var', (234, 239))
105563	20407015	Of the 6 fully functional mutations examined that were similar to WT p53 in terms of transactivation from the strong p21-5' RE in both the plate and luciferase assays, one (H214R) showed an altered transactivation potential when assessed for transactivation from the weaker GADD45 RE in the luciferase assay (Figure 4).	('transactivation potential', 'MPA', (198, 223))	('p21', 'Gene', '1026', (117, 120))	('GADD45', 'Gene', (274, 280))	('p21', 'Gene', (117, 120))	('H214R', 'Mutation', 'rs1057519992', (173, 178))	('mutations', 'Var', (26, 35))	('altered', 'Reg', (190, 197))	('GADD45', 'Gene', '1647', (274, 280))	('transactivation', 'MPA', (85, 100))
105564	20407015	H214R had an increased ability to transactivate from the GADD45 RE in comparison to WT p53, whereas the remaining fully functional mutations, including A138V and R174W remained indistinguishable from WT p53.	('GADD45', 'Gene', (57, 63))	('R174W', 'Mutation', 'p.R174W', (162, 167))	('H214R', 'Var', (0, 5))	('GADD45', 'Gene', '1647', (57, 63))	('A138V', 'Var', (152, 157))	('transactivate', 'MPA', (34, 47))	('R174W', 'Var', (162, 167))	('H214R', 'Mutation', 'rs1057519992', (0, 5))	('A138V', 'SUBSTITUTION', 'None', (152, 157))
105565	20407015	As shown in Figure 5, Y220C was able to transactivate from the strong p21-5' RE, but to reduced levels; the maximal level of transactivation was comparable to that for WT p53 transactivating from the weaker 14-3-3sigma RE.	('14-3-3sigma', 'Gene', '2810', (207, 218))	('Y220C', 'Mutation', 'rs121912666', (22, 27))	('Y220C', 'Var', (22, 27))	('p21', 'Gene', '1026', (70, 73))	('p21', 'Gene', (70, 73))	('transactivate', 'MPA', (40, 53))	('14-3-3sigma', 'Gene', (207, 218))
105566	20407015	The Y220C mutant was actually unable to transactivate from the 14-3-3sigma RE.	('Y220C', 'Mutation', 'rs121912666', (4, 9))	('14-3-3sigma', 'Gene', '2810', (63, 74))	('Y220C', 'Var', (4, 9))	('14-3-3sigma', 'Gene', (63, 74))
105567	20407015	The transactivation profiles with increasing levels of galactose (i.e., increased p53 expression) were similar between the DBD mutants and WT p53 where initial induction occurred between 0.004 - 0.008% galactose and maximal levels of transactivation were between 0.016% - 0.024% galactose (Figures 3-5).	('galactose', 'Chemical', 'MESH:D005690', (55, 64))	('increased', 'PosReg', (72, 81))	('DBD', 'Chemical', '-', (123, 126))	('galactose', 'Chemical', 'MESH:D005690', (202, 211))	('p53', 'Gene', (82, 85))	('mutants', 'Var', (127, 134))	('galactose', 'Chemical', 'MESH:D005690', (279, 288))
105569	20407015	Although maximal levels of transactivation appeared similar to WT p53, the R337H mutation clearly altered transactivation from the p21-5', 14-3-3sigma and GADD45 REs, requiring higher levels of p53 expression than WT to initiate transactivation (Figure 6).	('higher', 'PosReg', (177, 183))	('transactivation', 'MPA', (106, 121))	('p21', 'Gene', '1026', (131, 134))	('14-3-3sigma', 'Gene', '2810', (139, 150))	('GADD45', 'Gene', '1647', (155, 161))	('altered', 'Reg', (98, 105))	('p21', 'Gene', (131, 134))	('R337H', 'Mutation', 'rs121912664', (75, 80))	('R337H', 'Var', (75, 80))	('14-3-3sigma', 'Gene', (139, 150))	('GADD45', 'Gene', (155, 161))
105570	20407015	The R337C mutation resulted in overall reduction in transactivation.	('R337C', 'Mutation', 'rs587782529', (4, 9))	('R337C', 'Var', (4, 9))	('transactivation', 'MPA', (52, 67))	('reduction', 'NegReg', (39, 48))
105571	20407015	Protein levels were analyzed at 0.024% galactose (within the range of expression where transactivation was shown to plateau in the luciferase assays) by Western analysis for the 21 mutations that retained function and a representative loss-of-function mutant (Supplemental Figure 3).	('galactose', 'Chemical', 'MESH:D005690', (39, 48))	('mutant', 'Var', (252, 258))	('function', 'MPA', (205, 213))	('mutations', 'Var', (181, 190))	('loss-of-function', 'NegReg', (235, 251))
105572	20407015	However, seven mutants (C141W, L194P, Y220C, M237I, P278A, E285K and R337C) had reduced expression compared to WT p53.	('L194P', 'Var', (31, 36))	('P278A', 'Var', (52, 57))	('E285K', 'Var', (59, 64))	('reduced', 'NegReg', (80, 87))	('E285K', 'Mutation', 'rs112431538', (59, 64))	('Y220C', 'Mutation', 'rs121912666', (38, 43))	('L194P', 'SUBSTITUTION', 'None', (31, 36))	('Y220C', 'Var', (38, 43))	('R337C', 'Var', (69, 74))	('R337C', 'Mutation', 'rs587782529', (69, 74))	('M237I', 'Var', (45, 50))	('C141W', 'Var', (24, 29))	('expression', 'MPA', (88, 98))	('P278A', 'Mutation', 'rs17849781', (52, 57))	('C141W', 'SUBSTITUTION', 'None', (24, 29))	('M237I', 'Mutation', 'rs587782664', (45, 50))
105573	20407015	To address how different p53 mutations might influence response to chemotherapeutics, we examined transcriptional functional status of p53 missense mutations found in breast cancers in relation to clinical manifestations.	('influence', 'Reg', (45, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('mutations', 'Var', (29, 38))	('p53', 'Gene', (135, 138))	('missense mutations', 'Var', (139, 157))	('breast cancers', 'Phenotype', 'HP:0003002', (167, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('breast cancers', 'Disease', 'MESH:D001943', (167, 181))	('breast cancers', 'Disease', (167, 181))
105574	20407015	Twenty-nine unique p53 missense mutations analyzed for functionality in this study (20 mutations) or in a related haploid yeast system have been identified in 46 patients with locally advanced breast tumors (primarily ductal carcinomas).	('missense mutations', 'Var', (23, 41))	('patients', 'Species', '9606', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('breast tumors', 'Disease', 'MESH:D001943', (193, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('identified', 'Reg', (145, 155))	('yeast', 'Species', '4932', (122, 127))	('breast tumors', 'Disease', (193, 206))	('ductal carcinomas', 'Disease', 'MESH:D044584', (218, 235))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('p53', 'Gene', (19, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (225, 235))	('ductal carcinomas', 'Disease', (218, 235))	('breast tumor', 'Phenotype', 'HP:0100013', (193, 205))	('mutations', 'Var', (87, 96))	('breast tumors', 'Phenotype', 'HP:0100013', (193, 206))
105576	20407015	As summarized in Table 2 and Supplemental Table 3, among the 46 patients, 10 of the missense mutations (11 patients) resulted in p53s that retained function (9 altered and 1 fully functional mutant) and 19 were loss-of-function (35 patients).	('p53s', 'Var', (129, 133))	('patients', 'Species', '9606', (64, 72))	('patients', 'Species', '9606', (232, 240))	('function', 'MPA', (148, 156))	('loss-of-function', 'NegReg', (211, 227))	('patients', 'Species', '9606', (107, 115))	('missense mutations', 'Var', (84, 102))
105578	20407015	While the number of p53 missense mutations examined is limited, there are emerging trends that may differentiate patients with functional (altered or fully functional) versus nonfunctional p53 missense mutants (Table 2 and Supplemental Table 3).	('patients', 'Species', '9606', (113, 121))	('missense mutants', 'Var', (193, 209))	('p53', 'Gene', (189, 192))
105579	20407015	Among the tumors with somatic p53 missense mutations where HER2, ER and PR status could be assessed, functional missense mutations were more common in HER2-negative tumors (7 of 25, 28%) compared with HER2-positive (2 of 15, 13%).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('HER2', 'Gene', (201, 205))	('missense mutations', 'Var', (112, 130))	('HER2', 'Gene', '2064', (201, 205))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Disease', (10, 16))	('missense mutations', 'Var', (34, 52))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('p53', 'Gene', (30, 33))	('HER2', 'Gene', (59, 63))	('HER2', 'Gene', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('HER2', 'Gene', '2064', (59, 63))	('HER2', 'Gene', '2064', (151, 155))
105580	20407015	Among triple negative (ER, PR, and HER2) tumors with p53 missense mutations, 5 of 16 (31%) carried functional mutations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('missense mutations', 'Var', (57, 75))	('HER2', 'Gene', (35, 39))	('triple negative', 'Disease', (6, 21))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('HER2', 'Gene', '2064', (35, 39))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('p53', 'Gene', (53, 56))
105582	20407015	Functional mutations appear to be associated with good prognostic factors such as low incidence of nodal involvement (2 of 11, 18%).	('nodal', 'Gene', (99, 104))	('Functional mutations', 'Var', (0, 20))	('nodal', 'Gene', '4838', (99, 104))
105583	20407015	Conversely, compared with functional mutations, patients carrying nonfunctional mutations were more likely to be stage III at diagnosis (53 vs 27%), have high grade tumors (59 vs 36%) and to relapse in distant sites (34 vs 10%), as well as local sites (12 vs 0%) although the numbers are small.	('mutations', 'Var', (80, 89))	('relapse', 'CPA', (191, 198))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('patients', 'Species', '9606', (48, 56))
105584	20407015	In terms of responsiveness to chemotherapy, the pathologic complete response (pCR; i.e., eradication of tumor) was similar between patients with functional p53 mutations and nonfunctional missense mutations (21% and 27%, respectively).	('patients', 'Species', '9606', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutations', 'Var', (160, 169))	('tumor', 'Disease', (104, 109))	('p53', 'Gene', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
105586	20407015	We have used a diploid yeast system to analyze the potential transactivation capacity for a set of p53 missense mutations associated with breast cancers.	('associated', 'Reg', (122, 132))	('yeast', 'Species', '4932', (23, 28))	('breast cancers', 'Phenotype', 'HP:0003002', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('missense mutations', 'Var', (103, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancers', 'Disease', 'MESH:D001943', (138, 152))	('breast cancers', 'Disease', (138, 152))	('p53', 'Gene', (99, 102))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
105587	20407015	The 50 missense mutants examined represent approximately 18% of all somatic p53 mutations reported in the International Agency for Research on Cancer (IARC) TP53 mutation database and 20% of all p53 missense mutations documented in breast tumors.	('TP53', 'Gene', (157, 161))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('breast tumor', 'Phenotype', 'HP:0100013', (232, 244))	('mutations', 'Var', (80, 89))	('p53', 'Gene', (76, 79))	('breast tumors', 'Disease', 'MESH:D001943', (232, 245))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('breast tumors', 'Disease', (232, 245))	('Cancer', 'Phenotype', 'HP:0002664', (143, 149))	('missense mutants', 'Var', (7, 23))	('TP53', 'Gene', '7157', (157, 161))	('breast tumors', 'Phenotype', 'HP:0100013', (232, 245))
105588	20407015	Among the mutations analyzed, one (K305M) occurs at an acetylation site in a non-structured portion of the protein, 2 (R337H and R337C) are in the tetramerization domain and the remaining 47 are distributed across the sequence-specific DNA binding domain.	('R337H', 'Var', (119, 124))	('R337C', 'Var', (129, 134))	('R337C', 'Mutation', 'rs587782529', (129, 134))	('R337H', 'Mutation', 'rs121912664', (119, 124))	('K305M', 'Var', (35, 40))	('occurs', 'Reg', (42, 48))	('K305M', 'Mutation', 'p.K305M', (35, 40))
105589	20407015	Functional fingerprinting established that 21 out of the 50 missense mutants associated with breast cancer can retain p53 function.	('p53', 'Protein', (118, 121))	('function', 'MPA', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('missense mutants', 'Var', (60, 76))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))
105590	20407015	This is exemplified at codon 194 where changing the leucine residue to an arginine (L194R) results in loss-of-function, whereas a proline (L194P) results in altered function.	('arginine', 'Chemical', 'MESH:D001120', (74, 82))	('loss-of-function', 'NegReg', (102, 118))	('L194P', 'Var', (139, 144))	('function', 'MPA', (165, 173))	('L194R', 'Var', (84, 89))	('leucine', 'Chemical', 'MESH:D007930', (52, 59))	('L194R', 'SUBSTITUTION', 'None', (84, 89))	('L194P', 'SUBSTITUTION', 'None', (139, 144))	('altered', 'Reg', (157, 164))	('proline', 'Chemical', 'MESH:D011392', (130, 137))
105591	20407015	For example, a recent structure-based analysis of mutations in the DBD does not appear indicative of the in vivo transactivation capacity.	('mutations', 'Var', (50, 59))	('DBD', 'Chemical', '-', (67, 70))	('DBD', 'Gene', (67, 70))
105592	20407015	Of the mutations that had a reduced level of protein expression, the C141W and E285K mutants were only modestly compromised for transactivation capacity in comparison to WT p53, whereas others such as M237I and Y220C were severely compromised.	('C141W', 'Var', (69, 74))	('Y220C', 'Mutation', 'rs121912666', (211, 216))	('M237I', 'Var', (201, 206))	('Y220C', 'Var', (211, 216))	('C141W', 'SUBSTITUTION', 'None', (69, 74))	('M237I', 'Mutation', 'rs587782664', (201, 206))	('E285K', 'Var', (79, 84))	('E285K', 'Mutation', 'rs112431538', (79, 84))	('transactivation capacity', 'MPA', (128, 152))
105593	20407015	This could also explain associated temperature sensitivity of some alleles, specifically Y220C, M237I, and E285K.	('M237I', 'Mutation', 'rs587782664', (96, 101))	('Y220C', 'Mutation', 'rs121912666', (89, 94))	('Y220C', 'Var', (89, 94))	('E285K', 'Var', (107, 112))	('E285K', 'Mutation', 'rs112431538', (107, 112))	('M237I', 'Var', (96, 101))
105595	20407015	There are examples where expression in yeast is matched by low or undetected levels in breast cancer cell lines (i.e., E285K in BT474 and MDA-MD-134VI cells and Y220C in HCC1419 cells) or alternatively being accumulated in the cells (i.e., M237I in SUM149PT cells).	('yeast', 'Species', '4932', (39, 44))	('SUM149', 'CellLine', 'CVCL:3422', (249, 255))	('E285K', 'Var', (119, 124))	('Y220C', 'Mutation', 'rs121912666', (161, 166))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('Y220C', 'Var', (161, 166))	('MDA-MD-134VI', 'CellLine', 'CVCL:0617', (138, 150))	('E285K', 'Mutation', 'rs112431538', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('M237I', 'Var', (240, 245))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('M237I', 'Mutation', 'rs587782664', (240, 245))	('HCC1419', 'CellLine', 'CVCL:1251', (170, 177))
105596	20407015	Regardless of the amount of p53 protein expressed in yeast, the results are informative for those cases where the mutant proteins retain transactivation ability as this indicates the potential for mutant protein to function in mammalian cells.	('yeast', 'Species', '4932', (53, 58))	('mammalian', 'Species', '9606', (227, 236))	('proteins', 'Protein', (121, 129))	('mutant', 'Var', (114, 120))	('transactivation', 'MPA', (137, 152))
105598	20407015	Mutations in the DBD have been postulated to affect the binding affinity of p53 towards REs by abolishing DNA contacts, decreasing the thermodynamic stability of the protein, causing local distortions in the DNA binding surface, or enhancing the loss of the Zn ion.	('affect', 'Reg', (45, 51))	('loss', 'MPA', (246, 250))	('causing', 'Reg', (175, 182))	('DNA', 'MPA', (208, 211))	('DBD', 'Gene', (17, 20))	('thermodynamic stability of the', 'MPA', (135, 165))	('enhancing', 'PosReg', (232, 241))	('Zn', 'Chemical', 'MESH:D015032', (258, 260))	('decreasing', 'NegReg', (120, 130))	('p53', 'Gene', (76, 79))	('DNA contacts', 'MPA', (106, 118))	('Zn ion', 'MPA', (258, 264))	('Mutations', 'Var', (0, 9))	('distortions', 'MPA', (189, 200))	('binding', 'Interaction', (56, 63))	('DBD', 'Chemical', '-', (17, 20))	('abolishing', 'NegReg', (95, 105))	('REs', 'Protein', (88, 91))
105600	20407015	All 6 mutations (C176F, H179R, C238F, C242F, C242S, C242Y) that interfere with the histidine or cysteine side chains involved in coordination of the Zn ion rendered the protein nonfunctional in terms of transactivation, emphasizing the vital role of Zn in sequence-specific DNA binding and stabilization of the p53 protein.	('cysteine', 'Chemical', 'MESH:D003545', (96, 104))	('C242S', 'Var', (45, 50))	('Zn', 'Chemical', 'MESH:D015032', (149, 151))	('C238F', 'Var', (31, 36))	('C238F', 'Mutation', 'rs730882005', (31, 36))	('histidine', 'Chemical', 'MESH:D006639', (83, 92))	('H179R', 'Mutation', 'rs1057519991', (24, 29))	('C242Y', 'Var', (52, 57))	('H179R', 'Var', (24, 29))	('Zn', 'Chemical', 'MESH:D015032', (250, 252))	('C176F', 'Mutation', 'rs786202962', (17, 22))	('nonfunctional', 'MPA', (177, 190))	('C242F', 'Mutation', 'rs121912655', (38, 43))	('C242Y', 'Mutation', 'rs121912655', (52, 57))	('transactivation', 'MPA', (203, 218))	('C176F', 'Var', (17, 22))	('protein', 'Protein', (169, 176))	('C242S', 'Mutation', 'rs121912655', (45, 50))	('C242F', 'Var', (38, 43))
105601	20407015	Similarly, all the missense mutations analyzed in the L3 loop, which binds the minor groove of DNA and partakes in the dimerization interface between core domains, were loss-of-function mutations with the exception of M237I which was very weak for transactivation.	('loss-of-function', 'NegReg', (169, 185))	('M237I', 'Mutation', 'rs587782664', (218, 223))	('missense mutations', 'Var', (19, 37))	('M237I', 'Var', (218, 223))
105602	20407015	However, 4 mutants (R174K, R174W, P190L and L194P) in the L2 loop retained function of which several (underlined) displayed subtle alterations in transactivation capacity.	('R174W', 'Mutation', 'p.R174W', (27, 32))	('L194P', 'SUBSTITUTION', 'None', (44, 49))	('function', 'MPA', (75, 83))	('alterations', 'Reg', (131, 142))	('L194P', 'Var', (44, 49))	('R174W', 'Var', (27, 32))	('R174K', 'Var', (20, 25))	('R174K', 'Mutation', 'rs753138941', (20, 25))	('transactivation capacity', 'MPA', (146, 170))	('P190L', 'Var', (34, 39))	('P190L', 'Mutation', 'rs876660825', (34, 39))
105603	20407015	Although the majority of p53 missense mutations occur in the DBD, several missense mutations have been found in the tetramerization domain that are associated with germline syndromes and are found in sporadic breast tumors.	('p53', 'Gene', (25, 28))	('sporadic breast tumors', 'Disease', (200, 222))	('sporadic breast tumors', 'Disease', 'MESH:D001943', (200, 222))	('breast tumors', 'Phenotype', 'HP:0100013', (209, 222))	('DBD', 'Chemical', '-', (61, 64))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('breast tumor', 'Phenotype', 'HP:0100013', (209, 221))	('associated', 'Reg', (148, 158))	('germline syndromes', 'Disease', (164, 182))	('missense mutations', 'Var', (29, 47))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
105604	20407015	R337C is a partial function mutation associated with LFS.	('LFS', 'Disease', (53, 56))	('R337C', 'Mutation', 'rs587782529', (0, 5))	('R337C', 'Var', (0, 5))
105605	20407015	R337H has been associated with pediatric cases of adrenocortical carcinoma (ACC); however, it may be a low penetrant LFS or LFL allele as well.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('R337H', 'Var', (0, 5))	('ACC', 'Phenotype', 'HP:0006744', (76, 79))	('adrenocortical carcinoma', 'Disease', (50, 74))	('associated', 'Reg', (15, 25))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (50, 74))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (50, 74))	('R337H', 'Mutation', 'rs121912664', (0, 5))
105606	20407015	The functional fingerprints varied between these two altered-function mutations in that R337C had a greater impact on p53 transactivation displaying an overall dampening effect from the various REs.	('dampening', 'NegReg', (160, 169))	('p53', 'Protein', (118, 121))	('R337C', 'Var', (88, 93))	('R337C', 'Mutation', 'rs587782529', (88, 93))
105607	20407015	Contrary to previous reports, the p53 missense mutation R337H was not a silent mutation, but displayed altered function when examined in the ADE2 phenotypic assay (Supplemental Figure 1).	('R337H', 'Var', (56, 61))	('p53', 'Gene', (34, 37))	('function', 'MPA', (111, 119))	('R337H', 'Mutation', 'rs121912664', (56, 61))
105608	20407015	At high levels of galactose induction (i.e., high levels of p53 expression from the GAL1 promoter), R337H looked identical to WT p53 in the color assay.	('high levels of galactose', 'Phenotype', 'HP:0012024', (3, 27))	('R337H', 'Mutation', 'rs121912664', (100, 105))	('R337H', 'Var', (100, 105))	('p53', 'Gene', (60, 63))	('galactose', 'Chemical', 'MESH:D005690', (18, 27))
105609	20407015	At low levels of galactose, R337H had a reduced ability to transactivate from REs in comparison to WT p53, presumably due to its reduced ability to form tetramers.	('tetramers', 'Interaction', (153, 162))	('transactivate from REs', 'MPA', (59, 81))	('R337H', 'Mutation', 'rs121912664', (28, 33))	('R337H', 'Var', (28, 33))	('galactose', 'Chemical', 'MESH:D005690', (17, 26))	('reduced', 'NegReg', (40, 47))	('reduced', 'NegReg', (129, 136))
105611	20407015	This altered pattern of transactivation may be a manifestation of the novel features of R337H which include a pH-dependent instability and formation of amyloid-like fibrils.	('R337H', 'Var', (88, 93))	('R337H', 'Mutation', 'rs121912664', (88, 93))	('transactivation', 'MPA', (24, 39))	('amyloid-like fibrils', 'MPA', (152, 172))
105613	20407015	For example, Tsuda and Hirohashi showed with immunohistochemical analysis of over 50 human breast-cancer tissue specimens that nuclear accumulation of the p53 protein was dependent on the type and position of the mutation, where missense mutations did not always result in stabilization of the protein.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('stabilization', 'MPA', (273, 286))	('p53', 'Gene', (155, 158))	('missense mutations', 'Var', (229, 247))	('breast-cancer', 'Disease', 'MESH:D001943', (91, 104))	('protein', 'Protein', (159, 166))	('breast-cancer', 'Disease', (91, 104))	('nuclear accumulation', 'MPA', (127, 147))	('human', 'Species', '9606', (85, 90))
105614	20407015	Similarly, in a study comparing immunohistochemical analysis with cDNA-based sequencing using ~300 primary breast tumor samples, in over 30% of the cases where a mutation was observed through sequencing there was not a corresponding accumulation of p53 protein.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('breast tumor', 'Disease', (107, 119))	('accumulation', 'PosReg', (233, 245))	('p53', 'Protein', (249, 252))	('breast tumor', 'Phenotype', 'HP:0100013', (107, 119))	('mutation', 'Var', (162, 170))	('protein', 'Protein', (253, 260))	('breast tumor', 'Disease', 'MESH:D001943', (107, 119))
105615	20407015	Recent results with knock-in mouse models indicate levels of mutant p53 can be regulated in both normal and some tumor cells.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mouse', 'Species', '10090', (29, 34))	('mutant', 'Var', (61, 67))	('p53', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
105617	20407015	Although the subtle altered-function mutations identified in the present study retain the ability to function from the MDM2 RE, Lukashchuck and Vousden have shown that the ability of p53 to transactivate MDM2 is not essential for degradation of the mutant p53 protein.	('MDM2', 'Gene', '4193', (204, 208))	('MDM2', 'Gene', (204, 208))	('MDM2', 'Gene', '4193', (119, 123))	('MDM2', 'Gene', (119, 123))	('mutations', 'Var', (37, 46))	('p53', 'Gene', (256, 259))	('protein', 'Protein', (260, 267))	('mutant', 'Var', (249, 255))
105618	20407015	Rather, additional E3 ubiquitin ligases, such as CHIP (C terminus of Hsc70-interacting protein), can target mutant p53 for degradation independent of ubiquitination by Mdm2, where Mdm2 plays a role in delivering the ubiquitinated proteins to proteasomes.	('Mdm2', 'Gene', '4193', (180, 184))	('Hsc70-interacting protein)', 'Gene', '6767', (69, 95))	('CHIP', 'Disease', (49, 53))	('mutant', 'Var', (108, 114))	('p53', 'Gene', (115, 118))	('Mdm2', 'Gene', (168, 172))	('CHIP', 'Disease', 'None', (49, 53))	('degradation', 'MPA', (123, 134))	('Hsc70-interacting protein', 'Gene', (69, 94))	('Mdm2', 'Gene', (180, 184))	('Mdm2', 'Gene', '4193', (168, 172))
105622	20407015	It is possible that mutations that subtly affect transactivation are acquired early in tumor development and when combined with mutations in other genes contribute in an additive fashion to the complex cancer disease.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('transactivation', 'MPA', (49, 64))	('cancer disease', 'Disease', (202, 216))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancer disease', 'Disease', 'MESH:D009369', (202, 216))	('mutations', 'Var', (20, 29))	('contribute', 'Reg', (153, 163))
105623	20407015	For example, the altered-function P190L and H214R mutants that were indistinguishable from WT at higher levels of galactose-induced expression are associated with germline BRCA1 and BRCA2 mutations, respectively.	('galactose', 'Chemical', 'MESH:D005690', (114, 123))	('altered-function', 'Reg', (17, 33))	('BRCA1', 'Gene', '672', (172, 177))	('H214R', 'Var', (44, 49))	('BRCA2', 'Gene', '675', (182, 187))	('BRCA1', 'Gene', (172, 177))	('H214R', 'Mutation', 'rs1057519992', (44, 49))	('P190L', 'Mutation', 'rs876660825', (34, 39))	('P190L', 'Var', (34, 39))	('BRCA2', 'Gene', (182, 187))
105624	20407015	Such mutations in p53 may be an underlying contributor to the genomic instability observed in BRCA1-associated breast cancer cases and the functional status of individual p53 missense mutations may impact the degree of genetic imbalance.	('impact', 'Reg', (198, 204))	('p53', 'Gene', (18, 21))	('imbalance', 'Phenotype', 'HP:0002172', (227, 236))	('genomic', 'MPA', (62, 69))	('genetic imbalance', 'MPA', (219, 236))	('missense mutations', 'Var', (175, 193))	('BRCA1', 'Gene', '672', (94, 99))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('BRCA1', 'Gene', (94, 99))	('breast cancer', 'Disease', (111, 124))	('functional', 'MPA', (139, 149))	('p53', 'Gene', (171, 174))
105625	20407015	Interestingly, a recent hierarchical clustering analysis using immunohistochemistry profiling to determine the relatedness of tumors has established that the extent of genomic instability correlates with specific breast cancer subtypes, where the basal subtype (the subtype in which p53 mutations are frequently observed) had the highest number of genomic aberrations in both sporadic and familial BRCA-associated cases.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('BRCA', 'Gene', '672', (398, 402))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('BRCA', 'Gene', (398, 402))	('breast cancer', 'Disease', (213, 226))	('mutations', 'Var', (287, 296))	('p53', 'Gene', (283, 286))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
105626	20407015	In addition, inherited p53 mutations may influence tumor type and penetrance of the disease.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('influence', 'Reg', (41, 50))	('p53', 'Gene', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
105627	20407015	LFS and LFL germline disorders--which often harbor a p53 mutation--display an array of early onset, tissue specific tumors of which breast tumors are among the most frequent observed.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('breast tumors', 'Disease', 'MESH:D001943', (132, 145))	('LFS', 'Disease', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('breast tumors', 'Disease', (132, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('mutation--', 'Var', (57, 67))	('p53', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('breast tumors', 'Phenotype', 'HP:0100013', (132, 145))	('LFL', 'Disease', (8, 11))	('breast tumor', 'Phenotype', 'HP:0100013', (132, 144))
105628	20407015	Recent studies which have assessed the functional status of p53 germline mutations using yeast-based assays have related severity of inherited p53 missense mutations in terms of transcription functionality with clinical manifestations.	('missense mutations', 'Var', (147, 165))	('transcription functionality', 'MPA', (178, 205))	('p53', 'Gene', (143, 146))	('yeast', 'Species', '4932', (89, 94))
105630	20407015	In another recent study, the frequency and average size (bp deletion or duplication) of DNA copy number variation is enriched in carriers of germline TP53 mutations within LFS families in comparison to those with WT p53 or in a healthy population.	('TP53', 'Gene', (150, 154))	('TP53', 'Gene', '7157', (150, 154))	('carriers', 'Reg', (129, 137))	('mutations', 'Var', (155, 164))
105631	20407015	We examined transcriptional functional status of p53 missense mutations found in breast cancers in relation to clinical manifestations (Table 2 and Supplemental Table 3).	('breast cancers', 'Disease', 'MESH:D001943', (81, 95))	('p53', 'Gene', (49, 52))	('breast cancers', 'Disease', (81, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))	('missense mutations', 'Var', (53, 71))
105632	20407015	While the number of breast cancer-associated functional p53 mutants was small, there were trends described in the Results that suggest differences in presentation and outcome between functional versus nonfunctional missense mutations.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('missense mutations', 'Var', (215, 233))	('p53', 'Gene', (56, 59))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('mutants', 'Var', (60, 67))
105633	20407015	The nonfunctional missense mutations are associated with clinical responses similar to those in our studies with null mutations (data not shown) which are known to have poorer prognosis and reduced survival as compared to patients with tumors that are WT for p53.	('patients', 'Species', '9606', (222, 230))	('reduced', 'NegReg', (190, 197))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (236, 242))	('missense mutations', 'Var', (18, 36))	('tumors', 'Disease', 'MESH:D009369', (236, 242))
105634	20407015	In terms of clinical response to chemotherapy, we observed in the present study a higher response rate for tumors expressing loss-of-function p53 mutations which may seem counterintuitive.	('mutations', 'Var', (146, 155))	('p53', 'Gene', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('higher', 'PosReg', (82, 88))	('loss-of-function', 'NegReg', (125, 141))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('response', 'MPA', (89, 97))
105635	20407015	However, tumors with p53 mutations in general are more chemo-sensitive, possibly because the breast cancer subtypes which usually have a higher proportion of p53 mutations (e.g.	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('mutations', 'Var', (25, 34))	('mutations', 'Var', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('breast cancer', 'Disease', (93, 106))	('tumors', 'Disease', (9, 15))	('p53', 'Gene', (158, 161))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('p53', 'Gene', (21, 24))
105637	20407015	While previous studies have investigated correlations between p53 mutations and pathologic variables in breast cancers, few studies have attempted to correlate the transcriptional activity of specific mutations with clinical phenotypes.	('mutations', 'Var', (66, 75))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancers', 'Phenotype', 'HP:0003002', (104, 118))	('breast cancers', 'Disease', 'MESH:D001943', (104, 118))	('breast cancers', 'Disease', (104, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('p53', 'Gene', (62, 65))
105638	20407015	In a large scale study of a cohort of approximately 1,800 woman, the presence of a p53 mutation was associated with high grade, positive node status, loss of hormone receptors and greater risk of death due to breast cancer within a 10 year follow-up.	('presence', 'Var', (69, 77))	('p53', 'Gene', (83, 86))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('loss of hormone receptors', 'Phenotype', 'HP:0002930', (150, 175))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('hormone receptors', 'Protein', (158, 175))	('high grade', 'CPA', (116, 126))	('breast cancer', 'Disease', (209, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('death', 'Disease', 'MESH:D003643', (196, 201))	('death', 'Disease', (196, 201))	('woman', 'Species', '9606', (58, 63))	('loss', 'NegReg', (150, 154))	('mutation', 'Var', (87, 95))
105641	20407015	For example, we concluded that the R337C was an altered-function missense mutation whereas within the IARC database it is considered to be a nonfunctional mutation although it did display transactivation for 3 of the 8 REs analyzed (WAF1, MDM2 and P53R2).	('WAF1', 'Gene', '1026', (233, 237))	('MDM2', 'Gene', '4193', (239, 243))	('MDM2', 'Gene', (239, 243))	('P53R2', 'Gene', '50484', (248, 253))	('P53R2', 'Gene', (248, 253))	('altered-function', 'Reg', (48, 64))	('WAF1', 'Gene', (233, 237))	('R337C', 'Var', (35, 40))	('R337C', 'Mutation', 'rs587782529', (35, 40))	('transactivation', 'MPA', (188, 203))
105642	20407015	Interestingly, 5 of these temperature sensitive mutations which were reported as loss-of-function in the IARC database were classified as altered-function in the present study (P151A, H214R, V272L, R283P and E285K).	('V272L', 'Var', (191, 196))	('E285K', 'Mutation', 'rs112431538', (208, 213))	('E285K', 'Var', (208, 213))	('H214R', 'Mutation', 'rs1057519992', (184, 189))	('loss-of-function', 'NegReg', (81, 97))	('V272L', 'Mutation', 'rs121912657', (191, 196))	('P151A', 'Mutation', 'rs28934874', (177, 182))	('P151A', 'Var', (177, 182))	('R283P', 'Mutation', 'rs371409680', (198, 203))	('H214R', 'Var', (184, 189))	('R283P', 'Var', (198, 203))
105644	20407015	Given the heterogeneity of breast cancers, understanding the consequences of altered-function mutations on the p53 transcriptional network will help elucidate how specific mutations predispose and/or contribute to the development, penetrance and phenotype of breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (172, 181))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('altered-function', 'PosReg', (77, 93))	('mutations', 'Var', (94, 103))	('breast cancers', 'Phenotype', 'HP:0003002', (27, 41))	('breast cancers', 'Disease', 'MESH:D001943', (27, 41))	('breast cancers', 'Disease', (27, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('breast cancers', 'Phenotype', 'HP:0003002', (259, 273))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('breast cancers', 'Disease', 'MESH:D001943', (259, 273))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('breast cancers', 'Disease', (259, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('contribute', 'Reg', (200, 210))
105645	20407015	Among fifty p53 mutations identified in breast cancers, 21 had altered function:not simply complete loss:towards at least one RE.	('breast cancers', 'Disease', (40, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('mutations', 'Var', (16, 25))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('p53', 'Gene', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (40, 54))	('breast cancers', 'Disease', 'MESH:D001943', (40, 54))
105647	20407015	Given that p53 isoforms are known to be differentially expressed in breast tumors in comparison to normal breast tissue, the ratios at which these isoforms are expressed, which can change with the presence of a mutation, may alter the transactivation profiles of wild type and/or mutant p53.	('breast tumor', 'Phenotype', 'HP:0100013', (68, 80))	('breast tumors', 'Phenotype', 'HP:0100013', (68, 81))	('mutant', 'Var', (280, 286))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('breast tumors', 'Disease', (68, 81))	('breast tumors', 'Disease', 'MESH:D001943', (68, 81))	('transactivation profiles', 'MPA', (235, 259))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('p53', 'Gene', (287, 290))	('alter', 'Reg', (225, 230))	('mutation', 'Var', (211, 219))
105650	20407015	While the yeast-based assay can predict the potential for specific p53 mutations to display altered function, assays in mammalian cells can ascertain the full impact of the functional mutations in the presence of p53 transcriptional cofactors and in the endogenous chromatin context of the RE.	('mutations', 'Var', (184, 193))	('function', 'MPA', (100, 108))	('p53', 'Gene', (67, 70))	('yeast', 'Species', '4932', (10, 15))	('mutations', 'Var', (71, 80))	('mammalian', 'Species', '9606', (120, 129))
105651	20407015	However, we propose that assessments of functional fingerprints for p53 missense mutations associated with breast cancer in yeast provide diagnostic value and with further study may also be used as a prognostic tool for implementing chemotherapeutic treatment.	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('p53', 'Gene', (68, 71))	('missense mutations', 'Var', (72, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('yeast', 'Species', '4932', (124, 129))	('associated', 'Reg', (91, 101))
105652	20407015	Furthermore, the technique of functional fingerprinting will be useful in determining if p53 dysfunction as a transcription factor can also be corrected by agents that reverse its structural stability, such as the carbazole derivative PhiKan083 acting on Y220C.	('carbazole', 'Chemical', 'MESH:C041514', (214, 223))	('structural', 'MPA', (180, 190))	('p53', 'Gene', (89, 92))	('Y220C', 'Mutation', 'rs121912666', (255, 260))	('Y220C', 'Var', (255, 260))
105676	32673783	A molecular research assay for the identification of single nucleotide variants in 26 frequently mutated genes in solid tumors (Tumor Hotspot MASTR Plus >> (Multiplicom)) was negative.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('single nucleotide variants', 'Var', (53, 79))	('solid tumors', 'Disease', (114, 126))	('Tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('solid tumors', 'Disease', 'MESH:D009369', (114, 126))
105711	32673783	In addition, during the anesthetic management of pheochromocytoma, the manipulation of the tumor is usually causing paroxysmal hypertension followed by hypotension after tumor removal.	('hypotension', 'Disease', 'MESH:D007022', (152, 163))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('pheochromocytoma', 'Disease', 'MESH:D010673', (49, 65))	('causing', 'Reg', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('hypotension', 'Disease', (152, 163))	('paroxysmal hypertension', 'Disease', (116, 139))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('manipulation', 'Var', (71, 83))	('hypertension', 'Phenotype', 'HP:0000822', (127, 139))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('paroxysmal hypertension', 'Disease', 'MESH:D006973', (116, 139))	('hypotension', 'Phenotype', 'HP:0002615', (152, 163))	('pheochromocytoma', 'Disease', (49, 65))	('tumor', 'Disease', (91, 96))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (49, 65))	('paroxysmal hypertension', 'Phenotype', 'HP:0000875', (116, 139))
105725	32228502	The first pancreatic neuroendocrine tumor in Li-Fraumeni syndrome: a case report Li-Fraumeni syndrome is a cancer predisposition syndrome caused by germline TP53 tumor suppressor gene mutations, with no previous association with pancreatic neuroendocrine tumors (PNETs).	('TP53', 'Gene', (157, 161))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (21, 41))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('pancreatic neuroendocrine tumor', 'Disease', 'MESH:D018358', (10, 41))	('mutations', 'Var', (184, 193))	('tumor', 'Disease', (162, 167))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (81, 101))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', (36, 41))	('pancreatic neuroendocrine tumor', 'Disease', (10, 41))	('Li-Fraumeni syndrome', 'Disease', (45, 65))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (229, 261))	('NET', 'Gene', (264, 267))	('pancreatic neuroendocrine tumor', 'Disease', 'MESH:D018358', (229, 260))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (10, 41))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (45, 65))	('TP53', 'Gene', '7157', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (240, 260))	('tumor', 'Disease', (255, 260))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (240, 261))	('pancreatic neuroendocrine tumors', 'Disease', (229, 261))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('NETs', 'Phenotype', 'HP:0100634', (264, 268))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (229, 260))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('NET', 'Gene', '2004', (264, 267))	('caused by', 'Reg', (138, 147))	('Li-Fraumeni syndrome', 'Disease', (81, 101))
105731	32228502	Her PNET had a hemizygous pathogenic TP53 mutation with loss of the wild-type alternate allele, consistent with loss of heterozygosity and the two-hit hypothesis.	('NET', 'Gene', '2004', (5, 8))	('NET', 'Gene', (5, 8))	('pathogenic', 'Reg', (26, 36))	('mutation', 'Var', (42, 50))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))
105736	32228502	Although most PNETs occur sporadically, there are four inherited syndromes associated with them: neurofibromatosis type 1 (NF1 gene; OMIM #162200), von Hippel-Lindau disease (VHL gene; OMIM #193300), multiple endocrine neoplasia type 1 (MEN1 gene; OMIM #131100), and tuberous sclerosis complex (TSC1 and TSC2 genes; OMIM #191100 and #191092, respectively).	('tuberous sclerosis', 'Disease', 'MESH:D014402', (267, 285))	('NETs', 'Phenotype', 'HP:0100634', (15, 19))	('neoplasia', 'Phenotype', 'HP:0002664', (219, 228))	('von Hippel-Lindau disease', 'Disease', (148, 173))	('tuberous sclerosis', 'Disease', (267, 285))	('VHL', 'Gene', '7428', (175, 178))	('neurofibromatosis type 1', 'Gene', '4763', (97, 121))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (209, 228))	('MEN1', 'Gene', '4221', (237, 241))	('NET', 'Gene', '2004', (15, 18))	('NF1', 'Gene', '4763', (123, 126))	('TSC2', 'Gene', '7249', (304, 308))	('#191092', 'Var', (333, 340))	('endocrine neoplasia', 'Disease', (209, 228))	('MEN1', 'Gene', (237, 241))	('TSC1', 'Gene', (295, 299))	('NF1', 'Gene', (123, 126))	('TSC2', 'Gene', (304, 308))	('neurofibromatosis type 1', 'Gene', (97, 121))	('NET', 'Gene', (15, 18))	('TSC1', 'Gene', '7248', (295, 299))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (148, 173))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (97, 114))	('VHL', 'Gene', (175, 178))	('endocrine neoplasia', 'Disease', 'MESH:D009377', (209, 228))
105739	32228502	Although somatic TP53 mutations have been identified in various grades of PNETs as well as gastric, small bowel, colorectal, and appendiceal neuroendocrine tumors (NETs), there are no reported cases of NETs associated with a germline TP53 mutation.	('identified', 'Reg', (42, 52))	('NET', 'Gene', (75, 78))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (141, 161))	('colorectal', 'Disease', (113, 123))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (141, 162))	('associated', 'Reg', (207, 217))	('NET', 'Gene', (202, 205))	('TP53', 'Gene', (234, 238))	('NETs', 'Phenotype', 'HP:0100634', (202, 206))	('NETs', 'Phenotype', 'HP:0100634', (164, 168))	('NET', 'Gene', '2004', (164, 167))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('TP53', 'Gene', (17, 21))	('appendiceal neuroendocrine tumors', 'Disease', (129, 162))	('NET', 'Gene', '2004', (75, 78))	('NETs', 'Phenotype', 'HP:0100634', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutations', 'Var', (22, 31))	('NET', 'Gene', '2004', (202, 205))	('TP53', 'Gene', '7157', (234, 238))	('NET', 'Gene', (164, 167))	('small bowel', 'Disease', (100, 111))	('appendiceal neuroendocrine tumors', 'Disease', 'MESH:D018358', (129, 162))	('gastric', 'Disease', (91, 98))	('TP53', 'Gene', '7157', (17, 21))
105740	32228502	TP53 mutations are commonly found in poorly differentiated neuroendocrine carcinomas.	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (59, 84))	('neuroendocrine carcinomas', 'Disease', (59, 84))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (59, 83))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('found', 'Reg', (28, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (59, 84))
105751	32228502	A germline pathogenic mutation in TP53 was also identified, but exact variant information was not available from the testing laboratory.	('pathogenic', 'Reg', (11, 21))	('mutation', 'Var', (22, 30))	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', '7157', (34, 38))
105760	32228502	The patient underwent genetic testing in a Clinical Laboratory Improvement Amendments-certified molecular genetics laboratory (Invitae, San Francisco, CA) and was found to carry a pathogenic germline TP53 mutation, namely a cytosine-to-thymine transition at codon 1009, leading to an arginine-to-cysteine substitution (c.1009C > T, p.R337C).	('c.1009C > T', 'Var', (319, 330))	('thymine', 'Chemical', 'MESH:D013941', (236, 243))	('pathogenic', 'Reg', (180, 190))	('cysteine', 'Chemical', 'MESH:D003545', (296, 304))	('patient', 'Species', '9606', (4, 11))	('TP53', 'Gene', '7157', (200, 204))	('TP53', 'Gene', (200, 204))	('c.1009C > T', 'Mutation', 'rs587782529', (319, 330))	('cytosine', 'Chemical', 'MESH:D003596', (224, 232))	('p.R337C', 'Mutation', 'rs587782529', (332, 339))	('arginine', 'Chemical', 'MESH:D001120', (284, 292))
105766	32228502	Paraffin-embedded PNET tissue from 2015 was assayed for a profile of common somatic mutations (Oncomine Comprehensive Assay v3, Thermo Fisher Scientific, Carlsbad, CA) and found to have a hemizygous pathogenic TP53 mutation at codon 1009 (NM_000546.5: c.1009C > T, p.R337C).	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('p.R337C', 'Mutation', 'rs587782529', (265, 272))	('TP53', 'Gene', (210, 214))	('Oncomine', 'Chemical', '-', (95, 103))	('NET', 'Gene', '2004', (19, 22))	('NET', 'Gene', (19, 22))	('p.R337C', 'Var', (265, 272))	('c.1009C > T', 'Var', (252, 263))	('NM_000546.5: c.1009C > T', 'Mutation', 'rs587782529', (239, 263))	('TP53', 'Gene', '7157', (210, 214))
105767	32228502	Variant allele frequency was 93%, consistent with loss of the wild-type alternate allele (loss of heterozygosity) as a "second hit" in the tumor suppressor gene.	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Variant', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))
105769	32228502	Next-generation sequencing reveals a hemizygous pathogenic TP53 mutation (p.R337C) consistent with a loss of heterozygosity at the locus.	('TP53', 'Gene', (59, 63))	('p.R337C', 'Var', (74, 81))	('p.R337C', 'Mutation', 'rs587782529', (74, 81))	('pathogenic', 'Reg', (48, 58))	('TP53', 'Gene', '7157', (59, 63))
105772	32228502	Prior studies demonstrate somatic TP53 mutations in all grades of NET from various primary sites, with high-grade tumors more commonly harboring the mutation in both intra-abdominal and extra-abdominal NETs.	('TP53', 'Gene', (34, 38))	('NET', 'Gene', '2004', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutations', 'Var', (39, 48))	('NETs', 'Phenotype', 'HP:0100634', (202, 206))	('harboring', 'Reg', (135, 144))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('NET', 'Gene', (202, 205))	('NET', 'Gene', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('TP53', 'Gene', '7157', (34, 38))	('NET', 'Gene', '2004', (202, 205))
105773	32228502	Overall, more than half of poorly differentiated GI NECs have somatic TP53 mutations, while 0-11% of moderately and well-differentiated GI NETs harbor the mutation.	('NETs', 'Phenotype', 'HP:0100634', (139, 143))	('NET', 'Gene', '2004', (139, 142))	('NET', 'Gene', (139, 142))	('TP53', 'Gene', '7157', (70, 74))	('TP53', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))
105774	32228502	Similarly, for pulmonary NETs, more than 60% of small cell lung cancer and large cell neuroendocrine carcinoma have TP53 mutations, and 0-11% of well-differentiated grade 1 and 2 pulmonary NETs have been shown to have TP53 mutations.	('pulmonary NETs', 'Disease', (15, 29))	('mutations', 'Var', (121, 130))	('small cell lung cancer', 'Disease', (48, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('NETs', 'Phenotype', 'HP:0100634', (189, 193))	('TP53', 'Gene', (116, 120))	('pulmonary NETs', 'Disease', (179, 193))	('TP53', 'Gene', (218, 222))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (48, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('pulmonary NETs', 'Disease', 'MESH:D008171', (15, 29))	('NETs', 'Phenotype', 'HP:0100634', (25, 29))	('cell neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (81, 110))	('TP53', 'Gene', '7157', (116, 120))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (86, 110))	('TP53', 'Gene', '7157', (218, 222))	('pulmonary NETs', 'Disease', 'MESH:D008171', (179, 193))	('cell neuroendocrine carcinoma', 'Disease', (81, 110))	('small cell lung cancer', 'Disease', 'MESH:D055752', (48, 70))
105776	32228502	Our report demonstrates not only the next-generation sequencing of our PNET verifying a hemizygous TP53 mutation and loss of the wild-type allele, but also shows our patient's TP53 germline mutation with other clinical manifestations consistent with LFS.	('TP53', 'Gene', (99, 103))	('LFS', 'Disease', 'MESH:D016864', (250, 253))	('TP53', 'Gene', '7157', (176, 180))	('TP53', 'Gene', '7157', (99, 103))	('TP53', 'Gene', (176, 180))	('mutation', 'Var', (104, 112))	('LFS', 'Disease', (250, 253))	('patient', 'Species', '9606', (166, 173))	('NET', 'Gene', '2004', (72, 75))	('NET', 'Gene', (72, 75))
105778	32228502	Our patient had no additional pathogenic mutations detected by the Oncomine Comprehensive Assay, and we postulate that a "second-hit" somatic TP53 mutation in the setting of an existing germline TP53 mutation drove the development of her PNET.	('TP53', 'Gene', (195, 199))	('drove', 'PosReg', (209, 214))	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', (142, 146))	('mutation', 'Var', (147, 155))	('NET', 'Gene', (239, 242))	('patient', 'Species', '9606', (4, 11))	('NET', 'Gene', '2004', (239, 242))	('Oncomine', 'Chemical', '-', (67, 75))	('TP53', 'Gene', '7157', (195, 199))	('mutation', 'Var', (200, 208))
105787	32228502	Patients who present with breast cancer before 31 years of age are recommended to undergo TP53 germline mutation testing as well.	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('TP53', 'Gene', '7157', (90, 94))	('germline mutation testing', 'Var', (95, 120))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('TP53', 'Gene', (90, 94))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))
105794	32228502	Interpreting the relevance of our patient's development of PNET to her specific TP53 mutation (p.R337C) is difficult, as genotype-phenotype relationships in LFS are not fully characterized.	('LFS', 'Disease', (157, 160))	('p.R337C', 'Var', (95, 102))	('NET', 'Gene', (60, 63))	('NET', 'Gene', '2004', (60, 63))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('patient', 'Species', '9606', (34, 41))	('LFS', 'Disease', 'MESH:D016864', (157, 160))	('p.R337C', 'Mutation', 'rs587782529', (95, 102))
105795	32228502	Prior analyses have categorized TP53 pathogenic variants by genetic location and by predicted structural and/or functional properties of mutant proteins.	('pathogenic', 'Reg', (37, 47))	('TP53', 'Gene', '7157', (32, 36))	('variants', 'Var', (48, 56))	('TP53', 'Gene', (32, 36))
105796	32228502	Missense mutations affecting residues belonging to loops 2 and 3 of the p53 protein were found to be associated with the development of brain tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('brain tumors', 'Disease', 'MESH:D001932', (136, 148))	('brain tumors', 'Phenotype', 'HP:0030692', (136, 148))	('protein', 'Protein', (76, 83))	('brain tumors', 'Disease', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('associated with', 'Reg', (101, 116))	('Missense mutations', 'Var', (0, 18))
105797	32228502	Missense mutations affecting residues outside of the loop-sheet-helix motif that binds the major groove of target DNA in p53 were found to be associated with the development of adrenocortical carcinomas.	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (177, 202))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (177, 202))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))	('associated with', 'Reg', (142, 157))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (177, 201))	('adrenocortical carcinomas', 'Disease', (177, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('Missense mutations', 'Var', (0, 18))
105798	32228502	Attempts have been made to classify TP53 mutation pathogenic variant with LFS phenotype.	('pathogenic', 'Reg', (50, 60))	('LFS', 'Disease', 'MESH:D016864', (74, 77))	('variant', 'Var', (61, 68))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))	('LFS', 'Disease', (74, 77))
105800	32228502	Although genotypic variation has not been shown to correlate with the development of particular tumors, dominant-negative missense TP53 mutations leave their carriers susceptible to cancer at earlier ages and at higher levels of clinical severity than those with non-missense mutations.	('missense', 'Var', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('TP53', 'Gene', '7157', (131, 135))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('TP53', 'Gene', (131, 135))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (136, 145))	('cancer', 'Disease', (182, 188))
105802	32228502	Germline TP53 mutations most commonly occur within the DNA-binding domain, leading to the production of a dysfunctional p53 protein.	('dysfunctional', 'Disease', (106, 119))	('p53', 'Gene', '7157', (120, 123))	('leading to', 'Reg', (75, 85))	('dysfunctional', 'Disease', 'MESH:D009461', (106, 119))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('production', 'MPA', (90, 100))	('p53', 'Gene', (120, 123))	('mutations', 'Var', (14, 23))
105803	32228502	Our patient's particular TP53 mutation is relatively uncommon and has initially been implicated in LFS and Li-Fraumeni-like syndromes.	('TP53', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (107, 118))	('patient', 'Species', '9606', (4, 11))	('LFS', 'Disease', 'MESH:D016864', (99, 102))	('implicated', 'Reg', (85, 95))	('Li-Fraumeni', 'Disease', (107, 118))	('TP53', 'Gene', '7157', (25, 29))	('LFS', 'Disease', (99, 102))
105804	32228502	A cytosine-to-thymine transition at nucleic acid 1009 leads to a missense arginine-to-cysteine transition at amino acid 337 (p.R337C) within exon 10.	('cytosine', 'Chemical', 'MESH:D003596', (2, 10))	('leads to', 'Reg', (54, 62))	('p.R337C', 'Mutation', 'rs587782529', (125, 132))	('arginine-to-cysteine transition', 'MPA', (74, 105))	('arginine-to-cysteine transition at amino acid 337', 'Mutation', 'rs587782529', (74, 123))	('thymine', 'Chemical', 'MESH:D013941', (14, 21))	('p.R337C', 'Var', (125, 132))
105806	32228502	The p.R337C germline mutation has been seen in cohorts that tend to develop brain tumors, osteosarcoma, rhabdomyosarcoma, breast cancer, and childhood adrenocortical carcinoma.	('childhood adrenocortical carcinoma', 'Disease', 'MESH:D018268', (141, 175))	('osteosarcoma', 'Phenotype', 'HP:0002669', (90, 102))	('rhabdomyosarcoma', 'Disease', (104, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('brain tumors', 'Disease', (76, 88))	('p.R337C', 'Var', (4, 11))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (104, 120))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (151, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('childhood adrenocortical carcinoma', 'Disease', (141, 175))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (104, 120))	('osteosarcoma', 'Disease', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('osteosarcoma', 'Disease', 'MESH:D012516', (90, 102))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('develop', 'PosReg', (68, 75))	('p.R337C', 'Mutation', 'rs587782529', (4, 11))	('breast cancer', 'Disease', (122, 135))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('brain tumors', 'Disease', 'MESH:D001932', (76, 88))	('brain tumors', 'Phenotype', 'HP:0030692', (76, 88))
105809	32228502	Genotypic variation in LFS has been best correlated with a phenotype in Brazilian families that harbor the more common TP53 germline mutation that features a transition from guanine to adenine and a subsequent arginine-to-histidine transition (c.1010G > A, p.R337H), rendering carriers particularly susceptible to the development of adrenocortical carcinoma.	('TP53', 'Gene', '7157', (119, 123))	('adenine', 'Chemical', 'MESH:D000225', (185, 192))	('p.R337H', 'Var', (257, 264))	('c.1010G > A', 'Mutation', 'rs121912664', (244, 255))	('LFS', 'Disease', 'MESH:D016864', (23, 26))	('adrenocortical carcinoma', 'Disease', (333, 357))	('guanine', 'Chemical', 'MESH:D006147', (174, 181))	('histidine', 'Chemical', 'MESH:D006639', (222, 231))	('arginine', 'Chemical', 'MESH:D001120', (210, 218))	('p.R337H', 'Mutation', 'rs121912664', (257, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (348, 357))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (333, 357))	('c.1010G > A', 'Var', (244, 255))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (333, 357))	('susceptible', 'Reg', (299, 310))	('LFS', 'Disease', (23, 26))	('TP53', 'Gene', (119, 123))
105810	32228502	This patient's case represents the first reported PNET in association with a germline TP53 mutation, highlighting the importance of screening for pancreatic neoplasms in the setting of LFS.	('neoplasm', 'Phenotype', 'HP:0002664', (157, 165))	('mutation', 'Var', (91, 99))	('patient', 'Species', '9606', (5, 12))	('pancreatic neoplasms', 'Phenotype', 'HP:0002894', (146, 166))	('pancreatic neoplasms', 'Disease', (146, 166))	('TP53', 'Gene', '7157', (86, 90))	('LFS', 'Disease', (185, 188))	('pancreatic neoplasm', 'Phenotype', 'HP:0002894', (146, 165))	('neoplasms', 'Phenotype', 'HP:0002664', (157, 166))	('TP53', 'Gene', (86, 90))	('pancreatic neoplasms', 'Disease', 'MESH:D010190', (146, 166))	('NET', 'Gene', (51, 54))	('LFS', 'Disease', 'MESH:D016864', (185, 188))	('NET', 'Gene', '2004', (51, 54))
105811	32228502	The p.R337C mutation is an uncommon pathogenic variant of TP53 in LFS, and much remains to be described about its associated cancers.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('p.R337C', 'Mutation', 'rs587782529', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('LFS', 'Disease', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('p.R337C', 'Var', (4, 11))	('LFS', 'Disease', 'MESH:D016864', (66, 69))
105870	31263390	Although commonly they occur sporadically, some of them (25-30%) are hereditary and part of multiple endocrine neoplasia type 2 (MEN2), caused by germline mutations of the RET proto-oncogene.	('RET', 'Gene', '5979', (172, 175))	('part of multiple endocrine neoplasia type 2', 'Disease', (84, 127))	('neoplasia', 'Phenotype', 'HP:0002664', (111, 120))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (101, 120))	('RET', 'Gene', (172, 175))	('part of multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (84, 127))	('caused by', 'Reg', (136, 145))	('germline', 'Var', (146, 154))
105901	31263390	published that miR-183 and miR-375 were associated with lymph node metastases, distant metastases and mortality.	('lymph node metastases', 'Disease', (56, 77))	('miR-375', 'Gene', (27, 34))	('miR-183', 'Var', (15, 22))	('metastases', 'Disease', (87, 97))	('metastases', 'Disease', (67, 77))	('metastases', 'Disease', 'MESH:D009362', (87, 97))	('mortality', 'CPA', (102, 111))	('metastases', 'Disease', 'MESH:D009362', (67, 77))	('miR-375', 'Gene', '494324', (27, 34))	('lymph node metastases', 'Disease', 'MESH:D009362', (56, 77))	('associated', 'Reg', (40, 50))
105916	31263390	MiR-375 substitution in NCI-H295R ACC cell line resulted in decreased cell growth and it inhibited its target gene metadherin (MTDH).	('decreased', 'NegReg', (60, 69))	('MiR-375', 'Gene', (0, 7))	('MiR-375', 'Gene', '494324', (0, 7))	('inhibited', 'NegReg', (89, 98))	('metadherin', 'Gene', '92140', (115, 125))	('NCI-H295R', 'CellLine', 'CVCL:0458', (24, 33))	('MTDH', 'Gene', '92140', (127, 131))	('metadherin', 'Gene', (115, 125))	('ACC', 'Phenotype', 'HP:0006744', (34, 37))	('MTDH', 'Gene', (127, 131))	('cell growth', 'CPA', (70, 81))	('substitution', 'Var', (8, 20))
105923	31263390	Experiments, however, demonstrated that miR-483-5p has an independent role in ACC's pathogenesis as IGF2 transgenic animals did not develop tumors.	('IGF2', 'Gene', (100, 104))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('miR-483', 'Gene', '619552', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('transgenic', 'Var', (105, 115))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('IGF2', 'Gene', '3481', (100, 104))	('miR-483', 'Gene', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('ACC', 'Disease', (78, 81))
105940	31263390	Also, a significant overexpression of TARBP2, DICER, and DROSHA (drosha ribonuclease III) in ACC compared with ACA or normal adrenal cortices were found and inhibition of TARBP2 in human ACC cell line resulted in a decreased cell proliferation and induction of apoptosis.	('drosha ribonuclease III', 'Gene', (65, 88))	('TARBP2', 'Gene', (38, 44))	('induction', 'Reg', (248, 257))	('DICER', 'Gene', (46, 51))	('overexpression', 'PosReg', (20, 34))	('apoptosis', 'CPA', (261, 270))	('TARBP2', 'Gene', '6895', (171, 177))	('TARBP2', 'Gene', (171, 177))	('cell proliferation', 'CPA', (225, 243))	('drosha ribonuclease III', 'Gene', '29102', (65, 88))	('decreased', 'NegReg', (215, 224))	('DROSHA', 'Gene', '29102', (57, 63))	('human', 'Species', '9606', (181, 186))	('DROSHA', 'Gene', (57, 63))	('ACC', 'Phenotype', 'HP:0006744', (187, 190))	('DICER', 'Gene', '23405', (46, 51))	('ACC', 'Phenotype', 'HP:0006744', (93, 96))	('inhibition', 'Var', (157, 167))	('TARBP2', 'Gene', '6895', (38, 44))
105954	31263390	More than 30% of the cases are attributed to germline mutation leading to autosomal dominant genetic syndromes such as multiple endocrine neoplasia type 2A and 2B caused by RET mutations, von Hippel Lindau syndrome due to VHL mutations, neurofibromatosis type 1 with NF1 mutations or hereditary PG syndromes caused by mutations of succinate dehydrogenase (SDH) genes.	('hereditary PG syndromes', 'Disease', 'MESH:D009386', (284, 307))	('due', 'Reg', (215, 218))	('neoplasia', 'Phenotype', 'HP:0002664', (138, 147))	('mutations', 'Var', (177, 186))	('von Hippel Lindau syndrome', 'Disease', (188, 214))	('mutations', 'Var', (318, 327))	('mutations', 'Var', (271, 280))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (237, 254))	('VHL', 'Disease', 'MESH:D006623', (222, 225))	('neurofibromatosis type 1', 'Gene', '4763', (237, 261))	('RET', 'Gene', '5979', (173, 176))	('NF1', 'Gene', '4763', (267, 270))	('von Hippel Lindau syndrome', 'Disease', 'MESH:D006623', (188, 214))	('succinate dehydrogenase', 'Gene', '6390', (331, 354))	('SDH', 'Gene', '6390', (356, 359))	('caused by', 'Reg', (308, 317))	('NF1', 'Gene', (267, 270))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (128, 147))	('genetic syndromes', 'Disease', (93, 110))	('genetic syndromes', 'Disease', 'MESH:D030342', (93, 110))	('hereditary PG syndromes', 'Disease', (284, 307))	('mutations', 'Var', (226, 235))	('multiple endocrine neoplasia type', 'Disease', 'MESH:D018761', (119, 152))	('RET', 'Gene', (173, 176))	('VHL', 'Disease', (222, 225))	('SDH', 'Gene', (356, 359))	('caused', 'Reg', (163, 169))	('neurofibromatosis type 1', 'Gene', (237, 261))	('succinate dehydrogenase', 'Gene', (331, 354))	('multiple endocrine neoplasia type', 'Disease', (119, 152))
105957	31263390	Hypoxia induced miR-210 was found overexpressed commonly in pseudohypoxia-associated PCC/PGLs harboring SDHB and VHL mutations.	('mutations', 'Var', (117, 126))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('VHL', 'Disease', (113, 116))	('pseudohypoxia', 'Disease', (60, 73))	('miR-210', 'Gene', (16, 23))	('Hypoxia', 'Disease', (0, 7))	('PGL', 'Phenotype', 'HP:0002668', (89, 92))	('miR-210', 'Gene', '406992', (16, 23))	('overexpressed', 'PosReg', (34, 47))	('pseudohypoxia', 'Disease', 'None', (60, 73))	('PCC', 'Phenotype', 'HP:0002666', (85, 88))	('SDHB', 'Gene', '6390', (104, 108))	('VHL', 'Disease', 'MESH:D006623', (113, 116))	('SDHB', 'Gene', (104, 108))
105958	31263390	Upregulation of miR-139-3p, miR-541, miR-765 and miR-133b was described in VHL associated tumors, while miR-96 and miR-183 were found to be overexpressed in neoplasms with SDHB mutations.	('VHL', 'Disease', (75, 78))	('neoplasm', 'Phenotype', 'HP:0002664', (157, 165))	('mutations', 'Var', (177, 186))	('miR-139-3p', 'Gene', (16, 26))	('miR-541', 'Gene', '100126308', (28, 35))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('neoplasms', 'Disease', 'MESH:D009369', (157, 166))	('miR-96', 'Gene', (104, 110))	('miR-139-3p', 'Gene', '406931', (16, 26))	('miR-133b', 'Gene', (49, 57))	('SDHB', 'Gene', '6390', (172, 176))	('miR-96', 'Gene', '407053', (104, 110))	('VHL', 'Disease', 'MESH:D006623', (75, 78))	('neoplasms', 'Disease', (157, 166))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Upregulation', 'PosReg', (0, 12))	('SDHB', 'Gene', (172, 176))	('miR-765', 'Gene', (37, 44))	('miR-133b', 'Gene', '442890', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('neoplasms', 'Phenotype', 'HP:0002664', (157, 166))	('tumors', 'Disease', (90, 96))	('miR-765', 'Gene', '768220', (37, 44))	('miR-541', 'Gene', (28, 35))
105971	31263390	Compared with benign PCCs, miR-101 level was higher in patients with malignant PCCs and the level of miR-101 was higher in SDHD mutation associated tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mutation', 'Var', (128, 136))	('miR', 'Gene', '220972', (27, 30))	('SDHD', 'Gene', (123, 127))	('higher', 'PosReg', (113, 119))	('miR', 'Gene', (27, 30))	('SDHD', 'Gene', '6392', (123, 127))	('patients', 'Species', '9606', (55, 63))	('PCC', 'Phenotype', 'HP:0002666', (79, 82))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('higher', 'PosReg', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('PCC', 'Phenotype', 'HP:0002666', (21, 24))	('miR', 'Gene', '220972', (101, 104))	('level', 'MPA', (92, 97))	('miR', 'Gene', (101, 104))
106011	31263390	In GH3 cells Caveolin-1 (CAV1) was reported to promote invasion while silencing CAV1 indirectly induced miR-145, miR-124, and miR-183 that suppressed the migration and invasion of pituitary adenoma cells through targeting FSCN1, PTTG1IP and EZR, respectively.	('miR', 'Gene', (126, 129))	('Caveolin-1', 'Gene', '25404', (13, 23))	('CAV1', 'Gene', '25404', (25, 29))	('CAV1', 'Gene', (80, 84))	('miR-145', 'Gene', '100314036', (104, 111))	('FSCN1', 'Gene', '683788', (222, 227))	('EZR', 'Gene', '54319', (241, 244))	('miR', 'Gene', '220972', (113, 116))	('Caveolin-1', 'Gene', (13, 23))	('silencing', 'Var', (70, 79))	('pituitary adenoma', 'Disease', 'MESH:D010911', (180, 197))	('PTTG1IP', 'Gene', '365548', (229, 236))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (180, 197))	('miR', 'Gene', '220972', (104, 107))	('PTTG1IP', 'Gene', (229, 236))	('pituitary adenoma', 'Disease', (180, 197))	('miR', 'Gene', (113, 116))	('promote', 'PosReg', (47, 54))	('CAV1', 'Gene', '25404', (80, 84))	('invasion', 'CPA', (55, 63))	('invasion', 'CPA', (168, 176))	('miR', 'Gene', (104, 107))	('EZR', 'Gene', (241, 244))	('migration', 'CPA', (154, 163))	('suppressed', 'NegReg', (139, 149))	('miR', 'Gene', '220972', (126, 129))	('targeting', 'Reg', (212, 221))	('CAV1', 'Gene', (25, 29))	('miR-145', 'Gene', (104, 111))	('FSCN1', 'Gene', (222, 227))
106026	31263390	Also, miR-144/451 cluster and miR-21 was found overexpressed compared to normal pancreatic islets.	('pancreatic', 'Disease', 'MESH:D010195', (80, 90))	('pancreatic', 'Disease', (80, 90))	('miR-21', 'Gene', '406991', (30, 36))	('miR-144/451 cluster', 'Var', (6, 25))	('overexpressed', 'PosReg', (47, 60))	('miR-21', 'Gene', (30, 36))
106037	31263390	MiR-7-5p, miR-182, miR-183 and miR-96-5p were found to be upregulated in sbNET compared to normal small bowel consequently in different studies.	('small bowel', 'Disease', (98, 109))	('MiR-7-5p', 'Gene', '407045', (0, 8))	('upregulated', 'PosReg', (58, 69))	('MiR-7-5p', 'Gene', (0, 8))	('sbNET', 'Disease', (73, 78))	('miR-183', 'Var', (19, 26))	('miR-182', 'Gene', (10, 17))	('small bowel', 'Disease', 'MESH:D015212', (98, 109))	('miR-96', 'Gene', '407053', (31, 37))	('miR-182', 'Gene', '406958', (10, 17))	('miR-96', 'Gene', (31, 37))
106038	31263390	Furthermore, miR-182, miR-183 and miR-96 overexpressed in NET metastases compared to primary tumors.	('overexpressed', 'PosReg', (41, 54))	('primary tumors', 'Disease', 'MESH:D009369', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('metastases', 'Disease', 'MESH:D009362', (62, 72))	('miR-182', 'Gene', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('miR-96', 'Gene', '407053', (34, 40))	('miR-182', 'Gene', '406958', (13, 20))	('miR-96', 'Gene', (34, 40))	('primary tumors', 'Disease', (85, 99))	('metastases', 'Disease', (62, 72))	('miR-183', 'Var', (22, 29))
106073	31263390	Several miRNAs (miR-126, miR-381, miR-665, miR-300, miR-381, miR-329) are suggested to contribute to PTTG1 overexpression in pituitary adenomas, that is also upregulated in colorectal NET by the loss of miR-186.	('miR-186', 'Gene', '406962', (203, 210))	('miR-186', 'Gene', (203, 210))	('pituitary adenomas', 'Disease', 'MESH:D010911', (125, 143))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', '220972', (203, 206))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (125, 143))	('pituitary adenomas', 'Disease', (125, 143))	('overexpression', 'PosReg', (107, 121))	('miR-381', 'Gene', (25, 32))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (61, 64))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (203, 206))	('miR-381', 'Gene', '494330', (52, 59))	('miR', 'Gene', '220972', (34, 37))	('miR-300', 'Gene', '100126297', (43, 50))	('miR-665', 'Gene', (34, 41))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (125, 142))	('miR', 'Gene', '220972', (16, 19))	('miR-126', 'Gene', (16, 23))	('miR', 'Gene', (52, 55))	('loss', 'Var', (195, 199))	('PTTG1', 'Gene', '9232', (101, 106))	('miR', 'Gene', '220972', (8, 11))	('miR-665', 'Gene', '100126315', (34, 41))	('colorectal', 'Disease', (173, 183))	('miR-381', 'Gene', '494330', (25, 32))	('miR', 'Gene', (43, 46))	('colorectal', 'Disease', 'MESH:D015179', (173, 183))	('miR', 'Gene', (25, 28))	('miR', 'Gene', (34, 37))	('miR', 'Gene', (16, 19))	('miR', 'Gene', (8, 11))	('upregulated', 'PosReg', (158, 169))	('miR-126', 'Gene', '406913', (16, 23))	('PTTG1', 'Gene', (101, 106))	('miR-300', 'Gene', (43, 50))	('miR-381', 'Gene', (52, 59))
106113	29784041	Dysregulation of lipid metabolism contributes to the progression of various metabolic diseases, including cardiovascular diseases, obesity, hepatic steatosis, and diabetes.	('obesity', 'Disease', 'MESH:D009765', (131, 138))	('cardiovascular diseases', 'Disease', (106, 129))	('obesity', 'Disease', (131, 138))	('Dysregulation', 'Var', (0, 13))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (106, 129))	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (106, 129))	('metabolic diseases', 'Disease', (76, 94))	('lipid metabolism', 'MPA', (17, 33))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (140, 157))	('diabetes', 'Disease', (163, 171))	('obesity', 'Phenotype', 'HP:0001513', (131, 138))	('diabetes', 'Disease', 'MESH:D003920', (163, 171))	('hepatic steatosis', 'Disease', (140, 157))	('metabolic diseases', 'Disease', 'MESH:D008659', (76, 94))	('hepatic steatosis', 'Disease', 'MESH:D005234', (140, 157))
106154	29784041	We found that inhibiting N-glycosylation, but not O-glycosylation, abolished glucose-mediated SCAP up-regulation and SREBP activation, indicating that glucose-mediated N-glycosylation of SCAP is essential for SCAP/SREBP trafficking and activation.	('SREBP', 'Gene', '7555', (117, 122))	('SCAP', 'Gene', '22937', (209, 213))	('SCAP', 'Gene', (187, 191))	('SREBP', 'Gene', (214, 219))	('SCAP', 'Gene', (94, 98))	('up-regulation', 'PosReg', (99, 112))	('inhibiting', 'Var', (14, 24))	('glucose', 'Chemical', 'MESH:D005947', (77, 84))	('SCAP', 'Gene', '22937', (94, 98))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('SCAP', 'Gene', '22937', (187, 191))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('activation', 'PosReg', (123, 133))	('SREBP', 'Gene', '7555', (214, 219))	('SCAP', 'Gene', (209, 213))	('abolished', 'NegReg', (67, 76))	('SREBP', 'Gene', (117, 122))	('glucose', 'Chemical', 'MESH:D005947', (151, 158))
106163	29784041	Inhibiting SREBPs at the genetic level or with pharmacological agents significantly suppresses tumor growth and induces cancer cell death, making SREBPs promising therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('SREBP', 'Gene', '7555', (11, 16))	('Inhibiting', 'Var', (0, 10))	('suppresses', 'NegReg', (84, 94))	('induces', 'Reg', (112, 119))	('SREBP', 'Gene', '7555', (146, 151))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('SREBP', 'Gene', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('SREBP', 'Gene', (146, 151))	('tumor', 'Disease', (95, 100))
106166	29784041	Along this line, fatostatin, betulin and PF-429242 have been shown to inhibit SREBP activation and have promising anti-tumor effects in pre-clinical studies.	('tumor', 'Disease', (119, 124))	('fatostatin', 'Chemical', 'MESH:C545733', (17, 27))	('SREBP', 'Gene', (78, 83))	('PF-429242', 'Var', (41, 50))	('betulin', 'Chemical', 'MESH:C002503', (29, 36))	('activation', 'MPA', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('SREBP', 'Gene', '7555', (78, 83))	('inhibit', 'NegReg', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
106169	29784041	Inhibiting SREBP-2 has been explored as an anti-cancer therapy.	('Inhibiting', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('SREBP-2', 'Gene', '6721', (11, 18))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('SREBP-2', 'Gene', (11, 18))
106172	29784041	However, inhibition of cholesterol synthesis can lead to feedback activation of SREBPs, making the anti-cancer effects of statins less effective.	('activation', 'PosReg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cholesterol', 'Chemical', 'MESH:D002784', (23, 34))	('feedback', 'MPA', (57, 65))	('SREBP', 'Gene', '7555', (80, 85))	('cholesterol synthesis', 'MPA', (23, 44))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (104, 110))	('inhibition', 'Var', (9, 19))	('SREBP', 'Gene', (80, 85))
106177	29784041	In lung cancer cells, SLC25A1 is up-regulated by mutant p53.	('mutant', 'Var', (49, 55))	('p53', 'Gene', (56, 59))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('p53', 'Gene', '7157', (56, 59))	('SLC25A1', 'Gene', '6576', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('SLC25A1', 'Gene', (22, 29))	('up-regulated', 'PosReg', (33, 45))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
106178	29784041	These findings, though preliminary, suggest that specific inhibitors of SLC25A1 may have anti-tumor effects.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('inhibitors', 'Var', (58, 68))	('SLC25A1', 'Gene', '6576', (72, 79))	('SLC25A1', 'Gene', (72, 79))
106181	29784041	Inhibiting ACLY at the genetic level or pharmacologically significantly suppresses tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Inhibiting', 'Var', (0, 10))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('suppresses', 'NegReg', (72, 82))
106191	29784041	Knocking down ACSS2 suppresses proliferation of several cancer cell lines as well as growth of xenograft tumors.	('xenograft tumors', 'Disease', (95, 111))	('Knocking down', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ACSS2', 'Gene', (14, 19))	('suppresses', 'NegReg', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('xenograft tumors', 'Disease', 'MESH:D009369', (95, 111))	('ACSS2', 'Gene', '55902', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
106196	29784041	Inhibiting ACCs significantly reduces fatty acid synthesis and suppresses tumor growth in various xenograft models.	('Inhibiting', 'Var', (0, 10))	('suppresses', 'NegReg', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('ACCs', 'Gene', '84680', (11, 15))	('fatty acid synthesis', 'MPA', (38, 58))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('ACCs', 'Gene', (11, 15))	('tumor', 'Disease', (74, 79))	('fatty acid', 'Chemical', 'MESH:D005227', (38, 48))	('reduces', 'NegReg', (30, 37))
106205	29784041	The SCD1 inhibitors BZ36, A939572 and MF-438 have shown anti-tumor effects in pre-clinical xenograft models (Table 1).	('tumor', 'Disease', (61, 66))	('SCD1', 'Gene', '6319', (4, 8))	('A939572', 'Var', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('BZ36', 'Var', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('A939572', 'Chemical', '-', (26, 33))	('MF-438', 'Gene', (38, 44))	('SCD1', 'Gene', (4, 8))	('BZ36', 'Chemical', '-', (20, 24))
106221	29784041	Genetically silencing SOAT1/ACAT1 or blocking its activity using the inhibitors K604, ATR-101 or avasimibe effectively suppresses tumor growth in several cancer xenograft models.	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('cancer', 'Disease', (154, 160))	('suppresses', 'NegReg', (119, 129))	('silencing', 'Var', (12, 21))	('ATR-101', 'Chemical', 'MESH:C079534', (86, 93))	('activity', 'MPA', (50, 58))	('blocking', 'NegReg', (37, 45))	('SOAT1', 'Gene', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('K604', 'Chemical', 'MESH:C520671', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('avasimibe', 'Chemical', 'MESH:C423185', (97, 106))	('ACAT1', 'Gene', '38', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (130, 135))	('ACAT1', 'Gene', (28, 33))	('SOAT1', 'Gene', '6646', (22, 27))
106227	29784041	Synthetic liver X receptor agonists GW3965 and T0901317 significantly inhibit tumor growth in animal models of glioblastoma, breast cancer or prostate cancer.	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('GW3965', 'Chemical', 'MESH:C473027', (36, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (111, 123))	('prostate cancer', 'Disease', 'MESH:D011471', (142, 157))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('breast cancer', 'Disease', (125, 138))	('T0901317', 'Var', (47, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (142, 157))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('inhibit', 'NegReg', (70, 77))	('GW3965', 'Var', (36, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('glioblastoma', 'Disease', (111, 123))	('prostate cancer', 'Disease', (142, 157))
106228	29784041	Activation of the liver X receptor by GW3965 up-regulates a ubiquitin ligase E3 that degrades LDLR.	('GW3965', 'Var', (38, 44))	('up-regulates', 'PosReg', (45, 57))	('GW3965', 'Chemical', 'MESH:C473027', (38, 44))	('degrades', 'NegReg', (85, 93))	('LDLR', 'Gene', (94, 98))	('ubiquitin ligase E3', 'Enzyme', (60, 79))	('LDLR', 'Gene', '3949', (94, 98))
106235	29784041	Moreover, inhibiting liver X receptors alone may be insufficient for reducing glycolysis and lipogenesis in human tumors, since these metabolic programs are up-regulated by multiple oncogenic signaling pathways.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('inhibiting', 'Var', (10, 20))	('reducing', 'NegReg', (69, 77))	('glycolysis', 'MPA', (78, 88))	('human', 'Species', '9606', (108, 113))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('up-regulated', 'PosReg', (157, 169))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('lipogenesis', 'MPA', (93, 104))	('liver X receptors', 'Protein', (21, 38))
106298	29498108	The lipase activity and glucose concentration could not be retrieved from, respectively, 2 (with HAC) and 3 (2 with HAC and 1 with NAI) dogs in which the remainder of the biochemistry was available.	('glucose', 'Chemical', 'MESH:D005947', (24, 31))	('HAC', 'Var', (116, 119))	('lipase', 'Gene', '404010', (4, 10))	('lipase', 'Gene', (4, 10))	('NAI', 'Chemical', '-', (131, 134))	('dogs', 'Species', '9615', (136, 140))
106302	29498108	Lymphocyte (P < .001) and eosinophil (P < .001) counts and serum creatinine concentration (P < .001) were significantly lower whereas neutrophil (P = .007) and thrombocyte (P = .002) counts, ALP (P < .001), ALT (P < .001), and lipase (P < .001) activities and serum phosphorus (P < .001) and cholesterol (P < .001) concentrations were significantly higher in dogs with HAC.	('lower', 'NegReg', (120, 125))	('cholesterol', 'MPA', (292, 303))	('Lymphocyte', 'CPA', (0, 10))	('serum phosphorus', 'MPA', (260, 276))	('ALP', 'Disease', 'MESH:D050197', (191, 194))	('higher', 'PosReg', (349, 355))	('activities', 'MPA', (245, 255))	('serum creatinine concentration', 'MPA', (59, 89))	('creatinine', 'Chemical', 'MESH:D003404', (65, 75))	('phosphorus', 'Chemical', 'MESH:D010758', (266, 276))	('dogs', 'Species', '9615', (359, 363))	('lipase', 'Gene', '404010', (227, 233))	('cholesterol', 'Chemical', 'MESH:D002784', (292, 303))	('lipase', 'Gene', (227, 233))	('ALT', 'MPA', (207, 210))	('HAC', 'Var', (369, 372))	('ALP', 'Disease', (191, 194))
106304	29498108	In dogs with HAC and NAI, urine specific gravity was between 1.000 and 1.007 in 20 (35.7%) and 10 (16.9%) dogs (P = .022), between 1.008 and 1.012 in 16 (28.6%) and 9 (15.2%) dogs (P = .083), between 1.013 and 1.030 in 19 (33.9%) and 23 (39.0%) dogs (P = .57) and >1.030 in 1 (3.6%) and 17 (28.8%) dogs (P < .001), respectively.	('dogs', 'Species', '9615', (106, 110))	('dogs', 'Species', '9615', (298, 302))	('>1.030', 'Var', (264, 270))	('dogs', 'Species', '9615', (175, 179))	('NAI', 'Chemical', '-', (21, 24))	('urine specific gravity', 'MPA', (26, 48))	('1.030', 'Var', (210, 215))	('dogs', 'Species', '9615', (3, 7))	('dogs', 'Species', '9615', (245, 249))
106305	29498108	The 1 dog with HAC and urine specific gravity >1.030 had concurrent glucosuria.	('glucosuria', 'Phenotype', 'HP:0003076', (68, 78))	('glucosuria', 'Disease', (68, 78))	('>1.030', 'Var', (46, 52))	('dog', 'Species', '9615', (6, 9))	('glucosuria', 'Disease', 'MESH:D006030', (68, 78))
106368	29498108	However, ACTH secretion is suppressed in dogs with functional AT25 as a consequence of autonomous cortisol secretion.	('ACTH', 'Gene', (9, 13))	('dogs', 'Species', '9615', (41, 45))	('ACTH', 'Gene', '403659', (9, 13))	('cortisol', 'Chemical', 'MESH:D006854', (98, 106))	('autonomous cortisol secretion', 'MPA', (87, 116))	('suppressed', 'NegReg', (27, 37))	('functional', 'Var', (51, 61))	('AT', 'Disease', 'None', (62, 64))
106415	24842915	The main purpose of this study was to explore the reasons why the mean aldosterone secretion capacity of CT-undetectable small APA (microadenomas) could reach as much as that of CT-detectable large APA (macroadenomas) and the reasons why the clinical improvement after surgical treatment in both APA could be similar.	('aldosterone secretion capacity', 'MPA', (71, 101))	('aldosterone', 'Chemical', 'MESH:D000450', (71, 82))	('PA', 'Phenotype', 'HP:0011736', (128, 130))	('microadenomas', 'Disease', 'None', (132, 145))	('PA', 'Phenotype', 'HP:0011736', (297, 299))	('CT-undetectable', 'Var', (105, 120))	('macroadenomas', 'Disease', 'None', (203, 216))	('microadenomas', 'Disease', (132, 145))	('macroadenomas', 'Disease', (203, 216))	('PA', 'Phenotype', 'HP:0011736', (199, 201))
106535	26286195	While on univariate analysis, both the presence of positive margins (HR 2.65, 95 % CI 1.49-4.73; p = 0.001) and nodal metastasis (HR 3.46, 95 % CI 1.09-10.97; p = 0.04) were associated with worse OS (Table 3); on multivariate analysis, only the presence of positive surgical margin (HR 2.22, 95 % CI 1.03-4.77; p = 0.04) remained an independent predictor of worse OS (Table 3).	('presence', 'Var', (39, 47))	('worse OS', 'Disease', (190, 198))	('nodal metastasis', 'Disease', (112, 128))	('nodal metastasis', 'Disease', 'MESH:D009362', (112, 128))
106560	26369552	The molecular signature of ASPS is a specific der(17)t(X;17)(p11.2;q25) translocation, which results in the fusion of TFE3 transcription factor gene at Xp11.2 with ASPL at 17q25.	('TFE3', 'Gene', (118, 122))	('der(17)t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (46, 71))	('p11', 'Gene', (61, 64))	('results in', 'Reg', (93, 103))	('ASPS', 'Gene', '79058', (27, 31))	('ASPL', 'Gene', '79058', (164, 168))	('p11', 'Gene', '6281', (153, 156))	('TFE3', 'Gene', '7030', (118, 122))	('p11', 'Gene', '6281', (61, 64))	('ASPS', 'Phenotype', 'HP:0012218', (27, 31))	('fusion', 'Var', (108, 114))	('ASPL', 'Gene', (164, 168))	('ASPS', 'Gene', (27, 31))	('p11', 'Gene', (153, 156))
106564	26369552	Alveolar soft part sarcoma (ASPS) is a rare mesenchymal neoplasm with a highly distinctive histologic appearance, ultrastructure, and cytogenetic profile involving a non-reciprocal t(X;17)(p11.2;q25).	('mesenchymal neoplasm', 'Disease', (44, 64))	('ASPS', 'Gene', (28, 32))	('Alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (0, 26))	('mesenchymal neoplasm', 'Disease', 'MESH:C535700', (44, 64))	('t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (181, 199))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (9, 26))	('ASPS', 'Gene', '79058', (28, 32))	('Alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (0, 26))	('t(X;17)(p11.2;q25', 'Var', (181, 198))	('Alveolar soft part sarcoma', 'Disease', (0, 26))	('neoplasm', 'Phenotype', 'HP:0002664', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('ASPS', 'Phenotype', 'HP:0012218', (28, 32))
106565	26369552	The translocation fuses the TFE3 transcription factor gene at Xp11.2 to ASPL (ASPSCR1), a novel gene on chromosome 17q25 and presents as type 1 and 2 variants involving the fusion of the first seven exons of the ASPL gene to exon 6 (type 1) or 5 (type 2) of the TFE3 transcription factor gene.	('variants', 'Var', (150, 158))	('ASPSCR1', 'Gene', (78, 85))	('fusion', 'Interaction', (173, 179))	('TFE3', 'Gene', '7030', (28, 32))	('ASPL', 'Gene', '79058', (212, 216))	('ASPS', 'Phenotype', 'HP:0012218', (78, 82))	('TFE3', 'Gene', '7030', (262, 266))	('p11', 'Gene', (63, 66))	('ASPSCR1', 'Gene', '79058', (78, 85))	('ASPL', 'Gene', (212, 216))	('TFE3', 'Gene', (28, 32))	('ASPL', 'Gene', '79058', (72, 76))	('TFE3', 'Gene', (262, 266))	('p11', 'Gene', '6281', (63, 66))	('ASPL', 'Gene', (72, 76))
106596	26369552	FISH assay of the tumor cells showed a single interphase nucleus with split red and green signals observed in approximate 15 % tumorous nuclei, indicating the presence of a TFE3 gene rearrangement involving X chromosome (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (127, 132))	('TFE3', 'Gene', (173, 177))	('tumorous', 'Disease', 'MESH:D009369', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('TFE3', 'Gene', '7030', (173, 177))	('tumorous', 'Disease', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('rearrangement', 'Var', (183, 196))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
106597	26369552	RT-PCR amplification and DNA sequence analysis identified a type 1 ASPL-TFE3 fusion transcript with fusion of the first seven exons of the ASPL gene to exon 6 of the TFE3 transcription factor gene (Fig.	('TFE3', 'Gene', (72, 76))	('ASPL', 'Gene', (139, 143))	('ASPL', 'Gene', '79058', (67, 71))	('ASPL', 'Gene', (67, 71))	('TFE3', 'Gene', '7030', (166, 170))	('TFE3', 'Gene', '7030', (72, 76))	('fusion', 'Var', (100, 106))	('TFE3', 'Gene', (166, 170))	('ASPL', 'Gene', '79058', (139, 143))
106612	26369552	Recently, the molecular signature of ASPS has been described as a specific unbalanced translocation: der(17)t(X;17)(p11.2;q25).	('ASPS', 'Gene', '79058', (37, 41))	('der(17)t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (101, 126))	('der(17)t(X;17)(p11.2', 'Var', (101, 121))	('ASPS', 'Phenotype', 'HP:0012218', (37, 41))	('ASPS', 'Gene', (37, 41))
106619	26369552	FISH assay and RT-PCR analysis in these tumors have shown TFE3 gene rearrangement and amplification, respectively.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('rearrangement', 'Var', (68, 81))	('TFE3', 'Gene', '7030', (58, 62))	('amplification', 'MPA', (86, 99))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('TFE3', 'Gene', (58, 62))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
106637	25592387	MEN1 is caused by inactivating mutations in the MEN1 gene, whose product menin is involved in multiple intracellular pathways contributing to transcriptional control and cell proliferation.	('MEN1', 'Gene', '4221', (0, 4))	('involved', 'Reg', (82, 90))	('inactivating mutations', 'Var', (18, 40))	('MEN1', 'Gene', (48, 52))	('caused by', 'Reg', (8, 17))	('MEN1', 'Gene', '4221', (48, 52))	('menin', 'Gene', (73, 78))	('menin', 'Gene', '4221', (73, 78))	('rat', 'Species', '10116', (182, 185))	('MEN1', 'Gene', (0, 4))
106639	25592387	A subset of patients with pituitary adenomas and other MEN1 features have mutations in the CDKN1B gene; their disease has been called MEN type 4 (MEN4).	('pituitary adenomas', 'Disease', (26, 44))	('patients', 'Species', '9606', (12, 20))	('MEN1', 'Gene', (55, 59))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (26, 44))	('MEN1', 'Gene', '4221', (55, 59))	('mutations', 'Var', (74, 83))	('CDKN1B', 'Gene', '1027', (91, 97))	('pituitary adenomas', 'Disease', 'MESH:D010911', (26, 44))	('MEN4', 'Gene', '1027', (146, 150))	('CDKN1B', 'Gene', (91, 97))	('MEN4', 'Gene', (146, 150))	('MEN type 4', 'Gene', (134, 144))	('MEN type 4', 'Gene', '1027', (134, 144))
106640	25592387	Inactivating mutations in the type 1alpha regulatory subunit of protein kinase A (PKA) (the PRKAR1A gene), that lead to dysregulation and activation of the PKA pathway, are the main genetic cause of CNC, which is clinically characterised by primary pigmented adrenocortical disease (PPNAD), spotty skin pigmentation (lentigines), cardiac and other myxomas and acromegaly due to somatotropinomas or somatotrope hyperplasia.	('spotty', 'Species', '1203425', (291, 297))	('somatotropinomas or somatotrope hyperplasia', 'Disease', (378, 421))	('PRKAR1A', 'Gene', '5573', (92, 99))	('cause', 'Reg', (190, 195))	('pigmented adrenocortical disease', 'Disease', 'MESH:C566469', (249, 281))	('activation', 'PosReg', (138, 148))	('acromegaly', 'Phenotype', 'HP:0000845', (360, 370))	('cardiac and', 'Disease', (330, 341))	('skin pigmentation', 'Disease', 'MESH:D010859', (298, 315))	('PKA', 'Gene', (82, 85))	('Inactivating mutations', 'Var', (0, 22))	('dysregulation', 'MPA', (120, 133))	('somatotropinomas or somatotrope hyperplasia', 'Disease', 'MESH:D049912', (378, 421))	('PPNAD', 'Chemical', '-', (283, 288))	('myxomas and acromegaly', 'Disease', 'MESH:D000172', (348, 370))	('CNC', 'Disease', (199, 202))	('pigmented adrenocortical disease', 'Disease', (249, 281))	('PKA pathway', 'Pathway', (156, 167))	('PRKAR1A', 'Gene', (92, 99))	('pigmented adrenocortical disease', 'Phenotype', 'HP:0001580', (249, 281))	('skin pigmentation', 'Phenotype', 'HP:0000953', (298, 315))	('skin pigmentation', 'Disease', (298, 315))
106643	25592387	Other genetic causes include Carney complex (CNC), MEN type 4 (MEN4), mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene leading to familial isolated pituitary adenomas (FIPAs) and McCune-Albright syndrome (MAS).	('MAS', 'Disease', (230, 233))	('MAS', 'Disease', 'MESH:D005357', (230, 233))	('Carney complex', 'Disease', (29, 43))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (204, 228))	('leading to', 'Reg', (144, 154))	('isolated pituitary adenomas', 'Phenotype', 'HP:0011761', (164, 191))	('PAs', 'Disease', 'MESH:D011471', (195, 198))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (173, 191))	('AIP', 'Gene', (134, 137))	('MEN type 4', 'Gene', (51, 61))	('McCune-Albright syndrome', 'Disease', (204, 228))	('familial isolated pituitary adenomas', 'Disease', (155, 191))	('aryl hydrocarbon receptor interacting protein', 'Gene', '9049', (87, 132))	('mutations', 'Var', (70, 79))	('PAs', 'Disease', (195, 198))	('MEN4', 'Gene', '1027', (63, 67))	('PAs', 'Phenotype', 'HP:0002893', (195, 198))	('familial isolated pituitary adenomas', 'Disease', 'MESH:C566321', (155, 191))	('aryl hydrocarbon receptor interacting protein', 'Gene', (87, 132))	('MEN type 4', 'Gene', '1027', (51, 61))	('MEN4', 'Gene', (63, 67))	('AIP', 'Gene', '9049', (134, 137))
106644	25592387	Recently mutations in succinate dehydrogenase subunits (SDHx) and DICER1 as well as Xq26.3 microduplications have also been associated with pituitary tumours.	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('microduplications', 'Var', (91, 108))	('DICER1', 'Gene', (66, 72))	('DICER1', 'Gene', '23405', (66, 72))	('mutations', 'Var', (9, 18))	('pituitary tumours', 'Disease', 'MESH:D010911', (140, 157))	('pituitary tumour', 'Phenotype', 'HP:0002893', (140, 156))	('pituitary tumours', 'Disease', (140, 157))	('associated', 'Reg', (124, 134))	('succinate dehydrogenase', 'Gene', (22, 45))	('SDHx', 'Gene', (56, 60))	('succinate dehydrogenase', 'Gene', '6390', (22, 45))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('SDHx', 'Chemical', '-', (56, 60))
106647	25592387	MAS and CNC are caused by mutations in members of the cAMP-dependent protein kinase (protein kinase A or PKA) pathway; similarly, the PKA pathway, which contributes to pituitary proliferation and hormone secretion, is also altered in approximately 40% of sporadic somatotropinomas.	('PKA pathway', 'Pathway', (134, 145))	('MAS', 'Disease', 'MESH:D005357', (0, 3))	('MAS', 'Disease', (0, 3))	('cAMP', 'Chemical', '-', (54, 58))	('altered', 'Reg', (223, 230))	('sporadic somatotropinomas', 'Disease', (255, 280))	('caused by', 'Reg', (16, 25))	('mutations', 'Var', (26, 35))	('CNC', 'Disease', (8, 11))	('rat', 'Species', '10116', (185, 188))	('sporadic somatotropinomas', 'Disease', 'MESH:D049912', (255, 280))
106650	25592387	MEN1 and CDKN1B, whose mutations can cause pituitary tumour formation in the context of multiple endocrine neoplasia syndromes, were shown to be mutated or downregulated only in few sporadic tumours.	('MEN1', 'Gene', '4221', (0, 4))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('pituitary tumour', 'Disease', (43, 59))	('sporadic tumours', 'Disease', (182, 198))	('MEN1', 'Gene', (0, 4))	('CDKN1B', 'Gene', (9, 15))	('mutations', 'Var', (23, 32))	('tumours', 'Phenotype', 'HP:0002664', (191, 198))	('cause', 'Reg', (37, 42))	('pituitary tumour', 'Phenotype', 'HP:0002893', (43, 59))	('pituitary tumour', 'Disease', 'MESH:D010911', (43, 59))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (97, 116))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('downregulated', 'NegReg', (156, 169))	('CDKN1B', 'Gene', '1027', (9, 15))	('multiple endocrine neoplasia syndromes', 'Disease', (88, 126))	('multiple endocrine neoplasia syndromes', 'Disease', 'MESH:D009377', (88, 126))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('sporadic tumours', 'Disease', 'MESH:D009369', (182, 198))
106651	25592387	Similarly, mutations in AIP and PRKAR1A, which lead to familial pituitary tumours in the context of FIPA and CNC, respectively, do not seem to contribute significantly to sporadic pituitary tumours, although AIP expression is reduced in some sporadic somatotropinomas in the absence of AIP mutations, probably due to the actions of different microRNAs.	('mutations', 'Var', (11, 20))	('AIP', 'Gene', (286, 289))	('lead to', 'Reg', (47, 54))	('pituitary tumour', 'Phenotype', 'HP:0002893', (180, 196))	('sporadic somatotropinomas', 'Disease', (242, 267))	('sporadic pituitary tumours', 'Disease', (171, 197))	('PRKAR1A', 'Gene', (32, 39))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('familial pituitary tumours', 'Disease', 'MESH:D010911', (55, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('AIP', 'Gene', (24, 27))	('familial pituitary tumours', 'Disease', (55, 81))	('PRKAR1A', 'Gene', '5573', (32, 39))	('AIP', 'Gene', '9049', (208, 211))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('sporadic pituitary tumours', 'Disease', 'MESH:D010911', (171, 197))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))	('AIP', 'Gene', '9049', (286, 289))	('AIP', 'Gene', '9049', (24, 27))	('pituitary tumour', 'Phenotype', 'HP:0002893', (64, 80))	('AIP', 'Gene', (208, 211))	('expression', 'MPA', (212, 222))	('sporadic somatotropinomas', 'Disease', 'MESH:D049912', (242, 267))	('mutations', 'Var', (290, 299))	('reduced', 'NegReg', (226, 233))
106653	25592387	These have not been clearly defined yet, even though some candidate loci have been reported for AIP-associated tumours, and a possible association was suggested between a CDKN1B variant and tumour multiplicity in MEN1.	('MEN1', 'Gene', (213, 217))	('tumour', 'Disease', (190, 196))	('MEN1', 'Gene', '4221', (213, 217))	('tumours', 'Disease', (111, 118))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('variant', 'Var', (178, 185))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('CDKN1B', 'Gene', '1027', (171, 177))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('AIP', 'Gene', '9049', (96, 99))	('association', 'Interaction', (135, 146))	('tumour', 'Disease', (111, 117))	('AIP', 'Gene', (96, 99))	('CDKN1B', 'Gene', (171, 177))	('tumour', 'Disease', 'MESH:D009369', (190, 196))	('tumours', 'Disease', 'MESH:D009369', (111, 118))
106655	25592387	MAS is a genetic but not hereditary condition caused by somatic, postzygotic mutations in the alpha-subunit of the Gs protein (GNAS), leading to somatotrope or somatolactotrope hyperplasia and growth hormone (GH) hypersecretion in approximately 20% of patients.	('somatotrope', 'MPA', (145, 156))	('MAS', 'Disease', 'MESH:D005357', (0, 3))	('MAS', 'Disease', (0, 3))	('GNAS', 'Gene', (127, 131))	('growth hormone', 'Gene', '2688', (193, 207))	('GH', 'Gene', '2688', (209, 211))	('patients', 'Species', '9606', (252, 260))	('hyperplasia', 'Disease', (177, 188))	('leading to', 'Reg', (134, 144))	('mutations', 'Var', (77, 86))	('hyperplasia', 'Disease', 'MESH:D006965', (177, 188))	('GNAS', 'Gene', '2778', (127, 131))	('hypersecretion', 'PosReg', (213, 227))	('growth hormone', 'Gene', (193, 207))
106656	25592387	Inactivating germline mutations in AIP were recently discovered to be the genetic cause in about 20% of FIPA patients.	('Inactivating germline mutations', 'Var', (0, 31))	('cause', 'Reg', (82, 87))	('patients', 'Species', '9606', (109, 117))	('AIP', 'Gene', '9049', (35, 38))	('FIPA', 'Disease', (104, 108))	('AIP', 'Gene', (35, 38))
106658	25592387	MAS, FIPA due to AIP mutations and their contribution to pituitary pathology are described in detail elsewhere.	('MAS', 'Disease', 'MESH:D005357', (0, 3))	('MAS', 'Disease', (0, 3))	('FIPA', 'Disease', (5, 9))	('AIP', 'Gene', '9049', (17, 20))	('AIP', 'Gene', (17, 20))	('mutations', 'Var', (21, 30))
106659	25592387	Mutations in different subunits of SDH can lead to hereditary pheochromocytoma and paraganglioma syndromes and recently SDHx mutations were also reported to be associated with pituitary adenomas.	('mutations', 'Var', (125, 134))	('SDH', 'Gene', '6390', (35, 38))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (62, 78))	('pituitary adenomas', 'Disease', 'MESH:D010911', (176, 194))	('hereditary pheochromocytoma and paraganglioma syndromes', 'Disease', 'MESH:D010673', (51, 106))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('SDH', 'Gene', (120, 123))	('SDHx', 'Chemical', '-', (120, 124))	('lead to', 'Reg', (43, 50))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (176, 194))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', (35, 38))	('pituitary adenomas', 'Disease', (176, 194))	('associated', 'Reg', (160, 170))	('SDH', 'Gene', '6390', (120, 123))
106661	25592387	Germline mutations in DICER1 were reported in almost all cases of pituitary blastoma; interestingly, germline DICER1 mutations also cause other early childhood tumours summarised as pleuropulmonary blastoma-familial tumour and dysplasia syndrome (see table 1).	('mutations', 'Var', (117, 126))	('childhood tumours', 'Disease', (150, 167))	('tumour', 'Phenotype', 'HP:0002664', (216, 222))	('pituitary blastoma', 'Disease', (66, 84))	('DICER1', 'Gene', (110, 116))	('DICER1', 'Gene', '23405', (110, 116))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (182, 206))	('pleuropulmonary blastoma-familial tumour and dysplasia syndrome', 'Disease', 'MESH:C537516', (182, 245))	('pituitary blastoma', 'Disease', 'MESH:D018202', (66, 84))	('DICER1', 'Gene', (22, 28))	('DICER1', 'Gene', '23405', (22, 28))	('childhood tumours', 'Disease', 'MESH:C536928', (150, 167))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('cause', 'Reg', (132, 137))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))
106663	25592387	We have recently reported Xq26.3 microduplications in association with early childhood-onset gigantism, termed X-linked acrogigantism (X-LAG).	('microduplications', 'Var', (33, 50))	('X-linked acrogigantism (X-LAG', 'Gene', '105259600', (111, 140))	('association', 'Reg', (54, 65))	('early childhood-onset gigantism', 'Disease', (71, 102))	('Xq26.3', 'Gene', (26, 32))
106664	25592387	This is probably due to overexpression of GPR101, a G-protein coupled orphan receptor that is located in this region, and downstream PKA pathway activation; interestingly a recurring GPR101 variant is found in some cases of sporadic acromegaly.	('acromegaly', 'Phenotype', 'HP:0000845', (233, 243))	('sporadic acromegaly', 'Disease', (224, 243))	('variant', 'Var', (190, 197))	('found', 'Reg', (201, 206))	('sporadic acromegaly', 'Disease', 'MESH:D000172', (224, 243))	('GPR101', 'Gene', '83550', (42, 48))	('GPR101', 'Gene', (42, 48))	('GPR101', 'Gene', '83550', (183, 189))	('GPR101', 'Gene', (183, 189))
106670	25592387	There is considerable phenotypic variability of tumour type manifestations even within the same family, suggesting the possible involvement of modifier genes or epigenetic changes.	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('epigenetic changes', 'Var', (161, 179))	('tumour', 'Disease', (48, 54))	('involvement', 'Reg', (128, 139))
106675	25592387	Primary hyperparathyroidism (PHPT) is frequently the presenting feature of MEN1 and also the most common MEN1-associated clinical manifestation that occurs in more than 90 % of mutation carriers.	('mutation', 'Var', (177, 185))	('PHPT', 'Phenotype', 'HP:0008200', (29, 33))	('MEN1', 'Gene', (105, 109))	('Primary hyperparathyroidism', 'Disease', (0, 27))	('MEN1', 'Gene', '4221', (105, 109))	('Primary hyperparathyroidism', 'Disease', 'MESH:D049950', (0, 27))	('MEN1', 'Gene', (75, 79))	('Primary hyperparathyroidism', 'Phenotype', 'HP:0008200', (0, 27))	('MEN1', 'Gene', '4221', (75, 79))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (8, 27))
106705	25592387	Loss of heterozygosity (LOH) of the MEN1 locus is frequently found in MEN1 tumours.	('Loss of heterozygosity', 'Var', (0, 22))	('MEN1', 'Gene', (70, 74))	('MEN1', 'Gene', '4221', (70, 74))	('MEN1', 'Gene', (36, 40))	('MEN1', 'Gene', '4221', (36, 40))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('MEN1 tumours', 'Disease', (70, 82))	('MEN1 tumours', 'Disease', 'MESH:D018761', (70, 82))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
106706	25592387	Menin is a 610 amino acid protein with no homology to other known proteins; its expression is ubiquitous and the mechanism of how loss of function of menin leads to MEN1 is still unclear.	('MEN1', 'Gene', (165, 169))	('MEN1', 'Gene', '4221', (165, 169))	('Menin', 'Gene', (0, 5))	('menin', 'Gene', '4221', (150, 155))	('Menin', 'Gene', '4221', (0, 5))	('loss', 'Var', (130, 134))	('menin', 'Gene', (150, 155))
106715	25592387	Interestingly, chromosomal rearrangements involving KMT2A lead to mixed-lineage leukaemia, and in this context menin was shown to be required for KMT2A-dependent oncogenic transformation.	('KMT2A', 'Gene', '4297', (146, 151))	('KMT2A', 'Gene', '4297', (52, 57))	('menin', 'Gene', (111, 116))	('leukaemia', 'Disease', (80, 89))	('chromosomal rearrangements', 'Var', (15, 41))	('lead to', 'Reg', (58, 65))	('KMT2A', 'Gene', (146, 151))	('KMT2A', 'Gene', (52, 57))	('menin', 'Gene', '4221', (111, 116))	('leukaemia', 'Disease', 'MESH:D007938', (80, 89))
106717	25592387	Hundreds of MEN1 mutations have been described, which are located along the whole coding region and splice sites of the gene.	('MEN1', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('MEN1', 'Gene', '4221', (12, 16))
106718	25592387	While most MEN1 cases are familial, 10 % of cases occur in a non-familial context and are due to de novo MEN1 mutations.	('MEN1', 'Gene', (11, 15))	('mutations', 'Var', (110, 119))	('MEN1', 'Gene', '4221', (11, 15))	('MEN1', 'Gene', (105, 109))	('MEN1', 'Gene', '4221', (105, 109))	('occur', 'Reg', (50, 55))
106719	25592387	The majority of mutations leading to MEN1 are frameshift deletions or insertions and nonsense mutations leading to truncation or absence of the protein.	('absence', 'NegReg', (129, 136))	('protein', 'Protein', (144, 151))	('frameshift deletions', 'Var', (46, 66))	('mutations', 'Var', (16, 25))	('MEN1', 'Gene', (37, 41))	('MEN1', 'Gene', '4221', (37, 41))	('truncation', 'MPA', (115, 125))
106720	25592387	Missense mutations leading to single amino acid substitutions were assumed to cause less severely impaired protein function, but no notable difference was observed in clinical manifestation of those patients.	('protein', 'Protein', (107, 114))	('patients', 'Species', '9606', (199, 207))	('Missense mutations', 'Var', (0, 18))
106721	25592387	Some mutations leading to single amino acid substitutions were demonstrated to lead to proteasomal degradation and hence markedly reduced protein levels, while other mutations lead to nonsense-mediated mRNA decay.	('protein levels', 'MPA', (138, 152))	('rat', 'Species', '10116', (70, 73))	('proteasomal degradation', 'MPA', (87, 110))	('mutations', 'Var', (5, 14))	('reduced', 'NegReg', (130, 137))	('nonsense-mediated mRNA decay', 'MPA', (184, 212))	('lead to', 'Reg', (79, 86))	('single amino acid substitutions', 'Var', (26, 57))	('lead to', 'Reg', (176, 183))
106722	25592387	A reduction of interaction capacity of menin with its binding partners was also shown for some mutations leading to single amino acid substitutions.	('menin', 'Gene', '4221', (39, 44))	('reduction', 'NegReg', (2, 11))	('menin', 'Gene', (39, 44))	('mutations', 'Var', (95, 104))	('interaction', 'Interaction', (15, 26))	('binding', 'Interaction', (54, 61))	('single amino acid substitutions', 'Var', (116, 147))
106725	25592387	Due to the large number of different mutations in combination with the heterogeneity of disease manifestations it has proved difficult to establish subtle genotype-phenotype correlations in MEN1.	('MEN1', 'Gene', '4221', (190, 194))	('mutations', 'Var', (37, 46))	('MEN1', 'Gene', (190, 194))
106726	25592387	One study found that all patients with frameshift mutations have PNETs, while another study showed a higher rate of malignant tumours for mutations in MEN1 exons 2, 9 and 10.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('MEN1', 'Gene', (151, 155))	('rat', 'Species', '10116', (108, 111))	('MEN1', 'Gene', '4221', (151, 155))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('malignant tumours', 'Disease', 'MESH:D009369', (116, 133))	('malignant tumours', 'Disease', (116, 133))	('patients', 'Species', '9606', (25, 33))	('frameshift mutations', 'Var', (39, 59))	('PNETs', 'Disease', (65, 70))	('mutations in', 'Var', (138, 150))
106728	25592387	In addition, studies of unrelated kindreds with the same mutation showed large variability of different MEN1 associated tumours, and there are reports of identical twins with different MEN1 manifestations.	('mutation', 'Var', (57, 65))	('MEN1', 'Gene', (185, 189))	('MEN1', 'Gene', (104, 108))	('MEN1', 'Gene', '4221', (104, 108))	('MEN1', 'Gene', '4221', (185, 189))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
106729	25592387	Remarkably, some families with particular MEN1 mutations develop only isolated hyperparathyroidism, while the same mutations in other families lead to full MEN1.	('MEN1', 'Gene', (42, 46))	('MEN1', 'Gene', '4221', (42, 46))	('MEN1', 'Gene', (156, 160))	('mutations', 'Var', (47, 56))	('MEN1', 'Gene', '4221', (156, 160))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (79, 98))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (79, 98))	('hyperparathyroidism', 'Disease', (79, 98))	('isolated hyperparathyroidism', 'Phenotype', 'HP:0008200', (70, 98))
106730	25592387	Epigenetic mechanisms caused by environmental factors may influence disease phenotype in patients carrying the same MEN1 mutation.	('disease', 'MPA', (68, 75))	('Epigenetic', 'Var', (0, 10))	('patients', 'Species', '9606', (89, 97))	('mutation', 'Var', (121, 129))	('influence', 'Reg', (58, 67))	('MEN1', 'Gene', '4221', (116, 120))	('MEN1', 'Gene', (116, 120))
106731	25592387	Recently, a specific variant of the CDKN1B gene was demonstrated to be disease modifying in MEN1 patients with truncating MEN1 mutations, causing a higher number of MEN1 related tumours.	('MEN1', 'Gene', (165, 169))	('MEN1', 'Gene', '4221', (165, 169))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('causing', 'Reg', (138, 145))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('MEN1', 'Gene', (92, 96))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('CDKN1B', 'Gene', (36, 42))	('CDKN1B', 'Gene', '1027', (36, 42))	('tumours', 'Disease', (178, 185))	('MEN1', 'Gene', '4221', (92, 96))	('rat', 'Species', '10116', (59, 62))	('mutations', 'Var', (127, 136))	('MEN1', 'Gene', '4221', (122, 126))	('MEN1', 'Gene', (122, 126))	('patients', 'Species', '9606', (97, 105))
106733	25592387	A rat model displaying a MEN1-like phenotype was discovered to harbour a mutation in the CDKN1B gene, leading to premature termination.	('CDKN1B', 'Gene', (89, 95))	('MEN1', 'Gene', '4221', (25, 29))	('rat', 'Species', '10116', (2, 5))	('premature termination', 'MPA', (113, 134))	('CDKN1B', 'Gene', '1027', (89, 95))	('mutation', 'Var', (73, 81))	('MEN1', 'Gene', (25, 29))
106736	25592387	In a small number (up to 3 %) of MEN1 mutation-negative patients fulfilling the diagnostic criteria for MEN1, mutations in CDKN1B have been detected and the corresponding clinical syndrome has been termed MEN4 (MIM#610755).	('CDKN1B', 'Gene', (123, 129))	('MEN1', 'Gene', (104, 108))	('patients', 'Species', '9606', (56, 64))	('MEN1', 'Gene', '4221', (104, 108))	('mutations', 'Var', (110, 119))	('MEN1', 'Gene', (33, 37))	('MEN4', 'Gene', '1027', (205, 209))	('MEN1', 'Gene', '4221', (33, 37))	('CDKN1B', 'Gene', '1027', (123, 129))	('MEN4', 'Gene', (205, 209))	('detected', 'Reg', (140, 148))
106737	25592387	Mutations in some of those patients were shown to either lead to decreased cellular levels of p27Kip1 by reduced translation or proteasomal degradation, or to functional defects causing reduced binding to interacting partners or decreased nuclear localisation.	('nuclear localisation', 'MPA', (239, 259))	('decreased', 'NegReg', (65, 74))	('defects', 'NegReg', (170, 177))	('p27Kip1', 'Gene', '1027', (94, 101))	('reduced', 'NegReg', (186, 193))	('translation', 'MPA', (113, 124))	('patients', 'Species', '9606', (27, 35))	('Mutations', 'Var', (0, 9))	('proteasomal degradation', 'MPA', (128, 151))	('reduced', 'NegReg', (105, 112))	('interacting partners', 'Interaction', (205, 225))	('decreased', 'NegReg', (229, 238))	('p27Kip1', 'Gene', (94, 101))	('cellular levels', 'MPA', (75, 90))	('binding', 'Interaction', (194, 201))
106738	25592387	Interestingly, a novel mechanism of CDKN1B loss of function leading to MEN4 was recently discovered: a 4 bp deletion in an upstream ORF within the CDKN1B 5'UTR led to decreased translation reinitiation and decreased p27Kip1 levels.	('translation reinitiation', 'MPA', (177, 201))	('loss of function', 'NegReg', (43, 59))	('p27Kip1', 'Gene', '1027', (216, 223))	('CDKN1B', 'Gene', (147, 153))	('MEN4', 'Gene', (71, 75))	('MEN4', 'Gene', '1027', (71, 75))	('decreased', 'NegReg', (206, 215))	('CDKN1B', 'Gene', '1027', (36, 42))	('p27Kip1', 'Gene', (216, 223))	('CDKN1B', 'Gene', (36, 42))	('CDKN1B', 'Gene', '1027', (147, 153))	('deletion', 'Var', (108, 116))	('decreased', 'NegReg', (167, 176))
106745	25592387	The majority of CNC cases are caused by inactivating germline mutations in the type 1alpha regulatory subunit of protein kinase A (PRKAR1A) gene, and those mutations lead to CNC with a penetrance close to 100 %.	('CNC', 'Disease', (174, 177))	('inactivating germline mutations', 'Var', (40, 71))	('CNC', 'Disease', (16, 19))	('mutations', 'Var', (156, 165))	('PRKAR1A', 'Gene', '5573', (131, 138))	('caused by', 'Reg', (30, 39))	('lead to', 'Reg', (166, 173))	('PRKAR1A', 'Gene', (131, 138))
106750	25592387	It should be noted that most CNC patients with PPNAD have a paradoxical increase of cortisol secretion after dexamethasone administration, which is diagnostically particularly useful in patients with normal baseline cortisol levels.	('cortisol', 'Chemical', 'MESH:D006854', (84, 92))	('cortisol secretion', 'MPA', (84, 102))	('dexamethasone', 'Chemical', 'MESH:D003907', (109, 122))	('increase', 'PosReg', (72, 80))	('rat', 'Species', '10116', (131, 134))	('patients', 'Species', '9606', (33, 41))	('PPNAD', 'Chemical', '-', (47, 52))	('patients', 'Species', '9606', (186, 194))	('cortisol', 'Chemical', 'MESH:D006854', (216, 224))	('PPNAD', 'Var', (47, 52))	('CNC', 'Disease', (29, 32))
106775	25592387	R1alpha deficiency leads to decreased SMAD3 expression, thereby reducing transforming growth factor beta (TGFbeta)-mediated apoptosis in adrenocortical cells.	('reducing', 'NegReg', (64, 72))	('SMAD3', 'Gene', '4088', (38, 43))	('expression', 'MPA', (44, 54))	('decreased', 'NegReg', (28, 37))	('adrenocortical', 'Disease', 'MESH:D018268', (137, 151))	('SMAD3', 'Gene', (38, 43))	('R1alpha', 'Protein', (0, 7))	('TGFbeta', 'Gene', (106, 113))	('transforming growth factor beta', 'Gene', '7040', (73, 104))	('deficiency', 'Var', (8, 18))	('TGFbeta', 'Gene', '7040', (106, 113))	('transforming growth factor beta', 'Gene', (73, 104))	('adrenocortical', 'Disease', (137, 151))
106776	25592387	In addition, MAPK pathway activity was shown to increase in response to inactivating PRKAR1A mutations, causing increased cell proliferation.	('inactivating', 'Var', (72, 84))	('PRKAR1A', 'Gene', (85, 92))	('mutations', 'Var', (93, 102))	('rat', 'Species', '10116', (134, 137))	('PRKAR1A', 'Gene', '5573', (85, 92))	('increased', 'PosReg', (112, 121))	('MAPK pathway', 'Pathway', (13, 25))	('activity', 'MPA', (26, 34))	('cell proliferation', 'CPA', (122, 140))	('increase', 'PosReg', (48, 56))
106777	25592387	Interestingly, some CNC patients with PPNAD have somatic mutations in the beta-catenin gene (CTNNB1) within the adrenal nodules, which is the main effector of the Wnt signalling pathway.	('CTNNB1', 'Gene', '1499', (93, 99))	('patients', 'Species', '9606', (24, 32))	('mutations', 'Var', (57, 66))	('beta-catenin', 'Gene', (74, 86))	('PPNAD', 'Chemical', '-', (38, 43))	('CTNNB1', 'Gene', (93, 99))	('PPNAD', 'Disease', (38, 43))	('beta-catenin', 'Gene', '1499', (74, 86))
106778	25592387	More than 120 different PRKAR1A mutations have been identified to date in CNC patients.	('PRKAR1A', 'Gene', '5573', (24, 31))	('patients', 'Species', '9606', (78, 86))	('PRKAR1A', 'Gene', (24, 31))	('mutations', 'Var', (32, 41))	('CNC', 'Disease', (74, 77))
106780	25592387	Almost all mutations generate a premature stop codon, either directly or by frameshift, leading to nonsense-mediated mRNA decay and absence of the R1alpha protein, although some PRKAR1A mutations in CNC were demonstrated to lead to expressed R1alpha that had lost its inhibitory effect on PKA signalling.	('mutations', 'Var', (11, 20))	('R1alpha', 'Protein', (147, 154))	('frameshift', 'Var', (76, 86))	('CNC', 'Gene', (199, 202))	('mutations', 'Var', (186, 195))	('rat', 'Species', '10116', (215, 218))	('PRKAR1A', 'Gene', (178, 185))	('lead', 'Reg', (224, 228))	('PRKAR1A', 'Gene', '5573', (178, 185))	('rat', 'Species', '10116', (25, 28))	('R1alpha', 'Protein', (242, 249))	('absence', 'NegReg', (132, 139))	('nonsense-mediated mRNA decay', 'MPA', (99, 127))
106781	25592387	No obvious genotype-phenotype correlation could initially be detected in CNC patients with different PRKAR1A mutations; most different mutations invariably lead to the absence of the R1alpha protein.	('R1alpha protein', 'Protein', (183, 198))	('PRKAR1A', 'Gene', '5573', (101, 108))	('absence', 'NegReg', (168, 175))	('patients', 'Species', '9606', (77, 85))	('mutations', 'Var', (109, 118))	('PRKAR1A', 'Gene', (101, 108))
106783	25592387	In addition, PRKAR1A mutation carriers manifest with myxomas, thyroid tumours, schwannomas and Sertoli cell tumours more frequently and generally present earlier than CNC patients where no PRKAR1A mutations were found.	('Sertoli cell', 'Phenotype', 'HP:0100619', (95, 107))	('PRKAR1A', 'Gene', '5573', (189, 196))	('schwannomas and Sertoli cell tumours', 'Disease', 'MESH:D012707', (79, 115))	('PRKAR1A', 'Gene', (13, 20))	('myxomas', 'Disease', (53, 60))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('PRKAR1A', 'Gene', '5573', (13, 20))	('mutation', 'Var', (21, 29))	('patients', 'Species', '9606', (171, 179))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('PRKAR1A', 'Gene', (189, 196))	('thyroid tumours', 'Disease', 'MESH:D013964', (62, 77))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('schwannomas', 'Phenotype', 'HP:0100008', (79, 90))	('thyroid tumours', 'Disease', (62, 77))	('myxomas', 'Disease', 'MESH:D009232', (53, 60))
106789	25592387	MEN1-associated pituitary adenomas and FIPAs due to AIP mutations are more aggressive than sporadic PAs, with more frequent macroadenomas and a younger age at manifestation in AIP-associated FIPAs.	('MEN1', 'Gene', '4221', (0, 4))	('macroadenomas', 'Disease', (124, 137))	('MEN1', 'Gene', (0, 4))	('AIP', 'Gene', '9049', (52, 55))	('mutations', 'Var', (56, 65))	('PAs', 'Disease', 'MESH:D011471', (193, 196))	('PAs', 'Disease', (100, 103))	('PAs', 'Disease', 'MESH:D011471', (41, 44))	('PAs', 'Phenotype', 'HP:0002893', (100, 103))	('macroadenomas', 'Disease', 'None', (124, 137))	('AIP', 'Gene', '9049', (176, 179))	('AIP', 'Gene', (52, 55))	('PAs', 'Disease', (193, 196))	('PAs', 'Phenotype', 'HP:0002893', (193, 196))	('AIP', 'Gene', (176, 179))	('PAs', 'Disease', (41, 44))	('pituitary adenomas', 'Disease', 'MESH:D010911', (16, 34))	('PAs', 'Disease', 'MESH:D011471', (100, 103))	('PAs', 'Phenotype', 'HP:0002893', (41, 44))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (16, 34))	('pituitary adenomas', 'Disease', (16, 34))
106798	23925558	Ki-67 and p27 were the markers that exhibited the highest discriminative power for differential diagnosis between carcinomas and all type of adenomas, while IGF2 and StAR were only found to be useful for differentiating between carcinomas and ACAn and between carcinomas and ACAc respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('carcinomas', 'Disease', 'MESH:D002277', (114, 124))	('carcinomas', 'Disease', (228, 238))	('adenomas', 'Disease', 'MESH:D000236', (141, 149))	('carcinomas', 'Disease', (260, 270))	('Ki-67', 'Var', (0, 5))	('adenomas', 'Disease', (141, 149))	('IGF2', 'Gene', '3481', (157, 161))	('StAR', 'Gene', (166, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('carcinomas', 'Disease', (114, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (228, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('carcinomas', 'Disease', 'MESH:D002277', (228, 238))	('carcinomas', 'Phenotype', 'HP:0030731', (260, 270))	('carcinomas', 'Disease', 'MESH:D002277', (260, 270))	('StAR', 'Gene', '6770', (166, 170))	('p27', 'Gene', '3429', (10, 13))	('p27', 'Gene', (10, 13))	('ACAc', 'Disease', (275, 279))	('IGF2', 'Gene', (157, 161))
106824	23925558	Then, the samples were incubated overnight at 4  C with the appropriate primary antibodies: rabbit anti-human polyclonal antibodies to StAR (HPA023644; 1:100; Atlas Antibodies, Stockholm, Sweden), IGF2 (ab9574; 1:100; Abcam, Cambridge, UK), MDM2 (ab15471; 1:100; Abcam), and IGF1R (ab39675; 1:100; Abcam), The samples were then incubated with secondary antibodies at 1:200 dilution (polyclonal swine anti-rabbit, Dako, Glostrup, Denmark) for 30 min, followed by incubation with an avidin-biotin peroxidase complex (1:100; Vector Laboratories, Inc., Peterborough, UK) for 30 min.	('IGF2', 'Gene', '3481', (197, 201))	('IGF1R', 'Gene', '3480', (275, 280))	('StAR', 'Gene', '6770', (135, 139))	('rabbit', 'Species', '9986', (92, 98))	('rabbit', 'Species', '9986', (405, 411))	('human', 'Species', '9606', (104, 109))	('IGF2', 'Gene', (197, 201))	('MDM2', 'Gene', '4193', (241, 245))	('StAR', 'Gene', (135, 139))	('MDM2', 'Gene', (241, 245))	('IGF1R', 'Gene', (275, 280))	('ab15471;', 'Var', (247, 255))	('swine', 'Species', '9823', (394, 399))
106849	23925558	The differential diagnosis of benign (ACA) and malignant (ACC) tumors of the adrenal cortex is currently based on several histological parameters according to the Weiss scoring system, in which tumors with scores equal to or below two are classified as benign and those with scores equal to or above four as malignant.	('scores equal', 'Var', (206, 218))	('tumors of the adrenal cortex', 'Disease', 'MESH:D000303', (63, 91))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors of the adrenal cortex', 'Disease', (63, 91))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Disease', (194, 200))
106863	23925558	p53 is a tumor suppressor gene and encodes a protein that promotes DNA repair; MDM2 is a protein that inactivates p53 by binding to both the wild-type p53 and the mutated p53 protein; and p21 is a cyclin-dependent kinase inhibitor (CDKi) induced by p53, which when overexpressed triggers cell cycle arrest in proliferating cells.	('DNA repair', 'MPA', (67, 77))	('p53', 'Gene', (114, 117))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (288, 305))	('p53', 'Gene', (249, 252))	('inactivates', 'NegReg', (102, 113))	('p53', 'Gene', '7157', (151, 154))	('protein', 'Protein', (175, 182))	('p53', 'Gene', '7157', (0, 3))	('cyclin-dependent kinase inhibitor', 'Gene', (197, 230))	('mutated', 'Var', (163, 170))	('tumor', 'Disease', (9, 14))	('p21', 'Gene', (188, 191))	('p53', 'Gene', (151, 154))	('p53', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('CDKi', 'Gene', (232, 236))	('promotes', 'PosReg', (58, 66))	('cyclin-dependent kinase inhibitor', 'Gene', '1033', (197, 230))	('binding', 'Interaction', (121, 128))	('MDM2', 'Gene', (79, 83))	('cell cycle arrest', 'CPA', (288, 305))	('p53', 'Gene', '7157', (171, 174))	('p53', 'Gene', '7157', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('CDKi', 'Gene', '1033', (232, 236))	('MDM2', 'Gene', '4193', (79, 83))	('p53', 'Gene', '7157', (249, 252))	('p21', 'Gene', '1026', (188, 191))	('p53', 'Gene', (171, 174))
106864	23925558	Although no significant results were obtained for the p53 protein, we observed that some ACC samples exhibited a very high expression of this protein, which indicates the presence of p53 mutations in these cases; however, other samples exhibited low expression, and it was this heterogeneity of p53 staining in the ACC samples that resulted in the difference between ACC and ACA samples for this marker not being significant.	('presence', 'Reg', (171, 179))	('p53', 'Gene', '7157', (295, 298))	('expression', 'MPA', (123, 133))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '7157', (183, 186))	('p53', 'Gene', (54, 57))	('mutations', 'Var', (187, 196))	('p53', 'Gene', '7157', (54, 57))	('ACC', 'Disease', (89, 92))	('p53', 'Gene', (295, 298))
106882	23925558	An alternative hypothesis is that p27 gene could have mutations, resulting in a modified p27 protein that could have a still unknown role in tumorigenesis or tumor progression.	('p27', 'Gene', '3429', (89, 92))	('p27', 'Gene', (89, 92))	('modified', 'Var', (80, 88))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('p27', 'Gene', '3429', (34, 37))	('p27', 'Gene', (34, 37))	('protein', 'Protein', (93, 100))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
106883	23925558	However, p27 mutations have been described as a very rare phenomenon in human cancer.	('cancer', 'Disease', (78, 84))	('human', 'Species', '9606', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('p27', 'Gene', '3429', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (13, 22))	('p27', 'Gene', (9, 12))
106929	23866946	The primers used were as follows: SMAD2 (220 bp), F 5'-GTTCCTGCCTTTGCTGAGAC-3' and R 5'-TCTCTTTGCCAGGAATGCTT-3'; SMAD3 (176 bp), F 5'-TGCTGGTGACTGGATAGCAG-3' and R 5'-CTCCTTGGAAGGTGCTGAAG-3'; CTNNB1 (530 bp), F 5'-GTTCGTGCACATCAGGATAC-3' and R 5'-CGATAGCTAGGATCATCCTG -3; LRP5 (438 bp), F 5'-GCAAGAAGCTGTACTGGACG-3' and R 5'-TGTTGCAGGCATGGATGGAG-3'.	('SMAD3', 'Gene', (113, 118))	('GATA', 'Gene', (229, 233))	('SMAD2', 'Gene', (34, 39))	('SMAD2', 'Gene', '4087', (34, 39))	('SMAD3', 'Gene', '4088', (113, 118))	('GATA', 'Gene', '55278', (229, 233))	('438', 'Var', (278, 281))	('LRP5', 'Gene', '4041', (272, 276))	('GATA', 'Gene', (248, 252))	('LRP5', 'Gene', (272, 276))	('GATA', 'Gene', (146, 150))	('GATA', 'Gene', '55278', (248, 252))	('GATA', 'Gene', '55278', (146, 150))
106939	23866946	We opted to study these co-receptors instead of the Frizzled family receptors also involved in adrenocortical Wnt pathway since the presence of LRP5/6 in the receptor complex is thought to be more specific for canonical CTNNB1 mediated signaling.	('LRP5/6', 'Gene', '4041;4040', (144, 150))	('presence', 'Var', (132, 140))	('Wnt', 'Gene', '114487', (110, 113))	('LRP5/6', 'Gene', (144, 150))	('Wnt', 'Gene', (110, 113))	('adrenocortical', 'Disease', (95, 109))	('adrenocortical', 'Disease', 'MESH:D018268', (95, 109))
106964	23866946	In childhood ACC amplification and overexpression of the SF1 gene have also been detected.	('overexpression', 'PosReg', (35, 49))	('SF1', 'Gene', '7536', (57, 60))	('SF1', 'Gene', (57, 60))	('amplification', 'Var', (17, 30))
106968	23866946	Interestingly, when Smad3 was also knocked out in the Inha-/- mice, tumor progression was attenuated.	('tumor', 'Disease', (68, 73))	('knocked out', 'Var', (35, 46))	('mice', 'Species', '10090', (62, 66))	('attenuated', 'NegReg', (90, 100))	('Smad3', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
106983	33219221	Dysregulation of long non-coding RNA plays important roles in the development of adrenocortical carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('Dysregulation', 'Var', (0, 13))	('adrenocortical carcinoma', 'Disease', (81, 105))	('long non-coding RNA', 'Protein', (17, 36))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (81, 105))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (81, 105))
106984	33219221	Here, we found that lncRNA ASB16-AS1 was down-regulated in adrenocortical carcinoma and ASB16-AS1 functions as tumor suppressor in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (59, 83))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (59, 83))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('down-regulated', 'NegReg', (41, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('tumor', 'Disease', (111, 116))	('ASB16-AS1', 'Var', (88, 97))	('ASB16-AS1', 'Gene', (27, 36))	('adrenocortical carcinoma', 'Disease', (59, 83))	('lncRNA', 'MPA', (20, 26))
106987	33219221	Also, ASB16-AS1 inhibits HuR expression post-translationally by promoting its ubiquitination.	('ubiquitination', 'MPA', (78, 92))	('HuR', 'Gene', '1994', (25, 28))	('ASB16-AS1', 'Var', (6, 15))	('inhibits', 'NegReg', (16, 24))	('HuR', 'Gene', (25, 28))	('promoting', 'PosReg', (64, 73))
106989	33219221	We then found that inhibition of ASB16-AS1 attenuates the binding of ubiquitin E3 ligase BTRC to HuR and subsequently inhibits HuR protein unbiquitination and degradation.	('binding', 'Interaction', (58, 65))	('inhibition', 'Var', (19, 29))	('degradation', 'MPA', (159, 170))	('HuR', 'Gene', (97, 100))	('HuR', 'Gene', '1994', (97, 100))	('inhibits', 'NegReg', (118, 126))	('BTRC', 'Gene', '8945', (89, 93))	('attenuates', 'NegReg', (43, 53))	('BTRC', 'Gene', (89, 93))	('ASB16-AS1', 'Gene', (33, 42))	('HuR', 'Gene', (127, 130))	('HuR', 'Gene', '1994', (127, 130))
106990	33219221	BTRC knock-down could reverse the effect of AB16-AS1 on HuR, CDK6, and IGF1R levels.	('IGF1R', 'Gene', (71, 76))	('CDK6', 'Gene', (61, 65))	('knock-down', 'Var', (5, 15))	('CDK6', 'Gene', '1021', (61, 65))	('AB16-AS1', 'Gene', (44, 52))	('HuR', 'Gene', (56, 59))	('HuR', 'Gene', '1994', (56, 59))	('BTRC', 'Gene', '8945', (0, 4))	('IGF1R', 'Gene', '3480', (71, 76))	('BTRC', 'Gene', (0, 4))
106995	33219221	LncRNAs participate in diverse cellular processes and dysregulation of lncRNAs results in the pathogenesis of many diseases including cancer.	('lncRNAs', 'Gene', (71, 78))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('results in', 'Reg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('dysregulation', 'Var', (54, 67))
107005	33219221	In this study, we found that ASB16-AS1 was down-regulated in adrenocortical carcinoma, and inhibition of the expression of ASB16-AS1 promotes cell proliferation in vitro.	('down-regulated', 'NegReg', (43, 57))	('promotes', 'PosReg', (133, 141))	('expression', 'MPA', (109, 119))	('inhibition', 'Var', (91, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('ASB16-AS1', 'Gene', (123, 132))	('adrenocortical carcinoma', 'Disease', (61, 85))	('cell proliferation', 'CPA', (142, 160))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (61, 85))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (61, 85))	('ASB16-AS1', 'Gene', (29, 38))
107007	33219221	We then found that IGF1R and CDK6 were up-regulated upon knockdown of ASB16-AS1 in adrenocortical carcinoma cells.	('IGF1R', 'Gene', (19, 24))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (83, 107))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (83, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('IGF1R', 'Gene', '3480', (19, 24))	('knockdown', 'Var', (57, 66))	('up-regulated', 'PosReg', (39, 51))	('ASB16-AS1', 'Gene', (70, 79))	('adrenocortical carcinoma', 'Disease', (83, 107))	('CDK6', 'Gene', (29, 33))	('CDK6', 'Gene', '1021', (29, 33))
107008	33219221	ASB16-AS1 associates with HuR protein and ASB16-AS1 regulates the expression of IGF1R and CDK6 through HuR.	('IGF1R', 'Gene', (80, 85))	('ASB16-AS1', 'Var', (42, 51))	('IGF1R', 'Gene', '3480', (80, 85))	('HuR', 'Gene', (103, 106))	('HuR', 'Gene', '1994', (103, 106))	('expression', 'MPA', (66, 76))	('regulates', 'Reg', (52, 61))	('HuR', 'Gene', (26, 29))	('HuR', 'Gene', '1994', (26, 29))	('CDK6', 'Gene', (90, 94))	('CDK6', 'Gene', '1021', (90, 94))
107063	33219221	Adrenocortical carcinoma cells stably expressing ASB16-AS1 were injected subcutaneously into the flank region of the mice.	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (0, 24))	('ASB16-AS1', 'Var', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (0, 24))	('mice', 'Species', '10090', (117, 121))	('Adrenocortical carcinoma', 'Disease', (0, 24))
107074	33219221	The results demonstrate that inhibition of endogenous ASB16-AS1 significantly promotes adrenocortical carcinoma cell proliferation in vitro as determined by CCK-8 and EdU incorporation assay (Fig.	('promotes', 'PosReg', (78, 86))	('adrenocortical carcinoma', 'Disease', (87, 111))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (87, 111))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (87, 111))	('CCK-8', 'Chemical', 'MESH:D012844', (157, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('EdU', 'Chemical', '-', (167, 170))	('inhibition', 'Var', (29, 39))	('ASB16-AS1', 'Gene', (54, 63))
107076	33219221	In summary, these data indicate that inhibition of ASB16-AS1 promotes cell proliferation and cell cycle progression in adrenocortical carcinoma cells in vitro.	('inhibition', 'Var', (37, 47))	('cell cycle progression', 'CPA', (93, 115))	('promotes', 'PosReg', (61, 69))	('adrenocortical carcinoma', 'Disease', (119, 143))	('cell proliferation', 'CPA', (70, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('ASB16-AS1', 'Gene', (51, 60))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (119, 143))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (119, 143))
107084	33219221	All of these data indicates that ASB16-AS1 inhibits tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('ASB16-AS1', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('inhibits', 'NegReg', (43, 51))
107087	33219221	We validated the RNA-sequencing results by qRT-PCR and the results demonstrate that IGF1R and CDK6 mRNA levels were increased upon knockdown of ASB16-AS1 (Fig.	('IGF1R', 'Gene', (84, 89))	('knockdown', 'Var', (131, 140))	('IGF1R', 'Gene', '3480', (84, 89))	('ASB16-AS1', 'Gene', (144, 153))	('increased', 'PosReg', (116, 125))	('CDK6', 'Gene', (94, 98))	('CDK6', 'Gene', '1021', (94, 98))
107093	33219221	We fractionated adrenocortical carcinoma cell cytoplasm and nucleus, and found that ASB16-AS1 is distributed both in the cytoplasm and nucleus abundantly (Supplementary Fig.	('adrenocortical carcinoma', 'Disease', (16, 40))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (16, 40))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (16, 40))	('ASB16-AS1', 'Var', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
107098	33219221	The results demonstrate that HuR exists in ASB16-AS1 captured precipitates rather than antisense ASB16-AS1 counterparts as revealed by immunobloting (Fig.	('ASB16-AS1', 'Var', (43, 52))	('HuR', 'Gene', (29, 32))	('HuR', 'Gene', '1994', (29, 32))
107100	33219221	The results turned out that ASB16-AS1 was significantly enriched in HuR antibody captured precipitates compared with IgG control (Fig.	('ASB16-AS1', 'Var', (28, 37))	('HuR', 'Gene', (68, 71))	('HuR', 'Gene', '1994', (68, 71))
107107	33219221	Our results showed that knockdown of ASB16-AS1 had no effect on HuR mRNA expression which is consistent with our RNA-sequencing results.	('HuR', 'Gene', (64, 67))	('HuR', 'Gene', '1994', (64, 67))	('knockdown', 'Var', (24, 33))	('ASB16-AS1', 'Gene', (37, 46))
107108	33219221	However, HuR protein levels are significantly elevated upon knockdown of ASB16-AS1 (Fig.	('elevated', 'PosReg', (46, 54))	('HuR', 'Gene', '1994', (9, 12))	('ASB16-AS1', 'Gene', (73, 82))	('HuR', 'Gene', (9, 12))	('knockdown', 'Var', (60, 69))
107115	33219221	We knocked down the expression of HuR in adrenocortical carcinoma cells and the results showed that inhibition of HuR reduced the stability of CDK6 and IGF1R mRNAs (Fig.	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (41, 65))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (41, 65))	('HuR', 'Gene', '1994', (34, 37))	('IGF1R', 'Gene', '3480', (152, 157))	('CDK6', 'Gene', (143, 147))	('HuR', 'Gene', (114, 117))	('reduced', 'NegReg', (118, 125))	('HuR', 'Gene', '1994', (114, 117))	('CDK6', 'Gene', '1021', (143, 147))	('inhibition', 'Var', (100, 110))	('adrenocortical carcinoma', 'Disease', (41, 65))	('IGF1R', 'Gene', (152, 157))	('stability', 'MPA', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('HuR', 'Gene', (34, 37))
107118	33219221	The results showed that inhibition of ASB16-AS1 enhanced CDK6 and IGF1R mRNAs stabilities, and this effect is abolished upon inhibition of HuR (Fig.	('CDK6', 'Gene', (57, 61))	('CDK6', 'Gene', '1021', (57, 61))	('ASB16-AS1', 'Gene', (38, 47))	('enhanced', 'PosReg', (48, 56))	('inhibition', 'Var', (24, 34))	('HuR', 'Gene', '1994', (139, 142))	('mRNAs stabilities', 'MPA', (72, 89))	('HuR', 'Gene', (139, 142))	('IGF1R', 'Gene', (66, 71))	('IGF1R', 'Gene', '3480', (66, 71))
107122	33219221	We employed a protein synthesis inhibitor cycloheximide (CHX) to treat adrenocortical carcinoma cells and the results showed that HuR protein degradation is significantly inhibited upon ASB16-AS1 knockdown (Fig.	('cycloheximide', 'Chemical', 'MESH:D003513', (42, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('adrenocortical carcinoma', 'Disease', (71, 95))	('inhibited', 'NegReg', (171, 180))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (71, 95))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (71, 95))	('CHX', 'Chemical', 'MESH:D003513', (57, 60))	('knockdown', 'Var', (196, 205))	('ASB16-AS1', 'Gene', (186, 195))	('HuR', 'Gene', (130, 133))	('HuR', 'Gene', '1994', (130, 133))
107127	33219221	The results demonstrate that HuR ubiquitination level decreased upon knockdown of endogenous ASB16-AS1 (Fig.	('HuR', 'Gene', (29, 32))	('decreased', 'NegReg', (54, 63))	('HuR', 'Gene', '1994', (29, 32))	('ASB16-AS1', 'Gene', (93, 102))	('knockdown', 'Var', (69, 78))
107130	33219221	The results turned out that inhibition of ASB16-AS1 reduces the interaction between BTRC and HuR.	('BTRC', 'Gene', '8945', (84, 88))	('HuR', 'Gene', '1994', (93, 96))	('BTRC', 'Gene', (84, 88))	('reduces', 'NegReg', (52, 59))	('inhibition', 'Var', (28, 38))	('HuR', 'Gene', (93, 96))	('ASB16-AS1', 'Gene', (42, 51))	('interaction', 'Interaction', (64, 75))
107132	33219221	In summary, these data demonstrate that ASB16-AS1 post-translationally inhibits HuR protein expression through E3 ligase BTRC-mediated ubiquitination and degradation.	('BTRC', 'Gene', (121, 125))	('E3 ligase', 'Enzyme', (111, 120))	('HuR', 'Gene', (80, 83))	('HuR', 'Gene', '1994', (80, 83))	('degradation', 'MPA', (154, 165))	('ASB16-AS1', 'Var', (40, 49))	('BTRC', 'Gene', '8945', (121, 125))	('inhibits', 'NegReg', (71, 79))
107133	33219221	ASB16-AS1 promoted the interaction between HuR and BTRC, suggesting BTRC is necessary for the effect of ASB16-AS1 on HuR, CDK6, and IGF1R.	('ASB16-AS1', 'Var', (0, 9))	('IGF1R', 'Gene', (132, 137))	('BTRC', 'Gene', '8945', (68, 72))	('IGF1R', 'Gene', '3480', (132, 137))	('ASB16-AS1', 'Var', (104, 113))	('HuR', 'Gene', (117, 120))	('CDK6', 'Gene', (122, 126))	('HuR', 'Gene', '1994', (117, 120))	('BTRC', 'Gene', (68, 72))	('promoted', 'PosReg', (10, 18))	('CDK6', 'Gene', '1021', (122, 126))	('BTRC', 'Gene', '8945', (51, 55))	('HuR', 'Gene', '1994', (43, 46))	('BTRC', 'Gene', (51, 55))	('HuR', 'Gene', (43, 46))	('interaction', 'Interaction', (23, 34))
107135	33219221	S3e, f) and knocked down BTRC expression in ASB16-AS1-overexpressed cells to test if BTRC knock-down could reverse the effect of AB16-AS1 on HuR, CDK6, and IGF1R levels.	('HuR', 'Gene', '1994', (141, 144))	('IGF1R', 'Gene', (156, 161))	('HuR', 'Gene', (141, 144))	('BTRC', 'Gene', '8945', (85, 89))	('IGF1R', 'Gene', '3480', (156, 161))	('BTRC', 'Gene', '8945', (25, 29))	('knocked', 'Reg', (12, 19))	('BTRC', 'Gene', (85, 89))	('CDK6', 'Gene', (146, 150))	('knock-down', 'Var', (90, 100))	('BTRC', 'Gene', (25, 29))	('CDK6', 'Gene', '1021', (146, 150))
107136	33219221	The results turned out that knock-down of BTRC abolished the down-regulation of HuR, CDK6, and IGF1R expression upon enhanced expression of ASB16-AS1 in adrenocortical carcinoma cells (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('expression', 'MPA', (126, 136))	('adrenocortical carcinoma', 'Disease', (153, 177))	('IGF1R', 'Gene', (95, 100))	('CDK6', 'Gene', (85, 89))	('down-regulation', 'NegReg', (61, 76))	('CDK6', 'Gene', '1021', (85, 89))	('knock-down', 'Var', (28, 38))	('BTRC', 'Gene', '8945', (42, 46))	('HuR', 'Gene', (80, 83))	('enhanced', 'PosReg', (117, 125))	('HuR', 'Gene', '1994', (80, 83))	('IGF1R', 'Gene', '3480', (95, 100))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (153, 177))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (153, 177))	('abolished', 'NegReg', (47, 56))	('BTRC', 'Gene', (42, 46))
107140	33219221	In addition, we found that inhibition of ASB16-AS1 inhibits HuR protein degradation by reducing the interaction between E3 ligase BTRC and HuR.	('BTRC', 'Gene', '8945', (130, 134))	('interaction', 'Interaction', (100, 111))	('inhibits', 'NegReg', (51, 59))	('reducing', 'NegReg', (87, 95))	('inhibition', 'Var', (27, 37))	('ASB16-AS1', 'Gene', (41, 50))	('HuR', 'Gene', '1994', (139, 142))	('HuR', 'Gene', (60, 63))	('BTRC', 'Gene', (130, 134))	('HuR', 'Gene', '1994', (60, 63))	('HuR', 'Gene', (139, 142))
107146	33219221	Our transcriptome RNA-sequencing results showed that inhibition of ASB16-AS1 promotes the expression of genes involved in cell cycle progression and cell proliferation in adrenocortical carcinoma cells.	('inhibition', 'Var', (53, 63))	('ASB16-AS1', 'Gene', (67, 76))	('promotes', 'PosReg', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (171, 195))	('adrenocortical carcinoma', 'Disease', (171, 195))	('expression', 'MPA', (90, 100))	('cell proliferation', 'CPA', (149, 167))	('cell cycle', 'CPA', (122, 132))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (171, 195))
107148	33219221	Studies have found that dysregulation of lncRNAs plays a vital role in tumor initiation and progression, however, the molecular mechanism that a lncRNA exerts its function is complex and remains to be challenge to clarify.	('tumor initiation', 'Disease', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('dysregulation', 'Var', (24, 37))	('tumor initiation', 'Disease', 'MESH:D009369', (71, 87))
107153	33219221	Dysregulation of ubiquitination affects tumor cell cycle regulation, gene expression, and tumor progression.	('affects', 'Reg', (32, 39))	('ubiquitination', 'MPA', (17, 31))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('gene expression', 'MPA', (69, 84))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
107157	33219221	LINC01638 interacts with c-Myc and inhibit E3 ubiquitin ligase adapter speckle-type POZ (SPOP)-mediated protein degradation of c-Myc in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('c-Myc', 'Gene', (127, 132))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('c-Myc', 'Gene', (25, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('LINC01638', 'Var', (0, 9))	('E3 ubiquitin ligase', 'Enzyme', (43, 62))	('LINC01638', 'Chemical', '-', (0, 9))	('interacts', 'Interaction', (10, 19))	('inhibit', 'NegReg', (35, 42))	('c-Myc', 'Gene', '4609', (127, 132))	('c-Myc', 'Gene', '4609', (25, 30))
107158	33219221	LINC02023 binds with PTEN and prevents degradation which is mediated by E3 ubiquitin ligase WWP2 in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('LINC02023', 'Var', (0, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('prevents', 'NegReg', (30, 38))	('colorectal cancer', 'Disease', (100, 117))	('degradation', 'MPA', (39, 50))	('WWP2', 'Gene', (92, 96))	('WWP2', 'Gene', '11060', (92, 96))	('PTEN', 'Gene', (21, 25))	('PTEN', 'Gene', '5728', (21, 25))	('binds', 'Interaction', (10, 15))
107166	33219221	In this study, we found that lncRNA ASB16-AS1 inhibits adrenocortical carcinoma cell cycle progression and cell proliferation by inhibiting CDK6 and IGFR expressions, which is mediated by RNA-binding protein HuR.	('lncRNA ASB16-AS1', 'Var', (29, 45))	('inhibiting', 'NegReg', (129, 139))	('expressions', 'MPA', (154, 165))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (55, 79))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (55, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('inhibits', 'NegReg', (46, 54))	('IGFR', 'Gene', (149, 153))	('CDK6', 'Gene', (140, 144))	('cell proliferation', 'CPA', (107, 125))	('HuR', 'Gene', '1994', (208, 211))	('CDK6', 'Gene', '1021', (140, 144))	('HuR', 'Gene', (208, 211))	('adrenocortical carcinoma', 'Disease', (55, 79))	('RNA-binding protein', 'Gene', '27303', (188, 207))	('IGFR', 'Gene', '3480', (149, 153))	('RNA-binding protein', 'Gene', (188, 207))
107174	33219221	Our data demonstrate that HuR interacts with IGF1R mRNA, knockdown of HuR reduces IGF1R mRNA and subsequently protein expression.	('IGF1R', 'Gene', '3480', (45, 50))	('IGF1R', 'Gene', (82, 87))	('HuR', 'Gene', (70, 73))	('knockdown', 'Var', (57, 66))	('HuR', 'Gene', '1994', (70, 73))	('protein expression', 'MPA', (110, 128))	('mRNA', 'MPA', (88, 92))	('IGF1R', 'Gene', '3480', (82, 87))	('HuR', 'Gene', (26, 29))	('IGF1R', 'Gene', (45, 50))	('HuR', 'Gene', '1994', (26, 29))	('reduces', 'NegReg', (74, 81))
107178	32675277	A rare TP53 mutation predominant in Ashkenazi Jews confers risk of multiple cancers Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li Fraumeni Syndrome (LFS).	('Li Fraumeni Syndrome', 'Disease', (157, 177))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('TP53', 'Gene', '7157', (7, 11))	('Li Fraumeni Syndrome', 'Disease', 'MESH:D016864', (157, 177))	('TP53', 'Gene', (7, 11))	('multiple cancers', 'Disease', (67, 83))	('cancer syndrome', 'Disease', 'MESH:D009369', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutation', 'Var', (12, 20))	('multiple cancers', 'Disease', 'MESH:D009369', (67, 83))	('cancer syndrome', 'Disease', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cause', 'Reg', (111, 116))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
107179	32675277	Here we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers.	('TP53', 'Gene', (26, 30))	('LFS-spectrum cancers', 'Disease', 'MESH:D016864', (129, 149))	('c.1000G>C;p.G334R', 'Var', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('p.G334R', 'Mutation', 'rs730882028', (83, 90))	('LFS-spectrum cancers', 'Disease', (129, 149))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('c.1000G>C', 'Mutation', 'rs730882028', (73, 82))
107180	32675277	Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('c.1000G>C', 'Var', (18, 27))	('c.1000G>A', 'Mutation', 'rs730882028', (45, 54))	('TP53', 'Protein', (142, 146))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('c.1000G>C', 'Mutation', 'rs730882028', (18, 27))
107181	32675277	The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited Chromosome 17p13.1 haplotype.	('c.1000G>C', 'Var', (72, 81))	('c.1000G>C', 'Mutation', 'rs730882028', (72, 81))	('TP53', 'Gene', (67, 71))
107182	32675277	Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays.	('p.G334R', 'Var', (30, 37))	('colony suppression assays', 'CPA', (72, 97))	('p.G334R', 'Mutation', 'rs730882028', (30, 37))
107184	32675277	Structural analysis demonstrated thermal instability of the G334R mutant tetramer, and the G334R mutant protein showed increased preponderance of mutant conformation.	('thermal instability', 'Phenotype', 'HP:0005968', (33, 52))	('thermal instability', 'MPA', (33, 52))	('tetramer', 'Protein', (73, 81))	('G334R', 'Var', (91, 96))	('G334R', 'SUBSTITUTION', 'None', (60, 65))	('G334R', 'SUBSTITUTION', 'None', (91, 96))	('G334R', 'Var', (60, 65))
107186	32675277	Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance Li Fraumeni Syndrome.	('leads to', 'Reg', (140, 148))	('Li Fraumeni Syndrome', 'Disease', (164, 184))	('c.1000G>C;p.G334R', 'Var', (24, 41))	('function', 'MPA', (126, 134))	('causes', 'Reg', (98, 104))	('p53', 'Gene', '7157', (122, 125))	('p.G334R', 'Mutation', 'rs730882028', (34, 41))	('Li Fraumeni Syndrome', 'Disease', 'MESH:D016864', (164, 184))	('c.1000G>C', 'Mutation', 'rs730882028', (24, 33))	('defect', 'NegReg', (112, 118))	('TP53 c.1000G>C;p.G334R', 'Var', (19, 41))	('low penetrance', 'MPA', (149, 163))	('p53', 'Gene', (122, 125))
107187	32675277	Li-Fraumeni Syndrome (LFS) is caused by germline mutations in the TP53 gene that disrupt the tumor suppressive function of p53 (chromosome 17p13.1; OMIM 191170).	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutations', 'Var', (49, 58))	('TP53', 'Gene', (66, 70))	('Li-Fraumeni Syndrome', 'Disease', (0, 20))	('tumor', 'Disease', (93, 98))	('p53', 'Gene', (123, 126))	('p53', 'Gene', '7157', (123, 126))	('disrupt', 'NegReg', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
107191	32675277	The majority of cancer-associated TP53 mutations are missenses in the DNA binding domain (DBD).	('missenses', 'Var', (53, 62))	('TP53', 'Gene', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('binding', 'Interaction', (74, 81))
107192	32675277	However, pathogenic mutations can be found in the tetramerization domain (TD), resulting in alteration of p53 oligomerization, integrity of the tetramer, and DNA affinity.	('pathogenic', 'Reg', (9, 19))	('p53', 'Gene', '7157', (106, 109))	('integrity', 'MPA', (127, 136))	('DNA', 'MPA', (158, 161))	('alteration', 'Reg', (92, 102))	('p53', 'Gene', (106, 109))	('mutations', 'Var', (20, 29))	('oligomerization', 'MPA', (110, 125))
107193	32675277	The most well documented germline TD missense mutation is the c.1010G>A, p.R337H (rs121912664) founder mutation clustered in the southern Brazilian population.	('rs121912664', 'Var', (82, 93))	('rs121912664', 'Mutation', 'rs121912664', (82, 93))	('c.1010G>A', 'Var', (62, 71))	('p.R337H', 'Mutation', 'rs121912664', (73, 80))	('c.1010G>A', 'Mutation', 'rs121912664', (62, 71))
107194	32675277	A significant portion of families with c.1010G>A; p.R337H have a predominance of childhood ACT.	('p.R337H', 'Mutation', 'rs121912664', (50, 57))	('c.1010G>A; p.R337H', 'Var', (39, 57))	('c.1010G>A', 'Mutation', 'rs121912664', (39, 48))	('childhood ACT', 'Disease', (81, 94))
107196	32675277	We present aggregate data between multiple clinical sites and two laboratories supplemented with functional and structural studies for a rare TP53 tetramerization domain mutation, c.1000G>C; p.G334R, which has discordant classifications across clinical laboratories, and has been reviewed by ClinGen's "TP53 variant curation expert panel" and determined to be a variant of uncertain significance based upon preexisting published data.	('TP53', 'Gene', (142, 146))	('c.1000G>C', 'Mutation', 'rs730882028', (180, 189))	('p.G334R', 'Mutation', 'rs730882028', (191, 198))	('c.1000G>C; p.G334R', 'Var', (180, 198))
107197	32675277	The index proband carrying TP53 c.1000G>C; p.G334R was identified in a research sequencing study, and all family members were studied under an Institutional Review Board approved protocol.	('p.G334R', 'Mutation', 'rs730882028', (43, 50))	('c.1000G>C', 'Mutation', 'rs730882028', (32, 41))	('TP53 c.1000G>C; p.G334R', 'Var', (27, 50))	('p.G334R', 'Var', (43, 50))
107198	32675277	Additional probands/families with TP53 c.1000G>C; p.G334R were ascertained from clinical practice sites, genetic testing laboratories and online resources.	('TP53 c.1000G>C; p.G334R', 'Var', (34, 57))	('p.G334R', 'Var', (50, 57))	('c.1000G>C', 'Mutation', 'rs730882028', (39, 48))	('p.G334R', 'Mutation', 'rs730882028', (50, 57))
107200	32675277	From the total of twenty-two p.G334R cases, twenty-one have c.1000G>C and one proband from the IARC database has c.1000G>A.	('c.1000G>A', 'Var', (113, 122))	('c.1000G>C', 'Mutation', 'rs730882028', (60, 69))	('p.G334R', 'Mutation', 'rs730882028', (29, 36))	('c.1000G>C', 'Var', (60, 69))	('p.G334R', 'Var', (29, 36))	('c.1000G>A', 'Mutation', 'rs730882028', (113, 122))
107203	32675277	Analysis of cancer spectrum in pathogenic and likely pathogenic TP53 mutation carriers in the Penn LFS cohort and IARC was as described, updated for the IARC R20 version.	('pathogenic', 'Reg', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('Pen', 'Gene', (94, 97))	('Pen', 'Gene', '27344', (94, 97))	('cancer', 'Disease', (12, 18))	('mutation', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('TP53', 'Gene', (64, 68))
107204	32675277	IARC probands with likely pathogenic or pathogenic mutations in TP53 were identified and divided into p.R337H carriers and non-R337H carriers, excluding p.G334R carriers.	('mutations', 'Var', (51, 60))	('R337H', 'Var', (127, 132))	('R337H', 'SUBSTITUTION', 'None', (104, 109))	('R337H', 'SUBSTITUTION', 'None', (127, 132))	('p.R337H', 'Mutation', 'rs121912664', (102, 109))	('pathogenic', 'Reg', (26, 36))	('R337H', 'Var', (104, 109))	('p.G334R', 'Mutation', 'rs730882028', (153, 160))	('p.G334R', 'Var', (153, 160))	('TP53', 'Gene', (64, 68))
107205	32675277	For Penn LFS, both p.R337H and p.G334R carriers were excluded as there were insufficient numbers of p.R337H carriers for independent analysis.	('p.R337H', 'Mutation', 'rs121912664', (19, 26))	('p.G334R', 'Mutation', 'rs730882028', (31, 38))	('p.G334R', 'Var', (31, 38))	('p.R337H', 'Mutation', 'rs121912664', (100, 107))	('p.R337H', 'Var', (19, 26))	('Pen', 'Gene', (4, 7))	('Pen', 'Gene', '27344', (4, 7))
107209	32675277	For analysis of cancer rates in families, families were included if they carried a likely pathogenic or pathogenic mutation and had three or more generations in IARC (average number of individuals per family was six for non-R337H and five for R337H families).	('pathogenic', 'Reg', (90, 100))	('R337H', 'Var', (243, 248))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('R337H', 'SUBSTITUTION', 'None', (243, 248))	('cancer', 'Disease', (16, 22))	('R337H', 'Var', (224, 229))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('R337H', 'SUBSTITUTION', 'None', (224, 229))
107211	32675277	TP53 genotypes were obtained by direct review of research sequencing (RS) results for the probands of families G334R-1 and G334R-21; by publication review for the probands of families G334R-8 and G334R-20; by review of clinical genetic testing (CGT) reports for the probands of families G334R-2 through 7; and by report from the laboratory director of the two genetic testing company cohorts (probands of families G334R-9 through 19).	('G334R', 'Var', (123, 128))	('G334R', 'SUBSTITUTION', 'None', (123, 128))	('G334R', 'SUBSTITUTION', 'None', (196, 201))	('G334R', 'Var', (196, 201))	('G334R', 'Var', (111, 116))	('G334R', 'Var', (184, 189))	('G334R', 'SUBSTITUTION', 'None', (414, 419))	('G334R', 'SUBSTITUTION', 'None', (111, 116))	('G334R', 'Var', (414, 419))	('G334R', 'SUBSTITUTION', 'None', (184, 189))	('G334R', 'SUBSTITUTION', 'None', (287, 292))	('G334R', 'Var', (287, 292))
107212	32675277	Germline whole exome sequencing (WES) was also performed for the G334R-2 proband, and the raw WES BAM file for G334R-21 germline was downloaded under approved dbGAP project #21931 and analyzed as described.	('G334R', 'SUBSTITUTION', 'None', (111, 116))	('G334R', 'Var', (65, 70))	('G334R', 'Var', (111, 116))	('G334R', 'SUBSTITUTION', 'None', (65, 70))
107213	32675277	Genotyping of additional G334R-1 family members was performed by Sanger sequencing of the genomic region containing the variant.	('G334R', 'SUBSTITUTION', 'None', (25, 30))	('G334R', 'Var', (25, 30))	('variant', 'Var', (120, 127))
107214	32675277	Where available, the RS or CGT was reviewed for any mutations in other cancer susceptibility genes (Supplementary Table S2).	('mutations', 'Var', (52, 61))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
107216	32675277	For haplotype analysis, a panel of fifteen microsatellite markers and single nucleotide polymorphisms (SNP) inside and outside the TP53 locus were used to assess chromosome 17p13 haplotype shared among available DNA samples from TP53 c.1000G>C carriers (Supplementary Table S1b).	('c.1000G>C carriers', 'Var', (234, 252))	('TP53', 'Gene', (229, 233))	('c.1000G>C', 'Mutation', 'rs730882028', (234, 243))
107217	32675277	The presence of TP53 c.1000G>C allele was evaluated in Ashkenazi Jewish control population sequencing data, in the gnomAD database (v2.1.1 cancer and non-cancer cohorts), in a germline genetic testing laboratory dataset (Ambry Genetics, Inc.) comprising 309,222 samples, and in a tumor genetic testing laboratory dataset (MSKCC IMPACT) comprising 21,729 samples.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('c.1000G>C', 'Var', (21, 30))	('TP53 c.1000G>C', 'Var', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('cancer', 'Disease', (154, 160))	('non-cancer', 'Disease', (150, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('non-cancer', 'Disease', 'MESH:D009369', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('c.1000G>C', 'Mutation', 'rs730882028', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (280, 285))	('cancer', 'Disease', (139, 145))
107218	32675277	In silico tools used to predict pathogenicity were SIFT, PolyPhen2_HDIV, PolyPhen2_HVAR, LRT, MutationTaster, MutationAssessor, BayesDel, AlignGVGD, FATHMM, GERP++, PhyloP, SiPhy.	('BayesDel', 'Var', (128, 136))	('PolyPhen2_HVAR', 'Var', (73, 87))	('MutationTaster', 'Var', (94, 108))	('HDIV', 'Disease', 'None', (67, 71))	('GERP', 'Gene', (157, 161))	('GERP', 'Gene', '81603', (157, 161))	('HDIV', 'Disease', (67, 71))	('MutationAssessor', 'Var', (110, 126))
107219	32675277	The interpretation of mutation effect and the molecular modelling of TP53 p.G334R was predicted using Pymol molecular graphics program (http://pymol.sourceforge.net) and SWISS-MODEL (https://swissmodel.expasy.org/).	('TP53', 'Gene', (69, 73))	('p.G334R', 'Mutation', 'rs730882028', (74, 81))	('p.G334R', 'Var', (74, 81))
107220	32675277	For the SWISS-MODEL analysis, the p53-G334R substitution was modeled onto the wild-type tetramer structure (p53-WT, PDB:1OLH) and the resultant structure prediction analyzed with MolProbity.	('G334R', 'SUBSTITUTION', 'None', (38, 43))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('G334R', 'Var', (38, 43))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))
107221	32675277	DNA was extracted from tumors in family G334R-2 (breast cancer), G334-3 (adrenocortical carcinoma), G334R-4 (adrenocortical tumor), G334R-6 (adrenocortical tumor), G334R-17 (pancreatic cancer), G334R-18 (pancreatic cancer).	('pancreatic cancer', 'Disease', 'MESH:D010190', (174, 191))	('tumor', 'Disease', (124, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('breast cancer', 'Disease', (49, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (204, 221))	('tumor', 'Disease', (156, 161))	('G334R', 'Var', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('pancreatic cancer', 'Disease', (174, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (73, 97))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('G334-3', 'Var', (65, 71))	('pancreatic cancer', 'Disease', (204, 221))	('G334R', 'SUBSTITUTION', 'None', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('G334R', 'Var', (164, 169))	('tumors', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (73, 97))	('G334R', 'Var', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('G334R', 'Var', (194, 199))	('G334R', 'Var', (132, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (174, 191))	('tumor', 'Disease', (23, 28))	('adrenocortical carcinoma', 'Disease', (73, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (204, 221))	('G334R', 'SUBSTITUTION', 'None', (164, 169))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('G334R', 'SUBSTITUTION', 'None', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('G334R', 'SUBSTITUTION', 'None', (194, 199))	('G334R', 'SUBSTITUTION', 'None', (132, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
107222	32675277	G334R-2 breast tumor and normal blood leukocyte DNA was prepared as described.	('G334R', 'Var', (0, 5))	('breast tumor', 'Disease', 'MESH:D001943', (8, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('breast tumor', 'Disease', (8, 20))	('breast tumor', 'Phenotype', 'HP:0100013', (8, 20))	('G334R', 'SUBSTITUTION', 'None', (0, 5))
107223	32675277	DNA from G334R-3, and G334R-4 tumors underwent the Comprehensive Cancer Panel targeted massively parallel sequencing assay at the Division of Genomic Diagnostics at the Children's Hospital of Philadelphia.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('G334R', 'Var', (9, 14))	('Cancer', 'Disease', (65, 71))	('G334R', 'SUBSTITUTION', 'None', (9, 14))	('Children', 'Species', '9606', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('G334R', 'SUBSTITUTION', 'None', (22, 27))	('Cancer', 'Disease', 'MESH:D009369', (65, 71))	('G334R', 'Var', (22, 27))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))
107224	32675277	DNA from the G334R-6 tumor and normal blood leukocyte DNA underwent amplification by PCR of the microsatellite marker VNTR(p53) for analysis of LOH.	('G334R', 'SUBSTITUTION', 'None', (13, 18))	('tumor', 'Disease', (21, 26))	('p53', 'Gene', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('p53', 'Gene', '7157', (123, 126))	('G334R', 'Var', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
107225	32675277	DNA from G334R-17 and G334R-18 tumors underwent clinical IMPACT sequencing at Memorial Sloan Kettering Cancer Center.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Memorial Sloan Kettering Cancer', 'Disease', (78, 109))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D009369', (78, 109))	('G334R', 'Var', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('G334R', 'SUBSTITUTION', 'None', (9, 14))	('G334R', 'SUBSTITUTION', 'None', (22, 27))	('Cancer', 'Phenotype', 'HP:0002664', (103, 109))	('G334R', 'Var', (22, 27))
107226	32675277	The raw WES BAM file for G334R-21 tumor was downloaded under approved dbGAP project #21931 and analyzed as described.	('tumor', 'Disease', (34, 39))	('G334R', 'Var', (25, 30))	('G334R', 'SUBSTITUTION', 'None', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
107228	32675277	G334R/+ LCLs were genotyped to confirm TP53 c.1000G>C;p.G334R mutation positivity using Sanger sequencing as above (Supplementary Table S1a), and all four cell lines underwent WES to confirm the absence of other TP53 mutations.	('G334R', 'Var', (0, 5))	('G334R', 'Var', (56, 61))	('G334R', 'SUBSTITUTION', 'None', (56, 61))	('c.1000G>C', 'Mutation', 'rs730882028', (44, 53))	('p.G334R', 'Mutation', 'rs730882028', (54, 61))	('G334R', 'SUBSTITUTION', 'None', (0, 5))	('TP53', 'Gene', (39, 43))
107235	32675277	Antibodies used were purchased from: GAPDH (2118S), MDM2 (86934S), p21 (2947T), PUMA (12450T), and Cleaved Lamin A (2035S) (Cell Signaling, Danvers, MA, USA); p53 (DO-1) (OP-43), p53 (pAb240, mutant p53 conformation) (OP-29), PGC1-alpha (ST1202) (Millipore Sigma, Burlington, MA, USA); LCN15 (PA5-31997) (Thermo Fisher Scientific, Waltham, MA, USA); p53 (FL-393) (Bioss Antibodies, Woburn, MA, USA); and Plexin B3 (AF4958) (R&D Systems, Minneapolis, MN, USA).	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (159, 162))	('LCN15', 'Gene', '389812', (286, 291))	('PUMA', 'Gene', '27113', (80, 84))	('p53', 'Gene', '7157', (350, 353))	('mutant', 'Var', (192, 198))	('p53', 'Gene', '7157', (199, 202))	('p53', 'Gene', (159, 162))	('Plexin B3', 'Gene', '5365', (404, 413))	('Lamin A', 'Gene', (107, 114))	('p53', 'Gene', (350, 353))	('Lamin A', 'Gene', '4000', (107, 114))	('p53', 'Gene', (199, 202))	('PUMA', 'Gene', (80, 84))	('MN', 'CellLine', 'CVCL:U508', (450, 452))	('Plexin B3', 'Gene', (404, 413))	('p21', 'Gene', (67, 70))	('GAPDH', 'Gene', '2597', (37, 42))	('PGC1-alpha', 'Gene', '10891', (226, 236))	('p21', 'Gene', '644914', (67, 70))	('p53', 'Gene', '7157', (179, 182))	('LCN15', 'Gene', (286, 291))	('GAPDH', 'Gene', (37, 42))	('PGC1-alpha', 'Gene', (226, 236))
107237	32675277	Constructs containing the c.1000G>A and c.1000G>C alleles were created by site direct mutagenesis using QuikChange II kit (Stratagene, La Jolla, CA, USA) in the pCMV-Neo-Bam expression vector containing wild-type TP53 cDNA as template.	('c.1000G>A', 'Var', (26, 35))	('c.1000G>C', 'Var', (40, 49))	('c.1000G>C', 'Mutation', 'rs730882028', (40, 49))	('c.1000G>A', 'Mutation', 'rs730882028', (26, 35))
107241	32675277	Primary antibodies were used to label mutant or total p53 (Pab240 or p53FL-393, respectively; 1:200), incubated at 4 C overnight, followed by incubation in Alexa-488 and Alexa-594 conjugated secondary (1:400 or 1:200, respectively) for 45 minutes at room temperature.	('mutant', 'Var', (38, 44))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('Pab240', 'Var', (59, 65))	('p53', 'Gene', (54, 57))	('Alexa-594', 'Chemical', 'MESH:C417664', (170, 179))	('p53', 'Gene', '7157', (54, 57))	('Alexa-488', 'Chemical', '-', (156, 165))
107243	32675277	Constructs encoding p53 wild-type (TP53-WT), p53-R175H (TP53-R175H), and p53-G334R (c.1000G>A and c.1000G>C) were transiently transfected into p53 deficient Saos-2 cells.	('c.1000G>A', 'Var', (84, 93))	('p53', 'Gene', (45, 48))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('p53', 'Gene', '7157', (45, 48))	('R175H', 'Mutation', 'rs28934578', (49, 54))	('p53', 'Gene', '7157', (143, 146))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('Saos-2', 'CellLine', 'CVCL:0548', (157, 163))	('c.1000G>C', 'Mutation', 'rs730882028', (98, 107))	('R175H', 'Mutation', 'rs28934578', (61, 66))	('c.1000G>A', 'Mutation', 'rs730882028', (84, 93))	('G334R', 'Var', (77, 82))	('c.1000G>C', 'Var', (98, 107))	('G334R', 'SUBSTITUTION', 'None', (77, 82))	('p53', 'Gene', (143, 146))
107249	32675277	Genes that significantly (FDR<5%) responded at 24 hours in WT p53, but had significantly (nominal p<0.05) less response in p.G334R p53 were considered and ranked by the fold difference in response.	('p.G334R', 'Mutation', 'rs730882028', (123, 130))	('p.G334R', 'Var', (123, 130))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('less', 'NegReg', (106, 110))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('responded', 'MPA', (34, 43))	('response', 'MPA', (111, 119))
107250	32675277	The G334R mutation was introduced into a previously described p53 tetramerization domain construct, modified to include a TEV cleavage site using Quikchange mutagenesis (Agilent).	('G334R', 'SUBSTITUTION', 'None', (4, 9))	('p53', 'Gene', '7157', (62, 65))	('p53', 'Gene', (62, 65))	('G334R', 'Var', (4, 9))
107258	32675277	Whole exome sequencing (WES) identified TP53 c.1000G>C;p.G334R in a pair of third-degree relatives from a family (G334R-1) with multiple LFS-component cancers mostly occurring in the fourth to ninth decades, as well as five family members with multiple primary malignancies (Fig.	('malignancies', 'Disease', 'MESH:D009369', (261, 273))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('multiple LFS-component cancers', 'Disease', (128, 158))	('G334R', 'Var', (114, 119))	('G334R', 'SUBSTITUTION', 'None', (114, 119))	('malignancies', 'Disease', (261, 273))	('p.G334R', 'Mutation', 'rs730882028', (55, 62))	('multiple LFS-component cancers', 'Disease', 'MESH:D016864', (128, 158))	('G334R', 'Var', (57, 62))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('c.1000G>C', 'Mutation', 'rs730882028', (45, 54))	('G334R', 'SUBSTITUTION', 'None', (57, 62))
107261	32675277	One family showed segregation of LFS-component cancers to third-degree relatives (G334R-6, Fig.	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('LFS-component cancers', 'Disease', 'MESH:D016864', (33, 54))	('G334R', 'Var', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('G334R', 'SUBSTITUTION', 'None', (82, 87))	('LFS-component cancers', 'Disease', (33, 54))
107262	32675277	While most affected individuals had adult-onset cancers (Table 1), six individuals from four families had pediatric adrenocortical tumors (ACTs), including one family with pediatric ACTs in a sibling pair (G334R-4, Fig.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (116, 137))	('cancers', 'Disease', (48, 55))	('G334R', 'Var', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('G334R', 'SUBSTITUTION', 'None', (206, 211))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('adrenocortical tumors', 'Disease', (116, 137))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
107264	32675277	All probands were negative for other cancer predisposition gene mutations when tested (Table 1, Supplementary Table S2), except one family also segregated the AJ founder mutation BRCA2 c.5974delT;p.Ser1982fs (G334R-4) (Supplementary Fig.	('G334R', 'Var', (209, 214))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('BRCA2', 'Gene', '675', (179, 184))	('cancer', 'Disease', (37, 43))	('c.5974delT', 'Mutation', 'c.5974delT', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('BRCA2', 'Gene', (179, 184))	('p.Ser1982fs', 'Mutation', 'rs80359550', (196, 207))	('G334R', 'SUBSTITUTION', 'None', (209, 214))
107265	32675277	Thirteen additional TP53 c.1000G>C;p.G334R carriers were identified from two genetic testing laboratory cohorts and literature review (Table 1).	('p.G334R', 'Mutation', 'rs730882028', (35, 42))	('c.1000G>C', 'Mutation', 'rs730882028', (25, 34))	('p.G334R', 'Var', (35, 42))	('TP53 c.1000G>C;p.G334R', 'Var', (20, 42))
107269	32675277	No other pathogenic mutations nor variants of uncertain significance were identified in other cancer predisposition genes, including BRCA1/2 in these probands (Table 1, Supplementary Table S2).	('BRCA1/2', 'Gene', '672;675', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('BRCA1/2', 'Gene', (133, 140))	('mutations', 'Var', (20, 29))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
107270	32675277	Ancestry was available for 16 probands with TP53 c.1000G>C, p.G334R.	('c.1000G>C', 'Mutation', 'rs730882028', (49, 58))	('p.G334R', 'Var', (60, 67))	('p.G334R', 'Mutation', 'rs730882028', (60, 67))	('TP53 c.1000G>C', 'Var', (44, 58))
107271	32675277	The TP53 c.1000G>C mutation was not reported in the non-cancer cohort of gnomAD (v2.1.1), including 10,036 AJ alleles (Supplementary Table S3), nor 1154 chromosomes from an AJ cancer-free cohort.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('TP53', 'Gene', (4, 8))	('c.1000G>C', 'Mutation', 'rs730882028', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('c.1000G>C', 'Var', (9, 18))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (56, 62))	('non-cancer', 'Disease', (52, 62))	('non-cancer', 'Disease', 'MESH:D009369', (52, 62))
107273	32675277	Somatic biallelic inactivation of BRCA2 was not found in the ACT also carrying a BRCA2 mutation (Table 1).	('BRCA2', 'Gene', '675', (34, 39))	('biallelic', 'Var', (8, 17))	('BRCA2', 'Gene', (81, 86))	('BRCA2', 'Gene', '675', (81, 86))	('BRCA2', 'Gene', (34, 39))	('mutation', 'Var', (87, 95))
107274	32675277	Two pancreatic cancers and one breast cancer had a second somatic TP53 mutation (Table 1), although mutational phase was unavailable.	('pancreatic cancers', 'Phenotype', 'HP:0002894', (4, 22))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('one breast', 'Phenotype', 'HP:0012813', (27, 37))	('TP53', 'Gene', (66, 70))	('mutation', 'Var', (71, 79))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('pancreatic cancers', 'Disease', 'MESH:D010190', (4, 22))	('pancreatic cancers', 'Disease', (4, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (4, 21))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
107275	32675277	The breast cancer sample from G334R-2 underwent WES, demonstrating typical breast tumor mutational signatures, high levels of genomic instability, and no other breast cancer driver mutations, characteristics consistent with p53-mutant breast tumors (Table 1).	('p53', 'Gene', '7157', (224, 227))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast tumor', 'Phenotype', 'HP:0100013', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast tumor', 'Disease', (75, 87))	('p53', 'Gene', (224, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('G334R', 'Var', (30, 35))	('breast tumors', 'Disease', 'MESH:D001943', (235, 248))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast tumors', 'Disease', (235, 248))	('breast tumor', 'Disease', 'MESH:D001943', (235, 247))	('breast cancer', 'Disease', (4, 17))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('breast tumors', 'Phenotype', 'HP:0100013', (235, 248))	('G334R', 'SUBSTITUTION', 'None', (30, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('breast tumor', 'Phenotype', 'HP:0100013', (235, 247))	('breast tumor', 'Disease', 'MESH:D001943', (75, 87))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('breast cancer', 'Disease', (160, 173))
107276	32675277	Previous functional studies of another p.G334R allele, c.1000G>A, have shown normal to impaired transactivation activity (42-145% of wild-type activity) dependent on cell type.	('impaired', 'NegReg', (87, 95))	('transactivation activity', 'MPA', (96, 120))	('c.1000G>A', 'Mutation', 'rs730882028', (55, 64))	('c.1000G>A', 'Var', (55, 64))	('p.G334R', 'Mutation', 'rs730882028', (39, 46))
107277	32675277	In the interest of rigor, we created plasmids encoding both c.1000G>A and c.1000G>C alleles.	('rigor', 'Phenotype', 'HP:0025145', (19, 24))	('c.1000G>C', 'Mutation', 'rs730882028', (74, 83))	('c.1000G>A', 'Var', (60, 69))	('c.1000G>C', 'Var', (74, 83))	('c.1000G>A', 'Mutation', 'rs730882028', (60, 69))
107279	32675277	However, in colony suppression assays, these two p.G334R alleles showed mildly impaired suppression ability compared to wild-type TP53 (Fig.	('colony suppression', 'CPA', (12, 30))	('impaired suppression ability', 'Disease', (79, 107))	('p.G334R', 'Mutation', 'rs730882028', (49, 56))	('p.G334R', 'Var', (49, 56))	('impaired suppression ability', 'Disease', 'MESH:D011596', (79, 107))
107282	32675277	p53 steady state levels were noted to be higher in G334R mutant lines compared to wild-type LCLs when treated with both the MDM2 inhibitor Nutlin-3a and cisplatin (Supplementary Fig.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('G334R', 'Var', (51, 56))	('G334R', 'SUBSTITUTION', 'None', (51, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('higher', 'PosReg', (41, 47))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (139, 148))
107283	32675277	The G334R mutant cell lines retained the ability to induce MDM2 and p21 in response to eight and 24-hours of treatment with Nutlin-3a, as expected (Fig.	('G334R', 'SUBSTITUTION', 'None', (4, 9))	('p21', 'Gene', '644914', (68, 71))	('induce', 'PosReg', (52, 58))	('MDM2', 'Gene', (59, 63))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (124, 133))	('p21', 'Gene', (68, 71))	('G334R', 'Var', (4, 9))
107284	32675277	RNA-Seq data from the four lines confirmed that transactivation of canonical p53 target genes in response to Nutlin at 24 hours was comparable in G334R mutant compared to wild-type LCLs (Supplementary Fig.	('G334R', 'Var', (146, 151))	('transactivation', 'MPA', (48, 63))	('response to Nutlin at 24 hours', 'MPA', (97, 127))	('G334R', 'SUBSTITUTION', 'None', (146, 151))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))
107285	32675277	However, a subset of p53 target genes induced by Nutlin treatment in TP53 wild-type LCLs showed significantly impaired induction in G334R LCLs (Supplementary Table S6); these genes include PCLO, PLTP, PLXNB3 and LCN15 (Fig.	('PCLO', 'Gene', '27445', (189, 193))	('PLXNB3', 'Gene', (201, 207))	('impaired', 'NegReg', (110, 118))	('PLTP', 'Gene', '5360', (195, 199))	('PCLO', 'Gene', (189, 193))	('LCN15', 'Gene', (212, 217))	('p53', 'Gene', '7157', (21, 24))	('PLTP', 'Gene', (195, 199))	('induction', 'MPA', (119, 128))	('LCN15', 'Gene', '389812', (212, 217))	('G334R', 'SUBSTITUTION', 'None', (132, 137))	('G334R', 'Var', (132, 137))	('PLXNB3', 'Gene', '5365', (201, 207))	('p53', 'Gene', (21, 24))
107286	32675277	To investigate the biochemical impact of the p.G334R substitution, three-dimensional modelling of the p53-G334R mutant TD was performed, confirming that Gly-334 is the hinge residue located in the loop connecting the alpha-helix and beta-sheet in each protomer (Fig.	('p53', 'Gene', '7157', (102, 105))	('G334R', 'SUBSTITUTION', 'None', (106, 111))	('p.G334R', 'Mutation', 'rs730882028', (45, 52))	('p53', 'Gene', (102, 105))	('G334R', 'Var', (47, 52))	('G334R', 'Var', (106, 111))	('G334R', 'SUBSTITUTION', 'None', (47, 52))	('Gly-334', 'Var', (153, 160))	('Gly', 'Chemical', 'MESH:D005998', (153, 156))
107288	32675277	We therefore assessed thermal stability of the G334R tetramer, and found that G334R exhibits mildly decreased thermal stability compared to wild-type (Fig.	('thermal stability', 'MPA', (110, 127))	('decreased', 'NegReg', (100, 109))	('G334R', 'SUBSTITUTION', 'None', (78, 83))	('G334R', 'Var', (47, 52))	('G334R', 'Var', (78, 83))	('G334R', 'SUBSTITUTION', 'None', (47, 52))
107290	32675277	Using the pAb240 conformation-specific antibody, we found that a significant percentage of cells transfected with either p.G334R allele showed evidence for p53 protein in the mutant conformation (Fig.	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('p.G334R', 'Mutation', 'rs730882028', (121, 128))	('p.G334R', 'Var', (121, 128))	('protein', 'Protein', (160, 167))	('mutant', 'Var', (175, 181))
107292	32675277	These combined data suggest that the G334R mutant protein may be defective in transcription of a subset of genes due to increased propensity to adopt a mutant conformation.	('G334R', 'SUBSTITUTION', 'None', (37, 42))	('defective', 'NegReg', (65, 74))	('protein', 'Protein', (50, 57))	('G334R', 'Var', (37, 42))	('transcription', 'MPA', (78, 91))
107293	32675277	Our experimental evidence indicates that TP53 c.1000G>C;p.G334R has a partial defect in p53 function, similar to another hypomorphic TD mutation, p.R337H.	('c.1000G>C', 'Mutation', 'rs730882028', (46, 55))	('TP53 c.1000G>C;p.G334R', 'Var', (41, 63))	('p53', 'Gene', (88, 91))	('p.R337H', 'Var', (146, 153))	('c.1000G>C;p.G334R', 'Var', (46, 63))	('p.G334R', 'Mutation', 'rs730882028', (56, 63))	('p53', 'Gene', '7157', (88, 91))	('p.G334R', 'Var', (56, 63))	('p.R337H', 'Mutation', 'rs121912664', (146, 153))	('function', 'MPA', (92, 100))	('defect', 'NegReg', (78, 84))
107294	32675277	Concordant with this mild defect, the median age of onset of all cancers, including breast cancers, in p.G334R probands was significantly later than probands in the Penn LFS and IARC non-p.R337H cohorts (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('Pen', 'Gene', '27344', (165, 168))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('later', 'PosReg', (138, 143))	('breast cancers', 'Phenotype', 'HP:0003002', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('p.G334R', 'Mutation', 'rs730882028', (103, 110))	('p.G334R', 'Var', (103, 110))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('breast cancers', 'Disease', 'MESH:D001943', (84, 98))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('breast cancers', 'Disease', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Disease', (65, 72))	('p.R337H', 'Mutation', 'rs121912664', (187, 194))	('Pen', 'Gene', (165, 168))
107295	32675277	While the median age of all cancers was significantly later in p.G334R compared to p.R337H probands, the median age of breast cancer was similar (Fig.	('cancers', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('p.G334R', 'Mutation', 'rs730882028', (63, 70))	('p.G334R', 'Var', (63, 70))	('p.R337H', 'Mutation', 'rs121912664', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('later', 'PosReg', (54, 59))
107297	32675277	The rate of ACTs was similar in the p.G334R probands compared to Penn LFS and IARC non-p.R337H probands, although significantly lower than the rate in p.R337H probands (Fig.	('Pen', 'Gene', (65, 68))	('p.G334R', 'Var', (36, 43))	('Pen', 'Gene', '27344', (65, 68))	('p.R337H', 'Mutation', 'rs121912664', (151, 158))	('lower', 'NegReg', (128, 133))	('p.R337H', 'Mutation', 'rs121912664', (87, 94))	('p.G334R', 'Mutation', 'rs730882028', (36, 43))
107298	32675277	Conversely while breast cancer rates were similar in p.G334R, Penn LFS and IARC non-p.R337H probands, they were significantly higher than in p.R337H probands.	('Pen', 'Gene', (62, 65))	('p.R337H', 'Mutation', 'rs121912664', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('breast cancer', 'Disease', (17, 30))	('higher', 'PosReg', (126, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('p.R337H', 'Mutation', 'rs121912664', (141, 148))	('p.G334R', 'Mutation', 'rs730882028', (53, 60))	('p.G334R', 'Var', (53, 60))	('Pen', 'Gene', '27344', (62, 65))
107299	32675277	Sarcomas were statistically less likely in p.G334R probands compared to the IARC non-p.R337H probands, although observed at a similar rate to p.R337H probands (Fig.	('p.G334R', 'Mutation', 'rs730882028', (43, 50))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('p.G334R', 'Var', (43, 50))	('p.R337H', 'Mutation', 'rs121912664', (85, 92))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('less', 'NegReg', (28, 32))	('p.R337H', 'Mutation', 'rs121912664', (142, 149))	('Sarcomas', 'Disease', (0, 8))
107300	32675277	In addition, the family data shows a statistically significant lower incidence of brain cancer compared to IARC non-p.R337H families and a statistically significant higher rate of hematological malignancies in p.G334R families compared to Penn LFS and p.R337H families (Fig.	('brain cancer', 'Disease', 'MESH:D001932', (82, 94))	('hematological malignancies', 'Phenotype', 'HP:0004377', (180, 206))	('lower', 'NegReg', (63, 68))	('brain cancer', 'Phenotype', 'HP:0030692', (82, 94))	('p.R337H', 'Mutation', 'rs121912664', (116, 123))	('p.G334R', 'Mutation', 'rs730882028', (210, 217))	('Pen', 'Gene', (239, 242))	('p.G334R', 'Var', (210, 217))	('higher', 'PosReg', (165, 171))	('brain cancer', 'Disease', (82, 94))	('Pen', 'Gene', '27344', (239, 242))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('hematological malignancies', 'Disease', (180, 206))	('hematological malignancies', 'Disease', 'MESH:D019337', (180, 206))	('p.R337H', 'Mutation', 'rs121912664', (252, 259))
107301	32675277	Here-in we report that TP53 c.1000G>C;p.G334R is an AJ-predominant mutation causing a mild defect in p53 function likely due to decreased thermo-stability, which leads to a lower penetrance Li Fraumeni Syndrome phenotype.	('c.1000G>C;p.G334R', 'Var', (28, 45))	('p53', 'Gene', (101, 104))	('p.G334R', 'Mutation', 'rs730882028', (38, 45))	('p53', 'Gene', '7157', (101, 104))	('thermo-stability', 'MPA', (138, 154))	('decreased', 'NegReg', (128, 137))	('Li Fraumeni Syndrome', 'Disease', (190, 210))	('Li Fraumeni Syndrome', 'Disease', 'MESH:D016864', (190, 210))	('c.1000G>C', 'Mutation', 'rs730882028', (28, 37))	('lower penetrance', 'MPA', (173, 189))	('function', 'MPA', (105, 113))	('defect', 'NegReg', (91, 97))	('TP53 c.1000G>C;p.G334R', 'Var', (23, 45))
107302	32675277	The TP53 p.G334R mutation demonstrates variable penetrance, with enrichment of the canonical LFS cancer, pediatric ACTs, in some families; whereas, other families predominantly show later onset classic LFS cancers, such as breast cancer and hematological malignancies, or multiple unaffected carriers.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('TP53', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('LFS cancer', 'Disease', (93, 103))	('classic LFS cancers', 'Disease', (194, 213))	('hematological malignancies', 'Disease', (241, 267))	('breast cancer', 'Disease', (223, 236))	('hematological malignancies', 'Disease', 'MESH:D019337', (241, 267))	('LFS cancer', 'Disease', 'MESH:D016864', (202, 212))	('LFS cancer', 'Disease', 'MESH:D016864', (93, 103))	('hematological malignancies', 'Phenotype', 'HP:0004377', (241, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('p.G334R', 'Mutation', 'rs730882028', (9, 16))	('p.G334R', 'Var', (9, 16))	('classic LFS cancers', 'Disease', 'MESH:D016864', (194, 213))
107303	32675277	Therefore, the high rate of pediatric ACT in our p.G334R cohort, particularly the sibling pair both with pediatric ACTs, is strong support for this mutation being causative of the observed phenotype.	('pediatric ACT', 'Disease', (28, 41))	('p.G334R', 'Var', (49, 56))	('p.G334R', 'Mutation', 'rs730882028', (49, 56))
107304	32675277	Overall, the later onset presentation of adult-onset cancers coupled with pediatric ACT enrichment seen with p.G334R probands and families is similar to that observed with another tetramerization domain mutation p.R337H, although the ACT enrichment is not as striking in the p.G334R cohort compared to p.R337H.	('p.G334R', 'Mutation', 'rs730882028', (109, 116))	('p.R337H', 'Var', (212, 219))	('p.G334R', 'Var', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('p.G334R', 'Mutation', 'rs730882028', (275, 282))	('p.G334R', 'Var', (275, 282))	('p.R337H', 'Mutation', 'rs121912664', (212, 219))	('p.R337H', 'Mutation', 'rs121912664', (302, 309))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
107305	32675277	The low incidence of sarcoma in our p.G334R cohort, has also been observed in p.R337H lineages as compared to classic LFS families.	('p.G334R', 'Var', (36, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('p.R337H', 'Mutation', 'rs121912664', (78, 85))	('p.G334R', 'Mutation', 'rs730882028', (36, 43))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('p.R337H', 'Var', (78, 85))	('sarcoma', 'Disease', (21, 28))
107307	32675277	It is possible that lineage specific factors, cell-type specific changes or other physiological conditions, such as aging, lead to decreased thermo-stability of the p53-G334R mutant tetramer only in specific target tissues.	('p53', 'Gene', (165, 168))	('p53', 'Gene', '7157', (165, 168))	('decreased', 'NegReg', (131, 140))	('G334R', 'Var', (169, 174))	('thermo-stability', 'MPA', (141, 157))	('G334R', 'SUBSTITUTION', 'None', (169, 174))
107308	32675277	Pathogenesis in p53-G334R mutant cells may relate to the defective transactivation of the subset of p53 target genes that are not responsive to Nutlin in our analyses, and suggest that phenotyping of TP53 tetramerization domain mutations should differ from that used for DNA binding domain mutations.	('G334R', 'Var', (20, 25))	('defective', 'NegReg', (57, 66))	('p53', 'Gene', (16, 19))	('transactivation', 'MPA', (67, 82))	('TP53', 'Gene', (200, 204))	('p53', 'Gene', '7157', (100, 103))	('p53', 'Gene', '7157', (16, 19))	('mutant', 'Var', (26, 32))	('G334R', 'SUBSTITUTION', 'None', (20, 25))	('p53', 'Gene', (100, 103))
107309	32675277	Finally, the cancer predisposition associated with the TP53 c.1000G>C; p.G334R allele may be due to genetic modifiers that affect cancer risk either in concert with or independently from the p53-G334R mutation.	('G334R', 'Var', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('G334R', 'Var', (73, 78))	('cancer', 'Disease', (13, 19))	('p53', 'Gene', (191, 194))	('G334R', 'SUBSTITUTION', 'None', (73, 78))	('p53', 'Gene', '7157', (191, 194))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('c.1000G>C', 'Mutation', 'rs730882028', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('affect', 'Reg', (123, 129))	('p.G334R', 'Mutation', 'rs730882028', (71, 78))	('G334R', 'SUBSTITUTION', 'None', (195, 200))
107311	32675277	Given the apparent progressively younger of age of onset of cancer in many of our p.G334R families, this or other mechanisms of genetic anticipation may also play an important role in p.G334R families.	('p.G334R', 'Mutation', 'rs730882028', (82, 89))	('p.G334R', 'Var', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('p.G334R', 'Mutation', 'rs730882028', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
107313	32675277	Whether a variant(s) in linkage disequilibrium with c.1000G>C is acting cooperatively to alter p53 function remains unanswered.	('function', 'MPA', (99, 107))	('c.1000G>C', 'Var', (52, 61))	('alter', 'Reg', (89, 94))	('p53', 'Gene', '7157', (95, 98))	('p53', 'Gene', (95, 98))	('c.1000G>C', 'Mutation', 'rs730882028', (52, 61))
107314	32675277	Our data also show that the TP53 c.1000G>C mutation is present on a commonly inherited haplotype in nine individuals from four independent families and seen predominantly in individuals of Ashkenazi Jewish descent, suggesting that it is a founder mutation.	('c.1000G>C', 'Var', (33, 42))	('TP53', 'Gene', (28, 32))	('c.1000G>C', 'Mutation', 'rs730882028', (33, 42))
107315	32675277	At present, discordant classification of TP53 c.1000G>C and other presumed hypomorphic alleles in TP53 and other cancer susceptibility genes are profoundly challenging in clinical genetics.	('TP53', 'Gene', (41, 45))	('c.1000G>C', 'Mutation', 'rs730882028', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('c.1000G>C', 'Var', (46, 55))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
107319	32675277	TP53 c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.	('associated with', 'Reg', (78, 93))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('familial multiple cancer syndrome', 'Disease', 'MESH:D009369', (96, 129))	('p.G334R', 'Mutation', 'rs730882028', (15, 22))	('c.1000C>G', 'Mutation', 'rs730882028', (5, 14))	('cancer', 'Disease', (207, 213))	('familial multiple cancer syndrome', 'Disease', (96, 129))	('TP53 c.1000C>G;p.G334R', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('p.G334R', 'Var', (15, 22))	('cancer', 'Disease', (114, 120))
107321	31998416	Recent studies suggest that CD276- (B7-H3) targeted therapy represents a promising therapeutic option for solid tumors.	('solid tumors', 'Disease', (106, 118))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('CD276-', 'Var', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
107329	31998416	reported that CD8+ T cells and expression of programmed death ligand 1 (PD-L1/B7-H1) were significantly associated with improved survival, indicating a potential role for the immune signature in the assessment of ACC prognosis.	('improved', 'PosReg', (120, 128))	('PD-L1', 'Gene', '29126', (72, 77))	('B7-H1', 'Gene', '29126', (78, 83))	('CD8', 'Gene', (14, 17))	('survival', 'MPA', (129, 137))	('B7-H1', 'Gene', (78, 83))	('CD8', 'Gene', '925', (14, 17))	('expression', 'Var', (31, 41))	('PD-L1', 'Gene', (72, 77))
107337	31998416	Positive expression of CD276 in the tumor vasculature may also indicate a higher risk of local tumor infiltration, adjacent organ invasion or venous tumor thrombus (P = 0.029), and advanced ENSAT stage (P = 0.020).	('venous tumor thrombus', 'Disease', 'MESH:D013927', (142, 163))	('Positive expression', 'Var', (0, 19))	('CD276', 'Gene', (23, 28))	('venous tumor thrombus', 'Disease', (142, 163))	('venous tumor', 'Phenotype', 'HP:0012721', (142, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('adjacent organ invasion', 'CPA', (115, 138))	('local tumor infiltration', 'CPA', (89, 113))	('advanced ENSAT stage', 'CPA', (181, 201))	('venous tumor thrombus', 'Phenotype', 'HP:0004936', (142, 163))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))
107339	31998416	Multivariate Cox regression modeling suggested that surgical assessment (R1/2/X, HR = 2.8, 95% CI: 1.23-6.39, P = 0.014) and CD276 expression in tumor cells (HR = 7.52, 95% CI: 2.47-22.91, P < 0.001) were independent recurrence risk factors for ACC (Table 2).	('R1/2/X', 'Gene', '2840', (73, 79))	('CD276 expression', 'Var', (125, 141))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ACC', 'Disease', (245, 248))	('R1/2/X', 'Gene', (73, 79))
107340	31998416	Subsequent functional analysis of the CD276-correlated genes suggested that, except for immune response-related functions, such as the T cell receptor signaling pathway, antigen processing and presentation pathway, and stimulatory C-type lectin receptor signaling pathway, CD276 also participated in cell proliferation and the negative regulation of apoptosis of ACC cells (Supplemental ).	('C-type lectin receptor', 'Gene', (231, 253))	('apoptosis', 'CPA', (350, 359))	('CD276', 'Var', (273, 278))	('cell proliferation', 'CPA', (300, 318))	('C-type lectin receptor', 'Gene', '338339', (231, 253))	('negative regulation', 'NegReg', (327, 346))	('participated', 'Reg', (284, 296))
107388	31620613	The final tumor classification was pT2N0M0, stage 2, and the patient received additional adjuvant radiation therapy.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('patient', 'Species', '9606', (61, 68))	('pT2N0M0', 'Var', (35, 42))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
107421	30456751	Macronodular adrenal hyperplasia was linked to ARMC5 defects and new genes were found to be involved in adrenocortical cancer (ACC).	('adrenocortical cancer', 'Disease', (104, 125))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (13, 32))	('Macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (0, 32))	('ARMC5', 'Gene', (47, 52))	('defects', 'Var', (53, 60))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (104, 125))	('ARMC5', 'Gene', '79798', (47, 52))	('ACC', 'Phenotype', 'HP:0006744', (127, 130))	('linked', 'Reg', (37, 43))	('adrenal hyperplasia', 'Disease', (13, 32))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (13, 32))
107437	30456751	Aberrantly increased cAMP-PKA signaling is implicated in the pathogenesis of most benign cortisol-producing tumors of the adrenal gland.	('Aberrantly', 'Var', (0, 10))	('increased', 'PosReg', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors of the adrenal gland', 'Phenotype', 'HP:0100631', (108, 135))	('implicated', 'Reg', (43, 53))	('cAMP', 'Gene', (21, 25))	('cAMP', 'Gene', '820', (21, 25))	('cortisol', 'Chemical', 'MESH:D006854', (89, 97))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
107441	30456751	These mosaic gain-of-function mutations lead to constitutive activation of adenylyl cyclase, with such manifestations as cafe-au-lait skin macules, skeletal fibrous dysplasia, and multiple endocrinopathies, including precocious puberty, testicular and thyroid lesions, phosphate wasting, growth hormone excess, and, rarely, neonatal hypercortisolism.	('skeletal fibrous dysplasia', 'Disease', (148, 174))	('lait skin', 'Phenotype', 'HP:0000973', (129, 138))	('cafe-au-lait skin macules', 'Disease', (121, 146))	('multiple endocrinopathies', 'Disease', (180, 205))	('gain-of-function', 'PosReg', (13, 29))	('thyroid lesions', 'Disease', 'MESH:D013959', (252, 267))	('growth hormone', 'Chemical', 'MESH:D013006', (288, 302))	('skeletal fibrous dysplasia', 'Disease', 'MESH:C537974', (148, 174))	('growth hormone excess', 'Phenotype', 'HP:0000845', (288, 309))	('cafe-au-lait skin', 'Phenotype', 'HP:0000957', (121, 138))	('growth hormone excess', 'Disease', (288, 309))	('macules', 'Phenotype', 'HP:0012733', (139, 146))	('adenylyl cyclase', 'Enzyme', (75, 91))	('hypercortisolism', 'Phenotype', 'HP:0003118', (333, 349))	('neonatal hypercortisolism', 'Disease', 'MESH:D003480', (324, 349))	('phosphate', 'Chemical', 'MESH:D010710', (269, 278))	('precocious puberty', 'Disease', (217, 235))	('mutations', 'Var', (30, 39))	('neonatal hypercortisolism', 'Disease', (324, 349))	('phosphate wasting', 'Phenotype', 'HP:0000117', (269, 286))	('multiple endocrinopathies', 'Disease', 'MESH:C567425', (180, 205))	('phosphate wasting', 'Disease', (269, 286))	('activation', 'PosReg', (61, 71))	('thyroid lesions', 'Disease', (252, 267))	('precocious puberty', 'Phenotype', 'HP:0000826', (217, 235))
107447	30456751	Inactivating mutations of PRKAR1A lead to constitutive activation of the cAMP-PKA pathway through loss of regulation of the catalytic subunits of PKA.	('PRKAR1A', 'Gene', (26, 33))	('Inactivating mutations', 'Var', (0, 22))	('loss', 'NegReg', (98, 102))	('cAMP', 'Gene', (73, 77))	('cAMP', 'Gene', '820', (73, 77))	('regulation', 'MPA', (106, 116))	('activation', 'PosReg', (55, 65))
107450	30456751	Mice lacking PRKAR1A specifically in the adrenal cortex develop autonomous excess cortisol secretion, dysregulated adrenocortical cell differentiation with increased proliferation and resistance to apoptosis, as well as improper maintenance and expansion of cortisol-producing fetal adrenocortical cells with regression of the adult adrenal cortex, leading to BAH and CS.	('improper', 'Var', (220, 228))	('cortisol', 'Chemical', 'MESH:D006854', (82, 90))	('excess', 'PosReg', (75, 81))	('adrenocortical', 'Disease', (115, 129))	('increased', 'PosReg', (156, 165))	('Mice', 'Species', '10090', (0, 4))	('excess cortisol', 'Phenotype', 'HP:0003118', (75, 90))	('expansion of cortisol', 'Phenotype', 'HP:0003118', (245, 266))	('leading to', 'Reg', (349, 359))	('BAH', 'Disease', (360, 363))	('dysregulated adrenocortical', 'Disease', (102, 129))	('PRKAR1A', 'Gene', (13, 20))	('CS', 'Phenotype', 'HP:0003118', (368, 370))	('adrenocortical', 'Disease', 'MESH:D018268', (283, 297))	('expansion', 'CPA', (245, 254))	('cortisol', 'Chemical', 'MESH:D006854', (258, 266))	('adrenocortical', 'Disease', (283, 297))	('adrenocortical', 'Disease', 'MESH:D018268', (115, 129))	('dysregulated adrenocortical', 'Disease', 'MESH:D018268', (102, 129))	('BAH', 'Chemical', '-', (360, 363))
107451	30456751	Mutations in cyclic nucleotide phosphodiesterases (PDEs) have also been implicated in the pathogenesis of adrenocortical tumors and CS.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (106, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('PDEs', 'Gene', '50940', (51, 55))	('PDEs', 'Gene', (51, 55))	('phosphodiesterases', 'Gene', '50940', (31, 49))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('phosphodiesterases', 'Gene', (31, 49))	('Mutations', 'Var', (0, 9))	('adrenocortical tumors', 'Disease', (106, 127))	('CS', 'Phenotype', 'HP:0003118', (132, 134))	('implicated', 'Reg', (72, 82))
107453	30456751	In a single-nucleotide polymorphism-based, genome-wide association study of individuals with micronodular adrenocortical hyperplasia not caused by genetic defects in GNAS or PRKAR1A, mutations in genetic loci harboring PDE genes were most likely to be associated with the disease, with inactivating mutations of the PDE11A gene being the most commonly linked, followed by the PDE8B gene.	('PDE', 'Gene', '50940', (219, 222))	('PDE', 'Gene', '50940', (376, 379))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (106, 132))	('PDE8B', 'Gene', '8622', (376, 381))	('GNAS', 'Gene', (166, 170))	('mutations', 'Var', (183, 192))	('PRKAR1A', 'Gene', (174, 181))	('PDE', 'Gene', (219, 222))	('GNAS', 'Gene', '2778', (166, 170))	('PDE', 'Gene', (376, 379))	('associated', 'Reg', (252, 262))	('inactivating mutations', 'Var', (286, 308))	('PDE', 'Gene', '50940', (316, 319))	('genetic defects', 'Disease', (147, 162))	('genetic defects', 'Disease', 'MESH:D030342', (147, 162))	('PDE8B', 'Gene', (376, 381))	('PDE', 'Gene', (316, 319))	('adrenocortical hyperplasia', 'Disease', (106, 132))	('PDE11A', 'Gene', (316, 322))	('PDE11A', 'Gene', '50940', (316, 322))
107454	30456751	In addition, two missense substitutions that are relatively frequent polymorphisms of the PDE11A gene, R804H and R867G, were found with increased frequency among individuals with adrenal lesions.	('found', 'Reg', (125, 130))	('R804H', 'Mutation', 'rs75127279', (103, 108))	('adrenal lesions', 'Disease', 'MESH:D000307', (179, 194))	('R804H', 'Var', (103, 108))	('R867G', 'Var', (113, 118))	('PDE11A', 'Gene', (90, 96))	('PDE11A', 'Gene', '50940', (90, 96))	('adrenal lesions', 'Disease', (179, 194))	('R867G', 'Mutation', 'rs61306957', (113, 118))
107455	30456751	Furthermore, in a study aimed at identifying the presence of germline or somatic PDE11A mutations that included 117 subjects with adrenocortical tumors and 195 control subjects, a higher frequency of PDE11A mutations was found in subjects with adrenocortical tumors compared to age/sex matched controls (16% vs 10% in adrenocortical cancer, 19% vs 10% in adrenocortical adenoma, and 24% vs 9% in AIMAH).	('adrenocortical cancer', 'Disease', (318, 339))	('mutations', 'Var', (88, 97))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (244, 265))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (355, 377))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('mutations', 'Var', (207, 216))	('PDE11A', 'Gene', (200, 206))	('PDE11A', 'Gene', '50940', (200, 206))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (355, 377))	('adrenocortical tumors', 'Disease', (244, 265))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (130, 151))	('PDE11A', 'Gene', (81, 87))	('PDE11A', 'Gene', '50940', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (318, 339))	('adrenocortical adenoma', 'Disease', (355, 377))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('adrenocortical tumors', 'Disease', (130, 151))
107456	30456751	In another series of 150 patients with CNC, a higher frequency of PDE11A variants was noted in patients with CNC compared with healthy controls.	('CNC', 'Disease', (109, 112))	('patients', 'Species', '9606', (95, 103))	('variants', 'Var', (73, 81))	('PDE11A', 'Gene', '50940', (66, 72))	('patients', 'Species', '9606', (25, 33))	('PDE11A', 'Gene', (66, 72))
107457	30456751	Among patients with CNC, those with PPNAD and/or testicular large-cell calcifying Sertoli cell tumors (LCCSCT) were more frequently carriers of PDE11A variants compared to those without PPNAD and/or LCCSCT, respectively.	('testicular large', 'Phenotype', 'HP:0000053', (49, 65))	('CS', 'Phenotype', 'HP:0003118', (105, 107))	('variants', 'Var', (151, 159))	('carriers', 'Reg', (132, 140))	('cell tumors', 'Disease', (90, 101))	('CNC', 'Disease', (20, 23))	('PDE11A', 'Gene', (144, 150))	('PDE11A', 'Gene', '50940', (144, 150))	('CS', 'Phenotype', 'HP:0003118', (201, 203))	('patients', 'Species', '9606', (6, 14))	('cell tumors', 'Disease', 'MESH:D005935', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (82, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
107458	30456751	This suggests that PDE11A may be a genetic modifying factor for the development of adrenal and testicular tumors in patients with CNC and PRKAR1A mutations.	('CNC', 'Gene', (130, 133))	('adrenal and', 'Disease', (83, 94))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('PDE11A', 'Gene', (19, 25))	('PDE11A', 'Gene', '50940', (19, 25))	('mutations', 'Var', (146, 155))	('patients', 'Species', '9606', (116, 124))	('testicular tumors', 'Disease', 'MESH:D013736', (95, 112))	('adrenal and testicular tumors', 'Phenotype', 'HP:0100631', (83, 112))	('testicular tumors', 'Phenotype', 'HP:0010788', (95, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PRKAR1A', 'Gene', (138, 145))	('testicular tumors', 'Disease', (95, 112))
107459	30456751	PDE11A inactivating mutations may also play a role in the development of prostate cancer.	('prostate cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('inactivating mutations', 'Var', (7, 29))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('play', 'Reg', (39, 43))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('PDE11A', 'Gene', (0, 6))	('PDE11A', 'Gene', '50940', (0, 6))
107460	30456751	A single germline PDE8B missense substitution was initially reported in a patient with iMAD and CS.	('patient', 'Species', '9606', (74, 81))	('PDE8B', 'Gene', (18, 23))	('PDE8B', 'Gene', '8622', (18, 23))	('CS', 'Phenotype', 'HP:0003118', (96, 98))	('missense substitution', 'Var', (24, 45))	('iMAD', 'Disease', (87, 91))
107461	30456751	The patient inherited the PDE8B mutation from her father, who was not diagnosed with CS but did have a phenotype consistent with mild iMAD with elevated midnight cortisol.	('PDE8B', 'Gene', (26, 31))	('PDE8B', 'Gene', '8622', (26, 31))	('CS', 'Phenotype', 'HP:0003118', (85, 87))	('patient', 'Species', '9606', (4, 11))	('cortisol', 'Chemical', 'MESH:D006854', (162, 170))	('elevated', 'PosReg', (144, 152))	('mild iMAD', 'Disease', (129, 138))	('inherited', 'Reg', (12, 21))	('mutation', 'Var', (32, 40))
107462	30456751	In addition, in a case-control study of 216 unrelated patients with adrenocortical tumors and 192 controls, nine different PDE8B sequence changes were identified in the patients and controls, with two variations that were seen only in the patient group, demonstrating significant potential to impair protein function in vitro and in silico.	('patient', 'Species', '9606', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('patient', 'Species', '9606', (239, 246))	('patients', 'Species', '9606', (169, 177))	('protein', 'Protein', (300, 307))	('PDE8B', 'Gene', (123, 128))	('patients', 'Species', '9606', (54, 62))	('adrenocortical tumors', 'Disease', (68, 89))	('PDE8B', 'Gene', '8622', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('impair', 'NegReg', (293, 299))	('patient', 'Species', '9606', (169, 176))	('changes', 'Var', (138, 145))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (68, 89))
107463	30456751	Furthermore, in a study of samples from 27 patients with adrenocortical tumors without mutations in GNAS, PRKAR1A, PDE11A, or PDE8B, abnormalities of the cAMP-signaling pathway were found, with mutation-negative ACAs having significantly decreased PDE activity.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PDE', 'Gene', (126, 129))	('PRKAR1A', 'Gene', (106, 113))	('cAMP', 'Gene', '820', (154, 158))	('adrenocortical tumors', 'Disease', (57, 78))	('mutation-negative', 'Var', (194, 211))	('PDE11A', 'Gene', '50940', (115, 121))	('PDE', 'Gene', '50940', (115, 118))	('PDE11A', 'Gene', (115, 121))	('PDE8B', 'Gene', (126, 131))	('GNAS', 'Gene', (100, 104))	('PDE', 'Gene', '50940', (248, 251))	('decreased', 'NegReg', (238, 247))	('PDE', 'Gene', (115, 118))	('GNAS', 'Gene', '2778', (100, 104))	('patients', 'Species', '9606', (43, 51))	('PDE', 'Gene', (248, 251))	('cAMP', 'Gene', (154, 158))	('activity', 'MPA', (252, 260))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (57, 78))	('PDE', 'Gene', '50940', (126, 129))	('PDE8B', 'Gene', '8622', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))
107465	30456751	A study performing whole exome sequencing of tumor-tissue specimens from 10 patients with unilateral ACAs and overt CS revealed somatic mutations in the PRKACA gene, encoding the catalytic subunit Calpha of PKA, in 8 out of 10 adenomas.	('patients', 'Species', '9606', (76, 84))	('CS', 'Phenotype', 'HP:0003118', (116, 118))	('adenomas', 'Disease', (227, 235))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('mutations', 'Var', (136, 145))	('PRKACA', 'Gene', (153, 159))	('adenomas', 'Disease', 'MESH:D000236', (227, 235))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('PRKACA', 'Gene', '5566', (153, 159))
107466	30456751	Further sequencing of an additional 129 adenomas revealed a Leu206Arg variant in 14 of these 129 ACAs, with all 14 patients having overt CS.	('patients', 'Species', '9606', (115, 123))	('adenomas', 'Disease', 'MESH:D000236', (40, 48))	('Leu206Arg', 'Var', (60, 69))	('Leu206Arg', 'SUBSTITUTION', 'None', (60, 69))	('CS', 'Phenotype', 'HP:0003118', (137, 139))	('adenomas', 'Disease', (40, 48))
107467	30456751	PRKACA mutations were found only in patients with overt CS and were associated with a more severe phenotype.	('associated with', 'Reg', (68, 83))	('patients', 'Species', '9606', (36, 44))	('PRKACA', 'Gene', (0, 6))	('PRKACA', 'Gene', '5566', (0, 6))	('CS', 'Phenotype', 'HP:0003118', (56, 58))	('mutations', 'Var', (7, 16))
107468	30456751	Following the publication of these data in 2013, another three studies from China, Japan, and the USA demonstrated similar findings, with PRKACA mutations identified in 86 of 206 (42%) reported cases of ACAs with overt CS.	('mutations', 'Var', (145, 154))	('identified', 'Reg', (155, 165))	('CS', 'Phenotype', 'HP:0003118', (219, 221))	('PRKACA', 'Gene', (138, 144))	('PRKACA', 'Gene', '5566', (138, 144))
107469	30456751	Furthermore, comparative genomic hybridization of samples from 35 patients with cortisol-secreting BAH and overt CS demonstrated germline copy-number gains (both inherited and de novo) in a region on chromosome 19p that includes the PRKACA gene in 5 patients.	('CS', 'Phenotype', 'HP:0003118', (113, 115))	('PRKACA', 'Gene', (233, 239))	('PRKACA', 'Gene', '5566', (233, 239))	('patients', 'Species', '9606', (250, 258))	('copy-number gains', 'Var', (138, 155))	('patients', 'Species', '9606', (66, 74))	('BAH', 'Chemical', '-', (99, 102))	('cortisol', 'Chemical', 'MESH:D006854', (80, 88))
107472	30456751	These were the only genetic defects linked to AIMAH until inactivating mutations of the ARMC5 gene, which encodes Armadillo repeat containing protein 5, were found in 18 of 33 patients (55%) with AIMAH, with ARMC5 likely acting as a tumor suppressor gene (see below).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('patients', 'Species', '9606', (176, 184))	('inactivating mutations', 'Var', (58, 80))	('ARMC5', 'Gene', (208, 213))	('Armadillo repeat containing protein 5', 'Gene', (114, 151))	('tumor', 'Disease', (233, 238))	('ARMC5', 'Gene', (88, 93))	('Armadillo repeat containing protein 5', 'Gene', '79798', (114, 151))	('ARMC5', 'Gene', '79798', (88, 93))	('ARMC5', 'Gene', '79798', (208, 213))	('genetic defects', 'Disease', 'MESH:D030342', (20, 35))	('genetic defects', 'Disease', (20, 35))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
107473	30456751	AIMAH has also been linked to ectopic or abnormal expression of hormone receptors linked to steroidogenesis in adrenocortical cells, primarily members of the GPCR family, including those for gastric inhibitory polypeptide (GIP), vasopressin (V1-vasopressin), beta-adrenergic agonists, LH/hCG, or serotonin.	('serotonin', 'Chemical', 'MESH:D012701', (296, 305))	('abnormal', 'Var', (41, 49))	('LH', 'Chemical', 'MESH:D007986', (285, 287))	('gastric inhibitory polypeptide', 'Gene', '2695', (191, 221))	('ectopic', 'Var', (30, 37))	('vasopressin', 'Gene', '551', (245, 256))	('adrenocortical', 'Disease', (111, 125))	('vasopressin', 'Gene', (245, 256))	('vasopressin', 'Gene', (229, 240))	('vasopressin', 'Gene', '551', (229, 240))	('GIP', 'Gene', (223, 226))	('adrenocortical', 'Disease', 'MESH:D018268', (111, 125))	('gastric inhibitory polypeptide', 'Gene', (191, 221))	('GIP', 'Gene', '2695', (223, 226))	('expression', 'MPA', (50, 60))
107476	30456751	This abnormal receptor expression may lead to potential therapeutic targets, as described in a 63-year-old woman that had AIMAH with abnormal LH/hCG and serotonin receptor expression, who responded to treatment with leuprolide.	('serotonin', 'Chemical', 'MESH:D012701', (153, 162))	('LH/hCG', 'Gene', (142, 148))	('serotonin', 'MPA', (153, 162))	('woman', 'Species', '9606', (107, 112))	('abnormal', 'Var', (133, 141))	('LH', 'Chemical', 'MESH:D007986', (142, 144))
107481	30456751	Molecular analysis of peripheral and/or tumor DNA in this cohort revealed germline mutations in the APC gene, MEN1 gene, and FH gene in three of the patients with AIMAH, who did not have a family history of CS.	('mutations', 'Var', (83, 92))	('MEN1', 'Gene', (110, 114))	('FH gene', 'Gene', (125, 132))	('patients', 'Species', '9606', (149, 157))	('MEN1', 'Gene', '4221', (110, 114))	('CS', 'Phenotype', 'HP:0003118', (207, 209))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('APC', 'Disease', 'MESH:D011125', (100, 103))	('APC', 'Disease', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
107487	30456751	Most patients with AIMAH had histology consistent with type II AIMAH, whereas the three familial cases, the patients with germline MEN1 and APC mutations, and the one patient with the somatic GNAS mutation demonstrated histology consistent with type I AIMAH.	('patient', 'Species', '9606', (5, 12))	('patients', 'Species', '9606', (5, 13))	('GNAS', 'Gene', (192, 196))	('patient', 'Species', '9606', (167, 174))	('APC', 'Disease', 'MESH:D011125', (140, 143))	('APC', 'Disease', (140, 143))	('MEN1', 'Gene', '4221', (131, 135))	('AIMAH', 'Disease', (19, 24))	('type II AIMAH', 'Disease', (55, 68))	('MEN1', 'Gene', (131, 135))	('patient', 'Species', '9606', (108, 115))	('GNAS', 'Gene', '2778', (192, 196))	('patients', 'Species', '9606', (108, 116))	('mutations', 'Var', (144, 153))
107488	30456751	Another study of 14 patients with AIMAH revealed a link to aberrant cAMP-PKA pathway signaling through the demonstration of somatic losses of the 17q22-24 region in 73% of samples as well as PKA subunit and enzymatic activity changes.	('cAMP', 'Gene', (68, 72))	('17q22-24 region', 'Gene', (146, 161))	('losses', 'NegReg', (132, 138))	('cAMP', 'Gene', '820', (68, 72))	('aberrant', 'Var', (59, 67))	('changes', 'Reg', (226, 233))	('patients', 'Species', '9606', (20, 28))
107493	30456751	Investigation into the genetic origin of AIMAH led to the genotyping (both blood and tumor) of 33 patients with AIMAH, with detection of inactivating ARMC5 gene mutations in 55% (18/33) of tumors, as noted above.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', (189, 194))	('ARMC5', 'Gene', (150, 155))	('tumors', 'Disease', (189, 195))	('patients', 'Species', '9606', (98, 106))	('ARMC5', 'Gene', '79798', (150, 155))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mutations', 'Var', (161, 170))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('inactivating', 'Var', (137, 149))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
107494	30456751	In all 18 cases of ARMC5 mutations, both ARMC5 alleles were mutated, one germline and one somatic, with four cases with germline mutations harboring nodule-specific secondary ARMC5 mutations.	('mutations', 'Var', (25, 34))	('ARMC5', 'Gene', (19, 24))	('ARMC5', 'Gene', '79798', (19, 24))	('ARMC5', 'Gene', '79798', (175, 180))	('ARMC5', 'Gene', (175, 180))	('ARMC5', 'Gene', '79798', (41, 46))	('ARMC5', 'Gene', (41, 46))
107496	30456751	The function of ARMC5 is unknown, though the protein it encodes contains an armadillo repeat domain, which is similar to the gene for beta-catenin that also contains armadillo repeats and is often mutated in various cancers, including adrenocortical tumors.	('beta-catenin', 'Gene', '1499', (134, 146))	('ARMC5', 'Gene', '79798', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('ARMC5', 'Gene', (16, 21))	('adrenocortical tumors', 'Disease', (235, 256))	('mutated', 'Var', (197, 204))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('cancers', 'Disease', (216, 223))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (235, 256))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('beta-catenin', 'Gene', (134, 146))
107497	30456751	In this study of 33 patients with AIMAH, inactivation of ARMC5 was associated with reduced expression of steroidogenic enzymes and MC2R with abnormal cortisol production.	('expression', 'MPA', (91, 101))	('steroidogenic enzymes', 'MPA', (105, 126))	('reduced', 'NegReg', (83, 90))	('ARMC5', 'Gene', (57, 62))	('MC2R', 'Gene', (131, 135))	('inactivation', 'Var', (41, 53))	('cortisol', 'Chemical', 'MESH:D006854', (150, 158))	('ARMC5', 'Gene', '79798', (57, 62))	('patients', 'Species', '9606', (20, 28))	('cortisol production', 'MPA', (150, 169))	('MC2R', 'Gene', '4158', (131, 135))	('abnormal cortisol', 'Phenotype', 'HP:0011731', (141, 158))
107500	30456751	The large size of the adrenal glands may be related to loss of the ability to induce apoptosis in adrenocortical cells with ARMC5 mutations, as demonstrated experimentally in human adrenocortical cell lines compared to wild-type cell lines.	('human', 'Species', '9606', (175, 180))	('ARMC5', 'Gene', '79798', (124, 129))	('ARMC5', 'Gene', (124, 129))	('adrenocortical', 'Disease', 'MESH:D018268', (181, 195))	('apoptosis', 'CPA', (85, 94))	('mutations', 'Var', (130, 139))	('adrenocortical', 'Disease', (98, 112))	('adrenocortical', 'Disease', 'MESH:D018268', (98, 112))	('large size of the adrenal glands', 'Phenotype', 'HP:0008221', (4, 36))	('adrenocortical', 'Disease', (181, 195))
107501	30456751	In addition, an association between primary hyperaldosteronism and ARMC5 mutations was first described in 2015.	('hyperaldosteronism', 'Disease', (44, 62))	('ARMC5', 'Gene', '79798', (67, 72))	('ARMC5', 'Gene', (67, 72))	('primary hyperaldosteronism', 'Phenotype', 'HP:0011736', (36, 62))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (44, 62))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (44, 62))	('mutations', 'Var', (73, 82))
107524	30456751	FH IV is attributed to germline mutations in CACNA1H (calcium channel, voltage-dependent, T-type, alpha-1H subunit), which encodes a T-type calcium channel.	('germline mutations', 'Var', (23, 41))	('CACNA1H', 'Gene', (45, 52))	('calcium', 'Chemical', 'MESH:D002118', (54, 61))	('CACNA1H', 'Gene', '8912', (45, 52))	('calcium', 'Chemical', 'MESH:D002118', (140, 147))
107525	30456751	Germline mutations in KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) lead to FH III, while somatic mutations are associated with 40% of APAs.	('Germline mutations', 'Var', (0, 18))	('lead to', 'Reg', (91, 98))	('potassium inwardly rectifying channel, subfamily J, member 5', 'Gene', '3762', (29, 89))	('PA', 'Phenotype', 'HP:0011736', (159, 161))	('FH II', 'Gene', '79179', (99, 104))	('APAs', 'Disease', (158, 162))	('FH II', 'Gene', (99, 104))	('associated', 'Reg', (135, 145))	('KCNJ5', 'Gene', (22, 27))	('KCNJ5', 'Gene', '3762', (22, 27))
107526	30456751	In a study of 22 patients with APAs, two recurrent somatic mutations (G151R and L168R), in and near the selectivity filter of the potassium channel KCNJ5, were present in eight of 22 APA samples.	('L168R', 'Var', (80, 85))	('PA', 'Phenotype', 'HP:0011736', (184, 186))	('KCNJ5', 'Gene', (148, 153))	('potassium', 'Chemical', 'MESH:D011188', (130, 139))	('PA', 'Phenotype', 'HP:0011736', (32, 34))	('G151R', 'Var', (70, 75))	('KCNJ5', 'Gene', '3762', (148, 153))	('patients', 'Species', '9606', (17, 25))	('L168R', 'Mutation', 'rs386352318', (80, 85))	('G151R', 'Mutation', 'rs386352319', (70, 75))
107527	30456751	KCNJ5 encodes an inwardly rectifying potassium channel, with the described mutations causing altered K+ channel selectivity.	('potassium', 'Chemical', 'MESH:D011188', (37, 46))	('KCNJ5', 'Gene', '3762', (0, 5))	('mutations', 'Var', (75, 84))	('K+ channel selectivity', 'MPA', (101, 123))	('KCNJ5', 'Gene', (0, 5))	('causing altered', 'Reg', (85, 100))
107530	30456751	These data from APAs were suggestive that inherited mutations in KCNJ5 could lead to PA with BAH through a similar pathogenetic mechanism that affects all adrenocortical cells.	('mutations', 'Var', (52, 61))	('lead to', 'Reg', (77, 84))	('KCNJ5', 'Gene', (65, 70))	('KCNJ5', 'Gene', '3762', (65, 70))	('affects', 'Reg', (143, 150))	('BAH', 'Chemical', '-', (93, 96))	('adrenocortical', 'Disease', (155, 169))	('adrenocortical', 'Disease', 'MESH:D018268', (155, 169))	('PA', 'Phenotype', 'HP:0011736', (85, 87))	('PA', 'Phenotype', 'HP:0011736', (17, 19))
107531	30456751	This was seen in a family with PA and massive adrenal hyperplasia, who were heterozygous for the T158A mutation in the KCNJ5 gene.	('T158A', 'Mutation', 'rs387906778', (97, 102))	('T158A', 'Var', (97, 102))	('KCNJ5', 'Gene', '3762', (119, 124))	('adrenal hyperplasia', 'Disease', (46, 65))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (46, 65))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (46, 65))	('KCNJ5', 'Gene', (119, 124))	('PA', 'Phenotype', 'HP:0011736', (31, 33))
107532	30456751	These implicate Germline heterozygous KCNJ5 mutations have also been linked to the pathogenesis of hypertension associated with increased aldosterone response to ACTH stimulation.	('ACTH', 'Gene', '5443', (162, 166))	('hypertension', 'Disease', 'MESH:D006973', (99, 111))	('linked', 'Reg', (69, 75))	('KCNJ5', 'Gene', '3762', (38, 43))	('hypertension', 'Disease', (99, 111))	('increased', 'PosReg', (128, 137))	('implicate', 'Reg', (6, 15))	('hypertension', 'Phenotype', 'HP:0000822', (99, 111))	('mutations', 'Var', (44, 53))	('increased aldosterone', 'Phenotype', 'HP:0000859', (128, 149))	('aldosterone', 'Chemical', 'MESH:D000450', (138, 149))	('ACTH', 'Gene', (162, 166))	('KCNJ5', 'Gene', (38, 43))
107534	30456751	In addition to the previously described KCNJ5 and CACNA1H mutations, further molecular analysis has resulted in the elucidation of several other somatic and, less frequently, germline mutations associated with FH and/or sporadic APAs.	('CACNA1H', 'Gene', '8912', (50, 57))	('KCNJ5', 'Gene', '3762', (40, 45))	('mutations', 'Var', (184, 193))	('associated', 'Reg', (194, 204))	('APAs', 'Disease', (229, 233))	('CACNA1H', 'Gene', (50, 57))	('KCNJ5', 'Gene', (40, 45))	('PA', 'Phenotype', 'HP:0011736', (230, 232))
107535	30456751	These mutations include those in ATPase, Na+/K+ transporting, alpha1-polypeptide (ATP1A1), ATPase, Ca2+-transporting, plasma membrane, 3 (ATP2B3), and calcium channel, voltage-dependent, L-type, alpha-1D subunit (CACNA1D).	('ATP1A1', 'Gene', '476', (82, 88))	('ATP1A1', 'Gene', (82, 88))	('Ca2+-transporting', 'MPA', (99, 116))	('ATP2B3', 'Gene', '492', (138, 144))	('ATP2B3', 'Gene', (138, 144))	('Ca2+', 'Chemical', 'MESH:D000069285', (99, 103))	('CACNA1D', 'Gene', '776', (213, 220))	('CACNA1D', 'Gene', (213, 220))	('ATPase', 'Gene', (33, 39))	('calcium', 'Chemical', 'MESH:D002118', (151, 158))	('mutations', 'Var', (6, 15))	('Na+/K+ transporting', 'MPA', (41, 60))
107539	30456751	Three of these six tumors had aldosterone-regulating mutations in KCNJ5, ATP1A1, or CACNA1D only in CYP11B2-positive regions, while one had two different mutations in KCNJ5 and ATP2B3 in two histologically different CYP11B2-positive regions.	('tumors', 'Disease', (19, 25))	('CYP11B2', 'Gene', (216, 223))	('KCNJ5', 'Gene', '3762', (66, 71))	('CYP11B2', 'Gene', '1585', (100, 107))	('KCNJ5', 'Gene', '3762', (167, 172))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('aldosterone', 'Chemical', 'MESH:D000450', (30, 41))	('ATP1A1', 'Gene', (73, 79))	('CACNA1D', 'Gene', '776', (84, 91))	('CYP11B2', 'Gene', (100, 107))	('mutations', 'Var', (53, 62))	('CACNA1D', 'Gene', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('CYP11B2', 'Gene', '1585', (216, 223))	('aldosterone-regulating', 'MPA', (30, 52))	('ATP1A1', 'Gene', '476', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('KCNJ5', 'Gene', (66, 71))	('ATP2B3', 'Gene', '492', (177, 183))	('ATP2B3', 'Gene', (177, 183))	('KCNJ5', 'Gene', (167, 172))
107540	30456751	The seventh patient had a multinodular hyperplasic adrenal that showed CYP11B2-positive and CYP11B2-negative nodules, and different mutations in each CYP11B2-positive nodule (ATP1A1, CACNA1D), with no mutations in CYP11B2-negative nodules or the adjacent normal adrenal.	('CYP11B2', 'Gene', '1585', (71, 78))	('CYP11B2', 'Gene', (150, 157))	('CYP11B2', 'Gene', (214, 221))	('CYP11B2', 'Gene', (92, 99))	('ATP1A1', 'Gene', '476', (175, 181))	('multinodular hyperplasic adrenal', 'Disease', (26, 58))	('CACNA1D', 'Gene', '776', (183, 190))	('ATP1A1', 'Gene', (175, 181))	('CACNA1D', 'Gene', (183, 190))	('CYP11B2', 'Gene', '1585', (150, 157))	('CYP11B2', 'Gene', '1585', (92, 99))	('mutations', 'Var', (132, 141))	('CYP11B2', 'Gene', '1585', (214, 221))	('hyperplasic adrenal', 'Phenotype', 'HP:0008221', (39, 58))	('multinodular hyperplasic adrenal', 'Disease', 'MESH:C564546', (26, 58))	('patient', 'Species', '9606', (12, 19))	('CYP11B2', 'Gene', (71, 78))
107546	30456751	A study published in 2014 based on the molecular analysis of 45 ACCs further elucidated the molecular pathogenesis of ACC with reidentification of genetic alterations in known driver genes CTNNB1, TP53, CDKN2A, and RB1, as well as identification of driver genes not previously reported including, ZNRF3, DAXX, TERT, and MED12.	('TERT', 'Gene', '7015', (310, 314))	('MED12', 'Gene', '9968', (320, 325))	('alterations', 'Var', (155, 166))	('CTNNB1', 'Gene', (189, 195))	('CDKN2A', 'Gene', '1029', (203, 209))	('RB1', 'Gene', '5925', (215, 218))	('TP53', 'Gene', (197, 201))	('ACC', 'Phenotype', 'HP:0006744', (64, 67))	('MED12', 'Gene', (320, 325))	('DAXX', 'Gene', (304, 308))	('ACC', 'Phenotype', 'HP:0006744', (118, 121))	('ACC', 'Disease', (118, 121))	('DAXX', 'Gene', '1616', (304, 308))	('TP53', 'Gene', '7157', (197, 201))	('ZNRF3', 'Gene', '84133', (297, 302))	('CTNNB1', 'Gene', '1499', (189, 195))	('ZNRF3', 'Gene', (297, 302))	('RB1', 'Gene', (215, 218))	('CDKN2A', 'Gene', (203, 209))	('TERT', 'Gene', (310, 314))
107551	30456751	Furthermore, genome-wide DNA copy number analysis demonstrated increased frequency of DNA loss, followed by whole genome doubling, which was associated with more aggressive tumors.	('DNA', 'Var', (86, 89))	('loss', 'NegReg', (90, 94))	('aggressive tumors', 'Disease', (162, 179))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('aggressive tumors', 'Disease', 'MESH:D001523', (162, 179))
107558	30456751	Patients receiving first-line therapy with EDP-mitotane had a significantly higher response rate and longer median progression-free survival compared to the streptozocin-mitotane group (5 months vs 2.1 months, respectively).	('streptozocin-mitotane', 'Chemical', '-', (157, 178))	('EDP-mitotane', 'Var', (43, 55))	('Patients', 'Species', '9606', (0, 8))	('progression-free survival', 'CPA', (115, 140))	('EDP-mitotane', 'Chemical', '-', (43, 55))	('response', 'MPA', (83, 91))	('higher', 'PosReg', (76, 82))
107567	30456751	Six autosomal dominant pheochromocytoma/paraganglioma syndromes have distinct clinical features and include neurofibromatosis type 1 (NF1), multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau syndrome (VHL), renal cell carcinoma with SDHB mutation, Carney triad, and Carney-Stratakis syndrome (CSS).	('pheochromocytoma', 'Phenotype', 'HP:0002666', (23, 39))	('neurofibromatosis type 1', 'Gene', (108, 132))	('VHL', 'Gene', (212, 215))	('multiple endocrine neoplasia type 2', 'Disease', (140, 175))	('NF1', 'Gene', '4763', (134, 137))	('SDHB', 'Gene', '6390', (244, 248))	('paraganglioma', 'Phenotype', 'HP:0002668', (40, 53))	('mutation', 'Var', (249, 257))	('CSS', 'Disease', (304, 307))	('pheochromocytoma/paraganglioma syndromes', 'Disease', (23, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('renal cell carcinoma', 'Disease', (218, 238))	('NF1', 'Gene', (134, 137))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (218, 238))	('Carney-Stratakis syndrome', 'Disease', (277, 302))	('VHL', 'Gene', '7428', (212, 215))	('SDHB', 'Gene', (244, 248))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (108, 125))	('neoplasia', 'Phenotype', 'HP:0002664', (159, 168))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (140, 175))	('neurofibromatosis type 1', 'Gene', '4763', (108, 132))	('CS', 'Phenotype', 'HP:0003118', (304, 306))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (149, 168))	('von Hippel-Lindau syndrome', 'Disease', (184, 210))	('CSS', 'Disease', 'MESH:C536436', (304, 307))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (277, 302))	('pheochromocytoma/paraganglioma syndromes', 'Disease', 'MESH:D010673', (23, 63))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (184, 210))	('Carney triad', 'Disease', (259, 271))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (218, 238))
107569	30456751	In a study of 173 patients with pheochromocytoma and/or paraganglioma, all patients with MEN2 and NF1 mutations had elevated plasma metanephrine, whereas patients with VHL mutations usually had elevated normetanephrine, and 70% of patients with SDHB and SDHD mutations had elevated plasma methoxytyramine.	('plasma methoxytyramine', 'MPA', (282, 304))	('SDHB', 'Gene', '6390', (245, 249))	('elevated', 'PosReg', (116, 124))	('elevated', 'Reg', (273, 281))	('plasma metanephrine', 'MPA', (125, 144))	('SDHD', 'Gene', '6392', (254, 258))	('normetanephrine', 'Chemical', 'MESH:D009647', (203, 218))	('paraganglioma', 'Phenotype', 'HP:0002668', (56, 69))	('metanephrine', 'Chemical', 'MESH:D008676', (206, 218))	('elevated', 'PosReg', (194, 202))	('SDHB', 'Gene', (245, 249))	('MEN2', 'Gene', (89, 93))	('mutations', 'Var', (102, 111))	('methoxytyramine', 'Chemical', 'MESH:C001746', (289, 304))	('SDHD', 'Gene', (254, 258))	('pheochromocytoma', 'Disease', 'MESH:D010673', (32, 48))	('patients', 'Species', '9606', (75, 83))	('VHL', 'Gene', (168, 171))	('patients', 'Species', '9606', (154, 162))	('metanephrine', 'Chemical', 'MESH:D008676', (132, 144))	('normetanephrine', 'MPA', (203, 218))	('patients', 'Species', '9606', (18, 26))	('NF1', 'Gene', '4763', (98, 101))	('paraganglioma', 'Disease', (56, 69))	('paraganglioma', 'Disease', 'MESH:D010235', (56, 69))	('pheochromocytoma', 'Disease', (32, 48))	('patients', 'Species', '9606', (231, 239))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (32, 48))	('NF1', 'Gene', (98, 101))	('VHL', 'Gene', '7428', (168, 171))
107570	30456751	Measurement of normetanephrine and metanephrine allowed for the distinction of those patients with MEN2 and NF1 from those with VHL, SDHB, and SDHD mutations in 99% of cases, whereas plasma methoxytyramine measurement allowed for discrimination of VHL mutations from SDHB and SDHD mutations in 78% of patients.	('VHL', 'Gene', '7428', (128, 131))	('MEN2', 'Gene', (99, 103))	('metanephrine', 'Chemical', 'MESH:D008676', (18, 30))	('SDHB', 'Gene', '6390', (133, 137))	('patients', 'Species', '9606', (301, 309))	('SDHD', 'Gene', '6392', (143, 147))	('SDHD', 'Gene', '6392', (276, 280))	('NF1', 'Gene', '4763', (108, 111))	('SDHB', 'Gene', '6390', (267, 271))	('SDHD', 'Gene', (143, 147))	('patients', 'Species', '9606', (85, 93))	('SDHB', 'Gene', (133, 137))	('NF1', 'Gene', (108, 111))	('mutations', 'Var', (148, 157))	('SDHD', 'Gene', (276, 280))	('SDHB', 'Gene', (267, 271))	('VHL', 'Gene', (248, 251))	('VHL', 'Gene', (128, 131))	('metanephrine', 'Chemical', 'MESH:D008676', (35, 47))	('normetanephrine', 'Chemical', 'MESH:D009647', (15, 30))	('methoxytyramine', 'Chemical', 'MESH:C001746', (190, 205))	('VHL', 'Gene', '7428', (248, 251))
107581	30456751	SDHB mutations primarily predispose to extra-adrenal paragangliomas that secrete dopamine and norepinephrine and tend to occur at a young age, with high malignant potential and an aggressive disease course.	('aggressive disease', 'Disease', (180, 198))	('mutations', 'Var', (5, 14))	('extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (39, 67))	('SDHB', 'Gene', '6390', (0, 4))	('predispose to', 'Reg', (25, 38))	('aggressive disease', 'Disease', 'MESH:D001523', (180, 198))	('norepinephrine', 'Chemical', 'MESH:D009638', (94, 108))	('paraganglioma', 'Phenotype', 'HP:0002668', (53, 66))	('dopamine', 'Chemical', 'MESH:D004298', (81, 89))	('SDHB', 'Gene', (0, 4))	('extra-adrenal paragangliomas', 'Disease', (39, 67))	('paragangliomas', 'Phenotype', 'HP:0002668', (53, 67))
107582	30456751	These mutations less commonly lead to adrenal pheochromocytomas or head and neck paragangliomas.	('lead to', 'Reg', (30, 37))	('paraganglioma', 'Phenotype', 'HP:0002668', (81, 94))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (46, 63))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (67, 95))	('neck paragangliomas', 'Disease', 'MESH:D010235', (76, 95))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (67, 94))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (46, 62))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (38, 63))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (38, 63))	('neck paragangliomas', 'Disease', (76, 95))	('adrenal pheochromocytomas', 'Disease', (38, 63))	('mutations', 'Var', (6, 15))	('paragangliomas', 'Phenotype', 'HP:0002668', (81, 95))
107583	30456751	SDHB mutations are found in 40% of patients with metastatic pheochromocytoma/paraganglioma.	('pheochromocytoma/paraganglioma', 'Disease', (60, 90))	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('found', 'Reg', (19, 24))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (60, 90))	('mutations', 'Var', (5, 14))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (60, 76))	('SDHB', 'Gene', '6390', (0, 4))	('patients', 'Species', '9606', (35, 43))	('SDHB', 'Gene', (0, 4))
107584	30456751	SDHD gene mutations are associated with multifocal head and neck paragangliomas and less commonly with adrenal pheochromocytomas or paragangliomas at other sites.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (111, 128))	('associated', 'Reg', (24, 34))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (111, 127))	('adrenal pheochromocytomas or paragangliomas', 'Disease', (103, 146))	('paragangliomas', 'Phenotype', 'HP:0002668', (65, 79))	('adrenal pheochromocytomas or paragangliomas', 'Disease', 'MESH:D010673', (103, 146))	('paraganglioma', 'Phenotype', 'HP:0002668', (65, 78))	('SDHD', 'Gene', '6392', (0, 4))	('multifocal head and neck paragangliomas', 'Disease', 'None', (40, 79))	('paragangliomas', 'Phenotype', 'HP:0002668', (132, 146))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (51, 79))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (103, 128))	('mutations', 'Var', (10, 19))	('paraganglioma', 'Phenotype', 'HP:0002668', (132, 145))	('SDHD', 'Gene', (0, 4))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (51, 78))
107587	30456751	Of these 32 patients, 71.8% had primary extra-adrenal tumors with genetic analysis demonstrating germline SDHB mutations in 71.9% of patients, SDHD mutations in 9.4% of patients (found in all patients with head and neck paraganglioma), and VHL mutations in 6.3% of patients.	('VHL', 'Gene', '7428', (240, 243))	('patients', 'Species', '9606', (133, 141))	('SDHD', 'Gene', '6392', (143, 147))	('extra-adrenal tumors', 'Disease', 'MESH:D010236', (40, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (111, 120))	('patients', 'Species', '9606', (12, 20))	('paraganglioma', 'Phenotype', 'HP:0002668', (220, 233))	('neck paraganglioma', 'Disease', (215, 233))	('SDHD', 'Gene', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('patients', 'Species', '9606', (265, 273))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (206, 233))	('mutations', 'Var', (148, 157))	('patients', 'Species', '9606', (192, 200))	('SDHB', 'Gene', '6390', (106, 110))	('neck paraganglioma', 'Disease', 'MESH:D010235', (215, 233))	('VHL', 'Gene', (240, 243))	('patients', 'Species', '9606', (169, 177))	('extra-adrenal tumors', 'Disease', (40, 60))	('SDHB', 'Gene', (106, 110))
107589	30456751	All five deceased pediatric patients harbored the SDHB mutation.	('harbored', 'Reg', (37, 45))	('SDHB', 'Gene', (50, 54))	('mutation', 'Var', (55, 63))	('patients', 'Species', '9606', (28, 36))	('SDHB', 'Gene', '6390', (50, 54))
107590	30456751	Given these data, it was recommended that patients with metastatic pheochromocytoma/paraganglioma presenting in childhood or adolescence undergo initial genetic testing for SDHB mutations, with the exception of patients with primary tumors of the head and neck (SDHD genetic testing recommended) and patients with a family history that suggests a different mutation.	('SDHD', 'Gene', (262, 266))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (67, 97))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('patients', 'Species', '9606', (211, 219))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('SDHB', 'Gene', '6390', (173, 177))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (67, 83))	('SDHB', 'Gene', (173, 177))	('pheochromocytoma/paraganglioma', 'Disease', (67, 97))	('primary tumors', 'Disease', (225, 239))	('paraganglioma', 'Phenotype', 'HP:0002668', (84, 97))	('SDHD', 'Gene', '6392', (262, 266))	('patients', 'Species', '9606', (42, 50))	('mutations', 'Var', (178, 187))	('patients', 'Species', '9606', (300, 308))	('primary tumors', 'Disease', 'MESH:D009369', (225, 239))
107591	30456751	Screening for SDHB and SDHD mutations may be also be prudent in patients with paragangliomas in certain uncommon locations such as the mediastinum or the organ of Zuckerkandl.	('paragangliomas', 'Disease', (78, 92))	('paragangliomas', 'Phenotype', 'HP:0002668', (78, 92))	('patients', 'Species', '9606', (64, 72))	('SDHD', 'Gene', '6392', (23, 27))	('SDHD', 'Gene', (23, 27))	('SDHB', 'Gene', '6390', (14, 18))	('paragangliomas', 'Disease', 'MESH:D010235', (78, 92))	('SDHB', 'Gene', (14, 18))	('paraganglioma', 'Phenotype', 'HP:0002668', (78, 91))	('mutations', 'Var', (28, 37))
107592	30456751	Mutations in SDHB or SDHD were identified in 10 out of 10 patients with mediastinal paragangliomas, a rare location for paraganglioma development (2%).	('paraganglioma', 'Disease', (84, 97))	('paraganglioma', 'Phenotype', 'HP:0002668', (84, 97))	('mediastinal paragangliomas', 'Disease', 'MESH:D008480', (72, 98))	('paraganglioma', 'Phenotype', 'HP:0002668', (120, 133))	('identified', 'Reg', (31, 41))	('SDHB', 'Gene', '6390', (13, 17))	('paraganglioma', 'Disease', 'MESH:D010235', (84, 97))	('paraganglioma', 'Disease', (120, 133))	('SDHD', 'Gene', '6392', (21, 25))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', (13, 17))	('mediastinal paragangliomas', 'Disease', (72, 98))	('SDHD', 'Gene', (21, 25))	('patients', 'Species', '9606', (58, 66))	('paragangliomas', 'Phenotype', 'HP:0002668', (84, 98))	('paraganglioma', 'Disease', 'MESH:D010235', (120, 133))
107593	30456751	Furthermore, SDHB or SDHD mutations were detected in the majority of patients with organ of Zuckerkandl paragangliomas, another rare site of paraganglioma occurrence located around the origin of the inferior mesenteric artery and extending to the level of the aortic bifurcation.	('detected', 'Reg', (41, 49))	('paraganglioma', 'Disease', 'MESH:D010235', (104, 117))	('paraganglioma', 'Disease', 'MESH:D010235', (141, 154))	('SDHB', 'Gene', '6390', (13, 17))	('paragangliomas', 'Disease', (104, 118))	('paragangliomas', 'Disease', 'MESH:D010235', (104, 118))	('SDHD', 'Gene', '6392', (21, 25))	('mutations', 'Var', (26, 35))	('paraganglioma', 'Phenotype', 'HP:0002668', (104, 117))	('SDHB', 'Gene', (13, 17))	('paragangliomas', 'Phenotype', 'HP:0002668', (104, 118))	('SDHD', 'Gene', (21, 25))	('paraganglioma', 'Phenotype', 'HP:0002668', (141, 154))	('patients', 'Species', '9606', (69, 77))	('paraganglioma', 'Disease', (104, 117))	('paraganglioma', 'Disease', (141, 154))
107594	30456751	In addition, per the most recent Endocrine Society Clinical Practice Guideline published in 2014, patients with paragangliomas should undergo genetic testing for SDH mutations, and those with metastatic disease should undergo evaluation for SDHB mutations.	('SDHB', 'Gene', (241, 245))	('paragangliomas', 'Phenotype', 'HP:0002668', (112, 126))	('mutations', 'Var', (166, 175))	('paragangliomas', 'Disease', 'MESH:D010235', (112, 126))	('SDH', 'Gene', '6390', (162, 165))	('SDH', 'Gene', (241, 244))	('patients', 'Species', '9606', (98, 106))	('mutations', 'Var', (246, 255))	('SDH', 'Gene', (162, 165))	('paragangliomas', 'Disease', (112, 126))	('SDH', 'Gene', '6390', (241, 244))	('SDHB', 'Gene', '6390', (241, 245))	('paraganglioma', 'Phenotype', 'HP:0002668', (112, 125))
107596	30456751	A study comparing the sensitivity of functional imaging techniques in the localization of head and neck paragangliomas (harboring SDHD or SDHB mutations) demonstrated that 18F-fluorodihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET) was the most sensitive study, localizing all tumors, followed by 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT, which localized 77% of tumors75.	('neck paragangliomas', 'Disease', (99, 118))	('SDHD', 'Gene', (130, 134))	('paraganglioma', 'Phenotype', 'HP:0002668', (104, 117))	('paragangliomas', 'Phenotype', 'HP:0002668', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (387, 392))	('18F-fluorodihydroxyphenylalanine', 'Chemical', 'MESH:C043437', (172, 204))	('tumors', 'Phenotype', 'HP:0002664', (387, 393))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (206, 215))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (90, 118))	('neck paragangliomas', 'Disease', 'MESH:D010235', (99, 118))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('PA', 'Phenotype', 'HP:0011736', (213, 215))	('SDHB', 'Gene', '6390', (138, 142))	('mutations', 'Var', (143, 152))	('tumors', 'Disease', (387, 393))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumors', 'Disease', (297, 303))	('SDHB', 'Gene', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (387, 393))	('SDHD', 'Gene', '6392', (130, 134))	('18F-fluoro-2-deoxy-D-glucose', 'Chemical', '-', (317, 345))	('tumors', 'Disease', 'MESH:D009369', (297, 303))	('18F-FDG', 'Chemical', '-', (347, 354))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (90, 117))
107602	30456751	Furthermore, false-negative 123I-MIBG scintigraphy in patients with pheochromocytoma or paraganglioma has been associated with a more aggressive disease course and the presence of SDHB mutation.	('paraganglioma', 'Disease', (88, 101))	('SDHB', 'Gene', (180, 184))	('patients', 'Species', '9606', (54, 62))	('aggressive disease', 'Disease', 'MESH:D001523', (134, 152))	('pheochromocytoma', 'Disease', (68, 84))	('associated', 'Reg', (111, 121))	('mutation', 'Var', (185, 193))	('paraganglioma', 'Disease', 'MESH:D010235', (88, 101))	('123I-MIBG', 'Chemical', 'MESH:D019797', (28, 37))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (68, 84))	('aggressive disease', 'Disease', (134, 152))	('pheochromocytoma', 'Disease', 'MESH:D010673', (68, 84))	('paraganglioma', 'Phenotype', 'HP:0002668', (88, 101))	('SDHB', 'Gene', '6390', (180, 184))	('presence', 'Var', (168, 176))
107607	30456751	In 2007, evaluation for a genetic cause of Carney triad through comparative genomic hybridization of DNA samples from 41 patients, with the aim of detecting common gene abnormalities associated with paragangliomas (inactivating mutations in SDHA, SDHB, SDHC, and SDHD, or collectively SDHx) and GISTs (activating mutations in KIT and PDGFRA), did not identify abnormalities in these genes.	('paraganglioma', 'Phenotype', 'HP:0002668', (199, 212))	('SDHD', 'Gene', '6392', (263, 267))	('paragangliomas', 'Phenotype', 'HP:0002668', (199, 213))	('SDHA', 'Gene', (241, 245))	('SDHA', 'Gene', '6389', (241, 245))	('SDHD', 'Gene', (263, 267))	('paragangliomas', 'Disease', (199, 213))	('SDHC', 'Gene', '6391', (253, 257))	('SDHB', 'Gene', '6390', (247, 251))	('KIT', 'Gene', (326, 329))	('inactivating mutations', 'Var', (215, 237))	('patients', 'Species', '9606', (121, 129))	('GIST', 'Phenotype', 'HP:0100723', (295, 299))	('PDGFRA', 'Gene', '5156', (334, 340))	('PDGFRA', 'Gene', (334, 340))	('SDHx', 'Chemical', '-', (285, 289))	('SDHB', 'Gene', (247, 251))	('SDHC', 'Gene', (253, 257))	('paragangliomas', 'Disease', 'MESH:D010235', (199, 213))
107608	30456751	However, this evaluation did identify abnormalities in chromosome 1, most frequently deletion of the 1q12-q23.3 chromosomal region harboring the SDHC gene, as well as loss of the 1p region.	('SDHC', 'Gene', (145, 149))	('SDHC', 'Gene', '6391', (145, 149))	('deletion', 'Var', (85, 93))
107612	30456751	This was demonstrated in a study involving the largest cohort of Carney triad patients available internationally that demonstrated germline variants of SDHA, SDHB, or SHDC in six out of 63 patients (9.5%).	('variants', 'Var', (140, 148))	('SDHA', 'Gene', '6389', (152, 156))	('patients', 'Species', '9606', (78, 86))	('SHDC', 'Gene', (167, 171))	('SDHA', 'Gene', (152, 156))	('SDHB', 'Gene', '6390', (158, 162))	('patients', 'Species', '9606', (189, 197))	('SDHB', 'Gene', (158, 162))
107615	30456751	Patients with CSS harbor inactivating germline mutations in the SDHx genes .	('SDHx', 'Chemical', '-', (64, 68))	('SDHx', 'Gene', (64, 68))	('Patients', 'Species', '9606', (0, 8))	('CS', 'Phenotype', 'HP:0003118', (14, 16))	('inactivating germline mutations', 'Var', (25, 56))	('CSS', 'Disease', (14, 17))	('CSS', 'Disease', 'MESH:C536436', (14, 17))
107616	30456751	SDH mutations have also been associated with wild-type (WT) GISTs.	('mutations', 'Var', (4, 13))	('SDH', 'Gene', (0, 3))	('GIST', 'Phenotype', 'HP:0100723', (60, 64))	('SDH', 'Gene', '6390', (0, 3))
107619	30456751	The larger group is comprised of GISTs that harbor mutations in KIT (75-80% of tumors) and PDGFRA (5-15% of tumors).	('GIST', 'Phenotype', 'HP:0100723', (33, 37))	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Disease', (108, 114))	('KIT', 'Gene', (64, 67))	('PDGFRA', 'Gene', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('PDGFRA', 'Gene', '5156', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
107620	30456751	The second group is comprised of the remaining 10% of GISTs and is further divided into SDH-deficient (SDHx abnormalities) and non-SDH-deficient tumors (mutations in NF1, BRAF, KRAS, PIK3CA, and the ETV6-NTRK3 fusion gene).	('NF1', 'Gene', (166, 169))	('GIST', 'Phenotype', 'HP:0100723', (54, 58))	('NF1', 'Gene', '4763', (166, 169))	('mutations', 'Var', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (199, 216))	('SDH-deficient (SDHx abnormalities) and non-SDH-deficient tumors', 'Disease', 'MESH:D009369', (88, 151))	('BRAF', 'Gene', '673', (171, 175))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('KRAS', 'Gene', (177, 181))	('BRAF', 'Gene', (171, 175))	('KRAS', 'Gene', '3845', (177, 181))	('ETV6-NTRK3 fusion', 'Gene', (199, 216))	('PIK3CA', 'Gene', (183, 189))	('PIK3CA', 'Gene', '5290', (183, 189))
107621	30456751	In a study of 34 patients with sporadic WT GISTs without a family history of paraganglioma, 12% of patients were found to have germline mutations in SDHB or SDHC, while those who did not harbor a detectable SDH mutation demonstrated significantly decreased SDHB protein expression.	('SDHC', 'Gene', (157, 161))	('paraganglioma', 'Disease', (77, 90))	('SDH', 'Gene', (257, 260))	('SDH', 'Gene', '6390', (207, 210))	('mutations', 'Var', (136, 145))	('paraganglioma', 'Disease', 'MESH:D010235', (77, 90))	('decreased', 'NegReg', (247, 256))	('SDHB', 'Gene', '6390', (149, 153))	('SDH', 'Gene', '6390', (149, 152))	('protein', 'Protein', (262, 269))	('SDHB', 'Gene', '6390', (257, 261))	('SDH', 'Gene', '6390', (157, 160))	('SDH', 'Gene', (207, 210))	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('GIST', 'Phenotype', 'HP:0100723', (43, 47))	('SDHB', 'Gene', (149, 153))	('SDHC', 'Gene', '6391', (157, 161))	('patients', 'Species', '9606', (99, 107))	('SDH', 'Gene', (149, 152))	('patients', 'Species', '9606', (17, 25))	('SDHB', 'Gene', (257, 261))	('SDH', 'Gene', '6390', (257, 260))	('SDH', 'Gene', (157, 160))
107623	30456751	Of these 84 tumors, 67% had SDHx mutations, with 82% of these mutations representing germline mutations.	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('SDHx', 'Gene', (28, 32))	('tumors', 'Disease', (12, 18))	('SDHx', 'Chemical', '-', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
107624	30456751	Twenty-two percent of the SDH-deficient tumors had hypermethylation of the SDHC promoter.	('SDHC', 'Gene', (75, 79))	('SDH-deficient tumors', 'Disease', (26, 46))	('hypermethylation', 'Var', (51, 67))	('SDHC', 'Gene', '6391', (75, 79))	('SDH-deficient tumors', 'Disease', 'MESH:D009369', (26, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
107625	30456751	Findings from these two studies highlight the possible central role of SDH dysregulation in the development of WT GISTs.	('SDH', 'Gene', (71, 74))	('GIST', 'Phenotype', 'HP:0100723', (114, 118))	('SDH', 'Gene', '6390', (71, 74))	('dysregulation', 'Var', (75, 88))
107627	30456751	MEN1 is an autosomal dominant hereditary disorder due to mutations in the MEN1 gene that lead to the development of tumors in the parathyroid glands, pancreas, and anterior pituitary.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('MEN1', 'Gene', '4221', (0, 4))	('MEN1', 'Gene', '4221', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('lead to', 'Reg', (89, 96))	('pancreas', 'Disease', (150, 158))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('pancreas', 'Disease', 'MESH:D010190', (150, 158))	('MEN1', 'Gene', (74, 78))	('autosomal dominant hereditary disorder', 'Disease', (11, 49))	('autosomal dominant hereditary disorder', 'Disease', 'MESH:D030342', (11, 49))	('MEN1', 'Gene', (0, 4))
107629	30456751	This patient harbored a germline SDHD mutation that was identified in the pituitary tumor tissue.	('pituitary tumor', 'Disease', (74, 89))	('SDHD', 'Gene', '6392', (33, 37))	('patient', 'Species', '9606', (5, 12))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('pituitary tumor', 'Disease', 'MESH:D010911', (74, 89))	('SDHD', 'Gene', (33, 37))	('mutation', 'Var', (38, 46))
107632	30456751	The possible role of SDHx mutations in the development of pituitary abnormalities was also demonstrated in a mouse model, where the pituitaries of Sdhb+/- mice older than 12 months were found to have an increased number mainly of prolactin-secreting cells and several ultrastructural abnormalities, such as intranuclear inclusions, altered chromatin nuclear pattern, and abnormal mitochondria.	('chromatin nuclear pattern', 'CPA', (340, 365))	('intranuclear inclusions', 'Phenotype', 'HP:0100304', (307, 330))	('abnormal', 'Reg', (371, 379))	('Sdhb', 'Gene', (147, 151))	('intranuclear inclusions', 'CPA', (307, 330))	('SDHx', 'Chemical', '-', (21, 25))	('prolactin-secreting', 'MPA', (230, 249))	('Sdhb', 'Gene', '67680', (147, 151))	('SDHx', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('pituitary abnormalities', 'Disease', (58, 81))	('mice', 'Species', '10090', (155, 159))	('mouse', 'Species', '10090', (109, 114))	('pituitary abnormalities', 'Disease', 'MESH:D010900', (58, 81))	('pituitary abnormalities', 'Phenotype', 'HP:0011747', (58, 81))	('altered', 'Reg', (332, 339))	('mitochondria', 'CPA', (380, 392))	('increased', 'PosReg', (203, 212))
107633	30456751	Mutant mice tended to have higher insulin-like growth factor-1 levels at all ages, whereas prolactin and growth hormone levels varied according to age and sex.	('insulin-like growth factor-1', 'Gene', '16000', (34, 62))	('insulin-like growth factor-1', 'Gene', (34, 62))	('mice', 'Species', '10090', (7, 11))	('growth hormone', 'Chemical', 'MESH:D013006', (105, 119))	('higher', 'PosReg', (27, 33))	('Mutant', 'Var', (0, 6))
107634	30456751	SDHx mutations have also been linked to other non-paraganglionic tumors, including pancreatic neuroendocrine tumors, abdominal ganglioneuromas, and renal cell carcinomas.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (148, 168))	('renal cell carcinomas', 'Disease', (148, 169))	('pancreatic neuroendocrine tumors', 'Disease', (83, 115))	('tumors', 'Disease', (65, 71))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (94, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (148, 169))	('abdominal ganglioneuromas', 'Disease', 'MESH:D005729', (117, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('mutations', 'Var', (5, 14))	('SDHx', 'Gene', (0, 4))	('linked', 'Reg', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('paraganglionic tumors', 'Phenotype', 'HP:0002668', (50, 71))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('abdominal ganglioneuromas', 'Disease', (117, 142))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (83, 115))	('SDHx', 'Chemical', '-', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (148, 169))
107659	30352400	In patients with ACTH-dependent CS, the block of CYP11B1 results in a compensatory rise of pituitary ACTH secretion that may lead to accumulation of steroid precursors with weak mineralocorticoid activity, potentially producing increased blood pressure, edema and hypokalemia.	('rise', 'PosReg', (83, 87))	('mineralocorticoid activity', 'MPA', (178, 204))	('edema', 'Disease', (254, 259))	('ACTH', 'Gene', (17, 21))	('increased', 'PosReg', (228, 237))	('hypokalemia', 'Disease', (264, 275))	('blood', 'MPA', (238, 243))	('block', 'Var', (40, 45))	('steroid precursors', 'MPA', (149, 167))	('ACTH', 'Gene', '5443', (101, 105))	('steroid', 'Chemical', 'MESH:D013256', (149, 156))	('hypokalemia', 'Phenotype', 'HP:0002900', (264, 275))	('patients', 'Species', '9606', (3, 11))	('ACTH', 'Gene', '5443', (17, 21))	('hypokalemia', 'Disease', 'MESH:D007008', (264, 275))	('CYP11B1', 'Gene', '1584', (49, 56))	('accumulation', 'PosReg', (133, 145))	('ACTH', 'Gene', (101, 105))	('weak mineralocorticoid', 'Phenotype', 'HP:0004319', (173, 195))	('edema', 'Phenotype', 'HP:0000969', (254, 259))	('producing', 'Reg', (218, 227))	('increased blood pressure', 'Phenotype', 'HP:0032263', (228, 252))	('edema', 'Disease', 'MESH:D004487', (254, 259))	('CYP11B1', 'Gene', (49, 56))
107739	30352400	Normalization of UFC was accompanied by reduction in serum and salivary cortisol, and marked clinical improvement.	('Normalization', 'Var', (0, 13))	('reduction', 'NegReg', (40, 49))	('UFC', 'Gene', (17, 20))	('cortisol', 'Chemical', 'MESH:D006854', (72, 80))	('men', 'Species', '9606', (109, 112))
107844	30158955	In recent study, researchers found that abnormal PRC1 expression correlates with poor patient outcome in various malignancies, which may be caused by PRC1-mediated CIN and aneuploidy.	('PRC1', 'Gene', (150, 154))	('PRC1', 'Gene', '9055', (150, 154))	('PRC1', 'Gene', (49, 53))	('malignancies', 'Disease', (113, 125))	('PRC1', 'Gene', '9055', (49, 53))	('CIN', 'Gene', '57026', (164, 167))	('aneuploidy', 'Disease', 'MESH:D000782', (172, 182))	('patient', 'Species', '9606', (86, 93))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))	('caused by', 'Reg', (140, 149))	('abnormal', 'Var', (40, 48))	('CIN', 'Gene', (164, 167))	('aneuploidy', 'Disease', (172, 182))
107848	30158955	Interestingly, co-expression of FOXM1 and CENPF is a robust prognostic indicator of poor survival and metastasis.	('poor survival', 'CPA', (84, 97))	('FOXM1', 'Gene', '2305', (32, 37))	('CENPF', 'Gene', (42, 47))	('FOXM1', 'Gene', (32, 37))	('CENPF', 'Gene', '1063', (42, 47))	('metastasis', 'CPA', (102, 112))	('co-expression', 'Var', (15, 28))
107857	30158955	Deregulation of cell cycle is closely related to carcinogenesis and tumor progression.	('tumor', 'Disease', (68, 73))	('Deregulation', 'Var', (0, 12))	('carcinogenesis', 'Disease', 'MESH:D063646', (49, 63))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cell cycle', 'CPA', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('carcinogenesis', 'Disease', (49, 63))
107878	29386111	The most frequent cause of primary AI is autosomal recessive congenital adrenal hyperplasia (CAH), which results from defects in enzymes involved in steroid biosynthesis.	('primary AI', 'Disease', (27, 37))	('CAH', 'Disease', (93, 96))	('CAH', 'Disease', 'None', (93, 96))	('autosomal recessive congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (41, 91))	('defects', 'Var', (118, 125))	('AI', 'Phenotype', 'HP:0000846', (35, 37))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (72, 91))	('steroid', 'Chemical', 'MESH:D013256', (149, 156))	('CAH', 'Phenotype', 'HP:0008258', (93, 96))	('autosomal recessive congenital adrenal hyperplasia', 'Disease', (41, 91))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (61, 91))
107880	29386111	Fine-tuning of replacement therapy leaves only a narrow margin for improvement: under-replacement can result in severe impairment of well-being and incipient crisis, whereas even subtle, chronic over-replacement has the potential to contribute to excess morbidity, including obesity, osteoporosis, hypertension, and impaired glucose tolerance.	('under-replacement', 'Var', (80, 97))	('hypertension', 'Disease', (298, 310))	('osteoporosis', 'Phenotype', 'HP:0000939', (284, 296))	('obesity', 'Phenotype', 'HP:0001513', (275, 282))	('hypertension', 'Phenotype', 'HP:0000822', (298, 310))	('contribute', 'Reg', (233, 243))	('obesity', 'Disease', 'MESH:D009765', (275, 282))	('osteoporosis', 'Disease', 'MESH:D010024', (284, 296))	('impaired glucose tolerance', 'Phenotype', 'HP:0040270', (316, 342))	('osteoporosis', 'Disease', (284, 296))	('obesity', 'Disease', (275, 282))	('impaired glucose tolerance', 'Disease', (316, 342))	('impaired glucose tolerance', 'Disease', 'MESH:D018149', (316, 342))	('morbidity', 'MPA', (254, 263))	('hypertension', 'Disease', 'MESH:D006973', (298, 310))	('over-replacement', 'PosReg', (195, 211))
107884	29386111	SF1 is a true effector of cell fate as it initiates a genetic program driving embryonic mesenchymal cells toward a steroidogenic phenotype/lineage, and SF1 mutations can result in adrenal insufficiency.	('SF1', 'Gene', (0, 3))	('result in', 'Reg', (170, 179))	('mutations', 'Var', (156, 165))	('SF1', 'Gene', (152, 155))	('adrenal insufficiency', 'Disease', (180, 201))	('SF1', 'Gene', '7536', (0, 3))	('steroid', 'Chemical', 'MESH:D013256', (115, 122))	('SF1', 'Gene', '7536', (152, 155))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (180, 201))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (180, 201))
107896	29386111	Transduction of SF1, indeed, induced the expression of STAR (Figure 1B).	('Transduction', 'Var', (0, 12))	('induced', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('SF1', 'Gene', (16, 19))	('STAR', 'Gene', '6770', (55, 59))	('STAR', 'Gene', (55, 59))	('SF1', 'Gene', '7536', (16, 19))
107904	29386111	Activators of PKA, such as dibutyryl cyclic AMP (db-cAMP) or 8-bromo-cyclic AMP (8-br-cAMP), were the most potent inducers of STAR expression, whereas angiotensin II (AngII), potassium (K+), and all-trans retinoic acid (ATRA) had no effect (Figure 1E).	('dibutyryl cyclic AMP', 'Chemical', 'MESH:D003994', (27, 47))	('db-cAMP', 'Chemical', 'MESH:D003994', (49, 56))	('dibutyryl cyclic AMP', 'Var', (27, 47))	('STAR', 'Gene', '6770', (126, 130))	('8-bromo-cyclic AMP', 'Chemical', 'MESH:D015124', (61, 79))	('inducers', 'PosReg', (114, 122))	('8-br-cAMP', 'Chemical', 'MESH:D015124', (81, 90))	('STAR', 'Gene', (126, 130))	('AngII', 'Gene', (167, 172))	('ATRA', 'Chemical', 'MESH:D014212', (220, 224))	('potassium', 'Chemical', 'MESH:D011188', (175, 184))	('AngII', 'Gene', '183', (167, 172))	('angiotensin II', 'Gene', '183', (151, 165))	('8-bromo-cyclic AMP', 'Var', (61, 79))	('angiotensin II', 'Gene', (151, 165))	('retinoic acid', 'Chemical', 'MESH:D014212', (205, 218))
107917	29386111	Moreover, the expression of steroidogenic enzymes was enhanced by 8-br-cAMP (Figure S3C) as was the expression of STAR.	('steroid', 'Chemical', 'MESH:D013256', (28, 35))	('steroidogenic enzymes', 'Enzyme', (28, 49))	('8-br-cAMP', 'Var', (66, 75))	('expression', 'MPA', (14, 24))	('8-br-cAMP', 'Chemical', 'MESH:D015124', (66, 75))	('STAR', 'Gene', '6770', (114, 118))	('enhanced', 'PosReg', (54, 62))	('STAR', 'Gene', (114, 118))
107942	29386111	To localize transplanted cells in the context of host adrenocortical cells, sections were immunostained with a GFP antibody (Figures 4O-4Q); the steroidogenic potential and in vivo differentiation of hiSCs was further assessed by their expression of CYP17A1, an enzyme that is epigenetically silenced in adult mice; we observed CYP17A1 staining in transplanted cells, but not in mouse adrenocortical cells (Figures 4R-4T).	('adrenocortical', 'Disease', 'MESH:D018268', (54, 68))	('adrenocortical', 'Disease', (385, 399))	('steroid', 'Chemical', 'MESH:D013256', (145, 152))	('adrenocortical', 'Disease', 'MESH:D018268', (385, 399))	('mouse', 'Species', '10090', (379, 384))	('mice', 'Species', '10090', (310, 314))	('CYP17A1', 'Var', (328, 335))	('host adrenocortical', 'Disease', 'MESH:D018268', (49, 68))	('adrenocortical', 'Disease', (54, 68))	('host adrenocortical', 'Disease', (49, 68))
107950	29386111	CAH due to 21-hydroxylase deficiency (21-OH) is a common autosomal recessive disorder caused by defects in the CYP21A2 gene.	('caused by', 'Reg', (86, 95))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (57, 85))	('CAH', 'Phenotype', 'HP:0008258', (0, 3))	('21-OH', 'Chemical', '-', (38, 43))	('21-hydroxylase deficiency', 'Disease', 'MESH:C535979', (11, 36))	('CYP21A2', 'Gene', (111, 118))	('autosomal recessive disorder', 'Disease', (57, 85))	('CYP21A2', 'Gene', '1589', (111, 118))	('CAH', 'Disease', (0, 3))	('CAH', 'Disease', 'None', (0, 3))	('21-hydroxylase deficiency', 'Disease', (11, 36))	('defects', 'Var', (96, 103))
107951	29386111	Patient #1 harbored one of the most common mutations (p.I172N), resulting in a simple virilizing form of CAH and a residual activity of the enzyme of 1%-10%.	('residual activity', 'MPA', (115, 132))	('CAH', 'Disease', (105, 108))	('CAH', 'Disease', 'None', (105, 108))	('p.I172N', 'Mutation', 'rs6475', (54, 61))	('p.I172N', 'Var', (54, 61))	('CAH', 'Phenotype', 'HP:0008258', (105, 108))	('Patient', 'Species', '9606', (0, 7))
107954	29386111	Furthermore, rescue of cortisol hypo-secretion was successfully achieved in hiSCs established from other CAH patients with diverse genetic mutations (Table 1; Figure 5C).	('cortisol', 'Chemical', 'MESH:D006854', (23, 31))	('cortisol hypo', 'Phenotype', 'HP:0008163', (23, 36))	('patients', 'Species', '9606', (109, 117))	('mutations', 'Var', (139, 148))	('CAH', 'Disease', (105, 108))	('CAH', 'Disease', 'None', (105, 108))	('hypo-secretion', 'Disease', (32, 46))	('hypo-secretion', 'Disease', 'MESH:D052456', (32, 46))	('CAH', 'Phenotype', 'HP:0008258', (105, 108))
107961	29386111	Treatment of hiSCs with recombinant WNT4 did not result in changes of zonal-specific markers nor cortisol secretion; it is possible that, in our experimental setting, forced-expression of SF1 bypasses key differentiation events occurring physiologically at the capsule/subcapsular region during the normal self-renewal/zonal specification of the gland.	('SF1', 'Gene', '7536', (188, 191))	('bypasses', 'NegReg', (192, 200))	('WNT4', 'Gene', (36, 40))	('WNT4', 'Gene', '54361', (36, 40))	('SF1', 'Gene', (188, 191))	('cortisol', 'Chemical', 'MESH:D006854', (97, 105))	('forced-expression', 'Var', (167, 184))
107990	27624192	Here, the authors show that ZG differentiation is stimulated by WNT signalling and that PKA blocks WNT signalling to allow ZF differentiation and also prevents WNT-induced cancer development.	('WNT', 'Pathway', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('ZG differentiation', 'CPA', (28, 46))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('prevents', 'NegReg', (151, 159))	('PKA', 'Var', (88, 91))	('cancer', 'Disease', (172, 178))	('blocks', 'NegReg', (92, 98))
107997	27624192	In vivo and in vitro, beta-catenin activation is also associated with upregulation of AT1R and CYP11B2, two key determinants of ZG identity.	('upregulation', 'PosReg', (70, 82))	('AT1R', 'Gene', '11610', (86, 90))	('AT1R', 'Gene', (86, 90))	('beta-catenin', 'Protein', (22, 34))	('CYP11B2', 'Var', (95, 102))	('activation', 'PosReg', (35, 45))
108010	27624192	1b, i versus g) and a concomitant expansion of the expression domain of the ZF marker AKR1B7 within ZG (Fig.	('AKR1B7', 'Gene', (86, 92))	('AKR1B7', 'Gene', '11997', (86, 92))	('expansion', 'Var', (34, 43))	('expression domain', 'MPA', (51, 68))
108022	27624192	1f, a,b) and expansion of AKR1B7 towards the presumptive ZG (Fig.	('AKR1B7', 'Gene', (26, 32))	('AKR1B7', 'Gene', '11997', (26, 32))	('expansion', 'Var', (13, 22))
108032	27624192	Consistent with the activated status of the pathway, phosphorylation of the residues that target beta-catenin for proteasomal degradation (S33/S37/S45/T41) was not increased in response to Forskolin (Fig.	('Forskolin', 'Chemical', 'MESH:D005576', (189, 198))	('S33/S37/S45/T41', 'Var', (139, 154))	('phosphorylation', 'MPA', (53, 68))
108041	27624192	Five hundred and five genes were found downregulated and 713 genes were found upregulated in response to Prkar1a gene inactivation (Fig.	('gene inactivation', 'Var', (113, 130))	('upregulated', 'PosReg', (78, 89))	('Prkar1a', 'Gene', (105, 112))	('Prkar1a', 'Gene', '19084', (105, 112))	('downregulated', 'NegReg', (39, 52))
108042	27624192	Consistent with inhibition of ZG differentiation in this model, a number of ZG markers such as Cyp11b2, Agtr1b, Nr0b1, Nr4a3, Atp2b3, Vsnl1 and Dab2 were among the most significantly downregulated genes in knockout adrenals compared with wild-type (adjusted t-test, Fig.	('Agtr1b', 'Gene', '11608', (104, 110))	('Dab2', 'Gene', '13132', (144, 148))	('Agtr1b', 'Gene', (104, 110))	('Vsnl1', 'Gene', (134, 139))	('Atp2b3', 'Gene', '320707', (126, 132))	('Dab2', 'Gene', (144, 148))	('Nr0b1', 'Gene', '11614', (112, 117))	('Nr0b1', 'Gene', (112, 117))	('Nr4a3', 'Gene', (119, 124))	('Vsnl1', 'Gene', '26950', (134, 139))	('Cyp11b2', 'Gene', (95, 102))	('knockout', 'Var', (206, 214))	('Cyp11b2', 'Gene', '13072', (95, 102))	('Nr4a3', 'Gene', '18124', (119, 124))	('downregulated', 'NegReg', (183, 196))	('Atp2b3', 'Gene', (126, 132))
108051	27624192	5A), its expression domain expanded within the presumptive ZG in Sf1:Cre; Prkar1a Fl/Fl adrenals (Fig.	('Sf1', 'Gene', '22668', (65, 68))	('Prkar1a', 'Gene', '19084', (74, 81))	('Sf1', 'Gene', (65, 68))	('Prkar1a', 'Gene', (74, 81))	('expression', 'MPA', (9, 19))	('Fl/Fl', 'Var', (82, 87))
108057	27624192	Mice with constitutive Wnt4 inactivation have decreased Cyp11b2 expression and plasma aldosterone concentrations at birth.	('aldosterone concentration', 'Phenotype', 'HP:0000859', (86, 111))	('expression', 'MPA', (64, 74))	('Cyp11b2', 'Gene', (56, 63))	('plasma aldosterone concentrations', 'Phenotype', 'HP:0000859', (79, 112))	('aldosterone', 'Chemical', 'MESH:D000450', (86, 97))	('Cyp11b2', 'Gene', '13072', (56, 63))	('inactivation', 'Var', (28, 40))	('Wnt4', 'Gene', '22417', (23, 27))	('decreased', 'NegReg', (46, 55))	('Wnt4', 'Gene', (23, 27))	('Mice', 'Species', '10090', (0, 4))	('plasma aldosterone concentrations', 'MPA', (79, 112))
108066	27624192	Conversely, treatment with H89, a pharmacological PKA inhibitor, induced a modest increase in basal WNT4 expression and prevented inhibition of WNT4 expression by Forskolin treatment (Supplementary Fig.	('prevented', 'NegReg', (120, 129))	('basal WNT4 expression', 'MPA', (94, 115))	('H89', 'Chemical', 'MESH:C063509', (27, 30))	('Forskolin', 'Chemical', 'MESH:D005576', (163, 172))	('increase', 'PosReg', (82, 90))	('inhibition', 'MPA', (130, 140))	('H89', 'Var', (27, 30))
108067	27624192	The potential role of WNT4 repression in mediating the inhibitory effect of PKA on WNT signalling was further suggested by the observation that transfection of a plasmid encoding WNT4, counteracted the inhibitory effect of Forskolin stimulation on AXIN2 expression in H295R cells (Fig.	('WNT4', 'Gene', (179, 183))	('Forskolin', 'Chemical', 'MESH:D005576', (223, 232))	('H295R', 'CellLine', 'CVCL:0458', (268, 273))	('transfection', 'Var', (144, 156))
108072	27624192	This was further associated with expansion of ZF differentiation as shown by strong AKR1B7 expression within the presumptive ZG of mutant adrenals (Fig.	('AKR1B7', 'Gene', (84, 90))	('mutant', 'Var', (131, 137))	('expression', 'MPA', (91, 101))	('AKR1B7', 'Gene', '11997', (84, 90))
108073	27624192	Thus, Wnt4 inactivation phenocopied the effect of constitutive PKA activation, resulting from genetic ablation of Prkar1a (compare Fig.	('Wnt4', 'Gene', '22417', (6, 10))	('Wnt4', 'Gene', (6, 10))	('Prkar1a', 'Gene', '19084', (114, 121))	('activation', 'PosReg', (67, 77))	('Prkar1a', 'Gene', (114, 121))	('genetic ablation', 'Var', (94, 110))
108081	27624192	However, in this context, genetic ablation of Prkar1a allowed partial rescue of the WNT-induced developmental phenotype.	('Prkar1a', 'Gene', (46, 53))	('genetic ablation', 'Var', (26, 42))	('Prkar1a', 'Gene', '19084', (46, 53))
108085	27624192	At 6 months, the adrenal phenotype in DeltaCat mice was characterized by increased proliferation of steroidogenic cells within the central adrenal region (Figs 5c,d and ref.).	('increased', 'PosReg', (73, 82))	('adrenal phenotype', 'CPA', (17, 34))	('mice', 'Species', '10090', (47, 51))	('DeltaCat', 'Var', (38, 46))
108087	27624192	Interestingly, ablation of Prkar1a resulted in a decrease in both proliferation and aberrant differentiation of ZG cells within the central adrenal region (Fig.	('ablation', 'Var', (15, 23))	('aberrant differentiation', 'CPA', (84, 108))	('proliferation', 'CPA', (66, 79))	('decrease', 'NegReg', (49, 57))	('Prkar1a', 'Gene', '19084', (27, 34))	('Prkar1a', 'Gene', (27, 34))
108090	27624192	However, combination of heterozygous Prkaca ablation with constitutive beta-catenin activation resulted in a marked aggravation of WNT-induced phenotypes.	('activation', 'PosReg', (84, 94))	('ablation', 'Var', (44, 52))	('aggravation', 'PosReg', (116, 127))	('Prkaca', 'Gene', '18747', (37, 43))	('WNT-induced phenotypes', 'CPA', (131, 153))	('Prkaca', 'Gene', (37, 43))
108097	27624192	Interestingly, patients with high StAR expression levels (that is, high PKA activity) had significantly higher overall survival, when compared with patients with low StAR accumulation (that is, low PKA activity; LogRank test, Fig.	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (15, 23))	('overall survival', 'CPA', (111, 127))	('high StAR expression levels', 'Var', (29, 56))	('higher', 'PosReg', (104, 110))
108099	27624192	To further confirm the association between low PKA signalling and high WNT signalling, we selected patients with no mutations in CTNNB1 (activating), APC or ZNRF3 (inactivating) and evaluated a potential negative association between StAR expression and WNT signature.	('APC', 'Disease', 'MESH:D011125', (150, 153))	('ZNRF3', 'Gene', '84133', (157, 162))	('APC', 'Disease', (150, 153))	('CTNNB1', 'Gene', (129, 135))	('ZNRF3', 'Gene', (157, 162))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (116, 125))
108101	27624192	Indeed, patients with low StAR expression generally showed high levels of WNT activation signature and of individual WNT target genes expression (LEF1, AXIN2, APCDD1).	('LEF1', 'Gene', (146, 150))	('expression', 'MPA', (134, 144))	('low', 'Var', (22, 25))	('AXIN2', 'Gene', (152, 157))	('WNT activation signature', 'MPA', (74, 98))	('APCDD1', 'Gene', (159, 165))	('patients', 'Species', '9606', (8, 16))
108103	27624192	Here, we show that establishment of ZG identity relies on WNT pathway activation through expression of WNT4, which has recently been proposed to act as a local relay for the effect of capsular RSPO3 on ZG differentiation.	('WNT pathway', 'Pathway', (58, 69))	('expression', 'Var', (89, 99))	('RSPO3', 'Gene', (193, 198))	('activation', 'PosReg', (70, 80))	('WNT4', 'Gene', (103, 107))	('RSPO3', 'Gene', '72780', (193, 198))
108104	27624192	We further show that either ACTH treatment or genetic constitutive PKA activation resulting from RIalpha ablation throughout the adrenal cortex not only inhibits canonical WNT signalling and subsequent glomerulosa differentiation by repressing WNT4 expression, but also allows ZF expansion in the presumptive ZG area.	('expression', 'MPA', (249, 259))	('ablation', 'Var', (105, 113))	('RIalpha', 'Gene', (97, 104))	('activation', 'PosReg', (71, 81))	('ACTH', 'Gene', '18976', (28, 32))	('allows', 'Reg', (270, 276))	('glomerulosa differentiation', 'CPA', (202, 229))	('ZF expansion', 'CPA', (277, 289))	('RIalpha', 'Gene', '19084', (97, 104))	('ACTH', 'Gene', (28, 32))	('PKA', 'Gene', (67, 70))	('inhibits', 'NegReg', (153, 161))	('repressing', 'PosReg', (233, 243))	('WNT4', 'Gene', (244, 248))	('canonical WNT signalling', 'Pathway', (162, 186))
108109	27624192	The observation of cells with expression of both CYP11B1 and CYP11B2 in the inner glomerulosa is consistent with this hypothesis.	('CYP11B1', 'Gene', '110115', (49, 56))	('CYP11B2', 'Var', (61, 68))	('CYP11B1', 'Gene', (49, 56))
108111	27624192	However, one likely explanation is that absence of PKA signalling within the cortex of MC2R knockout mice blocks cortical cell renewal, which would prevent centripetal displacement of ZG cells within the cortex.	('absence', 'Var', (40, 47))	('MC2R', 'Gene', (87, 91))	('centripetal displacement', 'CPA', (156, 180))	('MC2R', 'Gene', '17200', (87, 91))	('blocks', 'NegReg', (106, 112))	('mice', 'Species', '10090', (101, 105))	('prevent', 'NegReg', (148, 155))	('cortical cell renewal', 'CPA', (113, 134))
108118	27624192	(1) There is clear inhibition of WNT pathway activity and beta-catenin accumulation in our mouse model of Sf1:Cre-mediated Prkar1a inactivation.	('Sf1', 'Gene', '22668', (106, 109))	('Sf1', 'Gene', (106, 109))	('beta-catenin accumulation', 'MPA', (58, 83))	('inhibition', 'NegReg', (19, 29))	('Prkar1a', 'Gene', '19084', (123, 130))	('inactivation', 'Var', (131, 143))	('Prkar1a', 'Gene', (123, 130))	('WNT pathway', 'Pathway', (33, 44))	('mouse', 'Species', '10090', (91, 96))
108120	27624192	Indeed, in most PKA-dependent tumours that were analysed, PKA activation resulted from germline mutations of PRKAR1A or GNAS.	('PKA-dependent tumours', 'Disease', (16, 37))	('resulted from', 'Reg', (73, 86))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('PKA', 'Disease', (58, 61))	('PKA-dependent tumours', 'Disease', 'MESH:D009369', (16, 37))	('PRKAR1A', 'Gene', (109, 116))	('GNAS', 'Gene', (120, 124))	('GNAS', 'Gene', '14683', (120, 124))	('PRKAR1A', 'Gene', '19084', (109, 116))	('activation', 'PosReg', (62, 72))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('mutations', 'Var', (96, 105))
108121	27624192	Although beta-catenin was found activated in these tumours on the basis of immunohistochemical analyses, CTNNB1 somatic mutations were mostly found in larger tumours or macronodules that developed in the context of micronodular lesions.	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('tumours', 'Disease', 'MESH:D009369', (158, 165))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('tumours', 'Disease', (158, 165))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('mutations', 'Var', (120, 129))	('found', 'Reg', (142, 147))	('tumours', 'Disease', (51, 58))	('CTNNB1', 'Gene', (105, 111))
108124	27624192	It is thus tempting to speculate that those tumours that combine both alterations in patients have overcome the negative effect of PKA on beta-catenin activity, presumably through mutations in some essential components of this inhibitory mechanism, which would result in a selective growth advantage.	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('mutations', 'Var', (180, 189))	('beta-catenin activity', 'MPA', (138, 159))	('tumours', 'Disease', (44, 51))	('growth advantage', 'CPA', (283, 299))	('patients', 'Species', '9606', (85, 93))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
108125	27624192	The marked acceleration in WNT-induced tumorigenesis in response to Prkaca heterozygosity is intriguing.	('heterozygosity', 'Var', (75, 89))	('acceleration', 'PosReg', (11, 23))	('Prkaca', 'Gene', (68, 74))	('WNT-induced tumorigenesis', 'CPA', (27, 52))	('Prkaca', 'Gene', '18747', (68, 74))
108126	27624192	Indeed, mice combining both alterations develop tumours with malignant characteristics as early as 12 months.	('tumours', 'Disease', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('alterations', 'Var', (28, 39))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('tumours', 'Disease', 'MESH:D009369', (48, 55))	('mice', 'Species', '10090', (8, 12))	('develop', 'Reg', (40, 47))
108129	27624192	This is consistent with published data showing that LOH at the ACTH receptor was associated with more aggressive adrenal cortex carcinoma (ACC) in a small cohort of patients.	('adrenal cortex carcinoma', 'Phenotype', 'HP:0006744', (113, 137))	('aggressive adrenal cortex carcinoma', 'Disease', (102, 137))	('ACTH receptor', 'Gene', '4158', (63, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('ACC', 'Phenotype', 'HP:0006744', (139, 142))	('LOH', 'Var', (52, 55))	('patients', 'Species', '9606', (165, 173))	('ACTH receptor', 'Gene', (63, 76))	('aggressive adrenal cortex carcinoma', 'Disease', 'MESH:D000306', (102, 137))
108130	27624192	However, there was no evidence of MC2R LOH in the TCGA cohort, except for one patient (ID: TCGA-OR-A5JY) with homozygous deletion of the locus.	('MC2R', 'Gene', '17200', (34, 38))	('deletion', 'Var', (121, 129))	('patient', 'Species', '9606', (78, 85))	('MC2R', 'Gene', (34, 38))
108134	27624192	Indeed Sf1:Cre;Prkar1a Fl/Fl adrenals show a combination of increased inactivating (pT41/S45) and decreased activating beta-catenin phosphorylation (pS552), which results in decreased accumulation of the active ABC form of the protein.	('pT41/S45', 'Var', (84, 92))	('decreased', 'NegReg', (174, 183))	('active ABC form of the protein', 'MPA', (204, 234))	('Sf1', 'Gene', '22668', (7, 10))	('inactivating', 'MPA', (70, 82))	('Sf1', 'Gene', (7, 10))	('Prkar1a', 'Gene', '19084', (15, 22))	('Prkar1a', 'Gene', (15, 22))	('activating beta-catenin phosphorylation', 'MPA', (108, 147))	('accumulation', 'PosReg', (184, 196))	('decreased', 'NegReg', (98, 107))
108135	27624192	Whether increased T41/S45 is a direct effect of PKA on beta-catenin in adrenocortical cells is unclear, even though experimental evidence suggests that these residues could be targets of the catalytic activity of PKA, both in reconstructed in vitro kinase assays and in cell culture.	('T41/S45', 'Var', (18, 25))	('adrenocortical', 'Disease', (71, 85))	('adrenocortical', 'Disease', 'MESH:D018268', (71, 85))
108136	27624192	Another possibility, at least in vivo, is that PKA indirectly triggers activating Y216 phosphorylation of GSK3beta (Fig.	('Y216', 'Var', (82, 86))	('GSK3beta', 'Gene', '56637', (106, 114))	('Y216', 'Chemical', '-', (82, 86))	('GSK3beta', 'Gene', (106, 114))	('activating', 'MPA', (71, 81))
108138	27624192	Indeed, Sf1:Cre;Wnt4Fl/Fl mutants display a differentiation phenotype reminiscent of Sf1:Cre;Prkar1aFl/Fl mutants and Lef1 repression by ACTH is almost abrogated in Wnt4 mutants.	('Sf1', 'Gene', '22668', (85, 88))	('ACTH', 'Gene', '18976', (137, 141))	('Lef1', 'Gene', '16842', (118, 122))	('Prkar1a', 'Gene', (93, 100))	('Lef1', 'Gene', (118, 122))	('Sf1', 'Gene', (85, 88))	('abrogated', 'NegReg', (152, 161))	('Wnt4', 'Gene', '22417', (16, 20))	('Prkar1a', 'Gene', '19084', (93, 100))	('ACTH', 'Gene', (137, 141))	('Sf1', 'Gene', '22668', (8, 11))	('mutants', 'Var', (170, 177))	('mutants', 'Var', (26, 33))	('Sf1', 'Gene', (8, 11))	('Wnt4', 'Gene', (165, 169))	('Wnt4', 'Gene', '22417', (165, 169))	('Wnt4', 'Gene', (16, 20))	('mutants', 'Var', (106, 113))
108147	27624192	Interestingly, we further show that this expression pattern expands within presumptive ZG upon deletion of Prkar1a (Fig.	('Prkar1a', 'Gene', (107, 114))	('Prkar1a', 'Gene', '19084', (107, 114))	('deletion', 'Var', (95, 103))	('expands', 'PosReg', (60, 67))
108162	27624192	Immunohistochemistry for beta-catenin (1/500, BD 610153), DAB2 (1/500, BD 610464), CYP11B2 (1/200, gift from C. Gomez-Sanchez, University of Mississippi, USA), AKR1B7 (1/500, ref.	('AKR1B7', 'Gene', '11997', (160, 166))	('CYP11B2', 'Var', (83, 90))	('AKR1B7', 'Gene', (160, 166))	('beta-catenin', 'Protein', (25, 37))	('DAB2', 'Gene', '13132', (58, 62))	('DAB2', 'Gene', (58, 62))
108167	27624192	All of the above primary antibodies were detected with SignalStain Boost HRP-Polymer solution (#8114S or #8125P, Cell Signalling) and either Vectastain ABC (PK-4000, Vector Labs) or TSA-Alexa 488 (T20948, Thermo Fisher) as substrates.	('#8114S', 'Var', (95, 101))	('Alexa 488', 'Chemical', '-', (186, 195))	('#8125P', 'Var', (105, 111))	('TSA', 'Chemical', 'MESH:C012589', (182, 185))
108178	27624192	Human adrenocortical cancer H295R cell line (obtained from ATCC as a mycoplasma free cell line) was grown with DMEM/Ham's F12 supplemented with 10% FBS (S1800-500, Biowest), 2 mM L-Glutamine (25030, Gibco), 50 U ml-1 penicillin, 100 mug ml-1 streptomycin and 1X insulin transferrin selenium (41400-045, Gibco).	('adrenocortical cancer', 'Disease', 'MESH:D000306', (6, 27))	('Human', 'Species', '9606', (0, 5))	('selenium', 'Chemical', 'MESH:D012643', (282, 290))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('FBS', 'Disease', (148, 151))	('25030', 'Var', (192, 197))	('DMEM', 'Chemical', '-', (111, 115))	('streptomycin', 'Chemical', 'MESH:D013307', (242, 254))	('penicillin', 'Chemical', 'MESH:D010406', (217, 227))	('adrenocortical cancer', 'Disease', (6, 27))	('H295R', 'CellLine', 'CVCL:0458', (28, 33))	('L-Glutamine', 'Chemical', 'MESH:D005973', (179, 190))	('transferrin', 'Gene', '7018', (270, 281))	('transferrin', 'Gene', (270, 281))	('FBS', 'Disease', 'MESH:D005198', (148, 151))
108205	27499746	In addition to glucose conversion, AKR1B proteins display multiple other activities, including reduction of aldehyde group of by-products derived from lipid peroxidation or steroid synthesis, retinoids, xenobiotics, and prostaglandins.	('aldehyde group of by-products derived', 'MPA', (108, 145))	('glucose', 'Chemical', 'MESH:D005947', (15, 22))	('lipid', 'Chemical', 'MESH:D008055', (151, 156))	('activities', 'MPA', (73, 83))	('retinoids', 'Chemical', 'MESH:D012176', (192, 201))	('retinoids', 'MPA', (192, 201))	('prostaglandins', 'Chemical', 'MESH:D011453', (220, 234))	('steroid', 'Chemical', 'MESH:D013256', (173, 180))	('reduction', 'NegReg', (95, 104))	('steroid synthesis', 'MPA', (173, 190))	('AKR1B', 'Var', (35, 40))	('lipid peroxidation', 'MPA', (151, 169))	('aldehyde', 'Chemical', 'MESH:D000447', (108, 116))
108210	27499746	Three human AKR1B genes organized in tandem on chromosome 7q33-35 have been identified (Table 2; Figure 1): AKR1B1 [human aldose reductase ], AKR1B10 [also designated as HSI reductase: human small intestine reductase ], and AKR1B15.	('small intestine reductase', 'Gene', '57016', (191, 216))	('human', 'Species', '9606', (6, 11))	('human', 'Species', '9606', (185, 190))	('HSI reductase', 'Disease', 'MESH:C536415', (170, 183))	('AKR1B10', 'Var', (142, 149))	('AKR1B15', 'Gene', (224, 231))	('AKR1B', 'Gene', (12, 17))	('small intestine reductase', 'Gene', (191, 216))	('AKR1B15', 'Gene', '441282', (224, 231))	('AKR1B1', 'Gene', (108, 114))	('human', 'Species', '9606', (116, 121))	('HSI reductase', 'Disease', (170, 183))
108220	27499746	AKR1B1, Akr1b3, and Akr1b16 are rather ubiquitously expressed, whereas Akr1b7 and Akr1b8 exhibit a restricted tissue distribution.	('Akr1b8', 'Gene', (82, 88))	('Akr1b16', 'Gene', '67861', (20, 27))	('Akr1b7', 'Gene', '11997', (71, 77))	('Akr1b7', 'Gene', (71, 77))	('Akr1b8', 'Gene', '14187', (82, 88))	('Akr1b3', 'Gene', '11677', (8, 14))	('AKR1B1', 'Var', (0, 6))	('Akr1b3', 'Gene', (8, 14))	('Akr1b16', 'Gene', (20, 27))
108234	27499746	Interestingly, unlike murine Akr1b7 isoform, NADPH-dependent isocaproaldehyde reductase activity carried by AKR1B1 was inhibited by tolrestat, a potent and specific aldose reductase inhibitor belonging to the carboxylic acids group of AR inhibitors.	('carboxylic acids', 'Chemical', 'MESH:D002264', (209, 225))	('murine', 'Species', '10090', (22, 28))	('AKR1B1', 'Var', (108, 114))	('isocaproaldehyde', 'Enzyme', (61, 77))	('Akr1b7', 'Gene', '11997', (29, 35))	('Akr1b7', 'Gene', (29, 35))	('NADPH', 'Chemical', 'MESH:D009249', (45, 50))	('inhibited', 'NegReg', (119, 128))	('isocaproaldehyde', 'Chemical', 'MESH:C018575', (61, 77))
108235	27499746	We demonstrated that AKR1B1 was also able to convert PGH2 into PGF2alpha (Figure 3C; Table 4).	('PGH2', 'Chemical', 'MESH:D044262', (53, 57))	('AKR1B1', 'Var', (21, 27))	('PGH2', 'Gene', (53, 57))	('PGF2alpha', 'Chemical', 'MESH:D015237', (63, 72))	('convert', 'Reg', (45, 52))
108250	27499746	As expected, Akr1b8 expression was downregulated in digestive tract from Nrf2 knockout mice.	('Akr1b8', 'Gene', (13, 19))	('expression', 'MPA', (20, 30))	('mice', 'Species', '10090', (87, 91))	('Nrf2', 'Gene', '18024', (73, 77))	('knockout', 'Var', (78, 86))	('Akr1b8', 'Gene', '14187', (13, 19))	('downregulated', 'NegReg', (35, 48))	('Nrf2', 'Gene', (73, 77))
108258	27499746	However, in vivo adrenal Akr1b8 physiological role remains to be examined since Akr1b8 gene disruption first report did not notice evident effect on the adrenal physiology.	('Akr1b8', 'Gene', '14187', (80, 86))	('gene disruption', 'Var', (87, 102))	('Akr1b8', 'Gene', (25, 31))	('Akr1b8', 'Gene', (80, 86))	('Akr1b8', 'Gene', '14187', (25, 31))
108263	27499746	Comparative studies demonstrated that AKR1B10 exhibits higher 4-HNE-reductase activity than AKR1B1, while lower than the murine Akr1b8.	('lower', 'NegReg', (106, 111))	('Akr1b8', 'Gene', '14187', (128, 134))	('Akr1b8', 'Gene', (128, 134))	('murine', 'Species', '10090', (121, 127))	('4-HNE-reductase activity', 'MPA', (62, 86))	('4-HNE', 'Chemical', 'MESH:C027576', (62, 67))	('higher', 'PosReg', (55, 61))	('AKR1B10', 'Var', (38, 45))
108265	27499746	Nevertheless, in a comparative enzymatic study, Hara and colleagues showed that AKR1B1 had a more effective isocaproaldehyde reductase activity than AKR1B10, suggesting that in human steroidogenic organs, the latter was unlikely to play a major role in the detoxification of steroidogenic by-products.	('AKR1B1', 'Var', (80, 86))	('isocaproaldehyde', 'Chemical', 'MESH:C018575', (108, 124))	('steroid', 'Chemical', 'MESH:D013256', (275, 282))	('isocaproaldehyde reductase activity', 'MPA', (108, 143))	('steroid', 'Chemical', 'MESH:D013256', (183, 190))	('human', 'Species', '9606', (177, 182))
108272	27499746	Comparative in vitro enzymatic studies on murine and human AKRs have fairly evidenced that among AKR1B proteins, AKR1B10 is so far the only retinaldehyde reductase with the highest kcat value for the retinaldehyde reduction.	('retinaldehyde', 'Chemical', 'MESH:D012172', (200, 213))	('AKR1B10', 'Var', (113, 120))	('kcat', 'MPA', (181, 185))	('human', 'Species', '9606', (53, 58))	('murine', 'Species', '10090', (42, 48))	('retinaldehyde', 'Chemical', 'MESH:D012172', (140, 153))
108295	27499746	However, the silencing of Akr1b7 gene was sufficient to abolish the cAMP-induced isocaproaldehyde reductase activity in Y1 cells.	('Y1', 'CellLine', 'CVCL:0585', (120, 122))	('cAMP-induced isocaproaldehyde reductase activity', 'MPA', (68, 116))	('cAMP', 'Chemical', 'MESH:D000242', (68, 72))	('abolish', 'NegReg', (56, 63))	('Akr1b7', 'Gene', '11997', (26, 32))	('Akr1b7', 'Gene', (26, 32))	('isocaproaldehyde', 'Chemical', 'MESH:C018575', (81, 97))	('silencing', 'Var', (13, 22))
108299	27499746	Thereafter, we demonstrated by ex vivo studies, that AKR1B1, Akr1b3, and Akr1b7 were also able to reduce PGH2 into PGF2alpha, whereas Akr1b8 and AKR1B10 were devoid of this PGF2alpha synthase activity (Table 4).	('Akr1b3', 'Gene', '11677', (61, 67))	('Akr1b3', 'Gene', (61, 67))	('PGH2', 'Chemical', 'MESH:D044262', (105, 109))	('PGF2alpha', 'Chemical', 'MESH:D015237', (173, 182))	('AKR1B1', 'Var', (53, 59))	('Akr1b7', 'Gene', '11997', (73, 79))	('Akr1b7', 'Gene', (73, 79))	('reduce', 'NegReg', (98, 104))	('Akr1b8', 'Gene', '14187', (134, 140))	('PGF2alpha', 'Chemical', 'MESH:D015237', (115, 124))	('PGH2 into PGF2alpha', 'MPA', (105, 124))	('Akr1b8', 'Gene', (134, 140))
108301	27499746	Moreover, their enzymatic constants suggested that AKR1B1, Akr1b3, and Akr1b7 had a higher 9-,11-endoperoxide reductase activity than the other PGF synthases already described.	('AKR1B1', 'Var', (51, 57))	('PGF', 'Gene', '18654', (144, 147))	('Akr1b3', 'Gene', '11677', (59, 65))	('Akr1b7', 'Gene', '11997', (71, 77))	('Akr1b7', 'Gene', (71, 77))	('Akr1b3', 'Gene', (59, 65))	('PGF', 'Gene', (144, 147))	('higher', 'PosReg', (84, 90))
108313	27499746	Surprisingly, however, the absence of Akr1b7 in vivo did not affect basal adrenocortical function as illustrated by normal glucocorticoid plasma levels in Akr1b7-/- mice.	('Akr1b7', 'Gene', '11997', (38, 44))	('Akr1b7', 'Gene', (38, 44))	('adrenocortical', 'Disease', 'MESH:D018268', (74, 88))	('mice', 'Species', '10090', (165, 169))	('Akr1b7', 'Gene', '11997', (155, 161))	('Akr1b7', 'Gene', (155, 161))	('glucocorticoid plasma levels', 'MPA', (123, 151))	('adrenocortical', 'Disease', (74, 88))	('absence', 'Var', (27, 34))
108323	27499746	Disturbance in redox homeostasis was the most recently discovered cause of FGD and mutations in NNT gene (nicotinamide nucleotide transhydrogenase) account for about 10% of cases.	('mutations', 'Var', (83, 92))	('FGD', 'Disease', (75, 78))	('NNT', 'Gene', '18115', (96, 99))	('FGD', 'Disease', 'None', (75, 78))	('NNT', 'Gene', (96, 99))	('Disturbance in redox homeostasis', 'MPA', (0, 32))
108325	27499746	Then, it would be interesting to know whether adrenal-specific deficit in AKR1B enzymes could contribute to cortical damage or adrenal insufficiency in mice carrying a spontaneous Nnt mutation.	('enzymes', 'Protein', (80, 87))	('AKR1B', 'Gene', (74, 79))	('cortical damage', 'Disease', (108, 123))	('adrenal insufficiency', 'Disease', (127, 148))	('Nnt', 'Gene', (180, 183))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (127, 148))	('cortical damage', 'Disease', 'MESH:D009422', (108, 123))	('mice', 'Species', '10090', (152, 156))	('deficit', 'NegReg', (63, 70))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (127, 148))	('Nnt', 'Gene', '18115', (180, 183))	('contribute', 'Reg', (94, 104))	('mutation', 'Var', (184, 192))
108331	25823656	In addition, the knockdown of beta-catenin decreased phosphorylated Akt and increased apoptosis.	('Akt', 'Gene', '207', (68, 71))	('increased', 'PosReg', (76, 85))	('phosphorylated', 'MPA', (53, 67))	('beta-catenin', 'Protein', (30, 42))	('knockdown', 'Var', (17, 26))	('Akt', 'Gene', (68, 71))	('decreased', 'NegReg', (43, 52))	('apoptosis', 'CPA', (86, 95))
108341	25823656	Studies of adrenal tumors have demonstrated that accumulation of beta-catenin in cytoplasm and nucleus is due to beta-catenin gene (CTNNB1) mutations and represents the most frequent molecular event, with a prevalence of about 20% in both adenomas and ACCs.	('adenomas', 'Disease', 'MESH:D000236', (239, 247))	('beta-catenin', 'MPA', (65, 77))	('accumulation', 'PosReg', (49, 61))	('CTNNB1', 'Gene', '1499', (132, 138))	('ACC', 'Phenotype', 'HP:0006744', (252, 255))	('adrenal tumors', 'Disease', 'MESH:D000310', (11, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutations', 'Var', (140, 149))	('adenomas', 'Disease', (239, 247))	('CTNNB1', 'Gene', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('ACCs', 'Gene', '84680', (252, 256))	('adrenal tumors', 'Disease', (11, 25))	('ACCs', 'Gene', (252, 256))
108342	25823656	Such gene mutations affect predominantly phosphorylation sites yielding accumulation of free beta-catenin which then interacts with the transcription factors, Tcf/Lef, and activates downstream target genes which are mainly involved in the regulation of cell fate and proliferation.	('activates', 'PosReg', (172, 181))	('beta-catenin', 'Protein', (93, 105))	('phosphorylation sites', 'MPA', (41, 62))	('Tcf', 'Gene', '3172', (159, 162))	('accumulation', 'PosReg', (72, 84))	('Tcf', 'Gene', (159, 162))	('mutations', 'Var', (10, 19))	('affect', 'Reg', (20, 26))	('interacts', 'Interaction', (117, 126))
108345	25823656	On the other hand, knocking down of beta-catenin expression in H295R cells reversed the epithelial-to-mesenchymal transition (EMT) through the up-regulation of the epithelial marker E-cadherin and the concomitantly decrease of mesenchymal markers vimentin and N-cadherin.	('N-cadherin', 'Gene', (260, 270))	('decrease', 'NegReg', (215, 223))	('mesenchymal markers', 'CPA', (227, 246))	('N-cadherin', 'Gene', '1000', (260, 270))	('beta-catenin', 'Protein', (36, 48))	('E-cadherin', 'Gene', (182, 192))	('H295R', 'CellLine', 'CVCL:0458', (63, 68))	('epithelial-to-mesenchymal transition', 'CPA', (88, 124))	('knocking down', 'Var', (19, 32))	('E-cadherin', 'Gene', '999', (182, 192))	('up-regulation', 'PosReg', (143, 156))	('epithelial', 'CPA', (164, 174))	('vimentin', 'Gene', '7431', (247, 255))	('vimentin', 'Gene', (247, 255))
108346	25823656	In addition, silencing beta-catenin reduced the migration and invasive potentials of the H295R cells in vitro.	('migration', 'CPA', (48, 57))	('beta-catenin', 'Protein', (23, 35))	('H295R', 'CellLine', 'CVCL:0458', (89, 94))	('invasive potentials of the H295R cells', 'CPA', (62, 100))	('reduced', 'NegReg', (36, 43))	('silencing', 'Var', (13, 22))
108351	25823656	Whereas the beta-catenin staining is essentially membranous in normal adrenal gland (Figure 1A(a)), beta-catenin accumulates in the cytoplasm and nucleus of the adrenocortical carcinoma and the H295R tumor (Figure 1A(b, c)).	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (161, 185))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (161, 185))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('adrenocortical carcinoma', 'Disease', (161, 185))	('accumulates', 'PosReg', (113, 124))	('tumor', 'Disease', (200, 205))	('beta-catenin', 'Protein', (100, 112))	('H295R', 'CellLine', 'CVCL:0458', (194, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('H295R', 'Var', (194, 199))
108354	25823656	Statistical analysis indicated that the shRNA against beta-catenin significantly inhibited the growth of H295R cells compared with the negative control (p < 0.01).	('H295R', 'CellLine', 'CVCL:0458', (105, 110))	('beta-catenin', 'Protein', (54, 66))	('inhibited', 'NegReg', (81, 90))	('growth of H295R cells', 'CPA', (95, 116))	('shRNA', 'Var', (40, 45))
108366	25823656	As shown in Figure 4, knockdown of beta-catenin expression with shRNA plasmid promotes apoptosis in H295R cells.	('promotes', 'PosReg', (78, 86))	('knockdown', 'Var', (22, 31))	('apoptosis', 'CPA', (87, 96))	('H295R', 'CellLine', 'CVCL:0458', (100, 105))	('beta-catenin', 'Protein', (35, 47))
108369	25823656	Moreover, the expression of slug (snail2), a repressor of E-cadherin transcription and central mediator in EMT in multiple cancers, was lower in beta-catenin knockdown cells compared to control cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lower', 'NegReg', (136, 141))	('beta-catenin', 'Protein', (145, 157))	('slug', 'Gene', '6591', (28, 32))	('multiple cancers', 'Disease', (114, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('snail2', 'Gene', (34, 40))	('expression', 'MPA', (14, 24))	('snail2', 'Gene', '6591', (34, 40))	('E-cadherin', 'Gene', (58, 68))	('multiple cancers', 'Disease', 'MESH:D009369', (114, 130))	('knockdown', 'Var', (158, 167))	('E-cadherin', 'Gene', '999', (58, 68))	('slug', 'Gene', (28, 32))
108371	25823656	This finding suggests that the knockdown of beta-catenin inhibited essential properties for the transformed cells to disseminate away from the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('inhibited', 'NegReg', (57, 66))	('beta-catenin', 'Protein', (44, 56))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('essential', 'MPA', (67, 76))	('knockdown', 'Var', (31, 40))
108372	25823656	Both H295R beta-catenin depleted cell populations generated only a few, very small abortive colonies.	('H295R', 'Var', (5, 10))	('beta-catenin', 'Protein', (11, 23))	('abortive colonies', 'CPA', (83, 100))	('H295R', 'CellLine', 'CVCL:0458', (5, 10))
108374	25823656	These results indicate that EMT reversal upon beta-catenin depletion impedes the transformed phenotype of H295R adrenocortical carcinoma cells.	('EMT reversal', 'CPA', (28, 40))	('beta-catenin', 'Protein', (46, 58))	('adrenocortical carcinoma', 'Disease', (112, 136))	('H295R', 'CellLine', 'CVCL:0458', (106, 111))	('depletion', 'Var', (59, 68))	('impedes', 'NegReg', (69, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (112, 136))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (112, 136))
108375	25823656	To determine whether beta-catenin perturbation affects primary tumor growth, we transplanted sh-Cntrl cells and the two beta-catenin-inhibited derivative cell populations beneath the kidney capsule of Scid mice (Figure 7A).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mice', 'Species', '10090', (206, 210))	('Scid', 'Gene', '19090', (201, 205))	('perturbation', 'Var', (34, 46))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Scid', 'Gene', (201, 205))
108382	25823656	We confirmed by immunohistological staining that beta-catenin suppression was maintained at the time of sacrifice in tumors formed from sh-betacat-2 and -3 cells (Figure 8).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('sh-betacat-2', 'Var', (136, 148))	('beta-catenin', 'Protein', (49, 61))
108384	25823656	Furthermore, to clarify whether beta-catenin depletion might activate apoptosis as part of the mechanisms limiting tumor growth, we investigated the expression of cleaved caspase-3.	('activate', 'PosReg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('investigated', 'Reg', (132, 144))	('depletion', 'Var', (45, 54))	('tumor', 'Disease', (115, 120))	('caspase-3', 'Gene', (171, 180))	('apoptosis', 'CPA', (70, 79))	('caspase-3', 'Gene', '836', (171, 180))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
108389	25823656	A large majority of diverse cancer types express mutated pathway components, underscoring the importance of the Wnt signaling to tumorigenesis.	('mutated', 'Var', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('express', 'Reg', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Disease', (129, 134))	('cancer', 'Disease', (28, 34))
108393	25823656	Most of the CTNBB1 gene mutations occur in exon 3, affecting the phosphorylation sites for GSK3beta and then, preventing beta-catenin proteasomal degradation.	('beta-catenin proteasomal degradation', 'MPA', (121, 157))	('preventing', 'NegReg', (110, 120))	('GSK3beta', 'Gene', (91, 99))	('CTNBB1', 'Gene', (12, 18))	('affecting', 'Reg', (51, 60))	('phosphorylation sites for', 'MPA', (65, 90))	('GSK3beta', 'Gene', '2932', (91, 99))	('mutations', 'Var', (24, 33))
108394	25823656	However, the frequency of missense mutation is significantly lower than the cytoplasmic and nuclear accumulation of beta-catenin, which, taking into account these limited data, suggests that mutations of the CTNBB1 gene may be not a major molecular event that results in the accumulation of beta-catenin in the aberration of the Wnt/beta-catenin pathway in ACCs.	('beta-catenin', 'MPA', (291, 303))	('accumulation', 'PosReg', (275, 287))	('Wnt/beta-catenin pathway', 'Pathway', (329, 353))	('mutations', 'Var', (191, 200))	('CTNBB1', 'Gene', (208, 214))	('ACC', 'Phenotype', 'HP:0006744', (357, 360))	('ACCs', 'Gene', (357, 361))	('ACCs', 'Gene', '84680', (357, 361))
108403	25823656	EGFR has been shown to be overexpressed in 76 to 100% of ACCs however, mutations in EGFR or in downstream pathways are extremely rare.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (84, 88))	('ACC', 'Phenotype', 'HP:0006744', (57, 60))	('mutations', 'Var', (71, 80))	('ACCs', 'Gene', (57, 61))	('EGFR', 'Gene', (84, 88))	('ACCs', 'Gene', '84680', (57, 61))	('EGFR', 'Gene', '1956', (0, 4))
108414	25823656	Interestingly, knockdown expression of beta-catenin in H295R cells leads to the reversal of EMT phenotype by up-regulation in the protein expression of E-cadherin and by down-regulation of N-cadherin, vimentin and slug.	('vimentin', 'Gene', '7431', (201, 209))	('E-cadherin', 'Gene', (152, 162))	('down-regulation', 'NegReg', (170, 185))	('E-cadherin', 'Gene', '999', (152, 162))	('slug', 'Gene', (214, 218))	('H295R', 'CellLine', 'CVCL:0458', (55, 60))	('knockdown expression', 'Var', (15, 35))	('vimentin', 'Gene', (201, 209))	('slug', 'Gene', '6591', (214, 218))	('N-cadherin', 'Gene', (189, 199))	('up-regulation', 'PosReg', (109, 122))	('N-cadherin', 'Gene', '1000', (189, 199))	('protein expression', 'MPA', (130, 148))
108419	25823656	The ability of shRNAs directed against beta-catenin to result in prolonged suppression of beta-catenin levels in cell culture and reduce in vivo growth of H295R cells (up to 46 days) suggests that their expression and their efficacy are stable over long periods of time.	('beta-catenin levels in cell culture', 'MPA', (90, 125))	('reduce', 'NegReg', (130, 136))	('suppression', 'NegReg', (75, 86))	('H295R', 'CellLine', 'CVCL:0458', (155, 160))	('directed', 'Var', (22, 30))
108421	25823656	In summary, results of the present study demonstrate that knockdown of the canonical Wnt pathway using beta-catenin shRNA effectively suppresses the malignant adrenocortical tumor growth and may represent a potential therapeutic target for ACCs.	('canonical Wnt pathway', 'Pathway', (75, 96))	('ACCs', 'Gene', (240, 244))	('ACCs', 'Gene', '84680', (240, 244))	('knockdown', 'Var', (58, 67))	('suppresses', 'NegReg', (134, 144))	('ACC', 'Phenotype', 'HP:0006744', (240, 243))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (159, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('adrenocortical tumor', 'Disease', (159, 179))
108423	25823656	Finally, interfering with Wnt signaling in ACC patients irrespective of the mutational status of beta-catenin might be effective since decreased growth, survival and tumor volume were observed in hepatocellular carcinoma and myeloma cell lines expressing non mutated beta-catenin.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('myeloma', 'Disease', (225, 232))	('hepatocellular carcinoma', 'Disease', (196, 220))	('non mutated', 'Var', (255, 266))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('decreased growth', 'Phenotype', 'HP:0001510', (135, 151))	('patients', 'Species', '9606', (47, 55))	('growth', 'CPA', (145, 151))	('tumor', 'Disease', (166, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('myeloma', 'Disease', 'MESH:D009101', (225, 232))	('decreased', 'NegReg', (135, 144))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (196, 220))	('survival', 'CPA', (153, 161))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (196, 220))
108461	25918656	A final diagnosis of undifferentiated adrenal malignant tumor was rendered, instead of histologically malignant pheochromocytoma, despite the uptake of 123I-MIBG demonstrated by scintigraphy.	('adrenal malignant tumor', 'Phenotype', 'HP:0100631', (38, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('uptake', 'MPA', (142, 148))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (102, 128))	('malignant pheochromocytoma', 'Disease', (102, 128))	('tumor', 'Disease', (56, 61))	('adrenal malignant tumor', 'Disease', 'MESH:D000310', (38, 61))	('123I-MIBG', 'Var', (152, 161))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (112, 128))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('adrenal malignant tumor', 'Disease', (38, 61))
108464	25918656	Pheochromocytoma results in hypertension in 0.5% of patients and adrenal incidentaloma in 4% of cases; approximately 24% of neuroendocrine tumors are related to gene mutations associated with a hereditary syndrome.	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (124, 144))	('hypertension', 'Disease', 'MESH:D006973', (28, 40))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (124, 145))	('hypertension', 'Disease', (28, 40))	('gene mutations', 'Var', (161, 175))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (124, 144))	('adrenal incidentaloma', 'Disease', (65, 86))	('hereditary syndrome', 'Disease', (194, 213))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('hypertension', 'Phenotype', 'HP:0000822', (28, 40))	('hereditary syndrome', 'Disease', 'MESH:D009386', (194, 213))	('neuroendocrine tumors', 'Disease', (124, 145))	('patients', 'Species', '9606', (52, 60))	('adrenal incidentaloma', 'Disease', 'MESH:C538238', (65, 86))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Pheochromocytoma results in hypertension', 'Phenotype', 'HP:0002640', (0, 40))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('Pheochromocytoma', 'Disease', (0, 16))	('related', 'Reg', (150, 157))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (124, 145))
108469	25918656	A comprehensive metabolic blood panel revealed a low albumin level of 2.5 g/dL, low sodium of 130 mEq/L, increased AST/ALT of 131/117 IU/L, and increased alkaline phosphatase of 539 IU/L.	('sodium', 'Chemical', 'MESH:D012964', (84, 90))	('increased', 'PosReg', (144, 153))	('low', 'Var', (80, 83))	('increased alkaline phosphatase', 'Phenotype', 'HP:0003155', (144, 174))	('albumin level', 'MPA', (53, 66))	('AST', 'Gene', (115, 118))	('AST', 'Gene', '26503', (115, 118))	('low', 'NegReg', (49, 52))	('low sodium', 'Phenotype', 'HP:0002902', (80, 90))	('low albumin', 'Phenotype', 'HP:0003073', (49, 60))	('increased', 'PosReg', (105, 114))	('alkaline phosphatase', 'MPA', (154, 174))
108489	25918656	For example, neuroendocrine tumors with origins other than a chromaffin neuroendocrine tumor, medullary thyroid carcinoma, and carcinoid tumors can all show uptake of 123I-MIBG, which is believed to occur via intracellular granules through their respective amine uptake mechanisms.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (13, 34))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (104, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinoid tumors', 'Disease', 'MESH:D002276', (127, 143))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('neuroendocrine tumors', 'Disease', (13, 34))	('carcinoid tumors', 'Disease', (127, 143))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('chromaffin neuroendocrine tumor', 'Phenotype', 'HP:0002666', (61, 92))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (104, 121))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (94, 121))	('123I-MIBG', 'Var', (167, 176))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('carcinoid', 'Phenotype', 'HP:0100570', (127, 136))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (72, 92))	('thyroid carcinoma', 'Disease', (104, 121))	('uptake', 'MPA', (157, 163))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (13, 33))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
108499	24761385	Geneticists estimate that 5-10% of all cancers diagnosed in the pediatric age range occur in children born with a genetic mutation that directly increases their lifetime risk for neoplasia.	('neoplasia', 'Disease', 'MESH:D009369', (179, 188))	('neoplasia', 'Phenotype', 'HP:0002664', (179, 188))	('children', 'Species', '9606', (93, 101))	('genetic mutation', 'Var', (114, 130))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('increases', 'PosReg', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('neoplasia', 'Disease', (179, 188))
108501	24761385	LFS is a rare autosomal dominant hereditary cancer syndrome that results from germline mutations of the tumor protein gene (TP53) encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('TP53', 'Gene', '7157', (124, 128))	('LFS', 'Disease', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Disease', (104, 109))	('results from', 'Reg', (65, 77))	('TP53', 'Gene', (124, 128))	('autosomal dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (14, 59))	('autosomal dominant hereditary cancer syndrome', 'Disease', (14, 59))	('mutations', 'Var', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
108515	24761385	Genetic testing for TP53 mutation from peripheral blood revealed heterozygous change on the nucleotide-coding sequence c. 818G >A, which is a missense mutation in TP53 gene.	('818G >A', 'Var', (122, 129))	('TP53', 'Gene', (20, 24))	('TP53', 'Gene', '7157', (163, 167))	('TP53', 'Gene', (163, 167))	('818G >A', 'SUBSTITUTION', 'None', (122, 129))	('TP53', 'Gene', '7157', (20, 24))
108519	24761385	The surveillance screen of TP53 mutation carrier has proven to improve the overall survival by early detection of the new neoplasms.	('neoplasms', 'Disease', (122, 131))	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('neoplasms', 'Phenotype', 'HP:0002664', (122, 131))	('improve', 'PosReg', (63, 70))	('mutation', 'Var', (32, 40))	('neoplasms', 'Disease', 'MESH:D009369', (122, 131))
108520	24761385	Villani et al., implemented a clinical surveillance protocol using frequent biochemical and imaging studies for asymptomatic TP53 mutation carriers.	('TP53', 'Gene', (125, 129))	('mutation', 'Var', (130, 138))	('TP53', 'Gene', '7157', (125, 129))
108526	24761385	Because of the strong association between constitutional p53 mutations and a diagnosis of ACTs at a young age, genetic testing of these patients for p53 status should be considered.	('p53', 'Gene', (149, 152))	('p53', 'Gene', '7157', (149, 152))	('mutations', 'Var', (61, 70))	('patients', 'Species', '9606', (136, 144))	('p53', 'Gene', (57, 60))	('p53', 'Gene', '7157', (57, 60))
108530	24761385	Germline Tp53 mutations are found in approximately 23% of patients with rhabdomyosarcoma diagnosed at younger than 3 years.	('Tp53', 'Gene', '7157', (9, 13))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (72, 88))	('Tp53', 'Gene', (9, 13))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (72, 88))	('patients', 'Species', '9606', (58, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('mutations', 'Var', (14, 23))	('rhabdomyosarcoma', 'Disease', (72, 88))
108531	23409032	Silencing Mutated beta-Catenin Inhibits Cell Proliferation and Stimulates Apoptosis in the Adrenocortical Cancer Cell Line H295R Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine neoplasm, with limited therapeutic options.	('Silencing Mutated', 'Var', (0, 17))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (129, 153))	('H295R', 'CellLine', 'CVCL:0458', (123, 128))	('Adrenocortical Cancer', 'Disease', (91, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('beta-Catenin', 'Gene', (18, 30))	('neoplasm', 'Phenotype', 'HP:0002664', (202, 210))	('Adrenocortical carcinoma', 'Disease', (129, 153))	('Apoptosis', 'CPA', (74, 83))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Inhibits', 'NegReg', (31, 39))	('Mutated', 'Var', (10, 17))	('aggressive endocrine neoplasm', 'Disease', (181, 210))	('aggressive endocrine neoplasm', 'Disease', 'MESH:C536575', (181, 210))	('endocrine neoplasm', 'Phenotype', 'HP:0100568', (192, 210))	('ACC', 'Phenotype', 'HP:0006744', (155, 158))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (129, 153))	('Stimulates', 'PosReg', (63, 73))	('Adrenocortical Cancer', 'Disease', 'MESH:D000306', (91, 112))	('Cell Proliferation', 'CPA', (40, 58))	('beta-Catenin', 'Gene', '1499', (18, 30))
108533	23409032	Similar to patient tumor specimen the H295 cell line derived from an ACC harbors a natural activating beta-catenin mutation.	('ACC', 'Phenotype', 'HP:0006744', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('patient', 'Species', '9606', (11, 18))	('tumor', 'Disease', (19, 24))	('mutation', 'Var', (115, 123))	('activating', 'PosReg', (91, 101))
108545	23409032	Catenin (cadherin-associated protein), beta 1) mutations, and is associated with specific clinical and pathological characteristics and a poor outcome.	('associated', 'Reg', (65, 75))	('Catenin (cadherin-associated protein), beta 1', 'Gene', '1499', (0, 45))	('mutations', 'Var', (47, 56))
108546	23409032	Likewise, a specific transcriptomic signature of tumors with CTNNB1 mutation has recently been shown, and might be responsible for the particular poor prognosis of affected patients.	('CTNNB1', 'Gene', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('patients', 'Species', '9606', (173, 181))	('mutation', 'Var', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))
108553	23409032	S45P CTNNB1 (beta-catenin) gene activating mutation, previously identified in the parental H295R cell line, was confirmed by direct sequencing in all Ctr and shbeta clones (data not shown).	('CTNNB1', 'Gene', (5, 11))	('S45P', 'Var', (0, 4))	('H295R', 'CellLine', 'CVCL:0458', (91, 96))	('shbeta', 'Gene', (158, 164))	('shbeta', 'Gene', '6461', (158, 164))	('S45P', 'Mutation', 'rs121913407', (0, 4))	('activating', 'PosReg', (32, 42))
108567	23409032	H295R cells, harboring a heterozygous CTNNB1 gene mutation on the GSK3beta phosphorylation site (S45P), exhibit a constitutive transcriptional activity of beta-catenin-LEF/TCF.	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('CTNNB1', 'Gene', (38, 44))	('beta-catenin-LEF/TCF', 'Gene', '3172', (155, 175))	('S45P', 'Mutation', 'rs121913407', (97, 101))	('mutation', 'Var', (50, 58))	('beta-catenin-LEF/TCF', 'Gene', (155, 175))
108573	23409032	As expected, transfected H295R cells showed higher transcriptional activity of the beta-catenin-LEF/TCF dependent luciferase reporter construct Top in comparison to the mutated Fop construct (figure 1-B, Ctr-Fop: 5% compared to Ctr-Top: 100%, p<0.01; and shbeta-Fop: 9% compared to shbeta-Top: 100%, p<0.01).	('beta-catenin-LEF/TCF', 'Gene', (83, 103))	('shbeta', 'Gene', (282, 288))	('higher', 'PosReg', (44, 50))	('shbeta', 'Gene', (255, 261))	('transcriptional activity', 'MPA', (51, 75))	('Ctr-Fop', 'Var', (204, 211))	('shbeta', 'Gene', '6461', (282, 288))	('beta-catenin-LEF/TCF', 'Gene', '3172', (83, 103))	('shbeta', 'Gene', '6461', (255, 261))	('H295R', 'CellLine', 'CVCL:0458', (25, 30))
108574	23409032	H295R cells which expressed shRNA-beta-catenin (shbeta with dox) showed lower transcriptional activity of the reporter construct Top (shbeta-Top: -53%, p<0.01).	('shbeta', 'Gene', (134, 140))	('shbeta', 'Gene', '6461', (134, 140))	('shbeta', 'Gene', (48, 54))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('shRNA-beta-catenin', 'Var', (28, 46))	('lower', 'NegReg', (72, 77))	('shbeta', 'Gene', '6461', (48, 54))	('dox', 'Chemical', 'MESH:D004318', (60, 63))	('transcriptional activity', 'MPA', (78, 102))
108575	23409032	Dox treatment did not affect activity of the Top construct in the control clone (Ctr-Top) or on the Fop construct with mutated LEF/TCF sites in both clones (Ctr-Fop and shbeta-Fop).	('Dox', 'Chemical', 'MESH:D004318', (0, 3))	('TCF', 'Gene', (131, 134))	('TCF', 'Gene', '3172', (131, 134))	('mutated', 'Var', (119, 126))	('shbeta', 'Gene', (169, 175))	('shbeta', 'Gene', '6461', (169, 175))
108576	23409032	Moreover, CTNNB1 silencing for two days significantly decreased mRNA level of an endogenous canonical downstream target gene of Wnt/beta-catenin pathway, i.e AXIN2, in the shbeta clone (figure 1-B, shbeta: -82%, p<0.01) compared to control clones (Ctr, ns).	('shbeta', 'Gene', (172, 178))	('shbeta', 'Gene', '6461', (172, 178))	('CTNNB1', 'Gene', (10, 16))	('shbeta', 'Gene', (198, 204))	('decreased', 'NegReg', (54, 63))	('shbeta', 'Gene', '6461', (198, 204))	('silencing', 'Var', (17, 26))
108577	23409032	A time course study of CTNNB1 silencing in H295R cell line demonstrated a significant decrease in proliferation (-45,8% at 12 days, p<0.05) compared to shbeta clone without CTNNB1 silencing (-dox) or the control clone (figure 1-C), determined by MTT conversion.	('CTNNB1', 'Gene', (23, 29))	('shbeta', 'Gene', '6461', (152, 158))	('H295R', 'CellLine', 'CVCL:0458', (43, 48))	('dox', 'Chemical', 'MESH:D004318', (192, 195))	('shbeta', 'Gene', (152, 158))	('decrease', 'NegReg', (86, 94))	('silencing', 'Var', (30, 39))	('proliferation', 'CPA', (98, 111))	('MTT', 'Chemical', 'MESH:C070243', (246, 249))
108580	23409032	At this time point, we observed a reduction of two important proteins for G1/S transition, Cyclin A and CDK2 only in cells silenced for CTNNB1 (figure 1-C).	('silenced', 'Var', (123, 131))	('Cyclin A', 'Gene', (91, 99))	('CTNNB1', 'Gene', (136, 142))	('CDK2', 'Gene', (104, 108))	('CDK2', 'Gene', '1017', (104, 108))	('reduction', 'NegReg', (34, 43))	('Cyclin A', 'Gene', '890', (91, 99))
108582	23409032	Likewise, CTNNB1 silencing increased the apoptotic effect of staurosporin (figure 1-C; shbeta-5d+stau: 224% vs 377%, p<0.05) while no significant difference was observed in control clones.	('increased', 'PosReg', (27, 36))	('apoptotic effect', 'CPA', (41, 57))	('CTNNB1', 'Gene', (10, 16))	('shbeta', 'Gene', (87, 93))	('silencing', 'Var', (17, 26))	('shbeta', 'Gene', '6461', (87, 93))	('staurosporin', 'Chemical', 'MESH:D019311', (61, 73))
108583	23409032	To evaluate the functional significance of beta-catenin knock-down on tumor development we proceeded with investigation in a subcutaneous xenograft tumor model in athymic nude mice.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (70, 75))	('knock-down', 'Var', (56, 66))	('nude mice', 'Species', '10090', (171, 180))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
108584	23409032	In a first step, short term experiments with CTNNB1 inactivation on established tumors (21 to 31 days after xenografting) for a duration of 9 days were performed to mirror the time course from our in vitro experiments (figure 1-C).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('CTNNB1', 'Gene', (45, 51))	('inactivation', 'Var', (52, 64))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))
108599	22358232	Genotype analysis of the human endostatin variant p.D104N in benign and malignant adrenocortical tumors Endostatin is a potent endogenous inhibitor of angiogenesis.	('p.D104N', 'Var', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('human', 'Species', '9606', (25, 30))	('endostatin', 'Gene', '80781', (31, 41))	('malignant adrenocortical tumors', 'Disease', 'MESH:D018268', (72, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('p.D104N', 'Mutation', 'rs12483377', (50, 57))	('endostatin', 'Gene', (31, 41))	('malignant adrenocortical tumors', 'Disease', (72, 103))
108601	22358232	A polymorphic COL18A1 allele encoding the functional polymorphism p.D104N impairs the activity of endostatin, resulting in a decreased ability to inhibit angiogenesis.	('inhibit', 'NegReg', (146, 153))	('impairs', 'NegReg', (74, 81))	('ability', 'MPA', (135, 142))	('endostatin', 'Gene', '80781', (98, 108))	('endostatin', 'Gene', (98, 108))	('p.D104N', 'Mutation', 'rs12483377', (66, 73))	('decreased', 'NegReg', (125, 134))	('activity', 'MPA', (86, 94))	('COL18A1', 'Gene', (14, 21))	('p.D104N', 'Var', (66, 73))	('COL18A1', 'Gene', '80781', (14, 21))	('angiogenesis', 'CPA', (154, 166))
108604	22358232	The purpose of this study was to genotype the p.D104N variant in a cohort of pediatric and adult patients with adrenocortical tumors and to determine its possible association with the biological behavior of adrenocortical tumors.	('association', 'Reg', (163, 174))	('adrenocortical tumors', 'Disease', (111, 132))	('p.D104N', 'Var', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('adrenocortical tumors', 'Disease', (207, 228))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (207, 228))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (111, 132))	('p.D104N', 'Mutation', 'rs12483377', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('patients', 'Species', '9606', (97, 105))
108608	22358232	The potential associations of the p.D104N polymorphism with clinical and histopathological features and oncologic outcome (age of onset, tumor size, malignant tumor behavior, and clinical syndrome) were analyzed.	('tumor behavior', 'Disease', 'MESH:D001523', (159, 173))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('p.D104N', 'Mutation', 'rs12483377', (34, 41))	('tumor', 'Disease', (159, 164))	('p.D104N', 'Var', (34, 41))	('tumor behavior', 'Disease', (159, 173))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
108614	22358232	A proteolytic fragment produced by the cleavage of the C-terminal non-collagenous domain (NC1) is known as endostatin and has been shown to exhibit anti-angiogenic activity in vitro and in vivo.	('cleavage', 'Var', (39, 47))	('endostatin', 'Gene', '80781', (107, 117))	('anti-angiogenic activity', 'CPA', (148, 172))	('endostatin', 'Gene', (107, 117))
108616	22358232	The observation that individuals with trisomy 21 (Down's syndrome) rarely develop solid tumors suggests the presence of an endogenous angiogenesis inhibitor encoded by a gene on chromosome 21.	("'s syndrome", 'Disease', 'MESH:D010300', (54, 65))	('solid tumors', 'Disease', (82, 94))	("'s syndrome", 'Disease', (54, 65))	('solid tumors', 'Disease', 'MESH:D009369', (82, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('trisomy 21', 'Var', (38, 48))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
108617	22358232	A single nucleotide polymorphism c.4309G>A (p.D104N) was identified in the endostatin domain of COL18A1.	('endostatin', 'Gene', '80781', (75, 85))	('endostatin', 'Gene', (75, 85))	('COL18A1', 'Gene', (96, 103))	('c.4309G>A', 'Var', (33, 42))	('COL18A1', 'Gene', '80781', (96, 103))	('c.4309G>A', 'Mutation', 'rs12483377', (33, 42))	('p.D104N', 'Mutation', 'rs12483377', (44, 51))
108619	22358232	This finding likely indicates that this polymorphism results in a less active protein and that individuals who carry one or more mutant alleles at this locus are more prone to developing aggressive prostate cancer.	('aggressive prostate cancer', 'Disease', 'MESH:D011471', (187, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('active', 'MPA', (71, 77))	('prone', 'Reg', (167, 172))	('aggressive prostate cancer', 'Disease', (187, 213))	('protein', 'Protein', (78, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (198, 213))	('less', 'NegReg', (66, 70))	('mutant', 'Var', (129, 135))
108620	22358232	observed no significant difference in the normal homozygous (DD), heterozygous (DN), and mutant homozygous (NN) frequencies between androgen-independent prostate cancer patients and control individuals.	('patients', 'Species', '9606', (169, 177))	('DN', 'Chemical', '-', (80, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('mutant', 'Var', (89, 95))	('prostate cancer', 'Disease', (153, 168))
108626	22358232	As endostatin is involved in angiogenesis, we hypothesized that the presence of the D104N polymorphism may influence the outcome of adrenocortical cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (132, 153))	('D104N', 'Mutation', 'rs12483377', (84, 89))	('endostatin', 'Gene', '80781', (3, 13))	('endostatin', 'Gene', (3, 13))	('influence', 'Reg', (107, 116))	('D104N', 'Var', (84, 89))	('adrenocortical cancer', 'Disease', (132, 153))
108627	22358232	The aim of this study was to analyze the frequency of the DD (normal homozygous), DN (heterozygous), and NN (mutant homozygous) genotypes of the p.D104N polymorphism in patients with adrenocortical tumors and to identify any associations with clinical and biological features.	('patients', 'Species', '9606', (169, 177))	('adrenocortical tumors', 'Disease', (183, 204))	('p.D104N', 'Mutation', 'rs12483377', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('p.D104N', 'Var', (145, 152))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (183, 204))	('DN', 'Chemical', '-', (82, 84))
108632	22358232	In addition, 300 alleles from 150 healthy volunteers were analyzed to determine the frequency of the D104N endostatin polymorphism.	('endostatin', 'Gene', '80781', (107, 117))	('D104N', 'Var', (101, 106))	('endostatin', 'Gene', (107, 117))	('D104N', 'Mutation', 'rs12483377', (101, 106))
108643	22358232	Of the 17 patients carrying the mutant allele, 14 were adults; 8 of these adult patients were diagnosed with adenoma, and 6 were diagnosed with carcinoma.	('carcinoma', 'Disease', (144, 153))	('patients', 'Species', '9606', (80, 88))	('adenoma', 'Disease', (109, 116))	('mutant', 'Var', (32, 38))	('carcinoma', 'Disease', 'MESH:D002277', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('diagnosed', 'Reg', (94, 103))	('patients', 'Species', '9606', (10, 18))	('adenoma', 'Disease', 'MESH:D000236', (109, 116))
108645	22358232	The three remaining patients carrying the mutant allele were pediatric patients, and all were diagnosed with a benign adrenocortical tumor.	('mutant', 'Var', (42, 48))	('adrenocortical tumor', 'Disease', (118, 138))	('patients', 'Species', '9606', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('patients', 'Species', '9606', (20, 28))	('diagnosed', 'Reg', (94, 103))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (118, 138))
108648	22358232	Following the observation that individuals with trisomy 21 (Down's syndrome) rarely develop solid tumors, Folkman and Kalluri proposed that an endogenous angiogenesis inhibitor is likely encoded by a gene on chromosome 21.	('solid tumors', 'Disease', (92, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('solid tumors', 'Disease', 'MESH:D009369', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	("'s syndrome", 'Disease', (64, 75))	('trisomy 21', 'Var', (48, 58))	("'s syndrome", 'Disease', 'MESH:D010300', (64, 75))
108652	22358232	A non-synonymous polymorphism (p.D104N) in exon 42 of COL18A1, which encodes endostatin, was described by Yugetti et al.	('endostatin', 'Gene', '80781', (77, 87))	('endostatin', 'Gene', (77, 87))	('p.D104N', 'Mutation', 'rs12483377', (31, 38))	('p.D104N', 'Var', (31, 38))	('COL18A1', 'Gene', (54, 61))	('COL18A1', 'Gene', '80781', (54, 61))
108653	22358232	The presence of this mutation leads to decreased activity of the protein, which may 1) interfere with the anti-angiogenic role of endostatin and 2) be associated with the progression of solid tumors, such as breast cancer and prostate cancer.	('activity', 'MPA', (49, 57))	('prostate cancer', 'Phenotype', 'HP:0012125', (226, 241))	('protein', 'Protein', (65, 72))	('prostate cancer', 'Disease', (226, 241))	('endostatin and 2', 'Gene', '80781', (130, 146))	('solid tumors', 'Disease', (186, 198))	('decreased', 'NegReg', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('may 1', 'Gene', (80, 85))	('may 1', 'Gene', '5580', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('associated with', 'Reg', (151, 166))	('presence', 'Var', (4, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))	('solid tumors', 'Disease', 'MESH:D009369', (186, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('mutation', 'Var', (21, 29))	('interfere', 'NegReg', (87, 96))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('breast cancer', 'Disease', (208, 221))	('prostate cancer', 'Disease', 'MESH:D011471', (226, 241))
108656	22358232	Adrenocortical tumors are highly vascularized tumors; we therefore hypothesized that a functional polymorphism located in the endostatin-coding region of COL18A1 may be associated with the poor behavior of the tumors, leading to early metastasis and death.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('endostatin', 'Gene', (126, 136))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('poor behavior', 'CPA', (189, 202))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('early metastasis', 'CPA', (229, 245))	('polymorphism located', 'Var', (98, 118))	('death', 'CPA', (250, 255))	('tumors', 'Disease', (46, 52))	('Adrenocortical tumors', 'Disease', 'MESH:D018268', (0, 21))	('tumors', 'Disease', (15, 21))	('COL18A1', 'Gene', (154, 161))	('Adrenocortical tumors', 'Disease', (0, 21))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('COL18A1', 'Gene', '80781', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('leading to', 'Reg', (218, 228))	('tumors', 'Disease', (210, 216))	('endostatin', 'Gene', '80781', (126, 136))	('associated', 'Reg', (169, 179))
108657	22358232	In the present study, we identified no association between the p.D104N endostatin polymorphism and tumor aggressiveness or other clinical features in pediatric and adult patients.	('endostatin', 'Gene', '80781', (71, 81))	('patients', 'Species', '9606', (170, 178))	('endostatin', 'Gene', (71, 81))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (99, 119))	('aggressiveness', 'Phenotype', 'HP:0000718', (105, 119))	('p.D104N', 'Mutation', 'rs12483377', (63, 70))	('p.D104N', 'Var', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor aggressiveness', 'Disease', (99, 119))
108659	22358232	Similar studies of patients with leukemia and multiple myeloma revealed no association between the endostatin p.D104N polymorphism and disease outcome.	('patients', 'Species', '9606', (19, 27))	('endostatin', 'Gene', '80781', (99, 109))	('endostatin', 'Gene', (99, 109))	('multiple myeloma', 'Disease', 'MESH:D009101', (46, 62))	('p.D104N', 'Mutation', 'rs12483377', (110, 117))	('multiple myeloma', 'Phenotype', 'HP:0006775', (46, 62))	('p.D104N', 'Var', (110, 117))	('multiple myeloma', 'Disease', (46, 62))	('leukemia', 'Phenotype', 'HP:0001909', (33, 41))	('leukemia', 'Disease', 'MESH:D007938', (33, 41))	('leukemia', 'Disease', (33, 41))
108660	22358232	revealed a high risk of sporadic breast cancer in individuals homozygous (NN) for the p.D104N polymorphism.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (24, 46))	('p.D104N', 'Mutation', 'rs12483377', (86, 93))	('p.D104N', 'Var', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('sporadic breast cancer', 'Disease', (24, 46))
108692	18006632	Interestingly, along with tumorigenesis, DBA2/J mice also develop obesity, reminiscent of Cushing's syndrome of postmenopausal women.	('develop', 'PosReg', (58, 65))	('obesity', 'Phenotype', 'HP:0001513', (66, 73))	('DBA2/J', 'Var', (41, 47))	('mice', 'Species', '10090', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (90, 108))	('obesity', 'Disease', 'MESH:D009765', (66, 73))	('women', 'Species', '9606', (127, 132))	("Cushing's syndrome", 'Disease', (90, 108))	('men', 'Species', '9606', (129, 132))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (90, 108))	('obesity', 'Disease', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('men', 'Species', '9606', (116, 119))
108695	18006632	We report that epistasis between quantitative trait loci (QTL) is an important contributor to the genetics of mouse adrenocortical tumorigenesis and that this pathology could be regarded as a complex genetic trait.	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (116, 144))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('adrenocortical tumorigenesis', 'Disease', (116, 144))	('mouse', 'Species', '10090', (110, 115))	('QTL', 'Gene', (58, 61))	('epistasis', 'Var', (15, 24))
108713	18006632	Weight gain (WG) was followed up to 6 months after Ovx in F1 (n = 46), DBA/2J (n = 25), C57BL/6J (n = 24), and non-Ovx animals (n = 10-14).	('Weight gain', 'Disease', (0, 11))	('Weight gain', 'Disease', 'MESH:D015430', (0, 11))	('Weight gain', 'Phenotype', 'HP:0004324', (0, 11))	('WG', 'Phenotype', 'HP:0004324', (13, 15))	('C57BL/6J', 'Var', (88, 96))
108759	18006632	Interval mapping indicated a broad region spanning about 30 cM, between SNPs rs13479333 and rs4226783 (Fig.	('rs13479333', 'Var', (77, 87))	('rs13479333', 'Mutation', 'rs13479333', (77, 87))	('rs4226783', 'Mutation', 'rs4226783', (92, 101))	('rs4226783', 'Var', (92, 101))
108761	18006632	Interval mapping indicated a broad peak spanning about 35 cM on chromosome 8, with a 1-LOD drop from the maximum peak height defining an interval of about 10 cM located between markers rs32607714 and rs6382288 (Fig.	('rs32607714', 'Mutation', 'rs32607714', (185, 195))	('rs6382288', 'Var', (200, 209))	('rs32607714', 'Var', (185, 195))	('rs6382288', 'Mutation', 'rs6382288', (200, 209))
108763	18006632	Analysis of the segregating alleles within the TS QTL at SNP rs33209429 (peak of linkage) revealed that 27.9% of the tumorigenic F2 animals were homozygous for the nonsusceptible C57BL/6J allele, and 40% of the nonaffected F2 animals were homozygous for the susceptible DBA/2J allele.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('C57BL/6J', 'Var', (179, 187))	('rs33209429', 'Mutation', 'rs33209429', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
108774	18006632	We sequenced all the nonsynonymous coding variants reported between the two parental strains for Sfrp1, as well as for each of the candidate genes where such variants have been reported, but we could not find any evidence for associations with the TS phenotype (data not shown).	('Sfrp1', 'Gene', (97, 102))	('variants', 'Var', (42, 50))	('associations', 'Interaction', (226, 238))	('Sfrp1', 'Gene', '20377', (97, 102))
108775	18006632	The putative promoter region of Sfrp1 was also screened for possible variants between the two parental strains, but no SNPs were found.	('variants', 'Var', (69, 77))	('Sfrp1', 'Gene', '20377', (32, 37))	('Sfrp1', 'Gene', (32, 37))
108784	18006632	Moreover, aberrant LHR expression has been reported in patients developing macronodular adrenal hyperplasia associated with Cushing's syndrome.	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (75, 107))	('LHR expression', 'Protein', (19, 33))	('macronodular adrenal hyperplasia', 'Disease', (75, 107))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (75, 107))	('aberrant', 'Var', (10, 18))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (124, 142))	('patients', 'Species', '9606', (55, 63))	('reported', 'Reg', (43, 51))	("Cushing's syndrome", 'Disease', (124, 142))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (124, 142))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (88, 107))
108785	18006632	Several studies on different mouse models developed by us and others have shown that there are more than one tumor type that are induced by high LH in mouse adrenal glands, with some arising from different zones of the gland such as the X zone or the subcapsular cortical zone.	('high LH', 'Var', (140, 147))	('high LH', 'Phenotype', 'HP:0011969', (140, 147))	('mouse', 'Species', '10090', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mouse', 'Species', '10090', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('LH', 'Chemical', 'MESH:D007986', (145, 147))
108789	18006632	Recent reports emphasize that inappropriate adrenocortical expression of nonmutated G protein-coupled receptors, such as LHR or gastric inhibitory peptide receptor, is sufficient to induce tumor formation.	('induce', 'Reg', (182, 188))	('tumor', 'Disease', (189, 194))	('inappropriate adrenocortical', 'Disease', (30, 58))	('nonmutated', 'Var', (73, 83))	('gastric', 'Protein', (128, 135))	('LHR', 'Gene', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('G protein-coupled receptors', 'Protein', (84, 111))	('inappropriate adrenocortical', 'Disease', 'MESH:D018268', (30, 58))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
108801	18006632	Interestingly, allelic imbalance of human chromosome 8p (syntenic region to our locus) has been described in many human cancers, supporting the hypothesis that genes in this region play an important role in human tumorigenesis, but none have been reported for mouse adrenal tumors.	('human', 'Species', '9606', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', (274, 279))	('adrenal tumor', 'Phenotype', 'HP:0100631', (266, 279))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('imbalance', 'Phenotype', 'HP:0002172', (23, 32))	('cancers', 'Disease', (120, 127))	('human', 'Species', '9606', (207, 212))	('mouse', 'Species', '10090', (260, 265))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('adrenal tumors', 'Disease', 'MESH:D000310', (266, 280))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (213, 218))	('allelic', 'Var', (15, 22))	('described', 'Reg', (96, 105))	('adrenal tumors', 'Disease', (266, 280))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('human', 'Species', '9606', (36, 41))
108807	18006632	When the combined effect of the genotypes at both chromosome 8 and 18 loci was investigated, we observed the resistant C57BL/6J allele in about 20% of tumorigenic F2 animals, suggesting the presence of undetected loci of small effect.	('C57BL/6J', 'Var', (119, 127))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))
108810	18006632	Sfrp1 is down-regulated by epigenetic modifications in several types of cancers, indicating a putative tumor suppressor role for this gene.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('epigenetic modifications', 'Var', (27, 51))	('down-regulated', 'NegReg', (9, 23))	('tumor', 'Disease', (103, 108))	('Sfrp1', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('Sfrp1', 'Gene', '20377', (0, 5))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
108811	18006632	We have not excluded epigenesis as a mode of action of this gene in our model, because we screened only the coding region, but to our knowledge, no data have been reported that support epigenetic changes of Sfrp1 in a tumorigenic mouse model.	('mouse', 'Species', '10090', (230, 235))	('Sfrp1', 'Gene', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('epigenetic changes', 'Var', (185, 203))	('Sfrp1', 'Gene', '20377', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))
108828	18006632	BC Backcross IBD identical by descent LHR LH receptor Ovx ovariectomized QTL quantitative trait loci Sfrp1 secreted frizzled-related protein 1 SNP single-nucleotide polymorphism TS tumor status WG weight gain	('single-nucleotide polymorphism', 'Var', (147, 177))	('Sfrp1', 'Gene', '20377', (101, 106))	('tumor', 'Disease', (181, 186))	('weight gain', 'Phenotype', 'HP:0004324', (197, 208))	('LH receptor', 'Gene', '16867', (42, 53))	('secreted frizzled-related protein 1', 'Gene', (107, 142))	('WG', 'Phenotype', 'HP:0004324', (194, 196))	('LH receptor', 'Gene', (42, 53))	('Ovx ovariectomized', 'Phenotype', 'HP:0008209', (54, 72))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('secreted frizzled-related protein 1', 'Gene', '20377', (107, 142))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('Sfrp1', 'Gene', (101, 106))
108842	33451333	However, only about ten clinical trials using inhibitors specifically targeting AURKB and most of them are still in phase I stage.	('inhibitors', 'Var', (46, 56))	('AURKB', 'Gene', (80, 85))	('AURKB', 'Gene', '9212', (80, 85))
108846	33451333	Gene amplification, transcriptional activation and inhibition of protein degradation could contribute to the elevated levels of AURKA expression in cancer tissues.	('cancer', 'Disease', (148, 154))	('inhibition', 'NegReg', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('expression', 'MPA', (134, 144))	('elevated', 'PosReg', (109, 117))	('protein degradation', 'MPA', (65, 84))	('contribute', 'Reg', (91, 101))	('levels', 'MPA', (118, 124))	('AURKA', 'Gene', '6790', (128, 133))	('activation', 'PosReg', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Gene amplification', 'Var', (0, 18))	('AURKA', 'Gene', (128, 133))
108848	33451333	Given that overexpression and gene amplification of AURKA have been identified in diverse cancers, small molecule kinase inhibitors of AURKA have attracted considerable interest.	('AURKA', 'Gene', '6790', (52, 57))	('cancers', 'Disease', (90, 97))	('AURKA', 'Gene', '6790', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AURKA', 'Gene', (52, 57))	('AURKA', 'Gene', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('overexpression', 'PosReg', (11, 25))	('gene amplification', 'Var', (30, 48))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
108849	33451333	A series of AURKA kinase inhibitors (AKIs) have been produced over the past decades; inhibition of the expression or activity of AURKA by AKIs suppresses cancer cell proliferation, migration and invasion.	('AKIs suppresses cancer', 'Disease', 'MESH:D009369', (138, 160))	('activity', 'MPA', (117, 125))	('expression', 'MPA', (103, 113))	('inhibition', 'Var', (85, 95))	('AURKA', 'Gene', '6790', (12, 17))	('AURKA', 'Gene', '6790', (129, 134))	('AKIs suppresses cancer', 'Disease', (138, 160))	('AURKA', 'Gene', (12, 17))	('AURKA', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
108868	33451333	There is overwhelming evidence of overexpression and gene amplification of AURKA in a wide range of cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('AURKA', 'Gene', '6790', (75, 80))	('overexpression', 'PosReg', (34, 48))	('gene amplification', 'Var', (53, 71))	('AURKA', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
108869	33451333	The underlying mechanisms for AURKA upregulation in cancer include gene amplification, gene mutation, microRNA regulation, transcriptional or posttranscriptional modification, and others.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('microRNA regulation', 'MPA', (102, 121))	('upregulation', 'PosReg', (36, 48))	('AURKA', 'Gene', '6790', (30, 35))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('gene mutation', 'Var', (87, 100))	('gene amplification', 'Var', (67, 85))	('AURKA', 'Gene', (30, 35))
108896	33451333	Likewise, NEDD9 and PUM2 not only stimulate autophosphorylation and autoactivation of AURKA but also stabilize AURKA protein expression through disassociation from cdh.	('disassociation', 'Var', (144, 158))	('AURKA', 'Gene', '6790', (111, 116))	('AURKA', 'Gene', '6790', (86, 91))	('cdh', 'Protein', (164, 167))	('stabilize', 'PosReg', (101, 110))	('autophosphorylation', 'MPA', (44, 63))	('PUM2', 'Gene', (20, 24))	('AURKA', 'Gene', (86, 91))	('AURKA', 'Gene', (111, 116))	('stimulate', 'PosReg', (34, 43))	('autoactivation', 'MPA', (68, 82))	('expression', 'MPA', (125, 135))	('NEDD9', 'Gene', (10, 15))	('PUM2', 'Gene', '23369', (20, 24))	('NEDD9', 'Gene', '4739', (10, 15))
108899	33451333	These regulators are usually tumor suppressors, and inhibition of AURKA is one of the mechanisms explaining their tumor-suppressive functions.	('AURKA', 'Gene', '6790', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('AURKA', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (114, 119))	('inhibition', 'Var', (52, 62))	('tumor', 'Disease', (29, 34))
108907	33451333	GSK-3beta interacts with AURKA and phosphorylates AURKA at Ser290/291 in vitro, after which autophosphorylation occurs at Ser349, which is an AURKA activity-inhibiting phosphorylation site.	('Ser349', 'Chemical', '-', (122, 128))	('AURKA', 'Gene', '6790', (142, 147))	('AURKA', 'Gene', '6790', (25, 30))	('Ser349', 'Var', (122, 128))	('autophosphorylation', 'MPA', (92, 111))	('Ser290', 'Chemical', '-', (59, 65))	('AURKA', 'Gene', (142, 147))	('AURKA', 'Gene', (25, 30))	('AURKA', 'Gene', '6790', (50, 55))	('interacts', 'Interaction', (10, 19))	('GSK-3beta', 'Gene', '2931', (0, 9))	('AURKA', 'Gene', (50, 55))	('GSK-3beta', 'Gene', (0, 9))
108915	33451333	Phosphorylation of AURKA by IKK2 targets it for beta-TRCP-mediated degradation and serves to maintain appropriate levels of AURKA to assure proper bipolar spindle assembly and mitotic progression.	('IKK2', 'Gene', (28, 32))	('levels', 'MPA', (114, 120))	('AURKA', 'Gene', '6790', (124, 129))	('AURKA', 'Gene', '6790', (19, 24))	('beta-TRCP', 'Gene', '8945', (48, 57))	('Phosphorylation', 'Var', (0, 15))	('beta-TRCP', 'Gene', (48, 57))	('targets', 'Reg', (33, 40))	('AURKA', 'Gene', (124, 129))	('AURKA', 'Gene', (19, 24))	('mitotic progression', 'CPA', (176, 195))	('IKK2', 'Gene', '3551', (28, 32))	('bipolar spindle assembly', 'CPA', (147, 171))
108921	33451333	VHL is an E3 ligase that multi-monoubiquitinates AURKA in quiescent cells and targets it for proteasome-mediated degradation under both normoxic and hypoxic conditions.	('AURKA', 'Gene', '6790', (49, 54))	('AURKA', 'Gene', (49, 54))	('proteasome-mediated degradation', 'MPA', (93, 124))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (149, 167))	('hypoxic conditions', 'Disease', (149, 167))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('multi-monoubiquitinates', 'Var', (25, 48))
108932	33451333	Many of the substrates regulated by AURKA coordinate with AURKA to control mitotic progression, and aberrant expression of AURKA in a variety of human cancers has been linked with mitotic defects.	('linked', 'Reg', (168, 174))	('AURKA', 'Gene', (123, 128))	('AURKA', 'Gene', '6790', (58, 63))	('mitotic progression', 'CPA', (75, 94))	('AURKA', 'Gene', (58, 63))	('mitotic defects', 'Disease', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('human', 'Species', '9606', (145, 150))	('AURKA', 'Gene', '6790', (36, 41))	('aberrant expression', 'Var', (100, 119))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('AURKA', 'Gene', '6790', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('AURKA', 'Gene', (36, 41))	('cancers', 'Disease', (151, 158))	('mitotic defects', 'Disease', 'MESH:C536987', (180, 195))
108939	33451333	ASAP is also a spindle-associated protein, deregulation of which induces severe mitotic defects.	('ASAP', 'Gene', '79884', (0, 4))	('ASAP', 'Gene', (0, 4))	('induces', 'Reg', (65, 72))	('mitotic defects', 'Disease', 'MESH:C536987', (80, 95))	('deregulation', 'Var', (43, 55))	('mitotic defects', 'Disease', (80, 95))
108941	33451333	The AURKA activator TPX2 is an AURKA substrate with phosphorylation sites at Ser121 and Ser125.	('Ser121', 'Var', (77, 83))	('AURKA', 'Gene', (4, 9))	('AURKA', 'Gene', '6790', (31, 36))	('Ser125', 'Chemical', '-', (88, 94))	('AURKA', 'Gene', (31, 36))	('TPX2', 'Gene', (20, 24))	('Ser121', 'Chemical', '-', (77, 83))	('Ser125', 'Var', (88, 94))	('AURKA', 'Gene', '6790', (4, 9))	('TPX2', 'Gene', '22974', (20, 24))
108951	33451333	Research has shown that AURKA phosphorylation of Twist at Ser123, Thr148 and Ser184 facilitates Twist-mediated promotion of EMT and chemoresistance in pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('AURKA', 'Gene', (24, 29))	('Thr148', 'Chemical', '-', (66, 72))	('Thr148', 'Var', (66, 72))	('promotion', 'PosReg', (111, 120))	('Twist', 'Gene', '7291', (96, 101))	('Twist', 'Gene', '7291', (49, 54))	('Ser184', 'Var', (77, 83))	('Twist', 'Gene', (96, 101))	('Twist', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('Ser123', 'Chemical', '-', (58, 64))	('Ser184', 'Chemical', '-', (77, 83))	('AURKA', 'Gene', '6790', (24, 29))	('facilitates', 'PosReg', (84, 95))	('pancreatic cancer', 'Disease', (151, 168))
108960	33451333	Phosphorylation of LDHB by AURKA at Ser162 amplifies its activity in reducing pyruvate to lactate, thus promoting glycolysis and biosynthesis and promoting tumor growth.	('glycolysis', 'MPA', (114, 124))	('AURKA', 'Gene', '6790', (27, 32))	('reducing pyruvate to lactate', 'MPA', (69, 97))	('biosynthesis', 'MPA', (129, 141))	('promoting', 'PosReg', (104, 113))	('promoting', 'PosReg', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('AURKA', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Phosphorylation', 'MPA', (0, 15))	('Ser162', 'Var', (36, 42))	('Ser162', 'Chemical', '-', (36, 42))	('LDHB', 'Gene', (19, 23))	('tumor', 'Disease', (156, 161))	('lactate', 'Chemical', 'MESH:D019344', (90, 97))	('LDHB', 'Gene', '3945', (19, 23))	('pyruvate', 'Chemical', 'MESH:D019289', (78, 86))
108961	33451333	Recently, our research has indicated that phosphorylation of the scaffold and oncogenic protein SDCBP by AURKA maintains its protein stability and pro-proliferative functions.	('SDCBP', 'Gene', (96, 101))	('pro-proliferative functions', 'CPA', (147, 174))	('maintains', 'PosReg', (111, 120))	('protein stability', 'MPA', (125, 142))	('SDCBP', 'Gene', '6386', (96, 101))	('AURKA', 'Gene', '6790', (105, 110))	('phosphorylation', 'Var', (42, 57))	('AURKA', 'Gene', (105, 110))
108964	33451333	HURP protein stability and serum-independent growth are enhanced after phosphorylation.	('phosphorylation', 'Var', (71, 86))	('HURP', 'Gene', '9787', (0, 4))	('enhanced', 'PosReg', (56, 64))	('serum-independent growth', 'CPA', (27, 51))	('HURP', 'Gene', (0, 4))
108968	33451333	AURKA regulates LIMK2 kinase activity, subcellular localization and protein levels by directly phosphorylating LIMK2 at Ser283, Thr494 and Thr505.	('AURKA', 'Gene', (0, 5))	('LIMK2', 'Gene', '3985', (111, 116))	('LIMK2', 'Gene', (111, 116))	('LIMK2', 'Gene', '3985', (16, 21))	('Ser283', 'Var', (120, 126))	('LIMK2', 'Gene', (16, 21))	('regulates', 'Reg', (6, 15))	('Thr494', 'Var', (128, 134))	('Thr505', 'Var', (139, 145))	('Thr494', 'Chemical', '-', (128, 134))	('protein levels', 'MPA', (68, 82))	('AURKA', 'Gene', '6790', (0, 5))	('Ser283', 'Chemical', '-', (120, 126))	('Thr505', 'Chemical', '-', (139, 145))	('subcellular localization', 'MPA', (39, 63))
108969	33451333	The small GTPase RalA is also a target of AURKA; phosphorylation of RalA at Ser194 enhances cell migration and anchorage-independent growth.	('AURKA', 'Gene', (42, 47))	('RalA', 'Gene', (68, 72))	('RalA', 'Gene', (17, 21))	('Ser194', 'Chemical', '-', (76, 82))	('RalA', 'Gene', '5898', (68, 72))	('enhances', 'PosReg', (83, 91))	('RalA', 'Gene', '5898', (17, 21))	('cell migration', 'CPA', (92, 106))	('AURKA', 'Gene', '6790', (42, 47))	('phosphorylation', 'Var', (49, 64))	('anchorage-independent growth', 'CPA', (111, 139))
108970	33451333	ALDH1A1 is an AURKA substrate enzyme whose phosphorylation by AURKA at Thr267, Thr442 and Thr493 regulates ALDH1A1 protein stability, enhancing the role of this protein in the process of EMT.	('enhancing', 'PosReg', (134, 143))	('Thr267', 'Chemical', '-', (71, 77))	('Thr493', 'Var', (90, 96))	('Thr442', 'Chemical', '-', (79, 85))	('phosphorylation', 'MPA', (43, 58))	('AURKA', 'Gene', (14, 19))	('AURKA', 'Gene', (62, 67))	('ALDH1A1', 'Gene', '216', (0, 7))	('ALDH1A1', 'Gene', (107, 114))	('protein stability', 'MPA', (115, 132))	('ALDH1A1', 'Gene', '216', (107, 114))	('Thr493', 'Chemical', '-', (90, 96))	('regulates', 'Reg', (97, 106))	('ALDH1A1', 'Gene', (0, 7))	('AURKA', 'Gene', '6790', (14, 19))	('AURKA', 'Gene', '6790', (62, 67))
108973	33451333	However, Ser106 residue phosphorylation by AURKA has the opposite effect.	('Ser106', 'Chemical', '-', (9, 15))	('AURKA', 'Gene', '6790', (43, 48))	('AURKA', 'Gene', (43, 48))	('Ser106 residue', 'Var', (9, 23))
108975	33451333	Another study has revealed that the p53 Ser215 site is phosphorylated by AURKA.	('AURKA', 'Gene', '6790', (73, 78))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('AURKA', 'Gene', (73, 78))	('Ser215', 'Var', (40, 46))	('Ser215', 'Chemical', '-', (40, 46))
108978	33451333	Phosphorylation of RASSF1A by AURKA at Ser203 and Thr202 removes the ability of RASSF1A to interact with microtubules and induce M-phase cell cycle arrest.	('removes', 'NegReg', (57, 64))	('RASSF1A', 'Gene', '11186', (80, 87))	('RASSF1A', 'Gene', '11186', (19, 26))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('Thr202', 'Var', (50, 56))	('Phosphorylation', 'Var', (0, 15))	('interact', 'Interaction', (91, 99))	('RASSF1A', 'Gene', (80, 87))	('arrest', 'Disease', (148, 154))	('AURKA', 'Gene', '6790', (30, 35))	('Ser203', 'Chemical', '-', (39, 45))	('induce', 'Reg', (122, 128))	('Thr202', 'Chemical', '-', (50, 56))	('ability', 'MPA', (69, 76))	('RASSF1A', 'Gene', (19, 26))	('microtubules', 'Protein', (105, 117))	('AURKA', 'Gene', (30, 35))
108982	33451333	Phosphorylation of LKB1 at Ser299 causes LKB1 to dissociate from AMPK, resulting in impairment of the AMPK signaling pathway and facilitating non-small-cell lung cancer (NSCLC) growth and migration.	('LKB1', 'Gene', '6794', (19, 23))	('LKB1', 'Gene', '6794', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Phosphorylation', 'Var', (0, 15))	('facilitating', 'PosReg', (129, 141))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (146, 168))	('AMPK', 'Gene', (65, 69))	('LKB1', 'Gene', (19, 23))	('AMPK', 'Gene', '5564', (65, 69))	('small-cell lung cancer', 'Disease', (146, 168))	('Ser299', 'Var', (27, 33))	('LKB1', 'Gene', (41, 45))	('NSCLC', 'Disease', (170, 175))	('Ser299', 'Chemical', '-', (27, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('AMPK', 'Gene', (102, 106))	('impairment', 'NegReg', (84, 94))	('AMPK', 'Gene', '5564', (102, 106))
108989	33451333	Once YY1 is phosphorylated by AURKA at Ser365, its DNA-binding activity and transcriptional activity are abolished.	('YY1', 'Gene', '7528', (5, 8))	('DNA-binding', 'Interaction', (51, 62))	('YY1', 'Gene', (5, 8))	('Ser365', 'Var', (39, 45))	('transcriptional activity', 'MPA', (76, 100))	('AURKA', 'Gene', '6790', (30, 35))	('Ser365', 'Chemical', '-', (39, 45))	('abolished', 'NegReg', (105, 114))	('AURKA', 'Gene', (30, 35))
108992	33451333	AURKA-mediated phosphorylation of CHIP at Ser273 promotes androgen degradation in castration-resistant prostate cancer.	('AURKA', 'Gene', (0, 5))	('phosphorylation', 'Var', (15, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('promotes', 'PosReg', (49, 57))	('Ser273', 'Chemical', '-', (42, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('AURKA', 'Gene', '6790', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('androgen degradation', 'MPA', (58, 78))	('prostate cancer', 'Disease', (103, 118))
108994	33451333	Phosphorylation by AURKA at Ser243 may account for the cancer-promoting effects of KCTD12.	('KCTD12', 'Gene', '115207', (83, 89))	('AURKA', 'Gene', '6790', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Ser243', 'Chemical', '-', (28, 34))	('Ser243', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Phosphorylation', 'MPA', (0, 15))	('AURKA', 'Gene', (19, 24))	('KCTD12', 'Gene', (83, 89))	('cancer', 'Disease', (55, 61))
109004	33451333	In recent years, several small molecules that selectively target AURKA have been identified with anticancer activity in preclinical studies including LY3295668, BPR1K0609S1, LDD970, MK-8745, AKI603 and CYC3.	('AURKA', 'Gene', (65, 70))	('BPR1K0609S1', 'Var', (161, 172))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('LDD970', 'Var', (174, 180))	('LDD970', 'CellLine', 'CVCL:7312', (174, 180))	('MK-8745', 'Var', (182, 189))	('AKI603', 'Var', (191, 197))	('LY3295668', 'Var', (150, 159))	('LY3295668', 'Chemical', '-', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('AURKA', 'Gene', '6790', (65, 70))
109006	33451333	The common dose-limiting toxicity of specific AKIs, including MLN8237 and ENMD-2076, are neutropenia, somnolence and mucisitis.	('neutropenia', 'Phenotype', 'HP:0001875', (89, 100))	('neutropenia', 'Disease', 'MESH:D009503', (89, 100))	('toxicity', 'Disease', 'MESH:D064420', (25, 33))	('somnolence', 'Disease', (102, 112))	('toxicity', 'Disease', (25, 33))	('MLN8237', 'Chemical', 'MESH:C550258', (62, 69))	('somnolence', 'Disease', 'MESH:D006970', (102, 112))	('mucisitis', 'Disease', (117, 126))	('MLN8237', 'Var', (62, 69))	('neutropenia', 'Disease', (89, 100))
109007	33451333	MLN8237 is a highly selective small molecule inhibitor of AURKA with an IC50 of 1 nM.	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('MLN8237', 'Var', (0, 7))	('AURKA', 'Gene', '6790', (58, 63))	('AURKA', 'Gene', (58, 63))
109008	33451333	MLN8237 was developed as an enhancement of its predecessor, MLN8054, development of which was terminated after phase I studies due to central nervous system side effects, including dose-limiting somnolence.	('somnolence', 'Disease', (195, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('somnolence', 'Disease', 'MESH:D006970', (195, 205))	('MLN8237', 'Var', (0, 7))	('MLN8054', 'Chemical', 'MESH:C518940', (60, 67))
109009	33451333	MLN8237 has been shown to inhibit cell proliferation by impairing mitosis, inducing cell cycle arrest and autophagy, and accelerating cancer cell apoptosis and senescence in multiple cancer types.	('cancer', 'Disease', (183, 189))	('impairing mitosis', 'Disease', (56, 73))	('cell proliferation', 'CPA', (34, 52))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('cancer', 'Disease', (134, 140))	('inhibit', 'NegReg', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('senescence', 'CPA', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('MLN8237', 'Var', (0, 7))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('impairing mitosis', 'Disease', 'MESH:D060825', (56, 73))	('accelerating', 'PosReg', (121, 133))	('inducing', 'PosReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('autophagy', 'CPA', (106, 115))	('arrest', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
109010	33451333	The EMT process is also impeded by MLN8237 treatment in human epithelial ovarian and pancreatic cancer cells.	('epithelial ovarian and pancreatic cancer', 'Disease', 'MESH:D010195', (62, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (35, 42))	('human', 'Species', '9606', (56, 61))	('MLN8237 treatment', 'Var', (35, 52))	('EMT process', 'CPA', (4, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('impeded', 'NegReg', (24, 31))
109011	33451333	Importantly, MLN8237 significantly increases the sensitivity of tumor cells to chemotherapy drugs or radiation.	('tumor', 'Disease', (64, 69))	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('increases', 'PosReg', (35, 44))	('sensitivity', 'MPA', (49, 60))	('MLN8237', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
109012	33451333	Mechanistic studies have revealed that MLN8237 induces proteasomal degradation of N-myc in childhood neuroblastoma.	('MLN8237', 'Chemical', 'MESH:C550258', (39, 46))	('induces', 'Reg', (47, 54))	('MLN8237', 'Var', (39, 46))	('neuroblastoma', 'Disease', (101, 114))	('proteasomal degradation', 'MPA', (55, 78))	('N-myc', 'Gene', '4613', (82, 87))	('neuroblastoma', 'Phenotype', 'HP:0003006', (101, 114))	('N-myc', 'Gene', (82, 87))	('neuroblastoma', 'Disease', 'MESH:D009447', (101, 114))
109013	33451333	In THCA cells, MLN8237 disrupts c-Myc/AURKA complex formation, and c-Myc is a major determinant of MLN8237 responsiveness both in vitro and in vivo.	('MLN8237', 'Chemical', 'MESH:C550258', (99, 106))	('AURKA', 'Gene', (38, 43))	('MLN8237', 'Var', (15, 22))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('c-Myc', 'Gene', '4609', (32, 37))	('c-Myc', 'Gene', '4609', (67, 72))	('c-Myc', 'Gene', (32, 37))	('c-Myc', 'Gene', (67, 72))	('AURKA', 'Gene', '6790', (38, 43))	('disrupts', 'NegReg', (23, 31))	('MLN8237', 'Chemical', 'MESH:C550258', (15, 22))
109014	33451333	MLN8237 has demonstrated efficacy in cell-derived and patient-derived xenograft (PDX) models of numerous tumor types, including glioblastoma, bladder cancer, esophageal adenocarcinoma, multiple myeloma, neuroblastoma and colon cancer.	('multiple myeloma', 'Disease', (185, 201))	('numerous tumor', 'Disease', (96, 110))	('MLN8237', 'Var', (0, 7))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (158, 183))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (158, 183))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('esophageal adenocarcinoma', 'Disease', (158, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('numerous tumor', 'Disease', 'MESH:D009369', (96, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('multiple myeloma', 'Phenotype', 'HP:0006775', (185, 201))	('patient', 'Species', '9606', (54, 61))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('bladder cancer', 'Disease', (142, 156))	('glioblastoma', 'Disease', (128, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('multiple myeloma', 'Disease', 'MESH:D009101', (185, 201))	('neuroblastoma', 'Phenotype', 'HP:0003006', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('neuroblastoma and colon cancer', 'Disease', 'MESH:D015179', (203, 233))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
109015	33451333	Due to its potent efficiency in preclinical studies, MLN8237 has been tested in clinical trials for multiple cancers and is the only AURKA inhibitor that has proceeded to phase III evaluation.	('MLN8237', 'Var', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('AURKA', 'Gene', '6790', (133, 138))	('AURKA', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))
109019	33451333	One phase II trial of MLN8237 in patients with ovarian cancer, fallopian tube cancer, peritoneal carcinoma, acute myelogenous leukemia and high-grade myelodysplastic syndrome showed that MLN8237 has modest single-agent antitumor activity.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('acute myelogenous leukemia', 'Disease', (108, 134))	('fallopian tube cancer', 'Disease', (63, 84))	('myelodysplastic syndrome', 'Disease', (150, 174))	('peritoneal carcinoma', 'Disease', (86, 106))	('MLN8237', 'Var', (22, 29))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (108, 134))	('peritoneal carcinoma', 'Disease', 'MESH:D010534', (86, 106))	('MLN8237', 'Chemical', 'MESH:C550258', (22, 29))	('MLN8237', 'Var', (187, 194))	('ovarian cancer', 'Disease', 'MESH:D010051', (47, 61))	('fallopian tube cancer', 'Disease', 'MESH:D005185', (63, 84))	('tumor', 'Disease', (223, 228))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (114, 134))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (150, 174))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('MLN8237', 'Chemical', 'MESH:C550258', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (150, 174))	('patients', 'Species', '9606', (33, 41))	('ovarian cancer', 'Disease', (47, 61))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (108, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
109020	33451333	In a multicenter phase II study, MLN8237 treatment obtained an objective response in 18% of 49 women with breast cancer and 21% of 48 participants with small-cell lung cancer.	('small-cell lung cancer', 'Disease', (152, 174))	('MLN8237', 'Chemical', 'MESH:C550258', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('participants', 'Species', '9606', (134, 146))	('women', 'Species', '9606', (95, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('MLN8237 treatment', 'Var', (33, 50))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (152, 174))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
109021	33451333	In another phase II study of MLN8237 in advanced/metastatic sarcoma, occasional responses and prolonged stable disease were observed, and progression-free survival (PFS) was promising.	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('MLN8237', 'Var', (29, 36))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('MLN8237', 'Chemical', 'MESH:C550258', (29, 36))
109022	33451333	In castration-resistant neuroendocrine prostate cancer patients, those with AURKA and N-myc activation achieve significant clinical benefit from single-agent MLN8237 treatment.	('MLN8237 treatment', 'Var', (158, 175))	('AURKA', 'Gene', '6790', (76, 81))	('activation', 'PosReg', (92, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('AURKA', 'Gene', (76, 81))	('benefit', 'PosReg', (132, 139))	('N-myc', 'Gene', (86, 91))	('neuroendocrine prostate cancer', 'Disease', (24, 54))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (24, 54))	('patients', 'Species', '9606', (55, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))	('N-myc', 'Gene', '4613', (86, 91))
109023	33451333	Another phase II study has shown that in relapsed or refractory peripheral T-cell NHL (PTCL) patients, MLN8237 has antitumor activity with an overall response rate of 30%.	('tumor', 'Disease', (119, 124))	('NHL', 'Gene', '51750', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('MLN8237', 'Chemical', 'MESH:C550258', (103, 110))	('MLN8237', 'Var', (103, 110))	('NHL', 'Gene', (82, 85))	('patients', 'Species', '9606', (93, 101))
109024	33451333	In a recently reported phase III study conducted in patients with PTCL, although MLN8237 did not demonstrate superior efficacy over comparators, it did show antitumor activity and acceptable tolerability and safety.	('MLN8237', 'Chemical', 'MESH:C550258', (81, 88))	('MLN8237', 'Var', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('patients', 'Species', '9606', (52, 60))
109025	33451333	All these encouraging outcomes make MLN8237 a promising agent for cancer treatment.	('MLN8237', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('MLN8237', 'Chemical', 'MESH:C550258', (36, 43))	('cancer', 'Disease', (66, 72))
109026	33451333	ENMD-2076, a novel, orally bioavailable multitarget inhibitor whose main targets are FLT3 (IC50 = 3 nM) and AURKA (IC50 = 14 nM), exhibits much greater potency against AURKA than against AURKB (IC50 = 350 nM).	('AURKA', 'Gene', (168, 173))	('ENMD-2076', 'Var', (0, 9))	('greater', 'PosReg', (144, 151))	('AURKA', 'Gene', '6790', (108, 113))	('FLT3', 'Gene', '2322', (85, 89))	('AURKB', 'Gene', '9212', (187, 192))	('AURKA', 'Gene', (108, 113))	('AURKA', 'Gene', '6790', (168, 173))	('FLT3', 'Gene', (85, 89))	('potency', 'MPA', (152, 159))	('AURKB', 'Gene', (187, 192))
109027	33451333	Because of its multitarget properties, ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines, with IC50 values ranging from 0.025 to 0.7 muM.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('growth', 'CPA', (62, 68))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (100, 105))	('inhibits', 'NegReg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('ENMD-2076', 'Var', (39, 48))
109028	33451333	ENMD-2076 shows antitumor activity in colorectal cancer, multiple myeloma and triple-negative breast cancer both in vitro and in vivo.	('ENMD-2076', 'Var', (0, 9))	('multiple myeloma', 'Disease', (57, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('multiple myeloma', 'Phenotype', 'HP:0006775', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancer', 'Disease', (38, 55))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('multiple myeloma', 'Disease', 'MESH:D009101', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (38, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('tumor', 'Disease', (20, 25))
109030	33451333	MK-5108 is a novel small molecule that shows robust selectivity for AURKA over AURKB (220-fold greater selectivity) and AURKC (190-fold greater selectivity).	('AURKC', 'Gene', (120, 125))	('AURKA', 'Gene', (68, 73))	('AURKB', 'Gene', '9212', (79, 84))	('AURKB', 'Gene', (79, 84))	('AURKC', 'Gene', '6795', (120, 125))	('MK-5108', 'Var', (0, 7))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('AURKA', 'Gene', '6790', (68, 73))
109032	33451333	In EOC stem cells, MK-5108 induces cell cycle arrest by affecting the NF-kB pathway.	('MK-5108', 'Var', (19, 26))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('induces', 'Reg', (27, 34))	('affecting', 'Reg', (56, 65))	('NF-kB pathway', 'Pathway', (70, 83))	('MK-5108', 'Chemical', 'MESH:C547876', (19, 26))	('arrest', 'Disease', (46, 52))
109033	33451333	MK-5108 also decreases the rate of proliferation and increases intratumoral apoptosis in uterine leiomyosarcoma xenografts.	('tumor', 'Disease', (68, 73))	('decreases', 'NegReg', (13, 22))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (97, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (97, 111))	('MK-5108', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (89, 111))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('increases', 'PosReg', (53, 62))	('leiomyosarcoma', 'Disease', (97, 111))
109036	33451333	Even though the selective AURKA inhibitors might be less toxic than pan-inhibitors, it may also lead to drug resistance more easily, so it is necessary to develop broad Aurora kinase inhibitors to obtain drugs with greater potency for cancer treatment.	('inhibitors', 'Var', (32, 42))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('drug resistance', 'CPA', (104, 119))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('AURKA', 'Gene', '6790', (26, 31))	('lead to', 'Reg', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('AURKA', 'Gene', (26, 31))
109037	33451333	AT9283 exhibits strong activity against several kinases.	('activity', 'MPA', (23, 31))	('AT9283', 'Var', (0, 6))	('kinases', 'Pathway', (48, 55))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
109038	33451333	The ability of AT9283 to inhibit the growth and survival of tumor cells as well as xenografts has been demonstrated in imatinib-resistant BCR-ABL-positive leukemic cells, aggressive B-cell lymphoma and medulloblastoma.	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (182, 197))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (182, 197))	('AT9283', 'Var', (15, 21))	('medulloblastoma', 'Disease', 'MESH:D008527', (202, 217))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cell lymphoma', 'Phenotype', 'HP:0012191', (184, 197))	('AT9283', 'Chemical', 'MESH:C535237', (15, 21))	('medulloblastoma', 'Phenotype', 'HP:0002885', (202, 217))	('imatinib', 'Chemical', 'MESH:D000068877', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('growth', 'CPA', (37, 43))	('inhibit', 'NegReg', (25, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))	('BCR-ABL', 'Gene', '25', (138, 145))	('tumor', 'Disease', (60, 65))	('medulloblastoma', 'Disease', (202, 217))	('B-cell lymphoma', 'Disease', (182, 197))	('BCR-ABL', 'Gene', (138, 145))
109041	33451333	MK-0457, a pyrazoloquinazoline compound, inhibits all three Aurora kinases and inhibits FLT-3 and Abl kinases.	('Abl', 'Gene', '25', (98, 101))	('pyrazoloquinazoline', 'Chemical', '-', (11, 30))	('inhibits', 'NegReg', (41, 49))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('inhibits', 'NegReg', (79, 87))	('MK-0457', 'Var', (0, 7))	('Abl', 'Gene', (98, 101))	('FLT-3', 'Gene', (88, 93))	('FLT-3', 'Gene', '2322', (88, 93))	('Aurora', 'Enzyme', (60, 66))
109044	33451333	MK-0457 induces accumulation of cells with >=4 N DNA content, inhibits cell cycle progression and induces apoptosis of anaplastic THCA cells.	('THCA', 'Phenotype', 'HP:0002890', (130, 134))	('induces', 'Reg', (98, 105))	('inhibits', 'NegReg', (62, 70))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('cells with >=4 N DNA content', 'MPA', (32, 60))	('apoptosis', 'CPA', (106, 115))	('MK-0457', 'Var', (0, 7))	('cell cycle progression', 'CPA', (71, 93))	('accumulation', 'PosReg', (16, 28))
109046	33451333	The activity of MK-0457 was also assessed in two other phase I/II studies, both of which showed promising outcomes in patients with BCR-ABL T315I leukemia.	('BCR-ABL', 'Gene', (132, 139))	('BCR-ABL', 'Gene', '25', (132, 139))	('T315I', 'Var', (140, 145))	('T315I', 'Mutation', 'rs121913459', (140, 145))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('MK-0457', 'Chemical', 'MESH:C484810', (16, 23))	('leukemia', 'Disease', (146, 154))	('patients', 'Species', '9606', (118, 126))
109048	33451333	PHA-739358 exhibits strong antiproliferative activity in BCR-ABL-positive leukemia cells, including those harboring the T315I mutation.	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('T315I', 'Var', (120, 125))	('T315I', 'Mutation', 'rs121913459', (120, 125))	('BCR-ABL', 'Gene', '25', (57, 64))	('BCR-ABL', 'Gene', (57, 64))	('leukemia', 'Disease', (74, 82))	('antiproliferative activity', 'MPA', (27, 53))	('leukemia', 'Disease', 'MESH:D007938', (74, 82))
109049	33451333	The crystal structure of the Abl-T315I-PHA-739358 complex provides a possible structural explanation for the activity of PHA-739358 on the T315I mutation.	('Abl', 'Gene', (29, 32))	('activity', 'MPA', (109, 117))	('T315I', 'Var', (139, 144))	('Abl', 'Gene', '25', (29, 32))	('T315I', 'Mutation', 'rs121913459', (33, 38))	('T315I', 'Mutation', 'rs121913459', (139, 144))
109050	33451333	PHA-739358 also induces cell cycle arrest, apoptosis and autophagy and suppresses the EMT process.	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('suppresses', 'NegReg', (71, 81))	('apoptosis', 'CPA', (43, 52))	('PHA-739358', 'Var', (0, 10))	('arrest', 'Disease', (35, 41))	('EMT process', 'CPA', (86, 97))	('induces', 'Reg', (16, 23))	('autophagy', 'CPA', (57, 66))
109051	33451333	In one study, PHA-739358 inhibited liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model.	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('PHA-739358', 'Var', (14, 24))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', (57, 101))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', 'MESH:C535650', (57, 101))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (80, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('inhibited', 'NegReg', (25, 34))	('metastases', 'Disease', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
109052	33451333	In another study, PHA-739358 inhibited early-stage bone metastases based on an ex vivo model named the 'bone-in-culture array'.	('metastases', 'Disease', 'MESH:D009362', (56, 66))	('inhibited', 'NegReg', (29, 38))	('PHA-739358', 'Var', (18, 28))	('metastases', 'Disease', (56, 66))
109053	33451333	Several phase I/II clinical evaluations have been performed on PHA-739358 due to its encouraging antitumor effects.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PHA-739358', 'Var', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
109054	33451333	Other drugs including AMG900, AS703569, BI-847325, CYC116, PF-03814735, and SNS-314 are also in phase I clinical trials.	('SNS-314', 'Chemical', 'MESH:C532454', (76, 83))	('AMG900', 'Chemical', 'MESH:C555658', (22, 28))	('PF-03814735', 'Chemical', 'MESH:C550549', (59, 70))	('CYC116', 'Var', (51, 57))	('PF-03814735', 'Var', (59, 70))	('BI-847325', 'Var', (40, 49))	('AS703569', 'Var', (30, 38))	('BI-847325', 'Chemical', 'MESH:C000606531', (40, 49))	('AS703569', 'Chemical', 'MESH:C000592140', (30, 38))
109055	33451333	AURKA inhibitors have been shown to have great potential for enhancing the efficacy of multiple established therapeutic agents in both preclinical and clinical studies.	('AURKA', 'Gene', (0, 5))	('efficacy', 'MPA', (75, 83))	('inhibitors', 'Var', (6, 16))	('AURKA', 'Gene', '6790', (0, 5))	('enhancing', 'PosReg', (61, 70))
109062	33451333	In patients with solid tumors, AS703569 in combination with the standard dose of gemcitabine produces preliminary signs of efficacy.	('solid tumors', 'Disease', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (3, 11))	('AS703569', 'Var', (31, 39))	('solid tumors', 'Disease', 'MESH:D009369', (17, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('AS703569', 'Chemical', 'MESH:C000592140', (31, 39))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))
109065	33451333	In addition, MLN8237 has a synergistic effect in association with vincristine and rituximab in aggressive B-cell NHL.	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('vincristine', 'Chemical', 'MESH:D014750', (66, 77))	('NHL', 'Gene', '51750', (113, 116))	('MLN8237', 'Var', (13, 20))	('NHL', 'Gene', (113, 116))	('rituximab', 'Chemical', 'MESH:D000069283', (82, 91))
109069	33451333	In a study on Myc-overexpressing lymphoma xenografts, a combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, leading to improvements in survival.	('lymphoma', 'Disease', 'MESH:D008223', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MLN8237', 'Chemical', 'MESH:C550258', (92, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (33, 41))	('survival', 'CPA', (174, 182))	('tumor', 'Disease', (117, 122))	('MLN8237', 'Var', (92, 99))	('Myc', 'Gene', (14, 17))	('Myc', 'Gene', '17869', (14, 17))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (71, 87))	('mice', 'Species', '10090', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('improvements', 'PosReg', (158, 170))	('lymphoma', 'Disease', (33, 41))
109072	33451333	Combined treatment with MLN8237 and eribulin leads to a synergistic increase in apoptosis in mammary tumors as well as cytotoxic autophagy in metastases through the LC3B/p62 axis and Akt pathway.	('LC3B', 'Gene', (165, 169))	('Akt', 'Gene', (183, 186))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('metastases', 'Disease', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Akt', 'Gene', '207', (183, 186))	('MLN8237', 'Chemical', 'MESH:C550258', (24, 31))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('p62', 'Gene', '23636', (170, 173))	('increase', 'PosReg', (68, 76))	('LC3B', 'Gene', '81631', (165, 169))	('MLN8237', 'Var', (24, 31))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('p62', 'Gene', (170, 173))	('apoptosis', 'CPA', (80, 89))	('tumors', 'Disease', (101, 107))
109073	33451333	In multiple myeloma, studies on combined treatment with AT9283 and lenalidomide have shown significant synergistic antitumor effects of this regimen both in vitro and in vivo.	('AT9283', 'Chemical', 'MESH:C535237', (56, 62))	('multiple myeloma', 'Disease', (3, 19))	('tumor', 'Disease', (119, 124))	('AT9283', 'Var', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lenalidomide', 'Chemical', 'MESH:D000077269', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
109076	33451333	PHA680632 treatment prior to radiation treatment leads to an additive effect in cancer cells, especially in p53-deficient cells in vitro or in vivo.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('additive effect', 'MPA', (61, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PHA680632', 'Chemical', 'MESH:C524543', (0, 9))	('PHA680632', 'Var', (0, 9))	('cancer', 'Disease', (80, 86))
109077	33451333	Another AURKA inhibitor, MLN8054, sensitizes androgen-insensitive prostate cancer to radiation; this sensitization is associated with sustained DNA double-strand breaks.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('MLN8054', 'Chemical', 'MESH:C518940', (25, 32))	('AURKA', 'Gene', '6790', (8, 13))	('sensitizes', 'Reg', (34, 44))	('prostate cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('AURKA', 'Gene', (8, 13))	('MLN8054', 'Var', (25, 32))
109078	33451333	Two other AURKA inhibitors, MLN8237 and ENMD-2076, also enhance radiation sensitivity in cancer cells.	('ENMD-2076', 'Var', (40, 49))	('AURKA', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('enhance', 'PosReg', (56, 63))	('MLN8237', 'Chemical', 'MESH:C550258', (28, 35))	('cancer', 'Disease', (89, 95))	('MLN8237', 'Var', (28, 35))	('AURKA', 'Gene', '6790', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
109083	33451333	In addition, vorinostat and MK-0457 or MK-5108 combination treatment enhances lymphoma cell killing with reductions in c-Myc, hTERT, and microRNA levels.	('lymphoma', 'Disease', (78, 86))	('hTERT', 'Gene', (126, 131))	('vorinostat', 'Chemical', 'MESH:D000077337', (13, 23))	('MK-5108', 'Gene', (39, 46))	('MK-0457', 'Chemical', 'MESH:C484810', (28, 35))	('lymphoma', 'Disease', 'MESH:D008223', (78, 86))	('MK-0457', 'Var', (28, 35))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('microRNA levels', 'MPA', (137, 152))	('reductions', 'NegReg', (105, 115))	('MK-5108', 'Chemical', 'MESH:C547876', (39, 46))	('enhances', 'PosReg', (69, 77))	('c-Myc', 'Gene', '4609', (119, 124))	('hTERT', 'Gene', '7015', (126, 131))	('c-Myc', 'Gene', (119, 124))
109087	33451333	EGFR inhibitors have been a major breakthrough for NSCLC treatment.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (51, 56))	('inhibitors', 'Var', (5, 15))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('EGFR', 'Gene', '1956', (0, 4))
109091	33451333	Both BRD4 and AURKA are regulators of the MYC gene at the translational and posttranslational levels, respectively, and targeting both of them simultaneously may produce synergistic antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('produce', 'Reg', (162, 169))	('BRD4', 'Gene', (5, 9))	('AURKA', 'Gene', (14, 19))	('MYC', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('targeting', 'Var', (120, 129))	('tumor', 'Disease', (186, 191))	('BRD4', 'Gene', '23476', (5, 9))	('MYC', 'Gene', '4609', (42, 45))	('AURKA', 'Gene', '6790', (14, 19))
109092	33451333	JQ1 treatment to repress BRD4 activity together with MLN8237 treatment synergistically promotes cell death in c-Myc expressing human glioblastoma cells.	('glioblastoma', 'Disease', (133, 145))	('BRD4', 'Gene', '23476', (25, 29))	('human', 'Species', '9606', (127, 132))	('MLN8237', 'Var', (53, 60))	('c-Myc', 'Gene', '4609', (110, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('BRD4', 'Gene', (25, 29))	('c-Myc', 'Gene', (110, 115))	('death', 'Disease', 'MESH:D003643', (101, 106))	('death', 'Disease', (101, 106))	('promotes', 'PosReg', (87, 95))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('activity', 'MPA', (30, 38))
109095	33451333	One study showed that AURKA and MDM2 antagonism with MLN8237 and Nutlin-3 halted melanoma growth by inducing growth arrest and senescence, limiting the lifespans of senescent cells, and enhancing tumor immune infiltration and clearance.	('tumor', 'Disease', (196, 201))	('growth arrest', 'Disease', (109, 122))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('Nutlin-3', 'Chemical', 'MESH:C482205', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('senescence', 'CPA', (127, 137))	('lifespans', 'CPA', (152, 161))	('MLN8237', 'Var', (53, 60))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('MDM2', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('halted', 'NegReg', (74, 80))	('growth arrest', 'Phenotype', 'HP:0001510', (109, 122))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('enhancing', 'PosReg', (186, 195))	('MDM2', 'Gene', '4193', (32, 36))	('clearance', 'CPA', (226, 235))	('inducing', 'PosReg', (100, 108))	('growth arrest', 'Disease', 'MESH:D006323', (109, 122))	('AURKA', 'Gene', '6790', (22, 27))	('limiting', 'NegReg', (139, 147))	('AURKA', 'Gene', (22, 27))
109096	33451333	The other study showed that combined MK-0457 and Nutlin-3 treatment activated p53-dependent postmitotic checkpoints at pseudo-G1 phase and induced proapoptotic p53 signaling and mitochondrial apoptosis in AML.	('MK-0457', 'Var', (37, 44))	('mitochondrial apoptosis', 'CPA', (178, 201))	('activated', 'PosReg', (68, 77))	('p53', 'Gene', (160, 163))	('postmitotic checkpoints at pseudo-G1 phase', 'CPA', (92, 134))	('AML', 'Disease', (205, 208))	('p53', 'Gene', (78, 81))	('induced', 'PosReg', (139, 146))	('p53', 'Gene', '7157', (160, 163))	('Nutlin-3', 'Chemical', 'MESH:C482205', (49, 57))	('p53', 'Gene', '7157', (78, 81))	('MK-0457', 'Chemical', 'MESH:C484810', (37, 44))	('AML', 'Disease', 'MESH:D015470', (205, 208))
109099	33451333	In human neuroblastoma cells, MK-5108 increases the efficacy of an anti-ganglioside (GD2) 14G2a antibody, which is related to a reduction in N-Myc expression and an increase in PHLDA1 and p53 protein levels.	('MK-5108', 'Var', (30, 37))	('neuroblastoma', 'Disease', (9, 22))	('human', 'Species', '9606', (3, 8))	('expression', 'MPA', (147, 157))	('neuroblastoma', 'Phenotype', 'HP:0003006', (9, 22))	('ganglioside', 'Chemical', 'MESH:D005732', (72, 83))	('neuroblastoma', 'Disease', 'MESH:D009447', (9, 22))	('efficacy', 'MPA', (52, 60))	('increase', 'PosReg', (165, 173))	('PHLDA1', 'Gene', '22822', (177, 183))	('N-Myc', 'Gene', (141, 146))	('p53', 'Gene', '7157', (188, 191))	('GD2', 'Gene', (85, 88))	('N-Myc', 'Gene', '4613', (141, 146))	('p53', 'Gene', (188, 191))	('increases', 'PosReg', (38, 47))	('PHLDA1', 'Gene', (177, 183))	('reduction', 'NegReg', (128, 137))	('MK-5108', 'Chemical', 'MESH:C547876', (30, 37))
109100	33451333	In addition, combined treatment with an anti-GD2 14G2a antibody and MK-5108 leads to enhancement of the autophagy process in IMR-32 neuroblastoma cells.	('neuroblastoma', 'Disease', (132, 145))	('MK-5108', 'Gene', (68, 75))	('autophagy process', 'CPA', (104, 121))	('IMR-32', 'CellLine', 'CVCL:0346', (125, 131))	('neuroblastoma', 'Phenotype', 'HP:0003006', (132, 145))	('neuroblastoma', 'Disease', 'MESH:D009447', (132, 145))	('MK-5108', 'Chemical', 'MESH:C547876', (68, 75))	('enhancement', 'PosReg', (85, 96))	('combined', 'Interaction', (13, 21))	('anti-GD2 14G2a', 'Var', (40, 54))	('anti-GD2', 'Gene', (40, 48))
109101	33451333	A death receptor 5 agonist antibody has been found to initiate significant apoptosis in tumor cells undergoing therapy-induced senescence induced by MLN8237 treatment.	('death receptor 5', 'Gene', '8795', (2, 18))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('MLN8237', 'Chemical', 'MESH:C550258', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('MLN8237 treatment', 'Var', (149, 166))	('death receptor 5', 'Gene', (2, 18))	('tumor', 'Disease', (88, 93))
109119	33451333	This drug delivery technology has been applied to MLN8237 and the polysaccharide nanovesicle efficiently delivers low concentrations of MLN8237 to inhibit AURKA and disrupt the anchorage-independent growth of MCF-7 cell than free MLN8237.	('AURKA', 'Gene', '6790', (155, 160))	('disrupt', 'NegReg', (165, 172))	('MLN8237', 'Chemical', 'MESH:C550258', (136, 143))	('polysaccharide', 'Chemical', 'MESH:D011134', (66, 80))	('MCF-7', 'CellLine', 'CVCL:0031', (209, 214))	('AURKA', 'Gene', (155, 160))	('MLN8237', 'Var', (136, 143))	('MLN8237', 'Chemical', 'MESH:C550258', (230, 237))	('inhibit', 'NegReg', (147, 154))	('anchorage-independent growth', 'CPA', (177, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (50, 57))
109128	33451333	Furthermore, due to the fact that AURKA exerts its function through specific substrates in certain cancers, inhibition of AURKA substrates instead of targeting AURKA kinase activity may decrease the adverse effects.	('AURKA', 'Gene', (34, 39))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('function', 'MPA', (51, 59))	('cancers', 'Disease', (99, 106))	('AURKA', 'Gene', '6790', (160, 165))	('AURKA', 'Gene', '6790', (122, 127))	('AURKA', 'Gene', '6790', (34, 39))	('inhibition', 'Var', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('AURKA', 'Gene', (160, 165))	('AURKA', 'Gene', (122, 127))
109132	33451333	Furthermore, in the triple-negative breast cancer cells, cell lines with a p53 mutation and increased p53 expression are more sensitive to ENMD-2076 than cell lines with decreased p53 expression.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (180, 183))	('expression', 'MPA', (106, 116))	('p53', 'Gene', '7157', (180, 183))	('sensitive', 'MPA', (126, 135))	('p53', 'Gene', (75, 78))	('increased', 'PosReg', (92, 101))	('mutation', 'Var', (79, 87))	('p53', 'Gene', '7157', (75, 78))	('p53', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
109141	33148256	The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('mutations', 'Var', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
109144	33148256	With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.	('ACC', 'Phenotype', 'HP:0006744', (154, 157))	('mutations', 'Var', (86, 95))	('loss of function', 'NegReg', (69, 85))	('rat', 'Species', '10116', (29, 32))
109154	33148256	Others have reported that hypermethylation is associated with a poor survival including in particular hypermethylation of the G0S2 gene.	('hypermethylation', 'Var', (102, 118))	('hypermethylation', 'Var', (26, 42))	('G0S2', 'Gene', '50486', (126, 130))	('G0S2', 'Gene', (126, 130))
109156	33148256	Genomic studies reported TP53 and CTNNB1 (encoding beta-catenin) mutations to be mutually exclusive and found in patients with ACC who had a "poor outcome".	('found', 'Reg', (104, 109))	('TP53', 'Gene', (25, 29))	('CTNNB1', 'Gene', (34, 40))	('beta-catenin', 'Gene', '1499', (51, 63))	('patients', 'Species', '9606', (113, 121))	('mutations', 'Var', (65, 74))	('ACC', 'Phenotype', 'HP:0006744', (127, 130))	('CTNNB1', 'Gene', '1499', (34, 40))	('TP53', 'Gene', '7157', (25, 29))	('ACC', 'Disease', (127, 130))	('beta-catenin', 'Gene', (51, 63))
109159	33148256	Two comprehensive genomic analyses including the TCGA dataset identified alterations in CTNNB1, TP53, CDKN2A, RB1 and MEN1:genes that had previously been reported as mutated in ACC:as well as in ZNRF3, DAXX, TERT and MED12.	('RB1', 'Gene', (110, 113))	('ACC', 'Phenotype', 'HP:0006744', (177, 180))	('CTNNB1', 'Gene', '1499', (88, 94))	('CDKN2A', 'Gene', '1029', (102, 108))	('DAXX', 'Gene', (202, 206))	('rat', 'Species', '10116', (77, 80))	('RB1', 'Gene', '5925', (110, 113))	('MEN1', 'Gene', '4221', (118, 122))	('MED12', 'Gene', (217, 222))	('DAXX', 'Gene', '1616', (202, 206))	('CTNNB1', 'Gene', (88, 94))	('TP53', 'Gene', (96, 100))	('alterations', 'Var', (73, 84))	('ZNRF3', 'Gene', '84133', (195, 200))	('ZNRF3', 'Gene', (195, 200))	('MEN1', 'Gene', (118, 122))	('TERT', 'Gene', (208, 212))	('TERT', 'Gene', '7015', (208, 212))	('CDKN2A', 'Gene', (102, 108))	('MED12', 'Gene', '9968', (217, 222))	('TP53', 'Gene', '7157', (96, 100))
109160	33148256	Collectively, alterations in ZNRF3, CTNNB1, APC and MEN1 suggested that the Wnt/beta-catenin pathway could be a common pathway involved in ACC carcinogenesis.	('alterations', 'Var', (14, 25))	('ZNRF3', 'Gene', (29, 34))	('CTNNB1', 'Gene', (36, 42))	('APC', 'Disease', 'MESH:D011125', (44, 47))	('rat', 'Species', '10116', (18, 21))	('APC', 'Disease', (44, 47))	('MEN1', 'Gene', '4221', (52, 56))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('MEN1', 'Gene', (52, 56))	('CTNNB1', 'Gene', '1499', (36, 42))	('beta-catenin', 'Gene', (80, 92))	('ACC', 'Phenotype', 'HP:0006744', (139, 142))	('beta-catenin', 'Gene', '1499', (80, 92))	('carcinogenesis', 'Disease', (143, 157))	('ZNRF3', 'Gene', '84133', (29, 34))
109161	33148256	And while the authors reported numerous mutations and DNA methylation alterations in ACCs with poor outcome and specific deregulation of two microRNA clusters in ACCs with good prognosis, it was unclear how these changes could translate into potentially "druggable" findings.	('ACCs', 'Gene', '84680', (85, 89))	('alterations', 'Reg', (70, 81))	('ACC', 'Phenotype', 'HP:0006744', (162, 165))	('ACCs', 'Gene', '84680', (162, 166))	('rat', 'Species', '10116', (74, 77))	('ACCs', 'Gene', (162, 166))	('mutations', 'Var', (40, 49))	('ACC', 'Phenotype', 'HP:0006744', (85, 88))	('deregulation', 'NegReg', (121, 133))	('ACCs', 'Gene', (85, 89))
109181	33148256	Selected variants identified in tumor exomes were validated by manual review using IGV software (Broad Institute).	('variants', 'Var', (9, 17))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))
109198	33148256	In all, 55% of the genome was affected by copy number alterations.	('affected', 'Reg', (30, 38))	('rat', 'Species', '10116', (58, 61))	('copy number alterations', 'Var', (42, 65))
109202	33148256	By contrast, several of these chromosome alterations were rarely observed in the tumors of Zheng et al.. We also found amplification of the TERT (5p15.33) and CDK4 loci (12q14) in 76.5% and 82% of the tumor samples assessed, respectively; and deletions of the CDKN2A (9p21.3), RB1 (13q14) and ZNRF3 loci (22q12.1) in 35%, 59% and 76.5% of tumors, with the incidence of each higher than that previously reported.	('deletions', 'Var', (243, 252))	('tumor', 'Disease', (339, 344))	('tumors', 'Disease', (81, 87))	('CDK4', 'Gene', '1019', (159, 163))	('CDKN2A', 'Gene', '1029', (260, 266))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('RB1', 'Gene', (277, 280))	('tumors', 'Phenotype', 'HP:0002664', (339, 345))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('p21', 'Gene', (269, 272))	('TERT', 'Gene', (140, 144))	('p21', 'Gene', '644914', (269, 272))	('TERT', 'Gene', '7015', (140, 144))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('ZNRF3', 'Gene', '84133', (293, 298))	('rat', 'Species', '10116', (45, 48))	('tumor', 'Disease', (81, 86))	('ZNRF3', 'Gene', (293, 298))	('RB1', 'Gene', '5925', (277, 280))	('tumors', 'Disease', (339, 345))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('CDK4', 'Gene', (159, 163))	('tumors', 'Disease', 'MESH:D009369', (339, 345))	('CDKN2A', 'Gene', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
109203	33148256	After filtering using public databases and normal samples to remove likely false positive and germline variants and including only variants (and targeted bases) in exons or within 3 bp of exons (see Methods), we identified 4981 putative somatic mutations in 3814 genes in the 43 ACC samples, with a median mutation rate of 3.38 per megabase (Mb) in exonic + 3 bases (range 0.50:18).	('mutations', 'Var', (245, 254))	('rat', 'Species', '10116', (315, 318))	('ACC', 'Phenotype', 'HP:0006744', (279, 282))	('exonic + 3 bases', 'Var', (349, 365))
109204	33148256	As regards the DNA mutation spectrum, it was characterized by a predominance of C > T, C > A and T > C transitions, with the 25 tumors with matched normal samples shown in the upper panel (Fig.	('C > A', 'Var', (87, 92))	('C > T', 'Var', (80, 85))	('T > C transitions', 'Var', (97, 114))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
109205	33148256	Twenty-nine genes with non-silent alterations (missense, nonsense, insertions and deletions [indels] and splice variants within 3 bp of exon) present in > 9% of our cohort ( 4/43) were each validated by manual inspection in the Integrated Genome Viewer and by PCR and Sanger sequencing.	('deletions', 'Var', (82, 91))	('nonsense', 'Var', (57, 65))	('rat', 'Species', '10116', (233, 236))	('insertions', 'Var', (67, 77))	('rat', 'Species', '10116', (38, 41))
109208	33148256	Nine of the twelve TP53 mutations (eleven patients) had variant frequencies of 70-90% suggesting LOH.	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))	('patients', 'Species', '9606', (42, 50))	('LOH', 'Disease', (97, 100))
109209	33148256	TP53 mutations preferentially affected the DNA-binding domain (10/12:83.3%) and one occurred in the transactivation 2 domain (1/12:8.3%) (Additional file 2: Table 1).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('affected', 'Reg', (30, 38))	('mutations', 'Var', (5, 14))	('DNA-binding', 'Interaction', (43, 54))
109210	33148256	By comparison, the CTNNB1 mutations all occurred in the GSK-3B phosphorylation domain of the gene, a serine/tyrosine rich region.	('CTNNB1', 'Gene', (19, 25))	('tyrosine', 'Chemical', 'MESH:D014443', (108, 116))	('occurred', 'Reg', (40, 48))	('mutations', 'Var', (26, 35))	('CTNNB1', 'Gene', '1499', (19, 25))	('GSK-3B', 'Gene', '2932', (56, 62))	('GSK-3B', 'Gene', (56, 62))	('serine', 'Chemical', 'MESH:D012694', (101, 107))
109212	33148256	We found that the majority of genes in ACC that had mutations also have been found to have mutations in all cancers, suggesting that they were just as likely to have been found to harbor mutations in other cancers as in ACC.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('ACC', 'Phenotype', 'HP:0006744', (39, 42))	('ACC', 'Disease', (39, 42))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('mutations', 'Var', (91, 100))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', (206, 213))	('ACC', 'Phenotype', 'HP:0006744', (220, 223))	('cancers', 'Disease', (108, 115))
109216	33148256	Removing these two from the comparison, the regression coefficient for the incidence of the mutations in ACC and the incidence in all other cancers increased to R = 0.87, R2 = 0.76 (Fig.	('ACC', 'Phenotype', 'HP:0006744', (105, 108))	('mutations', 'Var', (92, 101))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ACC', 'Gene', (105, 108))
109218	33148256	This suggested that at least some of the mutations, such as those in TTN, may have occurred as random events.	('mutations', 'Var', (41, 50))	('TTN', 'Gene', '7273', (69, 72))	('TTN', 'Gene', (69, 72))
109222	33148256	Inactivating mutations or homozygous deletions were found in TP53 (11/43, 26%); no other p53-Rb pathway mutations were found, including in CDKN2A, RB1, CDK4 or MDM2.	('CDKN2A', 'Gene', '1029', (139, 145))	('CDK4', 'Gene', '1019', (152, 156))	('CDK4', 'Gene', (152, 156))	('TP53', 'Gene', '7157', (61, 65))	('p53', 'Gene', '7157', (89, 92))	('RB1', 'Gene', '5925', (147, 150))	('Inactivating mutations', 'Var', (0, 22))	('p53', 'Gene', (89, 92))	('RB1', 'Gene', (147, 150))	('TP53', 'Gene', (61, 65))	('MDM2', 'Gene', '4193', (160, 164))	('CDKN2A', 'Gene', (139, 145))	('MDM2', 'Gene', (160, 164))
109223	33148256	In addition to the CTNNB1 alterations (6/43, 14%) described above, mutations in the WNT-CTNNB1 pathway also included APC (2/43), AXIN1 (2/43), and AXIN2 (1/43).	('CTNNB1', 'Gene', (19, 25))	('CTNNB1', 'Gene', '1499', (88, 94))	('AXIN2', 'Gene', (147, 152))	('AXIN2', 'Gene', '8313', (147, 152))	('mutations', 'Var', (67, 76))	('rat', 'Species', '10116', (30, 33))	('AXIN1', 'Gene', '8312', (129, 134))	('CTNNB1', 'Gene', '1499', (19, 25))	('APC (2/43', 'Gene', '10297', (117, 126))	('AXIN1', 'Gene', (129, 134))	('CTNNB1', 'Gene', (88, 94))
109225	33148256	In all, this pathway appeared to carry mutations in 10/43 (23%) tumors from individual patients.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
109226	33148256	As more tumors have been subjected to sequence analysis the prevalence of mutation in genes encoding proteins regulating chromatin and mediating DNA damage and its repair has been recognized and in some cases associated with oncogenesis.	('associated', 'Reg', (209, 219))	('mutation', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
109228	33148256	Among epigenetic regulators we found 6 (14%) with predicted loss of function mutations, and 24 (56%) unique tumors with any alteration in any epigenetic regulators (Additional file 2: Table 2A).	('loss of function', 'NegReg', (60, 76))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutations', 'Var', (77, 86))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('rat', 'Species', '10116', (128, 131))
109229	33148256	Among those genes known to be involved in mismatch repair deficiency (MMR), we found mutations in seven (16%) tumors, including one with clear loss of function and 2 with loss of heterozygosity (Additional file 2: Table 2B).	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('mutations', 'Var', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))
109230	33148256	Among other types of DNA repair proteins, including those involved in the homologous recombination pathways, we found 14 (33%) tumors with alterations in these genes, including 2 frameshift mutations with predicted loss of function in the WRN and BLM genes, and the rest nonsynonymous with unknown effect on function.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('frameshift mutations', 'Var', (179, 199))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('BLM', 'Gene', '641', (247, 250))	('alterations', 'Var', (139, 150))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('WRN', 'Gene', '7486', (239, 242))	('rat', 'Species', '10116', (143, 146))	('WRN', 'Gene', (239, 242))	('loss of function', 'NegReg', (215, 231))	('BLM', 'Gene', (247, 250))
109231	33148256	These included mutations in BRCA1, BRCA2, PALB2, and POLE.	('BRCA1', 'Gene', '672', (28, 33))	('BRCA1', 'Gene', (28, 33))	('mutations', 'Var', (15, 24))	('BRCA2', 'Gene', '675', (35, 40))	('POLE', 'Gene', (53, 57))	('PALB2', 'Gene', '79728', (42, 47))	('PALB2', 'Gene', (42, 47))	('BRCA2', 'Gene', (35, 40))
109232	33148256	Included amongst the variants in epigenetic regulators were two with ATRX mutations and six with SETD2 mutations, both known to be involved in DNA repair and with mutations in both associated with high mutation burden.	('variants', 'Var', (21, 29))	('mutations', 'Var', (103, 112))	('mutations', 'Var', (163, 172))	('mutations', 'Var', (74, 83))	('ATRX', 'Gene', (69, 73))	('SETD2', 'Gene', '29072', (97, 102))	('ATRX', 'Gene', '546', (69, 73))	('SETD2', 'Gene', (97, 102))
109233	33148256	Aggregating ATRX, SETD2, and MMR, homologous recombination (HR), and other genes involved in DNA repair, but excluding TP53, we found 36 mutations in samples obtained from 21 (49%) of the 43 patients.	('patients', 'Species', '9606', (191, 199))	('ATRX', 'Gene', '546', (12, 16))	('SETD2', 'Gene', '29072', (18, 23))	('TP53', 'Gene', (119, 123))	('mutations', 'Var', (137, 146))	('SETD2', 'Gene', (18, 23))	('TP53', 'Gene', '7157', (119, 123))	('ATRX', 'Gene', (12, 16))
109235	33148256	The occurrence of TP53 mutations in ACC was already well-known and considered a negative prognostic factor in adults and children.	('children', 'Species', '9606', (121, 129))	('TP53', 'Gene', '7157', (18, 22))	('ACC', 'Phenotype', 'HP:0006744', (36, 39))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))
109236	33148256	We asked whether TP53 or -catenin mutations had an impact on overall survival in either the NIH cohort, or in the TCGA cohort.	('-catenin', 'Protein', (25, 33))	('overall survival', 'MPA', (61, 77))	('TP53', 'Gene', '7157', (17, 21))	('impact', 'Reg', (51, 57))	('mutations', 'Var', (34, 43))	('TP53', 'Gene', (17, 21))
109237	33148256	4a, we demonstrate that, while TP53 mutations are associated with worse outcome in the patients that comprise the TCGA data, TP53 was not able to discriminate survival in the NIH cohort.	('TP53', 'Gene', '7157', (125, 129))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('TP53', 'Gene', (125, 129))	('patients', 'Species', '9606', (87, 95))	('rat', 'Species', '10116', (14, 17))
109239	33148256	We found occasional tumors with elevated TMB, and only a weak association between TMB and TP53 mutation (Fig.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('TMB', 'Chemical', '-', (41, 44))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TMB', 'MPA', (41, 44))	('TMB', 'Chemical', '-', (82, 85))	('mutation', 'Var', (95, 103))
109252	33148256	We also analyzed the data by IPA for alterations in upstream regulators in known cancer drivers (Additional file 2: Table 4).	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('rat', 'Species', '10116', (41, 44))	('alterations', 'Var', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
109253	33148256	Interestingly, p21 and TP53 were among the regulators predicted to be downregulated; consistent with the known loss of function mutations in TP53.	('mutations', 'Var', (128, 137))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('p21', 'Gene', (15, 18))	('downregulated', 'NegReg', (70, 83))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('p21', 'Gene', '644914', (15, 18))
109262	33148256	As in the majority of cancers, we found copy number gains and losses in many of our samples.	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('cancers', 'Disease', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('losses', 'NegReg', (62, 68))	('copy number gains', 'Var', (40, 57))
109265	33148256	We also identified 4981 putative somatic mutations in 3814 genes with a median mutation rate of 3.38 per megabase (Mb) in exonic + 3 bases (range 0.50:18).	('mutations', 'Var', (41, 50))	('genes', 'Gene', (59, 64))	('rat', 'Species', '10116', (88, 91))
109268	33148256	The major predicted signatures were the C > T at CpG sites associated with aging (SBS1), found in all cancers, and a mismatch repair deficiency signature (SBS6).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('aging', 'Disease', (75, 80))	('C > T', 'Var', (40, 45))	('associated', 'Reg', (59, 69))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('mismatch repair', 'MPA', (117, 132))
109269	33148256	But despite the number of mutations, as a whole, our data and that in the previous analyses finds that that rate of mutations in ACCs is similar to that in other cancers, indeed even lower (Fig.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('rat', 'Species', '10116', (108, 111))	('cancers', 'Disease', (162, 169))	('ACC', 'Phenotype', 'HP:0006744', (129, 132))	('mutations', 'Var', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('ACCs', 'Gene', (129, 133))	('ACCs', 'Gene', '84680', (129, 133))	('lower', 'NegReg', (183, 188))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
109272	33148256	Furthermore, we found in the current and in the previous analyses that the majority of the mutations were in genes not implicated in the etiology or maintenance of cancer.	('cancer', 'Disease', (164, 170))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))
109274	33148256	Finally, we found the transcript length for the 38 most frequently mutated genes in the 3 ACC datasets to be statistically longer than the transcript length for the average of all coding genes, and for the COSMIC cancer census genes, an observation that raises questions as to the importance of many of the mutations, and whether their occurrence reflects in part the length of their transcripts and hence the probability of incurring a mutation (Fig.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (307, 316))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('ACC', 'Phenotype', 'HP:0006744', (90, 93))
109275	33148256	Twenty-three genes mutated in our cohort were validated and as previously reported, the two most frequently altered genes were TP53 and CTNNB1, mutated in 26% and 14%, respectively.	('mutated', 'Var', (144, 151))	('CTNNB1', 'Gene', (136, 142))	('CTNNB1', 'Gene', '1499', (136, 142))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
109276	33148256	The data for TP53 suggested LOH in the majority and while an incidence rate of 26% represents a substantial fraction, it is lower than the majority of other cancers, something of a surprise in a cancer for which TP53 has been generally regarded as important:and is thought to be etiologic in children who inherit a mutant TP53.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('TP53', 'Gene', (13, 17))	('rat', 'Species', '10116', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('TP53', 'Gene', '7157', (322, 326))	('cancer', 'Disease', (157, 163))	('mutant', 'Var', (315, 321))	('cancers', 'Disease', (157, 164))	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (322, 326))	('TP53', 'Gene', '7157', (212, 216))	('TP53', 'Gene', (212, 216))	('children', 'Species', '9606', (292, 300))
109277	33148256	This is especially surprising as our subjects all had advanced or metastatic disease, and TP53 mutations have been reported to be higher in more aggressive disease for several cancers including ACC.	('cancers', 'Disease', (176, 183))	('aggressive disease', 'Disease', (145, 163))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('TP53', 'Gene', '7157', (90, 94))	('higher', 'Reg', (130, 136))	('ACC', 'Phenotype', 'HP:0006744', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('TP53', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))	('aggressive disease', 'Disease', 'MESH:D001523', (145, 163))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))
109278	33148256	Interestingly, our analyses in part supports this bias by demonstrating that while TP53 mutations are associated with worse outcome in the patients that comprise the TCGA data, composed primarily of tumors at initial presentation, the same was not true in our patient population.	('TP53', 'Gene', '7157', (83, 87))	('patient', 'Species', '9606', (260, 267))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('patients', 'Species', '9606', (139, 147))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('TP53', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('patient', 'Species', '9606', (139, 146))	('rat', 'Species', '10116', (65, 68))
109279	33148256	While we lack evidence to explain this discrepancy one could postulate that the aggressive presentations/biology of tumors in our patients were driven by more than the mutation of a single gene, and instead had a much more diverse expression/mutational profile.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('aggressive presentations/biology', 'CPA', (80, 112))	('driven by', 'Reg', (144, 153))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutation', 'Var', (168, 176))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
109280	33148256	As regards CTNNB1, the very modest rate of 14% mutations in our cohort and 16% across all ACCs is notably higher than in many cancers and may suggest a putative role in a subset of ACCs.	('CTNNB1', 'Gene', '1499', (11, 17))	('ACCs', 'Gene', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ACCs', 'Gene', '84680', (181, 185))	('CTNNB1', 'Gene', (11, 17))	('mutations', 'Var', (47, 56))	('ACCs', 'Gene', (90, 94))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('ACCs', 'Gene', '84680', (90, 94))	('cancers', 'Disease', (126, 133))	('role', 'Reg', (161, 165))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('rat', 'Species', '10116', (35, 38))	('ACC', 'Phenotype', 'HP:0006744', (181, 184))	('ACC', 'Phenotype', 'HP:0006744', (90, 93))
109282	33148256	Other than TP53 and CTNNB1, the mutational analysis revealed a high 18.6% incidence of HGC6.3 mutations in our cohort, notably higher than the 0% in the other ACC cohorts and in all cancers.	('HGC6.3', 'Gene', '100128124', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mutations', 'Var', (94, 103))	('TP53', 'Gene', '7157', (11, 15))	('CTNNB1', 'Gene', (20, 26))	('TP53', 'Gene', (11, 15))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('CTNNB1', 'Gene', '1499', (20, 26))	('cancers', 'Disease', (182, 189))	('higher', 'PosReg', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('ACC', 'Phenotype', 'HP:0006744', (159, 162))	('HGC6.3', 'Gene', (87, 93))
109284	33148256	If mutations in a given gene or pathway are seen in a large enough fraction of a given tumor histology, it brings attention to that gene/pathway as having a possible critical role in the disease under study:with BCR-ABL in CML and BRAF in melanoma the two best examples.	('BRAF', 'Gene', (231, 235))	('BRAF', 'Gene', '673', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('CML', 'Disease', (223, 226))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('CML', 'Disease', 'MESH:D015464', (223, 226))	('BCR-ABL', 'Gene', (212, 219))	('melanoma', 'Disease', (239, 247))	('BCR-ABL', 'Gene', '25', (212, 219))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutations', 'Var', (3, 12))
109296	33148256	Furthermore, aggregating ATRX, SETD2, the mismatch repair and homologous recombination genes, and other genes involved in DNA repair, but excluding TP53, we find 36 mutations in samples obtained from 21 (49%) of the 43 patients suggesting impaired DNA repair may be an important theme in these aggressive ACCs an observation that could explain the higher incidence of mutations.	('SETD2', 'Gene', (31, 36))	('ACCs', 'Gene', '84680', (305, 309))	('patients', 'Species', '9606', (219, 227))	('ATRX', 'Gene', (25, 29))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('ACC', 'Phenotype', 'HP:0006744', (305, 308))	('ATRX', 'Gene', '546', (25, 29))	('mutations', 'Var', (165, 174))	('SETD2', 'Gene', '29072', (31, 36))	('ACCs', 'Gene', (305, 309))
109299	33148256	As observed with other cancers, DNA repair alterations may yet identify a subset sensitive to DNA damaging agents, and this needs to be explored more fully.	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('rat', 'Species', '10116', (47, 50))	('alterations', 'Var', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
109300	33148256	Epigenetic alterations may represent a more fertile ground for investigation, particularly given the earlier reports demonstrating gene silencing via hypermethylation and its impact on prognosis.	('rat', 'Species', '10116', (124, 127))	('rat', 'Species', '10116', (15, 18))	('hypermethylation', 'Var', (150, 166))	('gene', 'MPA', (131, 135))
109311	32937772	Unwanted Hormonal and Metabolic Effects of Postoperative Adjuvant Mitotane Treatment for Adrenocortical Cancer Mitotane is the only drug approved for treatment of adrenocortical cancer.	('men', 'Species', '9606', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Mitotane', 'Var', (111, 119))	('men', 'Species', '9606', (80, 83))	('Cancer', 'Disease', (104, 110))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('Mitotane', 'Chemical', 'MESH:D008939', (66, 74))	('Cancer', 'Disease', 'MESH:D009369', (104, 110))	('Mitotane', 'Chemical', 'MESH:D008939', (111, 119))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))
109332	32937772	According to one of the most accepted views, mitotane impairs the activity of sterol-O-acyl transferase 1 (SOAT1), also named acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) and leads to the intracellular accumulation of free lipids, thus causing endoplasmic reticulum stress that promotes apoptosis and cell death.	('impairs', 'NegReg', (54, 61))	('sterol-O-acyl transferase 1', 'Gene', '6646', (78, 105))	('SOAT1', 'Gene', (107, 112))	('ACAT1', 'Gene', (173, 178))	('activity', 'MPA', (66, 74))	('ACAT1', 'Gene', '38', (173, 178))	('acyl-coenzyme A:cholesterol acyltransferase 1', 'Gene', (126, 171))	('leads to', 'Reg', (184, 192))	('causing', 'Reg', (245, 252))	('mitotane', 'Var', (45, 53))	('acyl-coenzyme A:cholesterol acyltransferase 1', 'Gene', '6646', (126, 171))	('cell death', 'CPA', (310, 320))	('intracellular', 'MPA', (197, 210))	('sterol-O-acyl transferase 1', 'Gene', (78, 105))	('mitotane', 'Chemical', 'MESH:D008939', (45, 53))	('lipids', 'Chemical', 'MESH:D008055', (232, 238))	('apoptosis', 'CPA', (296, 305))	('promotes', 'PosReg', (287, 295))	('SOAT1', 'Gene', '6646', (107, 112))	('endoplasmic reticulum stress', 'MPA', (253, 281))
109335	32937772	In old series, the use of mitotane was associated with severe neurological adverse events, including lethargy, dizziness and somnolence that were found in 40% to 60% of patients causing significant disturbance of ordinary life activities.	('mitotane', 'Var', (26, 34))	('dizziness', 'Disease', (111, 120))	('patients', 'Species', '9606', (169, 177))	('mitotane', 'Chemical', 'MESH:D008939', (26, 34))	('lethargy', 'Disease', (101, 109))	('dizziness', 'Phenotype', 'HP:0002321', (111, 120))	('somnolence', 'Disease', (125, 135))	('lethargy', 'Phenotype', 'HP:0001254', (101, 109))	('somnolence', 'Disease', 'MESH:D006970', (125, 135))	('dizziness', 'Disease', 'MESH:D004244', (111, 120))	('lethargy', 'Disease', 'MESH:D053609', (101, 109))
109341	32937772	Despite all the preventive measures that can be put in place to minimize mitotane-related toxicity, it remains true that mitotane has a narrow therapeutic index and can induce a wide spectrum of unwanted effects that render its use complex.	('unwanted effects', 'MPA', (195, 211))	('mitotane', 'Var', (121, 129))	('induce', 'Reg', (169, 175))	('toxicity', 'Disease', 'MESH:D064420', (90, 98))	('toxicity', 'Disease', (90, 98))	('mitotane', 'Chemical', 'MESH:D008939', (73, 81))	('mitotane', 'Chemical', 'MESH:D008939', (121, 129))
109358	32937772	After 6 months of substitutive treatment with levothyroxine, we registered a significant increase in fT4 and a decrease in TSH levels (fT4, 0.67 ng/dL (0.56-0.87) vs. 0.78 ng/dL (0.63-0.99), p = 0.002; TSH, 1.74 uUI/mL (0.15-6.52) vs. 0.82 uUI/mL (0.05-4.14), p = 0.001).	('levothyroxine', 'Var', (46, 59))	('fT4', 'Chemical', '-', (101, 104))	('fT4', 'Chemical', '-', (135, 138))	('levothyroxine', 'Chemical', 'MESH:D013974', (46, 59))	('TSH', 'Chemical', 'MESH:D013972', (123, 126))	('men', 'Species', '9606', (36, 39))	('TSH levels', 'MPA', (123, 133))	('TSH', 'Chemical', 'MESH:D013972', (202, 205))	('decrease', 'NegReg', (111, 119))	('decrease in TSH levels', 'Phenotype', 'HP:0031098', (111, 133))	('fT4', 'MPA', (101, 104))	('increase', 'PosReg', (89, 97))
109383	32937772	Since it is held that mitotane causes cortisol deficiency, we did not focus on this specific effect that was the subject of a previous work of our group.	('mitotane', 'Var', (22, 30))	('cortisol deficiency', 'Disease', (38, 57))	('mitotane', 'Chemical', 'MESH:D008939', (22, 30))	('cortisol deficiency', 'Phenotype', 'HP:0008163', (38, 57))	('causes', 'Reg', (31, 37))	('cortisol deficiency', 'Disease', 'MESH:C535280', (38, 57))
109386	32937772	This finding suggests that mitotane may enhance the metabolism of fludrocortisone, as is the case for glucocorticoids, thus requiring higher doses of both glucocorticoids and mineralocorticoids than in Addison disease.	('Addison disease', 'Disease', (202, 217))	('mitotane', 'Var', (27, 35))	('Addison disease', 'Phenotype', 'HP:0008207', (202, 217))	('higher', 'PosReg', (134, 140))	('mitotane', 'Chemical', 'MESH:D008939', (27, 35))	('fludrocortisone', 'Chemical', 'MESH:D005438', (66, 81))	('enhance', 'PosReg', (40, 47))	('Addison disease', 'Disease', 'MESH:D000224', (202, 217))	('metabolism', 'MPA', (52, 62))
109390	32937772	The novel finding is that the introduction of levothyroxine is able to reduce TSH while causing a significative increase in fT4 levels.	('levothyroxine', 'Var', (46, 59))	('levothyroxine', 'Chemical', 'MESH:D013974', (46, 59))	('reduce', 'NegReg', (71, 77))	('TSH', 'Disease', (78, 81))	('reduce TSH', 'Phenotype', 'HP:0031098', (71, 81))	('TSH', 'Chemical', 'MESH:D013972', (78, 81))	('fT4 levels', 'MPA', (124, 134))	('increase', 'PosReg', (112, 120))	('fT4', 'Chemical', '-', (124, 127))
109391	32937772	This signals an intact feedback mechanism and strengthens the concept that mitotane induces a central hypothyroid state.	('mitotane', 'Var', (75, 83))	('hypothyroid', 'Disease', 'MESH:D007037', (102, 113))	('mitotane', 'Chemical', 'MESH:D008939', (75, 83))	('central hypothyroid state', 'Phenotype', 'HP:0011787', (94, 119))	('hypothyroid state', 'Phenotype', 'HP:0000821', (102, 119))	('hypothyroid', 'Disease', (102, 113))
109405	32937772	Mitotane induces a peculiar lipid pattern characterized by a prominent increase in HDL rather than LDL cholesterol, and a concomitant increase in triglycerides, as previously reported.	('Mitotane', 'Var', (0, 8))	('lipid', 'Chemical', 'MESH:D008055', (28, 33))	('triglycerides', 'Chemical', 'MESH:D014280', (146, 159))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('lipid pattern', 'MPA', (28, 41))	('increase', 'PosReg', (71, 79))	('increase', 'PosReg', (134, 142))	('triglycerides', 'MPA', (146, 159))	('cholesterol', 'Chemical', 'MESH:D002784', (103, 114))	('HDL', 'MPA', (83, 86))	('increase in triglycerides', 'Phenotype', 'HP:0002155', (134, 159))
109460	31865789	Angiotensin II stimulation or KCNJ5 T158A overexpression in HAC15 cells did not affect CLGN mRNA levels.	('KCNJ5', 'Gene', '3762', (30, 35))	('CLGN mRNA levels', 'MPA', (87, 103))	('HAC15', 'CellLine', 'CVCL:S898', (60, 65))	('T158A', 'Mutation', 'rs387906778', (36, 41))	('T158A', 'Var', (36, 41))	('Angiotensin II', 'Gene', (0, 14))	('Angiotensin II', 'Gene', '183', (0, 14))	('KCNJ5', 'Gene', (30, 35))
109463	31865789	CYP11B2 and HSD3B2 protein expression were more abundant in CLGN-overexpressing cells.	('HSD3B2', 'Gene', '3284', (12, 18))	('CYP11B2', 'Var', (0, 7))	('HSD3B2', 'Gene', (12, 18))
109464	31865789	CLGN knockdown using CRISPR/Cas9 method in HAC15 cells that carry the KCNJ5 mutation did not affect aldosterone production.	('aldosterone production', 'MPA', (100, 122))	('aldosterone production', 'Phenotype', 'HP:0000859', (100, 122))	('KCNJ5', 'Gene', (70, 75))	('HAC15', 'CellLine', 'CVCL:S898', (43, 48))	('KCNJ5', 'Gene', '3762', (70, 75))	('aldosterone', 'Chemical', 'MESH:D000450', (100, 111))	('mutation', 'Var', (76, 84))
109485	31865789	The genotypes of APAs were ATP1A1 mutation (n = 5), KCNJ5 mutation (n = 27), and no mutation (n = 16).	('KCNJ5', 'Gene', (52, 57))	('APAs', 'Gene', (17, 21))	('PA', 'Phenotype', 'HP:0011736', (18, 20))	('ATP1A1', 'Gene', '476', (27, 33))	('mutation', 'Var', (58, 66))	('KCNJ5', 'Gene', '3762', (52, 57))	('ATP1A1', 'Gene', (27, 33))
109492	31865789	Total RNA extraction, reverse transcription, and qPCR assay of CYP11B2 and GAPDH were performed as previously reported.	('GAPDH', 'Gene', (75, 80))	('GAPDH', 'Gene', '2597', (75, 80))	('CYP11B2', 'Var', (63, 70))
109497	31865789	The open reading frame of the ATP1A1 gene with the L104R mutant was obtained from GenScript (Piscataway, NJ) and ligated into the multiple cloning site of the plasmid.	('ATP1A1', 'Gene', '476', (30, 36))	('L104R', 'Mutation', 'rs11540945', (51, 56))	('L104R', 'Var', (51, 56))	('ATP1A1', 'Gene', (30, 36))
109498	31865789	For KCNJ5 mutation, KCNJ5-T158A plasmid was used as reported previously.	('KCNJ5', 'Gene', '3762', (20, 25))	('KCNJ5', 'Gene', '3762', (4, 9))	('T158A', 'Mutation', 'rs387906778', (26, 31))	('mutation', 'Var', (10, 18))	('KCNJ5', 'Gene', (20, 25))	('KCNJ5', 'Gene', (4, 9))
109501	31865789	To assess the effects of CLGN overexpression and KCNJ5 and ATP1A1 mutation, lentivirus production and infection in HAC15 cells were conducted as reported previously.	('infection', 'Disease', (102, 111))	('KCNJ5', 'Gene', (49, 54))	('infection', 'Disease', 'MESH:D007239', (102, 111))	('ATP1A1', 'Gene', '476', (59, 65))	('KCNJ5', 'Gene', '3762', (49, 54))	('mutation', 'Var', (66, 74))	('ATP1A1', 'Gene', (59, 65))	('HAC15', 'CellLine', 'CVCL:S898', (115, 120))
109511	31865789	Briefly, HAC15 cells were first transfected with pCMV R-CEPIA1er plasmid (Addgene, Cambridge, MA) and 48 h later infected with CLGN or control lentivirus.	('pCMV R-CEPIA1er', 'Var', (49, 64))	('infected', 'Disease', (113, 121))	('HAC15', 'CellLine', 'CVCL:S898', (9, 14))	('infected', 'Disease', 'MESH:D007239', (113, 121))
109543	31865789	Cortisol levels in HAC15 cells were slightly higher than those in control cells (Figure 4B).	('Cortisol', 'Chemical', 'MESH:D006854', (0, 8))	('Cortisol levels', 'MPA', (0, 15))	('HAC15', 'CellLine', 'CVCL:S898', (19, 24))	('HAC15', 'Var', (19, 24))	('higher', 'PosReg', (45, 51))
109551	31865789	We investigated the effects of CLGN suppression on the aldosterone levels stimulated by A-II and KCNJ5 mutations.	('mutations', 'Var', (103, 112))	('aldosterone levels', 'MPA', (55, 73))	('A-II', 'Gene', '183', (88, 92))	('KCNJ5', 'Gene', (97, 102))	('A-II', 'Gene', (88, 92))	('KCNJ5', 'Gene', '3762', (97, 102))	('aldosterone', 'Chemical', 'MESH:D000450', (55, 66))	('aldosterone levels stimulated', 'Phenotype', 'HP:0000859', (55, 84))
109552	31865789	Knockdown of CLGN did not decrease aldosterone production in HAC15 cells stimulated by either A-II or overexpression of KCNJ5 mutation (Figure 6C).	('A-II', 'Gene', '183', (94, 98))	('aldosterone production', 'MPA', (35, 57))	('HAC15', 'CellLine', 'CVCL:S898', (61, 66))	('KCNJ5', 'Gene', '3762', (120, 125))	('aldosterone production', 'Phenotype', 'HP:0000859', (35, 57))	('A-II', 'Gene', (94, 98))	('overexpression', 'PosReg', (102, 116))	('mutation', 'Var', (126, 134))	('decrease aldosterone', 'Phenotype', 'HP:0004319', (26, 46))	('aldosterone', 'Chemical', 'MESH:D000450', (35, 46))	('KCNJ5', 'Gene', (120, 125))
109565	31865789	CLGN transcription is unlikely to be regulated by acute activation of intracellular signaling for aldosterone production, because CLGN expression was not altered by A-II, forskolin, or KCNJ5 T158A expression in HAC15 cells.	('T158A', 'Mutation', 'rs387906778', (191, 196))	('T158A', 'Var', (191, 196))	('forskolin', 'Chemical', 'MESH:D005576', (171, 180))	('HAC15', 'CellLine', 'CVCL:S898', (211, 216))	('KCNJ5', 'Gene', '3762', (185, 190))	('aldosterone', 'Chemical', 'MESH:D000450', (98, 109))	('aldosterone production', 'Phenotype', 'HP:0000859', (98, 120))	('CLGN', 'Gene', (130, 134))	('A-II', 'Gene', '183', (165, 169))	('A-II', 'Gene', (165, 169))	('KCNJ5', 'Gene', (185, 190))
109569	31865789	Aldosterone production by A-II and the mutations described thus far in APA involve activation of intracellular calcium signaling.	('APA', 'Gene', (71, 74))	('Aldosterone production', 'MPA', (0, 22))	('Aldosterone', 'Chemical', 'MESH:D000450', (0, 11))	('calcium', 'Chemical', 'MESH:D002118', (111, 118))	('intracellular calcium signaling', 'MPA', (97, 128))	('mutations', 'Var', (39, 48))	('A-II', 'Gene', '183', (26, 30))	('A-II', 'Gene', (26, 30))	('PA', 'Phenotype', 'HP:0011736', (72, 74))	('activation', 'PosReg', (83, 93))
109573	31865789	We concluded that enhanced aldosterone production by CLGN overexpression was not associated with calcium storage in HAC15 cells.	('overexpression', 'Var', (58, 72))	('aldosterone production', 'MPA', (27, 49))	('aldosterone production', 'Phenotype', 'HP:0000859', (27, 49))	('calcium', 'Chemical', 'MESH:D002118', (97, 104))	('enhanced aldosterone', 'Phenotype', 'HP:0000859', (18, 38))	('HAC15', 'CellLine', 'CVCL:S898', (116, 121))	('enhanced', 'PosReg', (18, 26))	('aldosterone', 'Chemical', 'MESH:D000450', (27, 38))	('CLGN', 'Gene', (53, 57))
109579	31865789	Silencing of CLGN expression did not suppress A-II or KCNJ5-mutation stimulated aldosterone production in HAC15 cells.	('stimulated', 'PosReg', (69, 79))	('KCNJ5', 'Gene', '3762', (54, 59))	('A-II', 'Gene', '183', (46, 50))	('aldosterone production', 'MPA', (80, 102))	('A-II', 'Gene', (46, 50))	('CLGN', 'Gene', (13, 17))	('aldosterone production', 'Phenotype', 'HP:0000859', (80, 102))	('stimulated aldosterone', 'Phenotype', 'HP:0000859', (69, 91))	('HAC15', 'CellLine', 'CVCL:S898', (106, 111))	('aldosterone', 'Chemical', 'MESH:D000450', (80, 91))	('KCNJ5', 'Gene', (54, 59))	('Silencing', 'Var', (0, 9))
109584	31865789	First, the mechanism of interaction between CLGN, ARSs and CYP11B2 is not clarified.	('CYP11B2', 'Var', (59, 66))	('ARSs', 'Disease', (50, 54))	('ARSs', 'Disease', 'None', (50, 54))
109585	31865789	Although it is unclear whether the enhancement of CYP11B2 protein expression by CLGN overexpression is a direct or indirect effect, aldosterone production machinery via a key molecule of translation is novel findings.	('enhancement', 'PosReg', (35, 46))	('CLGN', 'Gene', (80, 84))	('aldosterone production', 'MPA', (132, 154))	('aldosterone production', 'Phenotype', 'HP:0000859', (132, 154))	('aldosterone', 'Chemical', 'MESH:D000450', (132, 143))	('CYP11B2', 'Gene', (50, 57))	('overexpression', 'Var', (85, 99))
109587	31865789	The translational regulation of CYP11B2 through ARSs by CLGN would be a novel mechanism of aldosterone production in APA.	('ARSs', 'Disease', (48, 52))	('aldosterone', 'Chemical', 'MESH:D000450', (91, 102))	('ARSs', 'Disease', 'None', (48, 52))	('PA', 'Phenotype', 'HP:0011736', (118, 120))	('CLGN', 'Gene', (56, 60))	('CYP11B2', 'Var', (32, 39))	('aldosterone production', 'MPA', (91, 113))	('aldosterone production', 'Phenotype', 'HP:0000859', (91, 113))
109588	31865789	Although silencing of CLGN did not suppress A-II or KCNJ5 mutation-mediated aldosterone production, overall suppression of ARSs function or genes is a potential therapeutic approach in patients with APA and perhaps other hormone-producing endocrine neoplasia.	('PA', 'Phenotype', 'HP:0011736', (200, 202))	('aldosterone production', 'MPA', (76, 98))	('KCNJ5', 'Gene', (52, 57))	('APA', 'Disease', (199, 202))	('silencing', 'Var', (9, 18))	('endocrine neoplasia', 'Disease', 'MESH:D009377', (239, 258))	('aldosterone production', 'Phenotype', 'HP:0000859', (76, 98))	('suppression of ARSs function', 'Disease', (108, 136))	('suppression of ARSs function', 'Disease', 'MESH:D011596', (108, 136))	('A-II', 'Gene', '183', (44, 48))	('KCNJ5', 'Gene', '3762', (52, 57))	('CLGN', 'Gene', (22, 26))	('A-II', 'Gene', (44, 48))	('neoplasia', 'Phenotype', 'HP:0002664', (249, 258))	('patients', 'Species', '9606', (185, 193))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (239, 258))	('aldosterone', 'Chemical', 'MESH:D000450', (76, 87))	('endocrine neoplasia', 'Disease', (239, 258))
109593	31865789	CLGN did not potentiate CYP11B2 transcription, but increased aldosterone production and CYP11B2 protein expression.	('aldosterone', 'Chemical', 'MESH:D000450', (61, 72))	('increased', 'PosReg', (51, 60))	('increased aldosterone', 'Phenotype', 'HP:0000859', (51, 72))	('CLGN', 'Var', (0, 4))	('aldosterone production', 'MPA', (61, 83))	('aldosterone production', 'Phenotype', 'HP:0000859', (61, 83))	('CYP11B2', 'Gene', (88, 95))
109624	31750236	On the other hand, lithium can also cause damage to the thyroid cell with consequent signs and symptoms of thyroiditis.	('thyroiditis', 'Disease', 'MESH:D013959', (107, 118))	('cause', 'Reg', (36, 41))	('lithium', 'Var', (19, 26))	('lithium', 'Chemical', 'MESH:D008094', (19, 26))	('damage', 'MPA', (42, 48))	('thyroiditis', 'Disease', (107, 118))	('thyroiditis', 'Phenotype', 'HP:0100646', (107, 118))
109626	31750236	Lithium was found to increase the intrathyroidal iodine content as well as to inhibit release of thyroid hormones from the thyroid into the circulation due to altered tubulin polymerization in thyrocytes.	('Lithium', 'Chemical', 'MESH:D008094', (0, 7))	('tubulin polymerization', 'MPA', (167, 189))	('increase the intrathyroidal iodine content', 'Phenotype', 'HP:0031220', (21, 63))	('inhibit release of thyroid hormones', 'Phenotype', 'HP:0002930', (78, 113))	('altered', 'Reg', (159, 166))	('rat', 'Species', '10116', (37, 40))	('iodine', 'Chemical', 'MESH:D007455', (49, 55))	('intrathyroidal iodine content', 'MPA', (34, 63))	('inhibit', 'NegReg', (78, 85))	('Lithium', 'Var', (0, 7))	('increase', 'PosReg', (21, 29))
109632	31750236	Functional in vitro models revealed that Wnt/beta-catenin signaling may be important in lithium-associated goiter, as lithium significantly increased human thyrocyte proliferation mediated by Wnt/beta-catenin pathway.	('human', 'Species', '9606', (150, 155))	('lithium', 'Var', (118, 125))	('rat', 'Species', '10116', (173, 176))	('lithium', 'Chemical', 'MESH:D008094', (118, 125))	('beta-catenin', 'Gene', '1499', (196, 208))	('goiter', 'Disease', (107, 113))	('beta-catenin', 'Gene', '1499', (45, 57))	('goiter', 'Disease', 'MESH:D006042', (107, 113))	('goiter', 'Phenotype', 'HP:0000853', (107, 113))	('human thyrocyte proliferation', 'CPA', (150, 179))	('lithium', 'Chemical', 'MESH:D008094', (88, 95))	('lithium-associated', 'Disease', (88, 106))	('increased', 'PosReg', (140, 149))	('beta-catenin', 'Gene', (45, 57))	('beta-catenin', 'Gene', (196, 208))
109656	31750236	analyzed the role of lithium in a rat follicular cell line intrinsically expressing NIS (FRTL5), and a follicular thyroid cancer cell line FTC133 stably transfected with NIS.	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (103, 128))	('thyroid cancer', 'Phenotype', 'HP:0002890', (114, 128))	('FTC', 'Disease', 'MESH:C572845', (139, 142))	('NIS', 'Var', (84, 87))	('follicular thyroid cancer', 'Disease', 'MESH:C572845', (103, 128))	('FTC', 'Disease', (139, 142))	('FTC', 'Phenotype', 'HP:0006731', (139, 142))	('rat', 'Species', '10116', (34, 37))	('lithium', 'Chemical', 'MESH:D008094', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('follicular thyroid cancer', 'Disease', (103, 128))	('TC', 'Phenotype', 'HP:0002890', (140, 142))
109694	31750236	The overall survival was significantly better in lithium-aided RAI treated patients, but the analysis was not adjusted by other factors affecting the outcome such as age, number, and location of metastatic foci.	('RAI', 'Chemical', 'MESH:D007455', (63, 66))	('lithium-aided', 'Var', (49, 62))	('patients', 'Species', '9606', (75, 83))	('lithium', 'Chemical', 'MESH:D008094', (49, 56))	('better', 'PosReg', (39, 45))
109720	31750236	TBX1 deficiency may potentially contribute to the low proliferative index of parathyroid tumors.	('TBX1', 'Gene', '6899', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('low', 'NegReg', (50, 53))	('TBX1', 'Gene', (0, 4))	('deficiency', 'Var', (5, 15))	('parathyroid tumors', 'Disease', 'MESH:D010282', (77, 95))	('rat', 'Species', '10116', (61, 64))	('parathyroid tumors', 'Disease', (77, 95))	('proliferative index', 'MPA', (54, 73))	('rat', 'Species', '10116', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
109723	31750236	To summarize, pre-clinical in vitro studies consistently show that lithium induces proliferation and PTH secretion in parathyroid cells (Table 1).	('PTH', 'Gene', '5741', (101, 104))	('proliferation', 'CPA', (83, 96))	('lithium', 'Var', (67, 74))	('lithium', 'Chemical', 'MESH:D008094', (67, 74))	('rat', 'Species', '10116', (120, 123))	('PTH', 'Gene', (101, 104))	('rat', 'Species', '10116', (90, 93))
109818	31667035	In patients with NF2, there is a mutation in the NF2 gene, located on chromosome 22, which normally produces a tumor-suppressor protein merlin.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('mutation', 'Var', (33, 41))	('merlin', 'Gene', (136, 142))	('NF2', 'Gene', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('NF2', 'Gene', '4771', (17, 20))	('tumor', 'Disease', (111, 116))	('NF2', 'Gene', '4771', (49, 52))	('patients', 'Species', '9606', (3, 11))	('merlin', 'Gene', '4771', (136, 142))	('NF2', 'Gene', (17, 20))
109836	30863550	Genotyping of adrenocortical tumours: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16.	('MEN1', 'Gene', (69, 73))	('MEN1', 'Gene', '4221', (69, 73))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('deletions', 'Var', (52, 61))	('adrenocortical tumours', 'Disease', 'MESH:D000306', (14, 36))	('adrenocortical tumours', 'Disease', (14, 36))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
109886	30863550	A score of <3 defines benign adenomas and scores of more than 6 suggests adrenocortical carcinoma.	('adenomas', 'Disease', 'MESH:D000236', (29, 37))	('adenomas', 'Disease', (29, 37))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (73, 97))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (73, 97))	('scores', 'Var', (42, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('adrenocortical carcinoma', 'Disease', (73, 97))
109895	30263987	Binding of aberrant glycoproteins recognizable by Helix pomatia agglutinin in adrenal cancers Aberrant glycosylation is a hallmark of cancer cells and plays an important role in oncogenesis and cancer progression including metastasis.	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('Helix pomatia', 'Species', '6536', (50, 63))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('role', 'Reg', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('glycosylation', 'MPA', (103, 116))	('adrenal cancers', 'Disease', 'MESH:D000310', (78, 93))	('Aberrant', 'Var', (94, 102))	('Binding', 'Interaction', (0, 7))	('adrenal cancers', 'Disease', (78, 93))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (94, 116))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Disease', (86, 92))
109910	30263987	Molecular markers of prognosis include Ki-67 proliferation index above 10 per cent7, high steroidogenic factor 1 expression8, mutation of tumour suppressor gene TP53, and loss of retinoblastoma protein expression9.	('loss of retinoblastoma', 'Disease', (171, 193))	('steroidogenic factor 1', 'Gene', (90, 112))	('TP53', 'Gene', (161, 165))	('rat', 'Species', '10116', (52, 55))	('steroidogenic factor 1', 'Gene', '2516', (90, 112))	('retinoblastoma', 'Phenotype', 'HP:0009919', (179, 193))	('loss of retinoblastoma', 'Disease', 'MESH:D012175', (171, 193))	('mutation', 'Var', (126, 134))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('TP53', 'Gene', '7157', (161, 165))	('tumour', 'Disease', (138, 144))
109913	30263987	Alteration in glycosylation is associated with invasive and metastatic potential in some cancer types11.	('Alteration', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('associated with', 'Reg', (31, 46))	('cancer', 'Disease', (89, 95))	('glycosylation', 'MPA', (14, 27))	('rat', 'Species', '10116', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
109917	30263987	Studies on aberrant glycosylation in adrenocortical cancer have not been reported.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('adrenocortical cancer', 'Disease', (37, 58))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (11, 33))	('aberrant', 'Var', (11, 19))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (37, 58))
109964	30263987	This study has shown that aberrant glycosylation detectable by HPA lectin histochemistry is a predictor of poor survival in adrenal cancer.	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (26, 48))	('adrenal cancer', 'Disease', (124, 138))	('aberrant', 'Var', (26, 34))	('adrenal cancer', 'Disease', 'MESH:D000310', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('glycosylation', 'MPA', (35, 48))
109965	30263987	Aberrant glycosylation is more likely to be seen in tumours with a more aggressive phenotype26.	('Aberrant', 'Var', (0, 8))	('tumours', 'Disease', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('seen', 'Reg', (44, 48))	('glycosylation', 'MPA', (9, 22))	('tumours', 'Disease', 'MESH:D009369', (52, 59))
109980	30263987	It has been reported35 36 that patients who received treatment with mitotane immediately after surgery had improved survival compared with those treated later after surgery, but another study37 did not show such a difference.	('mitotane', 'Var', (68, 76))	('mitotane', 'Chemical', 'MESH:D008939', (68, 76))	('survival', 'CPA', (116, 124))	('improved', 'PosReg', (107, 115))	('patients', 'Species', '9606', (31, 39))
109981	30263987	The present study did not show a statistically significant difference in survival and HPA binding between patients who received mitotane and those who did not.	('HPA binding', 'CPA', (86, 97))	('mitotane', 'Chemical', 'MESH:D008939', (128, 136))	('patients', 'Species', '9606', (106, 114))	('mitotane', 'Var', (128, 136))
110000	29268782	Frequently, overexpressed genes across different tumors or cancer types are understood to be likely oncogenic and contribute to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('overexpressed genes', 'Var', (12, 31))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', (128, 133))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('contribute', 'Reg', (114, 124))
110024	29268782	2, where higher 8q bias are observed in breast and liver cancers than in lymph nodes and soft tissue, for instance.	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('breast and liver cancers', 'Disease', 'MESH:D006528', (40, 64))	('8q bias', 'Var', (16, 23))	('liver cancers', 'Phenotype', 'HP:0002896', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('higher', 'PosReg', (9, 15))
110055	29268782	Although three non-syntenic genes (Nbn, Dpy19l4, and 2610301B20Rik in mouse and Nbn, Dpy19l4, and MGC94199 in rat) reside in other chromosomes, the order of their locations still agrees with that in humans.	('MGC94199', 'Var', (98, 106))	('rat', 'Species', '10116', (110, 113))	('Nbn', 'Gene', '27354', (80, 83))	('mouse', 'Species', '10090', (70, 75))	('Nbn', 'Gene', (35, 38))	('Dpy19l4', 'Gene', '381510', (40, 47))	('Nbn', 'Gene', (80, 83))	('humans', 'Species', '9606', (199, 205))	('2610301B20Rik', 'Var', (53, 66))	('Dpy19l4', 'Gene', '381510', (85, 92))	('Nbn', 'Gene', '27354', (35, 38))	('Dpy19l4', 'Gene', (40, 47))	('Dpy19l4', 'Gene', (85, 92))
110145	29268782	Using the same formula above: K (= 29) is the number of HSF1-CanSig genes encoded in 8q, k (= 27) is the number of 8q genes in the top 100, n (= 100) is the sample size, and N (= 475) is the total number of HSF1-CanSig genes.	('HSF1', 'Gene', (56, 60))	('HSF1', 'Gene', (207, 211))	('HSF1', 'Gene', '3297', (56, 60))	('k (= 27', 'Var', (89, 96))	('HSF1', 'Gene', '3297', (207, 211))
110162	27496084	Risks of first and subsequent cancers among TP53 mutation-carriers in the NCI LFS cohort Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by very high lifetime cancer risk and early age at diagnosis of a wide cancer spectrum.	('cancer', 'Disease', (208, 214))	('Li-Fraumeni syndrome', 'Disease', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (122, 147))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (89, 109))	('mutation-carriers', 'Var', (49, 66))	('TP53', 'Gene', (44, 48))	('autosomal dominant cancer', 'Disease', (122, 147))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('first', 'Disease', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Disease', (30, 37))	('cancer', 'Disease', (30, 36))	('TP53', 'Gene', '7157', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (257, 263))
110164	27496084	The NCI's LFS Study includes families meeting diagnostic criteria for LFS or Li-Fraumeni-like syndrome, and individuals with a germline TP53 mutation, choroid plexus carcinoma, adrenocortical carcinoma, or >=3 cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (151, 175))	('adrenocortical carcinoma', 'Disease', (177, 201))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (77, 102))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancers', 'Disease', (210, 217))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (151, 175))	('Li-Fraumeni-like syndrome', 'Disease', (77, 102))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (177, 201))	('LFS', 'Disease', (70, 73))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (177, 201))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('TP53', 'Gene', '7157', (136, 140))	('mutation', 'Var', (141, 149))	('choroid plexus carcinoma', 'Disease', (151, 175))	('TP53', 'Gene', (136, 140))
110165	27496084	We estimated cumulative risk and annual hazards for first and second cancer among TP53 mutation carriers (TP53+) using MATLAB.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('TP53', 'Gene', (106, 110))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mutation', 'Var', (87, 95))	('TP53', 'Gene', '7157', (106, 110))	('cancer', 'Disease', (69, 75))
110178	27496084	Germline mutations in TP53, the underlying molecular basis of LFS, are identified in ~70% of families meeting the classic LFS diagnostic criteria and ~40% of families meeting the LFL diagnostic criteria.	('Germline mutations', 'Var', (0, 18))	('LFS', 'Disease', (122, 125))	('TP53', 'Gene', '7157', (22, 26))	('identified', 'Reg', (71, 81))	('TP53', 'Gene', (22, 26))
110179	27496084	The frequency of de novo mutations in TP53 is estimated to be between 7% and 20%.	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (25, 34))	('TP53', 'Gene', '7157', (38, 42))
110182	27496084	As more families with TP53 mutations are identified, the LFS cancer spectrum has expanded to include melanoma, lung, gastrointestinal tract, thyroid, ovarian, and other cancers.	('mutations', 'Var', (27, 36))	('cancers', 'Disease', (169, 176))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('LFS cancer', 'Disease', (57, 67))	('TP53', 'Gene', (22, 26))	('thyroid', 'Disease', (141, 148))	('lung', 'Disease', (111, 115))	('LFS cancer', 'Disease', 'MESH:D016864', (57, 67))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('TP53', 'Gene', '7157', (22, 26))	('gastrointestinal tract', 'Disease', (117, 139))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ovarian', 'Disease', (150, 157))	('ovarian', 'Disease', 'MESH:D010051', (150, 157))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (117, 139))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
110189	27496084	To resolve some of these uncertainties, we examined the cumulative first and second cancer risk among TP53 mutation carriers from families enrolled in the National Cancer Institute (NCI) LFS study.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('TP53', 'Gene', (102, 106))	('cancer', 'Disease', (84, 90))	('Cancer', 'Disease', (164, 170))	('Cancer', 'Disease', 'MESH:D009369', (164, 170))	('Cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (102, 106))	('mutation', 'Var', (107, 115))
110191	27496084	Eligibility criteria include meeting the diagnostic criteria for classic LFS or Birch's LFL, or having a pathogenic germline TP53 mutation or a first- or second-degree relative with a mutation, or a personal history of choroid plexus carcinoma, ACC, or >=3 primary cancers.	('choroid plexus carcinoma', 'Disease', (219, 243))	('LFL', 'Disease', (88, 91))	('TP53', 'Gene', '7157', (125, 129))	('mutation', 'Var', (130, 138))	('ACC', 'Disease', (245, 248))	('ACC', 'Phenotype', 'HP:0006744', (245, 248))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (219, 243))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('LFS', 'Disease', (73, 76))	('TP53', 'Gene', (125, 129))	('germline', 'Gene', (116, 124))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (219, 243))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('cancers', 'Disease', (265, 272))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('person', 'Species', '9606', (199, 205))
110209	27496084	A total of 107 families with germline TP53 mutations were included in this report.	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', '7157', (38, 42))
110210	27496084	At enrollment, 46 (43%) families met LFS criteria, 41 (38%) met LFL criteria, 9 (8%) were individuals with >=3 primary cancers and no significant family history, and 11 (10%) who tested positive for a TP53 mutation, without meeting any of the current diagnostic criteria or testing guidelines.	('TP53', 'Gene', '7157', (201, 205))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('mutation', 'Var', (206, 214))	('TP53', 'Gene', (201, 205))	('positive', 'Reg', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
110213	27496084	A total of 403 cancer diagnoses were reported among the mutation carriers, of which 211 were the first primary cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (111, 117))	('mutation', 'Var', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
110317	25932404	The authors suggested that the degree of hypercortisolism could affect the recovery of adrenal axis since those with subclinical Cushing's had adrenal recovery within 6 months compared with those with overt Cushing's who required 11 months for adrenal recovery.	('hypercortisolism', 'Phenotype', 'HP:0003118', (41, 57))	('adrenal recovery', 'MPA', (143, 159))	('hypercortisolism', 'Disease', 'MESH:D003480', (41, 57))	('subclinical Cushing', 'Var', (117, 136))	('hypercortisolism', 'Disease', (41, 57))	('affect', 'Reg', (64, 70))	('recovery of adrenal axis', 'MPA', (75, 99))
110347	24486430	Epidemiological studies have associated altered pregnancy and fetal outcomes with exposure to contaminants such as heavy metals, polychlorinated biphenyls, dioxins, and pesticides.	('dioxins', 'Chemical', 'MESH:D004147', (156, 163))	('polychlorinated biphenyls', 'Chemical', 'MESH:D011078', (129, 154))	('altered', 'Reg', (40, 47))	('polychlorinated biphenyls', 'Var', (129, 154))
110348	24486430	Disruptions of these functions are associated with serious obstetric complications, including altered fetal development, preterm birth, preeclampsia, and intrauterine growth restriction.	('obstetric complications', 'Disease', 'MESH:D007744', (59, 82))	('Disruptions', 'Var', (0, 11))	('preterm birth', 'Disease', (121, 134))	('obstetric complications', 'Disease', (59, 82))	('associated', 'Reg', (35, 45))	('preeclampsia', 'Disease', (136, 148))	('preterm birth', 'Phenotype', 'HP:0001622', (121, 134))	('growth restriction', 'Phenotype', 'HP:0001510', (167, 185))	('preeclampsia', 'Phenotype', 'HP:0100602', (136, 148))	('intrauterine', 'Disease', (154, 166))	('intrauterine growth restriction', 'Phenotype', 'HP:0001511', (154, 185))	('altered fetal development', 'CPA', (94, 119))
110406	24486430	The 3-fold greater CYP19 activity that atrazine produced in the H295R compartment did not result in an increased production of estradiol, estriol, or estrone by the co-culture (112 +- 30, 459 +- 224, and 53.5 +- 7.4 pg/mL, respectively) (Figure 2D-F).	('atrazine', 'Chemical', 'MESH:D001280', (39, 47))	('CYP19', 'Gene', (19, 24))	('estradiol', 'Chemical', 'MESH:D004958', (127, 136))	('estriol', 'Chemical', 'MESH:D004964', (138, 145))	('H295R', 'CellLine', 'CVCL:0458', (64, 69))	('112 +- 30', 'Var', (177, 186))	('estrone', 'Chemical', 'MESH:D004970', (150, 157))	('CYP19', 'Gene', '1588', (19, 24))	('estriol', 'MPA', (138, 145))	('activity', 'MPA', (25, 33))
110464	24486430	Because the estrogen receptor is involved in H295R cell proliferation and antiestrogens inhibit H295R cell proliferation, it is not surprising to observe a decreased proliferation of H295R but not BeWo cells in the co-culture treated with prochloraz.	('prochloraz', 'Chemical', 'MESH:C045362', (239, 249))	('H295R cell proliferation', 'CPA', (96, 120))	('inhibit', 'NegReg', (88, 95))	('decreased', 'NegReg', (156, 165))	('H295R', 'CellLine', 'CVCL:0458', (96, 101))	('H295R', 'CellLine', 'CVCL:0458', (45, 50))	('H295R', 'CellLine', 'CVCL:0458', (183, 188))	('H295R', 'Var', (183, 188))
110504	33608270	PKA Calpha subunit mutation triggers caspase-dependent RIIbeta subunit degradation via Ser114 phosphorylation Mutations in PKA causative of adrenal Cushing adenomas increase cortisol secretion by triggering RIIbeta subunit degradation.	('increase', 'PosReg', (165, 173))	('Mutations', 'Var', (110, 119))	('PKA', 'Gene', '5566', (123, 126))	('mutation', 'Var', (19, 27))	('adrenal Cushing adenomas', 'Disease', (140, 164))	('PKA', 'Gene', (123, 126))	('RIIbeta', 'Gene', (55, 62))	('Ser114', 'Chemical', '-', (87, 93))	('cortisol secretion', 'MPA', (174, 192))	('PKA', 'Gene', (0, 3))	('cortisol', 'Chemical', 'MESH:D006854', (174, 182))	('RIIbeta', 'Gene', '5577', (55, 62))	('adrenal Cushing adenomas', 'Disease', 'MESH:D000236', (140, 164))	('PKA', 'Gene', '5566', (0, 3))	('RIIbeta', 'Gene', '5577', (207, 214))	('RIIbeta', 'Gene', (207, 214))	('increase cortisol', 'Phenotype', 'HP:0003118', (165, 182))
110505	33608270	Mutations in the PRKACA gene are the most frequent cause of cortisol-producing adrenocortical adenomas leading to Cushing's syndrome.	('cortisol', 'Chemical', 'MESH:D006854', (60, 68))	('PRKACA', 'Gene', (17, 23))	("Cushing's syndrome", 'Disease', (114, 132))	('frequent cause', 'Reg', (42, 56))	('PRKACA', 'Gene', '5566', (17, 23))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (79, 102))	('Mutations', 'Var', (0, 9))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (79, 101))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (114, 132))	('adrenocortical adenomas', 'Disease', (79, 102))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (114, 132))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (79, 102))	('nt', 'Chemical', '-', (48, 50))
110507	33608270	We already showed that PRKACA mutations lead to impairment of regulatory (R) subunit binding.	('impairment', 'NegReg', (48, 58))	('nt', 'Chemical', '-', (56, 58))	('PRKACA', 'Gene', '5566', (23, 29))	('mutations', 'Var', (30, 39))	('regulatory (R) subunit', 'Protein', (62, 84))	('PRKACA', 'Gene', (23, 29))
110508	33608270	Furthermore, PRKACA mutations are associated with reduced RIIbeta protein levels; however, the mechanisms leading to reduced RIIbeta levels are presently unknown.	('PRKACA', 'Gene', (13, 19))	('nt', 'Chemical', '-', (149, 151))	('PRKACA', 'Gene', '5566', (13, 19))	('RIIbeta', 'Gene', '5577', (125, 132))	('RIIbeta', 'Gene', (125, 132))	('reduced', 'NegReg', (50, 57))	('RIIbeta', 'Gene', '5577', (58, 65))	('RIIbeta', 'Gene', (58, 65))	('mutations', 'Var', (20, 29))
110509	33608270	Here, we investigate the effects of the most frequent PRKACA mutation, L206R, on regulatory subunit stability.	('PRKACA', 'Gene', (54, 60))	('L206R', 'Mutation', 'rs386352352', (71, 76))	('L206R', 'Var', (71, 76))	('nt', 'Chemical', '-', (51, 53))	('PRKACA', 'Gene', '5566', (54, 60))
110510	33608270	We find that Ser114 phosphorylation of RIIbeta is required for its degradation, mediated by caspase 16.	('caspase', 'Gene', '835', (92, 99))	('caspase', 'Gene', (92, 99))	('Ser114', 'Var', (13, 19))	('Ser114', 'Chemical', '-', (13, 19))	('RIIbeta', 'Gene', '5577', (39, 46))	('RIIbeta', 'Gene', (39, 46))
110512	33608270	These findings reveal the molecular mechanisms and pathophysiological relevance of the R subunit degradation caused by PRKACA mutations, adding another dimension to the deregulation of PKA signaling caused by PRKACA mutations in adrenal Cushing's syndrome.	("adrenal Cushing's syndrome", 'Disease', (229, 255))	('PRKACA', 'Gene', (119, 125))	('PRKACA', 'Gene', (209, 215))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (237, 255))	('PRKACA', 'Gene', '5566', (119, 125))	('PRKACA', 'Gene', '5566', (209, 215))	('PKA', 'Gene', (185, 188))	("adrenal Cushing's syndrome", 'Disease', 'MESH:D003480', (229, 255))	('PKA', 'Gene', '5566', (185, 188))	('mutations', 'Var', (126, 135))	('R subunit degradation', 'MPA', (87, 108))
110523	33608270	Most of the mutations in the catalytic alpha subunit of PKA (PRKACA) found in CPAs lie in a hotspot at the interface between R and C subunits.	('PRKACA', 'Gene', '5566', (61, 67))	('nt', 'Chemical', '-', (108, 110))	('mutations', 'Var', (12, 21))	('CPA', 'Gene', (78, 81))	('PKA', 'Gene', '5566', (56, 59))	('PKA', 'Gene', (56, 59))	('PRKACA', 'Gene', (61, 67))	('CPA', 'Gene', '1357', (78, 81))
110524	33608270	Several of these PRKACA mutations were shown to hamper the formation of the inactive PKA tetrameric complex, therefore rendering PKA constitutively active.	('hamper', 'NegReg', (48, 54))	('PKA', 'Gene', '5566', (129, 132))	('PRKACA', 'Gene', (17, 23))	('PKA', 'Gene', '5566', (85, 88))	('formation', 'MPA', (59, 68))	('PKA', 'Gene', (129, 132))	('PKA', 'Gene', (85, 88))	('PRKACA', 'Gene', '5566', (17, 23))	('mutations', 'Var', (24, 33))
110525	33608270	In addition, three PRKACA mutations were demonstrated to alter substrate specificity, leading to, among others, hyperphosphorylation of histone H1.4.	('PRKACA', 'Gene', '5566', (19, 25))	('alter', 'Reg', (57, 62))	('histone H1.4', 'Gene', '3008', (136, 148))	('mutations', 'Var', (26, 35))	('substrate specificity', 'MPA', (63, 84))	('PRKACA', 'Gene', (19, 25))	('histone H1.4', 'Gene', (136, 148))	('hyperphosphorylation', 'MPA', (112, 132))
110526	33608270	Earlier research has shown that certain CPAs have reduced levels of the R subunit IIbeta (RIIbeta), and we could recently link this cellular RIIbeta protein loss to PRKACA mutations.	('mutations', 'Var', (172, 181))	('RIIbeta', 'Gene', '5577', (90, 97))	('RIIbeta protein loss', 'Disease', (141, 161))	('RIIbeta', 'Gene', (90, 97))	('RIIbeta', 'Gene', (141, 148))	('PRKACA', 'Gene', (165, 171))	('RIIbeta', 'Gene', '5577', (141, 148))	('RIIbeta protein loss', 'Disease', 'MESH:D001796', (141, 161))	('CPA', 'Gene', (40, 43))	('PRKACA', 'Gene', '5566', (165, 171))	('CPA', 'Gene', '1357', (40, 43))	('reduced', 'NegReg', (50, 57))	('nt', 'Chemical', '-', (117, 119))	('levels', 'MPA', (58, 64))
110527	33608270	In this study, we provide functional evidence that PRKACA L206R regulate RIIbeta degradation and show that this degradation is mediated by caspases.	('caspases', 'Gene', (139, 147))	('regulate', 'Reg', (64, 72))	('RIIbeta', 'Gene', '5577', (73, 80))	('RIIbeta', 'Gene', (73, 80))	('PRKACA', 'Gene', (51, 57))	('L206R', 'Mutation', 'rs386352352', (58, 63))	('caspases', 'Gene', '835', (139, 147))	('L206R', 'Var', (58, 63))	('PRKACA', 'Gene', '5566', (51, 57))
110529	33608270	We further demonstrate altered RIIbeta protein-binding partners in the presence or absence of the L206R mutation.	('L206R', 'Mutation', 'rs386352352', (98, 103))	('L206R', 'Var', (98, 103))	('RIIbeta', 'Gene', (31, 38))	('RIIbeta', 'Gene', '5577', (31, 38))	('altered', 'Reg', (23, 30))
110531	33608270	At that time, we could neither demonstrate a direct causative role for Calpha mutations on the reduction in RIIbeta levels nor its functional consequences.	('RIIbeta', 'Gene', '5577', (108, 115))	('RIIbeta', 'Gene', (108, 115))	('mutations', 'Var', (78, 87))	('Calpha', 'Gene', (71, 77))	('reduction', 'NegReg', (95, 104))
110532	33608270	To answer these questions, we silenced RIIbeta via small interfering RNA (siRNA) in the steroidogenic adrenocortical cell line NCI-H295R.	('nt', 'Chemical', '-', (58, 60))	('NCI-H295R', 'CellLine', 'CVCL:0458', (127, 136))	('RIIbeta', 'Gene', '5577', (39, 46))	('RIIbeta', 'Gene', (39, 46))	('silenced', 'NegReg', (30, 38))	('small interfering', 'Var', (51, 68))	('steroid', 'Chemical', 'MESH:D013256', (88, 95))
110533	33608270	RIIbeta silencing led to a significant increase in cortisol secretion (fig.	('RIIbeta', 'Gene', '5577', (0, 7))	('RIIbeta', 'Gene', (0, 7))	('silencing', 'Var', (8, 17))	('nt', 'Chemical', '-', (36, 38))	('increase', 'PosReg', (39, 47))	('increase in cortisol', 'Phenotype', 'HP:0003118', (39, 59))	('cortisol secretion', 'MPA', (51, 69))	('cortisol', 'Chemical', 'MESH:D006854', (51, 59))
110535	33608270	We next tested the stability of RIIbeta and other R subunits in the presence of the Calpha L206R mutant or WT Calpha in the same cells.	('tested', 'Reg', (8, 14))	('L206R', 'Mutation', 'rs386352352', (91, 96))	('L206R', 'Var', (91, 96))	('RIIbeta', 'Gene', '5577', (32, 39))	('RIIbeta', 'Gene', (32, 39))	('nt', 'Chemical', '-', (101, 103))	('Calpha', 'Gene', (84, 90))
110537	33608270	RIIbeta degradation in the presence of Calpha L206R was restricted to adrenocortical cells, as it was also observed in two other human adrenocortical carcinoma (ACC) cell lines: CU-ACC1 and CU-ACC2 (fig.	('RIIbeta', 'Gene', '5577', (0, 7))	('RIIbeta', 'Gene', (0, 7))	('ACC', 'Phenotype', 'HP:0006744', (193, 196))	('carcinoma', 'Disease', 'MESH:D009369', (150, 159))	('ACC1', 'Gene', (181, 185))	('Calpha L206R', 'Var', (39, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (135, 159))	('ACC', 'Phenotype', 'HP:0006744', (161, 164))	('L206R', 'Mutation', 'rs386352352', (46, 51))	('ACC2', 'Gene', '597', (193, 197))	('ACC2', 'Gene', (193, 197))	('human', 'Species', '9606', (129, 134))	('ACC', 'Phenotype', 'HP:0006744', (181, 184))	('ACC1', 'Gene', '597', (181, 185))	('carcinoma', 'Disease', (150, 159))
110541	33608270	Pharmacological inhibition of proteasome degradation with MG132 prevented the degradation of RIIbeta in the absence but not in the presence of the L206R mutant (Fig.	('prevented', 'NegReg', (64, 73))	('nt', 'Chemical', '-', (69, 71))	('RIIbeta', 'Gene', '5577', (93, 100))	('RIIbeta', 'Gene', (93, 100))	('MG132', 'Chemical', 'MESH:C072553', (58, 63))	('L206R', 'Mutation', 'rs386352352', (147, 152))	('degradation', 'MPA', (78, 89))	('L206R', 'Var', (147, 152))	('MG132', 'Gene', (58, 63))	('nt', 'Chemical', '-', (157, 159))
110543	33608270	These results were obtained at similar expression levels of the transfected WT and L206R Calpha subunits (Fig.	('L206R', 'Mutation', 'rs386352352', (83, 88))	('L206R', 'Var', (83, 88))	('Calpha subunits', 'Protein', (89, 104))
110544	33608270	Pulse-chase experiments revealed comparable translation of RIIbeta in the presence of either Calpha WT or L206R (Fig.	('RIIbeta', 'Gene', '5577', (59, 66))	('RIIbeta', 'Gene', (59, 66))	('L206R', 'Mutation', 'rs386352352', (106, 111))	('L206R', 'Var', (106, 111))	('nt', 'Chemical', '-', (20, 22))
110546	33608270	Among the tested inhibitors, only the pan-caspase inhibitor Z-VAD-FMK was able to partially prevent RIIbeta degradation in the presence of the L206R mutant (Fig.	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (60, 69))	('prevent', 'NegReg', (92, 99))	('RIIbeta', 'Gene', '5577', (100, 107))	('RIIbeta', 'Gene', (100, 107))	('nt', 'Chemical', '-', (153, 155))	('L206R', 'Mutation', 'rs386352352', (143, 148))	('L206R', 'Var', (143, 148))	('nt', 'Chemical', '-', (97, 99))	('caspase', 'Gene', '835', (42, 49))	('caspase', 'Gene', (42, 49))
110547	33608270	S3, A and C) while RIIbeta levels remained largely unaffected by caspases inhibition in Calpha WT conditions (Fig.	('caspases', 'Gene', '835', (65, 73))	('inhibition', 'Var', (74, 84))	('caspases', 'Gene', (65, 73))	('RIIbeta', 'Gene', '5577', (19, 26))	('RIIbeta', 'Gene', (19, 26))
110549	33608270	Unexpectedly, 8-Br-cAMP treatment significantly increased RIIbeta protein levels in the presence of the L206R Calpha mutant compared with vehicle control (Fig.	('increased', 'PosReg', (48, 57))	('nt', 'Chemical', '-', (31, 33))	('nt', 'Chemical', '-', (121, 123))	('nt', 'Chemical', '-', (148, 150))	('Calpha', 'Gene', (110, 116))	('nt', 'Chemical', '-', (43, 45))	('8-Br-cAMP', 'Chemical', '-', (14, 23))	('RIIbeta', 'Gene', '5577', (58, 65))	('RIIbeta', 'Gene', (58, 65))	('L206R', 'Mutation', 'rs386352352', (104, 109))	('L206R', 'Var', (104, 109))
110552	33608270	Neither inhibitory cAMP analog protected RIIbeta from degradation in the presence of the L206R mutant (Fig.	('RIIbeta', 'Gene', (41, 48))	('cAMP', 'Chemical', '-', (19, 23))	('L206R', 'Mutation', 'rs386352352', (89, 94))	('L206R', 'Var', (89, 94))	('degradation', 'MPA', (54, 65))	('nt', 'Chemical', '-', (99, 101))	('RIIbeta', 'Gene', '5577', (41, 48))
110556	33608270	Moreover, a kinase dead variant (K73H) of the L206R mutant (Calpha K73H/L206R) resulted in incomplete RIIbeta degradation (fig.	('RIIbeta', 'Gene', (102, 109))	('nt', 'Chemical', '-', (56, 58))	('K73H', 'Mutation', 'p.K73H', (33, 37))	('K73H', 'Mutation', 'p.K73H', (67, 71))	('incomplete', 'NegReg', (91, 101))	('nt', 'Chemical', '-', (29, 31))	('L206R', 'Mutation', 'rs386352352', (46, 51))	('L206R', 'Var', (46, 51))	('L206R', 'Mutation', 'rs386352352', (72, 77))	('K73H', 'Var', (33, 37))	('RIIbeta', 'Gene', '5577', (102, 109))
110557	33608270	These results suggest that specific L206R activity leads to RIIbeta degradation and that 8-Br-cAMP activates the endogenous, WT PKA that protects RIIbeta from degradation in the presence of the L206R mutant.	('L206R activity', 'Var', (36, 50))	('nt', 'Chemical', '-', (204, 206))	('L206R', 'Mutation', 'rs386352352', (36, 41))	('degradation', 'MPA', (159, 170))	('leads to', 'Reg', (51, 59))	('RIIbeta', 'Gene', (146, 153))	('RIIbeta', 'Gene', '5577', (146, 153))	('8-Br-cAMP', 'Chemical', '-', (89, 98))	('RIIbeta', 'Gene', (60, 67))	('RIIbeta', 'Gene', '5577', (60, 67))	('PKA', 'Gene', '5566', (128, 131))	('PKA', 'Gene', (128, 131))	('L206R', 'Mutation', 'rs386352352', (194, 199))	('L206R', 'Var', (194, 199))
110561	33608270	To test this, RIIbeta constructs were generated in which Ser114 (S114) was mutated to either alanine (A) (RIIbeta S114A), as found in RIalpha, or to the phosphomimetic amino acid aspartic acid (D) (RIIbeta S114D).	('RIIbeta', 'Gene', '5577', (14, 21))	('alanine', 'MPA', (93, 100))	('RIIbeta', 'Gene', (14, 21))	('Ser114', 'Chemical', '-', (57, 63))	('Ser114 (S114', 'Var', (57, 69))	('aspartic acid', 'Chemical', 'MESH:D001224', (179, 192))	('alanine', 'Chemical', 'MESH:D000409', (93, 100))	('mutated', 'Var', (75, 82))	('S114A', 'Mutation', 'p.S114A', (114, 119))	('RIIbeta', 'Gene', '5577', (198, 205))	('RIIbeta', 'Gene', (198, 205))	('S114D', 'Mutation', 'p.S114D', (206, 211))	('RIIbeta', 'Gene', '5577', (106, 113))	('RIIbeta', 'Gene', (106, 113))
110570	33608270	Because PKA interacts via its R subunits with AKAPs and other proteins to form signaling complexes, we hypothesized that the degradation of RIIbeta observed in the presence of the L206R mutation might involve changes in the proteins interacting with RIIbeta.	('proteins', 'Protein', (224, 232))	('nt', 'Chemical', '-', (234, 236))	('degradation', 'MPA', (125, 136))	('AKAP', 'Gene', (46, 50))	('changes', 'Reg', (209, 216))	('AKAP', 'Gene', '8165', (46, 50))	('RIIbeta', 'Gene', '5577', (250, 257))	('RIIbeta', 'Gene', (250, 257))	('interacting', 'Interaction', (233, 244))	('PKA', 'Gene', (8, 11))	('L206R', 'Mutation', 'rs386352352', (180, 185))	('L206R', 'Var', (180, 185))	('PKA', 'Gene', '5566', (8, 11))	('nt', 'Chemical', '-', (13, 15))	('RIIbeta', 'Gene', '5577', (140, 147))	('RIIbeta', 'Gene', (140, 147))
110572	33608270	Regardless of the PKA mutation status, nano-liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) showed comparable enrichment of proteins in either 8-Br-cAMP or unstimulated conditions (Fig.	('mutation', 'Var', (22, 30))	('8-Br-cAMP', 'Chemical', '-', (157, 166))	('nt', 'Chemical', '-', (132, 134))	('PKA', 'Gene', '5566', (18, 21))	('PKA', 'Gene', (18, 21))
110573	33608270	Golgin A3 was among the proteins consistently identified to bind RIIbeta only in the presence of the Calpha L206R mutant (Fig.	('nt', 'Chemical', '-', (41, 43))	('RIIbeta', 'Gene', '5577', (65, 72))	('RIIbeta', 'Gene', (65, 72))	('Golgin A3', 'Gene', '2802', (0, 9))	('nt', 'Chemical', '-', (49, 51))	('Calpha L206R', 'Var', (101, 113))	('nt', 'Chemical', '-', (118, 120))	('bind', 'Interaction', (60, 64))	('L206R', 'Mutation', 'rs386352352', (108, 113))	('Golgin A3', 'Gene', (0, 9))
110576	33608270	To test this hypothesis, we silenced golgin A3 with siRNA, which led to a significant reduction in golgin A3 protein levels to less than 30% [siRNA control (ctrl): 100 +- 21 versus siRNA golgin A3: 25 +- 5] (Fig.	('reduction', 'NegReg', (86, 95))	('golgin A3', 'Gene', (187, 196))	('golgin A3', 'Gene', (37, 46))	('nt', 'Chemical', '-', (83, 85))	('golgin A3', 'Gene', (99, 108))	('silenced', 'Var', (28, 36))	('golgin A3', 'Gene', '2802', (187, 196))	('golgin A3', 'Gene', '2802', (37, 46))	('nt', 'Chemical', '-', (150, 152))	('golgin A3', 'Gene', '2802', (99, 108))
110578	33608270	Conversely, overexpression of golgin A3 markedly increased RIIbeta protein levels (L206R: 0.007 +- 0.002 versus L206R + golgin A3: 21.5 +- 7.3) (Fig.	('L206R', 'Mutation', 'rs386352352', (112, 117))	('L206R', 'Var', (112, 117))	('overexpression', 'PosReg', (12, 26))	('RIIbeta', 'Gene', (59, 66))	('RIIbeta', 'Gene', '5577', (59, 66))	('golgin A3', 'Gene', (120, 129))	('L206R:', 'Var', (83, 89))	('increased', 'PosReg', (49, 58))	('golgin A3', 'Gene', (30, 39))	('L206R', 'Mutation', 'rs386352352', (83, 88))	('golgin A3', 'Gene', '2802', (120, 129))	('golgin A3', 'Gene', '2802', (30, 39))
110589	33608270	We observed a significant decrease in both PRKACA L206R (140 +- 15.8 versus 58.2 +- 7.7; P < 0.01)- and WT (103 +- 10 versus 47 +- 6.7; P < 0.01)-transfected NCI-H295R cells (Fig.	('PRKACA', 'Gene', '5566', (43, 49))	('L206R', 'Mutation', 'rs386352352', (50, 55))	('L206R', 'Var', (50, 55))	('decrease', 'NegReg', (26, 34))	('NCI-H295R', 'CellLine', 'CVCL:0458', (158, 167))	('nt', 'Chemical', '-', (23, 25))	('PRKACA', 'Gene', (43, 49))
110599	33608270	A decrease in the PKA RIIbeta subunit in a subgroup of CPA has long been demonstrated, and we could recently show this to be associated with PRKACA mutations.	('mutations', 'Var', (148, 157))	('decrease', 'NegReg', (2, 10))	('nt', 'Chemical', '-', (104, 106))	('CPA', 'Gene', '1357', (55, 58))	('associated', 'Reg', (125, 135))	('PRKACA', 'Gene', (141, 147))	('PKA', 'Gene', '5566', (18, 21))	('PKA', 'Gene', (18, 21))	('RIIbeta', 'Gene', (22, 29))	('RIIbeta', 'Gene', '5577', (22, 29))	('PRKACA', 'Gene', '5566', (141, 147))	('CPA', 'Gene', (55, 58))
110600	33608270	Here, we provide a direct link between the PRKACA L206R mutations and RIIbeta loss.	('PRKACA', 'Gene', '5566', (43, 49))	('L206R', 'Mutation', 'rs386352352', (50, 55))	('L206R', 'Var', (50, 55))	('RIIbeta loss', 'Disease', (70, 82))	('RIIbeta loss', 'Disease', 'MESH:D014786', (70, 82))	('PRKACA', 'Gene', (43, 49))
110603	33608270	The constitutive activity of Calpha L206R increases CASP16P mRNA, and because of the impaired binding of RIIbeta to Calpha L206R, phospho-S114 is unmasked, recognized, and cleaved by caspase 16 (Fig.	('CASP16P', 'Gene', (52, 59))	('increases', 'PosReg', (42, 51))	('L206R', 'Mutation', 'rs386352352', (36, 41))	('binding', 'Interaction', (94, 101))	('L206R', 'Mutation', 'rs386352352', (123, 128))	('RIIbeta', 'Gene', '5577', (105, 112))	('RIIbeta', 'Gene', (105, 112))	('impaired', 'NegReg', (85, 93))	('phospho-S114', 'Var', (130, 142))	('caspase', 'Gene', '835', (183, 190))	('caspase', 'Gene', (183, 190))	('CASP16P', 'Gene', '197350', (52, 59))
110605	33608270	Activation of endogenous, WT PKA by 8-Br-cAMP protects RIIbeta degradation induced by the L206R mutant, likely via activation of one or more substrates that are not accessible to the L206R mutant, which has lost its normal interaction with R subunits and, hence, normal subcellular localization (Fig.	('PKA', 'Gene', (29, 32))	('interaction', 'Interaction', (223, 234))	('nt', 'Chemical', '-', (100, 102))	('RIIbeta', 'Gene', '5577', (55, 62))	('RIIbeta', 'Gene', (55, 62))	('nt', 'Chemical', '-', (224, 226))	('8-Br-cAMP', 'Chemical', '-', (36, 45))	('nt', 'Chemical', '-', (193, 195))	('L206R', 'Mutation', 'rs386352352', (183, 188))	('PKA', 'Gene', '5566', (29, 32))	('L206R', 'Mutation', 'rs386352352', (90, 95))	('L206R', 'Var', (90, 95))	('L206R', 'Var', (183, 188))
110609	33608270	At the same time, PKA Calpha L206R activity is required for RIIbeta degradation, as genetically inhibiting it by introducing a kinase-dead mutation (K73H) into Calpha L206R led to reduced RIIbeta degradation (fig.	('K73H', 'Mutation', 'p.K73H', (149, 153))	('L206R', 'Mutation', 'rs386352352', (167, 172))	('nt', 'Chemical', '-', (114, 116))	('reduced', 'NegReg', (180, 187))	('PKA', 'Gene', '5566', (18, 21))	('RIIbeta', 'Gene', (60, 67))	('Calpha', 'Gene', (160, 166))	('PKA', 'Gene', (18, 21))	('inhibiting', 'NegReg', (96, 106))	('RIIbeta', 'Gene', '5577', (60, 67))	('RIIbeta', 'Gene', '5577', (188, 195))	('RIIbeta', 'Gene', (188, 195))	('nt', 'Chemical', '-', (156, 158))	('L206R', 'Mutation', 'rs386352352', (29, 34))	('K73H', 'Var', (149, 153))
110619	33608270	We could demonstrate that this mechanism is also adrenal specific, as Calpha L206R does not trigger RIIbeta degradation in HEK293T or melanoma cells (fig.	('Calpha L206R', 'Var', (70, 82))	('L206R', 'Mutation', 'rs386352352', (77, 82))	('RIIbeta', 'Gene', '5577', (100, 107))	('RIIbeta', 'Gene', (100, 107))	('HEK293T', 'CellLine', 'CVCL:0063', (123, 130))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))
110622	33608270	Here, now, we could provide functional evidence to explain how PRKACA mutations, by up-regulating CASP16P levels, lead to RIIbeta degradation in patient-derived tissues.	('RIIbeta', 'Gene', '5577', (122, 129))	('mutations', 'Var', (70, 79))	('up-regulating', 'PosReg', (84, 97))	('PRKACA', 'Gene', (63, 69))	('CASP16P', 'Gene', '197350', (98, 105))	('patient', 'Species', '9606', (145, 152))	('CASP16P', 'Gene', (98, 105))	('PRKACA', 'Gene', '5566', (63, 69))	('RIIbeta', 'Gene', (122, 129))	('lead to', 'Reg', (114, 121))
110626	33608270	Under unstimulated conditions, the protein golgin A3 only interacted with unphosphorylated RIIbeta in the presence of Calpha L206R (fig.	('interacted', 'Interaction', (58, 68))	('golgin A3', 'Gene', (43, 52))	('nt', 'Chemical', '-', (59, 61))	('golgin A3', 'Gene', '2802', (43, 52))	('RIIbeta', 'Gene', '5577', (91, 98))	('RIIbeta', 'Gene', (91, 98))	('L206R', 'Mutation', 'rs386352352', (125, 130))	('Calpha', 'Var', (118, 124))
110628	33608270	While knocking down GOLGA3, further reduced RIIbeta-FLAG levels even in Calpha WT-transfected cells (Fig.	('GOLGA3', 'Gene', '2802', (20, 26))	('GOLGA3', 'Gene', (20, 26))	('RIIbeta', 'Gene', '5577', (44, 51))	('RIIbeta', 'Gene', (44, 51))	('reduced', 'NegReg', (36, 43))	('knocking down', 'Var', (6, 19))
110631	33608270	This is in line with our own results showing Golgi apparatus delocalization in Calpha L206R-mutated CPA and underlines the importance of proper PKA subunit localization, which seems to be disrupted by Calpha L206R.	('CPA', 'Gene', '1357', (100, 103))	('Calpha L206R', 'Var', (201, 213))	('PKA', 'Gene', '5566', (144, 147))	('PKA', 'Gene', (144, 147))	('L206R', 'Mutation', 'rs386352352', (86, 91))	('CPA', 'Gene', (100, 103))	('L206R', 'Mutation', 'rs386352352', (208, 213))
110633	33608270	Mutations in the regulatory subunit Ialpha resulting in a truncated RIalpha protein were identified as rare events in unilateral CPA; however, they are frequent in Carney complex.	('frequent', 'Reg', (152, 160))	('RIalpha protein', 'Protein', (68, 83))	('CPA', 'Gene', (129, 132))	('truncated', 'MPA', (58, 67))	('nt', 'Chemical', '-', (111, 113))	('Mutations', 'Var', (0, 9))	('Carney complex', 'Disease', (164, 178))	('nt', 'Chemical', '-', (92, 94))	('CPA', 'Gene', '1357', (129, 132))	('nt', 'Chemical', '-', (158, 160))
110634	33608270	Copy number gains in the regulatory subunit Ibeta have also been very recently identified in CPA.	('Copy number gains', 'Var', (0, 17))	('CPA', 'Gene', '1357', (93, 96))	('nt', 'Chemical', '-', (74, 76))	('nt', 'Chemical', '-', (82, 84))	('CPA', 'Gene', (93, 96))
110635	33608270	However, in the context of the mutations in the PKA catalytic subunit alpha, the loss of the regulatory subunit IIbeta expression, as shown in this study, plays a relevant role in the defects in PKA signaling leading to cortisol oversecretion in CPA.	('expression', 'MPA', (119, 129))	('mutations', 'Var', (31, 40))	('CPA', 'Gene', (246, 249))	('nt', 'Chemical', '-', (18, 20))	('nt', 'Chemical', '-', (169, 171))	('defects', 'NegReg', (184, 191))	('cortisol', 'Chemical', 'MESH:D006854', (220, 228))	('PKA', 'Gene', '5566', (195, 198))	('PKA', 'Gene', '5566', (48, 51))	('PKA', 'Gene', (195, 198))	('PKA', 'Gene', (48, 51))	('CPA', 'Gene', '1357', (246, 249))	('cortisol oversecretion', 'MPA', (220, 242))	('loss', 'NegReg', (81, 85))
110636	33608270	In conclusion, we show that in adrenal cells and tissue, the activity of the Calpha mutant L206R triggers RIIbeta degradation.	('L206R', 'Mutation', 'rs386352352', (91, 96))	('L206R', 'Var', (91, 96))	('Calpha', 'Gene', (77, 83))	('nt', 'Chemical', '-', (88, 90))	('activity', 'MPA', (61, 69))	('RIIbeta', 'Gene', '5577', (106, 113))	('RIIbeta', 'Gene', (106, 113))	('triggers', 'Reg', (97, 105))
110640	33608270	Point mutations were introduced into RIalpha-FLAG and RIIbeta-FLAG plasmids with the Q5 Site-Directed Mutagenesis Kit (NEB).	('Kit', 'Gene', (114, 117))	('nt', 'Chemical', '-', (33, 35))	('Kit', 'Gene', '3815', (114, 117))	('nt', 'Chemical', '-', (22, 24))	('RIIbeta', 'Gene', (54, 61))	('RIIbeta', 'Gene', '5577', (54, 61))	('Point mutations', 'Var', (0, 15))	('nt', 'Chemical', '-', (3, 5))
110697	33608270	The genetic background of adenomas was known from previous whole-exome sequencing or Sanger sequencing for PRKACA mutation.	('PRKACA', 'Gene', (107, 113))	('adenomas', 'Disease', 'MESH:D000236', (26, 34))	('PRKACA', 'Gene', '5566', (107, 113))	('adenomas', 'Disease', (26, 34))	('mutation', 'Var', (114, 122))
110712	33608270	CASP16P RT-qPCR was performed using predesigned TaqMan gene expression probes (Thermo Fisher Scientific) for CASP16P (Hs00395216_m1) and beta actin (ACTB) (Hs9999903_m1) were used for normalization.	('ACTB', 'Gene', (149, 153))	('beta actin', 'Gene', (137, 147))	('CASP16P', 'Gene', '197350', (109, 116))	('ACTB', 'Gene', '60', (149, 153))	('CASP16P', 'Gene', (109, 116))	('Hs9999903_m1', 'Var', (156, 168))	('beta actin', 'Gene', '728378', (137, 147))	('nt', 'Chemical', '-', (97, 99))	('CASP16P', 'Gene', '197350', (0, 7))	('Hs00395216_m1', 'Var', (118, 131))	('CASP16P', 'Gene', (0, 7))
110719	32478669	This condition is characterized by glucocorticoid and/or mineralocorticoid excess, and is commonly regulated by aberrant G-protein coupled receptor expression may be subclinical, allowing the disease to progress for years undetected.	('aberrant', 'Var', (112, 120))	('mineralocorticoid excess', 'Phenotype', 'HP:0000859', (57, 81))	('G-protein coupled receptor', 'Gene', '151', (121, 147))	('G-protein coupled receptor', 'Gene', (121, 147))
110733	32478669	Amongst other defects, abberant G-protein-coupled receptor (GPCR) expression, disease-causing variants in ARMC5, dysregulation of the cyclic AMP-protein kinase A (PKA) signaling pathway, and intra-nodular or ectopic ACTH secretion have been implicated in the pathogenesis of PBMAH.	('intra-nodular', 'Disease', 'MESH:D008224', (191, 204))	('GPCR', 'Gene', (60, 64))	('disease-causing', 'Reg', (78, 93))	('ARMC5', 'Gene', (106, 111))	('G-protein-coupled receptor', 'Protein', (32, 58))	('ARMC5', 'Gene', '79798', (106, 111))	('ACTH', 'Gene', (216, 220))	('PBMAH', 'Chemical', '-', (275, 280))	('variants', 'Var', (94, 102))	('implicated', 'Reg', (241, 251))	('intra-nodular', 'Disease', (191, 204))	('ACTH', 'Gene', '5443', (216, 220))	('PBMAH', 'Disease', (275, 280))
110748	32478669	He screened positive for a disease-causing germline variant in ARMC5 (c.517C>T, p.R173*).	('ARMC5', 'Gene', (63, 68))	('c.517C>T', 'Mutation', 'rs1166273343', (70, 78))	('p.R173*', 'Var', (80, 87))	('positive', 'Reg', (12, 20))	('disease-causing', 'Reg', (27, 42))	('c.517C>T', 'Var', (70, 78))	('ARMC5', 'Gene', '79798', (63, 68))	('p.R173*', 'Mutation', 'rs1166273343', (80, 87))
110753	32478669	She screened positive for a disease-causing germline variant in ARMC5 (c.1084C>T, p.A362T).	('positive', 'Reg', (13, 21))	('c.1084C>T', 'Var', (71, 80))	('ARMC5', 'Gene', '79798', (64, 69))	('ARMC5', 'Gene', (64, 69))	('p.A362T', 'Var', (82, 89))	('c.1084C>T', 'Mutation', 'rs369721476', (71, 80))	('disease-causing', 'Reg', (28, 43))	('p.A362T', 'Mutation', 'rs369721476', (82, 89))
110769	32478669	Such examples include the use of beta-blockers for PBMAH with ectopic expression of the beta-adrenergic receptor or the use of GnRH agonists in the setting of abarrent LH/hCG receptor expression.	('expression', 'MPA', (184, 194))	('LH/hCG receptor', 'Protein', (168, 183))	('abarrent', 'Var', (159, 167))	('PBMAH', 'Chemical', '-', (51, 56))
110779	32478669	Interestingly, both patients that presented with PBMAH and severe CS had disease-causing variants in ARMC5.	('ARMC5', 'Gene', '79798', (101, 106))	('ARMC5', 'Gene', (101, 106))	('variants', 'Var', (89, 97))	('PBMAH', 'Disease', (49, 54))	('CS', 'Phenotype', 'HP:0003118', (66, 68))	('patients', 'Species', '9606', (20, 28))	('disease-causing', 'Reg', (73, 88))	('PBMAH', 'Chemical', '-', (49, 54))	('severe CS', 'Disease', (59, 68))
110789	32098292	Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inactive 5' monophosphates.	('PDE', 'Gene', (127, 130))	('PDE', 'Gene', '501', (127, 130))	('cyclic nucleotide', 'Chemical', 'MESH:D009712', (195, 212))	('Phosphodiesterase', 'Gene', '5138;5152;50940', (21, 38))	('Pediatric Adrenocortical Tumors', 'Disease', 'MESH:C565973', (75, 106))	('Phosphodiesterase', 'Gene', '5138;5152;50940', (107, 124))	('Phosphodiesterase', 'Gene', (107, 124))	('cAMP', 'Gene', (251, 255))	('Phosphodiesterase', 'Gene', (21, 38))	('Variants', 'Var', (9, 17))	('cAMP', 'Gene', '820', (251, 255))	('Tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Tumors', 'Phenotype', 'HP:0002664', (100, 106))	('Pediatric Adrenocortical Tumors', 'Disease', (75, 106))	('cGMP', 'Chemical', 'MESH:D006152', (298, 302))
110794	32098292	Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant TP53 alleles and uniparental disomy of chromosome 11p15 (Beckwith-Wiedemann syndrome).	('TP53', 'Gene', (216, 220))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (130, 158))	('variants', 'Var', (34, 42))	('uniparental disomy of chromosome', 'Disease', 'MESH:C536470', (233, 265))	('Beckwith-Wiedemann syndrome', 'Disease', (273, 300))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cAMP', 'Gene', (79, 83))	('cAMP', 'Gene', '820', (79, 83))	('pediatric adrenocortical', 'Disease', 'MESH:C565973', (120, 144))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (273, 300))	('contribute', 'Reg', (106, 116))	('TP53', 'Gene', '7157', (216, 220))	('PDE', 'Gene', (46, 49))	('PDE', 'Gene', '501', (46, 49))	('pediatric adrenocortical', 'Disease', (120, 144))	('uniparental disomy of chromosome', 'Disease', (233, 265))	('adrenocortical tumorigenesis', 'Disease', (130, 158))
110799	32098292	The N-terminal portion of PDE molecules defines the specific properties of each member and variant of the PDE gene family.	('PDE', 'Gene', '501', (106, 109))	('variant', 'Var', (91, 98))	('PDE', 'Gene', (106, 109))	('PDE', 'Gene', '501', (26, 29))	('PDE', 'Gene', (26, 29))
110801	32098292	Cancer is driven by genetic and epigenetic changes, which lead to altered signaling pathways that control cell division, cell death, and cell motility, thereby fueling wider signaling networks that favor cancer progression.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('epigenetic changes', 'Var', (32, 50))	('signaling pathways', 'Pathway', (74, 92))	('altered', 'Reg', (66, 73))	('changes', 'Var', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('fueling', 'Reg', (160, 167))
110811	32098292	Aberrant cAMP signaling has been linked to genetic forms of cortisol excess which can lead to Cushing's syndrome and related adrenal hyperplasia.	('Aberrant', 'Var', (0, 8))	("Cushing's syndrome", 'Disease', (94, 112))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (125, 144))	('cortisol excess', 'Phenotype', 'HP:0003118', (60, 75))	('cAMP', 'Gene', (9, 13))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (125, 144))	('linked', 'Reg', (33, 39))	('cAMP', 'Gene', '820', (9, 13))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (94, 112))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (94, 112))	('lead', 'Reg', (86, 90))	('adrenal hyperplasia', 'Disease', (125, 144))
110812	32098292	Variants in PDE8B predispose to primary pigmented nodular adrenocortical disease (PPNAD), a bilateral form of micronodular adrenal hyperplasia that causes ACTH (adrenocorticotropic hormone)-independent Cushing's syndrome.	('ACTH', 'Gene', (155, 159))	('PDE8B', 'Gene', '8622', (12, 17))	('Variants', 'Var', (0, 8))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (123, 142))	('ACTH', 'Gene', '5443', (155, 159))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (123, 142))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (202, 220))	('pigmented nodular adrenocortical disease', 'Disease', (40, 80))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (40, 80))	("Cushing's syndrome", 'Disease', (202, 220))	('predispose to', 'Reg', (18, 31))	('adrenocorticotropic hormone', 'Gene', '5443', (161, 188))	('adrenal hyperplasia', 'Disease', (123, 142))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (202, 220))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (40, 80))	('adrenocorticotropic hormone', 'Gene', (161, 188))	('PDE8B', 'Gene', (12, 17))
110813	32098292	A higher frequency of missense variants of PDE11A has been found in adult patients with macronodular adrenocortical hyperplasia and adrenocortical tumors (ACTs) than in control patients.	('PDE11A', 'Gene', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('missense variants', 'Var', (22, 39))	('ACTs', 'Disease', (155, 159))	('patients', 'Species', '9606', (74, 82))	('macronodular adrenocortical hyperplasia and adrenocortical tumors', 'Disease', 'MESH:D018268', (88, 153))	('patients', 'Species', '9606', (177, 185))	('macronodular adrenocortical hyperplasia', 'Phenotype', 'HP:0008231', (88, 127))	('ACTs', 'Disease', 'MESH:D018268', (155, 159))	('found', 'Reg', (59, 64))	('PDE11A', 'Gene', '50940', (43, 49))
110814	32098292	The role of inactivating variants in PDEs in pediatric ACTs has not been investigated thoroughly:unlike in adrenocortical hyperplasia and in such tumors in adults.	('pediatric ACTs', 'Disease', (45, 59))	('PDE', 'Gene', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('pediatric ACTs', 'Disease', 'MESH:C565973', (45, 59))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', (146, 152))	('adrenocortical hyperplasia', 'Disease', (107, 133))	('PDE', 'Gene', '501', (37, 40))	('inactivating variants', 'Var', (12, 33))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (107, 133))
110815	32098292	In the present investigation, we examined the frequency of germline and acquired PDEs variants in a cohort of pediatric patients.	('PDE', 'Gene', (81, 84))	('PDE', 'Gene', '501', (81, 84))	('patients', 'Species', '9606', (120, 128))	('variants', 'Var', (86, 94))
110817	32098292	Whole genome sequencing (WGS) and whole exome sequencing (WES) data of 37 children with ACTs ("discovery cohort") were retrieved for analyzing germline and acquired variants in PDE family genes (Figure 1) and other cAMP/cAMP-dependent kinase (PKA)-signaling pathway genes (PDE4DIP, CREB, GNAS and PRKACA).	('PDE4DIP', 'Gene', (273, 280))	('cAMP', 'Gene', (220, 224))	('PDE', 'Gene', '501', (177, 180))	('children', 'Species', '9606', (74, 82))	('PDE', 'Gene', '501', (273, 276))	('ACTs', 'Disease', 'MESH:D018268', (88, 92))	('cAMP', 'Gene', '820', (215, 219))	('PRKACA', 'Gene', (297, 303))	('PDE', 'Gene', (177, 180))	('PDE', 'Gene', (273, 276))	('cAMP', 'Gene', '820', (220, 224))	('PDE4DIP', 'Gene', '9659', (273, 280))	('CREB', 'Gene', (282, 286))	('ACTs', 'Disease', (88, 92))	('cAMP', 'Gene', (215, 219))	('GNAS', 'Gene', (288, 292))	('variants', 'Var', (165, 173))	('GNAS', 'Gene', '2778', (288, 292))	('CREB', 'Gene', '1385', (282, 286))	('PRKACA', 'Gene', '5566', (297, 303))
110819	32098292	Sequencing analysis of genomic DNA from 37 pediatric ACT patients revealed the presence of germline-inactivating variants in PDEs and related genes in 9 (24%) patients (Figure 2 and Figure 3 and Table 1).	('pediatric ACT', 'Disease', 'MESH:C565973', (43, 56))	('patients', 'Species', '9606', (57, 65))	('PDE', 'Gene', '501', (125, 128))	('pediatric ACT', 'Disease', (43, 56))	('PDE', 'Gene', (125, 128))	('variants', 'Var', (113, 121))	('patients', 'Species', '9606', (159, 167))
110820	32098292	Inactivating germline nonsense variants were documented in PDE3B (OMIM 602047, NM_000922.4) (p.R783*, c.2347C > T, rs150090666, gnomAD frequency, 0.06%), PDE5A (OMIM-603310, NM_001083.4) (2x p.Q860*, c.2578C > T, rs140289122, 0.17%) and PDE11A (OMIM-604961, NM_016953.4) (p.K20*, c.58A > T rs148183964, 0.06% and p.R307*, c.919C > T, rs76308115, 0.29%).	('PDE3B', 'Gene', '5140', (59, 64))	('PDE5A', 'Gene', (154, 159))	('rs140289122', 'Mutation', 'rs140289122', (213, 224))	('c.2578C > T', 'Var', (200, 211))	('p.R307*', 'Mutation', 'p.R307*', (313, 320))	('c.2578C > T', 'Mutation', 'rs140289122', (200, 211))	('c.2347C > T', 'Var', (102, 113))	('c.2347C > T', 'Mutation', 'rs150090666', (102, 113))	('p.K20*', 'Var', (272, 278))	('rs150090666', 'Mutation', 'rs150090666', (115, 126))	('rs76308115', 'Mutation', 'rs76308115', (334, 344))	('PDE3B', 'Gene', (59, 64))	('rs148183964', 'DBSNP_MENTION', 'None', (290, 301))	('p.R307*', 'Var', (313, 320))	('p.Q860*', 'Mutation', 'p.Q860*', (191, 198))	('rs148183964', 'Var', (290, 301))	('p.R783*', 'Mutation', 'p.R783*', (93, 100))	('PDE5A', 'Gene', '8654', (154, 159))	('p.K20*', 'Mutation', 'p.K20*', (272, 278))	('PDE11A', 'Gene', '50940', (237, 243))	('c.919C > T', 'Mutation', 'rs76308115', (322, 332))	('PDE11A', 'Gene', (237, 243))	('c.919C > T', 'Var', (322, 332))
110821	32098292	Additional structural germline variants were observed in PDE6B (OMIM-180072, NM_000283.3 (p.H341Qfs*23) and PDE8A (OMIM-602972, NM_002605.3) (c.1953-4A > G splice region) (Figure 2).	('PDE8A', 'Gene', (108, 113))	('p.H341Qfs*23', 'Mutation', 'rs769671323', (90, 102))	('PDE8A', 'Gene', '5151', (108, 113))	('PDE6B', 'Gene', (57, 62))	('p.H341Qfs*23', 'Var', (90, 102))	('PDE6B', 'Gene', '5158', (57, 62))	('OMIM-602972', 'Var', (115, 126))	('c.1953-4A >', 'Var', (142, 153))	('c.1953-4A > G', 'Mutation', 'rs189073229', (142, 155))
110822	32098292	Excluding the p.K20* variant for PDE11A and p.H341Qfs*23 for PDE6B, all other variants were found in the PDE catalytic domain (Figure 2).	('PDE', 'Gene', (61, 64))	('p.H341Qfs*23', 'Mutation', 'rs769671323', (44, 56))	('PDE11A', 'Gene', '50940', (33, 39))	('p.K20*', 'Mutation', 'p.K20*', (14, 20))	('PDE', 'Gene', '501', (61, 64))	('PDE6B', 'Gene', (61, 66))	('p.H341Qfs*23', 'Var', (44, 56))	('PDE', 'Gene', '501', (105, 108))	('PDE', 'Gene', '501', (33, 36))	('PDE6B', 'Gene', '5158', (61, 66))	('p.K20*', 'Var', (14, 20))	('PDE11A', 'Gene', (33, 39))	('PDE', 'Gene', (105, 108))	('PDE', 'Gene', (33, 36))
110823	32098292	Additional germline nonsense variants were verified in PDE4DIP (OMIM-608117, NM_001198834.3) (p.W1396*, c.4187G > A, rs782516582, 0.008% and p.Q1968*, c.5902C > T, new variant) (Figure 3).	('rs782516582', 'Var', (117, 128))	('p.W1396*', 'Var', (94, 102))	('p.Q1968*', 'Var', (141, 149))	('c.4187G > A', 'Mutation', 'rs782516582', (104, 115))	('p.W1396*', 'Mutation', 'p.W1396*', (94, 102))	('PDE4DIP', 'Gene', '9659', (55, 62))	('c.5902C > T', 'Var', (151, 162))	('rs782516582', 'Mutation', 'rs782516582', (117, 128))	('p.Q1968*', 'Mutation', 'p.Q1968*', (141, 149))	('c.4187G > A', 'Var', (104, 115))	('c.5902C > T', 'Mutation', 'rs782049245', (151, 162))	('0.008%', 'Var', (130, 136))	('PDE4DIP', 'Gene', (55, 62))
110827	32098292	The GNAS (OMIM-139320, NM_000516.6) (p.R201H, c.602G > A) pathogenic variant in addition to the PDE4DIP p.S977I missense variant was observed in the tumor sample from patient #3.	('p.R201H', 'Mutation', 'rs121913495', (37, 44))	('GNAS', 'Gene', '2778', (4, 8))	('p.R201H', 'Var', (37, 44))	('p.S977I', 'Var', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('c.602G > A', 'Mutation', 'rs121913495', (46, 56))	('patient', 'Species', '9606', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('GNAS', 'Gene', (4, 8))	('tumor', 'Disease', (149, 154))	('c.602G > A', 'Var', (46, 56))	('PDE4DIP', 'Gene', (96, 103))	('PDE4DIP', 'Gene', '9659', (96, 103))	('p.S977I', 'Mutation', 'p.S977I', (104, 111))
110828	32098292	The GNAS p.R201C, c.601C > T variant was observed in the tumor sample of patient #11, and a gene fusion [chr5:58476419(-)::chr2:212615429(-)] showing PDE4D exon 5 fused to ERBB4 exon 5 was observed in the ACT from patient #10 (Table 1).	('GNAS', 'Gene', '2778', (4, 8))	('patient', 'Species', '9606', (214, 221))	('c.601C > T', 'Mutation', 'rs11554273', (18, 28))	('c.601C > T', 'Var', (18, 28))	('ERBB4', 'Gene', '2066', (172, 177))	('PDE4D', 'Gene', (150, 155))	('p.R201C', 'Mutation', 'rs11554273', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('PDE4D', 'Gene', '5144', (150, 155))	('GNAS', 'Gene', (4, 8))	('patient', 'Species', '9606', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ERBB4', 'Gene', (172, 177))	('tumor', 'Disease', (57, 62))	('p.R201C', 'Var', (9, 16))
110829	32098292	No pathogenic or likely pathogenic variants were identified in CREB or PRKACA in this cohort.	('PRKACA', 'Gene', '5566', (71, 77))	('variants', 'Var', (35, 43))	('CREB', 'Gene', (63, 67))	('CREB', 'Gene', '1385', (63, 67))	('PRKACA', 'Gene', (71, 77))
110830	32098292	Analysis of the TCGA whole exome sequence database representing 92 paired germline and adult ACC cases revealed rare germline PDE variants that were retained in the tumor due to LOH and lacked representation of pathogenicity in Clinvar (Table S2).	('variants', 'Var', (130, 138))	('PDE', 'Gene', '501', (126, 129))	('PDE', 'Gene', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
110831	32098292	Of note, four somatic inactivating PDE variants (PDE2A, p.C935*; PE3A, p.E319*; PDE8A, c.1735-3C > A; and PDE8A, p.S386Hfs*4) were identified in this cohort.	('PDE', 'Gene', '501', (35, 38))	('PDE8A', 'Gene', '5151', (80, 85))	('p.S386Hfs*4', 'Mutation', 'p.S386HfsX4', (113, 124))	('p.C935*', 'Mutation', 'p.C935fsX', (56, 63))	('PDE2A', 'Gene', '5138', (49, 54))	('PDE', 'Gene', '501', (106, 109))	('c.1735-3C > A', 'Mutation', 'c.1735-3C>A', (87, 100))	('p.C935*', 'Var', (56, 63))	('PDE2A', 'Gene', (49, 54))	('p.S386Hfs*4', 'Var', (113, 124))	('PDE8A', 'Gene', (80, 85))	('p.E319*', 'Var', (71, 78))	('PDE', 'Gene', '501', (49, 52))	('p.E319*', 'Mutation', 'p.E319*', (71, 78))	('PDE', 'Gene', (35, 38))	('c.1735-3C > A', 'Var', (87, 100))	('PDE', 'Gene', (106, 109))	('PDE', 'Gene', (49, 52))	('PDE', 'Gene', '501', (80, 83))	('PDE8A', 'Gene', '5151', (106, 111))	('PDE8A', 'Gene', (106, 111))	('PDE', 'Gene', (80, 83))
110832	32098292	An acquired variant in PDE4C (p.A291G; COSV53206356) was also reported in an adrenocortical carcinoma among 41 adult cases analyzed by WES.	('PDE4C', 'Gene', (23, 28))	('adrenocortical carcinoma', 'Disease', (77, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('reported', 'Reg', (62, 70))	('p.A291G; COSV53206356', 'Var', (30, 51))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (77, 101))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (77, 101))	('p.A291G', 'Mutation', 'p.A291G', (30, 37))	('COSV53206356', 'Chemical', '-', (39, 51))	('PDE4C', 'Gene', '5143', (23, 28))
110836	32098292	Whole exome analysis of germline DNA from an independent cohort of 18 pediatric ACT patients harboring the TP53 p.R337H allele revealed additional inactivating variants in PDE6A (p.K827del) and PDE11A (p.K119Sfs*2).	('p.K119Sfs*2', 'Mutation', 'p.K119SfsX2', (202, 213))	('patients', 'Species', '9606', (84, 92))	('p.R337H', 'Mutation', 'rs121912664', (112, 119))	('PDE11A', 'Gene', '50940', (194, 200))	('TP53', 'Gene', '7157', (107, 111))	('p.K827del', 'Var', (179, 188))	('TP53', 'Gene', (107, 111))	('pediatric ACT', 'Disease', (70, 83))	('p.K827del', 'Mutation', 'p.827delK', (179, 188))	('pediatric ACT', 'Disease', 'MESH:C565973', (70, 83))	('PDE6A', 'Gene', '5145', (172, 177))	('p.K119Sfs*2', 'Var', (202, 213))	('p.R337H', 'Var', (112, 119))	('PDE11A', 'Gene', (194, 200))	('PDE6A', 'Gene', (172, 177))
110837	32098292	Nonsense variants were also observed in PDE4DIP (p.E515*, c.1543G > T, new variant / p.E1745*, c.5233G > T, new variant).	('p.E515*', 'Var', (49, 56))	('c.1543G > T', 'Mutation', 'rs371534743', (58, 69))	('PDE4DIP', 'Gene', '9659', (40, 47))	('c.1543G > T', 'Var', (58, 69))	('PDE4DIP', 'Gene', (40, 47))	('c.5233G > T', 'Mutation', 'rs1698605', (95, 106))	('c.5233G > T', 'Var', (95, 106))	('p.E1745*', 'Mutation', 'p.E1745*', (85, 93))	('p.E515*', 'Mutation', 'p.E515*', (49, 56))
110840	32098292	All observed variants, except for two, were in the catalytic domain, which suggests a loss of function of PDE.	('PDE', 'Gene', '501', (106, 109))	('variants', 'Var', (13, 21))	('loss of function', 'NegReg', (86, 102))	('PDE', 'Gene', (106, 109))
110841	32098292	Of these, only PDE11A p.R307* has been previously found in association with Cushing's syndrome due to micronodular adrenocortical hyperplasia in a female carrier.	('PDE11A', 'Gene', (15, 21))	('PDE11A', 'Gene', '50940', (15, 21))	('adrenocortical hyperplasia', 'Disease', (115, 141))	('p.R307*', 'Mutation', 'p.R307*', (22, 29))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (76, 94))	('found', 'Reg', (50, 55))	("Cushing's syndrome", 'Disease', (76, 94))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (76, 94))	('association', 'Reg', (59, 70))	('p.R307*', 'Var', (22, 29))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (115, 141))
110842	32098292	In our study, the female patient harboring the PDE11A p.R307* variant (Patient #3) developed an aldosterone-producing tumor at the age of 12 years.	('PDE11A', 'Gene', (47, 53))	('developed', 'PosReg', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('PDE11A', 'Gene', '50940', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('p.R307*', 'Mutation', 'p.R307*', (54, 61))	('Patient', 'Species', '9606', (71, 78))	('patient', 'Species', '9606', (25, 32))	('tumor', 'Disease', (118, 123))	('p.R307*', 'Var', (54, 61))
110843	32098292	In addition to the germline PDE11A nonsense variant, the tumor acquired a pathogenic variant in GNAS.	('GNAS', 'Gene', '2778', (96, 100))	('PDE11A', 'Gene', (28, 34))	('variant', 'Var', (85, 92))	('PDE11A', 'Gene', '50940', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('pathogenic', 'Reg', (74, 84))	('GNAS', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
110848	32098292	About 50% of pediatric ACTs are associated with germline TP53 variants that lead to more complex genomic landscapes.	('pediatric ACTs', 'Disease', 'MESH:C565973', (13, 27))	('variants', 'Var', (62, 70))	('germline', 'Var', (48, 56))	('associated', 'Reg', (32, 42))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('pediatric ACTs', 'Disease', (13, 27))	('lead to', 'Reg', (76, 83))
110849	32098292	Furthermore, TP53 variants observed in pediatric adrenocortical tumors did not correspond to the conventional hotspot variants associated with classic Li-Fraumeni syndrome (LFS), and most retain a wide range of functionality.	('TP53', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('LFS', 'Disease', 'MESH:D016864', (173, 176))	('Li-Fraumeni syndrome', 'Disease', (151, 171))	('pediatric adrenocortical tumors', 'Disease', 'MESH:C565973', (39, 70))	('variants', 'Var', (18, 26))	('LFS', 'Disease', (173, 176))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (151, 171))	('TP53', 'Gene', '7157', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('pediatric adrenocortical tumors', 'Disease', (39, 70))
110850	32098292	Consistent with these observations, among the five carriers of TP53 variants in our cohorts, only one (patient #4) harbored a predicted nonfunctional TP53 variant, and none were classified as LFS.	('variants', 'Var', (68, 76))	('TP53', 'Gene', (150, 154))	('LFS', 'Disease', (192, 195))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('LFS', 'Disease', 'MESH:D016864', (192, 195))	('patient', 'Species', '9606', (103, 110))	('TP53', 'Gene', '7157', (150, 154))
110851	32098292	One can hypothesize that a complete inactivation of those proteins, due to an inactivating variant in one allele and the loss of the second wild-type allele, in the right environment could favor the development of tumors.	('proteins', 'Protein', (58, 66))	('variant', 'Var', (91, 98))	('inactivating variant', 'Var', (78, 98))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('inactivation', 'NegReg', (36, 48))	('favor', 'PosReg', (189, 194))	('tumors', 'Disease', 'MESH:D009369', (214, 220))
110853	32098292	A previous study demonstrated that PDEs can act as phenotype modifiers, leading to adrenal tumors in Carney complex patients carrying PRKAR1A variant.	('leading to', 'Reg', (72, 82))	('PRKAR1A', 'Gene', (134, 141))	('variant', 'Var', (142, 149))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('patients', 'Species', '9606', (116, 124))	('PDE', 'Gene', '501', (35, 38))	('Carney complex', 'Disease', (101, 115))	('adrenal tumors', 'Disease', 'MESH:D000310', (83, 97))	('PRKAR1A', 'Gene', '5573', (134, 141))	('PDE', 'Gene', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('adrenal tumor', 'Phenotype', 'HP:0100631', (83, 96))	('adrenal tumors', 'Disease', (83, 97))
110854	32098292	A high frequency of PDE variants was observed in patients with prostate cancer.	('PDE', 'Gene', (20, 23))	('PDE', 'Gene', '501', (20, 23))	('variants', 'Var', (24, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (63, 78))	('observed', 'Reg', (37, 45))	('prostate cancer', 'Phenotype', 'HP:0012125', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('prostate cancer', 'Disease', (63, 78))	('patients', 'Species', '9606', (49, 57))
110860	32098292	Of interest, we have documented germline nonsense variants in PDE4DIP, a protein that interacts with the cyclic nucleotide phosphodiesterase PDE4D to anchor this protein to the Golgi/centrosome region of the cell.	('anchor', 'PosReg', (150, 156))	('cyclic nucleotide phosphodiesterase', 'Gene', (105, 140))	('cyclic nucleotide phosphodiesterase', 'Gene', '5140', (105, 140))	('PDE4D', 'Gene', '5144', (62, 67))	('PDE4D', 'Gene', '5144', (141, 146))	('PDE4D', 'Gene', (62, 67))	('PDE4D', 'Gene', (141, 146))	('nonsense variants', 'Var', (41, 58))	('PDE4DIP', 'Gene', (62, 69))	('PDE4DIP', 'Gene', '9659', (62, 69))
110861	32098292	This gene has been associated with myeloproliferative disorders, as shown by its fusions with platelet-derived growth factor receptor beta gene (PDGFRB).	('associated', 'Reg', (19, 29))	('platelet-derived growth factor receptor beta', 'Gene', (94, 138))	('PDGFRB', 'Gene', '5159', (145, 151))	('fusions', 'Var', (81, 88))	('PDGFRB', 'Gene', (145, 151))	('myeloproliferative disorders', 'Disease', (35, 63))	('platelet-derived growth factor receptor beta', 'Gene', '5159', (94, 138))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (35, 63))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (35, 63))
110862	32098292	In addition, PDE4DIP variants are one of the most frequent in metastatic adrenocortical carcinomas in adults.	('variants', 'Var', (21, 29))	('adrenocortical carcinomas', 'Disease', (73, 98))	('frequent', 'Reg', (50, 58))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (73, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (73, 98))	('PDE4DIP', 'Gene', '9659', (13, 20))	('PDE4DIP', 'Gene', (13, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (73, 98))
110863	32098292	Of note, all four of our patients with an inactivating variant in PDE4DIP also harbor the hypomorphic widespread TP53 p.R337H founder allele.	('p.R337H', 'Var', (118, 125))	('PDE4DIP', 'Gene', '9659', (66, 73))	('TP53', 'Gene', '7157', (113, 117))	('patients', 'Species', '9606', (25, 33))	('p.R337H', 'Mutation', 'rs121912664', (118, 125))	('PDE4DIP', 'Gene', (66, 73))	('inactivating variant', 'Var', (42, 62))	('TP53', 'Gene', (113, 117))
110864	32098292	These findings suggest that PDE4DIP variants (and perhaps others c-AMP signaling pathway genes) predispose TP53 p.R337H carriers to adrenocortical tumorigenesis.	('predispose', 'Reg', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('p.R337H', 'Mutation', 'rs121912664', (112, 119))	('AMP', 'Chemical', 'MESH:D000249', (67, 70))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('PDE4DIP', 'Gene', '9659', (28, 35))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (132, 160))	('adrenocortical tumorigenesis', 'Disease', (132, 160))	('PDE4DIP', 'Gene', (28, 35))	('p.R337H', 'Var', (112, 119))
110866	32098292	In contrast, our findings identified germline inactivating PDE variants in patients who developed adrenocortical carcinomas, including cases with virilization, and aldosterone-producing tumors.	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (98, 123))	('variants', 'Var', (63, 71))	('PDE', 'Gene', '501', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('patients', 'Species', '9606', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('PDE', 'Gene', (59, 62))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (98, 123))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('adrenocortical carcinomas', 'Disease', (98, 123))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (98, 122))
110867	32098292	The observed concomitant PDE variants and hypomorphic TP53 alleles or chromosome 11p uniparental disomy in the germline of pediatric ACT cases support the combined additive effect of multiple genetic variants in cancer susceptibility.	('pediatric ACT', 'Disease', (123, 136))	('uniparental disomy', 'Disease', (85, 103))	('pediatric ACT', 'Disease', 'MESH:C565973', (123, 136))	('PDE', 'Gene', (25, 28))	('uniparental disomy', 'Disease', 'MESH:D024182', (85, 103))	('PDE', 'Gene', '501', (25, 28))	('TP53', 'Gene', '7157', (54, 58))	('variants', 'Var', (29, 37))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('TP53', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
110868	32098292	In this study, we added PDE variants as a candidate causative gene for pediatric adrenocortical lesions.	('pediatric adrenocortical lesions', 'Disease', 'MESH:C565973', (71, 103))	('variants', 'Var', (28, 36))	('PDE', 'Gene', '501', (24, 27))	('PDE', 'Gene', (24, 27))	('pediatric adrenocortical lesions', 'Disease', (71, 103))
110869	32098292	Altogether, sequencing analysis and transcriptome profiling support the importance of alterations in the cAMP signaling pathway in adrenocortical tumors.	('adrenocortical tumors', 'Disease', (131, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cAMP', 'Gene', (105, 109))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (131, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('cAMP', 'Gene', '820', (105, 109))	('alterations', 'Var', (86, 97))
110870	32098292	As we learn more about the functional roles and molecular interactions of each PDE, as well as how the variants operate in adrenocortical tumorigenesis, we will better understand the full potential of PDEs as therapeutic targets.	('PDE', 'Gene', '501', (79, 82))	('adrenocortical tumorigenesis', 'Disease', (123, 151))	('PDE', 'Gene', '501', (201, 204))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (123, 151))	('PDE', 'Gene', (79, 82))	('variants', 'Var', (103, 111))	('PDE', 'Gene', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
110873	32098292	Sequencing data for variants in the PDE family of genes (PDE1 to PDE11, Figure 1), and PDE4DIP as well as cAMP/PKA-signaling pathway genes GNAS, PRKACA, and CREB were analyzed.	('variants', 'Var', (20, 28))	('cAMP', 'Gene', '820', (106, 110))	('PRKACA', 'Gene', '5566', (145, 151))	('PDE', 'Gene', (36, 39))	('CREB', 'Gene', (157, 161))	('PDE', 'Gene', '501', (65, 68))	('PDE4DIP', 'Gene', (87, 94))	('PDE', 'Gene', '501', (57, 60))	('cAMP', 'Gene', (106, 110))	('PDE', 'Gene', '501', (87, 90))	('PDE', 'Gene', (65, 68))	('CREB', 'Gene', '1385', (157, 161))	('PRKACA', 'Gene', (145, 151))	('GNAS', 'Gene', (139, 143))	('PDE', 'Gene', (57, 60))	('GNAS', 'Gene', '2778', (139, 143))	('PDE', 'Gene', '501', (36, 39))	('PDE', 'Gene', (87, 90))	('PDE4DIP', 'Gene', '9659', (87, 94))
110879	32098292	All patients with ACTs tested positive for the germline TP53 p.R337H variant.	('p.R337H', 'Var', (61, 68))	('positive', 'Reg', (30, 38))	('p.R337H', 'Mutation', 'rs121912664', (61, 68))	('TP53', 'Gene', '7157', (56, 60))	('ACTs', 'Disease', (18, 22))	('ACTs', 'Disease', 'MESH:D018268', (18, 22))	('TP53', 'Gene', (56, 60))	('patients', 'Species', '9606', (4, 12))
110881	32098292	We reported recurrent inactivating germline PDE variants in association with pediatric adrenocortical tumors.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('pediatric adrenocortical tumors', 'Disease', (77, 108))	('pediatric adrenocortical tumors', 'Disease', 'MESH:C565973', (77, 108))	('variants', 'Var', (48, 56))	('association', 'Reg', (60, 71))	('inactivating', 'NegReg', (22, 34))	('PDE', 'Gene', '501', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('PDE', 'Gene', (44, 47))
110882	32098292	In each case, the wild-type allele was selected against by LOH, suggesting an imbalance of the cAMP signaling pathway contributes to tumor progression.	('cAMP', 'Gene', '820', (95, 99))	('cAMP', 'Gene', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('imbalance', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('imbalance', 'Phenotype', 'HP:0002172', (78, 87))	('tumor', 'Disease', (133, 138))	('contributes', 'Reg', (118, 129))
110883	32098292	The following are available online at , Table S1: Additional variants observed in the discovery cohort of pediatric adrenocortical tumors, Table S2: Acquired and constitutive PDEs variants in TCGA database, Table S3: Additional variants observed in an independent cohort of carriers of the germline TP53 p.R337H variant.	('p.R337H', 'Mutation', 'rs121912664', (304, 311))	('TP53', 'Gene', '7157', (299, 303))	('PDE', 'Gene', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('TP53', 'Gene', (299, 303))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('pediatric adrenocortical tumors', 'Disease', (106, 137))	('pediatric adrenocortical tumors', 'Disease', 'MESH:C565973', (106, 137))	('p.R337H', 'Var', (304, 311))	('PDE', 'Gene', '501', (175, 178))
110885	31821699	Inhibition of MELK produces potential anti-tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway We aimed to investigate the biological function of MELK and the therapeutic potential of OTSSP167 in human bladder cancer (BCa).	('p53', 'Gene', '7157', (128, 131))	('human', 'Species', '9606', (241, 246))	('G1/S cell cycle arrest', 'CPA', (88, 110))	('CHK2', 'Gene', '11200', (123, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (247, 261))	('bladder cancer', 'Disease', (247, 261))	('BCa', 'Phenotype', 'HP:0009725', (263, 266))	('MELK', 'Gene', '9833', (14, 18))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('MELK', 'Gene', (191, 195))	('tumour', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('inducing', 'Reg', (79, 87))	('p53', 'Gene', (128, 131))	('ATM', 'Gene', (119, 122))	('bladder cancer', 'Phenotype', 'HP:0009725', (247, 261))	('tumour', 'Disease', (43, 49))	('bladder cancer', 'Disease', 'MESH:D001749', (61, 75))	('bladder cancer', 'Disease', (61, 75))	('MELK', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('BCa', 'Disease', (263, 266))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (93, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))	('MELK', 'Gene', '9833', (191, 195))	('BCa', 'Disease', 'MESH:D001749', (263, 266))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CHK2', 'Gene', (123, 127))	('ATM', 'Gene', '472', (119, 122))
110888	31821699	Furthermore, BCa cells presented significantly decreased proliferation capacity following silencing of MELK or treatment with OTSSP167 in vitro and in vivo.	('proliferation capacity', 'CPA', (57, 79))	('BCa', 'Disease', 'MESH:D001749', (13, 16))	('silencing', 'Var', (90, 99))	('BCa', 'Phenotype', 'HP:0009725', (13, 16))	('BCa', 'Disease', (13, 16))	('MELK', 'Gene', (103, 107))	('decreased', 'NegReg', (47, 56))
110943	31821699	In addition, univariate and multivariate Cox analyses (Figure 1F and Figure S1A) showed that high expression of MELK predicted poor prognosis (CSS and OS, HR = 1.517, HR = 1.384, respectively, both P < .05).	('Cox', 'Gene', '1351', (41, 44))	('MELK', 'Gene', (112, 116))	('Cox', 'Gene', (41, 44))	('high expression', 'Var', (93, 108))	('poor prognosis', 'CPA', (127, 141))
110949	31821699	Patient B was a 53-year-old man with a T1G1 BCa (unifocal tumour) when first diagnosed, and the tumour progressed into a T2G2 BCa (unifocal tumour) 8.9 months later.	('BCa', 'Phenotype', 'HP:0009725', (126, 129))	('BCa', 'Disease', 'MESH:D001749', (44, 47))	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('BCa', 'Disease', (126, 129))	('BCa', 'Disease', 'MESH:D001749', (126, 129))	('T1G1', 'Var', (39, 43))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', (140, 146))	('BCa', 'Phenotype', 'HP:0009725', (44, 47))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Disease', (58, 64))	('man', 'Species', '9606', (28, 31))	('BCa', 'Disease', (44, 47))	('Patient', 'Species', '9606', (0, 7))	('tumour', 'Disease', (96, 102))
110957	31821699	MTT assays showed that, compared with the control group, si-1- and si-2-transfected BCa cells presented a significantly decreased proliferation capacity (P < .001, Figure 3C).	('decreased', 'NegReg', (120, 129))	('BCa', 'Disease', 'MESH:D001749', (84, 87))	('proliferation capacity', 'CPA', (130, 152))	('si-2-transfected', 'Var', (67, 83))	('BCa', 'Phenotype', 'HP:0009725', (84, 87))	('BCa', 'Disease', (84, 87))	('MTT', 'Chemical', 'MESH:C022616', (0, 3))	('si-1-', 'Var', (57, 62))
110959	31821699	The clonogenic assay showed that clone size and number were smaller in MELK-siRNA-treated BCa cells than they were in NC-treated BCa cells (P < .001, Figure 3D); this phenotype was reversed when MELK was overexpressed (P < .05, Figure 3D).	('BCa', 'Disease', 'MESH:D001749', (129, 132))	('clone size', 'CPA', (33, 43))	('BCa', 'Phenotype', 'HP:0009725', (90, 93))	('BCa', 'Disease', (90, 93))	('MELK-siRNA-treated', 'Var', (71, 89))	('BCa', 'Phenotype', 'HP:0009725', (129, 132))	('BCa', 'Disease', (129, 132))	('BCa', 'Disease', 'MESH:D001749', (90, 93))	('smaller', 'NegReg', (60, 67))
110960	31821699	The migration assay showed that the migration ability of BCa cells was markedly attenuated when MELK was silenced (P < .01, Figure 3E).	('BCa', 'Disease', 'MESH:D001749', (57, 60))	('attenuated', 'NegReg', (80, 90))	('MELK', 'Gene', (96, 100))	('silenced', 'Var', (105, 113))	('BCa', 'Phenotype', 'HP:0009725', (57, 60))	('BCa', 'Disease', (57, 60))
110961	31821699	MELK silencing in BCa cells induced cell cycle arrest at the G1/S phase, which was not observed in the control group.	('cell cycle arrest at the G1/S phase', 'CPA', (36, 71))	('BCa', 'Phenotype', 'HP:0009725', (18, 21))	('BCa', 'Disease', (18, 21))	('silencing', 'Var', (5, 14))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (36, 53))	('MELK', 'Protein', (0, 4))	('BCa', 'Disease', 'MESH:D001749', (18, 21))
110972	31821699	Overall, MELK promoted BCa cell vitality by accelerating the transition out of G1/S phase via inhibition of the ATM/CHK2/p53 pathway in BCa cells.	('accelerating', 'PosReg', (44, 56))	('BCa', 'Disease', (136, 139))	('inhibition', 'NegReg', (94, 104))	('BCa', 'Disease', 'MESH:D001749', (23, 26))	('CHK2', 'Gene', (116, 120))	('BCa', 'Disease', 'MESH:D001749', (136, 139))	('transition out', 'CPA', (61, 75))	('BCa', 'Phenotype', 'HP:0009725', (23, 26))	('CHK2', 'Gene', '11200', (116, 120))	('MELK', 'Var', (9, 13))	('BCa', 'Disease', (23, 26))	('promoted', 'PosReg', (14, 22))	('BCa', 'Phenotype', 'HP:0009725', (136, 139))
110975	31821699	H&E staining indicated that the sh-MELK group of tumour tissues contained fewer tumour cells than the tumours in the NC group mice (Figure 5D), suggesting weaker tumour activity in the sh-MELK group.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('mice', 'Species', '10090', (126, 130))	('suggesting', 'NegReg', (144, 154))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumour', 'Disease', 'MESH:D009369', (162, 168))	('tumour', 'Disease', (162, 168))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumours', 'Disease', (102, 109))	('the', 'Var', (28, 31))	('tumour', 'Disease', (49, 55))	('tumour', 'Disease', (80, 86))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('contained', 'NegReg', (64, 73))
110982	31821699	In addition, flow cytometric analysis of BCa cell lines treated with OTSSP167 for 48 hours exhibited an increase in cells at the G1/S phase compared with what was observed following DMSO treatment (P < .05, Figure 6E).	('increase', 'PosReg', (104, 112))	('OTSSP167', 'Var', (69, 77))	('cells at the G1/S phase', 'CPA', (116, 139))	('BCa', 'Disease', 'MESH:D001749', (41, 44))	('DMSO', 'Chemical', 'MESH:D004121', (182, 186))	('BCa', 'Phenotype', 'HP:0009725', (41, 44))	('BCa', 'Disease', (41, 44))
110991	31821699	H&E staining indicated that the OTSSP167 injection group tumour tissues contained fewer tumour cells than did those of the NC group (Figure 7D).	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (57, 63))	('tumour', 'Disease', (88, 94))	('the OTSSP167', 'Var', (28, 40))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('contained', 'NegReg', (72, 81))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
110994	31821699	Moreover, immunofluorescence analysis of mouse tumour tissues demonstrated that the number of cells with MELK and Ki-67 positive staining was lower in the OTSSP167 injection group than in the control group, while the number of cells with p-ATM and p53 positive staining was higher (Figure 7F-I), which was consistent with the in vitro and in vivo MELK inhibition results.	('MELK', 'Protein', (105, 109))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('F-I', 'Chemical', 'MESH:C105057', (290, 293))	('Ki-67', 'Gene', '17345', (114, 119))	('OTSSP167 injection', 'Var', (155, 173))	('mouse', 'Species', '10090', (41, 46))	('Ki-67', 'Gene', (114, 119))	('tumour', 'Disease', (47, 53))	('lower', 'NegReg', (142, 147))	('injection', 'Var', (164, 173))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
110995	31821699	To further study the restoration function of OTSSP167, T24 and UMUC3, cells were treated with one of four sets of conditions: VECTOR + DMSO, MELK + DMSO, VECTOR + OTSSP167 and MELK + OTSSP167.	('DMSO', 'Chemical', 'MESH:D004121', (135, 139))	('VECTOR + OTSSP167', 'Var', (154, 171))	('MELK + OTSSP167', 'Var', (176, 191))	('VECTOR + DMSO', 'Var', (126, 139))	('DMSO', 'Chemical', 'MESH:D004121', (148, 152))
110997	31821699	Flow cytometry analysis showed that compared with the cells in the VECTOR + DMSO transfected group, the proportion of cells in the G1/S phase was significantly decreased in the MELK + DMSO transfected group and was markedly increased in the VECTOR + OTSSP167 transfected group; however, no obvious change was seen in the MELK + OTSSP167 group (Figure 8E).	('decreased', 'NegReg', (160, 169))	('MELK', 'Var', (177, 181))	('increased', 'PosReg', (224, 233))	('DMSO', 'Chemical', 'MESH:D004121', (184, 188))	('DMSO', 'Chemical', 'MESH:D004121', (76, 80))
110998	31821699	These results indicated that OTSSP167 restored the inhibitory effect of the ATM/CHK2/p53 pathway, which was caused by transfection with the MELK plasmid.	('CHK2', 'Gene', '11200', (80, 84))	('OTSSP167', 'Var', (29, 37))	('CHK2', 'Gene', (80, 84))	('inhibitory effect', 'MPA', (51, 68))
111008	31821699	Further analyses of the genomic microarray profile http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE13507 showed that MELK was an independent prognostic factor of BCa and was significantly correlated with gender, age, T stage, N stage, tumour grade and progression, and high expression of MELK predicted poor prognosis (CSS and OS) in BCa patients.	('high expression', 'Var', (274, 289))	('BCa', 'Disease', 'MESH:D001749', (339, 342))	('BCa', 'Disease', 'MESH:D001749', (167, 170))	('patients', 'Species', '9606', (343, 351))	('correlated', 'Reg', (193, 203))	('MELK', 'Gene', (122, 126))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumour', 'Disease', 'MESH:D009369', (240, 246))	('BCa', 'Phenotype', 'HP:0009725', (339, 342))	('BCa', 'Phenotype', 'HP:0009725', (167, 170))	('BCa', 'Disease', (339, 342))	('BCa', 'Disease', (167, 170))	('tumour', 'Disease', (240, 246))	('MELK', 'Gene', (293, 297))
111011	31821699	MELK silencing demonstrated a marked inhibitory effect on BCa cells by reducing proliferation, inducing G1/S cell cycle arrest and attenuating cell migration.	('BCa', 'Disease', (58, 61))	('reducing', 'NegReg', (71, 79))	('cell migration', 'CPA', (143, 157))	('attenuating', 'NegReg', (131, 142))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (109, 126))	('proliferation', 'CPA', (80, 93))	('G1/S cell cycle arrest', 'CPA', (104, 126))	('silencing', 'Var', (5, 14))	('BCa', 'Disease', 'MESH:D001749', (58, 61))	('MELK', 'Gene', (0, 4))	('inducing', 'Reg', (95, 103))	('BCa', 'Phenotype', 'HP:0009725', (58, 61))
111014	31821699	MELK has been reported as an important regulator of the G2/M transition in many studies.16, 22, 23, 24 In contrast, MELK silencing was found to contribute to the delay of S phase progression by Beke et al and Kig et al.13, 30 Our study revealed that MELK may act as a negative regulator of the G1/S transition, which was consistent with Beke et al and Kig et al To investigate the reason that MELK plays a different role in cell cycle progression according to previous studies, cell cycle assays of other cancer cell lines, such as liver cancer and kidney cancer, were assessed following MELK being knocked down.	('cancer', 'Phenotype', 'HP:0002664', (538, 544))	('liver cancer', 'Phenotype', 'HP:0002896', (532, 544))	('liver cancer', 'Disease', 'MESH:D006528', (532, 544))	('kidney cancer', 'Phenotype', 'HP:0009726', (549, 562))	('cancer', 'Phenotype', 'HP:0002664', (505, 511))	('liver cancer', 'Disease', (532, 544))	('cancer', 'Disease', 'MESH:D009369', (505, 511))	('kidney cancer', 'Disease', (549, 562))	('cancer', 'Disease', 'MESH:D009369', (538, 544))	('cancer', 'Disease', (556, 562))	('cancer', 'Disease', 'MESH:D009369', (556, 562))	('kidney cancer', 'Disease', 'MESH:D007680', (549, 562))	('cancer', 'Phenotype', 'HP:0002664', (556, 562))	('cancer', 'Disease', (538, 544))	('cancer', 'Disease', (505, 511))	('MELK', 'Gene', (588, 592))	('man', 'Species', '9606', (75, 78))	('knocked down', 'Var', (599, 611))
111015	31821699	MELK silencing demonstrated G1/S cell cycle arrest in p53 mutant cell lines (Huh7, 786O), which was similar to what was observed in the p53 mutant BCa cell lines T24 and UMUC3, but there was G2/M cell cycle arrest in p53 wild type cells (HepG2, 769P, Figure S3).	('BCa', 'Disease', (147, 150))	('mutant', 'Var', (58, 64))	('G1/S cell cycle arrest', 'CPA', (28, 50))	('HepG2', 'CellLine', 'CVCL:0027', (238, 243))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (33, 50))	('BCa', 'Disease', 'MESH:D001749', (147, 150))	('p53', 'Gene', (54, 57))	('G2/M cell cycle arrest', 'CPA', (191, 213))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (196, 213))	('BCa', 'Phenotype', 'HP:0009725', (147, 150))	('Huh7', 'CellLine', 'CVCL:0336', (77, 81))
111016	31821699	Owing to the lack of additional tumour cell lines, we could not conclude that p53 affects the role of MELK in the cell cycle.	('MELK', 'Protein', (102, 106))	('tumour', 'Disease', (32, 38))	('affects', 'Reg', (82, 89))	('p53', 'Var', (78, 81))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
111017	31821699	However, it is an indisputable fact that p53 pathway defects contribute to diagnosis and therapy difficulties as well as adverse clinical outcomes in BCa.	('BCa', 'Disease', 'MESH:D001749', (150, 153))	('p53 pathway', 'Pathway', (41, 52))	('contribute', 'Reg', (61, 71))	('defects', 'Var', (53, 60))	('therapy difficulties', 'CPA', (89, 109))	('BCa', 'Phenotype', 'HP:0009725', (150, 153))	('BCa', 'Disease', (150, 153))
111018	31821699	Moreover, MELK has been shown in some studies to promote tumorigenesis via the p53 pathway.13, 23, 25, 30, 31, 32  Previous investigations suggested that MELK inhibition could lead to the successive phosphorylation of ATM and CHK2 and the up-regulation of p53 and p21.30, 31, 32 This may be the reason that MELK silencing caused G1/S cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (334, 351))	('CHK2', 'Gene', (226, 230))	('phosphorylation', 'MPA', (199, 214))	('p53', 'Protein', (256, 259))	('up-regulation', 'PosReg', (239, 252))	('silencing', 'NegReg', (312, 321))	('MELK', 'Gene', (154, 158))	('ATM', 'Protein', (218, 221))	('p21.30', 'Var', (264, 270))	('CHK2', 'Gene', '11200', (226, 230))	('MELK', 'Gene', (307, 311))	('G1/S cell cycle arrest', 'CPA', (329, 351))	('inhibition', 'NegReg', (159, 169))
111071	31976120	Post-operatively, the patient developed dyspnea attributed to phenoxybenzamine and propranolol, and for which work up for myocardial and thrombotic causes were negative.	('myocardial and thrombotic', 'Disease', 'MESH:D013927', (122, 147))	('dyspnea', 'Disease', (40, 47))	('dyspnea', 'Disease', 'MESH:D004417', (40, 47))	('phenoxybenzamine', 'Var', (62, 78))	('dyspnea', 'Phenotype', 'HP:0002094', (40, 47))
111073	31976120	Variants of ACC that have been identified to date include myxoid, sarcomatoid and oncocytic subtypes.	('Variants', 'Var', (0, 8))	('ACC', 'Phenotype', 'HP:0006744', (12, 15))	('myxoid', 'Disease', (58, 64))	('sarcomatoid', 'Disease', 'MESH:D002292', (66, 77))	('ACC', 'Gene', (12, 15))	('oncocytic subtypes', 'Disease', (82, 100))	('sarcomatoid', 'Disease', (66, 77))
111108	28533648	There have been earlier studies demonstrating the F-18 FDG uptake in gynecomastia caused by hepatocellular carcinoma and Spironolactone-induced gynecomastia.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Spironolactone', 'Chemical', 'MESH:D013148', (121, 135))	('FDG', 'Chemical', 'MESH:D019788', (55, 58))	('gynecomastia', 'Disease', 'MESH:D006177', (144, 156))	('F-18', 'Var', (50, 54))	('gynecomastia', 'Disease', (144, 156))	('gynecomastia', 'Phenotype', 'HP:0000771', (69, 81))	('gynecomastia', 'Disease', 'MESH:D006177', (69, 81))	('gynecomastia', 'Phenotype', 'HP:0000771', (144, 156))	('gynecomastia', 'Disease', (69, 81))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('hepatocellular carcinoma', 'Disease', (92, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))	('caused', 'Reg', (82, 88))
111114	28533648	The role of F-18 FDG PET/CT in adrenal tumors, particularly, adrenocortical carcinoma has been explored in a few studies.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (61, 85))	('adrenocortical carcinoma', 'Disease', (61, 85))	('adrenal tumors', 'Disease', 'MESH:D000310', (31, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('adrenal tumor', 'Phenotype', 'HP:0100631', (31, 44))	('FDG', 'Chemical', 'MESH:D019788', (17, 20))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (61, 85))	('adrenal tumors', 'Disease', (31, 45))	('F-18 FDG', 'Var', (12, 20))
111115	28533648	F-18 FDG PET/CT may provide a one stop shop, especially when used in combination with contrast enhanced CT, for evaluation of patients with suspected ACC.	('ACC', 'Disease', (150, 153))	('FDG', 'Chemical', 'MESH:D019788', (5, 8))	('patients', 'Species', '9606', (126, 134))	('F-18 FDG', 'Var', (0, 8))
111124	28079787	This case describes an unreported adverse effect of mitotane, it is - to our knowledge - the 1st description of erosive lichenoid drug reaction due to Mitotane.	('Mitotane', 'Var', (151, 159))	('erosive lichenoid drug reaction', 'Disease', (112, 143))	('Mitotane', 'Chemical', 'MESH:D008939', (151, 159))	('mitotane', 'Chemical', 'MESH:D008939', (52, 60))	('drug reaction', 'Phenotype', 'HP:0020172', (130, 143))
111140	28079787	To our knowledge, we report the first case of oral and vulvo-vaginal erosive lichenoid eruptions due to mitotane.	('due', 'Reg', (97, 100))	('oral', 'Disease', (46, 50))	('mitotane', 'Var', (104, 112))	('lichenoid eruptions', 'Disease', 'MESH:D017512', (77, 96))	('mitotane', 'Chemical', 'MESH:D008939', (104, 112))	('lichenoid eruptions', 'Disease', (77, 96))	('lichenoid eruptions', 'Phenotype', 'HP:0031452', (77, 96))
111171	28079787	To our knowledge, this is the first reported case on oral and vaginal lichenoid reactions due to mitotane.	('mitotane', 'Var', (97, 105))	('mitotane', 'Chemical', 'MESH:D008939', (97, 105))	('vaginal lichenoid reactions', 'Disease', 'MESH:D004342', (62, 89))	('vaginal lichenoid reactions', 'Disease', (62, 89))	('due', 'Reg', (90, 93))
111172	28079787	Mitotane is known to cause various skin rashes but no cases of oral or genital erosive eruption had been described.	('skin rashes', 'Disease', (35, 46))	('Mitotane', 'Var', (0, 8))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('skin rashes', 'Disease', 'MESH:D005076', (35, 46))	('skin rashes', 'Phenotype', 'HP:0000988', (35, 46))	('skin rash', 'Phenotype', 'HP:0000988', (35, 44))
111175	28079787	In terms of overall survival, 4 studies concluded that mitotane does not increase the survival rate, while 5 reported an increase survival rate.	('survival', 'MPA', (130, 138))	('mitotane', 'Var', (55, 63))	('mitotane', 'Chemical', 'MESH:D008939', (55, 63))
111176	28079787	Available data suggest that mitotane modifies the peripheral metabolism of steroids by directly suppressing secretion of the adrenal cortex.	('steroids', 'Chemical', 'MESH:D013256', (75, 83))	('modifies', 'Reg', (37, 45))	('mitotane', 'Var', (28, 36))	('secretion of the adrenal cortex', 'MPA', (108, 139))	('mitotane', 'Chemical', 'MESH:D008939', (28, 36))	('suppressing', 'NegReg', (96, 107))	('peripheral metabolism', 'MPA', (50, 71))
111193	25867024	Role of ALADIN in Human Adrenocortical Cells for Oxidative Stress Response and Steroidogenesis Triple A syndrome is caused by mutations in AAAS encoding the protein ALADIN.	('Triple A syndrome', 'Disease', (95, 112))	('ALADIN', 'Gene', '8086', (165, 171))	('Oxidative Stress', 'Phenotype', 'HP:0025464', (49, 65))	('ALADIN', 'Gene', (8, 14))	('Human', 'Species', '9606', (18, 23))	('caused by', 'Reg', (116, 125))	('AAAS', 'Gene', (139, 143))	('AAAS', 'Gene', '8086', (139, 143))	('Triple A syndrome', 'Disease', 'MESH:C536008', (95, 112))	('ALADIN', 'Gene', '8086', (8, 14))	('ALADIN', 'Gene', (165, 171))	('mutations', 'Var', (126, 135))
111195	25867024	Our findings indicate that AAAS knock-down induces a down-regulation of genes coding for type II microsomal cytochrome P450 hydroxylases CYP17A1 and CYP21A2 and their electron donor enzyme cytochrome P450 oxidoreductase, thereby decreasing biosynthesis of precursor metabolites required for glucocorticoid and androgen production.	('AAAS', 'Gene', (27, 31))	('AAAS', 'Gene', '8086', (27, 31))	('down-regulation', 'NegReg', (53, 68))	('donor', 'Species', '9606', (176, 181))	('decreasing', 'NegReg', (229, 239))	('CYP21A2', 'Gene', (149, 156))	('CYP21A2', 'Gene', '1589', (149, 156))	('CYP17A1', 'Gene', (137, 144))	('CYP17A1', 'Gene', '1586', (137, 144))	('cytochrome P450 oxidoreductase', 'Gene', '5447', (189, 219))	('cytochrome P450 oxidoreductase', 'Gene', (189, 219))	('knock-down', 'Var', (32, 42))
111196	25867024	Furthermore we demonstrate that ALADIN deficiency leads to increased susceptibility to oxidative stress and alteration in redox homeostasis after paraquat treatment.	('deficiency', 'Var', (39, 49))	('alteration', 'Reg', (108, 118))	('ALADIN', 'Gene', (32, 38))	('redox homeostasis', 'MPA', (122, 139))	('oxidative stress', 'Phenotype', 'HP:0025464', (87, 103))	('paraquat', 'Chemical', 'MESH:D010269', (146, 154))	('susceptibility to oxidative stress', 'MPA', (69, 103))
111199	25867024	Triple A syndrome (MIM*231550) is an autosomal-recessive disease manifesting with the triad of ACTH-resistant adrenal insufficiency, achalasia of the cardia and alacrima (Triple A) in combination with progressive neurological impairment.	('achalasia', 'Phenotype', 'HP:0002571', (133, 142))	('MIM', 'Var', (19, 22))	('progressive neurological impairment', 'Phenotype', 'HP:0002344', (201, 236))	('neurological impairment', 'Disease', 'MESH:D009422', (213, 236))	('autosomal-recessive disease', 'Disease', 'MESH:D030342', (37, 64))	('neurological impairment', 'Phenotype', 'HP:0000707', (213, 236))	('Triple A syndrome', 'Disease', (0, 17))	('autosomal-recessive disease', 'Disease', (37, 64))	('neurological impairment', 'Disease', (213, 236))	('adrenal insufficiency', 'Disease', (110, 131))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (110, 131))	('ACTH-resistant adrenal insufficiency', 'Phenotype', 'HP:0008259', (95, 131))	('resistant adrenal insufficiency', 'Phenotype', 'HP:0011734', (100, 131))	('Triple A syndrome', 'Disease', 'MESH:C536008', (0, 17))	('alacrima', 'Phenotype', 'HP:0000522', (161, 169))	('achalasia of the cardia and alacrima', 'Disease', 'MESH:C536008', (133, 169))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (110, 131))
111200	25867024	The disease is caused by mutations in the AAAS (achalasia:adrenocortical insufficiency:alacrima syndrome) gene, which encodes the protein ALADIN (alacrima-achalasia-adrenal insufficiency neurologic disorder).	('AAAS', 'Gene', (42, 46))	('alacrima syndrome', 'Disease', 'MESH:C562827', (87, 104))	('alacrima', 'Phenotype', 'HP:0000522', (146, 154))	('adrenocortical insufficiency', 'Phenotype', 'HP:0008207', (58, 86))	('neurologic disorder', 'Phenotype', 'HP:0000707', (187, 206))	('achalasia', 'Phenotype', 'HP:0002571', (48, 57))	('mutations', 'Var', (25, 34))	('achalasia', 'Disease', 'MESH:D004931', (155, 164))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (165, 186))	('alacrima syndrome', 'Disease', (87, 104))	('adrenocortical insufficiency', 'Disease', (58, 86))	('achalasia', 'Disease', (155, 164))	('caused by', 'Reg', (15, 24))	('AAAS', 'Gene', '8086', (42, 46))	('alacrima', 'Phenotype', 'HP:0000522', (87, 95))	('achalasia', 'Phenotype', 'HP:0002571', (155, 164))	('achalasia', 'Disease', 'MESH:D004931', (48, 57))	('alacrima-achalasia-adrenal insufficiency neurologic disorder', 'Disease', 'MESH:C536008', (146, 206))	('adrenocortical insufficiency', 'Disease', 'MESH:D000224', (58, 86))	('achalasia', 'Disease', (48, 57))
111203	25867024	Most of the known AAAS mutations result in mis-localisation of the altered ALADIN protein, mainly to the cytoplasm.	('AAAS', 'Gene', (18, 22))	('AAAS', 'Gene', '8086', (18, 22))	('result in', 'Reg', (33, 42))	('mutations', 'Var', (23, 32))	('ALADIN protein', 'Protein', (75, 89))	('mis-localisation', 'MPA', (43, 59))
111204	25867024	It is suspected that a dysfunction of ALADIN may play a role in cellular accumulation of reactive oxygen species (ROS).	('cellular accumulation of reactive oxygen species', 'MPA', (64, 112))	('cellular accumulation of reactive oxygen species', 'Phenotype', 'HP:0025464', (64, 112))	('ROS', 'Chemical', 'MESH:D017382', (114, 117))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (89, 112))	('play', 'Reg', (49, 53))	('ALADIN', 'Protein', (38, 44))	('dysfunction', 'Var', (23, 34))
111210	25867024	It was hypothesised that mutant ALADIN impairs the nuclear import of FTH1 in triple A syndrome.	('A syndrome', 'Disease', 'MESH:D013577', (84, 94))	('mutant', 'Var', (25, 31))	('impairs', 'NegReg', (39, 46))	('ALADIN', 'Protein', (32, 38))	('FTH1', 'Gene', (69, 73))	('nuclear import', 'MPA', (51, 65))	('A syndrome', 'Disease', (84, 94))
111218	25867024	We selected six regions to be the target sequence for shRNA silencing of AAAS (V1: NM_015665.5) and used the two best regions (nt279-299 AAATGAAATTGCAAACTCAGA and nt410-430 AAGATCTGATCGCTGAATTTG) for further experiments.	('AAAS', 'Gene', (73, 77))	('nt279-299 AAATGAAATTGCAAACTCAGA', 'Var', (127, 158))	('AAAS', 'Gene', '8086', (73, 77))
111231	25867024	The most reliable sub-clones were selected and one clone per construct type was chosen (AAAS knock-down shRNA, scrambled shRNA, AAAS over-expression and pcDNA4/TO empty vector).	('over-expression', 'PosReg', (133, 148))	('AAAS', 'Gene', (128, 132))	('AAAS', 'Gene', '8086', (128, 132))	('expression', 'Species', '29278', (138, 148))	('AAAS', 'Gene', (88, 92))	('AAAS', 'Gene', '8086', (88, 92))	('knock-down', 'Var', (93, 103))
111232	25867024	Selected cell lines were cultured in 6-well culture dishes (Corning Costar, Kaiserslautern, Germany) at a density of 2x105 cells/well and treated 24 h after seeding with doxycycline for 48 h. In order to determine efficiency of AAAS knock-down, over-expression and expression of genes coding for steroidogenic enzymes total RNA was isolated from one well and used for real-time RT-PCR.	('steroid', 'Chemical', 'MESH:D013256', (296, 303))	('Corning Costar', 'Disease', (60, 74))	('knock-down', 'Var', (233, 243))	('expression', 'Species', '29278', (265, 275))	('doxycycline', 'Chemical', 'MESH:D004318', (170, 181))	('AAAS', 'Gene', (228, 232))	('AAAS', 'Gene', '8086', (228, 232))	('expression', 'Species', '29278', (250, 260))	('Corning Costar', 'Disease', 'MESH:D002145', (60, 74))
111238	25867024	For transient transfections of pYFP C1-LIG1, APTX-N3 and FTH1-N3, 1.6x105 cells of NCI-H295R1-TR AAAS knock-down, scrambled shRNA, AAAS over-expression and pcDNA4/TO empty were sub-cultured onto cover slips (Carl Zeiss, Jena, Germany) in 6-well culture dishes.	('LIG1', 'Gene', '3978', (39, 43))	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (83, 96))	('knock-down', 'Var', (102, 112))	('AAAS', 'Gene', (97, 101))	('APTX', 'Gene', (45, 49))	('expression', 'Species', '29278', (141, 151))	('AAAS', 'Gene', (131, 135))	('AAAS', 'Gene', '8086', (131, 135))	('APTX', 'Gene', '54840', (45, 49))	('AAAS', 'Gene', '8086', (97, 101))	('over-expression', 'PosReg', (136, 151))	('LIG1', 'Gene', (39, 43))
111244	25867024	The primer sequences and gene accession numbers used for the amplification of specific target sequences, which are beta-actin (ACTB), AAAS, CYP11A1, CYP17A1, CYP21A2, glutathione reductase (GSR), cytochrome P450 reductase (POR) and steroidogenic acute regulatory protein (StAR), are listed in the Supporting Information of this article (S1 Table).	('cytochrome P450', 'Enzyme', (196, 211))	('glutathione', 'Chemical', 'MESH:D005978', (167, 178))	('CYP17A1', 'Gene', (149, 156))	('POR', 'Gene', (223, 226))	('CYP17A1', 'Gene', '1586', (149, 156))	('CYP11A1', 'Var', (140, 147))	('AAAS', 'Gene', '8086', (134, 138))	('POR', 'Gene', '5447', (223, 226))	('steroid', 'Chemical', 'MESH:D013256', (232, 239))	('CYP21A2', 'Gene', '1589', (158, 165))	('AAAS', 'Gene', (134, 138))	('CYP21A2', 'Gene', (158, 165))
111283	25867024	In the doxycycline un-induced state the amount of repressor produced seemed not to be enough in order to block expression of shRNA or hAAAS cDNA leading to the partial AAAS knock-down and over-expression described here.	('hAAAS', 'Gene', (134, 139))	('AAAS', 'Gene', (168, 172))	('AAAS', 'Gene', '8086', (168, 172))	('hAAAS', 'Gene', '8086', (134, 139))	('shRNA', 'Gene', (125, 130))	('expression', 'Species', '29278', (111, 121))	('AAAS', 'Gene', (135, 139))	('AAAS', 'Gene', '8086', (135, 139))	('expression', 'Species', '29278', (193, 203))	('knock-down', 'Var', (173, 183))	('doxycycline', 'Chemical', 'MESH:D004318', (7, 18))	('over-expression', 'PosReg', (188, 203))
111284	25867024	To investigate the effects of AAAS knock-down and over-expression on steroidogenesis we assessed mRNA expression of key enzymes involved in steroidogenesis including CYP11A1, CYP11B1, CYP17A1, CYP21A2, 24-dehydrocholesterol reductase (DHCR24), cytochrome P450 oxidoreductase (POR) and StAR.	('expression', 'Species', '29278', (102, 112))	('AAAS', 'Gene', '8086', (30, 34))	('steroid', 'Chemical', 'MESH:D013256', (140, 147))	('expression', 'Species', '29278', (55, 65))	('CYP11B1', 'Var', (175, 182))	('POR', 'Gene', (276, 279))	('CYP21A2', 'Gene', (193, 200))	('CYP17A1', 'Gene', (184, 191))	('CYP21A2', 'Gene', '1589', (193, 200))	('CYP17A1', 'Gene', '1586', (184, 191))	('steroid', 'Chemical', 'MESH:D013256', (69, 76))	('POR', 'Gene', '5447', (276, 279))	('cytochrome P450 oxidoreductase', 'Gene', (244, 274))	('AAAS', 'Gene', (30, 34))	('CYP11A1', 'Var', (166, 173))	('cytochrome P450 oxidoreductase', 'Gene', '5447', (244, 274))
111286	25867024	With quantitative RT-PCR we revealed that AAAS knock-down induced a significant down-regulation of the genes coding for enzymes involved in the glucocorticoid and androgenic pathways, i.e.	('knock-down', 'Var', (47, 57))	('AAAS', 'Gene', '8086', (42, 46))	('AAAS', 'Gene', (42, 46))	('down-regulation', 'NegReg', (80, 95))
111288	25867024	Expression of StAR, CYP11A1, CYP11B1 and DHCR24 was not affected in these cells (S1 and S2 Figs).	('CYP11B1', 'Var', (29, 36))	('Expression', 'Species', '29278', (0, 10))	('DHCR24', 'Gene', (41, 47))
111297	25867024	To determine the role of ALADIN in redox homeostasis, we ascertained how AAAS knock-down and over-expression affect the ratio between GSH and GSSG.	('ratio', 'MPA', (120, 125))	('AAAS', 'Gene', (73, 77))	('GSH', 'Chemical', '-', (134, 137))	('AAAS', 'Gene', '8086', (73, 77))	('knock-down', 'Var', (78, 88))	('GSH', 'MPA', (134, 137))	('GSSG', 'Chemical', 'MESH:D019803', (142, 146))	('affect', 'Reg', (109, 115))	('expression', 'Species', '29278', (98, 108))	('over-expression', 'Var', (93, 108))
111305	25867024	The fully induced AAAS knock-down did not lead to a further decrease in cell viability after paraquat.	('knock-down', 'Var', (23, 33))	('AAAS', 'Gene', '8086', (18, 22))	('AAAS', 'Gene', (18, 22))	('cell', 'MPA', (72, 76))	('paraquat', 'Chemical', 'MESH:D010269', (93, 101))
111311	25867024	However, in cells with the partial AAAS knock-down and over-expression without induction of doxycycline GSH/GSSG ratios were already significantly down-regulated and no further impairment after doxycycline induction could be observed.	('knock-down', 'Var', (40, 50))	('GSH', 'Chemical', '-', (104, 107))	('down-regulated', 'NegReg', (147, 161))	('GSSG', 'Chemical', 'MESH:D019803', (108, 112))	('AAAS', 'Gene', (35, 39))	('GSH/GSSG', 'MPA', (104, 112))	('AAAS', 'Gene', '8086', (35, 39))	('doxycycline', 'Chemical', 'MESH:D004318', (194, 205))	('doxycycline', 'Chemical', 'MESH:D004318', (92, 103))	('over-expression', 'Var', (55, 70))	('expression', 'Species', '29278', (60, 70))
111318	25867024	Analysis of the gene expression level of glutathione reductase (GSR) demonstrated that in NCI-H295R1-TR AAAS knock-down cells there was no significant change in expression level compared to scrambled-shRNA control cells with or without doxycycline (n = 4) (Fig 4).	('knock-down', 'Var', (109, 119))	('expression', 'Species', '29278', (161, 171))	('AAAS', 'Gene', (104, 108))	('NCI-H295R1-TR', 'Gene', (90, 103))	('AAAS', 'Gene', '8086', (104, 108))	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (90, 103))	('expression', 'MPA', (161, 171))	('expression', 'Species', '29278', (21, 31))	('doxycycline', 'Chemical', 'MESH:D004318', (236, 247))	('glutathione', 'Chemical', 'MESH:D005978', (41, 52))
111319	25867024	In contrast GSR expression level in NCI-H295R1-TR AAAS over-expression cells without induction of doxycycline was significantly reduced compared to control cells carrying the empty vector used for the over-expression vector construct (n = 4) (Fig 4).	('expression', 'Species', '29278', (206, 216))	('reduced', 'NegReg', (128, 135))	('over-expression', 'PosReg', (55, 70))	('AAAS', 'Gene', (50, 54))	('AAAS', 'Gene', '8086', (50, 54))	('NCI-H295R1-TR', 'Var', (36, 49))	('doxycycline', 'Chemical', 'MESH:D004318', (98, 109))	('GSR expression level', 'MPA', (12, 32))	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (36, 49))	('expression', 'Species', '29278', (16, 26))	('expression', 'Species', '29278', (60, 70))
111321	25867024	Overall, we demonstrate that under exogenous oxidative stress using paraquat the redox response of the cell after AAAS knock-down in NCI-H295R1-TR is significantly impaired and leads to accumulation of hydrogen peroxide.	('knock-down', 'Var', (119, 129))	('redox response', 'MPA', (81, 95))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (202, 219))	('paraquat', 'Chemical', 'MESH:D010269', (68, 76))	('AAAS', 'Gene', (114, 118))	('NCI-H295R1-TR', 'Gene', (133, 146))	('AAAS', 'Gene', '8086', (114, 118))	('oxidative stress', 'Phenotype', 'HP:0025464', (45, 61))	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (133, 146))	('accumulation', 'PosReg', (186, 198))	('leads to', 'Reg', (177, 185))	('hydrogen peroxide', 'MPA', (202, 219))	('impaired', 'NegReg', (164, 172))
111328	25867024	The induced AAAS knock-down did not lead to a further decrease of nuclear import of aprataxin, DNA ligase 1 and ferritin heavy chain 1 compared to the native state without doxycycline induction (Fig 5).	('decrease', 'NegReg', (54, 62))	('doxycycline', 'Chemical', 'MESH:D004318', (172, 183))	('DNA ligase 1', 'Gene', (95, 107))	('knock-down', 'Var', (17, 27))	('aprataxin', 'Gene', (84, 93))	('AAAS', 'Gene', (12, 16))	('AAAS', 'Gene', '8086', (12, 16))	('aprataxin', 'Gene', '54840', (84, 93))	('DNA ligase 1', 'Gene', '3978', (95, 107))	('nuclear import', 'MPA', (66, 80))
111336	25867024	In this study we successfully demonstrate that AAAS knock-down firstly induces a significant down-regulation of genes coding for type II microsomal CYP enzymes involved in the glucocorticoid and androgen pathways of steroidogenesis, CYP17A1 and CYP21A2, and of the gene coding for their electron donor enzyme POR.	('down-regulation', 'NegReg', (93, 108))	('POR', 'Gene', (309, 312))	('steroid', 'Chemical', 'MESH:D013256', (216, 223))	('POR', 'Gene', '5447', (309, 312))	('knock-down', 'Var', (52, 62))	('CYP21A2', 'Gene', (245, 252))	('CYP17A1', 'Gene', '1586', (233, 240))	('AAAS', 'Gene', (47, 51))	('CYP21A2', 'Gene', '1589', (245, 252))	('CYP17A1', 'Gene', (233, 240))	('AAAS', 'Gene', '8086', (47, 51))	('donor', 'Species', '9606', (296, 301))
111341	25867024	Mitochondrial aldosterone synthase encoded by CYP11B2 exhibits 11ss-hydroxylase activity beside its activity to catalyse aldosterone from corticosterone by 18-hydroxylation.	('18-hydroxylation', 'MPA', (156, 172))	('11ss-hydroxylase activity', 'MPA', (63, 88))	('CYP11B2', 'Var', (46, 53))	('aldosterone', 'Chemical', 'MESH:D000450', (121, 132))	('aldosterone', 'Chemical', 'MESH:D000450', (14, 25))	('catalyse aldosterone from corticosterone', 'MPA', (112, 152))	('corticosterone', 'Chemical', 'MESH:D003345', (138, 152))	('activity', 'MPA', (100, 108))
111343	25867024	Furthermore it was shown that CYP11B2 exhibits some activity to hydroxylate 11-deoxycortisol.	('activity', 'MPA', (52, 60))	('hydroxylate 11-deoxycortisol', 'MPA', (64, 92))	('CYP11B2', 'Var', (30, 37))	('11-deoxycortisol', 'Chemical', 'MESH:D003350', (76, 92))
111348	25867024	Our findings has led us a step further to the exact mechanism how ALADIN deficiency affects steroidogenesis and elucidates more details about the pathogenicity in Triple A syndrome.	('steroid', 'Chemical', 'MESH:D013256', (92, 99))	('affects', 'Reg', (84, 91))	('Triple A syndrome', 'Disease', 'MESH:C536008', (163, 180))	('deficiency', 'Var', (73, 83))	('steroidogenesis', 'MPA', (92, 107))	('ALADIN', 'Gene', (66, 72))	('Triple A syndrome', 'Disease', (163, 180))
111353	25867024	Adenoviral transduction in primary bovine adrenocortical cells has been shown to lead to impairment of steroidogenesis and alteration of cell morphology.	('adrenocortical', 'Disease', (42, 56))	('steroidogenesis', 'MPA', (103, 118))	('Adenoviral transduction', 'Var', (0, 23))	('adrenocortical', 'Disease', 'MESH:D018268', (42, 56))	('cell morphology', 'CPA', (137, 152))	('bovine', 'Species', '9913', (35, 41))	('steroid', 'Chemical', 'MESH:D013256', (103, 110))	('alteration', 'Reg', (123, 133))	('impairment', 'NegReg', (89, 99))
111358	25867024	In our study we also ascertained that after AAAS knock-down in NCI-H295R1-TR cells not only cellular NADPH levels and GSH/GSSG levels under oxidative stress using paraquat are significantly decreased, but also that the concentration of cellular hydrogen peroxide (H2O2) is increased.	('H2O2', 'Chemical', 'MESH:D006861', (264, 268))	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (63, 76))	('concentration', 'MPA', (219, 232))	('oxidative stress', 'Phenotype', 'HP:0025464', (140, 156))	('GSH/GSSG levels', 'MPA', (118, 133))	('GSH', 'Chemical', '-', (118, 121))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (245, 262))	('cellular NADPH levels', 'MPA', (92, 113))	('knock-down', 'Var', (49, 59))	('increased', 'PosReg', (273, 282))	('decreased', 'NegReg', (190, 199))	('AAAS', 'Gene', (44, 48))	('AAAS', 'Gene', '8086', (44, 48))	('NADPH', 'Chemical', 'MESH:D009249', (101, 106))	('paraquat', 'Chemical', 'MESH:D010269', (163, 171))	('GSSG', 'Chemical', 'MESH:D019803', (122, 126))
111361	25867024	The nuclear import of aprataxin, DNA ligase 1 and ferritin heavy chain 1 was markedly decreased after ALADIN depletion.	('DNA ligase 1', 'Gene', (33, 45))	('depletion', 'Var', (109, 118))	('ferritin', 'Protein', (50, 58))	('decreased', 'NegReg', (86, 95))	('aprataxin', 'Gene', (22, 31))	('aprataxin', 'Gene', '54840', (22, 31))	('DNA ligase 1', 'Gene', '3978', (33, 45))	('nuclear import', 'MPA', (4, 18))
111365	25867024	Furthermore it has previously been shown that neurological disorders caused by mutations in the gene APTX coding for aprataxin are probably caused by accumulation of unrepaired DNA strand breaks resulting from abortive DNA ligation, generated especially by oxidation.	('neurological disorders', 'Disease', 'MESH:D009422', (46, 68))	('accumulation', 'PosReg', (150, 162))	('aprataxin', 'Gene', '54840', (117, 126))	('aprataxin', 'Gene', (117, 126))	('neurological disorders', 'Disease', (46, 68))	('caused by', 'Reg', (140, 149))	('APTX', 'Gene', '54840', (101, 105))	('APTX', 'Gene', (101, 105))	('mutations', 'Var', (79, 88))
111381	25867024	In addition, the import of ferritin heavy chain 1 was significantly decreased after AAAS over-expression.	('decreased', 'NegReg', (68, 77))	('over-expression', 'Var', (89, 104))	('AAAS', 'Gene', (84, 88))	('expression', 'Species', '29278', (94, 104))	('AAAS', 'Gene', '8086', (84, 88))	('import of', 'MPA', (17, 26))
111384	25867024	In this study that we demonstrate that AAAS over-expression leads to a significant accumulation of ALADIN in the cytoplasm; most likely due to a lack of binding sites of ALADIN at the pore complexes.	('over-expression', 'Var', (44, 59))	('expression', 'Species', '29278', (49, 59))	('lack', 'NegReg', (145, 149))	('accumulation', 'PosReg', (83, 95))	('ALADIN', 'Protein', (99, 105))	('binding sites', 'Interaction', (153, 166))	('AAAS', 'Gene', (39, 43))	('AAAS', 'Gene', '8086', (39, 43))
111391	25867024	Our findings suggest that alteration in adrenal steroidogenesis in humans through POR is caused by a defective redox potential and homeostasis due to ALADIN deficiency.	('homeostasis', 'MPA', (131, 142))	('humans', 'Species', '9606', (67, 73))	('deficiency', 'Var', (157, 167))	('POR', 'Gene', '5447', (82, 85))	('redox potential', 'MPA', (111, 126))	('alteration', 'Reg', (26, 36))	('steroid', 'Chemical', 'MESH:D013256', (48, 55))	('POR', 'Gene', (82, 85))	('defective', 'NegReg', (101, 110))	('adrenal steroidogenesis', 'MPA', (40, 63))
111622	33542904	Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer.	('Aberrant expression', 'Var', (0, 19))	('SGK1', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('human', 'Species', '9606', (94, 99))	('correlated', 'Reg', (78, 88))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
111635	33542904	SGK1 is identified and characterized as a tumor-promoting gene, and SGK1 dysregulation has been observed in several types of malignancies, including breast cancer, gastric cancer, lung cancer, and prostate cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('tumor', 'Disease', (42, 47))	('SGK1', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('gastric cancer', 'Disease', (164, 178))	('lung cancer', 'Disease', (180, 191))	('dysregulation', 'Var', (73, 86))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('breast cancer', 'Disease', (149, 162))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('observed', 'Reg', (96, 104))	('malignancies', 'Disease', 'MESH:D009369', (125, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('prostate cancer', 'Disease', 'MESH:D011471', (197, 212))	('prostate cancer', 'Phenotype', 'HP:0012125', (197, 212))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('malignancies', 'Disease', (125, 137))	('prostate cancer', 'Disease', (197, 212))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('SGK1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))
111652	33542904	SGK1 is often upregulated in both acute and chronic myelogenous leukemia, such as in myeloma, B-cell lymphoma, and Hodgkin lymphoma, and has been demonstrated to be significantly correlated with enhancer-associated rearrangements and highly recurrent mutations of the SGK1 gene.	('myeloma', 'Disease', (85, 92))	('rat', 'Species', '10116', (153, 156))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (94, 109))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (52, 72))	('upregulated', 'PosReg', (14, 25))	('SGK1', 'Gene', (268, 272))	('rearrangements', 'Var', (215, 229))	('B-cell lymphoma', 'Disease', (94, 109))	('acute and chronic myelogenous leukemia', 'Phenotype', 'HP:0004808', (34, 72))	('acute', 'Disease', (34, 39))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (52, 72))	('enhancer-associated', 'PosReg', (195, 214))	('Hodgkin lymphoma', 'Disease', (115, 131))	('myeloma', 'Disease', 'MESH:D009101', (85, 92))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (44, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (101, 109))	('mutations', 'Var', (251, 260))	('myelogenous leukemia', 'Disease', (52, 72))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (94, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (123, 131))	('SGK1', 'Gene', (0, 4))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (115, 131))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (115, 131))
111653	33542904	As stated above, aberrant expression of SGK1 is closely related to the clinical characteristics of human cancer.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('aberrant expression', 'Var', (17, 36))	('human', 'Species', '9606', (99, 104))	('SGK1', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('related', 'Reg', (56, 63))
111654	33542904	For instance, a high copy number of the SGK1 gene was positively correlated with short-interval recurrence and metastasis in high-grade Mullerian adenosarcoma.	('high copy number', 'Var', (16, 32))	('metastasis', 'CPA', (111, 121))	('adenosarcoma', 'Disease', (146, 158))	('adenosarcoma', 'Disease', 'MESH:D018195', (146, 158))	('SGK1', 'Gene', (40, 44))	('correlated', 'Reg', (65, 75))
111667	33542904	demonstrated that high SGK1 expression had strong prognostic value for reduced overall survival (OS) in NSCLC patients.	('SGK1', 'Gene', (23, 27))	('NSCLC', 'Disease', (104, 109))	('expression', 'MPA', (28, 38))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('reduced', 'NegReg', (71, 78))	('high', 'Var', (18, 22))	('rat', 'Species', '10116', (7, 10))	('patients', 'Species', '9606', (110, 118))	('overall survival', 'MPA', (79, 95))
111671	33542904	Moreover, increased median overall survival associated with increased SGK1 copy number segments may be a reflection of better tumor oxygenation.	('copy number segments', 'Var', (75, 95))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('increased', 'PosReg', (10, 19))	('SGK1', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('overall survival', 'MPA', (27, 43))	('increased', 'PosReg', (60, 69))	('tumor', 'Disease', (126, 131))
111684	33542904	demonstrated that high SGK1 expression had strong prognostic value for reduced overall survival in NSCLC patients that received chemotherapy.	('SGK1', 'Gene', (23, 27))	('patients', 'Species', '9606', (105, 113))	('expression', 'MPA', (28, 38))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))	('reduced', 'NegReg', (71, 78))	('high', 'Var', (18, 22))	('rat', 'Species', '10116', (7, 10))	('NSCLC', 'Disease', (99, 104))	('overall survival', 'MPA', (79, 95))
111689	33542904	Elevated SGK1 is intimately linked to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('linked', 'Reg', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('SGK1', 'Gene', (9, 13))	('Elevated', 'Var', (0, 8))
111695	33542904	In addition, similar results were obtained in another report, showing that EMD638683, a selective inhibitor of SGK1, significantly decreased the number of colonic tumors following chemical carcinogenesis in vivo .	('colonic tumors', 'Disease', (155, 169))	('EMD638683', 'Var', (75, 84))	('EMD638683', 'Chemical', 'MESH:C569030', (75, 84))	('decreased', 'NegReg', (131, 140))	('carcinogenesis', 'Disease', 'MESH:D063646', (189, 203))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('carcinogenesis', 'Disease', (189, 203))	('SGK1', 'Gene', (111, 115))	('colonic tumor', 'Phenotype', 'HP:0100273', (155, 168))	('colonic tumors', 'Disease', 'MESH:D003110', (155, 169))
111707	33542904	SGK1 expression also promotes the development of intestinal tumors in adenomatous polyposis coli (APC)-deficient mice, an effect at least partially due to enhanced beta-catenin protein abundance.	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (70, 96))	('adenomatous polyposis coli (APC)-deficient', 'Disease', 'MESH:D011125', (70, 112))	('mice', 'Species', '10090', (113, 117))	('expression', 'Var', (5, 15))	('promotes', 'PosReg', (21, 29))	('SGK1', 'Gene', (0, 4))	('enhanced', 'PosReg', (155, 163))	('intestinal tumors', 'Disease', (49, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('beta-catenin protein', 'Protein', (164, 184))	('intestinal tumors', 'Disease', 'MESH:D007414', (49, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
111708	33542904	In vitro experiments also revealed that SGK1 overexpression enhanced colonic tumor cell proliferation activity and inhibited cell apoptosis induced by 5-fluorouracil (5-FU), while SGK1 shRNA and inhibitors showed inverse effects.	('5-FU', 'Chemical', 'MESH:D005472', (167, 171))	('overexpression', 'Var', (45, 59))	('rat', 'Species', '10116', (95, 98))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (151, 165))	('colonic tumor', 'Disease', (69, 82))	('colonic tumor', 'Phenotype', 'HP:0100273', (69, 82))	('colonic tumor', 'Disease', 'MESH:D003110', (69, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cell apoptosis', 'CPA', (125, 139))	('inhibited', 'NegReg', (115, 124))	('enhanced', 'PosReg', (60, 68))	('SGK1', 'Gene', (40, 44))
111710	33542904	In glioblastoma, the SGK1 kinase inhibitor SI113 drastically reduced cell viability and clonogenic capabilities in vitro and inhibited tumor growth in vivo .	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SGK1', 'Gene', (21, 25))	('tumor', 'Disease', (135, 140))	('cell viability', 'CPA', (69, 83))	('glioblastoma', 'Disease', (3, 15))	('SI113', 'Chemical', '-', (43, 48))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('clonogenic capabilities', 'CPA', (88, 111))	('inhibited', 'NegReg', (125, 134))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('reduced', 'NegReg', (61, 68))	('SI113', 'Var', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
111711	33542904	Further research indicated that SI113 treatment caused endoplasmic reticulum stress and apoptosis in endometrial cancer cells, evidenced by cleavage of the apoptotic markers poly-ADP-ribose polymerase (PARP) and Caspase-9.	('apoptosis', 'CPA', (88, 97))	('PARP', 'Gene', (202, 206))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Caspase-9', 'Gene', (212, 221))	('poly-ADP-ribose polymerase', 'Gene', '142', (174, 200))	('SI113', 'Chemical', '-', (32, 37))	('endometrial cancer', 'Disease', 'MESH:D016889', (101, 119))	('stress', 'Disease', (77, 83))	('endoplasmic', 'MPA', (55, 66))	('endometrial cancer', 'Disease', (101, 119))	('endometrial cancer', 'Phenotype', 'HP:0012114', (101, 119))	('poly-ADP-ribose polymerase', 'Gene', (174, 200))	('PARP', 'Gene', '142', (202, 206))	('Caspase-9', 'Gene', '842', (212, 221))	('cleavage', 'NegReg', (140, 148))	('SI113', 'Var', (32, 37))	('stress', 'Disease', 'MESH:D000079225', (77, 83))
111713	33542904	Recently, we demonstrated that ectopic expression of SGK1 significantly increased cell viability in prostate cancer cells.	('SGK1', 'Gene', (53, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('increased', 'PosReg', (72, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('cell viability in', 'CPA', (82, 99))	('prostate cancer', 'Disease', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ectopic expression', 'Var', (31, 49))	('rat', 'Species', '10116', (20, 23))
111714	33542904	Conversely, SGK1 inhibition mediated by either GSK650394 or SGK1 shRNA induced caspase-dependent apoptosis, evidenced by cleavage of the apoptosis markers caspase-3, 8, and 9 and PARP and by Bax upregulation and Bcl-2 downregulation.	('PARP', 'Gene', '142', (179, 183))	('GSK650394', 'Var', (47, 56))	('caspase', 'Gene', '842', (79, 86))	('Bcl-2', 'Gene', '596', (212, 217))	('SGK1', 'Gene', (60, 64))	('Bax', 'Gene', (191, 194))	('PARP', 'Gene', (179, 183))	('caspase', 'Gene', '842', (155, 162))	('cleavage', 'MPA', (121, 129))	('Bax', 'Gene', '581', (191, 194))	('SGK1', 'Gene', (12, 16))	('downregulation', 'NegReg', (218, 232))	('apoptosis', 'CPA', (137, 146))	('caspase-3', 'Gene', '836', (155, 164))	('upregulation', 'PosReg', (195, 207))	('caspase', 'Gene', (79, 86))	('caspase-3', 'Gene', (155, 164))	('GSK650394', 'Chemical', 'MESH:C532254', (47, 56))	('caspase', 'Gene', (155, 162))	('inhibition', 'NegReg', (17, 27))	('Bcl-2', 'Gene', (212, 217))
111719	33542904	In addition, SI113-mediated cell cycle arrest was widely confirmed in several cancer types, including colon cancer, hepatocarcinoma and glioblastoma.	('hepatocarcinoma and glioblastoma', 'Disease', 'MESH:D005909', (116, 148))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('arrest', 'Disease', 'MESH:D006323', (39, 45))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('colon cancer', 'Disease', (102, 114))	('SI113-mediated', 'Var', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('SI113', 'Chemical', '-', (13, 18))	('arrest', 'Disease', (39, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (28, 45))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
111720	33542904	In line with these reports, we showed that either SGK1 silencing or GSK650394, the first reported specific inhibitor of SGK1, dramatically caused G2/M arrest and activated apoptosis in prostate cancer.	('arrest', 'Disease', 'MESH:D006323', (151, 157))	('silencing', 'NegReg', (55, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (185, 200))	('arrest', 'Disease', (151, 157))	('prostate cancer', 'Phenotype', 'HP:0012125', (185, 200))	('caused', 'Reg', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('GSK650394', 'Var', (68, 77))	('prostate cancer', 'Disease', (185, 200))	('apoptosis', 'CPA', (172, 181))	('GSK650394', 'Chemical', 'MESH:C532254', (68, 77))	('activated', 'PosReg', (162, 171))	('SGK1', 'Gene', (50, 54))
111721	33542904	Mechanistically, SGK1 inhibition upregulated the expression of p21, which is also known as a cyclin-dependent kinase (CDK) inhibitor that can inhibit the formation of the cyclin-CDK complex.	('inhibition', 'Var', (22, 32))	('upregulated', 'PosReg', (33, 44))	('cyclin', 'Gene', (93, 99))	('inhibit', 'NegReg', (142, 149))	('CDK', 'Gene', (118, 121))	('cyclin', 'Gene', '5111', (171, 177))	('formation', 'MPA', (154, 163))	('p21', 'Gene', (63, 66))	('SGK1', 'Gene', (17, 21))	('p21', 'Gene', '644914', (63, 66))	('CDK', 'Gene', '1021', (118, 121))	('expression', 'MPA', (49, 59))	('cyclin', 'Gene', (171, 177))	('CDK', 'Gene', (178, 181))	('CDK', 'Gene', '1021', (178, 181))	('cyclin', 'Gene', '5111', (93, 99))
111723	33542904	Aberrant SGK1 expression has been reported in metastatic cancers, which universally display an aggressive pathophysiology.	('reported', 'Reg', (34, 42))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('SGK1', 'Gene', (9, 13))
111725	33542904	Overexpression of SGK1 significantly promotes cell migration and invasion in various cancers, including breast cancer, lung cancer, colon cancer, glioma, hepatoma, OSCC, prostate cancer, and rhabdomyosarcoma.	('lung cancer', 'Disease', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('prostate cancer', 'Disease', 'MESH:D011471', (170, 185))	('breast cancer', 'Disease', (104, 117))	('Overexpression', 'Var', (0, 14))	('prostate cancer', 'Phenotype', 'HP:0012125', (170, 185))	('hepatoma', 'Disease', 'MESH:D006528', (154, 162))	('promotes', 'PosReg', (37, 45))	('rhabdomyosarcoma', 'Disease', (191, 207))	('prostate cancer', 'Disease', (170, 185))	('colon cancer', 'Disease', (132, 144))	('glioma', 'Disease', (146, 152))	('rat', 'Species', '10116', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('invasion', 'CPA', (65, 73))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (191, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('SGK1', 'Gene', (18, 22))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (191, 207))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('OSCC', 'Disease', (164, 168))	('hepatoma', 'Disease', (154, 162))	('colon cancer', 'Phenotype', 'HP:0003003', (132, 144))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cell migration', 'CPA', (46, 60))	('colon cancer', 'Disease', 'MESH:D015179', (132, 144))
111726	33542904	In breast cancer, SGK inhibition significantly impaired cell migration by downregulating N-myc downregulated gene 1 (NDRG1).	('inhibition', 'Var', (22, 32))	('NDRG1', 'Gene', (117, 122))	('SGK', 'Gene', '6446', (18, 21))	('N-myc', 'Gene', (89, 94))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cell migration', 'CPA', (56, 70))	('breast cancer', 'Disease', (3, 16))	('NDRG1', 'Gene', '10397', (117, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('rat', 'Species', '10116', (64, 67))	('impaired', 'NegReg', (47, 55))	('downregulating', 'NegReg', (74, 88))	('N-myc', 'Gene', '4613', (89, 94))	('SGK', 'Gene', (18, 21))
111729	33542904	reported that SGK1 was essential for osteoclastogenesis and promotes breast cancer bone metastasis by regulating the Ca2+ release-activated Ca2+ channel Orai1; inhibition of SGK1 resulted in a significant reduction in bone metastasis.	('Orai1', 'Gene', (153, 158))	('Ca2+', 'Chemical', 'MESH:D000069285', (140, 144))	('inhibition', 'Var', (160, 170))	('bone metastasis', 'CPA', (218, 233))	('SGK1', 'Gene', (174, 178))	('reduction', 'NegReg', (205, 214))	('Ca2+', 'Chemical', 'MESH:D000069285', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('osteoclastogenesis and promotes breast cancer bone metastasis', 'Disease', 'MESH:D001943', (37, 98))	('Orai1', 'Gene', '109305', (153, 158))
111730	33542904	In colorectal cancer, transfection with a constitutively active SGK1 mutant significantly enhanced cell motility and cell migration via vinculin dephosphorylation.	('SGK1', 'Gene', (64, 68))	('rat', 'Species', '10116', (125, 128))	('mutant', 'Var', (69, 75))	('vinculin', 'Gene', (136, 144))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cell migration', 'CPA', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('dephosphorylation', 'MPA', (145, 162))	('colorectal cancer', 'Disease', (3, 20))	('enhanced', 'PosReg', (90, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('vinculin', 'Gene', '7414', (136, 144))
111732	33542904	Overexpression of SGK1 in colorectal cancer cell lines resulted differentiation, decreased migration activity, and inhibition of metastasis in an orthotopic xenograft model.	('decreased', 'NegReg', (81, 90))	('inhibition', 'NegReg', (115, 125))	('rat', 'Species', '10116', (94, 97))	('colorectal cancer', 'Disease', (26, 43))	('colorectal cancer', 'Disease', 'MESH:D015179', (26, 43))	('SGK1', 'Gene', (18, 22))	('metastasis', 'CPA', (129, 139))	('Overexpression', 'Var', (0, 14))	('migration activity', 'CPA', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (26, 43))
111735	33542904	Their further investigation suggested that SGK1 promotes phosphorylation of GSK3 beta, and GSK3 beta phosphorylation induces beta catenin upregulation, which facilitates to upregulate the target genes downstream of beta-catenin/TCF signaling, including genes involved in promoting tumor invasion and metastasis.	('upregulation', 'PosReg', (138, 150))	('GSK3 beta', 'Gene', '2931', (91, 100))	('upregulate', 'PosReg', (173, 183))	('GSK3 beta', 'Gene', (91, 100))	('SGK1', 'Gene', (43, 47))	('metastasis', 'CPA', (300, 310))	('phosphorylation', 'Var', (101, 116))	('TCF', 'Gene', (228, 231))	('TCF', 'Gene', '3172', (228, 231))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('promotes', 'PosReg', (48, 56))	('GSK3 beta', 'Gene', '2931', (76, 85))	('GSK3 beta', 'Gene', (76, 85))	('beta catenin', 'Gene', '1499', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('phosphorylation', 'MPA', (57, 72))	('beta catenin', 'Gene', (125, 137))	('tumor', 'Disease', (281, 286))
111740	33542904	Several inhibitors of SGK1 have shown great potential in inhibiting tumor metastasis.	('inhibiting', 'NegReg', (57, 67))	('tumor metastasis', 'Disease', 'MESH:D009362', (68, 84))	('tumor metastasis', 'Disease', (68, 84))	('SGK1', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('inhibitors', 'Var', (8, 18))
111743	33542904	In addition, when exposed to SI113, these cancer cells showed a remarkable subversion of the cytoskeletal architecture, characterized by F-actin destabilization, phospho-FAK delocalization, and tubulin depolymerization.	('F-actin', 'MPA', (137, 144))	('FAK', 'Gene', (170, 173))	('FAK', 'Gene', '5747', (170, 173))	('cytoskeletal architecture', 'CPA', (93, 118))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tubulin', 'CPA', (194, 201))	('destabilization', 'NegReg', (145, 160))	('depolymerization', 'NegReg', (202, 218))	('SI113', 'Chemical', '-', (29, 34))	('subversion', 'NegReg', (75, 85))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('SI113', 'Var', (29, 34))
111744	33542904	In addition, administration of EMD638683 - an inhibitor specific for SGK1 - decreased the viability of RD and RH30 cells and enhanced the effects of the cytotoxic drug doxorubicin.	('effects of the cytotoxic drug doxorubicin', 'MPA', (138, 179))	('EMD638683', 'Chemical', 'MESH:C569030', (31, 40))	('decreased', 'NegReg', (76, 85))	('doxorubicin', 'Chemical', 'MESH:D004317', (168, 179))	('viability', 'CPA', (90, 99))	('SGK1', 'Gene', (69, 73))	('rat', 'Species', '10116', (21, 24))	('enhanced', 'PosReg', (125, 133))	('EMD638683 -', 'Var', (31, 42))
111745	33542904	We obtained similar results in PCa cells treated with GSK650394, the first developed inhibitor of SGK.	('SGK', 'Gene', '6446', (98, 101))	('SGK', 'Gene', (98, 101))	('GSK650394', 'Chemical', 'MESH:C532254', (54, 63))	('GSK650394', 'Var', (54, 63))
111746	33542904	Recently, a new SGK1 inhibitor analog was developed, the GSK650394 analog QGY-5-114-A, which significantly inhibited CRC cell migration in vitro .	('rat', 'Species', '10116', (129, 132))	('GSK650394', 'Chemical', 'MESH:C532254', (57, 66))	('CRC cell migration', 'CPA', (117, 135))	('QGY-5-114-A', 'Chemical', '-', (74, 85))	('GSK650394', 'Var', (57, 66))	('inhibited', 'NegReg', (107, 116))
111754	33542904	A similar effect was observed in endometrial cancer after treatment with SI113, revealed by an increase in the markers LC3B-II and beclin I, detected via both immunofluorescence and western blotting analysis.	('LC3', 'Gene', (119, 122))	('endometrial cancer', 'Phenotype', 'HP:0012114', (33, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('SI113', 'Chemical', '-', (73, 78))	('increase', 'PosReg', (95, 103))	('endometrial cancer', 'Disease', (33, 51))	('SI113', 'Var', (73, 78))	('beclin', 'Protein', (131, 137))	('LC3', 'Gene', '84557', (119, 122))	('endometrial cancer', 'Disease', 'MESH:D016889', (33, 51))
111756	33542904	We demonstrated that SGK1 inhibition, mediated by either GSK650394 or SGK1 shRNA, significantly induced cytotoxic autophagy.	('induced', 'PosReg', (96, 103))	('cytotoxic autophagy', 'CPA', (104, 123))	('SGK1', 'Gene', (21, 25))	('GSK650394', 'Chemical', 'MESH:C532254', (57, 66))	('inhibition', 'NegReg', (26, 36))	('GSK650394', 'Var', (57, 66))	('SGK1', 'Gene', (70, 74))	('rat', 'Species', '10116', (10, 13))
111778	33542904	Moreover, SGK1 depletion prevented the dexamethasone-induced increase in SGK1 expression and the inhibitory effects of dexamethasone on paclitaxel-induced SEK1-JNK signaling and apoptosis in MDA-MB-231 breast cancer cells.	('depletion', 'Var', (15, 24))	('SEK1', 'Gene', (155, 159))	('dexamethasone', 'Chemical', 'MESH:D003907', (39, 52))	('expression', 'MPA', (78, 88))	('dexamethasone', 'Chemical', 'MESH:D003907', (119, 132))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('JNK', 'Gene', (160, 163))	('prevented', 'NegReg', (25, 34))	('SEK1', 'Gene', '6416', (155, 159))	('breast cancer', 'Disease', (202, 215))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (191, 201))	('SGK1', 'Gene', (73, 77))	('apoptosis', 'CPA', (178, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('JNK', 'Gene', '5599', (160, 163))	('paclitaxel', 'Chemical', 'MESH:D017239', (136, 146))	('increase', 'PosReg', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
111780	33542904	However, in a preclinical model of ovarian cancer, the SGK1 inhibitor SI113 counteracted the development of paclitaxel resistance and restored drug sensitivity.	('restored', 'PosReg', (134, 142))	('SI113', 'Chemical', '-', (70, 75))	('paclitaxel', 'Chemical', 'MESH:D017239', (108, 118))	('SI113', 'Var', (70, 75))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (35, 49))	('drug sensitivity', 'Phenotype', 'HP:0020174', (143, 159))	('SGK1', 'Gene', (55, 59))	('inhibitor SI113', 'Var', (60, 75))	('drug sensitivity', 'MPA', (143, 159))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('ovarian cancer', 'Disease', (35, 49))
111783	33542904	However, SI113-mediated SGK1 inhibition appears to be effective in inducing cell death in RKO cells and potentiating paclitaxel sensitivity, indicating that this new molecule could be efficiently employed, alone or in combination with paclitaxel, in colon cancer chemotherapy.	('paclitaxel', 'Chemical', 'MESH:D017239', (117, 127))	('paclitaxel sensitivity', 'MPA', (117, 139))	('colon cancer', 'Disease', 'MESH:D015179', (250, 262))	('SI113-mediated', 'Var', (9, 23))	('inhibition', 'NegReg', (29, 39))	('colon cancer', 'Disease', (250, 262))	('SI113', 'Chemical', '-', (9, 14))	('SGK1', 'Gene', (24, 28))	('paclitaxel', 'Chemical', 'MESH:D017239', (235, 245))	('cell death', 'CPA', (76, 86))	('RKO', 'CellLine', 'CVCL:0504', (90, 93))	('inducing', 'Reg', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('potentiating', 'PosReg', (104, 116))	('colon cancer', 'Phenotype', 'HP:0003003', (250, 262))
111784	33542904	Moreover, knockdown of SGK1 significantly decreased doxorubicin resistance in colorectal cancer.	('SGK1', 'Gene', (23, 27))	('decreased', 'NegReg', (42, 51))	('doxorubicin resistance', 'Gene', (52, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('doxorubicin resistance', 'Gene', '5243', (52, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('knockdown', 'Var', (10, 19))	('colorectal cancer', 'Disease', (78, 95))
111788	33542904	reported that pharmacological inhibition of SGK1 with EMD638683 (50 microM) synergized with low doses of radiation (3 GY) caused mitochondrial depolarization and late apoptosis (necro-apoptosis) in a colon carcinoma (CaCo-2) cell line, with a relative increase in caspase-3, indicating that EMD638683 promotes radiation-induced suicidal death of colon tumor cells.	('CaCo-2', 'CellLine', 'CVCL:0025', (217, 223))	('EMD638683', 'Var', (291, 300))	('SGK1', 'Gene', (44, 48))	('colon carcinoma', 'Disease', 'MESH:D003110', (200, 215))	('EMD638683', 'Chemical', 'MESH:C569030', (54, 63))	('mitochondrial', 'CPA', (129, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('suicidal death', 'Phenotype', 'HP:0031589', (328, 342))	('colon tumor', 'Phenotype', 'HP:0100273', (346, 357))	('depolarization', 'NegReg', (143, 157))	('EMD638683', 'Chemical', 'MESH:C569030', (291, 300))	('colon tumor', 'Disease', 'MESH:D003110', (346, 357))	('colon tumor', 'Disease', (346, 357))	('inhibition', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('caspase-3', 'Gene', '836', (264, 273))	('colon carcinoma', 'Disease', (200, 215))	('EMD638683', 'Gene', (54, 63))	('caspase-3', 'Gene', (264, 273))
111789	33542904	SKG1 inhibition also decreases long-term survival and potently sensitized the parental and anoxia-tolerant NCI-H460 cells under normoxia and anoxia-tolerant lung cancer cells under severe hypoxia to the cytotoxic effects of ionizing radiation.	('SKG1', 'Chemical', '-', (0, 4))	('inhibition', 'Var', (5, 15))	('decreases', 'NegReg', (21, 30))	('hypoxia', 'Disease', (188, 195))	('hypoxia', 'Disease', 'MESH:D000860', (188, 195))	('SKG1', 'Gene', (0, 4))	('sensitized', 'Reg', (63, 73))	('anoxia-tolerant lung cancer', 'Disease', (141, 168))	('long-term survival', 'CPA', (31, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('NCI-H460', 'CellLine', 'CVCL:0459', (107, 115))	('anoxia-tolerant lung cancer', 'Disease', 'MESH:D008175', (141, 168))
111791	33542904	Consistent with knockdown and overexpression cellular models for SGK1, SI113 potentiated and synergized with radiotherapy in killing liver tumor cells without toxicity, which was confirmed by a short-term in vivo toxicity test.	('toxicity', 'Disease', 'MESH:D064420', (213, 221))	('toxicity', 'Disease', (213, 221))	('potentiated', 'PosReg', (77, 88))	('liver tumor', 'Disease', (133, 144))	('SGK1', 'Gene', (65, 69))	('toxicity', 'Disease', (159, 167))	('liver tumor', 'Disease', 'MESH:D008113', (133, 144))	('SI113', 'Chemical', '-', (71, 76))	('toxicity', 'Disease', 'MESH:D064420', (159, 167))	('liver tumor', 'Phenotype', 'HP:0002896', (133, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('SI113', 'Var', (71, 76))	('killing', 'CPA', (125, 132))
111792	33542904	They further showed that SGK1 was overexpressed in highly malignant gliomas and that SI113 dramatically potentiated the effects of radiotherapy, modulated the response to oxidative stress, and induced cytotoxic autophagy in glioblastoma multiforme cells.	('malignant gliomas', 'Disease', (58, 75))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (224, 247))	('induced', 'Reg', (193, 200))	('SI113', 'Chemical', '-', (85, 90))	('overexpressed', 'PosReg', (34, 47))	('stress', 'Disease', (181, 187))	('modulated', 'Reg', (145, 154))	('potentiated', 'PosReg', (104, 115))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('SI113', 'Var', (85, 90))	('cytotoxic autophagy', 'CPA', (201, 220))	('oxidative stress', 'Phenotype', 'HP:0025464', (171, 187))	('SGK1', 'Gene', (25, 29))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (224, 236))	('effects', 'MPA', (120, 127))	('malignant gliomas', 'Disease', 'MESH:D005910', (58, 75))	('glioblastoma multiforme', 'Disease', (224, 247))	('stress', 'Disease', 'MESH:D000079225', (181, 187))
111793	33542904	observed a CD44+ cancer stem cell (CSC) population increase in radioresistant LNCaP (LNCaPR18) and C4-2 (C4-2R26) PCa cells compared with respective parental cells.	('increase', 'PosReg', (51, 59))	('C4-2', 'Gene', '51654', (99, 103))	('radioresistant', 'CPA', (63, 77))	('C4-2', 'Gene', (99, 103))	('CD44+', 'Var', (11, 16))	('LNCaP', 'CellLine', 'CVCL:0395', (78, 83))	('LNCaP', 'CellLine', 'CVCL:0395', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('C4-2', 'Gene', '51654', (105, 109))	('C4-2', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
111821	33542904	showed that PDK1-SGK1 signaling sustained AKT-independent mTORC1 activation and confers resistance to PI3Kalpha inhibition, indicating that either PDK1 or SGK1 blockade prevents mTORC1 activation and restores the antitumoral effects of PI3Kalpha inhibition in resistant cells.	('PDK1', 'Gene', '5163', (12, 16))	('mTORC1', 'Gene', (178, 184))	('mTORC1', 'Gene', (58, 64))	('AKT', 'Gene', '207', (42, 45))	('PI3Kalpha', 'Gene', (102, 111))	('tumor', 'Disease', (217, 222))	('mTORC1', 'Gene', '382056', (58, 64))	('mTORC1', 'Gene', '382056', (178, 184))	('PDK1', 'Gene', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('SGK1', 'Gene', (155, 159))	('PI3Kalpha', 'Gene', (236, 245))	('blockade', 'Var', (160, 168))	('PDK1', 'Gene', (12, 16))	('activation', 'MPA', (185, 195))	('restores', 'PosReg', (200, 208))	('PI3Kalpha', 'Gene', '5290', (102, 111))	('prevents', 'NegReg', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('AKT', 'Gene', (42, 45))	('PDK1', 'Gene', '5163', (147, 151))	('PI3Kalpha', 'Gene', '5290', (236, 245))
111827	33542904	SGK1 was also reported as a direct target of miR-576-3p, and miR-576-3p significantly inhibited lung adenocarcinoma migration and invasion by binding to the 3' untranslated region (3'-UTR) of SGK1.	('SGK1', 'Gene', (192, 196))	('invasion', 'CPA', (130, 138))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (96, 115))	('lung adenocarcinoma migration', 'Disease', (96, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('binding', 'Interaction', (142, 149))	('lung adenocarcinoma migration', 'Disease', 'MESH:D000077192', (96, 125))	('inhibited', 'NegReg', (86, 95))	('miR-576-3p', 'Var', (61, 71))
111828	33542904	In nonsmall-cell lung cancer, C-containing genotypes of MIAT rs1061451 were found to be protective factors in NSCLC, and myocardial infarction associated transcript (MIAT), which may act as a ceRNA via miR-133a-5p, modulated the SGK1 expression level.	('MIAT', 'Gene', (56, 60))	('rs1061451', 'Mutation', 'rs1061451', (61, 70))	('MIAT', 'Gene', (166, 170))	('nonsmall-cell lung cancer', 'Disease', (3, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('NSCLC', 'Disease', (110, 115))	('myocardial infarction', 'Disease', (121, 142))	('modulated', 'Reg', (215, 224))	('rs1061451', 'Var', (61, 70))	('myocardial infarction', 'Disease', 'MESH:D009203', (121, 142))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('expression level', 'MPA', (234, 250))	('MIAT', 'Gene', '440823', (56, 60))	('myocardial infarction', 'Phenotype', 'HP:0001658', (121, 142))	('MIAT', 'Gene', '440823', (166, 170))	('SGK1', 'Gene', (229, 233))	('nonsmall-cell lung cancer', 'Disease', 'MESH:D002289', (3, 28))
111829	33542904	A similar observation was reported in CRC; lncRNA X-inactive specific transcript (XIST) was shown to positively regulate SGK1 expression by interacting with miR-124 in doxorubicin-resistant CRC cells.	('XIST', 'Gene', '7503', (82, 86))	('expression', 'MPA', (126, 136))	('X-inactive specific transcript', 'Gene', (50, 80))	('miR-124', 'Var', (157, 164))	('XIST', 'Gene', (82, 86))	('X-inactive specific transcript', 'Gene', '7503', (50, 80))	('doxorubicin', 'Chemical', 'MESH:D004317', (168, 179))	('interacting', 'Interaction', (140, 151))	('SGK1', 'Gene', (121, 125))
111833	33542904	In addition, expression of Lnc-SGK1 can induce TH2 and TH17 cells and reduce TH1 cell differentiation by enhancing SGK1 transcription through a cis regulatory mode.	('TH1', 'Gene', '51497', (77, 80))	('enhancing', 'PosReg', (105, 114))	('transcription', 'MPA', (120, 133))	('TH1', 'Gene', (77, 80))	('expression', 'Var', (13, 23))	('TH1', 'Gene', '51497', (55, 58))	('reduce', 'NegReg', (70, 76))	('Lnc-SGK1', 'Gene', (27, 35))	('TH1', 'Gene', (55, 58))	('SGK1', 'Gene', (115, 119))	('induce', 'PosReg', (40, 46))
111835	33542904	Subsequently, they verified that HOTTIP may be an oncogene and that knockdown of HOTTIP inhibited CRC cell proliferation and migration and induced apoptosis by targeting SGK1.	('induced', 'Reg', (139, 146))	('inhibited', 'NegReg', (88, 97))	('rat', 'Species', '10116', (114, 117))	('HOTTIP', 'Gene', '100316868', (33, 39))	('rat', 'Species', '10116', (128, 131))	('HOTTIP', 'Gene', '100316868', (81, 87))	('knockdown', 'Var', (68, 77))	('apoptosis', 'CPA', (147, 156))	('HOTTIP', 'Gene', (33, 39))	('targeting', 'Reg', (160, 169))	('CRC cell proliferation', 'CPA', (98, 120))	('SGK1', 'Gene', (170, 174))	('HOTTIP', 'Gene', (81, 87))
111837	33542904	In light of the emerging evidence highlighting multiple roles for SGK1 in mediating tumorigenesis and progression, several specific and selective inhibitors of SGK1 have been developed, including GSK650394, EMD638683, SI113, QGY-5-114-A, and ZINC00319000.	('GSK650394', 'Var', (196, 205))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('ZINC00319000', 'Var', (242, 254))	('ZINC00319000', 'Chemical', '-', (242, 254))	('QGY-5-114-A', 'Chemical', '-', (225, 236))	('GSK650394', 'Chemical', 'MESH:C532254', (196, 205))	('tumor', 'Disease', (84, 89))	('SI113', 'Chemical', '-', (218, 223))	('SGK1', 'Gene', (66, 70))	('inhibitors', 'NegReg', (146, 156))	('EMD638683', 'Chemical', 'MESH:C569030', (207, 216))	('EMD638683', 'Var', (207, 216))	('SGK1', 'Gene', (160, 164))
111838	33542904	The mentioned SGK1 inhibitors and their various anti-tumor effects are summarized in  Table 2 .	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('inhibitors', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('SGK1', 'Gene', (14, 18))	('tumor', 'Disease', (53, 58))
111840	33542904	developed a novel heterocyclic indazole derivate, GSK650394, which is the first reported SGK1 inhibitor that restrains the enzymatic activity of SGK1, with half maximal inhibitory concentration (IC50) values of 62 nM based on an in vitro scintillation proximity assay (SPA).	('rat', 'Species', '10116', (187, 190))	('GSK650394', 'Chemical', 'MESH:C532254', (50, 59))	('GSK650394', 'Var', (50, 59))	('SGK1', 'Gene', (89, 93))	('SPA', 'Chemical', '-', (269, 272))	('indazole', 'Chemical', 'MESH:D007191', (31, 39))	('inhibitor', 'Var', (94, 103))	('restrains', 'NegReg', (109, 118))	('enzymatic activity', 'MPA', (123, 141))	('SGK1', 'Gene', (145, 149))
111841	33542904	GSK650394 functionally inhibited SGK1 in an LNCaP growth assay, with an IC50 value of approximately 1 muM (which is similar to the previously measured IC50 in other cell-based assays).	('SGK1', 'Gene', (33, 37))	('inhibited', 'NegReg', (23, 32))	('LNCaP', 'CellLine', 'CVCL:0395', (44, 49))	('GSK650394', 'Chemical', 'MESH:C532254', (0, 9))	('GSK650394', 'Var', (0, 9))	('LNCaP growth assay', 'CPA', (44, 62))
111842	33542904	More recently, GSK650394 has shown anti-tumor effects in several other tumors, including breast cancer, squamous cell carcinoma of the head and neck, lung cancer, CRC, and cervical cancer.	('CRC', 'Disease', (163, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('lung cancer', 'Disease', (150, 161))	('breast cancer', 'Disease', (89, 102))	('GSK650394', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Disease', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 127))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('squamous cell carcinoma', 'Disease', (104, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', (40, 45))	('cancer', 'Disease', (181, 187))	('tumor', 'Disease', (71, 76))	('cancer', 'Disease', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('GSK650394', 'Chemical', 'MESH:C532254', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
111843	33542904	In addition, our results also indicated that GSK650394 could significantly inhibit PCa cells proliferation, invasion and migration.	('rat', 'Species', '10116', (124, 127))	('GSK650394', 'Var', (45, 54))	('inhibit', 'NegReg', (75, 82))	('PCa cells proliferation', 'CPA', (83, 106))	('rat', 'Species', '10116', (100, 103))	('GSK650394', 'Chemical', 'MESH:C532254', (45, 54))
111844	33542904	However, GSK650394 also inhibits the enzymatic activity of SGK2 in the SPA assay, with an IC50 value of 103 nM, indicating that GSK650394 is equally active toward both SGK1 and SGK2.	('SPA', 'Chemical', '-', (71, 74))	('SGK2', 'Gene', (59, 63))	('GSK650394', 'Chemical', 'MESH:C532254', (128, 137))	('GSK650394', 'Var', (128, 137))	('inhibits', 'NegReg', (24, 32))	('GSK650394', 'Var', (9, 18))	('GSK650394', 'Chemical', 'MESH:C532254', (9, 18))	('SGK2', 'Gene', '10110', (177, 181))	('enzymatic activity', 'MPA', (37, 55))	('SGK2', 'Gene', '10110', (59, 63))	('SGK2', 'Gene', (177, 181))
111847	33542904	In vitro testing identified EMD638683 as an SGK1 inhibitor with an IC50 of 3 muM in human cervical carcinoma HeLa cells.	('SGK1', 'Gene', (44, 48))	('cervical carcinoma HeLa', 'Disease', (90, 113))	('EMD638683', 'Chemical', 'MESH:C569030', (28, 37))	('EMD638683', 'Var', (28, 37))	('cervical carcinoma HeLa', 'Disease', 'MESH:D002583', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('human', 'Species', '9606', (84, 89))
111850	33542904	demonstrated that EMD638683 also has an inhibitory effect on mitogen- and stress-activated protein kinase 1 (MSK1), cAMP-dependent protein kinase (PKA), protein kinase C-related kinase 2 (PRK2), and the SGK isoforms SGK2 and SGK3.	('MSK1', 'Gene', (109, 113))	('MSK1', 'Gene', '9252', (109, 113))	('EMD638683', 'Chemical', 'MESH:C569030', (18, 27))	('cAMP', 'Chemical', '-', (116, 120))	('protein kinase C-related kinase 2', 'Gene', '5586', (153, 186))	('rat', 'Species', '10116', (7, 10))	('SGK', 'Gene', '6446', (203, 206))	('protein kinase C-related kinase 2', 'Gene', (153, 186))	('inhibitory', 'NegReg', (40, 50))	('SGK', 'Gene', '6446', (225, 228))	('SGK', 'Gene', '6446', (216, 219))	('SGK3', 'Gene', (225, 229))	('SGK', 'Gene', (203, 206))	('PRK2', 'Gene', '5586', (188, 192))	('SGK3', 'Gene', '23678', (225, 229))	('PRK2', 'Gene', (188, 192))	('SGK', 'Gene', (225, 228))	('EMD638683', 'Var', (18, 27))	('SGK', 'Gene', (216, 219))	('SGK2', 'Gene', (216, 220))	('mitogen- and stress-activated protein kinase 1', 'Gene', '9252', (61, 107))	('SGK2', 'Gene', '10110', (216, 220))
111852	33542904	Among these molecules, SI113 was particularly selective in inhibiting SGK1 kinase activity, while being much less effective in inhibiting AKT1.	('SI113', 'Chemical', '-', (23, 28))	('AKT1', 'Gene', '207', (138, 142))	('AKT1', 'Gene', (138, 142))	('inhibiting', 'NegReg', (59, 69))	('SGK1', 'Protein', (70, 74))	('activity', 'MPA', (82, 90))	('SI113', 'Var', (23, 28))
111853	33542904	In addition, a dose-dependence curve of SI113-dependent SGK1 and AKT1 inhibition showed that the inhibition of SGK1 activity occurred at an IC50 value of 600 nmol/L, with a 100-fold selectivity compared to AKT1 (against which SI113 had an IC50 value equal to 50 micromol/L).	('inhibition', 'NegReg', (70, 80))	('AKT1', 'Gene', '207', (206, 210))	('AKT1', 'Gene', '207', (65, 69))	('inhibition', 'NegReg', (97, 107))	('AKT1', 'Gene', (206, 210))	('AKT1', 'Gene', (65, 69))	('SI113-dependent', 'Var', (40, 55))	('SI113', 'Chemical', '-', (40, 45))	('SGK1', 'Gene', (111, 115))	('SGK1', 'Gene', (56, 60))	('activity', 'MPA', (116, 124))	('SI113', 'Chemical', '-', (226, 231))
111854	33542904	Subsequent studies have shown that SI113 induced cell death, thus counteracting cell proliferation in various cancer cell lines.	('cancer', 'Disease', (110, 116))	('SI113', 'Chemical', '-', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rat', 'Species', '10116', (92, 95))	('SI113', 'Var', (35, 40))	('cell death', 'CPA', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
111855	33542904	Specifically, SI113 induced cell apoptosis, both alone and synergistically with paclitaxel in RKO cells and ovarian cancer cells, or synergized with radiotherapy in hepatocarcinoma models in vitro and in vivo .	('ovarian cancer', 'Disease', (108, 122))	('RKO', 'CellLine', 'CVCL:0504', (94, 97))	('SI113', 'Chemical', '-', (14, 19))	('paclitaxel', 'Chemical', 'MESH:D017239', (80, 90))	('SI113', 'Var', (14, 19))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('cell apoptosis', 'CPA', (28, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('hepatocarcinoma', 'Disease', 'None', (165, 180))	('induced', 'Reg', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (108, 122))	('hepatocarcinoma', 'Disease', (165, 180))
111856	33542904	Remarkably, multiple studies have confirmed that SI113 exhibits powerful anti-tumor effects in glioblastoma multiforme, including activating cell apoptosis, induction of endoplasmic reticulum stress, inhibition of epithelial-to-mesenchymal transition, and especially stimulation of cytotoxic autophagy.	('stimulation', 'PosReg', (267, 278))	('activating', 'PosReg', (130, 140))	('inhibition', 'NegReg', (200, 210))	('glioblastoma multiforme', 'Disease', (95, 118))	('stress', 'Disease', (192, 198))	('SI113', 'Chemical', '-', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SI113', 'Var', (49, 54))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (95, 118))	('epithelial-to-mesenchymal transition', 'CPA', (214, 250))	('endoplasmic', 'CPA', (170, 181))	('tumor', 'Disease', (78, 83))	('cell apoptosis', 'CPA', (141, 155))	('cytotoxic autophagy', 'CPA', (282, 301))	('stress', 'Disease', 'MESH:D000079225', (192, 198))
111857	33542904	All these studies indicate that SI113 has strong anti-tumor activity, and its selective inhibitory effect on SGK1 is significantly superior to that of the two previously reported inhibitors.	('SGK1', 'Gene', (109, 113))	('inhibitory effect', 'NegReg', (88, 105))	('superior', 'PosReg', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('SI113', 'Chemical', '-', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('SI113', 'Var', (32, 37))
111858	33542904	designed and synthesized 39 new analogs of the SGK1 inhibitor GSK650394.	('SGK1', 'Gene', (47, 51))	('GSK650394', 'Chemical', 'MESH:C532254', (62, 71))	('GSK650394', 'Var', (62, 71))
111859	33542904	They showed that certain analogs, numbered MH-1-11-A, MH1-11-B, QGY-5-90, QGY-OMe, QGY-5-163, QGY-5-114-A, and QGY-5-121, could inhibit the viability of colonic tumor HCT116 cells.	('colonic tumor', 'Phenotype', 'HP:0100273', (153, 166))	('colonic tumor', 'Disease', 'MESH:D003110', (153, 166))	('HCT116', 'CellLine', 'CVCL:0291', (167, 173))	('MH-1-11-A', 'Var', (43, 52))	('inhibit', 'NegReg', (128, 135))	('QGY-5-114-A', 'Chemical', '-', (94, 105))	('QGY-5-90', 'Var', (64, 72))	('QGY-5-163', 'Var', (83, 92))	('QGY-5-121', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('QGY-5-114-A', 'Var', (94, 105))	('MH1-11-B', 'Var', (54, 62))	('colonic tumor', 'Disease', (153, 166))	('QGY-OMe', 'Var', (74, 81))
111860	33542904	To compare the inhibitory potency of these seven analogs, IC50 values were determined, and only compound QGY-5-114-A showed a significantly lower IC50 value of 122.9 muM, indicating better inhibitory potency than the inhibitor GSK650394.	('GSK650394', 'Chemical', 'MESH:C532254', (227, 236))	('QGY-5-114-A', 'Var', (105, 116))	('IC50 value', 'MPA', (146, 156))	('lower', 'NegReg', (140, 145))	('inhibitory potency', 'MPA', (189, 207))	('QGY-5-114-A', 'Chemical', '-', (105, 116))
111861	33542904	Furthermore, QGY-5-114-A could dramatically restrain colonic tumor cell proliferation via activating cell apoptosis and inducing cell cycle arrest at G0/G1 phase, and significantly impede colonic tumor cell migration in vitro .	('cell apoptosis', 'CPA', (101, 115))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (129, 146))	('colonic tumor', 'Phenotype', 'HP:0100273', (188, 201))	('rat', 'Species', '10116', (79, 82))	('colonic tumor', 'Phenotype', 'HP:0100273', (53, 66))	('arrest', 'Disease', (140, 146))	('inducing', 'Reg', (120, 128))	('colonic tumor', 'Disease', (188, 201))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('QGY-5-114-A', 'Chemical', '-', (13, 24))	('colonic tumor', 'Disease', (53, 66))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('colonic tumor', 'Disease', 'MESH:D003110', (188, 201))	('QGY-5-114-A', 'Var', (13, 24))	('arrest', 'Disease', 'MESH:D006323', (140, 146))	('rat', 'Species', '10116', (210, 213))	('impede', 'NegReg', (181, 187))	('colonic tumor', 'Disease', 'MESH:D003110', (53, 66))	('restrain', 'NegReg', (44, 52))	('activating', 'PosReg', (90, 100))
111864	33542904	Molecular dynamics simulation results further suggested that the binding of ZINC00319000 stabilizes the SGK1 structure and leads to few conformational changes, indicating that ZINC00319000 might be further exploited as a scaffold to develop promising inhibitors of SGK1 for therapeutic management of associated diseases, including cancer.	('conformational changes', 'MPA', (136, 158))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('ZINC00319000', 'Chemical', '-', (176, 188))	('stabilizes', 'Reg', (89, 99))	('ZINC00319000', 'Var', (176, 188))	('ZINC00319000', 'Var', (76, 88))	('ZINC00319000', 'Chemical', '-', (76, 88))	('SGK1', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('structure', 'MPA', (109, 118))
111868	33542904	Although several SGK1 inhibitors have paved the way for novel therapeutic interventions in the future, the prospects for clinical application of these inhibitors in cancer therapy are vague, which means that more preclinical studies, especially on toxicity and safety, should be conducted.	('inhibitors', 'Var', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('SGK1', 'Gene', (17, 21))	('toxicity', 'Disease', 'MESH:D064420', (248, 256))	('toxicity', 'Disease', (248, 256))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
111881	32438344	There were more women, large tumor, atypical mitosis, venous invasion, and higher mitotic count in cancer recurrence group.	('atypical', 'Var', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('women', 'Species', '9606', (16, 21))	('higher', 'PosReg', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('venous invasion', 'CPA', (54, 69))	('cancer', 'Disease', (99, 105))	('tumor', 'Disease', (29, 34))	('mitotic count', 'CPA', (82, 95))	('mitosis', 'Disease', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mitosis', 'Disease', 'None', (45, 52))
111892	32438344	Although the most common genetic alterations in ACC were TP53 and CTNNB1 mutations and CDKN2A and ZNRF3 homozygous deletions, the molecular and cellular mechanisms underlying the development of ACC have not been fully clarified; multi-omic studies demonstrated that only a minority of patients with ACC have pathogenic driver mutations.	('ACC', 'Disease', (299, 302))	('ZNRF3', 'Gene', '84133', (98, 103))	('ZNRF3', 'Gene', (98, 103))	('ACC', 'Disease', (48, 51))	('CDKN2A', 'Gene', '1029', (87, 93))	('ACC', 'Phenotype', 'HP:0006744', (299, 302))	('ACC', 'Phenotype', 'HP:0006744', (194, 197))	('mutations', 'Var', (326, 335))	('CTNNB1', 'Gene', (66, 72))	('patients', 'Species', '9606', (285, 293))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('deletions', 'Var', (115, 124))	('ACC', 'Phenotype', 'HP:0006744', (48, 51))	('mutations', 'Var', (73, 82))	('CTNNB1', 'Gene', '1499', (66, 72))	('CDKN2A', 'Gene', (87, 93))
111903	32438344	Patients with ACC were identified based on the following International Classification of Diseases, 10th revision (ICD-10) codes: C740 (primary malignant neoplasm of adrenal cortex, nonfunctioning adrenal carcinoma) and C749 (primary malignant neoplasm of adrenal gland, other type of adrenal cancer, unspecified adrenal cancer).	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('adrenal carcinoma', 'Phenotype', 'HP:0006744', (196, 213))	('malignant neoplasm of adrenal gland', 'Disease', (233, 268))	('C740', 'Var', (129, 133))	('neoplasm', 'Phenotype', 'HP:0002664', (243, 251))	('C749', 'Var', (219, 223))	('Classification of Diseases', 'Disease', 'MESH:D008310', (71, 97))	('neoplasm of adrenal', 'Phenotype', 'HP:0100631', (243, 262))	('adrenal cancer', 'Disease', (284, 298))	('Patients', 'Species', '9606', (0, 8))	('neoplasm of adrenal', 'Phenotype', 'HP:0100631', (153, 172))	('adrenal cancer', 'Disease', 'MESH:D000310', (312, 326))	('adrenal carcinoma', 'Disease', (196, 213))	('Classification of Diseases', 'Disease', (71, 97))	('malignant neoplasm of adrenal cortex', 'Disease', 'MESH:D000306', (143, 179))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('neoplasm', 'Phenotype', 'HP:0002664', (153, 161))	('ACC', 'Phenotype', 'HP:0006744', (14, 17))	('malignant neoplasm of adrenal gland', 'Disease', 'MESH:D000310', (233, 268))	('neoplasm of adrenal gland', 'Phenotype', 'HP:0100631', (243, 268))	('unspecified', 'Species', '32644', (300, 311))	('neoplasm of adrenal cortex', 'Phenotype', 'HP:0100641', (153, 179))	('adrenal carcinoma', 'Disease', 'MESH:D000310', (196, 213))	('malignant neoplasm of adrenal cortex', 'Disease', (143, 179))	('adrenal cancer', 'Disease', (312, 326))	('adrenal cancer', 'Disease', 'MESH:D000310', (284, 298))
111988	32345347	Undoubtedly WGS efforts have been found to increased diagnostic yield, with the figure ranging from 21 to 73% depending on participant age and phenotype.	('increased', 'PosReg', (43, 52))	('diagnostic yield', 'MPA', (53, 69))	('WGS efforts', 'Var', (12, 23))	('participant', 'Species', '9606', (123, 134))
112024	32345347	Finally, statistical algorithms infer the most probable clusters within multi-omic datasets, for example PARADIGM which infers associations of molecular variants with patient phenotype by incorporating pathway activity and inactivity data.	('associations', 'Interaction', (127, 139))	('patient', 'Species', '9606', (167, 174))	('variants', 'Var', (153, 161))
112027	32345347	In addition to studies which utilised TCGA specific algorithms, the only other study included in this review which discussed a bioinformatic pipe-line for multi-omic data integration was in vulvar carcinoma, in which the researchers used the CONEXIC algorithm to combine CNV and gene expression data to construct hypothesised regulatory networks, providing a ranked score which informs how well a particular variant predicts module behaviour, with high scores indicating high tumour adaptive advantage.	('tumour', 'Disease', 'MESH:D009369', (476, 482))	('tumour', 'Disease', (476, 482))	('vulvar carcinoma', 'Disease', (190, 206))	('vulvar carcinoma', 'Disease', 'MESH:D014846', (190, 206))	('module behaviour', 'MPA', (425, 441))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('variant', 'Var', (408, 415))	('tumour', 'Phenotype', 'HP:0002664', (476, 482))	('predicts', 'Reg', (416, 424))
112029	32345347	Development of a similar integrative workflow for non-cancerous rare diseases, coupled with international collaboration to increase sample size, would be useful to increase pathogenic variant identification, diagnostic yield and development of a defined care pathway.	('variant', 'Var', (184, 191))	('non-cancerous rare diseases', 'Disease', 'MESH:D009369', (50, 77))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('non-cancerous rare diseases', 'Disease', (50, 77))	('increase', 'PosReg', (164, 172))
112036	32345347	WES identified a recessively inherited splice variant in PDZD7 (c.226 + 2_226 + 5delTAGG) likely to explain the NSHL phenotype, which was confirmed through mRNA analysis to inhibit gene expression in affected individuals, as no PDZD7 exons were amplified.	('PDZD7', 'Gene', '79955', (228, 233))	('PDZD7', 'Gene', '79955', (57, 62))	('5delTAGG', 'Var', (80, 88))	('explain', 'Reg', (100, 107))	('PDZD7', 'Gene', (228, 233))	('gene expression', 'MPA', (181, 196))	('NSHL', 'Disease', (112, 116))	('splice variant', 'Var', (39, 53))	('PDZD7', 'Gene', (57, 62))	('5delTAGG', 'DELETION', 'None', (80, 88))	('inhibit', 'NegReg', (173, 180))
112038	32345347	The skeletal phenotype was associated with an autosomal dominantly inherited variant in COL1A1 which lead to a diagnosis of osteogenesis imperfecta.	('variant', 'Var', (77, 84))	('COL1A1', 'Gene', (88, 94))	('associated', 'Reg', (27, 37))	('osteogenesis imperfecta', 'Disease', (124, 147))	('COL1A1', 'Gene', '1277', (88, 94))	('skeletal', 'Disease', (4, 12))	('osteogenesis imperfecta', 'Disease', 'MESH:D010013', (124, 147))	('lead to', 'Reg', (101, 108))
112039	32345347	A second study aimed to utilise WGS, protein and mRNA analyses to aid the diagnosis of a family with heterogeneous myopathic and neurogenic phenotypes, uncovering five likely pathogenic exonic variants.	('myopathic', 'Disease', (115, 124))	('pathogenic', 'Reg', (175, 185))	('myopathic', 'Disease', 'MESH:D009135', (115, 124))	('exonic variants', 'Var', (186, 201))
112040	32345347	Of these, a single mutation in the gene NEFL was identified in all affected family members, (c.1261C > T; p.R421X associated with truncated NEFL protein levels) which has previously been associated with Charcot-Marie-Tooth disease.	('NEFL', 'Gene', (140, 144))	('NEFL', 'Gene', '4747', (140, 144))	('c.1261C > T; p.R421X', 'Var', (93, 113))	('c.1261C > T', 'Mutation', 'rs191346286', (93, 104))	('NEFL', 'Gene', '4747', (40, 44))	('Charcot-Marie-Tooth disease', 'Disease', 'MESH:D000699', (203, 230))	('p.R421X', 'Mutation', 'rs191346286', (106, 113))	('associated', 'Reg', (114, 124))	('associated', 'Reg', (187, 197))	('NEFL', 'Gene', (40, 44))	('Charcot-Marie-Tooth disease', 'Disease', (203, 230))	('p.R421X', 'Var', (106, 113))
112043	32345347	The research team identified 758 metabolomic features with a minimum fold change of 1.5 between cases and controls, including alpha-ketoglutarate which was reduced 4.3 fold in ACO2 deficient patients and thus likely to contribute to the pathogenic phenotype.	('ACO2', 'Gene', (176, 180))	('patients', 'Species', '9606', (191, 199))	('metabolomic', 'MPA', (33, 44))	('deficient', 'Var', (181, 190))	('ACO2', 'Gene', '50', (176, 180))	('reduced', 'NegReg', (156, 163))	('contribute', 'Reg', (219, 229))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (126, 145))	('alpha-ketoglutarate', 'MPA', (126, 145))
112051	32345347	Their integrative multi-omic analysis identified a rare mutation in the modifier gene STAT1 resulting in upregulated mRNA AND protein expression, likely responsible for the phenotype in the affected sister.	('upregulated', 'PosReg', (105, 116))	('mRNA AND protein expression', 'MPA', (117, 144))	('STAT1', 'Gene', (86, 91))	('STAT1', 'Gene', '6772', (86, 91))	('mutation', 'Var', (56, 64))
112056	32345347	Finally, one study of pseudomyxoma peritonei (a very rare form of appendix cancer) showed that aberrant p53 staining reflected a worse overall survival in patients compared to normal p53 staining (19% compared to 80% five year survival).	('p53', 'Gene', (104, 107))	('p53', 'Gene', '7157', (104, 107))	('appendix cancer', 'Disease', 'MESH:D001063', (66, 81))	('pseudomyxoma peritonei', 'Disease', (22, 44))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '7157', (183, 186))	('patients', 'Species', '9606', (155, 163))	('appendix cancer', 'Disease', (66, 81))	('worse', 'NegReg', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('aberrant', 'Var', (95, 103))	('pseudomyxoma peritonei', 'Disease', 'MESH:D011553', (22, 44))
112060	32345347	For example, one study identified 156 differentially methylated genes in ACC, including hypermethylation of CYP1B1, which was shown to have sensitivity to the methylation inhibitor decitabine in an ACC cell line.	('decitabine', 'Chemical', 'MESH:D000077209', (181, 191))	('ACC', 'Phenotype', 'HP:0006744', (73, 76))	('ACC', 'Disease', (73, 76))	('CYP1B1', 'Gene', '1545', (108, 114))	('ACC', 'Phenotype', 'HP:0006744', (198, 201))	('hypermethylation', 'Var', (88, 104))	('CYP1B1', 'Gene', (108, 114))
112061	32345347	Furthermore, the same study found that cell proliferation occurred in the mutated genes GATA6, G0S2, MEIS1, NCOA7, KCTD12, FAM1156A following treatment with the oncology drug oncostatin M. However even where novel therapeutic targets are identified as excellent candidates for clinical research, the expense of trials often results in pharmaceutical companies refusing to test and a produce a novel drug.	('G0S2', 'Gene', '50486', (95, 99))	('GATA6', 'Gene', '2627', (88, 93))	('KCTD12', 'Gene', '115207', (115, 121))	('GATA6', 'Gene', (88, 93))	('KCTD12', 'Gene', (115, 121))	('oncology', 'Phenotype', 'HP:0002664', (161, 169))	('G0S2', 'Gene', (95, 99))	('mutated', 'Var', (74, 81))	('NCOA7', 'Gene', (108, 113))	('MEIS1', 'Gene', '4211', (101, 106))	('MEIS1', 'Gene', (101, 106))	('cell proliferation', 'CPA', (39, 57))	('oncostatin M', 'Gene', '5008', (175, 187))	('oncostatin M', 'Gene', (175, 187))	('NCOA7', 'Gene', '135112', (108, 113))
112074	31265901	We previously demonstrated that the Notch atypical ligand Delta-like homologue 1 (DLK1)/preadipocyte factor 1 (PREF1) is expressed in subcapsular Sf1 and Shh-positive, CYP11B1-negative and CYP11B2-partially positive cortical progenitor cells in rat adrenals, and that secreted DLK1 can modulate GLI1 expression in H295R cells.	('Delta-like homologue 1', 'Gene', '114587', (58, 80))	('GLI1', 'Gene', '140589', (295, 299))	('DLK1', 'Gene', (82, 86))	('PREF1', 'Gene', (111, 116))	('rat', 'Species', '10116', (245, 248))	('Sf1', 'Gene', '117855', (146, 149))	('Delta-like homologue 1', 'Gene', (58, 80))	('preadipocyte factor 1', 'Gene', (88, 109))	('rat', 'Species', '10116', (21, 24))	('PREF1', 'Gene', '114587', (111, 116))	('Sf1', 'Gene', (146, 149))	('CYP11B2-partially', 'Var', (189, 206))	('preadipocyte factor 1', 'Gene', '114587', (88, 109))	('GLI1', 'Gene', (295, 299))	('H295R', 'CellLine', 'CVCL:0458', (314, 319))	('modulate', 'Reg', (286, 294))
112082	31265901	For example, we have shown that sonic hedgehog (Shh) is expressed in relatively undifferentiated cells throughout life in the subcapsular region of the mouse and rat adrenal starting from e12.5 and e13.5, respectively.	('e13.5', 'Var', (198, 203))	('Shh', 'Gene', (48, 51))	('rat', 'Species', '10116', (162, 165))	('sonic hedgehog', 'Gene', '20423', (32, 46))	('mouse', 'Species', '10090', (152, 157))	('sonic hedgehog', 'Gene', (32, 46))	('e12.5', 'Var', (188, 193))
112129	31265901	The dual pattern of clustered and layered-continuous is remarkably similar to that of CYP11B2 (Aldosterone Synthase), a marker of functional ZG cells.	('Aldosterone Synthase', 'Gene', '1585', (95, 115))	('CYP11B2', 'Var', (86, 93))	('ZG', 'Disease', 'MESH:D006562', (141, 143))	('Aldosterone Synthase', 'Gene', (95, 115))
112131	31265901	APCCs may be a precursor of benign Aldosterone Producing Adenomas (APAs), after a notable study discovered that nearly half of APCCs (but not neighboring cortical tissue) harbor mutations in ion channels/pumps found in clinically manifesting APAs.	('Adenomas', 'Disease', 'MESH:D000236', (57, 65))	('ion channels/pumps', 'Gene', (191, 209))	('Aldosterone', 'Chemical', 'MESH:D000450', (35, 46))	('APCCs', 'Disease', (127, 132))	('Adenomas', 'Disease', (57, 65))	('mutations', 'Var', (178, 187))
112133	31265901	Even DCCs located adjacent to layered-continuous "classical" ZG never expressed CYP11B2 (Fig.	('CYP11B2', 'Var', (80, 87))	('ZG', 'Disease', 'MESH:D006562', (61, 63))	('DCC', 'Gene', (5, 8))	('DCC', 'Gene', '1630', (5, 8))
112162	31265901	Similar to the observations described above in rats, they were poorly steroidogenic, although some differences between species were observed, as DCCs were CYP11B2 negative whilst expressing low/nil levels of ZF markers CYP17A1 and CYP11B1.	('DCC', 'Gene', '1630', (145, 148))	('CYP11B2', 'Gene', (155, 162))	('steroid', 'Chemical', 'MESH:D013256', (70, 77))	('ZF', 'Disease', 'MESH:D006562', (208, 210))	('negative', 'NegReg', (163, 171))	('DCC', 'Gene', (145, 148))	('CYP17A1', 'Var', (219, 226))	('CYP11B1', 'Var', (231, 238))	('rats', 'Species', '10116', (47, 51))
112171	30707926	Several adrenal diseases result from dysregulated adrenal steroid synthesis.	('steroid', 'Chemical', 'MESH:D013256', (58, 65))	('adrenal steroid synthesis', 'MPA', (50, 75))	('result from', 'Reg', (25, 36))	('adrenal diseases', 'Disease', 'MESH:C537027', (8, 24))	('dysregulated', 'Var', (37, 49))	('adrenal diseases', 'Disease', (8, 24))
112189	30707926	11OHT and 11OHA4 can in turn be oxidized to their respective keto-derivatives, 11KT and 11KA4 in peripheral tissues expressing 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) (Fig.	('HSD11B2', 'Gene', (171, 178))	('11KT', 'Chemical', 'MESH:C003600', (79, 83))	('11OHT', 'Chemical', '-', (0, 5))	('11beta-hydroxysteroid dehydrogenase type 2', 'Gene', '3291', (127, 169))	('11OHA4', 'Chemical', '-', (10, 16))	('HSD11B2', 'Gene', '3291', (171, 178))	('11KA4', 'Var', (88, 93))	('11KA4', 'Chemical', '-', (88, 93))	('11beta-hydroxysteroid dehydrogenase type 2', 'Gene', (127, 169))
112193	30707926	21-hydroxylase (CYP21A2) deficiency (21OHD) is the most common form of CAH, accounting for more than 90% of all CAH cases.	('21OHD', 'Chemical', '-', (37, 42))	('CAH', 'Disease', (71, 74))	('deficiency', 'Var', (25, 35))	('CAH', 'Disease', (112, 115))	('CAH', 'Disease', 'None', (71, 74))	('CYP21A2', 'Gene', '1589', (16, 23))	('CAH', 'Disease', 'None', (112, 115))	('CYP21A2', 'Gene', (16, 23))
112198	30707926	Although subclassification of 21OHD is generally helpful, the spectrum of the disease severity actually depends on the underlying CYP21A2 mutations, the resulting residual activity of the enzyme, and poorly understood factors such as modifier genes.	('21OHD', 'Chemical', '-', (30, 35))	('activity', 'MPA', (172, 180))	('CYP21A2', 'Gene', '1589', (130, 137))	('CYP21A2', 'Gene', (130, 137))	('mutations', 'Var', (138, 147))
112213	30707926	The excess 17OHP4 resulting from CYP21A2 deficiency is diverted through the pathways left accessible, to form potent androgens, such as T (Table 1).	('deficiency', 'Var', (41, 51))	('17OHP4', 'Chemical', '-', (11, 17))	('17OHP4', 'MPA', (11, 17))	('CYP21A2', 'Gene', '1589', (33, 40))	('CYP21A2', 'Gene', (33, 40))	('excess', 'PosReg', (4, 10))	('excess 17OHP4', 'Phenotype', 'HP:0031213', (4, 17))
112214	30707926	CYP17A1 mediates the conversion of 17OHPreg to DHEA (Delta5 pathway) and of 17OHP4 to A4 (Delta4 pathway).	('Delta4', 'Gene', (90, 96))	('Delta4', 'Gene', '54567', (90, 96))	('17OHPreg', 'Chemical', '-', (35, 43))	('A4', 'Chemical', '-', (86, 88))	('DHEA', 'Chemical', 'MESH:D003687', (47, 51))	('Delta5', 'Mutation', 'c.del5', (53, 59))	('17OHPreg', 'Var', (35, 43))	('17OHP4', 'Var', (76, 82))	('17OHP4', 'Chemical', '-', (76, 82))	('CYP17A1', 'Gene', (0, 7))	('CYP17A1', 'Gene', '1586', (0, 7))
112215	30707926	The catalytic efficiency of the human 17,20-lyase, however, is ~100 times greater for the Delta5 reaction, as compared with the Delta4 reaction, in part explaining the enormous 17OHP4 accumulation in 21OHD.	('17OHP4', 'Chemical', '-', (177, 183))	('Delta5', 'Mutation', 'c.del5', (90, 96))	('Delta4', 'Gene', (128, 134))	('catalytic efficiency', 'MPA', (4, 24))	('Delta4', 'Gene', '54567', (128, 134))	('21OHD', 'Chemical', '-', (200, 205))	('human', 'Species', '9606', (32, 37))	('greater', 'PosReg', (74, 81))	('Delta5', 'Var', (90, 96))
112219	30707926	Indeed, detailed characterization of the androgens and androgen precursors in classic 21OHD demonstrated that the four 11-oxygenated steroids, 11OHA4, 11KA4, 11OHT, and 11KT, along with A4 and T (Table 1) are significantly higher in both male and female patients with classic 21OHD compared to age-matched controls.	('A4', 'Chemical', '-', (147, 149))	('11OHT', 'Var', (158, 163))	('11OHA4', 'Var', (143, 149))	('long', 'Disease', (176, 180))	('11KA4', 'Var', (151, 156))	('A4', 'Chemical', '-', (186, 188))	('11OHA4', 'Chemical', '-', (143, 149))	('11KA4', 'Chemical', '-', (151, 156))	('11OHT', 'Chemical', '-', (158, 163))	('21OHD', 'Chemical', '-', (86, 91))	('11KT', 'Var', (169, 173))	('11KT', 'Chemical', 'MESH:C003600', (169, 173))	('higher', 'PosReg', (223, 229))	('21OHD', 'Chemical', '-', (276, 281))	('A4', 'Chemical', '-', (154, 156))	('patients', 'Species', '9606', (254, 262))	('long', 'Disease', 'MESH:D008133', (176, 180))	('steroids', 'Chemical', 'MESH:D013256', (133, 141))
112222	30707926	Of note, DHEA-S is paradoxically low in patients with 21OHD, including those in poor control despite chronic ACTH stimulation and elevation of other androgens (Table 1).	('low', 'NegReg', (33, 36))	('21OHD', 'Chemical', '-', (54, 59))	('elevation', 'PosReg', (130, 139))	('patients', 'Species', '9606', (40, 48))	('ACTH', 'Gene', (109, 113))	('DHEA-S', 'Chemical', '-', (9, 15))	('ACTH', 'Gene', '5443', (109, 113))	('21OHD', 'Var', (54, 59))	('DHEA-S', 'Disease', (9, 15))
112242	30707926	Although genetic studies demonstrated a normal sequence of the HSD11B1 gene in most affected individuals, inactivating mutations have been found in the H6PDH (hexose-6-phosphate dehydrogenase) gene.	('HSD11B1', 'Gene', '3290', (63, 70))	('H6PDH', 'Gene', (152, 157))	('HSD11B1', 'Gene', (63, 70))	('inactivating mutations', 'Var', (106, 128))
112243	30707926	Inactivating mutations in H6PDH disrupts HSD11B1 oxo-reductase activity resulting in decreased peripheral conversion of cortisone to cortisol.	('activity', 'MPA', (63, 71))	('decreased', 'NegReg', (85, 94))	('cortisol', 'Chemical', 'MESH:D006854', (133, 141))	('cortisone', 'Chemical', 'MESH:D003348', (120, 129))	('HSD11B1', 'Gene', '3290', (41, 48))	('Inactivating mutations', 'Var', (0, 22))	('HSD11B1', 'Gene', (41, 48))	('oxo-reductase', 'Enzyme', (49, 62))	('disrupts', 'NegReg', (32, 40))	('peripheral conversion of cortisone to cortisol', 'MPA', (95, 141))	('H6PDH', 'Gene', (26, 31))
112245	30707926	Another rare genetic cause of PremA is mutations in 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase type 2 (PAPSS2).	('PAPSS2', 'Gene', '9060', (114, 120))	('mutations', 'Var', (39, 48))	('PAPSS2', 'Gene', (114, 120))	('cause', 'Reg', (21, 26))	("3'-phosphoadenosine 5'-phosphosulfate", 'Chemical', '-', (52, 89))	('PremA', 'Disease', (30, 35))
112247	30707926	On examination of an 8-year-old girl with early pubic and axillary hair, Noordam et al concluded that the cause of hyperandrogenism was a set of compound heterozygous mutations in PAPSS2.	('girl', 'Species', '9606', (32, 36))	('PAPSS2', 'Gene', '9060', (180, 186))	('PAPSS2', 'Gene', (180, 186))	('compound heterozygous mutations', 'Var', (145, 176))	('axillary hair', 'Phenotype', 'HP:0002215', (58, 71))	('hyperandrogenism', 'Disease', (115, 131))	('hyperandrogenism', 'Disease', 'MESH:D017588', (115, 131))
112271	30707926	Researchers have tried to identify biomarkers that could help pinpoint the glandular source of excess androgens in PCOS, and 11OHA4 has been considered a candidate biomarker for PCOS adrenal dysregulation.	('11OHA4', 'Var', (125, 131))	('PCOS', 'Disease', (178, 182))	('PCOS adrenal dysregulation', 'Disease', (178, 204))	('11OHA4', 'Chemical', '-', (125, 131))	('PCOS', 'Disease', 'MESH:D011085', (178, 182))	('PCOS', 'Disease', (115, 119))	('excess androgens', 'Phenotype', 'HP:0030348', (95, 111))	('PCOS', 'Disease', 'MESH:D011085', (115, 119))	('PCOS adrenal dysregulation', 'Disease', 'MESH:D011085', (178, 204))
112275	30707926	Interestingly, the authors demonstrated that serum 11OHA4 and 11KA4, but not 11OHT or 11KT, correlated significantly, albeit weakly, with metabolic risk markers such as BMI, insulin, and HOMA-IR.	('11OHT', 'Chemical', '-', (77, 82))	('11KA4', 'Var', (62, 67))	('insulin', 'Gene', (174, 181))	('11OHA4', 'Var', (51, 57))	('11KA4', 'Chemical', '-', (62, 67))	('insulin', 'Gene', '3630', (174, 181))	('11KT', 'Chemical', 'MESH:C003600', (86, 90))	('11OHA4', 'Chemical', '-', (51, 57))
112278	30707926	Taken together, these studies suggest that there might be dysregulated synthesis of adrenal-derived 11-oxyandrogens and precursors in certain forms of PCOS and might also explain the clinical manifestations associated with androgen excess in women with normal serum T. Adrenocortical Carcinoma (ACC) is a rare disease with an incidence of 1 per million per year and a dismal prognosis, with a 5-year survival rate of <30%.	('dysregulated', 'Var', (58, 70))	('PCOS', 'Disease', (151, 155))	('women', 'Species', '9606', (242, 247))	('PCOS', 'Disease', 'MESH:D011085', (151, 155))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (269, 293))	('11-oxyandrogens', 'Chemical', '-', (100, 115))	('Adrenocortical Carcinoma', 'Disease', (269, 293))	('synthesis', 'MPA', (71, 80))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (269, 293))	('Carcinoma', 'Phenotype', 'HP:0030731', (284, 293))
112306	30707926	A more recent study of 234 Japanese PA patients suggested that peripheral plasma 18oxoF and 18OHF can discriminate APAs from BHA with promising sensitivity and specificity (0.83/0.99 for 18oxoF and 0.62/0.96 for 18OHF, respectively).	('18OHF', 'MPA', (92, 97))	('18oxoF', 'MPA', (81, 87))	('18oxoF', 'Chemical', '-', (81, 87))	('patients', 'Species', '9606', (39, 47))	('BHA', 'Chemical', '-', (125, 128))	('APAs', 'Disease', (115, 119))	('18oxoF', 'Var', (187, 193))	('18OHF', 'Chemical', '-', (92, 97))	('18OHF', 'Chemical', '-', (212, 217))	('18oxoF', 'Chemical', '-', (187, 193))
112307	30707926	In contrast, a European study found significant overlap for both 18oxoF and 18OHF between APAs and BHA, with limited utility of these steroids to discriminate between the two subtypes.	('steroids', 'Chemical', 'MESH:D013256', (134, 142))	('18OHF', 'Chemical', '-', (76, 81))	('APAs', 'Disease', (90, 94))	('18oxoF', 'Chemical', '-', (65, 71))	('BHA', 'Chemical', '-', (99, 102))	('BHA', 'Disease', (99, 102))	('18OHF', 'Var', (76, 81))	('18oxoF', 'MPA', (65, 71))
112310	30707926	Somatic mutations in genes encoding ions channels and pumps have been identified in APA, including: KCNJ5 (encoding the Kir3.4 (GIRK4) potassium channel), ATP1A1 (encoding a Na+/K+ ATPase alpha subunit), ATP2B3 (encoding a Ca2+ ATPase), and CACNA1D (encoding a voltage-dependent L-type calcium channel) that all lead to an increase in constitutive aldosterone production.	('Kir3.4', 'Gene', '3762', (120, 126))	('GIRK4', 'Gene', '3762', (128, 133))	('ATP1A1', 'Gene', '476', (155, 161))	('constitutive aldosterone production', 'MPA', (335, 370))	('aldosterone', 'Chemical', 'MESH:D000450', (348, 359))	('increase', 'PosReg', (323, 331))	('ATP2B3', 'Gene', '492', (204, 210))	('mutations', 'Var', (8, 17))	('Kir3.4', 'Gene', (120, 126))	('ATP2B3', 'Gene', (204, 210))	('KCNJ5', 'Gene', (100, 105))	('Ca2+', 'Chemical', 'MESH:D000069285', (223, 227))	('aldosterone production', 'Phenotype', 'HP:0000859', (348, 370))	('ATPase', 'Gene', (228, 234))	('CACNA1D', 'Gene', '776', (241, 248))	('CACNA1D', 'Gene', (241, 248))	('calcium', 'Chemical', 'MESH:D002118', (286, 293))	('GIRK4', 'Gene', (128, 133))	('ATPase', 'Gene', (181, 187))	('ATPase', 'Gene', '1769', (228, 234))	('KCNJ5', 'Gene', '3762', (100, 105))	('ATP1A1', 'Gene', (155, 161))	('ATPase', 'Gene', '1769', (181, 187))
112311	30707926	A recent European study demonstrated that specific somatic mutations in APAs define distinct steroid profiles in adrenal vein plasma, which might reflect differences in the underlying biology of these tumors.	('steroid', 'Chemical', 'MESH:D013256', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('steroid profiles', 'MPA', (93, 109))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('mutations', 'Var', (59, 68))	('tumors', 'Disease', (201, 207))	('APAs', 'Gene', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))
112312	30707926	The authors showed increased concentrations of the hybrid steroids 18OHF and 18oxoF in plasma samples from APA carrying a KCNJ5 mutation, owing to a predominantly ZF phenotype (increased expression of CYP11B1 and CYP17A1) as opposed to APAs with ATPase or CACNA1D mutations that display principally a ZG phenotype.	('18oxoF', 'Chemical', '-', (77, 83))	('KCNJ5', 'Gene', '3762', (122, 127))	('CYP11B1', 'Gene', (201, 208))	('mutation', 'Var', (128, 136))	('CYP11B1', 'Gene', '1584', (201, 208))	('concentrations', 'MPA', (29, 43))	('CACNA1D', 'Gene', '776', (256, 263))	('steroids', 'Chemical', 'MESH:D013256', (58, 66))	('CACNA1D', 'Gene', (256, 263))	('increased', 'PosReg', (177, 186))	('increased', 'PosReg', (19, 28))	('ATPase', 'Gene', '1769', (246, 252))	('18OHF', 'Chemical', '-', (67, 72))	('expression', 'MPA', (187, 197))	('CYP17A1', 'Gene', (213, 220))	('KCNJ5', 'Gene', (122, 127))	('CYP17A1', 'Gene', '1586', (213, 220))	('ATPase', 'Gene', (246, 252))
112346	31379752	In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane).	('ganetespib', 'Chemical', 'MESH:C533237', (75, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (255, 264))	('mitotane', 'Chemical', 'MESH:D008939', (266, 274))	('etoposide', 'Chemical', 'MESH:D005047', (231, 240))	('doxorubicin', 'Chemical', 'MESH:D004317', (242, 253))	('luminespib', 'Var', (60, 70))	('decrease', 'NegReg', (108, 116))	('luminespib', 'Chemical', 'MESH:C528044', (60, 70))	('EDP', 'Chemical', '-', (217, 220))	('cell viability', 'CPA', (120, 134))
112352	31379752	Further targets that have been identified as affected by point mutations, chromosomal alterations or epigenetic mechanisms including p53/Rb or the Wnt/beta-catenin dependent signaling still lack suitable pharmacological approaches.	('p53', 'Gene', '7157', (133, 136))	('beta-catenin', 'Gene', '1499', (151, 163))	('p53', 'Gene', (133, 136))	('beta-catenin', 'Gene', (151, 163))	('point mutations', 'Var', (57, 72))
112370	31379752	Analysis of a series of truncation mutants of HSP90 showed that different regions at the CTD were involved in trapping the bound ATP to maximize hydrolysis rates leading to a repositioning of both NTD and CTD.	('ATP', 'Chemical', 'MESH:D000255', (129, 132))	('repositioning', 'MPA', (175, 188))	('hydrolysis rates', 'MPA', (145, 161))	('mutants', 'Var', (35, 42))	('NTD', 'Gene', '80199', (197, 200))	('HSP90', 'Protein', (46, 51))	('NTD', 'Gene', (197, 200))	('maximize', 'PosReg', (136, 144))
112391	31379752	The proteins of interests were detected using primary antibodies specifically directed against human HSP90alpha/beta (1:300 in blocking buffer, clone ERP3953, Abcam, Cambridge, UK), HSP90beta (1:750, E296, Abcam, Cambridge, UK) and stained using the EnVision Detection System (DAKO-Kit, Santa Clara, United States).	('human', 'Species', '9606', (95, 100))	('E296', 'Var', (200, 204))	('HSP90beta', 'Gene', '3326', (182, 191))	('HSP90alpha', 'Gene', '3320', (101, 111))	('1:750', 'Var', (193, 198))	('HSP90alpha', 'Gene', (101, 111))	('HSP90beta', 'Gene', (182, 191))
112393	31379752	For NCI-H295R, 15 x 106 cells in a volume of 200 mul PBS had been inoculated into female athymic NMRI nu/nu mice, while for MUC-1, the originally established xenograft from patient material had been repeatedly passed over into other groups of animals.	('NCI-H295R', 'Var', (4, 13))	('NCI-H295R', 'CellLine', 'CVCL:0458', (4, 13))	('mice', 'Species', '10090', (108, 112))	('PBS', 'Disease', (53, 56))	('PBS', 'Disease', 'MESH:D011535', (53, 56))	('patient', 'Species', '9606', (173, 180))
112400	31379752	NCI-H295R cells were cultured in RPMI (1640) plus GlutaMAX (Thermo Fisher Scientific Gibco, Waltham, MA, USA) supplemented with 0.1 v/v fetal bovine serum (FBS, Thermo Fisher Scientific Gibco), 0.01 v/v, penicillin/streptomycin (Thermo Fisher Scientific Gibco) and 0.01 v/v insulin-transferrin-selenium (ITS, Thermo Fisher Scientific Gibco).	('penicillin', 'Chemical', 'MESH:D010406', (204, 214))	('RPMI', 'Chemical', '-', (33, 37))	('FBS', 'Disease', (156, 159))	('selenium', 'Chemical', 'MESH:D012643', (294, 302))	('0.01 v/v', 'Var', (265, 273))	('streptomycin', 'Chemical', 'MESH:D013307', (215, 227))	('NCI-H295R', 'CellLine', 'CVCL:0458', (0, 9))	('bovine', 'Species', '9913', (142, 148))	('GlutaMAX', 'Chemical', 'MESH:D005973', (50, 58))	('FBS', 'Disease', 'MESH:D005198', (156, 159))
112428	31379752	at RT and incubation for 1 h at RT with corresponding HRP-conjugated secondary anti-mouse (7074S, 1:2000, Cell Signaling) or anti-rabbit (7076S, 1:2000, Cell Signaling), diluted in 0.05 v/v non-fat dry milk.	('7076S', 'Var', (138, 143))	('HRP-conjugated secondary anti-mouse', 'Protein', (54, 89))	('rabbit', 'Species', '9986', (130, 136))	('mouse', 'Species', '10090', (84, 89))	('Cell Signaling', 'MPA', (153, 167))	('7074S', 'Var', (91, 96))
112457	31379752	Additionally, cell migration assays demonstrated strong significant effects upon luminespib and ganetespib in NCI-H295R (Figure 4A) and MUC-1 (Figure 4B) cells in comparison to vehicle treatment.	('ganetespib', 'Gene', (96, 106))	('cell migration assays', 'CPA', (14, 35))	('ganetespib', 'Chemical', 'MESH:C533237', (96, 106))	('luminespib', 'Var', (81, 91))	('effects', 'Reg', (68, 75))	('luminespib', 'Chemical', 'MESH:C528044', (81, 91))	('NCI-H295R', 'CellLine', 'CVCL:0458', (110, 119))
112467	31379752	Specifically, analysis of the ERK1/2 (extracellular-regulated kinase 1/2) pathway indicated a decrease of p-cRAF and p-MEK1/2 forms upon luminespib and ganetespib treatment in both cell lines.	('ganetespib', 'Chemical', 'MESH:C533237', (152, 162))	('p-MEK1/2', 'Var', (117, 125))	('AF', 'Disease', 'MESH:D001281', (110, 112))	('decrease', 'NegReg', (94, 102))	('luminespib', 'Chemical', 'MESH:C528044', (137, 147))
112476	31379752	Herein we provide evidence that expression levels of isoforms of HSP90 bear prognostic value in ACC patients and that targeting HSP90 function has therapeutic potential resulting in consistent anti-tumor effects in different cell systems of adrenocortical cancer origin.	('ACC', 'Disease', (96, 99))	('HSP90', 'Protein', (65, 70))	('adrenocortical cancer origin', 'Phenotype', 'HP:0006744', (241, 269))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (241, 262))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('patients', 'Species', '9606', (100, 108))	('HSP90', 'Protein', (128, 133))	('tumor', 'Disease', (198, 203))	('expression', 'MPA', (32, 42))	('adrenocortical cancer', 'Disease', (241, 262))	('targeting', 'Var', (118, 127))
112493	31379752	Recent evidence has indicated that the combination of the HSP90 inhibitors BIIB021 and CCT18159 with mitotane had limited additional value.	('BIIB021', 'Var', (75, 82))	('CCT18159', 'Chemical', '-', (87, 95))	('HSP90 inhibitors', 'Protein', (58, 74))	('mitotane', 'Chemical', 'MESH:D008939', (101, 109))
112501	31379752	Similar to recent findings in pituitary cells, treatment of adrenocortical cancer cell lines with N-terminal HSP90 inhibitors decreased their glucocorticoid receptor expression and additionally we observed a reduction of cortisol secretion in NCI-H295R cells upon C-terminal and N-terminal HSP90 inhibitor treatment at time points without relevant effects on cell viability.	('decreased', 'NegReg', (126, 135))	('NCI-H295R', 'CellLine', 'CVCL:0458', (243, 252))	('adrenocortical cancer', 'Disease', (60, 81))	('glucocorticoid receptor', 'Gene', (142, 165))	('reduction', 'NegReg', (208, 217))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (60, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('glucocorticoid receptor', 'Gene', '2908', (142, 165))	('cortisol secretion', 'MPA', (221, 239))	('inhibitors', 'Var', (115, 125))	('cortisol', 'Chemical', 'MESH:D006854', (221, 229))
112502	31379752	We could further demonstrate that, in line with their relevant anti-tumor activity, N-terminal HSP90 inhibitors induce changes in molecular pathways involved in tumorigenesis.	('tumor', 'Disease', (68, 73))	('HSP90', 'Protein', (95, 100))	('inhibitors', 'Var', (101, 111))	('molecular pathways', 'Pathway', (130, 148))	('changes', 'Reg', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (161, 166))
112504	31379752	Moreover, HSP90 inhibitors also affect AKT and ERK1/2 pathways.	('HSP90', 'Protein', (10, 15))	('inhibitors', 'Var', (16, 26))	('AKT', 'Gene', '207', (39, 42))	('affect', 'Reg', (32, 38))	('AKT', 'Gene', (39, 42))
112506	31379752	Similarly, analysis of ERK1/2 pathway by western blot further indicated a decrease of p-cRAF and p-MEK1/2 both in NCI-H295R and MUC-1 cells.	('decrease', 'NegReg', (74, 82))	('p-MEK1/2', 'Var', (97, 105))	('ERK1/2 pathway', 'Pathway', (23, 37))	('AF', 'Disease', 'MESH:D001281', (90, 92))	('NCI-H295R', 'CellLine', 'CVCL:0458', (114, 123))
112519	31212829	Method and Results: EF24 reduced cell viability with an IC50 (half maximal inhibitory concentration) of 6.5 +- 2.4 muM and 4.9 +- 2.8 muM for SW13 and H295R cells, respectively.	('muM', 'Gene', '56925', (134, 137))	('reduced', 'NegReg', (25, 32))	('muM', 'Gene', (134, 137))	('SW13', 'CellLine', 'CVCL:0542', (142, 146))	('muM', 'Gene', '56925', (115, 118))	('cell viability', 'CPA', (33, 47))	('EF24', 'Var', (20, 24))	('H295R', 'CellLine', 'CVCL:0458', (151, 156))	('EF24', 'Chemical', '-', (20, 24))	('muM', 'Gene', (115, 118))
112521	31212829	Cell cycle analysis revealed an increase in subG0/G1 phase, while motility assay showed a decrease in migratory cell capacity, and similarly, clonogenic assay indicated that EF24 could reduce colony numbers.	('increase', 'PosReg', (32, 40))	('motility', 'CPA', (66, 74))	('clonogenic assay', 'CPA', (142, 158))	('subG0/G1 phase', 'CPA', (44, 58))	('EF24', 'Var', (174, 178))	('colony numbers', 'CPA', (192, 206))	('EF24', 'Chemical', '-', (174, 178))	('reduce', 'NegReg', (185, 191))	('decrease', 'NegReg', (90, 98))	('migratory cell capacity', 'CPA', (102, 125))
112522	31212829	Furthermore, Wnt/beta-catenin, NF-kappaB, MAPK, and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with EF24 alone or combined with mitotane.	('mitotane', 'Chemical', 'MESH:D008939', (163, 171))	('MAPK', 'Pathway', (42, 46))	('beta-catenin', 'Gene', '1499', (17, 29))	('EF24', 'Chemical', '-', (135, 139))	('Akt', 'Gene', '207', (57, 60))	('NF-kappaB', 'Gene', '4790', (31, 40))	('modulated', 'Reg', (75, 84))	('Akt', 'Gene', (57, 60))	('NF-kappaB', 'Gene', (31, 40))	('EF24', 'Var', (135, 139))	('beta-catenin', 'Gene', (17, 29))
112525	31212829	These results suggest that EF24 could potentially impact on adrenocortical tumors, laying the foundation for further research in animal models.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (60, 81))	('impact', 'Reg', (50, 56))	('adrenocortical tumors', 'Disease', (60, 81))	('EF24', 'Var', (27, 31))	('EF24', 'Chemical', '-', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
112536	31212829	Given these premises, this in vitro work analyzed the effects of EF24 alone or in combination with mitotane in adrenocortical tumor cell models, SW13 and H295R cells, for the first time.	('adrenocortical tumor', 'Disease', (111, 131))	('H295R', 'CellLine', 'CVCL:0458', (154, 159))	('mitotane', 'Chemical', 'MESH:D008939', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('SW13', 'CellLine', 'CVCL:0542', (145, 149))	('EF24', 'Var', (65, 69))	('EF24', 'Chemical', '-', (65, 69))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (111, 131))
112540	31212829	By SRB (sulforhodamine B) assay we revealed that the IC50 of EF24 was 5.3 +- 2.7 muM and 9.1 +- 3.1 muM for SW13 and H295R cells, respectively (Figure 2B).	('SRB', 'Gene', '10575', (3, 6))	('muM', 'Gene', '56925', (100, 103))	('SRB', 'Gene', (3, 6))	('EF24', 'Var', (61, 65))	('SW13', 'CellLine', 'CVCL:0542', (108, 112))	('sulforhodamine B', 'Gene', (8, 24))	('EF24', 'Chemical', '-', (61, 65))	('muM', 'Gene', (100, 103))	('H295R', 'CellLine', 'CVCL:0458', (117, 122))	('muM', 'Gene', '56925', (81, 84))	('sulforhodamine B', 'Gene', '10575', (8, 24))	('muM', 'Gene', (81, 84))
112542	31212829	Similarly, we calculated IC50 for mitotane in both cell lines: 8.1 +- 3.2 microM for SW13 at 24 h and 10.6 +- 2.3 microM for H295R at 72h (Figure 2C,D).	('SW13', 'CellLine', 'CVCL:0542', (85, 89))	('SW13', 'Var', (85, 89))	('mitotane', 'Chemical', 'MESH:D008939', (34, 42))	('H295R', 'CellLine', 'CVCL:0458', (125, 130))	('H295R', 'Var', (125, 130))
112547	31212829	It is known that ACC can frequently metastasize: We showed a significant reduction in cell motility after treatments with EF24 and mitotane in SW13 cells (Figure 4A,B).	('mitotane', 'Gene', (131, 139))	('SW13', 'CellLine', 'CVCL:0542', (143, 147))	('EF24', 'Var', (122, 126))	('EF24', 'Chemical', '-', (122, 126))	('mitotane', 'Chemical', 'MESH:D008939', (131, 139))	('cell motility', 'CPA', (86, 99))	('ACC', 'Phenotype', 'HP:0006744', (17, 20))	('reduction', 'NegReg', (73, 82))
112550	31212829	The effects of EF24 and its combination in tumor cells showed a decrease in colony number in all treatments and in both cell lines (Figure 6A-C).	('EF24', 'Var', (15, 19))	('EF24', 'Chemical', '-', (15, 19))	('decrease', 'NegReg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('colony number', 'CPA', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
112552	31212829	We showed that phospho-NF-kappaB was augmented by EF24 at 5 h in both cell lines and at 72 h in SW13 cells only (Figure 7A,B).	('NF-kappaB', 'Gene', (23, 32))	('EF24', 'Chemical', '-', (50, 54))	('SW13', 'CellLine', 'CVCL:0542', (96, 100))	('phospho', 'Chemical', 'MESH:D004099', (15, 22))	('augmented', 'PosReg', (37, 46))	('NF-kappaB', 'Gene', '4790', (23, 32))	('EF24', 'Var', (50, 54))
112553	31212829	Additionally, the combination of EF24 and mitotane induced an increase of phospho-NF-kappaB expression in SW13 cells at 5 h and 72 h, while in H295R cells, no similar result was appreciable (Figure 7A,B).	('SW13', 'CellLine', 'CVCL:0542', (106, 110))	('EF24', 'Chemical', '-', (33, 37))	('NF-kappaB', 'Gene', (82, 91))	('H295R', 'CellLine', 'CVCL:0458', (143, 148))	('mitotane', 'Chemical', 'MESH:D008939', (42, 50))	('phospho', 'Chemical', 'MESH:D004099', (74, 81))	('NF-kappaB', 'Gene', '4790', (82, 91))	('EF24', 'Var', (33, 37))	('increase', 'PosReg', (62, 70))
112556	31212829	Phospho-Erk1/2 was increased in SW13 cells at 5 h by EF24 treatment or its combination with mitotane.	('mitotane', 'Chemical', 'MESH:D008939', (92, 100))	('EF24', 'Gene', (53, 57))	('EF24', 'Chemical', '-', (53, 57))	('combination', 'Interaction', (75, 86))	('increased', 'PosReg', (19, 28))	('treatment', 'Var', (58, 67))	('SW13', 'CellLine', 'CVCL:0542', (32, 36))	('Phospho-Erk1/2', 'MPA', (0, 14))
112560	31212829	We investigated whether EF24 or its combination with mitotane could increase ROS levels (Figure 8 and Figure S2).	('mitotane', 'Chemical', 'MESH:D008939', (53, 61))	('EF24', 'Var', (24, 28))	('increase', 'PosReg', (68, 76))	('ROS levels', 'MPA', (77, 87))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))	('EF24', 'Chemical', '-', (24, 28))	('increase ROS levels', 'Phenotype', 'HP:0025464', (68, 87))
112562	31212829	In particular, EF24 induced a major ROS increase compared to mitotane, while their combination (EF24 + mitotane) further enhanced ROS levels in both cell lines.	('EF24', 'Var', (15, 19))	('EF24', 'Chemical', '-', (15, 19))	('ROS', 'Chemical', 'MESH:D017382', (130, 133))	('enhanced ROS levels', 'Phenotype', 'HP:0025464', (121, 140))	('mitotane', 'Chemical', 'MESH:D008939', (61, 69))	('ROS increase', 'Phenotype', 'HP:0025464', (36, 48))	('ROS', 'MPA', (36, 39))	('increase', 'PosReg', (40, 48))	('enhanced', 'PosReg', (121, 129))	('mitotane', 'Chemical', 'MESH:D008939', (103, 111))	('EF24', 'Chemical', '-', (96, 100))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('ROS levels', 'MPA', (130, 140))
112564	31212829	This research work analyzed, for the first time, the use of EF24, a curcumin derivative with increased availability, in two adrenocortical tumor cell lines, SW13 and H295R cells, the only adrenocortical tumors available for studying.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('EF24', 'Var', (60, 64))	('SW13', 'CellLine', 'CVCL:0542', (157, 161))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (188, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('curcumin', 'Chemical', 'MESH:D003474', (68, 76))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (188, 208))	('EF24', 'Chemical', '-', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('adrenocortical tumors', 'Disease', (188, 209))	('H295R', 'CellLine', 'CVCL:0458', (166, 171))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (124, 144))	('adrenocortical tumor', 'Disease', (124, 144))
112568	31212829	As shown in Figure 2, EF24 decreased cell viability in a time- and concentration-dependent way in both cell lines, with an IC50 of 6.5 muM for SW13 cells and 5 muM for H295R cells.	('muM', 'Gene', (160, 163))	('SW13', 'CellLine', 'CVCL:0542', (143, 147))	('EF24', 'Var', (22, 26))	('decreased', 'NegReg', (27, 36))	('EF24', 'Chemical', '-', (22, 26))	('H295R', 'CellLine', 'CVCL:0458', (168, 173))	('muM', 'Gene', '56925', (135, 138))	('muM', 'Gene', '56925', (160, 163))	('muM', 'Gene', (135, 138))	('cell viability', 'CPA', (37, 51))
112570	31212829	Similar results were found in ovarian carcinoma cells (SK-OV-3 and IGROV1), where EF24 induced a time- and dose-dependent suppression of cell growth and viability.	('EF24', 'Var', (82, 86))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (30, 47))	('EF24', 'Chemical', '-', (82, 86))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (30, 47))	('ovarian carcinoma', 'Disease', (30, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('suppression', 'NegReg', (122, 133))
112572	31212829	This result supported a substantially unaltered cell cycle distribution in adrenocortical cell lines treated by EF24.	('EF24', 'Var', (112, 116))	('EF24', 'Chemical', '-', (112, 116))	('adrenocortical', 'Disease', (75, 89))	('cell cycle distribution', 'CPA', (48, 71))	('adrenocortical', 'Disease', 'MESH:D018268', (75, 89))
112573	31212829	Moreover, it emphasizes how EF24 can induce a strong cell death mechanism, as suggested by cell viability data and cell morphology (Figure 5).	('EF24', 'Var', (28, 32))	('EF24', 'Chemical', '-', (28, 32))	('induce', 'Reg', (37, 43))	('cell death', 'CPA', (53, 63))
112575	31212829	Similarly, in ovarian and hepatocellular carcinoma cell lines, EF24 could reduce cell migration aptitude.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('reduce', 'NegReg', (74, 80))	('cell migration aptitude', 'CPA', (81, 104))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (26, 50))	('ovarian and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (14, 50))	('EF24', 'Var', (63, 67))	('EF24', 'Chemical', '-', (63, 67))
112579	31212829	EF24 can potentially act on these fundamental cell signaling pathways.	('act', 'Reg', (21, 24))	('EF24', 'Var', (0, 4))	('EF24', 'Chemical', '-', (0, 4))	('fundamental cell signaling pathways', 'Pathway', (34, 69))
112583	31212829	Of note, phospho-NF-kappaB was augmented by EF24 at 5 h in both cell lines and at 72 h in H295R cells (Figure 7A,B); similar results have already been reported, underlining that small doses of curcumin could enhance proliferation and survival and could possibly potentiate cell death by DNA damage or oxidative stress.	('oxidative stress', 'Phenotype', 'HP:0025464', (301, 317))	('EF24', 'Var', (44, 48))	('cell death', 'CPA', (273, 283))	('EF24', 'Chemical', '-', (44, 48))	('survival', 'CPA', (234, 242))	('potentiate', 'PosReg', (262, 272))	('augmented', 'PosReg', (31, 40))	('NF-kappaB', 'Gene', '4790', (17, 26))	('phospho', 'Chemical', 'MESH:D004099', (9, 16))	('NF-kappaB', 'Gene', (17, 26))	('enhance', 'PosReg', (208, 215))	('curcumin', 'Chemical', 'MESH:D003474', (193, 201))	('H295R', 'CellLine', 'CVCL:0458', (90, 95))	('proliferation', 'CPA', (216, 229))
112584	31212829	On the same line, we showed an increase in phosphorylation of Erk1/2 at 5 h in SW13 cells (by EF24 alone or combined), suggesting that under certain circumstances, Erk1/2 can have pro-apoptotic functions, as it is the most important balance between pro- and anti-proliferative signals (Figure 3 and Figure S1), which was already reported by Thomas et al.	('phosphorylation', 'MPA', (43, 58))	('pro-apoptotic functions', 'CPA', (180, 203))	('SW13', 'CellLine', 'CVCL:0542', (79, 83))	('phospho', 'Chemical', 'MESH:D004099', (43, 50))	('Erk1/2', 'Var', (164, 170))	('EF24', 'Chemical', '-', (94, 98))
112585	31212829	in 2010, where EF24 was shown to significantly induce the upregulation of Erk1/2, JNK, and p38 (MAPK pathway).	('EF24', 'Var', (15, 19))	('EF24', 'Chemical', '-', (15, 19))	('upregulation', 'PosReg', (58, 70))	('JNK', 'Gene', (82, 85))	('p38', 'Gene', (91, 94))	('JNK', 'Gene', '5599', (82, 85))	('Erk1/2', 'Protein', (74, 80))	('p38', 'Gene', '5594', (91, 94))
112586	31212829	Interestingly, when treating SW13 cells with EF24, phospho-beta-catenin was reduced, while phospho-NF-kappaB was increased, suggesting a plausible crosstalk between Wnt/beta-catenin and inflammation pathways as already reported.	('NF-kappaB', 'Gene', '4790', (99, 108))	('phospho', 'Chemical', 'MESH:D004099', (51, 58))	('beta-catenin', 'Gene', '1499', (59, 71))	('EF24', 'Var', (45, 49))	('beta-catenin', 'Gene', (169, 181))	('NF-kappaB', 'Gene', (99, 108))	('crosstalk', 'Reg', (147, 156))	('reduced', 'NegReg', (76, 83))	('phospho', 'Chemical', 'MESH:D004099', (91, 98))	('EF24', 'Chemical', '-', (45, 49))	('increased', 'PosReg', (113, 122))	('SW13', 'CellLine', 'CVCL:0542', (29, 33))	('beta-catenin', 'Gene', '1499', (169, 181))	('beta-catenin', 'Gene', (59, 71))
112591	31212829	Both SW13 and H295R showed a significant increase of ROS levels with EF24, mitotane, or their combination.	('mitotane', 'Chemical', 'MESH:D008939', (75, 83))	('increase of ROS levels', 'Phenotype', 'HP:0025464', (41, 63))	('H295R', 'Var', (14, 19))	('ROS', 'Chemical', 'MESH:D017382', (53, 56))	('ROS levels', 'MPA', (53, 63))	('H295R', 'CellLine', 'CVCL:0458', (14, 19))	('EF24', 'Var', (69, 73))	('EF24', 'Chemical', '-', (69, 73))	('SW13', 'CellLine', 'CVCL:0542', (5, 9))	('increase', 'PosReg', (41, 49))
112593	31212829	Similarly, EF24 was able to generate ROS production in MDA-MB-231 (human breast cancer) cells; DU-145 (human prostate cancer) cells; SGC-7901, BGC-823, KATO III (human gastric cancer) cells; and HCT-116, SW-620, and HT-29 (human colon cancer) cells.	('colon cancer', 'Disease', (229, 241))	('HT-29', 'CellLine', 'CVCL:0320', (216, 221))	('SW-620', 'CellLine', 'CVCL:0547', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('gastric cancer', 'Disease', 'MESH:D013274', (168, 182))	('ROS production', 'MPA', (37, 51))	('human', 'Species', '9606', (103, 108))	('human', 'Species', '9606', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('MDA-MB-231', 'Gene', (55, 65))	('EF24', 'Var', (11, 15))	('HCT-116', 'CellLine', 'CVCL:0291', (195, 202))	('colon cancer', 'Phenotype', 'HP:0003003', (229, 241))	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (109, 124))	('EF24', 'Chemical', '-', (11, 15))	('ROS', 'Chemical', 'MESH:D017382', (37, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (109, 124))	('DU-145', 'CellLine', 'CVCL:0105', (95, 101))	('colon cancer', 'Disease', 'MESH:D015179', (229, 241))	('prostate cancer', 'Disease', (109, 124))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (55, 65))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('human', 'Species', '9606', (162, 167))	('breast cancer', 'Disease', (73, 86))	('gastric cancer', 'Disease', (168, 182))	('human', 'Species', '9606', (67, 72))
112631	31212829	E: EF24 at 6.5 muM for SW13 and 5 muM for H295R cells.	('muM', 'Gene', (15, 18))	('muM', 'Gene', '56925', (34, 37))	('muM', 'Gene', (34, 37))	('EF24', 'Var', (3, 7))	('EF24', 'Chemical', '-', (3, 7))	('H295R', 'CellLine', 'CVCL:0458', (42, 47))	('muM', 'Gene', '56925', (15, 18))	('SW13', 'CellLine', 'CVCL:0542', (23, 27))
112651	30768667	In addition to its rapid effects, ACTH also stimulates a delayed/genomic steroidogenic pathway, which modulates the CREB-dependent transcription of steroidogenic-related genes including MC2R, the MC2R accessory protein MRAP, StAR, and CYP11A1, presumably to prime the cell for the next surge in plasma ACTH.	('CYP11A1', 'Var', (235, 242))	('modulates', 'Reg', (102, 111))	('delayed/genomic steroidogenic pathway', 'Pathway', (57, 94))	('stimulates', 'PosReg', (44, 54))	('ACTH', 'Var', (34, 38))	('CREB-dependent transcription', 'MPA', (116, 144))	('steroid', 'Chemical', 'MESH:D013256', (73, 80))	('MC2R', 'Gene', (186, 190))	('steroid', 'Chemical', 'MESH:D013256', (148, 155))	('steroidogenic-related genes', 'Gene', (148, 175))
112654	30768667	ACTH also modulates the expression of these transcription factors: ACTH increases the expression of the activators SF-1 and Nur77 but transiently downregulates the expression of the repressor DAX-1.	('DAX-1', 'Gene', '11614', (192, 197))	('ACTH increases', 'Phenotype', 'HP:0011749', (67, 81))	('SF-1', 'Gene', (115, 119))	('increases', 'PosReg', (72, 81))	('expression', 'MPA', (164, 174))	('expression', 'MPA', (86, 96))	('Nur77', 'Gene', (124, 129))	('downregulates', 'NegReg', (146, 159))	('DAX-1', 'Gene', (192, 197))	('ACTH', 'Var', (67, 71))
112662	30768667	Consequently, many studies of ACTH-mediated steroidogenesis have been conducted with a nonphenotypic human NCI-H295 cell line that shares the phenotypes of all three adrenal cortical layers, and only few have used the NCI-H295R subpopulations of NCI-H295 cells (H295R-S1, H295R-S2, H295R-S3), which have ZF-specific characteristics.	('NCI-H295', 'CellLine', 'CVCL:0456', (218, 226))	('NCI-H295', 'CellLine', 'CVCL:0456', (246, 254))	('H295R-S3', 'Var', (282, 290))	('H295R-S2', 'Var', (272, 280))	('NCI-H295 cells', 'CellLine', 'CVCL:0456', (246, 260))	('human', 'Species', '9606', (101, 106))	('NCI-H295', 'CellLine', 'CVCL:0456', (107, 115))	('steroid', 'Chemical', 'MESH:D013256', (44, 51))
112696	30768667	The rapid increase in pCREB induced by a pulse of ACTH was followed by a dynamic increase in StAR, MRAP, and Nur77 hnRNA, all with a peak at 15 minutes (P < 0.0001), and a dynamic increase in SF-1 hnRNA, with peak at 30 minutes [P = 0.0139; Fig.	('pCREB', 'MPA', (22, 27))	('SF-1 hnRNA', 'Gene', '22668', (192, 202))	('StAR', 'MPA', (93, 97))	('increase', 'PosReg', (180, 188))	('SF-1 hnRNA', 'Gene', (192, 202))	('Nur77 hnRNA', 'MPA', (109, 120))	('MRAP', 'MPA', (99, 103))	('pCREB', 'Chemical', '-', (22, 27))	('increase', 'PosReg', (81, 89))	('increase', 'PosReg', (10, 18))	('ACTH', 'Var', (50, 54))
112710	30768667	Each 10-minute ACTH pulse induced a significant increase in StAR and Nur77 hnRNA expression, with three peaks occurring (as observed for pCREB) at 15, 75, and 135 minutes (StAR hnRNA, P = 0.0005, P = 0.0019, and P = 0.0086, respectively; Nur77 hnRNA, all Ps < 0.0001).	('pCREB', 'Chemical', '-', (137, 142))	('Nur77', 'Gene', (69, 74))	('StAR', 'MPA', (60, 64))	('ACTH', 'Var', (15, 19))	('expression', 'MPA', (81, 91))	('increase', 'PosReg', (48, 56))
112745	30768667	Previously, we showed in vivo that an ultradian pulse of ACTH results in rapid and transient activation of the genomic steroidogenic pathway in the rat adrenal, that is, a rapid and transient activation of the steroidogenic-related proteins CREB and increases in the primary transcript (hnRNA) of the steroidogenic-related genes StAR, CYP11A1, SF-1, MC2R, MRAP, and Nur77.	('Nur77', 'Gene', (366, 371))	('activation', 'PosReg', (93, 103))	('SF-1', 'Gene', (344, 348))	('rat', 'Species', '10116', (148, 151))	('MRAP', 'Gene', (356, 360))	('genomic steroidogenic pathway', 'Pathway', (111, 140))	('CREB', 'Protein', (241, 245))	('CYP11A1', 'Gene', (335, 342))	('steroid', 'Chemical', 'MESH:D013256', (210, 217))	('activation', 'PosReg', (192, 202))	('increases', 'PosReg', (250, 259))	('steroid', 'Chemical', 'MESH:D013256', (301, 308))	('MC2R', 'Gene', (350, 354))	('steroid', 'Chemical', 'MESH:D013256', (119, 126))	('ACTH', 'Var', (57, 61))
112758	30768667	showed that the basal levels of corticosterone secretion were seven times higher in ATC7 cells than in ATC1 cells.	('corticosterone', 'Chemical', 'MESH:D003345', (32, 46))	('ATC7', 'Var', (84, 88))	('higher', 'PosReg', (74, 80))
112771	30768667	This disruption can activate various transduction pathways, including the cAMP/PKA/CREB cascade.	('cAMP', 'Chemical', 'MESH:D000242', (74, 78))	('disruption', 'Var', (5, 15))	('activate', 'Reg', (20, 28))	('cAMP/PKA/CREB', 'Disease', (74, 87))	('transduction pathways', 'Pathway', (37, 58))
112849	28491398	Venous blood gas analysis was consistent with a metabolic alkalosis (pH 7.341, HCO3 29.2 mmol/l) with respiratory compensation (partial pressure of carbon dioxide 53.4 mmHg).	('alkalosis', 'Phenotype', 'HP:0001948', (58, 67))	('carbon dioxide', 'Chemical', 'MESH:D002245', (148, 162))	('Venous blood gas', 'Disease', 'MESH:D011007', (0, 16))	('Venous blood gas', 'Disease', (0, 16))	('metabolic alkalosis', 'Disease', (48, 67))	('metabolic alkalosis', 'Disease', 'MESH:D000471', (48, 67))	('metabolic alkalosis', 'Phenotype', 'HP:0200114', (48, 67))	('pH', 'Var', (69, 71))	('HCO3', 'Chemical', 'MESH:D001639', (79, 83))
112917	25456949	Tumor size greater than 4-6 cm, heterogeneous patterns and irregular surfaces on imaging, and hormone hypersecretion all increase the likelihood of malignancy.	('hormone hypersecretion', 'CPA', (94, 116))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('increase', 'PosReg', (121, 129))	('malignancy', 'Disease', 'MESH:D009369', (148, 158))	('malignancy', 'Disease', (148, 158))	('heterogeneous', 'Var', (32, 45))
112932	25456949	Patients were included if they had a SITE_02 variable that coded for adrenal tumor; International Classification of Disease (ICD)-0-3 codes C74.0, C74.1, and C74.9; as well as the following ICD-0-3 histology codes to ensure that only patients with ACC were captured: 8010 (carcinoma, not otherwise specified), 8020 (carcinoma, undifferentiated type), 8140 (adenocarcinoma, not otherwise specified), and 8370 (adrenal cortical carcinoma).	('C74.1', 'Var', (147, 152))	('adenocarcinoma', 'Disease', (357, 371))	('adrenal tumor', 'Disease', 'MESH:D000310', (69, 82))	('adrenal tumor', 'Phenotype', 'HP:0100631', (69, 82))	('carcinoma', 'Disease', 'MESH:D002277', (426, 435))	('carcinoma', 'Disease', 'MESH:D002277', (362, 371))	('SITE', 'Disease', 'OMIM:136570', (37, 41))	('carcinoma', 'Disease', 'MESH:D002277', (273, 282))	('Patients', 'Species', '9606', (0, 8))	('adenocarcinoma', 'Disease', 'MESH:D000230', (357, 371))	('patients', 'Species', '9606', (234, 242))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('adrenal cortical carcinoma', 'Phenotype', 'HP:0006744', (409, 435))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('coded', 'Reg', (59, 64))	('C74.0', 'Var', (140, 145))	('adrenal tumor', 'Disease', (69, 82))	('adrenal cortical carcinoma', 'Disease', (409, 435))	('carcinoma', 'Disease', (316, 325))	('C74.9', 'Var', (158, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (426, 435))	('carcinoma', 'Disease', (426, 435))	('SITE', 'Disease', (37, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (362, 371))	('adrenal cortical carcinoma', 'Disease', 'MESH:D018268', (409, 435))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('carcinoma', 'Disease', (362, 371))	('carcinoma', 'Disease', (273, 282))	('carcinoma', 'Disease', 'MESH:D002277', (316, 325))
112968	25456949	For patients with regional disease, both surgery (HR 0.20, P=0.0002) and S+CRT (HR 0.19, P=0.0057) were associated with improved survival over no treatment.	('S+CRT', 'Var', (73, 78))	('improved', 'PosReg', (120, 128))	('patients', 'Species', '9606', (4, 12))	('survival', 'MPA', (129, 137))
112969	25456949	Patients with metastatic disease had improved survival with surgery (HR 0.42, P=0.0008), CRT (HR 0.56, P=0.0058), and S+CRT (HR 0.24, P<0.0001) over no treatment.	('S+CRT', 'Var', (118, 123))	('Patients', 'Species', '9606', (0, 8))	('improved', 'PosReg', (37, 45))	('metastatic disease', 'Disease', (14, 32))	('survival', 'CPA', (46, 54))
112973	25456949	In stage-specific multivariable regression analysis, for patients with regional disease (Table 4a), both surgery (HR 0.13, P<0.001) and S+CRT (HR 0.15, P=0.0079) were associated with improved survival over no treatment.	('S+CRT', 'Var', (136, 141))	('improved', 'PosReg', (183, 191))	('survival', 'MPA', (192, 200))	('patients', 'Species', '9606', (57, 65))
112980	25456949	S+CRT may improve survival over surgery alone for metastatic patients, but we could not show a statistically significant relationship in our study likely due to low power.	('S+CRT', 'Var', (0, 5))	('improve', 'PosReg', (10, 17))	('survival', 'MPA', (18, 26))	('patients', 'Species', '9606', (61, 69))
112990	25456949	Mitotane inhibits steroid synthesis and induces hepatic clearance of cortisol, and it can improve symptoms related to Cushing's syndrome.	('hepatic clearance of cortisol', 'MPA', (48, 77))	('Mitotane', 'Var', (0, 8))	('symptoms', 'MPA', (98, 106))	('steroid synthesis', 'MPA', (18, 35))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('steroid', 'Chemical', 'MESH:D013256', (18, 25))	('improve', 'PosReg', (90, 97))	('inhibits', 'NegReg', (9, 17))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (118, 136))	('induces', 'PosReg', (40, 47))	("Cushing's syndrome", 'Disease', (118, 136))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (118, 136))
113028	25639868	These genomic data provide the foundation to launch new research efforts to address one of the fundamental questions in cancer biology:why are some cells more susceptible to malignant transformation by particular genetic lesions at discrete developmental stages than others?	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('genetic lesions', 'Var', (213, 228))	('lesions', 'Var', (221, 228))
113052	25639868	For example, RB1 inactivation contributes to retinoblastoma initiation by promoting cell cycle progression, but the RB1 protein is also required for rod photoreceptor differentiation.	('inactivation', 'Var', (17, 29))	('RB1', 'Gene', '5925', (13, 16))	('RB1', 'Gene', '5925', (116, 119))	('RB1', 'Gene', (116, 119))	('retinoblastoma initiation', 'Disease', 'MESH:D012175', (45, 70))	('cell cycle progression', 'CPA', (84, 106))	('retinoblastoma', 'Phenotype', 'HP:0009919', (45, 59))	('promoting', 'PosReg', (74, 83))	('RB1', 'Gene', (13, 16))	('retinoblastoma initiation', 'Disease', (45, 70))
113056	25639868	When a tumor-initiating mutation occurs in those distinct progenitor cell populations, the consequence may vary dramatically depending on the competence of that cell at that particular stage of development.	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('mutation', 'Var', (24, 32))	('tumor', 'Disease', (7, 12))
113057	25639868	For example, in one cell population, an oncogenic mutation may result in a tumor with cellular features of skeletal muscle such as rhabdomyosarcoma, whereas in another, the same mutation may lead to rapid cell death or a tumor with osteogenic features (Figure 2).	('lead to', 'Reg', (191, 198))	('rhabdomyosarcoma', 'Disease', (131, 147))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (131, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('osteogenic features', 'CPA', (232, 251))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('death', 'Disease', 'MESH:D003643', (210, 215))	('death', 'Disease', (210, 215))	('result in', 'Reg', (63, 72))	('tumor', 'Disease', (75, 80))	('mutation', 'Var', (50, 58))
113058	25639868	Indeed, recent studies in genetically engineered mouse models show that perturbations in the hedgehog pathway in the adipose lineage can lead to rhabdomyosarcoma with features of skeletal muscle typical of human rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (145, 161))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (212, 228))	('rhabdomyosarcoma', 'Disease', (145, 161))	('human', 'Species', '9606', (206, 211))	('lead to', 'Reg', (137, 144))	('hedgehog pathway', 'Pathway', (93, 109))	('mouse', 'Species', '10090', (49, 54))	('rhabdomyosarcoma', 'Disease', (212, 228))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (145, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (221, 228))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (212, 228))	('perturbations', 'Var', (72, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (154, 161))
113059	25639868	Thus, the competence of individual progenitor cells and the specific oncogenic mutations affect when and where pediatric solid tumors arise during development.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('pediatric solid tumors', 'Disease', (111, 133))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (111, 133))	('affect', 'Reg', (89, 95))	('mutations', 'Var', (79, 88))
113060	25639868	The interplay between the specific tumor mutations and differentiation programs, combined with the dynamic intrinsic cellular competence, make it difficult to pinpoint a cell of origin from the molecular or cellular features of the resulting tumors.	('mutations', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (242, 247))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('tumors', 'Disease', (242, 248))
113072	25639868	It was previously thought that this was due to the requirement of secondary and tertiary genetic lesions after inactivation of the Rb1 gene.	('Rb1', 'Gene', (131, 134))	('inactivation', 'Var', (111, 123))	('Rb1', 'Gene', '5925', (131, 134))
113087	25639868	The majority of TP53 mutations in osteosarcomas are translocations in the first intron of the gene.	('osteosarcomas', 'Disease', (34, 47))	('osteosarcomas', 'Phenotype', 'HP:0002669', (34, 47))	('osteosarcoma', 'Phenotype', 'HP:0002669', (34, 46))	('osteosarcomas', 'Disease', 'MESH:D012516', (34, 47))	('TP53', 'Gene', '7157', (16, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (39, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
113089	25639868	To the best of our knowledge, this type of TP53 mutation occurs only in a rare subset of prostate cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancers', 'Disease', 'MESH:D011471', (89, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('prostate cancers', 'Phenotype', 'HP:0012125', (89, 105))	('prostate cancers', 'Disease', (89, 105))	('mutation', 'Var', (48, 56))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
113091	25639868	Careful analysis of mutant allele frequency and tumor heterogeneity showed that TP53 mutations are initiating genetic events in osteosarcoma.	('tumor', 'Disease', (48, 53))	('TP53', 'Gene', '7157', (80, 84))	('osteosarcoma', 'Disease', (128, 140))	('TP53', 'Gene', (80, 84))	('mutations', 'Var', (85, 94))	('osteosarcoma', 'Phenotype', 'HP:0002669', (128, 140))	('osteosarcoma', 'Disease', 'MESH:D012516', (128, 140))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))
113092	25639868	In many tumor types, inactivation of the p53 pathway can lead to an increase in translocations and other chromosomal events because of perturbations in DNA damage checkpoint control.	('p53', 'Gene', '7157', (41, 44))	('inactivation', 'Var', (21, 33))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('chromosomal events', 'CPA', (105, 123))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('increase', 'PosReg', (68, 76))	('tumor', 'Disease', (8, 13))	('DNA damage checkpoint control', 'MPA', (152, 181))	('translocations', 'MPA', (80, 94))	('p53', 'Gene', (41, 44))
113093	25639868	However, many pediatric osteosarcomas are initiated through a structural variation occurring at very high frequency in TP53 itself.	('initiated through', 'Reg', (42, 59))	('osteosarcomas', 'Disease', (24, 37))	('osteosarcomas', 'Phenotype', 'HP:0002669', (24, 37))	('osteosarcoma', 'Phenotype', 'HP:0002669', (24, 36))	('structural variation', 'Var', (62, 82))	('osteosarcomas', 'Disease', 'MESH:D012516', (24, 37))	('sarcomas', 'Phenotype', 'HP:0100242', (29, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
113095	25639868	One intriguing possibility is that the cell of origin for osteosarcoma has a higher rate of chromosomal lesions and structural variations than do other cellular lineages.	('osteosarcoma', 'Disease', (58, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('osteosarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('osteosarcoma', 'Disease', 'MESH:D012516', (58, 70))	('chromosomal', 'Var', (92, 103))	('structural variations', 'CPA', (116, 137))
113101	25639868	Translocations that are predicted to produce in-frame fusion proteins are rare in retinoblastoma.	('retinoblastoma', 'Gene', (82, 96))	('retinoblastoma', 'Gene', '5925', (82, 96))	('Translocations', 'Var', (0, 14))	('retinoblastoma', 'Phenotype', 'HP:0009919', (82, 96))
113102	25639868	In contrast, osteosarcomas have 266 SVs per tumor (range 47-1135), 50% of their genome is involved in CNVs (range 3-89%) and have 46 single nucleotide variations in coding regions (range 16-237).	('osteosarcoma', 'Phenotype', 'HP:0002669', (13, 25))	('osteosarcomas', 'Disease', (13, 26))	('single nucleotide variations', 'Var', (133, 161))	('osteosarcomas', 'Phenotype', 'HP:0002669', (13, 26))	('sarcomas', 'Phenotype', 'HP:0100242', (18, 26))	('osteosarcomas', 'Disease', 'MESH:D012516', (13, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('involved', 'Reg', (90, 98))	('tumor', 'Disease', (44, 49))
113103	25639868	On average, 8.5 translocations per tumor (median value) produce a novel fusion protein in osteosarcoma.	('fusion protein', 'Protein', (72, 86))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('translocations', 'Var', (16, 30))	('osteosarcoma', 'Disease', (90, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (90, 102))	('osteosarcoma', 'Disease', 'MESH:D012516', (90, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))
113119	25639868	Ewing sarcomas are initiated by EWS-FLI1 translocations, and WGS of 112 tumors and matched germline tissue revealed that the tumors have very few secondary genetic lesions.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', (72, 78))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (0, 13))	('sarcomas', 'Phenotype', 'HP:0100242', (6, 14))	('translocations', 'Var', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('EWS', 'Gene', (32, 35))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('FLI1', 'Gene', (36, 40))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (0, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('FLI1', 'Gene', '2313', (36, 40))	('Ewing sarcomas', 'Disease', (0, 14))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (0, 14))	('initiated', 'Reg', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('EWS', 'Gene', '2130', (32, 35))
113120	25639868	Similarly, ARMS are initiated by PAX3/7-FOXO translocations and have few secondary genetic lesions.	('PAX3', 'Gene', '5077', (33, 37))	('ARMS', 'Disease', (11, 15))	('PAX3', 'Gene', (33, 37))	('initiated', 'Reg', (20, 29))	('ARMS', 'Phenotype', 'HP:0006779', (11, 15))	('translocations', 'Var', (45, 59))
113122	25639868	In addition to these striking differences in the genomic landscape of oncogenic fusion protein-driven pediatric solid tumors, several other unique patterns of DNA mutations contribute to our understanding of cellular origins and the unique developmental context that predisposes some cellular lineages to malignant transformation.	('mutations', 'Var', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('DNA', 'Gene', (159, 162))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('pediatric solid tumors', 'Disease', (102, 124))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (102, 124))
113136	25639868	All tumors with the kataegis pattern carried mutated TP53.	('TP53', 'Gene', (53, 57))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('TP53', 'Gene', '7157', (53, 57))	('carried', 'Reg', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutated', 'Var', (45, 52))
113141	25639868	Unlike chromothripsis, there is no evidence supporting that mutations associated with kataegis contribute to tumor initiation or progression in pediatric solid tumors.	('pediatric solid tumors', 'Disease', (144, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('contribute', 'Reg', (95, 105))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (144, 166))	('progression', 'CPA', (129, 140))	('chromothripsis', 'Disease', 'MESH:D000072837', (7, 21))	('tumor initiation', 'Disease', 'MESH:D009369', (109, 125))	('kataegis', 'Gene', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor initiation', 'Disease', (109, 125))	('mutations', 'Var', (60, 69))	('chromothripsis', 'Disease', (7, 21))
113149	25639868	It is possible that a single oncogenic event, such as formation of the EWS-FLI1 oncogene, promotes the formation of Ewing sarcoma in a stochastic manner through active epigenetic reprogramming, as seen in the formation of induced pluripotent stem cells from somatic cells (Figure 2).	('Ewing sarcoma', 'Disease', (116, 129))	('EWS', 'Gene', '2130', (71, 74))	('EWS', 'Gene', (71, 74))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (116, 129))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (116, 129))	('promotes', 'PosReg', (90, 98))	('FLI1', 'Gene', (75, 79))	('epigenetic', 'Var', (168, 178))	('FLI1', 'Gene', '2313', (75, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
113154	25639868	One of the most important advances resulting from the genomic analysis of pediatric cancer over the past 5 years was the discovery that epigenetics plays a major role in tumor initiation and progression.	('pediatric cancer', 'Disease', (74, 90))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor initiation', 'Disease', 'MESH:D009369', (170, 186))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pediatric cancer', 'Disease', 'MESH:D009369', (74, 90))	('tumor initiation', 'Disease', (170, 186))	('epigenetics', 'Var', (136, 147))
113157	25639868	An integrated analysis of DNA methylation, gene expression and histone modification in retinoblastoma showed that the expression of several oncogenes and tumor suppressor genes was altered through epigenetic mechanisms.	('altered', 'Reg', (181, 188))	('retinoblastoma', 'Gene', (87, 101))	('retinoblastoma', 'Gene', '5925', (87, 101))	('retinoblastoma', 'Phenotype', 'HP:0009919', (87, 101))	('epigenetic', 'Var', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('oncogenes', 'Gene', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('expression', 'MPA', (118, 128))	('tumor', 'Disease', (154, 159))
113160	25639868	Another unexpected discovery that highlighted the importance of epigenetics in solid tumor progression was that of recurrent mutations in the epigenetic modulators themselves.	('mutations', 'Var', (125, 134))	('tumor', 'Disease', (85, 90))	('epigenetic', 'Gene', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
113163	25639868	During development, BCOR is thought to maintain tissue homeostasis and gene silencing through epigenetic mechanisms.	('gene', 'Var', (71, 75))	('BCOR', 'Gene', '54880', (20, 24))	('BCOR', 'Gene', (20, 24))
113166	25639868	Further analyses of the epigenome of retinoblastomas with wild-type and mutant BCOR are required to identify the key target genes for tumor progression.	('retinoblastoma', 'Phenotype', 'HP:0009919', (37, 51))	('BCOR', 'Gene', '54880', (79, 83))	('mutant', 'Var', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('retinoblastomas', 'Disease', 'MESH:D012175', (37, 52))	('retinoblastomas', 'Disease', (37, 52))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('retinoblastomas', 'Phenotype', 'HP:0009919', (37, 52))	('tumor', 'Disease', (134, 139))	('BCOR', 'Gene', (79, 83))
113171	25639868	In neuroblastomas, ATRX mutations are associated with age at diagnosis, which is highly predictive of overall survival.21,32 In adrenocortical carcinomas, ATRX mutations, which occurred in tumors harboring TP53 mutations, are associated with genome instability, advanced tumor stage and poor outcomes.	('neuroblastoma', 'Phenotype', 'HP:0003006', (3, 16))	('genome instability', 'CPA', (242, 260))	('mutations', 'Var', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('adrenocortical carcinomas', 'Disease', (128, 153))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('TP53', 'Gene', '7157', (206, 210))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (128, 152))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('ATRX', 'Gene', (155, 159))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (128, 153))	('ATRX', 'Gene', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('ATRX', 'Gene', '546', (155, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('ATRX', 'Gene', '546', (19, 23))	('tumor', 'Disease', (271, 276))	('tumors', 'Disease', (189, 195))	('neuroblastomas', 'Phenotype', 'HP:0003006', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('neuroblastomas', 'Disease', (3, 17))	('tumor', 'Disease', (189, 194))	('TP53', 'Gene', (206, 210))	('associated', 'Reg', (226, 236))	('mutations', 'Var', (211, 220))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('neuroblastomas', 'Disease', 'MESH:D009447', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (128, 153))
113172	25639868	Interestingly, ATRX mutations have never been found in combination with MYCN amplification in neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (94, 107))	('ATRX', 'Gene', '546', (15, 19))	('neuroblastoma', 'Disease', (94, 107))	('MYCN', 'Gene', (72, 76))	('neuroblastoma', 'Phenotype', 'HP:0003006', (94, 107))	('ATRX', 'Gene', (15, 19))	('MYCN', 'Gene', '4613', (72, 76))	('mutations', 'Var', (20, 29))
113173	25639868	Further comprehensive studies are required to determine whether ATRX mutations are an independent prognostic risk factor for neuroblastoma.	('mutations', 'Var', (69, 78))	('ATRX', 'Gene', (64, 68))	('neuroblastoma', 'Disease', (125, 138))	('ATRX', 'Gene', '546', (64, 68))	('neuroblastoma', 'Phenotype', 'HP:0003006', (125, 138))	('neuroblastoma', 'Disease', 'MESH:D009447', (125, 138))
113174	25639868	In most tumors with ATRX mutations, cells have longer telomeres as a result of alternative lengthening of telomeres, which is a mechanism of telomere maintenance in cancer.	('mutations', 'Var', (25, 34))	('longer', 'PosReg', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ATRX', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('cancer', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('ATRX', 'Gene', '546', (20, 24))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))
113177	25639868	Germline ATRX mutations lead to the X-linked alpha thalassemia/mental retardation syndrome, which is associated with diverse developmental defects.	('thalassemia/mental retardation syndrome', 'Disease', (51, 90))	('ATRX', 'Gene', '546', (9, 13))	('developmental defects', 'Disease', (125, 146))	('developmental defects', 'Disease', 'MESH:D003147', (125, 146))	('thalassemia/mental retardation syndrome', 'Disease', 'MESH:C538258', (51, 90))	('lead to', 'Reg', (24, 31))	('ATRX', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('mental retardation', 'Phenotype', 'HP:0001249', (63, 81))
113178	25639868	Although alternative lengthening of telomeres and telomere maintenance are important for tumorigenesis, inactivation of ATRX may also contribute to perturbations in other cellular pathways through epigenetic mechanisms.	('ATRX', 'Gene', (120, 124))	('contribute', 'Reg', (134, 144))	('ATRX', 'Gene', '546', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('inactivation', 'Var', (104, 116))	('perturbations', 'NegReg', (148, 161))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
113182	25639868	Epigenetics has emerged as a major focus area in pediatric solid tumor research because of the striking changes in the epigenetic landscape after inactivation of tumor suppressor genes such as RB1 and the identification of recurrent mutations in epigenetic regulators such as BCOR and ATRX.	('epigenetic landscape', 'MPA', (119, 139))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (65, 70))	('RB1', 'Gene', (193, 196))	('BCOR', 'Gene', (276, 280))	('tumor', 'Disease', (162, 167))	('inactivation', 'NegReg', (146, 158))	('changes', 'Reg', (104, 111))	('BCOR', 'Gene', '54880', (276, 280))	('ATRX', 'Gene', (285, 289))	('RB1', 'Gene', '5925', (193, 196))	('ATRX', 'Gene', '546', (285, 289))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mutations', 'Var', (233, 242))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
113183	25639868	By integrating these tumor data with epigenomic profiling of normal cells during development, we can develop a new framework to understand why some oncogenic mutations cause specific types of tumors in restricted cell lineages during development.	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', (21, 26))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('cause', 'Reg', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('mutations', 'Var', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
113186	25639868	Therefore, the effect of tumor suppressor gene inactivation or proto-oncogene activation on tumor initiation and progression is also likely to be dependent on cellular lineage and developmental stage.	('inactivation', 'Var', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor initiation', 'Disease', 'MESH:D009369', (92, 108))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor initiation', 'Disease', (92, 108))
113188	25639868	Specifically, it is possible that individual oncogenic lesions in a particular cellular lineage at a unique developmental stage lead to cancer but other combinations of mutation, lineage and stage are not tolerated.	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('lesions', 'Var', (55, 62))	('lead to', 'Reg', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
113192	25639868	Although all partitioned domains are not likely to be maintained in the tumor cells because of changes associated with age and/or genetic mutations in cancer cells, a sufficient number may remain to identify the developmental- and lineage-specific remnants of the cell of origin.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', (72, 77))	('genetic mutations', 'Var', (130, 147))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('mutations', 'Var', (138, 147))
113205	25639868	For example, pediatric cancer is rare, and it may be difficult to establish the statistical significance of new therapies for rare subsets of patients receiving individualized treatment based on the mutations found in their tumors.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('pediatric cancer', 'Disease', (13, 29))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('mutations', 'Var', (199, 208))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('pediatric cancer', 'Disease', 'MESH:D009369', (13, 29))
113207	25639868	Unfortunately, with our current understanding of pediatric solid tumor genomes and available molecular targeted therapies, only 12% of patients (46/380) with pediatric solid tumor patients likely have 'druggable' mutations.	('tumor', 'Disease', (174, 179))	('patients', 'Species', '9606', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	("'druggable", 'PosReg', (201, 211))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('mutations', 'Var', (213, 222))	('patients', 'Species', '9606', (180, 188))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
113209	25639868	For example, activating mutations in the ALK gene are thought to be druggable with molecular targeted therapeutics such as crizotinib.	('ALK', 'Gene', (41, 44))	('ALK', 'Gene', '238', (41, 44))	('activating mutations', 'Var', (13, 33))	('crizotinib', 'Chemical', 'MESH:D000077547', (123, 133))
113211	25639868	The inclusion criteria for the Phase I/II study includes patients whose tumors have ALK gene fusions, mutations and amplifications (>fourfold).	('amplifications', 'Var', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ALK', 'Gene', (84, 87))	('patients', 'Species', '9606', (57, 65))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (102, 111))	('ALK', 'Gene', '238', (84, 87))
113212	25639868	In neuroblastomas with ALK mutations, it is not known whether some mutations confer greater sensitivity to crizotinib than others.	('neuroblastomas', 'Disease', (3, 17))	('mutations', 'Var', (27, 36))	('neuroblastoma', 'Phenotype', 'HP:0003006', (3, 16))	('ALK', 'Gene', (23, 26))	('neuroblastomas', 'Phenotype', 'HP:0003006', (3, 17))	('neuroblastomas', 'Disease', 'MESH:D009447', (3, 17))	('ALK', 'Gene', '238', (23, 26))	('crizotinib', 'Chemical', 'MESH:D000077547', (107, 117))
113216	25639868	For example, RAS is mutated in a subset of intermediate- and high-risk rhabdomyosarcomas, but none of the nearly 100 drugs that target this pathway show any differential activity on tumors from patients with RAS mutant rhabdomyosarcomas versus those with wild-type RAS.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (71, 87))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('sarcomas', 'Phenotype', 'HP:0100242', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (219, 235))	('tumors', 'Disease', (182, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (80, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('sarcomas', 'Phenotype', 'HP:0100242', (228, 236))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (71, 88))	('rhabdomyosarcomas', 'Disease', (71, 88))	('patients', 'Species', '9606', (194, 202))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (71, 88))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (219, 236))	('mutant', 'Var', (212, 218))	('rhabdomyosarcomas', 'Disease', (219, 236))	('RAS', 'Gene', (208, 211))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (219, 236))
113219	25639868	However, clinical genomics will provide a more complete catalog of germline and somatic mutations in pediatric solid tumors and contribute important insights into tumor heterogeneity and the clonal evolution of cancer.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('cancer', 'Disease', (211, 217))	('mutations', 'Var', (88, 97))	('pediatric solid tumors', 'Disease', (101, 123))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('pediatric solid tumors', 'Disease', 'MESH:D009369', (101, 123))	('tumor', 'Disease', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
113230	25421287	In this regard, it has been suggested that the histopathology report should include Ki67 LI along with confirmation of the adrenocortical origin on immunohistochemical grounds, Weiss score and resection status.	('Ki67 LI', 'Var', (84, 91))	('Ki67', 'Chemical', '-', (84, 88))	('adrenocortical', 'Disease', (123, 137))	('adrenocortical', 'Disease', 'MESH:D018268', (123, 137))
113233	25421287	It should be recognized that various factors, such as pre-analytical, analytical, interpretation, scoring, and data analysis, might affect Ki67 LI.	('Ki67', 'Var', (139, 143))	('affect', 'Reg', (132, 138))	('Ki67', 'Chemical', '-', (139, 143))
113262	25421287	ASH is designed to assist pathologists and accelerate the time-consuming Ki67 hotspot selection procedure, enhance the detection resolution and eventually lead to improved reproducible Ki67 LI reporting.	('detection', 'MPA', (119, 128))	('Ki67', 'Chemical', '-', (185, 189))	('Ki67', 'Var', (185, 189))	('improved', 'PosReg', (163, 171))	('enhance', 'PosReg', (107, 114))	('Ki67', 'Chemical', '-', (73, 77))
113332	23776337	In a retrospective series over a 20 year period of 58 patients with 64 treatment instances of ACC, it was found that a 4.7 times higher risk of local recurrence was associated with a lack of radiotherapy, compared to treatment regimens that involved radiotherapy after surgical resection; however there was no difference in overall survival.	('ACC', 'Phenotype', 'HP:0006744', (94, 97))	('patients', 'Species', '9606', (54, 62))	('local recurrence', 'CPA', (144, 160))	('lack', 'Var', (183, 187))
113358	23776337	The EDP-mitotane group had a 5 month progression-free survival advantage compared to 2 months for the Streptozocin-mitotane group, but no significant overall survival benefit.	('advantage', 'PosReg', (63, 72))	('EDP-mitotane', 'Var', (4, 16))	('Streptozocin-mitotane', 'Chemical', '-', (102, 123))	('progression-free survival', 'CPA', (37, 62))	('EDP-mitotane', 'Chemical', '-', (4, 16))
113378	23776337	This trial showed worse results with concomitant mitotane, possibly due to reduced serum sunitinib levels caused by mitotane induced cytochrome P450-3A4 activity.	('mitotane', 'Chemical', 'MESH:D008939', (116, 124))	('serum sunitinib levels', 'MPA', (83, 105))	('cytochrome P450-3A4', 'Gene', (133, 152))	('reduced', 'NegReg', (75, 82))	('activity', 'MPA', (153, 161))	('mitotane', 'Chemical', 'MESH:D008939', (49, 57))	('cytochrome P450-3A4', 'Gene', '1576', (133, 152))	('mitotane', 'Var', (116, 124))	('sunitinib', 'Chemical', 'MESH:D000077210', (89, 98))
113384	23776337	mTOR is a downstream signaling node for a number of receptor tyrosine kinases including IGF-1R; however, inhibition of mTOR alone leads to activation of other tumorigenic pathways, thereby limiting its use as a single agent for the treatment of malignancy.	('IGF-1R', 'Gene', (88, 94))	('inhibition', 'Var', (105, 115))	('tyrosine kinase', 'Gene', (61, 76))	('activation', 'PosReg', (139, 149))	('IGF-1R', 'Gene', '3480', (88, 94))	('malignancy', 'Disease', 'MESH:D009369', (245, 255))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('tyrosine kinase', 'Gene', '7294', (61, 76))	('mTOR', 'Gene', (119, 123))	('malignancy', 'Disease', (245, 255))	('mTOR', 'Gene', '2475', (119, 123))	('mTOR', 'Gene', '2475', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('mTOR', 'Gene', (0, 4))
113404	23587357	suggest that detection of steroidogenic factor 1 (SF-1) could be a novel prognostic marker in adrenocortical cancer.	('steroidogenic factor 1 (SF-1', 'Gene', '7536', (26, 54))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (94, 115))	('detection', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('adrenocortical cancer', 'Disease', (94, 115))
113499	32503466	High expression of TRIM44 protein in malignant tissues was found to be strongly associated with poor OS (HR = 1.94, 95% CI: 1.60-2.35, p < 0.0001), and the heterogeneity test revealed a mild heterogeneity (I2 = 32.6%; PQ = 0.139).	('High', 'Var', (0, 4))	('poor OS', 'Disease', (96, 103))	('TRIM44', 'Gene', '54765', (19, 25))	('associated', 'Reg', (80, 90))	('TRIM44', 'Gene', (19, 25))	('PQ', 'Chemical', '-', (218, 220))	('protein', 'Protein', (26, 33))
113513	32503466	When combined with all data from 33 different types of malignant tumors in GEPIA, the Kaplan-Meier analysis suggested that cancer patients with a high expression level of TRIM44 exhibited poorer OS, compared with cases expressing a low level of TRIM44 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TRIM44', 'Gene', '54765', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRIM44', 'Gene', '54765', (171, 177))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('malignant tumors', 'Disease', (55, 71))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (245, 251))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
113521	32503466	TRIM44 amplification is correlated with unfavorable prognosis and advanced clinicopathological parameters of malignancies.	('TRIM44', 'Gene', (0, 6))	('malignancies', 'Disease', (109, 121))	('TRIM44', 'Gene', '54765', (0, 6))	('amplification', 'Var', (7, 20))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
113531	32503466	Overexpression of TRIM44 has been shown to induce a similar change in hallmark characteristics of EMT in other cancers, such as ICC and HEC.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ICC', 'Disease', (128, 131))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('TRIM44', 'Gene', '54765', (18, 24))	('cancers', 'Disease', (111, 118))	('change', 'Reg', (60, 66))	('hallmark characteristics of', 'MPA', (70, 97))	('HEC', 'Disease', (136, 139))	('TRIM44', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Overexpression', 'Var', (0, 14))
113533	32503466	TRIM44 expression positively affects the expression of cyclins and CDKs, suggesting that TRIM44 is involved in the regulation of cell cycle G1/s transformation.	('TRIM44', 'Gene', (0, 6))	('affects', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('involved', 'Reg', (99, 107))	('TRIM44', 'Gene', '54765', (89, 95))	('cyclin', 'Gene', '5111', (55, 61))	('expression', 'Var', (7, 17))	('TRIM44', 'Gene', '54765', (0, 6))	('CDKs', 'Gene', '23097', (67, 71))	('TRIM44', 'Gene', (89, 95))	('cyclin', 'Gene', (55, 61))	('CDKs', 'Gene', (67, 71))
113535	32503466	Indeed, ectopic expression of TRIM44 promotes cell proliferation by accelerating the G1/S-phase transition in HCC.	('accelerating', 'PosReg', (68, 80))	('HCC', 'Gene', '619501', (110, 113))	('ectopic expression', 'Var', (8, 26))	('G1/S-phase transition', 'CPA', (85, 106))	('HCC', 'Gene', (110, 113))	('TRIM44', 'Gene', '54765', (30, 36))	('TRIM44', 'Gene', (30, 36))	('cell proliferation', 'CPA', (46, 64))	('promotes', 'PosReg', (37, 45))
113536	32503466	In colony formation assays, knockdown of TRIM44 in Huh7 cells significantly decreased the expression levels of cyclin D1 and cyclin E, which have been shown to play a crucial role in accelerating the G1/S-phase transition.	('G1/S-phase transition', 'CPA', (200, 221))	('cyclin D1', 'Gene', (111, 120))	('TRIM44', 'Gene', (41, 47))	('Huh7', 'CellLine', 'CVCL:0336', (51, 55))	('expression levels', 'MPA', (90, 107))	('decreased', 'NegReg', (76, 85))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', '5111', (125, 131))	('cyclin', 'Gene', '5111', (111, 117))	('knockdown', 'Var', (28, 37))	('accelerating', 'PosReg', (183, 195))	('cyclin', 'Gene', (125, 131))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', (111, 117))
113538	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('TRIM44', 'Gene', '54765', (14, 20))	('p27', 'Gene', '10671', (64, 67))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('cell division', 'CPA', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('p21', 'Gene', '644914', (60, 63))	('expression', 'MPA', (68, 78))	('p27', 'Gene', (64, 67))	('inhibited', 'NegReg', (91, 100))	('TRIM44', 'Gene', (14, 20))	('Knock-down', 'Var', (0, 10))	('glioma', 'Disease', (24, 30))	('p21', 'Gene', (60, 63))	('increase', 'PosReg', (48, 56))
113539	32503466	Further, the critical p21/p27 regulator AKT is inactivated after TRIM44 is knocked down, but it is activated in glioma cells that overexpress TRIM44.	('inactivated', 'NegReg', (47, 58))	('TRIM44', 'Gene', '54765', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('TRIM44', 'Gene', '54765', (142, 148))	('knocked', 'Var', (75, 82))	('AKT', 'Gene', '207', (40, 43))	('TRIM44', 'Gene', (65, 71))	('TRIM44', 'Gene', (142, 148))	('activated', 'PosReg', (99, 108))	('p21', 'Gene', (22, 25))	('glioma', 'Disease', (112, 118))	('p27', 'Gene', '10671', (26, 29))	('AKT', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('p21', 'Gene', '644914', (22, 25))	('p27', 'Gene', (26, 29))	('overexpress', 'PosReg', (130, 141))
113540	32503466	TRIM44 overexpression leads to high mTOR activity, which is consistent with observations of reduced mTOR signaling in cancer cell lines after siRNA knockdown of TRIM44.	('TRIM44', 'Gene', (161, 167))	('TRIM44', 'Gene', (0, 6))	('cancer', 'Disease', (118, 124))	('overexpression', 'Var', (7, 21))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('reduced', 'NegReg', (92, 99))	('TRIM44', 'Gene', '54765', (161, 167))	('TRIM44', 'Gene', '54765', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
113541	32503466	The phosphorylation of downstream mTOR substrates, including p-Akt (Ser473) and p-p70S6K (Thr389), in TRIM44-knockdown cells was markedly inhibited, indicating that TRIM44 functions upstream of the mTOR signaling pathway by phosphorylating mTOR.	('TRIM44', 'Gene', (102, 108))	('TRIM44', 'Gene', (165, 171))	('p70S6K', 'Gene', (82, 88))	('Ser473', 'Var', (68, 74))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', '207', (63, 66))	('Ser473', 'Chemical', '-', (68, 74))	('mTOR', 'Gene', (34, 38))	('mTOR', 'Gene', (240, 244))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', '2475', (240, 244))	('Thr389', 'Var', (90, 96))	('p70S6K', 'Gene', '6198', (82, 88))	('mTOR', 'Gene', (198, 202))	('Thr389', 'Chemical', '-', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('mTOR', 'Gene', '2475', (198, 202))	('TRIM44', 'Gene', '54765', (102, 108))	('TRIM44', 'Gene', '54765', (165, 171))	('Akt', 'Gene', (63, 66))
113552	32503466	Microarray analysis showed that TRIM44 knockdown is associated with the dysregulation of NUPR1, CDK19, CADM1, INHBA, TNFSF10, and DDIT4, which could normally activate the apoptotic cell pathways.	('TNFSF10', 'Gene', (117, 124))	('apoptotic cell pathways', 'Pathway', (171, 194))	('INHBA', 'Gene', (110, 115))	('activate', 'PosReg', (158, 166))	('knockdown', 'Var', (39, 48))	('CADM1', 'Gene', (103, 108))	('NUPR1', 'Gene', (89, 94))	('DDIT4', 'Gene', (130, 135))	('TRIM44', 'Gene', '54765', (32, 38))	('TNFSF10', 'Gene', '8743', (117, 124))	('CADM1', 'Gene', '23705', (103, 108))	('TRIM44', 'Gene', (32, 38))	('CDK19', 'Gene', (96, 101))	('INHBA', 'Gene', '3624', (110, 115))	('CDK19', 'Gene', '23097', (96, 101))	('NUPR1', 'Gene', '26471', (89, 94))	('DDIT4', 'Gene', '54541', (130, 135))	('dysregulation', 'MPA', (72, 85))
113561	32503466	A previous report has shown that the silencing of TRIM44 could decrease the c-IAP1, c-IAP2, and XIAP expression levels, especially in the presence of doxorubicin.	('c-IAP1', 'Gene', (76, 82))	('XIAP', 'Gene', '331', (96, 100))	('c-IAP1', 'Gene', '329', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('TRIM44', 'Gene', '54765', (50, 56))	('silencing', 'Var', (37, 46))	('decrease', 'NegReg', (63, 71))	('c-IAP2', 'Gene', (84, 90))	('c-IAP2', 'Gene', '330', (84, 90))	('TRIM44', 'Gene', (50, 56))	('XIAP', 'Gene', (96, 100))
113568	32503466	Moreover, miR-26b-5p is the upstream regulatory gene of TRIM44, which acts as a suppressor.	('miR-26b-5p', 'Var', (10, 20))	('TRIM44', 'Gene', '54765', (56, 62))	('TRIM44', 'Gene', (56, 62))
113591	32217810	As the most important post-transcriptional regulatory process, alternative splicing (AS) modifies more than 90% of human genes, contributing greatly to protein diversity and complexity.	('contributing', 'Reg', (128, 140))	('protein diversity', 'MPA', (152, 169))	('human', 'Species', '9606', (115, 120))	('modifies', 'Reg', (89, 97))	('complexity', 'MPA', (174, 184))	('alternative splicing', 'Var', (63, 83))
113602	32217810	"RNA splicing via transesterification reactions with bulged adenosine as nucleophile".	('adenosine', 'Chemical', 'MESH:D000241', (60, 69))	('transesterification', 'Enzyme', (18, 37))	('bulged', 'Var', (53, 59))
113607	32217810	It has been reported that there was an extremely high incidence of splicing defects in carcinogenesis and that RNA splicing modulators might be a promising target for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('carcinogenesis', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('splicing defects', 'Var', (67, 83))
113611	32217810	Freddi et al.. explored the expression of splice variants of growth hormone-releasing hormone receptor (GHRH-R) in human primary adrenocortical tumors and found that splice variants might be a key pathogenic factor in adrenal carcinogenesis.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('growth hormone-releasing hormone receptor', 'Gene', (61, 102))	('GHRH-R', 'Gene', (104, 110))	('adrenocortical tumors', 'Disease', (129, 150))	('pathogenic', 'Reg', (197, 207))	('adrenal carcinogenesis', 'Disease', 'MESH:D063646', (218, 240))	('growth hormone-releasing hormone receptor', 'Gene', '2692', (61, 102))	('GHRH-R', 'Gene', '2692', (104, 110))	('human', 'Species', '9606', (115, 120))	('splice variants', 'Var', (166, 181))	('adrenal carcinogenesis', 'Disease', (218, 240))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (129, 150))	('factor', 'Reg', (208, 214))
113617	32217810	Given the high prevalence of splicing defects in tumor, these prognostic AS events identified in this study could be novel therapeutic targets in ACC treatment.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('splicing defects', 'Var', (29, 45))	('ACC', 'Phenotype', 'HP:0006744', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('ACC', 'Disease', (146, 149))	('tumor', 'Disease', (49, 54))
113644	31941752	Inhibition of the first rate-limiting enzyme of the mitochondrial serine and 1C unit pathway, serine hydroxymethyltransferase (SHMT2), potently suppresses proliferation of metastatic subclones in culture and impairs growth of lung metastatic subclones at both primary and metastatic sites in mice.	('SHMT2', 'Gene', (127, 132))	('impairs', 'NegReg', (208, 215))	('growth', 'CPA', (216, 222))	('proliferation', 'CPA', (155, 168))	('serine', 'Chemical', 'MESH:D012694', (66, 72))	('lung metastatic subclones at', 'CPA', (226, 254))	('suppresses', 'NegReg', (144, 154))	('mice', 'Species', '10090', (292, 296))	('serine', 'Chemical', 'MESH:D012694', (94, 100))	('SHMT2', 'Gene', '6472', (127, 132))	('Inhibition', 'Var', (0, 10))
113666	31941752	Knockdown of SHMT2 also impairs breast cancer growth in vivo at both the primary and metastatic sites.	('SHMT2', 'Gene', (13, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('Knockdown', 'Var', (0, 9))	('SHMT2', 'Gene', '6472', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('impairs breast cancer', 'Disease', 'MESH:D001943', (24, 45))	('impairs breast cancer', 'Disease', (24, 45))
113712	31941752	Additionally, enrichment of asparagine has been reported to promote metastatic cancer cell phenotypes by epithelial-to-mesenchymal transition.	('promote', 'PosReg', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('asparagine', 'Var', (28, 38))	('epithelial-to-mesenchymal transition', 'CPA', (105, 141))	('asparagine', 'Chemical', 'MESH:D001216', (28, 38))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
113720	31941752	Small hairpin RNA (shRNA)-mediated knockdown of c-Myc reduced cell proliferation in all four cell lines, although the degree of inhibition was stronger in 831-BrM and 1833-BoM cells (Fig.	('knockdown', 'Var', (35, 44))	('c-Myc', 'Gene', (48, 53))	('cell proliferation', 'CPA', (62, 80))	('reduced', 'NegReg', (54, 61))	('1833-BoM', 'Chemical', '-', (167, 175))	('c-Myc', 'Gene', '4609', (48, 53))
113721	31941752	Parental cells expressing a non-targeting shRNA showed elevated c-Myc expression, possibly due to puromycin selection.	('non-targeting', 'Var', (28, 41))	('puromycin', 'Chemical', 'MESH:D011691', (98, 107))	('c-Myc', 'Gene', '4609', (64, 69))	('elevated', 'PosReg', (55, 63))	('c-Myc', 'Gene', (64, 69))
113731	31941752	Taken together with the observations of higher serine and glycine levels in 831-BrM and 1833-BoM cells compared to 231-Parental cells (Fig.	('serine', 'Chemical', 'MESH:D012694', (47, 53))	('glycine', 'Chemical', 'MESH:D005998', (58, 65))	('higher', 'PosReg', (40, 46))	('1833-BoM', 'Chemical', '-', (88, 96))	('831-BrM', 'Var', (76, 83))
113745	31941752	We observed higher SHMT flux in metastatic subclones, as the relative abundance of M+1 glycine was approximately 1.5-fold higher in 4175-LM cells compared to 231-Parental cells, indicating that higher purine turnover in metastatic cells was fueled by higher SHMT flux (Fig.	('SHMT', 'Gene', (19, 23))	('higher', 'PosReg', (194, 200))	('purine', 'Chemical', 'MESH:C030985', (201, 207))	('higher', 'PosReg', (122, 128))	('glycine', 'Chemical', 'MESH:D005998', (87, 94))	('4175-LM', 'Var', (132, 139))	('SHMT', 'Gene', '6470', (258, 262))	('SHMT', 'Gene', (258, 262))	('SHMT', 'Gene', '6470', (19, 23))	('purine turnover', 'MPA', (201, 216))	('4175-LM', 'CellLine', 'CVCL:5998', (132, 139))
113748	31941752	To address the extent to which mitochondrial serine catabolism is necessary for cell proliferation, 231-Parental, 831-BrM, 1833-BoM, and 4175-LM cells were infected with lentivirus expressing shRNAs against SHMT2 (shSHMT2) or a nontargeting control (shNT).	('infected', 'Disease', (156, 164))	('hSHMT2', 'Gene', '6472', (215, 221))	('SHMT2', 'Gene', (216, 221))	('SHMT2', 'Gene', '6472', (207, 212))	('SHMT2', 'Gene', '6472', (216, 221))	('shRNAs against', 'Var', (192, 206))	('serine', 'Chemical', 'MESH:D012694', (45, 51))	('infected', 'Disease', 'MESH:D007239', (156, 164))	('1833-BoM', 'Chemical', '-', (123, 131))	('4175-LM', 'CellLine', 'CVCL:5998', (137, 144))	('hSHMT2', 'Gene', (215, 221))	('SHMT2', 'Gene', (207, 212))
113749	31941752	Intriguingly, knockdown of SHMT2 protein expression with two different shRNAs drastically suppressed proliferation of the metastatic subclones significantly, with a reduced effect in 231-Parental cells (Fig.	('SHMT2', 'Gene', (27, 32))	('proliferation of the metastatic subclones', 'CPA', (101, 142))	('SHMT2', 'Gene', '6472', (27, 32))	('knockdown', 'Var', (14, 23))	('suppressed', 'NegReg', (90, 100))	('protein', 'Protein', (33, 40))
113750	31941752	In contrast, knockdown of the downstream enzyme of the mitochondrial serine and 1C unit pathway, MTHFD2, suppressed proliferation to a lesser extent (Supplementary Fig.	('suppressed', 'NegReg', (105, 115))	('MTHFD2', 'Gene', '10797', (97, 103))	('MTHFD2', 'Gene', (97, 103))	('serine', 'Chemical', 'MESH:D012694', (69, 75))	('proliferation', 'CPA', (116, 129))	('knockdown', 'Var', (13, 22))
113752	31941752	There was no obvious enhancement of SHIN1 sensitivity in 831-BrM, 1833-BoM, and 4175-LM cells compared to 231-Parental cells, possibly because SHIN1 inhibits both SHMT2 and SHMT1 (Fig.	('4175-LM', 'CellLine', 'CVCL:5998', (80, 87))	('SHMT1', 'Gene', '6470', (173, 178))	('SHMT1', 'Gene', (173, 178))	('1833-BoM', 'Chemical', '-', (66, 74))	('SHMT2', 'Gene', (163, 168))	('inhibits', 'NegReg', (149, 157))	('SHIN1', 'Var', (143, 148))	('SHMT2', 'Gene', '6472', (163, 168))
113759	31941752	SHMT2 knockdown significantly impaired the growth of 4175-LM cells in the mammary fat pads of immunodeficient mice (Fig.	('4175-LM', 'CellLine', 'CVCL:5998', (53, 60))	('impaired', 'NegReg', (30, 38))	('SHMT2', 'Gene', '6472', (0, 5))	('mice', 'Species', '10090', (110, 114))	('immunodeficient', 'Disease', 'MESH:D007153', (94, 109))	('immunodeficient', 'Disease', (94, 109))	('growth', 'CPA', (43, 49))	('knockdown', 'Var', (6, 15))	('SHMT2', 'Gene', (0, 5))
113768	31941752	Patients with high SHMT2 expression were significantly more likely to succumb to metastatic recurrent disease, while patients with high expression of the cytosolic isozyme SHMT1 were significantly protected from metastatic relapse (Fig.	('SHMT2', 'Gene', '6472', (19, 24))	('SHMT1', 'Gene', (172, 177))	('SHMT1', 'Gene', '6470', (172, 177))	('metastatic relapse', 'CPA', (212, 230))	('succumb', 'Reg', (70, 77))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('metastatic recurrent disease', 'Disease', (81, 109))	('SHMT2', 'Gene', (19, 24))	('patients', 'Species', '9606', (117, 125))
113780	31941752	At the cellular level, the original heterogeneous population of cancer cells from the primary tumor undergo a selection process whereby those clones with alterations (carrying both genetic lesions and epigenetic modifications) favoring fitness and plasticity are enriched.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('fitness', 'Disease', (236, 243))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('genetic lesions', 'Disease', 'MESH:D020022', (181, 196))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (94, 99))	('fitness', 'Disease', 'MESH:D012640', (236, 243))	('alterations', 'Var', (154, 165))	('genetic lesions', 'Disease', (181, 196))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
113782	31941752	While many previous studies have elucidated a role for molecular processes such as epithelial to mesenchymal transition and invasion and migration of cancer cells, our understanding of how metabolic pathway alterations shape metastatic growth is still limited.	('shape', 'Reg', (219, 224))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('alterations', 'Var', (207, 218))	('metastatic growth', 'CPA', (225, 242))	('cancer', 'Disease', (150, 156))	('invasion', 'CPA', (124, 132))	('epithelial to mesenchymal transition', 'CPA', (83, 119))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
113787	31941752	In contrast, we found lower levels of free purines in metastatic variants of human MDA-MB-231 cell lines compared to the parental population (Fig.	('levels of free purines', 'MPA', (28, 50))	('variants', 'Var', (65, 73))	('purines', 'Chemical', 'MESH:D011687', (43, 50))	('MDA-MB-231', 'Gene', (83, 93))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (83, 93))	('metastatic', 'CPA', (54, 64))	('lower', 'NegReg', (22, 27))	('human', 'Species', '9606', (77, 82))
113794	31941752	The role of serine in cancer growth has drawn increasing interest over the years ever since the identification of PHGDH amplifications in melanoma and breast cancer.	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('amplifications', 'Var', (120, 134))	('melanoma and breast cancer', 'Disease', 'MESH:D001943', (138, 164))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (22, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('cancer', 'Disease', (158, 164))	('PHGDH', 'Gene', '26227', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('serine', 'Chemical', 'MESH:D012694', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('PHGDH', 'Gene', (114, 119))
113797	31941752	Our study is the first to directly evaluate the therapeutic potential of targeting SHMT2 in metastatic breast cancer using both genetic and pharmaceutical approaches.	('SHMT2', 'Gene', (83, 88))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('SHMT2', 'Gene', '6472', (83, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('targeting', 'Var', (73, 82))
113798	31941752	Intriguingly, genetic knockdown of SHMT2 strongly inhibited the proliferation of metastatic cells, while treatment with a dual SHMT1/SHMT2 inhibitor suppressed proliferation of both parental and metastatic subclones.	('proliferation of metastatic cells', 'CPA', (64, 97))	('SHMT1', 'Gene', (127, 132))	('SHMT2', 'Gene', (35, 40))	('knockdown', 'Var', (22, 31))	('SHMT2', 'Gene', (133, 138))	('SHMT2', 'Gene', '6472', (133, 138))	('SHMT2', 'Gene', '6472', (35, 40))	('suppressed', 'NegReg', (149, 159))	('inhibited', 'NegReg', (50, 59))	('SHMT1', 'Gene', '6470', (127, 132))
113799	31941752	This discrepancy may be explained by prior observations that while MDA-MB-231 cells preferentially utilize the mitochondrial pathway for 1C unit production, inhibition of individual mitochondrial enzymes can lead to a switch to the cytosolic pathway.	('switch', 'Reg', (218, 224))	('mitochondrial', 'Enzyme', (111, 124))	('lead to', 'Reg', (208, 215))	('1C unit production', 'MPA', (137, 155))	('inhibition', 'Var', (157, 167))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (67, 77))	('cytosolic pathway', 'Pathway', (232, 249))	('mitochondrial enzymes', 'Enzyme', (182, 203))
113801	31941752	Consistent with observations in colon cancer xenografts, SHMT2 knockdown in the lung metastatic subclone slowed, but not completely suppressed, tumor growth in the mammary fat pad and lung.	('tumor', 'Disease', (144, 149))	('slowed', 'NegReg', (105, 111))	('SHMT2', 'Gene', '6472', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colon cancer', 'Disease', (32, 44))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('knockdown', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('SHMT2', 'Gene', (57, 62))	('colon cancer', 'Phenotype', 'HP:0003003', (32, 44))	('colon cancer', 'Disease', 'MESH:D015179', (32, 44))
113802	31941752	In addition, we found that in the IC4 subset of human breast cancer patients, the expression of mitochondrial one-carbon unit enzymes is positively associated with more aggressive disease.	('breast cancer', 'Disease', (54, 67))	('aggressive disease', 'Disease', (169, 187))	('human', 'Species', '9606', (48, 53))	('mitochondrial one-carbon unit enzymes', 'Enzyme', (96, 133))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('expression', 'Var', (82, 92))	('patients', 'Species', '9606', (68, 76))	('associated with', 'Reg', (148, 163))	('carbon', 'Chemical', 'MESH:D002244', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('aggressive disease', 'Disease', 'MESH:D001523', (169, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
113812	31941752	c-Myc knockdown reduces invasion and migration of MDA-MB-231 cells.	('c-Myc', 'Gene', '4609', (0, 5))	('reduces', 'NegReg', (16, 23))	('knockdown', 'Var', (6, 15))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (50, 60))	('c-Myc', 'Gene', (0, 5))
113836	30588100	We selected patients with positive histology of ACC (International Classification of Diseases for Oncology, third edition site codes: C740 and C749, and histologic subtype code: 8370).	('patients', 'Species', '9606', (12, 20))	('C740', 'Var', (134, 138))	('Oncology', 'Phenotype', 'HP:0002664', (98, 106))	('C749', 'Var', (143, 147))	('ACC', 'Phenotype', 'HP:0006744', (48, 51))
113938	30400026	At least five pathways have been identified that may impair CD8+ action: (1) activation of WNT-beta-catenin pathway or (2) activation of MYC signaling, (3) loss of liver kinase B1 (LKB1) signaling, (4) loss of PTEN protein function and (5) TP53 mutations.	('LKB1', 'Gene', (181, 185))	('TP53', 'Gene', '7157', (240, 244))	('loss', 'NegReg', (156, 160))	('beta-catenin', 'Gene', (95, 107))	('activation', 'PosReg', (123, 133))	('protein', 'Protein', (215, 222))	('impair', 'NegReg', (53, 59))	('beta-catenin', 'Gene', '1499', (95, 107))	('loss', 'NegReg', (202, 206))	('PTEN', 'Gene', (210, 214))	('mutations', 'Var', (245, 254))	('liver kinase B1', 'Gene', '6794', (164, 179))	('function', 'MPA', (223, 231))	('liver kinase B1', 'Gene', (164, 179))	('PTEN', 'Gene', '5728', (210, 214))	('TP53', 'Gene', (240, 244))	('LKB1', 'Gene', '6794', (181, 185))	('CD8', 'Gene', '925', (60, 63))	('activation', 'PosReg', (77, 87))	('MYC', 'MPA', (137, 140))	('CD8', 'Gene', (60, 63))
113939	30400026	Two of these pathways, namely WNT-B-catenin amplification and TP53 mutation, are involved in the pathogenesis of ACC.	('TP53', 'Gene', '7157', (62, 66))	('mutation', 'Var', (67, 75))	('involved', 'Reg', (81, 89))	('TP53', 'Gene', (62, 66))	('ACC', 'Phenotype', 'HP:0006744', (113, 116))	('ACC', 'Disease', (113, 116))
113943	30400026	Approaches aimed at upregulating p53 are under exploration, including gene therapy that uses viruses to deliver p53 to cancer cells, synthetic peptides that stabilize WT p53 and small molecules that target key signaling interactions involving mutant p53.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('p53', 'Gene', (170, 173))	('cancer', 'Disease', (119, 125))	('p53', 'Gene', (33, 36))	('p53', 'Gene', (250, 253))	('p53', 'Gene', (112, 115))	('p53', 'Gene', '7157', (250, 253))	('p53', 'Gene', '7157', (170, 173))	('p53', 'Gene', '7157', (33, 36))	('p53', 'Gene', '7157', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('mutant', 'Var', (243, 249))
113945	30400026	Immune checkpoint inhibitors can be tested in selected ACC patients, such as those with alterations in the mismatch repair (MMR) pathway that leads to high levels of microsatellite instability (MSI-H).	('ACC', 'Phenotype', 'HP:0006744', (55, 58))	('microsatellite instability', 'MPA', (166, 192))	('MSI-H', 'Disease', 'MESH:D000848', (194, 199))	('alterations', 'Var', (88, 99))	('patients', 'Species', '9606', (59, 67))	('MSI-H', 'Disease', (194, 199))
113953	29765148	As cancer tissues are now frequently screened for specific sets of mutations, a large amount of samples has become available for analysis.	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (67, 76))
113956	29765148	We show that, for most cancer types, de-sparsified mutation data associate with phenotypic data.	('de-sparsified mutation', 'Var', (37, 59))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))
113957	29765148	We identify poor prognostic subtypes in three cancer types, which are associated with mutations in signal transduction pathways for which targeted treatment options are available.	('mutations', 'Var', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('signal transduction pathways', 'Pathway', (99, 127))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
113958	29765148	Finally, we perform a pan-cancer subtyping analysis and identify nine pan-cancer subtypes, which associate with mutations in four overarching sets of biological pathways.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
113965	29765148	Since the onset of large-scale genomic experiments, cancer subtypes have been identified in multiple cancers, using mRNA and microRNA expression levels, methylation data, copy number alterations and combinations of different 'omics data types, but few studies have subtyped patients based on somatic mutations.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('multiple cancers', 'Disease', 'MESH:D009369', (92, 108))	('cancer', 'Disease', (101, 107))	('patients', 'Species', '9606', (274, 282))	('copy', 'Var', (171, 175))	('multiple cancers', 'Disease', (92, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
113968	29765148	However, subtype classification using somatic mutations in cancer is challenging, mainly because the data are very sparse: many tumours only have a handful of mutations in coding regions yet the total number of mutations within a population is typically substantial.	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumours', 'Disease', (128, 135))	('mutations', 'Var', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
113969	29765148	Often, frequent cancer drivers:such as TP53:are mutated, as well as so-called "passenger" events that are considered mutational noise yet which may still influence tumour properties.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('mutated', 'Var', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('influence', 'Reg', (154, 163))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', (164, 170))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TP53', 'Gene', (39, 43))
113979	29765148	While these studies have improved our understanding of the genes and pathways that are recurrently mutated in cancer, data are now available for many more samples and cancer types, increasing the power to detect new mutational patterns and cancer subtypes.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', (167, 173))	('increasing', 'PosReg', (181, 191))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (240, 246))	('mutational', 'Var', (216, 226))
114000	29765148	For each cancer type, we clustered the pathway mutation scores using hierarchical clustering with binomial distance.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('mutation', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
114015	29765148	We divided the cell lines into two groups: those that had mutations in all 94 "Set 1" pathways (n = 156), and those that did not (n = 845), and performed a t-test to identify significant differences in response to drugs targeting phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/MTOR) signalling (Benjamini-Hochberg adjusted p-values <0.05).	('mutations', 'Var', (58, 67))	('MTOR', 'Gene', '2475', (292, 296))	('Set 1"', 'Gene', '9739', (79, 85))	('Set 1"', 'Gene', (79, 85))	('mammalian', 'Species', '9606', (256, 265))	('MTOR', 'Gene', (292, 296))
114017	29765148	We repeated this analysis on cell lines that had mutations in all 38 "Set 2" pathways (n = 681) and those that did not (n = 320) and drugs targeting DNA replication.	('Set 2"', 'Gene', (70, 76))	('Set 2"', 'Gene', '29072', (70, 76))	('mutations', 'Var', (49, 58))
114018	29765148	We note that we identified a relatively high number of cell lines with mutations in all "Set 2" pathways compared to the number we identified in primary tumours.	('Set 2"', 'Gene', (89, 95))	('primary tumours', 'Disease', 'MESH:D009369', (145, 160))	('Set 2"', 'Gene', '29072', (89, 95))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (71, 80))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('primary tumours', 'Disease', (145, 160))
114029	29765148	As expected, we observed a larger number of mutated pathways than of mutated cancer-associated genes across all samples (median = 103).	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutated', 'Var', (44, 51))
114033	29765148	These percentages were lower for mutations in cancer-associated genes, with an average of 54.8% of all cancer-associated genes being mutated in a cancer type (minimum of 6.1% for KICH, maximum of 95.1% for UCEC).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (46, 52))	('UCEC', 'Disease', (206, 210))	('mutated', 'Var', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
114044	29765148	Additionally, technical variability (batch number) appears to associate with pathway mutation scores in a number of cancers.	('associate', 'Reg', (62, 71))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('pathway', 'PosReg', (77, 84))	('mutation scores', 'Var', (85, 100))
114053	29765148	In addition to these known cancer-driver pathways, we identified mutations in neurotrophin signalling, which plays a role in neuron development and differentiation, in the poor prognosis subtype.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('neurotrophin signalling', 'Gene', (78, 101))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (65, 74))
114057	29765148	In addition to these pathways, DNA damage response pathways, which included p53 and ATM signalling, were mutated in the poor prognostic subtype of LAML.	('ATM', 'Gene', (84, 87))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('ATM', 'Gene', '472', (84, 87))	('mutated', 'Var', (105, 112))	('DNA damage response pathways', 'Pathway', (31, 59))
114059	29765148	Tumours assigned to this subtype had higher mutation scores in multiple epidermal growth factor receptor (EGFR) family pathways, in cell-cell contact and cellular structure ("adherens junction", "gap junction"), the immune system ("cytokine-cytokine receptor interaction") and in brain tissue-associated pathways (including "gonadotropin-releasing hormone signalling").	('mutation', 'Var', (44, 52))	('higher', 'PosReg', (37, 43))	('epidermal growth factor receptor', 'Gene', (72, 104))	('EGFR', 'Gene', '1956', (106, 110))	('gonadotropin-releasing hormone', 'Gene', (325, 355))	('epidermal growth factor receptor', 'Gene', '1956', (72, 104))	('gonadotropin-releasing hormone', 'Gene', '2796', (325, 355))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('EGFR', 'Gene', (106, 110))
114060	29765148	Mutations in cell-cell contact genes could be important for metastasis, and immune cells are known to play a critical role into transforming low-grade glioma into glioblastoma.	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('Mutations', 'Var', (0, 9))	('glioblastoma', 'Disease', (163, 175))	('glioblastoma', 'Disease', 'MESH:D005909', (163, 175))	('glioma', 'Disease', (151, 157))
114062	29765148	However, while this gene was mutated in 15/17 patients, other genes belonging to EGFR family pathways, including EGF, GNAS and PTRB, were also mutated in tumours belonging to this subtype and might not have been detected if we had focussed on EGFR alone.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('patients', 'Species', '9606', (46, 54))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('PTRB', 'Gene', (127, 131))	('EGF', 'Gene', (113, 116))	('tumours belonging', 'Disease', 'MESH:D009369', (154, 171))	('GNAS', 'Gene', '2778', (118, 122))	('EGFR', 'Gene', '1956', (81, 85))	('mutated', 'Var', (143, 150))	('EGFR', 'Gene', '1956', (243, 247))	('tumours belonging', 'Disease', (154, 171))	('EGFR', 'Gene', (243, 247))	('GNAS', 'Gene', (118, 122))	('EGFR', 'Gene', (81, 85))
114064	29765148	For each of the significant cancer types, we performed 10,000 sample label permutations and found that the original log-rank tests were more significant than those on the permuted null background (Benjamini-Hochberg adjusted p-values p < 0.01), indicating that the poor prognostic subtypes were not identified by chance but were detected based on mutations in specific biological pathways (see Supplemental Fig.	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (347, 356))
114071	29765148	This was not unexpected, as we found specific mutations in p53 pathways in this subtype.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('mutations', 'Var', (46, 55))
114078	29765148	In total, the subtypes that were enriched for mutations in drug targets from CMap account for 12% (689/5805) of all primary tumours from TCGA.	('mutations', 'Var', (46, 55))	('primary tumours', 'Disease', 'MESH:D009369', (116, 131))	('primary tumours', 'Disease', (116, 131))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('CMap', 'Gene', (77, 81))
114094	29765148	All of the subtypes, except S5, which had no subtype-specific pathway mutations, had frequent mutations in Kyoto Encyclopedia of Genes and Genomes "pathways in cancer".	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('mutations', 'Var', (94, 103))	('cancer', 'Disease', (160, 166))	('Kyoto Encyclopedia of Genes', 'Gene', (107, 134))	('Genomes "pathways', 'Pathway', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
114096	29765148	Using hierarchical clustering (binomial distance) on average mutation scores in these 202 pathways, we identified four overarching "sets" of pathways that were differentially mutated in the pan-cancer subtypes (see Fig.	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('mutation', 'Var', (61, 69))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
114102	29765148	Most of the sets are either mutated alone (such as Set 2 in pan-cancer subtypes S4 and S6) or in combination with other sets (for example, Sets 2-4 in pan-cancer subtype S8).	('mutated', 'Var', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('Set 2', 'Gene', (51, 56))	('Set 2', 'Gene', '29072', (51, 56))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
114109	29765148	We identified significantly higher protein activation scores in tumours from patients belonging to the subtypes that had higher levels of mutations in these pathways.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('protein activation scores', 'MPA', (35, 60))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('higher', 'PosReg', (28, 34))	('patients', 'Species', '9606', (77, 85))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (138, 147))
114111	29765148	This indicates that the pan-cancer subtypes we had identified based on pathway mutation scores also corresponded to higher protein levels in these pathways.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('higher', 'PosReg', (116, 122))	('mutation scores', 'Var', (79, 94))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('protein levels', 'MPA', (123, 137))
114112	29765148	Second, we wanted to determine whether cell lines with mutations in the overarching sets of pathways we had identified in the pan-cancer subtypes were more sensitive to drugs targeting those pathways.	('sensitive', 'MPA', (156, 165))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
114113	29765148	We identified which cell lines had mutations in all "Set 1" pathways and compared how these cells responded to PI3K/MTOR inhibitors compared to other cell lines (Methods).	('MTOR', 'Gene', (116, 120))	('Set 1"', 'Gene', '9739', (53, 59))	('Set 1"', 'Gene', (53, 59))	('MTOR', 'Gene', '2475', (116, 120))	('mutations', 'Var', (35, 44))
114116	29765148	We repeated this analysis for cell lines with mutations in all "Set 2" pathways and compared how these cell lines responded to drugs interfering with DNA replication.	('Set 2"', 'Gene', '29072', (64, 70))	('Set 2"', 'Gene', (64, 70))	('mutations', 'Var', (46, 55))
114122	29765148	We showed that SAMBAR helps identifying mutational patterns associated with clinical phenotypes and prognosis and potential targeted treatment options for cancer-specific subtypes, as well as mutational patterns that are manifested across multiple cancer types.	('cancer', 'Disease', (248, 254))	('SAMBAR', 'Species', '662561', (15, 21))	('multiple cancer', 'Disease', (239, 254))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('multiple cancer', 'Disease', 'MESH:D009369', (239, 254))	('mutational', 'Var', (40, 50))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Disease', (155, 161))	('associated', 'Reg', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
114125	29765148	For example, we identified MDM2 inhibitors as potential targets for treatment of the poor prognosis subtype in ACC by integrating subtype-specific mutations with a drug-targeting database.	('mutations', 'Var', (147, 156))	('ACC', 'Phenotype', 'HP:0006744', (111, 114))	('ACC', 'Disease', (111, 114))	('MDM2', 'Gene', '4193', (27, 31))	('MDM2', 'Gene', (27, 31))
114129	29765148	By generating patient-specific "pathway mutation profiles", we may not only identify patients who could benefit from specific targeted therapeutics but we will also obtain a clearer picture of the cellular processes that are altered through mutation in a specific tumour.	('tumour', 'Disease', (264, 270))	('mutation', 'Var', (40, 48))	('patient', 'Species', '9606', (85, 92))	('patients', 'Species', '9606', (85, 93))	('patient', 'Species', '9606', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('tumour', 'Disease', 'MESH:D009369', (264, 270))	('mutation', 'Var', (241, 249))
114134	29765148	In addition, one of the pan-cancer mutational patterns we identified was enriched for several growth factor pathways, including EGF receptor family genes, and FGFR and nerve growth factor signalling.	('mutational', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('growth factor pathways', 'Pathway', (94, 116))	('EGF receptor family genes', 'Gene', (128, 153))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('FGFR', 'Gene', (159, 163))	('cancer', 'Disease', (28, 34))	('nerve growth factor signalling', 'Pathway', (168, 198))
114135	29765148	Because these pathways are mutated in a large set of the primary tumours we analysed, we believe that these treatment options are worthy of further investigation and may lead to better treatment options for a large numbers of patients.	('mutated', 'Var', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('patients', 'Species', '9606', (226, 234))	('primary tumours', 'Disease', 'MESH:D009369', (57, 72))	('primary tumours', 'Disease', (57, 72))
114137	29765148	Our framework to classify cancers based on mutational patterns in biological pathways could help expand precision medicine applications both by identifying groups of patients who may or may not respond to particular therapies and by identifying pathways that might be useful targets for therapeutic intervention.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('mutational', 'Var', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('patients', 'Species', '9606', (166, 174))
114149	28066990	BWS is caused by genetic or epigenetic changes on chromosome 11p15, with either specific gene mutations or changes in DNA methylation in imprinting centers, known as imprinting center 1, H19/IGF2:IG-DMR (IC1) and imprinting center 2, KCNQ1OT1:TSS-DMR 2 (IC2), leading to a dysregulation in genes affecting growth.	('IC1', 'Gene', (204, 207))	('mutations', 'Var', (94, 103))	('KCNQ1OT1', 'Gene', '10984', (234, 242))	('changes', 'Var', (39, 46))	('dysregulation in genes', 'MPA', (273, 295))	('H19', 'Gene', '283120', (187, 190))	('IGF2', 'Gene', (191, 195))	('epigenetic changes', 'Var', (28, 46))	('H19', 'Gene', (187, 190))	('KCNQ1OT1', 'Gene', (234, 242))	('IC2', 'Gene', '1781', (254, 257))	('IC2', 'Gene', (254, 257))	('IC1', 'Gene', '105259599', (204, 207))	('BWS', 'Disease', (0, 3))	('caused by', 'Reg', (7, 16))	('IGF2', 'Gene', '3481', (191, 195))	('changes', 'Var', (107, 114))
114172	28066990	IC1 gain of methylation on the maternal chromosome leads to increased expression of IGF2 and decreased expression of H19; alternately, hypomethylation of IC2 leads to a decrease in CDKN1C expression.	('IGF2', 'Gene', (84, 88))	('methylation', 'MPA', (12, 23))	('IC1', 'Gene', '105259599', (0, 3))	('expression', 'MPA', (103, 113))	('CDKN1C', 'Gene', (181, 187))	('increased', 'PosReg', (60, 69))	('gain of', 'PosReg', (4, 11))	('IC2', 'Gene', '1781', (154, 157))	('CDKN1C', 'Gene', '1028', (181, 187))	('IGF2', 'Gene', '3481', (84, 88))	('IC2', 'Gene', (154, 157))	('H19', 'Gene', (117, 120))	('decreased', 'NegReg', (93, 102))	('expression', 'MPA', (70, 80))	('decrease', 'NegReg', (169, 177))	('expression', 'MPA', (188, 198))	('increased expression of IGF2', 'Phenotype', 'HP:0030269', (60, 88))	('H19', 'Gene', '283120', (117, 120))	('hypomethylation', 'Var', (135, 150))	('IC1', 'Gene', (0, 3))
114174	28066990	Hereditary causes of BWS are responsible for 10-15% of cases, most commonly involving mutations in CDKN1C and less frequently involving one or both of the 11p15 imprinting centers, leading to aberrant 11p15 methylation.	('mutations', 'Var', (86, 95))	('aberrant', 'Var', (192, 200))	('CDKN1C', 'Gene', (99, 105))	('CDKN1C', 'Gene', '1028', (99, 105))	('BWS', 'Disease', (21, 24))	('11p15 methylation', 'MPA', (201, 218))
114175	28066990	These alterations in expression of IGF2 and CDKN1C can lead to deviations in fetal adrenal development.	('alterations', 'Var', (6, 17))	('IGF2', 'Gene', (35, 39))	('expression', 'MPA', (21, 31))	('CDKN1C', 'Gene', (44, 50))	('CDKN1C', 'Gene', '1028', (44, 50))	('lead to', 'Reg', (55, 62))	('IGF2', 'Gene', '3481', (35, 39))	('fetal adrenal development', 'CPA', (77, 102))
114181	28066990	Alternatively, patients with gain of function CDKN1C mutations are phenotypically growth restricted, and in particular have adrenal hypoplasia.	('patients', 'Species', '9606', (15, 23))	('gain of function', 'PosReg', (29, 45))	('CDKN1C', 'Gene', (46, 52))	('mutations', 'Var', (53, 62))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (124, 142))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (124, 142))	('CDKN1C', 'Gene', '1028', (46, 52))	('adrenal hypoplasia', 'Disease', (124, 142))
114186	28066990	Recent studies of BWS patients have shown that the epigenotype influences the phenotypic risk of cancer; yet to date, no molecular subgroup is predictive of risk of adrenocortical tumors.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (165, 186))	('cancer', 'Disease', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('patients', 'Species', '9606', (22, 30))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('influences', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('epigenotype', 'Var', (51, 62))	('adrenocortical tumors', 'Disease', (165, 186))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
114237	27880943	Our study explored the associations of TP53 mutations, gene expression, clinical outcomes, and TP53 interaction networks across 33 cancer types using data from The Cancer Genome Atlas (TCGA).	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer Genome Atlas', 'Disease', (164, 183))	('TP53', 'Gene', (95, 99))	('Cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (164, 183))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('associations', 'Interaction', (23, 35))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (39, 43))
114238	27880943	We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('mutations', 'Var', (86, 95))	('TP53', 'Gene', (13, 17))	('cancer initiation', 'Disease', (125, 142))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer initiation', 'Disease', 'MESH:D009369', (125, 142))	('TP53', 'Gene', '7157', (13, 17))	('cancers', 'Disease', (69, 76))
114241	27880943	This study shows that while TP53-truncating mutations often result in decreased TP53 expression, other non-truncating TP53 mutations result in increased TP53 expression in some cancers.	('expression', 'MPA', (85, 95))	('increased', 'PosReg', (143, 152))	('TP53', 'Gene', '7157', (28, 32))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('expression', 'MPA', (158, 168))	('cancers', 'Disease', (177, 184))	('TP53', 'Gene', (28, 32))	('decreased', 'NegReg', (70, 79))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('TP53', 'Gene', (153, 157))	('mutations', 'Var', (123, 132))
114242	27880943	Survival analyses in a number of cancers show that patients with TP53 mutations are more likely to have worse prognoses than TP53-wildtype patients, and that elevated TP53 expression often leads to poor clinical outcomes.	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('leads to', 'Reg', (189, 197))	('TP53', 'Gene', '7157', (125, 129))	('patients', 'Species', '9606', (139, 147))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('expression', 'MPA', (172, 182))	('TP53', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('poor clinical outcomes', 'MPA', (198, 220))	('patients', 'Species', '9606', (51, 59))	('TP53', 'Gene', '7157', (167, 171))	('elevated', 'PosReg', (158, 166))	('TP53', 'Gene', (167, 171))
114245	27880943	TP53 mutations and dysfunction occur in more than half of all human cancer cases, and are independent markers of poor prognoses in some cancers.	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('human', 'Species', '9606', (62, 67))	('cancers', 'Disease', (136, 143))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('mutations', 'Var', (5, 14))	('occur', 'Reg', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
114246	27880943	In addition to mutations in TP53 itself, mutations in p53 pathway genes are significantly enriched in cancer.	('mutations', 'Var', (41, 50))	('TP53', 'Gene', '7157', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TP53', 'Gene', (28, 32))	('p53', 'Gene', (54, 57))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('p53', 'Gene', '7157', (54, 57))	('enriched', 'Reg', (90, 98))
114253	27880943	Some therapeutic strategies have been proposed to treat TP53-mutated cancers, such as restoring wild-type activity to; promoting the degradation of; or targeting pathways regulated by mutant p53.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('mutant', 'Var', (184, 190))	('TP53', 'Gene', '7157', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('p53', 'Gene', (191, 194))	('TP53', 'Gene', (56, 60))	('p53', 'Gene', '7157', (191, 194))	('targeting', 'Reg', (152, 161))	('promoting', 'PosReg', (119, 128))	('degradation', 'MPA', (133, 144))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('wild-type', 'MPA', (96, 105))	('cancers', 'Disease', (69, 76))	('pathways', 'Pathway', (162, 170))
114255	27880943	Thus, the targeted disruption of a gene that is SL for TP53 should selectively kill cancer cells with somatic mutations in TP53, but spare normal TP53-wildtype cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('TP53', 'Gene', '7157', (146, 150))	('mutations', 'Var', (110, 119))	('disruption', 'Var', (19, 29))	('cancer', 'Disease', (84, 90))	('kill', 'NegReg', (79, 83))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
114258	27880943	We analyzed TP53 mutation and gene expression data to identify potential nodes in TP53 interaction networks, and performed survival analyses based on TP53 mutations and expression profiles across the 33 cancer types, respectively.	('TP53', 'Gene', (82, 86))	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (155, 164))	('TP53', 'Gene', '7157', (12, 16))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (12, 16))	('TP53', 'Gene', '7157', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
114261	27880943	Almost one-third of cancer types have a TP53 mutation rate greater than 50%, and more than one-half have a rate greater than 30%.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('TP53', 'Gene', '7157', (40, 44))	('mutation', 'Var', (45, 53))	('cancer', 'Disease', (20, 26))	('TP53', 'Gene', (40, 44))
114262	27880943	The two cancer types with the highest TP53 mutation rates affect women: uterine carcino-sarcoma (UCS) (91.2%) and ovarian serous cystadeno-carcinoma (OV) (83%).	('ovarian serous cystadeno-carcinoma', 'Disease', (114, 148))	('cancer', 'Disease', (8, 14))	('uterine carcino-sarcoma', 'Phenotype', 'HP:0002891', (72, 95))	('TP53', 'Gene', (38, 42))	('mutation', 'Var', (43, 51))	('TP53', 'Gene', '7157', (38, 42))	('ovarian serous cystadeno-carcinoma', 'Disease', 'MESH:D010051', (114, 148))	('carcino-sarcoma', 'Disease', 'MESH:D012509', (80, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('carcino-sarcoma', 'Disease', (80, 95))	('women', 'Species', '9606', (65, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('ovarian serous cystadeno-carcinoma', 'Phenotype', 'HP:0012887', (114, 148))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
114263	27880943	The other eight cancer types with a TP53 mutation rate that exceeds 50% include four gastro-intestinal cancers: esophageal carcinoma (ESCA), rectal adeno-carcinoma (READ), pancreatic adeno-carcinoma (PAAD) and colon adeno-carcinoma (COAD); two lung cancers: lung squamous-cell carcinoma (LUSC) and lung adeno-carcinoma (LUAD); and head-and-neck squamous-cell carcinoma (HNSC) and brain lower-grade glioma (LGG).	('COAD', 'Disease', (233, 237))	('gastro-intestinal cancers', 'Disease', 'MESH:D007414', (85, 110))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('colon adeno-carcinoma', 'Disease', (210, 231))	('cancer', 'Disease', (249, 255))	('TP53', 'Gene', (36, 40))	('cancer', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('lung adeno-carcinoma', 'Disease', (298, 318))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung squamous-cell carcinoma', 'Phenotype', 'HP:0030359', (258, 286))	('lung adeno-carcinoma', 'Phenotype', 'HP:0030078', (298, 318))	('cancer', 'Disease', (16, 22))	('gastro-intestinal cancers', 'Disease', (85, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('mutation', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('glioma', 'Disease', (398, 404))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('glioma', 'Disease', 'MESH:D005910', (398, 404))	('colon adeno-carcinoma', 'Disease', 'MESH:D015179', (210, 231))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('TP53', 'Gene', '7157', (36, 40))	('lung squamous-cell carcinoma', 'Disease', 'MESH:D002294', (258, 286))	('lung adeno-carcinoma', 'Disease', 'MESH:D008175', (298, 318))	('lung cancers', 'Disease', 'MESH:D008175', (244, 256))	('COAD', 'Disease', 'MESH:D029424', (233, 237))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (263, 286))	('squamous-cell carcinoma (HNSC)', 'Disease', 'MESH:D002294', (345, 375))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('lung cancers', 'Disease', (244, 256))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (112, 132))	('glioma', 'Phenotype', 'HP:0009733', (398, 404))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (345, 368))	('adeno-carcinoma (READ), pancreatic adeno-carcinoma', 'Disease', 'MESH:C562463', (148, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('pancreatic adeno-carcinoma', 'Phenotype', 'HP:0006725', (172, 198))	('lung cancers', 'Phenotype', 'HP:0100526', (244, 256))	('lung squamous-cell carcinoma', 'Disease', (258, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('esophageal carcinoma', 'Disease', (112, 132))
114265	27880943	We found that TP53 has the highest mutation rate in six cancer types: UCS, OV, ESCA, LUSC, HNSC and sarcoma (SARC), and the second-highest mutation rate in seven other cancer types: READ, LUAD, LGG, bladder urothelial carcinoma (BLCA), stomach adeno-carcinoma (STAD), liver hepato-cellular carcinoma (LIHC), and breast-invasive carcinoma (BRCA).	('TP53', 'Gene', (14, 18))	('breast-invasive carcinoma (BRCA)', 'Gene', '672', (312, 344))	('cancer', 'Disease', (168, 174))	('mutation', 'Var', (35, 43))	('cancer', 'Disease', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('bladder urothelial carcinoma', 'Disease', (199, 227))	('ESCA', 'Disease', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('LUSC', 'Disease', (85, 89))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (199, 227))	('TP53', 'Gene', '7157', (14, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('stomach adeno-carcinoma (STAD), liver hepato-cellular carcinoma', 'Disease', 'MESH:D006528', (236, 299))	('breast-invasive carcinoma (BRCA', 'Gene', (312, 343))	('hepato-cellular carcinoma', 'Phenotype', 'HP:0001402', (274, 299))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('LUAD', 'Disease', (188, 192))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('UCS', 'Disease', (70, 73))	('READ', 'Disease', (182, 186))	('HNSC and sarcoma', 'Disease', 'MESH:D012509', (91, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('LGG', 'Disease', (194, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))
114270	27880943	Surprisingly, there are marked differences in the TP53 mutation rates in cancers from the same organ but different cell types, e.g., in KIRP, KIRC, and kidney chromophobe (KICH), with rates of 2.5%, 2.4% and 33.3%, respectively.	('cancers', 'Disease', (73, 80))	('TP53', 'Gene', (50, 54))	('KICH', 'Disease', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TP53', 'Gene', '7157', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('kidney chromophobe', 'Disease', (152, 170))	('mutation', 'Var', (55, 63))	('KICH', 'Disease', 'None', (172, 176))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('kidney chromophobe', 'Disease', 'MESH:D000238', (152, 170))
114271	27880943	TP53 mutations are comprised of eight classes: missense, nonsense, frame-shift deletion, frame-shift insertion, in-frame deletion, in-frame insertion, silent and splice-site.	('missense', 'Var', (47, 55))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('frame-shift insertion', 'Var', (89, 110))	('mutations', 'Var', (5, 14))	('nonsense', 'Var', (57, 65))	('frame-shift deletion', 'Var', (67, 87))	('in-frame insertion', 'Var', (131, 149))	('in-frame deletion', 'Var', (112, 129))	('silent', 'Var', (151, 157))
114272	27880943	Figure 1 summarizes the proportion of each class of TP53 mutations in all 33 TCGA cancer types.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', '7157', (52, 56))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))
114273	27880943	The most frequent classes of TP53 mutations are missense (62%), nonsense (14%) and frame-shift deletions (9%).	('frame-shift deletions', 'Var', (83, 104))	('missense', 'Var', (48, 56))	('nonsense', 'Var', (64, 72))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))
114274	27880943	The proportions of each class of mutations in all of the TP53 mutations in each cancer type are listed in Supplementary Table S2.	('TP53', 'Gene', '7157', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('cancer', 'Disease', (80, 86))
114275	27880943	In general, nonsense mutations, frame-shift deletions, frame-shift insertions and splice-site mutations are all highly deleterious, and 34.5% of all TP53 mutations fall into one of these classes.	('frame-shift deletions', 'Var', (32, 53))	('TP53', 'Gene', '7157', (149, 153))	('fall', 'Phenotype', 'HP:0002527', (164, 168))	('nonsense mutations', 'Var', (12, 30))	('TP53', 'Gene', (149, 153))	('mutations', 'Var', (154, 163))	('frame-shift', 'Var', (55, 66))
114276	27880943	In contrast, in-frame deletions, in-frame insertions, and silent mutations have comparatively much less deleterious effects, but only 3.5% of all TP53 mutations fall into one of these mutation classes.	('TP53', 'Gene', '7157', (146, 150))	('in-frame insertions', 'Var', (33, 52))	('fall', 'Phenotype', 'HP:0002527', (161, 165))	('TP53', 'Gene', (146, 150))	('mutations', 'Var', (151, 160))
114277	27880943	Since most TP53 missense mutations are deleterious, we can conclude that deleterious or altered-function mutations predominate among TP53 mutations discovered in cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('missense mutations', 'Var', (16, 34))	('cancers', 'Disease', (162, 169))	('TP53', 'Gene', '7157', (11, 15))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('TP53', 'Gene', '7157', (133, 137))	('altered-function', 'Reg', (88, 104))	('TP53', 'Gene', (133, 137))
114280	27880943	Once mutations compromise p53's transcriptional repression function, genes that are usually repressed by it should have elevated expression in TP53-mutated cancers compared to TP53-wildtype cancers or normal tissue.	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('TP53', 'Gene', '7157', (176, 180))	('p53', 'Gene', (26, 29))	('TP53', 'Gene', '7157', (143, 147))	('compromise', 'NegReg', (15, 25))	('TP53-wildtype cancers', 'Disease', (176, 197))	('expression', 'MPA', (129, 139))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('mutations', 'Var', (5, 14))	('TP53', 'Gene', (176, 180))	('elevated', 'PosReg', (120, 128))	('TP53', 'Gene', (143, 147))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('TP53-wildtype cancers', 'Disease', 'MESH:D009369', (176, 197))	('cancers', 'Disease', (156, 163))	('transcriptional repression function', 'MPA', (32, 67))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('p53', 'Gene', '7157', (26, 29))
114281	27880943	We identified genes potentially repressed by p53 by comparing gene expression levels in cancers with non-silent (functionally significant) TP53 mutations compared to TP53-wildtype cancers in the TCGA datasets.	('gene expression levels', 'MPA', (62, 84))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('TP53-wildtype cancers', 'Disease', (166, 187))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('TP53-wildtype cancers', 'Disease', 'MESH:D009369', (166, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('TP53', 'Gene', '7157', (166, 170))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('TP53', 'Gene', '7157', (139, 143))	('cancers', 'Disease', (88, 95))	('TP53', 'Gene', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('TP53', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))
114296	27880943	The products of these eight genes are of particular interest as targets for the development of small-molecule kinase inhibitors, a strategy adopted by several cancer therapies.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('small-molecule', 'Var', (95, 109))
114300	27880943	Using the PANTHER Classification System, we categorized the 120 TP53-MW genes into eight molecular function classes: binding (GO:0005488), catalytic activity (GO:0003824), channel regulator activity (GO:0016247), enzyme regulator activity (GO:0030234), nucleic acid binding transcription factor activity (GO:0001071), receptor activity (GO:0004872), structural molecule activity (GO:0005198), and transporter activity (GO:0005215).	('catalytic activity', 'MPA', (139, 157))	('GO:0003824', 'Var', (159, 169))	('GO:0001071', 'Var', (305, 315))	('receptor activity', 'MPA', (318, 335))	('transporter activity', 'MPA', (397, 417))	('GO:0005488', 'Var', (126, 136))	('binding', 'Interaction', (117, 124))	('structural molecule activity', 'MPA', (350, 378))	('GO:0004872', 'Var', (337, 347))	('enzyme regulator activity', 'MPA', (213, 238))	('nucleic', 'MPA', (253, 260))	('TP53', 'Gene', '7157', (64, 68))	('GO:0005198', 'Var', (380, 390))	('GO:0016247', 'Var', (200, 210))	('TP53', 'Gene', (64, 68))	('GO:0030234', 'Var', (240, 250))	('channel regulator activity', 'MPA', (172, 198))
114316	27880943	Our results indicate that p53 may in turn inhibit TTK by a negative feedback loop, since TP53 mutations seem to cause the elevated expression of TTK.	('negative feedback loop', 'MPA', (59, 81))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('TTK', 'Gene', (145, 148))	('mutations', 'Var', (94, 103))	('p53', 'Gene', (26, 29))	('TTK', 'Gene', (50, 53))	('expression', 'MPA', (131, 141))	('TTK', 'Gene', '7272', (145, 148))	('elevated', 'PosReg', (122, 130))	('p53', 'Gene', '7157', (26, 29))	('inhibit', 'NegReg', (42, 49))	('TTK', 'Gene', '7272', (50, 53))
114319	27880943	We are interested in these genes because the mechanism underlying the elevated expression of TP53-MSN genes could be specifically related to TP53 mutations.	('elevated', 'PosReg', (70, 78))	('mutations', 'Var', (146, 155))	('expression', 'MPA', (79, 89))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (93, 97))	('TP53', 'Gene', (141, 145))	('MSN', 'Gene', '4478', (98, 101))	('MSN', 'Gene', (98, 101))
114324	27880943	In addition, our results suggest that TP53 may also inhibit other TP53-MSN genes, and that TP53 mutations may contribute to their elevated expression in a number of different cancer types.	('TP53', 'Gene', (91, 95))	('inhibit', 'NegReg', (52, 59))	('TP53', 'Gene', '7157', (66, 70))	('MSN', 'Gene', '4478', (71, 74))	('TP53', 'Gene', (38, 42))	('TP53', 'Gene', (66, 70))	('MSN', 'Gene', (71, 74))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('elevated', 'PosReg', (130, 138))	('expression', 'MPA', (139, 149))	('TP53', 'Gene', '7157', (91, 95))	('mutations', 'Var', (96, 105))	('TP53', 'Gene', '7157', (38, 42))
114325	27880943	We compared the TP53 mutation rates among different clinical phenotypes of cancer patients including gender, race, tumor stage, size or direct extent of the primary tumor (T), lymph nodes (N), and metastasis (M) in 18 cancer types: ACC, BLCA, BRCA, CESC, CHOL, COAD, DLBC, ESCA, GBM, HNSC, KICH, KIRC, KIRP, LAML, LGG, LIHC, LUAD, and LUSC (Supplementary Table S11).	('KICH', 'Disease', 'None', (290, 294))	('tumor', 'Disease', (115, 120))	('CHOL', 'Disease', (255, 259))	('BRCA', 'Gene', '672', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('COAD', 'Disease', 'MESH:D029424', (261, 265))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('TP53', 'Gene', '7157', (16, 20))	('KICH', 'Disease', (290, 294))	('BRCA', 'Gene', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (82, 90))	('COAD', 'Disease', (261, 265))	('tumor', 'Disease', (165, 170))	('CHOL', 'Disease', 'None', (255, 259))	('cancer', 'Disease', (218, 224))	('cancer', 'Disease', (75, 81))	('mutation', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TP53', 'Gene', (16, 20))
114327	27880943	In DLBC the TP53 mutation rate is lower in male than female subjects (unadjusted P-value = 0.05, odds ratio = 0), while in LIHC the rate is higher in male than female subjects (unadjusted P-value = 0.0007, odds ratio = 2.4).	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('lower', 'NegReg', (34, 39))	('mutation', 'Var', (17, 25))
114329	27880943	For the race phenotype, only HNSC shows a significantly higher TP53 mutation rate in African-American than in White-American subjects (unadjusted P-value = 0.03, odds ratio = 2.48).	('TP53', 'Gene', (63, 67))	('higher', 'PosReg', (56, 62))	('mutation', 'Var', (68, 76))	('TP53', 'Gene', '7157', (63, 67))
114330	27880943	We did not find significant differences in the TP53 mutation rates among different stages, T, N, or M status of tumor except that ACC shows a significantly higher TP53 mutation rate in large-size cancers (T3, T4) than small-size cancers (T1, T2) (unadjusted P-value = 0.04, odds ratio = 3.42).	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('higher', 'PosReg', (156, 162))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('TP53', 'Gene', '7157', (163, 167))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('cancers', 'Disease', (229, 236))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutation', 'Var', (168, 176))	('cancers', 'Disease', (196, 203))	('TP53', 'Gene', (163, 167))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('tumor', 'Disease', (112, 117))	('TP53', 'Gene', '7157', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('TP53', 'Gene', (47, 51))
114331	27880943	Since the phenotypes tumor stage, T, N, and M reflect the development or progress status of tumors, our results indicate that TP53 mutations are probably early events in tumorigenesis and drive its progression.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TP53', 'Gene', (126, 130))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumors', 'Disease', (92, 98))	('TP53', 'Gene', '7157', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
114333	27880943	Kaplan-Meier survival curves (Figure 6) show that patients with TP53 mutations have significantly worse OS prognoses compared with those without TP53 mutations in seven cancer types: ACC, COAD, HNSC, KIRC, LAML, LUAD, and PAAD; however, they have better OS prognoses in GBM (log-rank test, unadjusted P-value < 0.05).	('COAD', 'Disease', (188, 192))	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (169, 175))	('patients', 'Species', '9606', (50, 58))	('COAD', 'Disease', 'MESH:D029424', (188, 192))	('TP53', 'Gene', '7157', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('TP53', 'Gene', (145, 149))	('GBM', 'Disease', (270, 273))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
114335	27880943	Kaplan-Meier survival curves (Figure 6) show that patients with TP53 mutations have significantly worse DFS prognoses compared with those without TP53 mutations in three cancer types: ACC, PAAD, and UCEC (log-rank test, unadjusted P-value < 0.05).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('mutations', 'Var', (69, 78))	('TP53', 'Gene', '7157', (146, 150))	('cancer', 'Disease', (170, 176))	('patients', 'Species', '9606', (50, 58))	('TP53', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('PAAD', 'Disease', (189, 193))	('DFS', 'MPA', (104, 107))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('worse', 'NegReg', (98, 103))
114336	27880943	These results confirm that TP53 mutations lead to poor clinical outcomes in a number of cancers.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
114348	27880943	It makes sense that some TP53 mutations compromise p53 tumor suppressor function by reducing TP53 expression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('TP53', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('compromise', 'NegReg', (40, 50))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('tumor', 'Disease', (55, 60))	('TP53', 'Gene', '7157', (25, 29))	('mutations', 'Var', (30, 39))	('reducing', 'NegReg', (84, 92))	('expression', 'MPA', (98, 108))
114350	27880943	The explanation for these results could be that some TP53 mutations result in overexpression of mutant forms of TP53 while other mutations simply inactivate TP53.	('TP53', 'Gene', (157, 161))	('mutations', 'Var', (58, 67))	('mutant', 'Var', (96, 102))	('TP53', 'Gene', '7157', (157, 161))	('result in', 'Reg', (68, 77))	('overexpression', 'MPA', (78, 92))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (53, 57))	('TP53', 'Gene', (112, 116))
114354	27880943	We then divided TP53 mutations into truncating and non-truncating classes to observe their respective effects on TP53 expression.	('TP53', 'Gene', '7157', (113, 117))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (113, 117))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
114359	27880943	In contrast, TP53 non-truncating mutations may result in increased TP53 expression.	('TP53', 'Gene', (13, 17))	('expression', 'MPA', (72, 82))	('non-truncating mutations', 'Var', (18, 42))	('TP53', 'Gene', '7157', (67, 71))	('increased', 'PosReg', (57, 66))	('TP53', 'Gene', (67, 71))	('TP53', 'Gene', '7157', (13, 17))
114394	27880943	We found that BI-2536, GW843682X, Epothilone B, Afatinib and Gefitinib have significantly lower IC50 values in TP53-mutated cancer cell lines than in TP53-wildtype cancer cell lines (P-value < 0.05, FDR < 0.2, Supplementary Table S21).	('TP53', 'Gene', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('TP53', 'Gene', '7157', (111, 115))	('Epothilone B', 'Chemical', 'MESH:C093788', (34, 46))	('lower', 'NegReg', (90, 95))	('Afatinib', 'Chemical', 'MESH:D000077716', (48, 56))	('TP53', 'Gene', '7157', (150, 154))	('GW843682X', 'Var', (23, 32))	('GW843682X', 'Chemical', 'MESH:C524135', (23, 32))	('IC50 values', 'MPA', (96, 107))	('BI-2536', 'Var', (14, 21))	('cancer', 'Disease', (164, 170))	('BI-2536', 'Chemical', 'MESH:C518477', (14, 21))	('cancer', 'Disease', (124, 130))	('Gefitinib', 'Chemical', 'MESH:D000077156', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TP53', 'Gene', (111, 115))
114399	27880943	In our study we performed extensive analyses of TP53 mutation, gene expression, and clinical data from 33 TCGA cancer type-specific datasets.	('TP53', 'Gene', '7157', (48, 52))	('mutation', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TP53', 'Gene', (48, 52))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
114400	27880943	We identified potential TP53 interaction networks, the association between patient survival and TP53 mutation or gene expression status, and potential druggable SL partners of TP53.	('TP53', 'Gene', (96, 100))	('TP53', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (176, 180))	('association', 'Interaction', (55, 66))	('TP53', 'Gene', (176, 180))	('interaction', 'Interaction', (29, 40))	('mutation', 'Var', (101, 109))	('patient', 'Species', '9606', (75, 82))	('TP53', 'Gene', '7157', (96, 100))	('TP53', 'Gene', '7157', (24, 28))
114402	27880943	This indicates that TP53-truncating mutations reduce TP53 expression but some non-truncating mutations are capable of increasing it.	('reduce', 'NegReg', (46, 52))	('TP53', 'Gene', (20, 24))	('expression', 'MPA', (58, 68))	('mutations', 'Var', (36, 45))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (53, 57))
114403	27880943	However, we did not find significant survival time (OS or DFS) differences between TP53-truncated and TP53-mutated but TP53-non-truncated classes of cancer patients, indicating that both types of TP53 mutations are equally deleterious and lead to poor clinical outcomes.	('TP53', 'Gene', (196, 200))	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (102, 106))	('cancer', 'Disease', (149, 155))	('mutations', 'Var', (201, 210))	('patients', 'Species', '9606', (156, 164))	('TP53', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('TP53', 'Gene', '7157', (196, 200))	('TP53', 'Gene', '7157', (102, 106))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
114424	27880943	We performed survival analyses of TCGA patients based on TP53 mutation data and TP53 gene expression data, respectively.	('patients', 'Species', '9606', (39, 47))	('TCGA', 'Disease', (34, 38))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutation', 'Var', (62, 70))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
114436	27598485	However, significant CYP2W1 protein expression was found in only one tumor sample (a testosterone-producing adrenocortical carcinoma) and not in any normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (108, 132))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (108, 132))	('tumor', 'Disease', (69, 74))	('testosterone', 'Chemical', 'MESH:D013739', (85, 97))	('CYP2W1', 'Var', (21, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('adrenocortical carcinoma', 'Disease', (108, 132))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
114442	27598485	CYP2W1 expression in colon carcinoma is a prognostic factor: high expression is associated with poor survival,.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('colon carcinoma', 'Disease', 'MESH:D015179', (21, 36))	('colon carcinoma', 'Disease', (21, 36))	('expression', 'MPA', (66, 76))	('CYP2W1', 'Var', (0, 6))
114443	27598485	Since almost half of CRC metastases express CYP2W1, this enzyme is a possible target for treatment of CRC liver metastasis.	('metastases', 'Disease', 'MESH:D009362', (25, 35))	('CRC', 'Disease', (21, 24))	('CYP2W1', 'Var', (44, 50))	('CRC liver metastasis', 'Disease', 'MESH:D015179', (102, 122))	('CRC', 'Phenotype', 'HP:0030731', (21, 24))	('CRC', 'Phenotype', 'HP:0030731', (102, 105))	('metastases', 'Disease', (25, 35))	('CRC liver metastasis', 'Disease', (102, 122))
114444	27598485	We have shown, using both a cell culture model and a mouse xenograft model (CYP2W1-expressing human colon carcinoma cells), that duocarmycin (chloromethylindolines) prodrugs can be converted to cytotoxic products by CYP2W1.	('CYP2W1', 'Var', (216, 222))	('colon carcinoma', 'Disease', 'MESH:D015179', (100, 115))	('colon carcinoma', 'Disease', (100, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('human', 'Species', '9606', (94, 99))	('duocarmycin', 'Chemical', '-', (129, 140))	('mouse', 'Species', '10090', (53, 58))	('chloromethylindolines', 'Chemical', '-', (142, 163))
114445	27598485	The cytotoxicity of these prodrugs is mediated by a CYP2W1-dependent oxidation followed by spirocyclization and production of an N3-adenine covalent adduct.	('CYP2W1-dependent', 'Var', (52, 68))	('oxidation', 'MPA', (69, 78))	('N3-adenine', 'Chemical', '-', (129, 139))	('cytotoxicity', 'Disease', (4, 16))	('spirocyclization', 'MPA', (91, 107))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))
114446	27598485	By the administration of the prodrugs, the growth of the human CYP2W1 colon cancer cells in the mouse xenografts is arrested as seen from the lack of further increase of the xenograft size, whereas no effect is seen on growth of xenografts without CYP2W1.	('CYP2W1', 'Var', (63, 69))	('colon cancer', 'Disease', (70, 82))	('mouse', 'Species', '10090', (96, 101))	('xenograft size', 'CPA', (174, 188))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('growth', 'CPA', (43, 49))	('colon cancer', 'Phenotype', 'HP:0003003', (70, 82))	('colon cancer', 'Disease', 'MESH:D015179', (70, 82))	('human', 'Species', '9606', (57, 62))
114450	27598485	The major aim of that study was to assess the prognostic role of CYP2W1 in ACCs.	('ACCs', 'Gene', (75, 79))	('ACCs', 'Gene', '84680', (75, 79))	('CYP2W1', 'Var', (65, 71))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))
114451	27598485	In total, 239 ACCs were analyzed using CYP2W1 immunohistochemistry and the results compared with those from adrenocortical adenomas, normal adrenals, other normal non-adrenal tissues, and several non-adrenocortical cancer forms.	('non-adrenocortical cancer', 'Disease', (196, 221))	('ACCs', 'Gene', '84680', (14, 18))	('ACC', 'Phenotype', 'HP:0006744', (14, 17))	('ACCs', 'Gene', (14, 18))	('CYP2W1', 'Var', (39, 45))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (108, 131))	('non-adrenocortical cancer', 'Disease', 'MESH:D000306', (196, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('adrenocortical adenomas', 'Disease', (108, 131))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (108, 131))
114454	27598485	Expression of CYP2W1 in any normal tissue carries the risk of toxic side effects of CYP2W1-targeted cancer therapy.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CYP2W1', 'Var', (14, 20))
114463	27598485	Taqman gene expression assays (Life Technologies, Carlsbad, CA, USA) were used for CYP2W1 (Hs00908623_m1) and the housekeeping gene TATA-binding protein (TBP, Hs00427620_m1).	('TATA-binding protein', 'Gene', '6908', (132, 152))	('Hs00908623_m1', 'Var', (91, 104))	('TBP', 'Gene', (154, 157))	('TATA-binding protein', 'Gene', (132, 152))	('TBP', 'Gene', '6908', (154, 157))
114477	27598485	None of the 35 nADR samples showed detectable CYP2W1 apoprotein, but a weak band was visible in the non-tumor tissue from patient Ca 29.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('patient', 'Species', '9606', (122, 129))	('tumor', 'Disease', (104, 109))	('CYP2W1', 'Var', (46, 52))	('nADR', 'Chemical', '-', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
114478	27598485	This might be explained either by tissue contamination from the high CYP2W1 protein expression in the tumor sample or by induction of expression by the tumor (Fig 2).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('CYP2W1', 'Var', (69, 75))	('expression', 'MPA', (134, 144))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('high CYP2W1', 'Var', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
114481	27598485	As little as 0.78 mug protein from tumor Ca 29 resulted in a positive signal for CYP2W1, less than 1/30 of the amount of protein that was used for Western blot screening of the tumor and control samples (data shown in Additional supplemental information).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', (35, 40))	('CYP2W1', 'Var', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))
114483	27598485	By contrast, the monoclonal CYPW1 antibody and our 852 antibody recognized positive controls and CYP2W1 in colon cancer and in ACC and gave just a few bands in the tissue blot.	('colon cancer', 'Disease', (107, 119))	('CYP2W1', 'Var', (97, 103))	('ACC', 'Phenotype', 'HP:0006744', (127, 130))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colon cancer', 'Disease', 'MESH:D015179', (107, 119))
114487	27598485	noticed a correlation between hormone secretion from a tumor and the level of CYP2W1 expression, whereas we did not observe such a correlation.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CYP2W1 expression', 'Var', (78, 95))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('hormone secretion', 'MPA', (30, 47))	('tumor', 'Disease', (55, 60))
114491	27598485	However, expression levels of CYP2W1 mRNA and the corresponding protein levels were discrepant in both ACC and nADR samples.	('CYP2W1 mRNA', 'Var', (30, 41))	('expression', 'MPA', (9, 19))	('ACC', 'Phenotype', 'HP:0006744', (103, 106))	('nADR', 'Chemical', '-', (111, 115))
114492	27598485	The sensitivity of the immunoblots allowed detection of at least 3% of the level in the high CYP2W1-expressing tumor.	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('high CYP2W1-expressing', 'Var', (88, 110))	('tumor', 'Disease', 'MESH:D009369', (111, 116))
114493	27598485	This confirms that significant expression of CYP2W1 protein was present in only one tumor sample, and that all other samples lacked detectable expression of this enzyme.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('protein', 'Protein', (52, 59))	('tumor', 'Disease', (84, 89))	('CYP2W1', 'Var', (45, 51))
114568	21472710	Additionally, functional studies suggest that aberrant miRNA expression contributes to cancer pathogenesis making these molecules potential targets for cancer therapy.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('contributes', 'Reg', (72, 83))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('aberrant', 'Var', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
114579	21472710	For each array, 300 ng of total RNA (either tumor or reference) was labeled with Cy5 or Cy3 using the miRCURY LNA microRNA Array Labeling Kit (Exiqon, Denmark).	('Cy5', 'Var', (81, 84))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (102, 105))	('Cy5', 'Chemical', 'MESH:C085321', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Cy3', 'Chemical', '-', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Cy3', 'Var', (88, 91))	('tumor', 'Disease', (44, 49))
114587	21472710	The following TaqMan MicroRNA Assays used in this study were obtained from Applied Biosystems: let-7g (002282), miR-26b (000407), miR-483-5p (002338), miR-214 (002306), miR-195 (000494), miR-193b (002367), miR-126 (002228), miR-125b (000449), miR-125a-5p (002198), miR-30b (000602), miR-34a (000426), and miR-100 (000437).	('miR', 'Gene', '220972', (243, 246))	('miR', 'Gene', '220972', (283, 286))	('miR-483', 'Gene', '619552', (130, 137))	('miR-34a', 'Gene', '407040', (283, 290))	('miR-126', 'Gene', '406913', (206, 213))	('miR', 'Gene', '220972', (265, 268))	('miR-195', 'Gene', '406971', (169, 176))	('miR-26b', 'Gene', '407017', (112, 119))	('000602', 'Var', (274, 280))	('miR', 'Gene', (187, 190))	('miR', 'Gene', '220972', (169, 172))	('miR-30b', 'Gene', '407030', (265, 272))	('000407', 'Var', (121, 127))	('miR', 'Gene', (305, 308))	('miR-100', 'Gene', '406892', (305, 312))	('miR-193b', 'Gene', (187, 195))	('miR', 'Gene', (243, 246))	('miR', 'Gene', (283, 286))	('miR-30b', 'Gene', (265, 272))	('miR', 'Gene', '220972', (187, 190))	('miR', 'Gene', '220972', (130, 133))	('let-7g', 'Gene', '406890', (95, 101))	('miR-195', 'Gene', (169, 176))	('miR', 'Gene', (265, 268))	('miR-26b', 'Gene', (112, 119))	('miR', 'Gene', '220972', (224, 227))	('miR', 'Gene', (169, 172))	('002228', 'Var', (215, 221))	('let-7g', 'Gene', (95, 101))	('miR-214', 'Gene', '406996', (151, 158))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', (130, 133))	('miR-126', 'Gene', (206, 213))	('miR', 'Gene', '220972', (206, 209))	('miR', 'Gene', (224, 227))	('002282', 'Var', (103, 109))	('miR-193b', 'Gene', '574455', (187, 195))	('miR', 'Gene', (112, 115))	('miR', 'Gene', (151, 154))	('miR-34a', 'Gene', (283, 290))	('miR-483', 'Gene', (130, 137))	('miR', 'Gene', (206, 209))	('miR-100', 'Gene', (305, 312))	('000426', 'Var', (292, 298))	('miR-214', 'Gene', (151, 158))	('miR', 'Gene', '220972', (305, 308))
114588	21472710	RNU48 (001006), RNU6b (001093), U6 (001973), miR-34c (000428), miR-542-3p (001284), and miR-1285 (002822) were tested as possible endogenous controls for data normalization by measuring their expression in all of the samples.	('RNU6b', 'Gene', '26826', (16, 21))	('001973', 'Var', (36, 42))	('miR', 'Gene', (45, 48))	('miR-34c', 'Gene', '407042', (45, 52))	('miR-34c', 'Gene', (45, 52))	('002822', 'Var', (98, 104))	('001006', 'Var', (7, 13))	('expression', 'MPA', (192, 202))	('001284', 'Var', (75, 81))	('miR', 'Gene', '220972', (88, 91))	('RNU6b', 'Gene', (16, 21))	('miR', 'Gene', '220972', (63, 66))	('001093', 'Var', (23, 29))	('miR', 'Gene', (88, 91))	('miR', 'Gene', '220972', (45, 48))	('RNU48', 'Gene', (0, 5))	('miR', 'Gene', (63, 66))	('RNU48', 'Gene', '26801', (0, 5))	('000428', 'Var', (54, 60))
114591	21472710	The TaqMan probes for the IGF2 (Hs01005970_m1) and GAPDH (Hs99999905_m1) were obtained from Applied Biosystems.	('Hs99999905_m1', 'Var', (58, 71))	('Hs01005970_m1', 'Var', (32, 45))	('IGF2', 'Gene', '3481', (26, 30))	('GAPDH', 'Gene', '2597', (51, 56))	('GAPDH', 'Gene', (51, 56))	('IGF2', 'Gene', (26, 30))
114616	21472710	Additionally, misexpression of many of the chosen miRNAs have been associated with different types of cancers (reviewed in).	('miR', 'Gene', '220972', (50, 53))	('misexpression', 'Var', (14, 27))	('miR', 'Gene', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('associated', 'Reg', (67, 77))	('cancers', 'Disease', (102, 109))
114659	21472710	3 and 5) and that this is likely a byproduct of IGF2 misexpression (Fig.	('IGF2', 'Gene', (48, 52))	('IGF2', 'Gene', '3481', (48, 52))	('misexpression', 'Var', (53, 66))
114674	21472710	Increasingly studies are finding that altered expression of specific miRNAs can contribute to the initiation and progression of cancer (reviewed in).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('altered', 'Var', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('expression', 'MPA', (46, 56))	('contribute', 'Reg', (80, 90))	('cancer', 'Disease', (128, 134))
114689	21472710	Furthermore, as discussed above, the misexpressed miRNAs have interesting connections to oncogenesis.	('miR', 'Gene', '220972', (50, 53))	('connections', 'Reg', (74, 85))	('miR', 'Gene', (50, 53))	('misexpressed', 'Var', (37, 49))	('oncogenesis', 'Disease', (89, 100))
114722	19147773	PCR primers for NOV (NM_002514.3) and NR4A2 (NM_006186.3) was designed using Primer Express software program (ABI, Foster city, CA) and obtained from Integrated DNA technologies (Coralville, IA).	('NOV', 'Gene', (16, 19))	('NR4A2', 'Gene', (38, 43))	('NM_006186.3', 'Var', (45, 56))	('NR4A2', 'Gene', '4929', (38, 43))	('NM_002514.3', 'Var', (21, 32))	('NOV', 'Gene', '4856', (16, 19))
114738	19147773	This was an expected result as normal tissues generally show less gene expression variation compared to tumors, despite the fact that 4 NCs contained some contaminating normal adrenal medulla as assessed by elevated levels of tyrosine hydroxylase transcripts (TH, 208291_s_at).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tyrosine', 'MPA', (226, 234))	('tumors', 'Disease', (104, 110))	('TH, 208291_s_at', 'Var', (260, 275))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('elevated levels of tyrosine', 'Phenotype', 'HP:0003231', (207, 234))
114742	19147773	ACC053 was one of the tumors closer to the ACA cohort, a result consistent with its pathology and exceptionally low mitotic rate of 1 mitotic figure per 50 high-powered fields.	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('ACC053', 'Var', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
114751	19147773	Perturbation of the IGF2 locus at 11p15.5 is one of the most consistent and dominant genetic changes in ACC (for reviews, see).	('Perturbation', 'Var', (0, 12))	('IGF2', 'Gene', (20, 24))	('IGF2', 'Gene', '3481', (20, 24))
114752	19147773	In this study, 28 of 33 ACCs (84.8%) showed markedly increased levels of IGF2 transcripts as measured by two probes sets (202410_x_at and 210881_s_at) compared to NC and ACA (Figure 2).	('levels', 'MPA', (63, 69))	('210881_s_at', 'Var', (138, 149))	('ACCs', 'Gene', (24, 28))	('IGF2', 'Gene', (73, 77))	('ACCs', 'Gene', '84680', (24, 28))	('202410_x_at', 'Var', (122, 133))	('increased', 'PosReg', (53, 62))	('IGF2', 'Gene', '3481', (73, 77))	('transcripts', 'MPA', (78, 89))	('increased levels of IGF2', 'Phenotype', 'HP:0030269', (53, 77))
114757	19147773	This result was consistent with the DNA microarray data for the 3 cyclin E probe sets present on the array (CCNE1, 213523_at; CCNE2, 205034_at and 205034_at), thereby providing additional validation of the microarray data.	('CCNE2', 'Gene', '9134', (126, 131))	('CCNE2', 'Gene', (126, 131))	('205034_at', 'Var', (147, 156))	('CCNE1', 'Gene', '898', (108, 113))	('CCNE1', 'Gene', (108, 113))
114786	19147773	These findings suggest that these regions represent deletions of tumor suppressor genes or amplifications of oncogenes.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('deletions', 'Var', (52, 61))
114788	19147773	This finding is consistent with a large body of published literature on perturbation of the IGF2 locus in ACC (for reviews, see).	('ACC', 'Disease', (106, 109))	('perturbation', 'Var', (72, 84))	('IGF2', 'Gene', (92, 96))	('IGF2', 'Gene', '3481', (92, 96))
114803	34046364	Immunohistochemistry revealed p53 positivity.	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('positivity', 'Var', (34, 44))	('revealed', 'Reg', (21, 29))
114850	34046364	Mitotane causes selective damage to adrenocortical cells, acting primarily by the disruption of mitochondria and activating apoptosis.	('Mitotane', 'Var', (0, 8))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('activating', 'Reg', (113, 123))	('apoptosis', 'CPA', (124, 133))	('disruption of mitochondria', 'MPA', (82, 108))
114856	34046364	A recent multicentre study suggested that a specific combination of single nucleotide polymorphisms of two mitochondrial enzymes (CYP2W1 and CYP2B6) may predict therapeutic response to mitotane monotherapy.	('CYP2B6', 'Gene', (141, 147))	('CYP2B6', 'Gene', '1555', (141, 147))	('predict', 'Reg', (153, 160))	('mitotane', 'Chemical', 'MESH:D008939', (185, 193))	('therapeutic response', 'MPA', (161, 181))	('CYP2W1', 'Gene', '54905', (130, 136))	('CYP2W1', 'Gene', (130, 136))	('single nucleotide polymorphisms', 'Var', (68, 99))
114892	33233365	It follows that the metabolic reprogramming triggered by proto-oncogenes or mutated onco-suppressors, contributes to setting conditions favoring proliferation and biomass production.	('rat', 'Species', '10116', (152, 155))	('mutated', 'Var', (76, 83))	('proliferation', 'CPA', (145, 158))	('metabolic reprogramming', 'CPA', (20, 43))	('favoring', 'PosReg', (136, 144))	('biomass production', 'CPA', (163, 181))
114896	33233365	Although some tumors are indeed characterized by oncogenic mutations in mitochondrial metabolic enzymes, it is now well-established that aerobic glycolysis is a direct consequence of most oncogenic mutations; the following metabolic rewiring predisposes cells to proliferation and transformation, independent of mitochondrial defects.	('predisposes', 'Reg', (242, 253))	('mitochondrial defects', 'Disease', (312, 333))	('rat', 'Species', '10116', (270, 273))	('tumors', 'Disease', (14, 20))	('mutations', 'Var', (198, 207))	('mitochondrial defects', 'Disease', 'MESH:D028361', (312, 333))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('aerobic glycolysis', 'MPA', (137, 155))	('mutations', 'Var', (59, 68))	('proliferation', 'CPA', (263, 276))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('transformation', 'CPA', (281, 295))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
114904	33233365	Lysine N-epsilon-acetylation is more commonly associated with histone proteins and transcription factors and regulators, contributing to the so-called histone code and epigenetic control.	('histone proteins', 'Protein', (62, 78))	('Lysine', 'Var', (0, 6))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))
114907	33233365	Readers interested in the topic might refer to the published material, among which is the recent review by Neganova et al..  Microtubule acetylation is a typical post-translational modification of stable and long-lived microtubules that enhances microtubule flexibility, and therefore, is resistant to mechanical stresses.	('Microtubule', 'Var', (125, 136))	('stresses', 'Disease', (313, 321))	('microtubule flexibility', 'MPA', (246, 269))	('stresses', 'Disease', 'MESH:D000079225', (313, 321))	('enhances', 'PosReg', (237, 245))
114912	33233365	Isoprenoid units, i.e., geranyl and farnesyl groups, function as lipid anchors, favoring the attachment of modified proteins to the cell membrane.	('Isoprenoid', 'Chemical', 'MESH:D013729', (0, 10))	('lipid', 'Chemical', 'MESH:D008055', (65, 70))	('favoring', 'PosReg', (80, 88))	('attachment', 'Interaction', (93, 103))	('modified', 'Var', (107, 115))	('proteins', 'Protein', (116, 124))
114916	33233365	For example, in models of lung cancers, mutated Ras proteins present cell transforming functions, regardless of their prenylation state, however, farnesylation mediated by farnesyl-transferase is required in later stages of tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('cell transforming functions', 'CPA', (69, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', (224, 229))	('lung cancers', 'Disease', 'MESH:D008175', (26, 38))	('lung cancers', 'Phenotype', 'HP:0100526', (26, 38))	('Ras proteins', 'Protein', (48, 60))	('mutated', 'Var', (40, 47))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('lung cancers', 'Disease', (26, 38))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
114917	33233365	Mutant p53 regulates the mevalonate pathway, by interacting with the lipogenic transcription factors Sterol regulatory element-binding proteins (SREBPs) in human cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancers', 'Disease', (162, 169))	('mevalonate pathway', 'Pathway', (25, 43))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('p53', 'Gene', '7157', (7, 10))	('mevalonate', 'Chemical', 'MESH:D008798', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('regulates', 'Reg', (11, 20))	('Mutant', 'Var', (0, 6))	('human', 'Species', '9606', (156, 161))	('p53', 'Gene', (7, 10))	('interacting', 'Interaction', (48, 59))
114918	33233365	On the other hand, the mevalonate pathway, by affecting the prenylation of regulatory proteins, stabilizes the mutant p53.	('mevalonate', 'Chemical', 'MESH:D008798', (23, 33))	('mutant', 'Var', (111, 117))	('p53', 'Gene', (118, 121))	('prenylation of regulatory proteins', 'MPA', (60, 94))	('p53', 'Gene', '7157', (118, 121))	('mevalonate pathway', 'Pathway', (23, 41))	('affecting', 'Reg', (46, 55))
114919	33233365	Thus, inhibition of isoprenoid synthesis or specific inhibition of the activity of prenylating enzymes, represents a promising therapeutic approach.	('inhibition', 'NegReg', (53, 63))	('prenylating enzymes', 'Enzyme', (83, 102))	('isoprenoid', 'Chemical', 'MESH:D013729', (20, 30))	('inhibition', 'Var', (6, 16))	('activity', 'MPA', (71, 79))	('isoprenoid synthesis', 'MPA', (20, 40))
114920	33233365	In some cases, due to the mutations in metabolic enzymes, cancer cells accumulate specific intermediates, termed oncometabolites, exhibiting signaling properties.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('metabolic', 'Enzyme', (39, 48))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('accumulate', 'PosReg', (71, 81))	('cancer', 'Disease', (58, 64))
114922	33233365	Abnormal accumulation of fumarate and succinate is found in cancer cells with loss-of-function mutations in the genes encoding the enzymes fumarate hydratase and succinate dehydrogenase, both belonging to the Krebs cycle.	('succinate', 'Chemical', 'MESH:D019802', (162, 171))	('fumarate', 'Chemical', 'MESH:D005650', (139, 147))	('Krebs', 'Chemical', '-', (209, 214))	('fumarate', 'Chemical', 'MESH:D005650', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('fumarate', 'MPA', (25, 33))	('accumulation', 'PosReg', (9, 21))	('fumarate hydratase', 'Gene', '2271', (139, 157))	('mutations', 'Var', (95, 104))	('succinate', 'Chemical', 'MESH:D019802', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('fumarate hydratase', 'Gene', (139, 157))	('loss-of-function', 'NegReg', (78, 94))
114923	33233365	On the other hand, D-2-hydroxyglutarate results from mutated isocitrate dehydrogenase 1 and 2 (IDH1 and 2), due to the acquisition of neomorphic enzymatic activity.	('results from', 'Reg', (40, 52))	('D-2-hydroxyglutarate', 'Var', (19, 39))	('mutated', 'Var', (53, 60))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (19, 39))	('citrate', 'Chemical', 'MESH:D019343', (64, 71))	('IDH1 and 2', 'Gene', '3417;3418', (95, 105))
114933	33233365	For example, it was recently reported that inhibition of the respiratory chain complex III impairs proliferation, but not migration of the endothelial cells in vitro, by decreasing the NAD+/NADH ratio.	('rat', 'Species', '10116', (125, 128))	('inhibition', 'Var', (43, 53))	('impairs', 'NegReg', (91, 98))	('respiratory chain complex III', 'Enzyme', (61, 90))	('decreasing', 'NegReg', (170, 180))	('respiratory chain complex III impairs', 'Phenotype', 'HP:0011924', (61, 98))	('NAD+/NADH ratio', 'MPA', (185, 200))	('NAD+', 'Chemical', 'MESH:D009243', (185, 189))	('NADH', 'Chemical', 'MESH:D009243', (190, 194))	('rat', 'Species', '10116', (195, 198))	('rat', 'Species', '10116', (106, 109))	('rat', 'Species', '10116', (66, 69))	('proliferation', 'CPA', (99, 112))
114941	33233365	Overall, alteration of MFNs or OPA1 function leads to decreased mitochondrial fusion, shifting the balance of mito-dynamics to over-fragmentation.	('mitochondrial fusion', 'MPA', (64, 84))	('MFNs', 'Gene', (23, 27))	('rat', 'Species', '10116', (13, 16))	('decreased', 'NegReg', (54, 63))	('OPA1', 'Gene', (31, 35))	('alteration', 'Var', (9, 19))
114944	33233365	Of note, in vitro experiments indicated that MFN1 depletion reprogramed glucose metabolism, eliciting aerobic glycolysis instead of Oxphos.	('reprogramed', 'Reg', (60, 71))	('aerobic glycolysis', 'MPA', (102, 120))	('glucose metabolism', 'Disease', 'MESH:D044882', (72, 90))	('MFN1', 'Gene', '55669', (45, 49))	('MFN1', 'Gene', (45, 49))	('glucose metabolism', 'Disease', (72, 90))	('eliciting', 'Reg', (92, 101))	('depletion', 'Var', (50, 59))
114946	33233365	The knockdown of both MFN1 and OPA1 inhibited mitochondrial fusion in both experimental settings, leading to a reduced cell growth and tumor formation.	('inhibited', 'NegReg', (36, 45))	('MFN1', 'Gene', '55669', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('MFN1', 'Gene', (22, 26))	('reduced', 'NegReg', (111, 118))	('mitochondrial fusion', 'CPA', (46, 66))	('cell growth', 'CPA', (119, 130))	('OPA1', 'Gene', (31, 35))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
114962	33233365	In line with these findings, MFN2 silencing promoted cell migration, proliferation, and invasion, and increased tumor progression both in vivo and in vitro.	('promoted', 'PosReg', (44, 52))	('increased', 'PosReg', (102, 111))	('proliferation', 'CPA', (69, 82))	('invasion', 'CPA', (88, 96))	('rat', 'Species', '10116', (76, 79))	('MFN2', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('rat', 'Species', '10116', (61, 64))	('MFN2', 'Gene', '9927', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cell migration', 'CPA', (53, 67))	('tumor', 'Disease', (112, 117))	('silencing', 'Var', (34, 43))
114973	33233365	Strikingly, they found that OPA1 inactivation increased LN319 glioma cell invasion in vitro, and boosted cell dispersion in xenotransplanted Danio rerio embryos.	('LN319', 'CellLine', 'CVCL:3958', (56, 61))	('Danio rerio', 'Species', '7955', (141, 152))	('LN319', 'Gene', (56, 61))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('increased', 'PosReg', (46, 55))	('cell dispersion', 'CPA', (105, 120))	('inactivation', 'Var', (33, 45))	('boosted', 'PosReg', (97, 104))	('OPA1', 'Gene', (28, 32))	('glioma', 'Disease', (62, 68))
114987	33233365	Nevertheless, the authors also demonstrated that DRP1 deletion in pancreatic cancer cells conferred a significant survival advantage in a model of KRas-driven tumor.	('DRP1', 'Gene', '10059', (49, 53))	('deletion', 'Var', (54, 62))	('pancreatic cancer', 'Disease', (66, 83))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('pancreatic cancer', 'Disease', 'MESH:D010190', (66, 83))	('survival advantage', 'CPA', (114, 132))	('tumor', 'Disease', (159, 164))	('KRas', 'Gene', (147, 151))	('KRas', 'Gene', '3845', (147, 151))	('DRP1', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rat', 'Species', '10116', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (66, 83))
114990	33233365	Consistent results were obtained in the KRas mutant non-small-cell lung cancer (NSCLC), where DRP1 orchestrated a metabolic rewiring to promote lactate utilization and ROS production suppression.	('DRP1', 'Gene', '10059', (94, 98))	('KRas', 'Gene', (40, 44))	('mutant', 'Var', (45, 51))	('promote', 'PosReg', (136, 143))	('KRas', 'Gene', '3845', (40, 44))	('ROS', 'Chemical', 'MESH:D017382', (168, 171))	('suppression', 'NegReg', (183, 194))	('ROS production', 'MPA', (168, 182))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('NSCLC', 'Disease', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lactate utilization', 'MPA', (144, 163))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('lactate', 'Chemical', 'MESH:D019344', (144, 151))	('rat', 'Species', '10116', (106, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('lung cancer', 'Disease', (67, 78))	('DRP1', 'Gene', (94, 98))
114992	33233365	The authors identified a molecular axis represented by Proto-Oncogene Serine/Threonine-Protein Kinase (PIM1), DRP1, and mitochondrial fission; PIM1 inhibition favored DRP1 activity and mitochondrial fragmentation, increasing mitochondrial ROS production and resistance to pharmacological therapy.	('inhibition', 'Var', (148, 158))	('activity', 'MPA', (172, 180))	('increasing', 'PosReg', (214, 224))	('mitochondrial ROS production', 'MPA', (225, 253))	('favored', 'PosReg', (159, 166))	('resistance', 'CPA', (258, 268))	('DRP1', 'Gene', (167, 171))	('DRP1', 'Gene', '10059', (110, 114))	('ROS', 'Chemical', 'MESH:D017382', (239, 242))	('mitochondrial fragmentation', 'CPA', (185, 212))	('PIM1', 'Gene', (143, 147))	('DRP1', 'Gene', '10059', (167, 171))	('PIM1', 'Gene', '5292', (143, 147))	('DRP1', 'Gene', (110, 114))	('PIM1', 'Gene', '5292', (103, 107))	('Serine', 'Chemical', 'MESH:D012694', (70, 76))	('PIM1', 'Gene', (103, 107))
114995	33233365	In this context, PINCH-1 inhibition led to increased DRP1 activity, promoting mitochondrial fission and blunting the expression of Pyrroline-5-Carboxylate Reductase 1.	('blunting', 'NegReg', (104, 112))	('PINCH-1', 'Gene', (17, 24))	('activity', 'MPA', (58, 66))	('mitochondrial fission', 'MPA', (78, 99))	('DRP1', 'Gene', '10059', (53, 57))	('expression', 'MPA', (117, 127))	('DRP1', 'Gene', (53, 57))	('Pyrroline-5-Carboxylate Reductase 1', 'Gene', (131, 166))	('Pyrroline-5-Carboxylate Reductase 1', 'Gene', '5831', (131, 166))	('inhibition', 'Var', (25, 35))	('PINCH-1', 'Gene', '3987', (17, 24))	('increased', 'PosReg', (43, 52))	('increased DRP1 activity', 'Phenotype', 'HP:0003240', (43, 66))	('promoting', 'PosReg', (68, 77))
114999	33233365	Researchers showed that Large Tumor Suppressor 2 (LATS2) overexpression increased DRP1 protein levels, leading to aberrant mitochondrial fragmentation and ultimately to mitochondrial dysfunction, characterized by a mitochondrial membrane potential reduction, mitochondrial respiratory complex downregulation, mitochondrial cytochrome-C (Cyt-C) release into the nucleus, and consequential apoptosis.	('Large Tumor Suppressor 2', 'Gene', (24, 48))	('LATS2', 'Gene', (50, 55))	('LATS2', 'Gene', '26524', (50, 55))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (169, 194))	('mitochondrial membrane potential', 'MPA', (215, 247))	('Cyt-C', 'Gene', (337, 342))	('cytochrome-C', 'Gene', '54205', (323, 335))	('downregulation', 'NegReg', (293, 307))	('rat', 'Species', '10116', (278, 281))	('Cyt-C', 'Gene', '54205', (337, 342))	('cytochrome-C', 'Gene', (323, 335))	('DRP1', 'Gene', '10059', (82, 86))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (169, 194))	('Large Tumor Suppressor 2', 'Gene', '26524', (24, 48))	('mitochondrial dysfunction', 'Disease', (169, 194))	('overexpression', 'Var', (57, 71))	('Tumor', 'Phenotype', 'HP:0002664', (30, 35))	('reduction', 'NegReg', (248, 257))	('increased', 'PosReg', (72, 81))	('DRP1', 'Gene', (82, 86))	('mitochondrial respiratory complex', 'MPA', (259, 292))	('mitochondrial', 'MPA', (123, 136))	('protein levels', 'MPA', (87, 101))
115007	33233365	Specifically, CaMKII phosphorylation at Thr286 (CaMKIIThr286) and DRP1Ser616, promoted Bax translocation to mitochondria, Cyt-C release, and consequential cell apoptosis.	('promoted', 'PosReg', (78, 86))	('Cyt-C', 'Gene', (122, 127))	('Bax', 'Gene', '581', (87, 90))	('Thr286', 'Chemical', '-', (40, 46))	('Cyt-C', 'Gene', '54205', (122, 127))	('DRP1Ser616', 'Gene', (66, 76))	('phosphorylation', 'Var', (21, 36))	('Bax', 'Gene', (87, 90))	('Thr286', 'Chemical', '-', (54, 60))	('cell apoptosis', 'CPA', (155, 169))
115010	33233365	Notably, inhibition of mitochondrial fission rescued CDDP sensitivity to hypoxic ovarian cancer cells.	('inhibition', 'Var', (9, 19))	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('hypoxic ovarian cancer', 'Disease', 'MESH:D010051', (73, 95))	('hypoxic ovarian cancer', 'Disease', (73, 95))	('rescued', 'PosReg', (45, 52))	('CDDP sensitivity', 'MPA', (53, 69))	('CDDP', 'Chemical', 'MESH:D002945', (53, 57))	('mitochondrial', 'CPA', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
115017	33233365	indicated that FIS1 was significantly overexpressed in the bone marrow of acute myeloid leukemia (AML) patients, and that high FIS1 levels showed a significant negative impact on complete remission response after therapy.	('FIS1', 'Gene', '51024', (15, 19))	('FIS1', 'Gene', (15, 19))	('complete remission response', 'CPA', (179, 206))	('acute myeloid leukemia', 'Disease', (74, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (80, 96))	('FIS1', 'Gene', '51024', (127, 131))	('overexpressed', 'PosReg', (38, 51))	('high', 'Var', (122, 126))	('FIS1', 'Gene', (127, 131))	('AML', 'Disease', 'MESH:D015470', (98, 101))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (74, 96))	('patients', 'Species', '9606', (103, 111))	('AML', 'Disease', (98, 101))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (74, 96))	('AML', 'Phenotype', 'HP:0004808', (98, 101))	('negative', 'NegReg', (160, 168))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))
115021	33233365	This feature was blunted by FIS1 silencing, which also led to decreased mitophagy, inhibition of the tumorigenic protein GSK3, cell cycle arrest, and increased cell differentiation of LSCs in AML.	('inhibition', 'NegReg', (83, 93))	('decreased', 'NegReg', (62, 71))	('arrest', 'Disease', 'MESH:D006323', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('silencing', 'Var', (33, 42))	('GSK3', 'Protein', (121, 125))	('AML', 'Disease', 'MESH:D015470', (192, 195))	('arrest', 'Disease', (138, 144))	('FIS1', 'Gene', '51024', (28, 32))	('mitophagy', 'CPA', (72, 81))	('FIS1', 'Gene', (28, 32))	('cell differentiation', 'CPA', (160, 180))	('AML', 'Disease', (192, 195))	('increased', 'PosReg', (150, 159))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (127, 144))	('AML', 'Phenotype', 'HP:0004808', (192, 195))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
115049	33233365	ER-mitochondria contact sites are also a primary platform for decoding danger signals, such as variation in Ca2+ homeostasis, which can be perturbed by oncogenes and oncosuppressors to determine cancer development or progression.	('determine', 'Reg', (185, 194))	('variation', 'Var', (95, 104))	('Ca2+', 'Chemical', 'MESH:D000069285', (108, 112))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('Ca2+ homeostasis', 'MPA', (108, 124))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
115095	33233365	Accordingly, loss of Galectin-3 impairs mitochondrial morphology and dynamics, leading to a more fragmented and rounded mitochondria, both in normal and cancer epithelial cells in basal conditions; on the other hand, depletion of Galectin-3 in pancreatic cancer cells was reported to be associated with increased Oxphos activity.	('pancreatic cancer', 'Disease', 'MESH:D010190', (244, 261))	('cancer', 'Disease', (153, 159))	('Galectin-3', 'Gene', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (255, 261))	('depletion', 'MPA', (217, 226))	('loss', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('pancreatic cancer', 'Disease', (244, 261))	('Galectin-3', 'Gene', '3958', (230, 240))	('mitochondrial', 'MPA', (40, 53))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('increased', 'PosReg', (303, 312))	('dynamics', 'MPA', (69, 77))	('Galectin-3', 'Gene', '3958', (21, 31))	('Oxphos activity', 'MPA', (313, 328))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (244, 261))	('impairs', 'NegReg', (32, 39))	('more', 'PosReg', (92, 96))	('Galectin-3', 'Gene', (230, 240))
115131	33233365	The authors observed that the knockdown of cortactin or inhibition of actin polymerization prevented mitochondrial fragmentation induced by metabolic cellular stress, thus, SIRT1 emerged as a new player that acts by regulating the actin cytoskeleton.	('SIRT1', 'Gene', (173, 178))	('prevented', 'NegReg', (91, 100))	('cortactin', 'Gene', (43, 52))	('inhibition', 'Var', (56, 66))	('metabolic cellular stress', 'MPA', (140, 165))	('knockdown', 'Var', (30, 39))	('cortactin', 'Gene', '2017', (43, 52))	('mitochondrial fragmentation', 'CPA', (101, 128))	('SIRT1', 'Gene', '23411', (173, 178))
115136	33233365	Overexpression of cofilin is associated with the aggressiveness of different types of cancer, but the exact mechanism is yet unknown.	('aggressiveness', 'Disease', 'MESH:D001523', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cofilin', 'Gene', '1072', (18, 25))	('aggressiveness', 'Disease', (49, 63))	('cofilin', 'Gene', (18, 25))	('Overexpression', 'Var', (0, 14))	('associated', 'Reg', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('aggressiveness', 'Phenotype', 'HP:0000718', (49, 63))	('cancer', 'Disease', (86, 92))
115138	33233365	Furthermore, knockdown of cofilin reduced mitochondrial fission and mitophagy through the indirect regulation of PINK1 (PTEN-induced kinase 1) in breast cancer cells treated with different compounds, which induce these mitochondrial processes.	('cofilin', 'Gene', (26, 33))	('reduced', 'NegReg', (34, 41))	('PTEN-induced kinase 1', 'Gene', '65018', (120, 141))	('PINK1', 'Gene', '65018', (113, 118))	('mitochondrial fission', 'CPA', (42, 63))	('PINK1', 'Gene', (113, 118))	('mitophagy', 'CPA', (68, 77))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cofilin', 'Gene', '1072', (26, 33))	('breast cancer', 'Disease', (146, 159))	('PTEN-induced kinase 1', 'Gene', (120, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('knockdown', 'Var', (13, 22))
115147	33233365	The main effects of fascin depletion were on metastatic expansion and only had a marginal effect on tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('fascin', 'Gene', '6624', (20, 26))	('fascin', 'Gene', (20, 26))	('depletion', 'Var', (27, 36))	('metastatic expansion', 'CPA', (45, 65))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
115150	33233365	To confirm that fascin's role was due to F-actin and mitochondrial interaction, they showed that mutations at the two actin-binding sites abolished the effect of the protein on mitochondria activity.	('fascin', 'Gene', '6624', (16, 22))	('mutations', 'Var', (97, 106))	('fascin', 'Gene', (16, 22))	('effect', 'MPA', (152, 158))	('abolished', 'NegReg', (138, 147))	('mitochondria activity', 'MPA', (177, 198))
115167	33233365	Specifically, inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin, by interfering with mitochondria/lysosome interactions.	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('mitochondria/lysosome interactions', 'MPA', (132, 166))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('mTOR', 'Gene', '2475', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('hepatocellular carcinoma', 'Disease', (67, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('mTOR', 'Gene', (33, 37))	('sensitivity', 'MPA', (52, 63))	('interfering', 'NegReg', (115, 126))	('inhibition', 'Var', (14, 24))	('increased', 'PosReg', (38, 47))
115196	33171596	In 2017, pembrolizumab, an anti-PD-1 antibody, was granted the first agnostic indication by the U.S.A's FDA for patients with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors.	('pembrolizumab', 'Chemical', 'MESH:C582435', (9, 22))	('MSI-H', 'Chemical', '-', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('patients', 'Species', '9606', (112, 120))	('deficient mismatch repair', 'Var', (169, 194))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('microsatellite instability-high', 'Var', (126, 157))
115205	33171596	CIN involves intratumor heterogenicity, cancer evaluation, host immunity, and gene mutation, which can be immunogenic, as well as increased immune evasion.	('gene mutation', 'Var', (78, 91))	('tumor', 'Disease', (18, 23))	('CIN', 'Disease', (0, 3))	('immune evasion', 'MPA', (140, 154))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('CIN', 'Disease', 'MESH:D007674', (0, 3))	('increased', 'PosReg', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CIN', 'Phenotype', 'HP:0040012', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
115219	33171596	TMB-H and a high CIN70 were associated with a poor progression-free survival (PFS) and overall survival (OS); in contrast, MSI-H was marginally associated with a favorable PFS, but not OS (Figure 2D-I).	('poor', 'NegReg', (46, 50))	('overall survival', 'CPA', (87, 103))	('high', 'Var', (12, 16))	('progression-free survival', 'CPA', (51, 76))	('CIN', 'Disease', (17, 20))	('CIN', 'Disease', 'MESH:D007674', (17, 20))	('TMB-H', 'Chemical', '-', (0, 5))	('CIN', 'Phenotype', 'HP:0040012', (17, 20))	('MSI-H', 'Chemical', '-', (123, 128))
115224	33171596	Among the 25 cancer types with MSI-H samples, the CIN70 scores were significantly higher in the MSI-H group than non-MSI-H group within only three cancer types (breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), and stomach adenocarcinoma (STAD); Figure 3, Supplementary Figure S2).	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('MSI-H', 'Chemical', '-', (117, 122))	('MSI-H', 'Chemical', '-', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('CIN', 'Disease', 'MESH:D007674', (50, 53))	('MSI-H', 'Var', (96, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (228, 250))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (161, 186))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (195, 215))	('stomach adenocarcinoma', 'Disease', (228, 250))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('CIN', 'Disease', (50, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cancer', 'Disease', (13, 19))	('colon adenocarcinoma', 'Disease', (195, 215))	('breast invasive carcinoma', 'Disease', (161, 186))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('MSI-H', 'Chemical', '-', (96, 101))	('higher', 'PosReg', (82, 88))	('CIN', 'Phenotype', 'HP:0040012', (50, 53))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (161, 186))	('cancer', 'Disease', (147, 153))
115226	33171596	Regarding PFS, TMB is significantly associated with a PFS difference in 9 out of 32 cancer types (Figure 3, Supplementary Figure S4; Supplementary Table S1).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('PFS difference', 'Var', (54, 68))	('cancer', 'Disease', (84, 90))	('TMB', 'Disease', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TMB', 'Chemical', '-', (15, 18))	('associated', 'Reg', (36, 46))	('difference', 'Var', (58, 68))
115227	33171596	In most cancer types, patients with TMB-H had a significantly shorter PFS than patients without TMB-H, indicating TMB-H is an unfavorable prognostic factor in such cancers.	('TMB-H', 'Chemical', '-', (96, 101))	('shorter', 'NegReg', (62, 69))	('cancer', 'Disease', (8, 14))	('TMB-H', 'Chemical', '-', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('patients', 'Species', '9606', (22, 30))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (164, 170))	('cancers', 'Disease', (164, 171))	('TMB-H', 'Chemical', '-', (36, 41))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('TMB-H', 'Var', (36, 41))	('PFS', 'MPA', (70, 73))	('patients', 'Species', '9606', (79, 87))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
115228	33171596	However, patients with TMB-H had a significantly longer PFS than the patients without TMB-H in three cancer types (bladder urothelial carcinoma (BLCA), STAD, and uterine corpus endometrial carcinoma (UCEC); Supplementary Figure S4).	('patients', 'Species', '9606', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (177, 198))	('cancer', 'Disease', (101, 107))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (115, 143))	('TMB-H', 'Chemical', '-', (23, 28))	('bladder urothelial carcinoma', 'Disease', (115, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (177, 198))	('TMB-H', 'Var', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('longer', 'PosReg', (49, 55))	('PFS', 'MPA', (56, 59))	('patients', 'Species', '9606', (69, 77))	('endometrial carcinoma', 'Disease', (177, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('TMB-H', 'Chemical', '-', (86, 91))
115231	33171596	Using the median of CIN70, we performed the survival analysis, comparing the high CIN70 and low CIN70 patients in each cancer type.	('CIN', 'Disease', (82, 85))	('high', 'Var', (77, 81))	('CIN', 'Disease', (20, 23))	('patients', 'Species', '9606', (102, 110))	('CIN', 'Disease', (96, 99))	('CIN', 'Disease', 'MESH:D007674', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', (119, 125))	('CIN', 'Disease', 'MESH:D007674', (20, 23))	('CIN', 'Disease', 'MESH:D007674', (96, 99))	('CIN', 'Phenotype', 'HP:0040012', (20, 23))	('CIN', 'Phenotype', 'HP:0040012', (82, 85))	('CIN', 'Phenotype', 'HP:0040012', (96, 99))
115236	33171596	On the other hand, patients with TMB-H had a longer OS than those without TMB-H in four cancers (BLCA, ovarian serous cystadenocarcinoma (OV), skin cutaneous melanoma (SKCM), and testicular germ cell tumors (TGCT); Supplementary Figure S7).	('TMB-H', 'Chemical', '-', (33, 38))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (103, 136))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 166))	('skin cutaneous melanoma', 'Disease', (143, 166))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('germ cell tumors', 'Phenotype', 'HP:0100728', (190, 206))	('ovarian serous cystadenocarcinoma', 'Disease', (103, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('patients', 'Species', '9606', (19, 27))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (103, 136))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (148, 166))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('TMB-H', 'Chemical', '-', (74, 79))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('TMB-H', 'Var', (33, 38))	('tumors', 'Disease', (200, 206))
115237	33171596	In 25 cancer types with MSI-H samples, MSI status was significantly associated with OS in three cancer types (Figure 3, Supplementary Figure S8; Supplementary Table S2).	('MSI status', 'Var', (39, 49))	('MSI-H', 'Chemical', '-', (24, 29))	('associated with', 'Reg', (68, 83))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (6, 12))	('cancer', 'Disease', (96, 102))
115239	33171596	However, MSI-H patients had a longer OS than the non-MSI-H patients in UCEC (Supplementary Figure S8).	('patients', 'Species', '9606', (15, 23))	('UCEC', 'Disease', (71, 75))	('MSI-H', 'Chemical', '-', (9, 14))	('MSI-H', 'Chemical', '-', (53, 58))	('MSI-H', 'Var', (9, 14))	('patients', 'Species', '9606', (59, 67))
115242	33171596	However, unlike the prognostic value of CIN70, PFS showing CIN70 is a universally poor prognostic factor, and patients with a high CIN70 had a favorable OS in two cancer types (cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and THYM; Supplementary Figure S9).	('CIN', 'Disease', 'MESH:D007674', (131, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('THYM', 'Disease', (253, 257))	('CIN', 'Phenotype', 'HP:0040012', (40, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('CIN', 'Disease', 'MESH:D007674', (40, 43))	('CIN', 'Disease', (59, 62))	('high', 'Var', (126, 130))	('CIN', 'Disease', (131, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('cancer', 'Disease', (163, 169))	('CIN', 'Disease', (40, 43))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (177, 241))	('CIN', 'Phenotype', 'HP:0040012', (59, 62))	('CIN', 'Phenotype', 'HP:0040012', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('CIN', 'Disease', 'MESH:D007674', (59, 62))	('patients', 'Species', '9606', (110, 118))
115251	33171596	Multiple genetic alterations contribute to CIN, such as genes involving DNA damage and repair, mitotic checkpoint, chromosome condensation and segregation from mutational inactivation of STAG2, and possibly sister chromatid cohesion (hSecurin).	('contribute', 'Reg', (29, 39))	('segregation', 'CPA', (143, 154))	('mutational inactivation', 'Var', (160, 183))	('CIN', 'Disease', (43, 46))	('mitotic checkpoint', 'CPA', (95, 113))	('hSecurin', 'Gene', '9232', (234, 242))	('CIN', 'Disease', 'MESH:D007674', (43, 46))	('STAG2', 'Gene', (187, 192))	('STAG2', 'Gene', '10735', (187, 192))	('CIN', 'Phenotype', 'HP:0040012', (43, 46))	('chromosome condensation', 'CPA', (115, 138))	('hSecurin', 'Gene', (234, 242))
115283	33171596	Therefore, TMB was determined by counting the number of mutations in the TCGA MC3 data.	('TMB', 'Chemical', '-', (11, 14))	('mutations', 'Var', (56, 65))	('TCGA MC3', 'Gene', (73, 81))
115290	33171596	), the Ministry of Science and Technology (105-2314-B-182A-041-MY2 and 107-2314-B-182A-134-MY3 to C.-N.Y., 106-2221-E-010-019-MY3 and 109-2221-E-010-013-MY3 to Y.-C.W., 109-2314-B-182A-148 -MY3 to C.-E.W., and 104-2314-B-075-064-MY2 to M.-H.C.), and the Taipei Veterans General Hospital (V109C-028 to M.-H.C.).	('104-2314-B-075-064-MY2 to', 'Var', (210, 235))	('V109C', 'Mutation', 'p.V109C', (288, 293))	('109-2314-B-182A-148 -MY3', 'Var', (169, 193))
115345	33071959	An evaluation of the adrenal function in the 35 patients with available data showed that only 4 (11.4%) patients had baseline cortisol (17.64, 120.4, 79.24, and 94.86 nmol/L, respectively), and ACTH levels (216.2, 391.0, 219.9, and 325 pmol/L, respectively), that were suggestive of adrenal insufficiency, including 3 (8.5%) patients with bilateral adrenal involvement and 1 (2.9%) patient with unilateral adrenal involvement.	('216.2', 'Var', (207, 212))	('patient', 'Species', '9606', (325, 332))	('men', 'Species', '9606', (364, 367))	('patients', 'Species', '9606', (325, 333))	('ACTH', 'Gene', (194, 198))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (283, 304))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (283, 304))	('men', 'Species', '9606', (421, 424))	('ACTH', 'Gene', '5443', (194, 198))	('cortisol', 'Chemical', 'MESH:D006854', (126, 134))	('patient', 'Species', '9606', (48, 55))	('patient', 'Species', '9606', (104, 111))	('adrenal insufficiency', 'Disease', (283, 304))	('patient', 'Species', '9606', (382, 389))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (104, 112))
115380	33071959	The results showed that chemotherapy alone was associated with a lower risk of death (P = 0.029); and the mortality risk was 78.9% lower in patients who underwent chemotherapy compared to those who did not.	('mortality', 'Disease', 'MESH:D003643', (106, 115))	('chemotherapy', 'Var', (163, 175))	('death', 'Disease', 'MESH:D003643', (79, 84))	('death', 'Disease', (79, 84))	('mortality', 'Disease', (106, 115))	('patients', 'Species', '9606', (140, 148))	('lower', 'NegReg', (131, 136))
115396	33071959	Therefore, we speculate that high levels of LDH and HBDH are predictive factors for the poor prognosis of PAL.	('high', 'Var', (29, 33))	('LDH', 'Protein', (44, 47))	('PAL', 'Chemical', '-', (106, 109))	('HBDH', 'Protein', (52, 56))	('PAL', 'Phenotype', 'HP:0030069', (106, 109))	('PAL', 'Disease', (106, 109))
115427	33071959	Immune dysfunction, EBV infection, and mutations in the p53 and proto-oncogenes have been implicated.	('EBV infection', 'Disease', (20, 33))	('Immune dysfunction', 'Disease', 'MESH:D007154', (0, 18))	('p53', 'Gene', (56, 59))	('EBV infection', 'Disease', 'MESH:D020031', (20, 33))	('p53', 'Gene', '7157', (56, 59))	('mutations', 'Var', (39, 48))	('Immune dysfunction', 'Disease', (0, 18))
115431	33071959	Data on gene rearrangement are limited but suggested that the presence of the IGH/IGK rearrangement with BCL2 or MYC expression might play a significant role in lymphoma genesis.	('lymphoma genesis', 'Disease', (161, 177))	('role', 'Reg', (153, 157))	('IGK', 'Gene', (82, 85))	('MYC', 'Gene', '4609', (113, 116))	('rearrangement', 'Var', (86, 99))	('IGH', 'Gene', '3492', (78, 81))	('men', 'Species', '9606', (22, 25))	('men', 'Species', '9606', (95, 98))	('lymphoma genesis', 'Disease', 'MESH:D008223', (161, 177))	('play', 'Reg', (134, 138))	('IGH', 'Gene', (78, 81))	('IGK', 'Gene', '50802', (82, 85))	('MYC', 'Gene', (113, 116))	('BCL2', 'Gene', '596', (105, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (161, 169))	('BCL2', 'Gene', (105, 109))	('presence', 'Var', (62, 70))
115495	31817072	Following co-culture with H295R cells, the expression of all these stem genes was significantly decreased compared to control ASCs (Figure 2C).	('ASC', 'Gene', (126, 129))	('decreased', 'NegReg', (96, 105))	('H295R', 'CellLine', 'CVCL:0458', (26, 31))	('ASC', 'Gene', '29108', (126, 129))	('H295R cells', 'Var', (26, 37))	('expression', 'MPA', (43, 53))
115508	31817072	As it had been observed for the adipose precursors, H295R cells showed a significant increase in cell proliferation at day 9 co-culture, compared with H295R cells cultured alone (Figure 5A).	('cell proliferation at', 'CPA', (97, 118))	('H295R', 'Var', (52, 57))	('H295R', 'CellLine', 'CVCL:0458', (151, 156))	('H295R', 'CellLine', 'CVCL:0458', (52, 57))	('increase', 'PosReg', (85, 93))
115516	31817072	The percentage of migrating cells able to cover the scratch was significantly higher if H295R cells were previously co-cultured with ASCs compared with the control (Figure 6A).	('ASC', 'Gene', '29108', (133, 136))	('H295R', 'CellLine', 'CVCL:0458', (88, 93))	('H295R', 'Var', (88, 93))	('higher', 'PosReg', (78, 84))	('migrating cells', 'CPA', (18, 33))	('ASC', 'Gene', (133, 136))
115518	31817072	To further support the evidence that ASC co-culture increased H295R invasiveness potential, we assessed the ability of the latter cells to migrate through an endothelial monolayer by using a trans-endothelial migration assay.	('increased', 'PosReg', (52, 61))	('invasiveness potential', 'CPA', (68, 90))	('H295R', 'CellLine', 'CVCL:0458', (62, 67))	('ASC', 'Gene', (37, 40))	('H295R', 'Var', (62, 67))	('ASC', 'Gene', '29108', (37, 40))
115519	31817072	Co-cultured H295R cells exhibited a statistically significant higher ability to cross the endothelial barrier consisting of a human microvascular endothelial cell (HMEC-1) monolayer, compared with H295R cells cultured alone (Figure 6C).	('H295R', 'CellLine', 'CVCL:0458', (12, 17))	('H295R', 'Var', (12, 17))	('H295R', 'CellLine', 'CVCL:0458', (197, 202))	('human', 'Species', '9606', (126, 131))	('cross the endothelial barrier', 'CPA', (80, 109))	('HMEC-1', 'CellLine', 'CVCL:0307', (164, 170))	('higher', 'PosReg', (62, 68))
115523	31817072	Consistently, protein expression of Focal Adhesion Kinase (FAK), RhoA and, to a lesser extent, Fascin-1, all involved in the formation of lamellipodia, filopodia and focal adhesions essential for cell migration and invasion, was increased in co-cultured H295R cells compared with the control (Figure 6E).	('Fascin-1', 'Gene', '14086', (95, 103))	('Focal Adhesion Kinase', 'Gene', (36, 57))	('protein expression', 'MPA', (14, 32))	('H295R', 'CellLine', 'CVCL:0458', (254, 259))	('increased', 'PosReg', (229, 238))	('H295R', 'Var', (254, 259))	('FAK', 'Gene', '5747', (59, 62))	('Focal Adhesion Kinase', 'Gene', '5747', (36, 57))	('FAK', 'Gene', (59, 62))	('RhoA', 'Gene', (65, 69))	('Fascin-1', 'Gene', (95, 103))
115540	31817072	Finally, adipocytes co-cultured with H295R cells expressed significantly higher levels of leptin compared with the mono-culture, as quantified by RT-qPCR (4.50 +- 0.3-fold, p < 0.001, n = 5 independent experiments).	('H295R', 'CellLine', 'CVCL:0458', (37, 42))	('H295R', 'Var', (37, 42))	('levels', 'MPA', (80, 86))	('leptin', 'Gene', '3952', (90, 96))	('leptin', 'Gene', (90, 96))	('higher', 'PosReg', (73, 79))
115562	31817072	Aggressive ACC has been associated with a molecular signature characterized by hyper-methylation/inactivated expression of the G0/G1 switch gene 2 (G0S2).	('G0/G1 switch gene 2', 'Gene', (127, 146))	('Aggressive ACC', 'Disease', (0, 14))	('G0/G1 switch gene 2', 'Gene', '50486', (127, 146))	('G0S2', 'Gene', '50486', (148, 152))	('hyper-methylation/inactivated', 'Var', (79, 108))	('G0S2', 'Gene', (148, 152))	('ACC', 'Phenotype', 'HP:0006744', (11, 14))	('hyper-methylation/inactivated expression', 'MPA', (79, 119))
115579	31817072	Indeed, under co-culture conditions the shift in the CXCR4/CXCR7 ratio towards the CXCR7 axis was associated not only with increased invasion potential but also with increased ability of H295R cells to migrate through an endothelial monolayer system.	('H295R', 'CellLine', 'CVCL:0458', (187, 192))	('invasion potential', 'CPA', (133, 151))	('increased', 'PosReg', (123, 132))	('increased', 'PosReg', (166, 175))	('CXCR4', 'Gene', (53, 58))	('CXCR7', 'Gene', '57007', (83, 88))	('CXCR7', 'Gene', (59, 64))	('migrate through an', 'CPA', (202, 220))	('CXCR7', 'Gene', (83, 88))	('H295R', 'Var', (187, 192))	('CXCR4', 'Gene', '7852', (53, 58))	('CXCR7', 'Gene', '57007', (59, 64))
115594	31817072	At the co-culture starting time, inserts containing H295R were transferred into the wells containing ASCs, and all cells were grown in DMEM plus 10% FBS.	('ASC', 'Gene', (101, 104))	('ASC', 'Gene', '29108', (101, 104))	('H295R', 'Var', (52, 57))	('H295R', 'CellLine', 'CVCL:0458', (52, 57))
115607	31817072	For each RNA sample, cDNA was obtained by reverse transcription PCR starting from 250 ng of RNA in 50 muL final volume reaction (Taqman RT-PCR kit; Applied Biosystems, Foster City, CA, USA) using the following cycling conditions: 10 min at 25  C, 30 min at 48  C, 3 min at 95  C, hold 4  C. Further quantitative real-time PCR was carried out using primers and probes for the following genes: BMI-1 (Hs00180411_m1), Nanog (Hs02387400_g1), OCT-4 (Hs00999634), Leptin (Hs00174877), AdipoQ (Hs00605917_m1), FABP4 (Hs00609791_m1), HSL (Hs00193510_m1), IL-8 (Hs00174103_m1), IGF2 (Hs04188276_m1), IGF-1R (Hs00181385_m1), Ob-R (HS001974497_m1), DPP4 (Hs00175210_m1), CXCR7 (Hs00604567_m1), CXCL12 (Hs00171022_m1), GAPDH (4352934) (#4331182,Taqman Gene Expression Assay; Applied Biosystems) and Taqman Universal Master mix (#4364338, Applied Biosystems).	('Hs00175210_m1', 'Var', (644, 657))	('Ob-R', 'Gene', (615, 619))	('Ob-R', 'Gene', '3953', (615, 619))	('muL', 'Gene', (102, 105))	('Hs00604567_m1', 'Var', (667, 680))	('FABP4', 'Gene', '2167', (503, 508))	('Leptin', 'Gene', (458, 464))	('IGF2', 'Gene', (569, 573))	('BMI-1', 'Gene', '648', (392, 397))	('Leptin', 'Gene', '3952', (458, 464))	('IL-8', 'Gene', (547, 551))	('muL', 'Gene', '4591', (102, 105))	('BMI-1', 'Gene', (392, 397))	('DPP4', 'Gene', '1803', (638, 642))	('OCT-4', 'Gene', '5460', (438, 443))	('HSL', 'Gene', (526, 529))	('Hs00171022_m1', 'Var', (691, 704))	('HSL', 'Gene', '3991', (526, 529))	('IGF2', 'Gene', '3481', (569, 573))	('AdipoQ', 'Gene', '9370', (479, 485))	('CXCR7', 'Gene', (660, 665))	('AdipoQ', 'Gene', (479, 485))	('Nanog', 'Gene', (415, 420))	('Nanog', 'Gene', '79923', (415, 420))	('IGF-1R', 'Gene', '3480', (591, 597))	('FABP4', 'Gene', (503, 508))	('#4331182', 'Var', (724, 732))	('IGF-1R', 'Gene', (591, 597))	('CXCR7', 'Gene', '57007', (660, 665))	('OCT-4', 'Gene', (438, 443))	('HS001974497_m1', 'Var', (621, 635))	('4352934) (#4331182', 'Var', (714, 732))	('DPP4', 'Gene', (638, 642))	('IL-8', 'Gene', '3576', (547, 551))	('#4364338', 'Var', (816, 824))
115620	31817072	H295R cultured alone or in co-culture with ASCs for 7 days were trypsinized, seeded in a 12-well plate (1.5 x 106 cells/well) and grown up to confluence.	('ASC', 'Gene', '29108', (43, 46))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('ASC', 'Gene', (43, 46))	('H295R', 'Var', (0, 5))
115626	31817072	H295R were seeded on glass coverslips in 6-well plates (105 cells/well) and cultured alone or together with ASCs grown in cell culture inserts (8 x 103 cells/insert).	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('ASC', 'Gene', (108, 111))	('ASC', 'Gene', '29108', (108, 111))	('H295R', 'Var', (0, 5))
115630	31817072	Conditioned media of ASCs cultured alone or with H295R for 7 days were analysed with an ELISA kit for human SDF-1a (CXCL12A) detection (Invitrogen, Thermo Fisher Scientific), according to the manufacturer's instructions.	('ASC', 'Gene', (21, 24))	('ASC', 'Gene', '29108', (21, 24))	('SDF-1', 'Gene', '6387', (108, 113))	('SDF-1', 'Gene', (108, 113))	('H295R', 'CellLine', 'CVCL:0458', (49, 54))	('H295R', 'Var', (49, 54))	('human', 'Species', '9606', (102, 107))
115640	31340196	In confirmed ACA patients, the sensitivity for ACA code combinations was higher in patients initially admitted to the Department of Endocrinology before surgery than that in patients directly admitted to the Department of Urology (90.0 vs 73.1%, P = 0.033).	('sensitivity', 'MPA', (31, 42))	('ACA', 'Phenotype', 'HP:0008256', (13, 16))	('ACA', 'Phenotype', 'HP:0008256', (47, 50))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (17, 25))	('combinations', 'Var', (56, 68))	('ACA', 'Disease', (13, 16))	('patients', 'Species', '9606', (83, 91))	('higher', 'PosReg', (73, 79))
115682	31340196	The PPV of CD codes or code combinations in patients admitted to the Department of Urology was significantly lower than that in patients admitted to the Department of Neurosurgery or the Department of Endocrinology (20.0 vs 100.0%, 20.0 vs 98.9%, P < 0.001).	('code combinations', 'Var', (23, 40))	('lower', 'NegReg', (109, 114))	('patients', 'Species', '9606', (44, 52))	('CD codes', 'Var', (11, 19))	('patients', 'Species', '9606', (128, 136))
115691	31340196	Another finding of our study was the lower sensitivity for ACA code combinations (73.1 vs 90.0%) and the lower PPV for the BMAH code (60.9 vs 100.0%) observed in patients who were directly admitted to the Department of Urology than those observed in patients who were initially admitted to the Department of Endocrinology before being transferred to the Department of Urology.	('lower', 'NegReg', (105, 110))	('patients', 'Species', '9606', (162, 170))	('combinations', 'Var', (68, 80))	('patients', 'Species', '9606', (250, 258))	('ACA', 'Phenotype', 'HP:0008256', (59, 62))	('PPV', 'MPA', (111, 114))	('lower', 'NegReg', (37, 42))	('BMAH', 'Chemical', '-', (123, 127))	('sensitivity', 'MPA', (43, 54))
115746	29720169	Recent in vivo pharmacologic studies in healthy dogs have provided support for development of ATR-101 in ACC and endocrine diseases such as CS and congenital adrenal hyperplasia given that ATR-101 preferentially distributes to the adrenal glands and selectively inhibits adrenal ACAT1 activity.	('endocrine diseases', 'Disease', (113, 131))	('inhibits', 'NegReg', (262, 270))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (158, 177))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (147, 177))	('dogs', 'Species', '9615', (48, 52))	('ATR-101', 'Var', (189, 196))	('adrenal ACAT1', 'Enzyme', (271, 284))	('preferentially', 'PosReg', (197, 211))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (147, 177))	('congenital adrenal hyperplasia', 'Disease', (147, 177))	('endocrine diseases', 'Disease', 'MESH:D004700', (113, 131))
115797	29720169	Sections of adrenal gland were incubated for 30 min with 1 of the following 2 primary antibodies: mouse monoclonal anti-Melan-A (A103 clone Dako M7196, Carpinteria, CA, USA) at a dilution of 1:20 or rabbit polyclonal anti-caspase-3 (# 20RCR013, RDI/Fitzgerald, Acton, MA, USA) at a dilution of 1:1000.	('Melan-A', 'Gene', '403495', (120, 127))	('mouse', 'Species', '10090', (98, 103))	('caspase-3', 'Gene', (222, 231))	('# 20RCR013', 'Var', (233, 243))	('rabbit', 'Species', '9986', (199, 205))	('Melan-A', 'Gene', (120, 127))	('caspase-3', 'Gene', '403567', (222, 231))	('F', 'Chemical', 'MESH:D005461', (249, 250))
115846	29720169	The histologic changes in adrenal glands from dogs with adrenal-dependent disease further support previous findings in healthy dogs that ATR-101 distributes to the adrenal glands, inhibits adrenal ACAT1 activity, and induces apoptosis.	('apoptosis', 'CPA', (225, 234))	('ATR-101', 'Var', (137, 144))	('induces', 'Reg', (217, 224))	('adrenal-dependent disease', 'Disease', 'MESH:D000309', (56, 81))	('adrenal-dependent disease', 'Disease', (56, 81))	('inhibits', 'NegReg', (180, 188))	('dogs', 'Species', '9615', (46, 50))	('dogs', 'Species', '9615', (127, 131))	('adrenal', 'MPA', (189, 196))	('activity', 'MPA', (203, 211))
115896	29491433	Dependent on the cancer type and cancer stage, ER-mitochondrial Ca2+ transfer can either exert anti-tumorigenic effects like restoring apoptosis sensitivity or exert pro-tumorigenic effects like promoting metastatic behavior.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('restoring', 'PosReg', (125, 134))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer type and cancer', 'Disease', 'MESH:D009369', (17, 39))	('metastatic behavior', 'CPA', (205, 224))	('apoptosis sensitivity', 'MPA', (135, 156))	('tumor', 'Disease', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('promoting', 'PosReg', (195, 204))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('ER-mitochondrial Ca2+ transfer', 'Var', (47, 77))
115898	29491433	Ca2+ signaling modulation can (re)sensitize or increase the responsiveness of cancer cells towards chemotherapeutics.	('cancer', 'Disease', (78, 84))	('modulation', 'Var', (15, 25))	('Ca2+ signaling', 'MPA', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('sensitize', 'Reg', (34, 43))	('increase', 'PosReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('responsiveness', 'MPA', (60, 74))
115904	29491433	What other molecular mechanisms, like the generation of ROS, exchange of lipids or alterations in protein composition, or ER-mitochondrial tethering at the MAMs impact or cooperate with Ca2+ signaling in anti-cancer chemotherapeutic actions?	('exchange', 'Var', (61, 69))	('ROS', 'MPA', (56, 59))	('cooperate', 'Reg', (171, 180))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('lipids', 'Chemical', 'MESH:D008055', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('impact', 'Reg', (161, 167))	('cancer', 'Disease', (209, 215))	('ROS', 'Chemical', 'MESH:D017382', (56, 59))	('protein', 'Protein', (98, 105))	('alterations', 'Reg', (83, 94))
115911	29491433	Ca2+ increases the activity of several rate-limiting enzymes of the tricarboxylic acid (TCA) cycle, including pyruvate, isocitrate, and alpha-ketoglutarate dehydrogenases, while MCU transcription is controlled by the cAMP-responsive element binding protein, a Ca2+-dependent transcription factor.	('alpha-ketoglutarate dehydrogenases', 'Enzyme', (136, 170))	('Ca2+', 'Var', (0, 4))	('MCU', 'Gene', '90550', (178, 181))	('isocitrate', 'Chemical', 'MESH:C034219', (120, 130))	('pyruvate', 'Chemical', 'MESH:D019289', (110, 118))	('increases', 'PosReg', (5, 14))	('activity', 'MPA', (19, 27))	('pyruvate', 'Enzyme', (110, 118))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (68, 86))	('cAMP', 'Chemical', '-', (217, 221))	('isocitrate', 'Enzyme', (120, 130))	('MCU', 'Gene', (178, 181))	('TCA', 'Chemical', 'MESH:D014233', (88, 91))
115916	29491433	Ca2+ binds to ARALAR and activates ARALAR-mediated glutamate and NAD(P)H transport into the mitochondria.	('activates', 'PosReg', (25, 34))	('ARALAR', 'Gene', (14, 20))	('NAD(P)H', 'Chemical', '-', (65, 72))	('ARALAR', 'Gene', (35, 41))	('glutamate', 'Chemical', 'MESH:D018698', (51, 60))	('binds', 'Interaction', (5, 10))	('ARALAR', 'Gene', '8604', (35, 41))	('ARALAR', 'Gene', '8604', (14, 20))	('Ca2+', 'Var', (0, 4))
115920	29491433	Compared to wild-type cells, loss of MICU1, which also results in loss of MICU2, lowers the threshold for MCU-mediated mitochondrial Ca2+ uptake to about 200 nM Ca2+.	('MICU1', 'Gene', (37, 42))	('loss', 'NegReg', (66, 70))	('MCU', 'Gene', '90550', (106, 109))	('MICU2', 'Gene', '221154', (74, 79))	('loss', 'Var', (29, 33))	('MICU2', 'Gene', (74, 79))	('MICU1', 'Gene', '10367', (37, 42))	('lowers', 'NegReg', (81, 87))	('MCU', 'Gene', (106, 109))
115933	29491433	Similarly, IP3R3 seems to be the isoform that preferentially transmits pro-apoptotic Ca2+ signals to the mitochondria via the MAMs.	('preferentially', 'PosReg', (46, 60))	('IP3R3', 'Var', (11, 16))	('transmits pro-apoptotic Ca2+ signals', 'MPA', (61, 97))	('IP3', 'Chemical', 'MESH:D015544', (11, 14))
115939	29491433	Also, SERCA is a target for post-translational modification: p53 changes SERCA's oxidative state, promoting its ER Ca2+-uptake activity and thus altering the net flux of Ca2+ released from the ER.	('net flux of Ca2+ released', 'MPA', (158, 183))	('is a', 'Gene', (12, 16))	('p53', 'Var', (61, 64))	('oxidative state', 'MPA', (81, 96))	('is a', 'Gene', '312', (12, 16))	('changes', 'Reg', (65, 72))	('promoting', 'PosReg', (98, 107))	('ER Ca2+-uptake activity', 'MPA', (112, 135))	('altering', 'Reg', (145, 153))	('SERCA', 'Gene', (73, 78))
115940	29491433	In addition, complex formation between Ca2+-transport proteins like IP3Rs and VDAC1 at the MAMs and tumor suppressors or oncogenes influences ER-mitochondrial Ca2+ transfer.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('IP3Rs', 'Gene', (68, 73))	('VDAC1', 'Gene', (78, 83))	('tumor', 'Disease', (100, 105))	('complex', 'Var', (13, 20))	('ER-mitochondrial Ca2+ transfer', 'MPA', (142, 172))	('influences', 'Reg', (131, 141))	('VDAC1', 'Gene', '7416', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('IP3', 'Chemical', 'MESH:D015544', (68, 71))
115953	29491433	Consequently, while both the BH4 domains of Bcl-2 and Bcl-Xl could prevent mitochondrial Ca2+ uptake, BH4-Bcl-2 acted at the level of IP3Rs, while BH4-Bcl-Xl acted at the level of VDAC1.	('IP3', 'Chemical', 'MESH:D015544', (134, 137))	('BH4', 'Chemical', 'MESH:C003402', (29, 32))	('BH4', 'Chemical', 'MESH:C003402', (102, 105))	('VDAC1', 'Gene', '7416', (180, 185))	('BH4-Bcl-2', 'Var', (102, 111))	('BH4', 'Chemical', 'MESH:C003402', (147, 150))	('VDAC1', 'Gene', (180, 185))	('mitochondrial Ca2+ uptake', 'MPA', (75, 100))	('prevent', 'NegReg', (67, 74))
115954	29491433	To summarize, ER-mitochondrial Ca2+ transfer at the MAMs can be influenced through IP3R-mediated Ca2+ release, VDAC1-mediated mitochondrial Ca2+ uptake, or modulation of the SERCA activity.	('IP3R-mediated Ca2+ release', 'MPA', (83, 109))	('VDAC1', 'Gene', '7416', (111, 116))	('IP3', 'Chemical', 'MESH:D015544', (83, 86))	('ER-mitochondrial Ca2+ transfer', 'MPA', (14, 44))	('modulation', 'Var', (156, 166))	('influenced', 'Reg', (64, 74))	('VDAC1', 'Gene', (111, 116))
115962	29491433	In this regard, recently, genetic disruption of VDAC1 in cells from cancer xenograft models displayed decreased mitochondrial membrane potential and ATP content with a consequent low migration rate and tumor regression.	('VDAC1', 'Gene', '7416', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (202, 207))	('genetic disruption', 'Var', (26, 44))	('ATP content', 'MPA', (149, 160))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('low', 'NegReg', (179, 182))	('ATP', 'Chemical', 'MESH:D000255', (149, 152))	('cancer', 'Disease', (68, 74))	('VDAC1', 'Gene', (48, 53))	('mitochondrial membrane potential', 'MPA', (112, 144))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('decreased', 'NegReg', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
115967	29491433	This represents a novel mechanism by which loss of PTEN allows cancer cells to evade apoptosis, since pro-apoptotic mitochondrial Ca2+ transfer becomes impaired due to downregulation of the IP3R3.	('impaired', 'NegReg', (152, 160))	('PTEN', 'Gene', '5728', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('pro-apoptotic mitochondrial Ca2+ transfer', 'MPA', (102, 143))	('downregulation', 'NegReg', (168, 182))	('IP3', 'Chemical', 'MESH:D015544', (190, 193))	('evade apoptosis', 'CPA', (79, 94))	('loss', 'Var', (43, 47))	('PTEN', 'Gene', (51, 55))	('cancer', 'Disease', (63, 69))	('IP3R3', 'Enzyme', (190, 195))
115969	29491433	Loss of BAP1 results in IP3R3 downregulation, hampering the effective apoptotic clearance of damaged cells and favoring oncogenesis and malignant cell survival.	('malignant cell survival', 'CPA', (136, 159))	('IP3', 'Chemical', 'MESH:D015544', (24, 27))	('favoring', 'PosReg', (111, 119))	('downregulation', 'NegReg', (30, 44))	('hampering', 'NegReg', (46, 55))	('is a', 'Gene', (129, 133))	('in IP', 'Gene', (21, 26))	('is a', 'Gene', '312', (129, 133))	('in IP', 'Gene', '58493', (21, 26))	('BAP1', 'Gene', (8, 12))	('apoptotic clearance of', 'CPA', (70, 92))	('Loss', 'Var', (0, 4))
115973	29491433	In contrast, antagonizing miR-25 expression using antagomirs re-sensitized colon cancer cells to Ca2+-dependent apoptotic stimuli, like H2O2 and ceramide.	('Ca2+-dependent apoptotic stimuli', 'MPA', (97, 129))	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('miR-25', 'Gene', (26, 32))	('antagonizing', 'Var', (13, 25))	('colon cancer', 'Disease', 'MESH:D015179', (75, 87))	('colon cancer', 'Disease', (75, 87))	('ceramide', 'Chemical', 'MESH:D002518', (145, 153))	('H2O2', 'Chemical', 'MESH:D006861', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('miR-25', 'Chemical', '-', (26, 32))
115985	29491433	Furthermore, shifts in cytosolic [Ca2+] have been proposed as early markers for cytotoxicity in cells in response not only to H2O2 or staurosporine but also to chemotherapeutics like gossypol or arsenic trioxide (ATO).	('ATO', 'Chemical', 'MESH:D000077237', (213, 216))	('cytotoxicity', 'Disease', 'MESH:D064420', (80, 92))	('gossypol', 'Chemical', 'MESH:D006072', (183, 191))	('staurosporine', 'Chemical', 'MESH:D019311', (134, 147))	('H2O2', 'Var', (126, 130))	('arsenic trioxide', 'Chemical', 'MESH:D000077237', (195, 211))	('cytosolic [Ca2+]', 'MPA', (23, 39))	('shifts', 'Reg', (13, 19))	('H2O2', 'Chemical', 'MESH:D006861', (126, 130))	('cytotoxicity', 'Disease', (80, 92))
116019	29491433	Dysregulation of intracellular Ca2+ homeostasis might underlie ABT-737- and ABT-263-induced thrombocytopenia, as addition of ABT-263 to platelets triggered an acute rise in cytosolic Ca2+ levels.	('thrombocytopenia', 'Disease', (92, 108))	('ABT', 'Chemical', 'MESH:C002502', (76, 79))	('ABT-737', 'Chemical', 'MESH:C501332', (63, 70))	('ABT-263', 'Var', (125, 132))	('ABT', 'Chemical', 'MESH:C002502', (125, 128))	('thrombocytopenia', 'Disease', 'MESH:D013921', (92, 108))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (92, 108))	('ABT-737-', 'Gene', (63, 71))	('addition', 'Var', (113, 121))	('ABT', 'Chemical', 'MESH:C002502', (63, 66))	('rise', 'PosReg', (165, 169))	('cytosolic Ca2+ levels', 'MPA', (173, 194))
116027	29491433	In several human and mouse cell models, ABT-199 did not trigger cytosolic Ca2+ release events by itself nor did it affect agonist-induced IP3R-mediated Ca2+ signaling.	('cytosolic Ca2+ release', 'MPA', (64, 86))	('ABT-199', 'Chemical', 'MESH:C579720', (40, 47))	('human', 'Species', '9606', (11, 16))	('affect', 'Reg', (115, 121))	('mouse', 'Species', '10090', (21, 26))	('ABT-199', 'Var', (40, 47))	('IP3', 'Chemical', 'MESH:D015544', (138, 141))	('agonist-induced IP3R-mediated Ca2+ signaling', 'MPA', (122, 166))
116029	29491433	Nevertheless, it seems that there is an interplay between ABT-199-induced cell death in Bcl-2-dependent cancer cells and basal Ca2+ signaling, since chelating intracellular Ca2+ using BAPTA-AM enhanced ABT-199-induced cell death.	('cell death', 'CPA', (218, 228))	('BAPTA-AM', 'Chemical', 'MESH:C070379', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ABT-199', 'Chemical', 'MESH:C579720', (58, 65))	('is a', 'Gene', (34, 38))	('enhanced', 'PosReg', (193, 201))	('ABT-199', 'Chemical', 'MESH:C579720', (202, 209))	('chelating', 'Var', (149, 158))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('is a', 'Gene', '312', (34, 38))
116042	29491433	In a separate study, both HA14-1 and BH3I-2' trigger Ca2+ release from the ER of pancreatic acinar cells through IP3R- and RyR-mediated mechanisms, elevating cytosolic Ca2+ levels, a feature that contributes to their cell death properties.	('BH3', 'Chemical', 'MESH:C006008', (37, 40))	('pancreatic acinar', 'Disease', (81, 98))	('elevating', 'PosReg', (148, 157))	("BH3I-2'", 'Var', (37, 44))	('Ca2+ release', 'MPA', (53, 65))	('- and RyR', 'Gene', '6261', (117, 126))	('cytosolic Ca2+ levels', 'MPA', (158, 179))	('pancreatic acinar', 'Disease', 'MESH:D010190', (81, 98))	('IP3', 'Chemical', 'MESH:D015544', (113, 116))	('HA14-1', 'Var', (26, 32))
116043	29491433	Here, it was proposed that dissociation of Bax from Bcl-2 using these drugs sensitize IP3Rs and RyRs to cytosolic Ca2+.	('IP3Rs', 'MPA', (86, 91))	('dissociation', 'Var', (27, 39))	('sensitize', 'Reg', (76, 85))	('IP3', 'Chemical', 'MESH:D015544', (86, 89))
116044	29491433	Excitingly, the ability of HA14-1 and BH3I-2' to increase cytosolic Ca2+ levels in pancreatic acinar cells was strictly dependent on the presence of Bax, while the presence of Bcl-2 and Bak was not critical for this process.	('increase', 'PosReg', (49, 57))	('Bak', 'Chemical', '-', (186, 189))	('pancreatic acinar', 'Disease', 'MESH:D010190', (83, 100))	('HA14-1', 'Var', (27, 33))	('cytosolic Ca2+ levels', 'MPA', (58, 79))	("BH3I-2'", 'Var', (38, 45))	('BH3', 'Chemical', 'MESH:C006008', (38, 41))	('pancreatic acinar', 'Disease', (83, 100))
116081	29491433	Consequently, disrupting or altering lipid homeostasis in cancer cells might be an efficient way of inducing cell death.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cell death', 'CPA', (109, 119))	('altering', 'Reg', (28, 36))	('disrupting', 'Var', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('lipid homeostasis', 'MPA', (37, 54))	('cancer', 'Disease', (58, 64))	('lipid', 'Chemical', 'MESH:D008055', (37, 42))
116095	29491433	Furthermore, FATE1 expression conferred mitotane resistance to ACC cells, when this chemotherapeutic drug was used in a dose that falls inside the therapeutic window for ACC patients, whereas knockdown of FATE1 in these cells increased the sensitivity to the drug.	('falls', 'Phenotype', 'HP:0002527', (130, 135))	('sensitivity', 'MPA', (240, 251))	('ACC', 'Phenotype', 'HP:0006744', (170, 173))	('expression', 'Var', (19, 29))	('mitotane resistance', 'MPA', (40, 59))	('patients', 'Species', '9606', (174, 182))	('ACC', 'Phenotype', 'HP:0006744', (63, 66))	('CC', 'Phenotype', 'HP:0030153', (64, 66))	('CC', 'Phenotype', 'HP:0030153', (171, 173))	('conferred', 'Reg', (30, 39))	('increased', 'PosReg', (226, 235))	('knockdown', 'Var', (192, 201))	('mitotane', 'Chemical', 'MESH:D008939', (40, 48))	('FATE1', 'Gene', (13, 18))
116097	29491433	Mitotane inhibits the SOAT1 enzyme, which is also localized in the MAMs, resulting in the accumulation of toxic cholesterol lipids.	('Mitotane', 'Var', (0, 8))	('is a', 'Gene', '312', (42, 46))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('cholesterol lipids', 'Chemical', '-', (112, 130))	('accumulation of toxic cholesterol lipids', 'MPA', (90, 130))	('SOAT1', 'Gene', (22, 27))	('inhibits', 'NegReg', (9, 17))	('is a', 'Gene', (42, 46))
116140	28325912	When TM3 cells were treated with CQ and NH4Cl, LC3 (a substrate of lysosome) puncta scatted in the cytoplasm were increased (Fig.	('TM3', 'Gene', '22003', (5, 8))	('LC3', 'Gene', (47, 50))	('CQ', 'Chemical', 'MESH:D002738', (33, 35))	('increased', 'PosReg', (114, 123))	('TM3', 'Gene', (5, 8))	('NH4Cl', 'Var', (40, 45))	('NH4Cl', 'Chemical', 'MESH:D000643', (40, 45))	('LC3', 'Gene', '66734', (47, 50))
116141	28325912	In addition, when TM3, MA-10 and Y1 cells were treated with CQ or NH4Cl, the amounts of LC3 and another lysosomal substrate p62 were increased in a dose-dependent manner (Fig.	('p62', 'Gene', '18226', (124, 127))	('NH4Cl', 'Var', (66, 71))	('NH4Cl', 'Chemical', 'MESH:D000643', (66, 71))	('p62', 'Gene', (124, 127))	('TM3', 'Gene', '22003', (18, 21))	('LC3', 'Gene', '66734', (88, 91))	('CQ', 'Chemical', 'MESH:D002738', (60, 62))	('increased', 'PosReg', (133, 142))	('LC3', 'Gene', (88, 91))	('amounts', 'MPA', (77, 84))	('TM3', 'Gene', (18, 21))
116143	28325912	By counting cell numbers and performing MTT assay, we found that CQ, NH4Cl, and Baf reduced a number of all cell lines tested dose- and time-dependently (Fig.	('CQ', 'Chemical', 'MESH:D002738', (65, 67))	('NH4Cl', 'Var', (69, 74))	('MTT', 'Chemical', 'MESH:C070243', (40, 43))	('NH4Cl', 'Chemical', 'MESH:D000643', (69, 74))	('Baf', 'Chemical', 'MESH:C040929', (80, 83))	('reduced', 'NegReg', (84, 91))
116155	28325912	However, higher concentration of 3-MA treatment (5 or 10 mM) induced cell death, this result is consistent with previous study that 3-MA inhibits autophagy at lower concentration but induces cellular apoptosis at higher concentration (5 or 10 mM).	('cellular apoptosis', 'CPA', (191, 209))	('autophagy', 'CPA', (146, 155))	('3-MA', 'Chemical', 'MESH:C025946', (132, 136))	('3-MA', 'Var', (132, 136))	('induces', 'Reg', (183, 190))	('3-MA', 'Chemical', 'MESH:C025946', (33, 37))	('inhibits', 'NegReg', (137, 145))
116157	28325912	This result is consistent with recent studies showing that ablation of Beclin 1 did not affect the growth of steroidogenic granulosa and luteal cells in the ovary, even though the steroidogenesis is inhibited.	('steroid', 'Chemical', 'MESH:D013256', (109, 116))	('Beclin 1', 'Gene', '56208', (71, 79))	('steroid', 'Chemical', 'MESH:D013256', (180, 187))	('ablation', 'Var', (59, 67))	('Beclin 1', 'Gene', (71, 79))
116161	28325912	Consistent with our flow cytometry analysis, inhibition of lysosomes reduced EdU incorporation dose-dependently in TM3 cells (Fig.	('reduced', 'NegReg', (69, 76))	('TM3', 'Gene', (115, 118))	('EdU', 'Chemical', '-', (77, 80))	('inhibition', 'Var', (45, 55))	('EdU incorporation', 'MPA', (77, 94))	('TM3', 'Gene', '22003', (115, 118))
116163	28325912	3A, S2C and S2F), while treatment with higher concentration of CQ (100 muM) modestly induced cell death as shown by an increase of cleaved caspase 3 in Y1 cells (Fig.	('muM', 'Gene', (71, 74))	('cleaved caspase 3', 'MPA', (131, 148))	('CQ', 'Chemical', 'MESH:D002738', (63, 65))	('S2F', 'Var', (12, 15))	('increase', 'PosReg', (119, 127))	('muM', 'Gene', '56925', (71, 74))
116165	28325912	CKD2 has been known to be active when Thr160 is phosphorylated (pCDK2).	('Thr160', 'Var', (38, 44))	('CDK2', 'Gene', (65, 69))	('CDK2', 'Gene', '12566', (65, 69))	('Thr160', 'Chemical', '-', (38, 44))
116172	28325912	Consistent with it, the expression of downstream target genes of Ad4BP/SF-1, Star and Cyp11a1, were decreased in CQ-treated Y1 and TM3 cells (Fig.	('Cyp11a1', 'Gene', (86, 93))	('expression', 'MPA', (24, 34))	('TM3', 'Gene', (131, 134))	('CQ-treated', 'Var', (113, 123))	('decreased', 'NegReg', (100, 109))	('Star', 'Gene', (77, 81))	('CQ', 'Chemical', 'MESH:D002738', (113, 115))	('Ad4BP/SF-1', 'Gene', (65, 75))	('Ad4BP/SF-1', 'Gene', '26423', (65, 75))	('TM3', 'Gene', '22003', (131, 134))
116182	28325912	Since Ad4BP/SF-1 maintains steroidogenic cell growth and proper mitotic entry by controlling centriole homeostasis and inhibition of lysosome also leads to mitotic delay, we then examined the numbers of centriole.	('centriole homeostasis', 'MPA', (93, 114))	('steroid', 'Chemical', 'MESH:D013256', (27, 34))	('inhibition', 'Var', (119, 129))	('steroidogenic', 'MPA', (27, 40))	('mitotic entry', 'CPA', (64, 77))	('Ad4BP/SF-1', 'Gene', (6, 16))	('Ad4BP/SF-1', 'Gene', '26423', (6, 16))	('mitotic delay', 'CPA', (156, 169))
116187	28325912	As expected, treatment of cells with CQ, NH4Cl, and Baf reduced the expression of glycolytic genes, such as Pfk1, Tpi1, Pgk1, Pgam1, and Pkm2, suggesting that Ad4BP/SF-1-regulated glycolysis was impaired by lysosome inhibition (Fig.	('Ad4BP/SF-1', 'Gene', '26423', (159, 169))	('glycolytic genes', 'Gene', (82, 98))	('Pkm2', 'Gene', '18746', (137, 141))	('expression', 'MPA', (68, 78))	('NH4Cl', 'Var', (41, 46))	('Pgam1', 'Gene', (126, 131))	('glycolysis', 'MPA', (180, 190))	('Pgk1', 'Gene', (120, 124))	('Tpi1', 'Gene', (114, 118))	('Ad4BP/SF-1', 'Gene', (159, 169))	('Pgk1', 'Gene', '18655', (120, 124))	('reduced', 'NegReg', (56, 63))	('Baf', 'Chemical', 'MESH:C040929', (52, 55))	('NH4Cl', 'Chemical', 'MESH:D000643', (41, 46))	('Pkm2', 'Gene', (137, 141))	('CQ', 'Chemical', 'MESH:D002738', (37, 39))	('Pgam1', 'Gene', '18648', (126, 131))	('Tpi1', 'Gene', '21991', (114, 118))	('Pfk1', 'Gene', (108, 112))
116188	28325912	Interestingly, it was shown that Ad4BP/SF-1 knockdown led to drastic reduction of the amount of a glycolytic end-product, pyruvate.	('amount of a glycolytic end-product', 'MPA', (86, 120))	('Ad4BP/SF-1', 'Gene', (33, 43))	('Ad4BP/SF-1', 'Gene', '26423', (33, 43))	('pyruvate', 'Chemical', 'MESH:D019289', (122, 130))	('knockdown', 'Var', (44, 53))	('reduction', 'NegReg', (69, 78))	('pyruvate', 'MPA', (122, 130))
116196	28325912	As the results, the reporter activity was decreased by the knockdown of Ad4BP/SF-1 (Fig.	('decreased', 'NegReg', (42, 51))	('Ad4BP/SF-1', 'Gene', '26423', (72, 82))	('reporter activity', 'MPA', (20, 37))	('Ad4BP/SF-1', 'Gene', (72, 82))	('knockdown', 'Var', (59, 68))
116213	28325912	In addition, this was also observed in the endogenous Ad4BP/SF-1 when cells were treated with CQ or NH4Cl (Fig.	('NH4Cl', 'Var', (100, 105))	('NH4Cl', 'Chemical', 'MESH:D000643', (100, 105))	('CQ', 'Chemical', 'MESH:D002738', (94, 96))	('Ad4BP/SF-1', 'Gene', (54, 64))	('Ad4BP/SF-1', 'Gene', '26423', (54, 64))
116215	28325912	Thus, inhibition of lysosomes decreases Ad4BP/SF-1 protein stability.	('decreases', 'NegReg', (30, 39))	('Ad4BP/SF-1', 'Gene', (40, 50))	('Ad4BP/SF-1', 'Gene', '26423', (40, 50))	('protein', 'Protein', (51, 58))	('inhibition', 'Var', (6, 16))
116222	28325912	Taken together, inhibition of lysosomal activity reduces the levels of Ff1b and Star, the markers of interrenal gland.	('reduces', 'NegReg', (49, 56))	('Star', 'MPA', (80, 84))	('levels', 'MPA', (61, 67))	('Ff1b', 'Gene', '83916', (71, 75))	('Ff1b', 'Gene', (71, 75))	('inhibition', 'Var', (16, 26))
116235	28325912	In the budding yeast, Saccharomyces cerevisiae, the vacuole/lysosome is required for proper growth; loss of functional vacuole leads to G1 phase arrest.	('loss of', 'Var', (100, 107))	('yeast', 'Species', '4932', (15, 20))	('Saccharomyces cerevisiae', 'Species', '4932', (22, 46))	('G1 phase arrest', 'CPA', (136, 151))
116245	28325912	Here we show that inhibition of lysosome suppresses Ad4BP/SF-1 stability thus reducing cell cycle progression.	('reducing', 'NegReg', (78, 86))	('cell cycle progression', 'CPA', (87, 109))	('stability', 'MPA', (63, 72))	('lysosome', 'Protein', (32, 40))	('suppresses', 'NegReg', (41, 51))	('Ad4BP/SF-1', 'Gene', (52, 62))	('inhibition', 'Var', (18, 28))	('Ad4BP/SF-1', 'Gene', '26423', (52, 62))
116255	28325912	In this study, we found that inhibition of lysosomal activity suppressed the expression of steroidogenic genes by down-regulating Ad4BP/SF-1.	('expression', 'MPA', (77, 87))	('down-regulating', 'NegReg', (114, 129))	('Ad4BP/SF-1', 'Gene', (130, 140))	('Ad4BP/SF-1', 'Gene', '26423', (130, 140))	('suppressed', 'NegReg', (62, 72))	('steroidogenic genes', 'Gene', (91, 110))	('inhibition', 'Var', (29, 39))	('steroid', 'Chemical', 'MESH:D013256', (91, 98))
116286	28325912	A lentiviral system for Atg7 and Ad4BP gene silencing was obtained from the National RNAi Core Facility (Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan).	('Academia Sinica', 'Disease', 'None', (137, 152))	('Academia Sinica', 'Disease', (137, 152))	('Atg7', 'Gene', '74244', (24, 28))	('Ad4BP', 'Gene', '26423', (33, 38))	('Atg7', 'Gene', (24, 28))	('gene', 'Var', (39, 43))	('Ad4BP', 'Gene', (33, 38))
116304	28070481	During the course of the disease, she developed LAC harboring the epidermal growth factor receptor gene mutations and cortisol-secreting ACC.	('LAC', 'Phenotype', 'HP:0030078', (48, 51))	('mutations', 'Var', (104, 113))	('epidermal growth factor receptor', 'Gene', (66, 98))	('cortisol', 'Chemical', 'MESH:D006854', (118, 126))	('ACC', 'Phenotype', 'HP:0006744', (137, 140))	('epidermal growth factor receptor', 'Gene', '1956', (66, 98))
116307	28070481	Studies have suggested a causative link between MEN1 gene mutations and ACC, and menin expression may decrease in MEN1-related ACCs.	('ACC', 'Phenotype', 'HP:0006744', (72, 75))	('mutations', 'Var', (58, 67))	('MEN1', 'Gene', (48, 52))	('decrease', 'NegReg', (102, 110))	('ACC', 'Disease', (72, 75))	('menin', 'Gene', '4221', (81, 86))	('MEN1', 'Gene', '4221', (48, 52))	('MEN1', 'Gene', (114, 118))	('expression', 'MPA', (87, 97))	('ACC', 'Phenotype', 'HP:0006744', (127, 130))	('MEN1', 'Gene', '4221', (114, 118))	('menin', 'Gene', (81, 86))
116308	28070481	In contrast, there are few reports suggesting a specific role of MEN1 gene mutations in LAC.	('MEN1', 'Gene', '4221', (65, 69))	('MEN1', 'Gene', (65, 69))	('LAC', 'Phenotype', 'HP:0030078', (88, 91))	('mutations', 'Var', (75, 84))	('LAC', 'Disease', (88, 91))
116313	28070481	MEN1 is caused by heterozygous germline loss-of-function mutations in the tumor suppressor gene MEN1 located on chromosome 11q13, which comprises 10 exons and encodes a 610-amino acid protein, menin.	('MEN1', 'Gene', (96, 100))	('MEN1', 'Gene', '4221', (0, 4))	('MEN1', 'Gene', '4221', (96, 100))	('menin', 'Gene', '4221', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('menin', 'Gene', (193, 198))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', (74, 79))	('loss-of-function', 'NegReg', (40, 56))	('MEN1', 'Gene', (0, 4))
116331	28070481	An analysis of MEN1 gene mutations identified a germline nonsense mutation (p.Gln209x) in exon 3.	('MEN1', 'Gene', '4221', (15, 19))	('p.Gln209x', 'Mutation', 'p.Q209X', (76, 85))	('MEN1', 'Gene', (15, 19))	('p.Gln209x', 'Var', (76, 85))
116342	28070481	A somatic mutation of the epidermal growth factor receptor (EGFR) gene was identified in exon 21 (p.Leu858Arg).	('epidermal growth factor receptor', 'Gene', '1956', (26, 58))	('p.Leu858Arg', 'Mutation', 'rs121434568', (98, 109))	('p.Leu858Arg', 'Var', (98, 109))	('EGFR', 'Gene', '1956', (60, 64))	('epidermal growth factor receptor', 'Gene', (26, 58))	('EGFR', 'Gene', (60, 64))
116363	28070481	Although most cases of LAC are associated with smoking, a role for genetic factors, including EGFR gene (chromosome 7p11.2) mutations and ALK gene (chromosome 2p23) rearrangements, in LAC has also been proposed.	('LAC', 'Disease', (23, 26))	('mutations', 'Var', (124, 133))	('rearrangements', 'Var', (165, 179))	('EGFR', 'Gene', '1956', (94, 98))	('ALK', 'Gene', '238', (138, 141))	('associated', 'Reg', (31, 41))	('EGFR', 'Gene', (94, 98))	('LAC', 'Phenotype', 'HP:0030078', (184, 187))	('LAC', 'Phenotype', 'HP:0030078', (23, 26))	('ALK', 'Gene', (138, 141))
116364	28070481	However, few reports suggest a specific role for the MEN1 gene mutation in LAC.	('LAC', 'Disease', (75, 78))	('LAC', 'Phenotype', 'HP:0030078', (75, 78))	('mutation', 'Var', (63, 71))	('MEN1', 'Gene', '4221', (53, 57))	('MEN1', 'Gene', (53, 57))
116367	28070481	2F), and a gene analysis revealed EGFR mutations.	('EGFR', 'Gene', '1956', (34, 38))	('EGFR', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))
116370	28070481	It has been suggested that genetic defects such as P53 and MEN1 gene mutations are involved in the development of ACC.	('MEN1', 'Gene', (59, 63))	('mutations', 'Var', (69, 78))	('ACC', 'Phenotype', 'HP:0006744', (114, 117))	('MEN1', 'Gene', '4221', (59, 63))	('ACC', 'Disease', (114, 117))	('involved', 'Reg', (83, 91))	('genetic defects', 'Disease', 'MESH:D030342', (27, 42))	('P53', 'Gene', (51, 54))	('genetic defects', 'Disease', (27, 42))	('P53', 'Gene', '7157', (51, 54))
116452	27257145	Tumor density <=10HU was less conclusive for ruling out malignancy in patients with a history of extra-adrenal malignancy, however, with a pooled false-negative rate of 7%, although CIs were wide.	('patients', 'Species', '9606', (70, 78))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('malignancy', 'Disease', 'MESH:D009369', (56, 66))	('<=10HU', 'Var', (14, 20))	('malignancy', 'Disease', 'MESH:D009369', (111, 121))	('adrenal malignancy', 'Phenotype', 'HP:0100631', (103, 121))	('malignancy', 'Disease', (111, 121))	('malignancy', 'Disease', (56, 66))	('extra-adrenal malignancy', 'Disease', (97, 121))	('extra-adrenal malignancy', 'Disease', 'MESH:D010236', (97, 121))
116561	23653886	At doses sufficient to produce deep sedation or anesthesia, midazolam causes respiratory depression, a property that led to numerous fatalities when midazolam first entered the market.	('midazolam', 'Chemical', 'MESH:D008874', (149, 158))	('respiratory depression', 'Disease', (77, 99))	('numerous fatalities', 'Disease', (124, 143))	('numerous fatalities', 'Disease', 'MESH:D034062', (124, 143))	('midazolam', 'Chemical', 'MESH:D008874', (60, 69))	('respiratory depression', 'Disease', 'MESH:D012131', (77, 99))	('depression', 'Phenotype', 'HP:0000716', (89, 99))	('respiratory depression', 'Phenotype', 'HP:0002791', (77, 99))	('midazolam', 'Var', (60, 69))
116570	23653886	This modification results in a drug that is metabolized more quickly, has a shorter duration of action, and can be titrated more easily during continuous intravenous infusion than the original compound.	('modification', 'Var', (5, 17))	('rat', 'Species', '10116', (118, 121))	('duration of action', 'MPA', (84, 102))	('metabolized', 'MPA', (44, 55))	('shorter', 'NegReg', (76, 83))	('rat', 'Species', '10116', (86, 89))
116592	23653886	Although structurally not a benzodiazepine, JM-1232 (-) allosterically modulates GABAA receptor in a manner that seems to be identical to benzodiazepines and its activity can be inhibited by flumazenil, strongly suggesting that it binds to the same site on the GABAA receptor as classic benzodiazepines.	('flumazenil', 'Chemical', 'MESH:D005442', (191, 201))	('benzodiazepines', 'Chemical', 'MESH:D001569', (287, 302))	('benzodiazepine', 'Chemical', 'MESH:D001569', (287, 301))	('JM-1232', 'Var', (44, 51))	('activity', 'MPA', (162, 170))	('benzodiazepine', 'Chemical', 'MESH:D001569', (28, 42))	('benzodiazepine', 'Chemical', 'MESH:D001569', (138, 152))	('benzodiazepines', 'Chemical', 'MESH:D001569', (138, 153))	('modulates', 'Reg', (71, 80))
116595	23653886	MR04A3 was found to have quick onset of action with a dose-dependent hypnotic effect and minimal hemodynamic depression at clinically relevant doses.	('hemodynamic depression', 'Disease', (97, 119))	('hemodynamic depression', 'Phenotype', 'HP:0002615', (97, 119))	('MR04A3', 'Var', (0, 6))	('hemodynamic depression', 'Disease', 'MESH:D000275', (97, 119))	('hypnotic', 'CPA', (69, 77))	('depression', 'Phenotype', 'HP:0000716', (109, 119))
116596	23653886	Based on this initial study, further study of MR04A3 seems warranted, as its pharmacokinetics could be faster than midazolam and its higher therapeutic index in rats may portend greater safety in humans.	('rats', 'Species', '10116', (161, 165))	('faster', 'PosReg', (103, 109))	('humans', 'Species', '9606', (196, 202))	('pharmacokinetics', 'MPA', (77, 93))	('MR04A3', 'Var', (46, 52))	('midazolam', 'Chemical', 'MESH:D008874', (115, 124))
116610	23653886	They also showed that following single bolus administration or brief infusion, hypnotic, and adrenocortical recovery is significantly faster with MOC-etomidate than with etomidate.	('etomidate', 'Chemical', 'MESH:D005045', (170, 179))	('MOC-etomidate', 'Chemical', 'MESH:C543057', (146, 159))	('etomidate', 'Chemical', 'MESH:D005045', (150, 159))	('adrenocortical', 'Disease', (93, 107))	('rat', 'Species', '10116', (53, 56))	('hypnotic', 'CPA', (79, 87))	('adrenocortical', 'Disease', 'MESH:D018268', (93, 107))	('MOC-etomidate', 'Var', (146, 159))	('faster', 'PosReg', (134, 140))
116619	23653886	Dosing requirements for continuous infusion (and consequently predicted metabolite concentrations achieved in the brain) are nearly 2 orders of magnitude lower with CPMM than with MOC-etomidate.	('lower', 'NegReg', (154, 159))	('CPMM', 'Var', (165, 169))	('metabolite concentrations', 'MPA', (72, 97))	('MOC-etomidate', 'Chemical', 'MESH:C543057', (180, 193))	('CPMM', 'Chemical', '-', (165, 169))	('rat', 'Species', '10116', (90, 93))
116625	23653886	In vitro studies using an adrenocortical carcinoma cell line have shown that this subtle molecular change reduces adrenocortical inhibitory potency by 2000-fold.	('adrenocortical', 'Disease', 'MESH:D018268', (26, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('reduces', 'NegReg', (106, 113))	('change', 'Var', (99, 105))	('adrenocortical carcinoma', 'Disease', (26, 50))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (26, 50))	('adrenocortical', 'Disease', (114, 128))	('adrenocortical', 'Disease', 'MESH:D018268', (114, 128))	('adrenocortical', 'Disease', (26, 40))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (26, 50))
116627	23653886	Carboetomidate retains etomidate's minimal effect on cardiovascular function, but unlike etomidate, carboetomidate neither inhibits steroid synthesis nor enhances proinflammatory cytokine production in a rat model of endotoxemia.	('proinflammatory cytokine production', 'MPA', (163, 198))	('carboetomidate', 'Var', (100, 114))	('endotoxemia', 'Disease', (217, 228))	('etomidate', 'Chemical', 'MESH:D005045', (5, 14))	('etomidate', 'Chemical', 'MESH:D005045', (23, 32))	('rat', 'Species', '10116', (204, 207))	('etomidate', 'Chemical', 'MESH:D005045', (105, 114))	('steroid synthesis', 'MPA', (132, 149))	('enhances', 'PosReg', (154, 162))	('carboetomidate', 'Chemical', 'MESH:C548177', (100, 114))	('etomidate', 'Chemical', 'MESH:D005045', (89, 98))	('Carboetomidate', 'Chemical', 'MESH:C548177', (0, 14))	('steroid', 'Chemical', 'MESH:D013256', (132, 139))	('inhibits', 'NegReg', (123, 131))	('endotoxemia', 'Disease', 'MESH:D019446', (217, 228))
116630	23653886	Through ultra-rapid metabolism, MOC-etomidate reduces the duration of adrenal suppression and allows rapid emergence from anesthesia.	('MOC-etomidate', 'Var', (32, 45))	('duration of adrenal suppression', 'MPA', (58, 89))	('rat', 'Species', '10116', (60, 63))	('adrenal suppression', 'Phenotype', 'HP:0000846', (70, 89))	('MOC-etomidate', 'Chemical', 'MESH:C543057', (32, 45))	('reduces', 'NegReg', (46, 53))
116633	23653886	MOC-carboetomidate enhances GABAA receptor function similar to etomidate, MOC-etomidate, and carboetomidate.	('etomidate', 'Chemical', 'MESH:D005045', (63, 72))	('etomidate', 'Chemical', 'MESH:D005045', (9, 18))	('MOC-carboetomidate', 'Chemical', 'MESH:C575452', (0, 18))	('etomidate', 'Chemical', 'MESH:D005045', (78, 87))	('etomidate', 'Chemical', 'MESH:D005045', (98, 107))	('enhances', 'PosReg', (19, 27))	('carboetomidate', 'Chemical', 'MESH:C548177', (4, 18))	('MOC-etomidate', 'Chemical', 'MESH:C543057', (74, 87))	('carboetomidate', 'Chemical', 'MESH:C548177', (93, 107))	('GABAA receptor', 'Protein', (28, 42))	('MOC-carboetomidate', 'Var', (0, 18))
116643	23653886	The only structural difference between the two molecules is that AZD-3043 contains an additional methylene group, which increases hydrophobicity and hypnotic potency.	('hypnotic potency', 'MPA', (149, 165))	('AZD-3043', 'Var', (65, 73))	('AZD-3043', 'Chemical', 'MESH:C573579', (65, 73))	('hydrophobicity', 'MPA', (130, 144))	('increases', 'PosReg', (120, 129))
116645	23653886	Animal studies have shown that AZD-3043 produces rapid-onset hypnosis and rapid recovery upon infusion termination, even after prolonged continuous infusion.	('recovery', 'MPA', (80, 88))	('AZD-3043', 'Var', (31, 39))	('AZD-3043', 'Chemical', 'MESH:C573579', (31, 39))	('hypnosis', 'Disease', 'None', (61, 69))	('hypnosis', 'Disease', (61, 69))
116661	23653886	A total of ~7% of the entire library was found to consistently decrease the 1-AMA fluorescence signal, but less than a tenth of these decreased the signal more than 60% at the highest concentration [Figure 6].	('decrease', 'NegReg', (63, 71))	('1-AMA fluorescence signal', 'MPA', (76, 101))	('library', 'Var', (29, 36))	('rat', 'Species', '10116', (191, 194))
116695	23055545	In a previous study using high-resolution single-nucleotide polymorphism (SNP) microarray analysis, we observed a copy number microdeletion at 6q23 region involving the serum GC kinase 1 (SGK1) gene in two of 15 cortisol-secreting ACAs.	('SGK1', 'Gene', (188, 192))	('GC kinase', 'Gene', (175, 184))	('cortisol', 'Chemical', 'MESH:D006854', (212, 220))	('microdeletion', 'Var', (126, 139))	('ACAs', 'Phenotype', 'HP:0008256', (231, 235))	('GC kinase', 'Gene', '5871', (175, 184))
116697	23055545	We confirmed by further SNP array analysis frequent microdeletions at the SGK1 locus in a larger series of 46 tumors (two of 15 cortisol-secreting ACAs, zero of nine non-cortisol-secreting ACAs, three of 14 cortisol-secreting ACCs, and zero of eight non-cortisol-secreting ACCs) (Ronchi, C. L., S. Sbiera, E. Leich, M. Fassnacht, B. Allolio, unpublished data).	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('ACC', 'Gene', '31', (226, 229))	('cortisol', 'Chemical', 'MESH:D006854', (128, 136))	('cortisol', 'Chemical', 'MESH:D006854', (207, 215))	('M. Fassnacht', 'Disease', (316, 328))	('ACC', 'Gene', (226, 229))	('ACC', 'Gene', '31', (273, 276))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('cortisol', 'Chemical', 'MESH:D006854', (254, 262))	('ACCs', 'Phenotype', 'HP:0006744', (226, 230))	('ACC', 'Gene', (273, 276))	('SGK1', 'Gene', (74, 78))	('microdeletions', 'Var', (52, 66))	('ACAs', 'Phenotype', 'HP:0008256', (189, 193))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('ACCs', 'Phenotype', 'HP:0006744', (273, 277))	('ACAs', 'Phenotype', 'HP:0008256', (147, 151))	('cortisol', 'Chemical', 'MESH:D006854', (170, 178))
116702	23055545	It mainly works through the phosphorylation and inhibition of glycogen synthase kinase-3, in combination with an activated PKB/AKT pathway, which in turn inhibits the degradation of oncogenic beta-catenin and leads to its translocation to the nucleus.	('phosphorylation', 'Var', (28, 43))	('PKB', 'Gene', (123, 126))	('inhibits', 'NegReg', (154, 162))	('beta-catenin', 'Gene', '1499', (192, 204))	('leads to', 'Reg', (209, 217))	('AKT', 'Gene', '207', (127, 130))	('translocation to the nucleus', 'MPA', (222, 250))	('beta-catenin', 'Gene', (192, 204))	('degradation', 'MPA', (167, 178))	('inhibition', 'NegReg', (48, 58))	('PKB', 'Gene', '2185', (123, 126))	('glycogen synthase kinase-3', 'Enzyme', (62, 88))	('AKT', 'Gene', (127, 130))
116725	23055545	Predesigned TaqMan gene expression assays for SGK1 (Hs00178612_m1), SGK3 (Hs00179430_m1), and CTNNB1 (Hs00994404_g1) were purchased from Applied Biosystems (Darmstadt, Germany).	('Hs00178612_m1', 'Var', (52, 65))	('SGK3', 'Gene', '23678', (68, 72))	('CTNNB1', 'Gene', '1499', (94, 100))	('Hs00994404_g1', 'Var', (102, 115))	('Hs00179430_m1', 'Var', (74, 87))	('SGK3', 'Gene', (68, 72))	('CTNNB1', 'Gene', (94, 100))	('SGK1', 'Gene', (46, 50))
70211	23055545	Endogenously expressed beta-actin (Hs9999903_m1) was used for normalization.	('beta-actin', 'Gene', (23, 33))	('Hs9999903_m1', 'Var', (35, 47))	('beta-actin', 'Gene', '728378', (23, 33))
116774	23055545	OS was shorter in patients with low SGK1 expression.	('low', 'Var', (32, 35))	('shorter', 'NegReg', (7, 14))	('expression', 'MPA', (41, 51))	('patients', 'Species', '9606', (18, 26))	('SGK1', 'Gene', (36, 40))
116778	23055545	Interestingly, in a multivariate Cox regression analysis, including the SGK1 protein levels together with tumor size, tumor stage, Ki67 index, and cortisol excess, SGK1 was confirmed as an independent prognostic factor for OS (HR = 2.4; 95% CI = 1.15-4.61; P < 0.05; Table 3).	('SGK1', 'Var', (164, 168))	('Cox', 'Gene', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cortisol', 'Chemical', 'MESH:D006854', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cortisol excess', 'Phenotype', 'HP:0003118', (147, 162))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('Cox', 'Gene', '1351', (33, 36))	('SGK1', 'Gene', (72, 76))	('tumor', 'Disease', (106, 111))
116779	23055545	Similarly, 38% of patients were alive without tumor recurrence at 2 yr in the high-SGK1 group vs. 17% in the low-SGK1 group (P < 0.01; odds ratio = 3.50; 95% CI = 1.39-8.80).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('high-SGK1', 'Var', (78, 87))	('patients', 'Species', '9606', (18, 26))	('rat', 'Species', '10116', (140, 143))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
116781	23055545	Moreover, we recognized a subgroup of patients with a combination of low SGK1 and high nuclear beta-catenin protein expression showing a very poor prognosis (median survival, 19 months; HR = 3.3 when compared with the other groups; 95% CI = 0.5-7.3; P < 0.05; Fig.	('expression', 'MPA', (116, 126))	('high', 'Var', (82, 86))	('SGK1', 'Gene', (73, 77))	('beta-catenin', 'Gene', (95, 107))	('low', 'NegReg', (69, 72))	('patients', 'Species', '9606', (38, 46))	('beta-catenin', 'Gene', '1499', (95, 107))
116784	23055545	We observed that SGK1 expression was inversely correlated with OS after initiation of first-line cytotoxic drug administration (median survival, 7 months in 22 patients with low SGK1 vs. 22 months in 24 patients with high SGK1; HR = 2.56; 95% CI = 1.24-5.29; P < 0.05).	('patients', 'Species', '9606', (160, 168))	('SGK1', 'Gene', (17, 21))	('SGK1', 'Gene', (178, 182))	('correlated', 'Reg', (47, 57))	('low', 'Var', (174, 177))	('patients', 'Species', '9606', (203, 211))	('rat', 'Species', '10116', (120, 123))	('expression', 'MPA', (22, 32))
116787	23055545	Our research was triggered by the observation of frequent microdeletion in the SGK1 gene and low mRNA expression in CS adenomas.	('CS', 'Chemical', '-', (116, 118))	('adenomas', 'Disease', 'MESH:D000236', (119, 127))	('microdeletion', 'Var', (58, 71))	('SGK1', 'Gene', (79, 83))	('adenomas', 'Disease', (119, 127))	('low', 'NegReg', (93, 96))	('mRNA expression', 'MPA', (97, 112))
116792	23055545	Accordingly, high SGK1 expression has been implicated in cell survival in different neoplasias.	('neoplasias', 'Disease', (84, 94))	('high', 'Var', (13, 17))	('implicated', 'Reg', (43, 53))	('SGK1', 'Gene', (18, 22))	('neoplasia', 'Phenotype', 'HP:0002664', (84, 93))	('neoplasias', 'Disease', 'MESH:D009369', (84, 94))	('neoplasias', 'Phenotype', 'HP:0002664', (84, 94))	('cell survival', 'CPA', (57, 70))	('expression', 'MPA', (23, 33))
116811	23055545	In this case, low SGK1 levels would reduce the negative feedback leading to uninhibited cortisol secretion and potentially also increased proliferation.	('uninhibited cortisol secretion', 'MPA', (76, 106))	('cortisol', 'Chemical', 'MESH:D006854', (88, 96))	('reduce', 'NegReg', (36, 42))	('proliferation', 'CPA', (138, 151))	('increased', 'PosReg', (128, 137))	('negative feedback', 'MPA', (47, 64))	('SGK1', 'Gene', (18, 22))	('low', 'Var', (14, 17))	('rat', 'Species', '10116', (145, 148))
116812	23055545	In favor of this hypothesis is the evidence of genetic microdeletion in some cortisol secreting adrenocortical tumors, suggesting a primary defect rather than a secondary down-regulation.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (96, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cortisol', 'Chemical', 'MESH:D006854', (77, 85))	('genetic microdeletion', 'Var', (47, 68))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('rat', 'Species', '10116', (147, 150))	('adrenocortical tumors', 'Disease', (96, 117))	('cortisol secreting', 'MPA', (77, 95))
116815	23055545	Thus, it is conceivable that lack of intraadrenal SGK1 may induce a state of local GC resistance contributing to abnormal cortisol secretion.	('lack', 'Var', (29, 33))	('local GC resistance', 'MPA', (77, 96))	('abnormal cortisol secretion', 'MPA', (113, 140))	('cortisol', 'Chemical', 'MESH:D006854', (122, 130))	('induce', 'Reg', (59, 65))	('SGK1', 'Gene', (50, 54))	('abnormal cortisol', 'Phenotype', 'HP:0011731', (113, 130))
116849	33400171	Mitotane causes hypoadrenalism and requires a replacement therapy, which is tapered empirically on clinical basis and is therefore imprecise.	('hypoadrenalism', 'Phenotype', 'HP:0000846', (16, 30))	('hypoadrenalism', 'Disease', (16, 30))	('Mitotane', 'Var', (0, 8))	('hypoadrenalism', 'Disease', 'MESH:D000309', (16, 30))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('causes', 'Reg', (9, 15))
116858	33400171	Temozolomide frequently induces lymphopenia and this condition has been shown to be associated with poor prognosis in patients undergoing SARS-CoV2 infection.	('SARS-CoV2', 'Species', '2697049', (138, 147))	('Temozolomide', 'Var', (0, 12))	('lymphopenia', 'Disease', (32, 43))	('induces', 'Reg', (24, 31))	('lymphopenia', 'Phenotype', 'HP:0001888', (32, 43))	('infection', 'Disease', (148, 157))	('infection', 'Disease', 'MESH:D007239', (148, 157))	('lymphopenia', 'Disease', 'MESH:D008231', (32, 43))	('patients', 'Species', '9606', (118, 126))	('Temozolomide', 'Chemical', 'MESH:D000077204', (0, 12))
116905	31649873	To assess the correlation of hub gene expression in four distinct Fuhrman grades, we conducted a linear regression analysis using two additional independent validation datasets GSE40435 and GSE73731.	('regression', 'Disease', (104, 114))	('hub', 'Gene', '1993', (29, 32))	('GSE40435', 'Var', (177, 185))	('hub', 'Gene', (29, 32))	('GSE73731', 'Var', (190, 198))	('regression', 'Disease', 'MESH:C537770', (104, 114))
116976	31649873	ACAT1 gene mutation induced a deficiency in mitochondrial acetoacetyl-CoA thiolase, which was also called ketothiolase deficiency.	('deficiency', 'Disease', (30, 40))	('deficiency', 'Disease', 'None', (30, 40))	('deficiency', 'Disease', 'None', (119, 129))	('acetoacetyl-CoA', 'Chemical', 'MESH:C010667', (58, 73))	('ACAT1', 'Gene', (0, 5))	('mitochondrial', 'MPA', (44, 57))	('mutation', 'Var', (11, 19))	('ACAT1', 'Gene', '38', (0, 5))	('deficiency', 'Disease', (119, 129))
116979	31649873	Many mouse studies have shown that dietary restriction reduced tumor size and growth rate, prolonged survival, and increased sensitivity to radiotherapy.	('tumor', 'Disease', (63, 68))	('growth rate', 'CPA', (78, 89))	('prolonged', 'PosReg', (91, 100))	('dietary', 'Var', (35, 42))	('increased', 'PosReg', (115, 124))	('reduced', 'NegReg', (55, 62))	('increased sensitivity to radiotherapy', 'Phenotype', 'HP:0011133', (115, 152))	('sensitivity', 'MPA', (125, 136))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mouse', 'Species', '10090', (5, 10))	('survival', 'CPA', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
116989	31649873	Furthermore, an in vitro study indicated that overexpressed ACAT1 inhibited the proliferation and migration of renal cell ACHN and Caki1 cells, suggesting that ACAT1 might be a favorable prognostic marker in ccRCC (Figures 5E,F).	('ccRCC', 'Disease', (208, 213))	('ACHN', 'Gene', '55323', (122, 126))	('overexpressed', 'Var', (46, 59))	('ccRCC', 'Disease', 'MESH:D002292', (208, 213))	('ACAT1', 'Gene', (160, 165))	('proliferation', 'CPA', (80, 93))	('ACAT1', 'Gene', (60, 65))	('ACAT1', 'Gene', '38', (160, 165))	('ACHN', 'Gene', (122, 126))	('inhibited', 'NegReg', (66, 75))	('ACAT1', 'Gene', '38', (60, 65))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('ccRCC', 'Phenotype', 'HP:0006770', (208, 213))
117050	29868977	Second, to this effect, our study used a database, formulated by the collaborative effort of representatives at 13 institutions across the country, that had insufficient granularity to provide the reason for en bloc resection or to determine for patients with T4 lesions or positive margins which extra-adrenal organs or surgical margins were involved by tumor.	('insufficient', 'Disease', 'MESH:D000309', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('insufficient', 'Disease', (157, 169))	('patients', 'Species', '9606', (246, 254))	('tumor', 'Disease', (355, 360))	('T4 lesions', 'Var', (260, 270))	('tumor', 'Disease', 'MESH:D009369', (355, 360))
117060	29416014	In vitro and in vivo assays of silencing NCK1-AS1 significantly inhibited cell proliferation and invasion, with induction of cell arrest in S phase of the cell cycle.	('silencing', 'Var', (31, 40))	('inhibited', 'NegReg', (64, 73))	('arrest', 'Disease', 'MESH:D006323', (130, 136))	('NCK1-AS1', 'Gene', (41, 49))	('arrest', 'Disease', (130, 136))
117063	29416014	In conclusion, these findings suggest that NCK1-AS1/miR-6857/CDK1 crosstalk serve as a critical effector in cervical cancer progression and may serve as a potential target in cervical cancer.	('miR-6857', 'Gene', '102465516', (52, 60))	('miR-6857', 'Gene', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('effector', 'Reg', (96, 104))	('CDK1', 'Gene', '983', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cervical cancer', 'Disease', (175, 190))	('CDK1', 'Gene', (61, 65))	('cervical cancer', 'Disease', 'MESH:D002583', (175, 190))	('cervical cancer', 'Disease', (108, 123))	('cervical cancer', 'Disease', 'MESH:D002583', (108, 123))	('crosstalk', 'Var', (66, 75))
117073	29416014	The ability of lncRNAs regulating associated protein-coding genes may contribute to disease if mis-expression of an lncRNA deregulates a protein coding gene with clinical significance.	('mis-expression', 'Var', (95, 109))	('protein coding gene', 'MPA', (137, 156))	('clinical', 'Species', '191496', (162, 170))	('deregulates', 'Reg', (123, 134))	('disease', 'Disease', (84, 91))	('contribute', 'Reg', (70, 80))
117075	29416014	Previous studies provide several that lncRNAs are involved in CC progression, such as lncRNA-EBIC, TI10124, TI18382, TI21327, TI18318, TI22687, TI09485, and ASK00420.	('TI22687', 'Var', (135, 142))	('TI10124', 'Var', (99, 106))	('TI18318', 'Var', (126, 133))	('TI09485', 'Var', (144, 151))	('lncRNA-EBIC', 'Gene', (86, 97))	('TI18382', 'Var', (108, 115))	('lncRNA-EBIC', 'Gene', '100533619', (86, 97))	('TI21327', 'Var', (117, 124))	('ASK00420', 'Var', (157, 165))	('involved', 'Reg', (50, 58))
117080	29416014	Based on the expression of these four lncRNAs for DFS prediction, established a risk-score formula as follows: Risk score = (0.7521141xexpression level of AATBC) + (1.0531199xexpression level of NCK1-AS1) + (1.0104329xexpression level of LINC00937) + (-0.4792615xexpression level of LINC00173) Then, the four-lncRNA expression signature risk score for each patient in the training set were calculated.	('1.0531199xexpression', 'Var', (165, 185))	('AATBC', 'Gene', '284837', (155, 160))	('patient', 'Species', '9606', (357, 364))	('LINC00173', 'Gene', (283, 292))	('0.7521141xexpression', 'Var', (125, 145))	('AATBC', 'Gene', (155, 160))	('LINC00173', 'Gene', '100287569', (283, 292))	('LINC00937', 'Gene', '389634', (238, 247))	('LINC00937', 'Gene', (238, 247))
117092	29416014	These four luciferase reporter constructs were transfected into SiHa cells and their luciferase activities were measured after 48 h. Dual-Luciferase assay showed that luciferase activities were significant increased in cells transfected with D1000, D750, D500, and D250 compared with the pGL3-basic group.	('activities', 'MPA', (178, 188))	('SiHa', 'CellLine', 'CVCL:0032', (64, 68))	('increased', 'PosReg', (206, 215))	('D750', 'Var', (249, 253))	('luciferase', 'Enzyme', (167, 177))	('pGL3', 'Gene', (288, 292))	('D1000', 'Var', (242, 247))	('D500', 'Var', (255, 259))	('D250', 'Var', (265, 269))	('pGL3', 'Gene', '6391', (288, 292))
117094	29416014	The correlation between the NCK1-AS1 expression and these transcription factors E2F1, XBP1 and SP1 were performed and correlation analysis revealed that NCK1-AS1 has a significantly positive correlation with SP1 in TCGA CESC Tumor data set (Fig.	('XBP1', 'Gene', '7494', (86, 90))	('E2F1', 'Gene', '1869', (80, 84))	('NCK1-AS1', 'Var', (153, 161))	('E2F1', 'Gene', (80, 84))	('Tumor', 'Phenotype', 'HP:0002664', (225, 230))	('XBP1', 'Gene', (86, 90))	('positive', 'PosReg', (182, 190))
117097	29416014	Colony formation assay revealed that stable knockdown of NCK1-AS1 dramatically inhibited anchorage-independent growth abilities in CaSki, as the number and the size of formed colonies of the knockdown NCK1-AS1 cells were far fewer and smaller than those of control cells (Fig.	('smaller', 'NegReg', (235, 242))	('NCK1-AS1', 'Gene', (57, 65))	('fewer', 'NegReg', (225, 230))	('knockdown', 'Var', (191, 200))	('anchorage-independent growth abilities', 'CPA', (89, 127))	('inhibited', 'NegReg', (79, 88))	('CaSki', 'CellLine', 'CVCL:1100', (131, 136))	('knockdown', 'Var', (44, 53))	('NCK1-AS1', 'Gene', (201, 209))
117098	29416014	Transwell assays showed that knockdown of NCK1-AS1 dramatically decreased cell invasion in CaSki and SiHa cells (Fig.	('CaSki', 'CellLine', 'CVCL:1100', (91, 96))	('knockdown', 'Var', (29, 38))	('NCK1-AS1', 'Gene', (42, 50))	('SiHa', 'CellLine', 'CVCL:0032', (101, 105))	('decreased', 'NegReg', (64, 73))
117099	29416014	The percentages of cells were significant increased in G1-phase but decreased in S-phase in CaSki and SiHa cells with NCK1-AS1 knockdown (Fig.	('increased', 'PosReg', (42, 51))	('decreased', 'NegReg', (68, 77))	('CaSki', 'CellLine', 'CVCL:1100', (92, 97))	('SiHa', 'CellLine', 'CVCL:0032', (102, 106))	('S-phase', 'MPA', (81, 88))	('knockdown', 'Var', (127, 136))	('NCK1-AS1', 'Gene', (118, 126))	('G1-phase', 'CPA', (55, 63))
117100	29416014	Less EdU-positive cells with newly synthesized DNA (15% and 17% respectively) were detected in CaSki and SiHa cells with NCK1-AS1 knockdown compared with that in CaSki and SiHa control cells (38% and 48%, respectively, Fig.	('CaSki', 'CellLine', 'CVCL:1100', (95, 100))	('SiHa', 'CellLine', 'CVCL:0032', (172, 176))	('knockdown', 'Var', (130, 139))	('CaSki', 'CellLine', 'CVCL:1100', (162, 167))	('NCK1-AS1', 'Gene', (121, 129))	('SiHa', 'CellLine', 'CVCL:0032', (105, 109))
117102	29416014	The result showed knockdown of NCK1-AS1 expression dramatically inhibited the tumor growth in both weight and size in nude mice (Fig.	('knockdown', 'Var', (18, 27))	('nude mice', 'Species', '10090', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('inhibited', 'NegReg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('NCK1-AS1', 'Gene', (31, 39))	('tumor', 'Disease', (78, 83))
117105	29416014	To further explore the potential molecular mechanisms of NCK1-AS1 in CC cells, Human Transcriptome Array 2.0 analysis was performed to investigate the differential gene expression profiles between the NCK1-AS1 knockdown group and the control group in CaSki cells.	('knockdown', 'Var', (210, 219))	('Human', 'Species', '9606', (79, 84))	('NCK1-AS1', 'Gene', (201, 209))	('CaSki', 'CellLine', 'CVCL:1100', (251, 256))
117113	29416014	qRT-PCR showed that knockdown of NCK1-AS1 dramatically increased the expression level of miR-6857, while NCK1-AS1 over-expression decreased the expression level of miR-6857, no change of the expression level of miR-8067 (Fig.	('expression level', 'MPA', (69, 85))	('NCK1-AS1', 'Gene', (33, 41))	('increased', 'PosReg', (55, 64))	('miR-8067', 'Gene', '102465869', (211, 219))	('miR-8067', 'Gene', (211, 219))	('miR-6857', 'Gene', '102465516', (164, 172))	('miR-6857', 'Gene', '102465516', (89, 97))	('knockdown', 'Var', (20, 29))	('miR-6857', 'Gene', (89, 97))	('expression level', 'MPA', (144, 160))	('decreased', 'NegReg', (130, 139))	('miR-6857', 'Gene', (164, 172))
117114	29416014	For further confirmation, we constructed two dual-luciferase reporters containing: (1) Luc-NCK1-AS1-WT (2) Luc-NCK1-AS1 MT (mutated on the putative miR-6857 sites).	('Luc-NCK1-AS1', 'Var', (107, 119))	('miR-6857', 'Gene', '102465516', (148, 156))	('miR-6857', 'Gene', (148, 156))
117130	29416014	Western blot assays also showed that knockdown of NCK1-AS1 decreased CDK1 protein levels, which is consistent with miR-6857-induced down-regulation of CDK1 protein (Fig.	('down-regulation', 'NegReg', (132, 147))	('miR-6857', 'Gene', '102465516', (115, 123))	('decreased', 'NegReg', (59, 68))	('NCK1-AS1', 'Gene', (50, 58))	('miR-6857', 'Gene', (115, 123))	('knockdown', 'Var', (37, 46))	('CDK1', 'Gene', '983', (151, 155))	('CDK1', 'Gene', (151, 155))	('CDK1', 'Gene', (69, 73))	('CDK1', 'Gene', '983', (69, 73))
117131	29416014	Finally, we constructed luciferase reporters containing the putative miR-6857 binding sites, including wild-type (WT) or mutated miR-6857 binding sites.	('binding', 'Interaction', (78, 85))	('miR-6857', 'Gene', '102465516', (129, 137))	('mutated', 'Var', (121, 128))	('miR-6857', 'Gene', (129, 137))	('miR-6857', 'Gene', '102465516', (69, 77))	('miR-6857', 'Gene', (69, 77))
117147	29416014	Our findings showed that knockdown of NCK1-AS1 inhibited CC cell proliferation and invasion, and induced cell cycle arrest in vitro.	('induced', 'Reg', (97, 104))	('inhibited', 'NegReg', (47, 56))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (105, 122))	('CC cell proliferation', 'CPA', (57, 78))	('arrest', 'Disease', 'MESH:D006323', (116, 122))	('invasion', 'CPA', (83, 91))	('NCK1-AS1', 'Gene', (38, 46))	('knockdown', 'Var', (25, 34))	('arrest', 'Disease', (116, 122))
117149	29416014	Human Transcriptome Array 2.0 analysis showed 493 coding-genes and non-coding genes were differentially expressed between NCK1-AS1 knockdown group and control group in CaSki cells.	('Human', 'Species', '9606', (0, 5))	('knockdown', 'Var', (131, 140))	('CaSki', 'CellLine', 'CVCL:1100', (168, 173))	('differentially', 'Reg', (89, 103))	('NCK1-AS1', 'Gene', (122, 130))
117152	29416014	These data support the idea that crosstalk involving lncRNA NCK1-AS1/miR-6857/CDK1 plays key roles in cervical cancer progression and potentially work as a therapy target.	('CDK1', 'Gene', '983', (78, 82))	('CDK1', 'Gene', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('crosstalk', 'Var', (33, 42))	('cervical cancer', 'Disease', (102, 117))	('cervical cancer', 'Disease', 'MESH:D002583', (102, 117))	('miR-6857', 'Gene', '102465516', (69, 77))	('miR-6857', 'Gene', (69, 77))
117160	29416014	Four human cervical cancer cell lines ((HeLa, C33A and SiHa and CaSki) were obtained from Chinese Type Culture Collection, Chinese Academy of Sciences, were cultured in DMEM medium (Hyclone, Massachusetts, USA), and were supplemented with 10% fetal bovine serum (Hyclone, Massachusetts, USA), 100 U/ml penicillin sodium under an incubator with an atmosphere of 5% CO2/95% air at 37  C. The sequences of the siRNAs used to suppress NCK1-AS1 expression were sense 5'-GAAUGUCAUCCCAGCCGAATT-3', antisense 5'-UUCGGCUGGGAUGACAUUCTT-3'.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('NCK1-AS1', 'Gene', (431, 439))	('HeLa', 'CellLine', 'CVCL:0030', (40, 44))	('CaSki', 'CellLine', 'CVCL:1100', (64, 69))	('DMEM medium', 'Chemical', '-', (169, 180))	('expression', 'MPA', (440, 450))	('cervical cancer', 'Disease', 'MESH:D002583', (11, 26))	('SiHa', 'CellLine', 'CVCL:0032', (55, 59))	('suppress', 'NegReg', (422, 430))	('cervical cancer', 'Disease', (11, 26))	('CO2', 'Chemical', '-', (364, 367))	('human', 'Species', '9606', (5, 10))	('penicillin sodium', 'Chemical', 'MESH:D010400', (302, 319))	('antisense', 'Var', (491, 500))	('bovine', 'Species', '9913', (249, 255))
117181	27398116	Adrenocortical carcinoma with extension to the inferior vena cava and right atrium: 20-month-old girl with TP53 mutation A 20-month-old female presented with respiratory distress and a right adrenal mass extending into the inferior vena cava and right atrium.	('girl', 'Species', '9606', (97, 101))	('mutation', 'Var', (112, 120))	('TP53', 'Gene', '7157', (107, 111))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (0, 24))	('TP53', 'Gene', (107, 111))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (0, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Adrenocortical carcinoma', 'Disease', (0, 24))	('respiratory distress', 'Phenotype', 'HP:0002098', (158, 178))	('respiratory distress', 'Disease', 'MESH:D012128', (158, 178))	('respiratory distress', 'Disease', (158, 178))
117199	27398116	Germline exome analysis of the TP53 gene identified a disease-causal heterozygous c.818G>A (p.R273H) mutation.	('TP53', 'Gene', '7157', (31, 35))	('disease-causal', 'Reg', (54, 68))	('TP53', 'Gene', (31, 35))	('c.818G>A', 'Mutation', 'rs28934576', (82, 90))	('c.818G>A', 'Var', (82, 90))	('p.R273H', 'Mutation', 'rs28934576', (92, 99))
117204	27398116	Germline TP53 mutations are less frequently identified in children with ACC over ten years of age.	('ACC', 'Phenotype', 'HP:0006744', (72, 75))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('children', 'Species', '9606', (58, 66))
117206	27398116	Most germline TP53 mutations are associated with Li-Fraumeni syndrome, an autosomal dominant disorder characterized by a wide range of early-onset malignancies including ACC, soft-tissue and bone sarcomas, leukemia, brain tumors, and breast cancer.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (49, 69))	('TP53', 'Gene', (14, 18))	('leukemia', 'Phenotype', 'HP:0001909', (206, 214))	('ACC', 'Phenotype', 'HP:0006744', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('ACC', 'Disease', (170, 173))	('brain tumors', 'Phenotype', 'HP:0030692', (216, 228))	('brain tumors', 'Disease', 'MESH:D001932', (216, 228))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('sarcomas', 'Phenotype', 'HP:0100242', (196, 204))	('leukemia', 'Disease', 'MESH:D007938', (206, 214))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (74, 101))	('leukemia', 'Disease', (206, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('brain tumors', 'Disease', (216, 228))	('TP53', 'Gene', '7157', (14, 18))	('bone sarcomas', 'Disease', 'MESH:D001847', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('bone sarcomas', 'Disease', (191, 204))	('breast cancer', 'Disease', (234, 247))	('bone sarcomas', 'Phenotype', 'HP:0002669', (191, 204))	('autosomal dominant disorder', 'Disease', (74, 101))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))	('Li-Fraumeni syndrome', 'Disease', (49, 69))	('malignancies', 'Disease', (147, 159))	('mutations', 'Var', (19, 28))	('associated', 'Reg', (33, 43))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))
117208	27398116	Ninety percent of affected children in Brazil exhibit a founder germline TP53 mutation (p.R337H) that is not found in North American cases.	('TP53', 'Gene', '7157', (73, 77))	('p.R337H', 'Mutation', 'rs121912664', (88, 95))	('TP53', 'Gene', (73, 77))	('children', 'Species', '9606', (27, 35))	('p.R337H', 'Var', (88, 95))
117222	26963385	Pathway Implications of Aberrant Global Methylation in Adrenocortical Cancer Adrenocortical carcinomas (ACC) are a rare tumor type with a poor five-year survival rate and limited treatment options.	('Adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (77, 102))	('Adrenocortical Cancer', 'Disease', 'MESH:D000306', (55, 76))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Adrenocortical carcinomas', 'Disease', (77, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('Adrenocortical carcinomas', 'Disease', 'MESH:D018268', (77, 102))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Aberrant Global Methylation', 'Var', (24, 51))	('Adrenocortical Cancer', 'Disease', (55, 76))	('tumor', 'Disease', (120, 125))
117226	26963385	This correlation analysis revealed epigenetic regulation of genes known to modulate TP53, WNT, and IGF signaling, as well as silencing of the tumor suppressor MARCKS, previously unreported in ACC.	('MARCKS', 'Gene', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('silencing', 'Var', (125, 134))	('tumor', 'Disease', (142, 147))	('TP53', 'Gene', '7157', (84, 88))	('epigenetic regulation', 'MPA', (35, 56))	('TP53', 'Gene', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
117227	26963385	DNA methylation may regulate genes known to play a role in ACC pathogenesis as well as known tumor suppressors.	('genes', 'Gene', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('methylation', 'Var', (4, 15))	('regulate', 'Reg', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
117230	26963385	This disease usually strikes adults in their 40-50s, but may also be seen in children, typically with a Tumor Protein p53 (TP53) germline mutation.	('germline', 'Var', (129, 137))	('50s', 'Species', '1214577', (48, 51))	('Tumor', 'Phenotype', 'HP:0002664', (104, 109))	('TP53', 'Gene', '7157', (123, 127))	('children', 'Species', '9606', (77, 85))	('TP53', 'Gene', (123, 127))
117234	26963385	Several studies have clearly established a role for aberrant TP53 function, even though the reported mutation rate for the TP53 in sporadic adult ACC is only approximately 16-27%.	('function', 'MPA', (66, 74))	('aberrant', 'Var', (52, 60))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))	('TP53', 'Gene', (123, 127))
117258	26963385	hypermethylation and positive expression, or hypomethylation and reduced expression).	('reduced', 'NegReg', (65, 72))	('hypomethylation', 'Var', (45, 60))	('positive', 'PosReg', (21, 29))	('hyper', 'Disease', 'MESH:D053307', (0, 5))	('expression', 'MPA', (73, 83))	('hyper', 'Disease', (0, 5))
117260	26963385	In this modified method, we discretized samples based on whether a sample was hypo or hypermethylated when compared to non-neoplastic adrenal tissue.	('hypo', 'Var', (78, 82))	('hyper', 'Disease', (86, 91))	('hyper', 'Disease', 'MESH:D053307', (86, 91))	('neoplastic adrenal tissue', 'Phenotype', 'HP:0100631', (123, 148))
117273	26963385	We next performed unsupervised clustering analysis (Euclidean distance, Complete hierarchical clustering methods) of DML and demonstrated a distinct separation of normal and ACC samples with evidence of gene clusters that are preferentially hyper or hypomethylated in ACC (Fig 3).	('hyper', 'Disease', 'MESH:D053307', (241, 246))	('preferentially', 'PosReg', (226, 240))	('hyper', 'Disease', (241, 246))	('hypomethylated', 'Var', (250, 264))
117285	26963385	The end result was increased expression for samples with CpG island hypomethylation or gene body hypermethylation, which is consistent with the expected effects of methylation on gene expression.	('hyper', 'Disease', 'MESH:D053307', (97, 102))	('hyper', 'Disease', (97, 102))	('increased', 'PosReg', (19, 28))	('CpG island hypomethylation', 'Var', (57, 83))	('expression', 'MPA', (29, 39))
117288	26963385	Consistent with previous global methylation analyses, including ACC, hypomethylation was most frequent in 'open seas', away from the CpG islands, and hypermethylation events occurred most commonly in CpG islands.	('frequent', 'Reg', (94, 102))	('open sea', 'Disease', (107, 115))	('hypomethylation', 'Var', (69, 84))	('hyper', 'Disease', 'MESH:D053307', (150, 155))	('hyper', 'Disease', (150, 155))	('open sea', 'Disease', 'MESH:D009041', (107, 115))
117291	26963385	The TP53 tumor suppressor is mutated in more than 50% of all tumors.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('TP53', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (9, 14))	('mutated', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))	('TP53', 'Gene', '7157', (4, 8))
117292	26963385	Genetic alterations in TP53, including mutations (16%) and epigenetic silencing (rarely seen), occur in a lower percentage of ACC tumors.	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('epigenetic silencing', 'Var', (59, 79))	('ACC tumors', 'Disease', (126, 136))	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ACC tumors', 'Disease', 'MESH:D004476', (126, 136))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))
117294	26963385	Gene relationships to TP53 were determined by their inclusion in the Gene Set Enrichment Analysis (GSEA) gene sets PID_P53DOWNSTREAMPATHWAY, PID_P53REGULATIONPATHWAY, and/or other reported evidence of TP53 binding or modulation of activity.	('binding', 'Interaction', (206, 213))	('PID_P53DOWNSTREAMPATHWAY', 'NegReg', (115, 139))	('TP53', 'Gene', '7157', (201, 205))	('PID_P53DOWNSTREAMPATHWAY', 'Var', (115, 139))	('PID_P53REGULATIONPATHWAY', 'Var', (141, 165))	('activity', 'MPA', (231, 239))	('TP53', 'Gene', (201, 205))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
117295	26963385	In the current study, we observed several genes including SETD7, DYRK2, CCDC8, and UBE2D1 which are known to control TP53 protein stability and turnover through post-translational modifications and were epigenetically regulated in ACC tumors.	('protein', 'Protein', (122, 129))	('post-translational modifications', 'MPA', (161, 193))	('turnover', 'MPA', (144, 152))	('UBE2', 'Gene', (83, 87))	('SETD7', 'Gene', '80854', (58, 63))	('TP53', 'Gene', (117, 121))	('DYRK2', 'Gene', '8445', (65, 70))	('stability', 'MPA', (130, 139))	('CCDC8', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('SETD7', 'Gene', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('UBE2', 'Gene', '7318', (83, 87))	('ACC tumors', 'Disease', (231, 241))	('TP53', 'Gene', '7157', (117, 121))	('CCDC8', 'Gene', '83987', (72, 77))	('DYRK2', 'Gene', (65, 70))	('ACC tumors', 'Disease', 'MESH:D004476', (231, 241))	('epigenetically regulated', 'Var', (203, 227))
117298	26963385	WNT signaling has been aberrantly detected in ACC tumors evidenced in part by frequent mutations in the beta-catenin gene.	('WNT signaling', 'MPA', (0, 13))	('ACC tumors', 'Disease', (46, 56))	('beta-catenin', 'Gene', (104, 116))	('ACC tumors', 'Disease', 'MESH:D004476', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (87, 96))
117301	26963385	DKK3 affects apoptosis and cell proliferation, and our study now points to CpG methylation of DKK3 as a possible mechanism for gene deregulation in ACC tumors.	('ACC tumors', 'Disease', (148, 158))	('DKK3', 'Gene', '27122', (0, 4))	('DKK3', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('ACC tumors', 'Disease', 'MESH:D004476', (148, 158))	('affects', 'Reg', (5, 12))	('cell proliferation', 'CPA', (27, 45))	('DKK3', 'Gene', '27122', (94, 98))	('apoptosis', 'CPA', (13, 22))	('DKK3', 'Gene', (94, 98))	('methylation', 'Var', (79, 90))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
117302	26963385	Using the discretization method, we also identified a number of putative tumor suppressor genes whose methylation correlated with decreased gene expression.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('gene expression', 'MPA', (140, 155))	('methylation', 'Var', (102, 113))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('decreased', 'NegReg', (130, 139))
117303	26963385	MARCKS, a substrate for protein kinase C phosphorylation, displays tumor suppressive roles in multiple cancer types; our study is the first report of MARCKS epigenetic silencing in ACC.	('epigenetic silencing', 'Var', (157, 177))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MARCKS', 'Gene', (150, 156))	('tumor', 'Disease', (67, 72))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
117305	26963385	Elevated levels of PAX8 have been seen in several tumor types and epigenetic silencing has been observed in squamous cell lung cancer.	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (108, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('epigenetic silencing', 'Var', (66, 86))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('squamous cell lung cancer', 'Disease', (108, 133))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('observed', 'Reg', (96, 104))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (108, 133))	('tumor', 'Disease', (50, 55))	('PAX8', 'Gene', (19, 23))
117309	26963385	Lastly, correlations of methylation and gene expression by the discretization method identified, for the first time, epigenetic modulation of genes involved in TP53 stability and function, WNT signaling, and tumor suppressor genes not previously associated with ACC.	('epigenetic modulation', 'Var', (117, 138))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('TP53', 'Gene', '7157', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('methylation', 'Var', (24, 35))	('TP53', 'Gene', (160, 164))	('tumor', 'Disease', (208, 213))
117312	26087310	Interestingly, our results directly demonstrate that XCT790 efficiently blocks both the survival and propagation of tumor initiating stem-like cells (TICs), using the MCF7 cell line as a model system.	('survival', 'CPA', (88, 96))	('XCT790', 'Chemical', 'MESH:C488234', (53, 59))	('XCT790', 'Var', (53, 59))	('propagation', 'CPA', (101, 112))	('TICs', 'Phenotype', 'HP:0100033', (150, 154))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('blocks', 'NegReg', (72, 78))	('MCF7', 'CellLine', 'CVCL:0031', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('TIC', 'Phenotype', 'HP:0100033', (150, 153))	('tumor', 'Disease', (116, 121))
117313	26087310	Mechanistically, we show that XCT790 suppresses the activity of several independent signaling pathways that are normally required for the survival of CSCs, such as Sonic hedgehog, TGFbeta-SMAD, STAT3, and Wnt signaling.	('STAT3', 'Gene', '6774', (194, 199))	('suppresses', 'NegReg', (37, 47))	('XCT790', 'Chemical', 'MESH:C488234', (30, 36))	('XCT790', 'Var', (30, 36))	('STAT3', 'Gene', (194, 199))	('activity', 'MPA', (52, 60))	('TGFbeta', 'Gene', '7040', (180, 187))	('Wnt signaling', 'Pathway', (205, 218))	('TGFbeta', 'Gene', (180, 187))
117314	26087310	We also show that XCT790 markedly reduces oxidative mitochondrial metabolism (OXPHOS) and that XCT790-mediated inhibition of CSC propagation can be prevented or reversed by Acetyl-L-Carnitine (ALCAR), a mitochondrial fuel.	('CSC propagation', 'CPA', (125, 140))	('Acetyl-L-Carnitine', 'Chemical', 'MESH:D000108', (173, 191))	('XCT790', 'Chemical', 'MESH:C488234', (18, 24))	('XCT790', 'Chemical', 'MESH:C488234', (95, 101))	('reduces', 'NegReg', (34, 41))	('ALCAR', 'Chemical', 'MESH:D000108', (193, 198))	('oxidative mitochondrial metabolism', 'MPA', (42, 76))	('XCT790-mediated', 'Var', (95, 110))	('XCT790', 'Var', (18, 24))	('inhibition', 'NegReg', (111, 121))
117333	26087310	XCT790 is a well-established inverse agonist of Estrogen-Related Receptor alpha (ERRalpha), which functions as an essential cofactor of PGC1alpha.	('ERRalpha', 'Gene', (81, 89))	('ERRalpha', 'Gene', '2101', (81, 89))	('XCT790', 'Var', (0, 6))	('XCT790', 'Chemical', 'MESH:C488234', (0, 6))	('Estrogen-Related Receptor alpha', 'Gene', (48, 79))	('Estrogen-Related Receptor alpha', 'Gene', '2101', (48, 79))
117334	26087310	XCT790 has been shown to inhibit colony formation in soft agar induced by PGC1alpha, and to induce cell death in chemo-resistant cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cell death', 'CPA', (99, 109))	('PGC1alpha', 'Gene', (74, 83))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('XCT790', 'Var', (0, 6))	('colony formation in soft agar', 'CPA', (33, 62))	('agar', 'Chemical', 'MESH:D000362', (58, 62))	('XCT790', 'Chemical', 'MESH:C488234', (0, 6))	('inhibit', 'NegReg', (25, 32))	('induce', 'Reg', (92, 98))
117336	26087310	Here, our results show that XCT790 inhibits the proliferation of TICs from MCF7 breast cancer cells, as assessed using i) mammosphere formation and by ii) CD44/CD24 immuno-staining, coupled with FACS analysis.	('CD24', 'Gene', '100133941', (160, 164))	('CD24', 'Gene', (160, 164))	('proliferation', 'CPA', (48, 61))	('TIC', 'Phenotype', 'HP:0100033', (65, 68))	('inhibits', 'NegReg', (35, 43))	('mammosphere formation', 'CPA', (122, 143))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('TICs', 'Phenotype', 'HP:0100033', (65, 69))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('XCT790', 'Var', (28, 34))	('MCF7', 'CellLine', 'CVCL:0031', (75, 79))	('XCT790', 'Chemical', 'MESH:C488234', (28, 34))	('breast cancer', 'Disease', (80, 93))	('CD44', 'Gene', '960', (155, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('CD44', 'Gene', (155, 159))
117337	26087310	We also demonstrate that XCT790 suppresses the activation of well-established pathways governing TIC proliferation and survival, including Sonic hedgehog, TGFbeta-SMAD, STAT3, and Wnt signaling.	('STAT3', 'Gene', '6774', (169, 174))	('TGFbeta', 'Gene', '7040', (155, 162))	('suppresses', 'NegReg', (32, 42))	('STAT3', 'Gene', (169, 174))	('XCT790', 'Var', (25, 31))	('TIC', 'Phenotype', 'HP:0100033', (97, 100))	('XCT790', 'Chemical', 'MESH:C488234', (25, 31))	('TGFbeta', 'Gene', (155, 162))
117338	26087310	As expected, XCT790 profoundly reduced mitochondrial respiration.	('XCT790', 'Chemical', 'MESH:C488234', (13, 19))	('mitochondrial respiration', 'MPA', (39, 64))	('reduced', 'NegReg', (31, 38))	('XCT790', 'Var', (13, 19))
117349	26087310	As such, XCT790 is believed to suppress mitochondrial function.	('mitochondrial function', 'MPA', (40, 62))	('XCT790', 'Var', (9, 15))	('suppress', 'NegReg', (31, 39))	('XCT790', 'Chemical', 'MESH:C488234', (9, 15))
117351	26087310	We also validated that XCT790 dose-dependently reduces the protein expression of PGC1alpha in MCF7 cell monolayers by immuno-blot analysis (data not shown), by up to 70-80%, over this concentration range.	('reduces', 'NegReg', (47, 54))	('MCF7', 'CellLine', 'CVCL:0031', (94, 98))	('XCT790', 'Chemical', 'MESH:C488234', (23, 29))	('XCT790', 'Var', (23, 29))	('protein expression', 'MPA', (59, 77))	('PGC1alpha', 'Gene', (81, 90))
117358	26087310	Also, we asked if decreased mammosphere formation induced by XCT790 could be rescued by treatment with the mitochondrial cofactor Acetyl-L-Carnitine (ALCAR).	('XCT790', 'Var', (61, 67))	('XCT790', 'Chemical', 'MESH:C488234', (61, 67))	('decreased', 'NegReg', (18, 27))	('Acetyl-L-Carnitine', 'Chemical', 'MESH:D000108', (130, 148))	('ALCAR', 'Chemical', 'MESH:D000108', (150, 155))	('mammosphere formation', 'CPA', (28, 49))
117363	26087310	We then examined if XCT790 affects the viability of the total cancer cell population, or if it specifically inhibits the viability of MCF7 cells in mammospheres.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('inhibits', 'NegReg', (108, 116))	('XCT790', 'Var', (20, 26))	('viability', 'CPA', (121, 130))	('viability', 'MPA', (39, 48))	('XCT790', 'Chemical', 'MESH:C488234', (20, 26))	('cancer', 'Disease', (62, 68))	('affects', 'Reg', (27, 34))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('MCF7', 'CellLine', 'CVCL:0031', (134, 138))
117367	26087310	For example, treatment with 10 muM XCT790 reduces mammosphere formation by 50% (Figure 1A), whereas the viability of monolayer cells is reduced by only 20%.	('muM', 'Gene', '56925', (31, 34))	('reduces', 'NegReg', (42, 49))	('muM', 'Gene', (31, 34))	('XCT790', 'Var', (35, 41))	('XCT790', 'Chemical', 'MESH:C488234', (35, 41))	('mammosphere formation', 'CPA', (50, 71))
117368	26087310	Thus, XCT790 preferentially reduces the viability of MCF7 cell mammospheres, relative to bulk cancer cells.	('viability', 'CPA', (40, 49))	('reduces', 'NegReg', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('XCT790', 'Var', (6, 12))	('MCF7', 'CellLine', 'CVCL:0031', (53, 57))	('XCT790', 'Chemical', 'MESH:C488234', (6, 12))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
117369	26087310	To further corroborate the idea that XCT790 inhibits cancer stem cell-like features, we next analyzed the effects of XCT790 on a series of well-established signaling pathways, which have been shown to promote stemness.	('promote', 'PosReg', (201, 208))	('XCT790', 'Var', (37, 43))	('XCT790', 'Chemical', 'MESH:C488234', (37, 43))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('stemness', 'Disease', 'MESH:D020295', (209, 217))	('stemness', 'Disease', (209, 217))	('XCT790', 'Var', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('XCT790', 'Chemical', 'MESH:C488234', (117, 123))	('inhibits', 'NegReg', (44, 52))
117373	26087310	Thus, XCT790 inhibits the activation of several signal transduction pathways related to cancer stem-like features.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('XCT790', 'Var', (6, 12))	('XCT790', 'Chemical', 'MESH:C488234', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('inhibits', 'NegReg', (13, 21))
117374	26087310	Next, we set out to investigate the mechanism(s) by which XCT790 inhibits mammosphere formation and CSC features.	('mammosphere formation', 'CPA', (74, 95))	('inhibits', 'NegReg', (65, 73))	('XCT790', 'Var', (58, 64))	('CSC features', 'CPA', (100, 112))	('XCT790', 'Chemical', 'MESH:C488234', (58, 64))
117378	26087310	Figure 4A shows that XCT790 induces a decrease in mitochondrial membrane potential, as assessed with MitoTracker Orange, which accumulates in mitochondria with an active mitochondrial potential.	('mitochondrial membrane potential', 'MPA', (50, 82))	('XCT790', 'Chemical', 'MESH:C488234', (21, 27))	('decrease', 'NegReg', (38, 46))	('MitoTracker Orange', 'Chemical', 'MESH:C121372', (101, 119))	('XCT790', 'Var', (21, 27))
117379	26087310	Surprisingly, XCT790 induces also an increase in mitochondrial mass, as assessed with MitoTracker Green (Figure 4B), localizing to mitochondria regardless of mitochondrial membrane potential.	('mitochondrial mass', 'MPA', (49, 67))	('MitoTracker Green', 'Chemical', '-', (86, 103))	('increase', 'PosReg', (37, 45))	('XCT790', 'Var', (14, 20))	('XCT790', 'Chemical', 'MESH:C488234', (14, 20))
117381	26087310	Analysis of the ratio of mitochondrial membrane potential versus mitochondrial mass indicates that XCT790 induces a profound decrease in mitochondrial membrane potential per mitochondria (Figure 4C).	('XCT790', 'Var', (99, 105))	('decrease', 'NegReg', (125, 133))	('XCT790', 'Chemical', 'MESH:C488234', (99, 105))	('mitochondrial membrane potential per mitochondria', 'MPA', (137, 186))
117383	26087310	Notably, the oxygen consumption rate (OCR) was greatly reduced by treatment with XCT790 (Figure 5A).	('oxygen', 'Chemical', 'MESH:D010100', (13, 19))	('XCT790', 'Var', (81, 87))	('reduced', 'NegReg', (55, 62))	('XCT790', 'Chemical', 'MESH:C488234', (81, 87))	('OCR', 'Chemical', '-', (38, 41))	('oxygen consumption rate', 'MPA', (13, 36))
117384	26087310	Further quantification revealed significant reductions in basal and maximal respiration (Figure 5B-5C), as well as ATP levels (Figure 5D), upon XCT790 treatment.	('XCT790', 'Chemical', 'MESH:C488234', (144, 150))	('reductions', 'NegReg', (44, 54))	('treatment', 'Var', (151, 160))	('XCT790', 'Gene', (144, 150))	('ATP levels', 'MPA', (115, 125))	('ATP', 'Chemical', 'MESH:D000255', (115, 118))
117385	26087310	Thus, XCT790 significantly reduces the rates of oxidative mitochondrial metabolism.	('rates of oxidative mitochondrial metabolism', 'MPA', (39, 82))	('XCT790', 'Var', (6, 12))	('XCT790', 'Chemical', 'MESH:C488234', (6, 12))	('reduces', 'NegReg', (27, 34))
117387	26087310	Notably, XCT790 also significantly reduces ECAR, a marker of glycolysis (Figure 6A).	('XCT790', 'Var', (9, 15))	('ECAR', 'MPA', (43, 47))	('XCT790', 'Chemical', 'MESH:C488234', (9, 15))	('reduces', 'NegReg', (35, 42))
117389	26087310	XCT790 is an inverse agonist of ERRalpha.	('XCT790', 'Var', (0, 6))	('XCT790', 'Chemical', 'MESH:C488234', (0, 6))	('ERRalpha', 'Gene', '2101', (32, 40))	('ERRalpha', 'Gene', (32, 40))
117390	26087310	As XCT790 inhibits mammosphere formation, we then asked if ERRalpha expression is sufficient to promote 3D-spheroid formation in MCF7 cells.	('inhibits', 'NegReg', (10, 18))	('mammosphere formation', 'CPA', (19, 40))	('XCT790', 'Var', (3, 9))	('promote', 'PosReg', (96, 103))	('ERRalpha', 'Gene', (59, 67))	('MCF7', 'CellLine', 'CVCL:0031', (129, 133))	('XCT790', 'Chemical', 'MESH:C488234', (3, 9))	('3D-spheroid formation', 'CPA', (104, 125))	('ERRalpha', 'Gene', '2101', (59, 67))
117393	26087310	Notably, MCF7 cells over-expressing ERRalpha show increased mitochondrial membrane potential, as assessed by MitoTracker Orange, as well as increased mitochondrial mass, as assessed by MitoTracker Green and MitoTracker Deep Red, as expected (Figure 7B).	('mitochondrial mass', 'MPA', (150, 168))	('MitoTracker Deep Red', 'Chemical', '-', (207, 227))	('MitoTracker Green', 'Chemical', '-', (185, 202))	('ERRalpha', 'Gene', '2101', (36, 44))	('increased mitochondrial mass', 'Phenotype', 'HP:0040014', (140, 168))	('increased', 'PosReg', (50, 59))	('MCF7', 'CellLine', 'CVCL:0031', (9, 13))	('over-expressing', 'Var', (20, 35))	('mitochondrial membrane potential', 'MPA', (60, 92))	('MitoTracker Orange', 'Chemical', 'MESH:C121372', (109, 127))	('ERRalpha', 'Gene', (36, 44))	('increased', 'PosReg', (140, 149))
117404	26087310	Notably, keratin-19 (KRT19), a well-established marker of circulating tumor cells and CSCs, is increased by >20-fold in MCF7-FOXM1 cells.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('keratin-19', 'Gene', (9, 19))	('KRT19', 'Gene', (21, 26))	('tumor', 'Disease', (70, 75))	('keratin-19', 'Gene', '3880', (9, 19))	('KRT19', 'Gene', '3880', (21, 26))	('MCF7-FOXM1', 'Var', (120, 130))	('MCF7-FOXM1', 'CellLine', 'CVCL:0031', (120, 130))	('increased', 'PosReg', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
117409	26087310	Consistent with the notion that FOXM1 drives stemness, ribosome-related proteins and EMT markers are increased by FOXM1 expression (Tables 1 and 2).	('EMT', 'Gene', '3702', (85, 88))	('FOXM1', 'Gene', (114, 119))	('FOXM1', 'Gene', '2305', (114, 119))	('increased', 'PosReg', (101, 110))	('FOXM1', 'Gene', '2305', (32, 37))	('FOXM1', 'Gene', (32, 37))	('expression', 'Var', (120, 130))	('stemness', 'Disease', 'MESH:D020295', (45, 53))	('stemness', 'Disease', (45, 53))	('ribosome-related proteins', 'MPA', (55, 80))	('EMT', 'Gene', (85, 88))
117415	26087310	Figure 9 shows that XCT790 dose-dependently inhibits 3D-spheroid formation of the H295R adrenocortical carcinoma cell line, with an IC-50 of 10 muM.	('H295R', 'CellLine', 'CVCL:0458', (82, 87))	('muM', 'Gene', '56925', (144, 147))	('3D-spheroid formation', 'CPA', (53, 74))	('XCT790', 'Var', (20, 26))	('adrenocortical carcinoma', 'Disease', (88, 112))	('muM', 'Gene', (144, 147))	('XCT790', 'Chemical', 'MESH:C488234', (20, 26))	('inhibits', 'NegReg', (44, 52))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (88, 112))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (88, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
117417	26087310	Quantitatively similar results were obtained when XCT790 was tested on several other epithelial cancer cell lines, indicating that the ability of XCT790 to inhibit 3D-spherioid formation reflects a general property of CSCs (data not shown).	('XCT790', 'Var', (146, 152))	('inhibit', 'NegReg', (156, 163))	('XCT790', 'Chemical', 'MESH:C488234', (50, 56))	('3D-spherioid formation', 'MPA', (164, 186))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epithelial cancer', 'Phenotype', 'HP:0031492', (85, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('XCT790', 'Chemical', 'MESH:C488234', (146, 152))
117426	26087310	Mechanistically, XCT790 inhibited mitochondrial function (OCR) and effectively reduced signaling along a number of classical stem cell transduction pathways, such as the Hedgehog/GLI, TGFbeta/SMAD, and Wnt/beta-catenin signaling.	('TGFbeta', 'Gene', (184, 191))	('GLI', 'Gene', '2735', (179, 182))	('reduced', 'NegReg', (79, 86))	('mitochondrial function', 'MPA', (34, 56))	('beta-catenin', 'Gene', '1499', (206, 218))	('XCT790', 'Var', (17, 23))	('OCR', 'Chemical', '-', (58, 61))	('TGFbeta', 'Gene', '7040', (184, 191))	('XCT790', 'Chemical', 'MESH:C488234', (17, 23))	('inhibited', 'NegReg', (24, 33))	('signaling', 'MPA', (87, 96))	('GLI', 'Gene', (179, 182))	('beta-catenin', 'Gene', (206, 218))
117441	26087310	Lentiviral vectors for the expression of ERRalpha (#Z1441) and FOXM1 (#U1376) were obtained commercially from Genecopoeia, along with the appropriate empty vector controls, in the Lv-105 (PuroR) vector system.	('#Z1441', 'Var', (51, 57))	('#U1376', 'Var', (70, 76))	('ERRalpha', 'Gene', (41, 49))	('ERRalpha', 'Gene', '2101', (41, 49))	('FOXM1', 'Gene', '2305', (63, 68))	('FOXM1', 'Gene', (63, 68))
117470	26087310	To measure mitochondrial mass, cells were stained with MitoTracker Green (#M7514 Invitrogen), or MitoTracker Deep Red (#M22426, Invitrogen), both localizing to mitochondria regardless of mitochondrial membrane potential.	('MitoTracker Deep Red', 'Chemical', '-', (97, 117))	('mitochondrial mass', 'MPA', (11, 29))	('MitoTracker Green', 'Chemical', '-', (55, 72))	('#M7514', 'Var', (74, 80))	('#M22426', 'Var', (119, 126))
117474	26087310	Extracellular acidification rates (ECAR) and real-time oxygen consumption rates (OCR) for MCF7 cells treated with XCT790 or vehicle alone control were determined using the Seahorse Extracellular Flux (XF96) analyzer (Seahorse Bioscience, MA, USA).	('OCR', 'Chemical', '-', (81, 84))	('MCF7', 'CellLine', 'CVCL:0031', (90, 94))	('Extracellular acidification rates', 'MPA', (0, 33))	('oxygen', 'Chemical', 'MESH:D010100', (55, 61))	('XCT790', 'Chemical', 'MESH:C488234', (114, 120))	('XCT790', 'Var', (114, 120))
117620	20967502	Inherited germline TP53 mutation encodes a protein with an aberrant C-terminal motif in a case of pediatric adrenocortical tumor Childhood adrenocortical tumor (ACT), a very rare malignancy, has an annual worldwide incidence of about 0.3 per million children younger than 15 years.	('adrenocortical tumor', 'Disease', (108, 128))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (139, 159))	('malignancy', 'Disease', (179, 189))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('adrenocortical tumor', 'Disease', (139, 159))	('encodes', 'Reg', (33, 40))	('children', 'Species', '9606', (250, 258))	('TP53', 'Gene', '7157', (19, 23))	('mutation', 'Var', (24, 32))	('TP53', 'Gene', (19, 23))	('malignancy', 'Disease', 'MESH:D009369', (179, 189))	('C-terminal motif', 'MPA', (68, 84))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (108, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
117621	20967502	The association between inherited germline mutations of the TP53 gene and an increased predisposition to ACT was described in the context of the Li-Fraumeni syndrome.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (145, 165))	('ACT', 'Disease', (105, 108))	('Li-Fraumeni syndrome', 'Disease', (145, 165))	('germline mutations', 'Var', (34, 52))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))
117622	20967502	In fact, about two-thirds of children with ACT have a TP53 mutation.	('children', 'Species', '9606', (29, 37))	('TP53', 'Gene', '7157', (54, 58))	('ACT', 'Disease', (43, 46))	('mutation', 'Var', (59, 67))	('TP53', 'Gene', (54, 58))
117623	20967502	However, less than 10% of pediatric ACT cases occur in Li-Fraumeni syndrome, suggesting that inherited low-penetrance TP53 mutations play an important role in pediatric adrenal cortex tumorigenesis.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (55, 75))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('Li-Fraumeni syndrome', 'Disease', (55, 75))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('mutations', 'Var', (123, 132))
117624	20967502	We identified a novel inherited germline TP53 mutation affecting the acceptor splice site at intron 10 in a child with an ACT and no family history of cancer.	('TP53', 'Gene', '7157', (41, 45))	('child', 'Species', '9606', (108, 113))	('TP53', 'Gene', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('mutation', 'Var', (46, 54))
117626	20967502	Bioinformatics analysis showed that the non-natural and highly hydrophobic C-terminal segment of the frame-shifted mutant p53 protein may disrupt its tumor suppressor function by causing misfolding and aggregation.	('aggregation', 'CPA', (202, 213))	('protein', 'Protein', (126, 133))	('causing', 'Reg', (179, 186))	('misfolding', 'MPA', (187, 197))	('disrupt', 'NegReg', (138, 145))	('mutant', 'Var', (115, 121))	('p53', 'Gene', '7157', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('p53', 'Gene', (122, 125))
117627	20967502	Our findings highlight the clinical and genetic counseling dilemmas that arise when an inherited TP53 mutation is found in a child with ACT without relatives with Li-Fraumeni-component tumors.	('found', 'Reg', (114, 119))	('child', 'Species', '9606', (125, 130))	('Li-Fraumeni-component tumors', 'Disease', (163, 191))	('Li-Fraumeni-component tumors', 'Disease', 'MESH:D016864', (163, 191))	('TP53', 'Gene', '7157', (97, 101))	('mutation', 'Var', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('TP53', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
117629	20967502	Although several diverse genetic alterations can predispose children to ACT, TP53 mutations account for most cases.	('ACT', 'Disease', (72, 75))	('children', 'Species', '9606', (60, 68))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
117630	20967502	Children with ACT, particularly when it is diagnosed before the child's fifth birthday, commonly carry an inherited TP53 mutation.	('TP53', 'Gene', (116, 120))	('Children', 'Species', '9606', (0, 8))	('ACT', 'Disease', (14, 17))	('carry', 'Reg', (97, 102))	('mutation', 'Var', (121, 129))	('child', 'Species', '9606', (64, 69))	('TP53', 'Gene', '7157', (116, 120))
117631	20967502	The association between pediatric ACT and germline TP53 mutations is so strong that ACT is now considered an independent criterion to obtain TP53 genetic testing and counseling.	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('TP53', 'Gene', '7157', (51, 55))
117632	20967502	The vast majority of germline mutations that increase the predisposition to cancer occur within the DNA binding domain (DBD) and usually abrogate TP53 sequence-specific DNA-binding activity.	('TP53', 'Gene', '7157', (146, 150))	('TP53', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('binding', 'Interaction', (104, 111))	('abrogate', 'NegReg', (137, 145))	('sequence-specific', 'MPA', (151, 168))	('mutations', 'Var', (30, 39))	('DBD', 'Chemical', '-', (120, 123))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
117633	20967502	Individuals who carry these mutations have more than an 80% risk of cancer during their lifetime and are usually tested for TP53 because of a remarkable family history of cancer (Li-Fraumeni and Li-Fraumeni-like syndrome).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', '7157', (124, 128))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('TP53', 'Gene', (124, 128))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('Li-Fraumeni and Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (179, 220))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mutations', 'Var', (28, 37))
117635	20967502	Recently, low-penetrance TP53 mutations have been found to increase the predisposition for ACT outside of the context of Li-Fraumeni syndrome, suggesting that the adrenal cortex is particularly sensitive to TP53 inactivation.	('TP53', 'Gene', (25, 29))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (121, 141))	('TP53', 'Gene', '7157', (207, 211))	('Li-Fraumeni syndrome', 'Disease', (121, 141))	('TP53', 'Gene', (207, 211))	('mutations', 'Var', (30, 39))	('ACT', 'Disease', (91, 94))	('TP53', 'Gene', '7157', (25, 29))
117636	20967502	Here we report a novel inherited germline TP53 mutation affecting the acceptor splice site at intron 10 in a pediatric patient with an ACT and no family history of cancer.	('patient', 'Species', '9606', (119, 126))	('TP53', 'Gene', '7157', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('TP53', 'Gene', (42, 46))	('mutation', 'Var', (47, 55))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))
117637	20967502	Our findings highlight the importance of analyzing the transcripts encoded by mutant TP53 genes in tumor tissue and reinforce the role of TP53 inactivation in pediatric ACT.	('TP53', 'Gene', (85, 89))	('tumor', 'Disease', (99, 104))	('TP53', 'Gene', '7157', (138, 142))	('TP53', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('TP53', 'Gene', '7157', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutant', 'Var', (78, 84))
117663	20967502	Genomic DNA from ACT tissue from this patient harbored a homozygous TP53 alteration at the junctions of intron 10 and exon 11, and the same was observed in the heterozygous state in genomic DNA from peripheral blood leukocytes, indicating a loss of heterozygosity for this locus (Fig.	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('alteration', 'Var', (73, 83))	('patient', 'Species', '9606', (38, 45))
117666	20967502	This alteration represents a change in the nucleotides AG at the splice acceptor site in intron 10 (IVS10-2 A > G), necessary for correct pre-mRNA processing, and could result in aberrant splicing.	('result in aberrant', 'Reg', (169, 187))	('IVS10-2 A > G', 'Mutation', 'c.IVS10-2A>G', (100, 113))	('splicing', 'MPA', (188, 196))	('change', 'Reg', (29, 35))	('IVS10-2 A > G', 'Var', (100, 113))
117667	20967502	The resulting cDNA was amplified using primers that covered exon 10 through the normal stop codon of the TP53 gene and was found to have a deletion of the initial 10 bp of exon 11 (Fig.	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('deletion', 'Var', (139, 147))
117669	20967502	Because of the 10-bp deletion, frame shift, and new stop codon location, this polypeptide segment was completely different from the wild type in terms of its sequence and number of amino acid residues and resulted in a new C-terminal motif in transcripts for the mutant TP53 sequence.	('C-terminal motif', 'MPA', (223, 239))	('TP53', 'Gene', '7157', (270, 274))	('mutant', 'Var', (263, 269))	('TP53', 'Gene', (270, 274))	('resulted in a', 'Reg', (205, 218))	('transcripts', 'MPA', (243, 254))
117670	20967502	Schematic representations of the 3'-terminal region of the wild type and mutated TP53 gene are shown in Fig.	('TP53', 'Gene', '7157', (81, 85))	('mutated', 'Var', (73, 80))	('TP53', 'Gene', (81, 85))
117673	20967502	Furthermore, the sequence of the mutant C-terminal domain is inconsistent with that of normal, functional proteins (for example, 48% of the amino acids are either proline [20%], leucine [18%], or serine [10%]) and with formation of a secondary structure (alpha-helix or beta-sheet), based on analysis using JPRED3.	('leucine', 'Chemical', 'MESH:D007930', (178, 185))	('leucine', 'MPA', (178, 185))	('serine', 'Chemical', 'MESH:D012694', (196, 202))	('mutant', 'Var', (33, 39))	('proline', 'Chemical', 'MESH:D011392', (163, 170))
117674	20967502	The unnaturally high content of proline and leucine residues may confer a propensity for the full-length, frame-shifted mutant p53 protein to misfold and aggregate.	('misfold', 'MPA', (142, 149))	('proline', 'MPA', (32, 39))	('protein', 'Protein', (131, 138))	('leucine', 'Protein', (44, 51))	('aggregate', 'MPA', (154, 163))	('proline', 'Chemical', 'MESH:D011392', (32, 39))	('leucine', 'Chemical', 'MESH:D007930', (44, 51))	('p53', 'Gene', '7157', (127, 130))	('mutant', 'Var', (120, 126))	('p53', 'Gene', (127, 130))
117675	20967502	In conclusion, the non-natural and highly hydrophobic C-terminal segment of the frame-shifted mutant p53 protein may disturb tumor suppressor function by causing a loss of regulatory function, misfolding.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('mutant', 'Var', (94, 100))	('p53', 'Gene', (101, 104))	('tumor', 'Disease', (125, 130))	('p53', 'Gene', '7157', (101, 104))	('protein', 'Protein', (105, 112))	('disturb', 'NegReg', (117, 124))	('loss', 'NegReg', (164, 168))	('regulatory function', 'MPA', (172, 191))
117676	20967502	We found a novel inherited germline TP53 acceptor splice-site mutation at the junction of intron 10 and exon 11 in a child with ACT.	('mutation', 'Var', (62, 70))	('child', 'Species', '9606', (117, 122))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))
117680	20967502	Because most germline TP53 mutations registered in the IARC database are from individuals from families with cancer-prone syndromes, it is possible this TP53 splice mutation, similar to other low-penetrance TP53 mutations, is not associated with well-defined familial cancer syndromes and may not be detected until revealed in association with TP53-core tumors such as pediatric ACT.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('TP53', 'Gene', '7157', (207, 211))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', '7157', (344, 348))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('TP53', 'Gene', (22, 26))	('associated', 'Reg', (230, 240))	('tumors', 'Phenotype', 'HP:0002664', (354, 360))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('cancer', 'Disease', (109, 115))	('familial cancer syndromes', 'Disease', (259, 284))	('TP53', 'Gene', (207, 211))	('TP53', 'Gene', (344, 348))	('TP53', 'Gene', '7157', (22, 26))	('tumors', 'Disease', (354, 360))	('TP53', 'Gene', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (268, 274))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (259, 284))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('tumors', 'Disease', 'MESH:D009369', (354, 360))
117681	20967502	The association between low-penetrance mutations and tumorigenesis of the developmental adrenal cortex has been amply documented, to the extent that the diagnosis of ACT alone is now considered a criterion for TP53 testing.	('TP53', 'Gene', (210, 214))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('TP53', 'Gene', '7157', (210, 214))	('low-penetrance mutations', 'Var', (24, 48))
117682	20967502	In this regard, many of the inherited germline low-penetrance TP53 mutations revealed in children with ACT or choroid plexus tumors may not increase carriers' predisposition to Li-Fraumeni-component tumors.	('TP53', 'Gene', '7157', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('low-penetrance', 'NegReg', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Li-Fraumeni-component tumors', 'Disease', (177, 205))	('TP53', 'Gene', (62, 66))	('Li-Fraumeni-component tumors', 'Disease', 'MESH:D016864', (177, 205))	('choroid plexus tumors', 'Disease', (110, 131))	('mutations', 'Var', (67, 76))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('choroid plexus tumors', 'Phenotype', 'HP:0002190', (110, 131))	('choroid plexus tumors', 'Disease', 'MESH:D016545', (110, 131))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('children', 'Species', '9606', (89, 97))
117685	20967502	The finding of an inherited novel TP53 mutation in a child with ACT creates a dilemma, as this tumor can be associated with either DBD or low-penetrance mutations and therefore has substantial implications for genetic counseling.	('DBD', 'Chemical', '-', (131, 134))	('mutation', 'Var', (39, 47))	('TP53', 'Gene', (34, 38))	('child', 'Species', '9606', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('TP53', 'Gene', '7157', (34, 38))	('tumor', 'Disease', (95, 100))
117687	20967502	The mother, who is in her 30s and carries the mutation, has not been affected by cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutation', 'Var', (46, 54))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
117689	20967502	However, the clinical-epidemiologic data of the family are limited; hence, it is plausible that the TP53 splice mutation may have tumorigenic potential similar to TP53 mutations that affect the DBD.	('TP53', 'Gene', '7157', (100, 104))	('DBD', 'Chemical', '-', (194, 197))	('TP53', 'Gene', (100, 104))	('splice mutation', 'Var', (105, 120))	('TP53', 'Gene', '7157', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('TP53', 'Gene', (163, 167))	('tumor', 'Disease', (130, 135))
117693	20967502	Of interest, lung cancer was the most common cancer type in carriers of germline TP53 mutations who did not develop Li-Fraumeni-component tumors.	('mutations', 'Var', (86, 95))	('lung cancer', 'Disease', (13, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('germline', 'Var', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('Li-Fraumeni-component tumors', 'Disease', (116, 144))	('Li-Fraumeni-component tumors', 'Disease', 'MESH:D016864', (116, 144))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', (18, 24))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('common', 'Reg', (38, 44))
117694	20967502	Therefore, given the lack of information on the TP53 splice mutation and detailed clinical-epidemiologic data, it is not possible to determine whether the carriers of this mutation have an increased predisposition to cancer, as seen in individuals who carry TP53 mutations that disrupt the DBD of the protein.	('TP53', 'Gene', '7157', (48, 52))	('DBD of', 'MPA', (290, 296))	('DBD', 'Chemical', '-', (290, 293))	('TP53', 'Gene', (258, 262))	('TP53', 'Gene', '7157', (258, 262))	('mutations', 'Var', (263, 272))	('TP53', 'Gene', (48, 52))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
117696	20967502	Bioinformatics analysis of the structural features of the frame-shifted mutant p53 protein suggested that the non-natural C-terminal domain may cause misfolding and aggregation, therefore inhibiting tumor suppressor function.	('tumor', 'Disease', (199, 204))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('inhibiting', 'NegReg', (188, 198))	('mutant', 'Var', (72, 78))	('frame-shifted', 'Reg', (58, 71))	('cause', 'Reg', (144, 149))	('protein', 'Protein', (83, 90))	('aggregation', 'MPA', (165, 176))	('misfolding', 'MPA', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
117704	20967502	In summary, the type of malignancy associated with this patient, her family history of cancer, TP53 genetic testing findings, and predictive analysis of the mutant protein highlight the complexity of the relationship between TP53 mutations and malignancy.	('cancer', 'Disease', (87, 93))	('malignancy', 'Disease', 'MESH:D009369', (24, 34))	('mutant', 'Var', (157, 163))	('malignancy', 'Disease', (24, 34))	('malignancy', 'Disease', 'MESH:D009369', (244, 254))	('malignancy', 'Disease', (244, 254))	('TP53', 'Gene', '7157', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (230, 239))	('TP53', 'Gene', (225, 229))	('patient', 'Species', '9606', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
117739	20842232	The following syndromes are associated with ACC: Li-Fraumeni Syndrome (LFS) is an autosomal dominant disorder caused by a germ-line mutation in the TP53 gene located on chromosome region17q13.1.	('caused by', 'Reg', (110, 119))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (49, 69))	('LFS', 'Disease', 'MESH:D016864', (71, 74))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('ACC', 'Phenotype', 'HP:0006744', (44, 47))	('Li-Fraumeni Syndrome', 'Disease', (49, 69))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (82, 109))	('mutation', 'Var', (132, 140))	('autosomal dominant disorder', 'Disease', (82, 109))	('LFS', 'Disease', (71, 74))
117740	20842232	A mutation in this gene results in the inability of p53 to initiate cell growth arrest and DNA repair.	('growth arrest', 'Phenotype', 'HP:0001510', (73, 86))	('DNA repair', 'CPA', (91, 101))	('mutation', 'Var', (2, 10))	('arrest', 'Disease', 'MESH:D006323', (80, 86))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('inability', 'NegReg', (39, 48))	('arrest', 'Disease', (80, 86))
117743	20842232	The Beckwith-Wiedemann Syndrome (BWS) results from an epigenetic dysfunction of the chromosomal region 11p15.	('Beckwith-Wiedemann Syndrome', 'Disease', (4, 31))	('BWS', 'Disease', 'MESH:D001506', (33, 36))	('BWS', 'Disease', (33, 36))	('edema', 'Phenotype', 'HP:0000969', (15, 20))	('results from', 'Reg', (38, 50))	('epigenetic dysfunction', 'Var', (54, 76))	('Beckwith-Wiedemann Syndrome', 'Disease', 'MESH:D001506', (4, 31))
117750	20842232	This syndrome results from mutations in the APC gene in the chromosomal region 5q21.	('APC', 'Gene', (44, 47))	('mutations', 'Var', (27, 36))	('results from', 'Reg', (14, 26))	('APC', 'Gene', '324', (44, 47))
117754	20842232	Multiple Endocrine Neoplasia 1 is a syndrome resulting from mutation in the MEN1 gene located in the chromosomal region 11q13.	('mutation', 'Var', (60, 68))	('Neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('Endocrine Neoplasia', 'Phenotype', 'HP:0100568', (9, 28))	('Multiple Endocrine Neoplasia 1', 'Disease', 'MESH:D018761', (0, 30))	('resulting from', 'Reg', (45, 59))	('Multiple Endocrine Neoplasia 1', 'Disease', (0, 30))	('MEN1', 'Gene', (76, 80))	('MEN1', 'Gene', '4221', (76, 80))
117755	20842232	The resulting mutation leads to a defect in the MENIN protein, leading to the formation of pituitary tumors, parathyroid tumors and pancreatic neuroendocrine tumors, as well as adrenal tumors, multiple lipomas and angiomas.	('defect', 'NegReg', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('lipomas', 'Phenotype', 'HP:0012032', (202, 209))	('adrenal tumors', 'Disease', (177, 191))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('lipomas and angiomas', 'Disease', 'MESH:D008067', (202, 222))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('pituitary tumors', 'Disease', 'MESH:D010911', (91, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('multiple lipomas', 'Phenotype', 'HP:0001012', (193, 209))	('leading to', 'Reg', (63, 73))	('adrenal tumor', 'Phenotype', 'HP:0100631', (177, 190))	('MENIN', 'Gene', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (132, 164))	('adrenal tumors', 'Disease', 'MESH:D000310', (177, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('pituitary tumors', 'Disease', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (143, 164))	('parathyroid tumors', 'Disease', 'MESH:D010282', (109, 127))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('pancreatic neuroendocrine tumors', 'Disease', (132, 164))	('mutation', 'Var', (14, 22))	('MENIN', 'Gene', '4221', (48, 53))	('parathyroid tumors', 'Disease', (109, 127))
117763	20842232	Two patients showed a mutation of the p53 gene; one showed a single base substitution in codon 248 and the other had a mutation at codon 273.	('p53', 'Gene', (38, 41))	('single base substitution in', 'Var', (61, 88))	('patients', 'Species', '9606', (4, 12))	('p53', 'Gene', '7157', (38, 41))
117788	31172443	Dysregulation of apoptosis is crucial to carcinogenesis and cancer progression and associated with resistance to standard therapy.	('apoptosis', 'Protein', (17, 26))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (41, 55))	('carcinogenesis', 'Disease', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
117796	31172443	AT-101 is 3 to 4 times more potent than its racemic form in in vitro anti-proliferation assays and animal models of human cancer.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('AT-101', 'Chemical', 'MESH:C028178', (0, 6))	('anti-proliferation assays', 'CPA', (69, 94))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('AT-101', 'Var', (0, 6))	('human', 'Species', '9606', (116, 121))
117800	31172443	Patients were required to have an anticipated >=12-week life expectancy, ECOG performance status of 0 to 2, normal organ and bone marrow function defined as leukocytes >=3000/mm3, absolute neutrophil count >=1500/mm3, platelets >=100,000/mm3, total bilirubin <1.5 mg/dL, AST <=2.5 upper limit of normal (ULN), ALT <=2.5 ULN, and serum creatinine <=1.7 mg/dL (or creatinine clearance >=40 mL/min).	('creatinine', 'Chemical', 'MESH:D003404', (335, 345))	('AST', 'Gene', (271, 274))	('>=3000/mm3', 'Var', (168, 178))	('AST', 'Gene', '26503', (271, 274))	('total bilirubin', 'MPA', (243, 258))	('serum creatinine', 'MPA', (329, 345))	('creatinine', 'Chemical', 'MESH:D003404', (362, 372))	('Patients', 'Species', '9606', (0, 8))	('creatinine clearance', 'MPA', (362, 382))	('ALT', 'MPA', (310, 313))	('>=1500/mm3', 'Var', (206, 216))
117856	31172443	In fact, as demonstrated in limited correlative analyses of a phase II trial evaluating AT-101 in small cell lung cancer, AT-101 failed to induce caspase-dependent cell death.	('death', 'Disease', (169, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('AT-101', 'Var', (122, 128))	('small cell lung cancer', 'Disease', 'MESH:D055752', (98, 120))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('AT-101', 'Chemical', 'MESH:C028178', (122, 128))	('AT-101', 'Chemical', 'MESH:C028178', (88, 94))	('death', 'Disease', 'MESH:D003643', (169, 174))	('small cell lung cancer', 'Disease', (98, 120))
117857	31172443	Specific to advanced ACC, recent molecular studies revealed several dysregulation of signaling pathways and genomic alterations in advanced ACC including overexpression of insulin-like growth factors 2, beta-catenin, VEGFR pathway and mutations in TP53, CKD2A, NF1, RB1 and others rather than BCL2 family proteins.	('NF1', 'Gene', '4763', (261, 264))	('TP53', 'Gene', '7157', (248, 252))	('signaling pathways', 'Pathway', (85, 103))	('BCL2', 'Gene', '596', (293, 297))	('VEGFR', 'Gene', '3791', (217, 222))	('mutations', 'Var', (235, 244))	('TP53', 'Gene', (248, 252))	('insulin-like growth factors 2, beta-catenin', 'Gene', '1499', (172, 215))	('overexpression', 'PosReg', (154, 168))	('RB1', 'Gene', (266, 269))	('dysregulation', 'MPA', (68, 81))	('BCL2', 'Gene', (293, 297))	('VEGFR', 'Gene', (217, 222))	('CKD2A', 'Gene', (254, 259))	('NF1', 'Gene', (261, 264))	('RB1', 'Gene', '5925', (266, 269))
117870	30607140	Despite the fact that tremendous somatic mutations in a variety of cancer types can give chances for personalized treatment targeting at patients' specific mutations, these mutations can eventually translate into new antigens for possible anti-tumor immune response.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('translate', 'Reg', (198, 207))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (244, 249))	('mutations', 'Var', (156, 165))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
117876	30607140	Thus, monoclonal antibodies blocking PD-1 have arisen as an impressive treatment strategy for cancer patients and have been approved by the U.S. Food and Drug Administration (FDA) for human use.	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (184, 189))	('monoclonal', 'Var', (6, 16))	('PD-1', 'Gene', (37, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
117945	30607140	The combination of PD-1 and CTLA-4 blockade has demonstrated higher response rates in advanced melanoma, while combination with LAG3 blockade are still carrying on clinical trials (NCT03250832, NCT02658981, NCT01968109, NCT03005782).	('advanced melanoma', 'Disease', 'MESH:D008545', (86, 103))	('LAG3', 'Gene', '3902', (128, 132))	('higher', 'PosReg', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('advanced melanoma', 'Disease', (86, 103))	('NCT03250832', 'Var', (181, 192))	('CTLA-4', 'Gene', '1493', (28, 34))	('PD-1', 'Gene', (19, 23))	('LAG3', 'Gene', (128, 132))	('CTLA-4', 'Gene', (28, 34))
117949	30607140	Therefore, we can infer that the high expression of LFA-1 may improve the efficacy of T cells that have been released from the "brake" of PD-1 by PD-1 blockade.	('LFA-1', 'Gene', (52, 57))	('high expression', 'Var', (33, 48))	('improve', 'PosReg', (62, 69))	('efficacy', 'CPA', (74, 82))	('LFA-1', 'Gene', '3689', (52, 57))
118056	27619404	At E10.5, a subset of AGP cells marked by Sf1-Fetal Adrenal Enhancer (FAdE) enhancer activity separates out to form the fetal adrenal anlagen.	('enhancer', 'PosReg', (76, 84))	('Sf1-Fetal Adrenal Enhancer', 'Disease', 'MESH:D005315', (42, 68))	('rat', 'Species', '10116', (98, 101))	('Sf1-Fetal Adrenal Enhancer', 'Disease', (42, 68))	('E10.5', 'Var', (3, 8))
118064	27619404	Along with a morphological identity, zG cells possess a particular molecular signature and can be identified by the presence of patches of Cyp11b2 (Aldosterone Synthase, AS)-expressing cells (Fig.	('Aldosterone Synthase', 'Gene', (148, 168))	('Cyp11b2', 'Var', (139, 146))	('Aldosterone Synthase', 'Gene', '13072', (148, 168))
118077	27619404	The importance of these pathways in controlling normal adrenocortical homeostasis and zonation is underscored by the consequences of somatic gain-of-function mutations, including those that give rise to aldosterone producing adenomas (APAs) (e.g., mutations in K+ channels and components of the Wnt/beta-catenin signaling pathway) and PPNAD (e.g., mutations in PRKAR1A, the gene encoding the cAMP-dependent protein kinase type I-alpha regulatory subunit).	('adrenocortical homeostasis', 'Disease', 'MESH:D018268', (55, 81))	('mutations', 'Var', (248, 257))	('adenomas', 'Disease', 'MESH:D000236', (225, 233))	('mutations', 'Var', (348, 357))	('adenomas', 'Disease', (225, 233))	('Wnt', 'Chemical', '-', (295, 298))	('PRKAR1A', 'Gene', (361, 368))	('PRKAR1A', 'Gene', '19084', (361, 368))	('aldosterone', 'Chemical', 'MESH:D000450', (203, 214))	('rise to aldosterone', 'Phenotype', 'HP:0000859', (195, 214))	('mutations', 'Var', (158, 167))	('adrenocortical homeostasis', 'Disease', (55, 81))	('cAMP-dependent protein kinase type I-alpha regulatory subunit', 'Gene', '19084', (392, 453))	('gain-of-function', 'PosReg', (141, 157))
118098	27619404	Additionally, in mice, constitutive activation of beta-catenin or inactivation of APC leads to hyperaldosteronism, while deletion of either beta-catenin or Wnt4 results in decreased Cyp11b2 transcripts and lower aldosterone production.	('APC', 'Gene', (82, 85))	('deletion', 'Var', (121, 129))	('activation', 'PosReg', (36, 46))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (95, 113))	('transcripts', 'MPA', (190, 201))	('Cyp11b2', 'Gene', (182, 189))	('aldosterone production', 'MPA', (212, 234))	('aldosterone', 'Chemical', 'MESH:D000450', (212, 223))	('inactivation', 'NegReg', (66, 78))	('APC', 'Gene', '11789', (82, 85))	('beta-catenin', 'Protein', (140, 152))	('mice', 'Species', '10090', (17, 21))	('beta-catenin', 'Protein', (50, 62))	('hyperaldosteronism', 'Disease', (95, 113))	('Wnt4', 'Gene', (156, 160))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (95, 113))	('aldosterone production', 'Phenotype', 'HP:0000859', (212, 234))	('decreased', 'NegReg', (172, 181))	('Wnt4', 'Gene', '22417', (156, 160))	('lower', 'NegReg', (206, 211))	('lower aldosterone', 'Phenotype', 'HP:0004319', (206, 223))
118103	27619404	Indeed, recent studies have shown that loss of Rspo3 (leading to a decrease in Wnt/beta-catenin signaling) results in decreased zG cell proliferation and overall adrenal size, while stabilization of beta-catenin in the cortex stimulates cell proliferation.	('Rspo3', 'Gene', (47, 52))	('adrenal size', 'CPA', (162, 174))	('decrease', 'NegReg', (67, 75))	('rat', 'Species', '10116', (249, 252))	('rat', 'Species', '10116', (143, 146))	('decreased', 'NegReg', (118, 127))	('loss', 'Var', (39, 43))	('Wnt', 'Chemical', '-', (79, 82))	('Rspo3', 'Gene', '72780', (47, 52))	('zG cell proliferation', 'CPA', (128, 149))
118107	27619404	While inactivation of Wnt signaling impaired steroidogenesis and proliferation, stabilization of beta-catenin or inactivation of the Wnt inhibitor Sfrp2 disrupted zonation leading to ectopic zG cells in the region normally occupied by zF cells.	('ectopic zG cells in the region', 'CPA', (183, 213))	('Wnt', 'Chemical', '-', (22, 25))	('beta-catenin', 'Protein', (97, 109))	('proliferation', 'CPA', (65, 78))	('impaired', 'NegReg', (36, 44))	('disrupted', 'NegReg', (153, 162))	('rat', 'Species', '10116', (72, 75))	('inactivation', 'Var', (6, 18))	('Wnt', 'Chemical', '-', (133, 136))	('zonation', 'MPA', (163, 171))	('inactivation', 'Var', (113, 125))	('Sfrp2', 'Gene', '20319', (147, 152))	('Sfrp2', 'Gene', (147, 152))	('steroidogenesis', 'MPA', (45, 60))
118110	27619404	This results from beta-catenin titrating Sf1 away from its target genes and sustaining the expression of the secreted factor coiled-coil domain containing 80 (Ccdc80), a putative zF inhibitor.	('beta-catenin', 'Protein', (18, 30))	('expression', 'MPA', (91, 101))	('sustaining', 'PosReg', (76, 86))	('Sf1', 'Gene', '22668', (41, 44))	('Sf1', 'Gene', (41, 44))	('Ccdc80', 'Gene', (159, 165))	('Ccdc80', 'Gene', '67896', (159, 165))	('rat', 'Species', '10116', (34, 37))	('titrating', 'Var', (31, 40))
118114	27619404	Consistent with these hypotheses, beta-catenin mutations can also be found in non-functioning adenomas and in carcinomas, suggesting that the timing of the mutational event in the oncogenic process along with additional putative genetic hits may be critical in the outcome of the disease.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('adenomas', 'Disease', (94, 102))	('carcinomas', 'Disease', 'MESH:D002277', (110, 120))	('mutations', 'Var', (47, 56))	('carcinomas', 'Disease', (110, 120))	('beta-catenin', 'Protein', (34, 46))	('found', 'Reg', (69, 74))	('adenomas', 'Disease', 'MESH:D000236', (94, 102))
118119	27619404	The occupancy of the receptor triggers the release of the alpha subunit of the stimulatory G protein and the conversion of ATP into cAMP by adenylyl cyclase.	('ATP', 'Chemical', 'MESH:D000255', (123, 126))	('occupancy', 'Var', (4, 13))	('release', 'MPA', (43, 50))	('conversion', 'MPA', (109, 119))	('cAMP', 'Chemical', '-', (132, 136))
118126	27619404	This is evident in humans, where mutations in genes encoding MC2R and MRAP are associated with glucocorticoid insufficiency, leading to adrenals with a hypoplastic zF but a morphologically intact zG and normal aldosterone production.	('leading to', 'Reg', (125, 135))	('aldosterone production', 'Phenotype', 'HP:0000859', (210, 232))	('associated', 'Reg', (79, 89))	('aldosterone production', 'MPA', (210, 232))	('hypoplastic', 'Disease', 'MESH:D000741', (152, 163))	('glucocorticoid insufficiency', 'Disease', (95, 123))	('hypoplastic', 'Disease', (152, 163))	('humans', 'Species', '9606', (19, 25))	('mutations', 'Var', (33, 42))	('MRAP', 'Gene', (70, 74))	('adrenals', 'Disease', (136, 144))	('aldosterone', 'Chemical', 'MESH:D000450', (210, 221))	('MC2R', 'Gene', (61, 65))	('glucocorticoid insufficiency', 'Phenotype', 'HP:0008163', (95, 123))	('glucocorticoid insufficiency', 'Disease', 'MESH:D000309', (95, 123))
118128	27619404	Similarly, deletion of Pomc leads to overall reduced adrenal mass associated with impaired proliferative activity and hypoplasia of the zF.	('impaired proliferative activity and hypoplasia', 'Disease', 'MESH:D001523', (82, 128))	('reduced', 'NegReg', (45, 52))	('adrenal', 'CPA', (53, 60))	('reduced adrenal mass', 'Phenotype', 'HP:0000835', (45, 65))	('Pomc', 'Gene', '18976', (23, 27))	('deletion', 'Var', (11, 19))	('Pomc', 'Gene', (23, 27))
118129	27619404	Inactivation of the Mc2r gene also produces hypoplasia of the zF.	('hypoplasia', 'Disease', 'MESH:C535916', (44, 54))	('produces', 'Reg', (35, 43))	('hypoplasia', 'Disease', (44, 54))	('Inactivation', 'Var', (0, 12))	('Mc2r', 'Gene', '17200', (20, 24))	('Mc2r', 'Gene', (20, 24))
118131	27619404	On the other hand, dysregulated cAMP signaling in a pathological context, can also result in disruption of zonation.	('cAMP', 'Chemical', '-', (32, 36))	('zonation', 'MPA', (107, 115))	('dysregulated', 'Var', (19, 31))	('disruption', 'MPA', (93, 103))	('cAMP signaling', 'MPA', (32, 46))	('result in', 'Reg', (83, 92))
118132	27619404	This emerges from studies on constitutive activation of cAMP signaling in the adrenal cortex, obtained with genetic deletion of the regulatory subunit 1alpha of PKA (Prkar1a).	('Prkar1a', 'Gene', '19084', (166, 173))	('Prkar1a', 'Gene', (166, 173))	('deletion', 'Var', (116, 124))	('cAMP signaling', 'MPA', (56, 70))	('activation', 'PosReg', (42, 52))	('cAMP', 'Chemical', '-', (56, 60))
118135	27619404	These data show that regulation of cAMP signaling is essential for the maintenance of proper structural and functional zonation, and suggest that disruption of this regulation may lead to destabilized zonal identity and altered cell differentiation.	('lead to', 'Reg', (180, 187))	('cAMP', 'Chemical', '-', (35, 39))	('altered', 'Reg', (220, 227))	('zonal identity', 'CPA', (201, 215))	('destabilized', 'NegReg', (188, 200))	('cell differentiation', 'CPA', (228, 248))	('disruption', 'Var', (146, 156))
118167	27619404	The authors performed short-term lineage tracing to show that the Shh+ lineage can give rise to Cyp11b2+ and Cyp11b1+ cells during adult homeostasis, but it is unclear whether these cells do indeed sustain long-term cortical renewal.	('Cyp11b2+', 'Var', (96, 104))	('Cyp11b1', 'Gene', '110115', (109, 116))	('Cyp11b1', 'Gene', (109, 116))
118179	27619404	In fact, the evidence supporting Shh-expressing cells as unique progenitors is based on the fact that the Shh+ lineage gives rise to Cyp11b2+ and Cyp11b1+ cells.	('Cyp11b1', 'Gene', (146, 153))	('Cyp11b2+', 'Var', (133, 141))	('Cyp11b1', 'Gene', '110115', (146, 153))
118180	27619404	While during normal tissue maintenance all cortical cells descend from the Cyp11b2+ lineage, analysis of mice having undergone AS-Cre mediated Sf1 deletion revealed that the zF can also be derived from a separate (Cyp11b2-) cellular origin (Fig.	('Sf1', 'Gene', '22668', (143, 146))	('rat', 'Species', '10116', (208, 211))	('Sf1', 'Gene', (143, 146))	('deletion', 'Var', (147, 155))	('mice', 'Species', '10090', (105, 109))
118181	27619404	In this model, deletion of Sf1 using AS-Cre led to zG disruption (Fig.	('Sf1', 'Gene', '22668', (27, 30))	('deletion', 'Var', (15, 23))	('zG disruption', 'Disease', (51, 64))	('Sf1', 'Gene', (27, 30))	('led to', 'Reg', (44, 50))
118182	27619404	Upon further reflection, given the heterogeneous, and presumed dynamic, nature of Cyp11b2 expression in the zG it is also conceivable that under extreme conditions (where selective pressure to generate the zF is high), Cyp11b2- zG cells transit into the zF before Cyp11b2 can be expressed, thereby escaping Sf1-deletion.	('rat', 'Species', '10116', (197, 200))	('Sf1', 'Gene', '22668', (307, 310))	('Cyp11b2- zG', 'Var', (219, 230))	('Sf1', 'Gene', (307, 310))
118246	27242666	Recently, in the search for the cellular and molecular mechanisms involved in the regulation of SR-B1 expression and function in steroidogenic cells, we demonstrated that two microRNAs, miRNA-125a and miRNA-455, can bind to specific sites in the 3' UTR of SR-B1 mRNA and regulate the expression of SR-B1.	('steroid', 'Chemical', 'MESH:D013256', (129, 136))	('rat', 'Species', '10116', (160, 163))	('miRNA-125a', 'Var', (186, 196))	('regulate', 'Reg', (271, 279))	('SR-B1', 'Gene', (298, 303))	('miRNA-455', 'Var', (201, 210))	('bind', 'Interaction', (216, 220))	('expression', 'MPA', (284, 294))
118247	27242666	The expression of miRNA-125a and miRNA-455 is detected in steroidogenic tissue/cells, including adrenal, primary ovarian granulosa cells, and model Leydig cell lines.	('steroid', 'Chemical', 'MESH:D013256', (58, 65))	('ovarian granulosa', 'Disease', 'MESH:D010051', (113, 130))	('miRNA-125a', 'Gene', (18, 28))	('ovarian granulosa', 'Disease', (113, 130))	('miRNA-455', 'Var', (33, 42))
118249	27242666	When either miRNA-125a or miRNA-455 is overexpressed or inhibited, the amount of SR-B1 protein expressed on the cell surface is decreased or increased, respectively, leading to SR-B1-mediated selective HDL uptake and SR-B1-supported steroid hormone synthesis being inhibited and stimulated, respectively.	('SR-B1', 'Gene', (81, 86))	('increased', 'PosReg', (141, 150))	('SR-B1-mediated selective HDL uptake', 'MPA', (177, 212))	('miRNA-125a', 'Var', (12, 22))	('steroid hormone', 'Chemical', 'MESH:D013256', (233, 248))	('decreased', 'NegReg', (128, 137))	('inhibited', 'NegReg', (265, 274))	('SR-B1-supported steroid hormone synthesis', 'MPA', (217, 258))	('stimulated', 'PosReg', (279, 289))
118257	27242666	In response to SR-B1 deficiency, mouse adrenal microvilli become disorganized, and microvillar channels show a disrupted appearance along with substantially reduced binding of HDL particles to the cell surface.	('SR-B1', 'Gene', (15, 20))	('binding', 'Interaction', (165, 172))	('microvillar channels', 'CPA', (83, 103))	('deficiency', 'Var', (21, 31))	('HDL particles', 'Protein', (176, 189))	('mouse', 'Species', '10090', (33, 38))	('reduced', 'NegReg', (157, 164))
118258	27242666	In addition, experiments utilizing mutational analysis of SR-B1 or chimeras of CD36/SR-B1 have demonstrated that high affinity binding of lipoproteins to the ECD of SR-B1 is important, but not sufficient to mediate efficient lipid uptake.	('binding', 'Interaction', (127, 134))	('mutational', 'Var', (35, 45))	('CD36', 'Species', '42374', (79, 83))	('SR-B1', 'Gene', (165, 170))	('lipid', 'Chemical', 'MESH:D008055', (225, 230))	('lipoproteins', 'Protein', (138, 150))	('rat', 'Species', '10116', (102, 105))
118259	27242666	However, at the same time the ECD of SR-B1 does influence the efficient transfer of lipid by SR-B1.	('efficient transfer of lipid', 'MPA', (62, 89))	('ECD', 'Var', (30, 33))	('SR-B1', 'Gene', (93, 98))	('influence', 'Reg', (48, 57))	('lipid', 'Chemical', 'MESH:D008055', (84, 89))
118269	27242666	When cellular extracts from SR-B1 transfected HEK-293 cells or ACTH-treated Y1-BS1 cells were analyzed by size-exclusion chromatography and sucrose density centrifugation, a significant portion of SR-B1 eluted at peaks that correlate with the size of dimeric and oligomeric forms of SR-B1.	('sucrose', 'Chemical', 'MESH:D013395', (140, 147))	('SR-B1', 'Gene', (197, 202))	('HEK-293', 'CellLine', 'CVCL:0045', (46, 53))	('SR-B1', 'Gene', (28, 33))	('eluted', 'MPA', (203, 209))	('transfected', 'Var', (34, 45))
118273	27242666	SR-B1 contains a total of eight cysteine (C) residues (C21, C251, C280, C321, C323, C334, C384, and C470) and six of them are located in the ECD.	('C321', 'Var', (72, 76))	('C280', 'Var', (66, 70))	('C21', 'Var', (55, 58))	('C323', 'Var', (78, 82))	('cysteine', 'Chemical', 'MESH:D003545', (32, 40))	('C334', 'Var', (84, 88))	('C470', 'Var', (100, 104))	('C384', 'Var', (90, 94))	('C251', 'Var', (60, 64))
118274	27242666	Interestingly, mutation of any of these four cysteine residues to serine resulted in a robust induction of SR-B1 dimer formation, but, in contrast to normal SR-B1, these SR-B1 mutants lost their ability to mediate HDL-CE selective uptake.	('HDL-CE selective uptake', 'MPA', (214, 237))	('mutation', 'Var', (15, 23))	('mutants', 'Var', (176, 183))	('serine', 'Chemical', 'MESH:D012694', (66, 72))	('ability', 'MPA', (195, 202))	('lost', 'NegReg', (184, 188))	('SR-B1', 'Gene', (170, 175))	('cysteine', 'Chemical', 'MESH:D003545', (45, 53))
118281	27242666	Among potential phosphorylation sites, SIK1-catalyzed phosphorylation of Ser496 is critical for SIK1 stimulation of the selective CE transport activity of SR-B1.	('Ser496', 'Chemical', '-', (73, 79))	('SIK1', 'Gene', '17691', (39, 43))	('SIK1', 'Gene', (39, 43))	('selective CE transport activity', 'MPA', (120, 151))	('SIK1', 'Gene', '17691', (96, 100))	('SIK1-catalyzed', 'Disease', 'None', (39, 53))	('SIK1-catalyzed', 'Disease', (39, 53))	('stimulation', 'PosReg', (101, 112))	('SIK1', 'Gene', (96, 100))	('Ser496', 'Var', (73, 79))
118295	27242666	On the other hand, since adrenal cholesterol uptake is required for the production of anti-inflammatory glucocorticoids, gene deletion of functional SR-B1 in adrenals results in impaired steroid synthesis.	('cholesterol', 'Chemical', 'MESH:D002784', (33, 44))	('gene deletion', 'Var', (121, 134))	('impaired', 'NegReg', (178, 186))	('steroid', 'Chemical', 'MESH:D013256', (187, 194))	('steroid synthesis', 'MPA', (187, 204))	('SR-B1', 'Gene', (149, 154))
118297	27242666	There is an uncontrolled robust inflammatory cytokine response in the SR-B1 deficient animals, and they exhibit higher lethality when challenged with LPS-doses that induce endotoxic shock.	('shock', 'Phenotype', 'HP:0031273', (182, 187))	('inflammatory cytokine response', 'MPA', (32, 62))	('higher', 'PosReg', (112, 118))	('LPS', 'Gene', '21898', (150, 153))	('SR-B1', 'Gene', (70, 75))	('LPS', 'Gene', (150, 153))	('lethality', 'CPA', (119, 128))	('endotoxic shock', 'Disease', (172, 187))	('deficient', 'Var', (76, 85))	('endotoxic shock', 'Disease', 'MESH:D012772', (172, 187))
118299	27242666	Finally, when SR-B1 was only selectively deleted in adrenocortical cells in a tissue-specific manner, the animals had impaired rates of glucocorticoid secretion in response to stress, especially when they were subjected to an endotoxin challenge; these animals with SR-B1 ablated only in adrenocortical cells showed enhanced local and systematic inflammatory response, blunted activation of atrophy genes in skeletal muscle, and have a high incidence of mortality.	('adrenocortical', 'Disease', (288, 302))	('adrenocortical', 'Disease', 'MESH:D018268', (288, 302))	('blunted', 'NegReg', (369, 376))	('adrenocortical', 'Disease', (52, 66))	('activation', 'MPA', (377, 387))	('SR-B1', 'Gene', (266, 271))	('adrenocortical', 'Disease', 'MESH:D018268', (52, 66))	('ablated', 'Var', (272, 279))	('atrophy', 'Disease', 'MESH:D001284', (391, 398))	('rat', 'Species', '10116', (127, 130))	('enhanced', 'PosReg', (316, 324))	('atrophy', 'Disease', (391, 398))
118302	27242666	Ablation of one of the genes involved in circadian control, BMAL1, results in loss of circadian regulation of glucocorticoids.	('BMAL1', 'Gene', '11865', (60, 65))	('BMAL1', 'Gene', (60, 65))	('Ablation', 'Var', (0, 8))	('circadian regulation of glucocorticoids', 'MPA', (86, 125))	('loss', 'NegReg', (78, 82))
118308	27242666	Altered SR-B1 function may represent an adaptive response to cope with stressful conditions, as demonstrated by ablation of SR-B1 resulting in disturbed anti-inflammatory glucocorticoid homeostasis and impaired steroid synthesis.	('rat', 'Species', '10116', (103, 106))	('disturbed', 'Reg', (143, 152))	('ablation', 'Var', (112, 120))	('impaired', 'NegReg', (202, 210))	('steroid synthesis', 'MPA', (211, 228))	('steroid', 'Chemical', 'MESH:D013256', (211, 218))	('anti-inflammatory glucocorticoid homeostasis', 'MPA', (153, 197))	('SR-B1', 'Gene', (124, 129))
118311	26754547	Various factors have been implicated in the pathogenesis of ACC including dysregulation of the G2/M transition and aberrant activity of p53 and MDM2.	('aberrant activity', 'Var', (115, 132))	('p53', 'Gene', '7157', (136, 139))	('G2/M transition', 'CPA', (95, 110))	('ACC', 'Phenotype', 'HP:0006744', (60, 63))	('MDM2', 'Gene', (144, 148))	('dysregulation', 'Var', (74, 87))	('p53', 'Gene', (136, 139))
118315	26754547	We used siRNA knock down PLK-1 and pharmacological inhibition of PLK-1 and MDM2 ACC cell lines SW-13 and H295R.	('H295R', 'Chemical', '-', (105, 110))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('knock down', 'Var', (14, 24))	('SW-13', 'CellLine', 'CVCL:0542', (95, 100))	('PLK-1', 'Gene', (65, 70))	('PLK-1', 'Gene', '5347', (65, 70))	('PLK-1', 'Gene', (25, 30))	('PLK-1', 'Gene', '5347', (25, 30))
118317	26754547	Knocking down expression of PLK-1 with siRNA or inhibition of PLK-1 by a small molecule inhibitor, BI-2536, resulted in a loss of viability of up to 70 % in the ACC cell lines H295R and SW-13.	('viability', 'MPA', (130, 139))	('H295R', 'Chemical', '-', (176, 181))	('BI-2536', 'Chemical', 'MESH:C518477', (99, 106))	('expression', 'MPA', (14, 24))	('ACC', 'Phenotype', 'HP:0006744', (161, 164))	('PLK-1', 'Gene', '5347', (28, 33))	('PLK-1', 'Gene', (62, 67))	('loss', 'NegReg', (122, 126))	('SW-13', 'CellLine', 'CVCL:0542', (186, 191))	('PLK-1', 'Gene', (28, 33))	('inhibition', 'NegReg', (48, 58))	('PLK-1', 'Gene', '5347', (62, 67))	('Knocking', 'Var', (0, 8))
118318	26754547	In xenograft models, BI-2536 demonstrated marked inhibition of growth of SW-13 with less inhibition of H295R.	('BI-2536', 'Var', (21, 28))	('H295R', 'Chemical', '-', (103, 108))	('BI-2536', 'Chemical', 'MESH:C518477', (21, 28))	('SW-13', 'CellLine', 'CVCL:0542', (73, 78))	('growth', 'MPA', (63, 69))	('inhibition', 'NegReg', (49, 59))	('SW-13', 'Gene', (73, 78))
118319	26754547	BI-2536 treatment resulted in a decrease in mutant p53 protein in SW-13 cells but had no effect on wild-type p53 protein levels in H295R cells.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('protein', 'Protein', (55, 62))	('SW-13', 'CellLine', 'CVCL:0542', (66, 71))	('p53', 'Gene', (109, 112))	('BI-2536', 'Chemical', 'MESH:C518477', (0, 7))	('H295R', 'Chemical', '-', (131, 136))	('p53', 'Gene', '7157', (109, 112))	('mutant', 'Var', (44, 50))	('decrease', 'NegReg', (32, 40))
118320	26754547	Additionally, inhibition of PLK-1 restored wild-type p53's transactivation and apoptotic functions in H295R cells, while these functions of mutant p53 were restored only to a smaller extent.	('transactivation', 'MPA', (59, 74))	('H295R', 'Chemical', '-', (102, 107))	('apoptotic functions', 'CPA', (79, 98))	('p53', 'Gene', '7157', (147, 150))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('PLK-1', 'Gene', '5347', (28, 33))	('PLK-1', 'Gene', (28, 33))	('inhibition', 'Var', (14, 24))	('mutant', 'Var', (140, 146))	('p53', 'Gene', (147, 150))
118321	26754547	Furthermore, inhibition of MDM2 with nutlin-3 reduced the viability of both the ACC cells and also reactivated wild-type p53's apoptotic function.	('apoptotic function', 'CPA', (127, 145))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('viability', 'CPA', (58, 67))	('p53', 'Gene', (121, 124))	('inhibition', 'Var', (13, 23))	('p53', 'Gene', '7157', (121, 124))	('reduced', 'NegReg', (46, 53))	('MDM2', 'Gene', (27, 31))	('reactivated', 'NegReg', (99, 110))	('nutlin-3', 'Chemical', 'MESH:C482205', (37, 45))
118322	26754547	Inhibition of PLK-1 sensitized the ACC cell lines to MDM2 inhibition and this dual inhibition resulted in an additive apoptotic response in H295R cells with wild-type p53.	('H295R', 'Chemical', '-', (140, 145))	('MDM2', 'Gene', (53, 57))	('p53', 'Gene', '7157', (167, 170))	('PLK-1', 'Gene', '5347', (14, 19))	('apoptotic', 'CPA', (118, 127))	('Inhibition', 'Var', (0, 10))	('inhibition', 'NegReg', (58, 68))	('resulted in', 'Reg', (94, 105))	('PLK-1', 'Gene', (14, 19))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))	('p53', 'Gene', (167, 170))
118345	26754547	Normalized expression data was extracted for the PLK1 probe set (202240_at), and the relative fold change to the geometric mean of the corresponding normal samples for each study was computed.	('PLK1', 'Gene', '5347', (49, 53))	('PLK1', 'Gene', (49, 53))	('202240_at', 'Var', (65, 74))
118358	26754547	Induction of apoptosis after treatment with BI-2536 and nutlin-3 alone or together in combination was determined using the Caspase 3/7 Glo assay (Promega, Madison, WI).	('BI-2536', 'Chemical', 'MESH:C518477', (44, 51))	('nutlin-3', 'Chemical', 'MESH:C482205', (56, 64))	('Caspase 3', 'Gene', (123, 132))	('Caspase 3', 'Gene', '836', (123, 132))	('BI-2536', 'Var', (44, 51))
118373	26754547	PLK-1 protein knockdown was confirmed by immunoblot 72 h after transfection.	('PLK-1', 'Gene', (0, 5))	('PLK-1', 'Gene', '5347', (0, 5))	('protein', 'Protein', (6, 13))	('knockdown', 'Var', (14, 23))
118391	26754547	Relative amounts of the PLK-1 protein after siRNA knockdown are reported relative to beta-Actin.	('knockdown', 'Var', (50, 59))	('PLK-1', 'Gene', '5347', (24, 29))	('PLK-1', 'Gene', (24, 29))	('beta-Actin', 'Gene', (85, 95))	('beta-Actin', 'Gene', '728378', (85, 95))	('protein', 'Protein', (30, 37))
118394	26754547	Cohorts were assigned by random-equilibration into groups of 10 for SW-13 or groups of 9 for H295R.	('SW-13', 'CellLine', 'CVCL:0542', (68, 73))	('SW-13', 'Var', (68, 73))	('H295R', 'Chemical', '-', (93, 98))	('H295R', 'Var', (93, 98))
118405	26754547	Studies of p53 mutations, p53 codon 72 polymorphism, and MDM2 SNP309 polymorphism are detailed in the Additional file 1, as the results of the studies were largely negative.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('MDM2', 'Gene', (57, 61))	('mutations', 'Var', (15, 24))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))
118415	26754547	We found that knocking down expression of PLK-1 using siRNA not only reduced the amount of PLK-1 protein (Fig.	('knocking down', 'Var', (14, 27))	('reduced', 'NegReg', (69, 76))	('PLK-1', 'Gene', (91, 96))	('PLK-1', 'Gene', '5347', (91, 96))	('PLK-1', 'Gene', (42, 47))	('PLK-1', 'Gene', '5347', (42, 47))
118416	26754547	2a, b), but also decreased the viability of both H295R and SW-13 to levels close to that of the positive control, UBB1, after siRNA knockdown (Fig.	('decreased', 'NegReg', (17, 26))	('knockdown', 'Var', (132, 141))	('SW-13', 'CellLine', 'CVCL:0542', (59, 64))	('H295R', 'Chemical', '-', (49, 54))	('viability', 'MPA', (31, 40))
118419	26754547	H295R had an IC50 value of 0.063 microM while SW-13 was ~tenfold more sensitive compared to H295R with an IC50 value of 0.0095 microM 120 and 96 h following addition of drug respectively (Fig.	('H295R', 'Chemical', '-', (92, 97))	('H295R', 'Var', (0, 5))	('H295R', 'Chemical', '-', (0, 5))	('SW-13', 'CellLine', 'CVCL:0542', (46, 51))	('IC50', 'MPA', (13, 17))
118421	26754547	As mitotane is the current standard of care for patients with advanced ACC, we wanted to determine whether inhibition of PLK-1 could sensitize ACC cell lines to mitotane.	('mitotane', 'Chemical', 'MESH:D008939', (161, 169))	('ACC', 'Phenotype', 'HP:0006744', (143, 146))	('ACC', 'Phenotype', 'HP:0006744', (71, 74))	('sensitize', 'Reg', (133, 142))	('mitotane', 'Chemical', 'MESH:D008939', (3, 11))	('patients', 'Species', '9606', (48, 56))	('inhibition', 'Var', (107, 117))	('ACC', 'Disease', (143, 146))	('PLK-1', 'Gene', (121, 126))	('PLK-1', 'Gene', '5347', (121, 126))
118424	26754547	Marked inhibition of tumor growth in response to BI-2536 relative to either vehicle control or mitotane-treated tumors was observed for SW-13 xenografts while the inhibition in H295R (Fig.	('H295R', 'Chemical', '-', (177, 182))	('SW-13', 'CellLine', 'CVCL:0542', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('BI-2536', 'Chemical', 'MESH:C518477', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('BI-2536', 'Var', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', (112, 117))	('mitotane', 'Chemical', 'MESH:D008939', (95, 103))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('inhibition', 'NegReg', (7, 17))	('tumors', 'Disease', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
118428	26754547	Therefore, we would predict that inhibition of PLK-1 would not affect p53 protein levels in ACC.	('inhibition', 'Var', (33, 43))	('p53', 'Gene', '7157', (70, 73))	('p53', 'Gene', (70, 73))	('PLK-1', 'Gene', (47, 52))	('PLK-1', 'Gene', '5347', (47, 52))	('ACC', 'Phenotype', 'HP:0006744', (92, 95))
118429	26754547	Treatment with BI-2536 did not affect the levels of p53 transcript in either of the two cell lines (Fig.	('BI-2536', 'Var', (15, 22))	('p53', 'Gene', (52, 55))	('BI-2536', 'Chemical', 'MESH:C518477', (15, 22))	('p53', 'Gene', '7157', (52, 55))
118430	26754547	However, using an antibody that recognizes both mutant and wild-type p53 with its multiple isoforms, we saw a dose-dependent decrease of mutant p53 protein levels in SW-13 cells but not in the wild-type p53 protein levels in H295R cells (blots:Fig.	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('protein levels', 'MPA', (148, 162))	('p53', 'Gene', '7157', (144, 147))	('SW-13', 'CellLine', 'CVCL:0542', (166, 171))	('decrease', 'NegReg', (125, 133))	('p53', 'Gene', '7157', (203, 206))	('H295R', 'Chemical', '-', (225, 230))	('mutant', 'Var', (137, 143))	('p53', 'Gene', (144, 147))	('p53', 'Gene', (203, 206))
118431	26754547	Since PLK-1 is a negative modulator of p53, inhibition of PLK-1 would relieve the negative regulation on wild-type p53 and potentially restore its transactivation and apoptotic functions.	('transactivation', 'MPA', (147, 162))	('relieve', 'PosReg', (70, 77))	('apoptotic functions', 'CPA', (167, 186))	('inhibition', 'Var', (44, 54))	('PLK-1', 'Gene', '5347', (6, 11))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('PLK-1', 'Gene', '5347', (58, 63))	('p53', 'Gene', (39, 42))	('PLK-1', 'Gene', (6, 11))	('p53', 'Gene', '7157', (39, 42))	('PLK-1', 'Gene', (58, 63))	('negative regulation', 'MPA', (82, 101))	('restore', 'PosReg', (135, 142))
118432	26754547	In the context of the predicted non-functional transactivation of the mutant p53 in SW-13, we would expect little impact on transactivation and unknown impact on apoptosis, particularly in light of the loss of mutant p53 protein upon BI-2536 exposure.	('SW-13', 'CellLine', 'CVCL:0542', (84, 89))	('mutant', 'Var', (210, 216))	('p53', 'Gene', (217, 220))	('p53', 'Gene', '7157', (217, 220))	('mutant', 'Var', (70, 76))	('protein', 'Protein', (221, 228))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('BI-2536', 'Chemical', 'MESH:C518477', (234, 241))	('transactivation', 'MPA', (47, 62))	('loss', 'NegReg', (202, 206))
118433	26754547	We assessed p53's transactivation and apoptotic functions after treatment with BI-2536.	('transactivation', 'MPA', (18, 33))	('apoptotic functions', 'CPA', (38, 57))	('BI-2536', 'Var', (79, 86))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('BI-2536', 'Chemical', 'MESH:C518477', (79, 86))
118434	26754547	Inhibition of PLK-1 with BI-2536 resulted in a slight increase in the transcription of CDKN1A (gene that encodes the p21 protein) in H292R cells with wild type p53 (Fig.	('p21', 'Gene', '1026', (117, 120))	('p21', 'Gene', (117, 120))	('BI-2536', 'Var', (25, 32))	('H292R', 'SUBSTITUTION', 'None', (133, 138))	('increase', 'PosReg', (54, 62))	('H292R', 'Var', (133, 138))	('p53', 'Gene', (160, 163))	('PLK-1', 'Gene', (14, 19))	('transcription', 'MPA', (70, 83))	('p53', 'Gene', '7157', (160, 163))	('PLK-1', 'Gene', '5347', (14, 19))	('BI-2536', 'Chemical', 'MESH:C518477', (25, 32))	('CDKN1A', 'Gene', (87, 93))	('CDKN1A', 'Gene', '1026', (87, 93))
118435	26754547	On the other hand, a decrease in mutant p53 protein in SW-13 cells after exposure to BI-2536 also reduced the amount of CDNK1A message (Fig.	('BI-2536', 'Var', (85, 92))	('amount of CDNK1A message', 'MPA', (110, 134))	('decrease', 'NegReg', (21, 29))	('BI-2536', 'Chemical', 'MESH:C518477', (85, 92))	('p53', 'Gene', (40, 43))	('SW-13', 'CellLine', 'CVCL:0542', (55, 60))	('mutant', 'Var', (33, 39))	('p53', 'Gene', '7157', (40, 43))	('reduced', 'NegReg', (98, 105))	('protein', 'Protein', (44, 51))
118436	26754547	Furthermore, we tested whether inhibition of PLK-1 with BI-2536 could also restore p53's apoptotic function.	('p53', 'Gene', (83, 86))	('tested', 'Reg', (16, 22))	('p53', 'Gene', '7157', (83, 86))	('apoptotic function', 'CPA', (89, 107))	('BI-2536', 'Var', (56, 63))	('PLK-1', 'Gene', (45, 50))	('restore', 'PosReg', (75, 82))	('PLK-1', 'Gene', '5347', (45, 50))	('BI-2536', 'Chemical', 'MESH:C518477', (56, 63))
118437	26754547	Treatment with BI-2536 resulted in a robust induction of apoptosis after treatment with BI-2536 in H295R cells (Fig.	('BI-2536', 'Var', (15, 22))	('BI-2536', 'Var', (88, 95))	('BI-2536', 'Chemical', 'MESH:C518477', (15, 22))	('H295R', 'Chemical', '-', (99, 104))	('apoptosis', 'CPA', (57, 66))	('BI-2536', 'Chemical', 'MESH:C518477', (88, 95))
118438	26754547	5c) and to a lesser extent in SW-13 cells with mutant p53 (Fig.	('mutant', 'Var', (47, 53))	('SW-13', 'CellLine', 'CVCL:0542', (30, 35))	('p53', 'Gene', '7157', (54, 57))	('p53', 'Gene', (54, 57))
118439	26754547	However, maximum induction of apoptosis in SW-13 cells was observed at 48 h, while only high concentrations of BI-2536 resulted in an increase in apoptosis at early time points (Fig.	('BI-2536', 'Chemical', 'MESH:C518477', (111, 118))	('SW-13', 'CellLine', 'CVCL:0542', (43, 48))	('apoptosis', 'MPA', (146, 155))	('BI-2536', 'Var', (111, 118))
118446	26754547	Given that PLK-1 directly modulates p53 functions as well as indirectly by modulating MDM2 functions, we wanted to determine inhibiting PLK-1 would sensitize cells to the effects of nutlin-3, an inhibitor of MDM2.	('modulates', 'Reg', (26, 35))	('sensitize', 'Reg', (148, 157))	('nutlin-3', 'Chemical', 'MESH:C482205', (182, 190))	('PLK-1', 'Gene', (11, 16))	('inhibiting', 'Var', (125, 135))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('PLK-1', 'Gene', '5347', (136, 141))	('PLK-1', 'Gene', (136, 141))	('modulating', 'Reg', (75, 85))	('PLK-1', 'Gene', '5347', (11, 16))
118449	26754547	Inhibition of PLK-1 and MDM2 should result in the reactivation of p53's apoptotic function, due to dual relief of p53 inhibition.	('p53', 'Gene', '7157', (66, 69))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('reactivation', 'MPA', (50, 62))	('MDM2', 'Gene', (24, 28))	('PLK-1', 'Gene', '5347', (14, 19))	('apoptotic function', 'CPA', (72, 90))	('Inhibition', 'Var', (0, 10))	('PLK-1', 'Gene', (14, 19))	('p53', 'Gene', (66, 69))
118456	26754547	We found that p53 mutations in adult sporadic ACC are relatively uncommon.	('adult sporadic ACC', 'Disease', (31, 49))	('ACC', 'Phenotype', 'HP:0006744', (46, 49))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (14, 17))	('mutations', 'Var', (18, 27))
118467	26754547	Inhibition of PLK-1 in vitro leads to cell cycle arrest at G2/M and apoptosis in human cancer cell lines.	('cancer', 'Disease', (87, 93))	('apoptosis', 'CPA', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('human', 'Species', '9606', (81, 86))	('Inhibition', 'Var', (0, 10))	('PLK-1', 'Gene', '5347', (14, 19))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (38, 55))	('cell cycle arrest at G2/M', 'CPA', (38, 63))	('PLK-1', 'Gene', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
118470	26754547	Our study offers evidence that BI-2536 may act to decrease levels of mutant p53 while not affecting wild type p53.	('levels', 'MPA', (59, 65))	('p53', 'Gene', (110, 113))	('mutant', 'Var', (69, 75))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('p53', 'Gene', '7157', (110, 113))	('BI-2536', 'Var', (31, 38))	('BI-2536', 'Chemical', 'MESH:C518477', (31, 38))	('decrease', 'NegReg', (50, 58))
118471	26754547	It has been previously reported that BI-2536 has activity at nanomolar levels (IC50 range 0.002-0.025 microM) in cells lines that have either wild type or mutant p53.	('activity', 'MPA', (49, 57))	('p53', 'Gene', (162, 165))	('BI-2536', 'Chemical', 'MESH:C518477', (37, 44))	('mutant', 'Var', (155, 161))	('p53', 'Gene', '7157', (162, 165))	('BI-2536', 'Var', (37, 44))
118472	26754547	It may be that patients with tumors harboring mutant p53 will respond to inhibition of PLK-1 by BI-2536 better than patients whose tumors harbor a wild-type p53.	('patients', 'Species', '9606', (15, 23))	('inhibition', 'NegReg', (73, 83))	('BI-2536', 'Chemical', 'MESH:C518477', (96, 103))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (29, 35))	('PLK-1', 'Gene', (87, 92))	('p53', 'Gene', '7157', (157, 160))	('respond', 'MPA', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('better', 'PosReg', (104, 110))	('mutant', 'Var', (46, 52))	('p53', 'Gene', '7157', (53, 56))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('p53', 'Gene', (157, 160))	('p53', 'Gene', (53, 56))	('PLK-1', 'Gene', '5347', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
118473	26754547	One attractive hypothesis that warrants investigation is that if one could inhibit mutant p53 and allow cancer cells to undergo apoptosis, one could enhance tumor response to treatment with other chemotherapeutic agents.	('tumor', 'Disease', (157, 162))	('p53', 'Gene', (90, 93))	('allow', 'Reg', (98, 103))	('mutant', 'Var', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('p53', 'Gene', '7157', (90, 93))	('inhibit', 'NegReg', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('enhance', 'PosReg', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('apoptosis', 'CPA', (128, 137))
118475	26754547	The mechanism by which BI-2536 affects mutant p53 levels is unclear and should be studied further.	('p53', 'Gene', (46, 49))	('BI-2536', 'Chemical', 'MESH:C518477', (23, 30))	('p53', 'Gene', '7157', (46, 49))	('affects', 'Reg', (31, 38))	('BI-2536', 'Var', (23, 30))
118476	26754547	PLK-1 may act to stabilize mutant p53 and protect it from degradation or inactivation.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('mutant', 'Var', (27, 33))	('PLK-1', 'Gene', '5347', (0, 5))	('PLK-1', 'Gene', (0, 5))	('degradation', 'MPA', (58, 69))
118478	26754547	Alternatively, BI-2536 may have a direct effect on p53 independent of its effect on PLK-1.	('BI-2536', 'Var', (15, 22))	('PLK-1', 'Gene', '5347', (84, 89))	('p53', 'Gene', '7157', (51, 54))	('p53', 'Gene', (51, 54))	('BI-2536', 'Chemical', 'MESH:C518477', (15, 22))	('PLK-1', 'Gene', (84, 89))	('effect', 'Reg', (41, 47))
118481	26754547	We did not observe a change in allele frequency from the expected population frequency in our ACC population, nor did we observe a significant increase MDM2 expression in tumors with a G allele compared to tumors homozygous for the T allele.	('ACC', 'Phenotype', 'HP:0006744', (94, 97))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('G allele', 'Var', (185, 193))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('expression', 'MPA', (157, 167))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('increase', 'PosReg', (143, 151))	('tumors', 'Disease', (171, 177))	('MDM2', 'Gene', (152, 156))
118530	21864647	We show that S1P increases the expression of steroidogenic acute regulatory protein (StAR), 18-kDa translocator protein (TSPO), low-density lipoprotein receptor (LDLR), and scavenger receptor class B type I (SR-BI).	('SR-BI', 'Gene', (208, 213))	('scavenger receptor class B type I', 'Gene', '949', (173, 206))	('StAR', 'Gene', (85, 89))	('scavenger receptor class B type I', 'Gene', (173, 206))	('TSPO', 'Gene', (121, 125))	('increases', 'PosReg', (17, 26))	('low-density lipoprotein receptor', 'Gene', '3949', (128, 160))	('SR-BI', 'Gene', '949', (208, 213))	('expression', 'MPA', (31, 41))	('LDLR', 'Gene', (162, 166))	('steroidogenic acute regulatory protein', 'Gene', '6770', (45, 83))	('TSPO', 'Gene', '706', (121, 125))	('steroidogenic acute regulatory protein', 'Gene', (45, 83))	('StAR', 'Gene', '6770', (85, 89))	('S1P', 'Var', (13, 16))	('LDLR', 'Gene', '3949', (162, 166))	('low-density lipoprotein receptor', 'Gene', (128, 160))
118532	21864647	S1P also increases intracellular Ca2+, the phosphorylation of hormone sensitive lipase (HSL) at Ser563, and cortisol secretion.	('HSL', 'Gene', (88, 91))	('phosphorylation', 'MPA', (43, 58))	('HSL', 'Gene', '3991', (88, 91))	('Ser563', 'Chemical', '-', (96, 102))	('cortisol', 'Chemical', 'MESH:D006854', (108, 116))	('increases', 'PosReg', (9, 18))	('intracellular Ca2+', 'MPA', (19, 37))	('cortisol secretion', 'MPA', (108, 126))	('Ca2+', 'Chemical', 'MESH:D000069285', (33, 37))	('S1P', 'Var', (0, 3))
118541	21864647	Alternatively, Ca2+ influx through L-type Ca2+ channels abrogates StAR transcription by inducing the expression of the transcription factor DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), a repressor of the StAR gene.	('abrogates', 'NegReg', (56, 65))	('DAX1', 'Gene', '190', (140, 144))	('StAR', 'Gene', '6770', (66, 70))	('Ca2+', 'Chemical', 'MESH:D000069285', (42, 46))	('DAX1', 'Gene', (140, 144))	('inducing', 'PosReg', (88, 96))	('StAR', 'Gene', (258, 262))	('StAR', 'Gene', (66, 70))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (177, 195))	('Ca2+', 'Var', (15, 19))	('sex reversal', 'Phenotype', 'HP:0012245', (163, 175))	('Ca2+', 'Chemical', 'MESH:D000069285', (15, 19))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (177, 195))	('expression', 'MPA', (101, 111))	('StAR', 'Gene', '6770', (258, 262))	('adrenal hypoplasia', 'Disease', (177, 195))
118551	21864647	S1P has also been shown to stimulate cortisol production in zona fasciculata bovine adrenal cells in a PKC- and Ca2+-dependent manner, and promote aldosterone secretion in bovine glomerulosa cells via the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK/ERK) pathways.	('bovine', 'Species', '9913', (77, 83))	('ERK', 'Gene', (285, 288))	('cortisol', 'Chemical', 'MESH:D006854', (37, 45))	('promote', 'PosReg', (139, 146))	('PKC', 'Gene', (103, 106))	('bovine', 'Species', '9913', (172, 178))	('PI3', 'Gene', (232, 235))	('zona fasciculata', 'Disease', (60, 76))	('PI3', 'Gene', '5266', (232, 235))	('PKC', 'Gene', '112476', (103, 106))	('aldosterone secretion', 'MPA', (147, 168))	('cortisol production', 'MPA', (37, 56))	('zona fasciculata', 'Disease', 'MESH:D006562', (60, 76))	('stimulate', 'PosReg', (27, 36))	('ERK', 'Gene', '5594', (285, 288))	('S1P', 'Var', (0, 3))	('Ca2+', 'Chemical', 'MESH:D000069285', (112, 116))	('stimulate cortisol production', 'Phenotype', 'HP:0003118', (27, 56))
118557	21864647	ACTH and the cAMP analog Bt2cAMP decrease cellular amounts of sphingomyelin, ceramide, and sphingosine, while simultaneously increasing the secretion of S1P.	('sphingosine', 'Chemical', 'MESH:D013110', (91, 102))	('ceramide', 'MPA', (77, 85))	('decrease', 'NegReg', (33, 41))	('Bt2cAMP', 'Var', (25, 32))	('secretion of S1P', 'MPA', (140, 156))	('cAMP', 'Chemical', 'MESH:D000242', (13, 17))	('sphingomyelin', 'Chemical', 'MESH:D013109', (62, 75))	('ACTH', 'Gene', '5443', (0, 4))	('ACTH', 'Gene', (0, 4))	('sphingosine', 'MPA', (91, 102))	('increasing', 'PosReg', (125, 135))	('cAMP', 'Chemical', 'MESH:D000242', (28, 32))	('cellular amounts of sphingomyelin', 'MPA', (42, 75))	('ceramide', 'Chemical', 'MESH:D002518', (77, 85))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (25, 32))
118558	21864647	The S1P produced stimulates cortisol secretion from H295R cells by promoting the maturation and binding of sterol regulatory element binding protein 1 (SREBP1) to the CYP17 promoter, thereby inducing gene transcription.	('SREBP1', 'Gene', '6720', (152, 158))	('CYP17', 'Gene', '1586', (167, 172))	('binding', 'Interaction', (96, 103))	('inducing', 'PosReg', (191, 199))	('cortisol secretion', 'MPA', (28, 46))	('stimulates', 'PosReg', (17, 27))	('gene transcription', 'MPA', (200, 218))	('maturation', 'MPA', (81, 91))	('promoting', 'PosReg', (67, 76))	('sterol regulatory element binding protein 1', 'Gene', (107, 150))	('cortisol', 'Chemical', 'MESH:D006854', (28, 36))	('sterol regulatory element binding protein 1', 'Gene', '6720', (107, 150))	('SREBP1', 'Gene', (152, 158))	('H295R', 'CellLine', 'CVCL:0458', (52, 57))	('CYP17', 'Gene', (167, 172))	('S1P', 'Var', (4, 7))
118561	21864647	We show that S1P rapidly increases cortisol biosynthesis and the mRNA expression of multiple genes involved in the acute phase of steroid hormone production including StAR, TSPO, SR-BI, and LDLR.	('TSPO', 'Gene', '706', (173, 177))	('SR-BI', 'Gene', '949', (179, 184))	('steroid hormone', 'Chemical', 'MESH:D013256', (130, 145))	('SR-BI', 'Gene', (179, 184))	('increases', 'PosReg', (25, 34))	('LDLR', 'Gene', '3949', (190, 194))	('cortisol biosynthesis', 'MPA', (35, 56))	('TSPO', 'Gene', (173, 177))	('cortisol', 'Chemical', 'MESH:D006854', (35, 43))	('StAR', 'Gene', '6770', (167, 171))	('LDLR', 'Gene', (190, 194))	('S1P', 'Var', (13, 16))	('mRNA expression', 'MPA', (65, 80))	('increases cortisol', 'Phenotype', 'HP:0003118', (25, 43))	('StAR', 'Gene', (167, 171))
118562	21864647	In addition, we demonstrate that S1P acutely increases the phosphorylation of HSL at Ser563 and show that S1P-stimulated StAR gene expression is pertussis toxin sensitive and dependent on the activation of PLC, CamKII, and ERK1/2.	('Ser563', 'Chemical', '-', (85, 91))	('StAR', 'Gene', '6770', (121, 125))	('HSL', 'Gene', (78, 81))	('CamKII', 'Gene', (211, 217))	('increases', 'PosReg', (45, 54))	('StAR', 'Gene', (121, 125))	('HSL', 'Gene', '3991', (78, 81))	('phosphorylation', 'MPA', (59, 74))	('expression', 'MPA', (131, 141))	('S1P', 'Var', (33, 36))	('CamKII', 'Gene', '818', (211, 217))
118566	21864647	Pertussis toxin (PTX), U0126, KN-93, U73122, U73343, and Fluo 3/AM were obtained from EMD Biosciences (La Jolla, CA).	('KN-93', 'Chemical', 'MESH:C072105', (30, 35))	('EMD Biosciences', 'Disease', (86, 101))	('U0126', 'Var', (23, 28))	('U73343', 'Var', (45, 51))	('EMD Biosciences', 'Disease', 'None', (86, 101))	('U73122', 'Chemical', 'MESH:C060229', (37, 43))	('U0126', 'Chemical', 'MESH:C113580', (23, 28))	('U73343', 'Chemical', 'MESH:C074854', (45, 51))	('U73122', 'Var', (37, 43))	('Fluo 3', 'Chemical', 'MESH:C059715', (57, 63))
118581	21864647	Phospho-CamKII (pCamKII) and total CamKII expression was assessed in lysates purified from cells that were pretreated with 10 microM VPC23019, 10 microM U0126, or 5 pg/ml PTX for 1 h followed by treatment with 1 microM S1P for 30 min.	('CamKII', 'Gene', '818', (17, 23))	('CamKII', 'Gene', (17, 23))	('U0126', 'Chemical', 'MESH:C113580', (153, 158))	('CamKII', 'Gene', '818', (35, 41))	('VPC23019', 'Chemical', 'MESH:C000611541', (133, 141))	('VPC23019', 'Var', (133, 141))	('CamKII', 'Gene', (35, 41))	('CamKII', 'Gene', '818', (8, 14))	('CamKII', 'Gene', (8, 14))
118586	21864647	Blots were probed with anti-phospho-ERK1/2 (sc-7383, Santa Cruz), ERK2 (sc-154, Santa Cruz), StAR (sc-25806, Santa Cruz), phospho-Ser563-HSL (4139, Cell Signaling), HSL (sc-25843, Santa Cruz), phospho- Thr286-CamKII (06-881, Millipore), CamKII (04-1079, Millipore), or GAPDH (sc-25778, Santa Cruz).	('StAR', 'Gene', '6770', (93, 97))	('HSL', 'Gene', (137, 140))	('CamKII', 'Gene', '818', (209, 215))	('sc-25778', 'Var', (276, 284))	('ERK2', 'Gene', '5594', (66, 70))	('HSL', 'Gene', (165, 168))	('CamKII', 'Gene', (209, 215))	('CamKII', 'Gene', '818', (237, 243))	('GAPDH', 'Gene', '2597', (269, 274))	('GAPDH', 'Gene', (269, 274))	('HSL', 'Gene', '3991', (137, 140))	('ERK2', 'Gene', (66, 70))	('CamKII', 'Gene', (237, 243))	('StAR', 'Gene', (93, 97))	('HSL', 'Gene', '3991', (165, 168))	('Ser563', 'Chemical', '-', (130, 136))
118589	21864647	As previously discussed, we have demonstrated that ACTH and Bt2cAMP rapidly stimulate sphingolipid metabolism and S1P secretion from H295R cells.	('H295R', 'CellLine', 'CVCL:0458', (133, 138))	('sphingolipid metabolism', 'MPA', (86, 109))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (60, 67))	('sphingolipid', 'Chemical', 'MESH:D013107', (86, 98))	('ACTH', 'Gene', '5443', (51, 55))	('ACTH', 'Gene', (51, 55))	('stimulate', 'PosReg', (76, 85))	('S1P secretion', 'MPA', (114, 127))	('Bt2cAMP', 'Var', (60, 67))
118590	21864647	Additionally, S1P induces CYP17 transcription.	('S1P', 'Var', (14, 17))	('induces', 'Reg', (18, 25))	('CYP17', 'Gene', (26, 31))	('CYP17', 'Gene', '1586', (26, 31))
118593	21864647	1A, S1P maximally increased cortisol production by 2.5-fold at the 12-h time point.	('increased', 'PosReg', (18, 27))	('increased cortisol', 'Phenotype', 'HP:0003118', (18, 36))	('cortisol production', 'MPA', (28, 47))	('cortisol', 'Chemical', 'MESH:D006854', (28, 36))	('S1P', 'Var', (4, 7))
118594	21864647	While S1P resulted in a significant increase in cortisol production at the 48 h time point (Fig.	('increase', 'PosReg', (36, 44))	('increase in cortisol', 'Phenotype', 'HP:0003118', (36, 56))	('cortisol', 'Chemical', 'MESH:D006854', (48, 56))	('cortisol production at the 48 h time point', 'MPA', (48, 90))	('S1P', 'Var', (6, 9))
118596	21864647	Bt2cAMP treatment robustly stimulated the secretion of both cortisol and DHEA at all time points assayed, with a 7-fold increase in cortisol production and a 6-fold increase in DHEA biosynthesis at the 24 h time point.	('increase', 'PosReg', (165, 173))	('DHEA biosynthesis', 'MPA', (177, 194))	('cortisol', 'Chemical', 'MESH:D006854', (60, 68))	('Bt2cAMP', 'Var', (0, 7))	('DHEA', 'Chemical', 'MESH:D003687', (73, 77))	('DHEA', 'Chemical', 'MESH:D003687', (177, 181))	('cortisol production', 'MPA', (132, 151))	('secretion', 'MPA', (42, 51))	('increase', 'PosReg', (120, 128))	('stimulated', 'PosReg', (27, 37))	('increase in cortisol', 'Phenotype', 'HP:0003118', (120, 140))	('cortisol', 'Chemical', 'MESH:D006854', (132, 140))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (0, 7))
118597	21864647	To characterize the mechanism by which S1P acutely increases cortisol secretion, we determined the effect of S1P on the mRNA expression of multiple genes involved in the acute steroidogenic response.	('increases cortisol', 'Phenotype', 'HP:0003118', (51, 69))	('cortisol', 'Chemical', 'MESH:D006854', (61, 69))	('cortisol secretion', 'MPA', (61, 79))	('increases', 'PosReg', (51, 60))	('S1P', 'Var', (39, 42))
118600	21864647	2A, S1P and Bt2cAMP induced StAR mRNA expression by 2.0- and 1.8-fold after 1 h treatment, respectively.	('Bt2cAMP', 'Chemical', 'MESH:D003994', (12, 19))	('StAR', 'Gene', (28, 32))	('Bt2cAMP', 'Var', (12, 19))	('induced', 'Reg', (20, 27))	('StAR', 'Gene', '6770', (28, 32))	('S1P', 'Var', (4, 7))
118601	21864647	S1P further increased StAR expression at the 2-h time point by 5.0-fold, as compared to the 14-fold induction in StAR mRNA expression elicited by Bt2cAMP (Fig.	('Bt2cAMP', 'Chemical', 'MESH:D003994', (146, 153))	('StAR', 'Gene', '6770', (113, 117))	('increased', 'PosReg', (12, 21))	('StAR', 'Gene', '6770', (22, 26))	('S1P', 'Var', (0, 3))	('StAR', 'Gene', (113, 117))	('StAR', 'Gene', (22, 26))
118610	21864647	The mRNA expression of HSL was not affected by S1P; though Bt2cAMP significantly increased the expression of all four genes.	('expression', 'MPA', (95, 105))	('Bt2cAMP', 'Var', (59, 66))	('HSL', 'Gene', '3991', (23, 26))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (59, 66))	('increased', 'PosReg', (81, 90))	('HSL', 'Gene', (23, 26))
118616	21864647	VPC23019 abolished S1P-mediated StAR gene expression (Fig.	('StAR', 'Gene', '6770', (32, 36))	('abolished', 'NegReg', (9, 18))	('StAR', 'Gene', (32, 36))	('VPC23019', 'Chemical', 'MESH:C000611541', (0, 8))	('VPC23019', 'Var', (0, 8))
118617	21864647	Taken together, these data suggest that S1P acutely activates StAR transcription through activation of Galphai-protein coupled receptors S1PR1 and/or S1PR3.	('S1PR1', 'Gene', (137, 142))	('S1PR3', 'Gene', '1903', (150, 155))	('S1PR3', 'Gene', (150, 155))	('activates', 'PosReg', (52, 61))	('StAR', 'Gene', (62, 66))	('S1P', 'Var', (40, 43))	('activation', 'PosReg', (89, 99))	('S1PR1', 'Gene', '1901', (137, 142))	('StAR', 'Gene', '6770', (62, 66))	('Galphai-protein coupled receptors', 'Protein', (103, 136))
118619	21864647	However, VPC23019 significantly reduced ACTH-dependent StAR mRNA levels by 34% (Fig 4B).	('ACTH', 'Gene', (40, 44))	('ACTH', 'Gene', '5443', (40, 44))	('StAR', 'Gene', (55, 59))	('reduced', 'NegReg', (32, 39))	('VPC23019', 'Chemical', 'MESH:C000611541', (9, 17))	('VPC23019', 'Var', (9, 17))	('StAR', 'Gene', '6770', (55, 59))
118623	21864647	However, unexpectedly ACTH-stimulated StAR transcription was suppressed in the presence of S1P (Fig.	('suppressed', 'NegReg', (61, 71))	('StAR', 'Gene', (38, 42))	('ACTH', 'Gene', (22, 26))	('S1P', 'Var', (91, 94))	('ACTH', 'Gene', '5443', (22, 26))	('StAR', 'Gene', '6770', (38, 42))
118625	21864647	The inhibitory effect of PTX and VPC23019 on S1P-mediated StAR mRNA expression suggested that the stimulatory effect of S1P on gene expression occur through the interaction of S1P with S1PR1/3.	('S1PR1', 'Gene', (185, 190))	('interaction', 'Interaction', (161, 172))	('StAR', 'Gene', (58, 62))	('VPC23019', 'Chemical', 'MESH:C000611541', (33, 41))	('VPC23019', 'Var', (33, 41))	('S1PR1', 'Gene', '1901', (185, 190))	('StAR', 'Gene', '6770', (58, 62))
118630	21864647	4B, S1P significantly increased intracellular IP3 by 2.5- and 4.8-fold after 5 and 15 min, respectively, compared to untreated controls.	('increased intracellular IP3', 'Phenotype', 'HP:0003575', (22, 49))	('IP3', 'Chemical', 'MESH:D015544', (46, 49))	('increased', 'PosReg', (22, 31))	('S1P', 'Var', (4, 7))	('intracellular IP3', 'MPA', (32, 49))
118632	21864647	Notably, Bt2cAMP had no significant effect on IP3 release (Fig.	('Bt2cAMP', 'Chemical', 'MESH:D003994', (9, 16))	('IP3 release', 'MPA', (46, 57))	('Bt2cAMP', 'Var', (9, 16))	('IP3', 'Chemical', 'MESH:D015544', (46, 49))
118633	21864647	4B), suggesting that the mechanism by which S1P induces StAR expression exhibits distinct elements when compared to Bt2cAMP.	('S1P', 'Var', (44, 47))	('induces', 'Reg', (48, 55))	('StAR', 'Gene', (56, 60))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (116, 123))	('StAR', 'Gene', '6770', (56, 60))
118635	21864647	Bt2cAMP also stimulated an increase in cytosolic Ca2+, however, the magnitude of the response was lower than the increase elicited by S1P.	('Bt2cAMP', 'Var', (0, 7))	('Ca2+', 'Chemical', 'MESH:D000069285', (49, 53))	('cytosolic Ca2+', 'MPA', (39, 53))	('increase', 'PosReg', (27, 35))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (0, 7))
118655	21864647	We report herein that S1P induces the transcription of multiple acute steroidogenic genes, stimulates the phosphorylation of HSL at Ser563, and increases cortisol production.	('HSL', 'Gene', '3991', (125, 128))	('increases', 'PosReg', (144, 153))	('stimulates', 'PosReg', (91, 101))	('transcription', 'MPA', (38, 51))	('phosphorylation', 'MPA', (106, 121))	('S1P', 'Var', (22, 25))	('cortisol', 'Chemical', 'MESH:D006854', (154, 162))	('Ser563', 'Chemical', '-', (132, 138))	('increases cortisol', 'Phenotype', 'HP:0003118', (144, 162))	('HSL', 'Gene', (125, 128))	('acute steroidogenic genes', 'Gene', (64, 89))	('induces', 'PosReg', (26, 33))	('cortisol production', 'MPA', (154, 173))
118658	21864647	S1P regulates aldosterone secretion in zona glomerulosa adrenocortical cells and stimulates cortisol secretion in zona fasciculata bovine adrenal cells.	('cortisol secretion', 'MPA', (92, 110))	('zona glomerulosa adrenocortical', 'Disease', (39, 70))	('zona fasciculata', 'Disease', (114, 130))	('zona fasciculata', 'Disease', 'MESH:D006562', (114, 130))	('cortisol', 'Chemical', 'MESH:D006854', (92, 100))	('stimulates', 'PosReg', (81, 91))	('zona glomerulosa adrenocortical', 'Disease', 'MESH:D006562', (39, 70))	('bovine', 'Species', '9913', (131, 137))	('regulates', 'Reg', (4, 13))	('aldosterone secretion', 'MPA', (14, 35))	('S1P', 'Var', (0, 3))
118660	21864647	Although the effect of S1P and Bt2cAMP were similar at earlier time points, the magnitude of the response elicited by Bt2cAMP was significantly greater at later time points (Fig.	('greater', 'PosReg', (144, 151))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (31, 38))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (118, 125))	('Bt2cAMP', 'Var', (118, 125))
118661	21864647	Notably, S1P only increased DHEA secretion transiently at the 6 and 12 h time points (Fig.	('DHEA', 'Chemical', 'MESH:D003687', (28, 32))	('increased', 'PosReg', (18, 27))	('DHEA secretion', 'MPA', (28, 42))	('S1P', 'Var', (9, 12))
118662	21864647	Because the biosynthesis of cortisol requires the movement of intermediate metabolites between the ER and mitochondria and we have previously shown that ACTH/cAMP-mediated mitochondrial movement plays a pivotal role in glucocorticoid biosynthesis, it is tempting to speculate that S1P is stimulating cortisol production by facilitating substrate delivery to mitochondria.	('facilitating', 'PosReg', (323, 335))	('ACTH', 'Gene', (153, 157))	('stimulating', 'PosReg', (288, 299))	('substrate delivery to mitochondria', 'MPA', (336, 370))	('stimulating cortisol production', 'Phenotype', 'HP:0003118', (288, 319))	('ACTH', 'Gene', '5443', (153, 157))	('cortisol production', 'MPA', (300, 319))	('cAMP', 'Chemical', 'MESH:D000242', (158, 162))	('cortisol', 'Chemical', 'MESH:D006854', (28, 36))	('cortisol', 'Chemical', 'MESH:D006854', (300, 308))	('S1P', 'Var', (281, 284))
118664	21864647	Our data show that S1P rapidly increases the transcription of TSPO, SR-BI, LDLR, and StAR (Fig.	('StAR', 'Gene', (85, 89))	('LDLR', 'Gene', (75, 79))	('LDLR', 'Gene', '3949', (75, 79))	('transcription', 'MPA', (45, 58))	('increases', 'PosReg', (31, 40))	('SR-BI', 'Gene', (68, 73))	('S1P', 'Var', (19, 22))	('TSPO', 'Gene', '706', (62, 66))	('StAR', 'Gene', '6770', (85, 89))	('SR-BI', 'Gene', '949', (68, 73))	('TSPO', 'Gene', (62, 66))
118666	21864647	2B), phosphorylation of HSL at Ser563 was acutely stimulated S1P (Fig.	('phosphorylation', 'MPA', (5, 20))	('Ser563', 'Chemical', '-', (31, 37))	('HSL', 'Gene', (24, 27))	('stimulated', 'PosReg', (50, 60))	('Ser563', 'Var', (31, 37))	('HSL', 'Gene', '3991', (24, 27))
118668	21864647	However, the phosphorylation of HSL at Ser563 by PKA triggers HSL translocation to the surface of lipids droplets where it hydrolyzes cholesteryl esters.	('Ser563', 'Var', (39, 45))	('HSL', 'Gene', (62, 65))	('HSL', 'Gene', '3991', (32, 35))	('triggers', 'Reg', (53, 61))	('phosphorylation', 'MPA', (13, 28))	('cholesteryl esters', 'Chemical', 'MESH:D002788', (134, 152))	('HSL', 'Gene', '3991', (62, 65))	('Ser563', 'Chemical', '-', (39, 45))	('hydrolyzes cholesteryl esters', 'MPA', (123, 152))	('HSL', 'Gene', (32, 35))	('lipids', 'Chemical', 'MESH:D008055', (98, 104))
118672	21864647	In this manner, S1P has been shown to activate PLC, PI3K/Akt, and MAPK signaling as well as Ca2+ mobilization.	('MAPK signaling', 'Pathway', (66, 80))	('PI3', 'Gene', (52, 55))	('PI3', 'Gene', '5266', (52, 55))	('S1P', 'Var', (16, 19))	('activate', 'PosReg', (38, 46))	('PLC', 'Pathway', (47, 50))	('Ca2+', 'Chemical', 'MESH:D000069285', (92, 96))	('Ca2+ mobilization', 'MPA', (92, 109))
118676	21864647	Further, S1P and Bt2cAMP did not have an additive effect on StAR mRNA expression (Fig.	('Bt2cAMP', 'Var', (17, 24))	('StAR', 'Gene', '6770', (60, 64))	('StAR', 'Gene', (60, 64))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (17, 24))
118677	21864647	Conversely, S1P abrogated ACTH-stimulated StAR transcription (Fig.	('S1P', 'Var', (12, 15))	('ACTH', 'Gene', (26, 30))	('StAR', 'Gene', (42, 46))	('ACTH', 'Gene', '5443', (26, 30))	('abrogated', 'NegReg', (16, 25))	('StAR', 'Gene', '6770', (42, 46))
118683	21864647	It should be noted that S1P has been shown to increase cytosolic Ca2+ by stimulating release from intracellular stores and by activating Ca2+ influx.	('increase', 'PosReg', (46, 54))	('cytosolic Ca2+', 'MPA', (55, 69))	('Ca2+', 'Chemical', 'MESH:D000069285', (65, 69))	('stimulating', 'Reg', (73, 84))	('release from intracellular stores', 'MPA', (85, 118))	('Ca2+ influx', 'MPA', (137, 148))	('Ca2+', 'Chemical', 'MESH:D000069285', (137, 141))	('S1P', 'Var', (24, 27))	('activating', 'PosReg', (126, 136))
118684	21864647	Although our studies do not distinguish between these two sources, the increase in IP3 levels elicited by S1P (Fig.	('IP3', 'Chemical', 'MESH:D015544', (83, 86))	('IP3 levels', 'MPA', (83, 93))	('S1P', 'Var', (106, 109))	('increase', 'PosReg', (71, 79))
118686	21864647	Notably, even though Bt2cAMP also elevated cytosolic Ca2+ levels (Fig.	('Bt2cAMP', 'Var', (21, 28))	('cytosolic Ca2+ levels', 'MPA', (43, 64))	('elevated', 'PosReg', (34, 42))	('Ca2+', 'Chemical', 'MESH:D000069285', (53, 57))	('Bt2cAMP', 'Chemical', 'MESH:D003994', (21, 28))
118688	21864647	4B), which supports the notion that the molecular mechanism of S1P-mediated glucocorticoid production displays unique components when compared to ACTH/cAMP signaling.	('glucocorticoid production', 'MPA', (76, 101))	('ACTH', 'Gene', '5443', (146, 150))	('cAMP', 'Chemical', 'MESH:D000242', (151, 155))	('S1P-mediated', 'Var', (63, 75))	('ACTH', 'Gene', (146, 150))
118691	21864647	Consistent with previous reports on the crosstalk between CamK and the MAPK/ERK pathway and the activation of MAPK signaling by S1P, we show that S1P rapidly activated ERK1/2 (Fig.	('CamK', 'Gene', '818', (58, 62))	('CamK', 'Gene', (58, 62))	('ERK', 'Gene', (76, 79))	('S1P', 'Var', (146, 149))	('activated', 'PosReg', (158, 167))	('ERK', 'Gene', '5594', (168, 171))	('ERK', 'Gene', (168, 171))	('ERK', 'Gene', '5594', (76, 79))
118706	21864647	Importantly, we show that S1P induces the phosphorylation of HSL at Ser563, providing evidence that S1P regulates steroidogenesis by acting via multiple.	('HSL', 'Gene', (61, 64))	('steroidogenesis', 'MPA', (114, 129))	('Ser563', 'Chemical', '-', (68, 74))	('phosphorylation', 'MPA', (42, 57))	('steroidogenesis', 'Chemical', '-', (114, 129))	('HSL', 'Gene', '3991', (61, 64))	('S1P', 'Var', (26, 29))	('regulates', 'Reg', (104, 113))	('induces', 'Reg', (30, 37))
118709	21864647	S1P induces StAR, TSPO, LDLR, and SR-BI expression and cortisol secretion.	('SR-BI', 'Gene', '949', (34, 39))	('induces', 'PosReg', (4, 11))	('cortisol', 'CPA', (55, 63))	('StAR', 'Gene', '6770', (12, 16))	('LDLR', 'Gene', (24, 28))	('LDLR', 'Gene', '3949', (24, 28))	('TSPO', 'Gene', '706', (18, 22))	('SR-BI', 'Gene', (34, 39))	('cortisol', 'Chemical', 'MESH:D006854', (55, 63))	('S1P', 'Var', (0, 3))	('StAR', 'Gene', (12, 16))	('TSPO', 'Gene', (18, 22))
118711	21864647	S1P rapidly stimulates the phosphorylation of hormone sensitive lipase (HSL) at Ser563.	('HSL', 'Gene', '3991', (72, 75))	('phosphorylation', 'MPA', (27, 42))	('Ser563', 'Chemical', '-', (80, 86))	('HSL', 'Gene', (72, 75))	('S1P', 'Var', (0, 3))	('stimulates', 'PosReg', (12, 22))
118713	21471143	Differential expression of microRNA-675, microRNA-139-3p and microRNA-335 in benign and malignant adrenocortical tumours For the clinical management of adrenocortical neoplasms it is crucial to correctly distinguish between benign and malignant tumours.	('microRNA-139-3p', 'Var', (41, 56))	('microRNA-675', 'Gene', (27, 39))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('malignant adrenocortical tumours', 'Disease', 'MESH:D000306', (88, 120))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('microRNA-335', 'Var', (61, 73))	('malignant tumours', 'Disease', 'MESH:D009369', (235, 252))	('malignant tumours', 'Disease', (235, 252))	('adrenocortical neoplasms', 'Disease', (152, 176))	('neoplasms', 'Phenotype', 'HP:0002664', (167, 176))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('malignant adrenocortical tumours', 'Disease', (88, 120))	('neoplasm', 'Phenotype', 'HP:0002664', (167, 175))	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (152, 176))
118759	21471143	Detection thresholds were set to 35 and the best fitting endogenous control (RNU48-4373383 and MammU6-4395470) was calculated with the Normfinder algorithm.	('RNU48', 'Gene', '26801', (77, 82))	('MammU6-4395470', 'Var', (95, 109))	('RNU48', 'Gene', (77, 82))
118838	20454499	Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene.	('familial somatotropinoma', 'Disease', 'MESH:D049912', (9, 33))	('non-pituitary tumorigenesis', 'Disease', (129, 156))	('familial somatotropinoma', 'Disease', (9, 33))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('aip', 'Gene', (117, 120))	('germline mutations', 'Var', (231, 249))	('Non-pituitary tumors', 'Disease', (157, 177))	('aryl hydrocarbon receptor-interacting protein', 'Gene', '9049', (257, 302))	('AIP', 'Gene', (304, 307))	('aryl hydrocarbon receptor-interacting protein', 'Gene', (257, 302))	('patients', 'Species', '9606', (212, 220))	('involvement', 'Reg', (102, 113))	('AIP', 'Gene', '9049', (304, 307))	('aip', 'Gene', '9049', (117, 120))	('-pituitary tumors', 'Phenotype', 'HP:0002893', (160, 177))	('Non-pituitary tumors', 'Disease', 'MESH:D010911', (157, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
118843	20454499	The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients.	('c.241C>T', 'Mutation', 'rs267606541', (37, 45))	('c.241C>T', 'Var', (37, 45))	('blocks', 'NegReg', (60, 66))	('patients', 'Species', '9606', (205, 213))	('phosphodiesterase 4A', 'Gene', '5141', (105, 125))	('AIP', 'Gene', (71, 74))	('PDE4A', 'Gene', (127, 132))	('AIP', 'Gene', '9049', (71, 74))	('interacting', 'Interaction', (88, 99))	('phosphodiesterase 4A', 'Gene', (105, 125))	('R81X', 'Mutation', 'rs267606541', (47, 51))	('PDE4A', 'Gene', '5141', (127, 132))
118849	20454499	The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.	('AIP', 'Gene', (15, 18))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (39, 59))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('tumors', 'Disease', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', (209, 214))	('non-pituitary tumors', 'Disease', 'MESH:D010911', (171, 191))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('inactivation', 'Var', (19, 31))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('non-pituitary tumors', 'Disease', (171, 191))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cAMP', 'Chemical', 'MESH:D000242', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (209, 215))	('-pituitary tumors', 'Phenotype', 'HP:0002893', (174, 191))	('AIP', 'Gene', '9049', (15, 18))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('adrenocortical tumor', 'Disease', (39, 59))	('tumor', 'Disease', (54, 59))
118852	20454499	Germline mutations and somatic inactivation of the aryl hydrocarbon receptor- interacting protein (AIP) gene have been recently identified in patients with PAP.	('Germline mutations', 'Var', (0, 18))	('aryl hydrocarbon receptor', 'Gene', '196', (51, 76))	('AIP', 'Gene', '9049', (99, 102))	('aryl hydrocarbon receptor', 'Gene', (51, 76))	('identified', 'Reg', (128, 138))	('AIP', 'Gene', (99, 102))	('patients', 'Species', '9606', (142, 150))
118854	20454499	GH-, GH/PRL- and PRL-secreting pituitary adenomas are the most common clinical features of AIP mutation carriers, although ACTH-secreting and non-functioning pituitary adenomas have also been reported.	('pituitary adenomas', 'Phenotype', 'HP:0002893', (158, 176))	('pituitary adenomas', 'Disease', (158, 176))	('GH', 'Gene', '2688', (5, 7))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (31, 49))	('AIP', 'Gene', (91, 94))	('non-functioning pituitary adenomas', 'Phenotype', 'HP:0011761', (142, 176))	('AIP', 'Gene', '9049', (91, 94))	('pituitary adenomas', 'Disease', (31, 49))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (158, 175))	('PRL-secreting pituitary adenomas', 'Phenotype', 'HP:0008291', (17, 49))	('pituitary adenomas', 'Disease', 'MESH:D010911', (158, 176))	('GH', 'Gene', '2688', (0, 2))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (31, 48))	('pituitary adenomas', 'Disease', 'MESH:D010911', (31, 49))	('mutation', 'Var', (95, 103))
118855	20454499	AIP mutations account for approximately 15% of families with FIPA and 50% of IFS families.	('FIPA', 'Disease', (61, 65))	('AIP', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('AIP', 'Gene', '9049', (0, 3))
118856	20454499	While AIP mutations appear to be very rare in cases with sporadic pituitary disease, they are more frequently found in children and adolescents with GH-secreting tumors, even in the absence of family history.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('found', 'Reg', (110, 115))	('GH-secreting tumors', 'Disease', (149, 168))	('children', 'Species', '9606', (119, 127))	('AIP', 'Gene', '9049', (6, 9))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('sporadic pituitary disease', 'Disease', 'MESH:D010900', (57, 83))	('mutations', 'Var', (10, 19))	('AIP', 'Gene', (6, 9))	('GH-secreting tumors', 'Disease', 'MESH:D049912', (149, 168))	('sporadic pituitary disease', 'Disease', (57, 83))	('pituitary disease', 'Phenotype', 'HP:0011747', (66, 83))
118857	20454499	Although no systematic clinical surveys of non-pituitary neoplasia have been reported, concomitant non-pituitary tumors, including thyroid, adrenal and MEN1-related tumors were reported in a subset of AIP mutation-positive PAP and FIPA families and Prof. Albert Beckers, FIPA Meeting, Liege 2009 (unpublished data).	('tumors', 'Disease', (113, 119))	('MEN1', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mutation-positive', 'Var', (205, 222))	('AIP', 'Gene', '9049', (201, 204))	('non-pituitary neoplasia', 'Disease', (43, 66))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('non-pituitary tumors', 'Disease', 'MESH:D010911', (99, 119))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('neoplasia', 'Phenotype', 'HP:0002664', (57, 66))	('pituitary neoplasia', 'Phenotype', 'HP:0040277', (47, 66))	('non-pituitary tumors', 'Disease', (99, 119))	('AIP', 'Gene', (201, 204))	('tumors', 'Disease', (165, 171))	('non-pituitary neoplasia', 'Disease', 'MESH:D009369', (43, 66))	('-pituitary tumors', 'Phenotype', 'HP:0002893', (102, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('thyroid', 'Disease', (131, 138))	('MEN1', 'Gene', '4221', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
118860	20454499	Thus, one may hypothesize that mutations in AIP may also predispose patients to a broader spectrum of endocrine tumors.	('mutations', 'Var', (31, 40))	('AIP', 'Gene', '9049', (44, 47))	('patients', 'Species', '9606', (68, 76))	('endocrine tumors', 'Disease', 'MESH:D004701', (102, 118))	('AIP', 'Gene', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('predispose', 'Reg', (57, 67))	('endocrine tumors', 'Disease', (102, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
118891	20454499	Furthermore, the index patient did not have a germline or somatic R337H TP53 mutation, which is commonly identified in children but less frequently identified in adult patients with adrenocortical neoplasia in southern Brazil.	('adrenocortical neoplasia', 'Disease', (182, 206))	('TP53', 'Gene', '7157', (72, 76))	('R337H', 'Mutation', 'rs121912664', (66, 71))	('R337H', 'Var', (66, 71))	('patient', 'Species', '9606', (168, 175))	('TP53', 'Gene', (72, 76))	('children', 'Species', '9606', (119, 127))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (182, 206))	('patients', 'Species', '9606', (168, 176))	('neoplasia', 'Phenotype', 'HP:0002664', (197, 206))	('patient', 'Species', '9606', (23, 30))
118897	20454499	We performed PCR amplification, automated sequencing and haplotyping analysis using the D11S1258-11q13 microsatellite marker located close (67,069,747-67,069,958 bp, Ensembl) to the AIP gene 11q13.3 locus (67,007,097-67,015,150 bp, Ensembl).	('AIP', 'Gene', '9049', (182, 185))	('AIP', 'Gene', (182, 185))	('D11S1258-11q13', 'Var', (88, 102))
118898	20454499	Quantitative PCR (qPCR) was performed with an ABI Prism 7700 Sequence Detector using the TaqMan Gene Expression Assays (Hs00610222_m1 for AIP and 43263 for beta-actin) following the manufacturer's instructions (Applied Biosystems).	('beta-actin', 'Gene', '728378', (156, 166))	('AIP', 'Gene', (138, 141))	('beta-actin', 'Gene', (156, 166))	('Hs00610222_m1', 'Var', (120, 133))	('AIP', 'Gene', '9049', (138, 141))
118902	20454499	A heterozygous nucleotide change c.241C>T (R81X) in exon 2 of AIP was identified in genomic DNA samples from the two acromegaly patients (mother and daughter) (Figure 1).	('acromegaly', 'Phenotype', 'HP:0000845', (117, 127))	('acromegaly', 'Disease', (117, 127))	('c.241C>T (R81X', 'Var', (33, 47))	('acromegaly', 'Disease', 'MESH:D000172', (117, 127))	('R81X', 'Mutation', 'rs267606541', (43, 47))	('AIP', 'Gene', '9049', (62, 65))	('patients', 'Species', '9606', (128, 136))	('AIP', 'Gene', (62, 65))	('c.241C>T', 'Mutation', 'rs267606541', (33, 41))
118903	20454499	The R81X is a known functional mutation that codes for a truncated protein lacking the tetratricopeptide repeat (TPR) carboxy terminal domains, which are essential for AIP to bind to the aryl hydrocarbon receptor (AHR) and heat shock 90 (HSP90).	('shock', 'Phenotype', 'HP:0031273', (228, 233))	('AHR', 'Gene', '196', (214, 217))	('AHR', 'Gene', (214, 217))	('AIP', 'Gene', '9049', (168, 171))	('aryl hydrocarbon receptor', 'Gene', '196', (187, 212))	('AIP', 'Gene', (168, 171))	('R81X', 'Mutation', 'rs267606541', (4, 8))	('HSP90', 'Gene', '3320', (238, 243))	('aryl hydrocarbon receptor', 'Gene', (187, 212))	('bind', 'Interaction', (175, 179))	('HSP90', 'Gene', (238, 243))	('lacking', 'NegReg', (75, 82))	('R81X', 'Var', (4, 8))
118904	20454499	Previous in vitro studies of the R81X mutation have shown that it blocks the interaction of wild type AIP and phosphodiesterase type 4A (PDE4A), potentially disrupting the cAMP cascade.	('phosphodiesterase type 4A', 'Gene', (110, 135))	('PDE4A', 'Gene', '5141', (137, 142))	('phosphodiesterase type 4A', 'Gene', '5141', (110, 135))	('R81X', 'Mutation', 'rs267606541', (33, 37))	('disrupting', 'NegReg', (157, 167))	('PDE4A', 'Gene', (137, 142))	('R81X', 'Var', (33, 37))	('blocks', 'NegReg', (66, 72))	('cAMP', 'Chemical', 'MESH:D000242', (172, 176))	('AIP', 'Gene', '9049', (102, 105))	('cAMP cascade', 'Pathway', (172, 184))	('AIP', 'Gene', (102, 105))	('interaction', 'Interaction', (77, 88))
118911	20454499	Decreased AIP immunostaining was observed in the pituitary adenoma from the daughter harboring the R81X germline mutation, while intense cytoplasmic AIP positivity was observed in the normal pituitary glands obtained from autopsy samples and in a somatotropinoma from a patient with sporadic acromegaly without the AIP germline mutation (Figure 2C).	('AIP', 'Gene', (149, 152))	('AIP', 'Gene', (315, 318))	('R81X', 'Mutation', 'rs267606541', (99, 103))	('patient', 'Species', '9606', (270, 277))	('Decreased', 'NegReg', (0, 9))	('AIP', 'Gene', '9049', (10, 13))	('somatotropinoma', 'Disease', (247, 262))	('AIP positivity', 'Phenotype', 'HP:0030873', (149, 163))	('sporadic acromegaly', 'Disease', 'MESH:D000172', (283, 302))	('R81X', 'Var', (99, 103))	('AIP', 'Gene', (10, 13))	('AIP', 'Gene', '9049', (149, 152))	('pituitary adenoma', 'Disease', 'MESH:D010911', (49, 66))	('acromegaly', 'Phenotype', 'HP:0000845', (292, 302))	('somatotropinoma', 'Disease', 'MESH:D049912', (247, 262))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (49, 66))	('AIP', 'Gene', '9049', (315, 318))	('sporadic acromegaly', 'Disease', (283, 302))	('pituitary adenoma', 'Disease', (49, 66))
118915	20454499	Rare extra-pituitary tumors have been identified in PAP/ FIPA patients harboring AIP mutations.	('pituitary tumors', 'Disease', 'MESH:D010911', (11, 27))	('-pituitary tumors', 'Phenotype', 'HP:0002893', (10, 27))	('AIP', 'Gene', '9049', (81, 84))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('AIP', 'Gene', (81, 84))	('mutations', 'Var', (85, 94))	('pituitary tumors', 'Disease', (11, 27))	('patients', 'Species', '9606', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
118916	20454499	Mutant AIP cannot interact with cAMP-specific PDE4A and therefore is likely to disrupt the cAMP signaling pathway.	('cAMP signaling pathway', 'Pathway', (91, 113))	('cAMP', 'Chemical', 'MESH:D000242', (32, 36))	('PDE4A', 'Gene', '5141', (46, 51))	('disrupt', 'NegReg', (79, 86))	('cAMP', 'Chemical', 'MESH:D000242', (91, 95))	('PDE4A', 'Gene', (46, 51))	('AIP', 'Gene', (7, 10))	('Mutant', 'Var', (0, 6))	('AIP', 'Gene', '9049', (7, 10))
118920	20454499	We initially found that both the mother and daughter with acromegaly harbored a functional cAMP pathway-disrupting germline mutation in AIP (c.241C>T; R81X).	('acromegaly', 'Disease', (58, 68))	('acromegaly', 'Phenotype', 'HP:0000845', (58, 68))	('cAMP pathway-disrupting', 'Pathway', (91, 114))	('acromegaly', 'Disease', 'MESH:D000172', (58, 68))	('cAMP', 'Chemical', 'MESH:D000242', (91, 95))	('AIP', 'Gene', '9049', (136, 139))	('R81X', 'Mutation', 'rs267606541', (151, 155))	('c.241C>T', 'Mutation', 'rs267606541', (141, 149))	('AIP', 'Gene', (136, 139))	('c.241C>T; R81X', 'Var', (141, 155))	('R81X', 'Var', (151, 155))
118922	20454499	LOH was confirmed by analyzing the D11S1258 repeat marker located at the AIP locus (11q13.3).	('AIP', 'Gene', (73, 76))	('AIP', 'Gene', '9049', (73, 76))	('D11S1258 repeat', 'Var', (35, 50))
118928	20454499	Of note, a reported female patient harboring a germline nonsense AIP mutation, L210X, developed a broad panel of neoplasias involving the pituitary, adrenocortical and thyroid glands; this previous report suggests that the tumor susceptibility was similar to that observed in our index case.	('L210X', 'Var', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('neoplasias', 'Disease', 'MESH:D009369', (113, 123))	('neoplasias', 'Disease', (113, 123))	('developed', 'PosReg', (86, 95))	('adrenocortical', 'Disease', (149, 163))	('patient', 'Species', '9606', (27, 34))	('neoplasia', 'Phenotype', 'HP:0002664', (113, 122))	('adrenocortical', 'Disease', 'MESH:D018268', (149, 163))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('AIP', 'Gene', (65, 68))	('L210X', 'Mutation', 'p.L210X', (79, 84))	('AIP', 'Gene', '9049', (65, 68))
118929	20454499	The L201X-mutated patient presented with secondary amenorrhea at the age of 25 and was diagnosed with acromegaly at 27 years of age.	('acromegaly', 'Disease', (102, 112))	('L201X-mutated', 'Var', (4, 17))	('amenorrhea', 'Disease', (51, 61))	('acromegaly', 'Disease', 'MESH:D000172', (102, 112))	('amenorrhea', 'Phenotype', 'HP:0000141', (51, 61))	('amenorrhea', 'Disease', 'MESH:D000568', (51, 61))	('patient', 'Species', '9606', (18, 25))	('acromegaly', 'Phenotype', 'HP:0000845', (102, 112))	('secondary amenorrhea', 'Phenotype', 'HP:0000869', (41, 61))	('L201X', 'Mutation', 'p.L201X', (4, 9))
118933	20454499	Recently, patients with AIP mutations and thyroid disorders, including nodular goiters, follicular adenomas and follicular and papillary thyroid carcinomas, have been described (Prof. Beckers, FIPA Workshop 2009, Liege, unpublished data; Drs.	('nodular goiters', 'Disease', 'MESH:D006044', (71, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (127, 155))	('nodular goiters', 'Disease', (71, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (137, 155))	('Drs', 'Gene', (238, 241))	('goiters', 'Phenotype', 'HP:0000853', (79, 86))	('adenomas', 'Disease', 'MESH:D000236', (99, 107))	('adenomas', 'Disease', (99, 107))	('papillary thyroid carcinomas', 'Disease', (127, 155))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (127, 155))	('patients', 'Species', '9606', (10, 18))	('mutations', 'Var', (28, 37))	('AIP', 'Gene', '9049', (24, 27))	('thyroid disorders', 'Disease', (42, 59))	('thyroid disorders', 'Phenotype', 'HP:0000820', (42, 59))	('Drs', 'Gene', '8406', (238, 241))	('thyroid disorders', 'Disease', 'MESH:D013959', (42, 59))	('nodular goiters', 'Phenotype', 'HP:0005994', (71, 86))	('AIP', 'Gene', (24, 27))
118935	20454499	In these cases, it is not known whether the non-pituitary tumors occurring in the FIPA cases harboring an AIP mutation were related to the primary germline event.	('non-pituitary tumors', 'Disease', (44, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('non-pituitary tumors', 'Disease', 'MESH:D010911', (44, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mutation', 'Var', (110, 118))	('AIP', 'Gene', '9049', (106, 109))	('AIP', 'Gene', (106, 109))	('-pituitary tumors', 'Phenotype', 'HP:0002893', (47, 64))
118955	33665207	The results showed that ZIC2 also acted as a risk prognostic factor in bladder, breast and lung cancer Table 1.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('bladder', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('ZIC2', 'Var', (24, 28))	('breast and lung cancer', 'Disease', 'MESH:D001943', (80, 102))	('lung cancer', 'Disease', (91, 102))
118962	33665207	The results revealed that multiple tumor- and immune-related pathways were differentially enriched in ZIC2 high or low expression phenotype in a variety of tumors including complement and coagulation cascades, P53 signaling pathway, basal cell carcinoma, PPAR signaling pathway, tight junction, etc (Figure 10).	('carcinoma', 'Disease', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tight junction', 'Disease', (279, 293))	('P53', 'Gene', (210, 213))	('PPAR', 'Gene', '5465', (255, 259))	('carcinoma', 'Disease', 'MESH:D009369', (244, 253))	('ZIC2', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('P53', 'Gene', '7157', (210, 213))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (233, 253))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (233, 253))	('basal cell carcinoma', 'Disease', (233, 253))	('high', 'Var', (107, 111))	('PPAR', 'Gene', (255, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('enriched', 'Reg', (90, 98))	('low', 'NegReg', (115, 118))
119226	29670378	It has been estimated that ~10% of all tissue samples sequenced from all cancers display mutations in the CTNNB1 gene.	('cancers', 'Disease', (73, 80))	('CTNNB1', 'Gene', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('mutations', 'Var', (89, 98))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
119227	29670378	Alterations such as gain or loss of functional mutation at different sites of the gene, as well as overexpression, result toward enhanced and/or increased gene product that vitalizes cancer cells.	('enhanced', 'PosReg', (129, 137))	('cancer', 'Disease', (183, 189))	('mutation', 'Var', (47, 55))	('increased', 'PosReg', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('gene product', 'MPA', (155, 167))	('gain', 'Disease', (20, 24))	('gain', 'Disease', 'MESH:D015430', (20, 24))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('loss', 'NegReg', (28, 32))
119228	29670378	As one of the driver genes in ACC, CTNNB1 mutation is reported to be present in up to 70% of cases and to exert pro-tumorigenic function via activation of Wnt/beta-catenin pathway.	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('ACC', 'Phenotype', 'HP:0006744', (30, 33))	('CTNNB1', 'Gene', (35, 41))	('mutation', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('Wnt/beta-catenin pathway', 'Pathway', (155, 179))	('activation', 'PosReg', (141, 151))
119243	29670378	After antigen retrieval, the sections were stained with primary antibodies, PD-L1 (28-9; Abcam; dilution: 1:200), CD45 (EP322Y; Abcam; dilution: 1:250), and beta-catenin (E247; Abcam; dilution: 1:250), followed by antibody localization using the Dako Envision + HRP-labeled polymer (DAKO).	('PD-L1', 'Gene', '29126', (76, 81))	('CD45', 'Gene', (114, 118))	('E247;', 'Var', (171, 176))	('CD45', 'Gene', '5788', (114, 118))	('PD-L1', 'Gene', (76, 81))
119245	29670378	Positivity for PD-L1 and PD-1 was defined as positive staining in both tumor cells and tumor-infiltrating lymphocytes (TILs).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('PD-L1', 'Gene', (15, 20))	('PD-1', 'Gene', (25, 29))	('PD-1', 'Gene', '5133', (25, 29))	('TIL', 'Gene', (119, 122))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('PD-L1', 'Gene', '29126', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Positivity', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (71, 76))	('TIL', 'Gene', '7096', (119, 122))
119254	29670378	Overactive canonical WNT signaling featuring gain-of-function alteration in CTNNB1 has been identified as one of the driver genetic events in ACC.	('CTNNB1', 'Gene', (76, 82))	('ACC', 'Phenotype', 'HP:0006744', (142, 145))	('canonical WNT signaling', 'Pathway', (11, 34))	('gain', 'Disease', (45, 49))	('Overactive', 'PosReg', (0, 10))	('alteration', 'Var', (62, 72))	('gain', 'Disease', 'MESH:D015430', (45, 49))
119263	29670378	Using continuous IHC expression (Figure 3A-D), we validated that CTNNB1 expression was significantly associated with decreased PD-L1 expression (r = -0.752, P = 0.002) and was not associated with PD-1 expression (P = 0.302).	('expression', 'MPA', (133, 143))	('PD-1', 'Gene', (196, 200))	('PD-1', 'Gene', '5133', (196, 200))	('decreased', 'NegReg', (117, 126))	('decreased PD', 'Phenotype', 'HP:0032198', (117, 129))	('PD-L1', 'Gene', (127, 132))	('CTNNB1', 'Gene', (65, 71))	('expression', 'Var', (72, 82))	('PD-L1', 'Gene', '29126', (127, 132))
119276	29670378	Previous study has demonstrated that PD-L1 positivity in either tumor cell membrane or TIL is not significantly associated with higher stage at diagnosis, higher tumor grade, excessive hormone secretion, or OS in ACC.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (64, 69))	('PD-L1', 'Gene', (37, 42))	('tumor', 'Disease', (162, 167))	('TIL', 'Gene', '7096', (87, 90))	('excessive hormone secretion', 'MPA', (175, 202))	('PD-L1', 'Gene', '29126', (37, 42))	('ACC', 'Phenotype', 'HP:0006744', (213, 216))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('positivity', 'Var', (43, 53))	('TIL', 'Gene', (87, 90))	('associated', 'Reg', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
119315	27165744	beta-catenin gain-of-function mutations are evident in approximately 25% of both benign and malignant sporadic adrenocortical neoplasms.	('malignant sporadic adrenocortical neoplasms', 'Disease', 'MESH:D009369', (92, 135))	('beta-catenin', 'Gene', '1499', (0, 12))	('malignant sporadic adrenocortical neoplasms', 'Disease', (92, 135))	('gain-of-function', 'PosReg', (13, 29))	('neoplasms', 'Phenotype', 'HP:0002664', (126, 135))	('mutations', 'Var', (30, 39))	('beta-catenin', 'Gene', (0, 12))
119330	27165744	This approach yielded a total of 8,814 high-confidence mutations (6,664 nonsynonymous and 2,150 synonymous; 3,427 of these were found in two tumors with ultramutator phenotype.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('mutations', 'Var', (55, 64))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))
119334	27165744	Mutations of TP53 and CTNNB1 in ACC are well recognized.	('CTNNB1', 'Gene', (22, 28))	('TP53', 'Gene', (13, 17))	('CTNNB1', 'Gene', '1499', (22, 28))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))
119335	27165744	As expected, missense mutations in CTNNB1 were confined to exon 3 (Figure 1A).	('CTNNB1', 'Gene', (35, 41))	('CTNNB1', 'Gene', '1499', (35, 41))	('missense mutations', 'Var', (13, 31))
119336	27165744	Six (7%) tumors harbored inactivating mutations in MEN1, consistent with prior studies implicating MEN1 in ACC.	('MEN1', 'Gene', (51, 55))	('inactivating mutations', 'Var', (25, 47))	('MEN1', 'Gene', '4221', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('MEN1', 'Gene', (99, 103))	('MEN1', 'Gene', '4221', (99, 103))
119340	27165744	In our cohort, 7 (8%) cases harbored inactivating mutations in the protein kinase cAMP-dependent regulatory type I alpha gene (PRKAR1A) (Figure 1A).	('PRKAR1A', 'Gene', '5573', (127, 134))	('inactivating mutations', 'Var', (37, 59))	('PRKAR1A', 'Gene', (127, 134))	('protein kinase cAMP-dependent regulatory type I alpha', 'Gene', '5573', (67, 120))
119341	27165744	While inactivating germline PRKAR1A mutations cause Carney complex and benign primary pigmented nodular adrenocortical disease (PPNAD), malignant transformation has been reported in the adrenals of patients with this rare condition, and sporadic loss-of-function mutations in PRKAR1A have been found in adrenocortical adenomas and rare carcinomas.	('patients', 'Species', '9606', (198, 206))	('mutations', 'Var', (263, 272))	('cause', 'Reg', (46, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (336, 346))	('carcinomas', 'Disease', 'MESH:D002277', (336, 346))	('Carney complex', 'Disease', (52, 66))	('PRKAR1A', 'Gene', '5573', (28, 35))	('loss-of-function', 'NegReg', (246, 262))	('PRKAR1A', 'Gene', (276, 283))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (86, 126))	('inactivating', 'Var', (6, 18))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (86, 126))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (303, 326))	('pigmented nodular adrenocortical disease', 'Disease', (86, 126))	('carcinomas', 'Disease', (336, 346))	('mutations', 'Var', (36, 45))	('PRKAR1A', 'Gene', '5573', (276, 283))	('PRKAR1A', 'Gene', (28, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (303, 326))	('adrenocortical adenomas', 'Disease', (303, 326))
119342	27165744	Interestingly, DNA sequencing of sporadic adrenocortical adenomas recently revealed a recurrent activating L206R mutation in the catalytic subunit of the cAMP-dependent protein kinase A (PKA) (PRKACA).	('PRKACA', 'Gene', '5566', (193, 199))	('sporadic adrenocortical adenomas', 'Disease', (33, 65))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (42, 65))	('sporadic adrenocortical adenomas', 'Disease', 'MESH:D018246', (33, 65))	('activating', 'PosReg', (96, 106))	('L206R', 'Mutation', 'rs386352352', (107, 112))	('L206R', 'Var', (107, 112))	('PRKACA', 'Gene', (193, 199))
119343	27165744	This mutation results in constitutive PKA activity by disrupting the interaction between PRKACA and the regulatory subunits of PKA including PRKAR1A.	('PRKAR1A', 'Gene', '5573', (141, 148))	('PRKACA', 'Gene', (89, 95))	('activity', 'MPA', (42, 50))	('disrupting', 'NegReg', (54, 64))	('PRKACA', 'Gene', '5566', (89, 95))	('interaction', 'Interaction', (69, 80))	('PRKAR1A', 'Gene', (141, 148))	('results in', 'Reg', (14, 24))	('mutation', 'Var', (5, 13))
119344	27165744	While we found no PRKACA mutations in our cohort, we observed decreased PRKAR1A expression and increased MEK and BRAF protein expression (Figure S1F and S1G) in mutant cases, suggesting a potential role for inhibition of the RAF-MEK-ERK cascade in treatment of some ACCs.	('RAF', 'Gene', (114, 117))	('RAF', 'Gene', (225, 228))	('PRKAR1A', 'Gene', (72, 79))	('MEK', 'Gene', (229, 232))	('ERK', 'Gene', (233, 236))	('mutant', 'Var', (161, 167))	('PRKACA', 'Gene', '5566', (18, 24))	('expression', 'MPA', (80, 90))	('MEK', 'Gene', '5609', (105, 108))	('PRKAR1A', 'Gene', '5573', (72, 79))	('expression', 'MPA', (126, 136))	('decreased', 'NegReg', (62, 71))	('ACCs', 'Gene', (266, 270))	('ACCs', 'Gene', '84680', (266, 270))	('MEK', 'Gene', (105, 108))	('BRAF', 'Gene', '673', (113, 117))	('RAF', 'Gene', '22882', (114, 117))	('BRAF', 'Gene', (113, 117))	('RAF', 'Gene', '22882', (225, 228))	('PRKACA', 'Gene', (18, 24))	('ERK', 'Gene', '5594', (233, 236))	('MEK', 'Gene', '5609', (229, 232))	('increased', 'PosReg', (95, 104))
119345	27165744	We observed two frameshift mutations in ribosomal protein L22 (RPL22) and confirmed them by RNA sequencing (Figure 1A).	('RPL22', 'Gene', '6146', (63, 68))	('ribosomal protein L22', 'Gene', '6146', (40, 61))	('frameshift mutations', 'Var', (16, 36))	('RPL22', 'Gene', (63, 68))	('ribosomal protein L22', 'Gene', (40, 61))
119346	27165744	We detected a third in-frame deletion mutation in a sample with heterozygous loss of RPL22, and homozygous loss of RPL22 in three ACCs.	('RPL22', 'Gene', '6146', (115, 120))	('RPL22', 'Gene', (85, 90))	('loss', 'NegReg', (77, 81))	('RPL22', 'Gene', '6146', (85, 90))	('deletion mutation', 'Var', (29, 46))	('ACCs', 'Gene', '84680', (130, 134))	('RPL22', 'Gene', (115, 120))	('ACCs', 'Gene', (130, 134))
119347	27165744	These findings suggest a role for somatic alteration of RPL22 in 7% of ACC, which has previously been related to MDM2-mediated p53 ubiquitination and degradation.	('MDM2', 'Gene', '4193', (113, 117))	('RPL22', 'Gene', '6146', (56, 61))	('MDM2', 'Gene', (113, 117))	('ubiquitination', 'MPA', (131, 145))	('alteration', 'Var', (42, 52))	('ACC', 'Disease', (71, 74))	('degradation', 'MPA', (150, 161))	('RPL22', 'Gene', (56, 61))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
119349	27165744	However, we did identify private in-frame fusions involving known cancer genes (Figure 1B).	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('fusions', 'Var', (42, 49))	('cancer', 'Disease', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))
119350	27165744	A highly expressed EXOSC10-MTOR fusion retained the mTOR catalytic domain and resulted in elevated levels of total and phosphorylated mTOR protein in this tumor (Figure S1I).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('mTOR', 'Gene', (52, 56))	('elevated', 'PosReg', (90, 98))	('mTOR', 'Gene', '2475', (52, 56))	('MTOR', 'Gene', '2475', (27, 31))	('EXOSC10', 'Gene', '5394', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('mTOR', 'Gene', '2475', (134, 138))	('MTOR', 'Gene', (27, 31))	('mTOR', 'Gene', (134, 138))	('fusion', 'Var', (32, 38))	('EXOSC10', 'Gene', (19, 26))
119351	27165744	The fusion point of a MLL-ATP5L fusion fell within the MLL breakpoint cluster region associated with acute myeloid leukemia.	('MLL', 'Gene', '4297', (22, 25))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (101, 123))	('ATP5L', 'Gene', '10632', (26, 31))	('MLL', 'Gene', '4297', (55, 58))	('MLL', 'Gene', (55, 58))	('ATP5L', 'Gene', (26, 31))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (101, 123))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (107, 123))	('fusion', 'Var', (32, 38))	('MLL', 'Gene', (22, 25))	('acute myeloid leukemia', 'Disease', (101, 123))	('associated', 'Reg', (85, 95))
119353	27165744	We assessed somatic copy number alterations (SCNAs) and loss of heterozygosity in 89 tumors.	('tumors', 'Disease', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('loss', 'Var', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
119354	27165744	Using GISTIC2, we identified recurrent focal amplifications of TERT (5p15.33), TERF2 (16q22.1), CDK4 (12q14.1) and CCNE1 (19q12) and deletions of RB1 (13q14.2), CDKN2A (9p21.2) and ZNRF3 (22q12.1) (q <= 0.01; Figure 1C and Table S1).	('deletions', 'Var', (133, 142))	('ZNRF3', 'Gene', '84133', (181, 186))	('RB1', 'Gene', (146, 149))	('ZNRF3', 'Gene', (181, 186))	('TERT', 'Gene', (63, 67))	('CCNE1', 'Gene', '898', (115, 120))	('TERT', 'Gene', '7015', (63, 67))	('CDKN2A', 'Gene', (161, 167))	('TERF2', 'Gene', (79, 84))	('CDK4', 'Gene', (96, 100))	('RB1', 'Gene', '5925', (146, 149))	('TERF2', 'Gene', '7014', (79, 84))	('CCNE1', 'Gene', (115, 120))	('CDKN2A', 'Gene', '1029', (161, 167))	('CDK4', 'Gene', '1019', (96, 100))
119356	27165744	ZNRF3 homozygous deletions appeared in 16% (n=14) of tumors assayed; by including non-silent mutations, 19.3% of ACCs harbored alterations in this gene.	('ZNRF3', 'Gene', '84133', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('ZNRF3', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('alterations', 'Var', (127, 138))	('ACCs', 'Gene', (113, 117))	('ACCs', 'Gene', '84680', (113, 117))	('tumors', 'Disease', (53, 59))
119358	27165744	TERT promoter hotspot mutations have been recently discovered in human cancers.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
119361	27165744	Clustering of 89 tumors based on their arm-level alterations produced three groups with striking differences: chromosomal (n=54; 61%); noisy (n=27; 30%); and quiet (n=8; 9%) (Figure S2A).	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('alterations', 'Var', (49, 60))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('chromosomal', 'Var', (110, 121))
119370	27165744	Mutations in TP53 (n=7), MEN1 (n=3), RPL22 (n=2), and ZNRF3 (n=2) were predicted to have occurred prior to WGD.	('TP53', 'Gene', (13, 17))	('MEN1', 'Gene', '4221', (25, 29))	('RPL22', 'Gene', (37, 42))	('ZNRF3', 'Gene', '84133', (54, 59))	('ZNRF3', 'Gene', (54, 59))	('RPL22', 'Gene', '6146', (37, 42))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))	('MEN1', 'Gene', (25, 29))
119371	27165744	Only 4/9 CTNNB1 mutations were predicted to be pre-doubling, while three were post-doubling and the remaining two showed further reduced VAFs suggestive of subclonality.	('CTNNB1', 'Gene', '1499', (9, 15))	('mutations', 'Var', (16, 25))	('VAFs', 'MPA', (137, 141))	('CTNNB1', 'Gene', (9, 15))	('reduced', 'NegReg', (129, 136))
119372	27165744	PRKAR1A mutations split evenly as having occurred before WGD, after WGD or being subclonal.	('PRKAR1A', 'Gene', '5573', (0, 7))	('PRKAR1A', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))
119385	27165744	Similar to pediatric ACC and other cancers, mutations in ATRX and DAXX (n=7) were associated with longer telomeres (p value= 5.4x10-5, Fisher's exact test; Figure 3C).	('DAXX', 'Gene', '1616', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ATRX', 'Gene', '546', (57, 61))	('longer', 'PosReg', (98, 104))	('DAXX', 'Gene', (66, 70))	('mutations', 'Var', (44, 53))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Disease', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('ATRX', 'Gene', (57, 61))
119397	27165744	The MSH6 and MSH2 mutations support recent observations that ACC is a Lynch syndrome-associated cancer.	('MSH6', 'Gene', (4, 8))	('MSH2', 'Gene', (13, 17))	('MSH6', 'Gene', '2956', (4, 8))	('MSH2', 'Gene', '4436', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Lynch syndrome-associated cancer', 'Disease', 'MESH:D055847', (70, 102))	('ACC', 'Disease', (61, 64))	('Lynch syndrome-associated cancer', 'Disease', (70, 102))	('mutations', 'Var', (18, 27))
119401	27165744	Collectively the genes altered most frequently by somatic mutations, DNA copy number alterations and epigenetic silencing were TP53 (21%), ZNRF3 (19%), CDKN2A (15%), CTNNB1 (16%), TERT (14%) and PRKAR1A (11%).	('CDKN2A', 'Gene', (152, 158))	('ZNRF3', 'Gene', (139, 144))	('CDKN2A', 'Gene', '1029', (152, 158))	('CTNNB1', 'Gene', '1499', (166, 172))	('PRKAR1A', 'Gene', (195, 202))	('epigenetic silencing', 'Var', (101, 121))	('altered', 'Reg', (23, 30))	('TERT', 'Gene', (180, 184))	('ZNRF3', 'Gene', '84133', (139, 144))	('TP53', 'Gene', (127, 131))	('TERT', 'Gene', '7015', (180, 184))	('PRKAR1A', 'Gene', '5573', (195, 202))	('TP53', 'Gene', '7157', (127, 131))	('CTNNB1', 'Gene', (166, 172))
119402	27165744	The majority of gene alterations were either mutation or copy number change, except CDKN2A, which was targeted by both deletion and epigenetic silencing through promoter DNA methylation.	('CDKN2A', 'Gene', (84, 90))	('CDKN2A', 'Gene', '1029', (84, 90))	('deletion', 'Var', (119, 127))	('epigenetic silencing', 'Var', (132, 152))	('mutation', 'Var', (45, 53))	('copy number change', 'Var', (57, 75))	('alterations', 'Reg', (21, 32))
119403	27165744	Alterations of ZNRF3, CTNNB1, APC and MEN1 resulted in modification of the Wnt/beta-catenin pathway in 41% of cases (Figure 5B).	('ZNRF3', 'Gene', (15, 20))	('CTNNB1', 'Gene', (22, 28))	('MEN1', 'Gene', (38, 42))	('APC', 'Disease', 'MESH:D011125', (30, 33))	('APC', 'Disease', (30, 33))	('MEN1', 'Gene', '4221', (38, 42))	('Alterations', 'Var', (0, 11))	('beta-catenin', 'Gene', '1499', (79, 91))	('CTNNB1', 'Gene', '1499', (22, 28))	('modification', 'Reg', (55, 67))	('ZNRF3', 'Gene', '84133', (15, 20))	('beta-catenin', 'Gene', (79, 91))
119404	27165744	Somatic alterations in TP53, CDKN2A, RB1, CDK4 and CCNE1 emphasize the importance of the p53 apoptosis/Rb1 cell cycle pathway, and were altered in 44.9% of the cases (Figure 5B).	('CDKN2A', 'Gene', (29, 35))	('CDK4', 'Gene', '1019', (42, 46))	('Rb1', 'Gene', (103, 106))	('CDKN2A', 'Gene', '1029', (29, 35))	('alterations', 'Var', (8, 19))	('altered', 'Reg', (136, 143))	('Rb1', 'Gene', '5925', (103, 106))	('p53', 'Gene', (89, 92))	('CCNE1', 'Gene', '898', (51, 56))	('CCNE1', 'Gene', (51, 56))	('RB1', 'Gene', (37, 40))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('p53', 'Gene', '7157', (89, 92))	('RB1', 'Gene', '5925', (37, 40))	('CDK4', 'Gene', (42, 46))
119405	27165744	Finally, histone modification genes (MLL, MLL2, and MLL4) and chromatin remodeling genes (ATRX and DAXX) were collectively altered in 22% of cases, suggesting a role for epigenetic deregulation in ACC tumorigenesis (Figure 5C).	('MLL2', 'Gene', (42, 46))	('MLL', 'Gene', (42, 45))	('histone', 'MPA', (9, 16))	('MLL', 'Gene', '4297', (42, 45))	('MLL4', 'Gene', '9757', (52, 56))	('MLL4', 'Gene', (52, 56))	('tumor', 'Disease', (201, 206))	('DAXX', 'Gene', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('MLL2', 'Gene', '9757', (42, 46))	('DAXX', 'Gene', '1616', (99, 103))	('ATRX', 'Gene', (90, 94))	('altered', 'Reg', (123, 130))	('ATRX', 'Gene', '546', (90, 94))	('MLL', 'Gene', '4297', (37, 40))	('epigenetic deregulation', 'Var', (170, 193))	('MLL', 'Gene', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('MLL', 'Gene', (52, 55))	('MLL', 'Gene', '4297', (52, 55))
119408	27165744	Combining somatic mutations, copy number alterations, and epigenetic modification, we found at least one alteration of potential driver genes in 69% of tumors (Figure 5A).	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('epigenetic modification', 'Var', (58, 81))	('copy number alterations', 'Var', (29, 52))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
119414	27165744	Based on existing clinical trials and FDA-approved drugs for cancers, we found 51 potentially actionable alterations, including both mutations and copy number alterations, in 22 ACCs using precision heuristics for interpreting the actionable landscape (PHIAL), from cyclin-dependent kinases to DNA repair protein poly ADP-ribose polymerase (PARP) (Figure S5C and Table S3).	('PARP', 'Gene', '142', (341, 345))	('poly ADP-ribose polymerase', 'Gene', '142', (313, 339))	('ACCs', 'Gene', (178, 182))	('copy number alterations', 'Var', (147, 170))	('ACCs', 'Gene', '84680', (178, 182))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('alterations', 'Var', (105, 116))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (133, 142))	('poly ADP-ribose polymerase', 'Gene', (313, 339))	('PARP', 'Gene', (341, 345))
119422	27165744	Signature 5 resembled UV and APOBEC signatures featuring C>G, C>T, and C>T substitutions in the contexts of TC, CC and TC, respectively.	('C>T', 'Var', (62, 65))	('C>G', 'Var', (57, 60))	('TC', 'Chemical', 'MESH:D013667', (119, 121))	('TC', 'Chemical', 'MESH:D013667', (108, 110))	('C>T', 'Var', (71, 74))
119424	27165744	Signature 1 captured the majority of gastrointestinal cancers (stomach, esophageal, colorectal) but also four ACC with a relatively high mutation frequency, all of which harbored mutations in the DNA mismatch repair pathway (Figure 6B).	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('colorectal', 'Disease', (84, 94))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (37, 61))	('gastrointestinal cancers', 'Disease', (37, 61))	('esophageal', 'Disease', (72, 82))	('DNA mismatch repair pathway', 'Pathway', (196, 223))	('mutations', 'Var', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('colorectal', 'Disease', 'MESH:D015179', (84, 94))
119425	27165744	One case with a germline MSH6 mutation but relatively modest mutation density (0.51 mutations/Mb) also clustered with this signature.	('MSH6', 'Gene', '2956', (25, 29))	('mutation', 'Var', (30, 38))	('MSH6', 'Gene', (25, 29))
119432	27165744	TP53 mutations were present across the spectrum of ADS values (p value=0.56, Fisher's exact test), whereas Wnt-related mutations appeared to be enriched among tumors with higher ADS values (p value=0.0091, Fisher's exact test).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))
119441	27165744	The high frequency of PRKAR1A mutations expands the role of PKA signaling in ACC and is consistent with PRKACA somatic mutations being the founder lesion of benign adrenal tumor associated with endocrinopathies such as Cushing syndrome.	('PRKAR1A', 'Gene', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('endocrinopathies', 'Disease', 'MESH:C567425', (194, 210))	('PRKACA', 'Gene', (104, 110))	('Cushing syndrome', 'Disease', (219, 235))	('ACC', 'Disease', (77, 80))	('PRKAR1A', 'Gene', '5573', (22, 29))	('PRKACA', 'Gene', '5566', (104, 110))	('mutations', 'Var', (30, 39))	('adrenal tumor', 'Phenotype', 'HP:0100631', (164, 177))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (219, 235))	('benign adrenal tumor', 'Disease', (157, 177))	('benign adrenal tumor', 'Disease', 'MESH:D000310', (157, 177))	('endocrinopathies', 'Disease', (194, 210))	('Cushing syndrome', 'Disease', 'MESH:D003480', (219, 235))
119503	21429963	LC-MS/MS analysis of oxime derivatives of keto-steroids (aldosterone, dihydrotestosterone, 11OHA, 7alpha-DHEA, 16alpha-DHEA, 17alpha-hydroxypregnenolone, pregnenolone, and progesterone).	('aldosterone', 'Chemical', 'MESH:D000450', (57, 68))	('progesterone', 'Chemical', 'MESH:D011374', (172, 184))	('7alpha-DHEA', 'Var', (98, 109))	('dihydrotestosterone', 'MPA', (70, 89))	('7alpha-DHEA', 'Chemical', '-', (98, 109))	('dihydrotestosterone', 'Chemical', 'MESH:D013196', (70, 89))	('pregnenolone', 'Chemical', 'MESH:D011284', (154, 166))	('pregnenolone', 'Chemical', 'MESH:D011284', (140, 152))	('oxime', 'Chemical', 'MESH:D010091', (21, 26))	('keto-steroids', 'Chemical', 'MESH:D007664', (42, 55))	('16alpha-DHEA', 'Var', (111, 123))	('17alpha-hydroxypregnenolone', 'Chemical', 'MESH:D006907', (125, 152))	('11OHA', 'Chemical', '-', (91, 96))	('16alpha-DHEA', 'Chemical', '-', (111, 123))
119527	21429963	The relative increases of cortisol, corticosterone and 11OHA were approximately 2-fold lower with EIA compared to LC-MS/MS, but both analytical methods indicated significant increases in the production of all the three steroids after ACTH treatment.	('increases', 'PosReg', (174, 183))	('increases', 'PosReg', (13, 22))	('ACTH', 'Gene', '5443', (234, 238))	('cortisol', 'Chemical', 'MESH:D006854', (26, 34))	('EIA', 'Var', (98, 101))	('lower', 'NegReg', (87, 92))	('steroids', 'Chemical', 'MESH:D013256', (219, 227))	('11OHA', 'MPA', (55, 60))	('corticosterone', 'Chemical', 'MESH:D003345', (36, 50))	('11OHA', 'Chemical', '-', (55, 60))	('increases of cortisol', 'Phenotype', 'HP:0003118', (13, 34))	('ACTH', 'Gene', (234, 238))	('corticosterone', 'MPA', (36, 50))	('production', 'MPA', (191, 201))	('cortisol', 'MPA', (26, 34))
119533	21429963	The only experimental change was the use of forskolin instead of ACTH as an agonist for steroidogenesis, because the HAC15, HAC13 and H295R only have minor response to ACTH.	('forskolin', 'Chemical', 'MESH:D005576', (44, 53))	('H295R', 'CellLine', 'CVCL:0458', (134, 139))	('H295R', 'Var', (134, 139))	('ACTH', 'Gene', '5443', (168, 172))	('HAC13', 'Var', (124, 129))	('HAC15', 'CellLine', 'CVCL:S898', (117, 122))	('ACTH', 'Gene', (65, 69))	('steroid', 'Chemical', 'MESH:D013256', (88, 95))	('HAC15', 'Var', (117, 122))	('ACTH', 'Gene', '5443', (65, 69))	('ACTH', 'Gene', (168, 172))
119576	21429963	It should also be noted that our primary cultures of adrenal cells only produced low levels of DHEA, suggesting that the mixed cortical cells may exhibit more of a fasciculata phenotype, while H295R produces a variety of adrenal steroids, including mineralocorticoids, glucocorticoids, estrogens and androgens.	('H295R', 'CellLine', 'CVCL:0458', (193, 198))	('H295R', 'Var', (193, 198))	('fasciculata', 'Disease', 'None', (164, 175))	('fasciculata', 'Disease', (164, 175))	('DHEA', 'Chemical', 'MESH:D003687', (95, 99))	('steroids', 'Chemical', 'MESH:D013256', (229, 237))
119586	21742609	This expression is influenced by a multitude of tissue-specific factors, which may explain why it is so difficult to interpret (or reproduce) studies that are based on GR functional polymorphisms on different cohorts of patients or even different sets of laboratory animals.	('GR', 'Gene', '2908', (168, 170))	('rat', 'Species', '10116', (259, 262))	('polymorphisms', 'Var', (182, 195))	('influenced', 'Reg', (19, 29))	('patients', 'Species', '9606', (220, 228))
119605	21742609	Shortly after the discovery of the first mutations of the GR in humans with glucocorticoid resistance, we described the first patient with somatic inactivation of the GR in a large pituitary corticotroph adenoma that was associated with severe Nelson syndrome.	('adenoma', 'Disease', (204, 211))	('Nelson syndrome', 'Disease', (244, 259))	('glucocorticoid resistance', 'Phenotype', 'HP:0008163', (76, 101))	('inactivation', 'Var', (147, 159))	('patient', 'Species', '9606', (126, 133))	('humans', 'Species', '9606', (64, 70))	('pituitary corticotroph adenoma', 'Phenotype', 'HP:0008291', (181, 211))	('GR', 'Gene', '2908', (167, 169))	('Nelson syndrome', 'Disease', 'MESH:D009347', (244, 259))	('adenoma', 'Disease', 'MESH:D000236', (204, 211))	('associated', 'Reg', (221, 231))	('GR', 'Gene', '2908', (58, 60))	('corticotroph adenoma', 'Phenotype', 'HP:0008291', (191, 211))
119607	21742609	The important role of an intact HPA axis function and the normal expression of the GR in preventing corticotroph adenoma expansion (if not formation) is demonstrated by the cases of ACTH-producing tumors in patients with familial glucocorticoid deficiency, as well as the relatively frequent loss of heterozygosity, leading to hemizygosity and, thus, haploinsufficiency of the GR gene (NR3C1).	('loss', 'NegReg', (292, 296))	('rat', 'Species', '10116', (160, 163))	('adenoma', 'Disease', (113, 120))	('familial glucocorticoid deficiency', 'Disease', (221, 255))	('haploinsufficiency', 'Disease', 'MESH:D058495', (351, 369))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('hemizygosity', 'Var', (327, 339))	('ACTH', 'Gene', '5443', (182, 186))	('adenoma', 'Disease', 'MESH:D000236', (113, 120))	('haploinsufficiency', 'Disease', (351, 369))	('corticotroph adenoma', 'Phenotype', 'HP:0008291', (100, 120))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('familial glucocorticoid deficiency', 'Disease', 'MESH:C564577', (221, 255))	('tumors', 'Disease', (197, 203))	('GR', 'Gene', '2908', (377, 379))	('glucocorticoid deficiency', 'Phenotype', 'HP:0008163', (230, 255))	('GR', 'Gene', '2908', (83, 85))	('ACTH', 'Gene', (182, 186))	('NR3C1', 'Gene', (386, 391))	('NR3C1', 'Gene', '2908', (386, 391))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('patients', 'Species', '9606', (207, 215))
119608	21742609	Could polymorphisms of the GR gene (NR3C1) that confer partial inactivation in specific functions of the molecule (without causing generalized resistance), such as transcriptional repression of the pro-opiomelanocortin gene or protein-protein and DNA interactions, predispose to ACTH-producing tumors?	('pro-opiomelanocortin', 'Gene', '5443', (198, 218))	('NR3C1', 'Gene', '2908', (36, 41))	('pro-opiomelanocortin', 'Gene', (198, 218))	('GR', 'Gene', '2908', (27, 29))	('predispose', 'Reg', (265, 275))	('interactions', 'Interaction', (251, 263))	('inactivation', 'NegReg', (63, 75))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))	('tumors', 'Disease', 'MESH:D009369', (294, 300))	('protein-protein', 'Protein', (227, 242))	('polymorphisms', 'Var', (6, 19))	('ACTH', 'Gene', (279, 283))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('ACTH', 'Gene', '5443', (279, 283))	('tumors', 'Disease', (294, 300))	('transcriptional', 'MPA', (164, 179))	('NR3C1', 'Gene', (36, 41))
119615	21742609	Variable expression of this enzyme could modulate cortisol levels that are available for occupying the GR in corticotrophs; upregulation of 11betaHSD type 2 and consequently conversion of cortisol to inactive cortisone may, in at least some ACTH-producing tumors, lead to decreased GR responses and functional resistance without any direct defect of the GR.	('upregulation', 'PosReg', (124, 136))	('conversion', 'Var', (174, 184))	('GR', 'Gene', '2908', (354, 356))	('ACTH', 'Gene', '5443', (241, 245))	('cortisone', 'Chemical', 'MESH:D003348', (209, 218))	('cortisol', 'Chemical', 'MESH:D006854', (188, 196))	('decreased', 'NegReg', (272, 281))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('cortisol', 'Chemical', 'MESH:D006854', (50, 58))	('functional', 'MPA', (299, 309))	('tumors', 'Disease', 'MESH:D009369', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('ACTH', 'Gene', (241, 245))	('tumors', 'Disease', (256, 262))	('GR', 'Gene', '2908', (103, 105))	('GR', 'Gene', '2908', (282, 284))
119619	21742609	Therefore, loss of Brg1 or HDAC2 should produce resistance to the action of the GR in the pituitary corticotrophs; indeed, it has been shown that approximately 50% of GR-resistant corticotroph adenomas were deficient in nuclear expression of either protein.	('adenomas', 'Disease', 'MESH:D000236', (193, 201))	('Brg1', 'Gene', (19, 23))	('Brg1', 'Gene', '6597', (19, 23))	('adenomas', 'Disease', (193, 201))	('loss', 'Var', (11, 15))	('GR', 'Gene', '2908', (80, 82))	('pituitary corticotrophs', 'Phenotype', 'HP:0008291', (90, 113))	('GR', 'Gene', '2908', (167, 169))	('HDAC2', 'Gene', (27, 32))	('HDAC2', 'Gene', '3066', (27, 32))	('nuclear expression', 'MPA', (220, 238))	('corticotroph adenomas', 'Phenotype', 'HP:0008291', (180, 201))	('deficient', 'NegReg', (207, 216))	('corticotroph adenoma', 'Phenotype', 'HP:0008291', (180, 200))
119622	21742609	Recently, patients with familial pituitary tumors were found to harbor germline mutations in the AIP gene, which appears to act as a tumor suppressor gene because overexpression of the normal but not the mutated AIP reduces cell proliferation.	('familial pituitary tumors', 'Disease', 'MESH:D010911', (24, 49))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (43, 48))	('AIP', 'Gene', (212, 215))	('overexpression', 'PosReg', (163, 177))	('reduces', 'NegReg', (216, 223))	('rat', 'Species', '10116', (236, 239))	('mutated', 'Var', (204, 211))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cell proliferation', 'CPA', (224, 242))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('familial pituitary tumors', 'Disease', (24, 49))	('AIP', 'Gene', '9049', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (133, 138))	('patients', 'Species', '9606', (10, 18))	('AIP', 'Gene', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('AIP', 'Gene', '9049', (212, 215))
119623	21742609	The AIP molecule is highly polymorphic in the general population, and how these genetic polymorphisms affect GR function directly or through its interactions with SRC-1 or Hsp-90 remains unknown.	('polymorphisms', 'Var', (88, 101))	('Hsp-90', 'Gene', '3320', (172, 178))	('AIP', 'Gene', '9049', (4, 7))	('SRC-1', 'Gene', (163, 168))	('interactions', 'Interaction', (145, 157))	('GR', 'Gene', '2908', (109, 111))	('Hsp-90', 'Gene', (172, 178))	('AIP', 'Gene', (4, 7))	('affect', 'Reg', (102, 108))	('SRC-1', 'Gene', '6714', (163, 168))
119624	21742609	Although most mutant AIP-caused pituitary tumors are growth hormone- or prolactin-producing lesions, about 2% or more of the ACTH-producing tumors seem to be caused by germline AIP mutations.	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('AIP', 'Gene', '9049', (177, 180))	('ACTH', 'Gene', '5443', (125, 129))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('mutant', 'Var', (14, 20))	('tumors', 'Disease', (42, 48))	('AIP', 'Gene', (177, 180))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('pituitary tumors', 'Disease', 'MESH:D010911', (32, 48))	('AIP', 'Gene', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('caused', 'Reg', (158, 164))	('ACTH', 'Gene', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('AIP', 'Gene', '9049', (21, 24))	('pituitary tumors', 'Disease', (32, 48))
119638	21742609	In this latter group of patients, the response to dexamethasone has been attributed, at least in part, to the occurrence of somatic PRKAR1A mutations.	('patients', 'Species', '9606', (24, 32))	('dexamethasone', 'Chemical', 'MESH:D003907', (50, 63))	('PRKAR1A', 'Gene', (132, 139))	('mutations', 'Var', (140, 149))
119647	21742609	Because it was known that the GR can interact with the cAMP-dependent PKA through a protein-protein interaction, the paradoxical increase in cortisol secretion induced by dexamethasone in PPNAD could possibly be the consequence of a GR-mediated action of dexamethasone on PKA that was constitutively active because of the PRKAR1A mutations.	('PRKAR1A', 'Gene', (322, 329))	('mutations', 'Var', (330, 339))	('dexamethasone', 'Chemical', 'MESH:D003907', (171, 184))	('interaction', 'Interaction', (100, 111))	('cAMP', 'Chemical', 'MESH:D000242', (55, 59))	('increase', 'PosReg', (129, 137))	('dexamethasone', 'Chemical', 'MESH:D003907', (255, 268))	('GR', 'Gene', '2908', (30, 32))	('cortisol secretion', 'MPA', (141, 159))	('increase in cortisol', 'Phenotype', 'HP:0003118', (129, 149))	('protein-protein', 'Protein', (84, 99))	('GR', 'Gene', '2908', (233, 235))	('cortisol', 'Chemical', 'MESH:D006854', (141, 149))
119651	21742609	Interestingly, dexamethasone had no effect on cortisol production from normal human adrenocortical cells but stimulated the production of corticosteroids in the presence of RU-486.	('production of corticosteroids', 'MPA', (124, 153))	('human', 'Species', '9606', (78, 83))	('steroid', 'Chemical', 'MESH:D013256', (145, 152))	('stimulated', 'PosReg', (109, 119))	('adrenocortical', 'Disease', (84, 98))	('RU-486', 'Var', (173, 179))	('dexamethasone', 'Chemical', 'MESH:D003907', (15, 28))	('adrenocortical', 'Disease', 'MESH:D018268', (84, 98))	('RU-486', 'Chemical', 'MESH:D015735', (173, 179))	('cortisol', 'Chemical', 'MESH:D006854', (46, 54))
119655	21742609	The complex RU-486/receptor translocates to the nucleus, where it can actively recruit nuclear coregulator proteins such as TIF2 and nuclear receptor corepressor and thus regulate gene expression (Fig.	('recruit', 'PosReg', (79, 86))	('TIF2 and nuclear receptor corepressor', 'Gene', '10499', (124, 161))	('regulate', 'Reg', (171, 179))	('RU-486/receptor', 'Var', (12, 27))	('gene expression', 'MPA', (180, 195))	('RU-486', 'Chemical', 'MESH:D015735', (12, 18))
119664	21742609	In addition, incubation of both normal human and mouse adrenocortical cells with RU-486 unmasked a stimulatory effect of dexamethasone on release of cortisol and corticosterone that corresponds, therefore, to a GR-independent and likely nongenomic action, as recently observed in an ectopic dexamethasone-stimulated adrenocortical adenoma responsible for hypercortisolism.	('cortisol', 'Chemical', 'MESH:D006854', (360, 368))	('mouse', 'Species', '10090', (49, 54))	('hypercortisolism', 'Disease', 'MESH:D003480', (355, 371))	('release of cortisol', 'Phenotype', 'HP:0003118', (138, 157))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (316, 338))	('GR', 'Gene', '2908', (211, 213))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (316, 338))	('human', 'Species', '9606', (39, 44))	('release', 'MPA', (138, 145))	('RU-486', 'Var', (81, 87))	('dexamethasone', 'Chemical', 'MESH:D003907', (291, 304))	('adrenocortical adenoma', 'Disease', (316, 338))	('adrenocortical', 'Disease', 'MESH:D018268', (316, 330))	('adrenocortical', 'Disease', 'MESH:D018268', (55, 69))	('cortisol', 'Chemical', 'MESH:D006854', (149, 157))	('RU-486', 'Chemical', 'MESH:D015735', (81, 87))	('adrenocortical', 'Disease', (316, 330))	('hypercortisolism', 'Phenotype', 'HP:0003118', (355, 371))	('adrenocortical', 'Disease', (55, 69))	('dexamethasone', 'Chemical', 'MESH:D003907', (121, 134))	('corticosterone', 'Chemical', 'MESH:D003345', (162, 176))	('hypercortisolism', 'Disease', (355, 371))
119668	21742609	In a transgenic mouse model of PPNAD, no effect of dexamethasone was observed in vitro or in vivo; this finding suggests that inactivation of the PRKAR1A gene reduces the GR-dependent inhibitory action of dexamethasone on mouse cells.	('inactivation', 'Var', (126, 138))	('reduces', 'NegReg', (159, 166))	('mouse', 'Species', '10090', (16, 21))	('mouse', 'Species', '10090', (222, 227))	('dexamethasone', 'Chemical', 'MESH:D003907', (51, 64))	('GR', 'Gene', '2908', (171, 173))	('dexamethasone', 'Chemical', 'MESH:D003907', (205, 218))	('PRKAR1A', 'Gene', (146, 153))
119669	21742609	In contrast, the observation that dexamethasone stimulated the release of corticosterone in the presence of RU-486 in this transgenic mouse as efficiently as it did in wild-type mouse adrenocortical tissues indicates that PRKAR1A (partial) inactivation does not modify the GR-independent stimulatory effect on glucocorticoid production.	('glucocorticoid production', 'MPA', (310, 335))	('release of corticosterone', 'MPA', (63, 88))	('mouse', 'Species', '10090', (178, 183))	('inactivation', 'Var', (240, 252))	('dexamethasone', 'Chemical', 'MESH:D003907', (34, 47))	('PRKAR1A', 'Gene', (222, 229))	('adrenocortical', 'Disease', (184, 198))	('corticosterone', 'Chemical', 'MESH:D003345', (74, 88))	('GR', 'Gene', '2908', (273, 275))	('adrenocortical', 'Disease', 'MESH:D018268', (184, 198))	('RU-486', 'Chemical', 'MESH:D015735', (108, 114))	('mouse', 'Species', '10090', (134, 139))
119674	21742609	Some of this variation can be ascribed to functional GR polymorphisms, which may also predispose to adrenocortical tumor formation, but clearly GR genetic differences are not the only source of HPA axis functional variance.	('predispose', 'Reg', (86, 96))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('variation', 'Var', (13, 22))	('GR', 'Gene', '2908', (53, 55))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (100, 120))	('polymorphisms', 'Var', (56, 69))	('adrenocortical tumor', 'Disease', (100, 120))	('GR', 'Gene', '2908', (144, 146))
119775	33243205	Nonetheless, a growing body of work has demonstrated that aberrant expression of lncRNAs is correlated with biological processes, including tumour progression, angiogenesis, metastasis, and invasion, indicating that lncRNAs can serve as tumour suppressors or oncogenes for cancer control.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('invasion', 'CPA', (190, 198))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('angiogenesis', 'CPA', (160, 172))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('correlated', 'Reg', (92, 102))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('aberrant', 'Var', (58, 66))	('tumour', 'Disease', (140, 146))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('lncRNAs', 'Gene', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('tumour', 'Disease', (237, 243))	('expression', 'MPA', (67, 77))	('metastasis', 'CPA', (174, 184))
119778	33243205	As a tumour oncogene, lncRNA SNHG15 functions as a competing endogenous RNA (ceRNA) to sponge miR-153, miR-38, miR-141, and miR-141-3p, which consequently promotes cell proliferation, migration, invasion, autophagy, and cisplatin resistance in glioma, breast cancer, osteosarcoma, and hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (285, 309))	('glioma', 'Disease', (244, 250))	('invasion', 'CPA', (195, 203))	('glioma', 'Disease', 'MESH:D005910', (244, 250))	('promotes', 'PosReg', (155, 163))	('osteosarcoma', 'Disease', (267, 279))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('osteosarcoma', 'Disease', 'MESH:D012516', (267, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('hepatocellular carcinoma', 'Disease', (285, 309))	('tumour', 'Disease', (5, 11))	('autophagy', 'CPA', (205, 214))	('SNHG15', 'Gene', (29, 35))	('miR-38', 'Var', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('SNHG15', 'Gene', '285958', (29, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (220, 229))	('breast cancer', 'Disease', (252, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('miR-141', 'Gene', '406933', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (285, 309))	('osteosarcoma', 'Phenotype', 'HP:0002669', (267, 279))	('miR-141', 'Gene', (111, 118))	('migration', 'CPA', (184, 193))	('miR-141', 'Gene', '406933', (124, 131))	('cell proliferation', 'CPA', (164, 182))	('cisplatin', 'MPA', (220, 229))	('miR-141', 'Gene', (124, 131))
119815	33243205	However, as next-generation genome-wide sequencing and microarrays have been widely applied in clinical settings in recent years, new research has suggested that aberrant expression of lncRNAs may promote or suppress tumour growth, leading to carcinogenesis and cancer progression.	('cancer', 'Disease', (262, 268))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('tumour growth', 'Disease', (217, 230))	('carcinogenesis', 'Disease', 'MESH:D063646', (243, 257))	('leading to', 'Reg', (232, 242))	('suppress', 'NegReg', (208, 216))	('tumour growth', 'Disease', 'MESH:D006130', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('carcinogenesis', 'Disease', (243, 257))	('lncRNAs', 'Gene', (185, 192))	('aberrant expression', 'Var', (162, 181))	('promote', 'PosReg', (197, 204))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
119816	33243205	For example, some lncRNAs, such as NOC2L-4.1, TUG1, and MALAT1, are well established to promote tumour growth, while other lncRNAs, such as ASMTL-AS1, LINC02381, and LINC02499 have been found to inhibit tumour progression.	('MALAT1', 'Gene', '378938', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('LINC02499', 'Var', (166, 175))	('ASMTL-AS1', 'Gene', '80161', (140, 149))	('promote', 'PosReg', (88, 95))	('TUG1', 'Gene', '55000', (46, 50))	('MALAT1', 'Gene', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('tumour growth', 'Disease', (96, 109))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Disease', (203, 209))	('TUG1', 'Gene', (46, 50))	('inhibit', 'NegReg', (195, 202))	('tumour growth', 'Disease', 'MESH:D006130', (96, 109))	('ASMTL-AS1', 'Gene', (140, 149))	('tumour', 'Disease', (96, 102))
119832	33243205	Similarly, in non-small cell lung cancer, two studies have demonstrated that SNHG15 knockdown suppresses tumorigenesis by inhibiting the expression of EMT, MMP2, and MMP9 and regulating the miR-486/CDK14 axis.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (14, 40))	('knockdown', 'Var', (84, 93))	('MMP9', 'Gene', (166, 170))	('MMP9', 'Gene', '4318', (166, 170))	('CDK14', 'Gene', '5218', (198, 203))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (18, 40))	('miR-486', 'Gene', (190, 197))	('MMP2', 'Gene', '4313', (156, 160))	('inhibiting', 'NegReg', (122, 132))	('expression', 'MPA', (137, 147))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (14, 40))	('SNHG15', 'Gene', (77, 83))	('tumor', 'Disease', (105, 110))	('EMT', 'Gene', (151, 154))	('EMT', 'Gene', '3702', (151, 154))	('CDK14', 'Gene', (198, 203))	('miR-486', 'Gene', '619554', (190, 197))	('SNHG15', 'Gene', '285958', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('non-small cell lung cancer', 'Disease', (14, 40))	('suppresses', 'NegReg', (94, 104))	('regulating', 'Reg', (175, 185))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('MMP2', 'Gene', (156, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
119846	31244774	As a result, we have identified a novel 13-gene module, including CEACAM6, CYP4B1, EIF2S2, HID1, IFFO1, MYO18A, PDCD2, SGIP1, SWSAP1, and four unknown genes (A_24_P127621, A_24_P255786, A_24_P683553, and A_24_P916979), which was able to categorize the patients into two groups as invasive and non-invasive NFPA with distinct prognosis.	('IFFO1', 'Gene', '25900', (97, 102))	('SWSAP1', 'Gene', '126074', (126, 132))	('PDCD2', 'Gene', '5134', (112, 117))	('CEACAM6', 'Gene', '4680', (66, 73))	('CYP4B1', 'Gene', '1580', (75, 81))	('patients', 'Species', '9606', (252, 260))	('HID1', 'Gene', (91, 95))	('CEACAM6', 'Gene', (66, 73))	('CYP4B1', 'Gene', (75, 81))	('A_24_P916979', 'Var', (204, 216))	('PDCD2', 'Gene', (112, 117))	('A_24_P683553', 'Var', (186, 198))	('MYO18A', 'Gene', (104, 110))	('MYO18A', 'Gene', '399687', (104, 110))	('A_24_P255786', 'Var', (172, 184))	('SWSAP1', 'Gene', (126, 132))	('HID1', 'Gene', '283987', (91, 95))	('invasive', 'Disease', (280, 288))	('IFFO1', 'Gene', (97, 102))	('A_24_P127621', 'Var', (158, 170))
119857	31244774	Several microRNAs including miR-135a, miR-140-5p, miR-582-3p, miR-582-5p, and miR-938 were found as overexpressed in the invasive state, and they were also associated with tumor size and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('miR-582-3p', 'Var', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('overexpressed', 'PosReg', (100, 113))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('miR-135a', 'Var', (28, 36))	('miR-140-5p', 'Var', (38, 48))	('tumor', 'Disease', (187, 192))	('miR-582-5p', 'Var', (62, 72))	('miR-938', 'Gene', '100126327', (78, 85))	('associated', 'Reg', (156, 166))	('miR-938', 'Gene', (78, 85))
119898	31244774	This resulted with a core module of 13 genes (CEACAM6, CYP4B1, EIF2S2, HID1, IFFO1, MYO18A, PDCD2, SGIP1, SWSAP1, A_24_P127621, A_24_P255786, A_24_P683553, A_24_P916979), which indicates higher discrimination accuracy, since clusters representing invasive and non-invasive states were clearly separable and distinguishable without any overlaps in PCA plots (Figure 4).	('PDCD2', 'Gene', (92, 97))	('A_24_P683553', 'Var', (142, 154))	('CEACAM6', 'Gene', (46, 53))	('EIF2S2', 'Gene', (63, 69))	('A_24_P127621', 'Var', (114, 126))	('CYP4B1', 'Gene', (55, 61))	('HID1', 'Gene', '283987', (71, 75))	('IFFO1', 'Gene', (77, 82))	('SWSAP1', 'Gene', (106, 112))	('PDCD2', 'Gene', '5134', (92, 97))	('A_24_P916979', 'Var', (156, 168))	('IFFO1', 'Gene', '25900', (77, 82))	('MYO18A', 'Gene', '399687', (84, 90))	('SGIP1', 'Gene', (99, 104))	('SWSAP1', 'Gene', '126074', (106, 112))	('HID1', 'Gene', (71, 75))	('CEACAM6', 'Gene', '4680', (46, 53))	('A_24_P255786', 'Var', (128, 140))	('CYP4B1', 'Gene', '1580', (55, 61))	('MYO18A', 'Gene', (84, 90))
119908	31244774	CEACAM6 and SWSAP1 were located on chromosome 19 whereas HID1 and MYO18A were on chromosome 17, CYP4B1, and SGIP1 were on chromosome 1, PDCD2 was on chromosome 6, A_24_P127621 was on chromosome 7, A_24_P683553 was on chromosome 9, A_24_P255786 was on chromosome 10, IFFO1 was on chromosome 12, EIF2S2 was on chromosome 20, and A_24_P916979 located on chromosome X.	('PDCD2', 'Gene', (136, 141))	('PDCD2', 'Gene', '5134', (136, 141))	('A_24_P683553', 'Var', (197, 209))	('CYP4B1', 'Gene', (96, 102))	('IFFO1', 'Gene', '25900', (266, 271))	('CEACAM6', 'Gene', '4680', (0, 7))	('MYO18A', 'Gene', '399687', (66, 72))	('HID1', 'Gene', (57, 61))	('MYO18A', 'Gene', (66, 72))	('A_24_P127621', 'Var', (163, 175))	('SWSAP1', 'Gene', (12, 18))	('IFFO1', 'Gene', (266, 271))	('CEACAM6', 'Gene', (0, 7))	('CYP4B1', 'Gene', '1580', (96, 102))	('HID1', 'Gene', '283987', (57, 61))	('A_24_P255786', 'Var', (231, 243))	('SWSAP1', 'Gene', '126074', (12, 18))
119926	31244774	The differential co-expression profiling followed by clustering and survival analyses resulted with a prognostic core module composed of 13 genes; namely, CEACAM6, CYP4B1, EIF2S2, HID1, IFFO1, MYO18A, PDCD2, SGIP1, SWSAP1, and 4 unknown genes (A_24_P127621, A_24_P683553, A_24_P255786, A_24_P916979).	('HID1', 'Gene', (180, 184))	('CEACAM6', 'Gene', '4680', (155, 162))	('CYP4B1', 'Gene', '1580', (164, 170))	('CEACAM6', 'Gene', (155, 162))	('CYP4B1', 'Gene', (164, 170))	('EIF2S2', 'Gene', (172, 178))	('HID1', 'Gene', '283987', (180, 184))	('MYO18A', 'Gene', '399687', (193, 199))	('MYO18A', 'Gene', (193, 199))	('A_24_P683553', 'Var', (258, 270))	('PDCD2', 'Gene', (201, 206))	('IFFO1', 'Gene', (186, 191))	('SWSAP1', 'Gene', (215, 221))	('IFFO1', 'Gene', '25900', (186, 191))	('PDCD2', 'Gene', '5134', (201, 206))	('A_24_P127621', 'Var', (244, 256))	('A_24_P255786', 'Var', (272, 284))	('SGIP1', 'Gene', (208, 213))	('SWSAP1', 'Gene', '126074', (215, 221))
119936	31244774	The deletion of EIF2S2 gene has been reported with suppression of testicular germ cell tumor incidence and recessive lethality in mice.	('mice', 'Species', '10090', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('recessive lethality', 'Disease', (107, 126))	('suppression', 'NegReg', (51, 62))	('recessive lethality', 'Disease', 'MESH:C537194', (107, 126))	('tumor', 'Disease', (87, 92))	('deletion', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('EIF2S2', 'Gene', (16, 22))	('germ cell tumor', 'Phenotype', 'HP:0100728', (77, 92))
119945	31244774	The hypomethylation and up-regulation of IFFO1 have been also reported in endometrioid endometrial adenocarcinoma samples.	('endometrioid endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (74, 113))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (87, 113))	('IFFO1', 'Gene', (41, 46))	('hypomethylation', 'Var', (4, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('IFFO1', 'Gene', '25900', (41, 46))	('up-regulation', 'PosReg', (24, 37))	('endometrioid endometrial adenocarcinoma', 'Disease', (74, 113))
119947	31244774	MYO18A has been found highly expressed in metastatic prostate cancer and its knockdown affects the cytoskeleton and cell migration.	('cytoskeleton', 'CPA', (99, 111))	('rat', 'Species', '10116', (124, 127))	('prostate cancer', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('MYO18A', 'Gene', (0, 6))	('knockdown', 'Var', (77, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('MYO18A', 'Gene', '399687', (0, 6))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('affects', 'Reg', (87, 94))	('cell migration', 'CPA', (116, 130))
119952	31244774	Aberrant expression of PDCD2 is associated with many tumors, such as leukemia and gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('Aberrant expression', 'Var', (0, 19))	('PDCD2', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('leukemia', 'Disease', (69, 77))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('leukemia', 'Disease', 'MESH:D007938', (69, 77))	('leukemia', 'Phenotype', 'HP:0001909', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('gastric cancer', 'Disease', (82, 96))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('associated', 'Reg', (32, 42))	('tumors', 'Disease', (53, 59))	('PDCD2', 'Gene', '5134', (23, 28))
119954	31244774	Plus, loss of PDCD2 expression could induce gastric cancer development and progression through cell growth arrest at the early S phase of the cell cycle and reported as a putative tumor suppressor in gastric stromal tumors.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('gastric stromal tumors', 'Phenotype', 'HP:0100723', (200, 222))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('tumor', 'Disease', (216, 221))	('loss', 'Var', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('gastric stromal tumors', 'Disease', 'MESH:D046152', (200, 222))	('gastric stromal tumors', 'Disease', (200, 222))	('PDCD2', 'Gene', '5134', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('gastric cancer', 'Disease', (44, 58))	('induce', 'PosReg', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('growth arrest', 'Phenotype', 'HP:0001510', (100, 113))	('progression', 'CPA', (75, 86))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', (180, 185))	('PDCD2', 'Gene', (14, 19))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))
119956	31244774	Hypomethylation and retrotransposition of SGIP1 have been reported in colorectal cancer samples.	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('SGIP1', 'Gene', (42, 47))	('reported', 'Reg', (58, 66))	('Hypomethylation', 'Var', (0, 15))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('colorectal cancer', 'Disease', (70, 87))	('retrotransposition', 'MPA', (20, 38))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
119961	31244774	Depletion of SWSAP1 contributes to defects in homologous recombination repair and Knockdown of SWSAP1 ends up with increased cell sensitivity to the DNA damaging.	('cell sensitivity to the DNA damaging', 'MPA', (125, 161))	('SWSAP1', 'Gene', '126074', (95, 101))	('Knockdown', 'Var', (82, 91))	('SWSAP1', 'Gene', '126074', (13, 19))	('increased', 'PosReg', (115, 124))	('homologous recombination repair', 'MPA', (46, 77))	('Depletion', 'MPA', (0, 9))	('SWSAP1', 'Gene', (95, 101))	('defects', 'NegReg', (35, 42))	('SWSAP1', 'Gene', (13, 19))
119969	31244774	Eventually, a core module with 13 genes including CEACAM6, CYP4B1, EIF2S2, HID1, IFFO1,MYO18A, PDCD2, SGIP1, SWSAP1, and 4 unknown genes (A_24_P127621, A_24_P255786, A_24_P683553, A_24_P916979) were identified and in silico validated in association with the indicator of invasiveness and prognosis of PA, plus some related cancer types.	('A_24_P683553', 'Var', (166, 178))	('IFFO1', 'Gene', '25900', (81, 86))	('A_24_P127621', 'Var', (138, 150))	('SWSAP1', 'Gene', '126074', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('PDCD2', 'Gene', '5134', (95, 100))	('CEACAM6', 'Gene', '4680', (50, 57))	('HID1', 'Gene', (75, 79))	('CYP4B1', 'Gene', '1580', (59, 65))	('A_24_P916979', 'Var', (180, 192))	('CYP4B1', 'Gene', (59, 65))	('CEACAM6', 'Gene', (50, 57))	('HID1', 'Gene', '283987', (75, 79))	('cancer', 'Disease', (323, 329))	('PDCD2', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('IFFO1', 'Gene', (81, 86))	('MYO18A', 'Gene', (87, 93))	('SWSAP1', 'Gene', (109, 115))	('MYO18A', 'Gene', '399687', (87, 93))	('A_24_P255786', 'Var', (152, 164))
119972	27888710	Dysfunction of PLK1 may promote cancerous transformation and drive its progression.	('drive', 'Reg', (61, 66))	('Dysfunction', 'Var', (0, 11))	('cancerous', 'Disease', (32, 41))	('PLK1', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('promote', 'PosReg', (24, 31))	('progression', 'CPA', (71, 82))	('cancerous', 'Disease', 'MESH:D009369', (32, 41))
119974	27888710	Many studies have showed that inhibition of PLK1 could lead to death of cancer cells by interfering with multiple stages of mitosis.	('lead to', 'Reg', (55, 62))	('inhibition', 'Var', (30, 40))	('interfering', 'NegReg', (88, 99))	('mitosis', 'Disease', 'None', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('death of cancer', 'Disease', (63, 78))	('PLK1', 'Gene', (44, 48))	('death of cancer', 'Disease', 'MESH:D003643', (63, 78))	('mitosis', 'Disease', (124, 131))
119996	27888710	Oncogenes and tumor suppressor genes are mostly related to cell cycle regulation, and dysregulation of the cell cycle is the main cause of cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('tumor', 'Disease', (14, 19))	('cause', 'Reg', (130, 135))	('dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (86, 117))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('dysregulation', 'Var', (86, 99))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cancer', 'Disease', (139, 145))
120020	27888710	TP53 mutations and dysfunction occur in more than half of all human cancer cases.	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', (0, 4))	('human', 'Species', '9606', (62, 67))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))
120024	27888710	These results suggest that p53 may repress PLK1 expression, and once TP53 mutations result in loss of the p53 transcriptional repression function, PLK1 would have elevated expression in TP53-mutated cancers compared with TP53-wild-type cancers.	('p53', 'Gene', '7157', (106, 109))	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('TP53', 'Gene', (69, 73))	('loss', 'NegReg', (94, 98))	('PLK1', 'Gene', (43, 47))	('p53', 'Gene', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('elevated', 'PosReg', (163, 171))	('TP53', 'Gene', '7157', (221, 225))	('TP53', 'Gene', (186, 190))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', (199, 206))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('TP53', 'Gene', '7157', (69, 73))	('cancers', 'Disease', (236, 243))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('p53', 'Gene', '7157', (27, 30))	('mutations', 'Var', (74, 83))	('TP53', 'Gene', '7157', (186, 190))	('expression', 'MPA', (172, 182))	('TP53', 'Gene', (221, 225))	('PLK1', 'Gene', (147, 151))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('p53', 'Gene', (27, 30))
120029	27888710	The imbalance between these interactions for regulating proliferation could be a leading cause of cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('regulating proliferation', 'CPA', (45, 69))	('cause', 'Reg', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('imbalance', 'Var', (4, 13))	('cancer', 'Disease', (98, 104))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
120031	27888710	These interactions may be essential for PLK1 to play an important role in regulation of the cell cycle, and dysfunction of the interactions could be associated with cancer and other diseases.	('interactions', 'Interaction', (127, 139))	('interactions', 'Interaction', (6, 18))	('PLK1', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('dysfunction', 'Var', (108, 119))	('associated', 'Reg', (149, 159))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cell cycle', 'CPA', (92, 102))
120035	27888710	reported that PLK1 silencing could enhance the sensitivity to cisplatin in human TP53-mutated epidermal squamous carcinoma cells by upregulating p73a ; Gleixner et al.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('p73a', 'Var', (145, 149))	('silencing', 'Var', (19, 28))	('enhance', 'PosReg', (35, 42))	('squamous carcinoma', 'Disease', 'MESH:D002294', (104, 122))	('TP53', 'Gene', (81, 85))	('squamous carcinoma', 'Disease', (104, 122))	('upregulating', 'PosReg', (132, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('human', 'Species', '9606', (75, 80))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (104, 122))	('TP53', 'Gene', '7157', (81, 85))	('PLK1', 'Gene', (14, 18))	('sensitivity to cisplatin', 'MPA', (47, 71))
120036	27888710	found that BI2536, a small molecule inhibitor of PLK1, could enhance the inhibition of imatinib and nilotinib on chronic myeloid leukemia cell growth.	('enhance', 'PosReg', (61, 68))	('imatinib', 'Chemical', 'MESH:D000068877', (87, 95))	('leukemia', 'Phenotype', 'HP:0001909', (129, 137))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (113, 137))	('imatinib', 'MPA', (87, 95))	('myeloid leukemia', 'Disease', (121, 137))	('BI2536', 'Var', (11, 17))	('nilotinib', 'MPA', (100, 109))	('inhibition', 'MPA', (73, 83))	('myeloid leukemia', 'Disease', 'MESH:D007951', (121, 137))	('nilotinib', 'Chemical', 'MESH:C498826', (100, 109))	('BI2536', 'Chemical', 'MESH:C518477', (11, 17))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (121, 137))	('PLK1', 'Gene', (49, 53))
120037	27888710	showed that PLK1 silencing could enhance the sensitivity of rectal cancer to radiotherapy; Gerster et al.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('PLK1', 'Protein', (12, 16))	('cancer', 'Disease', (67, 73))	('sensitivity', 'MPA', (45, 56))	('rectal cancer', 'Phenotype', 'HP:0100743', (60, 73))	('enhance', 'PosReg', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('silencing', 'Var', (17, 26))
120038	27888710	found that using BI2536 before radiotherapy could enhance radiotherapy sensitivity in medulloblastoma cells.	('BI2536', 'Var', (17, 23))	('medulloblastoma', 'Disease', 'MESH:D008527', (86, 101))	('medulloblastoma', 'Phenotype', 'HP:0002885', (86, 101))	('BI2536', 'Chemical', 'MESH:C518477', (17, 23))	('radiotherapy sensitivity', 'CPA', (58, 82))	('enhance', 'PosReg', (50, 57))	('medulloblastoma', 'Disease', (86, 101))
120039	27888710	Thus, the inhibition of PLK1 may overcome drug resistance in cancer chemotherapy and enhance sensitivity of cancer radiotherapy.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('drug resistance', 'Phenotype', 'HP:0020174', (42, 57))	('drug', 'MPA', (42, 46))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('overcome', 'PosReg', (33, 41))	('inhibition', 'Var', (10, 20))	('PLK1', 'Gene', (24, 28))	('cancer', 'Disease', (108, 114))	('enhance', 'PosReg', (85, 92))
120040	27888710	PLK1 could be a new therapeutic target for cancer because PLK1 knockout can decrease cancer cell survival, induce apoptosis, and increase the sensitivity to chemotherapy drugs, whereas it has little effect on normal cells.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('induce', 'Reg', (107, 113))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('increase', 'PosReg', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('knockout', 'Var', (63, 71))	('decrease', 'NegReg', (76, 84))	('PLK1', 'Gene', (58, 62))	('apoptosis', 'CPA', (114, 123))	('sensitivity to chemotherapy drugs', 'MPA', (142, 175))
120049	27888710	BI2536 is a representative ATP-competitive inhibitor with strong selective inhibition on PLK1 .	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('inhibition', 'NegReg', (75, 85))	('BI2536', 'Var', (0, 6))	('PLK1', 'Gene', (89, 93))	('BI2536', 'Chemical', 'MESH:C518477', (0, 6))
120052	27888710	Several preclinical experiments have demonstrated that BI6727 is highly efficacious in inducing tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('BI6727', 'Var', (55, 61))	('tumor', 'Disease', (96, 101))	('BI6727', 'Chemical', 'MESH:C541363', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
120054	27888710	However, because of the high conservation of ATP binding domains of different kinases and the frequent mutation in ATP binding sites, cancer patients always develop resistance to ATP-competitive inhibitors.	('develop', 'Reg', (157, 164))	('ATP', 'Chemical', 'MESH:D000255', (45, 48))	('cancer', 'Disease', (134, 140))	('ATP', 'Chemical', 'MESH:D000255', (179, 182))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('resistance to ATP-competitive inhibitors', 'MPA', (165, 205))	('mutation', 'Var', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('ATP', 'Chemical', 'MESH:D000255', (115, 118))	('patients', 'Species', '9606', (141, 149))
120060	27888710	However, so far, the small molecule inhibitors of PLK1 including BI2536 have not achieved a satisfactory therapeutic effect in clinical trials.	('PLK1', 'Gene', (50, 54))	('BI2536', 'Chemical', 'MESH:C518477', (65, 71))	('BI2536', 'Var', (65, 71))
120062	27888710	A recent study revealed that reduced efficacy of the PLK1 inhibitor BI2536 on progressive hepatocellular carcinoma was due to low intratumoral drug levels.	('BI2536', 'Var', (68, 74))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('hepatocellular carcinoma', 'Disease', (90, 114))	('PLK1', 'Protein', (53, 57))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('tumor', 'Disease', (135, 140))	('BI2536', 'Chemical', 'MESH:C518477', (68, 74))	('low', 'NegReg', (126, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('low intratumoral drug levels', 'Phenotype', 'HP:0020171', (126, 154))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
120065	27888710	Inhibition of PLK1 expression could reverse the drug resistance of cancer cells and increase sensitivity to radiotherapy and chemotherapy.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('drug resistance', 'CPA', (48, 63))	('drug resistance', 'Phenotype', 'HP:0020174', (48, 63))	('sensitivity', 'MPA', (93, 104))	('increase', 'PosReg', (84, 92))	('reverse', 'NegReg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Inhibition', 'Var', (0, 10))	('increase sensitivity to radiotherapy', 'Phenotype', 'HP:0011133', (84, 120))	('PLK1', 'Gene', (14, 18))
120156	27094262	Ectopic adrenocortical adenoma in the renal hilum: a case report and literature review Ectopic (accessory) adrenocortical tissue, also known as adrenal rests, is a developmental abnormality of the adrenal gland.	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (8, 30))	('abnormality of the adrenal gland', 'Phenotype', 'HP:0000834', (178, 210))	('adrenocortical', 'Disease', (107, 121))	('adrenocortical', 'Disease', 'MESH:D018268', (107, 121))	('Ectopic adrenocortical adenoma', 'Disease', 'MESH:D018246', (0, 30))	('adrenocortical', 'Disease', (8, 22))	('adrenocortical', 'Disease', 'MESH:D018268', (8, 22))	('Ectopic', 'Var', (87, 94))	('Ectopic adrenocortical adenoma', 'Disease', (0, 30))
120308	26619967	The results of DNA sequencing for PRKAR1A gene point mutation and deletion/duplication were negative for both siblings.	('deletion/duplication', 'Var', (66, 86))	('point mutation', 'Var', (47, 61))	('PRKAR1A', 'Gene', (34, 41))	('PRKAR1A', 'Gene', '5573', (34, 41))
120349	26619967	Spotty skin pigmentation over the lips, conjunctiva, inner and/or outer canthi, and vaginal or penile mucosa Cutaneous, mucosal myxoma Cardiac myxoma Breast myxomatosis Endocrine overactivity (for example, PPNAD, acromegaly) Large-cell calcifying Sertoli cell tumor (LCCSCT) Thyroid carcinoma or multiple hypoechoic nodules on thyroid US Psammomatous melanotic schwannoma Multiple blue nevi Multiple breast ductal adenoma Osteochondromyxoma A definite diagnosis of CNC is made if at least two major criteria are present or one major criterion is met in an affected first-degree relative with CNC, or if the index case or relative has a PRKAR1A mutation.	('tumor', 'Disease', (260, 265))	('schwannoma', 'Phenotype', 'HP:0100008', (361, 371))	('blue nevi', 'Phenotype', 'HP:0100814', (381, 390))	('mucosal myxoma', 'Disease', (120, 134))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (275, 292))	('Multiple breast ductal adenoma', 'Disease', 'MESH:D000236', (391, 421))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('CS', 'Phenotype', 'HP:0003118', (269, 271))	('Spotty skin pigmentation', 'Disease', (0, 24))	('PRKAR1A', 'Gene', (636, 643))	('Sertoli cell', 'Phenotype', 'HP:0100619', (247, 259))	('nevi', 'Phenotype', 'HP:0003764', (386, 390))	('melanotic schwannoma', 'Disease', (351, 371))	('Osteochondromyxoma', 'Disease', (422, 440))	('hypoechoic nodules', 'Disease', (305, 323))	('Cardiac myxoma', 'Disease', 'MESH:D009232', (135, 149))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('PPNAD', 'Chemical', '-', (206, 211))	('mucosal myxoma', 'Disease', 'MESH:D009232', (120, 134))	('melanotic schwannoma', 'Disease', 'MESH:D009442', (351, 371))	('mutation', 'Var', (644, 652))	('outer canthi', 'Phenotype', 'HP:0000506', (66, 78))	('acromegaly', 'Disease', 'MESH:D000172', (213, 223))	('Cardiac myxoma', 'Disease', (135, 149))	('Spotty skin pigmentation', 'Disease', 'MESH:D056733', (0, 24))	('PRKAR1A', 'Gene', '5573', (636, 643))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('Breast myxomatosis', 'Disease', (150, 168))	('Osteochondromyxoma', 'Disease', 'None', (422, 440))	('Multiple breast ductal adenoma', 'Disease', (391, 421))	('acromegaly', 'Phenotype', 'HP:0000845', (213, 223))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (275, 292))	('Thyroid carcinoma', 'Disease', (275, 292))	('acromegaly', 'Disease', (213, 223))	('hypoechoic nodules', 'Disease', 'MESH:D016606', (305, 323))	('Breast myxomatosis', 'Disease', 'MESH:D009234', (150, 168))	('Cardiac myxoma', 'Phenotype', 'HP:0011672', (135, 149))	('skin pigmentation', 'Phenotype', 'HP:0000953', (7, 24))
120351	26619967	Phosphodiesterase 11A (PDE11A gene) and phosphodiesterase 8B (PDE8B gene) mutations, as well as chromosome 2p16 mutations, have also been identified in patients with isolated PPNAD.	('PDE11A', 'Gene', (23, 29))	('PDE11A', 'Gene', '50940', (23, 29))	('identified', 'Reg', (138, 148))	('mutations', 'Var', (74, 83))	('PPNAD', 'Chemical', '-', (175, 180))	('PDE8B', 'Gene', (62, 67))	('mutations', 'Var', (112, 121))	('phosphodiesterase', 'Gene', '50940', (40, 57))	('PDE8B', 'Gene', '8622', (62, 67))	('phosphodiesterase', 'Gene', (40, 57))	('Phosphodiesterase 11A', 'Gene', '50940', (0, 21))	('isolated PPNAD', 'Disease', (166, 180))	('Phosphodiesterase 11A', 'Gene', (0, 21))	('patients', 'Species', '9606', (152, 160))
120352	26619967	The results for DNA sequencing for PRKAR1A gene point mutation and deletion and/or duplication were negative in our sibling pair.	('PRKAR1A', 'Gene', '5573', (35, 42))	('PRKAR1A', 'Gene', (35, 42))	('point mutation', 'Var', (48, 62))	('deletion', 'Var', (67, 75))
120356	26619967	In the absence of a PRKAR1A gene mutation, our patients do not fit the criteria for CNC.	('mutation', 'Var', (33, 41))	('patients', 'Species', '9606', (47, 55))	('PRKAR1A', 'Gene', (20, 27))	('CNC', 'Disease', (84, 87))	('PRKAR1A', 'Gene', '5573', (20, 27))
120386	24220673	Identification of genetic alterations in rare familial syndromes and evaluation of whether the same defects are present in sporadic tumors.	('genetic alterations', 'Var', (18, 37))	('familial syndromes', 'Disease', (46, 64))	('sporadic tumors', 'Disease', 'MESH:D009369', (123, 138))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('sporadic tumors', 'Disease', (123, 138))
120410	24220673	Mutations of PRKAR1A have been identified in families with linkage at the 17q22-24 locus.	('Mutations', 'Var', (0, 9))	('PRKAR1A', 'Gene', (13, 20))	('PRKAR1A', 'Gene', '5573', (13, 20))	('identified', 'Reg', (31, 41))
120411	24220673	Studies have shown that PRKAR1A mutations are present in approximately 60% of CC patients.	('PRKAR1A', 'Gene', '5573', (24, 31))	('PRKAR1A', 'Gene', (24, 31))	('mutations', 'Var', (32, 41))	('patients', 'Species', '9606', (81, 89))
120413	24220673	The presence of inactivating PRKAR1A mutations leads to constitutional activation of the catalytic subunits.	('PRKAR1A', 'Gene', (29, 36))	('activation', 'PosReg', (71, 81))	('mutations', 'Var', (37, 46))	('PRKAR1A', 'Gene', '5573', (29, 36))	('catalytic subunits', 'MPA', (89, 107))
120414	24220673	Allelic loss of the wild-type allele is frequently observed in some tumors from patients with CC, and for this reason PRKAR1A is considered a tumor suppressor gene.	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Disease', (68, 74))	('PRKAR1A', 'Gene', '5573', (118, 125))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('patients', 'Species', '9606', (80, 88))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (142, 147))	('Allelic loss', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('PRKAR1A', 'Gene', (118, 125))
120416	24220673	PPNAD and non-pigmented adrenocortical micronodular hyperplasia (i-MAD) have also been described in patients without PRKAR1A mutations.	('mutations', 'Var', (125, 134))	('PRKAR1A', 'Gene', '5573', (117, 124))	('non-pigmented adrenocortical micronodular hyperplasia', 'Disease', 'MESH:C566469', (10, 63))	('pigmented adrenocortical micronodular hyperplasia', 'Phenotype', 'HP:0001580', (14, 63))	('patients', 'Species', '9606', (100, 108))	('PPNAD', 'Disease', (0, 5))	('PRKAR1A', 'Gene', (117, 124))
120417	24220673	In a subset of such patients, inactivating mutations of genes that encode phosphodiesterases (PDE11A and PDE8B) have been identified.	('PDE8B', 'Gene', '8622', (105, 110))	('phosphodiesterases', 'Gene', (74, 92))	('phosphodiesterases', 'Gene', '50940', (74, 92))	('patients', 'Species', '9606', (20, 28))	('PDE11A', 'Gene', (94, 100))	('PDE11A', 'Gene', '50940', (94, 100))	('inactivating mutations', 'Var', (30, 52))	('PDE8B', 'Gene', (105, 110))
120418	24220673	These mutations impair the ability of the protein to degrade cAMP, leading to a prolonged activation of the pathway.	('activation', 'PosReg', (90, 100))	('cAMP', 'Gene', (61, 65))	('cAMP', 'Gene', '820', (61, 65))	('ability', 'MPA', (27, 34))	('impair', 'NegReg', (16, 22))	('mutations', 'Var', (6, 15))
120421	24220673	Interestingly, activation of the aberrant receptors stimulates cortisol production.	('cortisol production', 'MPA', (63, 82))	('stimulates cortisol production', 'Phenotype', 'HP:0003118', (52, 82))	('cortisol', 'Chemical', 'MESH:D006854', (63, 71))	('stimulates', 'PosReg', (52, 62))	('aberrant', 'Var', (33, 41))
120428	24220673	Post-zygotic GNAS1 (the gene that encodes Gs-alpha) activating mutations have been identified in a pattern of mosaicism in various tissues.	('mutations', 'Var', (63, 72))	('GNAS1', 'Gene', '2778', (13, 18))	('Gs-alpha', 'Gene', (42, 50))	('GNAS1', 'Gene', (13, 18))	('Gs-alpha', 'Gene', '2778', (42, 50))
120429	24220673	In addition, activating GNAS1 mutations have also been identified in isolated forms of AIMAH, suggesting that at least some forms of AIMAH may represent a disease in the spectrum of MAS.	('GNAS1', 'Gene', (24, 29))	('AIMAH', 'Disease', (87, 92))	('activating', 'PosReg', (13, 23))	('GNAS1', 'Gene', '2778', (24, 29))	('mutations', 'Var', (30, 39))	('MAS', 'Disease', 'MESH:D005357', (182, 185))	('MAS', 'Disease', (182, 185))
120431	24220673	Although somatic PRKAR1A and GNAS1 mutations have been identified only in a small subset of CPAs, other abnormalities such as LOH at 17q22-24, post-transcriptional down-regulation of PKA regulatory subunits PRKAR1A and PRKAR2B, increased levels of cAMP, increased PKA activity and decreased total PDE activity are frequent findings in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('PKA', 'Enzyme', (264, 267))	('tumors', 'Disease', (341, 347))	('PRKAR1A', 'Gene', (17, 24))	('GNAS1', 'Gene', (29, 34))	('increased', 'PosReg', (228, 237))	('mutations', 'Var', (35, 44))	('cAMP', 'Gene', '820', (248, 252))	('PRKAR1A', 'Gene', (207, 214))	('PRKAR2B', 'Gene', '5577', (219, 226))	('down-regulation', 'NegReg', (164, 179))	('tumors', 'Disease', 'MESH:D009369', (341, 347))	('PRKAR1A', 'Gene', '5573', (17, 24))	('CPAs', 'Disease', (92, 96))	('activity', 'MPA', (268, 276))	('PDE activity', 'MPA', (297, 309))	('PRKAR2B', 'Gene', (219, 226))	('PRKAR1A', 'Gene', '5573', (207, 214))	('cAMP', 'Gene', (248, 252))	('increased', 'PosReg', (254, 263))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('GNAS1', 'Gene', '2778', (29, 34))	('decreased', 'NegReg', (281, 290))
120445	24220673	The genetic cause of this disease is an inactivating mutation of KCNJ5, the gene that encodes the G-protein-activated inward rectifier K+ channel 4 (GIRK4).	('inactivating mutation', 'Var', (40, 61))	('GIRK4', 'Gene', (149, 154))	('KCNJ5', 'Gene', (65, 70))	('G-protein-activated inward rectifier K+ channel 4', 'Gene', (98, 147))	('KCNJ5', 'Gene', '3762', (65, 70))	('GIRK4', 'Gene', '3762', (149, 154))	('cause', 'Reg', (12, 17))	('G-protein-activated inward rectifier K+ channel 4', 'Gene', '3762', (98, 147))
120446	24220673	The functional consequences of KCNJ5 mutations on the channel function are loss of K+ selectivity, Na+ influx and cellular membrane depolarization, leading to increased cytosolic Ca++ concentrations, possibly by a voltage-gated Ca++ channel activation.	('depolarization', 'NegReg', (132, 146))	('KCNJ5', 'Gene', (31, 36))	('increased', 'PosReg', (159, 168))	('mutations', 'Var', (37, 46))	('KCNJ5', 'Gene', '3762', (31, 36))	('cellular', 'MPA', (114, 122))	('Na+ influx', 'MPA', (99, 109))	('K+ selectivity', 'MPA', (83, 97))	('cytosolic Ca++ concentrations', 'MPA', (169, 198))	('loss', 'NegReg', (75, 79))
120448	24220673	The clinical features of affected members of families with FH-III having G151R and G151E mutations illustrates strikingly different presentations.	('G151R', 'Mutation', 'rs386352319', (73, 78))	('clinical', 'Species', '191496', (4, 12))	('G151E mutations', 'Var', (83, 98))	('FH-II', 'Gene', (59, 64))	('G151E', 'Mutation', 'rs587777437', (83, 88))	('FH-II', 'Gene', '79179', (59, 64))	('G151R', 'Var', (73, 78))
120449	24220673	Patients with the G151E mutation showed aldosteronism early in life but had no progressive disease.	('aldosteronism', 'Disease', (40, 53))	('Patients', 'Species', '9606', (0, 8))	('G151E', 'Var', (18, 23))	('G151E', 'Mutation', 'rs587777437', (18, 23))
120451	24220673	In contrast, patients with the G151R mutation presented with clinical features similar to the family described initially with the inherited T158A mutation in KCNJ5.	('KCNJ5', 'Gene', (158, 163))	('KCNJ5', 'Gene', '3762', (158, 163))	('patients', 'Species', '9606', (13, 21))	('G151R', 'Var', (31, 36))	('T158A', 'Var', (140, 145))	('T158A', 'Mutation', 'rs387906778', (140, 145))	('clinical', 'Species', '191496', (61, 69))	('G151R', 'Mutation', 'rs386352319', (31, 36))
120453	24220673	Among the patients with G151R mutations with follow-up, all have required the radical intervention of bilateral adrenalectomy to achieve control of hypertension and hypokalemia at very young ages (range 1-4 y).	('hypertension', 'Phenotype', 'HP:0000822', (148, 160))	('G151R', 'Var', (24, 29))	('hypokalemia', 'Disease', 'MESH:D007008', (165, 176))	('hypertension', 'Disease', 'MESH:D006973', (148, 160))	('hypokalemia', 'Disease', (165, 176))	('G151R', 'Mutation', 'rs386352319', (24, 29))	('patients', 'Species', '9606', (10, 18))	('hypertension', 'Disease', (148, 160))	('hypokalemia', 'Phenotype', 'HP:0002900', (165, 176))
120455	24220673	Patients with APAs harboring KCNJ5 mutations present with severe and early onset hyperaldosteronism as well as higher lateralization index in adrenal venous sampling.	('hyperaldosteronism', 'Disease', (81, 99))	('KCNJ5', 'Gene', (29, 34))	('Patients', 'Species', '9606', (0, 8))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (81, 99))	('higher', 'PosReg', (111, 117))	('KCNJ5', 'Gene', '3762', (29, 34))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (81, 99))	('mutations', 'Var', (35, 44))
120458	24220673	Subsequently 308 APAs were screened for ATP1A1 and ATP2B3 mutations.	('mutations', 'Var', (58, 67))	('ATP1A1', 'Gene', '476', (40, 46))	('ATP1A1', 'Gene', (40, 46))	('ATP2B3', 'Gene', (51, 57))
120459	24220673	21 (6.8%) contained ATP1A1 or ATP2B3 mutations and 118 (38.3%) KCNJ5 mutations.	('mutations', 'Var', (69, 78))	('ATP1A1', 'Gene', '476', (20, 26))	('KCNJ5', 'Gene', '3762', (63, 68))	('ATP2B3 mutations', 'Var', (30, 46))	('ATP1A1', 'Gene', (20, 26))	('KCNJ5', 'Gene', (63, 68))
120464	24220673	ATP2B3 belongs to the ATPase gene family that encodes a plasma membrane Ca2+ ATPase that is essential to clear calcium ions from the cytoplasm (Figure 2B).	('calcium', 'Chemical', 'MESH:D002118', (111, 118))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('plasma membrane Ca2+ ATPase', 'Gene', '491;1769', (56, 83))	('plasma membrane Ca2+ ATPase', 'Gene', (56, 83))	('ATP', 'Chemical', 'MESH:D000255', (77, 80))	('ATP2B3', 'Var', (0, 6))	('ATP', 'Chemical', 'MESH:D000255', (22, 25))
120466	24220673	Using the known structure of the homologous rabbit sarcoplasmic reticulum type Ca2+ ATPase (SERCA) it became apparent that the APA-associated deletion mutations in ATP2B3 alter the M4 trans-membrane helix causing a major distortion of the calcium ion binding site.	('distortion', 'MPA', (221, 231))	('deletion mutations', 'Var', (142, 160))	('ATP2B3', 'Gene', (164, 170))	('ATP', 'Chemical', 'MESH:D000255', (164, 167))	('alter', 'Reg', (171, 176))	('calcium', 'Chemical', 'MESH:D002118', (239, 246))	('calcium ion binding site', 'MPA', (239, 263))	('rabbit', 'Species', '9986', (44, 50))	('M4 trans-membrane helix', 'MPA', (181, 204))	('APA-associated', 'Disease', (127, 141))	('ATP', 'Chemical', 'MESH:D000255', (84, 87))
120467	24220673	Functional-electrophysiological examination of primary cultured adenoma cells with different underlying mutations showed substantially higher levels of depolarization in ATPase (ATP1A1 or ATP2B3)-mutant cells compared to cells from normal adjacent tissue.	('adenoma', 'Disease', 'MESH:D000236', (64, 71))	('mutations', 'Var', (104, 113))	('ATP', 'Chemical', 'MESH:D000255', (178, 181))	('adenoma', 'Disease', (64, 71))	('ATP1A1', 'Gene', '476', (178, 184))	('ATP', 'Chemical', 'MESH:D000255', (188, 191))	('ATP1A1', 'Gene', (178, 184))	('ATPase', 'Protein', (170, 176))	('depolarization', 'MPA', (152, 166))	('higher', 'PosReg', (135, 141))	('ATP', 'Chemical', 'MESH:D000255', (170, 173))
120468	24220673	ACTs are characterized by a complex pattern of chromosomal alterations, which are cumulative toward malignant transformation These alterations reflect the fact that ACCs are characterized by a high degree of chromosomal instability, a well-known hallmark of cancer.	('ACCs', 'Gene', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('chromosomal instability', 'MPA', (208, 231))	('ACCs', 'Gene', '84680', (165, 169))	('alterations', 'Var', (131, 142))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (258, 264))	('chromosomal instability', 'Phenotype', 'HP:0040012', (208, 231))
120470	24220673	Karyotyping studies of ACCs demonstrated that ACCs present a large number of chromosomal aberrations, including segmental duplications, rearrangements and aberrant chromosomes.	('ACCs', 'Gene', (23, 27))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (77, 100))	('ACCs', 'Gene', (46, 50))	('aberrant chromosomes', 'Var', (155, 175))	('ACCs', 'Gene', '84680', (46, 50))	('ACCs', 'Gene', '84680', (23, 27))	('segmental', 'Disease', (112, 121))	('rearrangements', 'Var', (136, 150))
120480	24220673	Important lessons from CGH studies include:  A consequence of the high level of chromosomal instability is the rapid accumulation of a large number of somatic mutations (a phenomenon known as mutator phenotype, which contributes to disease progression towards metastasis and resistance to therapy).	('contributes to', 'Reg', (217, 231))	('mutations', 'Var', (159, 168))	('metastasis', 'Disease', 'MESH:D009362', (260, 270))	('chromosomal instability', 'Phenotype', 'HP:0040012', (80, 103))	('metastasis', 'Disease', (260, 270))
120481	24220673	It is already known that many of these somatic mutations are passenger and does not contribute to tumor evolution but are instead a consequence of the accelerated mutagenesis process.	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mutations', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
120482	24220673	On the other hand, driver mutations are the genetic events relevant to somatic evolution of a tumor, conferring selective advantages to cellular clones in which they appear.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('mutations', 'Var', (26, 35))	('advantages', 'PosReg', (122, 132))
120484	24220673	In the pre high throughput sequencing era, many of the driver mutations relevant to molecular pathogenesis of ACTs were identified by understanding the molecular genetics of rare familial syndromes in which ACCs were a manifestation.	('ACCs', 'Gene', (207, 211))	('ACCs', 'Gene', '84680', (207, 211))	('mutations', 'Var', (62, 71))
120488	24220673	Germline mutations of the tumor suppressor TP53 are found in ~70% of cases of LFS.	('found', 'Reg', (52, 57))	('Germline mutations', 'Var', (0, 18))	('LFS', 'Disease', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('LFS', 'Disease', 'MESH:D016864', (78, 81))	('TP53', 'Gene', '7157', (43, 47))	('tumor', 'Disease', (26, 31))	('TP53', 'Gene', (43, 47))
120490	24220673	The prevalence of germline TP53 mutations in apparently sporadic ACT patients varies according to the age group.	('TP53', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('TP53', 'Gene', '7157', (27, 31))	('patients', 'Species', '9606', (69, 77))
120492	24220673	Data from the USA and Europe indicates that the prevalence of germline TP53 mutations in pediatric patients is ~50-80%.	('patients', 'Species', '9606', (99, 107))	('TP53', 'Gene', (71, 75))	('TP53', 'Gene', '7157', (71, 75))	('mutations', 'Var', (76, 85))
120493	24220673	A specific germline TP53 mutation (p.R337H) is present in up to 90% of the affected patients.	('TP53', 'Gene', (20, 24))	('patients', 'Species', '9606', (84, 92))	('p.R337H', 'Var', (35, 42))	('p.R337H', 'Mutation', 'rs121912664', (35, 42))	('TP53', 'Gene', '7157', (20, 24))
120496	24220673	Initially, the p.R337H mutation was thought to predispose only to childhood ACC, but it has been lately demonstrated that the carriers are at increased risk for the development of other malignancies associated with LFS, such as choroid plexus tumors and breast cancer.	('p.R337H', 'Mutation', 'rs121912664', (15, 22))	('LFS', 'Disease', 'MESH:D016864', (215, 218))	('breast cancer', 'Disease', 'MESH:D001943', (254, 267))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('malignancies', 'Disease', 'MESH:D009369', (186, 198))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('breast cancer', 'Disease', (254, 267))	('choroid plexus tumors', 'Disease', 'MESH:D016545', (228, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (254, 267))	('p.R337H', 'Var', (15, 22))	('choroid plexus tumors', 'Disease', (228, 249))	('childhood ACC', 'Disease', (66, 79))	('LFS', 'Disease', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('malignancies', 'Disease', (186, 198))
120497	24220673	In addition, the p.R337H mutation also predisposes to adult ACC.	('p.R337H', 'Mutation', 'rs121912664', (17, 24))	('p.R337H', 'Var', (17, 24))	('adult ACC', 'Disease', (54, 63))	('predisposes', 'Reg', (39, 50))
120499	24220673	Given the impact of identifying a germline TP53 mutation not only to the patient but also to family members, genetic testing is recommended for any patient with ACC, even in absence of family history of cancer, since TP53 germline mutations are known to occur de novo in about 25% of cases.	('TP53', 'Gene', '7157', (217, 221))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (217, 221))	('patient', 'Species', '9606', (73, 80))	('mutation', 'Var', (48, 56))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('patient', 'Species', '9606', (148, 155))	('TP53', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
120501	24220673	On the other hand, the prevalence of somatic TP53 mutations is low in ACAs, suggesting that TP53 inactivation is a late step in tumorigenesis, a fact that is in accordance with observations from other cancers and multistep tumorigenesis models.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('tumor', 'Disease', (223, 228))	('TP53', 'Gene', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('mutations', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('inactivation', 'NegReg', (97, 109))	('TP53', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('TP53', 'Gene', '7157', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', (128, 133))	('TP53', 'Gene', '7157', (45, 49))
120502	24220673	It has been proposed that TP53 inactivation follows the classic Knudson's two-hit hypothesis for a tumor suppressor gene, in which both alleles should be inactivated.	('TP53', 'Gene', (26, 30))	('tumor', 'Disease', (99, 104))	('inactivation', 'Var', (31, 43))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('TP53', 'Gene', '7157', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
120503	24220673	In the presence of a germline or a somatic inactivating TP53 mutation, a second genetic event should be responsible for the inactivation of the second allele.	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('mutation', 'Var', (61, 69))
120504	24220673	Interestingly, it has been demonstrated that ACCs exhibit a high frequency of 17p13 LOH (~85%).	('ACCs', 'Gene', (45, 49))	('17p13 LOH', 'Var', (78, 87))	('ACCs', 'Gene', '84680', (45, 49))
120508	24220673	Somatic TP53 mutations could be identified in the majority of these tumors.	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Disease', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutations', 'Var', (13, 22))
120511	24220673	The molecular basis of this syndrome is complex, including genetic and epigenetic alterations at chromosomal locus 11p15, which contains the genes CDKN1C, IGF2 and H19, structurally organized in a cluster (Figure 3).	('H19', 'Gene', (164, 167))	('CDKN1C', 'Gene', '1028', (147, 153))	('IGF2', 'Gene', (155, 159))	('epigenetic alterations', 'Var', (71, 93))	('H19', 'Gene', '283120', (164, 167))	('IGF2', 'Gene', '3481', (155, 159))	('CDKN1C', 'Gene', (147, 153))
120514	24220673	In BWS, multiple epigenetic and structural changes at 11p15, including parent-of-origin-specific duplications, translocations/inversions, microdeletions, DNA methylation changes at regulatory regions, uniparental isodisomy, and mutations at CDKN1C lead to biallelic expression of IGF2 and inactivation of CDKN1C and H19.	('CDKN1C', 'Gene', '1028', (241, 247))	('biallelic', 'MPA', (256, 265))	('H19', 'Gene', (316, 319))	('IGF2', 'Gene', '3481', (280, 284))	('microdeletions', 'Var', (138, 152))	('inactivation', 'NegReg', (289, 301))	('IGF2', 'Gene', (280, 284))	('uniparental isodisomy', 'Disease', (201, 222))	('mutations', 'Var', (228, 237))	('CDKN1C', 'Gene', (305, 311))	('translocations/inversions', 'Var', (111, 136))	('uniparental isodisomy', 'Disease', 'MESH:D024182', (201, 222))	('CDKN1C', 'Gene', '1028', (305, 311))	('lead to', 'Reg', (248, 255))	('CDKN1C', 'Gene', (241, 247))	('H19', 'Gene', '283120', (316, 319))
120521	24220673	It has been demonstrated that IGF2 overexpression is caused by somatic structural alterations of the 11p15 locus, such as paternal isodisomy (loss of the maternal allele and duplication of the paternal allele - Figure 3) and loss of imprinting because of demethylation of the maternal allele.	('paternal isodisomy', 'Disease', (122, 140))	('loss', 'NegReg', (142, 146))	('11p15', 'Gene', (101, 106))	('duplication', 'Var', (174, 185))	('loss', 'NegReg', (225, 229))	('IGF2', 'Gene', '3481', (30, 34))	('IGF2', 'Gene', (30, 34))	('paternal isodisomy', 'Disease', 'MESH:D024182', (122, 140))	('caused', 'Reg', (53, 59))	('overexpression', 'PosReg', (35, 49))	('demethylation', 'Var', (255, 268))	('imprinting', 'MPA', (233, 243))
120522	24220673	Parental isodisomy can be assessed by microsatellite markers within the 11p15 locus.	('microsatellite markers', 'Var', (38, 60))	('isodisomy', 'Disease', 'MESH:D024182', (9, 18))	('isodisomy', 'Disease', (9, 18))
120523	24220673	The presence of 11p15 LOH indicates paternal isodisomy and is associated with overexpression of IGF2 and poor outcome.	('paternal isodisomy', 'Disease', (36, 54))	('associated', 'Reg', (62, 72))	('paternal isodisomy', 'Disease', 'MESH:D024182', (36, 54))	('11p15', 'Gene', (16, 21))	('overexpression', 'MPA', (78, 92))	('IGF2', 'Gene', '3481', (96, 100))	('presence', 'Var', (4, 12))	('IGF2', 'Gene', (96, 100))
120527	24220673	Early clinical trials with IGF1R inhibitors have demonstrated beneficial effects in some patients with advanced disease.	('beneficial effects', 'PosReg', (62, 80))	('advanced disease', 'Disease', (103, 119))	('IGF1R', 'Gene', (27, 32))	('patients', 'Species', '9606', (89, 97))	('advanced disease', 'Disease', 'MESH:D020178', (103, 119))	('clinical', 'Species', '191496', (6, 14))	('IGF1R', 'Gene', '3480', (27, 32))	('inhibitors', 'Var', (33, 43))
120530	24220673	mTOR pathway is a downstream target of IGF1R signaling (Figure 5) and its pharmacological inhibition significantly reduces cell growth and induces apoptosis in both cell lines and xenographic models.	('IGF1R', 'Gene', (39, 44))	('induces', 'Reg', (139, 146))	('IGF1R', 'Gene', '3480', (39, 44))	('reduces', 'NegReg', (115, 122))	('cell growth', 'CPA', (123, 134))	('inhibition', 'Var', (90, 100))	('apoptosis', 'CPA', (147, 156))	('mTOR', 'Gene', '2475', (0, 4))	('mTOR', 'Gene', (0, 4))
120534	24220673	In fact, preclinical studies have demonstrated that inhibition of PI3K and mTOR with the dual inhibitor NVP-BEZ235 prevented Akt hyperphosphorilation associated with mTOR inhibitors.	('Akt', 'Gene', (125, 128))	('mTOR', 'Gene', (166, 170))	('mTOR', 'Gene', '2475', (166, 170))	('clinical', 'Species', '191496', (12, 20))	('inhibition', 'Var', (52, 62))	('prevented', 'NegReg', (115, 124))	('mTOR', 'Gene', (75, 79))	('NVP-BEZ235', 'Chemical', 'MESH:C531198', (104, 114))	('mTOR', 'Gene', '2475', (75, 79))	('Akt', 'Gene', '207', (125, 128))	('PI3K', 'Pathway', (66, 70))
120536	24220673	In fact, a phase I trial of the combination of cixutumumab (a IGF1R inhibitor) and temsirolimus (a mTOR inhibitor) have demonstrated antitumor activity in metastatic ACC.	('IGF1R', 'Gene', '3480', (62, 67))	('temsirolimus', 'Chemical', 'MESH:C401859', (83, 95))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cixutumumab', 'Var', (47, 58))	('cixutumumab', 'Chemical', 'MESH:C557414', (47, 58))	('mTOR', 'Gene', '2475', (99, 103))	('IGF1R', 'Gene', (62, 67))	('mTOR', 'Gene', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
120541	24220673	FAP is caused by germline inactivating mutations of the APC gene.	('germline', 'Var', (17, 25))	('FAP', 'Gene', '2191', (0, 3))	('APC', 'Gene', (56, 59))	('FAP', 'Gene', (0, 3))	('APC', 'Gene', '324', (56, 59))	('caused by', 'Reg', (7, 16))
120549	24220673	In Gardner's syndrome, the loss of APC causes a constitutional activation of the Wnt pathway, leading to tumor development in many organs, including the adrenals.	('loss', 'Var', (27, 31))	('Wnt pathway', 'Pathway', (81, 92))	('APC', 'Gene', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	("Gardner's syndrome", 'Disease', 'MESH:D005736', (3, 21))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	("Gardner's syndrome", 'Disease', (3, 21))	('APC', 'Gene', '324', (35, 38))	('tumor', 'Disease', (105, 110))	('activation', 'PosReg', (63, 73))	('leading to', 'Reg', (94, 104))
120550	24220673	Although somatic APC mutations are rare events in sporadic ACTs, nuclear beta-catenin staining is frequently observed (~30% of cases, both ACAs and ACCs).	('beta-catenin', 'Gene', (73, 85))	('APC', 'Gene', (17, 20))	('ACCs', 'Gene', '84680', (148, 152))	('APC', 'Gene', '324', (17, 20))	('ACCs', 'Gene', (148, 152))	('beta-catenin', 'Gene', '1499', (73, 85))	('mutations', 'Var', (21, 30))
120551	24220673	Activating mutations of CTNNB1, which affects the phosphorylation site of beta-catenin and prevents its proteasomal degradation (Figure 4C), have been described in approximately 50% of such cases, suggesting that alterations in other components of the Wnt pathway may be involved.	('prevents', 'NegReg', (91, 99))	('mutations', 'Var', (11, 20))	('proteasomal degradation', 'MPA', (104, 127))	('CTNNB1', 'Gene', (24, 30))	('beta-catenin', 'Gene', (74, 86))	('affects', 'Reg', (38, 45))	('CTNNB1', 'Gene', '1499', (24, 30))	('phosphorylation site of', 'MPA', (50, 73))	('beta-catenin', 'Gene', '1499', (74, 86))
120552	24220673	In fact, mutations of AXIN2, which is part of the "destruction complex", have been described in ACTs with positive immunostaining for nuclear beta-catenin, but not in adrenocortical hyperplasias.	('AXIN2', 'Gene', '8313', (22, 27))	('beta-catenin', 'Gene', (142, 154))	('mutations', 'Var', (9, 18))	('beta-catenin', 'Gene', '1499', (142, 154))	('adrenocortical hyperplasias', 'Disease', 'MESH:D018268', (167, 194))	('AXIN2', 'Gene', (22, 27))	('adrenocortical hyperplasias', 'Disease', (167, 194))
120553	24220673	However, another study identified the same AXIN2 somatic mutation (c2013_2024del 12) in only 1 out of 49 patients with apparently sporadic ACCs.	('patients', 'Species', '9606', (105, 113))	('c2013_2024del 12', 'Var', (67, 83))	('AXIN2', 'Gene', '8313', (43, 48))	('ACCs', 'Gene', (139, 143))	('ACCs', 'Gene', '84680', (139, 143))	('AXIN2', 'Gene', (43, 48))
120556	24220673	The authors concluded that the c2013_2024del 12 AXIN2 mutation is probably a benign polymorphism and AXIN genes mutations do not have a role in Wnt activation.	('AXIN', 'Gene', (48, 52))	('AXIN2', 'Gene', (48, 53))	('AXIN2', 'Gene', '8313', (48, 53))	('c2013_2024del 12', 'Var', (31, 47))	('AXIN', 'Gene', (101, 105))	('AXIN', 'Gene', '8312', (48, 52))	('AXIN', 'Gene', '8312', (101, 105))
120559	24220673	The molecular basis of the syndrome is mutations in DNA mismatch-repair genes, including MLH1, MSH2, MSH6, and PMS2.	('MSH2', 'Gene', (95, 99))	('MSH6', 'Gene', (101, 105))	('MSH2', 'Gene', '4436', (95, 99))	('MLH1', 'Gene', '4292', (89, 93))	('PMS2', 'Gene', (111, 115))	('MLH1', 'Gene', (89, 93))	('mutations', 'Var', (39, 48))	('PMS2', 'Gene', '5395', (111, 115))	('MSH6', 'Gene', '2956', (101, 105))
120565	24220673	In addition, the presence of ACC was retrospectively evaluated in 135 patients with known germline mutations in DNA mismatch-repair genes and two cases were identified.	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (99, 108))	('DNA mismatch-repair', 'Gene', (112, 131))
120566	24220673	Four ACC samples from these patients were studied for microsatellite stability and DNA mismatch-repair genes deficiency.	('patients', 'Species', '9606', (28, 36))	('DNA mismatch-repair genes', 'Gene', (83, 108))	('deficiency', 'Var', (109, 119))
120569	24220673	This syndrome is caused by germline inactivating mutations of the MEN1 tumor suppressor gene, on chromosome 11q13.	('MEN1', 'Gene', '4221', (66, 70))	('MEN1', 'Gene', (66, 70))	('germline', 'Var', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('caused by', 'Reg', (17, 26))	('tumor', 'Disease', (71, 76))
120576	24220673	The EGFR is a tyrosine kinase-coupled receptor, in which overexpression and activating somatic mutations have been documented in multiple human cancers, such as lung, colon, and breast.	('breast', 'Disease', (178, 184))	('lung', 'Disease', (161, 165))	('overexpression', 'PosReg', (57, 71))	('colon', 'Disease', (167, 172))	('EGFR', 'Gene', (4, 8))	('human', 'Species', '9606', (138, 143))	('activating', 'PosReg', (76, 86))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('mutations', 'Var', (95, 104))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('EGFR', 'Gene', '1956', (4, 8))
120578	24220673	Activating mutations of Ras and BRAF oncogenes are among the most frequently observed in human cancer.	('human', 'Species', '9606', (89, 94))	('Ras', 'Gene', (24, 27))	('BRAF', 'Gene', '673', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('BRAF', 'Gene', (32, 36))	('Activating mutations', 'Var', (0, 20))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
120579	24220673	In endocrine tissues, these mutations are frequently described in well-differentiated thyroid cancer.	('thyroid cancer', 'Phenotype', 'HP:0002890', (86, 100))	('thyroid cancer', 'Disease', (86, 100))	('thyroid cancer', 'Disease', 'MESH:D013964', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('described', 'Reg', (53, 62))	('mutations', 'Var', (28, 37))
120583	24220673	In addition, activating NRAS mutations were identified in 12% of samples.	('activating', 'PosReg', (13, 23))	('NRAS', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('NRAS', 'Gene', '4893', (24, 28))
120585	24220673	The presence of activating BRAF p.V600E activating mutation has also been studied and was identified in only two out of 35 ACCs.	('activating', 'PosReg', (40, 50))	('p.V600E', 'Mutation', 'rs113488022', (32, 39))	('p.V600E', 'Var', (32, 39))	('ACCs', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', (27, 31))	('activating', 'PosReg', (16, 26))	('ACCs', 'Gene', '84680', (123, 127))
120588	24220673	In addition, a BRAF activating mutation (p.V600E) was identified in a single case, but no mutations on PIK3CA and KRAS could be found.	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (15, 19))	('p.V600E', 'Mutation', 'rs113488022', (41, 48))	('PIK3CA', 'Gene', (103, 109))	('KRAS', 'Gene', (114, 118))	('KRAS', 'Gene', '3845', (114, 118))	('p.V600E', 'Var', (41, 48))	('PIK3CA', 'Gene', '5290', (103, 109))
120589	24220673	Although EGFR is frequently overexpressed in ACC, the low number of activating mutations suggests that pharmacological inhibition of EGFR with TK inhibitors would be of limited efficacy.	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('EGFR', 'Gene', '1956', (133, 137))	('EGFR', 'Gene', (133, 137))	('mutations', 'Var', (79, 88))
120592	24220673	Analogously to thyroid nodules, in which activating mutations of TSH receptor have been described, it has been hypothesized that activating MC2R mutations may contribute to adrenocortical tumorigenesis.	('MC2R', 'Gene', (140, 144))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (173, 201))	('TSH receptor', 'Gene', '7253', (65, 77))	('mutations', 'Var', (145, 154))	('MC2R', 'Gene', '4158', (140, 144))	('thyroid nodules', 'Phenotype', 'HP:0025388', (15, 30))	('activating', 'PosReg', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('contribute', 'Reg', (159, 169))	('adrenocortical tumorigenesis', 'Disease', (173, 201))	('TSH receptor', 'Gene', (65, 77))
120596	24220673	Anomalous blood vessels are a characteristic of virtually all types of cancer.	('cancer', 'Disease', (71, 77))	('Anomalous', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
120621	24220673	There is growing evidence to suggest that DNA methylation, in addition to genetic modification may cause altered patterns of gene expression resulting in tumorigenesis.	('patterns of gene expression', 'MPA', (113, 140))	('cause altered', 'Reg', (99, 112))	('resulting in', 'Reg', (141, 153))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('DNA methylation', 'Var', (42, 57))	('tumor', 'Disease', (154, 159))
120623	24220673	In addition, although TP53 promoter methylation has been described in some types of cancer, it does not seem to be an important event in ACC.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))	('methylation', 'Var', (36, 47))
120632	24220673	In addition, dysregulation of miRNAs, such as overexpression or deletion, play an important role in disease processes including various cancers.	('overexpression', 'PosReg', (46, 60))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('miRNAs', 'Protein', (30, 36))	('cancers', 'Disease', (136, 143))	('dysregulation', 'Var', (13, 26))	('deletion', 'Var', (64, 72))	('play', 'Reg', (74, 78))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
120633	24220673	The effects of miRNA dysregulation in a cancer cell include silencing of tumor-suppressor genes, activation of various oncogenes, and/or growth factors important in tumor angiogenesis, epithelial-to-mesenchymal transition, and metastasis.	('metastasis', 'Disease', 'MESH:D009362', (227, 237))	('metastasis', 'Disease', (227, 237))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('activation', 'PosReg', (97, 107))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Disease', (40, 46))	('miRNA', 'Gene', (15, 20))	('dysregulation', 'Var', (21, 34))	('tumor', 'Disease', (73, 78))	('silencing', 'NegReg', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', (165, 170))
120648	24220673	It is hypothesized that dysregulation of the IGF2 locus in turn perturb the expression of miR-483.	('perturb', 'Reg', (64, 71))	('miR-483', 'Gene', (90, 97))	('dysregulation', 'Var', (24, 37))	('expression', 'MPA', (76, 86))	('IGF2', 'Gene', '3481', (45, 49))	('miR-483', 'Gene', '619552', (90, 97))	('IGF2', 'Gene', (45, 49))
120665	24220673	The fact that ACCs have accumulated a large set of genetic changes is well accepted, but it is not totally clear whether some of these mutations were acquired in a premalignant stage.	('ACCs', 'Gene', (14, 18))	('ACCs', 'Gene', '84680', (14, 18))	('changes', 'Var', (59, 66))
120669	24220673	Although PPNAD is typically a benign disease, two cases of ACCs have been described in two non-related patients with CC, suggesting that the dysregulation of the cAMP pathway may have been involved in malignant transformation.	('ACCs', 'Gene', (59, 63))	('PPNAD', 'Disease', (9, 14))	('ACCs', 'Gene', '84680', (59, 63))	('benign disease', 'Disease', (30, 44))	('involved', 'Reg', (189, 197))	('benign disease', 'Disease', 'MESH:D009369', (30, 44))	('cAMP', 'Gene', (162, 166))	('cAMP', 'Gene', '820', (162, 166))	('dysregulation', 'Var', (141, 154))	('patients', 'Species', '9606', (103, 111))
120671	24220673	Interestingly, somatic CTNNB1 mutations have also been demonstrated in larger nodules of patients with PPNAD, suggesting that PKA chronic activation might cause selection pressure upon the appearance of such mutations.	('patients', 'Species', '9606', (89, 97))	('CTNNB1', 'Gene', (23, 29))	('mutations', 'Var', (30, 39))	('CTNNB1', 'Gene', '1499', (23, 29))
120675	24220673	The fact that both nuclear beta-catenin immunostaining and activating CTNNB1 mutations are present in ACAs as well as in ACCs suggests that Wnt activation may be an early step in adrenocortical tumorigenesis, which precedes malignant transformation, assuming that ACCs may arise from ACAs.	('CTNNB1', 'Gene', '1499', (70, 76))	('beta-catenin', 'Gene', '1499', (27, 39))	('ACCs', 'Gene', '84680', (264, 268))	('ACCs', 'Gene', (121, 125))	('activating', 'PosReg', (59, 69))	('ACCs', 'Gene', (264, 268))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (179, 207))	('ACCs', 'Gene', '84680', (121, 125))	('adrenocortical tumorigenesis', 'Disease', (179, 207))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('mutations', 'Var', (77, 86))	('CTNNB1', 'Gene', (70, 76))	('beta-catenin', 'Gene', (27, 39))
120677	24220673	Mice with constitutive activation of the Wnt signaling pathway obtained by adrenal-specific Apc knockout develop adrenal hyperplasia and adenomas by 30 weeks of life.	('adenomas', 'Disease', 'MESH:D000236', (137, 145))	('adrenal hyperplasia', 'Disease', (113, 132))	('Apc', 'Gene', (92, 95))	('Apc', 'Gene', '11789', (92, 95))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (113, 132))	('adenomas', 'Disease', (137, 145))	('Mice', 'Species', '10090', (0, 4))	('knockout', 'Var', (96, 104))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (113, 132))
120692	23781302	We conclude that mitotane causes consistent changes in cortisol catabolism, most of which have not been previously recognised.	('changes', 'Reg', (44, 51))	('mitotane', 'Var', (17, 25))	('mitotane', 'Chemical', 'MESH:D008939', (17, 25))	('cortisol catabolism', 'MPA', (55, 74))	('cortisol', 'Chemical', 'MESH:D006854', (55, 63))
120707	23781302	Patients with Cushing's syndrome receiving mitotane have shown decrease in the adrenal cortisol secretion rate over time but a faster clinical benefit, suggesting that cortisol bioavailability is also diminished.	('adrenal cortisol secretion rate', 'MPA', (79, 110))	('mitotane', 'Chemical', 'MESH:D008939', (43, 51))	('cortisol bioavailability', 'MPA', (168, 192))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (14, 32))	('clinical benefit', 'MPA', (134, 150))	('decrease', 'NegReg', (63, 71))	('Patients', 'Species', '9606', (0, 8))	("Cushing's syndrome", 'Disease', (14, 32))	('cortisol', 'Chemical', 'MESH:D006854', (87, 95))	('cortisol', 'Chemical', 'MESH:D006854', (168, 176))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (14, 32))	('diminished', 'NegReg', (201, 211))	('mitotane', 'Var', (43, 51))
120712	23781302	1) A-ring-reduced products 5beta-tetrahydrocortisone and 5alpha- and 5beta-tetrahydrocortisol; further reduction at C20 gives rise to the 20alpha- and 20beta-hydroxy products, cortolones and cortols.	('cortolones', 'Chemical', 'MESH:C003545', (176, 186))	('5beta-tetrahydrocortisone', 'Chemical', '-', (27, 52))	('20alpha-', 'MPA', (138, 146))	('hydroxy', 'Chemical', '-', (158, 165))	('cortols', 'Chemical', 'MESH:C003544', (191, 198))	('C20', 'Var', (116, 119))	('5alpha- and 5beta-tetrahydrocortisol', 'Chemical', '-', (57, 93))	('cortolones', 'MPA', (176, 186))	('20alpha', 'Chemical', '-', (138, 145))
120761	23781302	Indeed, after mitotane, nine females individually showed an increase in the ratio of androsterone/aetiocholanolone relative to their pre-mitotane values, with single pre- and post-menopausal patients showing falls.	('fall', 'Phenotype', 'HP:0002527', (208, 212))	('mitotane', 'Chemical', 'MESH:D008939', (137, 145))	('falls', 'Disease', 'MESH:C537863', (208, 213))	('patients', 'Species', '9606', (191, 199))	('androsterone/aetiocholanolone', 'MPA', (85, 114))	('mitotane', 'Var', (14, 22))	('increase', 'PosReg', (60, 68))	('androsterone', 'Chemical', 'MESH:D000738', (85, 97))	('ratio', 'MPA', (76, 81))	('aetiocholanolone', 'Chemical', 'MESH:D005043', (98, 114))	('mitotane', 'Chemical', 'MESH:D008939', (14, 22))	('falls', 'Phenotype', 'HP:0002527', (208, 213))	('falls', 'Disease', (208, 213))
120773	23781302	Figure 5b and c shows that there are no net changes in oxidoreduction at C11 and C20, respectively, indicating that there are no suppressive effects on 11- or 20-hydroxysteroid dehydrogenase activities.	('11-', 'Enzyme', (152, 155))	('C11', 'Gene', (73, 76))	('C20', 'Var', (81, 84))	('oxidoreduction', 'MPA', (55, 69))	('activities', 'MPA', (191, 201))	('C11', 'Gene', '1109', (73, 76))
120794	23781302	Mitotane has a specific cytotoxic effect on the mitochondria of adrenal cortical cells and produces focal degeneration of the reticularis and fasciculata zones and only small changes in the zona glomerulosa.	('Mitotane', 'Var', (0, 8))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('focal degeneration of the reticularis and fasciculata zones', 'Disease', 'MESH:D054068', (100, 159))	('fasciculata zones', 'Phenotype', 'HP:0002380', (142, 159))	('mitochondria', 'MPA', (48, 60))
120795	23781302	However, evidence for decrease in cortisol secretion due to mitotane as a contributor to increased hydrocortisone dose requirement is lacking.	('decrease in cortisol', 'Phenotype', 'HP:0008163', (22, 42))	('increased hydrocortisone', 'Phenotype', 'HP:0003118', (89, 113))	('cortisol', 'Chemical', 'MESH:D006854', (34, 42))	('cortisol secretion', 'MPA', (34, 52))	('hydrocortisone', 'Chemical', 'MESH:D006854', (99, 113))	('mitotane', 'Var', (60, 68))	('mitotane', 'Chemical', 'MESH:D008939', (60, 68))
120808	23781302	In a single female patient with documented AKR1D1 deficiency, there was a decrease in 5beta-reduced urinary androgen metabolites to 20% of normal but near absence of 5beta-tetrahydrocortisol.	('decrease', 'NegReg', (74, 82))	('patient', 'Species', '9606', (19, 26))	('5beta-reduced urinary androgen metabolites', 'MPA', (86, 128))	('AKR1D1', 'Gene', '6718', (43, 49))	('5beta-tetrahydrocortisol', 'Chemical', 'MESH:D013760', (166, 190))	('5beta', 'Chemical', '-', (86, 91))	('5beta', 'Chemical', '-', (166, 171))	('AKR1D1', 'Gene', (43, 49))	('deficiency', 'Var', (50, 60))
120811	23781302	This is evident from consistent diagnostic decreases in the ratio of urinary 5alpha/5beta-tetrahydrocortisol in patients with 5ARD2 deficiency, although a recent review concluded, surprisingly, that hepatic cortisol reduction used 5ARD1, based on in vitro findings.	('5ARD2', 'Gene', (126, 131))	('urinary 5alpha/5beta-tetrahydrocortisol', 'MPA', (69, 108))	('5ARD2', 'Chemical', '-', (126, 131))	('patients', 'Species', '9606', (112, 120))	('reduction', 'NegReg', (216, 225))	('cortisol', 'Chemical', 'MESH:D006854', (100, 108))	('5alpha/5beta-tetrahydrocortisol', 'Chemical', '-', (77, 108))	('hepatic cortisol', 'MPA', (199, 215))	('decreases', 'NegReg', (43, 52))	('cortisol', 'Chemical', 'MESH:D006854', (207, 215))	('deficiency', 'Var', (132, 142))	('cortisol reduction', 'Phenotype', 'HP:0008163', (207, 225))	('ratio', 'MPA', (60, 65))
120822	23781302	It may be concluded that these studies support and expand previous findings, emphasising that mitotane has profound effects on metabolism of cortisol of exogenous origin, and this would diminish oral bioavailability and further activation.	('oral bioavailability', 'MPA', (195, 215))	('activation', 'PosReg', (228, 238))	('diminish', 'NegReg', (186, 194))	('mitotane', 'Var', (94, 102))	('mitotane', 'Chemical', 'MESH:D008939', (94, 102))	('metabolism of cortisol', 'MPA', (127, 149))	('cortisol', 'Chemical', 'MESH:D006854', (141, 149))	('effects', 'Reg', (116, 123))
120866	23099271	In the majority of patients with MMAD, however, the disease does not appear to be GIPR-dependent; aberrant expression of other receptors may be responsible for the disease in these patients.	('aberrant', 'Var', (98, 106))	('MMAD', 'Disease', (33, 37))	('patients', 'Species', '9606', (19, 27))	('GIPR', 'Gene', (82, 86))	('GIPR', 'Gene', '2696', (82, 86))	('patients', 'Species', '9606', (181, 189))	('MMAD', 'Disease', 'None', (33, 37))
120868	23099271	In this syndrome, there is a somatic mutation of the GNAS1 gene leading to constitutive activation of the Gsalpha protein and continuous, non-ACTH-dependent activation of steroidogenesis by the adrenal cortex.	('ACTH', 'Gene', '5443', (142, 146))	('steroid', 'Chemical', 'MESH:D013256', (171, 178))	('activation', 'PosReg', (88, 98))	('Gsalpha', 'Gene', (106, 113))	('mutation', 'Var', (37, 45))	('GNAS1', 'Gene', (53, 58))	('Gsalpha', 'Gene', '2778', (106, 113))	('activation', 'PosReg', (157, 167))	('GNAS1', 'Gene', '2778', (53, 58))	('steroidogenesis', 'MPA', (171, 186))	('ACTH', 'Gene', (142, 146))
120870	23099271	Aberrant cyclic adenosine monophosphate (cAMP) signaling has been linked to almost all genetic forms of adrenal-dependent cortisol excess.	('cyclic adenosine monophosphate', 'Chemical', 'MESH:D000242', (9, 39))	('Aberrant', 'Var', (0, 8))	('linked', 'Reg', (66, 72))	('cortisol', 'Chemical', 'MESH:D006854', (122, 130))	('cAMP', 'Chemical', 'MESH:D000242', (41, 45))	('cortisol excess', 'Phenotype', 'HP:0003118', (122, 137))
120871	23099271	PPNAD is associated with germline inactivating mutations of the PRKAR1A gene.	('PRKAR1A', 'Gene', (64, 71))	('PPNAD', 'Chemical', '-', (0, 5))	('associated', 'Reg', (9, 19))	('germline inactivating mutations', 'Var', (25, 56))	('PPNAD', 'Disease', (0, 5))	('PRKAR1A', 'Gene', '5573', (64, 71))
121037	31892624	Because mitotane increases cortisol binding globulin levels, serum cortisol is not a useful marker to monitor response to therapy.	('increases', 'PosReg', (17, 26))	('cortisol', 'Chemical', 'MESH:D006854', (67, 75))	('cortisol binding globulin levels', 'MPA', (27, 59))	('cortisol', 'Chemical', 'MESH:D006854', (27, 35))	('mitotane', 'Var', (8, 16))	('mitotane', 'Chemical', 'MESH:D008939', (8, 16))	('increases cortisol', 'Phenotype', 'HP:0003118', (17, 35))
121102	31546652	For instance, alterations in estrogen and androgen metabolism were associated with endocrine-related cancers, including prostate, breast, endometrial, and ovarian cancer.	('alterations', 'Var', (14, 25))	('endometrial', 'Disease', (138, 149))	('estrogen', 'Chemical', 'MESH:D004967', (29, 37))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('prostate', 'Disease', (120, 128))	('associated', 'Reg', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Disease', 'MESH:D010051', (155, 169))	('breast', 'Disease', (130, 136))	('androgen', 'Chemical', 'MESH:D000728', (42, 50))	('ovarian cancer', 'Disease', (155, 169))
121174	31546652	Generally, steroidogenesis has been extensively targeted by using inhibitors of steroidogenesis as therapeutic agents for cancer and other diseases.	('steroid', 'Chemical', 'MESH:D013256', (80, 87))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('steroid', 'Chemical', 'MESH:D013256', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('inhibitors', 'Var', (66, 76))
121239	31749633	Using OSacc, we firstly found that patients with high expressing CENPF had worse OS, while the low expression of CENPF group had better OS in TCGA (HR: 10.498, 95% CI: 4.509-24.440, p<0.0001), GSE10927 (HR: 6.990, 95% CI: 2.031-24.060, p=0.0020), GSE19750 (HR: 3.738, 95% CI: 1.047-14.349, p=0.042), and GSE33371 datasets (HR: 5.075, 95% CI: 1.568-16.420, p=0.007) (Figure 3A-D).	('high expressing CENPF', 'Var', (49, 70))	('patients', 'Species', '9606', (35, 43))	('GSE19750', 'Var', (247, 255))	('GSE33371', 'Var', (304, 312))	('CENPF', 'Var', (65, 70))
121240	31749633	Not surprisingly, in the combined datasets of TCGA, GSE10927, GSE19750 and GSE33371, high CENPF-expressing group also showed poor OS (HR: 5.636, 95% CI: 3.414-9.303, p<0.0001) (Figure 3E), suggesting that CENPF is a novel unfavorable prognostic biomarker for OS in ACC.	('GSE33371', 'Var', (75, 83))	('ACC', 'Disease', 'MESH:D018268', (265, 268))	('GSE10927', 'Var', (52, 60))	('ACC', 'Phenotype', 'HP:0006744', (265, 268))	('GSE19750', 'Var', (62, 70))	('ACC', 'Disease', (265, 268))
121266	31442209	Recent years, great advancement has been achieved in immunotherapy especially with the introduction of checkpoint blockers into cancer treatment, such as antibodies blocking PD-1/PD-L1 and CTLA-4.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('CTLA-4', 'Gene', (189, 195))	('antibodies', 'Var', (154, 164))	('PD-1', 'Gene', (174, 178))	('PD-1', 'Gene', '5133', (174, 178))	('PD-L1', 'Gene', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('CTLA-4', 'Gene', '1493', (189, 195))	('PD-L1', 'Gene', '29126', (179, 184))	('cancer', 'Disease', (128, 134))
121272	31442209	In addition, pseudogene-encoded proteins presented on surface of malignant cells can provide new antigens which are crucial for immune system recognition against human cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('antigens', 'MPA', (97, 105))	('proteins', 'Protein', (32, 40))	('human', 'Species', '9606', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('pseudogene-encoded', 'Var', (13, 31))	('cancer', 'Disease', (168, 174))
121297	31442209	Interestingly, we also observed that UHRF1 was closely related to immune-associated biological processes, such as T cell activation (GO:0042110), adaptive immune response (GO:0002250), T cell receptor signaling pathway (GO:0050852) and T cell differentiation in thymus (GO:0033077) (Figure 3A).	('UHRF1', 'Gene', (37, 42))	('UHRF1', 'Gene', '29128', (37, 42))	('GO:0042110', 'Var', (133, 143))	('adaptive immune response', 'CPA', (146, 170))	('GO:0002250', 'Var', (172, 182))	('T cell activation', 'CPA', (114, 131))	('T cell differentiation', 'CPA', (236, 258))	('GO:0050852', 'Var', (220, 230))	('T cell receptor signaling pathway', 'Pathway', (185, 218))	('related', 'Reg', (55, 62))
121328	31442209	Pseudogenes most likely impact their parental gene expression via ceRNA network in which pseudogene RNAs interact with their counterparts through competitively binding to common miRNAs and attenuate repression on the parental genes.	('RNAs', 'Gene', (100, 104))	('Pseudogenes', 'Var', (0, 11))	('miR', 'Gene', '220972', (178, 181))	('attenuate', 'NegReg', (189, 198))	('miR', 'Gene', (178, 181))	('impact', 'Reg', (24, 30))	('binding', 'Interaction', (160, 167))	('parental gene expression', 'MPA', (37, 61))	('repression', 'MPA', (199, 209))
121329	31442209	In this context, pseudogene PTENP1 up-regulated its parental gene PTEN expression by sponging miR-19b, miR-21, miR-193-3p and miR-200c.	('miR', 'Gene', (126, 129))	('miR-200c', 'Gene', (126, 134))	('PTENP1', 'Gene', (28, 34))	('PTENP1', 'Gene', '11191', (28, 34))	('PTEN', 'Gene', (28, 32))	('miR-21', 'Gene', '406991', (103, 109))	('up-regulated', 'PosReg', (35, 47))	('expression', 'MPA', (71, 81))	('miR-19b', 'Gene', (94, 101))	('PTEN', 'Gene', '5728', (28, 32))	('PTEN', 'Gene', (66, 70))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', '220972', (111, 114))	('pseudogene', 'Var', (17, 27))	('PTEN', 'Gene', '5728', (66, 70))	('miR', 'Gene', '220972', (126, 129))	('miR-21', 'Gene', (103, 109))	('miR-19b', 'Gene', '406980', (94, 101))	('miR', 'Gene', (94, 97))	('miR', 'Gene', (103, 106))	('miR-200c', 'Gene', '406985', (126, 134))	('miR', 'Gene', (111, 114))
121344	31442209	Increasing evidence revealed that CLTA-4 and PD-L1 were regulated in several different ways, from genetic alterations and epigenetic modification to transcriptional regulation.	('epigenetic modification', 'Var', (122, 145))	('CLTA-4', 'Gene', (34, 40))	('PD-L1', 'Gene', '29126', (45, 50))	('CLTA-4', 'Chemical', '-', (34, 40))	('genetic alterations', 'Var', (98, 117))	('PD-L1', 'Gene', (45, 50))
121349	31442209	Several studies also suggest epigenetic modifications which are probably mediated by UHRF1 activated interferon signaling through increasing endogenous retroviral elements.	('epigenetic modifications', 'Var', (29, 53))	('interferon signaling', 'Pathway', (101, 121))	('increasing', 'PosReg', (130, 140))	('endogenous retroviral elements', 'MPA', (141, 171))	('UHRF1', 'Gene', (85, 90))	('UHRF1', 'Gene', '29128', (85, 90))	('activated', 'PosReg', (91, 100))
121352	31442209	Furthermore, this study demonstrates an integrated and liable method to predict the potential role of non-coding RNAs in tumor immune based on public omics data.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('RNAs', 'Gene', (113, 117))	('non-coding', 'Var', (102, 112))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
121383	30984108	ML techniques were utilized in developing a novel mRNA based molecular test to detect BRAF V600E mutations in thyroid fine needle aspirate samples, which demonstrated sensitivity equal to that of established DNA-based assay and had lower non-diagnostic rates.	('V600E', 'Var', (91, 96))	('V600E', 'Mutation', 'rs113488022', (91, 96))	('BRAF', 'Gene', (86, 90))	('BRAF', 'Gene', '673', (86, 90))
121389	30984108	Variants of SVM, neural networks, and other ML techniques, with immunohistochemical methods were utilized in categorizing Cushing syndrome with adrenocortical lesions.	('adrenocortical lesions', 'Disease', (144, 166))	('Variants', 'Var', (0, 8))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (122, 138))	('Cushing syndrome', 'Disease', (122, 138))	('adrenocortical lesions', 'Disease', 'MESH:C565972', (144, 166))	('SVM', 'Gene', (12, 15))	('Cushing syndrome', 'Disease', 'MESH:D003480', (122, 138))
121396	30984108	Despite the substantial evidence for the ability of AI/ML to deliver cost-effective healthcare and improve patient outcomes, medicine has trailed behind other scientific fields in implementing these techniques into practice.	('patient', 'Species', '9606', (107, 114))	('improve', 'PosReg', (99, 106))	('AI/ML', 'Var', (52, 57))
121417	29520253	However, StAR expression was downregulated following transfection with TCF21, in accordance with a decrease in SF1-mediated StAR transcription.	('StAR', 'Gene', (9, 13))	('transfection', 'Var', (53, 65))	('StAR', 'Gene', '6770', (9, 13))	('StAR', 'Gene', '6770', (124, 128))	('decrease', 'NegReg', (99, 107))	('StAR', 'Gene', (124, 128))	('downregulated', 'NegReg', (29, 42))	('TCF21', 'Gene', (71, 76))
121442	29520253	The assays IDs were as follows: human beta-glucuronidase, glucuronidase beta (GUSB) (Hs00939627_m1 ID), beta-actin (ACTB) (Hs99999903_m1 ID), TCF21 (Hs00162646_m1 ID), nuclear receptor subfamily 5 group A member 1 (NR5A1) (ID Hs00610436_m1), BUB1B (ID Hs01084828_m1), and PINK1 (ID Hs00260868_m1).	('PINK1', 'Gene', '65018', (272, 277))	('nuclear receptor subfamily 5 group A member 1', 'Gene', (168, 213))	('GUSB', 'Gene', '2990', (78, 82))	('beta-actin', 'Gene', '728378', (104, 114))	('beta-glucuronidase', 'Gene', '2990', (38, 56))	('beta-glucuronidase', 'Gene', (38, 56))	('human', 'Species', '9606', (32, 37))	('GUSB', 'Gene', (78, 82))	('PINK1', 'Gene', (272, 277))	('NR5A1', 'Gene', (215, 220))	('glucuronidase beta', 'Gene', (58, 76))	('nuclear receptor subfamily 5 group A member 1', 'Gene', '2516', (168, 213))	('BUB1B', 'Gene', '701', (242, 247))	('glucuronidase beta', 'Gene', '2990', (58, 76))	('BUB1B', 'Gene', (242, 247))	('beta-actin', 'Gene', (104, 114))	('ACTB', 'Gene', '60', (116, 120))	('Hs99999903_m1', 'Var', (123, 136))	('ACTB', 'Gene', (116, 120))	('Hs00610436_m1', 'Var', (226, 239))
121447	29520253	The lentiviruses were produced in HEK-293FT cells using plasmids sgRNA (MS2) (#61427; Addgene, Cambridge, MA, USA), dCas9-VP64 (#61425; Addgene, Cambridge, MA, USA), or MS2-P65-HSF1 (#61426; Addgene, Cambridge, MA, USA).	('HEK-293FT', 'CellLine', 'CVCL:6911', (34, 43))	('HSF1', 'Gene', (177, 181))	('HSF1', 'Gene', '3297', (177, 181))	('#61426', 'Var', (183, 189))	('#61425;', 'Var', (128, 135))	('P65', 'Gene', '5970', (173, 176))	('P65', 'Gene', (173, 176))	('#61427', 'Var', (78, 84))
121456	29520253	NCI-H295R cells transfected with pcCMVMycPOD1 (Figure 4A) did not significantly affect NR5A1 expression (Figure 4B), in contrast to that observed previously, probably due to the experimental variation obtained.	('NCI-H295R', 'CellLine', 'CVCL:0458', (0, 9))	('pcCMVMycPOD1', 'Var', (33, 45))	('expression', 'MPA', (93, 103))	('NR5A1', 'Gene', (87, 92))
121457	29520253	In addition, pcCMVMycPOD1 transfection showed a tendency of reduction in BUB1B expression (Figure 4C), but did not significantly affect PINK1 expression (Figure 4D) compared with the control levels.	('PINK1', 'Gene', (136, 141))	('pcCMVMycPOD1 transfection', 'Var', (13, 38))	('transfection', 'Var', (26, 38))	('expression', 'MPA', (79, 89))	('BUB1B', 'Gene', '701', (73, 78))	('reduction', 'NegReg', (60, 69))	('BUB1B', 'Gene', (73, 78))	('PINK1', 'Gene', '65018', (136, 141))
121458	29520253	The same test with different biological approach was performed in HEK-293 and SW-13 cell lines transduced with CRISPR/Cas9/TCF21 activation system, and TCF21 showed not reduction of BUB1B expression (Figure 10).	('SW-13', 'CellLine', 'CVCL:0542', (78, 83))	('BUB1B', 'Gene', '701', (182, 187))	('TCF21', 'Var', (152, 157))	('expression', 'MPA', (188, 198))	('BUB1B', 'Gene', (182, 187))	('HEK-293', 'CellLine', 'CVCL:0045', (66, 73))
121472	29520253	However, DeltaCtTCF21 - DeltaCtNR5A1 (Figures 8E,F) showed significant differences (P = 0.026; Mann-Whitney test) between adenomas (median = 4.06; n = 27) and carcinomas (median = 1.06; n = 6).	('differences', 'Reg', (71, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('carcinomas', 'Disease', 'MESH:D002277', (159, 169))	('DeltaCtTCF21 - DeltaCtNR5A1', 'Var', (9, 36))	('carcinomas', 'Disease', (159, 169))	('adenomas', 'Disease', 'MESH:D000236', (122, 130))	('adenomas', 'Disease', (122, 130))
121491	29520253	Increased NR5A1 copy number has been associated with childhood adrenocortical tumorigenesis, although this increase does not correlate with NR5A1 protein levels.	('adrenocortical tumor', 'Disease', (63, 83))	('copy number', 'Var', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Increased', 'PosReg', (0, 9))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (63, 83))	('associated', 'Reg', (37, 47))	('NR5A1', 'Gene', (10, 15))
121501	29520253	In summary, we could not establish a consistent relationship between the analyzed genes for adult and pediatric tumors, although TCF21 transfection in the H295R cell line has shown a tendency of reduction in BUB1B expression.	('expression', 'MPA', (214, 224))	('BUB1B', 'Gene', '701', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('pediatric tumors', 'Disease', 'MESH:D063766', (102, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('reduction', 'NegReg', (195, 204))	('H295R', 'CellLine', 'CVCL:0458', (155, 160))	('pediatric tumors', 'Disease', (102, 118))	('transfection', 'Var', (135, 147))	('BUB1B', 'Gene', (208, 213))	('TCF21', 'Gene', (129, 134))
121611	27754849	The disorder is caused by mutations in AAAS (achalasia-adrenal insufficiency alacrima syndrome) encoding the protein ALADIN (alacrima-achalasia-adrenal insufficiency neurologic disorder).	('achalasia', 'Phenotype', 'HP:0002571', (134, 143))	('alacrima-achalasia-adrenal insufficiency neurologic disorder', 'Gene', '8086', (125, 185))	('neurologic disorder', 'Phenotype', 'HP:0000707', (166, 185))	('achalasia-adrenal insufficiency alacrima syndrome', 'Disease', 'MESH:C536008', (45, 94))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (55, 76))	('alacrima', 'Phenotype', 'HP:0000522', (125, 133))	('caused by', 'Reg', (16, 25))	('achalasia', 'Phenotype', 'HP:0002571', (45, 54))	('mutations', 'Var', (26, 35))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (144, 165))	('achalasia-adrenal insufficiency alacrima syndrome', 'Disease', (45, 94))	('AAAS', 'Gene', (39, 43))	('AAAS', 'Gene', '8086', (39, 43))	('alacrima', 'Phenotype', 'HP:0000522', (77, 85))
121621	27754849	Co-IP was conducted in NCI-H295R cells either expressing endogenous ALADIN or additionally exogenous GFP-ALADIN.	('Co-IP', 'Chemical', '-', (0, 5))	('GFP-ALADIN', 'Var', (101, 111))	('NCI-H295R', 'CellLine', 'CVCL:0458', (23, 32))	('exogenous', 'Var', (91, 100))
121625	27754849	All proteins identified in mass spectrometry in GFP-ALADIN co-IP and ALADIN co-IP, but which were not found in the specific control pulldown assays, are presented in .	('co-IP', 'Chemical', '-', (76, 81))	('co-IP', 'Var', (59, 64))	('GFP-ALADIN', 'Var', (48, 58))	('co-IP', 'Chemical', '-', (59, 64))
121629	27754849	ALADIN (59 kDa) was found in the bound fraction of the ALADIN co-IP, but the negative control using normal mouse IgG was shown to be empty.	('IgG', 'Gene', (113, 116))	('mouse', 'Species', '10090', (107, 112))	('59 kDa', 'Var', (8, 14))	('IgG', 'Gene', '16059', (113, 116))	('co-IP', 'Chemical', '-', (62, 67))
121637	27754849	In the staining with the anti-PGRMC2 in NCI-H295R cells we could also observe nuclear staining in some adrenal cells (Fig.	('anti-PGRMC2', 'Gene', (25, 36))	('anti-PGRMC2', 'Var', (25, 36))	('NCI-H295R', 'CellLine', 'CVCL:0458', (40, 49))
121640	27754849	In adrenocortical cells we could not detect an alteration of PGRMC2 localisation after ALADIN knock-down.	('adrenocortical', 'Disease', (3, 17))	('adrenocortical', 'Disease', 'MESH:D018268', (3, 17))	('knock-down', 'Var', (94, 104))	('PGRMC2', 'Gene', (61, 67))	('localisation', 'MPA', (68, 80))
121641	27754849	However, immunostaining of PGRMC2 in NCI-H295R1-TR/Scrambled shRNA and NCI-H295R1-TR compared to NCI-H295R1-TR/AAAS knock-down was more cytoplasmic and nuclear (Fig.	('PGRMC2', 'Gene', (27, 33))	('AAAS', 'Gene', (111, 115))	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (97, 110))	('AAAS', 'Gene', '8086', (111, 115))	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (37, 50))	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (71, 84))	('NCI-H295R1-TR/Scrambled', 'Var', (37, 60))
121643	27754849	To test if PGRMC2 expression is affected when ALADIN is down-regulated we used the inducible NCI-H295R1-TR cells with AAAS knock-down shRNA or scrambled shRNA as negative control.	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (93, 106))	('knock-down', 'Var', (123, 133))	('AAAS', 'Gene', (118, 122))	('AAAS', 'Gene', '8086', (118, 122))	('PGRMC2', 'Gene', (11, 17))
121667	27754849	In order to address if ALADIN anchors PGRMC2 at the perinuclear ER, we conducted immunostaining in adrenocortical cells after inducible knock-down of ALADIN and in skin fibroblasts of a triple A patient.	('adrenocortical', 'Disease', 'MESH:D018268', (99, 113))	('knock-down', 'Var', (136, 146))	('patient', 'Species', '9606', (195, 202))	('adrenocortical', 'Disease', (99, 113))	('PGRMC2', 'Gene', (38, 44))
121669	27754849	Additionally, we showed that there is no alteration in PGRMC2 expression after ALADIN knock-down in adrenocortical cells.	('PGRMC2', 'Gene', (55, 61))	('adrenocortical', 'Disease', (100, 114))	('expression', 'MPA', (62, 72))	('adrenocortical', 'Disease', 'MESH:D018268', (100, 114))	('knock-down', 'Var', (86, 96))
121683	27754849	NCI-H295R1-TR cells with AAAS knock-down or scrambled shRNA were generated, selected and cultured as described previously.	('AAAS', 'Gene', '8086', (25, 29))	('AAAS', 'Gene', (25, 29))	('NCI-H295R1-TR', 'CellLine', 'CVCL:0458', (0, 13))	('knock-down', 'Var', (30, 40))
121711	26282167	Accordingly, treatment of ACC cells with exogenous HCG resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacological inhibition of cMET suppressed cell proliferation and tumor growth.	('exogenous', 'Var', (41, 50))	('cell proliferation', 'CPA', (209, 227))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('cMET', 'Gene', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('increased', 'PosReg', (67, 76))	('suppressed', 'NegReg', (198, 208))	('tumor', 'Disease', (232, 237))	('cell proliferation', 'CPA', (77, 95))
121723	26282167	Clinical studies using inhibitors of IGF1R/mTOR signaling have revealed minimal tumor responses.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('IGF1R', 'Gene', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('inhibitors', 'Var', (23, 33))	('tumor', 'Disease', (80, 85))	('IGF1R', 'Gene', '3480', (37, 42))	('mTOR', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (43, 47))	('minimal', 'NegReg', (72, 79))
121763	26282167	Immunohistochemical analysis of two independent tissue microarrays and Western blot analysis results further demonstrated a significant ACC-specific elevations of HGF and total cMET protein levels, and activation of cMET signaling, as seen by phosphorylation at the Y1234/1235 sites (Figure 1 and 2, Supplemental Figure 3).	('HGF', 'Gene', '3082', (163, 166))	('cMET signaling', 'MPA', (216, 230))	('Y1234/1235', 'Var', (266, 276))	('HGF', 'Gene', (163, 166))	('activation', 'PosReg', (202, 212))	('elevations', 'PosReg', (149, 159))	('cMET', 'Protein', (177, 181))
121768	26282167	Functional genomic analysis identified 63 biological processes that were significantly different (P<0.05) between the high and low MET expression ACC patients (Supplemental Table 4).	('high', 'Var', (118, 122))	('different', 'Reg', (87, 96))	('patients', 'Species', '9606', (150, 158))	('low', 'NegReg', (127, 130))
121770	26282167	Biological processes related to sustained proliferation, increased tumor metabolism, resistance to cell death, chemotherapy resistance, and activation of metastasis were among the cancer hallmarks most enhanced in ACC associated with the high MET phenotype.	('high MET', 'Var', (238, 246))	('resistance', 'CPA', (85, 95))	('tumor', 'Disease', (67, 72))	('enhanced', 'PosReg', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('sustained proliferation', 'CPA', (32, 55))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer hallmarks', 'Disease', (180, 196))	('metastasis', 'CPA', (154, 164))	('increased', 'PosReg', (57, 66))	('chemotherapy resistance', 'CPA', (111, 134))	('cancer hallmarks', 'Disease', 'MESH:D009369', (180, 196))	('Biological processes', 'CPA', (0, 20))
121772	26282167	Gene set enrichment analysis of transcriptomic profiles of two independent ACC patient cohorts (GSE10927 and GSE49278) showed that high MET expression was associated with a collective up-regulation of genes involved in cell proliferation, as well as genes involved in negative regulation of apoptosis (Figure 4, Supplemental Tables 6-9).	('cell', 'CPA', (219, 223))	('up-regulation', 'PosReg', (184, 197))	('patient', 'Species', '9606', (79, 86))	('high MET', 'Var', (131, 139))
121781	26282167	Further bioinformatics analysis demonstrated overexpression of genes related to drug metabolism (Figure 6, C and D, and Supplemental Table 10) in patients with high MET expression.	('high MET expression', 'Var', (160, 179))	('patients', 'Species', '9606', (146, 154))	('overexpression', 'PosReg', (45, 59))
121784	26282167	Our results confirmed that cMET knockdown significantly decreased (P<0.05) tumor growth (Figure 7, E and F).	('cMET', 'Gene', (27, 31))	('knockdown', 'Var', (32, 41))	('decreased', 'NegReg', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
121806	26282167	We found somatic MET alteration in only one out of 14 ACC specimen and this opens the door for other mechanisms to be responsible for cMET activation such as gene amplification as reported in other solid malignancies.	('malignancies', 'Disease', (204, 216))	('gene amplification', 'Var', (158, 176))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('alteration', 'Var', (21, 31))
121921	25883649	Histologically, the diagnosis can be established by determining the endothelial origin of the cells through immunohistochemical staining (CD31, CD34, D2-40).	('CD31', 'Gene', '5175', (138, 142))	('CD34', 'Gene', '947', (144, 148))	('CD34', 'Gene', (144, 148))	('CD31', 'Gene', (138, 142))	('D2-40', 'Var', (150, 155))
121981	24279337	In general, if we consider all non-functioning incidental lesions (group A + B) with suspicious imaging features (ACC vs. non-functioning benign adenomas) we observe that 1/89 (1.12%) lesion lesser than 4 cm, 2/34 (5.8%) lesions between 4 and 6 cm and 10/36 lesions larger than 6 cm (27.7%) were primary ACC.	('adenomas', 'Disease', 'MESH:D000236', (145, 153))	('lesion lesser than', 'Var', (184, 202))	('adenomas', 'Disease', (145, 153))
122015	23485729	We described isolated micronodular adrenocortical disease (iMAD), a disorder likely to be inherited in an autosomal dominant manner that is unrelated to Carney complex or other MENs: the identification of PRKAR1A mutations in PPNAD led to the recognition that non-pigmented forms of BAHs existed, and a new nomenclature was proposed that has since been in use worldwide.	('adrenocortical disease', 'Disease', (35, 57))	('MEN', 'Species', '9606', (177, 180))	('adrenocortical disease', 'Disease', 'MESH:D018268', (35, 57))	('PRKAR1A', 'Gene', '5573', (205, 212))	('BAHs', 'Chemical', '-', (283, 287))	('mutations', 'Var', (213, 222))	('PPNAD', 'Gene', (226, 231))	('PRKAR1A', 'Gene', (205, 212))
122016	23485729	In 2006, a genome-wide association (GWA) study led to the identification of mutations in phosphodiesterase (PDE) genes, PDE11A -a dual specificity PDE, and PDE8B, a cAMP-specific PDE, (coded by the PDE11A and PDE8B genes, respectively) in iMAD.	('PDE8B', 'Gene', (156, 161))	('mutations', 'Var', (76, 85))	('PDE11A', 'Gene', (120, 126))	('PDE8B', 'Gene', (209, 214))	('PDE11A', 'Gene', '50940', (120, 126))	('PDE', 'Gene', (108, 111))	('PDE11A', 'Gene', '50940', (198, 204))	('PDE11A', 'Gene', (198, 204))
122018	23485729	We then found PDE11A and PDE8B mutations or functional variants in adrenocortical cancer (ACC), and other forms of adrenal hyperplasia like massive macronodular adrenocortical disease (MMAD), also known as ACTH-independent adrenocortical hyperplasia (MMAD/AIMAH).	('macronodular adrenocortical disease', 'Disease', (148, 183))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (115, 134))	('PDE11A', 'Gene', '50940', (14, 20))	('PDE8B', 'Gene', (25, 30))	('PDE11A', 'Gene', (14, 20))	('adrenocortical hyperplasia', 'Disease', (223, 249))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MMAD', 'Disease', 'None', (251, 255))	('MMAD', 'Disease', (251, 255))	('ACTH', 'Gene', (206, 210))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (223, 249))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (115, 134))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (67, 88))	('mutations', 'Var', (31, 40))	('macronodular adrenocortical disease', 'Disease', 'MESH:C565662', (148, 183))	('variants', 'Var', (55, 63))	('macronodular adrenocortical disease', 'Phenotype', 'HP:0008231', (148, 183))	('adrenal hyperplasia', 'Disease', (115, 134))	('MMAD', 'Disease', 'None', (185, 189))	('adrenocortical cancer', 'Disease', (67, 88))	('MMAD', 'Disease', (185, 189))	('ACTH', 'Gene', '5443', (206, 210))
122019	23485729	Germline PDE11A sequence variants may also predispose to testicular cancer (testicular germ cell tumors or TGCTs) and prostate cancer, indicating a wider role of this pathway in tumor formation on cAMP-responsive, steroidogenic, or related tissues.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('predispose', 'Reg', (43, 53))	('testicular cancer', 'Disease', 'MESH:D013736', (57, 74))	('tumors', 'Disease', (97, 103))	('variants', 'Var', (25, 33))	('tumor', 'Disease', (178, 183))	('germ cell tumors', 'Phenotype', 'HP:0100728', (87, 103))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('testicular cancer', 'Disease', (57, 74))	('PDE11A', 'Gene', '50940', (9, 15))	('PDE11A', 'Gene', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('steroid', 'Chemical', 'MESH:D013256', (214, 221))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('testicular cancer', 'Phenotype', 'HP:0010788', (57, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (118, 133))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('prostate cancer', 'Disease', (118, 133))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))
122021	23485729	Histo-morphological studies on human adrenocortical tissues from patients with these mutations showed that iMAD is highly heterogeneous and, thus, likely to be caused by several genes of the cAMP/PKA-signaling pathway or its regulators and/or downstream effectors.	('iMAD', 'Disease', (107, 111))	('caused by', 'Reg', (160, 169))	('human', 'Species', '9606', (31, 36))	('mutations', 'Var', (85, 94))	('patients', 'Species', '9606', (65, 73))	('adrenocortical', 'Disease', (37, 51))	('adrenocortical', 'Disease', 'MESH:D018268', (37, 51))
122022	23485729	Likewise, the G-protein coupled receptor (GPCR)-linked MMAD/AIMAH is a disease that includes a range of adrenal phenotypes from very similar to iMAD to the GNAS-caused primary bimorhic adrenocortical disease (PBAD) and McCune-Albright syndrome, caused by somatic mutations of the GNAS gene (coding for the G-protein stimulatory subunit alpha or Gsalpha).	('McCune-Albright syndrome', 'Disease', (219, 243))	('MMAD', 'Disease', (55, 59))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (219, 243))	('primary bimorhic adrenocortical disease', 'Phenotype', 'HP:0008207', (168, 207))	('Gsalpha', 'Gene', '14683', (345, 352))	('mutations', 'Var', (263, 272))	('GNAS', 'Gene', '2778', (156, 160))	('MMAD', 'Disease', 'None', (55, 59))	('GNAS', 'Gene', '2778', (280, 284))	('bimorhic adrenocortical disease', 'Disease', 'MESH:D018268', (176, 207))	('bimorhic adrenocortical disease', 'Disease', (176, 207))	('PBAD', 'Phenotype', 'HP:0008207', (209, 213))	('Gsalpha', 'Gene', (345, 352))	('GNAS', 'Gene', (156, 160))	('GNAS', 'Gene', (280, 284))
122023	23485729	Although a few of the patients with MMAD/AIMAH have germline PDE11A, PDE8B, and somatic GNAS mutations others have germline fumarate hydratase (FH), menin (MEN1), and adenomatous polyposis coli (APC) mutations pointing to the range of possibilities and the pathways that may be involved.	('PDE11A', 'Gene', (61, 67))	('GNAS', 'Gene', (88, 92))	('PDE11A', 'Gene', '50940', (61, 67))	('mutations', 'Var', (200, 209))	('GNAS', 'Gene', '2778', (88, 92))	('fumarate hydratase', 'Gene', (124, 142))	('PDE8B', 'Gene', (69, 74))	('patients', 'Species', '9606', (22, 30))	('MEN1', 'Gene', '4221', (156, 160))	('MMAD', 'Disease', 'None', (36, 40))	('mutations', 'Var', (93, 102))	('MMAD', 'Disease', (36, 40))	('APC', 'Phenotype', 'HP:0005227', (195, 198))	('APC', 'Disease', 'MESH:D011125', (195, 198))	('MEN1', 'Gene', (156, 160))	('APC', 'Disease', (195, 198))	('fumarate hydratase', 'Gene', '2271', (124, 142))	('FH', 'Gene', '2271', (144, 146))	('menin', 'Gene', '4221', (149, 154))	('menin', 'Gene', (149, 154))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (167, 193))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (167, 193))	('adenomatous polyposis coli', 'Disease', (167, 193))
122024	23485729	From these, particularly interesting is the connection with FH mutations associated with mitochondrial oxidation defects that have been linked to adrenomedullary tumors.	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('adrenomedullary tumors', 'Disease', (146, 168))	('mitochondrial oxidation defects', 'MPA', (89, 120))	('associated', 'Reg', (73, 83))	('adrenomedullary tumors', 'Phenotype', 'HP:0100642', (146, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('FH', 'Gene', '2271', (60, 62))	('adrenomedullary tumors', 'Disease', 'MESH:D009369', (146, 168))	('linked', 'Reg', (136, 142))
122026	23485729	A subgroup of patients with PHEOs, PGLs and GISTs, were identified to harbor mutations in succinate dehydrogenase (SDH) subunits B, C and D (coded by the SDHB, SDHC and SDHD genes, respectively), they also rarely have adrenocortical lesions, ACAs and/or hyperplasia, and their disease is known as the dyad or syndrome of PGLs and GISTs or, as named by a group of pathologists and now in wide use, Carney-Stratakis syndrome (CSS) (http://www.ncbi.nlm.nih.gov/omim; entry#606864,).	('SDHD', 'Gene', '6392', (169, 173))	('SDH', 'Gene', (154, 157))	('SDH', 'Gene', '6390', (160, 163))	('succinate dehydrogenase', 'Gene', (90, 113))	('SDH', 'Gene', (115, 118))	('patients', 'Species', '9606', (14, 22))	('SDH', 'Gene', (169, 172))	('hyperplasia', 'Disease', (254, 265))	('SDHC', 'Gene', '6391', (160, 164))	('CSS', 'Disease', (424, 427))	('SDHD', 'Gene', (169, 173))	('hyperplasia', 'Disease', 'MESH:D006965', (254, 265))	('Carney-Stratakis syndrome', 'Disease', (397, 422))	('SDH', 'Gene', (160, 163))	('ACA', 'Phenotype', 'HP:0008256', (242, 245))	('succinate dehydrogenase', 'Gene', '6390', (90, 113))	('SDHB', 'Gene', '6390', (154, 158))	('SDHC', 'Gene', (160, 164))	('mutations', 'Var', (77, 86))	('SDH', 'Gene', '6390', (154, 157))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (397, 422))	('SDH', 'Gene', '6390', (169, 172))	('CSS', 'Disease', 'MESH:C536436', (424, 427))	('adrenocortical lesions', 'Disease', 'MESH:C565972', (218, 240))	('SDH', 'Gene', '6390', (115, 118))	('adrenocortical lesions', 'Disease', (218, 240))	('SDHB', 'Gene', (154, 158))
122027	23485729	PPNAD appears to be less heterogeneous and is mostly caused by PRKAR1A mutations, but up to 1/3 of patients with the classic features of PPNAD do not have PRKAR1A mutations, deletions or 17q22-24 copy-number variant (CNV) abnormalities.	('PRKAR1A', 'Gene', '5573', (63, 70))	('PRKAR1A', 'Gene', '5573', (155, 162))	('deletions', 'Var', (174, 183))	('patients', 'Species', '9606', (99, 107))	('PRKAR1A', 'Gene', (155, 162))	('mutations', 'Var', (71, 80))	('caused', 'Reg', (53, 59))	('PRKAR1A', 'Gene', (63, 70))
122031	23485729	Somatic beta-catenin (CTNNB1) mutations were found in large ACAs that formed in the background of PPNAD caused by germline PRKAR1A mutations.	('CTNNB1', 'Gene', (22, 28))	('mutations', 'Var', (131, 140))	('ACA', 'Phenotype', 'HP:0008256', (60, 63))	('PRKAR1A', 'Gene', (123, 130))	('beta-catenin', 'Gene', (8, 20))	('CTNNB1', 'Gene', '1499', (22, 28))	('mutations', 'Var', (30, 39))	('beta-catenin', 'Gene', '1499', (8, 20))	('PRKAR1A', 'Gene', '5573', (123, 130))	('found', 'Reg', (45, 50))
122033	23485729	Cells from tumors or other lesions from animals with R1alpha deficiency showed increased beta-catenin expression and/or aberrant Wnt-signaling, and similarities to adult stem cells or cancer stem cells in other models of dysregulated Wnt-signaling.	('cancer', 'Disease', (184, 190))	('increased', 'PosReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Wnt-signaling', 'MPA', (129, 142))	('expression', 'MPA', (102, 112))	('beta-catenin', 'Gene', '1499', (89, 101))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('R1alpha', 'Gene', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('beta-catenin', 'Gene', (89, 101))	('deficiency', 'Var', (61, 71))
122045	23485729	The recent description of KCNJ5 mutations in a subset of aldosterone-producing BAHs known as familial hyperaldosteronism type-III (FH-III) led to the screening of our patients and allowed us to focus on kindreds with BAH or FH-II that do not have KCNJ5 mutations; others have found various frequencies of KCNJ5 mutations.	('KCNJ5', 'Gene', '3762', (305, 310))	('BAH', 'Chemical', '-', (217, 220))	('FH-II', 'Gene', (131, 136))	('familial hyperaldosteronism type-III', 'Disease', (93, 129))	('FH-I', 'Phenotype', 'HP:0011739', (131, 135))	('KCNJ5', 'Gene', '3762', (26, 31))	('BAH', 'Chemical', '-', (79, 82))	('BAHs', 'Chemical', '-', (79, 83))	('KCNJ5', 'Gene', '3762', (247, 252))	('FH-I', 'Phenotype', 'HP:0011739', (224, 228))	('mutations', 'Var', (32, 41))	('FH-II', 'Phenotype', 'HP:0011740', (131, 136))	('FH-II', 'Gene', '79179', (224, 229))	('familial hyperaldosteronism type-III', 'Disease', 'MESH:D003480', (93, 129))	('FH-II', 'Gene', (224, 229))	('familial hyperaldosteronism type-I', 'Phenotype', 'HP:0011739', (93, 127))	('KCNJ5', 'Gene', (305, 310))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (102, 120))	('patients', 'Species', '9606', (167, 175))	('KCNJ5', 'Gene', (26, 31))	('FH-II', 'Phenotype', 'HP:0011740', (224, 229))	('familial hyperaldosteronism type', 'Phenotype', 'HP:0011739', (93, 125))	('FH-II', 'Gene', '79179', (131, 136))	('KCNJ5', 'Gene', (247, 252))
122051	23485729	In our most recently published cohort, mutations or sequence variants in FH, MEN1, APC, PDE11A (in the germline) and GNAS (somatic) were found in up to a quarter of the patients; in a separate investigation of a larger cohort of MMAD/AIMAH patients, we also found germline PDE8B sequence variants, albeit infrequently; these variants did affect PDE activity of the PDE8B enzyme in vitro.	('variants', 'Var', (288, 296))	('MMAD', 'Disease', 'None', (229, 233))	('affect', 'Reg', (338, 344))	('MMAD', 'Disease', (229, 233))	('GNAS', 'Gene', (117, 121))	('MEN1', 'Gene', '4221', (77, 81))	('variants', 'Var', (325, 333))	('PDE11A', 'Gene', '50940', (88, 94))	('PDE11A', 'Gene', (88, 94))	('PDE activity', 'MPA', (345, 357))	('PDE8B enzyme', 'Enzyme', (365, 377))	('GNAS', 'Gene', '2778', (117, 121))	('APC', 'Phenotype', 'HP:0005227', (83, 86))	('patients', 'Species', '9606', (240, 248))	('MEN1', 'Gene', (77, 81))	('APC', 'Disease', 'MESH:D011125', (83, 86))	('APC', 'Disease', (83, 86))	('PDE8B', 'Gene', (273, 278))	('patients', 'Species', '9606', (169, 177))	('FH', 'Gene', '2271', (73, 75))
122060	23485729	We recently completed a phenotype-genotype study of patients with PPNAD and Carney complex; the PRKAR1A mutations are included in on-line, publicly available, and continuously updated database at http://prkar1a.nichd.nih.gov/hmdb/intro.html.	('mutations', 'Var', (104, 113))	('prkar1a', 'Gene', (203, 210))	('prkar1a', 'Gene', '5573', (203, 210))	('PRKAR1A', 'Gene', (96, 103))	('patients', 'Species', '9606', (52, 60))	('PRKAR1A', 'Gene', '5573', (96, 103))
122061	23485729	To date more than 121 PRKAR1A mutations have been identified.	('PRKAR1A', 'Gene', (22, 29))	('mutations', 'Var', (30, 39))	('PRKAR1A', 'Gene', '5573', (22, 29))
122062	23485729	Most of these mutations are unique; however, 5 mutations have been found in several unrelated pedigrees: c.491_492del, c.1A>G (start-site Met1Val mutation), c.82C>T, c.709 del, and c.439A>G.	('c.491_492del', 'Var', (105, 117))	('c.439A>G', 'Mutation', 'c.439A>G', (181, 189))	('c.1A>G', 'Mutation', 'rs917411291', (119, 125))	('c.439A>G', 'Var', (181, 189))	('c.82C>T', 'Mutation', 'c.82C>T', (157, 164))	('c.82C>T', 'Var', (157, 164))	('c.491_492del', 'Mutation', 'c.491_492del', (105, 117))	('c.709 del', 'Var', (166, 175))	('c.709 del', 'Mutation', 'c.709del', (166, 175))	('c.1A>G', 'Var', (119, 125))	('Met1Val', 'Mutation', 'rs917411291', (138, 145))
122063	23485729	The last 4 of these mutations led to isolated PPNAD; indicating a specific genotype-phenotype correlation; the last mutation is the first one to be linked to ACC, since the patient who presented with PPNAD died of metastatic disease; one more patient with ACC and PPNAD was just reported.	('patient', 'Species', '9606', (173, 180))	('patient', 'Species', '9606', (243, 250))	('mutations', 'Var', (20, 29))	('metastatic disease', 'CPA', (214, 232))
122064	23485729	Even though most PRKAR1A mutations led to nonsense mRNA decay (NMD), several were identified that were expressed at the protein level, and were typically (although not all) associated with a more aggressive phenotype (; Moili et al., 2008).	('mutations', 'Var', (25, 34))	('led to', 'Reg', (35, 41))	('nonsense mRNA decay', 'MPA', (42, 61))	('PRKAR1A', 'Gene', (17, 24))	('associated with', 'Reg', (173, 188))	('PRKAR1A', 'Gene', '5573', (17, 24))
122065	23485729	PRKAR1A mutations that extended the ORF and did not undergo NMD were also not expressed at the protein level; we showed that this was due to proteosomal degradation, adding proteosome-mediated surveillance of R1alpha to NMD-control of PRKAR1A mRNA.	('PRKAR1A', 'Gene', (235, 242))	('adding', 'PosReg', (166, 172))	('PRKAR1A', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('PRKAR1A', 'Gene', '5573', (235, 242))	('proteosome-mediated surveillance', 'MPA', (173, 205))	('PRKAR1A', 'Gene', '5573', (0, 7))
122074	23485729	Since tumors with PRKAR1A defects had 2p16 dosage changes, it is tempting to speculate that the responsible genetic defect(s) in CNC2 patients are related to PKA function.	('PRKAR1A', 'Gene', '5573', (18, 25))	('CNC2', 'Gene', '1257', (129, 133))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('patients', 'Species', '9606', (134, 142))	('tumors', 'Disease', (6, 12))	('defects', 'Var', (26, 33))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('2p16', 'Protein', (38, 42))	('genetic defect', 'Disease', 'MESH:D030342', (108, 122))	('PRKAR1A', 'Gene', (18, 25))	('genetic defect', 'Disease', (108, 122))	('CNC2', 'Gene', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('PKA', 'Disease', (158, 161))
122075	23485729	CGH, CNV, WES and DSeq are ongoing in our laboratory for the identification of the responsible gene defect(s) in these patients; our recent study excluded mutations in the 2p16-located protein kinase C epsilon (PKCepsilon).	('mutations', 'Var', (155, 164))	('excluded', 'NegReg', (146, 154))	('protein kinase C epsilon', 'Gene', (185, 209))	('patients', 'Species', '9606', (119, 127))	('protein kinase C epsilon', 'Gene', '5581', (185, 209))	('GH', 'Gene', '2688', (1, 3))	('PKCepsilon', 'Gene', (211, 221))	('PKCepsilon', 'Gene', '5581', (211, 221))
122077	23485729	Patients with PRKAR1A defects presented with PPNAD later; in addition, after the teenage years, female patients with PPNAD exceeded males, and by the age of 40 years more than 70% of female carriers of PRKAR1A defects had manifested with PPNAD, whereas only 45% of males had clinical evidence of this disease.	('PRKAR1A', 'Gene', '5573', (14, 21))	('PPNAD', 'Disease', (238, 243))	('PRKAR1A', 'Gene', (202, 209))	('Patients', 'Species', '9606', (0, 8))	('PRKAR1A', 'Gene', (14, 21))	('patients', 'Species', '9606', (103, 111))	('PRKAR1A', 'Gene', '5573', (202, 209))	('defects', 'Var', (210, 217))
122080	23485729	The database analysis showed that very few young children with corticotropin (ACTH)-independent iMAD and no other tumors have Carney complex or PRKAR1A mutations.	('PRKAR1A', 'Gene', '5573', (144, 151))	('mutations', 'Var', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('ACTH', 'Gene', (78, 82))	('ACTH', 'Gene', '5443', (78, 82))	('Carney complex', 'Disease', (126, 140))	('PRKAR1A', 'Gene', (144, 151))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('iMAD', 'Disease', (96, 100))	('children', 'Species', '9606', (49, 57))
122081	23485729	A handful of these patients had PDE11A or PDE8B defects, as we reported previously.	('PDE11A', 'Gene', (32, 38))	('defects', 'Var', (48, 55))	('patients', 'Species', '9606', (19, 27))	('PDE8B', 'Gene', (42, 47))	('PDE11A', 'Gene', '50940', (32, 38))
122083	23485729	iMAD with or without PDE11A or PDE8B mutations looks different from PBAD in infantile McCune-Albright syndrome due to GNAS mutations that we studied and recently reported (Figure 2).	('McCune-Albright syndrome', 'Disease', (86, 110))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (86, 110))	('mutations', 'Var', (123, 132))	('PBAD', 'Phenotype', 'HP:0008207', (68, 72))	('GNAS', 'Gene', '2778', (118, 122))	('PDE11A', 'Gene', (21, 27))	('PDE11A', 'Gene', '50940', (21, 27))	('mutations', 'Var', (37, 46))	('PDE8B', 'Gene', (31, 36))	('GNAS', 'Gene', (118, 122))
122088	23485729	We showed that PRKAR1A haploinsufficiency is all that is needed for increased C subunit activity, however, the addition of LOH in affected tissues (and, thus, complete loss of RIalpha protein) leads to further and substantial increase in PKA activity.	('loss', 'NegReg', (168, 172))	('LOH', 'Var', (123, 126))	('PRKAR1A', 'Gene', (15, 22))	('RIalpha', 'Gene', (176, 183))	('LOH', 'Chemical', '-', (123, 126))	('haploinsufficiency', 'Disease', 'MESH:D058495', (23, 41))	('activity', 'MPA', (242, 250))	('RIalpha', 'Gene', '19084', (176, 183))	('haploinsufficiency', 'Disease', (23, 41))	('PKA', 'Enzyme', (238, 241))	('PRKAR1A', 'Gene', '5573', (15, 22))	('increase', 'PosReg', (226, 234))
122089	23485729	PRKAR1A mutations that do not lead to NMD and are expressed at the protein level have more or less the same effect: in one way or another, they lead to release of the inhibitory control of RIalpha on the C subunits.	('release', 'MPA', (152, 159))	('RIalpha', 'Gene', (189, 196))	('inhibitory control of', 'MPA', (167, 188))	('RIalpha', 'Gene', '19084', (189, 196))	('PRKAR1A', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('lead to', 'Reg', (144, 151))	('PRKAR1A', 'Gene', '5573', (0, 7))
122091	23485729	We identified mutations in cAMP-binding PDEs, as predisposing to BAHs and possibly other adrenal tumors.	('adrenal tumors', 'Disease', 'MESH:D000310', (89, 103))	('predisposing', 'Reg', (49, 61))	('BAHs', 'Chemical', '-', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('adrenal tumor', 'Phenotype', 'HP:0100631', (89, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('adrenal tumors', 'Disease', (89, 103))	('BAHs', 'Disease', (65, 69))	('mutations', 'Var', (14, 23))	('PDEs', 'Gene', (40, 44))
122092	23485729	PDE11A-inactivating, protein-truncating mutations appear to be present rarely in the population but two functional PDE11A missense substitutions, R804H and R867G, are present at much higher rates of 2.4% and 3%, respectively; additional sequence changes (mostly missense variants) are present in various frequencies.	('R804H', 'Mutation', 'rs75127279', (146, 151))	('R867G', 'Var', (156, 161))	('R804H', 'Var', (146, 151))	('PDE11A', 'Gene', (0, 6))	('PDE11A', 'Gene', '50940', (115, 121))	('PDE11A', 'Gene', '50940', (0, 6))	('PDE11A', 'Gene', (115, 121))	('R867G', 'Mutation', 'rs61306957', (156, 161))
122093	23485729	PDE11A variants appear to affect the phenotype of PPNAD and increase the incidence of testicular lesions when co-inherited with a PRKAR1A mutation.	('PRKAR1A', 'Gene', (130, 137))	('testicular lesions', 'Disease', (86, 104))	('phenotype', 'MPA', (37, 46))	('variants', 'Var', (7, 15))	('increase', 'PosReg', (60, 68))	('PPNAD', 'Disease', (50, 55))	('affect', 'Reg', (26, 32))	('PDE11A', 'Gene', (0, 6))	('PRKAR1A', 'Gene', '5573', (130, 137))	('PDE11A', 'Gene', '50940', (0, 6))	('testicular lesions', 'Disease', 'MESH:D013733', (86, 104))
122094	23485729	PDE11A functional variants are also more frequent among patients with testicular and prostate cancer, two tissues where PDE11A is expressed highly.	('patients', 'Species', '9606', (56, 64))	('PDE11A', 'Gene', (120, 126))	('PDE11A', 'Gene', '50940', (120, 126))	('variants', 'Var', (18, 26))	('PDE11A', 'Gene', (0, 6))	('PDE11A', 'Gene', '50940', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('frequent', 'Reg', (41, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))	('testicular and prostate cancer', 'Disease', 'MESH:D011471', (70, 100))
122095	23485729	Thus, PDE11A gene defects may have wider implications that go beyond a predisposition to adrenocortical diseases.	('defects', 'Var', (18, 25))	('adrenocortical diseases', 'Phenotype', 'HP:0008207', (89, 112))	('PDE11A', 'Gene', (6, 12))	('PDE11A', 'Gene', '50940', (6, 12))	('adrenocortical diseases', 'Disease', (89, 112))	('adrenocortical diseases', 'Disease', 'MESH:D018268', (89, 112))
122096	23485729	Since our description of PDE8B mutations in iMAD and now in MMAD and other ACTs, there has been considerable interest in this enzyme which is the PDE with the highest affinity for cAMP, PDE8B is also the highest expressed cAMP-specific PDE in the adrenal cortex, and is present at high levels in a number of other endocrine tissues.	('mutations', 'Var', (31, 40))	('MMAD', 'Disease', (60, 64))	('PDE8B', 'Gene', (25, 30))	('PDE8B', 'Var', (186, 191))	('MMAD', 'Disease', 'None', (60, 64))
122102	23485729	The patients or their tumors (so called "wild-type" or WT GISTs) did not have mutations of the KIT or platelet-derived growth factor receptor-alpha (PDGFRA), genes that have been associated with GIST development.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('PDGFRA', 'Gene', '5156', (149, 155))	('PDGFRA', 'Gene', (149, 155))	('platelet-derived growth factor receptor-alpha', 'Gene', (102, 147))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('patients', 'Species', '9606', (4, 12))	('tumors', 'Disease', (22, 28))	('platelet-derived growth factor receptor-alpha', 'Gene', '5156', (102, 147))
122103	23485729	SDHx mutations are now found in up to 12% of all patients with WT GIST.	('SDHx', 'Chemical', '-', (0, 4))	('SDHx', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (49, 57))
122104	23485729	In adiditon, SDHB mutations were studied in pediatric PHEO and PGL patients in a series of studies that have changed the way children with these tumors are approached.	('children', 'Species', '9606', (125, 133))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('SDHB', 'Gene', '6390', (13, 17))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('SDHB', 'Gene', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('mutations', 'Var', (18, 27))
122105	23485729	It is possible that SDHx mutations may be present in other endocrine (and non-endocrine tumors): in a family with PHEO and PGLs due to an SDHD defect, we discovered a growth hormone (GH)-producing pituitary tumor that had LOH for SDHD and deficient mitochondrial complex-II activity; this observation has led to an ongoing investigation of a series of families with pituitary tumors and PGLs or PHEOs uncovering what is essentially a new syndromic association (data not shown).	('tumor', 'Disease', (376, 381))	('growth hormone', 'Gene', '2688', (167, 181))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('SDHD', 'Gene', '6392', (230, 234))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('tumors', 'Disease', 'MESH:D009369', (376, 382))	('mutations', 'Var', (25, 34))	('SDHx', 'Chemical', '-', (20, 24))	('deficient mitochondrial complex-II', 'Phenotype', 'HP:0008314', (239, 273))	('SDHD', 'Gene', (230, 234))	('tumor', 'Disease', (88, 93))	('deficient', 'NegReg', (239, 248))	('GH', 'Gene', '2688', (183, 185))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('endocrine tumors', 'Disease', 'MESH:D004701', (78, 94))	('mitochondrial complex-II', 'Enzyme', (249, 273))	('activity', 'MPA', (274, 282))	('endocrine tumors', 'Disease', (78, 94))	('tumors', 'Phenotype', 'HP:0002664', (376, 382))	('tumor', 'Disease', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('SDHD', 'Gene', '6392', (138, 142))	('LOH', 'Chemical', '-', (222, 225))	('growth hormone', 'Gene', (167, 181))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (376, 382))	('tumors', 'Disease', (88, 94))	('SDHD', 'Gene', (138, 142))	('defect', 'Var', (143, 149))
122106	23485729	Since we showed that SDHB immunostaining may be used as a diagnostic marker for all lesions with possible SDHx mutations, this method is now being used as a screening tool for a number of lesions and syndromic associations.	('mutations', 'Var', (111, 120))	('SDHx', 'Chemical', '-', (106, 110))	('SDHx', 'Gene', (106, 110))	('SDHB', 'Gene', '6390', (21, 25))	('SDHB', 'Gene', (21, 25))
122108	23485729	SDHx mutations are not present in other adrenal tumors (unpublished data) or in Carney Triad, as we already mentioned.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('adrenal tumors', 'Disease', (40, 54))	('mutations', 'Var', (5, 14))	('adrenal tumor', 'Phenotype', 'HP:0100631', (40, 53))	('SDHx', 'Chemical', '-', (0, 4))	('SDHx', 'Gene', (0, 4))	('Carney Triad', 'Disease', (80, 92))	('adrenal tumors', 'Disease', 'MESH:D000310', (40, 54))
122119	23485729	A cross between Prkaca-/- and Prkar1a+/- showed that absence of Calpha can abrogate some of the early heart development effects of RIalpha's absence (at E7.5); Prkaca-/ Prkar1a-/- embryos still died at E9.5.	('Prkaca-/ Prkar1a-/-', 'Var', (160, 179))	('RIalpha', 'Gene', (131, 138))	('RIalpha', 'Gene', '19084', (131, 138))	('abrogate', 'NegReg', (75, 83))	('early heart development', 'CPA', (96, 119))
122121	23485729	However, multiple bone lesions developed in the Prkar1a+/-Prkaca+/- mice: they first appeared at 4-5 months of age; 90% of Prkar1a+/-Prkaca+/- mice exhibited these lesions by 6 months, and 100% by 9 months.	('mice', 'Species', '10090', (68, 72))	('multiple bone lesions', 'Disease', 'MESH:D001847', (9, 30))	('multiple bone lesions', 'Disease', (9, 30))	('Prkar1a+/-Prkaca+/-', 'Var', (123, 142))	('mice', 'Species', '10090', (143, 147))
122125	23485729	Lesions from Prkar1a+/-Prkaca+/- mice were also more cellular and contained more, albeit irregular, cartilage or bone islands.	('cartilage', 'Disease', 'MESH:D002357', (100, 109))	('bone islands', 'Phenotype', 'HP:0002645', (113, 125))	('cartilage', 'Disease', (100, 109))	('more', 'PosReg', (48, 52))	('mice', 'Species', '10090', (33, 37))	('Prkar1a+/-Prkaca+/-', 'Var', (13, 32))
122126	23485729	A previously undocumented observation was that the single heterozygote, Prkaca+/- mice showed an overall gain in bone formation that was derived from primarily cortical bone; on the other hand, trabecular bone in Prkaca+/- mice was decreased.	('mice', 'Species', '10090', (82, 86))	('mice', 'Species', '10090', (223, 227))	('Prkaca+/-', 'Var', (213, 222))	('trabecular bone', 'CPA', (194, 209))	('bone formation', 'CPA', (113, 127))	('gain', 'PosReg', (105, 109))	('decreased', 'NegReg', (232, 241))
122134	23485729	Increased Wnt signaling was consistent with our previous data, including somatic beta-catenin (CTTNB1) mutations in patients with germline PRKAR1A defects and data from others.	('PRKAR1A', 'Gene', (139, 146))	('mutations', 'Var', (103, 112))	('Wnt signaling', 'MPA', (10, 23))	('beta-catenin', 'Gene', '1499', (81, 93))	('CTTNB1', 'Gene', (95, 101))	('patients', 'Species', '9606', (116, 124))	('PRKAR1A', 'Gene', '5573', (139, 146))	('Increased', 'PosReg', (0, 9))	('beta-catenin', 'Gene', (81, 93))	('defects', 'Var', (147, 154))
122155	23485729	The identification of PRKAR1A, PDE11A, PDE8B mutations in adrenocortical lesions and of defects of mitochondrial oxidation leading to a variety of tumors represent significant advances.	('adrenocortical lesions', 'Disease', (58, 80))	('PRKAR1A', 'Gene', (22, 29))	('mitochondrial oxidation', 'MPA', (99, 122))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('PRKAR1A', 'Gene', '5573', (22, 29))	('defects', 'Var', (88, 95))	('PDE11A', 'Gene', (31, 37))	('PDE11A', 'Gene', '50940', (31, 37))	('leading to', 'Reg', (123, 133))	('PDE8B', 'Gene', (39, 44))	('adrenocortical lesions', 'Disease', 'MESH:C565972', (58, 80))
122157	23485729	Perhaps the most significant advance was our recent understanding from the study of human tissues and the use of animal models that at least certain endocrine tumors, such as those initiated by PRKAR1A defects in the adrenal and the bone, may be due to the abnormal proliferation of pluripotential cells.	('PRKAR1A', 'Gene', (194, 201))	('initiated by', 'Reg', (181, 193))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('endocrine tumors', 'Disease', 'MESH:D004701', (149, 165))	('endocrine tumors', 'Disease', (149, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('PRKAR1A', 'Gene', '5573', (194, 201))	('human', 'Species', '9606', (84, 89))	('defects', 'Var', (202, 209))
122161	23485729	BAH bilateral adrenal hyperplasia MMAD/AIMAH massive macronodular adrenocortical disease/ACTH-independent adrenocortical hyperplasia ACC adrenal cortical carcinoma ACA adrenal cortical adenoma ACT adrenal cortical tumor PRKAR1A regulatory subunit of cAMP-dependent PKA PPNAD primary pigmented nodular adrenocortical disease PDE phosphodiesterase iMAD isolated micronodular adrenocortical disease TSPCs tissue-specific pluripotential cells GIST gastrointestinal stromal tumors SDH succinate dehydrogenase GRA glucocorticoid-remediable aldosteronism HLRC hereditary leiomyomatosis and renal cancer LOH Loss-of-heterozygocity CREB cAMP response element (CRE)-binding protein NOMID neonatal onset multisystemic inflammatory disease cAMP signaling affects cell growth, development, and tumor formation in cAMP-sensitive tissues primary bilateral adrenal hyperplasias are genetically heterogeneous; most have defects in cAMP Tissue-specific pluripotential cells may initiate tumor formation in cAMP-sensitive tissues	('adrenocortical disease', 'Disease', 'MESH:D018268', (373, 395))	('CREB', 'Gene', '1385', (623, 627))	('adrenal cortical tumor', 'Disease', (197, 219))	('tumor', 'Phenotype', 'HP:0002664', (969, 974))	('SDH', 'Gene', '6390', (476, 479))	('tumor', 'Disease', (781, 786))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('adrenal cortical carcinoma', 'Disease', (137, 163))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (106, 132))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (14, 33))	('cancer', 'Phenotype', 'HP:0002664', (589, 595))	('adrenal cortical tumor', 'Phenotype', 'HP:0100641', (197, 219))	('adrenocortical disease', 'Disease', (373, 395))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (444, 475))	('bilateral adrenal hyperplasias', 'Disease', 'MESH:D000312', (831, 861))	('adrenal cortical adenoma ACT', 'Phenotype', 'HP:0008256', (168, 196))	('tumor', 'Disease', 'MESH:D009369', (781, 786))	('adrenal cortical carcinoma', 'Phenotype', 'HP:0006744', (137, 163))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (444, 475))	('BAH', 'Chemical', '-', (0, 3))	('multisystemic inflammatory disease', 'Disease', 'MESH:D056587', (693, 727))	('renal cancer', 'Phenotype', 'HP:0009726', (583, 595))	('cAMP', 'MPA', (914, 918))	('adrenal cortical adenoma', 'Disease', 'MESH:D018246', (168, 192))	('macronodular adrenocortical disease', 'Disease', 'MESH:C565662', (53, 88))	('adrenal cortical carcinoma', 'Disease', 'MESH:D018268', (137, 163))	('tumors', 'Phenotype', 'HP:0002664', (469, 475))	('macronodular adrenocortical disease', 'Phenotype', 'HP:0008231', (53, 88))	('ACA', 'Phenotype', 'HP:0008256', (164, 167))	('tumor', 'Disease', (469, 474))	('hereditary leiomyomatosis and renal cancer', 'Disease', 'MESH:C535516', (553, 595))	('LOH', 'Chemical', '-', (596, 599))	('ACTH', 'Gene', (89, 93))	('succinate dehydrogenase', 'Gene', '6390', (480, 503))	('SDH', 'Gene', (476, 479))	('adrenal hyperplasia', 'Disease', (14, 33))	('tumor', 'Disease', 'MESH:D009369', (469, 474))	('adrenocortical disease', 'Disease', 'MESH:D018268', (66, 88))	('tumor', 'Phenotype', 'HP:0002664', (781, 786))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (841, 860))	('adrenal cortical tumor', 'Disease', 'MESH:D000310', (197, 219))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (283, 323))	('gastrointestinal stromal tumors', 'Disease', (444, 475))	('tumor', 'Disease', (969, 974))	('adrenal hyperplasias', 'Phenotype', 'HP:0008221', (841, 861))	('PRKAR1A', 'Gene', (220, 227))	('tumor', 'Disease', (214, 219))	('multisystemic inflammatory disease', 'Disease', (693, 727))	('CREB', 'Gene', (623, 627))	('tumor', 'Disease', 'MESH:D009369', (969, 974))	('pigmented nodular adrenocortical disease', 'Disease', (283, 323))	('MMAD', 'Disease', 'None', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (14, 33))	('defects', 'Var', (903, 910))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (841, 860))	('macronodular adrenocortical disease', 'Disease', (53, 88))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (283, 323))	('adrenocortical hyperplasia', 'Disease', (106, 132))	('bilateral adrenal hyperplasias', 'Disease', (831, 861))	('tumor', 'Phenotype', 'HP:0002664', (469, 474))	('initiate', 'Reg', (960, 968))	('MMAD', 'Disease', (34, 38))	('adrenal cortical adenoma', 'Disease', (168, 192))	('adrenocortical disease', 'Disease', 'MESH:D018268', (301, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('ACTH', 'Gene', '5443', (89, 93))	('PRKAR1A', 'Gene', '5573', (220, 227))	('succinate dehydrogenase', 'Gene', (480, 503))
122228	22170384	For example, the "MRMs" or "transitions" for testosterone in positive ion mode using ESI are usually m/z 289/97 or 289/109, representing [M+H]+ and high-abundance fragments of 97 and 109 amu, respectively.	('m/z 289/97', 'Var', (101, 111))	('289/109', 'Var', (115, 122))	('testosterone', 'Chemical', 'MESH:D013739', (45, 57))
122257	22170384	The major urinary metabolite of 17OHP is pregnanetriol (PT), and the major metabolite of 21dF is pregnanetriolone (PTone).	('PT', 'Chemical', 'MESH:D011279', (56, 58))	('17OHP', 'Var', (32, 37))	('PT', 'Chemical', 'MESH:D011279', (115, 117))	('17OHP', 'Chemical', 'MESH:D019326', (32, 37))	('21dF', 'Chemical', '-', (89, 93))	('PTone', 'Chemical', 'MESH:C009030', (115, 120))	('pregnanetriol', 'Chemical', 'MESH:D011279', (41, 54))	('pregnanetriolone', 'Chemical', 'MESH:C009030', (97, 113))	('pregnanetriol', 'MPA', (41, 54))	('pregnanetriol', 'Chemical', 'MESH:D011279', (97, 110))
122298	22266195	The frequent observation of constitutive activation of Wnt signaling due to loss-of-function mutations in the tumor suppressor gene APC or gain-of-function mutation in beta-catenin in both adenomas and carcinomas, suggests perhaps that the Wnt pathway serves an early or initiating insult in the oncogenic process.	('Wnt', 'Gene', '114487', (55, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (202, 212))	('APC', 'Gene', '11789', (132, 135))	('beta-catenin', 'Gene', '12387', (168, 180))	('loss-of-function', 'NegReg', (76, 92))	('beta-catenin', 'Gene', (168, 180))	('mutation', 'Var', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('activation', 'PosReg', (41, 51))	('adenomas and carcinomas', 'Disease', 'MESH:D000236', (189, 212))	('gain-of-function', 'PosReg', (139, 155))	('mutations', 'Var', (93, 102))	('APC', 'Gene', (132, 135))	('Wnt', 'Gene', (240, 243))	('Wnt', 'Gene', '114487', (240, 243))	('tumor', 'Disease', (110, 115))	('Wnt', 'Gene', (55, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
122299	22266195	Loss of p53 might be predicted to cooperate with additional genetic insults such as IGF2 as both are the most common genetic abnormalities in malignant versus benign adrenocortical neoplasms.	('malignant versus benign adrenocortical neoplasms', 'Disease', (142, 190))	('neoplasm', 'Phenotype', 'HP:0002664', (181, 189))	('p53', 'Gene', (8, 11))	('malignant versus benign adrenocortical neoplasms', 'Disease', 'MESH:D009369', (142, 190))	('genetic abnormalities', 'Disease', 'MESH:D030342', (117, 138))	('rat', 'Species', '10116', (39, 42))	('neoplasms', 'Phenotype', 'HP:0002664', (181, 190))	('genetic abnormalities', 'Disease', (117, 138))	('Loss', 'Var', (0, 4))
122335	22266195	Complete ablation of beta-Catenin in Sf1(+) cells in the Sf1-CreHi model results in adrenal aplasia following formation of the adrenal capsule, indicating beta-catenin is essential for adrenal development.	('beta-catenin', 'Gene', (155, 167))	('results in', 'Reg', (73, 83))	('ablation', 'Var', (9, 17))	('adrenal aplasia', 'Phenotype', 'HP:0011743', (84, 99))	('adrenal aplasia', 'Disease', 'MESH:D000310', (84, 99))	('beta-Catenin', 'Gene', '12387', (21, 33))	('beta-catenin', 'Gene', '12387', (155, 167))	('adrenal aplasia', 'Disease', (84, 99))	('beta-Catenin', 'Gene', (21, 33))
122337	22266195	Subcapsular beta-catenin expression is maintained, implying that new Sf1(+), beta-catenin(+) cells are continuously being generated, presumably to replace ablated cells lost following the Cre-mediated deletion of beta-catenin.	('deletion', 'Var', (201, 209))	('beta-catenin', 'Gene', '12387', (12, 24))	('beta-catenin', 'Gene', '12387', (77, 89))	('beta-catenin', 'Gene', (12, 24))	('Sf1', 'Gene', (69, 72))	('beta-catenin', 'Gene', '12387', (213, 225))	('rat', 'Species', '10116', (126, 129))	('beta-catenin', 'Gene', (77, 89))	('beta-catenin', 'Gene', (213, 225))
122347	22266195	Recent data confirms that a number of patients with Dax1 mutations exhibit hyperfunctional adrenals prior to development of adrenal failure - consistent with a role of Wnt-mediated Dax1 expression in the regulation of undifferentiated stem/progenitor cells.	('hyperfunctional adrenals', 'MPA', (75, 99))	('patients', 'Species', '9606', (38, 46))	('Wnt', 'Gene', (168, 171))	('adrenal failure', 'Disease', 'MESH:D000312', (124, 139))	('adrenal failure', 'Phenotype', 'HP:0000846', (124, 139))	('mutations', 'Var', (57, 66))	('adrenal failure', 'Disease', (124, 139))	('Wnt', 'Gene', '114487', (168, 171))	('Dax1', 'Gene', (52, 56))
122354	22266195	The expression of the orphan nuclear receptor Sf1 defines the adrenogonadal lineages during development as evidenced by gonadal and adrenal aplasia in Sf1 knockout mice and patients with loss-of-function mutations in the Sf1 gene.	('adrenal aplasia', 'Disease', 'MESH:D000310', (132, 147))	('patients', 'Species', '9606', (173, 181))	('mice', 'Species', '10090', (164, 168))	('mutations', 'Var', (204, 213))	('adrenal aplasia', 'Disease', (132, 147))	('loss-of-function', 'NegReg', (187, 203))	('gonadal and adrenal aplasia', 'Phenotype', 'HP:0008633', (120, 147))	('Sf1', 'Gene', (46, 49))	('adrenal aplasia', 'Phenotype', 'HP:0011743', (132, 147))	('Sf1', 'Gene', (221, 224))
122359	22266195	The implication of Sf1 in proliferation of adrenocortical cells predicts a potential dysregulation of Sf1 expression in the etiology of ACC (Table 1).	('Sf1', 'Gene', (19, 22))	('Sf1', 'Gene', (102, 105))	('expression', 'MPA', (106, 116))	('dysregulation', 'MPA', (85, 98))	('rat', 'Species', '10116', (33, 36))	('implication', 'Var', (4, 15))	('adrenocortical', 'Disease', (43, 57))	('adrenocortical', 'Disease', 'MESH:D018268', (43, 57))	('ACC', 'Disease', (136, 139))
122367	22266195	Beckwith-Wiedemann syndrome has been mapped to numerous genetic alterations of the 11p15 locus, which encodes IGF2 [Table 1; ].	('11p15', 'Gene', (83, 88))	('genetic alterations', 'Var', (56, 75))	('IGF2', 'Gene', (110, 114))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (0, 27))	('Beckwith-Wiedemann syndrome', 'Disease', (0, 27))	('rat', 'Species', '10116', (68, 71))
122374	22266195	Furthermore, patients with Pallister-Hall Syndrome (PHS), a rare disease caused by mutations in the Shh pathway transcription factor Gli3, can present with adrenal hypoplasia and aplasia [Table 1; ].	('adrenal hypoplasia', 'Disease', (156, 174))	('mutations', 'Var', (83, 92))	('PHS', 'Disease', 'MESH:D054975', (52, 55))	('present', 'Reg', (143, 150))	('Pallister-Hall Syndrome', 'Disease', (27, 50))	('rare disease', 'Disease', (60, 72))	('patients', 'Species', '9606', (13, 21))	('rare disease', 'Disease', 'MESH:D035583', (60, 72))	('Gli3', 'Gene', '2737', (133, 137))	('aplasia', 'Disease', 'MESH:C566720', (179, 186))	('PHS', 'Disease', (52, 55))	('aplasia', 'Disease', (179, 186))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (156, 174))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (156, 174))	('caused by', 'Reg', (73, 82))	('Pallister-Hall Syndrome', 'Disease', 'MESH:D054975', (27, 50))	('Gli3', 'Gene', (133, 137))
122383	22266195	Dysregulation of Wnt/beta-catenin signaling has also been implicated as an initiating event in adrenocortical tumorigenesis.	('adrenocortical tumorigenesis', 'Disease', (95, 123))	('adrenocortical tumorigenesis', 'Disease', 'MESH:D018268', (95, 123))	('Dysregulation', 'Var', (0, 13))	('beta-catenin', 'Gene', '12387', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('Wnt', 'Gene', (17, 20))	('beta-catenin', 'Gene', (21, 33))	('Wnt', 'Gene', '114487', (17, 20))
122384	22266195	Adenomatous polyposis coli (APC), a critical component of the beta-catenin destruction complex is the causative mutation in familial adenomatous polyposis, a colon cancer syndrome that frequently manifests with ACTs [Table 1, ].	('Adenomatous polyposis coli', 'Disease', (0, 26))	('Adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (0, 26))	('beta-catenin', 'Gene', (62, 74))	('colon cancer syndrome', 'Disease', 'MESH:D015179', (158, 179))	('mutation', 'Var', (112, 120))	('Adenomatous polyposis coli', 'Disease', 'MESH:D011125', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('APC', 'Gene', '11789', (28, 31))	('colon cancer syndrome', 'Disease', (158, 179))	('APC', 'Gene', (28, 31))	('colon cancer', 'Phenotype', 'HP:0003003', (158, 170))	('beta-catenin', 'Gene', '12387', (62, 74))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (133, 154))	('familial adenomatous polyposis', 'Disease', (124, 154))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (124, 154))
122385	22266195	Because loss of APC results in stabilization and constitutive activation of beta-catenin, it might be predicted to be a possible mechanism for the nuclear accumulation of beta-catenin seen in sporadic ACA and ACC [Fig 1A,B; ].	('ACA', 'Disease', (201, 204))	('beta-catenin', 'Gene', '12387', (171, 183))	('beta-catenin', 'Gene', (76, 88))	('APC', 'Gene', '11789', (16, 19))	('loss', 'Var', (8, 12))	('beta-catenin', 'Gene', (171, 183))	('stabilization', 'MPA', (31, 44))	('APC', 'Gene', (16, 19))	('beta-catenin', 'Gene', '12387', (76, 88))	('activation', 'PosReg', (62, 72))
122386	22266195	However, APC mutations are rare in sporadic ACC, perhaps because APC acts as a tumor suppressor and requires inactivation of both alleles.	('APC', 'Gene', '11789', (65, 68))	('tumor', 'Disease', (79, 84))	('APC', 'Gene', (65, 68))	('APC', 'Gene', '11789', (9, 12))	('APC', 'Gene', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('mutations', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
122389	22266195	While a majority of these ACTs with nuclear beta-catenin have been found to harbor activating mutations on beta-catenin, a subset do not, suggesting perturbation of additional upstream mechanisms of Wnt activation (beyond APC and beta-catenin mutations) are involved in the constitutive stabilization of beta-catenin.	('Wnt', 'Gene', '114487', (199, 202))	('beta-catenin', 'Gene', '12387', (44, 56))	('beta-catenin', 'Gene', (107, 119))	('beta-catenin', 'Gene', '12387', (304, 316))	('mutations', 'Var', (94, 103))	('beta-catenin', 'Gene', '12387', (230, 242))	('APC', 'Gene', '11789', (222, 225))	('beta-catenin', 'Gene', (44, 56))	('mutations', 'Var', (243, 252))	('Wnt', 'Gene', (199, 202))	('beta-catenin', 'Gene', '12387', (107, 119))	('beta-catenin', 'Gene', (304, 316))	('beta-catenin', 'Gene', (230, 242))	('activation', 'PosReg', (203, 213))	('APC', 'Gene', (222, 225))
122393	22266195	The lack of beta-catenin mutations in the majority of ACAs (75-85%) suggests that there are indeed other mechanisms of ACT initiation and progression.	('beta-catenin', 'Gene', '12387', (12, 24))	('mutations', 'Var', (25, 34))	('beta-catenin', 'Gene', (12, 24))
122394	22266195	Moreover, the presence of beta-catenin mutations in both benign ACA and malignant ACC suggests that Wnt/beta-catenin dysregulation is not sufficient for ACC formation.	('beta-catenin', 'Gene', (104, 116))	('beta-catenin', 'Gene', '12387', (26, 38))	('presence', 'Reg', (14, 22))	('mutations', 'Var', (39, 48))	('beta-catenin', 'Gene', '12387', (104, 116))	('Wnt', 'Gene', (100, 103))	('beta-catenin', 'Gene', (26, 38))	('Wnt', 'Gene', '114487', (100, 103))
122398	22266195	However, whether such a sporadic disease-causing mutation in the human adrenal normally arises in an undifferentiated subcapsular progenitor cell that normally responds to Wnt ligands and/or in a differentiated cell that normally does not exhibit activated Wnt signaling is unknown.	('human', 'Species', '9606', (65, 70))	('arises', 'Reg', (88, 94))	('disease-causing', 'Reg', (33, 48))	('mutation', 'Var', (49, 57))	('Wnt', 'Gene', (172, 175))	('Wnt', 'Gene', (257, 260))	('Wnt', 'Gene', '114487', (172, 175))	('Wnt', 'Gene', '114487', (257, 260))
122399	22266195	Dysregulation of Wnt signaling by multiple mechanisms is predicted to be sufficient to define a progenitor-like fate capable of proliferating and accumulating additional harmful genetic perturbations, such as upregulation of IGF2, that participate in malignant transformation.	('proliferating', 'PosReg', (128, 141))	('rat', 'Species', '10116', (135, 138))	('Dysregulation', 'Var', (0, 13))	('IGF2', 'Gene', (225, 229))	('Wnt', 'Gene', (17, 20))	('upregulation', 'PosReg', (209, 221))	('Wnt', 'Gene', '114487', (17, 20))
122401	22266195	ACC is a defining cancer of the hereditary autosomal dominant Li-Fraumeni syndrome, which results from germline mutations in p53 [Table 1; ].	('cancer of the hereditary autosomal dominant Li-Fraumeni syndrome', 'Disease', 'MESH:C563754', (18, 82))	('p53', 'Gene', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('germline mutations', 'Var', (103, 121))	('results from', 'Reg', (90, 102))	('ACC', 'Disease', (0, 3))
122402	22266195	p53 acts as a tumor suppressor and, in most cases, both TP53 alleles must acquire loss of function mutations in order for the gene to be silenced.	('loss of function', 'NegReg', (82, 98))	('tumor', 'Disease', (14, 19))	('TP53', 'Gene', '22059', (56, 60))	('TP53', 'Gene', (56, 60))	('mutations', 'Var', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
122403	22266195	Li-Fraumeni syndrome patients inherit one nonfunctioning allele thus increasing the probably of a second mutation occurring de novo and potentially resulting in ACC.	('mutation', 'Var', (105, 113))	('Li-Fraumeni syndrome', 'Disease', (0, 20))	('probably', 'MPA', (84, 92))	('patients', 'Species', '9606', (21, 29))	('resulting in', 'Reg', (148, 160))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (0, 20))	('increasing', 'PosReg', (69, 79))
122404	22266195	Interestingly, a unique germ-line mutation in p53 (R337H) in Southern Brazil results in a markedly increased incidence of adrenocortical cancer yet a paucity of other Li-Fraumeni cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('p53', 'Gene', (46, 49))	('Li-Fraumeni cancers', 'Disease', (167, 186))	('R337H', 'Mutation', 'rs121912664', (51, 56))	('R337H', 'Var', (51, 56))	('adrenocortical cancer', 'Disease', (122, 143))	('increased', 'PosReg', (99, 108))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('Li-Fraumeni cancers', 'Disease', 'MESH:D016864', (167, 186))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (122, 143))
122405	22266195	Approximately 25% of sporadic ACC exhibit mutations in p53 while benign ACAs do not exhibit p53 mutations, suggesting that p53 may be a late event in the potential transformation of a benign to malignant adrenocortical neoplasm [Table 1; ].	('malignant adrenocortical neoplasm', 'Disease', (194, 227))	('p53', 'Gene', (55, 58))	('neoplasm', 'Phenotype', 'HP:0002664', (219, 227))	('mutations', 'Var', (42, 51))	('malignant adrenocortical neoplasm', 'Disease', 'MESH:D009369', (194, 227))
122406	22266195	The relatively low proliferative rate of the adrenal cortex and hence propagation of initiating carcinogenic events targeting both alleles may explain why the frequency of p53 mutations in sporadic ACC is lower than other types of cancers (similar to the low incidence of SFRP1 and APC mutations).	('mutations', 'Var', (176, 185))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('APC', 'Gene', '11789', (282, 285))	('carcinogenic', 'Disease', 'MESH:D063646', (96, 108))	('cancers', 'Disease', (231, 238))	('rat', 'Species', '10116', (26, 29))	('carcinogenic', 'Disease', (96, 108))	('APC', 'Gene', (282, 285))	('rat', 'Species', '10116', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('lower', 'NegReg', (205, 210))	('p53', 'Gene', (172, 175))
122408	22266195	However, since p53 loss is not observed in ACA, mutations in p53 may be important for malignant transformation in some ACC patients.	('important', 'Reg', (72, 81))	('loss', 'NegReg', (19, 23))	('patients', 'Species', '9606', (123, 131))	('ACC', 'Disease', (119, 122))	('p53', 'Gene', (61, 64))	('mutations', 'Var', (48, 57))
122415	22266195	In melanoma, it has recently been shown that epigenetic silencing of Pod1 results in a loss of transcriptional inhibition of a gene involved in metastasis.	('loss', 'NegReg', (87, 91))	('epigenetic silencing', 'Var', (45, 65))	('transcriptional inhibition', 'MPA', (95, 121))	('Pod1', 'Gene', (69, 73))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
122422	22266195	In addition to the acquisition of mutations that instill upon tumors the properties of stem/progenitor cells, it is equally plausible that such properties are the result of the cell of origin of these tumors being an adrenocortical stem/progenitor cell.	('adrenocortical stem', 'Disease', (217, 236))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('adrenocortical stem', 'Disease', 'MESH:D018268', (217, 236))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('mutations', 'Var', (34, 43))
122430	22266195	Indeed, clonal analysis of ACT suggests a monoclonal origin; mutations arise within a single cell while additional genetic hits occur in subsequent cellular generations ultimately resulting in polyclonal cancers.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mutations', 'Var', (61, 70))	('rat', 'Species', '10116', (161, 164))	('resulting in', 'Reg', (180, 192))
122437	22266195	Given the knowledge of the structure and function of the adrenal gland, three potential origins can be postulated: 1) cell autonomous mutations of stem/progenitors cells of the capsule or non-cell autonomous effects of such a mutation, 2) mutations in transiently amplifying stem/progenitors of the subcapsule 3) mutations in differentiated adrenocortical cells of the Zona Glomerulosa, Zona Fasiculata or Zona Reticularis.	('mutation', 'Var', (226, 234))	('adrenocortical', 'Disease', (341, 355))	('mutations', 'Var', (239, 248))	('adrenocortical', 'Disease', 'MESH:D018268', (341, 355))	('Zona Fasiculata', 'Disease', 'MESH:D006562', (387, 402))	('Zona Fasiculata', 'Disease', (387, 402))	('mutations', 'Var', (313, 322))
122444	22266195	In pediatric ACTs, however, IGF2 expression alone is unable to distinguish benign from malignant neoplasm, suggesting that in children, IGF2 dysregulation may be a much earlier genetic event in the transition from benign to malignant adrenocortical tumors.	('malignant neoplasm', 'Disease', (87, 105))	('malignant neoplasm', 'Disease', 'MESH:D009369', (87, 105))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('neoplasm', 'Phenotype', 'HP:0002664', (97, 105))	('dysregulation', 'Var', (141, 154))	('malignant adrenocortical tumors', 'Disease', 'MESH:D018268', (224, 255))	('IGF2', 'Gene', (136, 140))	('malignant adrenocortical tumors', 'Disease', (224, 255))	('children', 'Species', '9606', (126, 134))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))
122445	22266195	Interestingly, in mouse models of colorectal carcinoma, APC mutations and subsequent constitutive beta-Catenin activation have been shown to induce tumorigenesis yet progression to carcinoma is dependent on IGF2 expression.	('beta-Catenin', 'Gene', (98, 110))	('carcinoma', 'Disease', 'MESH:D002277', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('APC', 'Gene', (56, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('carcinoma', 'Disease', (181, 190))	('IGF2', 'Gene', (207, 211))	('induce', 'Reg', (141, 147))	('colorectal carcinoma', 'Disease', (34, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (34, 54))	('beta-Catenin', 'Gene', '12387', (98, 110))	('APC', 'Gene', '11789', (56, 59))	('mouse', 'Species', '10090', (18, 23))	('tumor', 'Disease', (148, 153))	('carcinoma', 'Disease', (45, 54))	('carcinoma', 'Disease', 'MESH:D002277', (181, 190))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
122454	33692753	N6-methyladenosine (m6A) RNA methylation, the most common form of mRNA modification, has been reported to be correlated with the occurrence and development of the malignant tumor.	('m6A', 'Gene', '56339', (20, 23))	('development', 'CPA', (144, 155))	('malignant tumor', 'Disease', (163, 178))	('N6-methyladenosine', 'Var', (0, 18))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('correlated', 'Reg', (109, 119))	('malignant tumor', 'Disease', 'MESH:D009369', (163, 178))	('m6A', 'Gene', (20, 23))
122467	33692753	N6-methyladenosine (m6A) is the most abundant internal modification of mRNAs in higher eukaryotes and mainly influences mRNA stability, translation efficiency, variable splicing, and localization by dynamic regulation of methyltransferases ("writers"), m6A-binding proteins ("readers"), and demethylases ("erasers").	('mRNA stability', 'MPA', (120, 134))	('m6A', 'Gene', '56339', (20, 23))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (0, 18))	('localization', 'MPA', (183, 195))	('translation efficiency', 'MPA', (136, 158))	('variable splicing', 'MPA', (160, 177))	('m6A', 'Gene', (253, 256))	('m6A', 'Gene', '56339', (253, 256))	('m6A', 'Gene', (20, 23))	('influences', 'Reg', (109, 119))
122469	33692753	In addition, m6A RNA methylation regulators can promote the occurrence and progression of cancers by multiple signaling pathways, such as regulating the epithelial mesenchymal transition of cancer, Wnt/PI3K-Akt signaling, and modulating genes expression levels.	('genes expression levels', 'MPA', (237, 260))	('Akt', 'Gene', '207', (207, 210))	('cancers', 'Disease', (90, 97))	('modulating', 'Reg', (226, 236))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('m6A', 'Gene', '56339', (13, 16))	('cancer', 'Disease', (190, 196))	('methylation', 'Var', (21, 32))	('m6A', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('signaling pathways', 'Pathway', (110, 128))	('promote', 'PosReg', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('occurrence', 'CPA', (60, 70))	('regulating', 'Reg', (138, 148))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('progression', 'CPA', (75, 86))	('Akt', 'Gene', (207, 210))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancer', 'Disease', (90, 96))	('epithelial mesenchymal transition of', 'CPA', (153, 189))
122497	33692753	We further calculated the risk score for ACC patients as follows: risk score = (0.3070 x expression value of RBM15) + (0.0235 x expression value of HNRNPC) + (-0.0673 x expression value of FTO), and divided ACC patients into high-risk and low-risk groups following the cut-off of the median risk score.	('RBM15', 'Gene', '64783', (109, 114))	('expression', 'MPA', (89, 99))	('patients', 'Species', '9606', (211, 219))	('FTO', 'Gene', '79068', (189, 192))	('ACC', 'Phenotype', 'HP:0006744', (207, 210))	('0.3070', 'Var', (80, 86))	('RBM15', 'Gene', (109, 114))	('patients', 'Species', '9606', (45, 53))	('ACC', 'Phenotype', 'HP:0006744', (41, 44))	('FTO', 'Gene', (189, 192))	('HNRNPC', 'Gene', (148, 154))	('HNRNPC', 'Gene', '3183', (148, 154))
122532	33692753	MYC is a direct and functionally essential target of FTO, and FTO knockdown enhances the expression level of m6A on MYC mRNA (especially at the 5' UTR and middle exons), leading to mRNA decay and MYC down-regulation, and thereby inhibition of MYC signaling, which plays an important role in the tumor.	('FTO', 'Gene', (53, 56))	('MYC', 'Gene', '4609', (196, 199))	('m6A', 'Gene', '56339', (109, 112))	('expression', 'MPA', (89, 99))	('MYC', 'Gene', '4609', (243, 246))	('inhibition', 'NegReg', (229, 239))	('MYC', 'Gene', '4609', (116, 119))	('m6A', 'Gene', (109, 112))	('knockdown', 'Var', (66, 75))	('tumor', 'Disease', (295, 300))	('MYC', 'Gene', (0, 3))	('FTO', 'Gene', '79068', (62, 65))	('MYC', 'Gene', (116, 119))	('FTO', 'Gene', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('MYC', 'Gene', (196, 199))	('down-regulation', 'NegReg', (200, 215))	('mRNA decay', 'MPA', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('MYC', 'Gene', (243, 246))	('MYC', 'Gene', '4609', (0, 3))	('FTO', 'Gene', '79068', (53, 56))	('enhances', 'PosReg', (76, 84))
122533	33692753	Previous studies showed that the abnormally high expression of FTO was associated with worse outcomes in cancers, such as gastric cancer, endometrial carcinoma, and lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('endometrial carcinoma', 'Disease', (138, 159))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('associated', 'Reg', (71, 81))	('expression', 'MPA', (49, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (138, 159))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (165, 193))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (138, 159))	('FTO', 'Gene', '79068', (63, 66))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('gastric cancer', 'Disease', (122, 136))	('abnormally high', 'Var', (33, 48))	('FTO', 'Gene', (63, 66))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('lung squamous cell carcinoma', 'Disease', (165, 193))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
122534	33692753	Moreover, FTO influences the progression of cancer by regulating multiple signaling pathways, such as FTO-PGC-1 alpha signaling axis, mediating PKM2 demethylation, impairing the translation efficiency of E2F1 and Myc.	('Myc', 'Gene', (213, 216))	('PKM2', 'Gene', (144, 148))	('mediating', 'Reg', (134, 143))	('PKM2', 'Gene', '5315', (144, 148))	('regulating', 'Reg', (54, 64))	('FTO', 'Gene', '79068', (10, 13))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('PGC-1 alpha', 'Gene', (106, 117))	('translation efficiency', 'MPA', (178, 200))	('FTO', 'Gene', (10, 13))	('Myc', 'Gene', '4609', (213, 216))	('demethylation', 'Var', (149, 162))	('E2F1', 'Gene', (204, 208))	('influences', 'Reg', (14, 24))	('impairing', 'NegReg', (164, 173))	('FTO', 'Gene', '79068', (102, 105))	('PGC-1 alpha', 'Gene', '10891', (106, 117))	('FTO', 'Gene', (102, 105))	('cancer', 'Disease', (44, 50))	('E2F1', 'Gene', '1869', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
122540	33692753	RBM15, an RNA binding protein, was categorized as the component of writers and its target is the lncRNA XIST, which mediates X-inactivation and gene silencing during development.	('RBM15', 'Gene', '64783', (0, 5))	('gene silencing', 'Var', (144, 158))	('RBM15', 'Gene', (0, 5))	('XIST', 'Gene', '7503', (104, 108))	('XIST', 'Gene', (104, 108))
122545	33692753	Dysregulation of m6A modification and the related proteins also contributes to the initiation and progression of cancers.	('contributes', 'Reg', (64, 75))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('m6A', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('m6A', 'Gene', '56339', (17, 20))
122546	33692753	Members of the YT521-B homology (YTH) domain family of proteins, including YTHDF1, YTHDF2, YTHDC1, and YTHDC2, have been identified as direct m6A readers.	('m6A', 'Gene', (142, 145))	('YTHDF1', 'Gene', '54915', (75, 81))	('m6A', 'Gene', '56339', (142, 145))	('YTHDC2', 'Gene', '64848', (103, 109))	('YTHDF1', 'Gene', (75, 81))	('YTHDF2', 'Gene', '51441', (83, 89))	('YTHDC2', 'Gene', (103, 109))	('YTHDC1', 'Gene', (91, 97))	('YTHDF2', 'Gene', (83, 89))	('YTHDC1', 'Gene', '91746', (91, 97))	('YT521-B', 'Var', (15, 22))
122551	33692753	indicated that inhibition of HNRNPC can suppress the proliferation and tumor growth by mediating the cascade of interferon responses.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('suppress', 'NegReg', (40, 48))	('HNRNPC', 'Gene', '3183', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('proliferation', 'CPA', (53, 66))	('mediating', 'Reg', (87, 96))	('tumor', 'Disease', (71, 76))	('inhibition', 'Var', (15, 25))	('HNRNPC', 'Gene', (29, 35))
122559	32895490	Genomic and sequence variants of protein kinase A regulatory subunit type 1beta (PRKAR1B) in patients with adrenocortical disease and Cushing syndrome Protein kinase A (PKA) subunit defects (in PRKAR1A and PRKACA) are known to contribute to adrenal tumor pathogenesis.	('variants', 'Var', (21, 29))	('adrenocortical disease', 'Disease', (107, 129))	('adrenocortical disease', 'Disease', 'MESH:D018268', (107, 129))	('PRKAR1B', 'Gene', '5575', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (134, 150))	('adrenal tumor', 'Disease', 'MESH:D000310', (241, 254))	('adrenal tumor', 'Disease', (241, 254))	('Cushing syndrome', 'Disease', 'MESH:D003480', (134, 150))	('PKA', 'Gene', (169, 172))	('contribute', 'Reg', (227, 237))	('Cushing syndrome', 'Disease', (134, 150))	('adrenal tumor', 'Phenotype', 'HP:0100631', (241, 254))	('PRKAR1B', 'Gene', (81, 88))	('patients', 'Species', '9606', (93, 101))	('defects', 'Var', (182, 189))
122563	32895490	Three PRKAR1B germline variants (p.I40V, p.A67V, p.A300T) were identified among 74 patients with BAH.	('PRKAR1B', 'Gene', (6, 13))	('p.A300T', 'Mutation', 'rs376485407', (49, 56))	('BAH', 'Chemical', '-', (97, 100))	('p.A67V', 'Var', (41, 47))	('p.A300T', 'Var', (49, 56))	('p.I40V', 'Var', (33, 39))	('p.A67V', 'Mutation', 'rs183383238', (41, 47))	('p.I40V', 'Mutation', 'rs61732492', (33, 39))	('patients', 'Species', '9606', (83, 91))
122564	32895490	PRKAR1B copy number gains (CNG) were found in 3 of 21 CPAs, one in a tumor carrying a somatic PRKACA "hot-spot" pathogenic variant p.L206R.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CPAs', 'Disease', (54, 58))	('tumor', 'Disease', (69, 74))	('p.L206R', 'Mutation', 'rs386352352', (131, 138))	('gains', 'PosReg', (20, 25))	('CPA', 'Chemical', '-', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('p.L206R', 'Var', (131, 138))	('PRKAR1B', 'Gene', (0, 7))
122565	32895490	CPAs bearing PRKAR1B CNGs showed higher PRKAR1B mRNA levels and reduced PKA activity.	('PKA activity', 'CPA', (72, 84))	('PRKAR1B mRNA levels', 'MPA', (40, 59))	('higher', 'PosReg', (33, 39))	('CPA', 'Chemical', '-', (0, 3))	('reduced', 'NegReg', (64, 71))	('PRKAR1B', 'Var', (13, 20))
122566	32895490	Baseline PKA activity was also decreased for p.A67V and p.A300T in vitro, and mutant PRKAR1beta bound PRKACalpha in FRET recordings of co-transfected HEK293 cells stronger than normal.	('HEK293', 'CellLine', 'CVCL:0045', (150, 156))	('PRKAR1beta', 'Gene', (85, 95))	('PRKACalpha', 'Gene', '5566', (102, 112))	('bound', 'Interaction', (96, 101))	('PRKACalpha', 'Gene', (102, 112))	('p.A300T', 'Mutation', 'rs376485407', (56, 63))	('decreased', 'NegReg', (31, 40))	('p.A67V', 'Var', (45, 51))	('PRKAR1beta', 'Gene', '5573', (85, 95))	('p.A300T', 'Var', (56, 63))	('PKA', 'Enzyme', (9, 12))	('p.A67V', 'Mutation', 'rs183383238', (45, 51))	('activity', 'MPA', (13, 21))	('stronger', 'PosReg', (163, 171))	('mutant', 'Var', (78, 84))
122568	32895490	Its involvement in adrenocortical disease may be different from that of other subunits, because PRKAR1B variants and PRKAR1B CNG were associated with decreased (rather than increased) overall PKA activity in vitro.	('PRKAR1B', 'Gene', (96, 103))	('adrenocortical disease', 'Disease', (19, 41))	('variants', 'Var', (104, 112))	('adrenocortical disease', 'Disease', 'MESH:D018268', (19, 41))	('activity', 'MPA', (196, 204))	('decreased', 'NegReg', (150, 159))	('PKA', 'Enzyme', (192, 195))
122571	32895490	PRKAR1A pathogenic variants were also found in isolated primary pigmented nodular adrenocortical disease (PPNAD) and cortisol-producing adenomas (CPA) causing Cushing syndrome (CS).	('Cushing syndrome', 'Disease', 'MESH:D003480', (159, 175))	('CS', 'Gene', '1431', (177, 179))	('adenomas', 'Disease', (136, 144))	('pigmented nodular adrenocortical disease', 'Disease', (64, 104))	('PRKAR1A', 'Gene', (0, 7))	('cortisol', 'Chemical', 'MESH:D006854', (117, 125))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (64, 104))	('adenomas', 'Disease', 'MESH:D000236', (136, 144))	('CPA', 'Chemical', '-', (146, 149))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (159, 175))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (64, 104))	('found', 'Reg', (38, 43))	('Cushing syndrome', 'Disease', (159, 175))	('variants', 'Var', (19, 27))	('cortisol-producing', 'Disease', (117, 135))
122572	32895490	A single patient with CNC-associated tumors was found to have somatic mosaicism for a copy number gain (CNG) of the PRKACB gene coding the Cbeta subunit (MIM: 176892).	('PRKACB', 'Gene', (116, 122))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('PRKACB', 'Gene', '5567', (116, 122))	('copy number', 'Var', (86, 97))	('patient', 'Species', '9606', (9, 16))	('gain', 'PosReg', (98, 102))	('CNC-associated', 'Disease', (22, 36))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
122573	32895490	Recently, we described a somatic PRKACB sequencing variant in a CPA of a patient with CS.	('PRKACB', 'Gene', '5567', (33, 39))	('patient', 'Species', '9606', (73, 80))	('variant', 'Var', (51, 58))	('CS', 'Gene', '1431', (86, 88))	('PRKACB', 'Gene', (33, 39))	('CPA', 'Chemical', '-', (64, 67))
122574	32895490	Defects in PRKACA, coding for the Calpha subunit (MIM: 601639), were identified in isolated PPNAD, CPA, and other adrenocortical tumors and cardiac myxomas.	('CPA', 'Disease', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('adrenocortical tumors', 'Disease', (114, 135))	('PRKACA', 'Gene', (11, 17))	('identified', 'Reg', (69, 79))	('Defects', 'Var', (0, 7))	('cardiac myxomas', 'Disease', (140, 155))	('cardiac myxomas', 'Disease', 'MESH:D006331', (140, 155))	('Calpha', 'Gene', '12310', (34, 40))	('cardiac myxomas', 'Phenotype', 'HP:0011672', (140, 155))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (114, 135))	('isolated PPNAD', 'Disease', (83, 97))	('Calpha', 'Gene', (34, 40))	('CPA', 'Chemical', '-', (99, 102))
122576	32895490	The genomic profile of CPAs that did not have the common genetic defects was also investigated recently:  among the identified sequence abnormalities and copy number variants (CNV), chromosome 7p22 CNG that included the PRKAR1B gene, coding the R1beta subunit (MIM: 176911), were the most frequent.	('genetic defects', 'Disease', 'MESH:D030342', (57, 72))	('PRKAR1B', 'Gene', (220, 227))	('chromosome', 'Var', (182, 192))	('CPA', 'Chemical', '-', (23, 26))	('frequent', 'Reg', (289, 297))	('genetic defects', 'Disease', (57, 72))
122577	32895490	In almost all cases, PRKAR1B CNG was seen in association with other defects that were thought to be drivers of the phenotype, such as for example PRKACA amplification (chromosome 19p13.3) or beta-catenin (CTNNB1 [MIM: 116806]) activating pathogenic variants.	('beta-catenin', 'Gene', (191, 203))	('activating', 'PosReg', (227, 237))	('CTNNB1', 'Gene', '1499', (205, 211))	('beta-catenin', 'Gene', '1499', (191, 203))	('variants', 'Var', (249, 257))	('PRKAR1B', 'Gene', (21, 28))	('CTNNB1', 'Gene', (205, 211))
122580	32895490	Following the identification of the first 7p22 CNGs in cortisol-producing lesions, we investigated patients with CS due to micronodular forms of bilateral adrenocortical hyperplasia (BAH) or CPA for PRKAR1B variants and 7p22 CNG.	('PRKAR1B', 'Gene', (199, 206))	('hyperplasia', 'Disease', (170, 181))	('CS', 'Gene', '1431', (113, 115))	('BAH', 'Chemical', '-', (183, 186))	('patients', 'Species', '9606', (99, 107))	('cortisol', 'Chemical', 'MESH:D006854', (55, 63))	('variants', 'Var', (207, 215))	('CPA', 'Chemical', '-', (191, 194))	('hyperplasia', 'Disease', 'MESH:D006965', (170, 181))
122586	32895490	All patients had been screened for germline pathogenic variants of PRKAR1A, PDE11A (MIM: 604961), PRKACA, and related genes, as part of older studies; their peripheral DNA samples were negative for any variants in these genes, confirmed also by Sanger sequencing.	('PRKAR1A', 'Gene', (67, 74))	('variants', 'Var', (55, 63))	('PDE11A', 'Gene', (76, 82))	('PDE11A', 'Gene', '50940', (76, 82))	('patients', 'Species', '9606', (4, 12))
122588	32895490	To quantify the DNA copy number of the PRKAR1B gene, we performed ddPCR using the FAM/MGB-labeled TaqMan probes for PRKAR1B (Hs04991422_cn, Hs04982006_cn, Hs04981093_cn) (Thermo Fisher Scientific, MA) and VIC/TAMRA-labeled TaqMan CNV RNAse P (#4403328) (Bio-Rad Laboratories, CA) as the internal control.	('Hs04991422_cn', 'Var', (125, 138))	('Hs04981093_cn', 'Var', (155, 168))	('VIC', 'Disease', 'None', (205, 208))	('VIC', 'Disease', (205, 208))	('CA', 'Gene', '12310', (276, 278))	('Hs04982006_cn', 'Var', (140, 153))
122597	32895490	The wild-type (WT) (NM_001164760.2) and 2 variant (p.A67V and p.A300T) PRKAR1B sequences were introduced into different expression vectors according to the method described elsewhere.	('NM_001164760.2', 'Var', (20, 34))	('expression vectors', 'Species', '29278', (120, 138))	('p.A300T', 'Var', (62, 69))	('PRKAR1B', 'Gene', (71, 78))	('p.A67V', 'Var', (51, 57))	('p.A67V', 'Mutation', 'rs183383238', (51, 57))	('p.A300T', 'Mutation', 'rs376485407', (62, 69))
122610	32895490	Three patients among 74 with isolated micronodular adrenocortical disease (iMAD) and no signs of CNC were found to carry germline PRKAR1B variants.	('PRKAR1B', 'Gene', (130, 137))	('variants', 'Var', (138, 146))	('patients', 'Species', '9606', (6, 14))	('iMAD', 'Disease', (75, 79))	('isolated micronodular adrenocortical disease', 'Disease', (29, 73))	('isolated micronodular adrenocortical disease', 'Disease', 'MESH:C566469', (29, 73))	('iMAD', 'Disease', 'None', (75, 79))
122613	32895490	She was found to carry the c.118A>G (p.I40V) PRKAR1B variant.	('p.I40V', 'Mutation', 'rs61732492', (37, 43))	('c.118A>G', 'Mutation', 'rs61732492', (27, 35))	('c.118A>G', 'Var', (27, 35))	('PRKAR1B', 'Gene', (45, 52))
122617	32895490	She was found to carry the c.200C>T (p.A67V) PRKAR1B variant.	('p.A67V', 'Mutation', 'rs183383238', (37, 43))	('c.200C>T', 'Var', (27, 35))	('c.200C>T', 'Mutation', 'rs183383238', (27, 35))	('PRKAR1B', 'Gene', (45, 52))
122618	32895490	The third patient (CAR521.01) carried the germline c.898G>A (p.A300T) PRKAR1B variant.	('PRKAR1B', 'Gene', (70, 77))	('c.898G>A', 'Mutation', 'rs376485407', (51, 59))	('c.898G>A', 'Var', (51, 59))	('patient', 'Species', '9606', (10, 17))	('CA', 'Gene', '12310', (19, 21))	('p.A300T', 'Mutation', 'rs376485407', (61, 68))
122622	32895490	Three patients with CPA among 21 were found to have CNG of the chromosome 7p22 PRKAR1B gene-harboring locus in their tumors (14.3% of total) (Fig.	('CNG', 'Var', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CPA', 'Chemical', '-', (20, 23))	('PRKAR1B', 'Gene', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('CPA', 'Disease', (20, 23))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('patients', 'Species', '9606', (6, 14))
122623	32895490	The tumor DNA was fully sequenced in all cases, and 1 of the 3 tumors carried the L206R PRKACA "hot-spot" variant that we and others have described previously.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (63, 68))	('L206R', 'Var', (82, 87))	('L206R', 'SUBSTITUTION', 'None', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
122625	32895490	Nothing unusual was identified in the histology of the other two CPA (ADT35.02 and ADT183.02).	('ADT183.02', 'Var', (83, 92))	('ADT35.02', 'Var', (70, 78))	('CPA', 'Chemical', '-', (65, 68))
122627	32895490	The mean age of presentation with ACTH-independent CS of the 3 patients with CPA and 7p22 CNG was 47.74 +- 3.35 years old; these patients were females.	('CPA', 'Var', (77, 80))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (63, 71))	('CPA', 'Chemical', '-', (77, 80))	('7p22 CNG', 'Var', (85, 93))	('CS', 'Gene', '1431', (51, 53))	('ACTH', 'Gene', (34, 38))	('ACTH', 'Gene', '5443', (34, 38))
122629	32895490	The biochemical data showed (Table S1) that the 3 patients with the CPA carrying 7p22 CNG had higher cortisol levels post high-dose dexamethasone suppression test (HDDST) (452.64 +- 0.00 versus 308.568 +- 57.13 nmol/L) and higher 17-hydroxysteroid (17-OHS) levels (15.00 +- 4.80 versus 8.88 +- 1.56 mug/g creatinine/24h) but similar 24h urinary free cortisol (UFC).	('CPA', 'Chemical', '-', (68, 71))	('patients', 'Species', '9606', (50, 58))	('cortisol', 'Chemical', 'MESH:D006854', (350, 358))	('7p22 CNG', 'Var', (81, 89))	('creatinine', 'Chemical', 'MESH:D003404', (305, 315))	('higher cortisol levels', 'Phenotype', 'HP:0003118', (94, 116))	('higher', 'PosReg', (223, 229))	('cortisol', 'Chemical', 'MESH:D006854', (101, 109))	('higher', 'PosReg', (94, 100))	('cortisol levels', 'MPA', (101, 116))
122632	32895490	Two of the identified PRKAR1B variants (p.A67V, p.A300T), the two rare ones, were in regions of the protein that are highly conserved evolutionarily (Table 1).	('p.A67V', 'Var', (40, 46))	('p.A300T', 'Mutation', 'rs376485407', (48, 55))	('p.A67V', 'Mutation', 'rs183383238', (40, 46))	('PRKAR1B', 'Gene', (22, 29))	('p.A300T', 'Var', (48, 55))
122633	32895490	The variant p.A67V was predicted as damaging for the function of the protein in 3 out of 5 in silico prediction tools used.	('p.A67V', 'Mutation', 'rs183383238', (12, 18))	('p.A67V', 'Var', (12, 18))	('function', 'MPA', (53, 61))
122635	32895490	In the gnomAD database v2.0.1, the allele frequency for the p.I40V, p.A67V and p.A300T is 0.013545, 0.00019396 and 0.0000648, respectively (Table S2).	('p.I40V', 'Mutation', 'rs61732492', (60, 66))	('0.0000648', 'Var', (115, 124))	('0.013545', 'Var', (90, 98))	('p.A300T', 'Mutation', 'rs376485407', (79, 86))	('p.A67V', 'Mutation', 'rs183383238', (68, 74))	('p.A67V', 'Var', (68, 74))	('p.I40V', 'Var', (60, 66))	('p.A300T', 'Var', (79, 86))	('0.00019396', 'Var', (100, 110))
122636	32895490	None of the identified variants were found in the TCGA database of PRKAR1B sequence variation from a variety of human cancers (Table S3).	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('PRKAR1B', 'Gene', (67, 74))	('variants', 'Var', (23, 31))	('human', 'Species', '9606', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
122638	32895490	Therefore, the p.A300T substitution may be affecting cAMP binding and, indirectly, the interaction of R1beta with the, Calpha subunit.	('affecting', 'Reg', (43, 52))	('p.A300T', 'Var', (15, 22))	('cAMP binding', 'Interaction', (53, 65))	('cAMP', 'Chemical', 'MESH:D000242', (53, 57))	('interaction', 'Interaction', (87, 98))	('R1beta', 'Protein', (102, 108))	('p.A300T', 'Mutation', 'rs376485407', (15, 22))	('Calpha', 'Gene', '12310', (119, 125))	('Calpha', 'Gene', (119, 125))
122640	32895490	1b the Alanine in position 67 is part of the N-linker, a flexible region connecting the inhibitory sequence with the D/D domain for which there is little information on the possible effects on the R1beta - Calpha association or other functions.	('Calpha', 'Gene', (206, 212))	('Alanine', 'Var', (7, 14))	('Alanine', 'Chemical', 'MESH:D000409', (7, 14))	('effects', 'Reg', (182, 189))	('Calpha', 'Gene', '12310', (206, 212))
122642	32895490	We focused our functional studies on the p.A67V and p.A300T variants only, as the p.I40V variant is located on an amino acid that is not conserved along the different species (Table 1) and is found relatively frequently in the general population; it was also predicted to be mostly benign by in silico analyses (Table S2).	('p.I40V', 'Mutation', 'rs61732492', (82, 88))	('p.A300T', 'Mutation', 'rs376485407', (52, 59))	('p.A67V', 'Var', (41, 47))	('p.A67V', 'Mutation', 'rs183383238', (41, 47))	('p.A300T', 'Var', (52, 59))	('p.I40V', 'Var', (82, 88))
122643	32895490	If this variant had any function it would most likely be related to AKAP-binding for which there is no readily available assay.	('variant', 'Var', (8, 15))	('AKAP', 'Gene', '11214', (68, 72))	('related', 'Reg', (57, 64))	('AKAP', 'Gene', (68, 72))
122644	32895490	2a (left panel), when we expressed these two PRKAR1B variants (p.A67V and p.A300T) in HEK293 cells, they had decreased basal PKA activity although the data for the p.A67V-bearing construct failed to reach statistical significance.	('decreased', 'NegReg', (109, 118))	('p.A300T', 'Var', (74, 81))	('PRKAR1B', 'Gene', (45, 52))	('p.A67V', 'Mutation', 'rs183383238', (164, 170))	('HEK293', 'CellLine', 'CVCL:0045', (86, 92))	('p.A67V', 'Var', (63, 69))	('p.A300T', 'Mutation', 'rs376485407', (74, 81))	('basal PKA activity', 'MPA', (119, 137))	('p.A67V', 'Mutation', 'rs183383238', (63, 69))
122647	32895490	2b) at an approximately equal rate; the difference from the WT R1beta-Calpha interaction was significant for both p.A67V and p.A300T variants.	('Calpha', 'Gene', (70, 76))	('p.A300T', 'Mutation', 'rs376485407', (125, 132))	('p.A67V', 'Var', (114, 120))	('p.A300T', 'Var', (125, 132))	('p.A67V', 'Mutation', 'rs183383238', (114, 120))	('Calpha', 'Gene', '12310', (70, 76))
122648	32895490	We measured PKA activity and PKA subunit expression in the tumors that had 7p22 CNG.	('expression', 'Species', '29278', (41, 51))	('expression', 'MPA', (41, 51))	('PKA subunit', 'Protein', (29, 40))	('tumors', 'Disease', (59, 65))	('7p22 CNG', 'Var', (75, 83))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('PKA', 'Enzyme', (12, 15))	('activity', 'MPA', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
122653	32895490	The 3 tumors with 7p22 CNG had lower basal PKA activity but no differences in total PKA activity compared to the normal (NL) CPA (N=5) without 7p22 CNG (Fig.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('basal PKA activity', 'MPA', (37, 55))	('CPA', 'Chemical', '-', (125, 128))	('lower', 'NegReg', (31, 36))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('7p22 CNG', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
122654	32895490	As expected from the 7p22 CNG containing the PRKAR1B gene, the 3 CPAs with 7p22 CNG had higher expression of the PRKAR1B mRNA compared to the 5 CPA that did not contain 7p22 CNG (Fig.	('higher', 'PosReg', (88, 94))	('CPA', 'Chemical', '-', (144, 147))	('CPA', 'Chemical', '-', (65, 68))	('7p22 CNG', 'Var', (75, 83))	('PRKAR1B', 'Gene', (113, 120))	('expression', 'Species', '29278', (95, 105))	('expression', 'MPA', (95, 105))
122655	32895490	In this report, we identified both sequence variants and chromosomal amplification of the PRKAR1B gene in iMAD and CPA, respectively, associated with ACTH-independent CS.	('associated with', 'Reg', (134, 149))	('CS', 'Gene', '1431', (167, 169))	('PRKAR1B', 'Gene', (90, 97))	('CPA', 'Chemical', '-', (115, 118))	('ACTH', 'Gene', (150, 154))	('iMAD', 'Disease', (106, 110))	('iMAD', 'Disease', 'None', (106, 110))	('ACTH', 'Gene', '5443', (150, 154))	('variants', 'Var', (44, 52))
122656	32895490	The study was prompted by a genome-wide search of CNV in CPA that identified 7p22 amplification in a small number of adenomas.	('adenomas', 'Disease', (117, 125))	('7p22 amplification', 'Var', (77, 95))	('adenomas', 'Disease', 'MESH:D000236', (117, 125))	('CPA', 'Chemical', '-', (57, 60))
122657	32895490	To date, the only other human disease thought to be caused by a PRKAR1B defect is a rare form of a late-onset neurodegenerative disorder presenting with dementia or Parkinson's syndrome that is characterized by abundant neuronal inclusions with immunoreactivity for intermediate filaments.	('defect', 'Var', (72, 78))	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (110, 136))	('human', 'Species', '9606', (24, 29))	('caused', 'Reg', (52, 58))	('dementia', 'Disease', (153, 161))	("Parkinson's syndrome", 'Disease', (165, 185))	("Parkinson's syndrome", 'Disease', 'MESH:D010300', (165, 185))	('dementia', 'Disease', 'MESH:D003704', (153, 161))	('neurodegenerative disorder', 'Disease', 'MESH:D019636', (110, 136))	('neurodegenerative disorder', 'Disease', (110, 136))	('PRKAR1B', 'Gene', (64, 71))	('dementia', 'Phenotype', 'HP:0000726', (153, 161))
122658	32895490	A heterozygous c.149T>G (p.L50R) PRKAR1B missense substitution was found to segregate with the disease in 12 members of a large family.	('missense substitution', 'Var', (41, 62))	('p.L50R', 'Mutation', 'rs1057519490', (25, 31))	('c.149T>G', 'Mutation', 'rs1057519490', (15, 23))	('c.149T>G', 'Var', (15, 23))	('PRKAR1B', 'Gene', (33, 40))	('segregate with', 'Reg', (76, 90))
122659	32895490	However, other studies failed to identify PRKAR1B defects in large numbers of patients with these rare forms of neurodegenerative disorders, and there were no functional studies of the p.L50R variant.	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (112, 138))	('PRKAR1B', 'Gene', (42, 49))	('p.L50R', 'Mutation', 'rs1057519490', (185, 191))	('patients', 'Species', '9606', (78, 86))	('defects', 'Var', (50, 57))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (112, 139))	('p.L50R', 'Var', (185, 191))	('neurodegenerative disorders', 'Disease', (112, 139))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (112, 139))
122660	32895490	Two of the identified PRKAR1B variants (p.A67V, p.A300T) in our cohort were rare and in highly conserved parts of the protein (Table 1); in functional studies, they decreased basal PKA activity and were bound with higher affinity to the PKA catalytic subunit (Fig.	('decreased', 'NegReg', (165, 174))	('activity', 'MPA', (185, 193))	('variants', 'Var', (30, 38))	('higher', 'PosReg', (214, 220))	('bound', 'Interaction', (203, 208))	('PKA', 'Enzyme', (181, 184))	('p.A300T', 'Mutation', 'rs376485407', (48, 55))	('p.A67V', 'Mutation', 'rs183383238', (40, 46))	('PRKAR1B', 'Gene', (22, 29))
122661	32895490	The p.A67V variant is in the D/D domain which is hypothesized to be unique for its role in binding to the catalytic subunit in the R1beta-Calpha complex and the p.A300T variant may interfere with cAMP binding which is essential for the release of the catalytic subunit from the R1beta-Calpha complex (Fig.	('Calpha', 'Gene', '12310', (138, 144))	('Calpha', 'Gene', (285, 291))	('Calpha', 'Gene', (138, 144))	('p.A300T', 'Var', (161, 168))	('interfere', 'NegReg', (181, 190))	('cAMP', 'Chemical', 'MESH:D000242', (196, 200))	('p.A67V', 'Var', (4, 10))	('cAMP binding', 'Interaction', (196, 208))	('p.A67V', 'Mutation', 'rs183383238', (4, 10))	('p.A300T', 'Mutation', 'rs376485407', (161, 168))	('Calpha', 'Gene', '12310', (285, 291))
122664	32895490	Nevertheless, the amplification of the gene led to higher expression of the PRKAR1B mRNA which confirmed the genomic finding (Fig.	('expression', 'Species', '29278', (58, 68))	('expression', 'MPA', (58, 68))	('mRNA', 'MPA', (84, 88))	('PRKAR1B', 'Gene', (76, 83))	('higher', 'PosReg', (51, 57))	('amplification', 'Var', (18, 31))
122665	32895490	Like in the previous study by Ronchi et al., in which 7p22 CNG were found in association mostly with CTNNB1 pathogenic variants, in one of our subjects' CPAs, PRKAR1B amplification was present along the L206R PRKACA "hot-spot" pathogenic variant.	('CTNNB1', 'Gene', '1499', (101, 107))	('L206R', 'Var', (203, 208))	('CPA', 'Chemical', '-', (153, 156))	('L206R', 'SUBSTITUTION', 'None', (203, 208))	('variants', 'Var', (119, 127))	('CTNNB1', 'Gene', (101, 107))
122671	32895490	The answer to that, in part, may be answered by the PKA enzymatic activity data for both PRKAR1B sequence variants found in our patients (Fig.	('patients', 'Species', '9606', (128, 136))	('PRKAR1B', 'Gene', (89, 96))	('variants', 'Var', (106, 114))
122673	32895490	In all cases, PRKAR1B alterations led to decreases in basal PKA activity which is probably due to higher retention of the catalytic subunit by the R1beta-Calpha heterodimer in the PKA tetramer, as suggested by the FRET experiments (Fig.	('PRKAR1B', 'Gene', (14, 21))	('decreases', 'NegReg', (41, 50))	('activity', 'MPA', (64, 72))	('alterations', 'Var', (22, 33))	('higher', 'PosReg', (98, 104))	('Calpha', 'Gene', '12310', (154, 160))	('PKA', 'Enzyme', (60, 63))	('Calpha', 'Gene', (154, 160))
122675	32895490	Nevertheless, it may be speculated that this tighter binding may be the case in tumors bearing PRKAR1B amplifications, the latter of which lead to an increase in available R1beta protein.	('R1beta protein', 'Protein', (172, 186))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('amplifications', 'Var', (103, 117))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('increase', 'PosReg', (150, 158))	('PRKAR1B', 'Gene', (95, 102))
122676	32895490	Thus, one could speculate that the mechanism of tumorigenesis in BAHs (iMAD) and CPAs bearing PRKAR1B variants or CNG, respectively, is perturbation of PKA signaling in adrenocortical cells.	('variants', 'Var', (102, 110))	('tumor', 'Disease', (48, 53))	('BAH', 'Chemical', '-', (65, 68))	('PRKAR1B', 'Gene', (94, 101))	('iMAD', 'Disease', (71, 75))	('PKA signaling', 'MPA', (152, 165))	('perturbation', 'Reg', (136, 148))	('iMAD', 'Disease', 'None', (71, 75))	('CPA', 'Chemical', '-', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
122681	32895490	The latter data are an example of how altered PRKAR1B in Ezh2-deficient mouse adrenals can lead to PKA signaling defects resulting in phenotypes that one would typically associate with PRKAR1A or PRKACA; the fact is that any perturbation of PKA signaling can lead to adrenal abnormalities given the sensitive balance of functionally interacting pathways in adrenocortical zonation and tumorigenesis.	('lead to', 'Reg', (91, 98))	('lead to', 'Reg', (259, 266))	('Ezh2', 'Gene', (57, 61))	('perturbation', 'Var', (225, 237))	('adrenal abnormalities', 'Disease', 'MESH:D000310', (267, 288))	('Ezh2', 'Gene', '14056', (57, 61))	('adrenal abnormalities', 'Phenotype', 'HP:0000834', (267, 288))	('altered', 'Var', (38, 45))	('mouse', 'Species', '10090', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (385, 390))	('tumor', 'Disease', (385, 390))	('adrenal abnormalities', 'Disease', (267, 288))	('defects', 'NegReg', (113, 120))	('PRKAR1B', 'Gene', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (385, 390))
122682	32895490	In conclusion, this investigation reveals sequencing variants of the PRKAR1B PKA regulatory subunit in the germline of unrelated patients with iMAD and somatic PRKAR1B amplifications in CPA and confirms PRKAR1B's potential for being involved in the perturbations of cAMP signaling that give rise to adrenocortical disease, although additional studies are needed for elucidation of R1beta's role in the pathogenesis of BAH and CPA leading to CS.	('adrenocortical disease', 'Disease', (299, 321))	('cAMP', 'Chemical', 'MESH:D000242', (266, 270))	('CPA', 'Chemical', '-', (426, 429))	('give rise', 'Reg', (286, 295))	('CS', 'Gene', '1431', (441, 443))	('BAH', 'Chemical', '-', (418, 421))	('patients', 'Species', '9606', (129, 137))	('adrenocortical disease', 'Disease', 'MESH:D018268', (299, 321))	('PRKAR1B', 'Gene', (69, 76))	('iMAD', 'Disease', (143, 147))	('CPA', 'Chemical', '-', (186, 189))	('PRKAR1B', 'Gene', (160, 167))	('rise to adrenocortical disease', 'Phenotype', 'HP:0008207', (291, 321))	('iMAD', 'Disease', 'None', (143, 147))	('variants', 'Var', (53, 61))
122683	32895490	Also, the data reveal possible new roles for R1beta in disease pathogenesis; PRKAR1B should be included in the candidate genes for suspected PKA signaling defects in patients with phenotypes that overlap with those that carry PRKAR1A, PRKACA and PRKACB defects.	('PRKAR1A', 'Gene', (226, 233))	('PRKACB', 'Gene', '5567', (246, 252))	('PRKAR1B', 'Gene', (77, 84))	('patients', 'Species', '9606', (166, 174))	('PRKACB', 'Gene', (246, 252))	('defects', 'Var', (155, 162))
122689	32784588	Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe.	('kidney chromophobe', 'Disease', 'MESH:D000238', (126, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (96, 120))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (96, 120))	('sarcoma', 'Disease', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('observed', 'Reg', (75, 83))	('adrenocortical carcinoma', 'Disease', (96, 120))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))	('kidney chromophobe', 'Disease', (126, 144))	('homologous recombination', 'Var', (35, 59))
122698	32784588	In addition, ALT-positive tumors have recurrent mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene and the gene encoding the death domain associated (DAXX) protein.	('alpha', 'Disease', (65, 70))	('DAXX', 'Gene', '1616', (183, 187))	('death', 'Disease', 'MESH:D003643', (158, 163))	('death', 'Disease', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('ATRX', 'Gene', (121, 125))	('DAXX', 'Gene', (183, 187))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (71, 119))	('ATRX', 'Gene', '546', (121, 125))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (71, 119))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mental retardation', 'Phenotype', 'HP:0001249', (83, 101))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', (26, 32))
122717	32784588	Three of these cancer types showed significantly greater enrichment of the ALT HR pathway in the Long TL group than in the Short TL group (SARC: p = 5.1 x 10-10, ACC: p = 4.4 x 10-4, KICH: p = 1.7 x 10-4).	('Long TL', 'Var', (97, 104))	('ACC', 'Phenotype', 'HP:0006744', (162, 165))	('SARC', 'Phenotype', 'HP:0100242', (139, 143))	('greater', 'PosReg', (49, 56))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('KICH', 'Disease', (183, 187))	('ALT HR pathway', 'Pathway', (75, 89))	('KICH', 'Disease', 'None', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
122729	32784588	PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence.	('PML', 'Gene', '5371', (0, 3))	('chromosomal abnormalities', 'Disease', (51, 76))	('depletion', 'Var', (4, 13))	('PML', 'Phenotype', 'HP:0004836', (0, 3))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (51, 76))	('induces', 'Reg', (14, 21))	('PML', 'Gene', (0, 3))	('senescence', 'CPA', (82, 92))	('telomere damage', 'CPA', (22, 37))
122730	32784588	It is commonly found in tumors with telomere shortening and high proliferation, which suggests its critical role in telomere maintenance and cell viability.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('telomere shortening', 'Phenotype', 'HP:0031413', (36, 55))	('high proliferation', 'CPA', (60, 78))	('telomere shortening', 'Var', (36, 55))
122733	32784588	We found that the cell proliferation rate differs noticeably based on the telomere length in three cancer types (Figure 2c).	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('telomere length', 'Var', (74, 89))	('cell proliferation rate', 'CPA', (18, 41))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
122745	32784588	In gliomas, TERT promoter mutations lead to higher telomerase activity but the associations between TERT promoter mutations and clinical outcomes are still controversial.	('TERT', 'Gene', '7015', (12, 16))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('higher', 'PosReg', (44, 50))	('TERT', 'Gene', (100, 104))	('mutations', 'Var', (26, 35))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('TERT', 'Gene', '7015', (100, 104))	('gliomas', 'Disease', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('TERT', 'Gene', (12, 16))	('telomerase activity', 'MPA', (51, 70))
122756	32784588	Cancers displaying unfavorable risk with high ALT (BRCA, SARC, and LUAD) may be regulated by the transcriptional factors E2F4, TFDP1, E2F1, E2F7, and SIN3A (FDR = 0.001) in the DNA repair pathway, including genes repairing DNA damage such as CENPI, CLSPN, TOPBP1, and MCM4 (Figure 4a).	('MCM4', 'Gene', (268, 272))	('Cancers', 'Disease', (0, 7))	('CENPI', 'Gene', (242, 247))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('SIN3A', 'Gene', '25942', (150, 155))	('TOPBP1', 'Gene', '11073', (256, 262))	('BRCA', 'Gene', '672', (51, 55))	('E2F7', 'Gene', (140, 144))	('TFDP1', 'Gene', (127, 132))	('CLSPN', 'Gene', '63967', (249, 254))	('CENPI', 'Gene', '2491', (242, 247))	('CLSPN', 'Gene', (249, 254))	('TOPBP1', 'Gene', (256, 262))	('regulated', 'Reg', (80, 89))	('SARC', 'Disease', (57, 61))	('E2F4', 'Gene', (121, 125))	('BRCA', 'Gene', (51, 55))	('E2F1', 'Var', (134, 138))	('E2F4', 'Gene', '1874', (121, 125))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('MCM4', 'Gene', '4173', (268, 272))	('E2F7', 'Gene', '144455', (140, 144))	('SIN3A', 'Gene', (150, 155))	('TFDP1', 'Gene', '7027', (127, 132))	('SARC', 'Phenotype', 'HP:0100242', (57, 61))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))	('DNA', 'Pathway', (177, 180))	('BRCA', 'Phenotype', 'HP:0003002', (51, 55))
122757	32784588	In contrast, cancers displaying favorable risk with high ALT (GBM and LIHC) may be regulated by E2F4, TFDP1, FOXM1, E2F7, SIN3A, E2F1, MYBL2, and E2F2 (FDR = 0.0001) (Figure 4b).	('E2F1', 'Var', (129, 133))	('E2F2', 'Gene', '1870', (146, 150))	('FOXM1', 'Gene', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('TFDP1', 'Gene', (102, 107))	('SIN3A', 'Gene', (122, 127))	('E2F7', 'Gene', (116, 120))	('MYBL2', 'Gene', (135, 140))	('E2F4', 'Gene', (96, 100))	('MYBL2', 'Gene', '4605', (135, 140))	('E2F4', 'Gene', '1874', (96, 100))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('FOXM1', 'Gene', '2305', (109, 114))	('cancers', 'Disease', (13, 20))	('TFDP1', 'Gene', '7027', (102, 107))	('SIN3A', 'Gene', '25942', (122, 127))	('E2F7', 'Gene', '144455', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('E2F2', 'Gene', (146, 150))
122761	32784588	There is an unmet need for the development of drugs for ALT tumors associated with telomere lengthening.	('telomere', 'Var', (83, 91))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('associated', 'Reg', (67, 77))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
122765	32784588	We identified candidate drugs (CP724714, MP470, TGX221, and XMD8-85) for TOP2A in molecular subtypes of sarcoma (osteosarcoma and soft tissue) (Figure 4f).	('osteosarcoma', 'Disease', 'MESH:D012516', (113, 125))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('sarcoma', 'Disease', (104, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('CP724714', 'Var', (31, 39))	('sarcoma', 'Disease', (118, 125))	('TOP2A', 'Gene', '7153', (73, 78))	('MP470', 'Var', (41, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('TOP2A', 'Gene', (73, 78))	('osteosarcoma', 'Disease', (113, 125))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))	('sarcoma', 'Disease', 'MESH:D012509', (118, 125))
122766	32784588	We found that XMD8-85, as an ERK5 target, was also predicted in the Long TL samples in SARC by DeSigN  (p = 0.032).	('XMD8-85', 'Var', (14, 21))	('SARC', 'Phenotype', 'HP:0100242', (87, 91))	('ERK5', 'Gene', (29, 33))	('ERK5', 'Gene', '5598', (29, 33))
122788	32784588	We also compared PML expression by telomere length and found that PML expression was higher in the Short TL group.	('higher', 'PosReg', (85, 91))	('Short', 'Var', (99, 104))	('PML', 'Gene', '5371', (17, 20))	('PML', 'Gene', '5371', (66, 69))	('PML', 'Phenotype', 'HP:0004836', (17, 20))	('PML', 'Phenotype', 'HP:0004836', (66, 69))	('PML', 'Gene', (17, 20))	('PML', 'Gene', (66, 69))
122789	32784588	In some cancer types, high PML expression is associated with telomere shortening for tumor suppression and apoptosis, cell cycle arrest, and senescence, owing to the lack of telomere maintenance.	('tumor', 'Disease', (85, 90))	('arrest', 'Disease', (129, 135))	('senescence', 'CPA', (141, 151))	('cancer', 'Disease', (8, 14))	('PML', 'Gene', '5371', (27, 30))	('telomere shortening', 'Phenotype', 'HP:0031413', (61, 80))	('high', 'Var', (22, 26))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('associated', 'Reg', (45, 55))	('telomere', 'MPA', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('PML', 'Gene', (27, 30))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('PML', 'Phenotype', 'HP:0004836', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('apoptosis', 'CPA', (107, 116))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
122817	32784588	Significant survival differences were observed in ALT-associated pathways, Figure S8: Box plot comparing the expression of hTERT repressors (CTCF, E2F1, and SIN3A).	('hTERT', 'Gene', (123, 128))	('CTCF', 'Gene', (141, 145))	('E2F1', 'Var', (147, 151))	('hTERT', 'Gene', '7015', (123, 128))	('ALT-associated pathways', 'Pathway', (50, 73))	('SIN3A', 'Gene', '25942', (157, 162))	('CTCF', 'Gene', '10664', (141, 145))	('SIN3A', 'Gene', (157, 162))
122832	31964355	In ACC, excessive cortisol inhibits the pituitary secretion of gonadotropin, and this could cause ovulation disorders, hypomenorrhea, and irregular periods or menopause in the majority of female patients.	('ovulation disorders', 'Disease', (98, 117))	('hypomenorrhea', 'Disease', (119, 132))	('cause', 'Reg', (92, 97))	('inhibits', 'NegReg', (27, 35))	('ACC', 'Disease', 'MESH:D018268', (3, 6))	('excessive', 'Var', (8, 17))	('menopause', 'Disease', (159, 168))	('pituitary secretion of gonadotropin', 'MPA', (40, 75))	('hypomenorrhea', 'Disease', 'MESH:D008599', (119, 132))	('patients', 'Species', '9606', (195, 203))	('ovulation disorders', 'Disease', 'MESH:D009358', (98, 117))	('ACC', 'Phenotype', 'HP:0006744', (3, 6))	('cortisol', 'Chemical', 'MESH:D006854', (18, 26))	('ACC', 'Disease', (3, 6))	('excessive cortisol', 'Phenotype', 'HP:0003118', (8, 26))	('irregular periods', 'Disease', (138, 155))
122896	31964355	In an in vitro experiment, researchers found that increased expression of Aberrant GPCR expression in adrenocortical cells led to the formation of adrenocortical hyperplasia and the development of Cushing syndrome characteristics in transplanted mice.	('GPCR', 'Gene', '227289', (83, 87))	('expression', 'MPA', (60, 70))	('Cushing syndrome', 'Disease', (197, 213))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (197, 213))	('increased', 'PosReg', (50, 59))	('Cushing syndrome', 'Disease', 'MESH:D003480', (197, 213))	('adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (147, 173))	('GPCR', 'Gene', (83, 87))	('adrenocortical hyperplasia', 'Disease', (147, 173))	('Aberrant', 'Var', (74, 82))	('mice', 'Species', '10090', (246, 250))
122913	30400009	GnRH antagonist treatment of malignant adrenocortical tumors Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets.	('malignant adrenocortical tumors', 'Disease', (29, 60))	('malignant adrenocortical tumors', 'Disease', 'MESH:D018268', (29, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('GnRH', 'Gene', (0, 4))	('GnRH', 'Gene', '2796', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Aberrantly expressed', 'Var', (61, 81))	('tumors', 'Disease', (54, 60))	('G protein-coupled receptors', 'Protein', (82, 109))
122929	30400009	GnRH analogues have also been shown to act directly on GNRHR expressing cells and to promote (splenocytes, thymocytes and lymphocytes) or inhibit the growth of normal (ovarian granulosa cells) and tumorous (prostate, breast, ovary, endometrium, adrenal, lung, pancreatic, melanoma, glioblastoma) cells.	('melanoma', 'Disease', 'MESH:D008545', (272, 280))	('glioblastoma', 'Phenotype', 'HP:0012174', (282, 294))	('promote', 'PosReg', (85, 92))	('pancreatic', 'Disease', 'MESH:D010195', (260, 270))	('analogues', 'Var', (5, 14))	('tumorous', 'Disease', (197, 205))	('GnRH', 'Gene', (0, 4))	('GNRHR', 'Gene', (55, 60))	('tumorous', 'Disease', 'MESH:D009369', (197, 205))	('pancreatic', 'Disease', (260, 270))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('glioblastoma', 'Disease', 'MESH:D005909', (282, 294))	('glioblastoma', 'Disease', (282, 294))	('growth', 'CPA', (150, 156))	('inhibit', 'NegReg', (138, 145))	('melanoma', 'Phenotype', 'HP:0002861', (272, 280))	('melanoma', 'Disease', (272, 280))
122934	30400009	Inhalpha/Tag mice, expressing Simian Virus 40T antigen under the inhibin alpha promoter, and with an intact immune system, are an example of a mouse model developing tumors.	('mice', 'Species', '10090', (13, 17))	('Tag', 'Gene', (9, 12))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mouse', 'Species', '10090', (143, 148))	('Tag', 'Gene', '404663', (9, 12))	('Simian Virus 40', 'Species', '1891767', (30, 45))	('Simian Virus 40T antigen', 'Var', (30, 54))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
122947	30400009	Depending on the primary antibody host, Dako EnVision+ System-HRP polymer anti-mouse (K4007, Dako) or anti-rabbit (K4011, Dako) were applied, and visualized with Liquid DAB + Substrate Chromogen System (Dako).	('mouse', 'Species', '10090', (79, 84))	('K4007', 'Var', (86, 91))	('K4011', 'Var', (115, 120))	('DAB', 'Chemical', 'MESH:C000469', (169, 172))	('rabbit', 'Species', '9986', (107, 113))
122949	30400009	In situ hybridization (ISH) was performed using RNAscope 2.5 HD Reagent Kit-BROWN (Advanced Cell Diagnostics, Newark, CA, USA) with predesigned probes for GNRHR (#407999), LHCGR (#300031), FSHR (#408101), positive control POLR2A (#310451) and nonsense dapB (from Bacillus S., #310043).	('#310451', 'Var', (230, 237))	('#407999', 'Var', (162, 169))	('HD', 'Disease', 'MESH:D006816', (61, 63))	('Bacillus S', 'Species', '126783', (263, 273))	('#300031', 'Var', (179, 186))	('#408101', 'Var', (195, 202))	('FSHR', 'Gene', '2492', (189, 193))	('FSHR', 'Gene', (189, 193))
122954	30400009	Cetrorelix acetate (#C5249, Sigma-Aldrich) was dissolved in 0.1% DMSO (#D8418, Sigma-Aldrich).	('DMSO', 'Chemical', 'MESH:D004121', (65, 69))	('#D8418', 'Var', (71, 77))	('#C5249', 'Var', (20, 26))
123034	30400009	GNRHR knockdown to reduce CTX action ultimately confirmed the on-target CTX effect.	('GNRHR', 'Gene', (0, 5))	('CTX', 'Disease', (72, 75))	('CTX', 'Disease', 'MESH:D019294', (72, 75))	('knockdown', 'Var', (6, 15))	('CTX', 'Disease', (26, 29))	('CTX', 'Disease', 'MESH:D019294', (26, 29))
123046	30400009	Although the anti-angiogenic, anti-metastatic and pro-apoptotic effects of GnRH antagonists are well documented, the molecular mechanisms of their action remains poorly understood.	('anti-metastatic', 'CPA', (30, 45))	('antagonists', 'Var', (80, 91))	('GnRH', 'Gene', (75, 79))	('men', 'Species', '9606', (105, 108))	('pro-apoptotic', 'CPA', (50, 63))	('anti-angiogenic', 'CPA', (13, 28))
123059	30400009	M D, M C, N A R designed the study concept; M D, M C, J S, T S, S A performed the experiments; all the authors (M D, M C, J S, T S, S A, U P, M Q, S W, I H, J T, N A R) analyzed and interpreted the results; M D, M C, I H, J T and N A R drafted the manuscript and all the authors have approved the final manuscript.	('M D', 'Var', (207, 210))	('M C', 'Var', (212, 215))	('men', 'Species', '9606', (88, 91))
123061	30237752	In this study, we used bioinformatics approaches to identify gene alteration that contribute to colon cancer progression via analysis of TCGA RNA sequencing data and other publicly GEO microarray data.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('contribute', 'Reg', (82, 92))	('alteration', 'Var', (66, 76))	('colon cancer', 'Disease', (96, 108))
123065	30237752	High VCAN levels also predict shorter overall survival of colon cancer patients.	('VCAN', 'Gene', '1462', (5, 9))	('overall', 'MPA', (38, 45))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (71, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (58, 70))	('VCAN', 'Gene', (5, 9))	('colon cancer', 'Disease', 'MESH:D015179', (58, 70))	('shorter', 'NegReg', (30, 37))	('colon cancer', 'Disease', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
123066	30237752	Furthermore, in vitro assays of silencing VCAN inhibit HCT116 cell proliferation and invasion.	('VCAN', 'Gene', (42, 46))	('HCT116 cell proliferation', 'CPA', (55, 80))	('inhibit', 'NegReg', (47, 54))	('silencing', 'Var', (32, 41))	('invasion', 'CPA', (85, 93))	('HCT116', 'CellLine', 'CVCL:0291', (55, 61))	('VCAN', 'Gene', '1462', (42, 46))
123079	30237752	Mutations in this gene are the cause of Wagner syndrome type 1.	('Wagner syndrome', 'Disease', 'MESH:C536075', (40, 55))	('Mutations', 'Var', (0, 9))	('Wagner syndrome', 'Disease', (40, 55))	('cause', 'Reg', (31, 36))
123091	30237752	Colony formation assays were performed to detect HCT-116 cells cloning Capability after HCT-116 cells transfected with si-VCAN or si-NC.	('si-NC', 'Var', (130, 135))	('VCAN', 'Gene', (122, 126))	('VCAN', 'Gene', '1462', (122, 126))	('HCT-116', 'CellLine', 'CVCL:0291', (88, 95))	('HCT-116', 'CellLine', 'CVCL:0291', (49, 56))
123109	30237752	Quantitative RT-PCR and Western blot analysis to quantitatively measure the effect of VCAN knockdown.	('VCAN', 'Gene', (86, 90))	('VCAN', 'Gene', '1462', (86, 90))	('knockdown', 'Var', (91, 100))
123111	30237752	Transwell migration assays showed that knockdown of VCAN dramatically decreased cell migration (Fig.	('knockdown', 'Var', (39, 48))	('decreased', 'NegReg', (70, 79))	('cell migration', 'CPA', (80, 94))	('VCAN', 'Gene', (52, 56))	('VCAN', 'Gene', '1462', (52, 56))
123112	30237752	Furthermore, Colony formation assays showed that knockdown of VCAN inhibited cell proliferation in vitro.	('knockdown', 'Var', (49, 58))	('inhibited', 'NegReg', (67, 76))	('VCAN', 'Gene', (62, 66))	('cell proliferation in vitro', 'CPA', (77, 104))	('VCAN', 'Gene', '1462', (62, 66))
123118	30237752	reported miR-135a-5p could affect the proliferation, invasion and migration of thyroid carcinoma cells by targeting VCAN.	('VCAN', 'Gene', (116, 120))	('migration', 'CPA', (66, 75))	('proliferation', 'CPA', (38, 51))	('invasion', 'CPA', (53, 61))	('VCAN', 'Gene', '1462', (116, 120))	('targeting', 'Reg', (106, 115))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (79, 96))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (79, 96))	('miR-135a-5p', 'Var', (9, 20))	('affect', 'Reg', (27, 33))	('thyroid carcinoma', 'Disease', (79, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
123124	30237752	A loss-of-function study revealed that colony formation assays showed that knockdown of VCAN inhibited cell proliferation in vitro.	('cell proliferation in vitro', 'CPA', (103, 130))	('VCAN', 'Gene', '1462', (88, 92))	('knockdown', 'Var', (75, 84))	('inhibited', 'NegReg', (93, 102))	('VCAN', 'Gene', (88, 92))
123125	30237752	Transwell migration assays showed that knockdown of VCAN dramatically decreased cell migration.	('knockdown', 'Var', (39, 48))	('decreased', 'NegReg', (70, 79))	('cell migration', 'CPA', (80, 94))	('VCAN', 'Gene', (52, 56))	('VCAN', 'Gene', '1462', (52, 56))
123149	30214461	Her early morning serum cortisol and 24-h urine cortisol levels were markedly elevated at 5,547 nmol/L (171 - 536 nmol/L) and 3974.4 nmol/24 h (88.32 - 670.68 nmol/24 h), respectively.	('3974.4 nmol/24', 'Var', (126, 140))	('elevated', 'PosReg', (78, 86))	('cortisol', 'Chemical', 'MESH:D006854', (24, 32))	('urine cortisol', 'Phenotype', 'HP:0012030', (42, 56))	('cortisol', 'Chemical', 'MESH:D006854', (48, 56))	('h urine cortisol level', 'Phenotype', 'HP:0012030', (40, 62))
123226	30108672	In this case, adrenocortical adenoma uptake of 131I, misled to unnecessary surgical resection of the lesion.	('131I', 'Var', (47, 51))	('adrenocortical adenoma', 'Disease', (14, 36))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (14, 36))	('131I', 'Chemical', 'MESH:C000614965', (47, 51))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (14, 36))
123230	28163695	Failure of such mechanisms, in particular misexpression of RNA-BP, has been linked to several human diseases.	('human', 'Species', '9606', (94, 99))	('misexpression', 'Var', (42, 55))	('RNA-BP', 'Gene', (59, 65))	('linked', 'Reg', (76, 82))
123249	28163695	Deletion of TIS11b/BRF1 gene in mice results in embryonic lethality due to abnormal placentation and major vascular defects.	('results in', 'Reg', (37, 47))	('abnormal placentation', 'Phenotype', 'HP:0012767', (75, 96))	('embryonic lethality', 'Disease', 'MESH:D020964', (48, 67))	('embryonic lethality', 'Disease', (48, 67))	('vascular defects', 'Disease', (107, 123))	('mice', 'Species', '10090', (32, 36))	('vascular defects', 'Disease', 'MESH:D000783', (107, 123))	('TIS11b/BRF1', 'Gene', (12, 23))	('Deletion', 'Var', (0, 8))
123257	28163695	TIS11b mRNA is also rapidly stimulated by 8-bromo-cAMP in murine adrenocortical Y-1 cells or Leydig MA-10 cells, suggesting that the protein is a key regulator of endocrine tissue biology.	('adrenocortical', 'Disease', (65, 79))	('TIS11b', 'Gene', (0, 6))	('adrenocortical', 'Disease', 'MESH:D018268', (65, 79))	('Y-1', 'CellLine', 'CVCL:0585', (80, 83))	('murine', 'Species', '10090', (58, 64))	('stimulated', 'PosReg', (28, 38))	('8-bromo-cAMP', 'Chemical', 'MESH:D015124', (42, 54))	('mRNA', 'MPA', (7, 11))	('8-bromo-cAMP', 'Var', (42, 54))
123268	28163695	In BAC, similar long and short forms appear equally, whereas in human adrenocortical carcinoma cells H295R, di-butyryl-cAMP selectively stimulates the short form of StAR mRNA.	('human', 'Species', '9606', (64, 69))	('stimulates', 'PosReg', (136, 146))	('StAR', 'Gene', (165, 169))	('di-butyryl-cAMP', 'Var', (108, 123))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (70, 94))	('di-butyryl-cAMP', 'Chemical', 'MESH:D003994', (108, 123))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (70, 94))	('StAR', 'Gene', '6770', (165, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('adrenocortical carcinoma', 'Disease', (70, 94))
123271	28163695	However, the impact of these phosphorylations on their mRNA-destabilizing activity is still a matter of debate, with some studies indicating that phosphorylations of TTP decrease its affinity for ARE-rich mRNAs and other studies reporting that phosphorylations by ERK, p38 MAP-Kinase/MK2, or JNK kinase do not impact this affinity.	('affinity', 'MPA', (183, 191))	('p38', 'Gene', (269, 272))	('phosphorylations', 'Var', (146, 162))	('TTP', 'Gene', (166, 169))	('p38', 'Gene', '1432', (269, 272))	('MK2', 'Gene', '9261', (284, 287))	('MK2', 'Gene', (284, 287))	('decrease', 'NegReg', (170, 178))
123275	28163695	ACTH-mediated activation of PKA was reported to induce the phosphorylation of TIS11b on two serine residues, S54 and S334 (Figure 1B).	('TIS11b', 'Gene', (78, 84))	('S334', 'Chemical', '-', (117, 121))	('S334', 'Var', (117, 121))	('S54', 'Var', (109, 112))	('ACTH-', 'Gene', '5443', (0, 5))	('phosphorylation', 'MPA', (59, 74))	('serine', 'Chemical', 'MESH:D012694', (92, 98))	('ACTH-', 'Gene', (0, 5))
123276	28163695	Analysis of phospho-dead (S54A, S334A) and phospho-mimick (S54D, S334D) TIS11b mutants revealed that S54 regulates the binding of TIS11b to 14.3.3 protein but that S334 does not play a significant role in this interaction.	('S54D', 'Var', (59, 63))	('S54', 'Var', (101, 104))	('regulates', 'Reg', (105, 114))	('mutants', 'Var', (79, 86))	('S54A', 'Var', (26, 30))	('S334', 'Chemical', '-', (164, 168))	('S334', 'Chemical', '-', (65, 69))	('S334A', 'Mutation', 'p.S334A', (32, 37))	('TIS11b', 'Gene', (72, 78))	('S334D', 'Mutation', 'p.S334D', (65, 70))	('S334', 'Chemical', '-', (32, 36))	('S54D', 'Mutation', 'p.S54D', (59, 63))	('binding', 'Interaction', (119, 126))	('S54A', 'Mutation', 'p.S54A', (26, 30))
123278	28163695	TIS11b S334D phospho-mimick mutants presented a reduced association with CNOT1, a core subunit of the CCR4-NOT deadenylase complex, but however displayed an enhanced interaction with the decapping enzyme Dcp1a.	('Dcp1a', 'Gene', (204, 209))	('enhanced', 'PosReg', (157, 165))	('reduced', 'NegReg', (48, 55))	('CCR4', 'Gene', (102, 106))	('TIS11b', 'Gene', (0, 6))	('Dcp1a', 'Gene', '55802', (204, 209))	('CNOT1', 'Gene', '23019', (73, 78))	('CCR4', 'Gene', '1233', (102, 106))	('interaction', 'Interaction', (166, 177))	('association', 'Interaction', (56, 67))	('CNOT1', 'Gene', (73, 78))	('S334D', 'Mutation', 'p.S334D', (7, 12))	('S334D', 'Var', (7, 12))
123279	28163695	Unexpectedly, this interaction was associated with an increased mRNA-destabilizing activity of TIS11b S334D as compared to the dephospho-form of TIS11b.	('TIS11b', 'Gene', (95, 101))	('S334D', 'Mutation', 'p.S334D', (102, 107))	('increased', 'PosReg', (54, 63))	('mRNA-destabilizing activity', 'MPA', (64, 91))	('S334D', 'Var', (102, 107))
123282	28163695	Nevertheless, apart from single-nucleotide polymorphisms associated with decreased translation efficiency, the mechanisms leading to TTP suppression in cancer remain obscure.	('single-nucleotide polymorphisms', 'Var', (25, 56))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('decreased', 'NegReg', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('translation efficiency', 'MPA', (83, 105))
123287	28163695	The relevance of these variations to human physiology and the pathology of adrenocortical cancer remains to be determined.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('adrenocortical cancer', 'Disease', (75, 96))	('human', 'Species', '9606', (37, 42))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (75, 96))	('variations', 'Var', (23, 33))
123292	28163695	This suggests that a slight alteration in the control mechanism may generate large-scale effects that could contribute to the development of complex disorders, including adrenal diseases.	('adrenal diseases', 'Disease', (170, 186))	('adrenal diseases', 'Disease', 'MESH:D000309', (170, 186))	('alteration', 'Var', (28, 38))	('effects', 'Reg', (89, 96))	('contribute', 'Reg', (108, 118))
123317	27471492	They can occur at any age but the incidence in children is particularly high in southern Brazil due to the high prevalence of a specific TP53 mutation.	('mutation', 'Var', (142, 150))	('children', 'Species', '9606', (47, 55))	('TP53', 'Gene', (137, 141))
123319	27471492	Over the last 5 years, genetic analyses of patients with sporadic or familial forms of ACTs has resulted in identification of alterations in a new set of genes, most of them being involved in cAMP/protein kinase A (PKA) and Wnt/beta-catenin signaling pathways (Figures 1 and 2).	('patients', 'Species', '9606', (43, 51))	('cAMP', 'Chemical', 'MESH:D000242', (192, 196))	('rat', 'Species', '10116', (130, 133))	('Wnt', 'Chemical', '-', (224, 227))	('involved', 'Reg', (180, 188))	('alterations', 'Var', (126, 137))
123328	27471492	The use of small animals for modeling tumors in a controlled experimental manner is a valuable strategy to explore the functional significance of mutations, to dissect mechanisms underlying both adrenocortical tumorigenesis and endocrine disorders, and to provide in vivo tools to screen for novel therapeutic approaches.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('rat', 'Species', '10116', (97, 100))	('mutations', 'Var', (146, 155))	('modeling tumors', 'Disease', (29, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('adrenocortical tumorigenesis and endocrine disorders', 'Disease', 'MESH:D018268', (195, 247))	('endocrine disorders', 'Phenotype', 'HP:0000818', (228, 247))	('modeling tumors', 'Disease', 'MESH:D004195', (29, 44))
123340	27471492	The mechanism by which cortisol production is stimulated in PBMAH, despite suppressed plasma ACTH, was previously unknown and was referred to as being "autonomous."	('cortisol', 'Chemical', 'MESH:D006854', (23, 31))	('suppressed', 'NegReg', (75, 85))	('stimulated', 'PosReg', (46, 56))	('PBMAH', 'Chemical', '-', (60, 65))	('suppressed plasma ACTH', 'Phenotype', 'HP:0002920', (75, 97))	('PBMAH', 'Var', (60, 65))	('cortisol production', 'MPA', (23, 42))	('plasma ACTH', 'MPA', (86, 97))
123346	27471492	Hypercortisolism associated with aberrant LH/hCG receptors was first identified in a woman with transient CS during sequential pregnancies and persistent CS after menopause.	('Hypercortisolism', 'Disease', (0, 16))	('LH/hCG', 'Gene', (42, 48))	('associated', 'Reg', (17, 27))	('persistent CS after menopause', 'Phenotype', 'HP:0008209', (143, 172))	('CS', 'Phenotype', 'HP:0003118', (154, 156))	('CS', 'Phenotype', 'HP:0003118', (106, 108))	('woman', 'Species', '9606', (85, 90))	('sequential pregnancies', 'Phenotype', 'HP:0001622', (116, 138))	('LH/hCG', 'Gene', '12640', (42, 48))	('Hypercortisolism', 'Disease', 'MESH:D003480', (0, 16))	('aberrant', 'Var', (33, 41))	('Hypercortisolism', 'Phenotype', 'HP:0003118', (0, 16))
123349	27471492	First, aberrant receptors are almost universally present in PBMAH and at early stages.	('PBMAH', 'Disease', (60, 65))	('aberrant', 'Var', (7, 15))	('present', 'Reg', (49, 56))	('PBMAH', 'Chemical', '-', (60, 65))
123354	27471492	The growth advantage provided by aberrant receptors expression at least relied on increased proliferation rates of transplants but the downstream mechanisms supporting proliferation were not explored.	('receptors', 'Protein', (42, 51))	('rat', 'Species', '10116', (106, 109))	('rat', 'Species', '10116', (99, 102))	('rat', 'Species', '10116', (175, 178))	('increased', 'PosReg', (82, 91))	('growth advantage', 'CPA', (4, 20))	('aberrant', 'Var', (33, 41))	('proliferation rates', 'CPA', (92, 111))
123358	27471492	This shows a direct role of aberrant LHR expression in the pathogenesis of PBMAH with LH-responsive CS, even though the molecular mechanisms leading to ectopic expression of GPCRs in adrenocortical cells are still unknown.	('LHR', 'Gene', '16867', (37, 40))	('LH', 'Chemical', 'MESH:D007986', (37, 39))	('PBMAH', 'Chemical', '-', (75, 80))	('PBMAH', 'Disease', (75, 80))	('adrenocortical', 'Disease', (183, 197))	('aberrant', 'Var', (28, 36))	('CS', 'Phenotype', 'HP:0003118', (100, 102))	('adrenocortical', 'Disease', 'MESH:D018268', (183, 197))	('LHR', 'Gene', (37, 40))	('LH', 'Chemical', 'MESH:D007986', (86, 88))
123364	27471492	Mutations in members of cAMP/PKA pathway are predicted to over-activate the pathway but they have been observed in a limited number of patients (Figure 1).	('cAMP/PKA', 'Gene', (24, 32))	('over-activate', 'PosReg', (58, 71))	('patients', 'Species', '9606', (135, 143))	('Mutations', 'Var', (0, 9))	('cAMP', 'Chemical', 'MESH:D000242', (24, 28))
123365	27471492	Germline inactivating mutations of the MEN1 gene cause a complex genetic syndrome named multiple endocrine neoplasia type 1 (MEN1) characterized by endocrine and non-endocrine tumors.	('non-endocrine tumors', 'Disease', (162, 182))	('non-endocrine tumors', 'Disease', 'MESH:C536126', (162, 182))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('multiple endocrine neoplasia type 1', 'Gene', (88, 123))	('multiple endocrine neoplasia type 1', 'Gene', '17283', (88, 123))	('Germline inactivating mutations', 'Var', (0, 31))	('genetic syndrome', 'Disease', 'MESH:D030342', (65, 81))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (97, 116))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('cause', 'Reg', (49, 54))	('MEN1', 'Gene', (39, 43))	('genetic syndrome', 'Disease', (65, 81))
123374	27471492	More recently, inactivating germline and somatic mutations in the armadillo repeat-containing 5 (ARMC5) gene have been identified in ~50% of patients with apparently sporadic PBMAH and also in a large family with genetically transmitted PBMAH.	('armadillo repeat-containing 5', 'Gene', (66, 95))	('inactivating', 'Var', (15, 27))	('PBMAH', 'Chemical', '-', (175, 180))	('PBMAH', 'Chemical', '-', (237, 242))	('PBMAH', 'Disease', (175, 180))	('armadillo repeat-containing 5', 'Gene', '79798', (66, 95))	('patients', 'Species', '9606', (141, 149))	('identified', 'Reg', (119, 129))	('ARMC5', 'Gene', (97, 102))
123378	27471492	Indeed, ARMC5 inactivation in cultured adrenocortical cells decreases the expression of MC2R and of various steroidogenic enzymes, both in basal conditions and after cAMP stimulation, suggesting that it may interfere with PKA pathway by impairing the stimulation of its target genes (Figure 1).	('decreases', 'NegReg', (60, 69))	('expression', 'MPA', (74, 84))	('interfere', 'NegReg', (207, 216))	('impairing', 'NegReg', (237, 246))	('cAMP', 'Chemical', 'MESH:D000242', (166, 170))	('ARMC5', 'Gene', (8, 13))	('PKA pathway', 'Pathway', (222, 233))	('inactivation', 'Var', (14, 26))	('steroid', 'Chemical', 'MESH:D013256', (108, 115))	('MC2R', 'Gene', (88, 92))	('adrenocortical', 'Disease', (39, 53))	('adrenocortical', 'Disease', 'MESH:D018268', (39, 53))	('MC2R', 'Gene', '17200', (88, 92))	('stimulation', 'MPA', (251, 262))	('steroidogenic enzymes', 'MPA', (108, 129))
123379	27471492	Increased cell survival upon ARMC5 inactivation is proposed to trigger hyperplasia while subclinical CS could be the result of the major increase in adrenal mass that would compensate for decreased per-cell steroidogenic activity.	('ARMC5', 'Gene', (29, 34))	('cell survival', 'CPA', (10, 23))	('increase in adrenal mass', 'Phenotype', 'HP:0008221', (137, 161))	('hyperplasia', 'Disease', (71, 82))	('inactivation', 'Var', (35, 47))	('increase', 'PosReg', (137, 145))	('Increased', 'PosReg', (0, 9))	('steroid', 'Chemical', 'MESH:D013256', (207, 214))	('adrenal mass', 'MPA', (149, 161))	('hyperplasia', 'Disease', 'MESH:D006965', (71, 82))	('CS', 'Phenotype', 'HP:0003118', (101, 103))
123380	27471492	This observation supports the hypothesis of a link between ARMC5 and PKA signaling, as the abnormal expression of GPCRs leads to activation of PKA signaling, normally triggered by the ACTH receptor (MC2R) (Figure 1).	('ACTH receptor', 'Gene', (184, 197))	('MC2R', 'Gene', (199, 203))	('PKA signaling', 'MPA', (143, 156))	('MC2R', 'Gene', '17200', (199, 203))	('activation', 'PosReg', (129, 139))	('abnormal', 'Var', (91, 99))	('GPCRs', 'Gene', (114, 119))	('abnormal expression of GPCRs', 'Phenotype', 'HP:0031821', (91, 119))	('ACTH receptor', 'Gene', '17200', (184, 197))
123382	27471492	Notably, the combination of adrenal targeted GPCRs overexpression and Armc5 knockout could provide information on a possible cooperation between ARMC5 and PKA signaling.	('Armc5', 'Gene', (70, 75))	('rat', 'Species', '10116', (130, 133))	('Armc5', 'Gene', '233912', (70, 75))	('knockout', 'Var', (76, 84))	('cooperation', 'Interaction', (125, 136))
123385	27471492	More than 60% of CNC patients harbor mutations in the PRKARIA gene, encoding the regulatory subunit 1alpha (R1alpha) of PKA (Figure 1).	('patients', 'Species', '9606', (21, 29))	('mutations', 'Var', (37, 46))	('PRKARIA', 'Gene', (54, 61))	('CNC', 'Disease', (17, 20))
123386	27471492	Specifically, inactivating heterozygous germline mutations are observed in about two-thirds of Carney Complex patients and loss of heterozygosity (LOH) has been reported, indicating that PRKARIA acts as a tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('Carney Complex', 'Disease', (95, 109))	('patients', 'Species', '9606', (110, 118))	('inactivating heterozygous germline mutations', 'Var', (14, 58))
123392	27471492	Interestingly, adrenocortical manifestations in the antisense RNA model included maintenance of the X-zone, a normally transient zone of fetal origin.	('antisense RNA', 'Var', (52, 65))	('adrenocortical manifestations', 'Phenotype', 'HP:0008207', (15, 44))	('adrenocortical', 'Disease', (15, 29))	('adrenocortical', 'Disease', 'MESH:D018268', (15, 29))
123406	27471492	Recently, Beuschlein and collaborators identified a hotpsot mutation (L205R) in the PRKACA gene, encoding the catalytic subunit alpha (Calpha) of PKA, in more than one-third of patients with CPA.	('L205R', 'Mutation', 'rs121912664', (70, 75))	('rat', 'Species', '10116', (32, 35))	('patients', 'Species', '9606', (177, 185))	('CPA', 'Chemical', '-', (191, 194))	('PA', 'Phenotype', 'HP:0011736', (192, 194))	('PRKACA', 'Gene', (84, 90))	('L205R', 'Var', (70, 75))
123407	27471492	The PRKACA L205R mutation results in constitutive PKA activation, which is a very likely cause of ACT formation (Figure 1).	('results in', 'Reg', (26, 36))	('PRKACA', 'Gene', (4, 10))	('activation', 'PosReg', (54, 64))	('L205R', 'Var', (11, 16))	('L205R', 'Mutation', 'rs121912664', (11, 16))
123409	27471492	Hence, PRKACA mutations, together with the previously identified GNAS and PRKAR1A inactivating mutations, strongly support a crucial role of cAMP/PKA pathway in the tumorigenesis of CPAs.	('PA', 'Phenotype', 'HP:0011736', (183, 185))	('PRKAR1A', 'Gene', (74, 81))	('PRKACA', 'Gene', (7, 13))	('CPAs', 'Disease', (182, 186))	('GNAS', 'Gene', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('CPA', 'Chemical', '-', (182, 185))	('cAMP', 'Chemical', 'MESH:D000242', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('PRKAR1A', 'Gene', '19084', (74, 81))	('GNAS', 'Gene', '14683', (65, 69))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (165, 170))
123410	27471492	The development of knock-in mouse models bearing PRKACA activating L205R mutation is required to evaluate its driver potential and to provide new insights into the mechanisms underlying PKA-dependent tumorigenesis in the context of cortisol-producing ACAs.	('ACAs', 'Phenotype', 'HP:0008256', (251, 255))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('mouse', 'Species', '10090', (28, 33))	('L205R', 'Var', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cortisol', 'Chemical', 'MESH:D006854', (232, 240))	('tumor', 'Disease', (200, 205))	('L205R', 'Mutation', 'rs121912664', (67, 72))
123412	27471492	Such complementary mouse models would help understanding if gain-of-function mutations and gain of copy number alterations result in distinct adrenal lesions.	('gain-of-function', 'PosReg', (60, 76))	('rat', 'Species', '10116', (115, 118))	('mutations', 'Var', (77, 86))	('copy number alterations', 'Var', (99, 122))	('mouse', 'Species', '10090', (19, 24))	('adrenal lesions', 'Disease', (142, 157))	('gain', 'PosReg', (91, 95))
123414	27471492	Interestingly, the recently identified PRKACA mutations were shown to be mutually exclusive with CTNNB1 mutations.	('mutations', 'Var', (104, 113))	('mutations', 'Var', (46, 55))	('CTNNB1', 'Gene', '12387', (97, 103))	('PRKACA', 'Gene', (39, 45))	('CTNNB1', 'Gene', (97, 103))
123418	27471492	Specifically, mutated genes encoding ion channels include KCNJ5, which encodes the G-protein activated potassium channel GIRK4, and is mutated in about 26-40% of APAs and CACNA1D and CACNA1H genes encoding for voltage-dependent calcium channels.	('KCNJ5', 'Gene', (58, 63))	('GIRK4', 'Gene', (121, 126))	('calcium', 'Chemical', 'MESH:D002118', (228, 235))	('PA', 'Phenotype', 'HP:0011736', (163, 165))	('CACNA1D', 'Gene', '12289', (171, 178))	('GIRK4', 'Gene', '16521', (121, 126))	('mutated', 'Var', (135, 142))	('CACNA1H', 'Gene', (183, 190))	('APAs', 'Gene', (162, 166))	('CACNA1D', 'Gene', (171, 178))	('CACNA1H', 'Gene', '58226', (183, 190))
123420	27471492	All these mutations ultimately lead to increased intracellular calcium and abnormal activation of calcium-calmodulin-dependent kinase (Ca2+-CAMK) signaling, which plays a central role in aldosterone production.	('intracellular calcium', 'MPA', (49, 70))	('activation', 'PosReg', (84, 94))	('aldosterone production', 'Phenotype', 'HP:0000859', (187, 209))	('calcium', 'Chemical', 'MESH:D002118', (98, 105))	('increased intracellular calcium', 'Phenotype', 'HP:0003575', (39, 70))	('increased', 'PosReg', (39, 48))	('lead', 'Reg', (31, 35))	('mutations', 'Var', (10, 19))	('calcium', 'Chemical', 'MESH:D002118', (63, 70))	('aldosterone', 'Chemical', 'MESH:D000450', (187, 198))
123424	27471492	Among the newly identified genes, KCNJ5 mutations represent the most frequent genetic defects in APAs, with higher prevalence in the Japanese population.	('KCNJ5', 'Gene', (34, 39))	('genetic defects', 'Disease', (78, 93))	('genetic defects', 'Disease', 'MESH:D030342', (78, 93))	('mutations', 'Var', (40, 49))	('PA', 'Phenotype', 'HP:0011736', (98, 100))	('frequent', 'Reg', (69, 77))
123426	27471492	Therefore, the demonstration that loss of KCNJ5 is sufficient to initiate both hyperaldosteronism and tumor development will require genetic approaches in non-mouse systems, such as primary bovine adrenocortical cells and tissue reconstruction in xenografted mice.	('KCNJ5', 'Gene', (42, 47))	('loss', 'Var', (34, 38))	('initiate', 'Reg', (65, 73))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (79, 97))	('rat', 'Species', '10116', (22, 25))	('mouse', 'Species', '10090', (159, 164))	('adrenocortical', 'Disease', (197, 211))	('mice', 'Species', '10090', (259, 263))	('hyperaldosteronism and tumor', 'Disease', 'MESH:D003480', (79, 107))	('bovine', 'Species', '9913', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('adrenocortical', 'Disease', 'MESH:D018268', (197, 211))
123431	27471492	Furthermore, a recent study has reported CTNNB1 mutations in 5.1% of a cohort of 198 APAs.	('CTNNB1', 'Gene', '12387', (41, 47))	('PA', 'Phenotype', 'HP:0011736', (86, 88))	('CTNNB1', 'Gene', (41, 47))	('mutations', 'Var', (48, 57))
123432	27471492	Because of the higher frequency of WNT/beta-catenin activation than of CTNNB1 mutations, it is essential to expand our knowledge of the other causes of aberrant WNT/beta-catenin activation, by investigating other members of the pathway or possible crosstalks with other pathways.	('WNT/beta-catenin', 'MPA', (35, 51))	('CTNNB1', 'Gene', '12387', (71, 77))	('CTNNB1', 'Gene', (71, 77))	('mutations', 'Var', (78, 87))
123436	27471492	ACCs can occur at any age, but the incidence in children is particularly high in southern Brazil due to the high prevalence of a specific germline mutation (p.R337H) of the TP53 tumor suppressor gene.	('children', 'Species', '9606', (48, 56))	('tumor', 'Disease', (178, 183))	('p.R337H', 'Var', (157, 164))	('ACCs', 'Phenotype', 'HP:0006744', (0, 4))	('p.R337H', 'Mutation', 'rs121912664', (157, 164))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
123438	27471492	Although most ACCs arise sporadically, an increased incidence of ACCs has been reported in some genetic syndromes, such as familial adenomatous polyposis (FAP), characterized by mutations in APC and elevated Wnt/beta-catenin signaling, and Beckwith-Wiedemann syndrome (BWS), characterized by elevated expression of insulin-like growth factor-2 (IGF2).	('APC', 'Disease', (191, 194))	('Wnt', 'Chemical', '-', (208, 211))	('familial adenomatous polyposis', 'Disease', (123, 153))	('insulin-like growth factor-2', 'Gene', (315, 343))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (123, 153))	('mutations', 'Var', (178, 187))	('elevated expression of insulin-like growth factor', 'Phenotype', 'HP:0030269', (292, 341))	('Beckwith-Wiedemann syndrome', 'Disease', (240, 267))	('genetic syndrome', 'Disease', 'MESH:D030342', (96, 112))	('ACCs', 'Phenotype', 'HP:0006744', (14, 18))	('Wnt/beta-catenin signaling', 'MPA', (208, 234))	('BWS', 'Disease', 'MESH:D001506', (269, 272))	('BWS', 'Disease', (269, 272))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (240, 267))	('FAP', 'Disease', (155, 158))	('insulin-like growth factor-2', 'Gene', '16002', (315, 343))	('FAP', 'Disease', 'MESH:C567782', (155, 158))	('elevated', 'PosReg', (199, 207))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (132, 153))	('ACCs', 'Phenotype', 'HP:0006744', (65, 69))	('genetic syndrome', 'Disease', (96, 112))	('APC', 'Disease', 'MESH:D011125', (191, 194))
123442	27471492	Several mouse models of deregulation of these pathways have been generated, which allowed better understanding of adrenal tumorigenesis.	('adrenal tumor', 'Phenotype', 'HP:0100631', (114, 127))	('deregulation', 'Var', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('adrenal tumor', 'Disease', 'MESH:D000310', (114, 127))	('mouse', 'Species', '10090', (8, 13))	('adrenal tumor', 'Disease', (114, 127))	('rat', 'Species', '10116', (69, 72))
123444	27471492	Several tumor profiling studies have reported mutations in beta-catenin gene (CTNNB1) in both ACAs and ACCs, suggesting that beta-catenin activating mutations could be involved in adrenal tumor initiation and progression to malignancy.	('tumor', 'Disease', (188, 193))	('mutations', 'Var', (46, 55))	('malignancy', 'Disease', 'MESH:D009369', (224, 234))	('CTNNB1', 'Gene', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('ACAs', 'Phenotype', 'HP:0008256', (94, 98))	('ACCs', 'Phenotype', 'HP:0006744', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('involved', 'Reg', (168, 176))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('malignancy', 'Disease', (224, 234))	('adrenal tumor initiation', 'Disease', (180, 204))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('adrenal tumor initiation', 'Disease', 'MESH:D000310', (180, 204))	('CTNNB1', 'Gene', '12387', (78, 84))	('adrenal tumor', 'Phenotype', 'HP:0100631', (180, 193))
123447	27471492	Cre-mediated excision of the third exon of Ctnnb1 gene prevents beta-catenin phosphorylation and ubiquitin-dependent degradation, which induces accumulation of the protein and constitutive activation of its target genes.	('Ctnnb1', 'Gene', '12387', (43, 49))	('protein', 'Protein', (164, 171))	('ubiquitin-dependent degradation', 'MPA', (97, 128))	('excision', 'Var', (13, 21))	('accumulation', 'PosReg', (144, 156))	('prevents', 'NegReg', (55, 63))	('Ctnnb1', 'Gene', (43, 49))	('activation', 'PosReg', (189, 199))	('beta-catenin phosphorylation', 'MPA', (64, 92))	('induces', 'Reg', (136, 143))
123468	27471492	Taken together, these results have clearly shown that genetic alterations in WNT pathway and IGF2 overexpression are not sufficient to trigger malignant adrenocortical tumorigenesis.	('adrenocortical tumor', 'Disease', 'MESH:D018268', (153, 173))	('trigger', 'Reg', (135, 142))	('overexpression', 'PosReg', (98, 112))	('IGF2', 'Gene', (93, 97))	('adrenocortical tumor', 'Disease', (153, 173))	('genetic alterations', 'Var', (54, 73))	('rat', 'Species', '10116', (66, 69))	('WNT pathway', 'Pathway', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
123478	27471492	In addition to overexpression of IGF2 and activation of WNT pathway, the third most frequent genetic alteration in ACCs is inactivation of TP53/RB pathway.	('inactivation', 'Var', (123, 135))	('TP53/RB pathway', 'Pathway', (139, 154))	('rat', 'Species', '10116', (105, 108))	('ACCs', 'Phenotype', 'HP:0006744', (115, 119))	('WNT pathway', 'Pathway', (56, 67))
123479	27471492	Germline mutations in the p53 tumor suppressor gene are associated with the development of Li-Fraumeni syndrome (LFS), an autosomal-dominant cancer syndrome resulting in multiple malignancies, including ACCs.	('Germline mutations', 'Var', (0, 18))	('LFS', 'Disease', (113, 116))	('ACCs', 'Phenotype', 'HP:0006744', (203, 207))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('LFS', 'Disease', 'MESH:D016864', (113, 116))	('malignancies', 'Disease', (179, 191))	('p53', 'Gene', (26, 29))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (91, 111))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('associated with', 'Reg', (56, 71))	('Li-Fraumeni syndrome', 'Disease', (91, 111))	('p53', 'Gene', '22059', (26, 29))	('autosomal-dominant cancer syndrome', 'Disease', 'MESH:D009386', (122, 156))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('autosomal-dominant cancer syndrome', 'Disease', (122, 156))
123480	27471492	The rate of germline TP53 mutations in ACCs is age-dependent, ranging from up to 80% in pediatric ACCs to 3-7% in adults.	('TP53', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('ACCs', 'Phenotype', 'HP:0006744', (39, 43))	('rat', 'Species', '10116', (4, 7))	('ACCs', 'Phenotype', 'HP:0006744', (98, 102))
123481	27471492	A 10-fold increased incidence of ACCs is observed in Southern Brazil due to a germline mutation within the oligomerization domain of p53 (p.R337H).	('ACCs', 'Disease', (33, 37))	('p.R337H', 'Var', (138, 145))	('p.R337H', 'Mutation', 'rs121912664', (138, 145))	('ACCs', 'Phenotype', 'HP:0006744', (33, 37))	('p53', 'Gene', (133, 136))	('p53', 'Gene', '22059', (133, 136))
123484	27471492	In adult ACTs, TP53 mutations are mostly somatic and were considered to represent a later step in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('TP53', 'Gene', (15, 19))	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (20, 29))
123485	27471492	Several mouse models of p53 dysfunction have been generated, including targeted mutations, replicating proteins identified in humans with LFS.	('LFS', 'Disease', 'MESH:D016864', (138, 141))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '22059', (24, 27))	('mutations', 'Var', (80, 89))	('rat', 'Species', '10116', (54, 57))	('humans', 'Species', '9606', (126, 132))	('LFS', 'Disease', (138, 141))	('mouse', 'Species', '10090', (8, 13))
123487	27471492	Mouse models of adrenal-specific TP53 loss have not been generated to date, despite the high prevalence of TP53 mutations in ACCs.	('ACCs', 'Phenotype', 'HP:0006744', (125, 129))	('TP53', 'Gene', (107, 111))	('rat', 'Species', '10116', (61, 64))	('mutations', 'Var', (112, 121))	('Mouse', 'Species', '10090', (0, 5))
123489	27471492	Interestingly, ablation of p53 (obtained by mating Acd mice with p53 null mice) rescued a number of characteristics of the Acd phenotype, including adrenal hypoplasia.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '22059', (65, 68))	('ablation', 'Var', (15, 23))	('mice', 'Species', '10090', (55, 59))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (148, 166))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (148, 166))	('mice', 'Species', '10090', (74, 78))	('adrenal hypoplasia', 'Disease', (148, 166))	('p53', 'Gene', '22059', (27, 30))	('p53', 'Gene', (27, 30))
123491	27471492	Moreover, the loss of p53 in Acd mice leads to development of ACC, suggesting that p53-mediated escape from senescence may contribute to adrenocortical carcinogenesis.	('loss', 'Var', (14, 18))	('adrenocortical carcinogenesis', 'Disease', 'MESH:D063646', (137, 166))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '22059', (83, 86))	('adrenocortical carcinogenesis', 'Disease', (137, 166))	('development', 'CPA', (47, 58))	('p53', 'Gene', (22, 25))	('contribute', 'Reg', (123, 133))	('p53', 'Gene', '22059', (22, 25))	('mice', 'Species', '10090', (33, 37))	('ACC', 'Disease', (62, 65))
123510	27471492	Indeed, inactivation of SF1 target gene Vnn1, encoding the Vanin-1 protein involved in the response to oxidative stress, was found to antagonize the development of adrenocortical neoplasia in SF-1 transgenic mice.	('neoplasia', 'Phenotype', 'HP:0002664', (179, 188))	('SF-1', 'Gene', '22668', (192, 196))	('SF1', 'Gene', (24, 27))	('Vnn1', 'Gene', '22361', (40, 44))	('Vnn1', 'Gene', (40, 44))	('Vanin-1', 'Gene', '22361', (59, 66))	('transgenic mice', 'Species', '10090', (197, 212))	('SF1', 'Gene', '22668', (24, 27))	('antagonize', 'NegReg', (134, 144))	('adrenocortical neoplasia', 'Disease', 'MESH:D018268', (164, 188))	('inactivation', 'Var', (8, 20))	('SF-1', 'Gene', (192, 196))	('oxidative stress', 'Phenotype', 'HP:0025464', (103, 119))	('Vanin-1', 'Gene', (59, 66))	('adrenocortical neoplasia', 'Disease', (164, 188))
123515	27471492	ACCs with alterations in ZNRF3 locus showed activation of beta-catenin target genes, but this activation was weaker than in tumors with CTNNB1 mutations.	('ACCs', 'Phenotype', 'HP:0006744', (0, 4))	('alterations', 'Var', (10, 21))	('ZNRF3', 'Gene', '407821', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CTNNB1', 'Gene', (136, 142))	('activation', 'PosReg', (44, 54))	('beta-catenin target genes', 'MPA', (58, 83))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('ZNRF3', 'Gene', (25, 30))	('CTNNB1', 'Gene', '12387', (136, 142))	('rat', 'Species', '10116', (14, 17))
123518	27471492	Recurrent mutations have also been found in several known cell cycle regulators, including CDKN2A, CDK4, RB1, and CCNE1, confirming the notion that release from p53-sensitive checkpoints is a critical step in the process of adrenal tumorigenesis, a notion that previously emerged from analysis of p53 ablation in Acd mice.	('RB1', 'Gene', '19645', (105, 108))	('CDKN2A', 'Gene', '12578', (91, 97))	('adrenal tumor', 'Disease', 'MESH:D000310', (224, 237))	('CDKN2A', 'Gene', (91, 97))	('adrenal tumor', 'Disease', (224, 237))	('p53', 'Gene', (297, 300))	('p53', 'Gene', '22059', (297, 300))	('mice', 'Species', '10090', (317, 321))	('adrenal tumor', 'Phenotype', 'HP:0100631', (224, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('RB1', 'Gene', (105, 108))	('CDK4', 'Gene', (99, 103))	('mutations', 'Var', (10, 19))	('CDK4', 'Gene', '12567', (99, 103))	('CCNE1', 'Gene', '12447', (114, 119))	('p53', 'Gene', (161, 164))	('CCNE1', 'Gene', (114, 119))	('p53', 'Gene', '22059', (161, 164))
123519	27471492	Recently, mutations have also been found in PRKAR1A, a gene mutated in PPNAD (as discussed in Section "Primary Pigmented Nodular Adrenocortical Disease and Related Mouse Models") and much more rarely in ACAs (as discussed in Section "Cortisol-Producing Adenomas: PKA Pathway, PRKACA Mutations, and Lack of Mouse Models").	('Cortisol', 'Chemical', 'MESH:D006854', (234, 242))	('Mouse', 'Species', '10090', (164, 169))	('ACAs', 'Phenotype', 'HP:0008256', (203, 207))	('PRKAR1A', 'Gene', (44, 51))	('Mouse', 'Species', '10090', (306, 311))	('Adenomas', 'Disease', 'MESH:D000236', (253, 261))	('Pigmented Nodular Adrenocortical Disease', 'Phenotype', 'HP:0001580', (111, 151))	('Primary Pigmented Nodular Adrenocortical Disease', 'Disease', (103, 151))	('PRKAR1A', 'Gene', '19084', (44, 51))	('Adenomas', 'Disease', (253, 261))	('mutations', 'Var', (10, 19))	('Primary Pigmented Nodular Adrenocortical Disease', 'Disease', 'MESH:C566469', (103, 151))
123520	27471492	These recent reports of PRKAR1A mutations expand the role of PKA signaling in ACC.	('ACC', 'Disease', (78, 81))	('PRKAR1A', 'Gene', (24, 31))	('mutations', 'Var', (32, 41))	('PRKAR1A', 'Gene', '19084', (24, 31))
123535	27471492	Considering pediatric adrenal cancers, knock-in mouse models reproducing TP53 p.R337H mutation found in Brazilian families will be a major advance in our understanding of the pathogenesis of these destructive tumors.	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('mouse', 'Species', '10090', (48, 53))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('p.R337H', 'Mutation', 'rs121912664', (78, 85))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('pediatric adrenal cancers', 'Disease', (12, 37))	('TP53', 'Gene', (73, 77))	('pediatric adrenal cancers', 'Disease', 'MESH:D000310', (12, 37))	('p.R337H', 'Var', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
123538	27471492	Among the newly identified genes, ARMC5, KCNJ5, and PRKACA mutations represent the most frequent genetic defects in PBMAH, APAs, and CPAs, respectively.	('PA', 'Phenotype', 'HP:0011736', (124, 126))	('KCNJ5', 'Gene', (41, 46))	('frequent', 'Reg', (88, 96))	('CPAs', 'Disease', (133, 137))	('PRKACA', 'Gene', (52, 58))	('PBMAH', 'Chemical', '-', (116, 121))	('PA', 'Phenotype', 'HP:0011736', (134, 136))	('PBMAH', 'Disease', (116, 121))	('ARMC5', 'Gene', (34, 39))	('CPA', 'Chemical', '-', (133, 136))	('mutations', 'Var', (59, 68))	('genetic defects', 'Disease', (97, 112))	('APAs', 'Disease', (123, 127))	('genetic defects', 'Disease', 'MESH:D030342', (97, 112))
123553	26446994	Germline mutations in TP53 occur in pediatric and adult patients with ACC, in addition to somatic TP53 inactivating mutations.	('Germline mutations', 'Var', (0, 18))	('patients', 'Species', '9606', (56, 64))	('ACC', 'Phenotype', 'HP:0006744', (70, 73))	('ACC', 'Disease', (70, 73))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', '7157', (98, 102))	('TP53', 'Gene', (22, 26))	('TP53', 'Gene', (98, 102))
123557	26446994	This is especially important, given that combined genetic alterations in IGF and WNT signaling in mouse models lead to tumorigenesis but are mutually exclusive in human ACC, thus mouse models do not completely recapitulate a multistep process in ACC occurrence.	('mouse', 'Species', '10090', (179, 184))	('tumor', 'Disease', (119, 124))	('IGF', 'Protein', (73, 76))	('ACC', 'Phenotype', 'HP:0006744', (169, 172))	('ACC', 'Phenotype', 'HP:0006744', (246, 249))	('genetic alterations', 'Var', (50, 69))	('human', 'Species', '9606', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mouse', 'Species', '10090', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('lead to', 'Reg', (111, 118))
123558	26446994	Three major mechanisms of gene expression regulation in cancer are copy number changes, differential microRNA expression and gene CpG methylation status.	('microRNA expression', 'MPA', (101, 120))	('copy number changes', 'Var', (67, 86))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
123559	26446994	Alterations in any of these mechanisms can lead to dysregulated gene expression and pathways that lead to cancer initiation and progression.	('Alterations', 'Var', (0, 11))	('lead to', 'Reg', (98, 105))	('cancer initiation', 'Disease', 'MESH:D009369', (106, 123))	('lead to', 'Reg', (43, 50))	('dysregulated gene expression', 'MPA', (51, 79))	('cancer initiation', 'Disease', (106, 123))	('pathways', 'Pathway', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
123560	26446994	While the primary genetic events, such as inactivating mutations in TP53 and increased signaling in the IGF and WNT pathways, have been characterized in ACC and an integrated genome atlas of ACC has been developed, a comprehensive and integrated analysis of the modes of gene expression regulation of dysregulated genes in normal, adrenocortical adenoma and ACC has not been performed.	('TP53', 'Gene', (68, 72))	('inactivating mutations', 'Var', (42, 64))	('ACC', 'Phenotype', 'HP:0006744', (191, 194))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (331, 353))	('ACC', 'Phenotype', 'HP:0006744', (153, 156))	('adrenocortical adenoma', 'Disease', (331, 353))	('increased', 'PosReg', (77, 86))	('TP53', 'Gene', '7157', (68, 72))	('WNT pathways', 'Pathway', (112, 124))	('IGF', 'Pathway', (104, 107))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (331, 353))	('ACC', 'Phenotype', 'HP:0006744', (358, 361))
123561	26446994	Such an investigation can shed light on the hypothesis that ACC is a multistep cancer and that gene expression changes are cumulative and can be driven by copy number changes, differential miRNA expression and gene CpG methylation, alone or in combination.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ACC', 'Phenotype', 'HP:0006744', (60, 63))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('miR', 'Gene', '220972', (189, 192))	('ACC', 'Disease', (60, 63))	('miR', 'Gene', (189, 192))	('cancer', 'Disease', (79, 85))	('copy number changes', 'Var', (155, 174))	('changes', 'Reg', (111, 118))
98615	26446994	Human adrenocortical tissue samples were collected according to an institutional review board-approved clinical protocol after written informed consent was obtained (NCT01005654 and NCT01348698).	('Human', 'Species', '9606', (0, 5))	('adrenocortical', 'Disease', (6, 20))	('NCT01005654', 'Var', (166, 177))	('NCT01348698', 'Var', (182, 193))	('adrenocortical', 'Disease', 'MESH:D018268', (6, 20))
123588	26446994	Our pairwise genome-wide comparisons between normal, adrenocortical adenoma and ACC suggest that ACC is associated with cumulative methylation changes and copy number alterations.	('ACC', 'Phenotype', 'HP:0006744', (97, 100))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (53, 75))	('ACC', 'Phenotype', 'HP:0006744', (80, 83))	('ACC', 'Disease', (97, 100))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (53, 75))	('copy number alterations', 'Var', (155, 178))	('associated', 'Reg', (104, 114))	('methylation', 'MPA', (131, 142))	('adrenocortical adenoma', 'Disease', (53, 75))
123596	26446994	In addition, the gene methylation differences were higher in the normal adrenal cortex versus ACC comparison and the adrenocortical adenoma versus ACC comparison (Figure 2A and B), suggesting cumulative epigenetic alterations in ACC.	('ACC', 'Phenotype', 'HP:0006744', (94, 97))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (117, 139))	('ACC', 'Phenotype', 'HP:0006744', (229, 232))	('adrenocortical adenoma', 'Disease', (117, 139))	('ACC', 'Phenotype', 'HP:0006744', (147, 150))	('epigenetic alterations', 'Var', (203, 225))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (117, 139))	('gene methylation differences', 'MPA', (17, 45))	('higher', 'PosReg', (51, 57))
123600	26446994	This finding confirms that the aberrant DNA methylation observed in this analysis likely has a functional impact on gene expression status in ~6.4% (52/808 genes) and 8.4% (92/1085 genes), respectively, of the dysregulated genes in the ACC versus adrenocortical adenoma and the ACC versus normal adrenal cortex comparisons (Table 1).	('ACC', 'Phenotype', 'HP:0006744', (278, 281))	('dysregulated', 'Gene', (210, 222))	('ACC', 'Phenotype', 'HP:0006744', (236, 239))	('ACC versus adrenocortical adenoma', 'Disease', (236, 269))	('aberrant', 'Var', (31, 39))	('impact', 'Reg', (106, 112))	('gene expression status', 'MPA', (116, 138))	('ACC versus adrenocortical adenoma', 'Disease', 'MESH:D018246', (236, 269))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (247, 269))
123601	26446994	Variations in gene copy number were more frequent in the ACC versus normal adrenal cortex, as compared with the ACC versus adrenocortical adenoma cases and were directly associated with the gene expression level differences (Figure 3A and B).	('ACC versus adrenocortical adenoma', 'Disease', (112, 145))	('gene expression level differences', 'MPA', (190, 223))	('ACC versus adrenocortical adenoma', 'Disease', 'MESH:D018246', (112, 145))	('ACC', 'Phenotype', 'HP:0006744', (112, 115))	('ACC', 'Phenotype', 'HP:0006744', (57, 60))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (123, 145))	('Variations', 'Var', (0, 10))	('frequent', 'Reg', (41, 49))	('associated', 'Reg', (170, 180))
123602	26446994	For instance, CDKN1C, which is a cyclin-dependent kinase 1 inhibitor, had frequent copy number loss and downregulation in ACC in both the reference (r = 0.47, Figure 3C) and validation (r = 0.68, Supplementary Figure S3A) cohorts.	('ACC', 'Gene', (122, 125))	('CDKN1C', 'Gene', (14, 20))	('CDKN1C', 'Gene', '1028', (14, 20))	('cyclin-dependent kinase 1', 'Gene', '983', (33, 58))	('ACC', 'Phenotype', 'HP:0006744', (122, 125))	('cyclin-dependent kinase 1', 'Gene', (33, 58))	('copy number', 'Var', (83, 94))	('loss', 'NegReg', (95, 99))	('downregulation', 'NegReg', (104, 118))
123603	26446994	Similarly, CCAAT/enhancer binding protein delta (C/EBPdelta), a tumor suppressor gene that was identified in lymphoid leukemia was also downregulated in ACC and had copy number loss (Figure 3D and Supplementary Figure S3B).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('downregulated', 'NegReg', (136, 149))	('C/EBPdelta', 'Gene', (49, 59))	('CCAAT/enhancer binding protein delta', 'Gene', (11, 47))	('CCAAT/enhancer binding protein delta', 'Gene', '1052', (11, 47))	('ACC', 'Phenotype', 'HP:0006744', (153, 156))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('lymphoid leukemia', 'Disease', (109, 126))	('copy number loss', 'Var', (165, 181))	('lymphoid leukemia', 'Disease', 'MESH:D007945', (109, 126))	('lymphoid leukemia', 'Phenotype', 'HP:0005526', (109, 126))	('C/EBPdelta', 'Gene', '1052', (49, 59))
123605	26446994	Possible gene expression regulation through copy number alterations accounted for 5.9% (48/808 genes) and 9.3% (101/1085), respectively, of dysregulated genes in the ACC versus adrenocortical adenoma and ACC versus normal adrenal cortex comparisons (Table 1).	('ACC', 'Phenotype', 'HP:0006744', (166, 169))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (177, 199))	('ACC versus adrenocortical adenoma', 'Disease', 'MESH:D018246', (166, 199))	('ACC', 'Phenotype', 'HP:0006744', (204, 207))	('ACC versus adrenocortical adenoma', 'Disease', (166, 199))	('copy number alterations', 'Var', (44, 67))
123619	26446994	In particular, we found that genes that are involved in oncostatin M signaling, such as IL6ST (GP130), JAK1 and EPAS1, were downregulated and hypermethylation and/or targeted at the 3'UTR region by specifically upregulated miRNAs (Figure 5C).	('IL6ST', 'Gene', '3572', (88, 93))	('upregulated', 'PosReg', (211, 222))	('GP130', 'Gene', (95, 100))	('EPAS1', 'Gene', (112, 117))	('oncostatin M', 'Gene', '5008', (56, 68))	('hypermethylation', 'Var', (142, 158))	('EPAS1', 'Gene', '2034', (112, 117))	('oncostatin M', 'Gene', (56, 68))	('downregulated', 'NegReg', (124, 137))	('miR', 'Gene', '220972', (223, 226))	('miR', 'Gene', (223, 226))	('IL6ST', 'Gene', (88, 93))	('JAK1', 'Gene', (103, 107))	('JAK1', 'Gene', '3716', (103, 107))	('GP130', 'Gene', '3572', (95, 100))
123626	26446994	In this study we show that an increasing number of differentially expressed genes, differentially methylated genes, copy number variations and differentially expressed miRNAs are found in normal adrenal cortex versus adrenocortical adenoma versus ACC.	('adrenal cortex versus adrenocortical adenoma', 'Disease', (195, 239))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', (168, 171))	('copy number variations', 'Var', (116, 138))	('adrenal cortex versus adrenocortical adenoma', 'Disease', 'MESH:D000303', (195, 239))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (217, 239))	('ACC', 'Phenotype', 'HP:0006744', (247, 250))
123631	26446994	There is growing evidence that hypermethylation of CpG islands located in tumor suppressor genes is one of the most common mechanisms for gene silencing in cancer initiation and progression.	('hypermethylation', 'Var', (31, 47))	('cancer initiation', 'Disease', (156, 173))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (74, 79))	('gene silencing', 'NegReg', (138, 152))	('cancer initiation', 'Disease', 'MESH:D009369', (156, 173))
123633	26446994	One study, in a Cyp1b1-deficient mouse model, showed that CYP1B1, a member of the cytochrome P450 family, exerts an opposing effect on intestinal tumorigenesis.	('Cyp1b1', 'Gene', '13078', (16, 22))	('CYP1B1', 'Var', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('Cyp1b1', 'Gene', (16, 22))	('mouse', 'Species', '10090', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
123636	26446994	A well-known cell cycle inhibitory regulator, CDKN1C and tumor suppressor transcription factor such as C/EBPdelta that play critical role in several other cancers were found to be dysregulated in ACC.	('C/EBPdelta', 'Gene', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('C/EBPdelta', 'Gene', '1052', (103, 113))	('CDKN1C', 'Gene', (46, 52))	('dysregulated', 'Var', (180, 192))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('CDKN1C', 'Gene', '1028', (46, 52))	('ACC', 'Phenotype', 'HP:0006744', (196, 199))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('tumor', 'Disease', (57, 62))	('cancers', 'Disease', (155, 162))
123637	26446994	Our integrated analysis sheds light on novel candidate tumor suppressor genes that are implicated in other cancer, such as CD81, TSSC4, TSSC6 and PHLDA2 which are lost in ACC due to copy number variations.	('PHLDA2', 'Gene', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('PHLDA2', 'Gene', '7262', (146, 152))	('TSSC4', 'Gene', '10078', (129, 134))	('ACC', 'Phenotype', 'HP:0006744', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('TSSC6', 'Gene', (136, 141))	('tumor', 'Disease', (55, 60))	('CD81', 'Gene', (123, 127))	('CD81', 'Gene', '975', (123, 127))	('TSSC4', 'Gene', (129, 134))	('copy number variations', 'Var', (182, 204))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('TSSC6', 'Gene', '10077', (136, 141))	('cancer', 'Disease', (107, 113))
123638	26446994	Since the tumor suppressor gene TP53 has been shown to be a candidate driver gene for malignancy, we performed target DNA sequencing for damaging mutations within the open reading frame of TP53 in adrenocortical adenoma and ACC tumors.	('malignancy', 'Disease', 'MESH:D009369', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('TP53', 'Gene', (189, 193))	('TP53', 'Gene', '7157', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('ACC', 'Phenotype', 'HP:0006744', (224, 227))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('malignancy', 'Disease', (86, 96))	('adrenocortical adenoma', 'Disease', 'MESH:D018246', (197, 219))	('tumors', 'Disease', (228, 234))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('TP53', 'Gene', '7157', (189, 193))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (197, 219))	('TP53', 'Gene', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('adrenocortical adenoma', 'Disease', (197, 219))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutations', 'Var', (146, 155))	('tumor', 'Disease', (228, 233))
123639	26446994	Consistent with earlier studies, we found loss-of-function mutations in exon 5 (G12219A) and exon 6 (A12749G) in 9 out of 10 tested ACC tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('ACC', 'Phenotype', 'HP:0006744', (132, 135))	('A12749G', 'Mutation', 'g.12749A>G', (101, 108))	('G12219A', 'Mutation', 'g.12219G>A', (80, 87))	('loss-of-function', 'NegReg', (42, 58))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('A12749G', 'Var', (101, 108))	('G12219A', 'Var', (80, 87))
123640	26446994	Since we observed a significant number of copy number aberrations between normal adrenal cortex and benign adrenocortical tumor samples, we believe that these changes with further accumulation of events may lead to malignancy.	('benign adrenocortical tumor', 'Disease', 'MESH:D018268', (100, 127))	('benign adrenocortical tumor', 'Disease', (100, 127))	('lead to', 'Reg', (207, 214))	('malignancy', 'Disease', 'MESH:D009369', (215, 225))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('malignancy', 'Disease', (215, 225))	('copy number aberrations', 'Var', (42, 65))
123658	26446994	determined that ZNRF3, CTNNB1, CDKN2A and RB1 were frequently altered with either damaging mutations or homozygous deletions.	('RB1', 'Gene', (42, 45))	('altered', 'Reg', (62, 69))	('CTNNB1', 'Gene', (23, 29))	('ZNRF3', 'Gene', (16, 21))	('CDKN2A', 'Gene', '1029', (31, 37))	('RB1', 'Gene', '5925', (42, 45))	('damaging mutations', 'Var', (82, 100))	('CTNNB1', 'Gene', '1499', (23, 29))	('CDKN2A', 'Gene', (31, 37))	('ZNRF3', 'Gene', '84133', (16, 21))
123692	25932386	But, as for all ACC, some authors have discussed a mutation in tumor suppressor genes.	('tumor', 'Disease', (63, 68))	('ACC', 'Phenotype', 'HP:0006744', (16, 19))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutation', 'Var', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
123693	25932386	Others have identified three main molecular patterns which are: Insulin-like growth factor (IGF)-2, the metabolic pathway Wnt/beta-catenin and TP53.1 mutations.	('TP53', 'Gene', (143, 147))	('beta-catenin', 'Gene', '1499', (126, 138))	('metabolic', 'Pathway', (104, 113))	('Insulin-like growth factor (IGF)-2', 'Gene', '3481', (64, 98))	('mutations', 'Var', (150, 159))	('TP53', 'Gene', '7157', (143, 147))	('beta-catenin', 'Gene', (126, 138))
123743	25932386	Increase in some precursors such as progesterone, 17-hydroxyprogesterone (17-OHP), deoxycorticosterone, D4androstenedione (D4A), dehydroepiandrosterone (DHEA) and DHEA sulfate plead for malignancy as in other adrenal tumors.	('17-OHP', 'Chemical', 'MESH:D019326', (74, 80))	('dehydroepiandrosterone', 'MPA', (129, 151))	('dehydroepiandrosterone', 'Chemical', 'MESH:D003687', (129, 151))	('malignancy', 'Disease', 'MESH:D009369', (186, 196))	('deoxycorticosterone', 'Chemical', 'MESH:D003900', (83, 102))	('adrenal tumor', 'Phenotype', 'HP:0100631', (209, 222))	('Increase', 'PosReg', (0, 8))	('adrenal tumors', 'Disease', 'MESH:D000310', (209, 223))	('DHEA', 'Chemical', 'MESH:D003687', (163, 167))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('progesterone', 'MPA', (36, 48))	('malignancy', 'Disease', (186, 196))	('D4A', 'Chemical', '-', (123, 126))	('DHEA sulfate', 'Chemical', 'MESH:D019314', (163, 175))	('DHEA', 'Var', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('DHEA', 'Chemical', 'MESH:D003687', (153, 157))	('progesterone', 'Chemical', 'MESH:D011374', (36, 48))	('progesterone', 'Chemical', 'MESH:D011374', (60, 72))	('adrenal tumors', 'Disease', (209, 223))	('17-hydroxyprogesterone', 'Chemical', 'MESH:D019326', (50, 72))	('D4androstenedione', 'Chemical', '-', (104, 121))
123804	25932386	Apart from its adrenolytic action, mitotane acts by inducing formation of free radicals that block adrenal steroidogenesis by inhibiting 11 beta hydroxylase that is why it is interesting in FAT.	('inhibiting', 'NegReg', (126, 136))	('free radicals', 'Chemical', 'MESH:D005609', (74, 87))	('mitotane', 'Var', (35, 43))	('inducing', 'Reg', (52, 60))	('block adrenal', 'Disease', 'MESH:D006327', (93, 106))	('mitotane', 'Chemical', 'MESH:D008939', (35, 43))	('block adrenal', 'Disease', (93, 106))	('formation', 'MPA', (61, 70))	('11 beta hydroxylase', 'MPA', (137, 156))
123813	25932386	For the cytolytic action, in vitro studies showed that aminoglutethimide inhibits tumor cell proliferation, but in clinical practice some authors use it just as an adjuvant or a palliative treatment for advanced metastatic tumors.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('inhibits', 'NegReg', (73, 81))	('men', 'Species', '9606', (194, 197))	('aminoglutethimide', 'Chemical', 'MESH:D000616', (55, 72))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', (82, 87))	('aminoglutethimide', 'Var', (55, 72))
123850	22570059	Direct IL13Ralpha2 knockdown decreased cellular proliferation and invasion (p < 0.05).	('cellular proliferation', 'CPA', (39, 61))	('knockdown', 'Var', (19, 28))	('IL13Ralpha2', 'Gene', (7, 18))	('decreased', 'NegReg', (29, 38))	('invasion', 'CPA', (66, 74))	('IL13Ralpha2', 'Gene', '3598', (7, 18))
123856	22570059	Since the molecular mechanism of adrenocortical tumorigenesis is not clearly defined, genome wide gene expression profiling analysis of adrenocortical tumors has been used to determine dysregulated gene expression associated with ACC.	('adrenocortical tumors', 'Disease', 'MESH:D018268', (136, 157))	('dysregulated', 'Var', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (33, 53))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('adrenocortical tumor', 'Disease', 'MESH:D018268', (136, 156))	('adrenocortical tumor', 'Disease', (33, 53))	('adrenocortical tumors', 'Disease', (136, 157))	('ACC', 'Phenotype', 'HP:0006744', (230, 233))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
123878	22570059	The PCR primers probes for IL13Ralpha2 (Hs_010180383_m1) and GAPDH (Hs99999905_m1) were obtained from Applied Biosystems (Applied Biosystems, Foster City, CA).	('IL13Ralpha2', 'Gene', (27, 38))	('Hs99999905_m1', 'Var', (68, 81))	('GAPDH', 'Gene', '2597', (61, 66))	('IL13Ralpha2', 'Gene', '3598', (27, 38))	('Hs_010180383_m1', 'Var', (40, 55))	('GAPDH', 'Gene', (61, 66))
123879	22570059	Twenty-four hours after plating, cells were transfected with either a nonspecific negative control siRNA (AM4613) or a combination of IL13Ralpha2 specific siRNAs at a final concentration of 80 nM (s7376 and s7374, Applied Biosystems, Foster City, CA).	('s7376', 'Var', (197, 202))	('IL13Ralpha2', 'Gene', '3598', (134, 145))	('s7374', 'Var', (207, 212))	('IL13Ralpha2', 'Gene', (134, 145))
123888	22570059	After 48 hours, the cells were treated with different concentration of IL-13-PE immunotoxin to assess the biological activity of silenced IL13Ralpha2.	('IL13Ralpha2', 'Gene', '3598', (138, 149))	('silenced', 'Var', (129, 137))	('IL13Ralpha2', 'Gene', (138, 149))
123918	22570059	In addition, after quantitation, the number of invaded cells decreased by 44.7% in IL13Ralpha2 silenced group as compared to siRNA negative control in the presence of IL-13 (p=0.007) and decreased by 30% in the absence of IL-13 (p=0.006) (Figure 3C).	('decreased', 'NegReg', (61, 70))	('IL13Ralpha2', 'Gene', (83, 94))	('IL13Ralpha2', 'Gene', '3598', (83, 94))	('silenced', 'Var', (95, 103))
123920	22570059	In addition, there was a 28.5-33% decrease in cell proliferation after days 11 and 14 of IL13Ralpha2 knockdown as compared to negative control (p<0.001) (Figure 3D).	('IL13Ralpha2', 'Gene', (89, 100))	('decrease', 'NegReg', (34, 42))	('IL13Ralpha2', 'Gene', '3598', (89, 100))	('cell proliferation', 'CPA', (46, 64))	('knockdown', 'Var', (101, 110))
123924	22570059	The IC50 for IL-13-PE was significantly lower (1.3 ng/ml and 0.2 ng/ml) in NCI-H295R and PM-RCC cells with high IL13Ralpha2 expression (Figure 4B) than the IC50 of 600 ng/ml in SW13 cells, which have, lower IL13Ralpha2 expression (p<0.05) (Figure 4C).	('IL13Ralpha2', 'Gene', (112, 123))	('NCI-H295R', 'CellLine', 'CVCL:0458', (75, 84))	('IL13Ralpha2', 'Gene', '3598', (207, 218))	('IL13Ralpha2', 'Gene', '3598', (112, 123))	('high', 'Var', (107, 111))	('IL13Ralpha2', 'Gene', (207, 218))	('lower', 'NegReg', (40, 45))	('SW13', 'CellLine', 'CVCL:0542', (177, 181))
123926	22570059	To further confirm the cytotoxic effect of IL-13-PE in a three-dimensional model that better mimics solid tumors, it was also administered to NCI-H295R tumor spheroids.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('NCI-H295R', 'CellLine', 'CVCL:0458', (142, 151))	('tumor', 'Disease', (106, 111))	('IL-13-PE', 'Var', (43, 51))
123937	22570059	IL13Ralpha2 knockdown in ACC cells resulted in suppression of invasion, suggesting that it may influence cell invasive phenotype in ACC.	('ACC', 'Phenotype', 'HP:0006744', (132, 135))	('ACC', 'Disease', (132, 135))	('influence', 'Reg', (95, 104))	('knockdown', 'Var', (12, 21))	('IL13Ralpha2', 'Gene', (0, 11))	('ACC', 'Phenotype', 'HP:0006744', (25, 28))	('cell invasive phenotype', 'CPA', (105, 128))	('invasion', 'CPA', (62, 70))	('suppression', 'NegReg', (47, 58))	('IL13Ralpha2', 'Gene', '3598', (0, 11))
123949	22570059	The present findings are also supported by other studies that found IL13Ralpha2 is elevated in breast cancer metastasis and glioma cells with mutant epidermal growth factor receptor.	('IL13Ralpha2', 'Gene', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('glioma', 'Disease', (124, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('mutant', 'Var', (142, 148))	('epidermal growth factor receptor', 'Gene', (149, 181))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('IL13Ralpha2', 'Gene', '3598', (68, 79))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (95, 119))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('elevated', 'PosReg', (83, 91))	('breast cancer metastasis', 'Disease', (95, 119))	('epidermal growth factor receptor', 'Gene', '1956', (149, 181))
123952	22570059	IL-13-PE has been shown to inhibit the growth of different cancer cells in vitro and in vivo.	('IL-13-PE', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('inhibit', 'NegReg', (27, 34))
123961	22570059	In addition, histological analysis of the xenograft tumors revealed significant necrosis in tumors treated with IL-13-PE while vehicle treated tumors showed evidence of viable cells.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('IL-13-PE', 'Var', (112, 120))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('necrosis in tumors', 'Disease', (80, 98))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('necrosis in tumors', 'Disease', 'MESH:D009336', (80, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
123966	19428991	Dihydrotestosterone Stimulates Aldosterone Secretion by H295R Human Adrenocortical Cells Men exhibit a higher incidence of cardiovascular diseases than do women.	('cardiovascular diseases', 'Disease', (123, 146))	('Dihydrotestosterone', 'Chemical', 'MESH:D013196', (0, 19))	('Adrenocortical', 'Disease', (68, 82))	('women', 'Species', '9606', (155, 160))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (123, 146))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (123, 146))	('Human', 'Species', '9606', (62, 67))	('Adrenocortical', 'Disease', 'MESH:D018268', (68, 82))	('Men', 'Species', '9606', (89, 92))	('H295R', 'Var', (56, 61))	('Dihydrotestosterone Stimulates Aldosterone', 'Phenotype', 'HP:0000859', (0, 42))	('Aldosterone Secretion', 'MPA', (31, 52))	('H295R', 'CellLine', 'CVCL:0458', (56, 61))
124003	19428991	Bisindolylmaleimide I (GF 109203X) and Go 6983 were from EMD Biosciences (San Diego, CA).	('GF 109203X', 'Var', (23, 33))	('EMD Biosciences', 'Disease', (57, 72))	('Go 6983', 'Chemical', 'MESH:C465664', (39, 46))	('GF 109203X', 'Chemical', 'MESH:C070515', (23, 33))	('EMD Biosciences', 'Disease', 'None', (57, 72))	('Bisindolylmaleimide I', 'Chemical', 'MESH:C070515', (0, 21))
124024	19428991	To evaluate the possible mechanisms by which DHT causes aldosterone secretion from human adrenal cells, cells were preincubated for 30 min with an inhibitor of the CaMK (KN-93, 5 muM), an inhibitor of calmodulin (W-7, 50 muM), an inhibitor of the protein kinase C superfamily (bisindolylmaleimide I, Bis I, 5 muM) or vehicle.	('muM', 'Gene', '56925', (179, 182))	('muM', 'Gene', (179, 182))	('causes', 'Reg', (49, 55))	('W-7', 'Chemical', 'MESH:C017967', (213, 216))	('aldosterone', 'Chemical', 'MESH:D000450', (56, 67))	('CaMK', 'Gene', (164, 168))	('CaMK', 'Gene', '818', (164, 168))	('aldosterone secretion', 'MPA', (56, 77))	('bisindolylmaleimide I', 'Chemical', 'MESH:C070515', (277, 298))	('calmodulin', 'Gene', '801', (201, 211))	('muM', 'Gene', '56925', (309, 312))	('muM', 'Gene', '56925', (221, 224))	('muM', 'Gene', (309, 312))	('KN-93', 'Chemical', 'MESH:C072105', (170, 175))	('muM', 'Gene', (221, 224))	('calmodulin', 'Gene', (201, 211))	('DHT', 'Chemical', 'MESH:D013196', (45, 48))	('human', 'Species', '9606', (83, 88))	('Bis I', 'Chemical', 'MESH:C070515', (300, 305))	('DHT', 'Var', (45, 48))
124041	19428991	However, DHT caused a 2-fold increase in aldosterone secretion under basal conditions and a 2.3-fold increase in aldosterone secretion under Ang II-stimulatory conditions (Fig.	('DHT', 'Var', (9, 12))	('aldosterone secretion', 'MPA', (113, 134))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (101, 124))	('aldosterone', 'Chemical', 'MESH:D000450', (113, 124))	('increase', 'PosReg', (101, 109))	('increase', 'PosReg', (29, 37))	('aldosterone', 'Chemical', 'MESH:D000450', (41, 52))	('aldosterone secretion', 'MPA', (41, 62))	('DHT', 'Chemical', 'MESH:D013196', (9, 12))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (29, 52))
124047	19428991	Therefore, we tested if the DHT-mediated increase in aldosterone secretion is mediated by the local RAS.	('DHT', 'Chemical', 'MESH:D013196', (28, 31))	('aldosterone secretion', 'MPA', (53, 74))	('aldosterone', 'Chemical', 'MESH:D000450', (53, 64))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (41, 64))	('tested', 'Reg', (14, 20))	('increase', 'PosReg', (41, 49))	('DHT-mediated', 'Var', (28, 40))
124056	19428991	To study intracellular signaling mechanisms by which DHT stimulates aldosterone secretion from human adrenal cells, we performed the following experiments.	('human', 'Species', '9606', (95, 100))	('stimulates', 'PosReg', (57, 67))	('DHT', 'Var', (53, 56))	('aldosterone', 'Chemical', 'MESH:D000450', (68, 79))	('aldosterone secretion', 'MPA', (68, 89))	('men', 'Species', '9606', (149, 152))	('DHT', 'Chemical', 'MESH:D013196', (53, 56))
124066	19428991	These results indicate that PKC also mediates DHT-mediated increase in aldosterone secretion by adrenal cells.	('aldosterone', 'Chemical', 'MESH:D000450', (71, 82))	('DHT-mediated', 'Var', (46, 58))	('PKC', 'Gene', (28, 31))	('PKC', 'Gene', '112476', (28, 31))	('aldosterone secretion', 'MPA', (71, 92))	('DHT', 'Chemical', 'MESH:D013196', (46, 49))	('increase in aldosterone', 'Phenotype', 'HP:0000859', (59, 82))	('increase', 'PosReg', (59, 67))
124073	19428991	However, DHT at supraphysiological concentrations stimulated basal and Ang II-mediated aldosterone secretion.	('DHT', 'Var', (9, 12))	('basal', 'MPA', (61, 66))	('Ang II-mediated aldosterone secretion', 'MPA', (71, 108))	('DHT', 'Chemical', 'MESH:D013196', (9, 12))	('stimulated', 'PosReg', (50, 60))	('aldosterone', 'Chemical', 'MESH:D000450', (87, 98))	('rat', 'Species', '10116', (42, 45))
124089	19428991	We then studied the intracellular signaling mechanisms by which DHT stimulates aldosterone secretion by human adrenal cells.	('stimulates', 'PosReg', (68, 78))	('DHT', 'Var', (64, 67))	('human', 'Species', '9606', (104, 109))	('aldosterone', 'Chemical', 'MESH:D000450', (79, 90))	('aldosterone secretion', 'MPA', (79, 100))	('DHT', 'Chemical', 'MESH:D013196', (64, 67))
124091	19428991	The intracellular signaling mechanisms by which DHT through CaMK stimulates aldosterone secretion remain unknown although we may speculate about some possible mechanisms.	('DHT', 'Chemical', 'MESH:D013196', (48, 51))	('CaMK', 'Gene', (60, 64))	('aldosterone secretion', 'MPA', (76, 97))	('CaMK', 'Gene', '818', (60, 64))	('DHT', 'Var', (48, 51))	('stimulates', 'PosReg', (65, 75))	('aldosterone', 'Chemical', 'MESH:D000450', (76, 87))
124095	19428991	These observations allow us to speculate that DHT through CaMK may activate CREB and ATF proteins which in turn could increase aldosterone synthase expression leading to increased aldosterone secretion.	('CREB', 'Gene', '1385', (76, 80))	('aldosterone', 'Chemical', 'MESH:D000450', (180, 191))	('CaMK', 'Gene', '818', (58, 62))	('increase', 'PosReg', (118, 126))	('increase aldosterone', 'Phenotype', 'HP:0000859', (118, 138))	('DHT', 'Chemical', 'MESH:D013196', (46, 49))	('increased', 'PosReg', (170, 179))	('CaMK', 'Gene', (58, 62))	('aldosterone', 'Chemical', 'MESH:D000450', (127, 138))	('ATF proteins', 'Protein', (85, 97))	('aldosterone synthase', 'Gene', (127, 147))	('aldosterone synthase', 'Gene', '1585', (127, 147))	('increased aldosterone', 'Phenotype', 'HP:0000859', (170, 191))	('DHT', 'Var', (46, 49))	('expression', 'MPA', (148, 158))	('CREB', 'Gene', (76, 80))	('aldosterone secretion', 'MPA', (180, 201))	('activate', 'PosReg', (67, 75))
124097	19428991	It has been previously reported that Ang II activates multiple PKC isoforms in human adrenal cells.	('human', 'Species', '9606', (79, 84))	('PKC', 'Gene', (63, 66))	('PKC', 'Gene', '112476', (63, 66))	('activates', 'PosReg', (44, 53))	('Ang II', 'Var', (37, 43))
124101	19428991	For example, although PKCepsilon decreases Ang II-mediated upregulation of aldosterone synthase expression in H295R cells, we have previously shown that Ang II activates PKCepsilon which causes activation of protein kinase D which in turn upregulates aldosterone secretion and aldosterone synthase expression in H295R cells.	('upregulates aldosterone', 'Phenotype', 'HP:0000859', (239, 262))	('expression', 'MPA', (298, 308))	('activation', 'PosReg', (194, 204))	('H295R', 'CellLine', 'CVCL:0458', (312, 317))	('aldosterone synthase', 'Gene', '1585', (277, 297))	('upregulation of aldosterone', 'Phenotype', 'HP:0000859', (59, 86))	('aldosterone synthase', 'Gene', '1585', (75, 95))	('aldosterone', 'Chemical', 'MESH:D000450', (277, 288))	('aldosterone synthase', 'Gene', (277, 297))	('PKCepsilon', 'Gene', (22, 32))	('upregulates', 'PosReg', (239, 250))	('aldosterone', 'Chemical', 'MESH:D000450', (251, 262))	('PKCepsilon', 'Gene', '5581', (170, 180))	('protein kinase D', 'Gene', '5587', (208, 224))	('aldosterone', 'Chemical', 'MESH:D000450', (75, 86))	('aldosterone synthase', 'Gene', (75, 95))	('H295R', 'CellLine', 'CVCL:0458', (110, 115))	('protein kinase D', 'Gene', (208, 224))	('activates', 'PosReg', (160, 169))	('PKCepsilon decreases Ang II', 'Disease', (22, 49))	('PKCepsilon decreases Ang II', 'Disease', 'MESH:D012021', (22, 49))	('PKCepsilon', 'Gene', (170, 180))	('PKCepsilon', 'Gene', '5581', (22, 32))	('aldosterone secretion', 'MPA', (251, 272))	('Ang', 'Var', (153, 156))
124125	32737143	In particular, the MKI lenvatinib (LEN), which inhibits Vascular Endothelial Growth Factor Receptor 1-3 (VEGFR 1-3), Fibroblast Growth Factor Receptor 1-4 (FGFR 1-4), Platellet Derived Growth Factor Receptor-alpha (PDGFR-alpha), RET, and KIT, has been combined with the anti-PD-1 monoclonal antibody pembrolizumab (PEM) in phase I/II trials.	('MKI', 'Var', (19, 22))	('PD-1 monoclonal antibody pembrolizumab', 'Disease', (275, 313))	('PD-1 monoclonal antibody pembrolizumab', 'Disease', 'MESH:D010300', (275, 313))	('FGFR 1-4', 'Gene', '2260;2263;2261;2264', (156, 164))	('Fibroblast Growth Factor Receptor 1-4', 'Gene', '2260;2263;2261;2264', (117, 154))	('inhibits', 'NegReg', (47, 55))	('LEN', 'Chemical', 'MESH:C531958', (35, 38))	('PEM', 'Chemical', 'MESH:C582435', (315, 318))	('PDGFR-alpha', 'Gene', (215, 226))	('RET', 'Gene', '5979', (229, 232))	('VEGFR 1-3', 'Gene', '2321;3791;2324', (105, 114))	('MKI lenvatinib', 'Chemical', '-', (19, 33))	('FGFR 1-4', 'Gene', (156, 164))	('KIT', 'Gene', (238, 241))	('Vascular Endothelial Growth Factor Receptor 1-3', 'Gene', '2321;3791;2324', (56, 103))	('VEGFR 1-3', 'Gene', (105, 114))	('RET', 'Gene', (229, 232))	('Fibroblast Growth Factor Receptor 1-4', 'Gene', (117, 154))	('Vascular Endothelial Growth Factor Receptor 1-3', 'Gene', (56, 103))	('KIT', 'Gene', '3815', (238, 241))	('PDGFR-alpha', 'Gene', '5156', (215, 226))
124126	32737143	Synergy between LEN and PEM is putatively due to LEN creating a more therapeutically advantageous tumor-immune microenvironment, in part through blockade of immunosuppressive VEGFR signaling.	('VEGFR', 'Gene', '3791', (175, 180))	('LEN', 'Chemical', 'MESH:C531958', (49, 52))	('more', 'PosReg', (64, 68))	('LEN', 'Chemical', 'MESH:C531958', (16, 19))	('LEN', 'Var', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('VEGFR', 'Gene', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PEM', 'Chemical', 'MESH:C582435', (24, 27))	('tumor', 'Disease', (98, 103))	('men', 'Species', '9606', (123, 126))
124164	32737143	Thus, cabozantinib (a MKI that targets cMET, as well as VEGFR, AXL, and RET, and that is FDA approved in several solid tumor types) is now undergoing two parallel phase II studies (NCT03370718 and NCT03612232) in ACC.	('tumor', 'Disease', (119, 124))	('MKI', 'Chemical', '-', (22, 25))	('cabozantinib', 'Chemical', 'MESH:C558660', (6, 18))	('cabozantinib', 'Gene', (6, 18))	('RET', 'Gene', '5979', (72, 75))	('VEGFR', 'Gene', '3791', (56, 61))	('NCT03612232', 'Var', (197, 208))	('cMET', 'Gene', '4233', (39, 43))	('AXL', 'Gene', '558', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('ACC', 'Phenotype', 'HP:0006744', (213, 216))	('NCT03370718', 'Var', (181, 192))	('cMET', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('RET', 'Gene', (72, 75))	('AXL', 'Gene', (63, 66))	('VEGFR', 'Gene', (56, 61))
124170	32737143	The investigators were unable to confirm any biomarkers that predicted for response, including PD-L1 staining, tumor-infiltrating lymphocyte score, or tumor mutational burden, but the findings did suggest that microsatellite-high and/or mismatch repair-deficient tumors were enriched for responses.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('microsatellite-high', 'Var', (210, 229))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (111, 116))	('PD-L1', 'Gene', (95, 100))	('tumor', 'Disease', (263, 268))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('PD-L1', 'Gene', '29126', (95, 100))	('deficient tumors', 'Disease', (253, 269))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('deficient tumors', 'Disease', 'MESH:D009369', (253, 269))
124183	32737143	Also, it should be noted that patients 3 and 6 had germline T53 mutation.	('T53', 'Gene', (60, 63))	('patients', 'Species', '9606', (30, 38))	('germline', 'Var', (51, 59))
124203	32550272	NCI-H295 cells harbor a large deletion in the TP53 locus (Table 1 and) and are also known to carry an activating CTNNB1 mutation.	('CTNNB1', 'Gene', (113, 119))	('activating', 'PosReg', (102, 112))	('TP53', 'Gene', '7157', (46, 50))	('mutation', 'Var', (120, 128))	('NCI-H295', 'CellLine', 'CVCL:0456', (0, 8))	('deletion', 'Var', (30, 38))	('TP53', 'Gene', (46, 50))	('CTNNB1', 'Gene', '1499', (113, 119))
124210	32550272	Pediatric adrenocortical tumors are rare and frequently associated to germline TP53 mutations or constitutional genetic abnormalities affecting chromosome 11p15 .	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (10, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('genetic abnormalities', 'Disease', (112, 133))	('associated', 'Reg', (56, 66))	('mutations', 'Var', (84, 93))	('adrenocortical tumors', 'Disease', (10, 31))	('genetic abnormalities', 'Disease', 'MESH:D030342', (112, 133))
124216	32550272	Molecular profiling of this model reveals that blood, primary tumor and xenograft model share the TP53 p.G245C mutation and whole genome sequencing analysis reveal a complex pattern of acquired mutations consistent with a more aggressive phenotype.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('p.G245C', 'Var', (103, 110))	('tumor', 'Disease', (62, 67))	('p.G245C', 'Mutation', 'rs28934575', (103, 110))	('TP53', 'Gene', '7157', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('TP53', 'Gene', (98, 102))
124218	32550272	In this pediatric PDTX model, a panel of commonly used chemotherapeutic agents were tested with cisplatin showing tumor growth inhibition, consistent with its use in frontline therapy for adrenocortical carcinoma.	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (188, 212))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('adrenocortical carcinoma', 'Disease', (188, 212))	('tumor', 'Disease', (114, 119))	('cisplatin', 'Var', (96, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (188, 212))
124228	32550272	Genetic analyses of known driver genes in the original patient tumor (also representing passage 1) revealed a somatic mutation in TP53 (a single G deletion [chr17:7,574,003 (GRCh37/hg19)] resulting in a frameshift) while the tumor was devoid of mutations in any other known ACC driver genes (T91/L91 in and).	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutation', 'Var', (118, 126))	('patient', 'Species', '9606', (55, 62))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('frameshift', 'Var', (203, 213))
124248	32550272	Exomic sequencing revealed CTNNB1 mutation in CU-ACC1 and TP53 in CU-ACC2 models (Table 1), with mutated allele being enriched in PDTX and cells compared to human tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('mutation', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CTNNB1', 'Gene', (27, 33))	('revealed', 'Reg', (18, 26))	('tumor', 'Disease', (163, 168))	('human', 'Species', '9606', (157, 162))	('CTNNB1', 'Gene', '1499', (27, 33))
124269	32188704	NCT02721732  Rare cancers pose many challenges.	('cancers', 'Disease', (18, 25))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('NCT02721732', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
124280	32188704	Recently, the FDA provided its first tissue-agnostic/site-agnostic drug approval:for pembrolizumab in patients with unresectable or metastatic microsatellite instability:high or mismatch repair deficient solid tumors.	('deficient solid tumors', 'Disease', 'MESH:D009369', (194, 216))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('patients', 'Species', '9606', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('deficient solid tumors', 'Disease', (194, 216))	('pembrolizumab', 'Chemical', 'MESH:C582435', (85, 98))	('mismatch repair', 'Var', (178, 193))
124412	32188704	Nevertheless, given that pembrolizumab has been approved for first-line treatment of advanced non-small cell lung cancer in patients with high PD-L1 expression according to an FDA-approved test in the absence of EGFR or ALK molecular alterations, PD-L1 expression likely reflects an immune-active tumor milieu that should be investigated further.	('pembrolizumab', 'Chemical', 'MESH:C582435', (25, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('non-small cell lung cancer', 'Disease', (94, 120))	('patients', 'Species', '9606', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (94, 120))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (94, 120))	('ALK', 'Gene', (220, 223))	('PD-L1', 'Gene', (143, 148))	('expression', 'MPA', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('ALK', 'Gene', '238', (220, 223))	('tumor', 'Disease', (297, 302))	('high', 'Var', (138, 142))	('EGFR', 'Gene', '1956', (212, 216))	('EGFR', 'Gene', (212, 216))
20601	31918158	Several genes have been implicated as tumor drivers in sporadic ACC, including mutations in insulin-like growth factor 2 (IGF2), beta-catenin (CTNNB1 or ZNRF3), and TP53.	('insulin-like growth factor 2', 'Gene', (92, 120))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('ZNRF3', 'Gene', (153, 158))	('TP53', 'Gene', (165, 169))	('ACC', 'Disease', 'MESH:D018268', (64, 67))	('insulin-like growth factor 2', 'Gene', '3481', (92, 120))	('CTNNB1', 'Gene', (143, 149))	('IGF2', 'Gene', '3481', (122, 126))	('beta-catenin', 'Gene', (129, 141))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('TP53', 'Gene', '7157', (165, 169))	('ZNRF3', 'Gene', '84133', (153, 158))	('ACC', 'Disease', (64, 67))	('IGF2', 'Gene', (122, 126))	('CTNNB1', 'Gene', '1499', (143, 149))	('beta-catenin', 'Gene', '1499', (129, 141))	('mutations', 'Var', (79, 88))
124549	31918158	Other germline variants of some of the same genes identified to be drivers of sporadic ACC are also associated with familial tumor syndromes characterized by ACC, including Beckwith-Wiedemann syndrome (BWS), familial adenomatous polyposis (FAP), and Li-Fraumeni syndrome.	('FAP', 'Disease', (240, 243))	('familial adenomatous polyposis', 'Disease', (208, 238))	('FAP', 'Disease', 'MESH:D011125', (240, 243))	('familial tumor', 'Disease', (116, 130))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (208, 238))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (217, 238))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('ACC', 'Disease', (158, 161))	('Li-Fraumeni syndrome', 'Disease', (250, 270))	('familial tumor', 'Disease', 'MESH:D009386', (116, 130))	('Beckwith-Wiedemann syndrome', 'Disease', (173, 200))	('ACC', 'Disease', (87, 90))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (250, 270))	('associated', 'Reg', (100, 110))	('variants', 'Var', (15, 23))	('ACC', 'Disease', 'MESH:D018268', (158, 161))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (173, 200))	('ACC', 'Disease', 'MESH:D018268', (87, 90))	('BWS', 'Disease', (202, 205))	('BWS', 'Disease', 'MESH:D001506', (202, 205))
124567	31918158	It concludes that the Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival.	('EDP', 'Var', (101, 104))	('better', 'PosReg', (89, 95))	('mitotane', 'Chemical', 'MESH:D008939', (147, 155))	('EDP', 'Chemical', 'MESH:C049736', (101, 104))	('mitotane', 'Var', (110, 118))	('response', 'CPA', (31, 39))	('mitotane', 'Chemical', 'MESH:D008939', (110, 118))	('streptozocin', 'Chemical', 'MESH:D013311', (129, 141))	('progression-free survival', 'CPA', (44, 69))
124604	31781041	By e14.5 PSCs are committed to one of the three endocrine lineages (expressing transcription factors T-box Factor 19, Pituitary (Tpit), or POU domain, class 1, transcription factor 1 (Pit1) or Steroidogenic Factor 1 (Sf1), and as they begin to differentiate they migrate ventrally and laterally away from the RP lumen, forming the bulk of the AL, with the dorsal progenitors of the RP forming the IL.	('e14.5', 'Var', (3, 8))	('Pit1', 'Gene', (184, 188))	('rat', 'Species', '10116', (266, 269))	('Steroidogenic Factor 1', 'Gene', (193, 215))	('men', 'Species', '9606', (314, 317))	('Pit1', 'Gene', '18736', (184, 188))	('Tpit', 'Gene', (129, 133))	('Tpit', 'Gene', '83993', (129, 133))	('Steroidogenic Factor 1', 'Gene', '26423', (193, 215))
124610	31781041	From e10.5 Bmp2 is expressed in the developing RP and is essential for RP maintenance and progenitor proliferation, before expression is lost by e14.5.	('rat', 'Species', '10116', (108, 111))	('Bmp2', 'Gene', (11, 15))	('e10.5', 'Var', (5, 10))	('Bmp2', 'Gene', '12156', (11, 15))
124613	31781041	Consequently, ablation of Shh expression in the VD has been shown to cause altered expression of Bmp4, Wnt5a, and Fgf8 and a complete arrest in pituitary formation from the early stages of development.	('Bmp4', 'Gene', (97, 101))	('men', 'Species', '9606', (196, 199))	('Fgf8', 'Gene', (114, 118))	('pituitary formation', 'CPA', (144, 163))	('Shh', 'Gene', (26, 29))	('arrest', 'NegReg', (134, 140))	('altered', 'Reg', (75, 82))	('Wnt5a', 'Gene', (103, 108))	('Fgf8', 'Gene', '14179', (114, 118))	('expression', 'MPA', (83, 93))	('ablation', 'Var', (14, 22))	('Wnt5a', 'Gene', '22418', (103, 108))
124614	31781041	Within the RP itself, Shh signaling is involved in progenitor proliferation as revealed by conditional deletion of its downstream transcriptional repressors Gli2 and Gli3.	('involved', 'Reg', (39, 47))	('Gli2', 'Gene', (157, 161))	('Gli3', 'Gene', (166, 170))	('Gli2', 'Gene', '14633', (157, 161))	('progenitor proliferation', 'CPA', (51, 75))	('Gli3', 'Gene', '14634', (166, 170))	('rat', 'Species', '10116', (69, 72))	('deletion', 'Var', (103, 111))
124618	31781041	Wnt5a is expressed in both the VD and RP from e9.5 to e12.5 and is necessary for correct VD patterning, and indirectly for RP induction via non-canonical pathway.	('Wnt5a', 'Gene', '22418', (0, 5))	('e9.5', 'Var', (46, 50))	('Wnt5a', 'Gene', (0, 5))	('e12.5', 'Var', (54, 59))
124619	31781041	Wnt4 also signals via the non-canonical Wnt pathway, is expressed exclusively in the RP, and appears to function in cell commitment since its deletion reduces the expression of Pit1 resulting in fewer somatotrophs, lactotrophs, and thyrotrophs.	('Wnt4', 'Gene', (0, 4))	('Pit1', 'Gene', '18736', (177, 181))	('reduces', 'NegReg', (151, 158))	('Wnt4', 'Gene', '22417', (0, 4))	('thyrotrophs', 'CPA', (232, 243))	('men', 'Species', '9606', (127, 130))	('somatotrophs', 'CPA', (201, 213))	('Pit1', 'Gene', (177, 181))	('expression', 'MPA', (163, 173))	('deletion', 'Var', (142, 150))	('fewer', 'NegReg', (195, 200))	('non-canonical Wnt pathway', 'Pathway', (26, 51))	('lactotrophs', 'CPA', (215, 226))
124624	31781041	Tcf4 genetic ablation leads to an increase in early progenitor proliferation with increased and prolonged expression of Prop1, which can lead to aberrant tissue growth and tumor formation if not down-regulated.	('genetic ablation', 'Var', (5, 21))	('Prop1', 'Gene', (120, 125))	('Tcf4', 'Gene', '21413', (0, 4))	('rat', 'Species', '10116', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('expression', 'MPA', (106, 116))	('lead to', 'Reg', (137, 144))	('Tcf4', 'Gene', (0, 4))	('early progenitor proliferation', 'CPA', (46, 76))	('increased', 'PosReg', (82, 91))	('increase', 'PosReg', (34, 42))	('Prop1', 'Gene', '19127', (120, 125))
124626	31781041	The Wnt/beta-catenin pathway is important in PSC proliferation and maintenance and deregulation of this pathway lead to stem cell-derived pituitary tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('rat', 'Species', '10116', (56, 59))	('pituitary tumors', 'Disease', 'MESH:D010911', (138, 154))	('stem cell-derived', 'CPA', (120, 137))	('lead to', 'Reg', (112, 119))	('deregulation', 'Var', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('pituitary tumors', 'Disease', (138, 154))
124627	31781041	Activating mutations in beta-catenin drive adamantinomatous craniopharyngioma both in mouse and humans and PSC Sox2+ cells have been shown to be the tumor initiating cells that are responsive to oncogenic beta-catenin.	('mutations', 'Var', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('mouse', 'Species', '10090', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('adamantinomatous craniopharyngioma', 'Disease', (43, 77))	('adamantinomatous craniopharyngioma', 'Disease', 'MESH:D003397', (43, 77))	('tumor', 'Disease', (149, 154))	('craniopharyngioma', 'Phenotype', 'HP:0030062', (60, 77))	('beta-catenin', 'Protein', (24, 36))	('humans', 'Species', '9606', (96, 102))
124638	31781041	By contrast Lhx3 and Lhx4 are expressed from e9.5 in the RP and are redundantly required for progenitor maintenance, and later at e14.5 Lhx4 is downregulated whilst Lhx3 expression is required for endocrine differentiation and maintained into adulthood.	('Lhx4', 'Gene', '16872', (21, 25))	('Lhx3', 'Gene', '16871', (12, 16))	('downregulated', 'NegReg', (144, 157))	('Lhx3', 'Gene', (165, 169))	('Lhx3', 'Gene', '16871', (165, 169))	('Lhx4', 'Gene', (136, 140))	('e14.5', 'Var', (130, 135))	('Lhx4', 'Gene', (21, 25))	('Lhx3', 'Gene', (12, 16))	('Lhx4', 'Gene', '16872', (136, 140))
124640	31781041	Sox3 loss of function mutations can result in mild hypopituitarism, as can Sox2 haploinsufficiency.	('hypopituitarism', 'Disease', (51, 66))	('haploinsufficiency', 'Disease', (80, 98))	('Sox3', 'Gene', (0, 4))	('Sox3', 'Gene', '20675', (0, 4))	('hypopituitarism', 'Phenotype', 'HP:0040075', (51, 66))	('hypopituitarism', 'Disease', 'MESH:D007018', (51, 66))	('mutations', 'Var', (22, 31))	('haploinsufficiency', 'Disease', 'MESH:D058495', (80, 98))	('loss of function', 'NegReg', (5, 21))
124641	31781041	In both Sox3-/- and Sox2+/- mice the RP is bifurcated, and at least for Sox3-/- mutants this has been associated with expanded Bmp4 and Fgf8 domains in the VD.	('Sox3', 'Gene', '20675', (8, 12))	('Bmp4', 'Protein', (127, 131))	('Fgf8', 'Gene', (136, 140))	('expanded', 'PosReg', (118, 126))	('mice', 'Species', '10090', (28, 32))	('mutants', 'Var', (80, 87))	('Fgf8', 'Gene', '14179', (136, 140))	('Sox3', 'Gene', (72, 76))	('Sox3', 'Gene', '20675', (72, 76))	('Sox3', 'Gene', (8, 12))
124663	31781041	Genetic ablation of different endocrine cell populations induces PSCs activation and replenishment of ~60% of the targeted hormone secreted cell type.	('PSCs', 'MPA', (65, 69))	('men', 'Species', '9606', (94, 97))	('replenishment', 'MPA', (85, 98))	('Genetic ablation', 'Var', (0, 16))	('activation', 'PosReg', (70, 80))
124665	31781041	Perhaps more importantly, PSCs are also able to respond to physiological demand under periods of endocrine stress: for instance, experimental adrenalectomy leads to increases in Sox2+ PSCs-derived corticotrophs and gonadotrophs.	('increases', 'PosReg', (165, 174))	('Sox2+ PSCs-derived corticotrophs', 'MPA', (178, 210))	('endocrine stress', 'Phenotype', 'HP:0000818', (97, 113))	('experimental adrenalectomy', 'Var', (129, 155))	('men', 'Species', '9606', (135, 138))	('gonadotrophs', 'MPA', (215, 227))
124687	31781041	It was shown that Shh is expressed in Sf1+ but relatively undifferentiated cortical cells in the subcapsular region of the mouse and rat adrenal starting from e12.5 and e13.5, respectively.	('mouse', 'Species', '10090', (123, 128))	('e12.5', 'Var', (159, 164))	('rat', 'Species', '10116', (133, 136))	('Sf1+', 'Var', (38, 42))	('e13.5', 'Var', (169, 174))
124696	31781041	Compelling evidence of the importance of other pathways in adrenocortical growth, self-renewal and zonation, has also been provided; for example, targeted disruption of beta-catenin in Sf1+ cells resulted in an impairment of adrenal cortex development and maintenance in mice; this phenotype was even more pronounced when a Cre transgene was expressed at high levels, resulting in adrenal aplasia.	('maintenance', 'CPA', (256, 267))	('adrenal aplasia', 'Disease', (381, 396))	('men', 'Species', '9606', (217, 220))	('mice', 'Species', '10090', (271, 275))	('beta-catenin', 'Protein', (169, 181))	('adrenal aplasia', 'Phenotype', 'HP:0011743', (381, 396))	('impairment of adrenal cortex', 'Disease', 'MESH:D000303', (211, 239))	('impairment of adrenal cortex', 'Disease', (211, 239))	('adrenal aplasia', 'Disease', 'MESH:C538429', (381, 396))	('Sf1+', 'Gene', (185, 189))	('disruption', 'Var', (155, 165))	('men', 'Species', '9606', (247, 250))
124703	31781041	Constitutive PKA activation, which was achieved by genetic deletion of the critical component Protein Kinase cAMP-Dependent Type I Regulatory Subunit Alpha (Prkar1a) was also found to be crucial for conversion of ZF cell to a zona reticularis (ZR)-like phenotype, seemingly via lineage conversion of the innermost ZF cells; interestingly this process was found to be sexually dimorphic as testicular androgens were shown to increase adrenocortical Wnt signaling (antagonizing PKA), leading to slower adrenocortical cell turnover and delayed ZR appearance whereas gonadectomy sensitized males to hypercorticism and ZG-like formation.	('adrenocortical cell turnover', 'MPA', (500, 528))	('androgens', 'Chemical', 'MESH:D000728', (400, 409))	('cAMP', 'Chemical', 'MESH:D000242', (109, 113))	('genetic deletion', 'Var', (51, 67))	('increase', 'PosReg', (424, 432))	('delayed', 'NegReg', (533, 540))	('Prkar1a', 'Gene', '19084', (157, 164))	('hypercorticism', 'Disease', 'MESH:D000308', (595, 609))	('Prkar1a', 'Gene', (157, 164))	('hypercorticism', 'Disease', (595, 609))	('adrenocortical Wnt signaling', 'MPA', (433, 461))	('slower', 'NegReg', (493, 499))
124708	31781041	Important factors involved in adrenal cortex differentiation and self-renewal under physiological conditions have also been discovered by assessing mutation and changes in gene expression in adrenocortical tumors.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('adrenocortical tumors', 'Disease', (191, 212))	('changes', 'Reg', (161, 168))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (191, 212))	('mutation', 'Var', (148, 156))
124714	31781041	Znrf3 was found to be expressed in both ZG and ZF cells in mice; adrenocortical-specific loss of Znrf3, achieved through the use of both Sf1Cre and Cyp11b2Cre lines crossed to a floxed Znrf3 allele, developed adrenal hyperplasia in the ZF in a ACTH-independent manner with loss of normal adrenocortical architecture; this phenomenon was found to be dependent on Wnt signaling as genetic inactivation of Znrf3 together with Porcupine (a key enzyme required for Wnt ligands maturation and activity) displayed normal adrenal cortex architecture and reduced ZF hyperplasia.	('loss', 'Var', (89, 93))	('Znrf3', 'Gene', (403, 408))	('rat', 'Species', '10116', (476, 479))	('Znrf3', 'Gene', '407821', (403, 408))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (209, 228))	('mice', 'Species', '10090', (59, 63))	('ACTH', 'Gene', '18976', (244, 248))	('men', 'Species', '9606', (327, 330))	('adrenal cortex architecture', 'CPA', (514, 541))	('Znrf3', 'Gene', (185, 190))	('ZF hyperplasia', 'Disease', 'MESH:D006965', (554, 568))	('Znrf3', 'Gene', '407821', (185, 190))	('Znrf3', 'Gene', (97, 102))	('Porcupine', 'Chemical', 'None', (423, 432))	('reduced', 'NegReg', (546, 553))	('Cyp11b2', 'Gene', (148, 155))	('Znrf3', 'Gene', '407821', (97, 102))	('Cyp11b2', 'Gene', '13072', (148, 155))	('adrenal hyperplasia', 'Disease', (209, 228))	('ACTH', 'Gene', (244, 248))	('Znrf3', 'Gene', (0, 5))	('ZF hyperplasia', 'Disease', (554, 568))	('Znrf3', 'Gene', '407821', (0, 5))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (209, 228))
124716	31781041	Interestingly, this pattern was also altered for beta-catenin protein expression, as well as Axin2 mRNA, strongly suggesting that loss of Znrf3 leads to increased Wnt/beta-catenin in the ZF promoting hyperplasia.	('Axin2', 'Gene', (93, 98))	('Znrf3', 'Gene', '407821', (138, 143))	('Wnt/beta-catenin', 'MPA', (163, 179))	('increased', 'PosReg', (153, 162))	('hyperplasia', 'Disease', 'MESH:D006965', (200, 211))	('Axin2', 'Gene', '12006', (93, 98))	('loss', 'Var', (130, 134))	('Znrf3', 'Gene', (138, 143))	('hyperplasia', 'Disease', (200, 211))
124736	31781041	The contribution of nerve-associated SCPs was further corroborated by genetic ablation of SCPs with diphtheria toxin subunit A, resulting in a significant depletion of chromaffin cells which were able to migrate to the adrenal medulla.	('rat', 'Species', '10116', (207, 210))	('ablation', 'Var', (78, 86))	('rat', 'Species', '10116', (61, 64))	('genetic ablation', 'Var', (70, 86))	('depletion of chromaffin cells', 'MPA', (155, 184))
124737	31781041	Moreover, the dependency of adrenal medulla formation on SCPs migration along nerves was elegantly demonstrated by achieving specific ablation of preganglionic motor neurons, resulting again in a strong (78%) reduction of chromaffin cells, with the remaining chromaffin cells presumably derived from earlier neural crest migrating cells.	('rat', 'Species', '10116', (65, 68))	('chromaffin cells', 'CPA', (222, 238))	('ablation', 'Var', (134, 142))	('reduction', 'NegReg', (209, 218))	('rat', 'Species', '10116', (106, 109))	('rat', 'Species', '10116', (324, 327))
124757	31781041	Indeed, genetic deletion of these transcription factors individually resulted in severe thyroid hypoplasia or lack of thyroid formation.	('thyroid hypoplasia', 'Phenotype', 'HP:0005990', (88, 106))	('lack', 'CPA', (110, 114))	('thyroid hypoplasia', 'Disease', (88, 106))	('genetic deletion', 'Var', (8, 24))	('thyroid hypoplasia', 'Disease', 'MESH:D013959', (88, 106))	('resulted in', 'Reg', (69, 80))
124791	31781041	Modulation of Tgfbeta, Bmp and Fgf signaling pathways lead to the generation of primordial thyroid progenitor cells from mESCs, that could be further matured to functional, transgene-free thyroid follicular organoids able to secrete thyroid hormones and rescue hypothyroid mice after transplantation.	('Modulation', 'Var', (0, 10))	('Tgfbeta', 'Gene', (14, 21))	('rat', 'Species', '10116', (70, 73))	('secrete thyroid hormones', 'MPA', (225, 249))	('hypothyroid', 'Disease', 'MESH:D007037', (261, 272))	('mice', 'Species', '10090', (273, 277))	('Fgf signaling pathways', 'Pathway', (31, 53))	('hypothyroid', 'Disease', (261, 272))
124800	31781041	Gcm2-/- mice lack parathyroid glands and develop primary hypoparathyroidism and human Gcm2 mutations have been associated with dysregulated parathyroid hormonal levels.	('lack parathyroid glands', 'Phenotype', 'HP:0008211', (13, 36))	('hypoparathyroidism', 'Phenotype', 'HP:0000829', (57, 75))	('hypoparathyroidism', 'Disease', 'MESH:D007011', (57, 75))	('rat', 'Species', '10116', (142, 145))	('associated', 'Reg', (111, 121))	('dysregulated parathyroid hormonal levels', 'MPA', (127, 167))	('Gcm2', 'Gene', (86, 90))	('mutations', 'Var', (91, 100))	('human', 'Species', '9606', (80, 85))	('parathyroid glands', 'CPA', (18, 36))	('rat', 'Species', '10116', (20, 23))	('rat', 'Species', '10116', (63, 66))	('mice', 'Species', '10090', (8, 12))	('hypoparathyroidism', 'Disease', (57, 75))
124818	31781041	Early studies showed that ablation of Bmp4 and Bmp2 in mouse embryo resulted in lack and severe reduction of PGCs number, respectively.	('Bmp2', 'Gene', '12156', (47, 51))	('lack', 'NegReg', (80, 84))	('reduction of PGCs number', 'Disease', (96, 120))	('mouse', 'Species', '10090', (55, 60))	('ablation', 'Var', (26, 34))	('Bmp2', 'Gene', (47, 51))	('reduction of PGCs number', 'Disease', 'MESH:D015431', (96, 120))	('Bmp4', 'Gene', (38, 42))
124819	31781041	Between around e9.0 and e11.5, PGCs migrate to the genital ridge.	('rat', 'Species', '10116', (39, 42))	('PGCs', 'Protein', (31, 35))	('e11.5', 'Var', (24, 29))
124829	31781041	Experiments with transgenic mice demonstrated that the early male marker Sox9 is up-regulated by the transient expression of Sry specifically in Sertoli cell precursors.	('expression', 'Var', (111, 121))	('Sox9', 'Gene', '20682', (73, 77))	('Sertoli cell', 'Phenotype', 'HP:0100619', (145, 157))	('rat', 'Species', '10116', (40, 43))	('Sox9', 'Gene', (73, 77))	('up-regulated', 'PosReg', (81, 93))	('Sry', 'Gene', (125, 128))	('transgenic mice', 'Species', '10090', (17, 32))	('men', 'Species', '9606', (6, 9))
124836	31781041	The importance of Sry in testis development is highlighted by numerous mutations causing sexual-development disorders, yet little is known about its regulation.	('men', 'Species', '9606', (103, 106))	('mutations', 'Var', (71, 80))	('causing', 'Reg', (81, 88))	('men', 'Species', '9606', (39, 42))	('sexual-development disorders', 'Disease', (89, 117))
124841	31781041	The shorter chains of cells have a greater probability of being Gfralpha1 single-positive while longer chains tend to be Ngn3 single-positive.	('Gfralpha1', 'Gene', '14585', (64, 73))	('Gfralpha1', 'Gene', (64, 73))	('single-positive', 'Var', (74, 89))	('Ngn3', 'Gene', '11925', (121, 125))	('Ngn3', 'Gene', (121, 125))
124842	31781041	Recently, pigs with heterozygous and homozygous mutations in Nanos2 were generated using the CRISPR/Cas9 system.	('pigs', 'Species', '9823', (10, 14))	('Nanos2', 'Gene', (61, 67))	('mutations', 'Var', (48, 57))	('rat', 'Species', '10116', (77, 80))
124843	31781041	Males pigs had an impaired development of testis, specifically homozygous Nanos2 knockout had no germ cells in the presence of intact seminiferous tubules.	('development', 'CPA', (27, 38))	('knockout', 'Var', (81, 89))	('Nanos2', 'Gene', (74, 80))	('pigs', 'Species', '9823', (6, 10))	('men', 'Species', '9606', (34, 37))
124865	31781041	Fgf2 expanded a retinoic acid receptor gamma (Rargamma) expressing subset of cells showing Fgf2 function to be more appropriate for spermatogonial differentiation.	('spermatogonial differentiation', 'CPA', (132, 162))	('function', 'Var', (96, 104))	('retinoic acid receptor gamma', 'Gene', '19411', (16, 44))	('Fgf2', 'Gene', (91, 95))	('retinoic acid receptor gamma', 'Gene', (16, 44))	('Rargamma', 'Gene', '19411', (46, 54))	('Rargamma', 'Gene', (46, 54))
124907	31781041	A mutation in the human R-spondin1 (RSPO1) gene, was shown to be responsible for female-to-male sex reversal.	('mutation', 'Var', (2, 10))	('RSPO1', 'Gene', '284654', (36, 41))	('human', 'Species', '9606', (18, 23))	('R-spondin1', 'Gene', (24, 34))	('female-to-male sex reversal', 'CPA', (81, 108))	('sex reversal', 'Phenotype', 'HP:0012245', (96, 108))	('R-spondin1', 'Gene', '284654', (24, 34))	('responsible', 'Reg', (65, 76))	('RSPO1', 'Gene', (36, 41))
124922	31781041	Ultimately, the transplanted mice produced offsprings that had the GFP transgene.	('mice', 'Species', '10090', (29, 33))	('GFP transgene', 'Var', (67, 80))	('offsprings', 'CPA', (43, 53))
124950	31781041	The finding of FGSCs in adult human ovaries promts the question whether these cells can be utilized somehow to enhance, prolong or restore fertility in women.	('women', 'Species', '9606', (152, 157))	('human', 'Species', '9606', (30, 35))	('ovaries', 'Disease', (36, 43))	('ovaries', 'Disease', 'MESH:D010051', (36, 43))	('enhance', 'PosReg', (111, 118))	('FGSCs', 'Var', (15, 20))	('prolong or restore fertility', 'Phenotype', 'HP:0000144', (120, 148))	('fertility', 'CPA', (139, 148))
124971	31781041	In addition to Notch inhibition, recent work by a number of groups have demonstrated that inhibition of Wnt, Tgfbeta and Hippo (through the downregulation of its effector Yes Associated Protein, Yap) signaling further enhances human endocrine differentiation (Figure 9).	('human endocrine differentiation', 'CPA', (227, 258))	('human', 'Species', '9606', (227, 232))	('enhances', 'PosReg', (218, 226))	('Yap', 'Gene', (195, 198))	('Hippo', 'Protein', (121, 126))	('downregulation', 'NegReg', (140, 154))	('Tgfbeta', 'Gene', (109, 116))	('Wnt', 'Protein', (104, 107))	('inhibition', 'Var', (90, 100))	('Yap', 'Gene', '10413', (195, 198))	('rat', 'Species', '10116', (79, 82))
124996	31781041	Supporting the use of hESC for the treatment of diabetes, ViaCyteTM has launched several clinical trials to test the safety of pancreatic progenitor transplantation in humans (NCT02239354, NCT02939118, NCT03162926, NCT03163511).	('diabetes', 'Disease', (48, 56))	('NCT02939118', 'Var', (189, 200))	('NCT03162926', 'Var', (202, 213))	('NCT02239354', 'Var', (176, 187))	('diabetes', 'Disease', 'MESH:D003920', (48, 56))	('men', 'Species', '9606', (40, 43))	('humans', 'Species', '9606', (168, 174))	('NCT03163511', 'Chemical', 'MESH:C079985', (215, 226))	('NCT03163511', 'Var', (215, 226))	('NCT03162926', 'Chemical', 'MESH:C079985', (202, 213))
125010	30250647	Mice with human ACC xenografts treated with flavopiridol and carfilzomib had significantly lower tumor burden, compared to other groups (p<0.05).	('lower', 'NegReg', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('human', 'Species', '9606', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('carfilzomib', 'Chemical', 'MESH:C524865', (61, 72))	('flavopiridol', 'Var', (44, 56))	('tumor', 'Disease', (97, 102))	('flavopiridol', 'Chemical', 'MESH:C077990', (44, 56))	('Mice', 'Species', '10090', (0, 4))
125029	30250647	Mice with human ACC xenografts treated with flavopiridol and carfilzomib had significantly lower tumor burden, and increased cleaved-caspase and reduced XIAP expression in tumor xenografts.	('lower', 'NegReg', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cleaved-caspase', 'MPA', (125, 140))	('reduced', 'NegReg', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('human', 'Species', '9606', (10, 15))	('increased', 'PosReg', (115, 124))	('XIAP expression', 'MPA', (153, 168))	('tumor', 'Disease', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('carfilzomib', 'Chemical', 'MESH:C524865', (61, 72))	('flavopiridol', 'Var', (44, 56))	('tumor', 'Disease', (97, 102))	('flavopiridol', 'Chemical', 'MESH:C077990', (44, 56))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
125043	30250647	Patients with high CDK1 and CDK2 mRNA expression in primary ACC had significantly shorter overall survival (p<0.01) using the median level as a cutoff (Figure 2A and 2B).	('CDK1', 'Gene', (19, 23))	('CDK1', 'Gene', '983', (19, 23))	('shorter', 'NegReg', (82, 89))	('CDK2', 'Gene', (28, 32))	('mRNA expression', 'Var', (33, 48))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('CDK2', 'Gene', '1017', (28, 32))	('overall survival', 'MPA', (90, 106))
125044	30250647	To confirm the prognostic significance of CDK1 and CDK2 expression in an independent cohort, we analyzed the data from the European Bioinformatics Institute and found shorter disease-specific survival in patients with high CDK1 and CDK2 mRNA expression (p<0.01 and p=0.01, respectively) (Figure 2C).	('patients', 'Species', '9606', (204, 212))	('CDK1', 'Gene', (223, 227))	('shorter', 'NegReg', (167, 174))	('CDK2', 'Gene', (51, 55))	('disease-specific survival', 'CPA', (175, 200))	('high', 'Var', (218, 222))	('CDK2', 'Gene', '1017', (232, 236))	('mRNA expression', 'MPA', (237, 252))	('CDK1', 'Gene', '983', (223, 227))	('CDK1', 'Gene', '983', (42, 46))	('CDK2', 'Gene', '1017', (51, 55))	('CDK1', 'Gene', (42, 46))	('CDK2', 'Gene', (232, 236))
125055	30250647	G2M phase in NCI-H295R treated with flavopiridol and carfilzomib was higher than the carfilzomib-treated group (27% vs. 16.3%) and vehicle control (27% vs. 18.5%), but only slightly higher than the group treated with flavopiridol alone (24.2% in flavopiridol treated group vs. 27.0% in the combination group).	('carfilzomib', 'Chemical', 'MESH:C524865', (53, 64))	('flavopiridol', 'Chemical', 'MESH:C077990', (217, 229))	('carfilzomib', 'Chemical', 'MESH:C524865', (85, 96))	('NCI-H295R', 'CellLine', 'CVCL:0458', (13, 22))	('flavopiridol', 'Var', (36, 48))	('flavopiridol', 'Chemical', 'MESH:C077990', (246, 258))	('flavopiridol', 'Chemical', 'MESH:C077990', (36, 48))	('higher', 'PosReg', (69, 75))	('G2M phase', 'CPA', (0, 9))
125063	30250647	XIAP mRNA was overexpressed in ACC compared to cortical adenoma in two independent cohorts (GSE12368: 12 ACC vs. 16 cortical adenoma, p=0.02, and GSE33371: 14 ACC vs. 19 cortical adenoma, p=0.02).	('cortical adenoma', 'Disease', (170, 186))	('overexpressed', 'PosReg', (14, 27))	('cortical adenoma', 'Disease', 'MESH:D000236', (47, 63))	('cortical adenoma', 'Disease', (116, 132))	('cortical adenoma', 'Disease', (47, 63))	('cortical adenoma', 'Disease', 'MESH:D000236', (116, 132))	('GSE33371', 'Var', (146, 154))	('cortical adenoma', 'Disease', 'MESH:D000236', (170, 186))
125081	30250647	Dysregulation of cyclins and CDK are common in several types of cancer, such as squamous cell carcinoma of the head and neck, esophagus, and uterine cervix; non-small cell lung cancer, breast cancer, soft-tissue sarcomas, and hematologic malignancy.	('cancer', 'Disease', (177, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('Dysregulation', 'Var', (0, 13))	('common', 'Reg', (37, 43))	('cancer', 'Disease', (192, 198))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (161, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('uterine cervix', 'Phenotype', 'HP:0030160', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('sarcomas', 'Phenotype', 'HP:0100242', (212, 220))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (157, 183))	('cancer', 'Disease', (64, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 103))	('soft-tissue sarcomas', 'Disease', (200, 220))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('esophagus', 'Disease', (126, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('CDK', 'Protein', (29, 32))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cyclins', 'Protein', (17, 24))	('squamous cell carcinoma', 'Disease', (80, 103))	('non-small cell lung cancer', 'Disease', (157, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('hematologic malignancy', 'Disease', 'MESH:D019337', (226, 248))	('hematologic malignancy', 'Phenotype', 'HP:0004377', (226, 248))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (94, 124))	('hematologic malignancy', 'Disease', (226, 248))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('breast cancer', 'Disease', (185, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (200, 220))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (157, 183))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (200, 220))
125084	30250647	Flavopiridol treatment in human tumor cell lines resulted in drug-mediated cell-cycle arrest and apoptosis, but even more remarkably, flavopiridol also induced apoptosis in non-cycling (i.e., G 0-1 phase) cancer cells.	('induced', 'Reg', (152, 159))	('apoptosis', 'CPA', (160, 169))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('human', 'Species', '9606', (26, 31))	('cancer', 'Disease', (205, 211))	('cell-cycle arrest', 'CPA', (75, 92))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Disease', (32, 37))	('flavopiridol', 'Chemical', 'MESH:C077990', (134, 146))	('flavopiridol', 'Var', (134, 146))	('Flavopiridol', 'Chemical', 'MESH:C077990', (0, 12))
125086	30250647	However, we observed increased apoptosis and cell death in NCI-H295R treated with flavopiridol in vitro and the effect further increased with the addition of carfilzomib.	('flavopiridol', 'Chemical', 'MESH:C077990', (82, 94))	('NCI-H295R', 'Var', (59, 68))	('NCI-H295R', 'CellLine', 'CVCL:0458', (59, 68))	('carfilzomib', 'Chemical', 'MESH:C524865', (158, 169))	('cell death', 'CPA', (45, 55))	('apoptosis', 'CPA', (31, 40))
125115	30250647	To examine whether the combination of flavopiridol and carfilzomib was synergistic, we used the automated computerized algorithm (Chou-Talalay method) to calculate the combination index (CI), in which CI=1 indicates an additive effect; CI<1, a synergistic effect; and CI>1, an antagonistic effect.	('synergistic effect', 'MPA', (244, 262))	('flavopiridol', 'Chemical', 'MESH:C077990', (38, 50))	('CI<1', 'Var', (236, 240))	('CI=1', 'Var', (201, 205))	('additive effect', 'MPA', (219, 234))	('carfilzomib', 'Chemical', 'MESH:C524865', (55, 66))
125188	29507530	In order to investigate the effects of U0126, cells were treated with U0126 for 60 min, and in combined treatment, cells were treated with U0126 for 60 min, followed by treatment with Nilotinib for more 60 min.	('U0126', 'Var', (139, 144))	('U0126', 'Chemical', 'MESH:C113580', (70, 75))	('U0126', 'Chemical', 'MESH:C113580', (139, 144))	('U0126', 'Chemical', 'MESH:C113580', (39, 44))	('U0126', 'Var', (70, 75))	('Nilotinib', 'Chemical', 'MESH:C498826', (184, 193))
125191	29507530	Membranes were incubated overnight in TBST containing 5% fat-free milk with the following respective primary antibodies diluted 1:1000: anti-total ERK, anti-phospho ERK, anti-phospho SAPK (all purchased from Cell Signaling Technology, MA, USA) and anti-GAPDH (Santa Cruz Biotechnology, CA, USA).	('ERK', 'Gene', (147, 150))	('SAPK', 'Gene', (183, 187))	('ERK', 'Gene', '5594', (165, 168))	('GAPDH', 'Gene', '2597', (253, 258))	('GAPDH', 'Gene', (253, 258))	('SAPK', 'Gene', '5601', (183, 187))	('TBST', 'Chemical', '-', (38, 42))	('ERK', 'Gene', '5594', (147, 150))	('anti-phospho', 'Var', (170, 182))	('anti-total', 'Var', (136, 146))	('ERK', 'Gene', (165, 168))
125234	29507530	We observed that after treating H295R cells with both nilotinib and U0126, ERK1/2 phosphorylation was efficiently inhibited (Fig.	('H295R', 'CellLine', 'CVCL:0458', (32, 37))	('phosphorylation', 'MPA', (82, 97))	('U0126', 'Var', (68, 73))	('ERK1/2', 'Gene', '5595;5594', (75, 81))	('ERK1/2', 'Gene', (75, 81))	('nilotinib', 'Chemical', 'MESH:C498826', (54, 63))	('U0126', 'Chemical', 'MESH:C113580', (68, 73))	('inhibited', 'NegReg', (114, 123))
125250	29507530	Inhibitors of both pathways alone and in combination decreases cell proliferation in vitro and in tumor xenografts in vivo.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('Inhibitors', 'Var', (0, 10))	('cell proliferation', 'CPA', (63, 81))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('decreases', 'NegReg', (53, 62))	('tumor', 'Disease', (98, 103))
125257	29507530	In another study, sunitinib serum levels of patients were reduced by mitotane-induced P450-3A4 activity, attenuating its activity.	('serum levels', 'MPA', (28, 40))	('mitotane-induced', 'Var', (69, 85))	('patients', 'Species', '9606', (44, 52))	('activity', 'MPA', (121, 129))	('sunitinib', 'Chemical', 'MESH:D000077210', (18, 27))	('P450-3A4', 'Enzyme', (86, 94))	('attenuating', 'NegReg', (105, 116))	('activity', 'MPA', (95, 103))	('mitotane', 'Chemical', 'MESH:D008939', (69, 77))	('reduced', 'NegReg', (58, 65))
125265	29507530	Our present data show that nilotinib was efficiently cytotoxic in spheroid preparations of both the adrenocortical carcinoma cell cultures utilized and was more efficient than imatinib.	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (100, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('imatinib', 'Chemical', 'MESH:D000068877', (176, 184))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (100, 124))	('nilotinib', 'Var', (27, 36))	('nilotinib', 'Chemical', 'MESH:C498826', (27, 36))	('adrenocortical carcinoma', 'Disease', (100, 124))	('cytotoxic', 'CPA', (53, 62))
125277	29039119	Clinical implications of germline mutations in breast cancer: TP53 This review describes the prevalence of germline TP53 mutations, the risk of breast cancer and other cancers in mutation carriers and management implications for women with breast cancer and unaffected women.	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('mutations', 'Var', (121, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('breast cancer', 'Disease', (144, 157))	('TP53', 'Gene', (62, 66))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('TP53', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('breast cancer', 'Disease', (47, 60))	('women', 'Species', '9606', (229, 234))	('women', 'Species', '9606', (269, 274))	('TP53', 'Gene', '7157', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('TP53', 'Gene', '7157', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('breast cancer', 'Disease', (240, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))
125278	29039119	Women who carry germline mutations in the TP53 gene have a very high risk of breast cancer of up to 85% by age 60 years.	('breast cancer', 'Disease', (77, 90))	('Women', 'Species', '9606', (0, 5))	('TP53', 'Gene', '7157', (42, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('germline mutations', 'Var', (16, 34))	('TP53', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
125280	29039119	Approximately 5-8% of women presenting with breast cancer under 30 years old have a germline TP53 gene mutation.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('women', 'Species', '9606', (22, 27))	('breast cancer', 'Disease', (44, 57))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutation', 'Var', (103, 111))
125281	29039119	Breast cancers in women with TP53 mutations are more likely to be hormone receptor positive and/or Her2 positive.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('positive', 'Reg', (83, 91))	('Her2', 'Gene', (99, 103))	('hormone receptor', 'Gene', (66, 82))	('positive', 'Reg', (104, 112))	('hormone receptor', 'Gene', '3164', (66, 82))	('TP53', 'Gene', '7157', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('TP53', 'Gene', (29, 33))	('Breast cancers', 'Disease', (0, 14))	('Her2', 'Gene', '2064', (99, 103))	('women', 'Species', '9606', (18, 23))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))	('mutations', 'Var', (34, 43))
125282	29039119	Mastectomy is recommended over lumpectomy in TP53 mutation carriers who have breast cancer so that adjuvant breast radiotherapy can be avoided.	('breast cancer', 'Disease', (77, 90))	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (45, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('mutation', 'Var', (50, 58))
125284	29039119	Mutation carriers are at high risk of various childhood and adult-onset cancers with a very lifetime risk of malignancy, the commonest malignancies being breast cancer and soft tissue sarcoma.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('malignancy', 'Disease', (109, 119))	('soft tissue sarcoma', 'Disease', (172, 191))	('breast cancer', 'Disease', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Mutation', 'Var', (0, 8))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (172, 191))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('malignancies', 'Disease', 'MESH:D009369', (135, 147))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (172, 191))	('malignancies', 'Disease', (135, 147))	('malignancy', 'Disease', 'MESH:D009369', (109, 119))
125286	29039119	Identifying a TP53 mutation in a gene panel test is a challenging result for the patient and clinician due to the high risk of second primaries and the lack of consensus about surveillance.	('TP53', 'Gene', (14, 18))	('TP53', 'Gene', '7157', (14, 18))	('mutation', 'Var', (19, 27))	('patient', 'Species', '9606', (81, 88))
125288	29039119	Mutations in the BRCA1 and BRCA2 genes remain by far the most common genetic explanation for a strong family history of breast cancer.	('BRCA1', 'Gene', '672', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BRCA2', 'Gene', '675', (27, 32))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('BRCA1', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('BRCA2', 'Gene', (27, 32))	('common', 'Reg', (62, 68))
125289	29039119	Germline mutations in TP53 may cause an even higher risk of breast cancer, but these are much rarer than BRCA1/BRCA2 mutations.	('Germline mutations', 'Var', (0, 18))	('BRCA2', 'Gene', (111, 116))	('breast cancer', 'Disease', (60, 73))	('BRCA1', 'Gene', (105, 110))	('BRCA2', 'Gene', '675', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TP53', 'Gene', '7157', (22, 26))	('cause', 'Reg', (31, 36))	('BRCA1', 'Gene', '672', (105, 110))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('TP53', 'Gene', (22, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
125293	29039119	Germline mutations in the TP53 gene cause a familial cancer predisposition.	('Germline mutations', 'Var', (0, 18))	('TP53', 'Gene', (26, 30))	('familial cancer', 'Disease', (44, 59))	('cause', 'Reg', (36, 41))	('familial cancer', 'Disease', 'MESH:D009369', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('TP53', 'Gene', '7157', (26, 30))
125295	29039119	Mutation carriers have a very high lifetime risk of malignancy and the commonest cancers are soft tissue sarcomas and breast cancer in women.	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (93, 113))	('soft tissue sarcomas', 'Disease', (93, 113))	('Mutation', 'Var', (0, 8))	('cancers', 'Disease', (81, 88))	('malignancy', 'Disease', (52, 62))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('sarcomas', 'Phenotype', 'HP:0100242', (105, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', (118, 131))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (93, 113))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (93, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('women', 'Species', '9606', (135, 140))
125297	29039119	The frequency of germline pathogenic variants in TP53 in the general population is unknown and has been estimated using penetrance figures.	('TP53', 'Gene', (49, 53))	('variants', 'Var', (37, 45))	('TP53', 'Gene', '7157', (49, 53))
125300	29039119	A recent study of germline variation in cancer-susceptibility genes in a healthy cohort found 15 TP53 missense variants and did not find any nonsense or frameshift variant in 681 individuals; one missense variant was likely pathogenic and the others were variants of unknown clinical significance.	('pathogenic', 'Reg', (224, 234))	('missense variants', 'Var', (102, 119))	('TP53', 'Gene', '7157', (97, 101))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('TP53', 'Gene', (97, 101))	('variants', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
125301	29039119	The prevalence of TP53 mutations among women with early onset breast cancer has been studied in various populations.	('TP53', 'Gene', '7157', (18, 22))	('women', 'Species', '9606', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('TP53', 'Gene', (18, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('mutations', 'Var', (23, 32))	('breast cancer', 'Disease', (62, 75))
125302	29039119	estimated that 5-8% of women with breast cancer diagnosed under age 30 years and no pathogenic variant in BRCA1 or BRCA2 will have a pathogenic variant in TP53, and a smaller proportion of women with breast cancer diagnosed aged 30-39 years.	('BRCA2', 'Gene', '675', (115, 120))	('pathogenic', 'Reg', (133, 143))	('BRCA1', 'Gene', '672', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('BRCA1', 'Gene', (106, 111))	('women', 'Species', '9606', (23, 28))	('variant', 'Var', (95, 102))	('TP53', 'Gene', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('women', 'Species', '9606', (189, 194))	('variant', 'Var', (144, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('BRCA2', 'Gene', (115, 120))	('TP53', 'Gene', '7157', (155, 159))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('breast cancer', 'Disease', (200, 213))
125303	29039119	The likelihood of having a TP53 mutation is increased if there is a family history of LFS-related cancers, or a personal history of an additional LFS-related cancer.	('TP53', 'Gene', '7157', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TP53', 'Gene', (27, 31))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', (98, 104))	('cancers', 'Disease', (98, 105))	('mutation', 'Var', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
125304	29039119	In a series of patients who had a germline TP53 mutation ascertained due to having a young onset cancer, it was estimated that 7-20% of the mutations were de novo.	('patients', 'Species', '9606', (15, 23))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutation', 'Var', (48, 56))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
125305	29039119	This is in contrast to hereditary breast and ovarian cancer syndrome due to BRCA1 or BRCA2 gene mutations, where de novo mutations are exceedingly rare.	('ovarian cancer', 'Phenotype', 'HP:0100615', (45, 59))	('BRCA1', 'Gene', '672', (76, 81))	('BRCA2', 'Gene', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BRCA1', 'Gene', (76, 81))	('hereditary breast and ovarian cancer syndrome', 'Disease', 'MESH:D061325', (23, 68))	('BRCA2', 'Gene', '675', (85, 90))	('mutations', 'Var', (96, 105))
125307	29039119	The prevalence of TP53 mutations among women who have had panel testing is low at under 1% in four recent studies.	('mutations', 'Var', (23, 32))	('women', 'Species', '9606', (39, 44))	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))
125308	29039119	found 61 women with TP53 mutations among 35,409 women with breast cancer who had testing using a panel of 25 cancer genes (0.17%).	('mutations', 'Var', (25, 34))	('women', 'Species', '9606', (9, 14))	('TP53', 'Gene', (20, 24))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('cancer', 'Disease', (109, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('women', 'Species', '9606', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('TP53', 'Gene', '7157', (20, 24))	('cancer', 'Disease', (66, 72))
125309	29039119	detected one TP53 mutation among 190 breast cancer patients with a strong family history and previous negative BRCA1/BRCA2 testing using a protein truncation test (0.53%).	('breast cancer', 'Disease', (37, 50))	('TP53', 'Gene', (13, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('BRCA2', 'Gene', '675', (117, 122))	('BRCA1', 'Gene', '672', (111, 116))	('mutation', 'Var', (18, 26))	('BRCA1', 'Gene', (111, 116))	('patients', 'Species', '9606', (51, 59))	('TP53', 'Gene', '7157', (13, 17))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('BRCA2', 'Gene', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
125310	29039119	found one TP53 mutation among 377 women who were offered gene testing by breast surgeons using multigene panels (5-43 genes, average 14.7) (0.27%).	('TP53', 'Gene', (10, 14))	('mutation', 'Var', (15, 23))	('TP53', 'Gene', '7157', (10, 14))	('women', 'Species', '9606', (34, 39))
125312	29039119	They reported nine pathogenic and one likely pathogenic TP53 mutation among 3315 women with breast cancer who had not had previous BRCA1/BRCA2 testing (0.30%), and three pathogenic and one likely pathogenic TP53 mutation among 1894 women with breast cancer who had previous BRCA1/BRCA2 testing (0.21%).	('women', 'Species', '9606', (81, 86))	('TP53', 'Gene', '7157', (207, 211))	('mutation', 'Var', (61, 69))	('women', 'Species', '9606', (232, 237))	('BRCA1', 'Gene', '672', (131, 136))	('BRCA2', 'Gene', (280, 285))	('BRCA1', 'Gene', '672', (274, 279))	('BRCA2', 'Gene', (137, 142))	('BRCA1', 'Gene', (131, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('BRCA1', 'Gene', (274, 279))	('TP53', 'Gene', '7157', (56, 60))	('BRCA2', 'Gene', '675', (280, 285))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('breast cancer', 'Disease', (243, 256))	('BRCA2', 'Gene', '675', (137, 142))	('breast cancer', 'Disease', (92, 105))	('pathogenic', 'Reg', (19, 29))	('TP53', 'Gene', (207, 211))	('TP53', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
125313	29039119	There is a high prevalence of the c.1010G > A, p.(Arg337His) mutation in exon 10 (often referred to as R337H) in Southeast and Southern Brazil.	('c.1010G > A', 'Var', (34, 45))	('p.(Arg337His', 'Var', (47, 59))	('R337H', 'Mutation', 'rs121912664', (103, 108))	('c.1010G > A', 'Mutation', 'rs786202288', (34, 45))	('p.(Arg337His)', 'Mutation', 'rs121912664', (47, 60))
125316	29039119	The R337H mutation is not common among women diagnosed with breast cancer in Portugal.	('R337H', 'Mutation', 'rs121912664', (4, 9))	('breast cancer', 'Disease', (60, 73))	('R337H', 'Var', (4, 9))	('women', 'Species', '9606', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
125318	29039119	The penetrance of breast cancer in women with TP53 mutations is very high with a cumulative incidence of 85% by age 60 years in the National Cancer Institute Li-Fraumeni Syndrome cohort.	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (158, 178))	('women', 'Species', '9606', (35, 40))	('mutations', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('Li-Fraumeni Syndrome', 'Disease', (158, 178))	('TP53', 'Gene', '7157', (46, 50))	('breast cancer', 'Disease', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('TP53', 'Gene', (46, 50))	('Cancer', 'Disease', (141, 147))	('Cancer', 'Disease', 'MESH:D009369', (141, 147))
125321	29039119	8% had >= 3 primaries and 10% had tested positive for a TP53 mutation without meeting any of the current diagnostic criteria or testing guidelines.	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('mutation', 'Var', (61, 69))	('positive', 'Reg', (41, 49))
125323	29039119	The overall lifetime risk of cancer in individuals with TP53 mutations is very high.	('cancer', 'Disease', (29, 35))	('TP53', 'Gene', '7157', (56, 60))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TP53', 'Gene', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
125324	29039119	estimated that the cancer-free survival probabilities for female TP53 mutation carriers were 65.2, 33.0 and 2.9% at ages 30, 45 and 60 years, respectively.	('TP53', 'Gene', '7157', (65, 69))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('TP53', 'Gene', (65, 69))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutation', 'Var', (70, 78))
125330	29039119	In a cohort of 525 patients tested, 9/9 patients with choroid plexus tumours had an identifiable TP53 mutation.	('choroid plexus tumours', 'Disease', 'MESH:D020288', (54, 76))	('patients', 'Species', '9606', (19, 27))	('choroid plexus tumours', 'Disease', (54, 76))	('TP53', 'Gene', '7157', (97, 101))	('mutation', 'Var', (102, 110))	('patients', 'Species', '9606', (40, 48))	('TP53', 'Gene', (97, 101))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))
125331	29039119	Other cancers become commoner in older TP53 mutation carriers, such as lung, colorectal and prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('mutation', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('TP53', 'Gene', '7157', (39, 43))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('lung', 'Disease', (71, 75))	('cancers', 'Disease', (6, 13))	('TP53', 'Gene', (39, 43))	('colorectal and prostate cancer', 'Disease', 'MESH:D015179', (77, 107))
125340	29039119	There are several databases with curated information on TP53 variants, including the p53 Mutation in Human Cancer (http://p53.free.fr/) and the IARC TP53 Database (http://p53.iarc.fr).	('Human', 'Species', '9606', (101, 106))	('variants', 'Var', (61, 69))	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', '7157', (149, 153))	('p53', 'Gene', '7157', (122, 125))	('p53', 'Gene', '7157', (85, 88))	('TP53', 'Gene', (56, 60))	('Cancer', 'Disease', (107, 113))	('TP53', 'Gene', (149, 153))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('p53', 'Gene', (85, 88))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('p53', 'Gene', '7157', (171, 174))	('p53', 'Gene', (171, 174))	('p53', 'Gene', (122, 125))
125341	29039119	A recent paper by Bouaoun used the IARC database to provide an update on TP53-inherited variants, including those that should be considered as neutral frequent variants.	('variants', 'Var', (88, 96))	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (73, 77))
125343	29039119	Birch and colleagues' study of 34 families (20 LFS and 14 LFL) showed that individuals with missense mutations in the DNA-binding region had higher overall rates of cancer with significantly higher rates of breast cancer and central nervous system tumours compared to individuals with missense mutations in other parts of the gene or protein-truncating mutations.	('higher', 'PosReg', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('LFL', 'Disease', 'MESH:D016864', (58, 61))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumours', 'Phenotype', 'HP:0002664', (248, 255))	('central nervous system tumours', 'Phenotype', 'HP:0100006', (225, 255))	('central nervous system tumours', 'Disease', (225, 255))	('higher rates', 'PosReg', (191, 203))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Disease', (165, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('missense mutations in', 'Var', (92, 113))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('LFL', 'Disease', (58, 61))	('central nervous system tumours', 'Disease', 'MESH:D016543', (225, 255))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('breast cancer', 'Disease', (207, 220))
125344	29039119	analysed the IARC database (including 1068 individuals from 265 families) and found that missense mutations outside the DNA-binding region are more commonly associated with adrenocortical carcinoma compared to missense mutations in the DNA-binding domain.	('associated', 'Reg', (157, 167))	('missense mutations', 'Var', (89, 107))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (173, 197))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (173, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('adrenocortical carcinoma', 'Disease', (173, 197))
125345	29039119	They also noted that individuals with missense mutations in the DNA-binding domain were more likely to have early onset breast cancer compared to those with missense mutations outside the DNA-binding domain (32 years vs. 42 years) and that mutations leading to a TP53 null phenotype are associated with earlier onset brain tumours.	('brain tumours', 'Disease', 'MESH:D001932', (317, 330))	('brain tumours', 'Phenotype', 'HP:0030692', (317, 330))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('brain tumours', 'Disease', (317, 330))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('missense mutations in', 'Var', (38, 59))	('TP53', 'Gene', '7157', (263, 267))	('tumour', 'Phenotype', 'HP:0002664', (323, 329))	('tumours', 'Phenotype', 'HP:0002664', (323, 330))	('TP53', 'Gene', (263, 267))	('associated', 'Reg', (287, 297))	('mutations', 'Var', (240, 249))
125346	29039119	The option for risk-reducing bilateral mastectomy or breast screening should be considered in women without cancer with a mutation in the TP53 gene.	('women', 'Species', '9606', (94, 99))	('TP53', 'Gene', '7157', (138, 142))	('mutation', 'Var', (122, 130))	('TP53', 'Gene', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
125354	29039119	describe a series of 8 patients with germline TP53 mutations who were treated for breast cancer between 1997 and 2007 from 47 documented Li-Fraumeni families; three underwent conservative breast surgery with post-operative radiotherapy, three had mastectomy and radiotherapy and two had mastectomy with no radiotherapy.	('breast cancer', 'Disease', (82, 95))	('mutations', 'Var', (51, 60))	('Li-Fraumeni', 'Disease', (137, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('patients', 'Species', '9606', (23, 31))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (137, 148))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
125357	29039119	Despite the small sample size, this study does suggest that radiotherapy should be avoided or used with extreme caution in TP53 mutation carriers after very careful consideration of the risks and benefits.	('mutation', 'Var', (128, 136))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
125359	29039119	In this study, there were 32 invasive ductal carcinomas in 30 women with confirmed germline TP53 mutations.	('mutations', 'Var', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('invasive ductal carcinomas', 'Disease', (29, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (29, 55))	('women', 'Species', '9606', (62, 67))
125361	29039119	have also reported that women who are TP53 mutation carriers are more likely to have HER2 amplification and/or overexpression (present in 67% of cases and 25% of controls in this study).	('TP53', 'Gene', (38, 42))	('mutation', 'Var', (43, 51))	('HER2', 'Gene', (85, 89))	('women', 'Species', '9606', (24, 29))	('amplification', 'MPA', (90, 103))	('HER2', 'Gene', '2064', (85, 89))	('overexpression', 'MPA', (111, 125))	('TP53', 'Gene', '7157', (38, 42))
125363	29039119	There is no international consensus about the best surveillance for TP53 mutation carriers.	('mutation', 'Var', (73, 81))	('TP53', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (68, 72))
125365	29039119	for children and adults who carry a TP53 germline mutation.	('germline mutation', 'Var', (41, 58))	('children', 'Species', '9606', (4, 12))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))
125367	29039119	Neonatal testing for the c.1010G > A, p.(Arg337His) mutation and subsequent surveillance for adrenocortical tumours in mutation carriers has been evaluated in a large, non-randomised clinical trial in Southern Brazil.	('p.(Arg337His)', 'Mutation', 'rs121912664', (38, 51))	('p.(Arg337His', 'Var', (38, 50))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('c.1010G > A', 'Var', (25, 36))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('c.1010G > A', 'Mutation', 'rs786202288', (25, 36))	('adrenocortical tumours', 'Disease', 'MESH:D000306', (93, 115))	('adrenocortical tumours', 'Disease', (93, 115))
125370	29039119	The UK SIGNIFY study investigated the role of one-off whole body non-contrast MRI screening in asymptomatic TP53 mutation carriers.	('TP53', 'Gene', (108, 112))	('mutation', 'Var', (113, 121))	('TP53', 'Gene', '7157', (108, 112))
125371	29039119	Four malignancies were diagnosed among 44 TP53 mutation carriers and none in matched controls.	('diagnosed', 'Reg', (23, 32))	('TP53', 'Gene', '7157', (42, 46))	('malignancies', 'Disease', (5, 17))	('mutation', 'Var', (47, 55))	('TP53', 'Gene', (42, 46))	('malignancies', 'Disease', 'MESH:D009369', (5, 17))
125374	29039119	It is recruiting individuals with TP53 mutations (age 5-71 years).	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))
125377	29039119	Based on the observation that metformin has been associated with reduced cancer risk in several epidemiological studies, a pilot study for chemoprevention using metformin has been commenced which assesses the safety and tolerability of the drug over 14 weeks, measuring IGF-1, insulin and IGFBP3 levels in blood at baseline, and weeks 0 and 8.	('cancer', 'Disease', (73, 79))	('metformin', 'Var', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('reduced', 'NegReg', (65, 72))	('insulin', 'Gene', (277, 284))	('IGFBP3', 'Gene', (289, 295))	('metformin', 'Chemical', 'MESH:D008687', (161, 170))	('metformin', 'Chemical', 'MESH:D008687', (30, 39))	('insulin', 'Gene', '3630', (277, 284))	('IGF-1', 'Gene', (270, 275))	('IGF-1', 'Gene', '3479', (270, 275))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('IGFBP3', 'Gene', '3486', (289, 295))
125378	29039119	As the optimal screening for other cancers in TP53 mutation carriers remains unclear, screening should ideally be undertaken as part of clinical trial.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
125379	29039119	A fifty-year old unaffected woman with no family history has a TP53 pathogenic variant detected on panel testing.	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('woman', 'Species', '9606', (28, 33))	('pathogenic', 'Reg', (68, 78))	('variant', 'Var', (79, 86))
125383	29039119	Finding a germline TP53 mutation in a woman with breast cancer has significant clinical implications for the patient and her family.	('patient', 'Species', '9606', (109, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('TP53', 'Gene', '7157', (19, 23))	('breast cancer', 'Disease', (49, 62))	('mutation', 'Var', (24, 32))	('TP53', 'Gene', (19, 23))	('woman', 'Species', '9606', (38, 43))
125446	25767716	PD-L1 positivity in either tumor cell membrane or TIMC was not significantly associated with higher stage at diagnosis, higher tumor grade, excessive hormone secretion, or OS.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('OS', 'Chemical', '-', (172, 174))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (27, 32))	('positivity', 'Var', (6, 16))	('excessive hormone secretion', 'MPA', (140, 167))	('PD-L1', 'Gene', (0, 5))	('TIMC', 'Chemical', '-', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('associated', 'Reg', (77, 87))
125456	25767716	Patients who were treated with M/EDP had a significantly longer progression-free survival (PFS) compared with those who received SM (5.0 vs 2.1 months).	('longer', 'PosReg', (57, 63))	('M/EDP', 'Chemical', '-', (31, 36))	('Patients', 'Species', '9606', (0, 8))	('M/EDP', 'Var', (31, 36))	('progression-free survival', 'CPA', (64, 89))	('SM', 'Chemical', 'MESH:D012493', (129, 131))
125461	25767716	Immune checkpoints, like programmed death-1 (PD-1) and its ligand PD-L1, have been described as key regulators of T cell responses, and blocking the PD-1/PD-L1 axis using monoclonal antibodies has resulted in promising results in different malignancies.	('PD-1', 'Gene', (45, 49))	('malignancies', 'Disease', 'MESH:D009369', (240, 252))	('blocking', 'Var', (136, 144))	('PD-1', 'Gene', '5133', (45, 49))	('malignancies', 'Disease', (240, 252))	('programmed death-1', 'Gene', '5133', (25, 43))	('PD-1', 'Gene', (149, 153))	('programmed death-1', 'Gene', (25, 43))	('PD-1', 'Gene', '5133', (149, 153))
125483	25767716	In addition, few studies have established histological or molecular markers, such as Ki67 index or TP53 mutations, as predictors of poor prognosis and its value still needs to be confirmed.	('TP53', 'Gene', '7157', (99, 103))	('TP53', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))
125496	25767716	Preliminary results from a phase I study of an anti-PD-L1 inhibitor (MPDL3280A) in patients with advanced urothelial carcinoma showed response rates of 52% in patients with PD-L1 positive in immune cells vs. 14% in PD-L1 negative patients.	('PD-L1', 'Gene', (173, 178))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (106, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('positive', 'Var', (179, 187))	('patients', 'Species', '9606', (230, 238))	('urothelial carcinoma', 'Disease', (106, 126))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (159, 167))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (69, 78))
125545	22421721	Inactivating mutations at the 17p13 locus, including the TP53 tumor suppressor gene, and alterations of the 11p15 locus, leading to IGF-II overexpression is frequently observed.	('overexpression', 'PosReg', (139, 153))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('17p13', 'Gene', (30, 35))	('Inactivating mutations', 'Var', (0, 22))	('IGF-II', 'Gene', (132, 138))	('p15', 'Gene', (110, 113))	('IGF-II', 'Gene', '3481', (132, 138))	('p15', 'Gene', '1030', (110, 113))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('alterations', 'Var', (89, 100))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
125577	33810219	Around 40% of pheochromocytomas/paragangliomas (PPGL) harbor germline mutations, representing the highest heritability among human tumors.	('paraganglioma', 'Phenotype', 'HP:0002668', (32, 45))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (14, 30))	('germline mutations', 'Var', (61, 79))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('human', 'Species', '9606', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('pheochromocytomas/paragangliomas', 'Disease', (14, 46))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('PPGL', 'Chemical', '-', (48, 52))	('paragangliomas', 'Phenotype', 'HP:0002668', (32, 46))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (14, 31))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (14, 46))
125579	33810219	In this review, we present the potential relevance of non-coding RNA molecules including microRNAs, long non-coding RNAs and circular RNAs in PPGL pathogenesis and diagnosis.	('long non-coding RNAs', 'Var', (100, 120))	('PPGL', 'Disease', (142, 146))	('PPGL', 'Chemical', '-', (142, 146))
125584	33810219	Non-coding RNA molecules encompassing microRNAs, long non-coding RNAs, and circular RNAs have been implicated in the pathogenesis of various tumors, and were also proposed as valuable diagnostic, prognostic factors, and even potential treatment targets.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('implicated', 'Reg', (99, 109))	('long non-coding RNAs', 'Var', (49, 69))
125586	33810219	Non-coding RNA molecules encompassing microRNAs, long non-coding RNAs, and circular RNAs have been implicated in the pathogenesis of various tumors, and were also proposed as valuable diagnostic and prognostic factors, and even potential therapeutic targets.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('implicated', 'Reg', (99, 109))	('long non-coding RNAs', 'Var', (49, 69))
125587	33810219	Given the fact that the pathogenesis of tumors including pheochromocytomas/paragangliomas (PPGL) is partly linked to epigenetic dysregulation, it is reasonable to investigate their epigenetic expression profiles.	('pheochromocytomas/paragangliomas', 'Disease', (57, 89))	('paragangliomas', 'Phenotype', 'HP:0002668', (75, 89))	('paraganglioma', 'Phenotype', 'HP:0002668', (75, 88))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('linked', 'Reg', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (57, 89))	('PPGL', 'Chemical', '-', (91, 95))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (57, 73))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (57, 74))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('epigenetic', 'Var', (117, 127))
125592	33810219	This proportion of germline mutations has the highest degree of heritability among human tumors.	('germline mutations', 'Var', (19, 37))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('human', 'Species', '9606', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
125597	33810219	On the other side up to 50% of patients with metastatic PPGL have specific germline mutations.	('PPGL', 'Gene', (56, 60))	('patients', 'Species', '9606', (31, 39))	('germline', 'Var', (75, 83))	('PPGL', 'Chemical', '-', (56, 60))
125598	33810219	The risk of metastasis is particularly high in individuals harboring germline SDHB mutations.	('mutations', 'Var', (83, 92))	('SDHB', 'Gene', '6390', (78, 82))	('metastasis', 'CPA', (12, 22))	('SDHB', 'Gene', (78, 82))	('germline', 'Var', (69, 77))	('high', 'Reg', (39, 43))
125599	33810219	PPGL susceptibility can be associated with mutations either in tumor suppressor genes (e.g., VHL, NF1, SDHB) or in proto-oncogenes (e.g., RET, HRAS).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('SDHB', 'Gene', (103, 107))	('RET', 'Gene', '5979', (138, 141))	('susceptibility', 'Reg', (5, 19))	('VHL', 'Gene', '7428', (93, 96))	('NF1', 'Gene', (98, 101))	('mutations', 'Var', (43, 52))	('PPGL', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('SDHB', 'Gene', '6390', (103, 107))	('NF1', 'Gene', '4763', (98, 101))	('HRAS', 'Gene', '3265', (143, 147))	('PPGL', 'Chemical', '-', (0, 4))	('RET', 'Gene', (138, 141))	('VHL', 'Gene', (93, 96))	('HRAS', 'Gene', (143, 147))
125604	33810219	The cortical admixture type was found to be correlated with MAX (MYC associated factor X) mutations, which is also included as one of the susceptibility genes for hereditary PPGL.	('mutations', 'Var', (90, 99))	('correlated', 'Reg', (44, 54))	('PPGL', 'Chemical', '-', (174, 178))	('MYC associated factor X', 'Gene', '4149', (65, 88))	('MAX', 'Gene', '4149', (60, 63))	('MAX', 'Gene', (60, 63))	('MYC associated factor X', 'Gene', (65, 88))
125630	33810219	Novel treatment options including VEGF (vascular endothelial growth factor) and tyrosine kinase inhibitors (e.g., axitinib, dovitinib, lenvatinib, sunitinib) exist for patients with SDHA, SDHB, SDHD, RET, VHL, and FH mutations in renal cell carcinoma and PPGL; furthermore, immunotherapies targeting PD-L1 (programmed death-ligand 1) checkpoint protein (e.g., pembrolizumab, ipilimumab, nivolumab) are currently under clinical investigation.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('VHL', 'Gene', (205, 208))	('vascular endothelial growth factor', 'Gene', '7422', (40, 74))	('SDHB', 'Gene', '6390', (188, 192))	('SDHD', 'Gene', (194, 198))	('RET', 'Gene', '5979', (200, 203))	('PPGL', 'Chemical', '-', (255, 259))	('PPGL', 'Gene', (255, 259))	('vascular endothelial growth factor', 'Gene', (40, 74))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (230, 250))	('VHL', 'Gene', '7428', (205, 208))	('VEGF', 'Gene', '7422', (34, 38))	('SDHB', 'Gene', (188, 192))	('PD-L1', 'Gene', (300, 305))	('VEGF', 'Gene', (34, 38))	('RET', 'Gene', (200, 203))	('PD-L1', 'Gene', '29126', (300, 305))	('programmed death-ligand 1', 'Gene', (307, 332))	('SDHA', 'Gene', (182, 186))	('renal cell carcinoma', 'Disease', (230, 250))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (230, 250))	('SDHA', 'Gene', '6389', (182, 186))	('SDHD', 'Gene', '6392', (194, 198))	('programmed death-ligand 1', 'Gene', '29126', (307, 332))	('patients', 'Species', '9606', (168, 176))	('mutations', 'Var', (217, 226))
125631	33810219	Poly ADP-ribose polymerase (PARP) inhibitors (e.g., olaparib) represent another perspective in patients harboring SDHx mutations due to elevated levels of succinate and NAD+ inhibiting homologous recombination-based DNA repair mechanism which is known to be corrected by PARP, thus keeping aberrant cells alive.	('Poly ADP-ribose polymerase', 'Gene', (0, 26))	('Poly ADP-ribose polymerase', 'Gene', '142', (0, 26))	('succinate', 'Chemical', 'MESH:D019802', (155, 164))	('SDH', 'Gene', '6390', (114, 117))	('levels', 'MPA', (145, 151))	('inhibiting', 'NegReg', (174, 184))	('patients', 'Species', '9606', (95, 103))	('PARP', 'Gene', (271, 275))	('PARP', 'Gene', (28, 32))	('olaparib', 'Chemical', 'MESH:C531550', (52, 60))	('elevated', 'PosReg', (136, 144))	('NAD+', 'MPA', (169, 173))	('elevated levels of succinate', 'Phenotype', 'HP:0020149', (136, 164))	('SDH', 'Gene', (114, 117))	('PARP', 'Gene', '142', (271, 275))	('NAD+', 'Chemical', 'MESH:D009243', (169, 173))	('mutations', 'Var', (119, 128))	('PARP', 'Gene', '142', (28, 32))
125632	33810219	Furthermore, there are two kinase signaling pathways (PI3K-Akt-mTOR and Ras-Raf-Erk) affected by mutations of RET, MAX, NF1, and TMEM127, which can be inhibited by kinase signaling inhibitors (e.g., the mTOR inhibitor everolimus).	('mutations', 'Var', (97, 106))	('everolimus', 'Chemical', 'MESH:D000068338', (218, 228))	('NF1', 'Gene', (120, 123))	('MAX', 'Gene', (115, 118))	('TMEM127', 'Gene', '55654', (129, 136))	('mTOR', 'Gene', '2475', (203, 207))	('RET', 'Gene', '5979', (110, 113))	('mTOR', 'Gene', (63, 67))	('Akt', 'Gene', (59, 62))	('Erk', 'Gene', (80, 83))	('affected', 'Reg', (85, 93))	('MAX', 'Gene', '4149', (115, 118))	('Akt', 'Gene', '207', (59, 62))	('Erk', 'Gene', '5594', (80, 83))	('RET', 'Gene', (110, 113))	('mTOR', 'Gene', '2475', (63, 67))	('Raf', 'Gene', '114486', (76, 79))	('TMEM127', 'Gene', (129, 136))	('NF1', 'Gene', '4763', (120, 123))	('mTOR', 'Gene', (203, 207))	('Raf', 'Gene', (76, 79))
125639	33810219	Non-coding RNA molecules have been shown to be implicated in the pathogenesis of tumors.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('Non-coding', 'Var', (0, 10))	('RNA molecules', 'Protein', (11, 24))	('implicated', 'Reg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
125651	33810219	To date, only one study has investigated the expression pattern of circular RNAs in PPGL, suggesting its role in histone methylation.	('circular RNAs', 'Var', (67, 80))	('PPGL', 'Chemical', '-', (84, 88))	('PPGL', 'Gene', (84, 88))
125659	33810219	Epigenetic alterations can precede tumor formation (hence the prognostic value) and play major role in cell-to-cell communication (hence the therapeutic value) and by analyzing differential expression profiles, protein-protein interactions, gene set enrichment, dimensionality reduction, and tissue composition, it was elucidated that normal tissues adjacent to the tumor represent a unique in-between state concerning the molecular landscape.	('tumor', 'Disease', (366, 371))	('Epigenetic alterations', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('rat', 'Species', '10116', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))
125664	33810219	LncRNA BSN-AS2 and C9orf147 are future candidates to investigate their roles in tumorigenesis as their overexpression was associated with poor prognosis; moreover, the underexpression of C9orf147 was associated with good prognosis (Table 1).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('BSN-AS2', 'Gene', (7, 14))	('C9orf147', 'Gene', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('underexpression', 'Var', (168, 183))	('tumor', 'Disease', (80, 85))	('C9orf147', 'Gene', (19, 27))	('C9orf147', 'Gene', '100133204', (187, 195))	('BSN-AS2', 'Gene', '100132677', (7, 14))	('overexpression', 'PosReg', (103, 117))	('C9orf147', 'Gene', '100133204', (19, 27))
125667	33810219	PTPRJ underexpression was found to be correlated with good prognosis.	('PTPRJ', 'Gene', (0, 5))	('PTPRJ', 'Gene', '5795', (0, 5))	('underexpression', 'Var', (6, 21))
125671	33810219	In the SDHx subtype, a putative lncRNA BC063866 was found to be able to distinguish between metastatic tumors and tumors that remain indolent.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('SDH', 'Gene', (7, 10))	('tumors', 'Disease', (103, 109))	('BC063866', 'Var', (39, 47))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('SDH', 'Gene', '6390', (7, 10))
125673	33810219	Furthermore, lncRNA BC063866 was found to be an independent risk factor for poor outcome in SDHx mutants, although this marker should be replicated in large prospective cohorts, as well.	('SDH', 'Gene', '6390', (92, 95))	('SDH', 'Gene', (92, 95))	('mutants', 'Var', (97, 104))
125677	33810219	In contrast to the previous study, this bioinformatical approach revealed underexpressed PTPRJ to be related to unfavorable prognosis.	('PTPRJ', 'Gene', (89, 94))	('PTPRJ', 'Gene', '5795', (89, 94))	('underexpressed', 'Var', (74, 88))	('related', 'Reg', (101, 108))
125681	33810219	It is also noteworthy that miR-483-5p, miR-195, and miR-34a were shown to be differentially expressed in adrenocortical cancer, as well.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('miR-483-5p', 'Chemical', '-', (27, 37))	('miR-34a', 'Gene', '407040', (52, 59))	('miR-34a', 'Gene', (52, 59))	('adrenocortical cancer', 'Disease', (105, 126))	('miR-483-5p', 'Var', (27, 37))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (105, 126))	('miR-195', 'Gene', (39, 46))	('miR-195', 'Gene', '406971', (39, 46))
125686	33810219	Upregulated expression of miR-1225-3p has been found in sporadic recurrent pheochromocytomas in comparison to benign pheochromocytomas that raised its potential as a marker of PPGL recurrence.	('miR-1225-3p', 'Var', (26, 37))	('pheochromocytomas', 'Disease', (75, 92))	('benign pheochromocytomas', 'Disease', 'MESH:D010673', (110, 134))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (117, 133))	('pheochromocytomas', 'Disease', 'MESH:D010673', (117, 134))	('pheochromocytomas', 'Disease', (117, 134))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (75, 92))	('benign pheochromocytomas', 'Disease', (110, 134))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (75, 91))	('expression', 'MPA', (12, 22))	('Upregulated', 'PosReg', (0, 11))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (117, 134))	('pheochromocytomas', 'Disease', 'MESH:D010673', (75, 92))	('PPGL', 'Chemical', '-', (176, 180))
125689	33810219	The aforementioned recent ceRNA study also shed light on miR-148b-3p and miR-338-3p in respect of favorable prognosis and overall survival in PPGL.	('PPGL', 'Chemical', '-', (142, 146))	('miR-338-3p', 'Var', (73, 83))	('PPGL', 'Disease', (142, 146))	('miR-148b-3p', 'Var', (57, 68))
125692	33810219	Significantly altered expression of miR-101, miR-183, and miR-483-5p was revealed in metastatic pheochromocytoma tissues versus benign ones and validated by RT-qPCR.	('miR-483-5p', 'Chemical', '-', (58, 68))	('miR-483-5p', 'Var', (58, 68))	('altered', 'Reg', (14, 21))	('pheochromocytoma', 'Disease', 'MESH:D010673', (96, 112))	('miR-101', 'Chemical', '-', (36, 43))	('pheochromocytoma', 'Disease', (96, 112))	('expression', 'MPA', (22, 32))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (96, 112))	('miR-183', 'Gene', '406959', (45, 52))	('miR-183', 'Gene', (45, 52))	('miR-101', 'Gene', (36, 43))
125693	33810219	Among them, miR-101 and miR-183 significantly differed in SDHB mutant vs. wild type samples and interestingly, miR-483-5p had significantly lower expression in SDHB mutant malignant pheochromocytoma compared to all other malignant pheochromocytomas.	('SDHB', 'Gene', (58, 62))	('lower', 'NegReg', (140, 145))	('SDHB', 'Gene', (160, 164))	('miR-101', 'Chemical', '-', (12, 19))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (172, 198))	('malignant pheochromocytomas', 'Disease', 'MESH:D010673', (221, 248))	('expression', 'MPA', (146, 156))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (231, 248))	('miR-483-5p', 'Chemical', '-', (111, 121))	('malignant pheochromocytoma', 'Disease', (172, 198))	('differed', 'Reg', (46, 54))	('miR-183', 'Gene', '406959', (24, 31))	('mutant', 'Var', (63, 69))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (221, 247))	('SDHB', 'Gene', '6390', (58, 62))	('malignant pheochromocytomas', 'Disease', (221, 248))	('miR-183', 'Gene', (24, 31))	('SDHB', 'Gene', '6390', (160, 164))	('mutant', 'Var', (165, 171))	('miR-483-5p', 'Var', (111, 121))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (231, 247))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (182, 198))
125694	33810219	Furthermore, miR-101, miR-183, and miR-483-5p were measurable from serum samples, as well.	('miR-483-5p', 'Chemical', '-', (35, 45))	('miR-183', 'Gene', '406959', (22, 29))	('miR-183', 'Gene', (22, 29))	('miR-483-5p', 'Var', (35, 45))	('miR-101', 'Chemical', '-', (13, 20))	('miR-101', 'Var', (13, 20))
125695	33810219	In practice, this might raise the possibility that a patient without SDHB mutation might be screened for miR expression profile changes to assess the risk of malignancy.	('SDHB', 'Gene', (69, 73))	('mutation', 'Var', (74, 82))	('malignancy', 'Disease', (158, 168))	('miR expression profile', 'MPA', (105, 127))	('SDHB', 'Gene', '6390', (69, 73))	('malignancy', 'Disease', 'MESH:D009369', (158, 168))	('changes', 'Reg', (128, 135))	('patient', 'Species', '9606', (53, 60))
125696	33810219	In another study investigating snap-frozen samples, significantly higher expression of miR-483-5p in metastatic PPGL was found, as well, validated by RT-qPCR.	('PPGL', 'Chemical', '-', (112, 116))	('miR-483-5p', 'Chemical', '-', (87, 97))	('expression', 'MPA', (73, 83))	('higher', 'PosReg', (66, 72))	('miR-483-5p', 'Var', (87, 97))
125702	33810219	Moreover, miR-483-5p is a marker of worse disease-free survival in metastatic pheochromocytoma.	('pheochromocytoma', 'Disease', (78, 94))	('miR-483-5p', 'Chemical', '-', (10, 20))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('miR-483-5p', 'Var', (10, 20))	('pheochromocytoma', 'Disease', 'MESH:D010673', (78, 94))
125704	33810219	When PPGL was compared with normal adrenal medullary tissues, overexpressed miR-210 was significantly associated with SDHx or VHL mutant genotypes known to exhibit the pseudohypoxia phenotype.	('VHL', 'Gene', '7428', (126, 129))	('miR-210', 'Gene', (76, 83))	('overexpressed', 'PosReg', (62, 75))	('hypoxia', 'Disease', (174, 181))	('hypoxia', 'Disease', 'MESH:D000860', (174, 181))	('PPGL', 'Chemical', '-', (5, 9))	('SDH', 'Gene', '6390', (118, 121))	('miR-210', 'Gene', '406992', (76, 83))	('associated', 'Interaction', (102, 112))	('VHL', 'Gene', (126, 129))	('SDH', 'Gene', (118, 121))	('mutant', 'Var', (130, 136))
125705	33810219	The aforementioned miR-96 and miR-183 were described to contribute to the differentiation block of cells of SDHB mutated tumors.	('SDHB', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('miR-183', 'Gene', '406959', (30, 37))	('miR-183', 'Gene', (30, 37))	('tumors', 'Disease', (121, 127))	('miR-96', 'Gene', '407053', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('miR-96', 'Gene', (19, 25))	('differentiation block of cells', 'CPA', (74, 104))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mutated', 'Var', (113, 120))	('SDHB', 'Gene', '6390', (108, 112))	('contribute', 'Reg', (56, 66))
125711	33810219	Robust upregulation was identified with miR-96 especially in SDHB mutants.	('upregulation', 'PosReg', (7, 19))	('mutants', 'Var', (66, 73))	('SDHB', 'Gene', '6390', (61, 65))	('miR-96', 'Gene', '407053', (40, 46))	('miR-96', 'Gene', (40, 46))	('SDHB', 'Gene', (61, 65))
125718	33810219	Similar to UCA1, SOX6 also acts as a provoking factor in hypoxic injuries and inhibition of SOX6 leads to an ease of hypoxic injury (Figure 3).	('SOX6', 'Gene', (17, 21))	('inhibition', 'Var', (78, 88))	('hypoxic injuries', 'Disease', 'MESH:D002534', (57, 73))	('hypoxic injury', 'Disease', (117, 131))	('SOX6', 'Gene', '55553', (92, 96))	('hypoxic injury', 'Disease', 'MESH:D002534', (117, 131))	('SOX6', 'Gene', (92, 96))	('SOX6', 'Gene', '55553', (17, 21))	('ease', 'PosReg', (109, 113))	('UCA1', 'Gene', '652995', (11, 15))	('UCA1', 'Gene', (11, 15))	('hypoxic injuries', 'Disease', (57, 73))
125722	33810219	These include miR-483-5p, miR-195, and miR-34a.	('miR-483-5p', 'Chemical', '-', (14, 24))	('miR-483-5p', 'Var', (14, 24))	('miR-34a', 'Gene', '407040', (39, 46))	('miR-34a', 'Gene', (39, 46))	('miR-195', 'Gene', (26, 33))	('miR-195', 'Gene', '406971', (26, 33))
125731	33810219	The emerging role of non-coding RNA in the setting of clinical evaluation and therapeutic approaches of clinically challenging tumors is an attractive candidate for precision medicine.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (127, 133))	('non-coding RNA', 'Var', (21, 35))	('tumors', 'Disease', 'MESH:D009369', (127, 133))
125749	31814847	However, mitotane is an adjuvant therapy for patients with low to moderate risk for ACC recurrence, and its efficacy is ultimately limited by its high lipophilicity, poor pharmacokinetic properties, and dose-limiting toxicities.	('ACC', 'Disease', 'MESH:D018268', (84, 87))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('toxicities', 'Disease', 'MESH:D064420', (217, 227))	('ACC', 'Disease', (84, 87))	('patients', 'Species', '9606', (45, 53))	('mitotane', 'Var', (9, 17))	('mitotane', 'Chemical', 'MESH:D008939', (9, 17))	('lipophilicity', 'MPA', (151, 164))	('toxicities', 'Disease', (217, 227))
125798	31814847	The mRNA expression of the ER stress promoter GRP78 was significantly decreased in the 400 microM TUDCA group.	('GRP78', 'Gene', (46, 51))	('decreased', 'NegReg', (70, 79))	('GRP78', 'Gene', '3309', (46, 51))	('mRNA expression', 'MPA', (4, 19))	('TUDCA', 'Chemical', 'MESH:C031655', (98, 103))	('400 microM', 'Var', (87, 97))
125800	31814847	In addition, the expression of ER-related factors was downregulated with TUDCA treatment; PERK and ATF6 mRNA and protein expression levels were significantly reduced in the 400 microM TUDCA group compared with those in the 0 microM TUDCA group.	('ATF6', 'Gene', (99, 103))	('400 microM TUDCA', 'Var', (173, 189))	('PERK', 'Gene', (90, 94))	('expression', 'MPA', (17, 27))	('TUDCA', 'Chemical', 'MESH:C031655', (184, 189))	('TUDCA', 'Chemical', 'MESH:C031655', (73, 78))	('ATF6', 'Gene', '22926', (99, 103))	('PERK', 'Gene', '9451', (90, 94))	('TUDCA', 'Chemical', 'MESH:C031655', (232, 237))	('TUDCA', 'Var', (184, 189))	('reduced', 'NegReg', (158, 165))
125802	31814847	There were no significant differences in the mRNA levels of ER stress-related factors between the 100 microM TUDCA group and the 0 microM TUDCA group.	('mRNA levels', 'MPA', (45, 56))	('TUDCA', 'Chemical', 'MESH:C031655', (109, 114))	('TUDCA', 'Chemical', 'MESH:C031655', (138, 143))	('100 microM', 'Var', (98, 108))
125827	31814847	A study by B'Chir et al showed that the LC3-II/LC3-I ratio was increased after knockout of CHOP.	('LC3', 'Gene', '84557', (47, 50))	('LC3', 'Gene', (47, 50))	('increased', 'PosReg', (63, 72))	('CHOP', 'Gene', '1649', (91, 95))	('CHOP', 'Gene', (91, 95))	('LC3', 'Gene', '84557', (40, 43))	('knockout', 'Var', (79, 87))	('LC3', 'Gene', (40, 43))
125833	31814847	These results provide evidence demonstrating that TUDCA alleviated ER stress and induced autophagy in ACC cells, thereby inhibiting the apoptosis of ACC cells.	('ACC', 'Disease', (149, 152))	('alleviated', 'NegReg', (56, 66))	('ACC', 'Disease', 'MESH:D018268', (102, 105))	('TUDCA', 'Var', (50, 55))	('ER stress', 'MPA', (67, 76))	('induced', 'Reg', (81, 88))	('ACC', 'Disease', 'MESH:D018268', (149, 152))	('ACC', 'Phenotype', 'HP:0006744', (102, 105))	('inhibiting', 'NegReg', (121, 131))	('ACC', 'Disease', (102, 105))	('autophagy', 'CPA', (89, 98))	('TUDCA', 'Chemical', 'MESH:C031655', (50, 55))	('ACC', 'Phenotype', 'HP:0006744', (149, 152))
125847	30557981	Ectopic adrenocortical adenoma is difficult to diagnose due to its low incidence, and the ectopic rests in renal hilum could be misdiagnosed as renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (144, 164))	('adrenocortical adenoma', 'Phenotype', 'HP:0008256', (8, 30))	('Ectopic adrenocortical adenoma', 'Disease', 'MESH:D018246', (0, 30))	('ectopic', 'Var', (90, 97))	('renal cell carcinoma', 'Disease', (144, 164))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (144, 164))	('Ectopic adrenocortical adenoma', 'Disease', (0, 30))
125872	30557981	When hyperplastic change happen to the adrenal rests and subsequently result in over-production of cortisol, they are of clinical importance.	('cortisol', 'Chemical', 'MESH:D006854', (99, 107))	('result in', 'Reg', (70, 79))	('hyperplastic', 'Var', (5, 17))	('over-production of cortisol', 'MPA', (80, 107))
125873	30557981	Excess plasma cortisol can lead to Cushing's syndrome, and clinical symptoms involve amenorrhea, obesity, easy bruising.	('Excess', 'Var', (0, 6))	('obesity', 'Disease', (97, 104))	('amenorrhea', 'Disease', 'MESH:D000568', (85, 95))	('Excess plasma cortisol', 'Phenotype', 'HP:0003118', (0, 22))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (35, 53))	('obesity', 'Phenotype', 'HP:0001513', (97, 104))	('amenorrhea', 'Phenotype', 'HP:0000141', (85, 95))	('cortisol', 'Chemical', 'MESH:D006854', (14, 22))	('lead to', 'Reg', (27, 34))	("Cushing's syndrome", 'Disease', (35, 53))	('bruising', 'Disease', (111, 119))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (35, 53))	('amenorrhea', 'Disease', (85, 95))	('bruising', 'Disease', 'MESH:D003288', (111, 119))	('easy bruising', 'Phenotype', 'HP:0000978', (106, 119))	('obesity', 'Disease', 'MESH:D009765', (97, 104))
125911	30254608	The discovery of the third member, ERRgamma (51.3kDa, 45a.a.	('51.3kDa', 'Var', (45, 52))	('ERRgamma', 'Gene', (35, 43))	('ERRgamma', 'Gene', '2104', (35, 43))
125912	30254608	In addition, several splice variants of human ERRs have been identified although their physiological role is still to be discovered.	('ERR', 'Gene', '6541', (46, 49))	('ERR', 'Gene', (46, 49))	('human', 'Species', '9606', (40, 45))	('splice variants', 'Var', (21, 36))
125915	30254608	The AF-1 domain of all three ERR isoforms contains conserved motifs that allow the control of the transcriptional activity by post-translational modification such as phosphorylation and sumoylation.	('phosphorylation', 'Var', (166, 181))	('ERR', 'Gene', (29, 32))	('AF-1', 'Gene', '3460', (4, 8))	('sumoylation', 'Var', (186, 197))	('ERR', 'Gene', '6541', (29, 32))	('post-translational modification', 'MPA', (126, 157))	('AF-1', 'Gene', (4, 8))	('transcriptional activity', 'MPA', (98, 122))
125916	30254608	In particular, phosphorylation-dependent sumoylation of ERRalpha within the NH-terminal domain of ERRalpha and ERRgamma negatively affects their transcriptional activity without altering DNA binding with cofactors.	('phosphorylation-dependent', 'Var', (15, 40))	('ERRalpha', 'Gene', (98, 106))	('ERRgamma', 'Gene', (111, 119))	('transcriptional activity', 'MPA', (145, 169))	('sumoylation', 'MPA', (41, 52))	('ERRgamma', 'Gene', '2104', (111, 119))	('negatively', 'NegReg', (120, 130))	('affects', 'Reg', (131, 138))
125924	30254608	In particular, the analysis of each individual domain reveals that the DBDs of ERRalpha and ERalpha are 70% homologues, but their LBD is only 36% similar, explaining the reasons for the absence of ERRalpha response to ER ligands.	('ERRalpha', 'Gene', (79, 87))	('ERalpha', 'Gene', (92, 99))	('ERalpha', 'Gene', '2099', (92, 99))	('DBDs', 'Var', (71, 75))
125925	30254608	In fact, ERRalpha increases lipid absorption, beta-oxidation, tricarboxylic acid cycle, oxidative phosphorylation, and mitochondrial biogenesis and functions.	('lipid', 'Chemical', 'MESH:D008055', (28, 33))	('functions', 'MPA', (148, 157))	('increases', 'PosReg', (18, 27))	('ERRalpha', 'Var', (9, 17))	('beta-oxidation', 'MPA', (46, 60))	('oxidative phosphorylation', 'MPA', (88, 113))	('lipid absorption', 'MPA', (28, 44))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (62, 80))	('mitochondrial biogenesis', 'MPA', (119, 143))	('tricarboxylic acid cycle', 'MPA', (62, 86))
125932	30254608	The constitutive activity of ERRalpha is structurally related to the presence of a phenylalanine residue (Phe328 on helix H3) within its LBD which maintains a conformational arrangement suitable for the interaction with different cofactors.	('constitutive activity', 'MPA', (4, 25))	('phenylalanine', 'Chemical', 'MESH:D010649', (83, 96))	('interaction', 'Interaction', (203, 214))	('Phe328', 'Chemical', '-', (106, 112))	('Phe328', 'Var', (106, 112))	('ERRalpha', 'Gene', (29, 37))
125951	30254608	In fact, ablation of either ERRalpha or beta-catenin expression decreases the migratory ability of different types of cancer cells.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('ablation', 'Var', (9, 17))	('ERRalpha', 'Protein', (28, 36))	('rat', 'Species', '10116', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('beta-catenin', 'Gene', (40, 52))	('beta-catenin', 'Gene', '1499', (40, 52))	('decreases', 'NegReg', (64, 73))
125968	30254608	A further confirmation was obtained by the authors with circular dichroism (CD) spectroscopy tests, where cholesterol, DES and the inverse agonist XCT790, all induced a conformational change in ERRalpha-LBD, while estradiol did not.	('cholesterol', 'Var', (106, 117))	('ERRalpha-LBD', 'Gene', (194, 206))	('circular dichroism', 'Disease', (56, 74))	('cholesterol', 'Chemical', 'MESH:D002784', (106, 117))	('XCT', 'Gene', '23657', (147, 150))	('DES', 'Chemical', 'MESH:D004054', (119, 122))	('estradiol', 'Chemical', 'MESH:D004958', (214, 223))	('circular dichroism', 'Disease', 'None', (56, 74))	('conformational change', 'MPA', (169, 190))	('CD', 'Disease', 'MESH:D006223', (76, 78))	('induced', 'Reg', (159, 166))	('XCT', 'Gene', (147, 150))
125997	30254608	The inhibition of mevalonate pathway by N-BPs results in the accumulation of isopentenyl pyrophosphate (IPP), which is then converted to a cytotoxic ATP analog called ApppI.	('ApppI', 'Chemical', '-', (167, 172))	('isopentenyl pyrophosphate', 'MPA', (77, 102))	('mevalonate', 'Chemical', 'MESH:D008798', (18, 28))	('isopentenyl pyrophosphate', 'Chemical', 'MESH:C004809', (77, 102))	('N-BPs', 'Chemical', '-', (40, 45))	('mevalonate pathway', 'Pathway', (18, 36))	('IPP', 'Chemical', 'MESH:C004809', (104, 107))	('ATP', 'Chemical', 'MESH:D000255', (149, 152))	('N-BPs', 'Var', (40, 45))	('inhibition', 'NegReg', (4, 14))	('accumulation', 'PosReg', (61, 73))
126004	30254608	Consequently, PCSK9 reduces the expression of LDL receptors on the cell membrane thereby decreasing the clearance of LDL-cholesterol.	('LDL receptor', 'Gene', '3949', (46, 58))	('reduces', 'NegReg', (20, 27))	('decreasing', 'NegReg', (89, 99))	('LDL receptor', 'Gene', (46, 58))	('PCSK9', 'Var', (14, 19))	('cholesterol', 'Chemical', 'MESH:D002784', (121, 132))	('clearance of LDL-cholesterol', 'MPA', (104, 132))	('expression', 'MPA', (32, 42))
126009	30254608	By contrast, PCSK9-KO and wild-type mice fed with a high cholesterol diet showed an increased number of liver metastasis, suggesting a prominent role of cholesterol in tumor-microenvironment interaction.	('tumor', 'Disease', (168, 173))	('liver metastasis', 'Disease', 'MESH:D009362', (104, 120))	('liver metastasis', 'Disease', (104, 120))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('PCSK9-KO', 'Var', (13, 21))	('high cholesterol', 'Phenotype', 'HP:0003124', (52, 68))	('mice', 'Species', '10090', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('cholesterol', 'Chemical', 'MESH:D002784', (153, 164))	('cholesterol', 'Chemical', 'MESH:D002784', (57, 68))
126012	30254608	By contrast, the reduction of LDL-R by PCSK9 inhibitors may result in an increased intracellular content of cholesterol within tumor cells that could sustain ERRalpha activation.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('increased', 'PosReg', (73, 82))	('cholesterol within tumor', 'Disease', (108, 132))	('ERRalpha activation', 'MPA', (158, 177))	('inhibitors', 'Var', (45, 55))	('LDL-R', 'Protein', (30, 35))	('increased intracellular content of cholesterol', 'Phenotype', 'HP:0003575', (73, 119))	('cholesterol within tumor', 'Disease', 'MESH:D001929', (108, 132))	('PCSK9', 'Gene', (39, 44))	('reduction', 'NegReg', (17, 26))
126031	30254608	The same authors, investigating the mechanism by which ERRalpha regulates the expression of IL-8 in CRC cells revealed that XCT-790 treatment or ERRalpha gene silencing decreased the promoter activity of IL-8.	('IL-8', 'Gene', '3576', (92, 96))	('IL-8', 'Gene', (204, 208))	('gene', 'Var', (154, 158))	('promoter activity', 'MPA', (183, 200))	('IL-8', 'Gene', (92, 96))	('XCT', 'Gene', (124, 127))	('ERRalpha', 'Gene', (145, 153))	('XCT', 'Gene', '23657', (124, 127))	('decreased', 'NegReg', (169, 178))	('IL-8', 'Gene', '3576', (204, 208))
126033	30254608	Importantly, IL-8 gene silencing suppressed CRC cells proliferation and migration similarly to XCT-790, while a pre-treatment with recombinant IL-8 can rescue the inhibitory effects exerted by XCT-790 on cell proliferation and migration.	('migration', 'CPA', (227, 236))	('IL-8', 'Gene', '3576', (143, 147))	('migration', 'CPA', (72, 81))	('XCT', 'Gene', '23657', (95, 98))	('IL-8', 'Gene', '3576', (13, 17))	('CRC cells proliferation', 'CPA', (44, 67))	('rat', 'Species', '10116', (75, 78))	('IL-8', 'Gene', (13, 17))	('XCT', 'Gene', (193, 196))	('rat', 'Species', '10116', (61, 64))	('IL-8', 'Gene', (143, 147))	('XCT', 'Gene', (95, 98))	('rat', 'Species', '10116', (230, 233))	('XCT', 'Gene', '23657', (193, 196))	('gene silencing', 'Var', (18, 32))	('rat', 'Species', '10116', (216, 219))	('suppressed', 'NegReg', (33, 43))
126037	30254608	Animal fats diet is also associated with an increased risk of developing chronic intestinal inflammation.	('Animal fats', 'Var', (0, 11))	('fats', 'Chemical', 'MESH:D005223', (7, 11))	('intestinal inflammation', 'Disease', (81, 104))	('intestinal inflammation', 'Disease', 'MESH:D007249', (81, 104))
126048	30254608	Thus, high ERRalpha expression in breast cancer by enhancing SULT2A1 activity could also support breast cancer cell resistance to anti-hormonal therapy.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('activity', 'MPA', (69, 77))	('expression', 'MPA', (20, 30))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', (34, 47))	('support', 'PosReg', (89, 96))	('SULT2A1', 'Gene', (61, 68))	('ERRalpha', 'Protein', (11, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('high', 'Var', (6, 10))	('SULT2A1', 'Gene', '6822', (61, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('enhancing', 'PosReg', (51, 60))	('breast cancer', 'Disease', (97, 110))
126053	30254608	Moreover, aberrant cholesteryl ester accumulation in lipid droplets exacerbates cancer invasiveness and characterize high-grade PCa with PTEN loss and consequently, constitutive PI3K/Akt activation promotes metabolic dysregulation where ERRalpha/PGC-1alpha, as already mentioned, play a central role.	('PTEN loss', 'Disease', (137, 146))	('cancer invasiveness', 'Disease', 'MESH:D009362', (80, 99))	('PGC-1alpha', 'Gene', (246, 256))	('PGC-1alpha', 'Gene', '10891', (246, 256))	('cancer invasiveness', 'Disease', (80, 99))	('metabolic dysregulation', 'MPA', (207, 230))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('aberrant', 'Var', (10, 18))	('cholesteryl ester accumulation', 'Phenotype', 'HP:0031211', (19, 49))	('cholesteryl ester accumulation in', 'MPA', (19, 52))	('PTEN loss', 'Disease', 'MESH:D006223', (137, 146))	('exacerbates', 'PosReg', (68, 79))	('lipid', 'Chemical', 'MESH:D008055', (53, 58))	('PCa', 'Phenotype', 'HP:0012125', (128, 131))	('high-grade', 'Disease', (117, 127))	('activation promotes', 'PosReg', (187, 206))	('cholesteryl ester', 'Chemical', 'MESH:D002788', (19, 36))
126078	30254608	Accordingly, high levels of cholesterol are associated with an increased risk of different type of cancers including breast, prostate and CRC.	('associated', 'Reg', (44, 54))	('high levels', 'Var', (13, 24))	('CRC', 'Disease', (138, 141))	('prostate', 'Disease', (125, 133))	('high levels of cholesterol', 'Phenotype', 'HP:0003124', (13, 39))	('breast', 'Disease', (117, 123))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cholesterol', 'Chemical', 'MESH:D002784', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
126085	30254608	It is noteworthy that cholesterol accumulation in TAM triggers the phenotype switch from M1, antitumorigenic, to M2-like macrophage, protumorigenic.	('cholesterol', 'Chemical', 'MESH:D002784', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (97, 102))	('TAM', 'Chemical', 'MESH:D013629', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cholesterol', 'Var', (22, 33))	('tumor', 'Disease', (136, 141))
126092	29643654	EUS-FNAC led to the remarkable increase in the detection rate of incidentaloma found during radiologic staging or follow-up in various malignancy or unrelated conditions.	('EUS-FNAC', 'Var', (0, 8))	('C', 'Chemical', 'MESH:D002244', (7, 8))	('N', 'Chemical', 'MESH:D009584', (5, 6))	('malignancy', 'Disease', 'MESH:D009369', (135, 145))	('incidentaloma', 'Disease', (65, 78))	('malignancy', 'Disease', (135, 145))	('detection', 'MPA', (47, 56))	('increase', 'PosReg', (31, 39))
126127	29643654	Metastatic adenocarcinomas aspirates were variably cellular and showed tight to loosely cohesive cell clusters of atypical cells with moderate nuclear pleomorphism, hyperchromatic to vesicular nuclei, high N:C ratio, occasional prominent nucleolei, and moderate amount of eosinophilic cytoplasm with/without focal mucinous changes [Figure 3d-f].	('Metastatic adenocarcinomas', 'Disease', 'MESH:C538445', (0, 26))	('eosin', 'Chemical', 'MESH:D004801', (272, 277))	('hyperchromatic to vesicular nuclei', 'Disease', 'MESH:D012872', (165, 199))	('hyperchromatic to vesicular nuclei', 'Disease', (165, 199))	('C', 'Chemical', 'MESH:D002244', (208, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('high N', 'Var', (201, 207))	('Metastatic adenocarcinomas', 'Disease', (0, 26))	('N', 'Chemical', 'MESH:D009584', (206, 207))
126172	24403568	APA samples (n=45) were also submitted to quantitative RT-PCR (qPCR) of PCP4, CYP11B1, and CYP11B2, as well as DNA sequencing for KCNJ5 mutations.	('CYP11B2', 'Gene', '1585', (91, 98))	('KCNJ5', 'Gene', '3762', (130, 135))	('PCP4', 'Gene', (72, 76))	('CYP11B1', 'Gene', (78, 85))	('CYP11B1', 'Gene', '1584', (78, 85))	('CYP11B2', 'Gene', (91, 98))	('mutations', 'Var', (136, 145))	('KCNJ5', 'Gene', (130, 135))
126174	24403568	In APA, the mRNA levels of PCP4 were significantly correlated with those of CYP11B2 (P<0.0001) and were significantly higher in cases with KCNJ5 mutation than wild-type (P=0.005).	('higher', 'PosReg', (118, 124))	('mRNA levels', 'MPA', (12, 23))	('KCNJ5', 'Gene', (139, 144))	('CYP11B2', 'Gene', '1585', (76, 83))	('CYP11B2', 'Gene', (76, 83))	('correlated', 'Reg', (51, 61))	('KCNJ5', 'Gene', '3762', (139, 144))	('mutation', 'Var', (145, 153))
126175	24403568	Following PCP4 vector transfection, CYP11B2 luciferase reporter activity was significantly higher than controls in the presence of angiotensin-II.	('CYP11B2 luciferase', 'Gene', (36, 54))	('reporter activity', 'MPA', (55, 72))	('angiotensin-II', 'Gene', (131, 145))	('higher', 'PosReg', (91, 97))	('transfection', 'Var', (22, 34))	('angiotensin-II', 'Gene', '183', (131, 145))	('CYP11B2 luciferase', 'Gene', '1585', (36, 54))	('PCP4', 'Gene', (10, 14))
126180	24403568	PCP4 accelerates both the association and dissociation of calcium (Ca2+) with CaM, which is postulated to influence the activity of CaM-dependent enzymes, especially CaM kinase II (CaMK-II).	('calcium', 'Chemical', 'MESH:D002118', (58, 65))	('PCP4', 'Var', (0, 4))	('activity', 'MPA', (120, 128))	('Ca2+', 'Chemical', 'MESH:D000069285', (67, 71))	('CaMK-II', 'Gene', '818', (181, 188))	('CaMK-II', 'Gene', (181, 188))	('CaM', 'Gene', '801', (166, 169))	('CaM', 'Gene', '801', (78, 81))	('CaM', 'Gene', '801', (181, 184))	('association', 'Interaction', (26, 37))	('CaM', 'Gene', (166, 169))	('CaM kinase II', 'Gene', (166, 179))	('CaM', 'Gene', '801', (132, 135))	('CaM', 'Gene', (78, 81))	('accelerates', 'PosReg', (5, 16))	('influence', 'Reg', (106, 115))	('CaM', 'Gene', (181, 184))	('CaM kinase II', 'Gene', '818', (166, 179))	('CaM', 'Gene', (132, 135))
126181	24403568	It has been also reported that PCP4 can prevent cellular degeneration and apoptosis, as neuroprotection in the central nervous system (CNS).	('degeneration', 'Disease', 'MESH:D009410', (57, 69))	('apoptosis', 'CPA', (74, 83))	('PCP4', 'Var', (31, 35))	('degeneration', 'Disease', (57, 69))	('prevent', 'NegReg', (40, 47))
126185	24403568	In addition, we also evaluated the correlation between the status of PCP4 and KCNJ5 somatic mutations in aldosterone producing adenomas.	('PCP4', 'Gene', (69, 73))	('aldosterone', 'Chemical', 'MESH:D000450', (105, 116))	('mutations', 'Var', (92, 101))	('adenomas', 'Disease', 'MESH:D000236', (127, 135))	('KCNJ5', 'Gene', (78, 83))	('adenomas', 'Disease', (127, 135))	('KCNJ5', 'Gene', '3762', (78, 83))
126204	24403568	After 60h from transfection, RNA was collected from: 1- cells transfected with PCP4 siRNA plus vehicle; 2- cells transfected with PCP4 siRNA plus angiotesin-II; 3- cells transfected with negative control siRNA plus vehicle; and 4- cells transfected with negative control siRNA plus angiotensin-II, respectively.	('angiotensin-II', 'Gene', '183', (282, 296))	('angiotensin-II', 'Gene', (282, 296))	('PCP4', 'Var', (130, 134))
126216	24403568	Analysis of the purified DNA was carried out with a Abi Prism 310 genetic analyser (Applied Biosystems, Foster City, CA, USA), and mutations at the G151R and L168R regions of the KCNJ5 gene were analysed as described.	('KCNJ5', 'Gene', '3762', (179, 184))	('L168R', 'Mutation', 'rs386352318', (158, 163))	('G151R', 'Var', (148, 153))	('L168R', 'Var', (158, 163))	('G151R', 'Mutation', 'rs386352319', (148, 153))	('KCNJ5', 'Gene', (179, 184))
126220	24403568	The statistical analysis of patient gender and its correlation to KCNJ5 mutations was assessed by contingency table, and a chi-square value of P<0.05 was considered significant.	('KCNJ5', 'Gene', '3762', (66, 71))	('mutations', 'Var', (72, 81))	('patient', 'Species', '9606', (28, 35))	('KCNJ5', 'Gene', (66, 71))
126223	24403568	When the qPCR results of PCP4, CYP11B1 and CYP11B2 mRNA levels in APA cases were analyzed with polynomial regression, a significantly positive correlation was detected between PCP4 and CYP11B2 (P<0.0001; R>0.6: Figure 2A), although not between PCP4 and CYP11B1 (Figure 2B).	('CYP11B1', 'Gene', '1584', (31, 38))	('CYP11B2', 'Gene', (43, 50))	('CYP11B1', 'Gene', (253, 260))	('CYP11B2', 'Gene', (185, 192))	('positive', 'PosReg', (134, 142))	('CYP11B2', 'Gene', '1585', (43, 50))	('CYP11B1', 'Gene', '1584', (253, 260))	('CYP11B2', 'Gene', '1585', (185, 192))	('CYP11B1', 'Gene', (31, 38))	('PCP4', 'Var', (176, 180))
126225	24403568	KCNJ5 mutations were detected in 28 out of 45 APA cases (62.2%), and the data obtained from the clinical records of the 45 APA patients and the respective statistical correlations to KCNJ5 mutations are summarized in the supplementary data, Table 1.	('KCNJ5', 'Gene', '3762', (0, 5))	('KCNJ5', 'Gene', (183, 188))	('patients', 'Species', '9606', (127, 135))	('KCNJ5', 'Gene', '3762', (183, 188))	('KCNJ5', 'Gene', (0, 5))	('detected', 'Reg', (21, 29))	('mutations', 'Var', (6, 15))
126226	24403568	Both PCP4 (P=0.005) and CYP11B2 (P<0.005) were significantly higher in KCNJ5 mutated cases, while no statistical significance of CYP11B1 mRNA levels between mutated and WT APA cases (Figures 2D, E and F).	('PCP4', 'MPA', (5, 9))	('higher', 'PosReg', (61, 67))	('CYP11B2', 'Gene', (24, 31))	('CYP11B1', 'Gene', (129, 136))	('mutated', 'Var', (77, 84))	('CYP11B2', 'Gene', '1585', (24, 31))	('CYP11B1', 'Gene', '1584', (129, 136))	('KCNJ5', 'Gene', (71, 76))	('KCNJ5', 'Gene', '3762', (71, 76))
126232	24403568	The transient transfection with PCP4 DNA vector produced significant rise of CYP11B2-LUC in PCP4 transfected H295R when angiotensin-II was added to cell media, compared to cells transfected with control vector (P<0.0001).	('angiotensin-II', 'Gene', '183', (120, 134))	('CYP11B2-LUC', 'Gene', (77, 88))	('rise', 'PosReg', (69, 73))	('H295R', 'CellLine', 'CVCL:0458', (109, 114))	('PCP4 transfected', 'Var', (92, 108))	('CYP11B2-LUC', 'Gene', '1585', (77, 88))	('angiotensin-II', 'Gene', (120, 134))
126235	24403568	However, no statistical significance was detected in CYP11B1 mRNA levels between PCP4 and negative control siRNA transfected H295R cells (Figure 5D).	('H295R', 'CellLine', 'CVCL:0458', (125, 130))	('CYP11B1', 'Gene', (53, 60))	('CYP11B1', 'Gene', '1584', (53, 60))	('PCP4', 'Var', (81, 85))
126236	24403568	When cell culture media were analyzed through ELISA, a significant decrease in aldosterone production levels was detected in PCP4 siRNA transfected cells treated with angiotensin-II (P=0.011) when compared to negative control siRNA transfected cells treated with angiotensin-II (Figure 5E), however no statistical significance was detected between the basal, non-treated samples.	('angiotensin-II', 'Gene', '183', (167, 181))	('aldosterone production', 'Phenotype', 'HP:0000859', (79, 101))	('decrease', 'NegReg', (67, 75))	('PCP4', 'Gene', (125, 129))	('aldosterone production levels', 'MPA', (79, 108))	('angiotensin-II', 'Gene', (263, 277))	('aldosterone', 'Chemical', 'MESH:D000450', (79, 90))	('transfected', 'Var', (136, 147))	('angiotensin-II', 'Gene', '183', (263, 277))	('angiotensin-II', 'Gene', (167, 181))	('decrease in aldosterone', 'Phenotype', 'HP:0004319', (67, 90))
126237	24403568	In addition, no significant changes could be detected in cortisol levels between cells transfected with PCP4 siRNA and N.C. siRNA, either in Ang-II treated or non-treated samples.	('cortisol levels', 'MPA', (57, 72))	('N.C.', 'Var', (119, 123))	('Ang-II', 'Gene', (141, 147))	('Ang-II', 'Gene', '183', (141, 147))	('PCP4', 'Var', (104, 108))
126246	24403568	After 60h of transient knockdown of PCP4 and 12h of angiotensin-II treatment of H295R cells, there was a significant decrease in CYP11B2 mRNA levels compared to controls, which, together with the time-course and luciferase assays data, indicated the regulation of CYP11B2 by PCP4.	('PCP4', 'Gene', (275, 279))	('CYP11B2', 'Gene', (129, 136))	('angiotensin-II', 'Gene', (52, 66))	('CYP11B2', 'Gene', '1585', (129, 136))	('knockdown', 'Var', (23, 32))	('angiotensin-II', 'Gene', '183', (52, 66))	('PCP4', 'Gene', (36, 40))	('CYP11B2', 'Gene', (264, 271))	('decrease', 'NegReg', (117, 125))	('CYP11B2', 'Gene', '1585', (264, 271))	('H295R', 'CellLine', 'CVCL:0458', (80, 85))
126253	24403568	In this study, we attempted to clarify the mechanisms by which PCP4 could act in the aldosterone production pathway in vivo.	('aldosterone production pathway', 'Pathway', (85, 115))	('aldosterone', 'Chemical', 'MESH:D000450', (85, 96))	('act', 'Reg', (74, 77))	('PCP4', 'Var', (63, 67))	('aldosterone production', 'Phenotype', 'HP:0000859', (85, 107))
126255	24403568	The somatic mutations in the amino acids G151 and L168 of the KCNJ5 potassium (K+) channels have been reported to produce the loss of ion selectivity by the cellular membrane, and hyper-activation of voltage gated Ca2+ channels, resulting in elevation of the intracellular levels of Ca2+ in APA, and we demonstrate that these KCNJ5 mutations are significantly correlated with the expression status of both CYP11B2 and PCP4 in APA, but not with the status of CYP11B1.	('CYP11B1', 'Gene', '1584', (458, 465))	('L168', 'Var', (50, 54))	('correlated', 'Reg', (360, 370))	('CYP11B2', 'Gene', (406, 413))	('KCNJ5', 'Gene', '3762', (326, 331))	('CYP11B1', 'Gene', (458, 465))	('mutations in', 'Var', (12, 24))	('elevation', 'PosReg', (242, 251))	('KCNJ5', 'Gene', (62, 67))	('mutations', 'Var', (332, 341))	('intracellular levels of Ca2+ in APA', 'MPA', (259, 294))	('voltage gated Ca2+', 'MPA', (200, 218))	('KCNJ5', 'Gene', '3762', (62, 67))	('Ca2+', 'Chemical', 'MESH:D000069285', (214, 218))	('ion selectivity by the cellular membrane', 'MPA', (134, 174))	('CYP11B2', 'Gene', '1585', (406, 413))	('hyper-activation', 'PosReg', (180, 196))	('KCNJ5', 'Gene', (326, 331))	('Ca2+', 'Chemical', 'MESH:D000069285', (283, 287))	('loss', 'NegReg', (126, 130))
126256	24403568	In addition, our results demonstrate that KCNJ5 mutations are significantly correlated to plasmatic aldosterone levels (PAC) in APA patients, which suggests an indirect correlation between PCP4 and aldosterone levels in vivo.	('KCNJ5', 'Gene', (42, 47))	('PAC', 'Phenotype', 'HP:0006699', (120, 123))	('aldosterone', 'Chemical', 'MESH:D000450', (198, 209))	('plasmatic aldosterone levels', 'Phenotype', 'HP:0000859', (90, 118))	('KCNJ5', 'Gene', '3762', (42, 47))	('PAC', 'Phenotype', 'HP:0000859', (120, 123))	('aldosterone', 'Chemical', 'MESH:D000450', (100, 111))	('plasmatic aldosterone levels', 'MPA', (90, 118))	('patients', 'Species', '9606', (132, 140))	('mutations', 'Var', (48, 57))	('correlated', 'Reg', (76, 86))
126257	24403568	The elevation of intracellular Ca2+ in conjunction with mutations in KCNJ5 could result in a hyperactivity of PCP4, reflected as the up-regulation of its intracellular levels in APA.	('hyperactivity', 'Phenotype', 'HP:0000752', (93, 106))	('intracellular Ca2+', 'MPA', (17, 35))	('mutations', 'Var', (56, 65))	('PCP4', 'Gene', (110, 114))	('KCNJ5', 'Gene', (69, 74))	('KCNJ5', 'Gene', '3762', (69, 74))	('Ca2+', 'Chemical', 'MESH:D000069285', (31, 35))	('intracellular levels in APA', 'MPA', (154, 181))	('elevation', 'PosReg', (4, 13))	('up-regulation', 'PosReg', (133, 146))	('hyperactivity', 'Disease', 'MESH:D006948', (93, 106))	('hyperactivity', 'Disease', (93, 106))
126258	24403568	However, despite the lack of KCNJ5 mutations, some APA and the ZG of NA and IHA do show higher levels of PCP4 than the adrenocortical ZF or ZR.	('higher', 'PosReg', (88, 94))	('adrenocortical ZF', 'Disease', (119, 136))	('PCP4', 'MPA', (105, 109))	('KCNJ5', 'Gene', (29, 34))	('levels', 'MPA', (95, 101))	('adrenocortical ZF', 'Disease', 'MESH:D018268', (119, 136))	('KCNJ5', 'Gene', '3762', (29, 34))	('mutations', 'Var', (35, 44))
126262	23065993	Mutations in the cAMP protein kinase A regulatory subunit type 1A (PRKAR1A) are causative of PPNAD.	('PRKAR1A', 'Gene', (67, 74))	('PRKAR1A', 'Gene', '5573', (67, 74))	('cAMP', 'Chemical', '-', (17, 21))	('causative', 'Reg', (80, 89))	('Mutations', 'Var', (0, 9))	('PPNAD', 'Chemical', '-', (93, 98))	('PPNAD', 'Disease', (93, 98))
126267	23065993	In vivo evaluation of aberrantly expressed hormone receptors showed no steroid response to known stimuli.	('aberrantly expressed', 'Var', (22, 42))	('steroid response to known stimuli', 'MPA', (71, 104))	('steroid', 'Chemical', 'MESH:D013256', (71, 78))
126268	23065993	Genetic analysis revealed a PRKAR1A protein-truncating Q28X mutation.	('PRKAR1A', 'Gene', '5573', (28, 35))	('Q28X', 'Mutation', 'rs281864780', (55, 59))	('protein-truncating', 'NegReg', (36, 54))	('Q28X mutation', 'Var', (55, 68))	('PRKAR1A', 'Gene', (28, 35))
126279	23065993	Known genetic causes of PPNAD and Carney complex are mutations in components of the cAMP protein kinase A (PKA) pathway: PRKAR1A, PDE11A, and PDE8B.	('PDE11A', 'Gene', (130, 136))	('PDE11A', 'Gene', '50940', (130, 136))	('cAMP', 'Chemical', '-', (84, 88))	('PRKAR1A', 'Gene', '5573', (121, 128))	('mutations', 'Var', (53, 62))	('PDE8B', 'Gene', '8622', (142, 147))	('PPNAD', 'Chemical', '-', (24, 29))	('causes', 'Reg', (14, 20))	('PDE8B', 'Gene', (142, 147))	('Carney complex', 'Disease', (34, 48))	('PPNAD', 'Disease', (24, 29))	('PRKAR1A', 'Gene', (121, 128))
126280	23065993	Aberrant cAMP-PKA signaling in the adrenal cortex leads to hyperplasia, the formation of multiple pigmented nodules, and the sporadic formation of a large tumor.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cAMP', 'Chemical', '-', (9, 13))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('hyperplasia', 'Disease', 'MESH:D006965', (59, 70))	('tumor', 'Disease', (155, 160))	('leads to', 'Reg', (50, 58))	('cAMP-PKA', 'Gene', (9, 17))	('hyperplasia', 'Disease', (59, 70))
126281	23065993	The latter has been linked to mutations in CTNNB1, which lead to constitutive activation and nuclear translocation of its product beta-catenin.	('nuclear translocation', 'MPA', (93, 114))	('constitutive activation', 'MPA', (65, 88))	('CTNNB1', 'Gene', '1499', (43, 49))	('mutations', 'Var', (30, 39))	('beta-catenin', 'Protein', (130, 142))	('CTNNB1', 'Gene', (43, 49))	('linked', 'Reg', (20, 26))
126286	23065993	Macronodular adrenal hyperplasia and adrenocortical adenomas with autonomous cortisol production can be associated with aberrant expression of one of several eutopic and ectopic G-protein-coupled receptors (GPCRs) that are functionally coupled to steroidogenesis.	('GPCR', 'Gene', (207, 211))	('aberrant', 'Var', (120, 128))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (37, 60))	('steroid', 'Chemical', 'MESH:D013256', (247, 254))	('adrenocortical adenomas', 'Disease', (37, 60))	('GPCR', 'Gene', '441931', (207, 211))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (13, 32))	('Macronodular adrenal hyperplasia', 'Disease', (0, 32))	('Macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (0, 32))	('cortisol', 'Chemical', 'MESH:D006854', (77, 85))	('G-protein-coupled receptors', 'Protein', (178, 205))	('associated', 'Reg', (104, 114))	('Macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (0, 32))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (37, 60))
126322	23065993	Leukocyte DNA sequencing, performed as published elsewhere, revealed a previously reported PRKAR1A protein-truncating Q28X mutation, confirming the diagnosis of PPNAD.	('PPNAD', 'Chemical', '-', (161, 166))	('PRKAR1A', 'Gene', '5573', (91, 98))	('Q28X mutation', 'Var', (118, 131))	('Q28X', 'Mutation', 'rs281864780', (118, 122))	('PRKAR1A', 'Gene', (91, 98))
126323	23065993	Separate sequencing of microdissected adenoma and PPNAD tissues, using methods and primers previously reported, subsequently showed no mutations in exon 3 of CTNNB1.	('mutations in', 'Var', (135, 147))	('CTNNB1', 'Gene', (158, 164))	('PPNAD', 'Chemical', '-', (50, 55))	('adenoma', 'Disease', 'MESH:D000236', (38, 45))	('adenoma', 'Disease', (38, 45))	('CTNNB1', 'Gene', '1499', (158, 164))
126339	23065993	The qPCR was performed in a 12.5 mul volume for HPRT1, STAR, CYP11A1, HSD3B2, CYP17A1, CYP21A2, CYP11B1, AKR1C3, HSD17B3, and steroid receptors GR and AR (assay on demand, Hs00366267_m1, Hs00970002_m1, Hs00230818_m1, and Hs00907242_m1, Applied Biosystems).	('CYP11A1', 'Gene', (61, 68))	('AKR1C3', 'Gene', (105, 111))	('CYP21A2', 'Gene', (87, 94))	('Hs00907242_m1', 'Var', (221, 234))	('HSD17B3', 'Gene', '3293', (113, 120))	('CYP17A1', 'Gene', (78, 85))	('CYP17A1', 'Gene', '1586', (78, 85))	('HSD3B2', 'Gene', (70, 76))	('steroid', 'Chemical', 'MESH:D013256', (126, 133))	('HPRT1', 'Gene', '3251', (48, 53))	('CYP21A2', 'Gene', '1589', (87, 94))	('HSD17B3', 'Gene', (113, 120))	('STAR', 'Gene', '6770', (55, 59))	('AKR1C3', 'Gene', '8644', (105, 111))	('CYP11B1', 'Gene', '1584', (96, 103))	('Hs00970002_m1', 'Var', (187, 200))	('CYP11A1', 'Gene', '1583', (61, 68))	('HPRT1', 'Gene', (48, 53))	('STAR', 'Gene', (55, 59))	('CYP11B1', 'Gene', (96, 103))	('HSD3B2', 'Gene', '3284', (70, 76))
126344	23065993	Forty-eight-hour incubation with ACTH of the patients' tumor cells led to significant increases in cortisol (5.3-fold), androstenedione (4.9-fold), and testosterone (3.6-fold) levels (Fig.	('cortisol', 'MPA', (99, 107))	('androstenedione', 'MPA', (120, 135))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('increases', 'PosReg', (86, 95))	('tumor', 'Disease', (55, 60))	('cortisol', 'Chemical', 'MESH:D006854', (99, 107))	('testosterone', 'MPA', (152, 164))	('patients', 'Species', '9606', (45, 53))	('testosterone', 'Chemical', 'MESH:D013739', (152, 164))	('androstenedione', 'Chemical', 'MESH:D000735', (120, 135))	('ACTH', 'Var', (33, 37))
126370	23065993	Unlike a previous report, this adenoma was not associated with CTNNB1 mutations or constitutive beta-catenin activation.	('mutations', 'Var', (70, 79))	('CTNNB1', 'Gene', '1499', (63, 69))	('adenoma', 'Disease', 'MESH:D000236', (31, 38))	('CTNNB1', 'Gene', (63, 69))	('adenoma', 'Disease', (31, 38))
126371	23065993	This could reflect that only a subset of PPNAD-associated adenomas is characterized by these mutations, as is the case in sporadic adrenocortical adenomas.	('PPNAD', 'Chemical', '-', (41, 46))	('adenomas', 'Disease', (146, 154))	('mutations', 'Var', (93, 102))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (131, 154))	('adrenocortical adenomas', 'Disease', (131, 154))	('adenomas', 'Disease', 'MESH:D000236', (58, 66))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (131, 154))	('adenomas', 'Disease', 'MESH:D000236', (146, 154))	('adenomas', 'Disease', (58, 66))
126378	23065993	Human adrenal cells with mutated PRKAR1A remain cAMP responsive and increase PKA activity even more compared with nonmutated cells as PRKAR1A mutations lead to constitutive PKA activity.	('PRKAR1A', 'Gene', (134, 141))	('mutations', 'Var', (142, 151))	('Human', 'Species', '9606', (0, 5))	('PRKAR1A', 'Gene', (33, 40))	('PRKAR1A', 'Gene', '5573', (33, 40))	('PRKAR1A', 'Gene', '5573', (134, 141))	('increase', 'PosReg', (68, 76))	('constitutive', 'MPA', (160, 172))	('PKA', 'Enzyme', (77, 80))	('cAMP', 'Chemical', '-', (48, 52))	('activity', 'MPA', (81, 89))	('lead to', 'Reg', (152, 159))	('mutated', 'Var', (25, 32))
126396	23065993	This finding suggests that in at least some PPNAD tissues, aberrant coupling of the GR to the cAMP-PKA pathway instead of GR overexpression may be the culprit for the dexamethasone-induced rise in cortisol production.	('dexamethasone', 'Chemical', 'MESH:D003907', (167, 180))	('cAMP', 'Chemical', '-', (94, 98))	('rise in cortisol', 'Phenotype', 'HP:0003118', (189, 205))	('aberrant', 'Var', (59, 67))	('cAMP-PKA pathway', 'Pathway', (94, 110))	('PPNAD', 'Chemical', '-', (44, 49))	('cortisol production', 'MPA', (197, 216))	('coupling', 'MPA', (68, 76))	('cortisol', 'Chemical', 'MESH:D006854', (197, 205))
126400	23065993	This tumor also had a unique steroid secretion profile in vitro, suggesting that defects of the PKA pathway may also affect secretion of additional steroids, apart from glucocorticoids.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('secretion of additional steroids', 'MPA', (124, 156))	('PKA pathway', 'Pathway', (96, 107))	('steroid', 'Chemical', 'MESH:D013256', (148, 155))	('steroids', 'Chemical', 'MESH:D013256', (148, 156))	('defects', 'Var', (81, 88))	('tumor', 'Disease', (5, 10))	('steroid', 'Chemical', 'MESH:D013256', (29, 36))	('affect', 'Reg', (117, 123))
126402	20231622	Antineoplastic Effects of Decitabine, an Inhibitor of DNA Promoter Methylation, in Adrenocortical Carcinoma Cells Decitabine recovers expression of silenced genes on chromosome 11q13 and has antineoplastic effects in adrenocortical carcinoma (ACC) cells.	('Carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('Decitabine', 'Chemical', 'MESH:D000077209', (26, 36))	('expression', 'MPA', (134, 144))	('Adrenocortical Carcinoma', 'Phenotype', 'HP:0006744', (83, 107))	('Decitabine', 'Var', (114, 124))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (217, 241))	('antineoplastic effects', 'CPA', (191, 213))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (217, 241))	('ACC', 'Phenotype', 'HP:0006744', (243, 246))	('Adrenocortical Carcinoma', 'Disease', (83, 107))	('Decitabine', 'Chemical', 'MESH:D000077209', (114, 124))	('recovers', 'NegReg', (125, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('Adrenocortical Carcinoma', 'Disease', 'MESH:D018268', (83, 107))	('adrenocortical carcinoma', 'Disease', (217, 241))
126413	20231622	Decitabine recovers expression of silenced genes on 11q13, which suggests a possible role of epigenetic gene silencing in adrenocortical carcinogenesis.	('expression', 'MPA', (20, 30))	('adrenocortical carcinogenesis', 'Disease', 'MESH:D063646', (122, 151))	('adrenocortical carcinogenesis', 'Disease', (122, 151))	('Decitabine', 'Chemical', 'MESH:D000077209', (0, 10))	('epigenetic gene silencing', 'Var', (93, 118))
126419	20231622	In particular, loss of heterozygosity at chromosome 11q13 has been reported in up to 70% to 100% of ACCs, suggesting that inactivation of genes on 11q13 could contribute to adrenocortical carcinogenesis.	('adrenocortical carcinogenesis', 'Disease', (173, 202))	('inactivation', 'Var', (122, 134))	('ACCs', 'Gene', (100, 104))	('ACCs', 'Gene', '84680', (100, 104))	('11q13', 'Gene', (147, 152))	('contribute', 'Reg', (159, 169))	('ACC', 'Phenotype', 'HP:0006744', (100, 103))	('adrenocortical carcinogenesis', 'Disease', 'MESH:D063646', (173, 202))
126421	20231622	Recently, there is increasing evidence that reversible, or epigenetic, mechanisms in gene silencing have an important role in cancer.	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('epigenetic', 'Var', (59, 69))
126441	20231622	The manufacturer's inventory numbers for the primer-probe sets were Hs01096554_g1 (for DDB1), Hs99999905_m1 (GAPDH), Hs00740658_m1 (MRPL48), Hs00159597_m1 (NDUFS8), Hs00201536_m1 (PRDX5), Hs00163781_m1 (SERPING1), and Hs00162807_m1 (TM7SF2).	('GAPDH', 'Gene', (109, 114))	('Hs01096554_g1', 'Var', (68, 81))	('MRPL48', 'Gene', (132, 138))	('Hs99999905_m1', 'Var', (94, 107))	('Hs00159597_m1', 'Var', (141, 154))	('SERPING1', 'Gene', '710', (203, 211))	('NDUFS8', 'Gene', '4728', (156, 162))	('Hs00740658_m1', 'Var', (117, 130))	('PRDX5', 'Gene', (180, 185))	('Hs00201536_m1', 'Var', (165, 178))	('PRDX5', 'Gene', '25824', (180, 185))	('DDB1', 'Gene', '1642', (87, 91))	('Hs00163781_m1', 'Var', (188, 201))	('TM7SF2', 'Gene', (233, 239))	('SERPING1', 'Gene', (203, 211))	('GAPDH', 'Gene', '2597', (109, 114))	('NDUFS8', 'Gene', (156, 162))	('Hs00162807_m1', 'Var', (218, 231))	('DDB1', 'Gene', (87, 91))	('MRPL48', 'Gene', '51642', (132, 138))	('TM7SF2', 'Gene', '7108', (233, 239))
126460	20231622	Perhaps most important, mitotane leads to significantly diminished hormonal hypersecretion in 80% of patients with functional tumors, thereby improving the quality of life for affected patients.	('patients', 'Species', '9606', (101, 109))	('functional tumors', 'Disease', (115, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('functional tumors', 'Disease', 'MESH:D009369', (115, 132))	('hormonal hypersecretion', 'MPA', (67, 90))	('mitotane', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('quality', 'MPA', (156, 163))	('mitotane', 'Chemical', 'MESH:D008939', (24, 32))	('diminished', 'NegReg', (56, 66))	('patients', 'Species', '9606', (185, 193))	('improving', 'PosReg', (142, 151))
126464	20231622	Recently, mounting evidence about the role of epigenetic mechanisms in carcinogenesis has prompted interest in whether agents that reverse these processes can be effective anticancer treatments.	('carcinogenesis', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('epigenetic', 'Var', (46, 56))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
126494	20231622	We tested the effects of decitabine on these genes using quantitative RTPCR, with the hypothesis that decitabine could recover gene expression if methylation had a role in silencing any of these genes.	('recover gene expression', 'MPA', (119, 142))	('silencing', 'NegReg', (172, 181))	('tested', 'Reg', (3, 9))	('methylation', 'Var', (146, 157))	('decitabine', 'Chemical', 'MESH:D000077209', (102, 112))	('decitabine', 'Chemical', 'MESH:D000077209', (25, 35))
126496	20231622	Of 6 genes, NDUFS8 and PRDX5 showed significantly recovered expression after decitabine treatment, suggesting that hypermethylation may have a gene silencing role in ACC.	('NDUFS8', 'Gene', (12, 18))	('expression', 'MPA', (60, 70))	('PRDX5', 'Gene', (23, 28))	('NDUFS8', 'Gene', '4728', (12, 18))	('ACC', 'Phenotype', 'HP:0006744', (166, 169))	('ACC', 'Disease', (166, 169))	('recovered', 'PosReg', (50, 59))	('hypermethylation', 'Var', (115, 131))	('gene silencing', 'NegReg', (143, 157))	('PRDX5', 'Gene', '25824', (23, 28))	('decitabine', 'Chemical', 'MESH:D000077209', (77, 87))
126499	20231622	NDUFS8 encodes a subunit protein of a critical enzyme in the mitochondrial respiratory chain, and mutations of this gene are associated with Leigh disease.	('Leigh disease', 'Disease', 'MESH:D007888', (141, 154))	('associated', 'Reg', (125, 135))	('mutations', 'Var', (98, 107))	('NDUFS8', 'Gene', (0, 6))	('NDUFS8', 'Gene', '4728', (0, 6))	('Leigh disease', 'Disease', (141, 154))
126501	20231622	Underexpression of neither NDUFS8 nor PRDX5 has been shown in other cancer models, suggesting that dysregulation of these genes may be specific to adrenocortical carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('adrenocortical carcinogenesis', 'Disease', 'MESH:D063646', (147, 176))	('dysregulation', 'Var', (99, 112))	('adrenocortical carcinogenesis', 'Disease', (147, 176))	('NDUFS8', 'Gene', (27, 33))	('PRDX5', 'Gene', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('NDUFS8', 'Gene', '4728', (27, 33))	('PRDX5', 'Gene', '25824', (38, 43))
126509	20231622	Second, studies using in vitro and in vivo models demonstrated the relevance of DNA promoter methylation in adrenocortical carcinogenesis.	('DNA', 'Gene', (80, 83))	('adrenocortical carcinogenesis', 'Disease', (108, 137))	('methylation', 'Var', (93, 104))	('adrenocortical carcinogenesis', 'Disease', 'MESH:D063646', (108, 137))
126536	20422709	Hh-receiving cells are enriched with cilia where PTCH inhibits SMO activity by preventing its accumulation within cilia.	('SMO', 'Gene', (63, 66))	('PTCH', 'Var', (49, 53))	('preventing', 'NegReg', (79, 89))	('inhibits', 'NegReg', (54, 62))	('SMO', 'Gene', '539308', (63, 66))	('accumulation', 'MPA', (94, 106))
126553	20422709	Gli3 mutant mice display a wide range of developmental abnormalities including absence of adrenal glands.	('adrenal glands', 'CPA', (90, 104))	('Gli3', 'Gene', (0, 4))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (41, 68))	('absence', 'NegReg', (79, 86))	('mutant', 'Var', (5, 11))	('developmental abnormalities', 'Disease', (41, 68))	('mice', 'Species', '10090', (12, 16))	('developmental abnormalities', 'Disease', 'MESH:D006130', (41, 68))
126555	20422709	A mutation in the Gli3 gene that results in a truncated form of GLI3 protein is found in some human PHS patients with adrenal hypoplasia and kidney malformation.	('mutation', 'Var', (2, 10))	('truncated form', 'MPA', (46, 60))	('results in', 'Reg', (33, 43))	('Gli3', 'Gene', (18, 22))	('PHS', 'Disease', 'MESH:D054975', (100, 103))	('PHS', 'Disease', (100, 103))	('protein', 'Protein', (69, 76))	('patients', 'Species', '9606', (104, 112))	('adrenal hypoplasia', 'Disease', 'MESH:D000312', (118, 136))	('kidney malformation', 'Disease', 'MESH:D000014', (141, 160))	('human', 'Species', '9606', (94, 99))	('adrenal hypoplasia', 'Phenotype', 'HP:0000835', (118, 136))	('GLI3', 'Gene', (64, 68))	('kidney malformation', 'Disease', (141, 160))	('adrenal hypoplasia', 'Disease', (118, 136))	('kidney malformation', 'Phenotype', 'HP:0012210', (141, 160))
126558	20422709	The downregulation of Ptch1 in Dhh null mutants indicates that Dhh could be the primary Hh ligand in action in fetal testes.	('Ptch1', 'Gene', (22, 27))	('Ptch1', 'Gene', '520994', (22, 27))	('mutants', 'Var', (40, 47))	('downregulation', 'NegReg', (4, 18))	('Dhh', 'Gene', (31, 34))
126559	20422709	Inactivation of the Dhh gene in mice with the 129/Sv inbred background results in properly formed testes; however, these male are infertile, with a complete absence of mature sperm.	('infertile', 'Disease', (130, 139))	('absence', 'NegReg', (157, 164))	('129/Sv', 'Species', '10090', (46, 52))	('mice', 'Species', '10090', (32, 36))	('Dhh', 'Gene', (20, 23))	('infertile', 'Disease', 'MESH:D007247', (130, 139))	('Inactivation', 'Var', (0, 12))
126561	20422709	In addition to testis cord dysgenesis, both Dhh knockout male mouse and human patients with DHH mutations exhibit male pseudohermaphroditism with underdevelopment of internal male accessory organs and feminized external genitalia due to insufficient production of androgens.	('external genitalia', 'Disease', 'MESH:D012734', (211, 229))	('testis cord dysgenesis', 'Disease', (15, 37))	('DHH', 'Gene', (92, 95))	('male pseudohermaphroditism', 'Phenotype', 'HP:0000037', (114, 140))	('mouse', 'Species', '10090', (62, 67))	('external genitalia', 'Disease', (211, 229))	('patients', 'Species', '9606', (78, 86))	('human', 'Species', '9606', (72, 77))	('pseudohermaphroditism', 'Disease', 'MESH:D012734', (119, 140))	('testis cord dysgenesis', 'Disease', 'MESH:D013736', (15, 37))	('pseudohermaphroditism', 'Disease', (119, 140))	('exhibit', 'Reg', (106, 113))	('mutations', 'Var', (96, 105))	('external genitalia due', 'Phenotype', 'HP:0003247', (211, 233))
126580	20422709	In addition, inactivation of Shh in the SF1-positive cells in the ovary yields no ovarian phenotypes (unpublished results).	('inactivation', 'Var', (13, 25))	('Shh', 'Gene', (29, 32))	('ovarian phenotypes', 'CPA', (82, 100))	('SF1', 'Gene', (40, 43))	('SF1', 'Gene', '26423', (40, 43))
126584	20422709	In addition, ectopic activation of the Hh pathway in mouse granulosa cells leads to infertility, reduced ovulation, and delayed luteinization.	('leads to', 'Reg', (75, 83))	('delayed luteinization', 'CPA', (120, 141))	('ectopic', 'Var', (13, 20))	('ovulation', 'CPA', (105, 114))	('reduced', 'NegReg', (97, 104))	('infertility', 'Phenotype', 'HP:0000789', (84, 95))	('infertility', 'Disease', 'MESH:D007247', (84, 95))	('mouse', 'Species', '10090', (53, 58))	('infertility', 'Disease', (84, 95))	('Hh pathway', 'Pathway', (39, 49))
126585	20422709	These observations indicate that aberrant activation of the Hh pathway may be responsible for ovarian abnormality and carcinogenesis.	('Hh pathway', 'Pathway', (60, 70))	('carcinogenesis', 'Disease', (118, 132))	('ovarian abnormality', 'Phenotype', 'HP:0000137', (94, 113))	('responsible', 'Reg', (78, 89))	('activation', 'PosReg', (42, 52))	('ovarian abnormality', 'Disease', 'MESH:D010049', (94, 113))	('ovarian abnormality', 'Disease', (94, 113))	('aberrant', 'Var', (33, 41))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))
126592	21930187	Towards an understanding of the role of p53 in Adrenocortical Carcinogenesis Adrenocortical carcinoma (ACC) is recognized to be a component tumor of the Li Fraumeni Syndrome (LFS), a familial cancer predisposition resulting from germline mutations in the p53 tumor-suppressor.	('component tumor of the Li Fraumeni Syndrome', 'Disease', 'MESH:D016864', (130, 173))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('p53', 'Gene', '7157', (40, 43))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (77, 101))	('p53', 'Gene', (255, 258))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('Adrenocortical Carcinogenesis', 'Disease', 'MESH:D063646', (47, 76))	('germline mutations', 'Var', (229, 247))	('p53', 'Gene', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (77, 101))	('familial cancer', 'Disease', 'MESH:D009369', (183, 198))	('ACC', 'Phenotype', 'HP:0006744', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('Adrenocortical carcinoma', 'Disease', (77, 101))	('Adrenocortical Carcinogenesis', 'Disease', (47, 76))	('familial cancer', 'Disease', (183, 198))	('tumor', 'Disease', (259, 264))	('component tumor of the Li Fraumeni Syndrome', 'Disease', (130, 173))	('p53', 'Gene', '7157', (255, 258))	('tumor', 'Disease', (140, 145))
126593	21930187	p53 activity is tightly regulated by multiple post-translational mechanisms, disruption of which may lead to tumorigenesis.	('p53', 'Gene', (0, 3))	('disruption', 'Var', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('activity', 'MPA', (4, 12))	('tumor', 'Disease', (109, 114))	('lead to', 'Reg', (101, 108))
126594	21930187	Additionally, p53-associated ACC demonstrates a strong predominance in infants and children.	('p53-associated', 'Var', (14, 28))	('ACC', 'Phenotype', 'HP:0006744', (29, 32))	('ACC', 'Disease', (29, 32))	('infants', 'Species', '9606', (71, 78))	('children', 'Species', '9606', (83, 91))
126597	21930187	Lesions in the p53-tumor suppressor signaling pathway play a fundamental role in the pathogenesis of adrenocortical carcinoma (ACC).	('adrenocortical carcinoma', 'Disease', (101, 125))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (101, 125))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (101, 125))	('ACC', 'Phenotype', 'HP:0006744', (127, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('tumor', 'Disease', (19, 24))	('Lesions', 'Var', (0, 7))
126598	21930187	Similarly, germline mutations in p53 are associated with development of the Li-Fraumeni Syndrome (LFS, OMIM #151623), an autosomal-dominant cancer predisposition syndrome.	('associated with', 'Reg', (41, 56))	('Li-Fraumeni Syndrome', 'Disease', 'MESH:D016864', (76, 96))	('p53', 'Gene', (33, 36))	('germline mutations', 'Var', (11, 29))	('autosomal-dominant cancer', 'Disease', (121, 146))	('Li-Fraumeni Syndrome', 'Disease', (76, 96))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('autosomal-dominant cancer', 'Disease', 'MESH:D009369', (121, 146))
126605	21930187	Elevated levels of MDM2 result in loss of p53 activity and propensity for tumor formation.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MDM2', 'Var', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('activity', 'MPA', (46, 54))	('tumor', 'Disease', (74, 79))	('loss', 'NegReg', (34, 38))	('p53', 'Protein', (42, 45))
126607	21930187	Both MDM2- and MDMX- deficient mice are embryonic lethal, presumably due to massive overexpression of p53.	('MDM2-', 'Var', (5, 10))	('mice', 'Species', '10090', (31, 35))	('overexpression', 'PosReg', (84, 98))	('p53', 'Gene', (102, 105))
126609	21930187	Similarly, the embryonic lethality of a transgenic MDM2 mouse deficient in E3 ubiquitin ligase activity is rescued by loss of p53.	('embryonic lethality', 'Disease', 'MESH:D020964', (15, 34))	('embryonic lethality', 'Disease', (15, 34))	('mouse', 'Species', '10090', (56, 61))	('transgenic', 'Species', '10090', (40, 50))	('deficient', 'NegReg', (62, 71))	('loss', 'Var', (118, 122))	('activity', 'MPA', (95, 103))	('p53', 'Gene', (126, 129))
126614	21930187	Of the few polymorphisms that have been associated with disease, the most studied has been a single-nucleotide polymorphism at codon 72, which results in the substitution of an arginine for a proline residue.	('arginine', 'MPA', (177, 185))	('arginine', 'Chemical', 'MESH:D001120', (177, 185))	('substitution', 'Var', (158, 170))	('proline', 'Chemical', 'MESH:D011392', (192, 199))
126617	21930187	Several association studies have implicated the codon 72 polymorphism in susceptibility to cervical, lung, breast and other cancers.	('breast', 'Disease', (107, 113))	('codon 72 polymorphism', 'Var', (48, 69))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung', 'Disease', (101, 105))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cervical', 'Disease', (91, 99))	('polymorphism', 'Var', (57, 69))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
126618	21930187	Nonetheless, Whibley and colleagues aptly point out that none of the many genome-wide association studies of breast, gastric, lung, colorectal, prostate or other cancers have demonstrated statistically-significant associations with the codon 72 SNP.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('lung', 'Disease', (126, 130))	('cancers', 'Disease', (162, 169))	('gastric', 'Disease', (117, 124))	('colorectal, prostate', 'Disease', 'MESH:D015179', (132, 152))	('codon 72 SNP', 'Var', (236, 248))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast', 'Disease', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
126621	21930187	This variant is adjacent to phosphorylation targets of p38 and HIPK2 and may thus influence phosphorylation at this site, consequently altering the p53-mediated transcription of pro-apoptotic genes, as has been reported.	('p53-mediated', 'Gene', (148, 160))	('phosphorylation', 'MPA', (92, 107))	('influence', 'Reg', (82, 91))	('HIPK2', 'Gene', '28996', (63, 68))	('variant', 'Var', (5, 12))	('altering', 'Reg', (135, 143))	('p38', 'Gene', '1432', (55, 58))	('HIPK2', 'Gene', (63, 68))	('p38', 'Gene', (55, 58))
126622	21930187	Among patients with LFS, carriers of the SNP309G variant develop tumors at an accelerated rate.	('SNP309G', 'Var', (41, 48))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('develop', 'PosReg', (57, 64))
126625	21930187	Examination of the data contained within this database reveals an excess of adrenocortical tumors in carriers of germline p53-mutations in comparison to their rate in the general population.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('germline', 'Var', (113, 121))	('adrenocortical tumors', 'Disease', (76, 97))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (76, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('p53-mutations', 'Gene', (122, 135))	('excess', 'PosReg', (66, 72))
126630	21930187	In the first published study, 3 of 6 (50%) children with ACC (none of whom had a family history consistent with LFS) had a germline p53 mutation.	('germline', 'Var', (123, 131))	('p53', 'Gene', (132, 135))	('children', 'Species', '9606', (43, 51))	('ACC', 'Phenotype', 'HP:0006744', (57, 60))	('ACC', 'Disease', (57, 60))
126634	21930187	In an analysis of 36 adrenocortical carcinomas with LOH at 17p13, only 12/36 tumors carried p53 mutations, although these tumors were significantly larger and were associated with a more advanced stage and shorter disease-free survival.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('adrenocortical carcinomas', 'Disease', (21, 46))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (21, 46))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('shorter', 'NegReg', (206, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('p53', 'Gene', (92, 95))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (21, 46))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('disease-free survival', 'CPA', (214, 235))	('mutations', 'Var', (96, 105))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (21, 45))
126635	21930187	Using comparative genomic hybridization, both Figueiredo and colleagues and James and colleagues separately identified a number of recurrent copy number changes among ACCs in children.	('ACC', 'Phenotype', 'HP:0006744', (167, 170))	('children', 'Species', '9606', (175, 183))	('ACCs', 'Gene', (167, 171))	('copy number changes', 'Var', (141, 160))	('ACCs', 'Gene', '84680', (167, 171))
126638	21930187	Additionally, Zhao and colleagues demonstrated that increasing numbers of chromosomal changes corresponded to increasingly malignant behavior of the tumors.	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('increasingly', 'PosReg', (110, 122))	('tumors', 'Disease', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('chromosomal changes', 'Var', (74, 93))
126639	21930187	Among individuals with germline p53 mutations, however, a substantial increase in CNV was noted and this was further increased amongst p53 heterozygous individuals with a history of cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('increase', 'PosReg', (70, 78))	('increased', 'PosReg', (117, 126))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('p53', 'Gene', (32, 35))	('cancer', 'Disease', (182, 188))	('CNV', 'Disease', (82, 85))
126640	21930187	Knowing that >= 50% of children with ACC harbor germline mutations in p53, it would thus stand to reason that these children have increased rates of copy number variation and that specific variants may explain development of disease in individuals with low-penetrance p53 alleles and may also explain the heterogeneity of disease among individuals with a similar genetic background.	('copy number variation', 'MPA', (149, 170))	('p53', 'Gene', (70, 73))	('p53', 'Gene', (268, 271))	('variants', 'Var', (189, 197))	('explain', 'Reg', (202, 209))	('children', 'Species', '9606', (23, 31))	('ACC', 'Phenotype', 'HP:0006744', (37, 40))	('children', 'Species', '9606', (116, 124))	('increased', 'PosReg', (130, 139))	('germline mutations', 'Var', (48, 66))	('rates', 'MPA', (140, 145))
126643	21930187	Further analysis was able to identify a unique transcriptomic signature of tumors bearing an inactivating mutation of p53.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('p53', 'Gene', (118, 121))	('inactivating mutation', 'Var', (93, 114))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
126645	21930187	the common R175H mutation) or by disrupting the ability of the protein to directly bind DNA (eg.	('R175H', 'Mutation', 'rs28934578', (11, 16))	('bind', 'Interaction', (83, 87))	('R175H', 'Var', (11, 16))	('ability', 'MPA', (48, 55))	('disrupting', 'NegReg', (33, 43))
126648	21930187	Among mutations lacking the dominant-interfering activity, however, determination of LOH within the tumors remains an important component of the assessment of p53 status.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('mutations', 'Var', (6, 15))
126650	21930187	In almost all of these individuals a common germline mutation within the oligomerization domain of p53, p.R337H, was identified.	('p.R337H', 'Mutation', 'rs121912664', (104, 111))	('p.R337H', 'Var', (104, 111))	('p53', 'Gene', (99, 102))
126653	21930187	Substitution of histidine at position 337 disrupts this interaction in a pH-dependent manner.	('Substitution', 'Var', (0, 12))	('histidine', 'Chemical', 'MESH:D006639', (16, 25))	('disrupts', 'NegReg', (42, 50))	('interaction', 'Interaction', (56, 67))
126656	21930187	Initially, the R337H mutation was thought to predispose carriers primarily to ACC; however, recently it has been identified in association with families meeting criteria for LFL (Li Fraumeni-like syndrome) as well as with individuals with breast cancer, choroid plexus carcinoma and osteosarcoma.	('breast cancer', 'Disease', (239, 252))	('association', 'Reg', (127, 138))	('R337H', 'Mutation', 'rs121912664', (15, 20))	('R337H', 'Var', (15, 20))	('osteosarcoma', 'Disease', (283, 295))	('osteosarcoma', 'Disease', 'MESH:D012516', (283, 295))	('choroid plexus carcinoma', 'Disease', (254, 278))	('LFL', 'Disease', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (182, 204))	('Fraumeni-like syndrome', 'Disease', (182, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (254, 278))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('ACC', 'Disease', (78, 81))	('osteosarcoma', 'Phenotype', 'HP:0002669', (283, 295))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (254, 278))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))
126657	21930187	Nevertheless, ACC constitutes the plurality of tumors identified in carriers of the R337H allele.	('plurality of tumors', 'Disease', 'MESH:D009369', (34, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('R337H', 'Mutation', 'rs121912664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('R337H', 'Var', (84, 89))	('ACC', 'Phenotype', 'HP:0006744', (14, 17))	('plurality of tumors', 'Disease', (34, 53))
126659	21930187	In studies not reliant on a family history of cancer, a number of low-penetrance alleles have been identified including the R337H allele.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('R337H', 'Mutation', 'rs121912664', (124, 129))	('R337H', 'Var', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
126660	21930187	In vitro studies of several of these alleles, including R175L and R337H, have revealed a p53 protein with retention of a substantial proportion of its wild-type activity.	('R337H', 'Mutation', 'rs121912664', (66, 71))	('R175L', 'Var', (56, 61))	('R337H', 'Var', (66, 71))	('p53', 'Gene', (89, 92))	('R175L', 'Mutation', 'rs28934578', (56, 61))
126661	21930187	They subsequently used a yeast-based assay to assess the ability of each mutant to transactivate eight different p53-response elements from known target genes.	('p53-response elements', 'Gene', (113, 134))	('mutant', 'Var', (73, 79))	('transactivate', 'Reg', (83, 96))	('yeast', 'Species', '4932', (25, 30))
126663	21930187	Consistent with the analyses of the R175L and R337H alleles, many of the other ACC-associated alleles are predicted, in this assay, to retain partial p53 function.	('R175L', 'Mutation', 'rs28934578', (36, 41))	('R337H', 'Mutation', 'rs121912664', (46, 51))	('R337H', 'Var', (46, 51))	('ACC-associated', 'Disease', (79, 93))	('ACC', 'Phenotype', 'HP:0006744', (79, 82))	('R175L', 'Var', (36, 41))
126667	21930187	In contrast, 79% of individuals with breast cancer, 75% of individuals with brain tumors and 78% of individuals with bone tumors are so classified, suggesting again that a subset of p53 mutations in ACC may have tissue-specific effects and may not predispose to other LFS component tumors.	('bone tumors', 'Disease', 'MESH:D001859', (117, 128))	('LFS component tumors', 'Disease', 'MESH:D016864', (268, 288))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('brain tumors', 'Disease', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('ACC', 'Phenotype', 'HP:0006744', (199, 202))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('p53', 'Gene', (182, 185))	('breast cancer', 'Disease', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('LFS component tumors', 'Disease', (268, 288))	('bone tumors', 'Disease', (117, 128))	('ACC', 'Gene', (199, 202))	('mutations', 'Var', (186, 195))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('bone tumors', 'Phenotype', 'HP:0010622', (117, 128))	('brain tumors', 'Disease', 'MESH:D001932', (76, 88))	('brain tumors', 'Phenotype', 'HP:0030692', (76, 88))
126671	21930187	Does their presence suggest other modifier gene variants to promote tumorigenesis in a milder background?	('tumor', 'Disease', (68, 73))	('promote', 'PosReg', (60, 67))	('variants', 'Var', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
126672	21930187	Finally, what can we learn regarding the biology of the adrenal gland that sensitizes it to tumor formation in the setting of alleles that do not lead to tumorigenesis in other tissues?	('alleles', 'Var', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (154, 159))
126675	21930187	The massive apoptosis that occurs during the regression of the fetal adrenal cortex over the first years of life, may thus transiently establish a vulnerable state, whereby perturbations in the apoptotic machinery (such as loss of p53) could interfere with the physiologic regression of fetal adrenal cells and predispose towards tumor formation although this remains to be demonstrated.	('loss of', 'Var', (223, 230))	('perturbations', 'Var', (173, 186))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('interfere', 'NegReg', (242, 251))	('p53', 'Gene', (231, 234))	('tumor', 'Disease', (330, 335))	('predispose', 'Reg', (311, 321))	('physiologic regression', 'CPA', (261, 283))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
126677	21930187	Given the strong association between ACC and p53 mutations in children (and less so in adults), different transcriptional profiles, different clinical behavior and distinct molecular pathogenesis (see the review by Almeida in this issue), we propose that ACC in children represents a biologically distinct disease entity from that in adults, and that it results from failed regression of fetal cells, which may be predisposed by lesions in the apoptotic pathway, most commonly, mutations in p53.	('mutations', 'Var', (478, 487))	('p53', 'Gene', (45, 48))	('p53', 'Gene', (491, 494))	('children', 'Species', '9606', (262, 270))	('children', 'Species', '9606', (62, 70))	('mutations', 'Var', (49, 58))	('ACC', 'Phenotype', 'HP:0006744', (37, 40))	('apoptotic pathway', 'Pathway', (444, 461))	('ACC', 'Gene', (37, 40))	('ACC', 'Phenotype', 'HP:0006744', (255, 258))	('ACC', 'Disease', (255, 258))
126681	21930187	A recent report detailing a clinical surveillance protocol to monitor individuals with germline p53 mutations demonstrated that among patients who underwent surveillance, tumors were detected at an earlier stage and tumor-associated morbidity and mortality were significantly decreased in comparison to a control population that did not undergo active organ-targeted screening.	('tumor', 'Disease', (216, 221))	('mutations', 'Var', (100, 109))	('p53', 'Gene', (96, 99))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('patients', 'Species', '9606', (134, 142))	('decreased', 'NegReg', (276, 285))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
126682	21930187	This finding provides compelling motivation for screening pre-symptomatic first-degree relatives of affected individuals, since identification of mutation-carriers may allow for early identification of tumors that would otherwise not come to diagnosis until an advanced stage.	('mutation-carriers', 'Var', (146, 163))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumors', 'Disease', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
126687	21930187	Several murine models of p53 dysfunction have been generated, including p53-mutant overexpression, knock-out and targeted substitutions resulting in mutant proteins replicating those identified in humans with LFS.	('proteins', 'Protein', (156, 164))	('mutant', 'Var', (149, 155))	('humans', 'Species', '9606', (197, 203))	('p53-mutant', 'Gene', (72, 82))	('substitutions', 'Var', (122, 135))	('murine', 'Species', '10090', (8, 14))
126689	21930187	Strikingly absent from the tumor profile of p53-deficient or mutant mice, however, are adrenocortical carcinomas, particularly given the excess of ACC in humans with p53-alterations.	('mice', 'Species', '10090', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (87, 111))	('humans', 'Species', '9606', (154, 160))	('adrenocortical carcinomas', 'Disease', (87, 112))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (87, 112))	('ACC', 'Phenotype', 'HP:0006744', (147, 150))	('mutant', 'Var', (61, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (87, 112))
126696	21930187	Mice carrying an inactivating mutation in Tpp/Acd, which normally functions in the shelterin complex to protect telomeres, and a single wild-type p53 allele develop diverse tumor types, including adrenocortical carcinoma at low frequency.	('Tpp/Acd', 'Gene', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (196, 220))	('develop', 'Reg', (157, 164))	('inactivating mutation', 'Var', (17, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('adrenocortical carcinoma', 'Disease', (196, 220))	('tumor', 'Disease', (173, 178))	('Mice', 'Species', '10090', (0, 4))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (196, 220))
126698	21930187	In support of this possibility, the age of tumor onset correlates with telomere length in LFS patients with germline p53 mutations.	('mutations', 'Var', (121, 130))	('p53', 'Gene', (117, 120))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('germline', 'Var', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('telomere length', 'MPA', (71, 86))
126700	21930187	Deletion of the TGF-beta family member, Inhibin-alpha, cooperates with castration and ovariectomy and nearly all male and female mice develop adrenocortical tumors, indicating that inhibin functions as a tumor suppressor in the adrenal cortex.	('tumor', 'Disease', (157, 162))	('adrenocortical tumors', 'Disease', (142, 163))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('Inhibin-alpha', 'Gene', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (142, 163))	('tumor', 'Disease', (204, 209))	('develop', 'PosReg', (134, 141))	('TGF-beta', 'Gene', (16, 24))	('mice', 'Species', '10090', (129, 133))	('Inhibin-alpha', 'Gene', '16322', (40, 53))	('Deletion', 'Var', (0, 8))
126701	21930187	In support of these findings, Inhibin-alpha mutations and loss of expression has been observed in a subset of human adrenocortical carcinomas.	('loss of expression', 'NegReg', (58, 76))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (116, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (116, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('Inhibin-alpha', 'Gene', (30, 43))	('human', 'Species', '9606', (110, 115))	('mutations', 'Var', (44, 53))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (116, 141))	('Inhibin-alpha', 'Gene', '16322', (30, 43))	('adrenocortical carcinomas', 'Disease', (116, 141))
126706	21930187	Nonetheless, recent advances lend promise to the possibility of therapeutic manipulation of the pathway in tumors with aberrant p53-signaling.	('aberrant', 'Var', (119, 127))	('p53-signaling', 'Protein', (128, 141))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
126712	21930187	In addition, expression array analyses of the effects of Actinomycin D were indistinguishable from those of the MDM2 inhibitor nutlin in p53 wild-type and mutant cells.	('p53', 'Gene', (137, 140))	('mutant', 'Var', (155, 161))	('Actinomycin D', 'Chemical', 'MESH:D003609', (57, 70))
126714	21930187	A further mode of downregulation of p53 activity occurs via deacetylation of lysine 382 in the C-terminus of the protein.	('p53', 'Protein', (36, 39))	('lysine 382', 'Var', (77, 87))	('lysine', 'Chemical', 'MESH:D008239', (77, 83))	('deacetylation', 'MPA', (60, 73))	('activity', 'MPA', (40, 48))	('downregulation', 'NegReg', (18, 32))
126716	21930187	Consequently, inhibition of SIRT1 and SIRT2 stands to block de-acetylation of p53 and increase p53-activity.	('increase', 'PosReg', (86, 94))	('SIRT1', 'Gene', (28, 33))	('SIRT2', 'Gene', '22933', (38, 43))	('de-acetylation', 'MPA', (60, 74))	('p53', 'Protein', (78, 81))	('block', 'NegReg', (54, 59))	('SIRT1', 'Gene', '23411', (28, 33))	('p53-activity', 'MPA', (95, 107))	('SIRT2', 'Gene', (38, 43))	('inhibition', 'Var', (14, 24))
126718	21930187	An alternative strategy to interfering with MDM2/MDM4/p53 interactions, involves screening large libraries for agents that interact selectively with mutant forms of p53.	('MDM4', 'Gene', (49, 53))	('p53', 'Gene', (165, 168))	('mutant', 'Var', (149, 155))	('MDM4', 'Gene', '4194', (49, 53))
126719	21930187	Indeed, the recognition that a majority of tumors express an aberrant p53 molecule, lends theoretical credence to this approach.	('aberrant', 'Var', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('p53 molecule', 'Protein', (70, 82))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
126721	21930187	Recent identification of a small molecule that binds to the DNA-binding domain of p53 and stabilizes interactions with DNA was identified and shown to reactivate DNA binding p53 mutant R273H and structural mutant R249S.	('interactions', 'Interaction', (101, 113))	('R249S', 'Mutation', 'rs28934571', (213, 218))	('p53', 'Gene', (174, 177))	('R273H', 'Var', (185, 190))	('R273H', 'Mutation', 'rs28934576', (185, 190))	('R249S', 'Var', (213, 218))	('reactivate', 'PosReg', (151, 161))
126723	21930187	Finally, the unique biochemical characteristics of the R337H mutant and its pH-dependent loss-of-function may offer a distinct mechanism of p53-restoration, by targeting cellular mechanisms that regulate intracellular proton transport, such as the sodium-hydrogen exchanger family of cell-surface proteins, inhibitors of which currently exist in clinical practice.	('intracellular proton transport', 'MPA', (204, 234))	('loss-of-function', 'NegReg', (89, 105))	('hydrogen', 'Chemical', 'MESH:D006859', (255, 263))	('R337H', 'Var', (55, 60))	('R337H', 'Mutation', 'rs121912664', (55, 60))
126724	21930187	Unlike several of the recent success stories with targeted therapeutics in chronic myelogenous leukemia and melanoma, wherein a single genetic aberration could be targeted in a large proportion of disease carriers, the multitude of mutations in p53 may limit development of precise targeted therapeutics, or may require the adoption of mutant-specific reactivating drugs (as has recently been demonstrated for the Y220C mutant).	('Y220C', 'Var', (414, 419))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('Y220C', 'Mutation', 'rs121912666', (414, 419))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (83, 103))	('p53', 'Gene', (245, 248))	('mutations', 'Var', (232, 241))	('chronic myelogenous leukemia', 'Disease', (75, 103))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (75, 103))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (75, 103))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('limit', 'NegReg', (253, 258))	('require', 'Reg', (312, 319))	('melanoma', 'Disease', (108, 116))
126726	21930187	It has become clear, in the more than 20 years since the identification of ACC as a component of the LFS, that p53 plays a dominant role in the pathogenesis of pediatric ACCs, while its role in adult tumors remains to be defined.	('adult tumors', 'Disease', (194, 206))	('ACC', 'Phenotype', 'HP:0006744', (75, 78))	('ACC', 'Phenotype', 'HP:0006744', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('ACCs', 'Gene', (170, 174))	('ACCs', 'Gene', '84680', (170, 174))	('adult tumors', 'Disease', 'MESH:C538052', (194, 206))	('p53', 'Var', (111, 114))
126728	21930187	Adrenocortical carcinomas present in excess among carriers of germline p53 mutations p53-associated ACC occurs predominantly in the pediatric age group Mouse models of p53-loss do not develop ACC Pediatric ACC is occasionally associated with low-penetrance p53 alleles which retain substantial protein activity Elements of adrenal development, including regression of the fetal zone, may explain a unique predisposition to tumorigenesis in children.	('tumor', 'Phenotype', 'HP:0002664', (423, 428))	('ACC', 'Phenotype', 'HP:0006744', (206, 209))	('Adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (0, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (15, 25))	('tumor', 'Disease', (423, 428))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (0, 24))	('p53', 'Gene', (71, 74))	('ACC', 'Phenotype', 'HP:0006744', (192, 195))	('mutations', 'Var', (75, 84))	('ACC', 'Phenotype', 'HP:0006744', (100, 103))	('Adrenocortical carcinomas', 'Disease', 'MESH:D018268', (0, 25))	('children', 'Species', '9606', (440, 448))	('Adrenocortical carcinomas', 'Disease', (0, 25))	('tumor', 'Disease', 'MESH:D009369', (423, 428))	('Mouse', 'Species', '10090', (152, 157))
126782	20879070	Whole-body positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (18F-FDG) images showed significant 18F-FDG uptake in the huge left adrenal mass and no significant uptake at any other sites.	('uptake', 'MPA', (132, 138))	('18F-FDG', 'Var', (124, 131))	('18F-FDG', 'Chemical', 'MESH:D019788', (89, 96))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (65, 87))	('18F-FDG', 'Chemical', 'MESH:D019788', (124, 131))
126827	33397036	In relation to these striking phenotypes, NR5A1/Nr5a1 has the potential to reprogram cells to steroidogenic cells, endow pluripotency, and regulate cell proliferation.	('regulate', 'Reg', (139, 147))	('endow pluripotency', 'MPA', (115, 133))	('reprogram cells', 'CPA', (75, 90))	('cell proliferation', 'CPA', (148, 166))	('steroid', 'Chemical', 'MESH:D013256', (94, 101))	('NR5A1/Nr5a1', 'Var', (42, 53))
126830	33397036	Additional in vivo reporter gene assays performed with transgenic mice and disruption studies of the NR5A1-binding site have confirmed the role of NR5A1 in Cyp11a1 gene transcription.	('transgenic mice', 'Species', '10090', (55, 70))	('disruption', 'Var', (75, 85))	('Cyp11a1', 'Gene', '13070', (156, 163))	('Cyp11a1', 'Gene', (156, 163))	('NR5A1', 'Gene', (147, 152))	('transcription', 'MPA', (169, 182))
126847	33397036	This timing of Nr5a1 disruption by Amh-Cre in Sertoli cells is likely to correspond to that of Nr5a1 disruption by Cyp11a1-Cre in Leydig cells.	('Amh', 'Gene', '11705', (35, 38))	('Cyp11a1', 'Gene', '13070', (115, 122))	('Nr5a1', 'Gene', (15, 20))	('disruption', 'Var', (21, 31))	('Cyp11a1', 'Gene', (115, 122))	('Amh', 'Gene', (35, 38))	('Nr5a1', 'Gene', (95, 100))	('Sertoli cell', 'Phenotype', 'HP:0100619', (46, 58))	('Sertoli cells', 'Phenotype', 'HP:0100619', (46, 59))
126871	33397036	Taken together, CDK7 might be assumed to serve as a direct link between cell cycle progression through activation of other CDKs and transcription through NR5A1 phosphorylation.	('CDKs', 'Gene', '12566;12572', (123, 127))	('CDKs', 'Gene', (123, 127))	('phosphorylation', 'Var', (160, 175))	('cell cycle', 'CPA', (72, 82))	('CDK7', 'Gene', '12572', (16, 20))	('CDK7', 'Gene', (16, 20))	('NR5A1', 'Gene', (154, 159))	('activation', 'PosReg', (103, 113))
126873	33397036	Dissociation of NR5A1 from the centrosome promoted DNA-dependent protein kinase (DNA-PK) recruitment and thereby activated CDK2, whose activity is required for the duplication of DNA and the centrosome.	('Dissociation', 'Var', (0, 12))	('DNA-dependent protein kinase', 'Gene', '19090', (51, 79))	('NR5A1', 'Gene', (16, 21))	('activated', 'PosReg', (113, 122))	('DNA-PK', 'Gene', '19090', (81, 87))	('recruitment', 'MPA', (89, 100))	('DNA-dependent protein kinase', 'Gene', (51, 79))	('CDK2', 'Gene', '12566', (123, 127))	('promoted', 'PosReg', (42, 50))	('DNA-PK', 'Gene', (81, 87))	('CDK2', 'Gene', (123, 127))
126874	33397036	When Nr5a1 is knocked down, CDK2 is aberrantly activated by DNA-PK, and thus, the centrosome is over-duplicated.	('CDK2', 'Gene', '12566', (28, 32))	('Nr5a1', 'Gene', (5, 10))	('CDK2', 'Gene', (28, 32))	('activated', 'PosReg', (47, 56))	('knocked down', 'Var', (14, 26))	('DNA-PK', 'Gene', '19090', (60, 66))	('DNA-PK', 'Gene', (60, 66))
126882	33397036	This result could provide the rationale behind highly-expressed NR5A1 causing poor clinical outcomes in adrenocortical carcinoma.	('highly-expressed', 'Var', (47, 63))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (104, 128))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (104, 128))	('NR5A1', 'Gene', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('adrenocortical carcinoma', 'Disease', (104, 128))
126883	33397036	Indeed, Nr5a1 knockdown resulted in a decrease in glucose consumption as well as in glycolytic gene expression.	('Nr5a1', 'Gene', (8, 13))	('decrease', 'NegReg', (38, 46))	('glycolytic gene expression', 'MPA', (84, 110))	('glucose', 'Chemical', 'MESH:D005947', (50, 57))	('knockdown', 'Var', (14, 23))	('glucose consumption', 'MPA', (50, 69))
126885	33397036	As expected, intracellular ATP concentration decreased with Nr5a1 knockdown.	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('decreased', 'NegReg', (45, 54))	('intracellular ATP concentration', 'MPA', (13, 44))	('Nr5a1', 'Gene', (60, 65))	('knockdown', 'Var', (66, 75))
126889	33397036	NADPH concentration also decreased with Nr5a1 knockdown.	('NADPH', 'Chemical', 'MESH:D009249', (0, 5))	('knockdown', 'Var', (46, 55))	('decreased', 'NegReg', (25, 34))	('Nr5a1', 'Gene', (40, 45))	('NADPH concentration', 'MPA', (0, 19))
126893	33397036	Expectedly, the amount of cholesterol in mitochondria decreased with Nr5a1 knockdown.	('cholesterol', 'Chemical', 'MESH:D002784', (26, 37))	('amount of cholesterol in mitochondria', 'MPA', (16, 53))	('knockdown', 'Var', (75, 84))	('decreased', 'NegReg', (54, 63))	('Nr5a1', 'Gene', (69, 74))
126923	32650779	Overexpression of HOTAIR has been associated with poor prognosis, invasiveness and aggressiveness of various cancer types.	('aggressiveness', 'Phenotype', 'HP:0000718', (83, 97))	('HOTAIR', 'Gene', (18, 24))	('invasiveness and aggressiveness of various cancer', 'Disease', 'MESH:D009362', (66, 115))	('HOTAIR', 'Gene', '100124700', (18, 24))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
126924	32650779	Complex secondary structure and ability to form independent structural domains ensure the multi-acting nature of HOTAIR and it has been defined to contribute to various cellular mechanisms via different molecular interactions such as scaffolding protein complexes, decoying microRNAs, epigenetically targeting genes and enabling RNA-protein/DNA-protein interactions.	('epigenetically targeting', 'Var', (285, 309))	('microRNAs', 'MPA', (274, 283))	('enabling', 'PosReg', (320, 328))	('HOTAIR', 'Gene', (113, 119))	('RNA-protein/DNA-protein interactions', 'Interaction', (329, 365))	('contribute', 'Reg', (147, 157))	('HOTAIR', 'Gene', '100124700', (113, 119))	('genes', 'Gene', (310, 315))	('decoying', 'NegReg', (265, 273))
126961	32650779	The cells were lysed using RIPA lysis buffer containing 1 mM Na3VO2, 1 mM NaF, and 1% protease inhibitor cocktail (Roche Diagnostics, Indianapolis, IN, USA), and the lysates were subjected to Western blot analysis as described previously.	('NaF', 'Gene', '3576', (74, 77))	('NaF', 'Gene', (74, 77))	('Na3VO2', 'Chemical', '-', (61, 67))	('RIPA lysis buffer', 'Chemical', '-', (27, 44))	('Na3VO2', 'Var', (61, 67))
126996	32650779	To understand the possible interplay between two molecules in detail, we knocked down HOTAIR expression with siRNA transfection in HuH-7 cell line and then analyzed mRNA and protein expression of c-Met.	('c-Met', 'Gene', (196, 201))	('HOTAIR', 'Gene', '100124700', (86, 92))	('c-Met', 'Gene', '4233', (196, 201))	('knocked', 'Var', (73, 80))	('analyzed', 'Reg', (156, 164))	('mRNA', 'MPA', (165, 169))	('HuH-7', 'Gene', '284424', (131, 136))	('HuH-7', 'Gene', (131, 136))	('HOTAIR', 'Gene', (86, 92))
126997	32650779	Analysis of three independent experiments showed that average of 45% knock-down of HOTAIR (Fig.	('knock-down', 'Var', (69, 79))	('HOTAIR', 'Gene', (83, 89))	('HOTAIR', 'Gene', '100124700', (83, 89))
127025	32650779	We further confirmed the rescue of HGF-suppressed HOTAIR expression after c-Met tyrosine kinase inhibition by SU11274 in HCC cell lines HuH-7, SNU-449, MAHLAVU and SK-HEP-1.	('HCC', 'Gene', '619501', (121, 124))	('HuH-7', 'Gene', '284424', (136, 141))	('SK-HEP-1', 'CellLine', 'CVCL:0525', (164, 172))	('HuH-7', 'Gene', (136, 141))	('HOTAIR', 'Gene', (50, 56))	('HGF', 'Gene', (35, 38))	('c-Met', 'Gene', (74, 79))	('SNU-449', 'CellLine', 'CVCL:0454', (143, 150))	('HCC', 'Gene', (121, 124))	('c-Met', 'Gene', '4233', (74, 79))	('HOTAIR', 'Gene', '100124700', (50, 56))	('SU11274', 'Var', (110, 117))	('SU11274', 'Chemical', 'MESH:C478479', (110, 117))	('HGF', 'Gene', '3082', (35, 38))	('inhibition', 'NegReg', (96, 106))
127026	32650779	c-Met tyrosine kinase inhibition rescued HGF-induced HOTAIR suppression in HCC cell lines (Fig.	('inhibition', 'Var', (22, 32))	('c-Met', 'Gene', '4233', (0, 5))	('HCC', 'Gene', '619501', (75, 78))	('HOTAIR', 'Gene', (53, 59))	('HGF', 'Gene', (41, 44))	('HOTAIR', 'Gene', '100124700', (53, 59))	('HGF', 'Gene', '3082', (41, 44))	('HCC', 'Gene', (75, 78))	('c-Met', 'Gene', (0, 5))
127056	32650779	Immunofluorescent analysis of cytoskeletal organization of F-actin and Vimentin in SNU-398 MET OE clones showed that ectopic MET expression and its suppressive effect on HOTAIR expression was also resulted in thickening of F-actin stress fibrils, and increase in Vimentin expression and polarity (Supplementary Fig.	('Vimentin', 'Gene', '7431', (71, 79))	('ectopic MET expression', 'Var', (117, 139))	('SNU-398', 'CellLine', 'CVCL:0077', (83, 90))	('expression', 'MPA', (272, 282))	('polarity', 'CPA', (287, 295))	('HOTAIR', 'Gene', (170, 176))	('Vimentin', 'Gene', (263, 271))	('HOTAIR', 'Gene', '100124700', (170, 176))	('Vimentin', 'Gene', (71, 79))	('F-actin stress', 'Protein', (223, 237))	('increase', 'PosReg', (251, 259))	('Vimentin', 'Gene', '7431', (263, 271))	('thickening', 'PosReg', (209, 219))
127078	32650779	It is very important to note that inhibition of expression with siRNAs is limited mostly with cytoplasmic HOTAIR mRNA targeting and further studies should be done to address the detailed mechanism of HOTAIR action in means of molecular interactions and/or epigenetic function in HCC cells.	('HOTAIR', 'Gene', (200, 206))	('HCC', 'Gene', '619501', (279, 282))	('HOTAIR', 'Gene', '100124700', (200, 206))	('HCC', 'Gene', (279, 282))	('epigenetic function', 'Var', (256, 275))	('HOTAIR', 'Gene', (106, 112))	('HOTAIR', 'Gene', '100124700', (106, 112))
127086	32650779	HOTAIR over-expression reduced Caveolin-1 expression and activation via suppressing activation of c-Met and its downstream effector Src kinase.	('HOTAIR', 'Gene', '100124700', (0, 6))	('Src', 'Gene', '6714', (132, 135))	('reduced', 'NegReg', (23, 30))	('Caveolin-1', 'Gene', '857', (31, 41))	('expression', 'MPA', (42, 52))	('Caveolin-1', 'Gene', (31, 41))	('over-expression', 'Var', (7, 22))	('c-Met', 'Gene', (98, 103))	('activation', 'MPA', (84, 94))	('suppressing', 'NegReg', (72, 83))	('Src', 'Gene', (132, 135))	('HOTAIR', 'Gene', (0, 6))	('c-Met', 'Gene', '4233', (98, 103))	('activation', 'MPA', (57, 67))
127088	32650779	defined function of HOTAIR in epigenetic regulation of its target genes and they reported Caveolin-1 as one of the most differentially expressed genes in response to HOTAIR knock-down in foreskin fibroblasts.	('epigenetic regulation', 'MPA', (30, 51))	('HOTAIR', 'Gene', (166, 172))	('Caveolin-1', 'Gene', '857', (90, 100))	('HOTAIR', 'Gene', '100124700', (166, 172))	('HOTAIR', 'Gene', (20, 26))	('Caveolin-1', 'Gene', (90, 100))	('knock-down', 'Var', (173, 183))	('HOTAIR', 'Gene', '100124700', (20, 26))
127089	32650779	In addition to the HOTAIR OE data, we showed that HOTAIR knock-down elevated CAV1 expression in HuH-7 cells (Supplementary Fig.	('CAV1', 'Gene', (77, 81))	('expression', 'MPA', (82, 92))	('HOTAIR', 'Gene', (19, 25))	('HOTAIR', 'Gene', (50, 56))	('elevated', 'PosReg', (68, 76))	('HuH-7', 'Gene', '284424', (96, 101))	('HOTAIR', 'Gene', '100124700', (19, 25))	('HOTAIR', 'Gene', '100124700', (50, 56))	('HuH-7', 'Gene', (96, 101))	('CAV1', 'Gene', '857', (77, 81))	('knock-down', 'Var', (57, 67))
127104	32650779	As expected, by attainment of those abilities, HOTAIR over-expression increased metastatic ability of SNU-449 cells which was defined to be highly metastatic in our previous studies in zebrafish xenograft model.	('zebrafish', 'Species', '7955', (185, 194))	('increased', 'PosReg', (70, 79))	('over-expression', 'Var', (54, 69))	('SNU-449', 'CellLine', 'CVCL:0454', (102, 109))	('HOTAIR', 'Gene', (47, 53))	('HOTAIR', 'Gene', '100124700', (47, 53))	('metastatic ability', 'CPA', (80, 98))
127112	32650779	Consistent with HOTAIR over-expression data in SNU-449 cells, c-Met overexpression in SNU-398 cells increased F-actin stress fibrils and Vimentin expression and, HOTAIR knock-down induced Vimentin expression in HuH-7 cells (Supplementary Fig.	('HuH-7', 'Gene', (211, 216))	('c-Met', 'Gene', (62, 67))	('SNU-449', 'CellLine', 'CVCL:0454', (47, 54))	('HOTAIR', 'Gene', '100124700', (162, 168))	('F-actin stress fibrils', 'MPA', (110, 132))	('expression', 'MPA', (146, 156))	('Vimentin', 'Gene', '7431', (188, 196))	('increased', 'PosReg', (100, 109))	('HOTAIR', 'Gene', (162, 168))	('HOTAIR', 'Gene', '100124700', (16, 22))	('Vimentin', 'Gene', (188, 196))	('SNU-398', 'CellLine', 'CVCL:0077', (86, 93))	('HuH-7', 'Gene', '284424', (211, 216))	('c-Met', 'Gene', '4233', (62, 67))	('HOTAIR', 'Gene', (16, 22))	('knock-down', 'Var', (169, 179))	('expression', 'MPA', (197, 207))	('Vimentin', 'Gene', '7431', (137, 145))	('induced', 'Reg', (180, 187))	('Vimentin', 'Gene', (137, 145))
127125	32650779	Analysis of available data generated by siRNA knock-down of HOTAIR in an HCC cell line HepG2, (Fig.	('HCC', 'Gene', '619501', (73, 76))	('HOTAIR', 'Gene', (60, 66))	('HCC', 'Gene', (73, 76))	('HOTAIR', 'Gene', '100124700', (60, 66))	('knock-down', 'Var', (46, 56))	('HepG2', 'CellLine', 'CVCL:0027', (87, 92))
127132	32650779	Considering the complex structure and multifunctional behavior, HOTAIR might be regulating c-Met signaling through physically interacting and epigenetic or transcriptional suppression of c-Met and/or its regulators.	('c-Met', 'Gene', (187, 192))	('epigenetic or transcriptional', 'Var', (142, 171))	('HOTAIR', 'Gene', (64, 70))	('c-Met', 'Gene', (91, 96))	('c-Met', 'Gene', '4233', (187, 192))	('c-Met', 'Gene', '4233', (91, 96))	('regulating', 'Reg', (80, 90))	('HOTAIR', 'Gene', '100124700', (64, 70))	('suppression', 'NegReg', (172, 183))
127134	32650779	In conclusion, HOTAIR over-expression suppresses c-Met expression, activation and also disrupts its organization on plasma membrane by modulating Caveolin-1 expression and activation.	('expression', 'MPA', (157, 167))	('over-expression', 'Var', (22, 37))	('c-Met', 'Gene', (49, 54))	('Caveolin-1', 'Gene', '857', (146, 156))	('activation', 'MPA', (172, 182))	('c-Met', 'Gene', '4233', (49, 54))	('HOTAIR', 'Gene', (15, 21))	('disrupts', 'NegReg', (87, 95))	('organization on plasma membrane', 'MPA', (100, 131))	('modulating', 'Reg', (135, 145))	('HOTAIR', 'Gene', '100124700', (15, 21))	('suppresses', 'NegReg', (38, 48))	('Caveolin-1', 'Gene', (146, 156))	('activation', 'MPA', (67, 77))
127143	32650779	https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE89377 Wu et al., 2018, performed an integrated proteomic and transcriptomic analysis to examine the overall transcriptomic changes in HepG2 cells after HOTAIR knockdown by RNA sequencing (data accessible at NCBI GEO database (Wu et al., 2018), accession GSE98091).	('HepG2', 'CellLine', 'CVCL:0027', (188, 193))	('knockdown', 'Var', (213, 222))	('HOTAIR', 'Gene', '100124700', (206, 212))	('HOTAIR', 'Gene', (206, 212))
127198	31456041	High levels of progesterone and 17 alpha-OHP are a potential consequence of CAH by 21-hydroxylase or 17-hydroxylase deficiency.	('CAH', 'Disease', (76, 79))	('deficiency', 'Var', (116, 126))	('CAH', 'Disease', 'MESH:D000312', (76, 79))	('17 alpha-OHP', 'MPA', (32, 44))	('17 alpha-OHP', 'Chemical', 'MESH:C037605', (32, 44))	('17-hydroxylase', 'Enzyme', (101, 115))	('progesterone', 'Chemical', 'MESH:D011374', (15, 27))	('CAH', 'Phenotype', 'HP:0008258', (76, 79))
127304	30657254	Here, we demonstrate an miRNA-independent mechanism of TARBP2, in which downregulation of the TARBP2 protein promotes sorafenib resistance in HCC cells through stabilization of Nanog expression.	('stabilization', 'MPA', (160, 173))	('promotes', 'PosReg', (109, 117))	('Nanog', 'Gene', '79923', (177, 182))	('downregulation', 'Var', (72, 86))	('sorafenib', 'Chemical', 'MESH:D000077157', (118, 127))	('TARBP2', 'Gene', (94, 100))	('Nanog', 'Gene', (177, 182))	('HCC', 'Gene', (142, 145))	('sorafenib resistance', 'MPA', (118, 138))	('HCC', 'Gene', '619501', (142, 145))
127311	30657254	Plasmids expressing Myc-TARBP2, TARBP2 DeltaC4, and Dicer were kindly provided by A. Gatignol (Daniels et al., 2009).	('Dicer', 'Gene', (52, 57))	('Myc-TARBP2', 'Gene', (20, 30))	('TARBP2', 'Gene', (32, 38))	('DeltaC4', 'DELETION', 'None', (39, 46))	('DeltaC4', 'Var', (39, 46))	('Dicer', 'Gene', '23405', (52, 57))
127312	30657254	TARBP2 or TARBP2 DeltaC4 was transfected into HCC cells for 48 h using jetPRIME (Polyplus-transfection, New York, NY, USA and HyFect  DNA transfection reagent (Leadgene Biomedical, Tainan, Taiwan)).	('HCC', 'Gene', '619501', (46, 49))	('DeltaC4', 'DELETION', 'None', (17, 24))	('TARBP2', 'Gene', (10, 16))	('HCC', 'Gene', (46, 49))	('DeltaC4', 'Var', (17, 24))
127364	30657254	To further confirm the function of TARBP2 in the parental HCC cells, TARBP2 was knocked down using two specific TARBP2-CDS-targeting short hairpin RNAs in Huh7 and PLC5 cells, which expressed higher levels of TARBP2.	('knocked', 'Var', (80, 87))	('HCC', 'Gene', (58, 61))	('TARBP2', 'Gene', (69, 75))	('Huh7', 'Gene', (155, 159))	('HCC', 'Gene', '619501', (58, 61))	('Huh7', 'Gene', '284424', (155, 159))	('CDS', 'Chemical', 'MESH:D002104', (119, 122))
127367	30657254	Inhibition of TARBP2 expression promoted sorafenib resistance in PLC5 cells (Fig.	('promoted', 'PosReg', (32, 40))	('sorafenib', 'Chemical', 'MESH:D000077157', (41, 50))	('TARBP2', 'Gene', (14, 20))	('Inhibition', 'Var', (0, 10))	('sorafenib resistance', 'MPA', (41, 61))
127368	30657254	2G,H), indicating that downregulation of TARBP2 facilitates sorafenib resistance in HCC cells.	('HCC', 'Gene', '619501', (84, 87))	('TARBP2', 'Gene', (41, 47))	('sorafenib resistance', 'MPA', (60, 80))	('facilitates', 'PosReg', (48, 59))	('downregulation', 'Var', (23, 37))	('HCC', 'Gene', (84, 87))	('sorafenib', 'Chemical', 'MESH:D000077157', (60, 69))
127370	30657254	Cell viability was decreased in Huh7/SR cells expressing wild-type TARBP2 and those expressing TARBP2 DeltaC4 (Fig.	('DeltaC4', 'DELETION', 'None', (102, 109))	('TARBP2', 'Gene', (95, 101))	('Cell viability', 'CPA', (0, 14))	('Huh7/SR', 'CellLine', 'CVCL:0336', (32, 39))	('decreased', 'NegReg', (19, 28))	('TARBP2', 'Gene', (67, 73))	('DeltaC4', 'Var', (102, 109))
127381	30657254	Huh7/SR cells were treated with MG132 to inhibit proteasome activity.	('Huh7/SR', 'CellLine', 'CVCL:0336', (0, 7))	('proteasome activity', 'MPA', (49, 68))	('inhibit', 'NegReg', (41, 48))	('MG132', 'Var', (32, 37))	('MG132', 'Chemical', 'MESH:C072553', (32, 37))
127383	30657254	Huh7/SR cells were treated with the lysosome inhibitors ammonium chloride (NH4Cl) and chloroquine (CQ) to inhibit the activity of lysosomal enzymes through neutralizing the lysosomal pH (Choi, 2012; Hart and Young, 1991).	('Huh7/SR', 'CellLine', 'CVCL:0336', (0, 7))	('neutralizing', 'Var', (156, 168))	('activity', 'MPA', (118, 126))	('chloroquine', 'Chemical', 'MESH:D002738', (86, 97))	('ammonium chloride', 'Chemical', 'MESH:D000643', (56, 73))	('lysosomal pH', 'MPA', (173, 185))	('inhibit', 'NegReg', (106, 113))	('lysosomal enzymes', 'Enzyme', (130, 147))	('CQ', 'Chemical', 'MESH:D002738', (99, 101))	('NH4Cl', 'Chemical', 'MESH:D000643', (75, 80))
127384	30657254	The results demonstrated that TARBP2 protein expression was restored through treatment with NH4Cl and CQ in Huh7/SR cells (Fig.	('Huh7/SR', 'CellLine', 'CVCL:0336', (108, 115))	('TARBP2', 'Gene', (30, 36))	('NH4Cl', 'Var', (92, 97))	('expression', 'MPA', (45, 55))	('NH4Cl', 'Chemical', 'MESH:D000643', (92, 97))	('CQ', 'Chemical', 'MESH:D002738', (102, 104))	('restored', 'PosReg', (60, 68))	('protein', 'Protein', (37, 44))
127390	30657254	To further clarify whether the autophagic-lysosomal pathway contributes to TARBP2 protein degradation, ATG5 was knocked down in Huh7/SR cells to inhibit autophagosome biogenesis.	('ATG5', 'Gene', '9474', (103, 107))	('autophagosome biogenesis', 'CPA', (153, 177))	('knocked down', 'Var', (112, 124))	('Huh7/SR', 'CellLine', 'CVCL:0336', (128, 135))	('ATG5', 'Gene', (103, 107))	('TARBP2', 'Gene', (75, 81))	('inhibit', 'NegReg', (145, 152))
127402	30657254	To examine whether TARBP2-mediated Nanog suppression is miRNA-dependent, TARBP2 DeltaC4 was overexpressed in Huh7/SR cells.	('Nanog', 'Gene', (35, 40))	('DeltaC4', 'Var', (80, 87))	('DeltaC4', 'DELETION', 'None', (80, 87))	('TARBP2', 'Gene', (73, 79))	('Huh7/SR', 'CellLine', 'CVCL:0336', (109, 116))	('Nanog', 'Gene', '79923', (35, 40))
127403	30657254	Nanog remained suppressed in the TARBP2 DeltaC4-overexpressing Huh7/SR cells, suggesting that TARBP2-mediated Nanog suppression is miRNA-independent (Fig.	('Nanog', 'Gene', '79923', (110, 115))	('Huh7/SR', 'CellLine', 'CVCL:0336', (63, 70))	('Nanog', 'Gene', (110, 115))	('DeltaC4', 'Var', (40, 47))	('DeltaC4', 'DELETION', 'None', (40, 47))	('Nanog', 'Gene', '79923', (0, 5))	('TARBP2', 'Gene', (33, 39))	('Nanog', 'Gene', (0, 5))
127404	30657254	Additionally, knockdown of TARBP2 increased the expression of the Nanog protein in the Huh7 cells (Fig.	('Nanog', 'Gene', (66, 71))	('Huh7', 'Gene', (87, 91))	('TARBP2', 'Gene', (27, 33))	('expression', 'MPA', (48, 58))	('Huh7', 'Gene', '284424', (87, 91))	('knockdown', 'Var', (14, 23))	('Nanog', 'Gene', '79923', (66, 71))	('increased', 'PosReg', (34, 43))
127408	30657254	The MTT assay demonstrated that the knockdown of TARBP2 enhanced sorafenib resistance, whereas co-knockdown of Nanog resensitized the Huh7 cells to sorafenib treatment (Fig.	('Nanog', 'Gene', '79923', (111, 116))	('Huh7', 'Gene', (134, 138))	('sorafenib', 'Chemical', 'MESH:D000077157', (65, 74))	('Nanog', 'Gene', (111, 116))	('sorafenib', 'Chemical', 'MESH:D000077157', (148, 157))	('Huh7', 'Gene', '284424', (134, 138))	('TARBP2', 'Gene', (49, 55))	('knockdown', 'Var', (36, 45))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('enhanced', 'PosReg', (56, 64))	('sorafenib resistance', 'MPA', (65, 85))
127417	30657254	Genetic changes regulate the cellular stemness of liver CSCs, where specific cell surface markers and functional markers are activated to maintain the features of these cells, including CD24, CD44, CD133, EpCAM, and ALDH1 (Ma et al., 2008; Yamashita and Wang, 2013; Yamashita et al., 2009).	('changes', 'Var', (8, 15))	('CD24', 'Gene', (186, 190))	('CD44', 'Gene', '960', (192, 196))	('CD133', 'Gene', (198, 203))	('CD44', 'Gene', (192, 196))	('cellular stemness', 'CPA', (29, 46))	('EpCAM', 'Gene', (205, 210))	('CD133', 'Gene', '8842', (198, 203))	('ALDH1', 'Gene', (216, 221))	('EpCAM', 'Gene', '4072', (205, 210))	('CD24', 'Gene', '100133941', (186, 190))	('ALDH1', 'Gene', '216', (216, 221))
127420	30657254	We consistently found that these markers were enhanced by the knockdown of TARBP2 in Huh7 cells (Fig.	('Huh7', 'Gene', '284424', (85, 89))	('enhanced', 'PosReg', (46, 54))	('TARBP2', 'Gene', (75, 81))	('Huh7', 'Gene', (85, 89))	('knockdown', 'Var', (62, 71))
127422	30657254	The sphere number was increased in Huh7/SR cells, whereas sphere formation was abolished by the restoration of TARBP2 (Fig.	('Huh7/SR', 'CellLine', 'CVCL:0336', (35, 42))	('restoration', 'Var', (96, 107))	('TARBP2', 'Gene', (111, 117))	('increased', 'PosReg', (22, 31))	('sphere number', 'CPA', (4, 17))
127423	30657254	An increased sphere-forming capacity was observed in TARBP2-knockdown Huh7 cells (Fig.	('increased', 'PosReg', (3, 12))	('sphere-forming capacity', 'CPA', (13, 36))	('Huh7', 'Gene', (70, 74))	('Huh7', 'Gene', '284424', (70, 74))	('TARBP2-knockdown', 'Gene', (53, 69))	('TARBP2-knockdown', 'Var', (53, 69))
127433	30657254	Accordingly, knockdown of TARBP2 reduced the degradation rate of the Nanog protein (Fig.	('Nanog', 'Gene', (69, 74))	('degradation rate', 'MPA', (45, 61))	('reduced', 'NegReg', (33, 40))	('Nanog', 'Gene', '79923', (69, 74))	('TARBP2', 'Gene', (26, 32))	('knockdown', 'Var', (13, 22))
127434	30657254	6F,G), demonstrating that the stabilization of TARBP2 expression accelerates Nanog protein degradation.	('expression', 'Var', (54, 64))	('stabilization', 'Var', (30, 43))	('Nanog', 'Gene', '79923', (77, 82))	('accelerates', 'PosReg', (65, 76))	('Nanog', 'Gene', (77, 82))	('TARBP2', 'Gene', (47, 53))
127451	30657254	These reports suggest that the effects of alteration of TARBP2 expression on cancer development are tissue-specific.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('TARBP2', 'Gene', (56, 62))	('alteration', 'Var', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
127474	30657254	Supporting this concept, the SUMOylation of TARBP2 stabilizes TARBP2 protein expression through reducing its ubiquitination to suppress tumor progression, indicating that the ubiquitination of TARBP2 is essential for cancer progression (Chen et al., 2015).	('stabilizes', 'PosReg', (51, 61))	('ubiquitination', 'MPA', (109, 123))	('expression', 'MPA', (77, 87))	('TARBP2', 'Gene', (62, 68))	('reducing', 'NegReg', (96, 104))	('protein', 'Protein', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('SUMOylation', 'Var', (29, 40))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('suppress', 'NegReg', (127, 135))	('tumor', 'Disease', (136, 141))	('TARBP2', 'Gene', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
127475	30657254	Additionally, autophagy facilitates sorafenib resistance in HCC cells (Liu et al., 2013; Zhai et al., 2014), suggesting that inhibition of autophagy resensitizes HCC cells to sorafenib treatment through blocking the degradation of TARBP2.	('TARBP2', 'Protein', (231, 237))	('blocking', 'NegReg', (203, 211))	('HCC', 'Gene', '619501', (60, 63))	('sorafenib', 'Chemical', 'MESH:D000077157', (175, 184))	('autophagy', 'CPA', (139, 148))	('HCC', 'Gene', (162, 165))	('sorafenib', 'Chemical', 'MESH:D000077157', (36, 45))	('inhibition', 'Var', (125, 135))	('degradation', 'MPA', (216, 227))	('HCC', 'Gene', (60, 63))	('HCC', 'Gene', '619501', (162, 165))
127483	30657254	Restoration of TARBP2 expression resensitizes HCC/SR cells to sorafenib treatment.	('HCC/SR', 'CellLine', 'CVCL:1711', (46, 52))	('sorafenib', 'Chemical', 'MESH:D000077157', (62, 71))	('Restoration', 'Var', (0, 11))	('TARBP2', 'Gene', (15, 21))	('expression', 'MPA', (22, 32))
127488	30657254	HHL conducted the experiments on TARBP2 DeltaC4.	('DeltaC4', 'DELETION', 'None', (40, 47))	('DeltaC4', 'Var', (40, 47))	('HHL', 'Gene', (0, 3))	('HHL', 'Gene', '3280', (0, 3))
127494	29094256	The 24 h UFC level after LDDST was higher in PPNAD and BMAH as compared to ADA (P < 0.017), while no significant difference was observed between PPNAD and BMAH.	('PPNAD', 'Var', (45, 50))	('UFC level', 'MPA', (9, 18))	('PPNAD', 'Chemical', '-', (145, 150))	('higher', 'PosReg', (35, 41))	('PPNAD', 'Chemical', '-', (45, 50))
127495	29094256	After HDDST, 24 h UFC was higher in patients with PPNAD as compared to that of ADA and BMAH (P < 0.017).	('UFC', 'MPA', (18, 21))	('patients', 'Species', '9606', (36, 44))	('higher', 'PosReg', (26, 32))	('PPNAD', 'Chemical', '-', (50, 55))	('PPNAD', 'Var', (50, 55))
127538	29094256	In the present study, patients in the PPNAD group seemed to have a higher incidence rate of developing decreased BMD (osteopenia or osteoporosis) than those with ADA (78.3 vs. 48.0%, P < 0.017), while no differences were found between PPNAD and BMAH groups.	('osteopenia or osteoporosis', 'Disease', (118, 144))	('PPNAD', 'Chemical', '-', (235, 240))	('BMD', 'Disease', (113, 116))	('PPNAD', 'Var', (38, 43))	('patients', 'Species', '9606', (22, 30))	('BMD', 'Disease', 'MESH:D020388', (113, 116))	('PPNAD', 'Chemical', '-', (38, 43))	('osteopenia', 'Phenotype', 'HP:0000938', (118, 128))	('osteopenia or osteoporosis', 'Disease', 'MESH:D001851', (118, 144))	('osteoporosis', 'Phenotype', 'HP:0000939', (132, 144))
127544	29094256	The baseline of 24 h UFC in patients with PPNAD was higher than that of the patients with ADA (383.50 vs. 224.42, normal range: 12.3-103.5 microg/24 h, P < 0.017, Fig.	('patients', 'Species', '9606', (76, 84))	('PPNAD', 'Var', (42, 47))	('higher', 'PosReg', (52, 58))	('PPNAD', 'Chemical', '-', (42, 47))	('UFC', 'MPA', (21, 24))	('patients', 'Species', '9606', (28, 36))
127575	29094256	In the current study, we also found that after DST, the 24 h UFC levels in patients with PPNAD increased, while in the other two groups the 24 h UFC levels remained unchanged or even decreased, which suggested the usefulness of DST in the diagnosis of PPNAD.	('PPNAD', 'Chemical', '-', (252, 257))	('patients', 'Species', '9606', (75, 83))	('DST', 'Var', (47, 50))	('PPNAD', 'Chemical', '-', (89, 94))	('decreased', 'NegReg', (183, 192))	('PPNAD', 'Disease', (89, 94))	('increased', 'PosReg', (95, 104))
127576	29094256	In patients with ADA, the 24 h UFC levels were slightly decreased after DST, which might be partially attributed to the suppressibility of those patients whose basal 24 h UFC values were within the normal range.	('patients', 'Species', '9606', (145, 153))	('decreased', 'NegReg', (56, 65))	('patients', 'Species', '9606', (3, 11))	('DST', 'Var', (72, 75))	('ADA', 'Disease', (17, 20))
127578	29094256	After LDDST, the ratio of 24 h UFC Post/Pre (L) in the PPNAD group was significantly higher than that in the ADA group, while it could not differentiate PPNAD from BMAH.	('PPNAD', 'Chemical', '-', (153, 158))	('higher', 'PosReg', (85, 91))	('PPNAD', 'Var', (55, 60))	('Post', 'Chemical', '-', (35, 39))	('PPNAD', 'Chemical', '-', (55, 60))
127583	29094256	The CNC is primarily caused by germline mutations in the protein kinase A regulatory subunit 1A (PRKAR1A) gene.	('PRKAR1A', 'Gene', (97, 104))	('PRKAR1A', 'Gene', '5573', (97, 104))	('protein kinase A regulatory subunit 1A', 'Gene', '5573', (57, 95))	('CNC', 'Disease', (4, 7))	('germline mutations', 'Var', (31, 49))	('caused by', 'Reg', (21, 30))	('protein kinase A regulatory subunit 1A', 'Gene', (57, 95))
127584	29094256	Nevertheless, several studies demonstrated that patients with isolated PPNAD exhibited specific molecular genetic abnormalities with mutations in phosphodiesterase PDE11A, PDE8B, and the PKA catalytic subunit PRKACA gene.	('genetic abnormalities', 'Disease', 'MESH:D030342', (106, 127))	('PDE11A', 'Gene', (164, 170))	('PDE8B', 'Gene', (172, 177))	('PDE11A', 'Gene', '50940', (164, 170))	('PPNAD', 'Chemical', '-', (71, 76))	('genetic abnormalities', 'Disease', (106, 127))	('PDE8B', 'Gene', '8622', (172, 177))	('mutations', 'Var', (133, 142))	('patients', 'Species', '9606', (48, 56))
127585	29094256	The mutations in various gene loci may differentially influence the cAMP/PKA pathway in patients with isolated PPNAD and CNC, leading to variable levels of UFC.	('cAMP', 'Chemical', '-', (68, 72))	('cAMP/PKA pathway', 'Pathway', (68, 84))	('isolated PPNAD', 'Disease', (102, 116))	('UFC', 'MPA', (156, 159))	('patients', 'Species', '9606', (88, 96))	('CNC', 'Disease', (121, 124))	('mutations', 'Var', (4, 13))	('PPNAD', 'Chemical', '-', (111, 116))	('influence', 'Reg', (54, 63))
127645	26546184	Almost every previous study has examined long-term outcomes exclusively in relation to well-known tumor-related factors, such as tumor stage, high mitotic index/Ki67, and surgical margin status.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('high mitotic', 'Var', (142, 154))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (129, 134))
127655	26546184	Of note, the incidence of postoperative morbidity was lower among patients undergoing a minimally invasive (25 %) versus open (41 %) ACC resection (P = 0.04):undoubtedly related to patient selection.	('minimally', 'Var', (88, 97))	('patient', 'Species', '9606', (181, 188))	('patient', 'Species', '9606', (66, 73))	('lower', 'NegReg', (54, 59))	('ACC', 'Phenotype', 'HP:0006744', (133, 136))	('patients', 'Species', '9606', (66, 74))
127754	26984275	However, in this group of patients followed for a long time the survival in patients with a Ki-67 > 10 % was not statistically different from those with lower proliferating tumours.	('Ki-67 > 10 %', 'Var', (92, 104))	('patients', 'Species', '9606', (76, 84))	('tumours', 'Disease', (173, 180))	('Ki-67', 'Chemical', '-', (92, 97))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('patients', 'Species', '9606', (26, 34))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))
127759	26984275	Higher cut-off levels has also been applied as <20, 20-50, and >50 % to estimate prognosis and Ki-67 was found to be the best marker for overall survival, superior to mitotic count and the mitosis specific antibody phospho-histone H3.	('mitosis', 'Disease', 'None', (189, 196))	('Ki-67', 'Chemical', '-', (95, 100))	('Ki-67', 'Var', (95, 100))	('mitosis', 'Disease', (189, 196))
127764	26984275	Previously only nine patients with ACC have been found to also have neurofibromatosis in the literature and recently a novel germline frame shift mutation (c.5452_5453delAT) in exon 37 of the NF1 gene was described in one such patient.	('neurofibromatosis', 'Disease', (68, 85))	('patient', 'Species', '9606', (21, 28))	('NF1', 'Gene', (192, 195))	('patients', 'Species', '9606', (21, 29))	('neurofibromatosis', 'Disease', 'MESH:C537392', (68, 85))	('patient', 'Species', '9606', (227, 234))	('NF1', 'Gene', '4763', (192, 195))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (68, 85))	('c.5452_5453delAT', 'Mutation', 'c.5452_5453delAT', (156, 172))	('c.5452_5453delAT', 'Var', (156, 172))	('ACC', 'Phenotype', 'HP:0006744', (35, 38))
127779	25871963	Protein kinase A defects and cortisol-producing adrenal tumors Cushing syndrome caused by cortisol-producing adrenal adenomas is a rare condition, associated with high morbidity due to weight gain, diabetes mellitus, osteoporosis, hypertension, muscle weakness, mood disturbance, etc.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('weight gain', 'Disease', 'MESH:D015430', (185, 196))	('cortisol', 'Chemical', 'MESH:D006854', (90, 98))	('defects', 'Var', (17, 24))	('adrenal tumors', 'Disease', (48, 62))	('caused', 'Reg', (80, 86))	('mood disturbance', 'Disease', 'MESH:D019964', (262, 278))	('Protein kinase A defects', 'Phenotype', 'HP:0012175', (0, 24))	('diabetes mellitus', 'Disease', (198, 215))	('muscle weakness', 'Phenotype', 'HP:0001324', (245, 260))	('hypertension', 'Disease', 'MESH:D006973', (231, 243))	('weight gain', 'Disease', (185, 196))	('Cushing syndrome', 'Disease', 'MESH:D003480', (63, 79))	('hypertension', 'Disease', (231, 243))	('adrenal adenomas', 'Disease', 'MESH:D018246', (109, 125))	('osteoporosis', 'Disease', (217, 229))	('osteoporosis', 'Phenotype', 'HP:0000939', (217, 229))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (63, 79))	('muscle weakness', 'Disease', (245, 260))	('weight gain', 'Phenotype', 'HP:0004324', (185, 196))	('cortisol', 'Chemical', 'MESH:D006854', (29, 37))	('diabetes mellitus', 'Disease', 'MESH:D003920', (198, 215))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (109, 125))	('Cushing syndrome', 'Disease', (63, 79))	('hypertension', 'Phenotype', 'HP:0000822', (231, 243))	('mood disturbance', 'Phenotype', 'HP:0001575', (262, 278))	('osteoporosis', 'Disease', 'MESH:D010024', (217, 229))	('adrenal tumors', 'Disease', 'MESH:D000310', (48, 62))	('Protein kinase A', 'Enzyme', (0, 16))	('muscle weakness', 'Disease', 'MESH:D018908', (245, 260))	('adrenal adenomas', 'Disease', (109, 125))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (198, 215))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mood disturbance', 'Disease', (262, 278))
127781	25871963	We present an update on protein kinase A (PKA) defects and Cushing syndrome.	('Cushing syndrome', 'Phenotype', 'HP:0003118', (59, 75))	('defects', 'Var', (47, 54))	('Cushing syndrome', 'Disease', (59, 75))	('Cushing syndrome', 'Disease', 'MESH:D003480', (59, 75))
127782	25871963	The cyclic AMP-dependent PKA catalytic subunit alpha (PRKACA) hotspot point mutation (c.617A>C [p.Leu206Arg]), leading to an increase of basal protein kinase A (PKA) activity, and formation of cortisol-producing adenoma has been frequently shown to cause the most common form of Adrenocorticotropic hormone-independent Cushing syndrome.	('PRKACA', 'Gene', (54, 60))	('p.Leu206Arg', 'Mutation', 'rs386352352', (96, 107))	('Adrenocorticotropic hormone', 'Gene', (279, 306))	('cyclic AMP', 'Chemical', 'MESH:D000242', (4, 14))	('PRKACA', 'Gene', '5566', (54, 60))	('adenoma', 'Disease', 'MESH:D000236', (212, 219))	('activity', 'MPA', (166, 174))	('increase', 'PosReg', (125, 133))	('adenoma', 'Disease', (212, 219))	('c.617A>C', 'Var', (86, 94))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (319, 335))	('Adrenocorticotropic hormone', 'Gene', '5443', (279, 306))	('Adrenocorticotropic hormone-independent Cushing syndrome', 'Phenotype', 'HP:0008259', (279, 335))	('Cushing syndrome', 'Disease', (319, 335))	('cortisol', 'Chemical', 'MESH:D006854', (193, 201))	('c.617A>C', 'SUBSTITUTION', 'None', (86, 94))	('cause', 'Reg', (249, 254))	('Cushing syndrome', 'Disease', 'MESH:D003480', (319, 335))
127783	25871963	Somatic PRKACA mutations have been found in up to 50% of patients with adrenal adenomas.	('adrenal adenomas', 'Phenotype', 'HP:0008256', (71, 87))	('adrenal adenomas', 'Disease', 'MESH:D018246', (71, 87))	('patients', 'Species', '9606', (57, 65))	('mutations', 'Var', (15, 24))	('PRKACA', 'Gene', (8, 14))	('adrenal adenomas', 'Disease', (71, 87))	('PRKACA', 'Gene', '5566', (8, 14))	('found', 'Reg', (35, 40))
127792	25871963	Genetic mutations, causing cortisol-producing tumors have been suspected for years, but only few genetic defects had been discovered until recently.	('Genetic mutations', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('cortisol', 'Chemical', 'MESH:D006854', (27, 35))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
127793	25871963	Patients with McCune-Albright syndrome have somatic mutations in Guanine Nucleotide Binding Protein, Alpha Stimulating (GNAS)1 in their adrenal glands causing cortisol overproduction due to a unique form of bilateral adrenocortical hyperplasia (BAH) or single adenomas.	('bilateral adrenocortical hyperplasia', 'Disease', (207, 243))	('mutations', 'Var', (52, 61))	('Alpha Stimulating (GNAS)1', 'Gene', '2778', (101, 126))	('bilateral adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (207, 243))	('McCune-Albright syndrome', 'Disease', (14, 38))	('causing', 'Reg', (151, 158))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (14, 38))	('BAH', 'Chemical', '-', (245, 248))	('adenomas', 'Disease', 'MESH:D000236', (260, 268))	('Alpha Stimulating (GNAS)1', 'Gene', (101, 126))	('Patients', 'Species', '9606', (0, 8))	('cortisol', 'Chemical', 'MESH:D006854', (159, 167))	('adenomas', 'Disease', (260, 268))	('cortisol overproduction', 'MPA', (159, 182))
127794	25871963	Cushing syndrome caused by primary pigmented nodular adrenocortical disease (PPNAD) is due to mutations in cyclic AMP (cAMP)-dependent protein kinase (PKA) type 1 alpha regulatory subunit (PRKAR1A).	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (35, 75))	('PRKAR1A', 'Gene', '5573', (189, 196))	('cyclic AMP', 'Chemical', 'MESH:D000242', (107, 117))	('mutations', 'Var', (94, 103))	('cAMP', 'Chemical', 'MESH:D000242', (119, 123))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (0, 16))	('PPNAD', 'Chemical', '-', (77, 82))	('PRKAR1A', 'Gene', (189, 196))	('Cushing syndrome', 'Disease', (0, 16))	('Cushing syndrome', 'Disease', 'MESH:D003480', (0, 16))	('due to', 'Reg', (87, 93))	('pigmented nodular adrenocortical disease', 'Disease', (35, 75))	('caused', 'Reg', (17, 23))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (35, 75))
127795	25871963	Recently, mutations in the armadillo repeat containing 5 (ARMC5), a tumor-suppressor gene, were found to be the cause of primary macronodular adrenal hyperplasia (PMAH), formerly known as Adrenocorticotropic hormone-independent macronodular adrenal hyperplasia (AIMAH).	('cause', 'Reg', (112, 117))	('macronodular adrenal hyperplasia', 'Disease', (228, 260))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (228, 260))	('tumor', 'Disease', (68, 73))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (228, 260))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (241, 260))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('armadillo repeat containing 5', 'Gene', (27, 56))	('ARMC5', 'Gene', (58, 63))	('macronodular adrenal hyperplasia', 'Disease', (129, 161))	('Adrenocorticotropic hormone', 'Gene', '5443', (188, 215))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('armadillo repeat containing 5', 'Gene', '79798', (27, 56))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (129, 161))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (129, 161))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (142, 161))	('ARMC5', 'Gene', '79798', (58, 63))	('Adrenocorticotropic hormone', 'Gene', (188, 215))	('mutations', 'Var', (10, 19))
127803	25871963	For example, inactivating mutations in PRKAR1A in patients with PPNAD lead to inactivation of R1alpha, which allows Calpha to be uninhibited, resulting in PKA activation.	('inactivating mutations', 'Var', (13, 35))	('activation', 'PosReg', (159, 169))	('patients', 'Species', '9606', (50, 58))	('PRKAR1A', 'Gene', (39, 46))	('PPNAD', 'Chemical', '-', (64, 69))	('PRKAR1A', 'Gene', '5573', (39, 46))	('R1alpha', 'Protein', (94, 101))	('inactivation', 'MPA', (78, 90))	('PKA', 'MPA', (155, 158))
127811	25871963	Mutations in the PRKAR1A gene were first recognized in families with linkage to the 17q22-24 locus.	('Mutations', 'Var', (0, 9))	('PRKAR1A', 'Gene', '5573', (17, 24))	('PRKAR1A', 'Gene', (17, 24))
127812	25871963	Approximately two thirds of the patients affected by Carney complex have PRKAR1A mutations, while no gene has been identified at the 2p16 locus to-date.	('patients', 'Species', '9606', (32, 40))	('PRKAR1A', 'Gene', '5573', (73, 80))	('p16', 'Gene', (134, 137))	('Carney complex', 'Disease', (53, 67))	('PRKAR1A', 'Gene', (73, 80))	('mutations', 'Var', (81, 90))	('p16', 'Gene', '1029', (134, 137))
127814	25871963	To date more than 126 PRKAR1A mutations have been described.	('PRKAR1A', 'Gene', (22, 29))	('mutations', 'Var', (30, 39))	('PRKAR1A', 'Gene', '5573', (22, 29))
127816	25871963	Importantly, an association between Carney complex and adrenal cancer, was recently described in patients with PRKAR1A mutations.	('adrenal cancer', 'Disease', (55, 69))	('PRKAR1A', 'Gene', '5573', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('adrenal cancer', 'Disease', 'MESH:D000310', (55, 69))	('Carney complex', 'Disease', (36, 50))	('PRKAR1A', 'Gene', (111, 118))	('mutations', 'Var', (119, 128))	('patients', 'Species', '9606', (97, 105))
127819	25871963	These groups performed whole exome DNA sequencing of the available tumors and leukocyte DNA, and identified a recurring hotspot point PRKACA mutation (c.617A>C, also known as c.617T>G), resulting in arginine substitution of amino acid 206 (Leu206Arg).	('PRKACA', 'Gene', '5566', (134, 140))	('c.617T>G', 'Mutation', 'rs386352352', (175, 183))	('arginine', 'Chemical', 'MESH:D001120', (199, 207))	('Leu206Arg', 'Var', (240, 249))	('c.617A>C', 'SUBSTITUTION', 'None', (151, 159))	('Leu206Arg', 'SUBSTITUTION', 'None', (240, 249))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('c.617A>C', 'Var', (151, 159))	('PRKACA', 'Gene', (134, 140))
127821	25871963	These patients were screened for PDE8B, PDE11A, PRKAR1A mutations and were found to be negative.	('PDE11A', 'Gene', '50940', (40, 46))	('mutations', 'Var', (56, 65))	('PRKAR1A', 'Gene', '5573', (48, 55))	('PDE11A', 'Gene', (40, 46))	('patients', 'Species', '9606', (6, 14))	('PRKAR1A', 'Gene', (48, 55))	('screened', 'Reg', (20, 28))	('PDE8B', 'Gene', (33, 38))	('PDE8B', 'Gene', '8622', (33, 38))
127822	25871963	The researchers identified mutations in PRKACA in 8 of the 10 originally screened unilateral cortisol-producing adenomas, with a majority (7 patients) having the c.617A>C, p.Leu206Arg mutation, whereas one had the insertion located at c.595_596CAC, Leu199_Cys200insTrp.	('PRKACA', 'Gene', (40, 46))	('c.617A>C', 'SUBSTITUTION', 'None', (162, 170))	('Leu199_Cys200insTrp', 'Var', (249, 268))	('Leu199_Cys200insTrp', 'Mutation', 'p.L,C199,200W', (249, 268))	('PRKACA', 'Gene', '5566', (40, 46))	('adenomas', 'Disease', 'MESH:D000236', (112, 120))	('c.617A>C', 'Var', (162, 170))	('adenomas', 'Disease', (112, 120))	('cortisol', 'Chemical', 'MESH:D006854', (93, 101))	('p.Leu206Arg', 'Var', (172, 183))	('patients', 'Species', '9606', (141, 149))	('p.Leu206Arg', 'Mutation', 'rs386352352', (172, 183))
127823	25871963	The p.Leu206Arg mutation is located in a highly conservative core of the interaction between the regulatory (RIIbeta) and catalytic subunits of PKA.	('p.Leu206Arg', 'Mutation', 'rs386352352', (4, 15))	('interaction', 'Interaction', (73, 84))	('RIIbeta', 'Gene', '5577', (109, 116))	('RIIbeta', 'Gene', (109, 116))	('p.Leu206Arg', 'Var', (4, 15))
127826	25871963	These findings were correlated with expression levels of the steroidogenic enzymes that were higher in tissues with PRKACA mutations.	('higher', 'PosReg', (93, 99))	('PRKACA', 'Gene', '5566', (116, 122))	('mutations', 'Var', (123, 132))	('steroidogenic enzymes', 'Enzyme', (61, 82))	('PRKACA', 'Gene', (116, 122))	('expression levels', 'MPA', (36, 53))
127827	25871963	Patients with germline copy number gain of the PRKACA locus on chromosome 19p had BAH.	('PRKACA', 'Gene', '5566', (47, 53))	('copy number gain', 'Var', (23, 39))	('Patients', 'Species', '9606', (0, 8))	('BAH', 'Chemical', '-', (82, 85))	('BAH', 'Disease', (82, 85))	('PRKACA', 'Gene', (47, 53))
127828	25871963	Shortly after the initial report, we described in detail the three pathologic phenotypes of BAH of the previously reported five patients with germline PRKACA copy number gain.	('PRKACA', 'Gene', (151, 157))	('PRKACA', 'Gene', '5566', (151, 157))	('BAH', 'Chemical', '-', (92, 95))	('BAH', 'Disease', (92, 95))	('copy number gain', 'Var', (158, 174))	('patients', 'Species', '9606', (128, 136))
127831	25871963	They identified an even higher rate of somatic PRKACA mutations: 69.2% (27 out of 39).	('mutations', 'Var', (54, 63))	('PRKACA', 'Gene', '5566', (47, 53))	('PRKACA', 'Gene', (47, 53))
127833	25871963	used a different amino acid numbering system, where initiating methionine is counted as residue zero (and not one), thus reporting Leu205Arg vs. Leu206Arg.	('Leu206Arg', 'SUBSTITUTION', 'None', (145, 154))	('Leu205Arg', 'Var', (131, 140))	('methionine', 'Chemical', 'MESH:D008715', (63, 73))	('Leu206Arg', 'Var', (145, 154))	('Leu205Arg', 'SUBSTITUTION', 'None', (131, 140))
127835	25871963	The researchers performed functional studies (gain of function mutation in 293T cells), and found that overexpression of Leu205Arg mutants increases phosphorylation of PKA derivatives relative to the wild type.	('Leu205Arg', 'Var', (121, 130))	('PKA derivatives', 'Protein', (168, 183))	('increases', 'PosReg', (139, 148))	('phosphorylation', 'MPA', (149, 164))	('Leu205Arg', 'SUBSTITUTION', 'None', (121, 130))	('293T', 'CellLine', 'CVCL:0063', (75, 79))
127836	25871963	In particular, the PRKACA Leu205Arg mutation induced phosphorylation of the cAMP response element binding protein (CREB), confirming the hypothesis that Leu205Arg mutation may enhance PKA activity.	('CREB', 'Gene', '1385', (115, 119))	('PRKACA', 'Gene', '5566', (19, 25))	('Leu205Arg', 'SUBSTITUTION', 'None', (26, 35))	('PKA', 'CPA', (184, 187))	('cAMP response element binding protein', 'Gene', (76, 113))	('Leu205Arg', 'Var', (153, 162))	('enhance', 'PosReg', (176, 183))	('cAMP response element binding protein', 'Gene', '1385', (76, 113))	('activity', 'MPA', (188, 196))	('Leu205Arg', 'Var', (26, 35))	('CREB', 'Gene', (115, 119))	('Leu205Arg', 'SUBSTITUTION', 'None', (153, 162))	('PRKACA', 'Gene', (19, 25))	('phosphorylation', 'MPA', (53, 68))
127837	25871963	In the same issue of the journal Science, Sato and colleagues independently reported finding the identical Leu206Arg hotspot mutation in PRKACA, as the cause of Cushing syndrome in patients with adrenal tumors.	('adrenal tumors', 'Disease', 'MESH:D000310', (195, 209))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('PRKACA', 'Gene', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('PRKACA', 'Gene', '5566', (137, 143))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (161, 177))	('Cushing syndrome', 'Disease', (161, 177))	('patients', 'Species', '9606', (181, 189))	('adrenal tumors', 'Disease', (195, 209))	('Leu206Arg', 'Var', (107, 116))	('cause', 'Reg', (152, 157))	('Cushing syndrome', 'Disease', 'MESH:D003480', (161, 177))	('Leu206Arg', 'SUBSTITUTION', 'None', (107, 116))
127838	25871963	The researchers performed whole exome sequencing on eight adrenal tumors, and found 50% of them had the mentioned mutations.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('adrenal tumors', 'Disease', 'MESH:D000310', (58, 72))	('mutations', 'Var', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('adrenal tumors', 'Disease', (58, 72))
127839	25871963	Moreover, they screened 57 follow-up cases and found that 24 of them had the PRKACA Leu206Arg somatic mutations.	('Leu206Arg', 'Var', (84, 93))	('Leu206Arg', 'SUBSTITUTION', 'None', (84, 93))	('PRKACA', 'Gene', (77, 83))	('PRKACA', 'Gene', '5566', (77, 83))
127841	25871963	They also expressed wild-type PRKACA and the Leu206Arg in Human Embryonic Kidney 293 cells in which they showed that the Leu206Arg PRKACA mutant did not interact with the PKA regulatory subunits.	('Leu206Arg', 'SUBSTITUTION', 'None', (45, 54))	('PRKACA', 'Gene', '5566', (30, 36))	('Embryonic Kidney 293', 'CellLine', 'CVCL:M564', (64, 84))	('Human', 'Species', '9606', (58, 63))	('PRKACA', 'Gene', (131, 137))	('Leu206Arg', 'Var', (45, 54))	('interact', 'Interaction', (153, 161))	('Leu206Arg', 'Var', (121, 130))	('Leu206Arg', 'SUBSTITUTION', 'None', (121, 130))	('PRKACA', 'Gene', '5566', (131, 137))	('PRKACA', 'Gene', (30, 36))
127843	25871963	Sato et al also detected GNAS mutations in 16.9% of the studied cohort.	('GNAS', 'Gene', '2778', (25, 29))	('mutations', 'Var', (30, 39))	('GNAS', 'Gene', (25, 29))	('detected', 'Reg', (16, 24))
127845	25871963	They found PRKACA heterozygous somatic mutations (c.617A>C [p.Leu206Arg]) in 6 patients.	('c.617A>C', 'SUBSTITUTION', 'None', (50, 58))	('PRKACA', 'Gene', (11, 17))	('PRKACA', 'Gene', '5566', (11, 17))	('c.617A>C', 'Var', (50, 58))	('patients', 'Species', '9606', (79, 87))	('p.Leu206Arg', 'Mutation', 'rs386352352', (60, 71))
127846	25871963	Similarly to the original study, they discovered a higher steroidogenic enzymatic activity in the adrenal tissue with PRKACA mutations, thus causing tumor development and endogenous Cushing syndrome.	('mutations', 'Var', (125, 134))	('Cushing syndrome', 'Disease', 'MESH:D003480', (182, 198))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('causing', 'Reg', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (182, 198))	('PRKACA', 'Gene', (118, 124))	('steroidogenic enzymatic activity', 'MPA', (58, 90))	('tumor', 'Disease', (149, 154))	('Cushing syndrome', 'Disease', (182, 198))	('higher', 'PosReg', (51, 57))	('PRKACA', 'Gene', '5566', (118, 124))
127847	25871963	Patients with mutant adrenal adenomas were younger and had smaller tumors, associated with overt Cushing syndrome.	('Cushing syndrome', 'Disease', (97, 113))	('smaller tumors', 'Disease', 'MESH:D009369', (59, 73))	('smaller tumors', 'Disease', (59, 73))	('Cushing syndrome', 'Disease', 'MESH:D003480', (97, 113))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (97, 113))	('mutant', 'Var', (14, 20))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (21, 37))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('adrenal adenomas', 'Disease', 'MESH:D018246', (21, 37))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('adrenal adenomas', 'Disease', (21, 37))
127849	25871963	Similarly to the previous investigators, they found mutations of exon 7 of PRKACA gene in 34% studied samples, associated with Cushing syndrome.	('PRKACA', 'Gene', '5566', (75, 81))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (127, 143))	('associated', 'Reg', (111, 121))	('Cushing syndrome', 'Disease', (127, 143))	('Cushing syndrome', 'Disease', 'MESH:D003480', (127, 143))	('PRKACA', 'Gene', (75, 81))	('mutations of exon', 'Var', (52, 69))
127850	25871963	In addition to previously described missense mutation c.617A>C (p.Leu206Arg) (18 out of 22 patients), they found two novel mutations in another 4 patients (c.600_601insGTG/p.Cys200_Gly201insVal and c.639C>G+c.638_640insATTATCCTGAGG/p.Ser213Arg+p.Leu212_Lys214insIle-Ile-Leu-Arg).	('c.600_601insGTG/p.Cys200_Gly201insVal', 'Var', (156, 193))	('p.Cys200_Gly201insVal', 'Mutation', 'p.C200_,201G,V', (172, 193))	('patients', 'Species', '9606', (91, 99))	('c.617A>C', 'SUBSTITUTION', 'None', (54, 62))	('c.639C>G', 'Mutation', 'rs1187481745', (198, 206))	('c.600_601insGTG', 'Mutation', 'c.600_601insGTG', (156, 171))	('p.Leu212_Lys214insIle', 'Mutation', 'p.212_,214insK,I', (244, 265))	('p.Leu206Arg', 'Mutation', 'rs386352352', (64, 75))	('c.617A>C', 'Var', (54, 62))	('c.638_640insATTATCCTGAGG', 'Mutation', 'c.638_640insATTATCCTGAGG', (207, 231))	('patients', 'Species', '9606', (146, 154))	('p.Ser213Arg', 'Mutation', 'rs1187481745', (232, 243))
127853	25871963	screened tumors of 13 patients in Japan, and found recurrent somatic mutations of the PRKACA gene, p.L206R (c.617T>G) in 23% of patients with overt Cushing syndrome.	('Cushing syndrome', 'Disease', (148, 164))	('c.617T>G', 'Mutation', 'rs386352352', (108, 116))	('Cushing syndrome', 'Disease', 'MESH:D003480', (148, 164))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (148, 164))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('patients', 'Species', '9606', (22, 30))	('p.L206R (c.617T>G', 'Var', (99, 116))	('PRKACA', 'Gene', (86, 92))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('p.L206R', 'Mutation', 'rs386352352', (99, 106))	('PRKACA', 'Gene', '5566', (86, 92))	('patients', 'Species', '9606', (128, 136))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
127854	25871963	We recently found that genomic amplification of the PRKACB locus may lead to Carney Complex without any PRKAR1A mutations.	('PRKACB', 'Gene', '5567', (52, 58))	('PRKACB', 'Gene', (52, 58))	('Carney Complex', 'Disease', (77, 91))	('lead to', 'Reg', (69, 76))	('PRKAR1A', 'Gene', (104, 111))	('genomic amplification', 'Var', (23, 44))	('PRKAR1A', 'Gene', '5573', (104, 111))
127856	25871963	This patient had somatic copy number gain of the chromosome 1p31.1 PRKACB locus, leading to an increase of the PKA catalytic subunit Cbeta expression and higher PKA activity in the patient's cells.	('activity', 'MPA', (165, 173))	('patient', 'Species', '9606', (5, 12))	('patient', 'Species', '9606', (181, 188))	('increase', 'PosReg', (95, 103))	('higher', 'PosReg', (154, 160))	('copy number', 'Var', (25, 36))	('PRKACB', 'Gene', '5567', (67, 73))	('PKA', 'Protein', (111, 114))	('gain', 'PosReg', (37, 41))	('PRKACB', 'Gene', (67, 73))	('PKA', 'Enzyme', (161, 164))
127857	25871963	A mouse model, carrying a transgene for human PRKACB, had an increase in growth hormone secretion.	('growth hormone secretion', 'MPA', (73, 97))	('transgene', 'Var', (26, 35))	('PRKACB', 'Gene', '5567', (46, 52))	('mouse', 'Species', '10090', (2, 7))	('increase', 'PosReg', (61, 69))	('human', 'Species', '9606', (40, 45))	('PRKACB', 'Gene', (46, 52))
127858	25871963	Somatic mutations in PRKACA may be a frequent cause of Cushing syndrome in patients with adrenal adenomas, while BAH may be caused by PRKAR1A or PRKACA defects.	('Cushing syndrome', 'Disease', (55, 71))	('adrenal adenomas', 'Disease', (89, 105))	('PRKAR1A', 'Gene', (134, 141))	('Cushing syndrome', 'Disease', 'MESH:D003480', (55, 71))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (89, 105))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (55, 71))	('PRKACA', 'Gene', (21, 27))	('patients', 'Species', '9606', (75, 83))	('adrenal adenomas', 'Disease', 'MESH:D018246', (89, 105))	('PRKACA', 'Gene', '5566', (21, 27))	('PRKAR1A', 'Gene', '5573', (134, 141))	('PRKACA', 'Gene', (145, 151))	('BAH', 'Chemical', '-', (113, 116))	('cause', 'Reg', (46, 51))	('PRKACA', 'Gene', '5566', (145, 151))	('Somatic mutations', 'Var', (0, 17))
127859	25871963	PRKACA mutations that lead to Cushing syndrome prevent the binding of the catalytic to the regulatory subunits, thus causing constitutive and cAMP-independent activation of PKA, and eventually, "autonomous" overproduction of cortisol.	('activation', 'PosReg', (159, 169))	('lead to', 'Reg', (22, 29))	('binding', 'Interaction', (59, 66))	('prevent', 'NegReg', (47, 54))	('PRKACA', 'Gene', (0, 6))	('causing', 'Reg', (117, 124))	('overproduction of cortisol', 'Phenotype', 'HP:0003118', (207, 233))	('PRKACA', 'Gene', '5566', (0, 6))	('overproduction', 'PosReg', (207, 221))	('Cushing syndrome', 'Disease', (30, 46))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (30, 46))	('cAMP', 'Chemical', 'MESH:D000242', (142, 146))	('Cushing syndrome', 'Disease', 'MESH:D003480', (30, 46))	('cortisol', 'Chemical', 'MESH:D006854', (225, 233))	('mutations', 'Var', (7, 16))
127861	25871963	This exciting discovery has been well covered in the scientific literature, is expected to lead to a number of questions: Do PRKACA gene mutations cause tumors and cancers in other organs (breast, colon, liver, pituitary, etc.	('colon', 'Disease', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast', 'Disease', (189, 195))	('PRKACA', 'Gene', (125, 131))	('cause', 'Reg', (147, 152))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('mutations', 'Var', (137, 146))	('PRKACA', 'Gene', '5566', (125, 131))	('pituitary', 'Disease', (211, 220))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors and cancers', 'Disease', 'MESH:D009369', (153, 171))	('liver', 'Disease', (204, 209))
127863	25871963	Does mutation in other PKA catalytic subunits (Cbeta, Cgamma, and PRKX) cause adrenal adenomas and/or hyperplasia?	('hyperplasia', 'Disease', 'MESH:D006965', (102, 113))	('PRKX', 'Gene', (66, 70))	('adrenal adenomas', 'Disease', 'MESH:D018246', (78, 94))	('Cbeta', 'Gene', (47, 52))	('PRKX', 'Gene', '5613', (66, 70))	('cause', 'Reg', (72, 77))	('adrenal adenomas', 'Disease', (78, 94))	('hyperplasia', 'Disease', (102, 113))	('adrenal adenomas', 'Phenotype', 'HP:0008256', (78, 94))	('mutation', 'Var', (5, 13))
127865	25871963	Fibrolamellar hepatocellular carcinoma was found to be due to a recurrent DnaJ homolog subfamily B member 1 (DNAJB1)-PRKACA chimeric transcript.	('Fibrolamellar hepatocellular carcinoma', 'Disease', (0, 38))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (14, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('DNAJB1', 'Gene', '3337', (109, 115))	('PRKACA', 'Gene', (117, 123))	('DnaJ homolog subfamily B member 1', 'Gene', '3337', (74, 107))	('DNAJB1', 'Gene', (109, 115))	('PRKACA', 'Gene', '5566', (117, 123))	('due to', 'Reg', (55, 61))	('Fibrolamellar hepatocellular carcinoma', 'Disease', 'MESH:C537258', (0, 38))	('DnaJ homolog subfamily B member 1', 'Gene', (74, 107))	('chimeric transcript', 'Var', (124, 143))
127870	25871963	PRKACA protein kinase catalytic subunit alpha PRKACB protein kinase catalytic subunit beta PRKAR1A protein kinase type 1 alpha regulatory subunit PPNAD primary pigmented nodular adrenal dysplasia cAMP cyclic AMP ARMC5 armadillo repeat containing 5 AIMAH ACTH-independent macronodular adrenal hyperplasia BAH bilateral adrenocortical hyperplasia PMAH primary macronodular adrenal hyperplasia PDE phosphodiesterase PKA protein kinase A CREB response element binding protein PRKACB protein kinase catalytic subunit beta DNAJB1 DnaJ homolog subfamily B member 1 PTHR1 Parathyroid hormone receptor PTHrP parathyroid related protein Somatic mutations of the main catalytic subunit of PKA, a serine-threonine kinase, PRKACA, may cause cortisol-producing adenomas and Adrenocorticotropic hormone-independent Cushing syndrome.	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (358, 390))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (371, 390))	('pigmented nodular adrenal dysplasia', 'Disease', 'MESH:D020518', (160, 195))	('PRKACA', 'Gene', (0, 6))	('PRKAR1A', 'Gene', '5573', (91, 98))	('cause', 'Reg', (722, 727))	('DnaJ homolog subfamily B member 1', 'Gene', '3337', (524, 557))	('mutations', 'Var', (635, 644))	('PTHR1', 'Gene', (558, 563))	('PTHrP', 'Gene', (593, 598))	('PRKACB', 'Gene', (46, 52))	('PTHrP', 'Gene', '5744', (593, 598))	('bilateral adrenocortical hyperplasia', 'Disease', (308, 344))	('cyclic AMP', 'Chemical', 'MESH:D000242', (201, 211))	('ARMC5', 'Gene', '79798', (212, 217))	('PRKACA', 'Gene', (710, 716))	('ACTH', 'Gene', (254, 258))	('CREB', 'Gene', (434, 438))	('Adrenocorticotropic hormone', 'Gene', '5443', (760, 787))	('PTHR1', 'Gene', '5745', (558, 563))	('PRKACB', 'Gene', (472, 478))	('armadillo repeat containing 5', 'Gene', '79798', (218, 247))	('cAMP', 'Chemical', 'MESH:D000242', (196, 200))	('armadillo repeat containing 5', 'Gene', (218, 247))	('PRKACA', 'Gene', '5566', (0, 6))	('adrenal dysplasia cAMP', 'Phenotype', 'HP:0008216', (178, 200))	('Adrenocorticotropic hormone-independent Cushing syndrome', 'Phenotype', 'HP:0008259', (760, 816))	('PRKACB', 'Gene', '5567', (46, 52))	('cortisol', 'Chemical', 'MESH:D006854', (728, 736))	('macronodular adrenal hyperplasia', 'Disease', (271, 303))	('DnaJ homolog subfamily B member 1', 'Gene', (524, 557))	('Cushing syndrome', 'Disease', 'MESH:D003480', (800, 816))	('PRKAR1A', 'Gene', (91, 98))	('PPNAD', 'Chemical', '-', (146, 151))	('Adrenocorticotropic hormone', 'Gene', (760, 787))	('macronodular adrenal hyperplasia', 'Disease', (358, 390))	('DNAJB1', 'Gene', '3337', (517, 523))	('CREB', 'Gene', '1385', (434, 438))	('parathyroid related protein', 'Gene', (599, 626))	('bilateral adrenocortical hyperplasia', 'Disease', 'MESH:D018268', (308, 344))	('parathyroid related protein', 'Gene', '5744', (599, 626))	('ARMC5', 'Gene', (212, 217))	('DNAJB1', 'Gene', (517, 523))	('adenomas', 'Disease', 'MESH:D000236', (747, 755))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (271, 303))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (800, 816))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (271, 303))	('PRKACB', 'Gene', '5567', (472, 478))	('adenomas', 'Disease', (747, 755))	('Cushing syndrome', 'Disease', (800, 816))	('BAH', 'Chemical', '-', (304, 307))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (358, 390))	('pigmented nodular adrenal dysplasia', 'Disease', (160, 195))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (284, 303))	('ACTH', 'Gene', '5443', (254, 258))	('PRKACA', 'Gene', '5566', (710, 716))
127889	26161091	hsa-miR-483-5p is overexpressed not only in the tissue of adrenal cancer but also as a circulating microRNA in patient's blood.	('adrenal cancer', 'Disease', 'MESH:D000310', (58, 72))	('overexpressed', 'PosReg', (18, 31))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('hsa-miR-483-5p', 'Var', (0, 14))	('patient', 'Species', '9606', (111, 118))	('adrenal cancer', 'Disease', (58, 72))
127906	26161091	miR-27a and myostatin appear to be involved in an autoregulatory loop as myostatin increases miR-27a expression via SMAD3 and miR-27a in turn inhibits myostatin expression in a murine model.	('miR-27a', 'Gene', (93, 100))	('myostatin expression', 'MPA', (151, 171))	('murine', 'Species', '10090', (177, 183))	('inhibits', 'NegReg', (142, 150))	('expression', 'MPA', (101, 111))	('miR-27a', 'Var', (126, 133))
127915	26019766	Although the molecular pathogenesis of ACC is poorly understood, it is strongly associated with inactivating mutation of the tumor suppressor gene p53 and alteration of the 11p15 locus leading to insulin-like growth factor 2 overexpression.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('insulin-like growth factor 2', 'Gene', '3481', (196, 224))	('overexpression', 'PosReg', (225, 239))	('p15', 'Gene', (175, 178))	('inactivating mutation', 'Var', (96, 117))	('insulin-like growth factor 2', 'Gene', (196, 224))	('p15', 'Gene', '1030', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('ACC', 'Phenotype', 'HP:0006744', (39, 42))	('tumor', 'Disease', (125, 130))	('ACC', 'Disease', (39, 42))	('p53', 'Gene', '7157', (147, 150))	('associated', 'Reg', (80, 90))	('alteration', 'Var', (155, 165))	('p53', 'Gene', (147, 150))
128082	18812209	Adrenal glomerulosa expression of the AT1R is enhanced on a low-sodium diet, suggesting that Ang II has the ability to enhance expression of its own receptor and, as a result, increase chronic aldosterone production.	('enhance', 'PosReg', (119, 126))	('aldosterone', 'Chemical', 'MESH:D000450', (193, 204))	('increase chronic aldosterone', 'Phenotype', 'HP:0000859', (176, 204))	('increase', 'PosReg', (176, 184))	('expression', 'MPA', (127, 137))	('sodium', 'Chemical', 'MESH:D012964', (64, 70))	('aldosterone production', 'Phenotype', 'HP:0000859', (193, 215))	('low-sodium', 'Phenotype', 'HP:0002902', (60, 70))	('Ang', 'Var', (93, 96))	('chronic aldosterone production', 'MPA', (185, 215))
128099	18812209	Ang II also enhances expression of the members of the AP-1 complex [v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS), FBJ murine osteosarcoma viral oncogene homolog B (FOSB), jun B proto-oncogene (JUNB), and v-jun sarcoma virus 17 oncogene homolog (JUN)].	('osteosarcoma viral', 'Disease', (139, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('fos', 'Gene', (70, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('murine', 'Species', '10090', (78, 84))	('murine', 'Species', '10090', (132, 138))	('v-jun sarcoma virus 17 oncogene homolog', 'Gene', (218, 257))	('osteosarcoma viral', 'Disease', 'MESH:D012516', (85, 103))	('jun B proto-oncogene', 'Gene', '16477', (185, 205))	('enhances', 'PosReg', (12, 20))	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('jun B proto-oncogene', 'Gene', (185, 205))	('osteosarcoma viral', 'Disease', 'MESH:D012516', (139, 157))	('osteosarcoma viral', 'Disease', (85, 103))	('expression', 'MPA', (21, 31))	('fos', 'Gene', '14281', (70, 73))	('v-jun sarcoma virus 17 oncogene homolog', 'Gene', '16476', (218, 257))	('osteosarcoma', 'Phenotype', 'HP:0002669', (139, 151))	('FBJ', 'Var', (128, 131))
128133	18812209	To that end, Ang II also regulates the expression of the enzymes responsible for aldosterone and cortisol production, namely: cholesterol side-chain cleavage (CYP11A1), HSD3B2, CYP21, CYP11B1 (the last step in cortisol biosynthesis), and CYP11B2.	('CYP11B2', 'Gene', '1585', (238, 245))	('CYP21', 'Gene', (177, 182))	('aldosterone', 'Chemical', 'MESH:D000450', (81, 92))	('HSD3B2', 'Gene', (169, 175))	('HSD3B2', 'Gene', '3284', (169, 175))	('cortisol', 'Chemical', 'MESH:D006854', (97, 105))	('CYP21', 'Gene', '1589', (177, 182))	('cortisol', 'Chemical', 'MESH:D006854', (210, 218))	('cholesterol', 'Chemical', 'MESH:D002784', (126, 137))	('regulates', 'Reg', (25, 34))	('expression', 'MPA', (39, 49))	('CYP11B2', 'Gene', (238, 245))	('CYP11A1', 'Gene', '1583', (159, 166))	('CYP11B1', 'Var', (184, 191))	('CYP11A1', 'Gene', (159, 166))
128138	18812209	Thus, Ang II chronically increases the capacity for steroidogenesis by increasing cholesterol update and synthesis as well as increasing steroid biosynthetic enzymes.	('steroid', 'Chemical', 'MESH:D013256', (137, 144))	('increasing', 'PosReg', (71, 81))	('steroid biosynthetic enzymes', 'MPA', (137, 165))	('increasing', 'PosReg', (126, 136))	('steroidogenesis', 'MPA', (52, 67))	('Ang', 'Var', (6, 9))	('increases', 'PosReg', (25, 34))	('cholesterol', 'Chemical', 'MESH:D002784', (82, 93))	('steroid', 'Chemical', 'MESH:D013256', (52, 59))	('increasing cholesterol', 'Phenotype', 'HP:0003124', (71, 93))	('cholesterol update', 'MPA', (82, 100))	('synthesis', 'MPA', (105, 114))
128140	18812209	PEG3 expression has been described to activate tumor necrosis factor (TNF)/ nuclear factorkappaB (NF-kappaB) pathway in human embryonic kidney cells, and therefore may participate in cell proliferation and differentiation, although the function of PEG3, as well as ERRG, ODAG, RORA, and TDBN100 in the adrenal cortex has not been described.	('NF-kappaB', 'Gene', '4790', (98, 107))	('ODAG', 'Gene', '57798', (271, 275))	('activate', 'PosReg', (38, 46))	('RORA', 'Gene', '6095', (277, 281))	('TNF', 'Gene', '7124', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('participate', 'Reg', (168, 179))	('tumor necrosis factor', 'Gene', '7124', (47, 68))	('human', 'Species', '9606', (120, 125))	('expression', 'Var', (5, 15))	('ERRG', 'Gene', '2104', (265, 269))	('cell proliferation', 'CPA', (183, 201))	('ERRG', 'Gene', (265, 269))	('PEG3', 'Gene', (248, 252))	('nuclear factorkappaB', 'Gene', (76, 96))	('nuclear factorkappaB', 'Gene', '4790', (76, 96))	('PEG3', 'Gene', '5178', (248, 252))	('rat', 'Species', '10116', (195, 198))	('PEG3', 'Gene', (0, 4))	('tumor necrosis factor', 'Gene', (47, 68))	('differentiation', 'CPA', (206, 221))	('ODAG', 'Gene', (271, 275))	('NF-kappaB', 'Gene', (98, 107))	('TNF', 'Gene', (70, 73))	('RORA', 'Gene', (277, 281))	('PEG3', 'Gene', '5178', (0, 4))
128141	18812209	In addition to the chronic effects on secretion of aldosterone, Ang II also stimulates proliferation of adrenocortical cells in vivo and primary bovine adrenal glomerulosa cells in vitro, although rat adrenal glomerulosa cells in vitro exhibit Ang II-elicited hypertrophy rather than proliferation.	('hypertrophy', 'Disease', 'MESH:D006984', (260, 271))	('rat', 'Species', '10116', (94, 97))	('Ang', 'Var', (64, 67))	('proliferation', 'CPA', (87, 100))	('rat', 'Species', '10116', (197, 200))	('adrenocortical', 'Disease', (104, 118))	('bovine', 'Species', '9913', (145, 151))	('aldosterone', 'Chemical', 'MESH:D000450', (51, 62))	('rat', 'Species', '10116', (291, 294))	('adrenocortical', 'Disease', 'MESH:D018268', (104, 118))	('stimulates', 'PosReg', (76, 86))	('rat', 'Species', '10116', (272, 275))	('hypertrophy', 'Disease', (260, 271))
128145	18812209	While expansion of the adrenal glomerulosa is part of the physiologic mechanisms of increasing aldosterone biosynthesis, chronic effects of Ang II on cell growth and deposition of extracellular matrix under pathological conditions ultimately can lead to vascular dysfunction and cardiac insufficiency.	('increasing', 'PosReg', (84, 94))	('increasing aldosterone', 'Phenotype', 'HP:0000859', (84, 106))	('aldosterone', 'Chemical', 'MESH:D000450', (95, 106))	('vascular dysfunction', 'Disease', 'MESH:D002561', (254, 274))	('cardiac insufficiency', 'Disease', 'MESH:D000309', (279, 300))	('cardiac insufficiency', 'Disease', (279, 300))	('Ang', 'Gene', (140, 143))	('cardiac insufficiency', 'Phenotype', 'HP:0001635', (279, 300))	('vascular dysfunction', 'Disease', (254, 274))	('expansion', 'Var', (6, 15))	('aldosterone biosynthesis', 'MPA', (95, 119))	('lead to', 'Reg', (246, 253))
128158	33937395	In the bladder cancer, high expression of NRP2 is associated with chemoresistance and epithelial-to-mesenchymal transition and poor patient prognosis.	('epithelial-to-mesenchymal transition', 'CPA', (86, 122))	('high expression', 'Var', (23, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (7, 21))	('NRP2', 'Gene', (42, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (7, 21))	('chemoresistance', 'CPA', (66, 81))	('patient', 'Species', '9606', (132, 139))	('associated', 'Reg', (50, 60))	('bladder cancer', 'Disease', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
128171	33937395	In addition, high NRP1 expression was associated with higher stroma, microenvironment, and immune scores, as well as more endothelial cell infiltration in most tumours.	('tumours', 'Disease', 'MESH:D009369', (160, 167))	('higher', 'PosReg', (54, 60))	('high', 'Var', (13, 17))	('tumours', 'Disease', (160, 167))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))	('stroma', 'CPA', (61, 67))	('immune scores', 'CPA', (91, 104))	('NRP1', 'Gene', (18, 22))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('expression', 'MPA', (23, 33))
128172	33937395	In KIRC, a high NRP1 expression was associated with a larger tumour size, higher risk of distant metastases, and worse stage staging and grade staging.	('metastases', 'Disease', (97, 107))	('NRP1', 'Protein', (16, 20))	('expression', 'MPA', (21, 31))	('tumour size', 'CPA', (61, 72))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('high', 'Var', (11, 15))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
128175	33937395	Anti-NRP1 therapy can block tumour angiogenesis and upregulate the antitumour immune response.	('Anti-NRP1', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('antitumour immune response', 'CPA', (67, 93))	('upregulate', 'PosReg', (52, 62))	('block tumour', 'Disease', (22, 34))	('block tumour', 'Disease', 'MESH:D006327', (22, 34))
128176	33937395	NRP2 has also been found to be closely associated with metastasis and BRAFV600E in thyroid cancer.	('NRP2', 'Gene', (0, 4))	('metastasis', 'CPA', (55, 65))	('thyroid cancer', 'Disease', 'MESH:D013964', (83, 97))	('BRAFV600E', 'Var', (70, 79))	('BRAFV600E', 'Mutation', 'rs113488022', (70, 79))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (83, 97))	('thyroid cancer', 'Disease', (83, 97))
128183	32528129	 Vav2 Pharmaco-Mimetic Mice Reveal the Therapeutic Value and Caveats of the Catalytic Inactivation of a Rho Exchange Factor The current paradigm holds that the inhibition of Rho guanosine nucleotide exchange factors (GEFs), the enzymes that stimulate Rho GTPases, can be a valuable therapeutic strategy to treat Rho-dependent tumors.	('Vav2', 'Gene', (1, 5))	('tumors', 'Disease', (326, 332))	('GEF', 'Gene', (217, 220))	('inhibition', 'Var', (160, 170))	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('GTP', 'Chemical', 'MESH:D006160', (255, 258))	('tumors', 'Disease', 'MESH:D009369', (326, 332))	('GEF', 'Gene', '16800', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('Mice', 'Species', '10090', (23, 27))	('guanosine nucleotide', 'Chemical', '-', (178, 198))	('Vav2', 'Gene', '22325', (1, 5))
128185	32528129	On the other hand, the inhibition of these enzymes can trigger collateral side effects that could preclude the practical implementation of anti-GEF therapies.	('GEF', 'Gene', '16800', (144, 147))	('inhibition', 'Var', (23, 33))	('GEF', 'Gene', (144, 147))	('collateral side effects', 'MPA', (63, 86))
128192	32528129	Since Rho proteins are seldom mutated in tumors, it is widely assumed that the inactivation of the catalytic activity of Rho GEFs could represent a therapeutic avenue to hamper the fitness of Rho GTPase-dependent tumors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', (213, 219))	('GTP', 'Chemical', 'MESH:D006160', (196, 199))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('GEF', 'Gene', (125, 128))	('catalytic activity', 'MPA', (99, 117))	('inactivation', 'Var', (79, 91))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('hamper', 'NegReg', (170, 176))	('GEF', 'Gene', '16800', (125, 128))	('fitness', 'Disease', (181, 188))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('fitness', 'Disease', 'MESH:D012640', (181, 188))
128197	32528129	Secondly, the recent discovery of loss-of-function mutations in key GTPases such as RhoA in human tumors indicates that, in some cases, Rho GEFs can play catalysis-dependent tumor suppressor rather than protumorigenic roles.	('tumor', 'Disease', (174, 179))	('GTP', 'Chemical', 'MESH:D006160', (68, 71))	('GEF', 'Gene', '16800', (140, 143))	('tumors', 'Disease', (98, 104))	('mutations', 'Var', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('loss-of-function', 'NegReg', (34, 50))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', (98, 103))	('human', 'Species', '9606', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('GEF', 'Gene', (140, 143))
128206	32528129	However, studies using standard Vav2 knockout mice have revealed that the elimination of Vav2 might trigger a number of physiological dysfunctions.	('physiological', 'CPA', (120, 133))	('Vav2', 'Gene', (89, 93))	('Vav2', 'Gene', '22325', (89, 93))	('mice', 'Species', '10090', (46, 50))	('trigger', 'Reg', (100, 107))	('Vav2', 'Gene', '22325', (32, 36))	('Vav2', 'Gene', (32, 36))	('elimination', 'Var', (74, 85))
128214	32528129	On the basis of the known structures of the Tiam1 DH domain and the Vav1 DH-PH-ZF cassette in complex with Rac1, we chose the Leu332 residue as a potential site to achieve this effect.	('Vav1', 'Gene', (68, 72))	('Tiam1', 'Gene', '21844', (44, 49))	('Leu332', 'Chemical', '-', (126, 132))	('Rac1', 'Gene', '19353', (107, 111))	('Leu332', 'Var', (126, 132))	('Vav1', 'Gene', '22324', (68, 72))	('Rac1', 'Gene', (107, 111))	('Tiam1', 'Gene', (44, 49))
128215	32528129	This residue is located at a position analogous to the residues of Tiam1 (Leu1194) and Vav1 (Leu334, Fig.	('Leu1194', 'Var', (74, 81))	('Leu334', 'Var', (93, 99))	('Tiam1', 'Gene', '21844', (67, 72))	('Leu1194', 'Chemical', '-', (74, 81))	('Vav1', 'Gene', '22324', (87, 91))	('Vav1', 'Gene', (87, 91))	('Tiam1', 'Gene', (67, 72))	('Leu334', 'Chemical', '-', (93, 99))
128216	32528129	1B) that establish key contacts with the switch II region of Rac1 (residues Gly60, Gln61, Tyr64 and Leu67).	('Tyr64', 'Var', (90, 95))	('Gly60', 'Chemical', '-', (76, 81))	('Rac1', 'Gene', (61, 65))	('Gln61', 'Chemical', '-', (83, 88))	('Leu67', 'Chemical', '-', (100, 105))	('Rac1', 'Gene', '19353', (61, 65))	('Tyr64', 'Chemical', '-', (90, 95))	('residues Gly60', 'Var', (67, 81))	('Gln61', 'Var', (83, 88))	('Leu67', 'Var', (100, 105))
128217	32528129	In the case of Tiam1, mutation of the Leu1194 residue into alanine severely affects the catalytic activity (>= 80% reduction) of the protein when tested in biochemical assays.	('reduction', 'NegReg', (115, 124))	('catalytic activity', 'MPA', (88, 106))	('Tiam1', 'Gene', '21844', (15, 20))	('Leu1194', 'Var', (38, 45))	('Tiam1', 'Gene', (15, 20))	('Leu1194 residue into alanine', 'Mutation', 'p.L1194A', (38, 66))	('affects', 'Reg', (76, 83))
128219	32528129	Using Rho G-LISA assays to investigate the levels of active (GTP-bound) Rho proteins in COS1 cells, we observed that the L332A mutation causes a  70% and 100% reduction of the catalytic activity of the oncogenic version of Vav2 (Delta1-186 mutation, referred to hereafter as Vav2Onc; Fig.	('reduction', 'NegReg', (159, 168))	('GTP', 'Chemical', 'MESH:D006160', (61, 64))	('L332A', 'Var', (121, 126))	('Vav2', 'Gene', (275, 279))	('Vav2', 'Gene', '22325', (275, 279))	('Vav2', 'Gene', '22325', (223, 227))	('Vav2', 'Gene', (223, 227))	('L332A', 'Mutation', 'p.L332A', (121, 126))	('COS1', 'CellLine', 'CVCL:0223', (88, 92))	('catalytic activity', 'MPA', (176, 194))
128223	32528129	The L332A mutation also reduces the ability of Vav2Onc to stimulate the c-Jun N terminal kinase (JNK) (Fig.	('ability', 'MPA', (36, 43))	('Vav2', 'Gene', '22325', (47, 51))	('Vav2', 'Gene', (47, 51))	('JNK', 'Gene', (97, 100))	('reduces', 'NegReg', (24, 31))	('L332A', 'Mutation', 'p.L332A', (4, 9))	('c-Jun N terminal kinase', 'Gene', (72, 95))	('c-Jun N terminal kinase', 'Gene', '26419', (72, 95))	('stimulate', 'PosReg', (58, 67))	('JNK', 'Gene', '26419', (97, 100))	('L332A', 'Var', (4, 9))
128227	32528129	As expected, the stimulation of all the foregoing biological readouts is totally abolished when using a version of EGFP-Vav2Onc in which a deleterious internal deletion was created within the catalytic DH domain (Delta309-339 mutation) (Fig.	('Vav2', 'Gene', '22325', (120, 124))	('Delta309', 'Mutation', 'c.del309', (213, 221))	('Vav2', 'Gene', (120, 124))	('Delta309-339 mutation', 'Var', (213, 234))
128228	32528129	The effect of the L332A and Delta309-339 mutations in the activity of full-length protein could not be tested given that EGFP-Vav2WT has no detectable activity under these conditions (Fig.	('Vav2WT', 'Gene', (126, 132))	('Vav2WT', 'Gene', '22325', (126, 132))	('Delta309-339', 'Var', (28, 40))	('L332A', 'Mutation', 'p.L332A', (18, 23))	('Delta309', 'Mutation', 'c.del309', (28, 36))	('L332A', 'Var', (18, 23))
128231	32528129	Taken together, these results indicate that the L332A mutation significantly impairs, but does not abolish, the GEF activity of Vav2 towards Rac1.	('impairs', 'NegReg', (77, 84))	('L332A', 'Mutation', 'p.L332A', (48, 53))	('Vav2', 'Gene', '22325', (128, 132))	('Rac1', 'Gene', '19353', (141, 145))	('GEF', 'Gene', (112, 115))	('Vav2', 'Gene', (128, 132))	('GEF', 'Gene', '16800', (112, 115))	('L332A', 'Var', (48, 53))	('Rac1', 'Gene', (141, 145))
128233	32528129	We next used standard homologous recombination techniques to replace the exon 11 of the Vav2 locus (which contains the codon for the Leu332 residue) by a mutant one encoding the Ala residue at the same position (Figs.	('Vav2', 'Gene', '22325', (88, 92))	('Vav2', 'Gene', (88, 92))	('Leu332', 'Chemical', '-', (133, 139))	('Ala', 'Chemical', 'MESH:D000409', (178, 181))	('Leu332', 'Var', (133, 139))
128234	32528129	With this approach, we ensured that the mutant Vav2 L332A allele was expressed under the same regulatory sequences and in the very same tissues as the WT counterpart.	('Vav2', 'Gene', '22325', (47, 51))	('Vav2', 'Gene', (47, 51))	('L332A', 'Mutation', 'p.L332A', (52, 57))	('L332A', 'Var', (52, 57))
128236	32528129	2D) in tissues from homozygous Vav2 L332A/L332A mice are similar to those found for their respective WT counterparts in control mice.	('L332A', 'Mutation', 'p.L332A', (36, 41))	('L332A', 'Mutation', 'p.L332A', (42, 47))	('mice', 'Species', '10090', (48, 52))	('mice', 'Species', '10090', (128, 132))	('Vav2', 'Gene', (31, 35))	('L332A', 'Var', (36, 41))	('L332A', 'SUBSTITUTION', 'None', (36, 41))	('Vav2', 'Gene', '22325', (31, 35))	('L332A', 'Var', (42, 47))	('L332A', 'SUBSTITUTION', 'None', (42, 47))
128237	32528129	Further quantitative RT-PCR analyses indicated that the mRNAs encoding the Rac1 GEFs Vav3, Tiam1, P-Rex1, and P-Rex2 show similar expression levels in tissues from Vav2 L332A/L332A and WT mice (Fig.	('mice', 'Species', '10090', (188, 192))	('expression', 'MPA', (130, 140))	('Tiam1', 'Gene', '21844', (91, 96))	('L332A', 'Mutation', 'p.L332A', (175, 180))	('Vav2', 'Gene', (164, 168))	('P-Rex2', 'Gene', '109294', (110, 116))	('Vav3', 'Gene', (85, 89))	('L332A', 'Var', (169, 174))	('Vav3', 'Gene', '57257', (85, 89))	('P-Rex1', 'Gene', (98, 104))	('L332A', 'Var', (175, 180))	('P-Rex1', 'Gene', '277360', (98, 104))	('Rac1', 'Gene', (75, 79))	('GEF', 'Gene', (80, 83))	('L332A', 'SUBSTITUTION', 'None', (169, 174))	('GEF', 'Gene', '16800', (80, 83))	('Tiam1', 'Gene', (91, 96))	('P-Rex2', 'Gene', (110, 116))	('L332A', 'SUBSTITUTION', 'None', (175, 180))	('Rac1', 'Gene', '19353', (75, 79))	('Vav2', 'Gene', '22325', (164, 168))	('L332A', 'Mutation', 'p.L332A', (169, 174))
128238	32528129	2E), thus indicating that the missing activity of Vav2 does to lead to the upregulation of other Rac1 GEFs.	('GEF', 'Gene', '16800', (102, 105))	('activity', 'MPA', (38, 46))	('upregulation', 'PosReg', (75, 87))	('Rac1', 'Gene', '19353', (97, 101))	('GEF', 'Gene', (102, 105))	('Vav2', 'Gene', '22325', (50, 54))	('missing', 'Var', (30, 37))	('Vav2', 'Gene', (50, 54))	('Rac1', 'Gene', (97, 101))
128240	32528129	1), we found using pull-down experiments that the swapping of Vav2WT by the mutant Vav2L332A version leads to a 70-80% reduction in the levels of GTP-bound Rac1 that are typically induced in skeletal muscle upon the in vivo administration of insulin (Fig.	('Rac1', 'Gene', (156, 160))	('Vav2WT', 'Gene', (62, 68))	('GTP-bound', 'MPA', (146, 155))	('Vav2L332A', 'Gene', (83, 92))	('mutant', 'Var', (76, 82))	('Vav2WT', 'Gene', '22325', (62, 68))	('GTP', 'Chemical', 'MESH:D006160', (146, 149))	('levels', 'MPA', (136, 142))	('reduction', 'NegReg', (119, 128))	('Rac1', 'Gene', '19353', (156, 160))
128242	32528129	We next crossed the Vav2 L332A/L332A mice with Vav2-/- and control mice to obtain animals (Vav2 L332A/-, Vav2 L332A/+) with the predicted levels of Vav2 catalytic activity depicted in Figure 2G.	('Vav2', 'Gene', '22325', (105, 109))	('L332A', 'SUBSTITUTION', 'None', (31, 36))	('Vav2', 'Gene', '22325', (91, 95))	('L332A', 'Mutation', 'p.L332A', (96, 101))	('Vav2', 'Gene', (20, 24))	('L332A', 'SUBSTITUTION', 'None', (110, 115))	('L332A', 'Mutation', 'p.L332A', (25, 30))	('Vav2', 'Gene', (105, 109))	('mice', 'Species', '10090', (37, 41))	('Vav2', 'Gene', (91, 95))	('L332A', 'Mutation', 'p.L332A', (31, 36))	('L332A', 'Mutation', 'p.L332A', (110, 115))	('mice', 'Species', '10090', (67, 71))	('L332A', 'Var', (96, 101))	('L332A', 'Var', (25, 30))	('Vav2', 'Gene', '22325', (47, 51))	('Vav2', 'Gene', '22325', (148, 152))	('L332A', 'Var', (31, 36))	('L332A', 'Var', (110, 115))	('Vav2', 'Gene', (47, 51))	('L332A', 'SUBSTITUTION', 'None', (25, 30))	('L332A', 'SUBSTITUTION', 'None', (96, 101))	('Vav2', 'Gene', '22325', (20, 24))	('Vav2', 'Gene', (148, 152))
128244	32528129	Finally, we also generated a compound Vav2 L332A/L332A;Vav3 -/- mouse strain to be used in some of the experiments presented in this work.	('L332A', 'Var', (49, 54))	('L332A', 'SUBSTITUTION', 'None', (49, 54))	('Vav3', 'Gene', (55, 59))	('Vav2', 'Gene', '22325', (38, 42))	('Vav2', 'Gene', (38, 42))	('L332A', 'Var', (43, 48))	('L332A', 'Mutation', 'p.L332A', (49, 54))	('L332A', 'SUBSTITUTION', 'None', (43, 48))	('Vav3', 'Gene', '57257', (55, 59))	('mouse', 'Species', '10090', (64, 69))	('L332A', 'Mutation', 'p.L332A', (43, 48))
128250	32528129	3A), we observed that the Vav2L332A/+ mice develop skin tumors with kinetics (Fig.	('skin tumors', 'Disease', (51, 62))	('Vav2L332A/+', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mice', 'Species', '10090', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('skin tumors', 'Disease', 'MESH:D012878', (51, 62))	('skin tumor', 'Phenotype', 'HP:0008069', (51, 61))	('skin tumors', 'Phenotype', 'HP:0008069', (51, 62))	('develop', 'PosReg', (43, 50))
128252	32528129	We also observed that the Vav2L332A/L332A mice show reduced tumorigenesis when tested using the complete DMBA skin carcinogenesis (Fig.	('Vav2L332A/L332A', 'Var', (26, 41))	('L332A', 'Mutation', 'p.L332A', (30, 35))	('DMBA', 'Chemical', 'MESH:D015127', (105, 109))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (110, 129))	('L332A', 'Mutation', 'p.L332A', (36, 41))	('reduced', 'NegReg', (52, 59))	('mice', 'Species', '10090', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('skin carcinogenesis', 'Disease', (110, 129))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('DMBA skin', 'Phenotype', 'HP:0000973', (105, 114))	('tumor', 'Disease', (60, 65))
128254	32528129	The few tumors that develop under these experimental conditions in the Vav2 L332A/L332A animals are also smaller (Fig.	('Vav2', 'Gene', (71, 75))	('L332A', 'Var', (76, 81))	('Vav2', 'Gene', '22325', (71, 75))	('L332A', 'SUBSTITUTION', 'None', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('L332A', 'Var', (82, 87))	('L332A', 'Mutation', 'p.L332A', (76, 81))	('tumors', 'Disease', (8, 14))	('L332A', 'SUBSTITUTION', 'None', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('smaller', 'NegReg', (105, 112))	('L332A', 'Mutation', 'p.L332A', (82, 87))
128264	32528129	4A-D), indicating that the defects found in Vav2 L332A/- mice are not due to the reduction in Vav2 protein levels caused by the presence of one copy of the null Vav2 allele.	('mice', 'Species', '10090', (57, 61))	('Vav2', 'Gene', '22325', (44, 48))	('Vav2', 'Gene', (44, 48))	('Vav2', 'Gene', '22325', (161, 165))	('Vav2', 'Gene', (161, 165))	('L332A/-', 'Var', (49, 56))	('L332A', 'Mutation', 'p.L332A', (49, 54))	('reduction', 'NegReg', (81, 90))	('Vav2', 'Gene', (94, 98))	('Vav2', 'Gene', '22325', (94, 98))
128267	32528129	As in the case of cardiovascular homeostasis, we found that Vav2 L332A/L332A and Vav2 L332A/- animals exhibit vascular permeability responses similar to WT and Vav2 -/- mice, respectively (Fig.	('Vav2', 'Gene', (60, 64))	('L332A', 'SUBSTITUTION', 'None', (86, 91))	('cardiovascular homeostasis', 'Disease', (18, 44))	('Vav2', 'Gene', '22325', (160, 164))	('L332A', 'Var', (65, 70))	('L332A', 'Mutation', 'p.L332A', (71, 76))	('Vav2', 'Gene', '22325', (81, 85))	('L332A', 'Mutation', 'p.L332A', (86, 91))	('Vav2', 'Gene', (160, 164))	('L332A', 'SUBSTITUTION', 'None', (65, 70))	('Vav2', 'Gene', (81, 85))	('L332A', 'Var', (71, 76))	('mice', 'Species', '10090', (169, 173))	('cardiovascular homeostasis', 'Disease', 'MESH:D002318', (18, 44))	('vascular permeability responses', 'MPA', (110, 141))	('L332A', 'Var', (86, 91))	('Vav2', 'Gene', '22325', (60, 64))	('L332A', 'Mutation', 'p.L332A', (65, 70))	('L332A', 'SUBSTITUTION', 'None', (71, 76))
128268	32528129	To address whether the foregoing observations could be extrapolated outside the vascular system, we investigated the long-term development of glaucoma in mice with impaired Vav2 function.	('function', 'MPA', (178, 186))	('mice', 'Species', '10090', (154, 158))	('Vav2', 'Gene', '22325', (173, 177))	('glaucoma', 'Disease', (142, 150))	('impaired', 'Var', (164, 172))	('glaucoma', 'Disease', 'MESH:D005901', (142, 150))	('glaucoma', 'Phenotype', 'HP:0000501', (142, 150))	('Vav2', 'Gene', (173, 177))
128269	32528129	Again, we observed that Vav2 -/- mice, but not the Vav2 L332A/L332A animals, develop buphthalmia (Fig.	('L332A', 'Var', (56, 61))	('L332A', 'Var', (62, 67))	('L332A', 'SUBSTITUTION', 'None', (56, 61))	('L332A', 'SUBSTITUTION', 'None', (62, 67))	('Vav2', 'Gene', '22325', (51, 55))	('Vav2', 'Gene', (51, 55))	('Vav2', 'Gene', '22325', (24, 28))	('Vav2', 'Gene', (24, 28))	('L332A', 'Mutation', 'p.L332A', (56, 61))	('L332A', 'Mutation', 'p.L332A', (62, 67))	('buphthalmia', 'Disease', 'None', (85, 96))	('mice', 'Species', '10090', (33, 37))	('develop buphthalmia', 'Phenotype', 'HP:0000557', (77, 96))	('develop', 'Reg', (77, 84))	('buphthalmia', 'Disease', (85, 96))
128275	32528129	The use of the "pharmaco-mimetic" Vav2 mice has allowed us to demonstrate, for the first time to our knowledge, that targeting the catalytic activity of a Rho GEF is a potential avenue to impair tumorigenic processes in vivo.	('catalytic activity', 'MPA', (131, 149))	('tumor', 'Disease', (195, 200))	('GEF', 'Gene', (159, 162))	('GEF', 'Gene', '16800', (159, 162))	('impair', 'NegReg', (188, 194))	('Vav2', 'Gene', '22325', (34, 38))	('Vav2', 'Gene', (34, 38))	('Rho', 'Gene', (155, 158))	('targeting', 'Var', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('mice', 'Species', '10090', (39, 43))
128295	32528129	Vav2 becomes deregulated by changes in expression rather than mutations in most of those tumors (L.F.L.-M. and X.R.B, manuscript submitted).	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('Vav2', 'Gene', (0, 4))	('Vav2', 'Gene', '22325', (0, 4))	('changes', 'Var', (28, 35))	('expression', 'MPA', (39, 49))	('deregulated', 'Reg', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
128296	32528129	However, frequent VAV2 mutations have been recently found in hereditary cases of oral squamous cell carcinoma.	('found', 'Reg', (52, 57))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('oral squamous cell carcinoma', 'Disease', (81, 109))	('mutations', 'Var', (23, 32))	('VAV2', 'Gene', '22325', (18, 22))	('VAV2', 'Gene', (18, 22))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 109))
128304	32528129	Upon generation of mice from embryonic stem cells, the subsequent steps involved further crosses with transgenic mice to induce the removal of the NeoR cassette (using a Flippase-mediated recombination step) and the swapping of the WT and mutant Vav2 exon 11 (using a Cre-mediated recombination step) (Fig.	('Vav2', 'Gene', (246, 250))	('Vav2', 'Gene', '22325', (246, 250))	('swapping', 'Var', (216, 224))	('transgenic mice', 'Species', '10090', (102, 117))	('NeoR cassette', 'Gene', (147, 160))	('mice', 'Species', '10090', (113, 117))	('mice', 'Species', '10090', (19, 23))
128305	32528129	Vav2 L332A/- and Vav2 L332A/L332A;Vav3 -/- mice were generated using appropriate crosses of Vav2 L332A/L332A animals with the Vav2 -/- and Vav2 -/-;Vav3 -/- strains, respectively.	('Vav2', 'Gene', '22325', (17, 21))	('Vav3', 'Gene', (148, 152))	('L332A', 'Mutation', 'p.L332A', (103, 108))	('L332A', 'SUBSTITUTION', 'None', (22, 27))	('L332A', 'SUBSTITUTION', 'None', (5, 10))	('L332A', 'SUBSTITUTION', 'None', (28, 33))	('Vav2', 'Gene', (139, 143))	('Vav2', 'Gene', (17, 21))	('Vav3', 'Gene', '57257', (148, 152))	('L332A', 'Var', (97, 102))	('Vav2', 'Gene', '22325', (0, 4))	('L332A', 'Mutation', 'p.L332A', (22, 27))	('L332A', 'Mutation', 'p.L332A', (5, 10))	('mice', 'Species', '10090', (43, 47))	('L332A', 'Var', (103, 108))	('Vav3', 'Gene', (34, 38))	('L332A', 'Mutation', 'p.L332A', (28, 33))	('L332A', 'SUBSTITUTION', 'None', (97, 102))	('Vav2', 'Gene', (0, 4))	('Vav2', 'Gene', '22325', (126, 130))	('Vav3', 'Gene', '57257', (34, 38))	('Vav2', 'Gene', '22325', (92, 96))	('L332A', 'SUBSTITUTION', 'None', (103, 108))	('Vav2', 'Gene', (126, 130))	('L332A', 'Var', (22, 27))	('L332A', 'Var', (5, 10))	('L332A', 'Mutation', 'p.L332A', (97, 102))	('L332A', 'Var', (28, 33))	('Vav2', 'Gene', '22325', (139, 143))	('Vav2', 'Gene', (92, 96))
128310	32528129	The plasmid encoding EGFP-Vav2L332A (pSAF3) was obtained by site-directed mutagenesis of the pAA7 plasmid template using the primers 5'-GGT GCC CAT GCA ACG GGT GGC GAA GTA CCA CCT GCT GCT C-3' and 5'-GAG CAG CAG GTG GTA CTT CGC CAC CCG TTG CAT GGG CAC C-3' (the altered nucleotides used to create the L332A mutation are underlined).	('L332A', 'Mutation', 'p.L332A', (30, 35))	('L332A', 'Var', (301, 306))	('CAT', 'Gene', (144, 147))	('CAT', 'Gene', (240, 243))	('CAT', 'Gene', '12359', (144, 147))	('L332A', 'Mutation', 'p.L332A', (301, 306))	('CAT', 'Gene', '12359', (240, 243))
128341	32528129	A7906) in TBS-T for at least 1 hour and then incubated overnight at 4  C with the appropriate antibodies to Vav2 (home-made; Lab catalog No.	('TBS-T', 'Gene', (10, 15))	('A7906', 'Var', (0, 5))	('Vav2', 'Gene', '22325', (108, 112))	('Vav2', 'Gene', (108, 112))
128390	31952355	In some cancers, lower expression of CLDN-1 is shown to be associated with cancer progression and invasion, while in others, loss of CLDN-1 improves the patient survival.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancer', 'Disease', (8, 14))	('cancers', 'Disease', (8, 15))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('loss', 'Var', (125, 129))	('lower', 'NegReg', (17, 22))	('invasion', 'CPA', (98, 106))	('cancer', 'Disease', (75, 81))	('CLDN-1', 'Gene', (37, 43))	('improves', 'PosReg', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('patient survival', 'CPA', (153, 169))	('patient', 'Species', '9606', (153, 160))	('CLDN-1', 'Gene', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('expression', 'MPA', (23, 33))
128396	31952355	Both defective tight junctions and the absence of tight junctions have shown to be associated with the development and progression of certain cancers.	('tight junctions', 'Protein', (50, 65))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('tight junctions', 'Protein', (15, 30))	('absence', 'NegReg', (39, 46))	('cancers', 'Disease', (142, 149))	('men', 'Species', '9606', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated', 'Reg', (83, 93))	('defective', 'Var', (5, 14))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
128418	31952355	Considering the importance of claudins in cancer, targeting claudin expression appears to have promise in the treatment of cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('men', 'Species', '9606', (115, 118))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', (123, 129))	('claudin expression', 'Protein', (60, 78))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('targeting', 'Var', (50, 59))
128432	31952355	While one study reported that the activation of CLDN-1 was repressed by the binding of E-cadherin to CLDN-1 promoter, knockdown of CLDN-1 has been found to be associated with decreased cell migration and induction of EMT in breast cancer cells.	('cell migration', 'CPA', (185, 199))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('EMT', 'CPA', (217, 220))	('CLDN-1', 'Gene', (131, 137))	('knockdown', 'Var', (118, 127))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('breast cancer', 'Disease', (224, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('decreased', 'NegReg', (175, 184))
128445	31952355	Several transcript variants for CLDN-1 were found in human invasive breast cancer as a result of splicing and mis splicing events suggesting that through alternative splicing CLDN-1 is downregulated in invasive type of breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (219, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('invasive breast cancer', 'Disease', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('alternative splicing', 'Var', (154, 174))	('CLDN-1', 'Gene', (32, 38))	('downregulated', 'NegReg', (185, 198))	('invasive type of breast cancers', 'Disease', (202, 233))	('human', 'Species', '9606', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CLDN-1', 'Gene', (175, 181))	('invasive breast cancer', 'Disease', 'MESH:D001943', (59, 81))	('invasive type of breast cancers', 'Disease', 'MESH:D001943', (202, 233))
128451	31952355	The same study demonstrated the increased pathogenic character of FTC-133 cells by RASV12 transfection was associated with high expression of CLDN-1 and enhanced cell proliferation and migration.	('CLDN-1', 'Gene', (142, 148))	('cell proliferation', 'CPA', (162, 180))	('FTC', 'Disease', 'MESH:C572845', (66, 69))	('RASV12', 'Gene', (83, 89))	('expression', 'MPA', (128, 138))	('transfection', 'Var', (90, 102))	('FTC', 'Disease', (66, 69))	('enhanced', 'PosReg', (153, 161))	('migration', 'CPA', (185, 194))
128452	31952355	Conversely, the downregulation of CLDN-1 by siRNA caused decreased cell invasion and migration accompanied by decreased phospho-PKC expression in the FTC-238 cells, suggesting that the aggressiveness of follicular thyroid carcinoma associated with high CLDN-1 expression can be influenced by PKC activity.	('downregulation', 'NegReg', (16, 30))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (214, 231))	('aggressiveness', 'Phenotype', 'HP:0000718', (185, 199))	('aggressiveness of follicular thyroid carcinoma', 'Disease', (185, 231))	('cell invasion', 'CPA', (67, 80))	('CLDN-1', 'Gene', (253, 259))	('decreased', 'NegReg', (57, 66))	('aggressiveness of follicular thyroid carcinoma', 'Disease', 'MESH:C572845', (185, 231))	('FTC', 'Disease', (150, 153))	('PKC', 'Gene', '112476', (128, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('CLDN-1', 'Gene', (34, 40))	('PKC', 'Gene', (128, 131))	('PKC', 'Gene', '112476', (292, 295))	('decreased', 'NegReg', (110, 119))	('FTC', 'Disease', 'MESH:C572845', (150, 153))	('PKC', 'Gene', (292, 295))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (203, 231))	('high', 'Var', (248, 252))
128458	31952355	In mouse xenograft studies, tumor growth and metastasis is regulated by genetic modulation of CLDN-1.	('tumor', 'Disease', (28, 33))	('mouse', 'Species', '10090', (3, 8))	('genetic modulation', 'Var', (72, 90))	('CLDN-1', 'Gene', (94, 100))	('regulated', 'Reg', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
128466	31952355	Delocalization of CLDN-1 from the membrane to cytoplasm and nuclei of cancer cells supports cancer growth and malignancy.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CLDN-1', 'Gene', (18, 24))	('malignancy', 'Disease', 'MESH:D009369', (110, 120))	('supports', 'PosReg', (83, 91))	('Delocalization', 'Var', (0, 14))	('malignancy', 'Disease', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
128470	31952355	Dhawan and colleagues reported that T84 cell transfection with CLDN -1 resulted in aggregation and multilayer formation in transfected T84 cells as compared to the T84 parent cells.	('resulted in', 'Reg', (71, 82))	('multilayer formation', 'CPA', (99, 119))	('CLDN -1', 'Gene', '9076', (63, 70))	('CLDN -1', 'Gene', (63, 70))	('transfection', 'Var', (45, 57))	('aggregation', 'Disease', 'MESH:D001791', (83, 94))	('aggregation', 'Disease', (83, 94))
128472	31952355	The progression of colon cancer has been linked with the dysregulation of the CLDN-1 expression causing disorganization of the tight junction fibrils leading to increased paracellular permeability.	('dysregulation', 'Var', (57, 70))	('colon cancer', 'Phenotype', 'HP:0003003', (19, 31))	('colon cancer', 'Disease', 'MESH:D015179', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('paracellular permeability', 'MPA', (171, 196))	('colon cancer', 'Disease', (19, 31))	('tight', 'Protein', (127, 132))	('increased', 'PosReg', (161, 170))	('CLDN-1', 'Gene', (78, 84))	('disorganization', 'MPA', (104, 119))
128477	31952355	Wnt signaling is activated by the loss of the adenomatous polyposis coli (APC) protein or by the activation of beta-catenin mutations.	('APC', 'Disease', 'MESH:D011125', (74, 77))	('adenomatous polyposis coli', 'Disease', (46, 72))	('APC', 'Disease', (74, 77))	('mutations', 'Var', (124, 133))	('activation', 'PosReg', (97, 107))	('beta-catenin', 'Gene', (111, 123))	('Wnt signaling', 'Pathway', (0, 13))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (46, 72))	('activated', 'PosReg', (17, 26))	('beta-catenin', 'Gene', '1499', (111, 123))	('loss', 'NegReg', (34, 38))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (46, 72))
128501	31952355	However in another study reduced expression of CLDN-1 was reported to be a marker for a poor prognosis in HCC, and a further study showed that reduced expression of CLDN-1 reinforced the invasive and cancer stem cell (CSC) like properties of HCC cell lines (Huh7 and Hep3B) in vitro, while the forced expression of CLDN-1 diminished the CSC-like properties of HCC cells.	('HCC', 'Disease', (242, 245))	('CLDN-1', 'Gene', (165, 171))	('HCC', 'Disease', 'MESH:D006528', (242, 245))	('reduced', 'NegReg', (143, 150))	('reinforced', 'PosReg', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('Huh7', 'Gene', (258, 262))	('Huh7', 'Gene', '284424', (258, 262))	('HCC', 'Disease', 'MESH:D006528', (106, 109))	('HCC', 'Disease', 'MESH:D006528', (360, 363))	('HCC', 'Disease', (106, 109))	('HCC', 'Disease', (360, 363))	('Hep3B', 'CellLine', 'CVCL:0326', (267, 272))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('expression', 'Var', (151, 161))	('cancer', 'Disease', (200, 206))	('diminished', 'NegReg', (322, 332))
128507	31952355	Studies showed that the invasive ability of HOP62 lung adenocarcinoma cells is increased by knockdown of endogenous expression of CLDN-1.	('increased', 'PosReg', (79, 88))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (50, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('knockdown', 'Var', (92, 101))	('lung adenocarcinoma', 'Disease', (50, 69))	('HOP62', 'CellLine', 'CVCL:1285', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('CLDN-1', 'Gene', (130, 136))	('invasive ability', 'CPA', (24, 40))
128512	31952355	An experiment in human lung cancer cell lines, observed that TNFalpha induced the expression of CLDN-1, and knockdown of CLDN-1 blocked 75% of TNFalpha-induced gene expression.	('TNFalpha', 'Gene', (61, 69))	('lung cancer', 'Disease', (23, 34))	('TNFalpha', 'Gene', (143, 151))	('knockdown', 'Var', (108, 117))	('CLDN-1', 'Gene', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('expression', 'MPA', (82, 92))	('human', 'Species', '9606', (17, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('TNFalpha', 'Gene', '7124', (61, 69))	('men', 'Species', '9606', (9, 12))	('TNFalpha', 'Gene', '7124', (143, 151))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))
128513	31952355	In CL1-5 lung cancer cells, cell migration activity was inhibited by over-expression of CLDN-1 and restored by CLDN-1 knockdown in addition to cell invasion ability.	('restored', 'PosReg', (99, 107))	('knockdown', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('over-expression', 'PosReg', (69, 84))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('CLDN-1', 'Gene', (88, 94))	('cell migration activity', 'CPA', (28, 51))	('inhibited', 'NegReg', (56, 65))	('lung cancer', 'Disease', (9, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))
128518	31952355	Another study found that enhanced cell migration by tumor necrosis factor and a similar morphology like fibroblast was found to be reduced by small CLDN-1 interfering RNA in the cells of lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor necrosis', 'Disease', 'MESH:D009336', (52, 66))	('enhanced', 'PosReg', (25, 33))	('cell migration', 'CPA', (34, 48))	('small', 'Var', (142, 147))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('CLDN-1', 'Gene', (148, 154))	('tumor necrosis', 'Disease', (52, 66))	('reduced', 'NegReg', (131, 138))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
128537	31952355	One study demonstrated the association of high CLDN-1 expression with aggressive histopathologic features such as perineural and vascular invasion and suggested that CLDN-1 might be directly or indirectly involved in the progression of OSCC.	('expression', 'MPA', (54, 64))	('OSCC', 'Disease', 'MESH:D002294', (236, 240))	('OSCC', 'Disease', (236, 240))	('high', 'Var', (42, 46))	('involved', 'Reg', (205, 213))	('CLDN-1', 'Gene', (47, 53))
128538	31952355	Another study found that the absence of CLDN-1 was associated with poorly differentiated tumors.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('absence', 'Var', (29, 36))	('associated', 'Reg', (51, 61))	('CLDN-1', 'Gene', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
128539	31952355	Immunohistochemical analysis revealed that the presence of CLDN-1 in the invasive front of tumor islands was associated with neck mode metastasis.	('CLDN-1', 'Gene', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('presence', 'Var', (47, 55))	('neck mode metastasis', 'Disease', (125, 145))	('associated with', 'Reg', (109, 124))	('tumor', 'Disease', (91, 96))
128540	31952355	The results obtained from this study further suggested that the expression of CLDN-1 is linked with the recurrence of OSCC.	('OSCC', 'Disease', (118, 122))	('recurrence', 'Disease', (104, 114))	('linked', 'Reg', (88, 94))	('expression', 'Var', (64, 74))	('OSCC', 'Disease', 'MESH:D002294', (118, 122))	('CLDN-1', 'Gene', (78, 84))
128548	31952355	In melanoma patients with brain metastases, the expression of CLDN-1 was downregulated, and the introduction of CLDN-1 retrovirus reduced the tumor aggressiveness and tumor migration ability and diminished micro-metastasis in the brain.	('aggressiveness', 'Phenotype', 'HP:0000718', (148, 162))	('CLDN-1', 'Gene', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('retrovirus reduced the tumor aggressiveness', 'Disease', 'MESH:D001523', (119, 162))	('downregulated', 'NegReg', (73, 86))	('introduction', 'Var', (96, 108))	('patients', 'Species', '9606', (12, 20))	('expression', 'MPA', (48, 58))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('CLDN-1', 'Gene', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('retrovirus reduced the tumor aggressiveness', 'Disease', (119, 162))	('micro-metastasis in the brain', 'CPA', (206, 235))	('diminished', 'NegReg', (195, 205))	('brain metastases', 'Disease', 'MESH:D009362', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('brain metastases', 'Disease', (26, 42))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
128558	31952355	Any defect in the expression of CLDN-1 can result in tight junction dysfunction causing increased paracellular permeability leading to various pathologies such as in Neonatal ichthyosis-sclerosing cholangitis (NISCH) syndrome.	('ichthyosis', 'Phenotype', 'HP:0008064', (175, 185))	('junction dysfunction', 'Disease', 'MESH:D020511', (59, 79))	('Neonatal ichthyosis-sclerosing cholangitis (NISCH) syndrome', 'Disease', 'MESH:C564365', (166, 225))	('junction dysfunction', 'Disease', (59, 79))	('result in', 'Reg', (43, 52))	('cholangitis', 'Phenotype', 'HP:0030151', (197, 208))	('paracellular permeability', 'MPA', (98, 123))	('CLDN-1', 'Gene', (32, 38))	('increased', 'PosReg', (88, 97))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (186, 208))	('defect', 'Var', (4, 10))
128560	31952355	Besides, the other study reported that high expression of CLDN-1 resulted in blood-brain-barrier (BBB) leakiness during post-stroke recovery and targeting of CLDN-1 by a CLDN-1 peptide improved the permeability of brain endothelial barrier.	('permeability', 'MPA', (198, 210))	('high', 'Var', (39, 43))	('improved', 'PosReg', (185, 193))	('stroke', 'Phenotype', 'HP:0001297', (125, 131))	('leakiness', 'Disease', 'MESH:C535298', (103, 112))	('leakiness', 'Disease', (103, 112))	('stroke', 'Disease', (125, 131))	('resulted in', 'Reg', (65, 76))	('stroke', 'Disease', 'MESH:D020521', (125, 131))	('CLDN-1', 'Gene', (58, 64))
128573	31952355	One of the studies observed that the human hepatocytes treated with mouse anti-CLDN-1 monoclonal antibodies (mAbs), showed improved drug absorption and prevented hepatitis C virus (HCV) infection.	('mouse', 'Species', '10090', (68, 73))	('anti-CLDN-1', 'Var', (74, 85))	('hepatitis C virus (HCV) infection', 'Disease', 'MESH:D006526', (162, 195))	('hepatitis', 'Phenotype', 'HP:0012115', (162, 171))	('drug absorption', 'MPA', (132, 147))	('prevented', 'NegReg', (152, 161))	('anti-CLDN-1', 'Gene', (74, 85))	('human', 'Species', '9606', (37, 42))	('improved', 'PosReg', (123, 131))
128576	31952355	It was observed that blocking CLDN-1 with cCPE variants in the Huh7.5 hepatoma cell line inhibited infection of Huh7.5 cells with HCV in a dose-dependent manner and this also opened the epidermal barrier in the reconstructed human epidermis.	('HCV', 'Species', '11103', (130, 133))	('infection', 'Disease', (99, 108))	('opened', 'Reg', (175, 181))	('variants', 'Var', (47, 55))	('infection', 'Disease', 'MESH:D007239', (99, 108))	('Huh7.5', 'CellLine', 'CVCL:7927', (112, 118))	('hepatoma', 'Disease', (70, 78))	('hepatoma', 'Disease', 'MESH:D006528', (70, 78))	('inhibited', 'NegReg', (89, 98))	('epidermal barrier in the', 'CPA', (186, 210))	('cCPE', 'Gene', (42, 46))	('human', 'Species', '9606', (225, 230))	('Huh7.5', 'CellLine', 'CVCL:7927', (63, 69))	('CLDN-1', 'Gene', (30, 36))
128583	31952355	Several other studies have used CLDN-4 as a target for tumor therapy and showed the accumulation of anti-CLDN-4 mAbs specifically in the tumors and reduced the growth of human colorectal and gastric tumors in mice.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', (199, 205))	('colorectal and gastric tumors', 'Disease', 'MESH:D015179', (176, 205))	('anti-CLDN-4', 'Var', (100, 111))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('gastric tumors', 'Phenotype', 'HP:0006753', (191, 205))	('growth', 'CPA', (160, 166))	('tumor', 'Disease', (199, 204))	('mice', 'Species', '10090', (209, 213))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('reduced', 'NegReg', (148, 155))	('tumor', 'Disease', (55, 60))	('human', 'Species', '9606', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
128587	31952355	Besides the fact that the abnormal or deregulated expression of claudins has been associated with different human diseases like cancer, there are also other human disorders such as autosomal recessive disorders that have been reported due to clearly defined mutations in the corresponding claudin genes.	('mutations', 'Var', (258, 267))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('autosomal recessive disorders', 'Disease', (181, 210))	('associated', 'Reg', (82, 92))	('human', 'Species', '9606', (157, 162))	('autosomal recessive disorders', 'Disease', 'MESH:D030342', (181, 210))	('claudins', 'Gene', (64, 72))	('deregulated expression', 'MPA', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('human', 'Species', '9606', (108, 113))	('claudin', 'Gene', (289, 296))	('cancer', 'Disease', (128, 134))
128588	31952355	The first evidence that showed a mutation in the claudin family of tight junction proteins causes human disorders were from the group of Lifton.	('causes', 'Reg', (91, 97))	('human disorders', 'Disease', (98, 113))	('mutation', 'Var', (33, 41))	('human', 'Species', '9606', (98, 103))
128589	31952355	In their study, they reported that the mutations in the human gene, paracellin-1 (PCLN-1)/CLDN-16 causes an autosomal recessive disorder called Familial hypomagnesemia with hypercalcinuria and nephrocalcinosis (FHHNC) characterized with renal Mg2+ and Ca+ wasting.	('PCLN-1', 'Gene', '10686', (82, 88))	('hypercalcinuria', 'Phenotype', 'HP:0002150', (173, 188))	('hypercalcinuria and nephrocalcinosis', 'Disease', 'MESH:D009397', (173, 209))	('Familial hypomagnesemia', 'Disease', 'MESH:C537153', (144, 167))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (153, 167))	('causes', 'Reg', (98, 104))	('Mg2', 'Gene', (243, 246))	('Familial hypomagnesemia', 'Disease', (144, 167))	('mutations', 'Var', (39, 48))	('human', 'Species', '9606', (56, 61))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (108, 136))	('Mg2', 'Gene', '4589', (243, 246))	('paracellin-1', 'Gene', '10686', (68, 80))	('nephrocalcinosis', 'Phenotype', 'HP:0000121', (193, 209))	('autosomal recessive disorder', 'Disease', (108, 136))	('PCLN-1', 'Gene', (82, 88))	('paracellin-1', 'Gene', (68, 80))
128590	31952355	Later the same group revealed additional evidence that loss of function mutations in paracellin-1 PCLN-1/CLDN-16, are causative of FHHNC.	('mutations', 'Var', (72, 81))	('paracellin-1', 'Gene', (85, 97))	('FHHNC', 'Disease', (131, 136))	('PCLN-1', 'Gene', (98, 104))	('paracellin-1', 'Gene', '10686', (85, 97))	('PCLN-1', 'Gene', '10686', (98, 104))
128592	31952355	CLDN-16 is a cattle ortholog of PCLN-1 with ~ 90% sequence homology, and PCLN-1/CLDN16 mutations have been shown to be strongly associated with bovine chronic interstitial nephritis with diffuse zonal fibrosis (CINF).	('CINF', 'Gene', (211, 215))	('fibrosis', 'Disease', 'MESH:D005355', (201, 209))	('fibrosis', 'Disease', (201, 209))	('interstitial nephritis', 'Disease', 'MESH:D009395', (159, 181))	('nephritis', 'Phenotype', 'HP:0000123', (172, 181))	('mutations', 'Var', (87, 96))	('bovine', 'Species', '9913', (144, 150))	('interstitial nephritis', 'Disease', (159, 181))	('CLDN16', 'Gene', (80, 86))	('associated with', 'Reg', (128, 143))	('chronic interstitial nephritis', 'Phenotype', 'HP:0004743', (151, 181))	('CINF', 'Gene', '281074', (211, 215))	('cattle', 'Species', '9913', (13, 19))	('PCLN-1', 'Gene', '10686', (73, 79))	('PCLN-1', 'Gene', (73, 79))	('PCLN-1', 'Gene', (32, 38))	('CLDN16', 'Gene', '282184', (80, 86))	('PCLN-1', 'Gene', '10686', (32, 38))	('interstitial nephritis', 'Phenotype', 'HP:0001970', (159, 181))
128593	31952355	Although both renal disorders FHHN and CINF are caused by PCLN-1/CLDN16 mutations, but the clinical features of both diseases are quite different which may be due to specific mutations/deletions in the same gene or through species specificity.	('mutations', 'Var', (72, 81))	('PCLN-1', 'Gene', '10686', (58, 64))	('renal disorders FHHN and CINF', 'Disease', 'MESH:D007674', (14, 43))	('caused', 'Reg', (48, 54))	('CLDN16', 'Gene', (65, 71))	('CLDN16', 'Gene', '282184', (65, 71))	('PCLN-1', 'Gene', (58, 64))
128594	31952355	Since the first report, several other tight junction disorders have been shown to cause human diseases including mutations in claudin proteins such as CLDN-1, CLDN-9, CLDN-10, CLDN-14, CLDN-16, CLDN-19 (for detailed reviews see).	('CLDN-9', 'Gene', '9080', (159, 165))	('CLDN-1', 'Gene', (151, 157))	('CLDN-19', 'Gene', '149461', (194, 201))	('cause', 'Reg', (82, 87))	('junction disorders', 'Disease', 'MESH:D020511', (44, 62))	('CLDN-10', 'Gene', '9071', (167, 174))	('CLDN-19', 'Gene', (194, 201))	('CLDN-9', 'Gene', (159, 165))	('CLDN-14', 'Gene', '23562', (176, 183))	('junction disorders', 'Disease', (44, 62))	('mutations', 'Var', (113, 122))	('CLDN-10', 'Gene', (167, 174))	('CLDN-14', 'Gene', (176, 183))	('human', 'Species', '9606', (88, 93))	('CLDN-16', 'Gene', (185, 192))
128611	31301217	In survival analyses, high expression levels of Steroidogenic factor-1 (SF-1), PTTG1 and TOP2A were significantly associated with poor survival.	('TOP2A', 'Gene', (89, 94))	('expression levels', 'MPA', (27, 44))	('high', 'Var', (22, 26))	('PTTG1', 'Gene', (79, 84))	('poor', 'NegReg', (130, 134))	('associated', 'Reg', (114, 124))	('Steroidogenic factor-1 (SF-1', 'Gene', '476031', (48, 76))
128654	31233505	Adenovirus-mediated expression of SIK1 improves hepatic glucose and lipid metabolism in type 2 diabetes mellitus rats In this study, we investigated the role and mechanism of Salt-induced kinase 1 (SIK1) in regulation of hepatic glucose and lipid metabolism in a high-fat food (HFD) and streptozocin (STZ)-induced type 2 diabetes mellitus (T2DM) rat model.	('expression', 'Var', (20, 30))	('SIK1 improves hepatic glucose', 'Disease', 'MESH:D056486', (34, 63))	('diabetes mellitus', 'Disease', 'MESH:D003920', (321, 338))	('SIK1 improves hepatic glucose', 'Disease', (34, 63))	('lipid', 'Chemical', 'MESH:D008055', (68, 73))	('Salt-induced kinase 1', 'Gene', (175, 196))	('lipid', 'Chemical', 'MESH:D008055', (241, 246))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (88, 103))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (321, 338))	('type 2 diabetes mellitus', 'Disease', (314, 338))	('type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (314, 338))	('hepatic glucose', 'Disease', (221, 236))	('Salt-induced kinase 1', 'Gene', '59329', (175, 196))	('rat', 'Species', '10116', (346, 349))	('type 2 diabetes mellitus', 'Disease', (88, 112))	('diabetes mellitus', 'Disease', 'MESH:D003920', (95, 112))	('type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (88, 112))	('DM', 'Phenotype', 'HP:0000819', (342, 344))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (314, 329))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (95, 112))	('rat', 'Species', '10116', (113, 116))	('hepatic glucose', 'Disease', 'MESH:D056486', (48, 63))	('STZ', 'Chemical', 'MESH:D013311', (301, 304))	('hepatic glucose', 'Disease', 'MESH:D056486', (221, 236))	('DM', 'Disease', 'MESH:D009223', (342, 344))
128665	31233505	In addition, Liver kinase B 1 (LKB1), a major upstream kinase of AMPK, phosphorylates SIK1 at Thr182 in the activation loop (A-loop) of the kinase domain, which is essential for switching on the SIK1 kinase activity, thus resulting in the increase of the kinase activity of SIK1.	('SIK1', 'Gene', (86, 90))	('Thr182', 'Var', (94, 100))	('AMPK', 'Gene', '78975', (65, 69))	('LKB1', 'Gene', '314621', (31, 35))	('Liver kinase B 1', 'Gene', (13, 29))	('LKB1', 'Gene', (31, 35))	('increase', 'PosReg', (239, 247))	('Liver kinase B 1', 'Gene', '314621', (13, 29))	('Thr182', 'Chemical', '-', (94, 100))	('AMPK', 'Gene', (65, 69))	('kinase activity', 'MPA', (255, 270))
128667	31233505	reported that knockdown of SIK1 in mice promoted both fasting hyperglycaemia and gluconeogenic gene expression, whereas mice treated with adenovirus-expressed SIK1 (Ad-SIK1) exhibited fasting hypoglycaemia and reduced gluconeogenic gene expression, and Ad-SIK1 was also effective in reducing blood glucose levels in fasted db/db diabetic mice.	('diabetic', 'Disease', 'MESH:D003920', (329, 337))	('reduced', 'NegReg', (210, 217))	('promoted', 'PosReg', (40, 48))	('fasting hyperglycaemia', 'Phenotype', 'HP:0003162', (54, 76))	('mice', 'Species', '10090', (338, 342))	('diabetic', 'Disease', (329, 337))	('fasting hypoglycaemia', 'Phenotype', 'HP:0003162', (184, 205))	('gluconeogenic gene expression', 'MPA', (218, 247))	('SIK1', 'Var', (159, 163))	('glucose', 'Chemical', 'MESH:D005947', (298, 305))	('blood glucose levels', 'MPA', (292, 312))	('gluconeogenic gene expression', 'MPA', (81, 110))	('hypoglycaemia', 'Disease', 'None', (192, 205))	('reduced gluconeogenic gene expression', 'Phenotype', 'HP:0005959', (210, 247))	('hypoglycaemia', 'Disease', (192, 205))	('SIK1', 'Gene', (27, 31))	('mice', 'Species', '10090', (35, 39))	('hyperglycaemia', 'Disease', (62, 76))	('reducing blood glucose levels', 'Phenotype', 'HP:0001943', (283, 312))	('mice', 'Species', '10090', (120, 124))	('hypoglycaemia', 'Phenotype', 'HP:0001943', (192, 205))	('knockdown', 'Var', (14, 23))	('hyperglycaemia', 'Disease', 'None', (62, 76))
128668	31233505	In addition, a previous study suggested that skeletal muscle specific SIK1-KO mice, but not liver tissue SIK1-KO, enhanced insulin sensitivity after HFD feeding.	('enhanced insulin sensitivity', 'Phenotype', 'HP:0000855', (114, 142))	('insulin', 'Gene', (123, 130))	('enhanced', 'PosReg', (114, 122))	('insulin', 'Gene', '3630', (123, 130))	('SIK1-KO', 'Var', (70, 77))	('mice', 'Species', '10090', (78, 82))
128680	31233505	found that SIK1 phosphorylated CRTC2 at Ser 171 in primary rat hepatocytes and in turn promoted its export to the cytoplasm, thereby inhibiting the expression of downstream gluconeogenic genes such as PEPCK and G6Pase, suggesting that regulation of CRTC2 activity by SIK1 may be crucial for inhibiting excessive hepatic glucose output.	('G6Pase', 'Gene', (211, 217))	('inhibiting', 'NegReg', (291, 301))	('inhibiting', 'NegReg', (133, 143))	('CRTC2', 'Gene', '310615', (31, 36))	('excessive hepatic glucose output', 'Disease', 'MESH:D056486', (302, 334))	('promoted', 'PosReg', (87, 95))	('export to the cytoplasm', 'MPA', (100, 123))	('CRTC2', 'Gene', '310615', (249, 254))	('CRTC2', 'Gene', (31, 36))	('PEPCK', 'Gene', (201, 206))	('G6Pase', 'Gene', '25634', (211, 217))	('rat', 'Species', '10116', (59, 62))	('Ser', 'Chemical', 'MESH:D012694', (40, 43))	('excessive hepatic glucose', 'Phenotype', 'HP:0006568', (302, 327))	('CRTC2', 'Gene', (249, 254))	('PEPCK', 'Gene', '362282', (201, 206))	('expression', 'MPA', (148, 158))	('SIK1', 'Var', (11, 15))	('excessive hepatic glucose output', 'Disease', (302, 334))
128687	31233505	This effect was reversed by co-expression of a phosphorylation-deficient Srebp1-c mutant.	('Srebp1-c', 'Gene', (73, 81))	('Srebp1-c', 'Gene', '78968', (73, 81))	('mutant', 'Var', (82, 88))
128688	31233505	A previous report has shown that lipogenic genes, such as FAS and ACC, are up-regulated by SIK1 knockdown in mouse liver, whereas overexpression of SIK1 reduces expression levels of SREBP-1c target genes, suggesting that SIK1 could regulate lipogenic gene transcript.	('knockdown', 'Var', (96, 105))	('ACC', 'Gene', (66, 69))	('expression', 'MPA', (161, 171))	('FAS', 'Gene', '50671', (58, 61))	('SIK1', 'Gene', (91, 95))	('ACC', 'Gene', '104371', (66, 69))	('up-regulated', 'PosReg', (75, 87))	('lipogenic genes', 'Gene', (33, 48))	('FAS', 'Gene', (58, 61))	('mouse', 'Species', '10090', (109, 114))
128720	31233505	Rabbit polyclonal CRTC2 antibody, SIK1 (S577) antibody, SIK1 (T182) antibody, FAS antibody and ACC antibody were purchased from Proteintech Group, Inc. (Cat #:12497-1-AP, Cat #: S4530-2, Cat #: S4529-2, Cat #:10624-2-AP and Cat #:21923-1-AP, Rosemont, USA).	('CRTC2', 'Gene', (18, 23))	('SIK1 (S577) antibody, SIK1', 'Disease', 'MESH:D007153', (34, 60))	('FAS', 'Gene', '50671', (78, 81))	('CRTC2', 'Gene', '310615', (18, 23))	('ACC', 'Gene', '104371', (95, 98))	('FAS', 'Gene', (78, 81))	('ACC', 'Gene', (95, 98))	('Cat #:10624-2-AP', 'Var', (203, 219))	('Cat #:21923-1-AP', 'Var', (224, 240))	('Cat #: S4529-2', 'Var', (187, 201))	('Rabbit', 'Species', '9986', (0, 6))
128721	31233505	Rabbit monoclonal PEPCK antibody and beta-actin antibody were purchased from Cell Signaling Technology, Inc. (Cat #: 12940 and Cat #: 4967, Danvers, Massachusetts, USA).	('Cat #: 12940', 'Var', (110, 122))	('beta-actin', 'Gene', (37, 47))	('beta-actin', 'Gene', '81822', (37, 47))	('PEPCK', 'Gene', (18, 23))	('PEPCK', 'Gene', '362282', (18, 23))	('Rabbit', 'Species', '9986', (0, 6))
128748	31233505	Intriguingly, serum TG was remarkably decreased in the Ad-SIK1 group (P<0.05).	('TG', 'Chemical', '-', (20, 22))	('serum TG', 'MPA', (14, 22))	('decreased', 'NegReg', (38, 47))	('Ad-SIK1', 'Var', (55, 62))
128749	31233505	Although Ad-SIK1 administration attenuated the HFD/STZ-induced increase in the serum TC level, no significant difference was observed.	('increase', 'PosReg', (63, 71))	('STZ', 'Chemical', 'MESH:D013311', (51, 54))	('serum TC level', 'MPA', (79, 93))	('TC', 'Chemical', '-', (85, 87))	('attenuated', 'NegReg', (32, 42))	('rat', 'Species', '10116', (25, 28))	('increase in the serum TC level', 'Phenotype', 'HP:0002155', (63, 93))	('Ad-SIK1', 'Var', (9, 16))
128753	31233505	Thus, Ad-SIK1 treatment significantly reduced fat deposition compared with the DM group, indicating that Ad-SIK1 administration could markedly improve steatosis.	('reduced', 'NegReg', (38, 45))	('steatosis', 'Phenotype', 'HP:0001397', (151, 160))	('steatosis', 'Disease', 'MESH:D005234', (151, 160))	('reduced fat deposition', 'Phenotype', 'HP:0040063', (38, 60))	('improve', 'PosReg', (143, 150))	('DM', 'Phenotype', 'HP:0000819', (79, 81))	('steatosis', 'Disease', (151, 160))	('Ad-SIK1', 'Var', (6, 13))	('fat deposition', 'MPA', (46, 60))	('DM', 'Disease', 'MESH:D009223', (79, 81))	('rat', 'Species', '10116', (121, 124))
128756	31233505	In the DM and Ad-GFP groups, SIK1-positive staining was much weaker than that in the Ad-SIK1 (p<0.001).	('weaker', 'NegReg', (61, 67))	('DM', 'Phenotype', 'HP:0000819', (7, 9))	('DM', 'Disease', 'MESH:D009223', (7, 9))	('SIK1-positive', 'Gene', (29, 42))	('Ad-GFP', 'Var', (14, 20))
128758	31233505	In contrast, CRTC2, PEPCK, G6pase, SREBP-1c, FAS and ACC stainings were much stronger in the DM and Ad-GFP groups than those in the Ad-SIK1 group (p<0.001).	('SREBP-1c', 'Gene', (35, 43))	('G6pase', 'Gene', (27, 33))	('CRTC2', 'Gene', '310615', (13, 18))	('ACC', 'Gene', '104371', (53, 56))	('DM', 'Disease', 'MESH:D009223', (93, 95))	('stronger', 'PosReg', (77, 85))	('FAS', 'Gene', '50671', (45, 48))	('G6pase', 'Gene', '25634', (27, 33))	('Ad-GFP', 'Var', (100, 106))	('DM', 'Phenotype', 'HP:0000819', (93, 95))	('PEPCK', 'Gene', (20, 25))	('PEPCK', 'Gene', '362282', (20, 25))	('CRTC2', 'Gene', (13, 18))	('FAS', 'Gene', (45, 48))	('ACC', 'Gene', (53, 56))
128760	31233505	Real Time-PCR analysis showed that SIK1 was significantly elevated in the Ad-SIK1 group compared to the DM group, while CRTC2, PEPCK and G6pase were significantly reduced, indicating an inhibitory effect of SIK1 in liver glucogenesis (Fig 4B).	('SIK1', 'Gene', (35, 39))	('SIK1 in liver glucogenesis', 'Disease', 'MESH:D017093', (207, 233))	('SIK1 in liver glucogenesis', 'Disease', (207, 233))	('Ad-SIK1', 'Var', (74, 81))	('G6pase', 'Gene', (137, 143))	('reduced', 'NegReg', (163, 170))	('DM', 'Phenotype', 'HP:0000819', (104, 106))	('G6pase', 'Gene', '25634', (137, 143))	('DM', 'Disease', 'MESH:D009223', (104, 106))	('CRTC2', 'Gene', (120, 125))	('elevated', 'PosReg', (58, 66))	('PEPCK', 'Gene', (127, 132))	('PEPCK', 'Gene', '362282', (127, 132))	('CRTC2', 'Gene', '310615', (120, 125))
128762	31233505	SIK1 overexpression significantly increased the protein level of SIK1, but decreased the protein levels of CRTC2, PEPCK and G6pase in liver compared with the DM group (Fig 4A).	('PEPCK', 'Gene', (114, 119))	('DM', 'Phenotype', 'HP:0000819', (158, 160))	('DM', 'Disease', 'MESH:D009223', (158, 160))	('G6pase', 'Gene', (124, 130))	('protein level', 'MPA', (48, 61))	('increased', 'PosReg', (34, 43))	('CRTC2', 'Gene', (107, 112))	('PEPCK', 'Gene', '362282', (114, 119))	('CRTC2', 'Gene', '310615', (107, 112))	('protein levels', 'MPA', (89, 103))	('SIK1', 'Gene', (0, 4))	('G6pase', 'Gene', '25634', (124, 130))	('SIK1', 'Gene', (65, 69))	('overexpression', 'Var', (5, 19))	('decreased', 'NegReg', (75, 84))
128763	31233505	Meanwhile, the phosphorylation level of SIK1 at Ser577 was drastically reduced, whereas the level of pT182 SIK1 and pS171 CRTC2 was significantly increased in the Ad-SIK1 group compared with the DM and Ad-GFP groups.	('phosphorylation level', 'MPA', (15, 36))	('Ser577', 'Var', (48, 54))	('DM', 'Disease', 'MESH:D009223', (195, 197))	('increased', 'PosReg', (146, 155))	('Ser577', 'Chemical', '-', (48, 54))	('reduced', 'NegReg', (71, 78))	('CRTC2', 'Gene', (122, 127))	('Ad-SIK1', 'Var', (163, 170))	('CRTC2', 'Gene', '310615', (122, 127))	('DM', 'Phenotype', 'HP:0000819', (195, 197))
128768	31233505	Meanwhile, Western blot analysis revealed that SREBP-1c, FAS and ACC were markedly downregulated in the Ad-SIK1 group compared with the DM group (Fig 5A).	('FAS', 'Gene', '50671', (57, 60))	('ACC', 'Gene', (65, 68))	('Ad-SIK1', 'Var', (104, 111))	('downregulated', 'NegReg', (83, 96))	('ACC', 'Gene', '104371', (65, 68))	('SREBP-1c', 'Gene', (47, 55))	('FAS', 'Gene', (57, 60))	('DM', 'Phenotype', 'HP:0000819', (136, 138))	('DM', 'Disease', 'MESH:D009223', (136, 138))
128769	31233505	Taken together, these findings indicate that the relieving effect of SIK1 overexpression on fatty liver was associated with a significant reduction in the expression of lipogenetic genes such as SREBP-1c, FAS and ACC.	('ACC', 'Gene', (213, 216))	('ACC', 'Gene', '104371', (213, 216))	('fatty liver', 'Phenotype', 'HP:0001397', (92, 103))	('FAS', 'Gene', (205, 208))	('expression', 'MPA', (155, 165))	('fatty liver', 'Disease', (92, 103))	('lipogenetic', 'MPA', (169, 180))	('FAS', 'Gene', '50671', (205, 208))	('SIK1', 'Gene', (69, 73))	('reduction', 'NegReg', (138, 147))	('overexpression', 'Var', (74, 88))
128780	31233505	First, overexpression of SIK1 reduced fasting blood glucose and gluconeogenic gene expression in db/db mice, while Ad-SIK1 RNAi promoted them.	('mice', 'Species', '10090', (103, 107))	('SIK1 reduced fasting blood glucose', 'Disease', (25, 59))	('Ad-SIK1', 'Var', (115, 122))	('SIK1 reduced fasting blood glucose', 'Disease', 'MESH:D007003', (25, 59))	('gluconeogenic gene', 'Gene', (64, 82))
128783	31233505	In the present study, the administration of Ad-SIK1 resulted in amelioration of hyperglycaemia in HFD/STZ-induced diabetic rats, suggesting that exogenous SIK1 might have a protective effect on T2DM.	('SIK1', 'Gene', (155, 159))	('Ad-SIK1', 'Var', (44, 51))	('hyperglycaemia', 'Disease', (80, 94))	('hyperglycaemia', 'Disease', 'None', (80, 94))	('rat', 'Species', '10116', (70, 73))	('rats', 'Species', '10116', (123, 127))	('DM', 'Phenotype', 'HP:0000819', (196, 198))	('DM', 'Disease', 'MESH:D009223', (196, 198))	('diabetic', 'Disease', 'MESH:D003920', (114, 122))	('rat', 'Species', '10116', (123, 126))	('rat', 'Species', '10116', (34, 37))	('diabetic', 'Disease', (114, 122))	('amelioration', 'NegReg', (64, 76))	('STZ', 'Chemical', 'MESH:D013311', (102, 105))
128784	31233505	This is obviously the first report that suggests the potential of adenovirus-mediated SIK1 gene transfer in the management of hyperglycaemia in the HFD/STZ-induced T2DM rat model.	('gene transfer', 'Var', (91, 104))	('SIK1', 'Gene', (86, 90))	('rat', 'Species', '10116', (169, 172))	('hyperglycaemia', 'Disease', (126, 140))	('STZ', 'Chemical', 'MESH:D013311', (152, 155))	('hyperglycaemia', 'Disease', 'None', (126, 140))	('DM', 'Phenotype', 'HP:0000819', (166, 168))	('DM', 'Disease', 'MESH:D009223', (166, 168))
128786	31233505	Phosphorylation at Thr182 by LKB1 is essential for switching on the SIK1 kinase activity.	('SIK1', 'Enzyme', (68, 72))	('Thr182', 'Chemical', '-', (19, 25))	('Phosphorylation', 'Var', (0, 15))	('switching', 'MPA', (51, 60))	('activity', 'MPA', (80, 88))	('Thr182', 'Var', (19, 25))	('LKB1', 'Gene', '314621', (29, 33))	('LKB1', 'Gene', (29, 33))
128787	31233505	The Thr182 of SIK1 is phosphorylated by LKB1, resulting in conversion from inactive SIK1 to the active form.	('Thr182', 'Var', (4, 10))	('SIK1', 'Gene', (84, 88))	('Thr182', 'Chemical', '-', (4, 10))	('LKB1', 'Gene', '314621', (40, 44))	('SIK1', 'Gene', (14, 18))	('LKB1', 'Gene', (40, 44))	('conversion', 'MPA', (59, 69))
128790	31233505	As expected, Ad-SIK1 treatment significantly elevated the level of pT182 SIK1 compared to the DM group.	('Ad-SIK1', 'Var', (13, 20))	('DM', 'Phenotype', 'HP:0000819', (94, 96))	('DM', 'Disease', 'MESH:D009223', (94, 96))	('elevated', 'PosReg', (45, 53))	('pT182', 'MPA', (67, 72))
128793	31233505	Phosphorylation of SIK1 at Ser577, which causes the nucleus export of SIK1, leads to a reduction of the transcriptional modulating activity of SIK1.	('Ser577', 'Var', (27, 33))	('SIK1', 'Gene', (19, 23))	('Phosphorylation', 'Var', (0, 15))	('SIK1', 'Gene', (143, 147))	('Ser577', 'Chemical', '-', (27, 33))	('causes', 'Reg', (41, 47))	('reduction', 'NegReg', (87, 96))	('nucleus export', 'MPA', (52, 66))	('transcriptional modulating activity', 'MPA', (104, 139))	('SIK1', 'Gene', (70, 74))
128796	31233505	In vivo, in the DM and Ad-GFP groups, the phosphorylation of SIK1 at Ser577 was elevated, whereas the expression of SIK1 was reduced, which were reversed by Ad-SIK1 administration, suggesting the possibility that SIK1 acts as a modulator of CREB-dependent transcription in the livers of HFD/STZ-induced diabetic rats.	('rats', 'Species', '10116', (312, 316))	('rat', 'Species', '10116', (173, 176))	('elevated', 'PosReg', (80, 88))	('Ser577', 'Var', (69, 75))	('phosphorylation', 'MPA', (42, 57))	('Ad-GFP', 'Var', (23, 29))	('diabetic', 'Disease', 'MESH:D003920', (303, 311))	('SIK1', 'Gene', (61, 65))	('rat', 'Species', '10116', (312, 315))	('Ser577', 'Chemical', '-', (69, 75))	('CREB', 'Gene', (241, 245))	('CREB', 'Gene', '81646', (241, 245))	('diabetic', 'Disease', (303, 311))	('STZ', 'Chemical', 'MESH:D013311', (291, 294))	('DM', 'Phenotype', 'HP:0000819', (16, 18))	('DM', 'Disease', 'MESH:D009223', (16, 18))
128799	31233505	Dysregulated gluconeogenesis contributes to hyperglycaemia in diabetic rodents and humans.	('hyperglycaemia in diabetic', 'Disease', (44, 70))	('hyperglycaemia in diabetic', 'Disease', 'MESH:D003920', (44, 70))	('hyperglycaemia in diabetic', 'Phenotype', 'HP:0003074', (44, 70))	('gluconeogenesis', 'MPA', (13, 28))	('Dysregulated', 'Var', (0, 12))	('Dysregulated gluconeogenesis', 'Phenotype', 'HP:0005959', (0, 28))	('humans', 'Species', '9606', (83, 89))
128802	31233505	Our results showed that the mRNA and protein expression of CRTC2 in the DM and Ad-GFP groups was significantly elevated, whereas pS171 CRTC2 was downregulated compared to the control group.	('elevated', 'PosReg', (111, 119))	('CRTC2', 'Gene', (135, 140))	('CRTC2', 'Gene', '310615', (59, 64))	('DM', 'Phenotype', 'HP:0000819', (72, 74))	('CRTC2', 'Gene', (59, 64))	('CRTC2', 'Gene', '310615', (135, 140))	('DM', 'Disease', 'MESH:D009223', (72, 74))	('Ad-GFP', 'Var', (79, 85))	('downregulated', 'NegReg', (145, 158))
128803	31233505	Moreover, relative to control Ad-GFP diabetic rats, Ad-SIK1 administration decreased fasting blood glucose, increased pS171 CRTC2 and reduced CRTC2 and gluconeogenic genes, such as PEPCK and G6Pase.	('pS171', 'Gene', (118, 123))	('G6Pase', 'Gene', '25634', (191, 197))	('PEPCK', 'Gene', '362282', (181, 186))	('CRTC2', 'Gene', (142, 147))	('fasting blood glucose', 'MPA', (85, 106))	('rat', 'Species', '10116', (46, 49))	('increased', 'PosReg', (108, 117))	('CRTC2', 'Gene', '310615', (124, 129))	('glucose', 'Chemical', 'MESH:D005947', (99, 106))	('reduced', 'NegReg', (134, 141))	('G6Pase', 'Gene', (191, 197))	('rat', 'Species', '10116', (68, 71))	('rats', 'Species', '10116', (46, 50))	('diabetic', 'Disease', 'MESH:D003920', (37, 45))	('gluconeogenic', 'MPA', (152, 165))	('CRTC2', 'Gene', (124, 129))	('diabetic', 'Disease', (37, 45))	('CRTC2', 'Gene', '310615', (142, 147))	('Ad-SIK1', 'Var', (52, 59))	('PEPCK', 'Gene', (181, 186))	('decreased', 'NegReg', (75, 84))
128809	31233505	In this study, the HFD/STZ-induced diabetic rats showed characteristics of NAFLD, including elevation of hepatic enzyme levels, significantly increased relative liver weights (liver index), hyperlipidaemia and histological changes such as steatosis and hepatocyte injury.	('elevation of hepatic enzyme', 'Phenotype', 'HP:0002910', (92, 119))	('elevation', 'PosReg', (92, 101))	('increased', 'PosReg', (142, 151))	('hyperlipidaemia', 'Disease', 'None', (190, 205))	('hyperlipidaemia', 'Disease', (190, 205))	('NAFLD', 'Var', (75, 80))	('relative', 'CPA', (152, 160))	('diabetic', 'Disease', 'MESH:D003920', (35, 43))	('steatosis', 'Phenotype', 'HP:0001397', (239, 248))	('steatosis and hepatocyte injury', 'Disease', 'MESH:D005234', (239, 270))	('hepatic enzyme levels', 'MPA', (105, 126))	('diabetic', 'Disease', (35, 43))	('STZ', 'Chemical', 'MESH:D013311', (23, 26))	('rats', 'Species', '10116', (44, 48))
128811	31233505	Next, our results found that Ad-SIK1 administration decreased the elevated hepatic mRNA and protein levels of SREBP-1c, FAS and ACC caused by HFD/STZ-induced T2DM, suggesting that overexpression of SIK1 could suppress hepatic lipogenesis by downregulating SREBP-1c and its downstream gene expression, thus leading to a reduction in the TG synthesis, which was further confirmed by a reduction in hepatic TG content.	('FAS', 'Gene', '50671', (120, 123))	('TG', 'Chemical', '-', (404, 406))	('expression', 'MPA', (289, 299))	('suppress', 'NegReg', (209, 217))	('DM', 'Disease', 'MESH:D009223', (160, 162))	('hepatic TG content', 'MPA', (396, 414))	('SIK1', 'Gene', (198, 202))	('SREBP-1c', 'Gene', (256, 264))	('hepatic lipogenesis', 'MPA', (218, 237))	('rat', 'Species', '10116', (45, 48))	('reduction', 'NegReg', (383, 392))	('downregulating', 'NegReg', (241, 255))	('STZ', 'Chemical', 'MESH:D013311', (146, 149))	('ACC', 'Gene', (128, 131))	('reduction', 'NegReg', (319, 328))	('TG synthesis', 'MPA', (336, 348))	('TG', 'Chemical', '-', (336, 338))	('decreased', 'NegReg', (52, 61))	('overexpression', 'Var', (180, 194))	('ACC', 'Gene', '104371', (128, 131))	('DM', 'Phenotype', 'HP:0000819', (160, 162))	('FAS', 'Gene', (120, 123))
128865	31051469	In this setting, aldosterone is normally low because the alternative mineralocorticoid excess increases intravascular volume and suppresses the renin-angiotensin system.	('renin', 'Gene', (144, 149))	('intravascular volume', 'MPA', (104, 124))	('aldosterone', 'Chemical', 'MESH:D000450', (17, 28))	('suppresses', 'NegReg', (129, 139))	('mineralocorticoid excess', 'Phenotype', 'HP:0000859', (69, 93))	('increases', 'PosReg', (94, 103))	('renin', 'Gene', '5972', (144, 149))	('excess', 'Var', (87, 93))	('aldosterone', 'MPA', (17, 28))
128868	31051469	Cushing's syndrome associated with this phenotype is usually clinically apparent as the principal mechanism is thought to be due to very high cortisol levels saturating renal 11beta-hydroxysteroid dehydrogenase type 2, thereby preventing the inactivation of cortisol to cortisone and allowing binding to the mineralocorticoid receptor and/or due to elevated angiotensinogen levels in such patients.	('11beta-hydroxysteroid dehydrogenase type 2', 'Gene', (175, 217))	('preventing', 'NegReg', (227, 237))	('cortisol', 'MPA', (258, 266))	('cortisone', 'Chemical', 'MESH:D003348', (270, 279))	('angiotensinogen', 'Gene', (358, 373))	('mineralocorticoid', 'Protein', (308, 325))	('cortisol', 'Chemical', 'MESH:D006854', (142, 150))	('elevated', 'PosReg', (349, 357))	('angiotensinogen', 'Gene', '183', (358, 373))	('saturating', 'Var', (158, 168))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (0, 18))	('patients', 'Species', '9606', (389, 397))	('high cortisol', 'Phenotype', 'HP:0003118', (137, 150))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (0, 18))	('inactivation', 'MPA', (242, 254))	("Cushing's syndrome", 'Disease', (0, 18))	('11beta-hydroxysteroid dehydrogenase type 2', 'Gene', '3291', (175, 217))	('binding', 'Interaction', (293, 300))	('cortisol', 'Chemical', 'MESH:D006854', (258, 266))
128872	31051469	Syndrome of apparent mineralocorticoid excess is a rare autosomal recessive disorder due to mutations in the gene encoding the 11beta-hydroxysteroid dehydrogenase type 2 enzyme (which converts cortisol to inactive cortisone in the renal tubules) resulting in its deficiency, causing therefore sodium retention, potassium wasting and severe hypokalaemic hypertension.	('sodium', 'Chemical', 'MESH:D012964', (293, 299))	('mineralocorticoid excess', 'Phenotype', 'HP:0000859', (21, 45))	('potassium wasting', 'Phenotype', 'HP:0000128', (311, 328))	('11beta-hydroxysteroid dehydrogenase type 2', 'Gene', '3291', (127, 169))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (56, 84))	('deficiency', 'MPA', (263, 273))	('11beta-hydroxysteroid dehydrogenase type 2', 'Gene', (127, 169))	('autosomal recessive disorder', 'Disease', (56, 84))	('cortisone', 'Chemical', 'MESH:D003348', (214, 223))	('causing', 'Reg', (275, 282))	('hypertension', 'Phenotype', 'HP:0000822', (353, 365))	('hypokalaemic hypertension', 'Disease', (340, 365))	('potassium wasting', 'MPA', (311, 328))	('due to', 'Reg', (85, 91))	('mutations', 'Var', (92, 101))	('sodium retention', 'MPA', (293, 309))	('potassium', 'Chemical', 'MESH:D011188', (311, 320))	('cortisol', 'Chemical', 'MESH:D006854', (193, 201))	('hypokalaemic hypertension', 'Disease', 'MESH:D006973', (340, 365))
128948	29956810	The patients were principally divided into 3 groups on the basis of BMI: Underweight (<18.5 kg/m2), normal (>=18.5 to <25.0 kg/m2) and high (>=25.0 kg/m2).	('>=18.5 to <25.0', 'Var', (108, 123))	('<18.5 kg/m2', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
128949	29956810	The high group included two sub-groups: Overweight (>=25 to <30 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (75, 80))	('Overweight', 'Phenotype', 'HP:0025502', (40, 50))	('>=30 kg/m2', 'Var', (82, 92))	('obese', 'Disease', (75, 80))	('>=25', 'Var', (52, 56))
128987	29956810	The result suggested that high BMI (>=25) was a high risk factor for cancer in the gallbladder, rectum, kidney and uterus.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('high', 'Var', (26, 30))	('cancer', 'Disease', (69, 75))
129026	29956810	We identified a positive correlation between a high BMI and the corresponding two/five-year survival rate in cancer samples (r=0.53, Spearman correlation coefficient, Figs.	('BMI', 'MPA', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('high', 'Var', (47, 51))	('cancer', 'Disease', (109, 115))	('two/five-year survival rate', 'CPA', (78, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
129040	29956810	For example, high levels of testosterone, and estrogen and progesterone are risk factors for prostate cancer and breast cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('risk factors', 'Reg', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('testosterone', 'Chemical', 'MESH:D013739', (28, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))
129048	29956810	In the present study, we found that high BMI (<=25) is potentially a risk factor for many types of cancer.	('types', 'Disease', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('risk', 'Reg', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('high', 'Var', (36, 40))
129050	29956810	Patients with a low BMI (<18.5) had a reduced incidence for all 38 types of cancer.	('low BMI', 'Phenotype', 'HP:0045082', (16, 23))	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Patients', 'Species', '9606', (0, 8))	('<18.5', 'Var', (25, 30))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
129087	26397949	Pregnancy, Primary Aldosteronism, and Adrenal CTNNB1 Mutations Recent discoveries of somatic mutations permit the recognition of subtypes of aldosterone-producing adenomas with distinct clinical presentations and pathological features.	('adenomas', 'Disease', 'MESH:D000236', (163, 171))	('adenomas', 'Disease', (163, 171))	('Mutations', 'Var', (53, 62))	('CTNNB1', 'Gene', '1499', (46, 52))	('aldosterone', 'Chemical', 'MESH:D000450', (141, 152))	('Primary Aldosteronism', 'Phenotype', 'HP:0011736', (11, 32))	('Primary Aldosteronism', 'Disease', (11, 32))	('CTNNB1', 'Gene', (46, 52))
129089	26397949	Their aldosterone-producing adenomas harbored activating mutations of CTNNB1, encoding beta-catenin in the Wnt cell-differentiation pathway, and expressed LHCGR and GNRHR, encoding gonadal receptors, at levels that were more than 100 times as high as the levels in other aldosterone-producing adenomas.	('adenomas', 'Disease', (293, 301))	('mutations', 'Var', (57, 66))	('beta-catenin', 'Gene', (87, 99))	('beta-catenin', 'Gene', '1499', (87, 99))	('aldosterone', 'Chemical', 'MESH:D000450', (6, 17))	('Wnt', 'Gene', (107, 110))	('adenomas', 'Disease', 'MESH:D000236', (28, 36))	('activating', 'PosReg', (46, 56))	('LHCGR', 'Gene', (155, 160))	('adenomas', 'Disease', (28, 36))	('CTNNB1', 'Gene', '1499', (70, 76))	('LHCGR', 'Gene', '3973', (155, 160))	('GNRHR', 'Gene', (165, 170))	('Wnt', 'Gene', '114487', (107, 110))	('GNRHR', 'Gene', '2798', (165, 170))	('aldosterone-producing', 'Disease', (6, 27))	('aldosterone', 'Chemical', 'MESH:D000450', (271, 282))	('CTNNB1', 'Gene', (70, 76))	('adenomas', 'Disease', 'MESH:D000236', (293, 301))
129090	26397949	The mutations stimulate Wnt activation and cause adrenocortical cells to de-differentiate toward their common adrenal-gonadal precursor cell type.	('Wnt', 'Gene', '114487', (24, 27))	('adrenocortical', 'Disease', (49, 63))	('adrenocortical', 'Disease', 'MESH:D018268', (49, 63))	('stimulate', 'PosReg', (14, 23))	('Wnt', 'Gene', (24, 27))	('mutations', 'Var', (4, 13))	('de-differentiate', 'NegReg', (73, 89))
129098	26397949	Some of these mutations arise in the part of exon 3 that encodes the consensus glycogen synthase kinase 3beta-casein kinase 1 (GSK-3beta-CK1) phosphorylation site and therefore result in loss of phosphorylation of beta-catenin.	('CK1', 'Species', '2498238', (137, 140))	('loss', 'NegReg', (187, 191))	('phosphorylation', 'MPA', (195, 210))	('beta-catenin', 'Gene', (214, 226))	('beta-catenin', 'Gene', '1499', (214, 226))	('mutations', 'Var', (14, 23))	('GSK-3beta', 'Gene', '2932', (127, 136))	('GSK-3beta', 'Gene', (127, 136))
129100	26397949	Until now, beta-catenin mutations in adrenocortical adenomas have been mainly associated with nonfunctioning tumors.	('associated', 'Reg', (78, 88))	('beta-catenin', 'Gene', (11, 23))	('adrenocortical adenomas', 'Disease', 'MESH:D018246', (37, 60))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('adrenocortical adenomas', 'Disease', (37, 60))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('beta-catenin', 'Gene', '1499', (11, 23))	('mutations', 'Var', (24, 33))	('tumors', 'Disease', (109, 115))	('adrenocortical adenomas', 'Phenotype', 'HP:0008256', (37, 60))
129102	26397949	Here we describe three patients with hyperaldosteronism, two presenting during pregnancy and one after menopause, who were discovered to have mutations in exon 3 of CTNNB1 in their adenomas.	('hyperaldosteronism', 'Disease', (37, 55))	('patients', 'Species', '9606', (23, 31))	('adenomas', 'Disease', (181, 189))	('men', 'Species', '9606', (103, 106))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (37, 55))	('CTNNB1', 'Gene', (165, 171))	('adenomas', 'Disease', 'MESH:D000236', (181, 189))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (37, 55))	('mutations in exon 3', 'Var', (142, 161))	('CTNNB1', 'Gene', '1499', (165, 171))	('one after menopause', 'Phenotype', 'HP:0008209', (93, 112))
129103	26397949	All three mutations were predicted to stabilize nonphosphorylated beta-catenin and to activate the Wnt signaling pathway.	('beta-catenin', 'Gene', (66, 78))	('Wnt', 'Gene', (99, 102))	('beta-catenin', 'Gene', '1499', (66, 78))	('stabilize nonphosphorylated', 'MPA', (38, 65))	('activate', 'PosReg', (86, 94))	('Wnt', 'Gene', '114487', (99, 102))	('mutations', 'Var', (10, 19))
129133	26397949	Bioinformatic analysis of sequence data identified a somatic mutation in exon 3 of CTNNB1 (C G, p.Ser33Cys) in the adenoma.	('adenoma', 'Disease', (115, 122))	('CTNNB1', 'Gene', '1499', (83, 89))	('p.Ser33Cys', 'Mutation', 'rs121913400', (96, 106))	('mutation in', 'Var', (61, 72))	('CTNNB1', 'Gene', (83, 89))	('adenoma', 'Disease', 'MESH:D000236', (115, 122))
129135	26397949	Sanger sequencing of exon 3 of genomic DNA (gDNA) and of the whole complementary DNA sequence of CTNNB1 showed that the adenomas in Patients 2 and 3 also carried mutations in CTNNB1 (C T, p.Ser45Phe, and G A, p.Gly34Arg, respectively).	('Patients', 'Species', '9606', (132, 140))	('p.Gly34Arg', 'Mutation', 'rs121913399', (209, 219))	('p.Ser45Phe', 'Var', (188, 198))	('CTNNB1', 'Gene', (175, 181))	('men', 'Species', '9606', (73, 76))	('CTNNB1', 'Gene', '1499', (97, 103))	('adenomas', 'Disease', 'MESH:D000236', (120, 128))	('CTNNB1', 'Gene', '1499', (175, 181))	('adenomas', 'Disease', (120, 128))	('p.Ser45Phe', 'Mutation', 'rs121913409', (188, 198))	('CTNNB1', 'Gene', (97, 103))	('p.Gly34Arg', 'Var', (209, 219))
129138	26397949	After generation of the beta-catenin mutants (Ser33Cys, Gly34Arg, and Ser45Phe) by means of site-directed mutagenesis, we measured Wnt-beta-catenin activity using TCF/LEF luciferase reporter assays.	('beta-catenin', 'Gene', (24, 36))	('TCF/LEF', 'Gene', '3172', (163, 170))	('Ser45Phe', 'SUBSTITUTION', 'None', (70, 78))	('Wnt', 'Gene', '114487', (131, 134))	('beta-catenin', 'Gene', (135, 147))	('beta-catenin', 'Gene', '1499', (24, 36))	('Gly34Arg', 'Var', (56, 64))	('beta-catenin', 'Gene', '1499', (135, 147))	('Ser33Cys', 'SUBSTITUTION', 'None', (46, 54))	('Gly34Arg', 'SUBSTITUTION', 'None', (56, 64))	('Ser33Cys', 'Var', (46, 54))	('Ser45Phe', 'Var', (70, 78))	('TCF/LEF', 'Gene', (163, 170))	('Wnt', 'Gene', (131, 134))
129139	26397949	Stabilization of mutants was shown by means of Western blotting, with the use of a monoclonal antibody that detects the transcriptionally active form of beta-catenin (see the Methods section in the Supplementary Appendix).	('beta-catenin', 'Gene', '1499', (153, 165))	('men', 'Species', '9606', (204, 207))	('mutants', 'Var', (17, 24))	('beta-catenin', 'Gene', (153, 165))
129144	26397949	To confirm a direct effect of CTNNB1 mutation on the expression of receptors for luteinizing hormone and human chorionic gonadotropin, immunofluorescence staining was performed on zona glomerulosa-like adenoma cells after transfection with wild-type or mutated CTNNB1 (see the Methods section in the Supplementary Appendix).	('adenoma', 'Disease', 'MESH:D000236', (202, 209))	('CTNNB1', 'Gene', (30, 36))	('mutation', 'Var', (37, 45))	('men', 'Species', '9606', (306, 309))	('adenoma', 'Disease', (202, 209))	('CTNNB1', 'Gene', '1499', (30, 36))	('CTNNB1', 'Gene', (261, 267))	('mutated', 'Var', (253, 260))	('human', 'Species', '9606', (105, 110))	('CTNNB1', 'Gene', '1499', (261, 267))
129145	26397949	Whole-exome sequencing of the aldosterone-producing adenoma from Patient 1 identified a heterozygous somatic mutation (C G, p.Ser33Cys) in exon 3 of CTNNB1.	('CTNNB1', 'Gene', '1499', (149, 155))	('p.Ser33Cys', 'Mutation', 'rs121913400', (124, 134))	('aldosterone-producing', 'Disease', (30, 51))	('aldosterone', 'Chemical', 'MESH:D000450', (30, 41))	('CTNNB1', 'Gene', (149, 155))	('adenoma', 'Disease', 'MESH:D000236', (52, 59))	('p.Ser33Cys', 'Var', (124, 134))	('C G', 'Var', (119, 122))	('adenoma', 'Disease', (52, 59))	('Patient', 'Species', '9606', (65, 72))
129146	26397949	Mutation in CTNNB1 was absent in the nine control adenomas from men and from women who had not presented during pregnancy.	('men', 'Species', '9606', (79, 82))	('adenomas', 'Disease', 'MESH:D000236', (50, 58))	('Mutation', 'Var', (0, 8))	('women', 'Species', '9606', (77, 82))	('adenomas', 'Disease', (50, 58))	('CTNNB1', 'Gene', '1499', (12, 18))	('men', 'Species', '9606', (64, 67))	('CTNNB1', 'Gene', (12, 18))
129147	26397949	Sanger sequencing identified heterozygous mutations in the same exon of CTNNB1 in the aldosterone-producing adenomas in the other two patients (C T, p.Ser45Phe, in Patient 2, and G A, p.Gly34Arg, in Patient 3) (Fig.	('p.Ser45Phe', 'Mutation', 'rs121913409', (149, 159))	('p.Ser45Phe', 'Var', (149, 159))	('p.Gly34Arg', 'Var', (184, 194))	('patients', 'Species', '9606', (134, 142))	('p.Gly34Arg', 'Mutation', 'rs121913399', (184, 194))	('CTNNB1', 'Gene', (72, 78))	('Patient', 'Species', '9606', (199, 206))	('Patient', 'Species', '9606', (164, 171))	('aldosterone', 'Chemical', 'MESH:D000450', (86, 97))	('adenomas', 'Disease', 'MESH:D000236', (108, 116))	('CTNNB1', 'Gene', '1499', (72, 78))	('adenomas', 'Disease', (108, 116))
129149	26397949	In HEK293T cells transfected with mutated CTNNB1, there was increased transcriptional activity of a TCF/LEF-responsive luciferase construct, as compared with the vector control and with wild-type CTNNB1 (Fig.	('CTNNB1', 'Gene', (196, 202))	('CTNNB1', 'Gene', '1499', (196, 202))	('HEK293T', 'CellLine', 'CVCL:0063', (3, 10))	('CTNNB1', 'Gene', (42, 48))	('transcriptional activity', 'MPA', (70, 94))	('TCF/LEF', 'Gene', (100, 107))	('CTNNB1', 'Gene', '1499', (42, 48))	('TCF/LEF', 'Gene', '3172', (100, 107))	('increased', 'PosReg', (60, 69))	('mutated', 'Var', (34, 41))
129150	26397949	Western blotting revealed increased expression of active beta-catenin (nonphosphorylated at residues Ser33, Ser37, and Thr41) by the three mutant cell lines (Fig.	('expression', 'MPA', (36, 46))	('Ser37', 'Chemical', '-', (108, 113))	('mutant', 'Var', (139, 145))	('Thr41', 'Chemical', '-', (119, 124))	('increased', 'PosReg', (26, 35))	('beta-catenin', 'Gene', (57, 69))	('Ser33', 'Chemical', '-', (101, 106))	('beta-catenin', 'Gene', '1499', (57, 69))	('Thr41', 'Var', (119, 124))	('Ser37', 'Var', (108, 113))
129155	26397949	Immunohistochemical analysis showed greater beta-catenin expression and more abundant membrane staining of LHCGR in the mutant adenomas than in the adjacent adrenal tissue (Fig.	('expression', 'MPA', (57, 67))	('LHCGR', 'Gene', '3973', (107, 112))	('beta-catenin', 'Gene', '1499', (44, 56))	('beta-catenin', 'Gene', (44, 56))	('adenomas', 'Disease', 'MESH:D000236', (127, 135))	('LHCGR', 'Gene', (107, 112))	('greater', 'PosReg', (36, 43))	('more', 'PosReg', (72, 76))	('adenomas', 'Disease', (127, 135))	('membrane staining', 'MPA', (86, 103))	('mutant', 'Var', (120, 126))
129156	26397949	Transfection of primary zona glomerulosa-like adenoma cells with mutant CTNNB1 led to expression of LHCGR, as shown by immunofluorescence staining, whereas untransfected cells on the same slide did not stain for LHCGR (Fig.	('adenoma', 'Disease', (46, 53))	('mutant', 'Var', (65, 71))	('LHCGR', 'Gene', (212, 217))	('expression', 'MPA', (86, 96))	('CTNNB1', 'Gene', (72, 78))	('LHCGR', 'Gene', '3973', (212, 217))	('LHCGR', 'Gene', (100, 105))	('adenoma', 'Disease', 'MESH:D000236', (46, 53))	('CTNNB1', 'Gene', '1499', (72, 78))	('LHCGR', 'Gene', '3973', (100, 105))
129158	26397949	There have been previous reports of CTNNB1 mutations in adrenal tumors and of aberrant G-protein-coupled receptors (including LHCGR and GNRHR) in aldosterone-producing adenomas, as well as a case report of a zona glomerulosa-like adenoma in a patient presenting during pregnancy.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('LHCGR', 'Gene', (126, 131))	('adenoma', 'Disease', (168, 175))	('LHCGR', 'Gene', '3973', (126, 131))	('adrenal tumors', 'Disease', (56, 70))	('CTNNB1', 'Gene', (36, 42))	('GNRHR', 'Gene', (136, 141))	('adenoma', 'Disease', 'MESH:D000236', (168, 175))	('GNRHR', 'Gene', '2798', (136, 141))	('adenoma', 'Disease', (230, 237))	('aberrant', 'Var', (78, 86))	('adenoma', 'Disease', 'MESH:D000236', (230, 237))	('aldosterone', 'Chemical', 'MESH:D000450', (146, 157))	('patient', 'Species', '9606', (243, 250))	('CTNNB1', 'Gene', '1499', (36, 42))	('adrenal tumors', 'Disease', 'MESH:D000310', (56, 70))	('mutations', 'Var', (43, 52))	('adenomas', 'Disease', 'MESH:D000236', (168, 176))	('G-protein-coupled receptors', 'Protein', (87, 114))	('aldosterone-producing', 'MPA', (146, 167))	('adenomas', 'Disease', (168, 176))
129160	26397949	We have previously reported that such adenomas have a distinct set of somatic mutations, as compared with the classic, more zona fasciculata-like aldosterone-producing adenomas, which usually harbor a mutation in KCNJ5.	('zona fasciculata', 'Disease', 'MESH:D006562', (124, 140))	('KCNJ5', 'Gene', '3762', (213, 218))	('adenomas', 'Disease', 'MESH:D000236', (168, 176))	('adenomas', 'Disease', (38, 46))	('adenomas', 'Disease', 'MESH:D000236', (38, 46))	('mutation', 'Var', (201, 209))	('aldosterone', 'Chemical', 'MESH:D000450', (146, 157))	('adenomas', 'Disease', (168, 176))	('fasciculata-', 'Phenotype', 'HP:0002380', (129, 141))	('KCNJ5', 'Gene', (213, 218))	('zona fasciculata', 'Disease', (124, 140))
129161	26397949	Despite the known association between CTNNB1 activation and aldosterone-producing adenomas, to our knowledge, only one of the three mutations we describe here, Ser45Phe, has previously been identified in adrenal tissue; the same residue is mutated in immortalized H295R cells, derived from an adrenocortical carcinoma.	('aldosterone', 'Chemical', 'MESH:D000450', (60, 71))	('adenomas', 'Disease', 'MESH:D000236', (82, 90))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (293, 317))	('CTNNB1', 'Gene', (38, 44))	('Ser45Phe', 'SUBSTITUTION', 'None', (160, 168))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (293, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('adenomas', 'Disease', (82, 90))	('H295R', 'CellLine', 'CVCL:0458', (264, 269))	('adrenocortical carcinoma', 'Disease', (293, 317))	('activation', 'PosReg', (45, 55))	('Ser45Phe', 'Var', (160, 168))	('CTNNB1', 'Gene', '1499', (38, 44))
129162	26397949	All three mutations are predicted to affect a GSK-3beta phosphorylation consensus motif and could thus impair beta-catenin degradation and up-regulate canonical Wnt activity (Fig.	('phosphorylation consensus motif', 'MPA', (56, 87))	('beta-catenin', 'Gene', (110, 122))	('up-regulate', 'PosReg', (139, 150))	('GSK-3beta', 'Gene', (46, 55))	('impair', 'NegReg', (103, 109))	('beta-catenin', 'Gene', '1499', (110, 122))	('affect', 'Reg', (37, 43))	('Wnt', 'Gene', (161, 164))	('GSK-3beta', 'Gene', '2932', (46, 55))	('mutations', 'Var', (10, 19))	('Wnt', 'Gene', '114487', (161, 164))
129167	26397949	Transduction of granulosa cells with a constitutively active beta-catenin mutant leads to an increase in LHCGR mRNA expression by a factor of 3.	('beta-catenin', 'Gene', '1499', (61, 73))	('increase', 'PosReg', (93, 101))	('LHCGR', 'Gene', (105, 110))	('LHCGR', 'Gene', '3973', (105, 110))	('beta-catenin', 'Gene', (61, 73))	('mutant', 'Var', (74, 80))
129168	26397949	We conclude that the three mutations affecting beta-catenin in aldosterone-producing adenomas, which we describe here, activate aldosterone production by unleashing the ability of these adrenal progenitor cells to switch on gonadal genes (Fig.	('mutations', 'Var', (27, 36))	('beta-catenin', 'Gene', '1499', (47, 59))	('gonadal genes', 'Gene', (224, 237))	('aldosterone production', 'MPA', (128, 150))	('aldosterone production', 'Phenotype', 'HP:0000859', (128, 150))	('adenomas', 'Disease', 'MESH:D000236', (85, 93))	('beta-catenin', 'Gene', (47, 59))	('switch', 'Reg', (214, 220))	('adenomas', 'Disease', (85, 93))	('aldosterone', 'Chemical', 'MESH:D000450', (63, 74))	('activate', 'PosReg', (119, 127))	('aldosterone', 'Chemical', 'MESH:D000450', (128, 139))
129172	26397949	Our explanation for the latency of aldosterone production is supported by the appearance of luteinizing hormone receptor protein in primary, zona glomerulosa-like, aldosterone-producing adenoma cells transfected with mutant CTNNB1 (Fig.	('mutant', 'Var', (217, 223))	('CTNNB1', 'Gene', '1499', (224, 230))	('aldosterone', 'Chemical', 'MESH:D000450', (164, 175))	('aldosterone production', 'Phenotype', 'HP:0000859', (35, 57))	('CTNNB1', 'Gene', (224, 230))	('appearance', 'Reg', (78, 88))	('aldosterone', 'Chemical', 'MESH:D000450', (35, 46))	('adenoma', 'Disease', 'MESH:D000236', (186, 193))	('adenoma', 'Disease', (186, 193))
129173	26397949	3D) and by the increase in GATA4 both in the three CTNNB1-mutated adenomas and in the cells overexpressing wild-type or mutated CTNNB1 (Fig.	('CTNNB1', 'Gene', '1499', (51, 57))	('adenomas', 'Disease', (66, 74))	('CTNNB1', 'Gene', '1499', (128, 134))	('increase', 'PosReg', (15, 23))	('adenomas', 'Disease', 'MESH:D000236', (66, 74))	('CTNNB1', 'Gene', (51, 57))	('GATA4', 'Gene', '2626', (27, 32))	('CTNNB1', 'Gene', (128, 134))	('mutated', 'Var', (120, 127))	('GATA4', 'Gene', (27, 32))
129176	26397949	CTNNB1 mutation may need to occur in specific adrenocortical cell types, such as the subcapsular progenitor cells, for the full effects to be seen.	('CTNNB1', 'Gene', '1499', (0, 6))	('CTNNB1', 'Gene', (0, 6))	('mutation', 'Var', (7, 15))	('adrenocortical', 'Disease', (46, 60))	('adrenocortical', 'Disease', 'MESH:D018268', (46, 60))
129177	26397949	Our transfections had a moderate effect in zona glomerulosa-like aldosterone-producing adenoma cells but had no effect in the adrenocortical carcinoma-derived H295R cells; these cells also had little endogenous LHCGR expression, despite their intrinsic CTNNB1 mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('LHCGR', 'Gene', (211, 216))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (126, 150))	('CTNNB1', 'Gene', (253, 259))	('expression', 'MPA', (217, 227))	('mutation', 'Var', (260, 268))	('adenoma', 'Disease', 'MESH:D000236', (87, 94))	('adrenocortical carcinoma', 'Disease', (126, 150))	('CTNNB1', 'Gene', '1499', (253, 259))	('LHCGR', 'Gene', '3973', (211, 216))	('H295R', 'CellLine', 'CVCL:0458', (159, 164))	('aldosterone', 'Chemical', 'MESH:D000450', (65, 76))	('adenoma', 'Disease', (87, 94))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (126, 150))
129178	26397949	Indeed, adrenocortical carcinomas commonly have CTNNB1 mutations, yet previous transcriptome analysis of 33 carcinomas showed above-background LHCGR expression in only 4.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('mutations', 'Var', (55, 64))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (8, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('carcinomas', 'Disease', (108, 118))	('carcinomas', 'Disease', 'MESH:D002277', (108, 118))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (8, 32))	('CTNNB1', 'Gene', (48, 54))	('adrenocortical carcinomas', 'Disease', (8, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('LHCGR', 'Gene', (143, 148))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (8, 33))	('CTNNB1', 'Gene', '1499', (48, 54))	('LHCGR', 'Gene', '3973', (143, 148))	('carcinomas', 'Disease', (23, 33))	('carcinomas', 'Disease', 'MESH:D002277', (23, 33))
129190	19878209	The effects of TASK1 knockdown by siRNA transfection were investigated in H295R cells.	('knockdown', 'Var', (21, 30))	('H295R', 'CellLine', 'CVCL:0458', (74, 79))	('TASK', 'Gene', (15, 19))	('TASK', 'Gene', '29553', (15, 19))
129201	19878209	In patients with primary hyperaldosteronism, aldosterone levels are not suppressed by dietary sodium loading, volume expansion, or antagonism of the renin-angiotensin system .	('renin', 'Gene', '5972', (149, 154))	('aldosterone levels', 'MPA', (45, 63))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (25, 43))	('primary hyperaldosteronism', 'Disease', (17, 43))	('primary hyperaldosteronism', 'Disease', 'MESH:D003480', (17, 43))	('renin', 'Gene', (149, 154))	('aldosterone', 'Chemical', 'MESH:D000450', (45, 56))	('patients', 'Species', '9606', (3, 11))	('antagonism', 'Var', (131, 141))	('sodium', 'Chemical', 'MESH:D012964', (94, 100))	('primary hyperaldosteronism', 'Phenotype', 'HP:0011736', (17, 43))
129210	19878209	Recent data in the literature showed the establishment of an in vivo model of primary hyperaldosteronism following the deletion of subunits of K+ channels termed TASK1 and TASK3 .	('TASK', 'Gene', '29553', (172, 176))	('TASK', 'Gene', '29553', (162, 166))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (86, 104))	('deletion', 'Var', (119, 127))	('TASK', 'Gene', (172, 176))	('rat', 'Species', '10116', (23, 26))	('TASK', 'Gene', (162, 166))	('primary hyperaldosteronism', 'Phenotype', 'HP:0011736', (78, 104))	('primary hyperaldosteronism', 'Disease', (78, 104))	('primary hyperaldosteronism', 'Disease', 'MESH:D003480', (78, 104))
129212	19878209	The observation that TASK1- and TASK1/TASK3-deficient mice have primary aldosteronism makes these genes potential candidates for causing human adrenal disease.	('primary aldosteronism', 'Phenotype', 'HP:0011736', (64, 85))	('human', 'Species', '9606', (137, 142))	('TASK', 'Gene', (38, 42))	('TASK', 'Gene', (21, 25))	('TASK', 'Gene', '29553', (38, 42))	('genes', 'Var', (98, 103))	('mice', 'Species', '10090', (54, 58))	('adrenal disease', 'Phenotype', 'HP:0000834', (143, 158))	('TASK', 'Gene', '29553', (32, 36))	('TASK', 'Gene', (32, 36))	('primary aldosteronism', 'Disease', (64, 85))	('causing', 'Reg', (129, 136))	('adrenal disease', 'Disease', 'MESH:D000309', (143, 158))	('adrenal disease', 'Disease', (143, 158))	('TASK', 'Gene', '29553', (21, 25))
129227	19878209	Primer and probe mixtures for the amplification of the TASK1 (cat # HS00605529_M1) and TASK3 (cat # HS00363153_m1) target sequences were purchased from Applied Biosystems.	('cat # HS00363153_m1', 'Var', (94, 113))	('TASK', 'Gene', '29553', (55, 59))	('TASK', 'Gene', (87, 91))	('TASK', 'Gene', '29553', (87, 91))	('TASK', 'Gene', (55, 59))	('cat # HS00605529_M1', 'Var', (62, 81))
129245	19878209	Decreased TASK1 expression in H295R cells increased aldosterone production by 2.5-fold under basal conditions, and by 1.5-fold in cells treated with Ang II or K+ (Fig.2, panel A), whereas cortisol production was not significantly affected by siTASK1 transfection (Fig.	('increased', 'PosReg', (42, 51))	('TASK', 'Gene', (244, 248))	('TASK', 'Gene', (10, 14))	('expression', 'Var', (16, 26))	('TASK', 'Gene', '29553', (244, 248))	('aldosterone production', 'MPA', (52, 74))	('TASK', 'Gene', '29553', (10, 14))	('cortisol', 'Chemical', 'MESH:D006854', (188, 196))	('aldosterone production', 'Phenotype', 'HP:0000859', (52, 74))	('Decreased', 'NegReg', (0, 9))	('H295R', 'CellLine', 'CVCL:0458', (30, 35))	('siTASK1', 'Chemical', '-', (242, 249))	('increased aldosterone', 'Phenotype', 'HP:0000859', (42, 63))	('Ang II', 'Gene', '183', (149, 155))	('Ang II', 'Gene', (149, 155))	('aldosterone', 'Chemical', 'MESH:D000450', (52, 63))
129249	19878209	The expression of CYP11B1, which is responsible for the final steps in cortisol production by adrenocortical cells, was not significantly altered by siTASK1 transfection in basal or treated conditions (Fig.	('CYP11B1', 'Gene', (18, 25))	('CYP11B1', 'Gene', '1584', (18, 25))	('cortisol', 'Chemical', 'MESH:D006854', (71, 79))	('transfection', 'Var', (157, 169))	('adrenocortical', 'Disease', (94, 108))	('adrenocortical', 'Disease', 'MESH:D018268', (94, 108))	('siTASK1', 'Chemical', '-', (149, 156))
129251	19878209	Consistently, the increase in CYP11B2 expression caused by TASK1 knockdown was gradually diminished by TASK1 recovery (Fig.4, panel D).	('increase', 'PosReg', (18, 26))	('CYP11B2', 'Gene', (30, 37))	('TASK', 'Gene', '29553', (59, 63))	('TASK', 'Gene', '29553', (103, 107))	('TASK', 'Gene', (59, 63))	('expression', 'MPA', (38, 48))	('diminished', 'NegReg', (89, 99))	('CYP11B2', 'Gene', '1585', (30, 37))	('TASK', 'Gene', (103, 107))	('knockdown', 'Var', (65, 74))
129276	19878209	Recently two studies described the generation of a mouse model for primary hyperaldosteronism by deletion of TASK1 alone  or by TASK1/TASK3 double knockout .	('TASK', 'Gene', (134, 138))	('TASK', 'Gene', '29553', (134, 138))	('TASK', 'Gene', (128, 132))	('TASK', 'Gene', '29553', (128, 132))	('mouse', 'Species', '10090', (51, 56))	('rat', 'Species', '10116', (39, 42))	('primary hyperaldosteronism', 'Phenotype', 'HP:0011736', (67, 93))	('TASK', 'Gene', '29553', (109, 113))	('TASK', 'Gene', (109, 113))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (75, 93))	('primary hyperaldosteronism', 'Disease', (67, 93))	('deletion', 'Var', (97, 105))	('primary hyperaldosteronism', 'Disease', 'MESH:D003480', (67, 93))
129279	19878209	The disruption of adrenocortical zonation by TASK1 knockout suggests a role for TASK channels in the steroidogenic enzyme profile of the adrenal cortex.	('TASK', 'Gene', '29553', (45, 49))	('TASK', 'Gene', (45, 49))	('TASK', 'Gene', '29553', (80, 84))	('TASK', 'Gene', (80, 84))	('steroidogenic enzyme profile', 'MPA', (101, 129))	('knockout', 'Var', (51, 59))	('adrenocortical zonation', 'Disease', 'MESH:D018268', (18, 41))	('adrenocortical zonation', 'Disease', (18, 41))
129283	19878209	In addition, TASK1 knockout females had normal aldosterone levels after treatment with testosterone.	('knockout', 'Var', (19, 27))	('aldosterone', 'Chemical', 'MESH:D000450', (47, 58))	('normal aldosterone levels', 'Phenotype', 'HP:0004319', (40, 65))	('aldosterone levels', 'MPA', (47, 65))	('testosterone', 'Chemical', 'MESH:D013739', (87, 99))	('TASK', 'Gene', (13, 17))	('TASK', 'Gene', '29553', (13, 17))
129289	19878209	The double knockout animals did not express changes in adrenocortical zonation, suggesting that the sex difference observed in TASK1 knockout animals may not be explained by a raise in TASK3 expression.	('adrenocortical zonation', 'Disease', (55, 78))	('TASK', 'Gene', '29553', (185, 189))	('TASK', 'Gene', (185, 189))	('knockout', 'Var', (133, 141))	('adrenocortical zonation', 'Disease', 'MESH:D018268', (55, 78))	('TASK', 'Gene', (127, 131))	('TASK', 'Gene', '29553', (127, 131))
129290	19878209	Unfortunately the effects of knocking out TASK3 alone in aldosterone production and adrenocortical zonation are not reported.	('adrenocortical zonation', 'Disease', 'MESH:D018268', (84, 107))	('aldosterone', 'Chemical', 'MESH:D000450', (57, 68))	('TASK', 'Gene', (42, 46))	('TASK', 'Gene', '29553', (42, 46))	('knocking out', 'Var', (29, 41))	('adrenocortical zonation', 'Disease', (84, 107))	('aldosterone production', 'MPA', (57, 79))	('aldosterone production', 'Phenotype', 'HP:0000859', (57, 79))
129292	19878209	These channels are suggested to have a role in setting the membrane potential in these cells, however the production of aldosterone was not significantly altered by transfection with dominant-negative vectors for TASK3 or TREK1 .	('TASK', 'Gene', '29553', (213, 217))	('TREK1', 'Gene', (222, 227))	('TASK', 'Gene', (213, 217))	('aldosterone', 'Chemical', 'MESH:D000450', (120, 131))	('dominant-negative', 'Var', (183, 200))	('TREK1', 'Gene', '3776', (222, 227))
129293	19878209	In fact, in this last study, Ang II-stimulated aldosterone production was not affected, and the K+ induction was unexpectedly blunted by the dominant-negative constructs.	('K+ induction', 'MPA', (96, 108))	('aldosterone', 'Chemical', 'MESH:D000450', (47, 58))	('Ang II', 'Gene', '183', (29, 35))	('stimulated aldosterone', 'Phenotype', 'HP:0000859', (36, 58))	('blunted', 'NegReg', (126, 133))	('Ang II', 'Gene', (29, 35))	('dominant-negative', 'Var', (141, 158))	('aldosterone production', 'MPA', (47, 69))	('aldosterone production', 'Phenotype', 'HP:0000859', (47, 69))
129295	19878209	Interestingly, the in vivo studies mentioned above with TASK1 or TASK1/TASK3 depletion were not associated with tumorigenic forms of primary hyperaldosteronism.	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (141, 159))	('depletion', 'Var', (77, 86))	('TASK', 'Gene', (65, 69))	('primary hyperaldosteronism', 'Disease', (133, 159))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('primary hyperaldosteronism', 'Disease', 'MESH:D003480', (133, 159))	('TASK', 'Gene', (56, 60))	('TASK', 'Gene', '29553', (56, 60))	('TASK', 'Gene', '29553', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TASK', 'Gene', '29553', (71, 75))	('tumor', 'Disease', (112, 117))	('TASK', 'Gene', (71, 75))	('primary hyperaldosteronism', 'Phenotype', 'HP:0011736', (133, 159))
129296	19878209	TASK1 knockout animals had altered adrenal zonation and a glucocorticoid-remediable form of hyperaldosteronism.	('TASK', 'Gene', '29553', (0, 4))	('glucocorticoid-remediable', 'MPA', (58, 83))	('altered', 'Reg', (27, 34))	('TASK', 'Gene', (0, 4))	('hyperaldosteronism', 'Disease', (92, 110))	('hyperaldosteronism', 'Disease', 'MESH:D003480', (92, 110))	('form of hyperaldosteronism', 'Phenotype', 'HP:0011741', (84, 110))	('adrenal zonation', 'MPA', (35, 51))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (92, 110))	('knockout', 'Var', (6, 14))
129300	19878209	Moreover, transfection of H295R cells with siTASK1 was not associated with an elevation in TASK3 mRNA expression (data not shown) as occurred in the male TASK1 knockout mice .	('TASK', 'Gene', (154, 158))	('TASK', 'Gene', '29553', (45, 49))	('TASK', 'Gene', '29553', (154, 158))	('siTASK1', 'Chemical', '-', (43, 50))	('TASK', 'Gene', (45, 49))	('H295R', 'CellLine', 'CVCL:0458', (26, 31))	('transfection', 'Var', (10, 22))	('mice', 'Species', '10090', (169, 173))	('TASK', 'Gene', (91, 95))	('TASK', 'Gene', '29553', (91, 95))
129304	19878209	In agreement with previous studies in adrenocortical cell models , the knockdown of TASK1 generated H295R cells with a more depolarized membrane potential, which is suggested by the increased Ca2+ flux through the plasma membrane.	('Ca2+', 'Chemical', 'MESH:D000069285', (192, 196))	('adrenocortical', 'Disease', (38, 52))	('increased', 'PosReg', (182, 191))	('depolarized', 'NegReg', (124, 135))	('rat', 'Species', '10116', (94, 97))	('adrenocortical', 'Disease', 'MESH:D018268', (38, 52))	('more', 'PosReg', (119, 123))	('knockdown', 'Var', (71, 80))	('TASK', 'Gene', '29553', (84, 88))	('H295R', 'CellLine', 'CVCL:0458', (100, 105))	('TASK', 'Gene', (84, 88))
129306	19878209	In conclusion, we have demonstrated for the first time that TASK1 is the predominant KCNK family member expressed in the human adrenal cortex, and that TASK1 knockdown stimulated aldosterone production through augmentation of Ca2+ flux and activation of CaMK in human adrenocortical cells (Fig.7).	('Ca2+', 'Chemical', 'MESH:D000069285', (226, 230))	('human', 'Species', '9606', (121, 126))	('aldosterone production', 'MPA', (179, 201))	('human', 'Species', '9606', (262, 267))	('augmentation', 'PosReg', (210, 222))	('Ca2+ flux', 'MPA', (226, 235))	('rat', 'Species', '10116', (30, 33))	('TASK', 'Gene', '29553', (152, 156))	('TASK', 'Gene', (60, 64))	('TASK', 'Gene', '29553', (60, 64))	('stimulated aldosterone', 'Phenotype', 'HP:0000859', (168, 190))	('adrenocortical', 'Disease', 'MESH:D018268', (268, 282))	('aldosterone', 'Chemical', 'MESH:D000450', (179, 190))	('stimulated', 'PosReg', (168, 178))	('aldosterone production', 'Phenotype', 'HP:0000859', (179, 201))	('adrenocortical', 'Disease', (268, 282))	('CaMK', 'Gene', (254, 258))	('TASK', 'Gene', (152, 156))	('knockdown', 'Var', (158, 167))	('CaMK', 'Gene', '818', (254, 258))
129313	24457059	EGFR protein expression and high polysomy on chromosome 7 are frequent abnormalities in ACC than in ACA.	('EGFR', 'Gene', (0, 4))	('expression', 'MPA', (13, 23))	('ACC', 'Disease', (88, 91))	('high polysomy', 'Var', (28, 41))	('EGFR', 'Gene', '1956', (0, 4))
129325	24457059	For ACCs, EGFR expression and EGFR point mutations have also been described .	('EGFR', 'Gene', '1956', (10, 14))	('EGFR', 'Gene', (30, 34))	('ACCs', 'Gene', (4, 8))	('ACCs', 'Gene', '84680', (4, 8))	('EGFR', 'Gene', (10, 14))	('point mutations', 'Var', (35, 50))	('EGFR', 'Gene', '1956', (30, 34))
129328	24457059	However, EGFR mutations and EGFR amplification were rare in these myxoid tumors.	('EGFR', 'Gene', '1956', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('EGFR', 'Gene', (28, 32))	('myxoid tumors', 'Disease', (66, 79))	('myxoid tumors', 'Disease', 'MESH:D045888', (66, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
129329	24457059	Furthermore, we explored EGFR protein expression, EGFR mutations and EGFR copy number in these tumors and correlated these results with the clinicopathological features of these patients.	('EGFR', 'Gene', '1956', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('EGFR', 'Gene', (25, 29))	('mutations', 'Var', (55, 64))	('EGFR', 'Gene', (69, 73))	('patients', 'Species', '9606', (178, 186))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('EGFR', 'Gene', '1956', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('EGFR', 'Gene', (50, 54))	('tumors', 'Disease', (95, 101))	('EGFR', 'Gene', '1956', (25, 29))
129340	24457059	Twenty-nine specific EGFR mutations in exons 18 through 21 were detected using the EGFR mutation test kit of the Scorpion Amplified Refractory Mutation System (SARMS) (DxS, Manchester, UK).	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', '1956', (83, 87))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', (83, 87))	('mutations', 'Var', (26, 35))
129341	24457059	This kit enabled the detection of 19 specific deletions between 2235 and 2257 in exon 19, T790M, L858R, L861Q, G719X, S768I as well as 3 insertions in exon 20.	('L861Q', 'Mutation', 'rs121913444', (104, 109))	('S768I', 'Var', (118, 123))	('T790M', 'Var', (90, 95))	('S768I', 'Mutation', 'rs121913465', (118, 123))	('L861Q', 'Var', (104, 109))	('L858R', 'Var', (97, 102))	('G719X', 'Mutation', 'p.G719X', (111, 116))	('T790M', 'Mutation', 'rs121434569', (90, 95))	('L858R', 'Mutation', 'rs121434568', (97, 102))	('G719X', 'Var', (111, 116))
129345	24457059	Chromosome 7 polysomy and monosomy were defined as the presence of more than three signals or one signal, respectively, from greater than 20% of the tumor cells.	('monosomy', 'Disease', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Chromosome', 'Var', (0, 10))	('tumor', 'Disease', (149, 154))	('polysomy', 'Var', (13, 21))
129346	24457059	The EGFR gene status was classified into the following six categories according to the frequency of tumor cells with specific copy numbers of the EGFR gene and the chromosome 7 centromere, as described previously .	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('EGFR', 'Gene', '1956', (146, 150))	('EGFR', 'Gene', (4, 8))	('tumor', 'Disease', (100, 105))	('EGFR', 'Gene', (146, 150))	('copy numbers', 'Var', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('EGFR', 'Gene', '1956', (4, 8))
129347	24457059	Based on the EGFR gene status, the patients were further classified into the following two groups: 1) EGFR FISH-negative or low gene copy number (disomy, low trisomy, high trisomy, and low polysomy) or 2) EGFR FISH-positive or high gene copy number (high polysomy and gene amplification).	('low trisomy', 'Var', (154, 165))	('high gene copy number', 'Var', (227, 248))	('low polysomy', 'Var', (185, 197))	('EGFR', 'Gene', '1956', (102, 106))	('disomy', 'Disease', (146, 152))	('disomy', 'Disease', 'MESH:D024182', (146, 152))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'Gene', (102, 106))	('EGFR', 'Gene', (205, 209))	('high trisomy', 'Var', (167, 179))	('patients', 'Species', '9606', (35, 43))	('low', 'NegReg', (124, 127))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
129362	24457059	None of the 29 specific EGFR mutations in exons 18 to 21 were detected in the ACA and ACC cases examined.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('ACA', 'Disease', (78, 81))	('ACC', 'Disease', (86, 89))
129366	24457059	There was a statistically significant difference in the EGFR gene copy number alterations between the benign and malignant tumors (P < 0.001) (Table  1).	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('malignant tumors', 'Disease', (113, 129))	('copy number alterations', 'Var', (66, 89))	('EGFR', 'Gene', '1956', (56, 60))	('malignant tumors', 'Disease', 'MESH:D018198', (113, 129))	('EGFR', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
129375	24457059	In this study, we have investigated EGFR protein expression, EGFR mutations, and EGFR gene copy number variations in adrenocortical neoplasms, specifically in 22 conventional ACC cases and 22 conventional ACA cases.	('mutations', 'Var', (66, 75))	('neoplasms', 'Phenotype', 'HP:0002664', (132, 141))	('adrenocortical neoplasms', 'Disease', (117, 141))	('variations', 'Var', (103, 113))	('neoplasm', 'Phenotype', 'HP:0002664', (132, 140))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', (36, 40))	('adrenocortical neoplasms', 'Disease', 'MESH:D018268', (117, 141))	('conventional ACC', 'Disease', (162, 178))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (61, 65))	('EGFR', 'Gene', (81, 85))
129379	24457059	In the current study, our results also demonstrated that EGFR immunoreactivity was significantly more frequent among conventional ACC than conventional ACA cases.	('frequent', 'Reg', (102, 110))	('EGFR', 'Gene', '1956', (57, 61))	('immunoreactivity', 'Var', (62, 78))	('conventional ACC', 'Disease', (117, 133))	('EGFR', 'Gene', (57, 61))
129382	24457059	In addition, EGFR gene mutations have been reported in patients with non-small-cell lung cancer, and the status of these mutations has been correlated with the clinical response to tyrosine kinase inhibitors such as gefitinib .	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (69, 95))	('mutations', 'Var', (23, 32))	('correlated', 'Reg', (140, 150))	('non-small-cell lung cancer', 'Disease', (69, 95))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (73, 95))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (69, 95))	('patients', 'Species', '9606', (55, 63))	('reported', 'Reg', (43, 51))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('gefitinib', 'Chemical', 'MESH:D000077156', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
129383	24457059	detected four tumor specimens that harbored TK domain mutations from a panel of 35 ACC (11.4%), suggesting that ACC that harbor an EGFR mutation exhibit increased phosphorylation of EGFR compared with wild-type carcinomas .	('tumor', 'Disease', (14, 19))	('phosphorylation', 'MPA', (163, 178))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('mutation', 'Var', (136, 144))	('increased', 'PosReg', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('EGFR', 'Gene', '1956', (131, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))	('EGFR', 'Gene', (131, 135))	('carcinomas', 'Disease', 'MESH:D002277', (211, 221))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('carcinomas', 'Disease', (211, 221))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
129384	24457059	EGFR gene amplification and structural genetic alterations have been reported in several types of adenocarcinoma, including non-small-cell lung cancer, glioblastoma, pancreatic cancer, and squamous cell carcinoma of the head and neck.	('squamous cell carcinoma', 'Disease', (189, 212))	('pancreatic cancer', 'Disease', (166, 183))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (128, 150))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('amplification', 'Var', (10, 23))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (124, 150))	('glioblastoma', 'Disease', 'MESH:D005909', (152, 164))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (166, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('adenocarcinoma', 'Disease', (98, 112))	('EGFR', 'Gene', (0, 4))	('glioblastoma', 'Disease', (152, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('adenocarcinoma', 'Disease', 'MESH:D000230', (98, 112))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (189, 212))	('reported', 'Reg', (69, 77))	('non-small-cell lung cancer', 'Disease', (124, 150))	('pancreatic cancer', 'Disease', 'MESH:D010190', (166, 183))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (124, 150))	('EGFR', 'Gene', '1956', (0, 4))
129387	24457059	Moreover, our study analyzed the relationship between EGFR copy number and the clinicopathological features of patients with ACC.	('EGFR', 'Gene', '1956', (54, 58))	('copy number', 'Var', (59, 70))	('EGFR', 'Gene', (54, 58))	('patients', 'Species', '9606', (111, 119))
129389	24457059	In addition, all of the positive cases showed high polysomy on chromosome 7, and none of the ACC cases demonstrated EGFR amplification, suggesting that EGFR amplification may be rare in ACC.	('polysomy', 'Var', (51, 59))	('EGFR', 'Gene', '1956', (152, 156))	('EGFR', 'Gene', (152, 156))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))
129390	24457059	However, according to the statistical analysis, EGFR FISH positivity was not associated with gender, age, tumor size, tumor weight, hormonal function, recurrence, metastasis or tumor stage.	('EGFR', 'Gene', '1956', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('positivity', 'Var', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('EGFR', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('metastasis or tumor', 'Disease', 'MESH:D009362', (163, 182))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (118, 123))	('metastasis or tumor', 'Disease', (163, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', (106, 111))
129392	24457059	The survival curves demonstrated that there were no significant associations between EGFR protein expression, high polysomy on chromosome 7 and the overall survival of patients with ACC.	('high polysomy', 'Var', (110, 123))	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (85, 89))	('patients', 'Species', '9606', (168, 176))
129393	24457059	In our study, EGFR protein expression and high polysomy were more frequently seen in conventional ACC than in conventional ACA, and EGFR immunohistochemical staining were more intensive in ACC cases than in ACA cases, whether this can be used as differential diagnosis still need to be demonstrated by large sample size.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (132, 136))	('intensive', 'PosReg', (176, 185))	('EGFR', 'Gene', (132, 136))	('expression', 'MPA', (27, 37))	('conventional ACC', 'Disease', (85, 101))	('seen', 'Reg', (77, 81))	('high polysomy', 'Var', (42, 55))	('ACC', 'Disease', (189, 192))
129395	24457059	In summary, EGFR expression and high polysomy on chromosome 7 are frequent abnormalities in ACC than in ACA, suggesting that these abnormalities could potentially be used in the differential diagnosis of ACA and ACC.	('high polysomy', 'Var', (32, 45))	('expression', 'MPA', (17, 27))	('ACA', 'Disease', (204, 207))	('EGFR', 'Gene', '1956', (12, 16))	('ACC', 'Disease', (92, 95))	('EGFR', 'Gene', (12, 16))
129468	22507745	Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients Germline TP53 mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or Li-Fraumeni-like (LFL) features.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', '7157', (217, 221))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (406, 417))	('breast cancer', 'Disease', 'MESH:D001943', (372, 385))	('breast cancer', 'Disease', (372, 385))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('BRCA1/2', 'Gene', (152, 159))	('BRCA1', 'Gene', '672', (152, 157))	('mutations', 'Var', (222, 231))	('BRCA1', 'Gene', (152, 157))	('LFS', 'Disease', (310, 313))	('TP53', 'Gene', (105, 109))	('TP53', 'Gene', (41, 45))	('BRCA2', 'Gene', (31, 36))	('BRCA1', 'Gene', '672', (24, 29))	('LFS', 'Disease', 'MESH:D016864', (310, 313))	('breast cancer', 'Phenotype', 'HP:0003002', (271, 284))	('TP53', 'Gene', (217, 221))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('BRCA1', 'Gene', (24, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('BRCA1/2', 'Gene', '672;675', (152, 159))	('Li-Fraumeni syndrome', 'Disease', (288, 308))	('Li-Fraumeni', 'Disease', (288, 299))	('breast cancer', 'Disease', 'MESH:D001943', (271, 284))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (288, 308))	('breast cancer', 'Disease', (271, 284))	('breast cancer', 'Disease', (185, 198))	('BRCA2', 'Gene', '675', (31, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (372, 385))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (288, 299))	('TP53', 'Gene', '7157', (105, 109))	('Li-Fraumeni', 'Disease', (406, 417))	('LFS', 'Disease', (399, 402))	('LFS', 'Disease', 'MESH:D016864', (399, 402))
129470	22507745	A total of 100 patients with early-onset breast cancer (<= 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing.	('patients', 'Species', '9606', (15, 23))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('mutations', 'Var', (163, 172))	('BRCA2', 'Gene', (183, 188))	('BRCA1', 'Gene', '672', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('TP53', 'Gene', '7157', (193, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('BRCA1', 'Gene', (176, 181))	('BRCA2', 'Gene', '675', (183, 188))	('TP53', 'Gene', (193, 197))
129471	22507745	Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues.	('tumor', 'Disease', (181, 186))	('loss', 'Var', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mutations', 'Var', (7, 16))
129473	22507745	Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53.	('TP53', 'Gene', '7157', (100, 104))	('BRCA', 'Gene', '672', (10, 14))	('exonic variants', 'Var', (53, 68))	('BRCA', 'Gene', (10, 14))	('TP53', 'Gene', (100, 104))	('patients', 'Species', '9606', (24, 32))
129474	22507745	Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH).	('E346X', 'Var', (55, 60))	('A138V', 'Var', (117, 122))	('E285K', 'Var', (127, 132))	('E346X', 'Mutation', 'p.E346X', (55, 60))	('p. G334_R335dup6', 'Mutation', 'p.334_,335dupG,R,6', (65, 81))	('E285K', 'Mutation', 'rs112431538', (127, 132))	('A138V', 'Mutation', 'rs750600586', (117, 122))	('p. G334_R335dup6', 'Var', (65, 81))
129477	22507745	Our study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients.	('BRCA2', 'Gene', '675', (34, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('BRCA1', 'Gene', '672', (27, 32))	('TP53', 'Gene', '7157', (155, 159))	('mutations', 'Var', (49, 58))	('BRCA1', 'Gene', (27, 32))	('TP53', 'Gene', (155, 159))	('patients', 'Species', '9606', (98, 106))	('TP53', 'Gene', '7157', (44, 48))	('BRCA2', 'Gene', (34, 39))	('patients', 'Species', '9606', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('TP53', 'Gene', (44, 48))	('breast cancer', 'Disease', (84, 97))
129478	22507745	However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('patients', 'Species', '9606', (167, 175))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('LFS-linked cancers', 'Disease', (201, 219))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('found', 'Reg', (127, 132))	('LFS-linked cancers', 'Disease', 'MESH:D016864', (201, 219))	('breast cancer', 'Disease', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
129479	22507745	To date, germline mutations in at least 10 genes linked to DNA repair have been shown to be associated with an inherited risk for breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('associated', 'Reg', (92, 102))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('germline mutations', 'Var', (9, 27))
129481	22507745	Although rare, germline mutations in TP53 are associated with a significantly increased risk of female breast cancer, bone or soft tissue sarcomas, brain tumors and adrenocortical carcinomas (ACC).	('brain tumors', 'Disease', (148, 160))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('breast cancer', 'Disease', (103, 116))	('ACC', 'Phenotype', 'HP:0006744', (192, 195))	('TP53', 'Gene', (37, 41))	('associated', 'Reg', (46, 56))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (165, 190))	('adrenocortical carcinomas', 'Disease', (165, 190))	('sarcomas', 'Disease', 'MESH:D012509', (138, 146))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('sarcomas', 'Phenotype', 'HP:0100242', (138, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (126, 145))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('sarcomas', 'Disease', (138, 146))	('TP53', 'Gene', '7157', (37, 41))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (126, 145))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (126, 146))	('brain tumors', 'Phenotype', 'HP:0030692', (148, 160))	('brain tumors', 'Disease', 'MESH:D001932', (148, 160))	('soft tissue sarcoma', 'Disease', (126, 145))	('brain tumor', 'Phenotype', 'HP:0030692', (148, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (165, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('germline mutations', 'Var', (15, 33))
129482	22507745	To date, the majority of studies have examined the prevalence of TP53 germline mutations among families identified through the genetics clinics and these studies have shown that the majority of families with germline TP53 mutations fulfill either the original Li-Fraumeni syndrome (LFS) criteria, Li-Fraumeni-like (LFL) criteria or the Chompret criteria and are present with a family history of at least one of the four LFS-linked cancers (breast, bone or soft tissue sarcomas, brain tumors and ACC).	('sarcomas', 'Disease', 'MESH:D012509', (468, 476))	('TP53', 'Gene', '7157', (217, 221))	('soft tissue sarcoma', 'Disease', (456, 475))	('TP53', 'Gene', '7157', (65, 69))	('cancers', 'Phenotype', 'HP:0002664', (431, 438))	('sarcomas', 'Phenotype', 'HP:0100242', (468, 476))	('tumor', 'Phenotype', 'HP:0002664', (484, 489))	('sarcomas', 'Disease', (468, 476))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('Li-Fraumeni syndrome', 'Disease', (260, 280))	('brain tumors', 'Disease', 'MESH:D001932', (478, 490))	('brain tumors', 'Phenotype', 'HP:0030692', (478, 490))	('Li-Fraumeni', 'Disease', (260, 271))	('brain tumor', 'Phenotype', 'HP:0030692', (478, 489))	('sarcoma', 'Phenotype', 'HP:0100242', (468, 475))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (260, 280))	('mutations', 'Var', (222, 231))	('Li-Fraumeni', 'Disease', (297, 308))	('LFS', 'Disease', (420, 423))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (260, 271))	('brain tumors', 'Disease', (478, 490))	('bone', 'Disease', (448, 452))	('TP53', 'Gene', (65, 69))	('LFS', 'Disease', 'MESH:D016864', (420, 423))	('breast', 'Disease', (440, 446))	('TP53', 'Gene', (217, 221))	('Li-Fraumeni', 'Disease', 'MESH:D016864', (297, 308))	('LFS-linked cancers', 'Disease', (420, 438))	('tumors', 'Phenotype', 'HP:0002664', (484, 490))	('LFS', 'Disease', (282, 285))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (456, 475))	('ACC', 'Phenotype', 'HP:0006744', (495, 498))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (456, 475))	('LFS-linked cancers', 'Disease', 'MESH:D016864', (420, 438))	('LFS', 'Disease', 'MESH:D016864', (282, 285))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (456, 476))
129483	22507745	More recently, population-based studies have found TP53 germline mutations among women with early-onset breast cancer aged 40 years and below.	('TP53', 'Gene', (51, 55))	('women', 'Species', '9606', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('TP53', 'Gene', '7157', (51, 55))	('germline mutations', 'Var', (56, 74))
129488	22507745	Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) studies in tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mutations', 'Var', (7, 16))
129492	22507745	Of the BRCA-negative patients, we screened for germline TP53 mutations in all 83 women who developed invasive breast cancer before 35 years of age, regardless of family history.	('BRCA', 'Gene', '672', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('BRCA', 'Gene', (7, 11))	('women', 'Species', '9606', (81, 86))	('TP53', 'Gene', '7157', (56, 60))	('invasive breast cancer', 'Disease', (101, 123))	('mutations', 'Var', (61, 70))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', (56, 60))	('screened', 'Reg', (34, 42))	('invasive breast cancer', 'Disease', 'MESH:D001943', (101, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
129494	22507745	Genotyping analyses of the seven mutations identified in this study were conducted using the Sequenom MassARRAY platform (San Diego, CA, USA) on 880 women (181 Malays, 530 Chinese, 169 Indians) with invasive breast cancer and on 270 female controls (90 Malays, 90 Chinese, 90 Indians).	('invasive breast cancer', 'Disease', (199, 221))	('women', 'Species', '9606', (149, 154))	('mutations', 'Var', (33, 42))	('invasive breast cancer', 'Disease', 'MESH:D001943', (199, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))
129495	22507745	Four TP53 microsatellite markers were used as previously described: p53CA, an intragenic dinucleotide marker; VNTR, a marker with a pentanucleotide repeat in intron 1 and two markers flanking the TP53 gene, D17S786 and D17S796.	('TP53', 'Gene', (196, 200))	('p53CA', 'Gene', (68, 73))	('dinucleotide', 'Chemical', 'MESH:D015226', (89, 101))	('D17S786', 'Var', (207, 214))	('D17S796', 'Var', (219, 226))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('TP53', 'Gene', '7157', (196, 200))
129500	22507745	Of these, 11 (11%) and 6 (6%) were found to have deleterious mutations in BRCA1 and BRCA2 respectively.	('BRCA2', 'Gene', (84, 89))	('mutations', 'Var', (61, 70))	('BRCA1', 'Gene', '672', (74, 79))	('BRCA2', 'Gene', '675', (84, 89))	('BRCA1', 'Gene', (74, 79))
129501	22507745	We have analyzed germline TP53 mutations in the remaining 83 individuals who tested negative for both BRCA1 and BRCA2 mutations (Table 1).	('TP53', 'Gene', (26, 30))	('BRCA1', 'Gene', (102, 107))	('mutations', 'Var', (31, 40))	('TP53', 'Gene', '7157', (26, 30))	('BRCA2', 'Gene', (112, 117))	('BRCA1', 'Gene', '672', (102, 107))	('BRCA2', 'Gene', '675', (112, 117))
129503	22507745	Mutation analyses have revealed four unique exonic germline mutations; of which one (E285K) was found in two unrelated individuals, and three unique intronic germline mutations; of which one (c.74 + 14 T > C) was found in two unrelated individuals (Table 2).	('E285K', 'Var', (85, 90))	('14 T > C', 'Var', (199, 207))	('E285K', 'Mutation', 'rs112431538', (85, 90))	('14 T > C', 'SUBSTITUTION', 'None', (199, 207))
129504	22507745	Notably of the five exonic TP53 mutation carriers, three had a family history of LFS-linked cancers, one had two cases of early-onset breast cancer in the family and one had no family history of cancer.	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('TP53', 'Gene', (27, 31))	('breast cancer', 'Disease', (134, 147))	('mutation', 'Var', (32, 40))	('LFS-linked cancers', 'Disease', (81, 99))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('TP53', 'Gene', '7157', (27, 31))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('LFS-linked cancers', 'Disease', 'MESH:D016864', (81, 99))	('exonic', 'Var', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
129508	22507745	This mutation, E346X, was found to be located within the tetramerization domain of TP53 and has previously been reported as a somatic mutation occurring in one tumor only (IARC TP53 database).	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('E346X', 'Var', (15, 20))	('TP53', 'Gene', '7157', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('E346X', 'Mutation', 'p.E346X', (15, 20))	('tumor', 'Disease', (160, 165))	('TP53', 'Gene', (177, 181))
129512	22507745	Upon further analysis, it was found that this family was previously tested in the same hospital for TP53 mutations due to the presence of the childhood cancers.	('TP53', 'Gene', '7157', (100, 104))	('childhood cancers', 'Disease', 'MESH:C536928', (142, 159))	('TP53', 'Gene', (100, 104))	('childhood cancers', 'Disease', (142, 159))	('mutations', 'Var', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
129514	22507745	This mutation, which is located within the TP53 tetramerization domain, involves a duplication of a 6 bp GGCGTG sequence, which results in an in-frame insertion of two amino acids (Arg and Gly), and is predicted to be likely deleterious.	('Arg', 'Chemical', 'MESH:D001120', (181, 184))	('results in', 'Reg', (128, 138))	('Arg', 'Var', (181, 184))	('Gly', 'Chemical', 'MESH:D005998', (189, 192))	('insertion', 'Reg', (151, 160))	('duplication', 'Var', (83, 94))	('GGCGTG', 'Gene', (105, 111))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('Gly', 'Var', (189, 192))
129518	22507745	The A138V mutation was found to be located within the DNA binding domain of TP53.	('A138V', 'Mutation', 'rs750600586', (4, 9))	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))	('A138V', 'Var', (4, 9))
129519	22507745	This mutation has previously been reported as a somatic mutation in 51 tumors and, by in silico analysis with Align-GVGD, is predicted to be likely deleterious (IARC TP53 database).	('TP53', 'Gene', '7157', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('TP53', 'Gene', (166, 170))	('tumors', 'Disease', (71, 77))	('mutation', 'Var', (5, 13))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
129524	22507745	The proband's younger sister, BRC 873A, developed bilateral breast cancer at the ages of 27 and 32, and was shown to have the same germline TP53 mutation.	('mutation', 'Var', (145, 153))	('TP53', 'Gene', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('bilateral breast cancer', 'Disease', (50, 73))	('TP53', 'Gene', '7157', (140, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('bilateral breast cancer', 'Disease', 'MESH:D001943', (50, 73))
129526	22507745	The E285K mutation is located within the DNA binding domain of TP53.	('TP53', 'Gene', (63, 67))	('E285K', 'Mutation', 'rs112431538', (4, 9))	('TP53', 'Gene', '7157', (63, 67))	('E285K', 'Var', (4, 9))
129528	22507745	Analysis of the DNA from FFPE breast cancer samples from BRC873 showed that there was no loss of the wild type TP53 allele (Figure 2b) We have identified three intervening sequence mutations: c.74+14 T > C in two unrelated individuals, and c.97-28 T > A and c.672+18 G > C in one individual each.	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('TP53', 'Gene', '7157', (111, 115))	('breast cancer', 'Disease', (30, 43))	('c.672+18 G > C', 'Mutation', 'rs199578278', (258, 272))	('TP53', 'Gene', (111, 115))	('c.74+14 T > C', 'Var', (192, 205))	('c.97-28 T > A', 'Var', (240, 253))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('c.97-28 T > A', 'Mutation', 'rs200989844', (240, 253))	('c.74+14 T > C', 'Mutation', 'rs184743157', (192, 205))	('c.672+18 G > C', 'Var', (258, 272))
129529	22507745	The mutation c. 672+18G > C was reported as a somatic mutation occurring in three tumors (IARC TP53 database) whereas the remaining two mutations have not previously been reported.	('672+18G > C', 'Var', (16, 27))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('672+18G > C', 'SUBSTITUTION', 'None', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
129530	22507745	None of the four exonic mutations identified in this study or the intervening sequence variant c.97-28 T > A, were found in any of the 880 unselected invasive breast cancer cases and 270 controls tested.	('invasive breast cancer', 'Disease', 'MESH:D001943', (150, 172))	('c.97-28 T > A', 'Var', (95, 108))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('c.97-28 T > A', 'Mutation', 'rs200989844', (95, 108))	('invasive breast cancer', 'Disease', (150, 172))
129531	22507745	Notably, c.74+14 T > C was found in 12/880 (1.4%) and 2/270 (0.74%) controls, and c.672+18 G > C was found in 14/880 (1.6%) breast cancer cases and 2/270 (0.74%) controls; suggesting that both variants are likely to be benign polymorphisms.	('c.74+14 T > C', 'Mutation', 'rs184743157', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('c.672+18 G > C', 'Var', (82, 96))	('breast cancer', 'Disease', (124, 137))	('c.672+18 G > C', 'Mutation', 'rs199578278', (82, 96))	('c.74+14 T > C', 'Var', (9, 22))
129532	22507745	Breast cancers arising in germline TP53 mutation carriers were previously reported to be more likely to have amplification of HER2 as compared to non-TP53 carriers.	('amplification', 'MPA', (109, 122))	('mutation', 'Var', (40, 48))	('TP53', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('germline', 'Var', (26, 34))	('Breast cancers', 'Phenotype', 'HP:0003002', (0, 14))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('HER2', 'Gene', (126, 130))	('Breast cancers', 'Disease', (0, 14))	('Breast cancers', 'Disease', 'MESH:D001943', (0, 14))	('HER2', 'Gene', '2064', (126, 130))	('TP53', 'Gene', '7157', (150, 154))
129533	22507745	Of the seven breast cancer patients (five index and two family members) with germline exonic mutations in TP53 available for review, six have strong amplification of the HER-2 receptor (Table 3).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('germline', 'Var', (77, 85))	('HER-2', 'Gene', (170, 175))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Disease', (13, 26))	('patients', 'Species', '9606', (27, 35))	('amplification', 'MPA', (149, 162))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))	('HER-2', 'Gene', '2064', (170, 175))
129534	22507745	Our study has shown that 5/83 (6%) of BRCA-negative Asian breast cancer patients diagnosed before age 35 years have germline exonic mutations in TP53 and that the average age of onset of breast cancer was 31 years.	('germline exonic mutations', 'Var', (116, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('BRCA', 'Gene', '672', (38, 42))	('BRCA', 'Gene', (38, 42))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('patients', 'Species', '9606', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('TP53', 'Gene', '7157', (145, 149))	('breast cancer', 'Disease', (58, 71))	('TP53', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('breast cancer', 'Disease', (187, 200))
129535	22507745	This is consistent with reports in other studies, where 0.8 to 5% frequency was reported among breast cancer patients diagnosed <= 40 years: in an clinic-based cohort of patients <= 40 years, 1/126 (0.8%) had a TP53 missense mutation; in a Singaporean clinic-based cohort of breast cancer patients <= 35 years, 1/30 (3.3%) patients had a deleterious TP53 mutation: in an Australian population-based cohort of two subgroups of early-onset breast cancer patients (<= 30 years and 31 to 39 years), 5/94 (5.3%) had germline TP53 mutations.	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (452, 460))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('mutations', 'Var', (525, 534))	('TP53', 'Gene', (211, 215))	('TP53', 'Gene', '7157', (350, 354))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))	('patients', 'Species', '9606', (323, 331))	('breast cancer', 'Disease', (95, 108))	('TP53', 'Gene', (520, 524))	('cancer', 'Phenotype', 'HP:0002664', (445, 451))	('breast cancer', 'Phenotype', 'HP:0003002', (275, 288))	('patients', 'Species', '9606', (289, 297))	('patients', 'Species', '9606', (170, 178))	('TP53', 'Gene', '7157', (211, 215))	('breast cancer', 'Disease', 'MESH:D001943', (275, 288))	('breast cancer', 'Disease', (275, 288))	('breast cancer', 'Phenotype', 'HP:0003002', (438, 451))	('TP53', 'Gene', (350, 354))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('TP53', 'Gene', '7157', (520, 524))	('breast cancer', 'Disease', 'MESH:D001943', (438, 451))	('breast cancer', 'Disease', (438, 451))
129536	22507745	Notably, in our study, three of the four families with LFS-linked cancers had TP53 germline mutations.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('LFS-linked cancers', 'Disease', (55, 73))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('germline mutations', 'Var', (83, 101))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('LFS-linked cancers', 'Disease', 'MESH:D016864', (55, 73))
129538	22507745	In a study of 180 Dutch families, TP53 mutations were found in 22/24 patients who fulfilled the Chrompret criteria and 18/24 patients who fulfilled either classic LFS or LFL criteria.	('LFS', 'Disease', 'MESH:D016864', (163, 166))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))	('LFS', 'Disease', (163, 166))	('found', 'Reg', (54, 59))	('patients', 'Species', '9606', (69, 77))	('TP53', 'Gene', '7157', (34, 38))	('patients', 'Species', '9606', (125, 133))
129539	22507745	In a clinic-based study of a cohort of 525 individuals, 71/75 TP53 mutation carriers were shown to meet either classic LFS or Chompret criteria.	('TP53', 'Gene', '7157', (62, 66))	('mutation', 'Var', (67, 75))	('TP53', 'Gene', (62, 66))	('LFS', 'Disease', 'MESH:D016864', (119, 122))	('LFS', 'Disease', (119, 122))
129540	22507745	The majority of studies have been from clinical genetics units and recent breast cancer cohort studies suggest that not all germline TP53 mutation carriers meet either classic LFS or LFL criteria.	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('LFS', 'Disease', 'MESH:D016864', (176, 179))	('LFS', 'Disease', (176, 179))	('mutation', 'Var', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
129541	22507745	Indeed, in our study, two out of five TP53 mutation carriers did not meet classic LFS or LFL criteria.	('LFS', 'Disease', (82, 85))	('TP53', 'Gene', (38, 42))	('mutation', 'Var', (43, 51))	('LFS', 'Disease', 'MESH:D016864', (82, 85))	('TP53', 'Gene', '7157', (38, 42))
129543	22507745	Our study has identified four exonic mutations (A138V, E285K, E346X and p. G334_R335dup), three of which have not previously been identified as germline mutations.	('p. G334_R335dup', 'Var', (72, 87))	('E346X', 'Var', (62, 67))	('A138V', 'Var', (48, 53))	('E346X', 'Mutation', 'p.E346X', (62, 67))	('p. G334_R335dup', 'Mutation', 'p.334_,335dupG,R', (72, 87))	('E285K', 'Var', (55, 60))	('A138V', 'Mutation', 'rs750600586', (48, 53))	('E285K', 'Mutation', 'rs112431538', (55, 60))
129544	22507745	Through co-segregation and LOH studies, we show that A138V and E285K are likely to be pathogenic.	('A138V', 'Mutation', 'rs750600586', (53, 58))	('E285K', 'Var', (63, 68))	('E285K', 'Mutation', 'rs112431538', (63, 68))	('A138V', 'Var', (53, 58))	('pathogenic', 'Reg', (86, 96))
129546	22507745	Other recurrent mutations have previously been reported, including the TP53 R337H mutation in southern Brazil and the M133T mutation found in two unrelated African-American families, but to the best of our knowledge, this is the first report of a recurrent TP53 mutation in an Asian population.	('M133T', 'Mutation', 'rs28934873', (118, 123))	('TP53', 'Gene', (257, 261))	('M133T', 'Var', (118, 123))	('R337H', 'Mutation', 'rs121912664', (76, 81))	('R337H', 'Var', (76, 81))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('TP53', 'Gene', '7157', (257, 261))
129547	22507745	In addition, our study has also identified three intronic variants (c. 74+14 T > C, c. 97-28 T > A and c. 672+18 G > C), of which c. 74+14 T > C and c. 672+18 G > C are benign as we show that they are also found in non-cancer control individuals.	('672+18 G > C', 'Var', (106, 118))	('74+14 T > C', 'Var', (133, 144))	('97-28 T > A', 'SUBSTITUTION', 'None', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('74+14 T > C', 'SUBSTITUTION', 'None', (71, 82))	('non-cancer', 'Disease', (215, 225))	('74+14 T > C', 'SUBSTITUTION', 'None', (133, 144))	('non-cancer', 'Disease', 'MESH:D009369', (215, 225))	('672+18 G > C', 'Var', (152, 164))	('97-28 T > A', 'Var', (87, 98))	('672+18 G > C', 'SUBSTITUTION', 'None', (106, 118))	('74+14 T > C', 'Var', (71, 82))	('672+18 G > C', 'SUBSTITUTION', 'None', (152, 164))
129549	22507745	Given the comparable frequency of BRCA1, BRCA2 and TP53 mutations among patients diagnosed at <= 35 years and the high penetrance of TP53 mutations, we suggest that all patients who develop breast cancer at <= 35 years of age should be offered genetic counseling and a family history of LFS-linked cancers should be carefully obtained.	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('BRCA2', 'Gene', (41, 46))	('BRCA1', 'Gene', '672', (34, 39))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('BRCA1', 'Gene', (34, 39))	('LFS-linked cancers', 'Disease', (287, 305))	('TP53', 'Gene', '7157', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('BRCA2', 'Gene', '675', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('TP53', 'Gene', '7157', (51, 55))	('mutations', 'Var', (138, 147))	('LFS-linked cancers', 'Disease', 'MESH:D016864', (287, 305))	('patients', 'Species', '9606', (169, 177))	('TP53', 'Gene', (133, 137))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('patients', 'Species', '9606', (72, 80))
129552	22507745	Previous reports found that 20/29 (69%) and 10/12 (83%) of breast tumors from germline TP53 carriers had HER2 amplification or over-expression and having a HER-amplified tumor increased the odds of having TP53 germline mutation by nearly seven-fold.	('germline mutation', 'Var', (210, 227))	('amplification', 'Var', (110, 123))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TP53', 'Gene', '7157', (87, 91))	('HER2', 'Gene', (105, 109))	('tumor', 'Disease', (66, 71))	('TP53', 'Gene', '7157', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('breast tumors', 'Disease', 'MESH:D001943', (59, 72))	('breast tumors', 'Disease', (59, 72))	('over-expression', 'PosReg', (127, 142))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('HER2', 'Gene', '2064', (105, 109))	('breast tumors', 'Phenotype', 'HP:0100013', (59, 72))	('TP53', 'Gene', (87, 91))	('TP53', 'Gene', (205, 209))